Stereoselective construction of quaternary carbon centers by three component coupling reactions

Article abstract of DOI:10.1016/S0040-4039(00)01602-6

TiCl₄ promoted coupling reactions of pyruvates with vinyl ethers such as 3,4-dihydro-2H-pyran or 2,3-dihydrofuran constructed quaternary carbon centers stereoselectively. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01602-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8425–8429
Stereoselective construction of quaternary carbon centers by
three component coupling reactions
Arun K. Ghosh,* Reiko Kawahama and Donald Wink
Department of Chemistry, University of Illinois at Chicago, 845 W. Taylor Street, Chicago, IL 60607, USA
Received 12 July 2000; revised 13 September 2000; accepted 14 September 2000
Abstract
TiCl promoted coupling reactions of pyruvates with vinyl ethers such as 3,4-dihydro-2H-pyran or
4
2,3-dihydrofuran constructed quaternary carbon centers stereoselectively. © 2000 Elsevier Science Ltd.
All rights reserved.
Development of new carbonꢀcarbon bond forming reactions is of particular interest in
organic synthesis, especially in the context of creating new quaternary chiral centers involving a
1
stereoselective reaction. Recently, we reported the TiCl promoted synthesis of a variety of
4
2
,3-disubstituted tetrahydrofurans and tetrahydropyrans by a novel three component coupling
2
reaction. The reaction involved the treatment of ethyl glyoxylate and 2,3-dihydrofuran or
,4-dihydro-2H-pyran with TiCl , followed by exposure of the resulting oxonium ion to
3
4
appropriate nucleophiles. The overall process is quite efficient and created up to three contigu-
ous chiral centers in the condensation product. To further develop the synthetic utility of this
reaction, we have now investigated coupling reactions of pyruvates with a view to stereoselec-
tively synthesizing functionalized tetrahydrofuran and tetrahydropyran derivatives with quater-
3
nary carbon centers. Synthetic access to these structural features is thus far limited. Such
structural features are of particular interest to us for probing an enzyme active site with a
4
designed ligand. Herein we report a highly stereoselective protocol for constructing quaternary
carbon centers using three component coupling reaction of pyruvates, vinyl ethers and appropri-
ate nucleophiles.
As outlined in Scheme 1, reaction of methyl pyruvate (R=Me) and 3,4-dihydro-2H-pyran
with TiCl in dry CH Cl at −78°C for 1 h provided the oxonium ion, which upon treatment
4
2
2
with triethylsilane at −78–23°C for 1 h afforded the a-hydroxy ester 1a as a single diastereomer
in 82% yield. As can be seen in Table 1, in the case of methyl benzoylformate, the corresponding
coupling product 1b was obtained in 77% yield, again as a single diastereomer. The relative
*
Corresponding author. E-mail: arunghos@uic.edu
0
040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01602-6

8426
Scheme 1.
stereochemistry of these coupling products 1a and 1b was determined by X-ray crystallography.
The coupling reactions of dihydrofuran with both pyruvates (R=Me) and (R=Ph) using
Et SiH as a nucleophile provided the corresponding hydroxy esters 1c and 1d in 83 and 53%
3
yields, respectively (entries 3 and 4). These products were also obtained as single isomers. The
observed stereochemistry can be rationalized based upon stereochemical models A and B. In
these models, we postulate that one of the electron pairs of the methoxy oxygen is donated to
the oxonium ion from the axial side (anomeric side) for stabilization of the transition state (Fig.
1
). Transition state model B (exo) is favored over model A (endo) because of the absence of the
developing non-bonded interaction between the C4-hydrogens and the chelated titanium metal.
Figure 1.
When the presumed oxonium ion derived from the reaction of methyl pyruvate (R=Me) and
3
,4-dihydro-2H-pyran was reacted with allyltrimethylsilane as a nucleophile, the reaction
proceeded smoothly (−78–23°C for 1 h). However, 1e was obtained as a 1:1 mixture of
diastereomers which were separable by silica gel chromatography (entry 5). The reaction of
allyltrimethylsilane with the oxonium ion derived from 2,3-dihydrofuran and pyruvates, how-
ever, proceeded with a high degree of selectivity. The reaction of methyl pyruvate and
dihydrofuran provided the allylated product 1f in 74% isolated yield as a 6.6:1 mixture of
diastereomers. The reaction with methyl benzoylformate proceeded with even higher stereoselec-
tivity (entry 7). Allyltributylstannane instead of allyltrimethylsilane under similar reaction
conditions provided 1g with reduced selectivity (10:1) and in lower isolated yield (35%). Both
pure diastereomers 1f and 1g were separable by flash column chromatography (entry 6, 7). The
relative stereochemistry of the major isomer 1g was determined by X-ray crystallography. The
stereochemistry of the quaternary carbon center of 1g is the same as the tetrahydropyran
derivatives 1a and 1b. Furthermore, the stereochemistry of the C-2 and C-3 substituents on the
5
tetrahydrofuran ring is trans, as shown in Fig. 2.

8427
Table 1
a
TiCl promoted coupling reactions of pyruvates with various vinyl ethers
4
Reaction of dihydrofuran and methyl pyruvate derived oxonium ion with trimethylsilyl
6
cyanide also provided the corresponding cyanide 1h with excellent selectivity (>20:1, entry 8).
To examine acyclic stereoselection, the reaction of methyl pyruvate and ethyl vinyl ether was
carried out with allyltrimethylsilane. However, the corresponding coupling product 1i was
obtained as a 1.6:1 mixture of diastereomers (entry 9). Similarly, the reaction of optically active
menthyl vinyl ether, methyl pyruvate and triethylsilane provided the coupling products 1j as a
7
1
:1 mixture of diastereomers which were separated by silica gel chromatography (entry 10).

8428
Figure 2. ORTEP drawing of X-ray crystal structures of 1g and 3b
We have also investigated stereoselection with 1-methoxycyclohexene 2. As shown in Scheme
, when the reaction was carried out with methyl pyruvate and allyltrimethylsilane at −78°C for
5 min, the coupling product 3a was obtained as a single diastereomer in 63% isolated yield. A
2
1
8
mixture of cyclic ketones 4a (20%, ratio 5.4:1) also resulted from the aldol reaction of the
9
resulting Ti-enolate. The use of allyltributyltin instead of allyltrimethylsilane improved the
reaction yield (3a and diastereomer, 67%), however, selectivity was reduced (ratio 4.6:1)
significantly. Ketone 4a was isolated in 13% yield (ratio 1.7:1). The corresponding reaction with
methyl benzoylformate and allyltributyltin furnished diastereomerically pure 3b in 53% isolated
yield (3b and diastereomer, 61%) along with methyl ketone 4b (21%). The relative stereochem-
5
istry of 3b was determined by X-ray crystallography (Fig. 2).
Scheme 2.
In summary, TiCl promoted three component coupling reactions of pyruvates, vinyl ethers
4
and carbon nucleophiles provided stereocontrolled access to the synthesis of quaternary carbon
centers. The overall protocol is practical and quite efficient. Further studies of these reactions
are currently under investigation.
Acknowledgements
Financial support for this work was provided by the National Institutes of Health. The
authors thank Professors Martin Newcomb and Vladimir Gevorgyan for helpful discussions.

8429
References
1
2
3
. (a) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. Engl. 1996, 37, 388; (b) Fuji, K. Chem. Rev. 1993, 93,
2037 and references cited therein.
. (a) Ghosh, A. K.; Kawahama, R. Tetrahedron Lett. 1999, 40, 1083; (b) Ghosh, A. K.; Kawahama, R. Tetrahedron
Lett. 1999, 40, 4751.
. (a) Westley, J. W. In Polyether Antibiotics: Naturally Occurring Acid Ionophores; Marcel Dekker: New York, 1982;
Vols. I and II; (b) Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V. In Comprehensive Heterocyclic Chemistry II;
Pergamon Press: Oxford, 1996; Vol. 2, pp. 386–392 and Vol. 5, pp. 390–396.
4. (a) Ghosh, A. K.; Shin, D.; Downs, D.; Koelsch, G.; Lin, X.; Ermolieff, J.; Tang, J. J. Am. Chem. Soc. 2000, 122,
3522; (b) Ghosh, A. K.; Kincaid, J. F.; Cho, W.; Walters, D. E.; Krishnan, K.; Hussain, K. A.; Koo, Y.; Cho,
H.; Rudall, C.; Holland, L.; Buthod, J. Bioorg. Med. Chem. Lett. 1998, 8, 979.
5
6
. Detailed data can be obtained at the Cambridge Crystallographic Data Center, Cambridge, UK.
. The reaction with methyl benzoylformate provided the corresponding cyanide in 38% isolated yield as a single
diastereomer. The coupling constant J2–3=5.4 Hz is consistent with trans stereochemistry.
7. Optically active menthyl vinyl ether was prepared from the reaction of menthol and ethyl vinyl ether in the
presence of Hg(OAc) , see: Watanabe, W. H.; Conlon, L. E. J. Am. Chem. Soc. 1957, 79, 2828.
2
8. All new compounds gave satisfactory spectroscopic and analytical results. Preparation of compound 3a: To a
solution of methyl pyruvate (102 mg, 1.00 mmol) and 1-methoxycyclohexene (168 mg, 1.50 mmol) in dry CH Cl2
2
(
2.5 mL) was added TiCl (1.0 M in CH Cl ; 1.0 mL, 1.00 mmol) at −78°C and the resulting orange solution was
4 2 2
stirred for 15 min at −78°C. Allyltrimethylsilane (0.32 mL, 2.00 mmol) was added and the mixture was stirred for
5 min at −78°C. The reaction was quenched at −78°C with sat. NaHCO (aq.) and warmed to 23°C. The mixture
1
3
was extracted with EtOAc and the organic layer was dried over Na SO . Evaporation of the solvents gave a
2
4
residue which was purified by chromatography (3% EtOAc in hexane) to give the title compound (162 mg, 63%).
1
R =0.48 (20% EtOAc in hexane); H NMR (500 MHz, CDCl ) l 1.14 (1H, m), 1.29–1.43 (3H, m), 1.46 (3H, s),
f
3
1
.54 (1H, m), 1.68–1.75 (2H, m), 1.80–1.90 (2H, m), 2.28 (1H, dd, J=13.4 and 9.1 Hz), 2.78 (1H, ddt, 13.4, 5.1
13
and 1.6 Hz), 3.12 (3H, s), 3.75 (3H, s), 4.05 (1H, br s), 5.04–5.10 (2H, m), 6.06 (1H, m); C NMR (100 MHz,
CDCl ) l 21.0, 24.7, 25.9, 28.0, 31.7, 41.9, 48.0, 51.0, 52.2, 77.1, 78.0, 117.5, 135.7, 177.8.
3
9
. Ethyl ester of 4a has been synthesized by the TiCl promoted reaction of ethyl pyruvate and trimethylsiloxycyclo-
4
hexene, see: Banno, K. Bull. Chem. Soc. Jpn. 1976, 49, 2284.
.