Highly enantioselective synthesis induced by chiral primary alcohols due to deuterium substitution [8]

Full text of DOI:10.1021/ja002992e

J. Am. Chem. Soc. 2000, 122, 11739-11740
11739
Scheme 1. Enantioselective Addition of Diisopropylzinc to
Aldehyde 5 Using Chiral R-Deuterated Alkohols as Chiral
Inducers
Highly Enantioselective Synthesis Induced by Chiral
Primary Alcohols Due to Deuterium Substitution
Itaru Sato, Daisuke Omiya, Takahiro Saito, and Kenso Soai*
Department of Applied Chemistry
Faculty of Science, Science UniVersity of Tokyo
Kagurazaka, Shinjuku-ku, Tokyo, 162-8601 Japan
ReceiVed August 11, 2000
Steric isotope effects have attracted considerable attention.1 For
example, a structural steric isotope effect in deuterated tetracyano-
anthraquinodimethane,2a conformational kinetic isotope effects in
the racemization of a 9,10-dihydrophenanthrene derivative2b and
in the flipping of [2.2]metaparacyclophanes,2c and a steric isotope
effect in the reduction of a 4-piperidone derivative have been
reported.2d
Chiral compounds whose chirality is due to the replacement
of hydrogen by deuterium are important from the standpoint of
organic stereochemistry and biochemistry.3 The chirality of these
enantiomers is mainly due to the very small difference between
the lengths of carbon-deuterium and carbon-hydrogen bonds;
the time-averaged carbon-deuterium bond length (0.1099 nm)
is shorter than the carbon-hydrogen bond by only 0.0004 nm.4
Thus, unlike other usual enantiomers whose chirality is due to
the difference in the number of protons in the atomic nucleus,
these isotopic enantiomers are considered to show only very small
differences in asymmetric reactions and recognition. In fact,
isotopic enantiomers were only quite recently separated analyti-
cally using HPLC with a chiral stationary phase (csp).5
On the other hand, despite the recent advances in asymmetric
catalysis,6 it is unclear whether any isotopic enantiomer can act
as a chiral inducer in highly enantioselective synthesis. The
enantioselectivities that have been reported so far in asymmetric
synthesis7 and kinetic resolution8 induced by isotopic enantiomers
have been extremely low. Enantioselective addition of MeOH to
a ketene in the presence of a chiral deuterated quinuclidine
derivative gave a product with an optical purity of only 0.13%
based on the optical rotation, and only one enantiomer of the
chiral inducer was investigated.7 Kinetic resolution of racemic
R-phenylbutyric anhydride with enantiomerically deuterated al-
cohols gives, after hydrolysis, R-phenylbutyric acid with an optical
purity of only 0.1-0.6%.8 Thus, highly enantioselective synthesis
induced by isotopic enantiomers is a challenging problem.
We report here an unprecedented highly enantioselective
synthesis of a chiral compound induced by the isotopic enantiomer
of primary alcohol-R-d.
2-(tert-Butylethynyl)pyrimidine-5-carbaldehyde 59 was reacted
with diisopropylzinc (i-Pr2Zn) in the presence of chiral deuterated
alcohol (Scheme 1).10 The results are shown in Table 1. When
aldehyde 5 was reacted with i-Pr2Zn in the presence of chiral
(S)-benzyl alcohol-R-d 1 (>95% ee, 1.6 mol % against the total
amount of aldehyde 5) and aldehyde 5 and i-Pr2Zn were
successively added in three portions, (R)-2-pyrimidyl alkanol 6
with 96% ee was obtained in an isolated yield of 95% (Method
A-1, Table 1, run 1). On the other hand, in the presence of (R)-1
(>95% ee) instead of (S)-1, (S)-2-pyrimidyl alkanol 6 with 95%
ee was obtained in 98% yield (run 2). Thus, (S)- and (R)-benzyl
alcohol-R-d 1 acted as chiral inducers to give (R)- and (S)-
pyrimidyl alkanol 6 with high ee’s, respectively.
* To whom correspondence should be addressed. Fax: 81-3-3235-2214.
E-mail: ksoai@ch.kagu.sut.ac.jp.
(1) Review: Carter, R. E.; Melander, L. AdV. Phys. Org. Chem. 1973, 10,
1-27.
Even in the presence of a decreased amount of (S)- or (R)-1
(0.5 mol % relative to the total amount of 5), (R)-6 and (S)-6
with 93% ee were obtained in isolated yields of 98 and 95%,
respectively (Method A-2, runs 3 and 4). Thus, the (S)- and (R)-
enantiomers of 1 based on the substitution of hydrogen with
deuterium act as chiral inducers in the highly enantioselective
addition of i-Pr2Zn to pyrimidine-5-carbaldehyde 5.
(2) (a) Heimer, N. E.; Mattern, D. L. J. Am. Chem. Soc. 1993, 115, 2217-
2220. (b) Mislow, K.; Graeve, R.; Gordon, A. J.; Wahl, G. H., Jr. J. Am.
Chem. Soc. 1964, 86, 1733-1741. (c) Sherrod, S. A.; da Costa, R. L.; Barnes,
R. A.; Boekelheide, V. J. Am. Chem. Soc. 1974, 96, 1565-1577. (d) Durand,
R.; Geneste, P.; Lamaty, G.; Roque, J. P. Tetrahedron Lett. 1977, 199-200.
(3) (a) Arigoni, D.; Eliel, E. L. Top. Stereochem. 1969, 4, 127-243. (b)
Verbit, L. Prog. Phys. Org. Chem. 1970, 7, 51-127.
(4) (a) Bartell, L. S.; Roth, E. A.; Hollowell, C. D.; Kuchitsu, K.; Young,
J. E., Jr. J. Chem. Phys. 1965, 42, 2683-2686. (b) Bartell, L. S.; Roskos, R.
R. J. Chem. Phys. 1966, 44, 457-463.
(5) (a) Kimata, K.; Kobayashi, M.; Hosoya, K.; Araki, T.; Tanaka, N. J.
Am. Chem. Soc. 1996, 118, 759-762. (b) Pirkle, W. H.; Gan, K. Z.
Tetrahedron: Asymmetry 1997, 8, 811-814.
(9) Shibata, T.; Yonekubo, S.; Soai, K. Angew. Chem., Int. Ed. 1999, 38,
659-661.
(10) (S)-Alcohols-R-d 1-4 were synthesized by enantioselective reduction
of the corresponding aldehydes-1-d using (R)-2-methyl-CBS-oxazaborolidine
[Corey, E. J.; Link, J. O. Tetrahedron Lett. 1989, 30, 6275-6278]. (R)-
Alcohols were prepared by Mitsunobu inversion of the resulting (S)-alcohols
[Mitsunobu, O. Synthesis 1981, 1-28]. The ee’s of (S)- and (R)-alcohols were
determined to be >95% by NMR analyses of their (S)-(-)-R-methoxy-R-
(trifluoromethyl)phenylacetic acid (MTPA) esters. Absolute configurations of
2-4 were assigned by analogy to 1.
(6) (a) ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer-Verlag: Berlin, 1999. (b) Catalytic Asymmetric
Synthesis, 2nd ed.; Ojima, I., Ed.; John Wiley: New York, 2000.
(7) Pracejus, H. Tetrahedron Lett. 1966, 3809-3813.
(8) (a) Horeau, A.; Nouaille, A.; Mislow, K. J. Am. Chem. Soc. 1965, 87,
4957-4958. (b) Horeau, A.; Nouaille, A. Tetrahedron Lett. 1966, 3953-
3959.
10.1021/ja002992e CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/10/2000

11740 J. Am. Chem. Soc., Vol. 122, No. 47, 2000
Communications to the Editor
Table 1. Enantioselective Synthesis of Pyrimidyl Alkanol 6 Using
Chiral R-Deuterated Alcohols as Chiral Inducers
ee, respectively (Method B, runs 6 and 7). The enantioselective
alkylation of 5 in the presence of (S)-2-naphthyl methanol 3 gave
enantiomerically enriched (R)-6 in 95% ee (run 7), while (S)-6
with 90-92% ee was obtained in the presence of (R)-3 (Methods
B and A-1, runs 8-10). Even (S)-3-phenylpropanol-R-d1 4, in
which the asymmetric carbon atom is not bonded to the aromatic
ring, acted as a chiral initiator to give (R)-6 with 94% ee in a
yield of 98% (run 11). On the other hand, (S)-6 with 92% ee was
obtained in 95% yield using (R)-4 (run 12).
Furthermore, (S)-benzyl alcohol-R-d1 1, with a moderate
enantiomeric excess of 56%, acts as a chiral initiator in the
enantioselective addition of i-Pr2Zn to the aldehyde 5, and
pyrimidyl alkanol (R)-6 with high ee (91%) was synthesized (run
5).
The very high enantiomeric excesses of the products in the
above asymmetric reactions induced by chiral primary alcohols-
R-d1 may be explained as follows: (1) Chiral (S)- or (R)-R-
deuterated alcohol readily forms chiral isopropylzinc alkoxide by
reacting with i-Pr2Zn. (2) The resulting isopropylzinc alkoxides
of chiral (S)- or (R)-R-deuterated alcohols 1-4 act as chiral
inducers in the enantioselective addition of i-Pr2Zn to aldehyde
5. (3) The isopropylzinc alkoxide of pyrimidyl alkanol with a
certain (small) ee forms, and possesses the corresponding absolute
configuration determined by the chiral inducer. (4) The ee of the
isopropylzinc alkoxide of pyrimidyl alkanol increases during
asymmetric autocatalysis,11,12 and workup gives (R)- or (S)-
pyrimidyl alkanol 6 with very high ee.
In summary, we have demonstrated a chemical process in which
a small isotopic chirality based on the replacement of hydrogen
in primary alcohols with deuterium induces chirality in the
enantioselective addition of i-Pr2Zn to pyrimidine-5-carbaldehyde
5 to afford pyrimidyl alkanol 6 with very high ee. We believe
that the present results are the first example of an isotopic chiral
effect leading to significantly high enantiomeric excesses in
enantioselective synthesis.13
pyrimidyl alkanol 6
chiral R-deuterated alcohol
isolated
ee (%)
runa
RCHDOH (ee (%))
methodb,c yield (%) (configuration)d
1
2
3
4
5
6
7
8
9
(S)-PhCHDOH 1 (>95)
(R)-1 (>95)
A-1
A-1
A-2
A-2
A-1
B
B
B
B
95
98
98
95
90
92
94
96
92
96
98
95
96 (R)
95 (S)
93 (R)
93 (S)
91 (R)
96 (R)
95 (S)
95 (R)
90 (S)
92 (S)
94 (R)
92 (S)
(S)-1 (>95)
(R)-1 (>95)
(S)-1 (56)
(S)-p-TolylCHDOH 2 (>95)
(R)-2 (>95)
(S)-2-NaphthylCHDOH 3 (>95)
(R)-3 (>95)
10 (R)-3 (>95)
11 (S)-PhCH2CH2CHDOH 4 (>95)
12 (R)-4 (>95)
A-1
A-1
A-1
a All of the experiments were reproducible. Reactions were carried
out at 0 °C. b Molar ratio of Method A-1 (aldehyde 5 and i-Pr2Zn were
added in four portions), chiral R-deuterated alcohol: aldehyde 5 (total
amount): i-Pr2Zn (total amount) ) 0.016:1.0:2.0; Method A-2 (aldehyde
5 and i-Pr2Zn were added in four portions), 0.0045:1.0:2.0; Method B
(aldehyde 5 and i-Pr2Zn were added in three portions), 0.047:1.0:2.5.
c Experimental procedure for Method A-2 (Table 1, run 3): To a
toluene solution (0.5 mL) of (S)-benzyl alcohol-R-d 1 (0.8 mg, 0.0075
mmol) was added a toluene solution (1.0 M) of i-Pr2Zn (0.075 mmol)
at 0 °C. A toluene (0.5 mL) solution of aldehyde 5 (4.7 mg, 0.025
mmol) was then added using a syringe at a rate of one drop per 30 s,
and the mixture was stirred for 12 h at 0 °C. Toluene (1.6 mL), i-Pr2Zn
(0.2 mmol, 0.2 mL of 1.0 M toluene solution), and a toluene solution
(1.0 mL) of aldehyde 5 (18.8 mg, 0.1 mmol) were added successively,
and the reaction mixture was stirred for 3.5 h. Toluene (7.2 mL), i-Pr2Zn
(0.8 mmol, 0.8 mL of 1. 0 M toluene solution), and a toluene (2.0 mL)
solution of aldehyde 5 (75.3 mg, 0.4 mmol) were then added
successively, and the mixture was stirred at 0 °C for another 2.5 h.
After the addition of toluene (22 mL), i-Pr2Zn (2.0 mmol, 2.0 mL of
1. 0 M toluene solution), and a toluene solution (5.0 mL) of aldehyde
5 (188 mg, 1.0 mmol), the mixture was stirred for 2 h. The reaction
was quenched with hydrochloric acid (1 M, 10 mL), and satd. aq.
sodium hydrogen carbonate (30 mL) was then added. The mixture was
filtered using Celite, and the filtrate was extracted with ethyl acetate.
The combined organic layers were dried over anhydrous sodium sulfate
and evaporated under reduced pressure. Purification of the residue by
silica gel thin-layer chromatography (developing solvent, hexane:ethyl
acetate ) 2:1 v/v) gave (R)-pyrimidyl alkanol 6 with 93% ee in an
isolate yield of 98% (348 mg). Method A-1: The same as Method
A-2 except that the amount of chiral R-deuterated alcohol was 0.025
mmol. Method B: The same as Method A-1 except that the final
addition of toluene (22 mL), i-Pr2Zn (2.0 mmol, 2.0 mL of 1.0 M
toluene solution), and aldehyde 5 (188 mg, 1.0 mmol) in Method A-1
was omitted. d ee was determined by HPLC analysis using a chiral
stationary phase (Chiralcel OD).
Acknowledgment. This work was supported by a Grant-in-Aid from
the Ministry of Education, Science, Sports and Culture, Japan. I.S.
gratefully acknowledges a Daicel Award for Synthetic Organic Chemistry.
Supporting Information Available: Preparation and characterization
data of R-deuterated chiral alcohols 1-4. Representative procedure for
the enantioselective addition of diisopropylzinc to aldehyde 5 induced
by chiral R-deuterated alcohols (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
JA002992E
(11) (a) Soai, K.; Osanai, S.; Kadowaki, K,; Yonekubo, S.; Shibata, T.;
Sato, I. J. Am. Chem. Soc. 1999, 121, 11235-11236. (b) Sato, I.; Kadowaki,
K.; Soai, K. Angew. Chem., Int. Ed. 2000, 39, 1510-1512.
(12) Reviews: (a) Kagan, H. B.; Luukas, T. O. In ref 6a, pp 101-118. (b)
Soai, K.; Shibata, T. In ref 6b pp 699-725. (c) Avalos, M.; Babiano, R.;
Cintas, P.; Jime´nez, J. L.; Palacios, J. C. Chem. Commun. 2000, 887-892.
(d) Soai, K.; Shibata, T.; Sato, I. Acc. Chem. Res. 2000, 33, 382-390.
(13) For an interesting example of a large optical rotation of a chiral polymer
by virtue of deuterium substitution, see: Green, M. M.; Andreola, C.; Munoz,
B.; Reidy, M. P. J. Am. Chem. Soc. 1988, 110, 4063-4065.
The generality of the effect of isotopic enantiomers in chiral
initiation was exemplified using chiral tolyl methanol-R-d1 2,
2-naphthyl methanol-R-d1 3 and 3-phenylpropanol-R-d1 4. As
shown in Table 1, (S)-tolyl methanol-R-d1 2 (>95% ee) and (R)-2
induced the formation of (R)-6 with 96% ee and (S)-6 with 95%