Total Synthesis and Stereochemical Assignment of (-)-Ushikulide A

1、Total Synthesis and Stereochemical Assignment of (-)-Ushikulide ABarry M. Trost, Brendan M. OBoyle, Daniel HundJ. Am. Chem. Soc. 2009, 131, 15061-15074Presented by Maria DeMuro, Justin Sears, and Kaylee WendelDecember 1, 2009(-)-Ushikulide Exhibits potent immunosuppressant activity Works against exc

2、essive growth of mouse lymphocytes Isolated from a culture broth of Streptomyces sp. IUK-102 Sterochemically undefined member of oligomycin-rutamycin familyStereochemistry(-)-Ushikulide is a natural product with a large degree of sterochemical complexity.Impossible to randomly prepare diastereomers

3、14 sterocenters : 214 stereoisomers = 16384 possibilitiesKnew 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 remainedSynthetic PlanningSynthetic Planning Objecti

4、ve- 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 sp3-sp2 Suzuki coupling and esterification Utilized alkenes and alkynes as orthogonal sur

5、rogates for hydroxyl and carbonyl functionalities New and highly regioselective gold catalyzed spiroketalization Use of (S,S) ProPhenol in enantio- and diastereoselective alkynlation and aldol reactionsNuclear Overhauser effect-Spectral Technique to determine coupling between hydrogens-Coupling dete

6、rmined 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

7、irradiated hydrogen.Preparing the Aldehyde Fragment1. Alkylation MechanismPreparing the Aldehyde Fragment2. Crimmins Aldol Reaction3. TBS ProtectionPreparing the Aldehyde Fragment4. DIBAL ReductionMechanismPreparing the Alkyne Fragment1. Noyori Asymmetric HydrogentationMechanismPreparing the Alkyne

8、Fragment2. PMB Protection3. DIBAL ReductionPreparing the Alkyne Fragment4. CrotylationMechanismPreparing the Alkyne Fragment5. TBS protection6. Hydroboration-iodination7. Nucleophilic SubstitutionCompletion of Spiroketal FragmentLow Selectivity of AlkynationSyn to anti (desired) ratios were poorIn p

9、resence of LiBr and molecular sieves, showed moderate Felkin-Ahn selectivity (6:1 syn:anti)Chelation controlled product was not feasible under a variety of conditions2 Possible Solutions:Addition to Weinreb amide, then diastereoselective Noyori reductionConverge both epimers to anti product Converge

10、nce of Epimers28d and 28c were very easy to separate via column chromatagrophy, so Trost et al. decided to try the convergent pathwayThis involves addition of Bz alcohol protecting group to 28d with inversion of stereochemistry, and addition to 28e with retention of stereochemistryInversion of syn e

11、pimer: Mitsunobu ReactionRetention of StereochemistryAttempted SpiroketalizationFirst, deprotection:Pd Catalyzed spiroketalizationutter failure:AuCl Catalyzed Spiroketalization After attempts with Pd and Pt, decided to move on to gold With gold, observed complete conversion, but wrong spiroketal (42

12、) Optimized conditionschanging solvent and Bronsted Acid affected product ratios Found PPTS was best Bronsted Acid additive and THF best solvent:Spiroketalization MechanismFinal Modifications to SpiroketalSynthesis of Mesylate 44Addition of Mesylate to Spiroketal Occurs via Marshall propargylation 4

13、4 undergoes oxidative addition with palladium(0) Then transmetallation with zinc Zinc reagent undergoes nucleophilic addition to aldehyde Part I: Formation of Allenyl ZincPart II: Coordination Controlled Nucleophilic Addition The aldehyde coordinates to zinc, leading to complete control at (a) A Zim

14、merman-Traxler transition state favors shown stereochemistry at (b).Final ModificationsSynthesis of Aliphatic Fragment and Completion of the Synthesis(-)- Ushikulide ARestrosynthetic Analysis of Aliphatic FragmentKetoneAldehyde-Form ketone and aldehyde separately and join them together by a dinuclea

15、r zinc aldol reactionFirst Approach: Scheme 9The 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. Scheme 9The lithium acetylide was quenched

16、 with N-methoxy-N-methylacetamide to yield 49The 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. Transition State of Zn Aldol ReactionThe aldehyde with two ethoxy groups is held by the two zinc atoms, ac

17、ting 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 complexAttempted HydrosilationPossible mechanism: ethoxy group is protonated and leaves as ethanol.Mukaiyama Allylation -Enantioselective due to the chiral all

18、ylating reagent generated in situ from tin(II) catecholate, allyl bromide, diisopropyl tartrate, DBU, and CuI.Proposed TSLigand AssociationOxidative AdditionAllylation and DIBAL MechanismsTermination of First Approach 53 undergoes several more reactions, including the zinc aldol reaction, as seen be

19、fore 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.Wacker OxidationWacker oxidation of terminal alkenes

20、yields the methyl ketone, rather than the aldehyde.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

21、) 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).Completion of Aliphatic FragmentDepr

22、otectionDMP OxidationHWE OlefinationOptimization of Aliphatic Fragment-Considered another possible bond disconnection between C7-C8 bond instead of the C8-C9 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.Mukaiyama Aldol Reduction of this ketone diol (70) with NaBH4 afforded the syn diol; 2,2 dimethoxypropan