D. Dunford et al. / Tetrahedron Letters 49 (2008) 2240–2242
2241
Table 1
Direct addition of lithio-acetylides to a-hydroxy ketones
OH
OH
R2
2.1 eq. R2CCLi
THF, -78 C, 1~2 h.
R1
R1
R1
R1
º
OH
O
9
8
OH
Ph
Entry
R1
Yield of 9 (isomer ratio)
R2 = Ph R2 = Bu
Ph
Ph OH
5
1
2
3
4
5
Me
Ph
2-Furyl
iPr
tBu
87% [68:32]
96% [99:1]
89% [95:5]
88% [84:16]
32% [97:3]
91% [96:4]
90% [96:4]
86% [97:3]
89% [97:3]
Fig. 1. ORTEP diagram from X-ray analysis of product 5 derived from
benzoin and lithio-phenylacetylide.
OH
OH
R
2.1 eq. TMSCCLi
Ph
Ph
Ph
Ph
THF, -78 ºC, 1 h.
OH
O
8; R1 = Ph
a) R = TMS [77%; 99:1]
b) R = H [80%]
10
Li
O
Li
F
O
O
O
5
Scheme 3. Condensation of benzoin [8; R1 = Ph] with TMS acetylene.
Ph
H
H
Ph
Ph
Ph
Ph
Benzoin [8; R1 = Ph] also underwent a clean condensa-
tion with lithiated trimethylsilylacetylene to provide a good
yield of the expected diol 10a, as essentially a single
diastereoisomer (Scheme 3).4 Subsequent desilylation
provided 1-alkyne 10b, which serve as a precursor to a wide
range of additional derivatives following a Sonogashira
coupling.1
Overall, this sequence is a brief, stereoselective and effi-
cient approach to alkyne-diols 9, especially when the
substituents are aryl groups. Alternatives, such as
bis-hydroxylation of alkenes 11, are longer but should also
provide excellent stereocontrol. The ‘waste’ of 1 equiv of
the alkyne is quite atom efficient when considered against
the waste of a protecting group; precious alkynes could
also be recovered. The use of preformed salts of the
hydroxy ketones was, in our hands, much less clean.
7
6
Ph
Scheme 2. A chelation-controlled model.
This stereochemical outcome suggested the involvement
of a chelation-controlled Felkin–Anh transition state con-
formation 6, which would be expected to lead to diastereo-
isomer 7 (Scheme 2). As a similar reaction of acetoin
(3-hydroxy-2-butanone) gave much lower levels of stereo-
selection (ca. 70:30), we reasoned that the steric bulk of
the two phenyl groups in benzoin, relative to the methyl
groups in acetoin, could be responsible for the selective
formation of diastereomers 5.
We therefore tested the reaction using examples of
acyloins 8 having increasingly larger substituents; the
results are shown in Table 1.
R2
This study revealed that additions to both benzoin and
furoin (entries 2 and 3) gave excellent chemical yields and
levels of stereoselection in the resulting diols 9, with both
aryl- and alkyl-substituted alkynes. These were maintained
in the additions of lithio-hexyne to both isobutyroin and
pivaloin (entries 4 and 5), but were substantially lower in
the addition of phenylacetylide to isobutyroin. This less
nucleophilic acetylide also reacted poorly, but stereoselec-
tively with the very crowded pivaloin. In each case, the iso-
meric ratio was determined from proton NMR integration.
In some cases, it was not certain that the very small reso-
nances adjacent to the much larger ones of the major iso-
mers were indeed due to the minor diastereoisomer;
however, these assignments were also consistent with very
small resonances, which were visible in the 13C NMR
spectra.
R1
11
R1
Acknowledgements
We thank the EPSRC and GSK for financial support.
References and notes
1. Bew, S. P.; Knight, D. W. J. Chem. Soc., Chem. Commun. 1996, 1007–
1008; El-Taeb, G. M. M.; Evans, A. B.; Knight, D. W.; Jones, S.
Tetrahedron Lett. 2001, 42, 5945–5948; Bew, S. P.; El-Taeb, G. M. M.;
Jones, S.; Knight, D. W.; Tan, W.-F. Eur. J. Org. Chem. 2007, 5759–
5770.
2. Hayes, S. J.; Knight, D. W.; Menzies, M. D.; O’Halloran, M.; Tan, W.-
F. Tetrahedron. Lett 2007, 48, 7709–7712.
Dunford, Damian
