J. Am. Chem. Soc. 1999, 121, 3559-3560
3559
Initially, we carried out the reaction of 1 with 2,7-enynyl ethers
2 having a (1R,2S,5R)-menthyl or (1R,2S)-trans-2-phenyl-1-
cyclohexyl moiety, which, however, resulted in low chiral
induction as shown in eq 1. It was apparent from these results
Titanium(II)-Mediated Asymmetric Intramolecular
Cyclization of 2,7- and 2,8-Enynyl Chiral Acetals.
Synthetic Equivalent of Stoichiometric
Intramolecular Asymmetric Metallo-Ene Reaction
Yuuki Takayama, Sentaro Okamoto, and Fumie Sato*
Department of Biomolecular Engineering
Tokyo Institute of Technology
4259 Nagatsuta-cho, Midori-ku
Yokohama, Kanagawa 226-8501, Japan
that a simple ether functionality combined with modest steric
biases far removed from the reacting center, would have minimal
influence on the stereochemistry of the reaction.
ReceiVed January 4, 1999
The experiments were then focused on the substrates of those
having, as a leaving group, a chiral acetal moiety with C2-
symmetry, since this kind of chiral acetal has been successful in
directing asymmetric transformations with a variety of organo-
metallics.5 A representative series of chiral acetals 4 was prepared
from tridec-7-yn-2-enal and the corresponding optically active
diol and subjected to the reaction with 1. The reaction proceeded
smoothly to afford the cyclized products 5 as a mixture of E-
and Z-enol ethers in excellent combined yield, where the former
was predominant irrespective of the acetal moiety (Scheme 2).
Stoichiometric intramolecular lithium-, magnesium-, and zinc-
ene reactions and the trapping of the resulting cyclized metallic
intermediates with electrophiles have been widely utilized for the
synthesis of polysubstituted cycloalkanes and the corresponding
natural products.1 As can be seen in Scheme 1 (path a), the
Scheme 1. Metallo-ene and Its Synthetically Equivalent
Reactions
Scheme 2
The resulting enol ether mixture was converted into the dimeth-
ylacetal 6 (Scheme 2) without separation and/or after separation
(in some cases, partly), and its enantiomeric excess (ee) was
determined by GC analysis using a chiral column (Chirasil-DEX
CB); meanwhile, its absolute stereochemistry was established by
correlation to the known compound 96 (see Scheme 3). The results
are summarized in Table 1.
As can be seen from Table 1, the E/Z ratio of 5 and the R/S
ratio of 6 are apparently related to each other, which is most
outstanding in the case of the five-membered acetals, where they
are almost coincident with each other regardless of the substituent
of the acetal (entries 1, 2, and 4). This result strongly suggests
that the absolute configurations of 6 derived from E- or Z-5 are
opposite from each other and the degree of the ee of both E- and
Z-5 is good to excellent. We confirmed this in several cases where
pure E and/or Z-5 could be isolated as shown in entries 3, 5, and
8 in Table 1.
reaction generates a stereogenic center(s) on the ring; however,
it seems difficult to carry out these metallo-ene reactions in an
asymmetric manner, and thus far, no successful results have been
reported.2 Recently, we have reported (η2-propene)Ti(O-i-Pr)2 (1)-
mediated intramolecular cyclization of 2,7- or 2,8-dienyl and
-enynyl ethers affording cyclized titanium compounds. The
resulting titanium compounds readily react with electrophiles
including aldehydes; thus, the reaction can be used as a synthetic
equivalent, at least in part, to stoichiometric metallo-ene reactions3
(path b in Scheme 1). Since this cyclization reaction probably
proceeds through, successively, the intermediates I and II and
subsequent elimination of the OR′ group, we were interested in
carrying out the reaction in an asymmetric way by starting with
substrates having an optically active OR′ group. We selected the
enynyl ethers, since the chiral induction might be induced only
at the step of the transformation from the intermediate I to II.
From a practical viewpoint, the 1,2-diphenylethylene acetal
derivative appears to be most attractive because it affords the
highest E/Z-ratio as well as the highest ee value, and moreover,
E- and Z-5c can be readily separated by column chromatography
(entry 4 in Table 1). Thus, as shown in entry 5, E-5c with 96%
ee was isolated in 83% yield.
(1) Oppolzer, W. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 5, pp 29-61. Oppolzer, W.
Angew. Chem., Int. Ed. Engl. 1989, 28, 38-52. Meyer, C.; Marek, I.;
Courtemanche, G.; Normant, J. F. J. Org. Chem. 1995, 60, 863-871 and
references therein.
(2) (a) The preparation of optically active compounds containing an intrinsic
stereogenic center of the optically active starting substrates through highly
diastereoselective metallo-ene reaction has been reported; see ref 1. (b)
Catalytic asymmetric intramolecullar metallo-ene reactions induced by chiral
ligands on the metal showing low to moderate enantioselectivity have been
reported recently, see: Oppolzer, W.; Kuo D. L.; Hutzinger M. W.; Le´ger,
R.; Durand J.-O.; Leslie C. Tetrahedron Lett. 1997, 38, 6213-6216.
(3) Takayama, Y.; Gao, Y.; Sato, F. Angew. Chem., Int. Ed. Engl. 1997,
36, 851-853. Takayama, Y.; Okamoto, S.; Sato, F. Tetrahedron Lett. 1997,
38, 8351-8354. Yamazaki, T.; Urabe, H.; Sato, F. Tetrahedron Lett. 1998,
39, 7333-7336. For Cp2Zr-mediated reaction; see, Knight, K. S.; Waymouth,
R. M. Organometallics 1994, 13, 2575-2577. Takahashi, T.; Kondakov, D.
Y.; Suzuki, N. Organometallics 1994, 13, 3411-3412. Bird, A. J.; Taylor,
R. J. K.; Wei, X. Synlett 1995, 1237-1238.
(4) Enantiomeric excess (ee) was determined as follows: for 3, GC analysis
after converting to 6; for 9, 1H NMR analysis using a chiral shift reagent,
tris[3-(heptafluoropropylhydroxymethylene)-(+)-comphorato]europium(III);
for 12, GC analysis after changing to 6 by dehalogenation with t-BuLi; for
15 and 17, GC analysis after converting to the corresponding dimethylacetal.
(5) Whitesell, J. K. Chem. ReV. 1989, 89, 1581-1590. Alexakis, A.;
Mangeney P. Tetrahedron: Asymmetry 1990, 1, 477-511. Molander, G. A.;
McWilliams, J. C.; Noll, B. C. J. Am. Chem. Soc. 1997, 119, 1265-1276 and
references therein.
(6) Hashimoto, S.; Miyazaki, Y.; Ikegami, S. Synth. Commun. 1992, 22,
2717-2722. Partridge, J. J.; Chadha, N. K.; Uskokovic, M. R. J. Am. Chem.
Soc. 1973, 95, 7171-7172.
10.1021/ja990021x CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/30/1999