Highly diastereoselective total synthesis of the anti-tumoral agent (±)-Spisulosine (ES285) from a Morita-Baylis-Hillman adduct

We disclose herein a new approach for the highly diastereoselective total synthesis of the anti-tumoral agent (±)-Spisulosine. The synthesis was accomplished in seven steps with an overall yield of 10%. The key step involves the transformation of a Morita-Baylis-Hillman into an acyloin, which was subsequently used as substrate in a highly diastereoselective reductive amination reaction.     

Total stereoselective synthesis of (+)-goniothalesdiol

[reaction: see text] The stereoselective synthesis of (+)-goniothalesdiol (1) was accomplished in nine steps starting from commercially available (-)-(2S,3S)-dimethyl D-tartrate (3). The key features were a completely diastereoselective reduction of a beta-ketosulfoxide to generate the stereogenic center at C-5 in 7 and formation of the 2,5-cis-substituted tetrahydrofuran ring in 10 from a stereoselective Et(3)SiH/TMSOTf-promoted reductive cyclization/deoxygenation.     

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.     

The synthesis of the molecular chaperone 2,5-dideoxy-2,5-imino-d-altritol via diastereoselective reductive amination and carbamate annulation

The iminosugar 2,5-dideoxy-2,5-imino-d-altritol (DIA, 2) is a powerful competitive inhibitor of α-galactosidase A and has shown much promise as a pharmacological chaperone for the treatment for Fabry disease. Notwithstanding, syntheses of DIA are in want of optimisation. Accordingly, we report on the total synthesis of DIA in 7 steps and in 22% overall yield from readily available d-tagatose. This is the shortest and most efficient synthesis of DIA to date, with key steps in our synthetic strategy including a diastereoselective reductive amination and an I₂-mediated carbamate annulation.     

Facile and efficient total synthesis of (+)-preussin

[structure] The enantioselective total synthesis of (+)-preussin, a potent antifungal agent, has been achieved. The key steps are a Pd(0)-catalyzed oxazoline-forming reaction from L-phenylalanine, hydrogenolysis, and subsequent diastereoselective reductive cyclization of the intermediate aminoketone to pyrrolidine using Pearlman's catalyst.     

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.     

Total synthesis of (±)-cortistatin J from furan

A concise, diastereoselective total synthesis of (±)-cortistatin J has been completed in 20 steps from furan. Key steps include an intramolecular [4 + 3] cyclization of a disubstituted furan with a (Z)-2-(trialkylsilyloxy)-2-enal to construct the tetracyclic core and a (Z)-vinylsilane/iminium ion cyclization to form the A ring.     

First enantioselective total synthesis of (−)-heliannuol C

The first, efficient total synthesis of (−)-heliannuol C (1) was accomplished enantioselectively, using a chemoenzymatic desymmetrization of the σ-symmetrical diol, a ring closing metathesis, a diastereoselective epoxidation, and a regioselective reductive cleavage of epoxide as the key reaction steps.     

Enantioselective access to 2,7-cis-disubstituted oxepanes: formal synthesis of (+)-isolaurepan

[reaction: see text] The asymmetric synthesis of 2,7-cis-disubstituted oxepanes bearing a sulfoxide is achieved from commercially available precursors in only five steps. The key step is the highly diastereoselective Et3SiH/TMSOTf-promoted reductive cyclization of enantiopure hydroxysulfinyl aryl or alkyl ketones.     

Stereoselective synthesis of the macrolactone core of (+)-neopeltolide

A stereoselective synthesis of the macrolactone core of the potent anticancer agent neopeltolide is disclosed. The key steps of the synthesis include asymmetric allylation using Krische' protocol, conjugate reduction using MacMillan's methodology, and an asymmetric hetero-Diels-Alder reaction using Jacobsen's catalyst. Substrate controlled diastereoselective 1,3-anti reduction of a keto alcohol, Luche reduction followed by Ireland-Claisen rearrangement, oxymercuration, and reductive lithiation are other key steps.     

Asymmetric total synthesis of phomonol

An efficient asymmetric total synthesis of phomonol 1 is presented, starting from (S)-1,2-epoxypentane. The synthesis features Sharpless asymmetric dihydroxylation (AD), diastereoselective reductive etherification and Wacker oxidation as key steps.     

Enantioselective total synthesis of (+)-leucascandrolide A macrolactone

[reaction: see text] The enantioselective synthesis of the (+)-leucascandrolide A macrolactone has been achieved in 20 linear steps from 1,3-propanediol. The key steps in the synthesis are a reductive cleavage of bicyclic ketal 5 to establish the C15 stereogenic center and a diastereoselective aldol of the boron enolate of methyl ketone 3 to aldehyde 4 in preparation for a heteroconjugate addition for the introduction of the C3 stereocenter.     

Design and Synthesis of a Potential Dopamine D-1 Antagonist

The diastereoselective synthesis of (±)-trans-transoid-7-bromo-8-hydroxy-1-methyl-1,2,3,4,4a,5,10,10a-octahydro-10-phenylbenzo[g]quinoline ( 8 ) is described, using an intramolecular Diels-Alder reaction and a reductive cyclisation for piperidine ring-formation as key steps. Compound 8 was prepared as a putative D-1 receptor antagonist which contains (2,2-diphenylethyl)amine as a partial structure.     

Total synthesis of chaetominine

An efficient, asymmetric synthesis of the cytotoxic natural product chaetominine was achieved in 14 steps. The strategy employs a copper(I)-mediated cyclization reaction as a key step to install the abc-tricyclic ring system, which was further elaborated by diastereoselective oxidation and reduction reactions. This effort also documents the first example of an oxidative rearrangement yielding to homochiral spirocyclic pyrrolidinyloxindoles.     

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.     

Enantioselective synthesis of (−)-barrenazines A and B

A short enantioselective synthesis of barrenazines A and B is described. Barrenazines A and B are prepared following a common synthetic route in nine steps (19% overall yield) and eight steps (21% overall yield), respectively, from readily available 4-methoxy-3-(triisopropylsilyl)pyridine. The synthesis relies on a highly diastereoselective nucleophilic addition of a Grignard reagent to a chiral acylpyridinium salt, a radical azidation of a silyl enol ether and the assembly of the pyrazine ring by reductive dimerization of a functionalized 5-azidopiperidin-4-one.     

Diastereoselective Total Synthesis of the Euphorbia Diterpenoid Pepluanol A: A Reductive Annulation Approach

A new titanium(III)-catalyzed reductive annulation constructed a series of diversely functionalized 1,5-diols in good to excellent yields with respect to a wide scope of vinyl epoxide-aldehyde substrates. Taken together with a Diels–Alder reaction and a substrate-controlled diastereoselective cyclopropanation as additional key steps, the synthetic utility of this novel method has been preliminarily explored by the first and concise total synthesis of the Euphorbia diterpenoid (±)-pepluanol A.     

Enantioselective synthesis of (-)-jiadifenin, a potent neurotrophic modulator

The first enantioselective synthesis of (-)-jiadifenin (1), a potent neurite outgrowth promoter isolated from the Illicium species, is described. The synthetic strategy builds upon bicyclic motif 6, which represents the AB ring of the natural product and proceeds in 19 steps and 1.1% overall yield. Key to our approach is a Mn(III)-mediated oxidation reaction of A ring that, following a regio- and diastereoselective α-hydroxylation and methylation sequence, produces the desired functionalities of (-)-jiadifenin. The effect of synthetic 1 in NGF-mediated neurite outgrowth was also measured in PC-12 cells.     

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.     

Diastereoselective Total Synthesis of the Euphorbia Diterpenoid Pepluanol A: A Reductive Annulation Approach

A new titanium(III)‐catalyzed reductive annulation constructed a series of diversely functionalized 1,5‐diols in good to excellent yields with respect to a wide scope of vinyl epoxide‐aldehyde substrates. Taken together with a Diels–Alder reaction and a substrate‐controlled diastereoselective cyclopropanation as additional key steps, the synthetic utility of this novel method has been preliminarily explored by the first and concise total synthesis of the Euphorbia diterpenoid (±)‐pepluanol A.