Copyright by Daniel Isaiah Knueppel 2010
The Dissertation Committee for Daniel Isaiah Knueppel Certifies that this is the approved version of the following dissertation:
First Enantioselective Oxidative Rearrangement of Indoles to Spirooxindoles, Studies Toward the Total Synthesis of IB-00208 and Total Synthesis of Cribrostatin 6
Committee:
Stephen F. Martin, Supervisor
Christopher W. Bielawski
Michael J. Krische
Richard A. Jones
Christian P. Whitman First Enantioselective Oxidative Rearrangement of Indoles to Spirooxindoles, Studies Toward the Total Synthesis of IB-00208 and Total Synthesis of Cribrostatin 6
by
Daniel Isaiah Knueppel, B.S.
Dissertation Presented to the Faculty of the Graduate School of The University of Texas at Austin in Partial Fulfillment of the Requirements for the Degree of
Doctor of Philosophy
The University of Texas at Austin May, 2010
Dedication
To my wife Amy for all her love and support over the last few years. Your steadfast love and kind heart continually filled my days with joy, especially when my research failed to do so.
Acknowledgements
I would like to especially thank my parents for their continued guidance and support over the years. I would never have made it to where I am today if it hadn’t been for your relentless support. A special thank you also goes to my advisor Dr. Stephen F. Martin for his supervision over the last five years. Your direction and critical questions have been invaluable to the success of my research. Lab 4 and the rest of the Martin group past and present are acknowledged for their help and support. Lastly, I want to thank David Trombly, Kevin Russell, and Jeremy Long for their friendship. Your encouragement and camaraderie made it possible to forget about work when I needed to.
“The mind of the prudent acquires knowledge, and the ear of the wise seeks knowledge.” Proverbs 18:15
v First Enantioselective Oxidative Rearrangement of Indoles to Spirooxindoles, Studies Toward the Total Synthesis of IB-00208 and Total Synthesis of Cribrostatin 6
Publication No.______
Daniel Isaiah Knueppel, Ph.D. The University of Texas at Austin, 2010
Supervisor: Stephen F. Martin
The first enantioselective oxidative rearrangement of indoles to spirooxindoles was developed. A 2,3-disubstituted indole was stereoselectively epoxidized using an in situ-generated chiral dioxirane catalyst. Rearrangement of the transient epoxide intermediate afforded the antipode of the tricyclic spirooxindole present in the marine alkaloid citrinadin A. A mild and rapid entry to 1,4-dioxygenated xanthones from benzocyclobutenones was developed. This method was applied to the construction of the highly aromatic pentacyclic core of IB-00208, a promising antitumor agent with reported nanomolar activity. The requisite angularly-fused benzocyclobutenone was accessed via a novel ring-closing metathesis approach. Lack of success in synthesizing the final ring of IB- 00208 from the pentacycle led us revise our approach and incorporate an extra ring earlier in the synthesis. After constructing a modified benzocyclobutenone, the hexacyclic core of IB-00208 was efficiently accessed using the same key chemistry. An
vi oxidation, deprotection and glycosylation remain to complete the synthesis of the natural product. A total synthesis of antimicrobial and antineoplastic cribrostatin 6 was accomplished in only four steps in the longest linear sequence from commercially available starting materials. The key step employed a tandem 4π-electrocyclic ring opening, radical cyclization, and homolytic aromatic substitution sequence to afford the tricyclic core of the natural product, which was converted to cribrostatin 6 via a subsequent oxidation in one pot. The versatility of this reaction sequence was demonstrated by preparation of analogs of the natural product, which were tested for their anticancer activity.
vii Table of Contents
Chapter 1: First Enantioselective Oxidative Rearrangement of Indoles to Spirooxindoles ...... 1 1.1 Introduction...... 1 1.2 Synthesis of homochiral Spirooxindoles via Asymmetric Catalysis ...... 3 1.2.1 Introduction...... 3 1.2.2 Overman’s Intramolecular Heck Reaction...... 4 1.2.3 Toste’s Intramolecular Palladium-Catalyzed Cyclization ...... 5 1.2.4 Melchiorre’s Intermolecular Double Michael Addition ...... 6 1.2.5 Trost’s Intermolecular TMM-[3+2]-Cycloaddition...... 7 1.2.6 List’s Intermolecular Condensation...... 8 1.2.7 Gong’s Intermolecular Organocatalytic 1,3-Dipolar Cycloaddition...... 9 1.3 Shi Epoxidation...... 10 1.3.1 Shi Epoxidation Using D-Epoxone...... 10 1.3.2 Shi Epoxidation with Oxazolidinone-Containing N-Boc Catalyst ...... 17 1.3.3 Shi Epoxidation with Oxazolidinone-Containing N-Ar Catalysts...... 19 1.4 Prior Art in the Martin Group and Precedent...... 22 1.5 First Enantioselective Oxidative Rearrangement of Indoles to Spirooxindoles ...... 25 1.6 Failed Attempts...... 34 1.7 Conclusion ...... 35
Chapter 2: Studies Toward the Total Synthesis of IB-00208...... 37 2.1 Introduction...... 37 2.2 Background...... 39 2.2.1 Synthesis of Xanthones...... 39 2.2.1.1 Introduction...... 39 2.2.1.2 Methods for Accessing Xanthones ...... 40 2.2.1.3 Syntheses of 1,4-Dioxygenated Xanthones ...... 41 viii 2.2.2 Syntheses of Xanthone-Containing Angucycline Natural Products...... 46
2.2.2.1 Kelly’s Synthesis of Cervinomycin A2 ...... 46
2.2.2.2 Mehta’s Synthesis of Cervinomycin A2 Methyl Ether ...49
2.2.2.3 Rao’s Synthesis of Cervinomycin A2 ...... 52 2.2.2.4 Suzuki’s Synthesis of FD-594 Aglycon...... 55 2.2.3 Prior Art in the Martin Group: First Generation Approach to IB-00208 ...... 60 2.3 Studies Toward the Total Synthesis of IB-00208...... 65 2.3.1 Second Generation Approach to IB-00208...... 65 2.3.1.1 Retrosynthesis...... 65 2.3.1.2 Retrosynthesis of Model System ...... 66 2.3.1.3 Synthesis of the Requisite Ynone ...... 68 2.3.1.4 Synthesis of the Requisite Benzocyclobutadione ...... 70 2.3.1.5 Coupling of the Fragments...... 71 2.3.2 Third Generation Approach to IB-00208...... 77 2.3.2.1 Retrosynthesis...... 77 2.3.2.2 Model Studies ...... 78 2.3.2.3 Failed Three-Component Benzyne Approach to Angularly-Fused Benzocyclobutenones ...... 83 2.3.2.4 Failed Coupling Reactions...... 87 2.3.2.5 Altered Coupling Strategy ...... 90 2.3.2.6 Synthesis of the Requisite MOM-Protected Benzocyclobutenone...... 94 2.3.2.7 Forward Synthesis of IB-00208...... 97 2.3.2.8 Endgame Attempts from Pentacycle 2.171...... 110 2.3.3 Fourth Generation Approach to IB-00208...... 121 2.3.3.1 Retrosynthesis...... 121 2.3.3.2 Synthesis of Requisite Angularly-Fused Benzocyclobutenone...... 122 2.3.3.3 Synthesis of the Hexacyclic Core of IB-00208...... 136 2.3.3.4 Attempted Endgame Chemistry for the Synthesis of the IB-00208 Aglycone...... 140 ix 2.4 Conclusion ...... 147 2.5 Future ...... 148
Chapter 3: Total Synthesis of Cribrostatin 6 ...... 150 3.1 Introduction...... 150 3.2 Background: Moore Cyclization...... 151 3.2.1 Synthetic Utility of Squarates ...... 151 3.2.2 Early Use of Squarates...... 153 3.2.3 Early Metal-Mediated Processes with Squarates...... 154 3.2.4 Quinone Formation via Thermal Conditions ...... 155 3.2.5 Torquoselectivity of the Electrocyclic Ring Opening of Cyclobutenones...... 157 3.2.6 Discovery of the Moore Cyclization...... 159 3.2.7 Moore Cyclization and Tandem Processes: Alkenes and Alkynes ...... 161 3.2.8 Moore Cyclization and Tandem Processes: Aromatic Substitutions...... 168 3.3 Previous Syntheses of Cribrostatin 6 ...... 172 3.3.1 Nakahara’s Total Synthesis of Cribrostatin 6 ...... 172 3.3.2 Kelly’s Total Synthesis of Cribrostatin 6...... 174 3.4 Total Synthesis of Cribrostatin 6 ...... 176 3.4.1 Retrosynthesis...... 176 3.4.2 Synthesis of Cribrostatin 6...... 178 3.4.3 Synthesis of Cribrostatin 6 Analogs ...... 185 3.4.4 Biological Activity of the Cribrostatin 6 Analogs ...... 190 3.4.5 Failed Preliminary Attempts at Synthesizing Cribrostatin 6 Analogs ...... 192 3.5 Conclusion ...... 196
x Chapter 4: Experimental Section ...... 197
4.1 First Enantioselective Oxidative Rearrangement of Indoles to Spirooxindoles ...... 198
4.2 Studies Toward the Total Synthesis of IB-00208...... 203
4.3 Total Synthesis of Cribrostatin 6 ...... 280
References...... 297
Vita ...... 317
xi Chapter 1: First Enantioselective Oxidative Rearrangement of Indoles to Spirooxindoles
1.1 INTRODUCTION
A large number of natural products contain a spirooxindole ring system, many of which are of interest in organic synthesis due to their complexity and/or their biological activity. To highlight the interesting structural motifs and molecular complexities of spirooxindoles, a few natural products are displayed below. The six natural products listed can be divided into two different groups, one of which contains a nitrogen atom in the top ring of the spirocycle and others that comprise an all-carbon framework. Due to their lack of complexity, coerulescine (1.1) and horsfiline (1.2) often serve as model systems to demonstrate new methodologies for the formation of spirooxindoles.1,2,3 Although their biological activities have not been studied in depth, it is known that coerulescine (1.1) has neurotoxic and cardiotoxic effects in animals, whereas horsfiline (1.2) has been traditionally used in intoxicating snuffs in Malaysia.1 (–)-Spirotryprostatin A (1.3) is a more complex spirooxindole that inhibits the mammalian cell cycle in the G2/M phase.4 It has received repeated attention from the synthetic community, particularly due to its molecular complexity.5 Rhynchophylline
(1.4) was discovered through its use in traditional medicine in Malaysia.6 It was found to be useful in treating cardiovascular disorders, such as hypertension, and to protect against
glutamate-induced neuronal death in cultured cerebellar granule cells.7 Marcfortine B (1.5) was isolated from various Penicillium species8 and has attracted interest due to its potent anthelmintic activity.9 We became interested in spirooxindoles when a total synthesis of recently isolated citrinadin A (1.6) was pursued in our laboratories.10 Citrinadin A (1.6) displays several
1 interesting structural features that attracted our attention. It has nine stereogenic centers, an α,β-epoxy carbonyl moiety, and a rare N,N-dimethylaminovaline residue. Furthermore, the central five-membered ring is very densely functionalized with all but one of the carbon atoms being fully substituted. Adding to its attractiveness as a target for total synthesis, preliminary biological assays revealed that 1.6 exhibits cytotoxicity against murine leukemia L1210 (IC50 = 6.2 μg/mL) as well as human epidermoid
carcinoma KB cells (IC50 = 10 μg/mL). To date, no total synthesis has been reported, and only one group aside from ours has reported their synthetic studies toward this natural
product.11,12
When envisioning a retrosynthesis of citrinadin A (1.6), we thought the construction of the spirooxindole core would comprise one of the major challenges of the molecule. Thus, in our approach, we envisioned a convergent synthesis wherein the remainder of 1.6 would be constructed from spirooxindole 1.7 (Scheme 1.1). With such an approach, the first major synthetic challenge would be construction of spirooxindole 1.7. Formation of 1.7 would most likely prove to be challenging due to the scarcity of 2 literature precedent for the enantioselective synthesis of homochiral spirooxindoles. Hence, it became our goal to develop a new approach toward homochiral spirooxindoles, and it was proposed that 1.7 might be assembled via an asymmetric epoxidation/rearrangement of indole 1.8 (details below).
Scheme 1.1
1.2 SYNTHESIS OF HOMOCHIRAL SPIROOXINDOLES VIA ASYMMETRIC CATALYSIS
1.2.1 Introduction
Two reviews, one by Carreira and a very recent one by Trost, give a good overview of the various methods and approaches for synthesizing spirooxindole ring systems.5,13 In the context of asymmetric catalysis, several methods have been reported for assembling homochiral oxindoles that do not possess a spirocenter, yet nevertheless contain a fully-substituted C3-carbon (spirooxindole numbering). Recent work by Franz,14 Krische,15 and Chen16 showcase the construction of indolin-2-ones where the fully substituted C3-carbon is bonded to a heteroatom. Oxindoles with C3 quaternary
stereocenters have received considerably more attention from Fu,17 Trost,18 Maruoka,19 Buchwald,20 and Stoltz.21 In the context of citrinadin A, however, we were most 3 interested in an asymmetric catalytic method for the construction of homochiral C3- spirooxindoles. At the outset of our project we were only aware of two such methods.22,23 We believe this highlights the challenge as well as importance of developing catalytic asymmetric approaches to these ring systems. The relevance and significance of our work in this area is further highlighted by the recent emergence of four new catalytic methods in addition to our report.11,24,25,26,27 A detailed report of all published asymmetric catalytic methods for the synthesis of homochiral 3-spiro-2-oxindoles is given below.
1.2.2 Overman’s Intramolecular Heck Reaction
The first asymmetric catalytic approach toward quaternary 3-spiro-2-oxindoles
was reported by Overman and coworkers in 1992 (Scheme 1.2).22 Utilizing an
intermolecular Heck reaction with 5 mol% of Pd2(dba)3 in the presence of 10 mol% (R)- BINAP, Overman was able to assemble spirooxindoles 1.10 and 1.11 in 81% and 77% yield and 71% and 66% enantioselectivity, respectively. Surprisingly, either enantiomer of the spirooxindole could be accessed with the same chiral diphosphine ligand by simply
switching the base from Ag3PO4 to 1,2,2,6,6-pentamethylpiperidine (PMP). Although this method provides a powerful tool for the synthesis of homochiral spirooxindoles, several draw-backs should be noted. The reaction only proceeded with aryliodides. Furthermore, the ee is low with cyclic olefins, and it drops even further when acyclic olefins are utilized. In the context of constructing more complex spirocycles, it is not clear whether adding complexity to a smaller olefinic ring system, as would be required for a system leading to the spirooxindole present in citrinadin A (1.6), would further impede the reaction and enantioselectivity due to unfavorable steric interactions with the aryl palladium intermediate.
4 Scheme 1.2
O O 5mol%Pd2(dba)3 10 mol% (R)-BINAP
2eqAg3PO4 O MeCONMe2,80°C N O O 81% yield Me 71% ee 1.10
O N O 10 mol% Pd (dba) O Me 2 3 I 22 mol% (R)-BINAP 1.9 5eqPMP MeCONMe ,80°C O 2 N 77% yield Me 66% ee 1.11
1.2.3 Toste’s Intramolecular Palladium-Catalyzed Cyclization
Toste and coworkers reported a palladium-catalyzed intermolecular cyclization of a silyloxy-1,6-enyne for the construction of spirooxindoles (Scheme 1.3).23 Homochiral spirooxindole 1.13 was synthesized from indole 1.12 in the presence of 5 mol% of [(R)- binaphane]Pd(OH2)2(OTf)2 (1.14) in 83% yield and 91% ee. The strength of this method lies in the simplicity of the starting material and the ease with which various 3-substituted indoles can be synthesized via alkylation of 2-indolinones. However, the catalyst system used is very complex, and the bidentate phosphine ligand requires several steps to assemble. Furthermore, the exocyclic olefin that is obtained will be challenging to remove or expand to a geminal dimethyl group as would be required for a complex spirooxindole ring system present in citrinadin A (1.6).
5 Scheme 1.3
1.2.4 Melchiorre’s Intermolecular Double Michael Addition
A very different asymmetric catalytic approach to spirooxindoles was developed by Melchiorre and coworkers.24 When indolinone 1.15 was reacted with enone 1.16 in the presence of 20 mol% of 9-amino(9-deoxy)epi-hydroquinine (1.17), spirooxindole 1.18 was obtained in 59% yield but 98% enantiomeric excess (ee) and a 19:1 diastereomeric ratio (Scheme 1.4). For the mechanism, two possible pathways are proposed. Under the reaction conditions, catalyst 1.17 is proposed to condense with enone 1.16 to form an enamine intermediate, which could now undergo an intermolecular Diels-Alder reaction to furnish spirooxindole 1.18. Alternatively, a more stepwise mechanism is feasible in which indolin-2-one 1.15 undergoes a Michael addition, and the resulting 2- hydroxyindole adds in a second Michael addition to furnish the spirocycle. Although this methodology provides access to various structurally interesting spirooxindoles, it cannot be applied to the synthesis of citrinadin A (1.6), because only spirooxindoles with a six-membered ring can be formed. Furthermore, the scope is limited to β-phenyl enones for 1.16. Lastly, it is not apparent how the opposite enantiomer of the chiral catalyst 1.17 could be readily accessed.
6 Scheme 1.4
1.2.5 Trost’s Intermolecular TMM-[3+2]-Cycloaddition
The trimethylenemethane (TMM)-[3+2]-cycloaddition developed by Trost and coworkers provides an elegant method for constructing complex ring systems. Initially, an achiral variant for assembling spirooxindoles had been developed in the context of the synthesis of marcefortine B (1.5).25 Very recently, however, this method was rendered asymmetric (Scheme 1.5).28 Starting from achiral starting materials, complexity is generated rapidly in this reaction. In the presence of 10 mol% of chiral ligand 1.21, spirooxindoles are generated in >94% yield and >85% ee. However, the greatest drawback is the poor diastereoselectivity around the spirooxindole C3-carbon, which is highly dependent on the nature of the indole substrate. When the C7-position of the indole is unsubstituted, spirooxindoles 1.22 and 1.23 are obtained in only a 4:1 ratio. When 1.19 is substituted with a chlorine atom at C7, the diastereoselectivity improves significantly to 19:1, respectively. Since 1.22 maps nicely onto the oxindole core of citrinadin A (1.6), this method will most likely prove very useful in Trost’s efforts toward a synthesis of citrinadin A (1.6). However, the scope of the substituent tolerated at C7 is very limited, as a methoxy group lowers both the diastereoselectivity and the ee to 4:1 and 85%, respectively. While Trost has developed an efficient methodology for the construction of spirooxindoles, the reported scope displays some obvious limitations. 7 Furthermore, a very complex and large chiral ligand 1.21 was required to effect high enantioselectivities.
Scheme 1.5
TMS NC NC 1.5 eq NC
OAc 1.20 O + N 2.5 mol% Pd2dba3 CH3CN O O N N R CO2Me 10 mol% 1.21, PhMe, 0 C R CO2Me R CO2Me 1.19 1.22 1.23
substrate yield 1.22 (%ee) : 1.23 (%ee) R=H 97% 4.3(92): 1(95) R=Cl 99% 19 (93): 1 (77) O N P R=OMe 94% 4(85): 1(84) O
(R,R,R)-1.21
1.2.6 List’s Intermolecular Condensation
Besides the construction of C3 quaternary spirooxindoles, two methodologies are reported for the construction of homochiral spirooxindoles that contain additional heteroatoms in the top ring of the spirocycle. Although these methods will lack obvious applications to the synthesis of citrinadin A (1.6), they are worth highlighting in order to give a full picture of the current state of asymmetric catalysis for the construction of spirooxindoles. One such methodology developed by List and coworkers is the condensation of diamine 1.25 with isatin (1.24) in the presence of 10 mol% chiral phosphoric acid 1.26 (Scheme 1.6).26 Spirocycle 1.27 was formed in 85% yield and 84% enantioselectivity. The major drawback of this methodology is the complex chiral catalyst required to obtain good ee’s. Furthermore, the scope of this reaction was not 8 explored any further than this one reaction, so it is not known whether this reaction is amendable to more complex and synthetically more useful substrates.
Scheme 1.6
1.2.7 Gong’s Intermolecular Organocatalytic 1,3-Dipolar Cycloaddition
Gong and coworkers developed an intermolecular organocatalytic 1,3-dipolar cycloaddition approach to homochiral spirooxindole ring systems (Scheme 1.7).27 Similar to Trost, they started with an exocyclic enone (1.28), which was reacted with an ylide produced upon condensation of amine 1.30 with aldehyde 1.29 in the presence of chiral phosphoric acid 1.31 to afford spirooxindole 1.32 in 94% yield, 93% ee, and as a single regioisomer. Although this reaction rapidly generates significant complexity, it is inherently limited in the scope of products it can generate. Only electron-poor aromatic
aldehydes were reported to work well, and the substrate scope of the amines was nearly exclusively limited to 1.30. If the scope of this reaction would be developed further, it would always require a nitrogen heteroatom in the spirooxindole ring system, which poses and inherent limitation.
9 Scheme 1.7
In summary, only a few methods have been developed to date that construct homochiral C3-spirooxindoles via asymmetric catalysis. A number of the methodologies have significant limitations in scope and would thus not be applicable to a synthesis of citrinadin A (1.6). Trost’s asymmetric TMM cycloaddition, which has the greatest potential of being applied to a synthesis of 1.6, displays several limitations in substrate scope and was developed after our methodology had already been submitted for publication. As a result there was need for a more general methodology that would allow easy access to homochiral 3-spiro-2-oxindoles via asymmetric catalysis.
1.3 SHI EPOXIDATION
1.3.1 Shi Epoxidation Using D-Epoxone
In Scheme 1.1 we proposed the conversion of indole 1.8 to spirooxindole 1.7 via an asymmetric epoxidation and subsequent rearrangement. One of the most promising and practical asymmetric epoxidations of olefins is the Shi epoxidation. Since its early developments in the 1990’s, it has received considerable attention. Many notable discoveries and breakthroughs have been made that have warranted Shi and coworkers to publish several reviews on the subject.29
10 The Shi epoxidation most commonly refers to the asymmetric epoxidation of an olefin 1.33 to the corresponding chiral epoxide 1.34 using D-epoxone (1.35) as the chiral catalyst (Scheme 1.8). The catalytic cycle proceeds as follows: Oxone, the stoichiometric oxidant, is deprotonated by K2CO3 and thus enters the catalytic cycle. Addition of the peroxide anion to the carbonyl of D-epoxone (1.35) delivers a tetrahedral intermediate (1.36), which is now deprotonated to deliver dianion 1.37. An intramolecular displacement of sulfate generates the chiral dioxirane 1.38, which is responsible for the asymmetric epoxidation of olefin 1.33. The differing steric environments of the two sides of the oxirane allow for facial differentiation of the olefin to deliver chiral epoxide 1.34. During the epoxidation, oxirane 1.38 is reduced to regenerate chiral ketone 1.35, which now reengages the catalytic cycle. Since D-epoxone (1.35) is regenerated, only catalytic amounts are needed to successfully carry out the Shi epoxidation.
Scheme 1.8
11 Chiral ketone 1.35 is an attractive catalyst for the Shi epoxidation because it can be readily prepared from inexpensive and commercially available D-fructose (1.39) in only two steps (Scheme 1.9). First, two ketals are formed with acetone in the presence of
HClO4, and then desired D-epoxone (1.35) is prepared via a pyridinium chlorochromate (PCC)-mediated oxidation of the free secondary alcohol in 49% yield over two steps. If the antipode of the catalyst, L-epoxone, is required, one needs to start with L-fructose, which needs to be prepared from L-sorbose in three steps.29a
Scheme 1.9
It was discovered that the Shi epoxidation with in situ-generated dioxiranes had a
significant dependence upon the pH of the reaction.29a During initial work, Shi and coworkers had employed superstoichiometric amounts of ketone 1.35 at pH 7-8 to obtain good conversions in the epoxidation of trisubstituted olefins.30 The need for excess of the ketone was explained by its rapid decomposition under the reaction conditions via a Baeyer-Villiger oxidation of intermediate 1.36 (cf. Scheme 1.8, Scheme 1.10). The corresponding lactones 1.40 and 1.41 were never isolated, because they were proposed to hydrolyze in situ.
Scheme 1.10
12 If the catalyst loading for the reaction was to be lowered, the undesired Baeyer- Villiger oxidation would have to be reduced. It was proposed that raising the pH of the reaction could be beneficial, because it should facilitate formation of anion 1.37 (cf. Scheme 1.8), thus suppressing the competing oxidation of 1.36. As a result, Shi conducted a study that examined the effect of pH on the catalytic asymmetric epoxidation
of trans-β-methylstyrene with ketone 1.35 (Figure 1.1). It was found that pH had a dramatic effect on the reaction. When the pH was raised, the conversion, and thus the catalyst efficiency, improved significantly.31 Less than 10% conversion to trans-β- methylstyrene was observed when 20 mol% of D-epoxone (1.35) was used and the reaction was run at pH 7-8. However, at pH > 10 over 80% conversion was noted. Furthermore, regardless of the pH of the reaction, the enantioselectivity remained consistently high (90-92%). As a result, Shi’s catalytic asymmetric epoxidation is
commonly conducted at a pH around 10.5, which can be controlled via addition of K2CO3 or KOH as the reaction proceeds.
13 Figure 1.1
100
90
80
70
60
50
40 Conversion (%) Conversion
30
20
10
0 78910111213 pH
With the optimized and catalytic reaction conditions in hand, Shi and coworkers were able to investigate the scope of their asymmetric epoxidation. Using D-epoxone (1.35) as the chiral catalyst, it was quickly determined that trans-disubstituted and trisubstituted olefins (1.43 – 1.54) can be epoxidized in good to excellent yields and with excellent enantioselectivity (Table 1.1).29b Aromatic and aliphatic trans-disubstituted (1.43, 1.44) and trisubstituted olefins (1.45, 1.46) are readily epoxidized. Hydroxyalkenes 14 (1.47, 1.48) and enol esters (1.53, 1.54) are also tolerated. Good regioselectivity and excellent ee’s were observed in the epoxidation of conjugated dienes (1.49, 1.50) and enynes (1.51, 1.52). Additionally, a large number of functional groups like TMS, OTBS, esters, alcohols, acetates, and ketals were tolerated during the epoxidation.
Table 1.1
trans olef ins trisubstituted olef ins hydroxyalkenes
O O O O O Ph O HO OH Ph OTBS O Ph 1.43 1.44 O 1.47 95% ee 94% ee 1.45 91% ee 1.48 98% ee 1.46 92% ee 97% ee
conjugated dienes enynes enol esters O TMS O O O OBz AcO O TMS O CO2Et Ph 1.54 1.49 1.50 1.51 1.52 1.53 96% ee 92% ee 93% ee 91% ee 93% ee 95% ee Despite the successful asymmetric epoxidation of various trans and trisubstituted olefins with D-epoxone (1.35), epoxidation of simple terminal olefins as well as cis- disubstituted olefins proceeded in good yield but very poor enantioselectivity (Scheme
1.11).29b For example, styrene (1.55) and 1,2-dihydronaphthalene (1.57) could only be epoxidized in 24% and 32% enantiomeric excess, respectively.
15 Scheme 1.11
30 mol% 1.35,oxone,–10°C O Ph K CO , aq. EDTA (4x10-4 M) Ph 1.55 2 3 Na2B4O7•10H2O, DMM/CH3CN 1.56
90% yield 24% ee
O 30 mol% 1.35, oxone, –10 °C
-4 K2CO3, aq. EDTA (4x10 M) Na B O •10H O, DMM/CH CN 1.57 2 4 7 2 3 1.58 85% yield 32% ee The rational for why terminal and cis-disubstituted olefins worked so poorly was given by the proposed major transition states 1.59 and 1.60 (Figure 1.2). Spiro transition states were proposed, because calculations have shown that the spiro transition state is the
optimized transition state for oxygen atom transfer from DMDO to ethylene.32 This is because the spiro transition state allows for a stabilizing interaction between an oxygen atom lone pair and the π* orbital of the alkene, which is geometrically not feasible for a planar transition state. In both proposed major transition states 1.59 and 1.60, the phenyl group points away from the cyclohexanone into space to avoid unfavorable steric interactions. Due to this orientation of the phenyl group, very little interactions are feasible with the chiral
catalyst, and both transition states are equally feasible, which results in the poor enantioselectivity.
Figure 1.2
16 1.3.2 Shi Epoxidation with Oxazolidinone-Containing N-Boc Catalyst
Since the epoxidation of styrene was unsuccessful with D-epoxone (1.35), it was envisioned that replacement of the spiro ketal on the chiral catalyst might create an environment which will appropriately differentiate the olefin substituents sterically, electronically, or both. Shi and coworkers synthesized and screened several different
catalysts that contained cyclic and acyclic groups in place of the spiroketal in 1.35.29b Eventually, it was discovered that catalyst 1.61, which contains a spiro oxazolidinone in place of the spiro ketal in D-epoxone (1.35), gave high enantioselectivities for the catalytic asymmetric epoxidation of terminal as well as cyclic and acyclic cis- disubstituted olefins (Scheme 1.12).33 In case of styrene (1.55) and 1,2- dihydronaphthalene (1.57), the corresponding chiral oxiranes were obtained in good yield and 81% and 84% enantiomeric excess, respectively.
Scheme 1.12
The successful asymmetric epoxidation of 1.55 and 1.57 with oxazolidinone- containing catalyst 1.61 was explained by the same transition state models as those in
Figure 1.2. The two major proposed spiro transition states are 1.62 and 1.63, where Rπ is a phenyl group in case of 1.55 and 1.57 (Figure 1.3).29b,33 A favorable electrostatic interaction between the Rπ group on the olefin and the oxazolidinone of the catalyst in 17 1.62 allow R and Rπ to be significantly differentiated. Due to this favorable interaction, 1.62 is the favored transition state over 1.63, which results in high enantioselectivities for the epoxidation of styrene (1.55) and 1,2-dihydronaphthalene (1.57).
Figure 1.3
electrostatic interactions O O
O 1 O 1 NR R NR R O O O R O R O O O O O O
1.62R1 =Boc 1.63 Favored The synthesis of ketone 1.61, however, is impractical and requires nine steps from
commerically available D-glucose (1.64) (Scheme 1.13).33 A skeletal rearrangement of 1.64 (Amadori rearrangement) is carried out with dibenzylamine under acidic conditions. A subsequent ketalization and hydrogenation affords amine 1.65 in 50% yield over three steps. Formation of the spiro oxazolidinone 1.66 required two steps. The secondary alcohol is protected as a TBS ether to allow selective Boc protection of the oxazolidinone nitrogen atom. Deprotection of the silyl group and oxidation of the resulting secondary alcohol completes the synthesis of ketone 1.61 in nine steps and 20% overall yield.
18 Scheme 1.13
1.3.3 Shi Epoxidation with Oxazolidinone-Containing N-Ar Catalysts
Although ketone 1.61 provided encouragingly high ee’s for the epoxidation of terminal and cis-disubstituted olefins, its lengthy synthesis made it an unattractive catalyst for practical use, particularly when compared to D-epoxone (1.35), which could be synthesized in only two steps. Nevertheless, the insight gained from 1.61 was a vital stepping stone for designing more efficient and synthetically practical epoxidation catalysts. Shi and coworkers used the insight of favorable electrostatic interactions in the transition state 1.62 to synthesize structurally similar ketone 1.68, which now contained an aromatic ring on the oxazolidinone nitrogen atom instead of a Boc group.
Encouragingly, Shi and coworkers found that ketone 1.68 catalyzed the epoxidation of terminal (1.56) and cis-disubstituted (1.69) olefins with 84% enantioselectivity similar to ketone 1.61 (Table 1.2).29c Additionally, 1.68 also catalyzed 19 the epoxidation of trisubstituted olefins (1.70, 1.71), cyclic (1.72) and acyclic (1.73) conjugated dienes, as well as enynes (1.74)34 and enediynes (1.75) with 85-95% enantioselectivity. Most notably, Shi reported the first example of an asymmetric epoxidation of tetrasubstituted olefins (1.76–1.78) with >70% ee. Nevertheless, the substrate scope for the asymmetric epoxidation of tri- and tetrasubstituted olefins is still limited, and no additional reports have been published that explore this scope any further.
Table 1.2
Ketone catalyst 1.68 is the best catalyst to date for the epoxidation of terminal and cis olefins, because it gives identical asymmetric inductions to ketone 1.61, but it can be synthesized more rapidly. Furthermore, with a phenyl group attached to the oxazolidinone nitrogen atom, the electronics of the oxazolidinone can be altered by varying the substituents on the aromatic ring. The synthesis of 1.68 starts from D-glucose (1.64) with an Amadori rearrangement and a ketalization to provide intermediate 1.80
(Scheme 1.14).35 Formation of the oxazolidinone and oxidation of the secondary alcohol
20 provided 1.68 in four steps and 37% overall yield. This route very robust and has been used to synthesize batches of over 20 g of 1.68.35
Scheme 1.14
Further studies by Shi and coworkers to improve the efficiency of catalyst 1.68 by varying the electronics of the aromatic ring on the nitrogen atom only led to very small improvement in enantioselectivity. Altering the substituent on the phenyl group of 1.68
from p-Me to p-OMe, p-MeSO2 or p-NO2 indicated that electron withdrawing groups were beneficial, yet the greatest increase in enantioselectivity was less than 6% for all substrates screened.36 Additional work looked at varying the substituent of the phenyl group further (ie: p-t-Bu, p-Bn, p-Ph, p-OPh) and p-t-BuPh catalyzed the epoxidation of styrene with a 2% higher ee when compared to p-Me.37 In the same study, utilizing aromatics with substituents at the 3-position of the phenyl ring as well as 3,4- disubstituted benzenes failed to give improvements in ee. Taking all this information into account, it appears that to date the best catalysts for the Shi epoxidation are D-epoxone (1.35) and p-MePh-oxazolidinone 1.68. For trans- disubstituted olefins and other systems where 1.35 works well, it would be the catalyst of choice, as it can be synthesized in only two steps. For terminal, cis-disubstituted olefins, or more complex aromatic olefins, ketone 1.68 would be the best option. It can be readily prepared in four steps on large scale, and, more importantly, it has been shown to catalyze the epoxidation of tetrasubstituted olefins, which are arguably the most complex olefin systems to epoxidize. 21 1.4 PRIOR ART IN THE MARTIN GROUP AND PRECEDENT
Our group became interested in oxidation/rearrangement of indoles to spirooxindoles in the context of our efforts toward a total synthesis of citrinadin A (1.6).10 In our retrosynthetic approach, it was envisioned that the natural product might be constructed from its spirooxindole core (cf. Scheme 1.1). Thus, when considering potential approaches to forming the spirocenter present in the natural product, a paper by Foote was noted, which demonstrated the use of dimethyldioxirane (DMDO) as a mild oxidant to quantitatively convert N-acyltetrahydrocarbazole 1.81 into spirooxindole 1.83
(Scheme 1.15).38
Scheme 1.15
The epoxidation of 1.81 with DMDO is not surprising; however, the exclusive rearrangement of the intermediate epoxide to 1.83 warrants further discussion. In the transition state of going from epoxide 1.82 to 1.83, a partial positive charge is generated as shown in 1.84 (Scheme 1.16). However, the partial positive charge could equally as well be forming on the other carbon as in 1.85, which would then induce a rearrangement toward 1.86, which however was not observed in this reaction. Furthermore, 1.85 might benefit from resonance stabilization from the nitrogen atom, thereby favoring this mode of rearrangement. Yet it is believed that due to the electron withdrawing acetyl group on the indoline nitrogen atom, the lone pair on the nitrogen atom do not get to interact substantially with the buildup of positive charge in 1.85, which in turn makes a build up of positive charge on the benzylic carbon in 1.84 more favorable. Thus, rearrangement of 22 1.82 proceeds to give spiroindolin-2-one 1.83 exclusively. Further support for the formation of 1.83 over 1.86 was provided by Adams and coworkers, who obtained an X- ray crystal structure of 1.82, which showed a 4.7 pm longer C-O bond from the oxygen atom to the C3-carbon atom (indole numbering) than the C2-carbon atom.39
Scheme 1.16
Based on the results by Foote and coworkers (cf. Scheme 1.15), our group envisioned that a tetrahydrocarbazole modified with a chiral auxiliary might allow selective epoxidation from one face, and after rearrangement of the intermediate epoxide, a single spirooxindole would be formed diastereoselectively. It was thus found that (–)- menthyl-derived 1.87 could be epoxidized with DMDO. The intermediate epoxide 1.88 was fairly robust and required treatment with silica gel to rearrange and provide 1.89a in 78% and a 2:1 diastereomeric ratio (Scheme 1.17). Gratifyingly, when (–)-8- phenylmenthol was used as the chiral directing group, spirooxindole 1.89b was formed in identical yield but with an excellent diastereomeric ratio of 16:1.
23 Scheme 1.17
The absolute stereochemistry of the spirocenter in 1.89b was elucidated by X-ray crystallography of hemiaminal 1.90, which was prepared by hydrolysis of the ketal of
1.89b and subsequent reduction of the C2-carbonyl of oxindole (Scheme 1.18).11,40 X-ray analysis of crystalline 1.90 established that the absolute stereochemistry of the spirocenter was that shown for 1.89. More importantly, the stereochemistry corresponded to that found in citrinadin A (1.6).
Scheme 1.18
O O O
1. p-TsOH, O acetone OH N N 2. NaBH 4 O O MeOH O Ph O Ph 65%
1.90 1.89b crystal structure of 1.90 Based on these positive results, it was envisioned that an enantioselective epoxidation of indole 1.8 might be feasible. The intermediate epoxide 1.91 would rearrange to homochiral spirooxindole 1.7 (Scheme 1.19). Since the Shi epoxidation utilizes various chiral dioxiranes for the enantioselective epoxidation of a range of 24 olefins, we proposed to investigate the asymmetric epoxidation of 1.8 via the catalytic enantioselective Shi epoxidation.
Scheme 1.19
O O O O O O R R O O 1 2 O asymmetric N N O Shi epoxidation Ac Ac N Ac 1.8 1.91 1.7
1.5 FIRST ENANTIOSELECTIVE OXIDATIVE REARRANGEMENT OF INDOLES TO SPIROOXINDOLES
Indole 1.8 was required in order to investigate the desired asymmetric epoxidation and subsequent rearrangement. Starting with commercially available 2- methylcyclohexane-1,3-dione (1.92), methylation and mono-protection of one of the ketones furnished ketal 1.93 in 65% yield (Scheme 1.20). A Fischer-indole synthesis was employed to construct 2,3-disubstituted indole 1.95. To this end, ketone 1.93 was condensed with phenylhydrazine to form hydrazone 1.94, which readily cyclized in the presence of ZnCl2 to 1.95 in 76% yield over two steps. The indole nitrogen atom was acetylated with AcCl to deliver the desired N-acylindole 1.8.
25 Scheme 1.20
O 1. MeI, K2CO3 O O acetone, PhNHNH2 O O 2. ethylene glycol H2O O CSA, CH(OEt)3 O N N CH2Cl2 H 1.92 1.93 65% 1.94
O O
ZnCl NaH, CH3COCl 2 O O DMF, 50 °C toluene, N N H 76% 35% Ac 1.95 1.8 Before being able to study the asymmetric epoxidation of indole 1.8, we needed to develop a chiral HPLC method for determining the enantioselectivity of our epoxidation. To this end, a racemic standard was synthesized by epoxidation and subsequent rearrangement of indole 1.8 with DMDO (Scheme 1.21), using the same reaction conditions that had been utilized in the diastereoselective epoxidation of 1.87 (cf. Scheme 1.17). It is worth noting that later experiments determined that the rearrangement of the indole epoxide of 1.8 proceeds very readily even at –10 ºC and that there was no need for stirring the product mixture with silica gel. Racemic spirooxindole 1.7 was obtained via two steps in 67% yield. Since the two enantiomers were inseparable by various chiral HPLC methods, the acetate group was cleaved to deliver racemic 1.96. Gratifyingly, the two enantiomers of 1.96 readily separated on the HPLC using a chiral OD-J column.41
26 Scheme 1.21
With an analytical method in hand, we began investigating the enantioselective epoxidation/rearrangement of indole 1.8 (Table 1.3). Since D-epoxone (1.35) is the most readily synthesized chiral ketone for the asymmetric Shi epoxidation, we began our efforts with this catalyst. Using 30 mol% of 1.35, the epoxidation of 1.8 was conducted at 0 ºC, but to our disappointment, we only observed a 9% conversion to the desired spirooxindole 1.96 (Entry 1). In spite of the low yield, we were delighted to find that the desired spirooxindole had been produced in 73% ee. In hope of improving the yield, we raised the reaction temperature of the epoxidation reaction, but even at room temperature, only 11% conversion to 1.96 was observed (Entry 2). Since D-epoxone (1.35) was giving
such a poor conversion, we decided to look at catalyst 1.68 (cf. Scheme 1.14).35 Epoxidation of 1.8 catalyzed by 1.68 at –10 ºC proceeded in 34% conversion and a comparable 72% ee (Entry 3). Yet when the reaction temperature of the epoxidation was raised with this catalyst, the conversion began to increase as well. At –5 ºC a 46% conversion was noted (Entry 4), and at 0 ºC an 87% conversion was observed (Entry 5). All along the enantioselectivity did not seem to be affected by the raise in temperature, and indeed, at 0 ºC the best ee of 74% was obtained. Furthermore, the desired spirooxindole 1.96 could be isolated in 77% overall yield for the epoxidation/rearrangement and subsequent deprotection. In hope of further improving the yield, the epoxidation was also run at room temperature, and indeed an excellent conversion of 95% was obtained (Entry 6). However, at this temperature the ee dropped 27 to 57%. Lowering the catalyst loading was not beneficial either as this only resulted in reduced yields. From a practical standpoint it was thus concluded that the optimized reaction condition for the epoxidation of indole 1.8 was with 30 mol% of 1.68 at 0 ºC (Entry 5).
Table 1.3
% Conv.a to 1.96 Entry Chiral Ketone Temp (°C) % eeb from 1.8 (Yield) 1 30 mol% 1.35 0 9 73 2 100 mol% 1.35 23 11 - 3 30 mol% 1.68 – 10 34 72 4 30 mol% 1.68 – 5 46 71 5 30 mol% 1.68 0 87 (77%) 74 6 30 mol% 1.68 23 95 57 a % Conversion determined by 1H-NMR. b % ee determined by chiral HPLC.
One major question was whether the minor undesired epoxide, which leads to the minor enantiomer of spirooxindole 1.96, was being produced by oxidation of 1.8 via oxone itself. To eliminate this concern, indole 1.8 was subjected to the optimized reaction condition in the absence of a chiral ketone catalyst (Scheme 1.22). Gratifyingly, no spirooxindole 1.7 was formed and 1.8 was recovered quantitatively.
28 Scheme 1.22
Although we were able to analyze the ratio of the two enantiomers of 1.96 by chiral HPLC (Table 1.3), we did not know the absolute stereochemistry of the major enantiomers. In order to establish the absolute stereochemistry of the spirocenter in 1.96, spirooxindole 1.89b, the absolute stereochemistry of which was known by X-ray crystallography (cf. Scheme 1.18), was deacetylated to give indole 1.96 (Scheme 1.23). HPLC analysis of 1.96 thus obtained showed that the stereochemistry of the spirocycle obtained via our enantioselective epoxidation (cf. Table 1.3) is actually opposite to that present in citrinadin A (1.6).
Scheme 1.23
In order to explain the enantioselectivity in the epoxidation, one can propose a model similar to the one developed by Shi and coworkers (1.62) (cf. Figure 1.3). Thus, the two major proposed transition states would be 1.97 and 1.98 (Figure 1.4). The two other possible spiro transition states are neglected, since those would require the sterically bulky groups of the indole (ketal, acetate, geminal dimethyl) to point directly 29 into the oxazolidinone ring. Of the two transition states, 1.97 is the favored transition state that gives the major epoxide that rearranges to the spirooxindole with the stereochemistry of 1.96 in Table 1.3. Thus it is proposed that transition state 1.97 occurs predominantly, because the benzene ring of the indole is able to have favorable electrostatic interactions with the oxazolidinone ring of the catalyst, which is precluded in 1.97.
Figure 1.4
Based on the proposed electrostatic interactions between the aromatic ring of the catalyst and the benzene ring of the indole during the epoxidation (cf. Figure 1.4), we wanted to examine the effects of varying the electronics of the aromatic ring of the catalyst on the enantioselectivity of the epoxidation. Chiral ketone 1.99 was selected as a good catalyst for this study as it contained a more electron rich para-methoxy benzene ring. Ketone 1.99 had previously been synthesized by Shi and coworkers and was accessed via the same sequence that had been used for the synthesis of 1.68 (cf. Scheme
1.14, Scheme 1.24).37 Reacting indole 1.8 with 30 mol% of 1.99 and oxone at 0 ºC afforded spirooxindole 1.7, which was treated with NaOH to give spirooxindole 1.96 in 72% ee and 52% yield over two steps. Since the same sequence with catalyst 1.68 had afforded oxindole 1.96 in 74% ee (cf. Table 1.3), we concluded that altering the electronics of the aromatic ring of the catalyst has little to no effect on the enantioselectivity of the epoxidation.
30 Scheme 1.24
We were curious to see whether changing the indole protecting group from an acetyl to a carbomethoxy group might have a favorable effect on the yield and/or stereoselectivity of the epoxidation/rearrangement. Consequently, indole 1.95 was converted to N-carbomethoxy indole 1.100 in 71% yield (Scheme 1.25). When we performed the asymmetric epoxidation of 1.100, we obtained a mixture (1.4:1) of epoxide 1.101 and spirooxindole 1.102. Treatment of this mixture with silica gel at room temperature gave oxindole 1.102 in 77% conversion from 1.100. Upon removal of the carbomethoxy group and analysis of the spirooxindole by chiral HPLC, we found that 1.96 had been formed with 66% ee. Hence, the N-acetyl protecting group proved better than the carbomethoxy group. A brief attempt was made to look at Boc as a bulkier indole protecting group (not shown), however, after epoxidation/rearrangement of the indole we were unable to determine the ee due to a lack of separation of the two enantiomers. Efforts to cleave the Boc group also proved unsuccessful.
31 Scheme 1.25
One of the strengths of our enantioselective epoxidation/rearrangement of indoles to spirooxindoles is that it can be applied to a wide number of substrates other than tetrahydrocarbazoles. Not only would different cyclic indole systems be feasible, but presumably acyclic 2,3-disubstituted indoles could also be employed. In order to investigate the scope of our methodology, we turned our attention to a simple carboline (1.106), which, if oxidized to a spirooxindole, might be elaborated to coerulescine (1.1). Starting with commerically available 1.103, the imine was reduced and the secondary amine was protected with Boc2O (Scheme 1.26). N-Acetylation of 1.105 delivered the desired N-acylindole 1.106 in quantitative yield. Subjecting this carboline to the epoxidation/rearrangement with chiral catalyst 1.68 at –5 °C, gave spirooxindole 1.107 in a 39% conversion but a very disappointing 27% ee. Although a quantitative conversion could be achieved when performing the reaction at 0 °C, the enantiomeric excess did not improve. We believe that the presence of a geminal dimethyl group is crucial for obtaining good enantioselectivity in the epoxidation with catalyst 1.68 due to steric interactions between this group and the catalyst. In the absence of a geminal dimethyl group as for indole 1.106, differentiation between the two transition states similar to 1.97 32 and 1.98 becomes difficult (cf. Figure 1.4), which results in poor facial selectivity and therefore low enantioselectivity.
Scheme 1.26
In summary, we developed the first enantioselective oxidative rearrangement of an indole to a spirooxindole (Scheme 1.27). Under the optimized reaction conditions, indole 1.8 was treated with ketone catalyst 1.68 and oxone at 0 °C to afford spirooxindole 1.7, which upon treatment with NaOH gave spirooxindole 1.96 in 74% ee and 77% yield over two steps.
Scheme 1.27
33 1.6 FAILED ATTEMPTS
In our efforts toward developing an enantioselective oxidation of 2,3-disubstituted indoles to spirooxindoles, we examined several other oxidants that might promote the desired oxidation. Initially, an asymmetric oxidation using a chiral oxaziridine such as (+)-(2R,8aS)-10-(camphorylsulfonyl)oxaziridine (1.109) was considered (Scheme 1.28).42 In order to begin investigations in this direction, we synthesized oxaziridine 1.108 in three steps from commercially available saccharin.43 We were particularly interested in 1.108, as it had been shown to be useful in the diastereoselective oxidation/rearrangement of indoles by Williams and coworkers.44,45 Yet all attempts to oxidize indole 1.95 with oxaziridine 1.108 or the chiral camphor-derived oxaziridine 1.109 were unsuccessful. Even heating 1.109 at 120 ºC in PhCl led to unreacted starting material.
Scheme 1.28
O 1.108,CH2Cl2,rt O O or O 1.109, CH2Cl2,rt N or O H 1.109,PhCl,120°C N 1.95 H only rsm 1.96
n-Bu O N N SO 2 S O O2 1.108 1.109 In light of Williams’ reports, we were a little surprised that indole 1.95 did not react with oxaziridine 1.108. However, all of the indoles that Williams had employed were activated by electron donating substituents on the phenyl ring. Thus, in order to increase the nucleophilicity of indole 1.95, we deprotonated it with NaH prior to addition
34 of oxaziridine 1.108 (Scheme 1.29). Yet once again we only recovered unreacted starting material. Due to the lack of success, this approach toward oxidizing indole 1.95 was abandoned.
Scheme 1.29
In parallel to the studies outlined above, we also examined the asymmetric dihydroxylation of indoles 1.111 and 1.112 (Scheme 1.30). Reacting either indole with AD-mix-α only gave recovered starting material. Further efforts toward the asymmetric dihydroxylation were abandoned when the asymmetric Shi epoxidation began producing promising results.
Scheme 1.30
1.7 CONCLUSION
The first enantioselective epoxidation/rearrangement of an indole to a spirooxindole was developed. The first example of applying the Shi epoxidation to an indole was also demonstrated. A 2,3-disubstiuted indole was successfully epoxidized and rearranged to a spirooxindole, which upon deprotection of the N-acetyl group gave a homochiral spirooxindole in 74% ee and 77% yield over two steps. The spiroindolinone 35 was the antipode of the tricyclic spirooxindole present in the marine alkaloid citrinadin A. Screening of additional chiral ketone catalysts remains to extend the scope of this chemistry to other indoles and to make it a general method for the construction of homochiral spirooxindoles.
36 Chapter 2: Studies Toward the Total Synthesis of IB-00208
2.1 INTRODUCTION
Polycyclic xanthone IB-00208 (2.1) was isolated from the culture broth of
Actinomadura sp. in 2003.46 It has been shown to exhibit potent cytotoxic activity against several tumor cell lines (P388D1, A-549, HT-29, SK-MEL-28) with minimum inhibitory concentrations (MIC) of 1 nM. IB-00208 (2.1) also displayed nanomolar antibiotic activity against Gram-positive bacteria such as Staphylococcus aureus, Bacillus subtilis, and Micrococcus luteus. With its angularly-fused hexacyclic core, 2.1 is structurally
47 48 49 related to cervinomycin A2 (2.2), xantholipin (2.3), kibdelone A (2.4), actinoplanone D (2.5),50 lysolipin I (2.6),51 Sch 56036 (2.7),52 and FD-594 (2.8),53 all of which have been reported to possess significant biological activities.
The 1,4-dioxygenated xanthone (D-F ring) in 2.1 is an important structural feature that is also present in 2.2-2.8 in various oxidation states. Xanthones are significant as they are found in nearly one thousand natural products with potent biological properties,54 and they have been shown to exhibit important anti-microbial, anti-tumor, anti-inflammatory, and antioxidant activities.55 In light of these potentially useful biological activities, we were shocked to find that only few methods have been reported for the construction of 1,4-dioxygenated xanthones. Furthermore, most of them are
37 inefficient, employ harsh reaction conditions, and are not amendable to substrates with sensitive functionalities.
Therefore, in the context of a synthesis of IB-00208 (2.1), we were interested in developing a new method for the mild and efficient preparation of 1,4-dioxygenated xanthones, which might also be applied to the synthesis of 2.2-2.8 and other biologically active xanthone natural products.
38 2.2 BACKGROUND
2.2.1 Synthesis of Xanthones
2.2.1.1 Introduction
Xanthones are a common motif in natural products and biologically potent
synthetic compounds.54,55 The relevance of this structural motif to the synthetic community is further highlighted by the fact that an entire issue in Current Medicinal Chemistry was dedicated to xanthones.56 A wealth of work has been published describing different approaches to xanthones. A comprehensive overview of the different methods for constructing xanthones was reported by Sousa and Pinto.57 1,4-Dioxygenated xanthones (2.9), however, which are present in the angucycline natural products 2.2-2.8 in various oxidation states, have received considerably less attention in the literature.
This oxygenated xanthone motif is also present in several smaller yet biologically
active compounds. Bikaverin (2.10), for example, is known for its antifungal properties.58
Dulxanthone G (2.11) displays promising activity against cancer cells (IC50 = 3.51 μg/mL),59 while synthetic 2.12 is recognized for its inhibitory activity toward
60 monoamine-oxidase (MAO) A (IC50 = 5.22 μg/mL) and B (IC50 = 5.22 μg/mL).
39 2.2.1.2 Methods for Accessing Xanthones
In their review, Sousa and Pinto highlight both the common and less common
strategies for synthesizing xanthones.57 The most popular approach involves coupling 2.13 and 2.14 by a Friedel-Crafts acylation to afford benzophenone 2.15, which can be converted to the corresponding xanthone via a nucleophilic substitution reaction (Scheme 2.1). Another common route first creates an ether linkage through an Ullmann coupling to generate diaryl ether 2.17, which subsequently undergoes an acylation reaction to assemble the xanthone. Benzophenone 2.15 and diaryl ether 2.17 can also be accessed from ester 2.16 via a Fries rearrangement or a Smiles rearrangement, respectively. Additionally, xanthones can be formed directly from ester 2.16 by pyrolysis.
Scheme 2.1
W R' Friedel-Crafts acylation R + Ullmann coupling W=COCl,CO2H X HO W=CO2CH3,CO2H X=OH,OCH3,H 2.13 2.14 X=Cl,Br,I
CO2H X O Fries O R' Smiles R rearrangement rearrangment O O R R' R HO OH R' 2.15 2.16 Benzophenone 2.17 pyrolysis -XH acylation Diaryl Ether
O
R R' O 2.18 Xanthone
Some of the less common entries to xanthones are highlighted in Scheme 2.2. Larock and coworkers recently published a benzyne coupling approach to xanthones
between 2.19 and methyl salicylates (2.20).61 Xanthenes (2.22) can also be oxidized to xanthones, and, similar to diaryl ether 2.17 (cf. Scheme 2.1), benzoquinone 2.24 can be 40 converted to 2.18 via an acylation reaction and reduction of the quinone. Lastly, xanthone
2.18 has been synthesized through a Dieckmann condensation of poly-β-ketide 2.23 or
via displacement of SO2 from thioxanthonedioxide 2.21.
Scheme 2.2
O O TMS H3CO R + R' R R' OTf HO S 2.19 2.20 O2 2.21 F- KOH Thioxanthonedioxide Benzyne -SO2 Coupling
O
R R' O 2.18 Xanthone Dieckmann Cyclization OH O O O O [O] OH R R' acylation O HO OH 2.22 2.23 O Poly- -ketide Xanthene CO2Me
R R' O O 2.24 Benzoquinone
2.2.1.3 Syntheses of 1,4-Dioxygenated Xanthones
Although numerous methods have been reported for synthesizing xanthones (cf. Scheme 2.1 and 2.2), we were interested in an applications of these or other methodologies to a synthesis of IB-00208 (2.1) and other angucycline natural products (2.2-2.8). One of the earliest approaches was developed by Stout and coworkers in
1969.62 A Friedel-Crafts acylation of 2.25 with acid chloride 2.26 formed a mixture of coupling product 2.28 and phenol 2.27 in 13% and 25% yield, respectively (Scheme 2.3).
41 Not only was the yield of 2.27 low, but 2.28 could be converted to phenol 2.27 in only 42% yield. Formation of xanthone 2.29 from 2.27 proceeded in 91% yield. The drawbacks of this approach are the harsh Lewis-acidic conditions and poor yield in the key coupling reaction. Furthermore, the Friedel-Crafts acylation is limited to very electron rich aromatics.
Scheme 2.3
Brassard and coworkers developed an approach to a xanthone from a benzoquinone intermediate, which was also depicted in Scheme 2.2.63 Specifically, phenol 2.31 was coupled with chloroquinone 2.30 using anhydrous potassium fluoride (KF) in 70% yield (Scheme 2.4). The quinone was reduced with dithionite, and the resulting hydroquinone was cyclized to 1,4-dihydroxyxanthone 2.33 in the presence of acid. The major problem with this methodology is that the cyclization to the xanthone is conducted in concentrated sulfuric acid at 60 ºC. In the context of a total synthesis, a large number of protecting groups, specifically for oxygen, would not survive these
42 strong acidic conditions. Additionally, for more complex systems, the synthesis of the correct regioisomeric chloroquinone would pose a challenge.
Scheme 2.4
A very different synthesis of xanthones was reported by Hauser and coworkers.64 To begin, key sulfone 2.37 was synthesized from carboxylic acid 2.34 in five steps (Scheme 2.5). Deprotonation of 2.37 with t-BuOLi and condensation with chromone 2.38, which was synthesized from 2-hydroxy-4-methoxy-6-methylacetophenone in three steps, afforded xanthone 2.39 in 27% yield. The lengthy synthesis of the sulfone and the low yield of the xanthone-forming reaction make this an unappealing method. Furthermore, Hauser and coworkers commented in a more recent publication that their attempts to extend this chemistry to angular polycyclic aromatic systems had failed.65
43 Scheme 2.5
OMe O OMe O OMe s-BuLi, TMEDA HO2C SOCl ,0°C 2 Et2N THF Et2N then OMe OMe then DMF OHC OMe HNEt2,PhH OMe 0°C rt OMe OMe 56% 2.34 2.35 2.36 88%
Me O
MeO O OMe Me O OH OMe O OMe 1. HCl, HOAc, H2O 2.38 O 2. PhSH, p-TsOH (cat.) t-BuOLi, THF MeO O OMe OMe 78 °C 3. mCPBA, CH2Cl2 PhO2S OMe OMe OH OMe 74% 2.37 27% 2.39 One of the more recent approaches to 1,4-dioxygenated xanthones was developed by Liebeskind.66 Dithiane 2.40, prepared from salicylaldehyde in one step, was doubly deprotonated with t-BuLi, and the dianion thus formed was added to diisopropyl squarate 2.41 (Scheme 2.6). Under acidic conditions (p-TsOH), cyclization ensued to dione 2.42 in 71% yield from 2.40. Regioselective addition of phenyllithium to the ketone instead of the vinylogous ester of 2.42 and in situ protection of the resulting tertiary alkoxide afforded squarate 2.43. Heating of 2.43 resulted in a 4π-electrocyclic ring opening reaction to give ketene 2.44, which underwent a 6π-electrocyclic ring closing reaction to produce tetracycle 2.45. Deprotection of the dithiane proceeded in the presence of
mercuric (II) chloride (HgCl2) to yield xanthone 2.46 in 77% from 2.43. Problems with this method are that if the phenyl group that is added to 2.42 contains additional substituents, regioisomers can form in the electrocyclic cyclization of 2.44. Furthermore, dithianes containing ortho,ortho-disubstitution were not explored, presumably, because formation of the dithiane from the corresponding ortho,ortho-disubstituted aldehyde
44 would not be trivial. Lastly, one other drawback is the use of the dithiane protecting group, which has to be removed using toxic HgCl2.
Scheme 2.6
SS O O-iPr 1. t-BuLi, pentane O SS 78 0°C PhLi, THF, 78 °C + H 2. p-TsOH, rt then O O-iPr O O CH2Cl2 Ac2O, 78 °C rt HO 2.41 2.42 2.40 71% 81%
OH O SS SS O SS THF O O O OAc OAc OAc 2.43 2.44 2.45
OH O
HgCl2,CaCO3
acetone, rt O 77% from 2.43 OAc 2.46 In summary, although there a number of methods for the synthesis of xanthones, only very few of them have been applied to the construction of 1,4-dioxygenated xanthones. Additionally, most of the methods reported for the construction of these systems have significant limitations in scope, employ harsh conditions, and/or are poor- yielding. Considering the abundance of 1,4-dioxygenated xanthones in biologically active natural products, a mild and practical synthesis of these systems would be of great benefit to the synthetic community.
45 2.2.2 Syntheses of Xanthone-Containing Angucycline Natural Products
2.2.2.1 Kelly’s Synthesis of Cervinomycin A2
Of the angucycline natural products 2.1-2.8, only syntheses of cervinomycin A2 (2.2) and the aglycone of FD-594 (2.8) have been reported. While the aglycone of 2.8 was only synthesized very recently, four approaches to 2.2 have been completed.
The first total synthesis of cervinomycin A2 (2.2) was published by Kelly and coworkers in 1989.67 Carboxylic acid 2.34 was converted to ester 2.47 via a selective monodemethylation and esterification (Scheme 2.7). The xanthone core was assembled following the protocol developed by Brassard (cf. Scheme 2.4), involving a coupling of phenol 2.47 with quinone 2.48 in 48% yield. The quinone was reduced to the corresponding hydroquinone, which was cyclized to the xanthone under strong acidic conditions. After protection of the hydroquinone moiety the MOM ether 2.50 was isolated in 69% yield.
Scheme 2.7
O
I I O O O OMe 1. BBr3,CH2Cl2 OMe 2.48 HO MeO 2. CH2N2 KF, DMF, 75 °C MeO OMe HO OMe 73% 48% 2.34 2.47
1. aq. Na S O O 2 2 4 MOMO O CO Me 2. conc H SO 2 OMe 2 4 OMe rt 60 °C
I O OMe 3. NaHMDS, THF I O OMe MOMCl, rt O MOMO 2.49 69% 2.50
46 Synthesis of the northern fragment of 2.2 began with conversion of phenol 2.51 to amide 2.52 (Scheme 2.8). A methyl group was introduced, which could be lithiated and reacted with ethyl acetate to afford 2.55. One-pot hydrolysis of the amide, lactone formation, and TBS-deprotection gave the alcohol 2.54, which was subsequently eliminated to provide 2.55. Oxazolidine 2.57 was formed from 2.55 via a two-step protocol in 89% yield. An intermolecular Heck coupling between styrene 2.57 and aryl iodide 2.50 delivered 2.58, which, upon irradiation and in situ oxidation of the cyclized product, was converted to cervinomycin A2 (2.2) in 36% yield.
47 Scheme 2.8
Kelly and coworkers thus synthesized cervinomycin A2 (2.2) in 12 linear steps and 18 steps overall. The synthesis features an intermolecular Heck coupling to assemble a stilbene intermediate in 65% yield and an photochemical cyclization/MOM- deprotection/oxidation that affords 2.2 in 36% yield. While this is a very short synthesis
48 of cervinomycin A2, the low yield in the final step of the synthesis is disappointing. Furthermore, formation of the xanthone was directly adapted from the work by Brassard
and coworkers, which required concentrated H2SO4 at 60 ºC and only proceeded in 47% yield over three steps.
2.2.2.2 Mehta’s Synthesis of Cervinomycin A2 Methyl Ether
Two years after Kelly’s report, Mehta and coworkers published their approach to
68 cervinomycin A2 methyl ether 2.73. Synthesis of the xanthone began with hydroquinone 2.60, which was produced from orcinol (2.59) in four steps (details not reported) (Scheme 2.9). Methylation, hydrolysis of the ester, and acid chloride formation delivered 2.61 in 75% yield. Friedel-Crafts acylation to generate the benzophenone followed by K2CO3-induced cyclization afforded xanthone 2.63 in 37% yield. The desired phosphonium salt 2.64 was produced from 2.63 in two additional steps.
Scheme 2.9
OH O OMe O OH 1. MeI, K2CO3 4steps OMe acetone, Cl 2. 4 M NaOH Me OH Me OMe Me OH EtOH, rt OH OMe 3. SOCl2, orcinol (2.59) 2.60 2.61 75%
OMe 1. MeO OMe OMe O OMe O 2.62 1. NBS, AIBN OMe OMe AlCl3,Et2O, rt CCl4,
2. K CO , 2. PPh , BrPh3P 2 3 Me O OMe 3 O OMe aq MeOH PhMe OMe OMe 37% 2.63 60% 2.64
49 With one precursor for a Wittig coupling in hand, the requisite aldehyde 2.68 was synthesized from 2.65 by an intermolecular Diels Alder reaction and subsequent two-step oxidation of the arylmethyl group (Scheme 2.10).
Scheme 2.10
A Wittig reaction between the ylide generated from phosphonium salt 2.64 and aldehyde 2.68 followed by hydrolysis of the esters yielded stilbene derivative 2.70, predominantly as its trans-isomer, in 90% yield (Scheme 2.11). After elaboration of the carboxylic acids, 2.71 was irradiated in the presence of iodine to induce a cyclization to give hexacycle 2.72 in 25% yield. The synthesis of cervinomycin A2 methyl ether (2.73) was completed by reacting 2.72 with 2-aminoethanol to furnish the oxazolo- isoquinolinone moiety followed by oxidation of the dimethylhydroquinone to the corresponding quinone in 28% overall yield.
50 Scheme 2.11
The synthesis by Mehta and coworkers thus assembles cervinomycin A2 methyl ether 2.73 in 19 linear steps and 22 steps overall. The synthesis features an intermolecular
Wittig reaction to couple the two key fragments and a photocyclization to assemble the hexacyclic core of the natural product. The xanthone was constructed via a Friedel-Crafts acylation/cyclization strategy, the most common approach to xanthones (cf. Scheme 2.1), in only 37% yield. Additionally, taking away from the attractiveness of this route, the last three steps of the synthesis proceeded in only 7% overall yield.
51 2.2.2.3 Rao’s Synthesis of Cervinomycin A2
Directly following the publication by Mehta, Rao and coworkers communicated
69 their synthesis of cervinomycin A2 (2.2). Acylation of 2.74 gave 2.75, which was
homologated to 2.76 in three steps (Scheme 2.12). Wittig olefination with Ph3PCHCO2Et afforded 2.77 as an inconsequential mixture of E/Z isomers in 91% yield. Processing of 2.77 by hydrogenation, hydrolysis of the ester, and treatment with an excess of polyphosphate ester (PPE) delivered tricycle 2.78 in 52% yield. Introduction of the ester and aromatization generated phenol 2.79, which was methylated and subsequently expanded to ketone 2.81. Reduction of 2.81 and concomitant cyclization produced the desired lactone. Oxidation of the dimethylhydroquinone generated quinone 2.82.
52 Scheme 2.12
O OMe O OMe 1. Tl(NO2)3 3H2O OMe MeOH, dioxane Ac2O, AlCl3 HClO4,0°C rt DCE 2.aq.KOH,MeOH,rt Br Br Br 3. MeLi, Et O OMe no yield reported OMe 2 OMe 0°C rt 2.74 2.75 2.76 54%
CO2Et O 1. NaH, Et2CO3 1. H2,PtO2,EtOH OMe OMe THF, Ph3PCHCO2Et 2. KOH, EtOH, rt 2. PyHBr3,AcOH PhMe, 3. PPE, CHCl ,rt 3. DBU, CH Cl ,rt 3 Br 2 2 Br 91% OMe OMe 52% 46% 2.78 2.77
O O O CO2Et CO2Et OH OMe 1. K2CO3,Me2SO4 OMe 1. NaBH4,K2CO3 OMe acetone, OMe MeOH, rt O
2. LDA, THF, 78 °C 2. CAN, CH3CN H O, rt Br then Br 2 Br OMe O OMe 76% O 2.79 N 2.80 2.81 2.82 OMe
63%
Coupling partner 2.47 was synthesized from aldehyde 2.83 via a Pinnick oxidation, methylation, and selective monodemethylation (Scheme 2.13).
Scheme 2.13
Fragments 2.82 and 2.47 were brought together under basic conditions, but the yield for the reaction was not reported (Scheme 2.14). Reduction of the quinone and
53 methylation was followed by hydrolysis of the ester and PPE-mediated cyclization to xanthone 2.85 in 62% over four steps. In order to assemble the oxazolidine present in the natural product, the lactone in 2.85 was opened again to ketone 2.72. Treatment of 2.72 with 2-aminoethanol (2.55) formed the desired oxazolidine. The synthesis of
cervinomycin A2 (2.2) was completed upon oxidation to the quinone and selective demethylation.
Scheme 2.14
O OMe O O MeO O O 1. aq. Na2S2O4 HO OMe OMe OMe 2. K2CO3,Me2SO4 O 2.74 O acetone, CO Me 2 OMe K2CO3,DMF 3.aq.KOH,EtOH,rt 4. PPE, CHCl ,rt Br no yield reported O OMe 3 O O 62% 2.82 2.84
O O O CO2Me 1. aq. KOH, EtOH, rt OMe OMe O OMe 2. CH2N2,Et2O OMe O OMe OMe 3. PCC, CH3Cl3,rt O OMe 90% O OMe OMe OMe 2.85 2.72
O N O 1. HO Me NH OH 2 O O K CO ,MeOH,rt 2 3 OMe
2. CAN, CH3CN, H2O 3. Et3N BCl3,0°C O OMe CH2Cl2 O
cervinomycin A2 (2.2) 66%
54 Rao and coworkers thus reported a synthesis of cervinomycin A2 that required 26 linear steps and 29 steps overall. The synthesis features a xanthone formation using a slight variation of the protocol developed by Brassard and coworkers (cf. Scheme 2.4), yet no comparison can be made since the yield of the key fragment coupling between 2.82 and 2.47 was not reported (Scheme 2.14). Detracting from the synthesis, the oxidation state of the lactone in 2.85 had to be adjusted at the end of the synthesis, which took three steps.
2.2.2.4 Suzuki’s Synthesis of FD-594 Aglycon
Very recently, Suzuki and coworkers published a synthesis of the FD-594 aglycon
(2.107).70 The synthesis began with construction of the northern fragment 2.92 (Scheme 2.15). Vanillin (2.86) was converted to bromide 2.87 in three steps. Lithium-halogen exchange and addition of the aryllithium thus formed to (R)-propyloxirane (2.88) delivered alcohol 2.89. Deprotection of the MOM ethers, formation of the aryl triflate, and subsequent carbonylation afforded lactone 2.90 in 68% yield. Processing 2.90 via cleavage of the methyl ether, hydrolysis of the acetal and reduction of the aldehyde thus formed delivered alcohol 2.91. Iodination of 2.91 and TIPS protection of the primary alcohol completed the synthesis of the northern fragment 2.92.
55 Scheme 2.15
1. Br ,MeOH OH OH 2 OMOM OMOM OMe 2. 1,3-propanediol Br OMe n-BuLi, Et2O, 78 °C OMe Bu4NBr3 (1%) HC(OEt)3 then 3. NaH, DMF CHO then MOMCl O OO 2.88 OO vanillin (2.86) BF3 OEt2 88% 78 °C rt 2.87 2.89 68%
O O 1. 1,3-propanediol O O 140 °C OMe OH 2. PhNTf2,K2CO3,DMF 1. BCl3,CH2Cl2,0°C
3. Pd(OAc)2, CO, dppp, 2. 0.5 M H2SO4,100°C Et3N, DMF, 100 °C 1,4-dioxane OO 3. NaBH4,MeOH OH 68% THF, 78 °C 2.91 2.90 98%
O O 1. BnMe NICl ,NaHCO 3 2 3 OH CH2Cl2,MeOH, 10 °C 2. TIPSCl, imidazole DMF I OTIPS 85% 2.92 The xanthone fragment 2.98 was synthesized from diester 2.93 in 13 steps (Scheme 2.16). After formation of ketal 2.94 from 2.93, the system was elaborated to aldehyde 2.95 in five additional steps. Addition of the aryllithium of 2.96 to 2.95 and oxidation of the resulting secondary alcohol produced benzophenone 2.97 in 85% yield.
The xanthone was formed via deprotection of the MOM group and CsCO3-induced cyclization via a nucleophilic aromatic substitution. Synthesis of xanthone fragment 2.98 was completed by hydrolysis of the ester with lithium hydroxide (LiOH).
56 Scheme 2.16
Acid 2.98 was transformed to the corresponding acid chloride and then coupled with phenol 2.92 (Scheme 2.17). After deprotection of the benzyl group, the key biaryl bond in 2.100 was created through a palladium-catalyzed cyclization. Asymmetric ring opening of the lactone with (S)-valinol (2.101) as a chiral nucleophile and subsequent oxazoline formation provided atropisomer 2.102, which was elaborated to aldehyde 2.103 in four steps.
57 Scheme 2.17
1. (COCl) ,DMF 2 OH O O CH2Cl2 OBn O O then O O O O DMAP, pyridine O Pd2(dba)3 O O O HO2C O O OMe t-BuCO2Na I OMe OH DMA, 60 °C 2.98 OTIPS 2.92 I 2.99 OTIPS
2. BBr3,CH2Cl2, 5°C
91%
O O NH HO 2 OTIPS OH OH O O OH O O O 1. (S)-valinol (2.101), THF O O
2. I2,PPh3,CH2Cl2 TIPSO O O O O O imidazole N OMe O OMe 87% from 2.99 2.100 2.102
1. BnBr, Cs2CO3 O O DMF, 40 °C 2. MeOTf, 2,6-DTBP OBn O CH Cl OBn O 2 2 O 3. NaBH(OMe)3 78 20 °C TIPSO 4. sat. citric acid O THF O OMe 2.103 74%
Aldehyde 2.103 was converted to key dialdehyde 2.104 in four additional steps (Scheme 2.18). In this sequence, the xanthone was reduced to the corresponding xanthene, because the key cyclization was otherwise unproductive. Thus, treatment of dialdehyde 2.104 with samarium (II) iodide (SmI2) in the presence of 2,6-bis[(4S)-(–)- isopropyl-2-oxazolin-2-yl]pyridine ((S,S)-i-Pr-pybox) (5.105) delivered the trans-diol present in the natural product. Acetate-protection of the diol and oxidation of the xanthene afforded 2.106 in 71% yield from 2.104. The synthesis of the FD-594 aglycone 58 (2.107) was completed by cleavage of the methylene acetal and removal of the acetyl and benzyl protecting groups.
Scheme 2.18
O O O O 1. L-selectride OBn OBn OBn O O 78 25 °C THF OBn O O O 2. NaBH3(CN) AcOH, CH2Cl2 TIPSO O 3. TBAF, THF O O O OMe O OMe 4. (COCl)2,DMSO 2.103 CH2Cl2, 78 °C 2.104 then Et3N, 78 °C
81%
O O 1. Pb(OAc)2 O O PhH, 1. SmI ,THF, 78 °C OBn 2. p-TsOH, H O OH 2 O O 2 OH O OH (S,S)-i-Pr-pybox (2.105) OBn MeOH O OH 2. Ac2O, DMAP 3. K2CO3,MeOH pyridine 4. Pd(OH) /C AcO O 2 HO O 3. DDQ, CH2Cl2 H2,MeOH 1,4-dioxane OAc OMe OH OMe H O 2 2.106 81% aglycone of FD-594 (2.107) 71%
Suzuki and coworkers thus accomplished the first synthesis of the FD-594
aglycone 2.107 in 33 linear steps and 45 steps overall. Their approach features a SmI2- promoted cyclization of a dialdehyde intermediate, which produces the angularly-fused ring system as well as the trans-diol present in the natural product in 72% yield. The requisite xanthone was synthesized via the most common route used to access these systems, which involved formation of a benzophenone and subsequent intramolecular cyclization. Detracting from their approach was the need to reduce the xanthone to a xanthene before the key step, which later had to be oxidized to the xanthone again. Overall, Suzuki’s synthesis of 2.107 requires far too many steps to assemble the angularly-fused hexacyclic core and the natural product.
59 2.2.3 Prior Art in the Martin Group: First Generation Approach to IB-00208
The first retrosynthesis for IB-2008 (2.1) was proposed by former post-doc Dr. Douglas Mans (Scheme 2.19). It was envisioned that the A-ring could be constructed from hydroquinone 2.108 via a Wacker oxidation, Corey-Bakshi-Shibata (CBS) reduction, and carbonylative cyclization. Removal of protecting groups from key intermediate 2.109, followed by regioselective allylation, regioselective bromination, and Claisen rearrangement would furnish 2.108. Pentacycle 2.109 was thought to be a key intermediate of the synthesis as it contained the angular fusion as well as the oxidized xanthone present in the natural product. Construction of the oxidized xanthone 2.109 was envisioned to proceed via the key sequence from benzocyclobutenone 2.112. Thus, if 2.112 underwent a Moore cyclization (cf. Scheme 2.20), diradical intermediate 2.111 would be afforded, which was proposed to undergo a radical abstraction in the presence of a copper (II) salt to generate aryl cation 2.110. The cation was then thought to be trapped by the proximal methoxy group. Subsequent deprotection, oxidation, and methylation would rapidly provide 2.109.
60 Scheme 2.19
Me O O * A OH Br OR O O OMe OH O O OMe B O O OMe O RO O C DEF Me HO O O O OMe O OMe O OMe MeO O OMe OMe * stereochemistry unknown 2.109 2.108 R = protecting group IB-00208 (2.1)
t-Bu t-Bu t-Bu t-Bu OR 1,2-addition • Si Si O O O • O t-Bu O O O t-Bu RO CuII O Si O • OH O O MeO OH Me OMe OH Me OMe 2.110 2.111 MeO 2.112 The first step in the proposed key sequence, the formation of diradical 2.111, was based on chemistry developed by Moore and coworkers (Scheme 2.20).71 Under thermal
conditions squarates are known to undergo a 4π-electrocyclic ring opening reaction. The newly formed ketene 2.114 breaks homolytically and the carbon-based radical cyclizes onto the alkyne to generate diradical 2.115. An intermolecular hydrogen atom abstraction then generates a new diradical 2.116, which is equivalent to quinone 2.117.
61 Scheme 2.20
The cyclization and concomitant loss of a methyl group was inspired by work by Fuganti and coworkers, who showed that 3-en-5-ynoic acids 2.118 yielded dibenzofurans 2.120 when heated under reflux with acetic anhydride and sodium acetate (Scheme
2.21).72,73 The authors proposed that both the furan and the second aromatic ring formed in a single annulation step.
Scheme 2.21
Initial work by Dr. Mans focused on the synthesis of an angularly-fused benzocyclobutenone. After several different approaches, it was found that 2.126 could be synthesized from 2,5-dimethoxybenzaldehyde (2.121) in six steps (Scheme 2.22). Aldehyde 2.121 was converted to the corresponding acetal, which served as a directing
62 group for the lithiation and subsequent bromination. Aldehyde 2.122 was obtained after removal of the acetal in 62% yield over three steps. Peterson olefination of 2.122 afforded olefin 2.123, which was coupled with squarate 2.12474 in 66% yield. The angular fusion was introduced through a ring-closing metathesis (RCM) reaction, and benzocyclobutenone 2.126 was thus generated in 93% yield. A novel approach to 2.126 had been developed, yet the current route contained two minor drawbacks. First, the aldehyde had to be protected and subsequently deprotected in order to perform the regioselective bromination. Secondly, the chromatography required after the bromination step was rather tedious and proved difficult during scale-up efforts. Nevertheless, a new approach to angularly-fused benzocyclobutenones was established, which allowed access to sufficient quantities of 2.126.
Scheme 2.22
63 In order to study the desired key reaction sequence, Dr. Mans coupled alkyne 2.127 with 2.126 to give 2.128 in 88% yield (Scheme 2.23). The cyclobutenone of 2.128 was unmasked with p-TsOH, and heating 2.129 thus obtained with copper (II) acetate
(Cu(OAc)2) in MeOH afforded quinone 2.130 in 70% yield. Originally, Dr. Mans had hoped that the proximal methoxy group would cyclize. Yet as is evident from the product, the intermediate carbocation (cf. 2.110) is captured by the solvent instead. Screening of different solvents in order to promote the desired cyclization was unsuccessful because of the poor solubility of copper (II) acetate in organic solvents.
Scheme 2.23
It was thought that a free phenol might be captured more readily than the corresponding methyl ether. Thus, the silicon group in 2.129 was removed to give 2.131 in 84% yield (Scheme 2.24). This intermediate was subjected to the previous conditions, yet only unidentified side products were observed. All cyclization attempts using
64 different oxidants or solvents also failed to afford the desired product, which concluded Dr. Mans’ work toward a synthesis of IB-00208 (2.1).
Scheme 2.24
2.3 STUDIES TOWARD THE TOTAL SYNTHESIS OF IB-00208
2.3.1 Second Generation Approach to IB-00208
2.3.1.1 Retrosynthesis
Based on the results obtained by Dr. Mans, my studies toward the total synthesis of IB-00208 began with a new proposal for the key sequence (Scheme 2.25). It was envisioned that key intermediate 2.109 might be synthesized directly from cyclobutenone
2.135. In the forward direction, 2.135 was proposed to undergo a 4π-electrocyclic ring opening reaction upon heating. The ketene 2.134 thus generated would then participate in a tandem cyclization, similar to the precedent by Fuganti and coworkers (cf. Scheme 2.21), to generate xanthone 2.133, which was thought to readily oxidize to 2.109 in the presence of air. This approach would deliver 1,4-dioxygenated xanthones in an efficient
65 manner. Furthermore, since a number of squarates are commercially available or can be accessed in just one step,75 this approach would provide a very general and rapid entry to xanthones.
Scheme 2.25
Me O O Br * A OH O O OMe OH OR B O O OMe O O OMe O O C DEF HO RO Me O O O OMe O OMe O OMe O OMe MeO OMe * stereochemistry unknown 2.108 2.109 IB-00208 (2.1) R = protecting group
OR OH O OMe O 1,2-addition O O OMe • RO O OMe O OH O XO OH OMe OH X OMe 2.135 MeO 2.133 X = TBS, Me, H, [M] 2.134
2.3.1.2 Retrosynthesis of Model System
In order to study the feasibility of our second generation retrosynthesis, we opted to study the proposed sequence with a model system. Tetracycle 2.136 was thought to be a suitable model substrate (Scheme 2.26). Cyclobutenol 2.137 would be the requisite precursor for the key step, which we thought could be synthesized from dione 2.138 and ynone 2.139.
66 Scheme 2.26
We envisioned that the key step might occur via either a concerted or a stepwise mechanism. In a concerted process, the phenolic oxygen atom would add to the alkyne in intermediate 2.140, which would then cyclize onto the ketene (Scheme 2.27).
Scheme 2.27
O O O O O O OMe OMe TBAF OMe [O] OH HO TBSO heat O O TBS O OMe MeO - MeO F 2.136 2.137 2.140 In a more stepwise fashion, 2.137 might first undergo etherification with the alkyne (Scheme 2.28). Upon heating, a 4π-electrocyclic ring-opening reaction of cyclobutenol 2.141 followed by a 6π-electrocyclic ring-closing reaction would afford intermediate 2.143. Tautomerization of 2.143 to the hydroquinone and successive oxidation to the quinone in the presence of air would efficiently deliver the oxidized xanthone 2.136 in one pot. Based on literature precedent, the etherification could either be directly performed in the presence of a fluoride source,76 or the deprotected phenol could be cyclized under basic,77 neutral, acid, or Lewis acidic78 conditions. Previous work by Moore and Liebeskind had shown that the electrocyclic ring opening, ring closure, tautomerization, and air oxidation can all occur in one pot under thermal conditions with furans and substituted benzene rings.79,80 With the ultimate goal to sequence the entire 67 transformation from 2.137 to 2.136 in one pot, temperature adjustments might play a crucial role, as the Moore cyclization requires reaction temperatures ranging from 80 to 138 °C.81
Scheme 2.28
Overall, the outlined methodology would provide a concise and general approach to 1,4-dioxygenated xanthones. This chemistry would allow for the novel and rapid construction of the xanthone core of IB-00208 with feasible extension to the synthesis of other xanthone-containing natural products.
2.3.1.3 Synthesis of the Requisite Ynone
Synthesis of the requisite ynone 2.139 (cf. Scheme 2.26) was envisioned to proceed from aldehyde 2.147, which was thought to be accessible from commercially available 2,5-dimethoxybenzaldehyde (2.121) (Scheme 2.29). Aldehyde 2.121 was thus transformed into 2.145 via a Baeyer-Villiger oxidation,82 and the phenol of 2.145 was protected as a MOM ether.83 ortho-Directed lithiation of 2.146 and formylation with DMF provided 2.147 in 40% yield from 2.121.
68 Scheme 2.29
In order to swap protecting groups, 2.147 was deprotected under acidic conditions (Scheme 2.30). Phenol 2.148 was converted to silyl ether 2.149 in 69% yield. Addition of alkynylmagnesium bromide afforded alcohol 2.150, which was readily oxidized with 2- iodoxybenzoic acid (IBX) to afford the desired ynone 2.139.
Scheme 2.30
69 2.3.1.4 Synthesis of the Requisite Benzocyclobutadione
For the synthesis of benzocyclobutenone 2.138, we initially envisioned employing a [2+2]-cycloaddition between a benzyne and a silyl ketene acetal (SKA), as had been utilized by Suzuki to prepare structurally similar systems.84 The required silyl ketene acetal 2.153 was synthesized from glyoxylic acid (2.151) in two steps and 9% overall yield (Scheme 2.31).85
Scheme 2.31
2-Iodo-1-trifluoromethanesulfonatebenzene (2.155) was then prepared from 2- iodophenol (2.154) (Scheme 2.32). Iodide 2.155 was reacted with n-BuLi to generate a benzyne intermediate, to which silyl ketene acetal 2.153 was added. After evaporation of the solvent, the crude reaction mixture was treated with aqueous HF to provide dione 2.138 in 24% yield over two steps.
Scheme 2.32
Since the yield of the [2+2]-cycloaddition could not be improved by varying the reaction temperature or stoichiometry of the reagents, we decided to look at an alternative approach to 2.138. Leinweber and coworkers had synthesized 2.138 from ninhydrin (2.156) via a photochemical decarbonylation (Scheme 2.33).86 In accordance with their
70 work, dione 2.138 was synthesized in a much more gratifying 38% yield over three steps. The photochemical decarbonylation step in this sequence was carried out by Caesar Almaraz.
Scheme 2.33
2.3.1.5 Coupling of the Fragments
Having accomplished the synthesis of ynone 2.139 and dione 2.138, we turned our attention to the coupling of these two pieces to synthesize cyclobutenol 2.137 (Scheme 2.34). However, much to our disappointment, addition of the alkynyllithium derived from 2.139 to dione 2.138 at –78 ºC failed. When the reaction temperature was elevated to 0 °C, again only unreacted starting material was recovered. Upon raising the temperature to room temperature, two unidentifiable side products were observed.
71 Scheme 2.34
O O O OMe n-BuLi THF, 78 °C OMe TBSO OH then TBSO O MeO MeO 2.139 O 2.137 2.138 temp: o 78 C temp 78 °C: rsm 0°C: rsm rt: side products
In order to verify formation of the alkynyllithium derivative of 2.139, the ynone was treated with n-BuLi and then methyl iodide (MeI) to afford 2.159 in 58% yield (Scheme 2.35). We had thus established that the alkyne 2.139 can be deprotonated and the alkynyllithium thus generated will react with small, reactive electrophiles such as MeI.
Scheme 2.35
To establish that dione 2.138 will react with an alkynyllithium derivative,
silacycle 2.127, which Dr. Mans had successfully added to a related system (cf. Scheme 2.23), was deprotonated and coupled with 2.160 in 61% yield (Scheme 2.36).
72 Scheme 2.36
t-Bu t-Bu t-Bu O t-Bu O Si n-BuLi O Si O THF, 78 °C O OH MeO then MeO O MeO MeO O 2.127 2.138 2.160 78 oC
61% Since the reactivities of ynone 2.139 and dione 2.138 were verified independently, it appeared that something specifically about the union of those two pieces was a problem. Upon conducting a few more experiments, we found that the alkynyllithium derivative of 2.139 could be added to benzaldehyde (Scheme 2.37). Even though the
isolated yield amounted to only 31%, the 1H NMR spectrum of the crude reaction mixture indicated a 93% conversion to the desired product.
Scheme 2.37
However, attempts to effect a similar coupling with a dione such as benzil (2.161) proved futile (Scheme 2.38). Performing the reaction at room temperature, elevated temperatures, or in the presence of 12-crown-4 did not give any detectable amounts of 2.163. Even transmetalating the alkynyllithium derivative of 2.139 to the corresponding cerate and reacting this intermediate with 2.161 failed to give any addition product 2.163 (not shown).
73 Scheme 2.38
O Ph OH O OMe n-BuLi THF, 78 °C OMe O Ph TBSO then TBSO (PhCO)2 (2.161) MeO 78 °C MeO 2.139 2.163 Based on all of these results we believed that it would not be possible to efficiently couple ynone 2.139 with cyclobutadione 2.138. Presumably, the ynone must be a good of leaving group, so that if the desired tertiary alkoxide is formed, the ynone readily eliminates again to give back starting material. Since we had been successful in the addition of the alkynyllithium derivative of 2.127 to 2.138 (cf. Scheme 2.36), we reasoned that a comparable silacycle like 2.164 might be a more suitable coupling partner than ynone 2.139.
t-Bu t-Bu O Si O
MeO OMe
2.164 Addition of ethynylmagnesium bromide to 2.147 was expected to provide propargylic alcohol 2.165 (Scheme 2.39). However, while addition of the acetylide did proceed, the MOM protecting group was removed simultaneously, yielding exclusively
diol 2.166 in 83% yield. This outcome was attributed to the use of a large excess (seven equivalents) of the Grignard reagent as well as stirring the reaction overnight. Potentially,
the alkynylmagnesium bromide acted as a Lewis acid similar to MgBr2, which has been shown to deprotect phenolic MOM ethers.87 Nevertheless, since deprotection of the MOM group was to be the next step, we welcomed this fortuitous outcome.
74 Scheme 2.39
Protection of the secondary alcohol and the phenol in 2.166 with t-Bu2Si(OTf)2 gave silacycle 2.164 in 79% yield (Scheme 2.40). Gratifyingly, addition of the alkynyllithium derivative of silacycle 2.164 to dione 2.138 provided cyclobutenol 2.167 in 65% yield. Deprotection of the silacycle with HF·pyr gave secondary alcohol 2.168 in quantitative yield. Due to its instability, this intermediate had to be used immediately.
Scheme 2.40
t-Bu OH t-Bu t-Bu2Si(OTf)2 O Si n-BuLi OH 2,6-lutidine THF, 78 °C O CH Cl ,0°C MeO OMe 2 2 then MeO OMe O 79% 2.166 2.164 O 2.138 78 °C
65%
O t-Bu O t-Bu O Si OH HF-pyr, py O OH OH rt, THF OH MeO OMe MeO OMe quant.
2.167 2.168
In order to conserve precious amounts of 2.168, we decided to screen oxidants for the oxidation of intermediate 2.166 (Table 2.1). IBX is known to oxidize secondary benzylic propargylic alcohols in related systems.88 Depending on the solvent of the reaction, IBX can be used in the presence of phenols89 or to oxidize phenols.90 Using IBX
75 in DMSO, which had worked well previously (cf. Scheme 2.30), only led to decomposition. After screening several solvents, THF proved to be the most effective solvent for the IBX-mediated oxidation of 2.166 (Table 2.1, Entry 5). Heating the
reaction at 60 ºC gave ynone 2.169 in 40% yield. Manganese dioxide (MnO2) had been shown to oxidize very similar propargylic alcohols in greater than 82% yield,91 yet all
attempts of oxidizing alcohol 2.166 with MnO2 failed in our hands (Table 2.1, Entries 6 and 7).
Table 2.1
Entry Oxidant Solvent Temp (ºC) Time (h) Yield (%) 1 IBX DMSO rt 2 0 2 IBX acetone 60 4 0 3 IBX EtOAc 60 4 1:2 P/SM 4 IBX THF rt 48 27 5 IBX THF 60 3 40 6 MnO2 CH2Cl2 rt 4 0 7 activated MnO2 CH2Cl2 rt 4 0
When secondary alcohol 2.168 was treated with IBX in THF, however, none of the desired product 2.170 was obtained (Scheme 2.41). Complete decomposition of starting material was also observed with IBX in EtOAc or DMSO as well as Dess-Martin
periodinane (DMP) in CH2Cl2.
Scheme 2.41
O O OH O IBX or DMP OH OH OH OH MeO OMe MeO OMe
2.168 2.170
76 Based on all failed attempts to synthesize ynone 2.170 through a direct coupling reaction or oxidation of the corresponding secondary alcohol, we chose to abandon this approach.
2.3.2 Third Generation Approach to IB-00208
2.3.2.1 Retrosynthesis
Since it appeared that we would not gain access to the desired ynone 2.170 (cf. Scheme 2.41), we felt the need to alter our proposal for the key xanthone-forming reaction sequence. Pentacycle 2.171 remained the key intermediate of our synthesis, yet we had decided on MOM ethers as protecting groups for the hydroquinone (Scheme 2.42). The precursor for the key sequence would now be cyclobutenol 2.173, which we believed could be accessed from silacycle 2.164 and benzocyclobutenone 2.174. For the key step, heating of cyclobutenol 2.173 was envisioned to undergo a Moore cyclization that would give the corresponding quinone. Oxidation of the secondary alcohol would provide intermediate 2.172, which was poised to undergo a facile cyclization and subsequent air oxidation to afford 2.171 in one pot.
77 Scheme 2.42
Me O O Br * A OH O O OMe OH OR B O O OMe O O OMe O O C DEF HO RO Me O O O OMe O OMe O OMe O OMe MeO OMe * stereochemistry unknown 2.108 2.171 IB-00208 (2.1) R=MOM
OMOM OMOM O O OMe O 1,2-addition MOMO OH MOMO OMe OH HO HO O OMe 2.172 MeO 2.173
OMOM t-Bu t-Bu B OMe O Si MOMO OMe + O C O MeO F OMe 2.174 2.164
2.3.2.2 Model Studies
To test our newly proposed reaction sequence, we again wanted to work first with a model system. Since we had quantities of 2.168 in hand, we began by heating 2.168 in DMSO at 120 ºC, which afforded the desired quinone 2.175 in quantitative yield (Scheme 2.43). Oxidation of this compound with IBX in THF gave a mixture (1:1) of the desired ketone 2.176 and spirocycle 2.177. When the mixture of 2.176 and 2.177 was resubjected to the reaction conditions, complete conversion to spirocycle 2.177 was achieved. The same observation was made when the mixture was stirred with silica gel (SiO2) in CH2Cl2 78 at room temperature. Formation of spirocycle 2.177, which we concluded to proceed from phenol 2.176, came as a surprise to us. We had expected the cyclization of the phenol onto the doubly activated enone to predominate. Yet apparently the 5-exo-trig cyclization was favored over a 6-endo-trig cyclization.
Scheme 2.43
O O OH OH OH 120 °C OMe OH OH DMSO MeO MeO OMe quant O 2.175 2.168
SiO2
CH2Cl2,rt
OMe O O OH O O IBX, 60 °C 8 OMe + O THF 9 O Me OMe O O 1:1 2.176 2.177
IBX, 60 °C THF It was found that the first two steps of the sequence could be combined into one pot when the quinone formation was carried out in THF in a microwave oven (Scheme
2.44). When the crude reaction mixture containing 2.176 was treated with SiO2, and spirocycle 2.177 was isolated in 68% yield over two steps.
79 Scheme 2.44
Since we had neither expected nor desired the cyclization of 2.176 to 2.177, we wondered whether the spirocycle might only be the kinetic product of the reaction. Thus if we would be able to convert spirocycle 2.177 back to phenol 2.176 and get some of this material to cyclize via the desired 6-endo-trig pathway, over time we should be able to funnel all of the material toward the desired tetracyclic xanthone 2.144 (Scheme 2.45). Oxidation of this compound would then afford the oxidized xanthone 2.136.
Scheme 2.45
MeO MeO O O O O OMe O O
O OMe O OMe HO O OMe O O H 2.176 2.177 2.178
OH O OMe OH O OMe O O OMe [O]
O O O O OMe OH OMe O OMe 2.179 2.144 2.136
80 Gratifyingly, after heating spirocycle 2.177 in toluene at 250 °C in a microwave oven, we obtained a mixture (4:1) of 2.144 and 2.136 (Scheme 2.46), which confirmed
that spirocycle 2.177 was indeed the kinetic product. The mixture was stirred in CH2Cl2 with O2, which began to improve the ratio to 1.9:1. After this solution was left out open to air at room temperature, the ratio further improved to 1.3:1. Complete conversion to
the quinone was accomplished by treating the mixture with silver (I) oxide (Ag2O). Serendipitously, we also discovered that if the mixture of hydroquinone 2.144 and quinone 2.136 was shaken with aqueous 1 M KOH and then neutralized again, we obtained exclusively quinone 2.136.
Scheme 2.46
Combining these two steps into one, we were able to heat 2.177 in a microwave oven to 250 ºC and carry out a KOH work-up to isolate quinone 2.136 in quantitative yield (Scheme 2.47).
Scheme 2.47
81 In summary, we had discovered a new and mild approach to xanthones that was utilized to synthesize 2.136, the tetracyclic core of IB-00208 (Scheme 2.48). Silacycle 2.164, which was formed in three steps from aldehyde 2.147, was coupled with dione 2.138 and then deprotected to give cyclobutenol 2.168. Intermediate 2.168 was transformed to spirocycle 2.177, which was efficiently thermolyzed to 2.136. Overall, we have accomplished a new and rapid approach to xanthones, which should be widely applicable and synthetically useful. Various salicylic aldehyde-derived silacycles as well as a wide range of squarates are easily accessible and might be employed to generate a large number of 1,4-dioxygenated xanthone ring systems. Expansion of the scope of this methodology and application to the synthesis of biologically active xanthones such as 2.10-2.12 are currently underway in our laboratories.
Scheme 2.48
O OH H OMOM 7.5 eq. MgBr OH t-Bu2Si(OTf)2,2,6-lutidine CH Cl ,0°C MeO OMe THF, 0 °C rt MeO OMe 2 2 83% 79% 2.147 2.166
t-Bu t-Bu 1. n-BuLi, THF, 78 °C O 1. W, 120 °C, THF O Si then OH then O dione 2.138, 78 °C OH IBX, 60 °C 2. HF-pyr, pyridine OH 2. SiO2,CH2Cl2,rt MeO OMe THF, rt MeO OMe 68% 2.164 53% 2.168
OMe O O O O OMe W, 250 °C, PhMe O then O OMe 1 M KOH work-up O O OMe 2.177 quant 2.136 tetracyclic core of IB-00208
82 2.3.2.3 Failed Three-Component Benzyne Approach to Angularly-Fused Benzocyclobutenones
With an approach developed for synthesizing the oxidized xanthone 2.136, we were interested in applying this chemistry to an angularly-fused system. Although we were ultimately interested in MOM-protected benzocyclobutenone 2.174 (cf. Scheme 2.42), we decided it would be wise to first investigate the xanthone-forming sequence with benzocyclobutenone 2.126, for which Dr. Mans had established a synthesis (cf. Scheme 2.22). We had to produce significant quantities of 2.126, and thought a more efficient approach toward the requisite diene 2.125 might be feasible (Scheme 2.49). Inspired by the work of Barrett (cf. Scheme 2.50), we envisioned that we might be able to construct 2.125 via a three-component benzyne coupling (Scheme 2.49). We proposed that reacting aryl fluoride 2.180 with n-BuLi would generate benzyne 2.181. In the presence of vinylmagnesium bromide, aryl Grignard species 2.182 would be produced, which upon reaction with vinyl squarate 2.124 would furnish 2.125. This approach would be significantly more efficient than the existing route, and 2.126 might be prepared in only two steps from commercially available 2.180.
83 Scheme 2.49
MeO O MeO
OMe OMe OMe MeO F n-BuLi, THF BrMg MgBr 2.124 78 35°C 78°C rt
OMe OMe OMe 2.180 2.181 2.182
OMe MeO MeO O OMe 5 mol% Grubbs II OMe MeO OMe PhCH3,110°C O MeO 2.126 2.125 The three-component benzyne reaction was inspired by Barrett’s synthesis of ent-
clavilactone B.92 Starting with 1,4-dimethoxy-2-fluorobenzene (2.180), n-BuLi was added in order to lithiate the aromatic ring ortho to the fluoro group (Scheme 2.50). After addition of 2-methylallylmagnesium chloride (2.183), the reaction was allowed to warm to room temperature. Upon warming, fluoride was eliminated to generate a benzyne, which immediately reacted with the Grignard reagent to generate aryl Grignard intermediate 2.184. Addition of aldehyde 2.185 to this mixture generated a 2,3- disubstituded-1,4-dimethoxybenzene derivative 2.186 in 65% yield from 2.180.
Scheme 2.50
84 In order to investigate the feasibility of this three-component benzyne approach for our needs, we thought it best to carry out the first step of the sequence to form 2.187 separately (Scheme 2.51). To our disappointment, however, when employing the same reaction conditions as Barrett and coworkers had used, we only obtained a 5% yield of the desired product. All attempts to improve the yield of 2.187 failed.
Scheme 2.51
Based on these surprisingly negative results, we were prompted to investigate at which point our reaction was failing. The first important experiment was to see whether we were even generating an aryllithium intermediate. Aryl fluoride 2.180 was thus treated with n-BuLi at –78 ºC for 30 min and quenched with deuterated methanol (Scheme 2.52). Gratifyingly, we obtained 73% deuterium incorporation, thereby confirming the formation of the desired aryllithium.
Scheme 2.52
It appeared as though generation of the benzyne or addition of vinylmagnesium bromide were the troublesome steps. Since Barrett and coworkers had used 2- methylallylmagnesium chloride, we thought it was best to use the same Grignard reagent. Formation of the desired Grignard species proceeded from 2-methylallyl chloride (2.189) 85 (Scheme 2.53). Although the concentration of 2.183 was low (0.124 M), we decided to employ it in the reaction. Following the previously outlined protocol, we were able to successfully produce 2.190 in 76% yield. It is thereby clear that generation of benzyne is not the problem, but rather the addition of the vinyl Grignard reagent to said benzyne. A thorough search of the literature produced only one reference in which a vinyl anion had been added to a benzyne.93 Yet in this case the reaction was biased since it proceeded via an intramolecular process. One reason why the allyl Grignard species might have worked so much better could be attributed to the fact that it can react with the benzyne in a concerted process. An additional search of the literature revealed that allyl anions and dienes are by far the most common coupling partners with benzynes.
Scheme 2.53
One final attempt was undertaken to finagle the benzyne reaction by investigating the addition of a vinylcuprate. Using a vinyl copper (II) species, we were able to isolate 2.187 in 19% yield (Scheme 2.54). We were able to improve that yield to 57% when employing LDA as the base for the initial deprotonation. It was worth noting, however, that 2.187 was inseparable from defluorinated 2.180, which was formed as a side product in this reaction.
86 Scheme 2.54
Knowing that we presumably generated aryl cuprate 2.191, we attempted to carry out the desired one-pot sequence (Scheme 2.55). However, the soft copper nucleophile 2.191 did not add to the vinyl squarate to produce 2.125, and only unreacted squarate 2.124 and 2.187 were isolated from the reaction.
Scheme 2.55
It thus appeared that the desired three-component benzyne coupling was not very likely to proceed efficiently. We thus scaled-up the synthesis of benzocyclobutenone 2.126 using the route that Dr. Mans had developed (cf. Scheme 2.22).
2.3.2.4 Failed Coupling Reactions
With benzocyclobutenone 2.126 and silacycle 2.164 in hand, we were ready to investigate the coupling of these two fragments. Dissappointingly, addition of the alkynyllithium derivative of 2.164 to cyclobutenone 2.126 gave only recovered starting material (Scheme 2.56). Varying the reaction temperature from -78 °C to room
87 temperature, screening different bases (KHMDS, NAHMDS), or adding 12-crown-4 produced the same results. When the coupling reaction was heated to 50 ºC, unidentified side products were formed.
Scheme 2.56
OMe t-Bu t-Bu OMe t-Bu O Si t-Bu Base,THF, 78 °C MeO OMe O O Si O then MeO OMe OH OMe MeO OMe OMe 2.164 OMe MeO 2.192
O 2.126 Base: only rsm n-BuLi n-BuLi, 12-crown-4 NaHMDS KHMDS We reasoned that a steric interaction between 2.164 and the ketal in 2.126 might be the reason for the failed coupling reaction in Scheme 2.56. This hypothesis was confirmed when we performed the coupling between alkyne 2.164 and cyclobutenone 2.193 (Scheme 2.57). Although the coupling product was obtained, the yield (17%) was significantly lower than for the corresponding dione (65%, cf. Scheme 2.40).
Scheme 2.57
Since the silicon protecting group in 2.164 is sterically demanding and also rigidifies the structure of the alkyne, we decided to attempt the coupling with a more
88 flexible bis-TBS-protected alkyne 2.195 (Scheme 2.58). Thus, 2.150 was converted to 2.195 in 32% yield (unoptimized). Deprotonation of alkyne 2.195 and addition to benzocyclobutenone 2.126 did not give any of the desired coupling product but only unreacted starting material. In order to reduce the sterics of the alkyne, we attempted the addition of a dianion of 2.195 to 2.126, which also failed.
Scheme 2.58
OH OTBS OTBS NaHMDS, THF, 0 °C OTBS then MeO OMe MeO OMe TBSCl, 0 °C rt
2.150 32% 2.195
OR OMe OTBS forR =TBS: OMe OMe n-BuLi, THF, 78 °C MeO OR MeO OMe forR =H: OTBS NaH, n-BuLi, THF, 0 °C 78 °C OH MeO OMe R=TBS(2.195) then R=H(2.150) OMe R=TBS(2.196) OMe R=H(2.197) MeO OMe
O 2.126 Addition of the alkynyllithium derivative of 2.164 to the sterically less hindered dione 2.138 had been more effective than addition to the corresponding ketal 2.193 (cf. Scheme 2.40 and 2.57). Therefore, cyclobutenone 2.126 was treated with p-TsOH to afford dione 2.198 in 92% yield (Scheme 2.59). Dione 2.198 was surprisingly unstable and decomposed if not used immediately. Nevertheless, the alkynyllithium derivative of 2.164 did not appear to react with dione 2.198. The unreacted alkyne could be recovered, yet the dione could not be isolated. It appeared that 2.198 had decomposed during the reaction. Due to the instability of dione 2.198, this strategy was also abandoned.
89 Scheme 2.59
2.3.2.5 Altered Coupling Strategy
In light of the negative results for the coupling between alkyne 2.164 and cyclobutenone 2.126 (cf. Scheme 2.56), we began to rethink our approach to 2.200 (Scheme 2.60). Presumably, 2.200 might also be built up from a coupling between cyclobutenol 2.201 and aldehyde 2.149. Thus, only a simple alkyne would need to be added to the requisite benzocyclobutenone, which might have a better chance of succeeding.
Scheme 2.60
90 To our satisfaction, we found that the anion of TMS-acetylide can be successfully added to benzocyclobutenone 2.126 (Scheme 2.61). After deprotection of the TMS group, cyclobutenol 2.202 was isolated in 78% yield over two steps. Addition of the alkynylmagnesium bromide proved more practical and gave cyclobutenol 2.202 in 82% yield. We thought it necessary to protect the tertiary alcohol, which proceeded in 84% yield to give TMS ether 2.203. Gratifyingly, deprotonation of alkyne 2.203 with LiHMDS and addition of the anion thus formed to aldehyde 2.149 afforded coupling product 2.204, albeit in 31% yield. At last we had succeeded in synthesizing 2.204, but the coupling reaction proved to be difficult to reproduce. We attribute the low yield and lack of reproducibility to the lability of the TMS group. This hypothesis was confirmed by complete loss of the TMS ether when 2.203 was treated with n-BuLi (not shown). Nevertheless, this sequence served as a proof of concept that a slightly modified version of this approach to cyclobutenol 2.204 might be feasible.
91 Scheme 2.61
n-BuLi, TMS THF, 78 °C 0°C then OMe OMe TBAF, THF, 0 °C OMe OMe TMSCl, Im. OMe MeO OMe 78% MeO DMF, 0 °C rt O 84% BrMg OH 2.126 2.202 THF, 0 °C rt
82%
OMe OMe OMe MeO OMe OMe LiHMDS, THF, 78 °C OH MeO OMe OMe then OTMS O TBSO OTMS H OMe 2.203 MeO TBSO 2.204
MeO 2.149 31% To begin using a more robust protecting group for the tertiary alcohol, we opted to use a TES ether (Scheme 2.62). TES-protection of alcohol 2.202 proceeded in 77% yield. Deprotonation of the acetylenic proton and addition of the anion to aldehyde 2.149 gave 2.206, the coupled product where the phenolic TBS group had migrated to the secondary alcohol, in 54% yield. This material was isolated along with aldehyde 2.148 as an inseparable mixture (2.6:1). Nonetheless, we had developed a viable coupling approach.
92 Scheme 2.62
OMe OMe OMe TESCl, Im OMe OMe MeO OMe MeO DMF, 0 °C rt OTES OH 77% 2.202 2.205
OMe OMe O OMe n-BuLi, THF MeO OTBS H OMe 78 C 0°C OMe + then OTES HO O HO H OMe MeO MeO 2.148 TBSO 2.206 2.6 : 1 54% inseparable MeO 2.149 78 °C rt Both silyl groups in 2.206 could be removed by treatment with HF·pyridine to
provide 2.207 in 41% yield (Scheme 2.63). The ketal in 2.207 was cleaved using p-TsOH
in acetone. Since this reaction was terminated prematurely after five minutes, a mixture
(2.5:1) of desired 2.208 and starting material 2.207 was isolated. Resubjection of this mixture to the reaction conditions for an additional two min afforded cyclobutenone
2.208 exclusively in 57% overall yield. Intermediate 2.208 was subjected to the
previously established microwave heating conditions in both THF and toluene. To our
disappointment, only trace amounts of the desired quinone 2.209 could be observed when
toluene was used as the solvent.
93 Scheme 2.63
2.3.2.6 Synthesis of the Requisite MOM-Protected Benzocyclobutenone
All remaining intermediate 2.208 was consumed in the previous two reactions and hence we needed to return to the very beginning of the synthesis to bring up more material. Since we were ultimately interested in MOM protecting groups for the benzocyclobutenone (cf. Scheme 2.42), we decided to pursue a synthesis of the angularly-fused benzocyclobutenone 2.174 (cf. Scheme 2.66). Hydroquinone 2.211, which was accessible via bromination94 of commercially available 2,5- dihydroxybenzaldehyde (2.210), was protected as the bis-MOM ether and subjected to a Wittig olefination95 to provide bromide 2.113 in 92% overall yield (Scheme 2.64). This route is significantly more scalable than the previous synthesis of the dimethyl-protected hydroquinone 2.122 (cf. Scheme 2.22). The tedious chromatography that was required in the synthesis of 2.122 after the bromination step was avoided. Additionally, compound
94 2.213 was the first intermediate in this new sequence that needed to be purified. This approach to bromide 2.213 was utilized on large scale to afford batches of up to 16 g of 2.213.
Scheme 2.64
Reacting the aryllithium derived from 2.213 with squarate 2.124 afforded the desired diene 2.214 in 19% yield along with proto-debromination product 2.215 in 35% yield (Scheme 2.65). Although the yield of the desired product 2.214 was improved to 28% on a slightly larger scale (453 mg of 2.213), a better yield was required to effectively scale-up this reaction.
Scheme 2.65
95 We reasoned that the lithium-halogen exchange with n-BuLi was the problem in the poor-yielding coupling between 2.213 and 2.124. The aryllithium was presumably
generated but then participated in an E2-elimination with n-butylbromide, also generated during the lithium-halogen exchange. Since 1,2-addition of the aryllithium to squarate 2.124 might be slow, there would be ample time for the undesired elimination reaction to occur, thereby accounting for the formation of large amounts of 2.215. Based on this hypothesis, the undesired proto-delithiation could be overcome by utilizing t-BuLi. To our delight, treatment of bromide 2.213 with t-BuLi followed by addition to squarate 2.124 afforded 2.214 in 57% yield (Scheme 2.66). Furthermore, only trace amounts of the proto-debromination product 2.215 were observed. Diene 2.214 was subjected to the previously established ring-closing metathesis conditions to afford the angularly-fused benzocyclobutenone 2.174 in 75% yield. Overall, 2.174 was synthesized in only five steps and 39% overall yield from commercially available 2.210.
Scheme 2.66
OMOM OMOM t-BuLi, THF OMe 78 °C, 60 sec MOMO OMe MOMO Br then MeO OMe O OMe 2.213 ,0°C 2.214 O 2.124 then TFAA, 78 °C
57%
OMOM 5% Grubbs II OMe MOMO OMe PhMe, 110 °C O 75% 2.174
96 2.3.2.7 Forward Synthesis of IB-00208
Following the protocol developed earlier, butenone 2.174 was treated with ethynylmagnesium bromide to afford 2.216 in 77% yield (Scheme 2.67). The TES group was installed uneventfully to give 2.217 in 56% yield.
Scheme 2.67
We had previously employed n-BuLi to deprotonate the alkyne, yet addition of the alkynyllithium generated in such a manner to aldehyde 2.149 resulted in the coupled product where the TBS group had migrated from the phenol to the secondary alcohol (cf. Scheme 2.62). As a result we chose to investigate a different alkynyl anion, which would provide a different secondary alkoxide that might prevent migration of the TBS group. From previous work we knew that addition of ethynylmagnesium bromide to aldehyde
2.149 had given the 1,2-addition product where the phenolic TBS group had not migrated (cf. Scheme 2.30). Thus, treatment of alkyne 2.217 with EtMgBr generated an alkynyl Grignard species, which was added to aldehyde 2.149 to afford the desired coupling product 2.218, where the TBS group had not migrated, in 51% yield (Scheme 2.68).
97 Scheme 2.68
With secondary alcohol 2.218 in hand, we decided to examine its oxidation to ynone 2.219 (Scheme 2.69). Treatment of 2.218 with IBX or Dess-Martin periodinane (DMP) gave none of the desired product 2.219. Instead, starting material was completely consumed, and a compound whose spectral data matches 2.220 was observed as a mixture (4:1) of diastereomers. We proposed that 2.220 might have formed via oxidation of 2.218 to 2.221, which then underwent cleavage of the TES ether and concomitant ring expansion to the cyclopentenone 2.220.
98 Scheme 2.69
OMOM OMOM OMe IBX, rt OMe OMe MOMO OMe MOMO O OH DMSO OMe OMe OTES OTES TBSO DMP, NaHCO3 TBSO CH Cl ,rt MeO 2 2 MeO 2.219 2.218
OMOM MeO MeO OMeO MOMO 4:1 mixture of diastereomers TBSO OMe O 2.220 tentative OMOM OMe OMe MOMO O OMe O H+ TES TBSO AcO MeO 2.221 In order to bring through material more efficiently, we considered that the TES protecting group in 2.217 might be avoided altogether (cf. Scheme 2.68). Presumably, a dianion of 2.216 might be used to carry out the desired coupling. To test the desired dianion formation, cyclobutenol 2.216 was treated with EtMgBr, and the reaction was quenched with D2O to obtain 89% deuterium incorporation at the alkyne (Scheme 2.70).
Scheme 2.70
OMOM OMOM OMe EtMgBr, THF. rt OMe MOMO OMe MOMO OMe then D OH D2O OH 2.216 2.222 89% D-incorporation Utilizing dianion chemistry, we are able to couple alkyne 2.216 with aldehyde 2.149 to give 2.223 in 79% yield (99% yield based on recovered 2.216) (Scheme 2.71). 99 Scheme 2.71
We were interested in further streamlining the entry to secondary alcohol 2.223. It was envisioned that addition of an alkynyl Grignard reagent to cyclobutenone 2.174 might initially afford the 1,2-addition product (Scheme 2.72). If an excess of alkynyl Grignard reagent would be used, a dianion might be generated via deprotonation of the newly formed alkyne, which could then be added to aldehyde 2.149 to give 2.223 in one pot. However, realization of this approach failed, and only the 1,2-addition product 2.226 was obtained in 52% yield.
Scheme 2.72
OMOM OMOM OMe OMe MOMO OMe OMe BrMg ,THF,rt OH MOMO OMe then OH O O TBSO 2.174 H OMe MeO TBSO 2.223
MeO 2.149 OMOM OMe MOMO OMe 52% OH 2.216 52%
100 It was thought that the dianion must not have been generated with excess alkynyl Grignard reagent. Therefore, in a second and final attempt, ethylmagnesium bromide was added after the alkynyl Grignard species had reacted with cyclobutenone 2.174 (Scheme 2.73). However, this only resulted in a complex product mixture that did not contain any of the desired secondary alcohol 2.223.
Scheme 2.73
Turning our attention to the forward synthesis, the ketal in 2.223 was cleaved with p-TsOH to give cyclobutenone 2.224 in 99% yield (Scheme 2.74). Cyclobutenone 2.224 was heated in a microwave oven in both THF and toluene to give an inseparable mixture of the desired product 2.225 and an unidentified side product 2.226. Using either solvent, the quinone 2.225 was formed as the minor product.
101 Scheme 2.74
OMOM OMOM OMe OMe O MOMO OH MOMO p-TsOH, rt OH OMe OMe OH acetone OH TBSO TBSO 99% MeO MeO 2.223 2.224
OMOM O OH OMe W, 20 min MOMO + 2.226 conditions unidentified TBSO O OMe conditions: 2.225:2.226 THF, 110 °C 1:1.6 2.225 inseparable PhMe, 120 °C 1:2.4 Since microwave heating, which had been very successful with our model system (cf. Scheme 2.48), was proving less successful with the real system, a number of different solvents were screened using conventional heating. It was found that toluene, chlorobenzene, THF, acetonitrile, and DMF were all poor solvents for this transformation. However, heating 2.224 in DMSO gave access to the desired quinone 2.225 as the major product in 42% yield along with 2.227 in 22% yield (Scheme 2.75). Comparable yields were achieved by heating 2.224 in DMSO that had been dried over 4Å molecular sieves or DMSO that had been degassed. Carrying out a syringe pump addition of cyclobutenone 2.224 to a heated solution of DMSO also failed to improve the yield. Utilizing base additives or varying the concentration, temperature, or work-up conditions failed to give a better yield.
102 Scheme 2.75
Side product 2.227 was proposed to form during the reaction, since it was even observed in the 1H NMR spectrum of the crude reaction mixture after the DMSO was removed by distillation at the end of the reaction. We propose that one potential pathway for formation of 2.227 could be via thermal cleavage of the MOM group followed by isomerization to enol 2.229. Addition to formaldehyde would afford the observed side product 2.227 (Scheme 2.76). Formation of formaldehyde might be explained by reaction of the oxonium ion, formed by thermal cleavage of the MOM ether, with DMSO. We do not have evidence to support this pathway other than the observation of small amounts of phenol 2.228 in the 1H NMR spectrum of the crude reaction mixture.
103 Scheme 2.76
The TBS group in 2.225 was removed using HF·pyridine, which directly gave spirocycle 2.230 in 52% yield (Scheme 2.77). Oxidation of 2.230 using IBX was very slugglish, and after 18 h at room temperature, only a trace amount of ketone 2.231 could be observed along with ample quantities of unreacted starting material.
104 Scheme 2.77
Much more conveniently, however, oxidation of the secondary alcohol function of 2.225 prior to TBS deprotection gave ketone 2.232 in 97% yield (Scheme 2.78).
Scheme 2.78
Since the quinone formation (cf. Scheme 2.75) as well as the subsequent oxidation (cf. Scheme 2.78) both employed DMSO as the solvent, we wondered whether these two steps could be executed in one pot. To this end, the ketal in 2.223 was cleaved first, and the resulting cyclobutenone was heated in DMSO (Scheme 2.79). Upon cooling to room temperature, IBX was added and the reaction was stirred overnight. The desired ketone 2.232 was thus isolated in 15% yield over two steps. While this sequence still needs to be
105 improved, this experiment served as a proof of principle that the Moore cyclization and oxidation can potentially be carried out in one pot.
Scheme 2.79
Treatment of ketone 2.232 with TBAF was envisioned to promote deprotection and subsequent cyclization to the desired pentacycle 2.233 similar to work by
Theodorakis and coworkers (Scheme 2.80).96 However, none of the desired xanthone 2.233 was observed. Instead, an unidentified compound was formed that displayed diastereomeric protons and a peak corresponding to a phenol in the 1H NMR spectrum.
Scheme 2.80
Since basic conditions were unsuccessful, we returned to acidic conditions for the removal of the TBS group. Reaction of ketone 2.232 with HF·pyridine led to removal of the TBS group and spontaneous cyclization to give spirocycle 2.234 in 91% yield (Scheme 2.81). This spirocycle was structurally very similar to that obtained with the model system (cf. Scheme 2.48). Heating of 2.234 under vacuum at 200 °C for 30 min gave a quantitative conversion to hydroquinone 2.233. In the model study (cf. Scheme 2.46), the hydroquinone could be readily oxidized to the corresponding quinone. In this
106 system, however, the hydroquinone seemed rather robust toward oxidation. Using the
KOH workup or treating 2.233 with Ag2O only gave recovered starting material. We believe the oxidation of the hydroquinone in 2.233 is difficult due to the angular fusion, which was not present in the model system. In 2.233 the angular fusion places six atoms in a plane, which might result in out-of-plane bending of both oxygen substituents. The hydroxyl group of the hydroquinone bending out of plane would thus complicate the desired oxidation.
Scheme 2.81
OMOM O O O OMe MeO O HF•pyr, pyr O 200 °C MOMO O THF, rt MOMO vacuum, neat TBSO O OMe O OMe 91% 100% conv 2.232 O 2.234
OMOM OMOM OH O OMe O O OMe Ag O, rt MOMO 2 MOMO PhMe O O OH OMe only rsm O OMe 2.233 2.171 Upon further studies, it was found that when the thermal rearrangement of 2.234
was carried out in nitrobenzene (PhNO2) at 215 °C, the rearrangement as well as an oxidation proceeded (Scheme 2.82). We speculated that the oxidation occurred via an air oxidation, which was not possible when the rearrangement was carried out under vacuum (cf. Scheme 2.81). At the high temperatures, the northern oxygen atom and the aromatic ring of the hydroquinone might have been forced into a plane, which resulted in the overlap required for an oxidation to the quinone to occur. Presumably, the said overlap was not achieved at room temperature, which explained why the oxidation of 2.233 did 107 not take place even with Ag2O (cf. Scheme 2.81). Oxidized xanthone 2.171, the pentacyclic core of IB-00208, was thus isolated in 58% yield.
Scheme 2.82
O OMOM MeO O O OMe O O 215 °C O MOMO MOMO PhNO2 O OMe O 58% O OMe O 2.171 2.234 To unequivocally verify the structure of pentacycle 2.171, crystals suitable for analysis by X-ray diffraction were grown. To our delight, a crystal structure was obtained, which confirmed that we had successfully assembled the pentacyclic core of IB-00208 (Figure 2.1). Not only were we able to apply our new and efficient approach to xanthones, but we had also synthesized the challenging angular fusion present in the natural product. In the crystal structure of 2.171 it can be observed that the two oxygen substituents at the angular fusion are in very close proximity to each other, which results in the C8 carbonyl (crystal structure numbering) to bend out of plane significantly. Thus the angle between the C11-O6 and C8-O5 bonds is surprisingly large at 42.86°.
108 Figure 2.1
Crystal Structure of 2.171
In summary, starting from cyclobutenone 2.174, crystalline pentacycle 2.171 was synthesized in only seven linear steps and 13% overall yield (Scheme 2.83). Overall, the pentacyclic core of IB-00208 was synthesized in 12 linear steps and 17 steps overall from commercially available starting materials.
109 Scheme 2.83
2.3.2.8 Endgame Attempts from Pentacycle 2.171
With a reliable route to pentacycle 2.171 in place, we turned our attention to the endgame of our synthesis of IB-00208 (2.1). In the forward direction, we envisioned a deprotection of the MOM ethers of 2.171, regioselective allylation, and regioselective bromination to obtain bromide 2.235 (Scheme 2.84). Introduction of the ester via a carbonylative esterification and subsequent Claisen rearrangement would provide 2.237, which would be regioselectively glycosylated. Wacker oxidation of 2.238 and stereoselective CBS reduction would complete the synthesis of IB-00208 (2.1).
110 Scheme 2.84
Attempts to remove both MOM ethers of 2.171 under acidic conditions failed.
Using a mixture (9:1) of TFA and H2O provided only trace quantities of the mono- deprotected phenol 2.240 and a complex mixture of unidentifiable products (Scheme 2.85).
111 Scheme 2.85
Since the deprotection of 2.171 appeared to be a problem, we decided to investigate if the MOM ethers might be removed prior to the rearrangement step. Stirring spirocycle 2.234 with TFA and H2O gave mono-deprotected phenol 2.242 in quantitative yield (Scheme 2.86). Subjecting 2.242 to the acidic deprotection conditions again was
unsuccessful, even when the reaction was stirred in TFA/H2O for two days. After two days at room temperature, a complex mixture of unidentifiable products was observed.
Scheme 2.86
O MeO MeO OH O O O O O TFA/H2O (9:1) HO MOMO CH2Cl2,0°C O OMe O OMe
O O 2.241 2.234 quant
MeO TFA/H O (9:1) OH O 2 O CH2Cl2,rt
MOMO O OMe
O 2.242
112 Spirocycle 2.234 was subjected to two additional acidic conditions that had precedent in the literature for removing similar MOM ethers (Scheme 2.87).97 However, in both cases none of the desired hydroquinone 2.241 was observed. Starting material had been consumed and only unidentifiable decomposition products were obtained.
Scheme 2.87
Since we had discovered conditions for removing the northern MOM protecting group using TFA/H2O (cf. Scheme 2.86), we thought that it might be possible to remove the northern MOM group and the TBS group in quinone 2.232 in one step (Scheme 2.88). However, the phenolic TBS group was a lot more robust than anticipated. Even more surprising was that hydroquinone 2.243 was obtained in 47% yield. Apparently the electron withdrawal through resonance of the ketone on the quinone, which is not present in any of the spirocycles, improves the propensity to cleave the southern MOM group. While we were delighted by this result, all attempts to remove the TBS group in 2.243 failed and only resulted in a complex mixture of unidentifiable products.
113 Scheme 2.88
Based on the unsuccessful endgame approaches, we decided to revise our proposed route to IB-00208 (2.1). From intermediate 2.242, which we could access efficiently, we envisioned carrying out a regioselective bromination followed by a carbonylative esterification (Scheme 2.89). With an additional electron-withdrawing group in place, the MOM group should be easily cleaved as in Scheme 2.88. Regioselective allylation, Claisen rearrangement, and formation of the oxidized xanthone might then proceed in one pot to give 2.237. Finally, glycosylation, Wacker oxidation and stereoselective CBS reduction would provide access to IB-00208 (2.1).
114 Scheme 2.89
MeO MeO O MeO OH O O OH O O 1. Br2 MOMO O OMe 2. Pd(OAc) ,CO MOMO 2 O OMe MeOH, O O 2.242 2.244
MeO O MeO O MeO 1. TFA/H2O (9:1) OH O OH O CH2Cl2,0°C 215 °C O O OMe 2. allyl-OH, PPh O HO 3 O OMe PhNO2 DIAD O O O OMe 2.245 2.237
Me O O * MeO O OH O O OMe OH 1. PdCl2,CuCl O OMe Sugar-OH O O2,DMF,H2O O O SugarO Me DEAD, PPh3 2. CBS catalyst O BH ,K CO O 3 2 3 OMe O OMe MeO O OMe OMe 2.238 IB-00208 (2.1)
Treatment of phenol 2.242 with NBS at –78 °C and warming the reaction to room temperature gave a mixture of three compounds (Scheme 2.90). Recovered starting material 2.242, MOM-deprotected 2.241, and the MOM-deprotected bromination product 2.247 were all identified in equal amounts in the 1H NMR spectrum of the crude reaction mixture. Observation of 2.241 was most surprising, as all previous attempts at removing the southern MOM group had failed.
115 Scheme 2.90
MeO Br MeO OH O OH O O NBS, 78 °C rt O O O O OMe PhMe/CH2Cl2 (1:1) O OMe O O O O 2.242 2.246
MeO MeO Br MeO OH O OH O OH O O O O
O ++HO HO O OMe O OMe O OMe O O O O 2.242 (rsm) 2.241 2.247
1:1:1
98 Use of elemental bromine (Br2) instead of NBS also gave a mixture of products, yet in this case recovered starting material 2.242, MOM-deprotected starting material 2.241, and the desired bromination product 2.246 were obtained in a ratio of 1:2:3, respectively (Scheme 2.91). Only a trace amount of the previously observed 2.247 was seen.
116 Scheme 2.91
MeO OH O O Br2,0°C O O OMe CHCl3 O O 2.242
MeO MeO Br MeO OH O OH O OH O O O O
O ++HO O O OMe O OMe O OMe O O O O O 2.242 (rsm) 2.241 2.246
1:2:3
+trace2.247
99 Interestingly when bromination was attempted using CuBr2, NBS, or Br2 in the
100 presence of CaCO3, none of the desired bromide 2.246 was isolated (Scheme 2.92). Instead, hydroquinone 2.241 was obtained as the major product in all three cases.
Scheme 2.92
MeO Br MeO OH O OH O O conditions O O O O OMe O OMe O A. CuBr2,rt,CH3CN O O B. NBS, CH3CN, 0 °C O C. Br2,CaCO3,CH2Cl2 2.242MeOH, 0 °C 2.246
MeO OH O O
instead, mostly: HO O OMe
O 2.241
117 Since we had obtained small quantities of hydroquinone 2.241, we attempted to move forward this intermediate. However, allylation of 2.241 using Mitsunobu conditions only gave recovered starting material,101 whereas employing allylbromide as an alkylating agent resulted in a complex mixture of unidentifiable products (Scheme
2.93).102 Hydroquinone 2.241 appeared to rapidly decompose when heated in the presence of a base.
Scheme 2.93
We decided to refocus efforts on the bromination. After several more
88b 103 104 unsuccessful bromination attempts (NBS/i-Pr2NH, PyHBr3, Br2·1,4-diox ), we reasoned that the presence of a base may be necessary to prevent cleavage of the MOM protecting group. Initial experiments using pyridine gave recovered starting material 2.242 in 36% yield, desired 2.246 in 18% yield, MOM-deprotected starting material 2.241 in 16% yield, and deprotected bromination product 2.247 in 19% yield (Scheme 2.94).105
118 Scheme 2.94
MeO MeO Br MeO OH O OH O OH O O O O Br2,py O O + O O O O OMe CH2Cl2 OMe OMe O 0°C rt O O O O O 2.242 2.242 (rsm) 2.246 36% 18%
MeO Br MeO OH O OH O O O
HO + HO O OMe O OMe
O O 2.241 2.247 16% 19%
The isolated hydroquinone 2.247 was subjected to two different conditions to convert the bromide to a cyano group (Scheme 2.95).106 However, treatment of 2.247 with copper (I) cyanide (CuCN) in DMSO or DMF gave only a complex mixture of unidentifiable products.
Scheme 2.95
For the bromination reaction we eventually found that if a solution of Br2 in
CH2Cl2 was added over 45 min to a solution of 2.242 and pyridine at –78 ºC, bromide 2.246 could be isolated in 19% yield (Scheme 2.96).107 The remainder of the material was unreacted starting material. The low yield was attributed to the use of an old solution of
Br2 in CH2Cl2, but it appeared that we had developed a protocol for the bromination of 119 2.246. Since this approach was abandoned shortly after this reaction, we never redid the
bromination with a fresh solution of Br2 in CH2Cl2.
Scheme 2.96
The small quantities of 2.246 that we had obtained were subjected to a carbonylative esterification protocol reported by Evans (Scheme 2.97).108 However, only decomposition products were observed.
Scheme 2.97
We also tried to formylate phenol 2.242 directly (Scheme 2.98), but none of the conditions attempted gave the desired aldehyde 2.250. If starting material was consumed, only a complex mixture of unidentifiable products was isolated.
Scheme 2.98
120 In light of these frustrating efforts to complete the synthesis of IB-00208 (2.1) from spirocycle 2.242 (cf. Scheme 2.89), we abandoned this route altogether. The quantities of 2.242 that would be required, the large number of steps still remaining, and the poor reactivity of several of the intermediates led us to adopt a different strategy.
2.3.3 Fourth Generation Approach to IB-00208
2.3.3.1 Retrosynthesis
In order to avoid the challenges we had faced during the endgame of our previous approach, we wished to introduce the A-ring at the very beginning of the synthesis. It was envisioned that IB-00208 (2.1) could be accessed from intermediate 2.251 via an oxidation, deprotection and glycosylation (Scheme 2.99). The benzyl ether was thought to be an ideal precursor to the lactone in 2.1 as it should be robust to all the chemistry required to assemble 2.251. The oxidized xanthone 2.251 was to be constructed via the established key sequence from cyclobutenol 2.253, which was to be synthesized from cyclobutenone 2.254 and aldehyde 2.149. The only downside of this approach to IB- 00208 (2.1) would be that the stereochemistry of the methyl group in the A-ring of 2.1 would be set in the very beginning of the synthesis. Hence, either diastereomer of the natural product might need to be synthesized independently from the very beginning. Alternatively, however, the lactone of 2.1 could also be opened under basic conditions to give a carboxylic acid. Methylation of the acid, oxidation of the secondary alcohol, and stereoselective reduction of the resulting ketone would give either diastereomer of IB- 00208 (2.1) (cf. Scheme 2.14).
121 Scheme 2.99
2.3.3.2 Synthesis of Requisite Angularly-Fused Benzocyclobutenone
The first major task of our fourth generation approach to IB-00208 (2.1) would be the synthesis of benzocyclobutenone 2.254 (Scheme 2.100). We believed 2.254 could be accessed from hydroquinone 2.256 via the same chemistry that we had used to synthesize cyclobutenone 2.174 (cf. Scheme 2.64 and 2.67). Hydroquinone 2.256 was to be constructed from known quinone 2.257 via reduction of quinone and formylation.
122 Scheme 2.100
A synthesis of quinone 2.257, which we were interested in using in our synthesis of cyclobutenone 2.254, had been reported by Sawant and coworkers (Scheme 2.101).109 Ester 2.258 was converted to the secondary alcohol (S)-2.261 in eight steps and 45% overall yield. Cyclization of (S)-2.261 to the corresponding benzyl ether and oxidation afforded quinone (S)-2.257 in 62% yield. Although most of the steps were high-yielding, the length of this sequence was unappealing for our efforts. Additionally, the oxa-Pictet Spengler cyclization required twenty equivalents of MOMCl, which was unattractive for scale-up efforts. Overall the synthesis of (S)-2.257 was too long and impractical for a compound that was to be the starting point of our synthesis of benzocyclobutenone 2.254.
123 Scheme 2.101
Tetrahedron 2009, 65, 1599-1602 O O 1. L-proline (25%) OH PhNO, CH3CN OH EtO 1. NBS, CH3CN, rt H 20 °C OMe OMe OMe 2. LiAlH4,THF 2. NaBH4,MeOH 0°C rt 3. CuSO4 5H2O(30%) MeO 3. IBX, DMSO, rt MeO Br MeOH, 0 °C MeO Br 2.260 2.25868% 2.259 73%
1. ZnCl (30%) OH 2 O 1. Bu2SnO (2%), p-TsCl MOMCl (2000%) Et N, CH Cl ,0°C rt Et O, 0 °C rt 3 2 2 OMe 2 O
2. LiAlH4,THF,0°C rt 2. CAN, 0 °C rt CH CN/H O MeO Br 3 2 O Br 90% (S)-2.261 62% (S)-2.257 We thus developed an approach to quinone 2.257 that would require a mere four steps from commercially available starting materials. Lithiation of 2.262 and addition to propylene oxide (2.263) would afford a secondary alcohol that could be brominated to provide 2.261 (Scheme 2.102). If enantiomerically pure oxirane 2.263 was used, either enantiomer of quinone 2.257 could be conveniently accessed. Either enantiomer oxirane 2.263 is commercially available or can be prepared in two steps from inexpensive ethyl lactate.110
Scheme 2.102
Lithiation of 2.262 and addition to propylene oxide (2.263) gave alcohol 2.264 in
18% yield (Scheme 2.103).111 Analogous to the work by Sawant et al.,109 regioselective bromination of 2.264 proceeded overnight in quantitative yield.
124 Scheme 2.104
Our proposed route to bromide 2.261 had worked, but we were not satisfied with the yield of the first step. We reasoned that the problem was the lithiation of 1,4- dimethoxybenzene (2.262) and that a lithium-halogen exchange of 1-bromo-2,5- dimethoxybenzene (2.265) would represent a more efficient entry to the desired aryllithium. To this end, 2.262 was brominated with NBS in the presence of catalytic (10
mol%) ammonium nitrate (NH4NO3) following a literature procedure reported by Tanemura (Scheme 2.104).112 Bromide 2.265, which is also commercially available, was then treated with n-BuLi, and the aryllithium reagent thus generated was reacted with propylene oxide (2.263). To our delight, secondary alcohol 2.264 was obtained in 73% yield. Regioselective bromination of 2.264 using Tanemura’s protocol gave 2.261 in only 10 min and quantitative yield.
Scheme 2.104
OMe NBS, NH4NO3 Br OMe n-BuLi, THF, 78 °C then MeO CH3CN, rt MeO O 2.263 2.262 98% 2.265 commercially available 78 °C rt 73%
OH OH NBS, NH4NO3 OMe OMe
CH3CN, rt MeO MeO Br quant 2.264 2.261 125 Cyclization of 2.261 to the benzyl ether 2.266 was attempted using a protocol reported by Cutler and coworkers (Scheme 2.105).113 However, heating alcohol 2.261 with MOMCl and NaH only gave a mixture (1:1) of starting material and MOM ether 2.267.
Scheme 2.105
Since it seemed that we would not be able to avoid using an oxa-Pictet Spengler cyclization, we wondered whether it might be possible to employ a two step approach where the alcohol is converted to the corresponding MOM ether and this intermediate is
cyclized.114 This would allow us to reduce the amount of MOMCl required to nearly one equivalent. Satisfyingly, MOM ether 2.267 was formed from 2.261 in quantitative yield
115 116 117 (Scheme 2.106). A number of Lewis acids (BF3·OEt2, SnCl4, TiCl4, and TMSOTf118) that are known to catalyze oxa-Pictet-Spengler reactions were screened. TMSOTf was found to be the best Lewis acid, giving 2.266 in 69% yield and deprotected alcohol 2.261, which could be resubjected to the two-step sequence, in 22% yield. Using TfOH or no acid113 were less successful and ineffective, respectively.
126 Scheme 2.106
OH OMOM O MOMCl, rt conditions OMe OMe OMe
i-Pr2NEt, CH2Cl2 MeO Br MeO Br MeO Br quant 2.261 2.267 2.266
Lewis acid (equiv) conditions 2.261 2.267 2.266 Yield
BF3•OEt2 (2.0) CH2Cl2, 20 °C 1 5 0 -
SnCl4 (1.5) CH2Cl2, 78 °C 301 -
TiCl4 (1.6) CH2Cl2,0°C 130 51%
TMSOTf (0.1) CH3CN, 0 °C rt 10369% (22% 2.261)
TfOH (0.1) CH3CN, 0 °C rt 112 - none THF or CH CN, 65 °C 010 - 3 Formylations of 1-bromo-2,5-dimethoxybenzene systems like 2.266 are well-
119 120 precedented in the literature using POCl3/DMF, Duff reactions, α,α-dichloromethyl
121,122 123 methyl ether in the presence of SnCl4 or TiCl4, and LDA with DMF. However, all attempts to employ any of these conditions failed to afford aldehyde 2.268 (Scheme 2.107). Either unreacted starting material was recovered, or a complex mixture of unidentifiable side products was formed. Treatment of 2.266 with LDA and addition of DMF gave a mixture (5:1) of starting material and debrominated 2.269.
Scheme 2.107
127 Lithiation of 2.266 with LDA was investigated in more detail. Deuterium-labeled 2.270 was not obtained when the reaction was quenched with deuterated methanol (Scheme 2.108). Instead, a mixture (4:1) of starting material and dehalogenated 2.269 was observed by 1H NMR spectroscopy. While we do not have a good explanation for the formation of 2.269, it nevertheless seemed that the lithiation of 2.266 was a problem.
Scheme 2.108
We decided that maybe replacing the methyl ethers with MOM ethers might be helpful in stabilizing the ortho-lithium intermediate (cf. Scheme 2.29). Thus, oxidation of 2.266 with CAN gave quinone 2.257 and overoxidized 2.271 in 66% and 22% yield,
respectively (Scheme 2.109).109 The overoxidation was disappointing and was addressed later (cf. Scheme 2.116), but for the time being this route was used to move material forward. Quinone 2.257 was reduced to hydroquinone 2.272 in 95% yield.
Scheme 2.109
O O O OH CAN, 0 °C OMe O + O CH3CN, H2O MeO Br O Br O Br 2.266 2.257 -2.271
66% 22%
O
Na2S2O4,rt OH
THF, H2O HO Br 95% 2.272 128 MOM protection of the hydroquinone 2.272 proceeded uneventfully to give bis- MOM ether 2.273 (Scheme 2.110). Lithiation of 2.273 with LDA and quenching of the reaction with MeOD gave mixture (1.5:1) of 2.276 and deuterium-labeled 2.274. Although the deuterium incorporation was not ideal, we decided to attempt the formylation of 2.273 using this protocol nevertheless. To our disappointment, we only obtained a mixture (4:1) of starting material and debrominated 2.276. Since these efforts proved more challenging than anticipated, this approach was abandoned as well.
Scheme 2.110
O
LDA, THF, 78 °C OMOM then MeOD, 78 °C rt MOMO Br O O D MOMCl, rt 40% D-incorporation OH OMOM 2.274
i-Pr2NEt, CH2Cl2 HO Br MOMO Br O 64% 2.272 2.273 LDA, THF, 78 °C OMOM then MOMO Br DMF, 78 °C rt CHO O 4:12.273/2.276 2.275 OMOM
MOMO 2.276
We also investigated the formylation of hydroquinone 2.272 using POCl3/DMF,
Cl2CHOMe in the presence of SnCl4, and paraformaldehyde with MgCl2 (Scheme 2.111).124 All attempts failed to afford any amount of the desired aldehyde 2.256.
129 Scheme 2.111
Formylation of hydroquinone 2.272 was next attempted with a Duff reaction using hexamethylenetetramine (HMTA) (2.277) (Scheme 2.112).125 Although none of the desired aldehyde 2.256 was obtained, much to our surprise, we isolated imine 2.278 in 20% yield. The imine was the only product from the reaction, and it could be converted to the sought-after aldehyde 2.256 in quantitative yield.
Scheme 2.112
O O N HMTA, TFA OH OH N N N 110 °C sealed tube HO Br HO Br HMTA (2.277) 2.272 O H 2.256
O O
OH 60 °C OH
20% O Br H2O, THF HO Br quant N H O H 2.278 2.256 After some optimization, a one pot procedure was developed for the synthesis of 2.272 (Scheme 2.113). After heating the reaction under reflux in neat TFA, the solvent
was evaporated, and the residue was heated in H2O at 60 ºC. Aldehyde 2.256 could thus be obtained in 65% yield from 2.272. The yield was not improved when a large excess
130 (three equivalents) of hexamethylenetetramine (HMTA) was used or when the reaction was run in neat acetic acid. We also failed to get a better yield of 2.256 when the residue obtained after evaporation of TFA was heated in a mixture (1:1) of water and THF.
Scheme 2.113
The synthesis of bromide 2.255 was completed from aldehyde 2.256 in 73% overall yield via formation of the bis-MOM ether of 2.256 and Wittig olefination (Scheme 2.114).
Scheme 2.114
At last we had established a feasible route for synthesizing aryl bromide 2.255. The synthesis of hydroquinone 2.272, one of the key intermediates in our route, was not very efficient though. Hydroquinone 2.272 had been constructed from 2.267 in three steps and 43% yield (Scheme 2.115). The first two steps required purifications by column chromatography, which we wished to avoid if possible. Additionally, when scaling up, we found that the oxa-Pictet Spengler cyclization to ether 2.266 and oxidation to quinone 2.257 were both lower yielding and not as clean as when they were performed on small
131 scale (<1 g). As a result we wondered whether yields and ease of operation might be improved if these steps were sequenced differently.
Scheme 2.115
Indeed, oxidation of 2.267 (cf. Scheme 2.106) gave quinone 2.280 in quantitative yield (Scheme 2.116). Since the benzyl ether was not in place yet, overoxidation as observed before was not a problem (cf. Scheme 2.109). Reduction of 2.280 to hydroquinone 2.281 proceeded in 94% yield as before. The oxa-Pictet Spengler cyclization of 2.281 worked much more efficiently than that of 2.267. The more electron- rich hydroquinone appeared to cyclize much more rapidly, providing ether 2.272 in 95% yield. Furthermore, the desired hydroquinone 2.272 and the MOM-deprotected secondary alcohol 2.282 were observed in a >14:1 ratio. Hydroquinone 2.272 could thus be efficiently accessed from 2.267 in three steps, 89% overall yield, and without any purifications.
132 Scheme 2.116
OMOM OMOM OMOM
CAN, 0 °C Na2S2O4,rt OMe O OH
CH3CN, H2O THF, H2O MeO Br O Br HO Br quant 94% 2.267 2.280 2.281 no over oxidation!
OH O OH 10 mol% TMSOTf OH overall yield: 89% CH CN, 0 C rt No purif ications required! 3 HO Br HO Br 95% 2.271 2.282 >14:1 2.271/2.282 With a more reliable route in place for scaling up the synthesis of bromide 2.272, we were able to generate gram quantities of 2.255. The bromide was coupled with squarate 2.124 using the previously established conditions to provide 2.283, albeit in 35% yield (Scheme 2.117). The low yield was accounted for by the formation of significant amounts of the dehalogenated starting material.
Scheme 2.117
We wondered whether the dehalogenation could be avoided by adding bromide 2.255 to a solution of t-BuLi instead of vice versa, yet 2.283 was still isolated in only
133 37% yield (not shown). Greater success was achieved upon switching the solvent of the
reaction. When Et2O was used, diene 2.283 was obtained in 49% yield (Scheme 2.118). The subsequent ring closing metathesis proceeded uneventfully to give benzocyclobutenone 2.254 in 82% yield.
Scheme 2.118
O O OMOM OMOM t-BuLi, Et O, 78 C, 30 sec 2 OMe then MOMO OMe MOMO Br MeO OMe OMe O 2.255 ,0 C O 2.283
2.124 then TFAA, 78 C
49%
O
6% Grubbs II OMOM OMe PhMe, 110 °C MOMO OMe
82% O 2.254 We have thus established a scalable and reliable entry to angularly-fused benzocyclobutenone 2.254 (Scheme 2.119). Starting from commercially available 2.265, we were able to produce gram quantities of 2.254 in only 11 steps and 12% overall yield.
134 Scheme 2.119
OH OMOM 1. NBS, NH4NO3 Br OMe n-BuLi, THF, 78 °C CH CN, rt OMe 3 OMe then MeO 2. MOMCl, CH2Cl2 MeO i-Pr2NEt, rt 2.265 O 2.263 MeO Br commercially 2.261 quant 2.267 available 78 °C rt 73%
OMOM O 1. CAN, CH3CN HMTA (1.1 eq), TFA H O0°C 10 mol% TMSOTf sealed tube, 100 C 2 OH OH then 2. Na2S2O4,rt CH3CN, 0 C rt evaporate TFA THF, H2O HO Br HO Br then 2.281 95% 2.272 94% H2O, 60 °C
65%
O O O
OH MOMCl, rt OMOM PPh3CH3Br, NaH OMOM
i-Pr NEt, CH Cl THF, rt HO Br 2 2 2 MOMO Br MOMO Br
O H 87% O H 84% 2.256 2.279 2.255
O O
OMOM OMOM t-BuLi, Et2O, 78 C, 30 sec 6% Grubbs II OMe OMe OMe then MOMO PhMe, 110 °C MOMO OMe MeO OMe OMe O 82% O ,0 C 2.254 O 2.283
2.124 then TFAA, 78 C
49%
135 2.3.3.3 Synthesis of the Hexacyclic Core of IB-00208
Benzocyclobutenone 2.254 was then converted to 2.284 and subsequently coupled with aldehyde 2.149 (Scheme 2.120). Deprotection of the ketal and subsequent Moore cyclization afforded secondary alcohol 2.286, which was oxidized to ketone 2.287.
Scheme 2.120
Although this sequence worked well initially, we had a minor setback when we scaled up the IBX-oxidation of 2.286 (Scheme 2.121). In the 1H NMR spectrum of the crude reaction mixture, we observed a mixture (2:1) of 2.287 and another compound.
136 After a tedious column chromatography separation, the minor product was identified as hydroquinone 2.289. Quinone 2.287 and hydroquinone 2.289 were isolated in 32% and 18% yield, respectively. We believe that the saturated aqueous sodium thiosulfate
(Na2S2O3) used to quench the reaction was responsible for reducing quinone 2.287 to 2.289. Hydroquinone 2.289 could be oxidized with DDQ to afford ketone 2.287 in quantitative yield. In the future, the amount of sodium thiosulfate used in the work-up will be administered more carefully.
Scheme 2.121
O
OMOM O OH OMe IBX, DMSO, rt MOMO then Na2S2O3/NaHCO3 O workup O TBS OMe 2.286
O O
OMOM OMOM O O OMe OH O OMe + MOMO MOMO
O O O TBS OMe OH TBS OMe 2.287 2.289
32%2:1 ratio in crude reaction mixture 18%
DDQ, PhH, rt quant Ketone 2.287 was treated with HF·pyr to give spirocycle 2.290 in 37% yield and 2.251 in 4% yield (Scheme 2.122). Hexacycle 2.251 was not observed in the 1H NMR spectrum of the crude reaction mixture, but instead we observed a mixture of 2.290 and an unidentified compound, which we now believe to be phenol 2.252 (cf. Scheme 2.99). Thus, 2.251 is most likely formed during chromatography purification. In future work it
137 would be interesting to stir the crude reaction mixture with SiO2 in CH2Cl2 to see if both products can be isolated in better yields.
Scheme 2.122
O
OMOM O O OMe HF•pyr, pyr
MOMO THF, rt O O TBS OMe 2.287
O O MOM MeO O O OMOM O O O OMe + MOMO MOMO O OMe O O O OMe 2.290 2.251
37% 4% Inspired by the observation of small quantities of 2.251, we wanted to look at the TBAF-mediated deprotection again (cf. Scheme 2.80). To our disappointment, treatment of 2.287 with TBAF only led to a complex mixture of unidentifiable products (Scheme 2.123).
Scheme 2.123
Thermal rearrangement of spirocycle 2.290 and a concomitant oxidation (cf. Scheme 2.82) was carried out starting at 150 ºC and the temperature was slowly raised to 138 215 ºC over two hours to deliver 2.251 in 67% yield (Scheme 2.124). This reaction requires further optimization, however, as repeating it on a larger scale (135 mg vs 10 mg) only provided 2.251 in 26% yield.
Scheme 2.124
Oxidized xanthone 2.251, the hexacyclic core of IB-00208 (2.1), was thus synthesized from benzocyclobutenone 2.254 in only seven steps (Scheme 2.125).
139 Scheme 2.125
2.3.3.4 Attempted Endgame Chemistry for the Synthesis of the IB-00208 Aglycone
All that remained for completion of the synthesis of the aglycone of IB-00208 from benzyl ether 2.251 was a benzylic oxidation and cleavage of the MOM ethers (Scheme 2.126).
140 Scheme 2.126
A literature search revealed a vast number of conditions that can be employed for the oxidation of cyclic benzyl ethers. We thus decided to screen most of these conditions using bromide 2.266 as a model before applying them to the precious, limited amount of our advanced intermediate 2.251 (Scheme 2.127). Reacting 2.266 with DDQ in the
126 127 presence of H2O and MeOH gave 38% and no conversion to 2.293 and 2.294, respectively. In light of the poor conversion, these reactions were not studied further, and we turned our attention to other oxidants.
Scheme 2.127
O OH
DDQ, H2O OMe 1:1.3 2.293/2.266 CH2Cl2,rt O MeO Br 2.293 OMe
MeO Br O OMe 2.266 DDQ, MeOH OMe only rsm CH2Cl2,rt MeO Br 2.294 Several conditions were investigated that have been reported to directly oxidize cyclic benzyl ethers to lactones (Scheme 2.128). The ruthenium-based oxidation of 2.266
117 128 was a lot cleaner with RuO2 than with RuCl3. Nevertheless, both afforded the desired product in moderate yield. Oxidation of 2.266 with PCC never went to completion.129 Furthermore, the reaction was very messy, the product was difficult to 141 purify, and this reagent was thus deemed impractical. Oxidation of a benzyl ether with
chromium (VI) oxide (CrO3) in the presence of 3,5-dimethylpyrazole (3,5-DMP) had been reported by Salmond and coworkers.130 Using these conditions, 2.266 was oxidized to 2.295 in quantitative yield. This protocol was very promising, also because Overman
had used it for the oxidation of a similarly complex system,131 and Mori et al. had shown these conditions to be compatible with a bis-MOM protected hydroquinone.132 Refluxing
133 2.266 with selenium (II) oxide (SeO2) gave mostly unreacted starting material.
Oxidation of 2.266 with potassium permanganate (KMnO4) in the presence of phase transfer catalyst triethylbenzylammonium chloride (TEBAC) gave a promising 4:1 ratio of lactone 2.295 and starting material.134 Lastly, reaction of 2.295 with a large excess (ten equivalents) of DMDO gave a mixture (1:1.3) of lactone 2.295 and lactol 2.293.135
Scheme 2.128
O O O conditions OMe OMe
MeO Br MeO Br 2.266 2.295
conditions: RuCl3·H2O, NaIO4,CH3CN, CCl4,H2O, rt: 74% RuO2·H2O, NaIO4,CH2Cl2,H2O, rt: 61% PCC, CH2Cl2, reflux: 1:2 2.266/2.295 CrO3,CH2Cl2,rt:only rsm CrO3,3,5-DMP,CH2Cl2, 20 °C: quant SeO2, xylenes, reflux: mostly rsm KMnO4, TEBAC, CH2Cl2,reflux:1:42.266/2.295 DMDO, acetone, rt: 1:1.3 2.295/2.293 The conditions that had given significant quantities of lactone 2.295 were employed for the oxidation of 2.251 (Scheme 2.129). Very much to our disappointment,
none of the reactions gave the desired lactone 2.296. Oxidation of 2.251 with RuO2 afforded unreacted starting material, while all other conditions delivered decomposition products that could not be identified by 1H NMR spectroscopy or LCMS.
142 Scheme 2.129
O O O
OMOM OMOM O O OMe conditions O O OMe MOMO MOMO
O O O OMe O OMe 2.251 2.296
conditions: RuO2·H2O, NaIO4,CH2Cl2,H2O, rt: only rsm (2.251) RuCl3·H2O, NaIO4,CH3CN, CCl4,H2O, rt: decomposition CrO3,3,5-DMP,CH2Cl2, 20 °C: decomposition DMDO, rt, acetone: decomposition KMnO4, TEBAC, CH2Cl2,reflux:decomposition Due to the lack of success in the oxidation of 2.251 and because we had used up all amounts of 2.251, we decided to test the two oxidation conditions that we deemed most promising on spirocycle 2.290, of which we still had small quantities (Scheme 2.130). The two reactions were analyzed by LCMS, and we found that DMDO only cleaved one of the MOM ethers. Oxidation of 2.290 with CrO3 and 3,5-DMP, however, appeared to furnish lactone 2.297 as the major product. The mass of the two minor products were in agreement with starting material lacking a MOM group and the desired product lacking a MOM group. Although we had consumed all of our material at this point, we believe that this reaction merits further investigation on a larger scale. Should the oxidation work as it appears, then only two steps remain (rearrangement and deprotection) to complete the synthesis of the aglycone of IB-00208.
143 Scheme 2.130
Since we were so close to completing the synthesis of IB-00208, we wanted to establish conditions for removing both MOM ethers. We still had quantities of 2.171, which we believed to be a suitable model system (Scheme 2.131). Therefore, pentacycle 2.171 was reacted with non-aqueous HCl (2.5 M in MeOH) to afford a mixture (1:1) of
2.171 and 2.240.136 (±)-Camphorsulfonic acid (CSA) worked equally poorly, and again a mixture (1:1) of 2.171 and 2.240 was observed.137 Complete deprotection of both MOM groups ensued with in situ-generated TMSI, yet instead of the hydroquinone 2.239, quinone 2.298 was isolated in quantitative yield.138 Nevertheless, we were excited to have discovered a protocol that should allow us to efficiently remove both MOM ethers in our synthesis of IB-00208 (2.1).
144 Scheme 2.131
OMOM OH O O OMe O O OMe conditions MOMO HO
O O O OMe O OMe 2.171 2.239
conditions: HCl/MeOH, MeOH, CH2Cl2,0°C:1:12.171:2.240 CSA, MeOH, rt: 1:1 2.171:2.240 TMSCl, NaI, CH2Cl2,0°C rt: quant 2.298
OH O O O OMe O O OMe
MOMO O
O O O OMe O OMe 2.240 2.298 Overall, an efficient synthesis of the hexacyclic core of IB-00208 (2.251) has been accomplished (Scheme 2.132). Starting from commercially available bromide 2.265, hexacycle 2.251 was synthesized in 18 linear steps and 23 steps overall. Oxidation of the benzyl ether of 2.251 to the corresponding lactone and deprotection of the MOM groups would complete the synthesis of the aglycone of IB-00208 with a projected step count of only 20 linear steps.
145 Scheme 2.132
1. n-BuLi, THF, 78 °C 1. CAN, CH3CN then 2.263, 78 °C rt H O0°C OMOM 2 O Br OMe 2. NBS, NH4NO3 2. Na2S2O4,rt CH CN, rt THF, H O 3 OMe 2 OH MeO 3. MOMCl, CH2Cl2 3. 10 mol% TMSOTf i-Pr2NEt, rt CH3CN, 0 C rt 2.265 MeO Br HO Br 73% 2.267 89% 2.272
O 1. HMTA (1.1 eq), O TFA, sealed tube t-BuLi, Et2O OMOM OMOM then H2O, 60 °C 78 C, 30 sec OMe 2. MOMCl, rt then 2.124,0°C MOMO OMe MOMO Br i-Pr2NEt, CH2Cl2 then TFAA, 78 C 3. PPh3CH3Br, NaH O THF, rt 49% 2.255 2.283 47%
O
O OMOM 1. 6% Grubbs II OMOM 1. EtMgBr, THF. rt O PhMe, 110 °C then 2.149 OMe MOMO OH 2. BrMg MOMO OMe 2. p-TsOH, rt OMe THF, 0 °C rt acetone OH TBSO 72% OH 79% 2.284 MeO 2.253
O O
1. rt 120 °C OMOM 1. HF•pyr, pyr OMOM DMSO O O OMe THF, rt O O OMe 2. IBX, rt MOMO 2. 150 215 °C MOMO DMSO PhNO2 O O 43% O TBS OMe 25% O OMe 2.287 2.251 hexacyclic core of IB-00208
O OMe MeO H OMe OMe O TBSO O 2.263 MeO 2.124 2.149
146 2.4 CONCLUSION
Few methods have been reported for the construction of 1,4-dioxygenated xanthones, a structural motif present in numerous natural products with promising biological activity. Furthermore, most existing methods are inefficient and/or employ harsh reaction conditions that are not compatible with sensitive functional groups. In the context of a synthesis of IB-00208 (2.1), we developed a mild and efficient approach to 1,4-dioxygenated xanthones from benzocyclobutenones. It was demonstrated that benzocyclobutenol 2.168 can be converted to the oxidized xanthone 2.136, the tetracyclic core of IB-00208, in just three steps and 68% yield. Since a large number of cyclobutenediones are commercially available or easily accessed, a wide range of 1,4- dioxygenated xanthones may be rapidly constructed via this approach, which is currently being investigated in our laboratories. In our studies toward the total synthesis of IB-00208, complex angularly-fused benzocyclobutenones were efficiently accessed via a novel ring-closing metathesis approach. Angularly-fused cyclobutenone 2.174 was thus assembled in only five steps and 39% overall yield. This compound was subsequently transformed to crystalline 2.171, the highly aromatic pentacyclic core of IB-00208, using our new approach to xanthones. Analysis of the crystal structure of 2.171 revealed that the two oxygen atoms at the angular fusion bend out of the plane of the aromatic core. The angle between the C11-O6 and C8-O5 bond was a surprisingly large 43º, which further highlighted our accomplishment of synthesizing strained 2.171. The pentacyclic core of IB-00208 was thus synthesized in only 12 linear steps and 17 steps overall from commercially available starting materials. Although attempts to complete the synthesis of 2.1 from 2.171 failed, we had demonstrated that complex 1,4-dioxygenated xanthones can be rapidly accessed via our new approach to these types of ring systems. 147 In our revised approach to IB-00208, a cyclic benzyl ether was incorporated early in the synthesis to circumvent the challenges encountered with the previous endgame chemistry. The requisite benzocyclobutenone 2.254 was synthesized from commercially available starting materials in only 11 steps and 12% overall yield. Expansion of 2.254 to the oxidized xanthone 2.251 took a mere seven steps and completed the synthesis of the hexacyclic core of IB-00208. Only an oxidation, MOM ether cleavage, and glycosylation remain to complete the total synthesis of IB-00208 (2.1) with a projected step count of just 21 linear steps and 26 steps overall.
2.5 FUTURE
The most promising route toward completing the synthesis of IB-2008 (2.1) will be to reevaluate the oxidation of spirocycle 2.290 using CrO3 and 3,5-DMP (Scheme 2.133). Thermal rearrangement of lactone 2.297 and concomitant oxidation followed by deprotection of the MOM ethers should provide access to 2.292, the aglycone of IB- 00208.
148 Scheme 2.133
O O O MOM MeO MOM MeO O O O O O 150 215 °C O CrO3,3,5-DMP MOMO MOMO O OMe CH2Cl2, 20 °C O OMe PhNO2
O O 2.290 2.297
O O O O
OMOM OH O O OMe TMSCl, NaI O O OMe MOMO HO CH2Cl2,0°C O O O OMe O OMe 2.296 2.292 aglycone of IB-00208 If the approach above fails, it might be helpful to synthesize a more suitable model system like 2.299 (Scheme 2.134). Oxidations using DDQ deserve to be reinvestigated as well as radical brominations.139 These reactions would furnish a lactol, which would need to be oxidized to the corresponding lactone using IBX,140 PCC,141 or
142 Ag2O. Lastly, it might also be worthwhile to first remove the MOM ethers and then investigate the oxidation of the benzyl ether.
Scheme 2.134
149 Chapter 3: Total Synthesis of Cribrostatin 6
3.1 INTRODUCTION
Antibiotic-resistant Gram-positive bacteria continue to be a major cause of death worldwide and pose an imminent threat to our society. Growing multi-drug-resistance has been particularly disconcerting and has fuelled the need for new structural classes of antibiotics. Resistant strains of enterococci and Staphylococcus aureus, Pseudomonas aeruginosa, and Streptococcus pneumoniae are emerging with troubling frequency. Indeed, Streptococcus pneumoniae is the most common bacterial cause of acute
respiratory infection and otitis media, which result in millions of deaths each year.143 In the United States alone, pneumonia is the eighth leading cause of death.144 Due to a growing resistance of S. pneumoniae against trimethoprim-sulfamethoxazole, penicillin, macrolide and tetracycline antibiotics, the search for new promising leads has become more and more urgent. O Me
N EtO Me O N cribrostatin 6 (3.1) In 2003, Pettit and coworkers reported the isolation and characterization of
cribrostatin 6 (3.1) from the blue-colored marine sponge Cribrochalina sp.145 A dark blue solid, 3.1 was found to inhibit the growth of a number of antibiotic-resistant Gram- positive bacteria and pathogenic fungi. Cribrostatin 6 (3.1) was most active against S.
pneumoniae with MBC/MIC ratios ≤2 for 75% of S. pneumoniae clinical isolates.143 In addition to its potent antimicrobial activity, naturally-occurring 3.1 also displayed antineoplastic activity against murine and human cancer cell lines at micromolar
concentrations (P388 ED50 = 0.3 μg/mL). 150 The interesting biological activity of cribrostatin 6 (3.1) coupled with its unique and unprecedented tricyclic imidazo[5,1-a]isoquinolinedione architecture prompted our interest in a total synthesis of the natural product. We envisioned that the natural product might be accessed from 3.2 via an oxidation and a dehydrogenation (Scheme 3.1). For the key step of our synthesis, we believed that hydroquinone 3.2 might be directly accessed from squarate intermediate 3.3 via a radical process (vide infra). Compound 3.3 was thought to be readily assembled from dione 3.4,146 alcohol 3.5, and imidazole 3.6. This approach to cribrostatin 6 (3.1) would allow rapid access to the natural product and also has the potential of being applied to the facile construction of analogs of 3.1.
Scheme 3.1
3.2 BACKGROUND: MOORE CYCLIZATION
3.2.1 Synthetic Utility of Squarates
In order to appreciate and understand the proposed key transformation of 3.3 to 3.2 (cf. Scheme 3.1), the background and evolution of chemistry involving squarates will be discussed. Squarates, or cyclobutenediones, have been utilized in organic chemistry for several decades, and several comprehensive reviews have been published that discuss 151 the reactivity and use of squarates.79,147 A useful review highlighting the applications of squarates in synthesis was published several years ago by Belluš and Ernst.148 Several squarate esters 3.7 (R = Me, Et, i-Pr, t-Bu) are commercially available
and/or can be prepared in one step from commerically available squaric acid.149 Addition of nucleophiles to squarate 3.7 generates the 1,2-addition product 3.8, which can be isolated as tertiary alcohol 3.11 (Scheme 3.2). Alternatively, alkoxide 3.8 can also be acetylated in situ with trifluoroacetic anhydride (TFAA) to convert the alkoxide into a leaving group, which subsequently eliminates to form oxonium 3.9. If this intermediate is
quenched with saturated aqueous NaHCO3, squarate 3.12 is obtained in a one-pot, two step operation from 3.7. Alternatively, if treated with an alcohol, one is able to isolate the corresponding ketal 3.10. In either of these processes, the net result is that one of the OR
groups of the original squarate 3.7 has been substituted with another group (R1). Yet in intermediate 3.12, ketone b is the reactive electrophilic site for further additions of nucleophiles, since the vinylogous ester carbonyl is less reactive than the ketone toward addition. In 3.10, however, ketone b has been masked as a ketal, and the only accessible electrophilic site is ketone a. Thus, addition of a second nucleophile followed by treatment with TFAA will substitute the remaining OR group to deliver squarate 3.13. A wide range of squarates can be accessed using this approach.
152 Scheme 3.2
3.2.2 Early Use of Squarates
The property that makes squarates useful in organic synthesis is that they readily undergo 4π-electrocyclic ring opening (ERO) reactions. Upon thermal or photochemical stimulus, squarate 3.14 is in equilibrium with the bisketene 3.15 (Scheme 3.3).
Scheme 3.3
One of the first examples of harnessing the synthetic potential of reactive bisketenes such as 3.19 was first demonstrated by Staab and Ipaktschi in the late 1960’s
(Scheme 3.4).150 Upon irradiation of benzocyclobutenone 3.16, bisketene intermediate 3.19 was generated that reacted with maleic anhydride (3.17) via a [4+2] cycloaddition reaction to give hydroquinone 3.18 in 67% yield.
153 Scheme 3.4
3.2.3 Early Metal-Mediated Processes with Squarates
The C-C bond between the two carbonyl groups of a squarate was also easily broken by certain metal complexes. Particularly useful for this process were cobalt
complexes developed by Liebeskind and coworkers,147c which inserted into the said C-C bond of 3.20 to furnish complex 3.21 in 84% yield (Scheme 3.5). This complex was then converted to the corresponding dimethylglyoxime (dmg) variant 3.22, which reacted with alkynes to furnish quinones. Most notably, if unsymmetrical alkynes such as 3.23 were used, quinone 3.24 was obtained in 62% yield and with a regioselectivity of 20:1.
Scheme 3.5
Addition of alkynyllithium or alkynyl Grignard reagents to benzocyclobutenediones provided tertiary alcohols such as 3.25 (Scheme 3.6). In the 154 presence of catalytic amounts of Lewis acidic palladium (II) the labile C-C bond was broken in a semipinacol-type rearrangement to deliver vinylpalladium intermediate 3.26.151 Upon protonation or cross coupling, exocyclic dienone 3.27 was obtained. In the absence of a coupling partner, 3.28 was converted to 3.29 in 45% yield. If propylene oxide was used as an acid scavenger and allyl bromide as a coupling partner, cyclopentenedione 3.31 was isolated instead in 73% yield. Similar expansions of squarates via this mechanism were also observed in systems where the ketone in 3.25 was masked as a ketal (not shown).
Scheme 3.6
O O R1 O R R PdII 1 R3 E–X 1 R3
R3 II R Pd E 2 OH II R2 R2 Pd O O 3.25 3.26 3.27
O Me O Me n-Bu 10 mol% Pd(TFA)2 n-Bu THF, 60 °C H MeO OH MeO O 45% 3.28 3.29 12:1 ratio of regioisomers
O Me O Me 5mol%Pd(TFA)2 n-Bu n-Bu Br MeO OH MeO O O ,CH2Cl2,rt 3.31 3.31 >20:1 ratio of regioisomers 73%
3.2.4 Quinone Formation via Thermal Conditions
Another way to exploit the ability of squarates to undergo a facile 4π- electrocyclic ring opening reaction is to intercept the intermediate ketene with an
155 appropriately situated olefin via a 6π-electrocyclic ring closing (ERC) reaction (Scheme 3.7). Specifically, treatment of squarate 3.14 with an organometallic 3.32 affords tertiary alcohol 3.33. Upon heating, this squarate undergoes the expected electrocyclic ring opening reaction to furnish ketene 3.34, which is set up to undergo an electrocyclic ring closing reaction with the appended vinyl group to provide intermediate 3.35. Tautomerization of 3.35 provides hydroquinone 3.36, which is readily oxidized to quinone 3.37 with air or other oxidizing agents.
Scheme 3.7
R4 [M] O R1 O R1 O R1 R4 3.32 R3 R4 6 -ERC 4 -ERO R R2 R3 R2 O 2 OH R3 OH 3.14 3.33 3.34
O OH O R1 R4 tautomerize R1 R4 [O] R1 R4
R2 R3 R2 R3 R2 R3 OH OH O 3.35 3.36 3.37 The sequence outlined in Scheme 3.7 can be performed with simple as well as more complex olefins. Addition of vinyllithium to cyclobutenone 3.38 followed by unmasking of the ketal gave alcohol 3.39 in 70% yield over two steps (Scheme 3.8).74 Refluxing squarate 3.39 in benzene provided the corresponding hydroquinone, which underwent a one pot oxidation to afford quinone 3.40 in 75% yield.
Scheme 3.8
156 Aromatics, as well as heteroaromatics, have been employed in this transformation (Scheme 3.9). Facile 1,2-additions of the lithiated aromatics gave the desired cyclobutenols 3.42 and 3.44, which were converted to the corresponding quinones 3.43 and 3.45, respectively.152
Scheme 3.9
3.2.5 Torquoselectivity of the Electrocyclic Ring Opening of Cyclobutenones
The torquoselectivity of the 4π-electrocyclic ring opening reaction was investigated in a theoretical study by Houk and coworkers and merits some further discussion.153 If one looks at the most simplified squarate 3.47, it can theoretically undergo an electrocyclic ring opening via two different rotations: an inward and an outward rotation of the R substituent giving rise to intermediates 3.46 or 3.48, respectively (Scheme 3.10).
Scheme 3.10
O O O 4 -ERO 4 -ERO inward outward R R R 3.46 3.47 3.48 157 With an a,a-disubstituted cyclobutenone this discussion becomes slightly more complicated. In case of 3.50, Moore and coworkers have shown that under thermal conditions, only the outward rotation of the hydroxyl group appears to proceed, since only the hydroquinone was isolated from the reaction. Formation of the hydroquinone is
explained by a 6π−electrocyclization of ketene intermediate 3.51 (Scheme 3.11).71 However, when light irradiation was used to open the cyclobutenone, only inward rotation of the hydroxyl group appears to proceed, since γ-butyrolactone 3.52 was the only product isolated from the reaction.
Scheme 3.11
The photolysis of cyclobutenones (3.50→3.52) has not been studied in any detail, and an explanation for the reversal between inward and outward rotation of the hydroxyl group due to photochemical versus thermal activation is yet to be discussed. The thermal
4π-electrocyclic ring opening (3.50→3.53), however, has been studied in detail by Houk and coworkers.153 Theoretical calculations showed that the conrotatory outward rotation of the hydroxyl substituent is energetically favored. This is because upon conrotatory inward rotation the filled substituent donor orbital of the oxygen atom overlaps with the HOMO of the cyclobutenone transition state (localized primarily on the breaking σ bond)
158 (Figure 3.1). This overlap results in a destabilizing interaction, which substantially raises the activation energy for the inward rotation of a donor substituent such as oxygen. In addition, the activation energy for the outward rotation is further lowered by a favorable overlap of the oxygen atom with the LUMO of the transition state (the breaking σ* anti- bonding orbital) (not shown).
Figure 3.1
3.2.6 Discovery of the Moore Cyclization
Arguably the most powerful and widely used application of squarates is their transformation into quinones via the Moore cyclization, which was discovered by Harold Moore in the late 1980s. It was found that addition of an alkyne to a cyclobutenedione provided alcohol 3.54, which upon heating under reflux in p-xylene was transformed into 1,4-benzoquinone 3.55 in 78% yield (Scheme 3.12).71
Scheme 3.12
O MeO O reflux MeO n-Bu n-Bu p-xylene MeO OH MeO O 78% 3.54 3.55
159 The mechanism of the Moore cyclization is proposed to occur as outlined in Scheme 3.13. Under thermal conditions the cyclobutenone 3.56 is proposed to undergo a
4π-electrocyclic ring opening reaction in which the alcohol rotates outward (cf. Figure 3.1, Scheme 3.13). The labile ketene carbonyl in 3.57 is argued to fragment homolytically so that the carbon-centered radical cyclizes with the alkyne to provide diradical intermediate 3.58. After an intermolecular hydrogen atom abstraction of the phenol hydrogen, diradical 3.59 is formed, which is equivalent to quinone 3.60. Although one might be able to propose an ionic mechanism to explain formation of quinone 3.60 from cyclobutenone 3.56, several details point to a radical process. Theoretical calculations by Engels and coworkers support the intermediacy of a diradical as this pathway is significantly lower in energy than an anionic process.154 Additionally, several examples are discussed below that appear to engage the proposed intermediate aryl radical 3.58 in subsequent cyclizations, which are best explained by a radical process. In the radical cyclization of ketene 3.57, one might also expect to see formation of the five-endo-dig cyclization product 3.61. These products, however, are not observed when R3 is an alkyl group. Moore and coworkers proposed that the aromatic stabilization associated with formation of 3.58 might be responsible for exclusive formation of this
71 diradical. When R3 = TMS, alkoxy, or phenyl, significant quantities of products from the five-endo-dig cyclization are observed, which are proposed to be produced due to the
capability of these substituents to stabilize the adjacent radical site in 3.61. An intermolecular hydrogen atom abstraction for 3.58→3.59 has been proposed due to an observed concentration dependence in cases where the aryl radical 3.58 was engaged in subsequent cyclizations (cf. Scheme 3.16). At high concentrations (1.2 M), hydrogen atom abstraction and formation of a quinone such as 3.60 was predominant, while at low concentrations (0.004 M), products of subsequent cyclizations
160 predominated. This observation, which was quite general, was best explained by an intermolecular hydrogen atom abstraction. It should be noted, however, that if the tertiary hydroxyl group in 3.56 is converted into a TMS ether, the TMS group is transferred to the aryl ring in an intramolecular process. This was established by double label cross-over experiments (not shown).71
Scheme 3.13
3.2.7 Moore Cyclization and Tandem Processes: Alkenes and Alkynes
As mentioned before, the proposed radical pathway of the Moore cyclization is supported by the use of intermediate 3.58 in subsequent chemistry (cf. Scheme 3.13). Although hydrogen atom abstraction is fairly rapid, the aryl radical can nevertheless be utilized in subsequent tandem processes, which serve to highlight the strength of the Moore cyclization in generating complex ring systems. Some of the early tandem processes involved groups with unsaturation, such as an allyl group, appended to the tertiary hydroxyl group of the cyclobutenol 3.62 (Scheme 3.14).155 Refluxing squarate 3.62 in p-xylene induced an electrocyclic ring opening and subsequent radical cyclization 161 to diradical 3.64. With the pendant allyl group in close proximity, the allyl group was subsequently transferred to the aryl ring in a radical process, which placed the radical on the oxygen atom to deliver the quinone. The fully-substituted quinone 3.65 was thus obtained in 78% yield. This approach highlights the ease by which a complex quinone can be accessed from a readily available cyclobutenone.
Scheme 3.14
The aryl radical intermediate of the Moore cyclization can also be engaged in
subsequent cyclization with oxygen-bound propargyl groups (Scheme 3.15).155 When 3.66 was heated, diradical 3.67 was formed which engaged in a five-exo-dig cyclization with the pendant alkyne. The newly formed vinyl radical 6.68 then abstracted a hydrogen atom from the proximal n-butyl group to afford diradical 3.69. Product 3.70 was obtained after the phenoxide radical also abstracted a hydrogen atom from the n-butyl side chain to generate a phenol and an olefin.
162 Scheme 3.15
MeO O O O reflux MeO n-Bu MeO n-Bu MeO p-xylene H O n-Bu MeO n-Bu MeO O O n-Bu 3.66 3.67 3.68
H OH O MeO MeO
73% MeO MeO O n-Bu O n-Bu 3.70 3.69 Tandem cyclizations were also observed when diynes were coupled to
cyclobutenediones as in 3.71 (Scheme 3.16).156 Interestingly, when the reaction was carried out at high concentration (1.2 M), quinone 3.73 was isolated exclusively in 62% yield. When the same reaction was conducted at low concentration (0.004 M), bicycle 3.75 was isolated in 80% yield. The observed concentration dependence was explained by an intermolecular hydrogen atom abstraction of the aryl radical 3.72 at high concentration, which led to the formation of quinone 3.73. Thus at dilute concentrations the lifetime of the aryl radical was prolonged and an intramolecular cyclization could ensue to form bicyclic diradical 3.74 and subsequently quinone 3.75.
163 Scheme 3.16
It is worth pointing out that if the tertiary hydroxyl group of cyclobutenone 3.71 was methylated, oxirane 3.79 was isolated as the sole product of the reaction in 87% yield (Scheme 3.17). Moore and coworkers proposed that after the radical cyclization of 3.77 to 3.78, the vinyl radical abstracted a hydrogen atom from the proximal methyl group, which upon intramolecular radical recombination delivered oxirane 3.79. The isolation of 3.79 served to further support the proposal that the cyclization proceeds via a radical process.
164 Scheme 3.17
Tandem cyclizations of the Moore cyclization with appending alkenes are also well precedented. One of the most complex and notable examples was published by
Moore and coworkers in 1995.157 Upon heating, cyclobutenone 3.80 was converted to diradical 3.81 (Scheme 3.18). Stereoselective cyclization of the carbon-based radical delivered secondary radical 3.82, which abstracted a hydrogen atom from the proximal phenol to afford quinone 3.83 in 54% yield.
165 Scheme 3.18
Deuterium labeling studies were carried out in order to study the hydrogen atom abstraction required for 3.82→3.83 (cf. Scheme 3.18). Deuterium-enriched (85%) 3.84 was heated under reflux in toluene at high dilution (0.001 M) to provide deuterium- labeled 3.87 in greater than 40% yield (yield was reported over two steps) (Scheme 3.19). Based on the stereochemistry of the product, it was proposed that the aryl radical 3.85 axially attacked the alkene to give boat conformer 3.86. The cis diaxial addition product 3.87 was then formed via deuterium abstraction of the phenol by the axial radical in 3.86.
166 Scheme 3.19
More recently, Wipf and coworkers demonstrated that tandem cyclizations also proceed with enamides.158 Refluxing cyclobutenol 3.88 in toluene delivers isoquinolinetrione 3.91 in 54% yield (Scheme 3.20). Although the mechanism was identical to that of other examples described above, this was one of the first examples that showed that nitrogen heteroatoms, as well as amides, are tolerated in this radical process.
167 Scheme 3.20
3.2.8 Moore Cyclization and Tandem Processes: Aromatic Substitutions
In addition to tandem cyclization processes with pendant alkynes and alkenes, Moore and coworkers have disclosed two reports of engaging the aryl radical intermediate in a homolytic aromatic substitution reaction. The first report focused primarily on anilines coupled to cyclobutenones.159 Systems like cyclobutenol 3.92 were heated under reflux at low concentration (0.003 M) to afford hydroquinones such as 3.95 (Scheme 3.21). The reaction was proposed to proceed via diradical intermediate 3.93, which was thought to undergo a homolytic aromatic substitution reaction to give tricyclic diradical 3.94. Intermolecular hydrogen atom abstraction was then proposed to furnish 3.95 in 65% yield.
168 Scheme 3.21
In addition to anilines, Moore and coworkers also showed that heteroaromatics such as indoles can be employed in this elegant transformation. In the case of 3.96, the reaction proceeded in refluxing chlorobenzene to afford a mixture of three products (Scheme 3.22). The major product 3.98 was obtained in 57% yield along with small quantities (12%) of 3.99, which was formed via a homolytic aromatic substitution onto the 7-position of the indole. Very surprisingly, hydroquinone 3.100 was also isolated in 8% yield. This product was said to arise from hydrogen atom abstraction of diradical 3.97 from an unspecified source.
169 Scheme 3.22
In a subsequent publication, Moore and coworkers continued to explore the scope of the tandem Moore cyclization/homolytic aromatic substitution sequence.160 This work, however, did not include much new chemistry as 1-aminonaphthalenes were used instead of anilines (Scheme 3.23). Similar to the aniline systems (cf. Scheme 3.21), tetracyclic 3.104 was isolated in 66% yield.
Scheme 3.23
MeO O O MeO reflux NMe MeO OH NMe PhCl [0.003 M] MeO HO
3.101 3.102
O OH MeO MeO NMe NMe
MeO 66% MeO H HO OH 3.104 3.103
170 Although the scope was not extended in this work, Moore and coworkers did unveil some interesting mechanistic details of the reaction. The formation of 3.104 from 3.103 could arguably proceed via two different pathways (cf. Scheme 3.23). Either diradical 3.105 could undergo an intermolecular hydrogen atom abstraction as outlined in path a, or an intramolecular hydrogen atom abstraction of 3.107 might generate quinone 3.108 (path b), which upon disprotonation would deliver 3.109 (Scheme 3.24).
Scheme 3.24
To determine which pathway was operational, deuterium-labeled 3.110 was synthesized and subjected to the reaction conditions (Scheme 3.25). Since no deuterium incorporation was observed for the resulting hydroquinone product 3.104, path a was reasoned to best account for formation of 3.104 via the direct loss of a hydrogen atom from 3.105 (cf. Scheme 3.24).
171 Scheme 3.25
3.3 PREVIOUS SYNTHESES OF CRIBROSTATIN 6
3.3.1 Nakahara’s Total Synthesis of Cribrostatin 6
We had proposed a very short synthesis of cribrostatin 6 (3.1) (cf. Scheme 3.1). It was our goal to access 3.1 more efficiently than the existing approaches allowed and also to design an approach that was more readily amendable to the synthesis of analogs. In order to appreciate the novelty of our proposed entry to 3.1, the two previous efforts toward cribrostatin 6 (3.1) are discussed. Nakahara and coworkers were the first to complete a total synthesis of 3.1 in
2004, a feat that also confirmed the structure of the natural product.161 Two years later, they published another report in which they were able to alter the endgame of their synthesis and thereby improve the overall yield.162 This latter and higher-yielding approach to cribrostatin 6 (3.1) is outlined in Scheme 3.26. Phenol 3.112 was accessed from commercially available 2-methylresorcinol (3.111) via a transformation that Nakahara had previously published in synthetic efforts toward other members of the cribrostatin family.163 Elaboration of 3.112 via a Duff reaction and subsequent benzylation provided aldehyde 3.114, which was transformed into acetal 3.115 in three straightforward steps. Under acidic conditions, a modified Pomeranz-Fritsch isoquinoline synthesis was performed on 3.115. Upon treatment with t-BuOK the tosyl protecting
172 group was removed to reveal 3.116, the isoquinoline core of the cribrostatin 6 (3.1). The final ring of the target molecule was built up in a rather uneventful stepwise manner. A cyano group was introduced to give 3.117, which was subsequently reduced to the secondary amine and acetylated to yield phenol 3.118. A final cyclization to afford the 2- methylimidazole portion of the natural product and a low-yielding (30%) dealkylation/air oxidation delivered desired 3.1.
Scheme 3.25
Nakahara and coworkers thus completed the first total synthesis of cribrostatin 6 (3.1) in 18 steps and 0.79% overall yield. Their efforts required ten steps to assemble the 173 isoquinoline core of the molecule and seven further steps to construct the fused imidazole ring to finish the total synthesis of 3.1. The only interesting chemistry in the entire sequence was the modified Pomeranz-Fritsch isoquinoline synthesis, which was adapted directly from work reported by Jackson and coworkers.164 The lack of new chemistry coupled with its length and low yields made this an unappealing approach to cribrostatin 6 (3.1) and left much room for improvement and further developments in order to achieve a more ideal synthesis of 3.1.
3.3.2 Kelly’s Total Synthesis of Cribrostatin 6
Kelly and coworkers had also become interested in cribrostatin 6 (3.1), and
recently published their efforts toward the natural product.104 Although their overall approach to 3.1 was very different from Nakahara’s, they also began their endeavors with commercially available 2-methylresorcinol (3.111) (Scheme 3.27). Following in the footsteps of his Japanese predecessors, Kelly converted 3.111 into phenol 3.112, yet in only two steps and with a slightly improved overall yield. Bromination of 3.112 and TIPS protection of the phenol afforded 3.119 in 74% yield. This bromide was coupled to stannane 3.120, which was freshly prepared in two steps from 2-methylimidazole, using palladium tetrakis(triphenylphosphine) to give biaryl intermediate 3.121 in 89% yield. With two of the three rings of the natural product in place, Kelly now faced the challenge of constructing the isoquinolinedione. Selective bromination of the more electron-rich arene subunit of 3.121 and a second palladium-mediated cross-coupling reaction with allyltributyltin provided 3.122 in 73% yield. After switching the imidazole protecting group from SEM to a Boc group, the skeleton of the natural product was finally within sight. Oxidative cleavage of the allyl group of 3.123 with a large excess of periodate fortuitously also facilitated cleavage of the Boc group as well as cyclization to 174 hemiaminal 3.124 in 66% yield. Dehydration of 3.124 with help of mesyl chloride, deprotection of the silyl group, and a final dealkylation/air oxidation completed the total synthesis of cribrostatin 6 (3.1). The last step of the synthesis was adapted from Nakahara’s work (cf. Scheme 3.26), although the yield was improved to 45% by use of more concentrated nitric acid.
Scheme 3.27
OH OEt OEt 1. Et SO ,K CO 1. C H O •Br ,K CO Me 2 4 2 3 Me 4 8 2 2 2 3 Me acetone, 65 °C CH2Cl2, 78 °C
HO 2. H2O2,H3PO4 EtO 2. NaH, TIPSCl, THF EtO Br CH CO H 0°C rt 2-methylresocinol (3.111) 3 2 OH OTIPS 39% 3.112 74% 3.119
SEM Bu Sn 3 N OEt OEt Me 1. C H O •Br , TFA 3.120 Me 4 6 2 2 Me N SEM Et2O, 0 °C SEM
Pd(PPh3)4 N 2. allyltributyltin, Pd(PPh ) N EtO Me 3 4 EtO Me 1,4-dioxane, 105 °C DMF, 110 °C TIPSO N TIPSO N 89% 3.121 73% 3.122
OEt OEt Me OsO ,NaIO ,H O Me OH 1. TFA Boc 4 4 2 2. NEt ,Boc O N t-BuOH, THF N 3 2 EtO Me EtO Me DMAP, CH2Cl2 TIPSO N 66% TIPSO N 80% 3.123 3.124
OEt O Me Me 1. NEt3,MsCl,CH2Cl2,0°C 14 M HNO3 N N 2.TBAF,THF,0°C EtO Me 0°C EtO Me O N 72% OH N 45% 3.125 cribrostatin 6 (3.1) Kelly and coworkers thus accomplished a total synthesis of cribrostatin 6 (3.1) in 13 linear steps (15 steps total) and 3.10% yield. The key steps were two palladium-
175 catalyzed Stille couplings as well as a one-pot oxidative cleavage/Boc- deprotection/hemiaminal formation to furnish 3.124. Although biaryl intermediate 3.121 was synthesized in only five steps, the assembly of isoquinolinedione of the natural product was lengthy and required eight additional steps. One of the greatest disadvantages of this synthesis was that the two cross-coupling reactions employed unappealing toxic stannanes in the presence of palladium catalysts. Furthermore, Stille couplings of arylhalides with stannanes are well known and have been exhaustively reported in the literature.165 Lastly, the protecting group switch from SEM to Boc was also unattractive as the latter was immediately removed in the subsequent step. Overall this synthesis was far from ideal in that it was lengthy, involved toxic tin reagents, and failed to develop any new chemistry. A careful analysis of the previous syntheses of cribrostatin 6 (3.1) revealed that there was still much room for developing a more novel, more concise, and higher yielding approach to the natural product. Furthermore, an approach that would be readily amendable to the construction of analogs of 3.1 would be of significant value. As demonstrated by Nakahara’s and Kelly’s work toward this target, the key to an improved synthesis would lie in the succinct assembly of the tricyclic skeleton of the natural product.
3.4 TOTAL SYNTHESIS OF CRIBROSTATIN 6
3.4.1 Retrosynthesis
Our retrosynthesis of cribrostatin 6 (3.1) emphasized convergence as well as a
rapid buildup of complexity.166 We envisioned the natural product to arise from intermediate 3.3, which contained all of the heavy atoms present in cribrostatin 6 (3.1)
176 (Scheme 3.28). In the key step, intermediate 3.3 was proposed to undergo a thermal 4π- electrocyclic ring opening to enynylketene 3.127, which was envisioned to cyclize to diradical intermediate 3.126. Subsequently, the more reactive aryl radical would then be poised to undergo a regioselective intramolecular homolytic aromatic substitution reaction with the pendant imidazole ring to assemble 3.2, the tricyclic core of cribrostatin
6 (3.1).167 Dehydrogenation and oxidation of hydroquinone 3.2 would complete the synthesis of 3.1. The key intermediate 3.3 was envisioned as being derived from 3- ethoxy-4-methylcyclobutene-1,2-dione (3.4)146 and commercially available 3-butyn-1-ol (3.5) and 2-methylimidazole (3.6). To the best of our knowledge there are only two accounts by Moore and coworkers to ever have utilized diradical intermediates similar to 3.126 in subsequent homolytic aromatic substitution reactions (cf. Schemes 3.21–3.25). Our efforts in this area would further expand the utility of this chemistry and elegantly apply it to a total synthesis.
177 Scheme 3.28
O O OH radical cyclization Me Me Me Me N N N EtO Me EtO Me EtO N O N OH N OH 3.2 homolytic aromatic cribrostatin 6 (3.1) substitution 3.126
O Me O Me 1,2-addition
EtO N Me EtO OH OH N N alkylation 3.127 Me 3.3 N
Me O H N + + Me EtO O HO N 3.4 3.5 3.6
3.4.2 Synthesis of Cribrostatin 6
We began our synthetic efforts toward cribrostatin 6 (3.1) by synthesizing the required squarate 3.4 (Scheme 3.29). Following a literature procedure, squaric acid (3.128) was converted to diethyl squarate 3.129,168 which is also commercially available. Squarate ester 3.129 was then treated sequentially with MeLi and TFAA to obtain known
3.4 in 60% yield.146
Scheme 3.28
178 Turning our attention to the linear forward synthesis of cribrostatin 6 (3.1), alcohol 3.5 was transformed into tosylate 3.130 in 95% yield by slight modification of the literature procedure (Scheme 3.30).169 Attempts to generate alkyne 3.132 from a reaction between 3.130 and the anion derived from 2-methylimidazole (3.6) proved futile.170 In order to utilize an alternative electrophile, tosylate 3.130 was also converted to the corresponding bromide 3.131. It is worth noting that if this bromide should prove useful, it can be synthesized directly from alcohol 3.5 via a known literature procedure.171 Unfortunately, all attempts at generating alkyne 3.132 from 3.131 were also unsuccessful.
Scheme 3.30
Presuming that the acetylenic proton might quench the anion of 2- methylimidazole and thereby reduce the nucleophilicity of our nucleophile (cf. Scheme 3.30), we decided to synthesize known TMS-protected alkyne 3.133 (Scheme 3.31).172 Since a number of alkylations of imidazoles in the literature employ alkyl halides,173 we also converted tosylate 3.133 to the corresponding bromide 3.134.
Scheme 3.31
Both alkynes 3.134 and 3.133 were subjected to alkylations with the anion derived from imidazole 3.6. Gratifyingly, when tosylate 3.133 was used as the alkylating agent, 3.135 was obtained, albeit in 14% yield (Scheme 3.32). 179 Scheme 3.32
1. NaH, THF, rt
2. TMS TMS H Br N Me 3.134 N N Me N 3.6 1. NaH, DMF, rt 3.135 2. TMS OTs 3.133 rt 80 °C 14% Having demonstrated the feasibility of the alkylation, but also the need for a protecting group at the acetylenic position, we thought it might be feasible to carry out the alkylation in the absence of any additional base. We were delighted to find that 3.132 can be accessed when an excess (five equivalents) of 2-methylimidazole (3.6) is reacted bromide 3.131 at 100 ºC in DMF overnight (Scheme 3.33).
Scheme 3.33
The alkylation reaction was eventually further optimized using tosylate 3.130,
which could be prepared in a shorter sequence than the corresponding bromide 3.131 (cf. Scheme 3.30). Reacting an excess (five equivalents) of imidazole 3.6 with tosylate 3.130 in acetonitrile at 70 ºC overnight gave alkyne 3.132 in 92% yield (Scheme 3.34). Alkyne 3.132 was coupled with squarate 3.4 to afford key intermediate 3.3 in 62% yield.
180 Scheme 3.34
Me O H N 3.130 OTs n-BuLi, THF, -78 °C Me EtO OH N CH3CN, 70 °C then N Me O N 3.6 92% Me Me N N EtO O 3.132 3.3 3.4 78 °C 0°C
62% With ample amounts of key intermediate 3.3 in hand, the stage was set to investigate the key cyclization step. In the event, 3.124 was heated in PhCl (0.02 M) to give exclusively hydroquinone 3.137 based on 1H NMR analysis of the crude reaction mixture (Scheme 3.35). Isolation of 3.137, however, was impeded due to its lability toward oxidation. Consequently, when the reaction was heated under identical conditions and then stirred open to air overnight, quinone 3.136 was isolated as the sole product of the reaction in about 25% yield (unoptimized). This result suggests formation of diradical intermediate 3.122 (cf. Scheme 3.28), but instead of a subsequent cyclization to the desired tricycle 3.121, intermolecular hydrogen atom abstraction delivered hydroquinone 3.137. A similar phenomenon was also observed by Moore and coworkers (cf. Scheme 3.16 and 3.22).
181 Scheme 3.35
Me O Me N ,30 min O PhCl (0.02 M) Me N EtO OH then N open to air, rt EtO Me O N ca. 25% 3.3 3.136
Me OH N Me N air
EtO OH 3.137 Further experimentation revealed that concentration and choice of solvent played a very important role in the key step. Upon screening various conditions, it was found
that heating 3.3 in CH3CN (0.001 M) gave a favorable mixture (8:1) of tricycle 3.138 (3.2/3.140/3.1) to bicycle 3.139 (3.137/3.136) (Scheme 3.36). At a higher concentration
in CH3CN (0.01 M), the ratio of 3.138 to 3.139 dropped significantly to 1:1. Similarly, all other solvents screened failed to give a better ratio favoring the desired product 3.138.
Scheme 3.36
Me O H H O O solvent Me Me EtO OH Me 120 ° Ca,30min N N N EtO Me EtO Me O N O N N H H 3.3 solvent (conc.) 3.138:3.139 3.138 3.139
CH3CN (0.001M) 8:1 CH3CN (0.01M) 1:1 PhOMe (0.001M) 4:1 DMF (0.001M) 1.3:1 1,2-DCE (0.001M) 1:1 PhCl (0.001M) 1:3 a Temperature of oil bath Having established that acetonitrile was the best solvent, we found that heating
3.3 in CH3CN (0.001 M) gave hydroquinone 3.2, which like 3.137 (cf. Scheme 3.35) was 182 oxidatively unstable (Scheme 3.37). Thus, heating 3.3 under reflux and then stirring the reaction mixture open to air overnight gave a mixture (2:1) of 3.140 and 3.1 in 24% yield. Encouraged by these promising results, attempts were made to obtain 3.1 exclusively. However, stirring hydroquinone 3.2 open to air for multiple days, again only gave a mixture (1:2 at best) of 3.140 and 3.1. On the other hand, we discovered that subjecting the mixture of 3.140 and 3.1 to dehydrogenation by heating with Pd/C in anisole174 gave the desired target 3.1 in 69% yield.175
Scheme 3.37
More direct entries to the natural product were subsequently developed. Initially it was found that hydroquinone 3.2 could be directly oxidized to the natural product with
Pd/C in anisole in 21% yield over two steps (not shown). Later, a better and more practical and facile one-pot protocol was developed. Namely, after converting 3.3 to 3.2, the majority of the solvent was evaporated, Pd/C was added, and the reaction was heated at 80 ºC for four hours to give cribrostatin 6 (3.1) in 26% overall yield (Scheme 3.38).
183 Scheme 3.38
In summary, we have accomplished a concise and elegant total synthesis of cribrostatin 6 (3.1) (Scheme 3.39). The natural product was synthesized protecting group- free in 14.1% overall yield and required only four steps in the longest linear sequence and five total steps from commercially available starting materials. In the key step, readily accessible squarate 3.3 underwent a tandem 4π-electrocyclic ring opening, radical cyclization, and homolytic aromatic substitution sequence to afford the tricyclic core of the target molecule (cf. Scheme 3.28), which was directly oxidized to the natural product in one pot. Owing to the rapid buildup of complexity, we have successfully developed a concise, convergent, and modular approach to cribrostatin 6 (3.1).
Scheme 3.39
H N Me n-BuLi, THF, 78 0°C N 3.6 N OH then OTs CH3CN, 70 °C Me 3.5p-TsCl, THF, 0 °C rt 3.130 N 92% 95% 3.132
Me O O Me n-BuLi,THF,-78°C CH3CN EtO OH then then N N EtO Me Me O Me Pd/C, 80 °C O N N 26% cribrostatin 6 (3.1) EtO O 3.3 3.4 78 °C 0°C 62% 184 3.4.3 Synthesis of Cribrostatin 6 Analogs
Due to the concise nature of our approach to cribrostatin 6 (3.1) the synthesis of analogs of the natural product became particularly interesting. It can be envisioned that simple modifications of the starting material would give rapid access to a number of cribrostatin 6 analogs (Scheme 3.40). More specifically, we envisioned that the alkylated
imidazole 3.141 could be readily modified by varying R1 or the aromatic ring itself. Even easier would be modifying squarate 3.142 since a large number of squarates are known in the literature.
Scheme 3.40
In order to establish the feasibility of synthesizing analogs of cribrostatin 6 (3.1) via our established route, we pursued the synthesis of cribrostatin 6 analog 3.147 (cf. Scheme 3.42). Diethyl squarate (3.129), which was already in hand from the synthesis of squarate 3.125 (cf. Scheme 3.29), was coupled with 3.132 to afford cyclobutenol 3.145
(Scheme 3.41). Heating 3.145 under reflux in CH3CN (0.001 M) for 35 min or 24 h failed to give any of the desired hydroquinone 3.146, and only unreacted starting material was obtained quantitatively.
185 Scheme 3.41
EtO O
n-BuLi, THF, 78 °C N EtO OH Me then N N EtO O Me N 3.132 3.129 3.145 EtO O 78 °C 0°C
49%
OH EtO ,CH3CN N 35 min or 24 h EtO Me only rsm OH N 3.146
It was thought that the boiling point of CH3CN might be below the temperature required to have the cyclobutenone undergo an electrocyclic ring opening reaction. Thus, the higher-boiling solvent anisole was employed in the reaction to probe this theory. Gratifyingly, the synthesis of 3.147 was accomplished by heating 3.145 in anisole (0.001 M) for 35 min, evaporating the majority of the solvent, and heating the resulting solution with Pd/C (Scheme 3.42). After purification, cribrostatin 6 analog 3.147 was obtained in 18% yield from 3.145.
Scheme 3.42
Similar to the synthesis of the natural product, we also synthesized analog 3.151 (Scheme 3.43). One-pot conversion of dimethyl squarate (3.148) to 3.20 proceeded in quantitative yield. Addition of alkynyllithium 3.149 gave cyclobutenol 3.150, which was 186 subjected to the key reaction sequence to provide the desired analog in 25% yield. Much to our surprise we also identified a small quantity of a side product that had not been previously observed. After purification and characterization of this material, we confirmed that we had obtained 7% of compound 3.152. The reason this material was formed in this reaction but not in any of the others is unknown and remains to be determined. Nevertheless, 3.152 is an interesting compound as it is a derivative of
145 cribrostatin 1, a member of the cribrostatin family that contains an NH2 group instead of the OMe group.
Scheme 3.43
Me N 3.149 N MeO O Me O MeLi, THF, 78 °C Li
then THF, 78 0°C MeO O TFAA MeO O 3.148quant 3.20 39%
Me O O O Me Me Me ,CH3CN N + MeO N N N OH then MeO Me MeO Pd/C, 3.150 O N O 3.151 3.152 25% 7% Since we have no evidence for how compound 3.152 might have formed in the reaction, we can only venture to guess about its origin. We propose that if diradical intermediate 3.153 undergoes a radical cyclization onto the more hindered C2-carbon of the imidazole and is subsequently quenched by a proton at C5 of the imidazole, an intermediate like 3.154 would be formed (Scheme 3.44). This intermediate could undergo a retro-[3+2] cycloaddition to reveal hydroquinone 3.156 and ethenamine (3.155). After
187 addition of Pd/C, oxidation to the quinone and dehydrogenation would deliver the observed side product 3.152.
Scheme 3.44
Me O O OH Me Me R Me N H MeO OH N N 5 N CH3CN MeO 2 MeO Me Me 3.150 HO N 4 HO N
3.153 3.154
OH O Me Me Pd/C, + H2N N N MeO MeO 3.155 7% OH O 3.156 3.152 In order to synthesize a cribrostatin 6 analog in which the reduction potential of the quinone is significantly different, we were interested in 3.158 (Scheme 3.45). To this end, the requisite squarate 3.41 was synthesized in two steps from dimethyl squarate (3.148) in 48% yield. Coupling 3.41 with alkynyllithium 3.149 followed by thermolysis and oxidation provided analog 3.158. It is worth noting that no effort was made to further optimize any steps of this reaction sequence as it supplied enough of the analog to evaluate its biological activity (vide infra).
188 Scheme 3.45
In addition to varying the starting materials for our synthesis of cribrostatin 6 (3.1), we also decided that it would be feasible to modify the natural product itself. After
several failed attempts, which are discussed below, we discovered that BBr3 did unmask the methoxy group in 3.151 to give a hydroxyl group (Scheme 3.46). Although the 1H NMR spectrum of the crude reaction mixture looked promising, we were only able to isolate the desired analog 3.159 in 7% yield (unoptimized).
Scheme 3.46
Arguably one of the greatest discoveries toward synthesizing analogs of cribrostatin 6 (3.1) was made when we began to look at addition/elimination sequences to alter the methoxy group in the natural product. Much to our delight, we discovered that treating cribrostatin 6 (3.1) with methylamine indeed delivered the analog 3.160 in 66% yield (Scheme 3.47). We were particularly excited about this result as this
189 addition/elimination approach should allow us to synthesize a wide range of analogs from cribrostatin 6 (3.1) itself by simply varying the amine or employing alcohols and thiols.
Scheme 3.47
3.4.4 Biological Activity of the Cribrostatin 6 Analogs
In order to evaluate the biological activity of several cribrostatin 6 analogs we began several collaborations. To study the possible antifungal activity of cribrostatin 6 (3.1), we began working with Professor Nathan Wiederhold at The University of Texas at San Antonio. In order to evaluate the antineoplastic activity of cribrostatin 6 (3.1) and its analogs, we began collaborating with Professor Paul Hergenrother at the University of Illinois Urbana-Champaign. Professor Wiederhold at UTSA found that cribrostatin 6 (3.1) did not display any promising antifungal activity. A synthetic sample of 3.1 was tested against four Candida isolates (C. albicans (ATCC 90028), C. krusei (ATCC 6258), C. parapsilosis (ATCC 22019), C. glabrata (ATCC 2001)) and three Aspergillus isolates (A. fumigatus (293), A. terreus (05-311), A. flavus (05-135)) over a concentration range of 0.03 – 16 μg/mL. Nearly all of the activities were greater than 16 μg/mL. Although the minimum inhibitory concentration (MIC) against CG 2001 was approximately 8 μg/mL, this value does not compare favorably to two commonly used antifungal medications, voriconazole and amphotericin B, which were evaluated simultaneously by Professor Wiederhold and had
190 MIC’s between 0.125 and 0.5 μg/mL. As a result, no cribrostatin 6 analogs were deemed worthwhile to be tested for their antifungal activities. The anticancer activity of cribrostatin 6 and its analogs was evaluated by Mirth Hoyt, a graduate researcher in Professor Hergenrother’s group. Cribrostatin 6 (3.1) and seven of our analogs were tested against two different cancer cell lines (U-937 and HL- 60) (Table 3.1). For the U-937 cell line, we were pleased to find that the diethoxy analogs 3.147 displayed nearly identical activity as the naturally occurring 3.1. This was exciting as the synthesis of analog 3.147 required one step less when compared to that of cribrostatin 6 (3.1). Overall, derivatives with more electron donating groups on the quinone such as 3.159 and 3.160 seemed to display a significant decrease in activity when compared to 3.1. Furthermore, extending the methyl group on the quinone of 3.1 to a greasier n-butyl chain as in 3.161 also had a negative impact on the biological activity.176 Lastly, it was found that the unexpected side product 3.152 did not display any promising activity.
191 Table 3.1
O O O O Me EtO n-Bu Me
N N N N EtO Me EtO Me EtO Me MeO Me O N O N O N O N cribrostatin 6 (3.1) 3.147 3.161 3.151
O O O O Me Me Me Me
N Me N N N HO Me N Me Me Me MeO H O N O N O N O 3.159 3.160 3.158 3.152
U-937 HL-60 Compound IC50 (µM) IC50 (µM) 3.1 5 ± 1 0.3 ± 0.05 3.147 4 ± 1 3.3 ± 0.5 3.161 12 ± 5 4.7 ± 0.3 3.151 6 ± 2 1.9 ± 0.6 3.159 63 ± 5 >100 3.160 12 ± 2 6.3 ± 0.5 3.158 9 ± 1 2.5 ± 0.8 3.152 48 ± 1 14.0 ± 3
We believe it would be interesting to study the effects of varying the redox potential of the quinone in cribrostatin 6 (3.1) in more detail. Based on the data presented in Table 3.1 it would seem particularly promising to synthesize analogs containing more electron deficient quinones. Efforts toward this end are currently ongoing in our laboratory.
3.4.5 Failed Preliminary Attempts at Synthesizing Cribrostatin 6 Analogs
Although we had success in synthesizing several cribrostatin 6 analogs, we also encountered a few disappointments that will be discussed, although only limited efforts were made toward optimizing any of these reactions.
192 Much to our surprise it was quite a challenge to remove the ethyl group of the ethoxy group in cribrostatin 6 (3.1) (Scheme 3.48). Using water in an addition/elimination approach, we only recovered unreacted starting material. With 1 M KOH and 2 M HCl, we had no success in isolating the desired vinylogous acid. Under acidic conditions the imidazole appeared to protonate very readily and was difficult to isolate on the scale that we were working on. Although a more careful investigation of these reaction conditions might prove successful, further efforts were abandoned since
BBr3 provided us with quantities of the desired 3.159 (cf. Scheme 3.46).
Scheme 3.48
Treating cribrostatin 6 (3.1) with 2 M ammonia was expected to produce the vinylogous amide 3.162 (Scheme 3.49); however, we only obtained unreacted starting material.
Scheme 3.49
Treating cribrostatin 6 (3.1) with dimethylamine gave a messy mixture of several unidentified products instead of the desired 3.163 (Scheme 3.50).
193 Scheme 3.50
Benzylamine also failed to give any of the desired addition/elimination product (Scheme 3.51). Again a complex mixture of unidentified products was obtained that did not appear to contain any 3.164.
Scheme 3.51
O O Me Me BnNH2,rt N N MeO Me EtOH, 2 h BnHN Me O N O N 3.151 3.164 We had been interested in synthesizing one additional cribrostatin 6 derivative with an amino group attached to the quinone, and we were prepared to do so even if it would require a slightly more involved route (Scheme 3.52). Accordingly, squarate 3.20 was treated with dimethylamine to furnish the squarate 3.165, albeit in 20% yield. Addition of alkynyllithium derivative 3.149 to 3.165 provided cyclobutenol 3.166, which cleanly returned unreacted starting material when subjected to thermolysis in acetonitrile. The higher-boiling solvent anisole was also examined (cf. Scheme 3.42), but none of the desired quinone 3.163 was observed in the messy 1H NMR spectrum of the crude reaction mixture. Unfortunately, we were unable to identify any of the side products.
194 Scheme 3.52
The addition/elimination sequence toward synthesizing cribrostatin 6 analogs also failed when ethanethiol was used (Scheme 3.53). At room temperature, only unreacted starting material was recovered, while heating the mixture under reflux only provided a mixture of unidentifiable decomposition products.
Scheme 3.53
Although we have encountered several challenges in synthesizing derivatives of cribrostatin 6 (3.1), many of these reactions were attempted only once and still hold some promise based on the positive results that we did obtain. Further studies are required in order to establish which of these routes are feasible.
195 3.5 CONCLUSION
We have thus developed a four step, protecting group-free, total synthesis of cribrostatin 6 (3.1). The natural product was assembled from a readily accessible squarate via a tandem 4π-electrocyclic ring opening, radical cyclization, homolytic aromatic substitution, oxidation and dehydrogenation. Owing to the concise nature of our route and the rapid buildup of complexity, this chemistry was readily extended to the rapid construction of a several analogs of cribrostatin 6. Although cribrostatin 6 (3.1) did not display any antifungal activity, preliminary assays of 3.1 and its analogs against cancer cell lines (U-937 and HL-60) indicated that derivatives of 3.1 with electron-deficient quinones might turn out to be promising anticancer drugs. Efforts toward synthesizing those and other cribrostatin 6 analogs are currently underway in our laboratories.
196 Chapter 4: Experimental Section
General Methods. Solvents and reagents were reagent grade and used without
purification unless otherwise specified. CH2Cl2, benzene and Et3N were freshly distilled
from CaH2. THF and Et2O were passed through two columns of neutral alumina. Toluene was passed through one column of neutral alumina and one column of Q5 reactant.
CH3CN and DMF were passed through two columns of molecular sieves. Reactions involving air- or moisture-sensitive reagents or intermediates were performed under an inert atmosphere of argon or nitrogen in glassware that had been oven dried. Reaction temperatures refer to bath temperatures. Melting points are uncorrected. Infrared (IR) spectra were recorded neat on sodium chloride plates and are reported in wave numbers (cm-1). HPLC was conducted using a Waters Corp. Prep LC4000 system having a photodiode array detector. A binary solvent system (92% hexanes and 8% 2-propanol) and a Chiralcel OJ-H column (cellulose tris-(4-methylbenzoate) on a 5 μm silica-gel substrate), 4.6 mm diameter × 250 mm (flow rate of 1 mL/min) were used for determining enantiomeric ratios. The microwave reactions were performed using CEM Discovery System, measuring temperatures with the built-in infrared thermometer that surrounds the reaction vessel. The reaction temperature refers to the temperature of the
1 13 bath. H and C NMR spectra were obtained as solutions in CDCl3 unless otherwise
noted, and chemical shifts are reported in parts per million (ppm) in reference to CDCl3 (7.24 ppm and 77.0 ppm, respectively). Coupling constants are reported in hertz (Hz). Spectral splitting patterns are designated as follows: s, singlet; d, doublet; t, triplet; q, quartet; app, apparent; br, broad; m, multiplet; comp, overlapping multiplets of non- magnetically equivalent protons. All products that were used without further purification were >95% pure by 1H NMR spectroscopy.
197 4.1 First Enantioselective Oxidative Rearrangement of Indoles to Spirooxindoles
9 6 10 5 8 7 O 17 11 4 3 12 13 N 2 O 16 18 14 15 O 19
1.8 1-(1,1-Dimethyl-3,4-dihydrospiro[carbazole-2,2’-[1,3]dioxolane]-9(1H)-yl)- ethanone (1.8) (dik 1-293). NaH (58 mg, 1.45 mmol, 60% dispersion in mineral oil) was
added to a solution of 1.95 (56 mg, 0.22 mmol) in DMF (5 mL) at 0 °C. The mixture was stirred for 15 min, whereupon acetyl chloride (0.17 mL, 2.41 mmol) was added. The ice bath was removed, and the reaction was stirred at room temperature for 1 h. After heating at 50 ºC for 45 min, the reaction was cooled to room temperature. Saturated aqueous
NH4Cl (2 mL) was added, and the mixture was extracted with Et2O (3 × 20 mL). The
combined organic extracts were dried (Na2SO4) and concentrated under reduced
pressure. The residue was purified by flash chromatography eluting with Et2O/pentane 1 (1:3) to give 23 mg (35%) of 1.8 as a clear oil; H NMR (500 MHz, CDCl3) δ 7.47-7.45
(m, 1 H), 7.41-7.38 (m, 1 H) 7.23-7.19 (m, 1 H), 7.18 (app t, J = 1.0 Hz, 1 H), 4.05-3.99 (comp, 4 H), 2.78 (s, 3 H), 2.77 (t, J = 6.5 Hz, 2 H), 2.07 (t, J = 6.5 Hz, 2 H), 1.45 (s, 6
H); 13C NMR (125 MHz) δ 171.6, 142.6, 136.2, 129.3, 123.6, 122.2, 118.8, 116.5, 113.5, 113.0, 65.3, 43.3, 27.8, 26.0, 21.8, 19.0; IR (neat) 2883, 1713, 1458, 1365, 1295, 1091, -1 + 919, 743 cm ; mass spectrum (CI) m/z 299.1518 [C18H21NO3 (M ) requires 299.1521],
328, 300 (base), 258, 238. 1 NMR Assignments. H NMR (500 MHz, CDCl3) δ 7.47-7.45 (m, 1 H, C9-H or C12-H),
7.41-7.38 (m, 1 H, C9-H or C12-H) 7.23-7.19 (m, 1 H, C10-H or C11-H), 7.18 (app t, J = 1.0 Hz, 1 H, C10-H or C11-H), 4.05-3.99 (comp, 4 H, C16-H & C17-H), 2.78 (s, 3 H, 198 C19-H), 2.77 (t, J = 6.5 Hz, 2 H, C6-H), 2.07 (t, J = 6.5 Hz, 2 H, C5-H), 1.45 (s, 6 H,
C14-H & C15-H); 13C NMR (125 MHz) δ 171.6 (C18), 142.6 (C2 or C8 or C13), 136.2 (C2 or C8 or C13), 129.3 (C2 or C8 or C13), 123.6 (C10 or C11), 122.2 (C10 or C11), 118.8 (C9 or C12), 116.5 (C4), 113.5 (C7), 113.0 (C9 or C12), 65.3 (C16 & C17), 43.3 (C3), 27.8 (C19), 26.0 (C5), 21.8 (C14 & C15), 19.0 (C6).
16 17 O 15 O 14 6 5 7 9 4 8 10 3 O 11 2 13 N 12 18 19 O
racemic 1.7
(±)-Spirooxindole 1.7 (dik1-270/271). A solution of DMDO (1.8 mL, 0.08 M, 0.14 mmol) in acetone was added to a solution of 1.8 (17 mg, 0.06 mmol) in acetone (1.5 mL) at 0 ºC. After 75 min at 0 ºC, the solvent was removed under reduced pressure, and the residue was dissolved in CH2Cl2 (2.5 mL). SiO2 (150 mg) was added, and the mixture was stirred for 3.5 h at room temperature. The reaction was filtered through Celite, and the solvent was removed under reduced pressure to give 12 mg (67%) 1.7 as a white 1 solid: mp 124-126 °C; H NMR (500 MHz, CDCl3) δ 8.18-8.20 (m, 1 H), 7.54-7.50 (m, 1
H) 7.27-7.22 (m, 1 H), 7.17-7.13 (m, 1 H), 4.02-3.88 (comp, 4 H), 2.62 (s, 3 H), 2.33-
2.28 (comp, 2 H), 2.08-2.02 (comp, 2 H), 1.09 (s, 3 H), 0.65 (s, 3 H); 13C NMR (125
MHz, CDCl3) δ 181.3, 170.6, 139.6, 132.3, 127.9, 125.9, 124.4, 119.0, 115.6, 65.3, 64.8, 59.3, 51.2, 33.8, 31.1, 26.5, 23.0, 20.7; IR (neat) 2947, 2360, 1753, 1707, 1464, 1278,
-1 1149, 1077 cm ; mass spectrum (CI) m/z 316.1552 [C18H22NO4 (M+1) requires 316.1549], 274, 316 (base).
199 1 NMR Assignments. H NMR (500 MHz, CDCl3) δ 8.18-8.20 (m, 1 H, C9-H or C12-H),
7.54-7.50 (m, 1 H, C9-H or C12-H) 7.27-7.22 (m, 1 H, C10-H or C11-H), 7.17-7.13 (m, 1 H, C10-H or C11-H), 4.02-3.88 (comp, 4 H, C16-H & C17-H), 2.62 (s, 3 H, C19-H), 2.33-2.28 (comp, 2 H, C4-H or C5-H), 2.08-2.02 (comp, 2 H, C4-H or C5-H), 1.09 (s, 3
13 H, C14-H or C15-H), 0.65 (s, 3 H, C14-H or C15-H) ; C NMR (125 MHz, CDCl3) δ 181.3 (C2), 170.6 (C18), 139.6 (ArC), 132.3 (ArC), 127.9 (C10 or C11), 125.9 (C9 or C12), 124.4 (C10 or C11), 119.0 (C6), 115.6 (C9 or C12), 65.3 (C16 or C17), 64.8 (C16 or C17), 59.3 (C3), 51.2 (C7), 33.8 (C4 or C5), 31.1 (C4 or C5), 26.5 (C19), 23.0 (C14 or C15), 20.7 (C14 or C15).
16 17 O 15 O 14 6 5 7 9 4 8 10 3 O 11 2 13 N 12 H
racemic 1.96 (±)-2,2-Dimethyldispiro[[1,3]dioxolane-2’,3-cyclopentane-1,3”-indolin]-2”- one (1.96) (dik2-20). NaOH (0.38 mL, 1 M, 0.02 mmol) was added to a solution of 1.7 in EtOH (1.5 mL). The reaction was stirred at room temperature for 1 h, whereupon it was
poured into H2O (10 mL). The mixture was extracted with Et2O (3 × 10 mL), and the
combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to give 4.6 mg (98%) of 1.96 as a white solid: mp 198-200 °C; 1H NMR (500 MHz,
CDCl3) δ 7.56 (d, J = 7.6 Hz, 1 H, ), 7.13 (dt, J = 7.6, 1.1 Hz, 1 H), 7.06 (br s, 1 H), 6.97 (dt, J = 7.6, 1.1 Hz, 1 H), 6.75 (d, J = 1.1 Hz, 1 H), 4.02-3.88 (comp, 4 H), 2.34-2.55 (comp, 2 H), 2.08-1.94 (comp, 2 H), 1.18 (s, 3 H), 0.66 (s, 3 H); 13C NMR (125 MHz,
CDCl3) δ 181.9, 140.3, 134.5, 127.3, 126.9, 121.7, 119.4, 108.6, 65.1, 64.8, 59.3, 50.1, 200 34.0, 30.8, 23.0, 20.2; IR (neat) 3263, 2946, 2857, 1704, 1618, 1471, 1329, 1223, 1147,
-1 1071 cm ; mass spectrum (CI) m/z 274.1447 [C16H20NO3 (M+) requires 274.1443], 274 (base), 230.
1 NMR Assignments. H NMR (500 MHz, CDCl3) δ 7.56 (d, J = 7.6 Hz, 1 H, C9-H or C12-H), 7.13 (dt, J = 7.6, 1.1 Hz, 1 H, C10-H or C11-H), 7.06 (br s, 1 H, NH), 6.97 (dt, J = 7.6, 1.1 Hz, 1 H, C10-H or C11-H), 6.75 (d, J = 1.1 Hz, 1 H, C9-H or C12-H), 4.02- 3.88 (comp, 4 H, C16-H & C17-H), 2.34-2.55 (comp, 2 H, C4-H or C5-H), 2.08-1.94 (comp, 2 H, C4-H or C5-H), 1.18 (s, 3 H, C14-H or C15-H), 0.66 (s, 3 H, C14-H or C15-
13 H); C NMR (125 MHz, CDCl3) δ 181.9 (C2), 140.3 (ArC), 134.5 (ArC), 127.3 (C9 or C10 or C11 or C12), 126.9 (C9 or C10 or C11 or C12), 121.7 (C9 or C10 or C11 or C12), 119.4 (C6), 108.6 (C9 or C12), 65.1 (C16 or C17), 64.8 (C16 or C17), 59.3 (C3), 50.1 (C7), 34.0 (C4 or C5), 30.8 (C4 or C5), 23.0 (C14 or C15), 20.2 (C14 or C15).
(1S)-2,2-Dimethyldispiro[[1,3]dioxolane-2’,3-cyclopentane-1,3”-indolin]-2”- one (1.96) (dik2-52/53). Chiral ketone 1.68 (11 mg, 0.03 mmol) was added to a solution
of 1.8 (32 mg, 0.11 mmol), Na2B4O7⋅10H2O (20 mg, 0.05 mmol), and Bu4NHSO4 (2 mg, -4 0.004 mmol) in DMM (1 mL), CH3CN (2 mL) and 4 × 10 M aqueous EDTA (0.53 mL) at 0 ºC (cold bath temperature). A solution of oxone (91 mg, 0.15 mmol) in 4 × 10-4 M aqueous EDTA (1.3 mL) and a solution of K2CO3 (86 mg, 0.62 mmol) in H2O (1.3 mL)
were added simultaneously in 0.1 mL aliquots every 10 min over 2 h. H2O (7 mL) and pentane (7 mL) were added to the reaction. The layers were separated, and the aqueous 201 layer was extracted with pentane (2 × 15 mL). The combined organic extracts were dried
(Na2SO4) and concentrated under reduced pressure. The residue was dissolved in EtOH
(9.6 mL), and 1 N NaOH (2.4 mL) was added. The reaction was stirred at room
temperature for 2 h, whereupon H2O (15 ml) was added. The mixture was extracted with
Et2O (3 × 15 mL), and the combined organic extracts were washed with H2O (3 × 15
mL), dried (Na2SO4) and concentrated under reduced pressure to give 28 mg (77%, 74% ee) of 1.96 as a white solid. Spectral data were consistent with those reported for (±)- spirooxindole 1.96.
(1R)-2,2-Dimethyldispiro[[1,3]dioxolane-2’,3-cyclopentane-1,3”-indolin]-2”-
one (1.96) (dik2-26). K2CO3 (37 mg, 0.226 mmol) was added to a solution of spirooxindole 1.89b (40 mg, 0.075 mmol) in MeOH (1 mL). The mixture was stirred at
room temperature for 1 h, whereupon saturated aqueous NH4Cl (3 mL) was added. The mixture was extracted with EtOAc (3 × 15 mL), and the combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc (2.5:1) to give 17 mg (86%) of 1.96 as a white solid. Spectral data were consistent with those reported for (±)-spirooxindole 1.86.
202 4.2 Studies Toward the Total Synthesis of IB-00208
O
HO O 2.145
2,5-Dimethoxyphenol (2.145) (dik1-161). H2O2 (30% in H2O, 2.73 mL, 34.01 mmol) from a freshly opened bottle was added dropwise to a solution of 2,5- dimethoxybenzaldehyde (2.00 g, 12.035 mmol) in THF (30 mL). Concentrated H2SO4 (0.6 mL) was added dropwise, and the reaction was stirred for 2 h at room temperature and 1 h at 70 ºC. Upon cooling to room temperature, H2O (30 mL) was added and the reaction was neutralized with NaOH (1 M). The mixture was extracted with EtOAc (3 ×
50 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was distilled (bp = 91 ºC) via short path distillation under reduced pressure (0.1 mm Hg) to provide 1.31 g (70%) of 2.145 as a burnt orange oil. Spectral data were consistent with those reported in the literature.177
1,4-Dimethoxy-2-(methoxymethoxy)benzene (2.146) (dik1-197). NaH (3.35g, 83.52 mmol, 60% dispersion in mineral oil) was added to a solution of 2,5- dimethoxyphenol (9.21 g, 59.73 mmol) in DMF (60 mL) at 0 ºC. After 30 min at 0 ºC and 30 min at room temperature, MOMCl (6.35 mL, 83.52 mmol) was added dropwise,
and the reaction was stirred for 30 min at room temperature. Upon addition of H2O (200 203 mL), the mixture was extracted with Et2O (3 × 150 mL). The combined organic layers were washed with H2O (200 mL), dried (MgSO4), and concentrated under reduced pressure to provide 10.89 g (~100%) 2.146 as a yellow oil. Spectral data were consistent with those reported in the literature.178
O O
H
O O O 2.147 3,6-Dimethoxy-2-methoxymethoxybenzaldehyde (2.147) (dik1-198). A solution of n-BuLi (39.2 mL, 1.6 M, 62.72 mmol) in hexanes was added to a solution of 1,4-dimethoxy-2-methoxymethoxybenzene (10.884 g, 59.73 mmol) in THF (100 mL) at - 10 °C. After 30 min, DMF (6.94 mL, 89.60 mmol) was added. The cold bath was removed, and stirring was continued for 4 h at room temperature. Saturated aqueous
NH4Cl (40 mL) and Et2O (200 mL) were added, and the layers were separated. The organic phase was washed with H2O (3 × 100 mL) and dried (Na2SO4). The solvent was removed under reduced pressure, and the residue was purified by flash chromatography eluting with hexanes/EtOAc (1:1) to give 7.760 g (57%) of 2.147as a yellow oil. Spectral data were consistent with those reported in the literature.178
204 2-Hydroxy-3,6-dimethoxybenzaldehyde (2.148) (dik1-175). p-Toluenesulfonic acid monohydrate (86 mg, 0.47 mmol) was added to a solution of 3,6-dimethoxy-2-
methoxymethoxybenzaldehyde (948 mg, 4.19 mmol) in 1,4-dioxane/H2O (31 mL, 3:1).
The reaction was stirred for 19 h at 55 °C, whereupon H2O (30 mL) was added. The
solution was extracted with Et2O (3 × 30 mL). The combined organic layers were dried
(Na2SO4) and concentrated under reduced pressure to give 780 mg (~100%) of 2.148 as yellow crystals. Spectral data were consistent with those reported in the literature.178
2-(tert-Butyldimethylsilanyloxy)-3,6-dimethoxybenzaldehyde (2.149) (dik1- 192). NaH (158 mg, 3.95 mmol, 60% dispersion in mineral oil) was added to a solution of 2-hydroxy-3,6-dimethoxybenzaldehyde (576 mg, 3.16 mmol) in DMF (32 mL) at 0 °C. After 15 min at 0 °C, the ice bath was removed, and stirring was continued for 30 min at room temperature. The mixture was cooled to 0 °C, whereupon TBSCl (596 mg, 3.95 mmol) in DMF (1 mL) was added. After 30 min at 0 °C, the ice bath was removed and stirring continued for 2 h. H2O (20 mL) was added, and the mixture was extracted with
Et2O (3 × 25 mL). The combined organic phases were washed with H2O (2 × 20 mL) and
dried (MgSO4). The solvent was removed under reduced pressure, and the residue was purified by flash chromatography eluting with hexanes/EtOAc (2:1) to give 646 mg
1 (69%) of 2.149 as a yellow oil; H NMR (500 MHz, CDCl3) δ 10.49 (app d, J = 0.6 Hz, 1 H), 6.96 (d, J = 9.0 Hz, 1 H), 6.45 (d, J = 8.9 Hz, 1 H), 3.82 (s, 3 H), 3.75 (s, 3 H), 0.96
13 (s, 9 H), 0.18 (s, 6 H); C NMR (125 MHz, CDCl3) δ 190.0, 154.6, 149.1, 144.6, 118.1, 205 117.4, 103.1, 56.1, 55.7, 25.8, 18.19, -4.1; IR (neat) 2933, 2857, 2770, 1693, 1597, 1449,
-1 1283 cm ; mass spectrum (CI) m/z 297.1522 [C15H25O4Si (M+1) requires 297.1522], 297 (base), 281, 239.
1 NMR Assignments. H NMR (500 MHz, CDCl3) δ 10.49 (app d, J = 0.6 Hz, 1 H, C7-H), 6.96 (d, J = 9.0 Hz, 1 H, C5-H or C6-H), 6.45 (d, J = 8.9 Hz, 1 H, C5-H or C6-H), 3.82 (s, 3 H, C11-H or C12-H), 3.75 (s, 3 H, C11-H or C12-H), 0.96 (s, 9 H, C10-H), 0.18 (s,
13 6 H, C8-H); C NMR (125 MHz, CDCl3) δ 190.0 (C7), 154.6 (C1), 149.1 (C3 or C4), 144.6 (C3 or C4), 118.1 (C2), 117.4 (C5 or C6), 103.1 (C5 or C6), 56.1 (C11 or C12), 55.7 (C11 or C12), 25.8 (C10), 18.9 (C9), -4.1 (C8).
15 OH O 8 7 1 6 2 9 5 10 O 3 12 Si 4 O 13 14 11
2.150 1-[2-(tert-Butyldimethylsilanyloxy)-3,6-dimethoxyphenyl]-prop-2-yn-1-ol (2.150) (dik1-182). A solution of 2-(tert-butyldimethylsilanyloxy)-3,6- dimethoxybenzaldehyde (99 mg, 0.39 mmol) in THF (0.5 mL) was added dropwise to a solution of ethynyl magnesium bromide (1.17 mL, 0.5 M, 0.59 mmol) in THF at 0 °C. After 10 min at 0 °C, the ice bath was removed and stirring continued at room
temperature for 1 h. Saturated aqueous NH4Cl (0.5 mL) was added, and the mixture was added to H2O (10 mL). The layers were separated, and the aqueous layer was extracted with Et2O (3 × 7 mL). The combined organic phases were dried (Na2SO4) and concentrated under reduced pressure to give 94 mg (80%) of 2.150 as a pale yellow
1 powder: mp 110.5-111.5 °C; H NMR (500 MHz, CDCl3) δ 6.71 (d, J = 9.0 Hz, 1 H), 6.47 (d, J = 9.0 Hz, 1 H), 5.84 (dd, J = 11.6, 2.3 Hz, 1 H), 4.14 (d, J = 11.6 Hz, 1 H), 3.87 206 (s, 3 H), 3.72 (s, 3 H), 2.42 (d, J = 2.4 Hz, 1 H), 1.00 (s, 9 H), 0.19 (s, 3 H), 0.18 (s, 3H);
13 C NMR (125 MHz, CDCl3) δ 152.2, 145.0, 142.3, 121.1, 110.7, 103.7, 84.7, 71.6, 57.5, 56.2, 55.3, 26.1, 18.8, -3.99, -4.02; IR (neat) 3512, 3281, 2940, 2857, 1596, 1232 cm-1;
mass spectrum (CI) m/z 323.1682 [C17H17O4Si (M+1) requires 323.1679], 323, 305 (base), 265, 191.
1 NMR Assignments. H NMR (500 MHz, CDCl3) δ 6.71 (d, J = 9.0 Hz, 1 H, C5- H or C6-H), 6.47 (d, J = 9.0 Hz, 1 H, C5-H or C6-H), 5.84 (dd, J = 11.6, 2.3 Hz, 1 H, C7- H), 4.14 (d, J = 11.6 Hz, 1 H, OH), 3.87 (s, 3 H, C14-H or C15-H), 3.72 (s, 3 H, C14-H or C15-H), 2.42 (d, J = 2.4 Hz, 1 H, C9-H), 1.00 (s, 9 H, C13-H), 0.19 (s, 3 H, C10-H or
13 C11-H), 0.18 (s, 3H, C10-H or C11-H); C NMR (125 MHz, CDCl3) δ 152.2 (C1), 145.0 (C3 or C4), 142.3 (C3 or C4), 121.1 (C2), 110.7 (C5 or C6), 103.7 (C5 or C6), 84.7 (C8), 71.6 (C9), 57.5 (C7), 56.2 (C14 or C15), 55.3 (C14 or C15), 26.1 (C13), 18.8 (C12), - 3.99 (C10 or C11), -4.02 (C10 or C11).
1-[2-(tert-Butyldimethylsilanyloxy)-3,6-dimethoxyphenyl]-propynone (2.139) (dik1-190). IBX (26 mg, 0.09 mmol) was added to a solution of 1-[2-(tert- butyldimethylsilanyloxy)-3,6-dimethoxyphenyl]prop-2-yn-1-ol (15 mg, 0.05 mmol) in
DMF (0.5 mL). The reaction was stirred at room temperature for 2 h, whereupon H2O (2
mL) was added. The solution was extracted with Et2O (3 × 10 mL). The combined
organic layers were dried (Na2SO4) and concentrated under reduced pressure to give 15
1 mg (>99%) of 2.150 as a yellow solid: mp 113-116 ºC; H NMR (500 MHz, CDCl3) δ 207 6.81 (d, J = 8.9 Hz, 1 H), 6.44 (d, J = 9.0 Hz, 1 H), 3.76 (s, 3 H), 3.74 (s, 3 H), 3.27 (s, 1
13 H), 0.94 (s, 9 H), 0.14 (s, 6 H); C NMR (125 MHz, CDCl3) δ 178.2, 151.4, 144.9, 143.6, 122.7, 113.7, 103.5, 83.3, 78.7, 56.3, 55.6, 25.8, 18.7, -4.1; IR (neat) 2933, 2359,
-1 2090, 1668, 1487, 1255 cm ; MASS SPECTRUM (CI) m/z 321.1521 [C17H25O4Si (M+1) requires 321.1522], 343, 321 (base), 265, 191.
1 NMR Assignments. H NMR (500 MHz, CDCl3) δ 6.81 (d, J = 8.9 Hz, 1 H, C5-H or C6-H), 6.44 (d, J = 9.0 Hz, 1 H, C5-H or C6-H), 3.76 (s, 3 H, C13-H or C14-H), 3.74 (s, 3 H, C13-H or C14-H), 3.27 (s, 1 H, C9-H), 0.94 (s, 9 H, C12-H), 0.14 (s, 6 H, C10-H);
13 C NMR (125 MHz, CDCl3) δ 178.2 (C7), 151.4 (C1), 144.9 (C3 or C4), 143.6 (C3 or C4), 122.7 (C2), 113.7 (C5 or C6), 103.5 (C5 or C6), 83.3 (C9), 78.7 (C8), 56.3 (C13 or C14), 55.6 (C13 or C14), 25.8 (C12), 18.7 (C11), -4.1 (C10).
O F 7 F 6 S 1 O F 5 O 2 4 I 3 2.155 2-Iodophenyl trifluoromethanesulfonate (2.155) (dik1-210). DIPEA (5.7 mL,
32.72 mmol) was added dropwise to a solution of 2.154 (3.00 g, 13.64 mmol) in CH2Cl2 (45 mL) at –78 °C. Freshly distilled triflic anhydride (5.3 mL, 31.36 mmol) was added dropwise, and the reaction was stirred for 10 min at –78 °C. H2O (90 mL) was added, and
the mixture was extracted with Et2O (3 × 60 mL). The combined organic phases were
dried (Na2SO4), and the solvent was removed under reduced pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc (1:3) to give 4.51 g (94%)
1 of 2.155 as a yellow oil; H NMR (400 MHz, CDCl3) δ 7.90 (dd, J = 8.0, 1.6 Hz, 1 H), 7.41 (dt, J = 8.0, 1.8 Hz, 1 H), 7.31 (dd, J = 8.0, 1.4 Hz, 1 H), 7.09 (dt, J = 8.0, 1.4 Hz, 1 H). 208 1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 7.90 (dd, J = 8.0, 1.6 Hz, 1 H, C3- H), 7.41 (dt, J = 8.0, 1.8 Hz, 1 H, C5-H), 7.31 (dd, J = 8.0, 1.4 Hz, 1 H, C6-H), 7.09 (dt, J = 8.0, 1.4 Hz, 1 H, C4-H).
1-(2-(tert-Butyldimethylsilyloxy)-3,6-dimethoxyphenyl)but-2-yn-1-one (2.159) (dik1-216). A solution of n-BuLi (0.019 mL, 2.5 M, 0.05 mmol) in hexanes was added dropwise to a solution of 2.139 (15 mg, 0.05 mmol) in THF (1 mL) at –78 °C. After 15 min at –78 °C, MeI (0.003 mL, 0.06 mmol) was added, and stirring was continued for 30 min at 0 °C. NH4Cl (1.5 mL) was added, and the mixture was extracted with EtOAc (3 ×
5 mL). The combined organic phases were dried (MgSO4), and the solvent was removed under reduced pressure to give 9 mg (58%) of 2.159 as a yellow oil; 1H NMR (400 MHz,
CDCl3) δ 6.77 (d, J = 8.8 Hz, 1 H), 6.42 (d, J = 8.8 Hz, 1 H), 3.74 (s, 3 H), 3.73 (s, 3 H),
13 1.99 (s, 3 H), 0.94 (s, 9 H), 0.14 (s, 6 H); C NMR (100 MHz, CDCl3) δ 179.2, 150.9, 144.8, 143.1, 123.5, 112.8, 103.4, 91.2, 82.2, 56.3, 55.5, 25.7, 18.7, 4.5, -4.2; IR (neat)
-1 2930, 2224, 1660, 1486, 1254, 1101 cm ; mass spectrum (CI) m/z 335.1679 [C18H27O4Si (M+1) requires 335.1679], 335 (base).
1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 6.77 (d, J = 8.8 Hz, 1 H, C5-H or C6-H), 6.42 (d, J = 8.8 Hz, 1 H, C5-H or C6-H), 3.74 (s, 3 H, C14-H or C15-H), 3.73 (s, 3 H, C14-H or C15-H), 1.99 (s, 3 H, C10-H), 0.94 (s, 9 H, C13-H), 0.14 (s, 6 H, C11-H);
13 C NMR (100 MHz, CDCl3) δ 179.2 (C7), 150.9 (ArC), 144.8 (ArC), 143.1 (ArC), 123.5
209 (ArC), 112.8 (C5 or C6), 103.4 (C5 or C6), 91.2 (C8 or C9), 82.2 (C8 or C9), 56.3 (C14 or C15), 55.5 (C14 or C15), 25.7 (C13), 18.7 (C12), 4.5 (C10), -4.2 (C11).
8-(2,2-Di-tert-butyl-5,6-dimethoxy-4H-benzo[1,3,2]dioxasilin-4-ylethynyl)-8- hydroxy-bicyclo[4.2.0]octa-1(6),2,4-trien-7-one (2.160) (dik1-227). A solution of n- BuLi (0.039 mL, 2.5 M, 0.09 mmol) in hexanes was added dropwise to a solution of alkyne 2.127 (30 mg, 0.09 mmol) in THF (1 mL) at –78 °C. After 15 min at –78 °C, dione 2.138 (11 mg, 0.09 mmol) was added, and stirring was continued for 2 h at –78 °C.
NH4Cl (3 mL) was added, and the mixture was extracted with EtOAc (3 × 10 mL). The
combined organic phases were dried (MgSO4), and the solvent was removed under reduced pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc (1:1) to give 25 mg (61%) of 2.160 as a yellow oil; 1H NMR (500 MHz,
CDCl3, mixture of two diastereomers) δ 7.69-7.64 (comp, 1 H), 7.62-7.57 (comp, 1 H), 7.56-7.51 (comp, 1 H), 7.50-7.45 (comp, 1 H), 6.76-6.71 (comp, 1 H), 6.59 (d, J = 8.9 Hz, 0.5 H), 6.56 (d, J = 8.9 Hz, 0.5 H), 6.12 (s, 0.5 H), 6.10 (s, 0.5 H), 3.83 (s, 1.5 H), 3.82 (s, 1.5 H), 3.78 (s, 1.5 H), 3.77 (s, 1.5 H), 3.29 (br s, 0.5 H), 3.26 (br s, 0.5 H), 1.05
13 (s, 4.5 H), 1.04 (s, 4.5 H), 0.90-0.82 (comp, 9 H); C NMR (125 MHz, CDCl3, mixture of two diastereomers) 186.64, 186.56, 158.11, 158.08, 148.2, 147.13, 147.06, 146.94, 146.92, 145.9, 145.8, 136.5, 132.1, 132.0, 122.9, 122.8, 120.4, 120.2, 114.5, 114.4, 113.52, 113.51, 92.02, 91.97, 86.8, 80.15, 80.14, 60.97, 60.95, 60.8, 56.5, 27.2, 21.91,
210 21.89, 20.31, 20.28; IR (neat) 3388, 2935, 2859, 2381, 1764.2, 1486 cm-1; mass spectrum (CI) m/z 482 (base).
1 NMR Assignments. H NMR (500 MHz, CDCl3, mixture of two diastereomers) δ 7.69- 7.64 (comp, 1 H, Ar-H), 7.62-7.57 (comp, 1 H, Ar-H), 7.56-7.51 (comp, 1 H, Ar-H), 7.50-7.45 (comp, 1 H, Ar-H), 6.76-6.71 (comp, 0.5 H, C5-H or C6-H), 6.59 (d, J = 8.9 Hz, 0.5 H, C5-H or C6-H), 6.56 (d, J = 8.9 Hz, 0.5 H, C5-H or C6-H), 6.12 (s, 0.5 H, C7- H), 6.10 (s, 0.5 H, C7-H), 3.83 (s, 1.5 H, C18-H or C19-H), 3.82 (s, 1.5 H, C18-H or C19-H), 3.78 (s, 1.5 H, C18-H or C19-H), 3.77 (s, 1.5 H, C18-H or C19-H), 3.29 (br s, 0.5 H, OH), 3.26 (br s, 0.5 H, OH), 1.05 (s, 4.5 H, C21-H or C23-H), 1.04 (s, 4.5 H, C21-
13 H or C23-H), 0.90-0.82 (comp, 9 H, C21-H or C23-H); C NMR (125 MHz, CDCl3, mixture of two diastereomers) 186.64 (C17), 186.56 (C17), 158.11 (ArC), 158.08 (ArC), 148.2 (2ArC), 147.13 (ArC), 147.06 (ArC), 146.94 (ArC), 146.92 (ArC), 145.9 (ArC), 145.8 (ArC), 136.5 (2ArC), 132.1 (ArC), 132.0 (ArC), 122.9 (ArC), 122.8 (ArC), 120.4 (ArC), 120.2 (ArC), 114.5 (C5 or C6), 114.4 (C5 or C6), 113.52 (C5 or C6), 113.51 (C5 or C6), 92.02 (C10), 91.97 (C10), 86.8 (C8 or C9), 80.15 (C8 or C9), 80.14 (C8 or C9), 60.97 (C7), 60.95 (C7), 60.8 (C18 or C19), 56.5 (C18 or C19), 27.2 (C2 & C22), 21.91 (C20 or C22), 21.89 (C20 or C22), 20.31 (C20 or C22), 20.28 (C20 or C22).
19 Si 18 O O 17 8 2 3 O 9 7 4 15 HO 1 10 5 11 O 6 12 16 13 14 2.162 1-(2-(tert-Butyldimethylsilyloxy)-3,6-dimethoxyphenyl)-4-hydroxy-4- phenylbut-2-yn-1-one (2.162) (dik2-149). A solution of n-BuLi (21 μL, 2.5 M, 0.05 211 mmol) in hexanes was added dropwise to a solution of 2.139 (10 mg, 0.03 mmol) in THF (1.5 mL) at –78 °C. After 15 min at –78 °C, benzaldehyde (4 μL, 0.041 mmol) was
added, and stirring was continued for 1 h at –78 °C. Saturated aqueous NH4Cl (10 mL) was added, and the mixture was extracted with EtOAc (3 × 10 mL). The combined
organic phases were dried (MgSO4), and the solvent was removed under reduced pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc
1 (2:1) to give 4 mg (31%) of 2.162 as a yellow oil; H NMR (400 MHz, CDCl3) δ 7.50 (dd, J = 7.8, 1.4 Hz, 2 H), 7.38-7.29 (comp, 3 H), 6.80 (d, J = 8.8 Hz, 1 H), 6.42 (d, J = 8.8 Hz, 1 H), 5.58 (br d, J = 4.8 Hz, 1 H), 3.74 (s, 3 H), 3.73 (s, 3 H), 2.32 (d, J = 4.8 Hz,
1 H), 0.90 (s, 9 H), 0.13 (s, 6 H); 13C NMR δ 178.3, 151.3, 144.8, 143.5, 138.8, 128.73, 129.69, 126.8, 122.8, 113.5, 103.3, 90.4, 86.9, 64.6, 56.2, 55.6, 25.7, 18.6, -4.2; IR (neat) 3415, 2928, 2856, 1660, 1486, 1254, 1909 cm-1; mass spectrum (CI) m/z 427.1939
[C24H31O5Si (M+1) requires 427.1941], 427 (base).
1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 7.50 (dd, J = 7.8, 1.4 Hz, 2 H, C12- H), 7.38-7.29 (comp, 3 H, C13-H & C14-H), 6.80 (d, J = 8.8 Hz, 1 H, C5-H or C6-H), 6.42 (d, J = 8.8 Hz, 1 H, C5-H or C6-H), 5.58 (br d, J = 4.8 Hz, 1 H, C10-H), 3.74 (s, 3 H, C15-H or C16-H), 3.73 (s, 3 H, C15-H or C16-H), 2.32 (d, J = 4.8 Hz, 1 H, OH), 0.90
(s, 9 H, C19-H), 0.13 (s, 6 H, C17-H); 13C NMR δ 178.3 (C3), 151.3 (C1), 144.8 (C3 or C4), 143.5 (C3 or C4), 138.8 (C11), 128.73 (ArC), 129.69 (ArC), 126.8 (ArC), 122.8
(C2), 113.5 (C5 or C6), 103.3 (C5 or C6), 90.4 (C9), 86.9 (C8), 64.6 (C10), 56.2 (C15 or C16), 55.6 (C15 or C16), 25.7 (C19), 18.6 (C18), -4.2 (C17).
212 OH OH 8 7 2 O 9 1 3 11 6 O 4 5 10 2.166 2-(1-Hydroxyprop-2-ynyl)-3,6-dimethoxyphenol (2.166) (dik1-172). A solution of 2.147 (740 mg, 2.78 mmol) in THF (2.8 mL) was added dropwise to a solution ethynylmagnesium bromide (41.7 mL, 0.5 M, 20.85 mmol) in THF at 0 °C. After stirring at 0 °C for 10 min, the cold bath was removed, and the mixture was stirred for 16 h at
room temperature. Saturated aqueous NH4Cl (3 mL) was added, and the solution was
transferred to a separatory funnel containing H2O (50 mL). The mixture was extracted with Et2O (3 × 30 mL), and the combined organic phases were dried (Na2SO4). The solvent was removed under reduced pressure, and the residue was purified by flash chromatography eluting with hexanes/EtOAc (1:1) to give 482 mg (83%) of 2.166 as a
1 pale yellow solid: mp 104-105 °C; H NMR (500 MHz, CDCl3) δ 6.73 (d, J = 8.9 Hz, 1 H), 6.38 (d, J = 8.9 Hz, 1 H), 6.10 (app s, 1 H), 5.87 (dd, J = 10.9, 2.3 Hz, 1H), 3.98 (app d, J = 11.0 Hz, 1 H), 3.83 (s, 3 H), 3.82 (s, 3 H), 2.46 (d, J = 2.4 Hz, 1 H); 13C NMR (125
MHz, CDCl3) δ 151.5, 143.6, 141.4, 115.5, 110.4, 101.9, 84.2, 71.7, 56.8, 56.5, 56.1; IR (neat) 3486, 3282, 2942, 2838, 1601, 1494, 1247 cm-1; mass spectrum (CI) m/z 209.0816
[C11H13O4 (M+1) requires 209.0814], 209, 191 (base), 181.
1 NMR Assignments. H NMR (500 MHz, CDCl3) δ 6.73 (d, J = 8.9 Hz, 1 H, C5-H or C6-H), 6.38 (d, J = 8.9 Hz, 1 H, C5-H or C6-H), 6.10 (app s, 1 H, Ar-OH), 5.87 (dd, J = 10.9, 2.3 Hz, 1 H, C7-H), 3.98 (app d, J = 11.0 Hz, 1 H, OH), 3.83 (s, 3 H, C10-H or C11-H), 3.82 (s, 3 H, C10-H or C11-H), 2.46 (d, J = 2.4 Hz, 1 H, C9-H); 13C NMR (125
MHz, CDCl3) δ 151.5 (C1), 143.6 (C3 or C4), 141.4 (C3 or C4), 115.5 (C2), 110.4 (C5 or
213 C6), 101.9 (C5 or C6), 84.2 (C8), 71.7 (C9), 56.8 (C7 or C10 or C11), 56.5 (C7 or C10 or C11), 56.1 (C7 or C10 or C11).
2,2-Di-tert-butyl-4-ethynyl-5,8-dimethoxy-4H-benzo[1,3,2]dioxasiline (2.164)
(dik1-231-1). 2,6-Lutidine (0.19 mL, 1.64 mmol) and tert-Bu2Si(OTf)2 (0.24 mL, 0.75
mmol) were added dropwise to a solution of 2.166 (142 mg, 0.68 mmol) in CH2Cl2 (7
mL) at 0 °C. After 30 min at 0 °C, NH4Cl (6 mL) was added, and the aqueous layer was
extracted with Et2O (3 × 10 mL). The combined organic phases were dried (Na2SO4), and the solvent was removed under reduced pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc (3:1) to give 189 mg (79%) of 2.164 as a
1 white solid: mp 125-127 °C; H NMR (500 MHz, CDCl3) δ 6.76 (d, J = 8.9 Hz, 1 H), 6.37 (d, J = 8.9 Hz, 1 H), 5.99 (d, J = 2.3 Hz, 1 H), 3.80 (s, 3 H), 3.78 (s, 3 H), 2.43 (d, J
13 = 2.3 Hz, 1 H), 1.18 (s, 9 H), 0.92 (s, 9 H); C NMR (125 MHz, CDCl3) δ 150.3, 144.5, 144.0, 116.2, 113.5, 102.3, 84.1, 71.8, 60.3, 57.5, 55.9, 27.02, 26.99, 21.7, 20.1; IR (neat)
-1 3284, 2936, 2860, 1596, 1492, 1258 cm ; mass spectrum (CI) m/z 349.1832 [C19H29O4Si (M+1) requires 349.1835], 349 (base).
1 NMR Assignments. H NMR (500 MHz, CDCl3) δ 6.76 (d, J = 8.9 Hz, 1 H, C5-H or C6-H), 6.37 (d, J = 8.9 Hz, 1 H, C5-H or C6-H), 5.99 (d, J = 2.3 Hz, 1 H, C7-H), 3.80 (s, 3 H, C14-H or C15-H), 3.78 (s, 3 H, C14-H or C15-H), 2.43 (d, J = 2.3 Hz, 1 H, C9-H), 1.18 (s, 9 H, C11-H or C13-H), 0.92 (s, 9 H, C11-H or C13-H); 13C NMR (125 MHz,
214 CDCl3) δ 150.3 (C1), 144.5 (C3 or C4), 144.0 (C3 or C4), 116.2 (C2), 113.5 (C5 or C6), 102.3 (C5 or C6), 84.1 (C8), 71.8 (C9), 60.3 (C7), 57.5 (C14 or C15), 55.9 (C14 or C15), 27.02 (C11 or C13), 26.99 (C11 or C13), 21.7 (C10 or C12), 20.1 (C10 or C12).
21 19 20 18 Si O O 8 7 2 9 1 O 12 OH 3 23 1110 13 6 O 4 14 17 5 16 15 O 22
2.167 Cyclobutenol 2.167 (dik1-233). A solution of n-BuLi (0.045 mL, 2.7 M, 0.12 mmol) in hexanes was added dropwise to a solution of 2.164 (40 mg, 0.16 mmol) in THF (3 mL) at –78 °C. After 15 min at –78 °C, dione 2.138 (15 mg, 0.16 mmol) was added, and stirring was continued for 1 h at –78 °C. NH4Cl (3 mL) was added, and the mixture was extracted with EtOAc (3 × 10 mL). The combined organic phases were dried
(MgSO4), and the solvent was removed under reduced pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc (2:1) to give 27 mg (48%) of 2.167
1 as a yellow oil; H NMR (500 MHz, CDCl3, mixture of two diastereomers) δ 7.67-7.68 (m, 0.6 H), 7.66-7.63 (m, 0.4 H), 7.62-7.57 (comp, 1 H), 7.56-7.51 (comp, 1 H), 7.50-
7.45 (comp, 1 H), 6.78-6.73 (comp, 1 H), 6.38-6.32 (comp, 1 H), 6.04 (s, 0.6 H), 6.02 (s, 0.4 H), 3.79 (s, 1.2 H), 3.77 (s, 1.8 H), 3.74 (s, 1.2 H), 3.73 (s, 1.8 H), 3.20-3.07 (comp, 1
13 H), 1.10-1.03 (comp, 9 H), 0.93-0.82 (comp, 9 H); C NMR (125 MHz, CDCl3, mixture of two diastereomers) δ 186.6, 186.4, 157.88, 157.85, 150.4, 150.3, 148.03, 147.98, 144.5, 144.4, 144.1, 144.0, 136.2, 131.74, 131.73, 122.8, 122.7, 122.5, 122.4, 115.8, 115.6, 113.51, 113.46, 102.45, 102.42, 91.3, 86.5, 79.21, 79.19, 60.5, 60.4, 57.5, 56.0,
27.0, 26.9, 21.69, 21.67, 20.1, 20.0; IR (neat) 3414, 2934, 2860, 1778, 1595, 1492 cm-1; 215 mass spectrum (CI, ESI) m/z 481.2050 [C27H33O6Si (M+1) requires 481.2046], 481 (base).
1 NMR Assignments. H NMR (500 MHz, CDCl3, mixture of two diastereomers) δ 7.67- 7.68 (m, 0.6 H, C15-H), 7.66-7.63 (m, 0.4 H, C15-H), 7.62-7.57 (comp, 1 H, C13-H), 7.56-7.51 (comp, 1 H, C14-H), 7.50-7.45 (comp, 1 H, C12-H), 6.78-6.73 (comp, 1 H, C5- H or C6-H), 6.38-6.32 (comp, 1 H, C5-H or C6-H), 6.04 (s, 0.6 H, C7-H), 6.02 (s, 0.4 H, C7-H), 3.79 (s, 1.2 H, C22-H or C23-H), 3.77 (s, 1.8 H, C22-H or C23-H), 3.74 (s, 1.2 H, C22-H or C23-H), 3.73 (s, 1.8 H, C22-H or C23-H), 3.20-3.07 (comp, 1 H, OH), 1.10-
1.03 (comp, 9 H, C19-H or C21-H), 0.93-0.82 (comp, 9 H, C19-H or C21-H); 13C NMR
(125 MHz, CDCl3, mixture of two diastereomers) δ 186.6 (C17), 186.4 (C17), 157.88 (ArC), 157.85 (ArC), 150.4 (ArC), 150.3 (ArC), 148.03 (ArC), 147.98 (ArC), 144.5 (ArC), 144.4 (ArC), 144.1 (ArC), 144.0 (ArC), 136.2 (C13), 131.74 (C14), 131.73 (C14), 122.8 (C15), 122.7 (C15), 122.5 (C12), 122.4 (C12), 115.8 (C2), 115.6 (C2), 113.51 (C5 or C6), 113.46 (C5 or C6), 102.45 (C5 or C6), 102.42 (C5 or C6), 91.3 (C10), 86.5 (C8 or C9), 79.21 (C8 or C9), 79.19 (C8 or C9), 60.5 (C7), 60.4 (C7), 57.5 (C22 or C23), 56.0 (C22 or C23), 27.0 (C19 or C21), 26.9 (C19 or C21), 21.69 (C19 or C21), 21.67 (C19 or C21), 20.1 (C18 or C20), 20.0 (C18 or C20).
OH OH 8 7 2 1 9 O 12 OH 3 19 1110 13 6 O 4 14 17 5 16 15 O 18 2.168 Cyclobutenol 2.168 (dik1-248). HF·pyridine (6.3 μL, 70% HF, 0.23 mmol) was added using a polypropylene syringe to a solution of 2.167 (36 mg, 0.07 mmol) and pyridine (15.1 μL, 0.19 mmol) in THF (1.5 mL) at room temperature. After 10 min at
216 room temperature, the reaction was diluted with Et2O (5 mL). The mixture was washed
with sat. aq. NH4Cl (3 × 5 mL) and dried (MgSO4), and the solvent was removed under reduced pressure to 1 mL. The crude mixture was purified by column chromatography
eluting with hexanes/EtOAc (1:2) to give 31 mg (~100%) of 2.168 as a clear oil; 1H
NMR (400 MHz, CDCl3) δ 7.74 (app d, J = 7.6 Hz, 1 H), 7.62 (app t, J = 7.6 Hz, 1 H), 7.55 (app t, J = 8.4 Hz, 1 H), 7.52-7.47 (comp, 1 H), 6.71 (d, J = 8.8 Hz, 1 H), 6.35 (d, J = 8.8 Hz, 1 H), 6.10 (s, 1 H), 5.90 (br s, 1 H), 3.91 (br s, 1 H), 3.82 (s, 3 H), 3.79-3.73
13 (comp, 3 H), 3.34 (br s, 1 H); C NMR (100 MHz, CDCl3) δ 187.3, 158.4, 151.8, 148.2, 144.0, 141.7, 136.6, 132.0, 123.0, 122.8, 115.4, 110.7, 102.2, 91.3, 86.7, 79.5, 57.1, 56.8,
56.4; IR (neat) 3448, 2922, 1712, 1513, 1263, 1093 cm-1; mass spectrum (CI) m/z
340.0946 [C19H16O6 (M+1) requires 340.0947], 321 (base), 340.
1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 7.74 (app d, J = 7.6 Hz, 1 H, C15-H), 7.62 (app t, J = 7.6 Hz, 1 H, C13-H or C14-H), 7.55 (app t, J = 8.4 Hz, 1 H, C13-H or C14-H), 7.52-7.47 (comp, 1 H, C12-H), 6.71 (d, J = 8.8 Hz, 1 H, C5-H or C6-H), 6.35 (d, J = 8.8 Hz, 1 H, C5-H or C6-H), 6.10 (s, 1 H, C7-H), 5.90 (br s, 1 H, ArOH), 3.91 (br s, 1 H, OH), 3.82 (s, 3 H, C18-H or C19-H), 3.79-3.73 (comp, 3 H, C18-H or C19-H), 3.34
13 (br s, 1 H, OH); C NMR (100 MHz, CDCl3) δ 187.3 (C17), 158.4 (ArC), 151.8 (ArC), 148.2 (ArC), 144.0 (ArC), 141.7 (ArC), 136.6 (C13), 132.0 (C14), 123.0 (C15), 122.8 (C12), 115.4 (C2), 110.7 (C5 or C6), 102.2 (C5 or C6), 91.3 (C10), 86.7 (C8 or C9), 79.5
(C8 or C9), 57.1 (C7 or C18 or C19), 56.8 (C7 or C18 or C19), 56.4 (C7 or C18 or C19).
217 1-(2-Hydroxy-3,6-dimethoxyphenyl)-propynone (2.169) (dik2-51). IBX (169 mg, 0.60 mmol) was added to a solution of 2.166 (50 mg, 0.24 mmol) in THF (4.8 mL). The reaction was stirred at 60 °C for 3 h, whereupon hexanes/EtOAc (1:3, 7 mL) was added. The solution was filtered through Celite, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc (1:1) to give 20 mg (40%) of 2.169 as a yellow solid: mp 66-69 °C; 1H
NMR (400 MHz, CDCl3) δ 7.02 (d, J = 9.0 Hz, 1 H), 6.29 (d, J = 9.0 Hz, 1 H), 3.84 (s, 3
13 H), 3.61 (s, 1 H); C NMR (100 MHz, CDCl3) δ 179.8, 155.6, 155.2, 142.8, 120.3, 112.3, 100.4, 83.7, 83.9, 57.2, 56.0; IR (neat) 3235, 2094, 1596, 1573, 1454, 1318, 1252
-1 cm ; mass spectrum (CI) m/z 207.0660 [C11H11O4 (M+1) requires 207.0657], 207 (base).
1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 7.02 (d, J = 9.0 Hz, 1 H, C5-H or C6-H), 6.29 (d, J = 9.0 Hz, 1 H, C5-H or C6-H), 3.84 (s, 6 H, C10-H & C11-H), 3.61 (s,
13 1 H, C9-H); C NMR (100 MHz, CDCl3) δ 179.8 (C7), 155.6 (ArC), 155.2 (ArC), 142.8 (ArC), 120.3 (ArC), 112.3 (C5 or C6), 100.4 (C5 or C6), 83.7 (C8 or C9), 83.9 (C8 or C9), 57.2 (C10 or C11), 56.0 (C10 or C11).
O OH OH 11 10 8 7 3 2 1 O 12 9 19 13 16 17 4 15 O 6 14 5 O 18
2.175 2-[Hydroxy-(2-hydroxy-3,6-dimethoxyphenyl)-methyl]-[1,4]naphthoquinone (2.175) (dik1-261). A solution of 2.168 (3 mg, 0.03 mmol) in 1.5 mL of DMSO was
heated at 120 °C for 30 min. The reaction was cooled to room temperature, and H2O (5 mL) was added. The mixture was extracted with Et2O (3 × 10 mL). The combined
organic layers were washed with H2O (2 × 10 mL) and dried (Na2SO4), and the solvent 218 was removed under reduced pressure to give 3 mg (~100%) of 2.175 as a yellow oil; 1H
NMR (500 MHz, CDCl3) δ 8.09-8.02 (comp, 2 H), 7.73-7.69 (comp, 2 H), 6.96 (s, 1 H), 6.84 (d, J = 1.6 Hz, 1 H), 6.77 (d, J = 8.9 Hz, 1 H), 6.41 (dd, J = 7.8, 1.6 Hz, 1 H), 6.36
(d, J = 8.9 Hz, 1 H), 4.05 (d, J = 7.8 Hz, 1 H), 3.84 (s, 3 H), 3.74 (s, 3 H); 13C NMR (125
MHz, CDCl3) δ 185.8, 185.6, 151.6, 149.9, 145.2, 142.4, 134.1, 133.9, 133.8, 132.4, 132.1, 126.7, 126.1, 113.6, 111.1, 101.6, 65.5, 56.5, 55.9; IR (neat) 3950, 2907, 2849,
-1 2243, 1684, 1649, 1490, 1249 cm ; mass spectrum (CI) m/z 340.0949 [C19H16O6 (M+1) requires 340.0947], 340 (base).
1 NMR Assignments. H NMR (500 MHz, CDCl3) δ 8.09-8.02 (comp, 2 H, ArH), 7.73- 7.69 (comp, 2 H, ArH), 6.96 (s, 1 H, ArOH), 6.84 (d, J = 1.6 Hz, 1 H, C17-H), 6.77 (d, J = 8.9 Hz, 1 H, C5-H or C6-H), 6.41 (dd, J = 7.8, 1.6 Hz, 1 H, C7-H), 6.36 (d, J = 8.9 Hz, 1 H, C5-H or C6-H), 4.05 (d, J = 7.8 Hz, 1 H, OH), 3.84 (s, 3 H, C18-H or C19-H), 3.74
13 (s, 3 H, C18-H or C19-H); C NMR (125 MHz, CDCl3) δ 185.8 (C9 or C16), 185.6 (C9 or C16), 151.6 (ArC), 149.9 (ArC), 145.2 (ArC), 142.4 (ArC), 134.1 (C17), 133.9 (C12 or C13), 133.8 (C12 or C13), 132.4 (ArC), 132.1 (ArC), 126.7 (C11 or C14), 126.1 (C11 or C14), 113.6 (ArC), 111.1 (C5 or C6), 101.6 (C5 or C6), 65.5 (C7), 56.5 (C18 or C19), 55.9 (C18 or C19).
19 O O O 1 15 2 16 8 6 14 17 7 5 10 O 3 13 11 9 4 12 O O 18 2.177 Spirocycle 2.177 (dik2-225/227). A solution of 2.168 (12 mg, 0.03 mmol) in THF (1.8 mL) was heated at 120 °C for 30 min in a microwave oven. The reaction was cooled to room temperature, and IBX (15 mg, 0.05 mmol) was added. The reaction was 219 stirred at 60 °C for 4 h and then cooled to room temperature, whereupon hexanes/EtOAc
(3:1, 5 mL) was added. The mixture was filtered through Celite and added to CH2Cl2 (2 mL). Silica gel (135 mg) was added, and the reaction was stirred at room temperature for 1.5 h. The solution was filtered through Celite and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc (2:1) to
1 1 give 8 mg (68%) of 2.177 as a yellow oil; H NMR (500 MHz, CDCl3) δ H NMR (500
MHz, CDCl3) δ 8.19 (app d, J = 7.8 Hz, 1 H), 8.06 (app d, J = 7.8 Hz, 1 H), 7.81 (dt, J = 7.6, 1.2 Hz, 1 H), 7.73 (dt, J = 7.6, 1.2 Hz, 1 H), 7.15 (d, J = 8.8 Hz, 1 H), 6.40 (d, J = 8.8 Hz, 1 H), 3.95 (s, 3 H), 3.82 (s, 3 H), 3.54 (d, J = 16.4 Hz, 1 H), 3.30 (d, J = 16.4 Hz, 1
13 H); C NMR (125 MHz, CDCl3) δ 192.1, 190.4, 186.8, 162.2, 152.2, 139.8, 136.7, 135.2, 134.2, 133.0, 128.2, 126.7, 122.8, 108.9, 103.6, 92.5, 57.1, 56.1, 45.1; IR (neat)
-1 2926, 1698, 1596, 1514, 1271 cm ; mass spectrum (CI) m/z 339.0865 [C19H15O6 (M+1) requires 339.0869], 339 (base).
1 NMR Assignments. H NMR (500 MHz, CDCl3) δ 8.19 (app d, J = 7.8 Hz, 1 H, C12-H or C15-H), 8.06 (app d, J = 7.8 Hz, 1 H, C12-H or C15-H), 7.81 (dt, J = 7.6, 1.2 Hz, 1 H, C13-H or C14-H), 7.73 (dt, J = 7.6, 1.2 Hz, 1 H, C13-H or C14-H), 7.15 (d, J = 8.8 Hz, 1 H, C5-H or C6-H), 6.40 (d, J = 8.8 Hz, 1 H, C5-H or C6-H), 3.95 (s, 3 H, C18-H or C19- H), 3.82 (s, 3 H, C18-H or C19-H), 3.54 (d, J = 16.4 Hz, 1 H, C9-H), 3.30 (d, J = 16.4
13 Hz, 1 H, C9-H); C NMR (125 MHz, CDCl3) δ 192.1 (C10 or C17), 190.4 (C10 or C17), 186.8 (C7), 162.2 (ArC), 152.2 (ArC), 139.8 (ArC), 136.7 (ArC), 135.2 (C13 or C14), 134.2 (C13 or C14), 133.0 (ArC), 128.2 (C12 or C15), 126.7 (C12 or C15), 122.8 (C5 or C6), 108.9 (ArC), 103.6 (C5 or C6), 92.5 (C8), 57.1 (C18 or C19), 56.1 (C18 or C19), 45.1 (C9).
220 19 O O O 15 16 8 2 1 14 17 7 6 10 5 13 11 9 3 12 O 4 O O 18 2.136 1,4-Dimethoxy-6H-benzo[b]xanthene-6,11,12-trione (2.136) (dik2-232/233). Spirocycle 2.177 (1 mg) was added to toluene (3 mL), and the mixture was heated at 250
°C for 2 × 3 h. The solvent was removed and the residue was dissolved in CH2Cl2 (10 mL). The organic layer was shaken with 1 M KOH (10 mL), neutralized with 1 M HCl, and extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were dried
(Na2SO4) and concentrated under reduced pressure to give 1 mg (~100%) of 2.136 as a
1 red solid; H NMR (400 MHz, CDCl3) δ 8.19 (app d, J = 7.2 Hz, 1 H), 8.14 (app d, J = 7.2 Hz, 1 H), 7.79 (dt, J = 7.6, 1.0 Hz, 1 H), 7.73 (dt, J = 7.6, 1.0 Hz, 1 H), 7.16 (d, J = 9.2 Hz, 1 H), 6.78 (d, J = 9.2 Hz, 1 H), 3.95 (s, 3 H), 3.88 (s, 3 H); IR (neat) 2923, 2852,
-1 2360, 1738, 1692, 1489, 1288 cm ; mass spectrum (CI) m/z 337.0710 [C19H13O6 (M+1) requires 337.0712], 337 (base).
1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 8.19 (app d, J = 7.2 Hz, 1 H, C12-H or C15-H), 8.14 (app d, J = 7.2 Hz, 1 H, C12-H or C15-H), 7.79 (dt, J = 7.6, 1.0 Hz, 1 H, C13-H or C14-H), 7.73 (dt, J = 7.6, 1.0 Hz, 1 H, C13-H or C14-H), 7.16 (d, J = 9.2 Hz, 1 H, C5-H or C6-H), 6.78 (d, J = 9.2 Hz, 1 H, C5-H or C6-H), 3.95 (s, 3 H, C18-H or C19- H), 3.88 (s, 3 H, C18-H or C19-H).
221
1,4-Dimethoxy-2-(2-methylallyl)benzene (2.190) (dik3-94). A solution of n- BuLi (0.13 ml, 2.49 M, 0.33 mmol) in hexanes was added dropwise to a solution of 2.180 (51 mg, 0.33 mmol) in THF (3.3 mL) at –78 ºC. After 30 min at –78 ºC, freshly prepared 2-methylallylmagnesium chloride (3.95 mL, 0.12 M, 0.49 mmol) was added dropwise. After 15 min at –78 ºC, stirring was continued for 1.5 h at room temperature. Saturated aqueous NH4Cl (2 mL) was added, and the mixture was extracted with Et2O (3 × 10 mL).
The combined organic phases were dried (Na2SO4), and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography eluting with hexanes/EtOAc (5:1) to give 48 mg (76%) of 2.190 as a clear oil; 1H NMR (400 MHz,
CDCl3) δ 6.78 (d, J = 8.4 Hz, 1 H), 6.73-6.68 (comp, 2 H), 4.79 (d, J = 0.6 Hz, 1 H), 4.64 (d, J = 0.6 Hz, 1 H), 3.72 (s, 3 H), 3.75 (3 H), 3.30 (s, 2 H), 1.72 (s, 3 H); IR (neat) 2940,
-1 2832, 1499, 1256, 1224, 1051 cm ; mass spectrum (CI) m/z 193.1228 [C12H17O2 (M+1) requires 193.1229], 193 (base).
1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 6.78 (d, J = 8.4 Hz, 1 H, C5-H), 6.73-6.68 (comp, 2 H, C2-H & C6-H), 4.79 (d, J = 0.6 Hz, 1 H, C10-H), 4.64 (d, J = 0.6 Hz, 1 H, C10-H), 3.72 (s, 3 H, C11-H or C12-H), 3.75 (3 H, C11-H or C12-H), 3.30 (s, 2 H, C7-H), 1.72 (s, 3 H, C9-H).
222 21 23 20 22 18 Si 19 O O 15 O 7 2 16 O 1 O 14 25 17 8 3 13 9 6 1110 O 4 12 HO 5 24 2.194 Cyclobutenol 2.194 (dik2-145). A solution of n-BuLi (0.023 mL, 2.6 M, 0.06 mmol) in hexanes was added dropwise to a solution of 2.164 (20 mg, 0.06 mmol) in THF (1.5 mL) at –78 °C. After 15 min at –78 °C, ketone 2.193 (10 mg, 0.06 mmol) was added, and stirring was continued for 1 h at –78 °C. Saturated aqueous NH4Cl (10 mL) was added, and the mixture was extracted with EtOAc (3 × 10 mL). The combined organic phases were dried (MgSO4), and the solvent was removed under reduced pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc (3:2) to give 4
1 mg (17%) of 2.194 as a yellow oil; H NMR (400 MHz, CDCl3, mixture of diastereomers) δ 7.43-7.29 (comp, 4 H), 6.75 (d, J = 8.8 Hz, 0.5 H), 6.73 (d, J = 8.8 Hz, 0.5 H), 6.33 (d, J = 8.8 Hz, 0.5 Hz), 6.32 (d, J = 8.8 Hz, 0.5 H), 6.05 (s, 1 H), 4.23-4.03 (comp, 4 H), 3.79 (s, 1.5 H), 3.77 (s, 1.5 H), 3.73 (s, 3 H), 3.14 (s, 0.5 H), 3.12 (s, 0.5 H),
13 1.11 (s, 4.5 H), 1.08 (s, 4.5 H), 0.90 (s, 9 H); C NMR (100 MHz, CDCl3, mixture of diastereomers) δ 150.74, 150.71, 148.0, 144.7, 144.4, 142.5, 132.3, 132.2, 130.7, 123.4, 122.4, 116.7, 113.6, 112.0, 102.41, 102.36, 89.0, 88.8, 81.3, 80.1, 80.0, 65.23, 65.19, 65.1, 60.9, 60.8, 57.9, 57.8, 56.1, 27.3, 27.2, 21.9, 20.3; IR (neat) 3448, 2933, 2858,
-1 1492, 1256, 1081, 1059 cm ; mass spectrum (CI) m/z 525.2307 [C29H37O7Si (M+1) requires 525.2309], 507 (base), 526.
1 NMR Assignments. H NMR (400 MHz, CDCl3, mixture of diastereomers) δ 7.43-7.29 (comp, 4 H, C12-H & C13-H & C14-H & C15-H), 6.75 (d, J = 8.8 Hz, 0.5 H, C5-H or C6-H), 6.73 (d, J = 8.8 Hz, 0.5 H, C5-H or C6-H), 6.33 (d, J = 8.8 Hz, 0.5 Hz, C5-H or 223 C6-H), 6.32 (d, J = 8.8 Hz, 0.5 H, C5-H or C6-H), 6.05 (s, 1 H, C7-H), 4.23-4.03 (comp, 4 H, C18-H & C19-H), 3.79 (s, 1.5 H, C24-H or C25-H), 3.77 (s, 1.5 H, C24-H or C25- H), 3.73 (s, 3 H, C24-H or C25-H), 3.14 (s, 0.5 H, OH), 3.12 (s, 0.5 H, OH), 1.11 (s, 4.5 H, C21-H or C23-H), 1.08 (s, 4.5 H, C21-H or C23-H), 0.90 (s, 9 H, C21-H or C23-H);
13 C NMR (100 MHz, CDCl3, mixture of diastereomers) δ 150.74 (ArC), 150.71 (ArC), 148.0 (ArC), 144.7 (ArC), 144.4 (ArC), 142.5 (C13), 132.3 (C14), 132.2 (C14), 130.7 (C17), 123.4 (C15), 122.4 (C12), 116.7 (C3), 113.6 (C5 or C6), 112.0 (ArC), 102.41 (C5 or C6), 102.36 (C5 or C6), 89.0 (C10), 88.8 (C10), 81.3 (C8 or C9), 80.1 (C8 or C9), 80.0 (C8 or C9), 65.23 (C18 or C19), 65.19 (C18 or C19), 65.1 (C18 or C19), 60.9 (C7), 60.8 (C7), 57.9 (C24 or C25), 57.8 (C24 or C25), 56.1 (C24 or C25), 27.3 (C21 or C23), 27.2 (C21 or C23), 21.9 (C20 or C22), 20.3 (C20 or C22).
11 12 13 19 Si O O 10 1 7 8 6 2 9 5 3 O 14 4 Si 16 O 17 18 15
2.195 2-(tert-Butyldimethylsilanyloxy)-3-[1-(tert-butyldimethylsilanyloxy)-prop-2- ynyl]-1,4-dimethoxybenzene (2.195) (dik1-184). A solution of NaHMDS (0.20 mL, 2.0 M, 0.40 mmol) in THF was added to a solution of 2-[1-(tert-butyldimethylsilanyloxy)- prop-2-ynyl]-3,6-dimethoxyphenol (2.150) (100 mg, 0.31 mmol) in THF (3 mL) at 0 °C. The solution was stirred for 40 min at 0 °C, whereupon a solution of TBSCl (70 mg, 0.47 mmol) in THF (0.7 mL) was added. After stirring for 30 min at 0 °C, the ice bath was removed, and the reaction was stirred for 1 h at room temperature. Additional TBSCl
(930 mg, 6.17 mmol) was added, and stirring continued for 2 h at room temperature. H2O 224 (50 mL) was added, and the mixture was washed with saturated aqueous NH4Cl (3 × 50
mL). The organic phase was dried (Na2SO4), and the solvent was removed under reduced pressure. The residue was purified by flash chromatography eluting with hexanes/EtOAc (1:3). This residue was further purified by flash chromatography eluting with hexanes/EtOAc (1:9) to give 43 mg (32%) of 2.195 as a white solid: mp 94-96 °C; 1H
NMR (500 MHz, CDCl3) δ 6.70 (d, J = 8.9 Hz, 1 H), 6.46 (d, J = 8.9 Hz, 1 H), 6.04 (d, J = 2.4 Hz, 1 H), 3.80 (s, 3 H), 3.70 (s, 3 H), 2.37 (d, J = 2.4 Hz, 1 H), 1.01 (s, 9 H), 0.83 (s, 9 H), 0.18 (s, 3 H), 0.16 (s, 3 H), 0.10 (s, 3 H), -0.03 (s, 3 H); 13C NMR (125 MHz,
CDCl3) δ 153.2, 144.7, 142.7, 122.1, 110.9, 104.7, 85.1, 71.0, 56.8, 56.6, 55.2, 26.2, 25.8, 18.9, 18.2, -3.9, -4.0, -4.7, -4.8; IR (neat) 3277, 2927, 1488, 1360, 1313, 1248, 1228 cm-1;
mass spectrum (CI) m/z 437.2544 [C23H41O4Si2 (M+1) requires 437.2543], 437, 305 (base), 265.
1 NMR Assignments. H NMR (500 MHz, CDCl3) δ 6.70 (d, J = 8.9 Hz, 1 H, C5-H or C6-H), 6.46 (d, J = 8.9 Hz, 1 H, C5-H or C6-H), 6.04 (d, J = 2.4 Hz, 1 H, C7-H), 3.80 (s, 3 H, C18-H or C19-H), 3.70 (s, 3 H, C18-H or C19-H), 2.37 (d, J = 2.4 Hz, 1 H, C9-H), 1.01 (s, 9 H, C13-H or C17-H), 0.83 (s, 9 H, C13-H or C17-H), 0.18 (s, 3 H, C10-H or C11-H or C14-H or C15-H), 0.16 (s, 3 H, C10-H or C11-H or C14-H or C15-H), 0.10 (s, 3 H, C10-H or C11-H or C14-H or C15-H), -0.03 (s, 3 H, C10-H or C11-H or C14-H or
13 C15-H); C NMR (125 MHz, CDCl3) δ 153.2 (C1), 144.7 (C3 or C4), 142.7 (C3 or C4), 122.1 (C2), 110.9 (C5 or C6), 104.7 (C5 or C6), 85.1 (C8), 71.0 (C9), 56.8 (C7), 56.6 (C18 or C19), 55.2 (C18 or C19), 26.2 (C13 or C17), 25.8 (C13 or C17), 18.9 (C12 or C16), 18.2 (C12 or C16), -3.9 (C10 or C11 or C14 or C15), -4.0 (C10 or C11 or C14 or C15), -4.7 (C10 or C11 or C14 or C15), -4.8 (C10 or C11 or C14 or C15).
225
2-Ethynyl-1,1,5,8-tetramethoxy-1,2-dihydrocyclobuta[a]naphthalen-2-ol (2.202). Method A (dik2-288/289). A solution of n-BuLi (0.17 ml, 2.47 M, 0.42 mmol) in hexanes was added dropwise to a solution of ethynyltrimethylsilane (61 μL, 0.43 mmol) in THF (3 mL) at –78 ºC. After 20 min at –78 ºC, 2.126 (100 mg, 0.35 mmol) in THF (0.5 mL) was added dropwise, and the reaction was stirred for 1 h at 0 ºC. Saturated
aqueous NH4Cl (3 mL) was added, and the mixture was extracted with EtOAc (3 × 15
mL). The combined organic phases were dried (MgSO4), and the solvent was removed under reduced pressure to give 104 mg of a brown oil. The oil was dissolved in THF (2.7 mL) and cooled to 0 ºC. TBAF (89 mg, 0.28 mmol) was added to this solution, and the
reaction was stirred for 30 min at 0 ºC, whereupon the mixture was diluted with Et2O (30 mL). The organic layer was washed with H2O (2 × 10 mL) and brine (10 mL) and dried
(MgSO4). The solvent was removed under reduced pressure to give 86 mg (78%) of 2.202 as a light brown oil.
Method B (dik3-77). Ketone 2.126 (105 mg, 0.36 mmol) in THF (0.5 mL) was added dropwise to a solution of ethynylmagnesium bromide (3.64 mL, 1.82 mmol) in THF (3.1 mL) at 0 ºC. After 10 min at 0 ºC, stirring was continued for 1.5 h at room temperature,
whereupon the reaction was diluted with Et2O (25 mL). The organic layer was washed with H2O (2 × 10 mL) and dried (MgSO4) to give 93 mg (82%) of 2.202 as a light brown
1 oil; H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 8.4 Hz, 1 H), 7.54 (d, J = 8.4 Hz, 1 H),
226 6.79 (d, J = 8.4 Hz, 1 H), 6.75 (d, J = 8.4 Hz, 1 H), 3.93 (s, 6 H), 3.78 (s, 1 H, OH), 3.66
13 (s, 3 H), 3.60 (s, 3 H), 2.67 (s, 1 H); C NMR (100 MHz, CDCl3) δ 150.2, 148.2, 145.6, 137.4, 127.2 , 126.4, 122.4, 118.8, 107.4, 105.4, 104.7, 81.6, 77.4, 75.7, 55.9, 55.3, 52.8,
52.6; IR (neat) 3478, 3284, 2942, 1587, 1462, 1264, 1081 cm-1; mass spectrum (CI) m/z
315.1234 [C18H19O5 (M+1) requires 315.1232], 315 (base), 283.
1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 8.4 Hz, 1 H, C9-H), 7.54 (d, J = 8.4 Hz, 1 H, C10-H), 6.79 (d, J = 8.4 Hz, 1 H, C5-H or C6-H), 6.75 (d, J = 8.4 Hz, 1 H, C5-H or C6-H), 3.93 (s, 6 H, C13-H & C14-H), 3.78 (s, 1 H, OH), 3.66 (s, 3 H, C15-
H or C16-H), 3.60 (s, 3 H, C15-H or C16-H), 2.67 (s, 1 H, C18-H); 13C NMR (100 MHz,
CDCl3) δ 150.2 (C4 or C7), 148.2 (C4 or C7), 145.6 (ArC), 137.4 (ArC), 127.2 (ArC) , 126.4 (ArC), 122.4 (ArC), 118.8 (ArC), 107.4 (ArC), 105.4 (C5 or C6), 104.7 (C5 or C6), 81.6 (C17), 77.4 (C12), 75.7 (C18), 55.9 (C13 or C14), 55.3 (C13 or C14), 52.8 (C15 or C16), 52.6 (C15 or C16).
(2-Ethynyl-1,1,5,8-tetramethoxy-1,2-dihydrocyclobuta[a]naphthalen-2- yloxy)-trimethylsilane (2.203) (dik2-295). Imidazole (45 mg, 0.67 mmol) was added dropwise to a solution of 2.202 (42 mg, 0.13 mmol) in DMF (1.5 mL) at 0 ºC. Freshly distilled TMSCl (34 μL, 0.27 mmol) was added dropwise, and stirring was continued for
2 h at room temperature, whereupon the reaction was diluted with Et2O (25 mL). The
organic layer was washed with H2O (2 × 10 mL) and dried (Na2SO4) to give 45 mg
227 1 (84%) of 2.203 as a yellow oil; H NMR (400 MHz, C6D6) δ 8.50 (d, J = 8.6 Hz, 1 H), 7.54 (d, J = 8.6 Hz, 1 H); 6.43 (d, J = 8.0 Hz, 1 H), 6.37 (d, J = 8.0 Hz, 1 H), 3.71 (s, 3 H), 3.63 (s, 3 H), 3.45 (s, 3 H), 3.42 (s, 3 H), 2.37 (s, 1 H), 0.37 (s, 9 H); 13C NMR (100
MHz, CDCl3) δ 150.13, 148.47, 145.25, 138.5, 127.1, 125.9, 122.9, 119.1, 109.0, 105.5, 104.6, 83.5, 79.7, 76.5, 55.9, 55.3, 52.9, 52.8, 1.7; IR (neat) 2938, 1598, 1462, 1263,
-1 1127 cm ; mass spectrum (CI) m/z 387.1629 [C21H27O5Si (M+1) requires 387.1628], 387, 371, 355 (base).
1 NMR Assignments. H NMR (400 MHz, C6D6) δ 8.50 (d, J = 8.6 Hz, 1 H, C9-H), 7.54 (d, J = 8.6 Hz, 1 H, C10-H); 6.43 (d, J = 8.0 Hz, 1 H, C5-H or C6-H), 6.37 (d, J = 8.0 Hz, 1 H, C5-H or C6-H), 3.71 (s, 3 H, C13-H or C14-H), 3.63 (s, 3 H, C13-H or C14-H), 3.45 (s, 3 H, C15-H or C16-H), 3.42 (s, 3 H, C15-H or C16-H), 2.37 (s, 1 H, C19-H), 0.37 (s,
13 9 H, C17-H); C NMR (100 MHz, CDCl3) δ 150.13 (C4 or C7), 148.47 (C4 or C7), 145.25 (ArC), 138.5 (ArC), 127.1 (ArC), 125.9 (ArC), 122.9 (ArC), 119.1 (ArC), 109.0 (ArC), 105.5 (C5 or C6), 104.6 (C5 or C6), 83.5 (C12), 79.7 (C18), 76.5 (C19), 55.9 (C13 or C14), 55.3 (C13 or C14), 52.9 (C15 or C16), 52.8 (C15 or C16), 1.7 (C17).
14 5 4 15 6 O 7 O 16 13 2 O 3 O 8 1 20 9 1112 19 10 O Si 17 18 2.205 Triethyl(2-ethynyl-1,1,5,8-tetramethoxy-1,2-dihydrocyclobuta[a]naphthalen- 2-yloxy)silane (2.205) (dik4-111). Imidazole (189 mg, 2.77 mmol) and freshly distilled TESCl (0.19 mL, 1.11 mmol) were added to a solution of 2.202 (143 mg, 0.46 mmol) in
228 DMF (6 mL) at 0 ºC. After 10 min at 0 ºC and 1.5 h at room temperature, the reaction
was diluted with Et2O (30 mL). The mixture was washed with H2O (3 × 10 mL), the
organic phase was dried (MgSO4), and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography eluting with hexanes/EtOAc
1 (2:1) to give 150 mg (77%) of 2.205 as a yellow oil; H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 8.6 Hz, 1 H), 7.57 (d, J = 8.6 Hz, 1 H), 6.43 (d, J = 8.4 Hz, 1 H), 6.37 (d, J = 8.4 Hz, 1 H), 3.70 (s, 3 H), 3.67 (s, 3 H), 3.46 (s, 3 H), 3.42 (s, 3 H), 2.37 (s, 1 H), 1.11 (app
13 t, J = 7.8 Hz, 9 H), 0.90-0.80 (comp, 6 H); C NMR (100 MHz, CDCl3) δ 150.1, 148.5, 145.4, 138.7, 127.1, 125.8, 122.9, 119.2, 109.0, 105.5, 104.6, 83.6, 79.7, 76.2, 55.9, 55.4,
52.9, 52.8, 6.9, 6.0; IR (neat) 3272, 2950, 1598, 1461, 1263, 1127 cm-1; mass spectrum
(CI) m/z 429.2101 [C24H32O5Si (M+1) requires 429.2097], 429, 315 (base), 283.
1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 8.6 Hz, 1 H, C9-H or C10-H), 7.57 (d, J = 8.6 Hz, 1 H, C9-H or C10-H), 6.43 (d, J = 8.4 Hz, 1 H, C5-H or C6- H), 6.37 (d, J = 8.4 Hz, 1 H, C5-H or C6-H), 3.70 (s, 3 H, C13-H or C14-H), 3.67 (s, 3 H, C13-H or C14-H), 3.46 (s, 3 H, C15-H or C16-H), 3.42 (s, 3 H, C15-H or C16-H), 2.37 (s, 1 H, C20-H), 1.11 (app t, J = 7.8 Hz, 9 H, C18-H), 0.90-0.80 (comp, 6 H, C17-H); 13C
NMR (100 MHz, CDCl3) δ 150.1 (C4 or C7), 148.5 (C4 or C7), 145.4 (C1), 138.7 (ArC), 127.1 (ArC), 125.8 (ArC), 122.9 (ArC), 119.2 (ArC), 109.0 (ArC), 105.5 (C5 or C6), 104.6 (C5 or C6), 83.6 (C12), 79.7 (C19), 76.2 (C20), 55.9 (C13 or C14), 55.4 (C13 or
C14), 52.9 (C15 or C16), 52.8 (C15 or C16), 6.9 (C17), 6.0 (C18).
229
2-Bromo-3,6-bis(methoxymethoxy)benzaldehyde (2.212) (dik5-31). MOMCl
(9.2 mL, 121.23 mmol) and i-Pr2Net (17.6 mL, 100.94 mmol) were added dropwise to a
solution of 2.211 (8.72 g, 40.38 mmol) in CH2Cl2 (80 mL) at room temperature. After 17
h at room temperature, H2O (100 mL) was added, and the mixture was extracted with
Et2O (3 × 100 mL). The combined organic phases were dried (MgSO4), and the solvent was removed under reduced pressure to give 12.32 g (~100%) of 2.212 as a yellow oil;
1 H NMR (400 MHz, CDCl3) δ 10.37 (s, 1 H, C7-H), 7.26 (d, J = 9.2 Hz, 1 H, C5-H or C6-H), 7.12 (d, J = 9.2 Hz, 1 H, C5-H or C6-H), 5.18 (s, 4 H, C8-H & C10-H), 3.50 (s, 3
13 H, C9-H or C11-H), 3.47 (s, 3 H, C9-H or C11-H); C NMR (100 MHz, CDCl3) δ 190.5, 153.8, 149.2, 126.0, 121.6, 116.0, 115.2, 95.9, 95.7, 56.5; IR (neat) 2963, 2913, 1700,
-1 1556, 1469, 1394, 1263, 1150 cm ; mass spectrum (CI) m/z 305.0031 [C11H13O5Br (M+1) requires 305.0025], 305 (base).
1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 10.37 (s, 1 H, C7-H), 7.26 (d, J = 9.2 Hz, 1 H, C5-H or C6-H), 7.12 (d, J = 9.2 Hz, 1 H, C5-H or C6-H), 5.18 (s, 4 H, C8-H &
C10-H), 3.50 (s, 3 H, C9-H or C11-H), 3.47 (s, 3 H, C9-H or C11-H); 13C NMR (100
MHz, CDCl3) δ 190.5 (C7), 153.8 (C4), 149.2 (C1), 126.0 (ArC), 121.6 (ArC), 116.0 (ArC & ArC), 115.2 (ArC), 95.9 (C8 or C10), 95.7 (C8 or C10), 56.5 (C9 & C11).
230
2-Bromo-1,4-bis(methoxymethoxy)-3-vinylbenzene (2.213) (dik4-132).
Ph3PCH3Br (28.97 g, 81.36 mmol) and NaH (4.77 g, 119.33 mmol, 60% dispersion in mineral oil) were added to solution of 2.212 (16.55 g, 54.24 mmol) in THF (540 mL).
After 18 h at room temperature, H2O (200 mL) and brine (50 mL) were added, and the mixture was extracted with EtOAc (3 × 100 mL). The combined organic phases were
dried (Na2SO4), and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography eluting with hexanes/EtOAc (2:1) to give 16.44
1 g (~100%) of 2.213 as a pale yellow oil; H NMR (400 MHz, CDCl3) δ 7.03 (d, J = 8.8 Hz, 1 H), 6.98 (d, J = 8.8 Hz, 1 H), 6.78 (dd, J = 17.7, 11.9 Hz, 1 H), 5.86 (dd, J = 17.7, 2.2 Hz, 1 H), 5.59 (dd, J = 11.9, 2.2 Hz, 1 H), 5.16 (s, 2 H), 5.11 (s, 2 H), 3.51 (s, 3 H),
13 3.46 (s, 3 H); C NMR (100 MHz, CDCl3) δ 150.7, 149.0, 132.1, 129.2, 121.6, 115.8, 115.4, 115.0, 95.8, 95.4, 56.3, 56.2; IR (neat) 2955, 2901, 2826, 1470, 1251, 1154, 1008
-1 cm ; mass spectrum (CI) m/z 302.0150 [C12H14O4Br (M+1) requires 302.0154], 302, 273, 271 (base).
1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 7.03 (d, J = 8.8 Hz, 1 H, C5-H or C6-H), 6.98 (d, J = 8.8 Hz, 1 H, C5-H or C6-H), 6.78 (dd, J = 17.7, 11.9 Hz, 1 H, C7-H), 5.86 (dd, J = 17.7, 2.2 Hz, 1 H, C8-H), 5.59 (dd, J = 11.9, 2.2 Hz, 1 H, C8-H), 5.16 (s, 2 H, C9-H or C11-H), 5.11 (s, 2 H, C9-H or C11-H), 3.51 (s, 3 H, C10-H or C12-H), 3.46
13 (s, 3 H, C10-H or C12-H); C NMR (100 MHz, CDCl3) δ 150.7 (C1 or C4), 149.0 (C1 or C4), 132.1 (C3 or C7), 129.2 (C3 or C7), 121.6 (C2 or C5 or C6 or C8), 115.8 (C2 or C5
231 or C6 or C8), 115.4 (C2 or C5 or C6 or C8), 115.0 (C2 or C5 or C6 or C8), 95.8 (C9 or C11), 95.4 (C9 or C11), 56.3 (C10 or C12), 56.2 (C10 or C12).
11 12 19 O 20 O O O 8 O 1 7 9 6 10 2 3 5 15 13 14 4 O O 16 18 17 2.214 3-(3,6-Bis(methoxymethoxy)-2-vinylphenyl)-4,4-dimethoxy-2-vinylcyclobut- 2-enone (2.214) (dik4-225). A solution of t-BuLi (9.1 mL, 14.55 mmol, 1.6 M) in heptane was added quickly to a solution of freshly dried (azeotropic distillation, 2 × 2 mL PhH) 2.213 (2.052 g, 6.77 mmol) in THF (30 mL) at –78 ºC. After 30 sec at –78 ºC, a solution of 2.124 (1.500 g, 8.26 mmol) in THF (5 mL) at –78 ºC was added quickly via syringe. After 10 min at –78 ºC, the reaction was stirred for 20 min at 0 ºC. Upon cooling to –78 ºC, TFAA (2.82 mL, 20.31 mmol) was added dropwise, and the reaction was stirred for 20 min at –78 ºC and 5 min at room temperature. Upon addition of saturated
aqueous NaHCO3 (15 mL), the reaction was allowed to warm to room temperature. H2O
(20 mL) was added, and the mixture was extracted with Et2O (3 × 50 mL). The combined organic phases were dried (Na2SO4), and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography eluting with hexanes/EtOAc (4:1) to give 1.46 g (57%) of 2.214 as a yellow oil; 1H NMR (400 MHz,
CDCl3) δ 7.10 (d, J = 9.2 Hz, 1 H), 7.00 (d, J = 9.2 Hz, 1 H), 6.63 (dd, J = 17.6, 11.7 Hz, 1 H), 6.21-6.00 (comp, 2 H), 5.88 (dd, J = 17.7, 2.1 Hz, 1 H), 5.52 (dd, J = 10.0, 2.9 Hz, 1 H), 5.42 (dd, J = 11.7, 2.1 Hz), 5.14 (s, 2 H), 5.07 (s, 2 H), 3.47 (s, 3 H), 3.44 (app s, 6
13 H), 3.42 (s, 3 H); C NMR (100 MHz, CDCl3) δ 191.4, 171.6, 152.5, 150.5, 148.2, 232 131.0, 126.6, 125.7, 123.9, 121.8, 121.2, 117.3, 117.1, 114.5, 95.21, 95.18, 56.2, 56.0, 52.7; IR (neat) 2946, 2904, 2835, 1766, 149, 1251, 1016 cm-1; mass spectrum (ESI) m/z
3991415 [C20H24O7 (M+23) requires 399.1414], 399 (base).
1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 7.10 (d, J = 9.2 Hz, 1 H, C5-H or C6-H), 7.00 (d, J = 9.2 Hz, 1 H, C5-H or C6-H), 6.63 (dd, J = 17.6, 11.7 Hz, 1 H, C15- H), 6.21-6.00 (comp, 2 H, C13-H & C14-H), 5.88 (dd, J = 17.7, 2.1 Hz, 1 H, C16-H), 5.52 (dd, J = 10.0, 2.9 Hz, 1 H, C14-H), 5.42 (dd, J = 11.7, 2.1 Hz, C16-H), 5.14 (s, 2 H, C17-H or C19-H), 5.07 (s, 2 H, C17-H or C19-H), 3.47 (s, 3 H, C18-H or C20-H), 3.44
(app s, 6 H, C18-H or C20-H), 3.42 (s, 3 H, C18-H or C20-H); 13C NMR (100 MHz,
CDCl3) δ 191.4 (C9), 171.6 (C7), 152.5 (C8), 150.5 (C1 or C4), 148.2 (C1 or C4), 131.0 (C7), 126.6 (ArC), 125.7 (ArC), 123.9 (ArC), 121.8 (ArC), 121.2 (ArC), 117.3 (ArC), 117.1 (ArC), 114.5 (ArC), 95.21 (C17 or C19), 95.18 (C17 or C19), 56.2 (C18 or C20), 56.0 (C18 or C20), 52.7 (C11 & C12).
1,1-Dimethoxy-5,8-bis(methoxymethoxy)cyclobuta[a]naphthalen-2(1H)-one (2.174) (dik4-139). Grubbs second generation catalyst (16 mg, 0.12 mmol) was added to a degassed (Ar, 15 min) solution of diene 2.214 (145 mg, 0.39 mmol) in toluene (15 mL).
The solution was then heated for 5 h at 110 °C, whereupon the reaction was cooled to room temperature. The reaction mixture was concentrated to ca. 1 mL and purified by flash column chromatography eluting with hexanes/EtOAc (4:1) to give 100 mg (75%) of 233 1 2.174 as a yellow oil; H NMR (400 MHz, CDCl3) δ 8.41 (d, J = 8.8 Hz, 1 H), 7.49 (d, J = 8.8 Hz, 1 H), 7.28 (d, J = 8.6 Hz, 1 H), 7.18 (d, J = 8.6 Hz, 1 H), 5.33 (s, 2 H), 5.31 (s,
13 2 H), 3.54 (s, 3 H), 3.50 (app s, 9 H); C NMR (100 MHz, CDCl3) δ 193.3, 160.5, 148.4, 147.6, 147.0, 129.4, 127.6, 121.9, 118.4, 116.6, 113.6, 111.6, 95.3, 94.8, 56.22, 56.18,
53.6; IR (neat) 2946, 2906, 2833, 1762, 1458, 1257, 1055 cm-1; mass spectrum (ESI) m/z
371.1102 [C18H20O7 (M+23) requires 371.1101], 719, 371 (base).
1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 8.41 (d, J = 8.8 Hz, 1 H, C11-H or C12-H), 7.49 (d, J = 8.8 Hz, 1 H, C11-H or C12-H), 7.28 (d, J = 8.6 Hz, 1 H, C5-H or C6-H), 7.18 (d, J = 8.6 Hz, 1 H, C5-H or C6-H), 5.33 (s, 2 H, C15-H or C17-H), 5.31 (s, 2 H, C15-H or C17-H), 3.54 (s, 3 H, C13-H or C14-H), 3.50 (app s, 9 H, C13-H or C14-
13 H & C16-H & C18-H); C NMR (100 MHz, CDCl3) δ 193.3 (C9), 160.5 (C8), 148.4 (C1 or C4 or C10), 147.6 (C1 or C4 or C10), 147.0 (C1 or C4 or C10), 129.4 (ArC), 127.6 (ArC), 121.9 (ArC), 118.4 (ArC), 116.6 (ArC), 113.6 (ArC), 111.6 (ArC), 95.3 (C15 or C17), 94.8 (C15 or C17), 56.22 (C16 or C18), 56.18 (C16 or C18), 53.6 (C13 & C14).
2-Ethynyl-1,1-dimethoxy-5,8-bis(methoxymethoxy)-1,2- dihydrocyclobuta[a]naphthalen-2-ol (2.216) (dik4-145). A solution of 2.174 (97 mg, 0.28 mmol) in THF (3.4 mL) was added to a solution of ethynylmagnesium bromide (3.4 mL, 0.5 M, 1.68 mmol) in THF at 0 ºC. After 5 min at 0 ºC and 2 h at room temperature, saturated aqueous NH4Cl (5 mL) was added. The reaction was diluted with Et2O (50 mL), 234 and the mixture was washed with H2O (3 × 10 mL). The organic phase was dried
(MgSO4) and the solvent was removed under reduced pressure to give 80 mg (77%) of
1 2.216 as a yellow oil; H NMR (400 MHz, CDCl3) δ 8.37 (d, J = 8.4 Hz, 1 H), 7.55 (d, J = 8.4 Hz, 1 H), 7.08 (d, J = 8.4 Hz, 1 H), 7.04 (d, J = 8.4 Hz, 1 H), 5.35-5.21 (comp, 4 H), 3.82 (br s, 1 H), 3.66 (s, 3 H), 3.64 (S, 3 H), 3.55 (s, 3 H), 3.50 (s, 3 H), 2.68 (s, 1 H);
13 C NMR (100 MHz, CDCl3) δ 148.5, 146.5, 145.7, 137.4, 127.7, 126.4, 112.9, 118.9, 111.0, 109.4, 107.5, 95.6, 95.2, 81.6, 77.4, 75.6, 56.2, 56.1, 53.0, 52.3; IR (neat) 3439, 3285, 2943, 2839, 1595, 1458, 1258, 1153, 1078, 1009 cm-1; mass spectrum (ESI) m/z
397.1258 [C20H22O7 (M+23) requires 397.1258], 397 (base).
1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 8.37 (d, J = 8.4 Hz, 1 H, C9-H or C10-H), 7.55 (d, J = 8.4 Hz, 1 H, C9-H or C10-H), 7.08 (d, J = 8.4 Hz, 1 H, C5-H or C6- H), 7.04 (d, J = 8.4 Hz, 1 H, C5-H or C6-H), 5.35-5.21 (comp, 4 H, C17-H & C19-H), 3.82 (br s, 1 H, OH), 3.66 (s, 3 H, C15-H or C16-H), 3.64 (S, 3 H, C15-H or C16-H), 3.55 (s, 3 H, C18-H or C20-H), 3.50 (s, 3 H, C18-H or C20-H), 2.68 (s, 1 H, C14-H); 13C
NMR (100 MHz, CDCl3) δ 148.5 (C4 or C7), 146.5 (C4 or C7), 145.7 (C1), 137.4 (ArC), 127.7 (ArC), 126.4 (C9 or C10), 112.9 (ArC), 118.9 (C9 or C10), 111.0 (C5 or C6), 109.4 (C5 or C6), 107.5 (ArC), 95.6 (C17 or C19), 95.2 (C17 or C19), 81.6 (C13), 77.4 (C12), 75.6 (C14), 56.2 (C18 or C20), 56.1 (C18 or C20), 53.0 (C15 or C16), 52.3 (C15 or C16).
235 20
19 O
5 15 6 4 O O 17 7 3 2 1 O 16 O 8 18 O 9 11 12 13 14 10 O 2.217 21 Si 22 Triethyl(2-ethynyl-1,1-dimethoxy-5,8-bis(methoxymethoxy)-1,2- dihydrocyclobuta[a]naphthalen-2-yloxy)silane (2.217) (dik5-146). Imidazole (73 mg, 1.07 mmol) and freshly distilled TESCl (72 μL, 0.43 mmol) were added to a solution of 2.216 (80 mg, 0.21 mmol) in DMF (3 mL) at 0 ºC. After 5 min at 0 ºC and 2.5 h at room
temperature, the reaction was diluted with Et2O (50 mL). The mixture was washed with
H2O (3 × 10 mL), the organic phase was dried (MgSO4), and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography eluting with hexanes/EtOAc (3:1) to give 58 mg (56%) of 2.217 as a yellow oil; 1H NMR
(400 MHz, CDCl3) δ 8.34 (d, J = 8.6 Hz, 1 H), 7.49 (d, J = 8.6 Hz, 1 H), 7.07 (d, J = 8.4 Hz, 1 H), 7.03 (d, J = 8.4 Hz, 1 H), 5.30 (s, 2 H), 5.29-5.24 (comp, 2 H), 3.61 (s, 3 H), 3.55 (s, 3 H), 3.53 (s, 3 H), 3.51 (s, 3 H), 2.75 (s, 1 H), 0.97 (t, J = 8.1 Hz, 9 H), 0.72 (q,
13 J = 8.1 Hz, 6 H); C NMR (100 MHz, CDCl3) δ 148.6, 146.9, 145.6, 138.5, 127.6, 125.9, 123.5, 119.2, 111.0, 109.4, 109.3, 95.6, 95.3, 83.5, 79.8, 76.4, 56.2, 53.2, 52.9, 6.9, 6.0; IR (neat) 2952, 2877, 2836, 1262, 1154, 1007 cm-1; mass spectrum (ESI) m/z
511.2119 [C26H36SiO7 (M+23) requires 511.2123], 999, 511 (base).
1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 8.34 (d, J = 8.6 Hz, 1 H, C9-H or C10-H), 7.49 (d, J = 8.6 Hz, 1 H, C9-H or C10-H), 7.07 (d, J = 8.4 Hz, 1 H, C5-H or C6- H), 7.03 (d, J = 8.4 Hz, 1 H, C5-H or C6-H), 5.30 (s, 2 H, C19-H), 5.29-5.24 (comp, 2 H, C17-H), 3.61 (s, 3 H, C15-H or C16-H), 3.55 (s, 3 H, C18-H or C20-H), 3.53 (s, 3 H, 236 C15-H or C16-H), 3.51 (s, 3 H, C18-H or C20-H), 2.75 (s, 1 H, C14-H), 0.97 (t, J = 8.1
13 Hz, 9 H, C22-H), 0.72 (q, J = 8.1 Hz, 6 H, C21-H); C NMR (100 MHz, CDCl3) δ 148.6 (C4 or C7), 146.9 (C4 or C7), 145.6 (C1), 138.5 (ArC), 127.6 (ArC), 125.9 (C9 or C10), 123.5 (ArC), 119.2 (C9 or C10), 111.0 (C5 or C6), 109.4 (C5 or C6), 109.3 (ArC), 95.6 (C17 or C19), 95.3 (C17 or C19), 83.5 (C12), 79.8 (C13), 76.4 (C14), 56.2 (C18 & C20), 53.2 (C15 or C16), 52.9 (C15 or C16), 6.9 (C21), 6.0 (C22).
2-(3-(2-(tert-Butyldimethylsilyloxy)-3,6-dimethoxyphenyl)-3-hydroxyprop-1- ynyl)-1,1-dimethoxy-5,8-bis(methoxymethoxy)-1,2-dihydrocyclobuta[a]naphthalen- 2-ol (2.223) (dik4-206). A solution of EtMgBr (0.55 mL, 3 M, 1.64 mmol) in THF was added dropwise to a solution of freshly dried (azeotropic distillation, 2 × 2 mL PhH) 2.216 (204 mg, 0.545 mmol) in THF (5.4 mL) at 0 ºC. After 2 h at room temperature, the reaction was cooled to 0 ºC, and a solution of freshly dried (azeotropic distillation, 2 × 2 mL PhH) aldehyde 2.149 (323 mg, 1.09 mmol) in THF (1 mL) was added dropwise.
After 30 min at 0 ºC and 10 min at room temperature, saturated aqueous NH4Cl (5 mL) was added. The mixture was extracted with Et2O (3 × 30 mL), and the organic phase was dried (MgSO4). The solvent was removed under reduced pressure, and the residue was purified by flash column chromatography eluting with hexanes/EtOAc (1:1) to give 42
237 mg (21%) of recovered 2.216 and 288 mg (79%) of 2.223 as a yellow oil; 1H NMR (400
MHz, CDCl3, mixture of diastereomers) δ 8.33 (d, J = 8.4 Hz, 0.4 H), 8.32 (d, J = 8.4 Hz, 0.6 H), 7.49 (d, J = 8.4 Hz, 0.4 H), 7.48 (d, J = 8.4 Hz, 0.6 H), 7.06 (d, J = 8.6 Hz, 0.4 H), 7.05 (d, J = 8.6 Hz, 0.6 H), 7.02 (d, J = 8.6 Hz, 0.4 H), 7.01 (d, J = 8.6 Hz, 0.6 H), 6.64 (d, J = 8.6 Hz, 0.4 H), 6.63 (d, J = 8.6 Hz, 0.6 H), 6.39 (app d, J = 8.6 Hz, 1 H), 5.86 ( br s, 0.4 H), 5.83 (br s, 0.6 H), 5.47-5.45 (comp, 4 H), 3.73 (s, 1.8 H), 3.69 (s, 1.2 H), 3.68 (s, 1.2 H), 3.67 (s, 1.8 H), 3.59 (app s, 3 H), 3.53 (s, 1.2 H), 3.52 (s, 1.8 H), 3.50 (s, 1.2 H), 3.49 (s, 1.8 H), 3.48 (s, 1.2 H), 3.47 (s, 1.8 H), 0.91 (s, 3.6 H), 0.89 (s, 5.4 H),
0.12 (s, 1.2 H), 0.11 (s, 1.2 H), 0.10 (s, 1.8 H), 0.04 (s, 1.8 H); 13C NMR (100 MHz,
CDCl3, mixture of diastereomers) δ 152.4, 148.7, 146.6, 146.3, 144.9, 142.1, 137.4, 127.6, 126.1, 123.1, 121.5, 121.4, 119.2, 111.2, 110.5, 109.3, 107.8, 103.8, 103.6, 95.7, 95.3, 88.3, 88.2, 81.1, 77.6, 57.7, 56.2, 56.1, 55.3, 53.0, 52.1, 26.0, 18.7, -4.2, -4.3; IR (neat) 3515, 2940, 2856, 1490, 1257, 1076 cm-1; mass spectrum (ESI) m/z 693.2700
[C35H46O11Si (M+23) requires 693.2702], 693 (base).
1 NMR Assignments. H NMR (400 MHz, CDCl3, mixture of diastereomers) δ 8.33 (d, J = 8.4 Hz, 0.4 H, C9-H or C10-H), 8.32 (d, J = 8.4 Hz, 0.6 H, C9-H or C10-H), 7.49 (d, J = 8.4 Hz, 0.4 H, C9-H or C10-H), 7.48 (d, J = 8.4 Hz, 0.6 H, C9-H or C10-H), 7.06 (d, J = 8.6 Hz, 0.4 H, C5-H or C6-H), 7.05 (d, J = 8.6 Hz, 0.6 H, C5-H or C6-H), 7.02 (d, J = 8.6 Hz, 0.4 H, C5-H or C6-H), 7.01 (d, J = 8.6 Hz, 0.6 H, C5-H or C6-H), 6.64 (d, J =
8.6 Hz, 0.4 H, C18-H or C19-H), 6.63 (d, J = 8.6 Hz, 0.6 H, C18-H or C19-H), 6.39 (app d, J = 8.6 Hz, 1 H, C18-H or C19-H), 5.86 ( br s, 0.4 H, C15-H), 5.83 (br s, 0.6 H, C15- H), 5.47-5.45 (comp, 4 H, C25-H & C27-H), 3.73 (s, 1.8 H, C31-H or C32-H), 3.69 (s, 1.2 H, C31-H or C32-H), 3.68 (s, 1.2 H, C31-H or C32-H), 3.67 (s, 1.8 H, C31-H or C32- H), 3.59 (app s, 3 H, C22-H or C23-H), 3.53 (s, 1.2 H, C25-H or C27-H), 3.52 (s, 1.8 H, C25-H or C27-H), 3.50 (s, 1.2 H, C25-H or C27-H), 3.49 (s, 1.8 H, C25-H or C27-H),
238 3.48 (s, 1.2 H, C22-H or C23-H), 3.47 (s, 1.8 H, C22-H or C23-H), 0.91 (s, 3.6 H, C30- H), 0.89 (s, 5.4 H, C30-H), 0.12 (s, 1.2 H, C28-H), 0.11 (s, 1.2 H, C28-H), 0.10 (s, 1.8 H,
13 C28-H), 0.04 (s, 1.8 H, 28-H); C NMR (100 MHz, CDCl3, mixture of diastereomers) δ 152.4 (C17), 148.7 (C4 or C7), 146.6 (C4 or C7), 146.3 (C1), 144.9 (C20 or C21), 142.1 (C20 or C21), 137.4 (ArC), 127.6 (ArC), 126.1 (C9 or C10), 123.1 (ArC), 121.5 (ArC), 121.4 (ArC), 119.2 (C9 or C10), 111.2 (C5 or C6), 110.5 (C18 or C19), 109.3 (C5 or C6), 107.8 (ArC), 103.8 (C18 or C19), 103.6 (C18 or C19), 95.7 (C24 or C26), 95.3 (C24 or C26), 88.3 (C13), 88.2 (C13), 81.1 (C12), 77.6 (C14), 57.7 (C31 or C32), 56.2 (C25 & C27), 56.1 (C15), 55.3 (C31 or C32), 53.0 (C22 or C23), 52.1 (C22 or C23), 26.0 (C30), 18.7 (C29), -4.2 (C28), -4.3 (C28).
2-(3-(2-(tert-Butyldimethylsilyloxy)-3,6-dimethoxyphenyl)-3-hydroxyprop-1-
ynyl)-2-hydroxy-5,8-bis(methoxymethoxy)cyclobuta[a]naphthalen-1(2H)-one (2.224) (dik4-208). p-TsOH (2.6 mg, 0.04 mmol) was added to a solution of ketal 2.223 (91 mg, 0.14 mmol) in acetone (2 mL) at room temperature. After 10 min at room temperature,
the reaction was diluted with Et2O (50 mL). The mixture was washed with H2O (2 × 10 mL) and brine (10 mL). The organic phase was dried (MgSO4), and the solvent was removed under reduced pressure to give 84 mg (99%) of 2.224 as an orange oil; 1H NMR
239 (400 MHz, CDCl3, mixture of diastereomers) δ 8.52 (d, J = 8.5 Hz, 0.4 H), 8.51 (d, J = 8.5 Hz, 0.6 H), 7.71 (app d, J = 8.5 Hz, 1 H), 7.19 (d, J = 8.6 Hz, 0.4 H), 7.28 (d, J = 8.6 Hz, 0.6 H), 7.15 (d, J = 8.6 Hz, 0.4 H), 7.14 (d, J = 8.6 Hz, 0.6 H), 6.67 (d, J = 8.9 Hz, 0.4 H), 6.66 (d, J = 8.9 Hz, 0.6 H), 6.42 (app d, J = 8.9 Hz, 1 H), 5.87 (app s, 1 H), 5.31 (app s, 4 H), 4.07 (app br s, 1 H), 3.79 (s, 1.8 H), 3.77 (s, 1.2 H), 3.69 (s, 1.2 H), 3.68 (s, 1.8 H), 3.54 (s, 1.2 H), 3.53 (s, 1.8 H), 3.50 (app s, 3 H), 0.94 (s, 3.6 H), 0.92 (s, 5.4 H), 0.15 (s, 1.2 H), 0.14 (s, 1.2 H), 0.13 (s, 1.8 H), 0.09 (s, 1.8 H); 13C NMR (100 MHz,
CDCl3, mixture of diastereomers) δ 183.3, 159.8, 152.3, 148.4, 147.3, 144.9, 143.0, 142.2, 132.2, 127.7, 120.8, 120.7, 118.6, 113.9, 111.3, 110.8, 103.9, 95.4, 95.3, 91.3, 85.7, 79.6, 57.5, 56.3, 55.3, 26.0, 18.8, -4.09, -4.14; IR (neat) 3375, 2930, 2855, 1774,
-1 1491, 1256, 1078 cm ; mass spectrum (ESI) m/z 647.2288 [C33H40O10Si (M+23) requires 647.2283], 647 (base).
1 NMR Assignments. H NMR (400 MHz, CDCl3, mixture of diastereomers) δ 8.52 (d, J = 8.5 Hz, 0.4 H, C9-H or C10-H), 8.51 (d, J = 8.5 Hz, 0.6 H, C9-H or C10-H), 7.71 (app d, J = 8.5 Hz, 1 H, C9-H or C10-H), 7.19 (d, J = 8.6 Hz, 0.4 H, C5-H or C6-H), 7.28 (d, J = 8.6 Hz, 0.6 H, C5-H or C6-H), 7.15 (d, J = 8.6 Hz, 0.4 H, C5-H or C6-H), 7.14 (d, J = 8.6 Hz, 0.6 H, C5-H or C6-H), 6.67 (d, J = 8.9 Hz, 0.4 H, C18-H or C19-H), 6.66 (d, J = 8.9 Hz, 0.6 H, C18-H or C19-H), 6.42 (app d, J = 8.9 Hz, 1 H, C18-H or C19-H), 5.87 (app s, 1 H, C15-H), 5.31 (app s, 4 H, C22-H & C24-H), 4.07 (app br s, 1 H, OH), 3.79
(s, 1.8 H, C29-H or C30-H), 3.77 (s, 1.2 H, C29-H or C30-H), 3.69 (s, 1.2 H, C29-H or C30-H), 3.68 (s, 1.8 H, C29-H or C30-H), 3.54 (s, 1.2 H, C23-H or C25-H), 3.53 (s, 1.8 H, C23-H or C25-H), 3.50 (app s, 3 H, C23-H or C25-H), 0.94 (s, 3.6 H, C28-H), 0.92 (s, 5.4 H, C28-H), 0.15 (s, 1.2 H, C26-H), 0.14 (s, 1.2 H, C26-H), 0.13 (s, 1.8 H, C26-H),
13 0.09 (s, 1.8 H, C26-H); C NMR (100 MHz, CDCl3, mixture of diastereomers) δ 183.3 (C1), 159.8 (ArC), 152.3 (ArC), 148.4 (ArC), 147.3 (ArC), 144.9 (ArC), 143.0 (ArC),
240 142.2 (ArC), 132.2 (ArC), 127.7 (ArC), 120.8 (ArC), 120.7 (ArC), 118.6 (ArC), 113.9 (ArC), 111.3 (ArC), 110.8 (C18 or C19), 103.9 (C18 or C19), 95.4 (C22 or C24), 95.3 (C22 or C24), 91.3 (C12), 85.7 (C13), 79.6 (C14), 57.5 (C29 or C30), 56.3 (C23 & C25 & C15), 55.3 (C29 or C30), 26.0 (C28), 18.8 (C27), -4.09 (C26), -4.14 (C26).
23
O 22
5 30 5 29 4 O 4 OH OH 6 OH O 6 O O 24O O 7 3 15 17 7 3 17 2 14 16 18 2 16 18 O 1 O 1 15 8 + 8 24 21 22 9 12 13 19 12 13 21 O 11 O 9 11 19 10 O 20 10 O 20 O O O O 25 Si 23 Si 26 29 25 28 27 26 2.22528 2.227 27 3-((2-(tert-Butyldimethylsilyloxy)-3,6-dimethoxyphenyl)(hydroxy)methyl)- 5,8-bis(methoxymethoxy)phenanthrene-1,4-dione (2.225) and 3-(2-(tert- butyldimethylsilyloxy)-3,6-dimethoxybenzoyl)-5-hydroxy-3-(hydroxymethyl)-8- (methoxymethoxy)-2,3-dihydrophenanthrene-1,4-dione (2.227) (dik4-184). A solution of benzocyclobutenone 2.224 (45 mg, 0.07 mmol) in DMSO (3 mL) was heated to 100 ºC for 20 min and 120 ºC for 10 min. Upon cooling to room temperature, H2O (10 mL) was added, and the mixture was extracted with Et2O (3 × 10 mL). The combined organic
phases were washed with H2O (3 × 10 mL) and brine (10 mL) and then dried (Na2SO4). The solvent was removed under reduced pressure, and the residue was purified by flash column chromatography eluting with hexanes/EtOAc (1:2) to give 19 mg (42%) of 2.225 as a burnt orange oil and 10 mg (22%) of 2.227 as a burnt orange oil:
241 23
O 22 5 30 6 4 O O OH O 7 3 17 2 1415 16 1 18 O 8 24 12 13 21 O 9 11 19 10 O 20 O O 25 Si 26 29 27 2.225 28 1 H NMR (400 MHz, CDCl3) δ 8.42 (d, J = 8.8 Hz, 1 H), 8.05 (d, J = 8.8 Hz, 1 H), 7.24 (d, J = 8.6 Hz, 1 H), 7.13 (d, J = 8.6 Hz, 1 H), 6.78 (d, J = 2.3 Hz, 1 H), 6.75 (d, J = 8.8 Hz, 1 H,), 6.46 (d, J = 10.0, 2.3 Hz, 1 H), 6.41 (d, J = 8.8 Hz, 1 H), 5.31 (d, J = 10.0 Hz, 1 H), 5.30 (d, J = 8.4 Hz, 1 H), 5.29 (d, J = 8.4 Hz, 1 H), 4.77 (d, J = 6.8 Hz, 1 H), 4.59 (d, J = 6.8 Hz, 1 H), 3.77 (s, 3 H), 3.62 (s, 3 H), 3.49 (s, 3 H), 3.33 (s, 3 H), 1.00 (s, 9 H),
13 0.22 (s, 6 H); C NMR (100 MHz, CDCl3) δ 187.4, 185.2, 157.1, 152.3, 149.9, 147.8, 145.1, 143.8, 135.1, 132.5, 129.6, 128.1, 126.5, 122.2, 121.1, 120.3, 113.5, 112.1, 110.6, 102.9, 96.0, 95.3, 64.6, 56.2, 55.8, 55.7, 55.1, 26.0, 18.9, -3.8, -4.2; IR (neat) 3425, 2956, 2931, 2856, 1659, 1489, 1454, 1255 cm-1; mass spectrum (ESI) m/z 647.2285
[C33H40O10Si (M+23) requires 647.2283], 647 (base).
1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 8.42 (d, J = 8.8 Hz, 1 H, C9-H or C10-H), 8.05 (d, J = 8.8 Hz, 1 H, C9-H or C10-H), 7.24 (d, J = 8.6 Hz, 1 H, C5-H or C6-
H), 7.13 (d, J = 8.6 Hz, 1 H, C5-H or C6-H), 6.78 (d, J = 2.3 Hz, 1 H, C13-H), 6.75 (d, J = 8.8 Hz, 1 H, C18-H or C19-H), 6.46 (d, J = 10.0, 2.3 Hz, 1 H, C15-H), 6.41 (d, J = 8.8 Hz, 1 H, C18-H or C19-H), 5.31 (d, J = 10.0 Hz, 1 H, OH), 5.30 (d, J = 8.4 Hz, 1 H, C24-H), 5.29 (d, J = 8.4 Hz, 1 H, C24-H), 4.77 (d, J = 6.8 Hz, 1 H, C22-H), 4.59 (d, J = 6.8 Hz, 1 H, C22-H), 3.77 (s, 3 H, C29-H or C30-H), 3.62 (s, 3 H, C29-H or C30-H), 3.49 (s, 3 H, C23-H or C25-H), 3.33 (s, 3 H, C23-H or C25-H), 1.00 (s, 9 H, C28-H),
242 13 0.22 (s, 6 H, C26-H); C NMR (100 MHz, CDCl3) δ 187.4 (C12), 185.2 (C1), 157.1 (C14), 152.3 (C7), 149.9 (ArC), 147.8 (ArC), 145.1 (ArC), 143.8 (ArC), 135.1 (ArC), 132.5 (ArC), 129.6 (ArC), 128.1 (ArC), 126.5 (ArC), 122.2 (ArC), 121.1 (ArC), 120.3 (ArC), 113.5 (C5 or C6), 112.1 (C18 or C19), 110.6 (C5 or C6), 102.9 (C18 or C19), 96.0 (C22 or C24), 95.3 (C22 or C24), 64.6 (C15), 56.2 (C29 or C30), 55.8 (C23 or C25), 55.7 (C23 or C25), 55.1 (C29 or C30), 26.0 (C28), 18.9 (C27), -3.8 (C26), -4.2 (C26).
1 H NMR (500 MHz, CDCl3) δ 11.57 (s, 1 H), 8.77 (d, J = 8.7 Hz, 1 H), 7.90 (d, J = 8.7 Hz, 1 H), 7.35 (d, J = 8.7 Hz, 1 H), 7.11 (d, J = 8.7 Hz, 1 H), 6.77 (d, J = 9.0 Hz, 1 H), 6.35 (d, J = 9.0 Hz, 1 H), 5.32 (s, 2 H), 3.91 (app d, J = 5.9 Hz, 2 H), 3.71 (s, 3 H), 3.68 (s, 3 H), 3.64 (d, J = 18.7 Hz, 1 H), 3.58 (d, J = 18.7 Hz, 1 H), 3.53 (s, 3 H), 1.84 (app br
13 t, J = 5.9 Hz, 1 H) 0.89 (s, 9 H), 0.04 (s, 3 H), 0.03 (s, 3 H); C NMR (125 MHz, CDCl3) δ 207.8, 200.3, 199.9, 150.6, 150.3, 146.2, 144.8, 144.7, 142.2, 139.9, 133.1, 130.1, 122.1, 119.8, 117.4, 115.6, 115.0, 112.5, 103.3, 95.8, 65.8, 56.8, 56.3, 56.2, 55.3, 46.4, 25.8, 18.7, -4.1, -4.2; IR (neat) 3451, 2930, 2856, 1736, 1709, 1681, 1485, 1257 cm-1;
mass spectrum (ESI) m/z 633.07 [C32H38O10Si (M+23) requires 633.21].
1 NMR Assignments. H NMR (500 MHz, CDCl3) δ 11.57 (s, 1 H, ArOH), 8.77 (d, J = 8.7 Hz, 1 H, C9-H or C10-H), 7.90 (d, J = 8.7 Hz, 1 H, C9-H or C10-H), 7.35 (d, J = 8.7 Hz, 1 H, C 5-H or C6-H), 7.11 (d, J = 8.7 Hz, 1 H, C5-H or C6-H), 6.77 (d, J = 9.0 Hz, 1 H, C18-H or C19-H), 6.35 (d, J = 9.0 Hz, 1 H, C18-H or C19-H), 5.32 (s, 2 H, C22-H), 3.91 (app d, J = 5.9 Hz, 2 H, C24-H), 3.71 (s, 3 H, C28-H or C29-H), 3.68 (s, 3 H, C28-
243 H or C29-H), 3.64 (d, J = 18.7 Hz, 1 H, C13-H), 3.58 (d, J = 18.7 Hz, 1 H, C13-H), 3.53 (s, 3 H, C23-H), 1.84 (app br t, J = 5.9 Hz, 1 H, OH) 0.89 (s, 9 H, C27-H), 0.04 (s, 3 H,
13 C25-H), 0.03 (s, 3 H, C25-H); C NMR (125 MHz, CDCl3) δ 207.8 (C1), 200.3 (C12), 199.9 (C15), 150.6 (C4 or C17), 150.3 (C4 or C17), 146.2 (ArC), 144.8 (ArC), 144.7 (ArC), 142.2 (ArC), 139.9 (ArC), 133.1 (C9 or C10), 130.1 (ArC), 122.1 (ArC), 119.8 (ArC), 117.4 (C9 or C10), 115.6 (C5 or C6), 115.0 (C5 or C6), 112.5 (C18 or C19), 103.3 (C18 or C19), 95.8 (C22), 65.8 (C24), 56.8 (C14), 56.3 (C23), 56.2 (C28 or C29), 55.3 (C28 or C29), 46.4 (C13), 25.8 (C27), 18.7 (C26), -4.1 (C25), -4.2 (C25).
23 27 O 22 O 5 18 6 4 O OH O 16 19 25 24 7 3 15 2 20 O O 1 21 8 14 O O 9 12 13 11 10 26 O
2.230 3-Hydroxy-4,7-dimethoxy-5',8'-bis(methoxymethoxy)-1'H,3H- spiro[benzofuran-2,3'-phenanthrene]-1',4'(2'H)-dione (2.230) (dik4-194). Pyridine (3 μL, 0.04 mmol) and HF·pyridine (2 drops, 70% wt, 0.04 mmol) were added to a solution of 2.225 (9 mg, 0.01 mmol) in THF (1 mL) in a plastic tube at room temperature. After 4
d at room temperature, the reaction was diluted with Et2O (25 mL). The mixture was
washed with brine (3 × 10 mL), and the organic phase was dried (MgSO4). The solvent was removed under reduced pressure, and the residue was purified by flash column chromatography eluting with hexanes/EtOAc (1:3) to give 4 mg (52%) of 2.230 as a dark
1 yellow oil; H NMR (400 MHz, CDCl3) δ 8.42 (d, J = 8.8 Hz, 1 H), 8.04 (d, J = 8.8 Hz, 1 H), 7.20 (d, J = 8.4 Hz, 1 H), 7.12 (d, J = 8.4 Hz, 1 H), 6.83 (d, J = 8.8 Hz, 1 H), 6.77
244 (d, J = 8.8 Hz, 1 H,), 5.93 (br s, 1 H), 5.32 (s, 2 H), 4.67 (d, J = 6.8 Hz, 1 H), 4.53 (d, J = 6.8 Hz, 1 H), 3.87 (d, J = 18.0 Hz, 1 H), 3.80 (s, 3 H), 3.76 (s, 3 H), 3.51 (s, 3 H), 3.50
13 (d, J = 18.0 Hz, 1 H), 3.09 (s, 3 H); C NMR (100 MHz, CDCl3) δ 196.1, 191.6, 150.9, 148.95, 148.86, 147.7, 139.4, 137.3, 134.7, 129.9, 126.5, 122.4, 121.7, 116.3, 115.5, 112.9, 111.6, 103.2, 95.4, 95.3, 94.5, 70.7, 57.1, 56.3, 55.9, 55.6, 44.3; IR (neat) 3452,
2925, 2851, 1719, 1686, 1509, 1265, 1049 cm-1; mass spectrum (ESI) m/z 509.1455
[C27H26O10 (M-1) requires 509.1453], 509 (base).
1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 8.42 (d, J = 8.8 Hz, 1 H, C9-H or C10-H), 8.04 (d, J = 8.8 Hz, 1 H, C9-H or C10-H), 7.20 (d, J = 8.4 Hz, 1 H, C5-H or C6- H), 7.12 (d, J = 8.4 Hz, 1 H, C5-H or C6-H), 6.83 (d, J = 8.8 Hz, 1 H, C18-H or C19-H), 6.77 (d, J = 8.8 Hz, 1 H, C18-H or C19-H), 5.93 (br s, 1 H, C15-H), 5.32 (s, 2 H, C15- H), 4.67 (d, J = 6.8 Hz, 1 H, C22-H), 4.53 (d, J = 6.8 Hz, 1 H, C22-H), 3.87 (d, J = 18.0 Hz, 1 H, C13-H), 3.80 (s, 3 H, C26-H or C27-H), 3.76 (s, 3 H, C26-H or C27-H), 3.51 (s, 3 H, C23-H or C25-H), 3.50 (d, J = 18.0 Hz, 1 H, C13-H), 3.09 (s, 3 H, C23-H or C25-
13 H); C NMR (100 MHz, CDCl3) δ 196.1 (C12), 191.6 (C1), 150.9 (C17), 148.95 (ArC), 148.86 (ArC), 147.7 (ArC), 139.4 (ArC), 137.3 (ArC), 134.7 (ArC), 129.9 (ArC), 126.5 (C9 or C10), 122.4 (ArC), 121.7 (C9 or C10), 116.3 (ArC), 115.5 (C18 or C19), 112.9 (C5 or C6), 111.6 (C5 or C6), 103.2 (C18 or C19), 95.4 (C22 or C24), 95.3 (C22 or C24), 94.5 (C14), 70.7 (C15), 57.1 (C26 or C27), 56.3 (C23 or C25), 55.9 (C23 or C25), 55.6
(C26 or C27), 44.3 (C13).
245 23
O 22 5 30 6 4 O O O O 7 3 17 2 14 16 1 18 O 8 15 24 12 13 21 O 9 11 19 10 O 20 O O 25 Si 26 29 27 2.232 28 3-(2-(tert-Butyldimethylsilyloxy)-3,6-dimethoxybenzoyl)-5,8- bis(methoxymethoxy)phenanthrene-1,4-dione (2.232) (dik4-250). IBX (81 mg, 0.29 mmol) was added to a solution of alcohol 2.225 (60 mg, 0.10 mmol) in DMSO (2.5 mL)
at room temperature. After 18 h at room temperature, saturated aqueous Na2S2O3 (5 mL)
and saturated aqueous NaHCO3 (5 mL) were added, and the reaction was stirred for 10 min at room temperature. Brine (10 mL) was added, and the mixture was extracted with
Et2O (3 × 15 mL). The combined organic phases were washed with saturated aqueous
NaHCO3 (10 mL) and H2O (10 mL) and dried (Na2SO4). The solvent was removed under
1 reduced pressure to give 58 mg (97%) of 2.232 as a red oil; H NMR (400 MHz, CDCl3) δ 8.49 (d, J = 8.7 Hz, 1 H), 8.07 (d, J = 8.7 Hz, 1 H), 7.35 (d, J = 8.9 Hz, 1 H), 7.19 (d, J = 8.9 Hz, 1 H), 7.11 (s, 1 H), 6.89 (d, J = 8.9 Hz, 1 H), 6.43 (d, J = 8.9 Hz, 1 H), 5.32 (s, 2 H), 4.74 (s, 2 H), 3.78 (s, 3 H), 3.51 (s, 3 H), 3.51 (s, 3 H), 3.36 (s, 3 H), 0.85 (s, 9 H),
13 0.15 (s, 6 H); C NMR (100 MHz, CDCl3) δ 189.7, 185.8, 185.4, 151.9, 150.1, 148.6, 148.0, 145.4, 144.6, 133.8, 132.6, 132.0, 130.0, 127.1, 122.1, 121.7, 121.1, 114.5, 113.8, 112.5, 102.4, 96.2, 95.3, 56.3, 55.8, 55.7, 25.7, 18.6, -4.4; IR (neat) 2932, 2856, 1662,
-1 1592, 1483, 1254, 1102, cm ; mass spectrum (ESI) m/z 623.2306 [C33H39O9Si (M+1) requires 623.2307], 645 (base).
246 1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 8.49 (d, J = 8.7 Hz, 1 H, C9-H or C10-H), 8.07 (d, J = 8.7 Hz, 1 H, C9-H or C10-H), 7.35 (d, J = 8.9 Hz, 1 H, C5-H), 7.19 (d, J = 8.9 Hz, 1 H, C5-H), 7.11 (s, 1 H, C13-H), 6.89 (d, J = 8.9 Hz, 1 H, C18-H or C19-H), 6.43 (d, J = 8.9 Hz, 1 H, C18-H or C19-H), 5.32 (s, 2 H, C22-H or C24-H), 4.74 (s, 2 H, C22-H or C24-H), 3.78 (s, 3 H, C29-H or C30-H), 3.51 (s, 3 H, C29-H or C30- H), 3.51 (s, 3 H, C23-H or C25-H), 3.36 (s, 3 H, C23-H or C25-H), 0.85 (s, 9 H, C28-H),
13 0.15 (s, 6 H, C26-H); C NMR (100 MHz, CDCl3) δ 189.7 (C15), 185.8 (C12), 185.4 (C1), 151.9 (ArC), 150.1 (ArC), 148.6 (ArC), 148.0 (ArC), 145.4 (ArC), 144.6 (ArC), 133.8 (ArC), 132.6 (ArC), 132.0 (ArC), 130.0 (ArC), 127.1 (ArC), 122.1 (ArC), 121.7 (ArC), 121.1 (ArC), 114.5 (C5 or C6), 113.8 (C5 or C6), 112.5 (C18 or C19), 102.4 (C18 or C19), 96.2 (C22 or C24), 95.3 (C22 or C24), 56.3 (C19 or C30), 55.8 (C23 & C25), 55.7 (C29 or C30), 25.7 (C28), 18.6 (C27), -4.4 (C26).
23 27 O 22 O 5 18 6 4 O O O 16 19 25 24 7 3 15 2 20 O O 1 21 8 14 O O 9 12 13 11 10 26 O 2.234 4,7-Dimethoxy-5',8'-bis(methoxymethoxy)-1'H,3H-spiro[benzofuran-2,3'- phenanthrene]-1',3,4'(2'H)-trione (2.234) (dik4-223). Pyridine (5 μL, 0.06 mmol) and HF·pyridine (2 drops, 70% wt, 0.07 mmol) were added to a solution of 2.232 (14 mg, 0.02 mmol) in THF (1 mL) in a plastic tube at room temperature. After 1 day at room temperature, additional HF·pyridine (2 drops) was added, and the reaction was stirred at room temperature. After 1 day, the reaction was diluted with Et2O (30 mL), and the
247 mixture was washed with brine (10 mL), saturated aqueous CuSO4 (2 × 10 mL), and H2O
(10 ml). The organic phase was dried (Na2SO4), and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography eluting with
hexanes/EtOAc (2:3) to give 10 mg (91%) of 2.234 as an orange oil; 1H NMR (400 MHz,
CDCl3) δ 8.46 (d, J = 8.7 Hz, 1 H), 8.04 (d, J = 8.7 Hz, 1 H), 7.18 (d, J = 8.6 Hz, 1 H), 7.15 (d, J = 8.9 Hz, 1 H), 7.07 (d, J = 8.6 Hz, 1 H), 6.41 (d, J = 8.9 Hz, 1 H), 5.30 (s, 2 H), 4.85 (d, J = 6.8 Hz, 1 H), 4.76 (d, J = 6.8 Hz, 1 H), 3.93 (s, 3 H), 3.81 (s, 3 H), 3.58 (d, J = 17.8 Hz, 1 H), 3.51 (d, J = 17.8 Hz, 1 H), 3.49 (s, 3 H), 3.14 (s, 3 H); 13C NMR
(100 MHz, CDCl3) δ 191.4, 190.4, 189.2, 161.3, 151.7, 148.5, 147.5, 139.9, 135.6, 135.3, 129.8, 127.2, 122.2, 122.1, 121.3, 112.7, 111.7, 109.7, 103.2, 95.3, 95.1, 93.5, 57.0, 56.2, 56.02, 55.97, 46.1; IR (neat) 2936, 2841, 1710, 1691, 1515, 1273, 1077 cm-1; mass
spectrum (ESI) m/z 509.1451 [C27H24O10 (M+1) requires 509.1442], 531, 509 (base).
1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 8.46 (d, J = 8.7 Hz, 1 H, C9-H or C10-H), 8.04 (d, J = 8.7 Hz, 1 H, C9-H or C10-H), 7.18 (d, J = 8.6 Hz, 1 H, C5-H or C6- H), 7.15 (d, J = 8.9 Hz, 1 H, C18-H or C19-H), 7.07 (d, J = 8.6 Hz, 1 H, C5-H or C6-H), 6.41 (d, J = 8.9 Hz, 1 H, C18-H or C19-H), 5.30 (s, 2 H, C24-H), 4.85 (d, J = 6.8 Hz, 1 H, C22-H), 4.76 (d, J = 6.8 Hz, 1 H, C22-H), 3.93 (s, 3 H, C26-H), 3.81 (s, 3 H, C27-H), 3.58 (d, J = 17.8 Hz, 1 H, C13-H), 3.51 (d, J = 17.8 Hz, 1 H, C13-H), 3.49 (s, 3 H, C23-
13 H or C25-H), 3.14 (s, 3 H, C23-H or C25-H); C NMR (100 MHz, CDCl3) δ 191.4 (C1), 190.4 (C12), 189.2 (C15), 161.3 (ArC), 151.7 (ArC), 148.5 (ArC), 147.5 (ArC), 139.9 (ArC), 135.6 (ArC), 135.3 (ArC), 129.8 (ArC), 127.2 (C9 or C10), 122.2 (ArC), 122.1 (C9 or C10), 121.3 (ArC), 112.7 (C9 or C10) 111.7 (C5 or C6), 109.7 (C5 or C6), 103.2 (C18 or C19), 95.3 (C22 or C24), 95.1 (C22 or C24), 93.5 (C14), 57.0 (C16 or C27), 56.2 (C26 or C27), 56.02 (C25), 55.97 (C23), 46.1 (C13).
248 23
22 O 5 4 O 27 6 O O O 25 24 7 3 17 2 14 16 18 O O 1 15 8 9 12 19 11 13 O 21 10 20 O O 26 2.171 9,12-Dimethoxy-1,4-bis(methoxymethoxy)-1H-naphtho[1,2-b]xanthene- 7,13,14-trione (2.171) (dik4-260). A solution of spirocycle 2.234 (10 mg, 0.01 mmol) in
PhNO2 was heated at 215 ºC for 1.5 h. The reaction was cooled to room temperature, and the majority of the solvent was removed by distillation under high vacuum at 54–56 ºC.
The residual mixture was diluted with CH2Cl2 (20 mL) and washed with H2O (2 × 10
mL), 1 M KOH (2 × 10 mL). The aqueous KOH layer was extracted with CH2Cl2 (2 × 10 mL). The combined organic phases were dried (Na2SO4), and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography eluting with hexanes/EtOAc (1:3) to give 6 mg (58%) of 2.171 as a red solid: mp 192-
1 194 ºC; H NMR (500 MHz, CDCl3) δ 8.47 (d, J = 8.8 Hz, 1 H), 8.12 (d, J = 8.8 Hz, 1 H), 7.37 (d, J = 8.5 Hz, 1 H), 7.25 (d, J = 8.5 Hz, 1 H), 7.21 (d, J = 9.0 Hz, 1 H), 6.82 (d, J = 9.0 Hz, 1 H), 5.33 (s, 2 H), 5.32 (s, 2 H), 4.00 (s, 3 H), 3.95 (s, 3 H), 3.60 (s, 3 H),
13 3.52 (s, 3 H); C NMR (125 MHz, CDCl3) δ 182.2, 178.8, 173.5, 153.3, 152.5, 150.2, 147.8, 147.0, 143.1, 136.4, 130.5, 129.9, 127.1, 122.5, 122.3, 120.6, 117.3, 117.1, 114.0, 113.6, 107.1, 96.7, 95.4, 57.1, 56.8, 56.4, 56.3; IR (neat) 2925, 2854, 1693, 1586, 1489,
-1 1287, 1072 cm ; mass spectrum (ESI) m/z 507.1290 [C27H22O10 (M+1) requires 507.1286], 529, 507 (base).
1 NMR Assignments. H NMR (500 MHz, CDCl3) δ 8.47 (d, J = 8.8 Hz, 1 H, C9-H or C10-H), 8.12 (d, J = 8.8 Hz, 1 H, C9-H or C10-H), 7.37 (d, J = 8.5 Hz, 1 H, C5-H or C6- 249 H), 7.25 (d, J = 8.5 Hz, 1 H, C5-H or C6-H), 7.21 (d, J = 9.0 Hz, 1 H, C18-H or C19-H), 6.82 (d, J = 9.0 Hz, 1 H, C18-H or C19-H), 5.33 (s, 2 H, C22-H or C24-H), 5.32 (s, 2 H, C22-H or C24-H), 4.00 (s, 3 H, C26-H or C27-H), 3.95 (s, 3 H, C26-H or C27-H), 3.60
13 (s, 3 H, C23-H or C25-H), 3.52 (s, 3 H, C23-H or C25-H); C NMR (125 MHz, CDCl3) δ 182.2 (C1), 178.8 (C12), 173.5 (C15), 153.3 (C13), 152.5 (ArC), 150.2 (ArC), 147.8 (ArC), 147.0 (ArC), 143.1 (ArC), 136.4 (C2), 130.5 (C11), 129.9 (ArC), 127.1 (C9 or C10), 122.5 (C9 or C10), 122.3 (C14), 120.6 (C18 or C19), 117.3 (ArC), 117.1 (ArC), 114.0 (C18 or C19), 113.6 (C5 or C6), 107.1 (C5 or C6), 96.7 (C22 or C24), 95.4 (C22 or C24), 57.1 (C26 or C27), 56.8 (C26 or C27), 56.4 (C23 or C25), 56.3 (C23 or C25).
25 O 5 18 6 4 OH O O 16 19 23 22 7 3 15 2 20 O O 1 21 8 14 O O 9 12 13 11 10 24 O 2.242 5'-Hydroxy-4,7-dimethoxy-8'-(methoxymethoxy)-1'H,3H-spiro[benzofuran-
2,3'-phenanthrene]-1',3,4'(2'H)-trione (2.242) (dik5-53). A solution of H2O (0.1 mL) in TFA (0.9 mL) was added dropwise to a solution of spirocycle 2.234 (32 mg, 0.06
mmol) in CH2Cl2 (3 mL) at 0 ºC. After 30 min at 0 ºC, saturated aqueous NaHCO3 (20
mL) was slowly added (CO2 evolved), and the mixture was extracted with CH2Cl2 (3 ×
10 mL). The combined organic phases were was with H2O (2 × 10 mL), dried (Na2SO4), and the solvent was removed under reduced pressure to give 30 mg (~100%) of 2.242 as
1 a dark red oil; H NMR (400 MHz, CDCl3) δ 8.83 (d, J = 8.9 Hz, 1 H), 8.82 (s, 1 H), 8.24 (d, J = 8.9 Hz, 1 H), 7.29 (d, J = 8.9 Hz, 1 H), 7.17 (d, J = 8.9 Hz, 1 H), 7.14 (d, J = 8.9 Hz, 1 H), 6.41 (d, J = 8.9 Hz, 1 H), 5.31 (s, 2 H), 3.96 (s, 3 H), 3.80 (s, 3 H), 3.63 d, J = 250 13 16.6 Hz, 1 H), 3.51 (s, 3 H), 3.44 (d, J = 16.6 Hz, 1 H); C NMR (100 MHz, CDCl3) δ 193.9, 191.0, 190.1, 161.6, 152.1, 148.9, 147.2, 140.0, 139.7, 132.6, 130.5, 129.7, 123.0, 121.6, 121.1, 118.5, 114.2, 108.7, 103.8, 95.5, 93.2, 57.1, 56.3, 56.1, 45.2; IR (neat) 3416, 2953, 1705, 1596, 1515, 1271, 1077 cm-1; mass spectrum (ESI) m/z 487.1000
[C25H20O9 (M+23) requires 487.1000], 951 (base), 465.
1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 8.83 (d, J = 8.9 Hz, 1 H, C9-H or C10-H), 8.82 (s, 1 H, ArOH), 8.24 (d, J = 8.9 Hz, 1 H, C9-H or C10-H), 7.29 (d, J = 8.9 Hz, 1 H, C5-H or C6-H), 7.17 (d, J = 8.9 Hz, 1 H, C18-H or C19-H), 7.14 (d, J = 8.9 Hz, 1 H, C5-H or C6-H), 6.41 (d, J = 8.9 Hz, 1 H, C18-H or C19-H), 5.31 (s, 2 H, C22-H), 3.96 (s, 3 H, C24-H or C25-H), 3.80 (s, 3 H, C24-H or C25-H), 3.63 d, J = 16.6 Hz, 1 H,
C13-H), 3.51 (s, 3 H, C23-H), 3.44 (d, J = 16.6 Hz, 1 H, C13-H); 13C NMR (100 MHz,
CDCl3) δ 193.9 (C1), 191.0 (C12), 190.1 (C15), 161.6 (ArC), 152.1 (ArC), 148.9 (ArC), 147.2 (ArC), 140.0 (ArC), 139.7 (ArC), 132.6 (ArC), 130.5 (ArC), 129.7 (ArC), 123.0 (ArC), 121.6 (ArC), 121.1 (ArC), 118.5 (ArC), 114.2 (ArC), 108.7 (ArC), 103.8 (ArC), 95.5 (C22), 93.2 (C14), 57.1 (C24 or C25), 56.3 (C24 or C25), 56.1 (C23), 45.2 (C13).
5 26 6 4 OH O O O 7 3 17 2 14 16 1 18 HO 8 15 12 13 21 9 11 19 10 O 20 O Si O 22 25 23 2.243 24 3-(2-(tert-Butyldimethylsilyloxy)-3,6-dimethoxybenzoyl)-5,8-
dihydroxyphenanthrene-1,4-dione (2.243) (dik5-50). A solution of H2O (0.1 mL) in
TFA (0.9 mL) was added dropwise to a solution of 2.232 (28 mg, 0.05 mmol) in CH2Cl2
(2.5 mL) at 0 ºC. After 30 min at 0 ºC, saturated aqueous NaHCO3 (20 mL) was slowly
251 added, and the mixture was extracted with CH2Cl2 (3 × 10 mL). The combined organic phases were washed with H2O (3 × 10 mL) and dried (Na2SO4), and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography eluting with hexanes/EtOAc (2:1) to give 11 mg (47%) of 2.243 as a
1 yellow oil; H NMR (400 MHz, CDCl3) δ 13.69 (s, 1 H), 8.39 (d, J = 8.6 Hz, 1 H), 8.19 (d, J = 8.6 Hz, 1 H), 7.15 (d, J = 8.6 Hz, 1 H), 6.88 (d, J = 10.4 Hz, 1 H), 6.84 (d, J = 8.6 Hz, 1 H), 6.81 (s, 1 H), 6.52 (d, J = 10.4 Hz, 1 H), 4.94 (s, 1 H), 3.80 (s, 3 H), 3.70 (s, 3 H), 0.63 (s, 9 H), 0.06 (s, 6 H); IR (neat) 3343, 2929, 1666, 1623, 1594, 1487, 1296,
-1 1254, 1102, 1020 cm ; mass spectrum (ESI) m/z 535.1784 [C29H30O8Si (M+1) requires 535.1783], 557, 535 (base).
1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 13.69 (s, 1 H, ArOH), 8.39 (d, J = 8.6 Hz, 1 H, C9-H or C10-H), 8.19 (d, J = 8.6 Hz, 1 H, C9-H or C10-H), 7.15 (d, J = 8.6 Hz, 1 H, C5-H or C6-H), 6.88 (d, J = 10.4 Hz, 1 H, C18-H or C19-H), 6.84 (d, J = 8.6 Hz, 1 H, C5-H or C6-H), 6.81 (s, 1 H, C13-H), 6.52 (d, J = 10.4 Hz, 1 H, C18-H or C19- H), 4.94 (s, 1 H, ArOH), 3.80 (s, 3 H, C25-H or C26-H), 3.70 (s, 3 H, C25-H or C26-H), 0.63 (s, 9 H, C24-H), 0.06 (s, 6 H, C22-H).
1-Bromo-2,5-dimethoxy-4-(2-(methoxymethoxy)propyl)benzene (2.267)
(dik5-291). MOMCl (5.74 mL, 75.53 mmol) and i-Pr2Net (17.54 mL, 100.70 mmol) were added dropwise to a solution of 2.261 (13.85 g, 50.35 mmol) in CH2Cl2 (25 mL) at 252 0 ºC. After 20 h at room temperature, Et2O (200 mL) was added. The organic phase was
washed with 1 M HCl (50 mL), saturated aqueous NaHCO3 (50 mL), and brine (50 mL),
whereupon it was dried (MgSO4). The solvent was removed under reduced pressure to
1 give 16.08 g (~100%) of 2.267 as a faint yellow oil; H NMR (400 MHz, CDCl3) δ 7.00 (s, 1 H), 6.75 (s, 1 H), 4.59 (d, J = 6.8 Hz, 1 H), 4.48 (d, J = 6.8 Hz, 1 H), 3.98-3.89 (m, 1 H), 3.82 (s, 3 H), 3.75 (s, 3 H), 3.18 (s, 3 H), 2.76 (ABX J(AB) = 13.6 Hz, J(AX) = 7.2
Hz, J(BX) = 5.6 Hz, Δν(AB) = 30.2 Hz, 1 H, C9-H), 2.60 (ABX J(AB) = 13.6 Hz, J(AX) = 7.2 Hz, J(BX) = 5.6 Hz, Δν(AB) = 30.2 Hz, 1 H), 1.15 (d, J = 6.0 Hz, 3 H); 13C NMR
(100 MHz, CDCl3) δ 151.9, 149.5, 127.4, 115.6, 115.5, 108.8, 94.7, 72.2, 56.7, 55.9, 54.8, 38.0, 20.2; IR (neat) 2932, 1495, 1464, 1387, 1214, 1035 cm-1.
1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 7.00 (s, 1 H, C3-H), 6.75 (s, 1 H, C6- H), 4.59 (d, J = 6.8 Hz, 1 H, C12-H), 4.48 (d, J = 6.8 Hz, 1 H, C12-H), 3.98-3.89 (m, 1 H, C10-H), 3.82 (s, 3 H, C7-H or C8-H), 3.75 (s, 3 H, C7-H or C8-H), 3.18 (s, 3 H, C13-
H), 2.76 (ABX J(AB) = 13.6 Hz, J(AX) = 7.2 Hz, J(BX) = 5.6 Hz, Δν(AB) = 30.2 Hz, 1 H, C9-H), 2.60 (ABX J(AB) = 13.6 Hz, J(AX) = 7.2 Hz, J(BX) = 5.6 Hz, Δν(AB) = 30.2
13 Hz, 1 H, C9-H), 1.15 (d, J = 6.0 Hz, 3 H, C11-H); C NMR (100 MHz, CDCl3) δ 151.9 (C4), 149.5 (C1), 127.4 (C5), 115.6 (C3 or C6), 115.5 (C3 or C6), 108.8 (C2), 94.7 (C12), 72.2 (C10), 56.7 (C13), 55.9 (C7 or C8), 54.8 (C7 or C8), 38.0 (C9), 20.2 (C11).
253 2-Bromo-5-(2-(methoxymethoxy)propyl)cyclohexa-2,5-diene-1,4-dione
(2.280) (dik6-297). A solution of CAN (28.18 g, 51.41 mmol) in H2O (22 mL) was added
to a solution of 2.267 (5.47 g, 17.14 mmol) in CH3CN (86 mL) at 0 ºC. After 25 min at
room temperature, H2O (50 mL) and brine (50 mL) were added, and the mixture was extracted with EtOAc (3 × 50 mL). The combined organic phases were washed with
brine (10 × 50 mL) and dried (Na2SO4). The solvent was removed under reduced pressure
1 to give 4.94 g (~100%) of 2.280 as yellow-orange oil; H NMR (400 MHz, CDCl3) δ 7.66 (s, 1 H), 7.63 (s, 1 H), 5.00 (d, J = 7.2 Hz, 1 H), 4.92 (d, J = 7.2 Hz, 1 H), 4.23-4.33 (m, 1 H), 3.65 (s, 3 H), 3.01 (dd, J = 14.0, 4.8 Hz, 1 H), 2.95 (dd, J = 14.0, 7.8 Hz, 1 H),
13 1.59 (d, J = 6.4 Hz, 3 H); C NMR (100 MHz, CDCl3) 184.7, 179.4, 146.4, 138.1, 137.1, 133.7, 95.0, 71.5, 55.4, 36.4, 20.6; δ IR (neat) 2933, 1666, 1590, 1031 cm-1; mass
spectrum (ESI) m/z 310.9889 [C11H13O4Br (M+23) requires 310.9889], 599 (base).
1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 7.66 (s, 1 H, C3-H or C6-H), 7.63 (s, 1 H, C3-H or C6-H), 5.00 (d, J = 7.2 Hz, 1 H, C10-H), 4.92 (d, J = 7.2 Hz, 1 H, C10-H), 4.23-4.33 (m, 1 H, C8-H), 3.65 (s, 3 H, C11-H), 3.01 (dd, J = 14.0, 4.8 Hz, 1 H, C7-H), 2.95 (dd, J = 14.0, 7.8 Hz, 1 H, C7-H), 1.59 (d, J = 6.4 Hz, 3 H, C9-H); 13C NMR (100
MHz, CDCl3) δ 184.7 (C1 or C4), 179.4 (C1 or C4), 146.4 (C2 or C5), 138.1 (C3 or C6), 137.1 (C2 or C5), 133.7 (C3 or C6), 95.0 (C10), 71.5 (C8), 55.4 (C11), 36.4 (C7), 20.6 (C9).
254 2-Bromo-5-(2-(methoxymethoxy)propyl)benzene-1,4-diol (2.281) (dik6-21). A
solution of Na2S2O4 (28.79 g, 165.37 mmol) in H2O (50 mL) was added to a solution of 2.280 (9.53 g, 33.07 mmol). After 10 min at room temperature, saturated aqueous
NaHCO3 (50 mL) was added, and the mixture was extracted with EtOAc (3 × 50 mL).
The combined organic phases were washed with brine (2 × 50 mL) and dried (MgSO4). The solvent was removed under reduced pressure to give 9.09 g (94%) of 2.281 as a yellow solid (mp 88-90 ºC), which was used immediately without further purification.
7-Bromo-3-methylisochroman-5,8-diol (2.271) (dik6-280). TMSOTf (73 μL, 0.04 mmol) was added dropwise to a solution of freshly dried (azeotropic distillation, 2 ×
5 mL PhH) 2.281 (118 mg, 0.41 mmol) in CH3CN (2 mL) at 0 ºC. After 18 h at room
temperature, saturated aqueous NaHCO3 (10 mL) was added, and the mixture was
extracted with Et2O (3 × 30 mL). The combined organic phases were dried (MgSO4), and the solvent was removed under reduced pressure to give 100 mg (95%) of 2.271 as a faint yellow solid (mp 61-63 ºC), which was used immediately without further purification.
13 O 14 12 6 11 O O 5 1 8 10 9 4 7 O O 2 Br 3
2.273 7-Bromo-5,8-bis(methoxymethoxy)-3-methylisochroman (2.273) (dik5-241).
MOMCl (0.19 mL, 2.44 mmol) and i-Pr2Net (0.35 mL, 2.04 mmol) were added dropwise 255 to a solution of 2.272 (211 mg, 0.81 mmol) in CH2Cl2 (8 mL) at room temperature. After
18 h at room temperature, H2O (30 mL) was added, and the mixture was extracted with
Et2O (3 × 30 mL). The combined organic phases were dried (MgSO4), and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography eluting with hexanes/EtOAc (3:1) to give 181 mg (64%) of 2.273 as a
1 clear oil; H NMR (400 MHz, CDCl3) δ 7.12 (s, 1 H), 5.11 (d, J = 6.8 Hz, 1 H), 5.02 (d, J = 15.7 Hz, 1 H), 5.01 (d, J = 6.8 Hz, 1 H), 4.98 (s, 3 H), 4.69 (d, J = 15.7 Hz, 1 H), 3.75- 3.59 (m, 1 H), 3.55 (s, 3 H), 3.42 (s, 3 H), 2.69 (ddd, J = 17.1, 3.1, 1.5 Hz, 1 H), 2.31
13 (app dd, 17.1, 10.4 Hz, 1 H), 1.32 (d, J = 6.0 Hz, 3 H); C NMR (100 MHz, CDCl3) δ 151.4, 145.2, 131.2, 124.0, 115.8, 113.4, 99.9, 94.5, 70.0, 65.0, 57.5, 56.0, 30.2, 21.5; IR
-1 (neat) 2933, 1464, 1362, 1156, 940 cm ; mass spectrum (ESI) m/z 369.0309 [C14H19O5Br (M+23) requires 369.0308], 371 (base).
1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 7.12 (s, 1 H, C3-H), 5.11 (d, J = 6.8 Hz, 1 H, C7-H), 5.02 (d, J = 15.7 Hz, 1 H, C14-H), 5.01 (d, J = 6.8 Hz, 1 H, C7-H), 4.98 (s, 3 H, C9-H), 4.69 (d, J = 15.7 Hz, 1 H, C14-H), 3.75-3.59 (m, 1 H, C12-H), 3.55 (s, 3 H, C8-H or C10-H), 3.42 (s, 3 H, C8-H or C11-H), 2.69 (ddd, J = 17.1, 3.1, 1.5 Hz, 1 H, C11-H), 2.31 (app dd, 17.1, 10.4 Hz, 1 H, C11-H), 1.32 (d, J = 6.0 Hz, 3 H, C13-H); 13C
NMR (100 MHz, CDCl3) δ 151.4 (C4), 145.2 (C1), 131.2 (C6), 124.0 (C5), 115.8 (C3), 113.4 (C2), 99.9 (C7 or C9), 94.5 (C7 or C9), 70.0 (C12), 65.0 (C14), 57.5 (C8 or C10),
56.0 (C8 or C10), 30.2 (C11), 21.5 (C13).
256
5-Bromo-9-methyl-2,7,9,10-tetrahydroisochromeno[6,5-e][1,3]oxazin-6-ol (2.278) (dik5-223). HMTA (25 mg, 0.18 mmol) was added to a solution of 2.272 (47 mg, 0.18 mmol) in TFA (1.5 mL) in a sealed tube. After 18 h at 105 ºC, ice was added to the
reaction, and the mixture was stirred at room temperature for 30 min. Na2CO3 (2.5 g) was
added, and the mixture was extracted with CH2Cl2 (3 × 20 mL). The combined organic
phases were washed with H2O (2 × 10 mL) and dried (MgSO4). The solvent was removed under reduced pressure and the residue was purified by flash column chromatography eluting with hexanes/EtOAc (2:1) to give 11 mg (20%) of 2.278 as a yellow oil; 1H NMR
(400 MHz, CDCl3) δ 8.31 (s, 1 H), 5.45 (app s, 3 H) 4.94 (d, J = 16.8 Hz, 1 H), 4.62 (d, J = 16.8 Hz, 1 H), 3.73-3.62 (m, 1 H), 2.66 (app d, J = 16.7 Hz, 1 H), 2.30 (app dd, J =
13 16.7, 11.0 Hz, 1 H), 1.35 (d, J = 6.0 Hz, 3 H); C NMR (100 MHz, CDCl3) δ 15.9, 147.9, 142.5, 128.8, 122.8, 114.2, 105.3, 79.2, 69.1, 64.8, 29.2, 21.4; IR (neat) 2983,
-1 1628, 1442, 1211, 1135 cm ; mass spectrum (ESI) m/z 298.0073 [C12H13NO3Br (M+1) requires 298.0073], 298 (base).
1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 8.31 (s, 1 H, C7-H), 5.45 (app s, 3 H, ArOH & C8-H) 4.94 (d, J = 16.8 Hz, 1 H, C12-H), 4.62 (d, J = 16.8 Hz, 1 H, C12-H), 3.73-3.62 (m, 1 H, C10-H), 2.66 (app d, J = 16.7 Hz, 1 H, C9-H), 2.30 (app dd, J = 16.7,
13 11.0 Hz, 1 H, C9-H), 1.35 (d, J = 6.0 Hz, 3 H, C11-H); C NMR (100 MHz, CDCl3) δ 15.9 (C7), 147.9 (C4), 142.5 (C1), 128.8 (C6), 122.8 (C3 or C5), 114.2 (C3 or C5), 105.3 (C2), 79.2 (C8), 69.1 (C10), 64.8 (C12), 29.2 (C9), 21.4 (C11).
257
7-Bromo-5,8-dihydroxy-3-methylisochroman-6-carbaldehyde (2.256) (dik5- 290). HMTA (1.45 g, 10.37 mmol) was added to a solution of 2.272 (2.55 g, 9.88 mmol)
in TFA (40 mL) in a sealed tube. After 16 h at 100 ºC, H2O (150 ml) was added, and the mixture was stirred at 60 ºC for 4 h. The mixture was extracted with EtOAc (5 × 100 mL), and the combined organic phases were washed with brine (8 × 100 mL) and dried
(MgSO4). The solvent was removed under reduced pressure and the residue was purified by flash column chromatography eluting with hexanes/EtOAc (2:1) to give 1.85 g (65%)
1 of 2.256 as a yellow solid: mp 141-143 ºC; H NMR (400 MHz, CDCl3) δ 11.99 (s, 1 H), 10.17 (s, 1 H), 5.36 (br s, 1 H), 4.95 (d, J = 17.5 Hz, 1 H), 4.64 (d, J = 17.5 Hz, 1 H), 3.78-3.65 (m, 1 H), 2.77 (ddd, J = 17.4, 3.6, 1.6 Hz, 1 H), 2.35 (app dd, J = 17.4, 10.8
13 Hz, 1 H), 1.37 (d, J = 6.4 Hz, 3 H); C NMR (100 MHz, CDCl3) δ 196.5, 156.1, 141.2, 133.7, 124.6, 113.0, 108.1, 69.9, 64.9, 29.1, 21.4; IR (neat) 3362, 2974, 1638, 1423,
-1 1300, 1204 cm ; mass spectrum (ESI) m/z 284.9764 [C11H10O4Br (M-1) requires 284.9768], 287 (base).
1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 11.99 (s, 1 H, ArOH), 10.17 (s, 1 H, C7-H), 5.36 (br s, 1 H, ArOH), 4.95 (d, J = 17.5 Hz, 1 H, C11-H), 4.64 (d, J = 17.5 Hz, 1 H, C11-H), 3.78-3.65 (m, 1 H, C9-H), 2.77 (ddd, J = 17.4, 3.6, 1.6 Hz, 1 H, C8-H), 2.35 (app dd, J = 17.4, 10.8 Hz, 1 H, C8-H), 1.37 (d, J = 6.4 Hz, 3 H, C10-H); 13C NMR (100
MHz, CDCl3) δ 196.5 (C7), 156.1 (C4), 141.2 (C1), 133.7 (ArC), 124.6 (ArC), 113.0 (ArC), 108.1 (ArC), 69.9 (C9), 64.9 (C11), 29.1 (C8), 21.4 (C10).
258
7-Bromo-5,8-bis(methoxymethoxy)-3-methylisochroman-6-carbaldehyde
(2.279) (dik5-36). MOMCl (3.52 mL, 46.39 mmol) and i-Pr2Net (6.73 mL, 38.66 mmol)
were added dropwise to a solution of 2.256 (4.44 g, 15.46 mmol) in CH2Cl2 (50 mL) at
room temperature. After 18 h at room temperature, H2O (100 mL) was added, and the
mixture was extracted with Et2O (3 × 100 mL). The combined organic phases were dried
(MgSO4), and the solvent was removed under reduced pressure to give 5.06 g (87%) of
1 2.279 as a yellow solid: mp 47-49 ºC; H NMR (400 MHz, CDCl3) δ 10.27 (s, 1 H), 5.08 (d, J = 16.8 Hz, 1 H), 5.06 (d, J = 6.2 Hz, 1 H), 5.04 (d, J = 6.2 Hz, 1 H), 5.00 (s, 2 H), 4.76 (d, J = 16.8 Hz, 1 H), 3.73-3.61 (m, 1 H), 3.59 (s, 3 H), 3.55 (s, 3 H), 2.88 (ddd, J = 16.8, 3.0, 1.1 Hz, 1 H), 2.44 (app dd, J = 16.8, 10.6 Hz, 1 H), 1.36 (d, J = 6.4 Hz, 3 H);
13 C NMR (100 MHz, CDCl3) δ 190.7, 153.9, 148.3, 137.2, 130.0, 126.6, 117.1, 101.9, 100.4, 70.1, 65.2, 57.73, 57.70, 30.7, 21.4; IR (neat) 2934, 1698, 1360, 1159 cm-1; mass
spectrum (ESI) m/z 397.0256 [C15H19O6Br (M+23) requires 397.0257], 397 (base).
1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 10.27 (s, 1 H, C9-H), 5.08 (d, J = 16.8 Hz, 1 H, C15-H), 5.06 (d, J = 6.2 Hz, 1 H, C7-H or C10-H), 5.04 (d, J = 6.2 Hz, 1 H, C7-H or C10-H), 5.00 (s, 2 H, C7-H or C10-H), 4.76 (d, J = 16.8 Hz, 1 H, C15-H), 3.73-3.61 (m, 1 H, C13-H), 3.59 (s, 3 H, C8-H or C11-H), 3.55 (s, 3 H, C8-H or C11-H), 2.88 (ddd, J = 16.8, 3.0, 1.1 Hz, 1 H, C12-H), 2.44 (app dd, J = 16.8, 10.6 Hz, 1 H, C12-
13 H), 1.36 (d, J = 6.4 Hz, 3 H, C14-H) ; C NMR (100 MHz, CDCl3) δ 190.7 (C9), 153.9 (C4), 148.3 (C1), 137.2 (ArC), 130.0 (ArC), 126.6 (ArC), 117.1 (ArC), 101.9 (C7 or
259 C10), 100.4 (C7 or C10), 70.1 (C13), 65.2 (C15), 57.73 (C8 or C10), 57.70 (C8 or C10), 30.7 (C12), 21.4 (C14).
15 O 16 14 6 13 O O 5 1 8 12 11 4 7 O O 32 Br 9 10
2.255 7-Bromo-5,8-bis(methoxymethoxy)-3-methyl-6-vinylisochroman (2.255)
(dik6-39). Ph3PCH3Br (7.19 g, 20.19 mmol) and NaH (1.08 g, 26.92 mmol, 60% dispersion in mineral oil) were added to a solution of 2.279 (5.05 g, 13.46 mmol) in THF (70 mL). After 18 h at room temperature, brine (100 mL) was slowly added, and the mixture was extracted with EtOAc (3 × 50 mL). The combined organic phases were dried
(Na2SO4), and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography eluting with hexanes/EtOAc (2:1) to give 4.24 g (84%)
1 of 2.255 as a white solid: mp 40-42 ºC; H NMR (400 MHz, CDCl3) δ 6.68 (dd, J = 17.8, 11.6 Hz, 1 H), 5.75 (dd, J = 17.8, 2.0 Hz, 1 H), 5.56 (dd, J = 11.6, 2.0 Hz, 1 H), 5.05 (d, J = 16.0 Hz, 1 H), 5.03 (d, J = 6.0 Hz, 1 H), 5.01 (d, J = 6.0 Hz, 1 H), 4.87 (d, J = 5.8 Hz, 1 H), 4.85 (d, J = 5.8 Hz, 1 H), 4.74 (d, J = 16.0 Hz, 1 H), 3.74-3.60 (m, 1 H), 2.86 (ddd, J = 16.9, 2.8, 1.2 Hz, 1 H), 2.44 (app dd, J = 17.2, 10.4 Hz, 1 H), 1.35 (d, J = 6.0 Hz, 3 H);
13 C NMR (100 MHz, CDCl3) δ 150.4, 147.6, 132.5, 130.6, 129.9, 128.6, 121.4, 116.2, 100.0, 99.2, 70.2, 65.0, 57.6, 57.5, 31.0, 21.5; IR (neat) 2935, 1360, 1159, 965, 927 cm-1;
mass spectrum (ESI) m/z 395.0465 [C16H21O5Br (M+23) requires 395.0465], 395 (base).
1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 6.68 (dd, J = 17.8, 11.6 Hz, 1 H, C9- H), 5.75 (dd, J = 17.8, 2.0 Hz, 1 H, C10-H), 5.56 (dd, J = 11.6, 2.0 Hz, 1 H, C10-H), 5.05
260 (d, J = 16.0 Hz, 1 H, C16-H), 5.03 (d, J = 6.0 Hz, 1 H, C7-H or C11-H), 5.01 (d, J = 6.0 Hz, 1 H, C7-H or C11-H), 4.87 (d, J = 5.8 Hz, 1 H, C7-H or C11-H), 4.85 (d, J = 5.8 Hz, 1 H, C7-H or C11-H), 4.74 (d, J = 16.0 Hz, 1 H, C16-H), 3.74-3.60 (m, 1 H, C14-H), 2.86 (ddd, J = 16.9, 2.8, 1.2 Hz, 1 H, C13-H), 2.44 (app dd, J = 17.2, 10.4 Hz, 1 H, C13-
13 H), 1.35 (d, J = 6.0 Hz, 3 H, C15-H); C NMR (100 MHz, CDCl3) δ 150.4 (C4), 147.6 (C1), 132.5 (C9), 130.6 (C3), 129.9 (C6), 128.6 (C5), 121.4 (C2), 116.2 (C10), 100.0 (C7 or C11), 99.2 (C7 or C11), 70.2 (C14), 65.0 (C16), 57.6 (C8 or C12), 57.5 (C8 or C12), 31.0 (C13), 21.5 (C15).
8 23 O 24 7 O 22 6 21 O 5 1 O 13 20 19 4 9 O O 2 O 17 3 10 11 14 15 12 18 O 16 2.283 3-(5,8-Bis(methoxymethoxy)-3-methyl-6-vinylisochroman-7-yl)-4,4- dimethoxy-2-vinylcyclobut-2-enone (2.283) (dik6-42). A solution of freshly dried
(azeotropic distillation, 2 × 10 mL PhH) 2.255 (2.26 g, 6.06 mmol) in Et2O (30 mL) at 0 ºC was added dropwise via cannula to a solution of t-BuLi (7.8 mL, 13.32 mmol, 1.7 M)
in pentane at –78 ºC. After 10 min at 0 ºC, a solution of freshly dried (azeotropic
distillation, 2 × 3 mL PhH) 2.124 (1.34 g, 7.27 mmol) in Et2O (10 mL) at 0 ºC was added dropwise. After 30 min at 0 ºC, the reaction was cooled to –78 ºC, and TFAA (2.1 mL, 15.14 mmol) was added dropwise. After 20 min at –78 ºC, the cold bath was removed.
After 5 min at room temperature, saturated aqueous NaHCO3 (80 mL) was added, and the
reaction was allowed to warm to room temperature. H2O (20 mL) was added, and the
261 mixture was extracted with Et2O (3 × 50 mL). The combined organic phases were dried
(Na2SO4), and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography eluting with hexanes/EtOAc (4:1→3:1) to give 1.33 g
1 (49%) of 2.283 as a yellow oil; H NMR (400 MHz, CDCl3) δ 6.55 (dd, J = 17.6, 11.6 Hz, 1 H), 6.11-5.94 (comp, 2 H), 5.67 (dd, J = 17.6, 2.0 Hz, 1 H), 5.50 (dd, J = 10.4, 2.8 Hz, 1 H), 5.37 (dd, J = 11.6, 2.0 Hz, 1 H), 5.00 (d, J = 15.8, Hz, 1 H), 4.85 (d, J = 6.2 Hz, 1 H), 4.83 (d, J = 6.2 Hz, 1 H), 4.76 (d, J = 6.4 Hz, 1 H), 4.74 (d, J = 6.4 Hz, 1 H4.66 (d, J = 15.8 Hz, 1 H), 3.70-3.59 (m, 1 H), 3.48 (s, 3 H), 3.41 (s, 3 H), 3.40 (s, 3 H), 3.37 (s, 3 H), 2.89 (dd, J = 17.2, 2.0 Hz, 1 H), 2.47 (dd, J = 17.2, 10.4, Hz, 1 H), 1.31 (d, J =
13 6.0 Hz, 3 H); C NMR (100 MHz, CDCl3) δ 190.5, 170.7, 152.3, 149.9, 146.8, 131.2, 131.0, 129.6, 128.4, 126.1, 123.9, 122.7, 121.2, 116.6, 100.3, 99.1, 70.1, 64.7, 57.4, 57.2, 52.5, 52.4, 31.2, 21.5; IR (neat) 2945, 1767, 1159, 974 cm-1; mass spectrum (ESI) m/z
469.1838 [C24H30O8 (M+23) requires 169.1833].
1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 6.55 (dd, J = 17.6, 11.6 Hz, 1 H, C17-H), 6.11-5.94 (comp, 2 H, C15-H & C16-H), 5.67 (dd, J = 17.6, 2.0 Hz, 1 H, C18- H), 5.50 (dd, J = 10.4, 2.8 Hz, 1 H, C16-H), 5.37 (dd, J = 11.6, 2.0 Hz, 1 H, C18-H), 5.00 (d, J = 15.8, Hz, 1 H, C24-H), 4.85 (D, J = 6.2 Hz, 1 H, C7-H or C19-H), 4.83 (d, J = 6.2 Hz, 1 H, C7-H or C19-H), 4.76 (d, J = 6.4 Hz, 1 H, C7-H or C19-H), 4.74 (d, J = 6.4 Hz, 1 H, C7-H or C19-H), 4.66 (d, J = 15.8 Hz, 1 H, 24-H), 3.70-3.59 (m, 1 H, C22-H), 3.48
(s, 3 H, C8-H or C20-H), 3.41 (s, 3 H, C8-H or C20-H), 3.40 (s, 3 H, C13-H or C14-H), 3.37 (s, 3 H, C13-H or C14-H), 2.89 (dd, J = 17.2, 2.0 Hz, 1 H, C21-H), 2.47 (dd, J = 17.2, 10.4, Hz, 1 H, C21-H), 1.31 (d, J = 6.0 Hz, 3 H, C23-H); 13C NMR (100 MHz,
CDCl3) δ 190.5 (C11), 170.7 (C9), 152.3 (C10), 149.9 (C1 or C4), 146.8 (C1 or C4), 131.2 (C12 or ArC), 131.0 (C12 or ArC), 129.6 (ArC), 128.4 (ArC), 126.1 (ArC), 123.9 (ArC), 122.7 (ArC), 121.2 (ArC), 116.6 (C18), 100.3 (C7 or C19), 99.1 (C7 or C19), 70.1
262 (C22), 64.7 (C24), 57.4 (C8 or C20), 57.2 (C8 or C20), 52.5 (C13 or C14), 52.4 (C13 or C14), 31.2 (C21), 21.5 (C23).
14 21 O 22 13 O 20 6 19 O 15 17 5 1 O 18 7 O O O 4 3 2 8 9 16 12 10 11 O 2.254 Benzocylcobutenone 2.254 (dik6-43). Grubbs second generation catalyst (251 mg, 0.30 mmol) was added to a degassed (argon, 50 min) solution of diene 2.283 (2.20 g,
4.93 mmol) in toluene (50 mL). The solution was then heated for 13 h at 110 °C, whereupon the reaction was cooled to room temperature. The reaction mixture was concentrated to ca. 2 mL and purified by flash column chromatography eluting with hexanes/EtOAc (4:1) to give 1.68 g (82%) of 2.254 as a yellow oil; 1H NMR (400 MHz,
CDCl3) δ 8.17 (d, J = 8.6 Hz, 1 H), 7.39 (d, J = 8.6 Hz, 1 H), 5.31 (d, J = 16.0 Hz, 1 H), 5.17 (d, J = 7.2 Hz, 1 H), 5.053 (d, J = 7.2 Hz, 1 H), 5.051 (d, J = 5.6 Hz, 1 H), 5.01 (d, J = 5.6 Hz, 1 H), 4.92 (d, J = 16.0 Hz, 1 H), 3.78-3.66 (m, 1 H), 3.58 (s, 3 H), 3.57 (s, 3 H), 3.49 (s, 3 H), 3.43 (s, 3 H), 3.07 (dd, J = 17.2, 2.8 Hz, 1 H), 2.64 (dd, J = 17.2, 11.2 Hz, 1
13 H), 1.34 (d, J = 6.0 Hz, 3 H); C NMR (100 MHz, CDCl3) δ 192.2, 159.7, 148.9, 146.8, 146.3, 130.7, 130.4, 130.2, 128.0, 122.7, 118.1, 116.1, 102.0, 100.1, 70.1, 65.2, 57.6,
57.2, 53.56, 53.47, 31.7, 21.5; IR (neat) 2945, 1766, 1258, 1157, 960 cm-1; mass
spectrum (ESI) m/z 441.1521 [C22H26O8 (M+23) requires 441.1520].
1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 8.6 Hz, 1 H, C11-H or C12-H), 7.39 (d, J = 8.6 Hz, 1 H, C11-H or C12-H), 5.31 (d, J = 16.0 Hz, 1 H, C22-H), 5.17 (d, J = 7.2 Hz, 1 H, C13-H or C17-H), 5.053 (d, J = 7.2 Hz, 1 H, C13-H or C17-H), 263 5.051 (d, J = 5.6 Hz, 1 H, C13-H or C17-H), 5.01 (d, J = 5.6 Hz, 1 H, C13-H or C17-H), 4.92 (d, J = 16.0 Hz, 1 H, C22-H), 3.78-3.66 (m, 1 H, C20-H), 3.58 (s, 3 H, C14-H or C18-H), 3.57 (s, 3 H, C14-H or C18-H), 3.49 (s, 3 H, C15-H or C16-H), 3.43 (s, 3 H, C15-H or C16-H), 3.07 (dd, J = 17.2, 2.8 Hz, 1 H, C19-H), 2.64 (dd, J = 17.2, 11.2 Hz, 1
13 H, C19-H), 1.34 (d, J = 6.0 Hz, 3 H, C21-H); C NMR (100 MHz, CDCl3) δ 192.2 (C9), 159.7 (C8), 148.9 (C1 or C4 or C10), 146.8 (C1 or C4 or C10), 146.3 (C1 or C4 or C10), 130.7 (ArC), 130.4 (ArC), 130.2 (ArC), 128.0 (ArC), 122.7 (ArC), 118.1 (ArC), 116.1 (ArC), 102.0 (C13 or C17), 100.1 (C13 or C17), 70.1 (C20), 65.2 (C20), 57.6 (C14 or C18), 57.2 (C14 or C18), 53.56 (C15 or C16), 53.47 (C15 or C16), 31.7 (C19), 21.5 (C21).
Cyclobutenol 2.284 (dik6-45). A solution of ethynylmagnesium bromide (28 mL, 0.5 M, 14.05 mmol) in THF was added to a solution of 2.254 (1.68 g, 4.02 mmol) in THF
(10 mL). After 2 h at room temperature, saturated aqueous NH4Cl (5 mL) and H2O (45 mL) were added. The mixture was extracted with Et2O (3 × 100 mL), and the combined
organic phases were washed with H2O (2 × 50 mL) dried (MgSO4). The solvent was removed under reduced pressure to give 1.57 g (88%) of 2.284 as a faint yellow oil; 1H
NMR (400 MHz, CDCl3, 2:1 mixture of diastereomers) δ 8.14 (d, J = 8.7 Hz, 0.7 H), 8.13 (d, J = 8.7 Hz, 0.3 H), 7.47 (d, J = 8.7 Hz, 0.3 H), 7.46 (d, J = 8.7 Hz, 0.7 H), 5.36 (d, J = 16.0 Hz, 0.7 H), 5.25 (d, J = 16.0 Hz, 0.3 H), 5.19 (d, J = 6.8 Hz, 0.3 H), 5.15 (d, J = 6.8 264 Hz, 0.7 H), 5.07 (d, J = 5.6 Hz, 0.7 H), 5.06 (d, J = 5.6 Hz, 0.3 H) 5.03 (d, J = 5.6 Hz, 0.3 H), 5.02 (d, J = 5.6 Hz, 0.7 H), 4.00 (d, J = 6.8 Hz, 0.7 H), 4.91 (d, J = 6.8 Hz, 0.3 H), 4.90 (app d, J = 16.0 Hz, 1 H), 3.84 (br s, 0.3 H), 3.83-3.66 (comp, 1 H), 3.71 (br s, 0.7 H), 3.627 (s, 0.9 H), 3.626 (s, 0.9 H), 3.62 (s, 2.1 H), 3.59 (s, 2.1 H), 3.56 (app s, 3 H), 3.552 (s, 0.9 H), 3.548 (s, 2.1 H), 3.13-3.03 (comp, 1 H), 2.71 (s, 0.7 H), 2.68 (s, 0.3 H), 2.65 (app dd, J = 16.8, 10.8 Hz, 1 H), 1.41-1.35 (comp, 3 H); 13C NMR (100 MHz,
CDCl3, mixture of diastereomers) δ 148.6, 148.5, 145.3, 144.6, 144.5, 137.0, 136.8, 129.0, 128.91, 128.85, 128.8, 126.8, 126.7, 125.9, 125.7, 123.81, 123.77, 118.5, 107.7, 107.2, 102.00, 101.96, 100.1, 100.0, 81.6, 81.5, 77.6, 77.2, 75.8, 75.5, 70.6, 70.2, 65.6, 65.2, 57.75, 57.69, 57.34, 57.29, 52.8, 52.3, 52.2, 51.6, 31.52, 31.46, 21.8, 21.6; IR (neat)
3402, 3294, 2943, 2249, 1594, 1445, 1337, 1158, 1086 cm-1; mass spectrum (ESI) m/z
467.1677 [C24H28O8 (M+23) requires 467.1676], 467, 413 (base).
1 NMR Assignments. H NMR (400 MHz, CDCl3, 2:1 mixture of diastereomers) δ 8.14 (d, J = 8.7 Hz, 0.7 H, C11-H or C12-H), 8.13 (d, J = 8.7 Hz, 0.3 H, C11-H or C12-H), 7.47 (d, J = 8.7 Hz, 0.3 H, C11-H or C12-H), 7.46 (d, J = 8.7 Hz, 0.7 H, C11-H or C12- H), 5.36 (d, J = 16.0 Hz, 0.7 H, C24-H), 5.25 (d, J = 16.0 Hz, 0.3 H, C24-H), 5.19 (d, J = 6.8 Hz, 0.3 H, C13-H or C19-H), 5.15 (d, J = 6.8 Hz, 0.7 H, C13-H or C19-H), 5.07 (d, J = 5.6 Hz, 0.7 H, C13-H or C19-H), 5.06 (d, J = 5.6 Hz, 0.3 H, C13-H or C19-H) 5.03 (d, J = 5.6 Hz, 0.3 H, C13-H or C19-H), 5.02 (d, J = 5.6 Hz, 0.7 H, C13-H or C19-H), 4.00
(d, J = 6.8 Hz, 0.7 H, C13-H or C19-H), 4.91 (d, J = 6.8 Hz, 0.3 H, C13-H or C19-H), 4.90 (app d, J = 16.0 Hz, 1 H, C24-H), 3.84 (br s, 0.3 H, OH), 3.83-3.66 (comp, 1 H, C22-H), 3.71 (br s, 0.7 H, OH), 3.627 (s, 0.9 H, C14-H or C20-H), 3.626 (s, 0.9 H, C14- H or C20-H), 3.62 (s, 2.1 H, C14-H or C20-H), 3.59 (s, 2.1 H, C14-H or C20-H), 3.56 (app s, 3 H, C15-H or C16-H), 3.552 (s, 0.9 H, C15-H or C16-H), 3.548 (s, 2.1 H, C15-H or C16-H), 3.13-3.03 (comp, 1 H, C21-H), 2.71 (s, 0.7 H, C18-H), 2.68 (s, 0.3 H, C18-
265 H), 2.65 (app dd, J = 16.8, 10.8 Hz, 1 H, C21-H), 1.41-1.35 (comp, 3 H, C23-H); 13C
NMR (100 MHz, CDCl3, mixture of diastereomers) δ 148.6 (C1 or C4 or C8), 148.5 (C1 or C4 or C8), 145.3 (C1 or C4 or C8), 144.6 (C1 or C4 or C8), 144.5 (C1 or C4 or C8), 137.0 (ArC), 136.8 (ArC), 129.0 (ArC), 128.91 (ArC), 128.85 (ArC), 128.8 (ArC), 126.8 (ArC), 126.7 (ArC), 125.9 (ArC), 125.7 (ArC), 123.81 (ArC), 123.77 (ArC), 118.5 (ArC), 107.7 (ArC), 107.2 (ArC), 102.00 (C13 or C19), 101.96 (C13 or C19), 100.1 (C13 or C19), 100.0 (C13 or C19), 81.6 (C17), 81.5 (C17), 77.6 (C9), 77.2 (C9), 75.8 (C18), 75.5 (C18), 70.6 (C22), 70.2 (C22), 65.6 (C24), 65.2 (C24), 57.75 (C14 or C20), 57.69 (C14 or C20), 57.34 (C14 or C20), 57.29 (C14 or C20), 52.8 (C15 or C16), 52.3 (C15 or C16), 52.2 (C15 or C16), 51.6 (C15 or C16), 31.52 (C21), 31.46 (C21), 21.8 (C23), 21.6 (C23).
14 35 O 36 13 O 34 6 O 15 33 16 31 5 1 O 32 7 8 O O O 4 2 17 OH 3 9 18 O 26 12 10 19 20 11 OH 21 28 O 22 25 29 Si 24 23 30 O
27 2.285 Benzocyclobutenol 2.285 (dik6-47). A solution of EtMgBr (3.53 mL, 3 M, 10.60 mmol) in THF was added dropwise to a solution of freshly dried (azeotropic distillation, 2 × 5 mL PhH) 2.284 (1.57 g, 3.53 mmol) in THF (15 mL) at 0 ºC. After 2 h at room temperature, a solution of freshly dried (azeotropic distillation, 2 × 5 mL PhH) aldehyde 2.149 (2.09 g, 7.07 mmol) in THF (3 mL) was added. After 30 min at room temperature, saturated aqueous NH4Cl (5 mL) and H2O (50 mL) were added. The mixture was
extracted with Et2O (3 × 30 mL), and the organic phase was dried (Na2SO4). The solvent 266 was removed under reduced pressure, and the residue was purified by flash column chromatography eluting with hexanes/EtOAc (2:1→1:1) to give 209 mg (13%) of 2.284
1 and 2.11 g (81%) of 2.285 as a yellow oil; H NMR (400 MHz, CDCl3, complex mixture of diastereomers) δ 8.14-8.06 (comp, 1 H), 7.44-7.38 (comp, 1 H), 6.66-6.61 (comp, 1 H), 6.42-6.35 (comp, 1 H), 5.90-5.82 (comp, 1 H), 5.40-5.21 (comp, 1 H), 5.20-5.13 (comp, 1 H), 4.95-4.82 (comp, 2 H), 4.09-3.95 (comp, 1 H), 3.83-3.71 (comp, 1 H), 3.75- 3.68 (comp, 3 H), 3.68-3.65 (comp, 3 H), 3.63-3.61 (comp, 3 H), 3.56-3.50 (comp, 6 H), 3.47-3.40 (comp, 3 H), 3.14-3.03 (comp, 1 H), 2.70-2.59 (comp, 3 H), 1.39-1.35 (comp, 3
13 H), 0.93-0.87 (comp, 9 H), 0.12-0.02 (comp, 6 H); C NMR (100 MHz, CDCl3, mixture of diastereomers) δ 152.3, 148.5, 145.8, 144.9, 144.6, 144.5, 142.0, 136.7, 136.6, 128.8, 128.6, 128.5, 126.4, 126.3, 125.5, 125.4, 123.8, 123.7, 121.4, 118.8, 110.4, 107.8, 107.4, 103.73, 103.67, 102.0, 99.99, 99.95, 88.3, 88.2, 88.0, 87.8, 81.0, 80.9, 77.6, 77.3, 70.6, 70.1, 65.6, 65.1, 57.7, 57.6, 57.3, 57.2, 56.0, 55.2, 52.7, 52.4, 51.7, 51.2, 31.5, 31.4, 25.9, 21.8, 21.6, 18.6, -4.3, -4.4; IR (neat) 3528, 3429, 2940, 1595, 1491, 1257, 1078 cm-1;
mass spectrum (ESI) m/z 763.3121 [C39H52O12Si (M+23) requires 763.3120], 763, 709 (base).
1 NMR Assignments. H NMR (400 MHz, CDCl3, complex mixture of diastereomers) δ 8.14-8.06 (comp, 1 H, C11-H or C12-H), 7.44-7.38 (comp, 1 H, C11-H or C12-H), 6.66- 6.61 (comp, 1 H, C22-H or C23-H), 6.42-6.35 (comp, 1 H, C22-H or C23-H), 5.90-5.82
(comp, 1 H, C19-H), 5.40-5.21 (comp, 1 H, C36-H), 5.20-5.13 (comp, 1 H, C13-H or C31-H), 4.95-4.82 (comp, 2 H, C13-H or C31-H & C13-H or C31-H), 4.09-3.95 (comp, 1 H, OH), 3.83-3.71 (comp, 1 H, C34-H), 3.75-3.68 (comp, 3 H, C26-H or C27-H), 3.68- 3.65 (comp, 3 H, C26-H or C27-H), 3.63-3.61 (comp, 3 H, C14-H or C32-H), 3.56-3.50 (comp, 6 H, C15-H or C16-H & C14-H or C32-H), 3.47-3.40 (comp, 3 H, C15-H or C16- H), 3.14-3.03 (comp, 1 H, C33-H), 2.70-2.59 (comp, 3 H, C35-H), 1.39-1.35 (comp, 3 H,
267 C35-H), 0.93-0.87 (comp, 9 H, C30-H), 0.12-0.02 (comp, 6 H, C28-H); 13C NMR (100
MHz, CDCl3, mixture of diastereomers) δ 152.3 (C21), 148.5 (C1 or C4), 145.8 (C1 or C4), 144.9 (ArC), 144.6 (ArC), 144.5 (ArC), 142.0 (ArC), 136.7 (ArC), 136.6 (ArC), 128.8 (ArC), 128.6 (ArC), 128.5 (ArC), 126.4 (C11 or C12), 126.3 (C11 or C12), 125.5 (ArC), 125.4 (ArC), 123.8 (ArC), 123.7 (ArC), 121.4 (ArC), 118.8 (C11 or C12), 110.4 (C22 or C23), 107.8 (ArC), 107.4 (ArC), 103.73 (C22 or C23), 103.67 (C22 or C23), 102.0 (C13 or C31), 99.99 (C13 or C31), 99.95 (C13 or C31), 88.3 (C17), 88.2 (C17), 88.0 (C17), 87.8 (C17), 81.0 (C9), 80.9 (C9), 77.6 (C18), 77.3 (C18), 70.6 (C34), 70.1 (C34), 65.6 (C36), 65.1 (C36), 57.7 (C14 or C32), 57.6 (C14 or C32 & C19), 57.3 (C14 or C32), 57.2 (C14 or C32), 56.0 (C26 or C27), 55.2 (C26 or C27), 52.7 (C15 or C16), 52.4 (C15 or C16), 51.7 (C15 or C16), 51.2 (C15 or C16), 31.5 (C33), 31.4 (C33), 25.9 (C30), 21.8 (C35), 21.6 (C35), 18.6 (C29), -4.3 (C28), -4.4 (C28).
Benzocyclobutenone 2.253 (dik6-50). p-TsOH (54 mg, 0.29 mmol) was added to a solution of ketal 2.285 (2.11 g, 2.85 mmol) in acetone (50 mL). After 15 min at room temperature, the reaction was diluted with Et2O (100 mL), and the mixture was washed
with brine (3 × 50 mL). The organic phase was dried (MgSO4), and the solvent was removed under reduced pressure to give 1.95 g (98%) of 2.253 as an orange foam; 1H 268 NMR (400 MHz, CDCl3, complex mixture of diastereomers) δ 8.37-8.24 (comp, 1 H), 7.68-7.60 (comp, 1 H), 6.66-6.59 (comp, 1 H), 6.38 (app d, J = 9.2 Hz, 1 H), 5.84 (app br s, 1 H), 5.32-4.73 (comp, 6 H), 4.48-4.25 (br 2, 1 H), 4.15-3.88 (br s, 1 H), 3.84-3.69 (comp, 1 H), 3.78-3.72 (comp, 1 H), 3.69-3.59 (comp, 6 H), 3.59-3.48 (comp, 3 H), 3.03 (app t, J = 17.8 Hz, 1 H), 2.73-2.56 (comp, 1 H), 1.38 (app d, J = 6.0 Hz, 3 H), 0.93-0.88
13 (comp, 9 H), 0.18-0.05 (comp, 6 H); C NMR (100 MHz, CDCl3, mixture of diastereomers) δ 184.2, 183.8, 161.0, 160.4, 152.2, 148.5, 148.3, 145.7, 145.5, 144.8, 142.1, 141.7, 141.6, 133.2, 133.0, 131.1, 130.7, 129.1, 129.0, 127.8, 127.6, 120.8, 120.7, 120.6, 118.3, 118.2, 110.7, 103.9, 101.6, 101.4, 100.2, 91.4, 91.2, 85.7, 85.5, 79.2, 70.5, 70.1, 65.2, 65.1, 57.9, 57.8, 57.5, 57.4, 56.3, 55.2, 31.5, 31.3, 25.9, 21.5, 21.4, 18.7, -
4.16, -4.19; IR (neat) 3532, 3347, 2934, 1767, 1491, 1256, 1158 cm-1; mass spectrum
(ESI) m/z 717.2699 [C37H46O11Si (M+23) requires 717.2702].
1 NMR Assignments. H NMR (400 MHz, CDCl3, complex mixture of diastereomers) δ 8.37-8.24 (comp, 1 H, C11-H or C12-H), 7.68-7.60 (comp, 1 H, C11-H or C12-H), 6.66- 6.59 (comp, 1 H, C20-H or C21-H), 6.38 (app d, J = 9.2 Hz, 1 H, C20-H or C21-H), 5.84 (app br s, 1 H, C17-H), 5.32-4.73 (comp, 6 H, C13-H & C29-H & C34-H), 4.48-4.25 (br 2, 1 H, OH), 4.15-3.88 (br s, 1 H, OH), 3.84-3.69 (comp, 1 H, C32-H), 3.78-3.72 (comp, 1 H, C24-H or C25-H), 3.69-3.59 (comp, 6 H, C24-H or C25-H & C14-H or C30-H), 3.59-3.48 (comp, 3 H, C14-H or C30-H), 3.03 (app t, J = 17.8 Hz, 1 H, C31-H), 2.73-
2.56 (comp, 1 H, C31-H), 1.38 (app d, J = 6.0 Hz, 3 H, C33-H), 0.93-0.88 (comp, 9 H,
13 C28-H), 0.18-0.05 (comp, 6 H, C26-H); C NMR (100 MHz, CDCl3, mixture of diastereomers) δ 184.2 (C8), 183.8 (C8), 161.0 (ArC), 160.4 (ArC), 152.2 (ArC), 148.5 (ArC), 148.3 (ArC), 145.7 (ArC), 145.5 (ArC), 144.8 (ArC), 142.1 (ArC), 141.7 (ArC), 141.6 (ArC), 133.2 (ArC), 133.0 (ArC), 131.1 (ArC), 130.7 (ArC), 129.1 (ArC), 129.0 (ArC), 127.8 (ArC), 127.6 (ArC), 120.8 (ArC), 120.7 (ArC), 120.6 (ArC), 118.3 (C11 or
269 C12), 118.2 (C11 or C12), 110.7 (C20 or C21), 103.9 (C20 or C21), 101.6 (C13 or C29), 101.4 (C13 or C29),, 100.2 (C13 or C29),, 91.4 (C9), 91.2 (C9), 85.7 (C15), 85.5 (C15), 79.2 (C16), 70.5 (C32), 70.1 (C32), 65.2 (C34), 65.1 (C34), 57.9 (C14 or C30), 57.8 (C14 or C30), 57.5 (C14 or C30 & C17), 57.4 (C14 or C30), 56.3 (C24 or C25), 55.2 (C24 or C25), 31.5 (C31), 31.3 (C31), 25.9 (C28), 21.5 (C33), 21.4 (C33), 18.7 (C27), -4.16 (C26), -4.19 (C26).
16 33 O 34 O 32 15 6 24 31 O 5 1 O OH O 9 19 7 18 20 O 4 3 2 8 17 29 11 21 O 14 12 10O 23 13 22 O Si O 30 26 27 25 28 2.286 2-((2-(tert-Butyldimethylsilyloxy)-3,6-dimethoxyphenyl)(hydroxy)methyl)- 7,12-bis(methoxymethoxy)-9-methyl-8,9-dihydro-1H-naphtho[2,1-g]isochromene- 1,4(11H)-dione (2.286) (dik6-51). A solution of benzocyclobutenone 2.253 (1.95 g, 2.81 mmol) in DMSO (280 mL) was heated to 115 ºC for 25 min. Upon cooling to room temperature, EtOAc (300 mL) was added, and the mixture was washed with brine (5 ×
200 mL). The organic phase was dried (MgSO4), and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography eluting with hexanes/EtOAc (3:1→1:1) to give 848 mg (43%) of 2.286 as a red oil.
270 16 33 O 34 O 32 15 6 24 31 O 5 1 O O O 9 19 7 18 20 O 4 32 8 17 29 11 21 O 14 12 10O 23 13 22 O Si O 30 26 27 25 28 2.287 2-(2-(tert-Butyldimethylsilyloxy)-3,6-dimethoxybenzoyl)-7,12- bis(methoxymethoxy)-9-methyl-8,9-dihydro-1H-naphtho[2,1-g]isochromene- 1,4(11H)-dione (2.287) (dik6-31). IBX (172 mg, 0.61 mmol) was added to a solution of 2.286 (142 mg, 0.20 mmol) in DMSO (10 mL). After 21 h at room temperature, saturated
aqueous Na2S2O3 (5 mL) and saturated aqueous NaHCO3 (5 mL) were added, and the reaction was stirred for 10 min at room temperature. Brine (50 mL) was added, and the
mixture was extracted with Et2O (3 × 50 mL). The combined organic phases were
washed with brine (2 × 50 mL) and dried (Na2SO4). The solvent was removed under reduced pressure to give 142 mg (~100%) of 2.287 as a red oil; 1H NMR (400 MHz,
CDCl3) δ 8.32 (d, J = 8.8 Hz, 1 H), 7.98 (d, J = 8.8 Hz, 1 H), 6.91 (s, 1 H), 6.86 (d, J = 9.2 Hz, 1 H), 6.46 (d, J = 9.2 Hz), 5.33 (d, J = 16.4 Hz, 1 H), 5.09 (d, J = 5.8 Hz, 1 H), 5.05 (d, J = 5.8 Hz, 1 H), 4.90 (d, J = 16.4 Hz, 1 H), 4.86 (d, J = 6.8 Hz, 1 H), 4.83 (d, J = 6.8 Hz, 1 H), 3.77 (s, 3 H), 3.66 (s, 3 H), 3.64 (s, 3 H), 3.45 (s, 3 H), 3.11 (dd, J = 17.3, 2.4 Hz, 1 H), 2.68 (dd, J = 17.3, 11.0 Hz, 1 H), 1.40 (d, J = 6.0 Hz, 3 H), 0.80 (s, 9 H),
13 0.13 (s, 6 H); C NMR (100 MHz, CDCl3) δ 191.0, 186.0, 184.2, 151.6, 147.8, 147.7, 146.2, 144.7, 143.5, 135.0, 133.9, 132.1, 131.4, 130.6, 129.8, 128.0, 121.6, 120.7, 120.6, 113.4, 103.4, 100.4, 99.9, 70.2, 65.8, 57.8, 57.6, 56.2, 55.3, 31.6, 25.7, 21.7, 18.6, -4.0, -
271 4.1; IR (neat) 2934, 1697, 1663, 1599, 1486, 1256, 1099 cm-1; mass spectrum (ESI) m/z
715.2557 [C39H39O11Si (M+1) requires 715.2545], 747, 715 (base).
1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 8.8 Hz, 1 H, C13-H or C14-H), 7.98 (d, J = 8.8 Hz, 1 H, C13-H or C14-H), 6.91 (s, 1 H, C10-H), 6.86 (d, J = 9.2 Hz, 1 H, C20-H or C21-H), 6.46 (d, J = 9.2 Hz, C20-H or C21-H), 5.33 (d, J = 16.4 Hz, 1 H, C34-H), 5.09 (d, J = 5.8 Hz, 1 H, C15-H or C29-H), 5.05 (d, J = 5.8 Hz, 1 H, C15-H or C29-H), 4.90 (d, J = 16.4 Hz, 1 H, C34-H), 4.86 (d, J = 6.8 Hz, 1 H, C15-H or C29- H), 4.83 (d, J = 6.8 Hz, 1 H, C15-H or C29-H), 3.77 (s, 3 H, C24-H or C25-H), 3.66 (s, 3 H, C16-H or C24-H or C25-H or C30-H), 3.64 (s, 3 H, C16-H or C24-H or C25-H or C30-H), 3.45 (s, 3 H, C16-H or C30-H), 3.11 (dd, J = 17.3, 2.4 Hz, 1 H, C31-H), 2.68 (dd, J = 17.3, 11.0 Hz, 1 H, C31-H), 1.40 (d, J = 6.0 Hz, 3 H, C33-H), 0.80 (s, 9 H, C28-
13 H), 0.13 (s, 6 H, C26-H); C NMR (100 MHz, CDCl3) δ 191.0 (C17), 186.0 (C11), 184.2 (C8), 151.6 (ArC), 147.8 (ArC), 147.7 (ArC), 146.2 (ArC), 144.7 (ArC), 143.5 (ArC), 135.0 (ArC), 133.9 (ArC), 132.1 (ArC), 131.4 (ArC), 130.6 (ArC), 129.8 (ArC), 128.0 (C13 or C14), 121.6 (ArC), 120.7 (ArC), 120.6 (C13 or C14), 113.4 (C20 or C21), 103.4 (C20 or C21), 100.4 (C15 or C29), 99.9 (C15 or C29), 70.2 (C32), 65.8 (C34), 57.8 (C16 or C30), 57.6 (C16 or C30), 56.2 (C24 or C25), 55.3 (C24 or C25), 31.6 (C31), 25.7 (C28), 21.7 (C33), 18.6 (C27), -4.0 (C26), -4.1 (C26).
272 16 33 O 34 O 32 15 6 24 31 O 5 1 OH O O 19 7 9 18 20 O 4 32 8 17 29 11 21 O 14 12 10 O 23 13 22 OH Si O 30 26 27 25 28 2.289 (2-(tert-Butyldimethylsilyloxy)-3,6-dimethoxyphenyl)(1,4-dihydroxy-7,12- bis(methoxymethoxy)-9-methyl-9,11-dihydro-8H-naphtho[2,1-g]isochromen-2- yl)methanone (2.289) (dik6-52). IBX (1.02 g, 3.65 mmol) was added to a solution of 2.286 (845 mg, 1.22 mmol) in DMSO (30 mL). After 20 h at room temperature, saturated
aqueous Na2S2O3 (10 mL) and saturated aqueous NaHCO3 (10 mL) were added, and the reaction was stirred for 30 min at room temperature. Brine (50 mL) was added, and the
mixture was extracted with Et2O (5 × 50 mL). The combined organic phases were
washed with brine (4 × 50 mL) and dried (Na2SO4). The solvent was removed under reduced pressure and the residue was purified by flash column chromatography eluting with hexanes/EtOAc (3:1→2:1) to give 270 mg (32%) of 2.287 as a red oil and 140 mg
1 (18%) of 2.289 as a orange oil; H NMR (400 MHz, CDCl3) δ 13.88 (br s, 1 H), 8.04 (d, J = 9.2 Hz, 1 H), 7.93 (d, J = 9.2 Hz, 1 H), 6.87 (s, 1 H), 6.78 (d, J = 8.9 Hz, 1 H), 6.43 (d, 8.9 Hz, 1 H), 5.96 (br s, 1 H), 5.39 (d, J = 16.0 Hz, 1 H), 5.09 (d, J = 5.8 Hz, 1 H), 5.06 (d, J = 5.8 Hz, 1 H), 4.94 (d, J = 16.0 Hz, 1 H), 4.75 (d, J = 6.4 Hz, 1 H), 4.70 (d, J = 6.4 Hz, 1 H), 3.85-3.70 (m, 1 H), 3.72 (s, 3 H), 3.63 (s, 3 H), 3.59 (s, 3 H), 3.33 (s, 3 H), 3.12 (dd, J = 16.8, 2.8 Hz, 1 H), 2.69 (dd, J = 16.8, 10.8 Hz, 1 H), 1.41 (d, J = 6.0 Hz, 3 H),
13 0.66 (s, 9 H), 0.08 (s, 6 H); C NMR (100 MHz, CDCl3) δ 199.9, 157.0, 150.7, 148.2, 146.9, 144.5, 142.8, 142.3, 130.0, 128.4, 127.0, 126.7, 124.8, 121.0, 119.8, 119.6, 119.3, 273 116.3, 12.3, 112.1, 103.2, 100.5, 98.5, 70.3, 65.8, 57.7, 57.5, 56.0, 55.2, 31.1, 25.6, 21.6, 18.4, -4.2; mass spectrum (ESI) 695 (base).
1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 13.88 (br s, 1 H, ArOH), 8.04 (d, J = 9.2 Hz, 1 H, C13-H or C14-H), 7.93 (d, J = 9.2 Hz, 1 H, C13-H or C14-H), 6.87 (s, 1 H, C10-H), 6.78 (d, J = 8.9 Hz, 1 H, C20-H or C21-H), 6.43 (d, 8.9 Hz, 1 H, C20-H or C21- H), 5.96 (br s, 1 H, ArOH), 5.39 (d, J = 16.0 Hz, 1 H, C34-H), 5.09 (d, J = 5.8 Hz, 1 H, C15-H or C29-H), 5.06 (d, J = 5.8 Hz, 1 H, C15-H or C29-H), 4.94 (d, J = 16.0 Hz, 1 H, C34-H), 4.75 (d, J = 6.4 Hz, 1 H, C15-H or C29-H), 4.70 (d, J = 6.4 Hz, 1 H, C15-H or C29-H), 3.85-3.70 (m, 1 H, C32-H), 3.72 (s, 3 H, C24-H or C25-H), 3.63 (s, 3 H, C16-H or C24-H or C25-H or C30-H), 3.59 (s, 3 H, C16-H or C24-H or C25-H or C30-H), 3.33 (s, 3 H, C16-H or C30-H), 3.12 (dd, J = 16.8, 2.8 Hz, 1 H, C31-H), 2.69 (dd, J = 16.8, 10.8 Hz, 1 H, C31-H), 1.41 (d, J = 6.0 Hz, 3 H, C33-H), 0.66 (s, 9 H, C28-H), 0.08 (s, 6
13 H, C26-H); C NMR (100 MHz, CDCl3) δ 199.9 (C17), 157.0 (ArC), 150.7 (ArC), 148.2 (ArC), 146.9 (ArC), 144.5 (ArC), 142.8 (ArC), 142.3 (ArC), 130.0 (ArC), 128.4 (ArC), 127.0 (ArC), 126.7 (ArC), 124.8 (ArC), 121.0 (ArC), 119.8 (ArC), 119.6 (C13 or C14), 119.3 (ArC), 116.3 (ArC), 12.3 (ArC), 112.1 (C20 or C21), 103.2 (C20 or C21), 100.5 (C15 or C29), 98.5 (C15 or C29), 70.3 (C32), 65.8 (C34), 57.7 (C16 or C30), 57.5 (C16 or C30), 56.0 (C24 or C25), 55.2 (C24 or C25), 31.1 (C31), 25.6 (C28), 21.6 (C33), 18.4 (C27), -4.2 (C26).
274 16 30 O 31 O 29 15 6 24 28 O 5 1 O O O 9 19 7 18 20 O 4 32 8 17 26 11 O 21 O 14 12 10 23 13 22 O O 27 25 2.290 4,7-Dimethoxy-7',12'-bis(methoxymethoxy)-9'-methyl-8',9'-dihydro-3H- spiro[benzofuran-2,2'-naphtho[2,1-g]isochromene]-1',3,4'(3'H,11'H)-trione (2.290) (dik6-78). Pyridine (88 μL, 1.09 mmol) and HF·pyridine (37 μL, 70% wt, 1.31 mmol) were added to a solution of 2.287 (302 mg, 0.44 mmol) in THF (4.5 mL) in a plastic tube. After 2.5 h at room temperature, EtOAc (50 mL), and the mixture was washed with
saturated aqueous CuSO4 (2 × 10 mL) and brine (2 × 10 mL). The organic phase was
dried (Na2SO4), and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography eluting with hexanes/EtOAc (1:2) to give 10 mg (4%) of 2.251 as a red oil and 93 mg (37%) of 2.290 as an orange oil; 1H NMR (400
MHz, CDCl3, 1:1 mixture of diastereomers) δ 8.34 (d, J = 8.8 Hz, 0.5 H), 8.33 (d, J = 9.2 Hz, 0.5 H), 8.06 (d, J = 8.8 Hz, 0.5 H), 8.05 (d, J = 9.2 Hz, 0.5 H), 7.14 (d, J = 8.9 Hz, 0.5 H), 7.13 (d, J = 8.9 Hz, 0.5 H), 6.41 (app d, J = 8.9 Hz, 1 H), 5.25 (d, J = 16.4 Hz, 0.5
H), 5.16 (d, J = 16.4 Hz, 0.5 H), 5.12 (d, J = 5.6 Hz, 0.5 H), 5.08 (d, J = 6.0 Hz, 0.5 H), 5.06 (d, J = 6.0 Hz, 0.5 H), 5.05 (d, J = 5.6 Hz, 0.5 H), 4.87 (d, J = 16.4 Hz, 0.5 H), 4.76 (d, J = 16.4 Hz, 0.5 H), 4.50 (d, J = 6.0 Hz, 0.5 H), 4.46 (d, J = 6.0 Hz, 0.5 H), 4.42 (d, J = 6.4 Hz, 0.5 H), 4.41 (d, J = 6.4 Hz, 0.5 H), 3.93 (s, 1.5 H), 3.91 (s, 1.5 H), 3.83 (app s, 3 H), 3.78-3.69 (m, 1 H), 3.64 (s, 1.5 H), 3.63 (s, 1.5 H), 3.57 (d, J = 17.6 Hz, 0.5 H), 3.55 (d, J = 17.6 Hz, 0.5 H), 3.50 (d, J = 17.6 Hz, 0.5 H), 3.48 (d, J = 17.6 Hz, 0.5 H), 3.15 (dd, J = 17.2, 2.8 Hz, 0.5 H), 3.12 (s, 1.5 H), 3.08 (s, 1.5 H), 3.07 (dd, J = 17.2, 10.8 275 Hz, 0.5 H), 2.71 (dd, J = 17.2, 10.8 Hz, 0.5 H), 1.38 (d, J = 6.0 Hz, 1.5 H), 1.37 (d, J =
13 6.0 Hz, 1.5 H); C NMR (100 MHz, CDCl3, mixture of diastereomers) δ 191.6, 191.3, 190.5, 190.4, 187.7, 187.1, 161.4, 161.2, 151.8, 148.0, 147.8, 147.2, 147.0, 140.0, 139.9, 136.4, 136.1, 134.3, 134.0, 131.1, 130.4, 130.3, 129.9, 129.8, 128.4, 128.2, 122.6, 122.5, 122.5, 122.3, 121.5, 109.9, 109.7, 103.5, 103.4, 100.4, 100.0, 93.5, 93.3, 70.3, 70.1, 65.5, 57.8, 57.3, 57.1, 57.02, 56.98, 56.1, 46.8, 46.7, 31.6, 31.5, 21.7, 21.6; IR (neat) 2934,
-1 1704, 1598, 1515, 1272 cm ; mass spectrum (ESI) m/z 601.1680 [C31H30O11 (M+23) requires 601.1680].
1 NMR Assignments. H NMR (400 MHz, CDCl3, 1:1 mixture of diastereomers) δ 8.34 (d, J = 8.8 Hz, 0.5 H, C13-H or C14-H), 8.33 (d, J = 9.2 Hz, 0.5 H, C13-H or C14-H), 8.06 (d, J = 8.8 Hz, 0.5 H, C13-H or C14-H), 8.05 (d, J = 9.2 Hz, 0.5 H, C13-H or C14- H), 7.14 (d, J = 8.9 Hz, 0.5 H, C20-H or C21-H), 7.13 (d, J = 8.9 Hz, 0.5 H, C20-H or C21-H), 6.41 (app d, J = 8.9 Hz, 1 H, C20-H or C21-H), 5.25 (d, J = 16.4 Hz, 0.5 H, C31-H), 5.16 (d, J = 16.4 Hz, 0.5 H, C31-H), 5.12 (d, J = 5.6 Hz, 0.5 H, C15-H or C16- H), 5.08 (d, J = 6.0 Hz, 0.5 H, C15-H or C16-H), 5.06 (d, J = 6.0 Hz, 0.5 H, C15-H or C16-H), 5.05 (d, J = 5.6 Hz, 0.5 H, C15-H or C16-H), 4.87 (d, J = 16.4 Hz, 0.5 H, C31- H), 4.76 (d, J = 16.4 Hz, 0.5 H, C31-H), 4.50 (d, J = 6.0 Hz, 0.5 H, C15-H or C16-H), 4.46 (d, J = 6.0 Hz, 0.5 H, C15-H or C16-H), 4.42 (d, J = 6.4 Hz, 0.5 H, C15-H or C16- H), 4.41 (d, J = 6.4 Hz, 0.5 H, C15-H or C16-H), 3.93 (s, 1.5 H, C24-H or C25-H), 3.91
(s, 1.5 H, C24-H or C25-H), 3.83 (app s, 3 H, C24-H or C25-H), 3.78-3.69 (m, 1 H, C29- H), 3.64 (s, 1.5 H, C16-H or C27-H), 3.63 (s, 1.5 H, C16-H or C27-H), 3.57 (d, J = 17.6 Hz, 0.5 H, C10-H), 3.55 (d, J = 17.6 Hz, 0.5 H, C10-H), 3.50 (d, J = 17.6 Hz, 0.5 H, C10- H), 3.48 (d, J = 17.6 Hz, 0.5 H, C10-H), 3.15 (dd, J = 17.2, 2.8 Hz, 0.5 H, C28-H), 3.12 (s, 1.5 H, C16-H or C27-H), 3.08 (s, 1.5 H, C16-H or C27-H), 3.07 (dd, J = 17.2, 10.8 Hz, 0.5 H, C28-H), 2.71 (dd, J = 17.2, 10.8 Hz, 0.5 H, C28-H), 1.38 (d, J = 6.0 Hz, 1.5 H,
276 13 C30-H), 1.37 (d, J = 6.0 Hz, 1.5 H, C30-H); C NMR (100 MHz, CDCl3, mixture of diastereomers) δ 191.6 (C8), 191.3 (C8), 190.5 (C11), 190.4 (C11), 187.7, (C17) 187.1 (C17), 161.4 (ArC), 161.2 (ArC), 151.8 (ArC), 148.0 (ArC), 147.8 (ArC), 147.2 (ArC), 147.0 (ArC), 140.0 (ArC), 139.9 (ArC), 136.4 (ArC), 136.1 (ArC), 134.3 (ArC), 134.0 (ArC), 131.1 (ArC), 130.4 (ArC), 130.3 (ArC), 129.9 (ArC), 129.8 (ArC), 128.4 (C13 or C14), 128.2 (C13 or C14), 122.6 (ArC), 122.5 (ArC), 122.5 (C13 or C14), 122.3 (C13 or C14), 121.5 (ArC), 109.9 (ArC), 109.7 (ArC), 103.5 (C20 or C21), 103.4 (C20 or C21), 100.4 (C15 or C26 & C15 or C26), 100.0 (C15 or C26), 93.5 (C9), 93.3 (C9), 70.3 (C29), 70.1 (C29), 65.5 (C31), 57.8 (C16 or C27), 57.3 (C16 or C24 or C25 or C27), 57.1 (C16 or C24 or C25 or C27), 57.02 (C16 or C24 or C25 or C27), 56.98 (C16 or C24 or C25 or C27), 56.1 (C24 or C25), 46.8 (C10), 46.7 (C10), 31.6 (C28), 31.5 (C28), 21.7 (C30), 21.6 (C30).
16 30 O 31 O 29 15 6 24 28 O 5 1 O O O 9 19 7 18 20 O 4 32 8 17 26 11 21 O 14 12 10 O 23 13 22 O O 27 25 2.251 Hexacycle 2.251 (dik6-56). A solution of spirocycle 2.290 (10 mg, 0.02 mmol) in
PhNO2 (2.5 mL) was heated for 15 min at 150 ºC, 30 min at 200 ºC, and 45 min at 215 ºC. The reaction was cooled to room temperature, and the majority of the solvent was removed by distillation under high vacuum at 54–56 ºC. The residual mixture was dissolved in CH2Cl2 (15 mL), and the solution was extracted with 1 M KOH (2 × 10 mL).
The combined aqueous phases were extracted with CH2Cl2 (3 × 10 mL) and dried
277 (Na2SO4). The solvent was removed under reduced pressure, and the residue was purified by flash column chromatography eluting with hexanes/EtOAc (1:3→0:1) to give 6.6 mg
1 (67%) of 2.251 as a red oil; H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 8.8 Hz, 1 H), 8.10 (d, J = 8.8 Hz, 1 H), 7.22 (d, J = 9.2 Hz, 1 H), 6.82 (d, J = 9.2 Hz, 1 H), 5.36 (d, J = 16.4 Hz, 1 H), 5.11 (d, J = 6.0 Hz, 1 H), 5.06 (d, J = 6.0 Hz, 1 H), 5.05 (d, J = 6.8 Hz, 1 H), 4.97 (d, J = 6.8 Hz, 1 H), 4.93 (d, J = 16.4 Hz, 1 H), 4.00 (s, 3 H), 3.94 (s, 3 H), 3.84- 3.69 (m, 1 H), 3.65 (s, 3 H3.48 (s, 3 H), 3.13 (dd, J = 16.8, 2.8 Hz, 1 H), 2.69 (dd, J =
13 16.8, 11.2 Hz, 1 H), 1.42 (d, J = 6.0 Hz, 3 H); C NMR (125 MHz, CDCl3) δ 181.7, 178.7, 173.3, 153.2, 152.4, 148.0, 147.8, 146.6, 143.1, 135.4, 131.8, 130.1, 129.9, 128.0, 122.4, 121.5, 120.4, 117.4, 117.1, 107.4, 104.8, 100.5, 99.9, 70.1, 65.7, 57.9, 57.8, 57.1,
56.8, 31.7, 21.7; IR (neat) 2928, 1691, 1648, 1630, 1585, 1489, 1273, 1158, 1099 cm-1;
mass spectrum (ESI) m/z 577.1704 [C31H29O11 (M+1) requires 577.1704].
1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 8.8 Hz, 1 H, C13-H or C14-H), 8.10 (d, J = 8.8 Hz, 1 H, C13-H or C14-H), 7.22 (d, J = 9.2 Hz, 1 H, C20-H or C21-H), 6.82 (d, J = 9.2 Hz, 1 H, C20-H or C21-H), 5.36 (d, J = 16.4 Hz, 1 H, C31-H), 5.11 (d, J = 6.0 Hz, 1 H, C15-H or C26-H), 5.06 (d, J = 6.0 Hz, 1 H, C15-H or C26-H), 5.05 (d, J = 6.8 Hz, 1 H, C15-H or C26-H), 4.97 (d, J = 6.8 Hz, 1 H, C15-H or C26-H), 4.93 (d, J = 16.4 Hz, 1 H, C31-H), 4.00 (s, 3 H, C24-H or C25-H), 3.94 (s, 3 H, C24-H or C25-H), 3.84-3.69 (m, 1 H, C29-H), 3.65 (s, 3 H, C16-H or C27-H), 3.48 (s, 3 H, C16-H
or C27-H), 3.13 (dd, J = 16.8, 2.8 Hz, 1 H, C28-H), 2.69 (dd, J = 16.8, 11.2 Hz, 1 H,
13 C28-H), 1.42 (d, J = 6.0 Hz, 3 H, C30-H); C NMR (100 MHz, CDCl3) δ 181.7 (C8), 178.7 (C11), 173.3 (C17), 153.2 (ArC), 152.4 (ArC), 148.0 (ArC), 147.8 (ArC), 146.6 (ArC), 143.1 (ArC), 135.4 (ArC), 131.8 (ArC), 130.1 (ArC), 129.9 (ArC), 128.0 (ArC), 122.4 (ArC), 121.5 (ArC), 120.4 (ArC), 117.4 (ArC), 117.1 (ArC), 107.4 (ArC), 104.8
278 (ArC), 100.5 (C15 or C26), 99.9 (C15 or C26), 70.1 (C29), 65.7 (C31), 57.9 (C16 or C27), 57.8 (C16 or C27), 57.1 (C24 or C25), 56.8 (C24 or C25), 31.7 (C28), 21.7 (C30).
11 O O 10 12 6 9 O 5 1 7 8 O 4 2 Br 3 2.295 7-Bromo-5,8-bis(methoxymethoxy)-3-methylisochroman-1-one (2.295) (dik6- 71). 3,5-Dimethylpyrazole (67 mg, 0.70 mmol) was added in one portion to a solution of
CrO3 (70 mg, 0.70 mmol) in CH2Cl2 (2 mL) at –25 ºC. After 15 min, a solution of 2.266
(20 mg, 0.07 mmol) in CH2Cl2 (1 mL) was added. After 19 h in a freezer, 2 M NaOH (0.5 mL) was added, and the reaction was allowed to warm to room temperatureover 30 min with vigorous stirring. The phases were separated, and the aqueous phase was extracted with Et2O (3 × 10 mL). The combined organic phases were washed with 2 M HCl (10
mL) and brine (2 × 10 mL), and the ethereal phase was dried (MgSO4). The solvent was removed under reduced pressure to give 21 mg (~100%) of 2.295 as a white oil; 1H NMR
(400 MHz, CDCl3) δ 7.26 (s, 1 H), 4.55-4.44 (m, 1 H), 3.91 (s, 3 H), 3.83 (s, 3 H), 3.09 (dd, J = 16.8, 3.0 Hz, 1 H), 2.52 (dd, J = 16.8 Hz, 11.4 Hz, 1 H), 1.49 (d, J = 6.4 Hz, 3 H); IR (neat) 2935, 1728, 1475, 1265, 1064 cm-1; mass spectrum (ESI) m/z 301.0072
[C12H13O4Br (M+1) requires 301.0070], 323 (base).
1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 7.26 (s, 1 H, C3-H), 4.55-4.44 (m, 1 H, C10-H), 3.91 (s, 3 H, C7-H or C8-H), 3.83 (s, 3 H, C7-H or C8-H), 3.09 (dd, J = 16.8, 3.0 Hz, 1 H, C9-H), 2.52 (dd, J = 16.8 Hz, 11.4 Hz, 1 H, C9-H), 1.49 (d, J = 6.4 Hz, 3 H, C11-H).
279 4.3 Total Synthesis of Cribrostatin 6
But-3-ynyl-4-methylbenzenesulfonate (3.130) (dik3-214). A solution of n-BuLi (2.80 mL, 2.60 M, 7.27 mmol) in hexanes was added dropwise to a solution of 3.5 (0.50 mL, 6.61 mmol) in THF (7.5 mL) at –78 °C. After 5 min at –78 °C, stirring was continued for 30 min at 0 °C. p-TsCl (1.51 g, 7.93 mmol) in THF (8 mL) was added, and
the reaction was stirred for 30 min at 0 ºC. H2O (2 mL) was added, and the mixture was
extracted with Et2O (3 × 10 mL). The combined organic phases were dried (Na2SO4), and the solvent was removed under reduced pressure to give 1.41 g (95%) of 3.130 as a pale
1 yellow oil; H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.0 Hz, 2 H), 7.33 (d, J = 8.0 Hz, 2 H), 4.08 (t, J = 7.1 Hz, 2 H), 2.53 (dt, J = 7.1, 2.6 Hz, 2 H), 2.43 (s, 3 H), 1.95 (t, J = 2.6
13 Hz, 1 H); C NMR (100 MHz, CDCl3) δ 145.0, 132.7, 129.9, 127.9, 78.3, 70.7, 67.4, 21.6, 19.4; IR (neat) 3290, 2962, 2919, 1598, 1359, 1190, 1176, 980, 904, 815 cm-1; mass
spectrum (ESI) m/z 247.0399 [C11H12O3S (M+23) requires 247.0400], 471 (base), 247, 225.
1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.0 Hz, 2 H, C6-H), 7.33 (d, J = 8.0 Hz, 2 H, C7-H), 4.08 (t, J = 7.1 Hz, 2 H, C4-H), 2.53 (dt, J = 7.1, 2.6 Hz, 2 H,
13 C3-H), 2.43 (s, 3 H, C9-H), 1.95 (t, J = 2.6 Hz, 1 H, C1-H); C NMR (100 MHz, CDCl3) δ 145.0 (C5), 132.7 (C8), 129.9 (C7), 127.9 (C6), 78.3 (C2), 70.7 (C1), 67.4 (C4), 21.6 (C3), 19.4 (C9).
280 10 2 1 3 Si 4 O O S O 5 6 7 8 3.133 9 4-(Trimethylsilyl)-but-3-ynyl-4-methylbenzenesulfonate (3.133) (dik3-266). A solution of n-BuLi (5.57 mL, 2.44 M, 13.59 mmol) in hexanes was added dropwise to a
solution of 3.130 (2.65 g, 11.82 mmol) in THF (60 mL) at –78 °C. After 45 min at –78 °C, TMSCl (2.26 mL, 17.72 mmol) was added dropwise. After 10 min at –78 °C, the
reaction was stirred for 50 min at room temperature. Saturated aqueous NH4Cl (2 mL)
and H2O (5 mL) were added, and the mixture was extracted with Et2O (3 × 20 mL). The
combined organic phases were dried (Na2SO4), and the solvent was removed under reduced pressure to give 3.09 g (88%) of 3.133 as a yellow oil; 1H NMR (400 MHz,
CDCl3) δ 7.75 (d, J = 8.4 Hz, 2 H), 7.31 (d, J = 8.4 Hz, 2 H), 4.03 (t, J = 7.1 Hz, 2 H),
13 2.54 (t, J = 7.1 Hz, 2 H), 2.40 (s, 3 H), 0.07 (s, 3 H); C NMR (100 MHz, CDCl3) δ 144.8, 132.7, 129.8, 127.8, 100.3, 87.3, 67.5, 21.5, 20.6, -0.2; IR (neat) 2960, 2361, 2339,
-1 2181, 1364 cm ; mass spectrum (ESI) m/z 297.0975 [C14H20SiO3S (M+1) requires 297.0973].
1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.4 Hz, 2 H, C6-H), 7.31 (d, J = 8.4 Hz, 2 H, C7-H), 4.03 (t, J = 7.1 Hz, 2 H, C4-H), 2.54 (t, J = 7.1 Hz, 2 H, C3-
13 H), 2.40 (s, 3 H, C9-H), 0.07 (s, 3 H, C10-H); C NMR (100 MHz, CDCl3) δ 144.8 (C5), 132.7 (C8), 129.8 (C7), 127.8 (C6), 100.3 (C2), 87.3 (C1), 67.5 (C4), 21.5 (C3), 20.6 (C9), -0.2 (C10).
281 1 2 3 Si 4 9 5 N 8 6 7 N
3.135 2-Methyl-1-(4-(trimethylsilyl)-but-3-ynyl)-1H-imidazole (3.135) (dik3-232). NaH (19 mg, 0.47 mmol, 60% dispersion in mineral oil) was added to a solution of 3.6 (37 mg, 0.45 mmol) in DMF (3.5 mL). After 1 h at room temperature, a solution of 3.133 (173mg, 0.58 mmol) in DMF (1 mL) was added, and the mixture was stirred for 2 h. The reaction was then heated overnight at 70 °C, whereupon it was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was poured unto H2O (20 mL), and the mixture was extracted with CH3Cl (3 × 10 mL). The combined organic phases were washed with H2O (10 mL) and brine (10 mL), dried
(Na2SO4), and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography eluting with CHCl3/MeOH (10:1) to give 13 mg (14%)
1 of 3.135 as a light yellow oil; H NMR (400 MHz, CDCl3) δ 6.89 (s, 1 H), 6.84 (s, 1 H), 3.98 (t, J = 7.0 Hz, 2 H), 2.59 (t, J = 7.0 Hz, 2 H), 2.39 (s, 3 H), 0.12 (s, 3 H); 13C NMR
(100 MHz, CDCl3) δ 127.2, 119.1, 102.0, 87.8, 44.7, 22.4, 13.0, -0.2; IR (neat) 2957,
-1 2358, 2177, 1250 cm ; mass spectrum (ESI) m/z 207.1314 [C11H18N2Si (M+1) requires 207.1312], 208 (base).
1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 6.89 (s, 1 H, C1-H), 6.84 (s, 1 H, C2- H), 3.98 (t, J = 7.0 Hz, 2 H, C5-H), 2.59 (t, J = 7.0 Hz, 2 H, C6-H), 2.39 (s, 3 H, C4-H),
13 0.12 (s, 3 H, C9-H); C NMR (100 MHz, CDCl3) δ 127.2 (C2), 119.1 (C1), 102.0 (C8), 87.8 (C7), 44.7 (C5), 22.4 (C6), 13.0 (C4), -0.2 (C9).
282
1-(But-3-ynyl)-2-methyl-1H-imidazole (3.132) (dik4-106). 2-Methylimidazole (3.6) (4.456 g, 54.27 mmol) was added to a solution of 3.130 (2.434 g, 10.85 mmol) in
CH3CN (15 mL). The reaction was heated for 18 h at 70 °C, whereupon it was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was
purified by flash column chromatography eluting with CHCl3/MeOH (10:1) to give 1.346
1 g (92%) of 3.132 as a clear oil; H NMR (400 MHz, CDCl3) δ 6.85 (d, J = 1.2 Hz, 1 H), 6.82 (d, J = 1.2 Hz, 1 H), 3.95 (t, J = 7.0 Hz, 2 H), 2.53 (dt, J = 7.0 Hz, 2 H), 2.35 (s, 3
13 H), 1.99 (t, J = 2.6 Hz, 1 H); C NMR (100 MHz, CDCl3) δ 144.3, 127.1, 118.9, 79.6, 71.1, 44.3, 20.9, 12.8; IR (neat) 3287, 2923, 1501, 1425, 1281 cm-1; mass spectrum (CI)
m/z 135.0926 [C8H10N2 (M+1) requires 135.0922], 135 (base).
1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 6.85 (d, J = 1.2 Hz, 1 H, C5-H), 6.82 (d, J = 1.2 Hz, 1 H, C6-H), 3.95 (t, J = 7.0 Hz, 2 H, C4-H), 2.53 (dt, J = 7.0 Hz, 2 H, C3-
13 H), 2.35 (s, 3 H, C4-H), 1.99 (t, J = 2.6 Hz, 1 H, C8-H); C NMR (100 MHz, CDCl3) δ 144.3 (C7), 127.1 (C6), 118.9 (C5), 79.6 (C2), 71.1 (C1), 44.3 (C4), 20.9 (C3), 12.8 (C8).
3-Ethoxy-4-hydroxy-2-methyl-4-(4-(2-methyl-1H-imidazol-1-yl)but-1- ynyl)cyclobut-2-enone (3.3) (dik3-284). A solution of n-BuLi (0.53 mL, 2.44 M, 1.30
283 mmol) in hexanes was added dropwise to a solution of 3.132 (145 mg, 1.08 mmol) in
THF (5.4 mL) at –78 °C. After 35 min at –78 °C, a solution of 3-ethoxy-4- methylcyclobutene-1,2-dione (3.4) (242 mg, 1.73 mmol) in THF (5 mL) at –78 °C was added dropwise via cannula. After 10 min at –78 °C, stirring was continued for 1.5 h at 0
°C. Saturated aqueous NH4Cl (5 mL) and brine (5 mL) were added, and the mixture was
extracted with EtOAc (3 × 20 mL). The combined organic phases were dried (Na2SO4), and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography eluting with CHCl3/MeOH (10:1) to give 185 mg (62%) of 3.3
1 as an amber oil; H NMR (400 MHz, CDCl3) δ 6.85 (d, J = 1.4 Hz, 1 H), 6.84 (d, J = 1.4 Hz, 1 H), 4.56-4.38 (comp, 2 H), 3.99 (t, J = 6.7 Hz, 2 H), 2.67 (t, J = 6.7 Hz, 2 H), 2.39
13 (s, 3 H), 1.65 (s, 3 H), 1.43 (t, J= 7.2 Hz, 3 H); C NMR (100 MHz, CDCl3) δ 187.9, 181.1, 144.4, 126.6, 123.9, 119.1, 85.0, 82.7, 78.6, 69.0, 44.3, 21.6, 15.1, 12.7, 6.4; IR
-1 (neat) 2986, 1763, 1620, 1327 cm ; mass spectrum (ESI, CI) m/z 275.1390 [C15H18O3N2 (M+1) requires 275.1393], 275 (base).
1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 6.85 (d, J = 1.4 Hz, 1 H, C12-H), 6.84 (d, J = 1.4 Hz, 1 H, C13-H), 4.56-4.38 (comp, 2 H, C6-H), 3.99 (t, J = 6.7 Hz, 2 H, C11-H), 2.67 (t, J = 6.7 Hz, 2 H, C10-H), 2.39 (s, 3 H, C15-H), 1.65 (s, 3 H, C5-H), 1.43
13 (t, J = 7.2 Hz, 3 H, C7-H); C NMR (100 MHz, CDCl3) δ 187.9 (C1), 181.1 (C3), 144.4 (C14), 126.6 (C13), 123.9 (C2), 119.1 (C12), 85.0 (C8), 82.7 (C4), 78.6 (C9), 69.0 (C6),
44.3 (C11), 21.6 (C10), 15.1 (C7), 12.7 (C15), 6.4 (C5).
284 2-Ethoxy-3-methyl-5-(2-(2-methyl-1H-imidazol-1-yl)ethyl)-cyclohexa-2,5- diene-1,4-dione (3.136) (dik4-48). A solution of 3.3 (40 mg, 0.15 mmol) in
chlorobenzene (6.2 mL) was heated for 30 min at 130 °C in a preheated oil bath. After cooling to room temperature, the reaction was stirred open to air for 16 h. The solvent was removed under reduced pressure, and the residue was purified by flash column
chromatography eluting with CHCl3/MeOH (10:1) to give ~10 mg (ca. 25%) of 3.136 as
1 a yellow oil; H NMR (400 MHz, CDCl3) δ 6.87 (d, J = 1.2 Hz, 1 H), 6.75 (d, J = 1.2 Hz, 1 H), 6.27 (s, 1 H), 4.29 (q, J = 7.0 Hz, 2 H), 4.00 (t, J = 7.3 Hz, 2 H), 2.78 (t, J = 7.3 Hz, 2 H), 2.34 (s, 3 H), 1.94 (s, 3 H), 1.33 (t, J = 7.0 Hz, 3 H); mass spectrum (ESI) m/z
275.1395 [C15H18N2O3 (M+1) requires 275.1390].
1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 6.87 (d, J = 1.2 Hz, 1 H, C13-H), 6.75 (d, J = 1.2 Hz, 1 H, C12-H), 6.27 (s, 1 H, C8-H), 4.29 (q, J = 7.0 Hz, 2 H, C6-H), 4.00 (t, J = 7.3 Hz, 2 H, C11-H), 2.78 (t, J = 7.3 Hz, 2 H, C10-H), 2.34 (s, 3 H, C15-H), 1.94 (s, 3 H, C5-H), 1.33 (t, J = 7.0 Hz, 3 H, C7-H).
Cribrostatin 6 (3.1) (dik4-96). A solution of 3.3 (96 mg, 0.35 mmol) in CH3CN (350 mL) was heated under reflux for 35 min in a preheated oil bath (130 °C). After cooling to room temperature, the solution was concentrated to approximately 5 mL by evaporation under reduced pressure. Pd/C (15 mg, 10 wt % loading) was added, and the reaction was heated for 4 h at 80 °C. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by flash column
285 chromatography eluting with CHCl3/MeOH (10:1) to give 25 mg (26%) of 3.1 as a blue solid: mp 165–167 °C (lit145 169–171 °C, lit104 165–167 °C) ; 1H NMR (600 MHz,
CDCl3) δ 8.23 (d, J = 0.9 Hz, 1 H), 7.83 (dd, J = 7.3, 0.9 Hz, 1 H), 7.17 (d, J = 7.3 Hz, 1 H), 4.38 (q, J = 7.0 Hz, 2 H), 2.67 (s, 3 H), 2.04 (s, 3 H), 1.40 (t, J = 7.0 Hz, 3 H); 13C
NMR (151 MHz, CDCl3) δ 184.9, 180.7, 156.2, 137.7, 130.1, 125.9, 125.0, 124.7, 123.9, 123.5, 107.6, 69.6, 16.0, 12.6, 9.2; IR (neat) 2923, 1662, 1626, 1611, 1527, 1172 cm-1;
mass spectrum (ESI) m/z 271.1077 [C15H14N2O3 (M+1) requires 271.1078], 271 (base), 243, 215.
1 NMR Assignments. H NMR (600 MHz, CDCl3) δ 8.23 (d, J = 0.9 Hz, 1 H, C13-H), 7.83 (dd, J = 7.3, 0.9 Hz, 1 H, C11-H), 7.17 (d, J = 7.3 Hz, 1 H, C10-H), 4.38 (q, J = 7.0 Hz, 2 H, C6-H), 2.67 (s, 3 H, C15-H), 2.04 (s, 3 H, C5-H), 1.40 (t, J = 7.0 Hz, 3 H, C7-
13 H); C NMR (151 MHz, CDCl3) δ 184.9 (C1), 180.7 (C4), 156.2 (C3), 137.7 (C14), 130.1 (C2), 125.9 (C13), 125.0 (C9), 124.7 (C11), 123.9 (C12), 123.5 (C8), 107.6 (C10), 69.6 (C6), 16.0 (C7), 12.6 (C15), 9.2 (C5).
1H NMR 13C NMR Lit145 δ Lit104δ Observed δ Lit145 δ Lit104 δ Observed δ (500 MHz) (400 MHz) (600 MHz) (125 MHz) (100 MHz) (151 MHz) 8.29 8.30 8.23 184.9 184.8 184.9 7.90 7.90 7.83 180.6 180.5 180.7 7.26 7.26 7.17 156.2 156.2 156.2 4.40 4.41 4.38 137.6 137.5 137.7 2.75 2.74 2.67 130.1 130.1 130.1 2.06 2.08 2.04 125.7 125.3 125.9 1.41 1.43 1.40 125.0 125.2 125.0 124.7 124.7 124.7 123.9 123.9 123.9 123.5 123.6 123.5 107.7 108.0 107.6 69.6 69.7 69.6 16.0 16.1 16.0 12.6 12.6 12.6 9.2 9.3 9.2
286 6 5 O 2 1 O 9 10 11 3 4 8 7 O OH 12 13 N 3.145 14 16 N 15 2,3-Diethoxy-4-hydroxy-4-(4-(2-methyl-1H-imidazol-1-yl)but-1- ynyl)cyclobut-2-enone (3.145) (dik4-67). A solution of n-BuLi (1.27 mL, 2.29 M, 2.91 mmol) in hexanes was added dropwise to a solution of 3.132 (340 mg, 2.53 mmol) in
THF (12 mL) at –78 °C. After 35 min at –78 °C, a solution of 3,4-diethoxycyclobut-3- ene-1,2-dione (3.129) (862 mg, 5.07 mmol) in THF (6 mL) at 0 °C was added dropwise via cannula. After 10 min at –78 °C, stirring was continued for 1.5 h at 0 °C. Saturated
aqueous NH4Cl (5 mL) and brine (5 mL) were added, and the mixture was extracted with
EtOAc (3 × 30 mL). The combined organic phases were dried (Na2SO4), and the solvent was removed under reduced pressure. The residue was purified by flash column
chromatography eluting with CH2Cl2/MeOH (10:1 → 5:1) to give 379 mg (49%) of 3.145
1 as a yellow oil; H NMR (400 MHz, CDCl3) δ 6.83 (d, J = 1.4 Hz, 1 H), 6.79 (d, J = 1.4 Hz, 1 H), 4.53-4.38 (comp, 2 H), 4.25 (q, J = 7.1 Hz, 2 H), 3.96 (t, J = 6.6 Hz, 2 H), 2.63 (t, J = 6.6 Hz, 2 H), 2.35 (s, 3 H), 1.40 (t, J = 7.0 Hz, 3 H), 1.27 (t, J = 7.1 Hz, 3 H); 13C
NMR (100 MHz, CDCl3) δ 181.3, 165.1, 144.4, 134.2, 126.5, 119.1, 84.2, 78.6, 78.1, 69.4, 67.0, 44.4, 21.5, 15.5, 15.2, 12.6; IR (neat) 3119, 2982, 1776, 1634, 1324, 1045 cm-
1 ; mass spectrum (ESI) m/z 305.1496 [C16H20O4N2 (M+1) requires 305.1499], 305 (base).
1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 6.83 (d, J = 1.4 Hz, 1 H, C13-H), 6.79 (d, J = 1.4 Hz, 1 H, C14-H), 4.53-4.38 (comp, 2 H, C7-H), 4.25 (q, J = 7.1 Hz, 2 H, C5-H), 3.96 (t, J = 6.6 Hz, 2 H, C13-H), 2.63 (t, J = 6.6 Hz, 2 H, C12-H), 2.35 (s, 3 H,
C16-H), 1.40 (t, J = 7.0 Hz, 3 H, C8-H), 1.27 (t, J = 7.1 Hz, 3 H, C6-H); 13C NMR (100
MHz, CDCl3) δ 181.3 (C1), 165.1 (C3), 144.4 (C15), 134.2 (C2), 126.5 (C14), 119.1 287 (C13), 84.2 (C9), 78.6 (C10), 78.1 (C4), 69.4 (C5 or C7), 67.0 (C5 or C7), 44.4 (C12), 21.5 (C11), 15.5 (C6 or C8), 15.2 (C6 or C8), 12.6 (C16).
8,9-Diethoxy-3-methylimidazo[5,1-a]isoquinoline-7,10-dione (3.147) (dik4- 97). A solution of 3.145 (89 mg, 0.29 mmol) in degassed anisole (290 mL) was heated at 120 °C for 2.5 h in a preheated oil bath. After cooling to room temperature, the solution was concentrated to approximately 5 mL by evaporation under reduced pressure. Pd/C
(12 mg, 10 wt % loading) was added, and the reaction was heated for 15 h at 90 °C. After cooling to room temperature, the solvent was removed under reduced pressure, and the
residue was purified by flash column chromatography eluting with CHCl3/MeOH (10:1) to give 16 mg (18%) of 3.147 as an aquamarine solid: mp 125–127 °C; 1H NMR (400
MHz, CDCl3) δ 8.30 (s, 1 H), 7.85 (d, J = 7.4 Hz, 1 H), 7.18 (d, J = 7.4 Hz, 1 H), 4.35 (q, J = 7.1 Hz, 2 H), 4.34 (q, J = 7.1 Hz, 2 H), 2.69 (s, 3 H), 1.42 (t, J = 7.1 Hz, 3 H), 1.41 (t,
13 J = 7.1 Hz, 3 H); C NMR (151 MHz, CDCl3) δ 181.7, 181.3, 145.9, 145.6, 137.9, 126.6, 124.5, 124.0, 123.5, 123.3, 107.5, 69.91, 69.88, 15.6 (2 C), 12.7; IR (neat) 2925, 1666,
-1 1621, 1601, 1531, 1271, 1176 cm ; mass spectrum (CI) m/z 301.1182 [C16H16N2O4 (M+1) requires 301.1183].
1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 8.30 (s, 1 H, C14-H), 7.85 (d, J = 7.4 Hz, 1 H, C12-H), 7.18 (d, J = 7.4 Hz, 1 H, C11-H), 4.35 (q, J = 7.1 Hz, 2 H, C5-H or C- 7-H), 4.34 (q, J = 7.1 Hz, 2 H, C5-H or C7-H), 2.69 (s, 3 H, C16-H), 1.42 (t, J = 7.1 Hz, 3 H, C6-H or C8-H), 1.41 (t, J = 7.1 Hz, 3 H, C6-H or C8-H); 13C NMR (151 MHz,
288 CDCl3) δ 181.7 (C1), 181.3 (C4), 145.9 (C2 or C3), 145.6 (C2 or C3), 137.9 (C15), 126.6 (C14), 124.5 (C12), 124.0 (C13), 123.5 (C9 or C10), 123.3 (C9 or C10), 107.5 (C11), 69.91 (C5 or C7), 69.88 (C5 or C7), 15.6 (C6 & C8), 12.7 (C16).
4-Hydroxy-3-methoxy-2-methyl-4-(4-(2-methyl-1H-imidazol-1-yl)but-1- ynyl)cyclobut-2-enone (3.150) (dik5-139). A solution of n-BuLi (1.30 mL, 2.61 M, 3.39 mmol) in hexanes was added dropwise to a solution of 3.132 (396 mg, 2.95 mmol) in
THF (10 mL) at –78 °C. After 35 min at –78 °C, a solution of 3-methoxy-4- methylcyclobut-3-ene-1,2-dione (3.20) (595 mg, 4.72 mmol) in THF (5 mL) at 0 °C was added dropwise via cannula. After 10 min at –78 °C, stirring was continued for 1.5 h at 0
°C. Saturated aqueous NH4Cl (5 mL) and brine (5 mL) were added, and the mixture was
extracted with EtOAc (3 × 20 mL). The combined organic phases were dried (Na2SO4), and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography eluting with CHCl3/MeOH (10:1→5:1) to give 241 mg (38%) of
1 3.150 as an orange oil; H NMR (400 MHz, CDCl3) δ 6.79 (d, J = 1.4 Hz, 1 H), 6.74 (d, J = 1.4 Hz, 1 H), 4.11 (s, 3 H), 3.93 (t, J = 6.7 Hz, 2 H), 2.61 (t, J = 6.7 Hz, 2 H), 2.30 (s, 3
13 H), 1.59 (s, 3 H); C NMR (100 MHz, CDCl3) δ 188.0, 181.7, 144.4, 126.4, 124.1, 119.0, 84.9, 82.5, 78.6, 59.5, 44.3, 21.5, 12.5, 6.3; IR (neat) 3115, 2956, 1765, 1625,
-1 1339 cm ; mass spectrum (ESI) m/z 261.1237 [C14H16N2O2 (M+1) requires 261.1234], 261 (base).
289 1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 6.79 (d, J = 1.4 Hz, 1 H, C11-H), 6.74 (d, J = 1.4 Hz, 1 H, C12-H), 4.11 (s, 3 H, C6-H), 3.93 (t, J = 6.7 Hz, 2 H, C9-H), 2.61 (t, J = 6.7 Hz, 2 H, C9-H), 2.30 (s, 3 H, C14-H), 1.59 (s, 3 H, C5-H); 13C NMR (100
MHz, CDCl3) δ 188.0 (C1), 181.7 (C3), 144.4 (C13), 126.4 (C12), 124.1 (C2), 119.0 (C11), 84.9 (C7), 82.5 (C4), 78.6 (C8), 59.5 (C6), 44.3 (C10), 21.5 (C9), 12.5 (C14), 6.3 (C5).
9-Methoxy-3,8-dimethylimidazo[5,1-a]isoquinoline-7,10-dione (3.151) and 7- Methoxy-1,6-dimethylisoquinoline-5,8-dione (3.152) (dik5-144). A solution of 3.150
(240 mg, 0.92 mmol) in CH3CN (400 mL) was heated under reflux for 35 min in a preheated oil bath (130 °C). After cooling to room temperature, the solution was concentrated to approximately 5 mL by evaporation under reduced pressure. Pd/C (31
mg, 10 wt % loading) was added, and the reaction was heated for 20 h at 80 °C. After cooling to room temperature, the solvent was removed under reduced pressure, and the
residue was purified by flash column chromatography eluting with CHCl3/MeOH (20:1) to give 60 mg (25%) of 3.151 as a green-blue solid and 14 mg (7%) of 3.152 as a yellow solid:
290 1 mp 149-151 ºC; H NMR (400 MHz, CDCl3) δ 8.22 (s, 1 H), 7.82 (d, J = 7.2 Hz, 1 H), 7.15 (d, J = 7.2 Hz, 1 H), 4.09 (s, 3 H), 2.67 (s, 3 H), 2.02 (s, 3 H); 13C NMR (100 MHz,
CDCl3) δ 184.8, 180.5, 156.6, 137.7, 129.4, 125.9, 124.8, 124.7, 123.8, 123.5, 107.6, 61.1, 12.6, 9.0; IR (neat) 2925, 1666, 1628, 1291, 1156 cm-1; mass spectrum (ESI) m/z
257.0924 [C14H12N2O3 (M+1) requires 257.0921].
1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 8.22 (s, 1 H, C12-H), 7.82 (d, J = 7.2 Hz, 1 H, C10-H), 7.15 (d, J = 7.2 Hz, 1 H, C9-H), 4.09 (s, 3 H, C6-H), 2.67 (s, 3 H, C11-
13 H), 2.02 (s, 3 H, C5-H); C NMR (100 MHz, CDCl3) δ 184.8 (C1), 180.5 (C4), 156.6 (C3), 137.7 (C13), 129.4 (C2), 125.9 (C12), 124.8 (C8), 124.7 (C10), 123.8 (C11), 123.5 (C7), 107.6 (C9), 61.1 (C6), 12.6 (C14), 9.0 (C5). O 9 5 2 8 1 10 6 4 N O 3 7 11 O 12 3.152 1 mp 133-134 ºC; H NMR (400 MHz, CDCl3) δ 8.82 (d, J = 5.0 Hz, 1 H7.78 (d, J = 5.0
13 Hz, 1 H), 4.12 (s, 3 H), 2.96 (s, 3 H), 2.06 (s, 3 H); C NMR (100 MHz, CDCl3) δ 185.0, 182.1, 160.2, 158.8, 153.7, 138.9, 130.2, 123.0, 117.3, 61.2, 25.6, 9.0; IR (neat) 2927,
-1 1668, 1627, 1570, 1342, 1211, 1119 cm ; mass spectrum (CI) m/z 218.0813 [C12H11NO3 (M+1) requires 218.0817], 218 (base).
1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 8.82 (d, J = 5.0 Hz, 1 H, C10-H), 7.78 (d, J = 5.0 Hz, 1 H, C9-H), 4.12 (s, 3 H, C6-H), 2.96 (s, 3 H, C12-H), 2.06 (s, 3 H,
13 C5-H); C NMR (100 MHz, CDCl3) δ 185.0 (C1), 182.1 (C4), 160.2 (C11), 158.8 (C10), 153.7 (C3), 138.9 (C8), 130.2 (C2), 123.0 (C7), 117.3 (C9), 61.2 (C6), 25.6 (C12), 9.0 (C5).
291
4-Hydroxy-2,3-dimethyl-4-(4-(2-methyl-1H-imidazol-1-yl)but-1- ynyl)cyclobut-2-enone (3.157) (dik5-63). A solution of n-BuLi (1.54 mL, 2.59 M, 4.00 mmol) in hexanes was added dropwise to a solution of 3.132 (447 mg, 3.33 mmol) in
THF (17 mL) at –78 °C. After 35 min at –78 °C, a solution of 3,4-dimethylcyclobut-3- ene-1,2-dione (3.41) (550 mg, 5.00 mmol) in THF (5 mL) at –78 °C was added dropwise via cannula. After 10 min at –78 °C, stirring was continued for 1.5 h at 0 °C. Saturated
aqueous NH4Cl (5 mL) and brine (5 mL) were added, and the mixture was extracted with
EtOAc (3 × 30 mL). The combined organic phases were dried (Na2SO4), and the solvent was removed under reduced pressure. The residue was purified by flash column
chromatography eluting with CHCl3/MeOH (5:1) to give 322 mg (40%) of 3.157 as a
1 yellow oil; H NMR (400 MHz, CDCl3) δ 6.74 (d, J = 1.4 Hz, 1 H), 6.66 (d, J = 1.4 Hz, 1 H), 3.86 (t, J = 6.7 Hz, 2 H), 2.53 (t, J = 6.7 Hz, 2 H), 2.23 (s, 3 H), 2.03 (s, 3 H), 1.60 (s,
13 3 H); C NMR (100 MHz, CDCl3) δ 190.1, 178.1, 149.0, 144.1, 126.0, 118.9, 85.4, 84.0, 79.3, 44.2, 21.3, 12.3, 10.3, 7.5; IR (neat) 3520, 2922, 1760, 1644, 1426 cm-1; mass
spectrum (ESI) m/z 245.1290 [C14H16N2O2 (M+1) requires 245.1285].
1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 6.74 (d, J = 1.4 Hz, 1 H, C11-H), 6.66 (d, J = 1.4 Hz, 1 H, C12-H), 3.86 (t, J = 6.7 Hz, 2 H, C10-H), 2.53 (t, J = 6.7 Hz, 2
H, C9-H), 2.23 (s, 3 H, C14-H), 2.03 (s, 3 H, C6-H), 1.60 (s, 3 H, C5-H); 13C NMR (100
MHz, CDCl3) δ 190.1 (C1), 178.1 (C3), 149.0 (C13), 144.1 (C2), 126.0 (C12), 118.9
292 (C11), 85.4 (C7), 84.0 (C4), 79.3 (C8), 44.2 (C10), 21.3 (C9), 12.3 (C14), 10.3 (C6), 7.5 (C5).
3,8,9-Trimethylimidazo[5,1-a]isoquinoline-7,10-dione (3.158) (dik5-657). A
solution of 3.157 (108 mg, 0.44 mmol) in CH3CN (400 mL) was heated under reflux for 35 min in a preheated oil bath (130 °C). After cooling to room temperature, the solution was concentrated to approximately 5 mL by evaporation under reduced pressure. Pd/C
(10 mg, 10 wt % loading) was added, and the reaction was heated for 15 h at 80 °C. After cooling to room temperature, the solvent was removed under reduced pressure, and the
residue was purified by flash column chromatography eluting with CHCl3/MeOH 10:1)
1 to give 15 mg (14%) of 3.158 as a purple solid: mp >300 ºC; H NMR (400 MHz, CDCl3) δ 8.25 (s, 1 H), 7.82 (d, J = 7.4 Hz, 1 H), 7.16 (d, J = 7.4 Hz, 1 H), 2.67 (d, 3 H), 2.12 (s,
13 3 H), 2.11 (s, 3 H); C NMR (100 MHz, CDCl3, 1 ArC not observed) δ 184.5, 183.9, 142.3, 141.3, 137.8, 126.4, 124.8, 124.5, 124.1, 107.6, 12.64, 12.60, 12.5; IR (neat) 2922,
-1 1649, 1609, 1298, 1284 cm ; mass spectrum (ESI) m/z 241.0975 [C14H12N2O2 (M+1) requires 241.0972], 241 (base).
1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 8.25 (s, 1 H, C12-H), 7.82 (d, J = 7.4 Hz, 1 H, C10-H), 7.16 (d, J = 7.4 Hz, 1 H, C9-H), 2.67 (d, 3 H, C14-H), 2.12 (s, 3 H, C5-
13 H or C6-H), 2.11 (s, 3 H, C5-H or C6-H); C NMR (100 MHz, CDCl3, 1 ArC not observed) δ 184.5 (C1), 183.9 (C4), 142.3 (C2 or C3), 141.3 (C2 or C3), 137.8 (C13),
293 126.4 (C12), 124.8 (ArC), 124.5 (C9), 124.1 (ArC), 107.6 (C10), 12.64 (C5 or C6 or C14), 12.60 (C5 or C6 or C14), 12.5 (C5 or C6 or C14).
O 8 5 2 7 1 9 4 10 N HO 3 6 13 12 O 11 N 3.159 9-Hydroxy-3,8-dimethylimidazo[5,1-a]isoquinoline-7,10-dione (3.159) (dik5-
145). A solution of BBr3 (22 μL, 0.23 mmol) in CH2Cl2 (0.4 mL) was added dropwise to
a solution of 3.151 (25 mg, 0.09 mmol) in CH2Cl2 (4 mL) at –78 ºC. The reaction was allowed to warm to room temperature over 3 h, whereupon brine (10 mL) was added. The
mixture was extracted with CH2Cl2 (3 × 10 mL), and the combined organic phases were
dried (Na2SO4). The solvent was removed under reduced pressure, and the residue was purified by flash column chromatography eluting with CHCl3/MeOH (20:1) to give 2 mg
1 (7%) of 3.159 as a faint blue solid; H NMR (400 MHz, CDCl3) δ 8.22 (s, 1 H), 7.93 (d, J = 7.4 Hz, 1 H), 7.27 (d, J = 7.4 Hz, 1 H), 2.72 (s, 3 H), 2.06 (s, 3 H); mass spectrum
(ESI) m/z 243.0765 [C13H10N2O3 (M+1) requires 243.0764], 243 (base).
1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 8.22 (s, 1 H, C11-H), 7.93 (d, J = 7.4 Hz, 1 H, C9-H), 7.27 (d, J = 7.4 Hz, 1 H, C8-H), 2.72 (s, 3 H, C13-H), 2.06 (s, 3 H, C5-
H).
294 9-(Dimethylamino)-3,8-dimethylimidazo[5,1-a]isoquinoline-7,10-dione
(3.160) (dik5-56). A solution of MeNH2 (28 μL, 8.03 M, 0.23 mmol) in EtOH was added to a solution of 3.1 (12 mg) in EtOH (2.5 mL). After 18 h at room temperature, the solvent was removed under reduced pressure and the residue was purified by flash column chromatography eluting with CHCl3/MeOH (10:1) to give 8 mg (66%) of 3.160
1 as a green solid: mp 208-210 ºC; H NMR (400 MHz, CDCl3, mixture of rotamers) δ 8.10 (s, 1 H), 7.87 (d, J = 7.5 Hz, 1 H), 7.27 (d, J = 7.5 Hz, 1 H), 5.79 (d, J = 4.0 Hz, 1 H), 3.24 (d, J = 4.0 Hz, 1.5 H), 3.23 (d, J = 4.0 Hz, 1.5 H), 2.68 (s, 3 H), 2.22 (s, 3 H); 13C
NMR (100 MHz, CDCl3) δ 182.2, 181.5, 145.9, 137.2, 127.6, 125.5, 124.2, 123.7, 121.6, 108.8, 108.4, 32.8, 12.6, 10.5; IR (neat) 3583, 3325, 2922, 1620, 1515 cm-1; mass spectrum (ESI) m/z 256.1087 [C14H13N3O2 (M+1) requires 256.1081], 256 (base).
1 NMR Assignments. H NMR (400 MHz, CDCl3, mixture of rotamers) δ 8.10 (s, 1 H, C11-H), 7.87 (d, J = 7.5 Hz, 1 H, C10-H), 7.27 (d, J = 7.5 Hz, 1 H, C9-H), 5.79 (d, J = 4.0 Hz, 1 H, NH), 3.24 (d, J = 4.0 Hz, 1.5 H, C6-H), 3.23 (d, J = 4.0 Hz, 1.5 H, C6-H),
13 2.68 (s, 3 H, C13-H), 2.22 (s, 3 H, C5-H); C NMR (100 MHz, CDCl3) δ 182.2 (C1), 181.5 (C4), 145.9 (C3), 137.2 (C13), 127.6 (C2), 125.5 (C12), 124.2 (C8), 123.7 (C10), 121.6 (C11), 108.8 (C7), 108.4 (C9), 32.8 (C6), 12.6 (C14), 10.5 (C5).
5 2 1 O 8 9 3 10 6 4 11 N OH 12 N 7 13 15 N 14 3.166 3-(Dimethylamino)-4-hydroxy-2-methyl-4-(4-(2-methyl-1H-imidazol-1- yl)but-1-ynyl)cyclobut-2-enone (3.166) (dik5-142). A solution of n-BuLi (0.45 mL, 2.61 M, 1.17 mmol) in hexanes was added dropwise to a solution of 3.132 (149 mg, 1.11 295 mmol) in THF (8 mL) at –78 °C. After 35 min at –78 °C, a solution of 3- (dimethylamino)-4-methylcyclobut-3-ene-1,2-dione (3.165) (170 mg, 1.22 mmol) in THF
(2 mL) at 0 °C was added dropwise. After 10 min at –78 °C, stirring was continued for
1.5 h at 0 °C. Saturated aqueous NH4Cl (5 mL) and brine (5 mL) were added, and the mixture was extracted with EtOAc (3 × 20 mL). The combined organic phases were dried
(Na2SO4), and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography eluting with CHCl3/MeOH (10:1) to give 54 mg (18%)
1 of 3.166 as a faint yellow oil; H NMR (400 MHz, CDCl3) δ 6.82 (app s, 1 H), 6.80 (app s, 1 H), 3.94 (t, J = 6.8 Hz, 2 H), 3.10 (s, 3 H), 3.07 (s, 3 H), 2.61 (t, J = 6.8 Hz, 2 H),
13 2.33 (s, 3 H), 1.69 (s, 3 H); C NMR (100 MHz, CDCl3) δ 185.0, 170.3, 144.4, 126.6, 119.0, 113.9, 83.7, 81.1, 79.5, 44.3, 39.9, 39.3, 21.5, 12.7, 7.5; IR (neat) 3237, 1752,
-1 1597, 1415, 1136 cm ; mass spectrum (ESI) m/z 274.1552 [C15H19N3O2 (M+1) requires 274.1550], 274 (base).
1 NMR Assignments. H NMR (400 MHz, CDCl3) δ 6.82 (app s, 1 H, C12-H), 6.80 (app s, 1 H, C13-H), 3.94 (t, J = 6.8 Hz, 2 H, C11-H), 3.10 (s, 3 H, C7-H), 3.07 (s, 3 H, C6-H), 2.61 (t, J = 6.8 Hz, 2 H, C10-H), 2.33 (s, 3 H, C15-H), 1.69 (s, 3 H, C5-H); 13C NMR
(100 MHz, CDCl3) δ 185.0 (C1), 170.3 (C3), 144.4 (C14), 126.6 (C13), 119.0 (C12), 113.9 (C2), 83.7 (C8), 81.1 (C4), 79.5 (C9), 44.3 (C11), 39.9 (C7), 39.3 (C6), 21.5 (C10), 12.7 (C15), 7.5 (C5).
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170 (a) Scobie, M.; Threadgill, M. D. “Synthesis of Carborane-containing Nitroimidazole Compounds via Mild 1,3-Dipolar Cycloaddition” J. Chem. Soc., Chem. Commun. 1992, 13, 939-941; (b) He, H.; Zatorska, D.; Kim, J.; Aguirre, J.; Llauger, L.; She, Y.; Wu, N.; Immormino, R. M.; Gewirth, D. T.; Chiosis, G. “Identification of Potent Water Soluble Purine-Scaffold Inhibitors of the Heat Shock Protein 90” J. Med. Chem. 2006, 49, 381-390; (c) Luo, S.; Mi, X.; Zhang, L.; Liu, S.; Xu, H.; Cheng, J.-P. “Functionalized Chiral Ionic Liquids as Highly Efficient Asymmetric Organocatalysts for Michael Addition to Nitroolefins” Angew. Chem. Int. Ed. 2006, 45, 3093-3097.
171 (a) Daniels, S. B.; Cooney, E.; Sofia, M. J.; Chakravarty, P. K.; Katzenellenbogen, J. A. “Haloenol Lactones: Potent Enzyme-Activated Irreversible Inhibitors of α-Chymotrypsin” J. Biol. Chem. 1983, 258, 15046- 15053. (b) Linkert, F.; Laschat, S.; Kotila, S.; Fox, T. ”Evidence for a Stepwise Mechanism in Formal Hetero-Diels-Alder Reactions of N-Arylimines” Tetrahedron 1996, 52, 955-970.
172 Fınaru,̂ A.; Berthault, A.; Besson, T.; Guillaumet, G.; Berteina-Raboin, S. “Microwave-assisted Synthesis of 5-Carboxymethoxy-N-acetyltryptamine Derivatives” Tetrahedron Lett. 2002, 43, 787-790.
173 For an example, see: Nakamura, S.; Kawasaki, I.; Yamashita, M.; Ohta, S. “1- Methyl-3-trimethylsilylparabanic Acid as an Effective Reagent for the Preparation of N-Substituted (1-Methyl-2,5-dioxo-1,2,5H-imidazolin-4-yl)-amines and its Application to the Total Synthesis of Isonaamidines A and C, Antitumor Imidazole Alkaloids” Heterocycles 2003, 60, 583.
174 Anisole was used due to limited solubility of the mixture of 3.140 and 3.1 in benzene, toluene, or xylene.
175 (a) Sobrazo-Sanchez, E.; De la Fuente, J.; Castedo, L. “Spectral Assignments and Reference Data” Magn. Reson. Chem. 2005, 43, 1080-1083; (b) Funabashi, K.; Ratni, H.; Kanai, M.; Shibasaki, M. “Enantioselective Construction of Quaternary Stereocenter through a Resissert-Type Reaction Catalyzed by Electronically Tuned Biofunctional Catalyst: Efficient Synthesis of Various Biologically Significant Compounds” J. Am. Chem. Soc. 2001, 123, 10784-10785.
176 Cribrostatin 6 analog 3.161 was prepared by undergraduate researcher Vicki Chang.
177 Gonzalez, R. R.; Gambarotti, L. L.; Bjorsvik, H.-R. “Efficient and Green Telescoped Process to 2-Methoxy-3-methyl-[1,4]benzoquinone” J. Org. Chem. 2006, 71, 1703-1706.
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178 Capecchi, T.; de Koning, C. B.; Michael, J. P., “Synthesis of the Bisbenzannelated Spiroketal Core of the γ-Rubromycins. The Use of a Novel Nef- Type Reaction Mediated by Pearlman’s Catalyst”, J. Chem. Soc., Perkin Trans. 1, 2000, 2681-2688.
316 Vita
Daniel Knueppel was born in Wuppertal, Germany in 1982 to Dr. Peter C. and Cornelia Knüppel. After completing tenth grade at the Gymnasium Wermelskirchen, he moved to the United States in the summer of 1999. He completed the last two years of High School at Mills High School in Millbrae, California and attended the University of California at Santa Cruz in the fall of 2001. He pursued undergraduate research under the supervision of Professor Bakthan Singaram and was recognized with a Doug Drexler Chemistry Scholarship (2003), an Ellen Renard Chemistry Scholarship (2004), a Joseph F. Bunnett Research Price (2005), and Senior Thesis Honors (2005). He also completed a summer internship with Bayer CropScience in Monheim, Germany in 2004. He graduated with a Bachelor of Science with Highest Honors in 2005 and entered The University of Texas at Austin to pursue a Ph.D. under the supervision of Professor Stephen F. Martin. During his graduate career he received an Organic Laboratory Teaching Assistant of the Semester Award (2006), a National Science Foundation Graduate Research Fellowship (2007), two Tetrahedron Editorial Graduate Fellowships (2007 & 2009), a Thieme Chemistry SYNStar Award (2008), and a Roche Award: Excellence in Chemistry (2009).
Permanent address: Staelsmühle 13, 42929 Wermelskirchen, Germany This dissertation was typed by the author.