The Pennsylvania State University

The Graduate School

Eberly College of Science

PART I - SYNTHESIS OF THE TETRACYCLIC SKELETON OF THE LYCOPODIUM ALKALOID LYCOPLADINE H

PART II - SYNTHESIS OF THE TETRACYCLIC CORE OF THE APPARICINE CLASS OF INDOLE ALKALOIDS VIA A KEY INTERMOLECULAR NITROSOALKENE CONJUGATE ADDITION

A Dissertation in

Chemistry

by

Pradeep S. Chauhan

© 2015 Pradeep S. Chauhan

Submitted in Partial Fulfillment of the Requirements for the degree of

Doctor of Philosophy

May 2015 ii

The dissertation of Pradeep S. Chauhan was reviewed and approved* by the following:

Steven M. Weinreb Russell and Mildred Marker Professor of Natural Products Chemistry Dissertation Advisor Chair of Committee

Scott T. Phillips Associate Professor of Chemistry

Alexander T. Radosevich Assistant Professor of Chemistry

Ming Tien Professor of Biochemistry

Barbara J. Garrison Shapiro Professor of Chemistry Head of the Department of Chemistry

*Signatures are on file in the Graduate School

iii

Abstract

Part I

A synthesis of the tetracyclic framework 220 of the structurally unique

Lycopodium alkaloid lycopladine H (21) has been achieved in 19 steps from phenol 60. A

key step involved a novel double alkene hydroformylation/intramolecular reductive

amination of 217 to form the azocane and spiropiperidine moieties of the natural product

in the form of advanced tetracyclic intermediate 220 via intermediate dialdehyde 218.

Disappointingly, we have been unable to convert this compound into the natural product.

Ph Ph OHC O OH O O O H H OMe H H CbzHN CbzHN

OMOM Br OMOM OHC

60 217 218

O Ph OH O H O H N N OMOM O

H 21 220 (19 steps from 60) lycopladine ( )

iv

Part II

A convergent and concise synthetic route to the tetracyclic core 61 of the apparicine-type alkaloids has been achieved in only four steps in 80% overall yield from the known 3-formylindole ester 113 and 3-piperidone-derived α-chloroketoxime 80. Key transformations involve use of an intermolecular ester enolate/nitrosoalkene conjugate addition to form the C-15/16 bond of 117, followed by a reductive cyclization to form the

C-ring of the tetracycle core 61, which has appropriate handles in place at C-16 and C-20, to easily access a number of the members of the apparicine class of indole alkaloids.

Ts OH N CHO N CHO Cl 15 16 H N OH N CO Me N N CO Me H 2 Ts H 2

113 80 117

OTBS N 20 N N D Me C 16 H H A B N CO2Me N H H 61 apparicine (1) 4 steps in 80% overall from 113 yield

v

Table of Contents

LIST OF FIGURES ...... viii

LIST OF TABLES ...... ix

ACKNOWLEDGEMENTS ...... x

Part I - Synthesis of the Tetracyclic Skeleton of the Lycopodium Alkaloid

Lycopladine H ...... 1

Chapter 1 - Introduction and Background ...... 1

1.1 Biosynthesis of the Lycopodium Alkaloids...... 2

1.2 The Lycopladine Alkaloids ...... 4

1.3 Proposed Biosynthesis of Lycopladine H (21) ...... 6

1.4 Synthetic Studies on Lycopodium Alkaloids ...... 7

1.5 Synthetic Studies on the Lycopladine Alkaloids ...... 9

1.5.1 Toste Synthesis of (+)-Lycopladine A (14) ...... 9

1.5.2 Martin Synthesis of (±)-Lycopladine A (14) ...... 11

1.5.3 Evans Synthesis of the Tetracyclic Core of Lycopladine H ...... 12

1.6 Previous Synthetic Work on Lycopladine H in the Weinreb Lab ...... 14

1.6.1 Synthesis of the Bicyclo[2.2.2]octane Core 58 of Lycopladine H ...... 15

1.7 Hydroaminomethylation: Introduction and Background ...... 18

1.7.1 Use of the Hydroaminomethylation Reaction in Synthesis ...... 22

1.7.2 Intramolecular Hydroaminomethylation and Related Reactions ...... 24

1.7.3 Medium and Large Ring Formation Using Hydroaminomethylation Reactions ...... 27

1.8 Use of an Intramolecular Hydroaminomethylaion Reaction to Form the Azocane Ring of Lycopladine H ...... 29 vi

1.9 Approaches Toward Formation of the Piperidine Ring of Lycopladine H ...... 31

Chapter 2 - Results and Discussions ...... 34

2.1 Studies on the Double Hydroaminomethylation ...... 50

2.2 Conclusions ...... 63

Chapter 3 - Experimental Section ...... 65

References ...... 109

Part II - Synthesis of the Tetracyclic Core of the Apparicine Class of Indole

Alkaloids via a Key Intermolecular Nitrosoalkene Conjugate Addition ...... 118

Chapter 1 - Introduction and Background ...... 118

1.1 Apparicine Class of Indole Alkaloids ...... 118

1.2 Biosynthesis of the Apparicine Class of Indole Alkaloids ...... 119

1.3 Previous Approaches Towards Synthesis of the Apparicine Class of Indole Alkaloids .121

1.3.1 Joule Approach to the Tetracyclic Core of Apparicine (1) ...... 121

1.3.2 Bennasar Total Synthesis of (±)-Apparicine (1) ...... 122

1.3.3 Joule Formal Total Synthesis of Apparicine ...... 124

1.3.4 Micalizio Total Synthesis of (±)-Conolidine (5) ...... 126

1.3.5 Omura/Sunazuka Synthesis of (±)-16-Hydroxy-16,22-dihydroapparicine (6) ...... 127

Chapter 2 - Synthesis of the Tetracyclic Core of the Apparicine Class of Indole Alkaloids 132

2.1 Nitrosoalkenes: Introduction and Background ...... 133

2.2 Methods of Generation of Nitrosoalkenes ...... 134

2.3 Previous Applications of Nitrosoalkene/Enolate Conjugate Additions as a Key Step in Natural Product Synthesis by the Weinreb Group ...... 135

2.4 First Generation Strategy to the Tetracyclic Apparicine Core 61 ...... 140

2.5 Results and Discussion ...... 141 vii

2.6 Future Strategy for the Synthesis of Apparicine (1) and Related Alkaloids...... 153

Chapter 3 - Experimental Section ...... 156

References ...... 171

viii

LIST OF FIGURES

Part I

Figure 1. Parent compounds of each class of the Lycopodium alkaloids...... 2

Figure 2. Lycopladine family of alkaloids ...... 5

Figure 3. Structure of lycopladine H (21) ...... 6

Figure 4. Highlights in Lycopodium alkaloids synthesis ...... 8

Figure 5. Structure of (+)-clavolonine (47)...... 12

Figure 6. Structure of ligands...... 21

Part II

Figure 1. Structures of some members of the apparicine class of indole alkaloids ...... 119

Figure 2. A unified approach to apparicine alkaloids ...... 133

Figure 3. Nitrosoalkenes ...... 134

Figure 4. Angustilodine class of monoterpenoid indole alkaloids ...... 136

Figure 5. Piperidones ...... 143

ix

LIST OF TABLES

Part I

Table 1. Optimization of the hydroaminomethylation of amino-alkene 73...... 31

Table 2. Attempted reduction of ketone 58 ...... 36

Table 3. Attempted reduction of ketone 143 ...... 37

Table 4. Attempted reduction of the nitro group of 143 ...... 38

Table 5. Attempted Ts-deprotection of 161 ...... 42

Table 6. Attempted Cbz-cleavage of 173 ...... 47

Table 7. Attempted hydrolysis of spirocyclic carbamate 175...... 48

Table 8. Attempted Cbz-cleavage of 176 ...... 49

Table 9. Attempted double hydroaminomethylation reaction of 177 to 185 ...... 53

Table 10. Attempted Cbz-cleavage of 193 to form amine 194 ...... 54

Part II

Table 1. α-Chlorination of N-protected-3-piperidones ...... 144

x

ACKNOWLEDGEMENTS

I would like to thank Professor Steven M. Weinreb for his direction, support, patience and advice; his insights have been valuable to both my projects and to my understanding of chemistry. I also thank Professors Scott Phillips, Alex Radosevich, and

Ming Tien for their service as members on my committee.

I would like to thank all the Weinreb group members, both past and present. They deserve great recognition for their guidance, discussions, and support. They have been some of the most challenging and effective teachers I have known.

I acknowledge my friends and siblings for their kindness, understanding, and encouragement. Without their love, support, and patience, none of this would be possible.

Finally, I thank my parents for their love, support and all the sacrifices they have made for me.

Part I - Synthesis of the Tetracyclic Skeleton of the Lycopodium

Alkaloid Lycopladine H

Chapter 1 - Introduction and Background

Plants of the genus Lycopodium, which are typically found in coniferous forests, mountainous areas, and marshlands are comprised of nearly 1000 different species.1 This genus consists of flowerless, terrestrial or epiphytic plants with needle-like leaves (club- mosses).1 These club-mosses have been used as traditional folk medicine worldwide.2 For example, Native American tribes have used the club-moss Lycopodium calavatum in wound care.2 Blackfoot tribes used Lycopodium complanatum for treatment of pulmonary disease, and Saint Hildegard of Bingen used tea brewed from extracts of Lycopodium clavatum and couch grass (Agropyron repens L.) for treatment of acne and skin irritations.2

The first chemical compound to be isolated from the genus Lycopodium is the alkaloid lycopodine (1), extracted from Lycopodium complanatum by Bödeker in 1881.3

Subsequently, hundreds of alkaloids from numerous species of Lycopodium plants have since been isolated. These structurally related, yet diverse groups of Lycopodium alkaloids usually contain a 16 carbon skeleton, although there are a few exceptions.4

These alkaloids feature a variety of polycyclic ring sizes, stereochemistry, and oxidation patterns.5 Ayer has divided these alkaloids into four different structural classes, named after a prominent member of each class: the lycopodine (1) class, the fawcettimine (2) class, the lycodine (3) class and the phlegmarine (4) class (Figure 1).5f

1

Figure 1. Parent compounds of each class of the Lycopodium alkaloids

Some of the Lycopodium alkaloids isolated in the mid 1980’s are reported to have promising biological properties. Most notably, huperzine A (13), isolated from Huperzia serrata in 1986 is reported to increase the efficiency of learning and memory in animals.6

This compound has also been shown to have potent acetylcholinesterase inhibitory activity and is considered to be a promising drug candidate for Alzheimer’s disease and myasthenia gravis.7 In China, huperzine A has been approved as a drug for Alzheimer's disease, while in the USA it is marketed as a dietary supplement for memory loss and mental impairment.4d

1.1 Biosynthesis of the Lycopodium Alkaloids

The plants of the genus Lycopodium are difficult to cultivate using both traditional cultivation or tissue culture processes. Therefore, very limited biosynthetic studies have been performed on these alkaloids. Based on some isotopic feeding experiments, a biosynthetic pathway to the Lycopodium alkaloids has been proposed starting from lysine

(5) (Scheme 1).8

The entry point to the biogenetic pathway is the decarboxylation of lysine (5) to form cadaverine (6). Piperideine (8) is formed via 5-aminopentanal (7) by action of the

2 enzyme diamine oxidase on cadaverine (6). Piperideine (8) is then coupled with acetone dicarboxylic acid (9) to form piperidine β-ketoacid 10, which decaboxylates to produce pelletierine (11). Finally, pelletierine (11) reacts with the piperidine β-ketoester 10 to give

(-)-phlegmarine (4), a general intermediate in the biosynthesis of all the Lycopodium alkaloids.

Scheme 1.

The tricyclic intermediate (-)-phlegmarine (4) is then cyclized to yield the tetracyclic lycodane skeleton 12, from which other classes of the Lycopodium alkaloids are formed by various oxidations and/or aromatization sequences (Scheme 2). For example, the lycodane skeleton 12 can be oxidized to form (-)-lycopodine (1), which could be converted to (+)-fawcettimine (2). Aromatization of the piperidine ring of the lycodane skeleton 12 leads to formation of (-)-lycodine (3). (-)Huperzine A (13), the most biologically active alkaloid of the Lycopodium family, is also proposed to originate from oxidative degradation of the lycodane skeleton 12.

3

Scheme 2.

1.2 The Lycopladine Alkaloids

The first lycopladine alkaloid to be isolated was lycopladine A (14), isolated by the Kobayashi group in 2006 from Lycopodium complanaum (Figure 2).9 The compound was shown to have modest biological activity against murine lymphoma L1210 cells with

9 IC50 of 7 µg/mL. Later, the Kobayashi group was able to isolate other members of this family from the club moss Lycopodium complanatum: lycopladine B (15),10 C (16),10 D

(17),10 E (18),11 F (19)12 and lycopladine G (20).12 These lycopladine alkaloids represent all the four classes of Lycopodium alkaloids (cf. Figure 1). Lycopladine E (18) has some

4 biological activity against human astrocytoma cells, but the others have not shown any biological activity to date.11

Figure 2. Lycopladine family of alkaloids

In 2009, the Kobayashi group isolated lycopladine H (21) from methanolic extracts of the club moss Lycopodium complanatum (Figure 3).13 This alkaloid has a unique tetracyclic structure comprised of a bicyclo[2.2.2]octane moiety, a spiro-fused 3- piperidone, and a bridged azocane ring. Due to only a small amount of this alkaloid being isolated, very limited biological studies were performed. Lycopladine H was shown to have no biological activity against L1210 murine leukemia and KB human epidermoid carcinoma cells.13 It should be noted that although the lycopladine alkaloids share a name, they have very different structural motifs.

5

Figure 3. Structure of lycopladine H (21)

1.3 Proposed Biosynthesis of Lycopladine H (21)

It has been proposed that lycopladine H (21) could arise from pelletierine (11), which originates from lysine (5) (Scheme 3).13 Pelletierine (11) could dimerize via an aldol condensation and oxidization to form bis-enamine intermediate 22, which can undergo an intramolecular attack of the enamine on the ketone functionality to generate tricyclic iminium compound 23, having the phlegmarane skeleton. A series of hypothetical transformations on 23 including imine hydrolysis, deoxygenation of C-7 and

C-15, hydroxylation at C-12, and cleavage at C-9 would provide enamine 24. This enamine 24 can follow pathway (a), involving an intramolecular attack of the enamine moiety on C-12 to form intermediate 25, which could aromatize to give lycopladine A

(14). Alternatively, the enamine 24 could undergo macrocyclization via pathway (b), involving attack of the amine on C-9, followed by tautomerization to produce tricyclic iminium ion 26. Intramolecular Mannich-type reaction of iminium ion 26 followed by oxidation at C-4 provides lycopladine H (21).

6

Scheme 3. Biosynthesis of lycopladine A (14) and H (21)

1.4 Synthetic Studies on Lycopodium Alkaloids

The first synthesis of a Lycopodium alkaloid was that of (±)-12-epi-lycopodine

(27), achieved by Wiesner in 1967, more than 80 years after the isolation of the alkaloid lycopodine (1) (Figure 4).14 Shortly after, in 1968, Ayer15 and Stork16 nearly simultaneously achieved total syntheses of racemic lycopodine (1). The scientific value and impact of these seminal syntheses of Lycopodium alkaloids are even more striking considering the limited repertoire of synthetic methodologies available to organic chemists 50 years ago. A highly efficient synthesis of lycopodine (1) was achieved by

7

Heathcock in 1978, which is considered to be one of the highlights in alkaloid syntheses of the era.17 Other notable synthetic highlights in Lycopodium alkaloid synthesis are those of (±)-fawcettimine (2) by Heathcock in 1986,18 (±)-huperzine A (13) by Kozikowski in

1993,19 and (+)-magellaninone (28) by Overman in 1993.20 Many of the later Lycopodium alkaloid syntheses have been used as a testing ground for new synthetic methodologies.

Figure 4. Highlights in Lycopodium alkaloids synthesis

8

1.5 Synthetic Studies on the Lycopladine Alkaloids

Very little synthetic work has been done on the lycopladine family of alkaloids. In fact, only lycopladine A (14) has been synthesized, first by Toste21 in 2006 and then by

Martin22 in 2010.

1.5.1 Toste synthesis of (+)-lycopladine A (14)

Lycopladine A (14) was the first member of the lycopladine family of alkaloids to be synthesized by Toste in 2006.21 The synthesis was based on a pivotal Au(I)-catalyzed intramolecular 5-endo-dig cyclization of a silylenol ether onto an alkyne to construct the hydrindanone core of lycopladine A.

To begin the synthesis, enantiopure cyclohexenone 29 was iodinated, followed by a Pd-catalyzed B-alkyl Suzuki-Miyaura coupling to obtain the substituted cyclohexenone

30 (Scheme 4). TBSOTf-promoted conjugate propargylation of cyclohexenone 30 with tributylallenylstannane, followed by iodination of resultant terminal alkyne gave iodoacetylene 31. The silylenol ether 31 was then treated with a gold-catalyst to form the hydrindane core 32 of lycopladine A in very good yields. The vinyl iodide 32 was coupled with boronic ester 33 to obtain N,N-dimethylhydrazone 34. The triene 34 was heated in toluene to promote a cascade sequence involving a double-bond isomerization and 6π-electrocyclization followed by loss of dimethylamine to form the tricyclic core 37 of lycopladine A. The benzyl ether 37 was subjected to transfer hydrogenation conditions to obtain the alkaloid (+)-lycopladine A (14).

9

Scheme 4.

10

1.5.2 Martin Synthesis of (±)-lycopladine A (14)

In 2010, Martin completed a total synthesis of (±)-lycopladine A (14) involving a novel sequence involving a conjugate addition and enolate arylation to form the tricyclic core in only two steps (Scheme 5).22 The synthesis began with addition of the organocuprate derived from pyridine 38 to β-ketoester 39, giving the 1,4-addition product

40. The potassium enolate of 40 was treated with a Pd-catalyst and the electron-rich S-

Phos ligand to obtain the tricyclic core 41 of lycopladine A. The tricyclic methyl ester 41 was treated with allyl alcohol and the Otera catalyst 42 under microwave conditions to obtain the transesterified product 43 in very good yield. The allyl ester 43 underwent a

Pd-catalyzed decarboxylation-allylation reaction to give 44 in good yield. Hydroboration of alkene 44 with catacholborane and Wilkinson catalyst 45, followed by oxidation with aqueous sodium perborate afforded the alkaloid lycopladine A (14) in 70% yield. It was also observed that a minor amount of lycopladine A exists as the isomeric lactol 46.

Scheme 5.

11

Scheme 5.

1.5.3 Evans synthesis of the tetracyclic core of lycopladine H

Although lycopladine H (21) was isolated in 2009, Evans was able to form the tetracyclic core of lycopladine H while synthesizing the Lycopodium alkaloid (+)- clavolonine (47) in 2005 (Figure 5).23

Figure 5. Structure of (+)-clavolonine (47)

The approach was based on elaboration of isooxazolidinone 48 to the 16- membered macrocycle 49 over 10 steps in 23% yield (Scheme 6). The macrocycle 49 was exposed to TFA, which led to the intramolecular attack of the free secondary amine

12 at C-5 of enone 49, forming enamine 50 in almost quntitative yield. Heating the enamine

50 with piperidinium acetate in EtOH led to a cascade reaction sequence to produce the tetracyclic core 54 of lycopladine H. This cascade reaction sequence involves a stereoselective transannular Michael addition of the ketoester to the α,β-unsaturated iminium ion 51 to form tricyclic enamine 52, which underwent a spontaneous intramolecular Mannich cyclization via 53 to generate the tetracyclic core 54 of lycopladine H.

Scheme 6.

13

1.6 Previous Synthetic Work on Lycopladine H in the Weinreb Lab

Joshua Sacher from the Weinreb lab has previously been involved in developing a total synthesis of lycopladine H (21),24 and was successful in constructing the tricyclic core of the alkaloid via a key intramolecular hydroaminomethylation reaction (vide infra).

In the initial retrosynthesis, it was envisioned that lycopladine H (21) could be obtained via an intramolecular N-alkylation of tricyclic amine 55 (Scheme 7). The amine

55 would be obtained from protected alcohol aldehyde 56 using suitable manipulations.

The azocane ring of 56 could be obtained by an intramolecular hydroaminomethylation reaction (vide infra) of amino alkene 57. The amino alkene 57 would be accessed from nitroalcohol 58. The bicyclo[2.2.2]octane core 59 of lycopladine H would be obtained via

Diels-Alder cycloaddition of the quinone ketal 62 derived from phenol 60 and nitroethylene 61.

14

Scheme 7. Initial retrosynthesis of lycopladine H (21)

1.6.1 Synthesis of the bicyclo[2.2.2]octane core 58 of lycopladine H

Thus, the readily available phenol 60 was oxidized to o-quinone ketal 62, which was reacted in a regio- and stereoselective Diels-Alder cycloaddition with nitroethylene

61 to give the bicyclo[2.2.2]octane adduct 59 in almost quantitative yield (Scheme 8).25,26

A Henry reaction of nitro compound 59 with formaldehyde led to formation of nitro alcohol 63, which contains the proper C-5 stereochemistry for further elaboration to the alkaloid.27 The bromoalkene 63 was dehalogenated in a Pd-catalyzed reaction to form trisubstituted alkene 64 in good yield.26d Alkene 64 was reduced in nearly quantitative yield using 10% Pd/C with 1 atm of hydrogen to afford the nitro alcohol 58 with the correct C-15 stereochemistry.

15

Scheme 8. Synthesis of the bicyclo[2.2.2]octane core

With the bicyclo[2.2.2]octane core of the alkaloid 58 in hand, Sacher investigated methodology to convert this intermediate to lycopladine H. Numerous attempts were made to reduce the nitro group of 58 to amine 65 and to oxidize the alcohol functionality of 58 to aldehyde 66, but without any success (Scheme 9). Also the reduction of the ketone functionality of 58 to form 67 proved to be difficult to achieve.

16

Scheme 9.

In view of the disappointing results described above, Sacher decided to explore using Diels-Alder adduct 59 in an alternative route. Thus, the nitro ketone 59 was reduced to nitro alcohol 68 using sodium borohydride (Scheme 10). The structure and stereochemistry of 68 were confirmed by X-ray analysis. Henry reaction of nitro compound 68 with formaldehyde gave nitro alcohol 69, which contains the proper C-5 stereochemistry for elaboration to the alkaloid as in the previous case (cf. Scheme 8).

Lithium tetrafluoroborate-promoted hydrolysis of ketal 69 in wet acetonitrile led to formation of α-hydroxy ketone 70 in nearly quantitative yield.28 The diol 70 was treated with TBDPS chloride and imidazole to afford bis-silyl ether 71 in moderate yield. At this point, the preformed vinyl cerium reagent obtained from vinylmagnesium bromide and cerium chloride was added to ketone 71 to obtain allylic alcohol 72 wth the desired configuration at C-2.29 Finally the nitro group of 72 was reduced using Zn and HCl to

17 obtain the desired amino alkene 73 for the proposed hydroaminomethylation reaction in excellent yield.30

Scheme 10.

1.7 Hydroaminomethylation: Introduction and Background

The hydroaminomethylation reaction was discovered by Walter Reppe in 1949 at

BASF laboratories.31 This process is a one-pot, atom-economical and environmentally benign method to obtain complex amines and N-containing heterocycles from readily available olefins, primary or secondary amines and syngas (CO/H2), with water produced as the only side product.32 This reaction is often more efficient than traditional methods for synthesis of amines.

18

The hydroaminomethylation reaction was originally achieved under forcing conditions involving high temperature and high pressure of syngas using stoichiometric

33 amounts of iron catslysts like Fe(CO)5. Catalytic versions of this reaction were later developed using Mn-, Co- and Ni-carbonyl complexes, but the reaction conditions were still harsh.34 More recently, however, Rh-, Ru- and Ir-catalyzed hydroaminomethylation reactions have been developed which allow milder reaction conditions.35

This one-pot tandem reaction consists of three steps: transition metal catalyzed hydroformylation of an alkene 74 to form an aldehyde 75 using syngas; imine/enamine

77 formation from aldehyde 75 and amine 76 with loss of a water molecule; and transition metal-catalyzed reduction of imine/enamine 77 to form the corresponding amine 78 (Scheme 11). The regioselectivity of the hydroaminomethylation reaction is determined during the hydroformylation step of the reaction. Alkene 74 may give either linear aldehyde n-75 or branched aldehyde iso-75, which result from hydroformylation at the terminal or internal carbon of alkene 74 respectively. The n- or iso-aldehyde 75 would give rise to corresponding n- or iso-amine 78.

Scheme 11.

19

The mechanism for the hydroformylation of alkenes (oxo reaction) was proposed by Heck and Breslow in the 1960's (Scheme 12).36 The catalytic cycle starts with the loss of one CO ligand from the stable 18-electron trigonal bipyramidal rhodium hydride complex 79 to form the 16-electron square-planar Rh species 80, with an empty coordination site. Alkene 81 inserts at the empty coordination site of 80 to form Rh alkene complex 82. Simultaneous migratory insertion of the alkene into the rhodium- hydride bond and addition of a CO ligand to the Rh metal center leads to formation of alkyl-Rh species 83. A migratory insertion of CO into alkyl-Rh bond of 83 gives rise to acyl-Rh complex 84. Subequently, oxidative addition of hydrogen and reductive elimination gives aldehyde 85, regenerating the active 16-electron rhodium species 80.

Scheme 12. Proposed catalytic cycle of the Rh-catalyzed hydroformylation

20

The steric and electronic properties of the ligands on the Rh-complex 79 influence the hydroformylation step, leading to formation of linear or branched aldehydes 85. It has generally been observed that bidentate ligands with rigid and bulky backbones and large bite angles like biphosphite (86), xantphos (87) and biphephos (88) lead to preferential formation of linear aldehydes (Figure 6).37

Figure 6. Structure of ligands

In the hydroaminomethylation process, the resulting n- or iso-aldehyde 75 produced in the hydroformylation step then reacts with amine 76 to form the n- or iso- imine/enamine 77 with loss of a water molecule (vide supra, Scheme 11). It has also been observed that linear aldehyde n-75 reacts faster than the branched aldehyde iso-75 to form the imine/enamine 77.

The role of Rh-metal in the hydrogenation of imine/enamine 77 has not been studied. It has been found that the hydrogenation step is normally slower than the hydroformylation step and requires higher temperature and higher partial H2 pressure.

The proposed catalytic hydrogenation cycle suggests that the hydrogenation of the imine/enamine takes place on the Rh metal center (Scheme 13).38 Thus, the initial

21 cationic Rh-imine complex 89 oxidatively adds a H2 molecule to form the cationic dihydride Rh-complex 90, followed by hydrogen atom transfer to the imine to generate the Rh-iminium complex 91. A second hydrogen atom transfer from the Rh metal center leads to formation of cationic Rh-amine complex 92. Finally, oxidative addition of imine

93 to 92, followed by reductive elimination leads to formation of amine 94 with regeneration of cationic Rh-imine complex 89.

Scheme 13. Proposed catalytic cycle of the Rh-catalyzed hydrogenation of imines

1.7.1 Use of the Hydroaminomethylation Reaction in Synthesis

Recently, hydroaminomethylation reactions have been used as a key step in the synthesis of some pharmaceutical compounds. In 2005, Whiteker et. al. applied an intermolecular hydroaminomethylation reaction in the synthesis of the antiarrhythmic

22 drug ibutilide (97) (Scheme 14).39 Thus, the alkene 95 was heated with N- ethylheptylamine (96) in THF with Rh(CO)2acac, biphosphite ligand (86) and syngas

(CO/H2) to obtain ibutilide (97) in 55% yield (Scheme 14). It should be noted that protection of the alcohol moiety in alkene (95) was found to be unnecessary as it did not impact the yield of the reaction.

Scheme 14.

Similarly, the antidepressant drug aripiprazole (100) was obtained in good yield by heating alkene 98 with arylpiperazine 99 in THF with Rh(CO)2acac, biphosphite ligand (86) and syngas (Scheme 15).39 The Rh-biphosphite catalyst mixture was found to be tolerant of the aryl chloride functionality in 99 and showed excellent chemoselctivity in preference for the N-H bond of arylpiperazine 99 in presence of a secondary amide N-

H in alkene 98.

23

Scheme 15.

More recently, Whiteker also applied an intermolecular hydroaminomethylation reaction in the synthesis of the antihistamine drugs terfenadine (103) and fexofenadine

(104) using the same Rh/biphosphite system by heating aryl alkenes 101a and 101b with piperidine 102, respectively (Scheme 16).40

Scheme 16.

1.7.2 Intramolecular Hydroaminomethylation and Related Reactions

Intramolecular hydroaminomethylation of amino-alkenes can be an efficient, atom economical method to form N-containing heterocycles when an olefin and an amine moiety are present in a same system.32c However, relatively few examples of this reaction are known, perhaps due to problems of chemoselectivity in the hydroformylation step,

24 since lactams are generally formed via intramolecular cleavage of the intermediate acyl-

Rh species (Cf. intermediate 84) by the amine moiety present in the system.41

Alper, however, was able to obtain tetrahydroquinolines 107a-c from 2- isoprenylanilines 105a-c using ionic diamino Rh catalyst 106 in excellent yields (Scheme

17).41 It should be noted that no phosphine ligands were required, and ionic catalyst 106 was found to be air-compatible in these high yielding chemo- and regioselective reactions.

Scheme 17.

In a similar study, the Alper group was able to exend this intramolecular hydroaminomethylation methodology to form 7-membered rings 111 by heating alkenyl benzylamines 108 with the ionic Rh catalyst 106 and syngas (Scheme 18).42 The benzazepines 111 could also be obtained via an intermolecular hydroaminomethylation reaction of 2-isopropenylbenzaldehyde 109 and anilines 110 under similar reaction conditions and in comparable yields.

25

Scheme 18.

Similar to the hydroaminomethylation reaction, stepwise hydroformylation of azido-alkenes followed by reductive cyclization has also been shown to be an efficient method to form N-containing cyclic heterocycles (Scheme 19).43 For example, Mann and coworkers have shown that azido-alkenes 112 can be hydroformylated by heating with a

Rh-catalyst and biphephos ligand (88) in THF to give azido-aldehydes 113.43 The hydroformyaltion reaction was found to be highly regioselective, as only linear aldehydes

113 were formed. The azido-aldehydes 113 were then reductively cyclized using

Pearlman's catalyst in a 5 bar H2 atmosphere to form 2-substituted piperidine derivatives

114.

Scheme 19.

26

Similarly, Mann also reported double hydroformylation/reductive bis-aminations of bis-homoallylic azides 115 and 116 to obtain quinolizidine alkaloids (+)-lupinine (119) and (+)-epiquinamide (120), respectively (Scheme 20).44 Thus, enantiopure bis- homoallylic azides 115 and 116 were converted to azido-dialdehydes 117 and 118, respectively, via a double hydroformylation reaction using a biphephos/Rh(I) catalyst system in good yields. Tandem catalytic azide reduction/reductive bis-amination of azido-dialdehydes 117 and 118 using Pearlman’s catalyst furnished the quinolizidine alkaloids (+)-lupinine (119) and (+)-epiquinamide (120), respectively.

Scheme 20.

1.7.3 Medium and Large Ring Formation Using Hydroaminomethylation Reactions

There are a few examples in the literature of medium and large ring formation using hydroaminomethylation reactions. For instance, Eilbracht has found a method to form either a bicyclic pyrrole 125 or an eight-membered N-heterocycle 128 by Rh- catalyzed reaction of 1,4-diolefins 121a or 121b and isopropylamine (122, Scheme 21).45

The reaction outcome was dependent on the substitution pattern on the diene 121a or

121b. It was reasoned that the unsubstituted diene 121a was hydroformylated, followed by cyclization to form alkyl-Rh intermediate 123. An insertion of a second molecule of

27

CO into 123 leads to formation of acyl-Rh species 124, which undergoes reductive cyclization with isopropylamine (122) to generate bicyclic pyrrole 125.

In the case of phenyl-substituted diene 121b, it was thought that the less substituted alkene is hydroformylated, followed by reductive amination with isopropylamine to form intermediate amino-alkene 126. Further hydroformylation of 126 and subsequent intramolecular reductive amination leads to formation of 8-membered heterocycle 128 in 58% yield. The difference in chemoselectivity was reasoned to be due to the presence of a bulky phenyl group in 121b, which slows the rate of hydroformylation at that alkene site. This favors formation of intermediate amino-alkene

126 which upon further intramolecular hydroaminomethylation gave the 8-membered N- heterocyle 128 via aminoaldehyde 127.

Scheme 21.

28

In another study, the Jackson group was able to utilize a Rh/biphephos catalytic system to obtain medium to large cyclic tertiary amines (Scheme 22).46 Thus, the alkenyl benzylamines 129a-c gave rise to the corresponding 7-, 8-, and 10-membered tertiary amines 130a-c in only low to moderate yields by heating with this Rh/biphephos catalyst and syngas in benzene. Using similar reaction conditions, however, the 13-membered tertiary amine 130d was formed from 129d in high yield.

Scheme 22.

1.8 Use of an Intramolecular Hydroaminomethylation Reaction to Form the

Azocane Ring of Lycopladine H

With an amino-alkene 73 in hand (vide supra, Scheme 10), Sacher investigated the key intramolecular hydroaminomethylation reaction with the hope that the conformational rigidity of the bicyclo[2.2.2]octane core of 73 would help in formation of

24 an 8-membered azocane ring. Thus, amino-alkene 73 was treated with [Rh(cod)Cl]2 and xantphos as the phosphine ligand in a 1:1 mixture of toluene/methanol under a pressurized (~1:5) mixture of CO/H2 at 135 °C to obtain the azocane 133 in 28% yield, along with the corresponding N,O-acetal 134 (R = OMe) in 41% yield (Table 1, Entry

29

1).47 It was believed that hydroformylation occurs at the terminal carbon of amino-alkene

73 to form intermediate amino-aldehyde 131, followed by in situ intramolecular cyclodehydration to form the 8-membered imine 132 (and/or the corresponding enamine). Azocane 133 is formed by the Rh-catalyzed hydrogenation of the imine/(enamine) 132, while nucleophillic addition of methanol to the imine 132 led to formation of the corresponding N,O-acetal 134 as a single stereoisomer, whose configuration was not determined. The N,O-acetal 134 could be isolated using column chromatography and was then reduced to azocane 133 using sodium cyanoborohydride under acidic conditions in excellent yield.

Scheme 23. Hydroaminomethylation to form the azocane ring of lycopladine H

30

Table 1. Optimization of the hydroaminomethylation of amino-alkene 73

At this point, it was decided to optimize the reaction conditions in order to obtain the azocane 133 directly from 73. Use of aprotic solvents like PhMe or THF under the same conditions in the absence of MeOH (Entries 2 and 3) led to a small increase in the isolated yields of azocane 133. It was reasoned that the use of a less nucleophilic and more sterically hindered protic solvent, trifluoroethanol (TFE) as a cosolvent (Entry 4) should disfavor the N,O-acetal formation. Thus, with TFE as a cosolvent, azocane 133 was formed in 59% isolated yield along with 8% of the N,O-acetal 134 (R = CH2CF3) .

With the use of hexafluoroisopropanol (HFIPA), an even less nucleophilic and bulkier species as a cosolvent (Entry 5), the azocane 133 was obtained in 75% yield and the corresponding N,O-acetal was not observed. When the more active catalyst

[Rh(cod)2]BF4 was used along with HFIPA as a cosolvent (Entry 6), the azocane 133 was formed in nearly identical yield as that observed with the more stable and less expensive

[Rh(cod)Cl]2 catalyst.

1.9 Approaches Toward Formation of the Piperidine Ring of Lycopladine H

With the tricyclic ring skeleton of lycopladine H in hand, Sacher explored formation of the piperidine ring of the alkaloid from azocane 133. Thus, bis-silyl ether

133 was subjected to various F- sources to obtain triol 135 (Scheme 24). However, only

31 starting material, decomposition or mono-deprotected alcohol 136 (Scheme 25) was observed in low yields.

Scheme 24.

When the bis-silyl ether 133 was hydrolyzed using aqueous KOH, it was possible to obtain the mono-deprotected alcohol 136 in good yields (Scheme 25).48 Further oxidation of alcohol 136 using Dess-Martin oxidation or Jones oxidation led to recovered starting material or decomposition, respectively.

Scheme 25.

At this point it was decided to functionalize the amine moiety of azocane 133.

Thus, the secondary amine of 133 was acylated using acryloyl chloride to obtain amide

138 in good yields. The previously developed desilylation conditions using aqueous KOH was then tried to obtain the alcohol 140. However, only the N-acyl group of 138 was removed to obtain amine 133 and no desilylation was observed. In addition, all attempts

32 to reduce the bromo-alkene moiety of 133 using various catalytic hydrogenation conditions to obtain the reduced tricyclic core 139 of the alkaloid met with failure. It might be noted that all attempts to reduce the bromoalkene moiety of various other intermediates in this sequence also failed.

Scheme 26.

33

Chapter 2 - Results and Discussions

In view of the problems described in Chapter 1, it was decided to modify the initial approach of forming the azocane and piperidine rings of lyopladine H in separate operations. Thus, a revised strategy to construct the azocane and piperidine rings of lycoladine H simultaneously from the amino-dialkene 142 via intermediate amino- dialdehyde 142a using a novel double intramolecular hydroaminomethylation reaction was proposed (Scheme 27).49 Also, it was decided to continue the synthesis using the nitro alcohol 58 previously prepared by Sacher from bromoalkene 59, since it had been found that the bromo-alkene moiety present in 59 (and related derivatives) was difficult to reduce at a later stage (vide supra, Chapter 1).

Scheme 27.

To initiate this route, an improvement of the route of Sacher (Cf. Scheme 8), was found that allows bromoalkene 63 to be reductively dehalogenated in just one step using

34

Pd-catalyzed transfer hydrogenation conditions in a 1:2 triethylamine/formic acid mixture at room temperature in nearly quantitative yield to afford the nitro alcohol 58 having the correct C-15 stereochemistry (Scheme 28).

Scheme 28.

In order to continue the synthesis, the reduction of ketone 58 to alcohol 67 was examined (Scheme 29). However, treatment of ketone 58 with numerous hydride sources such as NaBH4, L-Selectride, BH3˙THF and DIBAL-H at various temperatures failed to produce the alcohol 67 (Table 2, Entries 1-5), but instead only decomposition of the ketone was observed. Luche reduction50 of 58 and use of samarium diiodide51 as reducing agent led to recovery of starting material (Table 2, Entries 6-8).

Scheme 29.

35

Table 2. Attempted reduction of ketone 58

It was reasoned that a retro-Henry reaction of 58 might be a problem in these attempted ketone reductions, and therefore it was decided to protect the alcohol group (Scheme 30). Thus, the nitro alcohol 58 was treated with TBDPS-Cl and imidazole to obtain the silyl ether 143 in excellent yield.

Scheme 30.

Once again, the O-silylated ketone 143 was subjected to numerous hydride reducing agents like NaBH4, BH3˙THF and LiBH4. However, only recovery of starting material was observed (Scheme 31, Table 3, Entries 1-3). The silylated ketone 143 did appear to be more resistant to decomposition than the the unprotected alcohol 58 in the presence of various hydride reducing agents. Use of LiAlH4 as a reducing agent at low temperatures led to recovery of starting material. However, warming the reaction mixture

36 to room temperature resulted in decomposition (Table 3, Entries 4, 5). Meerwein-

Ponndorf-Verley reduction52 and use of samarium diiodide51 as reducing agent also led to the recovery of starting material (Table 3, Entries 6, 7).

Scheme 31.

Table 3. Attempted reduction of ketone 143

In view of these disappointing results, it was decided to first focus on the

53 reduction of the nitro group of 143 to the amine 145 (Scheme 32). Use of Ni/H2 or

Fe/HCl54 as reductants resulted in the recovery of starting material, whereas the use of Zn dust/HCl55 as the reducing agent gave the corresponding hydroxylamine 146 in high yield

(Table 4). The hydroxylamine 146 could not be reduced further to amine 145 as heating the reaction for longer time in Zn dust/HCl gave multiple TLC spots/decomposition.

37

Scheme 32.

Table 4. Attempted reduction of the nitro group of 143

Since, it was not possible to reduce either the ketone group of 143 to alcohol 144 or the nitro group of 143 to amine 145, it was decided to explore continuation of the synthesis of lycopladine H using the hydroxylamine ketone 146.

At this point it was found that the ketone 146 could be reduced stereoselectively to alcohol 148 using borane in THF at 0 °C (Scheme 33). The structure and stereochemistry of alcohol 148 was confirmed by 2D-NMR analysis. It should be noted that using other hydride reducing agents such as NaBH4 and LiBH4 only led to recovery of starting ketone 146, whereas DIBAL-H and SmI2 caused decomposition.

38

It is possible that ketone 146 is reduced by borane via intermediate 147 in which the boron atom coordinates with the hydroxylamine group, resulting in internal delivery of hydride to form alcohol 148 stereoselectively.

The hydroxylamine 148 was then subjected to catalytic hydrogenation over 10%

Pd/C in 90% aqueous acetic acid solution leading to cleavage of the N–O bond, providing the desired amine 149 in very good yield.56 The amine 149 was protected as the Ts- derivative 150 in moderate yield and subsequently LiBF4-promoted hydrolysis of the ketal 150 led to α-hydroxy ketone 151 in nearly quantitative yield.28

Scheme 33.

39

The α-hydroxy ketone 151 was next treated with the preformed vinyl cerium reagent obtained from vinylmagnesium bromide and CeCl3 at -78 °C to obtain the allylic alcohol adducts 152 and 153 in moderate yield, but unfortunately in an epimeric ratio of

1.5:1, with the desired stereoisomer 152 as the major product.29 It should be noted that if

CeCl3 is not added to the reaction mixture, only decomposition of the ketone was observed.

Scheme 34.

In view of this result, it was decided to protect the alcohol 151 as THP-ether 155 as ~1:1 mixture of diastereomers,57 hopefully providing a steric bias in the addition of the vinyl cerium reagent to the ketone. (Scheme 35).

Scheme 35.

Indeed, when the THP-protected α-hydroxy ketone 155 was treated with vinylmagnesium bromide/CeCl3, the desired allylic alcohol 156 was obtained in a

40 completely stereoselective manner in almost quantitative yield (Scheme 36).29 The THP- ether in 156 was removed with PPTS in EtOH to reveal cis-diol 157,58 which was in turn converted to the ethylidene acetal 158 using a catalytic amount of p-TsOH and acetaldehyde dimethyl acetal in good yield.59 The ethylidene acetal 158 was found to be a single stereoisomer whose stereochemistry was not determined, but probably has the configuration shown. The silyl ether in 158 was removed using TBAF in THF at 0 °C to afford alcohol 159, which was subjected to Swern oxidation, giving aldehyde 160 in 68% yield over two steps.60 Aldehyde 160 was then treated with vinylmagnesium bromide/CeCl3 to give allylic alcohol 161 as a 14:1 diastereomeric mixture which were separated using column chromatography.29

Scheme 36.

41

Scheme 36.

With bis-alkene 161 in hand, Ts-group removal was now required to obtain the amino-dialkene 162 for the pivotal double hydroaminomethylation reaction to form the azocane and the piperidine rings of the tetracyclic skeleton of lycopladine H (Scheme

37). However, Ts-deprotection of 161 proved to be problematic and only decomposition was observed with various reductive cleavage methods such as Birch reduction,61

Na/naphthalenide62 or Red-Al63 at various temperatures (Table 5).

Scheme 37.

Table 5. Attempted Ts-deprotection of 161

42

Due to this inability to remove the Ts-group, it was decided to use a potentially more labile protecting group which would be compatible with the above reaction sequence. Thus, the intermediate amine 149 was protected as a benzyl carbamate (Cbz)

164 in good yield (Scheme 38).64

Scheme 38.

The ketal functionality of 164 was then cleaved to form α-hydroxy ketone 165 again using lithium tetrafluoroborate in wet acetonitrile in nearly quantitative yield

(Scheme 39).28 The resulting α-hydroxy ketone 165 was protected as the THP ether57 166 as ~1:1 mixture of diastereomers in excellent yield and was subjected to the addition of the vinylcerium reagent29 to afford allylic alcohol 167 in good yield and with high stereoselectivity, having the desired configuration at C-2. The THP-ether in 167 was removed to reveal diol 168,58 which was in turn converted to ethylidene acetal 169 using a catalytic amount of p-TsOH and acetaldehyde dimethyl acetal in good yield as one stereoisomer,59 whose configuration once again was not determined.

43

Scheme 39.

The silyl ether 169 was next treated with TBAF in THF at 0 °C in an attempt to obtain the desired alcohol 170 (Scheme 40). However, it was found that the deprotected alcohol cyclized onto the benzyl carbamate to form the 5-membered spirocyclic carbamate 171, probably promoted by the basic fluoride ion. Other F- sources such as

TBAF/AcOH and HF/pyridine were also tried without any success, in both cases giving only recovered starting material.

44

Scheme 40.

It was finally discovered that the silyl ether 169 could be desilylated to obtain alcohol 170 in nearly quantitative yield by treatment with 4-methoxysalicylaldehyde and

65 BF3-etherate in CH2Cl2 at room temperature (Scheme 41). This mild acidic method of silyl ether cleavage is based on the in situ generation of low concentrations of HF from reaction of the 4-methoxysalicylaldehyde with BF3˙etherate. The alcohol 170 was then subjected to Swern oxidation to obtain aldehyde 172 in excellent yield.60 Aldehyde 172 was treated with vinylmagnesium bromide to give allylic alcohol 173 as a 3:1 diastereomeric mixture which were separated using column chromatography and each of the pure diastereomers of 173 was then used individually for the ensuing steps.

Scheme 41.

45

Scheme 41.

Removal of the Cbz protecting group of bis-alkene 173 was now all that was required to obtain the amino-bisalkene 174 for investigation of the pivotal double hydroaminomethylation reaction (Scheme 42). However, Cbz-deprotection proved to be problematic and only decomposition was seen using various standard reductive methods for Cbz-cleavage including Birch reduction,73 Na/naphthalenide74 or Red-Al63 at various temperatures (Table 6, Entries 1-3). Use of ethylenediamine for Cbz-deprotection led to

66 recovery of starting material (Entry 4), whereas Me2S and boron trifluoride etherate at room temperature led to decomposition (Entry 5).67

Scheme 42.

46

Table 6. Attempted Cbz-cleavage of 173

Alkaline hydrolysis of carbamate 173 to obtain amine 174 was also attempted.68

However, this experiment resulted in clean conversion to the undesired spirocyclic carbamate 175 (Scheme 43).

Scheme 43.

Alkaline hydrolysis of spirocyclic carbamate 175 to amino bis-alkene 174 was then attempted (Scheme 44). A series of inorganic bases including NaOH, Ba(OH)2 and

68, 69 K2CO3 were screened for this hydrolysis, but with no success (Table 7, Entries 1-3).

Use of organic base like ethylenediamine also resulted in recovery of starting material

(Entry 4).66

47

Scheme 44.

Table 7. Attempted hydrolysis of spirocyclic carbamate 175

In light of the above problem of cyclization of 173 to 175, it was decided to first protect the allylic alcohol 173 as its MOM ether 176, which could be effected in almost

70 quantitative yield using P2O5 and dimethoxymethane in chloroform. It should be noted that use of basic conditions to MOM-protect the allylic alcohol 173 failed to give any desired product 176, but rather spirocyclic carbamate 175 was observed.

Scheme 45.

With MOM-protected allylic alcohol 176 in hand, a series of basic hydrolysis conditions was screened (Scheme 46). KOH hydrolysis using MeOH as a cosolvent

48 cleanly converted the benzyl carbamate to the methyl carbamate (Table 8, Entry 1).68 Use of aprotic solvents like DME and dioxane for the alkaline hydrolysis resulted in recovery of starting material/decomposition (Entries 2, 3).68 Organic bases like TBAF and ethylenediamine at various temperatures resulted in recovery of starting material (Entries

4, 5).66 Use of a Lewis acid such as iodotrimethylsilane resulted in decomposition (Entry

71 72 63 73 6). Reductive methods for Cbz-cleavage including Na/Hg, SmI2, Red-Al, Na/NH3 and Na/naphthalenide74a failed to give the desired amine (Entries 7-11).

Scheme 46.

Table 8. Attempted Cbz-cleavage of 176

49

It is known that benzyl cabamates can be converted to silyl carbamates75 by treatment with a Pd(II) catalyst and a silane and we hoped that such a silyl carbamate product might be easily hydrolyzed to obtain the free amine we desired. Therefore, the benzyl carbamate 176 was treated with Pd(OAc)2 and triethylsilane in dichloromethane at room temperature to form a mixture of silyl carbamate 178 (major) and amine 177

(minor) (Scheme 47). Treating this mixture with TBAF led to complete conversion to amine 177. Thus, we were able to convert the benzyl carbamate 176 to amine 177 using this two-step method in good overall yield.

Scheme 47.

2.1 Studies on the Double Hydroaminomethylation

Although there are no examples of double intramolecular hydroaminomethylation reactions in the literature, we decided to explore this type of reaction in an attempt to form the tetracyclic core of lycopladine H. Starting with the conditions which Sacher previously used to form the azocane ring of lycopladine H (Cf. Scheme 23), amino-bis-

50 alkene 177 was treated with the Rh/xantphos catalytic mixture and syngas in

PhMe/HFIPA as a solvent. However, only a monocyclized compound was isolated in low yield, which we believe to be either azocane 179 or piperidine 180. A 2D-NMR analysis of the monocyclized compound failed to conclusively identify the compound. Also comparison of the proton spectra of the monocyclized compound with 196 failed to conclusively identify the compound (vide supra). This compound had only one ring formed with the other alkene being hydrogenated. This result was not too surprising since there are numerous examples in the literature of alkenes being reduced instead of

41b hydroformylated under similar conditions when the ratio of H2:CO is more than 1:1.

Scheme 48.

In attempts to solve this problem, we thus decreased the partial pressure of H2 gas relative to CO in the reaction mixture. Changing the ratio of CO:H2 from 1:4 to 4.5:1, we were able to isolate the tetracyclic core 185 of lycopladine H in a low 14% yield, along with the monocyclized product 179 or 180 in 15% yield (Scheme 49). It is believed that the tetracyclic product 185 is formed via double hydroformylation of amino-bisalkene

177 via the amino-dialdehyde intermediate 186. This amino-dialdehyde 186 then undergoes a stepwise double reductive amination to form the azocane and piperidine

51 rings of tetracycle 185. It was not possible to determine whether the azocane ring or the piperidine ring of tetracycle 185 is formed first.

Scheme 49.

Further decreasing the partial pressure of H2 from 200 psi to 100 psi led to a decrease in yield of tetracycle 185 (Table 9, Entry 2). Removing HFIPA as a cosolvent

(Entry 3) or addition of MeOH as a cosolvent instead of HFIPA (Entry 4) gave no tetracyclic product 185. When the reaction was performed without any ligand (Entry 5) or using ionic Rh catalyst 106 no product was observed. Finally, use of a Rh/biphephos catalytic mixture (Entry 7) also failed to give any product 185.

52

Table 9. Attempted double hydroaminomethylation reaction of 177 to 185

In view of these disappointing results for the double hydroaminomethylation reaction of 177, it was decided to approach the hydroaminomethylation reaction in a stepwise manner, first forming the azocane ring of lycopladine H. Thus, the azocane ring in 195 would be obtained from intramolecular hydroaminomethylation of amino-alkene

194, which would be formed by Cbz-deprotection of intermediate 193 (Scheme 50).

Scheme 50.

Therefore, the previously developed carbamate deprotection conditions were applied to 193 to obtain amine 194 (Scheme 51). However, on treatment of 193 with

Et3SiH and Pd(OAc)2 (Table 10; Entry 1) or PdCl2 (Entry 2), only the starting material was recovered.75 Use of Mg/MeOH74b for Cbz-deprotection of 193 also resulted in

53 recovery of starting material (Entry 3), while Birch reduction73 of 193 resulted in decomposition (Entry 4).

Scheme 51.

Table 10. Attempted Cbz-cleavage of 193 to form amine 194

Therefore, it was decided to modify the initial approach to form the azocane ring of 196. We hoped that the hydroformylation of the amino-alkene 193 would lead to aldehyde 197,43,44 which could undergo Cbz-cleavage followed by a subsequent reductive amination to obtain the azocane 196 (Scheme 52).

Scheme 52.

54

Thus, amino-alkene 193 was treated with a Rh/biphephos catalyst and syngas in

THF as solvent for 48 h at 75 °C. However, under these conditions only a complex mixture was observed by TLC. Decreasing the reaction time from 48 h to 5 h led to recovery of a majority of the starting material. We were pleased to find that changing the solvent from THF to PhMe/HFIPA and increasing the reaction temperature from 75 °C to

125 °C afforded the desired Cbz-aldehyde 197 in 96% yield (Scheme 53).43,44

Scheme 53.

To continue the synthesis, we explored forming the azocane ring system 198 via a

Cbz-cleavage/intramolecular reductive amination of aldehyde 197, and several conditions were tried to effect this process (Scheme 54). Treating amino-aldehyde 197 with

Pearlman’s catalyst in the presence of 5 bar of H2 at room temperature resulted in recovery of starting material.44 However, stirring the Cbz-aldehyde 197 with 10% Pd/C under 1 atm of hydrogen at room temperature resulted in formation of the desired azocane product 198 in good yield.

55

Scheme 54.

In view of this promising result, it was then decided to explore the convertion of the Cbz-protected bis-alkene 176 to the corresponding dialdehyde 199 using the same reaction conditions as were used for the hydroformylation of alkene 193 (Cf. Scheme

53).49 However, under these conditions the dialdehyde 199 was not observed. Instead, a mixture of tricyclic spiropiperidine-aldehydes 200 (minor) and 201 (major) were obtained in 25% total yield (Scheme 55). The cleavage of the MOM group is probably promoted by the relatively acidic HFIPA cosolvent. However, simply omitting the HFIPA led to formation of the desired dialdehyde 199 in 56% yield.

Scheme 55.

56

Dialdehyde 199 was then subjected to the previous reductive amination conditions

(Cf. Scheme 54) in order to obtain the tetracycle 185 of lycopladine H (Scheme 56).49

However, under these conditions a majority of starting material was recovered after 24 h.

After 36 h, amino-dialdehyde 202 was observed, along with a faint spot of tetracyclic product 185 on TLC. Increasing the pressure of H2 to 200 psi did not change the outcome of the reaction. Finally, increasing the pressure of H2 to 500 psi and the temperature to 50

°C, along with addition of a few drops of glacial AcOH, led to isolation of the requisite tetracyclic product 185 in 54% yield.

Scheme 56.

To continue the synthesis, the MOM-group of tetracycle 185 was removed using

76 Me2BBr in dichloromethane at -78 °C to obtain the alcohol 203 (Scheme 57). However, numerous attempts to hydrolyze acetal 203 to obtain the triol 204 failed.

Scheme 57.

57

In view of the problems in removal of the ethylidene acetal group of 203, it became necessary to explore another type of cis-diol protection. Thus, the diol 168 was easily converted to carbonate 205 in good yield using a catalytic amount of DMAP and triphosgene in dichloromethane (Scheme 58).77 The carbonate 205 could also be obtained by treating diol 168 with 1,1’-carbonyldiimidazole (CDI) and DMAP in dichloromethane.78 The silyl ether in 205 was then removed to afford alcohol 206 in almost quantitative yield,65 which was subjected to Swern oxidation60 to obtain aldehyde

207 in excellent yield. Aldehyde 207 was then treated with vinylmagnesium bromide to give allylic alcohol 208 as a 3:1 diastereomeric mixture. The allylic alcohol 208 was then protected as MOM ether 209 in excellent yield.70

Scheme 58.

58

Scheme 58.

The amino-bisalkene 209 was subjected to the same hydroformylation conditions as used for the bis-alkene 176 (Cf. Scheme 55), consisting of a Rh/biphephos catalytic mixture and syngas in toluene at 125 °C (Scheme 59). However, the desired dialdehyde

210 could not be isolated because of formation of numerous side products, although some of the desired dialdehyde could be observed in the NMR and MS of the crude reaction mixture.

Scheme 59.

59

In an alternative route, the Cbz-protected amino-bisalkene 209 was converted in good yield to amino-bis-alkene 211 using the two step sequence of treatment with Et3SiH

75 and Pd(OAc)2, followed by TBAF at room temperature (Scheme 60). The divinyl amine

211 was then subjected to double hydroaminomethylation reaction conditions using a

Rh/xantphos catalytic mixture and syngas in PhMe/HFIPA solvent at 125 °C. However, the desired tetracycle 212 was not observed under these conditions.

Scheme 60.

In view of the problems described above, the cis-diol 168 was alternatively protected as the benzylidene acetal 213 using a catalytic amount of p-TsOH and benzaldehyde in good yield (Scheme 61).79 The silyl ether in 213 was removed to afford alcohol 214,65 which was subjected to Swern oxidation60 to obtain aldehyde 215 in almost quantitative yield. Aldehyde 215 was treated with vinylmagnesium bromide to give allylic alcohol 216 as a 3:1 diastereomeric mixture that could be separated by

60 chromatography for characterization purposes and each of the pure diastereomers of 216 was then used individually for the ensuing steps.. The allylic alcohol 216 was then protected as MOM ether 217 in excellent yield.70

Scheme 61.

Continuing the route, we were pleased to find that the divinyl carbamate 217 could be doubly hydroformylated by heating in the presence of Rh/biphephos and syngas in PhMe/THF at 125 °C to produce the dialdehyde 218 in good yield (Scheme 62).

Subsequent exposure of this dialdehyde to hydrogenation conditions using 10% Pd/C in a

61 mixture of ethyl acetate/acetic acid using 1 atm of H2 resulted in removal of the Cbz group to afford amino-dialdehyde 219, followed by an in situ double reductive amination to afford the desired tetracycle 220. The intermediate 219 could be observed and isolated by premature stoppage of the reaction and filtration of reaction mixture through a Celite pad. Analysis of the crude NMR of the filtrate after evaporation showed the presence of intermediate amino-dialdehyde 219.

Scheme 62.

With advanced tetracyclic intermediate 220 now in hand, a number of attempts were made to convert this compound into the natural product lycopladine H (21) (Scheme

63). For example, it was possible to remove the benzylidine group of 220 to produce diol

221 via a dissolving metal reduction.80 However, the reaction was not clean and the pure diol 221 could not be isolated. Oxidation of the crude diol 221 with IBX81 then led to the corresponding α-hydroxy ketone, which upon MOM removal under acidic conditions82 gave amino diol 222 (yields unoptimized). However, all attempts to oxidize 222 to the

62 alkaloid failed using a wide variety of oxidants such as IBX,81 Jones reagent,83 PCC,84 tetra-n-propylammonium perruthenate (TPAP)85, etc. The impure diol 221 could also be converted to triol 223 by HCl cleavage of MOM group (yields unoptimized). However, all attempts to oxidize triol 223 to the alkaloid lycopladine H (21) also failed using a wide variety of oxidation conditions such as IBX,81 Jones reagent,83 Swern oxidation,60

Oppenauer oxidation, 86 etc.

Scheme 63.

2.2 Conclusions

In conclusion, a synthesis of the tetracyclic framework of the structurally unique

Lycopodium alkaloid lycopladine H (21) has been achieved in 19 steps from phenol 60. A key step involved a novel double alkene hydroformylation/intramolecular reductive amination of 217 to form the azocane and spiropiperidine moieties of the natural product

63 in the form of advanced tetracyclic intermediate 220. Disappointingly, we have been unable to convert this compound into the natural product.

A possible solution to complete a synthesis of lycopladine H (21) is to change the order of the oxidation steps. Thus, the 2° alcohol at C-4 could be oxidized before oxidation of the diol in 221. It is possible that the keto-alcohol in 222 (Cf. Scheme 63) is sensitive to the conditions required to oxidize the 2° alcohol at C-4 of 222. Thus, the diol

221 could be protected as carbonate 224 (Scheme 64).77 The MOM-protected alcohol 224 could be deprotected and oxidized to obtain the ketone 225. The carbonate 225 would be hydrolyzed in presence of the ketone to obtain the corresponding diol,87 which would be further oxidized to obtain lycopladine H (21).

Scheme 64.

64

Chapter 3 - Experimental Section

General Methods. All non-aqueous reactions were carried out in oven- or flame-dried glassware under an argon atmosphere. All high pressure reactions were done in a non-stirred pressure vessel from Parr Instrument Company. All chemicals were purchased from commercial vendors and used as is unless otherwise specified.

Anhydrous tetrahydrofuran, diethyl ether, toluene, and dichloromethane were obtained from a solvent purification system. Reactions were magnetically stirred and monitored by thin layer chromatography with 250 μm precoated silica gel plates. Flash column chromatography was performed using silica gel (230−400 mesh). Chemical shifts are reported relative to chloroform (δ 7.26) for 1H NMR and chloroform (δ 77.2) for 13C

NMR. High-resolution mass spectra were obtained on a time-of-flight instrument using electrospray ionization.

6-(Hydroxymethyl)-3,3-dimethoxy-7-methyl-6-nitrobicyclo[2.2.2] octan-2-one (58). To a solution of bromoalkene 63 (50.0 mg, 0.142 mmol) in EtOH (5 mL) were added 10% Pd/C (7.6 mg, 0.007 mmol), 99% formic acid (0.026 mL, 0.713 mmol) and triethylamine (0.099 mL, 0.713 mmol). The resulting suspension was placed under a hydrogen atmosphere (1 atm) and stirred for 24 h. The reaction mixture was

65 filtered through a pad of Celite and the filtrate was evaporated in vacuo.The residue was dissolved in EtOAc and washed with saturated aqueous NaHCO3 solution. The combined organic layers were dried over Na2SO4, and evaporated in vacuo to give saturated nitro

1 alcohol 58 (38.6 mg, 99%) as a white foamy solid. H NMR (400 MHz, CDCl3) δ 4.15 and 3.88 (ABq, J = 12.4 Hz, 2H), 3.22 (s, 3H), 3.08 (s, 3H), 2.97 (d, J = 1.8 Hz, 1H),

2.76 (dt, J = 15.4, 3.1 Hz, 1H), 2.41 (m, 1H), 1.76 (ddd, J = 14.4, 10.7, 3.6 Hz, 1H), 1.64

(dd, J = 15.4, 2.1 Hz, 1H), 1.26 (m, 1H), 0.99 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz,

CDCl3) δ 202.0, 98.1, 93.5, 65.8, 52.2, 49.7, 48.9, 33.6, 31.4, 28.3, 27.9, 20.8; HRMS-

+ ES+ (C12H20NO6) calcd 274.1291 (M+H ), found 274.1282.

6-(((tert-Butyldiphenylsilyl)oxy)methyl)-3,3-dimethoxy-7-methyl-6- nitrobicyclo[2.2.2]octan-2-one (143). To a solution of alcohol 58 (1.30 g, 4.75 mmol) in

100 mL of dichloromethane were added tert-butylchlorodiphenylsilane (1.61 mL, 6.18 mmol) and imidazole (0.84 g, 12.30 mmol). The reaction mixture was stirred at rt for 18 h, poured into water and extracted with dicholoromethane. The combined organic layers were dried over Na2SO4, and evaporated in vacuo. The residue was purified by flash column chromatography (25% EtOAc/hexanes) to give silyl ether 143 (2.31 g, 95%) as a

1 white foamy solid. H NMR (300 MHz, CDCl3) δ 7.62-7.40 (m, 4H), 7.29-7.18 (m, 6H),

4.19 and 3.79 (ABq, J = 12.0 Hz, 2H), 3.31-3.12 (m, 7H), 2.76 (d, J = 15.0 Hz, 1H), 2.40

66

(s, 1H), 1.92-1.65 (m, 1H), 1.64-1.60 (m, 1H), 1.47 (d, J = 15.0 Hz, 1H), 1.28-1.21 (m,

13 1H), 1.06-0.99 (m, 12H); C NMR (75 MHz, CDCl3) δ 201.9, 135.9, 135.8, 132.8,

132.3, 130.5, 128.3, 98.5, 93.3, 66.6, 52.3, 50.0, 49.1, 33.8, 31.7, 28.7, 28.4, 26.9, 21.0,

+ 19.6; HRMS-ES+ (C28H41N2O6Si) calcd 529.2734 (M+NH4 ), found 529.2712.

6-(((tert-Butyldiphenylsilyl)oxy)methyl)-6-(hydroxyamino)-3,3- dimethoxy-7-methylbicyclo[2.2.2]octan-2-one (146). To a suspension of nitro compound 143 (0.888 g, 1.730 mmol) in 57 mL of isopropanol and 14.4 mL of 1.2 M

HCl was added zinc dust (2.270 g, 34.600 mmol). The reaction mixture was heated at 45

°C for 4 h and then filtered through Celite eluting with EtOAc. The filtrate was evaporated and the residue was dissolved in EtOAc. The organic layer was washed with saturated aqueous NaHCO3, dried over Na2SO4 and evaporated in vacuo. The resulting residue was purified by flash column chromatography (25% EtOAc/hexanes) to give

1 hydroxylamine 146 (0.850 g, 98%) as a white foamy solid. H NMR (300 MHz, CDCl3) δ

7.67-7.62 (m, 4H), 7.45-7.28 (m, 6H), 3.59 and 3.40 (ABq, J = 12.0 Hz, 2H), 3.33 (d, J =

3.0 Hz, 6H), 2.42 (s, 1H), 2.28 (s, 1H), 1.83 (br s, 1H), 1.72-1.67 (m, 1H), 1.59-1.51 (m,

3H), 1.37-1.33 (m, 1H), 1.22 (d, J = 18.0 Hz, 1H), 1.13 (s, 9H), 0.87 (d, J = 9.0 Hz, 3H);

13 C NMR (75 MHz, CDCl3) δ 208.4, 136.0, 135.9, 133.5, 133.3, 130.3, 130.2, 128.1,

67

97.7, 69.9, 59.9, 54.8, 49.9, 49.8, 34.5, 33.9, 28.9, 27.2, 26.7, 22.2, 19.7; HRMS-ES+

+ (C28H40NO4Si) calcd 482.2736 (M-O+H ), found 482.2727.

6-(((tert-Butyldiphenylsilyl)oxy)methyl)-6-(hydroxyamino)-3,3- dimethoxy-7-methylbicyclo[2.2.2]octan-2-ol (148). To a solution of ketone 146 (361 mg, 0.722 mmol) in 15 mL of THF was added BH3·THF solution (1 M in THF, 2.16 mL,

2.160 mmol) at 0 °C. The reaction mixture was stirred for 30 min at 0 °C and the solvent was evaporated in vacuo. The residue was dissolved in EtOAc and washed with saturated aqueous NaHCO3. The organic layer was dried over Na2SO4 and evaporated in vacuo.

The resulting residue was purified by flash column chromatography (33%

EtOAc/hexanes) to give alcohol 148 (347 mg, 96%) as a colorless oil. 1H NMR (300

MHz, CDCl3) δ 7.73-7.72 (m, 4H), 7.45-7.43 (m, 6H), 4.60 (s, 1H), 4.41 (s, 1H), 4.21 (s,

1H), 3.96 and 3.76 (ABq, J = 9.0 Hz, 2H), 3.31 (s, 6H), 2.74 (s, 1H), 2.15 (d, J = 15.0

Hz, 2H), 1.84 (d, J = 15.0 Hz , 1H), 1.48-1.27 (m, 5H), 1.12 (s, 12H); 13C NMR (75

MHz, CDCl3) δ 136.1, 133.0, 132.7, 130.4, 128.2, 100.7, 70.6, 65.0, 59.8, 50.1, 48.8,

41.5, 33.0, 32.6, 29.2, 27.3, 25.2, 22.3, 19.7; HRMS-ES+ (C28H42NO4Si) calcd 484.2863

(M-O+H+), found 484.2883.

68

6-Amino-6-(((tert-butyldiphenylsilyl)oxy)methyl)-3,3-dimethoxy-7- methyl bicyclo[2.2.2]octan-2-ol (149). To a solution of hydroxylamine 148 (322 mg,

0.644 mmol) in 34 mL of 90% aqueous AcOH was added 10% Pd/C (54 mg, 0.050 mmol). The suspension was stirred for 18 h under 1 atm of H2. The reaction mixture was filtered through a Celite pad and the filtrate was evaporated in vacuo. The residue was dissolved in EtOAc and washed with saturated aqueous NaHCO3. The organic layer was then dried over Na2SO4 and evaporated in vacuo. The resulting residue was purified by flash column chromatography (10% MeOH/CH2Cl2) to give amine 149 (283 mg, 91%) as

1 a colorless oil. H NMR (300 MHz, CDCl3) δ 7.45-7.40 (m, 4H), 7.28-7.03 (m, 6H), 4.58

(s, 1H), 3.62 (d, J = 9.0 Hz, 1H), 3.29 (d, J = 6.0 Hz, 7H), 1.93 (br s, 2H), 1.86-1.82 (m,

3H), 1.44 (d, J = 15.0 Hz, 1H), 1.35-1.16 (m, 2H), 1.14 (d, J = 9.0 Hz, 3H), 1.09-1.03 (m,

13 11H); C NMR (75 MHz, CDCl3) δ 135.9, 133.6, 130.0, 130.0, 128.0, 127.9, 100.9,

71.9, 71.3, 55.0, 49.0, 48.9, 46.3, 33.7, 33.6, 28.8, 27.2, 24.4, 22.3, 19.6; HRMS-ES+

+ (C28H42NO4Si) calcd 484.2883 (M+H ), found 484.2875.

69

2-(((tert-Butyldiphenylsilyl)oxy)methyl)-6-hydroxy-5,5-dimethoxy-7- methyl bicyclo[2.2.2]octan-2-yl)-4-methylbenzenesulfonamide (150). To a solution of amine 149 (44 mg, 0.091 mmol) in 5 mL of THF were added TsCl (21 mg, 0.109 mmol),

Et3N (0.03 mL, 0.218 mmol) and DMAP (1.1 mg, 0.009 mmol). The reaction mixture was stirred at 55 °C for 18 h. The organic solvent was evaporated in vacuo and the resulting residue was purified by flash column chromatography (33% EtOAc/hexanes) to

1 give the Ts-protected amine 150 (35 mg, 60%). H NMR (300 MHz, CDCl3) δ 7.80-7.78

(m, 2H), 7.71-7.65 (m, 4H), 7.47-7.38 (m, 6H), 7.31-7.27 (m, 2H), 5.06 (s, 1H), 4.02 (d, J

= 6.0 Hz, 1H), 3.94, 3.42 (ABq, J = 12.0 Hz, 2H), 3.16 (s, 3H), 2.84 (d, J = 6.0 Hz, 1H),

2.75 (s, 3H), 2.43 (s, 3H), 2.06-2.01 (m, 1H), 1.79-1.73 (m, 1H), 1.14-1.09 (m, 11H),

13 1.06-1.04 (m, 5H); C NMR (75 MHz, CDCl3) δ 143.0, 140.7, 136.2, 136.1, 133.5,

132.9, 130.2, 129.9, 128.1, 128.1, 127.4, 100.3, 71.3, 69.0, 64.7, 63.0, 49.1, 48.9, 46.3,

33.2, 32.3, 30.1, 28.3, 27.5, 23.5, 23.1, 21.9, 21.8, 19.7, 14.5.

2-(((tert-Butyldiphenylsilyl)oxy)methyl)-6-hydroxy-7-methyl-5-oxo bicyclo[2.2.2]octan-2-yl)-4-methylbenzenesulfonamide (151). To a solution of hydroxy ketal 150 (183 mg, 0.286 mmol) in 10 mL of acetonitrile were added 1 M LiBF4 solution in acetonitrile (0.860 mL, 0.860 mmol) and 0.2 mL of water. The reaction mixture was

70 heated for 2 h at 75 °C. After cooling the reaction mixture to rt, the solvent was evaporated in vacuo and the residue was dissolved in EtOAc. The solution was washed with saturated aqueous NaHCO3 and water, dried over Na2SO4 and evaporated in vacuo.

The resulting residue was purified by flash column chromatography (33%

EtOAc/hexanes) to give the α-hydoxy ketone 151 (165 mg, 98%). 1H NMR (300 MHz,

CDCl3) δ 7.75-7.72 (m, 2H), 7.68-7.63 (m, 4H), 7.52-7.40 (m, 6H), 7.28-7.14 (m, 2H),

5.24 (s, 1H), 4.49 (s, 1H), 3.83, 3.52 (ABq, J = 12.0 Hz, 2H), 2.65 (s, 3H), 2.43 (s, 3H),

2.37-2.19 (m, 3H), 1.65-1.43 (m, 4H), 1.15-1.12 (m, 10H), 0.91-0.85 (m, 2H).

2-(((tert-Butyldiphenylsilyl)oxy)methyl)-7-methyl-5-oxo-6-((tetra hydro-2H-pyran-2-yl)oxy)bicyclo[2.2.2]octan-2-yl)-4-methylbenzenesulfonamide

(155). To a solution of alcohol 151 (104 mg, 0.175 mmol) in 10 mL of CH2Cl2 were added pyridinium p-toluensulfonate (132 mg, 0.527 mmol) and 1 mL of dihydropyran

(excess). The reaction mixture was stirred at rt for 18 h, diluted with water and extracted with CH2Cl2. The organic layer was then dried over Na2SO4 and evaporated in vacuo. The resulting residue was purified by flash column chromatography (25% EtOAc/hexanes) to give the THP-protected alcohol 155 as a ~1:1 mixture of diastereomers (98 mg, 83%). 1H

NMR (300 MHz, CDCl3) δ 7.79-7.66 (m, 6H), 7.46-7.40 (m, 6H), 7.29-7.23 (m, 2H),

71

5.28-5.23 (m, 1H), 4.83 (s, 1H), 4.57 (d, J = 18.0 Hz, 1H), 4.16-3.99 (m, 3H), 3.58-3.50

(m, 3H), 2.39 (s, 3H), 2.24 (d, J = 15.0 Hz, 1H), 2.16-1.93 (m, 2H), 1.82-1.44 (m, 2H),

13 1.32-1.23 (m, 3H), 1.16 (s, 9H), 1.00-0.93 (m, 3H); C NMR (75 MHz, CDCl3) δ 215.4,

213.3, 143.8, 140.1, 136.2, 136.0, 130.5, 130.2, 128.3, 128.2, 127.2, 127.1, 101.2, 98.9,

95.2, 75.7, 63.7, 62.7, 62.3, 49.1, 45.9, 42.8, 42.7, 31.3, 30.9, 30.6, 27.4, 27.4, 25.8, 25.7,

24.8, 24.7, 21.9, 21.8, 21.7, 20.2, 19.7.

2-(((tert-Butyldiphenylsilyl)oxy)methyl)-5-hydroxy-7-methyl-6-

((tetrahydro-2H-pyran-2-yl)oxy)-5-vinylbicyclo[2.2.2]octan-2-yl)-4-methylbenzene sulfonamide (156). Dry CeCl3 (CeCl3·7H2O was dried in an oven at 180° C for 2 weeks,

600 mg, 2.430 mmol) was stirred vigorously in 6 mL of THF at rt for 30 min. The heterogeneous mixture was then cooled to -78° C and 1 M vinylmagnesium bromide in

THF (1.770 mL, 1.770 mmol) was added. The mixture was stirred vigorously at -78 °C for 30 min. The ketone 155 (100 mg, 0.148 mmol) dissolved in 5 mL of THF was then added to the reaction mixture at -78 °C and the resulting mixture was stirred for 10 min at

-78 °C. The reaction was quenched at -78 °C with saturated NH4Cl solution. The mixture was diluted with water and extracted with EtOAc. The organic layer was then dried over

Na2SO4 and evaporated in vacuo. The resulting residue was purified by flash column

72 chromatography (25% EtOAc/hexanes) to give the allylic alcohol 156 (102 mg, 98%) as

1 a ~1:1 mixture of THP-diastereomers. H NMR (300 MHz, CDCl3) δ 7.83-7.77 (m, 2H),

7.69-7.65 (m, 4H), 7.46-7.40 (m, 6H), 7.29-7.28 (m, 2H), 5.12-5.07 (m, 3H), 4.85-4.50

(m, 3H), 4.2-3.40 (m, 8H), 2.45 (br s, 3H), 1.95-1.80 (m, 2H), 1.76-1.45 (m, 2H), 1.13 (s,

13 10H), 1.07-0.87 (m, 5H); C NMR (75 MHz, CDCl3) δ 144.2, 143.5, 143.4, 143.3,

140.8, 140.3, 136.1, 136.1, 136.0, 133.4, 133.3, 133.0, 133.0, 130.3, 130.3, 130.1, 130.1,

128.2, 128.1, 127.8, 127.7, 112.4, 112.1, 100.9, 98.9, 98.3, 76.6, 76.3, 72.3, 71.9, 69.1,

68.9, 63.8, 63.8, 63.3, 63.3, 62.3, 60.8, 44.1, 41.9, 37.5, 37.0, 31.3, 30.9, 27.8, 27.5, 27.4,

23.4, 23.2, 21.9, 21.8, 21.6, 21.6, 20.4, 20.2, 19.7, 19.7, 19.2, 14.6.

2-(((tert-Butyldiphenylsilyl)oxy)methyl)-5,6-dihydroxy-7-methyl-5- vinylbicyclo[2.2.2]octan-2-yl)-4-methylbenzenesulfonamide (157). To a solution of alcohol 156 (102 mg, 0.145 mmol) in 6 mL of EtOH was added pyridinium p- toluenesulfonate (3.6 mg, 0.014 mmol) and the resulting mixture was stirred at 55° C for

6 h. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (25% EtOAc/hexanes) to give the diol 157 (81 mg, 90%). 1H NMR (300

MHz, CDCl3) δ 7.79-7.76 (m, 2H), 7.67-7.63 (m, 4H), 7.49-7.39 (m, 6H), 7.30-7.28 (m,

2H), 5.39-5.32 (m, 1H), 5.13-5.08 (m, 2H), 4.75 (d, J = 9.0 Hz, 1H), 4.17-4.07 (m, 1H),

3.74, 3.45 (ABq, J = 9.0 Hz, 2H), 2.64 (s, 1H), 2.50 (d, J = 6.0 Hz, 1H), 2.44 (s, 3H),

73

1.96 (d, J = 12.0 Hz, 1H), 1.74 (s, 1H), 1-65-1.57 (m, 2H), 1.54 (s, 1H), 1.36-1.23 (m,

13 1H), 1.14-1.12 (m, 12H), 1.05-0.95 (m, 2H); C NMR (75 MHz, CDCl3) δ 143.5, 143.1,

140.3, 136.2, 136.1, 133.3, 133.0, 130.3, 130.1, 128.2, 128.1, 127.7, 127.4, 113.2, 72.6,

71.9, 68.6, 63.6, 44.2, 36.9, 31.9, 28.1, 27.4, 27.2, 26.7, 23.3, 23.0, 21.9, 21.9, 21.4, 19.7,

14.6, 14.5.

5-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,9-dimethyl-7a-vinylhexa- hydro-4,7-ethanobenzo[d][1,3]dioxol-5-yl)-4-methylbenzenesulfonamide (158). To a solution of diol 157 (160 mg, 0.258 mmol) in 10 mL of acetaldehyde dimethyl acetal was added p-TsOH (4.9 mg, 0.0257 mmol) and the resulting mixture was stirred at 55° C for

4 h. The organic solvent was evaporated in vacuo and the residue was purified by flash column chromatography (25% EtOAc/hexanes) to give the ethylidene acetal 158 (140

1 mg, 84%). H NMR (300 MHz, CDCl3) δ 7.78 (d, J = 9.0 Hz, 2H), 7.66 (d, J = 9.0 Hz,

2H), 7.59 (d, J = 12.0 Hz, 2H), 7.47-7.36 (m, 6H), 7.28 (d, J = 6.0 Hz, 2H), 5.44-5.32

(m, 1H), 5.18-5.12 (m, 1H), 4.84-4.73 (m, 3H), 4.30 (br s, 1H), 3.98, 3.62 (ABq, J =

12.0 Hz, 2H), 2.44 (s, 3H), 2.22 (br s, 1H), 2.00 (d, J = 15.0 Hz, 1H), 1.77 (br s, 1H), 1-

71-1.63 (m, 1H), 1.59-1.49 (m, 1H), 1.4 (d, J = 3.0 Hz, 3H), 1.21-1.35 (m, 14H).

74

5-Formyl-2,9-dimethyl-7a-vinylhexahydro-4,7-ethanobenzo

[d][1,3]dioxol-5-yl)-4-methylbenzenesulfonamide (160). To a solution of silyl ether

158 (140 mg, 0.216 mmol) in 7 mL of THF was added 1 M TBAF in THF (0.434 mL,

0.434 mmol). The reaction mixture was stirred for 30 min at 0 °C. The organic solvent was evaporated in vacuo and the resulting residue was purified by flash column chromatography (25% to 50 % EtOAc/hexanes) to give the alcohol 159 (84 mg, 96%) which was used directly in the next step.

To a solution of oxalyl chloride (0.106 mL, 1.236 mmol) in 3 mL of

CH2Cl2 was added DMSO (0.132 mL, 1.850 mmol) at -78 °C. After 10 min, a solution of alcohol 159 (84 mg, 0.206 mmol) in CH2Cl2 (3 mL) was added. The solution was warmed to -40 °C over 1 h. Et3N (0.517 mL, 3.710 mmol) was added and the mixture was allowed to warm to rt. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (25% to 50 % EtOAc/hexanes) to give the

1 aldehyde 160 (59 mg, 68% from 158). H NMR (300 MHz, CDCl3) δ 9.59 (s, 1H), 7.74

(d, J = 9.0 Hz, 2H), 7.34 (d, J = 9.0 Hz, 2H), 5.56-5.47 (m, 1H), 5.28-5.23 (m, 2H), 4.86-

4.77 (m, 2H), 4.17 (d, J = 3.0 Hz, 1H), 2.46 (s, 3H), 2.37-2.32 (m, 1H), 2.18 (d, J = 3.0

Hz, 1H), 1.89 (br s, 1H), 1-74-1.65 (m, 3H), 1.57-1.47 (m, 1H), 1.43 (d, J = 3.0 Hz, 3H),

13 1.14 (d, J = 6.0 Hz, 3H); C NMR (75 MHz, CDCl3) δ 200.0, 144.6, 138.8, 138.6, 130.2,

127.6, 115.2, 99.3, 81.9, 67.0, 40.6, 35.9, 27.4, 26.5, 24.0, 22.0, 21.9, 18.6, 14.6, 12.7.

75

5-(1-Hydroxyallyl)-2,9-dimethyl-7a-vinylhexahydro-4,7-ethanobenzo

[d][1,3]dioxol-5-yl)-4-methylbenzenesulfonamide (161). Dry CeCl3 (CeCl3·7H2O was dried in an oven at 180 °C for 2 weeks, 486 mg, 1.970 mmol) was stirred vigorously in 5 mL of THF at rt for 30 min. The heterogeneous mixture was then cooled to -78 °C and 1

M vinylmagnesium bromide in THF (1.570 mL, 1.570 mmol) was added. The mixture was stirred vigorously at -78 °C for 30 min. The aldehyde 160 (80 mg, 0.197 mmol) dissolved in 5 mL of THF was then added to the reaction mixture at -78 °C and the resulting mixture was stirred for 30 min. The reaction was quenched at -78 °C with saturated NH4Cl solution. The mixture was diluted with water and extracted with EtOAc.

The organic layer was then dried over Na2SO4 and evaporated in vacuo. The resulting residue was purified by flash column chromatography (25% EtOAc/hexanes) to give the allylic alcohol 161 (75 mg, 88%) as a 14:1 mixture of chromatographically separable diastereomers.

1 Less polar isomer 161: H NMR (300 MHz, CDCl3) δ 7.78 (d, J = 6.0 Hz,

2H), 7.34 (d, J = 9.0 Hz, 2H), 6.08-5.97 (m, 1H), 5.80-5.71 (m, 1H), 5.49-5.31 (m, 2H),

5.13-5.06 (m, 2H), 4.28-4.23 (m, 2H), 4.16-4.07 (m, 2H), 3.82 (d, J = 2.4 Hz, 1H), 2.79

(d, J = 2.4 Hz, 1H), 2.44 (s, 3H), 2.18-2.08 (m, 1H), 1.90 (br s, 1H), 1-80-1.74 (m, 1H),

1.67-1.52 (m, 2H), 1.39 (d, J = 3.0 Hz, 3H), 1.25 (d, J = 6.0 Hz, 3H) 1.22-1.19 (m, 1H);

13 C NMR (75 MHz, CDCl3) δ 144.4, 139.7, 138.2, 136.2, 130.2, 127.4, 118.8, 116.1,

76

98.4, 80.8, 78.8, 78.0, 67.9, 38.8, 37.7, 35.3, 27.6, 23.9, 23.7, 23.5, 22.5, 21.9, 21.4, 18.5,

14.6.

1 More polar isomer 161: H NMR (300 MHz, CDCl3) δ 7.79 (d, J = 9.0 Hz,

2H), 7.34 (d, J = 9.0 Hz, 2H), 6.20-6.09 (m, 1H), 5.50-5.37 (m, 2H), 5.21-5.16 (m, 1H),

4.87-4.80 (m, 2H), 4.45 (t, J = 9.0 Hz, 1H), 4.21 (d, J = 2.1 Hz, 1H), 3.32 (d, J = 9.0 Hz,

1H), 2.46 (s, 3H), 2.22-2.19 (m, 1H), 2.06-2.03 (m, 1H), 1.97-1.78 (m, 4H), 1.45 (d, J =

3.0 Hz, 3H), 1.22 (d, J = 9.0 Hz, 3H), 0.97-0.67 (m, 1H).

Benzyl (2-(((tert-Butyldiphenylsilyl)oxy)methyl)-6-hydroxy-5,5- dimethoxy-7-methylbicyclo[2.2.2]octan-2-yl)carbamate (164). To a solution of amine

149 (1.00 g, 2.067 mmol) in 70 mL of ether at 0 °C were added 10 mL of saturated aqueous Na2CO3 solution and CbzCl (1 mL, 7.005 mmol). The heterogeneous mixture was stirred vigorously for 1 h at 0 °C and was extracted with EtOAc. The organic layer was then dried over Na2SO4 and evaporated in vacuo. The resulting residue was purified by flash column chromatography (33% EtOAc/hexanes) to give Cbz-protected amine 164

1 (1.26 g, 91%) as a white foamy solid. H NMR (300 MHz, CDCl3) δ 7.87-7.58 (m, 4H),

7.39-7.28 (m, 11H), 5.05-4.96 (m, 3H), 4.23 (d, J = 9.0 Hz, 1H), 3.94 and 3.56 (ABq, J =

9.6 Hz, 2H), 3.26 (d, J = 9.0 Hz, 6H), 2.99 (d, J = 9.0 Hz, 1H), 1.99 (s, 2H), 1.91 (s, 2H),

77

1.34-1.20 (m, 3H), 1.14 (d, J = 6.0 Hz, 3H), 1.05 (s, 9H), 0.91-0.84 (m, 1H); 13C NMR

(75 MHz, CDCl3) δ 155.3, 136.9, 135.9, 133.8, 133.6, 130.0, 128.8, 128.2, 128.2, 128.0,

100.4, 71.3, 66.5, 65.8, 58.8, 49.1, 49.0, 45.2, 33.3, 31.9, 30.0, 28.7, 27.1, 23.7, 22.1,

+ 19.7; HRMS-ES+ (C36H47NO6Si) calcd 618.3251 (M+H ), found 618.3271.

Benzyl (2-(((tert-Butyldiphenylsilyl)oxy)methyl)-6-hydroxy-7-methyl-

5-oxobicyclo[2.2.2]octan-2-yl)carbamate (165). To a solution of hydroxy ketal 164

(792 mg, 1.28 mmol) in 50 mL of acetonitrile were added 1 M LiBF4 solution in acetonitrile (3.84 mL, 3.84 mmol) and 1 mL of water. The reaction mixture was heated for 2 h at 75 °C. After cooling the reaction mixture to rt, the solvent was evaporated in vacuo and the residue was dissolved in EtOAc. The solution was washed with saturated aqueous NaHCO3 and water, dried over Na2SO4 and evaporated in vacuo. The resulting residue was purified by flash column chromatography (33% EtOAc/hexanes) to give the

1 ketone 165 (717 mg, 98%) as a white foamy solid. H NMR (300 MHz, CDCl3) δ 7.90-

7.62 (m, 4H), 7.47-7.36 (m, 11H), 5.74 (s, 1H), 5.06-4.97 (m, 2H), 4.68 (s, 1H), 4.14 (d, J

= 9.0 Hz, 1H), 3.62-3.56 (m, 2H), 2.52 (s, 1H), 2.35 (s, 1H), 2.19 (d, J = 12.0 Hz, 1H),

2.07-2.06 (m, 1H), 1.89-1.77 (m, 1H), 1.61 (d, J = 12.0 Hz, 1H), 1.44 (d, J = 16.0 Hz,

13 1H), 1.10-1.05 (m, 11H), 0.90 (d, J = 9.0 Hz, 1H); C NMR (75 MHz, CDCl3) δ 218.1,

78

155.6, 136.6, 135.8, 133.4, 133.2, 130.2, 130.1, 128.3, 128.2, 128.0, 74.5, 66.7, 65.5,

58.7, 48.1, 42.1, 35.7, 31.4, 27.1, 24.9, 22.1, 19.6; HRMS-ES+ (C34H42NO5Si) calcd

572.2832 (M+H+), found 572.2816.

Benzyl (2-(((tert-Butyldiphenylsilyl)oxy)methyl)-7-methyl-5-oxo-6-

((tetrahydro-2H-pyran-2-yl)oxy)bicyclo[2.2.2]octan-2-yl)carbamate (166). To a solution of alcohol 165 (2.880 g, 5.050 mmol) in 250 mL of CH2Cl2 were added pyridinium p-toluensulfonate (0.254 g, 1.010 mmol) and 3 mL of dihydropyran (excess).

The reaction mixture was stirred at rt for 18 h, diluted with water and extracted with

CH2Cl2. The organic layer was then dried over Na2SO4 and evaporated. The resulting residue was purified by flash column chromatography (10% to 20% to 50%

EtOAc/hexanes) to give the THP-protected alcohol 166 as a 1:1 mixture of diastereomers

1 (2.970 g, 90%, white foamy solid). H NMR (300 MHz, CDCl3) δ 7.67-7.63 (m, 4H),

7.46-7.36 (m, 11H), 5.27-4.83 (m, 4H), 4.63 (d, J = 6.0 Hz, 1H), 4.32-3.89 (m, 2H), 3.79-

3.70 (m, 1H), 3.45-3.42 (m, 1H), 2.63-2.49 (m, 1H), 2.32 (d, J = 18.0 Hz, 1H), 2.19-1.83

13 (m, 3H), 1.79-1.50 (m, 8H), 1.14-0.99 (m, 12H); C NMR (75 MHz, CDCl3) δ 215.5,

213.5, 155.4, 136.5, 135.7, 133.3, 133.2, 133.2, 130.1, 130.0, 128.7, 128.2, 128.2, 127.9,

100.7, 98.7, 95.5, 75.8, 66.6, 61.8, 58.8, 58.4, 43.2, 43.0, 34.4, 34.1, 30.6, 30.4, 27.0,

79

27.0, 25.7, 25.5, 24.8, 24.7, 21.8, 21.8, 19.5, 19.4, 18.9; HRMS-ES+ (C39H50NO6Si) calcd 655.3407 (M+H+), found 655.3408.

Benzyl (2-(((tert-Butyldiphenylsilyl)oxy)methyl)-5-hydroxy-7-methyl-

6-((tetrahydro-2H-pyran-2-yl)oxy)-5-vinylbicyclo[2.2.2]octan-2-yl)carbamate (167).

Dry CeCl3 (CeCl3·7H2O was dried in an oven at 180 °C for 2 weeks, 1.120 g, 4.570 mmol) was stirred vigorously in 10 mL of THF at rt for 30 min. The heterogeneous mixture was then cooled to -78 °C, and 1 M vinylmagnesium bromide in THF (3.2 mL,

3.200 mmol) was added. The mixture was stirred vigorously at -78 °C for 30 min. The ketone 167 (0.300 g, 0.457 mmol) dissolved in 15 mL of THF was then added to the reaction mixture at -78 °C and the resulting mixture was stirred for 10 min. The reaction was quenched with excess saturated NH4Cl solution. The mixture was diluted with water and extracted with EtOAc. The organic layer was then dried over Na2SO4 and evaporated in vacuo. The resulting residue was purified by flash column chromatography (10% to

20% to 25% EtOAc/hexanes) to give the allylic alcohol as a 1:1 mixture of diastereomers

1 167 (0.297 g, 95%, colorless oil). H NMR (300 MHz, CDCl3) δ 7.62-7.56 (m, 4H), 7.41-

7.26 (m, 11H), 6.11-6.01 (m, 1H), 5.36-5.26 (m, 2H), 5.11-5.00 (m, 3H), 4.97-4.85 (m,

1H), 4.69-4.62 (m, 1H), 4.28-4.11 (m, 1H), 3.99-3.81 (m, 2H), 3.74-3.55 (m, 2H), 3.41-

3.07 (m, 1H), 2.10 (s, 1H), 1.98-1.76 (m, 4H), 1.68-1.54 (m, 6H), 1.36-1.30 (m, 1H),

80

1.26-1.22 (m, 3H), 1.16 (d, J = 6.0 Hz, 1H), 1.10-1.04 (m, 9H); 13C NMR (75 MHz,

CDCl3) δ 155.6, 144.8, 144.3, 135.9, 133.8, 133.7, 133.6, 130.2, 130.1, 128.9, 128.9,

128.4, 128.4, 128.1, 113.0, 98.9, 98.7, 75.8, 72.3, 72.1, 66.7, 66.5, 65.9, 63.7, 63.4, 62.1,

59.8, 59.4, 57.8, 53.8, 42.8, 40.7, 37.5, 37.2, 32.8, 32.3, 32.0, 31.3, 31.1, 30.9, 28.0, 27.7,

27.3, 27.2, 25.9, 25.7, 25.5, 23.6, 23.4, 23.0, 22.1, 22.1, 20.4, 20.2, 19.8, 19.0; HRMS-

+ ES+ (C41H54NO6Si) calcd 684.3713 (M+H ), found 684.3720.

Benzyl (2-(((tert-Butyldiphenylsilyl)oxy)methyl)-5,6-dihydroxy-7- methyl-5-vinylbicyclo[2.2.2]octan-2-yl)carbamate (168). To a solution of alcohol 167

(0.934 g, 1.360 mmol) in 50 mL of EtOH was added pyridinium p-toluenesulfonate

(0.171 g, 0.682 mmol). The resulting mixture was stirred at 55 °C for 6 h. The solvent was evaporated and the resulting residue was purified by flash column chromatography

(25% EtOAc/hexanes) to give the diol 168 (0.711 g, 87%) as a white solid. 1H NMR (300

MHz, CDCl3) δ 8.34-7.60 (m, 4H), 7.65-7.36 (m, 11H), 6.12-6.03 (m, 1H), 5.34 (d, J =

18.0 Hz, 1H), 5.17-5.01 (m, 4H), 4.26 (d, J = 6.0 Hz, 1H), 3.95 and 3.57 (ABq, J = 12.0

Hz, 2H), 2.85-2.81 (m, 2H), 2.00-1.90 (m, 3H), 1.78-1.70 (m, 2H), 1.33-1.17 (m, 4H),

13 0.94 (s, 11H); C NMR (75 MHz, CDCl3) δ 155.6, 143.6, 136.7, 135.8, 135.7, 133.6,

133.5, 130.1, 130.0, 128.8, 128.3, 128.2, 128.0, 113.9, 72.6, 70.3, 70.0, 66.6, 66.1, 59.5,

43.9, 37.0, 32.3, 30.0, 27.5, 27.1, 23.3, 22.2, 19.7; HRMS-ES+ (C36H46NO5Si) calcd

81

600.3145 (M+H+), found 600.3127.

Benzyl (5-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,9-dimethyl-7a-vinyl hexahydro-4,7-ethanobenzo[d][1,3]dioxol-5-yl)carbamate (169). To a solution of diol

168 (900 mg, 1.50 mmol) in 40 mL of acetaldehyde dimethyl acetal was added p-TsOH

(28.5 mg, 0.15 mmol) and the resulting mixture was stirred at 55 °C for 2 h. The organic solvent was evaporated in vacuo and the residue was purified by flash column chromatography (25% EtOAc/hexanes) to give the ethylidene acetal 169 (798 mg, 85%).

1 H NMR (300 MHz, CDCl3) δ 7.65-7.63 (m, 4H), 7.46-7.37 (m, 11H), 6.10-6.00 (m, 1H),

5.42-5.31 (m, 1H), 5.19-5.04 (m, 3H), 4.96-4.91 (m, 1H), 4.85 (s, 1H), 4.33 (d, J = 6.0

Hz, 1H), 4.01, 3.76 (ABq, J = 9.0 Hz, 2H), 2.48-2.47 (m, 1H), 2.20-2.16 (m, 1H), 1.88

(s, 1H), 1.76-1.70 (m, 2H), 1.50 (d, J = 6.0 Hz, 3H), 1.30-1.25 (m, 4H), 1.08 (s, 9H); 13C

NMR (75 MHz, CDCl3) δ 155.3, 139.7, 136.9, 135.9, 133.6, 133.5, 130.2, 128.9, 128.8,

128.5, 128.4, 128.1, 115.2, 98.8, 82.0, 78.6, 66.7, 65.7, 59.6, 39.8, 36.0, 31.4, 28.4, 27.2,

+ 23.6, 22.4, 19.8, 18.7; HRMS-ES+ (C38H48NO5Si) calcd 626.3302 (M+H ), found

626.3306.

82

Benzyl (5-(Hydroxymethyl)-2,9-dimethyl-7a-vinylhexahydro-4,7- ethanobenzo[d][1,3]dioxol-5-yl)carbamate (170). To a solution of silyl ether 169

(1.214 g, 1.939 mmol) in 78 mL of CH2Cl2 were added BF3·OEt2 (0.957 mL, 7.750 mmol) and 4-methoxysalicyladehyde (1.180 g, 7.750 mmol) and the reaction mixture was stirred at rt for 10 min. The mixture was then washed with NaHCO3 solution and back extracted with CH2Cl2. The combined organic extract was dried over Na2SO4 and evaporated in vacuo. The residue was purified by flash column chromatography (25%

1 EtOAc/hexanes) to give the alcohol 170 (0.744 g, 99%). H NMR (300 MHz, CDCl3) δ

7.38-7.36 (m, 5H), 6.00-5.91 (m, 1H), 5.39-5.28 (m, 2H), 5.12, 5.05 (ABq, J = 12.0 Hz,

2H), 4.91, 4.87 (ABq, J = 6.0 Hz, 1H), 4.71 (s, 1H), 4.23 (d, J = 3.0 Hz, 1H), 3.85-3.80

(m, 2H), 2.76 (s, 1H), 2.05 (s, 1H), 1.87-1.78 (m, 2H), 1.68-1.46 (m, 6H), 1.27 (d, J =

13 6.0 Hz, 4H), 0.89-0.84 (m, 1H); C NMR (75 MHz, CDCl3) δ 156.6, 136.5, 129.0, 128.7,

128.5, 116.6, 98.6, 80.0, 77.9, 69.6, 67.3, 59.7, 37.8, 35.6, 35.0, 31.9, 28.0, 23.9, 23.0,

+ 22.3, 18.6, 14.5; HRMS-ES+ (C22H30NO5) calcd 388.2124 (M+H ), found 388.2100.

83

2,9-Dimethyl-7a-vinyltetrahydro-3aH-spiro[4,7-ethanobenzo[d][1,3] dioxole-5,4'-oxazolidin]-2'-one(171). To a solution of silyl ether 169 (59.0 mg, 0,094 mmol) in 10 mL of THF was added 1 M TBAF in THF (0.373 mL, 0.373 mmol). The reaction mixture was stirred for 30 min at 0 °C. The organic solvent was evaporated in vacuo and the resulting residue was purified by flash column chromatography (25% to 50

% EtOAc/hexanes) to give the spirocyclic carbamate 171 (15.7 mg, 60%).1H NMR (300

MHz, CDCl3) δ 6.10-5.90 (m, 2H), 5.51, 5.33 (ABq, J = 18.0 Hz, 2H), 4.96 (q, J = 3.0

Hz, 1H), 4.42 (d, J = 9.0 Hz, 1H), 4.22 (d, J = 3.0 Hz, 1H) 4.16 (d, J = 9.0 Hz, 1H), 2.05-

2.04 (m, 2H), 1.94-1.75 (m, 3H), 1.55-1.53 (m, 2H), 1.45 (d, J = 6.0 Hz, 3H), 1.24 (d, J =

13 6.0 Hz, 3H); C NMR (75 MHz, CDCl3) δ 158.8, 139.2, 117.4, 99.4, 80.3, 60.7, 59.1,

45.1, 38.1, 36.4, 27.4, 25.0, 23.0, 22.1, 18.6, 14.5.

Benzyl (5-Formyl-2,9-dimethyl-7a-vinylhexahydro-4,7-ethanobenzo

[d][1,3] dioxol-5-yl)carbamate (172). To a solution of oxalyl chloride (0.86 mL, 10.019 mmol) in 20 mL of CH2Cl2 was added DMSO (1.06 mL, 15.020 mmol) at -78 °C. After

10 min, a solution of alcohol 170 (0.647 g, 1.660 mmol) in CH2Cl2 (20 mL) was added.

The solution was warmed to -40 °C over 1 h, Et3N (4.18 mL, 30.050 mmol) was added and the mixture was allowed to warm to rt. The solvent was evaporated in vacuo and the

84 residue was purified by flash column chromatography (25% EtOAc/hexanes) to give the

1 aldehyde 172 (0.596 g, 93%). H NMR (300 MHz, CDCl3) δ 9.50 (s, 1H), 7.33-7.32 (m,

5H), 6.04-5.95 (m, 1H), 5.48-5.36 (m, 2H), 5.21 (d, J = 9.0 Hz, 1H), 5.07 (s, 2H), 4.91 (d,

J = 6.0 Hz, 1H), 4.19 (s, 1H), 2.45-2.40 (m, 2H), 2.00 (s, 1H), 1.76 (s, 1H), 1.64-1.55

13 (m, 3H), 1.45 (d, J = 3.0 Hz, 3H), 1.17 (d, J = 3.0 Hz, 3H); C NMR (75 MHz, CDCl3) δ

199.8, 155.7, 139.1, 136.2, 128.9, 128.7, 128.5, 115.9, 99.3, 81.8, 67.6, 63.8, 38.7, 35.8,

+ 29.1, 27.7, 23.9, 22.0, 18.7; HRMS-ES+ (C22H28NO5) calcd 386.1967 (M+H ), found

386.1973.

Benzyl (5-(1-Hydroxyallyl)-2,9-dimethyl-7a-vinylhexahydro-4,7- ethanobenzo[d][1,3]dioxol-5-yl)carbamate (173). To a solution of aldehyde 172 (100 mg, 0.259 mmol) in 6 mL of THF was added 1 M vinylmagnesium bromide in THF

(0.778 mL, 0.778 mmol) at -78 °C. The reaction mixture was stirred for 1 h at -78 °C, quenched with NH4Cl solution and was extracted with EtOAc. The extract was dried over

Na2SO4 and evaporated in vacuo. The resulting residue was purified by flash column chromatography (10% to 20% to 25% EtOAc/hexanes) to give the chromatographically separable allylic alcohols 173 in a 3:1 ratio (75 mg, 70%).

1 Less polar alcohol isomer 173: H NMR (300 MHz, CDCl3) δ 7.38-7.28

85

(m, 5H), 5.98-5.78 (m, 2H), 5.40-5.30 (m, 4H), 5.17-513 (m, 2H), 5.08-5.00 (m, 1H),

4.88 (q, J = 3.0 Hz, 1H), 4.52 (s, 1H), 4.26-4.20 (m, 2H), 3.11 (d, J = 3.0 Hz, 1H), 2.05

(s, 2H), 1.88-1.81 (m, 1H), 1.66-1.61 (m, 2H), 1.46 (d, J = 6.0 Hz, 3H), 1.30 (d, J = 6.0

13 Hz, 3H), 1.23-1.18 (m, 1H); C NMR (75 MHz, CDCl3) δ 157.6, 139.7, 136.9, 136.4,

128.9, 128.7, 128.5, 128.4, 116.9, 116.2, 98.5, 80.4, 79.1, 78.3, 67.6, 61.6, 37.6, 37.3,

+ 35.8, 28.1, 23.6, 22.3, 18.6; HRMS-ES+ (C24H32NO5) calcd 414.2280 (M+H ), found

414.2276.

1 More polar alcohol isomer 173: H NMR (300 MHz, CDCl3) δ 7.41-7.29

(m, 5H), 5.97-5.85 (m, 2H), 5.35-5.20 (m, 3H), 5.12-5.07 (m, 3H), 4.89 (q, J = 3.0 Hz,

1H), 4.61 (s, 1H), 4.57 (t, J = 6.0 Hz, 1H), 4.18 (d, J = 3.0 Hz, 1H), 3.81 (s, 1H), 2.46-

2.31 (m, 1H), 2.18-2.13 (m, 1H), 2.07-1.94 (m, 3H), 1.87-1.76 (m, 1H), 1.67-1.62 (m,

13 1H), 1.46 (d, J = 6.0 Hz, 3H), 1.22 (d, J = 3.0 Hz, 3H); C NMR (75 MHz, CDCl3) δ

157.1, 139.2, 136.9, 136.5, 128.8, 128.6, 128.5, 117.4, 115.3, 98.9, 81.3, 79.4, 78.6, 76.9,

67.2, 61.6, 40.8, 35.9, 32.3, 28.2, 23.8, 22.1, 18.6; HRMS-ES+ (C24H32NO5) calcd

414.2280 (M+H+), found 414.2299.

2,9-Dimethyl-5',7a-divinyltetrahydro-3aH-spiro[4,7-ethanobenzo

86

[d][1,3]dioxole-5,4'-oxazolidin]-2'-one (175). To a solution of the less polar allylic alcohol isomer 173 (10 mg, 0.024 mmol) in 1 mL of THF at 0 °C was added 1 mL of

40% KOH solution in MeOH. The reaction mixture was warmed to rt and stirred for 2 h.

The reaction mixture was evaporated in vacuo, dissolved in EtOAc and washed with saturated aqueous NH4Cl. The organic layer was then dried over Na2SO4 and evaporated in vacuo. The resulting residue was purified by flash column chromatography (25%

EtOAc/hexanes) to give the cyclic carbamate 175 (7 mg, 90%). 1H NMR (300 MHz,

CDCl3) δ 6.18-6.03 (m, 1H), 5.92-5.86 (m, 1H), 5.57-5.37 (m, 3H), 5.33 (s, 1H), 5.16 (s,

1H), 5.00 (q, J = 3.0 Hz, 1H), 4.76 (d, J = 9.0 Hz, 1H), 2.36-2.21 (m, 2H), 2.03-1.99 (m,

2H), 1.85-1.79 (m, 1H), 1.62-1.55 (m, 2H), 1.47 (d, J = 3.0 Hz, 3H), 1.16 (d, J = 3.0 Hz,

13 3H); C NMR (75 MHz, CDCl3) δ 158.2, 139.4, 132.2, 121.0, 117.8, 99.5, 89.9, 80.0,

78.4, 62.3, 60.8, 53.8, 40.3, 39.9, 36.1, 32.3, 30.1, 27.2, 25.7, 25.0, 23.0, 21.4, 21.2, 18.7,

14.6, 14.5.

Benzyl (5-(1-(Methoxymethoxy)allyl)-2,9-dimethyl-7a-vinylhexa hydro-4,7-ethanobenzo [d][1,3] dioxol-5-yl)carbamate (176). To a solution of the less polar allylic alcohol isomer 173 (62 mg, 0.15 mmol) in 6 mL of formaldehyde dimethyl acetal and 3 mL of chloroform was added P2O5 (300 mg, excess). After 1 h, an additional

87

200 mg of P2O5 was added to the reaction mixure. Finally, an additional 100 mg of P2O5 was added after another 1 h. The resulting mixture was stirred at rt for 10 h. The mixture was then washed thoroughly with NaHCO3 solution and back extracted with CH2Cl2. The combined organic layer was dried over Na2SO4 and evaporated in vacuo to give the

MOM-protected alcohol 176 (67 mg, 98%) which was used without further purification.

1 H NMR (300 MHz, CDCl3) δ 7.37-7.29 (m, 5H), 6.06-5.91 (m, 1H), 5.78-5.67 (m, 1H),

5.38-5.27 (m, 3H), 5.12-5.04 (m, 3H), 4.90 (q, J = 3.0 Hz, 1H), 4.74-4.62 (m, 2H), 4.50-

4.48 (m, 1H), 4.31-4.26 (m, 2H), 3.38 (s, 3H), 2.59 (s, 1H), 2.07-1.98 (m, 1H), 1.90 (s,

1H), 1.85-1.78 (m, 1H), 1.62-1.52 (m, 1H), 1.47 (d, J = 3 Hz, 3H), 1.44-1.38 (m, 1H),

1.30-1.28 (m, 4H).

5-(1-(Methoxymethoxy)allyl)-2,9-dimethyl-7a-vinylhexahydro-4,7- ethanobenzo[d][1,3]dioxol-5-amine (177). To a suspension of Pd(OAc)2 (9 mg, 0.043 mmol) in 5 mL of CH2Cl2 were added Et3N (0.012 mL, 0.133 mmol) and Et3SiH (0.18 mL, 0.878 mmol). The suspension was stirred at rt for 15 min. Less polar benzyl carbamate isomer 176 (67 mg, 0.146 mmol) in 1 mL of CH2Cl2 was added and the mixture was stirred for 18 h at rt. The mixture was concentrated in vacuo and passed through short column of silica gel eluting with 25% EtOAc/hexanes to remove the Pd

88 catalyst. The filtrate was concentrated in vacuo and dissolved in 6 mL of THF. TBAF in

THF (1 M , 0.878 mL, 0.878 mmol) was added, the mixture was stirred for 4 h at rt and concentrated in vacuo. The residue was purified by flash column chromatography (25%

1 EtOAc/hexanes) to give the amine 177 (45 mg, 90%). H NMR (300 MHz, CDCl3) δ

6.62-6.48 (m, 1H), 5.79-5.68 (m, 1H), 5.44-5.43 (m, 1H), 5.39-5.38 (m, 1H), 5.35-5.29

(m, 1H), 5.09 (dd, J = 9.0 , 1.8 Hz, 1H), 4.93 (q, J = 6.0 Hz, 1H), 4.71, 4.50 (ABq, J =

6.0 Hz, 2H), 4.63 (d, J = 3.0 Hz, 1H), 3.40 (s, 3H), 2.23 (d, J = 3.0 Hz, 1H), 2.05-1.78

(m, 3H), 1.50 (d, J = 6.0 Hz, 4H), 1.36-1.25 (m, 5H), 0.64-0.56 (m, 2H); 13C NMR (75

MHz, CDCl3) δ 141.1, 133.8, 120.9, 113.3, 98.6, 94.2, 82.1, 80.4, 79.7, 57.2, 56.5, 41.0,

+ 37.2, 35.2, 28.9, 23.4, 22.5, 18.9, 6.1; HRMS-ES+ (C18H30NO4) calcd 324.2175 (M+H ), found 324.2185.

11-(Methoxymethoxy)-2,13-dimethyloctahydro-4H-11a,3a,12-

(epibutane[1,2,4]triyl)[1,3]dioxolo[4,5-d]pyrido[1,2-a]azocine (185). To a solution of less polar amino diene isomer 176 (31 mg, 0.095 mmol) in PhMe (2 mL) and 1,1,1,3,3,3- hexafluoroisopropanol (HFIPA, 2 mL) in a pressure reactor were added [Rh(cod)Cl]2 (4.7 mg, 0.0095 mmol) and xantphos (13.8 mg, 0.023 mmol). The reactor was sealed and pressurized with carbon monoxide (900 psi) and hydrogen (200 psi). The reactor was

89 heated in an oil bath at 135 °C for 18 h, and then cooled to rt. The gasses were vented in a fume hood, and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography (25% EtOAc/hexanes) to give cyclic amine 185 (5 mg, 14%). 1H

NMR (300 MHz, CDCl3) δ 5.33 (s, 2H), 5.03 (q, J = 6.0 Hz, 1H), 4.76, 4.61 (ABq, J =

6.0 Hz, 2H), 4.34 (d, J = 6.0 Hz, 1H), 3.42 (s, 3H), 2.77-2.73 (m, 2H), 2.23-2.17 (m, 2H),

2.07-2.04 (m, 1H), 1.86-1.54 (m, 9H), 1.46 (d, J = 6.0 Hz, 3H), 1.31-1.21 (m, 6H), 1.03-

13 0.97 (m, 1H); C NMR (75 MHz, CDCl3) δ 98.0, 96.5, 82.7, 82.0, 80.3, 61.3, 56.1, 53.8,

50.8, 49.5, 37.9, 37.4, 37.3, 31.4, 30.1, 28.2, 27.9, 26.7, 26.0, 23.0, 22.3, 21.9, 19.1;

+ HRMS-ES+ (C20H34NO4) calcd 352.2488 (M+H ), found 352.2485.

Benzyl (5-(1-(Methoxymethoxy)-4-oxobutyl)-2,9-dimethyl-7a-(3- oxopropyl)hexahydro-4,7-ethanobenzo[d][1,3]dioxol-5-yl)carbamate (199). To a solution of less polar carbamate alkene isomer 176 (116 mg, 0.253 mmol) in 12 mL of

PhMe in a pressure reactor were added Rh(CO)2acac (9.8 mg, 0.038 mmol) and biphephos (60 mg, 0.076 mmol). The reactor was sealed, pressurized with carbon monoxide (300 psi) and hydrogen (300 psi), was heated at 125 °C in an oil bath for 4 h, and then cooled to rt. The gasses were vented in a fume hood, and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography (1:2:2

90

1 EtOAc/CH2Cl2/hexanes) to give the dialdehyde 199 (81 mg, 61%). H NMR (300 MHz,

CDCl3) δ 9.75 (s, 1H), 9.70 (s, 1H), 7.35-7.31 (m, 5H), 5.09-4.93 (m, 3H), 4.65 (s, 1H),

4.63, 4.52 (ABq, J = 9.0 Hz, 2H), 4.05 (d, J = 3.0 Hz, 1H), 3.74 (d, J = 9.0 Hz, 1H), 3.38

(s, 1H), 2.67-2.45 (m, 4H), 2.30 (s, 1H), 2.05-1.81 (m, 4H), 1.57 (t, J = 6.0 Hz, 1H), 1.55-

1.50 (m, 2H), 1.40 (d, J = 36.0 Hz, 4H), 1.17 (s, 1H), 0.98 (d, J = 6.0 Hz, 3H); HRMS-

+ ES+ (C28H40NO8) calcd 518.2754 (M+H ), found 518.2730.

11-(Methoxymethoxy)-2,13-dimethyloctahydro-4H-11a,3a,12-

(epibutane[1,2,4]triyl)[1,3]dioxolo[4,5-d]pyrido[1,2-a]azocine (185). To a solution of less polar dialdehyde isomer 199 (65 mg, 0.125 mmol) in 16 mL of EtOH in a pressure reactor were added 5% Pd/C (130 mg) and glacial AcOH (5 drops). The reactor was sealed and pressurized with hydrogen (500 psi). The reactor was heated at 75 °C for 15 h, and then cooled to rt. The gas was vented in a fume hood and the mixture was filtered through Celite and the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography (25 % EtOAc/ hexanes) to give the azocine 185 (27 mg, 61%).

1 H NMR (300 MHz, CDCl3) δ 5.33 (s, 2H), 5.03 (q, J = 6.0 Hz, 1H), 4.76, 4.61 (ABq, J

= 6.0 Hz, 2H), 4.34 (d, J = 6.0 Hz, 1H), 3.42 (s, 3H), 2.77-2.73 (m, 2H), 2.23-2.17 (m,

2H), 2.07-2.04 (m, 1H), 1.86-1.54 (m, 9H), 1.46 (d, J = 6.0 Hz, 3H), 1.31-1.21 (m, 6H),

91

13 1.03-0.97 (m, 1H); C NMR (75 MHz, CDCl3) δ 98.0, 96.5, 82.7, 82.0, 80.3, 61.3, 56.1,

53.8, 50.8, 49.5, 37.9, 37.4, 37.3, 31.4, 30.1, 28.2, 27.9, 26.7, 26.0, 23.0, 22.3, 21.9, 19.1;

+ HRMS-ES+ (C20H34NO4) calcd 352.2488 (M+H ), found 352.2485.

2,13-Dimethyloctahydro-4H-11a,3a,12-(epibutane[1,2,4]triyl)[1,3] dioxolo[4,5-d]pyrido[1,2-a]azocin-11-ol (203). To a solution of MOM-protected alcohol

185 (9 mg, 0.025 mmol) in 2 mL of CH2Cl2 was added (0.456 mL, 0.306 mmol) of 0.67

M Me2BBr in CH2Cl2. The reaction mixture was stirred at -78 °C for 2 h. The mixture was poured into NaHCO3 solution and extracted with CH2Cl2. The organic layer was dried over Na2SO4, evaporated in vacuo and the residue was purified by flash column

1 chromatography (10% MeOH/CH2Cl2) to give the alcohol 203 (5 mg, 64%). H NMR

(300 MHz, CDCl3) δ 4.95 (q, J = 6.0 Hz, 1H), 4.21 (d, J = 3.0 Hz, 1H), 3.65-3.62 (m,

1H), 3.36-3.31 (m, 1H), 2.96-2.87 (m, 1H), 2.68-2.58 (m, 3H), 2.02-1.90 (m, 3H), 1.87-

1.80 (m, 4H), 1.76-1.69 (m, 3H), 1.61-1.58 (m, 3H), 1.45 (d, J = 3.0 Hz, 3H), 1.17 (d, J =

+ 9.0 Hz, 3H), 0.96-0.88 (m, 2H); LRMS-ES+ (C18H30NO3) calcd 308.2 (M+H ), found

308.2.

92

Benzyl 5-(((tert-Butyldiphenylsilyl)oxy)methyl)-9-methyl-2-oxo-7a- vinylhexahydro-4,7-ethanobenzo[d][1,3]dioxol-5-yl)carbamate (205). To a solution of diol 168 (50.0 mg, 0.083 mmol) in 6 mL of CH2Cl2 were added triphosgene (12.3 mg,

0.042 mmol), Et3N (0.046 mL, 0.333 mmol) and DMAP (1.0 mg, 0.009 mmol). The reaction mixture was stirred at rt for 4 h. The organic solvent was evaporated in vacuo and the resulting residue was purified by flash column chromatography (25%

EtOAc/hexanes) to give the carbonate 205 (46 mg, 88%).

In an alternative procedure, a solution of diol 168 (1.91 g, 3.180 mmol) in

100 mL of CH2Cl2 were added 1,1'-carbonyldiimidazole (CDI) (2.57 g, 15.901 mmol) and DMAP (77 mg, 0.636 mmol). The reaction mixture was stirred at rt for 4 h. The organic solvent was evaporated in vacuo and the resulting residue was purified by flash column chromatography (25% EtOAc/hexanes) to give the carbonate 205 (1.55 g, 78%).

1 H NMR (300 MHz, CDCl3) δ 7.62-7.59 (m, 4H), 7.47-7.36 (m, 11H), 6.05-6.01 (m, 1H),

5.48 (d, J = 18.0 Hz, 1H), 5.35-5.30 (m, 1H), 5.10-5.08 (m, 2H), 4.92 (d, J = 3.0 Hz, 1H),

4.87 (s, 1H), 3.92 and 3.72 (ABq, J = 9.0 Hz, 2H), 2.52 (d, J = 3.0 Hz, 1H), 2.12 (d, J =

15.0 Hz, 1H), 2.05-2.02 (m, 1H), 1.91-1.82 (m, 1H), 1.69-1.48 (m, 2H), 1.40-1.24 (m,

13 2H), 1.13 (d, J = 15.0 Hz, 3H), 1.06 (s, 9H); C NMR (75 MHz, CDCl3) δ 155.6, 154.5,

136.4, 136.1, 135.8, 133.1, 133.1, 130.3, 130.3, 128.9, 128.6, 128.4, 128.1, 117.8, 83.9,

79.6, 67.0, 65.8, 58.6, 53.8, 39.1, 34.5, 31.3, 28.1, 27.1, 22.6, 21.8, 19.6; HRMS-ES+

93

+ (C37H44NO6Si) calcd 626.2938 (M+H ), found 626.2964.

Benzyl 5-(Hydroxymethyl)-9-methyl-2-oxo-7a-vinylhexahydro-4,7- ethanobenzo[d][1,3]dioxol-5-yl)carbamate (206). To a solution of silyl ether 205

(2.595 g, 4.14 mmol) in 120 mL of CH2Cl2 were added BF3·OEt2 (2.05 mL, 16.58 mmol) and 4-methoxysalicyladehyde (2.520 g, 16.58 mmol) and the reaction mixture was stirred at rt for 10 min. The mixture was then washed with NaHCO3 solution and back extracted with CH2Cl2. The combined organic extract was dried over Na2SO4 and evaporated in vacuo. The residue was purified by flash column chromatography (25% EtOAc/hexanes)

1 to give the alcohol 206 (1.581 g, 99%). H NMR (300 MHz, CDCl3) δ 7.60-7.26 (m, 5H),

6.03-5.94 (m, 1H), 5.49-5.29 (m, 2H), 5.07 (q, J = 12.0 Hz, 2H), 4.83-4.79 (m, 2H), 3.80

(q, J = 12.0 Hz, 2H), 3.50 (br s, 1H), 2.75 (s, 1H), 2.12-2.03 (m, 2H), 1.83-1.74 (m, 1H),

13 1.66-1.51 (m, 2H), 1.17 (d, J = 9.0 Hz, 3H); C NMR (75 MHz, CDCl3) δ 156.4, 154.4,

136.1, 136.0, 129.0, 128.8, 128.4, 118.8, 83.4, 79.4, 68.4, 67.5, 58.5, 53.8, 37.6, 34.3,

+ 33.8, 28.0, 22.7, 21.8; HRMS-ES+ (C21H29N2O6) calcd 405.2026 (M+NH4 ), found

405.2039.

94

Benzyl 5-Formyl-9-methyl-2-oxo-7a-vinylhexahydro-4,7-ethanobenzo

[d][1,3]dioxol-5-yl)carbamate (207). To a solution of oxalyl chloride (2.104 mL, 24.501 mmol) in 90 mL of CH2Cl2 was added DMSO (2.610 mL, 36.752 mmol) at -78 °C. After

10 min, a solution of alcohol 206 (1.581 g, 4.080 mmol) in CH2Cl2 (30 mL) was added.

The solution was warmed to -40 °C over 1 h. Et3N (10.245 mL, 73.504 mmol) was added and the mixture was allowed to warm to rt. The solvent was evaporated and the residue was purified by flash column chromatography (25% EtOAc/hexanes) to give the

1 aldehyde 207 (1.543 g, 98%). H NMR (300 MHz, CDCl3) δ 9.45 (s, 1H), 7.39-7.28 (m,

5H), 6.07-5.97 (m, 1H), 5.78 (br s, 1H), 5.49 (d, J = 18.0 Hz, 1H), 5.33 (d, J = 18.0 Hz,

1H), 5.11-5.03 (m, 2H), 4.83 (d, J = 3.0 Hz, 1H), 2.58-2.42 (m, 2H), 2.17 (s, 1H), 1.88-

1.67 (m, 2H), 1.63-1.58 (m, 1H), 1.52-1.45 (m, 1H), 1.10 (d, J = 6.0 Hz, 3H); 13C NMR

(75 MHz, CDCl3) δ 197.9, 155.8, 154.1, 135.8, 135.4, 128.8, 128.7, 128.2, 118.5, 83.7,

78.2, 67.7, 62.6, 37.4, 34.2, 28.2, 27.4, 22.7, 21.4; HRMS-ES+ (C21H27N2O6) calcd

+ 403.1869 (M+NH4 ), found 403.1899.

.

95

Benzyl 5-(1-Hydroxyallyl)-9-methyl-2-oxo-7a-vinylhexahydro-4,7- ethanobenzo[d][1,3]dioxol-5-yl)carbamate (208). To a solution of aldehyde 207 (193 mg, 0.501 mmol) in 20 mL of THF was added 1 M vinylmagnesium bromide in THF (1.5 mL, 1.503 mmol) at -78 °C. The reaction mixture was stirred for 1 h at -78 °C and quenched with NH4Cl solution. The mixture was extracted with EtOAc. The extract was dried over Na2SO4 and evaporated in vacuo. The resulting residue was purified by flash column chromatography (10% to 20% to 25% EtOAc/hexanes) to give the chromatographically separable allylic alcohols 208 in a 3:1 ratio (144 mg, 69%).

1 Less polar isomer 208: H NMR (300 MHz, CDCl3) δ 7.34-7.25 (m, 5H),

6.02-5.92 (m, 1H), 5.87-5.73 (m, 1H), 5.54-5.37 (m, 3H), 5.26-5.12 (m, 2H), 5.08-4.93

(m, 3H), 4.74 (d, J = 3.0 Hz, 1H), 4.18-4.06 (m, 1H), 3.11 (d, J = 3.0 Hz, 1H), 2.25-2.19

(m, 1H), 1.83-1.74 (m, 1H), 1.67-1.51 (m, 2H), 1.42-1.37 (m, 1H), 1.17 (d, J = 6.0 Hz,

13 3H); C NMR (75 MHz, CDCl3) δ 158.0, 154.4, 136.2, 136.0, 135.7, 129.0, 128.8,

128.7, 128.6, 128.4, 128.3, 119.2, 117.1, 83.1, 80.0, 79.3, 67.8, 60.5, 37.1, 35.8, 34.6,

+ 28.1, 22.3, 22.0, 18.6; HRMS-ES+ (C23H28NO6) calcd 414.1917 (M+H ), found

414.1917.

1 More polar isomer 208: H NMR (300 MHz, CDCl3) δ 7.34-7.27 (m, 5H),

6.07-5.80 (m, 2H), 5.42-5.37 (m, 1H), 5.27-5.23 (m, 1H), 5.21-5.15 (m, 2H), 5.09-4.94

(m, 3H), 4.80 (d, J = 3.0 Hz, 1H), 4.37 (d, J = 3.0 Hz, 1H), 2.72 (d, J =3.0 Hz, 1H), 2.10

(s, 1H), 2.05-1.97 (m, 1H), 1.87-1.65 (m, 2H), 1.65-1.49 (m, 1H), 1.34-1.18 (m, 1H),

13 1.13 (d, J = 6.0 Hz, 3H); C NMR (75 MHz, CDCl3) δ 157.0, 154.6, 136.5, 136.3, 136.0,

135.6, 129.0, 128.9, 128.7, 128.5, 128.2, 128.2, 118.0, 114.5, 83.6, 80.2, 79.1, 67.3, 60.5,

+ 39.1, 34.8, 28.4, 22.4, 21.4; HRMS-ES+ (C23H28NO6) calcd 414.1917 (M+H ), found

96

414.1914.

Benzyl 5-(1-(Methoxymethoxy)allyl)-9-methyl-2-oxo-7a-vinylhexa hydro-4,7-ethanobenzo[d][1,3]dioxol-5-yl)carbamate (209). To a solution of the allylic alcohol isomers 208 (549 mg, 1.328 mmol) in 30 mL of formaldehyde dimethyl acetal and 15 mL of chloroform was added P2O5 (250 mg, excess). The resulting mixture was stirred at rt for 12 h. The reaction mixture was then washed thoroughly with NaHCO3 solution and back extracted with CH2Cl2. The combined organic layer was dried over

Na2SO4 and evaporated in vacuo to give the MOM-protected alcohol isomers 209 (522 mg, 86%) as a colorless oil which was used without further purification. 1H NMR (300

MHz, CDCl3) δ 7.34 (s, 5H), 6.09-5.99 (m, 1H), 5.69-5.67 (m, 1H), 5.46-5.40 (m, 1H),

5.32-5.26 (m, 2H), 5.04 (s, 2H), 4.82-4.78 (m, 1H), 4.64 (d, J = 9.0 Hz, 1H), 4.49 (d, J =

6.0 Hz, 1H), 4.24 (d, J = 9.0 Hz, 1H), 3.36 (s, 1H), 3.11 (s, 1H), 2.13-2.06 (m, 2H), 1.86-

13 1.82 (m, 1H), 1.65-1.46 (m, 2H), 1.20-1.13 (m, 3H); C NMR (75 MHz, CDCl3) δ 156.3,

155.7, 154.6, 154.5, 136.7, 136.4, 136.3, 133.5, 132.5, 128.9, 128.6, 128.5, 128.4, 122.5,

120.9, 117.8, 117.4, 94.2, 93.9, 84.5, 83.3, 81.1, 80.6, 80.4, 67.0, 60.3, 60.0, 56.6, 38.1,

37.0, 34.9, 34.8, 28.7, 28.5, 22.8, 22.1, 21.9, 21.7; HRMS-ES+ (C25H32NO7) calcd

458.2179 (M+H+), found 458.2179.

97

Benzyl (5-(((tert-Butyldiphenylsilyl)oxy)methyl)-9-methyl-2-phenyl-

7a-vinylhexahydro-4,7-ethanobenzo[d][1,3]dioxol-5-yl)carbamate (213). To a solution of diol 168 (1.910 g, 3.188 mmol) in 110 mL of DME were added p-TsOH

(0.061 g, 0.318 mmol) and PhCHO (2.0 mL, excess). The resulting mixture was stirred at

70 °C for 12 h. The reaction mixture was cooled to rt, the organic solvent was evaporated in vacuo and the resulting residue was purified by flash column chromatography (10%

EtOAc/hexanes) to give the benzylidene acetal 213 (1.790 g, 82%) as a colorless oil. 1H

NMR (300 MHz, CDCl3) δ 7.91-7.65 (m, 5H), 7.43-7.28 (m, 15H), 6.22-6.02 (m, 1H),

5.70 (s, 1H), 5.53 (d, J = 18.0 Hz, 1H), 5.27 (d, J = 12.0 Hz, 1H), 5.21-5.08 (m, 2H), 4.93

(s, 1H), 4.54 (s, 1H), 4.06 and 3.81 (ABq, J = 12.0 Hz, 2H), 2.58 (s, 1H), 2.26 (d, J =

12.0 Hz, 1H), 2.09-1.94 (m, 2H), 1.79-1.70 (m, 1H), 1.51 (t, J = 9.0 Hz, 1H), 1.37-1.32

13 (m, 1H), 1.18 (d, J = 6.0 Hz, 3H), 1.10 (s, 9H); C NMR (75 MHz, CDCl3) δ 155.3,

139.4, 136.8, 136.4, 135.8, 133.5, 133.4, 130.0, 129.3, 128.8, 128.5, 128.4, 128.3, 128.0,

127.1, 115.6, 100.9, 81.9, 78.7, 66.6, 65.6, 59.5, 39.7, 36.2, 31.3, 28.2, 27.1, 23.5, 21.9,

+ 19.6; HRMS-ES+ (C43H50NO5Si) calcd 688.3464 (M+H ), found 688.3458.

.

98

Benzyl (5-(Hydroxymethyl)-9-methyl-2-phenyl-7a-vinylhexahydro-

4,7-ethanobenzo[d][1,3]dioxol-5-yl)carbamate (214). To a solution of silyl ether 213

(54 mg, 0.078 mmol) in 5 mL of CH2Cl2 were added BF3·OEt2 (0.03 mL, 0.235 mmol) and 4-methoxysalicyladehyde (36 mg, 0.235 mmol) and the reaction mixture was stirred at rt for 10 min. The mixture was then washed with NaHCO3 solution and back extracted with CH2Cl2. The combined organic extract was dried over Na2SO4 and evaporated in vacuo. The residue was purified by flash column chromatography (25% EtOAc/hexanes)

1 to give the alcohol 214 (35 mg, 99%) as a colorless oil. H NMR (300 MHz, CDCl3) δ

7.60-7.59 (m, 2H), 7.39-7.16 (m, 8H), 6.09-6.00 (m, 1H), 5.60 (s, 1H), 5.45 (d, J = 18.0

Hz, 1H), 5.35-5.28 (m, 1H), 5.16-5.04 (m, 2H), 4.41-4.40 (m, 1H), 3.85-3.60 (m, 3H),

2.81 (s, 1H), 2.10 (br s, 1H), 2.04-1.89 (m, 2H), 1.59-1.46 (m, 3H), 1.19 (d, J = 6.0 Hz,

13 3H); C NMR (75 MHz, CDCl3) δ 156.4, 139.3, 136.4, 136.1, 129.4, 129.2, 128.9,

128.5, 128.5, 128.3, 128.1, 127.7, 127.1, 126.2, 116.7, 116.1, 100.7, 81.0, 79.2, 69.0,

67.2, 59.6, 59.3, 37.9, 35.8, 35.2, 34.9, 34.6, 28.4, 27.9, 23.7, 22.2, 22.0; HRMS-ES+

+ (C27H32NO5) calcd 450.2284 (M+H ), found 450.2280.

99

Benzyl (5-Formyl-2,9-dimethyl-7a-vinylhexahydro-4,7-ethanobenzo

[d][1,3]dioxol-5-yl)carbamate (215). To a solution of oxalyl chloride (0.631 mL, 7.340 mmol) in 30 mL of CH2Cl2 was added DMSO (0.782 mL, 11.019 mmol) at -78 °C. After

10 min, a solution of alcohol 214 (0.550 g, 1.220 mmol) in CH2Cl2 (20 mL) was added.

The solution was warmed to -40 °C over 1 h. Et3N (3.072 mL, 22.038 mmol) was added and the mixture was allowed to warm to rt. The solvent was evaporated and the residue was purified by flash column chromatography (25% EtOAc/hexanes) to give the

1 aldehyde 215 (0.542 g, 99%) as a colorless oil. H NMR (300 MHz, CDCl3) δ 9.56 (br s,

1H), 7.63-7.62 (m, 2H), 7.43-7.26 (m, 8H), 6.19-6.09 (m, 1H), 5.77 (s, 1H), 5.55 (d, J =

15.0 Hz, 1H), 5.34-5.30 (m, 1H), 5.15 (s, 2H), 4.18 (s, 1H), 2.55-2.50 (m, 2H), 2.18 (s,

1H), 1.99 (br s, 1H), 1.75-1.64 (m, 3H), 1.15 (s, 3H), 0.17 (s, 1H); 13C NMR (75 MHz,

CDCl3) δ 199.8, 155.9, 139.0, 136.3, 136.1, 129.8, 129.1, 128.8, 128.6, 127.3, 126.5,

116.4, 101.5, 82.0, 78.5, 78.0, 67.7, 63.9, 38.7, 36.2, 35.9, 29.2, 27.7, 24.0, 22.0, 21.8,

+ 1.5; HRMS-ES+ (C27H30NO5) calcd 448.2125 (M+H ), found 448.2124.

.

100

Benzyl (5-(1-Hydroxyallyl)-9-methyl-2-phenyl-7a-vinylhexahydro-4,7- ethanobenzo[d][1,3]dioxol-5-yl)carbamate (216). To a solution of aldehyde 215 (90 mg, 0.2 mmol) in 15 mL of THF was added 1 M vinylmagnesium bromide in THF (0.6 mL, 0.6 mmol) at -78 °C. The reaction mixture was stirred for 1 h at -78 °C and quenched with NH4Cl solution. The mixture was extracted with EtOAc. The extract was dried over

Na2SO4 and evaporated in vacuo. The resulting residue was purified by flash column chromatography (10% to 20% to 25% EtOAc/hexanes) to give the chromatographically separable allylic alcohols 216 in a 3:1 ratio (69 mg, 72%).

1 Less polar isomer 216: colorless oil; H NMR (300 MHz, CDCl3) δ 7.65-

7.63 (m, 2H), 7.43-7.29 (m, 8H), 6.14-6.04 (m, 1H), 5.94-5.86 (m, 1H), 5.66 (s, 1H),

5.54-5.42 (m, 2H), 5.37-5.29 (m, 2H), 5.20 (d, J = 12.0 Hz, 2H), 5.07-5.03 (m, 1H), 4.74

(s, 1H), 4.44 (s, 1H), 4.32 (d, J = 6.0 Hz, 1H), 3.25 (s, 1H), 2.20 (s, 1H), 2.08-2.05 (m,

13 2H), 1.70-1.66 (m, 2H), 1.30-1.28 (m, 4H); C NMR (75 MHz, CDCl3) δ 157.5, 139.2,

136.8, 136.2, 136.0, 129.3, 128.7, 128.5, 128.4, 128.2, 128.0, 127.1, 126.1, 117.1, 116.0,

100.5, 80.3, 79.0, 78.1, 67.4, 61.4, 37.4, 37.0, 35.8, 27.8, 23.3, 21.9; HRMS-ES+

+ (C29H34NO5) calcd 476.2437 (M+H ), found 476.2437.

1 More polar isomer 216: colorless oil; H NMR (300 MHz, CDCl3) δ 7.63-

7.62 (m, 2H), 7.40-7.32 (m, 8H), 6.12-5.94 (m, 2H), 5.73-5.62 (m, 1H), 5.54-5.46 (m,

1H), 5.44-4.92 (m, 6H), 4.48-4.33 (m, 2H), 4.02 (br s, 1H), 2.53-2.50 (m, 1H), 2.13-2.02

13 (m, 5H), 1.66-1.63 (m, 1H), 1.20-1.12 (m, 3H); C NMR (75 MHz, CDCl3) δ 157.0,

139.0, 136.8, 136.5, 136.2, 129.3, 128.7, 128.6, 128.4, 128.3, 127.3, 127.1, 127.0, 126.2,

117.1, 115.5, 100.9, 81.2, 79.2, 78.8, 67.0, 61.4, 40.3, 36.1, 35.7, 32.8, 28.0, 23.7, 21.7;

+ HRMS-ES+ (C29H34NO5) calcd 476.2437 (M+H ), found 476.2439.

101

.

Benzyl (5-(1-(Methoxymethoxy)allyl)-9-methyl-2-phenyl-7a-vinylhexa hydro-4,7-ethanobenzo[d][1,3]dioxol-5-yl)carbamate (217). To a solution of the less polar allylic alcohol isomer 216 (49 mg, 0.103 mmol) in 10 mL of formaldehyde dimethyl acetal and 5 mL of chloroform was added P2O5 (100 mg, excess). The resulting mixture was stirred at rt for 12 h. The reaction mixture was then washed thoroughly with

NaHCO3 solution and back extracted with CH2Cl2. The combined organic layer was dried over Na2SO4 and evaporated in vacuo to give the MOM-protected alcohol 217 (43 mg,

98%) as colorless oil which was used without further purification. The same procedure was used for MOM protection of the more polar allylic alcohol 217 in comparable yield.

1 Less polar isomer 217: colorless oil; H NMR (300 MHz, CDCl3) δ 7.63-

7.58 (m, 2H), 7.41-7.29 (m, 8H), 6.17-6.05 (m, 1H), 5.90-5.63 (m, 2H), 5.48-5.37 (m,

2H), 5.26-5.24 (m, 1H), 5.18-5.14 (m, 2H), 5.07-4.89 (m, 1H), 4.74-4.72 (m, 2H), 4.60-

4.53 (m, 2H), 4.34-4.32 (m, 1H), 3.40 (s, 1H), 2.72 (m, 2H), 2.07-2.01 (m, 3H), 1.67-1.63

13 (m, 1H), 1.47 (d, J = 15.0 Hz, 1H), 1.26-1.15 (m, 3H); C NMR (75 MHz, CDCl3) δ

155.4, 139.2, 137.0, 136.4, 133.4, 129.2, 128.7, 128.4, 127.1, 126.3, 121.2, 115.1, 100.9,

93.8, 81.6, 81.2, 79.3, 66.4, 61.0, 56.4, 53.7, 40.4, 36.2, 36.0, 29.5, 28.5, 23.0, 21.9;

+ HRMS-ES+ (C31H38NO6) calcd 520.2699 (M+H ), found 520.2704.

1 More polar isomer 217: colorless oil; H NMR (300 MHz, CDCl3) δ 7.61-

102

7.60 (m, 2H), 7.38-7.28 (m, 8H), 6.17-6.08 (m, 1H), 5.87-5.69 (m, 1H), 5.59 (s, 1H), 5.44

(d, J = 18.0 Hz, 1H), 5.29 (d, J = 9.0 Hz, 1H), 5.23-5.18 (m, 2H), 5.07 (s, 2H), 4.71-4.66

(m, 2H), 4.50 (d, J = 6.0 Hz, 1H), 4.32-4.29 (m, 1H), 4.18 (d, J = 6.0 Hz, 1 H), 3.37 (s,

3H), 3.08 (s, 1H), 2.07-1.97 (m, 2H), 1.92-1.77 (m, 2H), 1.58 (s, 2H), 1.13 (d, J = 6.0 Hz,

13 3H); C NMR (75 MHz, CDCl3) δ 156.0, 139.7, 137.0, 136.7, 134.1, 129.3, 128.8,

128.5, 128.4, 127.2, 126.4, 120.1, 115.3, 101.0, 94.1, 85.1, 81.2, 79.7, 66.6, 60.8, 56.4,

+ 38.7, 37.8, 36.3, 28.4, 23.7, 21.8; HRMS-ES+ (C31H38NO6) calcd 520.2699 (M+H ), found 520.2684.

Benzyl (5-(1-(Methoxymethoxy)-4-oxobutyl)-9-methyl-7a-(3-oxo propyl)-2-phenylhexahydro-4,7-ethanobenzo[d][1,3]dioxol-5-yl)carbamate (218). To a solution of the less polar amino diene 217 (63.0 mg, 0.121 mmol) in 6.5 mL of PhMe and 6.5 mL of THF in a pressure reactor were added Rh(CO)2(acac) (4.6 mg, 0.018 mmol) and biphephos (28.6 mg, 0.036 mmol). The reactor was sealed, pressurized with carbon monoxide (350 psi) and hydrogen (350 psi), heated in an oil bath at 125 °C for 8 h, and then cooled to rt. The gasses were vented in a fume hood and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography (1:2:2

EtOAc/CH2Cl2/hexanes) to give the dialdehyde 218 (50.0 mg, 71%) as a colorless oil.

103

The same procedure was used for the hydroformylation of the more polar amino diene

217 in comparable yield.

1 Less polar isomer 218: colorless oil; H NMR (300 MHz, CDCl3) δ 9.75

(s, 1H), 9.74 (s, 1H), 7.54-7.53 (m, 2H), 7.37-7.26 (m, 8H), 5.67 (s, 1H), 5.06 (q, 2H),

4.65-4.59 (m, 2H), 4.52 (d, J = 6.0 Hz, 1H), 4.23 (s, 1H), 3.76 (d, J = 9.0 Hz, 1H), 3.37

(s, 3H), 2.68-2.62 (m, 3H), 2.52-2.49 (m, 2H), 2.05-2.03 (m, 4H), 1.87-1.85 (m, 2H),

1.63-1.57 (m, 2H), 1.44 (d, J = 15.0 Hz, 1H), 1.27-1.25 (m, 1H), 1.11 (d, J = 6.0 Hz, 3H);

13 C NMR (75 MHz, CDCl3) δ 202.5, 202.4, 155.8, 136.9, 136.3, 129.4, 128.8, 128.6,

128.5, 127.2, 100.7, 97.9, 83.2, 81.8, 66.7, 62.4, 56.5, 41.0, 39.2, 33.3, 30.0, 28.4, 27.3,

+ 23.9, 23.2, 21.3; HRMS-ES+ (C33H42NO8) calcd 580.2910 (M+H ), found 580.2894.

1 More polar isomer 218: colorless oil; H NMR (300 MHz, CDCl3) δ 9.79

(s, 1H), 9.64 (s, 1H), 7.55-7.54 (m, 2H), 7.37-7.26 (m, 8H), 5.68 (s, 1H), 5.08 (s, 2H),

4.75 (s, 1H), 4.65-4.58 (m, 2H), 4.16 (s, 1H), 3.79-3.76 (m, 1H), 3.37 (s, 3H), 3.10 (s,

1H), 2.66-2.55 (m, 1H), 2.50-2.48 (m, 2H), 2.09-2.07 (m, 1H), 2.02-1.91 (m, 2H), 1.87-

1.85 (m, 1H), 1.79-1.74 (m, 3H), 1.27-1.25 (m, 3H), 1.17-1.15 (m, 1H), 0.87-0.85 (m,

13 3H); C NMR (75 MHz, CDCl3) δ 202.3, 156.4, 137.0, 136.5, 129.3, 128.8, 128.6,

128.4, 127.1, 100.7, 98.5, 87.2, 82.0, 80.7, 66.8, 61.4, 56.5, 40.4, 39.3, 39.2, 38.0, 33.2,

+ 30.0, 28.1, 27.5, 24.0, 23.6, 21.9; HRMS-ES+ (C33H42NO8) calcd 580.2910 (M+H ), found 580.2891.

104

11-(Methoxymethoxy)-13-methyl-2-phenyloctahydro-4H-11a,3a,12- epibutane[1,2,4]triyl)[1,3]dioxolo[4,5-d]pyrido[1,2-a]azocine (220). To a solution of the less polar dialdehyde 218 (95 mg, 0.164 mmol) in 22 mL of EtOAc were added 10%

Pd/C (95 mg, 0.089 mmol) and glacial AcOH (0.03 mL). The suspension was stirred for

40 h under 1 atm of H2. The reaction mixture was filtered through a Celite pad and the filtrate was evaporated in vacuo. The residue was dissolved in EtOAc and washed with saturated aqueous NaHCO3. The organic layer was then dried over Na2SO4 and evaporated in vacuo. The resulting residue was purified by flash column chromatography

(50% EtOAc/hexanes) to give the tetracyclic amine 220 (53 mg, 70%) as colorless oil.

The same procedure was used for the intramolecular reductive amination of the more polar amino dialdehyde 218 in comparable yield.

1 Less polar isomer 220: colorless oil; H NMR (300 MHz, CDCl3) δ 7.62-

7.58 (m, 2H), 7.40-7.35 (m, 3H), 5.62 (s, 1H), 4.67 and 4.57 (ABq, J = 6.0 Hz, 2H), 4.35

(d, J = 6.0 Hz, 1H), 3.41-3.36 (m, 5H), 2.97-2.91 (m, 1H), 2.76 (d, J = 6.0 Hz, 1H), 2.66-

2.56 (m, 3H), 2.11-2.08 (m, 1H), 2.00-1.85 (m, 7H), 1.70-1.57 (m, 2H), 1.53-1.49 (m,

13 3H), 1.14 (d, J = 6.0 Hz, 3H); C NMR (75 MHz, CDCl3) δ 137.1, 136.8, 129.3, 128.6,

127.4, 100.8, 100.4, 96.4, 94.9, 82.8, 82.5, 81.8, 80.8, 61.3, 56.3, 56.1, 50.6, 49.6, 37.9,

37.4, 37.2, 33.2, 31.4, 30.0, 29.6, 28.3, 27.8, 26.8, 25.9, 23.1, 22.3, 22.3, 22.1, 21.5;

+ HRMS-ES+ (C25H36NO4) calcd 414.2644 (M+H ), found 414.2633.

105

1 More polar isomer 220: colorless oil; H NMR (300 MHz, CDCl3) δ 7.60-

7.59 (m, 2H), 7.37-7.25 (m, 3H), 5.62 (s, 1H), 4.67 and 4.57 (ABq, J = 6.0 Hz, 2H), 4.35

(s, 1H), 3.65-3.39 (m, 5H), 2.99-2.97 (m, 1H), 2.76-2.75 (m, 1H), 2.71-2.51 (m, 3H),

2.11-2.09 (m, 1H), 1.93-1.63 (m, 7H), 1.25-1.15 (m, 2H), 1.13-1.01 (m, 3H), 0.95 (d, J =

13 6.0 Hz, 3H); C NMR (75 MHz, CDCl3) δ 137.2, 129.4, 128.7, 127.5, 100.9, 96.5, 82.9,

82.0, 80.9, 61.4, 56.2, 53.8, 50.7, 49.7, 38.0, 37.5, 37.3, 32.3, 31.2, 30.1, 29.8, 28.4, 27.9,

26.9, 26.0, 23.1, 22.4, 22.2, 21.6, 14.5; HRMS-ES+ (C25H36NO4) calcd 414.2644

(M+H+), found 414.2636.

1-(Methoxymethoxy)-12-methyldodecahydro-9,10,13a-dimethano pyrido[1,2-a]azecine-9,15-diol (221). To a solution of mixture of diastereomers of benzylidene acetal 220 (55 mg, 0.133 mmol) in 10 mL of THF at -78 °C was added sodium metal (~31 mg, 1.330 mmol) and liquid ammonia (~10 mL). The solution was stirred at -78 °C for 10 min and quenched with excess MeOH. The mixture was evaporated in vacuo and the residue was dissolved in EtOAc and washed with saturated aqueous NaHCO3. The organic layer was then dried over Na2SO4 and evaporated in vacuo. The resulting residue was subjected to flash column chromatography (10%

MeOH/dichloromethane) to give a mixture of diastereomers of diol 221 (43.2 mg) as an

106 impure colorless oil.

1 H NMR (300 MHz, CDCl3) δ 4.74-4.67 (m, 1H), 4.59 (d, J = 6.0 Hz,

1H), 4.22 (s, 1H), 3.85-3.83 (m, 3H), 3.69-3.55 (m, 2H), 3.40 (s, 3H), 3.10-3.03 (m, 1H),

2.90-2.87 (m, 1H), 2.69-2.57 (m, 1H), 2.55-2.41 (m, 2H), 2.05-1.89 (m, 2H), 1.82-1.74

(m, 2H), 1.69-1.64 (m, 4H), 1.55-1.51 (m, 2H), 1.18 (s, 1H), 0.91 (d, J = 6.0 Hz, 3H),

13 0.70 (d, J = 6.0 Hz, 3H); C NMR (75 MHz, CDCl3) δ 96.2, 95.1, 81.3, 78.0, 76.8, 75.6,

71.5, 70.2, 62.8, 56.4, 56.1, 50.0, 48.8, 41.0, 40.1, 39.6, 31.7, 31.3, 30.0, 29.8, 29.6, 27.3,

+ 26.2, 22.7, 21.5, 21.2; HRMS-ES+ (C18H32NO4) calcd 326.2331 (M+H ), found

326.2320.

1,9-Dihydroxy-12-methyldodecahydro-9,10,13a-dimethanopyrido

[1,2-a]azecin-15-one (222). To a solution of a mixture of diastereomers of diol 221 (43.2 mg, 0.132 mmol) in 30 mL of EtOAc at rt was added IBX (371.0 mg, 1.320 mmol). The reaction mixture was stirred at rt for 90 min and filtered through a pad of Celite. The filtrate was evaporated in vacuo to obtain the corresponding ketoalcohol. The ketoalcohol was dissolved in 5 mL of THF and 0.5 mL of 6 M HCl was added. The reaction mixture was heated at 55 °C for 90 min. The mixture was evaporated in vacuo. The residue dissolved in EtOAc and washed with saturated aqueous NaHCO3. The organic layer was

107 then dried over Na2SO4 and evaporated in vacuo. The resulting residue was subjected to flash column chromatography (10% MeOH/dichloromethane) to give the impure triol 221

1 (5.2 mg, ~14% yield from 220) as a colorless oil. H NMR (300 MHz, CDCl3) δ 4.76 (d,

J = 6.0 Hz, 1H), 4.60 (d, J = 9.0 Hz, 1H), 3.77 (s, 1H), 3.07-3.02 (m, 2H), 2.92-2.88 (m,

3H), 2.57-2.51 (m, 3H), 2.18-2.10 (m, 3H), 2.06-2.04 (m, 2H), 1.94-1.78 (m, 5H), 0.88

13 (d, J = 12.0 Hz, 4H); C NMR (75 MHz, CDCl3) δ 207.4, 94.9, 73.5, 70.6, 68.3, 60.7,

57.2, 56.6, 46.2, 31.3, 30.9, 30.0, 29.7, 28.1, 27.7, 25.9, 23.1, 22.8, 21.7, 21.4, 14.5;

+ LRMS (EI) (C16H26NO3) calcd 280.2 (M+H ), found 280.2.

12-Methyldodecahydro-9,10,13a-dimethanopyrido[1,2-a]azecine-

1,9,15-triol (223). To a solution of a mixture of the diastereomers of benzylidene acetal

220 (25 mg, 0.060 mmol) in 5 mL of THF at -78 °C was added sodium metal (~15 mg,

0.665 mmol) and liquid ammonia (~5 mL). The solution was stirred at -78 °C for 10 min and quenched with excess MeOH. The mixture was evaporated in vacuo. The residue was dissolved in EtOAc and washed with saturated aqueous NaHCO3. The organic layer was then dried over Na2SO4 and evaporated in vacuo. The resulting residue was dissolved in 5 mL of THF and 0.5 mL of 6M HCl was added. The reaction mixture was heated at 55 °C for 90 min, and was evaporated in vacuo. The residue was dissolved in EtOAc and

108 washed with saturated aqueous NaHCO3. The organic layer was then dried over Na2SO4 and evaporated in vacuo. The resulting residue was subjected to flash column chromatography (10% MeOH/dichloromethane) to give the triol 221 (6 mg, ~35% yield

1 from 220) as an impure colorless oil. H NMR (300 MHz, CDCl3) δ 4.23-4.15 (m, 1H),

3.76-3.66 (m, 1H), 3.61-3.56 (m, 1H), 3.50 (s, 1H), 3.33 (s, 1H), 3.30-3.28 (m, 1H), 2.90-

2.89 (m, 2H), 2.66-2.63 (m, 2H), 2.50 (d, J = 3.0 Hz, 1H), 2.26-2.21 (m, 1H), 2.10-2.06

(m, 1H), 1.99-1.92 (m, 1H), 1.86-1.81 (m, 3H), 1.76-1.73 (m, 3H), 1.57-1.54 (m, 2H),

1.18 (d, J = 3.0 Hz, 3H), 0.89-0.87 (m, 2H); LRMS (EI) (C16H28NO3) calcd 282.2

(M+H+), found 282.2.

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52. Toyota, M.; Odashima, T.; Wada, T.; Ihara, M. J. Am. Chem. Soc. 2000, 122,

9036.

53. Kinsman, A. C.; Kerr, M. A. Org. Lett. 2001, 3, 3189.

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58. Bernady, K. F.; Floyd, M. B.; Poletto, J. F.; Weiss, A. H. J. Org. Chem. 1979,

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1990, 112, 2998.

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63. Gold, E. H.; Babad, E. J. Org. Chem. 1972, 37, 2208.

64. Atwell, G. J.; Denny, W. A. Synthesis 1984, 1032.

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115

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72. Vedejs, E.; Lin, S. J. Org. Chem. 1994, 59, 1602.

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116

85. Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem.

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117

Part II - Synthesis of the Tetracyclic Core of the Apparicine Class of

Indole Alkaloids via a Key Intermolecular Nitrosoalkene Conjugate

Addition

Chapter 1 - Introduction and Background

1.1 Apparicine Class of Indole Alkaloids

Monoterpenoid indole alkaloids, having a basic skeletal feature of a C9 or C10 terpene unit attached to a tryptamine moiety, constitute one of the largest classes of natural products obtained from higher plants.1 The structural diversity and biological activity of these alkaloids have made them attractive targets for synthetic organic chemists.2 A small subgroup of monoterpene indole alkaloids, possessing the rare feature of only one of the usual two carbons of the tryptamine-derived side chain, is known as the “apparicine-class” of indole alkaloids after the simplest member of the group, (-) apparicine (1, Figure 1).3

Apparicine (1), the first member of this class to be isolated from Aspidosperma dasycarpon in 1965,3a has been shown to have both antimicrobial and antiviral activity.4

The alkaloid has a unique bridged 1-azabicyclo[4.2.2]decane framework fused to an indole ring, which was later found in a number of other monoterpenoid indole alkaloids.3b

For example, the vallesamines (2, 3) were isolated from Vallesia dichotoma in 1965.5

Some related, more highly oxidized alkaloids having a ring skeleton similar to apparicine, including (+)-ervaticine (4),6 (+)-conolidine (5),7 (+)-16-hydroxy-16,22- dihydroapparicine (6),8 (+)-alstonamine (7),9 and (+)-angustilobine A (8)10 have also

118 been found in various plants. These alkaloids show a wide range of biological activity as listed below (Figure 1).

Figure 1. Structures of some members of the apparicine class of indole alkaloids.

1.2 Biosynthesis of the Apparicine Class of Indole Alkaloids

It has been proposed that the apparicine class of indole alkaloids originate biogenetically from stemmadenine (9) by the loss of one of the two carbons of the tryptamine unit (Scheme 1).11 Thus, oxidation of the tertiary nitrogen of stemmadenine

(9) gives stemmadenine N-oxide (10), which undergoes a Potier-Polonovski

119 fragmentation to form azafulvene iminium intermediate 11.11c Loss of the iminium carbon from intermediate 11 followed by intramolecular Mannich-type addition of amino azafulvene 12 generates the alkaloid (E)-vallesamine (2). Other members of the apparicine class of alkaloids could be obtained by further dehydration, decarboxylation, and/or oxidative ring closures of (E)-vallesamine (2). (-)-Apparicine (1) would be obtained by a dehydrative decarboxylation of (E)-vallesamine (2).

Scheme 1.

To support the biosynthetic hypothesis, partial synthesis of vallesamine (2, 3) from stemmadenine (9) has been achieved.12 It has also been shown by isotopic feeding experiments that apparicine (1) can be obtained from both radio-labeled stemmadenine

(9) and (E)-vallesamine (2).11a,b

120

1.3 Previous Approaches Towards Synthesis of the Apparicine Class of Indole

Alkaloids

1.3.1 Joule approach to the tetracyclic core of apparicine (1)

In 1977, the first synthetic approach towards a member of the apparicine family of alkaloids was reported by Joule and coworkers, who were able to construct the model tetracyclic ring skeleton 18 of apparicine in moderate yield using a key intramolecular

Mannich reaction of simple piperidinyl indole 13b followed by hydrolysis of ketal 17

(Scheme 2).13 It was found that the presence of ketal functionality at C-16 of piperidinyl indole 13b was necessary, presumably to enforce the required reactive twist boat conformation 16 for the intramolecular Mannich reaction. In a system without the ketal functionality at C-16 (i.e. indole 13a), the indole moiety in the most stable twist boat conformation 14 is remote from the iminium ion due to steric effects, and therefore the 8- membered ring 15 cannot form via a Mannich reaction.

121

Scheme 2.

However, this approach proved unsuitable to construct the natural product apparicine (1), since the intramolecular Mannich reaction did not work in a system having the requisite functionality in the piperidine ring at C-20.

1.3.2 Bennasar total synthesis of (±)-apparicine (1)

In 2009, Bennasar et al. completed the first total synthesis of racemic apparicine (1) more than 40 years after the original isolation of this alkaloid.14 The key step in this synthesis involved an intramolecular Heck cyclization to form the bridged piperidine ring

(vide infra).

A ring closing metathesis reaction of diene 19 was used to form the cyclic alkene 21, followed by basic isomerization of the disubstituted alkene 21 to synthesize the key azocinoindole intermediate 22 having the ABC ring skeleton of apparicine (Scheme 3).

122

Scheme 3.

It was also possible to obtain the key azocinoindole intermediate 22 using a radical cyclization route in which the methyl ester 23 was first converted to selenoester

24 in good yield (Scheme 4). The selenoester 24 then underwent intramolecular acyl radical cyclization to give 8-membered tricyclic ketone 25 on treatment with n-Bu3SnH and Et3B. Finally, the tricyclic ketone 25 was treated with MeLi in THF, followed by acid catalyzed dehydration to obtain the trisubstituted alkene 22.

Scheme 4.

123

To complete the total synthesis of (±)-apparicine (1), the Boc-protected amine 22 was deprotected by treatment with HCl, followed by N-alkylation of the free amine with allylic tosylate 26 to give tertiary amine 27 in moderate yield (Scheme 5). Finally, the vinyl iodide 27 was cyclized using a Heck reaction to obtain the natural product (±)- apparicine (1), but only in low yield.

Scheme 5.

1.3.3. Joule formal total synthesis of apparicine

After the publication of a total synthesis of apparicine (1) by the Bennasar group in 2009, Joule reported a formal total synthesis of the alkaloid using an intramolecular

Mannich reaction as a key step to form the ABC rings of apparicine (1).15

Thus, the N-protected indole 28 was lithiated at C-2, followed by treatment with

N-sulfonyl pyrrolidone 29 to give the ketone 30 in moderate yield (Scheme 6). The sulfonamide 30 was alkylated using butynyl bromide 31 to give the N-alkylated product

32 in quantitative yield. Methylmagnesium chloride was added to the ketone 32 to obtain the tertiary alcohol, followed by deprotection of the amine and indole to yield the free indole amine 33. The alkyne 33 was then regio- and stereoselectively hydrostannylated to

124 yield vinyl stannane 34, followed by ipso-displacement of tin with iodine to give vinyl iodide 35 with retention of olefin configuration. Next, the indole 35 was subjected to high dilution intramolecular Mannich conditions with formaldehyde to give the ABC tricycle

36 of apparicine. Finally, the tertiary alcohol 36 was dehydrated to give the trisubstituted alkene 27, prepared previously by Bennasar, thereby completing a formal total synthesis of racemic apparicine.

Scheme 6.

125

Scheme 6.

1.3.4. Micalizio total synthesis of (±)-conolidine (5)

In 2011, Micalizio and coworkers completed the first total synthesis of (±)- conolidine (5), a potent non-opoid analgesic for tonic and persistent pain.16 Their synthesis was also based on an intramolecular Mannich reaction to form the azocane C- ring of alkaloid using piperidyl indole 43 (Scheme 7).

The synthesis of conolidine (5) began with commercially available pyridine 37, that was alkylated wth PMBCl and reduced with NaBH4 to form allylic alcohol 38. The allylic alcohol 38 was converted to the corresponding tributylstannylmethyl ether, followed by treatment with n-BuLi to initiate a [2,3]-Wittig rearrangement to form the desired E-alkene isomer 39 in good yield and with high selectivity. The alcohol 39 was oxidized and treated with lithiated indole 41 to obtain alcohol 42. The piperidyl indole 42 was globally deprotected and oxidized to form the intramolecular Mannich reaction precursor 43. Finally treatment of piperidyl indole 43 with TFA and paraformaldehyde in acetonitrile gave conolidine (5) in very good yield. It was believed that the presence of an

(E)-C-19/20 ethylidene group on the piperidine ring of piperidyl indole 43 helped to obtain the required reactive twist boat conformation needed for the intramolecular

126

Mannich reaction (cf. structure 16). Micalizio and coworkers were also able to complete an asymmetric syntheses of both (+)- and (-)-conolidine (5) using the identical reaction sequence by resolution of racemic alcohol 38.16

Scheme 7.

1.3.5 Omura/Sunazuka synthesis of (±)-16-hydroxy-16,22-dihydroapparicine (6)

In 2013 Omura, Sunazuka, et al. completed the first total synthesis of (±)-16- hydroxy-16,22-dihydroapparicine (6), an alkaloid which was shown to have antimalarial activity.17 Their synthesis was based on the hypothesis that the core structure of the

127 alkaloid could be obtained using a phosphinimine-mediated cascade reaction of azide 48

(Scheme 8), via the following sequence: 1) Staudinger reaction of azide 48 with PPh3 to form 47; 2) intramolecular N-alkylation of 47 to form the piperidine ring of 46; 3) aza-

Wittig reaction of 46 with formaldehyde to give 45; 4) an intramolecular Mannich reaction of indolyl iminium ion 45 to form the alkaloid 6. The precursor 48 for the cascade reaction would be obtained by 1,2-addition of C-2 lithiated indole 49 to methyl ketone 50.

Scheme 8.

128

The synthesis began with Michael addition of extended enolate 52 to known carboximide 51 to give Michael adduct 53 in moderate yield but with no diastereoselectivity (Scheme 9). The disubstituted alkene 53 was converted to the more stable trisubstituted E-alkene 54 via DBU-mediated isomerization. Imide 54 was reduced

. using NaBH4 and CeCl3 7H2O to obtain the corresponding primary alcohol which was further converted to tosylate 55 in good overall yield. The thioester 55 was reduced using a two-step sequence to afford the allylic alcohol 56 in good yield. The tosylate 56 was treated with NaN3 in DMSO followed by protection of the hydroxyl group with PivCl to form allyl pivalate 57 in excellent yield. The benzyl ether 57 was oxidatively cleaved to form a primary alcohol which was further oxidized to aldehyde 58. Aldehyde 58 was then treated with MeMgBr in THF followed by Dess-Martin oxidation to give methyl ketone

50 in good yield.

Scheme 9.

129

Scheme 9.

To continue the synthesis, the methyl ketone 50 was treated with the lithiated indole derived from iodide 49 to obtain the 1,2-addition product 59 with high diastereoselectivity (d.r. = >20:1) (Scheme 10). The TBSOM group was removed from indole 59 using TBAF and the pivalate group was reductively cleaved to obtain indolyl alcohol 60. The alcohol 60 was treated with 2-chloro-3-nitropyridine to give the azide precursor 48 for the cascade reaction sequence. The azide 48 was then treated with PPh3, followed by acetic acid and finally with aq. HCHO and PPTS to yield the alkaloid (±)-16- hydroxy-16,22-dihydroapparicine (6) in good overall yield.

130

Scheme 10.

131

Chapter 2 - Synthesis of the Tetracyclic Core of the Apparicine Class of Indole

Alkaloids

We became interested in developing an efficient approach to the apparicine alkaloids based on our previous studies on the inter- and intramolecular conjugate addition of carbon nucleophiles to nitrosoalkenes.18 We have recently reported an approach to the total syntheses of the angustolidine class of monoterpenoid indole alkaloids based on a nitrosoalkene/enolate conjugate addition as a key step (vide infra).19

We believed that if we could form the tetracyclic alkaloid core 61 which has appropriate handles in place at C-16 and C-20, we would be able to easily access a number of the members of the apparicine class of indole alkaloids (Figure 2). This part of the thesis focuses on our progress towards the formation of the tetracyclic core of the apparicine class of indole alkaloids.

132

Figure 2. A unified approach to apparicine alkaloids

2.1 Nitrosoalkenes: Introduction and Background

Nitrosoalkenes 62 are highly reactive, typically unstable species which have been known for over a hundred years (Figure 3).20 These intermediates contain a nitroso group in conjugation with a C-C double bond. Due to their high reactivity, only a few electron

133 deficient nitrosoalkenes, such as fluorinated nitrosoalkene (63),21 and bulky t-alkyl or aryl substituted nitrosoalkenes (64)22 and (65)23 have been isolated or observed under ordinary reaction conditions. Nitrosoalkenes can react with variety of nucleophiles as Michael acceptors and can also participate in cycloaddition reactions as both dienes or dienophiles.20

Despite being known for over a century, these intermediates have been used only sporadically in synthetic organic chemistry.

Figure 3. Nitrosoalkenes

2.2 Methods of Generation of Nitrosoalkenes

The most commonly used method to generate nitrosoalkenes is by treating α- chlorooximes 66 with base (Scheme 11).20 Nitrosoalkenes used as Michael acceptors can also be obtained using two equivalents of a nucleophile, where one equivalent is used as a base for the eliminaion step to generate nitrosoalkene 68, while other equivalent adds to form the Michael addition product 69. However, this method is not efficient if the nucleophile is expensive or difficult to obtain. A less frequently used method was developed by Denmark,24 where fluoride-mediated desilylation of α-chloro-O- silyloximes 67 generates nitrosoalkene 68, which reacts in situ with one equivalent of a nucleophile to form the Michael adduct 69.

134

Scheme 11.

2.3 Previous Applications of Nitrosoalkene/Enolate Conjugate Additions as a Key

Step in Natural Product Synthesis by the Weinreb Group

The Weinreb group recently applied an intermolecular nitrosoalkene/enolate

Michael-type conjugate addition as a key step in syntheses of the angustilodine class of monoterpenoid indole alkaloids including (±)-angustilodine (70), (±)-alstilobanine E (71) and (±)-alstilobanine A (72) (Figure 4).19 Angustilodine (70) was first isolated by Kam and Choo from the Malayan plant Alstonia angustiloba in 2004.25 More recently in 2008,

Morita and coworkers isolated the N-demethyl analogue of angustilodine (70), alstilobanine E (71) and alstilobanine A (72) from the same plant.26 Alstilobanine E (71) and A (72) were shown to have modest relaxant activity against phenylepherine-induced contractions of thoracic rat aortic rings, but no biological activity has yet been reported for angustilodine (70).26

135

Figure 4. Angustilodine Class of Monoterpenoid Indole Alkaloids

The synthetic plan was to obtain the three alkaloids 70-72 via a key pentacyclic β- lactone intermediate 73 which has suitable handles for elaboration at C16 and C19

(Scheme 12). The C- and E-rings of pentacyclic β-lactone 73 would be generated via a

Romo-type intramolecular nucleophile-assisted aldol-lactonization of keto-acid 74, which would be produced from tricyclic indole 75.27 The indole ABD tricycle 75 could be derived via an intermolecular conjugate addition of the enolate of known indole-2-acetate

(76)28 to the D-ring nitrosoalkene 77, obtained from the α-chlorooxime 78.29

136

Scheme 12. Retrosynthesis of the angustilodine class of monoterpenoid indole alkaloids

To begin the synthesis, Max Majireck found that when -chlorooxime 80

(1 equiv) was added dropwise to a solution of the monoanion of the free indole 79 (2 equiv) at -78 °C, the Michael adduct 83 was obtained in 59% yield with the remainder of the unreacted starting indole 79 being recovered (Scheme 13).29 The Michael adduct 83 was an inconsequential 3:1 mixture of C-15/16 diastereomers, but as single (E)-oxime geometric isomers.

137

Scheme 13.

With the Michael adduct 83 in hand, Majireck explored introduction of the acetic acid unit at the C-3 position of indole 83 to obtain the precursor 74 for the proposed

Romo cyclization (vide supra). Unfortunately a number of attempts to introduce the requisite acetate unit into indole 83 proved unsuccesful.

At this point Majireck decided to try an alternative, potentially more efficient approach to synthesize the Romo cyclization precursor 74. The plan was to have a 2- carbon unit already installed at C-3 of the indole substrate prior to the nitrosoalkene/ester enolate conjugate addition reaction (Scheme 14).19 Thus, the indole 79 was first treated with oxalyl chloride at 0 °C, followed by addition of 2-trimethylsilylethanol and triethylamine to obtain oxoacetate indole diester 84 in high yield. The indole oxoacetate derivative 84 was converted to the dianion 85 followed by addition of one equivalent of the α-chloro-oxime 80 to obtain the Michael adduct 88 as a 1.2:1 mixture of C15, C16 diastereomers in excellent yield, with the oxime geometry of each being exclusively (E).

138

Mechanistically, it was believed that the indole dianion 85 initially deprotonates the α-chlorooxime 80, followed by 1,4-elimination of chloride ion to give an indole monoanion and the transient nitrosoalkene 82. The indole monoanion is probably an equilibrium mixture of 86 and 87. However, attack of this anion mixture on the nitrosoalkene 82 occurs exclusively via ester enolate 87 to give the Michael adduct 88.

Scheme 14.

The Michael adduct 88 was then used to synthesize the three monoterpenoid indole alkaloids (±)-angustilodine (70), (±)-alstilobanine E (71) and (±)-alstilobanine A

(72) via the pentacyclic β-lactone 89 in about 20 steps overall (Scheme 15).19

139

Scheme 15.

2.4 First Generation Strategy to the Tetracyclic Apparicine Core 61

In our retrosynthetic plan, we proposed that the tetracyclic core 61 of the apparicine class of indole alkaloids could be approached using an intramolecular

Mannich reaction of the iminium ion 90 to form the azocane C-ring (Scheme 16). We hoped that the presence of the large carbomethoxy group at C-16, and/or the oxime at C-

20 acting as a pseudoethylidene group (cf. Scheme 7) would help the indolyl iminium ion

90 achieve the requisite twist boat conformation shown to facilitate the desired ring closure. The indole tricycle 91 could be prepared via intermolecular conjugate addition of the enolate of known methyl indole-2-acetate (92) to the D-ring nitrosoalkene 93 obtained from the α-chlorooxime 94.

140

Scheme 16.

2.5 Results and Discussion

In order to study the key intermolecular conjugate addition reaction of the enolate of indole ester 92 to nitrosoalkene 93, we began our studies with the synthesis of 4- chloro-ketopiperidine 96. Majireck had been able to synthesize the desired ketone 96 from N-tosyl-3-piperidone (95) in 73% yield using 1.1 equiv. of freshly purchased sulfuryl chloride. A minor amount of undesired 2-chloro-ketone 97 was also formed, but the desired isomer 96 could be purified using column chromatography (Scheme 17).29

141

Scheme 17.

However, this reaction proved difficult to reproduce using older samples of sulfuryl chloride. It was found that the reaction often did not go to completion and multiple equivalents of sulfuryl chloride were thus required. Due to these problems, we were prompted to find a more reliable method for α-chlorination of 3-piperidone systems.

Moreover, we also explored installing a protecting group potentially more easily removable than tosyl on the nitrogen of α-chloroketone 96. A series of N-protected-3- piperidones was therefore prepared to explore various chlorination conditions.

Thus, commercially available 3-hydroxypiperidine (98) was selectively N- sulfonylated using SES-Cl and Me2NSO2Cl, followed by Jones oxidation to obtain protected 3-piperidones 101 and 102 (Scheme 18).30

Scheme 18.

142

Additionally, N-Cbz-3-piperidone (103) and N-Ns-3-piperidone (104) were prepared according to literature procedures (Figure 5). 31

Figure 5. Piperidones

With a series of N-protected 3-piperidones in hand we began a study of various chlorination conditions in order to obtain the desired 4-chlorinated regioisomer. After some experimentation, it was found that treatment of the 3-piperidones 105a-e with N- chlorosuccinimide (NCS) and Amberlyst-15 ion-exchange resin in EtOAc, followed by stirring with silica gel, gave the desired 4-chlorinated regioisomers 106a-e as the major product along with small amounts of the undesired 2-chlorinated regioisomers 107a-e

(Scheme 19).30a A series of α-chloro-ketones 106a-e with different N-protecting groups were prepared in good yields using these conditions (Table 1).

Scheme 19.

143

Table 1. α-Chlorination of N-protected-3-piperidones

It should be noted that stirring the reaction mixture with silica gel was necessary to convert the small amount of enol-tautomer 108 formed in the reaction to the keto- tautomer 106 exclusively (Scheme 20). The formation of enol tautomer could be seen from TLC analysis in which the non-polar enol-tautomer 108 spot goes to the one for ketone 106 on stirring the reaction mixture with silica gel. Exposing the mixture of keto- tautomer 106 and enol-tautomer 108 to subsequent oximation reaction conditions gave poor yields of product.

Scheme 20.

With a reliable and reproducible method in hand to obtain α-chloroketones 106 for the generation of nitrosoalkene 93, we continued our synthesis of the apparicine core

61. We initially decided to use the tricycle 83, which Majireck had previously

144 synthesized in the approach to the angustilodine alkaloids for the apparicine core synthesis (vide supra). Thus, the diastereomeric mixture of oxime 83 was O-protected to yield TBS-ether 109, followed by removal of the Ts-group using sodium naphthalenide32 to reveal the secondary amine 110 (Scheme 21).

Scheme 21.

With aminoindole 110 in hand, the key Mannich reaction to obtain the tetracyclic core 61 of the apparicine class of indole alkaloids was examined. Thus, amino indole 110 was treated with 37% aqueous formaldehyde and camphorsulfonic acid in ethanol at room temperature to form the desired Mannich product 61 (Scheme 22). Rather, a compound was produced which we believe has the quinuclidine structure 111, although, we have been unable to fully purify and characterize this compound.33 It is probable that the reactive iminium ion conformer 90b, formed during the reaction is attacked by a C-16 enol to form the quinuclidine 111. Closure onto the 3-position of the indole to form the desired 8-membered ring in 61 is probably disfavored due to the presence of the unreactive conformer 90a.

145

Scheme 22. Mannich reaction of amino indole 110

At this point we decided to explore an alternative, potentially more efficient approach to form the tetracyclic core of the apparicine alkaloids. The plan was to have the C-6 carbon already installed at the C-3 position of indole substrate 11334 prior to the nitrosoalkene/ester enolate conjugate addition reaction. The 8-membered C-ring would then be formed using an intramolecular reductive amination reaction of amino aldehyde

112 to form 61 (Scheme 23).

146

Scheme 23. Alternative plan for synthesis of the core of apparicine and related alkaloids

Thus, the known 3-formylindole ester 113 was prepared as described in the literature in good yield by treating indole ester 79 with POCl3 and DMF in dichloromethane at 0 °C (Scheme 24).34 The 3-formylindole ester 113 was then converted to indole dianion 114 by treatment with 2.5 equiv. of lithium hexamethyldisilazide in

THF at -78 °C. Subequent addition of 1 equiv. of α-chlorooxime 80 led to formation of the Michael adduct 117 as a 1:1 mixture of C15/C16 diastereomers in excellent yield, with the oxime geometry of each being exclusively (E).

Mechanistically, we believe that the indole dianion 114 initially deprotonates the

α-chlorooxime 80, effecting a 1,4-elimination to give an indole monoanion and the transient nitrosoalkene 82. We postulate that the indole monoanion exists as an equilibrium mixture of anions 115 and 116 (cf. Scheme 14). However, attack of this

147 anion mixture on the nitrosoalkene 82 occurs exclusively via ester enolate 116 to give the

Michael adduct 117.

Scheme 24.

To continue with the synthesis, the diastereomeric mixture of oximes 117 was first protected as TBS-ether 118 in good yield, and the two C-16 epimers were separated by column chromatography at this stage (Scheme 25). Each of the purified diastereomers of 118 was then used individually for the following steps to allow for full characterization of the intermediates. The Ts-group on 118 was removed using sodium naphthalenide32 to reveal the secondary amine 119.

148

Scheme 25.

Standard reductive-amination procedures using reducing agents such as

NaBH(OAc)3 and NaBH3CN were initially explored in attempts to form the 8-membered

C-ring of the tetracyclic amine 61 (Scheme 26). However, the desired tetracyclic product was not observed under any of these conditions.

Scheme 26.

Modest success in the reductive amination was obtained via a titanium isopropoxide-mediated process using the conditions of Mattson (Scheme 27).35 Thus, the aminoaldehyde 119 was stirred with Ti(i-OPr)4 in THF at room temperature for 6 h, followed by the addition of NaBH4 and methanol at 0 °C. Using these conditions, the

149 tetracyclic product 61 was obtained in 30% yield along with a number of inseparable byproducts. It is thought that this reaction proceeds via elimination of a Ti-alkoxide from intermediate 120 to form azafulvene 121, which is then reduced by NaBH4 to give the tetracyclic product 61.35 Various attempts were made to improve the yield of the reaction and also the product purity, but with no success. At that point, it was decided to monitor the reaction using 1H NMR to observe whether the putative intermediate 120 was actually being formed.

Scheme 27.

Therefore, the aminoaldehyde 119 was treated with 9 equiv. of Ti(O-iPr4) in d8-

THF and stirred for 6 h. However, the aldehyde proton peak was still observed in the

NMR spectrum of an aliquot of the mixture even after 6 hours, indicating that intermediate 120 is probably not formed in the reaction. In an attempt to reduce an imine like 121 formed in the reaction, NaBH3CN in d4-MeOH was added, but again only the starting material 119 was observed by proton NMR of an aliquot. These experiments hinted that the Ti(O-iPr)4 might be of no consequence in the reaction. Also, the

150 observance of the aldehyde proton of 119 in the presence of the mild reducing agent

NaBH3CN indicated that the reaction to form tetracycle 61 is probably not occuring via a highly strained bridgehead iminium-ion intermediate 122 which should be easily reduced

(Scheme 28).

Scheme 28.

Based on these observations, it was decided to simply treat the aminoaldehyde

119 with 20 equiv. of NaBH4 in d4-MeOH (Scheme 29). To our delight, we observed clean formation of the tetracyclic product 61 in the proton NMR of an aliquot of this mixture. On a preparative scale, the aminoaldehyde 119 was treated with 20 equiv. of

NaBH4 in MeOH at 0 °C to obtain the tetracycle 61 in nearly quantitative yield.

Mechanistically, we believe that in this transformation the aldehyde 119 is first reduced by NaBH4 to alcohol 123, which loses water in situ to form the azafulvene 124.

This intermediate is then attacked by the nucleophilic amine to give the tetracyclic product 61.36

151

Scheme 29.

With the tetracyclic apparicine core 61 in hand, we were able to obtain the free oxime 125 by treating the silyl-protected oxime 61 with dilute HCl in moderate yield

(Scheme 30). We then tried to convert the oxime 125 to the ketone 126 using various acidic hydrolysis conditions. However, this conversion proved to be difficult, as only starting material or decomposition was observed. Additionally, numerous reductive and oxidative cleavage methods of the oxime failed to give the desired ketone 126. We believe this problem might be due to a retro-Mannich reaction of the unprotected indole

125. Thus, it might be necessary to protect the indole nitrogen of 125 with an electron withdrawing group (i.e.-Ts, -Boc) before attempting the oxime cleavage.

152

Scheme 30.

2.6 Future Strategy for the Synthesis of Apparicine (1) and Related Alkaloids

We have achieved a synthetic route to the tetracyclic core 61 of the apparicine- type alkaloids in only four steps in 80% overall yield from the known 3-formylindole ester 113. Further work will focus upon elaboration of 61 to apparicine (1) as well as some of the structurally interesting and highly oxidized members of this family such as alstonamine (7).

To this end, the tetracyclic indole 61 will be N-protected, followed by oxime cleavage to give ketone 127 (Scheme 31). The ketone 127 will then be converted to exocyclic allene 128 using the titanocene methodology developed by Petasis.38 The exocyclic allene 128 will then be reduced by employing a Pd-catalyzed regio- and stereoselective allene reduction to afford the ethylidene compound 129.39 The ester functionality of 129 will be reduced to the corresponding alcohol, followed by dehydration40 to the exocyclic alkene, which will be deprotected to yield apparicine (1).

153

Scheme 31.

For the synthesis of alstonamine (7), the exocyclic allene 128 will be converted to

(E)-allylic alcohol 130 by employing a regio- and stereoselective allene hydroboration/oxidation (Scheme 32).41 The allylic alcohol 130 will be transformed to chloromethyl ether 131 using a two-step method reported by Fleming.42 Finally, the chloromethyl ether 131 will be treated with an amide base to form the ester enolate, which should undergo intramolecular alkylative ring closure from the desired face due to inherent ring constraints to give the corresponding pentacycle, which will be deprotected to yield alstonamine (7).

154

Scheme 32.

155

Chapter 3 - Experimental Section

General Methods. All non-aqueous reactions were carried out in oven- or flame- dried glassware under an argon atmosphere. All chemicals were purchased from commercial vendors and used as is unless otherwise specified. Anhydrous tetrahydrofuran, diethyl ether, toluene, and dichloromethane were obtained from a solvent purification system. Reactions were magnetically stirred and monitored by thin layer chromatography with 250 μm precoated silica gel plates. Flash column chromatography was performed using silica gel (230−400 mesh). Chemical shifts are reported relative to chloroform (δ 7.26) for 1H NMR and chloroform (δ 77.2) for 13C

NMR. High-resolution mass spectra were obtained on a time-of-flight instrument using electrospray ionization.

O Cl

N Ts 96

4-Chloro-1-tosylpiperidin-3-one (96). To a stirred solution of 3-piperidone 95

(300 mg, 1.18 mmol) in CH2Cl2 (5 mL) at 0 °C was added sulfuryl chloride (0.11 mL, 1.3 mmol) and the solution was stirred for 20 h gradually warming to rt. An aqueous solution of NaHCO3 was added to the reaction and the mixture was stirred vigorously for 30 min.

The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The

combined organic layers were washed with water and brine, dried over MgSO4, and

156

concentrated in vacuo to give a residue which was purified by flash chromatography on

1 silica gel (2:2:1 hexanes/CH2Cl2/EtOAc) to yield α-chloroketone 96 (249 mg, 73%). H

NMR (300 MHz, CDCl3) δ 7.69 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 4.35 (t, J =

5.0 Hz, 1H), 3.84 (s, 2H), 3.53-3.50 (m, 1H), 3.42-3.38 (m, 1H), 2.53-2.48 (m, 4H), 2.27-

13 2.22 (m, 1H); C NMR (75 MHz, CDCl3) δ 195.1, 145.0, 132.9, 130.5, 128.1, 58.6, 53.5,

42.3, 34.0, 22.0; LRMS-ES+ m/z (relative intensity) 288 (MH+, 100); HRMS-ES+

+ (C12H18ClN2O3S) calcd 305.0729 (M+NH4 ), found 305.0727.

OH

N SES 99

1-((2-(Trimethylsilyl)ethyl)sulfonyl)piperidin-3-ol (99). To a stirred solution of

3-hydroxypiperidine (98, 0.871 g, 8.44 mmol) and TEA (2.35 mL, 16.90 mmol) in

CH2Cl2 at 0 °C was added SES-Cl (1.60 mL, 8.44 mmol). The resulting solution was

stirred for 2 h at 0 °C and then concentrated in vacuo to give a residue which was purified by flash chromatography on silica gel (1:1:1 hexanes/CH2Cl2/EtOAc) to yield 3-

1 hydroxypiperidine 99 (2.02 g, 89%). H NMR (300 MHz, CDCl3) δ 3.90-3.80 (m, 1H),

3.55 (dd, J = 12.1, 3.3 Hz, 1H), 3.40-3.34 (m, 1H), 3.20-3.10 (m, 1H), 3.03 (dd, J = 12.2

Hz, 7.2 Hz, 1H), 2.90-2.84 (m, 2H), 2.44 (d, J = 4.9 Hz, 1H), 1.90-1.85 (m, 2H), 1.66-

13 1.51 (m, 2H), 1.03-0.97 (m, 2H), 0.05 (s, 9H); C NMR (75 MHz, CDCl3) δ 66.1, 52.7,

+ 46.8, 46.5, 32.3, 23.0, 10.4, -1.6; HRMS-ES+ (C10H24NO3SSi) calcd 266.1246 (M+H ), found 266.1241.

157

OH

N SO2NMe2

100

3-Hydroxy-N,N-dimethylpiperidine-1-sulfonamide (100). To a stirred solution of 3-hydroxypiperidine (98, 2.0 g, 19.77 mmol) and TEA (5.52 mL, 39.50 mmol) in 50 mL CH2Cl2 at 0 °C was added N, N-dimethylsulfamoyl chloride (2.12 mL, 19.77 mmol).

The resulting solution was stirred for 2 h at 0 °C and 2 h at rt. The reaction mixture was

then concentrated in vacuo to give a residue which was purified by flash chromatography

on silica gel (1:1 hexanes/EtOAc) to yield 3-hydroxypiperidine 100 (4.0 g, 97%). 1H

NMR (300 MHz, CDCl3) δ 3.58-3.52 (m, 2H), 3.38-3.34 (m, 1H), 3.21-3.16 (m, 1H),

2.80-2.67 (m, 1H), 2.63-2.60 (m, 7H), 1.74-1.61 (m, 2H), 1.42-1.05 (m, 2H); 13C NMR

(75 MHz, CDCl3) δ 66.0, 52.9, 46.6, 38.4, 32.4, 22.9; HRMS-ES+ (C7H20N3O3S) calcd

+ 226.1255 (M+NH4 ), found 226.1233.

O

N SES 101

1-((2-(Trimethylsilyl)ethyl)sulfonyl)piperidin-3-one (101). To a stirred solution of 3-hydroxypiperidine 99 (2.02 g, 7.61 mmol) and acetone (30 mL) at rt was added

Jones reagent (2.5 M aqueous solution, 3.35 mL). The resulting solution was stirred for 1

158

h, i-PrOH (0.8 mL) was added and the reaction mixture was stirred for an additional 5

min. The resulting slurry was filtered through a plug of glass wool washing with acetone.

The filtrate was concentrated in vacuo to give a residue which was taken up in NaHCO3

(aq) and EtOAc. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, brine, and then dried over MgSO4. Concentration of the organic layers in vacuo gave a residue which was

purified by flash chromatography on silica gel (2:2:1 hexanes/CH2Cl2/EtOAc) to give

1 ketone 101 (1.47 g, 73%). H NMR (300 MHz, CDCl3) δ 3.81 (s, 2H), 3.50 (t, J = 5.3 Hz,

2H), 2.90-2.84 (m, 2H), 2.49 (t, J = 6.5 Hz, 2H), 2.06-2.00 (m, 2H), 0.99-0.93 (m, 2H),

13 0.02 (s, 9H); C NMR (75 MHz, CDCl3) δ 203.6, 55.8, 47.3, 44.7, 38.6, 24.1, 10.4, -1.6;

+ HRMS-ES+ (C10H25N2O3SSi) calcd 281.1355 (M+NH4 ), found 281.1373.

O

N SO2NMe2 102

N,N-Dimethyl-3-oxopiperidine-1-sulfonamide (102). To a stirred solution of 3-

hydroxypiperidine 100 (4.00 g, 19.2 mmol) and acetone (60 mL) at rt was added Jones

reagent (2.5 M aqueous solution, 8.45 mL). The resulting solution was stirred for 1 h, i-

PrOH (10 mL) was added and the reaction mixture was stirred for an additional 5 min.

The resulting slurry was filtered through a plug of glass wool washing with acetone. The

filtrate was concentrated in vacuo to give a residue which was taken up in NaHCO3 (aq)

and EtOAc. The organic layer was separated and the aqueous layer was extracted with

159

EtOAc. The combined organic layers were washed with water, brine, and dried over

MgSO4. Concentration of the organic layers in vacuo gave a residue which was purified

by flash chromatography on silica gel (1:1 hexanes/EtOAc) to give ketone 102 (3.15 g,

1 80%). H NMR (300 MHz, CDCl3) δ 3.69 (s, 2H), 3.42 (t, J = 5.8 Hz, 2H), 2.78 (s, 6H),

13 2.45 (t, J = 6.9 Hz, 2H), 2.06-2.01 (m, 2H); C NMR (75 MHz, CDCl3) δ 204.1, 56.5,

+ 45.4, 38.7, 38.4, 23.7; HRMS-ES+ (C7H15N2O3S) calcd 207.0803 (M+H ), found

207.0804.

General Procedure for α-Chlorination of 3-Piperidones with NCS and

Amberlyst-15. To a stirred solution of 3-piperidone (0.80 mmol) in EtOAc (12 mL) was

added Amberlyst-15 (300 mg) followed by NCS (158 mg, 1.18 mmol) and the resulting

mixture was stirred until the starting material was consumed. Silica gel was added and the resulting mixture was stirred for an additional 30 min. The mixture was filtered, and

concentrated in vacuo to give a residue, which was purified by flash column

chromatography on silica gel using a mixture of hexanes/CH2Cl2/EtOAc (2:2:1) to afford

the α-chloroketone.

O Cl

N Ts 96

4-Chloro-1-tosylpiperidin-3-one (96). (Yield: 72%); 1H NMR (300 MHz,

CDCl3) δ 7.69 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 4.35 (t, J = 5.0 Hz, 1H), 3.84

(s, 2H), 3.53-3.50 (m, 1H), 3.42-3.38 (m, 1H), 2.53-2.48 (m, 4H), 2.27-2.22 (m, 1H); 13C

160

NMR (75 MHz, CDCl3) δ 195.1, 145.0, 132.9, 130.5, 128.1, 58.6, 53.5, 42.3, 34.0, 22.0;

+ LRMS-ES+ m/z (relative intensity) 288 (MH , 100); HRMS-ES+ (C12H18ClN2O3S) calcd

+ 305.0729 (M+NH4 ), found 305.0727.

O Cl

N SES 106b

4-Chloro-1-((2-(trimethylsilyl)ethyl)sulfonyl)piperidin-3-one (106b). (Yield:

1 65%); H NMR (300 MHz, CDCl3, + 1 drop of trifluoroacetic acid to generate the ketone exclusively) δ 4.59 (t, J = 6.0 Hz, 1H), 4.20 (ABq, J = 48.6, 16.0 Hz, 2H), 3.82-3.64 (m,

2H), 3.11-3.05 (m, 2H), 2.68-2.60 (m, 1H), 2.38-2.31 (m, 1H), 1.09-0.95 (m, 2H), 0.07

13 (s, 9H); C NMR (75 MHz, CDCl3) δ 199.0, 58.3, 53.0, 48.9, 42.2, 34.8, 10.1, -2.3;

+ HRMS-ES+ (C10H24N2O3SClSi) calcd 315.0965 (M+NH4 ), found 315.0957.

O Cl

N SO2NMe2 106c

4-Chloro-N,N-dimethyl-3-oxopiperidine-1-sulfonamide (106c). (Yield: 77%);

1 H NMR (300 MHz, CDCl3, + 1 drop of trifluoroacetic acid to generate the ketone

exclusively) δ 4.57-4.53 (m, 1H), 4.18-3.84 (m, 2H), 3.80-3.56 (m, 2H), 2.88-2.83 (m,

13 6H), 2.68-2.62 (m, 1H), 2.37-2.31 (m, 1H); C NMR (75 MHz, CDCl3) δ 197.9, 58.7,

161

53.8, 43.0, 38.4, 31.2.

O Cl

N Ns 106d

4-Chloro-1-((2-nitrophenyl)sulfonyl)piperidin-3-one (106d). (Yield: 67%); 1H

NMR (300 MHz, CDCl3, + 1 drop of trifluoroacetic acid to generate the ketone exclusively) δ 8.14-8.04 (m, 1H), 7.86-7.71 (m, 3H), 4.57-4.51 (m, 1H), 4.33-4.02 (m,

2H), 3.85-3.74 (m, 2H), 2.65-2.58 (m, 1H), 2.38-2.31 (m, 1H); 13C NMR (75 MHz,

CDCl3) δ 197.1, 148.3, 135.2, 132.8, 131.7, 131.2, 125.2, 58.5, 53.0, 42.2, 34.3; HRMS-

+ ES+ (C11H15N3O5SCl) calcd 336.0421 (M+NH4 ), found 336.0411.

O Cl

N Ns 107d

2-Chloro-1-((2-nitrophenyl)sulfonyl)piperidin-3-one (107d). (Yield: 19%); 1H

NMR (300 MHz, CDCl3) δ 8.09-8.05 (m, 1H), 7.77-7.67 (m, 3H), 5.12 (s, 1H), 3.75-

3.51 (m, 2H), 2.81-2.69 (m, 1H), 2.38-2.30 (m, 1H), 2.11-2.03 (m, 1H), 1.88-1.79 (m,

13 1H); C NMR (75 MHz, CDCl3) δ 200.2, 148.3, 134.6, 132.9, 132.4, 131.2, 124.9, 87.2,

64.7, 40.7, 35.6.

162

O Cl

N Cbz 107e

Benzyl 4-Chloro-3-oxopiperidine-1-carboxylate (107e). (Yield: 67%); 1H NMR

(300 MHz, CDCl3) δ 7.50-7.30 (m, 5H), 5.28-5.17 (m, 2H), 4.49-4.35 (m, 1H), 4.25-3.82

(m, 2H), 3.54-3.45 (m, 1H), 2.55-2.46 (m, 1H), 2.29-1.79 (m, 1H), 1.28-1.18 (m, 1H);

13 C NMR (75 MHz, CDCl3) δ 196.9, 155.2, 136.3, 136.2, 129.0, 128.8, 128.6, 128.5,

128.3, 68.6, 68.3, 59.3, 59.2, 52.5, 49.9, 46.0, 41.2, 40.3, 39.5, 38.0, 35.6, 34.1.

H N

H N OTBS N CO Me H 2 110

Methyl 2-(3-(((tert-Butyldimethylsilyl)oxy)imino)piperidin-4-yl)-2-(1H-indol-

2-yl)acetate (110). To a solution of oxime 83 (0.283 g, 0.621 mmol) in 12 mL

dichloromethane were added TBSCl (0.122 g, 0.807 mmol) and imidazole (0.110 g,

1.615 mmol). The reaction mixture was stirred at room temperature for 12 h, poured into

water and extracted with dicholoromethane. The combined organic layers were dried over

Na2SO4, and evaporated in vacuo. The residue was passed through a short column (10%

EtOAc/hexanes to 25% EtOAC/hexanes) to give silyl ether 109. The Ts-protected amine

109 was dissolved in 10 mL of DME and Na/naphthalene solution (1 M in DME) was added (1 mL, 1 mmol) at -78 °C. The reaction mixture was stirred for 10 min at -78 °C.

163

The reaction mixture was quenched with excess NH4Cl solution, extracted with EtOAc,

dried over Na2SO4 and evaporated in vacuo. The resulting residue was purified by flash

column chromatography (50% EtOAc/hexanes to 100% EtOAc) to give the amine 110 as

1 yellow oil (0.185 g, 72%). H NMR (300 MHz, CDCl3) δ 9.00-8.79 (m, 1H), 7.69-7.55

(m, 1H), 7.33-7.28 (m, 1H), 7.19-7.05 (m, 2H), 6.40-6.24 (m, 1H), 4.80 (br s, 1H), 4.58-

4.32 (m, 1H), 4.17-4.05 (m, 1H), 3.71-3.68 (m, 3H), 3.57-3.41 (m, 1H), 3.38-3.02 (m,

2H), 2.89-2.61 (m, 1H), 2.07-1.98 (m, 1H), 1.89-1.53 (m, 1H), 0.96-0.92 (m, 9H), 0.29-

13 0.10 (m, 6H); C NMR (75 MHz, CDCl3) δ 173.2, 172.3, 160.1, 159.2, 136.7, 136.6,

133.3, 133.3, 128.4, 128.2, 122.3, 122.0, 120.6, 120.5, 120.3, 119.9, 111.4, 111.3, 103.4,

103.0, 52.8, 52.7, 46.8, 46.7, 44.8, 42.6, 41.7, 30.1, 26.4, 26.3, 26.1, 18.4, 18.2, 1.4, -4.5,

+ -4.7, -4.8, -4.9; HRMS-ES+ (C22H34N3O3Si) calcd 416.2369 (M+H ), found 416.2379.

CHO

N CO Me H 2

113

Methyl 2-(3-Formyl-1H-indol-2-yl)acetate (113). To a solution of DMF (0.634 mL, 8.19 mmol) in 35 mL of CH2Cl2 was added POCl3 (0.764 mL, 8.19 mmol) at 0 °C and the reaction mixture was stirred at 0 °C for 30 min. Indole 79 (1.477 g, 7.80 mmol) dissolved in 7 mL of CH2Cl2 was added and the mixture was stirred at 0 °C for 30 min.

The reaction mixture was allowed to warm to rt and stirred overnight. The organic layer

was washed with NaHCO3 solution, dried over Na2SO4 and evaporated in vacuo. The

resulting residue was purified by flash column chromatography chromatography (50%

164

EtOAc/hexanes to 100% EtOAc) to give the 3-formyl indole 113 as a yellow solid (1.302

1 g, 77%). H NMR (300 MHz, CDCl3) δ 10.13 (s, 1H), 10.00 (s, 1H), 8.10-8.07 (m, 1H),

7.32-7.29 (m, 1H), 7.22-7.15 (m, 2H), 4.16 (s, 2H), 3.70 (3, 3H); 13C NMR (75 MHz,

CDCl3) δ 184.8, 170.6, 140.7, 135.5, 126.4, 124.1, 123.2, 120.4, 115.0, 111.9, 53.2, 31.7.

Ts N CHO

H N OH N CO Me H 2 117

Methyl 2-(3-Formyl-1H-indol-2-yl)-2-(3-(hydroxyimino)-1-tosylpiperidin-4- yl)acetate (117). To a solution of indole ester 113 (0.605 g, 2.78 mmol) in 36 mL of THF was added 1 M LiHMDS solution in THF (6.96 mL, 6.96 mmol) at -78 °C. After 30 min,

α-chloroketoxime 80 (1.050 g, 3.48 mmol) dissolved in 30 mL of THF was added and the reaction mixture was stirred at -78 °C for 2 h. The reaction mixture was quenched with aqueous NH4Cl solution and extracted with EtOAc. The combined organic layers were

dried over Na2SO4 and evaporated in vacuo. The residue was purified by flash column

chromatography (25% EtOAc/hexanes) to give a diastereomeric mixture of Michael

adducts 117 (1.306 g, 97%, ~1:1 ratio by 1H NMR, yellow amorphous solid) which was carried on to the next step without separation. IR (CH2Cl2) 3297, 2922, 2362, 1704, 1633,

-1 1 1532, 1453, 1343, 1256, 1159, 946 cm ; H NMR (300 MHz, CDCl3) δ 10.25 (s, 0.5H),

10.17 (s, 0.5H), 9.85 (s, 0.5H), 9.34 (s, 0.5H), 8.56 (br s, 1H), 8.40-8.08 (m, 1H), 7.69-

7.63 (m, 2H), 7.38-7.21 (m, 5H), 5.20 (d, J = 6.0 Hz, 0.5H), 4.89 (d, J = 15.0 Hz, 0.5H),

165

4.79-4.71 (m, 1H), 3.66 (d, J = 12.0 Hz, 3H), 3.39-3.34 (m, 1H), 3.23-3.18 (m, 1H), 2.86

(br s, 1H), 2.46-2.36 (m, 3H), 1.98-1.95 (m, 1H), 1.56-1.36 (m, 1H), 1.00-0.91 (m, 1H);

13 C NMR (75 MHz, CDCl3) δ 185.8, 171.7, 153.0, 144.6, 141.4, 135.6, 133.3, 130.3,

128.0, 126.5, 124.3, 123.1, 119.6, 115.8, 112.4, 53.9, 53.3, 45.2, 43.2, 42.6, 42.5, 30.1,

+ 28.3, 21.9, 1.5; HRMS-ES+ (C24H26N3O6S) calcd 484.1542 (M+H ), found 484.1559.

Ts N CHO

H N OTBS N CO Me H 2 118

Methyl 2-(3-(((tert-Butyldimethylsilyl)oxy)imino)-1-tosylpiperidin-4-yl)-2-(3-

formyl-1H-indol-2-yl)acetate (118). To a solution of oxime 117 (1.346 g, 2.785 mmol)

in 30 mL of dichloromethane were added TBSCl (1.260 g, 8.355 mmol) and imidazole

(1.137 g, 16.700 mmol). The reaction mixture was stirred at rt for 12 h, poured into water

and extracted with dichloromethane. The combined organic layers were dried over

Na2SO4, and evaporated in vacuo. The residue was purified by flash column chromatography (25% EtOAc/hexanes) to give the separable diastereomeric silyl ethers

118 (1.452 g, 87%). The silyl ethers 118 were used separately for further steps.

1 Less polar isomer 118: Yellow oil; H NMR (300 MHz, CDCl3) δ 10.11 (s, 1H),

9.32 (br s, 1H), 8.24-8.21 (s, 1H), 7.61 (d, J = 9.0 Hz, 2H), 7.32-7.27 (m, 5H), 4.97 (d, J

= 15.0 Hz, 1H), 4.64 (d, J = 9.0 Hz, 1H), 3.68 (s, 3H), 3.58-3.53 (m, 1H), 3.16-3.06 (m,

2H), 2.79-2.64 (m, 1H), 2.44 (s, 3H), 1.45-1.26 (m, 2H), 0.97 (s, 9H), 0.23 (s, 3H), 0.17

166

13 (s, 3H); C NMR (75 MHz, CDCl3) δ 184.4, 172.2, 156.3, 144.4, 142.4, 135.5, 133.7,

130.1, 127.9, 125.9, 124.6, 123.4, 121.1, 116.3, 111.7, 53.2, 44.9, 43.8, 42.7, 42.3, 28.1,

+ 26.2, 21.8, 18.2, -4.8, -5.0; HRMS-ES+ (C30H40N3O6SSi) calcd 598.2407 (M+H ), found

598.2399.

1 More polar isomer 118: Yellow oil; H NMR (300 MHz, CDCl3) δ 10.27 (s, 1H),

9.61 (br s, 1H), 8.12-8.10 (m, 1H), 7.64 (d, J = 6.0 Hz, 2H), 7.42-7.25 (m, 5H), 5.24 (d, J

= 6.0 Hz, 1H), 4.97 (d, J = 15.0 Hz, 1H), 3.72 (s, 3H), 3.65-3.61 (m, 1H), 3.44-3.32 (m,

2H), 3.02-2.98 (m, 1H), 2.34 (s, 3H), 2.01-1.96 (m, 1H), 1.37 (s, 1H), 0.90 (s, 9H), 0.32

13 (s, 3H), 0.21 (s, 3H); C NMR (75 MHz, CDCl3) δ 185.2, 170.8, 157.6, 144.4, 141.1,

135.4, 133.9, 130.2, 127.9, 126.7, 124.8, 123.0, 119.6, 115.7, 112.0, 53.1, 45.0, 43.1,

43.0, 42.7, 28.1, 26.2, 21.8, 18.2, -4.2, -4.6; HRMS-ES+ (C30H40N3O6SSi) calcd

598.2407 (M+H+), found 598.2402.

H N CHO

H N OTBS N CO Me H 2 119

Methyl 2-(3-(((tert-Butyldimethylsilyl)oxy)imino)piperidin-4-yl)-2-(3-formyl-

1H-indol-2-yl)acetate (119). To a solution of less polar Ts-protected amine 118 (0.532 g,

0.89 mmol) in 20 mL of DME was added Na/naphthalene solution (10 mL, 0.1 M in

DME, 1 mmol) at -78 °C. The reaction mixture was stirred for 10 min at -78 °C. The

167 mixture was quenched with aqueous NH4Cl solution, extracted with EtOAc, dried over

Na2SO4 and evaporated in vacuo. The residue was purified by flash column chromatography (50% EtOAc/hexanes to 100% EtOAc) to give the amine 119 (0.378 g,

96%). The same procedure was used for deprotection of the more polar Ts-protected amine 118 to produce the piperidine in comparable yield.

1 Less polar isomer 119: Yellow foamy solid; H NMR (300 MHz, CDCl3) δ 10.29

(s, 1H), 10.05 (br s, 1H), 8.32-8.29 (m, 1H), 7.36-7.29 (m, 3H), 4.84 (d, J = 9.0 Hz, 1H),

4.52 (d, J = 15.0 Hz, 1H), 3.73 (s, 3H), 3.40-3.30 (m, 1H), 3.03 (d, J = 15.0 Hz, 1H), 2.91

(d, J = 15.0 Hz, 1H), 2.70 (t, J = 9.0 Hz, 1H), 1.54-1.45 (m, 2H), 0.99 (s, 9H), 0.25 (s,

13 3H), 0.20 (s, 3H); C NMR (75 MHz, CDCl3) δ 184.8, 172.7, 160.7, 143.6, 135.8, 125.9,

124.8, 123.3, 121.4, 116.6, 111.7, 53.2, 45.5, 44.3, 43.5, 42.9, 32.7, 26.3, 18.3, -4.8, -5.0;

+ HRMS-ES+ (C23H34N3O4Si) calcd 444.2319 (M+H ), found 444.2303.

1 More polar isomer 119: Yellow foamy solid; H NMR (300 MHz, CDCl3) δ

10.29 (s, 1H), 9.96 (br s, 1H), 8.16-8.15 (m, 1H), 7.41-7.39 (m, 1H), 7.31-7.29 (m, 2H),

7.16 (br s, 1H), 5.16 (d, J = 6.0 Hz, 1H), 4.47 (d, J = 15.0 Hz, 1H), 3.74 (s, 3H), 3.62-

3.55 (m, 1H), 3.16 (s, 1H), 3.08 (d, J = 18.0 Hz, 1H), 2.86 (t, J = 9.0 Hz, 1H), 2.01-1.97

(m, 1H), 1.40-1.36 (m, 1H), 0.96 (s, 9H), 0.29 (s, 3H), 0.24 (s, 3H); 13C NMR (75 MHz,

CDCl3) δ 185.1, 171.0, 160.7, 142.3, 135.4, 126.7, 124.1, 122.9, 120.0, 115.9, 112.0,

53.0, 45.3, 43.8, 43.6, 43.1, 32.2, 30.1, 26.4, 26.0, 18.2, 1.4, -4.2, -4.5, -4.6; HRMS-ES+

+ (C23H34N3O4Si) calcd 444.2319 (M+H ), found 444.2302.

168

N N OTBS H N CO Me H 2 61

Methyl 4-(((tert-Butyldimethylsilyl)oxy)imino)-1,3,4,5,6,7-hexahydro-2,5- ethanoazocino[4,3-b]indole-6-carboxylate (61). To a solution of less polar amino aldehyde 119 (0.650 g, 1.465 mmol) in 120 mL of MeOH was slowly added NaBH4

(1.110 g, 29.305 mmol) at 0 °C (a large amount of gas evolved). The reaction mixture

was stirred at 0 °C for 1 h. The organic solvent was evaporated in vacuo and the residue

was dissolved in CH2Cl2. The organic phase was washed with water, dried over Na2SO4

and was concentrated in vacuo to yield the tetracyclic amine 61 (0.617 g, 99%). The same

procedure was used with the more polar amino aldehyde 119 to form tetracycle 61 in

comparable yield

Less polar isomer 61: White solid; IR (CH2Cl2) 3345, 2953, 2858, 1725, 1455,

-1 1 1317, 1275, 1253, 1161, 941 cm ; H NMR (300 MHz, CDCl3) δ 8.69 (s, 1H), 7.72 (d, J

= 6.0 Hz, 1H), 7.34-7.29 (m, 1H), 7.25-7.14 (m, 2H), 4.93-4.85 (m, 2H), 4.52 (d, J = 15.0

Hz, 1H), 4.31 (d, J = 12.0 Hz, 1H), 3.68 (s, 3H), 3.29-3.20 (m, 1H), 3.00-2.90 (m, 2H),

2.68 (t, J = 12.0 Hz 1H), 1.96 (s, 1H), 1.51-1.48 (m, 1H), 1.32-1.19 (m, 1H), 0.98 (s, 9H),

13 0.24 (s, 3H), 0.18 (s, 3H); C NMR (75 MHz, CDCl3) δ 173.5, 161.1, 136.1, 131.3,

127.7, 123.0, 120.5, 119.1, 115.1, 111.4, 55.6, 52.9, 45.7, 44.5, 43.0, 26.4, 18.4, -4.7, -

+ 4.9; HRMS-ES+ (C23H34N3O3Si) calcd 428.2369 (M+H ), found 428.2359.

More polar isomer 61: White solid; IR (CH2Cl2) 3350, 2953, 1732, 1456, 1373,

-1 1 1278, 1045, 841 cm ; H NMR (300 MHz, CDCl3) δ 9.07 (s, 1H), 7.66 (d, J = 6.0 Hz,

169

1H), 7.34-7.28 (m, 1H), 7.21-7.10 (m, 2H), 4.84-4.82 (m, 2H), 4.41 (d, J = 9.0 Hz, 1H),

4.29 (d, J = 15.0 Hz, 1H), 3.70 (s, 3H), 3.66-3.59 (m, 1H), 3.45-3.32 (m, 1H), 3.08-3.06

(m, 1H), 3.06-3.04 (m, 1H), 1.98-1.96 (m, 1H), 1.32-1.28 (m, 1H), 0.86 (s, 9H), 0.17-

13 0.01 (m, 6H); C NMR (75 MHz, CDCl3) δ 172.1, 161.1, 135.7, 131.4, 127.4, 122.6,

120.1, 118.8, 114.7, 111.4, 55.6, 52.9, 44.1, 42.1, 30.1, 26.4, 18.2, -4.7, -4.8; HRMS-ES+

+ (C23H34N3O3Si) calcd 428.2369 (M+H ), found 428.2364.

N N OH H N CO Me H 2 125

Methyl 4-(Hydroxyimino)-1,3,4,5,6,7-hexahydro-2,5-ethanoazocino[4,3- b]indole-6-carboxylate (125). To a solution of less polar oxime 61 (63.0 mg, 0.147 mmol) in 5 mL of MeOH was added 10% aqueous HCl solution (0.5 mL) and the mixture was stirred for 6h at rt. The organic solvent was evaporated in vacuo and the residue was dissolved in CH2Cl2. The organic phase was washed with NaHCO3, dried over Na2SO4

and was concentrated in vacuo to yield the oxime 125 (30.0 mg, 65%). 1H NMR (300

MHz, CDCl3) δ 8.62 (s, 1Η), 8.48 (s, 1Η), 7.71-7.68 (m, 1H), 7.58-7.43 (m, 1H), 7.24-

7.14 (m, 2H), 4.12-4.00 (m, 1H), 3.88 (s, 2H), 3.76 (s, 3H), 3.30 (s, 1H), 2.20-2.08 (m,

2H), 1.72-1.57 (m, 1H), 1.29 (s, 1H), 1.04-0.94 (m, 2H), 0.21-0.02 (m, 1H); LRMS (EI)

+ (C17H20N3O3) calcd 314.1 (M+H ), found 314.2.

170

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176

Vita

Pradeep S. Chauhan

Pradeep was born and raised in Delhi, India. He graduated from Hans Raj

College, University of Delhi with a B.Sc. in Chemistry in 2005 and a M.Sc. in Chemistry in 2007. He then worked in the lab of Prof. Virinder S. Parmar for a year. In the fall of

2008, he began research in the laboratory of Professor Steven M. Weinreb at The

Pennsylvania State University. His doctoral studies have been directed towards synthesis of natural products. Upon completion of his graduate studies, Pradeep will begin a postdoctoral position with Prof. Sidney Hecht at The Biodesign Institute, Arizona State

University.