January 1998
SYNLETT
103
conjugate addition studied in detail by Seebach and coworkers is to
nitroalkenes. Following the successful formation and pyrolysis of 5 to
indicated an e.e. of 86% in favour of the (S)-(–)-enantiomer which was
in agreement with the value obtained by the CLSR method.
5
give 6, the enantiomerically and diastereomerically pure dioxolanone 10
was prepared from (S)-mandelic acid and pivalaldehyde using the
literature method. This was added to LDA at –78 °C and then allowed
to warm to –20 °C before recooling to –78 °C and adding ethyl
crotonate to give 11 as a 4:3 mixture of two major diastereomers. This
was initially subjected to FVP at 600 °C which did result in loss of
pivalaldehyde and CO to give the desired product 12 in 65% yield, but
this was accompanied by the acid 13 formed by loss of ethene and, more
seriously, both products were formed with low e.e. Conversion of 13 to
We have thus shown that the dioxolanones can behave as among the
most straightforward and effective chiral acyl anion equivalents
reported so far. Work is currently in progress to improve the yield of the
conjugate addition reactions (the balance of material in the formation of
5, 11 and 15 is accounted for by recovered starting materials), to
overcome the problem of the retro-acyloin reaction for 1,2-adducts to
carbonyl electrophiles, and to extend the range of α-hydroxy acids and
electrophiles which can be used.
6
its methyl ester with CH N and comparison with the literature optical
2
2
Acknowledgement. We thank the University of St. Andrews for a St.
Leonards Scholarship (A.W.T.).
7
rotation indicated an e.e. of 4% in favour of the (S)-enantiomer. A
dramatic improvement was obtained by lowering the furnace
temperature to 500 °C which gave 12 as the sole product in 91% yield
1
References and Notes
and determination of the enantiomeric purity of this by H NMR using
the chiral lanthanide shift reagent (CLSR) Eu(hfc) gave a value of 33%
(1) Aitken, R. A.; Thomas, A. W. Synlett 1997, 293–294.
3
e.e. We interpret these results in terms of 11 being formed with
essentially complete selectivity for the (S) stereochemistry at the CHMe
centre but as a 4:3 mixture of epimers at C-5 of the ring. The conditions
required for the pyrolysis result in partial racemisation of the product.
(2) Cameron, T. B.; El-Kabbani, F. M.; Pinnick, H. W. J. Am. Chem.
Soc. 1981, 103, 5414–5417.
(3) Seebach, D.; Sting, A. R.; Hoffmann, M. Angew. Chem., Int. Ed.
Engl. 1996, 35, 2709–2748.
(4) There are currently very few effective chiral acyl anion
equivalents. For some examples see: Enders, D.; Gerdes, P.;
Kipphardt, H. Angew. Chem., Int. Ed. Engl. 1990, 29, 179–181;
Enders, D.; Mannes, D.; Raabe, G. Synlett 1992, 837–839; Enders,
D.; Kirchhoff, J.; Mannes, D.; Raabe, G. Synthesis 1995, 659–
666; Fernández, R.; Gasch, C.; Lassaletta, J.-M.; Llera, J.-M.
Tetrahedron Lett. 1994, 35, 471–472; Enders, D.; Syrig, R.;
Raabe, G.; Fernández, R.; Gasch, C.; Lassaletta, J.-M.; Llera, J.-
M. Synthesis 1996, 48–58.
(5) Calderari, G.; Seebach, D. Helv. Chim. Acta 1985, 68, 1592–1604.
(6) Seebach, D.; Naef, R.; Calderari, G. Tetrahedron 1984, 40, 1313–
1324.
(7) Blanco, L.; Rousseau, G.; Barnier, J.-P.; Guibé-Jampel, E.
Tetrahedron: Asymmetry 1993, 4, 783–792.
(8) Typical Experimental Procedures
10
Preparation of 5 A solution of 2 (4.0 g, 30.8 mmol) in dry THF
3
(4 cm ) was added to a solution of LDA (33.8 mmol) in dry THF
3
(25 cm ) at –78 °C under nitrogen. After 30 min a solution of
3
ethyl crotonate (3.87 g, 33.8 mmol) in dry THF (4 cm ) was then
added and the mixture stirred at –78 °C for 2 h and at RT for 2 h
before adding to saturated aqueous NH Cl. Extraction with ether,
4
drying and evaporation followed by Kugelrohr distillation
afforded 5 (4.0 g, 53%) as a colourless liquid, bp (oven temp.) 150
+
°C at 0.005 Torr (M , 244.1317.
C
H
O
requires M,
10 20
5
-1
244.1311); υ
/ cm 1775; δ 4.16 (2 H, q, J 7, CH Me), 2.72
max
H
2
(1 H, half AB pattern of d, J 14, 3, CH CH), 2.38 (1 H, m,
2
CH CH), 2.13 (1 H, half AB pattern of d, J 14, 10, CH CH), 1.60
2
2
(6 H, s, 2 x Me), 1.48 (3 H, s, Me), 1.29 (3 H, t, J 7, CH Me) and
2
1.03 (3 H, d, J 7, CHMe); δ 174.9 (C=O), 172.7 (C=O), 109.8
C
(4ry), 82.1 (4ry), 60.8 (OCH ), 37.6 (Me), 36.2 (CH ), 29.1 (Me),
2
2
+
28.0 (Me), 22.7 (CH), 15.4 (Me) and 14.6 (Me); m/z (EI) 244 (M ,
5%), 159 (8), 130 (26) 113 (80) 59 (50) and 43 (100).
5
Preparation of 15 A solution of 14 (1.0 g, 6.3 mmol) in dry THF
3
When the dioxolanone 14 formed from (S)-lactic acid was deprotonated
using the same procedure and ethyl crotonate added, the corresponding
product 15 was formed, this time essentially as a single diastereomer.
Upon FVP at 550 °C this gave an excellent yield of ethyl 3-
(3 cm ) was added to a solution of LDA (6.9 mmol) in dry THF
3
(10 cm ) at –78 °C under nitrogen. After 30 min the mixture was
allowed to warm to –20 °C for 30 min and then recooled to –78
°C. A solution of ethyl crotonate (0.79 g, 6.9 mmol) in dry THF (3
8
3
methyllaevulinate 16. In contrast to 12, this compound has been
cm ) was then added and the mixture stirred at –78 °C for 2 h and
prepared before in enantiomerically pure form by an enzymatic
method. Comparison of the sign and magnitude of the optical rotation
at RT for 2 h. Work up as above followed by flash column
chromatography (SiO , hexane–ether, 7:3) gave 15 (0.86 g, 50%)
2
9