The total synthesis of (+)-iriciniastatin A (psymberin) is reported in 19 steps and 6% overall yield. Key reactions include a highly convergent enolsilane-oxocarbenium ion union to generate the C8-C25 fragment and a late-stage coupling of a hemiaminal and acid chloride to complete the synthesis

Crimmins, Michael T.

Schaaf, Gregory M.

Stevens, Jason M.

Carolina Digital Repository

The Total Synthesis of Irciniastatin A (Psymberin)Michael T. Crimmins*, Jason M. Stevens, and Gregory M. SchaafKenan and Caudill Laboratories of Chemistry, University of North Carolina at Chapel Hill, NorthCarolina 27599AbstractThe total synthesis of (+)-iriciniastatin A (psymberin) is reported in 19 steps and 6% overall yield.Key reactions include a highly convergent enolsilane-oxocarbenium ion union to generate the C8-C25 fragment and a late stage coupling of a hemiaminal and acid chloride to complete the synthesis.In 2004, Pettit and Crews independently reported the isolation of two remarkably potent andselective cancer cell growth inhibitors from the extracts of deep water sponges. Irciniastatin A(1) was obtained from Ircinia ramosa by Pettit,1 and psymberin from Psammocina sp. byCrews.2 The two secondary metabolites were shown to be structurally related based onspectroscopic studies, however, incomplete and conflicting stereochemical analyses precludeda definitive assignment of absolute configuration. Each displayed incredibly powerful andselective cancer cell growth inhibition. Irciniastatin A was reported to exhibit a greater than104 differential in activity across related cell lines. The limited natural abundance and lack ofan absolute stereochemical assignment, as well as interest in further exploration of the uniquechemotherapeutic profile and mode of action, sparked immediate interest within the syntheticcommunity.Early reports shed light on the stereochemical ambiguities through fragment synthesis3 andnatural product degradation.4 Ultimately, it was the seminal total synthesis by DeBrabander5that confirmed the absolute configuration and demonstrated that irciniastatin A (1) andpsymberin were identical. Subsequent reports, including fragment synthesis,6 a formalsynthesis,7 two total syntheses,8,9 and two reports of analog syntheses,10,11 all offered creativeand distinct approaches toward the unique structural elements of irciniastatin A.crimmins@email.unc.edu.Supporting Information Available: Experimental details and spectral data for new compounds as well as psymberin. This material isavailable free of charge via the Internet at http://pubs.acs.org.NIH Public AccessAuthor ManuscriptOrg Lett. Author manuscript; available in PMC 2010 September 3.Published in final edited form as:Org Lett. 2009 September 3; 11(17): 3990–3993. doi:10.1021/ol901655e.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptOur interest in (+)-irciniastatin A (psymberin) focused on developing a highlydiastereoselective and modular synthesis that might be suitable for analog preparation. Ourefforts toward (+)-1, recently culminated in a completed total synthesis which is reported here.Retrosynthetically (Scheme 1), (+)-irciniastatin A (1) was envisioned to arise from two keydisconnections. A late stage attachment of the psymberic acid chain would be accomplishedby coupling of acid chloride 2 with hemiaminal 3, the product of a Curtius rearrangement ofthe carboxylic acid derived from benzyl ether 4. This tactic would allow for a highlystereocontrolled entry to the C8 hemiaminal and efficient incorporation of the side chain.Tetrahydropyran 4 would arise from the stereoselective addition of enolsilane 6 to theoxocarbenium-ion derived from acetate 5. These two key disconnections segregate the threemajor subunits of irciniastatin A (1); each of similar size and complexity and accessible in ahighly stereocontrolled fashion from standard aldol synthons.All reported syntheses of the psymberate side chain have relied on functionalizingcommercially available chiral pools or enzymatic resolutions. In addition, analog studies10,11 have shown the side chain to be required for high activity. Therefore, an enantioselectiveand highly tunable synthesis of the side chain would be ideal for further investigation of sidechain function. We reasoned that an oxazolidinethione asymmetric glycolate aldol reaction12would allow for enantioselective entry to the psymberate side chain as well as provide sufficientopportunities for derivitization and congener synthesis. The synthesis of acid chloride 2(Scheme 2) began with the known13 anti-aldol12a reaction of glycolate 9 and 3-methyl-but-3-enal to deliver aldol adduct 10 that was converted to known TIPS ether 11.13 Methylation ofthe alcohol was followed by removal of the allyl protecting group under Kulinkovichconditions13,14 to give alcohol 12. Protection of alcohol 12 as the SEM ether was followed byselective removal of the primary TIPS ether. The resultant primary alcohol 13 was oxidizedunder Smith's conditions giving the corresponding acid over two steps. The acid (9 steps, 28%overall) was converted to acid chloride 2.The synthesis of the acetate 5 (Scheme 3) began from known p-methoxybenzylidine acetal1415 available from 2-deoxy-D-ribose in two steps. Methylation of alcohol 14 was followedby a dihydroxylation-oxidative cleavage sequence to reveal aldehyde 16. A catalyst controlledKiyooka16 aldol reaction of aldehyde 16 and enolsilane 1717 provided carbinol 18 in 84% yieldand 9:1 dr. Protection of alcohol 18 to give TBS ether 19 was followed by acid-catalyzedcyclization to provide a 10:1 mixture of lactone 20 and the corresponding diol, which wasconverted to lactone 20 by exposure to CF3CO2H. Protection of the primary alcohol gavebenzyl ether 21 and subsequent one-pot reductive acetylation18 afforded acetate 5 inquantitative yield (9 steps, 34% overall from 2-deoxy-D-ribose).The synthesis of enolsilane 6 (Scheme 4) began from known catechol 246,19 prepared bycycloaddition of allene 2320 and diene 22.21 Protection of catechol 24 as the bis-TIPS etherwas followed by selective ester reduction to give aldehyde 25 in 78% yield over 2 steps. Anasymmetric propionate aldol22 reaction of aldehyde 25 and propionyl thiazolidinethione 26afforded the Evans-syn-aldol adduct 27 in 94% yield and >20:1 dr. Direct displacement of thechiral auxiliary with Weinreb's amine was followed by protection of the secondary alcohol asa TBS ether to deliver silyl ether 28. The methyl ketone prepared from Weinreb's amide 28,was then readily converted to desired enolsilane 6 (7 steps; 66% overall from catechol 24).Having devised highly stereocontrolled routes to all three key fragments, the union ofenolsilane 6 and acetate 5, was investigated (Scheme 5). Rigorous experimentation revealedthat BF3●OEt2 was the optimum Lewis acid and that TBS enolsilane 6 performed better thanthe corresponding TMS enolsilane for the assembly of 5 and 6. Most intriguing, however, wasthat addition of a solution of enolsilane 6 to a premixed solution of 5 and BF3●OEt2 at -40 °CCrimmins et al. Page 2Org Lett. Author manuscript; available in PMC 2010 September 3.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscriptwas required for efficient coupling. The union proceeded with high diastereoselectivity, givingtetrahydropyran 4 as the only detectable diastereomer. The high diastereoselectivity can berationalized by well precedented23 pseudoaxial addition of the nucleophile to theoxocarbenium conformer 29, proceeding through a favorable chair-like conformation.Conformer 29 would also be expected to be favored as a result of through-space stereoelectronicstabilization23 of the oxocarbenium ion by the axially positioned C11 ether.With the C8-C25 carbon framework in place, conditions to set the C15 stereocenter wereinvestigated (Scheme 6). Standard achiral reducing agents proved to be non-selective orcompletely selective for the undesired diasteromer,24 however, the use of the chiral (R)-CBS25 agent exclusively provided desired diastereomer 3026 in 82% yield. After protection ofthe secondary alcohol as its TBS ether and cleavage of the benzyl ether, carbinol 31 wasoxidized over 2 steps to carboxylic acid 32. Initial studies showed the one-pot Curtius reactionwith (O,O)-diphenylphosphoryl azide27 to be ineffective, providing significant quantities ofinseparable carbamoyl azide impurity.28 Therefore, Weinstock's procedure9,29 was employedto generate the intermediate isocyanate, which under mild conditions using copper (I) chlorideafforded Teoc-protected hemiaminal 33.30 Much to our dismay, a screen of reportedconditions31 for acylation of stucturally related intermediates never yielded N-acyl hemiaminal34. A survey of the previous syntheses of irciniastatin A finds that all feature a late stage aminaland side chain incorporation with a preformed lactone of the dihydroisocoumarin. Albeitunlikely that such remote functionality should have any effect on the hemiaminal coupling, thelimited number of available options warranted pursuit of this lead.32Strategically, after the CBS reduction, the lactone was formed concomitantly with removal ofthe TBS ether to give 35 adding only one synthetic step over the original plan (bottom ofScheme 6). An analogous sequence of TBS protection of the C15 carbinol and hydrogenolysisof the benzyl ether gave carbinol 36, which was subjected to a two step oxidation to acid 37.Acid 37 was subjected to the previously established Curtius conditions to give hemiaminal 3.With hemiaminal 3 featuring the lactonized dihydroisocoumarin, it was found that i-PrMgCl,a base not previously used for this transformation, successfully effected reaction with acidchloride 2 in a remarkable 87% yield. Finally, global deprotection with TASF in DMF at 50 °C provided (+)-irciniastatin A (1) in 94% yield.In summary, the total synthesis of (+)-irciniastatin A (1) was completed in 19 steps with a 6%overall yield from 2-deoxy-D-ribose. The successful application of this strategy allowed forrapid assembly of the three key fragments with high diastereocontrol. Studies directed towardanalog synthesis and further evaluation of the antitumor activity of irciniastatn A are underwayin collaboration with the Lineberger Comprehensive Cancer Center.Supplementary MaterialRefer to Web version on PubMed Central for supplementary material.AcknowledgmentsFinancial support from the National Institute of General Medical Sciences (GM60567) is gratefully acknowledged.References1. Pettit GR, Xu JP, Chapuis JC, Pettit RK, Tackett LP, Doubek DL, Hooper JNA, Schmidt JM. J MedChem 2004;47:1149. [PubMed: 14971894]2. Cichewicz RH, Valeriote FA, Crews P. Org Lett 2004;6:1951. [PubMed: 15176791]3. 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NOE experiments on related compounds by DeBrabander indicate a close spatial relationship betweenthese two regions of the molecule (see reference 11).Crimmins et al. Page 4Org Lett. Author manuscript; available in PMC 2010 September 3.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptScheme 1.Retrosynthetic Analysis of Irciniastatin ACrimmins et al. Page 5Org Lett. Author manuscript; available in PMC 2010 September 3.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptScheme 2.Synthesis of the Psymberic Acid Side ChainCrimmins et al. Page 6Org Lett. Author manuscript; available in PMC 2010 September 3.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptScheme 3.Synthesis of Acetate 5Crimmins et al. Page 7Org Lett. Author manuscript; available in PMC 2010 September 3.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptScheme 4.Synthesis of Enolsilane 6Crimmins et al. Page 8Org Lett. Author manuscript; available in PMC 2010 September 3.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptScheme 5.Coupling of Acetate 5 with Enolsilane 6Crimmins et al. Page 9Org Lett. Author manuscript; available in PMC 2010 September 3.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptScheme 6.Completion of the Synthesis of (+)-Irciniastatin ACrimmins et al. Page 10Org Lett. Author manuscript; available in PMC 2010 September 3.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscript

Total Synthesis of Irciniastatin A (Psymberin)

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Total Synthesis of Irciniastatin A (Psymberin)

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