The total synthesis of indolocarbazole natural products and towards the synthesis of (+)-sparteine

Abstract

The indolocarbazole alkaloids are a diverse family of natural products including staurosporine, K252a, K252d, rebeccamycin and the staurosporine aglycone. Whilst these alkaloids have been of medicinal interest in the past, most notably as protein kinase C inhibitors, recent studies have detailed inhibition of cancer stem cell formation. This is best exemplified with the FDA approval of Midostaurin©, a derivative of staurosporine, for treatment of acute myeloid leukaemia in 2017.
This thesis describes the synthetic advances towards indolocarbazole natural products, culminating in the syntheses of the staurosporine aglycone, arcyriaflavin A and the first total synthesis of K252d and its previously unknown β-anomer.
The development of the synthetic strategy is described, first exploring a photochemical cyclisation in flow applied to the synthesis of arcyriaflavin A and the staurosporine aglycone. Application of the Tsuji-Trost reaction for the glycosylation of indoles, and ensuing McMurry cyclisation and Barton-Zard pyrrole synthesis approaches were explored before the first total synthesis of K252d is described in 4% over 6 steps, utilising a Mannich-type cyclisation and indoline glycosylation. The previously unknown β-anomer was also accessed in a 1:1 ratio, and the approach presents a regioselective method to functionalise the staurosporine aglycone circumventing the need for protecting group chemistry. The approach is applied to the staurosporine aglycone in 16% yield over 5 steps.
The synthesis towards (+)-sparteine, a lupin alkaloid isolated from the papilionaceous plant species, is enclosed. The approach utilises an imino-aldol reaction with an N-sulfinylimine before a subsequent anti-selective alkylation to give anti-products with good diastereoselectivity (dr = 10:1). Progress towards (+)-sparteine utilising a cross-metathesis to install the allyl silane moiety and Mitsonobu reaction to install the glutarimide moiety is also disclosed.

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ORCID for Richard Brown: orcid.org/0000-0003-0156-7087

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