Asymmetric Synthesis of (R)-Limonene and (S)-Cembrene-A by an Intramolecular Cyclization Reaction Using a Chiral Leaving Group

Abstract

A six-membered monocyclic terpene, (R)-limonene, and a 14-membered monocyclic diterpene, (S)-cembrene-A, have been synthesized, respectively, by new enantioselective intramolecular cyclization reactions of neryl ether and (all-E)-geranylgeranyl ether using an (R)-1,1'-binaphthyl-2-benzoxy-2'-oxy auxiliary as a chiral leaving group in the presence of tin(IV) chloride.The structural diversity found in terpene metabolism is mostly due to olefinic cyclization of five basic acyclic precursors, isoprene units. 1 The biological strategy for the construction of new C-C bonds involves intramolecular electrophilic alkylation of remote double bonds to a cationic center generated by the ionization of allylic pyrophosphates, 2 in which the enzyme may require a divalent cation, Mg(II) or Mn(II), for catalytic activity. 3 Assuming that the cyclization of neryl pyrophosphate to limonene (2) is initiated by bidentate coordination of the pyrophosphate moiety to a metal, we have been intrigued for several years in simulating such a cyclization with asymmetric induction in organic chemistry. This assumption regarding the biosynthesis of 2 is also expected to be a suitable model for the biosynthesis of related cyclic terpenes. In 1983, Yamamoto and co-workers reported the first biomimetic asymmetric synthesis of (R)-(+)-2 (up to 77% ee, 54% yield) from (R)-binaphthol(BINOL) mononeryl ether (1a) using a bulky aluminum reagent, (2,4,6-tri-tertbutylphenoxy)isobutylaluminum trifluoromethanesulfonate (3 equiv) in fluorotrichloromethane (CCl 3 F) at -130°C. 4 This is a successful example of diastereodifferentiating asymmetric induction with an addition-elimination reaction using a chiral auxiliary as a leaving group, and provides a direct and efficient route to an enantiomer (Scheme 1). 5,6 Unfortunately, however, the cyclization of (R)-1a using commercially available DIBAH (1.2 equiv) in dichloromethane at -78 ~ 0°C has given (R)-2 with only 12% ee. 4 We describe here a more effective and new diastereodifferentiating intramolecular cyclization using a chiral leaving group for the asymmetric synthesis of 6-and 14-membered monocyclic terpenes, 2 and cembrene-A (8).Recently, we developed (R)-BINOL derivatives-tin(IV) chloride as chiral protonation reagents 7 and trimethylsilylethoxymethyl (SEM) ether of (R)-BINOL-tin(IV) chloride as a chiral SEM-addition reagent (Figure 1). 6 As a new entry to Lewis acid-assisted chiral electrophiles, we envisaged that a high level of asymmetric induction from an allylic ether of (R)-BINOL to a prochiral nucleophile could be achieved by bidentate coordination of tin(IV) chloride with its (R)-BINOL moiety. Figure 1 Examples of Lewis acid-assisted chiral electrophiles.Initially, we examined various protecting groups, R, of (R)-BINOL mononeryl ether derivatives 1 to effect the intramolecular cyclization of 1 in the presence of one equivalent of tin(IV) chloride in toluene (entries 1-5, Table). (R)-BINOL mononeryl ether 1a (R = H) 3 was easily prepared in good yield from (R)-BINOL and nerol by Mitsunobu reacti...

Lewis Acid-Activated Chiral Leaving Group: Enantioselective Electrophilic Addition to Prochiral Olefins

“…A stable conformation of complex A was predicted by theoretical calculations of a 2,2‘-di(methoxymethoxy)-1,1‘-biphenyl and SnCl 4 complex B , which was optimized at the partial PM3 calculation of the MOM units on the basis of a 2,2‘-dimethyl-1,1‘-biphenyl and SnCl 4 complex optimized at the B3LYP/LANL2DZ level using Gaussian 98 (Figure ) 4a. These calculations indicated that the di(MOM) ether with SnCl 4 occurs at an equatorial site on tin.…”

“…Other substrates did not give significant amounts of chlorinated byproduct. In one particular case, cyclization occurred with SEM addition (eq 4). ,,4e,g,h One additional remark should be made: A Prins-type SEM addition generally did not proceed well when SEMCl−SnCl 4 or SEM phenyl ether−SnCl 4 was used instead of the chiral reagent 1d , in contrast with the case of a SEM addition to silyl enol ethers. Racemic homoallylic ethers 12a − d , which were required as authentic samples, were quantitatively prepared according to the SEM-addition to 11a − d with 2 (Scheme ) at −78 °C.…”

“…The idea of a Lewis acid-activated cationic alkyl group took a hint from Lewis acid-assisted chiral Brønsted acid (LBA), which is a reagent developed in our laboratory for enantioselective protonation prepared from SnCl 4 and an optically pure BINOL derivative . On the basis of this concept, an intermolecular hydroxymethylating reagent ( R )- 1d , 4a,b an achiral derivative 2 , and a reagent for intramolecular cyclization ( R )- 3d 4c have been developed. Herein we report three topics based on the new concept in which a chiral leaving group is used: (1) alkoxymethylation of silyl enol ethers; (2) alkoxymethylation of trisubstituted alkenes; (3) and intramolecular cyclization of terpenes.…”