Stereodivergent Synthesis of Functionalized Tetrahydropyrans Accelerated by Mechanism‐Based Allylboration and Bioinspired Oxa‐Michael Cyclization

Abstract

A stereodivergent strategy enabled by bioinspired oxa-Michael cyclization was developed for the synthesis of functionalized tetrahydropyrans on the basis of the inherent symmetry in 1,3-diols, the symmetries of which were tunable by stereoselective hydroboration of an allene with a variety of alkylborane reagents and subsequent allylation of an aldehyde. The mechanism-based utilization of monoalkyl borane in the hydroboration and allylation cascade is unprecedented.

Stereodivergent Synthesis of Functionalized Tetrahydropyrans Accelerated by Mechanism‐Based Allylboration and Bioinspired Oxa‐Michael Cyclization

“…[17] Thef ollowing cyclization under identical reaction conditions afforded the trans-THP 11 bb,aC7-epimer of 11 ba,i n9 1% yield. [18] Theh igh diastereoselectivity for the cyclization of the Z-configured a,b-unsaturated ester 12 indicated an alternative mechanism may occur, and differs from an allylic cationic species as is generally adopted in precedented Brønsted acid promoted oxa-Michael cyclizations. [4e, 6b] It is assumed that aboatlike or twist boatlike transition state might be feasible so that all bulky groups reside in equatorial positions as compared to the chairlike conformation, which may be destabilized by severe steric repulsions (Figure 2).…”

“…Thes ubsequent oxa-Michael cyclization in the presence of p-tolylsulfonic acid (pTSA) delivered the desired cis-THP 11 ba,w hose stereogenicity was unambiguously established by X-ray analysis. [16] Thecompound 12 was isolated in 82 %yield as asingle isomer Scheme 1. Stereochemical rationale of allylborationw ith E-a nd Zallylborane derived from thermodynamic and kinetic conditions, respectively.Bn= benzyl, TBDPS = tert-butyldiphenylsilyl, TBS = tertbutyldimethylsilyl.…”

Stereodivergent Hydroboration of Allenes

“…The Roush group disclosed that the proper choice of substituents on boron (10‐TMS‐9‐borabicyclo[3,3,2]decane) could efficiently inhibit the isomerization of kinetically formed ( Z )‐ 2 , which was also used in the enantioselective stereodivergent allylation of aldehydes –. Very recently, the Huang/Hong group reported a stereodivergent allylation via hydroboration of allenes in the synthesis of functionalized tetrahydropyrans . Soon after their report, our research group independently disclosed a stereodivergent hydroboration/oxidation of allenes and its application to a unified total synthesis of the madangamine alkaloids .…”

Six-Membered Ring Systems

“…Ring-closing metathesis was applied to the synthesis of 3,6-dihydro-2H-pyrans starting from diene and enyne skeletons using Grubbs catalysts (16TA954,16EJO3900) and also to construct the 5,6-dihydropyran-2-one ring in many natural compounds including cryptocaryol (16AGE5049), cryptomoscatone D1 and (5R,7S)-kurzilactone (16TL1087), the C1-C27 subunit of hemicalide (16JOC11275), 12 withanolide analogs (16S48), and in the synthesis of eight pure stereoisomers of pironetin-dumetorine hybrids, a new scaffold for tubulin binders (16EJO2029). Prins cyclization was used to build the tetrahydropyran core of four diarylheptanoids from Dioscorea villosa (16TL3505), while oxa-Michael cyclization reactions were used to prepare the tetrahydropyran rings of (−)-gilbertine (16JOC4566), neopeltolide (16JOC415), rhopaloic acid A (16AGE3455), and fragments of various polyketides (16AGE6280).…”