Asymmetric synthesis of α-amino acids: Preparation and alkylation of monocyclic iminolactones derived from α-methyl trans-cinnamaldehyde

Article abstract of DOI:10.1021/jo801514g

(Chemical Equation Presented) Two novel chiral monocyclic iminolactones 14a and 14b have been prepared. The chiral auxiliary 12 was obtained from α-methyl-trans-cinnamaldehyde through reduction, methylation, Sharpless asymmetric dihydroxylation, and oxidation in 87% overall yield. Esterification of compound 12 with the respective protected amino acids followed by deprotection and cyclization provided the corresponding iminolactones, each in 82% overall yield. Alkylation of the iminolactone 14a afforded the α-methyl-α,α-disubstituted products 15 and 16 in good yields (78-99%) and excellent diastereoselectivity (de >98%). Alkylations of the iminolactone 14b furnished the α-benzyl-α,α-disubstituted products 15a, 16b, 17, and 18 in good yields (51-86%) but moderate diastereoselectivities (43-56%). When HMPA or DMPU was used as a cosolvent, the rate of alkylation of the iminolactone 14b was accelerated with improved yields (56-99%) and diastereoselectivities (50-83%). Hydrolysis of the dialkylated iminolactones yielded the α,α-disubstituted α-amino acids in good yields (80-98%) and high enantiomeric excesses (98-99%) with good recovery of compound 12 (83-92%).

Full text of DOI:10.1021/jo801514g

Asymmetric Synthesis of r-Amino Acids: Preparation and
Alkylation of Monocyclic Iminolactones Derived from r-Methyl
trans-Cinnamaldehyde†
Ta-Jung Lu* and Cheng-Kun Lin
Department of Chemistry, National Chung-Hsing UniVersity, Taichung, Taiwan 40227, Republic of China
tjlu@dragon.nchu.edu.tw
ReceiVed July 10, 2008
Two novel chiral monocyclic iminolactones 14a and 14b have been prepared. The chiral auxiliary 12
was obtained from R-methyl-trans-cinnamaldehyde through reduction, methylation, Sharpless asymmetric
dihydroxylation, and oxidation in 87% overall yield. Esterification of compound 12 with the respective
protected amino acids followed by deprotection and cyclization provided the corresponding iminolactones,
each in 82% overall yield. Alkylation of the iminolactone 14a afforded the R-methyl-R,R-disubstituted
products 15 and 16 in good yields (78-99%) and excellent diastereoselectivity (de >98%). Alkylations
of the iminolactone 14b furnished the R-benzyl-R,R-disubstituted products 15a, 16b, 17, and 18 in good
yields (51-86%) but moderate diastereoselectivities (43-56%). When HMPA or DMPU was used as a
cosolvent, the rate of alkylation of the iminolactone 14b was accelerated with improved yields (56-99%)
and diastereoselectivities (50-83%). Hydrolysis of the dialkylated iminolactones yielded the R,R-
disubstituted R-amino acids in good yields (80-98%) and high enantiomeric excesses (98-99%) with
good recovery of compound 12 (83-92%).
Introduction
example, Na´jera and co-workers reported a versatile oxazinone
system which was used as chiral cyclic alanine-equivalent for
the asymmetric synthesis of interesting enantiomerically en-
riched acyclic and cyclic R-methyl R-amino acids (AMAAs).5f
Recently, we reported two tricyclic iminolactones 1 and 2
(Scheme 1), prepared from (1R)-(+)-camphor, to provide
R-monosubstituted R-amino acids in high yields with excellent
enantiomeric excesses.6
Asymmetric synthesis of optically active R-amino acids and
their derivatives is an important area of great interest for their
extensive use in pharmaceuticals,1 agrochemicals,2 and as chiral
ligands,3 which has led to the development of many highly
enantioselective methodologies.4 Among those methods, chiral
glycine- and alanine-equivalents play an important role.5 For
† This paper is dedicated to the memory of Professor A. I. Meyers.
(1) (a) Lee, K.-A.; Yeo, S.; Kim, K. H.; Lee, W.; Kang, S. J. J. Pharm.
Biomed. Anal. 2008, 46, 914–918. (b) Gioia, M. G.; Andreatta, P.; Boschetti,
S.; Gatti, R. J. Pharm. Biomed. Anal. 2007, 45, 456–464. (c) Hicks, R. P.;
Bhonsle, J. B.; Venugopal, O.; Koser, B. W.; Magill, A. J. J. Med. Chem. 2007,
50, 3026–3036. (d) Davtyan, T. K.; Hakobyan, I. S.; Muradyan, R. E.;
Hovhannisyan, H. G.; Gabrielyan, E. S. J. Antimicrob. Chemother. 2007, 59,
1114–1122. (e) Gajewski, M.; Seaver, B.; Esslinger, C. S. Bioorg. Med. Chem.
Lett. 2007, 17, 4163–4166.
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M.; Yoshimune, K.; Hirose, Y.; Moriguchi, M. J. Mol. Catal. B: Enzym. 2003,
23, 71–85. (c) Claus, M. T.; Zocher, G. E.; Marier, T. H. P.; Schulz, G. E.
Biochemistry 2005, 44, 8620–8626.
We envisioned a new stereoselective strategy for constructing
R-amino acids, as outlined in Scheme 2. Iminolactone 4 should
give an enolate when treated with a strong base. The oxygen
atom on the sidearm can chelate to the metal cation M+ to form
(3) (a) Almansa, R.; Guijamo, D.; Yus, M. Tetrahedron: Asymmetry 2008,
19, 1376–1380. (b) Wettergren, J.; Zaitsev, A. B.; Adolffson, H. AdV. Synth.
Catal. 2007, 349, 2556–2562. (c) Han, Z.-J.; Wang, R.; Zhou, Y.-F.; Liu, L.
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10.1021/jo801514g CCC: $40.75
Published on Web 09/11/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 9527–9534 9527

Lu and Lin
SCHEME 1
SCHEME 2
block the top face of the alkylation reaction and thus result in
good stereoselectivity; and (d) both the imine and lactone
functioalities can be hydrolyzed easily to produce the amino
acids with possible recovery of the chiral auxiliary.
Herein, we report the development of an alanine equivalent
and a phenylalanine equivalent of monocyclic iminolactones
and their application for the asymmetric syntheses of R-methyl
and R-benzyl-R,R-disubstituted R-amino acids.
Results and Discussion
The first task of our synthesis was the preparation of the chiral
auxiliary in high optical purity. Based on our retrosynthetic
analysis, the chiral auxiliary hydroxyketone 12 could be prepared
from R-methyl-trans-cinnamaldehyde. First, reduction of the
aldehyde 8 with sodium borohydride produced the allylic alcohol
9. In this transformation, we found that the addition of a solution
of aldehyde 8 in 95% ethanol dropwise into sodium borohydride
without cerium trichloride7 could give the reduced product in
99% yield. The primary alcohol was then converted smoothly
into its corresponding methyl ether 10.8 The stereocenters of
the chiral auxiliary were established by Sharpless asymmetric
dihydroxylation to yield the diol 11 in 93% yield and 98% e.e.9
The diol 11 was subsequently oxidized with IBX (2-iodoxy-
benzoic acid) in acetonitrile containing two equivalents of water
to obtain hydroxyketone 12 in 75% (93% based on recovered
starting material) yield (Scheme 3).10
Chiral auxiliary 12 was then coupled with Boc-dl-alanine or
Boc-dl-phenylalanine, mediated by DCC (N,N′-dicyclohexyl-
carbodiimide) and DMAP [4-(dimethylamino)pyridine],11 to
furnish the ester 13 (Scheme 4). After flash column purification
of the crude ester, removal of the Boc group was achieved by
bubbling with gaseous HCl to afford the amine hydrogen
chloride salt. Treatment of this salt with anhydrous potassium
carbonate in acetonitrile gave two inseparable diastereomers of
the desired iminolactone 14 in 82% yields over three steps.
The iminolactone 14a was deprotonated with LDA at -78
°C and alkylated with benzyl bromide to give the diastereomer
15a in 83% yield and excellent de (98%) (Scheme 5).
a rigid complex transition state 5. Thus, the sidearm would act
as an effective blocking group to shield the top face of the
enolate and the electrophile should come in from the bottom
face. The difference of free energy of activation (∆∆G‡) between
the two faces is anticipated to be large. As a result, the
diastereomeric excess (de) of the alkylated product should be
very high. Compound 6 can then be hydrolyzed to provide the
R-monosubstituted R-amino acid or the corresponding amino
ester along with the recovered chiral auxiliary 3.
The cyclic iminolactone 4 was chosen for the following
reasons: (a) a cyclic system will allow for a more rigid transition
state than the corresponding acyclic one, which can enhance
the steric effect of the auxiliary in controlling the stereochemistry
of the reaction; (b) unlike acyclic esters, lactones give rise to
only the Z-enolate, which in turn will afford a single alkylated
product if electrophiles approaches specifically from one of the
enolate faces; (c) the C(6)-sidearm of the oxazinone ring can
(4) (a) Duthaler, R. O. Tetrahedron 1994, 50, 1539–1650. (b) Williams,
R. M.; Hendrix, J. A. Chem. ReV. 1992, 92, 889–917. (c) Xu, P.-F.; Li, S.; Lu,
T.-J.; Wu, C.-C.; Fan, B.-T.; Golfis, G. J. Org. Chem. 2006, 71, 4364–4373. (d)
Calmes, M.; Daunis, J. Amino Acids 1999, 16, 215. (e) Na´jera, C.; Sansano,
J. M. Chem. ReV. 2007, 107, 4584–4671. (f) Wanner, K.; Koch, C. J.;
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Simonyiova´, S.; Pabel, J.; Ka¨rtner, A.; Polborn, K. Eur. J. Org. Chem. 2003,
1244–1263. (g) Maruoka, K.; Ooi, T. Chem. ReV. 2003, 103, 3013–3028. (h)
Scho¨llkopf, U.; Ku¨hnle, W.; Egert, E.; Dyrbusch, M. Angew. Chem., Int. Ed.
Engl. 1987, 26, 480–482. (i) Wirth, T. Angew. Chem., Int. Ed. Engl. 1997, 36,
225. (j) Seebach, D.; Hoffmann, M. Eur. J. Org. Chem. 1998, 1337. (k) Carloni,
A.; Porzi, G.; Sandri, S. Tetrahedron: Asymmetry 1998, 9, 2987–2998. (l)
Cativiela, C.; D´ıaz-de-Villegas, M. D. Tetrahedron: Asymmetry 1998, 9, 3517–
3599. (m) Cativiela, C.; D´ıaz-de-Villegas, M. D. Tetrahedron: Asymmetry 2000,
11, 645–732. (n) Cativiela, C.; D´ıaz-de-Villegas, M. D. Tetrahedron: Asymmetry
2007, 18, 569–632.
As summarized in Table 1, alkylation reactions of the
iminolactone 14 generated the dialkylated products in good
yields with extremely high control of the stereochemistry of
the R-carbon for a number of electrophiles.
When n-propyl iodide and isobutyl bromide were used as
electrophiles (Table 1, entries 5 and 6), the iminolactone 14a
(5) For glycine equivalents, see: (a) Saghiyan, A. S.; Dadayan, S. A.;
Petrosyan, S. G.; Manasyan, L. L.; Geolchanyan, A. V.; Djamgaryan, S. M.;
Andreasyan, S. A.; Maleev, V. I.; Khrustalev, V. N. Tetrahedron: Asymmetry
2006, 17, 455–467. (b) Kitamura, M.; Arimura, Y.; Shirakawa, S.; Maruoka, K.
Tetrahedron Lett. 2008, 49, 2026–2030. (c) Ma, D.; Ding, K. Tetrahedron 2001,
57, 6361–6366. (d) O’Donnell, M. J. Aldrichim. Acta 2001, 34, 3–15. (e)
Chinchilla, R.; Na´jera, C.; Ortega, F. J. Tetrahedron: Asymmetry 2006, 17, 3423–
3429. (f) For alanine equivalents, see: Na´jera, C.; Chinchilla, R.; Galindo, N.
Synthesis 1999, 704–717. (g) Berkowitz, D. B.; Smith, M. K. J. Org. Chem.
1995, 60, 1233–1238. (h) Na´jera, C.; Abella´n, T.; Sansano, J. M. Eur. J. Org.
Chem. 2000, 2809–2820. (i) Belokon, Y. N.; Davies, R. G.; North, M.
Tetrahedron Lett. 2000, 41, 7245–7248.
(7) Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226–2227.
(8) Uang, B.-J.; Chen, T.-Y.; Yeu, J.-P.; Yeh, J.-T. Synthesis 2001, 1775–
1777.
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Hartung, J. H.; Jeong, K.-S. J. Org. Chem. 1992, 57, 2768–2771. (b) Gonzalez,
J.; Aurigemma, C.; Truesdale, L. Org. Synth. , 79, 93–103.
(10) (a) Martin, J. C.; Dess, D. B. J. Am. Chem. Soc. 1991, 113, 7277–7287.
(b) Ireland, R. E.; Liu, L. J. Org. Chem. 1999, 58, 2899.
(11) Gu, D.-X. Master Thesis, National Chung-Hsing University, 2003.
(6) (a) Xe, P.-F.; Chen, Y.-S.; Lin, S.-I.; Lu, T.-J J. Org. Chem. 2002, 67,
2309–2314. (b) Xe, P.-F.; Lu, T.-J. J. Org. Chem. 2003, 68, 658–661.
9528 J. Org. Chem. Vol. 73, No. 24, 2008

Asymmetric Synthesis of R-Amino Acids
SCHEME 3
SCHEME 4
SCHEME 5
TABLE 1. Alkylation of the Iminolactone 14a
entry
RX
R
time (h)
yielda (%)
deb (%)
1
2
3
4
5
6
PhCH2Br
EtO2CCH2Br
NCCH2Br
CH2dCHCH2Br
CH3(CH2)2I
(CH3)2CHCH2Br
PhCH2
EtO2CCH2
NCCH2
CH2dCHCH2
CH3(CH2)2
(CH3)2CHCH2
16.5
15.5
15.5
18.5
15.5
15.5
83 (15a)
99 (15b)
91 (15c)
78 (15d/16d)
c
>98
>98
>98
69
c
a The reported yields are isolated yields after column chromatography. b Diastereomeric excess was estimated by 1H NMR integrations of the crude
reaction mixtures on a 400 NMR spectrometer. c No reaction.
failed to give desired products which might because of the rate
of the competitive elimination is faster than that of the
alkylation. It is noteworthy that allylation of the oxazinone 14a
with allyl bromide resulted in an unexpectedly poor diastereo-
selectivity compared with other active alkyl halides (Table 1,
entry 4).
selectivities presumably was due to a decrease in the degree of
aggregation of the enolate.12 The use of chelating agents such
as ZnBr2 and ZnI2, in a hope to increase the chelation of the
metal ion and the oxygen atom on the sidearm to improve the
facial selectivity, did not deliver satisfactory results (Table 2,
entries 13 and 14).
Table 2 describes the yields and de of the alkylated products
of the iminolactone 14b under different alkylation conditions.
Alkylations were carried out at -78 °C using LDA as the base
to give the dialkylated products in moderate to good yields but
in unsatisfactory stereoselectivities (Table 2, entries 1, 7, and
10). The reaction rates were effectively accelerated by the
addition of HMPA (hexamethylphosphoramide) or DMPU
(N,N′-dimethylpropylene urea), and the diastereoselectivities
were significantly enhanced as a result (Table 2, entries 2, 5, 6,
8, 9, 11, and 12). The considerable improvement of the facial
The stereochemistry of the newly created stereocenter of the
dialkylated product is deduced from the following evidence:
The H NMR spectra of the dialkylated derivatives 15a, 16a,
17, and 18 with a C(3)-benzyl group showed a remarkable
stereochemistry-dependent shielding effect on the chemical shifts
of the methyl group and the methoxy group on C(6). The
chemical shifts of characteristic protons of compounds 15a, 16a,
1
(12) Solladie´-Cavallo, A.; Csaky, A. G.; Gantz, I.; Suffert, J. J. Org. Chem.
1994, 59, 5343–5346.
J. Org. Chem. Vol. 73, No. 24, 2008 9529

Lu and Lin
TABLE 2. Alkylation of the Iminolactone 14b
reaction conditions
entry
deprotonation
alkylation
yielda (%)
deb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
LDA, THF, -78 °C, 0.5 h
CH3I, -78 °C, 15.5 h
75 (16a/15a)
87 (16a/15a)
84 (16a/15a)
c
43
50
15
LDA, THF/HMPA, -78 °C, 1 h
LDA, THF/DMPU, -78 °C, 1 h
LDA, THF, -78 °C, 0.5 h
CH3I, -78 °C, 1 h
CH3I, -78 °C, 1 h
CH3CH2I, -78 °C, 16.5 h
CH3CH2I, -78 °C, 1 h
LDA, THF/HMPA, -78 °C, 1 h
LDA, THF/DMPU, -78 °C, 1 h
LDA, THF, -78 °C, 0.5 h
LDA, THF/HMPA, -78 °C, 1 h
LDA, THF/DMPU, -78 °C, 1 h
LDA, THF, -78 °C, 0.5 h
LDA, THF/HMPA, -78 °C, 1 h
LDA, THF/DMPU, -78 °C, 1 h
LDA, THF, ZnBr2, -78 °C, 1 h
LDA, THF, ZnI2, -78 °C, 1 h
95 (17a/18a)
56 (17a/18a)
86 (17b/18b)
96 (17b/18b)
99 (17b/18b)
51 (17c/18c)
83 (17c/18c)
93 (17c/18c)
38 (17c/18c)
68 (17c/18c)
75
55
53
83
82
56
76
70
64.5
65
CH3CH2I, -78 °C, 1 h
NCCH2Br, -78 °C, 20 h
NCCH2Br, -78 °C, 1 h
NCCH2Br, -78 °C, 1 h
CH2dCHCH2Br, -78 °C, 13.5 h
CH2dCHCH2Br, -78 °C, 1 h
CH2dCHCH2Br, -78 °C, 1 h
CH2dCHCH2Br, -78 °C, 12 h
CH2dCHCH2Br, -78 °C, 12 h
a The reported yields are isolated yields after column chromatography. b Diastereomeric excess was estimated by 1H NMR integrations of the crude
reaction mixtures on a Varian Mercury-400 NMR spectrometer. c No reaction.
TABLE 3. Chemical Shifts of Characteristic Protons of
Compounds 15a, 16a, 17, and 18
compd
R
RC7-CH3
RC8-CH2
RC9-CH3
16a
15a
17a
18a
17b
18b
17c
18c
CH3
CH3
CH3CH2
CH3CH2
NCCH2
NCCH2
CH2dCHCH2
CH2dCHCH2
1.47
0.54
1.43
0.33
1.55
0.53
1.40
0.39
3.51, 3.15
3.45, 3.09
3.47, 3.16
3.42, 3.09
3.43, 3.21
3.42, 3.26
3.51, 3.20
3.44, 3.15
2.92
3.35
2.96
3.28
3.10
3.32
2.91
3.28
17, and 18 are compiled in Table 3. For instance, before
alkylation, the chemical shifts of the C(6)-methyl groups of the
two diastereomers of iminolactone 14a are δ 1.40 and 1.46 ppm,
respectively. After benzylation, the C(6)-methyl group of the
product 15a moved to δ 0.54. The methyl group of the MOM
group at C(6) of compound 16a (δ 2.92) appeared at 0.43 ppm
higher field than that of compound 15a (δ 3.35). The shielding
effect of the C(3)-benzyl group is responsible for this upfield
shift, indicating that the C(3)-benzyl group and C(6)-methyl
group must lie in the same side of the oxazinone ring while the
C(6)-MOM group of compound 16a and the C(3)-benzyl group
are on the same side of the oxazinone ring.
FIGURE 1. X-ray structure of compound 15a.
The stereochemistry of the alkylated product serves to
demonstrate that benzyl bromide reacted with the enolate from
the opposite side of the sidearm in the alkylation step as
predicted by our transition-state model.
Furthermore, X-ray determination of a single crystal of
15a,13recrystallized from ether/hexane, clearly shows that the
C(6)-methyl group sits right on top of the benzene ring of the
C(3)-benzyl group which is strongly shielded by its ring current
(Figure 1). This result confirms the stereochemistry assignment
1
by H NMR data.
On the other hand, the chemical shifts of the methylene of
the C(6)-MOM groups were nearly unaffected by the relative
position of the C(3)-benzyl group (0.01-0.07 ppm). The small
chemical shift differences of the methylene of C(6)-MOM
groups between the major and minor products (0.22-0.43 ppm)
suggested that the steric interaction between the C(6)-MOM
groups and the C(3)-benzyl groups of the major products pushed
the phenyl ring away from the C(6)-MOM groups.
To obtain R-amino acids, the disubsituted iminolactones were
heated with 8 N HCl aqueous solution in a sealed tube at 90 °C
(Table 4). After hydrolysis, the corresponding R,R-dialkylated
R-amino acid hydrogen chloride salts were obtained in high
(13) The X-ray crystallographic structure of compound 15a has been
submitted to the Cambridge Crystallographic Data Centre. The CCDC number
for compound 15a is CCDC 669087.
9530 J. Org. Chem. Vol. 73, No. 24, 2008

Asymmetric Synthesis of R-Amino Acids
TABLE 4. Hydrolysis of the Dialkylated Iminolactones 15a-d, 16a, and 17c
recovered chiral
auxiliary (%)
substrate
R1
R2
PhCH2
EtO2CCH2
NCCH2
CH2dCHCH2
CH3
CH2dCHCH2
R3
PhCH2
HO2CCH2
HO2CCH2
CH2dCHCH2
CH3
amino acid (%)
time (h)
[R]23
eed (%)
D
15a
15b
15c
15d
16a
17c
CH3
CH3
CH3
CH3
PhCH2
PhCH2
92 (19a)
98 (19b)
94 (19b)
83
92
90
89
85
87
1
3
3
3
1
3
+9.40a
-36.2b
-35.5b
+13.4c
-9.41a
+15.3a
98
99
99
98
99
98
85 (19c)
91 (ent-19a)
80 (19d)
CH2dCHCH2
a The optical rotations were measured in H2O solution. b The optical rotations were measured in MeOH solution. c The optical rotations was measured
in D2O solution. d e.e.% values were determined by chiral HPLC analyses.
(E)-2-Methyl-3-phenylprop-2-en-1-ol (9).15 A solution of R-m-
yields and excellent ee. The configuration of the resulting amino
ethyl trans-cinnamaldehyde (6.66 g, 44.7 mmol) in 95% EtOH (90
mL) was added to NaBH4 (2.18 g, 1.2 equiv) in an ice-water bath
over a 20 min period. Saturated NH4Cl aqueous solution (25 mL)
and water (25 mL) were added to the reaction mixture, which was
kept stirring for 60 min. The mixture was extracted with ether. The
combined organic phases were washed with brine, dried (anhyd
MgSO4), and concentrated to give a colorless oily product (6.55 g,
99%). This crude allylic alcohol was pure enough for further use.
1H NMR (400 MHz, CDCl3): δ 7.20-7.35 (m, 5H, Ph), 6.53 (s,
1H, CH), 4.18 (s, 2H, CH2), 1.90 (s, 3H, CH3). 13C NMR (100
MHz, CDCl3): δ 137.4, 128.7, 127.9, 126.2, 124.6, 68.4, 15.1. MS:
m/z 148 (M+, 23.0), 131 (100), 115 (55.9), 91 (83.6). HRMS m/z
calcd for C10H12O M+ 148.0888, found M+ 148.0881.
acids was determined by comparing the optical rotations of the
products with literature values. Additionally, the chiral auxiliary
12 was recovered in excellent yields (83-92%).
Conclusion
In conclusion, an efficient method for preparation of chiral
auxiliary 12 was developed which was utilized in the construction
of two novel chiral iminolactone templates 14a and 14b. The
alkylation of them gave the dialkylated products in high yields and
facial selectivities in a stereochemistry predictable by our transition
state model. Hydrolysis of the iminolactones afforded the desired
R,R-disubstituted R-amino acids in excellent yields and optical
purity. The ease of syntheses of and the good yields and the high
stereoselectivities realized in the alkylation of the iminolactone
templates as well as the possibility of recycling of the chiral
auxiliaries rendered our method a practical and useful protocol for
preparation of enantiopure R-amino acids in predetermined ster-
eochemistry. If (DHQ)2-PHAL [1,4-bis(9-O-dihydroquinine)ph-
thalazine) was used in the asymmetric dihydroxylation reaction,
the antipode of chiral auxiliary 12 can be obtained. Consequently,
either enantiomer of an R-amino acid can be synthesized selectively.
The application of our methodology in the synthesis of biologically
active R,R-disubstituted amino acids is in progress.
[(E)-3-Methoxy-2-methylpropenyl]benzene (10). A solution of
(E)-2-methyl-3-phenylprop-2-en-1-ol (9) (2.23 g, 15.0 mmol) in
dry THF (15 mL) was dropped to a stirred suspension of 95%
sodium hydride (645 mg, 1.7 equiv) in dry THF (35 mL) in an
ice-water bath under nitrogen over 15 min period, and then
iodomethane (1.4 mL, 1.5 equiv) was added dropwise. The mixture
was allowed to warm to room temperature and stirred for 2 h before
4 N NaOH aqueous solution (19 mL) was added. The mixture was
vigorously stirred overnight. The aqueous layer was extracted with
ether. The combined organic extracts were dried (anhyd MgSO4)
and concentrated to give crude orange liquid. The crude product
was purified by flash column chromatography (silica gel, hexane/
EtOAc ) 7:1) to give methyl ether (2.41 g, 99%) as a pale yellow
1
liquid. H NMR (400 MHz, CDCl3): δ 7.20-7.35 (m, 5H, Ph),
6.50 (s, 1H, CH), 3.98 (s, 2H, CH2), 3.37 (s, 3H, OCH3), 1.91 (s,
3H, CH3). 13C NMR (100 MHz, CDCl3): δ 137.4, 134.9, 128.8,
128.0, 126.8, 126.3, 78.6, 57.6, 15.2. MS: m/z 162 (M+, 27.3), 145
(70.8), 115 (100), 105 (86.4), 91 (86.2), 77 (60.7), 51 (30.9). HRMS
m/z calcd for C11H14O M+ 162.1045, found M+ 162.1043.
(1S,2S)-3-Methoxy-2-methyl-1-phenylpropane-1,2-diol (11). A
1000 mL flask with a mechanical stirrer was charged with tert-
buyl alcohol (130 mL), water (130 mL), potassium osmate dihydrate
(29 mg, 0.3 mol%), (DHQD)2-PHAL [1,4-bis(9-O-dihydroquinidi-
ne)phthalazine, 215 mg, 1.0 mol%], potassium ferricyanide (26.0
g, 3.0 equiv), potassium carbonate (10.8 g, 3.0 equiv), and
methanesulfonamide (2.53 g, 1.0 equiv). Stirring at room temper-
ature produced two clear phases; the lower aqueous phase appears
bright yellow. The mixture was cooled to 4 °C whereupon some
of the dissolved salts precipitated. Methyl ether 10 (4.22 g, 26.0
Experimental Section
General Methods. All alkylation reactions were conducted in
flame-dried Schlenk tubes fitted with rubber septa under an argon
atmosphere, and all reactions were carried out under a nitrogen
atmosphere. 1H and 13C NMR spectra were recorded on a 400 MHz
spectrometer. Chloroform (δ ) 7.26) or deuterium oxide (δ ) 4.60)
was used as internal standard in 1H NMR spectra. The center peak
of deuterochloroform (δ ) 77.0) was used as internal standard in
13C NMR spectra. The ee value of the R-amino acids obtained from
hydrolysis of the alkylated iminolactones was determined by HPLC
analysis on a Crownpak CR(+) column (Daicel column, 150 mm
× 4 mm) using water and ethanol as the mobile phase.
Materials. Reagents and solvents are commercially available.
All alkyl halides were pretreated with copper powder. Diisopro-
pylamine, toluene, dichloromethane (DCM), acetonitrile, HMPA,
and DMPU were distilled from calcium hydride immediately prior
to use, THF was distilled from sodium benzophenone ketyl, and
n-butylithium in hexanes (nominally 1.6 M) was purchased from
Aldrich. IBX,10 Boc-dl-alanine, and Boc-dl-phenylalanine14 were
prepared according to the literature procedures.
(14) Adolfsson, H.; Pastor, I. M.; Va¨stila¨, P. Chem.sEur. J. 2003, 9, 4031–
4045.
(15) (a) Goodwin, T. E.; Ratcliff, D. G.; Crowder, C. M.; Seitzinger, N. K.
J. Org. Chem. 1982, 47, 815–820. (b) Daub, G. W.; Edwards, J. P.; Okada,
C. R.; Allen, J. W.; Maxey, C. T.; Wells, M. S.; Goldstein, A. S.; Dibley, M. J.;
Wang, C. J.; Ostercamp, D. P.; Chung, S.; Cunningham, P. S.; Berliner, M. A
J. Org. Chem. 1997, 62, 1976–1985.
J. Org. Chem. Vol. 73, No. 24, 2008 9531

Lu and Lin
mmol) was added at once, and the heterogeneous slurry was stirred
vigorously at 4 °C for 17 h. While the mixture was stirred in an
ice-water bath, solid sodium sulfite (39.7 g) was added and stirred
for 1 h. EtOAc was added to the reaction mixture, and after
separation of the layers, the aqueous phase was further extracted
with EtOAc. The organic phases were washed with 2 N KOH
aqueous solution (2 × 10 mL) with vigorous shaking to remove
methanesulfonamide. The organic extract was dried (anhyd MgSO4)
and concentrated to give the diol and the ligand. The crude product
was purified by flash column chromatography (silica gel, hexane/
EtOAc ) 5: 1, then 2: 1) to give the desired diol (4.87 g, 95%) as
a colorless viscous oil. [R]23D ) -20.2 (c ) 1.70, CHCl3). IR (NaCl,
ice-water bath was added DCC (1.36 g, 2.0 equiv) in DCM (8
mL), and the reaction mixture was stirred at 0 °C (ice-water bath).
The mixture was allowed to warm to room temperature and kept
stirring for 24 h. Ether was added to the reaction mixture, which
was filtered through a pad of Celite and washed several times with
EtOAc, and the solvent was concentrated. The crude product was
purified by flash column chromatography (silica gel, hexane/EtOAc
) 5:1) to give 13b as a colorless viscous oil. The ester 13b (3.31
mmol) was dissolved in toluene (22 mL) and bubbled with gaseous
HCl, and the mixture was stirred for 1 h. The solvent and excess
of gaseous HCl were removed to give ester · hydrochloride as a
yellow solid. The ester ·hydrochloride (3.31 mmol) and K2CO3 (1.38
g, 3.0 equiv) were dissolved in acetonitrile (17 mL). The mixture
was stirred for 18 h at room temperature, filtered through a pad of
Celite, and then concentrated. The crude product was purified by
flash column chromatography (silica gel, hexane/EtOAc ) 5:1) to
give the iminolactone 14b [4: 1 (C3-R-benzyl/C3-ꢀ-benzyl, in-
separable), 882 mg, 82% (three steps)] as a white solid. IR (NaCl,
1
CHCl3): 3439 (br), 3031 (m), 2981 (s), 2931 (s) cm-1. H NMR
(400 MHz, CDCl3): δ 7.26-7.40 (m, 5H, Ph), 4.79 (s, 1H, CH),
3.44 (s, 3H, OCH3), 3.40 (d, J ) 9.2 Hz, 1H, CH2), 3.30 (d, J )
9.2 Hz, 1H, CH2), 0.95 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3):
δ 139.7, 127.8, 127.5, 127.4, 78.3, 77.1, 74.3, 59.1, 18.9. MS: m/z
196 (M+, 0.2), 133 (19.9), 111 (83.8), 89 (100), 79 (63.0), 57 (46.4).
HRMS m/z calcd for C11H16O3 M+ 196.1129, found M+ 196.1106.
Anal. Calcd for C11H16O3: C, 67.32; H, 8.22. Found: C, 65.02; H,
7.66.
CHCl3): 3029 (m), 2990 (s), 2932 (s), 1741 (s), 1666 (ms) cm-1
.
MS: m/z 323 (M+, 49.3), 278 (99.7), 250 (50.0), 206 (75.5), 131
(64.4), 120 (100), 105 (64.8), 91 (86.6), 77 (29.6), 57 (20.5). HRMS
m/z calcd for C20H21NO3 M+ 323.1521, found M+ 323.1526. Anal.
Calcd for C20H21NO3: C, 74.28; H, 6.55; N, 4.33. Found: C, 74.08;
H, 6.26; N, 4.06.
(S)-2-Hydroxy-3-methoxy-2-methyl-1-phenylpropan-1-one (12).16
IBX (6.06 g, 1.8 equiv) was added to a solution of the diol 11
(2.33 g, 11.9 mmol) in MeCN (27 mL) and water (390 µL, 2 equiv).
After being stirred at room temperature for 36 h, the reaction
mixture was filtered by a pad of Celite and concentrated. The crude
product was purified by flash column chromatography (silica gel,
hexane/EtOAc ) 5:1 then 2: 1) to give hydroxyketone 12 (1.73 g,
75%) as a colorless liquid and the recovered starting material (443
mg, 19%). [R]23D ) -47.0 (c ) 1.50, CHCl3). IR (NaCl, CHCl3):
3449 (br), 2984 (s), 2932 (s), 1677 (s) cm-1. 1H NMR (400 MHz,
CDCl3): δ 8.01-8.03 (m, 2H, Ph), 7.43-7.56 (m, 3H, Ph), 3.99
(d, J ) 9.2 Hz, 1H, CH2), 3.49 (d, J ) 9.6 Hz, 1H, CH2), 3.35 (s,
3H, OCH3), 1.51 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3): δ
203.7, 135.2, 132.4, 129.2, 128.1, 79.6, 78.5, 59.3, 23.3. Anal. Calcd
for C11H14O3: C, 68.02; H, 7.27. Found: C, 67.68; H, 6.90.
(3RS,6R)-6-(Methoxymethyl)-6-methyl-5-phenyl-3H-1,4-oxazin-
2(6H)-one (14a). To a solution of the hydroxyketone 12 (1.74 g,
8.95 mmol), DMAP (1.11 g, 1.0 equiv), and Boc-dl-alanine (3.39
g, 2.0 equiv) in DCM (10 mL) in an ice-water bath was added
DCC (3.72 g, 2.0 equiv) in DCM (8 mL), and the reaction mixture
was stirred at 0 °C (ice-water bath). The mixture was allowed to
warm to room temperature and kept stirring for 24 h. Ether was
added to the mixture, the precipitate was filtered through a pad of
Celite, washed several times with EtOAc, and the solvent was
concentrated. The crude product was purified by flash column
chromatography (silica gel, hexane/EtOAc ) 5:1) to give 13a as a
colorless viscous oil. The ester 13a (8.95 mmol) was dissolved in
toluene (30 mL) and bubbled with gaseous HCl, and the mixture
was stirred for 50 min. The solvent and excess gaseous HCl were
removed to give ester ·hydrochloride as a pale yellow solid. The
ester·hydrochloride (8.95 mmol) and K2CO3 (3.72 g, 3.0 equiv)
were dissolved in acetonitrile (25 mL). The mixture was stirred
for 20 h at room temperature, filtered through a pad of Celite, and
then concentrated. The crude product was purified by flash column
chromatography (silica gel, hexane/EtOAc ) 5:1) to give the
iminolactone 14a [1:1 (C3-R-methyl/C3-ꢀ-methyl, inseparable),
1.81 g, 82% (three steps)] as a colorless oil. IR (NaCl, CHCl3):
3059 (m), 2986 (s), 1747 (s), 1666 (ms) cm-1. MS: m/z 247 (M+,
9.7), 172 (40.8), 131 (100), 104 (41.7), 89 (41.1), 77 (35.1), 56
(66.7). HRMS: m/z calcd for C14H17NO3 M+ 247.1208, found M+
247.1209. Anal. Calcd for C14H17NO3: C, 68.00; H, 6.93; N, 5.66.
Found: C, 68.02; H, 6.40; N, 5.39.
Alkylations of the Iminolactone 14a. Synthesis of Compounds
15 and 16: General Procedure. A solution of LDA (1.3 equiv)
[diisopropylamine (180 µL, 1.3 equiv) in dry THF (500 µL) in a
flame-dried Schlenk tube under a argon atmosphere was immersed
in an ice-water bath, a 1.6 M solution of n-butyllithium in hexane
(810 µL, 1.3 equiv) was slowly added to the stirred solution, and
the mixture was vigorously stirred for 30 min in an ice-water bath]
was added dropwise over a period of 10 min to a solution of the
iminolactone 14a (1.00 mmol) in THF (1 mL) at -78 °C. The
resulting mixture was stirred at -78 °C for another 20 min. A
solution of alkyl halide (3.0 equiv) in dry THF (500 µL) was
injected slowly using a syringe pump over 30 min with the needle
contacting the wall of the tube allowing the reagent to cool to the
reaction temperature before it reached the reaction mixture by
dripping along the flask wall. The well-stirred reaction was then
kept at -78 °C until completion (progress was monitored by TLC),
1
the solvent was evaporated, and the residue was analyzed by H
NMR to determine the diastereomeric excess. Further purification
by flash column chromatography (silica gel, hexane/EtOAc ) 5:1)
afforded the corresponding major diastereomers 15 (Table 1).
(3R,6R)-3-Benzyl-6-(methoxymethyl)-3,6-dimethyl-5-phenyl-
3H-1,4-oxazin-2(6H)-one (15a). Yield: 280 mg (83%). White solid.
Mp ) 69-73 °C. [R]23 ) +43.2 (c ) 0.69, CHCl3). IR (NaCl,
D
CHCl3): 3064 (m), 2984 (s), 2930 (s), 1733 (s), 1685 (ms) cm-1
.
1H NMR (400 MHz, CDCl3): δ 7.17-7.39 (m, 10H, Ph), 3.45 (d,
J ) 12.8 Hz, 1H, CH2), 3.37 (d, J ) 10.4 Hz, 1H, CH2), 3.35 (s,
3H, OCH3), 3.15 (d, J ) 10.4 Hz, 1H, CH2), 3.09 (d, J ) 12.8 Hz,
1H, CH2), 1.75 (s, 3H, CH3), 0.54 (s, 3H, CH3). 13C NMR (100
MHz, CDCl3): δ 171.2, 164.8, 138.1, 136.4, 130.6, 128.8, 128.4,
128.0, 127.1, 127.1, 85.5, 76.0, 62.9, 59.1, 47.7, 28.0, 21.0. MS:
m/z 337 (M+, 13.7), 293 (72.0), 262 (55.8), 246 (32.9), 202 (100),
131 (84.6), 105 (53.0), 91 (99.2), 77 (26.9), 57 (10.6). HRMS: m/z
calcd for C21H23NO3 M+ 337.1678, found M+ 337.1670. Anal.
Calcd for C21H23NO3: C, 74.75; H, 6.87; N, 4.15. Found: C, 74.39;
H, 6.89; N, 4.08.
Ethyl 2-[(3R,6R)-3,6-Dihydro-6-(methoxymethyl)-3,6-dimeth-
yl-2-oxo-5-phenyl-2H-1,4-oxazin-3-yl]acetate (15b). Yield: 330
mg (99%). White solid. Mp ) 74-76 °C. [R]23 ) +3.42 (c )
D
1.2, CHCl3). IR (NaCl, CHCl3): 2986 (s), 2936 (s), 1734 (s), 1681
(s) cm-1. 1H NMR (400 MHz, CDCl3): δ 7.28-7.39 (m, 5H, Ph),
4.12 (dq, J ) 7.2, 2.4 Hz, 2H, CH2), 3.69 (d, J ) 10.4 Hz, 1H,
CH2), 3.46 (d, J ) 10.4 Hz, 1H, CH2), 3.42 (s, 3H, OCH3), 3.32
(d, J ) 17.2 Hz, 1H, CH2), 2.85 (d, J ) 17.2 Hz, 1H, CH2), 1.59
(3RS,6R)-3-Benzyl-6-(methoxymethyl)-6-methyl-5-phenyl-3H-
1,4-oxazin-2(6H)-one (14b). To a solution of the hydroxyketone
12 (643 mg, 3.31 mmol), DMAP (402 mg, 1.0 equiv), Boc-dl-
phenylalanine (1.73 g, 2.0 equiv), and in DCM (25 mL) in an
(s, 3H, CH3), 1.49 (s, 3H, CH3), 1.24 (t, J ) 7.2 Hz, 3H, CH3). 13
C
(16) Liu, X.-L. Master Thesis, National Chung-Hsing University, 1990.
NMR (100 MHz, CDCl3): δ 171.3, 170.8, 165.7, 138.1, 129.0,
9532 J. Org. Chem. Vol. 73, No. 24, 2008

Asymmetric Synthesis of R-Amino Acids
128.5, 127.2, 87.3, 76.3, 60.6, 59.0, 58.2, 45.5, 27.7, 21.9. MS:
m/z 333 (M+, 1.9), 289 (15.3), 258 (54.3), 184 (29.6), 142 (38.8),
114 (21.7), 104 (100), 77 (15.7). HRMS: m/z calcd for C18H23NO5
M+ 333.1576, found M+ 333.1567. Anal. Calcd for C18H23NO5:
C, 64.85; H, 6.95; N, 4.20. Found: C, 65.29; H, 6.35; N, 4.37.
2-[(3R,6R)-3,6-Dihydro-6-(methoxymethyl)-3,6-dimethyl-2-
oxo-5-phenyl-2H-1,4-oxazin-3-yl]acetonitrile (15c). Yield: 261 mg
(91%). White solid. Mp ) 149-152 °C. [R]23D ) -35.7 (c ) 1.36,
CHCl3). IR (NaCl, CHCl3): 2991 (s), 2244 (m), 1731 (s), 1680 (s)
cm-1. 1H NMR (400 MHz, CDCl3): δ 7.38-7.45 (m, 5H, Ph), 3.77
(d, J ) 10.4 Hz, 1H, CH2), 3.48 (d, J ) 10.8 Hz, 1H, CH2), 3.43
(s, 3H, OCH3), 3.13 (d, J ) 16.0 Hz, 1H, CH2), 2.88 (d, J ) 16.0
Hz, 1H, CH2), 1.68 (s, 3H, CH3), 1.48 (s, 3H, CH3). 13C NMR
(100 MHz, CDCl3): δ 169.4, 167.7, 137.2, 129.5, 128.7, 127.1,
116.5, 87.8, 76.1, 59.3, 59.1, 31.1, 27.1, 22.9. MS: m/z 286 (M+,
29.1), 246 (25.2), 211 (78.4), 170 (100), 129 (90.0), 115 (35.7),
104 (84.7), 95 (75.2), 89 (46.9), 77 (34.9), 51 (12.4). HRMS: m/z
calcd for C16H18N2O3 M+ 286.1317, found M+ 286.1311. Anal.
Calcd for C16H18N2O3: C, 67.12; H, 6.34; N, 9.78. Found: C, 67.09;
H, 6.33; N, 9.33.
min to a solution of the iminolactone 14a (0.60 mmol) at -78 °C.
HMPA (520 µL, 5 equiv) or DMPU (360 µL, 5 equiv) was added
to the previous mixture. The resulting mixture was stirred at -78
°C for another 50 min. A solution of alkyl halide (3 equiv) in dry
THF (800 µL) was injected slowly using a syringe pump over 10
min with the needle contacting the wall of the neck allowing the
reagent to cool to the reaction temperature before it reached the
reaction mixture by dripping along the flask wall. The well-stirred
reaction was then kept at -78 °C for another 50 min, the solvent
was evaporated, and the residue was analyzed by 1H NMR to
determine the diastereomeric excess. Further purification by column
chromatography (silica gel, hexane/EtOAc ) 5:1) afforded the
corresponding major diastereomers 16a and 17 and minor diaste-
reomer 15a and 18 (Table 2).
(3S,6R)-3-Benzyl-6-(methoxymethyl)-3,6-dimethyl-5-phenyl-
3H-1,4-oxazin-2(6H)-one (16a). Yield: 132 mg (65%). Colorless
oil. [R]23 ) -37.1 (c ) 5.24, CHCl3). IR (NaCl, CHCl3): 3030
D
1
(m), 2984 (s), 2929 (s), 1738 (s), 1666 (ms) cm-1. H NMR (400
MHz, CDCl3): δ 7.20-7.39 (m, 10H, Ph), 3.51 (d, J ) 13.2 Hz,
1H, CH2), 3.15 (d, J ) 12.8 Hz, 1H, CH2), 3.08 (d, J ) 10.8 Hz,
1H, CH2), 3.02 (d, J ) 10.4, 1H, CH2), 2.92 (s, 3H, OCH3), 1.67
(s, 3H, CH3), 1.47 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3): δ
170.9, 165.8, 138.0, 136.4, 131.0, 128.9, 128.3, 127.7, 127.3, 126.6,
86.8, 75.7, 62.0, 59.0, 46.7, 28.6, 22.8. MS: m/z 337 (M+, 5.8),
293 (27.3), 262 (25.7), 246 (19.9), 202 (94.3), 131 (56.2), 118
(33.6), 91 (100), 65 (15.5). HRMS: m/z calcd for C21H23NO3 M+
337.1678, found M+ 337.1670. Anal. Calcd for C21H23NO3: C,
74.75; H, 6.87; N, 4.15. Found: C, 74.35; H, 6.93; N, 4.02.
(3S,6R)-3-Benzyl-3-ethyl-6-(methoxymethyl)-6-methyl-5-phenyl-
3H-1,4-oxazin-2(6H)-one (17a). Yield: 175 mg (83%). White solid.
(3R,6R)-3-Allyl-6-(methoxymethyl)-3,6-dimethyl-5-phenyl-
3H-1,4-oxazin-2(6H)-one (15d). Yield: 190 mg (66%). White solid.
Mp ) 56-58 °C. [R]23 ) -51.0 (c ) 0.42, CHCl3). IR (NaCl,
D
1
CHCl3): 2984 (s), 2937 (s), 1737 (s), 1670 (ms) cm-1. H NMR
(400 MHz, CDCl3): δ 7.26-7.41 (m, 5H, Ph), 5.69 (m, 1H, CH),
5.19 (m, 2H, CH2), 3.66 (d, J ) 10.4 Hz, 1H, CH2), 3.41 (s, 3H,
OCH3), 3.39 (d, J ) 10.4 Hz, 1H, CH2), 2.84 (dd, J ) 13.2, 7.2
Hz, 1H, CH2), 2.60 (dd, J ) 13.2, 7.2 Hz, 1H, CH2), 1.63 (s, 3H,
CH3), 1.36 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3): δ 171.5,
164.9, 138.1, 132.7, 129.0, 128.5, 127.3, 119.5, 86.5, 76.3, 61.5,
59.1, 46.2, 27.4, 22.6. MS: m/z 287 (M+, 39.9), 242 (35.2), 202
(53.3), 171 (39.2), 157 (29.1), 131 (100), 115 (48.9), 104 (62.4),
96 (66.2), 68 (85.1), 53 (31.3). HRMS: m/z calcd for C17H21NO3
M+ 287.1521, found M+ 287.1521. Anal. Calcd for C17H21NO3:
C, 71.06; H, 7.37; N, 4.87. Found: C, 70.96; H, 7.25; N, 4.66.
(3S,6R)-3-Allyl-6-(methoxymethyl)-3,6-dimethyl-5-phenyl-3H-
1,4-oxazin-2(6H)-one (16d). Yield: 34 mg (12%). Colorless oil.
Mp ) 42-44 °C. [R]23 ) -50.0 (c ) 0.70, CHCl3). IR (NaCl,
D
1
CHCl3): 3029 (m), 2930 (s), 1736 (s), 1667 (ms) cm-1. H NMR
(400 MHz, CDCl3): δ 7.22-7.42 (m, 10H, Ph), 3.47 (d, J ) 12.8
Hz, 1H, CH2), 3.16 (d, J ) 13.2 Hz, 1H, CH2), 3.04 (d, J ) 10.8
Hz, 1H, CH2), 2.96 (s, 3H, OCH3), 2.82 (d, J ) 10.4 Hz, 1H, CH2),
2.22-2.31 (m, 1H, CH2), 1.91-2.00 (m, 1H, CH2), 1.43 (s, 3H,
CH3), 0.93 (t, J ) 7.6 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3):
δ 170.0, 166.9, 138.8, 136.3, 131.3, 129.0, 128.4, 127.8, 127.4,
126.8, 86.7, 75.9, 66.6, 59.1, 46.5, 34.2, 23.0, 9.3. MS: m/z 351
(M+, 1.89), 307 (14.8), 276 (17.6), 216 (16.9), 131 (42.0), 115
(20.5), 91 (100), 77 (10.6). HRMS: m/z calcd for C22H25NO3 M+
351.1834, found M+ 351.1826. Anal. Calcd for C22H25NO3: C,
75.19; H, 7.17; N, 3.99. Found: C, 75.19; H, 7.05; N, 3.96.
(3R,6R)-3-Benzyl-3-ethyl-6-(methoxymethyl)-6-methyl-5-phenyl-
3H-1,4-oxazin-2(6H)-one (18a). Yield 25 mg (12%). White solid.
Mp ) 123-125 °C. [R]23D ) +52.4 (c ) 0.21, CHCl3). IR (NaCl,
[R]23 ) -1.66 (c ) 7.70, CHCl3). IR (NaCl, CHCl3): 2981 (s),
D
2932 (s), 1742 (s), 1668 (ms) cm-1. 1H NMR (400 MHz, CDCl3):
δ 7.36-7.42 (m, 5H, Ph), 5.78-5.88 (m, 1H, CH), 5.09-5.18 (m,
2H, CH2), 3.53 (d, J ) 10.4 Hz, 1H, CH2), 3.36 (d, J ) 10.4 Hz,
1H, CH2), 3.32 (s, 3H, OCH3), 2.83 (dd, J ) 14.0, 7.2 Hz, 1H,
CH2), 2.67 (dd, J ) 14.0, 7.2 Hz, 1H, CH2), 1.59 (s, 3H, CH3),
1.52 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3): δ 171.2, 166.0,
137.7, 133.1, 129.2, 128.5, 127.5, 118.4, 86.8, 76.2, 60.8, 59.1,
45.4, 27.8, 22.9. MS: m/z 287 (M+, 75.3), 242 (42.7), 212 (100),
202 (77.4), 170 (47.7), 157 (42.6), 131 (99.6), 115 (54.6), 104
(58.8), 96 (53.1), 91 (27.3), 77 (29.4), 68 (49.8), 53 (18.2). HRMS:
m/z calcd for C17H21NO3 M+ 287.1521, found M+ 287.1514. Anal.
Calcd for C17H21NO3: C, 71.06; H, 7.37; N, 4.87. Found: C, 70.92;
H, 7.31; N, 4.63.
CHCl3): 3033 (m), 2970 (s), 2926 (s), 1728 (s), 1672 (ms) cm-1
.
1H NMR (400 MHz, CDCl3): δ 7.21-7.39 (m, 10H, Ph), 3.42 (d,
J ) 12.8 Hz, 1H, CH2), 3.28 (s, 3H, OCH3), 3.24 (d, J ) 10.4 Hz,
1H, CH2), 3.10 (d, J ) 10.4 Hz, 1H, CH2), 3.09 (d, J ) 12.8 Hz,
1H, CH2), 2.36-2.45 (m, 1H, CH2), 1.97-2.06 (m, 1H, CH2), 0.96
(t, J ) 7.4 Hz, 3H, CH3), 0.32 (s, 3H, CH3). 13C NMR (100 MHz,
CDCl3): δ 170.2, 168.0, 138.2, 136.3, 131.0, 129.0, 128.4, 128.2,
127.3, 127.3, 86.8, 76.0, 67.2, 58.9, 47.2, 34.5, 21.0, 9.0. MS: m/z
351 (M+, 10.9), 307 (60.7), 276 (50.8), 216 (60.1), 161 (28.5), 131
(90.4), 117 (28.1), 91 (100). HRMS: m/z calcd for C22H25NO3 M+
351.1834, found M+ 351.1829. Anal. Calcd for C22H25NO3: C,
75.19; H, 7.17; N, 3.99. Found: C, 75.36; H, 6.96; N, 3.94.
2-[(3R,6R)-3-Benzyl-3,6-dihydro-6-(methoxymethyl)-6-meth-
yl-2-oxo-5-phenyl-2H-1,4-oxazin-3-yl]acetonitrile (17b). Yield:
Alkylations of the Iminolactone 14b. Synthesis of Compounds
15a, 16a, 17, and : General Procedure A (without Additive). A
solution of LDA (1.3 equiv) was added dropwise over a period of
10 min to a solution of iminolactone 14b (0.60 mmol) in THF (2.4
mL) at -78 °C. The resulting mixture was stirred at -78 °C for
another 20 min. A solution of alkyl halide (3.0 equiv.) in dry THF
(800 µL) was injected slowly using a syringe pump over 10 min
with the needle contacting the wall of the neck allowing the reagent
to cool to the reaction temperature before it reached the reaction
mixture by dripping along the flask wall. The well-stirred reaction
was then kept at -78 °C until completion (progress was monitored
by TLC), the solvent was evaporated, and the residue was analyzed
by 1H NMR to determine the diastereomeric excess. Further
purification by flash column chromatography (silica gel, hexane/
EtOAc ) 5:1) afforded the corresponding major diastereomers 16a
and 17 and minor diastereomers 15a and 18 (Table 2).
196 mg (90%). White solid. Mp ) 152-154 °C. [R]23 ) +50.3
D
(c ) 0.73, CHCl3). IR (NaCl, CHCl3): 3028 (m), 2990 (s), 2931
1
(s), 2248 (m), 1737 (s), 1665 (ms) cm-1. H NMR (400 MHz,
CDCl3): δ 7.19-7.45 (m, 10H, Ph), 3.43 (d, J ) 13.2 Hz, 1H,
CH2), 3.24 (s, 2H, CH2), 3.21 (d, J ) 13.2 Hz, 1H, CH2), 3.17 (d,
J ) 16.4 Hz, 1H, CH2), 3.10 (s, 3H, OCH3), 2.89 (d, J ) 16.0 Hz,
1H, CH2), 1.55 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3): δ 169.3,
167.9, 137.4, 134.0, 131.0, 129.3, 128.5, 128.1, 127.4, 127.2, 116.5,
88.1, 75.7, 62.9, 59.0, 45.9, 29.5, 23.4. MS: m/z 362 (M+, 60.3),
General Procedure B (with Additive). A solution of LDA (1.3
equiv) in THF (2.4 mL) was added dropwise over a period of 10
J. Org. Chem. Vol. 73, No. 24, 2008 9533

Lu and Lin
271 (85.4), 91 (100). HRMS: m/z calcd for C22H22N2O3 M+
362.1630, found M+ 362.1626. Anal. Calcd for C22H22N2O3: C,
72.91; H, 6.12; N, 7.73. Found: C, 72.44; H, 6.12; N, 7.02.
2-[(3R,6R)-3-Benzyl-3,6-dihydro-6-(methoxymethyl)-6-meth-
yl-2-oxo-5-phenyl-2H-1,4-oxazin-3-yl]acetonitrile (18b). Yield:
screw cap and heated at 90 °C. After the mixture was stirred for
1-3 h (progress was monitored by TLC), water (2 mL) was added,
and the mixture was extracted with dichloromethane. The chiral
auxiliary was recovered from the organic layer after removal of
the solvent. The aqueous layer was evaporated under reduced
pressure to give the desired R,R-disubstituted R-amino acid
hydrochloride. The crude R-amino acid hydrochlorides were purified
by recrystallization from a mixture of water and ethanol.
20 mg (9%). White solid. Mp ) 76-78 °C. [R]23 ) +73.4 (c )
D
0.94, CHCl3). IR (NaCl, CHCl3): 2930 (s), 2249 (m), 1732 (s),
1
1671 (ms) cm-1. H NMR (400 MHz, CDCl3): δ 7.18-7.45 (m,
10H, Ph), 3.42 (d, J ) 12.8 Hz, 1H, CH2), 3.32 (d, J ) 10.0 Hz,
1H, CH2), 3.32 (s, 2H, CH2), 3.26 (d, J ) 12.8 Hz, 1H, CH2), 3.16
(s, 3H, OCH3), 3.14 (d, J ) 10.0 Hz, 1H, CH2), 0.53 (s, 3H, CH3).
13C NMR (100 MHz, CDCl3): δ 168.3, 168.0, 137.3, 134.3, 130.9,
129.3, 128.5, 128.3, 127.8, 127.2, 115.9, 87.8, 75.8, 63.0, 59.0,
46.1, 29.4, 20.2. MS: m/z 362 (M+, 42.3), 271 (65.2), 131 (26.9),
115 (42.5), 91 (100), 77 (15.2). HRMS: m/z calcd for C22H22N2O3
M+ 362.1630, found M+ 362.1629. Anal. Calcd for C22H22N2O3:
C, 72.91; H, 6.12; N, 7.73. Found: C, 72.48; H, 6.06; N, 7.05.
(3S,6R)-3-Allyl-3-benzyl-6-(methoxymethyl)-6-methyl-5-phen-
yl-3H-1,4-oxazin-2(6H)-one (17c). Yield: 172 mg (79%). White
(R)-r-Methylphenylalanine Hydrochloride (19a). Yiled: 40 mg
(92%). tR ) 7.2 min (HPLC). [R]23 ) +9.40 (c ) 0.73, H2O)
D
[lit.4k [R]D ) +9.50 (c ) 0.2, H2O)]. H NMR (400 MHz, D2O):
1
δ 7.22-7.26 (m, 3H, Ph), 7.11-7.13 (m, 2H, Ph), 3.22 (d, J )
14.4 Hz, 1H, CH2), 2.94 (d, J ) 14.4 Hz, 1H, CH2), 1.48 (s, 3H,
CH3).
(S)-r-Methylphenylalanine Hydrochloride (ent-19a). Yield:
39 mg (91%). tR ) 11.2 min (HPLC). [R]23 ) +9.41 (c ) 0.72,
D
H2O) [lit.17 [R]25 ) +9.60 (c ) 0.2, H2O)].
D
(R)-r-Methylaspartic Acid Hydrochloride (19b). Yield: 36 mg
(98%). tR ) 15.4 min (HPLC). [R]23D ) +36.2 (c ) 0.83, MeOH)
[lit.18 [R]D ) +35.1 (c ) 1.27, MeOH)]. 1H NMR (400 MHz, D2O):
δ 3.06 (d, J ) 16.8 Hz, 1H, CH2), 2.79 (d, J ) 18.0 Hz, 1H, CH2),
1.44 (s, 3H, CH3).
solid. Mp ) 67-68 °C. [R]23 ) -58.0 (c ) 0.54, CHCl3). IR
D
(NaCl, CHCl3): 3068 (m), 2990 (s), 2927 (s), 1736 (s), 1670 (ms)
1
cm-1. H NMR (400 MHz, CDCl3): δ 7.22-7.41 (m, 10H, Ph),
5.69-5.79 (m, 1H, CH), 5.23-5.26 (m, 2H, CH2), 3.51 (d, J )
12.8 Hz, 1H, CH2), 3.20 (d, J ) 13.2 Hz, 1H, CH2), 3.02 (d, J )
10.8 Hz, 1H, CH2), 2.95 (dd, J ) 13.2, 7.2 Hz, 1H, CH2), 2.91 (s,
3H, OCH3), 2.88 (d, J ) 10.8 Hz, 1H, CH2), 2.70 (dd, J ) 13.2,
8.0 Hz, 1H, CH2), 1.40 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3):
δ 169.4, 167.4, 138.0, 136.0, 132.5, 131.3, 129.1, 128.4, 127.8,
127.4, 126.8, 120.5, 86.8, 75.8, 66.0, 59.1, 46.3, 45.5, 23.1. MS:
m/z 363 (M+, 5.7), 319 (21.5), 288 (52.9), 131 (100), 91 (94.6).
HRMS: m/z calcd for C23H25NO3 M+ 363.1834, found M+
363.1827. Anal. Calcd for C23H25NO3: C, 76.01; H, 6.93; N, 3.85.
Found: C, 76.18; H, 6.65; N, 3.27.
(R)-r-Allylalanine Hydrochloride (19c). Yield: 28 mg (85%
yield). tR ) 6.2 min (HPLC). [R]23 ) +13.4 (c ) 0.57, D2O)
D
[lit.5f [R]D ) +14.4 (c ) 1.3, D2O) for (S)-isomer]. 1H NMR (400
MHz, D2O): δ 5.54-5.64 (m, 1H, CH), 5.11-5.15 (m, 2H, CH2),
2.55 (dd, J ) 14.4, 6.8 Hz, 1H, CH2), 2.40 (dd, J ) 14.4, 8.0 Hz,
1H, CH2), 1.40 (s, 3H, CH3).
(S)-r-Allylphenylalanine Hydrochloride (19d). Yield: 39 mg
(80% yield). tR ) 14.1 min (HPLC). [R]23 ) +15.3 (c ) 0.78,
D
H2O) [lit.19 [R]D ) +16.0 (c ) 1.0, 1 M HCl)]. H NMR (400
1
MHz, D2O): δ 7.20-7.25 (m, 2H, Ph), 7.09-7.11 (m, 2H, Ph),
5.55-5.66 (m, 1H, CH), 5.11-5.16 (m, 2H, Ph), 3.21 (d, J ) 14.4
Hz, 1H, CH2), 2.90 (d, J ) 14.4 Hz, 1H, CH2), 2.68 (dd, J ) 14.0,
8.0 Hz, 1H, CH2), 2.41 (dd, J ) 14.4, 8.4 Hz, 1H, CH2).
(3R,6R)-3-Allyl-3-benzyl-6-(methoxymethyl)-6-methyl-5-phenyl-
3H-1,4-oxazin-2(6H)-one (18c). Yield: 31 mg (14%). White solid.
Mp ) 117-118 °C. [R]23D ) +30.7 (c ) 0.14, CHCl3). IR (NaCl,
1
CHCl3): 3067 (m), 2987 (s), 1724 (s), 1675 (ms) cm-1. H NMR
Acknowledgment. Financial support by the National Science
(400 MHz, CDCl3): δ 7.21-7.40 (m, 10H, Ph), 5.81-5.92 (m, 1H,
CH), 5.12-5.22 (m, 2H, CH2), 3.44 (d, J ) 12.8 Hz, 1H, CH2),
3.28 (s, 3H, OCH3), 3.25 (d, J ) 10.4, 1H, CH2), 3.15 (d, J ) 12.8
Hz, 1H, CH2), 3.10 (d, J ) 10.4 Hz, 1H, CH2), 3.04 (dd, J ) 13.6,
8.4 Hz, 1H, CH2), 2.84 (dd, J ) 13.2, 7.2 Hz, 1H, CH2), 0.39 (s,
3H, CH3). 13C NMR (100 MHz, CDCl3): δ 169.7, 166.7, 138.3,
136.1, 128.9, 128.4, 128.2, 127.3, 127.3, 118.2, 86.8, 76.0, 66.2,
59.0, 46.5, 45.8, 21.0. MS: m/z 363 (M+, 40.7), 318 (25.6), 288
(29.1), 262 (31.8), 228 (22.8), 131 (90.1), 91 (100). HRMS: m/z
calcd for C23H25NO3 M+ 363.1834, found M+ 363.1836. Anal.
Calcd for C23H25NO3: C, 76.01; H, 6.93; N, 3.85. Found: C, 76.10;
H, 6.60; N, 3.25.
Council of the Republic of China is gratefully acknowledged.
Supporting Information Available: X-ray position param-
eters, full bond distances and angles, and an ORTEP drawing
for 15a and tables of total energies and Cartesian coordinates
for the minimized structure by AM1 and ab initio calculations.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO801514G
(17) Williams, R. M.; Im, M. N. J. Am. Chem. Soc. 1991, 113, 9276–9286.
(18) Crich, D.; Chan, C.-O.; Natarajan, S. Tetrahedron Lett. 1992, 33, 3405–
3408.
(19) Vedejs, E.; Fields, S. C.; Hayashi, R.; Hitchcock, S. R.; Powell, D. R.;
Schrimpf, M. R. J. Am. Chem. Soc. 1999, 121, 2460–2470.
Hydrolysis of the Dialkylated iminolactones 15a-d, 16a,
and 17c. Synthesis of Compounds 19a-d and ent-19a:
General Procedure. Iminolactone (0.20 mmol) was dissolved in
8 N HCl aqueous solution (1 mL) in a sealed tube with a Teflon
9534 J. Org. Chem. Vol. 73, No. 24, 2008