Asymmetric total synthesis of (-)-mycothiazole

[structure: see text] In this Letter we describe the first total synthesis of mycothiazole, a polyketide thiazole from a marine sponge. Key steps include our CMD oxidation for the conversion of thiazolidine 11 to thiazole 12 and the Nagao acetate aldol reaction of 5 with aldehyde 4 to construct the chiral secondary alcohol. The skipped diene was constructed by the standard Stille coupling, and the conjugated diene was synthesized by lithium(I)- and copper(I)-mediated Stille coupling.     

Asymmetric total synthesis of (-)-Linderol A

The first asymmetric total synthesis of (-)-Linderol A, a potent inhibitor of melanin biosynthesis of cultured B-16 melanoma cells, has been achieved via two key reactions: a diastereoselective [2+2] photocycloaddition of a coumarin-3-carboxylate bearing a chiral auxiliary with 3-methyl-1-butene and a subsequent stereoconvergent transformation of the photoadducts with use of dimethylsulfoxonium methylide to afford a tetrahydrodibenzofuran derivative.     

Asymmetric total synthesis of (-)-saframycin A from L-tyrosine

The asymmetric total synthesis of (-)-saframycin A, a natural antitumor product of the tetrahydroisoquinoline antitumor antibiotics family, has been accomplished by employing L-tyrosine as the starting chiral building block in 24 steps for the longest linear sequence in an overall yield of 9.7%. The key steps in the synthesis involve stereoselective intermolecular and intramolecular Pictet-Spengler reactions, which induced the correct stereochemistry at C-1 and C-11, respectively. The selective protection-deprotection protocol of an amino group in the two-step transformation from intermediate 10 to 12 and a hydroxyl group in the first two steps resulted in both high selectivity and efficiency of the synthetic route.     

Total synthesis of (-)-quinocarcin by gold(i)-catalyzed regioselective hydroamination

In control: The novel and enantioselective total synthesis of (-)-quinocarcin includes the highly stereoselective preparation of the 2,5-cis-pyrrolidine by intramolecular amination, a selective substrate-controlled 6-endo-dig intramolecular alkyne hydroamination with a cationic Au(I) catalyst, and Lewis-acid-mediated ring-opening/halogenation sequence.     

Asymmetric total synthesis of (-)-azaspirene,a novel angiogenesis inhibitor

The asymmetric total synthesis of (-)-azaspirene, an angiogenesis inhibitor, has been accomplished, establishing its absolute stereochemistry. The key steps are a MgBr2.OEt2-mediated, diastereoselective Mukaiyama aldol reaction, a NaH-promoted, intramolecular cyclization of an alkynylamide, and the aldol reaction of a ketone containing functionalized gamma-lactam moiety without protection of tert-alcohol and amide functionalities.     

Asymmetric total synthesis of (-)-spirofungin A and (+)-spirofungin B

[chemical reaction: see text]. The stereocontrolled total synthesis of (-)-spirofungin A (1) and (+)-spirofungin B (2a), polyketide-type antibiotics having various antifungal activities, has been achieved employing the Weinreb amide 8, the alkyne 9, and the vinyl boronate 5 readily available from the common intermediate 10. The first synthesis proceeded with a longest linear sequence of 31 steps, affording (-)-1 and (+)-2a in 7.9% and 5.2% overall yields, respectively.     

Asymmetric synthesis of pyrrolidinoindolines. Application for the practical total synthesis of (-)-phenserine

A versatile route to enantiopure 3,3-disubstituted oxindoles and 3a-substituted pyrrolidinoindolines is described in which diastereoselective dialkylation of enantiopure ditriflate 10 with oxindole enolates is the central step. These reactions are rare examples of alkylations of prostereogenic enolates with chiral sp(3) electrophiles that proceed with high facial selectivity (10-20:1). The scope of this method is explored, and a model to rationalize the sense of stereoselection is advanced. This dialkylation chemistry was used to synthesize (-)-phenserine on a multigram scale in six steps and 43% overall yield from 5-methoxy-1,3-dimethyloxindole (27) and to complete a short formal total synthesis of (-)-physostigmine (2).     

Asymmetric synthesis of (-)-adaline

[reaction: see text] An enantioselective total synthesis of (-)-adaline has been achieved starting from a chiral 6,6-disubstituted piperidone derivative previously prepared by diastereoselective allylation of a chiral tricyclic N-acyl-N,O-acetal. The key steps include lithium ion-activated SN2-type alkynylation of the tricyclic N,O-acetal leading to exclusive formation of the (6S)-ethynylpiperidine and ring-closing olefin metathesis of the (2R,6S)-cis-2,6-dialkenylpiperidine for constructing the bridged azabicyclononane.     

Asymmetric total synthesis of (-)-panacene and correction of its relative configuration

[reaction: see text] The first synthesis of (-)-panacene has been accomplished in concise, highly stereoselective fashion from commercially available 2-methoxy-6-methylbenzoic acid (15 steps, 8.3% overall yield). The synthesis unambiguously establishes the correct relative and absolute configuration of panacene, and demonstrates the serviceability of Pd(II)-mediated tandem intramolecular alkoxycarbonylation-lactonization for the expedient assembly of its tricyclic core, and the dual role of asymmetric alkynylation as an initial source of chirality and as a powerful tool for manipulating diastereoselectivity.     

Asymmetric total synthesis of ent-(-)-roseophilin: assignment of absolute configuration

An asymmetric total synthesis of ent-(-)-roseophilin (1), the unnatural enantiomer of a novel naturally occurring antitumor antibiotic, is described. The approach enlists a room temperature heterocyclic azadiene inverse electron demand Diels-Alder reaction of dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate (7) with the optically active enol ether 6 bearing the C23 chiral center followed by a reductive ring contraction reaction for formation of an appropriately functionalized pyrrole ring in a key 1,2,4,5-tetrazine --> 1,2-diazine --> pyrrole reaction sequence. A Grubbs' ring closing metathesis reaction was utilized to close the unusual 13-membered macrocycle prior to a subsequent 5-exo-trig acyl radical-alkene cyclization that was used to introduce the fused cyclopentanone and complete the preparation of the tricylic ansa-bridged azafulvene core 32. Condensation of 32 with 33 under the modified conditions of Tius and Harrington followed by final deprotection provided (22S,23S)-1. Comparison of synthetic (22S,23S)-1 ([alpha](25)(D), CD) with natural 1 established that they were enantiomers and enabled the assignment of the absolute stereochemistry of the natural product as 22R,23R. Surprisingly, ent-(-)-1 was found to be 2-10-fold more potent than natural (+)-1 in cytotoxic assays, providing an unusually rewarding culmination to synthetic efforts that provided the unnatural enantiomer.     

Asymmetric total synthesis of (-)-alkaloid 223A and its 6-epimer

The enantiopure gamma-amino alcohols 7 and 18 are prepared by using the diastereoselective Michael addition of lithium N-benzyl (R)-alpha-methylbenzylamide to alpha,beta-unsaturated esters as a key step. The Michael addition of 7 or 18 to an alkynone 8 followed by an intramolecular cyclization afford the cyclic enamine 10 or 20, which are subjected to the diastereoselective hydrogenation, and the subsequent transformations provide 6-epi-alkaloid 223A and alkaloid 223A, respectively.     

Asymmetric total synthesis of (-)-indicol by a carbene cyclization-cycloaddition cascade strategy

The first total synthesis of a secodolastane, (-)-indicol, has been accomplished. The key reaction is a rhodium(II)-mediated carbene cyclization-cycloaddition cascade, by which the core bicyclo[5.4.0]undecane skeleton was assembled. In this one-pot reaction, a domino series of transformations resulting in the construction of three sigma bonds and three stereocenters was realized in good yield.     

Asymmetric total synthesis of (-)-agelastatin a using sulfinimine (N-sulfinyl imine) derived methodologies

The asymmetric synthesis of the cytotoxic marine metabolite (-)-agelastatin A (1) has been achieved from the C-ring intermediate 4,5-diamino cyclopenten-2-enone (-)-2. This key intermediate was efficiently prepared from the sulfinimine-derived alpha,beta-diamino ester 4 using ring-closing metathesis. [reaction: see text]     

Asymmetric total syntheses of (-)-variabilin and (-)-glycinol

Total syntheses of (-)-variabilin and (-)-glycinol have been accomplished, using the catalytic, asymmetric "interrupted" Feist-Be?nary reaction (IFB) as the key transformation to introduce both stereogenic centers. A monoquinidine pyrimidinyl ether catalyst affords the IFB products in over 90% ee in both cases. Other key steps include an intramolecular Buchwald-Hartwig coupling and a nickel-catalyzed aryl tosylate reduction.     

Asymmetric total synthesis of (S)-dapoxetine

A concise asymmetric total synthesis of (S)-dapoxetine from commercially available 3-chloropropiophenone is described. The key step includes a highly stereoselective amination of chiral benzylic ether, with the retention of stereochemistry, using chlorosulfonyl isocyanate.     

Asymmetric total synthesis of (-)-laulimalide: exploiting the asymmetric glycolate alkylation reaction

A concise total synthesis of the potent antitumor macrolide (-)-laulimalide is described. The observation that homoallylic (or latent homoallylic) C-O bonds are present at C5, C9, C15, C19, and C23 led to the strategic decision to rely heavily on the asymmetric glycolate alkylation to construct both the C1-C14 fragment 3 and the C15-C27 subunit 4. A diastereoselective addition of a C1-C14 allylstannane to a C15-C27 alpha,beta-epoxyaldehyde served to join the two advanced fragments. A Mitsunobu macrolactonization of hydroxy acid 2 avoided isomerization of the sensitive 2,3-Z-enoate, which has been observed in base-catalyzed macrolactonizations. Removal of two TBS protecting groups to reveal the C15 and C20 hydroxyls occurred without rearrangement to isolaulimalide.     

Asymmetric total synthesis of (-)-pironetin employing the SAMP/RAMP hydrazone methodology

A convergent asymmetric total synthesis of pironetin (1), a polyketide with immunosuppressive, antitumor, and plant-growth regulating activities is described. The synthesis was realized by coupling between the C(8)-C(14) 2 and C(7)-C(2) 15 fragments, respectively, by using a Mukaiyama-aldol reaction. The stereogenic centers of each fragment were generated by employing the SAMP/RAMP hydrazone (SAMP=(S)-1-amino-2-methoxymethylpyrrolidine, RAMP=(R)-1-amino-2-methoxymethylpyrrolidine) methodology as a key step. An asymmetric alpha-alkylation of diethyl ketone permitted the introduction of the C(10) stereogenic center of 2, whereas the stereocenters C(4) and C(5) of 15 were installed by an asymmetric aldol reaction. Finally, the formation of the alpha,beta-unsaturated delta-lactone was achieved by ring-closing metathesis in the presence of catalytic amounts of titanium tetraisopropoxide.