Stereochemical control of tertiary alcohol: Aldol condensation of lactate derivatives

Article abstract of DOI:10.1016/S0040-4039(01)00818-8

Stereoselective construction of aldol adducts having tertiary alcohol at the α position was achieved via a titanium(IV) enolate derived from a lactate derivative with an Evans chiral auxiliary. The stereochemistry at α-tertiary alcohol could be controlled by selecting the protective group of the starting lactate.

Full text of DOI:10.1016/S0040-4039(01)00818-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5249–5252
Stereochemical control of tertiary alcohol: aldol condensation of
lactate derivatives
Tomoyuki Kamino, Yoshihisa Murata, Nobuyuki Kawai, Seijiro Hosokawa and
Susumu Kobayashi*
Faculty of Pharmaceutical Sciences, Science University of Tokyo, Ichigaya-Funagawara-machi, Shinjuku-ku,
Tokyo 162-0826, Japan
Received 16 April 2001; revised 8 May 2001; accepted 11 May 2001
Abstract—Stereoselective construction of aldol adducts having tertiary alcohol at the a position was achieved via a titanium(IV)
enolate derived from a lactate derivative with an Evans chiral auxiliary. The stereochemistry at a-tertiary alcohol could be
controlled by selecting the protective group of the starting lactate. © 2001 Elsevier Science Ltd. All rights reserved.
The azaphilone skeleton 1 is seen in many biologically
active natural products such as mitorubinic acid1 and
diazaphilonic acid.2 Although the azaphilone family
exhibits significant biological activities, only a few syn-
thetic studies which start from aromatic compounds
have been reported and there is no precedent for asym-
metric synthesis.3 One of characteristic features seen in
the azaphilone skeleton is a tertiary alcohol surrounded
by two carbonyls. Coupled with our continuing interest
in chiral quaternary carbons,4 we embarked on an
enantioselective construction of a chiral tertiary alcohol
toward the azaphilone skeleton. We first examined the
aldol-type reaction of lactic acid-derived chiral enolate
with an aldehyde, and we observed some interesting
findings.
Although our strategy (Scheme 1, eq. 1) is very simple,
the aldol reaction of lactate derivatives having an Evans
chiral auxiliary was not known. Actually, a stereoselec-
tive aldol addition of 3 under conventional conditions
OP
Me OP
XN*
R
XN*
R
CHO
+
(eq. 1)
*
*
Me
O
R1
2
O
OH
O
3
4
O
2O
Me
n-Bu2BOTf
i-Pr2NEt
O
1
no reaction
(eq. 2)
CHO
CH2Cl2
LDA
OBn
O
N
Me
O
O
O
OH
CHO
5
O
N
(eq. 3)
THF
-78°C
O
BnO
6
69% (1:1 mixture of two isomers)
Scheme 1.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00818-8

5250
T. Kamino et al. / Tetrahedron Letters 42 (2001) 5249–5252
was found difficult. For example, the Evans aldol
reaction5 did not work for 5 (eq. 2) and a lithium
enolate derived from 5 gave an almost 1:1 mixture of
two isomers as cyclic carbamates 6 (eq. 3). Therefore,
we examined the addition of Lewis acid to the lithium
enolate (Table 1). Most of the Lewis acids exerted no
tained when
D
-lactate derived 10 and a mixture (5 and
10/1:1) were reacted with crotonaldehyde under the
same conditions (Scheme 3). Accordingly, the present
aldol reaction is independent of the stereochemistry of
the starting lactate, and it seems that the same enolate
was generated stereoselectively from
5 and 10.
6
influence on the stereoselectivity, but TiCl(Oi-Pr)3
Although the lithium enolate derived from 5 gave the
corresponding silyl enol ether as a single isomer, the
determination of the stereochemistry of the resulting
changed the diastereo ratio significantly (entry 8). Fur-
6
ther, addition of 3.3 equivalents of TiCl(Oi-Pr)3
improved the diastereoselectivity (20:1) affording anti-
1
silyl ether was difficult by H NMR analysis because
adduct 6a7 in good yield (entry 9).
the signals of the silyl ether lay one upon another (eq.
4). On the other hand, clean NOE was observed with
silyl enol ether 13 obtained stereoselectively by treat-
ment of 12 with LDA and TESCl. In analogy to 13, we
tentatively assume the stereochemistry of 11 as E-11
(eq. 5).
The relative stereochemistry of 6a was determined by
the NOE spectrum of 7, which was derived from 6a in
five steps,9 and the absolute stereochemistry was estab-
lished as shown by optical rotation of 8,8 which was
derived from 6a in seven steps.10 The stereochemistry of
the other adduct was proven to be 6b by conversion of
both stereoisomers into the b-ketoester 9, which show
the same sign of optical rotation (Scheme 2).11
We next examined TBS-ether 14 as a substrate. In this
case, no oxazolidone-opening products were detected
and syn-adduct 1512 was obtained in good yield with
7:1 selectivity (Scheme 4). The relative stereochemistry
Similar results (yield and stereoselectivity) were ob-
Table 1. The effect of Lewis acid
O
O
1) LDA
2) Lewis acid (1.1eq)
OBn
OH
OH
CHO
O
N
O
N
3)
O
N
+
Me
O
O
THF
O
O
BnO Me
BnO Me
5
6a
6b
Entry
Lewis acid
Temperature (°C)
Yield (%)
a:b
1
2
3
4
5
6
7
8
9
–
−78
−78 to 0
−78
−78
−78
69
41
9
1:1
1:1
–
–
1:1
1:1
–
8:1
20:1
n-Bu2BOTf
SnCl2
TiCl4
Et2AlCl
n-Bu3SnCl
Ti(Oi-Pr)4
Ti(Oi-Pr)3Cl
Ti(Oi-Pr)3Cl (3.3 equiv.)
No reaction
33
57
13a
52
63
−78
−78 to −40
−78 to −40
−78 to −40
a 1,4-Adducts were obtained as major products (70%).
NOE 4%
O
Me
OH
O
OH
Me
H
HO
O
ref. 9
O
N
ref. 10
OH
O
Me
O
HO Me
[α]D25 = -13.3 (c 3.20, MeOH)
lit.8 [α]D20 = +14.6 (c 1.37, MeOH) for ent-8
8
Me
O
OTBS
NOE 5%
OTBS
BnO Me
7
6a
O
O
O
O
OH
OH
ref. 11
O
N
O
N
ref. 11
OBn
O
O
BnO Me
BnO Me
BnO Me
9
6a
6b
Scheme 2.

T. Kamino et al. / Tetrahedron Letters 42 (2001) 5249–5252
5251
O
OBn
OH
OBn
O
N
O
O
N
N
65%
68%
Me
Me
O
O
O
O
O
BnO
10
( 5 : 10 = 1 : 1)
6a
LDA
TESCl
OBn
OBn
Me
O
O
O
N
(eq. 4)
or
N
N
Me
THF
-78°C
74%
Me
BnO
O
O
OTES O
OTES O
single isomer
5
E-11
Z-11
Me
Me
LDA
TESCl
Me
O
Me
OBn
OBn
(eq. 5)
O
THF
-78°C
N
N
Me
Me
70%
TESO
O
O
O
12
NOE
single isomer
13
Scheme 3.
1) LDA
2) Ti(Oi-Pr)3Cl (3.3eq)
CHO
TBSO Me
OTBS
O
3)
O
O
N
O
N
Me
THF
-78 ~ -40°C
OH
O
O
15
14
75% (7:1 mixture of two isomers)
OH
NOE 7%
Me
O
O
ref. 13
ref. 15
Me
O
TBSO Me
O
O
N
Me
17
O
Me
16
[α]D25 = +48 (c 0.106, hexane)
lit.14 (88%ee) [α]D25 = -43 (c 0.07, hexane) for ent-17
H
OH
O
O
OH
OH
15
Scheme 4.
of 15 was determined by the NOE spectrum of 16,
which was derived from 15 in five steps,13 and the
absolute stereochemistry was determined by optical
rotation of 17,14 which was derived from 15 in six
steps.15 Thus, the aldol adduct 15 has the opposite
stereochemistry of a tertiary alcohol and the same
stereochemistry as a secondary alcohol as compared to
6a.
Acknowledgements
This work was supported in part by Shin-Etsu Chemi-
cal Co., Ltd., and Grant-in-Aid for Scientific Research
from the Ministry of Education, Science, Sports, and
Culture, Japan.
In conclusion, we have found a stereoselective aldol
reaction with a lactic acid-derived chiral enolate. It
should be noted that the stereochemistry of the quater-
nary chiral center (tertiary alcohol) could be controlled
by proper choice of the protecting group of the starting
lactate. Work on the scope and limitation, as well as a
precise mechanism of the reaction is now in progress.
References
1. Locci, R.; Merlini, L.; Nasini, G.; Locci, J. R. Giorn.
Microbiol. 1967, 15, 93–102.
2. Tabata, Y.; Ikegami, S.; Yaguchi, T.; Sasaki, T.;
Hoshino, S.; Sakuma, S.; Shin-ya, K.; Seto, H. J.
Antibiot. 1999, 52, 412–414.

5252
T. Kamino et al. / Tetrahedron Letters 42 (2001) 5249–5252
9. (i) NaBH4, THF–H2O (3:1); (ii) LiOOH, THF–H2O (3:1),
3. Chong, R. R.; Gray, W.; King, R. R.; Whalley, W. B. J.
63% in two steps; (iii) TBSCl, i-Pr2NEt, DMAP, DMF,
0°C, 3.5 h, 75%; (iv) Li, NH3, THF, −78°C, 2 h, 64%; (v)
2,2-dimethoxypropane, CSA, CH2Cl2, rt, 2 h, 82%.
10. (i) NaBH4, THF–H2O (3:1); (ii) LiOOH, THF–H2O (3:1),
63% in two steps; (iii) BnCl, NaH, TBAI, THF, 91%; (iv)
OsO4, NMO, acetone–H2O (5:1), 99%; (v) Pb(OAc)4,
benzene; (vi) NaBH4, MeOH, 80% in two steps; (vii) H2,
Pd–C, MeOH, quant.
Chem. Soc. (C) 1971, 3571–3575.
4. Hosokawa, S.; Sekiguchi, K.; Enemoto, M.; Kobayashi,
S. Tetrahedron Lett. 2000, 41, 6429–6433.
5. Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc.
1981, 103, 2127–2129.
6. Nerz-Stormes, M.; Thornton, E. Tetrahedron Lett. 1986,
27, 897–900.
7. General procedure: To a solution of LDA (prepared from
DIPA (27.1 ml, 206 mmol), and n-BuLi (1.6 M in hexane,
118 ml, 189 mmol) at −15°C for 15 min) was added a
solution of 5 (50.0 mg, 172 mmol) at −78°C. After stirring
for 30 min at −78°C, TiCl(Oi-Pr)3 (1.0 M in hexane, 568
ml, 568 mmol) was added and the resulting mixture was
stirred for 1 h at −40°C. After cooling to −78°C, croton-
aldehyde (15.2 ml, 189 mmol) was added to the mixture
which was additionally stirred at −40°C for 2 h. The
reaction mixture was quenched with sat. NH4Cl and
stirred with Celite for 1 h at rt. Filtration, extraction with
AcOEt, washing the organic layer with brine followed by
drying with Na2SO4 and evaporation gave a crude oil,
which was purified by preparative TLC (hexane:AcOEt=
2:1) to yield 6a (39.1 mg, 63%). 6a: Rf=0.50 (hex-
11. (i) BnOLi, BnOH, THF, −78 to 0°C, 32% for 6a, 34% for
6b; (ii) MnO2, CH2Cl2, rt, 46% for 6a, 59% for 6b. 9
(from 6a) [h]2D5=+7.02 (c 0.340, CHCl3); 9 (from 6b)
[h]2D5=+7.81 (c 0.573, CHCl3).
12. 15: Rf=0.39 (hexane:AcOEt=5:1); [h]2D2=+26.8 (c 0.774,
1
CHCl3); H NMR (400 MHz, CDCl3): l (ppm) 0.11 (3H,
s), 0.24 (3H, s) 0.91–0.93 (15H, m), 1.57 (3H, s), 1.74 (3H,
dd, J=6.3, 1.2 Hz), 2.29–2.37 (1H, m), 2.52 (1H, bs), 4.23
(1H, dd, J=8.4, 3.4 Hz), 4.32 (1H, t, J=8.7 Hz), 4.57
(1H, dt, J=8.7, 3.4 Hz), 4.97 (1H, dd, J=11.1, 7.7 Hz),
5.53 (1H, ddq, J=15.3, 7.7, 1.2), 5.80 (1H, dq, J=15.3,
6.4 Hz). 13C NMR (100 MHz, CDCl3): l (ppm) −2.5,
14.5, 17.9, 17.9, 18.8, 21.3, 26.1, 28.1, 60.4, 63.3, 75.1,
83.8, 128.6, 130.1, 152.9, 174.6; IR (neat) 3555, 2956,
2856, 1780, 1702, 1471, 1388, 1252, 1190, 1130, 996, 837,
758 cm−1; HR-EIMS: calcd for C18H32NO5Si ([M−Me]+)
370.2050, found 370.2032.
1
ane:AcOEt=2:1); [h]D23=−35.3 (c 4.94, CHCl3); H NMR
(400 MHz, CDCl3): l (ppm) 0.86 (3H, d, J=6.59 Hz),
1.03 (3H, d, J=6.6 Hz), 1.45 (3H, s), 1.77 (3H, d, J=6.3
Hz), 2.38–2.47 (1H, m), 2.69 (1H, bs), 3.73 (1H, dd,
J=11.6, 9.3 Hz), 4.06 (1H, dd, J=11.5, 8.5 Hz), 4.41
(1H, bs), 4.49 (1H, d, J=10.0 Hz), 4.61 (1H, d, J=10.9
Hz), 4.88 (1H, d, J=7.8 Hz), 5.45 (1H, dd, J=14.8, 7.8
Hz), 6.01 (1H, dq, J=14.8, 6.3 Hz), 7.26–7.39 (5H, m);
13C NMR (100 MHz, CDCl3): l (ppm) 15.7, 18.0, 19.9,
20.1, 26.0, 62.0, 75.5, 81.7, 121.9, 127.3, 127.8, 135.8,
137.1, 170.5; IR (neat) 3491, 2968, 2455, 1755, 1697,
13. (i) TESCl, DMAP, imidazole, DMF, rt, overnight; (ii)
BnSLi, BnSH, THF, 0°C, 1.5 h; (iii) TBAF, THF, 0°C, 1
h, 70% in three steps; (iv) 2,2-dimethoxypropane, CSA,
CH2Cl2, rt, overnight, 92%; (v) NaBH4, i-PrOH, rt,
overnight, 55%.
14. Leal, W. S.; Shi, X.; Nakamura, K.; Ono, M.; Meinwald,
J. Proc. Natl. Acad. Sci. USA 1995, 92, 1038–1042.
15. (i) BOMCl, DMAP, i-Pr2NEt, CH2Cl2, rt, 2 days, 89%;
(ii) DIBAL, CH2Cl2, rt, 2 h; (iii) TBAF, THF, 0°C, 2 h,
69% in two steps; (iv) H2, Pd–C, AcOEt, rt, 1.5 h; (v)
Pb(OAc)4, benzene, 1 h, 88% in two steps; (vi) H2,
Pd(OH)2, MeOH, 5 h, 53%.
1454, 1372, 1213, 1124, 1027, 760 cm−1
8. Fontana, A.; Messina, R.; Spinella, A.; Cimino, G. Tet-
rahedron Lett. 2000, 41, 7559–7562.
.
.