Enantioselective synthesis of a-quaternary amino acid derivatives by sequential enzymatic desymmetrization and curtius rearrangement of α,α-disubstituted malonate diesters

Article abstract of DOI:10.1021/jo902584r

(Figure Presented) A convenient and versatile enantioselective synthesis of biologically important α-quatemary amino acid derivatives was based on the sequential double alkylation or arylation of dimethyl malonate, followed by desymmetrization with porcine liver esterase (PLE) and Curtius rearrangement. The PLE-mediated hydrolysis of the prochiral dialkylated malonate diesters produced the corresponding chiral half-esters in high yield and with enantiomeric excesses of 43% to >98%. Curtius rearrangement of the latter products, after trapping of the intermediate isocyanates with benzyl alcohol or amines, afforded the corresponding Cbz-protected amino esters or ureas. The absolute configurations of the major products in five examples were established by conversion to compounds with known specific rotations, or by X-ray crystallography of derivatives obtained with chiral amines of known configuration.

Full text of DOI:10.1021/jo902584r

pubs.acs.org/joc
Enantioselective Synthesis of r-Quaternary Amino Acid Derivatives by
Sequential Enzymatic Desymmetrization and Curtius Rearrangement of
r,r-Disubstituted Malonate Diesters
Violeta Iosub, Anton R. Haberl, Jennifer Leung, Michael Tang, Kannan Vembaiyan,
Masood Parvez, and Thomas G. Back*
Department of Chemistry, University of Calgary, Calgary, AB, Canada, T2N 1N4
tgback@ucalgary.ca
Received December 6, 2009
A convenient and versatile enantioselective synthesis of biologically importantR-quaternary amino acid
derivatives was based on the sequential double alkylation or arylation of dimethyl malonate, followed by
desymmetrization with porcine liver esterase (PLE) and Curtius rearrangement. The PLE-mediated
hydrolysis of the prochiral dialkylated malonate diesters produced the corresponding chiral half-esters
in high yield and with enantiomeric excesses of 43% to >98%. Curtius rearrangement of the latter
products, after trapping of the intermediate isocyanates with benzyl alcohol or amines, afforded the
corresponding Cbz-protected amino esters or ureas. The absolute configurations of the major products
in five examples were established by conversion to compounds with known specific rotations, or by
X-ray crystallography of derivatives obtained with chiral amines of known configuration.
Introduction
systems. Since all of the proteinogenic amino acids except
glycine contain a single R-substituent, R,R-disubstituted
(quaternary) derivatives comprise a potentially useful class
of compounds for the preparation of modified peptides and
proteins not found in nature. Furthermore, the synthesis of
alkaloids and other products containing R-quaternary amine
moieties is particularly challenging because the efficient
installation of such centers is often precluded by steric con-
straints. Thus, there is considerable interest in novel method-
ologies for the efficient enantioselective synthesis of
R-quaternary amino acid derivatives.3
Peptides and proteins perform myriad structural, signaling,
regulatory, and catalytic functions in biological systems and
are fundamental components of living organisms. Moreover,
the amino acids from which they are composed also serve as
biosynthetic and synthetic precursors of numerous alkaloids
and other secondary metabolites that are of additional
importance in biology and medicine.1 It is remarkable that
suchstructural complexityandfunctional diversityis achieved
in nature with only 20 proteinogenic amino acids.2 However,
there is growing interest in the construction of designer
peptides and proteins that incorporate modified amino acids
in order to alter their structural properties, interactions with
ligands, and rates of metabolic degradation in biological
During our recent enantioselective synthesis of the antiviral
alkaloid (-)-virantmycin and its antipode,4 we employed a
ꢀ~
(3) For reviews, see: (a) Cativiela, C.; Ordonez, M. Tetrahedron: Asym-
metry 2009, 20, 1–63. (b) Cativiela, C.; Dıaz-de-Villegas, M. D. Tetrahedron:
Asymmetry 2007, 18, 569–623. (c) Cativiela, C.; Dıaz-de-Villegas, M. D.
Tetrahedron: Asymmetry 2000, 11, 645–732. (d) Cativiela, C.; Dıaz-de-
´
*To whom correspondence should be addressed. Fax: 403-289-9488. Tel:
403-220-6256.
´
´
(1) (a) Cordell, G. A. Introduction to Alkaloids;A Biogenetic Approach;
Wiley: New York, 1981. (b) Dewick, P. M. Medicinal Natural Products;A
Biosynthetic Approach; Wiley: Chichester, 1997.
(2) It can be argued that in addition to the 20 classical natural amino
acids, several other less common ones such as selenocysteine are also
proteinogenic.
Villegas, M. D. Tetrahedron: Asymmetry 1998, 9, 3517–3599. (e) Calaza,
M. I.; Cativiela, C. Eur. J. Chem. 2008, 3427–3448. (f) Spino, C. Angew.
€
Chem., Int. Ed. 2004, 43, 1764–1766. (g) Vogt, H.; Brase, S. Org. Biomol.
Chem. 2007, 5, 406–430. (h) Ohfune, Y.; Shinada, T. Eur. J. Org. Chem. 2005,
5127–5143.
(4) Back, T. G.; Wulff, J. E. Angew. Chem., Int. Ed. 2004, 43, 6493–6496.
1612 J. Org. Chem. 2010, 75, 1612–1619
Published on Web 02/04/2010
DOI: 10.1021/jo902584r
r
2010 American Chemical Society

Iosub et al.
JOCArticle
SCHEME 1
SCHEME 2
our results on the enantioselective preparation of a series of
alkyl, cycloalkyl, benzyl, and aryl R,R-disubstituted amino
acids by the sequential application of PLE desymmetrization
and Curtius rearrangement.
highly efficient desymmetrization of the R,R-dialkylated malo-
nate diester derivative 1 by porcine liver esterase (PLE) in 95%
enantiomeric excess (ee) in order to establish the key stereo-
center. The free carboxylic acid group in the resulting half-ester
2 was eventually converted into the corresponding formamide
3 by a stereospecific Curtius rearrangement and finally into the
desired product by an intramolecular Buchwald-Hartwig aryl
amination, followed by additional functional group modifica-
tions (Scheme 1). This suggested that the combination of
enzymatic desymmetrization of a disubstituted malonate di-
ester with PLE, followed by Curtius rearrangement, might
serve as an exceptionally simple and effective general method
for the enantioselective preparation of R-quaternary amino
acid derivatives. In addition to the transformations shown in
Scheme 1, a few other isolated examples of this and related
approaches have been reported. Thus, Kedrowski5 prepared
(R)- and (S)-2-methylcysteine in 91% ee from desymmetrized
dimethyl R-methyl-R-tert-butylthiomethylmalonate, while
Honda et al.6 converted diethyl 2-cyclohexene-1,1-dicarboxy-
late into the corresponding amino ester in 64% ee. The
diastereoselective PLE-mediated hydrolysis of a chiral β-vinyl-
cyclopropane diester has been employed in the preparation of
the corresponding amino acid, but afforded a poor diastereo-
meric excess (de).7 In a different approach, R-quaternary
amino acid derivatives have been prepared by the Curtius
rearrangement of malonate half-esters derivatized with cam-
phor- and menthol-based chiral auxiliaries.8 We now report
Results and Discussion
The use of PLE for the hydrolytic desymmetrization of
prochiral diesters has been extensively investigated.9 A model
of the binding site proposed by Jones et al.10 provides the
means for predicting the configurations of the products, based
chiefly on the difference in size of the two R-substituents.
Furthermore, Bjorkling et al.11 noted that the absolute con-
€
figurations of R-methyl-R-n-alkyl-substituted half-esters
changed from S to R as the second R-substituent increased
in length from ethyl to n-heptyl, with crossover taking place
between the n-butyl and n-pentyl derivatives. They also
observed that enantioselectivities were generally considerably
higher with dimethyl than with diethyl esters.
The results from the desymmetrization of a series of
variously R,R-disubstituted malonate dimethyl esters 4 are
shown in Scheme 2 and Table 1. In general, good to excellent
isolated yields of the half-esters 5 were obtained and ee values
were measured in entries 1-6 by NMR integration of gene-
rally well-separated methyl ester signals of diastereomeric
salts produced with (R)-(þ)-R-methylbenzylamine. In each
case, the NMR spectrum was compared with that of the
corresponding mixture of diastereomers obtained from race-
mic 5 (produced by nonenzymatic hydrolysis of 4 with KOH)
and (R)-(þ)-R-methylbenzylamine in order to confirm that
the correct signals were being integrated in the enantioselec-
tive experiments. Poor resolution of relevant signals pre-
cluded such measurements for the half-esters 5g-l in entries
7-12 and these half-esters were therefore subjected to Cur-
tius rearrangement prior to determination of their ee values.
In entries 1-3, a methyl group was chosen as the small
substituent, while the larger substituent was varied. The
linear n-hexyl group of 4a afforded a higher ee than the
branched isopropyl substituent of 4b (entries 1 and 2),
(5) Kedrowski, B. L. J. Org. Chem. 2003, 68, 5403–5406.
(6) Honda, T.; Koizumi, T.; Komatsuzaki, Y.; Yamashita, R.; Kanai, K.;
Nagase, H. Tetrahedron: Asymmetry 1999, 10, 2703–2712.
(7) Fliche, C.; Braun, J.; Le Goffic, F. Synth. Commun. 1994, 24, 2873–
2876.
(8) (a) Ihara, M.; Takahashi, M.; Taniguchi, N.; Yasui, K.; Nitsuma, H.;
Fukumoto, K. J. Chem. Soc., Perkin Trans. 1 1991, 525–535. (b) Ihara, M.;
Takahashi, M.; Nitsuma, H.; Taniguchi, N.; Yasui, K.; Fukumoto, K.
J. Org. Chem. 1989, 54, 5413–5415.
(9) For reviews, see: (a) Domınguez de Maria, P.; Garcıa-Burgos, C. A.;
´ ´
Bargeman, G.; van Gemert, R. W. Synthesis 2007, 1439–1452. (b)
Bornscheuer, U. T.; Kazlauskas, R. J. Hydrolases in Organic Synthesis: Regio-
and Stereoselective Biotransformations, 2nd ed.; Wiley-VCH: Weinheim,
Germany, 2006; Chapter 5. (c) Gais, H. J.: Theil, F. In Enzyme Catalysis in
Organic Synthesis; Drauz, K., Waldmann, H., Eds.; Wiley-VCH: Weinheim,
Germany, 2002; Vol. 2, Chapter 11. (d) Tamm, C. Pure Appl. Chem. 1992, 64,
1187–1191. (e) Santaniello, E.; Ferraboschi, P.; Grisenti, P.; Manzocchi, A. Chem.
(10) (a) Provencher, L.; Jones, J. B. J. Org. Chem. 1994, 59, 2729–2732. (b)
Toone, E. J.; Werth, M. J.; Jones, J. B. J. Am. Chem. Soc. 1990, 112, 4946–
4952. (c) Provencher, L.; Wynn, H.; Jones, J. B.; Krawczyk, A. R. Tetra-
hedron: Asymmetry 1993, 4, 2025–2040. (d) Toone, E. J.; Jones, J. B.
Tetrahedron: Asymmetry 1991, 2, 1041–1052.
€
Rev. 1992, 92, 1071–1140. (f) Boland, W.; Froβl, C.; Lorenz, M. Synthesis 1991,
1049–1072. (g) Jones, J. B. Aldrichim. Acta 1993, 26, 105–112. (h) Jones, J. B.
Can. J. Chem. 1993, 71, 1273–1282. (i) Jones, J. B. Pure Appl. Chem. 1990, 62,
1445–1448. (j) Zhu, L. M.; Tedford, M. C. Tetrahedron 1990, 46, 6587–6611. (k)
Ohno, M.; Otsuka, M. Org. React. 1989, 37, 1–55.
€
(11) Bjorkling, F.; Boutelje, J.; Gatenbeck, S.; Hult, K.; Norin, T.;
Szmulik, P. Tetrahedron 1985, 41, 1347–1352.
J. Org. Chem. Vol. 75, No. 5, 2010 1613

Iosub et al.
JOCArticle
TABLE 1. Preparation of Half-Esters and R-Quaternary Amino Acid Derivatives
yielda (ee or de)
entry
R
R’
half-ester 5b
product 7 or 9c
derivative 8 or 10d
8a 68 (68)
1
2
3
4
5
6
7
8
9
CH3(CH2)5
i-Pr
Me
Me
Me
5a 85 (67)
5b 82 (42)
5c 85 (63)
5d 94 (>98)
5e 84 (>98)
5f 90 (>98)
5g 98
7a 61
7b 82 (37)
7c 63 (63)
9d 52 (>98)
9e 78 (>98)
7f 45
9g 70 (52)
9h 92 (79)
7i 67
HCtCCH2
10c 66 (61)
10f 70 (96 or 89)
10i 59
Cye
Me
Et
Me
Et
n-Pr
Me
e
CyCH2
Ph
PhCH2
PhCH2
PhCH2CH2
5h 76
5i 94
9i 78 (80)
9j 70 (93)
9k 84 (94)
9l 74 (>98)
10
11
12
PhCH2CH2
PhCH2CH2
PhCH2CH2
Et
n-Pr
n-Bu
5j 98
5k 89
5l 87
aIsolated yields are reported. bEnantiomeric excesses (ee) were measured by NMR integration of salts formed with (R)-(þ)-R-methylbenzylamine, unless
otherwise indicated. cEnantiomeric excesses (ee) of 7b and 7c were measured by HPLC with a chiral column. Diastereomeric excesses (de) of 9 were measured by
NMR integration. dEnantiomeric excesses were measured as follows: 8a: NMR integration of salt formed with (R)-(-)-O-acetylmandelic acid; 10c: NMR
integration of salt formed with (R)-(þ)-R-methylbenzylamine; 10f and 10i: comparison of specific rotation to literature values.16,17 eCy = cyclohexyl.
suggesting that chain length is more important than branch-
ing for high enantioselectivity. Surprisingly, however, the
linear three-carbon propargyl group of 4c in entry 3 also
provided higher enantioselectivity than the isopropyl sub-
stituent of 4b. Entries 4-6 indicate that structures 4d-f,
containing bulky cyclohexyl, cyclohexylmethyl, or phenyl
groups, respectively, along with smaller methyl or ethyl
groups, afforded single enantiomers of 5d-f, within the
limits of detection by NMR spectroscopy.
Porcine pancreatic lipase (PPL) has also been used to
desymmetrize prochiral diesters,12 but appears to have been
less thoroughly investigated than PLE for this purpose. Like
PLE, PPL is commercially available, inexpensive, and con-
venient to use. We hoped that complementarity between the
two enzymes might permit improvement in the enantioselec-
tivities of examples where PLE was only marginally success-
ful. Unfortunately, attempts at the partial hydrolysis of
diesters 4a and 4b with PPL Type (II) afforded essentially
racemic mixtures of the corresponding half-esters 5a and 5b.
Thus, PLE proved the more generally efficacious of the two
enzymes for the present transformations.
Curtius rearrangement, as methyl 2-phenylpropanoate
was observed as a significant byproduct of this step.
Moreover, urea derivatives of amino acids are of special
interest, as ureidopeptides can be exploited in the design of
new foldamers and other structural motifs.15 Certain
ureidopeptides display potentially useful medicinal pro-
perties such as protease inhibition.15d We were surprised
to note that in compounds 5i-l, where R = phenethyl
(entries 9-12), the ee values of products 9i-l rose as the
size of the second substituent R0 increased from methyl to
n-butyl. This was in contrast to the expectation that
enantioselectivities would be enhanced with growing dis-
parity between the size of the two R-substituents. The
possibility of kinetic resolution of the enantiomers of the
corresponding isocyanates 6 upon treatment with (R)-(þ)-
R-methylbenzylamine was ruled out by treating the race-
mic isocyanates with the chiral amine and observing equal
amounts of the two diastereomeric products in the result-
ing 1H NMR spectra.
The absolute configurations of the major products (R)-
5a,11 (R)-5f,10d (S)-10f,16a,b and (S)-10i17 were established by
comparison of their specific rotations with literature values.
X-ray crystallography provided the absolute configurations
of the major product (S,S)-11e, formed from isocyanate 6e
and (S)-(-)-1-(1-naphthyl)ethylamine (Scheme 3), and of the
minor diastereomer (S)-5g in the form of its salt with
The Curtius rearrangements of 5a-l were effected with
diphenylphosphoryl azide (DPPA).13,14 The intermediate
isocyanates 6 were treated with benzyl alcohol or (R)-(þ)-
R-methylbenzylamine to afford the corresponding N-Cbz-
protected amino esters 7 or ureas 9, respectively, which
proved easier to isolate than the corresponding primary
amines obtained by hydrolysis of 6. The unusually poor yield
of 7f was attributed to facile decarboxylation during the
(15) For example, see: (a) Fischer, L.; Didierjean, C.; Jolibois, F.;
Semetey, V.; Lozano, J. M.; Briand, J.-P.; Marraud, M.; Poteau, R.;
Guichard, G. Org. Biomol. Chem. 2008, 6, 2596–2610. (b) Violette, A.;
Averlant-Petit, M. C.; Semetey, V.; Hemmerlin, C.; Casimir, R.; Graff, R.;
Marraud, M.; Briand, J.-P.; Rognan, D.; Guichard, G. J. Am. Chem. Soc.
2005, 127, 2156–2164. (c) Semetey, V.; Rognan, D.; Hemmerlin, C.; Graff,
R.; Briand, J.-P.; Marraud, M.; Guichard, G. Angew. Chem., Int. Ed. 2002,
41, 1893–1895. (d) Zhang, X.; Rodrigues, J.; Evans, L.; Hinkle, B.;
(12) For examples of PPL-mediated desymmetrizations of prochiral
diesters, see: (a) Nakazawa, K.; Hayashi, M.; Tanaka, M.; Aso, M.;
Suemune, H. Tetrahedron: Asymmetry 2001, 12, 897–901. (b) Danieli, B.;
Lesma, G.; Passarella, D.; Silvani, A. Tetrahedron: Asymmetry 1996, 7, 345–
348. (c) Cotterill, I. C.; Cox, P. B.; Drake, A. F.; Le Grand, D. M.;
Hutchinson, E. J.; Latouche, R.; Pettman, R. B.; Pryce, R. J.; Roberts, S.
M.; Ryback, G.; Sik, V.; Williams, J. O. J. Chem. Soc., Perkin Trans. 1 1991,
3071–3075. (d) Hultin, P. G.; Mueseler, F.-J.; Jones, J. B. J. Org. Chem. 1991,
~
Ballantyne, L.; Pena, M. J. Org. Chem. 1997, 62, 6420–6423.
(16) (a) Charette, A. B.; Mellon, C. Tetrahedron 1998, 54, 10525–10535.
(b) Obrecht, D.; Bohdal, U.; Broger, C.; Bur, D.; Lehmann, C.; Ruffieux, R.;
€
€
Schonholzer, P.; Spiegler, C.; Muller, K. Helv. Chim. Acta 1995, 78, 563–580.
(17) Polese, A.; Formaggio, F.; Crisma, M.; Bonora, G. M.; Toniolo, C.;
Broxterman, Q. B.; Kamphuis, J. J. Chem. Soc., Perkin Trans. 2 1996, 833–
838.
ꢀ
56, 5375–5380. (e) Guibe-Jampel, E.; Rousseau, G.; Salaun, J. J. Chem. Soc.,
Chem. Commun. 1987, 1080–1081.
€
(13) Shioiri, T.; Ninomiya, K.; Yamada, S. J. Am. Chem. Soc. 1972, 94,
6203–6205.
(18) For a general review, see: (a) Banthorpe, D. V. In The Chemistry of the
Azido Group; Patai, S., Ed.; Wiley: New York, 1971; Chapter 7. For examples of
stereochemical studies of the Curtius rearrangement, see : (b) van Well, R. M.;
Overkleeft, H. S.; van Boom, J. H.; Coop, A.; Wang, J. B.; Wang, H.; van der
Marel, G. A.; Overhand, M. Eur. J. Org. Chem. 2003, 9, 1704–1710. (c) Hocking,
M. B. Can. J. Chem. 1968, 46, 2275–2282. (d) Denmark, S. E.; Dorow, R. L.
J. Org. Chem. 1989, 54, 5–6.
(14) For another particularly mild method for converting carboxylic
acids, including racemic malonate half-esters, into t-Boc-protected amines,
see: (a) Lebel, H.; Leogane, O. Org. Lett. 2005, 7, 4107–4110. (b) Leogane,
O.; Lebel, H. Synthesis 2009, 1935–1940. For other recent methods for
effecting Curtius rearrangements, see references cited therein.
1614 J. Org. Chem. Vol. 75, No. 5, 2010

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SCHEME 3
indicated. Chiral HPLC was performed on a Chiralcel OB,
250 ꢀ 4.6 mm column; solvent: 5:95 isopropanol/hexanes,
0.5 mL/min; UV detector: 210 nm. PLE20,21 (lyophilized powder;
17 units/mg) and PPL (Type II, 100-400 units/mg) were pur-
chased from the Sigma Co.
Malonate diesters 4a,11 4b,10c 4c,22 4f,10d and 4g23 are known
compounds. The preparation of the novel derivative 4d is
provided below. Compounds 4e and 4h-l were prepared as in
the sample procedure for 4d.
Preparation of r,r-Dialkylated Dimethyl Malonates. Typical
Procedure: Dimethyl 2-Cyclohexyl-2-methylmalonate (4d). Di-
methyl 2-cyclohexylmalonate (0.106 g, 0.495 mmol) was added
dropwise to a solution of sodium hydride (0.029 g, 60% disper-
sion in mineral oil, 0.72 mmol) in 20 mL of THF at 0 °C under
nitrogen. The mixture was stirred for 20 min and then methyl
iodide (0.060 mL, 0.96 mmol) was added. The mixture was
refluxed for 5 h. It was then quenched with water and extracted
with ether. The ether layer was washed with saturated solutions
of ammonium chloride, sodium thiosulfate, and brine, dried, and
concentrated in vacuo. Flash chromatography (ethyl acetate:
hexanes, 5:95) afforded 0.107 g (95%) of 4d as a pale yellow
oil: IR (film)1735 cm-1; 1H NMR (400 MHz) δ 3.71 (s, 6 H), 2.15
(tt, J=12.0, 2.9 Hz, 1 H), 1.78-1.74 (m, 2 H), 1.69-1.66 (m, 1
H), 1.59-1.56 (m, 2 H), 1.35 (s, 3 H), 1.34-1.29 (m, 2 H),
1.13-1.05 (m, 3 H); 13C NMR (75 MHz) δ 172.5, 58.0, 52.5,
42.9, 28.4, 26.8, 26.5, 16.4; mass spectrum (CI) (m/z, %) 229 (12,
Mþ þ H), 246 (100, Mþ þ NH4). HRMS (CI) calcd for
C12H21O4 229.1440 (Mþ þ H), found 229.1448. When the
reaction was scaled up to 1.80 g, the crude product was obtained
in similar yield and was of sufficient purity for further use
without the need for chromatographic purification.
(R)-(þ)-R-methylbenzylamine (see the Experimental Sec-
tion and Supporting Information).
The reliable retention of configuration associated with the
Curtius rearrangement18 permits correlation of the absolute
configurations of the above products with their respective
derivatives in entries 1, 5, 6, 7, and 9. Thus, the dominant
enantiomers of 5a, 5e, 5f, 5g, and 5i are all assigned the
(R)-configuration and 7a, 8a, 9e, 11e, 7f, 10f, 9g, 7i, 9i, and 10i
all possess the (S)-configuration.19 We observed that the optical
rotations of all of the half-esters in Table 1 were dextrorotatory,
except for 5c. Thus, by analogy with 5a, 5e, 5f, 5g, and 5i,
the major enantiomers of the other dextrorotatory half-esters
are also assigned the R-configuration. This is also consistent
with predictions based on the Jones model of PLE, where
placement of the larger and smaller R-substituents (R and R0,
respectively, in Scheme 2) in the hydrophobic pockets
of corresponding size in the active site of the enzyme results
in selective ester hydrolysis leading to the (R)-half esters.
The anomalous levorotatory behavior of 5c is attributed
to the S-configuration of its dominant enantiomer, where
R=Me and R0 =propargyl in Scheme 2 and Table 1. This
Dimethyl 2-Cyclohexylmethyl-2-ethylmalonate (4e). Pale yel-
low oil; IR (film) 1742 cm-1; 1H NMR (400 MHz) δ 3.68 (s, 6 H),
1.95 (q, J=7.6 Hz, 2 H), 1.83 (d, J=6.0 Hz, 2 H), 1.64-1.53 (m, 5
H), 1.30-1.03 (m, 4 H), 0.98-0.85 (m, 2 H), 0.78 (t, J=7.5 Hz, 3
H); 13C NMR (100 MHz) δ 172.7, 57.2, 52.1, 39.0, 34.1, 33.3,
26.3, 26.1, 25.7, 8.7; mass spectrum (CI), (m/z, %) 257 (47, Mþ þ
H), 274 (100, Mþ þ NH4). HRMS (CI) calcd for C14H25O4:
257.1753 (Mþ þ H), found 257.1754.
in turn is consistent with the previous observation by
€
11
Bjorkling et al., that the PLE desymmetrization of homo-
loguous R-methyl-R-n-alkyl diesters produced predomi-
nantly the exceptional S-enantiomers when the second alkyl
substituent was ethyl, n-propyl, or n-butyl (vide supra).
The parallel behavior of the unbranched three-carbon pro-
pargyl substituent and the n-propyl group is therefore not
surprising.
It is worth noting that in our earlier synthesis of
(-)-virantmycin, the same desymmetrized malonate half-
ester 2 could be converted into (þ)-ent-virantmycin by
protection of the free carboxyl group, saponification of the
remaining methyl ester, and eventual Curtius rearrangement
of the newly liberated carboxylic acid. A similar protocol can
therefore be envisaged for the preparation of the enantio-
mers of the amino acid derivatives listed in Table 1.
In conclusion, the enantioselective synthesis of R-quatern-
ary amino acid derivatives from prochiral disubstituted
malonate diesters can be achieved conveniently, effectively,
and often with high ee and predictable absolute configura-
tion by employing PLE desymmetrizations in conjunction
with stereospecific Curtius rearrangements.
Dimethyl 2-Benzyl-2-n-propylmalonate (4h). Pale yellow oil;
IR (film) 1738 cm-1; 1H NMR (300 MHz) δ 7.24-7.19 (m, 3 H),
7.04-7.01 (m, 2 H), 3.68 (s, 6 H), 3.22 (s, 2 H), 1.76-1.70 (m, 2
H), 1.32-1.24 (m, 2 H), 0.91 (t, J=7.2 Hz, 3 H); 13C NMR (75
MHz) δ 172.0, 136.4, 130.0, 128.5, 127.1, 59.2, 52.4, 38.5, 34.3,
17.8, 14.4; mass spectrum (EI), (m/z, %) 264 (38, Mþ), 204 (93),
91 (100). HRMS (EI) calcd for C15H20O4 264.1362 (Mþ), found
264.1350.
Dimethyl 2-Methyl-2-(2-phenethyl)malonate (4i). Colorless
oil; IR (film) 1730 cm-1 1H NMR (300 MHz) δ 7.33-7.12
;
(m, 5 H), 3.71 (s, 6 H), 2.62-2.48 (m, 2 H), 2.24-2.09 (m, 2 H),
1.49 (s, 3 H); 13C NMR (75 MHz) δ 172.5, 141.3, 128.4, 128.3,
126.0, 53.6, 52.4, 37.6, 30.8, 20.1; mass spectrum (CI) (m/z, %)
251 (12, Mþ þ H), 268 (100, Mþ þ NH4). HRMS (CI) calcd for
C14H19O4 251.1283 (Mþ þ H), found 251.1285.
(20) PLE consists of several isozymes, which display different enantio-
selectivities. While individual isozymes have been obtained by cloning and
recombinant expression methods, and may offer advantages over the com-
mercial product, the accessibility and convenience of the latter make it
desirable for synthetic applications such as those reported herein.
Experimental Section
All NMR spectra were recorded in deuteriochloroform at
200, 300 or 400 MHz (1H), or at 50, 75 or 100 MHz (13C). Mass
spectra were obtained by standard EI or CI techniques as
(21) For lead references to studies of PLE isozymes, see: (a) Hummel, A.;
€
€
Brusehaber, E.; Bottcher, D.; Trauthwein, H.; DodererK.; Bornscheuer,
U. T. Angew. Chem., Int. Ed. 2007, 46, 8492–8494. (b) Hermann, M.;
ꢁ ꢀ
Kietzmann, M. U.; Ivancic, M.; Zenzmaier, C.; Luiten, R. G. M.; Skranc,
W.; Wubbolts, M.; Winkler, M.; Birner-Gruenberger, R.; Pichler, H.; Schwab,
H. J. Biotechnology 2008, 133, 301–310.
(22) Neumeier, R.; Kramp, W.; Maecke, H. R. Eur. Pat. Appl. 417870,
1991; Chem. Abstr. 1991, 115, 255826.
(19) Note that replacement of the carboxyl group in half-esters 5 by a free
or protected amino group with retention of configuration changes the
absolute configuration from R to S because the amino group has a higher
priority than the carboxyl group as assigned by the Cahn-Ingold-Prelog
rules.
€
(23) Bjorkling, F.; Norin, T.; Szmulik, P.; Boutelje, J.; Hult, K.; Kraulis,
P. Biocatalysis 1987, 1, 87–98.
J. Org. Chem. Vol. 75, No. 5, 2010 1615

Iosub et al.
JOCArticle
Dimethyl 2-Ethyl-2-(2-phenethyl)malonate (4j). Colorless oil;
IR (film) 1752 cm-1; 1H NMR (300 MHz) δ 7.27-7.15 (m, 5 H),
3.70 (s, 6 H), 2.52-2.46 (m, 2 H), 2.21-2.16 (m, 2 H), 2.02 (q, J=
7.5 Hz, 2 H), 0.86 (t, J=7.5 Hz, 3 H); 13C NMR (75 MHz) δ
172.2, 141.5, 128.5, 128.4, 126.2, 58.2, 52.4, 34.1, 30.7, 25.9, 8.7;
mass spectrum (EI) (m/z, %) 264 (2, Mþ), 173 (13), 160 (100).
HRMS (EI) calcd for C15H20O4 264.1362 (Mþ), found 264.1375.
Dimethyl 2-(2-Phenethyl)-2-n-propylmalonate (4k). Colorless
oil; IR (film) 1732 cm-1; 1H NMR (300 MHz) δ 7.28-7.14 (m,
5 H), 3.70 (s, 6 H), 2.50-2.45 (m, 2 H), 2.20-2.15 (m, 2 H),
1.95-1.89 (m, 2 H), 1.25-1.20 (m, 2 H), 0.92 (t, J=7.4 Hz, 3 H);
13C NMR (75 MHz) δ 172.4, 141.6, 128.7, 128.6, 126.3, 57.9,
52.6, 35.3, 34.7, 30.9, 17.8, 14.6; mass spectrum (EI) (m/z, %)
279 (8, Mþ þ H), 296 (100, Mþ þ NH4). HRMS (EI) calcd for
C16H22O4 278.1518 (Mþ), found 278.1525.
(c 2.5, chloroform); ee 42%. Lit.10c for the (R)-enantiomer:
[R]25D ∼0 (c 1.3, chloroform); ee 6%.
2-Methyl-2-propargylmalonic Acid Monomethyl Ester (5c).24
The PLE hydrolysis was performed for 7 h to afford 85% of 5c as
a colorless oil; IR (film) 1734, 1717 cm-1; 1H NMR (200 MHz) δ
3.79 (s, 3 H), 2.82 (crude t, J=2.7 Hz, 2 H), 2.07 (crude t, J=2.7
Hz, 1 H), 1.61 (s, 3 H). [R]20D -1.3 (c 4.6, chloroform); ee 63%;
determined from NMR analysis of the 2-methyl signal.
2-Cyclohexyl-2-methylmalonic Acid Monomethyl Ester (5d).
The PLE hydrolysis was performed over 2 d to afford 94% of 5d
as a brown oil; IR (film) 1738, 1708 cm-1; 1H NMR (400 MHz) δ
3.76 (s, 3 H), 2.13-2.06 (m, 1 H), 1.80-1.58 (m, 5 H), 1.40 (s,
3 H), 1.31-1.26 (m, 2 H), 1.14-1.10 (m, 3 H); 13C NMR (100
MHz) δ 177.3, 172.9, 58.1, 52.8, 43.5, 28.4, 28.3, 26.79, 26.78,
26.4, 16.5; mass spectrum (CI), (m/z, %) 215 (3, Mþ þ H),
232 (100, Mþ þ NH4). HRMS (CI) calcd for C11H19O4 215.1283
Dimethyl 2-n-Butyl-2-(2-phenethyl)malonate (4l). Colorless
oil; IR (film) 1735 cm-1
;
1H NMR (300 MHz) δ 7.29-7.17
(Mþ þ H), found 215.1292. [R]20 þ6.0 (c 4.0, chloroform);
D
(m, 5 H), 3.73 (s, 6 H), 2.54-2.48 (m, 2 H), 2.23-2.18 (m, 2 H),
2.00-1.95 (m, 2 H), 1.38-1.31 (m, 2 H), 1.23-1.15 (m, 2 H),
0.92 (t, J=7.3 Hz, 3 H); 13C NMR (75 MHz) δ 172.4, 141.6,
128.62, 128.56, 126.3, 57.8, 52.6, 34.6, 32.8, 30.9, 26.5, 23.1, 14.1;
mass spectrum (CI) (m/z, %) 293 (15, Mþ þ H), 310 (100, Mþ þ
NH4). HRMS (EI) calcd for C17H24O4 292.1675 (Mþ), found
292.1669.
ee >98%.
2-Cyclohexylmethyl-2-ethylmalonic Acid Monomethyl Ester
(5e). The PLE hydrolysis was performed over 5 d to afford 84%
of 5e as a brown oil; IR (film) 1735, 1705 cm-1; 1H NMR (300
MHz) δ 11.97 (br s, 1 H), 3.82 (s, 3 H), 2.01-1.97 (m, 2 H),
1.89-1.80 (m, 2 H), 1.70-1.40 (m, 5 H), 1.18-1.10 (m, 4 H),
0.87-0.81 (m, 2 H), 0.80 (t, J=7.5 Hz, 3 H); 13C NMR (100
MHz) δ 176.5, 174.8, 57.2, 52.6, 41.2, 34.0, 33.82, 33.78, 28.4,
26.2, 26.1, 26.0, 9.0; mass spectrum (CI) (m/z, %) 243 (5, Mþ þ
H), 260 (100, Mþ þ NH4). HRMS (CI) calcd for C13H23O4
PLE-Mediated Hydrolysis of r,r-Dialkylated Dimethyl Malo-
nates. Typical Procedure: 2-n-Hexyl-2-methylmalonic Acid Mono-
methyl Ester (5a).11 Diester 4a (437 mg, 1.90 mmol) in 28 mL of
DMSO was added to 109 mL of 0.2 M sodium phosphate buffer
(pH 8). PLE (58 mg) was dissolved in a minimum amount of the
buffer solution, which was then added to the DMSO solution of 4a.
The mixture was stirred for 27 h at room temperature. It was then
acidified with 1 M HCl and extracted with ether. The organic
fractions were filtered through Celite and then extracted with
saturated sodium bicarbonate solution. The aqueous layer was
reacidified with 1 M HCl and extracted again with ether. The
combined organic phases were dried and concentrated in vacuo to
yield 351 mg (85%) of 5a as a colorless oil; IR (film) 1739, 1711
cm-1; 1H NMR (300 MHz) δ 3.76 (s, 3 H), 1.94-1.84 (m, 2 H),
243.1596 (Mþ þ H), found 243.1608. [R]20 þ8.5 (c 1.8,
D
chloroform); ee >98%.
2-Methyl-2-phenylmalonic Acid Monomethyl Ester (5f).10d
The PLE hydrolysis was performed over 4 d to afford 90% of
5f as a brown oil; 1H NMR (300 MHz) δ 7.38 (m, 5 H), 3.83 (s,
3 H), 1.93 (s, 3 H); [R]20D þ10.1 (c 8.20, chloroform); ee >98%.
Lit.10d for the (R)-enantiomer: [R]25D þ9.7 (c 3.1, chloroform);
ee 81%.
2-Benzyl-2-ethylmalonic Acid Monomethyl Ester (5g). The
PLE hydrolysis was performed over 4 d to afford 98% of 5g
as a colorless oil; IR (film) 1732, 1709 cm-1; H NMR (300
1
1.44 (s, 3 H), 1.35-1.19 (m, 8 H), 0.88 (t, J=6.7 Hz, 3 H); [R]20
MHz) δ 11.28 (br s, 1 H), 7.25-7.23 (m, 3 H), 7.10-7.08 (m, 2
H), 3.75 (s, 3 H), 3.32 (d, J=13.8 Hz, 1 H), 3.17 (d, J=13.8 Hz, 1
H), 1.95 (m, 2 H), 0.93 (t, J=7.5 Hz, 3 H); 13C NMR (75 MHz) δ
175.8, 173.3, 135.7, 129.6, 128.4, 127.2, 59.9, 52.7, 39.6, 27.0, 9.1;
mass spectrum (EI) (m/z, %) 236 (14, Mþ), 160 (70), 91 (100).
HRMS (EI) calcd for C13H16O4 236.1048 (Mþ), found 236.1035.
Anal. Calcd for C13H16O4: C, 66.09; H, 6.83. Found: C, 66.28;
H, 6.93. [R]20D þ1.6 (c 6.1, chloroform).
D
þ1.7 (c 9.7, chloroform). The ee (67%) was measured by integra-
tion of well-separated methyl ester signals in the 1H NMR
spectrum of an equimolar mixture of 5a and R-(þ)-R-methyl-
benzylamine. Lit.11 [R]D þ1.1; ee 87%.
A racemic sample of 5a was prepared as follows. Diester 4a
(215 mg, 0.933 mmol) was dissolved in 5 mL of methanol, and
2.5 mL of 10% aqueous KOH was added. After 6 h, TLC
showed the disappearance of starting material and the solution
was partitioned between ether and 10% NaOH. The aqueous
layer was acidified with use of 1 M HCl and extracted with
dichloromethane. The combined organic phases were dried and
concentrated in vacuo to afford 89 mg (44%) of the racemic
half-ester 5a as a yellow oil with NMR spectra identical with
those of the sample prepared by PLE hydrolysis. Racemic half-
ester 5a was treated with an equimolar amount of R-(þ)-R-
methylbenzylamine to ensure that NMR signals from the
resulting diastereomers were well-separated and identified un-
equivocally.
The product was mixed with (R)-(þ)-R-methylbenzylamine
in the molar ratio of 1:1 and the minor diastereomer of the
resulting salt crystallized selectively from dichloromethane.
X-ray crystallography (see the Supporting Information) esta-
blished that this product had the S configuration at the qua-
ternary carbon atom. The 1H NMR spectrum of the crystallized
material was compared to that of the original mixture of
diastereomers, which confirmed that it was the minor diastereo-
mer. The free carboxylic acid of the crystallized isomer was
recovered from its salt with (R)-(þ)-R-methylbenzylamine by
treatment with 10% aqueous HCl and extraction with dichloro-
methane. The dichloromethane solution was concentrated in
Compounds 5b-l were prepared similarly. Their character-
ization data and any significant differences in their methods of
preparation are provided below. The ee values of 5b-f were
determined similarly by NMR integration of their salts with
R-(þ)-R-methylbenzylamine. In each case a racemic sample was
also prepared for comparison.
vacuo to afford recovered 5g with [R]20 -2.0 (c 2.9,
chloroform), thus further confirming that the crystallized dia-
stereoisomer was the minor one.
D
2-Benzyl-2-n-propylmalonic Acid Monomethyl Ester (5h). The
PLE hydrolysis was performed over 6 d to afford 76% of 5h as a
brown oil; IR (neat) 1735, 1708 cm-1; H NMR (300 MHz) δ
1
2-Isopropyl-2-methylmalonic Acid Monomethyl Ester (5b).10c
The PLE hydrolysis was performed for 27 h to afford 82% of 5b
11.21 (br s, 1 H), 7.26-7.22 (m, 3 H), 7.09-7.06 (m, 2 H), 3.75
as a colorless oil; IR (film) 1734, 1713 cm-1; H NMR (200
1
MHz) δ 3.76 (s, 3 H), 2.47 (septet, J=6.7 Hz, 1 H), 1.38 (s, 3 H),
D
(24) For a racemic preparation of 5c, see: Arcadi, A.; Cacchi, S.;
Delmastro, M.; Marinelli, F. Synlett 1991, 407–409.
0.97 (d, J=6.2 Hz, 3 H), 0.95 (d, J=6.6 Hz, 3 H); [R]20 þ0.88
1616 J. Org. Chem. Vol. 75, No. 5, 2010

Iosub et al.
JOCArticle
(s, 3 H), 3.33 (d, J=13.7 Hz, 1 H), 3.16 (d, J=13.7 Hz, 1 H),
1.93-1.82 (m, 2 H), 1.31-1.24 (m, 2H), 0.92 (t, J=7.2 Hz, 3 H);
13C NMR (100 MHz) δ 176.1, 173.5, 135.9, 129.7, 128.6, 127.4,
59.6, 53.0, 40.2, 36.1, 18.2, 14.3; mass spectrum (EI) (m/z, %)
250 (40, Mþ), 204 (93), 189 (24), 91 (100). HRMS (EI) calcd for
Refluxing was then continued for 6 h. The mixture was partitioned
between ether and saturated aqueous NH4Cl solution. The aque-
ous layer was extracted with ether, the combined organic layers
were dried and concentrated in vacuo to yield 1.02 g of yellow oil.
This was purified via silica gel chromatography (hexanes:ethyl
acetate, 4:1) to yield 704 mg (61%) of 7a as a clear oil; IR (neat)
3416, 3358, 1730 cm-1;1H NMR (200 MHz) δ7.37-7.30 (m, 5 H),
5.60 (s, 1 H), 5.09 (s, 2 H), 3.74 (s, 3 H), 2.15-2.07 (m, 1 H),
1.80-1.70 (m, 1 H), 1.58 (s, 3 H), 1.33-1.17 (m, 7 H), 1.06-0.96
(m, 1 H), 0.87 (t, J=7.2 Hz, 3 H); 13C NMR (50 MHz) δ 174.8,
154.6, 136.7, 128.5, 128.04, 128.01, 66.4, 60.1, 52.6, 37.1, 31.6, 29.2,
24.0, 23.4, 22.6, 14.1; mass spectrum (EI) (m/z, %) 321 (Mþ, 1), 262
(12), 218 (24), 154 (55), 91 (100). HRMS (EI) calcd for C16H24NO2
[Mþ - CO2Me] 262.1807, found 262.1829. Anal. Calcd for
C18H27NO4: C, 67.26; H, 8.47; N, 4.36. Found: C, 67.38; H,
8.42; N, 4.63. [R]20D þ5.9 (c 1.0, chloroform).
C14H18O4 250.1205 (Mþ), found 250.1201. [R]20 þ4.3 (c 5.8,
D
chloroform).
2-Methyl-2-(2-phenethyl)malonic Acid Monomethyl Ester (5i).
The PLE hydrolysis was performed over 4 d to afford 94% of 5i
as a brown oil; IR (neat) 1738, 1708 cm-1; 1H NMR (300 MHz)
δ 11.87 (s, 1 H), 7.30-7.18 (m, 5 H), 3.75 (s, 3 H), 2.65-2.59 (m,
2 H), 2.23-2.17 (m, 2 H), 1.55 (s, 3 H); 13C NMR (75 MHz) δ
177.5, 172.6, 141.3, 128.6, 128.5, 126.3, 53.9, 52.9, 37.8, 31.1,
20.4; mass spectrum (EI) (m/z, %) 236 (5, Mþ), 132 (100), 114
(20), 91 (28). HRMS (EI) calcd for C13H16O4 236.1049 (Mþ),
found 236.1056. [R]20D þ2.19 (c 3.60, chloroform).
2-Ethyl-2-(2-phenethyl)malonic Acid Monomethyl Ester (5j).
The PLE hydrolysis was performed over 5 d to afford 98% of 5j
as a brown oil; IR (neat) 1735, 1708 cm-1; 1H NMR (300 MHz)
δ 7.28-7.14 (m, 5 H), 3.73 (s, 3 H), 2.57-2.47 (m, 2 H),
2.27-2.19 (m, 2 H), 2.06-1.99 (m, 2 H), 0.88 (t, J=7.3 Hz, 3
H); 13C NMR (100 MHz) δ 176.4, 173.8, 141.1, 128.7, 128.6,
126.4, 58.4, 53.0, 35.7, 31.2, 27.9, 9.1; mass spectrum (EI)
(m/z, %) 250 (5, Mþ), 146 (100), 128 (65). HRMS (EI) calcd
The following compounds were prepared similarly to 7a.
N-Carbobenzyloxy-2-(isopropyl)alanine Methyl Ester (7b).
The product was obtained in 82% yield from 5b by the same
procedure used in the preparation of 7a from 5a; mp 48-51 °C;
IR (film) 3371, 1730 cm-1; 1H NMR (200 MHz) δ 7.37-7.20 (m,
5 H), 5.31 (s, 1 H), 5.09 (s, 2 H), 3.72 (s, 3 H), 2.14 (septet, J=7.1
Hz, 1 H), 1.57 (s, 3 H), 0.95 (d, J=7.0 Hz, 3 H), 0.90 (d, J=6.8
Hz, 3 H); 13C NMR (50 MHz) δ 174.0, 155.1, 136.4, 128.5, 128.4,
128.0, 66.5, 63.0, 52.2, 35.2, 18.8, 17.3, 17.2; mass spectrum (EI)
(m/z, %) 279 (Mþ, 2), 236 (12), 220 (18), 192 (12), 91 (100).
HRMS (EI) calcd for C15H21NO4 279.1471 (Mþ), found
279.1455. Anal. Calcd for C15H21NO4: C, 64.49; H, 7.58; N,
for C14H18O4 250.1205 (Mþ), found 250.1213. [R]20 þ23.9
D
(c 1.50, chloroform).
2-(2-Phenethyl)-2-n-propyl Malonic Acid Monomethyl Ester
(5k). The PLE hydrolysis was performed over 5 d to afford 89%
of 5k as a colorless oil; IR (neat) 1735, 1708 cm-1; 1H NMR (400
MHz) δ 12.08 (br s, 1 H), 7.31-7.21 (m, 5 H), 3.78 (s, 3 H),
2.63-2.56 (m, 2 H), 2.30-2.24 (m, 2 H), 2.04-1.95 (m, 2 H),
1.33-1.30 (m, 2 H), 0.99 (t, J=7.2 Hz, 3 H); 13C NMR (100
MHz) δ 177.2, 173.2, 141.1, 128.6, 128.5, 126.3, 57.9, 52.9, 36.4,
35.7, 31.1, 17.9, 14.4; mass spectrum (EI) (m/z, %) 264 (1, Mþ),
160 (100), 131 (95), 91 (68). HRMS (CI) calcd for C15H21O4
5.02. Found: C, 64.51; H, 7.61; N, 4.90. [R]20 þ8.0 (2.2,
D
chloroform). The ee (37%) was measured by chiral HPLC.
N-Carbobenzyloxy-2-(propargyl)alanine Methyl Ester (7c).
The product was obtained as a yellow oil in 63% yield from 5c
by the same procedure used in the preparation of 7a from 5a; IR
1
3296, 1718 cm-1; H NMR (200 MHz) δ 7.38-7.29 (m, 5 H),
5.69 (s, 1 H), 5.10 (s, 2 H), 3.74 (s, 3 H), 2.94 (d, J=1.9 Hz, 2 H),
2.03 (t, J=2.6 Hz), 1.59 (s, 3 H); 13C NMR (50 MHz) δ 173.1,
154.7, 136.2, 128.4, 128.0, 127.9, 79.1, 71.3, 66.6, 58.6, 52.8, 26.9,
23.1; mass spectrum (EI) (m/z, %) 275 (Mþ), 236 (6), 216 (15),
192 (8), 172 (14), 108 (26), 91 (100). HRMS (EI) calcd
265.1440 (Mþ þ H), found 265.1437. [R]20 þ9.13 (c 8.00,
D
chloroform).
2-n-Butyl-2-(2-phenethyl)malonic Acid Monomethyl Ester
(5l). The PLE hydrolysis was performed over 4 d to afford
87% of 5l as a colorless oil; IR (neat) 1738, 1705 cm-1; 1H NMR
(400 MHz) δ 12.01 (br s, 1 H), 7.31-7.20 (m, 5 H), 3.78 (s, 3 H),
2.63-2.56 (m, 2 H), 2.30-2.24 (m, 2 H), 2.06-1.99 (m, 2 H),
1.40-1.35 (m, 2 H), 1.29-1.25 (m, 2 H), 0.95 (t, J=7.1 Hz, 3 H);
13C NMR (75 MHz) δ 177.0, 173.4, 141.1, 128.6, 128.5, 126.3,
57.8, 52.9, 35.8, 34.1, 31.1, 26.7, 23.0, 14.0; mass spectrum
(EI) (m/z, %) 278 (1, Mþ), 174 (100), 131 (88), 91 (55). HRMS
(CI) calcd for C16H23O4 [M þ H]þ 279.1596, found 279.1587.
[R]20D þ16 (c 1.7, chloroform).
for C15H17NO4 275.11576 (Mþ), found 275.11582. [R]20
D
þ7.5 (c 1.3, chloroform). The ee (63%) was measured by
chiral HPLC.
N-Carbobenzyloxy-2-(phenyl)alanine Methyl Ester (7f). The
product was obtained in 45% yield by the same procedure as for
the conversion of 5a to 7a; pale yellow oil; IR (film) 3352, 1732
cm-1; 1H NMR (300 MHz) δ 7.46-7.27 (m, 10 H), 6.23 (s, 1 H),
5.06 (d, J=12.3 Hz, 1 H), 5.02 (d, J=12.3 Hz, 1 H), 3.67 (s, 3 H),
2.05 (s, 3 H); 13C NMR (100 MHz) δ 173.5, 154.5, 140.5, 136.4,
129.9, 128.7, 128.5, 128.1, 128.0, 125.8, 66.6, 62.0, 53.2, 22.7;
mass spectrum (EI) (m/z, %), 313 (2, Mþ), 254 (68), 210 (31), 91
(100). HRMS (EI) calcd for C18H19NO4 313.1314 (Mþ), found
313.1313. [R]20D þ41.4 (c, 4.02, chloroform).
PPL-Mediated Hydrolysis of 4a. Diester 4a (0.409 g, 1.78
mmol) in DMSO (27 mL) was added to 94 mL of 0.2 M sodium
phosphate buffer (pH 8). PPL (0.400 g) was dissolved in a
minimum amount of buffer solution and added to the DMSO
solution. This was stirred for 3 d at room temperature. It was
then acidified with 10% HCl solution and extracted with
dichloromethane. The organic fractions were filtered through
Celite and extracted with sodium bicarbonate. The aqueous
layer was acidified to pH ∼2 and re-extracted with dichloro-
methane. The combined organic phases were dried and concen-
trated in vacuo to yield 82 mg (21%) of racemic 5a.
N-Carbobenzyloxy-2-(2-phenethyl)alanine Methyl Ester (7i).
The product was obtained as a colorless oil in 67% yield from 5i
by the same procedure used in the preparation of 7a from 5a; IR
(film) 3356, 1725 cm-1; 1H NMR (300 MHz) δ 7.40-7.13 (m,10
H), 5.89 (s, 1 H), 5.13 (s, 2 H), 3.69 (s, 3 H), 2.67-2.43 (m, 3 H),
2.21-2.13 (m, 1 H), 1.65 (m, 3 H); 13C NMR (75 MHz) δ 174.6,
154.6, 141.1, 136.6, 128.6, 128.5, 128.4, 128.2, 128.1, 126.0, 66.5,
59.9, 52.7, 38.3, 30.7, 23.7; mass spectrum (EI) (m/z, %) 341 (1,
Mþ) 237 (67), 91 (100). HRMS (EI) calcd for C20H23NO4
341.1627 (Mþ), found 341.1643. [R]20D þ19 (c 6.5, chloroform).
Preparation of 2-(n-Hexyl)alanine Methyl Ester (8a). The Cbz
derivative 7a (117 mg, 0.364 mmol) was dissolved in 25 mL of
methanol containing 10 drops of formic acid and 25 mg of 10%
palladium on carbon and stirred under hydrogen (1 atm) for
3 d. The mixture was then filtered through Celite, concentrated
in vacuo, dissolved in ether, and washed with 10% NaOH
The similar hydrolysis of diester 4b also produced essentially
racemic product 5b.
Curtius Rearrangement with Formation of Cbz Derivatives. Ty-
pical Procedure: N-Carbobenzyloxy-2-(n-hexyl)alanine Methyl
Ester (7a). Half-ester 5a (781 mg, 3.61 mmol) was refluxed in
16 mL of toluene with 0.80 mL (3.7 mmol) of DPPA and 0.50 mL
(3.6 mmol) of triethylamine for 2 h. The reaction mixture was
cooled to room temperature, followed by the addition of DMAP
(196 mg, 1.60 mmol) and benzyl alcohol (0.70 mL, 6.8 mmol).
J. Org. Chem. Vol. 75, No. 5, 2010 1617

Iosub et al.
JOCArticle
solution. The ether layer was dried and concentrated in vacuo
to afford 46 mg (68%) of 8a as a yellow oil; IR (neat) 3387,
1735 cm-1; 1H NMR (200 MHz) δ 3.70 (s, 3 H), 1.67-1.40 (m,
4 H), 1.30 (s, 3 H) superimposed on 1.30-1.05 (m, 8 H), 0.86 (t,
J=6.4 Hz, 3 H); 13C NMR (50 MHz) δ 178.1, 57.8, 52.0, 41.1,
31.6, 29.4, 26.3, 24.1, 22.5, 14.0; mass spectrum (EI) (m/z, %)
128 (Mþ - CO2Me, 100), 102 (30). HRMS (EI) calcd for
41.2, 41.0, 29.3, 29.2, 23.43, 23.35, 8.7, 8.6; mass spectrum (CI)
(m/z, %) 355 (100, Mþ þ 1). HRMS (EI) calcd for C21H26N2O3
354.1943 (Mþ), found 354.1927. [R]20D -61 (c 7.0, chloroform).
The de of 52% was calculated by integration of doublets from
the major and minor diastereomers at δ 3.00 and 3.07 ppm,
respectively. Their chemical shifts matched those observed in a
sample obtained similarly from the racemic half-ester 5g.
2-Benzyl-2-[3-(1-phenethyl)ureido]pentanoic Acid Methyl
Ester (9h). The product was obtained in 92% yield as a mixture
of diastereomers from the treatment of half-ester 5h by the same
procedure as for the conversion of 5d to 9d; colorless oil; IR
C8H18N (Mþ - CO2Me) 128.1439, found 128.1443. [R]20
D
þ8.0 (c 1.8, chloroform). The ee (68%) was measured by
integration of well-separated methyl ester signals in the 1H
NMR spectrum of an equimolar mixture of 8a and R-(-)-O-
acetylmandelic acid. This was compared with a 1:1 mixture of
diastereomers prepared similarly from racemic 8a, in turn
obtained from the racemic half-ester 5a.
(film) 3359, 1742, 1632 cm-1 1H NMR (400 MHz) major
;
diastereomer: δ 7.40-7.13 (m, 8 H), 6.95-6.87 (m, 2 H), 5.18
(br s, 1 H), 4.83 (br s, 1 H), 4.79-4.72 (m, 1 H), 3.73 (s, 3 H), 3.70
(d, J=13.1 Hz, 1 H), 3.00 (d, J=13.3 Hz, 1 H), 2.56-2.50 (m,
1 H), 1.79-1.72 (m, 1 H), 1.47-1.42 (m, 1 H), 1.43 (d, J=6.8 Hz,
3 H), 1.30-1.15 (m, 1 H), 0.90-0.84 (m, 3 H); minor diastereo-
mer: 3.07 (d, J=13.8 Hz, 1 H), 1.51 (d, J=7.3 Hz, 3 H); 13C
NMR (100 MHz) major diastereomer: δ 174.6, 156.1, 144.9,
137.0, 130.0, 128.6, 128.1, 127.2, 126.6, 126.1, 65.7, 52.5, 50.2,
41.4, 38.4, 23.4, 17.7, 14.1; mass spectrum (CI) (m/z, %) 369
(100, Mþ þ H). HRMS (CI) calcd for C22H29N2O3 369.2178
(Mþ þ H), found 369.2168. Anal. Calcd for C22H28N2O3: C,
Curtius Rearrangement with Formation of Ureas. Typical
Procedure: 2-Cyclohexyl-2-[3-(1-phenethyl)ureido]propanoic
Acid Methyl Ester (9d). A solution of half-ester 5d (164 mg, 0.765
mmol), triethylamine (0.16 mL, 1.2 mmol), and DPPA (0.17 mL,
0.79 mmol) in 5 mL of toluene was refluxed for 5 h. It was cooled
to room temperature and (R)-(þ)-R-methylbenzylamine (0.18
mL, 1.4 mmol) was added. The mixture was refluxed an addi-
tional 20 h, the solvent was evaporated in vacuo, and
the residue was chromatographed (20-30% ethyl acetate-
hexanes) to afford 133 mg (52%) of product 9d as a single
diastereomer; white solid, mp 184.5-185.5 °C; IR (film) 3346,
71.71; H, 7.66; N, 7.60. Found: C, 71.47; H, 7.67; N, 7.36. [R]20
D
-62 (c 2.1, chloroform). The de of 79% was calculated by
integration of the doublets from the major and minor diaster-
eomers at δ 3.00 and 3.07 ppm, respectively. Their chemical
shifts matched those observed in a sample obtained similarly
from the racemic half-ester 5h.
1
1745, 1635 cm-1; H NMR (300 MHz) δ 7.32-7.24 (m, 5 H),
4.91 (br s, 1 H), 4.88 (d, J=6.0 Hz, 1 H), 4.70-4.66 (quintet, J=
6.5 Hz, 1 H), 3.62 (s, 3 H), 1.68-1.57 (m, 4 H), 1.41 (s, 3 H), 1.40
(d, J=6.8 Hz, 3 H), 1.23-0.72 (m, 7 H); 13C NMR (100 MHz) δ
175.2, 157.0, 144.3, 128.9, 127.5, 126.1, 62.9, 52.3, 51.0, 45.7,
27.6, 27.4, 26.61, 26.55, 26.4, 23.9, 19.4; mass spectrum (EI)
(m/z, %) 332 (4, Mþ), 273 (12), 126 (66), 102 (100). HRMS (EI)
calcd for C19H28N2O3 332.2100 (Mþ), found 332.2118. Anal.
Calcd for C19H28N2O3: C, 68.64; H, 8.49; N, 8.43. Found: C,
68.67; H, 8.38; N, 8.09. [R]20D þ42 (c 2.9, chloroform). A sample
prepared similarly from racemic 5d for comparison showed
clearly separated methyl ester peaks.
2-Methyl-2-[3-(1-phenethyl)ureido]-4-phenylbutanoic Acid
Methyl Ester (9i). The product was obtained in 78% yield as a
mixture of diastereomers from the treatment of half-ester 5i by
the same procedure as for the conversion of 5d to 9d; white solid,
mp 151-153 °C; IR (film) 3362, 1738, 1629 cm-1; 1H NMR (300
MHz) major diastereomer: δ 7.36-7.14 (m, 8 H), 7.00-6.98 (m,
2 H), 5.48 (br s, 1 H), 5.23 (d, J=6.7 Hz, 1 H), 4.74 -4.69 (m,
1 H), 3.56 (s, 3 H), 2.48-2.34 (m, 2 H), 2.24-2.12 (m, 1 H),
The following compounds were prepared similarly to 9d.
2-Cyclohexylmethyl-2-[3-(1-phenethyl)ureido]butanoic Acid
Methyl Ester (9e). The product was obtained in 78% yield as a
single diastereomer from the treatment of half-ester 5e by the
same procedure as for the conversion of 5d to 9d; white solid; mp
160-162.5 °C; IR (film) 3316, 1738, 1635 cm-1; 1H NMR (300
MHz) δ 7.35-7.22 (m, 5 H), 5.47 (s, 1 H), 4.93 (d, J=6.6 Hz,
1 H), 4.68 (quintet, J=6.8 Hz, 1 H), 3.66 (s, 3 H), 2.46-2.29 (m,
2 H), 1.80-1.43 (m, 6 H), 1.42 (d, J=6.8 Hz, 3 H), 1.23-0.77 (m,
6 H), 0.64 (t, J=7.4 Hz, 3 H, superimposed on m, 1 H); 13C NMR
(75 MHz) δ 176.3, 155.8, 144.4, 128.9, 127.5, 126.1, 64.3, 52.6,
50.9, 43.4, 34.3, 34.0, 33.1, 30.0, 26.5, 26.42, 26.39, 23.9, 8.4;
mass spectrum (CI) (m/z, %) 361 (100, Mþ þ H), 329 (25), 257
(28), 120 (48). HRMS (CI) calcd for C21H33N2O3: 361.2491
(Mþ þ H); found: 361.2504. Anal. Calcd for C21H32N2O3: C,
2.12-1.99 (m, 1 H), 1.53 (s, 3 H), 1.41 (d, J=6.8 Hz, 3 H); 13
C
NMR (100 MHz) major diastereomer: δ 175.8, 156.3, 144.4,
141.4, 128.9, 128.7, 128.4, 127.5, 126.1, 126.0, 60.0, 52.7, 50.8,
38.6, 30.7, 24.2, 23.8; mass spectrum (CI) (m/z, %) 355 (100,
M
H), found 355.2024. Anal. Calcd for C21H26N2O3: C, 71.16; H,
þ þ H). HRMS (CI) calcd for C21H27N2O3 355.2022 (Mþ þ
7.39; N, 7.90. Found: C, 70.77; H, 7.34; N, 7.56. [R]20 þ45
D
(c 1.3, chloroform). The de of 80% was calculated by integration
of the methyl ester singlets from the major and minor diastereo-
mers at δ 3.56 and 3.62 ppm, respectively. Their chemical shifts
matched those observed in a sample obtained similarly from the
racemic half-ester 5i.
2-Ethyl-2-[3-(1-phenethyl)ureido]-4-phenylbutanoic Acid
Methyl Ester (9j). The product was obtained in 70% yield as a
mixture of diastereomers from the treatment of half-ester 5j by
the same procedure as for the conversion of 5d to 9d; colorless
oil; IR (film) 3359, 1738, 1635 cm-1; 1H NMR (400 MHz) major
diastereomer: δ 7.39-7.20 (m, 8 H), 7.03-7.01 (m, 2 H), 5.52 (br
s, 1 H), 5.08 (d, J=6.7 Hz, 1 H), 4.76 (quintet, J=6.7 Hz, 1 H),
3.59 (s, 3 H), 2.77-2.69 (m, 1 H), 2.49-2.37 (m, 2 H), 2.14-1.97
(m, 2 H), 1.77-1.68 (m, 1 H), 1.48 (d, J=6.8 Hz, 3 H), 0.72 (t, J=
7.4 Hz, 3 H); 13C NMR (100 MHz) major diastereomer: δ 175.2,
155.9, 144.5, 141.6, 128.9, 128.7, 128.3, 127.5, 126.1, 125.9,
65.0, 52.7, 50.9, 37.3, 30.7, 29.2, 23.9, 8.6; mass spectrum (EI)
(m/z, %) 264 (25), 162 (47), 105 (64), 91 (100). HRMS (EI) calcd
69.97; H, 8.95; N, 7.77. Found: C, 70.03; H, 8.99; N, 7.60. [R]20
D
þ38 (c 3.0, chloroform). A sample prepared similarly from
racemic 5e for comparison showed clearly separated methyl
ester peaks.
2-Benzyl-2-[3-(1-phenethyl)ureido]butanoic Acid Methyl Ester
(9g). The product was obtained in 70% yield as a mixture of
diastereomers from the treatment of half-ester 5g by the same
procedure as for the conversion of 5d to 9d; colorless oil; IR
(film) 3336, 1738, 1632 cm-1 1H NMR (400 MHz) major
;
diastereomer δ 7.35-7.15 (m, 8 H), 7.01-6.92 (m, 2 H),
5.42-5.31 (m, 2 H), 4.79-4.73 (m, 1 H), 3.71 (s, 3 H), 3.66 (d,
J=14.2 Hz, 1 H), 3.00 (d, J=13.3 Hz, 1 H), 2.56-2.47 (m, 1 H),
1.81 (sextet, J=7.2 Hz, 1 H), 1.37 (d, J=6.9 Hz, 3 H), 0.68 (t, J=
7.3 Hz, 3 H); 13C NMR (100 MHz) both diastereomers: δ 174.4,
174.3, 156.2, 156.1, 145.0, 144.5, 137.1, 130.0, 129.9, 128.63,
128.58, 128.1, 127.1, 126.6, 126.13, 126.05, 66.5, 66.0, 52.4, 50.1,
for C22H28N2O3 368.2100, found 368.2112. [R]20 þ36 (c 1.5,
D
chloroform). The de of 93% was calculated by integration of the
methyl ester singlets from the major and minor diastereomers at
δ 3.59 and 3.65 ppm, respectively. Their chemical shifts matched
those observed in a sample obtained similarly from the racemic
half-ester 5j.
1618 J. Org. Chem. Vol. 75, No. 5, 2010

Iosub et al.
JOCArticle
60.4 mg (70%) of the product as a colorless oil containing a 1:1
2-(2-Phenethyl)-2-[3-(1-phenethyl)ureido]pentanoic Acid Methyl
Ester (9k). The product was obtained in 84% yield as a mixture of
diastereomers from the treatment of half-ester 5k by the same
procedure as for the conversion of 5d to 9d; yellow oil; IR (film)
3362, 1745, 1652 cm-1; 1H NMR (300 MHz) major diastereomer: δ
7.38-7.09 (m, 8 H), 6.99-6.96 (m, 2 H), 5.66 (brs, 1 H), 5.41(d, J=
6.8 Hz, 1 H), 4.72 (quintet, J = 6.7 Hz, 1 H), 3.54 (s,
3 H), 2.73-2.65 (m, 1 H), 2.42-2.32 (m, 2 H), 2.09-1.94 (m,
2 H), 1.66-1.56 (m, 1 H), 1.44 (d, J=6.8 Hz, 3 H), 1.37-1.20 (m,
1 H), 0.95-0.80 (m, 1 H), 0.80 (t, J=7.0 Hz, 3 H); 13C NMR (100
MHz) major diastereomer: δ 175.4, 156.1, 144.6, 141.6, 128.8,
128.7, 128.3, 127.4, 126.1, 125.9, 64.3, 52.6, 50.8, 38.4, 37.5, 30.5,
23.8, 17.6, 14.1; mass spectrum (CI) (m/z, %) 383 (100, Mþ þ H).
HRMS (CI) calcd for C23H31N2O3 383.2335 (Mþ þ H), found
383.2339. Anal. Calcd for C23H30N2O3: C, 72.22; H, 7.91; N, 7.33.
Found: C, 72.20; H, 7.81; N, 6.94. [R]20D þ49 (c 3.4, chloroform).
The de of 94% was calculated by integration of the methyl ester
singlets from the major and minor diastereomers at δ 3.54 and 3.61
ppm, respectively. Their chemical shifts matched those observed in
a sample obtained similarly from the racemic half-ester 5k.
1
mixture of two rotamers; IR (film) 1718 cm-1; H NMR (200
MHz) major rotamer: δ 8.33 (br s, 1 H), 7.50-7.05 (m, 9 H), 6.71
(br s, 1 H), 5.04 (br s, 1 H), 4.90 (br s, 1 H), 2.05 (s, 3 H); minor
rotamer: 6.05 (br s, 1 H); 13C NMR (50 MHz) both rotamers: δ
176.13, 176.06, 158.2, 156.4, 140.4, 140.1, 135.4, 128.5, 128.3,
127.9, 125.8, 125.5, 125.3, 125.2, 67.4, 67.1, 61.9, 23.1; mass
spectrum (EI), (m/z, %) 254 (32, Mþ - COOH), 210 (21), 91
(100). HRMS (EI) calcd for C16H16NO2 254.1181 (Mþ
-
COOH), found 254.1179. [R]20D þ34.2 (c 1.38, methanol). Lit.16a
[R]20 þ35.5 (c 2.83, methanol); lit.16b [R]D þ38.5 (c 2.83,
D
methanol) for the S-isomer.
N-Carbobenzyloxy-2-(2-phenethyl)alanine (10i).17 Ester 7i
(128 mg, 0.375 mmol) was dissolved in 8 mL of methanol and
3 mL of 10% aqueous KOH solution. The mixture was refluxed
for 20 h and was then partitioned between ether and 10%
aqueous NaOH solution. The aqueous layer was acidified with
10% aqueous HCl and extracted with dichloromethane, then
the combined extracts were dried and concentrated in vacuo to
afford 72 mg (59%) of 10i as a colorless oil; 1H NMR (300 MHz)
δ 11.60 (s, 1 H), 7.40-7.18 (m, 10 H), 5.78 (s, 1 H), 5.16 (s, 2 H),
2.69-2.56 (m, 3 H), 2.28-2.22 (m, 1 H), 1.71 (s, 3 H); 13C NMR
(75 MHz) δ 179.3, 154.6, 140.9, 136.3, 128.6, 128.44, 128.41,
2-(2-Phenethyl)-2-[3-(1-phenethyl)ureido]hexanoic Acid Methyl
Ester (9l). The product was obtained in 74% yield as a single
diastereomer from the treatment of half-ester 5l by the same
procedure as for the conversion of 5d to 9d; white solid, mp
128.3, 128.1, 126.1, 66.7, 59.9, 38.1, 30.6, 23.7. [R]20 þ8.21
D
(c 2.86, methanol); lit.17 [R]20D -6.8 (c 0.5, methanol) for the R
isomer.
99-102.5 °C; IR (film) 3346, 1735, 1632 cm-1; H NMR (400
1
MHz) δ 7.41-7.14 (m, 8 H), 7.03-6.98 (m, 2 H), 5.58 (br s, 1 H),
5.20 (d, J=6.8 Hz, 1 H), 4.75 (quintet, J=6.7 Hz, 1 H), 3.57 (s,
3 H), 2.76-2.70 (m, 1 H), 2.45-2.38 (m, 2 H), 2.08-1.97 (m,
2 H), 1.69-1.62 (m, 1 H), 1.48 (d, J=6.8 Hz, 3 H), 1.30-1.18 (m,
4 H), 0.84 (t, J=7.1 Hz, 3 H); 13C NMR (100 MHz) δ 175.4,
155.9, 144.6, 141.6, 128.9, 128.7, 128.3, 127.4, 126.0, 125.9, 64.3,
52.6, 50.9, 37.5, 35.9, 30.6, 26.5, 23.9, 22.7, 14.2; mass spectrum
(EI) (m/z, %) 292 (32), 190 (43), 91 (52), 69 (100). HRMS (EI)
Determination of the Absolute Configuration of 2-Benzyl-2-
ethylmalonic Acid Monomethyl Ester (5e). Preparation of 2-
Cyclohexylmethyl-2-{3-[1-(1-naphthyl)ethyl]ureido}butanoic
Acid Methyl Ester (11e). A solution of half-ester 5e (198 mg,
0.818 mmol), triethylamine (0.13 mL, 0.93 mmol), and DPPA
(0.20 mL, 0.93 mmol) in 2 mL of toluene was refluxed for 2 h. It
was cooled to room temperature and (S)-(-)-1-(1-naphthyl)-
ethylamine (0.21 mL, 1.31 mmol) was added. The mixture was
refluxed an additional 13 h, the solvent was evaporated in vacuo,
and the residue was chromatographed (15-30% ethyl
acetate-hexanes) to afford 143 mg (43%) of a single product
11e as the (S,S)-diastereomer, confirmed by means of X-ray
crystallography (see the Supporting Information); white solid,
mp 179-184 °C; IR (film) 3356, 1735, 1635 cm-1; 1H NMR (400
MHz) δ 8.17 (d, J=8.2 Hz, 1 H), 7.88-7.86 (m, 1 H), 7.78 (d, J=
8.2 Hz, 1 H), 7.57-7.42 (m, 4 H), 5.65 (pentet, J=6.8 Hz, 1 H),
5.42 (s, 1 H), 4.82 (d, J=7.3 Hz, 1 H), 3.63 (s, 3 H), 2.51-2.37 (m,
2 H), 1.76-1.50 (m, 10 H), 1.46-1.02 (m, 6 H), 0.65 (t, J=7.4
Hz, 3 H); 13C NMR (100 MHz) δ 176.0, 155.2, 139.5, 134.0,
131.0, 128.7, 128.0, 126.3, 125.7, 125.2, 123.4, 122.2, 64.2, 52.3,
45.9, 43.2, 34.2, 34.1, 33.1, 29.9, 26.35, 26.31, 26.2, 22.0, 8.2;
mass spectrum (EI) (m/z, %) 410 (65, Mþ), 214 (54), 154 (100).
HRMS (EI) calcd for C25H34N2O3 410.2569, found 410.2559.
[R]20D þ15 (c 0.65, chloroform).
calcd for C24H32N2O3 396.2413, found 396.2425. [R]20 þ37
D
(c 2.3, chloroform). A sample obtained similarly from the
racemic half-ester 5l showed clearly resolved methyl ester peaks
from the two diastereomers.
Preparation of Free Carboxylic Acids. Typical Procedure:
N-Carbobenzyloxy-2-(propargyl)alanine (10c). Ester 7c (83 mg,
0.30 mmol) was dissolved in 10 mL of methanol and 17 mL of
10% aqueous KOH solution. The mixture was stirred at 65 °C
for 1.5 d and was then partitioned between ether and 10%
aqueous NaOH solution. The basic layer was acidified with 10%
aqueous HCl and extracted with dichloromethane, then the
combined extracts were dried and concentrated in vacuo to
afford 52 mg (66%) of 10c as a colorless oil; IR (film) 3293, 2120,
1715 cm-1; H NMR (300 MHz) δ 7.33-7.29 (m, 5 H), 5.57
1
(br s, 1 H), 5.10 (s, 2 H), 2.96 (br s, 2 H), 2.02 (t, J=2.5 Hz, 1 H),
1.61 (s, 3 H); 13C NMR (100 MHz) δ 177.9, 155.3, 136.2, 128.7,
128.4, 128.2, 79.0, 71.9, 67.2, 58.6, 27.0, 23.3; mass spectrum
(CI) (m/z, %) 262 (10, Mþ þ H), 279 (100, Mþ þ NH4). HRMS
(EI) calcd for C14H15NO4 261.1001 (Mþ), found 261.0990.
[R]20D þ20.7 (c 1.23, chloroform). The ee (61%) was measured
by integration of well-separated methyl signals in the 1H NMR
spectrum of an equimolar mixture of 10c and R-(þ)-R-methyl-
benzylamine.
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council of Canada (NSERC) for
financial support. A.R.H., J.L., and M.T. were undergradu-
ate research assistants who thank PURE, the University of
Calgary, and the NSERC USRA program, respectively, for
support.
The following compounds were prepared similarly to 10c.
N-Carbobenzyloxy-2-(phenyl)alanine (10f).16 To a solution of
7f (92 mg, 0.29 mmol) in 10 mL of methanol was added 2.3 mL of
1 M aqueous KOH solution and the mixture was stirred at room
temperature for 19 h. It was then partitioned between 1 M KOH
solution and diethyl ether. The aqueous layer was acidified with
10% aqueous HCl solution and extracted with ether. The
organic extracts were dried and concentrated in vacuo to afford
1
Supporting Information Available: Copies of H and 13C
NMR spectra of new compounds; ORTEP diagrams and X-ray
crystallographic data for compounds 5g (salt with (R)-(þ)-R-
methylbenzylamine) and 11e. This material is available free of
charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 5, 2010 1619