Total synthesis of ustiloxin D.

The total synthesis of ustiloxin D, a highly potent inhibitor of microtubule assembly, has been achieved. Notable features are the use of nucleophilic aromatic substitution (SNAr) for the construction of a chiral tertiary alkyl-aryl ether linkage, Sharpless asymmetric aminohydroxylation for the formation of the beta-hydroxytyrosine moiety, macrolactamization, and regioselective methylation.     

Enantioselective total synthesis of aigialomycin D

An efficient, convergent approach for the total synthesis of aigialomycin D 1 is described. Key features of the synthetic strategy include (a) a Sharpless asymmetric epoxidation reaction and selective opening of a 2,3-epoxy alcohol to elaborate the two hydroxy-bearing stereogenic centers at the C5′ and C6′ positions; (b) a Kocienski modified Julia protocol to construct the two E-configured double bonds; and (c) Yamaguchi macrolactonization to acccess the 14-membered macrocyclic ring.     

Enantioselective total synthesis of the antitumor macrolide rhizoxin D

The convergent, highly enantioselective synthesis of rhizoxin D, a natural product possessing potent antitumor and antifungal bioactivity, is described. The C(1)-C(9) fragment of the molecule was synthesized utilizing a threefold pseudosymmetric intermediate ultimately derived from gamma-butyrolactone. The central core of rhizoxin D was prepared via a chiral resolution/asymmetric aldol protocol. Several methods for the generation of the polyene fragment were explored, and the side-chain was ultimately prepared from serine in six steps. The unification of the left and right wings of the molecule was achieved using a one-step olefination protocol, and the macrocyclization was carried out using a Horner-Emmons olefination at the C(2)-C(3) olefin.     

Enantioselective total synthesis of aplyviolene

The enantioselective total synthesis of the rearranged spongian diterpene aplyviolene has been completed in 14 steps from the known hydroazulenone 8. The key junction of the hydrocarbon and oxygenated fragments to form the critical C8 quaternary carbon stereocenter and set the stage for elaborating the delicate bicyclic lactone functionality was accomplished in high yield and exquisite stereoselectivity by Michael addition of an enantioenriched hydroazulenone enolate to an enantiopure α-bromocyclopentenone.     

Enantioselective total synthesis of aspidophytine

[structure: see text] An enantioselective total synthesis of aspidophytine is described. The indole fragment bearing a cis-alkene substituent was efficiently prepared through radical cyclization of a 2-alkenylphenylisocyanide followed by Sonogashira coupling of the generated 2-iodoindole derivative with a functionalized acetylene unit. After formation of the 11-membered cyclic amine, the aspidosperma skeleton and lactone ring were constructed to complete the total synthesis.     

Enantioselective total synthesis of borrelidin

The first total synthesis of the natural product borrelidin is described. The propionate fragment of the molecule was concisely synthesized through catalytic enantioselective reductive aldol reactions, a catalytic Negishi coupling, and a catalytic directed hydrogenation. The propionate segment was then fused to the vinyl iodide fragment through a catalytic Sonogashira coupling. Subsequent catalytic hydrostannylation and catalytic cyanation allowed access to the target structure.     

Enantioselective total synthesis of lycopodine

The first enantioselective total synthesis of lycopodine has been completed. Key steps include a highly diastereoselective organocatalyzed cyclization of a keto sulfone to establish the key C7 and C8 stereocenters and a tandem 1,3-sulfonyl shift/intramolecular Mannich cyclization to form the tricyclic core.     

A convergent total synthesis of ustiloxin D via an unprecedented copper-catalyzed ethynyl aziridine ring-opening by phenol derivatives

[reaction: see text] The ustiloxins are a family of heterodetic cyclopeptides that have been isolated from the water extracts of false smut balls on the panicles of rice plants caused by the fungus Ustilaginoidea virens. A concise total synthesis of ustiloxin D has been achieved via an unprecedented ethynyl aziridine ring-opening of phenol derivatives. The longest linear sequence of the synthesis is 15 steps from commercially available compounds.     

Enantioselective total synthesis of aperidine

An efficient total synthesis of aperidine was accomplished using a Rh-catalyzed C-H insertion of a cis-dihydrobenzofuran ring. To circumvent the facile epimerization of the cis-dihydrobenzofuran ring, we designed and prepared the C-H insertion precursor diazoamide by Raines' protocol. Finally, the efficient incorporation of a guanidine group and mild deprotection conditions yielded this labile natural product.     

Enantioselective formal total synthesis of roseophilin

[formula: see text] An enantioselective formal total synthesis of roseophilin 3 is presented. The 13-membered ring of macrotricycle 1 was formed via an efficient ring-closing metathesis reaction of bicycle 4. A palladium-catalyzed methoxycarbonylation reaction of enol triflate 5 was utilized to functionalize the right-hand ring of bicycle 2. The allyl substituent was introduced by a radical allylation of alpha-bromoketone 17.     

Enantioselective total synthesis of pyrinodemin A

Pyrinodemin A 1, a cytotoxic marine alkaloid, was synthesized in a convergent and enantioselective fashion. The key steps are an asymmetric intramolecular dipolar cycloaddition of an oxazoline N-oxide to introduce the bicyclic ring system of the molecule, a cuprate coupling for the extension of the saturated chain and a B-alkyl Suzuki coupling for the introduction of a 3-pyridyl moiety. Reductive amination allowed the coupling of the second side-chain onto the nitrogen atom to give 1. Additionally, attempts to prepare 1 from a trienic precursor by a double B-alkyl Suzuki reaction are described.     

Enantioselective total synthesis of FR900482

The development of two approaches for the enantioselective total synthesis of FR900482 is described. A precursor for the formation of the benzazocine ring was assembled effectively by a modification of the Sonogashira coupling of an aryl triflate with a chiral acetylene unit derived from tartaric acid and the subsequent novel ketone formation via conjugate addition of pyrrolidine to the o-nitrophenylacetylene derivative. The first-generation approach to the key pentacyclic intermediate of our racemic total synthesis utilizes an intramolecular Mitsunobu reaction of an omega-hydroxynitrobenzenesulfonamide to form the benzazocine ring and a stepwise sequence to construct the hydroxymethyl group at the C(7) position. The key intermediate could be synthesized in optically pure form via formation of the characteristic hydroxylamine hemiacetal and a stereoselective epoxide formation. In the second-generation approach, the N-hydroxybenzazocine ring could be constructed directly from an omega-formylnitrobenzene derivative by intramolecular reductive hydroxylamination. The crucial stereoselective hydroxymethylation and the formation of the hydroxylamine hemiacetal could be performed efficiently by a one-pot sequence. After leading to the pentacyclic key intermediate, the total synthesis of (+)-FR900482 was accomplished by a modification of our protocol established in the racemic total synthesis. Stereochemical issues involved in the hydroxymethylation at the C(7) position and formation of the hydroxylamine hemiacetal are also discussed in detail.     

Enantioselective total synthesis of semperoside a

A versatile and concise strategy has been developed (Scheme 1) for the enantioselective synthesis of semperoside A 1 which is endowed with an unusually glucosylated iridane structure. The crucial step was a Hg(II)-mediated electrophilic heteroatom cyclization of beta-glucoside 4 that readily led to the iridane skeleton while installing the C-2 and C-3 stereocenters with complete stereocontrol. This expeditious route is unprecedented among synthetic approaches to iridoid glycosides and smoothly overcomes the hemiacetals glucosidation issue. The present inaugural total synthesis of semperoside A was achieved in 10 steps and 17% overall yield from the enantiomerically pure lactone 8, thus proving the absolute stereochemistry of 1 unequivocally.     

Enantioselective total synthesis of valeriananoids A-C

[reaction: see text] The first enantioselective total synthesis of valeriananoids A-C (-)-1-3 is reported starting from the readily available monoterpene (R)-carvone, employing a tandem intermolecular Michael addition-intramolecular Michael addition-alkylation sequence and an electron-transfer-mediated 6-endo-trig cyclization as key steps.     

Enantioselective total synthesis of (+)-tricycloclavulone

The first total synthesis of (+)-tricycloclavulone having a unique tricyclo[5,3,0,01,4]decane skeleton and six chiral centers was achieved in a highly stereoselective manner. It includes a catalytic enantioselective [2+2]-cycloaddition reaction using novel chiral copper catalyst, extremely effecting an intramolecular ester transfer reaction, and asymmetric reduction of the carbonyl group on the alpha-chain using Noyori's chiral ruthenium catalyst.     

Enantioselective total synthesis of bistramide A

The enantioselective synthesis of bistramide A has been achieved with a longest linear sequence of 18 steps. The synthetic strategy involves the use of a distereoselective glycolate alkylation, an aldol addition of a chlorotitanium enolate of N-acylthiazolidinthione, and a Sharpless asymmetric epoxidation to synthesize the three key fragments.     

Enantioselective total synthesis of cineromycin B

The enantioselective total synthesis of cineromycin B, a 14-membered unsaturated macrolide with two doubly allylic alcohols, was completed using a Julia coupling, an oxidative [2,3]-sigmatropic rearrangement of selenide, and a Yamaguchi macrolactonization as key reactions.     

Enantioselective total synthesis of (+)-dibromophakellstatin

The first enantioselective total synthesis of (+)-phakellstatin and (+)-dibromophakellstatin was achieved. Key steps in the synthesis were a desymmetrization of the diketopiperazine (S,S)-cyclo (Pro, Pro) via a diastereoselective acylation, an intramolecular Mitsunobu reaction to introduce the C6 aminal, and a tandem Hofmann rearrangement/cyclization to simultaneously introduce the C10 quaternary aminal center and deliver the cyclic urea. The synthesis also demonstrates the unusual stability of pyrrolo aminals. Importantly, this strategy has the potential for producing phakellstatin derivatives, derived from (R,R)-cyclo (Pro, Pro), necessary for biological studies. A similar annulation protocol is also expected to be applicable to the synthesis of palau'amine.     

Enantioselective total synthesis of (+)-neosymbioimine

[reaction: see text] The enantioselective total synthesis of (+)-neosymbioimine was accomplished in 18 steps from (-)-(S)-citronellol utilizing an organocatalytic alpha-oxidation of aldehyde 6. The carbon core was constructed by a tandem Horner-Wadsworth-Emmons (HWE) reaction and an intramolecular Diels-Alder cyclization. All double bonds of 12 were made in a stereoselective manner by Wittig-type reactions. Selective formation of the monosulfate monoester was accomplished by one-pot excessive sulfation followed by kinetic hydrolysis of bissulfate 18 in 79% yield.