Enantioselective synthesis of Bakuchiol using diazosulfonate C–H insertion to install the quaternary center

Abstract

Bakuchiol was prepared from commercial (−)-citronellol using the diazosulfonate C-H insertion to control the regioselectivity and install the quaternary center.We recently reported a modification of C-H insertion that permits assembly of six-membered sulfur-containing heterocycles, 1 effectively introducing substitution at a remote position to an existing functionality. The synthetic potential of this reaction has yet to be demonstrated. In this report we describe an application of this methodology for construction of the quaternary center in the structure of natural product Bakuchiol, which was isolated from seeds of Psoralea corylifolia L, 2 and had a variety of applications. The two features of C-H insertion that make it particularly useful for this purpose are ease of insertion into a tertiary C-H bonds, and complete retention of configuration at the insertion site. Use of the sulfonate modification in this case appropriately controls the regioselectivity of insertion.Thus, commercially available (−)-citronellol was converted to δ-sultone 3 using diazosulfonate C-H insertion in a manner identical to that previously reported by Du Bois (Scheme 1). 3 Our materials matched the reported compounds by spectral data. 12 Initially, we attempted to reductively cleave the C-S bond in δ-sultone 3 using SmI 2 /DMPU. 4 However, poor results were obtained. The expected reductive desulfonation product did appear to form, but in minor quantities, and contaminated by several byproducts (transformation of the double bond appeared to have taken place). Therefore, an alternative route was attempted (Scheme 2). DIBALH reduction of the ester in 3 to alcohol 13 proceeded cleanly. While it appeared to be possible to transform it to alcohol 6 by conversion to alkyl halide and treatment with zinc in DME, both of these reactions were riddled with difficulties. Reaction of alcohol 4 with Ph 3 P/NBS or Ph 3 P/I 2 /ImH proceeded only at high temperatures (Toluene, 90°C), and in modest yields. Treatment with zinc tended to produce, along with 6, elimination product 5 and other byproducts. This elimination product, 5 ,14 was easily available from 4 by mesylation and elimination, so we explored the possibility of its conversion to 6.Only a single example of reductive desulfonation of vinylic sulfonates appears to have been reported, using lithium in ammonia. 5 Under these conditions we saw formation of only small amounts (~5%) of the desired product. The major product, obtained as an apparent mixture of diastereomers, was not identified, but it appeared to retain the sulfonate moiety and lack the exomethylene double bond according to 1 H NMR spectrum. Several methods, reported for

Natural products possessing protein tyrosine phosphatase 1B (PTP1B) inhibitory activity found in the last decades

“…The first enantiocontrolled synthesis of 190 was completed by starting from (S)-O-benzylglycidol [109] . Later, several simple and convenient methods were reported for the total synthesis of 190 [110][111][112][113][114] . A study on the constituents of the mangrove plant Lumnitzera racemosa produced two alkylphenols 191 and 192 [115] .…”

A Short Synthesis of (+)-Bakuchiol

“…Compound 7 was then demethylated by heating at 160 °C in the presence of MeMgI 9 to give (+)-bakuchiol (1) in good yield. The spectral data ( 1 H NMR, 13 C NMR, IR, EI-MS, [α] D ) 18 collected for the synthetic 1 were identical to those of the natural product.…”

“…Takano et al 10 reported the first enantiocontrolled total synthesis of (+)-bakuchiol (1) in 1990 in 11 steps from (S)-O-benzylglycidol. Following on from this work, Asaoka et al 11 (16 steps, in 1999), Li et al 12 (10 steps, in 2008), Novikov et al 13 (10 steps, in 2009) and Hoveyda et al 14 (3 steps, in 2010) have all succeeded in developing elegant enantioselective total syntheses of (+)-1. In our previous paper, 15 we reported the successful total synthesis of (+)-bakuchiol (1) in 14 steps from but-3-yn-1-ol based on the asymmetric 1,4-addition reaction of (H 2 C=CH) 2 Cu(CN)Li 2 to an α,β-unsaturated carboxylic acid derivative equipped with a chiral oxazolidinone auxiliary 2 for constructing the allcarbon chiral quaternary center 15 (Scheme 1).…”

Synthetically Useful Intermediates by Diazosulfone and Sulfonate C–H Insertion

“…Earlier, we demonstrated the potential of this approach by converting the δ-sultone, obtained from (-)-citronellol by diazosulfonate C-H insertion, [2] to natural product bakuchiol. [7] We, thus, set out to explore preparation of other synthetic intermediates from common precursors using this reaction.…”