Synthesis of β-Amino-Functionalized α-exo-Methylene-γ-butyrolactones via a β-Lactam Synthon Strategy

Abstract

A convenient and effective synthetic approach was developed to access a structurally novel class of β-amino-functionalized α-exo-methylene-γ-butyrolactones using chiral β-lactam synthons.

Key words

α-methylene carbonyl compounds - Michael acceptor - β-lactam synthon - α-exo-methylene-β-lactam - β-amino-α-exo-­methylene-γ-butyrolactone

References

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7

The stereochemical assignments of trans- and cis-4 were secured by the coupling constants between the two vicinal protons of the oxyranyl groups in their ^¹H NMR spectra (J _trans  = 2.4 Hz and J _cis  = 4.2 Hz), in agreement with those reported for authentic materials, see: ref. 6b.

10

The compound 6 was obtained as a single diastereomer whose stereochemistry was not determined. ^¹H NMR data for 6: δ = 3.80 (q, J = 5.1 Hz, 1 H, CH), 3.68-3.56 (m, 4 H, CH, CH), 3.45 (dt, J = 7.8, 13.8 Hz, 1 H, CH₂), 3.35 (s, 3 H, OCH₃), 3.00-2.92 (m, 2 H, CH₂), 1.59-1.27 (m, 18 H, CH₂), 0.92-0.86 (m, 6 H, CH₃), 0.90 (s, 9 H, t-C₄H₉), 0.08 (s, 3 H, CH₃), 0.07 (s, 3 H, CH₃).

12

The compound 7 was obtained as a 1:1 mixture of inseparable diastereomers. ^¹H NMR data for 7: δ = 3.93 (m, 1 H, CH), 3.70 (m, 1 H, CH), 3.68-3.56 (m, 3 H, CH₂, CH, and CH₂), 3.45 (dt, J = 7.8, 13.8 Hz, 1 H, CH₂), 3.33 (s, 3 H, OCH₃), 2.79 (m, 1 H, CH ₂NH), 1.57-1.28 (m, 18 H, CH₂), 0.90-0.86 (m, 6 H, CH₃), 0.88, 0.87 (s, 9 H, t-C₄H₉), 0.08, 0.06 (s, 3 H, CH₃), 0.04, 0.00 (s, 3 H, CH₃).

13

It should be noted that our initial attempts to generate the target compounds via cyclization of γ-hydroxy esters under basic and/or mild acidic conditions failed due to low stability of the products.

14

The formation of cis-8e and cis-8f may be interpreted in terms of intramolecular nucleophilic attack of alkoxides, generated in situ from removal of the TBS groups, which would act as the primary reactive species.