Stereoselective synthesis of β-substituted α,β-diamino acids from β- hydroxy amino acids

Full text of DOI:10.1021/jo9904718

6106
J . Org. Chem. 1999, 64, 6106-6111
Several procedures have been described to prepare R,â-
Ster eoselective Syn th esis of â-Su bstitu ted
diamino acids.9-13 One common route for their prepara-
tion involves azide displacement under Mitsunobu14
conditions of the hydroxyl group of serine, followed by
r,â-Dia m in o Acid s fr om â-Hyd r oxy Am in o
Acid s
Yue Luo, Mark A. Blaskovich, and Gilles A. Lajoie*
(6) (a) Zhang, L. H.; Anzalone, L.; Ma, P.; Kauffman, G. S.; Storace,
L.; Ward, R. Tetrahedron Lett. 1996, 37, 4455. (b) Wityak, J .; Sielecki,
T. M.; Pinto, D. J .; Emmett, G.; Sze, J . Y.; Liu, J .; Tobin, A.; Wang, S.;
J iang, B.; Ma, P.; Mousa, S. A.; Wexler, R. R.; Olson, R. E. J . Med.
Chem. 1997, 40, 50.
The Guelph-Waterloo Center for Graduate Work in
Chemistry, Department of Chemistry, University of
Waterloo, Waterloo, Ontario, Canada N2L 3G1
(7) (a) Baldwin, J . E.; Spivey, A. C.; Schofield, C. J .; Sweeney, J . B.
Tetrahedron 1993, 49, 6309. (b) J ones, R. C. F.; Crockett, A. K.; Rees,
D. C.; Gilbert, I. H. Tetrahedron 1994, 5, 1661. (c) Burgaud, B. G. M.;
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(8) Hayashi, T. J pn. Kokai Tokkyo Koho J p 08, 245, 552 [96, 245,
552], Sept 24, 1996; Chem. Abstr. 1996, 126, 31651n.
Received March 16, 1999
In tr od u ction
R,â-Diamino acids have been found in natural products
as free amino acids,1 as structural components in peptides
and â-lactam antibiotics,2 and in other peptides such as
cyclotheonamide.3 R,â-Diamino acids are versatile syn-
thons and have been incorporated in several medicinally
relevant compounds such as protein-tyrosine kinase
inhibitors,4 quisqualic acid analogues,5 and glycoprotein
IIb/IIIa RGD receptor antagonists.6 Some unnatural
R-alkylated7 and racemic â-substituted8 R,â-diamino acids
have also been reported.
(9) R,â-Diamino acids have been synthesized from a Schmidt or
Hofmann rearrangement of aspartic acid9a-d or asparagine9e-i and
nucleophilic addition to aziridine-2-carboxylate.5c,7c,9j,9k â-Substituted
R,â-diamino acids have been synthesized from 3-amino-2-azetidinones
(γ-amino-â-lactam) formed via asymmetric cyclocondensation of R-azido
ketene and aldimine9l-n or via Mitsunobu cyclization of Boc-serine
amide N-oxide.9o,p Opening of the â-lactams by acid hydrolysis,9l-m,q,r
ammonium,9s and other R-amino acids9n,t can provide R,â-diamino acids
in free states and in forms incorporated into dipeptides. 3-Hydroxy-
â-lactam has also been used to prepare â-aminophenylalanine.9u
Alternatively, 3-hydroxy-â-lactam can be oxidized to an R-keto-â-lactam
and then converted to an R,â-diamino N-carboxyanhydride (NCA)9n,v
via a Bayer-Villiger oxidation and finally to R,â-diamino acids. Michael
addition of methylamine, dimethylamine, and benzylamine to 2,3-
dehydroamino acid (dehydroalanine) usually gave racemic R,â-diamino
acid derivatives.9w-y Chiral Ni(II) Schiff base complex of dehydroala-
nine can induce asymmetric Michael addition of primary and secondary
amines to give the substituted R,â-diamino acid derivatives in 90-
95% yield with 80-90 de.9z,10a Cbz- or Boc-protected serine has been
converted to â-lactones,10b,c which can react with amine and azide to
give R,â-diamino acid derivatives. (Hydroxymethyl)oxazolidinone has
been used to prepare (2R, 3S) diastereomers of â-aminophenylalanine
starting from 1-phenylallyl alcohol via Sharpless epoxidation.10d (a)
Rudinger, J .; Poduska, K.; Zaoral, M. Collect. Czech. Chem. Commun.
1960, 25, 2022. (b) Rao, L. N. Biochemistry 1975, 14, 5218. (c) Noguchi,
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Lett. 1990, 31, 4289. (n) Palomo, C.; Aizpurua, J . M.; Ganboa, I. Russ.
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(2) For example, R,â-diamino propanoic and butanoic acids are found
in peptide and â-lactam antibiotics, including tuberactinomycin,2a-f
bleomycin,2g-i capreomycin,2j nocardicin,2k-p monobactam,2q,r lavendo-
mycin,2s,t antrimycin,2u,v glumamycin,2w and aspartocin:2x (a) Yoshioka,
H.; Aoki, T.; Goko, H.; Nakatsu, K.; Noda, T.; Sakakibara, H.; Take,
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M.; Tetrahedron Lett. 1978, 2243. (o) Kamiya, T.; Hashimoto, M.;
Nakaguchi, O.; Oku, T. Tetrahedron 1979, 35, 323. (p) Isenring, H. P.;
Hofheinz, W.; Tetrahedron 1983, 39, 259. (q) Imada, A.; Kitano, K.;
Muroi, M.; Asai, M.; Nature (London) 1981, 289, 590. (r) Sykes, R. B.;
Cimarusti, C. M.; Bonner, D. P.; Bush, K.; Floyd, D. M.; Georgopa-
padakou, N. H.; Koster, W. H.; Liu, W. C.; Principe, W. L.; Rathnum,
M. L.; Slusarchyk, W. A.; Trejo, W. H.; Wells, J . J . Nature (London)
1981, 291, 498. (s) Komori, T.; Ezaki, M.; Kino, E.; Kohsala, M.; Aoki,
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N.; Ezaki, M.; Hashimoto, M. Chem. Pharm. Bull. 1985, 33, 3053. (u)
Shimada, N.; Morimoto, K.; Naganawa, H.; Takita, T.; Hamada, M.;
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1997, 46, 483. (b) Arnold, L. D.; Kalantar, T. H.; Vederas, J . C. J . Am.
Chem. Soc. 1985, 107, 7105. (c) Arnold, L. D.; May, R. G.; Vederas, J .
C. J . Am. Chem. Soc. 1988, 110, 2237. (d) Rossi, F. M.; Powers, E. T.;
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E.; Golding, B.; Sadeghi, M. Synthesis 1987, 190.
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37, 5225.
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(13) (a) Schmidt, U.; Mundinger, K.; Riedl, B.; Haas, G.; Lau, R.
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Lieberknecht, A. J . Chem. Soc., Chem. Commun. 1990, 18, 1216.
(14) Mitsunobu, O. Synthesis 1981, 1.
10.1021/jo9904718 CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/23/1999

Notes
J . Org. Chem., Vol. 64, No. 16, 1999 6107
reduction of the azide.12,13 For example, NR-Cbz-R,â-
diaminopropanoic acid and its methyl ester were pre-
pared in 35-41% yield from Cbz-serine.12,13 Boc-protected
serine methyl ester was reported to be converted to the
corresponding azide in 73% yield.12 On the other hand,
under similar Mitsunobu conditions, the Fmoc-threonine
methyl ester did not give any desired diamino acid but
only the elimination product. These results are not
surprising given the relative acidity of the R-proton of
serine/threonine methyl ester.15 The alkoxy phosphonium
intermediate in Mitsunobu reactions is a good leaving
group and â-elimination or intramolecular displacement
occurs easily to give dehydro amino acid derivatives,16
â-lactones,10b â-lactams,17 and oxazolines.18 Recently, it
was reported that the Mitsunobu reaction of Cbz- or Boc-
protected serine methyl ester with phthalimide or 4-nitro-
benzoic acid gave the substitution products in very low
yields (13% for phthalimide and 28% for 4-nitrobenzoic
acid) and that the â-elimination byproduct, dehydroala-
nine, was obtained in yields as high as 73%.19 However
with the bulky N-phenyfluorenyl (PhF) and N-trityl (Tr)
as N-protecting groups, the same reaction conditions gave
high yield of the substitution product (86-95%).19 These
bulky groups serve to protect the R-proton from base-
promoted racemization and elimination.19,20 However, the
analogous reaction with threonine was not described in
that paper.19 In an alternative approach, the carboxylic
acid of Fmoc-threonine was protected as N-Boc-hydrazide
and the substitution in Mitsunobu conditions with hy-
drogen azide gave the corresponding â-azide in 70-80%
yield.13
Sch em e 1
Ta ble 1. Mitsu n obu Rea ction s of P r otected â-Hyd r oxy
r-Am in o Acid Or th o Ester s 1
entry
P
R
X
yields for 2, % yields for 3, %
a
b
c
d
e
f
Cbz
Cbz
Cbz
Cbz
Fmoc
H
NPhth
81
0
13
22
0
0
0
Me NPhth
N3
Me N3
N3
We have previously reported that masking the L-serine
carboxylate as a cyclic ortho ester reduces the acidity of
the R-proton allowing a variety of transformations of the
side chain without racemization at the R-carbon.21 In this
paper we report Mitsunobu reaction of several â-hydroxy
R-amino acid ortho esters (OBO) 1 and the stereoselective
synthesis of â-substituted R,â-diamino acids.
H
96
81
72
55
59
H
Fmoc Me N3
Cbz Ph N3
0
g
14a
a
Yield is estimated from the amount of aziridine separated from
Ph3P/H2O reduction of the crude product of the azide 3g.
1
3b was the only product in a yield of 22%. The H NMR
Resu lts
spectra of the aziridines 3a ,b are similar to those found
in the literature,7a,19 and their identities were further
confirmed by HRMS. To our disappointment, the phthal-
imido group of 2a could not be readily removed to give
the primary amine 4a even after refluxing with hydra-
zine in THF over 2 days. The reaction of Cbz- and Fmoc-
protected L-serine and L-threonine ortho esters with
hydrogen azide in Mitsunobu conditions was then inves-
tigated. Excellent yields of the desired azides were
obtained (96% for 2c and 81% for 2d ) from the N-Cbz-
protected ortho esters 1a ,b, but lower yields were ob-
tained for the N-Fmoc-protected derivatives 2e,f (Scheme
1 and Table 1). With both N-Cbz and N-Fmoc protecting
groups, the yields for generating the azides from threo-
nine were lower than from the serine precursor. These
results are in agreement with the well-known suscepti-
bility of the Mitsunobu reaction to steric effects.14 No
â-elimination byproducts were detected by NMR and
ESMS, confirming our prediction that the OBO ester
protects the R-proton from racemization and â-elimina-
tion. We extended this concept to a more demanding
system such as in â-phenyl L-serine OBO ester 1e which
was prepared as a mixture (85:15) of (2S,3R)- and
(2S,3S)-diastereomers by PhMgBr addition to a serine
aldehyde equivalent.21b The reaction gave a crude azide
2g in a 80% yield along with some aziridine 3e (14%).
The Mitsunobu reaction of Cbz-serine ortho ester 1a
was first performed with phthalimide (Scheme 1), hoping
that the substitution product 2a could be deprotected to
provide the primary amine 4a . We found that the desired
substitution product was obtained in very good yield
(81%) without formation of the â-elimination byproduct
as shown by NMR and ESMS. However, we did observe
a small amount (13%) of the aziridine 3a . Control
experiments showed that the isolated aziridine 3a does
not yield the desired azide 2c in the presence of hydrogen
azide or when resubjected to the Mitsunobu reaction
conditions. Under the same conditions, Cbz-threonine
OBO ester 1b gave no substitution product. The aziridine
(15) (a) Barrett, G. C. Helv. Chim. Acta 1991, 74, 399. (b) Smith, G.
G.; Reddy, G. V. J . Org. Chem. 1989, 54, 4529.
(16) Wojciechowska, H.; Pawlowicz, R.; Andruszkiewicz, R.; Grzy-
bowska, J . Tetrahedron Lett. 1978, 4063.
(17) Miller, M. J . Acc. Chem. Res. 1986, 19, 49.
(18) (a) Galeotti, N.; Montagne, C.; Poncet, J .; J ouin, P. Tetrahedron
Lett. 1992, 2807. (b) Wipf, P.; Miller, C. P. Tetrahedron Lett. 1992,
6267.
(19) Cherney, R. J .; Wang, L. J . Org. Chem. 1996, 61, 2544.
(20) (a) Christie, B. D.; Rapoport, J . J . Org. Chem. 1985, 50, 1239.
(b) Guthrie, R. D.; Nicolas, E. C. J . Am. Chem. Soc. 1981, 103, 4637.
(21) (a) Blaskovich, M. A.; Lajoie, G. A. J . Am. Chem. Soc. 1993,
115, 5021. (b) Blaskovich, M. A.; Evindar, G.; Rose, N. G. W.; Wilkinson,
S.; Luo, Y.; Lajoie, G. J . Org. Chem. 1998, 63, 3631.

6108 J . Org. Chem., Vol. 64, No. 16, 1999
Notes
mediate.23a Reactions with LiAlH4 were normally carried
out at room temperature for 1-2 h. Prolonged reaction
time and higher temperatures resulted in low yields of
the amine 4 and a higher yield of the byproduct 5. In
contrast, the Ph3P/H2O method did not produce any
imidazolidinone 5 and generated the free amine in
excellent yield. This result can be explained by the
inability of the iminophosphorane intermediate12b to
cyclize to give the byproduct. The Ph3P/H2O reduction of
N-Cbz-â-phenyl azide 2g gave two separable (2S,3S)- and
(2S,3R)-diastereomers (79:21) in total yield of 78%. The
aziridine previously formed in the Mitsunobu reaction
was isolated, accounting for 16 wt % in the crude azide
product 2g. For the Cbz-protected azides, the Ph3P/H2O
reduction method can be combined with the Mitsunobu
reaction in a “one pot” procedure to directly provide free
amines.12b The “one pot” procedure produced slightly
lower yield than the two-step procedure (Table 2), but it
avoids tedious separation of hazardous azides.
Sch em e 2
Unfortunately, the Ph3P/H2O method fails to cleanly
reduce the Fmoc-protected azides 2e,f. A significant
amount of dibenzofulvene was isolated and characterized
by TLC and 1H NMR. This problem is associated with
the base lability of the Fmoc group, causing the loss of
Fmoc during the reaction and workup. However, hydro-
genation in methanol with Lindlar catalyst (5% Pd/
CaCO3) successfully generated the free amines 4c,d with
very small amounts of byproduct detected by TLC and
ESI-MS. The choice of solvent and catalyst is crucial since
10% Pd-C in MeOH or Lindlar catalyst in CH2Cl2 and
EtOAc is ineffective in reducing the azides. Attempts to
isolate the free amine OBO esters were again unsuccess-
ful due to deprotection of the Fmoc group during workup
and chromatography. To prevent the premature removal
of the Fmoc group, the amine was trapped as the HCl
salt 6 before workup, and the OBO ester group was
hydrolyzed directly in 6 N HCl to provide the NR-Fmoc-
R,â-diamino acids 7.
The enantiomeric purity of the azide 2c was deter-
mined by HPLC analysis using a â-cyclodextrin chiral
column and isocratic elution with 23% 2-propanol and
77% water. The identity and separation of chromato-
graphic peaks was confirmed by ESI-MS and by using
racemic azide 3c prepared from the D,L-serine ortho ester.
The D-enantiomer eluted first, at 16 min, and the
L-enantiomer at 18 min. The HPLC analysis confirms
that the Mitsunobu reaction does not cause racemization
at the R-carbon. For 2b, the stereochemistry at the â
position is deduced as the S configuration on the basis
of the fact that all Mitsunobu reactions give products
with complete inversion.13,14 This is also in agreement
with the characteristic J constants in the 1H NMR
spectra of the aziridines and imidazolidinones.
Ta ble 2. P r ep a r a tion of F r ee Am in e 4 by Red u ction of 2
or by On e-P ot P r oced u r e fr om 1
reducing agents
R1
P
yields, % (compd)
LiAlH4
LiAlH4
Ph3P/H2O
Ph3P/H2O
One-pot
H
Me
H
Me
H
Me
Ph
H
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Fmoc
Fmoc
71 (4a )a
62 (4b)b
89 (4a )c
82 (4b)d
75 (4a )e
57 (4b)e
78 (4e)e
100 (4c)f
98 (4d )f
One-pot
Ph3P/H2O
H2/5% Pd/CaCO3
5% Pd/CaCO3
Me
5a was obtained in 27% yield. 5b in 14%. c 85% calculated
a
b
over two steps from 1a . 66% over two steps from 1b. e Yield from
d
1. f Yields were estimated on the basis of isolated diols 6.
No elimination product was detected. Recrystallization
of the crude product from ether and hexane provides pure
azide 2g (59%). The aziridine 3e was inseparable from
the azide 2g by chromatography but was isolated later
after the reduction of the azide (vide infra), and its
identity was confirmed by NMR and HRMS.
Several methods used to reduce azides were investi-
gated. These include NaBH4,22 LiAlH4,23 Ph3P/H2O,24 and
catalytic hydrogenation methods.25 NaBH4 did not reduce
the azides, but LiAlH4 and Ph3P/H2O gave N-Cbz-
protected primary amines 4 in good to excellent yields
(62-89%) (Scheme 2 and Table 2). However, reduction
with LiAlH4 also gave imidazolidinones 5a ,b as a byprod-
uct. The imidazolidinones were presumably formed by
nucleophilic addition of the â-amine to the carbonyl of
Cbz group, possibly due to the increased nucleophilicity
of this â-amine in the amine-aluminum complex inter-
In the aziridine 3a , the J constants are 6.3 Hz for the
cis protons and 3.6 Hz for the trans protons, comparable
to values found in the literature.7a,19 Once again, the
coupling constant (6.7 Hz) between R- and â-protons
indicates the cis configuration in the aziridine 3b, which
corresponds to S configuration at the â-position. NOESY
spectra of the imidazolidinone 5b shows the absence of
any cross-peak between â-CH3 and R-H, again implying
the cis orientation and S configuration at the â-position.
The two diastereomers of 4e showed significant change
(1.1 ppm) in the chemical shifts of the carbamate protons.
As shown in Figure 1, the downfield shift in (2S,3R)-4e
can be explained by hydrogen-bonding effect of adjacent
(22) (a) Rolla, F. J . Org. Chem. 1982, 47, 4327. (b) Soai, K.;
Yokoyama, S.; Ookawa, A. Synthesis 1987, 48.
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Brimacombe, J .; Bryan, J .; Husain, A.; Stacey, M.; Tolley, M. Carbo-
hydr. Res. 1967, 3, 318. (c) Bose, A. K.; Kistner, J . F.; Farber, L. J .
Org. Chem. 1962, 27, 2925. (d) Hedayatullah, M.; Guy, A. Tetrahedron
Lett. 1975, 2455.
(24) (a) Vaultier, M.; Knouzi, N.; Carrie, R. Tetrahedron Lett. 1983,
24, 763. (b) Taylor, E. C.; Pont, J . L. Tetrahedron Lett. 1987, 28, 379.
(c) Knouzi, N.; Vaultier, M.; Toupet, L.; Carrie, R. Tetrahedron Lett.
1987, 28, 1757. (d) Boulaajaj, S.; Gall, T. L.; Vaultier, M.; Gree, R.;
Toupet, L.; Carrie, R. Tetrahedron Lett. 1987, 28, 1761. (e) Nagarajan,
S.; Ganem, B. J . Org. Chem. 1987, 52, 5044.
(25) (a) Saito, S.; Nakajima, H.; Inaba, M.; Moriwake, T. Tetrahedron
Lett. 1989, 30, 837. (b) Sakaitani, M.; Hori, K.; Ohfune, Y. Tetrahedron
Lett. 1988, 29, 2983. (c) Corey, E. J .; Nicolaou, K. C.; Balanson, R. D.;
Machida, Y. Synthesis 1975, 590.

Notes
J . Org. Chem., Vol. 64, No. 16, 1999 6109
provides protection from â-elimination side reactions as
observed in other reaction conditions. We are currently
investigating the construction of conformationally con-
strained cyclic peptides from the above R,â-diamino acid
derivatives.
Exp er im en ta l Section
Gen er a l Meth od s. All chemicals were purchased from Ald-
rich, Fluka, or Sigma and used directly. The HN3 benzene or
toluene solution was prepared according to a literature proce-
dure26 and titrated before use. CH2Cl2 was distilled from CaH2,
and THF from Na/benzophenone. Most reactions were carried
out under N2 in glassware dried overnight at 120 °C or flame-
dried before use. NMR spectra were recorded in CDCl3 or CD3OD
on at 250 MHz. IR spectra were recorded in the 4000-625 cm-1
range. HRMS (FAB) spectra were recorded in the FAB ionization
mode by the WATSPEC mass spectrometry service at the
University of Waterloo. ESMS spectra were recorded on a Fisons
Quattro II mass spectrometer. Optical rotations were measured
on a digital polarimeter using a cuvette of 1 cm in length.
Melting points were determined on a Mel-Temp apparatus in
an open capillary tube and are uncorrected. Elemental analyses
were performed by MHW laboratories in Phoenix, AZ. HPLC
analyses were performed using LiChroCART 250-4 ChiraDex
column, with a system controller and a multisolvent delivery
system, equipped with variable-wavelength UV/vis detector. TLC
was carried out on Merck aluminum-backed silica gel 60 F254,
with visualization by UV, 5% (NH4)6MoO24/0.2% Ce(SO4)2/5%
H2SO4, or ninhydrin solution (2% in EtOH). TLC solvent systems
commonly used are the following: A, 5:1 CH2Cl2/EtOAc; B, 10:1
CH2Cl2/EtOAc; C, 3:1 CH3OH/EtOAc; D, 10:1 CH3OH/EtOAc;
E, 1:2 EtOAc/Hexane.
F igu r e 1. Chemical shift of the carbamate proton for two
diastereomers of 4e.
Sch em e 3
Gen er a l P r oced u r e for Mit su n ob u R ea ct ion . 1-[(N-
Ben zyloxyca r bon yl)-(1S)-1-a m in o-2-a zid oeth yl]-4-m eth yl-
2,6,7-tr ioxa bicyclo[2.2.2]octa n e (2c). A mixture of Cbz-Ser-
OBO21b (2.0 g, 6.2 mmol) and Ph3P (2.4 g, 9.3 mmol) in dry THF
(60 mL) was cooled in an ice bath. A solution of DEAD (1.5 mL,
9.3 mmol) in THF (3 mL) was added dropwise via a cannula.
After mixing of the solution for 5 min, a HN3 benzene solution
(18 mmol) was slowly added via syringe. The mixture was
allowed to warm to room temperature and stirred for 8 h. The
solvent was removed under reduced pressure with NaOH
trapping the residual hydrogen azide. The oily residue was
purified by flash chromatography (5:1 CH2Cl2/EtOAc) to provide
the product 2c (2.1 g, 96%) as an oil which solidified up
â-amine nitrogen in the most stable rotamer I. This effect
is absent in (2S,3S)-4e. The bulky phenyl group enhances
the effect by limiting the population of other rotamers.
standing: mp 42-44 °C; [R]25 ) +14.50 (c ) 1.0, EtOAc); TLC
D
(solvent A) Rf ) 0.74; IR (Nujol mull) 3358, 3034, 2108 (N3), 1722,
1521 cm-1 1H NMR (CDCl3) δ 7.36-7.30 (m, 5H), 5.16-5.10
;
1
The H NMR of 4e indirectly confirms our assignment
(m, 3H), 4.08-4.00 (m, 1H), 3.90 (s, 6H), 3.43-3.36 (m, 2H), 0.79
(s, 3H); 13C NMR (CDCl3) δ 156.26, 136.08, 128.49, 128.13,
128.13, 107.35, 72.86, 67.06, 54.56, 50.93, 30.64, 14.26; HRMS
(calcd for C16H21N4O5) 349.15118, found 349.15350 ( 0.0066
(MH+). Anal. Calcd for C16H20N4O5: C, 55.17; H, 5.79; N, 16.08.
Found: C, 55.27; H, 5.85; N, 15.90.
of S configuration for the â-substituted products. The only
exception from the S configuration is the â-phenylaziri-
dine 3g, whose H NMR J constant (3.2 Hz) suggests a
trans stereochemistry. This may arise from an SN1
mechanism since the phenyl group facilitates the forma-
tion of a carbonium ion via an SN1 mechanism.
1
1-[(N-Ben zyloxyca r bon yl)-(1S)-1-a m in o-(2S)-2-a zid op r o-
p yl]-4-m eth yl-2,6,7-tr ioxa bicyclo[2.2.2]octa n e (2d ). As for
2c, Cbz-Thr-OBO (0.67 g, 2.0 mmol) reacted with Ph3P (0.79 g,
3.0 mmol), DEAD (0.47 g, 3.0 mmol), and HN3 benzene solution
(6.0 mmol) to provide the product 2d (0.58 g, 81%) as a thick oil
Na-Cbz-R,â-diamino acids were prepared by acid-base
hydrolysis from free amine 4 or by the Ph3P/H2O reduc-
tion of the azides (2c,d ) and subsequent hydrolysis
(Scheme 3). Na-Fmoc-R,â-diamino acids were obtained by
hydrogenation of the azide (2e,f), followed by hydrolysis
in 6 N HCl (Scheme 3). High overall yields of ap-
proximately 90% were obtained for the two-step depro-
tection.
In summary, we report a stereoselective method to
prepare enantiomerically pure R,â-diamino acids by azide
displacement in Mitsunobu conditions followed by reduc-
tion with triphenylphosphine/H2O for the Cbz-protected
derivatives or by reduction with Lindlar catalyst for the
Fmoc derivatives. For â-alkyl substituent, this reaction
sequence gives a diastereomerically pure product, while
with â-aryl substituent randomization of stereochemistry
at the â-carbon is observed. The cyclic ortho ester
which solidified on standing: mp 61-63 °C; [R]25 ) -13.4 (c
D
)1.0, EtOAc); TLC (solvent A) Rf ) 0.77; IR (Nujol mull) 3388,
2100 (N3), 1714, 1518 cm-1 1H NMR (CDCl3) δ 7.38-7.29 (m,
;
5H), 5.18-5.03 (m, 3H), 4.11 (dd, 1H, J ) 3.7, 10.2 Hz), 3.87 (s,
6H), 3.87-3.74 (m, 1H), 1.23 (d, 3H, J ) 6.8 Hz), 0.78 (s, 3H);
13C NMR (CDCl3) δ 156.39, 136.38, 128.47, 128.18, 107.57, 72.69,
67.12, 57.74, 56.38, 30.58, 14.38, 14.26; HRMS (calcd for
C17H23N4O5) 363.1668, found 363.1676 (MH+). Anal. Calcd for
C
17H22N4O5: C, 56.35; H, 6.12; N, 15.46. Found: C, 56.15; H,
6.09; N, 15.30.
1-[(N-Ben zyloxyca r bon yl)-(1S)-1-a m in o-2-p h th a lim id o-
eth yl]-4-m eth yl-2,6,7-tr ioxa bicyclo[2.2.2]octa n e (2a ). A mix-
(26) (a) Roger Adams, Ed. Organic Reactions; J ohn Wiley & Sons:
London, 1946; Vol. III, p 327. (b) Brauer, G. Handbook of Preparative
Inorganic Chemistry; Academic Press: New York, 1963; Vol. I, p 472.

6110 J . Org. Chem., Vol. 64, No. 16, 1999
Notes
ture of Cbz-Ser-OBO21b (0.16 g, 0.50 mmol) and Ph3P (0.20 g,
0.75 mmol) in dry THF (5 mL) was cooled in an ice bath. A
solution of DEAD (0.12 mL, 0.75 mmol) in THF (1 mL) was
added dropwise via cannula. After mixing of the solution for 5
min, a phthalimide solid (0.11 g, 0.75 mmol) was quickly added.
The mixture was allowed to warm to room temperature and
stirred for 6 h. The solvent was removed under reduced pressure.
The oily residue was purified by flash chromatography (10:1
CH2Cl2/EtOAc) to provide the product 2a (0.18 g, 81%) as a white
found 437.1825 (MH+). Anal. Calcd for C23H24N4O5: C, 63.29;
H, 5.54; N, 12.84. Found: C, 63.27; H, 5.64; N, 13.09.
1-[N-(9-F lu or en ylm eth yloxyca r bon yl)-(1S)-a m in o-(2S)-
2-azidopr opyl]-4-m eth yl-2,6,7-tr ioxabicyclo[2.2.2]octan e (2f).
As for 2c, Fmoc-L-Thr-OBO (0.43 g, 1.0 mmol), Ph3P (0.39 g,
1.5 mmol), DEAD (0.24 g, 1.5 mmol), and HN3 benzene solution
(3 mmol) gave the desired product 2f (0.25 g, 55%) as a white
solid: mp 57-60 °C; [R]25 ) -25.3 (c ) 1.0, EtOAc); TLC
D
(solvent A) Rf ) 0.82; IR (Nujol mull) 3362, 2099, 1726 cm-1; 1H
NMR (CDCl3) δ 7.78-7.28 (m, 8H), 5.10 (d, 1H, J ) 10.2 Hz),
4.47-4.25 (m, 3H), 4.16-4.11 (dd, 1H, J ) 10.2, 3.9 Hz), 3.92
(s, 6H), 3.84-3.77 (m, 1H), 1.29 (d, 3H, J ) 6.8 Hz), 0.82 (s,
3H); 13C NMR (CDCl3) δ 156.42, 143.90, 141.20, 127.55, 126.94,
125.11, 119.85, 107.52,72.63, 66.96, 57.70, 56.23, 47.11, 30.48,
14.39, 14.11; HRMS (calcd for C24H27N4O5) 451.1982, found
451.1942 (MH+). Anal. Calcd for C24H27N4O5: C, 63.99; H, 5.82;
N, 12.44. Found: C, 64.09; H, 5.84; N, 12.60.
solid: mp 64-68 °C; [R]25 ) -90.5 (c ) 1.0, EtOAc); TLC
D
(solvent B) Rf ) 0.43; IR (Nujol mull) 3442, 3361, 1773, 1718
cm-1; 1H NMR (CDCl3) δ 7.82-7.66 (m, 4H), 7.24-7.18 (m, 5H),
5.09 (d, 1H, J ) 10.2 Hz), 4.96-4.85 (d + d, 2H, J ) 12.6 Hz),
4.30 (td, 1H, J ) 3.8, 10.2 Hz), 3.99 (dd, 1H, J ) 3.9, 14.1 Hz),
3.92 (s, 6H), 3.83 (dd, 1H, J ) 10.2, 14.1 Hz), 0.82 (s, 3H); 13C
NMR (CDCl3) δ 168.19, 156.25, 136.43, 133.66, 128.19, 127.58,
123.13, 107.35, 72.69, 66.42, 53.59, 37.79, 30.51, 14.18; HRMS
(calcd for C24H25N2O7) 453.1662, found 453.1666 (MH+). Anal.
Calcd for C24H24N2O7: C, 63.71; H, 5.35; N, 6.19. Found: C,
63.80; H, 6.11; N, 5.98.
Gen er a l P r oced u r e for th e Red u ction of Azid e w ith
LiAlH 4. 1-[(N-Ben yloxyca r b on yl)-(1S)-1,2-d ia m in oet h yl]-
4-m eth yl-2,6,7-tr ioxa bicyclo[2.2.2]octa n e (4a ). A solution of
the azide 2c (0.35 g, 1 mmol) in 2 mL of THF was slowly added
into a suspension of LiAlH4 (0.076 g, 2.0 mmol) in freshly
distilled THF (5 mL) at room temperature. The mixture was
stirred for 30 min, treated with 1 N NaOH (20 mL), extracted
with CH2Cl2 (4 × 20 mL), and dried with MgSO4. The extract
was evaporated and purified by chromatography (3:1 CH3OH/
EtOAc) to give the amine 4a (0.23 g, 71%) as a white solid: mp
1
Da ta for 3a : TLC (solvent E) Rf ) 0.37; H NMR (CDCl3) δ
7.38-7.27 (m, 5H), 5.17 (d, 1H, J ) 12.2 Hz), 5.11(d, 1H, J )
12.2 Hz), 3.93 (s, 6H), 2.78 (dd, 1H, J ) 3.6, 6.3 Hz), 2.42 (dd,
1H, J ) 0.6, 3.6 Hz), 2.29 (dd, 1H, J ) 0.6, 6.2 Hz), 0.81 (s, 3H);
13C NMR (CDCl3) δ 162.40, 135.71, 128.43, 128.21, 105.67, 72.80,
68.30, 62.50, 38.76, 30.77, 14.10; HRMS (calcd for C16H20NO5)
306.1342, found 306.1334 (MH+).
87-90 °C; [R]25 ) -29.8 (c ) 1.0, EtOAc); TLC (solvent C) Rf
1
Da ta for 3b: TLC (solvent B) Rf ) 0.59; H NMR (CDCl3) δ
D
) 0.31; IR (Nujol mull) 3853, 3734, 3649, 1718 cm-1; H NMR
1
7.37-7.30 (m, 5H), 5.18 (d, 1H, J ) 12.4 Hz), 5.18 (d, 1H, J )
12.4 Hz), 3.95 (s, 6H), 2.72 (d, 1H, J ) 6.7 Hz), 2.58 (m, 1H),
1.42 (d, 3H, J ) 5.8 Hz), 0.83 (s, 3H); 13C NMR (CDCl3) δ 162.95,
135.80, 128.37, 128.08, 106.62, 72.55, 68.09, 43.02, 37.44, 30.66,
14.32, 12.92); HRMS (calcd for C17H22NO5) 320.1498, found
320.1487 (MH+).
(CDCl3) δ 7.35-7.32 (m, 5H), 5.19-5.11 (m, 3H), 3.88 (s, 6H),
3.82-3.70 (m, 1H), 2.92 (dd, 1H, J ) 5.0, 13.8 Hz), 2.76 (dd, 1H,
J ) 6.0, 13.8 Hz), 0.79 (s, 3H); 13C NMR (CDCl3) δ 156.61, 136.47,
128.40, 128.06, 108.14, 72.57, 66.79, 57.02, 41.95, 30.45, 14.29;
HRMS (calcd for C16H23N2O5) 323.1607, found 323.1621 (MH+).
Anal. Calcd for C16H22N2O5: C, 59.62; H, 6.88; N, 8.69. Found:
C, 59.85; H, 6.60; N, 8.64.
1-[(N-Ben zyloxyca r b on yl)-(1S)-1-a m in o-(2S)-2-a zid o-2-
ph en yleth yl]-4-m eth yl-2,6,7-tr ioxabicyclo[2.2.2]octan e (2g).
As for 2c, Cbz-â-Ph-Ser-OBO (0.40 g, 1.0 mmol), Ph3P (0.39 g,
1.5 mmol), DEAD (0.24 mL, 1.5 mmol), and HN3 benzene
solution (3.0 mmol) gave a crude product 2g (0.34 g, 80%) after
chromatography (10:1 CH2Cl2/EtOAc), which was contaminated
with a small amount of aziridine 3g. Recrystallization in Et2O/
Hexane gave 0.25 g (59%) of pure product 2g free of the
1
Da ta for 5a : TLC (solvent C) Rf ) 0.68; H NMR (CDCl3) δ
4.72 (bs, 1H), 4.69 (bs, 1H), 3.92 (s, 6H), 3.77 (dd, 1H, J ) 4.8,
9.7 Hz), 3.62-3.47 (m, 2H), 0.82 (s, 3H); 13C NMR (CDCl3) δ
163.30, 107.96, 72.82, 55.75, 41.04, 30.88, 14.30; HRMS (calcd
for C9H15N2O4) 215.1032, found 215.1033 (MH+).
1-[(N-Ben zyloxyca r bon yl)-(1S,2S)-1,2-d ia m in op r op yl]-4-
m eth yl-2,6,7-tr ioxa bicyclo[2.2.2]octa n e (4b). As for 4a , the
azide 2d (0.51 g, 1.4 mmol) was reduced with LiAlH4 (0.11 g,
2.0 mmol) suspension in THF (5 mL) to give the product 4b (0.29
g, 62%) as an oil which solidified on standing: mp 84-86 °C;
aziridine: mp 45-47 °C; [R]25 ) +0.2 (c ) 1.0, EtOAc); TLC
D
(solvent B) Rf ) 0.80; IR (Nujol mull) 3402, 3033, 2108 (N3), 1724
cm-1; 1H NMR (CDCl3) δ 7.29 (m, 10H), 5.35 (d, 0.2H, J ) 11.0
Hz, 2S,3R-CONH), 5.18-4.94 (m, 2H), 4.95 (d, 0.8H, J ) 5.3
Hz, 2S,3S-CONH), 4.78 (d, 0.8H, J ) 10.4 Hz, â-H of 2S,3S-
2g), 4.33 (dd, 0.8H, J ) 5.3 10.4 Hz, R-H of 2S,3S-2g), 4.18 (m,
0.2H, J ) 1.7, 11.0 Hz, R-H of 2S,3S-2g), 3.99 (s, 1.2H, ortho
CH2O of 2S,3R-2g), 3.86 (s, 4.8H, ortho CH2O of 2S,3S-2g), 0.84
(s, 0.6H, ortho CH3 of 2S,3R-2g), 0.80 (s, 2.4H, ortho CH3 of
2S,3S-2g); 13C NMR (CDCl3) δ 155.75, 137.65, 136.38, 136.25,
135.68, 128.12, 128.07, 127.85, 127.76, 127.67, 127.67, 107.48,
107.36, 72.67, 72.42, 66.48, 66.32, 64.54, 63.75, 58.50, 57.53,
30.42, 30.33, 13.90; HRMS (calcd for C22H25N4O5) 425.1825,
found 425.1825 (MH+). Anal. Calcd for C22H24N4O5: C, 62.25;
H, 5.70; N, 13.20. Found: C, 62.42; H, 5.86; N, 12.95.
[R]25 ) 38.4 (c ) 1.0, EtOAc); TLC (solvent C) Rf ) 0.21; IR
D
(Nujol mull) 3649, 3391, 1703, 1515 cm-1
;
1H NMR (CDCl3) δ
7.32-7.26 (m, 5H), 5.15-5.02 (m, 3H), 3.83 (s, 6H), 3.75 (dd,
1H, J ) 5.2, 10.1 Hz), 3.18 (m, 2H), 1.01 (d, 3H, J ) 6.6 Hz),
0.75 (s, 3H); 13C NMR (CDCl3) δ 157.03, 136.53, 128.46, 128.05,
108.29, 72.52, 66.88, 60.86, 47.04, 30.51, 18.75, 14.33; HRMS
(calcd for C17H25N2O5) 337.1764, found 337.1754 (MH+). Anal.
Calcd for C17H24N2O5: C, 60.70; H, 7.19; N, 8.33. Found: C,
60.67; H, 7.14; N, 8.32.
1
Da ta for 5b: TLC (solvent C) Rf ) 0.44; H NMR (CDCl3) δ
4.65 (bs, 1H), 4.61 (bs, 1H), 4.10-4.01 (m, 1H, J ) 6.8, 8.2 Hz),
3.90 (s, 6H), 3.63 (d, 1H, J ) 8.2 Hz), 1.36 (d, 3H, J ) 6.7 Hz),
0.82 (s, 3H); 13C NMR (CDCl3) δ 163.00, 107.93, 72.31, 58.74,
49.98, 30.70, 16.14, 14.38; HRMS (calcd for C10H17N2O4) 229.1188,
found 229.1189 (MH+).
Da ta for 3e: 1H NMR (CDCl3) δ 7.41-7.19 (m, 10H), 5.09-
4.98 (m, 2H), 3.83 (s, 6H), 3.72 (d, 1H, J ) 3.2 Hz), 3.11 (d, 0.8H,
J ) 3.2 Hz, 3R-H), 3.03 (d, 0.2H, J ) 6.6 Hz, 3S-H), 0.77 (s,
3H); 13C NMR (CDCl3) δ 156.39, 135.86, 134.50, 128.43, 128.28,
128.13, 127.92, 127.00, 105.87, 72.66, 67.87, 45.92, 41.74, 30.73,
14.27; HRMS (calcd for C22H24NO5) 382.1654, found 382.1668
(MH+).
Gen er a l P r oced u r e for t h e R ed u ct ion of Azid e w it h
P h 3P /H2O. 1-[(N-Ben zyloxyca r bon yl)-(1S)-1,2-d ia m in oeth -
yl]-4-m eth yl-2,6,7-tr ioxa bicyclo[2.2.2]octa n e (4a ). A mixture
of the azide 2c (0.70 g, 2.0 mmol) and Ph3P (0.63 g, 2.4 mmol)
in 20 mL of THF was stirred at room temperature for 24 h.
Water (8 mmol) was added and the mixture refluxed for 3 h.
The solvent was removed under reduced pressure, and the
residue was purified by chromatography (3:1 CH3OH:EtOAc) to
give the desired amine 4a (0.55 g, 86%).
1-[(N-Ben zyloxyca r bon yl)-(1S,2S)-1,2-d ia m in op r op yl]-4-
m eth yl-2,6,7-tr ioxa bicyclo[2.2.2]octa n e (4b). A mixture of
the azide 2d (0.10 g, 0.28 mmol) and Ph3P (0.087 g, 0.33 mmol)
in 5 mL of THF was stirred at room temperature for 24 h. Water
(15 µL, 0.83 mmol) was added and the mixture refluxed for 3 h.
The solvent was removed under reduced pressure, and the
1-[N-(9-F lu or en ylm eth yloxyca r bon yl)-(1S)-a m in o-2-a zi-
d oeth yl]-4-m eth yl-2,6,7-tr ioxa bicyclo[2.2.2]octa n e (2e). As
for 2c, Fmoc-L-Ser-OBO (0.10 g, 0.25 mmol), Ph3P (0.098 g, 0.38
mmol), DEAD (59 µL, 0.38 mmol), and HN3 benzene solution
(0.75 mmol) gave the desired product 2e (0.079 g, 72%) as a
white solid: mp 48-52 °C; [R]25 ) +2.2 (c ) 1.0, EtOAc); TLC
D
(solvent A) Rf ) 0.85; IR (Nujol mull) 3366, 2109, 1718 cm-1; 1H
NMR (CDCl3) δ 7.78-7.28 (m, 8H), 5.21 (d, 1H, J ) 9.8 Hz),
4.47-4.23 (m, 3H), 4.13-4.05 (m, 1H), 3.95 (s, 6H), 3.54-3.38
(m, 2H), 0.83 (s, 3H); 13C NMR (CDCl3) δ 156.32, 144.07, 141.43,
127.79, 127.18, 125.36, 120.08, 107.54, 73.02, 67.26, 54.73, 51.06,
47.33, 30.81, 14.40; HRMS (calcd for C23H25N4O5) 437.1825,

Notes
J . Org. Chem., Vol. 64, No. 16, 1999 6111
residue was purified by chromatography (3:1 CH3OH:EtOAc) to
give the desired amine 4b (0.082 g, 82%).
239.1032, found 239.1019 (M+ - Cl). Anal. Calcd for C11H15N2O4-
Cl: C, 48.10; H, 5.50; N, 10.20. Found: C, 48.43; H, 5.24; N,
10.08.
1-[(N-Ben zyloxyca r bon yl)-(1S)-1,2-d ia m in o-2-p h en yleth -
yl]-4-m eth yl-2,6,7-tr ioxa bicyclo[2.2.2]octa n e (4e). Similarly,
the azide 2g (0.10 g, 0.24 mmol) was treated with Ph3P (0.094
g, 0.36 mmol) for 24 h, followed by refluxing with H2O (18 µL,
1.0 mmol) and chromatographic purification (3:1 EtOAc/hexane
and then 10:1 MeOH/EtOAc) to isolate the major (2S,3S)-4e
(0.059 g, 62%) as a white solid and (2S,3R)-4e (0.016 g, 17%) as
an oil. Also isolated was the aziridine 3e (0.016 g, 16 wt %) as
an oil.
N-(Ben zyloxyca r bon yl)-2,3-d ia m in obu ta n oic Acid Hy-
d r och lor id e (7b). As for 7a , 4b (0.10 g, 0.30 mmol) was
hydrolyzed and the mixture was acidified with 1 N HCl,
evaporated to dryness, and extracted with acetone to give crude
product (0.11 g, 121%). The crude product was purified by anion
exchange chromatography to give the product 7b (0.078 g,
90%): 1H NMR (acetone-d6) δ 8.52 (bs, 1H), 7.40-7.23 (m, 5H),
5.19-5.11 (m, 2H), 4.93 (m, 1H), 4.11 (m, 1H), 1.47 (d, 3H); 13
C
Da ta for (2S,3S)-4e: mp 147-150 °C; TLC (solvent D) Rf )
NMR (acetone-d6) δ 171.68, 157.83, 137.63, 129.17, 128.72, 67.63,
56.46, 49.81, 18.04; HRMS (calcd for C12H17N2O4) 253.1188,
found 253.1188 (M+ - Cl).
0.14; IR (Nujol mull) 3368, 3243, 1717,1552 cm-1 1H NMR
;
(CDCl3) δ 7.30-7.18 (m, 10H), 5.05-4.89 (d + d, 2H), 4.82 (d,
1H, J ) 10.3 Hz), 4.28 (d, 1H, J ) 6.9 Hz), 4.17 (dd, 1H, J )
6.9, 10.3 Hz), 3.87 (s, 6H), 0.80 (s, 3H); 13C NMR (CDCl3) δ
156.21, 142.36, 136.66, 128.31, 127.85 127.70, 127.06, 108.54,
72.55, 66.48, 59.81, 56.39, 30.57, 14.31; HRMS (calcd for
C22H27N2O5) 399.1920, found 399.1916 (MH+). Anal. Calcd for
C22H26N2O5: C, 66.32; H, 6.58; N, 7.03. found: C, 66.22; H, 6.71;
N, 6.88.
P r ep a r a tion of 2,3-Dia m in o Acid s fr om â-Azid o r-Am in o
Acid Or th o Ester s 2c-g. N-(Ben zyloxyca r bon yl)-2,3-d i-
a m in op r op ion ic Acid Hyd r och lor id e (7a ). Cbz-Ser(N3)-OBO
(2c) (0.82 g, 2.4 mmol) reacted with Ph3P in THF (20 mL) at
room temperature for 24 h and then was treated with 1 N HCl
for 9 h. THF was evaporated in vacuo, and the aqueous solution
was extracted with EtOAc, evaporated, and dissolved in dioxane/
H2O (15 mL), followed by treatment with Na2CO3‚H2O (1.5 g,
12 mmol) for 18 h. The dioxane was removed and insoluble solid
filtered off. The filtrate was acidified with 2 N HCl, evaporated
in vacuo, and extracted with acetone to give the crude product
7a (0.66 g, 98%). Purification by anion exchange chromatography
as above rendered the desired product 7a (0.51 g, 78%).
N-(9-F lu or en ylm eth oxylca r bon yl)-r,â-d ia m in op r op ion -
ic Acid (7c). A mixture of the azide 2e (0.045 g, 0.10 mmol)
and Lindlar catalyst (0.050 g) was stirred under H2 for 1 h. The
catalyst was filtered off, and the filtrate was treated with 1 N
HCl (2 mL), evaporated, and extracted with CH2Cl2 to remove
impurities. The residue was then dissolved in H2O and lyo-
philized to give the diol 6c (0.048 g, 100%). The diol was heated
in 6 N HCl at 80 °C for 2 h. H2O and excess HCl was removed
in vacuo, and the residue was lyophilized to give crude product
7c (0.047 g, 130%). The crude product was recrystallized in water
to give pure 7c (0.028 g, 75%): mp 186-189 °C; 1H NMR
(DMSO-d6) δ 8.04 (bs, 3H), 7.93-7.30 (m, 8H), 7.78 (d, 1H, J )
8.5 Hz), 4.40-4.24 (m, 4H), 3.19 (m, 1H), 3.02 (m, 1H); 13C NMR
(DMSO-d6) δ 170.85, 156.22, 143.76, 140.77, 127.72, 127.15,
125.34, 120.17, 66.03, 51.81, 46.60; HRMS (calcd for C18H19N2O4)
327.1345, found 327.1341 (M+ - Cl). Anal. Calcd for C18H19N2O4-
Cl: C, 59.59; H, 5.28; N, 7.72. Found: C, 59.40; H, 5.31; N, 7.58.
N-(9-F lu or en ylm et h oxylca r b on yl)-r,â-d ia m in ob u t a n -
oic Acid (7d ). As for 7c, Fmoc azide 2f (0.052 g, 0.12 mmol)
gave the diol 6d (0.056, 98%), subsequently giving the crude
product 7d (0.055 g, 121%). Recrystallization in water gave the
desired product 7d (0.038 g, 84%): mp 193-196 °C; 1H NMR
(DMSO-d6) δ 8.25 (bs, 3H), 7.93-7.33 (m, 8H), 7.55 (d, 1H, J )
8.8 Hz), 4.34-4.23 (m, 3H), 4.14 (dd, 1H, J ) 6.3, 8.9 Hz), 3.47
(m, 1H, J ) 6.4 Hz), 1.12 (d, 3H, J ) 6.6 Hz); 13C NMR (DMSO-
d6) δ 170.78, 156.32, 143.73, 140.67, 127.62, 127.02, 125.26,
120.07, 66.70, 55.83, 47.78, 46.60, 14.97; HRMS (calcd for
C19H21N2O4) 341.1502, found 341.1511 (M+ - Cl).
Da ta for (2S,3R)-4e: TLC (solvent D) Rf ) 0.46; 1H NMR
(CDCl3) δ 7.67-7.21 (m, 10H), 5.93 (d, 1H, J ) 10.1 Hz), 5.05
(d, 1H, J ) 12.5 Hz), 4.91 (d, 1H, J ) 12.5 Hz), 4.63 (s, 1H),
3.95-3.87 (m, 7H), 0.82 (s, 3H); 13C NMR (CDCl3) δ 156.40,
142.89, 136.96, 128.22, 127.79, 127.20, 126.67, 108.80, 72.72,
66.34, 58.81, 53.16, 30.64, 14.39; HRMS (calcd for C22H27N2O5)
399.1920, found 399.1901 (MH+).
On e-P ot P r oced u r e for th e Syn th esis of th e F r ee Am in e
(4a ). A mixture of Cbz-Ser-OBO (0.32 g, 1.0 mmol) and Ph3P
(0.39 g, 1.5 mmol) was dissolved in THF (10 mL) and cooled in
an ice bath. A solution of DEAD in THF (2 mL) was slowly added
via cannula. After 5 min, a HN3 benzene solution (3.0 mmol)
was slowly added via syringe. The mixture was allowed to warm
to room temperature and stirred for 6 h, followed by addition of
Ph3P (0.78 g, 3.0 mmol) and stirring for 20 h. H2O was added to
the mixture, and it was refluxed for 3 h. The solvent was
removed under reduced pressure, and the residue was purified
by chromatography (3:1 CH3OH:EtOAc) to yield the amine 4a
(0.24 g, 75%).
P r ep a r a tion of 2,3-Dia m in o Acid s by Hyd r olysis of Cbz-
2,3-Dia m in o Acid Or th o Ester s 4. N-(Ben zyloxyca r bon yl)-
2,3-d ia m in op r op a n oic Acid Hyd r och lor id e (7a ). A solution
of Cbz-2,3-diaminopropanoic acid ortho ester (4a ) (0.10 g, 0.31
mmol) in 5 mL of CH2Cl2 was treated with TFA (36 µL, 0.47
mmol) and stirred for 0.5 h. The solvent was removed under
reduced pressure. The residue was dissolved in dioxane and H2O
(1:1) and treated with Na2CO3 (0.93 g, 0.93 mmol) for 24 h. The
organic solvent was removed, and the aqueous phase was
acidified with 2 N HCl (pH ) 3) and then basified with 0.5 N
NaOH (pH ) 10). The aqueous solution was loaded to an anion
exchange column (Bio-Rad AG1 × 4). The column was washed
with 0.1 N NaOH and H2O and eluted with 1 N HCl to give the
product 7a (0.078 g, 92%) as a white solid: mp 165-169 °C; 1H
NMR (CD3OD) δ 7.16-7.11 (m, 5H), 4.93 (s, 2H), 4.29 (m, 1H),
3.04 (m, 2H); 13C NMR (CD3OD) δ 171.78, 158.74, 137.73, 129.44,
128.92, 68.09, 52.97, 41.45; HRMS (calcd for
C
11H15N2O4)
J O9904718