Spongipyran synthetic studies. Evolution of a scalable total synthesis of (+)-spongistatin 1
Three syntheses of the architecturally complex, cytotoxic marine macrolide (+)-spongistatin 1 (1) are reported. Highlights of the first-generation synthesis include: use of a dithiane multicomponent linchpin coupling tactic for construction of the AB and CD spiroketals, and their union via a highly selective Evans boron-mediated aldol reaction en route to an ABCD aldehyde; introduction of the C(44)-C(51) side chain via a Lewis acid-mediated ring opening of a glucal epoxide with an allylstannane to assemble the EF subunit; and final fragment union via Wittig coupling of the ABCD and EF subunits to form the C(28)-C(29) olefin, followed by regioselective Yamaguchi macrolactonization and global deprotection. The second- and third-generation syntheses, designed with the goal of accessing 1 g of (+)-spongistatin 1 (1), maintain both the first-generation strategy for the ABCD aldehyde and final fragment union, while incorporating two more efficient approaches for construction of the EF Wittig salt. The latter combine the original chelation-controlled dithiane union of the E- and F-ring progenitors with application of a highly efficient cyanohydrin alkylation to append the F-ring side chain, in conjunction with two independent tactics to access the F-ring pyran. The first F-ring synthesis showcases a Petasis-Ferrier union/rearrangement protocol to access tetrahydropyrans, permitting the preparation of 750 mg of the EF Wittig salt, which in turn was converted to 80 mg of (+)-spongistatin 1, while the second F-ring strategy, incorporates an organocatalytic aldol reaction as the key construct, permitting completion of 1.009 g of totally synthetic (+)-spongistatin 1 (1). A brief analysis of the three syntheses alongside our earlier synthesis of (+)-spongistatin 2 is also presented.
Smith III, Amos B.,Sfouggatakis, Chris,Risatti, Christina A.,Sperry, Jeffrey B.,Zhu, Wenyu,Doughty, Victoria A.,Tomioka, Takashi,Gotchev, Dimitar B.,Bennett, Clay S.,Sakamoto, Satoshi,Atasoylu, Onur,Shirakami, Shohei,Bauer, David,Takeuchi, Makoto,Koyanagi, Jyunichi,Sakamoto, Yasuharu
supporting information; experimental part
p. 6489 - 6509
(2011/02/25)
Gram-scale synthesis of (+)-spongistatin 1: Development of an improved, scalable synthesis of the f-ring subunit, fragment union, and final elaboration
(Chemical Equation Presented) In a quest to develop an effective, scalable synthesis of (+)-spongistatin 1 (1), we devised a concise, third-generation scalable synthesis of (+)-7, the requisite F-ring tetrahydropyran aldehyde, employing a proline-catalyzed cross-aldol reaction. Subsequent elaboration to (+)-EF Wittig salt (+)-3, followed by union with advanced ABCD aldehyde (-)-4, macrolactonization and global deprotection permitted access to >1.0 g of totally synthetic (+)-spongistatin 1 (1).
Smith III, Amos B.,Tomioka, Takashi,Risatti, Christina A.,Sperry, Jeffrey B.,Sfouggatakis, Chris
supporting information; experimental part
p. 4359 - 4362
(2009/06/06)
The stereocontrolled total synthesis of altohyrtin A/spongistatin 1: Fragment couplings, completion of the synthesis, analogue generation and biological evaluation
The antimitotic marine macrolide altohyrtin A/spongistatin 1 (1) has been synthesised in a highly convergent and stereocontrolled manner, thus contributing to the replenishment of the largely exhausted material from the initial isolation work. Coupling of
Paterson, Ian,Chen, David Y.-K.,Coster, Mark J.,Acena, Jose L.,Bach, Jordi,Wallace, Debra J.
p. 2431 - 2440
(2007/10/03)
Total synthesis of Spongistatin 1: A synthetic strategy exploiting its latent pseudo-symmetry
(Chemical Equation Presented) The challenging structure and potent growth inhibition properties against a variety of human cancer cell lines make Spongistatin 1 (1) an exciting target for total synthesis. Enantioselective total synthesis has been achieved
Ball, Matthew,Gaunt, Matthew J.,Hook, David F.,Jessiman, Alan S.,Kawahara, Shigeru,Orsini, Paolo,Scolaro, Alessandra,Talbot, Adam C.,Tanner, Huw R.,Yamanoi, Shigeo,Ley, Steven V.
p. 5433 - 5438
(2007/10/03)
Total synthesis of (+)-spongistatin 1. An effective second-generation construction of an advanced EF Wittig salt, fragment union, and final elaboration.
A stereocontrolled, total synthesis of (+)-spongistatin 1 (1) has been achieved. Union of a second-generation EF Wittig salt (+)-3 with the advanced ABCD aldehyde (-)-4, followed by regioselective macrolactonization and global deprotection afforded (+)-sp
Smith 3rd., Amos B,Zhu, Wenyu,Shirakami, Shohei,Sfouggatakis, Chris,Doughty, Victoria A,Bennett, Clay S,Sakamoto, Yasuharu
p. 761 - 764
(2007/10/03)
Stereocontrolled total synthesis of (+)-altohyrtin A/spongistatin 1
As an exceptionally potent antimitotic macrolide, altohyrtin A/spongistatin 1 shows great promise in cancer chemotherapy but its extreme scarcity in the natural sponges has halted its further preclinical development. A highly stereocontrolled total synthe
Paterson, Ian,Chen, David Y.-K.,Coster, Mark J.,Acea, Jose L.,Bach, Jordi,Gibson, Karl R.,Keown, Linda E.,Oballa, Renata M.,Trieselmann, Thomas,Wallace, Debra J.
p. 4055 - 4060
(2007/10/03)
Total Synthesis of Altohyrtin A (Spongistatin 1): Part 2
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Hayward, Matthew M.,Roth, Rebecca M.,Duffy, Kevin J.,Dalko, Peter I.,Stevens, Kirk L.,Guo, Jiasheng,Kishi, Yoshito
p. 190 - 196
(2007/10/03)
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