Enantiopure β-methoxy carboxyl derivatives from a chiral titanium enolate and dimethyl acetals

Article abstract of DOI:10.1016/S0040-4039(01)00829-2

Lewis acid-mediated reaction of the titanium enolate arising from (S)-N-acetyl-4-isopropyl-1,3-thiazolidine-2-thione with dimethyl acetals furnishes β-methoxy carboxyl adducts in good yields and stereoselectivities. The adducts can be, in turn, transformed into a wide range of enantiopure α-unsubstituted β-methoxy carboxyl derivatives in excellent yields.

Full text of DOI:10.1016/S0040-4039(01)00829-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4629–4631
Enantiopure b-methoxy carboxyl derivatives from a chiral
titanium enolate and dimethyl acetals†
Annabel Cosp, Pedro Romea,* Fe`lix Urp´ı* and Jaume Vilarrasa
Departament de Qu´ımica Orga`nica, Universitat de Barcelona, 08028 Barcelona, Catalonia, Spain
Received 27 April 2001; accepted 16 May 2001
Abstract—Lewis acid-mediated reaction of the titanium enolate arising from (S)-N-acetyl-4-isopropyl-1,3-thiazolidine-2-thione
with dimethyl acetals furnishes b-methoxy carboxyl adducts in good yields and stereoselectivities. The adducts can be, in turn,
transformed into a wide range of enantiopure a-unsubstituted b-methoxy carboxyl derivatives in excellent yields. © 2001 Elsevier
Science Ltd. All rights reserved.
The widespread presence of alkoxy groups in poly-
ketide natural products has given rise to the develop-
ment of a plethora of synthetic approaches to b-alkoxy
carbonyl compounds, which usually rely on a multistep
process: (i) stereoselective aldol1,2 or allyl transfer3,4
reaction, (ii) alkylation of the adduct and, if it is
required, (iii) further elaboration of the carbonyl or the
alkene moieties. Taking into account that the integra-
tion of a multistep sequence in a single transformation
increases the efficiency of a process, we envisioned that
a stereoselective addition of metal enolates to acetals
might afford b-alkoxy carbonyl systems in a straight-
forward manner.5 In this context, we have recently
reported6 that the reaction of the titanium enolate
arising from 17 with dimethyl acetals gives access to
enantiopure anti a-methyl-b-methoxy carbonyl com-
pounds (see Scheme 1). We now report on a related
case in which it is more difficult to achieve stereochem-
ical control, that of the reaction of dimethyl acetals
with the titanium enolate from (S)-N-acetyl-4-isopro-
pyl-1,3-thiazolidine-2-thione (2), the N-acetyl analogue
of 1 (see Scheme 1).8,9
Initial experiments showed the higher reactivity of the
titanium enolate of 2 compared to the corresponding
one of 1. For instance, the titanium enolate of 2
underwent addition to benzaldehyde dimethyl acetal (a)
at −78°C and furnished a mixture of adducts 3 and 4
(see Scheme 2) in 75% overall yield and a good
diastereomeric ratio (86:14). Given that the elec-
trophilicity of an acetal may be enhanced by coordina-
tion to a Lewis acid (LA), it was next tested the effect
of several Lewis acids on the stereoselectivity and the
overall yield of the process. The results are summarised
in Table 1. Both BF3·OEt2 and SnCl4 afforded good
S
S
S
O
O
OMe
R
O
OMe
R
a
+
S
N
S
N
S
N
2
3
4
i
Scheme 2. (a) (i) TiCl4, Pr2EtN; (ii) RCH(OMe)2, LA.
S
S
S
O
OMe
R
O
O
OMe
R
R'
see Ref. 6
This Letter
S
N
S
N
S
N
1
R' = Me
2 R' = H
Scheme 1.
Keywords: acetals; aldol reactions; asymmetric reactions; enolates.
* Corresponding authors. Fax: +34 93 339 78 78; e-mail: promea@qo.ub.es; furpi@qo.ub.es
† Dedicated to Professor David A. Evans on the occasion of his 60th birthday.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00829-2

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A. Cosp et al. / Tetrahedron Letters 42 (2001) 4629–4631
Table 1. Reaction of benzaldehyde and acetaldehyde dimethyl acetal with the titanium enolate of 2
Entry
Acetal
R
Lewis acid
Conditions (T, t)a
dr 3:4b
Yield (%)c
1
2
3
4
5
6
7
8
9
a
a
a
a
a
b
b
b
b
Ph
Ph
Ph
Ph
–
−78°C, 4 h
−78°C, 2 h
−78°C, 2 h
−78°C, 2 h
−78°C, 2 h
−78°C, 4 h
−78°C, 2 h
−78°C, 2 h
−78°C, 2 h
86:14
88:12
55:45
85:15
69:31
64:36
65:35
76:24
68:32
75
92
45
92
95
30
17
72
85
BF3·OEt2
Et2AlCl
SnCl4
TiCl4
–
BF3·OEt2
SnCl4
TiCl4
Ph
CH3
CH3
CH3
CH3
a For experimental details, see Ref. 10.
b Determined by HPLC analysis of the reaction mixtures.
c Overall yield estimated by HPLC analysis of the reaction mixtures.
results; the former was considered to be the most
suitable one because of its mildness and the slightly
better diastereomeric ratio it exhibits (compare entries 2
and 4 in Table 1). A similar study was carried out in the
case of the acetaldehyde dimethyl acetal (b). As
expected, this less reactive substrate required a more
powerful Lewis acid in order to attain good yields
(compare entries 6–9 in Table 1). The best diastereo-
selection was obtained with SnCl4 (see entry 8 in Table 1).
As it has been previously reported,6,7 the chiral thiazo-
lidine-2-thione auxiliary can be easily removed by using
a variety of methods, which allows the adducts to be
transformed into a wide range of derivatives. As a
model, 3a was converted into the corresponding enan-
tiopure alcohol 5, carboxylic acid 6, methyl ester 7,
thioester 8, morpholine amide 9, and Weinreb amide
10, under very mild conditions and in excellent yields as
shown in Scheme 3. In all cases, the end point of the
reaction is reached when the initial yellow solution
becomes almost colourless. The chiral auxiliary can be
recovered by chromatography or, in most cases, by
washing the reaction mixture with 1 M NaOH and
acidification in ]90% yield.
Once established the most suitable Lewis acid for model
acetals a and b, further optimisation of the experimen-
tal conditions was carried out. Addition of the titanium
enolate of 2 to aromatic acetals (a, c–e in Table 2) was
judged to afford >85% yield after 30 min at −78°C by
HPLC analysis of the reaction mixtures and it was
observed that reaction times longer than 1 h did not
significantly increase the yields. On the other hand, the
a,b-unsaturated acetal (f) proved to be highly reactive
and no starting material was detected in the reaction
mixture after 15 min at −78°C. In the case of aliphatic
acetals (b, g–i), the rate of the process slowed down
dramatically after 30 min at −78°C and higher tempera-
tures were required to improve conversions. Thus, the
above-mentioned mild conditions afforded good results
for a wide range of acetals, allowing us the isolation of
enantiopure diastereomers 311 in good yields by means
of chromatographic purification.12,13 The results are
summarised in Table 2.
In summary, we have described a simple and efficient
methodology to obtain enantiopure a-unsubstituted b-
methoxy carboxyl adducts based on the stereoselective
addition of a chiral titanium enolate to a wide range of
acetals. The adducts can be, in turn, easily transformed
into a large number of chiral building blocks of high
scope in the total synthesis of natural products.
Acknowledgements
Financial support from the Ministerio de Educacio´n y
Cultura (DGESIC, Grant PM98-1272) and the Gener-
Table 2. Reaction of dimethyl acetals with the titanium enolate of 2
Entry
Acetal
R
Lewis acid
Conditionsa
dr 3:4b
Yield (%)c
1
2
3
4
5
6
7
8
9
a
c
d
e
f
b
g
h
i
Ph
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
SnCl4
SnCl4
SnCl4
SnCl4
A
A
A
A
B
C
C
C
C
88:12
93:7
77
87
75
81
77
57
62
70d
60d
4-MeOPh
3-MeOPh
4-ClPh
(E) PhCHꢀCHMe
CH3
CH3CH2CH2
(CH3)2CHCH2
(CH3)2CH
88:12
88:12
82:18
76:24
73:27
79:21
71:29
a A: −78°C for 1 h; B: −78°C for 15 min; C: −78°C for 30 min and −20°C for 1 h.
b Determined by HPLC analysis of the reaction mixtures.
c Isolated yield of 3.
d Isolated yield of the corresponding Weinreb amide.

A. Cosp et al. / Tetrahedron Letters 42 (2001) 4629–4631
4631
HO
OMe
Ph
H.; Abe, T.; Shimada, O.; Hayashi, T.; Inoue, Y. J. Org.
Chem. 1992, 57, 4243–4249; (b) Nagao, Y.; Hagiwara, Y.;
Kumagai, T.; Ochiai, M.; Inoue, T.; Hashimoto, K.;
Fujita, E. J. Org. Chem. 1986, 51, 2391–2393. For recent
examples of titanium-mediated aldol reactions based on
these auxiliaries, see: (c) Crimmins, M. T.; King, B. W.;
Tabet, E. A.; Chaudhary, K. J. Org. Chem. 2001, 66,
894–902; (d) Gonza´lez, A.; Aiguade´, J.; Urp´ı, F.; Vilar-
rasa, J. Tetrahedron Lett. 1996, 37, 8949–8952.
5
O
OMe
Ph
O
OMe
Ph
97%
a
Me
N
HO
97%
f
b
MeO
10
6
100%
S
O
OMe
Ph
S
N
e
c
8. Enantioselectivity on acetate metal enolate aldol reac-
tions still continues to be a challenge. For recent exam-
ples, see: (a) Palomo, C.; Oiarbide, M.; Aizpurua, J. M.;
Gonza´lez, A.; Garc´ıa, J. M.; Landa, C.; Odriozola, I.;
Linden, A. J. Org. Chem. 1999, 64, 8193–8200 and refer-
ences cited therein; (b) Le Sann, C.; Simpson, T. J.;
Smith, D. I.; Watts, P.; Willis, C. L. Tetrahedron Lett.
1999, 40, 4093–4096.
3a
100%
tBuS
100%
O
OMe
Ph
O
OMe
Ph
d
82%
N
MeO
O
9
7
O
OMe
Ph
8
9. To the best of our knowledge, stereoselective acetate-type
aldol addition to non-cyclic acetals has not been reported
before. On the other hand, non stereoselective acetate-
type Mukaiyama aldol additions to acetals have attracted
more attention. For example, see: (a) Matsuda, I.;
Hasegawa, Y.; Makino, T.; Itoh, K. Tetrahedron Lett.
2000, 41, 1405–1408; (b) Chen, J.; Otera, J. Angew.
Chem., Int. Ed. 1998, 37, 91–93; (c) Sammakia, T.; Smith,
R. S. J. Am. Chem. Soc. 1994, 116, 7915–7916; (d)
Kobayashi, S.; Hachiya, I.; Takahori, T. Synthesis 1993,
371–373; (e) Murata, S.; Suzuki, M.; Noyori, R. Tetra-
hedron 1988, 44, 4259–4275; (f) Mukaiyama, T.;
Murakami, M. Synthesis 1987, 1043–1054.
Scheme 3. (a) NaBH4 (4 equiv.), THF–H2O, rt, 4 h; (b) LiOH
(5 equiv.), CH3CN–H2O, 0°C, 4 h; (c) CH3OH, K2CO3 (5
equiv.), rt, 4 h; (d) BuSH (1.5 equiv.), K2CO3 (3.5 equiv.),
CH3CN, rt, 24 h; (e) morpholine (2 equiv.), THF, rt, 4 h; (f)
NH(OMe)Me·HCl (1.5 equiv.), Et3N (1.1 equiv.), DMAP
cat., CH2Cl2, rt, 24 h.
t
alitat
de
Catalunya
(1998SGR00040
and
2000SGR00021) and a doctorate studentship (Generali-
tat de Catalunya) to A.C. are acknowledged.
References
10. Neat TiCl4 (0.12 mL, 1.1 mmol) was added dropwise to a
solution of 2 (203 mg, 1 mmol) in CH2Cl2 (8 mL), at 0°C
under N2. The yellow solution was stirred for 5 min at
1. For a review on stereoselective aldol reactions, see: Cow-
den, C. J.; Paterson, I. In Organic Reactions; Paquette, L.
A., Ed.; John Wiley & Sons: New York, 1997; Vol. 51,
pp. 1–200.
i
0°C and cooled at −78°C, and a solution of Pr2EtN (0.19
mL, 1.1 mmol) in CH2Cl2 (1 mL) was added. The dark
red enolate solution was stirred for 30 min at −78°C and
2 h at −50°C, and 1 equiv. each of Lewis acid and
dimethyl acetal was successively added dropwise. The
resulting mixture was stirred at the temperature and time
showed in Tables 1 and 2. The reaction was quenched by
the addition of saturated aqueous NH4Cl (6 mL) and the
layers were separated. The aqueous layer was re-extracted
with CH2Cl2 and the combined organic extracts were
washed with brine, dried (Na2SO4), filtered and concen-
trated. Purification by MPLC (hexanes/EtOAc) afforded
the pure major diastereomer 3.
2. For recent developments on stereoselective catalytic aldol
.
reactions, see: Carreira, E. M. In Comprehensive Asym-
metric Catalysis; Jacobsen, E. N.; Pfaltz, A.; Yamamoto,
H., Eds.; Heidelberg: Springer, 1999; Vol. 3, pp. 997–
1065.
3. For reviews on allylmetal additions, see: (a) Hoppe, D.;
Roush, W. R.; Thomas, E. J. In Stereoselective Synthesis,
Methods of Organic Chemistry (Houben-Weyl); Helm-
chen, G.; Hoffmann, R. W.; Mulzer, J.; Schaumann, E.,
Eds.; Thieme: Stuttgart, 1995; Vol. E21b, pp. 1357–1602;
(b) Yamamoto, Y.; Asao, N. Chem. Rev. 1993, 93, 2207–
2293.
4. For recent developments on stereoselective catalytic allyl
transfer reactions, see: Yanagisawa, A. In Comprehensive
Asymmetric Catalysis; Jacobsen, E. N.; Pfaltz, A.;
Yamamoto, H., Eds.; Springer: Heidelberg, 1999; Vol. 2,
pp. 965–979.
5. For a nice example just published, see: Keck, G. E.;
Wager, C. A.; Wager, T. T.; Savin, K. A.; Covel, J. A.;
McLaws, M. D.; Krishnamurthy, D.; Cee, V. J. Angew.
Chem., Int. Ed. 2001, 40, 231–234.
6. Cosp, A.; Romea, P.; Talavera, P.; Urp´ı, F.; Vilarrasa, J.;
Font-Bardia, M.; Solans, X. Org. Lett. 2001, 3, 615–617.
7. N-Acylated 4-alkyl-1,3-thiazolidine-2-thiones have been
introduced in asymmetric synthesis by Nagao, Fujita et
al.: (a) Nagao, Y.; Nagase, Y.; Kumagai, T.; Matsunaga,
11. All new compounds have spectroscopic and analytical
data consistent with the assigned structure. The absolute
configurations of adducts 3a and 3g have been estab-
lished by chemical correlation.
12. Chromatographic removal of non-reacted starting mate-
rial 2 proved to be difficult in the case of adducts 3h and
3i; it became more appropriate to isolate them as the
corresponding Weinreb amides.
13. Commercial or deactivated (2.5% Et3N) flash silica gel
causes loss of material; thus, it is strongly recommended
,
to use MPLC quality silica gel (silica gel 60 A, 20–45 mm,
SDS) to obtain good and reproducible results. It is also
worth mentioning that chromatographic purification can
be visually monitored because all of the adducts prepared
to date are bright yellow.