Abstract
The amino substituted bicyclo[4.3.0]nonane is a molecular scaffold found in a wide range of natural products and medicinal agents. Despite this, synthetic methods for the general preparation of this structural motif are sparse. Here we evaluate a diastereoselective approach for the preparation of vinylsilyl derived aminobicyclo[4.3.0]nonanes using a one-pot multi-bond forming process involving a Pd(ii)-catalysed Overman rearrangement, a Ru(ii)-catalysed ring closing enyne metathesis reaction, followed by a hydrogen bonding directed Diels-Alder reaction. We show that a benzyldimethylsilyl-substituted alkene analogue is amenable to further functionalisation and the late stage generation of diverse sp3-rich, drug-like aminobicyclo[4.3.0]nonane scaffolds with up to six stereogenic centres.
Highlights
The amino substituted bicyclo[4.3.0]nonane core is found in various natural products,[1] such as guanidine alkaloid netamine A (1),[2] the antitumour antibiotics (+)-ptilocaulin (2)[3] and kinamycin A (3),[4] as well as the lycopodium alkaloid serratinine (4) (Fig. 1).[5]
With the aim of developing new strategies for the preparation of drug-like scaffolds, we reported a one-pot, three-step multi-bond forming process of alkyne derived allylic alcohols that utilised an Overman rearrangement, a ring closing enyne metathesis (RCEYM) step and a Diels–Alder reaction for the general preparation of aminobicyclo[4.3.0]nonanes.[10]
We report the use of alkynylsilyl derived allylic trichloroacetimidates as substrates for the one-pot multi-bond forming process and the diastereoselective synthesis of aminobicyclo[4.3.0]nonanes bearing a vinylsilane functional handle (Scheme 1b)
Summary
The amino substituted bicyclo[4.3.0]nonane core is found in various natural products,[1] such as guanidine alkaloid netamine A (1),[2] the antitumour antibiotics (+)-ptilocaulin (2)[3] and kinamycin A (3),[4] as well as the lycopodium alkaloid serratinine (4) (Fig. 1).[5]. With the aim of developing new strategies for the preparation of drug-like scaffolds, we reported a one-pot, three-step multi-bond forming process of alkyne derived allylic alcohols that utilised an Overman rearrangement, a ring closing enyne metathesis (RCEYM) step and a Diels–Alder reaction for the general preparation of aminobicyclo[4.3.0]nonanes.[10] More recently the diversity of this library was extended by using C-7 substituted hept-2-en-6-yn-1-ols (Scheme 1a).[11] As well as yielding aminobicyclo[4.3.0]nonanes with additional functionality, the presence of a C-7 substituent within the allylic trichloroacetimidate substrate, allowed the use of mild palladium(II)catalysed conditions for the Overman rearrangement step.[12] diversity could be introduced into the aminobicyclo [4.3.0]nonane core during the final-stage Diels–Alder reaction, the other point of diversity was via a Sonogashira reaction during the first step. We decided to investigate an alternative C-7 substituent that would be compatible with the synthesis of alkyne-derived allylic trichloroacetimidates, allow a Pd(II)-catalysed Overman rearrangement and be used as a functional handle for late-stage diversification
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