Studies directed toward the total synthesis of azaspiracid: stereoselective construction of C(1)-C(12), C(13)-C(19), and C(21)-C(25) fragments

[reaction: see text] The efficient entry to the C(1)-C(12), C(13)-C(19), and C(21)-C(25) fragments of azaspiracid is outlined. The C(1)-C(12) portion is constructed using a key asymmetric allenyl borane addition to the corresponding alpha,beta-unsaturated aldehyde. The synthesis of the C(13)-C(19) portion utilizes an Evans asymmetric alkylation followed by Sharpless asymmetric dihydroxylation. In addition, a novel solution to the mismatched effects of a neighboring chiral oxazolidinone during a Sharpless dihydroxylation is detailed.     

Asymmetric Synthesis of Calyculin C. 2. Synthesis of the C(26)-C(37) Fragment and Model Wittig Couplings

We report our synthesis of the C(26)-C(37) fragment of serine/threonine protein phosphatase PP1 and PP2A inhibitor calyculin C (1). Outlined in this paper are synthetic approaches to the two components based on disconnection at the C(33)-N(3) amide bond. We report the successful synthesis of the C(33)-C(37) aza-sugar derived from D-lyxose which was coupled onto a C(26)-C(32) aminooxazole originating from L-pyroglutamic acid. Elaboration of the resulting amide to a fully deprotected C(26)-C(37) fragment of calyculin C completed our synthesis. This provided an appropriate phosphonium salt for use in a Wittig olefination for joining both halves of the natural product.     

Stereoselective synthesis of the C(1)-C(11) fragment of peloruside A

A highly stereoselective synthesis of the C(1)-C(11) fragment 4 of peloruside A has been accomplished via a stereoselective double allylboration and an intramolecular epoxide opening to provide the functionally dense C(3)-C(11) segment 14. A glycolate aldol reaction was then employed to introduce the remaining stereocenters at C(2)-C(3). [reaction: see text]     

Study of the total synthesis of (-)-exiguolide

In this article, we disclose the various routes and strategies we had to explore before finally achieving the total synthesis of (-)-exiguolide ((-)-1). Two first types of approaches were set, both relying on the Trost's domino ene-yne coupling/oxa-Michael reaction that we choose for its ability to control the geometry of the methylacrylate-bearing tetrahydropyrane ring B. In our first approach, we expected to assemble the two main fragments (C14-C21 and C1-C13) by creating the C13-C14 bond through a palladium(0)-catalyzed cross-coupling, but this step failed, unfortunately. In the second approach, which was more linear, we created the C16-C17 bond through condensation of a lithium acetylide on a Weinreb amide, and we assembled the C1-C5 and C6-C21 subunits through Trost's domino ene-yne coupling/oxa-Michael reaction. These two approaches served us to design an ameliorated third strategy, which finally led to the total synthesis of (-)-exiguolide.     

Asymmetric Synthesis of Calyculin C. 1. Synthesis of the C(1)-C(25) Fragment

We report our synthesis of the C(1)-C(25) fragment of serine/threonine phosphatase PP1 and PP2A inhibitor, calyculin C. Synthetic efforts were directed initially toward the synthesis of a spiroketal core fragment (7), which culminated in completion of the bottom half of the natural product. The synthesis of fragment 7 and subsequent elaboration relied on an allylboration strategy for introduction of chirality. The C(1)-C(8) fragment representing the potentially unstable tetraene moiety was introduced as a separate entity.     

Efficient synthesis of the C(1)-C(9) fragment of amphidinolides C, C2, and F

The synthesis of the C(1)-C(9) fragment of amphidinolides C, C2, and F was achieved by using a vinyloguous Mukaiyama aldol reaction on a chiral aldehyde with a silyloxyfuran and by using a C-glycosylation of a lactol derivative with an acetyl oxazolidinethione. From the available chiral acetonide-glyceraldehyde, all the stereogenic centers were perfectly induced along the synthesis. The C(1)-C(9) fragment was synthesized as a vinyl stannane at C(9) in 10 steps, with 16% yield.     

Total synthesis of scytophycin C. 2. Coupling reaction of the C(1)-C(18) segment and the C(19)-C(31) segment, a key macrolactonization, and the crucial terminal amidation reaction

[reaction: see text] Stereoselective syntheses of the C(1)-C(18) segment (segment A) and the C(19)-C(31) segment (segment B) are described in the preceding paper. This paper reports the key coupling reaction of both segments, 22-membered lactonization, and the crucial terminal amidation reaction culminating in the total synthesis of scytophycin C.     

Synthesis of the C(21)-C(26) fragment of superstolide A: concerning the stereochemistry of (E)-crotylboration reactions of alaninal derivatives

A stereoselective synthesis of the C(21)-C(26) fragment of superstolide A has been completed. The absolute and relative stereochemistry of intermediate 14 has been conclusively proven by NMR and X-ray diffraction methods. In the course of this work, it was found that the stereochemistry of 3 had been misassigned in our previously reported synthesis of the C(18)-C(26) segment. This error stems from the unexpected diastereoselectivity in the double asymmetric reaction of N-acetyl-d-alaninal 1 and the tartrate ester modified (E)-crotylboronate (R,R)-2.     

Total synthesis of scytophycin C. 1. Stereoselective syntheses of the C(1)-C(18) segment and the C(19)-C(31) segment

[structure: see text] Stereoselective total synthesis of scytophycin C, a marine 22-membered macrolide displaying potent activity against a variety of human carcinoma cell lines, has been reported in which the polypropionate structure bearing contiguous asymmetric centers was stereospecifically constructed by using new acyclic stereocontrol. This paper describes stereoselective syntheses of the C(1)-C(18) segment (Segment A) including a trans-disubstituted dihydropyran ring and the C(19)-C(31) segment (Segment B) having eight stereogenic centers.     

Total synthesis of (-)-callystatin A

[reaction: see text] A convergent enantioselective synthesis of the natural product (-)-callystatin A (1) is described. Key features of the synthesis include a lipase-mediated kinetic resolution to install the C5 lactone stereochemistry, a hydrozirconation-based approach to the C8-C9 trisubstituted (Z)-olefin, and a stereoselective cross-coupling of a vinyl dibromide to install the C14-C15 trisubstituted (E)-olefin.     

Synthesis of the C(18)-C(34) fragment of amphidinolide C and the C(18)-C(29) fragment of amphidinolide F

A convergent synthesis of the C(18)-C(34) fragment of amphidinolide C and the C(18)-C(29) fragment of amphidinolide F is reported. The approach involves the synthesis of the common intermediate tetrahydrofuranyl-β-ketophosphonate via cross metathesis, Pd(0)-catalyzed cyclization, and hydroboration-oxidation. The β-ketophosphonate was coupled to three side chain aldehydes using a Horner-Wadsworth-Emmons (HWE) olefination reaction to give dienones, which were reduced with l-selectride to give the fragments of amphidinolide C and F.     

A second-generation synthesis of the C1-C28 portion of the altohyrtins (spongistatins)

A practical second-generation synthesis of an advanced intermediate in our total synthesis of altohyrtin C (spongistatin 2) has been developed. A new approach to the C1-C15 (AB) portion features a vinyllithium addition to an aldehyde followed by a palladium-catalyzed allylic reduction to install the troublesome C13-C15 segment. Our general approach to the C16-C28 (CD) spiroketal has been retained, but some improvements have been made. Most notably, the kinetically controlled CD-spiroketalization reaction now proceeds in high yield with excellent diastereoselection. This new strategy uses the anti-aldol coupling used in our first-generation synthesis to join AB and CD fragments. A total of 9.6 g of intermediate 57 has been produced using this improved route.     

The first total synthesis of concanamycin f (concanolide a)

A highly stereoselective total synthesis of the macrolide antibiotic concanamycin F (1), a specific and potent inhibitor of vacuolar H(+)-ATPase, has been achieved by a convergent route involving the synthesis and coupling of its 18-membered tetraenic lactone and beta-hydroxyl hemiacetal side chain subunits. The C1-C19 18-membered lactone aldehyde 4 was synthesized through the intermolecular Stille coupling of the C5-C13 vinyl iodide 24 and the C14-C19 vinyl stannane 25, followed by construction of the C1-C4 diene and macrolactonization. Synthesis of 4 via a second convergent route including the esterification of the C1-C13 vinyl iodide 45 and the C14-C19 vinyl stannane 47 followed by the intramolecular Stille coupling was also realized. The highly stereoselective aldol coupling of 4 and the C20-C28 ethyl ketone 5 followed by desilylation provided 1 which was identical with natural concanamycin F.     

Total synthesis of (-)-callystatin A

A total synthesis of the cytotoxic polyketide marine natural product callystatin A is described. The route features chiral allenylmetal additions to construct the polypropionate C15-22 segment and an sp(2)-sp(3) Suzuki coupling to join the C1-C11 and C12-C22 subunits.     

A synthesis of the C(1)-C(15) segment of tsukubaenolide (FK 506).

A synthesis of the C(1)-C(15) segment (4) of Tsukubaenolide (1) from Tri-O-acetyl-D-glucal and (S)-Pipecolinic acid methyl ester is described.     

Multigram synthesis of the C29-C51 subunit and completion of the total synthesis of altohyrtin C (spongistatin 2)

A multigram synthesis of the C29-C51 subunit of altohyrtin C (spongistatin 2) has been accomplished. Union of this intermediate with the C1-C28 fragment and further elaboration furnished the natural product. Completion of the C29-C51 subunit began with the aldol coupling of the boron enolate derived from methyl ketone 8 and aldehyde 9. Acid-catalyzed deprotection/cyclization of the resulting diastereomeric mixture of addition products was conducted in a single operation to afford the E-ring of altohyrtin C. The diastereomer obtained through cyclization of the unwanted aldol product was subjected to an oxidation/reduction sequence to rectify the C35 stereocenter. The C45-C48 segment of the eventual triene side chain was introduced by addition of a functionalized Grignard reagent derived from (R)-glycidol to a C44 aldehyde. Palladium-mediated deoxygenation of the resulting allylic alcohol was followed by adjustment of protecting groups to provide reactivity suitable for the later stages of the synthesis. The diene functionality comprising the remainder of the C44-C51 side chain was constructed by addition of an allylzinc reagent to the unmasked C48 aldehyde and subsequent dehydration of the resulting alcohol. Completion of the synthesis of the C29-C51 subunit was achieved through conversion of the protected C29 alcohol into a primary iodide. The synthesis of the C29-C51 iodide required 44 steps with a longest linear sequence of 33 steps. From commercially available tri-O-acetyl-d-glucal, the overall yield was 6.8%, and 2 g of the iodide was prepared. The C29-C51 primary iodide was amenable to phosphonium salt formation, and the ensuing Wittig coupling with a C1-C28 intermediate provided a fully functionalized, protected seco-acid. Selective deprotection of the required silicon groups afforded an intermediate appropriate for macrolactonization, and, finally, global deprotection furnished altohyrtin C (spongistatin 2). This synthetic approach required 113 steps with a longest linear sequence of 37 steps starting from either tri-O-acetyl-d-glucal or (S)-malic acid.     

Stereoselective synthesis of the C(1)-C(19) fragment of tetrafibricin

[reaction: see text] A stereoselective synthesis of the C(1)-C(19) fragment of tetrafibricin has been accomplished via a highly diastereoselective double allylboration reaction of 6-8 and an iodonium ion promoted urethane cyclization for the installation of the C(15) alkoxy function in 3.     

Stereoselective synthesis of the C(1)-C(12) segment of iriomoteolide 1a: a very potent macrolide antitumor agent

A stereoselective synthesis of the C(1)-C(12) segment of the potent cytotoxic macrolide, iriomoteolide 1a, has been accomplished. The key steps involve an enzymatic kinetic resolution of a β-hydroxy amide, a Pd-catalyzed cross-coupling to a substituted allylsilane, a highly regio- and stereoselective conjugate addition of lithium dimethylcopper to an α, β-acetylenic esters and an elaboration of the C(6)-C(7) trans-olefin geometry by a Julia-Kocienski olefination.     

(-)-Lytophilippine A: synthesis of a C1-C18 building block

The convergent enantioselective synthesis of a protected C1-C18 building block for the total synthesis of (-)-lytophilippine A was achieved. A catalytic asymmetric Gosteli-Claisen rearrangement and an Evans aldol reaction served as key C/C-connecting transformations during the assembling of the C1-C7 subunit (10 steps from 4, 29%). The synthesis of the C8-C18 segment was achieved utilizing d-galactose as inexpensive ex-chiral-pool starting material (15 steps, 15%). The merger of the subunits was accomplished by a remarkably efficient sequence consisting of esterification and ring-closing metathesis (five steps, 56%).     

Synthesis of the C(29)-C(45) bis-pyran subunit (E-F) of spongistatin 1 (Altohyrtin A)

A synthesis of the C(29)-C(45) bis-pyran subunit 2 of spongistatin 1 (1a) is described. The synthesis proceeds in 19 steps from the chiral aldehyde ent-7, and features highly diastereoselective alpha-alkoxyallylation reactions using the gamma-alkoxy substituted allylstannanes 17 and 19, as well as a thermodynamically controlled intramolecular Michael addition to close the F-ring pyran. The E ring was assembled via the Mukaiyama aldol reaction of F-ring methyl ketone 3 and the 2,3-syn aldehyde 4.