Methods for Asymmetric Olefination Reactions

Methods for Asymmetric Olefination

Reactions; Development and

Application to Natural Product

Synthesis

Daniel Strand

Doctoral Thesis

Stockholm 2006

Akademisk avhandling som med tillstånd av Kungl Tekniska Högskolan i Stockholm framlägges till offentlig granskning för avläggande av teknologie doktorsexamen i kemi med inrikting mot organisk kemi, onsdagen den 20 september, kl 10.00 i sal F3, KTH Lindstedsvägen 26, Stockholm. Avhandlingen försvaras på engelska. Opponent är Professor Viresh H. Rawal, University of Chi- cago, IL, USA.

ISBN 91-7178-427-6 ISRN KTH/IOK/FR--06/103--SE ISSN 1100-7974 TRITA-IOK Forskningsrapport 2006:103

Strand, D. 2006 “Methods for Asymmetric Olefination Reactions; Development and Application to Natural Product Synthesis”, Organic Chemistry, KTH Chemi- cal Science and Engineering, SE-100 44 Stockholm, Sweden. Abstract

This thesis deals with the development and application of methods for asymmetric olefinations, in particular Horner-Wadsworth-Emmons (HWE) reactions, in the synthesis of certain natural products.

Relying on asymmetric HWE reactions to access key building blocks, two natural products, pyranicin and pyragonicin, were synthesized from common late intermediates. The utility of the HWE reactions is highlighted through a desymmetrization of a meso-dialdehyde as well as a stereoconvergent reaction sequence employing the sequential use of a HWE parallel kinetic resolution followed by a Pd-catalyzed allylic substitution to convergently transform a race- mate to a single stereoisomer of the product. Methodological extensions of these syntheses include a divergent synthesis of 2,3,6-substituted tetrahydropyran derivatives and application of Zn-mediated asymmetric alkynylations to install key stereocenters.

Synthetic studies directed towards a more complex target, mucocin, employing a triply convergent strategy, have also been performed. Expedient and reliable routes to three key fragments were developed, as well as methodology to access to all nine stereocenters. The fragment coupling to assemble the oligonuclear core still remains a challenge, however. Key features of the synthesis include the formation of two fragments from a common precursor derived from an asymmetric HWE desymmetrization, Zn-mediatedated asymmetric alkynylations, a stereoselective oxa-Michael cyclization dependent on a simultaneous protective group migration and a one-pot procedure for the synthesis of a TBS protected iodohydrin from a terminal epoxide.

An investigation of the possibilities for developing a transition metal catalyzed asymmetric olefination using a chiral Re-complex is outlined. An enantioenriched BINAP-Re complex was synthesized and characterized by X-ray. An efficient protocol for the olefination of functionalized aldehydes employing this catalyst was developed, but gave racemic products in two attempted kinetic resolutions of racemic substrates, most likely due to a reaction pathway proceeding via a non-metal associated phosphonium ylide.

Keywords: Antitumor agents, Asymmetric Horner-Wadsworth-Emmons, Desymmetriza- tion, Metal-catalyzed olefination, Mucocin, Palladium-catalyzed allylic substitution, Parallel kinetic resolution, Pyranicin, Pyragonicin, Rhenium, Stereoconvergent synthesis, Stereodi- vergent synthesis, Stereoselective synthesis, Tetrahydropyran, Wittig reaction.

HO OH OH O O OH O

This is not pyranicin

List of Publications

I. Total Synthesis of Pyranicin Strand, D.; Rein, T. Org. Lett. 2005, 7, 199 -202 II. Synthesis of Pyragonicin Strand, D.; Rein, T. Org. Lett. 2005, 7, 2779-2781 III. Divergence en Route to Nonclassical Annonaceous Acetogenins. Syn- thesis of Pyranicin and Pyragonicin Strand, D.; Norrby, P.-O.; Rein, T. J. Org. Chem. 2006, 71, 1879-1891 IV. Towards the Synthesis of (-)-Mucocin Strand, D.;Helquist P.; Rein, T. Preliminary manuscript

V. Evaluation of (+)-[BINAP]Re(O)Cl3 as a Catalyst for the Olefination of Aldehydes Strand, D.; Stensland, B.; Rein, T. Manuscript

The Authors’ Contribution to Papers I-V

I. I contributed to the formulation of the research problems, performed the experimental work and wrote the manuscript. II. I contributed to the formulation of the research problems, performed the experimental work and wrote the manuscript. III. I contributed to the formulation of the research problems, performed the experimental work and wrote the manuscript, excluding the computational chemistry section. IV. I contributed to the formulation of the research problems, performed the experimental work and wrote the manuscript. V. I contributed to the formulation of the research problems, performed the experimental work excluding the X-ray analysis, and wrote the manuscript.

Abbreviations and Symbols

9-BBN 9-Borabicyclo[3.3.1]nonane ACG Annonaceous acetogenin AD Asymmetric dihydroxylation Asym. Asymmetric Cat. Catalyst CSA 10-Camphorsulfonic acid Cy Cyclohexyl dba dibenzylidene acetone DCE Dichloroethane DKR Dynamic kinetic resolution DMP Dess-Martin periodinane DMPU 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone DMS Dimethylsulfide DPPE 1,1-Bis(diphenylphosphino)ethylene DPPP 1,1-Bis(diphenylphosphino)propylene dr Diastereomeric ratio ED Effective dose EDA Ethyl diazoacetate er Enantiomeric ratio EWG Electron-withdrawing group equiv. Equivalents FAE Felkin-Anh-Eisenstein FG Functional group HMDS Hexamethyldisilazid HMPA Hexamethylphosphoramide HWE Horner-Wadsworth-Emmons IC Inhibitory concentration MTO Methyltrioxorhenium MTPA α-Methoxy-α-(trifluoromethyl)phenyl acid N.d. Not determined NME N-Methylephedrine PG Protective group Piv Pivaloyl PKR Parallell kinetic resolution PMP p-Methoxyphenyl Prod. Product quant. Quantitative R' (1S,2R)-2-(2-Phenylpropan-2-yl)cyclohexyl R'' (1R,2S,5R)-5-Methyl-2-(2-phenylpropan-2-yl)cyclohexyl R* Chiral auxiliary Red. Reductant SAE Sharpless’ asymmetric epoxidation

s.m. Starting material Tf Triflyl TFE 2,2,2-Trifluoroethoxy THP Tetrahydropyran TPP Triphenylphosphine TPPO Triphenylphosphineoxide

∆ Heating (typically to reflux) σ Mirror plane

Table of Contents

1. Introduction...... 1 1.1 Aim of This Thesis...... 1 1.2 A Brief History of Complex Molecule Synthesis...... 1 1.3 A Key to Complex Molecule Synthesis; Stereoselective Synthesis ...... 3 1.4 The Asymmetric Horner-Wadsworth-Emmons Reaction...... 4 1.5 Introduction to Annonaceous Acetogenins; Targets for Synthesis ...... 9 2. Synthesis of (+)-Pyranicin and (+)-PyragonicinI-III ...... 13 2.1 Introduction...... 13 2.2 Synthetic Efforts by Other Research Groups ...... 14 2.3 Retrosynthetic Analysis of Pyranicin/Pyragonicin...... 15 2.4 Synthesis of Pyranicin and Pyragonicin...... 16 2.4.1 Synthesis of the Tetrahydropyran Fragments ...... 16 2.4.2 Synthesis of the Shared Butenolide Fragment...... 20 2.4.3 Endgames Towards Pyranicin and Pyragonicin ...... 25 2.5 Biological Evaluation...... 26 2.6 Conclusions and Outlook ...... 27 3. Towards the Synthesis of (-)-MucocinIV ...... 29 3.1 Introduction...... 29 3.2 Synthetic Efforts by Other Research Groups ...... 29 3.3 Retrosynthetic Analysis of Mucocin ...... 31 3.4 Synthetic Studies Towards Mucocin ...... 32 3.4.1 Synthesis of the Tetrahydropyran Fragment...... 32 3.4.2 Synthesis of the THF Fragment...... 35 3.4.3 Synthesis of the Butenolide...... 36 3.4.4 Assembly and Completion of the Bis-Ring Portion ...... 37 3.4.5 Proposed Endgame ...... 39 3.5 Conclusions and Outlook ...... 40 4. Evaluation of a Re-Catalyzed Asymmetric OlefinationV ...... 43 4.1 Introduction...... 43 4.2 Survey of the Field...... 43 4.3 Design and Synthesis of Chiral ReV Catalysts ...... 45 4.4 Optimization of the Olefination Step ...... 47 4.5 Mechanism and Implications for Asymmetric Olefinations...... 49 4.6 Conclusions and Outlook ...... 50 5. Concluding Remarks ...... 51 6. Acknowledgements...... 53

1. Introduction

“Our quest to reach the Promised Land should not render us insensitive to opportuni- ties for discovery, even as we find our way through the desert.” S. J. Danishefsky

1.1 Aim of This Thesis The contents of this thesis revolve around the asymmetric Horner-Wadsworth- Emmons (HWE) reaction, exploring and expanding its utility by applying it in various complex settings to solve synthetic problems. Specifically, the asymmetric HWE reaction is used to provide access to building blocks for the synthesis of biologically attractive targets belonging to the annonaceous acetogenins class of natural products. In a wider sense, the aim is to take advantage of the synergistic relationship between complex molecule synthesis and methods development, by using the route towards the target molecule as an opportunity for exploring modern methodology and potentially providing solutions to problems of a more general nature. A downstream goal of this study is to supply molecules that can provide an increased understanding of biological mechanisms with further implications on drug design. To advance the utility of the asymmetric olefinations we also investigated the possibility of developing a transition metal catalyzed version of the reaction.

1.2 A Brief History of Complex Molecule Synthesis Organic molecules, and the access to them provided by organic synthesis,1 have a tremendous impact on the way humans live and function. Not only are we made of them, they have implications in almost every aspect of our everyday life. Small organic molecules can, if designed properly, provide us with an almost indefinite array of properties, with applications ranging from fuels and material science to electronics, biology and medicine. To this day, the undisputed master of creating molecules with unique, selective and potent properties is Na- ture, and an immense part of modern research has been directed at designing artificial ways to mimic Nature’s solutions. One approach for doing this is offered through the access to complex molecules provided by synthetic organic chemistry.

The field of organic synthesis is generally recognized as having commenced with Wöhler’s synthesis of urea (1) (Figure 1) and Hennell’s synthesis of ethyl alcohol in 1828.2 The synthesis of urea, while not very complex in itself, brought about a proof that an organic substance could be formed in vitro from inorganic precur-

1 Syntesis, greek; the process of putting together. 2 Wöhler, F. Ann. Phys. Chem. 1828, 12, 253; The contemporary synthesis of ethyl alcohol from olefiant gas and aqueous sulfuric acid by Hennell could be argued as the first organic synthesis; Hennell, H. Phil. Trans., 1828, 118, 365–371.

1 sors (cyanic acid and ammonia).3 These discoveries influenced the chemical community and triggered a field that eventually resulted in landmark achieve- ments such as Robinson’s tropinone (2) synthesis in 19174 and Woodward and Eschenmoser’s synthesis of vitamin B12 (4) in 1973.5 More recently, several even more devilishly complex structures such as CP-263,114 (3),6 brevetoxin B (8)7 and pentacycloanammoxic acid (7)8 have succumbed to total synthesis.

O N

H2N NH2 O Urea (1) H N H2N O 2 (Wöhler, 1828) Tropinone (2) O (Robinsson, 1917) O H NH2 H C H N O 5 9 O N O O O H2N O H N CN O H O Co N C H H O H N N 8 15 CP-263,114 (3) H H N O CO H O 2 H 2 (Nicolaou, 1999) H NH O 2 Strychnine (5) O N H (Woodward, 1954) N H H NH N N NH HO N O H H Vitamin B12 (4) P O (Woodward and -O O HO O H H Eschenmoser, 1973) N N Me OH H H CHO HN Quadrigemine C (6) O (Overman 2002) H O H N H H O Me Me H Me O O H H Me H H O OH O O H Pentacycloanammoxic acid (7) O O Brevetoxin B (8) (Corey, 2004) H H Me O O O H (Nicolaou,1995) H H H Me Figure 1. A selection of natural products prepared through organic synthesis. Perhaps only the aficionado will fully appreciate the more subtle intricacies of these structures, but their complexity and sheer beauty can be perceived by everyone. Since the days of Wöhler, total syntheses of complex molecules in general, and of natural products in particular, have been a major driving force in the field of organic chemistry. Many of the pioneering studies in methods development were initiated out of necessity to circumvent or solve problems exposed in the process of synthesizing a natural product.

While complex molecule synthesis still remains a formidable challenge for organic chemists, we are slowly gathering the tools to take on the challenge posed

3 Prior to Wöhler, it was commonly believed that organic molecules, the molecules of life, required a “vital force” to form and could only be made by living organisms. See; Hopkins, F. G. Biochem J. 1928, 22, 1341-1348. 4 Robinson, R. J. Chem. Soc. 1917, 762-768. 5 Eschenmoser, A.; Wintner, C. E. Science 1977, 196, 1410-1426. 6 Nicolaou, K. C.; Baran, P. S. Angew. Chem. Int. Ed. 2002, 41, 2678-2720. 7 Nicolaou, K. C. Angew. Chem. Int. Ed. 1996, 35, 589-607. 8 Mascitti, V.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 15664-15665.

2 by Nature, and to better her by designing and synthesizing intricate structures carrying the properties we strive for.

1.3 A Key to Complex Molecule Synthesis; Stereoselective Synthesis The world around us is chiral.9 In order to synthesize a complex molecule, we cannot only take into account the connectivity of the atoms in the molecule, we must also consider its three-dimensional structure. The solution to approaching this problem lies in using stereoselective synthesis, by designing our synthetic routes and choosing our reaction conditions to allow for the formation of one stereoisomer in preference to others.10 There are several methods to achieve stereoselection and these may be characterized as follows;11 (1) Absolute asymmetric synthesis; Conditions under which achiral or racemic material is transformed into chiral non-racemic products. These processes are rare and sparingly applicable to modern synthesis. (2) Chirality relay; Stereogenic elements present within the molecule are intercon- verted without creation of additional stereogenic units. (3) Asymmetric synthesis; Conversion of a prostereogenic substrate or functional group into an enantio- or diastereoenriched product. This process can be further subdivided into three subgroups: Substrate control. A transformation where the formation of a new stereogenic center is controlled by chirality already present within the molecule (diastereoselective). Auxiliary control. A transformation where the formation of a stereogenic center is controlled by a stochiometric amount of a chiral auxiliary covalently bound to the substrate but not part of the final structure (diastereoselective). Reagent control. A transformation where the formation of a stereogenic center is governed by a chiral reagent (catalytic or stochiometric) (enantioselective).

A modern complex molecule synthesis will typically rely on asymmetric synthesis and frequently, several of the various modes of action are invoked. Ideally, one would like to design a synthetic route such that the use of a catalytic amount of a chiral reagent controls the selective formation of the first stereogenic ele-

9 Chiral, greek; handed. Body with non-superimposable mirror images. 10 A target containing n stereogenic elements will, if formed unselectively, give rise to up to 2n discrete isomeric products, which from a synthetic perspective is quite inadequate. 11 For further discussion see e.g.: Nógrádi, M. Stereoselective Synthesis; VCH Verlagsge- sellschaft mbH; Weinheim, 1987.

3 ment and further asymmetric transformations towards the final target are governed by substrate control.

1.4 The Asymmetric Horner-Wadsworth-Emmons Reaction A fundamental part of organic synthesis is the formation of carbon-carbon bonds. In the 1950s, George Wittig developed a groundbreaking new reaction for pre- paring alkenes from aldehydes or ketones by reacting them with phosphonium ylides (Scheme 1).12

2 O R R3 O Ph3P 1 Ph3P R 1 13 R2 R3 R R1 R2 1 Base 12 Ph3P R 10 R3 15 9 1 + Wittig Ph3P R - R2 Ph PO 11 O 3 R3 Ph3P R1 14

O O Ph R5 H P EWG O O Base Ph 18 EWG Ph Ph P EWG 5 + P 16 R Ph O Ph 17 19 Horner-Wittig O 20

C2 R5 H O O 4 O R4O Base RO 18 EWG R O P EWG 5 + P P EWG R R4O O R4O RO 21 22 19 23 Horner-Wadsworth-Emmons EWG = e.g. CN, CO2R, C(O)NR2 Scheme 1. The Wittig, Horner-Wittig and Horner-Wadsworth-Emmons reactions. The utility of the Wittig reaction was expanded by Horner through the use of phosphine oxides instead of phosphonium salts, resulting in a simplified workup.13 It was however through work by Wadsworth and Emmons using phosphonate anions as nucleophiles that the reaction revealed its full potential as a reliable and general method for the olefination of aldehydes and ketones with typically excellent levels of geometric selectivity.14 The reaction is hence known as the Horner-Wadsworth-Emmons or HWE reaction.15 The HWE reaction has several advantages over the parent Wittig reaction: (1) The phosphonate anion is more reactive than a phosphonium ylide; (2) By varying the substituents on the phosphonate and the reaction conditions the geometric outcome can often be controlled; (3) The byproduct (a dialkyl phosphate ion) can be removed by aqueous workup; (4) The synthesis of trisubstituted alkenes is simpler as the phos-

12 Commonly referred to as the Wittig reaction; (a) Wittig, G.; Geissler, G. Liebigs Ann. Chem. 1953, 580, 44-57. (b) Wittig, G.; Schöllkopf, U. Chem. Ber. 1954, 1318-1330. 13 Horner, L.; Hoffman, H.; Wippel, H. G. Chem. Ber. 1961, 91, 61-63. 14 Wadsworth, W. S., Jr; Emmons, W. D. J. Am. Chem. Soc. 1961, 83, 1733-1738. 15 For a review see: Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863-927.

4 phonate is readily alkylated at C2. From a synthetic standpoint the reaction is quite efficient, as it introduces a new C-C bond as well as a set of functional groups that, if not already a part of the target molecule, are readily transformed further.

The first example of an asymmetric version of a Wittig type reaction was introduced some 40 years ago.16 The typical requirement for a Wittig type olefination to give asymmetric induction is that the substrate contains either a prostereogenic unit or several symmetrically arranged stereogenic elements (i.e., a meso structure) apart from the reacting carbonyl group (Figure 2). A third alternative is a kinetic resolution.

σ O O 1 R 1 R 24 σ O O

H H FG FG 25 σ O O R2 R2 H H FG FG rac-26 Figure 2. Structures that fulfil the principal requirements as substrates for an asymmetric Wittig type olefination. In recent years, a number of studies have targeted this problem using the modern battery of techniques to achieve asymmetric induction.17 Examples include auxiliary control,18a host-guest interactions,18b chiral Lewis acid complexes18c and phase transfer catalysis (Scheme 2).18d

16 Tomoskoz, I.; Janzso, G. Chemistry & Industry 1962, 2085-2086. 17 For a recent review see: Rein, T.; Pedersen, T. M. Synthesis 2002, 579-594. 18 (a) Denmark, S. E.; Chen, C. T. J. Am. Chem. Soc. 1992, 114, 10674-10676, (b) Toda, F.; Akai, H. J. Org. Chem. 1990, 55, 3446-3447, (c) Sano, S. Yakugaku Zasshi 2000, 120, 432- 444. (d) Arai, S.; Hamaguchi, S.; Shioiri, T. Tetrahedron Lett. 1998, 39, 2997-3000,

5 O P SPh O O SPh N 28 i-Pr P-stereogenic phosphonoamidites

27 t-Bu t-Bu 29, 70%, er = 95:5 OO31 EtO2C O HO OH Ph PhPh Ph Chiral hosts

Ph3P CO2Et * * 33, 58%, er = 78:22 30 32

O N i-PrO2C F O N 35 + (EtO)2P CO2i-Pr Chiral Lewis acids F 34 Sn(OTf) , amine base t-Bu 27 2 * t-Bu 36, 88%, er = 89:11

O N CO2Et - O N Br Chiral phase transfer catalysts 38 Ph + (EtO)2P CO2Et

27 37 t-Bu t-Bu 39, 69%, er = 78:22 Scheme 2. Various approaches to asymmetric Wittig-type olefinations. Phosphonate 40a, bearing an 8-phenylmenthyl auxiliary, was independently introduced by the groups of Gais19 and Rehwinkel20 and applied to the synthesis of prostacyclin analogues (Figure 3).

O O O O RO RO P P RO O RO O Ph Ph

R = Me (40a) R = Me (41a) = Et (40b) = Et (41b) = i-Pr (40c) = i-Pr (41c) = CF3CH2 (40d) = CF3CH2 (41d) Figure 3. A selection of chiral phosphonates for asymmetric HWE olefinations. Expanding on these results, the Rein group has published a series of studies utilizing 40 and structurally related chiral phosphonates to differentiate enantiotopic carbonyl groups in various contexts. Four principal cases were demonstrated, all in good yields and with excellent levels of geometric selectivity and

19 Gais, H. J.; Schmiedl, G.; Ball, W. A.; Bund, J.; Hellmann, G.; Erdelmeier, I. Tetrahedron Lett. 1988, 29, 1773-1774. 20 Rehwinkel, H.; Skupsch, J.; Vorbruggen, H. Tetrahedron Lett. 1988, 29, 1775-1776.

6 asymmetric induction (Scheme 3): (1) Desymmetrization of meso-compounds;21a (2) Kinetic resolution of racemates;21b (3) Parallel kinetic resolution21c (PKR) (two substrate enantiomers react to give different products); and (4) Dynamic kinetic resolution (DKR)21d (a kinetic resolution occurs under such conditions that the enantiomers of the starting material are in equilibrium).

O O O O (1) Desymmetrization of meso H H H OR* compounds FG FG 42 FG FG 43 O O O O (2) R R R + R H H OR* H Kinetic resolution FG rac-44 FG FG 45 FG 44

O O O R OR* (3) R R R H H OR* + PKR FG O FG rac-44 FG FG (2E)-45 (2Z)-45 O O R OR* R R (4) H H DKR rac-44 FG O FG FG 45 Scheme 3. Principal cases for enantiotopic group discrimination by an asymmetric HWE reacion. Case 3 is interesting as it provides insights into the factors governing the stereochemical outcome of the reaction. The fact that each enantiomer will react to give different alkene isomers is accounted for by several factors when the FG of 44 is e.g. a protected hydroxyl group. The facial selectivity of a nucleophilic attack on an α-substituted aldehyde such as 46 can be predicted by the Felkin- Anh-Eisenstein (FAE) model to give a C3-C4 anti configuration (Scheme 4). Since one of the two diastereotopic faces of the enolate is blocked by the chiral auxiliary, the absolute configuration of the C2 stereocenter will be the same for both intermediates 47 and 49. Importantly, the relative configuration at C2 and C3 will thus differ with consequences for the elimination step as it proceeds through a syn elimination via a phosphaoxetane; this can only be formed upon a rotation around the C2-C3 bond resulting in (R,E)-48 beeing formed from 47 and (S,Z)-50 from 49. An interesting observation is that by running the reaction under conditions favouring the (E)- or the (Z)-product respectively,22 the enantiotopic preference will follow accordingly.23

21 (a) Kann, N.; Rein, T. J. Org. Chem. 1993, 58, 3802-3804. (b) Rein, T.; Kann, N.; Kreuder, R.; Gangloff, B.; Reiser, O. Angew. Chem. Int. Ed. 1994, 33, 556-558. (c) Pedersen, T. M.; Jensen, J. F.; Humble, R. E.; Rein, T.; Tanner, D.; Bodmann, K.; Reiser, O. Org. Lett. 2000, 2, 535-538. (d) Rein, T.; Kreuder, R.; Vonzezschwitz, P.; Wulff, C.; Reiser, O. Angew. Chem. Int. Ed. 1995, 34, 1023-1025. 22 The geometric selectivity of a HWE olefination is primarily influenced by the R- substituents on the phosphonate (Figure 3) with CF3CH2 (TFE) being (Z)-selective and Me, Et and i-Pr usually (E)-selective. Other factors that influence the geometric selectivity are the counter ion and additives such as crown ethers. 23 For further details on the reaction mechanism see: (a) Norrby, P. O.; Brandt, P.; Rein, T. J. Org. Chem. 1999, 64, 5845-5852. For a recent study of the parent HWE reaction see: Brandt, P.; Norrby, P. O.; Martin, I.; Rein, T. J. Org. Chem. 1998, 63, 1280-1289.

7 O O- (RO) P 2 O O- O O 41 R 4 2 R 3 OR* OR* + OPG FAE PGO P(OR)2 (R,E)-48 O O O 47 R R H H syn-Elimination

OPG OPG - O O O O- 46a 46b 2 4 R (RO) P 2 4 R R OR* *RO 3 2 3 (RO) P OPG 2 rotation OPG OPG O R*O O O 49a 49b (S,Z)-50 Scheme 4. Rationale for the stereochemical outcome of the asymmetric HWE reaction. In order to fully account for the stereochemical outcome of an asymmetric HWE, one must also consider the possibility of amplification of the desired product 43a in relation to the minor product 43b (Scheme 5). In a kinetic resolution of a ra- cemate one can usually drive the reaction to more than 50% conversion to increase the enantiomeric ratio of the unreacted starting material and vice versa. A similar reasoning applies also to a desymmetrization as any minor isomer 43b formed will be more prone to bis-addition compared to the major product 43a, resulting in a depletion of the undesired isomer.24

O O

H H FG FG 42

fast slow

O O O O Desired product (major) R*O H H OR* FG FG 43a FG FG 43b

slow fast

O O

R*O OR* FG FG 51 Scheme 5. The implications of a kinetic resolution of the major (43a) and minor (43b) mono-addition adducts in a HWE-desymmetrization. A mathematical model for such coupled processes has been reported by Schrei- ber and co-workers.25

24 This effect is potentially less important in this instance as 43a and 43b, due to the chiral auxiliary, are diastereomers, and thus in principle separable. In the case of a reaction where one adduct is an enantiomer of the desired product, e.g. a Sharpless epoxidation of divinyl- carbinol, the utility of such effects could increase. 25 (a) Schreiber, S. L.; Schreiber, T. S.; Smith, D. B. J. Am. Chem. Soc. 1987, 109, 1525- 1529. (b) Smith, D. B.; Wang, Z. Y.; Schreiber, S. L. Tetrahedron 1990, 46, 4793-4808.

8 1.5 Introduction to Annonaceous Acetogenins; Targets for Synthesis The annonaceous acetogenins (ACGs) constitute a growing class of natural products isolated from species of Annonaceae and comprising more than 400 individual members (Figure 4).26

HO C15 C34 OH OH HO O C13 OH OH C34 O O C10 C4 OH O O C10 C4 Pyranicin (53) OH O Pyragonicin (54) HO OH O O O OH OH O OH OH Mucocin (55) O O O HO OH OH O OH O 10-Hydroxyasimicin (56) O O OH O Jimenezin (57)

Figure 4. A selection of structurally related ACGs. The common structural feature of these fatty acid derivatives is a C32 or C34 carbon chain typically ending in a γ-lactone (Figure 5). The core chain is deco- rated with oxygenated functionalites such as hydroxyl, ketone, tetrahydrofuran (THF) and tetrahydropyran (THP) moieties, sometimes also accompanied by unsaturations. The ACGs are further divided, depending or their respective structures, into subgroups including mono-THF, adjacent bis-THF, nonadjacent bis- THF, non-THF ring, tri-THF, and nonclassical acetogenins (THP and ring- hydroxylated THF-containing compounds). The structures targeted in this study all belong to the nonclassical subgroup.

γ-Methyl-γ-lactone Oligonuclear appendage core unit C32/C34 OH C35/C37 OH OH O O O n n 58 OH OH C4 O Unbranched hydrocarbon Polyethylene chain linker Figure 5. A typical structure of an ACG. Biosynthetically, these structures are believed to originate from enzymatic ep- oxidations of polyenes such as 61 (Scheme 6). Following an initial formation of the γ-lactone from a condensation of a glycerol derivative (such as a synthetic equivalent of 60) to form the butenolide, the unsaturations are epoxidized. An

26 For reviews see: (a) Bermejo, A.; Figadère, B.; Zafra-Polo, M.-C.; Barrachina, I.; Estor- nell, E.; Cortes, D. Nat. Prod. Rep. 2005, 22, 269-303. (b) Alali, F. Q.; Liu, X.-X.; McLaugh- lin, J. L. J. Nat. Prod. 1999, 62, 504-540. (c) Zafra-Polo, M. C.; Figadère, B.; Gallardo, T.; Tormo, J. R.; Cortes, D. Phytochemistry 1998, 48, 1087-1117. (d) Casiraghi, G.; Zanardi, F.; Battistini, L.; Rassu, G.; Appendino, G. Chemtracts 1998, 11, 803-827.

9 internal hydroxyl group then acts as a nucleophile to trigger a series of ring- openings/ring-closures that subsequently forms the ring system(s).

O Goniocin (58) O O C12H25 OH C10 O C H O 12 25 O O O O HO 59 HO H 60

C12H25 OH HO 61 O Scheme 6. Proposed biosyntheic pathway for ACGs. When the first ACG, uvaricin, was reported in 1982,27 it was suggested as a potential new entry to treat cancer. Since then, the ACGs have been shown to exhibit a broad array of biological properties, including cytotoxic, antitumoral, antiparasitic, pesticidal, antimicrobial, and immunosuppressive activity.26a Mechanistically, ACGs have been shown to operate through inhibition of the mitochondrial respiratory chain complex I.28 ACGs are the most potent inhibitors of complex I reported, with some ACGs approaching a stochiometry of close to 1:1. The exact details of the mechanism whereby the cell proliferation is inhib- ited is not known, but the consequence of the inhibition is a depletion of ATP levels with a subsequent induction of apoptosis. Interestingly, ACGs have been shown to arrest cells in the G1 phase,29,30 an important observation as it differs from microtubulin stabilizing agents such as paclitaxel, which arrest proliferation in the M phase. It may also be noted that there have been reports suggesting that the ACGs are simply nonselective cell toxins. However, there is increasing evi- dence that these structures are in fact selective for cancer cell lines and as such may prove useful, upon elucidation of the details of the mechanism of action, to provide leads for drug development.31

As targets for total synthesis, the ACGs have received substantial attention over the last decade. While not overly complex, they pose a set of synthetic chal- lenges that can be approached via very different strategies thus making them popular for demonstrating the utility of novel methodology. Noteworthy chal- lenges in the synthesis of ACGs are the stereocontrolled synthesis of THF and

27 Tempesta, M. S.; Kriek, G. R.; Bates, R. B. J. Org. Chem. 1982, 47, 3151-3153. 28 Another potent inhibitor of this complex I is rotenone. 29 Yuan, S. S. F.; Chang, H. L.; Chen, H. W.; Yeh, Y. T.; Kao, Y. H.; Lin, K. H.; Wu, Y. C.; Su, J. H. Life Sci. 2003, 72, 2853-2861. 30 A recent report suggests that the ACG squamocin arrests cells in the G2/M phase; Lu, M. C.; Yang, S. H.; Hwang, S. L.; Lu, Y. J.; Lin, Y. H.; Wang, S. R.; Wu, Y. C.; Lin, S. R. Life Sci. 2006, 78, 2378-2383. 31 For an in-dept discussion see reference 26a and references therein.

10 THP oxacycles and control of remote stereocenters. Moreover, a complicating factor when devising a strategy to an ACG is the preservation of the stereochemical integrity of the butenolide subunit, which is sensitive to base-induced epimerization.32

32 Mild conditions such as TBSOTf, pyridine and DMAP have been shown to cause partial epimerization: (a) Latypov, S.; Franck, X.; Jullian, J.-C.; Hocquemiller, R.; Figadère, B. Chem. Eur. J. 2002, 8, 5662-5666. See also: (b) Yu, Q.; Wu, Y.; Wu, Y.-L.; Xia, L.-J.; Tang, M.-H. Chirality 2000, 12, 127-129. (c) Duret, P.; Figadère, B.; Hocquemiller, R.; Cave, A. Tetrahedron Lett. 1997, 38, 8849-8852.

11 12 2. Synthesis of (+)-Pyranicin and (+)- PyragonicinI-III “…the only thing that really worried me was the ether. There is nothing in the world more helpless and irresponsible and depraved than a man in the depths of an ether binge, and I knew we'd get into that stuff pretty soon.” R. Duke

2.1 Introduction In 1998 McLaughlin and co-workers reported the isolation and structure deter- mination of the first mono-THP ACGs pyranicin (53) and pyragonicin (54). Both compounds were isolated in minute quantities from the stem bark of Goniotha- lamus Giganteus (Hook f. & Thomas) and were shown to exhibit cytotoxic properties when tested toward a panel of cancer cell lines (Table 1).33

Table 1. ED50 (µg/mL) for pyranicin and pyragonicin.

HO OH OH O O OH O Pyranicin (53) HO OH OH O O OH O Pyragonicin (54)

A549 PACA-2 MCF-7 HT-29 A-498 PC-3 lung pancreatic breast colon kidney prostate carcinoma (adeno-) (adeno-) Pyranicin 2.8 x 10-1 1.3 x 10-3 3.9 x 10-1 1.2 1.8 x 10-1 4.1 x 10-1 Pyragonicin 2.0 5.8 x10-2 1.6 2.8 1.3 1.2 Adriamycina 7.8 x 10-3 1.6 x 10-2 4.7 x 10-1 3.9 x 10-2 6.8 x 10-2 3.6 x 10-1 a Positive control standard.

The two structures differ in the length of the C10-C15/C13 spacer and the length of the aliphatic chain. Interesting structural features include the all syn stereochemistry of the THP and opposite absolute configuration of the THP compared to that of previously reported nonclassical ACGs, e.g. mucocin,34 muconin35 and jimenezin.36

33 Alali, F. Q.; Rogers, L.; Zhang, Y.; McLaughlin, J. L. Tetrahedron Lett. 1998, 54, 5833- 5844. 34 Shi, G. E.; Alfonso, D.; Fatope, M. O.; Zeng, L.; Gu, Z. M.; Zhao, G. X.; He, K.; Macdou- gal, J. M.; Mclaughlin, J. L. J. Am. Chem. Soc. 1995, 117, 10409-10410.

2.2 Synthetic Efforts by Other Research Groups The first synthesis of pyranicin was published in 2003 by Takahashi and co- workers (Scheme 7).37

HO C10 C15 OH OH O O OH O Pyrancin (53)

Wittig coupling

MOMO OMOM OTBS O O O PPh3I + C9H19 OMOM 62 H 63 O

SmI2 mediated cyclization OHC OBn EtO C 2 O OBn OBn 64

HO OBn MgBr + OH + O OBn O 65 66 Scheme 7. Takahashi’s retrosynthetic analysis of pyranicin. The strategy chosen to construct the THP motif relied on a diastereoselective, SmI2-mediated radical cyclization resulting in the syn-anti THP 68 (Scheme 8). This strategy has previously been exploited by the same group in a synthesis of related annonaceous acetogenins, as it provides the correct relative stereochemistry for mucocin.38 To reach the all-syn configuration of pyranicin, the authors cleverly exploited the ester functionality to perform a lactonization under Mit- sunobu conditions, which provided the desired all-syn THP 69.

1. NaOH, 5% EtOH HO OHC SmI 2. PPh3, DEAD, O 2 THF O EtO2C EtO C O 2 O MeOH, THF O OBn 89% over 2 steps 670 oC, 86% 68 OBn 69 OBn Scheme 8. Takahashis synthesis of the THP ring of pyranicin/pyragonicin.

35 Shi, G.; Kozlowski, J. F.; Schwedler, J. T.; Wood, K. V.; MacDougal, J. M.; McLaughlin, J. L. J. Org. Chem. 1996, 61, 7988-7989. 36 Chavez, D.; Acevedo, L. A.; Mata, R. J. Nat. Prod. 1998, 61, 419-421. 37 Takahashi, S.; Kubota, A.; Nakata, T. Org. Lett. 2003, 5, 1353-1356. 38 Takahashi, S.; Kubota, A.; Nakata, T. Angew. Chem. Int. Ed. 2002, 41, 4751-4754.

14 A series of straightforward transformations then yielded the pyrancin THP- fragment 62. Interestingly, the authors were able to employ a Wittig olefination to assemble the completed pyranicin skeleton without interfering with the base- sensitive butenolide moiety. In 2005 the Takahashi group also published a study employing a similar strategy in a total synthesis of pyragonicin,39 one difference being that the C10 stereocenter was directly introduced onto the pyragonicin THP framework using Brown’s asymmetric allylation. Even more recently, the same group reported an alternative, more expedient route to pyragonicin.40

Synthetic and natural pyranicin, however, exhibited opposite signs in the optical rotation, and the same held true for synthetic and natural pyragonicin. The origin of these discrepancies were interpreted as most likely being due to experimental error in the original publication as the optical rotations of the natural products were recorded at very low concentrations.41 In the case of pyragonicin, minor discrepancies were also found in the 1H spectra of the tetra- Mosher esters of the synthetic material, prompting the authors to synthesize 10-epi-pyragonicin and subsequently exclude it as the correct structure of natural pyragonicin.39

2.3 Retrosynthetic Analysis of Pyranicin/Pyragonicin We sought to devise a strategy towards pyranicin/pyragonicin taking advantage of the asymmetric HWE reaction to access key intermediates, while at the same time allowing for the synthesis of both natural products from common intermediates. Ideally, the divergence point would be as late as possible in the synthesis.

We postulated that we could install both the C4 stereocenter and the C17/C14 (pyragonicin) and C19/C16 (pyranicin) stereocenters using asymmetric HWE reactions (Scheme 9).

39 Takahashi, S.; Ogawa, N.; Koshino, H.; Nakata, T. Org. Lett. 2005, 7, 2783-2786. 40 Takahashi, S.; Hongo, Y.; Ogawa, N.; Koshino, H.; Nakata, T. J. Org. Chem. 2006, 71, 6305-6308. 41 23 25 Natural pyranicin: [α]D -9.7 (c = 0.008, CHCl3); natural pyragonicin, [α]D –25.6 (c 0.008, CHCl3) (Reference 33).

15 HO PGO Sonogashira C15/C13 OH OH C34 cross-coupling R O I O C10 C4 C9H19 O + 75 n OH O OH Pyranicin (53) R = C9H19, n = 3 Pyranicin THP fragment 70 Pyragonicin (54) R = C11H23, n = 1 Zn-mediated asymmetric Zn-mediated asymmetric acetylide addition coupling

PGO OH OPG H + O R O O O Pyragonicin THP fragment 71 Butenolide fragment 75 Hetero-Michael addition, Asymmetric acetylide addition Wittig olefination and butenolide contruction R*O O OPG OPG OR* O OPG OH 72 H 76 Asymmetric HWE and O Mitsunobu inversion HWE-parallel kinetic resolution C15/C13 and Pd-cat. stereoconvergent O O sequence O O R* = chiral auxiliary; H H O C4 C4 O 5 steps H H PG = protective group OPG OPG 74 73 rac-77 Scheme 9. Retrosynthetic analysis of pyranicin/pyragonicin. Vares and Rein have previously shown that HWE adducts of meso-dialdehydes such as 73 can be used to stereoselectively form THPs through an intermolecular oxa-Michael cyclization.42 However, to reach the all-syn configuration of 71 and 70, the meso symmetry of 73 had to be modified via invesion of one stereocenter. The C4-stereocenter of the butenolide fragment would originate from racemic acrolein dimer (rac-77), through a PKR followed by a stereoconvergent reaction sequence. In the key stereoconvergent Pd-catalyzed transformation, we hoped to expand previous methodology by using a nucleophile that would result in a C4 hydroxyl bearing a protective group suitable for last step global deprotection. The butenolide moiety would then be constructed using well established methodology through a condensation of a lactaldehyde derivative with a derivative of ester 76.

2.4 Synthesis of Pyranicin and Pyragonicin

2.4.1 Synthesis of the Tetrahydropyran Fragments The initial asymmetric HWE desymmetrization of meso-dialdehyde 78 performed well on multi-gram scale giving the HWE adduct 79 as a single detected stereoisomer in good yield (Scheme 10). Subsequent reduction/protective group migration followed by a two step Mitsunobu inversion sequence of the C7 hydroxyl group provided a 9:1 mixture of secondary alcohols 81a and 81b in good overall yield.43

42 Vares, L.; Rein, T. J. Org. Chem. 2002, 67, 7226-7237. 43 Reduction of 79 gave 80a and 80b as a ~9:1 mixture from which 80a could be isolated in 70% yield (total yield over two steps). The remaining mixture of 80a and 80b could be re- equilibrated (DMAP, EtOH, ∆, 70%) to increase the overall yield of 80a.

16 O O (CF CH O) P 3 2 2 O 41d NaHMDS, O O Ph O

H H H THF, -78 °C NaBH OP1 OP1 dr >98:2, (Z):(E) >98:2 OP1 OP1 4 OR' THF, i-PrOH 1:1, 0 °C 78 79 O 70% of 80a over 2 steps from 41d 1. ClCH CO H, TPP, 2 2 1 OP1 OH DIAD, toluene, OP OH OH OP1 2. LiOH, THF, OH OP1 CO R' CO R' CO2R' CO2R' 2 + 2 C7 + 88% over 2 steps 1 1 OP1 OP1 OP 80a OP 80b 81a 81b

DMAP, EtOH, ∆, 70% of 80a P1 = TBDPS R' = Ph Scheme 10. Synthesis of the secondary alcohols 81a and 81b. With the secondary alcohols 81a and 81b at hand, we were pleased to find that, we could promote an oxa-Michael cyclization in excellent yield and good diastereoselectivity under conditions where protective group migration occurred, resulting in an essentially quantitative yield of 82 (Scheme 11). The key parameter to allow for migration under the cyclization conditions was the use of toluene as the solvent. On the basis of a study by Martín and co-workers44 one would expect (Z)-81a to give the trans-trans product 83 as the kinetically favoured product. We hypothesized that the syn-syn stereochemistry actually obtained was due to an equilibration proceeding via a retro-Michael reaction.

1 OH t-BuOK P O CO2R' CO2R' + 81b O 1 P1O 81a OP toluene, 0 ° quant., dr = 96:4 1 t-BuOK 82 OP toluene/t-BuOH 2:3, dr > 98:2, 76 %

CO2R' t-BuOK O toluene, 0 °C P1O quant., dr = 95:5

1 83 OP P1 = TBDPS R' = Ph Scheme 11. Oxa-Michael cyclizations of secondary alcohols 81a and 81b. Based on this information and the fact that we at low conversions could isolate 82 with lower diastereomeric purity, we investigated the possibility of trapping the kinetic product of the cyclization by running the reaction in a non- nucleophilic protic solvent such as t-BuOH. Indeed, the cyclized product formed under these conditions was isolated as a single detected trans-trans stereoisomer 83 in good yield.45 This result is especially intriguing as it, in conjunction with

44 (a) Betancort, J. M.; Martín, V. S.; Padron, J. M.; Palazon, J. M.; Ramirez, M. A.; Soler, M. A. J. Org. Chem. 1997, 62, 4570-4583. (b) Ramirez, M. A.; Padron, J. M.; Palazon, J. M.; Martín, V. S. J. Org. Chem. 1997, 62, 4584-4590. 45 The relative configurations of 82 and 83 were confirmed by 2D NOESY correlations after reduction of the esters to the corresponding alcohols.

17 previous results,42 provides an expedient access to all stereoisomers of 2,3,6- substituted THPs analogous to 84 through essentially the same reaction sequence. The importance of this observation is emphasized by the presence of these substructures in several natural products besides pyranicin/pyragonicin, e.g. decarestrictine L,46 jimenezin (57)36 and mucocin (55) (Figure 6).34

O PGO CO2R*

84 OPG Pyranicin, Pyragonicin O PGO CO2R* O PGO CO2R* OPG 85 OPG 86 O O O O PGO CO2R* PGO CO2R* H H OPG 87 OPG OPG 88 OPG Mucocin, Jimenezin 73

O O PGO CO2R* PGO CO2R* O 90 OPG 89 OPG PGO CO2R* Decarestrictine L 91 OPG Figure 6. Controlled access to all possible isomers of 2,3,6-substituted THPs analogous to 84. To provide a detailed rationale for the stereochemical outcome of the cyclizations, we performed a computational study that confirmed our initial assumption of 83 as the kinetic product and 82 as the thermodynamic product formed via the intermediate (2E)-alkene 96 (Scheme 12).47

Minimal strain O O CO2R' H CO2R' 1 P O 1 1 P O 1 O OR' P O 92 OP Proton O source 93 P1O CO2 OP1 O P1O R' OP1 O O 94 83a H CO2R' 1 1 CO2R' 1 P O P O 1 OP 1 CO2R' OP 96 P O O 95 P1O 83b O OP1 1 OP1 H OP O Proton O source 1 O P O 1 O CO R' P O CO R' 1 P1O 2 OR' P1O 2 P O 99 98 82 97 CO2R'

P1 = TBDPS R' = Ph Scheme 12. Mechanistic rationale for the stereochemical outcome of the oxa-Michael- cyclization.

46 Grabley, S.; Hammann, P.; Huetter, K.; Kirsch, R.; Kluge, H.; Thiericke, R.; Mayer, M.; Zeeck, A. J. Antibiot. 1992, 45, 1176-1181. 47 See publication III for further details on the computational study.

18 Having established a reliable route for the formation of the THP ring, we focused on completing the respective THP fragments. A one-pot DIBAL/Wittig reaction served to install the aliphatic side chains in good yields to give intermediates 100a and 100b (Scheme 13). The subsequent selective deprotection of the primary TBDPS groups of 100a,b proceeded as expected based on previous work by Vares and Rein.48

O OR' (i) DIBAL-H, CH Cl , -78 °C 1 OR1 2 2 OR R (ii) PPh BrCH R, NaHMDS, 3 2 O O THF, -78 °C to rt

1 OP1 100a: 75%, (E):(Z) ~ 1:10 OP 82 100b: 78%, (E):(Z) ~ 1:10 Al2O3, 100a,b: R1 = TBDPS hexanes 101a: R1 = H; 83%; 101b: R1 = H; 81% O R DMP, pyridine, O H P1 = TBDPS CH2Cl2, 0 °C to rt 102a: 81%; 102b: 83% OP1 series a: R = C9H19; R' = series b: R = C11H23 Ph

Pyranicin THP subunit (102a) Pyragonicin THP fragment (102b) Scheme 13. Completion of the pyragonicin fragment 102b and pyranicin subunit 102a. A Dess-Martin oxidation of the primary alcohol moieties in 101a,b then gave the corresponding aldehydes 102a,b thus completing the synthesis of the pyragonicin THP fragment. To reach the pyranicin THP fragment 105, a further three steps were required, starting with a stereoselective addition of a two carbon unit to aldehyde 102a (Scheme 14). An asymmetric Zn-mediated alkynylation worked well using TMS-acetylene as the alkyne under Carreiras conditions,49 resulting in the desired propargylic alcohol 103 in good yield and with excellent diastereoselectivity.50 The subsequent one-pot TBS protection and removal of the TMS group then gave the TBS protected terminal alkyne 104 in good yield. The pyranicin THP fragment 105 was completed via a hydrozirconation using Schwartz’ reagent followed by addition of elemental iodine giving the (E)-vinyl iodide.

48 Vares, L., Ph.D. Thesis, Tartu University, Tartu, Estonia, 2000. 49 (a) Boyall, D.; Frantz, D. E.; Carreira, E. M. Org. Lett. 2002, 4, 2605-2606. (b) Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 9687-9688. 50 Since intermediates 103, 104, 105 and 135 were carried through the synthesis as mix- tures of (E):(Z)-isomers, an exact quantification of the stereochemical outcome of the addition could not be made. However, we did not observe a minor diastereomer derived from this transformation in any of the remaining steps of the synthesis. The relative configuration of 103 was assigned in analogy with literature.

19 (-)-NME, Zn(OTf) , O R 2 OH R (i) TBSCl, imidazole, Et3N, DMAP, CH Cl , O O 2 2 H TMS (ii) K2CO3, MeOH TMS toluene, 83% OTBDPS OTBDPS 103 93% 102a dr see footnote 50

OTBS R OTBS R O Cp2ZrHCl, I2 O I THF, 86% OTBDPS 104 OTBDPS

Pyranicin THP fragment (105) R = C9H19 R' = Ph Scheme 14. Completion of the pyranicin fragment 105.

2.4.2 Synthesis of the Shared Butenolide Fragment The synthesis of the shared butenolide fragment began with a PKR of racemic acrolein dimer 77 (Scheme 15). Under the reaction conditions, the enantiomers of the starting material react to give products of opposite alkene geometry (see section 1.4). This reaction has previously been performed using a mixture of (E)- and (Z)-selective chiral phosphonates;51 we were however pleased to find that using only phosphonate 40d resulted in a much simplified protocol with somewhat improved diastereoselectivity. The acid-catalyzed addition of water to the vinyl ethers 106a and 106b required a fair amount of optimization, as the reaction was slow at room temperature and significant amounts of unidentified by- products were obtained at 40 oC. Pleasingly, we found that precise control of the reaction temperature gave consistent results even on a multigram scale.

O O R'' = H O O (CF CH ) P Ph rac-77 3 2 2 O KHMDS, Ph 18-Crown-6, THF, -78 °C, 77%, 106a/106b = 40:60

O CO2R'' O (2E,4R)-106a, (2Z,4S)-106b, dr = 98:2 CO2R'' dr = 96:4

p-TSA, THF/H2O, 32 ±2 °C, 85%

HO O HO O CO2R''

CO2R'' 107a 107b Scheme 15. Synthesis of hemiacetals 107a and 107b. Progress towards the butenolide fragment then relied on trapping the aldehyde tautomers of hemiacetals 107a,b. A complicating factor is the tendency of 107b to cyclize intramolecularly to form lactone 109. In our initial efforts we hoped to

51 The PKR of rac-77 was previously performed using a mixture of 40c and 40d. See reference 21c.

20 react 107a,b with an ylide such as 108 (Scheme 16). The advantage of such an approach would be the direct access to an aldehyde from which the C10 stereocenter could arise through a stereocontrolled addition of a two carbon unit. Un- fortunately, no olefinated products were obtained under non-forcing conditions such that the undesired lactonization was suppressed.52 An alternative reagent, in which the aldehyde is masked as an imine (which is hydrolyzed upon workup to give the α,β-unsaturated aldehyde) is phosphonate 111.53 Pleasingly, we found that by using 111 in a HWE reaction, both hemiacetals 107a,b could be opened without lactonization if LiHMDS was used as the base at 0 oC.54 Somewhat surprisingly, no aldehyde was found as a result of the reaction; instead a compound, tentatively assigned as the intramolecular [4+2] adduct 114 formed via tautomerization of 112 to 113, was isolated in moderate yield as an inseparable 1:1 mixture of diastereomers.55

O 108 O HO O Ph P 3 O H + CO2R'' benzene OH 107b 109 110 Cy Ph O N (EtO) P 2 H 111 LiHMDS, 0 oC THF Cy Cy NH NH

Cy CO2R'' * CO2R'' N OR CO2R'' * * OH OH H * 114 112 113 45%, dr = ~1:1 R'' = Ph Scheme 16. Attempted opening of hemiacetal 107b. Despite the fact that we were not able to access the C10 aldehyde directly, we could exploit the conditions developed for the HWE with imine-phosphonate 111 using a benzyloxycarbonyl phosphonate instead (Scheme 17). This reagent was designed to introduce a functional group differentiable from the 8-phenylmentyl ester without adding additional steps to the sequence.

52 At room temperature no olefin was formed, whereas lactonization occured at elevated temperatures. 53 Nagata, W.; Wakabayashi, T.; Hayase, Y. Org. Synth. 1973, 53, 44-48. 54 Other counterions, K or Na, resulted in extensive lactone formation. 55 While not constructive for the synthesis of ACGs, this reaction may prove useful in other settings, as the generic requirement for the formation of the fused 5/6 ring system under these conditions appears to be a substrate combining an α,β-unsaturated EWG with an aldehyde in the C8 position (or possibly C9 position to give a fused 6/6 system).

21 O OH O O Ph2PO 107a BnO CO2R'' (EtO) P(O)CH CO Bn, Ph2P(O)Cl, imidazole, 2 2 2 115a BnO CO2R'' DMAP, LiHMDS 116a DCE, 60 °C, THF, 0°C, O 96% (8E):(8Z) = 20:1, O OH CO2R'' 107b 80% O Ph2PO CO2R'' BnO BnO 115b 116b R'' = Ph Scheme 17. Synthesis of phosphinate esters 116a and 116b. With alcohols 115a and 115b at hand, the C4 hydroxyl groups were activated for a Pd-catalyzed allylic substitution by conversion into the phosphinate esters 116a and 116b. In a in this reaction, (Z)-substrates are known to react with stabilized nucleophiles with inversion of both the alkene geometry and the configuration at the allylic position due to a π-σ-π rearrangement, while (E)-substrates are known to react with retention at both stereogenic units (Scheme 18).56

H R EWG R

EWG OPPh2 H Nu O 118 117

Oxidative addition Nucleophilic attack (inversion) (inversion)

H H R LnPd R EWG R EWG R

EWG PdL EWG H PdLn H Pd n 120 121 122 119 π−Allyl complex σ−Alkyl complex σ−Alkyl complex π−Allyl complex (anti-syn) (syn-syn) Scheme 18. Mechanistic rationale for the outcome of the Pd-catalyzed stereoconvergent allylic substitution. Consequently, by exposing a mixture of 116a and 116b to a Pd0 catalyst, we expected both substrates to converge into a single product stereoisomer. This concept has previously been exploited by Pedersen et. al using MeOH as the nucleophile in a synthesis of the C12-C19 fragment of the iejimalides.56 We wanted to expand this concept by using a nucleophile that would install a protected C4 hydroxyl, and ideally, a protective group suitable for last step global deprotection. A candidate for such an approach is TMS(CH2)2OH, commonly used to protect acids but sparingly used for alcohols.57 Unfortunately, initial work revealed the previously published conditions (DPPE as ligand and THF as cosolvent) to be inadequate for rather poor nucleophiles such as TMS(CH2)2OH, resulting in extensive β-elimination to 127 (Table 2). Pleasingly, we found that

56 Pedersen, T. M.; Hansen, E. L.; Kane, J.; Rein, T.; Helquist, P.; Norrby, P.-O.; Tanner, D. J. Am. Chem. Soc. 2001, 123, 9738-9743. 57 This is likely due to its difficult introduction. A recent interesting solution to this problem is an enantioselective O-H activation reaction; Maier, T. C.; Fu, G. C. J. Am. Chem. Soc. 2006, 128, 4594-4595.

22 running the reaction in chlorinated solvents with anhydrous neocuproine as ligand resulted in essentially complete suppression of byproduct formation and the desired protected allylic alcohols were obtained in good yields with excellent diastereomeric purity. On a gram scale, as little as 1.25 mol% catalyst could be used. To expand the utility of this transformation, we also investigated the use of other nuclophiles such as PMBOH, PMPOH, and TBSOH. PMBOH and PMPOH worked well, giving the corresponding C4 protected alcohols 124 and 126 in good yields, while TBSOH failed to give product.

Table 2. Representative results of the stereoconvergent step. O

O OPPh2

BnO CO2R'' 116a Retention O OR a Inversion BnO CO2R'' BnO 123: R = TMS(CH2)2 124: R = PMB O Ph2PO CO2R'' 125: R = TBS O 116b 126: R = PMP

127 = CO2R'' Neocuproine = R'' = N N Ph

Nucleophile Ligand Cosolvent (2E,4R): Prod. Prod.:127 Yield (2E,4S)a (%)

b b TMS(CH2)2OH Neocuproine CH2Cl2 97:3 123 94:6 72 c c TMS(CH2)2OH Neocuproine THF 97:3 123 87:13 65 b c d TMS(CH2)2OH DPPE THF 98:2 123 52:48 - b c d TMS(CH2)2OH DPPP THF 94:6 123 61:39 - b,e d PMBOH Neocuproine CH2Cl2 97:3 124 - 89 TBSOH Neocuproine THF - (125) 0:100b 0 d f PMPOH Neocuproine CH2Cl2 98:2 126 - 40

Reagents and conditions: (a) 116a/116b, Pd2dba3 (0.2-0.4 equiv Pd), ligand (0.4-0.6 equiv), cosolvent/R-OH (1:1).a The dr of the product in all cases matches that of the starting material. b Determined by 1H NMR of the crude product. c Determined by 1H NMR after filtration through a short plug of silica. d Not recorded. e Separable by flash chromatography. f The yield is not representative due to experimental error (unpublished results; Strand and Rein).

One key challenge remaining in the synthesis of the butenolide fragment was the installation of the C10 stereocenter. Differentiation of the two ester functionalities in 123 was readily accomplished, since the benzyl ester was cleaved by hydrogenolysis under the conditions used for reduction of the unsaturations of 123 (Scheme 19). A borane reduction of the resulting acid to the corresponding alcohol followed by a Dess-Martin oxidation then provided aldehyde 129. The C10 stereocenter could subsequently be installed through an asymmetric alkynylation under Carreira’s conditions using TMS-acetylene as the alkyne. The enolizable aldehyde 129 behaved surprisingly well upon refinement of the reac-

23 tion conditions and the desired propargylic alcohol 130 was obtained in good yield and with excellent diastereoselectivity.58,59

To complete the fragment, various protective group strategies for the propargylic hydroxyl group were evaluated (i.e. TBS, TBDPS) but after the aldol reaction with lactic aldehyde 134, we were unable to accomplish the lactonization without interfering with the C10 protective group.60 The solution, simple as it may seem, was to carry the C10-hydroxyl through the remaining steps of the synthesis unprotected. The construction of the butenolide by condensation of 130 with aldehyde 134 was well precedented61 and proceeded as expected without inter- ference from the C10 alcohol. The chemoselective elimination of the C13 hydroxyl group was accomplished using trichloroacetic acid chloride to form bis- ester 132 which spontaneously eliminates to form the butenolide under the reaction conditions. The C10 ester could then be released upon a mild basic workup to give the completed butenolide fragment 133 in good yield over three steps.

. 1. BH3 DMS, THF TMS TMS 2. DMP, pyridine, CH2Cl2, O O Pd(C), H2 O O 0 °C to rt

BnO CO2R'' hexanes, 90% HO CO2R'' 123 128 2 steps, 82%

TMS TMS O O (+)-NME, Zn(OTf)2, Et3N, OH O TMS CO2R'' H CO2R'' 129 toluene, 60 °C, 75%, TMS 130 C10 dr = 98:2

(i) LDA, 134, THF, -78 °C TMS HO O OH O OTHP (ii) K2CO3, MeOH, -78 °C to rt OTHP H R'' = CO R'' 134 131 2 Ph

1. CSA, MeOH, ∆ Cl3C O C13 2. Cl3C(O)Cl, Et3N, O TMS NaHCO3 workup OH O CH2Cl2 TMS O Cl3C O O O O 3 steps, 79% 133 C10 O 132 O

Scheme 19. Completion of the shared butenolide fragment 133.

58 Enolizable aldehydes such as 129 are reported to give poor results in this reaction under standard conditions; see: Kirkham, J. E. D.; Courtney, T. D. L.; Lee, V.; Baldwin, J. E. Tetra- hedron 2005, 61, 7219-7232 and references therein. 59 The dr was determined by 1H and 19F analysis of the corresponding (+)- and (-)-MTPA ester derivatives. 60 Both acidic (CSA, MeOH) and basic conditions (LiOH, THF/H2O) resulted in removal of the C10 protective group. 61 Ito, Y.; Kobayashi, Y.; Kawabata, T.; Takase, M.; Terashima, S. Tetrahedron 1989, 45, 5767-5790.

24 2.4.3 Endgames Towards Pyranicin and Pyragonicin With the completed fragments at hand we focused on the respective endgames. The pyranicin framework was readily assembled using a Sonogashira coupling in presence of the unprotected C10 hydroxyl group (Scheme 20).62 A diimide reduction of diene-yne 135 served to set the stage for a final global deprotection. Un- fortunately, several protocols evaluated resulted in only partial deprotection or decomposition of the substrate. Pleasingly, using HF at a slightly elevated temperature we were able to remove both the TBS, TBDPS and the TMS(CH2)2 ethers in one pot in good yield to give pyranicin (53), identical in all respects to the data for synthetic pyranicin reported by Takahashi. As mentioned in section 2.1, it should however be noted that the specific rotation differs significantly from that reported for the natural product by McLaughlin.63 To ensure that this difference was not due to epimerization of the butenolide, we employed Fi- gadère’s method32a using chiral shift agents and were able to confirm that within limits of detection no epimerization had occurred.

TBDPSO TMS OH O I O + O C H OTBS 9 19 105 133 O

(Ph3P)2PdCl2, CuI, Et3N, 89%

TMS OH O TBDPSO O

O 135 O

C9H19 OTBS

1. TsNHNH2, NaOAc, 2 steps, 72% ∆ H2O, DME, overall 2. HF (aq), MeCN, 40 °C HO OH OH O O OH O Pyranicin (53)

Scheme 20. Endgame towards pyranicin. For pyragonicin, the fragment coupling was more intricate as it should also install the C13 sterocenter. Another complicating factor was the possibility of epimerization of the butenolide. We turned once again to Carreira’s Zn-mediated asymmetric alkynylation, as this reaction has been shown to override stereofacial bias in similar reactions and has been shown to give good results in the presence of unprotected propargylic alcohols.64 The conditions are also not overly basic, which showed promise to preserve the integrity of the butenolide. Pleasingly, the reaction proceeded cleanly, albeit only to 40% conversion (Scheme 21). The

62 Marshall, J. A.; Jiang, H. J. Org. Chem. 1999, 64, 971-975 and references therein. 63 23 63 23 Natural pyranicin, [α]D -9.7 (c = 0.008, CHCl3); synthetic material (Takahashi), [α]D 23 +19.5 (c = 0.55, CHCl3); our synthetic material, [α]D +21.1 (c = 0.24, CHCl3) 64 Amador, M.; Ariza, X.; Garcia, J.; Ortiz, J. Tetrahedron Lett. 2002, 43, 2691-2694.

25 stereoselectivity appeared excellent, but was not quantified.65 Since the remaining unreacted butenolide fragment could not be easily removed from the coupled pyranicin framework 136 by chromatography, the two remaining steps were performed on a mixture of 136 and 133. A diimide reduction of the chain unsaturations, followed by global deprotection under identical conditions as was used for pyranicin, gave pyragonicin, identical to the natural product in all respects except its specific rotation.66 We once again confirmed the retained integrity of the butenolide using Figadère’s method.32a

TBDPSO TMS OH O H + O O C H O 133 11 23 102b O

40% conversion Zn(OTf)2, (-)-NME, Et3N of 133 toluene, dr see footnote 65 TMS OH O TBDPSO C13 O

O 136 O

C11H23 OH 1. TsNHNH , NaOAc, 34% over 2 H O, DME, ∆ 3 steps 2 2. HF (aq), MeCN, 40 °C

HO OH OH O + O OH OH O OH 54 O 137 O Scheme 21. Endgame towards pyragonicin.

2.5 Biological Evaluation67 In collaboration with the Walther Cancer Institute we subjected a MCF-7 cell line to pyranicin, pyragonicin and butenolide 137. Not surprisingly, butenolide 137 was found to be inactive. This result supports the notion that the oligonuclear motif (as well as the hydrocarbon side chain) is required for the potency of these structures. Pyragonicin and pyranicin displayed the expected IC50 values in the low micromolar (1.20 µM) and sub-micromolar (0.17 µM) range respectively which is in good agreement with McLaughlins original data.

65 The stereoselectivity could not be directly quantified due to the (E):(Z) mixture of the alkene and the presence of 133, but at no point in the subsequent steps could we detect any minor diastereomer attributed to the C13 stereocenter. 66 25 24 Natural pyragonicin, [α]D –25.6 (c 0.008, CHCl3), synthetic material (Takahashi) [α]D 25 +13.8 (c 0.11, CHCl3); our synthetic material, [α]D +10.5 (c 0.125, CHCl3). 67 The Walther Cancer Institute, Prof. Paul Helquist and Dr. Bakshy Chibber are gratefully acknowledged for performing these tests.

26 2.6 Conclusions and Outlook We have accomplished convergent stereoselective syntheses of the proposed structures of pyranicin (53) and pyragonicin (54) through a common synthetic route. The longest linear sequence to pyranicin comprises 19 isolated intermediates starting from cyclohexadiene, with an overall yield of 6.3%. The longest linear sequence to pyragonicin comprises 16 isolated intermediates from acrolein dimer (rac-77) with an overall yield of 5.5% (16 isolated intermediates, 6.4% overall yield from cyclohexadiene). Several of the key steps, such as the asymmetric HWE reactions, the stereoconvergent sequence and the construction of the 1,4- and 1,6-diol motifs serve to highlight current synthetic methodology.

A relevant extension of this work would be to confirm the relative stereochemistry of pyranicin and pyragonicin. This would, however, require access to authen- tic material of the natural products, and unfortunately this was not available to us.

With synthetic routes to 53 and 54 at hand, future work in this area may include the synthesis of labelled analogues to facilitate biological evaluation68 and the synthesis of simplified analogues that can be more readily accessible in larger quantities for testing. Studies based on variations of the latter theme have met with some success in retaining the potent biological properties exhibited by these structures.69

68 For a study employing this approach see; Han, H. N.; Sinha, M. K.; D'Souza, L. J.; Keinan, E.; Sinha, S. C. Chem. Eur. J. 2004, 10, 2149-2158. 69 Jiang, S.; Li, Y.; Chen, X.-G.; Hu, T.-S.; Wu, Y.-L.; Yao, Z.-J. Angew. Chem., Int. Ed. 2004, 43, 329-334.

27 28 3. Towards the Synthesis of (-)- MucocinIV

“I shall be telling this with a sigh. Somewhere ages and ages hence: Two roads di- verged in a wood, and I — I took the one less traveled by. And that has made all the difference.” R. Frost

3.1 Introduction The isolation70 and structural elucidation of mucocin (55) was first reported by McLaughlin in 1995.34 Mucocin immediately attracted attention as it was the first ACG containing a THP motif and consequently it was defined as a nonclassical ACG. The combination of its unusual structure and highly selective cytotoxic properties (Table 3)34 attracted attention from the scientific community. Particularly noteworthy is the large difference in the potency of mucocin towards different cell lines.71 If this is indeed a reproducible observation, it points to a selectivity that could have important implications. One would expect a large therapeutic window if such an effect could be mimicked by a simplified drug operating through the same mechanism.

Table 3. ED50 (µg/mL) for mucocin.

HO OH O O O OH OH O Mucocin (55)

A549 PACA-2 MCF-7 HT-29 A-498 PC-3 lung pancreatic breast colon kidney prostate carcinoma (adeno-) (adeno-) Mucocin 1.0 x 10-6 4.7 x 10-7 1.8 9.4 x 10-1 2.6 1.6 x 10-1

Adriamycina 4.0 x 10-3 2.1 x 10-3 4.7 x 10-1 2.8 x 10-2 4.7x 10-3 4.1 x 10-2 a Positive control standard.

3.2 Synthetic Efforts by Other Research Groups Within two years of the disclosure of its structure, the first total synthesis of mucocin was reported by Keinan.72 This study takes clever use of the electronic

70 Mucocin was isolated from the leaves of Rollinia mucosa. 71 This property is not unique for mucocin. 72 Neogi, P.; Doundoulakis, T.; Yazbak, A.; Sinha, S. C.; Sinha, S. C.; Keinan, E. J. Am. Chem. Soc. 1998, 120, 11279-11284.

29 properties of bis-epoxide 142 to form the 6- and 5-membered rings in a single step (Scheme 22).

O OH SAE OH OH OH 139 O 138 140 5-exo-tet OH HO O O AD O O

OH OH C H OTBS C8H17 142 OTBS 8 17 141 6-exo-tet TsOH HO

O O OTBS mucocin (55) OH OH OH C H 8 17 143 Scheme 22. Keinan’s synthesis of mucocin. Since then, several total syntheses have been reported using very different approaches. Takahashi and co-workers reported a synthesis relying on the chiral pool and subsequent diastereoselective transformations to complete mucocin.73 The most expedient synthesis is published by P. A. Evans and co-workers, employing a triply convergent strategy requiring a longest linear sequence of only 12 steps from the first chiral intermediate 144 (Scheme 23).74 Other interesting aspects of this elegant study are a stereoselective fragment coupling and the fact that the THP and THF rings are formed from a common precursor 144.

OTBS HO TBSO OH O O TBSO O 144 TBSO C H OPMP C H OPMP 7 15 7 15 147 145 OPMP 146

OH OPMP OH O OPMP 150 O 148 OPMP 149

OTBS OTIPS O mucocin (55) O O O O O 151 C7H15 Si i-Pr i-Pr Scheme 23. Evans’ expedient synthesis of mucocin.

73 Takahashi, S.; Nakata, T. J. Org. Chem. 2002, 67, 5739-5752. 74 Evans, P. A.; Cui, J.; Gharpure, S. J.; Polosukhin, A.; Zhang, H. R. J. Am. Chem. Soc. 2003, 125, 14702-14703.

30 Other total syntheses of mucocin include reports by Koert,75 Zhu76 and Crim- mins.77

3.3 Retrosynthetic Analysis of Mucocin In dissecting the mucocin framework, we identified two strategic disconnections at C8/C9 and C16/C17, resulting in the three main fragments 153, 158 and 160 (Scheme 24). Consequently, a triply convergent strategy was devised. Previous work in the Rein group has demonstrated the utility of HWE desymmetrization adducts for the construction of the THP and THF oxacycles of mucocin from common precursors.48 This work, however, relied on the use of different protect- ing groups for the construction of each oxacycle. It seemed plausible that a more efficient approach would be to construct the two fragments from the same intermediate 156, thus differentiating between the two routes as late as possible. In addition, such a strategy would provide an interesting option to exploit the aldehyde functionality of 156 directly via a stereoselective alkynylation, thus providing access to the C8 stereocenter of 155 without intermediate protective group manipulation.

HO C16/C17 C8/C9 OH O R O O OH OH Mucocin (55) R=C8H17 O

sp3-sp3 Cross coupling O

RO O TBSO X + R O O 160 OR OR 152 Stereoselective Alkylation/ coupling elimination O R OR PhS I + O O O O + O OTBS 161 153 H OR* 162 RO 158

Wittig olefination Pd-cat. allylic subst. O OR* OPiv OR* O PivO OH OPiv O 159 TMS 154 OPiv Reduction/ Oxa-Michael PG-migration C8 OH Asym. alkynylation O Asym. HWE O O OR* OR* H H H OPiv OPiv O OPiv OPiv TMS OPiv OPiv O 155 156 157 Scheme 24. Retrosynthetic analysis of mucocin.

75 Baurle, S.; Hoppen, S.; Koert, U. Angew. Chem. Int. Ed. 1999, 38, 1263-1266. 76 Zhu, L.; Mootoo, D. R. Org. Biomol. Chem. 2005, 3, 2750-2754. 77 Crimmins, M. T.; Zhang, Y.; Diaz, F. A. Org. Lett. 2006, 8, 2369-2372.

31 Butenolide fragment 160, incidentally identical to an intermediate used by Keinan,72 was disassembled into iodide 161 and lactone 162, taking advantage of established methodology for the completion of the fragment.78 An attractive possibility to extend previous methodology was the potential to prepare 161 in one step from (S)-1,2-epoxy-5-hexene via a concomitant ring-opening/protection with TBSI.

3.4 Synthetic Studies Towards Mucocin

3.4.1 Synthesis of the Tetrahydropyran Fragment Paramount for the application of new methodology in complex molecule synthesis is the scalability and reliability of the reaction. Unfortunately, neither the previously published cleavage of diol 163 nor the HWE desymmetrization of dialdehyde 157 initally performed well upon scale-up. The problems with the diol cleavage were circumvented by performing the oxidation of 163 with o Pb(OAc)4 instead of H5IO6 in CH2Cl2 at 0 C, resulting in an excellent yield of pure dialdehyde after aqueous workup (Scheme 25).

O O O (TFEO)2P OPiv OR' OR' O O 41d H HO Pb(OAc)4 KHMDS, 18-Crown-6 OPiv OPiv O 156 H H o + HO CH2Cl2, 0 C, OPiv OPiv THF, -78 oC, 157 O OPiv 95% 163 156; 86%, dr > 98:2 OR' (2Z):(2E) > 98:2 R'O OPiv OPiv O 164 R' = Ph Scheme 25. Formation and desymmetrization of meso-dialdehyde 157. The subsequent desymmetrization of 157 turned out to be more cumbersome, the main byproduct being bis-addition to both carbonyls of the dialdehyde with (2E,8Z)-164 as the main adduct along with minor amounts of the corresponding (2Z,8Z)- isomer. Depending on the exact reaction conditions, up to 90% of 164 was isolated. This result seems counterintuitive as the mono-adduct is always isolated as a single (Z) stereoisomer and we were unable to reproducibly achieve even a statistical distribution of products, indicating that the formation of large amounts of bis-addition products is not necessarily a reflection of low selectivity in the HWE reaction but rather a consequence of mechanical issues such as poor solubility or stirring. An alternative explanation could be that the mono-adduct is significantly activated for further olefination, but as the related dialdehyde 168 (Scheme 26) containing a three-carbon instead of a two-carbon spacer shows a similar behavior,79 this was deemed unlikely. After extensive experimentation (including screening of solvents, temperatures, rate of addition of the phosphonate anion etc.), all with minute changes in the performance of the reaction, we

78 Schaus, S. E.; Branalt, J.; Jacobsen, E. N. J. Org. Chem. 1998, 63, 4876-4877. 79 Rein et al., unpublished results.

32 found that the key parameter is the relative concentration of dialdehyde to the concentration of the phosphonate anion. Consequently, keeping the initial concentration of the dialdehyde as high as possible and adding the phosphonate anion at -78 oC as a 0.01 M solution resulted in reproducible conditions even on multigram scale. While it remains to be shown in practice, application of these conditions to other cumbersome dialdehydes exhibiting a similar problematic behavior could provide an important lead to improving their performance in the asymmetric HWE.

O O O O O H OR* OR* + R*O O O O a OBn O OBn H H 166a; 35% dr >98:2 167; 53% O b O OBn 165 O O H OR* + R*O O R*O O OBn OBn 166b; 39%, dr >98:2 167; 50% O O O + OR* H OR* OPiv OPiv OPiv OPiv R*O O a O O 169a; 35%, dr = 89:11 170;50% O H H O b OR* OPiv OPiv H + OPiv OPiv 168 OPiv OPiv R*O O R*O O 169b; 30-50%, dr >98:2 170; N.d. Scheme 26. Meso-Dialdehydes prone to bis-addition. Reagents and conditions: (a) 165 or 168 (1.3 equiv.), 41c, KHMDS, 18-Crown-6, THF, -78 oC; (b) 165 or 168 (1.3 equiv.), 40d, KHMDS, 18-Crown-6, THF, -78 oC. With reproducible access to gram quantities of aldehyde 156 we could focus on the completion of the THP fragment. A reagent-controlled addition of TMS- acetylene under standard conditions gave the alkynylated product in excellent yield as a 71:29 mixture of 155a and 155b (Scheme 27).

Upon treatment of the resulting mixture of alcohols with t-BuOK in toluene, the desired protective group migration occurred in tandem with an oxa-Michael cyclization, resulting in the formation of the desired mucocin THP 154 as a single detected diastereomer in good yield. On a multigram scale, quenching the reaction at ~70% conversion (TLC control) and recycling the remaining mixture of alcohols gave more consistent results. The stereochemical outcome was ra- tionalized by assuming that the C4 hydroxyl group occupies an equatorial position. The (Z)-geometry of the alkene will then allow for only one face of the Michael acceptor to be accessible, resulting in the syn-anti THP 154 of muco-

33 cin.80 This result is consistent with what would be expected on the basis of previous work by Martín44 and Vares and Rein.42

OH OR' O TMS-Acetylene, (+)-NME TMS OPiv OPiv O OR' Et N, Zn(OTf) 155a H 3 2 OPiv OPiv OPiv O 156 93%, dr N.d. 155b:155b = 71:29 OR'

TMS OH OPiv O 155b

t-BuOK, toluene, 77% dr >95:5 OH OPiv O OR' nBu NOH CO R' 4 O OR' R O 2 O MeOH, TMS O OH 172 OPiv 154 83% PivO 171 C4 R' = Ph Scheme 27. Synthesis of diol 172. A series of conditions were then screened to differentiate the ester functionalities. Of the three, we expected the nor-8-phenylmenthyl ester to be the least suscepti- ble to basic hydrolysis. Indeed, Bu4NOH proved highly selective giving the desired diol 172 and at the same time removing the TMS group in good yield. Other bases were less selective, with the selectivity decreasing in the order LiOH >NaOH >KOH. We also attempted selective reduction of the pivaloyl esters with DIBAL and methanolysis (of all three esters) with MeONa/MeOH, both resulting in lower yield of 172.81

To complete the THP fragment, the nor-8-phenylmenthyl ester had to be reduced, and an eight-carbon alkyl chain introduced. To reduce the number of steps in the longest linear sequence, we evaluated the one-pot DIBAL reduction /Wittig olefination protocol directly on the unprotected diol 172 (Scheme 28). Pleasingly, we were able to obtain the completed THP fragment 153a in fair yield along with some recovered starting material. Unfortunately, the reaction was sluggish, and approaches using protective groups were deemed more reliable.

80 The relative configuration of 154 was determined by 2D NOESY correlations of the corresponding bis-MOM derivative 153c, vide infra. 81 The DIBAL reduction was indeed selective for the Piv-esters, but was too sluggish to be relied on in a multistep synthesis. The transesterification using MeONa worked well, but was very sensitive to moisture as any water present resulted in hydrolysis of the formed methyl ester and an unproductive formation of the corresponding acid.

34 OH o (i) DIBAL, CH2Cl2, -78 C OR O OR' (ii) PPh BrC H , NaHMDS, THF 3 8 17 O O OH 153a; 39%, (E)/(Z) ~1:10 OR 153a: R = H 172 (+34% recycled s.m.) 153b: R= TBS 153c: R = MOM TBSOTf, OR 2,6-lutidine O OR' o CH2Cl2, -20 C, 173a: quant. O (i) DIBAL, CH Cl , -78 oC or OR 2 2 (ii) PPh BrC H , NaHMDS, Methylal, CSA, 173a: R = TBS 3 8 17 THF, (E)/(Z) ~1:10 R' = LiBr,173b: 86% 173b: R = MOM Ph 153b: 69%; 153c: 51% Scheme 28. Completion of the THP fragments 153a-c of mucocin. TBS protection proceeded smoothly to give 173a under standard conditions. In contrast, introduction of MOM ethers proved more cumbersome. MOMI gave poor results, with low conversion at room temperature and significant byproduct formation under forcing conditions (60 oC, DCE). There are several alternative protocols describing MOM protection under acidic conditions.82 However, steri- cally hindered substrates in general, and propargylic alcohols in particular, often behave poorly well under these conditions. We were thus very pleased to find that slight alterations to a protocol using pTSA/LiBr with methylal as the solvent gave very good results.83 Exchanging pTSA for anhydrous (±)-camphorsulfonic acid (CSA) and running the reaction at reflux84 gave the bis-MOM protected product 173b in good yield (86%) along with minor amounts of mono-protected species that were readily recycled.

The DIBAL/Wittig reaction proceeded as expected with the bis-TBS adduct giving the completed fragment 153b in 70% yield. The bis-MOM substrate 173b performed equally well in the reaction; the moderate isolated yield of 153c largely reflects the tedious separation of the completed fragment from the released auxiliary.

3.4.2 Synthesis of the THF Fragment The synthesis of the THF fragment largely follows a previously reported procedure by Vares and Rein.48 However, in order to perform well on multigram scale, several of the steps had to be reoptimized. Reduction of aldehyde 156 using LiBH4 gave the thermodynamic ~ 2:1 mixture of secondary and primary alcohol 174 and 159 respectively, albeit in modest yield due to overreduction of the pivaloyl esters. In contrast, NaBH4 in i-PrOH gave an essentially quantitative yield of 174 and 159 but with only partial migration of the C7-pivaloyl group (159:174 ~ 1:2) (Scheme 29). After separation, the remaining primary alcohol (along with some 159) could be re-equilibrated under reflux in EtOH in the pres-

82 For examples see: (a) Fuji, K.; Nakano, S.; Fujita, E. Synthesis 1975, 276-277. (b) Mar- cune, B. F.; Karady, S.; Dolling, U. H.; Novak, T. J. J. Org. Chem. 1999, 64, 2446-2449. 83 Gras, J. L.; Chang, Y. Y. K. W.; Guerin, A. Synthesis 1985, 74-75. 84 After 1 hour azeotroping off methanol by evaporating 75% of the methylal, followed by re- dilution with methylal.

35 ence of DMAP. The subsequent separation of the resulting 2:1 mixture of 159:174 gave after separation secondary alcohol 159 (59% overall) along with recovered primary alcohol (30% overall) thus accounting for 89% of the aldehyde 156 used in the initial reduction.

OR' HO OPiv OPiv O 174 DMAP, O EtOH, ∆ NaBH4, i-PrOH OR' 159:174 = 2:1 H + 0 oC, 159:174 ~1:2 OPiv OPiv O OR' 156 89% (combined yield) PivO OH OPiv O 159; 59% isolated after one re-interation

Pd2(dba)3, neocuproine, DCE, 93% (4S,2E):(4R,2Z) = 93:7

O O (1) LiOH (aq) O O THF, 74% (2) Swern, 89% O H OR' PivO OR' R' = 158 175 Ph Scheme 29. Synthesis of the THF fragment of mucocin. The THF ring was then formed using an intramolecular Pd-catalyzed allylic substitution. The reaction was initially performed in THF at reflux using 20 mol% catalyst, giving the cylisized product 175 in good yield and selectivity (71%, (4S,E):(4R,Z) = 90:10). Based on our experiences from the pyranicin/pyragonicin synthesis, we expected the reaction to perform even better in chlorinated solvents using anhydrous neocuproine as the ligand. Under these conditions, somewhat surprisingly, the reaction proceeded to completion within 3 hours using 5 mol% catalyst at room temperature and, as expected, β-elimination was completely suppressed resulting in an excellent isolated yield (93%) of pure (4S,2E)-175. Completion of the fragment was straightforward, using LiOH to hydrolyze the primary ester,85 followed by a Swern oxidation gave the completed THF fragment 158 in 66% yield over two steps.

3.4.3 Synthesis of the Butenolide A key intermediate in the synthesis of the butenolide fragment was the TBS- protected halo-hydrin 161. Similar substructures have been utilized for the construction of butenolide fragments in several prior studies directed towards ACGs.78 In previous studies, the TBS-iodohydrin motif is typically prepared from the corresponding diol, which is selectively tosylated in the primary position, after which the secondary alcohol is silylated, followed by treatment with NaI to displace the toslylate. We hoped to exploit a more expedient procedure, by opening enantiopure epoxide 176, readily obtained on multigram scale,86 with in

85 Due to instability of the alcohol resulting from hydrolysis of the pivaloyl ester of 175, it should be repurified prior to oxidation and not stored over prolonged periods of time. 86 Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 1307-1315.

36 situ generated TBSI (Scheme 30).87 Under these conditions, the silyl halide would act as a Lewis acid and activate the oxirane, thus allowing for iodide to attack. The result would be a concomitant ring opening and protection, giving 161 in a single step. In fact, we were encouraged to find that the reaction worked very well on multigram scale. Initial experiments gave a mixture of primary and secondary halide in an 80:20 ratio, respectively. Upon further optimization, the selectivity could be increased to 86:1488 by lowering the temperature, and further improved by chromatography to give 161 in good yield as a 90:10 mixture of primary and secondary iodide, respectively. The joining of 161 and 162 through an alkylation was well precedented. Pleasingly, exchanging the HMPA used in prior studies for the less toxic DMPU, we found the results were indeed similar. The final oxidation/pyrolysis sequence to give the completed fragment 160 proceeded as expected. A chemoselective oxidation of sulfide 179 with mCPBA to the corresponding sulfoxide was accomplished at low temperature. The sulfoxide was then eliminated upon heating in toluene for 10 minutes to give the completed butenolide fragment 160 in 4 steps and good overall yield from epoxide 176.

O rac-176 O O + PhS OH 177 178 Jacobsens hydrolytic kinetic resolution Annulation rxn TBSCl, NaI O 176 O I PhS MeCN, 5 oC, 75% + 161 OTBS O (90:10 isomeric mixture) 162 (i) mCPBA O o PhS CH2Cl2, -78 C LDA, DMPU o to -20 C O THF, -78 oC to rt (ii) Toluene ∆ 179 OTBS 85% 74% (based on 90% pure iodide) O

O 160 OTBS

Scheme 30. Synthesis of the butenolide fragment of mucocin.

3.4.4 Assembly and Completion of the Bis-Ring Portion With all three fragments at hand, we turned our attention to the stereoselective joining of the THP and THF fragments. This coupling is fairly elaborate as the fragments besides being chiral exhibit a multitude of functionalities such as unprotected hydroxyl groups (153a), a Michael acceptor and an ester. We were however encouraged by the precedence set by the successful joining of 102b and 133 to form the pyragonicin framework (see section 2.4.3). Indeed, the coupling

87 Using a protocol originally developed for the opening of THF; Nystrom, J. E.; Mccanna, T. D.; Helquist, P.; Amouroux, R. Synthesis 1988, 56-58. 88 Determined by 1H NMR of the reaction crude.

37 did proceed even with 153a, to give 180a albeit in fair yield along with a quantitative recovery of the THP fragment (

Table 4). The THF fragment 158 decomposes under the reaction conditions, which partly accounts for the poor yield. The stereoselectivity was not quantified at this stage, but it appears to be good.89 Using the bis-TBS THP 153b we could reproducibly isolate 20-35% of 180b (along with recovery of the THP fragment). This result is comparable to that of the unprotected THP 153a since 153b is more readily available, but unfortunately it is not adequate for the synthesis of mucocin. Fragment couplings with bis-MOM THP 153c have not yet been performed (see section 3.5 for further discussion).

Table 4. Stereoselective coupling of the THP and THF fragments of mucocin.a

O O O H OR' 158 C7H15 OR C7H15 OR O Zn(OTf)2, Et3N, (+)-NME O OR' O RO toluene RO 153a,b OH O 180a,b

Series a; R = H R' = Series b; R = TBS Ph

R THP 158 Zn(OTf)2/ Temp. Yield dr (equiv.) (equiv.) (+)-NME/ (oC) (%) Et3N (equiv.) 153a; R = H 1.0 1.3 3.0/4.0/6.0 60 39 N.d.b 153a; R = H 1.1 1.0 1.3/1.5/2.0 rt 31 ≥91:9 153b; R = TBS 1.0 1.0-1.5 2.0/2.5/4.0 50 20-35 >95:5 a All coupling reactions were performed on a 0.017 to 0.056 mmol scale with respect to 153a,b. b The dr was not quantified as the THF fragment 158 used was contaminated with 30 mol% of the corresponding 1,4-adduct of methanol originating from a previous step (see footnote 93).

To ensure the viability of the route leading to the complete THP-THF subunit, we performed the remaining four steps with bis-TBS 180b. Pleasingly, we were able to isolate the primary bromide 183 in good yield over the four steps (Scheme 31).

89 The product obtained after chromatography is an inseparable 91:9 mixture of two stereoisomers; this ratio corresponds to the (E):(Z) ratio of the starting THP fragment, but we cannot exclude it as originating from a C8 epimer.

38 C H OTBS (1) H2, Pd (10% on C), 7 15 EtOAc C7H15 OTBS O (2) TBSOTf, 2,6-lutidine O OR' OR' O O OTBS O TBSO 75% over 2 steps TBSO OH O 181 180b DIBAL o CH2Cl2, -78 C 79% C H OTBS C7H15 OTBS 7 15 O Br PPh3, CBr4 O OH O O OTBS 183 CH2Cl2, 78% OTBS TBSO TBSO 182 R' = Ph Scheme 31. Completion of the TBS protected THP-THF subunit of mucocin.

3.4.5 Proposed Endgame With the THP-THF subunit at hand there are only two steps left to the natural product. Since we planned the synthesis such that all unsaturations not present in the target would be removed in a single hydrogenation step earlier in the synthesis, the most direct route to the completed mucocin core would proceed via an sp3-sp3 coupling. An important precedence for such an approach is provided by Fu and co-workers who recently developed conditions for this type of transformation based on a Suzuki-type protocol (Scheme 32).90 Importantly, the reaction was shown to be compatible with a multitude of functionalities such as alkynes, nitriles, esters, silyl ethers and amines.

Pd(OAc) , TESO 9-BBN 2 184 PCy3 TESO Cl ( )6 . Cl K3PO4 H2O 186; 81% Br ( )6 THF 185 Scheme 32. The sp3-sp3 cross coupling developed by Fu and co-workers. For the application of this reaction to the joining of 183 and 160, a chemoselective conversion of the butenolide fragment into borane 187 (precedented through the work of Keinan72) is required (Scheme 33). A potential complication is that the cross coupling is performed under slightly basic conditions, but not necessarily basic enough to jeopardize the integrity of the butenolide. While certainly challenging, such an approach, if successful, would be an important contribution as it would provide an example of this potentially very useful coupling reaction in a complex setting. The final global deprotection of 188 to give mucocin is well precedented through several previous total syntheses of ACGs.

90 (a) Netherton, M. R.; Dai, C. Y.; Neuschutz, K.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 10099-10100. (b) Netherton, M. R.; Fu, G. C. Angew. Chem. Int. Ed. 2002, 41, 3910-3912.

39 C7H15 OTBS OTBS 9-BBN OTBS O Br + O O O 9-BBN OTBS 183 187 O O TBSO 160 Pd(OAc)2 PCy3, K3PO4, THF

C7H15 OR OR O O O OR O RO

188; R = TBS . BF3 Et2O 55; R = H, (-)-mucocin Scheme 33. Proposed endgame towards mucocin.

3.5 Conclusions and Outlook We have investigated a triply convergent, stereoselective syntheses of the annonaceous acetogenin (-)-mucocin. Exploiting experiences from previous en- deavours towards related targets, expedient and reliable routes to the three fragments 153b,c, 158 and 160 have been developed and optimized. All nine stereocenters of the target molecule have been installed, and preliminary results indicate the viability of the route chosen leading from the coupled THF-THP subunit 180b to bromide 133, designed for assembly of the complete mucocin framework. However, the stereoselective joining of the THP and THF fragments still remains a challenge in terms of efficiency. We speculate that a reason for the fair results in the coupling between 153b and 158 is the steric bulk of the propargylic TBS group of 153b. This notion was also supported by a recent report.91 Judging from this precedence, as well as work by Crimmins and co-workers,92 we speculate that the MOM-protected THP 153c would give better results (Scheme 34).

O O O H OR' 189 C7H15 OMOM O Zn(OTf)2, Et3N, (+)-NME THF-THP core MOMO toluene 153c Scheme 34. Future improvements to potentially increase the efficiency of the formation of the THP-THF core of mucocin. To further improve the efficiency of the route towards the THF fragment, reduction of the α,β-unsaturation might increase the stability of the alcohol precursor to aldehyde 158 and allow for a more efficient protocol to increase the yield for

91 Tominaga, H.; Maezaki, N.; Yanai, M.; Kojima, N.; Urabe, D.; Ueki, R.; Tanaka, T. Eur. J. Org. Chem. 2006, 1422-1429. 92 For an efficient fragment coupling of two THF-containing subunits, where the alkyne-THF bears a MOM-protected propargylic alcohol, see: Crimmins, M. T.; She, J. J. Am. Chem. Soc. 2004, 126, 12790-12791.

40 the hydrolysis of the pivaloyl ester in the THF fragment synthesis93 without adding steps to the longest linear sequence. In addition, more convenient oxidation methods for the preparation of 159 might be feasible.

The success of our suggested completion of the endgame to mucocin as devised in our analysis relies on the proposed sp3-sp3 cross-coupling between bromide 183 and the 9-BBN derivative 187. Should this route fail, an alternative strategy, in which the γ-lactone is coupled before elimination of the sulfide might be an option, as this would allow for more forcing conditions, since epimerization of the butenolide stereocenter would not be an issue.

93 The highly selective conditions developed for the hydrolysis of the two pivaloyl esters of 154 cannot be used for 175 due to a competing Michel addition of methanol to the 1,4- acceptor.

41 42 4. Evaluation of a Re-Catalyzed Asymmetric OlefinationV

“Well, I tried, didn't I? Goddamnit, at least I did that!” R.P. McMurphy

4.1 Introduction The use of chiral phosphonates is an efficient strategy for enantiotopic discrimination in the asymmetric HWE reaction. This approach does however suffer from several drawbacks; to achieve good selectivity, the reaction is typically run at -78 oC, in some cases expensive additives (crown ethers) are needed, chiral phosphonates are not commercially available and the expensive chiral auxiliary is used stochiometrically. In order to expand the scope and utility of this transformation, one would strive for milder, more robust reaction conditions and ideally to recycle the chiral information in a catalytic cycle. As mentioned in section 1.4, a number of studies have been directed at inducing asymmetry in Wittig-type reactions without the use of chiral phosphonates, but typically with modest results in terms of efficiency.18d,94 We hypothesized that an alternative method based on transition metal catalysis could provide a novel entry to asymmetric olefinations. In recent years, a number of studies employing metal complexes to catalyze olefinations of aldehydes via metallacarbenes have been published.95 We speculated that rendering the metal complex chiral could offer an entry to a catalytic asymmetric olefination, assuming that the metal is associated to the reaction center in the stereodiscriminating step.

4.2 Survey of the Field Since Herrmann’s discovery of the methyltrioxorhenium (MTO, 191) catalyzed olefination of aldehydes using an ethyldiazoacetate (EDA) / triphenylphosphine (TPP) system (Scheme 35),96 studies expanding the scope of this reaction have been reported.97 Several metals have shown activity in similar reactions, including Ru, Rh, Fe and Co.95 In a follow up paper, Herrmann also employed an alter- 96b native catalyst, (Ph3P)2Re(O)Cl3 with good results.

94 Bestmann, H. J.; Lienert, J. Chem.-Ztg. 1970, 487-488 95 Kühn, F. E.; Santos, A. M. Mini-Rev. Org. Chem. 2004, 1, 55-64 and references therein. 96 (a) Herrmann, W. A.; Wang, M. Angew. Chem. Int. Ed. 1991, 30, 1641-1643. (b) Herrmann, W. A.; Roesky, P. W.; Wang, M.; Scherer, W. Organometallics 1994, 13, 4531- 4535. 97 For a recent example see: Santos, A. M.; Pedro, F. M.; Yogalekar, A. A.; Lucas, I. S.; Romao, C. C.; Kühn, F. E. Chem. Eur. J. 2004, 10, 6313-6321.

43 O Ph3P Cl Re O CO R Cl 2 Ph3P Cl R1 H N2 [M] H CO2R 190 + 2 R + Ph3PO -N 1 2 PPh 2 R R 3 O Re O 1 R = aromatic or aliphatic O 2 191 R = H or CO2R Scheme 35. The general transition metal catalyzed olefination. A noteworthy extension of this chemistry was published by the Carreira group.98 By exchanging TPP for P(OEt)3 as the reducing agent the authors were able to combine convenient reaction conditions, good yields and good to excellent geometric selectivities with a simplified workup, as the byproduct is removable by washing. Another important observation, which extends the scope of the reaction further, is that the reaction conditions are less basic than those of the traditional Wittig or HWE reaction, thus allowing for olefination of base sensitive substrates.99

A number of studies directed at elucidating the mechanism of this reaction have been reported and the actual pathway is still to some extent a matter of contro- versy.100 In the original paper, Herrmann suggests a catalytic cycle involving reduction of MTO by TPP followed by decomposition of the diazo compound101 to form a Schrock carbene, which subsequently undergoes a [2+2] cycloaddition with the aldehyde (Scheme 36).

CO2R H H 192 1 R PPh3 Re O O O Ph3PO RO2C H 191 O O Re CHR1 O Ph3P Re PPh3 O 197 O 193 CO2R N2 H O Re CO2R 194 O 1 R O H N , 2PPh 195 2 3 196 H Scheme 36. Herrmanns proposed mechanism for the MTO-catalyzed olefination of aldehydes. Eliminaton of the olefin then returns MTO, thus completing the catalytic cycle. The corresponding mechanism for 190 is commented briefly on by Herrmann as

98 Ledford, B. E.; Carreira, E. M. Tetrahedron Lett. 1997, 38, 8125-8128. 99 The validity of this statement may to some extent depend upon the actual reaction pathway. 100 For a thorough discussion of various mechanistic hypotheses see ref. 95 and references therein. 101 Later, Kühn and co-workers suggested that the carbene is formed from a phosphazine derived from the rapid reaction between EDA and TPP; see: A. M.; Romao, C. C.; Kühn, F. E. J. Am. Chem. Soc. 2003, 125, 2414-2415.

44 proceeding with replacement of one TPP with an aldehyde. For similar reactions involving e.g. Ru, a completely different reaction pathway has been invoked in which in situ formation of a stabilized Wittig ylide accounts for the product formation (Scheme 37).102

Alt. 1 Ph3P N2CHCO2Et + PPh 3 NN Alt. 2 M 197 CHCO2Et

M CO2Et 198 M H Ph3P 199 CO2Et PPh3 Aldehyde - Ph3PO R H H

CO2Et 200

Scheme 37. An alternative reaction pathway via a phosphonium ylide could account for the product formation.

4.3 Design and Synthesis of Chiral ReV Catalysts We speculated that an attractive entry to a chiral ReV catalyst for asymmetric olefinations was to use the (Ph3P)2Re(O)Cl3 catalyst as a starting point. In combination with the large scope offered through Carreira’s modified conditions, this appeared a viable entry.

Two distinct routes to access a chiral analogue of 190 were identified, the most straightforward being to exchange the TPP ligands of 190 for a chiral bidentate ligand such as BINAP103 to give metal complex 201 (Figure 7). This catalyst has previously been used with some success in asymmetric oxidations of sulfides to sulfoxides.104

102 For examples see: (a) Lebel, H.; Paquet, V.; Proulx, C. Angew. Chem. Int. Ed. 2001, 40, 2887-2890. (b) Lebel, H.; Paquet, V. Organometallics 2004, 23, 1187-1190. 103 Previously, the corresponding dppe complex has been shown to be completely inactive in this olefination reaction (see reference 97) but given the similar electronic properties of BINAP and TPP we regarded this precedence as non-decisive. 104 With a chiral additive, an er of up to 58:42 was achieved; Gunaratne, H. Q. N.; McKervey, M. A.; Feutren, S.; Finlay, J.; Boyd, J. Tetrahedron Lett. 1998, 39, 5655-5658.

45 O O Ph3P PPh3 Ph3P PPh3 Re Re O O O O Cl Cl O EtO OEt Cl Ph2P PPh2 O O Re O O Re Cl Ph3P PPh3 Cl Cl O 201 203 202 204 Figure 7. Proposed chiral Re complexes for asymmetric olefinations. An alternative possibility was to exploit a reaction were two of the chlorides in 190 were substituted by a catechol.105 A potential variation of this theme would be using chiral diols such as BINOL or diethyl tartrate (DET). We attempted preparation of 202-204 by treating 190 with the corresponding diols, but unfortunately, we were not able to isolate a homogenous product in any of these at- tempts despite modulations of the reaction conditions.106

Following literature procedures,107,108 we prepared enantiomerically pure 201 from (Ph3As)2Re(O)Cl3 and (S)-BINAP (Scheme 38). Pleasingly, we found that the racemic form of 201 could be prepared in a simpler one-pot fashion directly from perrhenic acid in good yield, thus avoiding the use of toxic arsine compounds. These conditions worked very well for the more crystalline rac-201, which can be washed repeatedly with cold CH2Cl2 to obtain analytically pure product in fair yield (~30-50%). Unfortunately, a similar procedure could not be applied to the more easily soluble, amorphous, enantiopure 201 which had to be prepared via the bis-arsine complex using the two step procedure.

conc. HCl, (+)-BINAP O Ph3As AcOH O Re OH (Ph3As)2ReOCl3 O AcOH, 33% quant

conc. HCl rac-BINAP Ph P AcOH, 30-50% Ph P Ph ReCl3 Ph O [BINAP]Re(O)Cl3 (201) Scheme 38. Synthesis of the chiral Re-complex 201.

105 Bandoli, G.; Dolmella, A.; Gerber, T. I. A.; Perils, J.; du Preez, J. G. H. Inorg. Chim. Acta 1999, 294, 114-118. 106 Varying the temperature, adding bases and/or silver salts, we could not isolate a homogenous product. 107 Grubbs, R. H.; Toste, F. D. Int. Patent WO 02/102707 A2, 2002. 108 (a) Johnson, N. P.; Lock, C. J. L.; Wilkinson, G. J. Chem. Soc. 1964, 1054-1066. (b) Fontaine, X. L. R.; Fowles, E. H.; Layzell, T. P.; Shaw, B. L.; Thorntonpett, M. J. Chem. Soc. Dalton. Trans. 1991, 1519-1524.

46 Pleasingly, we were also able to unambiguously establish the structure of the crystalline rac-201 by X-ray (Figure 8).109,110 The crystal quality was however not optimal resulting in a somewhat increased reliability R-value. The crystal system is triclinic and the space group is P(-1) with two centrosymmetric (inversion-related) molecules in the unit-cell. The crystal packing scheme is not close packed.

Figure 8. X-ray structure of [BINAP]Re(O)Cl3 (201).

4.4 Optimization of the Olefination Step As substrates for the optimization study, we chose commercially available acrolein dimer 77 and tosylated aminoaldehyde 205111 (Figure 9). These substrates contain functionalities such as a vinyl ether and a protected amine which are important for further synthetic applications. In addition, they carry a heteroatom substituent in a stereogenic α-position which could serve as a handle for enantiotopic discrimination in a kinetic resolution when carrying out the reaction with an enantioenriched catalyst.

O O Ts O N H H

rac-77 rac-205 Figure 9. Substrates for Re-catalyzed olefination.

Our initial results using 201 to catalyze the olefination of 77 with P(OEt)3 as the reductant were discouraging and we could only detect small amounts of olefinated product, the main byproduct being azine 207a (Table 5).

109 The X-ray quality crystals were grown from a saturated CH2Cl2 solution of rac-201 which was placed in a hexane filled diffusion chamber, to give dark green crystals. 110 An independent study by Parr et al. recently reported the crystal structure of rac-201; Parr, M. L.; Perez-Acosta, C.; Faller, J. W. New J. Chem. 2005, 29, 613-619. 111 o Prepared in two steps, 80% overall yield: (i) (piperidin-2-yl)methanol, TsCl, K2CO3, 0 C, CH2Cl2; (ii) Swern oxidation. For details, see: (a) Kreuder, R. Ph.D. Thesis. Georg-August- Universität zu Göttningen, Göttingen, Germany, 1997; (b) Rein, T.; Anvelt, J.; Soone, A.; Kreuder, R.; Wulff, C.; Reiser, O. Tetrahedron Lett. 1995, 36, 2303-2306.

47 Table 5. Optimization of the Re-catalyzed olefination of 77 and 205.

O O EDA, catalyst H X X CO2Et H OEt H + X N TPP or P(OEt)3 N rac-77, 206a,b rac-205 207a,b

Series a; X = O Series b; X = NTs

Entry Aldehyde Cat. Red. Solvent T. (E):(Z) Prod. (equiv.) (mol %) (er) f (%)b

a 1 77 rac-201 TPP CH2Cl2/ rt 85:15 ~20 (1.0) (1) THF (1:2) a 2 77 191 TPP CH2Cl2/ rt 86:14 ~45 (1.0) (1) THF (1:2)

3 77 (+)-201 TPP CH2Cl2/ rt 83:17 13 (1.0) (1) THF (1:2) (-e) c 4 77 (+)-201 TPP CH2Cl2/ rt 82:18 13 (3.0) (1) THF (1:2) (-e) d 5 77 (+)-201 TPP CH2Cl2/ rt 82:18 51 (3.0) (5) THF (1:2) (-e) 6 d 77 (+)-201 TPP THF rt 82:18 39 (3.0) (5) (-e) d 7 77 (+)-201 TPP CH2Cl2 rt 75:25 51 (3.0) (5) (-e) d o 8 77 (+)-201 TPP CH2Cl2 0 C 67:33 15 (3.0) (5) (-e) d 9 77 (+)-201 TPP CH2Cl2 ∆ 82:18 100 (3.0) (5) (50:50) (84 g) d 10 77 (+)-201 P(OEt)3 CH2Cl2 ∆ 58:42 29 (3.0) (5) (50:50) d 11 205 (+)-201 TPP CH2Cl2 ∆ 98:2 100 (3.0) (5) (50:50) (72 g) d 12 205 (+)-201 P(OEt)3 CH2Cl2 ∆ 98:2 33 (3.0) (5) (-e) d,h 13 77 (+)-201 TPP CH2Cl2 ∆ - i (3.0) (5) d,h 14 205 (+)-201 TPP CH2Cl2 ∆ - i (3.0) (5) Reagents and conditions: To a stirred solution of aldehyde (77 or 205), reductant and catalyst in the solvent indicated was added a solution of EDA in the solvent. The reaction was then stirred for 5 h with TLC monitoring at the temperature indicated. a Estimated from crude 1H NMR. b Determined by 1H NMR of the crude reaction mixture using 1- c d methoxynaphthalene as internal standard. EDA was added as a CH2Cl2 solution over 1 h. e f EDA was added as a CH2Cl2 solution over 4 h. Not determined. Determined by chiral HPLC. g Isolated yield. h Dimethyl diazomalonate was used instead of EDA. i No product formation was detected.

48 In this context, we also had problems reproducing the results of Carreira’s initial publication.112 In contrast, exploiting Herrmann’s conditions, with TPP, we were able to obtain the desired olefinated product of acrolein dimer (77) albeit in low yield (Table 5, entries 1 and 2). The main byproduct was azine 207a, which prompted further investigation of the reaction conditions.

Gratifyingly, running the reaction in refluxing CH2Cl2 and adding the EDA (as a CH2Cl2 solution) over 4 hours allowed us to suppress azine formation and obtain the olefinated product 206a with essentially quantitative conversion,113 albeit with a moderate (E):(Z) selectivity of 82:18 (Table 5, entry 9). Under these optimized conditions, amino aldehyde 205 was also essentially quantitatively olefinated, with suppression of azine formation and with an excellent geometric selectivity, (E):(Z) = 98:2 (Table 5, entry 11). The isolated yield of 206b was somewhat reduced due to the tedious separation from remaining aldehyde 205. Both the (Ph3P)2Re(O)Cl3 catalyst and the [BINAP]Re(O)Cl3 catalyst showed very similar performance under optimized conditions. We noted however that the (Ph3P)2Re(O)Cl3 catalyst was slightly more active and resulted in less azine formation under sub-optimal conditions. Under our optimized reaction conditions we also re-evaluated running the reaction with P(OEt)3, and were able to obtain olefinated products with both 206a and 206b albeit in poor yield and low geometric selectivity for 206a (Table 5, entries 10 and 12).

Disappointingly, the (E)-isomers of the olefinated products 206a and 206b were determined by chiral HPLC to be racemic (Table 5, entries 9 and 11). The (E)- adduct of 206a using P(OEt)3 as the reductant was also shown to be racemic (Table 5, entry 10).

4.5 Mechanism and Implications for Asymmetric Olefinations Depending on the reaction mechanism, two modes of asymmetric induction can be envisioned. If the reaction proceeds via a metal-associated carbene, chirality transfer could arise from facial selection in the [2+2] addition. Alternatively, if the reaction proceeds via a phosphonium ylide, the Re complex could act in a second role as a chiral Lewis acid to activate the aldehyde, similar to the MTO 114 mediated olefination of aldehydes with Ph3PC(CO2Me)2.

112 While Hermanns conditions with TPP and 191 could be reproduced very well in our hands, we could only isolate trace amounts of products using either hexanal (freshly distilled) or bensaldehyde (freshly distilled) as substrates in combination with purified (distilla- tion) or unpurified P(OEt)3 as the reductant. The main products in these reactions were the corresponding azines. We are unable to explain this lack of success. 113 Based on TPP as the limiting reagent. The conversion was determined by 1H NMR of the reaction crude using 1-methoxynaphthalene as internal standard. 114 The reaction between benzaldehyde and Ph3PC(CO2Me)2 does not take place, even in refluxing benzene, in the absence of MTO, but proceeds at room temperature upon addition of stochiometric amounts of MTO; see footnote 96a.

49 As the absence of enantioselection indicated a non-metal associated reaction pathway, a set of experiments were conducted to gain further insight into the reaction. (1) Running the reaction in the absence of an aldehyde resulted in the formation of Wittig ylide 199 as detected by crude 1H-NMR and ESI-MS. (2) Refluxing a mixture of 201 for 4 hours with a 100-fold excess of TPP in CD2Cl2 left 201 unaffected as determined by 31P NMR. (3) Conducting the reaction in the absence of PPh3 but with stochiometric amounts of [BINAP]Re(O)Cl3 resulted in no product formation. (4) Performing the olefinations under otherwise similar conditions, replicating the experiments of Table 5, entries 5 and 11, but using Ph3PCHCO2Et instead of EDA/TPP gave similar levels of geometric selectivity. (5) Repeating the conditions for experiment 4, and in addition adding 1 mol % 115 (+)-[BINAP]Re(O)Cl3 did not affect the reaction outcome, and the (E)-product obtained was determined to be racemic.

An important observation is that the use of dimethyl diazomalonate as the carbene precursor (Table 5, entries 13 and 14) did not yield any product, which is in accordance with what would be expected if the reaction proceeds via a phosphonium ylide.116 These observations, together with the absence of stereoselectivity as well as of side reactions such as cyclopropanation of the electron rich vinyl ether, suggests that the most likely reaction pathway proceeds via a stabilized phosphonium ylide. One may note that this conclusion is in good analogy with observations made for similar reactions based on Ru.102

4.6 Conclusions and Outlook We have developed an efficient protocol for a catalytic Re-catalyzed olefination of functionalized aldehydes with good yields and moderate to excellent geometric selectivities. The use of an enantioenriched catalyst did not result in any asymmetric induction during attempted resolutions of racemic starting materials. The results indicate that the reaction proceeds through a stabilized phosphonium ylide generated from EDA and TPP rather than through a metallaoxetane. This study contributes to the mechanistic understanding of Re-catalyzed olefinations, and provides conditions that should be viable in similar contexts where azine formation is a problem. However, given the absence of enantioselectivity, the scope of this reaction appears somewhat limited as it does not outperform the more traditional Wittig reaction.

115 Compared to a control experiment run without the addition of (+)-201. 116 The absence of product in this experiment also indicates that the Re complex 201 is not

Lewis acidic enough to promote the Wittig reaction in this case (assuming Ph3PC(CO2Me)2 is formed).

50 5. Concluding Remarks

“Realize that your objective in research is to formulate and test hypotheses, to draw conclusions from these tests and to teach these conclusions to others. Your objective is not to ‘collect data’.” G.M. Whitesides As shown in the preceding chapters, the asymmetric HWE reaction is a powerful reaction as it gives a product containing a useful set of functional groups combined with the potential of controlling multiple stereocenters in a highly selective manner. Concerning future possibilities, there are several ways to expand the scope of this chemistry; one direction is to exploit the substitution pattern of the HWE adducts further to form e.g. aza-heterocycles (Scheme 39).

PG N OR* PivO l O ae on Asym. HWE and ich ati OPiv 210 M liz Mitsunobu yc O O sequence c CO2R* H H PivO Pd N OPiv -c OPiv OPiv PG H all at s yli . 208 209 ub c PG O st itu tio N n PivO OR* 211 Scheme 39. A potential divergent route to aza-heterocycles. Focusing on the reaction itself, for the asymmetric HWE to reach its full potential and hopefully find applications outside of lab scale, it must be improved into a procedure using cheap, non-toxic reagents, robust reaction conditions, simple purification, and importantly, the environmental performance of the reaction must be considered. Perhaps the most promising approach to meet these requirements may be offered through organocatalysis. In principle, exploiting the diastereomeric recognition exhibited by organocatalysts such as proline117 in a condensation118 could result in an asymmetric olefination (Scheme 40).

* R R O O O N O O H 213 + H O H H + H H H 2 FG FG 212 FG FG 214 42 Scheme 40. Potential systems for organocatalytic asymmetric olefinations. Looking beyond asymmetric olefinations, one may note that much of the mo- mentum of the asymmetric HWE reaction, as it is used in the contents of this

117 See e.g. Casas, J.; Engqvist, M.; Ibrahem, I.; Kaynak, B.; Cordova, A. Angew. Chem. Int. Ed. 2005, 44, 1343-1345. 118 For an example of an organocatalytic condensation reaction see: Wang, W.; Mei, Y.; Li, H.; Wang, J. Org. Lett. 2005, 7, 601-604.

51 thesis, is gained from its highly selective enantiotopic group discrimination. Thus, if an alternative process could reproduce this selectivity, the potential of using meso-dialdehydes as efficient building blocks in synthesis would benefit even more. Assuming a protocol where the desymmetrization is performed with a reaction that can be reversed, such as the formation of a diastereomeric (thio-)acetal or a hydrazone, then essentially any reaction that can be performed on a carbonyl group,119 including but not limited to the HWE reaction, could be envisioned in this context (Scheme 41).

* * X X X X CO Et H OH H 2 FG FG FG FG 217 216

* * O O O X X O X X H H H H H OH FG FG 42 FG FG FG FG 215 218

* * X X OH X X OH H H R 220 FG FG FG FG 219 Scheme 41. The potential scope of a more general desymmetrization reaction.

119 This assumption naturally rests on the compatibility of substrate functionalities with the reaction conditions.

52 6. Acknowledgements

”You always knew where you had chemical compounds; they didn’t abandon you, dis- appear, let you down or lie to you. In the organic world there was a sense of security.” O. Sachs

This work wasn’t made in a vacuum, and I’ll let you know straight away, Dr. Sachs got it all wrong. It’s not the chemistry, it’s the people, I promise! The following list is a number of persons to whom I would like to express my deepest gratitude. I sincerely apologize in advance to those well deserved but not explic- itly mentioned; if you feel you should be, consider yourself added as of now.

First and foremost, I would like to acknowledge my supervisor Professor Tobias Rein. It has in every respect been a privilege to work in the Rein group during the last 5 years. I can only hope that I have picked up some of the knowledge and creativity imposed on me. Thank you for sharing your philosophies and at that for being a great friend. I am endlessly impressed by the way you set an example in everything that you do.

I am deeply grateful to Professor Paul Helquist, for his hospitality during my two sessions at ND, both of which have been some of the most rewarding times of my life, professionally as well as personally. Thank you Paul for the buffalo- wings, for all that I have learned from you and for all your help.

Professor Peter Somfai for chemistry discussions, for making me a part of the group activities and for the opportunity to work in the Somfai lab. I am indebted to your professionalism and excellent lab standards which has been a prerequisite for much of my work.

AstraZeneca, KTH and Aulin-Erdtman stiftelsen are gratefully acknowledged for financial support.

Dr. Berit Olofsson and Dr. Olaf Panknin for taking the time and effort of proof- reading this thesis and Per, Staffan and Pavel for valuable comments.

Professor Per-Ola Norrby for help and enthusiasm during a hectic but instruc- tional week working in silico at DTU and for the mechanism part of article III.

Birgitta Stensland for the X-ray analysis.

The KTH/SU faculty for excellent courses and rewarding discussions.

All the past and present members of the Somfai group for keeping me on my toes and forcing me to raise my academic standards. Per and Staffan for your help in dissecting my chemistry, your chemistry and other peoples chemistry.

53 Former group members and collaborators; Alex Bates, Dr. Tomaž Tobrman, Stefan Cortekar, Dr. Lauri Vares and Dr. Torben Pedersen.

Dr. Ulla Jacobson, for always taking the time, despite more pressing issues, to help me with the NMRs.

Lena Skowron and all the staff at the chemistry department for keeping the show on the road.

Everyone in the Helquist group. I would especially like to thank Alex, Doug and Elsa for help with housing and practicalities and Dr. Dirk Schweitzer for a rewarding collaboration on the iejimalide C12-C17 synthesis.

All the past and present co-workers at organic chemistry KTH.

AZ Discovery, AZ Process and Dr. Jan-Erik Nyström for a helpful, positive and supporting attitude.

The regulars at Friday beer and the department floorball (Strykpojkarna STHLM).

Ellen Santangelo for the leafs, I know you worked hard for them.

Some inanimate objects, including my dear friends the dishwasher and the coffee machine.

My Stockholm and Göteborg crews, you know who you are!

Morsan, Farsan and Brorsan for the ground support and with aunts Inger and Ulla, for providing fixed points in a moving universe.

Till Mormor.