As shown in Scheme 1, racemic azirine 1 was prepared before, as well as chiral azirine 2 where chirality resided in the R group. Chiral azirine 2 was also used in Lewis acid-promoted Diels-Alder reaction to give bi- and tri-cyclic compounds in good yield and selecitivity. In 2002, the authors of this article also successfully prepared chiral azirine phosphonate 3 using Swern oxidation of NH-aziridine-2-phosphonates and have shown their utility as new chiral aza dienophiles. In this paper, the authors detailed their synthesis of chiral 4 from dechlorination of 5.
As shown in Scheme 2, the synthesis started with reaction of known sulfinimine 6 with dichloro enolate 7. Attempts to convert chiral esters 8 to azirines 9 were successul with KH treatment. However, only 9b and 9c were produced. In case of 9a, only starting sulinimine 6 was obtained instead. Retro-Mannich of sulfinimine-derived sulfinamide products are usually rare because the N-sulfinyl group stabilizes anions at nitrogen. But in 8a the combination of steric inhibition to chloride displacement and the stability of the dichloro enolate 7 apparently favors the retro-Mannich fragmentation.
9b was oxidized to sulfone 10. Attempt to reduce sulfone group in 10 with subsequent dechlorination to azirine, however, failed. Instead Raney nickel directly reduced chlorine to hydrogen to give 11. In addition, reduction/ring-opening product 12 was also afforded.
The next attempt was by desulfinylation with Grignard reagent. However, treatment of 9 with MeMgBr only provided 14 as a single isomer. The stereochemistry of 14 was confirmed by comparison with desulfinylation product of 15, a known compound. The formation of 14 confirmed intermediacy of 13, followed by addition of MeMgBr to the less-hindered face (Scheme 4).
Therefore, it seemed that a new way to remove sulfinyl group under different conditions was required to avoid exposing this sensitive compound to acids, or bases, or protic solvents under reaction conditions. The solution to this was photodesulfinylation. Although, photodesulphonylation is well-known, this was the first example of photodesulfinylation.
As seen in Scheme 5, photolysis of 9b in ether degassed with argon for 10 h generated chloroaziridine 16 in 70% after chromatography. This was the first stable example of an N-unprotected-alpha-halo-alpha-amino ester. The reluctance of 16 to eliminate HCl was likely due to added strain energy in the installation of double bond in three-membered aziridine ring.
Subsequently, it was found that it was more efficient to conduct aza Diels-Alder of crude 16. Therefore following photolysis of 9, the crude reaction mixture was treated with large excess (100 equiv) of appropriate alkenes and a few drops of Hunig base. After 8 h, bi- and tricyclic products (-)-17, (-)-18, and (-)-19 were isolated as single isomers 46-74% yield for the two steps after chromatography. The structures assigned to these aziridines were based on endo addition of the 2H-azirine-3-carboxylated aza dienophile (S)-13 as reported previously.
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Chiral synthesis (enantioselective synthesis, also called asymmetric synthesis) is the synthesis of a compound by a method that favors the formation of a specific enantiomer or diastereomer. Chiral Synthesis
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