Chiral oxazaborolidinone-mediated enantioselective ring-cleavage reaction of a mixture of diastereomeric 1,3-dioxolane acetals: Application to asymmetric desymmetrization of meso-1,2-diols

Article abstract of DOI:10.1055/s-2001-9730

Ring-cleavage reaction of a mixture of diastereomeric dioxolane acetals syn- and anti-1b-e proceeds in an enantiodifferentiating manner in the presence of chiral Lewis acid 2. The reaction is utilized as a key step in asymmetric desymmetrization of meso-1,2-diols.

Full text of DOI:10.1055/s-2001-9730

LETTER
61
Chiral Oxazaborolidinone-Mediated Enantioselective Ring-Cleavage
Reaction of a Mixture of Diastereomeric 1,3-Dioxolane Acetals:
Application to Asymmetric Desymmetrization of meso-1,2-Diols
Toshiro Harada,*a Hideki Yamanaka,b Akira Okua
aDepartment of Chemistry, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan
bSugai Chemical Industry, 4-4-6 Uzu, Wakayma 641-0043, Japan
E-mail: harada@chem.kit.ac.jp
Received 25 September 2000
In this desymmetrization process, the stereoselective
preparation of syn-1 is indispensable to obtain high over-
all efficiency because diastereomeric acetals anti-1 are
quite less reactive in the ring-cleavage reaction. Acetal-
ization of meso-1,2-diols under conventional thermody-
namically controlled conditions results in the nonselective
formation of syn- and anti-1. Therefore, kinetically con-
trolled conditions (PhC∫CCH(OEt)2, TsOH (0.1 equiv),
molecular sieves 4 A, CH2Cl2, r.t.) are employed for syn
selective acetalization. However, for diols whose rate of
acetalization is slow, competitive isomerization of initial-
ly produced syn acetals to anti isomers often makes it dif-
ficult to obtain high syn selectivity at higher conversion.2b
We have now found that, by the modification of a substit-
uent at the acetal carbon, both syn and anti acetals derived
from meso-1,2-diols undergo ring-cleavage reaction
enantioselectively at the same side. Herein, we report an
improved method for asymmetric desymmetrization of
meso-1,2-diols in which a mixture of diastereomeric ace-
tals is used in the ring-cleavage reaction.
Abstract: Ring-cleavage reaction of a mixture of diastereomeric di-
oxolane acetals syn- and anti-1b-e proceeds in an enantiodifferenti-
ating manner in the presence of chiral Lewis acid 2. The reaction is
utilized as a key step in asymmetric desymmetrization of meso-1,2-
diols.
Key words: asymmetric synthesis, acetals, cleavage, diols, Lewis
acids
Nonenzymatic approach to the enantiotopic group differ-
entiation, or asymmetric desymmetrization, of prochiral
bifunctional compounds has been receiving increasing at-
tention because of its utility in preparing chiral building
blocks as well as in constructing multiple stereogenic cen-
ters.1 We recently reported a general method for desym-
metrization of meso-1,2-diols via oxazaborolidinone-
mediated enantioselective ring-cleavage of acetal deriva-
tives (Scheme 1).2,3 The prochiral diols are first converted
to 2-phenylethynyl-1,3-dioxolane acetals syn-1. Ox-
azaborolidinone 2a as a chiral Lewis acid is highly effec-
tive in differentiating the enantiotopic C-O bonds of the
prochiral acetals syn-1 in subsequent ring-cleavage reac-
tion with silyl ketene acetals. The resulting ring-cleavage
products are transformed to desymmetrized derivatives of
the meso-diols (85-96% ee) in two steps.
In the presence of oxazaborolidinone 2a (1.2 equiv),
2-phenylethynyl-1,3-dioxolane acetals syn-1a reacted
with silyl ketene acetal 3 at -78 °C to give ring-cleavage
4a (96% ee) (eq 1, entry 1 in Table 1). In comparison with
syn-1a, diastereomeric acetal anti-1a is less reactive and
did not undergo ring-cleavage at -78 °C (eq 2, entry 2).
At -20 °C, a slow but enantioselective reaction took place
for anti-1a to give ring-cleavage product 5a in 96% ee and
in 59% yield together with the recovery of anti-1a (41%)
(entry 4).2d Interestingly, 2-heptynyl derivative anti-1b
exhibited an enhanced reactivity as well as high enanti-
oselectivity. Thus, the reaction of anti-1b at -40 °C for
15 h gave the corresponding ring-cleavage product 5b
(98% ee) in 89% yield (entry 6). Diastereomeric acetal
syn-1b underwent enantioselective reaction as well at -78
°C to afford ring-cleavage product 4b (95% ee) in 86%
yield (entry 5). Both reactions proceeded in a stereospe-
cific manner (>50:1 diastereoselectivity) with inversion
of the stereochemistry at the acetal carbon. Notably, the
bond-cleavage of both acetals took place at the same side
irrespective of the relative configuration at the acetal car-
bon, suggesting a successful use of a mixture of syn and
anti acetals for asymmetric desymmetrization.
R
R
R
R
asymmetric
desymmetrization
HO
OP
HO
OH
O
O
R
R
R
R
O
R
O
R
B
Ph
Ph
Ph
N
O
O
O
2a
OH
Ts
Y
R'
R'
R'
R'
COY
OTMS
Ph
syn-1
Ph
anti-1
Scheme 1
Synlett 2001, No. 1, 61–64 ISSN 0936-5214 © Thieme Stuttgart · New York

62
T. Harada et al.
LETTER
metrization product (1R,2S)-7b2a of 92% ee was obtained
in 99% yield. Under similar conditions, the benzyl ether
derivative of 4a, possessing a 2-phenylethynyl moiety,
also gave 7b in 99% yield. The reaction presumably pro-
ceeds through a SN2' mechanism involving the attack of
tert-BuOK and/or KCH2SOCH3 at the acetylenic carbon
g to the C-O bond cleaved.
OEt
OTMS
CH2Cl2
3
2a,
O
OH
R
O
O
R
CO2Et
syn-1a; R = PhC≡C
4a,b
syn-1b; R = C5H11C≡C
Equation 1
R
O
R
R
R
R
R
a
b
OH
A
OEt
O
O
HO
OH
3
2a,
O
OH
OTMS
CO2Et
A
R
O
O
syn- and anti-1b-e
A = C5H11C≡C
4b-e and 5b-e
CH2Cl2
R
CO2Et
anti-1a; R = PhC≡C
5a,b
anti-1b; R = C5H11C≡C
R
O
R
R
R
OBn
c
d
A
Equation 2
HO
OBn
CO2Et
7b-e
Table 1 Ring-Cleavage of syn- and anti-1a with Oxazaborolidinone
2a
6b-e
a C5H11C∫CCH(OEt)2 (1.1 equiv), p-TsOH, toluene, reflux. b
Me2C=C(OTMS)OEt (3 equiv), 2a,b (1.2 equiv), CH2Cl2, -78 °C (11
h) and then -40 °C (9 h). c KN(TMS)2 (1.5 equiv), BnBr (1.3 equiv),
THF, rt, 1.5 h. d tert-BuOK (1.5 equiv), DMSO, 100 °C, 2 h.
Scheme 2
Asymmetric desymmetrization of representative meso-
1,2-diols was examined by using oxazaborolidinone-me-
diated ring-cleavage of a mixture of syn and anti acetal de-
rivatives (Scheme 2 and Table 2). Transacetalization of
the diols with 1,1-dimethoxy-2-octyne under the thermo-
dynamically controlled conditions gave ca. 1:1 mixture of
syn- and anti-1b-e in high yields. For acetals 1c-e, B-(p-
chlorophenyl)oxazaborolidinone 2b5 of higher Lewis
acidity was required to achieve the ring-cleavage of the
anti isomers (entry 4 vs entry 3). B-(m-Chlorophenyl) de-
rivative 2c5 which showed higher conversion of anti-5d
unfortunately resulted in considerable lowering of the
enantioselectivity (entry 5). Benzylation and the removal
of the nucleophile-derived moiety proceeded efficiently
to afford the corresponding desymmetrization product 7b-
e of high ee.
aReactions were carried out by using 2a (1.2 equiv) and 3 (3 equiv) in
CH2Cl2 (0.4 M). bDetermined by 500 MHz 1H NMR analysis. cDeter-
mined by 500 MHz 1H NMR analysis of the MTPA ester derivative.
We then examined ring-cleavage reaction of a 1:1 mixture
of syn- and anti-1b. When the reaction was carried out at
-78 °C for 11 h and then at -40 °C for 9 h, a mixture of 4b
1
and 5b (1.2:1) was obtained in 92% combined yield. H
NMR analysis of the MTPA esters derived from the mix-
ture showed that 4b and 5b were produced in 83% ee and
97% ee, respectively.4 Enantioselectivity of 4b in this re-
action was lower than that observed for pure syn-1b (Ta-
ble 1, entry 5), suggesting that a part of syn-1b reacted not
at -78 °C but at the higher temperature.
R2
2a; R1, R2 = H
2b; R1 = Cl, R2 = H
2c; R1 = H, R2 =Cl
The mixture of 4b and 5b was converted to benzyl ether
6b in 90% yield (Scheme 2). For the removal of the nu-
cleophile-derived moiety, 6b was then treated in trifluoro-
acetic acid at r.t. Although the procedure was effective for
analogous benzyl ethers derived from 2-phenylethynyl
acetals,2a undesirable benzylic C-O bond cleavage took
place concurrently with propargylic C-O bond cleavage,
resulting in low yield of desymmetrization product 7b.
The problem was overcome by the development of an al-
ternative method. We found that benzyl ether 6b under-
went an efficient propargylic C-O bond cleavage by
treatment with tert-BuOK in DMSO at 100 °C. Desym-
O
O
R1
B
Ph
N
Ts
According to our recent study on the mechanism of ox-
azaborolidine-mediated ring-cleavage reaction, the enan-
tiodifferentiating coordination of an acetal oxygen atom
by the chiral Lewis acid is a major factor governing the
enantioselectivity.2d In the present study, it was shown
that the bond-cleavage of syn- and anti-1 took place enan-
Synlett 2001, No. 1, 61–64 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Chiral Oxazaborolidinone-Mediated Enantioselective Ring-Cleavage
63
Table 2 Desymmetrization of meso-1,2-Diols via Enantioselective Ring-Cleavage Reaction
aDetermined by 500 MHz 1H NMR analysis. bDetermined by 500 MHz 1H NMR analysis of the MTPA ester derivative. cNot determined.
tioselectively at the same side irrespective of the relative In summary, we have shown that a mixture of diastereo-
configuration at the acetal carbon. The result implies that meric acetals derived from meso-1,2-diols can be success-
acetal-oxazaborolidinone complexes syn- and anti-8 are fully used in oxazaborolidinone-mediated enantio-
much more stable than the corresponding diastereomeric selective ring-cleavage reaction. Since these acetals are
complexes syn- and anti-9, respectively (Scheme 3). Al- readily prepared by transacetalization reaction under ther-
though we are not able to elucidate the structure of these modynamically controlled conditions, their reaction
complexes at this moment, some information can be de- opens an efficient entry into desymmetrization of meso-
duced from the observed enantioselectivity. In the unsta- 1,2-diols leading to benzyl ether derivatives of high ee.
ble complexes syn- and anti-9, the sterically demanding R
group is located at the position b of local structure model
10, suggesting that the oxazaborolidinone moiety (BL*3)
Acknowledgement
We thank the Nagase Science and Technology Foundation for fi-
nancial support of this work.
causes unfavorable interaction around this position. In the
stable complexes syn- and anti-8, on the other hand, ster-
ically less demanding alkynyl group (A) and a hydrogen
atom are located at the position b, respectively. The ob-
served lower reactivity of anti-1 in comparison with syn-
1 can be rationalized if we assume that the oxazaborolidi-
none moiety also causes unfavorable interaction around
the position c. Thus, for complex anti-8, even the sterical-
ly less demanding alkynyl group at this position suffers
from the steric effect to some extent. The enhanced reac-
tivity of 2-heptynyl derivative (anti-1a) in comparison
with 2-phenylethynyl derivative (anti-1b) might be steric
in origin associated with a remote steric effect across the
C-C triple bond.7
References and Notes
(1) (a) Ward, R. S. Chem. Soc. Rev. 1990, 19, 1. (b) Gais, H. -J.
Methods of Organic Chemistry (Houben-Weyl); Helmchen,
G.; Hoffmann, R. W.; Mulzer, J.; Schumann, E., Ed.; Georg
Thieme Verlag: Stuttgart, 1995; Vol. E21a, p 589. (c) Willis,
M. C. J. Chem. Soc., Perkin Trans. 1. 1999, 1765.
(2) (a) Kinugasa, M. Harada, T.; Oku, A. J. Am. Chem. Soc. 1997,
119, 9067. (b) Kinugasa, M.; Harada, T.; Oku, A. Tetrahedron
Lett. 1998, 39, 4523. (c) Harada, T.; Nakamura, T.; Kinugasa,
M.; Oku, A. Tetrahedron Lett. 1999, 40, 503. (d) Harada, T.;
Nakamura, T.; Kinugasa, M.; Oku, A. J. Org. Chem. 1999, 64,
7594.
(3) For recent studies on desymmetrization of meso-1,2-diols, see
(a) Vedejs, E.; Daugulis, O.; Diver, S. T. J. Org. Chem. 1996,
61, 430. (b) Fujioka, H.; Nagatomi, Y.; Kitagawa, H.; Kita, Y.
J. Am. Chem. Soc. 1997, 119, 12016. (c) Fujioka, H.;
Nagatomi, Y.; Kotoku, N.; Kitagawa, H.; Kita, Y.
H
H
H
A
H
A
O
O
R
R
H
c
O+
B-L*3
O+
B-L*3
R
R
Tetrahedron Lett. 1998, 39, 7309. (d) Oriyama, T.; Imai, K.;
Sano, T.; Hosoya, T. Tetrahedron Lett. 1988, 39, 3529.
(e) Maezaki, N.; Sakamoto, A.; Nagahashi, N.; Soejima, M.;
Li, Y.; Imamura, T.; Kojima, N.; Ohishi, H.; Sakaguchi, K.;
Iwata, C.; Tanaka. T. J. Org. Chem. 2000, 65, 3284.
O+
B-L*3
b
a
syn-8
syn-9
10
H
H
A
A
H
O
O
R
R
(4) Typical experimental procedure: To a solution of acetal 1a
(71 mg, 0.36 mmol, syn:anti = 1:1) and 1-ethoxy-2-methyl-1-
(trimethylsilyloxy)-1-propene (205 mg, 1.1 mmol) in CH2Cl2
(0.27 mL) at -78 °C was added a CH2Cl2 solution (0.7 M) of
oxazaborolidinone 2a (0.63 mL, 0.44 mmol).2d After being
stirred at this temperature for 11 h and then at -40 °C for 9 h,
the mixture was quenched by the addition of aqueous
NaHCO3 and filtered. The filtrate was extracted twice with
ether. The organic layers were dried and concentrated in
vacuo. The residue was treated with aqueous acetic acid (70%,
A = RC≡C
BL*3 = 2
O+
O+
B-L*3
R
R
H
B-L*3
anti-8
anti-9
Scheme 3
Synlett 2001, No. 1, 61–64 ISSN 0936-5214 © Thieme Stuttgart · New York

64
T. Harada et al.
LETTER
2 mL) and THF (2 mL) at r.t. for 1 h. The mixture was diluted
with water, extracted twice with ether, and washed with
aqueous NaHCO3. The organic layers were dried and
1.21 (3H, s), 1.28 (3H, t, J = 7.0 Hz), 1.30 (3H, s), 1.3-1.45
(4H, m), 1.5-1.6 (2H, m), 2.24 (2H, dt, J = 1.9 and 7.0 Hz),
2.60 (1H, br), 3.71 (1H, dq, J = 2.8 and 6.4 Hz), 3.89 (1H, m),
4.1-4.2 (2H, m), 4.55 (1H, t, J = 1.9 Hz); 13C NMR (125 MHz,
CDCl3) d 13.95, 14.07, 14.80, 16.96, 18.23, 18.59, 22.09,
23.38, 28.30, 30.95, 47.35, 60.97, 67.82, 73,64, 76.65, 77.55,
87.37, 177.00; IR (liquid film) 3500 (br), 2230, 1720 cm-1. (S)-
MTPA ester of 5b: 1H NMR (500 MHz, CDCl3) d 0.91 (3H, t,
J = 7.1 Hz), 1.2-1.25 (15H, m, including s (3H) at 1.20 and s
(3H) at 1.23, 1.3-1.4 (4H, m), 1.45-1.55 (2H, m), 2.17 (2H, dt,
J = 1.9 and 7.1 Hz), 3.58 (3H, br s), 3.81 (1H, dq, J = 2.9 and
6.5 Hz), 4.0-4.15 (2H, m), 4.50 (1H, t, J = 1.9 Hz), 5.21 (1H,
dq, J = 2.9 and 6.5 Hz), 7.42 (3H, m), 7.59 (2H, m) [a minor
diastereomer resonated at d 4.36 (1H, t, J = 1.9 Hz)].
(5) Oxazaborolidinones 2b and 2c were prepared by the reaction
of N-tosyl-L-phenylalanine with p-ClC6H4BBr2 and
m-ClC6H4BBr2,6 respectively.
concentrated in vacuo. Purification of the residue by flash
column chromatography (SiO2, 5-20% ethyl acetate in
hexane) gave a 1.2:1 mixture of 4b and 5b (104 mg, 92%
yield). 4b: 1H NMR (500 MHz, CDCl3) d 0.92 (3H, t, J = 7.1
Hz), 1.04 (3H, d, J = 6.3 Hz), 1.11 (3H, d, J = 6.6 Hz), 1.23
(3H, s), 1,27 (3H, s), 1.27 (3H, t, J = 7.0 Hz), 1.3-1.4 (4H, m),
1.5-1.55 (2H, m), 2.18 (1H, br), 2.23 (2H, dt, J = 1.9 and 7.0
Hz), 3.71 (1H, dq, J = 3.3 and 6.3 Hz), 3.87 (1H, m), 4.1-4.2
(2H, m), 4.44 (1H, t, J = 1.9 Hz); 13C NMR (125 MHz, CDCl3)
d 13.08, 13.94, 14.15, 17.26, 18.54, 18.99, 22.98, 22.50,
28.30, 30.95, 47.51, 60.55, 69.59, 73.06, 76.62, 76.88, 87.76,
175.80; IR (liquid film) 3470 (br), 2220, 1725 cm-1. (S)-
MTPA ester of 4b: 1H NMR (500 MHz, CDCl3) d 0.90 (3H, t,
J = 7.1 Hz), 1.10 (3H, d, J = 6.3 Hz), 1.23 (3H, s), 1.2-1.25
(6H, m), 1.26 (3H, s), 1.3-1.4 (4H, m), 1.45-1.5 (2H, m), 2.17
(2H, br t, J = ca. 7 Hz), 3.59 (3H, br s), 3.84 (1H, dq, J = 3.9
and 6.3 Hz), 4.1-4.15 (2H, m), 4.47 (1H, t, J = 1.8 Hz), 5.25
(1H, dq, J = 3.9 and 6.3 Hz), 7.42 (3H, m), 7.59 (2H, m) [a
minor diastereomer resonated at d 1.01 (3H, d, J = 6.3 Hz),
1.20 (3H, s), 3.57 (3H, br s), 4.44 (1H, t, J = 1.9 Hz) and 5.11
(1H, m)]. 5b: 1H NMR (500 MHz, CDCl3) d 0.92 (3H, t,
J = 7.2 Hz), 1.08 (3H, d, J = 6.5 Hz), 1.12 (3H, d, J = 6.4 Hz),
(6) Haubold, W.; Herdtle, J.; Gollinger, W.; Einholz, W. J.
Organomet. Chem. 1986, 315, 1.
(7) Helal, C. J.; Magriotis, P. A.; Corey, E. J. J. Am Chem. Soc.
1996, 118, 10938.
Article Identifier:
1437-2096,E;2001,0,01,0061,0064,ftx,en;Y17200ST.pdf
Synlett 2001, No. 1, 61–64 ISSN 0936-5214 © Thieme Stuttgart · New York