Stereogenic tert-alcohols via group-selective hydroalumination: Further scope

Article abstract of DOI:10.1016/S0040-4039(01)02250-X

Two classes of bis-alkynyl alcohols were subjected to hydroalumination reaction, which, under suitable conditions, proceeded in a highly group-selective manner.

Full text of DOI:10.1016/S0040-4039(01)02250-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1031–1034
Stereogenic tert-alcohols via group-selective hydroalumination:
further scope
Ken Ohmori, Yoshifumi Hachisu, Takao Suzuki and Keisuke Suzuki*
Department of Chemistry, Tokyo Institute of Technology, and CREST, Japan Science and Technology Corporation (JST),
O-okayama, Meguro-ku, Tokyo 152-8551, Japan
Received 22 October 2001; revised 19 November 2001; accepted 22 November 2001
Abstract—Two classes of bis-alkynyl alcohols were subjected to hydroalumination reaction, which, under suitable conditions,
proceeded in a highly group-selective manner. © 2002 Elsevier Science Ltd. All rights reserved.
Previous reports from this laboratory have described
the group-selective hydroalumination of bis-alkynyl
alcohols possessing an adjacent chiral center.1 Eq. (1) is
illustrative, where one of the diastereotopic alkynyl
groups in 1 undergoes reduction upon treatment with
LiAlH4 (protocol A). The selectivity was further
improved by increasing the steric bulk of the aluminum
ligands (see protocol B by using n-BuLi–DIBAL),
thereby giving 2 as the sole product.1
Starting materials 3 and 4 were prepared from the
known compound 72 derived from (R,R)-tartaric acid
(Scheme 2), and substrates 5 and 6 were obtained from
the (S)-malic acid derivative 103 (Scheme 3).
(1)
In an effort to explore the scope and limitations of this
process, we examined the group-selective hydroalumi-
nation of various related bis-alkynyl alcohols. Two
classes of substrates have been tested (Scheme 1), which
differ from 1 in (A) the substituent at the dioxolane
moiety (3 and 4) and (B) the ring size, that is, the
dioxanes 5 and 6. Under suitable conditions, high
group selectivities were attained for the reaction of
these bis-alkynyl alcohols, which will be described in
this communication.
Scheme 1.
Scheme 2. (a) TBDPSCl, imidazole, DMF, 90%; (b) MOMCl,
i-Pr2NEt, CH2Cl2, 89%; (c) n-BuCꢀCH, n-BuLi, THF, 91%
for 3 and 93% for 4. TBDPS=t-butyldiphenylsilyl, MOM=
methoxymethyl.
Keywords: hydroalumination; group selectivity; chelation.
* Corresponding author. Tel.: +81-3-5734-2228; fax: +81-3-5734-2228;
e-mail: ksuzuki@chem.titech.ac.jp
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02250-X

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K. Ohmori et al. / Tetrahedron Letters 43 (2002) 1031–1034
Scheme 3. (a) 2-Methoxypropene, PPTS, acetone, 84% or
Ph2C(OMe)2, p-TsOH, benzene, 74%; (b) n-BuCꢀCH,
EtMgBr, THF, 92% for 5 and 79% for 6. PPTS=pyridinium
p-toluenesulfonate.
Figure 1.
Table 1 summarizes the reactions of the tartaric acid-
derived substrates 3 and 4. Treatment of 3, possessing a
t-butyldiphenylsilyl (TBDPS) group, with LiAlH4
(added at −78°C, and warmed immediately to 0°C
followed by stirring for 1 h) afforded the corresponding
mono-hydroalumination product 11 with high group
In line with this view, the silyl protecting group in 3
could be replaced by a chelating group, such as a
MOM group without loss of the group selectivity.
Thus, upon treatment of 4 with LiAlH4 under essen-
tially the same conditions as those for run 1, the
hydroalumination proceeded with high group selectivity
(92%) to give the enynyl alcohol 12 (run 3).7 Again, the
selectivity was reinforced to a near perfect level by
employing the n-BuLi–DIBAL procedure (run 4). The
improved selectivity with the n-BuLi–DIBAL protocol
(runs 2 and 4) may stem from the increased steric bulk
of the aluminum ligands.1
5
selectivity (run 1).4 In terms of the mode of group
selection, the alkynyl group anti to the adjacent oxygen
reacted, as had been the case with the substrate 1
without the siloxymethyl substituent (vide supra, Eq.
(1)). The selectivity was further improved by using the
n-BuLi–DIBAL procedure (run 2).
Although the reactivity was inferior with the latter
protocol in that some starting material remained
unchanged, the product 11 was obtained as a single
isomer.
The hydroalumination of malic acid-derived substrates
5, having a 1,3-dioxane ring, are summarized in Table
2.
In contrast to the dioxolane cases, the dioxane sub-
strate 5 reacted with LiAlH4 in a non-selective manner,
thereby giving a 55/45 mixture of 13 and epi-13 (run 1).
The n-BuLi–DIBAL procedure proceeded with some-
what better group selectivity to give a 73/27 mixture of
13 and epi-13 (run 2). Importantly, however, the sense
of group selection was opposite to that of previous
The group selectivity is explained by the ‘space-filling
model’ (Fig. 1), which we previously proposed for the
simpler cases without the additional substituent (Eq.
(1); vide supra).1 Since the siloxymethyl substituent
(yellow) fills the space that is remote from the reaction
site, it poses little, if any, influence on the reaction
course.6
Table 1.
Run
R
Conditions
Time (h)c
Yield (%)
Group selectivity
a
1
2
3
4
TBDPS
TBDPS
MOM
LiAlH4
1
5
1.5
4.5
94
95/5
\99/B1
92/8
n-BuLi, DIBALb
84d
92
a
LiAlH4
MOM
n-BuLi, DIBALb
83e
\99/B1
a LiAlH4 (2.0 mol equiv.).
b n-BuLi (1.2 equiv.), DIBAL (1.3 equiv.).
c Reaction time at 0°C.
d Recovery of 3 (12%).
e Recovery of 4 (14%).
TBDPS=t-butyldiphenylsilyl, MOM=methoxymethyl.

K. Ohmori et al. / Tetrahedron Letters 43 (2002) 1031–1034
1033
Table 2.
Run Reagents
Time (h)c
Yield (%)
13/epi-13
a
1
2
LiAlH4
n-BuLi,
DIBALb
2
18
87d
83d
55/45
73/27
a LiAlH4 (2.0 mol equiv.).
b n-BuLi (1.2 equiv.), DIBAL (1.3 equiv.).
c Reaction time at 0°C.
Figure 2.
Table 3.
d Recovery of 5 [5% (run 1), 11% (run 2)].
dioxolane cases (cf. Eq. (1)). Indeed, the alkynyl group
syn to the adjacent oxygen took part in the reaction in
this case, whereas the one anti to the adjacent oxygen
underwent the hydroalumination in the dioxolane
cases.
This apparent reversal of the reaction mode could be
explained again by the space-filling model as shown in
Fig. 2A. The important difference from the dioxolane
case (cf. Fig. 2B) is that the location of the isopropyli-
dene that directs the placement of the aluminate, and
thus, the preferred alkynyl group becomes different, if
not exclusive, that undergoes the hydroalumination.
Run Reagents
Time (h)d
4
Yield (%)
13/epi-13
1
2
3
NaH, DIBALa
64e
75e
56e
44/56
43/57
5/95
KH, DIBALb 3.5
EtMgBr,
6
This model suggested that the selectivity would be
improved, if the steric demand of the acetal moiety was
increased. Indeed, the attempted reaction of the
diphenylmethylidene acetal 6 afforded the enynyl alco-
hol 14 as the exclusive product (Eq. (2)).7
DIBALc
a NaH (1.2 equiv.), DIBAL (1.3 equiv.).
b KH (1.2 equiv.), DIBAL (1.3 equiv.).
c EtMgBr (1.2 equiv.), DIBAL (1.3 equiv.).
d Reaction time at 0°C.
e Recovery of 5 [18% (run 1), 20% (run 2), 36% (run 3)].
(2)
References
1. (a) Ohmori, K.; Suzuki, T.; Taya, K.; Tanabe, D.; Ohta,
T.; Suzuki, K. Org. Lett 2001, 3, 1057; (b) Suzuki, T.;
Ohmori, K.; Suzuki, K. Org. Lett 2001, 3, 1741.
2. (a) Musich, J. A.; Rapoport, H. J. Am. Chem. Soc. 1978,
100, 4865; (b) Ortuno, R. M.; Alonso, D.; Font, J. Tetra-
hedron Lett. 1986, 27, 1079.
3. (a) Miller, M. J.; Bajwa, J. S.; Mattingly, P. G.; Peterson,
K. J. Org. Chem. 1982, 47, 4928; (b) Arce, G. S. E.;
Bauder, C.; Carreno, M. C. J. Org. Chem. 1998, 63, 2332.
4. All new compounds were fully characterized by spectro-
scopic means. The diastereomer ratios of the products
were determined by NMR (500 MHz) analysis. Stereo-
chemical assignments were based on extensive correlation
studies.
Further study showed that the selectivity is highly
dependent on the countercation of the reducing agent
(Table 3). Na+ and K+ gave poor selectivities (runs 1
and 2), which strongly suggested the importance of the
chelation effect in the group selectivity. A surprising
finding along these lines was that the magnesium alkoxide
led to the opposite group selection, thereby giving epi-13
in high selectivity (run 3). This suggests that a dual
approach to stereoisomeric tert-alcohols such as 13 and
epi-13 in high selectivity is possible. We are currently
studying the improvement of the yield as well as the
rationale for the reversal of the group selectivity.

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K. Ohmori et al. / Tetrahedron Letters 43 (2002) 1031–1034
1
5. Experimental procedure for the hydroalumination of 3 with
LiAlH4: To a solution of LiAlH4 (28.2 mg, 0.743 mmol) in
THF (0.5 mL) was added 3 (208 mg, 0.371 mmol) in THF
(1.9 mL) at −78°C. The temperature was raised to 0°C,
and stirring was continued for 1 h. The reaction was
stopped by adding Na2SO4·10H2O. After stirring for 3 h at
room temperature, white solid was filtered off and washed
with EtOAc. The filtrate was concentrated in vacuo. The
residue was purified by flash column chromatography
(SiO2, hexane/acetone/EtOAc=91/3/6) to afford the mix-
ture of 11 and epi-11 (196 mg, 94%, 11/epi-11=95/5) as
colorless oil.
705, 615 cm−1; H NMR (300 MHz, CDCl3) l 0.87 (t, 6H,
J=6.9 Hz), 1.06 (s, 9H), 1.28–1.44 (m, 8H), 1.49 (s, 3H),
1.50 (s, 3H), 1.93–2.06 (m, 2H), 2.17 (t, 2H, J=6.9 Hz),
2.75 (s, 1H), 3.65 (dd, 1H, J=11.1, 3.6 Hz), 3.91 (dd, 1H,
J=11.1, 2.1 Hz), 4.12–4.19 (m, 2H), 5.46 (d, 1H, J=15.3
Hz), 6.04 (dt, 1H, J=15.3, 6.9 Hz), 7.33–7.46 (m, 6H),
7.68–7.73 (m, 4H); 13C NMR (75 MHz, CDCl3) l 13.5,
13.9, 18.4, 19.3, 22.0, 22.3, 26.8, 27.3, 27.6, 30.5, 31.1, 31.6,
64.0, 71.9, 78.4, 79.1, 81.5, 88.2, 109.7, 127.6, 129.5, 129.6,
129.7, 133.2, 133.3, 133.9, 135.7; Anal. calcd for
C35H50O4Si: C, 74.68; H, 8.95. Found: C, 74.59; H, 9.24.
6. In our previous experiences (Ref. 1a), the silyloxy group, if
proximal to reaction site, was labile under these reaction
conditions. Desilylation was the major event observed.
7. Experimental procedure for the hydroalumination of 5 with
EtMgBr and DIBAL; To a solution of 5 (165 mg, 0.538
mmol) in THF (2.0 mL) was added EtMgBr (1.7 M
hexane, 0.38 mL, 0.65 mmol) at 0°C, and the mixture was
stirred for 1 h at 25°C. After cooling to −78°C, to the
resulting solution was added DIBAL (2.9 M hexane, 0.24
mL, 0.70 mmol), and stirring was continued for 15 min.
The temperature was raised to 0°C, and stirring was
continued for 6 h. The reaction was stopped by adding
aqueous potassium sodium tartrate, after stirring for 10 h
at room temperature, the products were extracted with
EtOAc (×3). The combined organic extracts were washed
with brine, dried (Na2SO4) and concentrated in vacuo. The
residue was purified by flash column chromatography
(hexane/acetone=95/5) to afford the mixture of 13 and
epi-13 (93.2 mg, 56%) as colorless oil.
Experimental procedure for the hydroalumination of 3 with
n-BuLi and DIBAL: To a solution of 3 (263 mg, 0.469
mmol) in THF (1.9 mL) was added n-BuLi (0.22 mL, 2.6
M hexane solution, 0.57 mmol) at −78°C, and the mixture
was stirred for 30 min. To the resulting solution was added
DIBAL (0.22 mL 2.9 M hexane solution, 0.65 mmol), and
stirring was continued for 30 min. The temperature was
raised to 0°C, and stirring was continued for 6.5 h. The
reaction was stopped by adding aqueous potassium
sodium tartrate. After stirring for 10 h at room tempera-
ture, the products were extracted with EtOAc (×3). The
combined organic extracts were washed with brine, dried
(Na2SO4) and concentrated in vacuo. The residue was
purified by flash column chromatography (SiO2, hexane/
acetone/EtOAc=95/3/2) to afford 11 (223 mg, 84%, >99%
d.s.) with a recovery of 3 (31 mg, 12%). 11 (colorless oil):
[h]2D8=−39 (c 1.0, CHCl3); IR (neat) 3455, 2930, 2860,
2240, 1590, 1430, 1380, 1245, 1215, 1115, 975, 825, 740,