A stereoselective synthesis of (+)-L-733,060 from ethyl (R)-(+)-2,3-epoxypropanoate

An asymmetric synthesis of neurokinin substance P receptor antagonist (+)-L-733,060 starting from enantiomerically pure ethyl (R)-(+)-2,3-epoxypropanoate (ethyl glycidate) is described. The synthesis relies on a diastereoselective reductive amination, regioselective intramolecular epoxide opening, and in situ cyclization as the key steps.     

Asymmetric synthesis of (-)-7-epiaustraline and (+)-1,7-diepiaustraline

A diastereoselective and modular approach to the synthesis of the 3-hydroxymethyl-2,3,5,6,7,7a-hexahydro-1H-pyrrolizine-1,2,7-triol structure, characteristic of several natural pyrrolizidine natural products, has been developed. This approach culminated in the synthesis of (-)-7-epiaustraline and (+)-1,7-diepiaustraline. The oxazolidinone group has been found to be a useful protecting group in the RCM reaction and, as part of a pyrrolo[1,2-c]oxazol-3-one ring system, has functioned as a stereo- and regio-directing group in a key diastereoselective cis-dihydroxylation reaction and a regioselective nucleophilic ring-opening of a S,S-dioxo-dioxathiole.     

Enantioselective total synthesis of (-)- and (+)-petrosin

The enantioselective total synthesis of (-)- and (+)-petrosin is described. The union of two key segments was executed by Suzuki-Miyaura coupling. The quinolizidine rings were stereoselectively constructed via a diastereoselective Mannich reaction and an aza-Michael reaction. The 16-membered ring was constructed by ring-closing metathesis with the second-generation Grubbs catalyst.     

Diastereoselective synthesis of (+)-nephrosterinic acid and (+)-protolichesterinic acid

A diastereoselective synthesis of (+)-nephrosterinic acid and (+)-protolichesterinic acid, common members of the paraconic acids is described. The synthesis is based on a diastereoselective orthoester Johnson–Claisen rearrangement of a (Z)-allyl alcohol with a vicinal dioxolane moiety as key steps. The synthesis is completed in 10 steps and with overall yields of 15.9% for (+)-nephrosterinic acid and 16.4% for (+)-protolichesterinic acid.     

Synthesis of (+)-1-epiaustraline

A highly efficient total synthesis of (+)-1-epiaustraline ((+)-1), a tetrahydroxypyrrolizidine alkaloid of the alexine/australine subclass, is described. The key step is a tandem intramolecular [4 + 2]/intermolecular [3 + 2] nitroalkene cycloaddition involving dienylsilyloxy nitroalkene 3 and chiral vinyl ether 4, which establishes four of the five stereocenters present. The final center was installed by a diastereoselective dihydroxylation. Hydrogenolytic unmasking of the nitroso acetal tosylate 17 containing the silyl ether linkage was thwarted by a slow alkylation and an undesired Peterson-type elimination. Prior removal of the silicon moiety by Tamao-Fleming oxidation proceeded in excellent yield and provided a substrate suitable for hydrogenolysis and deprotection. The complete synthesis required only 10 steps to deliver the (+)-1-epiaustraline in 7.0% overall yield.     

First total synthesis of antimitotic compound, (+)-phomopsidin

[reaction: see text] The first total synthesis of (+)-phomopsidin has been achieved via a diastereoselective transannular Diels-Alder (TADA) reaction. Key steps in the synthesis include diastereoselective ynone reduction with (-)-alpha-pinene and 9-BBN, macrocyclization by E-selective intramolecular Horner-Wadsworth-Emmons (HWE) reaction, as well as carbometalation under Wipf's conditions, followed by HWE reaction at low temperature to selectively construct the (E)-1-methylpropenyl and (1E,2E)-4-carboxy-1,3-butadienyl substituents.     

Asymmetric synthesis of (+)-1-epiaustraline and attempted synthesis of australine

A diastereoselective synthesis of the pyrrolizidine alkaloid, (+)-1-epiaustraline has been achieved via a diastereoselective syn-dihydroxylation of a pyrrolo[1,2-c]oxazol-3-one precursor that was readily prepared by a RCM reaction. Attempts to extend this methodology to the synthesis of australine were not successful since the final pyrrolidine ring closure to produce the desired pyrrolizidine of the target molecule was not productive.     

De novo asymmetric syntheses of (+)-goniothalamin, (+)-goniothalamin oxide, and 7,8-bis-epi-goniothalamin using asymmetric allylations

A highly enantio- and diastereoselective approach to either enantiomer of (+)-goniothalamin, (+)-goniothalamin oxide, and 7,8-bis-epi-goniothalamin oxide has been developed from achiral cinnamyl alcohol or cinnamaldehyde. The asymmetry of the synthesis was installed by means of a Krische or Leighton allylation. The remaining stereochemistry was installed by a diastereoselective epoxidation.     

Total Synthesis of (+)-7-epi-Tarchonanthuslactone via a Chelation-Controlled Mukaiyama Aldol Reaction

An asymmetric total synthesis of (+)-7-epi-tarchonanthuslactone was achieved from commercially available methyl (R)-3-hydroxybutyrate. The key step employed a diastereoselective chelation-controlled Mukaiyama aldol reaction to construct the chiral hydroxyl group at the C-5 position.     

Synthesis of polyhydroxylated indolizidines and piperidines from Garner's aldehyde: total synthesis of (−)-swainsonine, (+)-1,2-di-epi-swainsonine, (+)-8,8a-di-epi-castanospermine,pentahydroxy indolizidines, (−)-1-deoxynojirimycin, (−)-1-deoxy-altro-nojirimycin,and related diversity

Diastereoselective and diverse synthesis of polyhydroxylated indolizidines and piperidines have been described, where a common chiral intermediate 2-(hydroxymethyl) piperidine-3-ol is converted into (−)-swainsonine, (+)-1,2-di-epi-swainsonine, (+)-8,8a-di-epi-castanospermine, pentahydroxy indolizidines, (−)-1-deoxynojirimycin, (−)-1-deoxy-altro-nojirimycin, and related diversity. The key steps were hydroxy directed intramolecular aminomercuration, Mitsunobu cyclization, and diastereoselective dihydroxylation.     

A concise enantioselective synthesis of (+)-goniodiol and (+)-8-methoxygoniodiol via Co-catalyzed HKR of anti-(2SR, 3RS)-3-methoxy-3-phenyl-1, 2-epoxypropane

A short, enantioselective synthesis of (+)-goniodiol and (+)-8-methoxygoniodiol, cytotoxic styryllactones, has been achieved in high optical purities (99% ee). The strategy employs Co-catalyzed HKR of racemic anti-(2SR, 3RS)-3-methoxy-3-phenyl-1, 2-epoxypropane and Lewis acid-mediated diastereoselective allylation of aldehyde as chiral inducing key reactions.     

Asymmetric [2 + 2] cycloaddition: total synthesis of (-)-swainsonine and (+)-6-epicastanospermine

[reaction: see text] An asymmetric total synthesis of (-)-swainsonine and (+)-6-epicastanospermine is described from a common intermediate, which is obtained through diastereoselective [2 + 2] cycloaddition of dichloroketene to a chiral enol ether.     

A diastereoselective route to 2,6-syn-disubstituted tetrahydropyrans: synthesis of the civet compound (+)-2-((2S,6S)-6-methyltetrahydro-2H-pyran-2-yl) acetic acid

A diastereoselective synthesis of 2,6-syn-disubstituted tetrahydropyrans has been developed based on the ability of furanyl-ether chiral centres to epimerise readily under acidic conditions. This novel methodology was applied to the synthesis of (+)-2-((2S,6S)-6-methyltetrahydro-2H-pyran-2-yl) acetic acid, a component of the African civet cat's glandular marking secretion.     

CATALYTIC DYNAMIC RESOLUTION APPLIED TO THE SYNTHESIS OF 2,6-DISUBSTITUTED PIPERIDINES: PREPARATION OF (+)-LUPETIDINE AND (-)-EPIDIHYDROPINIDINE

The diastereoselective synthesis of trans-2,6-disubstituted piperidines has been rendered enantioselective by incorporating a catalytic dynamic resolution into the first alkylation step. The method has been applied to the synthesis of (-)-epidihydropinidine and (+)-trans-lupetidine.     

Stereoselective synthesis of (+)-(8R,8aR)-perhydro-8-indolizidinol

A highly stereoselective total synthesis of (+)-(8R,8aR)-perhydro-8-indolizidinol is described. Key steps involved in this synthesis are diastereoselective zinc allylation, azido-olefin cyclization and reductive amination followed by cyclization which effectively constructed the indolizidine ring. This contributes a unique approach to the synthesis of indolizidine alkaloids that offers the advantages of brevity and relatively high overall yields.     

Stereoselective total synthesis of (+)-boronolide, (+)-anamarine, 8-epi-spicegerolide

A stereoselective total synthesis of the naturally occurring cytotoxic lactones (+)-boronolide, (+)-anamarine, and 8-epi-spicigerolide is described. d-Xylose has been used as a chiral source to construct the four contiguous oxygenated stereogenic centers of target molecules. The diastereoselective allylation was performed using Brown’s protocol and the lactone moiety was prepared by ring closing metathesis.     

Total synthesis of (+)-allocyathin B2

The first enantioselective synthesis of (+)-allocyathin was achieved. The synthesis features a Pd-catalyzed asymmetric allylic alkylation to install the first quaternary center, a Ru-catalyzed diastereoselective cycloisomerization to construct the six-membered ring, and a diastereoselective hydroxylative Knoevenagel reaction to introduce the final hydroxyl group. The unusual olefin isomerization of the Ru-catalyzed cycloisomerization was discussed and exploited for the synthesis.     

A new asymmetric synthesis of (+)-12b-epidevinylantirhine

We report a new asymmetric synthesis of the indole alkaloid derivative (+)-12b-epidevinylantirhine through stereoselective cyclization of a tethered indole nucleus onto an N-acyliminium ion intermediate, generated from a readily available non-racemic bicyclic lactam building block, and subsequent template modification through a highly diastereoselective conjugate addition protocol. In addition, we present the first X-ray crystal structure of this indole target.     

Total synthesis of (+)-benzastatin E via diastereoselective Grignard addition to 2-acylindoline

[reaction: see text] A stereoselective total synthesis of (+)-benzastatin E (1) is described. The synthesis involves a diastereoselective Grignard addition to 2-acylindoline 2, which is derived from commercially available (S)-2-indolinecarboxylic acid (3). The unknown absolute configuration of (+)-1 is determined as (9S,10R).     

Enantioselective total synthesis of (+)- and (-)-nigellamine A2

The nigellamine alkaloids are dolabellane diterpenes displaying potent lipid metabolism-promoting activity. Total synthesis of (+)- and (-)-nigellamine A2 has been accomplished. Absolute stereochemistry of synthetic nigellamine A2 was established through an intramolecular asymmetric allylic alkylation using a Pd(phosphinooxazoline) catalyst. Other notable transformations include a radical alkynylation, a diastereoselective Nozaki-Hiyama-Kishi cyclization, and a regio- and stereoselective catalytic epoxidation. On the basis of X-ray crystallographic analysis of an optically active intermediate, we have confirmed the assigned absolute stereochemistry of the natural product. Minor modifications of the synthetic sequence outlined here should provide access to the other nigellamine alkaloids.