Total Synthesis of the Anticancer Marine Natural Product Mycalol

Abstract

This communication describes a synthetic study of the originally proposed structure of mycalol (1) and the total synthesis of the actual structure of the anticancer marine natural product mycalol (2). The total synthesis of the originally proposed structure of mycalol (1) was targeted by a late‐stage asymmetric dihydroxylation, which resulted in an inseparable mixture of diastereomers. Thus a new strategy was developed for the total synthesis of the revised structure of mycalol (2); all the stereocentres except the C‐2′‐OH were created in an asymmetric fashion by using a Maruoka allylation, a Noyori asymmetric reduction, and an asymmetric alkynylation.

Chiral Pool Meets Chiral Catalysis: Eight-Step Convergent Total Synthesis of Anticancer Natural Lipid Mycalol

“…The stage was now set for the final assemblage of a complete skeleton of mycalol by combining the two fragments. Employing the Hoveyda-Grubbs-II catalyst, the cross-metathesis of 8a with 2e under reflux in CH 2 Cl 2 solvent resulted in the diene that, on olefin reduction, furnished the known mycalol triacetonide 18 in a 51% yield over two steps with an excellent match of spectral and analytical data to those reported in the literature . Finally, acetonide deprotection furnished mycalol ( 1b ) in an 86% yield.…”

“…[α] D 25 +10.2 ( c 0.7, CHCl 3 ). [α] D 25 +7.21 ( c 0.69, CHCl 3 ); IR (CHCl 3 ) ν max = 2927, 2855, 1736, 1461, 1378, 1371, 1245, 1164, 1122, 1076, 1022, 868, 839, 519 cm –1 ; 1 H NMR (500 MHz, CDCl 3 ) δ = 4.84 (quint, J = 6.2 Hz, 1H), 4.26 (quint, J = 5.9 Hz, 1H), 4.19 (ddd, J = 9.5, 5.4, 4.6 Hz, 1H), 4.10–3.99 (m, 4H), 3.74 (dd, J = 8.2, 6.6 Hz, 1H), 3.67–3.57 (m, 2H), 3.54 (dd, J = 9.9, 5.5 Hz, 1H), 3.46 (dd, J = 9.8, 5.6 Hz, 1H), 2.03 (s, 3H), 1.75–1.68 (m, 3H), 1.65–1.62 (m, 3H), 1.56–1.44 (m, 6H), 1.40 (s, 9H), 1.34 (s, 3H), 1.31 (s, 6H), 1.32–1.21 (m, 22H), 0.88 (t, J = 6.9 Hz, 3 H) ppm; 13 C { 1 H} NMR (100 MHz, CDCl 3 ) δ = 171.0, 109.4, 107.6, 107.4, 78.3, 78.2, 78.1, 74.8, 74.6, 74.5, 71.9, 68.7, 66.9, 34.1, 34.07, 31.9, 31.7, 30.2, 29.7, 29.6, 29.5, 29.1, 28.7, 28.6, 27.2, 27.1, 26.8, 26.4, 26.0, 25.9, 25.4, 25.3, 25.0, 22.7, 22.6, 21.3, 14.0 ppm. HRMS (ESI-TOF): m / z [M + Na] + calcd for C 38 H 70 O 9 Na 693.4912; found 693.4912.…”

“…The latter was coupled by a Sonogashira reaction with 3e , and global hydrogenation furnished mycalol ( 1b ) in 19 steps with a 1.7% overall yield from 3a . The third synthesis was reported by Ghosh and co-workers based on double Noyori reduction to take compound 4a to 4b followed by asymmetric alkynylation to give 4c (Scheme C). This was added to 4d , and the third Noyori reduction led to mycalol ( 1b ) in a total of 21 steps from hexanal via compound 4a and a 6.5% overall yield.…”

A novel process for the synthesis of substantially pure Letrozole

“…14,15 The C-N bond formation between N-1 of 1,2,4-triazole 4 with 4-(chloro(4-cyanophenyl)methyl)benzamide 12 under nucleophilic substitution reaction conditions can yield compound 11. The 4-(chloro(4-cyanophenyl)methyl)benzamide 12 in turn can be synthesized from bis(4bromophenyl)methanone 13 involving a series of reactions such as cyanation 16 , in situ conversion to amide 17 14, reduction of keto functionality of 14 [18][19][20] with sodium borohydride, and finally chlorination 12 using thionyl chloride.…”

Pitfalls in the structural elucidation of small molecules. A critical analysis of a decade of structural misassignments of marine natural products

“…The synthetic compound was identical to natural mycalol, confirming its structure, 119 and similar conclusions were reached in other synthetic investigations. 120,121…”