Enantioselective syntheses of (+)- and (−)-brazilin

Two enantiomers of brazilin were prepared in 9 steps from 7-hydroxychroman-4-one using the AD-mix-α and AD-mix-β-directed enantioselective dihydroxylation of 3-(4-hydroxy-3-methoxyphenyl)-2H-chromen-7-ol as a key step.     

Total Synthesis of (+)- and (−)-Ononitol

Abstract

A practical, five-step synthetic sequence for conversion of myo-inositol into enantiomerically pure (+)- and (?)-ononitols in 17% and 18% overall yield, respectively, has been developed.     

A convergent approach to batzelladine alkaloids. Total syntheses of (+)-batzelladine E, (−)-dehydrobatzelladine C,and (+)-batzelladine K

We recently reported a convergent strategy to access the polycyclic guanidinium alkaloid (+)-batzelladine B via an aldol addition–retro-aldol–aza-Michael addition cascade. Here we describe the application of this approach toward the total syntheses of (+)-batzelladine E, (?)-dehydrobatzelladine C, and (+)-batzelladine K. The identification of suitable methods to functionalize a common tropane core by electrophilic alkynylation and nucleophilic 1,2-addition were essential to generalizing this approach. We provide evidence for the intermediacy of an acylallene species in the cascade reaction.     

Short syntheses of (−)-clavaminol A and deacetyl (+)-clavaminol H

Concise stereoselective syntheses of (?)-clavaminol A and deacetyl (+)-clavaminol H have been achieved from simple starting materials. Highlights of the synthesis for (?)-clavaminol A include a highly diastereoselective chelation-controlled hydride reduction of an amino ketone to give the anti amino alcohol directly, and NaBH₄-mediated dehalogenation. The main synthetic approach for deacetyl (+)-clavaminol H features a highly diastereoselective chelation-controlled hydride reduction of the amino ketone to construct the anti amino alcohol and a palladium catalyzed hydrogenation reaction at the final step.     

A convenient synthesis of (+)-albicanol based on enzymatic function: total syntheses of (+)-albicanyl acetate, (−)-albicanyl 3,4-dihydroxycinnamate, (−)-drimenol, (−)-drimenin and (−)-ambrox

By using lipase ‘PL-266’ from Alcaligenes sp. enantioselective acetylation of (±)-albicanol 4 with isopropenyl acetate gave the enantiomerically pure (+)-albicanyl acetate 3 and (+)-albicanol 4. Deprotection of (+)-3 afforded the natural (+)-albicanol 4 which was converted to the natural products (−)-albicanyl 3,4-dihydroxycinnamate 7, (−)-drimenol 8, (−)-drimenin 9 and (−)-ambrox 10.     

Enantioselective total syntheses of (−)-clavaminol A and deacetyl (+)-clavaminol H

An efficient enantioselective approach to the syntheses of (?)-clavaminol A and deacetyl (+)-clavaminol H is presented, starting from n-decanol. The synthesis features Sharpless asymmetric dihydroxylation (AD), regioselective epoxide formation/opening and α-tosylation as key steps.     

Total synthesis of natural (−)- and unnatural (+)-Melearoride A

This communication details the first total synthesis of the 13-membered macrolide, (?)-Melearoride A, as well as unnatural (+)-Melearoride A. The synthesis features a concise 13 step synthesis (11 steps longest linear sequence) that offers flexible stereo-control and multiple opportunities for unnatural analog synthesis to delve into antifungal SAR. The route features a cuprate addition, an Evans asymmetric alkylation, and a ring-closing metathesis (RCM) to close the 13-membered macrocyclic core.     

Total Syntheses of (−)-Conidiogenone B, (−)-Conidiogenone,and (−)-Conidiogenol

Cyclopianes are novel diterpenes featuring a highly strained 6/5/5/5 tetracyclic core embedded with 6–8 consecutive stereocenters. The concise total syntheses of (−)-conidiogenone B, (−)-conidiogenone, and (−)-conidiogenol have been accomplished in 14–17 steps. The present work features a HAT-mediated alkene–nitrile cyclization to access the cis-biquinane, a Nicholas/Pauson–Khand reaction to construct the linear triquinane, and a Danheiser annulation to afford the congested angular triquinane skeleton.     

Divergent Total Syntheses of (−)-Daphnezomines A and B and (+)-Dapholdhamine B

The daphnezomine A-type subfamily of Daphniphyllum alkaloids structurally features a unique aza-adamantane core skeleton and anticipates efficient strategies for completing their syntheses to thoroughly investigate their biological activities. Herein, divergent total syntheses of (−)-daphnezomines A and B and (+)-dapholdhamine B have been accomplished in 16–20 steps from a known epoxide via rapid construction of a common core intermediate. The present work features a Ti-mediated radical cyclization to establish the azabicyclo[3.3.1]nonane ring system, an intramolecular Heck reaction to install the bridgehead all-carbon quaternary stereocenter, a tandem deprotection/reduction/keto amine-carbinolamine tautomerization to furnish the aza-adamantane backbone, and an NIS-promoted 6-endo-trig aminocyclization to assemble the (+)-dapholdhamine B backbone.     

Semisynthesis of (+)- and (−)-goniomitine from (−)- and (+)-vincadifformine

The first biomimetic semisynthesis of goniomitine has been accomplished in nine steps with 11% overall yield starting from vincadifformine. Natural (?)- and unnatural (+)-goniomitine were prepared from (+)- and (?)-vincadifformine, respectively. The evaluation of the antiproliferative effect of both enantiomers proved unnatural (+)-goniomitine to be more potent, but this enantiomer as well as some close derivatives displayed a moderate activity only.     

Total Syntheses of (−)-Secologanin, (−)-5-Carboxystrictosidine,and (−)-Rubenine

The first enantioselective total syntheses of (−)-secologanin ( 1 ), (−)-5-carboxystrictosidine ( 2 ), and (−)-rubenine ( 3 ) were accomplished in 10, 9, and 14 steps, respectively. The key transformation in the synthesis of 1 was a sequential anti-selective organocatalytic Michael reaction/Fukuyama reduction/spontaneous cyclization to form an optically active dihydropyran ring. In addition, the secologanin tetraacetate ( 16 ), which is a potential key intermediate for the bioinspired divergent syntheses of monoterpenoid indole alkaloids, was prepared in gram-scale in seven steps. The total syntheses of 2 and 3 , which are classified as glycosylated monoterpenoid indole alkaloids, were achieved through bioinspired transformations such as a diastereoselective Pictet–Spengler reaction, a site- and stereoselective epoxidation, and a site-selective epoxide ring-opening followed by a lactonization reaction.     

Total syntheses of (+)-polygalolide a and (+)-polygalolide b: elucidation of the absolute stereochemistry and biogenetic implications

The total syntheses of (+)-polygalolide?A and (+)-polygalolide?B have been completed by using a carbonyl ylide cycloaddition strategy. Three of the four stereocenters, including two consecutive tetrasubstituted carbon atoms at C2 and C8, were incorporated through internal asymmetric induction from the stereocenter at C7 by a [Rh(2) (OAc)(4)]-catalyzed carbonyl ylide formation/intramolecular 1,3-dipolar cycloaddition sequence. The arylmethylidene moiety of these natural products was successfully installed by a Mukaiyama aldol-type reaction of a silyl enol ether with a dimethyl acetal, followed by elimination under basic conditions. We have also developed an alternative approach to the carbonyl ylide precursor based on a hetero-Michael reaction. This approach requires 18 steps, and the natural products were obtained in 9.8 and 9.3?% overall yields. Comparison of specific rotations of the synthetic materials and natural products suggests that polygalolides are biosynthesized in nearly racemic forms through a [5+2] cycloaddition between a fructose-derived oxypyrylium zwitterion with an isoprene derivative.     

Total synthesis of (−) verbenalol and (−) epiverbenalol

The first asymmetric synthesis of (−) verbenalol and (−) epiverbenalol, starting from the organometallic complex (−) 1, is described.     

TiCl3-Mediated Synthesis of 2,3,3-Trisubstituted Indolenines: Total Synthesis of (+)-1,2-Dehydroaspidospermidine, (+)-Condyfoline,and (−)-Tubifoline

2,3,3-Trisubstituted indolenine constitutes an integral part of many biologically important monoterpene indole alkaloids. We report herein an unprecedented access to this skeleton by a TiCl₃-mediated reductive cyclization of tetrasubstituted alkenes bearing a 2-nitrophenyl substituent. The proof of concept is demonstrated firstly by accomplishing a concise total synthesis of (+)-1,2-dehydroaspidospermidine featuring a late-stage application of this key transformation. A sequence of reduction of nitroarene to nitrosoarene followed by 6π-electron-5-atom electrocyclization and a 1,2-alkyl shift of the resulting nitrone intermediate was proposed to account for the reaction outcome. A subsequent total synthesis of (+)-condyfoline not only illustrates the generality of the reaction, but also provides a mechanistic insight into the nature of the 1,2-alkyl shift. The exclusive formation of (+)-condyfoline indicates that the 1,2-alkyl migration follows a concerted Wagner–Meerwein pathway, rather than a stepwise retro-Mannich/Mannich reaction sequence. Conditions for almost quantitative conversion of (+)-condyfoline to (−)-tubifoline by way of a retro-Mannich/1,3-prototropy/transannular cyclization cascade are also documented.     

Oxidative Coupling Approach to Sarpagine Alkaloids: Total Synthesis of (−)-Trinervine,Vellosimine, (+)-Normacusine B,and (−)-Alstomutinine C

Sarpagine alkaloids are bioactive indole natural products that contain a highly rigid indole-fused 1-azabicyclo[2.2.2]octane, more than 100 members of which have been identified. Herein, a detailed examination of the intramolecular oxidative coupling between a ketone and a Weinreb amide for assembling the complex 1-azabicyclo[2.2.2]octane core structure of sarpagine family alkaloids is described. Precise late-stage manipulations of the ketone and Weinreb amide enable the divergent syntheses of (−)-trinervine, (+)-vellosimine, (+)-normacusine B, and (−)-alstomutinine C. Other notable transformations of the synthesis featured an aza-Achmatowicz/indole cyclization cascade to generate the azabicyclo[3.3.1]nonane structure, a regioselective elimination reaction to form the ethylidene motif embedded in the (+)-vellosimine and (+)-normacusine B structures, and a diastereoselective indole oxidative rearrangement to form the spirooxindole structure in (−)-alstomutinine C.     

Asymmetric total syntheses of (+)-goniopypyrone and (+)-9-deoxygoniopypyrone

Asymmetric total syntheses of (+)-goniopypyrone (1) and (+)-deoxygoniopypyrone (2) from methyl cinnamate (7) via (DHQ)2-PHAL-OsO4 catalyzed asymmetric dihydroxylation and highly stereoselective 2-furylcopper addition in eight steps and eleven steps with overall yield of 20% and 13%,respectively,are described.     

Synthesis of (+)- and (−)-Phaselic Acid

The syntheses of both enantiomers of phaselic acid (2-O-caffeoylmalate) are described. The previously unreported acetate-protected caffeic acid anhydride was used with appropriately protected malic acid derivatives as coupling partners to provide fully protected phaselic acid. Sequential unmasking of the protecting groups afforded phaselic acid in an acceptable overall yield.

Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications® to view the free supplemental file.     

Asymmetric synthesis of (−)- and (+)-neodichroine/hydrachine A from (+)- and (−)-febrifugine

A new asymmetric approach to both enantiomers of the quinazolinone-containing natural product febrifugine is reported. Utilising a proline-mediated aminooxylation-Horner-Wadsworth-Emmons sequence provides the key optically active 2,3-disubstituted piperidine intermediate 7 in high enantioselectivity but poor overall yield (7 steps, 3%, 98% ee). This intermediate has been used to prepare both naturally occurring (+)-febrifugine (1) and its (?)-enantiomer. In turn, each were then used to synthesise, for the first time, both enantiomers of the claimed natural product neodichroine/hydrachine A. Spectroscopic data for the synthetic compound matched the claimed structure. However, the specific rotation differed in both magnitude and sign from the isolation work.