Carbamoyl radical-mediated synthesis and semipinacol rearrangement of β-lactam diols

Abstract

In an approach to the biologically important 6-azabicyclo[3.2.1]octane ring system, the scope of the tandem 4-exo-trig carbamoyl radical cyclization-dithiocarbamate group transfer reaction to ring-fused β-lactams is evaluated. β-Lactams fused to five-, six-, and seven-membered rings are prepared in good to excellent yield, and with moderate to complete control at the newly formed dithiocarbamate stereocentre. No cyclization is observed with an additional methyl substituent on the terminus of the double bond. Elimination of the dithiocarbamate group gives α,β- or β,γ-unsaturated lactams depending on both the methodology employed (base-mediated or thermal) and the nature of the carbocycle fused to the β-lactam. Fused β-lactam diols, obtained from catalytic OsO4-mediated dihydroxylation of α,β-unsaturated β-lactams, undergo semipinacol rearrangement via the corresponding cyclic sulfite or phosphorane to give keto-bridged bicyclic amides by exclusive N-acyl group migration. A monocyclic β-lactam diol undergoes Appel reaction at a primary alcohol in preference to semipinacol rearrangement. Preliminary investigations into the chemo- and stereoselective manipulation of the two carbonyl groups present in a representative 7,8-dioxo-6-azabicyclo[3.2.1]octane rearrangement product are also reported.

Keywords: cyclization; fused-ring systems; nitrogen heterocycles; ring expansion; strained molecules.

Scheme 1

Tandem carbamoyl radical cyclization—dithiocarbamate group transfer mediated synthesis of cis-fused β-lactams and 6-azabicyclo[3.2.1]octane ring system.

Figure 1

Representative natural and non-natural products containing the 6-azabicyclo[3.2.1]octane ring system.

Scheme 2

Proposed semipinacol rearrangement approach to keto-bridged 6-azabicyclo[3.2.1]octane ring system 11. LG=leaving group.

Scheme 3

Semipinacol rearrangement of β-lactams with N-acyl group migration. PPTS=pyridinium p-toluenesulfonate.

Figure 2

Crystal structure of β-lactam 2 with ellipsoids drawn at the 50 % probability level. The group N2, C8–C12 is disordered over two positions. Only the major component has been shown for clarity.

Scheme 4

Preparation and dithiocarbamate group elimination of N-PMP β-lactam 14. mCPBA=meta-chloroperbenzoic acid; NMO=N-methylmorpholine N-oxide.

Figure 3

Crystal structure of alkene 15 with ellipsoids drawn at the 50 % probability level. Selected bond lengths and angles: C3-C2-C1 138.30(13), C3-C2-C7 125.47(12), C2-C3-C4 120.17(13), C7-C2-C3-C4 −5.1(2), C1-C2-C3-C4 −145.14(16)°.

Figure 4

Crystal structure of hydrate 23 with ellipsoids drawn at the 50 % probability level.

Scheme 5

Attempted semipinacol rearrangement of epoxide 17 and diol 18. DMAP=4-dimethylaminopyridine; py=pyridine.

Scheme 6

Attempted semipinacol rearrangement through cyclic activation.

Figure 5

Crystal structures of 30 (top) and 31 (bottom) with ellipsoids drawn at the 50 % probability level. Selected bond lengths and torsion angles: 30: C2–C7: 1.542(2), C2–C3: 1.558(2), C1–O2: 1.4559(18) Å, O2-C1-C2-C7: 140.95(13), O2-C1-C2-C3: −117.46(14)°; 31: C2–C7: 1.5394(17), C2–C3: 1.5617(17), C1–O2 1.4670(15) Å; O2-C1-C2-C7 147.23(11), O2-C1-C2-C3 −108.61(12)°.

Scheme 7

Preparation of allylic amines through reductive debromination and amine–benzene photoaddition.

Figure 6

Crystal structure of 48 with ellipsoids drawn at the 50 % probability level.

Figure 7

Effect of substitution on carbamoyl radical cyclization—dithiocarbamate group transfer.

Figure 8

Crystal structure of 64 with ellipsoids drawn at the 50 % probability level.

Scheme 8

Base-mediated and thermal elimination of dithiocarbamate 52.

Scheme 9

Functionalization of alkene 16.

Scheme 10

Reactions of lactams 21 and 57 c.