Synthesis azaspiracid

The indium-mediated allylation of trifluoroacetaldehyde hydrate (R = H) or trifluoroacetaldehyde ethyl hemiacetal (R = Et) with an allyl bromide in water yielded a-trifluoromethylated alcohols (Eq. 8.56).135 Lanthanide triflate-promoted indium-mediated allylation of aminoaldehyde in aqueous media generated (i-airiinoalcohols stereoselectively.136 Indium-mediated intramolecular carbocyclization in aqueous media generated fused a-methylene-y-butyrolactones (Eq. 8.57).137 Forsythe and co-workers applied the indium-mediated allylation in the synthesis of an advanced intermediate for azaspiracids (Eq. 8.58).138 Other potentially reactive functionalities such as azide, enone, and ketone did not compete with aldehyde for the reaction with the in situ-generated organo-indium intermediate. 

The linear-fused tricycle 446 was a key intermediate in the synthesis of the marine toxin azaspiracid (Equation 121) <2004H(63)539, 2004TL351>. 

An elegant synthesis of the spiroaminal containing domain of azaspiracids 201 makes use of a Staudinger-aza-Wittig reaction in a cascade sequence to generate the spiroaminal 202 <06T5338 06JA15114>. 

In Carter s studies toward the total synthesis of azaspiracid, the construction of "fragment B" requires the conversion of the y-lactone 91 into a furan acetal. In this connection, it has been uncovered that the desired furan acetal can indeed be formed in 64% yield under methanolic acidic conditions . 

Unsure of how to proceed along the lines of total synthesis, we resorted to new tactics in order to discover the true structure of azaspiracid-1 (Nicolaou 2004a, 2004b). It was requested that the Satake group attempt a chemical degradation of natural azaspiracid-1, a task that was admirably carried out as shown in Scheme 16.9, to produce 56-61. The Satake group then obtained H NMR spectra of these compounds (58, 59, 57, and 61) and we set out to synthesize them in order to confirm their structures. 

Scheme 16.11 shows the completion of the total synthesis of azaspiracid-1, which followed with slight modifications, the synthesis of the originally proposed structure of azaspiracid-1 (la). This chemistry was also carried out with the corresponding ABCD enantiomer in similar yields. Thns, lithiation of dithiane 51 (n-BuLi n-BnjMg) followed by addition into pentafluorophenol ester 68 resulted in CJ-C27 ketone 69 (50% yield). Ketone 69 was then elaborated into diacetate 70, this time as the TBS ether at C-25, as this protecting group was easier to remove than the acetate used in the earlier work directed toward the original stractnre (see Scheme 16.8). Stille coupling of this allylic acetate (70) then proceeded smoothly, as before, affording the complete Cj-C q backbone 71, which was successfully elaborated to the correct structure of azaspiracid-1 (1), identical in all measured physical properties ( H NMR, C NMR, Rf, [aj ) to the natural material.

Scheme 16.11. The completion of the total synthesis of azaspiracid-1 (Nicolaou 2004a).

The isolation of azaspiracid-1 from poisonous mussels (Mytilus edulis) by Yasumoto and Satake was an admirable and Herculian accomplishment. Its originally proposed structure by these investigators stimulated considerable efforts to synthesize it in the laboratoiy. The efforts in om laboratory led first to the demise of the originally proposed structures and subsequently to the proposal and total synthesis of the correct structure of this fascinating natural product. 

Carter, R.G., and Graves, D.E. 2001. Studies directed toward the total synthesis of azaspiracid. Construction of the Cj-Cj, carhon backbone and synthesis of the Cj, Cjj nonnatural transoidal bisspirocyclic ring system. Tetrahedron Lett 42(35) 6035-6039. 

Forsyth, C.J., Hao, XL., and Aiguade, J. 2001. Synthesis of the (+)-C26-C40 domain of the azaspiracids by a novel double intramolecular hetero-Michael addition strategy. Angew Chem IntEd 40(19) 3663-3667. 

Nicolaou, K.C., Koftis, T.Y, Vyskocil, S., Petrovic, G., Ling, T.T., Yamada, Y.M.A., Tang, W.J., and Frederick, M.O. 2004a. Structural revision and total synthesis of azaspiracid-1, part 2 definition of the ABCD domain and total synthesis. Angew Chem 7nf rf43(33) 4318 324. 

Nicolaou, K.C., Pihko, PM., Diedrichs, N., Zou, N., and Bernal, F. 2001a. Synthesis of the FGHl ring system of azaspiracid. 

Nicolaou, K.C., Li, Y, Uesaka, N., Koflis, TV, Vyskocil, S., Ling, T, Govindasamy, M., Qian, W, Bernal, F, and Chen, D. Y 2003b. Total synthesis of the proposed azaspiracid-1 structwe, part 1 consfiaiction of the enantiomerically pure C1-C20, C21-C27, and C28-C40 fragments, Chem IntEdEngl 42, 3643-3648. 

Compared with the previous coupling types, much less has been reported with these relatively more difficnlt conplings. Exceptionally, conplings with allyl electrophiles, usually allyl acetates or halides, have been often nsed in the synthesis of complex natural products.A noteworthy example is the synthesis of the azaspiracids 1-3 (115a-c), neurotoxins isolated from mussels, whose structure was determined by total synthesis by Nicolaon and coworkers.This synthesis features a notable Stille... 

Synthesis of (—)-Azaspiracid-l. A different approach to C-C coupling through 3-oxo sulfones consists of the addition of an a-sulfonyl carbanion to an aldehyde followed by oxidation. This reaction sequence has been widely used in the preparation of various natural products such as the marine toxin (-)-azaspiracid-l (Eq. 150).260... 

Azaspiracid-1 synthesis was successfully accomplished by Nicolaou et al. (2003a,b, 2004a,b) toxicity identification and correlation to the chemical structure in mice were studied through an acute experiment after 24 h. Among these compounds, upper two compounds of the correct structure of AZA-1 and the isomer showed toxicity at the p.o. dose up to 3 mg/kg components were also tested intraperitoneally (i.p.) (Figure 36.8). 

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