Synthesis of the AB‐Ring Pyranolactone Substructure of Granaticin A

Abstract

A synthesis of the AB‐ring substructure of granaticin A was developed. The pyranolactone moiety was stereoselectively accessed by Sharpless asymmetric dihydroxylation and subsequent oxa‐Pictet–Spengler cyclization. The use of BF3·OEt2 resulted in the formation of the cis pyranolactone, whereas the combination of BF3·OEt2 with trifluoroacetic acid led to the trans isomer. The resulting hydroquinones were cleaved selectively by ozonolysis to dicarboxylic acids. An aryl Grignard reagent could be regioselectively added to unsymmetrical anhydrides. As an alternative strategy for the construction of the B‐ring, a benzyne–furan cycloaddition could be established.

Nonracemic γ‐Lactones from the Sharpless Asymmetric Dihydroxylation of β,γ‐Unsaturated Carboxylic Esters

“…The structural diversity and biological activity of naturally occurring pyranonaphthoquinone γ‐lactones have piqued the interest of synthetic chemists and pharmacologists , . Some of that work leaned on the SAD strategy reviewed here: a route to 202 , conceived as an eastern building block of synthetic granaticin A ( 203 , Scheme ), syntheses, of unnatural but pharmacologically active model compounds 206a – e (Scheme ), syntheses of the natural products (+)–kalafungin ( 212 ), the antipodal (–)‐nanaomycin ( ent ‐ 212 ), and (+)‐frenolicin B ( 213 , all Scheme ), and totally synthetic accesses to the natural products arizonin C1 ( 222 , Scheme ) and griseusins A ( 233 ) and C ( 232 , both Scheme ). Each of these efforts involved the following steps in the indicated order: (1) preparation of a γ‐arylated β,γ‐unsaturated ester, (2) SAD (69–87 % yield, <95–99.5 % ee ) to give a γ‐lactone, and (3) dihydropyran formation through an “oxa‐Pictet–Spengler cyclization”.…”

“…Synthesis of 199 , a putative pyranolactone precursor to granaticin A ( 203 ), by Koert et al, Reagents and conditions : (a) VinylMgBr (1.1 equiv. ), THF, –60 °C, 30 min; 95 %; (b) Ac 2 O (5.0 equiv.…”

“…Striving for synthetic granaticin A ( 203 ) Koert et al prepared a western building block 201 containing the “sugar” moiety and the putative naphthoquinone precursor 199 of an eastern building block 202 (Scheme ). The two last‐mentioned compounds contain a pyranolactone subunit.…”

“…SADs of ,γ-unsaturated carboxylic esters each containing a transdisubstituted C=C bond and an aromatic γ-substituent. [40,42,71,[99][100][101][102][103][104][105][106][107][108][109][110][111][112][113][114] [a] Up to 10 mol-% of ligand and up to 3.0 mol-% of K 2 OsO 2 (OH) 4 were used. If necessary, NaHCO 3 (3.0 equiv.)…”

“…[131] Scheme 45. Synthesis of 199, a putative pyranolactone precursor to granaticin A (203), by Koert et al [102,132] Striving for synthetic granaticin A (203) Koert et al prepared a western building block 201 [132] containing the "sugar" moiety and the putative naphthoquinone precursor 199 of an eastern building block [102] 202 (Scheme 45). The two last-mentioned Scheme 47.…”