Scheme 1
.
Proposed Reaction of Lithiated Epoxides with
Boronic Esters
Table 1. Homologation of Boronic Esters Using Lithiated
Terminal Epoxides
entry
R
R1
yields [%] (product)
1
2
3
4
5
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
Et
76 (3a)
73 (3b)
83 (3c)
PhCH2CH2
c-Hex
c-Pr
Ph
Et
Et
86 (3d)
57 (3e)a
47 (3f)b
65 (3g)
6
7
CH2CH2CHCH2
i-Pr
However, Shimizu had previously reported that reactions
of ꢀ-CF3-substituted lithiated epoxides with boranes and
boronic esters gave the corresponding alkenes instead
(Scheme 2).6 Evidently, the intermediate ꢀ-alkoxyboronic
8
9
10
t-Bu
CH2OTBS
Et (R)
Et
Et
38 (3h)
54 (3i)
PhCH2CH2
70 (3j) (er 99:1)c
a 25% of 1-phenyl-1-hexene was also isolated. b The reaction was run
at 4 °C. c The enantiomeric ratio (er) was determined by chiral HPLC
(Chiralcel AD column).
Scheme 2
.
Shimizu’s Reactions of Lithiated Epoxides with
Boronic Esters
phile that is also compatible with LTMP.8 Brief optimization
of the stoichiometry of base and boronic ester, temperature,
and time provided a set of conditions under which a syn diol
was formed with complete diastereoselectivity and in good
yield (Table 1, entry 1).11 These conditions were applied to
a range of alkyl boronic esters and were found to be general
(Table 1, entries 1-5). Phenyl boronic acid pinacol ester
was also tested, but competing elimination was now observed
with this substrate, indicating that the ꢀ-alkoxyboronic ester
bearing an adjacent phenyl group is prone to elimination
(Table 1, entry 5).
A variety of aliphatic epoxides were also tested, including
the epoxide derived from glycidol (Table 1, entry 9), and
again single diastereomers were formed in all cases in
moderate to good yields (Table 1, entries 6-10). The use of
enantiopure l-butenoxide, easily accessible by Jacobsen
HKR12 and now commercially available, was also tested,
and as expected, the diol 3j was formed with complete
retention of enantiopurity (Table 1, entry 10).
ester (related to 2) is unstable and undergoes a rapid boron-
Wittig-type elimination.7 Related intermediates involving
boranes had previously been generated by reaction of
dimesitylboronmethyl lithium with aldehydes and ketones,
which led to alkenes, alcohols, or diols depending on the
reaction conditions and nature of the subsituents.8 This
ominous literature precedent made us embark on our own
studies with a degree of trepidation.
We began our studies using the simple Hodgson protocol9
for the generation of lithiated epoxides using LTMP and a
terminal epoxide with in situ trapping of ethyl boronic acid
pinacol ester, an electrophile that we expected to be
compatible with LTMP.10 This protocol has been limited to
the trapping of lithiated epoxides with TMSCl, an electro-
The perfect diasterocontrol observed is in keeping with
the mechanism shown in Scheme 1 in which the initial
lithiation occurs trans to the epoxide substituent.9,13 Trapping
(6) (a) Shimizu, M.; Fujimoto, T.; Minezaki, H.; Hata, T.; Hiyama, T.
J. Am. Chem. Soc. 2001, 123, 6947–6948. (b) Shimizu, M.; Fujimoto, T.;
Liu, X.; Minezaki, H.; Hata, T.; Hiyama, T. Tetrahedron 2003, 59, 9811–
9823.
(10) In situ trapping is necessary since the lithiated epoxide is thermally
unstable. See ref 8.
(11) General Procedure for the Homologation of Boronate with
Epoxides Leading to Diols 3. A 10-mL Schlenk tube was charged with
the corresponding epoxide (0.50 mmol) and boronate (1.00 mmol, 1.00 M
in THF). The resulting solution was thereafter cooled to -30 °C followed
by dropwise addition of freshly prepared lithium 2,2,6,6-tetramethylpip-
eridide (1.00 mmol). The reaction mixture was then stirred for 2 h at -30
°C at which time the reaction flask was transferred to an ice bath and NaOH
(1.0 mL, 2.0 M) and H2O2 (0.50 mL, >30% w/v) were added. The reaction
mixture was stirred an additional 2 h at 4 °C and was then diluted with
H2O (5 mL) and extracted with DCM (4 × 7 mL). The combined organic
layer was dried over magnesium sulphate. The organic solvents were then
removed, and the crude product was subjected to silica gel flash chroma-
tography.
(7) Related reactions with R3Al or R2Zn also furnish alkenes. See: (a)
Ukaji, Y.; Fujisawa, T. Tetrahedron Lett. 1988, 29, 5165–5168. (b)
Taniguchi, M.; Oshima, K.; Utimoto, K. Tetrahedron Lett. 1991, 32, 2783–
2786. (c) Kasatkin, A. N.; Whitby, R. J. Tetrahedron Lett. 2000, 41, 5275–
5280. (d) Tanigushi, M.; Oshima, K.; Utimoto, K. Tetrahedron Lett. 2000,
41, 6201–6205.
(8) (a) Pelter, A.; Singaram, B.; Wilson, J. W. Tetrahedron Lett. 1983,
24, 635–636. (b) Pelter, A.; Buss, D.; Pitchford, A. Tetrahedron Lett. 1985,
41, 5093–5096. (c) Kawashima, T.; Yamashita, N.; Okazaki, R. J. Am.
Chem. Soc. 1995, 117, 6142–6143. (d) Pelter, A.; Peverall, S.; Pitchford,
A. Tetrahedron 1996, 52, 1085–1094.
(9) Hodgson, D. M.; Reynold, N. J.; Coote, S. J. Tetrahedron Lett. 2002,
43, 7895–7897.
(12) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N. Science
1997, 277, 936–938.
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Org. Lett., Vol. 11, No. 1, 2009