Group-selective hydroalumination: A novel route to stereogenic tert-alcohol centers

Article abstract of DOI:10.1021/ol0156704

(matrix presented) A new group-selective reaction is described, that is, the hydroalumination of bis-alkynyl alcohols armed with an adjacent stereogenic center, giving stereo-defined tert-alcohols of potential utility in natural product synthesis.

Full text of DOI:10.1021/ol0156704

ORGANIC
LETTERS
2001
Vol. 3, No. 7
1057-1060
Group-Selective Hydroalumination: A
Novel Route to Stereogenic tert-Alcohol
Centers
Ken Ohmori, Takao Suzuki, Kimiko Taya, Daisuke Tanabe, Toshihiro Ohta, 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
ksuzuki@chem.titech.ac.jp
Received February 6, 2001
ABSTRACT
A new group-selective reaction is described, that is, the hydroalumination of bis-alkynyl alcohols armed with an adjacent stereogenic center,
giving stereo-defined tert-alcohols of potential utility in natural product synthesis.
We report herein a new group-selective reaction1 which
provides us access to a class of stereo-defined tert-alcohols,
e.g., 1-3, with potential utility in natural product synthesis.
1-hexynyl groups reacted predominantly, giving, after depro-
tection, the diol 5a in favor of 5b.6
With no obvious rationale available, we undertook a
systematic study on the structure-selectivity relationship,7
Our interest in this topic traces back to a small, unexpected
finding in our previous project shown in eq 1.2 The reaction
of bis-alkynyl alcohol 43 with LiAlH4 4,5 stopped at the mono-
hydroalumination stage, and amazingly, one of the two
(4) For the hydroalumination reaction of propargyl alcohols, see: (a)
Attenburrow, J.; Cameron, A. F. B.; Chapman, J. H.; Evans, R. M.; Hems,
B. A.; Jansen, A. B. A.; Walker, T. J. Chem. Soc. 1952, 1094-1111. (b)
Jorgenson, M. J. Tetrahedron Lett. 1962, 13, 559-562. (c) Corey, E. J.;
Katzenellenbogen, J. A.; Posner, G. A. J. Am. Chem. Soc. 1967, 89, 4245-
4247. (d) Corey, E. J.; Katzenellenbogen, J. A.; Gilman, N. W.; Roman, S.
A.; Erickson, B. W. J. Am. Chem. Soc. 1968, 90, 5618-5620. (e) Corey,
E. J.; Kirst, H. A.; Katzenellenbogen, J. A. J. Am. Chem. Soc. 1970, 92,
6314-6319. (f) Semmelhack, M. F.; Wu, E. S. C. J. Am. Chem. Soc. 1976,
98, 3384-3386. (g) Rollinson, S. W.; Amos, R. A.; Katzenellenbogen, J.
A. J. Am. Chem. Soc. 1981, 103, 4114-4125. (h) Denmark, S. E.; Jones,
T. K. J. Org. Chem. 1982, 47, 4595-4597. For the mechanism of
hydroalumination, see: (i) Franzus, B.; Snyder, E. I. J. Am. Chem. Soc.
1965, 87, 3423-3429. (j) Snyder, E. I. J. Org. Chem. 1967, 32, 3531-
3534. (k) Borden, W. T. J. Am. Chem. Soc. 1970, 92, 4898-4901. (l) Grant,
B.; Djerassi, C. J. Org. Chem. 1974, 39, 968-970. (m) Kakinuma, K.;
Matsuzawa, T.; Eguchi, T. Tetrahedron 1991, 47, 6975-6982.
(1) For selected examples of group-selective reactions, see: (a) Curran,
D. P.; Qi, H.; DeMello, N. C.; Lin, C.-H. J. Am. Chem. Soc. 1994, 116,
8430-8431. (b) Curran, D. P.; Geib, S. J.; Lin, C.-H. Tetrahedron:
Asymmetry 1994, 5, 199-202. (c) Wipf, P.; Kim, Y. Tetrahedron Lett. 1992,
33, 5477-5480. (d) Harada, T.; Wada, I.; Uchimura, J.; Inoue, A.; Tanaka,
S.; Oku, A. Tetrahedron Lett. 1991, 32, 1219-1222 (e) Schreiber, S. L.;
Schreiber, T. S.; Smith, D. B. J. Am. Chem. Soc. 1987, 109, 1525-1529.
(f) Schreiber, S. L.; Wang, Z. J. Am. Chem. Soc. 1985, 107, 5303-5305.
(g) Waldmann, H. Organic Synthesis Highlights II; VCH: New York; pp
203-222, and the references therein.
(2) Nagasawa, T.; Taya, K.; Kitamura, M.; Suzuki, K. J. Am. Chem.
Soc. 1996, 118, 8949-8950.
(3) Easily prepared from the corresponding ester derivative by treatment
with 2.5 equiv of alkynyllithium.
10.1021/ol0156704 CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/10/2001

which has now allowed us to propose a working model for
explaining and predicting the group selectivity.
tion; tert-butyl ether gave a single product (run 5), which
stands in contrast to a nonselective reaction with the methyl
ether (run 4). (3) As the countercation, lithium is essential.
The group selectivity decreased substantially when NaAlH4
was used instead of LiAlH4 (Table 2; cf. Table 1, run 3).
Three experimental results served as the basis for working
out the model: (1) The presence of an R-alkoxy group is
essential for the selectivity as well as the reactivity: the non-
alkoxy substrate 6 underwent a very slow, nonselective
reaction to give a poor yield of 7 as a 1/1 mixture of
diastereomers (eq 2). (2) A bulky R-alkoxy group is
Table 2
preferable. While a MOM group led to poor selectivity (Table
1, run 1; cf. run 2 ) eq 1), a bulky protecting group such as
a Determined by 1H NMR. b The starting material was recovered (35%).
Table 17
Also, a coordinating cosolvent, HMPA, reduced the selectiv-
ity, accompanied by a substantial decrease of the reaction
rate.
On the basis of these data, we now propose a working
model to explain this reaction as shown in Figure 1. Primarily
a Determined by 1H NMR. b After removal of the EE group, ratios of
1
the diastereomers were assessed by H NMR.
1-methyl-1-methoxyethyl (MME; run 3) led to high group
selectivity. The same trend applied to the ether-type protec-
(5) For a review of the hydroalumination reaction, see: Zweifel, G;
Miller, J. A. Org. React. 1984, 32, 375-517.
(6) Experimental procedure for the hydroalumination of 4 with
LiAlH4: To a solution of LiAlH4 (35.0 mg, 0.922 mmol) in THF (2.0 mL)
was slowly added a solution of 4 (212 mg, 0.688 mmol) in THF (2.0 mL)
at 0 °C. After stirring at 25 °C for 1.3 h, the reaction was stopped by adding
saturated aqueous Na2SO4 and the products were extracted with EtOAc
(3×). The combined extracts were washed with brine, dried (Na2SO4), and
concentrated in vacuo. To a solution of the crude product in MeOH (9.0
mL) was added a catalytic amount of PPTS. After stirring for 0.5 h, the
reaction was stopped by adding saturated aqueous NaHCO3, and the products
were extracted with EtOAc (3×). The combined extracts were washed with
brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified
by flash column chromatography (SiO2, hexane/EtOAc ) 80/20) to give 5
(131 mg, 80%, 5a/5b ) 88/12) as colorless oil.
Figure 1.
considered is a five-membered lithium chelate formed by
the coordination of the Li-alkoxide to the R-alkoxy group.
The group selection could be explained by the steric
interaction of the substituents, which is nicely illustrated by
a “space-filling model” with the views from three angles
(front, side, and top). The alternate filling of the octant spaces
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Org. Lett., Vol. 3, No. 7, 2001

by the methyl group (blue), the R-alkoxy protecting group
(R, green), and the aluminate (red) as shown and the alkynyl
group in the vicinity of the aluminate is selectively hydroalu-
minated (see arrows). The necessary steric bulkiness of the
R-alkoxy protecting group (R) for attaining a high selectivity
is consistent with this view.
While examining the validity of this model for various
related substrates, a puzzling observation was made upon
application to the glycerate-derived substrate 8 (eq 3).3
Though the reaction proceeded also in high selectivity, the
Figure 2.
Upon carrying out the reaction of 8 by first converting it
to the corresponding lithium alkoxide followed by treatment
with DIBAL (eq 6, Scheme 1), the product 9b was obtained
Scheme 1
sense of the group selection was opposite to that of the
lactate-derived cases (cf. the examples in Table 1). Note that
the reacting alkynyl group is anti to the R-alkoxy group in
8 with the zigzag representation shown, while the syn-alkynyl
group preferentially reacted in the former lactate-derived
cases. The importance of the R-oxygen, rather than the
â-oxygen, was proven by the comparison experiments by
using two related substrates 10 and 12, in which the â- and
R-oxygen in 8 were replaced by a methylene, respectively.
While a high group selectivity was attained for 10 (eq 4)
with the same sense as in the case of 8 (see eq 3), a
significant decrease of the selectivity was noted for the
substrate 12 lacking the R-oxygen (eq 5).
With significance of the R-oxygen in mind, the apparent
changeover of the sense of group selectivity could be
explained again by the space-filling model shown in Figure
2. In the present Li-chelate for the glycerate derivative, the
cyclic nature of the substituents (blue and green) demands
both octant spaces be filled on one side, thereby locating
the aluminate (red) to the opposite side (cf. Figure 1).
as the sole diastereomer within the limit of detection by high-
field NMR (400 MHz).8 Indeed, as shown in Figure 3, the
increased steric bulkiness reinforced the group selectivity up
to an almost perfect level.
Furthermore, the alkenyl aluminate intermediate in this
reaction could be used for the selective manipulation. For
One important logical consequence of this working model
was the assumption that, if we employed the bulkier
Al-ligands, we could expect a higher group selectiVity, which
proVed indeed to be the case.
(7) All new compounds were fully characterized by spectroscopic means
and combustion analysis. The diastereomer ratios of the products were
determined by NMR (400 MHz) analysis. Stereochemical assignments were
based on extensive correlation studies.
Figure 3.
Org. Lett., Vol. 3, No. 7, 2001
1059

Furthermore, the hydroalumination reaction proved to be
reiterative, thereby enabling the creation of two consecutive
tert-alcohol centers as in 3 (Scheme 2). After the tert-
hydroxyl group in 9b was protected by a benzyl group,
ozonolysis in methanol9 gave the ester 14 (R = Me). After
two 1-hexynyl groups were installed into 14 to give the
alcohol 15, the treatment with n-BuLi and DIBAL in THF
gave the enynyl alcohol 3 again in an almost perfect group
selectivity.
Scheme 2a
Such a compound as 3 with two consecutive tert-alcohol
centers would be valuable in the total synthesis of natural
products, e.g., zaragozic acids10,11 and the cinatorins.12 Further
work is now in progress in our laboratories.
OL0156704
(8) Typical hydroalumination procedure with n-BuLi and DIBAL:
To a solution of 8 (1.00 g, 3.43 mmol) in THF (14.0 mL) was added n-BuLi
(2.60 M hexane solution, 1.58 mL, 4.11 mmol) at -78 °C. After stirring
for 30 min, to this solution was added DIBAL (2.83 M hexane solution,
1.52 mL, 4.30 mmol) at this temperature. The reaction mixture was gradually
warmed to 0 °C, and the stirring was continued for 2.5 h. After quenching
by addition of saturated aqueous potassium sodium tartrate and extracting
with Et2O (5×), the combined organic extracts were washed with brine,
dried (Na2SO4), and concentrated in vacuo. The residue was purified by
flash column chromatography (SiO2, hexane/EtOAc ) 85/15) to afford 9b
(948 mg, 94%) as a colorless oil.
a (a) BnBr, n-Bu4NI, NaH, THF, 0 f 25 °C, 16 h (95%); (b)
O3, NaOH (8 equiv), MeOH, CH2Cl2, -78 °C, 2 h (77%); (c)
1-hexyne (3.0 equiv), n-BuLi (2.7 equiv), THF, -78 f 0 °C, 1 h
(91%); (d) n-BuLi (1.2 equiv), DIBAL (1.3 equiv), THF, -78 f
0 °C, 2.5 h (89%, 99%, ds); DIBAL ) diisobutylaluminum
hydride.
(9) Marshall, J. A.; Garofalo, A. W.; Sedrani, R. C. Synlett 1992, 643-
645.
(10) Santini, C.; Ball, R. G.; Berger, G. D. J. Org. Chem. 1994, 59,
2261-2266, and references therein.
(11) Recently, a report has appeared on the total synthesis of zaragozic
acid A which employs a related hydroalumination reaction. However,
different alkynyl groups were used, and the mechanism for the selection is
different (personal communication from Dr. Tomooka): Tomooka, K;
Kikuchi, M.; Igawa, K.; Suzuki, M.; Keong, P-.H.; Nakai, T. Angew. Chem.,
Int. Ed. 2000, 39, 4502-4505.
example, upon quenching the hydroalumination reaction of
8 by ethyl acetate (to decompose excess hydride) followed
by treatment with I2,4e-g the vinyl iodide 13 was obtained
as a sole product (eq 7, Scheme 1).
(12) Itazaki, H.; Nagashima, K.; Kawamura, Y.; Matsumoto, K.; Nakai,
H.; Terui, Y. J. Antibiot. 1992, 45, 38-49.
1060
Org. Lett., Vol. 3, No. 7, 2001