Highly Selective Synthesis of Seven-Membered Azaspiro Compounds by a Rh(I)-Catalyzed Cycloisomerization/Diels-Alder Cascade of 1,5-Bisallenes

Abstract

The synthesis of spiro compounds featuring seven- and six-membered rings in the spirobicyclic motif is successfully achieved through a cascade process encompassing a rhodium(I)-catalyzed cycloisomerization followed by a highly selective Diels-Alder homodimerization. The scope of the reaction is analyzed based on a series of synthetic substrates, and control experiments and DFT calculations led us to justify the exquisite degree of selectivity observed.

Figure 1

Bioactive molecules that contain seven-membered azaspiro scaffolds.

Scheme 1. Synthesis of Spiro Derivatives through Diels–Alder Reactions

Figure 2

Possible cycloadducts that can be formed in the homo-Diels–Alder of cycloheptatriene cHT.

Figure 3

COSY and HMBC crosspeaks and NOE contacts observed in 2a confirming the formation of regioisomer 2A and selected ¹H and ¹³C (in italics) NMR shifts of 2a.

Figure 4

Scope of the cascade process. Byproducts 3a–3f (5–13% yields) and 3g (20% yield) were observed in the ¹H NMR of the reaction crude.

Figure 5

(a) Gibbs energy profile in kcal·mol^–1 for the transformation of cHT (from 1g) into 2g. (b) Molecular structures of TS^cs(2A_endo) and TS^cs(2A_exo). (c) Values of the condensed Fukui functions f^– and f⁺ (units are electrons) on the HOMO and LUMO orbitals.

Scheme 2. Species Detected by ESI(+)-MS when the Reaction Is Run in the Presence of TEMPO