Of amphidinolide

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... 

Entries 4 and 5 are examples of use of the Sakurai reaction to couple major fragments in multistage synthesis. In Entry 4 an unusual catalyst, a chiral acyloxyboronate (see p. 126) was used to effect an enantioselective coupling. (See p. 847 for another application of this catalyst.) Entry 5 was used in the construction of amphidinolide P, a compound with anticancer activity. 

Inter- and intramolecular ruthenium-catalyzed Alder-ene reactions were utilized to synthesize the proposed structures of amphidinolide A.98 Conversion of dienyne 163 into pentaene 164 was accomplished in 46% yield with the products obtained as a 3.5 1 mixture of the branched to linear forms (Scheme 39). It is notable that the Cp variant of the ruthenium catalyst 64 was used for the intermolecular Alder-ene reaction. Conversion of 164 into protected amphidinolide A was performed using high dilution conditions with the normal catalyst to give a 58% yield of the macrolide which was then deprotected to provide the natural product. 

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. 

B. M. Trost, J. D. Chisholm, S. T. Wrobleski, and M. Jung, Ruthenium-catalyzed alkene-alkyne coupling Synthesis of the proposed structure of amphidinolide A, J. Am. Chem. Soc., 124 (2002) 1242-12421. 

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. 

Williams, D. R., Meyer, K. G. Palladium-Induced Cyclizations for the Synthesis of cis-2,5-Disubstituted-3-methylenetetrahydrofurans Studies of the C7-C22 Core of Amphidinolide K. Org. Lett. 1999, 1, 1303-1305. 

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... 

Allyl epoxides are produced by the acclaimed Sharpless asymmetric epoxidation reaction [75], and are important intermediates and products. For example, an allyl epoxide is a vital part of the structure of amphidinolides, a series of unique macrolides isolated from dinoflagellates (Amphidinium sp.). Amphidinolide H (AmpH) is a potent cytotoxic 26-membered macrolide with potent cytotoxicity for several carcinoma cell lines [76]. An allyl epoxide is involved in the total synthesis of prostaglandin A2 with a cuprate reagent [77]. Allyl epoxides derived from Sharpless chemistry are a practical method for construction of polypropionate structures by Lewis acid-induced rearrangement [78,79]. Other allyl epoxides such as l,2-epoxy-3-methyl-3-butanol are useful organic intermediates for the production of a-hydroxyketones, which are used for the synthesis of various natural... 

Amphidinolides have a variety of backbone skeletons and different sizes of macrolactone rings (12- to 29-membered rings), and more than half of the amphidinolides have odd-numbered macrolactone rings (Table 2). Most of the amphidinolides contain a vicinally located one-carbon branch and cxo-methylene unit, and some of them exhibit potent cytotoxicity and antitumor activity. Due to their diverse functionality, stereochemical complexity, low natural abundance, and encouraging bioactivity, amphidinolides have attracted great interest as challenging targets for total synthesis. Synthetic study of amphidinolides is also important to establish the structure of these macrolides in case the amount of natural compound was very limited. 

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... 

A revealed that the proposed stereostructure was incorrect." " Reexamination of the and NMR data indicated that the correct stereostructure of amphidinolide A could be either (1) or an 11,12-epimer of (1). From a comparison of NMR data, optical rotations, and retention times from Cig HPLC of natural amphidinolide A, the synthetic (1) and 11,12-epimer of (1) revealed that (1) was the correct stereostructure of amphidinolide A (8R, 9R, 115, 125, 18R, 195, 20R, 215, and 225). ... 

Scheme 1 Retrosynthetic analysis of amphidinolide H (8a) by Professor Furstner.

Amphidinolides B6 (2f) and B7 (2g) have been isolated from a marine dinoflagellate Amphidinium sp. (strain HYA002), which was isolated from the marine acoel flatworm Amphiscolops sp. collected off Sunabe beach, Okinawa. The planer structures of amphidinolides B6 (2f) and B7 (2g) were elucidated from the detailed analyses of 2D NMR spectra. Relative stereochemistries of these macrolides were deduced from NOESY data... 

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