Tandem protocol for the stereoselective synthesis of different polyfunctional β-amino acids and 3-amino-substituted carbohydrates

Article abstract of DOI:10.1021/jo980656z

Conjugate addition of homochiral amidocuprates or lithium amides based on (R)-N-(1-phenylethyl)-(trimethylsilyl)amine to α,β-unsaturated esters proceeds stereoselectively and allows the synthesis of β-amino acids. Trapping of the intermediate ester enolate with D₂O affords the corresponding deuterated compounds. anti-α-Alkyl-β-amino acids are obtained stereoselectively after transmetalation of the lithium/copper ester enolate to the titanium ester enolate and trapping with carbon electrophiles. Both diastereomers of β-homothreonine, other precursors of 3-amino-substituted carbohydrates, and stereoselectively in position 2 deuterated analogues are formed from enantiomerically pure γ-alkoxy-substituted enoates. The product distribution observed is complementary to published results regarding 1,4- addition to γ-silyloxy-substituted enoates. The anti/syn selectivity can be explained by assuming transition state geometries where the delivery of the nitrogen nucleophile is controlled by lithium 'chelation' between reagent and substrate. In one case the product configuration can be controlled by the reagent irrespective of the substrate stereochemistry, in other cases the topicity of the addition is complementary to published results. For instance, erythro- or threo-configured 2,3-dideoxy-3-aminopentoses are accessible via this route.

Full text of DOI:10.1021/jo980656z

J . Org. Chem. 1998, 63, 7263-7274
7263
Ta n d em P r otocol for th e Ster eoselective Syn th esis of Differ en t
P olyfu n ction a l â-Am in o Acid s a n d 3-Am in o-Su bstitu ted
Ca r boh yd r a tes
Norbert Sewald,*,† Klaus D. Hiller,† Matthias Ko¨rner,† and Matthias Findeisen‡
Department of Organic Chemistry and Department of Analytical Chemistry, University of Leipzig,
Leipzig, FRG
Received April 8, 1998
Conjugate addition of homochiral amidocuprates or lithium amides based on (R)-N-(1-phenylethyl)-
(trimethylsilyl)amine to R,â-unsaturated esters proceeds stereoselectively and allows the synthesis
of â-amino acids. Trapping of the intermediate ester enolate with D2O affords the corresponding
deuterated compounds. anti-R-Alkyl-â-amino acids are obtained stereoselectively after transmetal-
ation of the lithium/copper ester enolate to the titanium ester enolate and trapping with carbon
electrophiles. Both diastereomers of â-homothreonine, other precursors of 3-amino-substituted
carbohydrates, and stereoselectively in position 2 deuterated analogues are formed from enantio-
merically pure γ-alkoxy-substituted enoates. The product distribution observed is complementary
to published results regarding 1,4-addition to γ-silyloxy-substituted enoates. The anti/syn selectivity
can be explained by assuming transition state geometries where the delivery of the nitrogen
nucleophile is controlled by lithium “chelation” between reagent and substrate. In one case the
product configuration can be controlled by the reagent irrespective of the substrate stereochemistry;
in other cases the topicity of the addition is complementary to published results. For instance,
erythro- or threo-configured 2,3-dideoxy-3-aminopentoses are accessible via this route.
Although being less abundant than the corresponding
R-amino acids, â-amino acids occur in nature both in free
form and bound in peptides. They tend to be stronger
bases and weaker acids compared to R-amino acids.
Peptides containing â-amino acids have a different
skeleton atom pattern, and the incorporation of â-amino
acids into biologically active peptides may enhance
activity and metabolic stability.1
3-Amino-2,3-dideoxyaldoses belong to a class of biologi-
cally relevant carbohydrates. Some of them are known
as components of glycoside and polysaccharide antibiotics
(e.g. daunosamine, acosamine, ristosamine).2 Nucleo-
sides with 3′-amino-substituted carbohydrate moieties
often show antiviral3 or cancerostatic4 properties. 3′-
Amino-2′,3′-dideoxycytidine inhibits DNA replication.5
3-Amino-3-deoxyaldoses and their precursors have been
obtained via Michael addition of amines to homochiral
R,â-unsaturated aldehydes,6 lactones,7 or esters,2,8 car-
rying suitably protected hydroxy groups.
The most versatile methodology for the asymmetric
synthesis of â-amino acids and R-derivatized â-amino
acids published so far relies on conjugate addition of
nitrogen nucleophiles to R,â-unsaturated esters.9 This
type of reaction allows subsequent R-derivatization of the
corresponding â-amino ester enolate with electrophiles.
Michael addition of the achiral (amido)cuprate derived
from N-benzyl-(trimethylsilyl)amine to 2,4-dienoates pro-
ceeds highly regio- and diastereoselectively. Subsequent
aldol reactions of the enolate can be performed with
excellent stereoselectivity.10 The stereoselectivity of the
trapping reaction strongly depends on the double bond
geometry11 of the intermediate ester enolate, which is
(6) Petersen, G. V.; Platz, J .; Nielsen, C.; Wengel, J . Synthesis 1994,
823.
* To whom correspondence should be addressed: Talstr. 35, D-04103
Leipzig, FRG. Tel.: Int+49-341-9736532. Fax: Int+49-341-9736599.
E-mail: sewald@organik.orgchem.uni-leipzig.de.
(7) (a) Collis, M. P.; Perlmutter, P. Tetrahedron: Asymmetry 1996,
7, 2117. (b) J eong, L. S.; Beach, J . W.; Chu, C. K. J . Heterocycl. Chem.
1993, 30, 1445. (c) Kilonda A.; Compernolle, F.; Toppet, S.; Hoornaert,
G. J . Tetrahedron Lett. 1994, 35, 9047.
(8) (a) Matsunaga, H.; Sakamaki, T.; Nagaoka, H.; Yamada, Y.
Tetrahedron Lett. 1983, 24, 3009. (b) Davies, S. G.; Smyth, G. D.
Tetrahedron: Asymmetry 1996, 7, 1273. (c) Reetz, M. T.; Ro¨hrig, D.;
Harms, K.; Frenking, G. Tetrahedron Lett. 1994, 35, 8765. (d) Tsukada,
N.; Shimada, T.; Gyoung, Y. S.; Asao, N.; Yamamoto, Y. J . Org. Chem.
1995, 60, 143. (e) Davies, S. G.; Hedgecock, C. J . R.; McKenna, J . M.
Tetrahedron: Asymmetry 1995, 6, 827. (f) Thompson, D. K.; Hubert,
C. N.; Wightman, R. H. Tetrahedron 1993, 49, 3827. (g) Herczegh, P.;
Kovacs, I.; Szilagyi, L.; Varga, T.; Dinya, Z.; Sztaricskai, F. Tetrahedron
Lett. 1993, 34, 1211.
(9) Reviews: (a) Cole, D. C. Tetrahedron 1994, 50, 9517. (b) Sewald,
N. Amino Acids 1996, 9, 397. (c) J uaristi, E., Ed. Enantioselective
Synthesis of â-Amino Acids; Wiley-VCH: New York, 1997.
(10) (a) Yamamoto, Y.; Asao, N.; Uyehara, T. J . Am. Chem. Soc.
1992, 114, 5427. (b) Asao, N.; Tsukada, N.; Yamamoto, Y. J . Chem.
Soc., Chem. Commun. 1993, 1660.
(11) For simplicity, all metals (including Li) are here defined to have
higher priority than carbon in the description of Z and E ester enolates.
Hence, the lithium ester enolate and the corresponding silyl ketene
acetal are both regarded e.g. as Z configured.
† Department of Organic Chemistry.
‡ Department of Analytical Chemistry.
(1) (a) von Riniker, B.; Schwyzer, R. Helv. Chim. Acta 1964, 47, 2357.
(b) Ondetti, M.; Engel, S. L. J . Med. Chem. 1975, 18, 761. (c)
Stachowiak, K.; Khosla, M. C.; Plucinska, K.; Khairallah, P. A.;
Bumpus, F. M. J . Med. Chem. 1979, 22, 1128. (d) Hintermann, T.;
Seebach, D. Chimia 1997, 50, 244.
(2) Hauser, F. M.; Ellenberger, S. R. Chem. Rev. 1986, 86, 35-67.
(3) (a) Imbach, J . L.; Gosselin, G. PCT Int. Appl. WO 9312131 A1
930624; Chem Abstr. 1994, 120, 135072. (b) Matthes, E.; von J anta-
Lipinski, M.; Will, H.; Schro¨der, H. C.; Merz, H.; Steffen, R.; Mu¨ller,
W. E. G. Biochem. Pharmacol. 1992, 43, 1571.
(4) (a) Lin, T. S.; Mancini, W. R. J . Med. Chem. 1983, 26, 544. (b)
Lin, T. S.; Gao, Y. S.; Mancini, W. R. J . Med. Chem. 1983, 26, 1691.
(c) Herdewijn, P.; Balzarini, J .; Pauwels, R.; J anssen, G.; Van Aerschot,
A.; De Clerq, E. Nucleosides Nucleotides 1989, 8, 1231.
(5) (a) Chidgeavadze, Z. G.; Beabealashvilli, R. S.; Krayevsky, A.
A.; Kukhanova, M. K. Biochim. Biophys. Acta 1986, 868, 145. (b)
Mancini, W. R.; Williams, M. S.; Lin, T. S. Biochemistry 1988, 27, 8832.
(c) Williams, M. S.; Mancini, W. R. Biochem. Pharmacol. 1994, 47,
1285.
S0022-3263(98)00656-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 09/25/1998

7264 J . Org. Chem., Vol. 63, No. 21, 1998
Sewald et al.
Sch em e 1a
Ta ble 1. Com p a r ison of An ti/Syn Selectivities (%) of
Ester En ola te Meth yla tion
entry
enolate type
M
Li
R1
R2
R3
anti syn
1
2
3
4
5
6
Z-2 (tandem)a
H
H
H
H
SiMe3 Me
SiMe3 Me
Bzl
Bzl
47
69
5
53
31
95
40
42
3
E-2 (stepwise)a Li
Z-2 (tandem)b
E-2 (stepwise)b Li
Li
Ph
Ph
Ph
Ph
60
58
97
Z-2 (tandem)b
Li Me Bzl
E-2 (stepwise)b Li Me Bzl
a
b
Reference 13. Reference 17a.
tion in enolate alkylation obviously is influenced by the
distant (R)-(1-phenylethyl)amino group. Here, the step-
wise protocol [(RR,E)-2: entry 6] represents the matched
case with better anti selectivity compared to the tandem
protocol [(RR,Z)-2: entry 5].17a
The counterion of the intermediate ester enolate also
seems to profoundly influence the stereoselectivity of its
reaction with electrophiles. Tandem Michael addition of
a homochiral lithium amide with subsequent ester eno-
late methylation proceeds with moderate anti selectivity,17a
while the analogous reaction with the magnesium amide
is reported to be highly syn selective.17b
We are interested in â-amino acids as building blocks
for analogs of pharmacologically active peptides.18 Con-
nected with our studies on peptide modification by
nonproteinogenic or non-natural amino acids, we elabo-
rated a stereoselective route toward â-amino acid deriva-
tives via conjugate addition of homochiral amidocuprates
to readily available R,â-unsaturated methyl or ethyl
esters. (Scheme 2) This method for the synthesis of
â-amino acid derivatives is based on enantiomerically
pure lithium N-(1-phenylethyl)(trimethylsilyl)amide (1a )
and the corresponding lithium (amido)cuprates as ho-
mochiral nitrogen nucleophiles,15 because it is cheap and
readily available in both enantiomeric forms in sufficient
enantiomeric purity. While our investigation was in
progress, the in situ generation of this amine was
reported;19 however, no systematic examination of the
corresponding amidocuprate has been published yet.
The acid-sensitive N-Si bond is easily cleaved by flash-
chromatography or by treatment with dilute acid. Hy-
drogenolysis of the N-(1-phenylethyl)-substituted â-amino
acid esters usually proceeds smoothly with palladium
catalysts and hydrogen or via transfer hydrogenation.19
However, in the case of â-aryl-substituted â-amino acid
derivatives, where two N-benzyl moieties are present in
the substrate, a lower yield of the product often is
observed because of the formation of the corresponding
3-arylpropionate.
a
Key: (a) MeOH; (b) LDA; (c) TMSCl; (d) MeI.
governed by the conformational preference of the enoate.
The s-cis and s-trans conformers of methyl cinnamate are
nearly equally populated in the gas phase at 4 K, whereas
in solution a slight preference for the s-cis conformer of
uncomplexed methyl cinnamate was found.12 The Michael
addition of metal amides to uncomplexed R,â-unsaturated
esters at low temperature is supposed to proceed via this
conformation giving perferentially the intermediate Z-
configured ester enolate, as shown by several examples
(e.g. lithium amides,13,14 lithium/copper amides10,15,16).
While the ester enolate Z-2 is involved in the tandem
addition e.g. of lithium N-benzyl(trimethylsilyl)amide to
enoates and ester enolate trapping with alkyl halides,
the corresponding ester enolate E-2 is formed on depro-
tonation of the corresponding â-amino acid esters (Scheme
1). The configuration of the ester enolates was proved
by O-silylation.13
However, divergent results regarding the diastereose-
lectivity of ester enolate alkylation reactions have been
published. Methylation of Z-2 obtained on Michael
addition of the achiral lithium N-benzyl(trimethylsilyl)-
amide proceeds with only marginal stereoselectivity
(Table 1, entry 1), while a 69:31 selectivity favoring the
anti isomer is observed upon alkylation of E-2 (entry 2).13
In contrast, tandem addition of lithium dibenzylamide/
ester enolate methylation results in very good syn
selectivity (entry 3). In this case, the stepwise protocol
affords only a marginal excess of the anti isomer (entry
4). Products are obtained diastereoselectively according
to the literature via a stepwise reaction sequence consist-
ing of Michael addition e.g. of lithiated N-benzyl[(R)-(1-
phenylethyl)]amine to R,â-unsaturated esters, quenching,
ester enolate formation, and alkylation. Chiral recogni-
The intermediate lithium/copper ester enolates only
slowly react with deuterium oxide to give R-deuterated
compounds. (Scheme 2) The R-deuterated derivatives are
obtained stereoselectively (de >90%) in good yields with
nearly quantitative deuterium incorporation (>95%, ac-
1
cording to H NMR analysis) as a consequence of the
tandem protocol. There are numerous examples that a
stepwise protocol (e.g. deprotonation of an ester with LDA
and enolate trapping with D2O) often results in a moder-
ate degree of deuteration, because e.g. diisopropylamine
(12) Shida, N.; Kabuto, C.; Niwa, T.; Ebata, T.; Yamamoto, Y. J .
Org. Chem. 1994, 59, 4068.
(13) Asao, N.; Uyehara, T.; Yamamoto, Y. Tetrahedron 1990, 46,
4563.
(14) Costello, J . F.; Davies, S. G.; Ichihara, O. Tetrahedron: Asym-
metry 1994, 5, 1999.
(15) Sewald, N.; Hiller, K. D.; Helmreich, B. Liebigs Ann. 1995, 925.
(16) Shida, N.; Uyehara, T.; Yamamoto, Y. J . Org. Chem. 1992, 57,
5049.
(17) (a) Davies, S. G.; Walters, I. A. S. J . Chem. Soc., Perkin Trans
1 1994, 1129. (b) Bunnage, M. E.; Davies, S. G.; Goodwin, C. J .;
Walters, I. A. S. Tetrahedron: Asymmetry 1994, 5, 35.
(18) (a) Mu¨ller, A.; Vogt, C.; Sewald, N. Synthesis 1988, 837. (b)
Mu¨ller, A.; Schumann, F.; Sewald, N. Lett. Pept. Sci. 1997, 4, 275.
(19) Rico, J . G.; Lindmark, R. J .; Rogers, T. E.; Bovy, P. R. J . Org.
Chem. 1993, 58, 7948.

â-Amino Acids and 3-Amino-Substituted Carbohydrates
J . Org. Chem., Vol. 63, No. 21, 1998 7265
Sch em e 2a
a
Key: (a) CuI, 0.2 equiv of HMPA; (b) (E)-R1CHdCHCO2R2;
(c) R3 ) H, NH4Claq, or R3 ) D, D2O, and then NH4Claq
.
Ta ble 2. Ta n d em Mich a el Ad d ition of (Am id o)cu p r a tes/
En ola te Tr a p p in g w ith Electr op h iles
F igu r e 1. 29Si NMR spectra of N-(trimethylsilyl)(1-phenyl-
ethyl)amine, of lithium N-(trimethylsilyl)(1-phenylethyl)amide
(1a ), and of the reaction mixture of the conjugate addition to
methyl cinnamate, recorded in THF-d8 at 70.459 MHz and
258 K with TMS as an external standard.
yield predominant
(%)a diastereomer
diastereomer
ratio
entry R1 R2
R3
1
2
3
4
5
6
7
8
9
Me Et
Et Et
iPr Et
Ph Me
Me Et
Et Et
iPr Et
Ph Me
H
H
H
H
D
D
D
D
54 (RR,3R)
46 (RR,3R)
50 (RR,3S)
54 (RR,3S)
53 (RR,2R,3R)
47 (RR,2R,3R)
49 (RR,2R,3S)
54 (RR,2R,3S)
45 (RR,2R,3R)
44
40 (RR,2R,3S)
44
44 (RR,2R,3S)
51 (RR,2R,3S)
6a
6b
6c
6d
7a
7b
7c
7d
9a
9b
9c
10a
10c
11
12
80:20
>99:1
99:1
Sch em e 3a
>99:1
83:17:-:-
99:1:-:-
98:2:-:-
95:5:-:-
50:25:25:-
54:37:9:-
62:33:5:-
42:36:19:3
90:10:-:-
88:12:-:-
86:12:2:-
Me Et Me
10 Et Et Me
11 Ph Me Me
12 Me Et Bzl
13 Ph Me Bzl
14 Ph Me Allyl
15 Ph Me CH2CO2Et 49 (RR,2R,3S)
a
Key: (a) CuI, 0.2 equiv of HMPA; (b) (E)-R1CHdCHCO2R2;
(c) ClTi(OiPr)3; (d) R3X, 1 equiv of HMPA; (e) NH4Claq
.
a
Isolated yield.
conditions, presumably because of the existence of steri-
cally demanding bi- or oligonuclear copper complexes of
still unknown structure. Alternatively, a migration of
the trimethylsilyl group from nitrogen to oxygen and the
formation of a O-trimethylsilyl ketene acetal intermedi-
ate might be feasible. However, this seems to be un-
likely, as this species should give rise to a 29Si NMR
signal at > 20 ppm.22
In the course of our investigation we found that
transmetalation of this type of ester enolate from copper
to titanium with chlorotriisopropoxytitanium enhances
the reactivity toward carbon electrophiles. (Scheme 3 and
Table 2, entries 9-15) Trapping with carbon electro-
philes is then possible after additional activation with 1
equiv of HMPA. This route provides access to a variety
of R-alkyl-substituted â-amino acids in a one-pot reaction;
the stereoselectivity varies from good to excellent values.
Therefore, in some cases this method complements the
published procedures.
Except for crotonates, the diastereoselectivity of the
Michael addition is quantitative, considering the fact that
the enantiomeric excess of the chiral auxiliary used is
g96%. The topicity of the first reaction step, i.e. the
conjugate addition of the lithium (amido)cuprate, was
proven by comparison of the optical rotation index of
methyl (3S)-3-amino-3-phenylpropionate {R1 ) Ph, R3 )
H: [R]2D0 -18.4 (c 1.8, CHCl3)} with a literature value23
{[R]2D0 -18.2 (c 1.46, CHCl3)}. Consequently, chirality
formed upon lithium enolate generation with LDA may
act as an acid.20 Therefore, the tandem 1,4-addition/
deuteration seems to be especially suited for the synthesis
of R-deuterated â-amino acids. The stereochemistry of
the deuterated product 7d is (2R,3S) as revealed by the
coupling constant of ca. 2 Hz between 2-H and 3-H in
the corresponding â-lactam, thus indicating anti config-
uration (vide infra, Scheme 4). In contrast, trapping of
the intermediate lithium enolate formed upon addition
of lithium N-benzyl[(R)-(1-phenylethyl)]amide to tert-
butyl cinnamate e.g. with iodomethane is reported to give
only moderate diastereoselectivity.17a The high anti
selectivity on deuteration of the lithium/copper enolate
(f7, Scheme 2 and Table 2, entries 5-8) is explained by
steric hindrance of the chelate complex. An additional
possible explanation of the high stereoselectivity would
be a coordinative stabilization of the ester enolate by the
oxophilic silicon substituent (5b)19 strongly favoring re-
face attack of the deuteron. However, 29Si NMR mea-
surements with the corresponding lithium enolate rule
out the presence of a pentacoordinate silicon species
(Figure 1). The spectrum of the reaction mixture shows
a major peak at 1.31 ppm besides a small signal at -10.5
ppm corresponding to residual lithium N-(1-phenylethyl)-
(trimethylsilyl)amide. A pentacoordinate silicon species
stabilized by intramolecular N-donor coordination usually
resonates at considerably higher field.21
The intermediate lithium/copper ester enolates do not
react with carbon electrophiles under similar reaction
(21) Auner, N.; Probst, R.; Hahn, F.; Herdtweck, E. J . Organomet.
Chem. 1993, 459, 25.
(22) (a) Chan, T. H.; Brook, M. A. Tetrahedron Lett. 1985, 26, 2943.
(b) Chan T. H.; Sto¨ssel, D. J . Org. Chem. 1986, 51, 2423.
(23) Ishihara, K.; Kuroki, Y.; Yamamoto, H. Synlett 1995, 41.
(20) Seebach, D. Angew. Chem. 1988, 100, 1685; Angew. Chem., Int.
Ed. Engl. 1988, 27, 1624.

7266 J . Org. Chem., Vol. 63, No. 21, 1998
Sewald et al.
Sch em e 4
Sch em e 5
at C-2 of the R-alkyl derivatives is then revealed by the
relative stereochemistry at C-2 and C-3 of the corre-
sponding â-lactams, which were obtained via two inde-
pendent methods: ester saponification and ring closure
with triphenylphosphane/2,2′-dithiodipyridine24 or by
Grignard reagent mediated â-lactam cyclization25 (Scheme
4).
The coupling constants between HC-2 and HC-3 of the
â-lactam derivatives 13-15 are measured to be 2 Hz
proving the anti relationship of these protons.
Ta ble 3. An ti/Syn Selectivities of th e Con ju ga te
Ad d ition to 16
anti syn
(%) (%)
entry
R1
R2
solvent
1
2
3
4
5
6
7
8
9
10
11
12
13
14
(S)-1a (S)-16a Me
(S)-1a (S)-16a Me
(R)-1a (S)-16a Me
(R)-1a (S)-16a Me
MOM
MOM
MOM
MOM
MOM
MOM
MOM
MOM
MOM
MOM
ether 17a
96
92
14
62
32
50
1
4
8
THF
ether 18a
THF 18a
ether 19a
THF 19a
ether 17b
THF
ether 18b 12
THF 18b 69
17a
86
38
68
50
99
50
88
31
95
50
90
50
1b
1b
(S)-16a Me
(S)-16a Me
(S)-1a (R)-16b Ph
(S)-1a (R)-16b Ph
(R)-1a (R)-16b Ph
(R)-1a (R)-16b Ph
In cases where the de value after protonation of the
enolate approximates 100% (Table 2, compounds 6b,c),
the ratio of the R-alkylated diastereomers represents a
measure for the stereoselectivity of the alkylation reac-
tion. We found that methylation of the mononuclear
titanated ester enolates favors the 2,3-anti-configured
products [R1 ) Me, (50 + 25):(25 + 0); R1 ) Et, (54 +
9):(37 + 0); R1 ) Ph, (62 + 5):(33 + 0)]. Hence, the anti
selectivity of the tandem Michael addition/Z-enolate
methylation can be slightly enhanced by titanation (cf.
Table 1, entries 1 and 5) but still remains insufficient.
However, reactions with other carbon electrophiles, e.g.
benzylation, allylation, or ethoxycarbonylmethylation,
proceed with good to excellent stereoselectivity.
Comparison of four different possible transition states
reveals that formation of the anti product by attack of
the electrophile from the lower side tentatively is favored
(A, B, Scheme 5).
We further investigated the influence of an additional
chiral center present in γ-alkoxy-substituted enoates on
the stereoselectivity of the lithium amide addition.26
According to the literature, the 1,4-addition of achiral
primary amines proceeds with syn selectivity.8,27 Analo-
gously, the addition of organolithiums to both E- and
Z-configured O-MOM-protected γ-hydroxy enoates is
reported to be syn selective.28
17b 50
(S)-1a (S)-16c CH2OC(CH3)2 ether 17c
(S)-1a (S)-16c CH2OC(CH3)2 THF 17c
(R)-1a (S)-16c CH2OC(CH3)2 ether 18c
(R)-1a (S)-16c CH2OC(CH3)2 THF 18c
5
50
10
50
with ether instead of THF as solvent. Similarly, the
addition of the achiral lithium amide 1b to the enoate
16a is syn selective in ether, while in THF no selectivity
is observed (Table 3, entries 5 and 6).
The combination of (S)-1a with (S)-16a (matched pair,
Table 3, entry 1) provides anti-17a , while syn-18a
predominates for (R)-1a /(S)-16a (mismatched pair, Table
3, entry 3). The application of the homochiral lithium
amides turned out to be favorable, because the product
configuration at C-3 is completely reagent controlled and
independent of the substrate stereochemistry, if ether is
used as solvent (Scheme 6).
The syn selectivity described only recently by Yama-
moto et al.27 for the addition of the achiral lithium amide
1b to γ-(trialkylsilyl)oxy- or γ-trityloxy-substituted enoates
(syn:anti 54:46 for OTBDMS to 90:10 for OTIPS; syn:anti
100:0 for OTrt) can be explained by close analogy to the
Felkin-Anh model.29 Despite the similarity between the
addition of a nucleophile to an R-chiral carbonyl group
and the corresponding 1,4-addition to a γ-chiral R,â-
unsaturated carbonyl group, the latter reaction should
have different steric requirements. Structure E (Scheme
7) represents a close analog to the Felkin-Anh model,29
where the CdO moiety has been replaced by the E-
configured CdCHCO2R1 group.28 The medium size group
(CH3) occupies the inside position, the electronegative
oxygen substituent (OR2) is oriented perpendicularly to
the double bond, and the small substituent (H) is placed
in the outside position. Because of the presence of the
O-trialkylsilyl group of the substrate, Yamamoto et al.
We found pronounced solvent effects on the syn/anti
ratio of additions using the chiral lithium amide 1a . The
stereoselectivity in most cases is considerably improved
(24) Kobayashi, S.; Iimori, T.; Izawa, T.; Ohno, M. J . Am. Chem.
Soc. 1981, 103, 2406.
(25) (a) Shustov, G. V.; Rauk, A. Tetrahedron: Asymmetry 1996, 7,
699. (b) Davies, S. G.; Fenwick, D. R. J . Chem. Soc., Chem. Commun.
1995, 1109.
(26) Ko¨rner, M.; Findeisen, M.; Sewald, N. Tetrahedron Lett. 1998,
39, 3463.
(27) Asao, N.; Shimada, T.; Sudo, T.; Tsukada, N.; Yazawa, K.;
Gyoung, Y. S.; Uyehara, T.; Yamamoto, Y. J . Org. Chem. 1997, 62,
6274.
(28) Yamamoto, Y.; Chounan, Y.; Nishii, S.; Ibuka, T.; Kitahara, H.
J . Am. Chem. Soc. 1992, 114, 7652 and references cited.
(29) Anh, N. T.; Eisenstein, O. Nouv. J . Chim. 1997, 1, 61.

â-Amino Acids and 3-Amino-Substituted Carbohydrates
J . Org. Chem., Vol. 63, No. 21, 1998 7267
Sch em e 6
Sch em e 8
Sch em e 9
Sch em e 7
ciently outweighs the predominance of a certain transition
state conformer (E/F ). On addition of the achiral nu-
cleophile 1b to 16a we found only marginal syn prefer-
ence (Table 3, entry 5). This is in accordance with the
findings of Yamamoto et al. regarding the addition of
lithium dibenzylamide to γ-methoxy butanoate (anti:syn
37:63), where chelation-controlled delivery in transition
state model F ′ (syn) is used to account for syn prefer-
ence.27 In contrast, the addition of lithium dibenzylamide
to γ-((triisopropylsilyl)oxy) butanoate is described to
proceed anti selectively, which has been explained by
chelation control on the basis of structural arguments
and increased hardness of the nucleophile compared to
the N-silyl derivative 1b.27 However, the latter argument
does not seem to be valid, as the reagent controlled anti/
syn selectivity of the 1,4 addition of 1a to 16a presumably
depends on steric effects of the reagent/substrate interac-
tion and not likely on a change between chelation control
and nonchelation control.
Substrate control dominates the stereoselectivity for
the phenyl-substituted γ-alkoxy enoates 16b (Scheme 8
and Table 3, entries 7 and 9). Regardless of the config-
uration of reagent 1a , syn products are obtained with
high selectivity, provided the reaction is performed in
ether. The reaction of (S)-1a with (R)-16b proceeds
slowly but with excellent stereoselectivity. However, the
yields are only in a medium range, because a double bond
isomerization takes place under the reaction conditions
applied to give compound 20b.
exclude the possibility of a “chelated” transition state,
where the delivery of the nucleophile is assisted by
lithium co-ordination between reagent nitrogen and
substrate oxygen (E, anti). This model suitably explains
syn selectivity, but seems to be valid only for E-configured
R,â-unsaturated esters, because the inside position of Z
enoates is sterically more hindered. A modified Felkin-
Anh model F has also been suggested28 but seems to be
more appropriate for Z-configured esters. Furthermore,
divergent results regarding the syn/anti selectivity of
organocuprate additions to enoates had been observed
which led to the development of a different model G.28
This has been proposed also on the basis of ab initio
studies.30 According to these theoretical studies, transi-
tion state conformers with electron-withdrawing (elec-
tronegative) groups oriented perpendicularly are elec-
tronically disfavored.
A “chelation”-controlled delivery of the nucleophile (E,
anti, or F , syn) cannot be excluded in the case of the
reaction 1a + 16a involving MOM-protected derivatives
in ether as solvent, taking into account the pronounced
solvent dependence of the stereoselectivity. The reagent
control of the stereoselectivity observed can be explained
by transition state conformers E (anti; cf. Table 3, entry
1) and F (syn; cf. Table 3, entry 3), respectively, assuming
the above mentioned reagent delivery by lithium coor-
dination between reagent and substrate. Chiral recogni-
tion between substrate 16 and lithium amide 1a effi-
While the reaction of 1a with the MOM-protected
derivatives 16b is syn selective, anti products are formed
exclusively with the corresponding O-silyl-protected γ-hy-
droxy enoates.27 Consequently, the addition 1a + 16b
proceeds via “chelation”-controlled delivery (model H,
syn), while with O-silyl protection “nonchelation” delivery
(H, anti) suitably explains the experimental results.27
and K are energetically disfavored (Scheme 9).
I
The 1,3-dioxolan-4-yl residue like in 16c usually favors
syn selectivity in the addition of nucleophiles.8a,31 This
(31) Mulzer, J .; Kappert, M.; Huttner, G.; J ibril, I. Angew. Chem.
1984, 96, 726; Angew. Chem., Int. Ed. Engl. 1984, 23, 704.
(30) Dorigo, A. E., Morokuma, K. J . Am. Chem. Soc. 1989, 111, 6524.

7268 J . Org. Chem., Vol. 63, No. 21, 1998
Sewald et al.
Sch em e 10
Sch em e 13
Sch em e 11
which is proven by an IR absorption at ≈1780 cm-1. The
γ-lactones were used for stereochemical assignment of
all polyfunctional compounds 17-19 by nOe difference
spectra (Scheme 14, 400 MHz).
DIBALH reduction of the γ-lactones affords the corre-
sponding lactols 24 and 25, respectively (Scheme 13).
Sch em e 12
1
Comparison of the H NMR data in DMSO-d6 with those
of analogous compounds33 reveals a mixture of R and â
anomers both for 24a ,b and 25a .
In summary, the tandem protocol presented here
enables the synthesis of anti-R-deuterio-â-amino acids
and anti-R-alkyl-â-amino acids including polyfunctional
derivatives by 1,4-addition of homochiral nitrogen nu-
cleophiles to γ-alkoxy enoates. Double stereoinduction
is observed with chiral substrates. Both diastereomers
of â-homothreonine (anti-17a , syn-18a ) and other precur-
sors of 3-amino-substituted carbohydrates as well as
stereoselectively in position 2 deuterated analogues have
been synthesized in a reagent- or substrate-controlled
manner, depending on the nature of the substrate. The
topicity observed is complementary to previous results.
The anti/syn selectivity can be explained assuming
transition states where the delivery of the nitrogen
nucleophile is controlled by lithium chelation between
reagent and substrate. Reagent control in the case of
substrate 16a is accounted for by different transition
state geometries. The strategy described enables the
straightforward stereoselective synthesis of 2,3-dideoxy-
3-aminoaldoses in erythro or threo configuration, either
in the D or L series, and their stereospecifically 2-deu-
terated derivatives.
type of stereocontrol by the substrate predominates also
in the case of 1a (Scheme 10 and Table 3, entries 11 and
13). The stereoselectivity drops to zero if THF is used
as solvent (Table 3, entries 12 and 14). Only conformer
L suitably explains the experimental results; formation
of syn products via M is highly disfavored by the
heterocycle. However, chelation-controlled reagent de-
livery should result in the formation of the anti isomer,
which has not been observed. Probably the rigid dioxolan
ring lowers the coordinative ability, or alternatively, the
second oxygen atom in the flexible MOM derivatives
16a ,b also plays a role (Scheme 11).
The intermediate ester enolates can be trapped with
D2O as a deuteron source to give stereospecifically
deuterated products 21. 1,2-Anti induction dominates for
the deuteration reaction as proven by NMR analysis of
a corresponding â-lactam.32 While the deuterium incor-
poration in 21a ,b is practically complete (>95% D),
insufficient deuteration is observed in the case of the
derivatives 21c-e (80-90% D). Byproduct 20b could
explain the result observed for 21c, as it possesses acidic
R-protons, which would be able to protonate the inter-
mediate ester enolate. However, no conclusive explana-
tion for the incomplete deuterium incorporation in prod-
ucts 21d ,e can be provided yet (Scheme 12).
Exp er im en ta l Section
All reactions were performed under dry oxygen-free argon
atmosphere in flame-dried glassware. Most reagents were
commercially available and of synthetic grade. (R)-(1-Phenyl-
ethyl)amine with an ee value of g96% was used without
further purification. Diethyl ether and tetrahydrofuran were
distilled immediately before use from sodium benzophenone
ketyl. Analytical TLC was performed using silica gel 60 F254
plates on aluminum foil; silica gel 60 (32-60 µm) was used
for flash chromatography. Melting points were determined
with an apparatus according to Tottoli and are uncorrected.
Diastereomeric ratios were determined by GC-MS with a 30
m HP-5 MS capillary column, temperature program: (a) 70
°C, 2 min, 70 °C f 270 °C, 25 °C/min or (b) 90 °C, 6 min, 90
°C f 270 °C, 12 °C/min with EI mode for mass detection after
aqueous workup and filtration through silica gel. The dr
values were verified by 1H NMR integration where possible.
The derivatives 17-19 and 21 can be easily converted
into the γ-lactones 22/23 upon treatment with acid
(Scheme 13). Exclusive formation of the γ-lactones takes
place also with the dihydroxy derivatives 17c and 18c,
(33) (a) Fronza, G.; Fuganti, C.; Grasselli, P. J . Chem. Soc., Perkin
Trans. 1 1982, 885. (b) Hirama, M.; Shigemoto, T.; Itoˆ, S. J . Org. Chem.
1987, 52, 3342.
(32) Ko¨rner, M. Ph.D. Thesis, University of Leipzig, 1998.

â-Amino Acids and 3-Amino-Substituted Carbohydrates
Sch em e 14
J . Org. Chem., Vol. 63, No. 21, 1998 7269
NMR spectra routinely were recorded in CDCl3 at 200 MHz
(1H) and 50 MHz (13C), respectively, at 297 K unless otherwise
mentioned and were calibrated against internal standards
(TMS and/or solvent; δ values in ppm, J values in Hz). IR
spectra were recorded as liquid film unless otherwise stated;
the data are given in wavenumbers (cm-1).
C14H20DNO2 (236.33): C, 71.15; H/D, 8.96; N, 5.93. Found:
C, 71.32; H/D, 8.93; N, 5.91.
Eth yl (2R,3R)-2-Deu ter io-3-[(R)-(1-p h en yleth yl)a m in o]-
p en ta n oa te (7b). Yield: 0.24 g (47%). Deuteration: >95%.
dr: 99:1:0:0. Rf ) 0.33 (1:5 EtOAc/hexane). [R]2D0 +55.3 (c
1.0, CHCl3). IR: ν 1740. 1H NMR: ν 0.85 (t, J 7.3, 3H), 1.26
(t, J 7.0, 3H), 1.30 (d, J 6.5, 3H), 1.37-1.44 (m, 2H), 1.54 (br
s, 1H), 2.36 (d, J 5.5, 1H), 2.73 (ddd, J 6.2, 1H), 3.87 (q, J 6.5,
1H), 4.11 (q, J 7.0, 2H), 7.26-7.33 (m, 5 H). 13C NMR: δ 10.34,
14.30, 24.86, 27.96, 38.06 (t, J CD 20 Hz), 53.56, 55.14, 60.18,
126.71, 128.24, 129.06, 146.08, 172.56. GC-MS (a): tR 8.60
min. Anal. Calcd for C15H22DNO2 (250.36): C, 71.96; H/D,
9.26; N, 5.59. Found: C, 72.13; H/D, 9.12; N, 5.14.
N-[(R)-1-P h en yleth yl](tr im eth ylsilyl)a m in e. A 20.91
mL (15.18 g, 150 mmol) amount of triethylamine was added
with stirring to a solution of 12.89 mL (12.12 g, 100 mmol) of
(R)-(+)-(1-phenylethyl)amine in hexane. The mixture was
refluxed for 10 min, and 19.04 mL (16.30 g, 150 mmol) of
chlorotrimethylsilane was added. After the mixture was cooled
to rt (room temperature), stirring was continued for 24 h. The
precipitated triethylammonium chloride was removed by
filtration and washed with 25 mL of hexane. Excess chloro-
trimethylsilane and hexane were evaporated at ambient
pressure; the residual colorless liquid was distilled in vacuo
to give 15.26 g (79.0 mmol, 79%) of N-[(R)-1-phenylethyl]-
(trimethylsilyl)amine with bp 82 °C/14 mbar. IR: ν 3380.
[R]2D0: +54.4 (c 1.1, hexane). 1H NMR: δ 0.65 (s, 9H), 1.39 (d,
J 6.5, 3H), 1.51 (br s, 1H), 4.14 (q, J 6.5, 1H), 7.29-7.32 (m,
5H). 13C NMR: δ 0.40, 29.10, 51.10, 125.32, 125.65, 127.66,
148.81. Anal. Calcd for C11H19NSi (193.36): C, 68.34; H, 9.98;
N, 7.17. Found: C, 68.55; H, 9.83; N, 7.36.
Gen er a l P r oced u r e for th e Syn th esis of r-Deu ter a ted
â-Am in o Acid Ester s. A 2.5 mL volume of a 1.6 M solution
(4.0 mmol) of n-BuLi in hexane was added to a solution of 0.77
g (4.0 mmol) of N-[(R)-1-phenylethyl](trimethylsilyl)amine in
8 mL of diethyl ether at -20 °C. The mixture was cooled to
-78 °C; then 0.38 g (2.0 mmol) of CuI was added with stirring,
and the suspension was kept at -78 °C for 10 min. After
addition of 0.24 mL (0.23 g, 1.4 mmol) of triethyl phosphite
and 2.0 mmol of the R,â-unsaturated ester stirring was
continued for 1 h. The reaction mixture was quenched with
1.0 mL of D2O to achieve R-deuteration, and stirring was
continued for 2 h at room temperature, followed by extraction
of the mixture with diethyl ether (2 × 50 mL). The combined
organic layers were evaporated to about 50 mL, and the
residue was stirred with 40 mL of 1 N HCl to achieve complete
desilylation. Then Na2CO3 was added and the mixture was
subsequently extracted with diethyl ether (2 × 50 mL). The
combined organic layers were dried (MgSO4), and the solvent
was evaporated in vacuo. The products were obtained analyti-
cally pure after flash chromatography.
E t h yl (2R,3S)-2-Deu t er io-4-m et h yl-3-[(R)-(1-p h en yl-
eth yl)a m in o]p en ta n oa te (7c). Yield: 0.26 g (49%). Deu-
teration: >95%. dr: 98:2:0:0. Rf ) 0.33 (EtOAc/hexane 1:4).
IR: ν 3320, 1720. [R]D20: +51.3 (c 1.1, CHCl3). 1H NMR (360
MHz): δ 0.80 (d, J 6.7, 3H), 0.87 (d, J 6.7, 3H), 1.26 (t, J 7.1,
3H), 1.31 (d, J 6.4, 3H), 1.66 (m, 1H), 1.76 (br s, 1H), 2.33 (br
d, J 6.3, 1H), 2.63 (dd, J 6.3/5.5, 1 H), 3.85 (q, J 6.4, 1H), 4.13
(q, J 7.1, 2H), 7.19-7.34 (m, 5H). 13C NMR (90 MHz): δ 14.24,
18.41, 18.67, 24.81, 31.36, 35.76 (t, J CD 20 Hz), 55.48, 57.60,
60.17, 126.78, 126.88, 128.23, 146.23, 173.00. GC-MS (b): tR
23.5 min. Anal. Calcd for C16H24DNO2 (264.38): C, 72.69;
H/D, 9.53; N, 5.30. Found: C, 72.74; H/D, 9.37; N, 5.18.
Eth yl (2R,3S)-2-Deu ter io-3-p h en yl-3-[(R)-(1-p h en yleth -
yl)a m in o]p r op a n oa te (7d ). Yield: 0.30 g (51%). Deutera-
tion: >95%. dr: 95:5:0:0. Rf ) 0.27 (1:4 EtOAc/hexane). IR:
ν 3310, 1720. [R]D20
:
+19.7 (c 1.0, CHCl3). 1H NMR (360
MHz): δ 1.17 (t, J 7.0, 3H), 1.34 (d, J 6.6, 3H), 1.95 (br s, 1H),
2.70 (br d, J 8.0, 1H), 3.66 (q, J 6.6, 1H), 4.07 (q, J 7.0, 2H),
4.17 (d, J 8.0 Hz), 7.13-7.41 (m, 10H). 13C NMR (90 MHz):
δ 14.14, 22.25, 42.37 (t, J CD 20 Hz), 54.58, 56.80, 60.34, 126.56,
126.78, 126.99, 127.30, 128.38, 128.49, 142.72, 145.93, 171.70.
GC-MS (b): tR 28.2 min. Anal. Calcd for C19H22DNO2
(298.40): C, 76.47; H/D, 7.77; N, 4.69. Found C, 76.64; H/D,
7.80; N, 5.05.
Gen er a l P r oced u r e for th e Ta n d em Mich a el Ad d ition /
En ola te Tr a p p in g of (Am id o)cu p r a tes Ba sed on 1a .
A
2.5 mL volume of a 1.6 M solution (4.0 mmol) of n-BuLi in
hexane was added to a solution of 0.77 g (4.0 mmol) of N-[(R)-
1-phenylethyl](trimethylsilyl)amine in 8 mL of diethyl ether
at -20 °C. The mixture was cooled to -78 °C; then 0.38 g
(2.0 mmol) of CuI and 0.035 mL (0.2 mmol) of HMPA were
added with stirring and the suspension was kept at -78 °C
for 10 min. Stirring was continued at -78 °C for 1 h after
addition of 2.0 mmol of the R,â-unsaturated ester. The
intermediate enolate was then transmetalated by addition of
0.52 g (2.0 mmol) of chlorotriisopropoxytitanium, and stirring
was continued at -78 °C for 1 h. The reaction mixture was
quenched with a mixture of 10.0 mmol of the electrophile and
1.75 mL (10.0 mmol) of HMPA at -78 °C. After the mixture
was stirred for 3 h at the same temperature (the reaction
Eth yl (2R,3R)-2-Deu ter io-3-[(R)-(1-p h en yleth yl)a m in o]-
bu ta n oa te (7a ). Yield: 0.23 g (50 %). Deuteration: >95%.
dr: 83:17:0:0. Rf ) 0.32 (1:1 EtOAc/hexane). IR: ν 2950, 1720.
1H NMR (major isomer): δ 1.03 (d, J 6.6, 3H), 1.26 (t, J 7.2,
3H), 1.31 (d, J 6.5, 3H), 1.54 (br s, 1H), 2.40 (d, J 6.5, 1H),
2.98 (m, 1H), 3.86 (q, J 6.5, 1H), 4.15 (q, J 7.2, 2H), 7.22-7.25
(m, 5H). 13C NMR (major isomer): δ 14.64, 21.73, 25.01, 40.45
(t, J CD 20 Hz), 48.20, 55.61, 60.41, 126.93, 127.22, 128.78,
146.50, 172.44. GC-MS (a): tR 8.34 min. Anal. Calcd for

7270 J . Org. Chem., Vol. 63, No. 21, 1998
Sewald et al.
progress can be monitored by GC-MS), saturated ammonium
chloride solution (50 mL) was added, followed by extraction
of the mixture with diethyl ether (2 × 50 mL). Benzylation
requires longer reaction times and excess of electrophile: 30.0
mmol of benzyl bromide, 30.0 mmol of HMPA, addition at -78
°C, after warming to rt stirring continued for 36 h. The
combined organic layers were stirred with 40 mL of 1 N HCl
to achieve complete desilylation. Aqueous Na2CO3 was added,
and the mixture was subsequently extracted with diethyl ether
(2 × 50 mL). The combined organic layers were dried (MgSO4)
and the solvent was evaporated in vacuo. The crude reaction
mixture was filtered through silica gel; the products were
obtained analytically pure after flash chromatography.
Eth yl (2R,3R)-2-Meth yl-3-[(R)-(1-p h en yleth yl)a m in o]-
bu ta n oa te (9a ). Yield: 0.22 g (45%). dr: 50:25:25:0. Rf )
0.16 (1:5 EtOAc/petroleum ether). IR: ν 1730. 1H NMR (400
MHz, mixture of diastereomers, major isomer in italics): δ
0.95/1.00/1.05 (d/d/d, J 6.5/6.5/6.3, 3H), 1.13/1.11/1.14 (d/d/d,
J 7.0/6.8/7.2, 3H), 1.25/1.30/1.20 (t/t/t, J 7.1/7.1/7.1, 3H), 1.31/
1.32/1.33 (d/d/d, J 6.5/6.3/6.5, 3H), 1.60 (br, 1H), 2.57/2.70/2.40
(dq/dq/dq, J 6.7, 6.7/4.3, 7.0/7.2, 7.2, 1H), 2.94/2.77/2.45 (dq/
dq/dq, J 6.4, 6.4/4.4, 6.6/5.2, 7.2, 1H), 3.84/3.95/3.92 (q/q/q, J
6.6/6.6/6.6, 1H), 4.07-4.22 (m, 2H), 7.23-7.36 (m, 5H). 13C
NMR (major diastereomer): δ 12.27, 14.74, 18.29, 24.70, 45.11,
52.87, 55.82, 60.58, 127.07, 127.30, 128.84, 146.88, 176.27. GC-
MS (a): tR 8.49/8.55 min. Anal. Calcd for C15H23NO2
(249.35): C, 72.25; H, 9.30; N, 5.62; O, 13.00. Found: C, 72.27;
H, 9.14; N, 5.55; O, 13.04.
Eth yl (2R,3R)-2-Meth yl-3-[(R)-(1-p h en yleth yl)a m in o]-
p en ta n oa te (9b). Yield: 0.23 g (44%). dr: 54:37:9:0. Rf )
0.28 (1:4 EtOAc/petroleum ether). IR: ν 1730. 1H NMR (400
MHz, mixture of diastereomers, major isomer in italics): δ
0.80/0.87/0.88 (t/t/t, J 7.4/7.4/7.4, 3H), 1.13/1.08/1.05 (d/d/d, J
6.8/7.0/7.0, 3H), 1.25 (t, J 7.2, 3H), 1.27-1.33 (m, 3H), 1.33-
1.47 (m, 3H), 2.50-2.80 (m, 2H), 3.83/3.92/3.87 (q/q/q, J 6.5/
6.5/6.5, 1H), 4.06-4.21 (m, 2H), 7.22-7.37 (m, 5H). 13C NMR
(major diastereomer): δ 10.67, 11.67, 14.46, 24.35, 25.12,
42.10, 55.41, 57.96, 60.57, 127.31, 127.34, 128.73, 146.46,
176.37. GC-MS (a): tR 8.18 min. C16H25NO2 (263.38).
Meth yl (2R,3S)-2-Meth yl-3-p h en yl-3-[(R)-(1-p h en yleth -
yl)a m in o]p r op a n oa te (9c). Yield: 0.24 g (40%). dr: 62:33:
5:0. Rf ) 0.15 (1:5 EtOAc/petroleum ether). IR: ν 3350, 1720.
Major isomer: [R]2D0: +16.8 (c 1.4, CHCl3). 1H NMR: δ 0.94
(d, J 7.0, 3H), 1.27 (d, J 6.5, 3H), 1.84 (br, 1H), 2.68 (dq, J 9.9,
7.0, 1H), 3.53 (q, J 6.5, 1H), 3.76 (s, 3H), 3.89 (d, J 9.9, 1H),
7.17-7.34 (m, 10H). 13C NMR: δ 15.02, 21.91, 47.46, 51.60,
54.58, 63.23, 126.63, 126.87, 127.44, 127.58, 128.32, 128.56,
141.46, 146.45, 176.26. GC-MS (a): tR 9.92 min. Anal. Calcd
for C19H23NO2 (297.40): C, 76.74; H, 7.80; N, 4.71; O, 10.76.
Found: C, 76.99; H, 7.99; N, 4.59; O, 10.80.
Eth yl (2R,3R)-2-Ben zyl-3-[(R)-(1-p h en yleth yl)a m in o]-
bu ta n oa te (10a ). Yield: 0.29 g (44%). dr: 42:36:19:3. Rf )
0.18 (1:5 EtOAc/petroleum ether). IR: ν 3320, 1730. 1H NMR
(major isomer): δ 1.04 (d, J 6.5, 3H), 1.11 (t, J 7.2, 3H), 1.27
(d, J 6.5, 3H), 1.39 (br, 1H), 2.76-2.97 (m, 4H), 3.87 (q, J 6.5,
1H), 4.02 (q, J 7.2, 2H), 7.21-7.34 (m, 5H). 13C NMR (major
isomer): δ 14.63, 19.16, 24.55, 34.01, 52.48, 53.55, 55.88, 60.55,
126.60, 127.09, 127.35, 128.85 (2×), 129.40, 140.72, 146.83,
174.89. GC-MS (a): tR 10.96/10.90/11.06 min. Anal. Calcd
for C21H27NO2 (325.45): C, 77.50; H, 8.36; N, 4.30; O, 9.83.
Found: C, 77.48; H, 8.27; N, 4.48; O, 9.77.
Meth yl (2R,3S)-2-Ben zyl-3-p h en yl-3-[(R)-(1-p h en yleth -
yl)a m in o]p r op a n oa te (10c). Yield: 0.33 g (44%). dr: 90:
10:0:0. Rf ) 0.35 (1:3 EtOAc/petroleum ether). IR: ν 3320,
1730. [R]2D0: +85.1 (c 0.9, CHCl3). 1H NMR: δ 1.24 (d, J 6.6,
3H), 1.76 (br, 1H), 2.52 (dd, J 12.4, 3.2, 1H), 2.74-3.00 (m,
2H), 3.54 (q, J 6.6, 1H), 3.58 (s, 3H), 3.96 (d, J 8.4, 1H), 7.01-
7.39 (m, 15H). 13C NMR: δ 22.02, 36.24, 51.38, 54.56, 55.84,
62.26, 126.29, 126.62, 126.91, 127.41, 127.57, 128.34 (2×),
128.65, 128.75, 139.26, 141.63, 146.46, 174.80. GC-MS (a): tR
12.71 min. Anal. Calcd for C25H27NO2 (373.50): C, 80.40;
H, 7.29; N, 3.75. Found: C, 79.99; H, 7.66; N, 3.65.
12:0:0. Rf ) 0.34 (1:4 EtOAc/petroleum ether). IR: ν 3320,
1740. [R]2D0: +6.4 (c 0.9, CHCl3). 1H NMR: δ 1.25 (d, J 6.5,
3H), 1.77 (br, 1H), 1.95 (m, 1H), 2.23 (m, 1H), 2.70 (m, 1H),
3.52 (q, J 6.3, 1H), 3.74 (s, 3H), 3.92 (d, J 9.6, 1H), 4.94 (m,
1H), 4.96 (m, 1H), 5.64 (m, 1H), 7.19-7.34 Hz (m, 10H). 13C
NMR: δ 22.40, 34.85, 51.90, 54.02, 54.97, 62.51, 117.17,
127.07, 127.35, 127.89, 127.98, 128.77, 129.11, 135.62, 141.97,
146.92, 175.31. GC-MS (a): tR
10.16/9.91 min. Anal. Calcd
for C21H25NO2 (323.44): C, 77.98; H, 7.79; N, 4.33; O, 9.89.
Found: C, 78.08; H, 7.71; N, 4.29; O, 9.77.
1-Meth yl 4-Eth yl (2R)-2-{(S)-P h en yl-[(R)-(1-ph en yleth yl)-
a m in o]m eth yl}bu ta n d ioa te (12). Yield: 0.36 g (49%). dr:
86:12:2:0. Rf ) 0.23 (1:5 EtOAc/petroleum ether). IR: ν 1740,
1680. [R]2D0: -2.2 (c 0.9, CHCl3). 1H NMR: δ 1.19 (t, J 7.0,
3H), 1.25 (d, J 6.5, 3H), 1.82 (br, 1H), 2.32 (dd, J 16.8, 4.4,
1H), 2.65 (dd, J 16.8, 10.4, 1H), 3.13 (ddd, J 10.4, 8.6, 4.4, 1H),
3.55 (q, J 6.5, 1H), 3.72 (s, 3H), 3.94 (d, J 8.6, 1H), 4.04 (q, J
7.0, 2H), 7.16-7.32 (m, 10H). 13C NMR: δ 14.12, 22.29, 34.00,
48.37, 51.75, 54.52, 60.62, 61.50, 126.53, 126.93, 127.41,
127.72, 128.36, 128.65, 140.68, 146.08, 171.88, 174.24. GC-
MS (a): tR 11.21 min. Anal. Calcd for C22H27NO4 (369.46):
C, 71.52; H, 7.37; N, 3.79. Found: C, 71.55; H, 7.24; N, 3.97.
Gen er a l P r oced u r e for â-La cta m F or m a tion . (a ) Sa -
p on ifica tion w ith Su bsequ en t Cycliza tion . A 21 mg
amount of lithium hydroxide monohydrate (0.5 mmol) was
added at 0 °C to a solution of the â-amino acid ester (0.1 mmol)
in 8.0 mL of MeOH/H2O (3:1, v/v). The mixture was stirred
at 5 °C for 20 h. The solvent was evaporated in vacuo, the
residue was dissolved in H2O, and the solution was acidified
to pH 2 with 1 M HCl. The solvent was evaporated in vacuo,
and the residue was redissolved in water and lyophilized. The
crude â-amino acid hydrochloride and 14 µL triethylamine (0.1
mmol) were dissolved in 15.0 mL of absolute acetonitrile. A
31.5 mg amount of triphenylphosphine (0.12 mmol) and 26.4
mg of 2,2′-dithiodipyridine (0.12 mmol) were added, and the
mixture was refluxed for 8 h. The solvent was evaporated in
vacuo, and the residue was purified by flash-chromatography
(eluent chloroform).
(b) Ester Cycliza tion . A 1 mL amount of a 1.0 M solution
of methylmagnesium bromide (1.0 mmol) in absolute ether was
added to a solution of the â-amino acid ester (1.0 mmol) in
absolute ether. The mixture was refluxed, and the reaction
progress was monitored by GC-MS. After addition of 50 mL
of aqueous NH4Cl, the organic layer was separated and the
aqueous layer was extracted with ether (2 × 50 mL). The
organic layers were pooled, dried over MgSO4, and evaporated
in vacuo. The products were obtained analytically pure after
flash chromatography.
(3R,4S)-3-Deu ter io-4-p h en yl-1-[(R)-1-p h en yleth yl]a ze-
tid in -2-on e (13). Yield (b): 0.20 g (81%). Rf ) 0.27 (CHCl3).
IR: ν 1740, 1670, 1630. [R]2D0 -15.8 (c 1.4, CHCl3). 1H
:
NMR: δ 1.30 (d, J 7.3, 3H), 2.81 (br d, J 2.5, 1H), 4.29 (d, J
2.5, 1H), 5.04 (q, J 7.3, 1H), 7.24-7.36 (m, 10H). 13C NMR:
δ 19.24, 46.50 (m), 52.73, 53.87, 127.21, 127.80, 128.20, 128.91,
129.10, 129.22, 140.26, 140.40, 167.89. GC-MS (a): tR 9.84
min. C17H16DNO (252.34).
(3R,4S)-3-Meth yl-4-p h en yl-1-[(R)-1-p h en yleth yl]a zeti-
d in -2-on e (14). Yield (b): 0.15 g (56%). Rf ) 0.23 (CHCl3),
0.52 (1:1 EtOAc/petroleum ether). [R]2D0: -2.1 (c 1.0, CHCl3).
IR: ν 1750. 1H NMR: δ 1.24 (d, J 7.3, 3H), 1.30 (d, J 7.3,
3H), 3.01 (dq, J 2.1, 7.3 Hz), 3.80 (d, J 2.1, 1H), 5.06 (q, J 7.3,
1H), 7.19-7.37 (m, 10H). 13C NMR: δ 13.10, 19.13, 52.26,
54.95, 62.69, 127.26, 127.74, 128.14, 128.81, 129.09, 129.16,
140.02, 140.55, 171.72. GC-MS (a): tR 9.75 min. C18H19NO
(265.36).
(3R,4S)-3-Ben zyl-4-p h en yl-1-[(R)-1-p h en yleth yl]a zeti-
d in -2-on e (15). Yield (b): 0.21 g (62%). Rf ) 0.46 (1:1 EtOAc/
petroleum ether). [R]D20: -14.5 (c 1.0, CHCl3). IR: ν 1750. 1H
NMR: δ 1.26 (d, J 7.2, 3H), 2.90-3.10 (m, 2H), 3.29 (m, 1H),
3.96 (d, J 2.2, 1H), 4.95 (q, 1H, J 7.2), 6.98-7.29 (m, 15H). 13
C
NMR: δ 19.26, 34.16, 52.39, 59.82, 60.44, 127.04, 127.29,
127.65, 128.01, 128.75, 129.01, 129.00, 129.12, 129.64, 138.19,
139.76, 140.25, 170.37. GC-MS (a): tR 12.96 min. C24H23NO
(341.45).
Meth yl (2R)-2-{(S)-P h en yl-[(R)-(1-p h en yleth yl)a m in o]-
m eth yl}p en t-4-en oa te (11). Yield: 0.33 g (51%). dr: 88:

â-Amino Acids and 3-Amino-Substituted Carbohydrates
J . Org. Chem., Vol. 63, No. 21, 1998 7271
Gen er a l P r oced u r e for th e Con ju ga te Ad d ition of 1
to γ-Alk oxy En oa tes 16. A 193 mg (1.0 mmol) amount of
N-[(R)-1-phenylethyl](trimethylsilyl)amine or 178 mg (1.0
mmol) of N-benzyl(trimethylsilyl)amine, respectively, in 25 mL
of ether was lithiated at -20 °C under an inert gas atmosphere
with 625 µL (1.0 mmol, 1.6 M in hexane) of n-BuLi. A 0.5
mmol amount of ester (108 mg of 16a , 139 mg of 16b, 114 mg
of 16c), dissolved in 2 mL of ether, was added slowly at low
temperature, and stirring was continued for a further 4-8 h.
Saturated NH4Cl was added, and the mixture was allowed to
reach rt and was then extracted with ethyl acetate (2 × 50
mL). The combined organic layers were washed with water,
saturated NaHCO3, and brine and then evaporated. The crude
product was purified by flash chromatography.
(ddd, J 7.4, 5.4, 4.2, 1H), 3.35 (s, 3H), 3.82 (m, 3H), 4.62 (d, J
11.0, 1H), 4.66 (d, J 11.0, 1H), 7.20-7.38 (m, 5H). 13C NMR:
δ 17.00, 28.50, 37.28, 52.02, 55.94, 59.20, 74.37, 80.82, 95.85,
127.36, 128.67, 128.82, 141.14, 172.67. GC-MS (b): tR 17.91
min. Anal. Calcd for C18H29NO4 (323.43): C, 66.84; H, 9.04;
N, 4.33. Found: C, 66.92; H, 8.64; N, 4.78.
Ad d ition of (S)-1a to (R)-16b. Yield: 54 mg (27%). dr:
99:1.
Major Isom er ter t-Bu tyl (3S,4S)-4-[(Meth oxy)m eth oxy]-
3-[(1′S)-(1′-p h en yleth yl)a m in o]-4-p h en ylbu ta n oa te (syn -
17b). Rf ) 0.09 (1:10 EtOAc/petroleum ether). [R]2D0: +46.0
(c 1.0, CHCl3). IR: ν 3341, 1726. 1H NMR: δ 1.24 (d, J 6.4,
3H), 1.39 (s, 9H), 1.74 (br s, 1H), 1.92 (dd, J 15.1, 7.2, 1H),
2.42 (dd, J 15.1, 5.8, 1H), 3.21 (ddd, J 7.2, 5.8, 4.5, 1H), 3.30
(s, 3H), 3.86 (q, J 6.4, 1H), 4.55 (s, 2H), 4.87 (d, J 4.5, 1H),
7.25-7.36 (m, 10H). 13C NMR: δ 24.67, 28.46, 38.59, 56.22,
56.33, 57.36, 76.47, 80.67, 95.08, 127.44, 127.97, 128.16,
128.17, 128.63, 128.79, 139.34, 146.20, 172.22. GC-MS (a): tR
11.51 min. Anal. Calcd for C24H33NO4 (399.53): C, 72.15; H,
8.33; N, 3.51. Found: C, 71.79; H, 8.02; N, 3.49.
ter t-Bu tyl 4-[(Meth oxy)m eth oxy]-4-ph en ylbu t-3-en oate
(20b). Rf ) 0.04 (1:10 EtOAc/petroleum ether). 1H NMR: δ
1.47 (s, 9H), 3.30 (d, J 7.2, 2H), 3.50 (s, 3H), 4.82 (s, 2H), 5.47
(t, J 7.2, 1H), 7.30-7.48 (m, 5H). GC-MS (a): tR 9.06 min.
Ad d ition of (R)-1a to (R)-16b. Yield: 78 mg (39%). dr:
88:12.
Ad d ition of (S)-1a to (S)-16a . Yield: 160 mg (95%). dr:
96:4.
Major Isom er ter t-Bu tyl (3R,4S)-4-[(m eth oxy)m eth oxy]-
3-[(1′S)-(1′-p h en yleth yl)a m in o]p en ta n oa te (a n ti-17a ). Rf
) 0.18 (1:5 EtOAc/petroleum ether). [R]D20
: -36.0 (c 1.0,
CHCl3). IR: ν 3336, 1725. 1H NMR: δ 1.12 (d, J 6.4, 3H),
1.32 (d, J 6.5, 3H), 1.45 (s, 9H), 1.66 (br s, 1H), 2.34 (ddABX, J
14.8, 6.4, 1H), 2.42 (ddABX, J 14.8, 5.7, 1H), 2.81 (ddd, J 6.4,
5.7, 4.3, 1H), 3.27 (s, 3H), 3.69 (dq, J 4.3, 6.4, 1H), 3.88 (q, J
6.5, 1H), 4.48 (dAB, J 16.4, 1H), 4.56 (dAB, J 16.4, 1H), 7.20-
7.32 (m, 5H). 13C NMR: δ 17.47, 25.00, 28.60, 36.54, 55.72,
55.86, 56.88, 75.17, 80.67, 95.80, 127.34, 127.38, 128.76,
146.48, 172.42. GC-MS (a): tR 9.64 min. Anal. Calcd for
Major Isom er ter t-Bu tyl (3S,4S)-4-[(Meth oxy)m eth oxy]-
3-[(1′R)-(1′-p h en yleth yl)a m in o]-4-p h en ylbu ta n oa te (syn -
18b). Rf ) 0.03 (1:10 EtOAc/petroleum ether). [R]2D0: +36.0
(c 1.0, CHCl3). IR: ν 3345, 1725. 1H NMR: δ 1.27 (d, J 6.6,
3H), 1.44 (s, 9H), 2.21 (dd, J 15.0, 5.4, 1H), 2.50 (dd, J 15.0,
7.0, 1H), 2.60 (br s, 1H), 3.07 (ddd, J 7.0, 5.4, 4.8, 1H), 3.35 (s,
3H), 3.83 (q, J 6.6, 1H), 4.53 (dAB, J 10.2, 1H), 4.56 (dAB, J
10.2, 1H), 4.71 (d, J 4.8, 1H), 7.05-7.35 (m, 10H). 13C NMR:
δ 25.17, 28.51, 37.75, 55.72, 56.38, 57.40, 79.37, 80.78, 95.21,
127.05, 127.20, 128.06, 128.13, 128.56, 128.76, 139.52, 145.89,
172.15. GC-MS (a): tR 11.41 min. C24H33NO4 (399.53).
ter t-Bu tyl (3R,4S)-4-[(Meth oxy)m eth oxy]-3-[(1′R)-(1′-
p h en yleth yl)a m in o]-4-p h en ylbu ta n oa te (a n ti-18b). Rf )
0.05 (1:10 EtOAc/petroleum ether). IR: ν 3345, 1725. 1H
NMR: δ 1.32 (d, J 6.4, 3H), 1.41 (s, 9H), 1.90 (br s, 1H), 2.17
(dd, J 15.0, 4.8, 1H), 2.32 (dd, J 15.0, 8.4, 1H), 3.02 (ddd, J
8.4, 4.8, 3.7, 1H), 3.45 (s, 3H), 4.07 (q, J 6.4, 1H), 4.61 (dAB, J
10.3, 1H), 4.64 (dAB, J 10.3, 1H), 4.97 (d, J 3.7, 1H), 7.05-7.38
(m, 10H). GC-MS (a): tR 11.47 min.
C
19H31NO4 (337.46): C, 67.62; H, 9.26; N, 4.15. Found: C,
67.22; H, 9.29; N, 4.40.
ter t-Bu t yl (3S,4S)-4-[(Met h oxy)m et h oxy]-3-[(1′S)-(1′-
p h en yleth yl)a m in o]p en ta n oa te (syn -17a ). Rf ) 0.11 (1:5
EtOAc/petroleum ether). 1H NMR: δ 1.18 (d, J 6.4, 3H), 1.32
(d, J 6.5, 3H), 1.42 (s, 9H), 2.18 (dd, J 14.9, J 8.0, 1H), 2.42
(dd, J 14.9, J 4.9, 1H), 2.59 (br s, 1H), 2.98 (ddd, J 8.0, 4.9,
3.8, 1H), 3.27 (s, 3H), 3.87 (q, J 6.5, 1H), 3.89 (m, 1H), 4.52 (d,
J 22.0, 1H), 4.55 (d, J 22.0, 1H), 7.20-7.35 (m, 5H). GC-MS
(a): tR 9.59 min.
Ad d ition of (R)-1a to (S)-16a . Yield: 125 mg (74%). dr:
86:14.
Major Isom er ter t-Bu tyl (3S,4S)-4-[(Meth oxy)m eth oxy]-
3-[(1′R)-(1′-p h en yleth yl)a m in o]p en ta n oa te (syn -18a ). Rf
) 0.09 (1:6 EtOAc/petroleum ether). [R]D20
: +47.4 (c 1.0,
CHCl3). IR: ν 3345, 1726. 1H NMR: δ 1.10 (d, J 6.2, 3H),
1.33 (d, J 6.6, 3H), 1.44 (s, 9H), 1.60 (br s, 1H), 2.34 (dd, J
14.7, J 6.3, 1H), 2.46 (dd, J 14.7, J 6.4, 1H), 2.80 (ddd, J 6.4,
6.3, 3.4, 1H), 3.33 (s, 3H), 3.60 (dq, J 3.4, 6.2, 1H), 3.88 (q, J
6.6, 1H), 4.55 (d, J 15.4, 1H), 4.59 (d, J 15.4, 1H), 7.15-7.30
(m, 5H). 13C NMR: δ 16.53, 25.40, 28.50, 37.30, 55.92, 56.10,
56.95, 75.14, 80.75, 95.90, 127.38, 127.43, 128.78, 146.41,
172.61. GC-MS: tR 9.64 min. Anal. Calcd for C19H31NO4
(337.46): C, 67.62; H, 9.26; N, 4.15. Found: C, 66.89; H, 8.92;
N, 4.37.
Ad d ition of (S)-1a to (S)-16c. Yield: 131 mg (75%). dr:
95:5.
Ma jor Isom er ter t-Bu tyl (3R)-3-[(4′S)-2′,2′-Dim eth yl-
1′,3′-d ioxola n -4′-yl-3-[(1′′S)-(1′′-p h en ylet h yl)a m in o]p r o-
p a n oa te (syn -17c). Rf ) 0.28 (1:4 EtOAc/petroleum ether).
[R]2D0: -32.0 (c 1.06, CHCl3). IR: ν 3343, 1726. 1H NMR: δ
1.31 (s, 3H), 1.35 (d, J 6.6, 3H), 1.37 (s, 3H), 1.45 (s, 9H), 2.15
(br s, 1H), 2.31 (dd, J 14.8, 5.1, 1H), 2.46 (dd, J 14.8, 6.2, 1H),
2.81 (ddd, J 6.2, 5.1, 5.1, 1H), 3.75 (dd, J 8.0, 7.0, 1H), 3.88
(dd, J 8.0, 6.6, 1H), 3.93 (q, J 6.6, 1H), 4.08 (ddd, J 7.0, 6.6,
5.1, 1H), 7.20-7.35 (m, 5H). 13C NMR: δ 25.60, 25.71, 26.85,
28.58, 37.52, 54.21, 55.61, 66.59, 78.19, 81.06, 109.52, 127.30,
127.40, 128.84, 146.03, 171.82. GC-MS (a): tR 9.95 min. Anal.
Calcd for C20H31NO4 (349.47): C, 68.73; H, 8.94; N, 4.00.
Found: C, 68.65; H, 9.20; N, 3.49.
ter t-Bu tyl (3S)-3-[(4′S)-2′,2′-Dim eth yl-1′,3′-d ioxola n -4′-
yl-3-[(1′′S)-(1′′-p h en yleth yl)a m in o]p r op a n oa te (a n ti-17c).
Rf ) 0.38 (1:4 EtOAc/petroleum ether). [R]2D0: -12.0 (c 1.0,
CHCl3). 1H NMR: δ 1.31 (d, 6.4, 3H), 1.33 (s, 3H), 1.42 (s,
3H), 1.43 (s, 9H), 1.72 (br s, 1H), 2.33-2.36 (m, 2H), 2.98 (m,
1H), 3.79 (dd, J 8.0, 5.9, 1H), 3.92 (q, J 6.4, 1H), 4.01 (dd, J
8.0, 6.4, 1H), 4.11 (m, 1H), 7.20-7.32 (m, 5H). 13C NMR: δ
24.86, 25.56, 27.02, 28.57, 37.66, 55.33, 55.60, 67.82, 77.33,
80.92, 109.55, 127.12, 127.43, 128.89, 146.57, 172.15. GC-MS
(a): tR 9.87 min.
ter t-Bu t yl (3S,4S)-4-[(Met h oxy)m et h oxy]-3-[(1′R)-(1′-
p h en yleth yl)a m in o]p en ta n oa te (a n ti-18a ). Rf ) 0.05 (1:6
EtOAc/petroleum ether). 1H NMR: δ 1.10 (d, J 6.4, 3H), 1.30
(d, J 6.4, 3H), 1.43 (s, 9H), 2.21 (dd, J 14.9, J 7.7, 1H), 2.31
(dd, J 14.9, J 5.5, 1H), 2.85 (ddd, J 7.7, 5.5, 2.9, 1H), 3.89 (dq,
J 6.4, 2.9, 1H), 3.97 (q, J 6.4, 1H), 4.64 (d, J 11.7, 1H), 4.67 (d,
J 11.7, 1H), 7.18-7.35 (m, 5H). GC-MS (a): tR 9.68 min.
Ad d ition of 1b to (S)-16a . Yield: 144 mg (89%). dr: 68:
32.
ter t-Bu tyl(4S)-3-(Ben zyla m in o)-4-[(m eth oxy)m eth oxy]-
p en ta n oa te (syn /a n ti-19a ). IR: ν 3337, 1726. Major isomer
(syn): Rf ) 0.06 (1:5 EtOAc/petroleum ether). [R]2D0: +8.0 (c
1.0, CHCl3). 1H NMR: δ 1.19 (d, J 6.6, 3H), 1.44 (s, 9H), 1.61
(br s, 1H), 2.34 (dd, J 15.2, 7.4, 1H), 2.49 (dd, J 15.2, 5.4, 1H),
3.09 (ddd, J 7.4, 5.4, 4.3, 1H), 3.35 (s, 3H), 3.76 (d, J 13.0,
1H), 3.82 (dq, J 6.6, 4.3, 1H), 3.86 (d, J 13.0, 1H), 4.62 (d, J
14.3, 1H), 4.66 (d, J 14.3, 1H), 7.21-7.37 (m, 5H). 13C NMR:
δ 16.20, 28.50, 37.38, 52.33, 55.94, 58.91, 74.62, 80.90, 95.85,
127.39, 128.67, 128.82, 141.14, 172.69. GC-MS (b): tR 17.87
min. Minor isomer (anti): Rf ) 0.05 (1:5 EtOAc/petroleum
ether). 1H NMR: δ 1.19 (d, J 6.4, 3H), 1.45 (s, 9H), 1.76 (br s,
1H), 2.36 (dd, J 15.1, 7.4, 1H), 2.45 (dd, J 15.1, 5.4, 1H), 3.05
Ad d ition of (R-1a ) to (S)-16c. Yield: 143 mg (82%). dr:
90:10.
Ma jor Isom er ter t-Bu tyl (3R)-3-[(4′S)-2′,2′-Dim eth yl-
1′,3′-d ioxola n -4′-yl-3-[(1′′R)-(1′′-p h en ylet h yl)a m in o]p r o-

7272 J . Org. Chem., Vol. 63, No. 21, 1998
Sewald et al.
p a n oa te (syn -18c). Rf ) 0.17 (1:5 EtOAc/petroleum ether).
[R]2D0: +24.0 (c 1.0, CHCl3). IR: ν 3336, 1725. 1H NMR (400
MHz): δ 1.33 (s, 3H), 1.35 (d, J 6.6, 3H), 1.41 (s, 3H), 1.44 (s,
9H), 1.72 (br s, 1H), 2.25 (dd, J 15.2, 6.8, 1H), 2.35 (dd, J 15.5,
5.6, 1H), 3.11 (ddd, J 6.8, 5.6, 5.1, 1H), 3.84 (dd, J 8.1, 7.1,
1H), 3.99 (q, J 6.6, 1H), 4.02 (dd, J 8.1, 6.5, 1H), 4.23 (ddd, J
6.6, 6.5, 5.1, 1H), 7.20-7.35 (m, 5H). 13C NMR: δ 24.67, 25.75,
26.93, 28.55, 38.22, 53.97, 55.99, 66.64, 78.35, 81.08, 109.62,
127.14, 127.34, 128.85, 146.55, 172.00. GC-MS (a): tR 9.97
min. Anal. Calcd for C20H31NO4 (349.47): C, 68.73; H, 8.94;
N, 4.00. Found: C, 68.37; H, 8.78; N, 4.50.
ter t-Bu tyl (3S)-3-[(4′S)-2′,2′-Dim eth yl-1′,3′-d ioxola n -4′-
yl-3-[(1′′R)-(1′′-p h en yleth yl)a m in o]p r op a n oa te (a n ti-18c).
Rf ) 0.09 (1:6 EtOAc/petroleum ether). 1H NMR (400 MHz):
δ 1.36 (s, 3H), 1.36 (d, J 6.7, 3H), 1.38 (s, 3H), 1.47 (s, 9H),
1.72 (br s, 1H), 2.32 (dd, J 14.7, J 4.9, 1H), 2.47 (dd, J 14.7, J
6.4, 1H), 2.82 (ddd, J 6.4, 5.3, 4.9, 1H), 3.76 (dd, J 8.1, J 6.9,
1H), 3.89 (dd, J 8.1, J 6.6, 1H), 3.93 (q, J 6.7, 1H), 4.09 (ddd,
J 6.7, 6.6, 5.3, 1H), 7.20-7.35 (m, 5H). GC-MS (a): tR 9.92
min.
Gen er a l P r oced u r e for th e Ta n d em Ad d ition /Deu ter a -
tion . A 193 mg (1.0 mmol) amount of N-[(R)-1-phenylethyl]-
(trimethylsilyl)amine in 25 mL of ether was lithiated at -20
°C under an inert gas atmosphere with 625 µL (1.0 mmol, 1.6
M in hexane) of n-BuLi. A 0.5 mmol amount of ester (108 mg
of 16a , 139 mg of 16b, 114 mg of 16c), dissolved in 2 mL of
ether, was added slowly at low temperature, and stirring was
continued for a further 4-8 h. A 100 µL (5.0 mmol) volume
of D2O was added at -78 °C and the mixture was allowed to
reach rt within 2 h. Saturated NH4Cl solution was added, and
the mixture was extracted with ethyl acetate (2 × 50 mL). The
combined organic layers were washed with water, saturated
NaHCO3, and brine and then evaporated. The crude product
was purified by flash chromatography.
Ta n d em Ad d ition of (S)-1a to (S)-16a /Deu ter a tion .
Yield: 150 mg (89%). dr: 96:4. Deuteration: >95%.
Major Isom er ter t-Bu tyl (2S,3R,4S)-2-Deu ter io-4-[(m eth -
o x y )m e t h o x y ]-3-[(1′S )-(1′-p h e n y le t h y l)a m i n o ]p e n -
ta n oa te (21a ). Rf ) 0.16 (1:4 EtOAc/petroleum ether).
[R]2D0: -28.6 (c 1.0, CHCl3). IR: ν 3333, 1722. 1H NMR: δ
1.12 (d, J 6.4, 3H), 1.31 (d, J 6.4, 3H), 1.45 (s, 9H), 1.60 (br s,
1H), 2.35 (br d, J 6.1, 1H), 2.80 (dd, J 6.1, 4.3, 1H), 3.27 (s,
3H), 3.69 (dq, J 4.3, 6.4, 1H), 3.88 (q, J 6.4, 1H), 4.50 (dAB, J
16.5, 1H), 4.54 (dAB, J 16.5, 1H), 7.20-7.35 (m, 5H). 13C
NMR: δ 17.46, 24.99, 28.60, 36.25 (t, J CD 19.1), 55.72, 55.87,
56.82, 75.15, 80.68, 95.80, 127.34, 127.37, 128.76, 146.47,
172.42. GC-MS (a): tR 9.64 min. Anal. Calcd for C19H30DNO4
(338.47): C, 67.42; H/D, 9.23; N, 4.14. Found: C, 67.41; H/D,
9.12; N, 4.23.
128.12, 128.60, 128.76, 139.36, 146.27, 172.16. GC-MS (a): tR
11.35 min. Anal. Calcd for C24H32DNO4 (400.54): C, 71.97;
H/D, 8.30; N, 3.50. Found: C, 71.58; H/D, 7.84; N, 3.90.
Ta n d em Ad d ition of (R)-1a to (S)-16b/Deu ter a tion .
Yield: 72 mg (36%). dr: 88:12. Deuteration: >80%.
Major Isom er ter t-Bu tyl (2R,3S,4S)-2-Deu ter io-4-[(m eth -
oxy)m eth oxy]-3-[(1′R)-(1′-p h en yleth yl)a m in o]-4-p h en yl-
bu ta n oa te (21d ). IR: ν 3346, 1725. 1H NMR: δ 1.27 (d, J
6.6, 3H), 1.43 (s, 9H), 2.21 (br d, J 5.4, 1H), 2.89 (br s, 1H),
3.06 (dd, J 5.4, 4.8, 1H), 3.35 (s, 3H), 3.83 (q, J 6.6, 1H), 4.52
(d, J 10.1, 1H), 4.57 (d, J 10.1, 1H), 4.71 (d, J 4.8, 1H), 7.05-
7.35 (m, 10H). GC-MS (a): tR 11.26 min. C24H32DNO4
(400.54).
Ta n d em Ad d ition of (S)-1a to (S)-16c/Deu ter a tion .
Yield: 131 mg (75%). dr: 95:5. Deuteration: >80%.
Ma jor Isom er ter t-Bu tyl (2S,3R)-2-Deu ter io-3-[(4′S)-2′,
2′-d im et h yl-1′,3′-d ioxola n -4′-yl-3-[(1′′S)-(1′′-p h en ylet h y-
l)a m in o]p r op a n oa te (21e). Rf ) 0.21 (1:5 EtOAc/ petroleum
ether). IR: ν 3342, 1725. 1H NMR: δ 1.31 (s, 3H), 1.35 (d, J
6.6, 3H), 1.36 (s, 3H), 1.45 (s, 9H), 1.79 (br s, 1H), 2.29 (br d,
J 5.0, 1H), 2.80 (dd, J 5.1, 5.0, 1H), 3.75 (dd, J 8.0, 7.0, 1H),
3.87 (dd, J 8.0, 6.6, 1H), 3.92 (q, J 6.6, 1H), 4.08 (ddd, J 7.0,
6.6, 5.1, 1H), 7.18-7.33 (m, 5H). 13C NMR: δ 25.62, 25.74,
26.87, 28.60, 37.52 (t), 54.19, 55.61, 66.61, 78.18, 81.06, 109.53,
127.32, 127.42, 128.86, 146.05, 171.84. GC-MS (a): tR 9.86
min. Anal. Calcd for C20H30DNO4 (350.48): C, 68.54; H/D,
8.92; N, 4.00. Found: C, 68.44; H/D, 8.77; N, 4.13.
Ta n d em Ad d ition of (R)-1a to (S)-16c/Deu ter a tion .
Yield: 140 mg (80%). dr: 90:10. Deuteration: >80%.
Ma jor Isom er ter t-Bu tyl (2S,3R)-2-Deu ter io-3-[(4′S)-
2′,2′-d im eth yl-1′,3′-d ioxola n -4′-yl-3-[(1′′R)-(1′′-p h en yleth y-
l)a m in o]p r op a n oa te (21f). Rf ) 0.09 (1:6 EtOAc/ petroleum
ether). IR: ν 3332, 1724. 1H NMR: δ 1.31 (d, J 6.6, 3H), 1.33
(s, 3H), 1.39 (s, 3H), 1.42 (s, 9H), 1.73 (br s, 1H), 2.29 (br d, J
6.6, 1H), 3.08 (dd, J 6.6, 5.1, 1H), 3.81 (dd, J 8.1, 7.3, 1H),
3.96 (q, J 6.6, 1H), 3.99 (dd, J 8.1, 6.6, 1H), 4.20 (ddd, J 7.3,
6.6, 5.1, 1H), 7.17-7.34 (m, 5H). 13C NMR: δ 24.56, 25.64,
26.83, 28.45, 37.83 (t), 53.86, 55.92, 66.59, 78.30, 81.08, 109.64,
127.17, 127.37, 128.88, 146.57, 172.11. GC-MS (a): tR 9.83
min. C20H30DNO4 (350.48).
Gen er a l P r oced u r e for Dep r otection /La cton iza tion of
17-19 a n d 21. A 0.5 mmol amount of the â-amino acid ester
17-19 and 21 was stirred in 10 mL of 6 N hydrochloric acid
(A) or 4.0 mL of trifluoroacetic acid (B) for 3 h at rt. The pH
was then adjusted to >8, and the mixture was extracted (3×)
with 30 mL of ethyl acetate. The combined organic layers were
washed with water and brine, dried over MgSO4, and evapo-
rated in vacuo. The products were obtained analytically pure
after flash chromatography.
(4R,5S)-5-Met h yl-4-[(1′S)-(1′-p h en ylet h yl)a m in o]t et -
r a h yd r ofu r a n -2-on e (22a ) (fr om a n ti-17a ). Yield: 74 mg
(67%). Rf ) 0.19 (1:2 EtOAc/petroleum ether). [R]2D0: -178.0
(c 1.0, CHCl3). IR (CHCl3): (3435, 1777. 1H NMR: δ 1.27 (d,
J 6.2, 3H), 1.36 (d, J 6.6, 3H), 1.78 (br s, 1H), 2.33 (dd, J 17.4,
7.3, 1H), 2.74 (dd, J 17.4, 7.3, 1H), 2.96 (ddd, J 7.3, 7.3, 6.6),
3.80 (q, J 6.6, 1H), 4.23 (dq, J 6.6, 6.2, 1H), 7.20-7.36 (m, 5H).
13C NMR: δ 19.44, 25.36, 36.78, 57.00, 59.12, 82.51, 126.98,
127.95, 129.21, 144.71, 175.68. GC-MS (a): tR 8.96 min. Anal.
Calcd for C13H17NO2 (219.28): C, 71.20; H, 7.81; N, 6.39.
Found: C, 70.70; H, 7.56; N, 6.26.
(4S,5S)-5-Meth yl-4-[(1′S)-(1′-ph en yleth yl)am in o]tetr ah y-
d r ofu r a n -2-on e (22b) (fr om syn -17a ). Rf ) 0.12 (1:2 EtOAc/
petroleum ether). 1H NMR (400 MHz): δ 1.28 (d, J 6.8, 3H),
1.33 (d, J 6.8, 3H), 1.47 (br s, 1H), 2.16 (dd, J 17.3, J 7.2, 1H),
2.37 (dd, J 17.3, 7.6, 1H), 3.41 (ddd, J 7.6, 7.2, 6.0), 3.68 (q, J
6.8, 1H), 4.60 (dq, J 6.0, 6.8, 1H), 7.20-7.30 (m, 5H). 13C
NMR: δ 14.99, 24.64, 35.93, 55.01, 57.35, 79.71, 126.96,
128.01, 129.26, 145.42, 175.81. GC-MS (a): tR 9.13 min.
Ta n d em Ad d ition of (R)-1a to (S)-16a /Deu ter a tion .
Yield: 130 mg (77%). dr: 86:14. Deuteration: >95%.
Major Isom er ter t-Bu tyl (2R,3S,4S)-2-Deu ter io-4-[(m eth -
o x y )m e t h o x y ]-3-[(1′R )-(1′-p h e n y le t h y l)a m i n o ]p e n -
ta n oa te (21b). Rf ) 0.17 (1:5 EtOAc/petroleum ether).
[R]2D0: +50.0 (c 1.0, CHCl3). IR: ν 3346, 1725. 1H NMR: δ
1.09 (d, J 6.2, 3H), 1.32 (d, J 6.6, 3H), 1.43 (s, 9H), 1.59 (br s,
1H), 2.34 (br d, J 6.0, 1H), 2.79 (dd, J 5.5, 3.5, 1H), 3.33 (s,
3H), 3.60 (dq, J 3.5, 6.2, 1H), 3.87 (q, J 6.6, 1H), 4.56 (dAB, J
15.4, 1H), 4.59 (dAB, J 15.4, 1H), 7.20-7.36 (m, 5H). 13C
NMR: δ 16.53, 25.39, 28.50, 37.20 (t), 55.93, 56.10, 56.90,
75.13, 80.77, 95.90, 127.40, 127.44, 128.78, 146.40, 172.62. GC-
MS (a): tR 9.55 min. Anal. Calcd for C19H30DNO4 (338.47):
C, 67.42; H/D, 9.23; N, 4.14. Found: C, 67.23; H/D, 9.10; N,
4.50.
Ta n d em Ad d ition of (S)-1a to (S)-16b/Deu ter a tion .
Yield: 50 mg (25%). dr: 99:1. Deuteration: >80%.
Major Isom er ter t-Bu tyl (2R,3S,4S)-2-Deu ter io-4-[(m eth -
oxy)m eth oxy]-3-[(1′S)-(1′-p h en yleth yl)a m in o]-4-p h en yl-
bu ta n oa te (21c). Rf ) 0.15 (1:10 EtOAc/petroleum ether).
IR: ν 3330, 1724. 1H NMR: δ 1.24 (d, J 6.5, 3H), 1.41 (s, 9H),
1.85 (br s, 1H), 1.91 (br d, J 7.3, 1H), 3.21 (dd, J 7.3, 4.4, 1H),
3.31 (s, 3H), 3.85 (q, J 6.5, 1H), 4.56 (s, 2H), 4.87 (d, J 4.4,
1H), 7.23-7.38 (m, 10H). 13C NMR: δ 24.81, 28.57, 38.46 (t),
56.26, 56.38, 57.39, 78.16, 80.66, 95.11, 127.36, 127.40, 127.94,
C
13H17NO2 (219.28).
(4S,5S)-5-Met h yl-4-[(1′R)-(1′-p h en ylet h yl)a m in o]t et -
r a h yd r ofu r a n -2-on e (22c) (fr om syn -18a ). Yield: 71 mg
(65%). Rf ) 0.13 (1:2 EtOAc/petroleum ether). [R]2D0: +102.0
(c 1.0, CHCl3). IR: ν 3324, 1776. 1H NMR (400 MHz): δ 1.36
(d, J 6.8, 3H), 1.37 (d, J 6.4, 3H), 1.54 (br s, 1H), 2.51 (dd, J

â-Amino Acids and 3-Amino-Substituted Carbohydrates
J . Org. Chem., Vol. 63, No. 21, 1998 7273
17.2, J 4.8, 1H), 2.59 (dd, J 17.2, 6.4, 1H), 3.26 (ddd, J 6.4,
6.0, 4.8), 3.77 (q, J 6.4, 1H), 4.50 (dq, J 6.0, 6.8, 1H), 7.20-
7.30 (m, 5H). 13C NMR: δ 15.06, 25.39, 36.09, 54.72, 56.29,
80.09, 127.07, 127.85, 129.15, 145.00, 176.29. GC-MS (a): tR
9.12 min. Anal. Calcd for C13H17NO2 (219.28): C, 71.20; H,
7.81; N, 6.39. Found: C, 70.79; H, 7.72; N, 6.90.
(4S,5S)-4-(Ben zyla m in o)-5-m et h ylt et r a h yd r ofu r a n -2-
on e (22d ) (fr om syn -19a ). Yield: 69 mg (67%). Rf ) 0.07
(1:2 EtOAc/petroleum ether). [R]2D0: +14.2 (c 0.52, CHCl3).
IR: ν 3333, 1776. 1H NMR (400 MHz): δ 1.40 (d, J 6.6, 3H),
1.50 (br s, 1H), 2.49 (dd, J 17.2, 5.5, 1H), 2.66 (dd, J 17.2, 7.0,
1H), 3.28 (ddd, J 7.8, 6.6, 5.8, 1H), 3.56 (dd, J 12.2, 4.2, 1H),
3.75 (dd, J 12.2, 3.5, 1H), 3.80 (q, J 6.6, 1H), 4.19 (ddd, 5.8,
4.2, 3.5), 7.20-7.35 (m, 5H). 13C NMR: δ 25.17, 36.99, 54.07,
56.96, 63.10, 86.02, 127.03, 128.09, 129.31, 144.54, 176.07. GC-
MS (a): tR 10.07 min. C13H17NO3 (235.28).
(3S,4R,5S)-3-Deu ter io-5-m eth yl-4-[(1′S)-(1′-p h en yleth y-
l)a m in o]tetr a h yd r ofu r a n -2-on e (23a ) (fr om 21a ). Yield:
88 mg (80%). Rf ) 0.16 (1:2 EtOAc/petroleum ether). [R]20
:
D
-132.6 (c 0.95, CHCl3). 1H NMR: δ 1.27 (d, J 6.4, 3H), 1.35
(d, J 6.6, 3H), 2.27 (br s, 1H), 2.71 (dt, J 7.2, J HD 2.4, 1H),
2.94 (dd, J 7.2, 6.0, 1H), 3.79 (q, J 6.6, 1H), 4.22 (dq, J 6.0,
6.4, 1H), 7.20-7.30 (m, 5H). 13C NMR: δ 19.35, 25.27, 36.35
(t, J CD 20), 56.91, 58.95, 82.53, 126.98, 127.98, 129.25, 144.76,
175.87. GC-MS (a): tR 8.94 min. Anal. Calcd for C13H16DNO2
(220.29): C, 70.88; H/D, 7.78; N, 6.36. Found: C, 71.00; H,
8.12; N, 5.90.
1H), 3.56 (ddd, J 7.0, 5.8, 5.5), 3.72 (dAB, J 13.2, 1H), 3.84 (dAB
,
J 13.2, 1H), 4.68 (dq, J 6.6, 5.8, 1H), 7.20-7.30 (m, 5H). 13C
NMR: δ 14.98, 36.03, 52.30, 56.60, 79.90, 127.90, 125.50,
129.09, 139.82, 175.93. GC-MS (a): tR 9.23 min. C12H15NO2
(205.26).
(4S,5S)-5-P h en yl-4-[(1′S)-(1′-ph en yleth yl)am in o]tetr ah y-
d r ofu r a n -2-on e (22e) (fr om syn -17b). Yield: 115 mg (82%).
Rf ) 0.10 (1:5 EtOAc/petroleum ether). [R]2D0: +12.5 (c 0.56,
CHCl3). IR: ν 3344, 1778. 1H NMR: δ 1.00 (d, J 6.6, 3H),
1.53 (br s, 1H), 2.31 (dd, J 17.3, 4.9, 1H), 2.62 (dd, J 17.3, 6.9,
1H), 3.27 (q, J 6.6, 1H), 3.67 (ddd, J 6.9, 5.5, 4.9, 1H), 5.56 (d,
J 5.5, 1H), 7.14-7.47 (m, 10 H). 13C NMR: δ 24.70, 37.44,
56.89, 56.89, 84.38, 126.77, 127.08, 127.78, 129.11, 129.25,
129.33, 135.32, 145.58, 176.42. GC-MS (a): tR 11.26 min.
(3R,4S,5S)-3-Deu ter io-5-m eth yl-4-[(1′R)-(1′-p h en yleth y-
l)a m in o]tetr a h yd r ofu r a n -2-on e (23b) (fr om 21b). Yield:
91 mg (83%). Rf ) 0.15 (1:2 EtOAc/petroleum ether). [R]20
:
D
+92.0 (c 1.0, CHCl3). IR: ν 3323, 1773. 1H NMR: δ 1.35 (d,
J 6.6, 3H), 1.36 (br s, 1H), 1.37 (d, J 6.6, 3H), 2.56 (dt, J 6.8,
J HD 2.4, 1H), 3.24 (dd, J 6.8, 5.8, 1H), 3.77 (q, J 6.6, 1H), 4.50
(dq, J 6.6, 5.8, 1H), 7.22-7.38 (m, 5H). 13C NMR: δ 14.96,
25.30, 35.74 (t, J CD 20), 54.59, 56.21, 80.08, 127.09, 127.89,
129.19, 145.00, 176.44. GC-MS (a): tR 9.00 min. Anal. Calcd
C
18H19NO2 (281.35).
for
C13H16DNO2 (220.29): C, 70.88; H/D, 7.78; N, 6.36.
(4S,5S)-5-P h en yl-4-[(1′R)-(1′-p h en ylet h yl)a m in o]t et -
Found: C, 70.51; H, 7.75; N, 6.41.
r a h yd r ofu r a n -2-on e (22f) (fr om syn -18b). Yield: 120 mg
(85%). Rf ) 0.07 (1:5 EtOAc/petroleum ether). [R]2D0: -42.1
(c 0.38, CHCl3). IR: ν 3328, 1778. 1H NMR: δ 1.16 (d, J 6.7,
Gen er a l P r oced u r e for th e DIBALH Red u ction of th e
La cton es 22 a n d 23. A 311 µL amount of diisobutylalumi-
num hydride (1.75 mmol) was added slowly to a solution of
the lactone 22 or 23 (0.5 mmol) in 20 mL of CH2Cl2 at -78 °C.
Stirring was continued at low temperature for a further 3 h.
After hydrolysis with 402 µL of trifluoroacetic acid (5.25 mmol),
the mixture was allowed to reach rt. A 1.5 mL volume of water
and 636 mg of NaHCO3 (6.0 mmol) were added, and the
organic layer was separated. A little water was added to the
aqueous residue, which was subsequently extracted twice with
25 mL of CH2Cl2. The organic layers were pooled, washed with
minute amounts of saturated NaHCO3 solution and brine,
dried over MgSO4, and evaporated. The crude products were
purified chromatographically.
(4R,5S)-2-Hyd r oxy-5-m et h yl-4-[(1′S)-(1′-p h en ylet h yl)-
a m in o]tetr a h yd r ofu r a n (24a ) (fr om 22a ). Yield: 95 mg
(86%). Anomer ratio R:â ≈ 2:1. Rf ) 0.17 (10:1 CHCl3/MeOH).
IR: ν 3400-3150. 1H NMR (400 MHz, DMSO-d6): major
anomer (R), δ 1.01 (d, J 6.2, 3H), 1.23 (d, J 6.6, 3H), 1.58 (ddd,
J 13.0, J 6.3, 3.1, 1H), 2.15 (ddd, J 13.0, J 7.7, 5.4, 1H), 2.36
(ddd, J 7.7, 6.3, 6.3, 1H), 3.75 (q, J 6.6, 1H), 3.79 (dq, J 6.3,
6.2, 1H), 5.20 (m, 1H), 6.00 (br d, J 4.0, 1H), 7.18-7.37 (m,
5H); minor anomer (â), δ 1.11 (d, J 6.2, 3H), 1.22 (d, J 6.5,
3H), 1.67 (dddd, J 12.2, J 9.0, 5.4, J 0.9, 1H), 1.92 (ddd, J 12.2,
J 6.8, 1.6, 1H), 2.67 (ddd, J 7.3, 6.8, 5.4, 1H), 3.54 (dq, J 7.3,
6.2, 1H), 3.73 (q, J 6.5, 1H), 5.22 (ddd, J 9.0, 5.0, 1.6, 1H),
5.90 (dd, J 5.0, J 0.9, 1H), 7.15-7.38 (m, 5H). 13C NMR
(DMSO-d6) major anomer (R), δ 19.21, 25.35, 40.20, 56.05,
61.67, 77.43, 97.03, 126.76, 126.85, 128.47, 146.19; minor
anomer (â), δ 21.00, 25.64, 40.96, 56.36, 60.59, 79.27, 97.16,
126.76, 126.85, 128.47, 146.48. GC-MS (a): tR 8.32 min.
3H), 1.40 (br s, 1H), 2.60 (ddABX, J 17.0, 3.9, 1H), 2.69 (ddABX
,
J 17.0, 5.0, 1H), 3.46 (ddd, J 5.2, 5.0, 3.9, 1H), 3.61 (q, J 6.7,
1H), 5.47 (d, J 5.2, 1H), 6.94-6.99 (m, 2H), 7.23-7.45 (m, 8H).
13C NMR: δ 24.84, 36.75, 55.02, 55.58, 84.04, 126.46, 126.76,
127.75, 129.11, 129.14, 129.20, 134.76, 144.82, 176.62. GC-
MS (a): tR 11.20 min. C18H19NO2 (281.35).
(4R,5S)-5-(H yd r oxym et h yl)-4-[(1′S)-(1′-p h en ylet h yl)-
a m in o]tetr a h yd r ofu r a n -2-on e (22g) (fr om syn -17c). Yield:
100 mg (85%). Rf ) 0.14 (25:1 CHCl3/MeOH). [R]2D0: -78.6 (c
1.85, CHCl3). IR (CHCl3): ν 3435, 1778. 1H NMR (400
MHz): δ 1.39 (d, J 6.5, 3H), 2.27 (br s, 1H), 2.57 (dd, J 17.3,
7.4, 1H), 2.69 (dd, J 17.3, 8.0, 1H), 3.51 (ddd, J 8.0, 7.4, 7.4,
1H), 3.80 (q, J 6.5, 1H), 3.93 (dd, J 12.5, 3.9, 1H), 4.00 (dd, J
12.5, 3.5, 1H), 4.37 (ddd, J 7.4, 3.9, 3.5, 1H), 7.20-7.35 (m,
5H). 13C NMR: δ 25.20, 36.25, 53.81, 57.17, 62.27, 81.61,
127.11, 128.19, 129.37, 144.33, 176.05. GC-MS (a): tR 9.98
min. Anal. Calcd for C13H17NO3 (235.28): C, 66.36; H, 7.28;
N, 5.95. Found: C, 66.46; H, 7.07; N, 5.84.
(4S,5S)-5-(H yd r oxym et h yl)-4-[(1′S)-(1′-p h en ylet h yl)-
a m in o]tetr a h yd r ofu r a n -2-on e (22h ) (fr om a n ti-17c). Rf
) 0.07 (25:1 CHCl3/MeOH). [R]20: -14.4 (c 1.25, CHCl3). IR
D
(CHCl3): ν 3430, 1778. 1H NMR (400 MHz): δ 1.38 (d, J 6.6,
3H), 1.94 (br s, 1H), 2.14 (dd, J 17.8, 6.0, 1H), 2.58 (dd, J 17.8,
8.0, 1H), 3.41 (ddd, J 8.0, 6.0, 4.9, 1H), 3.67 (dd, J 12.3, 4.1,
1H), 3.83 (q, J 6.6, 1H), 3.87 (dd, J 12.3, 3.5, 1H), 4.32 (ddd,
4.9, 4.1, 3.5), 7.20-7.35 (m, 5H). 13C NMR: δ 24.48, 37.60,
54.34, 57.16, 63.17, 85.94, 127.04, 128.07, 129.32, 145.16,
176.70. GC-MS (a): tR 10.01 min. C13H17NO3 (235.28).
(4R,5S)-5-(H yd r oxym et h yl)-4-[(1′R)-(1′-p h en ylet h yl)-
a m in o]tetr a h yd r ofu r a n -2-on e (22i) (fr om syn -18c). Yield:
64 mg (54%). Rf ) 0.20 (15:1 CHCl3/MeOH). [R]2D0: +13.3 (c
0.75, CHCl3). IR (CHCl3): ν 3430, 1778. 1H NMR (400
MHz): δ 1.40 (d, J 6.7, 3H), 2.33 (dd, J 17.5, 9.0, 1H), 2.42
(dd, J 17.5, 8.6, 1H), 2.89 (br s, 2H), 3.71 (ddd, J 9.0, 8.6, 7.3,
1H), 3.78 (q, J 6.7, 1H), 3.97 (dd, J 12.7, 3.9, 1H), 4.04 (dd, J
12.7, 3.1, 1H), 4.54 (ddd, J 7.3, 3.9, 3.1, 1H), 7.20-7.35 (m,
5H). 13C NMR: δ 24.39, 36.67, 54.57, 58.20, 62.34, 81.83,
126.87, 128.11, 129.32, 145.14, 176.26. GC-MS (a): tR 10.04
min. Anal. Calcd for C13H17NO3 (235.28): C, 66.36; H, 7.28;
N, 5.95. Found: C, 66.10; H, 7.37; N, 5.84.
C
13H19NO2 (221.30).
(4S,5S)-2-Hyd r oxy-5-m et h yl-4-[(1′R)-(1′-p h en ylet h yl)-
a m in o]tetr a h yd r ofu r a n (24b) (fr om 22c). Yield: 60 mg
(54%). Anomer ratio R:â ≈ 1:1. Rf ) 0.16 (20:1 CHCl3/MeOH).
1H NMR (DMSO-d6): anomeric mixture, R-anomer, δ 1.05 (d,
J 6.4, 3H), 1.21 (d, J 6.4, 3H), 1.65-1.97 (m, 3H), 2.90 (ddd, J
6.1, 6.0, 5.4, 1H), 3.77 (q, J 6.4, 1H), 3.95 (dq, J 6.1, 6.4, 1H),
5.29 (ddd, J 9.5, 5.0, 2.5, 1H), 5.82 (d, J 9.5, 1H), 7.14-7.35
(m, 5H); â-anomer, δ 1.16 (d, J 6.4, 3H), 1.21 (d, J 6.4, 3H),
1.65-1.97 (m, 3H), 2.68 (m, 1H), 3.71 (dq, J 5.4, 6.4, 1H), 3.76
(q, J 6.4, 1H), 5.17 (m, 1H), 6.10 (br d, J 7.3, 1H), 7.14-7.35
(m, 5H). 13C NMR (DMSO-d6) (anomeric mixture): δ ) 16.39,
17.57, 25.95, 26.04, 39.00, 40.50, 56.03, 56.26, 57.00, 57.23,
75.36, 77.53, 96.79, 97.87, 127.49, 127.56, 127.62, 129.18,
129.20, 146.97, 147.18. GC-MS (a): tR 8.36 min. C13H19NO2
(221.30).
(4S,5S)-5-(H yd r oxym et h yl)-4-[(1′R)-(1′-p h en ylet h yl)-
a m in o]tetr a h yd r ofu r a n -2-on e (22k ) (fr om a n ti-18c). Rf
) 0.10 (15:1 CHCl3/MeOH). 1H NMR: δ 1.36 (d, J 6.6, 3H),
2.12 (br s, 1H), 2.40 (dd, J 17.4, 6.6, 1H), 2.80 (dd, J 17.4, 7.8,

7274 J . Org. Chem., Vol. 63, No. 21, 1998
Sewald et al.
(3S,4R,5S)-3-Deu ter io-2-h yd r oxy-5-m eth yl-4-[(1′S)-(1′-
p h en yleth yl)a m in o]tetr a h yd r ofu r a n (25a ) (fr om 23a ).
Yield: 78 mg (70%). Anomer ratio R:â ≈ 2:1. Rf ) 0.11 (10:1
CHCl3/MeOH). IR: ν 3400-3250. 1H NMR (400 MHz, DMSO-
d6): major anomer (R), δ 1.01 (d, J 6.1, 3H), 1.23 (d, J 6.6,
3H), 2.13 (dd, J 7.7, 5.8, 1H), 2.35 (dd, J 7.7, 6.3, 1H), 3.75 (q,
J 6.6, 1H), 3.79 (dq, J 6.3, 6.1, 1H), 5.21 (br d, J 5.8, 1H), 6.00
(br s, 1H), 7.15-7.38 (m, 5H); minor anomer (â), δ 1.11 (d, J
6.2, 3H), 1.22 (d, J 6.5, 3H), 1.90 (dd, J 6.8, 1.5, 1H), 2.66 (dd,
J 7.3, 6.8, 1H), 3.53 (dq, J 7.3, 6.2, 1H), 3.73 (q, J 6.5, 1H),
5.22 (dd, J 4.9, 1.5, 1H), 5.89 (d, J 4.9, 1H), 7.15-7.38 (m, 5H).
13C NMR (DMSO-d6): major anomer (R), δ 19.20, 25.35, 56.04,
61.62, 77.41, 96.99, 126.76, 126.85, 128.47, 146.20 (the signal
of C3 is hidden below the solvent signal); minor anomer (â), δ
21.01, 25.65, 56.35, 60.53, 79.25, 97.12, 126.76, 126.85, 128.47,
146.52 (the signal of C3 is hidden below the solvent signal).
GC-MS (a): tR 8.33 min. Anal. Calcd for C13H18DNO2
(222.31): C, 70.24; H, 9.07; N, 6.30. Found: C, 70.29; H, 9.08;
N, 6.07.
Ack n ow led gm en t. Financial support from Deut-
sche Forschungsgemeinschaft, Bonn (Grants Se 609/2-
3, 2-4, 2-5), and Fonds der Chemischen Industrie,
Frankfurt, is gratefully acknowledged.
J O980656Z