Highly stereoselective methylene transfers onto butanediacetal-protected chiral non-racemic sulfinyl imines using S-ylide technology

Abstract

Reaction of sulfur ylide with chiral non-racemic imine afforded the desired aziridine in excellent yield. Diastereomeric ratios of >95:5 were obtained. Both enantiomeric lines of the butanediacetal-protected chiral non-racemic sulfinyl imines were examined. The sulfur ylides were generated in situ upon thermal decarboxylation of carboxylmethyl betaine functionality. The enantiomeric pairs of D-mannitol with (S)-(-)-2-methyl-2-propane sulfinamide and ascorbic acid with (R)-(-)-2-methyl-2-propane sulfinamide resulted in the highest levels of diastereocontrol when performing aziridination reactions.Previously communicated from our laboratory was a novel protocol for the preparation of methylphenylsulfonium methylide ii (Scheme 1). 1 When prepared in situ, this sulfur ylide has been shown to effectively trap aldehydes and ketones to form terminal epoxides and imines to form terminal aziridines. 2 The ease by which sulfur ylide ii is generated is one key advantage of our method over other existing technologies. 3 Generation of the sulfur ylide occurs upon decarboxylation of carboxylmethyl betaine functionality. The process does not require the use of strong and often pyrophoric bases such as butyl lithium or sodium hydride, does not require expensive metal catalysts, and is compatible with ecologically benign solvent systems. However, the 'ease by which the sulfur ylide is generated' as stated above does come at a price. That is, while proficient when considering both scope and levels of conversion, the shortcomings of a protocol which relies on refluxing THF for complete conversion of π-acceptor to heterocycle are notable when considering asymmetry.Our entry into stereoselective methylene transfers began with the use of chiral non-racemic sulfinyl imines (Scheme 2). 2bReaction of thioacetate derivative 1 with a series of aryl substituted chiral non-racemic sulfinyl imines afforded the corresponding aziridines in high yield and good stereoselection. A total of seven systems were examined which consisted of both electron deficient and electron releasing aryl substituted chiral non-racemic imines. Upon in situ generation of the sulfur ylide via the thermally induced decarboxylation of carboxymethylsulfonium betaine functionality, a drop in the diastereomeric ratio was observed when going from electron deficient to electron releasing aryl substituted imines.Correspondence to: David C. Forbes, dforbes@jaguar1.usouthal.edu. NIH Public Access Author ManuscriptChem Commun (Camb) When working at reaction temperatures below refluxing THF, a moderate increase in stereoselection was observed. This was, however, at the expense of percent conversion and still below the level of diastereocontrol reported when working with the less stabilized dimethylsulfonium methylide under identical reaction conditions (dr = 93:7 with dimethylsulfonium methylide (84% isolated yield at room temperature) and dr = 90:10 with methylphenylsulfonium methylide ii (50% conversion at room temperature)).In our search for alternative protocols f...

Relative stabilities of transition states determine diastereocontrol in sulfur ylide additions onto chiral N‐sulfinyl imines

“…Specifically, we have assigned the new chiral center for the major aziridine product for the reaction with imine 2 on the basis that it arises from Si face addition; the assignment is consistent with the S configuration now determined for its sulfone adduct. [5]…”

“…Ring closure via an intramolecular nucleophilic attack results in a terminal aziridine/epoxide ring with methylphenyl sulfide as sideproduct. [4] With the particular choice of N -sulfinyl imine 2 , Figure 1, as the target of the addition[5], a high level of diastereocontrol (dr > 95:5) is achieved. Imine 2 has chiral substituents on both the iminyl nitrogen (sulfinyl sulfur atom in the S configuration) and on the iminyl carbon (BDA, as derived from D-mannitol).…”

“…Control reactions with variant imines 3-5 , Figure 1, all exhibit reduced selectivity, Table 1. [5] Switching from the BDA moiety to one which is achiral (cyclohexyl group (imine 3 )) results in the greatest loss of diastereoselectivity (61:39). Reducing the bulkiness of the N -substituent, 4-methylphenyl (imine 4 ) versus t -butyl, also results in a substantial loss of selectivity (67:33).…”

“…Concurrent with this submission, an x-ray crystal structure was obtained for the sulfone derivative of the dominant product for the imine 2 reaction using dimethylsulfonium methylide; the new chiral center has the S configuration. [5] Quantum computational methods have been employed here to study the complete Re -addition and Si -addition reaction pathways for the imine 2 /sulfur ylide 1 system leading to the R and S diastereoisomers of the aziridine product, respectively, Figures 2 and 3. Our goal is to identify the causes of diastereoselectivity in the principal and control reactions represented in Table 1.…”

Funding for teratology information services: Up, down, and all around

“…Ring closure via an intramolecular nucleophilic attack results in a terminal aziridine/epoxide ring with methylphenyl sulfide as sideproduct4. With the particular choice of N ‐sulfinyl imine 2 , Figure 1, as the target of the addition5, a high level of diastereocontrol (dr > 95:5) is achieved. Imine 2 has chiral substituents on both the iminyl nitrogen (sulfinyl sulfur atom in the S configuration) and on the iminyl carbon [butanediacetal (BDA) as derived from D ‐mannitol].…”