Synthesis of enantiopure α-chlorocyclobutanones and cyclobutanols as scaffolds for the diverted synthesis of serine protease inhibitors

Article abstract of DOI:10.1002/ejoc.200900083

Synthetic paths towards highly functionalized α-chlorocyclobutanone scaffolds susceptible to lead to serine proteases inhibitors were explored. The syntheses started from bicyclic α-chlorocyclobutanones 3, which are readily available from Seebach's oxazol

Full text of DOI:10.1002/ejoc.200900083

FULL PAPER
DOI: 10.1002/ejoc.200900083
Synthesis of Enantiopure α-Chlorocyclobutanones and Cyclobutanols as
Scaffolds for the Diverted Synthesis of Serine Protease Inhibitors
Gaoqiang Yang[a] and Léon Ghosez*[b]
Dedicated to Professor Alain Krief
Keywords: Inhibitors / Small ring systems / Heterocycles / Asymmetric synthesis
Synthetic paths towards highly functionalized α-chlorocy-
clobutanone scaffolds susceptible to lead to serine proteases
inhibitors were explored. The syntheses started from bicyclic
α-chlorocyclobutanones 3, which are readily available from
Seebach’s oxazolines. It was found that the carbonyl group of
the bicyclic α-chlorocyclobutanones was highly electrophilic
and readily reacted with a hydroxy group to give, for exam-
ple, cyclized compound 4. Also, the presence of this reactive
carbonyl group did not allow the regeneration of the pro-
tected amine and hydroxy groups. Thus, the functional ma-
nipulation of these bicyclic α-chlorocyclobutanones required
prior reduction of the carbonyl group to the corresponding
cyclobutanol. Accordingly, enantiopure cyclobutanone 3d
was stereoselectively reduced to exo-cyclobutanol 15. Al-
lylation of the alcohol followed by TEMPO-catalyzed oxi-
dation of the primary alcohol of the side chain and ben-
zylation of the resulting carboxylic acid yielded compound
19. Cleavage of the oxazolidine ring occurred smoothly to
yield densely functionalized cyclobutanol scaffold 20. A sim-
ilar route allowed the efficient preparation of cyclobutanol
scaffolds 14 and 25a–d in 25–27% yields. TEMPO-catalyzed
oxidation of the cyclobutanol gave an excellent yield of cor-
responding cyclobutanones 26a,b
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
should favour nucleophilic addition of a serine residue.
Also, the additional presence of an electronegative substitu-
ent X (F, Cl, Br···) would further increase the electrophilic
character of the carbonyl group. The scaffolds should carry
functional groups that could be readily modified by click
chemistry to generate diversity. We selected an amine group
at C-2, which could be readily converted into a variety of
amides (analogy with penicillins and cephalosporins), and
a cis-hydroxy group at C-3, which could be easily acylated
or alkylated. An acetic acid side chain at C-4 should allow
hydrogen bonding of the carboxylate group with an OH
group of the protein, as in the case of β-lactam antibiotics.
Introduction
β-Lactams have been the subject of extensive synthetic,
theoretical and pharmacological studies owing to their abil-
ity to act as inhibitors of important classes of serine prote-
ases.[1] They act as acylating agents of a serine residue of
the protease leading to an acyl enzyme intermediate that
cannot further react or leads to an inactive form of the
enzyme. The emergence of resistance to β-lactam antibiotics
has become a major threat to public health.
A major, though not unique, form of resistance results
from the bacterial expression of β-lactamases.[2] These en-
zymes react with the β-lactam to form an acyl enzyme that
undergoes fast hydrolysis to regenerate the enzyme and a
derivative of the antibiotic. In principle, this type of resis-
tance could be overcome by replacing the acylating lactam
group by an alkylating or hydroxy-alkylating group.[3] In
this context, we became interested in the synthesis of cyclo-
butanone scaffolds 1 (Scheme 1), which could be used for
the diverted total synthesis of serine protease inhibitors.[4]
The cyclobutanone is structurally similar to the β-lactam:
both carbonyl groups are part of a strained ring, which
Scheme 1. Possible interaction of an α-halocyclobutanone with a
serine protease.
In principle, these scaffolds should be readily accessible
in enantiopure form by following the retrosynthetic path-
way outlined in Scheme 2. We have already reported on the
remarkable [2+2] cycloadditions of Seebach’s oxazolines[5]
to in situ generated chloroketenes.[6] The reaction unexpec-
[a] Department of Chemistry, University of Louvain,
Place L. Pasteur 1348 Louvain-la-Neuve, Belgium
[b] Institut Européen de Chimie et Biologie,
2 rue Robert Escarpit, 33607 Pessac Cedex, France
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Scaffolds for the Diverted Synthesis of Serine Protease Inhibitors
tedly yielded adduct 3 as the major regioisomer. This paper 6. Cleavage of the benzyl group by catalytic hydrogenolysis
reports studies of the transformations of compounds 3 in quantitatively yielded alcohol 7, which was oxidized with
targeted scaffolds 1. These model studies were performed pyridinium dichromate (PDC) in DMF, a reagent which is
on the enantiomers of 3, which are readily available in large rather tolerant to acid- and base-sensitive functional
amounts from cheap -serine. Eventually it will be shown groups. Here again the reaction was very slow and gave a
that the final synthetic route will allow the targeted configu- moderate yield of carboxylic acid 8 after approximately
rations to be obtained..
24 h. The structure and configuration of 8 were confirmed
by X-ray diffraction analysis (Figure 1).[9] The carboxylic
acid was esterified with benzyl bromide in the presence of
sodium hydrogen carbonate. Cleavage of the TBDMS ether
in methanol containing pTsOH (1.2 equiv.) gave the corre-
sponding cyclobutanol. Notably, PDC did not oxidize the
secondary hydroxy group at room temperature: after 12 h
starting material was recovered unchanged. However,
Swern oxidation exclusively gave cyclobutanone 12 in the
presence of triethylamine (3 equiv.). Compound 12 obvi-
ously resulted from easy dehydrochlorination of the β-chlo-
roester in the presence of the base. Reducing the amount of
base to 2 equivalents led to a mixture of 11 and 12, which
were separated by flash chromatography (Scheme 4).
Scheme 2. Retrosynthetic analysis for α-chlorocyclobutanone scaf-
fold 1.
Results and Discussion
Required bicyclic cyclobutanones 3a–d were prepared
following the procedure described in our previous publica-
tion (Scheme 3).[6b] All attempts to cleave the protecting
group P2 (e.g., by catalytic hydrogenolysis of 3a) led to
hemiketal 4 resulting from intramolecular attack of the free
hydroxy group on the highly reactive carbonyl group.[7] This
was a dead end as far as the synthesis of scaffolds 1 was
concerned. We were thus forced to reduce the ketone group
before cleaving the protecting group P2. The reduction of
3a was performed with NaBH4 to give exo-cyclobutanol 5
in 50% yield. The reaction was rather slow (15 h). This
probably resulted from the steric crowding on each face of
the carbonyl group. The use of Zn(BH4)2 in ether did not
significantly improve the yields (55%). The selective forma-
tion of the exo-alcohol was not unexpected: this configura-
tion would result from attack of the hydride reagent to the
Figure 1. ORTEP drawing of the X-ray crystal structure of 8.
The cleavage of the oxazolidine ring was studied on
face opposite to the bulky tert-butyl group. Also, Brook et model compounds 3e,f, which were prepared according to
al. already reported that hydride transfer from NaBH4 on a literature procedure. Unfortunately, all attempts (4  HCl,
haloketones took place on the face opposite to the halogen TFA, BF3 in AcOH, etc.) to cleave the oxazolidine ring of
substituent.[8] The alcohol was protected as TBDMS ether 3e and 3f led to unchanged starting materials or complex
Scheme 3. Synthesis of enantiopure N- and O-protected α-chlorocyclobutanones 3 followed by hydrogenolysis of the benzyl group.
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G. Yang, L. Ghosez
FULL PAPER
Scheme 4. Synthesis of enantiopure fully protected α-chlorocyclobutanone 11 carrying an acetic side chain.
mixtures of unidentified products (Scheme 5). The prob-
lems associated with the cleavage of the oxazolidine ring
probably resulted from the high functional density of these
bicyclic molecules and, in particular, from the presence of
a highly electrophilic carbonyl group. We thus prepared
benzyl ether 13 (Scheme 6), its methyl carbamate analogue
was submitted to various acidic exposure to refluxing 4 
HCl in ethyl ether or BF3·2AcOH at room temperature, no
reaction occurred. It was completely degraded in a mixture
of BF3/TFA at room temperature after 1 d.
Scheme 6. Cleavage of the oxazolidine ring of α-chlorocyclobutanol
benzyl ethers 13.
Densely functionalized and enantiopure cyclobutane
scaffold 14 offers plentiful opportunities for diverted syn-
thesis of serine protease inhibitors. It contains two differen-
tiated hydroxy groups that could be selectively oxidized to
a cyclobutanone formally derived from -serine (oxidation
of the protected hydroxy group) or a cyclobutanone for-
mally derived from -serine (oxidation of the free OH
group). This latter opportunity is illustrated in the sequence
of reactions described in Schemes 7 and 8.
Scheme 5. Attempted cleavage of the oxazoline ring of α-chlorocy-
clobutanones 3.
Scheme 7. Synthesis of an orthogonally protected highly functionalized cyclobutanol 20.
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Scaffolds for the Diverted Synthesis of Serine Protease Inhibitors
Scheme 8. Synthesis of cyclobutanol scaffolds.
The synthesis started from 3d. The reduction of the
ketone group with NaBH4 was faster in the presence of
[10]
10% CeCl3
to give 60% of cyclobutanol 15, which was
converted into corresponding allyl ether 16 in 90% yield.
After removal of the tert-butyldiphenylsilyl protecting
group, resulting primary alcohol 17 was efficiently oxidized
to corresponding carboxylic acid 18 by sodium chlorite in
the presence of a catalytic amount of TEMPO.[11] These
oxidative conditions gave much better yields (89%) than
PDC in DMF (slow reaction, 50%) or IBX (55%). The
cleavage of the oxazolidine ring took place smoothly and
quantitatively to give an ammonium salt, which was directly
converted into cyclobutanol 20 by treatment with di-tert-
butyl dicarbonate in an ultrasonic bath. This two-step se-
quence gave 84% of α-chlorocyclobutanol 20.
The presence of an allyl substituent in compound 18 of-
fered possibilities for diversification of this ether substitu-
ent, for example, after oxidative cleavage. In this model syn-
thesis of a representative α-amino cyclobutanone scaffold,
we simply chose to hydrogenate the allyl group (Scheme 8).
Resulting propyl ether 21 was formed quantitatively. Its
structure and configuration were confirmed by X-ray dif-
fraction analysis (Figure 2).[9] The carboxylic acid was read-
ily converted into corresponding benzyl ester 22. Cleavage
of the oxazolidine ring with trifluoroacetic acid followed by
acylation of the amine group of 23 yielded 24a–e. Hydro-
genolysis of the benzyl group yielded four enantiopure cy-
clobutanol scaffolds 25a–d.
Figure 2. ORTEP drawing of the X-ray crystal structure of 21.
Scheme 9. Conversion of cyclobutanols 24 into two models of the
targeted α-chlorocyclobutanones.
We have thus developed efficient routes towards highly
functionalized and enantiopure cyclobutanols that should
be useful for the diverted synthesis of analogues of β-lactam
antibiotics. In contrast with the corresponding cyclobut-
anones that are highly electrophilic, these cyclobutanols are
Conclusions
In summary, we presented a synthetic strategy that pro-
rather stable and susceptible to further diversification by vides easy access to highly functionalized enantiopure cy-
functional group manipulations. The ketone group should be clobutanols and cyclobutanones as scaffolds for the synthe-
introduced at the end of the syntheses. We found that sodium sis of serine protease inhibitor analogues to β-lactams.
hypochlorite and a catalytic amount of TEMPO smoothly Scheme 10 displays the various compounds that were pre-
converted cyclobutanols 24a,b into cyclobutanones 26a and pared in enantiopure form from readily available starting
26b (Scheme 9).
materials 3. The functional density of these scaffolds should
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G. Yang, L. Ghosez
FULL PAPER
vated carbon (10% Pd, 1.4 mg, 12.6 µmol) and ethyl acetate (5 mL)
were added to a 25-mL flask at room temperature. Then, hydrogen
was flushed into the flask. After 12 h, the mixture was filtered
through Celite, washed with diethyl ether, dried with MgSO4 and
the solvents evaporated. Flash chromatography of the residue gave
allow high levels of diversity to be efficiently achieved,
which would allow biologically relevant regions of the
chemical space to be explored.
1
4 (0.06 g, 80%). Rf = 0.33 [petroleum ether (PE)/AcOEt, 2:1]. H
NMR (300 MHz, CDCl3): δ = 5.32 (s, 1 H, NCHO), 4.69 (d, J =
6.7 Hz, 1 H, CHN), 4.38 (d, J = 6.7 Hz, 1 H, CHO), 4.12 (m, 2 H,
CH2O), 3.72 (s, 3 H, OMe), 2.75 (m, 2 H, CH2), 0.87 (s, 9 H, tBu)
ppm. 13C NMR (75 MHz, CDCl3): δ = 156.1 (C=O), 102.8 (COH),
101.8 (NCHO), 81.4 (CHO), 71.0 (CCl), 68.0 (CH2O), 63.1 (CHN),
52.6 (OMe), 38.7 (tBu), 34.6 (CH ), 24.8 (tBu) ppm. IR (KBr): ν
˜
2
= 3456, 2972, 1718 (C=Ocarbamate), 1363, 1201 cm–1. MS (FAB
Q1MS): m/z (%) = 306 (100) [M + 1], 288 (28) [M – OH], 248 (17)
[M – tBu], 217 (59), 91 (69). C13H20ClNO5 (305.75): calcd. C 51.06,
H 6.59, N 4.58; found C 51.05, H 6.47, N 4.42.
Methyl (1S,3R,5S,6S,7S)-3-(tert-Butyl)-7-chloro-6-hydroxy-7-(2-
benzyloxy)ethyl-2-oxa-4-azabicyclo[3.2.0]heptane-4-carboxylate (5):
Sodium borohydride (20.9 mg, 0.55 mmol) was added at room tem-
perature to a solution of 3a (146 mg, 0.37 mmol) in methanol
(4 mL). The mixture was stirred at room temperature, and the reac-
tion was monitored by TLC. After 15 h the reaction mixture was
diluted with diethyl ether (10 mL) and washed with 0.1  HCl and
then with brine. The organic layer was dried and concentrated.
Flash chromatography (PE/AcOEt/iPrOH, 100:5:5; Rf = 0.25) gave
alcohol 5 (73 mg, 50%). 1H NMR (500 MHz, CDCl3): δ = 7.24–
7.34 (m, 5 H, Ph), 5.28 (s, 1 H, NCHO), 4.76 (dd, J = 6.4, 0.9 Hz,
1 H, CHO), 4.50 (s, 2 H, CH2Ph), 4.19 (dd, J = 6.4, 4.6 Hz, 1 H,
CHN), 3.95 (dd, J = 4.6, 0.9 Hz, 1 H, CHOH), 3.73 (s, 3 H, OMe),
3.71 (m, 2 H, CH2O), 2.69 (br., 1 H, OH), 2.27 (ddd, J = 14.6, 6.1,
6.1 Hz, 1 H, CH2), 2.15 (ddd, J = 14.6, 6.7, 6.7 Hz, 1 H, CH2),
0.89 (s, 9 H, tBu) ppm. 13C NMR (125 MHz, CDCl3): δ = 155.4
(C=O), 138.1 (Carom), 128.3, 127.7, 127.5 (CHarom), 101.5 (NCHO),
83.1 (CHO), 78.8 (CHOH), 73.2 (CH2Ph), 72.0 (CCl), 65.9
(CH2O), 63.1 (CHN), 52.7 (OMe), 38.7 (tBu), 34.9 (CH2), 25.2
Scheme 10. Cyclobutanol and cyclobutanone scaffolds accessible
from 3c,d.
The present series originates from -serine, which by vir-
tue of the synthetic strategy, generates acylamino and acetic
acid side chain absolute configurations identical to those
observed in β-lactam antibiotics. The synthetic strategy
presents the additional advantage of being potentially stereo-
divergent: an appropriate selection of the alcohol function
to be oxidized should provide access to diastereomeric cy-
clobutanones. If the allyl group could not be cleaved in a
satisfactory manner, the method should readily allow the
use of alternative protecting groups.
(tBu) ppm. IR (film): ν = 3438, 2958, 1712 (C=Ocarbamate), 1367,
˜
1128 cm–1. MS (FAB + Q1MS): m/z (%) = 398 (29) [M + 1], 340
(9) [M – tBu], 307 (15), 154 (100), 136 (77).
Methyl (1S,3R,5S,6S,7S)-3-(tert-Butyl)-7-chloro-6-(tert-butyldi-
methylsilyl)oxy-7-(2-benzyloxy)ethyl-2-oxa-4-azabicyclo[3.2.0]hep-
tane-4-carboxylate (6): To a solution of 5 (2.15 g, 5.40 mmol) in
DMF (23 mL) was successively added imidazole (1.1 g,
16.21 mmol) and a solution of tert-butyldimethylsilyl chloride
(1.22 g, 8.11 mmol) in DMF (5 mL) at 0 °C. The resulting mixture
was stirred for 40 h at room temperature and then cooled to 0 °C.
H2O (3 mL) was added, and the mixture was stirred for 10 min.
The resulting solution was poured into water (70 mL) and extracted
with diethyl ether (3ϫ10 mL). The combined organic layers were
washed with brine, dried and the solvents evaporated. Flash
chromatography (PE/ether, 6:1; Rf = 0.27) gave pure 6 (2.3 g, 83%).
Experimental Section
General Remarks: NMR spectra were recorded with a Varian Gem-
ini 300BB (300 MHz for 1H and 75 MHz for 13C). High-resolution
spectra were recorded with a Bruker AM-500 (500 MHz for 1H and
125 MHz for 13C). Chemical shifts are given in ppm relative to the
internal reference. Coupling constants (J values) are reported in
Hertz (Hz), and spin multiplicities are indicated by the following
symbols: s (singlet), d (doublet), t (triplet), q (quartet), m (mul-
tiplet), br. (broad). The MS spectra were recorded with a Varian
MAT-44 or Finnigan MAT-TSQ 70 apparatus. Infrared spectra
were recorded with a Biorad FTS-135. The optical rotation values
were measured with a Perkin–Elmer 241 polarimeter. Concentra-
tions are given in g/100 mL. Melting points were measured with a
Buchi apparatus (oil bath) and are uncorrected. Flash chromatog-
raphy separations were performed by using Merck 60 40–63 µm
silica and predistilled technical grade solvents. Triethylamine and
CH2Cl2 were distilled from CaH2. Et2O, THF, cyclohexane and
toluene were distilled over Na with benzophenone as indicator.
DMF and DMA were dried with 3 Å MS.
1
M.p 87–89 °C. H NMR (500 MHz, CDCl3): δ = 7.27–7.35 (m, 5
H, Ph), 5.31 (s, 1 H, NCHO), 4.78 (dd, J = 6.6, 0.9 Hz, 1 H, CHO),
4.50 (s, 2 H, CH2Ph), 4.1 (dd, J = 6.6, 3.1 Hz, 1 H, CHN), 3.95
(dd, J = 3.1, 0.9 Hz, 1 H, CHOSi), 3.70 (s, 3 H, OMe), 3.69 (m, 2
H, CH2O), 1.95–2.33 (m, 2 H, CH2), 0.93 (s, 9 H, tBu), 0.86 (s, 9
H, SitBu), 0.05 (s, 6 H, SiMe2) ppm. 13C NMR (125 MHz, CDCl3):
δ = 154.3 (C=O), 138.3 (Carom), 128.3, 127.7, 127.5 (CHarom), 101.2
(NCHO), 84.3 (CHO), 74.6 (CHOSi), 72.9 (CH2Ph), 71.2 (CCl),
66.8 (CH2O), 62.9 (CHN), 52.7 (OMe), 38.9 (tBu), 36.1 (CH2), 25.8
Methyl (2R,3aR,3bR,6aR,6bS)-2-tert-Butyl-6a-chloro-3b-hydroxy- (tBu), 25.2 (SitBu), 18.1 (SitBu), –5.0 (SiMe ) ppm. IR (film): ν =
˜
2
hexahydrofuro[3Ј.2Ј:3.4]cyclobuta[1.2-d][1.3]oxazole-3(2H)-carbox- 2958, 1731 (C=Ocarbamate), 1448, 1364, 1098 cm–1. MS (FAB +
ylate (4): Carboxylate 3a (100 mg, 0.25 mmol), palladium on acti-
Q1MS): m/z (%) = 512 (4) [M + 1], 454 (17) [M – tBu], 307 (15),
1742
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Scaffolds for the Diverted Synthesis of Serine Protease Inhibitors
154 (100), 136 (64). [α]2D0
C26H42ClNO5Si (512.15): calcd. C 60.97, H 8.26, Cl 6.82, N 2.73; 4.10 (d, J = 3.4 Hz, 1 H, CHOSi), 3.73 (s, 3 H, OMe), 3.0 (AB, J
=
+0.51 (c
=
0.95, CHCl3).
(d, J = 6.3 Hz, 1 H, CHO), 4.15 (dd, J = 6.3, 3.4 Hz, 1 H, CHN),
found C 61.01, H 8.11, Cl 6.54, N 2.63.
= 16.0 Hz, 2 H, CH2), 0.94 (s, 9 H, tBu), 0.85 (s, 9 H, SitBu), 0.08
(s, 6 H, SiMe2) ppm. 13C NMR (75 MHz, CDCl3): δ = 168.8
(C=O), 154.3 (C=O), 135.6 (Carom), 129.0, 128.5, 128.1 (CHarom),
101.1 (NCHO), 83.8 (CHO), 68.3 (CH2Ph), 66.5 (CCl), 63.1
(CHN), 63.0 (CHOSi), 52.7 (OMe), 41.2 (CH2), 38.9 (tBu), 25.6
Methyl (1S,3R,5S,6S,7S)-3-(tert-Butyl)-7-chloro-6-(tert-butyldi-
methylsilyl)oxy-7-(2-hydroxy)ethyl-2-oxa-4-azabicyclo[3.2.0]hep-
tane-4-carboxylate (7): Hydrogen was flushed through a suspension
of palladium on activated carbon (10% Pd, 530 mg, 498 µmol) in
a solution of 6 (2.55 g, 4.98 mmol) in ethyl acetate (40 mL) at room
temperature. The reaction was complete after 8 h (TLC monitoring,
PE/iPrOH/AcOEt, 100:5:5; Rf = 0.37). The mixture was passed
through a Celite pad and then evaporated to give pure 7 (2.1 g,
100%). 1H NMR (200 MHz, CDCl3): δ = 5.31 (s, 1 H, NCHO),
4.86 (dd, J = 6.8, 0.7 Hz, 1 H, CHO), 4.15 (dd, J = 6.8, 3.2 Hz, 1
H, CHN), 3.90 (dd, J = 3.2, 0.7 Hz, 1 H, CHOSi), 3.83 (m, 2 H,
CH2O), 3.73 (s, 3 H, OMe), 1.81–2.28 (m, 2 H, CH2), 0.94 (s, 9 H,
tBu), 0.88 (s, 9 H, SitBu), 0.08 (s, 6 H, SiMe2) ppm. 13C NMR
(50 MHz, CDCl3): δ = 154.3 (C=O), 101.2 (NCHO), 84.2 (CHO),
71.2 (CH2O), 67.4 (CCl), 62.8 (CHN), 59.4 (CHOSi), 52.8 (OMe),
38.9 (tBu), 37.7 (CH2), 25.8 (tBu), 25.2 (SitBu), 18.3 (SitBu), –5.0
(tBu), 25.2 (SitBu), 18.1 (SitBu), 5.1 (SiMe ) ppm. IR (film): ν =
˜
2
2963, 1732 (C=O), 1726 (C=Ocarbamate), 1361, 1107 cm–1. MS (FAB
+ Q1MS): m/z (%) = 526 (20) [M + 1], 468 (25) [M – tBu], 418
(11), 300 (15), 185 (26), 128 (38), 91 (100).
Methyl (1S,3R,5S,6S,7S)-3-(tert-Butyl)-7-chloro-6-hydroxy-7-ben-
zyloxycarbonylmethyl-2-oxa-4-azabicyclo[3.2.0]heptane-4-carboxyl-
ate (10): A mixture of 9 (1.15 g, 2.19 mmol) and para-toluenesul-
fonic acid monohydrate (0.71 g, 2.62 mmol) in methanol (100 mL)
was stirred at room temperature for 2 d. The mixture was neutral-
ized with saturated aqueous sodium hydrogen carbonate, and the
methanol was removed under reduced pressure. The residue was
treated with water (10 mL), and the resulting mixture was extracted
with AcOEt (3ϫ20 mL). The organic layers were dried and con-
centrated. The residue was purified by flash chromatography (PE/
AcOEt/iPrOH, 100:5:5; Rf = 0.27) to give 10 (0.8 g, 89 %). 1H
NMR (300 MHz, CDCl3): δ = 7.30–7.38 (m, 5 H, Ph), 5.26 (s, 1
H, NCHO), 5.16 (s, 2 H, CH2Ph), 4.80 (dd, J = 6.3, 0.8 Hz, 1 H,
CHO), 4.23 (dd, J = 6.0, 4.8 Hz, 1 H, CHN), 4.07 (m, 1 H,
CHOH), 3.73 (s, 3 H, OMe), 3.1 (br., 1 H OH), 3.05 (AB, J =
17.0 Hz, 2 H, CH2), 0.88 (s, 9 H, tBu) ppm. 13C NMR (75 MHz,
CDCl3): δ = 169.7 (C=O), 155.3 (C=O), 135.2 (Carom), 128.6, 128.3,
128.1 (CHarom), 101.6 (NCHO), 82.4 (CHO), 78.1 (CHOH), 67.8
(CCl), 66.8 (CH2Ph), 64.3 (CHN), 52.9 (OMe), 40.5 (CH2), 38.9
(SiMe ) ppm. IR (film): ν = 3454, 2958, 1724 (C=Ocarbamate), 1361,
˜
2
1101 cm–1. MS (FAB + Q1MS): m/z (%) = 422 (9) [M + 1], 364
(19) [M – tBu], 307 (17), 154 (100), 136 (64).
Methyl (1S,3R,5S,6S,7S)-3-(tert-Butyl)-7-chloro-6-(tert-butyldi-
methylsilyl)oxy-7-hydroxycarbonylmethyl-2-oxa-4-azabicyclo[3.2.0]-
heptane-4-carboxylate (8): A solution of 7 (1.6 g, 3.79 mmol) and
pyridinium dichromate (5 g, 13.26 mmol) in DMF (15 mL) was
stirred at 0 °C then room temperature till disappearance of the
starting material (TLC monitoring; 2 d). The reaction was
quenched by the addition of water (40 mL), and the mixture was
extracted with diethyl ether (4ϫ60 mL). The organic layers were
washed with brine, dried with MgSO4 and concentrated to give a
colourless oil. Purification by flash chromatography (PE/AcOEt/
iPrOH, 100:5:5; Rf = 0.27) gave 8 (colourless crystals 1.0 g, 60%).
1H NMR (500 MHz, CDCl3, 47 °C): δ = 5.30 (s, 1 H, NCHO), 4.9
(d, J = 6.1 Hz, 1 H, CHO), 4.14 (dd, J = 6.1, 3.1 Hz, 2 H, CHN,
CHOSi), 3.73 (s, 3 H, OMe), 2.98 (AB, J = 16.5 Hz, 2 H, CH2),
0.95 (s, 9 H, tBu), 0.89 (s, 9 H, SitBu), 0.13 (s, 6 H, SiMe2) ppm.
1H NMR (500 MHz, C6D6, 47 °C): δ = 5.32 (s, 1 H, NCHO), 4.86
(d, J = 6.3 Hz, 1 H, CHO), 4.26 (d, J = 3.1 Hz, 1 H, CHOSi), 4.12
(dd, J = 6.3, 3.1 Hz, 1 H, CHN), 3.46 (s, 3 H, OMe), 2.71–2.85
(AB, J = 16.6 Hz, 2 H, CH2), 1.1 (s, 9 H, SitBu), 0.80 (s, 9 H, tBu),
0.19 (s, 6 H, SiMe2) ppm. 13C NMR (125 MHz, CDCl3, 47 °C): δ
= 173.6 (C=O), 154.3 (C=O), 101.1 (NCHO), 84.0 (CHO), 76.0
(CHN), 68.1 (CCl), 63.2 (CHOSi), 52.7 (OMe), 41 (CH2), 38.9
(tBu), 25.6 (tBu), 25.2 (SitBu), 18.1 (SitBu), –5.1 (SiMe2) ppm. IR
(tBu), 25.2 (tBu) ppm. IR (film): ν = 346, 1738 (C=O), 1726
˜
(C=Ocarbamate), 1361, 1120 cm–1. MS (FAB + Q1MS): m/z (%) =
412 (48) [M + 1], 354 (17) [M – tBu], 290 (11), 185 (10), 154 (45),
136 (33), 91 (100). C20H26ClNO6 (411.88): calcd. C 58.32, H 6.36,
N 3.40; found C 57.75, H 6.08, N 3.43.
Methyl (1S,3R,5R,7R)-3-(tert-Butyl)-7-chloro-6-oxo-7-(benzyloxy-
carbonylmethyl)-2-oxa-4-azabicyclo[3.2.0]heptane-4-carboxylate
(11) and Elimination Product (12): A solution of 10 (70 mg,
170 µmol) in dichloromethane (0.5 mL) was added dropwise to a
solution of oxalyl chloride (45 µL, 510 µmol) and methyl sulfoxide
(62 µL, 850 µmol) in dichloromethane (0.7 mL) at –60 °C. The mix-
ture was stirred for 30 min. Triethylamine (71 µL, 510 µmol) was
added, and the reaction mixture was stirred for 5 min and then
warmed up to room temperature. Water (1 mL) was added, and the
aqueous layer was further extracted with dichloromethane (5 mL).
The organic layers were washed with brine, dried and concentrated.
Flash chromatography (PE/AcOEt/iPrOH, 100:5:5) gave 11 (24 mg,
(film): ν = 3434, 1736 (C=O), 1724 (C=Ocarbamate), 1361, 1101 cm–1.
˜
[α]2D0 = +0.92 (c = 0.92, CHCl3). MS (FAB + Q1MS): m/z (%) =
436 (45) [M + 1], 378 (49) [M – tBu], 300 (24), 185 (33), 128 (60),
73 (100). X-ray diffraction analysis: wavelength: 0.71069 Å; crystal
system: orthorhombic; unit cell dimensions: a = 10.275 (3) Å, α =
90°; b = 11.353 (4) Å, β = 90°; c = 20.779 (7) Å, γ = 90°.
1
35%), Rf = 0.28 and 12 (16 mg, 25%), Rf = 0.33. Data for 11: H
NMR (300 MHz, CDCl3): δ = 7.32–7.41 (m, 5 H, Ph), 5.35 (d, J
= 5.5 Hz, 1 H, CHO), 5.20 (s, 1 H, NCHO), 5.08–5.26 (AB, J =
12.3 Hz, 2 H, CH2Ph), 5.0 (d, J = 5.5 Hz, 1 H, CHN), 3.75 (s, 3
H, OMe), 2.94–3.25 (AB, J = 17.0 Hz, 2 H, CH2), 0.88 (s, 9 H,
Methyl (1S,3R,5S,6S,7S)-3-(tert-Butyl)-7-chloro-6-(tert-butyldi- tBu) ppm. 13C NMR (75 MHz, CDCl3): δ = 194.2 (C=O), 167.8
methylsilyl)oxy-7-hydroxycarbonylmethyl-2-oxa-4-azabicyclo[3.2.0]-
heptane-4-carboxylate (9): To a solution of 8 (1 g, 2.29 mmol) in
DMA (20 mL) was added benzyl bromide (785 mg, 4.59 mmol) and
sodium hydrogen carbonate (580 mg, 6.88 mmol). The mixture was
stirred at room temperature for 24 h. Then, water (50 mL) was
added, and the resulting mixture was extracted with diethyl ether
(3ϫ100 mL). The combined organic layers were dried and concen-
trated. Flash chromatography (PE/ether, 6:1; Rf = 0.3) of the resi-
(C=O), 155.4 (C=O), 135.4 (Carom), 128.7, 128.5, 128.2 (CHarom),
102.3 (NCHO), 81.2 (CHO), 74.5 (CHN), 73.8 (CCl), 67.1
(CH2Ph), 52.8 (OMe), 38.9 (tBu), 36.2 (CH2), 25.2 (tBu) ppm. Data
1
for 12: H NMR (300 MHz, CDCl3): δ = 7.32–7.42 (m, 5 H, Ph),
6.45 (d, J = 1.5 Hz, 1 H, =CH), 5.65 (dd, J = 5.7, 1.5 Hz, 1 H,
CHO), 5.45 (s, 1 H, NCHO), 5.27 (AB, J = 13.1 Hz, 2 H, CH2Ph),
4.93 (d, J = 5.7 Hz, 1 H, CHN), 3.73 (s, 3 H, OMe), 0.89 (s, 9 H,
tBu) ppm. 13C NMR (75 MHz, CDCl3): δ = 190.2 (C=O), 163.6
(C=O), 156.9 (C=O), 154.0 (=C=), 135.0 (Carom), 128.7, 128.5,
1
due gave 9 (0.91 g, 78%). H NMR (300 MHz, CDCl3): δ = 7.31–
7.38 (m, 5 H, Ph), 5.26 (s, 1 H, NCHO), 5.15 (s, 2 H, CH2Ph), 4.88 128.1 (CHarom), 120.5 (=CH), 101.8 (NCHO), 76.5 (CHO), 74.4
Eur. J. Org. Chem. 2009, 1738–1748
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1743

G. Yang, L. Ghosez
(CHN), 67.6 (CH2Ph), 52.7 (OMe), 39.2 (tBu), 25.2 (tBu) ppm. 2958, 1728 (C=O), 1121, 760 cm–1. MS (CI + Q1MS): m/z (%) =
FULL PAPER
MS(FAB + Q1MS): m/z (%) = 374 (5) [M + 1], 281 (11), 207 (13),
362 (20) [M + 1], 282 (23),256 (12), 163 (13), 129 (65), 89 (100).
154 (23), 128 (30), 91 (100).
tert-Butyl (1S,3R,5S,6S,7S)-3-(tert-Butyl)-7-chloro-6-hydroxy-7-{2-
[(tert-butyldiphenylsilyl)oxy]ethyl}-2-oxa-4-azabicyclo[3.2.0]hep-
tane-4-carboxylate (15): Sodium borohydride (1.6 g, 42.64 mmol)
was added portionwise, at –30 °C to –10 °C, to a solution of 3d
(5 g, 8.53 mmol) and cerium chloride heptahydrate (1.6 g,
4.26 mmol) in THF (70 mL), The mixture was stirred for 1.5 h,
treated with a saturated aqueous solution of NH4Cl (40 mL) and
then extracted with AcOEt. The combined organic layers were
dried with MgSO4 and concentrated. The residue was purified by
flash chromatography (PE/ether, 6:1; Rf = 0.17) to give 15 (3.0 g,
60 %). M.p 74–76 °C. 1H NMR (500 MHz, CDCl3, 47 °C): δ =
7.38–7.71 (m, 10 H, 2Ph), 5.26 (s, 1 H, NCHO), 4.72 (dd, J = 6.1,
0.9 Hz, 1 H, CHO), 4.14 (dd, J = 6.1, 4.6 Hz, 1 H, CHN), 3.94
(ddd, J = 7.3, 4.6, 0.9 Hz, 1 H, CHOH), 3.89 (m, 2 H, CH2O), 2.57
(d, J = 7.3 Hz, 1 H, OH), 2.19 (m, 2 H, CH2), 1.50 (s, 9 H, OtBu),
1.07 (s, 9 H, SitBu), 0.88 (s, 9 H, tBu) ppm. 13C NMR (125 MHz,
CDCl3, 47 °C): δ = 154.1 (C=O), 133.5 (Carom), 135.5, 129.6, 127.6
(CHarom), 101.2 (NCHO), 83.1 (CHO), 80.9 (OtBu), 78.9 (CHOH),
72.5 (CCl), 63.8 (CHN), 59.9 (CH2O), 38.7 (tBu), 37.4 (CH2), 28.2
tert-Butyl (1S,3R,5S,6S,7S)-3-(tert-Butyl)-7-chloro-6-hydroxy-7-(2-
benzyloxy)ethyl-2-oxa-4-azabicyclo[3.2.0]heptane-4-carboxylate
(5c): Reduction of 3c (4 mmol) by NaBH4 following the procedure
used for the reduction of 3a. Purification by flash chromatography
(PE/AcOEt/PrOH, 100:5:4; Rf = 0.27). Yield 45 %. 1H NMR
(300 MHz, CDCl3): δ = 7.31–7.38 (m, 5 H, Ph), 5.25 (s, 1 H,
NCHO), 4.76 (dd, J = 6.2, 0.8 Hz, 1 H, CHO), 4.51 (s, 2 H,
CH2Ph), 4.12 (dd, J = 6.2, 4.4 Hz, 1 H, CHN), 3.90 (dd, J = 4.4,
0.8 Hz, 1 H, CHOH), 3.71 (m, 2 H, CH2O) 2.69 (br., 1 H, OH),
2.10–2.31 (m, 2 H, CH2), 1.47 (s, 9 H, OtBu), 0.89 (s, 9 H, tBu)
ppm. 13C NMR (75 MHz, CDCl3): δ = 154.5 (C=O), 138.0 (Carom),
128.5, 127.9, 127.5 (CHarom), 101.1 (NCHO), 82.4 (CHO), 81.4
(OtBu), 78.2 (CHOH), 73.4 (CH2Ph), 67.1 (CCl), 66.3 (CH2O),
63.2 (CHN), 38.8 (tBu), 34.2 (CH2), 28.2 (OtBu), 25.5 (tBu) ppm.
IR (film): ν = 3447, 2958, 1721 (C=Ocarbamate), 1364, 1121 cm–1.
˜
MS (FAB + Q1MS): m/z (%) = 440 (5) [M + 1], 382 [M – tBu],
340 (100), 292 (15), 91 (14).
(OtBu), 26.9 (SitBu), 25.2 (tBu), 19.1 (SitBu) ppm. IR (KBr): ν =
˜
tert-Butyl (1S,3R,5S,6S,7S)-3-(tert-Butyl)-7-chloro-6-benzyloxy-7-
(2-benzyloxy)ethyl-2-oxa-4-azabicyclo[3.2.0]heptane-4-carboxylate
(13): A solution of 5c (600 mg, 1.36 mmol) in THF (9 mL) was
added dropwise to a suspension of potassium hydride (30% disper-
sion in mineral oil, 260 mg, 1.91 mmol) in THF (9 mL). After
10 min, benzyl bromide (350 mg, 2.05 mmol) was added slowly at
0 °C. The mixture was stirred at room temperature for 2 h and then
poured into a solution of saturated aqueous solution of NH4Cl,
extracted with diethyl ether (3ϫ20 mL). The combined organic
layers were washed with brine, dried and the solvents evaporated.
Flash chromatography (PE/ether, 5:1; Rf = 0.33) gave pure 13
(0.6 g, 83%). 1H NMR (300 MHz, CDCl3): δ = 7.31–7.43 (m, 5 H,
Ph), 5.25 (s, 1 H, NCHO), 4.77 (dd, J = 6.8, 0.8 Hz, 1 H, CHO),
4.65 (s, 2 H, CH2Ph), 4.50 (s, 2 H, CH2Ph), 4.24 (dd, J = 6.8,
3.6 Hz, 1 H, CHN), 3.82 (dd, J = 3.6, 0.8 Hz, 1 H, CHOBn), 3.71
(m, 2 H, CH2O), 2.01–2.31 (m, 2 H, CH2), 1.47 (s, 9 H, OtBu),
0.89 (s, 9 H, tBu) ppm. 13C NMR (125 MHz, CDCl3): δ = 154.2
(C=O), 138.3 (Carom), 128.5, 127.9, 127.5 (CHarom), 100.7 (NCHO),
83.8 (OtBu), 83.4 (CHO), 80.7 (CHOBn), 73.0 (CH2Ph), 72.0
(CH2Ph), 70.4 (CH2O), 66.3 (CCl), 61.2 (CHN), 38.8 (tBu), 36.2
3460 (OH), 2961, 1712 (C=O), 1368 (OH), 1111 cm–1. MS (CI +
Q1MS): m/z (%) = 589 (2) [M + 1], 488 (100) [M + 1 – Boc], 454
(20), 410 (18). MS (CI/Q1MS): m/z (%) = 587 (64) [M – 1], 501
(50), 465 (100),255 (28). [α]2D0 = +0.45 (c = 0.52, CHCl3).
C32H46ClNO5Si (588.25): calcd. C 65.34, H 7.88, Cl 6.02, N 2.38;
found C 65.86, H 7.98, Cl 5.59, N 2.24.
tert-Butyl (1S,3R,5S,6S,7S)-3-(tert-Butyl)-7-chloro-6-allyloxy-7-{2-
[(tert-butyldiphenylsilyl)oxy]ethyl}-2-oxa-4-azabicyclo[3.2.0]hep-
tane-4-carboxylate (16): A solution of 15 (2.9 g, 4.93 mmol) in THF
(32 mL) was added dropwise to a suspension of potassium hydride
(30% dispersion in mineral oil, 1.32 g, 9.86 mmol) in THF (16 mL)
under an atmosphere of argon at 0 °C. After 20 min at 0 °C, allyl
bromide (1.19 g, 9.86 mmol) was added slowly, and the suspension
was stirred at room temperature for 3 h and then poured into a
mixture of ice and saturated NH4Cl. After extraction with diethyl
ether (3ϫ20 mL), the combined organic layers were washed with
brine, dried and the solvents evaporated. The residue was chro-
matographed (PE/ether, 10:1; Rf = 0.45) to give 16 (2.8 g, 90%).
1H NMR (300 MHz, CDCl3): δ = 7.37–7.71 (m, 10 H, 2Ph), 5.9
(m, 1 H, CH=), 5.27 (ddd, J = 17.3, 1.5, 1.5 Hz, 1 H, CH2=), 5.25
(s, 1 H, NCHO), 5.18 (ddd, J = 10.3, 1.5, 1.5 Hz, 1 H, CH2=), 4.69
(dd, J = 6.6, 0.7 Hz, 1 H, CHO), 4.18 (dd, J = 6.6, 3.9 Hz, 1 H,
CHN), 4.1 (m, 2 H, CH2Oallyl), 3.85 (m, 2 H, CH2OSi), 3.64 (dd,
J = 3.9, 0.7 Hz, 1 H, CHOCH2), 2.01–2.36 (m, 2 H, CH2), 1.49 (s,
9 H, OtBu), 1.05 (s, 9 H, SitBu), 0.85 (s, 9 H, tBu) ppm. 13C NMR
(75 MHz, CDCl3): δ = 153.1 (C=O), 144.4 (CH=), 133.8 (Carom),
135.6, 129.7, 127.7 (Carom), 112.3 (CH2=), 100.1 (NCHO), 96.2
(CHO), 91.6 (CHOCH2), 86.2 (CHN), 80.1 (OtBu), 74.2 (CH2Oal-
lyl), 71.1 (CCl), 62.9 (CH2O), 40.9 (CH2), 39.4 (tBu), 28.3 (OtBu),
(CH ), 28.3 (OtBu), 25.3 (tBu) ppm. IR (film): ν = 2958, 1725
˜
2
(C=Ocarbamate), 1356, 1116, 760 cm–1. MS (CI + Q1MS LMR): m/z
(%) = 530 (8) [M + 1], 472 (6) [M – tBu], 430 (100), 334 (15), 107
(28), 91 (24). HRMS (CI) calcd. for C30H40ClNO5 532.2644, found
532.2644.
(1R,2S,3R,4S)-4-Amino-3-(benzyloxy)-2-[2-(benzyloxy)ethyl]-2-chlo-
rocyclobutanol (14): Trifluoroacetic acid (320 µL) was added drop-
wise at room temperature to a mixture of 13 (100 mg, 188.6 µmol)
in dichloromethane (630 µL) and water (100 µL). The mixture was
stirred for 5 h. Then, NaHCO3 was added to reach pH 8, and the
resulting mixture was extracted with CH2Cl2. The combined or-
ganic layers were dried with MgSO4 and concentrated in vacuo.
Flash chromatography (CH2Cl2/MeOH, 100:5; Rf = 0.32) gave pure
26.8 (SitBu), 25.6 (tBu), 19.1 (SitBu) ppm. IR (KBr): ν = 3080,
˜
2958, 1716 (C=O), 1364, 781 cm–1. MS (EI + Q1MS LMR): m/z
(%) = 570 (5) [M – tBu], 470 (33), 351 (32), 281 (100), 227 (32),
126 (47), 97 (42). [α]2D0 = +0.52 (c = 0.62, CHCl3). C35H50ClNO5Si
(628.31): calcd. C 66.90, H 8.02, Cl 5.64, N 2.22; found C 66.89,
H 8.20, Cl 6.06, N 2.18.
1
14 (0.05 g, 73%). H NMR (300 MHz, CDCl3): δ = 8.2 (br., 3 H,
NH2, OH), 7.28–7.34 (m, 10 H, Ph), 5.25 (s, 1 H, NCHO), 4.52 (s,
2 H, CH2Ph), 4.46 (s, 2 H, CH2Ph), 4.11 (m, 1 H, CHO), 3.82 (m,
1 H, CHN), 3.67 (m, 2 H, CH2O), 3.40 (m, 1 H, CHOBn), 2.21 tert-Butyl (1S,3R,5S,6S,7S)-3-(tert-Butyl)-7-chloro-6-allyloxy-7-(2-
(m, 1 H, CH2), 1.61 (m, 1 H, CH2) ppm. 13C NMR (125 MHz, hydroxy)ethyl-2-oxa-4-azabicyclo[3.2.0]heptane-4-carboxylate (17):
CDCl3): δ = 136.9 (Carom), 128.5, 127.9, 127.5 (CHarom), 81.0
(CHOH), 73.7 (CH2Ph), 72.5 (CH2Ph), 71.5 (CCl), 70.1 (CHOBn), THF (6 mL) was added at 0 °C to a solution of 16 (1.4 g,
65.3 (CH O), 51.3 (CHN), 35.9 (CH ) ppm. IR (film): ν = 3426, 2.23 mmol) in THF (22 mL). The mixture was stirred for 3 h at
Tetrabutylammonium fluoride trihydrate (844 mg, 2.67 mmol) in
˜
2
2
1744
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1738–1748

Scaffolds for the Diverted Synthesis of Serine Protease Inhibitors
room temperature, treated with brine (20 mL) and extracted with
diethyl ether (3ϫ30 mL). The extraction residue was purified by
flash chromatography (PE/iPrOH, 100:4; Rf = 0.22) to give pure
17 (0.8 g, 92% yield). 1H NMR (500 MHz, CDCl3, 47 °C): δ = 5.94
phase were dried and concentrated. Flash chromatography (PE/
ether, 5:1; Rf = 0.27) of the residue gave pure 19 (0.62 g, 92%). H
NMR (300 MHz, CDCl3): δ = 7.34–7.47 (m, 5 H, Ph), 5.99 (m, 1
H, CH=), 5.34 (ddd, J = 17.3, 1.5, 1.5 Hz, 1 H, CH2=), 5.28 (s, 1
1
(m, 1 H, CH=), 5.32 (ddd, J = 17.3, 1.5, 1.5 Hz, 1 H, CH2=), 5.29 H, NCHO), 5.22 (ddd, J = 10.3, 1.5, 1.5 Hz, 1 H, CH2=), 5.19 (s,
(s, 1 H, NCHO), 5.21 (ddd, J = 10.3, 1.5, 1.5 Hz, 1 H, CH2=), 4.79 2 H, CH2Ph), 4.82 (dd, J = 6.6, 0.8 Hz, 1 H, CHO), 4.24, (dd, J =
(dd, J = 6.4, 0.8 Hz, 1 H, CHO), 4.23 (dd, J = 6.4, 3.9 Hz, 1 H, 6.6, 3.9 Hz, 1 H, CHN), 4.21–4.02 (m, 2 H, CH2Oallyl), 3.87 (dd, J
CHN), 4.16 (ddd, J = 12.2, 5.5, 1.5 Hz, 1 H, CH2Oallyl), 4.10 (ddd, = 3.9, 0.8 Hz, 1 H, CHOCH2), 3.0 (AB, J = 15.7 Hz, 2 H, CH2),
J = 12.2, 5.5, 1.5 Hz, 1 H, CH2Oallyl), 3.87 (m, 2 H, CH2OH), 3.70 1.49 (s, 9 H, tBuO), O.89 (s, 9 H, tBu) ppm. 13C NMR (75 MHz,
(dd, J = 3.9, 0.8 Hz, 1 H, CHOCH2), 2.07–2.26 (m, 2 H, CH2), CDCl3, APT): δ = 168.9 (C=O), 153.0 (C=O), 133.8 (CH=), 135.6
1.49 (s, 9 H, OtBu), 0.89 (s, 9 H, tBu) ppm. 13C NMR (125 MHz,
CDCl3, 47 °C): δ = 153.1 (C=O), 133.9 (CH=), 117.6 (CH2=), 100.8
(NCHO), 83.7 (CHO), 83.2 (CHOCH2), 80.9 (OtBu), 71.2
(CH2Oallyl), 70.1 (CCl), 61.1 (CHN), 58.6 (CH2O), 39.5 (CH2), 38.8
(Carom), 128.6, 128.2, 128.0 (Carom), 118.2 (H2C=), 100.7 (NCHO),
83.6 (CHO), 83.2 (CHOCH2), 80.9 (OtBu), 71.3, (CH2allyl), 67.2
(CH2Ph), 66.7, (C-Cl), 61.1 (CHN), 41.7 (CH2), 38.9, 28.3, 25.2
(tBu) ppm. IR (KBr): ν = 2967, 1741 (C=O), 1714 (C=O), 1361,
˜
(tBu), 28.3 (OtBu), 25.3 (tBu) ppm. IR (KBr): ν = 2974, 1710
1117, 760 cm–1. MS (EI + Q1MS LMR): m/z (%) = 436 (45) [M –
tBu], 380 (52), 358 (61), 336 (100), 127 (17). C26H36ClNO6 (494.02):
˜
(C=O), 1368, 1171 cm–1. MS (EI + Q1MS LMR): m/z (%) = 332
(21) [M – tBu], 276 (61), 232 (58), 227 (82), 171 (100), 127 (20). calcd. C 63.21, H 7.34, N 2.83; found C 63.40, H 7.32, N 2.78.
[α]2D3 = +0.57 (c = 0.6, CHCl3). C19H32ClNO5 (389.91): calcd. C
58.52, H 8.27, Cl 9.09, N 3.59; found C 58.69, H 8.11, Cl 8.88, N
3.47.
Benzyl 2-[(1R,2S,3R,4S)-3-(tert-Butyloxycarbonyl)amino-1-chloro-
2-hydroxy-4-allyloxycyclobutyl]acetate (20): Trifluoroacetic acid
(2.4 mL) was added dropwise at room temperature to a solution of
tert-Butyl (1S,3R,5S,6S,7S)-3-(tert-Butyl)-7-chloro-6-allyloxy-7-hy-
19 (620 mg, 1.25 mmol, 1 equiv.) in dichloromethane (3.2 mL). The
droxycarbonylmethyl-2-oxa-4-azabicyclo[3.2.0]heptane-4-carboxyl- mixture was stirred for 2 h. Evaporation of the solvent gave a crude
ate (18): A solution of 17 (530 mg, 1.36 mmol) and TEMPO
(14.9 mg, 95.14 µmol) in acetonitrile (6.8 mL) and sodium phos-
phate buffer (0.67 , pH 6.7, 4 mL/mmol) was stirred at 35 °C.
Then, aqueous solutions of sodium chlorite (2  in water, 307 mg,
2.72 mmol) and sodium hypochlorite (410 µL, 27.18 µmol) were
added simultaneously over a period of 2 h (caution: do not mix
them before addition). The mixture was stirred at 35 °C until the
reaction was complete (5 h). Water (8 mL) was added, and the pH
was adjusted to 8.0 with 2  NaOH. The reaction was quenched
by pouring into cold (0 °C) Na2SO3 (0.35 g in 5 mL of water) then
stirred for 30 min at room temperature. Then, methyl tert-butyl
ether (MTBE, 5 mL) was added, and the organic layer was sepa-
rated and discarded. More MTBE (8 mL) was added, and the mix-
ture was brought up to pH 3–4 with 2  HCl. The combined or-
ganic layers were washed with water and brine and concentrated
to give the crude acid. Flash chromatography (PE/iPrOH, 100:6;
residue that was used without further purification. It was treated
with sodium hydrogen carbonate (412 mg, 4.91 mmol, 4 equiv.), di-
tert-butyl dicarbonate (304 mg, 1.35 mmol, 1.1 equiv.) and meth-
anol (3.5 mL) The mixture was heated at 40 °C for 4 h in an ultra-
sonic bath. The reaction mixture was filtered off, and the filtrate
was concentrated. Flash chromatography (PE/iPrOH, 100:5; Rf =
0.33) yielded pure 20 (0.44 g, 84 %). M.p. 96–98 °C. 1H NMR
(500 MHz, CDCl3): δ = 7.17–7.28 (m, 5 H, Ph), 5.86 (m, 1 H,
HC=), 5.29 (ddd, J = 17.4, 1.5, 1.5 Hz, 1 H, H2C=), 5.05 (d, J =
12.5 Hz, 2 H, CH2Ph), 4.49 (ddd, J = 8.0, 7.3, 7.3 Hz, 1 H CHN),
4.43 (dd, J = 7.3, 2.4 Hz, 1 H, CHOH), 4.02 (m, 2 H, CH2Oallyl),
3.82 (d, J = 7.3 Hz, 1 H, CHOCH2), 3.61 (d, J = 2.4 Hz, 1 H, OH),
2.86 (AB, J = 15.3 Hz, 2 H, CH2), 1.50 (s, 9 H, OtBu) ppm. 13C
NMR (125 MHz, CDCl3): δ = 171.3 (C=O), 155.9 (C=O), 136.6
(Carom), 135.5 (CH=), 128.6, 128.2, 128.0 (CHarom), 117.5 (CH2=),
85.2 (CHOCH2), 80.2 (OtBu), 74.9 (CHOH), 71.3 (CH2Oallyl), 69.7
1
Rf = 0, 2) gave 18 (0.49 g, 89%). H NMR (300 MHz, CDCl3): δ
= 5.94 (m, 1 H, CH=), 5.32 (ddd, J = 17.3, 1.5, 1.5 Hz, 1 H, CH2=),
(CH Ph), 53.7 (CHN), 42.9 (CH ), 29.1 (OtBu) ppm. IR (KBr): ν
˜
2 2
= 3360, 2343, 1716 (C=Oester), 1701 (C=O), 1165 cm–1. MS (Cl +
5.26 (s, 1 H, NCHO), 5.21 (ddd, J = 10.3, 1.5, 1.5 Hz, 1 H, CH2=), Q1MS LMR): m/z (%) = 426 (12) [M + 1], 370 (100), 326 (41),
4.86 (dd, J = 6.6, 0.8 Hz, 1 H, CHO), 4.23 (dd, J = 6.6, 3.9 Hz, 1
H, CHN), 4.01–4.19 (m, 2 H, CH2Oallyl), 3.86 (dd, J = 3.9, 0.8 Hz,
262 (24), 91 (37). MS (ClQ1MS LMR): m/z = 424 (100) [M – 1].
C21H28ClNO6 (425.90): calcd. C 59.50, H 6.18, Cl 8.36, N 3.30;
1 H, CHOCH2), 2.98 (AB, J = 16.5 Hz, 2 H, CH2), 1.49 (s, 9 H, found C 59.36, H 6.27, Cl 8.16, N 3.23.
OtBu), 0.89 (s, 9 H, tBu) ppm. 13C NMR (75 MHz, CDCl3): δ
= 173.8 (C=O), 152.8 (C=O), 133.8 (CH=), 118.2 (CH2=), 100.7
(NCHO), 83.3 (CHO), 83.0 (CHOCH2), 81.1 (OtBu), 71.4
(CH2Oallyl), 66.7 (CCl), 61.1 (CHN),41.2 (CH2), 38.9 (tBu), 28.3
tert-Butyl (1S,3R,5S,6S,7S)-3-(tert-Butyl)-7-chloro-6-propyloxy-7-
hydroxycarbonylmethyl-2-oxa-4-azabicyclo[3.2.0]heptane-4-carbox-
ylate (21): Hydrogen was flushed at room temperature through a
suspension of palladium on activated carbon (10 %, 420 mg,
396 µmol) in a solution of 18 (1.6 g, 3.96 mmol) in ethyl acetate
(32 mL). After 8 h, the hydrogenation was complete. The mixture
was filtered through Celite, and the filtrate was evaporated to yield
pure 21 (1.54 g, 95%). Rf = 0.37 (PE/iPrOH/AcOEt, 100:5:5). M.p
(OtBu), 25.3 (tBu) ppm. IR (KBr): ν = 3567, 2964, 1728 (C=O),
˜
1710 (C=O), 1367, 1121 cm–1. MS (CI + Q1MS): m/z (%) = 404
(8) [M + 1], 346 (8) [M – tBu], 304 (100), 268 (12), 227 (6), 88 (20).
MS (CI/Q1MS): m/z = 402 [M – 1]. [α]2D3 = +0.70 (c = 0.89, CHCl3).
C19H30ClNO6 (403.90): calcd. C 56.50, H 7.49, N 3.47; found C
56.32, H 7.60, N 3.80.
1
100–102 °C. H NMR (300 MHz, CDCl3): δ = 10.6 (s, 1 H, OH),
5.26 (s, 1 H, NCHO), 4.86 (dd, J = 6.6, 0.8 Hz, 1 H, CHO), 4.20
(dd, J = 6.6, 3.8 Hz, 1 H, CHN), 3.80 (dd, J = 3.8, 0.8 Hz, 1 H,
CHOCH2), 3.54 (m, 2 H, CH2O), 2.95 (AB, J = 16.3 Hz, 2 H,
CH2), 1.64 (m, 2 H, CH2), 1.46 (s, 9 H, OtBu), 0.90 (t, J = 7.2 Hz,
3 H, CH3), 0.89 (s, 9 H, tBu) ppm. 13C NMR (75 MHz, CDCl3):
δ = 174.5 (C=O), 154.6 (C=O), 100.6 (NCHO), 83.5 (CHO), 80.9
(OtBu), 77.4 (CHOCH2), 72.3 (CH2O), 67.0 (CCl), 60.9 (CHN),
41.6 (CH2COOH), 38.9 (tBu), 28.3 (OtBu), 25.3 (tBu), 22.9 (CH2),
tert-Butyl (1S,3R,5S,6S,7S)-3-(tert-Butyl)-7-chloro-6-allyloxy-7-
benzyloxycarbonylmethyl-2-oxa-4-azabicyclo[3.2.0.]heptane-4-car-
boxylate (19): Benzyl bromide (480 mg, 2.72 mmol, 2 equiv.), po-
tassium carbonate (190 mg, 1.36 mmol, 1 equiv.) and sodium hy-
drogen carbonate (230 mg, 2.72 mmol, 2 equiv.) were added to a
solution of carboxylic acid 18 in N,N-dimethylacetamide (DMA,
12 mL). The mixture was stirred for 5 h at room temperature and
then quenched with water (1 mL). The aqueous phase was ex-
tracted with diethyl ether (3ϫ10 mL), and the combined organic
10.5 (CH ) ppm. IR (KBr): ν = 3587, 2964, 1727 (C=O), 1711
˜
3
(C=O), 1364, 1121 cm–1. MS (CI CH4/N2O + Q1MS): m/z (%) =
Eur. J. Org. Chem. 2009, 1738–1748
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1745

G. Yang, L. Ghosez
FULL PAPER
406 (4) [M + 1], 306 (30), 288 (6), 154 (10), 89 (17), 59 (100).
[α]2D3 = +0.67 (c = 0.55, CHCl3). C19H32ClNO6 (495.91): calcd. C
56.22, H 7.95, Cl 8.73, N 3.45; found C 55.98, H 8.08, Cl 8.24,
N 3.39. X-ray diffraction analysis: Wavelength: 0.71069 Å; crystal
system: orthorhombic; unit cell dimensions: a = 10.722 (2) Å; α =
90°; b = 10.088 (5) Å; β = 110°; c = 11.531 (3) Å; γ = 90°.
Benzyl [(1R,2S,3R,4S)-3-(Acetyl)amino-1-chloro-2-hydroxy-4-pro-
pyloxycyclobutyl]acetate (24b): Same procedure as for 24a. Reac-
tion performed on 0.5 mmol scale, 82% yield. Rf = 0.25 (PE/ether/
1
iPrOH, 10:10:1). M.p 68–69 °C. H NMR (300 MHz, CDCl3): δ =
7.26–7.38 (m, 5 H, Ph), 6.47 (d, J = 8.5 Hz, 1 H NH), 5.48 (dd, J
= 7.2, 1.0 Hz, 1 H, CHOCH2), 5.14 (s, 2 H, OCH2Ph), 4.81 (ddd,
J = 8.5, 8.1, 7.2 Hz, 1 H, CHN), 4.21 (dd, J = 8.1, 1.0 Hz, 1 H,
CHOH), 3.46 (m, 2 H, CH2O), 2.95–3.07 (AB, J = 15.8 Hz, 2 H,
CH2CO2Bn), 1.99 (s, 3 H CH3CO), 1.46 (m, 2 H, CH2), 0.90 (t, J
= 7.6 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 170.6
(C=Oamide), 168.1 (C=O), 134.4 (Carom), 128.8, 128.4, 128.1
(CHarom), 82.0 (CHOCH2), 73.4 (CHOH), 72.3 (CH2Opropyl), 68.0
(CCl), 67.2 (OCH2Ph), 51.3 (CHN), 41.8 (CH2COOBn), 22.7
tert-Butyl (1S,3R,5S,6S,7S)-3-(tert-Butyl)-7-chloro-6-propyloxy-7-
benzyloxycarbonylmethyl-2-oxa-4-azabicyclo[3.2.0]heptane-4-car-
boxylate (22): A mixture of benzyl bromide (1.07 g, 6.16 mmol,
2 equiv.), sodium hydrogen carbonate (520 mg, 6.16 mmol), potas-
sium carbonate (430 mg, 3.08 mmol) and 21 (1.25 g, 3.08 mmol) in
DMA (27 mL) was stirred at room temperature for 5 h. Water
(15 mL) was then added, and the aqueous layer was extracted with
diethyl ether (3ϫ10 mL). The combined organic layers were dried
and concentrated. Flash chromatography (PE/ether, 6:1; Rf = 0.22)
gave 22 (1.26 g, 83%). M.p 78–79 °C. 1H NMR (300 MHz, CDCl3):
δ = 7.30–7.37 (m, 5 H, Ph), 5.22 (s, 1 H, NCHO), 5.16 (s, 2 H,
CH2Ph), 4.81 (dd, J = 6.6, 0.6 Hz, 1 H, CHO), 4.18 (dd, J = 6.6,
3.8 Hz, 1 H, CHN), 3.78 (dd, J = 3.8, 0.6 Hz, 1 H, CHOCH2), 3.48
(m, 2 H, CH2O), 2.96 (AB, J = 15.8 Hz, 2 H, CH2COOBn), 1.64
(m, 2 H, CH2), 1.46 (s, 9 H, OtBu), 0.93 (t, J = 7.2 Hz, 3 H, CH3),
0.86 (s, 9 H, tBu) ppm. 13C NMR (75 MHz, CDCl3): δ = 168.9
(C=O), 154.2 (C=O), 135.6 (Carom), 128.6, 128.2, 128.0 (CHarom),
100.6 (NCHO), 83.5 (CHO), 80.7 (OtBu), 77.4 (CHOCH2), 72.2
(CH2Ph), 67.4 (CH2O), 66.6 (CCl), 60.9 (CHN), 41.9 (CH2COOH),
38.9 (tBu), 28.3 (OtBu), 25.3 (tBu), 22.6 (CH2), 10.5 (CH3) ppm.
(CH ), 20.2 (CH CO), 10.3 (CH ) ppm. IR (film): ν = 3434, 3299,
˜
2
3
3
2954, 1733 (C=O), 1654 (C=O). MS (D-APCI + C1MS): m/z (%)
= 370 (100) [M + 1]. [α]2D3 = –0.23 (c = 0.33, CHCl3). C18H24ClNO5
(369.84): calcd. C 58.46, H 6.54, N 3.78; found C 58.89, H 6.91, N
3.53.
Benzyl 1-[(1R,2S,3R,4S)-3-(p-Methoxybenzylcarbonyl)amino-1-
chloro-2-hydroxy-4-propyloxycyclobutyl]acetate (24c): Same pro-
cedure as for 24a. Yield: 80%. Rf = 0.15 (PE/iPrOH, 100:5), 1H
NMR (500 MHz, CDCl3, 47 °C): δ = 7.32–7.40 (m, 5 H, Ph), 7.17
(d, J = 8.6 Hz, 2 H, CHarom), 6.88 (d, J = 8.6 Hz, 2 H, CHarom),
6.13 (d, J = 8.5 Hz, 1 H NH), 5.15 (s, 2 H, CH2Ph), 4.66 (ddd, J
= 8.5, 7.7, 7.2 Hz, 1 H, CHN), 4.37 (dd, J = 7.2, 0.8 Hz, 1 H,
CHOH), 3.80 (s 3 H, OMe), 3.75 (dd, J = 7.7, 0.8 Hz, 1 H,
CHOCH2), 3.53 (s, 2 H, CH2PhOMe), 3.36 (t, J = 6.7 Hz, 2 H
CH2O), 2.98–3.06 (AB, J = 15 Hz, 2 H, CH2CO2Bn), 1.56 (m, 2
H, CH2), 0.89 (t, J = 7.4 Hz, 3 H, CH3) ppm. 13C NMR (125 MHz,
CDCl3, 47 °C): δ = 171.0 (C=O), 170.6 (C=O), 158.7, 134.9, 130.4
(Carom), 128.5, 128.4, 128.1, 126.5, 114.3 (CHarom), 84.0
(CHOCH2), 73.3 (CHOH), 71.3 (CH2Opropyl), 68.2 (CCl), 67.2
(CH2Ph), 55.14 (OMe), 50.5 (CHN), 42.7 (CH2PhOMe), 42.0
IR (KBr): ν = 2960, 1721 (C=O), 1711 (C=O), 1364, 1121,
˜
760 cm–1. MS (CI CH4/N2O + Q1MS): m/z (%) = 496 (3) [M + 1],
396 (100). [α]2D3 = +0.57 (c = 0.32, CHCl3). C26H38ClNO6 (496.04):
calcd. C 62.96, H 7.72, Cl 7.15, N 2.82; found C 63.13, H 7.30, Cl
6.68, N 2.73.
Benzyl [(1R,2S,3R,4S)-3-(Benzylcarbonyl)amino-1-chloro-2-hy-
droxy-4-propyloxycyclobutyl]acetate (24a): Trifluoroacetic acid
(5.8 mL) was added dropwise at room temperature to a solution of
22 (1.25 g, 2.52 mmol) in dichloromethane (6 mL), The resulting
solution was stirred for 70 min at room temperature and then water
(9 µL) was added. After stirring for an additional 50 min, the sol-
vent was removed under reduced pressure. Crude TFA salt 23 was
used without further purification. A solution of 23 (300 mg,
679 µmol) in dichloromethane (2.6 mL) and a solution of sodium
carbonate (110 mg, 1.02 mmol) in water (1.3 mL) were treated un-
der vigorous stirring with phenylacetyl chloride (120 mg,
747 µmol). After 30 min at room temperature, the organic layer was
separated, and the water layer was extracted with CH2Cl2
(2ϫ10 mL). The organic layers were combined and washed with
brine, dried with MgSO4 and concentrated. Flash chromatography
(PE/iPrOH, 100:5; Rf = 0.15) gave pure 24a (0.23 g). Yield: 75%
(CH COOBn), 22.7 (CH ), 10.3 (CH ) ppm. IR (KBr): ν = 3410,
˜
2
2
3
2963, 1734 (C=O), 1653 (C=O), 1513 cm–1. [α]2D3 = –0.23 (c = 0.38,
CHCl3). MS (FAB + Q1MS): m/z = 476 [M + 1]. MS (FAB/Q1MS):
m/z = 474 [M – 1].
Benzyl 2-[(1R,2S,3R,4S)-1-Chloro-2-hydroxy-4-propoxy-3-(tetra-
decanoylamino)cyclobutyl]acetate (24d): Same procedure as for 24a.
Reaction performed on 0.5 mmol scale. Yield: 82%. M.p 57–58 °C.
1H NMR (300 MHz, CDCl3): δ = 7.26–7.38 (m, 5 H, Ph), 6.10 (d,
J = 8.6 Hz, 1 H NH), 5.20 (s, 2 H, OCH2Ph), 4.70 (ddd, J = 8.6,
8.14, 7.3 Hz, 1 H, CHN), 4.42 (dd, J = 8.1, 1.0 Hz, 1 H, CHOCH2),
3.86 (m, 2 H, CHOH), 3.41 (t, J = 6.7 Hz, 2 H, CH2O), 3.0–3.16
(AB, J = 15.0 Hz, 2 H, CH2CO2Bn), 2.2 (t, J = 7.66 Hz, 2 H,
CH2CON), 1.60 (m, 4 H, 2CH2), 1.25 (m, 20 H, CH2), 0.91 (t, J =
7.4 Hz, 3 H, CH3), 0.88 (t, J = 6.7 Hz, 3 H, CH3) ppm. 13C NMR
(75 MHz, CDCl3): δ = 170.9 (C=Oamide), 168.3 (C=O), 134.2 (Ca-
rom), 128.9, 128.4, 128.0 (CHarom), 82.2 (CHOCH2), 73.2 (CHOH),
72.1 (CH2Opropyl), 68.1 (CCl), 67.2 (OCH2Ph), 51.2 (CHN), 41.9
(CH2COO), 36.5 (CH2CON), 32.1, 29.8, 29.7, 29.6, 29.5, 25.8, 22.9,
1
for two steps. H NMR (500 MHz, CDCl3, 47 °C): δ = 7.26–7.40
(m, 10 H, 2Ph), 6.13 (d, J = 8.5 Hz, 1 H NH), 5.16 (s, 2 H,
OCH2Ph), 4.66 (ddd, J = 8.5, 7.7, 7.2 Hz, 1 H, CHN), 4.37 (ddd,
J = 8.1, 7.2, 0.9 Hz, 1 H, CHOH), 3.75 (d, J = 8.1 Hz, 1 H, OH),
3.74 (dd, J = 7.7, 0.9 Hz, 1 H, CHOCH2), 3.65 (s, 2 H, CH2Ph),
3.36 (t, J = 6.7 Hz, 2 H, CH2O), 2.98–3.06 (AB, J = 15 Hz, 2 H,
CH2CO2Bn), 1.56 (m, 2 H, CH2), 0.89 (t, J = 7.6 Hz, 3 H, CH3)
ppm. 13C NMR (125 MHz, CDCl3, 47 °C): δ = 170.7 (C=Oamide),
170.6 (C=O), 134.9, 134.4 (Carom), 129.3, 128.8, 128.4, 128.1, 127.2
(CHarom), 84.0 (CHOCH2), 73.3 (CHOH), 71.3 (CH2Opropyl), 68.2
(CCl), 67.2 (OCH2Ph), 50.5 (CHN), 43.6 (CH2Ph), 42.0
22.8, 22.7 (CH ), 14.3, 10.4, (CH ) ppm. IR (film): ν = 3368, 2918,
˜
2
3
1731 (C=O), 1651 (C=O), 1541, 1189 cm–1. MS (APCI + Cfull
MS): m/z (%) = 538 (100) [M + 1], 430 (3). [α]2D3 = –0.27 (c = 0.24,
CHCl3). C30H48ClO5 (524.15): calcd. C 66.95, H 8.99, N 2.60;
found C 67.09, H 9.03, N 2.19. HRMS (ESI) calcd. for
C30H48ClNO5 538.3299; found 538.3311.
(CH COOBn), 22.7 (CH ), 10.3 (CH ) ppm. IR (KBr): ν = 3380,
Benzyl [(1R,2S,3R,4S)-1-Chloro-2-hydroxy-4-propoxy-3-{[2-(2-thi-
enyl)acetyl]amino}cyclobutyl]acetate (24e): Same procedure as for
˜
2
2
3
2927, 1718 (C=O), 1654 (C=O), 765 cm–1. MS (D-APCI + C1MS):
m/z (%) = 446 (100) [M + 1], 338 (28) [M – PhCH2CONH], 282 24a. Reaction performed on 0.5 mmol scale. Yield: 80%. 1H NMR
(17). [α]2D3 = –0.33 (c = 0.45, CHCl3). C24H28ClNO5 (445.94): calcd.
(300 MHz, CDCl3): δ = 7.29–7.38 (m, 5 H, Ph), 6.96–7.24 (m, 3 H,
Hpylan), 6.31 (d, J = 9.1 Hz, 1 H, NH), 5.17 (s, 2 H, OCH2Ph), 4.68
C 64.64, H 6.33, N 3.14; found C 64.67, H 6.40, N 3.08.
1746
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1738–1748

Scaffolds for the Diverted Synthesis of Serine Protease Inhibitors
(m, 1 H, CHN), 4.39 (dd, J = 7.19, 0.9 Hz, 1 H, CHO), 3.81 (s, 2
(APCI + C1MS): m/z (%) = 386 (34) [M + 1], 368 (6) [M + 1 –
H, CH2CON), 3.76 (dd, J = 8.14, 0.9 Hz, 1 H, CHOH), 3.38 (t, J H2O]. [α]2D3 = –0.28 (c = 0.2, CHCl3). C18H24ClNO6 (385.84): calcd.
= 6.7 Hz, 2 H, CH2O), 2.96–3.11 (AB, J = 15.3 Hz, 2 H,
CH2CO2Bn), 1.58 (m, 2 H, CH2), 0.90 (t, J = 7.2 Hz, 3 H, CH3)
ppm. 13C NMR (75 MHz, CDCl3): δ = 170.7 (C=Oamide), 169.2
(C=O), 135.7, 134.4 (Carom), 128.6, 128.2, 127.4, 126.8, 125.5
(CHarom), 84.2 (CHOCH2), 73.3 (CHOH), 71.4 (CH2Opropyl), 68.2
(CCl), 67.4 (OCH2Ph), 50.5 (CHN), 42.2 (CH2COOBn), 37.6
C 56.03, H 6.27, N 3.63; found C 54.75, H 6.04, N 3.25.
[(1R,2S,3R,4S)-1-Chloro-2-hydroxy-4-propoxy-3-(tetradecanoylami-
no)cyclobutyl]acetic Acid (25d): Same procedure as for 25a. Reac-
tion performed on 0.2 mmol scale. Yield: 95%. 1H NMR
(300 MHz, CDCl3): δ = 6.34 (d, J = 8.6 Hz, 1 H, NH), 4.63 (ddd,
J = 8.6, 8.14, 6.7 Hz, 1 H, CHN), 4.45 (dd, J = 6.7, 0.9 Hz, 1 H,
CHOCH2), 3.93 (d, J = 8.14 Hz, 1 H, CHOH), 3.43 (m, 2 H,
CH2O), 2.95–3.18 (AB, J = 15.3 Hz, 2 H, CH2CO2), 2.24 (t, J =
7.6 Hz, 2 H, CH2CON), 1.61 (m, 4 H, 2CH2), 1.25 (m, 20 H, 10
CH2), 0.92 (t, J = 7.2 Hz, 3 H, CH3), 0.88 (t, J = 6.6 Hz, 3 H,
CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 173.8 (C=Oamide),
173.7 (C=O), 83.7 (CHOCH2), 73.4 (CHOH), 71.6 (CH2Opropyl),
68.2 (CCl), 51.0 (CHN), 42.1 (CH2COO), 36.7 (CH2CON), 32.0,
29.7, 29.6, 29.5, 29.4, 29.3, 25.8, 22.9, 22.8, 22.7 (CH2), 14.2, 10.5
(CH CON), 22.9 (CH ), 10.5, (CH ) ppm. IR (film): ν = 3298,
˜
2
2
3
2958, 1731 (C=O), 1654 (C=O). MS (D-APCI + C1MS): m/z (%)
= 452 (60) [M + 1]. C22H26ClNO5S (451.96): calcd. C 58.46, H
5.79, N 3.09; found C 48.14, H 5.09, N 2.80.
[(1R,2S,3R,4S)-1-Chloro-2-hydroxy-4-propoxy-3-(benzylcarbonyl)-
aminocyclobutyl]acetic Acid (25a): Hydrogen was flushed at room
temperature through a suspension of palladium on activated car-
bon (10% Pd, 45.3 mg, 42.6 µmol) in a solution of 24a (190 mg,
0.43 mmol) in ethyl acetate (2.5 mL). The reaction was complete
after 8 h. Filtration through Celite followed by evaporation of the
solvent gave 25a (0.15 g, 96%). M.p 55–57 °C. 1H NMR (500 MHz,
CDCl3, 47 °C): δ = 7.25–7.35 (m, 5 H, Ph), 6.24 (d, J = 8.6 Hz, 1
H NH), 4.62 (ddd, J = 8.6, 8.2, 7.0 Hz, 1 H, CHN), 4.39 (dd, J =
7.0, 0.9 Hz, 1 H, CHOH), 3.80 (dd, J = 8.2, 0.9 Hz, 1 H,
CHOCH2), 3.61 (s, 2 H, CH2Ph), 3.37 (m, 2 H, CH2O), 2.99–3.07
(AB, J = 15 Hz, 2 H, CH2CO2H), 1.56 (m, 2 H, CH2), 0.89 (t, J =
7.6 Hz, 3 H, CH3) ppm. 13C NMR (125 MHz, CDCl3, 47 °C): δ =
173.6 (C=O), 170.7 (C=Oamide), 134.4 (Carom), 129.3, 128.8, 127.4
(CHarom), 83.6 (CHOCH2), 73.3 (CHOH), 71.4 (CH2Opropyl), 67.9
(CCl), 51.0 (CHN), 43.5 (CH2Ph), 41.6 (CH2COOH), 22.7 (CH2),
(CH ) ppm. IR (film): ν = 3364, 2924, 1718 (C=O), 1653 (C=O).
˜
3
MS (D-APCI + C1MS): m/z (%) = 448(100) [M + 1], 430 (26) [M
+ 1 – H2O], 220 (4). [α]2D3 = +0.19 (c = 0.37, CHCl3). HRMS (ESI)
calcd. for C23H42ClNO5 448.2830; found 448.2818.
Benzyl [(1S,3S,4S)-3-(Benzylcarbonyl)amino-1-chloro-2-oxo-4-pro-
pyloxycyclobutyl]acetate (26a): A 0.5  aqueous solution of sodium
hypochlorite (130 µL, 64 µmol) and sodium hydrogen carbonate
(15 mg; 175 µmol) was added dropwise at 0 °C with vigorous stir-
ring to a solution of 24a (26 mg, 58.3 µmol), TEMPO (0.5 mg,
2.9 µmol) and potassium bromide (7.6 mg, 64 µmol) in toluene/
ethyl acetate (1:1, 500 µL) and water (42 µL). The reaction mixture
was stirred for 15 min at 0 °C. The aqueous layer was separated
and washed with toluene (10 mL). The combined organic layers
were washed with a solution of KI (0.25 g) dissolved in 10% aque-
ous KHSO4 (1 mL). The organic layer was washed successively
with 10% aqueous sodium thiosulfate (1 mL, pH 7 phosphate
buffer 0.2 , 2 mL) and brine, dried with MgSO4 and evaporated
10.3 (CH ) ppm. IR (film): ν = 3335, 2965, 1717 (C=O), 1653
˜
3
(C=O). MS (D-APCI + C1MS): m/z (%) = 356 (100) [M + 1], 282
(51). MS (D-APCI/C1MS): m/z (%) = 354 (100) [M – 1]. [α]2D3
=
–0.28 (c = 0.26, CHCl3). C17H22ClNO5 (355.81): calcd. C 57.39, H
6.23, N 3.94; found C 56.76, H 6.65, N 3.67.
1
to give 26a (22 mg, 85%). H NMR (500 MHz, CDCl3, 47 °C): δ
[(1R,2S,3R,4S)-3-(Acetyl)amino-1-chloro-2-hydroxy-4-propyloxycy-
clobutyl]acetic Acid (25b): Same procedure as for 25a. Reaction per-
formed on 0.2 mmol scale. Yield: 95%. M.p 52–53 °C. 1H NMR
(300 MHz, CD3OD): δ = 4.46 (dd, J = 8.6, 6.6 Hz, 1 H, CHN),
4.24 (dd, J = 6.6, 1.0 Hz, 1 H, CHOH), 3.91 (dd, J = 8.6, 1.0 Hz,
1 H, CHOCH2), 3.45 (m, 2 H, CH2O), 2.79–3.03 (AB, J = 15.8 Hz,
2 H, CH2CO2H), 1.96 (s, 3 H, CH3CO), 1.54 (m, 2 H, CH2), 0.89
(t, J = 7.6 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz, CD3OD): δ =
173.2 (C=O), 172.6 (C=Oamide), 84.0 (CHO), 74.1 (CHOH), 72.9
(CH2Opropyl), 70.7 (CCl), 53.2 (CHN), 42.2 (CH2COOH), 24.1
= 7.22–7.44 (m, 10 H, 2Ph), 6.19 (br., 1 H NH), 5.09–5.14 (AB, J
= 13 Hz, 2 H, OCH2Ph), 4.88 (dd, J = 8.1, 6.4 Hz, 1 H, CHN),
4.54 (d, J = 6.4 Hz, 1 H, CHO), 3.61 (s, 2 H, CH2Ph), 3.56 (ddd,
J = 8.8, 7.1, 7.1 Hz, 1 H, CH2Opropyl), 3.41 (ddd, J = 8.8, 6.4,
6.4 Hz, 1 H, CH2Opropyl), 3.18–3.38 (AB, J = 15 Hz, 2 H,
CH2CO2Bn), 1.56 (m, 2 H, CH2), 0.89 (t, J = 7.6 Hz, 3 H, CH3)
ppm. 13C NMR (125 MHz, CDCl3, 47 °C): δ = 198.3 (C=O), 170.8
(C=Oamide), 168.9 (C=O), 135.0, 133.7 (Carom), 129.3, 129.0, 128.8,
128.4, 128.1, 127.5 (CHarom), 78.2 (CHO), 72.8 (CH2Opropyl), 72.1
(CCl), 69.2 (CHN), 67.0 (OCH2Ph), 42.7 (CH2Ph), 41.8
(CH ), 22.6 (CH CO), 11 (CH ) ppm. IR (film): ν = 3420, 2967,
˜
2
3
3
(CH COOBn), 22.8 (CH ), 10.4 (CH ) ppm. IR (film): ν = 2964,
˜
2
2
3
1721 (C=O), 1654 (C=O). MS (D-APCI + C1MS): m/z (%) = 280
(100) [M + 1], 262 (24). [α]2D3 = –0.20 (c = 0.42, CHCl3).
C11H18ClNO5 (279.92): calcd. C 47.23, H 6.49, Cl 12.67, N 5.0;
found C 47.56, H 6.91, Cl 10.93, N 4.46.
1804 (C=O), 1734 (C=O), 1654 (C=O), 770 cm–1. MS (APCI +
C1MS): m/z (%) = 444 (58) [M + 1], 408 (100), 336 (12) [M –
PhCH2CONH], 290 (71).
Benzyl [(1S,3S,4S)-3-(Acetyl)amino-1-chloro-2-oxo-4-propyloxycy-
[(1R,2S,3R,4S)-1-Chloro-2-hydroxy-4-propoxy-3-(p-methoxybenzyl- clobutyl]acetate (26b): Same procedure as for 26a. Reaction per-
carbonyl)aminocyclobutyl]acetic Acid (25c): Same procedure as for
formed on 0.12 mmol scale. Yield: 85%. 1H NMR (300 MHz,
25a. Reaction performed on 0.2 mmol scale. Yield: 92%. M.p 147–
149 °C. H NMR (500 MHz, CDCl3, 47 °C): δ = 7.25–7.35 (m, 5 (AB, J = 12.2 Hz, 2 H, OCH2Ph), 4.95 (d, J = 5.7 Hz, 1 H, CHN),
CDCl3): δ = 7.35–7.41 (m, 5 H, Ph), 6.3 (br., 1 H, NH), 5.10–5.19
1
H, Ph), 6.24 (d, J = 8.6 Hz, 1 H NH), 4.62 (ddd, J = 8.6, 8.2,
7.0 Hz, 1 H, CHN), 4.39 (dd, J = 7.0, 0.9 Hz, 1 H, CHOH), 3.80
(dd, J = 8.2, 0.9 Hz, 1 H, CHOCH2), 3.61 (s, 2 H, CH2Ph), 3.37
(m, 2 H, CH2O), 2.99–3.07 (AB, J = 15 Hz, 2 H, CH2CO2H), 1.56
4.56 (d, J = 5.7 Hz, 1 H, CHOCH2), 3.48 (m, 2 H, CH2O), 3.18–
3.43 (AB, J = 16.7 Hz, 2 H, CH2CO2Bn), 2.03 (s, 3 H CH3CO),
1.59 (m, 2 H, CH2), 0.92 (t, J = 7.6 Hz, 3 H, CH3) ppm. 13C NMR
(75 MHz, CDCl3): δ = 198.8 (C=O), 170.0 (C=Oamide), 169.0
(m, 2 H, CH2), 0.89 (t, J = 7.6 Hz, 3 H, CH3) ppm. 13C NMR (C=O), 134.9 (Carom), 128.6, 128.3, 128.0 (CHarom), 78.3 (CHO),
(125 MHz, CDCl3, 47 °C): δ = 173.6 (C=O), 170.7 (C=Oamide),
134.4 (Carom), 129.3, 128.8, 127.4 (CHarom), 83.6 (CHOCH2), 73.3
72.8 (OCH2Ph), 71.9 (CH2Opropyl), 69.1 (CHN), 67.2 (CCl), 41.9
(CH2COOBn), 22.9 (CH2), 22.5 (CH3CO), 10.6, (CH3) ppm. IR
(CHOH), 71.4 (CH2Opropyl), 67.9 (CCl), 51.0 (CHN), 43.5 (film): ν = 2967, 1802 (C=O), 1729 (C=O), 1657 (C=O). MS (APCI
˜
(CH2Ph), 41.6 (CH2COOH), 22.7 (CH2), 10.3 (CH3) ppm. IR + C1MS): m/z (%) = 368 (7) [M + 1], 332 (50), 326 (100) [M – iPr],
(film): ν = 3308, 2965, 1717 (C=O), 1653 (C=O), 860 cm–1. MS 308 (45), 290 (55), 260 (65), 234 (46).
˜
Eur. J. Org. Chem. 2009, 1738–1748
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1747

G. Yang, L. Ghosez
FULL PAPER
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Acknowledgments
This work was generously supported by grants from the Services
fédéraux des Affaires Scientifiques, Techniques et Culturelles
(P.A.I. no. 19), the Fonds National de la Recherche Scientifique
and the University of Louvain. We also thank Prof. B. Tinant and
Prof. J. P. Declercq for X-ray diffraction analyses, Prof. E.
De Hoffmann for the mass spectra and Dr R. Touillaux for
500 MHz NMR spectroscopic studies.
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Received: January 26, 2009
Published Online: March 9, 2009
1748
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1738–1748