An efficient asymmetric route to 2,3-diaminobutanoic acids

Full text of DOI:10.1021/jo9720391

J . Org. Chem. 1998, 63, 2045-2048
2045
An Efficien t Asym m etr ic Rou te to
2,3-Dia m in obu ta n oic Acid s
Hyunsoo Han,* J uyoung Yoon, and Kim D. J anda*
Department of Chemistry, The Scripps Research Institute
and The Skaggs Institute for Chemical Biology,
10550 N. Torrey Pines Road, La J olla, California 92037
Received November 5, 1997
Nonproteingenic amino acids have been uncovered in
a growing number of naturally occurring compounds.1
Consequently, interest in their application as building
blocks for peptidomimetics in medicinal chemistry efforts
has also increased due to their protease resistance and
potential conformational constraints.2 The R,â-diamino
acid family constitutes a key structural element found
in a variety of antibiotics,3 antifungal dipeptides,4 and
other biologically active compounds.5 In particular, R,â-
diaminobutanoic acids such as 1 (Figure 1) have attracted
numerous synthetic efforts, since they are the simplest
member of the R,â-diamino acid family yet form key
elements in both peptide antibiotics and toxins.6
Several methods for the synthesis of R,â-diaminobu-
tanoic acids have been reported. Noteworthy was a
method reported by Schmidt and co-workers7 in which
threonine or allo-threonine was exploited as starting
materials and Mitsunobu reaction conditions were used
for the installation of the second amino group. While this
tact is reliable, only the anti isomers 1b and 1d are ac-
cessible from threonine, whereas the syn isomers 1a and
1c must be obtained from allo-threonine. In related
studies, Shin6a,b described syntheses leading to all four
isomers of 1 using L- or D-threonine as starting materials
and double inversion chemistry to obtain the syn dia-
stereomers 1a and 1c. Utilizing a completely different
strategy, Davies and co-workers6c reported the synthesis
of epimers 1a and 1d based on the asymmetric addition
of a chiral lithium amide to tert-butyl crotonate, followed
by the introduction of the second amino group using trisyl
azide. Very recently, all four isomers of 1 were synthe-
sized on the basis of the nucleophilic addition of meth-
ylmagnesium bromide to differentially protected nitrones
that were derived from either L- or D-serine.8 Critical in
F igu r e 1. The four enantiomers of 2,3-diaminobutanoic acid.
this approach was the protecting group strategy used on
the starting nitrone, as this dictated the stereochemical
outcome of the reaction.
Except for the approach outlined by Davies (vide
supra), all syntheses of the R,â-diaminobutanoic acids
have required the use of optically active R-amino acids
as starting material. Furthermore, while Davies’s meth-
odology is apt to apply toward the synthesis of other R,â-
diamino acids, it requires stoichiometric quantities of
chiral reagents for two key steps, a Michael and an elec-
trophilic addition. Herein, we report an efficient stereo-
selective synthesis of R,â-diaminobutanoic acids that
eliminates the drawbacks found in the previous synthe-
ses. Our route utilizes the highly enantioselective Sharp-
less asymmetric aminohydroxylation (AA) reaction and
regioselective ring opening of an aziridine functionality.
Commercially available tert-butyl crotonate (2) was the
starting point of our synthesis (Scheme 1). Crotonate 2
was functionalized using (DHQD)2PHAL and the ben-
zylcarbamate-based Sharpless AA9 reaction gave 3 in
high regioselectivity and enantioselectivity. The ratio of
the regioisomer was about 9:1 based on 1H NMR spec-
trum of the crude product, and the initial ee of 90% could
be easily raised to >99% by a single recrystallization from
hexane/ethyl acetate. Ester 3 was converted to its
methanesulfonate 4, which was successfully transformed
to the anti-R-azido species with inversion of configuration
at C-2.6c Catalytic hydrogenation and subsequent acidic
hydrolysis of azide 5 gave enantiomerically pure diami-
nobutanoic acid 1b as its HCl salt {[R]20 -8.9 (c 1.0, 6
D
N HCl), lit.10 [R]20 -11.0 (c 1.0, 6 N HCl)}. For the
D
(1) (a) Amino acids, Peptides and Proteins; The Chemical Society:
Cambridge, 1968-1991; Vols. 1-22. (b) Hunt, S. Chemistry and
Biochemistry of the Amino Acids; Barrett, G. C., Ed.; Chapman and
Hall: London, 1985; p 55. (c) Wagner, I.; Musso, H. Angew. Chem.,
Int. Ed. Engl. 1983, 22, 816.
(2) (a) Gante J . Angew. Chem. Int. Ed. Engl. 1994, 33, 1699. (b)
Hirschman, R. Angew. Chem. Int. Ed. Engl. 1990, 29, 1278. (c)
Sherman, D. B.; Spatola, A. F. J . Am. Chem. Soc. 1990, 112, 433.
(3) Wang, M.; Gould, S. J . J . Org. Chem. 1993, 58, 5176.
(4) Rane, D. F.; Girijavallabhan, V. M.; Ganguly, A. K.; Pike, R. E.;
Saksena, A. K.; McPhail, A. T. Tetrahedron Lett. 1993, 34, 3201.
(5) (a) Dunn, P. J .; Haner, R.; Rapoport, H. J . Org. Chem. 1990, 55,
5017. (b) Palomo, C.; Aizpurua, J . M.; Galaza, R.; Mielgo, A. J . Chem.
Soc. Chem. Commun. 1996, 633.
synthesis of the syn isomer 1a , compound 4 was con-
verted to aziridine species 6 in 80% yield with potassium
tert-butoxide. For the ring opening of 6, solvent turned
out to be a critical factor. Initial attempts with TMS-
N3 and MeOH in DMF11 gave no product, even after a
prolonged reaction time (48 h), and reactions conducted
in either THF or benzene showed no measurable change.
However, use of MeOH as a solvent granted azide 7 as a
single diastereomer (NMR), this by regiospecific C-3 ring
(6) (a) Nakamura, Y.; Shin, C. Chem. Lett. 1992, 49. (b) Nakamura,
Y.; Hirai, M.; Tamotsu, K.; Yonezawa, Y.; Shin, C. Bull. Chem. Soc.
J pn. 1995, 68, 1369. (c) Burke, A. J .; Davies, S. G.; Hedgecock, C. J .
R. Synlett 1996, 621.
(7) (a) Schmidt, U.; Mundinger, K.; Mangold, R.; Lieberknecht, A.
J . Chem. Soc, Chem. Commun. 1996, 1216. (b) Schmidt, U.; Mundinger,
K.; Riedl, B.; Haas, G.; Lau, Palomo, C. Synthesis 1992, 1201.
(8) Merino, P.; Lanaspa, A.; Merchan, F. L.; Tejero, T. Tetrahedron
Lett. 1997, 38, 1813.
(9) (a) Gunther, S.; Sharpless, K. B. In Asymmetric Oxidation
Reactions: A Practical Approach: Katsuki, T., Ed.; Oxforn University
Press: London, 1998; in press. (b) Li, G.; Angert, H. H.; Sharpless, K.
B. Angew. Chem., Int. Ed. Engl. 1996, 35, 2813.
(10) Atherton, E.; Meienhofer, J . J . Antibiot. 1972, 25, 539. Hoppe-
Seyler’s Z. Physiol. Chem. 1973, 354, 689.
(11) (a) Legters, J .; Willems, J . G. H.; Thijs, L.; Zwanenburg, B. Recl.
Trav. Chim. Pays-Bas 1992, 111, 59. (b) Tanner, D. Angew. Chem.,
Int. Ed. Engl. 1994, 33, 599.
S0022-3263(97)02039-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 02/20/1998

2046 J . Org. Chem., Vol. 63, No. 6, 1998
Notes
Sch em e 1a
F igu r e 2. 1H NMR (250 MHz) in D2O of the 3-H syn isomer
1a and the anti isomer 1b.
metric amounts of chiral reagents. Furthermore, our
synthetic strategy can be applied to the synthesis of other
R,â-diamino acids by simply varying the starting olefin.
Extension of this technology to the preparation of other
molecules of interest is currently under investigation.
Exp er im en ta l Section
a
(i) (DHQD)2PHAL, 5%; K2OsO2(OH)4, 4%; Cbz-NHCl, 3 equiv;
Gen er a l Meth od s. NMR spectra were recorded in CDCl3
or D2O at either 250 or 400 MHz. Flash chromatography were
carried out with Mallinckrodt silica gel 60 (230-400 mesh).
Analytical TLC was performed on Merck glass plates coated with
0.25 mm silica. Chloroform and methylene chloride were
distilled from calcium hydride, and THF was distilled from
sodium. Methanol was distilled from magnesium before its use.
(2S,3R)-ter t-Bu tyl 2-Hyd r oxy-3-(N-ben zyloxyca r bon yl)-
a m in obu ta n oa te (3). A solution of sodium hydroxide (2.44 g,
61 mmol) in water (150 mL) was prepared in a single-necked
round-bottom flask (500 mL) equipped with a magnetic stir bar.
Approximately 10 mL of this solution was transferred into a
flask (25 mL) with a Pasteur pipet, and potassium osmate
dihydrate (294 mg, 0.8 mmol) was solubilized by gentle swirling.
Benzyl carbamate (9.38 g, 62 mmol) was added in 80 mL of
acetonitrile and was stirred vigorously until 90% of the carbam-
ate was in solution (20 min). The reaction flask was immersed
in a room-temperature water bath and tert-butyl hypochlorite
(6.92 mL, 61 mmol) was added dropwise with stirring over a
period of 20 min. In a single-necked, round-bottom flask (250
mL), hydroquinidine 1,4-phthalazinediyl diether (DHQD)2PHAL
(780 mg, 1 mmol) and tert-butyl crotonate (3.20 mL, 20 mmol)
were added to acetonitrile (70 mL) with stirring. This solution
was transferred to the reaction mixture with a Pasteur pipet.
The pink K2[OsO2(OH)4] solution was added to the reaction flask
and stirred at room temperature. After 1 h, to the reaction
mixture was added sodium sulfite (20 g, 160 mmol) and this
reaction mixture was stirred for 45 min. The organic layer was
separated and the aqueous layer was extracted with ethyl
acetate (4 × 100 mL). The combined organic layers were
extracted with water and brine, dried over MgSO4, and concen-
trated to dryness to afford the crude product contaminated by
some excess benzyl carbamate. The ratio of the regioisomer was
CH3CN/H2O, 0 °C. (ii) MsCl/(Et)3N, CH2Cl2. (iii) t-BuO-K+, THF.
(iv) (Me)3SiN3, MeOH. (v) NaN3, DMF. (vi) H2, 10% Pd/C, MeOH.
(vii) CF3COOH/CH2Cl2 and then 1 N HCl.
opening of aziridine 6. Catalytic hydrogenation and
subsequent acidic hydrolysis of azide 7 generated syn
isomer 1a in an overall yield of 33% {[R]20 -34.3 (c 1.0,
D
6 N HCl), lit.10 [R]20 -38.1 (c 1.0, 6 N HCl)}.
D
The NMR spectra of the syn isomer 1a and the anti
isomer 1b showed a distinct difference in coupling
constants and splitting patterns (Figure 2). The coupling
constant between H-2 and H-3 for the syn isomer 1a
was 3.5 Hz and that for the anti isomer 1b was 7.0 Hz.
The H-3 proton of the syn isomer 1a shows a simple
multiplet pattern, whereas the H-3 proton of the anti
isomer 1b shows a quartet-doublet pattern (J ) 6.8 and
3.5 Hz). The coupling constants and splitting patterns
observed are consistent with those reported by Davies
et al.6c
The chemistry described (vide supra) can be extended
in a succinct manner to the remaining two enantiomers,
1c and 1d (Figure 1). Thus use of (DHQ)2PHAL for the
aminohydroxylation reaction of tert-butyl crotonate gave
the 2S,3R enantiomer of amino alcohol 3 (89% ee, 63%
yield). Subsequent application of the strategy described
in Scheme 1 to this isomer produced enantiomers 1c in
32% yield {[R]20D +9.1 (c 1.0, 6 N HCl), lit.10 [R]20D +10.3
(c 1.0, 6 N HCl)} and 1d in 40% yield {[R]20 +33.4 (c
D
1.0, 6 N HCl), lit.10 [R]20 +39.3 (c 1.0, 6 N HCl)}.
1
about 9:1 based on the H NMR spectrum of the crude product.
D
Purification by flash chromatography (hexane/ethyl acetate 2/1,
v/v) provided 3.85 g of desired product (62% yield, 90% ee). The
enatiomeric excess was also determined to be 90% as judged by
1H NMR using Mosher’s ester. The initial 90% ee was raised to
>99% after single crystallization from hexane/ethyl acetate: mp
82-85 °C; 1H NMR (CDCl3, 400 MHz) δ 1.24 (d, J ) 6.9 Hz,
3H), 1.43 (s, 9H), 3.09 (d, J ) 3.9 Hz, 1H), 3.97 (m, 1H), 4.23
In conclusion, we have shown an efficient stereoselec-
tive synthesis of the four isomers of 2,3-diaminobutanoic
acid from a readily available starting material, tert-butyl
crotonate. Our strategy eliminates the drawbacks found
in previous syntheses, which included a need for optically
active R-amino acids as starting materials or stoichio-

Notes
J . Org. Chem., Vol. 63, No. 6, 1998 2047
(m, 1H), 4.93 (d, J ) 9.9 Hz, 1H), 5.03 (d, J ) 4.2 Hz, 2H), 7.33
(m, 5H); HRMS [FAB, (M + 1)+] calcd for 310.1654, found
310.1664.
(c 1.0, 6 N HCl); 1H NMR (D2O, 250 MHz) δ 1.35 (d, J ) 6.8 Hz,
1H), 3.89 (qd, J 2 ) 6.8 Hz, J ) 3.5 Hz, 1H), 4.28 (d, J ) 3.5 Hz,
1H).
(2R,3R)-1b‚2HCl. To a stirred solution of 5 (1.0 g, 3.0 mmol)
in 30 mL of methanol in a 100 mL round-bottom flask charged
with an atmospheric H2 balloon was added 10 mol % Pd-carbon.
The Pd-carbon was removed by filtration and the product was
concentrated under reduced pressure. The product was dis-
solved in a 25 mL of trifluoroacetic acid/methylene chloride
mixture (1/1). The reaction mixture was stirred at room
temperature for 1 h and the product was concentrated under
reduced pressure. Approximately 10 mL of 1 N HCl was added
to the isolated material and the solvent was removed under
reduced pressure after stirring for 1 h. Pure (2R,3R)-1b‚2HCl
(92% yield, 329 mg) was obtained. The optical rotation observed
and the 1H NMR data obtained were consistent with the
literature values:6c [R]20D -8.9 (c 1.0, 6 N HCl), lit.10 [R]20D -11.0
(c 1.0, 6 N HCl); 1H NMR (D2O, 250 MHz) δ 1.43 (d, J ) 6.9 Hz,
1H), 3.93 (m, 1H) 4.16 (d, J ) 7.0 Hz, 1H); HRMS [FAB, (M +
1)+] calcd for 119.0821, found 119.0824.
(1S,2R)-2-(N-Ben zyloxyca r b on yl)a m in o-1-(ter t-b u t oxy-
ca r bon yl)p r op yl-1-m eth a n esu lfon a te (4). To a stirred solu-
tion of methanesulfonyl chloride (471 µL, 6.7 mmol) in methylene
chloride (25 mL) at 0 °C was added 3 (2.0 g, 6.4 mmol) and
triethylamine (849 µL, 6.7 mmol) in methylene chloride (25 mL)
dropwise. After the addition was complete, the ice bath was
removed and the reaction mixture was warmed to room tem-
perature. Upon stirring for 1 h at room temperature the solution
was concentrated under reduced pressure and purified by flash
chromatography (hexane/ethyl acetate 3/1, v/v) to give a sticky
oil. Recrystallization from hexane/ethyl acetate gave methane-
sulfonate 4 (2.24 g, 90% yield) as a white solid: mp 95-98 °C;
1H NMR (CDCl3, 400 MHz) δ 1.28 (d, J ) 6.9 Hz, 3H), 1.43 (s,
9H), 3.16 (s, 3H), 4.51 (m, 1H), 4.88 (d, J ) 2.4 Hz, 1H), 5.02 (d,
J ) 9.9 Hz, 1H), 5.12 (d, J ) 4.2 Hz 2H), 7.34 (m, 5H); HRMS
[FAB, (M + 1)+] calcd for 388.1430, found 388.1444.
(2R,3R)-ter t-Bu tyl 2-Azid o-3-(N-ben zyloxyca r bon yl)a m i-
n obu ta n oa te (5). To a stirred solution of 4 (1.5 g, 3.9 mmol)
in DMF (25 mL) was added sodium azide (275 mg, 4.2 mmol).
The mixture was heated to 70 °C for 12 h until 4 was consumed.
The reaction mixture was poured into 50 mL of water and
extracted with ethyl acetate (4 × 50 mL). The combined organic
layers were extracted with brine, dried over MgSO4, and
concentrated to dryness to afford the crude product. Purification
by flash chromatography (hexane/ethyl acetate 3/1, v/v) provided
1.07 g of (2S,3R)-5 (82% yield) as colorless oil: 1H NMR (CDCl3,
250 MHz) δ 1.10 (d, J ) 6.7 Hz, 3H), 1.48 (s, 9H), 4.17 (d, J )
3.5 Hz, 1H), 4.25 (m, 1H), 5.00 (d, J ) 8.3 Hz, 1H), 5.09 (s, 2H),
7.33 (m, 5H); HRMS [FAB, (M + 1)+] calcd for 335.1719, found
335.1725.
(2R,3S)-ter t-Bu tyl 2-Hyd r oxy-3-(N-ben zyloxyca r bon yl)-
a m in obu ta n oa te. Benzyl carbamate (9.38 g, 62 mmol) was
dissolved in 80 mL of n-propyl alcohol in a single-necked round-
bottomed flask (500 mL) equipped with a magnetic stir bar. To
this stirred solution was added a freshly prepared solution of
NaOH [NaOH (2.44 g, 61 mmol) in 150 mL of water], followed
by tert-butyl hypochlorite (6.92 mL, 61 mmol). Next, a solution
of the ligand (DHQ)2PHAL (780 mg, 1 mmol) in 70 mL of
n-propyl alcohol was added. The reaction mixture was homo-
geneous at this point. The vial was then immersed in a room-
temperature water bath and stirred for 3 min, and the olefin
(tert-butyl crotonate, 3.20 mL, 20 mmol) was added, followed by
the osmium catalyst (K2OsO2(OH)4, 294 mg, 0.8 mmol). The
reaction mixture was stirred for 40 min, and the light green color
gave way to light yellow. After TLC analysis confirmed the
absence of starting material, 140 mL of ethyl acetate was added,
and the phases were separated. The lower, aqueous phase was
extracted with water and brine, dried over MgSO4, and concen-
trated to dryness to afford the crude product contaminated by
some excess benzyl carbamate. The ratio of the regioisomer was
(2R,3R)-N-Ben zyloxyca r bon yl-2-(ter t-bu toxyca r bon yl)-
3-m eth yla zir id in e (6). To a stirred solution of 4 (2.0 g, 5.2
mmol) in dry THF (30 mL) was added potassium tert-butoxide
(602 mg, 5.4 mmol) also in THF (30 mL) dropwise under argon.
After the mixture stirred for 1 h at room temperature, 50 mL of
water was added to the reaction mixture, followed by 100 mL of
ethyl acetate, and the organic layer was separated. The aqueous
layer was extracted with ethyl acetate (2 × 50 mL), and the
combined organic extracts were washed with brine, dried over
MgSO4, and concentrated under reduced pressure. Pure aziri-
dine 6 (1.22 g, 80% yield) as a white solid was isolated by flash
chromotography (hexane/ethyl acetate 3/1, v/v): mp 110-113;
1H NMR (CDCl3, 250 MHz) δ 1.32 (d, J ) 5.6 Hz, 3H), 1.46 (s,
9H), 2.74 (m, 1H), 3.06 (d, J ) 6.7 Hz, 1H), 5.09 (d, J ) 12.2 Hz,
1H), 5.14 (d, J ) 12.2 Hz, 1H), 7.33 (m, 5H); HRMS [FAB, (M +
1)+] calcd for 292.1549, found 292.1555.
1
about 8:1 based on the H NMR spectrum of the crude product.
Purification by flash chromatography (hexane/ethyl acetate 2/1,
v/v) provided 3.91 g of desired product (63% yield, 89% ee). The
enatiomeric excess was also determined to be 89% as judged by
1H NMR using Mosher’s ester. The initial 89% ee was raised to
>99% after single crystallization from hexane/ethyl acetate: mp
83-86 °C; 1H NMR (CDCl3, 400 MHz) δ 1.23 (d, J ) 6.9 Hz,
3H), 1.42 (s, 9H), 3.19 (d, J ) 3.9 Hz, 1H), 3.98 (m, 1H), 4.25
(m, 1H), 5.04 (s, 2H), 7.33 (m, 5H); HRMS [FAB, (M + 1)+] calcd
for 310.1654, found 310.1663.
(1R,2S)-2-(N-Ben zyloxyca r b on yl)a m in o-1-(ter t-b u t oxy-
ca r bon yl)p r op yl-1-m eth a n esu lfon a te. To a stirred solution
of methanesulfonyl chloride (471 µL, 6.7 mmol) in methylene
chloride (25 mL) at 0 °C were added (2R,3S)-tert-butyl 2-hydroxy-
3-(N-benzyloxycarbonyl)aminobutanoate (2.0 g, 6.4 mmol) and
triethylamine (849 µL, 6.7 mmol) in methylene chloride (25 mL)
dropwise. After the addition was complete, the ice bath was
removed and the reaction mixture was warmed to room tem-
perature. Upon stirring for 1 h at room temperature, the
solution was concentrated under reduced pressure and purified
by flash chromatography (hexane/ethyl acetate 3/1, v/v) to give
a sticky oil. Recrystallization from hexane/ethyl acetate gave
the desired product (2.18 g, 88% yield) as a white solid: mp 93-
96 °C; 1H NMR (CDCl3, 400 MHz) δ 1.30 (d, J ) 6.9 Hz, 3H),
1.44 (s, 9H), 3.18 (s, 3H), 4.52 (m, 1H), 4.90 (d, J ) 2.4 Hz, 1H),
4.97 (d, J ) 9.9 Hz, 1H), 5.08 (s, 2H), 7.34 (m, 5H); HRMS [FAB,
(M + 1)+] calcd for 388.1430, found 388.1440.
(2S,3S)-ter t-Bu tyl 2-Azid o-3-(N-ben zyloxyca r bon yl)a m i-
n obu ta n oa te. To a stirred solution of (2R,3S)-N-benzyloxy-
carbonyl-2-carbo-tert-butoxy-3-methanesulfonate (1.5 g, 3.9 mmol)
in DMF (25 mL) was added sodium azide (275 mg, 4.2 mmol).
The mixture was heated to 70 °C for 12 h until the starting
material was consumed. The reaction mixture was poured into
50 mL of water and extracted with ethyl acetate (4 × 50 mL).
The combined organic layers were extracted with brine, dried
over MgSO4, and concentrated to dryness to afford the crude
product. Purification by flash chromatography (hexane/ethyl
(2R,3S)-ter t-Bu tyl 2-(N-Ben zyloxyca r bon yl)a m in o-3-a zi-
d obu ta n oa te (7). Trimethylsilyl azide (1.2 mL) was added
quickly to a stirred solution of 6 (1.0 g, 3.4 mmol) in dry methanol
(1.2 mL) in a 4 mL vial at 0 °C. The vial was closed tightly
with a Teflon disk lid and the reaction mixture was heated at
70 °C for 5 h. After removal of solvent under reduced pressure,
the pure product (0.9 g, 79% yield) was obtained as a colorless
oil by flash chromotography (hexane/ethyl acetate 3/1, v/v): 1H
NMR (CDCl3, 250 MHz) δ 1.33 (d, J ) 6.7 Hz, 3H), 1.46 (s, 9H),
4.10 (qd, J 2 ) 6.6 Hz, J ) 2.6 Hz, 1H), 4.29 (dd, J 2 ) 9.2 Hz, J
) 2.7 Hz, 1H), 5.11 (s, 2H), 5.35 (d, J ) 9.1 Hz, 1H), 7.33 (m,
5H); HRMS [FAB, (M + 1)+] calcd for 335.1719, found 335.1731.
(2R,3S)-1a ‚2HCl. To a stirred solution of 7 (0.9 g, 2.7 mmol)
in 30 mL of methanol in a 100 mL round-bottom flask charged
with an atmospheric H2 balloon was added 10 mol % Pd-carbon.
The Pd-carbon was removed by filtration and the product was
concentrated under reduced pressure. The product was dis-
solved in a 25 mL of trifluoroacetic acid/methylene chloride
mixture (1/1). The reaction mixture was stirred at room
temperature for 1 h and the product was concentrated under
reduced pressure. Approximately 10 mL of 1 N HCl was added
to the isolated material and the solvent was removed under
reduced pressure after stirring for 1 h. Pure (2R,3S)-1a ‚2HCl
(93% yield, 0.3 g) was obtained. The optical rotation observed
and the 1H NMR data obtained were consistent with the
literature values:6c [R]20D -34.3 (c 1.0, 6 N HCl), lit.10 [R]20D -38.1

2048 J . Org. Chem., Vol. 63, No. 6, 1998
Notes
acetate 3/1, v/v) provided 1.06 g of desired product (81% yield)
as colorless oil: 1H NMR (CDCl3, 250 MHz) δ 1.10 (d, J ) 6.7
Hz, 3H), 1.48 (s, 9H), 4.17 (d, J ) 3.5 Hz, 1H), 4.25 (m, 1H),
5.00 (d, J ) 8.3 Hz, 1H), 5.09 (s, 2H), 7.33 (m, 5H); HRMS [FAB,
(M + 1)+] calcd for 335.1719, found 335.1727.
reduced pressure. Approximately 8 mL of 1 N HCl was added
to the isolated material and the solvent was removed under
reduced pressure after stirring for 1 h. Pure (2S,3R)-1c‚2HCl
(92% yield, 263 mg) was obtained. The optical rotation observed
and the 1H NMR data obtained were consistent with the
literature values:6c [R]20D +33.4 (c 1.0, 6 N HCl), lit.10 [R]20D +39.3
(c 1.0, 6 N HCl); 1H NMR (D2O, 250 MHz) δ 1.36 (d, J ) 6.8 Hz,
1H), 3.90 (qd, J 2 ) 6.8 Hz, J ) 3.5 Hz, 1H), 4.27 (d, J ) 3.5 Hz,
1H); HRMS [FAB, (M + 1)+] calcd for 119.0821, found 119.0827.
(2S,3S)-1d ‚2HCl. To a stirred solution of (2S,3S)-tert-butyl
2-azido-3-(N-benzyloxycarbonyl)aminobutanoate (1 g, 3.0 mmol)
in 30 mL of methanol in a 100 mL round-bottom flask charged
with an atmospheric H2 balloon was added 10 mol % Pd-carbon.
The Pd-carbon was removed by filtration and the product was
concentrated under reduced pressure. The product was dis-
solved in a 25 mL of trifluoroacetic acid/methylene chloride
mixture (1/1). The reaction mixture was stirred at room
temperature for 1 h and the product was concentrated under
reduced pressure. Approximately 10 mL of 1 N HCl was added
to the isolated material and the solvent was removed under
reduced pressure after stirring for 1 h. Pure (2S,3S)-1d ‚2HCl
(90% yield, 321 mg) was obtained. The optical rotation observed
and the 1H NMR data obtained were consistent with the
literature values:6c [R]20D +9.1 (c 1.0, 6 N HCl), lit.10 [R]20D +10.3
(c 1.0, 6 N HCl); 1H NMR (D2O, 250 MHz) δ 1.43 (d, J ) 6.9 Hz,
1H), 3.92 (m, 1H) 4.02 (d, J ) 7.0 Hz, 1H); HRMS [FAB, (M +
1)+] calcd for 119.0821, found 119.0831.
(2S,3S)-N-Ben zyloxyca r bon yl-2-(ter t-bu toxyca r bon yl)-3-
m eth yla zir id in e. To a stirred solution of (2R,3S)-N-benzy-
loxycarbonyl-2-carbo-tert-butoxy-3-methanesulfonate (2.0 g, 5.2
mmol) in dry THF (30 mL) was added potassium tert-butoxide
(602 mg, 5.4 mmol) in dry THF (30 mL) dropwise under argon.
After stirring for 1 h at room temperature, 50 mL of water was
added to the reaction mixture followed by 100 mL of ethyl
acetate. The organic layer was separated and the aqueous layer
was extracted with ethyl acetate (2 × 50 mL). The combined
organic materials were extracted with brine, dried over MgSO4,
and concentrated under reduced pressure. The product (1.25
g, 82% yield) was obtained as a white solid by flash chromotog-
raphy (hexane/ethyl acetate 3/1, v/v): mp 109-112; 1H NMR
(CDCl3, 250 MHz) δ 1.31 (d, J ) 5.6 Hz, 3H), 1.43 (s, 9H), 2.75
(m, 1H), 3.06 (d, J ) 6.7 Hz, 1H), 5.09 (d, J ) 12.2 Hz, 1H), 5.14
(d, J ) 12.2 Hz, 1H), 7.33 (m, 5H).
(2S,3R)-ter t-Bu tyl 2-(N-Ben zyloxyca r bon yl)a m in o-3-a zi-
d obu ta n oa te. Trimethylsilyl azide (1.2 mL) was added quickly
to a stirred solution of (2S,3S)-N-benzyloxycarbonyl-2-carbo-tert-
butoxy-3-methylaziridine (1.0 g, 3.4 mmol) in dry methanol (1.2
mL) in a 4 mL vial at 0 °C. The vial was closed tightly with a
Teflon disk lid and the reaction mixture was heated at 70 °C
for 5 h. After removal of solvent under reduced pressure, the
pure product (877 mg, 77% yield) was isolated as a colorless oil
by flash chromotography (hexane/ethyl acetate 3/1, v/v); 1H NMR
(CDCl3, 250 MHz) δ 1.32 (d, J ) 6.7 Hz, 3H), 1.43 (s, 9H), 4.10
(qd, J 2 ) 6.6 Hz, J ) 2.6 Hz, 1H), 4.29 (dd, J 2 ) 9.2 Hz, J ) 2.7
Hz, 1H), 5.11 (s, 2H), 5.35 (d, J ) 9.1 Hz, 1H), 7.33 (m, 5H);
HRMS [FAB, (M + 1)+] calcd for 335.1719, found 335.1727.
(2S,3R)-1c‚2HCl. To a stirred solution of (2S,3R)-tert-butyl-
2-(N-benzyloxycarbonyl)amino-3-azido-butanoate (800 mg, 2.4
mmol) in 30 mL of methanol in a 100 mL round-bottom flask
charged with an atmospheric H2 balloon was added 10 mol %
Pd-carbon. The Pd-carbon was removed by filtration and the
product was concentrated under reduced pressure. The product
was dissolved in a 20 mL of trifluoroacetic acid/methylene
chloride mixture (1/1). The reaction mixture was stirred at room
temperature for 1 h and the product was concentrated under
Ack n ow led gm en t. We thank Professor K. Barry
Sharpless, Dr. J ae Uk J eong, and Dr. Gunther Schlin-
gloff for valuable information and helpful discussions.
Financial support of this research from the Skaggs
Institute for Chemical Biology is gratefully acknowl-
edged.
Su p p or tin g In for m a tion Ava ila ble: Methods for the
1
syntheses of the compounds discussed here and their H NMR
spectra (23 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
J O9720391