Chiral oxime ethers in asymmetric synthesis. 3. Asymmetric synthesis of (R)-N-protected α-amino acids by the addition of organometallic reagents to the ROPHy oxime of cinnamaldehyde

Article abstract of DOI:10.1021/jo9901079

A new asymmetric synthesis of α-amino acids is described in which the key step is the diastereoselective addition of organometallic reagents to (R)-O-(1-phenylbutyl)cinnamaldoxime 5 to give hydroxylamines 6. Subsequent reductive cleavage of the N-O bond in the hydroxylamine 6 followed by N- protection gave the carbamates 7, which upon oxidation with ruthenium(III) chloride/periodate gave the N-protected amino acids 8. The method was also adapted to the synthesis of a quaternary amino acid 15 from the ketoxime ether 9.

Full text of DOI:10.1021/jo9901079

J . Org. Chem. 1999, 64, 4419-4425
4419
Ch ir a l Oxim e Eth er s in Asym m etr ic Syn th esis. 3.1 Asym m etr ic
Syn th esis of (R)-N-P r otected r-Am in o Acid s by th e Ad d ition of
Or ga n om eta llic Rea gen ts to th e ROP Hy Oxim e of Cin n a m a ld eh yd e
Christopher J . Moody,*,†,‡ Peter T. Gallagher,§ Andrew P. Lightfoot,‡ and
Alexandra M. Z. Slawin‡
School of Chemistry, University of Exeter, Stocker Road, Exeter EX4 4QD, U.K.,
Department of Chemistry, Loughborough University, Loughborough, Leicestershire LE11 3TU, U.K.,
and Lilly Research Centre Ltd, Erl Wood Manor, Windlesham, Surrey GU20 6PH, U.K.
Received J anuary 20, 1999
A new asymmetric synthesis of R-amino acids is described in which the key step is the
diastereoselective addition of organometallic reagents to (R)-O-(1-phenylbutyl)cinnamaldoxime 5
to give hydroxylamines 6. Subsequent reductive cleavage of the N-O bond in the hydroxylamine
6 followed by N-protection gave the carbamates 7, which upon oxidation with ruthenium(III)
chloride/periodate gave the N-protected amino acids 8. The method was also adapted to the synthesis
of a quaternary amino acid 15 from the ketoxime ether 9.
In tr od u ction
butyl)hydroxylamines (ROPHy and SOPHy) as useful
reagents for asymmetric synthesis and their application
in the asymmetric synthesis chiral amines (Scheme 1).1,5,6
The methodology has been applied to the asymmetric
synthesis of the hemlock piperidine alkaloids (-)-coniine
and (+)-pseudoconhydrine7 and of â-amino acids.8 We
now report the details of a new route to R-amino acids
based on the highly diastereoselective addition of orga-
nolithium reagents to (R)-O-(1-phenylbutyl)cinnamal-
doxime 5.9
The development of new methodology for the asym-
metric synthesis of R-amino acids, both natural and
unnatural, continues to attract the attention of chemists
worldwide.2,3 Many of these methods involve stereose-
lective additions to CdN bonds,4 and in this context we
have recently reported the highly diastereoselective
addition of organometallic reagents to the CdN bond of
chiral oxime ethers to give chiral nonracemic hydroxy-
lamines.5,6 This subsequently resulted in the development
of oxime ethers derived from (R)- and (S)-O-(1-phenyl-
Resu lts a n d Discu ssion
* To whom correspondence should be addressed at the University
of Exeter. Tel: 01392 263429. Fax: 01392 263434. E-mail: c.j.moody@
ex.ac.uk.
To adapt our asymmetric synthesis of protected amines
(Scheme 1) into a route to N-protected amino acids, two
strategies were considered (Scheme 2). The first involved
the use of an oxime ether 1 that incorporates the
carboxylic acid precursor RA; addition of organometallic
reagents, followed by cleavage of the N-O bond, and
conversion of RA into a carboxyl group would then give
the required amino acid. Alternatively, the carboxyl
synthon can be added as an organometallic reagent,
RAMet (Scheme 2b). Although we have investigated both
approaches, it is the former method that is described in
detail herein.
The group RA that was initially chosen for study was
the furan group; oxidation of the furan ring with a whole
range of reagents has been reported to give the carboxylic
acid,10 and the strategy has been used, for example, in
the synthesis of carbohydrate derivatives.11 The synthesis
† Present address: School of Chemistry, University of Exeter,
Stocker Road, Exeter EX4 4QD, U.K.
‡ Loughborough University.
§ Lilly Research Centre Ltd.
(1) Part 2: Gallagher, P. T.; Hunt, J . C. A.; Lightfoot, A. P.; Moody,
C. J . J . Chem. Soc., Perkin Trans. 1 1997, 2633-2637.
(2) For reviews, see: Williams, R. M. Synthesis of optically active
R-amino acids; Pergamon: Oxford, 1989. Duthaler, R. O. Tetrahedron
1994, 50, 1539-1650. Wipf, P. Chem. Rev. 1995, 95, 2115-2134. North,
M. Contemp. Org. Synth. 1995, 2, 269-287. North, M. Contemp. Org.
Synth. 1996, 3, 323-343. North, M. Contemp. Org. Synth. 1997, 4,
326-351.
(3) For recent examples, see: Iyer, M. S.; Gigstad, K. M.; Namdev,
N. D.; Lipton, M. J . Am. Chem. Soc. 1996, 118, 4910-4911. Iyer, M.
S.; Gigstad, K. M.; Namdev, N. D.; Lipton, M. Amino Acids 1996, 11,
259-268. Palomo, C.; Aizpurua, J . M.; Ganboa, I.; Odriozola, B.;
Maneiro, E.; Miranda, J . I.; Urchegui, R. Chem. Commun. 1996, 161-
162. Palomo, C.; Aizpurua, J . M.; Ganboa, I.; Odriozola, B.; Urchegui,
R.; Go¨rls, H. Chem. Commun. 1996, 1269-1270. Pandey, G.; Reddy,
P. Y.; Das, P. Tetrahedron Lett. 1996, 37, 3175-3178. Lee, J .; Choi,
W. B.; Lynch, J . E.; Volante, R. P.; Reider, P. J . Tetrahedron Lett. 1998,
39, 3679-3682. Bull, S. D.; Davies, S. G.; Epstein, S. W.; Leech, M.
A.; Ouzman, J . V. A. J . Chem. Soc., Perkin Trans. 1 1998, 2321-2330.
Bull, S. D.; Davies, S. G.; Epstein, S. W.; Ouzman, J . V. A. Chem.
Commun. 1998, 659-660.
(4) For recent examples, see: Davis, F. A.; Portonovo, P. S.; Reddy,
R. E.; Chiu, Y. J . Org. Chem. 1996, 61, 440-441. Hanessian, S.; Yang,
R.-Y. Tetrahedron Lett. 1996, 37, 5273-5276. Hanessian, S.; Yang, R.
Y. Tetrahedron Lett. 1996, 37, 8997-9000. Badorrey, R.; Cativiela, C.;
DiazdeVillegas, M. D.; Galvez, J . A. Tetrahedron 1997, 53, 1411-1416.
Gittins, C. A.; North, M. Tetrahedron: Asymmetry 1997, 8, 3789-3799.
Harwood: L. M.; Tyler, S. N. G.; Anslow, A. S.; MacGilp, I. D.; Drew,
M. G. B. Tetrahedron: Asymmetry 1997, 8, 4007-4010. Marco, J . A.;
Carda, M.; Murga, J .; Gonzalez, F.; Falomir, E. Tetrahedron Lett. 1997,
38, 1841-1844. ElShehawy, A. A.; Omara, M. A.; Ito, K.; Itsuno, S.
Synlett 1998, 367-368. Davis, F. A.; Fanelli, D. L. J . Org. Chem. 1998,
63, 1981-1985.
(5) Gallagher, P. T.; Lightfoot, A. P.; Moody, C. J .; Slawin, A. M. Z.
Synlett 1995, 445-446.
(6) Brown, D. S.; Gallagher, P. T.; Lightfoot, A. P.; Moody, C. J .;
Slawin, A. M. Z.; Swann, E. Tetrahedron 1995, 51, 11473-11488.
(7) Moody, C. J .; Lightfoot, A. P.; Gallagher, P. T. J . Org. Chem.
1997, 62, 746-748.
(8) Moody, C. J .; Hunt, J . C. A. Synlett 1998, 733-734.
(9) Some of the results have been described in preliminary form:
Moody, C. J .; Lightfoot, A. P.; Gallagher, P. T. Synlett 1997, 659-660.
(10) For examples of the use of furan as a carboxyl precursor, see:
Yamazaki, T.; Mizutani, K.; Itazume, T. J . Org. Chem. 1993, 58, 4346-
4359. Marshall, J . A.; Luke, G. P. J . Org. Chem. 1993, 58, 6229-6234.
For the use of the furan ring as a carboxyl precursor in the synthesis
of amino acids, see: Alvaro, G.; Martelli, G.; Savoia, D.; Zoffoli, A.
Synthesis 1998, 1773-1777.
10.1021/jo9901079 CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/22/1999

4420 J . Org. Chem., Vol. 64, No. 12, 1999
Moody et al.
Sch em e 1
F igu r e 1. X-ray structure of (R)-(O)-(1-phenylbutyl)cinna-
maldoxime 5.
Ta ble 1. Ad d ition of Or ga n om eta llic Rea gen ts to th e
5-m eth ylfu r fu r a l Oxim e Eth er 3
RMet
hydroxylamine
yield/%
de/%
MeLi
n-BuLi
H2CdCHCH2MgBr
4a
4b
4c
77
87
56
83
81
59
Sch em e 2
Sch em e 3
Sch em e 4
alkene acts as precursor to the carboxylic acid group.12
The oxime ether 5 was prepared from cinnamaldehyde
and (R)-O-(1-phenylbutyl)hydroxylamine, obtained from
cleavage of the corresponding phthalimide 2, and was
obtained in 76% yield as the crystalline E isomer after
chromatographic separation of the Z isomer (23%). The
oxime ether 5 gave crystals suitable for X-ray analysis
(Figure 1), although the size of the crystals and low
number of observed data precluded full anisotropic
refinement of the structure.
The oxime 5 underwent addition of organometallic
reagents in the presence of boron trifluoride etherate to
give the hydroxylamines 6 in varying yields (Scheme 4,
Table 2). The diastereoselectivity of the addition was
readily measured from the 1H NMR spectra of 6; for
example, the olefinic proton adjacent to the new stereo-
center appeared as two clearly separated signals for the
two diastereomers. Varying levels of asymmetric induc-
tion were observed (Table 2). The configuration of the
new asymmetric center was assigned on the basis of our
previous results, and this was confirmed in the case of
6a -d by the subsequent conversion into amino acids 8
(see below). Generally, primary organolithium reagents
of furan-derived oximes proved straightforward. The one-
pot procedure described previously1 was used to convert
the chiral alkoxyphthalimide 2 into the corresponding
furan oxime ethers. However, the oxime derived from
furfural itself proved unstable, and therefore, the 5-me-
thylfurfural oxime ether 3, obtained as the E isomer
(83%) after chromatographic separation of the Z isomer,
was used. The addition of organometallic reagents to the
ROPHy oxime 3 was carried out under the usual condi-
tions (excess organometallic in the presence of an excess
of boron trifluoride etherate at -78 °C) and gave the
corresponding hydroxylamines 4 in good yield (Scheme
3, Table 1). However, the diastereoselectivity of the
1
addition (59-83%), as judged by H NMR spectra of the
crude hydroxylamine 4, was considered too low for such
a key step in the projected route to R-amino acids, and
therefore, an alternative was investigated.
The alternative oxime precursor of the amino acids was
the ROPHy oxime of cinnamaldehyde, in which the
(11) (a) Danishefsky, S. J .; Pearson, W. H.; Segmuller, B. E. J . Am.
Chem. Soc. 1985, 107, 1280-1285. (b) Dondoni, A.; J unquera, F.;
Merchan, F. L.; Merino, P.; Tejero, T. Synthesis 1994, 1450-1456.
(12) For the another use of the cinnamyl group as a carboxyl
precursor, see: J umnah, R.; Williams, A. C.; Williams, J . M. J . Synlett
1995, 821-822.

Chiral Oxime Ethers in Asymmetric Synthesis
J . Org. Chem., Vol. 64, No. 12, 1999 4421
Ta ble 2. Ad d ition of Or ga n om eta llic Rea gen ts to
Ta ble 3. Con ver sion of Hyd r oxyla m in es 6 in to
(R)-(O)-(1-P h en ylbu tyl)cin n a m a ld oxim e 5
N-Cbz-P r otected Am in o Acid s 8
entry
organometallic
hydroxylamine
yield/%
de/%
N-Cbz-amine 7 N-Cbz-amino acid 8
hydroxylamine 6
R
yield/%
yield/%
1
2
3
4
5
6
7
8
9
MeLi
n-BuLi
i-BuLi
PhLi
MeMgBr
EtMgBr
n-BuMgBr
PhCH2MgBr
PhMgBr
i-PrMgBr
t-BuMgBr
t-BuLi
6a
6b
6c
6d
6a
6e
6b
6f
6d
6g
6h
6h
95
92
93
76
41
91
89
34
69
92
93
92
90
73
71
78
72
80
a
b
c
d
Me
31
83
86
66
25
57
36
55
n-Bu
i-Bu
Ph
Sch em e 5
10
11
12
<10
<10
<10
gave better results than the corresponding Grignard
reagents in terms of both yield and diastereomeric excess.
It would thus appear that the counterion has an effect
on the stereoselectivity of the reaction, although this has
not been studied in detail. It is important to note that
the lithium and the magnesium reagents both give the
same major diastereomer. Organometallic reagents with
branching at the R-position such as t-Bu and i-Pr gave
complex reaction mixtures and a yield of the hydroxy-
lamine of less than 10%. In these cases the counterion,
lithium, or magnesium made little difference as exempli-
fied by entries 11 and 12 (Table 2). n-Butyllithium gave
the best result with a diastereomeric excess of 93% (entry
2), which is significantly better than that obtained for
the addition to the 5-methylfuran derived oxime 3 (81%
de). Also, methyllithium gave an excellent result (95%
yield, 92% de, entry 1), which is again better than that
gained from the furan oxime 3 (83% de). Phenyllithium
previously has given poor yields but high diastereoselec-
tivity in additions to the oxime ethers,6 and this was also
found to be true for the cinnamaldehyde oxime 5.
However, if the number of equivalents of phenyllithium
is decreased from 3 to 1.5 then the yield of isolated
hydroxylamine 6d increased dramatically up to 76% with
a good diastereomeric excess (90% de). Isobutyllithium,
which was generated from the corresponding bromide,
added to the cinnamaldehyde oxime 5 as smoothly as did
commercially available organolithium reagents to give an
excellent yield (93%) and de (92%) of the hydroxylamine
6c.
A range of commercially available Grignard reagents
was also added to the cinnamaldehyde oxime 5, but
unfortunately, the results were not as good as the
corresponding organolithium reagents in terms of yield
and diastereoselectivity (Table 2, entries 5-11). For
example, n-butyllithium gave 93% de and 92% yield, but
the Grignard reagent, n-butylmagnesium bromide, gave
only 78% de and 89% yield. The products from the
Grignard additions were accompanied by side products
that were not present in the organolithium reactions.
Some results are worthy of note: the additions of phenyl-,
ethyl-, and n-butylmagnesium bromides gave good yields
of the hydroxylamines, 69, 91, and 89%, respectively, and
reasonable diastereoselectivity (PhMgBr 80% de, Et 71%
de, n-Bu 78% de). Methyl- and benzylmagnesium bromide
both gave the addition products 6e and 6f; however, a
substantial amount of starting material was recovered
in each case.
phenyl-substituted derivatives 6a-d, the hydroxylamines
that were formed in the highest diastereomeric excess.
The resulting amines were not isolated but were im-
mediately converted into the benzyl carbamates 7 by
reaction with benzyl chloroformate (Table 3). The chiral
alcohol, (R)-1-phenylbutanol, was recovered from the
reductive cleavage reactions essentially optically pure in
about 80% yield. Finally, the double bond was cleaved
using the RuCl3/periodate method14 to give the desired
N-Cbz amino acids 8 in moderate yield (Scheme 5, Table
3). It is possible that the moderate yields in the oxidative
cleavage are a result of competing oxidation of the Cbz-
benzyl group, and while some benzyl groups are reported
to survive ruthenium(VIII) oxidation,11a others do not.11b
The configuration of the amino acid derivatives 8 was
confirmed as R by comparison of their optical rotations
with literature values.
Finally, we extended the method to the synthesis of
quaternary amino acids15 using ketoxime ethers as
starting materials. The addition of organometallic re-
agents to ketoxime ethers is known,16 although it is much
rarer than the corresponding reactions of aldoxime
ethers. Therefore, benzylideneacetone was converted into
its oxime ether by reaction with ROPHy under the usual
conditions; a mixture of oximes was obtained that was
readily separable into the E and Z isomers 9 and 10
isolated in 54 and 31% yield, respectively (Scheme 6).
Both oxime ethers underwent addition of n-butyllithium,
although the reaction temperature had to be lowered to
ca. -100 °C to obtain reasonable yields of the desired
hydroxylamines. As expected, the Z-oxime 10 gave the
(13) Enders, D.; Kempen, H. Synlett 1994, 969-971.
(14) Carlsen, P. H. J .; Katsuki, T.; Martin, V. S.; Sharpless, K. B.
J . Org. Chem. 1981, 46, 3936-3938.
(15) For recent examples, see: Kazmaier, U.; Maier, S. Tetrahedron
1996, 52, 941-954. Cativiela, C.; DiazdeVillegas, M. D.; Galvez, J . A.;
Lapena, Y. Tetrahedron 1997, 53, 5891-5898. Alonso, F.; Davies, S.
G.; Elend, A. S.; Haggitt, J . L. J . Chem. Soc., Perkin Trans. 1 1998,
257-264. Sano, S.; Hayashi, K.; Miwa, T.; Ishii, T.; Fujii, M.; Mima,
H.; Nagao, Y. Tetrahedron Lett. 1998, 39, 5571-5574. Abellan, T.;
Najera, C.; Sansano, J . M. Tetrahedron: Asymmetry 1998, 9, 2211-
2214.
The conversion of the hydroxylamines 6 into amino
acids was achieved by initial cleavage of the N-O bond
using the zinc/acetic acid/ultrasound method13 and was
exemplified using the methyl-, n-butyl-, isobutyl-, and
(16) Uno, H.; Terakawa, T.; Suzuki, H. Synlett 1991, 559-560.

4422 J . Org. Chem., Vol. 64, No. 12, 1999
Moody et al.
Sch em e 6
amino acid by oxidative cleavage of the alkene (64%)
(Scheme 7).
Exp er im en ta l Section
For general experimental details, see refs 1 and 6. Coupling
constants are reported in Hz. In reporting the NMR data for
mixtures of diastereomers, signals arising from the major and
minor isomers are reported separately if possible; the integra-
tion of signals is consistent within each isomer; e.g., a methyl
group is reported as 3H for both isomers even though the peaks
are unequal in area when the ratio of isomers is not 1:1.
Compounds characterized by high-resolution mass spectrom-
etry were chromatographically homogeneous.
Gen er a l Meth od for th e P r ep a r a tion of Oxim e Eth er s.
N-(1-Phenylbutoxy)phthalimide 2 (4.65 g, 15.8 mmol) and
ethanol (100 mL) were added to a round-bottom flask, and the
suspension was heated until the phthalimide dissolved. Hy-
drazine hydrate (0.77 mL, 15.8 mmol) was added at this
elevated temperature, and the solution was allowed to cool to
room temperature. Aldehyde or ketone (15.8 mmol) was added
and the mixture stirred overnight. The solvent was evaporated,
and carbon tetrachloride (30 mL) and magnesium sulfate were
added to the residue. The resulting suspension was filtered
and the filtrate evaporated; column chromatography of the
residue on silica gel (diethyl ether-light petroleum 1:20) gave
the oxime ether.
(E )-(R )-(+)-O -(1-P h e n y lb u t y l)-5-m e t h y l-2-fu r a l-
d oxim e 3. Obtained from 5-methyl-2-furaldehyde and sepa-
rated from the Z isomer by column chromatography on silica
gel (diethyl ether-light petroleum 1:20) as a colorless oil
Sch em e 7
(83%): [R]20 +124.6 (c 1, CH2Cl2); IR (film) 2932, 1582 cm-1
;
D
1H NMR (250 MHz, CDCl3) δ 7.97 (1H, s), 6.45 (1H, d, J 3.3),
6.03 (1H, d, J 3.3), 5.25 (1H, t, J 6.9), 2.33 (3H, s), 1.99 (1H,
m), 1.78 (1H, m), 1.41 (2H, m), 0.96 (3H, t, J 7.3); 13C NMR
(62.9 MHz, CDCl3) δ 154.4, 145.9, 142.4, 139.2, 128.1, 127.3,
126.7, 114.3, 107.8, 85.4, 38.4, 18.8, 14.0, 13.8; MS (EI) m/z
(relative intensity) 133 (37), 105 (39), 91 (100); HRMS calcd
for C16H19NO2 (M) 257.1416, found 257.1411.
(E)-(R)-(+)-O-(1-P h en ylbu tyl)cin n a m a ld oxim e 5. Ob-
tained from cinnamaldehyde as a colorless solid (80%), recrys-
tallized from light petroleum: mp 65-67 °C; [R]20 +48.1 (c
D
1, CH2Cl2); IR (Nujol) 2931, 1625 cm-1; H NMR (250 MHz,
1
CDCl3) δ 7.97 (1H, dd, J 1.6, 7.6), 7.32 (10H, m), 6.79 (2H, m),
5.14 (1H, dd, J 6.6, 7.1), 1.99 (1H, m), 1.78 (1H, m), 1.44 (2H,
m), 0.98 (3H, t, J 7.3); 13C NMR (62.9 MHz, CDCl3) δ 150.6,
142.4, 138.1, 136.5, 128.7, 128.5, 128.2, 127.4, 126.8, 126.6,
122.2, 85.4, 38.3, 18.8, 13.9; MS (EI) m/z (relative intensity)
279 (M+, 14), 133 (58), 91 (100), 77 (20); HRMS calcd for C19H21
-
NO (M) 279.1623, found 279.1625. Anal. Calcd for C19H21NO:
C, 81.7; H, 7.6; N, 5.0. Found: C, 81.6; H, 7.5; N, 4.9.
opposite major diastereomer to its E isomer (Scheme 6),
although the exact diastereomeric ratio could not be
obtained from the H NMR spectra of the crude hydroxy-
lamines 11 and 12. The estimated de’s were 80 and 75%,
respectively, and these were confirmed by subsequent
conversion into the carbamates 13 and 14 (see below).
Hence, the ROPHy ketoxime ethers 9 and 10 would
appear to exhibit lower diastereoselectivity in their
addition reactions than their aldoxime counterparts.
(R)-(+)-O-(1-P h en ylb u t yl)b en zylid en ea cet on e
Ke-
toxim es 9 a n d 10. Obtained from benzylidene acetone and
the isomers separated by column chromatography on silica gel
(diethyl ether-light petroleum 1:20).
1
E isomer 9: as a colorless solid (51%), recrystallized from
light petroleum; mp 49-50 °C; [R]20 +91.6 (c 2, CH2Cl2); IR
D
(CH2Cl2) 2959, 1583 cm-1; H NMR (250 MHz, CDCl3) δ 7.33
1
(10H, m), 6.83 (2H, s), 5.17 (1H, dd, J 6.3, 7.0), 2.18 (3H, s),
1.95 (1H, m), 1.83 (1H, m), 1.45 (2H, m), 0.98 (3H, t, J 7.3);
13C NMR (62.9 MHz, CDCl3) δ 155.8, 143.1, 136.5, 132.4, 128.6,
128.2, 128.1, 127.2, 126.7, 126.4, 85.3, 38.7, 18.4, 14.0, 10.4;
MS (EI) m/z (relative intensity) 133 (14), 105 (39), 91 (100),
The hydroxylamines 11 and 12 were subjected to the
zinc in acetic acid/ultrasound reductive cleavage condi-
tions, and the resulting amines were immediately pro-
tected as their benzyl carbamates 13 and 14 (Scheme 7).
Analysis of the carbamates 13 and 14 by HPLC on a
chiral stationary phase established their enantiomeric
purity as 82 and 76% ee, respectively, in good agreement
with the estimated diastereoselectivity of the original
addition reaction (Scheme 6). Although the enantiomeric
purity of the carbamates was disappointing, carbamate
13 was carried through to the corresponding quaternary
77 (30); HRMS calcd for
293.1780.
C20H23NO (M) 293.1780, found
Z isomer 10: as a colorless solid (34%), recrystallized from
light petroleum; mp 78-79 °C; [R]20 -378.7 (c 0.75, CH2Cl2);
D
IR (CH2Cl2) 2959, 1621 cm-1
;
1H NMR (250 MHz, CDCl3) δ
7.63 (1H, d, J 16.6), 7.56 (2H, m), 7.33 (8H, m), 6.97 (1H, d, J
16.6), 5.17 (1H, dd, J 6.3, 6.8), 2.07 (3H, s), 1.97 (1H, m), 1.73
(1H, m), 1.45 (2H, m), 0.97 (3H, t, J 7.3); 13C NMR (62.9 MHz,
CDCl3) δ 154.2, 145.0, 138.5, 137.7, 130.8, 130.7, 130.1, 129.9,
129.4, 128.5, 119.9, 87.0, 40.7, 20.9, 18.9, 16.0; MS (EI) m/z

Chiral Oxime Ethers in Asymmetric Synthesis
J . Org. Chem., Vol. 64, No. 12, 1999 4423
(relative intensity) 293 (M+, 18), 105 (22), 91 (100), 77 (24);
HRMS calcd for C20H23NO (M) 293.1780, found 293.1780.
(b) Obtained by the addition of methylmagnesium bromide
to the cinnamaldoxime 5 as a colorless solid (41%, 73% de):
[R]20 +64.3 (c 1, CH2Cl2).
D
Gen er a l P r oced u r e for th e Ad d ition of Or ga n om eta l-
lic Rea gen ts to th e Oxim e Eth er s. The oxime ether (3.22
mmol) in toluene (16 mL) was cooled to -78 °C under nitrogen,
and boron trifluoride etherate (1.2 mL, 9.7 mmol) was added.
The solution was stirred for 15 min, after this time, the
organometallic reagent (9.7 mmol) was added dropwise over
15 min. The resulting clear solution was stirred for a further
30 min when water (10 mL) was added. The solution was
allowed to warm to room temperature, and ether (10 mL) was
added. The two layers were separated, and the aqueous layer
was washed with further portions of ether (2 × 15 mL). The
combined organic portions were dried (K2CO3), filtered, and
evaporated. Column chromatography (5% ether/light petro-
leum) afforded the hydroxylamine.
(3R,1′R)-(+)-N-(1-P h en ylbu toxy)-1-ph en yl-3-h ept-1-en y-
la m in e 6b. (a) Obtained by the addition of n-butyllithium to
the cinnamaldoxime 5, as a colorless solid (95%, 92% de),
recrystallized from light petroleum: mp 47-49 °C; [R]20D +57.3
(c 2, CHCl3); IR (CH2Cl2) 3028, 2957 cm-1; 1H NMR (250 MHz,
CDCl3) δ major diastereomer 7.25 (10H, m), 6.46 (1H, d, J
15.9), 5.96 (1H, dd, J 8.4, 15.9), 4.57 (1H, dd, J 5.9, 7.6), 3.54
(1H, m), 1.93-1.28 (10H, m) 0.89 (6H, 2 x t), minor diastere-
omer 6.49 (1H, d, J 15.9), 6.12 (1H, dd, J 8.4, 15.9); 13C NMR
(62.9 MHz, CDCl3) δ 143.5, 137.0, 132.2, 130.1, 128.4, 128.2,
127.3, 127.2, 126.6, 126.3, 85.3, 63.7, 38.6, 32.2, 28.0, 22.7, 19.2,
14.0, 13.9; MS (EI) m/z (relative intensity) 205 (23), 133 (38),
91 (100), 77 (10); HRMS calcd for C23H31NO (M) 337.2405,
found 337.2398. Anal. Calcd for C23H31NO: C, 81.8; H, 9.3; N,
4.15. Found: C, 81.6; H, 9.1; N, 4.0.
(1R,1′R)-(+)-N-(1-P h en ylb u t oxy)-5-(2-m et h ylfu r yl)-1-
eth yla m in e 4a . Obtained from the addition of methyllithium
(b) Obtained by the addition of n-butylmagnesium bromide
to oxime 3 as a colorless oil (77%, 83% de): [R]20 +87.5° (c 1,
to the cinnamaldoxime 5 as a colorless oil (89%, 78% de): [R]20
+55.1 (c 1, CH2Cl2).
D
D
CH2Cl2); IR (film) 3030, 2958, 1566 cm-1; 1H NMR (250 MHz,
CDCl3) δ major diastereomer 7.31 (5H, m), 6.05 (1H, d, J 3.1),
5.88 (1H, d, J 3.1), 5.43 (1H, br s), 4.58 (1H, dd, J 5.9, 7.3),
4.18 (1H, q, J 6.6), 2.25 (3H, s), 1.82 (1H, m), 1.62-1.27 (3H,
m), 1.44 (3H, d, J 6.6), 0.93 (3H, t, J 7.4); minor diastereomer
6.15 (1H, d, J 3.1), 5.91 (1H, d, J 3.1), 4.42 (1H, dd, J 5.9, 7.3),
2.30 (3H, s); 13C NMR (62.9 MHz, CDCl3) δ major diastereomer
153.4, 151.2, 143.2, 128.2, 127.2, 126.5, 107.2, 105.9, 85.3, 76.5,
54.0, 38.7, 19.1, 16.9, 14.0, 13.5, minor diastereomer 126.6,
107.0, 85.4, 38.5, 16.9; MS (EI) m/z (relative intensity) 133 (16),
91 (100), 77 (17); HRMS calcd for C17H24NO2 (MH) 274.1807,
found 274.1807.
(3R,1′R)-(+)-N-(1-P h en ylbu toxy)-6-m eth yl-1-p h en yl-3-
h ex-1-en yla m in e 6c. Obtained by the addition of isobutyl-
lithium to the cinnamaldoxime 5 as a colorless solid (93%, 92%
de): mp 61-63 °C, [R]20 +43.6 (c 1.42, CH2Cl2); IR (CH2Cl2)
D
3030, 2956 cm-1; H NMR (250 MHz, CDCl3) δ major diaste-
1
reomer 7.26 (10H, m), 6.49 (1H, d, J 16.0), 5.97 (1H, dd, J 8.3,
16.0), 5.15 (1H, br s), 4.57 (1H, t, J 7.4), 3.66 (1H, m), 1.81-
1.12 (7H, m), 0.91 (9H, m), minor diastereomer 6.17 (1H, dd,
J 8.3, 16.0); 13C NMR (62.9 MHz, CDCl3) δ 143.2, 137.0, 132.1,
130.5, 128.4, 128.2, 127.4, 127.2, 126.7, 126.3, 85.3, 62.0, 41.6,
38.5, 24.8, 23.5, 22.2, 19.2, 14.0; MS (CI) m/z (relative intensity)
338 (M+, 12), 149 (100); HRMS calcd for C23H32NO (MH)
338.2484, found 338.2484.
(1R,1′R)-(+)-N-(1-P h en ylbu toxy)-(5-(2-m eth ylfu r yl)-1-
p en tyla m in e 4b. Obtained from the addition of n-butyl-
lithium to oxime 3 as a colorless oil (87%, 81% de): [R]20D +90.3
(c 0.9, CH2Cl2); IR (film) 3030, 2957, 1565 cm-1; 1H NMR (250
MHz, CDCl3) δ major diastereomer 7.27 (5H, m), 6.02 (1H, d,
J 3.0), 5.84 (1H, d, J 3.0), 5.35 (1H, br s), 4.51 (1H, dd, J 5.7,
7.6), 3.92 (1H, dd, J 5.6, 8.6), 2.23 (3H, s), 1.79-1.21 (10H,
m), 0.87 (6H, 2 × t), minor diastereomer 6.07 (1H, d, J 3.0),
4.48 (1H, dd, J 5.7, 7.6), 2.27 (3H, s); 13C NMR (62.9 MHz,
CDCl3) δ 152.3, 151.1, 143.8, 128.1, 127.1, 126.5, 107.9, 105.8,
85.0, 59.1, 38.6, 30.7, 28.3, 22.5, 19.1, 14.0, 13.9, 13.5; MS (EI)
m/z (relative intensity) 166 (88), 151 (100), 133 (12); HRMS
calcd for C20H30NO2 (MH) 316.2276, found 316.2277.
(3S,1′R)-(+)-N-(1-P h en ylb u t oxy)-1,3-d ip h en yl-3-p r op -
1-en yla m in e 6d . (a) Obtained by the addition of phenyl-
lithium to the cinnamaldoxime 5 as a colorless oil (76%, 90%
de): [R]20 +43.0 (c 2.58, CDCl3); IR (film) 2957, 1600 cm-1
;
D
1H NMR (250 MHz, CDCl3) δ major diastereomer 7.40 (15H,
m), 6.49 (1H, d, J 15.9), 6.23 (1H, dd, J 8.3, 15.9), 5.48 (1H, br
s), 4.81 (1H, d, J 8.4), 4.48 (1H, dd, J 5.9, 7.6), 1.74-0.81 (4H,
m), 0.73 (3H, t, J 8.0), minor diastereomer 4.63 (1H, dd, J 8.3,
15.9); 13C NMR (62.9 MHz, CDCl3) δ 143.1, 141.5, 136.9, 132.2,
128.9, 128.4, 128.3, 128.3, 127.8, 127.6, 127.4, 127.3, 126.7,
126.4, 85.3, 68.0, 38.5, 18.8, 13.8; MS (EI) m/z (relative
intensity) 357 (M+, 4), 193 (100), 133 (74), 91 (86), 77 (32);
HRMS calcd for C25H27NO (M) 357.2093, found 357.2097.
(b) Obtained by the addition of phenylmagnesium bromide
(1R,1′R)-(+)-N-(1-P h en ylbu toxy)-(5-(2-m eth ylfu r yl)-1-
bu t-3-en yla m in e 4c. Obtained from the addition of allylmag-
nesium bromide to oxime 3 as a colorless oil (56%, 59% de):
to the cinnamaldoxime 5 as a colorless oil (69%, 80% de): [R]20
+39.0 (c 1, CH2Cl2).
D
[R]20 +92.3 (c 1, CH2Cl2); IR (film) 3076, 2958, 1565 cm-1; 1H
D
NMR (250 MHz, CDCl3) δ major diastereomer 7.32 (5H, m),
6.07 (1H, d, J 3.0), 5.88 (1H, d, J 3.0), 5.75 (1H, m), 5.46 (1H,
br s), 5.06 (2H, m), 4.53 (1H, t, J 7.3), 4.03 (1H, t, J 6.8), 2.66
(1H, m), 2.53 (1H, m), 2.25 (3H, s), 1.83-1.24 (4H, m), 0.90
(3H, t, J 7.2), minor diastereomer 6.11 (1H, d, J 3.0), 5.92 (1H,
d, J 3.0), 2.29 (3H, s); 13C NMR (62.9 MHz, CDCl3) δ major
diastereomer 152.2, 150.9, 143.1, 134.8, 128.1, 127.2, 126.5,
117.2, 108.2, 105.9, 85.2, 55.6, 38.5, 35.4, 19.1, 14.0, 13.5, minor
diastereomer 153.3, 134.5, 117.4, 107.8, 85.3, 58.5, 19.0; MS
(CI) m/z (relative intensity) 166 (80), 135 (100); HRMS calcd
for C19H26NO2 (MH) 300.1963, found 300.1964.
(3R,1′R)-(+)-N-(1-P h en ylbu toxy)-1-ph en yl-3-pen t-1-en y-
la m in e 6e. Obtained by the addition of ethylmagnesium
bromide to the cinnamaldoxime 5 as a colorless solid (91%,
71% de): mp 56-57 °C; [R]20D +42.6 (c 1.32, CH2Cl2); IR (CH2-
Cl2) 3250, 2960, 1599 cm-1; 1H NMR (250 MHz, CDCl3) δ major
diastereomer 7.31 (10H, m), 6.54 (1H, d, J 16.0), 6.00 (1H, dd,
J 7.8, 16.0), 5.26 (1H, br s), 4.60 (1H, dd, J 6.0, 7.4), 3.50 (1H,
m), 1.81 (2H, m), 1.63-1.29 (4H, m), 0.94 (6H, 2 × t, J 7.4),
minor diastereomer 6.55 (1H, d, J 16.0), 6.17 (1H, dd, J 7.8,
16.0), 0.87 (3H, t, J 7.4); 13C NMR (62.9 MHz, CDCl3) δ major
diastereomer 143.0, 137.0, 132.5, 129.6, 128.4, 128.2, 127.4,
127.2, 126.6, 126.3, 85.5, 65.2, 38.6, 25.3, 19.2, 14.0, 10.2, minor
diastereomer 132.0, 130.9, 85.5, 65.5, 38.7, 25.1, 19.1, 10.4;
MS (CI) m/z (relative intensity) 280 (15), 149 (100); HRMS
calcd for C21H28NO (MH) 310.2171, found 310.2171.
(3R,1′R)-(+)-N-(1-P h en ylbu toxy)-1-p h en yl-3-bu t-1-en y-
la m in e 6a . (a) Obtained by the addition of methyllithium to
the cinnamaldoxime 5 as a colorless oil (95%, 92% de): [R]20
D
+87.4 (c 1, CH2Cl2); IR (film) 3252, 2959 cm-1; H NMR (250
1
MHz, CDCl3) δ major diastereomer 7.27 (10H, m), 6.47 (1H,
d, J 16.1), 6.03 (1H, dd, J 7.1, 16.1), 5.18 (1H, br s), 4.58 (1H,
dd, J 5.8, 7.6), 3.75 (1H, m), 1.80 (1H, m), 1.63-1.27 (3H, m),
1.26 (3H, d, J 6.4), 0.91 (3H, t, J 7.2), minor diastereomer 6.51
(1H, d, J 15.1), 6.20 (1H, dd, J 7.1, 15.1), 1.15 (3H, d, J 6.4),
0.81 (3H, t, J 7.2); 13C NMR (62.9 MHz, CDCl3) δ 143.6, 137.1,
131.2, 130.8, 128.4, 128.2, 127.4, 127.2, 126.6, 126.3, 85.4, 58.5,
38.7, 19.2, 18.6, 14.0; MS (EI) m/z (relative intensity) 163 (22),
131 (63), 91 (100), 77 (15); HRMS calcd for C20H25NO (M)
295.1936, found 295.1933.
(3R,1′R)-(+)-N-(1-P h en ylbu toxy)-1,4-d ip h en yl-3-bu t-1-
en yla m in e 6f. Obtained by the addition of benzylmagnesium
bromide to the cinnamaldoxime 5 as a colorless solid (34%,
72% de): mp 81-83 °C; [R]20 +45.7 (c 0.7, CH2Cl2); IR (CH2-
D
Cl2) 3028, 2958 cm-1
;
1H NMR (400 MHz, CDCl3) δ major
diastereomer 7.33 (15H, m), 6.45 (1H, d, J 16.0), 6.12 (1H, dd,
J 7.7, 16.0), 5.40 (1H, br s), 4.65 (1H, dd, J 6.3, 7.4), 3.81 (1H,
m), 3.17 (1H, dd, J 6.6, 13.4), 2.85 (1H, dd, J 6.6, 13.4), 1.89
(1H, m), 1.64-1.32 (3H, m), 0.97 (3H, t, J 7.4), minor
diastereomer 6.50 (1H, d, J 16.0), 6.21 (1H, dd, J 7.7, 16.0),

4424 J . Org. Chem., Vol. 64, No. 12, 1999
Moody et al.
0.91 (3H, t, J 7.4); 13C NMR (100 MHz, CDCl3) δ major
diastereomer 143.3, 138.9, 137.4, 132.7, 130.0, 129.7, 128.8,
128.8, 128.7, 127.8, 127.0, 126.7, 126.6, 86.0, 65.1, 39.6, 39.0,
19.6, 14.4, minor diastereomer 132.4, 130.4, 65.1, 39.4, 14.5;
MS (CI) m/z (relative intensity) 372 (MH+, 9), 149 (100); HRMS
calcd for C26H30NO (MH) 372.2327, found 372.2327.
(R)-(+)-N-(Ben zyloxyca r b on yl)-6-m et h yl-1-p h en yl-3-
h ex-1-en yla m in e 7c. Obtained from the cleavage of hydroxy-
lamine 6c and subsequent N-protection as a colorless solid
(86%): mp 54-56 °C; [R]20 +34.8 (c 2, CH2Cl2); IR (CH2Cl2)
D
3320, 2956, 1694 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.30 (10H,
m), 6.54 (1H, d, J 16.0), 6.09 (1H, dd, J 6.1, 16.0), 5.15 (2H, s),
4.83 (1H, br s), 4.42 (1H, m), 1.71 (1H, m), 1.48 (2H, m), 0.96
(6H, m); 13C NMR (100 MHz, CDCl3) δ 156.2, 137.2, 131.0,
130.6, 129.5, 128.9, 1287, 128.5, 128.1, 127.1, 125.7, 67.1, 51.9,
45.2, 25.2, 23.1; MS (CI) m/z (relative intensity) 324 (MH+,
12), 173 (100); HRMS calcd for C21H26NO2 (MH) 324.1963,
found 324.1964.
(3R,1′R)-(+)-N-(1-P h en ylbu toxy)-3-m eth yl-1-p h en yl-3-
h ep t-1-en yla m in e 11. Obtained by the addition of n-butyl-
lithium to (E)-benzylideneacetone oxime 9 as a colorless oil
(53%, ∼80% de): [R]20 +51.4 (c 1, CH2Cl2); IR (film) 3029,
D
2958 cm-1; H NMR (250 MHz, CDCl3) δ major diastereomer
1
7.32 (10H, m), 6.44 (1H, d, J 16.4), 6.21 (1H, d, J 16.4), 5.00
(1H, br s), 4.59 (1H, dd, J 5.2, 7.6), 1.76 (1H, m), 1.56 (3H, m),
1.34 (2H, m), 1.30 (3H, s), 0.92 (3H, t, J 7.1), minor diastere-
omer 6.30 (1H, d, J 16.4); 13C NMR (62.9 MHz, CDCl3) δ major
diastereomer 143.5, 137.5, 135.4, 128.5, 128.4, 128.2, 127.1,
126.5, 126.2, 85.4, 61.0, 39.0, 37.8, 26.0, 23.3, 22.2, 19.2, 14.0,
minor diastereomer 22.4; MS (CI) m/z (relative intensity) 352
(MH+, 5), 202 (95), 150 (100); HRMS calcd for C24H34NO (MH)
352.2640, found 352.2640.
(S)-(+)-N-(Ben zyloxyca r bon yl)-1,3-d ip h en yl-3-p r op -1-
en yla m in e 7d . Obtained from the cleavage of hydroxylamine
6d and subsequent N-protection as a colorless solid (66%): mp
110-111 °C; [R]20D +8.0 (c 1, CH2Cl2); IR (CH2Cl2) 3317, 2955,
1
1689 cm-1; H NMR (400 MHz, CDCl3) δ 7.35 (15H, m), 6.64
(1H, d, J 15.9), 1H, dd, J 6.0, 15.9), 5.60 (1H, br s), 5.32 (1H,
br s), 5.19 (2H, dd, J 12.2, 16.4); 13C NMR (100 MHz, CDCl3)
δ 154.2, 139.6, 135.0, 129.9, 127.8, 127.4, 127.2, 127.1, 127.0,
126.7, 126.4, 126.3, 125.6, 125.2, 65.6, 55.5; MS (CI) m/z
(relative intensity) 344 (MH+, 12), 193 (100), 91 (31); HRMS
calcd for C23H22NO2 (MH) 344.1650, found 344.1651.
(3S,1′R)-(+)-N-(1-P h en ylbu toxy)-3-m eth yl-1-p h en yl-3-
h ep t-1-en yla m in e 12. Obtained by the addition of n-butyl-
lithium to (Z)-benzylideneacetone oxime 10 as a colorless oil
(36%, 77% de): [R]20 +52.3 (c 1.84, CH2Cl2); IR (film) 3029,
(R)-(+)-N-(Ben zyloxyca r b on yl)-3-m et h yl-1-p h en yl-3-
h ep t-1-en yla m in e 13. Obtained from the cleavage of hy-
droxylamine 11 and subsequent N-protection as a colorless oil
(70%): [R]20D +0.24 (c 6.6, CH2Cl2); IR (film) 3345, 2956, 1713
D
2958 cm-1; H NMR (250 MHz, CDCl3) δ major diastereomer
1
7.32 (10H, m), 6.44 (1H, d, J 16.4), 6.28 (1H, d, J 16.4), 5.00
(1H, br s), 4.59 (1H, dd, J 5.2, 7.6), 1.76 (1H, m), 1.56 (3H, m),
1.34 (2H, m), 1.30 (3H, s), 0.92 (3H, t, J 7.1), minor diastere-
omer 6.21 (1H, d, J 16.4); 13C NMR (62.9 MHz, CDCl3) δ 143.7,
137.7, 135.5, 128.5, 128.4, 128.3, 127.2, 126.6, 126.3, 85.6, 61.2,
39.2, 37.9, 26.2, 23.4, 22.5, 19.3, 14.2.
1
cm-1; H NMR (400 MHz, CDCl3) δ 7.36 (10H, m), 6.48 (1H,
d, J 16.3), 6.36 (1H, d, J 16.3), 5.15 (2H, s), 4.96 (1H, br s),
1.86 (2H, m), 1.57 (3H, s), 1.36 (4H, m), 0.96 (3H, t, J 6.7); 13
C
NMR (100 MHz, CDCl3) δ 155.0, 137.5, 137.2, 135.6, 129.2,
128.9. 128.5, 128.4, 128.1, 127.8, 126.9, 66.7, 56.8, 40.6, 26.5,
25.4, 23.4, 14.5; MS (CI) m/z (relative intensity) 338 (MH+,
19), 187 (100); HRMS calcd for C22H28NO2 (MH) 338.2120,
found 338.2120.
(S)-(+)-N-(Ben zyloxyca r b on yl)-3-m et h yl-1-p h en yl-3-
h ep t-1-en yla m in e 14. Obtained from the cleavage of hy-
droxylamine 12 and subsequent N-protection as a colorless oil
(66%).
Gen er a l P r oced u r e for th e Syn th esis of N-Cbz-a m in o
Acid s 8 by Oxid a tive Clea va ge. The protected carbamate
7 (1.6 mmol) was stirred at room temperature in CCl4 (2 mL),
CH3CN (2 mL), and water (3 mL) with periodic acid (6.6 mmol)
for 10 min. RuCl3‚3H2O (0.03 mmol) was added and the
solution heated at 50 °C for 24 h. Water (20 mL) and
dichloromethane (20 mL) were added, the layers were sepa-
rated. The aqueous layer was exhaustively extracted with
dichloromethane (4 × 20 mL) and the organic layers were
combined, dried, filtered, and evapoared. The residue was
passed through a short silica gel column (ether-light petro-
leum (1:1) as eluent) to yield a clear oil. The oil was dissolved
in saturated aqueous sodium bicarbonate solution (15 mL) that
was washed with ether (2 × 10 mL), the aqueous layer was
acidified (pH 1) with concentrated hydrochloric acid and
extracted with dichloromethane (3 × 20 mL), and the combined
organic extracts were dried, filtered and evaporated to furnish
the title compound.
Gen er a l Met h od for N-Cb z-P r ot ect ed Am in es 7 b y
N-O Bon d Clea va ge. Zinc dust (8 g, 122 mmol) was added
to a solution of chiral hydroxylamine (3.1 mmol) in acetic acid
and water (20 mL 1:1). The mixture was placed in a sonic bath
at 40 °C for 2 h. The solution was filtered, ether (50 mL) and
water (50 mL) were added, the layers were separated, and the
aqueous layer was washed with further portions of ether and
dichloromethane. The aqueous layer was basified with sodium
hydroxide to pH 8 and further extracted with dichloromethane
(2 × 30 mL). The combined organic extracts were evaporated,
and THF/water (100 mL 1:1) was added to the residue. Sodium
carbonate (1.27 g, 12 mmol) was added, the mixture was cooled
to 0 °C, benzylchloroformate (0.6 mL, 4 mmol) was then added
dropwise, and the mixture was allowed to warm to room
temperature and was stirred for 12 h. The THF was removed
in vacuo, ether (50 mL) was added, the layers were separated,
and the aqueous layer was washed with further portions of
ether. The combined organic extracts were dried (MgSO4),
filtered, and evaporated. Column chromatograpy of the residue
on silica gel (ether-light petroleum 1:6) furnished the title
compound.
(R)-(+)-N-(Ben zyloxyca r b on yl)-1-p h en yl-3-b u t -1-en y-
la m in e 7a . Obtained from the cleavage of hydroxylamine 6a
and subsequent N-protection as a colorless solid (31%): mp
89-91 °C; [R]20 +48.8 (c 1, CH2Cl2); IR (CH2Cl2) 3309, 2974,
D
1
1681 cm-1; H NMR (250 MHz, CDCl3) δ 7.32 (10H, m), 6.53
(R)-(+)-N-Cbz-a la n in e 8a . Obtained from the double-bond
cleavage of protected amine 7a as a colorless solid (25%): mp
(1H, d, J 15.8), 6.16 (1H, dd, J 15.8, 5.8), 5.15 (2H, s), 4.50
(1H, br s), 4.50 (1H, br m), 1.35 (3H, d, J 6.8); 13C NMR (62.9
MHz, CDCl3) δ 155.8, 136.6, 136.5, 131.1, 129.5, 128.5, 128.3,
128.0, 127.5, 126.6, 126.4, 66.7, 48.4, 21.0; MS (EI) m/z
(relative intensity) 282 (MH+, 19), 91 (100); HRMS calcd for
79-80 °C (lit.17 mp 86-87 °C); [R]20D +12.8 (c 0.36, AcOH) (lit.17
1
[R]25 +13.9 (c 2, AcOH)); H NMR (400 MHz, CDCl3) δ 9.08
D
(1H, br s), 7.31 (5H, m), 5.39 (1H, br d, J 6.7), 5.13 (2H, s),
4.42 (1H, m), 1.46 (3H, d, J 7.2).
C
18H19NO2 (M) 281.1416, found 281.1416.
(R)-(+)-N-Cbz-n or leu cin e 8b. Obtained from the double-
bond cleavage of protected amine 7b as a colorless solid
(R)-(+)-N-(Ben zyloxyca r bon yl)-1-p h en yl-3-h ep t-1-en y-
la m in e 7b. Obtained from the cleavage of hydroxylamine 6b
(57%): mp 51-52 °C (lit.18 mp 56-58 °C); [R]20 +8.2 (c 1,
D
and subsequent N-protection as a colorless solid (82%): mp
MeOH) (lit.17 [R]20 +5.6 (c 1, MeOH)); 1H NMR (250 MHz,
80-83 °C; [R]20 +39.0 (c 1, CH2Cl2); IR (CH2Cl2) 3313, 2955,
D
D
1
1682 cm-1; H NMR (400 MHz, CDCl3) δ 7.33 (10H, m), 6.59
CDCl3) δ 7.36 (5H, m), 5.25 (1H, br d, J 6.7), 5.13 (2H, s), 4.40
(1H, m), 1.87 (1H, m), 1.70 (1H, m), 1.35 (4H, m), 0.90 (3H, br
t).
(1H, d, J 15.9), 6.13 (1H, dd, J 6.4, 15.9), 5.18 (2H, s), 4.85
(1H, br s), 4.38 (1H, br s), 1.67 (2H, m), 1.41 (4H, m), 0.95
(3H, t, J 6.7); 13C NMR (100 MHz, CDCl3) δ 156.2, 137.2, 137.0,
130.7, 128.9, 128.5, 127.9, 126.8, 67.1, 53.6, 35.7, 28.3, 22.9,
14.4; MS (EI) m/z (relative intensity) 324 (MH+, 4), 91 (100);
HRMS calcd for C21H25NO2 (M) 323.1885, found 323.1888.
(17) Moriniere, J .-L.; Danree, B.; Lemoine, J .; Guy, A. Synth.
Commun. 1988, 18, 441-444.
(18) Sokotowska, T.; Bierat, J . F. Rocz. Chem. 1966, 40, 1665-1673.

Chiral Oxime Ethers in Asymmetric Synthesis
J . Org. Chem., Vol. 64, No. 12, 1999 4425
(R)-(+)-N-Cbz-leu cin e 8c. Obtained from the double-bond
1.25 (4H, m), 0.87 (3H, t, J 6.6); 13C NMR (62.9 MHz, CDCl3)
δ 179.5, 179.1, 128.5, 128.4, 127.9, 67.2, 66.5, 36.6, 26.0, 23.2,
22.5, 13.8; MS (EI) m/z (relative intensity) 279 (M+, 3), 91
(100); HRMS calcd for C15H21NO4 (M) 279.1470, found 279.1476.
cleavage of protected amine 7c as a colorless oil (36%): [R]20
D
+12.5 (c 1, EtOH) (lit.17 [R]20 +14.7 (c 1, EtOH)); 1H NMR
D
(250 MHz, CDCl3) δ 7.35 (5H, m), 5.19 (1H, br d, J 6.7), 5.12
(2H, s), 4.42 (1H, m), 1.62 (3H, m), 0.95 (6H, 2d).
(R)-(-)-N-Cb z-p h en ylglycin e 8d . Obtained from the
Ack n ow led gm en t. This work was supported by
Lilly Research Centre and the EPSRC/DTI under the
Link Program for Asymmetric Synthesis. We thank the
EPSRC Mass Spectrometry Centre at Swansea for mass
spectra.
double-bond cleavage of protected amine 7d as a colorless solid
(55%): mp 127-128 °C (lit.19 127.5-129.5 °C); [R]20 -110.0
D
(c 4, EtOH) (lit.19 [R]24D -121.0 (c 0.48, EtOAc)); 1H NMR (250
MHz, CDCl3) δ rotamers 7.34 (10H, m), 5.86 (1H, br d, J 6.2),
5.40 (1H, br d, J 6.4), 5.10 (2H, s).
(R)-(-)-2-Ben zyloxyca r b on yla m in o-2-m et h ylh exa n o-
ic Acid 15 (N-Cbz-r-m eth yln or leu cin e). Obtained from the
double-bond cleavage of protected amine 13 as a colorless oil
Su p p or tin g In for m a tion Ava ila ble: Crystallographic
data for (R)-O-(1-phenylbutyl) cinnamaldoxime 5 and 13C NMR
spectra of 3, 4, 6, 7, 9, 10-13, and 15. This material is
available free of charge via the Internet at http://pubs.acs.org.
(64%): [R]20 -4.1 (c 1.6, EtOH); IR (film) 3346, 2959, 1713
D
cm-1; 1H NMR (250 MHz, CDCl3) δ 7.34 (5H, m), 5.63 (1H, br
s), 5.10 (2H, d, J 7.1), 2.10 (1H, m), 1.84 (1H, m), 1.60 (3H, s),
(19) Pearson, A. J .; Lee, K. J . Org. Chem. 1994, 59, 2257-2260.
J O9901079