Application of Conformation Design in Acyclic Stereoselection:  Total Synthesis of Borrelidin as the Crystalline Benzene Solvate

Abstract

The total synthesis of (-)-borrelidin (treponemycin), a structurally distinct 18-membered macrolide antibiotic, has been achieved. It was isolated as the crystalline benzene solvate, and its structure was confirmed by a single-crystal X-ray analysis. The deoxypropionate subunit consisting of four alternating C-methyl groups with a C(4)-C(10) syn/syn/anti orientation was elaborated by a new method of iterative cuprate additions to acyclic alpha,beta-unsaturated esters relying on two consecutive 1,3-inductions and starting with d-glyceraldehyde as the chiral progenitor. The unique Z/E cyanodiene unit was obtained as a single isomer by application of the Still-Gennari olefination protocol. The gamma-hydroxycyclopentane carboxylic acid subunit was prepared from L-malic acid utilizing a sequential introduction of C-vinyl and C-allyl groups, capitalizing on 1,2-induction in an acyclic alpha,beta-unsaturated ester and carbocyclization by a Grubbs ring closure metathesis reaction. The prevalence of 1,3-syn-disposed deoxypropionate triads in the cuprate additions is rationalized on the basis of minimized syn-pentane interactions in the transition states. A virtual diamond lattice was used as a visual tool to portray the low-energy conformations of the acyclic substrates, and corroborated by (1)H NMR homodecoupling studies.

Total synthesis of the cytotoxic cyclodepsipeptide (-)-doliculide: The “ester” effect in acyclic 1,3-induction of deoxypropionates

“…Chain elongation in the usual manner afforded the t-butyl enoate 5, which was subjected to a second cuprate addition. The resulting syn-and antidiastereomeric adducts were formed in a ratio of 4:1, respectively, as observed in the enantiomeric series (60). We had found previously that the syn͞anti ratio of the same cuprate addition was only 1:1 when a methyl rather than a t-butyl ester was used (5, R ϭ Me).…”

“…As evidenced by the successful completion of the synthesis of (Ϫ)-doliculide by using this strategy, the viability of acyclic stereocontrol for a syn͞syn-2,4,6-trimethyl deoxypropionate chain is obvious. We recently presented a rationale and a mechanistic model to explain the stereochemical preferences in such conjugate additions in connection with the total synthesis of borrelidin (60). We reasoned that transition-state conformations during cuprate additions could be favored when 1,5-synpentane interactions are minimized or avoided.…”

“…We have used a virtual diamond lattice model (72,73) to qualitatively visualize the backbone conformations of such acyclic enoates and their putative cuprio intermediates (60). The validity of this visual tool to simulate folded conformations of hydrocarbon chains was also tested in the context of solid-state crystal structures of natural products containing syn͞syn-trimethyl deoxypropionate motifs.…”

“…The notion of using a relatively large substituent as an ''anchor'' to favor the reactivity of different conformers of a tethered chain has been alluded to by De Clercq (77,78) in the context of the rate acceleration of intramolecular Diels-Alder reactions. This effect has been of special interest as part of a more generalized phenomenon, also known as the Thorpe-Ingold gem-dialkyl effect (79) In the case of conjugate additions of organocuprates to enoates such as 5, the ester extremity seems to play an important role in determining syn selectivity, as observed in going from methyl to t-butyl (syn͞anti: 1:1 and 4:1, respectively) (60). Although a syn͞anti ratio of 10:1 for 9 with the t-butyl enoate 8 was originally acceptable in the third-stage cuprate addition (60), the modest 4:1 ratio obtained for 5 (R ϭ t-butyl) warranted additional study.…”

Total synthesis of borrelidin

“…This biological profile, as well as its structural complexity, prompted substantial synthetic efforts toward the total synthesis of borrelidin. Recently, four total syntheses of borrelidin were reported by the respective groups of Morken, 15) Hanessian, 16) Theodorakis, 17) and ours, 18) and two synthetic studies toward the total synthesis have been presented. 19), 20) This review will describe all these synthetic accomplishment.…”