Asymmetric desymmetrization of 2-substituted 1,3-propanediols via catalytic enantioselective ring-cleavage reaction of cyclic acetal derivatives

Article abstract of DOI:10.1055/s-2005-871937

Non-enzymatic desymmetrization of 2-substituted 1,3-propanediols leading to the enantiomerically enriched 3-benzyloxy-1-propanols was achieved by using oxazaborolidinone-catalyzed enantioselective ring-cleavage reaction of the cyclic acetal derivatives wi

Full text of DOI:10.1055/s-2005-871937

LETTER
1999
Asymmetric Desymmetrization of 2-Substituted 1,3-Propanediols via
Catalytic Enantioselective Ring-Cleavage Reaction of Cyclic Acetal
Derivatives
C
T
atalytic Enant
o
ioselective
R
s
ing-Clea
v
h
age Reactio ni ro Harada,* Koudai Shiraishi
Department of Chemistry and Materials Technology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan
Fax +81(75)7247580; E-mail: harada@chem.kit.ac.jp
Received 1 June 2005
mercially available amino acid. A reduction in the amount
Abstract: Non-enzymatic desymmetrization of 2-substituted 1,3-
of 3 is highly desirable for the practicality of the desym-
propanediols leading to the enantiomerically enriched 3-benzyloxy-
metrization process.
1
-propanols was achieved by using oxazaborolidinone-catalyzed
enantioselective ring-cleavage reaction of the cyclic acetal deriva-
tives with dimethylsilyl ketene S,O-acetal as a key reaction.
We herein disclose that the catalytic, enantioselective
ring-cleavage reaction of acetals 4 can be achieved simply
by using dimethylsilyl ketene acetals 5b,d as nucleo-
philes.
Key words: asymmetric, catalysis, cleavage, diols, Lewis acids
The mono-protected derivatives of 2-substituted 1,3-pro-
panediols 2 in enantiomerically enriched forms serve as
versatile chiral building blocks that can be readily in-
corporated into target molecular frameworks.1 Much
attention has been focused on their enantioselective
preparation by asymmetric desymmetrization of parent
prochiral diols 1 (Equation 1). Enzymatic desym-
O
O
R
R
B
C6H4-p-Cl
2-Naph
N
Ts 3 (1.2 equiv)
Oa
O
HO
O
Ar
OSiMe3
OEt
Ar
Nu
6; Nu = –C(Me)2COEt
4; Ar = 1-Naph
5a
2
metrization of the diols by transesterification requires the
3
screening of enzymes and the resulting desymmetrized
Equation 2
mono-esters 2 (Y = RCO) are often prone to racemize
4
,5
through O,O-acyl group migration. A non-enzymatic
approach has a synthetic advantage providing access to a
variety of desymmetrized derivatives which are stable
The ring-cleavage reaction of acetal 4a10 was carried out
with nucleophiles 5a–d in the presence of OXB catalyst 3
11
(
20 mol%) and diethyl ether (1.5 equiv), at –50 °C in
6
,7
against racemization.
dichloromethane (Equation 3, Table 1). The C–O bond
a
underwent enantioselective cleavage with the preferential
attack of the nucleophiles and inversion of the acetal
carbon8 to afford syn-6a or syn-7a as a major product.
Under these conditions, the reactions of trimethylsilyl
derivatives 5a and 5c resulted in very low conversion
R
R
,12
asymmetric desymmetrization
O
OH
OH OH
Y
1
2
(
entries 1 and 3). In sharp contrast to the behavior of 5a,c,
Equation 1
a facile, catalytic ring-cleavage proceeded for dimethyl-
silyl derivatives 5b and 5d to give 6a and 7a, respectively,
We recently disclosed that oxazaborolidinone (OXB) 3 is in high yield (entries 2 and 4). In comparison with silyl
effective in enantioselective ring-cleavage reaction of ketene O,O-acetals 5a,b, S,O-acetals 5c,d exhibited better
cyclic acetals 4 derived from 2-substituted 1,3-diols and syn-selectivity. Because of the poor ee for the minor anti-
8
,9
1
-naphthaldehyde. Chiral Lewis acid 3 activates one of products, overall enantioselectivity with respect to de-
the enantiotopic acetal oxygen atoms (O ) preferentially, symmetrization of the parent diol13 is higher in the reac-
a
leading to the selective formation of the ring-cleavage tions with better diastereoselectivity (entry 2 vs. entry 4).
products 6 by the attack of the trimethylsilyl ketene O,O- Dimethylsilyl ketene S,O-acetal 5d was chosen as an
acetal 5a (Equation 2). Synthetically useful benzyl optimal nucleophile.
protected desymmetrized derivatives 2 (Y = Bn) are ob-
tained in enantiomerically enriched forms via 6. In the
ring-cleavage reaction, a stoichiometric amount of OXB 3
is required while it is readily accessible from a com-
Diastereoselectivity of the reaction was found to be influ-
enced by solvent polarity as well. Thus, the reaction in
less polar toluene exhibited better syn-selectivity and im-
proved overall ee (entry 5). However, acetal 4a was only
slightly soluble in toluene and the reaction resulted in
SYNLETT 2005, No. 13, pp 1999–2002
Advanced online publication: 12.07.2005
DOI: 10.1055/s-2005-871937; Art ID: U16905ST
1
9
.0
8
.2
0
0
5
lower conversion. Gratifyingly, a 1:1 mixture of toluene
and dichloromethane as solvents worked well without
©
Georg Thieme Verlag Stuttgart · New York

2
000
T. Harada, K. Shiraishi
LETTER
O
than the trimethylsilyl group. Thus, throughout a plausible
reaction pathway depicted in Scheme 1, the silyl group of
the initially produced zwitterionic intermediate 9 migrates
Ph
O
N
B
C6H4-p-Cl
(20 mol%)
50 °C , Et 2O (1.5 equiv)
2
-Naph
R
R
OSi
Ts
3
Oa
O
+
15
to give silyl ester 10, from which silyl ether 11 is formed
Y
–
by the second silyl group migration with simultaneous
regeneration of OXB 3. In the reaction of trimethylsilyl
derivatives 5a,c, the second migration step might be very
slow, resulting in the non-catalytic ring-cleavage reaction
while the dimethylsilyl group can undergo a smooth
Ar
5a–d
4a
Ph
Ph
OSi
OEt
a; Si = SiMe3
migration to give 11 (Si = Me SiH) as an initial product.
2
HO
O
Ar
+
HO
O
Ar
It is probable that diethyl ether used as an additive and/or
the starting acetal may serve as a silicon shuttle,16 which
captures and liberates the dimethylsilyl group to facilitate
the migration (Equation 4). Recently, an unique reactivity
of sterically less hindered dimethylsilyl group has been
5
5b; Si = Si(H)Me2
Nu
Nu
syn
anti
OSi
t
6a; Nu = –C(Me)2COEt
S Bu
t
7
a; Nu = –CH2COS Bu
disclosed by Hosomi and coworkers and utilized in base-
5c; Si = SiMe3
17,18
catalyzed reactions of dimethylsilyl enolates.
The
5d; Si = Si(H)Me2
propensity of the dimethylsilyl group to form penta-
coordinate silicate species might be responsible for the
smooth migration.
Equation 3
Table 1 OXB-Catalyzed Ring-Cleavage of Cyclic Acetals 4a with
a
O
5a–d
R2
O
Si
O
B
O
R1
R2
O
Entry Nucleophile Yield (%) syn:antib
ee (%)
O
N
R
B
N
sync
antic
Overalld
72
t
S Bu
R1
R
Ts
O
tBuS
O
8e
3e
Ts
Ar
1
2
3
5a
5b
5c
5d
5d
5d
9
82
11
98
70
83
16:1
2.9:1
8.5:1
6.1:1
13:1
15:1
81
85
86
88
93
93
O
Si
O
+
Ar
56
R1 = 2-Naph, R2 = p-ClC6H4,
(
8
9
Ar = 1-Naph)
24
5
79
O
O
N
R2
4
77
Si
Si
R
B
3
5f
R
3
87
O
R1
O
Ts
6g
17
89
tBuS
O
O
tBuS
O
a
Unless otherwise note, reactions were carried out by using 3 (20
mol%), 5 (3.0 equiv), and Et O (1.5 equiv) in CH Cl (0.25 M)
Ar
O
Ar
2
2
2
11
10
at –50 °C for 18 h.
b
c
d
e
f
1
Determined by H NMR (500 MHz) analysis.
Scheme 1
Determined by chiral phase HPLC (Chiralpak AD-H) analysis.
For definition, see ref.
The enantiomer of anti-6a was obtained in excess.
Toluene was used as a solvent.
The reaction was carried out in a 1:1 mixture of toluene and CH Cl .
13
R'
R'
R'2O
R
O
Si
R
O
Si
O
R
O
+ Si
O
g
2
2
R'
R'
Equation 4
lowering diastereo- and enantioselectivity to achieve full
conversion of the acetal (entry 6).1
4
Having established optimum conditions for the catalytic
ring-cleavage of acetal 4a, we then applied them to the
asymmetric desymmetrization of 2-substituted 1,3-pro-
panediols (Scheme 2, Table 2). Protection of the hydroxy
group of 4a by treatment with benzyl trichloroacetylimi-
date and trimethylsilyl triflate in CH Cl at 0 °C followed
The product of a catalytic ring-cleavage reaction with silyl
ketene acetals should be the corresponding silyl ether de-
rivative (e.g. 11 in Scheme 1). This was indeed the case
when dimethylsilyl derivatives 5b,d were employed as
nucleophiles. Product 6a and 7a were isolated after desi-
lylation of the crude reaction mixture containing dimeth-
ylsilyl ethers by treatment with aqueous acetic acid. The
reaction using trimethylsilyl derivative 5a and 5c, on the
other hand, gave 6a and 7a as major products with minor
formation of the corresponding trimethylsilyl ethers.
2
2
by removal of the nucleophile-derived moiety of the
8
resulting benzyl ether in TFA at room temperature
furnished (S)-3-benzyloxy-2-phenyl-1-propanol (12a)19
of 88% ee in 66% yield (entry 1). The ee value of 12a is
close to the estimated overall ee of a mixture of the ring-
cleavage products syn- and anti-7a (Table 1, entry 6), in-
dicating no racemization during the conversion to 12a.
The facile catalytic reaction observed for 5b,d suggests
that the dimethylsilyl group is more prone to migration
Synlett 2005, No. 13, 1999–2002 © Thieme Stuttgart · New York

LETTER
Catalytic Enantioselective Ring-Cleavage Reaction
2001
5
d,
(3) (a) Takabe, K.; Iida, Y.; Hiyoshi, H.; Ono, M.; Hirose, Y.;
Fukui, Y.; Yoda, H.; Mase, N. Tetrahedron: Asymmetry
2000, 11, 4825. (b) Takabe, K.; Mase, N.; Hashimoto, H.;
Tsuchiya, A.; Ohbayashi, T.; Yoda, H. Bioorg. Med. Chem.
Lett. 2003, 13, 1967. (c) Murakami, M.; Kamaya, H.;
Kaneko, C.; Sato, M. Tetrahedron: Asymmetry 2003, 14,
201. (d) Takabe, K.; Hashimoto, H.; Sugimoto, H.; Nomoto,
M.; Yoda, H. Tetrahedron: Asymmetry 2004, 15, 909.
R
R
R
3
(20 mol%),
Et2O
1
) BnOC(CCl3) = NH,
TMSOTf
O
O
HO
O
Ar
CH2Cl2,
50 °C
BnO
OH
2a–e
2) TFA,
–
and then
aq NaOH
Ar
a–e
Nu
1
7a–e
4
t
Ar = 1-Naph
Nu = –CH2COS Bu
(
4) (a) Crout, D. H. G.; Gaudet, V. S. B.; Laumen, K.;
Scheme 2
Schneider, M. P. J. Chem. Soc., Chem. Commun. 1986, 808.
(
b) Xie, Z.-F.; Nakamura, I.; Suemune, H.; Sakai, K. J.
Table 2 Asymmetric Desymmetrization of 2-Substituted 1,3-
Propanediols
Chem. Soc., Chem. Commun. 1988, 9667. (c) Morgan, B.;
Dodds, D. R.; Zaks, A.; Andrews, D. R.; Klesse, R. J. Org.
Chem. 1997, 62, 7736. (d) Claudia, N.; Williams, J. M. J.
Adv. Synth. Catal. 2003, 345, 835.
Entry R
7
Yield syn:antia 12
%)
Yield eeb
(
(%)
66
54
61
62
52
(%)
88
85
92
67
56
(
(
5) For the use of 1-ethoxyvinyl 2-furanoate as an acylating
agent to circumvent the problem, see; Akai, S.; Naka, T.;
Fujita, T.; Takebe, Y.; Tsujino, T.; Kita, Y. J. Org. Chem.
2002, 67, 411.
6) (a) Mukaiyama, T.; Tanabe, Y.; Shimizu, M. Chem. Lett.
1984, 401. (b) Ichikawa, J.; Asami, M.; Mukaiyama, T.
Chem. Lett. 1984, 949. (c) Harada, T.; Hayashiya, T.; Wada,
I.; Iwaake, N.; Oku, A. J. Am. Chem. Soc. 1987, 109, 527.
1
2
3
4
5
Ph
7a
81
84
84
86
91
15:1
–c
12a
12b
12c
12d
12e
4-MeOC H4 7b
6
3-MeC H4
7c
7d
7e
–c
6
i-Pr
4.1:1
4.5:1
(d) Harada, T.; Ikemura, Y.; Nakajima, H.; Ohnishi, T.; Oku,
Me
A. Chem. Lett. 1990, 1441. (e) Otera, J.; Sakamoto, K.;
Takao, T.; Orita, A. Tetrahedron Lett. 1998, 39, 3201.
(f) Akeboshi, T.; Ohtsuka, Y.; Ishihara, T.; Sugai, T. Adv.
Synth. Catal. 2001, 343, 624.
a
1
Determined by H NMR (500 MHz) analysis.
b
Determined by chiral phase HPLC analysis (Chiralpak AD-H and
Chiralcel OD for 12a–c and 12d,e, respectively).
c
(7) For highly enantioselective, catalytic desymmetrization
leading to mono-benzyloxy derivatives, see: Trost, B. M.;
Mino, T. J. Am. Chem. Soc. 2003, 125, 2410.
Not determined.
Ring-cleavage reaction of other 1-naphthyl acetals 4b–e
proceeded smoothly as well by using 20 mol% of OXB 3
and dimethylsilyl derivative 5d to give the corresponding
products 7b–e in high yield (entries 2–5). Benzylation of
(8) Harada, T.; Imai, K.; Oku, A. Synlett 2002, 972.
(
9) For OXB-mediated asymmetric desymmetrization other
prochiral polyols, see: (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.
4
b–e followed by TFA treatment afforded enantiomeri-
(
c) Harada, T.; Nakamura, T.; Kinugasa, M.; Oku, A.
cally enriched 3-benzyloxy-1-propanols 12b–e. 2-Aryl
derivatives 12b,c were obtained with high enantioselec-
tivities comparable to 12a. On the other hand, ring-cleav-
age reactions of isopropyl and methyl derivative 4d,e
were less selective resulting in moderate ee of the corre-
sponding desymmetrization products 12d,e.
Tetrahedron Lett. 1999, 40, 503. (d) Harada, T.; Yamanaka,
H.; Oku, A. Synlett 2001, 61. (e) Harada, T.; Sekiguchi, K.;
Nakamura, T.; Suzuki, J.; Oku, A. Org. Lett. 2001, 3, 3309.
(
10) Acetal 4a was prepared from 2-phenyl-1,3-propanediol and
1-naphthaldehyde (1.1 equiv) under the conventional
conditions (p-TsOH, toluene reflux). A pure trans-isomer
isolated by recrystallization from EtOAc and hexane (74%
yield) was used in ring-cleavage reaction.
In summary, asymmetric desymmetrization of 2-sub-
stituted 1,3-propanediols leading to the enantiomerically
enriched 3-benzyloxy-1-propanol derivatives 12 was de-
veloped by using OXB-catalyzed enantioselective ring-
cleavage reaction of the cyclic acetal derivatives 4. The
use of dimethylsilyl ketene acetals 5c,d is essential for the
facile catalytic ring-cleavage reaction. The characteristic
behavior of the dimethylsilyl group disclosed in the
present study might be utilized in relevant Lewis acid-
catalyzed reactions.
(
(
11) For the use of diethyl ether as an additive, see ref. 8 and 9d.
12) Harada, T.; Nakamura, T.; Kinugasa, M.; Oku, A. J. Org.
Chem. 1999, 64, 7594.
13) The overall enantioselectivity of 6, for example, is
calculated by [(syn-6 + anti-6) – (ent-syn-6 + ent-anti-6)}/
(
{
(syn-6 + anti-6) + (ent-syn-6 + ent-anti-6)].
(14) Representative Procedure for Catalytic Ring-Cleavage
Reaction (Table 1, Entry 6).
To a solution of N-tosyl-3-(2-naphthyl)-L-alanine (57.5 mg,
0
.15 mmol) in CH Cl (1.6 mL) under argon atmosphere at
2 2
r.t. was added dibromo-4-chlorophenylborane (23 mL, 0.15
mmol). After being stirred for 30 min, the mixture was
concentrated in vacuo. To a solution of the resulting OXB 3
in CH Cl (1.5 mL) at -50 °C were added dimethylsilyl
References
2
2
(
1) (a) Scott, J. W. In Asymmetric Synthesis, Vol. 4; Morrison,
J. D.; Scott, J. W., Eds.; Academic Press: New York, 1984,
ketene acetal 5d (428 mg, 2.25 mmol), Et O (117 mL), and a
2
toluene (1.5 mL) solution of acetal 4a (218 mg, 0.75 mmol).
After being stirred for 18 h at -50 °C, the mixture was
1. (b) For a recent example, see: Fellows, I. M.; Kaelin, D.
E. Jr.; Martin, S. F. J. Am. Chem. Soc. 2000, 122, 10781.
2) (a) Drauz, D.; Waldmann, H. Enzyme Catalysis in Organic
Synthesis; VCH: Weinheim / New York, 1995.
quenched by the addition of aq NaHCO and filtered. The
3
(
filtrate was extracted three times with Et O. The organic
2
layers were dried (MgSO ) and concentrated in vacuo. The
4
(
b) Schoffers, E.; Golebiowski, A.; Johnson, C. R.
residue was treated with aq 70% HOAc (0.5 mL) in THF (0.5
Tetrahedron 1996, 52, 3769. (c) Garcia-Urdiales, E.;
Alfonso, I.; Gotor, V. Chem. Rev. 2005, 105, 313.
mL) at r.t. for 1 h. The mixture was diluted with H O,
2
Synlett 2005, No. 13, 1999–2002 © Thieme Stuttgart · New York

2
002
T. Harada, K. Shiraishi
LETTER
(15) For the intervention of the silyl ester derivative in
extracted three times with Et O, and washed with aq
2
NaHCO . The organic layers were dried (MgSO ) and
concentrated in vacuo. Purification of the residue by flash
asymmetric aldol reaction catalyzed by a relevant OXB, see:
Parmee, E. R.; Tempkin, O.; Masamune, S. J. Am. Chem.
Soc. 1991, 113, 9365.
3
4
chromatography (SiO , 5–20% EtOAc in hexane) gave 262
2
8
mg (83%) of 7a (syn:anti = 15:1, 93% ee and 17% ee for
(16) Carreira, E. M.; Singer, R. A.; Lee, W. J. Am. Chem. Soc.
1994, 116, 8837.
1
syn- and anti-isomers, respectively). H NMR (500 MHz,
CDCl ): d = 1.53 (9 H, s), 2.41 (1 H, br), 2.90 (1 H, dd,
J = 2.7, 15.4 Hz), 3.12 (1 H, dd, J = 8.3, 15.4 Hz) 3.19 (1 H,
m), 3.68–3.80 (2 H, m), 3.88 (1 H, dd, J = 5.7, 11.0 Hz), 4.09
(17) (a) Miura, K.; Sato, H.; Tamaki, K.; Ito, H.; Hosomi, A.
Tetrahedron Lett. 1998, 39, 2585. (b) Miura, K.; Tamaki,
K.; Nakagawa, T.; Hosomi, A. Angew. Chem. Int. Ed. 2000,
39, 1958. (c) Nakagawa, T.; Suda, S.; Hosomi, A. Chem.
Lett. 2000, 150. (d) Miura, K.; Nakagawa, T.; Hosomi, A. J.
Am. Chem. Soc. 2002, 124, 536. (e) Miura, K.; Nakagawa,
T.; Hosomi, A. Synlett 2003, 2068.
3
(
1 H, dd, J = 7.6, 11.0 Hz), 5.61 (1 H, dd, J = 2.7, 8.3 Hz),
.09–7.30 (5 H, m), 7.42–7.59 (4 H, m), 7.81 (1 H, d, J = 8.1
Hz), 7.89 (1 H, br d, J = 8.0 Hz), 8.15 (1 H, br d, J = 8.2 Hz)
a minor anti-isomer resonated at d = 1.55 (9 H, s), 3.95 (1
7
[
1
3
H, dd, J = 5.0, 11.2 Hz)]. C NMR (125.8 MHz, CDCl ):
(18) For the use of a dimethylsilyl ketene acetal in OXB-
catalyzed asymmetric Michael reaction, see: Harada, T.;
Adachi, S.; Wang, X. Org. Lett. 2004, 6, 4877.
3
d = 29.8, 47.9, 48.5, 52.0, 65.3, 66.2, 71.7, 122.7, 123.9,
1
1
25.4, 125.7, 126.3, 126.8, 128.2, 128.38, 128.39, 129.0,
30.4, 133.8, 135.7, 139.9, 198.4. HPLC: ee determination
2
5
6d
(19) [a]D –22.9 (c 1.06, CHCl ) {lit. [a] +24.8 (c 1.00,
3
D
(HPLC, Chiralpak AD-H, 1.0 mL/min, 3% 2-PrOH in
CHCl )}.
3
hexane, (anti-7a) t = 31.3 min, (ent-syn-7a) t = 34.3 min,
1
2
(
syn-7a) t = 38.8 min, (ent-anti-7a) t = 46.8 min).
3 4
Synlett 2005, No. 13, 1999–2002 © Thieme Stuttgart · New York