Synthesis of Alkyl Citrates (−)-CJ-13,981, (−)-CJ-13,982, and (−)-L-731,120 via a Cyclobutene Diester

Abstract

An efficient and step-economic new approach to alkyl citrate natural products from a cyclobutene diester is presented. The key sequence involves a formal [2 + 2]-cycloaddition of a silylketene acetal with dimethylacetylene dicarboxylate to provide the cyclobutene diester 14 with 4.5:1 stereoselectivity. Exposure of diester 14 in acidic methanol effected a hydrolysis, intramolecular oxy-Michael reaction, and cyclobutanone methanolysis cascade to give the triester 15. Iodination and elimination then afforded a key alkyl citrate alkene intermediate, which was converted into the natural products (-)-CJ-13,982 (1), (-)-CJ-13,981 (2), and (-)-L-731,120 (3) via a cross-metathesis and subsequent reduction.

Total Synthesis of Marine Natural Products Serinolamide A and Columbamide D

“…Similarly, (R)-7 was coupled with fragment 21 using the same reaction condition to furnish columbamide D 2. The structures were confirmed by its 1 H NMR, 13 C NMR, and high-resolution mass spectrometry (HRMS) analysis. The enantiomeric purity of 1 was determined by chiral HPLC analysis (see the Supporting Information).…”

“…Melting points are uncorrected and recorded using digital BUCHI Melting Point Apparatus B-540. 1 H NMR spectra and 13 C NMR spectra were recorded on Bruker AV, 400/500 MHz spectrometers in appropriate solvents using TMS as the internal standard or solvent signals as secondary standards, and the chemical shifts are shown in δ scales. Multiplicities of 1 H NMR signals are designated as s (singlet), d (doublet), dd (doublet of doublet), dt (doublet of triplet), t (triplet), quin (quintet), m (multiplet), and so forth.…”

“…[α] D 25 = −56.7 (c 0.94 CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ): δ H 7.39−7.23 (m, 5H), 4.53 (s, 2H), 3.65−3.39 (m, 6H), 3.37−3.28 (m, 3H), 2.92−2.89 (m, 1H) 2.47 (s, 3H); 13 (R)-3-Methoxy-2-(methylamino)propan-1-ol (R)-7. To a solution of (S)-6 (0.21 g, 1.0 mmol) in EtOH (3 mL) was added palladium hydroxide on activated charcoal (40 mg, 10− 20 wt %), and the reaction mixture was stirred under hydrogen (20 psi) for 5 h. After the completion of the reaction (indicated by TLC), the catalyst was filtered over a plug of Celite bed (EtOAc eluent) and the solvent was evaporated under reduced pressure to yield (R)-7 (0.11 g, 97%) as a pale yellow oil.…”

New frontiers in the transition-metal-free synthesis of heterocycles from alkynoates: an overview and current status

“…Synthesis of (−)-CJ-13,982. Rizzacasa and coworkers 363 reported an efficient and step-economical approach to produce alkyl citrate natural products from a cyclobutene diester (Scheme 110). The enantiospecific synthesis of (−)-CJ-13,982 459 was started using optically pure lactone 454 364 ( prepared from (S)-(+)-γ-hydroxymethyl-γ-butyrolactone) which was transformed into the silyl ketene acetal, and cycloaddition with dimethyl acetylenedicarboxylate (DMAD) afforded the major adduct cyclobutene 455.…”

Algorithmic Discovery of Tactical Combinations for Advanced Organic Syntheses

“…When planning syntheses of complex organic molecules, it is often not sufficient to gradually simplify the structure-instead, it may be beneficial to go through an intermediate that does not, per se, produce any immediate gain (or even intermittently increases structural complexity) but sets the scene for a ''downstream'' disconnection offering a significant structural simplification (Figures 1 and 2A). A few decades ago, Corey and Cheng 1 christened such sequences as ''tactical combinations'' (TCs)-since then, some of them have become a part of mainstream retrosynthetic thinking [2][3][4][5][6] (Figures 1A and 1B), some are less obvious and require a trained eye to spot 7,8 (Figures 1C-1E), and yet some others, used as key steps in syntheses of complex natural products, are truly remarkable, making one wonder how the authors were inspired to identify such an elegant combination 9,10 (Figures 1F and 1G). Indeed, the notion that TCs are ''inspired'' rather than ''discovered'' is reinforced by the fact that the largest collection cataloged in Ott 11 provides only ca.…”