A Mild Amide to Carbamate Transformation

Full text of DOI:10.1021/jo970903j

7054
J . Org. Chem. 1997, 62, 7054-7057
Sch em e 1
A Mild Am id e to Ca r ba m a te
Tr a n sfor m a tion
Mark J . Burk*,1 and J ohn G. Allen
Paul M. Gross Chemical Laboratory, Duke University,
Durham, North Carolina 27708-0348
Ta ble 1. Clea va ge of Aceta m id e 2 f 3 in MeOHa
entry
base
time (h) convn (%)b 1 (%) 3 (%)
Received May 20, 1997
1
2
3
4
morpholine
pyridine
Et3N
18
18
18
4
7
3
17
18
2
3
2
3
5
0
15
15
The acetamide and benzamide amine protecting groups
have long been used in synthesis because they offer the
advantage of very good stability to a wide range of
conditions.2 More recently, they have been found to give
high selectivities in carbonyl-directed catalysis.3 We have
achieved excellent selectivities in DuPHOS-Rh and BPE-
Rh catalyzed asymmetric hydrogenations of various
acrylamides.4 In the hydrogenation of hindered tetra-
substituted acrylamides, a very challenging class of
substrates, acetamide directing groups were found to be
essential for the success of the reaction.5 The scope of
amide-directed catalysis in synthesis and the role of
amide-based protecting groups in general would be
increased with a more convenient method for the removal
of acetamides and benzamides.
In our handling of acetamide and benzamide protected
amines, direct cleavage of the amide bonds required
harsh conditions such as refluxing in solutions of HCl6
which was not compatible with sensitive functionality.
It has been known for some time that amides can be
activated to hydrolysis by prior conversion to the N-Boc
imide derivatives.7 Selective hydrolysis of the amide
leaves the N-tert-butoxycarbamate in place. N-Boc-
protected amino acids can be easily converted to the free
amine and are useful in solid phase synthesis.8 This
paper communicates the optimization of a procedure for
the conversion of N-acetamido and -benzamido amino
acids to N-(tert-butoxycarbonyl)amino acids.
5
4
45
2
43
6
7
8
9
10
HONH2
H2NNH2
4
2
2
4
4
32
100
100
30
2
0
0
2
0
30
100
100
28
c
H2NNH2‚H2O
NaOHd
LiOHd
100
97
a
Conditions: 200 mg of 2 was dissolved in 2.9 mL of MeOH, 2
equiv base was added, and the reaction was allowed to stir for
the time indicated. An aliquot was removed, diluted with CH2Cl2,
and washed with 1 N HCl, CuSO4, and NaHCO3, dried over
MgSO4, and evaporated. The crude material was dissolved in
b
acetone and assayed by GC. Side products in addition to 1 and
3 were detected in some cases. c Identical reactivity was observed
d
in 1:1 THF:MeOH. Reaction products were treated with diaz-
omethane before analysis.
0.2 equiv of DMAP in solvent for 24 h at rt. The order of
reactivity for different solvents was found to be THF >
1-methyl-2-pyrrolidinone (NMP) > CH3CN ≈ pyridine >
CH2Cl2 > MeOH. The reaction in THF was almost twice
as fast as the next best solvent, NMP. NMP was tested
due to its combination of strong solvating properties and
convenient boiling point (81-82 °C/10 mm). CH3CN and
CH2Cl2 were both used in other studies7 but were
unsatisfactory in comparison to THF. The reaction in
neat pyridine was also slower. Furthermore, adding 1
and 2 equiv of pyridine to acylations in other solvents
slowed the reactions. Methanol simply hydrolyzed the
Boc2O reagent.
By heating the acylation reaction in THF to reflux, only
4 h was required for completion. Decreasing the amount
of Boc2O below 2 equiv gave incomplete reactions.10 The
procedure was repeated for 5 g of 1 to give 6.6 g of
N-acetyl-N-(tert-butoxycarbonyl)-L-valine methyl ester (2,
85%).
This procedure was optimized in two steps: (1) intro-
duction of the Boc group and (2) cleavage of the acetate
(Scheme 1). The two steps were then combined in an
efficient standard one-pot procedure. After reviewing
current methods we made significant improvements in
reaction time and yields and obtained high degrees of
chemoselectivity for the one-pot transformation of amides
to carbamates.
The initial acylation step with di-tert-butyl dicarbon-
ate9 (Boc2O) was first examined. N-Acetyl-L-valine meth-
yl ester (1) was allowed to stir with 2 equiv of Boc2O and
With large amounts of the mixed imide 2 in hand, the
subsequent hydrolysis step was optimized for base and
solvent, carefully examining the products for any sign of
racemization. The results are summarized in Table 1.
The mixed imide 2 was treated with 2 equiv of base in
MeOH at rt. At the times shown, the products were
assayed by GC. The monobasic morpholine, pyridine,
and triethylamine gave low conversions and attacked
both the carbamate group and the acetamide group to
give both the amide starting material 1 as well as the
carbamate product 3.11 The dibasic ethanolamine and
ethylenediamine gave better conversions but also showed
(1) Present address: Chiroscience Limited, Cambridge Science Park,
Milton Road, Cambridge CB4 4WE, England.
(2) Green, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 2nd ed.; Wiley: New York, 1991; p 351, 355.
(3) McCulloch, B.; Halpern, J .; Thompson, M. R.; Landis, C. R.
Organometallics 1990, 9, 1392.
(4) (a) Burk, M. J .; Feaster, J . E.; Nugent, W. A.; Harlow, R. L. J .
Am. Chem. Soc. 1993, 115, 10125. (b) Burk, M. J .; Gross, M. F.; Harper,
G. P.; Kalberg, C. S.; Lee, J . R.; Martinez, J . P. Pure Appl. Chem. 1996,
68, 37.
(5) (a) Burk, M. J .; Gross, M. F.; Martinez, J . P. J . Am. Chem. Soc.,
1995, 117, 9375. (b) Burk, M. J .; Gross, M. F.; Martinez, J . P.; Straub,
J . A. Manuscript in preparation.
(6) Dilbeck, G. A.; Field, L.; Gallo, A. A.; Gargiulo, R. J . J . Org.
Chem. 1978, 43, 4593.
(7) (a) Grehn, L.; Gunnarsson, K.; Ragnarsson, U. J . Chem. Soc.,
Chem. Commun. 1985, 1317. (b) Grehn, L.; Gunnarsson, K.; Ragnars-
son, U. Acta Chem. Scand. 1986, B40, 745. (c) Flynn, D. L.; Zelle, R.
E.; Greico, P. A. J . Org. Chem. 1983, 48, 2424.
(9) Grehn et al. (J . Chem. Soc., Chem. Commun. 1985, 1317)
reported that the dicarbonate was required for acylation, rather than
the chloroformate or other acylating reagent. This result was confirmed
in the current study.
(10) Refluxing for 18 h with 1.2 and 1.5 equiv of Boc2O gave 80%
and 90% completion, respectively.
(11) Free amine formed during the reactions would have been lost
during the workup. Its formation however was unlikely due to the
stability of amides and carbamates to the reaction conditions.
(8) Green, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 2nd ed.; Wiley: New York, 1991; pp 327-330.
S0022-3263(97)00903-1 CCC: $14.00 © 1997 American Chemical Society

Notes
J . Org. Chem., Vol. 62, No. 20, 1997 7055
Ta ble 2. Su bstr a tes Used in N-Ac to
N-BocTr a n sfor m a tion s
some reaction with the carbamate group. Adding 20%
DMAP to the ethanolamine and ethylenediamine reac-
tions provided no improvement.12 Hydroxylamine and
hydrazine both have increased nucleophilicity due to the
R-effect,13 and hydrazine gave excellent results after only
2 h. Hydrazine hydrate had identical reactivity to
hydrazine. In the effort to develop a one-pot procedure,
1:1 MeOH:THF was substituted for MeOH without losing
any reactivity. No racemization was detected with any
amine base.14
The alkoxide bases NaOH and LiOH were also tested
in the amide cleavage reaction. In these trials, 2 was
stirred at rt in 1:1 THF:2.0 M base, and the methyl ester
was quickly hydrolyzed. The reaction products were
extracted into ether and treated with diazomethane
before analysis. Interestingly, NaOH and LiOH were
found to have very different reactivity. After 4 h with
LiOH the acetamide was fully hydrolyzed to give 3 with
no loss of the carbamate.15 With NaOH conversion was
incomplete (69.6%) and 2.1% of 1 was formed. It was
expected that in the carboxylate formed by ester hydroly-
sis the R-proton would be less acidic and the amino acid
would be protected from racemization. Indeed, even after
22 h <0.6% racemate was formed with either LiOH or
NaOH. Although these strongly basic conditions would
not be compatible with more sensitive functionality and
were not pursued, LiOH hydrolysis was a useful method
when the acid was desired.
Ta ble 3. Selective Am id e to N-Boc Tr a n sfor m a tion s
From these studies we arrived at a set of conditions
which were attempted in a one-pot procedure: the
acetamide was refluxed with 2 equiv of Boc2O and 0.2
equiv of DMAP in THF for 4 h. The reaction was cooled,
and the volume was doubled with MeOH. Excess hy-
drazine (4 equiv) was added to both quench unreacted
Boc2O and cleave the acetamide. Results of trials using
this method are summarized in Table 2. The Boc-
protected amino acids were obtained in high isolated yield
without racemization.
Table 216 shows a range of protected linear, cyclic, and
branched side-chain amino acids obtained commercially
or prepared via catalytic asymmetric hydrogenation.
Hindered acetamides in entries 1, 4, and 5 were trans-
formed smoothly into the N-Boc derivatives. Preserva-
tion of the ethyl ester in 8 (entry 6) demonstrated that
esters were stable to the conditions of basic methanolysis
used in the second step.
We investigated the stability of other functionality and
extended the reaction to the cleavage of benzamides
(Table 3). In applying these conditions to benzamides,
we found that the acylation with Boc2O proceeded more
quickly than with the acetamides and refluxing was not
required. Cooling the reaction mixture to 0 °C after
adding hydrazine still allowed the amide cleavage to take
place, and base-catalyzed hydrolyses were minimized.
a
b
Hydrolysis step performed at rt. Acylation step performed
at reflux. c Acylation step performed at reflux and with 3 equiv of
Boc2O.
Functionalized acetamides were found to easily survive
these conditions as is shown in Table 3.
(12) After 4 h ethanolamine, 20.3% conversion, 2.0% 1, 17.6% 3,
ethylenediamine; 43.5% conversion, 2.9% 1, 42.8% 3.
(13) Carey, F. A.; Sundberg, R. J . Advanced Organic Chemistry Part
A: Structure and Mechanisms, 2nd ed.; Plenum: New York, 1991; p
228.
(14) NaOMe was used (18 h, rt, MeOH) to intentionally racemize
the amino acid in the reaction 2 to 3 for comparison to the chiral
products. In these reactions, racemization was faster than acetamide
cleavage. Cleavage of the carbamate was also detected. Racemic DL-
valine was also purchased and derivatized for comparison.
(15) 0.3% of the enantiomer was detected.
(16) Substrates for compounds 4 and 5 were obtained in >99% ee
and 98.9% ee, respectively, using (R,R)-PrDuPHOS-Rh and (R,R)-
EtDuPHOS-Rh (see ref 4a). Substrates for compounds 6, 7, and 8 were
obtained in 96.9% ee and 95.9% ee and 97.4% ee, respectively, using
(R,R)-MeBPE-Rh, (S,S)-MeBPE-Rh, (R,R)-MeBPE-Rh (see ref 5a).
The allylic silyl ether17 in entry 1 gave a very good yield
of the N-Boc derivative 9. The protected methionine in
entry 3 decomposed during acylation at reflux, but a good
yield was obtained when the acylation was performed at
rt. Entries 4 and 5 demonstrated selectivity for aceta-
mide and benzamide cleavage in the presence of acetate
and benzyl esters in slightly diminished yields due to the
(17) Substrate for compound 9 obtained in 96.6% ee by the use of
(S,S)-MeDuPHOS-Rh. See: Burk, M. J .; Allen, J . A.; Kiesman, W. F.
Manuscript in preparation.

7056 J . Org. Chem., Vol. 62, No. 20, 1997
Notes
(R)-Meth yl 2-((ter t-bu toxyca r bon yl)a m in o)p en ta n oa te
(4). The general procedure gave 0.22 g (80%): Rf, 0.30 (9:1
system A); tR 3.70 min (120 °C, 20 psi, N-Ac >99% ee, N-Boc
formation of small amounts of hydrolysis products. The
lower yield for entry 5 reflects the greater stability of the
benzamide. The peracetylated GlcNAc in entry 6 was
converted into the Boc derivative 12 in good yield with
loss only of the highly labile anomeric acetate group.
Lowering the temperature to -20 °C did not allow the
anomeric acetate to survive: the acetamide and anomeric
acetate were cleaved at the same rate. The correspond-
ing methyl glycoside required forcing conditions to achieve
acylation, and some decomposition occurred. The hy-
drolysis step went smoothly, however, and a good yield
of methyl 3,4,6-tri-O-acetyl-2-(N-(tert-butoxycarbony-
l)amino)-2-deoxy-R-D-glucopyranoside (13) resulted.
>99% ee); [R]22 ) -5.72° (c ) 2.08, CHCl3); 1H NMR δ 0.87 (t,
D
3H, J ) 7.3 Hz), 1.30-1.80 (m, 4H), 1.38 (s, 9H), 3.68 (s, 3H),
4.20-4.30 (m, 1H), 4.98 (br d, 1H, J ) 8.3Hz); 13C NMR δ 13.6,
18.6, 28.2, 34.8, 52.1, 53.2, 79.7, 155.3, 173.5; HRMS calcd for
C
11H22NO4 (M + H+) 232.1549, found 232.1546.
N-(ter t-Bu toxyca r bon yl)-D-leu cin e Meth yl Ester (5). The
general procedure gave 0.24 g (91%): Rf 0.39 (9:1 system A); tR
4.58 min (120 °C, 20 psi, N-Ac 98.9% ee, N-Boc 99.0% ee); [R]22
D
) +4.21° (c ) 2.40, CHCl3); 1H NMR δ 1.80-1.90 (m, 6H), 1.30-
1.80 (m, 3H), 1.36 (s, 9H), 3.65 (s, 3H), 4.15-4.30 (m, 1H), 4.93
(br d, 1H, J ) 8.6Hz); 13C NMR δ 21.7, 22.7, 24.6, 28.2, 41.6,
51.8, 52.0, 79.6, 155.3, 173.9; HRMS calcd for C12H23NO4 (M +
H+) 246.1705, found 246.1703.
(R)-Meth yl 2-((ter t-bu toxyca r bon yl)a m in o)-3-eth ylp en -
ta n oa te (6). The general procedure gave 54 mg (93%): Rf 0.33
(9:1 system A); tR 2.41 min (145 °C, 20 psi, N-Ac 96.9% ee, N-Boc
96.9% ee); [R]22D)-14.1° (c ) 1.08, CHCl3); 1H NMR δ 0.60-1.00
(m, 6H), 1.20-1.70 (m, 5H), 1.40 (s, 9H), 3.68 (s, 3H), 4.30-
4.40 (m, 1H), 4.91 (br d, 1H, J ) 8.3Hz); 13C NMR δ 21.7, 22.7,
24.6, 28.2, 41.6, 51.8, 52.0, 79.6, 155.3, 173.9; HRMS calcd for
The convenient conversion of amides into useful N-Boc
derivatives under mild conditions has been demonstrated
and will facilitate the synthesis of amines and amino
acids. Amide-forming preparations such as the Beck-
mann rearrangement,18 the Ritter reaction,19 and others
may become more useful entries into syntheses. Their
mild cleavage should allow amides themselves more use
as versatile protecting groups. Work is currently under-
way to extend these methods to the preparation of
benzylcarbamates from amides.20
C
13H26NO4 (M + H+): 260.1862, found 260.1855.
(S)-Meth yl 2-((ter t-Bu toxyca r bon yl)a m in o)-2-cyclop en -
tyleth a n oa te eth a n oa te (7). The general procedure gave 68
mg (93%): Rf 0.43 (9:1 system A); tR 4.12 min (120 °C, 20 psi,
N-Ac 95.9% ee, N-Boc 95.9% ee); [R]22D ) +7.0° (c ) 1.36, CHCl3);
1H NMR δ 1.20-1.70 (m, 8H), 1.39 (s, 9H), 2.10-2.20 (m, 1H),
3.68 (s, 3H), 4.20-4.30 (m, 1H), 4.90-5.00 (br, 1H); 13C NMR δ
24.1, 25.2, 28.2, 28.8, 42.6, 52.0, 56.4, 79.7, 155.5, 173.3; HRMS
calcd for C13H24NO4 (M + H+) 258.1705, found 258.1703.
N-(ter t-Bu toxyca r bon yl)-D-leu cin e Eth yl Ester (8). The
general procedure gave 0.24 g (86%): Rf 0.55 (9:1 system A); tR
3.52 min (120 °C, 20 psi, N-Ac 97.4% ee, N-Boc 97.8% ee); [R]22
D
) -11.6° (c ) 2.43, CHCl3); 1H NMR δ 0.79 (d, 3H, J ) 6.9Hz),
0.86 (d, 3H, J ) 6.9Hz), 1.84 (t, 3H, J ) 7.1Hz), 1.35 (s, 9H),
2.00-2.10 (m, 1H), 4.10-4.20 (m, 3H), 5.01 (br d, 1H, J ) 8.0
Hz); 13C NMR δ 14.1, 17.4, 18.8, 28.1, 31.2, 58.3, 60.9, 79.4, 155.5,
172.2; HRMS calcd for C12H24NO4 (M + H+): 246.1705, found
246.1712.
Exp er im en ta l Section
Gen er a l Meth od s. 1H and 13C NMR spectra were recorded
on a General Electric QE-300 spectrometer at 300.15 and 75.48
MHz, respectively, in CDCl3, and the shifts are reported in ppm
downfield from TMS. High-resolution mass spectra were ob-
tained using a J EOL J MS-SX102A spectrometer. Chiral capil-
lary GC was performed on a Chrompack Chirasil-L-Val column
(25 m). For TLC, system A was (petroleum ether:ethyl acetate),
system B was (CHCl3:acetone). DMAP was crystallized from
toluene and THF was distilled from sodium/benzophenone before
use. Other unspecified reagents were from commercial sources
and used as obtained.
(2S,4E)-Meth yl 2-((ter t-Bu toxycar bon yl)am in o)-6-O-(ter t-
bu tyld im eth ylsilyl)h ex-4-en eoa te (9). (S)-Methyl 2-aceta-
mido-6-O-(tert-butyldimethylsilyl)hex-4-eneoate (0.20 g, 0.63
mmol) and N,N-dimethyl-4-aminopyridine (14 mg, 0.13 mmol)
were dissolved in THF (1.6 mL). Di-tert-butyl dicarbonate (0.29
mL, 1.30 mmol) was added, and the mixture was stirred at rt
for 8 h. MeOH (4 mL) was added, and the mixture was treated
with hydrazine (79 µL, 2.5 mmol) for 8 h. The reaction mixture
was poured into CH2Cl2, washed with 1 N HCl, CuSO4, and
NaHCO3, dried (MgSO4), and evaporated. Chromatography on
silica gave 0.22g of pure 9 (93%): Rf 0.31 (9:1 system A); tR 3.61
N-(ter t-Bu toxyca r bon yl)-L-va lin e Meth yl Ester (3). Gen -
er a l P r oced u r e. N-Acetyl-L-valine methyl ester (0.2 g, 1.15
mmol) and N,N-dimethyl-4-aminopyridine (28 mg, 0.23 mmol)
was dissolved in THF (4 mL). Di-tert-butyl dicarbonate (0.53
mL, 2.30 mmol) was added, and the mixture was heated to reflux
for 4 h. After the solution was cooled to room temperature,
MeOH (4 mL) and hydrazine (0.14 mL, 4.6 mmol) were added
and the mixture was stirred at rt for 4 h. The reaction mixture
was poured into CH2Cl2, washed with 1 N HCl, CuSO4, and
NaHCO3, dried (MgSO4), and evaporated. Chromatography on
silica gave 0.24 g of pure 3 (92%): Rf, 0.33 (9:1 system A); tR
min (180 °C, 30 psi, N-Ac 98.8% ee, N-Boc 99.4% ee); [R]22
)
D
+17.4° (c ) 2.21, CHCl3); 1H NMR δ -0.02 (s, 6H), 0.82 (s, 9H),
1.35 (s, 9H), 2.30-2.50 (m, 2H), 3.64 (s, 3H), 4.04 (d, 2H, J )
4.4Hz), 4.20-4.30 (m, 1H), 5.00 (br d, 1H, J ) 8.0Hz), 5.40-
5.60 (m, 2H); 13C NMR δ 18.2, 25.8, 28.2, 32.1, 32.3, 35.0, 52.0,
52.9, 63.2, 79.6, 123.9, 133.8, 155.0, 172.4; HRMS calcd for
C
18H36NO5 (M + H+): 374.2363, found 374.2355.
2.89 min (120 °C, 20 psi, N-Ac >99% ee, N-Boc >99% ee)21; [R]22
D
N-(ter t-Bu toxyca r bon yl)-L-leu cin e Meth yl Ester (en t-5).
1
) +12.9° (c ) 2.43, CHCl3) H NMR δ 0.79 (d, 3H, J ) 6.9Hz),
N-Acetamido-L-valine benzyl ester (0.20 g, 0.8 mmol) and N,N-
dimethyl-4-aminopyridine (18 mg, 0.16 mmol) was dissolved in
THF (2 mL). Di-tert-butyl dicarbonate (0.37 mL, 1.60 mmol) was
added, and the mixture was heated at reflux for 6 h. The
mixture was cooled to rt, MeOH (2 mL) and hydrazine (0.1 mL,
3.2 mmol) were added, and the mixture was stirred for 3 h. The
reaction mixture was poured into CH2Cl2, washed with 1 N HCl,
CuSO4, and NaHCO3, dried (MgSO4), and evaporated. Chro-
matography on silica gave 0.17 g of pure en t-5 (88%): tR 2.53
0.85 (d, 3H, J ) 6.8Hz), 1.34 (s, 9H), 2.00-2.10 (m, 1H), 4.12 (s,
3H), 4.10-4.20 (m, 3H), 5.02 (br d, 1H, J ) 8.5Hz); 13C NMR δ
17.4, 18.8, 28.1, 31.1, 51.8, 58.3, 79.5, 155.5, 172.7; HRMS calcd
for C11H22NO4 (M + H+) 232.1549, found 232.1543.
(18) For a review, see: Gawley, R. E. Org. React. 1988, 35, 1.
(19) For a review, see: Krimen, L. I.; Cota, D. J . Org. React. 1969,
17, 213.
(20) In several trials, the commercially available dibenzyl dicarbon-
ate (Cbz2O) gave only dibenzyl carbonate, the product of catalytic
decomposition of the reagent by benzyl oxide released by the first
acylation event. Trapping agents did not improve the reaction. In an
effort to use a bulkier leaving group, the mixed dicarbonate benzyl
tert-butyl dicarbonate (14) was prepared from sodium tert-butoxide,
carbon dioxide, and benzyl chloroformate. Acylation of O-acetyl-N-
benzoyl-L-serine benzyl ester gave a 4:1 mixture of the Cbz imide to
the Boc imide. Please see Supporting Information.
min (140 °C, 20 psi, N-Ac >99% ee, N-Boc 99.3% ee); [R]22
)
D
-4.21° (c ) 1.56, CHCl3). Other characterization data were
identical to those of 5.
N-(ter t-Bu toxycar bon yl)-L-m eth ion in e Meth yl Ester (10).
N-Benzamido-L-methionine methyl ester (0.31 g, 1.15 mmol) and
N,N-dimethyl-4-aminopyridine (28 mg, 0.23 mmol) was dissolved
in THF (3 mL). Di-tert-butyl dicarbonate (0.53 mL, 2.30 mmol)
was added, and the mixture was stirred at rt for 7 h. MeOH (3
mL) was added, and the mixture was cooled to 0 °C and treated
(21) All GC samples were of crude material before purification by
column chromatography.

Notes
J . Org. Chem., Vol. 62, No. 20, 1997 7057
with hydrazine (0.15 mL, 4.6 mmol) for 2 h. The reaction
mixture was poured into CH2Cl2, washed with 1 N HCl, CuSO4,
and NaHCO3, dried (MgSO4), and evaporated. Chromatography
on silica gave 0.28 g of pure 10 (94%): Rf 0.52 (4:1 system A); tR
(dd, 1H, J ) 9.5Hz), 5.10-5.30 (m, 2H); 13C NMR δ 20.6, 28.1,
53.2, 62.0, 67.2, 68.3, 71.4, 79.9, 91.8, 155.2, 169.4, 170.9; HRMS
calcd for C17H28NO10 (M + H+): 406.1713, found 406.1717.
Meth yl 3,4,6-Tr i-O-acetyl-2-((ter t-bu toxycar bon yl)am in o)-
2-d eoxy-r-D-glu cop yr a n osid e (13). The procedure for 10 was
followed except the acylation reaction required 6 h reflux
followed by stirring 14 h with an additional equivalent Boc2O,
and the hydrolysis step required 2 h to give 0.20 g of 13 (70%):
Rf 0.77 (4:1 system B); [R]22D ) +83.0° (c ) 1.05, CHCl3); 1H NMR
δ 1.35 (s, 9H), 1.95, 1.96, 2.03 (3s, 9H), 3.32 (s, 3H), 3.80-4.30
(m, 4H), 4.67 (d, 1H, J ) 3.6Hz), 4.71 (d, 1H, J ) 10.2Hz), 5.01
(dd, 1H, J ) 9.8Hz), 5.12 (dd, 1H, J ) 10.2Hz); 13C NMR δ 20.6,
28.1, 52.9, 55.3, 62.0, 67.5, 68.2, 71.6, 79.8, 98.6, 155.0, 169.3,
170.6, 170.8; HRMS calcd for C18H30NO10 (M + H+): 420.1870,
found 420.1854.
6.59 min (145 °C, 20 psi, N-Bz >99% ee, N-Boc 98.7% ee); [R]22
D
1
) +24.6° (c ) 2.84, CHCl3); H NMR δ 1.31 (s, 9H), 1.80-1.90
(m, 2H), 1.96 (s, 3H), 2.41 (t, 2H, J ) 7.5Hz), 3.62 (s, 3H), 4.30-
4.40 (m, 1H), 5.25 (br d, 1H, J ) 8.1Hz); 13C NMR δ 15.1, 28.0,
29.7, 31.7, 52.1, 52.4, 79.6, 155.1, 172.6; HRMS calcd for
C
11H23NO4S (M + H+) 264.1272, found 264.1273.
O-Acetyl-N-(ter t-bu toxyca r bon yl)-L-Ser in e Ben zyl Ester
(11). F r om th e Cor r esp on d in g Aceta m id e. The procedure
for 10 was followed except the acylation reaction mixture was
refluxed for 3 h, and the hydrolysis step required 3 h to give
0.31 g of 11 (81%): tR 6.73 min (180 °C, 30 psi, N-Ac 98.4% ee,
N-Boc >99% ee). F r om th e Cor r esp on d in g Ben za m id e. The
procedure for 10 was followed except the acylation reaction
required 2 h, and the hydrolysis step required 2 h to give 0.15
g of 11 (72%): Rf 0.46 (4:1 system A); tR 6.71 min (180 °C, 30
Ack n ow led gm en t. We are grateful to the National
Institutes of Health for financial support of this work
(GM51342). The authors thank Dr. G. R. Dubay for
assistance with high-resolution mass spectrometry and
Drs. J udy A. Straub and J ose P. Martinez for helpful
discussions.
psi, N-Bz >99% ee, N-Boc >99% ee); [R]22 ) +1.56° (c ) 2.11,
D
CHCl3); 1H NMR δ 1.41 (s, 9H), 1.91 (s, 3H), 4.20-4.30 (m, 1H),
4.30-4.50 (m, 1H), 4.50-4.60 (m, 1H), 5.09 (d, 1H, J ) 12.2Hz),
5.19 (d, 1H, J ) 12.2Hz), 5.33 (br d, 1H, J ) 8.2Hz); 13C NMR
δ 20.4, 28.2, 52.8, 64.3, 67.4, 80.2, 128.3, 128.4, 128.5, 135.0,
155.0, 169.6, 170.3; HRMS calcd for C17H24NO6 (M + H+):
338.1603, found 338.1593.
Su p p or tin g In for m a tion Ava ila ble: NMR spectra for
compounds 3, 4, 7, 8, 9, and 11 and experimental details for
the preparation of benzyl tert-butyl dicarbonate (14) (13 pages).
This material is contained in libraries on microfiche, im-
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3,4,6-Tr i-O-a cet yl-2-(ter t-b u t oxyca r b a m id o)-2-d eoxy-D-
glu cop yr a n ose (12). The procedure for 10 was followed except
the acylation reaction was refluxed for 2.5 h, and the hydrolysis
step required 2 h to give 0.20 g of 12 (80%): Rf 0.43 (4:1 system
B); [R]22 ) +56.1° (c ) 1.29, CHCl3); 1H NMR δ 1.34 (s, 9H),
D
1.96, 1.97, 2.02 (3s, 9H), 3.88 (dd, 1H, J ) 10.3Hz), 4.00-4.30
(m, 3H), 4.62 (d, 1H, J ) 3.5Hz), 4.93 (d, 1H, J ) 10.0Hz), 5.03
J O970903J