Asymmetric synthesis of alpha-substituted beta-amino ketones from sulfinimines (N-sulfinyl imines). synthesis of the indolizidine alkaloid (-)-223A

Of the possible four stereoisomers, addition of the lithium enolate of 4-heptanone to sulfinimines resulted in only the syn- and anti-alpha-substituted beta-amino ketones. The formation of the major syn-beta-amino ketone was rationalized in terms of addition of the E-enolate to the C-N double bond of the sulfinimine via a six-member chelated chairlike transition state. The enolates of 4-heptanone were generated using LiHMDS in THF where a 1:2.5 E:Z enolate ratio was noted. In diethyl ether the E:Z ratio was 15:1 in favor of the E-enolate and explained in terms of Ireland's transition state model. Here increased steric interactions between the ethyl group and the carbonyl-LiN(TMS)(2) moiety destabilize the transition state leading to the Z-enolate in the poorly coordinating diethyl ether solvent. This new synthesis of syn-alpha-substituted-beta-amino ketones was applied to the concise enantioselective total synthesis of indolizidine (-)-223A, a 5,6,8-trisubstituted alkaloid isolated from the skin of the dendrobatide frog.     

Formal synthesis of (±)-indolizidine 209B

A new method for the synthesis of cis-C-8 methylated indolizidines and quinolizidines has been developed. Straightforward transformations including an isomerization to the trans configuration led to a formal synthesis of (±)-indolizidine 209B.     

Asymmetric synthesis of syn-alpha-substituted beta-amino ketones by using sulfinimines and prochiral Weinreb amide enolates

Syn-alpha-substituted beta-amino Weinreb amides are new chiral building blocks for asymmetric synthesis of syn-alpha-substituted beta-amino acids, aldehydes, and ketones and are prepared by addition of prochiral lithium enolates of Weinreb amides to sulfinimines (N-sulfinyl imines).     

Asymmetric synthesis of (-)-indolizidine 209D via B-alkyl Suzuki coupling and amination reactions

(-)-Indolizidine 209D has been synthesized using consecutive amination reactions of compound 11. The precursor was prepared concisely using B-alkyl Suzuki cross coupling of chiral homoallyl amine and vinyl iodide compounds. Reaction: see text.     

Enantiocontrolled synthesis of 2,3,6-trisubstituted piperidines using (eta(3)-dihydropyridinyl)molybdenum complexes as chiral scaffolds. Total synthesis of (-)-indolizidine 209B.

Enantiopure TpMo(CO)2(pyridinyl) complexes were prepared using an efficient and scalable enzymatic kinetic resolution of the precursor to the molybdenum complex. A single TpMo(CO)2(pyridinyl) complex can function as a chiral scaffold for the enantiocontrolled synthesis of either 2,3,6-cis- or 2,6-cis-3-trans-trisubstituted piperidines. The synthetic potential of this methodology was demonstrated by a total synthesis of (-)-indolizidine 209B.     

A Concise Synthesis of (－)-Indolizidines 209D and 209B

A general stereoselective synthetic route to 5-substituted and 5,8-disubstituted indolizidine alkaloids has been developed starting from commercially available L-proline. (－)-Indolizidines 209D and 209B were efficiently synthesized in 9.8% and 14.8% overall yields in seven and five-step reactions from readily available aldehyde 3 and ketone 10, respectively. The key steps of this synthesis involve a substrate-induced asymmetric addition of ethyl lithiopropiolate to aldehyde 3 or methyl ketone 10, and a two-step one-pot hydrogenation/cyclization sequence to construct the bicyclic skeleton.     

Asymmetric synthesis of alpha-amino 1,3-dithioketals from sulfinimines (N-sulfinyl imines). Synthesis of (2S,3R)-(-)-3-hydroxy-3-methylproline

[reaction: see text] N-Sulfinyl alpha-amino 1,3-dithioketals are prepared in high de and good yield by treating sulfinimines with lithio-1,3-dithianes. Selective removal of the N-sulfinyl or the thioketal groups affords stable alpha-amino 1,3-dithioketals and N-sulfinyl alpha-amino ketones, respectively. This new sulfinimine-derived chiral building block is employed in the asymmetric synthesis of polyoxypeptin amino acid (2S,3R)-(-)-3-hydroxy-3-methylproline.     

Asymmetric synthesis of aziridine 2-phosphonates from enantiopure sulfinimines (N-sulfinyl imines). Synthesis of alpha-amino phosphonates

An aza-Darzens reaction, involving the addition of chloromethylphosphonate anions to enantiopure sulfinimines, has been developed for the asymmetric synthesis of aziridine 2-phosphonates. Best results involve cyclization of the syn and anti diastereomerically pure alpha-chloro-beta-amino phosphonates to cis- and trans-N-sulfinyl aziridine 2-phosphonates, respectively, with n-BuLi. A transition-state hypothesis is proposed wherein the chloromethylphosphonate anion adds to the C-N bond on the side that is opposite the bulky p-tolyl sulfinyl group. The N-sulfinyl group is easily removed by treatment with MeMgBr or TFA/MeOH, which affords the NH-aziridines in good yield. Using transfer hydrogenation conditions, the NH-aziridines were regioselectively opened to the corresponding enantiopure alpha-amino phosphonates without N-activation and in excellent yield.     

Stereocontrolled synthesis and alkylation of cyclic beta-amino esters: asymmetric synthesis of a (-)-sparteine surrogate

A convenient method for the stereoselective synthesis of cyclic beta-amino esters from an iodo alphabeta-unsaturated ester and alpha-methylbenzylamine is described. Subsequent enolate generation and alkylation proceeds with complete stereocontrol, with the two stereogenic centres working together. In this way, a functionalised piperidine suitable for alkaloid natural product synthesis was prepared. The usefulness of the methodology is exemplified with the concise synthesis of a (-)-sparteine surrogate.     

(-)-(S)-Nakinadine B: first asymmetric synthesis

(-)-(S)-Nakinadine B has been synthesized for the first time (in 9 steps and 17% overall yield from commercially available atropic acid) using the conjugate addition of lithium dibenzyl-amide to an N-α-phenylacryloyl SuperQuat derivative with in situ diastereoselective enolate protonation as the key step.     

Organocatalytic asymmetric assembly reactions: one-pot synthesis of functionalized beta-amino alcohols from aldehydes,ketones, and azodicarboxylates

[reaction: see text] l-Proline catalyzed the enzyme-like direct asymmetric assembly of aldehydes, ketones, and azodicarboxylic acid esters to provide optically active beta-amino alcohols. This assembly reaction uses both aldehydes and ketones as donors in one pot. The aldol-derived stereocenter is formed with a reduced facial selectivity in reactions involving (R)-amino aldehydes. The reactions can be performed on a multigram scale under operationally simple and safe conditions without the requirement of an inert atmosphere or dry solvents.     

Radical cyclization of beta-aminoacrylates: synthesis of (-)-indolizidine 223AB

[reaction: see text] (-)-Indolizidine 223AB was synthesized via radical cyclization of the beta-aminoacrylate derivative of a trans-2,5-disubstituted pyrrolidine. The trans-2,5-disubstituted pyrrolidine substrate was prepared by radical cyclization of a Ses-protected beta-aminoacrylate.     

A general approach to 3-n-butyl-5-alkylindolizidines: total synthesis of (-)-indolizidine 195B

Indolizidine type alkaloids have been attractive synthetic targets due to their biological activity. The total synthesis of (-)-indolizidine 195B via a general route, which could potentially be used to prepare other indolizidine alkaloids such as (-)-gephyrotoxin 223AB and (-)-myrmicarin 237A, is described.     

Asymmetric synthesis and applications of beta-amino Weinreb amides: asymmetric synthesis of (S)-coniine

Conjugate addition of lithium (S)-N-benzyl-N-alpha-methylbenzylamide to a range of alpha, beta-unsaturated Weinreb amides proceeds with high levels of diastereoselectivity (>95% de). The beta-amino Weinreb amide products may be transformed into beta-amino ketones via reactions with Grignard reagents, while treatment with DIBAL-H furnishes beta-amino aldehydes. Trapping of the aldehyde via Wadsworth-Emmons reaction and subsequent manipulation offers an efficient route to homochiral delta-amino acid derivatives and 2-substituted piperidines. The application of this methodology for the synthesis of (S)-coniine is demonstrated.     

Asymmetric synthesis of acyclic 1,3-amino alcohols by reduction of N-sulfinyl beta-amino ketones. Formal synthesis of (-)-pinidinol and (+)- epipinidinol

Stereoselective reduction of acyclic N-sulfinyl beta-amino ketones with (LiEt(3)BH) and Li(t-BuO)(3)AlH, respectively, gave anti- and syn-1,3-amino alcohols with excellent selectivity. A formal asymmetric synthesis of the hydroxy piperidine alkaloids (-)-pinidinol and (+)-epipinidinol from a common N-sulfinyl beta-amino ketone ketal precursor was developed. The pinidinol piperidine ring was formed via a novel acid-catalyzed cascade reaction of a N-sulfinylamino silyl protected alcohol ketal.     

Asymmetric synthesis of the protoberberine alkaloid (S)-(-)-xylopinine using enantiopure sulfinimines

A concise enantioselective synthesis of (S)-(-)-xylopinine (1) is described involving the addition of the laterally lithiated derivative of o-tolunitrile of 16 to enantiopure sulfinimine (+)-14. Treatment of the resulting cyano sulfinamide adduct (-)-17b with DIBAL-H accomplishes five operations in a single pot and furnishes the cyclic imine (+)-18 in good yield. Reduction and cyclization affords (S)-(-)-1. Alternatively basic hydrolysis of 17b,c gives isoquinolone 21 that is cyclized and reduced to give (S)-(-)-1.     

Masked oxo sulfinimines (N-sulfinyl imines) in the asymmetric synthesis of proline and pipecolic acid derivatives

[structure: see text]. On addition of Et2AlCN/i-PrOH, masked oxo sulfinimines give alpha-amino nitriles that afford oxo alpha-amino acids on hydrolysis. These amino acids cyclize and are reduced to cis proline and cis pipecolic acids derivatives in high ee and good yield. This new procedure avoids many of the limitations related to the preparation of oxo amino acids from proteinogenic amino acids.     

Asymmetric synthesis of (-)-nupharamine and (-)-(5S,8R,9S)-5-(3-furyl)-8-methyloctahydroindolizidine from beta-amino ketones and the intramolecular Mannich reaction

The asymmetric synthesis of the 2,3,6-trisubstituted piperidine core of the antitumor Nuphar alkaloids was readily achieved by using the intramolecular Mannich reaction and a sulfinimine-derived beta-amino ketone.