Highly enantioselective asymmetrization of meso-1,2-diols through a novel and efficient reaction cycle

Full text of DOI:10.1021/ja971881l

12016
J. Am. Chem. Soc. 1997, 119, 12016-12017
Scheme 1
Highly Enantioselective Asymmetrization of
meso-1,2-Diols through a Novel and Efficient
Reaction Cycle
Hiromichi Fujioka,* Yasushi Nagatomi,
Hidetoshi Kitagawa, and Yasuyuki Kita*
Faculty of Pharmaceutical Sciences, Osaka UniVersity
1-6 Yamada-oka, Suita, Osaka 565, Japan
ReceiVed June 9, 1997
Enantiodifferentiation of the σ-symmetric diols (including
meso-diols) is an important area in organic synthesis. Many
enantiodifferentiation methodologies have been developed so
far. They are widely divided into two groups. One is the group
using enzymes as a tool1 and the other is one using chemical
methods.2 Although both of them have proved to be very useful
in asymmetrization of prochiral diols, no successful report on
highly enantioselective asymmetrization of acyclic meso-1,2-
diols has appeared, to the best of our knowledge. We present
here a conceptionally novel and highly enantioselective asym-
metrization of meso-1,2-diols, which is very powerful not only
for cyclic diols but also for acyclic ones.
Scheme 2
Recently, we have developed a new asymmetric synthesis of
optically active 1,4- and 1,5-diols, where intramolecular halo-
etherification of chiral ene acetals, prepared from C2-symmetric
optically active diols and ene aldehydes, is characterized as a
crucial step. The reaction of an ene acetal proceeds via an
oxonium ion intermediate.3 This finding suggested that if a large
energy difference existed among the possible intermediates ii
formed from the ene acetal i derived from the proper chiral
nonracemic ene aldehyde and symmetric meso-diol, the reaction
may proceed through the most stable intermediate resulting in
the discrimination of the two oxygen atoms of the meso-diol
(Scheme 1). We selected (1R,2R,3S,4S)-3-methyl-5-norbornene-
2-carboxaldehyde (1) as a chiral ene aldehyde for the following
four reasons: (1) 1 is easily prepared by asymmetric Diels-
Alder reaction;4 (2) acetalization would proceed stereoselectively
to give the cis isomer;5 (3) a newly produced chiral center (*
center in ii) would be formed stereospecifically in the halo-
etherification because the double bond is fixed in the ring; and
most importantly (4) sterically rigid forms of the oxonium ion
intermediates would be expected to cause a large energy
difference. The consideration for point 4 was supported from
the consideration of the discriminating process for the two
oxygen atoms of the acetal. As described later, because
acetalization of 1 with meso-diols proceeded stereoselectively
to give cis-ene acetals, two possible cis intermediates,6 A and
B, are depicted. As shown from the conformations of the
intermediates A (R ) Me) and B (R ) Me), a large steric
repulsion not only between the substituents and the bicyclo-
[2.2.1]heptane skeleton but also between the 1,3-dioxolane
skeleton and the bicyclo[2.2.1]heptane skeleton is observed in
endo isomer B, whereas such repulsion is not observed in exo
isomer A. This suggests a large energy difference, in other
words a large stability difference, between the two cis inter-
mediates A and B, realizing an extremely high discrimination
between the two oxygen atoms of the acetal.
(1) For examples, see: (a) Fadel. A.; Arzel, P. Tetrahedron: Asymmetry
1997, 8, 283-291. (b) Schoffers, E.; Golebiowski, A.; Johnson, C. R.
Tetrahedron 1996, 52, 3769-3826. (c) Theil, F. Chem. ReV. 1995, 95,
2203-2227. (d) Banfi, L.; Guanti, G. Synthesis 1993, 1029-1056. (e)
Santaniello, E.; Ferraboschi, P.; Grisenti, P.; Manzocchi, A. Chem. ReV.
1992, 92, 1071-1140. (f) Bolando, W.; Fro¨ssl, C.; Lorenz, M. Synthesis
1991, 1049-1072.
(2) For recent examples for 1,2-diols, see: (a) Maezaki, N.; Sakamoto,
A.; Soejima, M.; Sakamoto, I.; Xia, L.; Tanaka, T.; Ohishi, H.; Sakaguchi,
K.; Iwata, C. Tetrahedron: Asymmetry 1996, 7, 2787-2790. (b) Maezaki,
N.; Soejima, M.; Takeda, M.; Sakamoto, A.; Matsumori, Y.; Tanaka, T.;
Iwata, C. Tetrahedron 1996, 52, 6527-6546. (c) Maezaki, N.; Soejima,
M.; Sakamoto, A.; Sakamoto, I.; Matsumori, Y.; Tanaka, T.; Ishida, T.; In,
Y.; Iwata, C. Tetrahedron: Asymmetry 1996, 7, 29-32. (d) Vedejs, E.;
Daugulis, O.; Diver, S. T. J. Org. Chem. 1996, 61, 430-431. (e) Maezaki,
N.; Soejima, M.; Takeda, M.; Sakamoto, A.; Tanaka, T.; Iwata, C. J. Chem.
Soc., Chem. Commun. 1994, 1345-1346. (f) Suemune, H.; Watanabe, K.;
Kato, K.; Sakai, K. Tetrahedron: Asymmetry 1993, 4, 1767-1770. (g)
Harada, T.; Wada, I.; Oku, A. J. Org. Chem. 1989, 54, 2599-2605. (h)
Mukaiyama, T.; Tomioka, I.; Shimizu, M. Chem. Lett. 1984, 49-52. For
recent examples for 1,3-diols, see: (a) Davis, A. P. Angew. Chem., Int. Ed.
Engl. 1997, 36, 591-594. (b) Prasad, K.; Underwood, R. L.; Repic, O. J.
Org. Chem. 1996, 61, 384-385. (c) Harada, T.; Oku, A. Synlett 1994, 95-
104. (d) Suzuki, T.; Uozumi, Y.; Shibasaki M. J. Chem. Soc., Chem.
Commun. 1991, 1593-1595. (e) Appelt, A.; Willis, A. C.; Wild, S. B. J.
Chem. Soc., Chem. Commun. 1988, 938-940. (f) Mukaiyama, T.; Tanabe,
Y.; Shimizu, M. Chem. Lett. 1984, 401-404. (g) Ichikawa, J.; Asami, M.;
Mukaiyama, T. Chem. Lett. 1984, 949-952. (h) Nara, M.; Terashima, S.;
Yamada, S. Tetrahedrn 1980, 36, 3161-3170. For recent example for 1,4-
diols, see: Ishihara, K.; Kubota, M.; Yamamoto, H. Synlett 1994, 611-
614.
To realize the concept above, meso-cyclohexane-1,2-diol (2a)
was examined as a substrate (Scheme 2). The cis-ene acetal
4a, readily synthesized as a single isomer in 93% yield from 1
and 2a, is subjected to an intramolecular haloetherification to
give the mixed acetal 5a via an oxonium ion intermediate (refer
to intermediate A in Scheme 1). As expected, it was determined
1
to be a single isomer by H NMR data. This showed that the
discriminating process proceeded in a quite highly stereoselec-
tive manner. Dehaloetherification of 5a using Zn and
MgBr2‚Et2O afforded the acetal 6a in good yield. Protection
of the hydroxy group of 6a as a benzyl ether followed by
transacetalization with one equivalent of meso-diol 2a afforded
the monoprotected diol 3a in good yield. At the same time, 4a
(4) Prepared in three steps: (i) asymmetric Diels-Alder reaction of the
commercially available N-crotonyl-(4S)-isopropyl-2-oxazolidinone and cy-
clopentadiene according to Evans’s method (Evans, D. A.; Chapman, K.
T.; Bisaha, J. J. Am. Chem. Soc. 1988, 110, 1238-1256.); (ii) LiAlH4
reduction in THF at room temperature (97%); (iii) Swern oxidation (73%).
(5) There are some reports showing that acetalization of an aldehyde
and a cis-diol tends to form a cis-acetal as a major product under kinetic
control. For review, see: Clode, D. M. Chem. ReV. 1979, 79, 491-513.
(6) Because it is known that cis-bicyclo[3.3.0]octane is more stable than
the corresponding trans isomer, two cis intermediates A and B are shown.
(3) For intramolecular haloetherification of ene acetals, see: (a) Fujioka,
H.; Kitagawa, H.; Matsunaga, N.; Nagatomi, Y.; Kita, Y. Tetrahedron Lett.
1996, 37, 2245-2248. (b) Fujioka, H.; Kitagawa, H.; Nagatomi, Y.; Kita,
Y. J. Org. Chem. 1996, 61, 7309-7315.
S0002-7863(97)01881-7 CCC: $14.00 © 1997 American Chemical Society

Communications to the Editor
J. Am. Chem. Soc., Vol. 119, No. 49, 1997 12017
Table 2. Reaction Cycle for Asymmetrization
Scheme 3
Scheme 4
Table 1. Acetalization of 1 with meso-Diol (2)
of 1 with meso-1,2-diols 2a-h were successful and gave only
single diastereomers, cis isomers 4a-h, almost quantitatively
in each case (Table 1). The stereochemistry of 4a-h was
determined by their NOE measurements.
The results subjecting the ene acetals 4 to the asymmerization
reaction cycle (Scheme 3) are shown in Table 2. Intramolecular
haloetherification of 4 gave the mixed acetals 5 as a single
1
isomer by H NMR level in every case. Dehaloetherification,
benzylation, and transacetalization afforded the optically active
3 and 4. Every reaction step proceeded in high yields. The
optical purity of 3 was extremely high (g97% ee) irrespective
of ring size and the presence of an oxygen atom in the cyclic
systems (entries 1-4) and of the kind of substituent in acyclic
ones (entries 5-8). The absolute stereochemistry of the
compounds was deduced from the mechanistic consideration
in Scheme 1 and the following ones: that of cyclic monopro-
tected diols 3b-d was determined by assuming the same sense
of stereoselection as observed for 3a and that of acyclic ones
3e-h was determined from the consideration of X-ray crystal-
lographic structure of the analog of 5e.8
The other feature of the method is easy choice of a proper
protective group. For example, in the case of the diol 2g having
a benzyl group, the silyl, acyl, or p-methoxybenzyl (MPB) group
can also be used as a protective group. Thus 6g was converted
to the silyl, acyl- and p-methoxybenzyl compounds 9a-c, whose
ee values were estimated to be >99%,9 in good yields without
any problem (Scheme 4).
was regenerated quantitatively. The optical purity of 3a was
determined to be 97% ee by HPLC analysis with a Daicel
Chiralpak AD. The absolute stereochemistry of 3a was
determined by comparison of its specific rotation [+16.6° (c
1.03, CHCl3)] with the reported value [+16.5° (c 1.10, CHCl3)],7
and it agreed with the structure expected from the consideration
of the stabilities of the intermediates in Scheme 1.
After once being converted to 4a, the success of an asym-
metrization of 2a giving optically active 3a in highly enantio-
meric excess and simultaneous regeneration of 4a must promise
an efficient reaction cycle for asymmetrization of meso-1,2-
diols 2 to their optically active derivatives 3 as depicted in
Scheme 3.
The applicability of this method to many kinds of meso-1,2-
diols, cyclic and acyclic ones, was then examined. The result
for 2a is also shown for comparison. Attempts at acetalization
In summary, we have developed a new asymmetrization
method for meso-1,2-diols. Characteristic points of the method
are (i) asymmetrization with an extremely highly enantiomeric
excess, (ii) wide applicability not only to cyclic 1,2-diols but
also to acyclic ones for which no successful report has appeared
yet, (iii) ready protection with proper group, and (iv) high
efficiency through the asymmetrization reaction cycle.
(7) Naemura, K.; Takeuchi, S.; Hirose, K.; Tobe, Y.; Kaneda, T.; Sakata,
Y. J. Chem. Soc., Perkin Trans. 1 1995, 213-219.
(8) X-ray analysis was performed on the mixed acetal 10 obtained by
the same intramolecular haloetherification of the ene acetal derived from
meso-2,3-butanediol 2e and (()-5-norbornene-2-carboxyaldehyde:
Acknowledgment. This paper is dedicated to Professor Yoshito
Kishi on the occasion of his 60th birthday.
Supporting Information Available: Preparation of aldehyde 1,
general procedures from 2 to 3 via 4-6 and 7, 1H NMR and 13C NMR
data for 5a-h, 7a-h, and 8a-c, and HPLC analysis data for 3a-h
and 9a-c, X-ray experimental data for 10 (12 pages). See any current
masthead page for ordering and Internet access instructions.
1
(9) The ee value of silyl ether 9a was determined by H NMR analysis
of its acetate because 9a was decomposed under the HPLC analysis
conditions. Ee values of 9b and 9c were determined by HPLC analysis
(Chiralpak AD; hexane/iPrOH ) 93/7).
JA971881L