Synthesis of Side Chain Truncated 3‘ ‘-Aldehyde, 3‘ ‘-Carboxylic Acid, and 1‘ ‘-Aldehyde from Nodulisporic Acid A

Abstract

An efficient synthesis of the truncated 3"-aldehyde (3) from nodulisporic acid A (1) under mild conditions is described. Further oxidation of 3 to 3"-carboxylic acid (4) and its subsequent oxidative degradation produced 1"-aldehyde (5). These new derivatives are versatile intermediates for the preparation of new, side chain modified derivatives of nodulisporic acid A. [reaction: see text]

Nodulisporic Acids D−F: Structure, Biological Activities, and Biogenetic Relationships

“…was cultured in shake flasks from vegetative mycelial growths on a rotary shaker for 22 days in darkness in a medium consisting of glycerol (75 g/L), glucose (10 g/L), ardamine pH (5 g/L), (NH 4)2SO4 (2 g/L), soybean meal (5 g/L), tomato paste (5 g/L), sodium citrate (2 g/L), and distilled H 2O at pH 7.0 at 29 °C. Isolation of Nodulisporic Acids D (7a), D1 (8a), D2 (9a), D3 (10), and E (11a). A 2 L fermentation broth of ATCC 74473 was filtered, and mycelia were extracted with 2000 mL of methyl ethyl ketone by shaking for 30 min and were concentrated to afford 2.2 g of dark-colored solid.…”

“…While nodulisporic acid A exhibited good in vitro and in vivo activity against fleas, its potency and pharmacokinetic properties did not justify its development as a drug, so therefore a medicinal chemistry effort was initiated to optimize the profile of the lead. Chemical modifications were performed on most of the accessible sites, particularly the dienoic acid side chain, leading to a substantial improvement in activity; [7][8][9][10][11][12][13] the effort has been briefly reviewed. 14,15 In parallel with the medicinal chemistry efforts, we sought to find congeners and/or natural analogues of nodulisporic acid A, from the original producer as well as variants derived from it by chemical mutagenesis, in the hope of providing compounds that may not be accessible by the chemical derivatization.…”

“…This process led to the discovery of nodulisporic acids A 1 (2a), A 2 (3a), 16 B (1b), B 1 (2b), B 2 (3b), 17 C (4), C 1 (5), and C 2 (6). 18 A continuation of this work with mutant Nodulisporium strains has led to the isolation of early biosynthetic intermediates named herein nodulisporic acids D (7a), D 1 (8a), D 2 (9a), D 3 (10), and E (11a) from ATCC74473, nodulisporic acid F (12) from MF6518, and A 4 (13), ∆ 23 -A 4 (14), and ∆ 23 -C 4 (15) from two other mutant cultures. Like nodulisporic acids of the B and C series, some of these compounds were detected in the extracts of the original producer but in quantities too low for purification.…”

“…While nodulisporic acid A exhibited good in vitro and in vivo activity against fleas, its potency and pharmacokinetic properties did not justify its development as a drug, so therefore a medicinal chemistry effort was initiated to optimize the profile of the lead. Chemical modifications were performed on most of the accessible sites, particularly the dienoic acid side chain, leading to a substantial improvement in activity; − the effort has been briefly reviewed. , …”

The Glycol Cleavage in Natural Product Synthesis: Reagent Classics and Recent Advances

“…For the preparation of structurally diverse, sidechain modified analogues of 132a with potentially improved biological activity, an adequate supply of aldehyde 133 was crucial. 101 This required a selective oxidative cleavage of the 3′′,4′′-double bond. Since the natural product is oxidatively labile as well as sensitive to strong ac- ids, mild oxidation methods with neutral or weakly acidic conditions were considered.…”