that ethyne could be utilized in the enantioselective aldehyde
additions when the reactions are conducted with saturated
solutions of acetylene in a pressurized, sealed vessel at 23
°C.5 However, despite the novelty and the inherent atom
efficiency of this process, two critical features, namely, the
observed long-reaction times and the handling of pressurized
reaction vessels, rendered the process somewhat unwieldy
at the current level of development. We thus embarked on a
study aimed at identifying inexpensive practical equivalents
of acetylene that could be safely handled in the laboratory
and readily employed in these aldehyde additions. In this
regard, 2-methyl-3-butyn-2-ol (1) seemed attractive as a
potential acetylene equivalent in the addition reactions for
two key reasons: (1) as a commodity chemical, 2-methyl-
3-butyn-2-ol can be purchased at $3/kg and (2) C-alkylated
derivatives had been previously shown to undergo fragmen-
tation reactions thermally to furnish acetone and the corre-
sponding terminal alkyne.6,7
Table 1. Enantioselective Addition Reactions of 1a
At the outset, it was unclear whether an alkyne such as
2-methyl-3-butyn-2-ol, possessing a free alcohol, would be
suitable in the nucleophilic addition reactions which we have
postulated to proceed via alkynyl zinc intermediates. Never-
theless, trial experiments quickly revealed that 1 readily
participates in aldehyde additions, furnishing optically active
propargylic alcohols in high enantioselectivities (up to 99%
ee) and in excellent yields (Scheme 2, Table 1).
Scheme 2
A number of important observations were made in the
context of these studies that lead to significant improvements
over the addition reactions we initially reported.4 The addition
reactions utilizing 1, in general, proceeded at rates that are
faster than those observed with other terminal alkynes we
have previously documented. Moreover, the reactions in-
volving 2-methyl-3-butyn-2-ol (1) display wider scope,
providing adducts for a broader range of functionalized
aromatic and aliphatic aldehydes. Given these unanticipated
benefits, we undertook a careful study of the reaction
conditions aimed at process optimization. In this regard, we
have observed that the stoichiometry of the ligand, Zn(OTf)2,
and amine base can be varied substantially, leading to an
a Unless noted the reactions are conducted at 23 °C, at 0.37 M [alkyne]
utilizing 1.2 equiv of N-methylephedrine, 1.1 equiv of Zn(OTf)2, and 1.1
equiv of Et3N. b Reactions conducted with 2.1 equiv of N-methylephedrine
and 2.0 equiv of Zn(OTf)2. c A 0.4 M solution of the aldehyde was added
over 4 h. d Reactions conducted with 3.1 equiv of N-methylephedrine and
3.0 equiv of Zn(OTf).
increase in the yields and enantioselectivities for a number
of adducts (cf. entry 4 versus 5 and 8 versus 9). For example,
although hexanal affords product in 51% ee when 1.1 equivof
Et3N, 1.1 equiv of Zn(OTf)2, and 1.2 equiv of N-methyl-
ephedrine are employed (see Table 1, entry 4), doubling the
amount of these components furnishes product in 98% ee
(entry 5). Thus, product yields and enantioselectivities can
be optimized by convenient alteration of the stoichiometry.
We anticipate certain applications of this methodology
wherein it maybe desirable to isolate protected alcohol
adducts from the reaction mixture. In this regard, we
(5) Carreira, E. M.; Sasaki, H. Unpublished results.
(6) For catalytic, enantioselective additions of borylacetylides, see: (a)
Corey, E. J.; Cimprich, K. A. J. Am. Chem. Soc. 1994, 116, 3151. For the
asymmetric addition of preformed bisalkynylzinc reagents to aryl ketones,
see ref 1c.
(7) For the preparation of propargylic alcohols by ynone reduction, see:
(a) Helal, C. J.; Magriotis, P. A.; Corey, E. J. J. Am. Chem. Soc. 1996,
118, 10938. (b) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J.
Am. Chem. Soc. 1997, 119, 8738.
4234
Org. Lett., Vol. 2, No. 26, 2000
Boyall
