Total Synthesis of Haterumalides NA and NC via a Chromium-Mediated Macrocyclization

Abstract

The haterumalides are a series of chlorinated macrolides isolated from an Okinawan sea sponge of the species Ircinia (Figure 1). 1,2 Kigoshi's synthesis of haterumalide NA led to its structural revision. 3 The stereochemistry of the remaining haterumalides is assumed to mimic that of haterumalide NA, and the stereochemistries in Figure 1 have been changed to reflect the corrections made to the initial structure of haterumalide NA.Figure 1 summarizes previous synthetic approaches to haterumalide NA. Kigoshi and coworkers utilized an intramolecular Reformatsky reaction as a key step to form the macrolide. 3 Snider and Gu used an intermolecular Stille coupling reaction followed by a Yamaguchi macrolactonization. 4 Hoye and Wang reported the first total synthesis of the correct enantiomer of haterumalide NA using a Pd-mediated alkyne haloallylation reaction. 5 Most recently, Roulland and Kigoshi, in two separate reports, described the use of variants of Suzuki-Miyaura cross-coupling along with macrolactonizations to achieve the synthesis of haterumalide NA. 6,7 Our approach entailed the construction of the C8-C9 bond, such that any member of the haterumalide family could be accessed. Critical to this assembly would be the ability to construct a nucleophilic Z-vinyl chloride moiety that would participate in a macrocyclization event with a pendant aldehyde. Thus, we explored the utility of the chlorovinylidene chromium carbenoids developed by Falck and Mioskowski (see Figure 1, box). 8,9 To the best of our knowledge, this chemistry has not been utilized in a natural product synthesis and its participation in a macrocyclization has not been reported.Synthesis of 1c commenced with preparation of the tetrahydrofuran-containing aldehyde for intramolecular CrCl 2 -mediated coupling (Scheme 1). 2-Deoxy-D-ribose 2 was converted to the disilylated methyl acetal 3 in high yield. Addition of allyltrimethylsilane to 3 in the presence of tin tetrabromide by the method of Woerpel and co-workers gave the allylated product in excellent diastereoselectivity. 10,11 Desilylation to yield 4 was followed by protection of the primary alcohol as a trityl group, yielding 5 poised for Mitsunobu esterification with carboxylic acid 9c.Preparation of 9c began with the ring-opening of 6 with the anion of chloroform to yield the corresponding alcohol. 12 DMP oxidation furnished the unstable, reactive, and volatile aldehyde 7, which was immediately subjected to a Still-Gennari olefination to yield the desired Z-acrylate. 13 Reduction of the ester to the allylic alcohol 8 was followed by a rapid oxidation to the unsaturated aldehyde and an immediate asymmetric Mukaiyama aldol reaction to furnish 9a. 14 The secondary alcohol was protected as a TBS ether, and the phenyl ester was hydrolyzed to give the desired 1,1,1-trichloroalkane substrate 9c. Mitsunobu esterification of alcohol 5 and carboxylic acid 9c yielded 10a without incident. Both TBS-protected and acetylated C3-OH compounds (10a and 10c) were carried forward for comparative studies in later...

Highly Stereoselective Glycosylation Reactions of Furanoside Derivatives via Rhenium (V) Catalysis

“…Relative stereochemistry of 12 has been established by chemical correlation with the known Borhan allylated diol, previously reported as diol 4 . 12 This complete selectivity is remarkable in light of the fact that other catalytic approaches 3 afford the corresponding TBS-protected 12 in 90:10 selectivity. Indeed, in order to achieve the same level of stereoselectivity, the reaction requires an equimolar amount of Lewis acids such as BF 3 etherate 13 or SnBr 4 .…”

Total Synthesis of Biselide A, A Cytotoxic Macrolide of Marine Origin

“…Four groups have achieved the total synthesis of haterumalides: Hoye, 3 Roulland, 4 Kigoshi-Hayakawa, 5 and Borhan. 6 In addition, prior to those reports, we reported the first synthesis of ent-haterumalide NA methyl ester (ent-6). 7 Moreover, several groups have reported on the studies of haterumalide and biselide synthesis.…”

Total Synthesis of Skipped Diene Natural Products

“…Haterumalide NC ( 88 ) [31] has an extra hydroxy group at C9 carbon center, which makes the total synthesis more challenging (Scheme 12). The Borhan group reported the highly convergent approach to haterumalide NC ( 88 ) [40] through chromium carbenoid‐mediated macrocyclization. The Mitsunobu esterification of carboxylic acid 89 and alcohol 90 provided ester 91 in 74% yield, associated with stereoinversion of the secondary alcohol.…”