Synthesis of Amphidinolide

Amphidinolides, endowed with potent qrtotoxicity against various cancer cell lines, are host of secondary metabohtes produced by marine dinoflageUates of the genus Amphidinium sp. Hving in symbiosis with the Okinawan flatworm Amphtscolops sp. 

The amphidinolides are a class of structurally diverse and physiologically potent natural products. The key step in the total synthesis of enantiomerically-pure amphidinolide T1 3 recently reported (J. Am. Chem. Soc. 2004,126,998) by Timothy Jamison of MIT, the Ni-mediated cyclizalion of 1 to 2, clearly illustrates the power of organomelallic C-C bond formation in organic synthesis. 

The acid portion of 1 was assembled by enantio-and diastereocontrolled addition of Z-crotyl borane to the aldehyde 8, following the Brown protocol. Hydroboration and oxidation led to 9, which was condensed with the allenyl silane 10 to give 11 with high diastereocontrol. Conversion of the alcohol to the iodide followed by three-carbon homologation by the Myers procedure then led to 1, which was cyclized with 10 1 regio- and diasterocontrol to give 12. Ozonolysis and melhylenalion of the less hindered ketone then delivered 3. 

111 both of the Ni-mediated steps in this synthesis, the Ni-alkyne complex is acting as an acyl anion, in one case opening an epoxide and in the other case adding to the aldehyde in an intramolecular sense. Such Ni-reduced phenylalkynes are among the easiest to prepare and least expensive of acyl anion eciuiviilents. 

Enantioselective target-directed synthesis, which is important both for single-enantiomer pharmaceuticals and for natural product total synthesis, depends on the ability to form carbon-carbon bonds with absolute stereocontrol. An ideal method would be readily available, easy to practice, and proceed with high stereocontrol. In this column and the next one, we will review the most prominent recent developments. 

The enantioselective a-allylation of a ketone has become increasingly important. Martin Hiersmann of the Technische Universitat Dresden reports (Tetrahedron Lett. 2004, 45, 3647) that a-ketoesters readily form enol ethers, such as 6. On exposure to an enantiomerically-pure Cu catalyst, the enol ethers undergo facile Claisen rearrangement, leading to the allylated ketone (e.g. 7) with high enantiomeric 

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Scheme 39 Influence of a remote substituent on efficiency and stereochemistry of the RCM step in Fiirstner s total synthesis of amphidinolide T4 (199) [98a] and amphidinolide T3 (12-epf-199) [98b]...

The Stille reaction has been successfully applied to a number of macrocyclic ring closures.207 In a synthesis of amphidinolide A, the two major fragments were coupled via a selective Stille reaction, presumably governed by steric factors. After deprotection the ring was closed by coupling the second vinyl stannane group with an allylic acetate.208... 

SCHEME 81. Synthesis of amphidinolide T1 via Pd-catalyzed acylation of an alkylzinc derivative... 

Corey s asymmetric allylation methodology was utilized in the total synthesis of amphidinolide T3 (95), a marine natural product that exhibits significant antitumor properties37 (Scheme 3.1gg). The asymmetric allylation of the aldehyde 96 was carried out successfully with chiral allylborane reagent generated in situ from allyltributylstannane and (R,R)-82 to furnish the homoallylic alcohol desired (97) in 85% yield with excellent diastereoselectivity. Subsequent conversion of the alcohol to the tosylate ester followed by treatment with potassium hydroxide resulted in formation of the trisubstituted tetrahydrofuran 98. 

In the laboratory of T.F. Jamison, the synthesis of amphidinolide T1 was accomplished utilizing a catalytic and stereoselective macrocyclization as the key step. ° The Myers asymmetric alkylation was chosen to establish the correct stereochemistry at the C2 position. In the procedure, the alkyl halide was used as the limiting reagent and almost two equivalents of the lithium enolate of the A/-propionyl pseudoephedrine chiral auxiliary was used. The alkylated product was purified by column chromatography and then subjected to basic hydrolysis to remove the chiral auxiliary. 

The synthesis of the 36-membered macrolide dermostatin A (42), carried out by Rychnovsky, is remarkable for the complexity of this natural product and its acid- and light-sensitivity (Scheme 5.4.10). i Several approaches to the synthesis of amphidinolides also make use of alkenyl-alkenyl Stille coupling... 

In addition to the numerous efforts for total synthesis of these macrolides, 15 amphidinolides have been synthesized to date. The total synthesis of amphidinolides J (9), K (10), and P (15) have been reported by Professor Williams and colleagues. Professor Ffirstner s group accomplished the total synthesis of amphidinolides B1 (2a), B4 (2d), H (8a), H2 (8b), G (9a), Tl (19a), T3-T5 (19c-19e), V (21), X (23), and Y (24). Professor Ghosh and colleagues achieved the total synthesis of amphidinolides Tl (19a) and W (22). The total synthesis of amphidinolides A (1) and P (15) has been accomplished by Professor Trost s group. Professor Dai and colleagues completed the total synthesis of amphidinolides... 

Total synthesis of amphidinolides X (23) and Y (24) have been accomplished by Professor Fiirstner s group using a powerful iron-catalyzed process (Scheme 8), while amphidinolide Y (24) has been synthesized by Professor Dai s group using the formation of trisubstituted ( )-double bond through ring-closing metathesis of densely functionalized alkenes (Scheme 9). ... 

Williams, D. R., and Meyer, K. G. (1999). Total synthesis of (+)-amphidinolide K. In Abstracts of Papers, 218th National Meeting of the American Chemical Society, 1999, p. 578-ORGN. American Chemical Society, Washington, DC. 

SCHEME 2 The first steps of Furstner synthesis of amphidinolide Tl, T3, T4, and T5. 

Pd-catalyzed coupling of acyl halides with organometallic reagents is a useful synthetic method of ketones. The alkylzinc reagent 127, prepared from the corresponding alkyl iodide with Zn/Cu couple, was coupled with the acid chloride 128 to give the ketone 129 in 50 % yield and used for the total synthesis of amphidinolide T14 [55]. 

In the total synthesis of amphidinolide A (57), a key step is the coupling of di(alkenylstannane) 54 with 55, which has the alkenyl iodide and allyl acetate moieties as reactive groups. The coupling proceeded in two steps when AsPh3 is used as a ligand. At first, reaction took place chemoselectively with the alkenyl iodide to give 56. Then cyclization of 56 occurred by the coupling of the allylic acetate moiety with the alkenylstannane in cyclohexane in the presence of LiCl to afford 57 [30]. 

Scheme 3.78 Application of Pd-catalyzed acylations of alkylzinc derivatives in the synthesis of amphidinolide T1 [256].

This allylation protocol was used in the total synthesis of amphidinolide to give homoallylic alcohol 12 in 72% yield and 17 1 dr (eq 5). Initial transmetallation of stannane 10 with (R,R)-1 via allylic transposition yielded an intermediate borane. Introduction of aldehyde 11 at -78 °C provided for a facile condensation reaction leading to 12. Stereocontrol was induced from the 1,2-diphenylethane sulfonamide auxiliary and could be predicted from a Zimmerman-Traxler model with minimized steric repulsions. The high level of selectivity obtained in this case was a result of a matched diastereomeric transition state featuring the inherent Felkin-Ahn selectivity for nucleophilic attack in aldehyde 11, with the (5)-configuration of the benzoate of 10, as well as the (7 ,7 -antipode of auxiliary 1, resulting in threefold stereodifferentiation. 

In the synthesis of (-)-amphidinolide K fragment 58, the C14 and Cl5 stereocenters were established by an Evans aldol reaction. Application of two enolization protocols to 56 and aldehyde 57 provided 58 as a single diastereomer in 61% yield under TiCVDIPEA conditions, and 85% yield when Bu2BOT Et3N conditions were utilized. ... 

Pd-catalyzed cyclization was also applied to the stereocontrolled preparation of chiral substituted tetrahydrofurans. The synthesis of optically active tetrahydrofurans was pioneered by Stork and Poirier,who described effective chirality transfer in the Pd-assisted cyclization of y-hydroxy allylic esters. Williams and Meyer deployed a variant of the 0-capture of 7r-allylpalladium complexes in the reactions of substimted trimethylenemethane palladium complexes developed by Trost, using aUylstannane (Scheme 32). A key intermediate 156 in the synthesis of amphidinolide K, a marine nam-ral product, was therefore synthesized starting from enantiopure diastereomer 160. Compound 160 was prepared by in situ transmetallation using the Corey chiral sulfonamide 159 with optically active aUylstannane 157 and then condensation with functionalized aldehyde 158. Formation of the c -2,5-disubstituted tetrahydrofuran 156 occurred with an excellent diastereoselectivity (cis/trans 13 1) and a good yield (88%) from the syn-1,4-precursor 160. 

Sensitive Deprotections. Since the previous review, TASF has emerged as a good alternative to TBAF for the mild deprotection of silyl ethers of acid- and/or base-sensitive corr5>ounds. Side reactions, commonly observed during deprotection using TBAF, include complete decomposition (encountered during the synthesis of amphidinolides and aurisides ), acyl migra-... 

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