Asymmetric desymmetrization of 2-substituted 1,3-propanediols by using oxazaborolidinone-mediated enantioselective ring-cleavage of prochiral acetal derivatives

Article abstract of DOI:10.1055/s-2002-31928

Nonenzymatic desymmetrization of 2-substituted 1,3-propanediols leading to the enantiomerically enriched 3-benzyloxy-1-propanols was achieved by using oxazaborolidinone-mediated enantioselective ring-cleavage reaction of the dioxane acetal derivatives.

Full text of DOI:10.1055/s-2002-31928

972
LETTER
Asymmetric Desymmetrization of 2-Substituted 1,3-Propanediols by Using
Oxazaborolidinone-Mediated Enantioselective Ring-Cleavage of Prochiral
Acetal Derivatives
Asymmetric
De
o
symmetriza
t
s
ionof 2-S
h
ubstituted 1,
i
3-Propa
r
nediolso Harada,* Keiko Imai, Akira Oku
Department of Chemistry and Materials Technology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan
E-mail: harada@chem.kit.ac.jp
Received 20 March 2002
CH2Cl2 proceeded without appreciable differentiation of
Abstract: Nonenzymatic desymmetrization of 2-substituted 1,3-
the enantiotopic C–O bonds of the acetal, resulting in the
propanediols leading to the enantiomerically enriched 3-benzyloxy-
formation of ring-cleavage product 4 of low ee.5 N-Mesyl
1-propanols was achieved by using oxazaborolidinone-mediated
derivative 3b showed somewhat improved selectivity of
51% ee (entry 2). Tryptophan and (2-naphthyl)alanine de-
rived oxazaborolidinone 3c and 3d provided similar levels
of enantioselectivity (entries 3 and 4).
enantioselective ring-cleavage reaction of the dioxane acetal deriv-
atives.
Key words: asymmetric synthesis, acetals, cleavage, diols, Lewis
acids
OSiMe3
Ph
Ph
Enantiomerically enriched mono-protected derivatives of
2-substitued 1,3-propanediols are useful chiral building
blocks which have been frequently employed in natural
product synthesis.1 One of the most straightforward meth-
ods for their preparation involves asymmetric desymme-
trization of parent prochiral propanediols or their
derivatives and enzyme-mediated transesterification or
hydrolysis has been used for this purpose.2 So far, a rela-
tively few reports have been appeared on nonenzymatic
approach which could be of wide generality allowing to
prepare a tailor-made chiral building blocks appropriate to
a specific target molecule.3
OEt
O
CH2Cl2, -50 °C
O
2
(1)
HO
O
Ar
O
O
B
R3
(CH3)2CCO2Et
Ar
R1
N
4
1a–d
SO2R2
3a–i
R1
R2SO2
R3
3a
3b
3c
3d
3e
3f
3g
3h
3i
Ph
Ph
Ts
Ms
Ms
Ts
Ph
Ph
Ph
Ph
2-Indolyl
2-Naph
Ph
Ts
p-ClC6H4
p-ClC6H4
p-ClC6H4
Ph
Ph
Ms
Ts
2-Naph
2-Naph
2-Naph
Ms
Ms
Ring-cleavage reaction of the cyclic acetal derivatives of
the propanediols, if it could be realized in an enantioselec-
tive manner, would advantageously give enantiomerically
enriched mono-protected derivatives without byproduct
formation of bis-protected derivative. We recently dis-
closed that oxazaborolidinones 3 as chiral Lewis acids are
effective in enantioselective ring-cleavage reaction of
meso-1,3-dioxolane and -dioxane acetals.4 In this paper,
we wish to report that oxazaborolidinone-mediated ring-
cleavage reaction can be successfully applied to asymmet-
ric desymmetrization of 2-substituted 1,3-propanediols
through modification of the chiral Lewis acid and the sub-
stituent attached at the acetal carbon of the 1,3-dioxane
acetal derivatives.
p-ClC6H4
Scheme 1
According to our previous study, enantioselectivity of ox-
azaborolidinone-mediated ring-cleavage reaction is sensi-
tive to the electronic and steric nature of the substituent
attached to the acetal carbon. 4a,d,e,7 We then turned our at-
tention to the modification the 2-aryl group of the dioxane
acetal. Although the enantioselectivity was not affected
significantly by the introduction of electron-donating or
electron-withdrawing aryl group (entries 5 and 6), moder-
ately high ee (81%) was obtained in the reaction of 1d
with sterically more demanding 1-naphthyl group by us-
ing oxazaborolidinone 3b (entry 7).8,9
Ring-cleavage reaction of acetal 1a (R = Ph) derived from
2-phenyl-1,3-propanediol and benzaldehyde was first ex-
amined by using N-tosylphenylalanine derived ox-
azaborolidinone 3a (1.2 equiv) (Scheme 1; Table 1, entry
1). While 3a exhibits excellent enantioselectivity for cy-
clic acetals derived from meso-1,2- and -1,3-diols,4 the re-
action of 1a with silyl ketene O,O-acetal 2 at –50 °C in
Oxazaborolidinones were again optimized for 1-naphthyl
acetal 1d. Modification of the substituents attached to the
nitrogen atom (3a) and/or to the boron atom (3e,f) gave
similar levels of enantioselectivity (entries 8–10). On the
other hand, further improvement in the enantioselectivity
was obtained when (2-naphthyl)alanine derivative 3g
with the B-(p-chlorophenyl) group was employed (entry
11). N-Mesyl derivatives 3h,i did not give better results
(entries 13 and 14). The best result of 90% ee was
Synlett 2002, No. 6, 04 06 2002. Article Identifier:
1437-2096,E;2002,0,06,0972,0974,ftx,en;Y03802ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Asymmetric Desymmetrization of 2-Substituted 1,3-Propanediols
973
Table 1 Ring-Cleavage Reaction of Prochiral Acetals 1a–d Medi-
ated by Oxazaborolidinone 3a
Ring-cleavage reaction of other 1-naphthyl acetals 1e–g
proceeded smoothly by using (2-naphthyl)alanine derived
oxazaborolidinone 3g as a chiral Lewis acid to give the
corresponding products 4b–d in high yield (Table 2).
Benzylation of 4b–d followed by TFA treatment afforded
enantiomerically enriched 3-benzyloxy-1-propanols 5b–
d. 2-Isopropyl and 2-cyclochexyl derivatives 5b,c were
obtained with enantioselectivities comparable to 5a. On
the other hand, ring-cleavage reaction of 1g was less se-
lective resulting in lower ee of 2-methyl derivative 5d.
Entry 1 (Ar)
3
4
Yield (%) dsb
ee (%)c
11
1
2
1a (Ph)
3a
3b
3c
3d
3b
3b
3b
3a
3e
3f
43
64
50
96
70
76
73
85
82
78
85
91
64
56
16
16
18
23
51
3
50
4
49
Table 2 Asymmetric Desymmetrization of 2-Substituted 1,3-Pro-
panediols
5
1b (p-MeOC6H4)
1c (p-ClC6H4)
1d (1-Naph)
2.1
48
6
39
28
7
63
Entry Acetal 4a–d
Yield (%) dsa
5a–d
7
81
Yield (%) ee (%)b [ ]D
c
8
71
1
2
3
4
1d
1e
1f
91
91
77
88
30
73
61
65
64
88
82
82
62
–25.6
–14.4
–10.3
–8.2
9
36
36
30
31
16
18
82
15
10
11
12d
13
14
82
nd d
12
3g
3g
3h
3i
88
1g
a The ratio of syn and anti diastereomers determined by 500 MHz 1H
NMR analysis.
90
83
b Determined by chiral phase HPLC (Chiracel AD) analysis.
c In CHCl3 (c 1.1, 0.61, 0.87, and 0.52 for 5a–d, respectively), lit. for
(R)-5a; [ ]D +24.8 (c 1.00, CHCl3),3d lit. for (S)-5d; [ ]D +12.9
(c 1.01, CHCl3).11
83
a Reactions were carried out by using 3 (1.2 equiv) and 2 (3.0 equiv)
in CH2Cl2 (0.4 M) at –50 °C for 20 h.
d Not determined.
b The ratio of syn and anti diastereomers determined by 500 MHz 1H
NMR analysis.
c Ee values for the major diastereomers determined by chiral phase
HPLC (Chiracel AD) analysis.
It is most probable that the activation of a specific acetal
oxygen atom through enantiodifferentiating complexation
by a chiral Lewis acid is a major factor governing the
enantioselectivity of the ring-cleavage reaction.4e,6 The
absolute configurations of desymmetrized products 5 sug-
gest the selective formation of acetal-oxazaborolidinone
complex 7 in the ring-cleavage reaction of (1-naphth-
yl)acetals 1d–g mediated by oxazaborolidinone 3g (Fig-
ure). Around the coordinating oxygen atom, complex 7
possesses a local structure 6 similar to complexes 8–11
which are presumed to be formed preferentially in the pre-
viously reported ring-cleavage reaction of five- and six-
membered cyclic acetals mediated by oxazaborolidino-
nes.4,12 In this regard, we recently proposed a working
model for the activated complexes through which com-
mon local structure 6 found for 8–11 can be rationalized.4e
Application of the model to 2,5-disubstituted dioxane ac-
etals 1d–g again explains the selective formation of com-
plex 7 (Scheme 3). Thus, the coordination of O(1) oxygen
atom by oxazaborolidinone 3g gives rise to complex 7
without unfavorable interaction. Of three staggered con-
formers around the O–B bond of a complex derived from
O(1) coordination, only 7 does not experience unfavor-
able nonbonded interaction. On the other hand, unfavor-
able interactions exists in all three staggered conformers
of an alternative complex derived from the O(3) coordina-
tion as shown for example, in 12 of a local conformation
similar to that of 7 around the O–B bond.
d Et2O 3 equiv was added
achieved in the reaction using 3g in the presence of diethyl
ether (3 equiv) as an additive (entry 12).10
Having established optimum conditions for the enantiod-
ifferentiating ring-cleavage of acetal 1d, we then applied
them to the asymmetric desymmetrization of 2-substitut-
ed 1,3-propanediols (Scheme 2, Table 2). Protection of
the hydroxy group of 4a (R = Ph) possessing the ester
moiety was achieved by treatment with KN(TMS)2 and
benzyl bromide in DMF–THF at room temperature. Treat-
ment of the resulting benzyl ether in TFA furnished (S)-3-
benzyloxy-2-phenyl-1-propanol (5a) of 88% ee in 73%
overall yield from 4a (entry 1).
R
1) KN(TMS)2
BnBr
DMF, THF
R
R
2, 3g, Et2O
(2)
O
O
HO
O
BnO
OH
CH2Cl2
-50 °C
2) TFA
(CH3)2CCO2Et
1d; R = Ph
4a; R = Ph
5a; R = Ph
1e; R = iso-Pr
1f; R = c-Hex
1g; R = Me
4b; R = iso-Pr
4c; R = c-Hex
4d; R = Me
5b; R = iso-Pr
5c; R = c-Hex
5d; R = Me
Scheme 2
Synlett 2002, No. 6, 972–974 ISSN 0936-5214 © Thieme Stuttgart · New York

974
T. Harada et al.
LETTER
Chem. Lett. 1984, 949. (c) Harada, T.; Hayashiya, T.; Wada,
I.; Iwa-ake, N.; Oku, A. J. Am. Chem. Soc. 1987, 109, 527.
(d) Harada, T.; Ikemura, Y.; Nakajima, H.; Ohnishi, T.; Oku,
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.
O
O
N
O
L
S
B
Ar'
BL*3
=
Ar
R
BL*3
Ts
6
H
Ar
H
H
R
O
H
O
H
(4) (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.; Yamanaka, H.; Oku, A.
Synlett 2001, 61. (e) Harada, T.; Sekiguchi, K.; Nakamura,
T.; Suzuki, J.; Oku, A. Org. Lett. 2001, 3, 3309.
(5) The relative configuration of the major diastereomers was
assigned tentatively based on the assumption of the
introduction of the nucleophile with inversion of the acetal
carbon.4e,6
H
O
H
O
O
O
Ar
Ar
R
BL*3
BL*3
BL*3
R'
7
8
9
H
O
H
R
R
R'
O
H
O
R
O
R
BL*3
BL*3
10
11
Figure
(6) Harada, T.; Nakamura, T.; Kinugasa, M.; Oku, A. J. Org.
Chem. 1999, 64, 7594.
(7) Harada, T.; Egusa, T.; Kinugasa, M.; Oku, A. Tetrahedron
Lett. 1998, 39, 5531.
(Ar = 1-Naph)
(8) Treatment of 2-phenyl-1,3-propanediol and 1-
naphthaldehyde (1.1 equiv) under the conventional reaction
conditions (p-TsOH, refluxing) gave acetal 1e (trans:cis =
6:1) in quantitative yield. A pure trans isomer obtained by
recrystallization from ethyl acetate and hexane was used in
ring-cleavage reaction.
R
O
H
1
O
Ar
3
3g
1d–g
(9) Acetal 1c with the electron-withdrawing p-chlorophenyl
group showed slightly higher enantioselectivity. Electron-
withdrawing character of the 1-naphthyl group relative to the
phenyl group may also be responsible for the high selectivity
observed for 1d.
SO2
N
SO2
N
2-Naph
2-Naph
C6H4-p-Cl
H
Ar
O
1
3
1
O
O
R
C6H4-p-Cl
R
B
B
O
3
Ar
H
H
O
O
O
O
(10) Typical experimental procedure: To a solution of N-tosyl-L-
(2-naphthyl)alanine (177 mg, 0.480 mmol) in CH2Cl2 (5.0
mL) at room temperature under argon was added dibromo(p-
chlorophenyl)borane (72 L, 0.48 mmol).4d After being
stirred for 30 min, the mixture was concentrated in vacuo
and the residue was dissolved in CH2Cl2 (0.5 mL). To the
resulting solution of oxazaborolidinone 3g at –50 °C were
added Et2O (0.12 mL) and a solution of acetal 1d (116 mg,
0.400 mmol) and silyl ketene acetal 2 (226 mg, 1.20 mmol)
in CH2Cl2 (0.5 mL). After being stirred for 20 h at –50 °C,
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 AcOH (70%, 2
mL) and THF (2 mL) at room temperature for 1 h. The
mixture was diluted with water, extracted twice with ether,
and washed with aqueous NaHCO3. The organic layers were
dried and concentrated in vacuo. Purification of the residue
by flash column chromatography (SiO2, 5–20% ethyl acetate
in hexane) gave 147 mg (91% yield) of 4a: 1H NMR (500
MHz, CDCl3) 1.02 (3 H, s), 1.25 (3 H, s), 1.32 (3 H, t, J =
7.2 Hz), 2.20 (1 H, br), 3.12 (1 H, quint, J = 5.5 Hz), 3.58–
3.64 (2 H, m), 3.84 (1 H, dd, J = 5.7 and 11.0 Hz), 4.03 (1 H,
dd, J = 7.5 and 11.0 Hz), 4.20 (2 H, m), 5.70 (1 H, br), 7.15–
7.30 (5 H, m), 7.47–7.56 (4 H, m), 7.83 (1 H, d, J = 8.3 Hz).
7.89 (1 H, m), 8.20 (1 H, m) [a minor diastereomer resonated
at 3.91 (1 H, dd, J = 5.0 and 11.0 Hz)]; IR (liquid film):
3475(br), 1725 cm–1; HRMS (CI) calcd for C26H31O4 (MH+)
407.2222, found; 407.2219.
H
H
H
12
7'
Scheme 3
In summary, we have developed a nonenzymatic method
for asymmetric desymmetrization of 2-substitued 1,3-pro-
panediols. The method relies on oxazaborolidinone-medi-
ated enantioselective ring-cleavage reaction of the 1,3-
dioxane acetal derivatives. 1-Naphthyl group as a substit-
uent attached to the acetal carbon was found to be crucial
for obtaining a high enantioselectivity.
Acknowledgment
This work was supported partially by a Grant-in-Aid for Scientific
Research from Ministry of Education, Culture, Sports, Science and
Technology.
References and Notes
(1) (a) Scott, J. W. In Asymmetric Synthesis, Vol. 4; Morrison,
J. D.; Scott, J. W., Eds.; Academic Press: New York, 1984,
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: New York, 1995. (b) Schoffers, E.;
Golebiowski, A.; Johnson, C. R. Tetrahedron 1996, 52,
3769.
(11) (a) Spino, C.; Christian, B.; Lafreniére, J. J. Org. Chem.
2000, 65, 7091. (b) Trost, B. M.; Kondo, Y. Tetrahedron
Lett. 1991, 32, 1613.
(12) Kinugasa, M.; Harada, T.; Oku, A. J. Org. Chem. 1996, 61,
6772.
(3) (a) Mukaiyama, T.; Tanabe, Y.; Shimizu, M. Chem. Lett.
1984, 401. (b) Ichikawa, J.; Asami, M.; Mukaiyama, T.
Synlett 2002, No. 6, 972–974 ISSN 0936-5214 © Thieme Stuttgart · New York