Communications
J . Org. Chem., Vol. 63, No. 23, 1998 8095
Sch em e 2
Sch em e 4a
(a) (i) PhMgBr, CuI, Me2S, Et2O; (ii) 6 N HCl; (iii) KOH, EtOH, 50
°C (trans-10: 70%); (b) Ph2P(O)CH2OCH3, HMPA, THF; (c) (i) CF3CO2H,
H2O, THF, reflux; (ii) sat. NaHCO3.
Sch em e 3a
Sch em e 5
a
(a) (i) LDA, THF, -78 °C; (ii) 3,4-dimethoxybenzyl bromide, THF,
-78 °C; (b) 1 N HCl, Et2O, rt.
This methodology also provides access to a nonproteino-
genic R-amino acid with a quaternary chiral center: a
derivative of (R)-methyl dopa 9,6 by alkylation of iminoester
7 (prepared from aldehyde 1a and racemic methyl alaninate)
followed by hydrolysis of 8. The ee of 9 (>98%) was
determined by 1H NMR of the free aminoester, using a chiral
europium chelate [Eu(tfc)3],7 and the absolute configuration
was determined by the sign of rotation.8
Aldehydes 1a and 1b were prepared from (R)-pulegone.
Conjugate addition of PhMgBr and epimerization according
to Corey and Ensley5a,9 led to a mixture of ketones 10 (trans/
cis ) 85/15) which were separated by chromatography on
silica gel. Condensation of trans-10 with the anion of Ph2-
POCH2OMe10 gave enol ethers 11 (Z and E isomers) that
were hydrolyzed to aldehydes 1a and 1b (isolated by chro-
matography in 80% and 10% yields, respectively) (Scheme
4).
In asymmetric synthesis, chiral auxiliaries are typically
obtained from the chiral pool and consequently are inex-
pensive and available in large amounts. Often, however,
only one enantiomer is available, the other being rare and
expensive (for example, (S)-pulegone) or difficult to synthe-
size.11 To avoid using the rare and expensive enanti-
omer,12,13 we have used epimeric aldehydes 1a and 1b that
are obtained from the inexpensive (R)-pulegone. This
represents the first use of this new tool in asymmetric
synthesis: chiral auxiliaries with a switching center (Scheme
5). Two conditions are required for a switching center: (i)
the inversion of configuration of only one of its stereogenic
centers must lead to reaction products of opposite configu-
ration; (ii) the inversion of configuration of this strategic
switching center must be easy. These two conditions are
fulfilled with aldehydes 1.14
In summary, we have shown that using aldehydes 1a and
1b (chiral auxiliaries with a switching center) lead to
monoalkylated or dialkylated R-amino acids of (R)- or (S)-
configuration in good to excellent yields with high stereo-
selectivity.15
Ack n ow led gm en t. We are grateful to the ORIL Com-
pany and the Re´gion Haute-Normandie for financial sup-
port. We also thank Doctor Lo¨ıc Toupet for the X-ray
analysis of 1a and Doctor Bernard Elissondo for his
support.
(4) Asymmetric alkylation of cyclic amino acids derivatives (recent
references): (a) Williams, R. M. J . Am. Chem. Soc. 1991, 113, 9276. (b)
Scho¨llkopf, U. Liebigs Ann. Chem. 1993, 321-323. (c) Williams, R. M.
Advances in Asymmetric Synthesis, J AI Press Inc.: Greenwich, CT, 1995;
vol. 1, pp 45-94. (d) Seebach, D.; Sting, A. R.; Hoffmann, H. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 2709-2748. (e) Chinchilla, R.; Falvello, L. R.;
Galindo, N.; Na`jera, C. Angew. Chem., Int. Ed. Engl. 1997, 36, 995-997.
(5) In the following examples using phenylmenthol derivatives, the
efficiency of the shielding has been attributed to π-stacking: (a) Corey, E.
J .; Ensley, H. E. J . Am. Chem. Soc. 1975, 97, 6908-6909. (b) Oppolzer, W.;
Robbiani, C.; Ba¨ttig, K. Helv. Chim. Acta 1980, 63, 2015-2018. (c) Oppolzer,
W.; Kurth, M.; Reichlin, D.; Chapuis, C.; Mohnhaupt, M.; Moffatt, F. Helv.
Chim. Acta 1981, 64, 2802-2811. (d) d’Angelo, J .; Maddaluno, J . J . Am.
Chem. Soc. 1986, 108, 8112. (e) Whitesell, J . K.; Lawrence, R. M.; Chen, H.
H. J . Org. Chem. 1986, 51, 4479-4484. (f) Ort, O.; J ayasingh, R.; White, J .
D. Org. Synth. 1987, 65, 203-214. (g) Barluenga, J .; Bernard, P. L., J r.;
Concellon, J . M.; Pineras-Nicolas, A.; Garcia-Granda, S. J . Org. Chem. 1997,
62, 6870-6875.
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures and spectroscopic data for compounds 1-5, 7-11; ORTEP
representation of the X-ray structure of aldehyde 1a (21 pages).
J O981710E
(11) (-)-Phenylmenthol is easily prepared from (R)-pulegone (three steps)
ref 5a. For a synthesis of (+)-phenylmenthol from (R)-pulegone (ten steps)
see: Ensley, H. E.; Parnel, C. A.; Corey, E. J . J . Org. Chem. 1978, 43, 1610-
1612. For a synthesis of (S)-pulegone from citronellol (four steps), see:
Buschmann, H.; Scharf, H. D. Synthesis 1988, 827-829.
(12) If only one epimer of the chiral auxiliairy is available, it is possible
to prepare the reaction product of opposite configuration by changing the
configuration (Z-E) of the prochiral intermediate (ref 3h) or by introducing
the substituents in the reverse order (for example, Kawatanami, Y.; Ito,
Y.; Kitagawa, T.; Taniguchi, Y.; Katsuki, T.; Yamaguchi, M. Tetrahedron
Lett. 1984, 25, 857-860). These two routes are not general. For a discussion
of convergent reactions, see: Duhamel, P.; Duhamel, L. C. R. Acad. Sci.
Paris 1995, t. 320, IIb, 689-694; Duhamel, P. Bull. Soc. Chim. Fr. 1996,
133, 457-459; and 13b.
(13) A simplified version of the rare and expensive enantiomer has been
realized: (a) Chaumette, J . L. These of the University of Rouen, 1996. (b)
Duhamel, P. Diastereoselective halogenations. In Roots of Organic Develop-
ment; Desmurs, J . R., Ratton, S., Eds.; Industrial chemistry library,
Elsevier: New York, 1996; vol. 8, pp 176-188.
(14) Starting from a mixture 1a /1b ) 60/40, a new mixture, 90/10, was
quantitatively obtained by treating with KOH (1.5 equiv) in EtOH at
ambient temperature for 2 h.
(6) For the pharmacological properties of R-alkylated alanines see ref 4c
and references therein.
(7) Eu(tfc)3: [3-((trifluoromethyl)hydroxymethylene)-(+)-camphorato]-
europium(III). In CDCl3, the racemic aminoester showed four signals of
equal intensity for the two methoxy groups of the aromatic substituent (δ
4.15; 4.02; 3.96; 3.84) whereas the corresponding aminoester synthezised
from 7 presented only two (δ 3.95 and 3.83).
(8) [R]D reported for 9 ((S) isomer): + 0.7 (c 1.1; EtOH; 20 °C) Scho¨llkopf,
U.; Groth, U.; Westphalen, K. O.; Deng, C. Synthesis 1981, 12, 969-971;
our result: [R]D-0.6 (same conditions).
(9) Ort, O.; J ayasingh, R.; White, J . D. Org. Synth. 1987, 65, 203-214.
(10) (a) Earnshaw, C.; Wallis, C. J .; Warren, S. J . Chem. Soc., Perkin
Trans 1 1979, 3099-3106. (b) J efford, C. W.; Velard, J . A.; Bernardelli, G.;
Bray, D. H.; Warhust, D. C.; Milhous, W. K. Helv. Chim. Acta 1993, 76,
2775-2788.
(15) Obviously, if the methyl substituent of the cyclohexane ring of
aldehydes 1a and 1b was omitted, the same results would be obtained.
Using (R)-pulegone as starting material avoids a resolution step.