A stereocomplementary approach to β-lactones: Highly diastereoselective synthesis of cis-β-lactones, a β-chloro acid, and a tetrahydrofuran

Article abstract of DOI:10.1021/ol990860o

(matrix presented) In the course of mechanistic studies of the ZnCl₂-mediated tandem Mukaiyama aldol-lactonization reaction of aldehydes and thiopyridyl ketene acetals, a stereocomplementary reaction employing SnCl₄ was discovered. T

Full text of DOI:10.1021/ol990860o

ORGANIC
LETTERS
1999
Vol. 1, No. 8
1197-1199
A Stereocomplementary Approach to
â-Lactones: Highly Diastereoselective
Synthesis of cis-â-Lactones, a â-Chloro
Acid, and a Tetrahydrofuran
Yingcai Wang, Cunxiang Zhao, and Daniel Romo*
Department of Chemistry, Texas A&M UniVersity, P.O. Box 30012,
College Station, Texas 77842-3012
romo@mail.chem.tamu.edu
Received July 23, 1999
ABSTRACT
In the course of mechanistic studies of the ZnCl2-mediated tandem Mukaiyama aldol−lactonization reaction of aldehydes and thiopyridyl
ketene acetals, a stereocomplementary reaction employing SnCl4 was discovered. This method provides a highly diastereoselective entry to
cis-1,2-disubstituted â-lactones as well as a â-chloro carboxylic acid and a tetrahydrofuran. The former products were obtained by varying the
reaction temperature. The latter product was obtained when the aldehyde substrate bore a pendant silyl ether.
A number of stereoselective routes to â-lactones have been
reported recently.1 One method that we have developed in
our lab is the tandem Mukaiyama aldol-lactonization
(TMAL) reaction which provides a highly diastereoselective
approach to trans-1,2-disubstituted â-lactones.2 We, and
others,3 have used this reaction to access a variety of racemic
and optically active â-lactones including natural1 and un-
natural products.3a,4 During our mechanistic studies of the
ZnCl2-mediated tandem Mukaiyama aldol-lactonization
reaction,5 we determined that bidentate chelation between
ZnCl2 and the thiopyridyl group of ketene acetals was an
important factor in promoting the lactonization step. With
this in mind, we searched the literature for Lewis acids that
were capable of bidentate chelation with 2-mercaptopyridine.
We found that SnCl4 was known to form a bidentate chelate
with this ligand,6 and so we studied its reaction with
thiopyridyl ketene acetals and aldehydes. Herein we report
that SnCl4 promotes a low-temperature, net TMAL reaction
(-78 °C) of thiopyridyl ketene acetals and aldehydes.
Importantly, this proVides a stereocomplementary route to
â-lactones as it deliVers cis-1,2-disubstituted â-lactones in
contrast to the use of ZnCl2 as Lewis acid (Scheme 1). We
have also found that by simply warming the reaction to 0
(1) For reviews including methods for the synthesis of racemic and
optically active â-lactones, see: (a) Pommier, A.; Pons, J.-M. Synthesis
1993, 441-449. (b) Pommier, A.; Pons, J.-M. Synthesis 1995, 729-744.
(c) Lowe, C.; Vederas, J. C. Org. Prep. Proc. Int. 1995, 27, 305-346. (d)
Yang, H. W.; Romo, D. Tetrahedron 1999, 55, 6403-6434. For some
related and complementary methods for the stereoselective synthesis of
â-lactones, see: (e) Danheiser, R. L.; Nowick, J. S.; Lee, J. H.; Miller, R.
F.; Huboux, A. H. Org. Synth. 1996, 73, 61-72. (f) Danheiser, R. L.; Lee,
T. W.; Menichincheri, M.; Brunelli, S.; Nishiuchi, M. Synlett 1997, 469-
470. (g) Wedler, C.; Schick, H. Org. Synth. 1998, 75, 116-123 and
references cited.
(2) (a) Yang, H. W.; Romo, D. J. Org. Chem. 1997, 38, 44-5. (b) Yang,
H. W.; Zhao, C. X.; Romo, D. Tetrahedron 1997, 53, 16471-16488.
(3) (a) Romo, D.; Harrison, P. H. M.; Jenkins, S. I.; Riddoch, R. W.;
Park, K.; Yang, H. W.; Zhao, C.; Wright, G. D. Bioorg. Med. Chem. 1998,
6, 1255-1272. (b) Dollinger, L. M.; Howell, A. R. J. Org. Chem. 1998,
63, 6782-6783.
(4) Yang, H. W.; Romo, D. J. Org. Chem. 1998, 63, 1344-1347.
(5) Zhao, C.; Romo, D., manuscript submitted.
(6) Masaki, M.; Matsunami, S. Bull. Chem. Soc. Jpn. 1976, 49, 3274-
3279.
10.1021/ol990860o CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/23/1999

Scheme 1. Stereocomplementary Synthesis of â-Lactones by
Table 1. Synthesis of 1,2-Disubstituted and Monosubstituted
â-Lactones 3 via the SnCl4-Promoted Reaction of Aldehydes 1
and Ketene Acetals 2
Use of ZnCl2 or SnCl4
cis/trans yield,
entrya â-lactone
R1
R2
ratiob
%
c,d
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
Ph(CH2)2
Ph(CH2)2
p-NO2Ph
CH3(CH2)6
cyclo-C6H11
cyclo-C6H11
t-Bu
Me >19:1
H
Me >19:1
Me >19:1
62
32 (66)
66
64
Me
2.3:1
9
H
40 (52)
5e
3g
3h
Me
<1:19
(S)-CH3CH(OTBS)CH2 Me >19:1f 81
°C, diastereomerically pure â-chloro carboxylic acids can
be obtained. A tetrahydrofuran could also be obtained when
4-tert-butyldimethylsiloxybutanal is employed as substrate.
To the best of our knowledge, there are no general, highly
diastereoselective methods for the synthesis of cis-1,2-
dialkyl-substituted â-lactones. The [2 + 2] cycloaddition of
silylketenes and aldehydes promoted by bulky Lewis acids
provides R-trialkysilyl-â-alkyl â-lactones with high cis
selectivity;7 however, subsequent alkylative desilylation
delivers the thermodynamically preferred trans-dialkyl-
substituted â-lactone.8
a Ketene acetal 2b was employed in all entries except 2 and 6 for which
2a was employed. b Estimated by analysis of crude reaction mixtures by
300 MHz 1H NMR. In most cases, the trans isomers were undetectable.
c Yields refer to the isolated and purified (flash chromatography) major
diastereomer. Starting aldehyde accounts for the mass balance. d Yields
given in parentheses are those obtained using ZnCl2 (see ref 2b). e Estimated
by analysis of the crude reaction mixture by 300 MHz 1H NMR. f The
relative stereoselectivity was 3.3:1 (GC). The stereochemistry (syn/anti) of
the major diastereomer has not been determined.
is due in part to the generation of the corresponding
thiopyridyl silyl acetal derived from the aldehyde substrate.
If the temperature of the reaction after complete addition
of SnCl4 was allowed to rise above -78 °C, varying amounts
of â-chloro silyl esters (i.e., 5a) were produced. Subse-
quently, we found that if the TBS-ketene acetal 2c was
employed and the reaction was allowed to slowly warm to
0 °C after complete addition of SnCl4, the â-chlorosilyl ester
5a could be obtained in high yield (Scheme 2).10 In practice,
Initially, only low yields of â-lactone were obtained (10-
30%) using the conditions we had previously employed for
the ZnCl2-mediated TMAL reaction with the exception of
temperature (-78 vs 25 °C).2 After some experimentation,
we determined that the best results were obtained by slow
addition of SnCl4 to a mixture of the ketene acetal and
aldehyde. In a typical experiment, a CH2Cl2 solution of SnCl4
(1 M, 1.2 equiv) was added via syringe pump over a period
of ∼1 h to a cooled (-78 °C) CH2Cl2 solution of the
aldehyde (1.0 equiv, ∼0.2 M in CH2Cl2) and thiopy-
ridylketene acetal (1.2 equiv). After stirring for 2 h, the
reaction was quenched at -78 °C and filtered through Celite,
and the organics were separated and dried. Direct treatment
of the crude reaction mixture with CuBr2-facilitated removal
of the thiopyridyl ester byproduct by conversion to the
carboxylic acid.9 In this way, several cis-1,2-disubstituted
â-lactones were prepared (Table 1) including a chiral
â-lactone (entry 8). In most cases, very high cis diastereo-
selectivity was observed with exceptions being cyclohexan-
ecarboxaldehyde which gave only a 2.3:1 ratio of cis/trans
isomers (entry 5) and pivaldehyde which gave exclusively
the trans-â-lactone (entry 7). Furthermore, R-substitution of
the aldehyde also leads to a dramatic decrease in the yield
of â-lactone as previously observed in the ZnCl2-mediated
TMAL reaction.2 As in the ZnCl2-promoted TMAL reaction,
unreacted aldehyde accounted for the majority of the material
balance, and benzaldehyde and anisaldehyde were found to
be unreactive. In contrast to the ZnCl2-mediated TMAL
reaction, lower yields were obtained with acetate ketene
acetal 2a compared to propionate ketene acetal 2b and this
Scheme 2. Diastereoseletive Synthesis of â-Chloro Carboxylic
Acid Derivatives from Hydrocinnamaldehyde and Thiopyridyl
Ketene Acetalsa
a (a) CH2Cl2, -78 f 0 C; (b) 10% aqueous K2CO3, MeOH,
THF, 25 °C; (c) catalytic H2SO4, MeOH, reflux.
ï
the unstable silyl ester 5a was not isolated but rather directly
treated with a basic methanol solution to deliver the
crystalline â-chloro carboxylic acid 5b or subjected to Fischer
esterification to deliver the â-chloro methyl ester 5c.
We currently favor a mechanism for formation of this
product that proceeds through the silylated â-lactone inter-
(10) The cleavage of â-lactones to â-chloro and â-bromo carboxylic acids
is known, see: (a) Pu, Y.; Martin, F. M.; Vederas, J. C. J. Org. Chem.
1991, 56, 1280-1283. (b) Labrouillere, M.; Le Roux, C.; Oussaid, A.;
Gaspard-Iloughmane, H.; Dubac, J. Bull. Soc. Chim. Fr. 1995, 132, 522-
530. (c) Kricheldorf, H. R. Angew. Chem., Int. Ed. Engl. 1979, 18, 689-
690.
(7) Concepcion, A. B.; Maruoka, K.; Yamamoto, H. Tetrahedron 1995,
51, 4011-4020.
(8) (a) Mead, K. T.; Yang, H. L. Tetrahedron Lett. 1989, 30, 6829-
6832. (b) Mead, K. T.; Park, M. J. Org. Chem. 1992, 57, 2511-2514.
(9) Kim, S.; Lee, J. I. J. Org. Chem. 1984, 49, 1712-1716.
1198
Org. Lett., Vol. 1, No. 8, 1999

mediate 4 in analogy to the same intermediate proposed in
the ZnCl2-mediated reaction.5 This mechanism is supported
by the generation of the silyl ester rather than the carboxylic
acid, the fact that use of the TBS-ketene acetal leads to
higher yields of â-chloro silyl esters,11 and the high diastereo-
selectivity observed for this product. The fact that this
reaction proceeds with complete inversion of configuration,
with respect to the initially formed cis-â-lactone, lends further
support for this mechanism. The stereochemistry of â-chloro
acid 5b was verified by single-crystal X-ray analysis (Figure
1).
In this case, the stereochemical outcome was confirmed by
comparison to known carboxylic acid 7b.13
While it is tempting to suggest that the present reaction
proceeds via a TMAL mechanism, several observations are
inconsistent with those made in the ZnCl2-mediated TMAL
reaction. Another possible mechanism is a [2 + 2] cycload-
dition involving an in situ generated, silylated ketene. This
could potentially be derived from the silylketene acetal by
SnCl4-assisted loss of the thiopryidyl group. Further studies
will be required to distinguish between the possible mech-
anisms.
In summary, an SnCl4-mediated reaction between alde-
hydes and a thiopyridyl ketene acetal has been discovered
that provides a highly diastereoselective entry to cis-1,2-
disubstituted â-lactones. A limitation is that R-substitution
of the aldehyde leads to reduced yields and reduced or, in
some cases, reversed diastereoselectivity. This method
provides a stereocomplementary approach to â-lactones since
the ZnCl2-mediated TMAL reaction allows access to trans-
1,2-dialkyl-substituted â-lactones. By raising the reaction
temperature to 0 °C and using TBS rather than TES-ketene
acetals, a subsequent in situ reaction ensues leading to
â-chloro carboxylic acids. This transformation provides a
concise, stereoselective route to â-chloro carboxylic acids,
a class of compounds for which there are only few ap-
proaches.14 In addition, the use of a silyl ether substituted
aldehyde substrate led to the formation of a tetrahydrofuran
product. We are searching for other suitable nucleophiles
that are capable of trapping the proposed silylated â-lactone
intermediate (i.e., 4).
Figure 1. Chem3D representation of the single-crystal X-ray
structure of â-chloro carboxylic acid 5b (hydrogen atoms are
omitted for clarity except at stereogenic centers).
Tetrahydrofuran silyl ester 7a was obtained when silyl
ether-substituted aldehyde 1b was employed and the reaction
was allowed to warm to -45 °C (Scheme 3).12 This product
Acknowledgment. The authors thank the NSF (CAREER
award, CHE 9624532), the Robert A. Welch Foundation (A-
1280), and Zeneca Pharmaceuticals for support of these
investigations. D.R. is an Alfred P. Sloan Fellow and a
Camille-Henry Dreyfus Teacher-Scholar. We thank Dr. Joe
Reibenspies for obtaining the X-ray structure of 5b using
instruments obtained with funds from the NSF (CHE-
9807975). We thank Dr. Lloyd Sumner and Ms. Barbara
Wolfe of the Texas A&M Center for Characterization for
mass spectral analyses obtained on instruments acquired by
generous funding from the NSF (CHE-8705697) and the
TAMU Board of Regents Research Program.
Scheme 3. Diastereoselective Synthesis of a Tetrahydrofuran
from an Aldehyde and a Thiopyridyl Ketene Acetala
a (a) CH2Cl2, -78 f -45 °C; (b) 10% aqueous K2CO3, MeOH,
THF, 25 °C.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds;
1H and 13C NMR spectra for compounds 3a,d,e,h, 5b,c, and
7b. This material is available free of charge via the Internet
at http://pubs.acs.org.
was also more easily isolated after conversion to carboxylic
acid 7b (53% yield, unoptimized). Once again, high diaste-
1
Note Added in Proof: A Lewis acid-catalyzed [2 + 2]
cycloaddition approach to cis-1,2-dialkyl-substituted â-lac-
tones (92-94% de) has recently appeared (ref 15).
reoselectivity (>19:1, 300 MHz H NMR) is observed for
this product. The stereochemical outcome (anti as depicted)
is again consistent with an initially formed cis-â-lactone
undergoing inversion of configuration at the â-carbon during
cyclization through the intermediate silylated â-lactone 6.
OL990860O
(13) (a) Mikami, K.; Shimizu, M. Tetrahedron 1996, 52, 7287-7296.
(b) See ref 8a.
(11) Use of the TES-ketene acetal 2b leads to greater amounts of
â-lactone at the expense of â-chloro silyl ester. This is consistent with
competitive attack of chloride ion at the â-carbon rather than silicon since
a bulkier silyl group should divert attack to the â-carbon.
(12) For related stepwise routes to tetrahydrofurans, see: White, D.;
Zemribo, R.; Mead, K. T. Tetrahedron Lett. 1997, 38, 2223-2226 and
references cited.
(14) For some approaches to â-chloro carboxylic acids, see: (a) Le Roux,
C.; Gaspard-Iloughmane, H.; Dubac, J. J. Org. Chem. 1994, 59, 2238-
2240 and references cited. (b) Bellassoued, M.; Dubois, J.-E.; Bertounesque,
E. Tetrahedron Lett. 1988, 29, 1275-1278. (c) Also see ref 10.
(15) Nelson, S. G.; Wan, Z.; Peelen, T. J.; Spencer, K. L. Tetrahedron
Lett. 1999, 40, 6535-6539.
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