enantioselective catalytic transformation would be the key
step.
L-carbidopa. While ostensibly not a β-dicarbonyl deriva-
tive, thecompounddoes feature a hydrazinemoietyR toan
esterand could, therefore, beenvisionedasderived from an
enantioselective amination of an open-chain β-ketoester,
followed by the desoxygenation of the keto group (Scheme 2).
Obviously, in order for this approach to succeed, the high
enantioinduction obtained previously in cyclic β-ketoester
would have to be extendable to the more flexible (and
more challenging) open-chain substrates.
Our previous work in this area involved the use of
lanthanides as versatile Lewis acids for asymmetric
catalysis.5 In particular, the potential of these metals for
higher coordination numbers6 makes them a favorable
match for pybox ligands.7 In 2007, we reported that a
combination of europium triflate and (S,S)-iPr-pybox (L1)
catalyzed a highly enantioselective electrophilic hydrazina-
tion of cyclic β-ketoesters (Scheme 1).3b To account for the
stereochemical outcome (R as major enantiomer), a model
key complex was detected (ESI), consisting of the La ion
bound to the C2-symmetric pybox and a molecule of the
ketoester. Enantioface differentiation would presumably
take place upon differentiated azodicarboxylate binding to
this complex. In addition to such binary L-M systems,
Shibasaki and co-workers developed a series of lantha-
num-catalyzed enantioselective hydrazination protocols.
In these, excellent enenatioselective induction was achieved
employing amino acid based ligands/additives.8The method
was used to carry out a multigram synthesis of a spir-
osuccinimide derivative Ranirestat, identified as a pro-
mising aldose reductase inhibitor.8b
Scheme 2. Retrosynthesis of L-Carbidopa via R-Hydrazination
We envisioned the use of the commercially available
1-(3,4-dimethoxyphenyl)ethanone, 2, as a precursor to the
open-chain β-ketoester 4 (Scheme 3). Thus, reaction of 2
with dimethylcarbonate in the presence of 2 equiv of NaH
afforded, after a 3 h reflux in toluene, the desired β-
ketoester 3a in 97% yield (Scheme 3). Subsequent alkyla-
tion of 3a under classical conditions using methyl iodide
and potassium carbonate in anhydrous acetone afforded
the methyl ester 4a in 99% yield. Our previous experience
also suggested that a β-ketoester substrate bearing an OR
group bulkier than the methoxy might be necessary to
achieve efficient enantioinduction. Therefore, after test-
ing a series of conditions, transesterification of 3a with
1-adamantanol was accomplished using catalytic amounts
of ZnO in refluxing toluene.9 Treatment of the newly
prepared 3b with MeI and K2CO3 afforded the adaman-
tyl-protected substrate 4b in 86% yield over the two steps.
Scheme 1. Our Group’s Previous Example of Enantioselective
Aza-Michael Reaction (from Ref 3b)
With these precedents, we set out to apply this metho-
dology as a key step in the enantioselective synthesis of
Scheme 3. Synthesis of Amination Substrates 4a and 4b
(5) (a) Aspinall, H. C. Chem. Rev. 2002, 102, 1807–1850. (b) Kobaya-
shi, S.; Sugiura, M.; Kitagawa, H.; Lam, W. W.-L. Chem. Rev. 2002, 102,
2227–2302. (c) Shibasaki, M.; Kanai, M.; Matsunaga, S.; Kumagai, N.
In Acid Catalysts in Modern Organic Synthesis; Yamamoto, H., Ishihara,
K., Eds.; 2008, Vol. 2, pp 635ꢀ720. (d) Kobayashi, S.; Yasuhiro, Y. Acc.
Chem. Res. 2011, 44, 58–71.
(6) (a) Mikami, K.; Terada, M.; Matsuzawa, H. Angew. Chem., Int.
Ed. 2002, 41, 3554–3571. (b) Aspinall, H. C.; Greeves, N. J. Organomet.
Chem. 2002, 647, 151–157. (c) Aspinall, H. C.; Bickley, J. F.; Greeves, N.;
Kelly, R. V.; Smith, P. M. Organometallics 2005, 24, 3458–3467. (d)
Suga, H.; Inoue, S.; Kakehi, A.; Shiro, M. J. Org. Chem. 2005, 70, 47–56.
(e) Desimoni, G.; Faita, G.; Mella, M.; Piccinini, F.; Toscanini, M. Eur.
J. Org. Chem. 2006, 23, 5228–5230. (f) Desimoni, G.; Faita, G.; Mella,
M.; Piccinini, F.; Toscanini, M. Eur. J. Org. Chem. 2007, 9, 1529–1534.
(g) Barros, M. T.; Phillips, A. M. F. Tetrahedron: Asymmetry 2010, 21,
2746–2752.
ꢁ
(7) (a) Gomez, M.; Muller, G.; Rocamora, M. Coord. Chem. Ver.
1999, 769–835. (b) Desimoni, G.; Faita, G.; Quadrelli, P. Chem. Rev.
2003, 103, 3119–3154. (c) McManus, H. A.; Guiry, P. J. Chem. Rev.
2004, 104, 4151–4202. (d) Desimoni, G.; Faita, G.; Jørgensen, K. L.
Chem. Rev. 2006, 106, 3561–3651.
(8) (a) Mashiko, T.; Hara, K.; Tanaka, D.; Fujiwara, Y.; Kumagai,
N.; Shibasaki, M. J. Am. Chem. Soc. 2007, 129, 11342–11343. (b)
Mashiko, T.; Kumagai, N.; Shibasaki, M. Org. Lett. 2008, 10, 2725–
2728. (c) Mashiko, T.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc.
2009, 131, 14990–14999. (d) Berhal, F.; Takechi, S.; Kumagai, N.;
Shibasaki, M. Chem.;Eur. J. 2011, 17, 1915–1921.
A series of experiments were then carried out in order to
establish the best conditions for the lanthanide-catalyzed
(9) The method was also found to be applicable to a wide range of
substrates; see: Pericas, A.; Shafir, A.; Vallribera, A. Tetrahedron 2008,
64, 9258–9263.
Org. Lett., Vol. 15, No. 7, 2013
1449