Enantioselective ring cleavage of dioxane acetals mediated by a chiral Lewis acid: Application to asymmetric desymmetrization of meso-1,3-diols

Article abstract of DOI:10.1021/ol0165286

Equation presented Phenylalanine-derived B-aryl-N-tosyloxazaborolidinones selectively activate one of two enantiotopic oxygen atoms in prochiral anti dioxane acetals derived from meso-1,3-diols, leading to enantioselective formation of ring-cleavage produ

Full text of DOI:10.1021/ol0165286

ORGANIC
LETTERS
2001
Vol. 3, No. 21
3309-3312
Enantioselective Ring Cleavage of
Dioxane Acetals Mediated by a Chiral
Lewis Acid: Application to Asymmetric
Desymmetrization of meso-1,3-Diols
Toshiro Harada,* Kousuke Sekiguchi, Tomohito Nakamura, Jun Suzuki, and
Akira Oku
Department of Chemistry, Kyoto Institute of Technology,
Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan
harada@chem.kit.ac.jp
Received August 3, 2001
ABSTRACT
Phenylalanine-derived B-aryl-N-tosyloxazaborolidinones selectively activate one of two enantiotopic oxygen atoms in prochiral anti dioxane
acetals derived from meso-1,3-diols, leading to enantioselective formation of ring-cleavage products. The reaction is utilized as a key step in
asymmetric desymmetrization of meso-1,3-diols.
Chiral Lewis acids have been successfully used in many face-
selective reactions, where the enantiotopic faces of a planar
substrate are differentiated by conversion to diastereotopic
ones through coordination.1 Although not yet intensively
studied,2 the use of chiral Lewis acids in enantiotopic group
selective reactions involves a completely different mechanism
of asymmetric induction and is expected to provide a new
approach to nonenzymatic asymmetric desymmetrization of
prochiral bifunctional compounds.3 Diastereomeric com-
plexes are formed through coordination of the enantiotopic
functional groups. Selective activation of one of two enan-
tiotopic groups can be achieved through the differentiating
complexation by a proper chiral Lewis acid, leading to the
formation of desymmetrization product.
Direct evidence for enantiotopic group recognition by a
chiral Lewis acid was demonstrated by Reetz et al. in their
study on the complexation of a prochiral diamine by a chiral
boron compound.4 We recently disclosed5 that oxazaboro-
lidinone 2a as a chiral Lewis acid6 is effective in enantio-
selective ring-cleavage reaction of meso-1,3-dioxolane acetals
syn-1 with silyl ketene acetals (eq 1), and a subsequent study
(4) Huskens, J.; Goddard, R.; Reetz, M. T. J. Am. Chem. Soc. 1998,
120, 6617-6618. This paper also dealt with enantioselective conversion
of the resulting complex by taking advantage of the deactivation of
coordinating functional group.
(5) (a) Kinugasa, M.; Harada, T.; Oku, A. J. Am. Chem. Soc. 1997, 119,
9067-9068. (b) Kinugasa, M.; Harada, T.; Oku, A. Tetrahedron Lett. 1998,
39, 4523-4526. (c) Harada, T.; Nakamura, T.; Kinugasa, M.; Oku, A.
Tetrahedron Lett. 1999, 40, 503-506. (d) Harada, T.; Yamanaka, H.; Oku,
A. Synlett 2001, 61-64.
(6) For the use of relevant oxazaborolidinones in enantioface selective
reactions, see: (a) Takasu, M.; Yamamoto, H. Synlett 1990, 194-196. (b)
Sartor, D.; Saffrich, J.; Helmchen, G. Synlett 1990, 197-198. (c) For leading
references, see: Ishihara, K.; Kondo, S.; Yamamoto, H. J. Org. Chem. 2000,
65, 9125-9128.
(1) (a) Catalytic Asymmetric Synthesis, 2nd ed; Ojima, I., Ed.; Wiley-
VCH: Weinheim, 2000. (b) Lewis Acids in Organic Synthesis; Yamamoto,
H., Ed.; Wiley-VCH: Weinheim, 2000.
(2) (a) Seebach, D.; Jaeschke, G.; Wang, Y. M. Angew. Chem., Int. Ed.
Engl. 1995, 34, 2395-2396. (b) Ramon, D. J.; Guillena, G.; Seebach, D.
HelV. Chim. Acta 1996, 79, 875-894.
(3) (a) Ward, R. S. Chem. Soc. ReV. 1990, 19, 1-19. (b) Gais, H. J. In
Methods of Org. Chem. (Houben-Weyl); Helmchen, G., Hoffmann, R. W.,
Mulzer, J., Schumann, E., Eds.; Georg Thieme Verlag: Stuttgart, 1995;
Vol. E21a, pp 589-644. (c) Vedejs, E.; Daugulis, O.; Diver, S. T. J. Org.
Chem. 1996, 61, 430-431 and references therein. (d) Willis, M. C. J. Chem.
Soc., Perkin Trans. 1 1999, 1765-1784.
10.1021/ol0165286 CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/21/2001

on the mechanism led us to propose that the enantiodiffer-
entiating coordination of an acetal oxygen atom by the chiral
Lewis acid is a major factor governing the enantioselectivity.7
Under similar conditions, p-methoxyphenyl (PMP) deriva-
tive syn-7b underwent ring cleavage to some extent (eq 2).
In contrast to a high 1,3-anti diastereoselectivity observed
for dioxolane acetals,5,7 an inseparable mixture of syn isomer
9a and anti isomer 10a was obtained with a 2.3:1 ratio. The
sense of asymmetric induction was opposite between 9a and
10a. The major enantiomer of 9a is the one produced through
the cleavage of the C(2)-O(3) bond, while the C(2)-O(1)
bond preferentially underwent cleavage to give 10a.11
Although both products were obtained with relatively high
enantioselectivity, the opposite sense of asymmetric induction
resulted in low overall enantioselectivity12 (39% ee) with
respect to desymmetrization of the meso-diol.
In this paper, we report oxazaborolidinone-mediated
enantioselective ring cleavage of 1,3-dioxane acetals and its
application to desymmetrization of meso-1,3-diols.8 The
study not only provides a further support for the enantiotopic
group selective activation through differentiating complex-
ation by chiral Lewis acids but also gives information on
the structure of activated complexes.
Formation of 9a as a major diastereomer can be rational-
ized by a pathway involving contact ion pairs 11 and 12 as
product-determining intermediates (Scheme 1).7,13 Thus, syn
Scheme 1. Proposed Ring-Cleavage Pathway for syn-7b
For diastereomeric complexes 3 and 4 derived from syn
substituted acetals, the substituents R1 and R2 around the
coordinating oxygen atom are symmetrically disposed with
respect to a plane bisecting the acetal ring. Therefore,
differentiating complexation by a chiral Lewis acid is
anticipated when these two groups are structurally different.
Indeed, in the ring-cleavage reaction of meso-1,3-dioxolane
acetals (n ) 0), we observed that the sterically less
demanding alkynyl group as an R1 group is essential to obtain
high enantioselectivity for various R2 groups.5a We, therefore,
initiated the study with analogous 2-phenylethynyl derivative
syn-7a (eq 2). However, treatment of syn-7a and silyl ketene
acetal 8 in the presence of oxazaborolidinone 2a9 (1.3 equiv)
in CH2Cl2 at -40 °C resulted in recovery of the starting
material, suggesting that dioxane acetals with three substit-
uents being equatorial are quite less reactive than dioxolane
acetals.10
ion pair 11, formed initially via the corresponding acetal-
Lewis acid complex 3a (R1 ) PMP, R2 ) Me, n ) 1), might
be stable and less reactive, undergoing isomerization13a,b to
the unfavorable but reactive anti ion pair 12, which is then
attacked by 8 to give 9a. It occurred to us that anti-dioxane
(7) Harada, T.; Nakamura, T.; Kinugasa, M.; Oku, A. J. Org. Chem.
1999, 64, 7594-7600.
(8) For nonenzymatic desymmetrization of meso-1,3-diols, see: (a)
Ichikawa, J.; Asami, M.; Mukaiyama, T. Chem. Lett. 1984, 949-952. (b)
Harada, T.; Sakamoto, K.; Ikemura,; Y. Oku, A. Tetrahedron Lett. 1988,
29, 3097-3100. (c) Harada, T.; Ikemura, Y.; Nakajima, H.; Oku, A. Chem.
Lett. 1990, 1441-1444. (d) Oriyama T.; Hosoya, T.; Sano, T. Hetrocycles
2000, 52, 1054-1069.
(9) Kinugasa, M.; Harada, T.; Egusa, T.; Oku, A. Bull. Chem. Soc. Jpn.
1996, 69, 3639-3650.
(10) Dioxane acetals are less basic than dioxolane acetals. Denmark, S.
E.; Willson, T. M.; Almstead, N. G. J. Am. Chem. Soc. 1989, 111, 9258-
9260.
(11) The enantioselectivities of 9a and 10a were determined by 500 MHz
1H NMR analysis of the MTPA ester derivatives. The authentic (S)-MTPA
ester derivative of ent-10a was prepared from (2R,4R)-2,4-pentanediol via
titanium chloride mediated ring-cleavage reaction of the 2-(p-methoxy-
phenyl)dioxane acetal derivative followed by the Mitsunobu esterification
with (S)-MTPA. The absolute structure of 9a was established by its
conversion into 18a (vide infra).
(12) The overall enantioselectivity is defined by {(C(2)-O(3) cleavage)
- (C(2)-O(1) cleavage)}/{(C(2)-O(3) cleavage) + (C(2)-O(1) cleavage)}
) {(9 + ent-10) - (ent-9 + 10)}/{(9 + ent-10) + (ent-9 + 10)}.
3310
Org. Lett., Vol. 3, No. 21, 2001

acetals would react smoothly through direct formation of the
reactive syn ion pairs via activated complexes 5 or 6. In
addition, for diastereomeric complexes 5 and 6, substituents
R1 and R2 around the coordinating oxygen atom are oriented
pseudo-C2 symmetrically along the O-B bond axis and a
high degree of asymmetric induction was anticipated ir-
respective of the structures of R1 and R2.
the O(3) oxygen atom of anti-13a by oxazaborolidinone 2,
followed by a rate-determining dissociation of the resulting
activated complex to the contact ion pair, is a major factor
governing the enantioselectivity.7 Our working model for the
activated complexes is shown in Scheme 2. In this model,
Scheme 2. Proposed Model of the Activated Complexes
Indeed, anti-13a with axial PMP group underwent facile
ring-cleavage reaction at -40 °C to give 9a as a major
Table 1. Ring-Cleavage of anti-Dioxane Acetal anti-13aa
ee (%)c
entry
2
yield (%) 9a :ent-10a b 9a
ent-10a
overall
1
2
3
4
2a
2b
2c
2d
90
60
70
70
9.5:1
5.9:1
7.3:1
5.5:1
98
99
97
98
67
67
33
56
95
93
92
91
a Reactions were carried out by using 2a (1.3 equiv) and 8 (3 equiv) in
CH2Cl2 (0.4 M) at -40 °C for 15-20 h. b Determined by 500 MHz 1H
NMR analysis. c Determined by 500 MHz 1H NMR analysis of the MTPA
ester derivatives.
the acetal oxygen atom coordinates to the face of the
oxazaborolidinone trans to the benzyl group and cis to the
tosyl group. A coordination to the opposite face might be
sterically less feasible because the benzyl group takes the
conformation in which the phenyl group is placed over the
oxazaborolidinone ring.14 Of three staggered conformers
around the O-B bond of a complex derived from the O(3)
diastereomer (9.5:1) with high enantioselectivity (98% ee)
(eq 3, entry 1 in Table 1). The selective cleavage of the
Table 2. Asymmetric Desymmetrization of meso-1,3-Diols
C(2)-O(1) bond was observed also for a minor diastereomer
ent-10a (65% ee). Therefore, satisfactory overall enantio-
selectivity (95% ee) could be achieved. Similar results were
obtained when related oxazaborolidinones 2b-d were used.
Tryptophan-derived 2b exhibited high enantioselectivity as
well (entry 2). Displacement of the tosyl group of 2a with
the mesyl group did not affect the selectivity either (entry
3). Slight decrease in diastereoselectivity was observed for
B-(p-chlorophenyl) derivative 2d (entry 4).
Facile and diastereoselective ring-cleavage reaction of anti-
13a implies that anti ion pair 12, once formed, undergoes a
rapid attack by 8, as observed for dioxolane acetal syn-1,7
before isomerizing to the more stable syn ion pair 11. It is
most probable that the enantiodifferentiating coordination of
yield (%)
ee (%)g [R]D (CHCl3)
entry
diols
17
13
9
18
18
1
2
3
4
16a
16b
16c
16d
97h
67
52
57
53i
77
94
82
83
94
94j
89
62
79
79k
67
93
86
94
92
+57.4 (c 0.70)
+49.6 (c 1.00)
+58.6 (c 1.00)
+13.1 (c 1.01)
j
a HC(OMe)3 (1.5 equiv), TsOH, cyclohexane, 70 °C, 1 h. b p-
MeOC6H4MgBr (1.5 equiv), Et2O, room temperature, 24 h. c Unless
otherwise noted, 2a (1.3 equiv), 8 (3 equiv), CH2Cl2, -40 °C, 15-20 h.
d BnBr (1.3 equiv), NaN(TMS)2 (1.5 equiv), THF, room temperature, 1.5
h, and then CF3CO2H, 0 °C, 3 h. e Unless otherwise noted, isolated yields
of anti isomer. f The absolute structure of 18a was determined by the
measurement of specific rotation.8c For 18b-d, the structures were
established by the modified Mosher’s method.17 g Determined by 500 MHz
1H NMR analysis of the MTPA ester derivative. h Combined yield of anti-
and syn-17a (1.6:1). i A mixture of anti- and syn-17a was used. j 2d (1.3
equiv) was used. k Ring-cleavage product 9c was treated with LiAlH4 (2.0
equiv) in THF, and the resulting diol was used in transformation to 18c.
(13) (a) Denmark, S. E.; Almstead, N. G. J. Am. Chem. Soc. 1991, 113,
8089-8110. (b) Denmark, S. E,; Almstead, N. G. J. Org. Chem. 1991, 56,
6458-6467. (c) Mori, I.; Ishihara, K.; Flippin, L. A.; Nozaki, K.; Yamamoto,
H.; Bartlett, P. A.; Heathcock, C. H. J. Org. Chem. 1990, 55, 6107-6115.
(d) Sammakia, T.; Smith, R. S. J. Am. Chem. Soc. 1992, 114, 10998-
10999.
Org. Lett., Vol. 3, No. 21, 2001
3311

coordination, only 14 does not experience significant non-
bonded interaction. On the other hand, unfavorable inter-
actions exist in all three staggered conformers of an alterna-
tive complex derived from the O(1) coordination as shown,
for example, in 15 of a local conformation similar to that of
14 around the O-B bond. This working model also explains
the high enantioselectivity as well as the absolute configu-
ration of the products in the ring-cleavage reaction of
dioxolane acetal syn-1 with the sterically less demanding
alkynyl group.15,16
derivatives 18a,b,d of high ee. Transformation to 18c was
accomplished after LiAlH4 reduction to the corresponding
diol owing to the difficulty in direct benzylation of 9c with
the sterically demanding isopropyl group.
In summary, we have developed a highly enantioselective
method for asymmetric desymmetrization of meso-1,3-diols.
The method relies on oxazaborolidinone-mediated ring-
cleavage reaction of anti-dioxane acetals where chiral Lewis
acids 2 selectively activates one of the enantiotopic acetal
C-O bonds through enantiodifferentiating complexation.
Desymmetrization of representative meso-1,3-diols 16a-d
was examined by using the ring cleavage of anti acetal
derivatives (Table 2). The diols were converted into cyclic
ortho esters anti-17a-d (anti:syn ) 1.6-2.0:1) by treatment
with trimethyl orthoformate.18,19 A subsequent Grignard
reaction of pure anti ortho esters gave anti-13a-d exclu-
sively.18 The crucial ring-cleavage reaction using oxazaboro-
lidinone 2a or 2d afforded 9a-d in high yield. Benzylation
of 9a-d, containing a minor diastereomer, followed by
treatment with trifluoroacetic acid, furnished desymmetrized
Acknowledgment. This work was supported partially by
Grant-in-Aid for Scientific Research from Ministry of
Education, Culture, Sports, Science and Technology, Japan
(Priority Areas, no. 706: Dynamic Control of Stereochem-
istry) and by the Nagase Science and Technology Founda-
tion.
Supporting Information Available: Experimental pro-
cedures and absolute structure determination of desymme-
trized products 18a-d and ring-cleavage products 9a and
10a by modified Mosher’s method. This material is available
free of charge via the Internet at http://pubs.acs.org.
(14) A relatively small vicinal coupling constant observed for the benzyl
protons of 2b (J ) 2.7 and 5.4 Hz) supports this conformation. Other
rotamers might be less stable owing to unfavorable interaction with the
sulfonyl or carbonyl oxygen atom.
(15) Enantioselectivities observed in ring-cleavage reaction of anti-
dioxolane acetals5d as well as ethylene glycol derived dioxolane acetals16
are also consistent with the present model.
OL0165286
(16) Kinugasa, M.; Harada, T.; Oku, A. J. Org. Chem. 1996, 61, 6772-
6773.
(19) Ortho ester syn-17c could be isomerized by treatment with BF3‚
Et2O (0.2 equiv) in Et2O at -78 °C to give a 4.7: 1 mixture of anti- and
syn-17c (80% yield). Under similar conditions, syn-17d was converted
almost completely into anti-17d (25:1, 78% yield), which was precipitated
from the reaction mixture.
(17) Ohtani I.: Kusumi. T.; Kashman. Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092-4096.
(18) Eliel, E. L.; Knoeber, M. C. J. Am. Chem. Soc. 1968, 90, 3444-
3458.
3312
Org. Lett., Vol. 3, No. 21, 2001