Enantioselective addition of a chiral thiazolidinethione-derived titanium enolate to acetals

Article abstract of DOI:10.1021/ol0070177

(Matrix presented) High stereoselectivities (up to 98% de) have been achieved for the Lewis acid-mediated cross-coupling reaction of dimethyl acetals to a chiral 1,3-thiazolidine-2-thione-derived titanium enolate. The reaction affords enantiopure anti α-m

Full text of DOI:10.1021/ol0070177

ORGANIC
LETTERS
2001
Vol. 3, No. 4
615-617
Enantioselective Addition of a Chiral
Thiazolidinethione-Derived Titanium
Enolate to Acetals
,†
Annabel Cosp,† Pedro Romea,*,†, ‡ Pere Talavera,† Fe`lix Urp´ı,* Jaume Vilarrasa,†
Merce` Font-Bardia,§ and Xavier Solans§
Departaments de Qu´ımica Orga`nica and Cristal.lografia, Mineralogia i Dipo`sits
Minerals, UniVersitat de Barcelona, 08028 Barcelona, Catalonia, Spain
furpi@qo.ub.es
Received December 19, 2000
ABSTRACT
High stereoselectivities (up to 98% de) have been achieved for the Lewis acid-mediated cross-coupling reaction of dimethyl acetals to a chiral
1,3-thiazolidine-2-thione-derived titanium enolate. The reaction affords enantiopure anti r-methyl-â-alkoxy carbonyl compounds in a wide
range of acetals.
Over the past 15 years, the Lewis acid-mediated reaction of
acetals with silicon-containing nucleophiles has proven to
be a powerful method for carbon-carbon bond formation.1
Methods employing either chiral acetals2 or crotylsilanes3
are well-known and provide nonracemic adducts that, in turn,
can be transformed into enantiopure syn R-alkyl-â-alkoxy
carbonyl compounds.3f,4 Despite the success of these ap-
proaches, most of the strategies addressing the synthesis of
enantiomerically pure R-alkyl-â-alkoxy carbonyl compounds
rely on a two-steps process: (i) enantioselective aldol
reaction and (ii) alkylation of the aldol adduct.5 Taking into
account that the second step is often troublesome,6 and that
the integration of a multistep sequence in a single transfor-
mation increases the efficiency of a process, we envisioned
that an enantioselective reaction of metal enolates with
acetals might afford the aforementioned systems in a
straightforward manner.7 Inspired by the stereoselective
addition of chiral titanium enolates to ortho esters reported
by Evans,7b and taking advantage of our own experience,8
† Departament de Qu´ımica Orga`nica.
‡ E-mail: promea@qo.ub.es.
§ Departament de Cristal.lografia, Mineralogia i Dipo`sits Minerals.
(1) (a) Murata, S.; Suzuki, M.; Noyori, R. Tetrahedron 1988, 44, 4259-
4275. (b) Mukaiyama, T.; Murakami, M. Synthesis 1987, 1043-1054. (c)
Sakurai, H. Pure Appl. Chem. 1982, 54, 1-22.
(2) For a review on chiral acetals, see: (a) Alexakis, A.; Mangeney, P.
Tetrahedron: Asymmetry 1990, 1, 477-511. For examples using chiral
acetals, see: (b) Ishihara, K.; Nakamura, H.; Yamamoto, H. J. Am. Chem.
Soc. 1999, 121, 7720-7721. (c) Evans, D. A.; Trotter, B. W.; Coˆte´, B.
Tetrahedron Lett. 1998, 39, 1709-1712. (d) Shaw, J. T.; Woerpel, K. A.
J. Org. Chem. 1997, 62, 6706-6707. (e) Andrus, M. B.; Lepore, S. D.
Tetrahedron Lett. 1995, 36, 9149-9152. (f) Ishihara, K.; Hanaki, N.;
Yamamoto, H. J. Am. Chem. Soc. 1993, 115, 10695-10704.
(3) For reviews on chiral silicon-containing compounds, see: (a) Fleming,
I.; Barbero, A.; Walter, D. Chem. ReV. 1997, 97, 2063-2192. (b) Masse,
C. E.; Panek, J. S. Chem. ReV. 1995, 95, 1293-1316. For examples, see:
(c) Lefranc, H.; Szymoniak, J.; Delas, C.; Mo¨ıse, C. Tetrahedron Lett. 1999,
40, 1123-1124. (d) Panek, J. S.; Yang, M.; Xu, F. J. Org. Chem. 1992,
57, 5790-5792. (e) Panek, J. S.; Yang, M. J. Am. Chem. Soc. 1991, 113,
9868-9870. (f) Panek, J. S.; Yang, M. J. Am. Chem. Soc. 1991, 113, 6594-
6600.
(4) (a) Zhu, B.; Panek, J. S. Org. Lett. 2000, 2, 2575-2578. (b) Panek,
J. S.; Xu, F.; Rondo´n, A. C. J. Am. Chem. Soc. 1998, 120, 4113-4122.
(5) For methylation procedures, see: (a) Blakemore, P. R.; Kocienski,
P. J.; Morley, A.; Muir, K. J. Chem. Soc., Perkin Trans. 1 1999, 955-968.
(b) Evans, D. A.; Ratz, A. M.; Huff, B. E.; Sheppard, G. S. Tetrahedron
Lett. 1994, 35, 7171-7172.
(6) (a) Hoye, T. R.; Zhao, H. Org. Lett. 1999, 1, 169-171. (b) Evans,
D. A.; Ratz, A. M.; Huff, B. E.; Sheppard, G. S. J. Am. Chem. Soc. 1995,
117, 3448-3467.
(7) Stereoselective addition of metal enolates to acetals are scarce: (a)
Pilli, R. A.; Riatto, V. B.; Vencato, I. Org. Lett. 2000, 2, 53-56 (cyclic
hemiacetals). (b) Evans, D. A.; Urp´ı, F.; Somers, T. C.; Clark, J. S.;
Bilodeau, M. T. J. Am. Chem. Soc. 1990, 112, 8215-8216 (ortho esters
and chloromethyl ethers).
10.1021/ol0070177 CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/01/2001

we have developed a general and efficient methodology to
gain access to anti R-methyl-â-alkoxy carbonyl structures
on the basis of the reaction of the titanium enolate arising
from (S)-4-isopropyl-N-propanoyl-1,3-thiazolidine-2-thione
(1)9 with dimethyl acetals.
Table 1. Stereoselective Synthesis of anti R-Methyl-â-alkoxy
Carbonyl Compounds
In preliminary studies, we observed that the titanium
enolate of 1 underwent addition to benzaldehyde dimethyl
acetal at -50 °C in moderate yield. Given that the presence
of a Lewis acid in the reaction medium might enhance the
electrophilicity of the acetal and promote the formation of
the desired adduct, we decided to evaluate the effect of
several Lewis acids. We were then pleased to find that
treatment of a solution of titanium enolate of 1 with 1 equiv
10
each of BF3‚OEt2 and benzaldehyde dimethyl acetal in
CH2Cl2 at -78 °C smoothly furnished the corresponding anti
adduct 2a in diastereomeric ratio of 86:14; enantiopure 2a
was subsequently isolated by means of chromatographical
purification in 75% yield (see Scheme 1 and Table 1).11
a dr by HPLC. b Isolated yield of 2. c Diethyl acetal was used. d After
15 min at -78 °C. e Isolated yield of the corresponding ethyl ester.
Scheme 1a
The stereochemistry of the adducts 2a, 2d, and 3d was
established by X-ray diffraction analysis (Figure 1)13 and,
in the case of 2i, it was confirmed by chemical correlation.
a See ref 12.
The above-mentioned mild conditions also afford good
yields and diastereoselectivities in the case of aromatic (a-
d) and R,â-unsaturated acetals (e-f), as shown in Table 1.
However, lower yields were obtained in the case of aromatic
acetal g and acetals h-j, derived from aliphatic aldehydes,
even at higher temperatures. These less reactive substrates
require a more powerful Lewis acid such as SnCl4 in order
to attain similar yields and diastereoselectivities up to 93:7
(Table 1).12
Figure 1. X-ray crystal structure of 2a.
(8) Gonza´lez, A.; Aiguade´, J.; Urp´ı, F.; Vilarrasa, J. Tetrahedron Lett.
1996, 37, 8949-8952.
(9) (a) Crimmins, M. T.; Chaudhary, K. Org. Lett. 2000, 2, 775-777.
(b) Zuev, D.; Paquette, L. A. Org. Lett. 2000, 2, 679-682. (c) Nagao, Y.;
Nagase, Y.; Kumagai, T.; Matsunaga, H.; Abe, T.; Shimada, O.; Hayashi,
T.; Inoue, Y. J. Org. Chem. 1992, 57, 4243-4249. (d) Nagao, Y.; Hagiwara,
Y.; Kumagai, T.; Ochiai, M.; Inoue, T.; Hashimoto, K.; Fujita, E. J. Org.
Chem. 1986, 51, 2391-2393.
(10) Other Lewis acid (BCl3, TiCl4, Et2AlCl, SnCl4, TMSOTf, Ti(OiPr)4,
ZnCl2, MgBr2‚OEt2, LaCl3) were also investigated but turned out to be less
suitable.
Although the mechanistic details are currently under
scrutiny, it is likely that the reaction proceeds via an SN1-
like process.14 Thus, the observed stereochemistry might be
ruled by an open transition state which involves the approach
of an intermediate oxocarbenium ion to the less hindered
(11) Flash silica gel chromatography can be easily visually monitored
because all of the adducts prepared to date are bright yellow.
(12) Typical experimental procedure. Neat TiCl4 (0.12 mL, 1.1 mmol)
was added dropwise to a solution of 1 (218 mg, 1.0 mmol) in CH2Cl2 (8
mL), at 0 °C under N2. The yellow suspension was stirred for 5 min at 0
°C and cooled at -78 °C, and a solution of diisopropylethylamine (0.19
mL, 1.1 mmol) in CH2Cl2 (1 mL) was added. The dark red enolate solution
was stirred for 2 h at -40 °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 shown in Table 1. The reaction was quenched
by the addition of 6 mL of saturated ammonium chloride with vigorous
stirring, and the layers were separated. The aqueous layer was re-extracted
with CH2Cl2, and the combined organic extracts were washed with brine,
dried over anhydrous Na2SO4, filtered, and concentrated. Purification by
flash column chromatography on silica gel (hexanes/EtOAc) afforded the
pure major diastereomer 2.
(13) Crystallographic data (excluding structure factors) for the structures
2a, 2d, and 3d reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publication
numbers CCDC-150269, 150271, and 150270, respectively. Copies of the
data can be obtained free of charge on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK (fax (+44) 1223-336-033; e-mail
deposit@ccdc.cam.ac.uk).
(14) Reactions of acetals with carbon nucleophiles have been shown to
proceed via carbocation intermediates. See, for example: (a) Romero, J.
A. C.; Tabacco, S. A.; Woerpel, K. A. J. Am. Chem. Soc. 2000, 122, 168-
169. (b) Matsutani, H.; Ichikawa, S.; Yaruva, J.; Kusumoto, T.; Hiyama,
T. J. Am. Chem. Soc. 1997, 119, 4541-4542. (c) Sammakia, T.; Smith, R.
S. J. Am. Chem. Soc. 1994, 116, 7915-7916. (d) Sammakia, T.; Smith, R.
S. J. Am. Chem. Soc. 1992, 114, 10998-10999. For earlier mechanistic
discussions, see: (e) Mori, I.; Ishihara, K.; Flippin, L. A.; Nozaki, K.;
616
Org. Lett., Vol. 3, No. 4, 2001

face (Si face) of a putative chelated15 Z-enolate and deter-
mines the R configuration at the R-center.16 Furthermore,
transition states TS-A and TS-B shown in Scheme 2 can be
ethyl ester 7, morpholine amide 8, and Weinreb amide 9
under very mild conditions and in excellent yields as shown
in Scheme 3. In all cases, the end point is reached when the
a
Scheme 3
Scheme 2
invoked in order to explain the stereochemistry of 2 and 3,
assuming that interactions of the substituents of the oxocar-
benium ion and the auxiliary must be minimized. Then, the
preferential formation of the anti adduct can be rationalized
through an antiperiplanar arrangement (TS-A) on the basis
of stereoelectronic and steric considerations.17
The chiral thiazolidinethione auxiliary can easily be
removed by using a variety of methods, which allows the
adducts to be transformed into a wide range of deriva-
tives.8,9,18 As a model, 2a was converted into the correspond-
ing enantiopure alcohol 4, aldehyde 5, carboxylic acid 6,
a (a) NaBH4 (4.5 equiv), THF-H2O, rt, 4 h; (b) DIBAL-H (1.1
equiv), CH2Cl2, -78 °C, 3 h; (c) LiOH‚H2O (6 equiv), CH3CN-
H2O, rt, 12 h; (d) EtOH, DMAP cat., rt, 24 h; (e) morpholine (4
equiv), THF, rt, 12 h; (f) NH(OMe)Me‚HCl (1.5 equiv), Et3N (1
equiv), DMAP cat., CH2Cl2, rt, 24 h.
initial yellow solution becomes almost colorless.19
In summary, we have described a simple and efficient
methodology to obtain enantiopure anti R-methyl-â-alkoxy
carbonyl compounds 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 1,3-dioxygenated compounds with a high interest
in organic synthesis.
Yamamoto, H.; Bartlett, P. A.; Heathcock, C. H. J. Org. Chem. 1990, 55,
6107-6115 and references therein. Other reaction of acetals do not appear
to involve free cations, see: (f) Denmark, S. E.; Almstead, N. G. J. Am.
Chem. Soc. 1991, 113, 8089-8110 and references therein.
(15) It deserves to be mentioned that the CdS bond of the auxiliary
constitutes a key feature of the process. 1,3-Oxazolidine-2-thione derived
auxiliary also displays an excellent performance, although its final removal
has been proven less efficient. However, 1,3-oxazolidin-2-one and cam-
phorsultam-derived auxiliaries afforded worse results.
(16) The stereochemical outcome of the reaction reveals complete facial
control by the chiral titanium enolate (only products arising from the addition
to the Si face of the enolate have been observed).
(17) For a similar discussion of related Lewis acid-mediated aldol addition
transition states, see: Mahrwald, R. Chem. ReV. 1999, 99, 1095-1120 and
references therein.
Acknowledgment. Financial support from the Ministerio
de Educacio´n y Cultura (DGESIC, Grant PM98-1272) and
the Generalitat de Catalunya (1998SGR00040 and
2000SGR00021) and a doctorate studentship (Generalitat de
Catalunya) to A.C. are acknowledged.
(18) (a) Su, D.-W.; Wang, Y.-C.; Yan, T.-H. Tetrahedron Lett. 1999,
40, 4197-4198. (b) Nagao, Y.; Yagi, M.; Ikede, T.; Fujita, E. Tetrahedron
Lett. 1982, 23, 201-204.
(19) The chiral auxiliary can be recovered by flash column chromatog-
raphy in g90% yield or, in certain cases, by washing the reaction mixture
using 1 M NaOH and acidification.
Supporting Information Available: Spectroscopic data
for adducts 2. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL0070177
Org. Lett., Vol. 3, No. 4, 2001
617