Halichondrin B: synthesis of the C(1)-C(15) subunit

A short and efficient synthesis of the C(1)-C(15) subunit of halichondrin B in its natural configuration is described. The polycyclic caged ketal 3, containing nine asymmetric centers, is prepared in 14 steps from alpha-D-glucoheptonic acid gamma-lactone (7). Key steps in the two similar routes described include EtMgBr-promoted pinacol ring expansions of hydroxy mesylates 23 and 34, intramolecular Michael additions of 29 and 37, and a one-pot, HF-induced conversion of 4 to 3involving in situ silyl ether cleavage, acetal hydrolysis, Michael addition, and caged ketal formation. Alternative protocols for carbinol inversion at C(11), one early and one late in the synthetic sequence, are also described.     

Halichondrin B: synthesis of a C1-C14 model via desymmetrization of (+)-conduritol E

[reaction: see text] A model C1-C14 segment (1) of halichondrin B was synthesized from (+)-conduritol E (7) in 18 steps and 2.9% overall yield. Key features of the synthesis include the novel ozonolytic desymmetrization of C(2)-symmetric diol 6, the early-stage construction of the C-ring which accompanies installation of the crucial C12 stereocenter, and the use of an enol ether C14-ketone surrogate as a precursor to the CDE-"caged" ketal.     

Toward the synthesis of spirastrellolide B: a synthesis of the C1-C23 subunit

A synthesis of the C1-C23 subunit of spirastrellolide B is described. The synthesis features two applications of a Kulinkovich-cyclopropanol ring-opening strategy for the coupling of esters with olefins to produce ketones.     

Studies towards the total synthesis of cruentaren A and B: Stereoselective synthesis of fragments C1-C11, C12-C22 and C23-C28

A convergent and stereoselective approach for the synthesis of C1-C11, C12-C22, and C23-C28 fragments of cytotoxic natural products cruentaren A and B are accomplished. Highlights of the strategy include a Sharpless epoxidation followed by a regioselective opening of epoxide to generate anti and syn-stereochemistry at C9-C10 and C15-C16, an Alder-Rickert reaction between a 1,5-dimethoxy-1,4-cyclohexadiene and dienophile to construct the aromatic ring, and a lithium-mediated aldol reaction to install the C17-C18 anti-stereochemistry. The synthesis of C1-C11 and C12-C22 fragments proceed with a longest linear sequence of 10 and 17 steps from commercially available 2-butyne-1,4-diol and cis-2-butene-1,4-diol respectively.     

Toward the synthesis of didemnaketal B: a convergent synthesis of the C9-C28 subunit

Synthesis of the C9-C28 subunit of didemnaketal B has been developed. This subunit was convergently prepared from four chiral synthons and at the longest linear sequence required 16 steps.     

Enantioselective allyltitanation. Efficient synthesis of the C1-C14 polyol subunit of amphotericin B

[structure] An efficient synthesis of the C(1)-C(14) fragment of amphotericin B is described. This synthesis is based on the formation of syn-1,3-diols from enantioselective allyltitanation of unprotected beta-hydroxyaldehydes.     

Synthetic efforts toward the C22-C36 subunit of halichondrin B utilizing local and imposed symmetry

The C22-C34 portion (2) of halichondrin B was synthesized from meso-symmetric bis-silyl protected cyclopentenediol (7) in 20 steps and 7% overall yield. This was accomplished through a two-directional synthesis/terminus differentiation strategy that proceeded via achiral, meso-symmetric intermediates for eight steps and employed a Pd(0)-mediated asymmetric double cycloetherification to establish both tetrahydropyran rings. [Structure: see text]     

Toward the synthesis of reidispongiolide a: stereocontrolled synthesis of the C17-C22 and C23-C35 degradation fragments

[structure: see text] By relying on the asymmetric aldol reactions of chiral ketones, a highly stereocontrolled synthesis of each of the C(17)-C(22) and C(23)-C(35) degradation fragments of reidispongiolide A has been achieved. This permits a configurational assignment of the complete C(17)-C(36) region of this antimitotic macrolide, along with providing advanced intermediates for a projected total synthesis.     

Stereocontrolled synthesis of the C8-C22 fragment of rhizopodin

A convergent synthesis of the central C8-C22 core of the potent macrolide antibiotic rhizopodin is reported. Notable features of the stereocontrolled approach include an asymmetric reverse prenylation of an alcohol using a method of Krische, a thiazolium catalyzed transformation of an epoxyaldehyde as described by Bode, and a late-stage oxazole formation from advanced intermediates. This route demonstrates the applicability of these methodologies in complex natural product synthesis.     

Synthetic studies toward amphidinolide B1: synthesis of the C9-C26 fragment

[reaction: see text] The synthesis of the C9-C26 portion of amphidinolide B1 is described. A Fleming allylation followed by elimination was employed for the construction of the C13-C15 diene portion. Sharpless asymmetric dihydroxylation was utilized for regioselective functionalization of a styrene-derived alkene, in the presence of the C13-C15 diene functionality. A highly diastereoselective aldol reaction was developed to establish the C18 stereochemistry.     

Tetrafibricin: synthesis of the C1-C13, C15-C25, and C27-C40 fragments

[structure: see text] A sequence of chemoselective cross-metathesis reactions and enantioselective allyltitanations of aldehydes has been used to prepare the C1-C13, C15-C26, and C27-C40 fragments of tetrafibricin.     

Synthesis of a C1-C21 subunit of the protein phosphatase inhibitor tautomycin: a formal total synthesis

The synthesis of a C1-C21 subunit of tautomycin is described. The convergent route employs enantioenriched allenylstannane and zinc reagents derived from (S)-3-butyn-2-ol methanesulfonate. These reagents react with appropriate aldehyde segments to yield syn and anti adducts with high diastereoselectivity. The derived lithioalkynes are joined stepwise to a CO equivalent, (MeONMe)2C=O, to afford an intermediate ketone which is converted to the core spiroketal moiety of tautomycin upon acid treatment. Chain elongation by another addition of the aforementioned allenylzinc reagent to a spiroketal aldehyde proceeds with high diastereoselectivity to install the remaining stereocenters. The resulting homopropargylic alcohol adduct is converted to a methyl ketone through intramolecular hydrosilylation of the alkyne and Tamao oxidation of the derived five-membered siloxane. This ketone proved identical to an intermediate employed by Chamberlin in a prior total synthesis of tautomycin.     

Stereoselective synthesis of the C1-C20 segment of the microsclerodermins A and B

An enantioselective route for the synthesis of key fragment C1-C20 resident in microsclerodermins A and B is described. The route features deoxygenative rearrangement of an hydroxy-alkynoate and a highly enantio- and diastereo-controled iterative dihydroxylation as key reactions, starting from S-(−)-citronellol.     

Amphidinolide B: asymmetric synthesis of a C7-C20 synthon

[reaction: see text] An asymmetric synthesis of a C(7)-C(20) synthon of amphidinolide B is described. The synthesis entails the construction of C(7)-C(13) and C(14)-C(20) fragments and makes extensive use of catalytic asymmetric bond constructions to establish the requisite stereochemical relationships. Fragment coupling proceeds by Suzuki cross-coupling and installs the trisubstituted diene unit that is among amphidinolide B's defining structural features.     

Stereoselective synthesis of the C(1)-C(13) segment of dolabelide B

The efficient construction of the C₁-C₁₃ segment of dolabelide B is described. A key element of the synthesis entails BITIP catalyzed asymmetric methallylation to establish the C₇ stereocenter, which was then used to direct the stereoselective installation of the C₉ and C₁₁ centers through Evans reduction and 1,5-anti aldol condensation, respectively.