1. Total Synthesis and Stereochemical Assignment of (-)-Ushikulide A Barry M. Trost, Brendan M. O’Boyle, Daniel Hund J. Am. Chem. Soc. 2009, 131, 15061-15074 Presented by Maria DeMuro, Justin Sears, and Kaylee Wendel December 1, 2009

2. (-)-Ushikulide Exhibits potent immunosuppressant activity – Works against excessive growth of mouse lymphocytes Isolated from a culture broth of Streptomyces sp. IUK-102 – Sterochemically undefined member of oligomycin- rutamycin family

3. Stereochemistry (-)-Ushikulide is a natural product with a large degree of sterochemical complexity. Impossible to randomly prepare diastereomers – 14 sterocenters : 2 14 stereoisomers = 16384 possibilities Knew structure was very similar to the natural product cytovaricin, for which a crystal structure has been determined – NMR comparisons showed that 8 stereocenters matched – Only 6 stereocenters remained

4. Synthetic Planning

5. Objective- – Make a full three-dimensional structure of a complex natural product This provides information to explore the relationship between chemical structure and function To make C-14, C-15 olefin, used less common sp 3 -sp 2 Suzuki coupling and esterification Utilized alkenes and alkynes as orthogonal surrogates for hydroxyl and carbonyl functionalities New and highly regioselective gold catalyzed spiroketalization Use of (S,S) ProPhenol in enantio- and diastereoselective alkynlation and aldol reactions

6. Nuclear Overhauser effect -Spectral Technique to determine coupling between hydrogens -Coupling determined by proximity, not bonding -Irradiate one hydrogen -Can measure interactions between other nearby hydrogens -In this example, NOE is used to confirm the trans stereochemistry of the diol -If cis, hydrogen would be pointing in the opposite direction and would not be close enough to couple with the irradiated hydrogen.

7. Preparing the Aldehyde Fragment 1. Alkylation Mechanism

8. Preparing the Aldehyde Fragment 2. Crimmins Aldol Reaction 3. TBS Protection

9. Preparing the Aldehyde Fragment 4. DIBAL Reduction Mechanism

10. Preparing the Alkyne Fragment 1. Noyori Asymmetric Hydrogentation Mechanism

11. Preparing the Alkyne Fragment 2. PMB Protection 3. DIBAL Reduction

12. Preparing the Alkyne Fragment 4. Crotylation Mechanism

13. Preparing the Alkyne Fragment 5. TBS protection 6. Hydroboration-iodination 7. Nucleophilic Substitution

14. Completion of Spiroketal Fragment

15. Low Selectivity of Alkynation Syn to anti (desired) ratios were poor In presence of LiBr and molecular sieves, showed moderate Felkin-Ahn selectivity (6:1 syn:anti) Chelation controlled product was not feasible under a variety of conditions 2 Possible Solutions: Addition to Weinreb amide, then diastereoselective Noyori reduction Converge both epimers to anti product

16. Convergence of Epimers 28d and 28c were very easy to separate via column chromatagrophy, so Trost et al. decided to try the convergent pathway This involves addition of –Bz alcohol protecting group to 28d with inversion of stereochemistry, and addition to 28e with retention of stereochemistry

17. Inversion of syn epimer: Mitsunobu Reaction

18. Retention of Stereochemistry

19. Attempted Spiroketalization First, deprotection: Pd Catalyzed spiroketalization—utter failure:

20. AuCl Catalyzed Spiroketalization After attempts with Pd and Pt, decided to move on to gold With gold, observed complete conversion, but wrong spiroketal (42) Optimized conditions—changing solvent and Bronsted Acid affected product ratios Found PPTS was best Bronsted Acid additive and THF best solvent:

21. Spiroketalization Mechanism

22. Final Modifications to Spiroketal

23. Synthesis of Mesylate 44

24. Addition of Mesylate to Spiroketal Occurs via Marshall propargylation 44 undergoes oxidative addition with palladium(0) Then transmetallation with zinc Zinc reagent undergoes nucleophilic addition to aldehyde

25. Part I: Formation of Allenyl Zinc

26. Part II: Coordination Controlled Nucleophilic Addition The aldehyde coordinates to zinc, leading to complete control at (a) A Zimmerman-Traxler transition state favors shown stereochemistry at (b).

27. Final Modifications

28. Synthesis of Aliphatic Fragment and Completion of the Synthesis (-)- Ushikulide A

29. Restrosynthetic Analysis of Aliphatic Fragment KetoneAldehyde -Form ketone and aldehyde separately and join them together by a dinuclear zinc aldol reaction

30. First Approach: Scheme 9 The first step towards the synthesis of the aliphatic fragment 4 began with reacting the dibromide 48 with n-BuLi in THF to yield the Fritsch-Buttenberg Wiechell rearrangement, resulting in the lithium acetylide.

31. Scheme 9 The lithium acetylide was quenched with N- methoxy-N-methylacetamide to yield 49 The ketone in 49 was reacted with (S,S) prophenol (a chiral catalyst), diethyl zinc and an aldehyde in an aldol reaction to obtain the alkene in 51.

32. Transition State of Zn Aldol Reaction The aldehyde with two ethoxy groups is held by the two zinc atoms, acting as a bidentate ligand and bridging the two zincs. This transition states allows for the OH to be pushed to the front. The prophenol- zinc complex

33. Attempted Hydrosilation Possible mechanism: ethoxy group is protonated and leaves as ethanol.

34. Mukaiyama Allylation -Enantioselective due to the chiral allylating reagent generated in situ from tin(II) catecholate, allyl bromide, diisopropyl tartrate, DBU, and CuI. Proposed TS Ligand Association Oxidative Addition

35. Allylation and DIBAL Mechanisms

36. Termination of First Approach 53 undergoes several more reactions, including the zinc aldol reaction, as seen before and an epoxidation (which gives no stereoselectivity). Several attempts to open the epoxide of 57 and 58 failed to yield the desired product, 59. Scheme 10 overviews the resolution to this problem and the completion of the aliphatic fragment.

37. Wacker Oxidation Wacker oxidation of terminal alkenes yields the methyl ketone, rather than the aldehyde.

38. Completion of Aliphatic Fragment -Tried to optimize conditions for the reaction of 61 to 62. This is summarized in the table. -Entry 6 produced the best results. -t-BuOH > i-PrOH (prevents reduction of aldehyde 53 to alcohol 63) -Dioxane > THF -30 mol% (S,S) ProPhenol > 10 mol % (S,S) ProPhenol  65% yield, (>20:1 d.r.) -From 62 to 64 a protecting group was added. -The completion of the aliphatic fragment (64 to 65) relied on three reactions: deprotection, oxidation, and a Horner Wadsworth Emmons olefination (shown below).

39. Completion of Aliphatic Fragment Deprotection DMP Oxidation HWE Olefination

40. Optimization of Aliphatic Fragment -Considered another possible bond disconnection between C 7 -C 8 bond instead of the C 8 -C 9 bond. - This failed to give good yield or stereoselectivity, and therefore was not carried out any further. -Another possibility was to convert 53 to a silyl ether, 68. Excess of 68 was reacted with boron trifluoride diethyl etherate to yield the Felkin Ahn product.

41. Mukaiyama Aldol Reduction of this ketone diol (70) with NaBH 4 afforded the syn diol; 2,2 dimethoxypropane in p-TsOH and CH 2 Cl 2 was then added as a protecting group to yield 64.

42. Completion of the Synthesis -Completion of the synthesis required a Suzuki coupling and an esterification to join together 47a and 65 -Yamaguchi esterification allowed for the direct coupling of 47a and 65 to yield 72. -Unfortunately, Suzuki coupling is not usually utilized for the formation of macrocycles and failed to produce the desired product 73.

43. Alternate Pathway for Completion of Synthesis - Hydroboration, Suzuki coupling, then macrolactonization.

44. Finally, Deprotection and Oxidation. -Upon isolation, this compound exhibited identical H 1, C 13, IR, HPLC properties as natural ushikulide. -Optical rotation experiments confirmed the absolute stereochemistry, as depicted in Scheme 12