Stereoselective synthesis of novel anti-MRSA tricyclic carbapenems (trinems)

Article abstract of DOI:10.1016/S0040-4020(00)00413-0

(4S)-Hydroxymethyltrinem 3 was prepared via stereoselective aldol-type reaction with optically pure (R)-2-t-butyldimethylsilyloxymethylcyclohexanone ((R)-16). (4S)-Hydroxymethyltrinem 3 was converted into various kinds of trinem derivatives with anti-MRSA activity by using the Mitsunobu reaction. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00413-0

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 5639±5648
Stereoselective Synthesis of Novel anti-MRSA Tricyclic
Carbapenems (Trinems)
*
Osamu Kanno and Isao Kawamoto
Medicinal Chemistry Research Laboratories, Sankyo Co. Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
Received 20 September 1999; accepted 15 November 1999
AbstractÐ(4S)-Hydroxymethyltrinem 3 was prepared via stereoselective aldol-type reaction with optically pure (R)-2-t-butyldimethyl-
silyloxymethylcyclohexanone ((R)-16). (4S)-Hydroxymethyltrinem 3 was converted into various kinds of trinem derivatives with anti-
MRSA activity by using the Mitsunobu reaction. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
Since the discovery of penicillin, some new classes of
b-lactam antibiotics have been found from natural sources,
for example, cephalosporines, cephamycins, monobactams,
and carbapenems. On the other hand, different kinds of
synthetic antibiotics, for example, carbacephems, oxa-
cephems, penems, and 1b-methyl carbapenems represented
by meropenem (1) have been developed in the last three
decades.1 Generally, b-lactam antibiotics have a wide-
Tricyclic carbapenem (trinem)2,3 is a novel class of
range of antibacterial activity for both Gram-positive and
synthetic antibiotic, which was recently reported by the
Gram-negative bacteria. However, in recent years the
Glaxo group. Sanfetrinem cilexetil (2) developed by
appearance of resistant strains such as methicillin-resistant
the same group is under clinical trials as an oral trinem.
Staphylococcus aureus (MRSA) and penicillin-resistant
We designed novel trinem derivatives to explore their
Streptococcus pneumoniae (PRSP) has become a serious
possibility as anti-MRSA agents.
problem in clinical practice. The mechanism of resistance
of MRSA is the production of altered Penicillin Binding
Initially, we focused our attention on a versatile inter-
Proteins PBP2a (PBP20) which has poor af®nity for any
mediate for trinem synthesis. As an intermediate, we
classical b-lactams.
selected (4S)-hydroxymethyltrinem 3. The best stereo-
chemistry for combining good antimicrobial activity and
dehydropeptidase-I (DHP-I) stability in the case of sanfetri-
Now, many scientists in the world are making efforts to
develop effective drugs against these resistant strains.
nem is when the con®guration of the cyclohexyl ring is (4S,
8S).2 Therefore, we applied the same con®guration to our key
intermediate in our trinem synthesis. In this paper, we describe
the stereoselective synthesis of our trinem derivatives.
Result and Discussion
The biological activity of trinems is in¯uenced by the
stereochemical arrangement of the cyclohexyl ring moiety.
We initially studied aldol type condensations of 4-acetoxy-
azetidinone derivative 5 and silyl enol ether 4.3,4
It is well known that the con®guration at the C-4 position
on the azetidinone in the carbapenem synthesis is
generally down for hydrogen atom as shown by cyclohexyl
Keywords: trinems; stereoselective synthesis; Mitsunobu reaction; MRSA.
* Corresponding author. E-mail: kannoo@shina.sankyo.co.jp
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00413-0

5640
O. Kanno, I. Kawamoto / Tetrahedron 56 (2000) 5639±5648
Scheme 1. Reagents: (a) ZnCl2 2 equiv. or TMSOTf 0.1 equiv./CH2Cl2, rt; (b) SiO2/MeOH, 2 h rt.
Table 1. Aldol type condensation of silyl enol ether 4 and acetoxyazeti-
dinone 5
and 3, trimethylsilyl tri¯uoromethanesulfonate (TMSOTf)
gave better results for the ratio of 6 and 7 than ZnCl2, but the
yield was lower than ZnCl2. From the results of Table 1, the
reaction of 4-acetoxy azetidinone 5 with optically pure 4 is
of interest in the advantageous preparation of the desired
isomer 7. The absolute con®gurations for these compounds
were determined for 6 and 7 (at C-20 and C-60) by NOE
experiments7 (Fig. 1).
Entry
4:5
L.A.
ZnCl2
ZnCl2
TMSOTf
Yield (%)a
6:7
1
2
3
1:1.2
2:1
2:1
86b
70c
35c
1.1:1
2.7:1
1.6:1
a Isolated yield.
b Yield based on 4.
c Yield based on 5.
The compounds 6 and 7 were treated with allyl oxalyl
chloride to give oxalates 8 and 9, respectively. Cyclization8
of 8 and 9 with diethyl ethylphosphonite9 afforded protected
trinems 10 and 11, respectively (Scheme 2). The stereo-
chemistry of 10 and 11 was also determined by NOE
experiments (Fig. 2).
In order to obtain a large number of trinem derivatives, the
ef®cient synthesis of the key intermediate 7 was studied. For
this purpose, the synthesis of an optically pure derivative
(R)-16 or (R)-4 was investigated (Scheme 3). The reduction
of ethyl 2-cyclohexanonecarboxylate 12 with NaBH4 gave
cis- and trans-mixture of hexanol 13 (cis/transˆ3:1). An
optical resolution10 of major isomer cis-13 was accom-
plished with enantioselective acylation of the immobilized
lipase (TOYOZYMEw, LIP (TOYOBO Co. Ltd))11 to afford
acetate (1S, 2R)-14. Reduction of (1S, 2R)-14 with LiAlH4
followed by selective protection of the primary hydroxy
group with TBSCl afforded silyl ether (1R, 2R)-15. On the
other hand, (1R, 2S)-13 was derived from 12 by enantio-
selective reduction with baker's yeast12 under the same
condition to provide (1S, 2S)-15. Both (1R, 2R)-15 and
(1S, 2S)-15 were converted to (S)-MTPA ester 17a and
17b by acylation with (R)-MTPA chloride to determine
the optical purity and con®rm the absolute con®gurations
of (1R, 2R)-15 and (1S, 2S)-15 by NMR In the comparison
of the NMR spectra of 17a and 17b, the optical purity of
(1R, 2R)-15 and (1S, 2S)-15 were more than 98 and 86% ee,
respectively.
Figure 1. Determination of stereochemistry for 6 and 7 by NOE.
azetidinones 6 and 7 from the steric bulkiness of the
protected hydroxy group at the C-3 position.5 However, it
is not as easy to construct the desired stereochemistry at the
C-60 position (corresponding to b-methyl in 1b-methyl-
carbapenem) on the cyclohexyl ring. Surprisingly, the
reaction of 4-acetoxyazetidinone derivative 5 with 4
resulted in a controlled stereochemistry at C-20 and C-60
positions on the cyclohexanone ring3,6 and provided pre-
dominantly two diastereomers 6 and 7 among the four
possible diastereomers by the steric bulkiness of t-butyl-
dimethylsilyloxymethyl group (Scheme 1). The ratio of 6
and 7 in this reaction depended on the ratio of 5 to 4 and
kinds of Lewis acids (Table 1).
In comparison with entries 1 and 2, the rate of production of
undesired isomer 6 was obviously faster than that of the
desired isomer 7. Moreover in comparison with entries 2
Further, the absolute con®guration was con®rmed by
Scheme 2. Reagent: allyl oxalylchloride, Et3N, 08C; (b) EtP(OEt)2, xylene, re¯ux, 4 h, 76% in two steps; (c) EtP(OEt)2, xylene, re¯ux, 2 h, 84% in two steps.

O. Kanno, I. Kawamoto / Tetrahedron 56 (2000) 5639±5648
5641
Kusumi's method.13 The hydroxy group of (1R, 2R)-15 was
oxidized with pyridinium dichromate (PDC) to furnish
(R)-1614,15; this was followed by an addition of lithium
bis(trimethylsilyl)amide and TMSCl to lead to silyl enol
ether (R)-4. As expected, the reaction of 5 with (R)-4 gave
predominantly the desired product 7 (Scheme 4). Though a
very small amount of another isomer, which was also
expected, the undesired diastereomer 18, was observed in
the TLC, the ratio of 7 and 18 was determinated by NMR
analysis of the crude pruducts as the ratio of these
compounds could not be determined by HPLC nor isolated
by column chromatograpy.
Figure 2. Determination of stereochemistry for 10 and 11 by NOE.
Scheme 3. Reagents: (a) NaBH4, MeOH, 69%; (b) immobilized lipase, vinyl acetate; THFˆ4:1, 378C, 33%; (c) baker's yeast, 78%; (d) LAH/THF; (e) TBSCl,
Et3N, DMAP/CH2Cl2, (1R, 2R)-15:81% from (1S, 2R)-14, (1R, 2)-15:81% from (1R, 2R)-13; (f) PDC/CH2Cl2, rt, 88%; (g) LHMDS, TNSCl/THF, 2788C; (h)
(R)-MTPA-Cl, 4-DMAP/CH2±Cl2, quant.
Scheme 4.
Scheme 5. Reagents: (a) HF±NH4F, DMF, rt, 3 days, 74%; (b) TESCI, imidazole, 98%; (c) allyl oxalychloride, Et3N, 08C; (d) EtP(OEt)2, xylene, re¯ux, 74%
in two steps; (e) HF±NH4F, DMF, rt, 3 days, 48% from 11 91% from 21.

5642
O. Kanno, I. Kawamoto / Tetrahedron 56 (2000) 5639±5648
Scheme 6. Reagents: (a) 25a, diethyl azodicarboxylate (DEAD) 2.5 equiv., PPh3 2.5 equiv./THF, rt, 76%; (b) 25b, diisopropyl azodicarboxylate (DIAD)
1.5 equiv., PPh3 1.5 equiv./toluene, rt, 70%; (c) TBAF, AcOH/THF, rt, 23a: 66%, 23b: 56%; (d) PdCl2(PPh3)2 2 mol%, n-Bu3SnH 5 equiv./CH2Cl2±H2O, 08C,
24a: 74%, 24b: 52%.
Scheme 7. Reagents: (a) 25c or 25d, diethyl azodicarboxylate (DEAD) 3.0 equiv., PPh3 3.0 equiv./toluene; (b) TBAF, AcOH/THF, rt, 23c: 50% from 3, 23d:
69% from 3; (c) PdCl2(PPh3)2 2 mol%, n-Bu3SnH 5 equiv./CH2±Cl2±H2O, 08C, 52%; (d) Pd(PPh3)4 2 mol%, potassium 2-ethylhexanoate/EtOAc±CH2Cl2, rt,
52%.
After the replacement of the TBS group of 7 to a triethylsilyl
(TES) group via deprotected compound 19, TES ether 20
was converted to trinem 21 in a similar procedure as shown
in Scheme 5. Deprotection of 21 with HF±NH4F16 gave
hydroxymethyltrinem 3. Alternatively, the selective depro-
tection of TBS group of 11 with HF±NH4F furnished 3 in
48% yield. The hydroxymethyltrinem 3 is a versatile key
intermediate in the trinem synthesis because the hydroxy
group of 3 can be replaced with many kinds of substituent
groups.
suitable acidity, could be introduced to 3 under mild con-
ditions to afford the corresponding derivatives 22a±d.
Deprotection of the TBS group with tetrabutylammonium
¯uoride (TBAF) gave corresponding desilylated compounds
23a±d. Finally, deprotection of the allyl (All) and allyl-
oxycarbonyl (Alloc) groups was performed by catalytic
tetrakis(triphenylphosphine)palladium
and
potassium
2-ethylhexanoate or catalytic bis(triphenylphosphine)palla-
dium chloride and tributyltin hydride to furnish trinems
24a±d.
The synthesis of trinem derivatives using 3 was carried out.
Substituent groups with a nitrogen atom, such as amino and
guanidino groups, and a heterocyclic moiety were intro-
duced by the Mitsunobu reaction (Schemes 6 and 7). As
shown in Schemes 6 and 7, various substituent groups
25a,17a 25b,17b 25c,17a,c 25d,17d which have protons with
The antibacterial activity of trinem derivatives 24a±d was
compared with that of vancomycin as shown in Table 2. The
MIC values of 24a and 24b indicated that these compounds
with basic amine moiety had good antibacterial activities
against both Gram positive and Gram negative bacteria.
Interestingly, the introduction of an aromatic moiety (24c
and 24d) remarkably increased the activity against Gram
positive bacteria including MRSA. In particular, 24d
indicated as high activity against MRSA as vancomycin,
but 24c showed therapeutically valuable activity against
Gram negative bacteria so that it could be further studied
as a broad spectrum anti-MRSA agent.
Table 2. Antibacterial activity (MIC, mg/ml) (MIC was determined by agar
diltution method with an inoculum of 107 cfu/ml) of trinem derivatives and
vancomycin (VCM)
24a
24b
24c
24d
VCM
Staphylococcus aureus 209P
S. aureus 56R
0.056 ,0.01 0.02 ,0.012 0.2
0.2
25
0.05
6.2
3.1
0.1
0.2
0.2
50
0.05
3.1
1.5
0.8
0.8
1.5
0.025
1.56
0.78
12.5
25
0.78
1.56
In summary, the stereoselective synthesis of a versatile key
intermediate for trinem derivatives was accomplished and
various kinds of trinems were prepared by the Mitsunobu
reaction. It was revealed that 24c and 24d with thiazole
moiety had ef®cient anti-MRSA activities as potent as
vancomycin.
S. aureus 535 (MRSA)
Enterococcus faecalis 681
Escherichia coli NIHJ
Klebsiella pneumoniae 806
Serratia marcescens 1184
6.2
0.1
0.1
0.2
0.78
.100
.100
.100
12.5
Pseudomonas aeruginosa 1001 6.2
.100 .100 .100

O. Kanno, I. Kawamoto / Tetrahedron 56 (2000) 5639±5648
5643
Experimental
To a solution of 6 (800 mg, 1.70 mmol) in CH2Cl2
(10 mL) was added triethylamine (344 mg, 3.40 mmol)
and allyl oxalyl chloride (379 mg, 2.55 mmol) at 08C. The
mixture was stirred for 2 h at the same temperature. After
adding 2-propanol (51 mg, 0.85 mmol) to the mixture, the
solution was evaporated in vacuo. The residue was puri®ed
by silica gel column chromatography (hexane±EtOAc, 3:1)
to afford crude 8 (957 mg). A solution of crude 8 and diethyl
ethylphosphonite (735 mg, 4.90 mmol) in xylene was
re¯uxed for 4 h and the mixture was evaporated in vacuo.
The residue was puri®ed by silica gel column chromato-
graphy (hexane±EtOAc, 4:1) to afford 10 (682 mg, 76%)
as an oil. IR (liquid ®lm) cm21 2932, 2859, 1772, 1715,
General
IR spectra were recorded on a Jasco FT-IR 8300 or 8900
spectrometer. NMR spectra were recorded on JEOL EX 270
(270 MHz) or GSX-400 (400 MHz) spectrometer using
tetramethylsilane (TMS) or sodium 3-(trimethylsilyl)pro-
pionate-d4 (TSP-d4) as an internal standard. Mass spectra
were recorded on JEOL HX-100, SX-102A or AX-505H
mass spectrometer. The melting point (mp) was determined
using a Yanagimoto micro-melting point apparatus and was
not corrected. Optical rotations were obtained with a Jasco
DIP-370 polarimeter. Column chromatography was carried
out on Silica gel 60 (230±400 mesh, Art. 9385, Merck) or
Cosmosil 75C18 PREP (75 mm, Nacalai Tesque, Inc.).
1
1100. H NMR (270 MHz, CDCl3) d 0.04 (6H, s), 0.07
(6H, s), 0.87 (9H, s), 0.88 (9H, s) 1.26 (3H, d, Jˆ6.2 Hz),
1.27±1.70 (5H, m), 1.98±2.19 (2H, m), 2.89±3.04 (1H, m),
3.02 (1H, dd, Jˆ4.6, 2.5 Hz), 3.51±3.72 (3H, m) 4.14 (1H,
dq, Jˆ6.9, 6.3 Hz), 4.63±4.82 (2H, m), 5.24 (1H, d,
Jˆ10.3 Hz), 5.43 (1H, d, Jˆ17.2 Hz), 5.87±6.05 (1H, m).
MS (FAB) m/z: 550 (M1H)1. Anal. Calcd for
C29H51NO5Si2: C, 63.34, H, 9.35, N, 2.55. Found: C,
63.90, H, 9.30, N, 2.45.
(3S,4R)-3-[(R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-[(20S,
60S)-20-(t-butyldimethylsilyloxymethyl)cyclohexanone-
60-yl]azetidin-2-one (6) and (3S, 4R)-3-[(R)-1-(t-butyldi-
methylsilyloxy)ethyl]-4-[(20R, 60R)-20-(t-butyldimethyl-
silyloxymethyl) cyclohexanone-60-yl]azetidin-2-one (7).
(Typical procedure with ZnCl2) To a solution of 4 (3.89 g,
12.4 mmol) and azetidinone 5 (5.34 g, 14.8 mmol) in
CH2Cl2 (50 mL) was added zinc chloride (3.37 g,
24.7 mmol) at room temperature. The mixture was stirred
for 3 h at the same temperature. After the addition of
saturated aqueous NaHCO3 (50 mL) to the mixture, the
insoluble material formed was removed by ®ltration. The
®ltrate was extracted with EtOAc (200 mL£3) and the
organic layer was washed with brine and then dried over
Na2SO4. The solvent was evaporated in vacuo and then the
residue was diluted with MeOH (50 mL). An adequate
amount of silica gel was added to the solution and then
the mixture was stirred for 2 h at room temperature. The
silica gel was removed by ®ltration and the ®ltrate was
evaporated in vacuo. The residue was puri®ed by silica
gel column chromatography (hexane±EtOAc, 5:2) to afford
6 (2.59 g, 45%) and 7 (2.39 g, 41%) as crystals. 6:
[a]2D5ˆ259.28 (c 1.23, CHCl3). Mp 134±1368C. IR (KBr)
cm21 3080, 2930, 1761, 1716, 1257, 836. 1H NMR
(400 MHz, CDCl3) d 0.04 (6H, s), 0.06 (3H, s), 0.07 (3H,
s), 0.87 (9H, s), 0.88 (9H, s) 1.23 (3H, d, Jˆ6.1 Hz), 1.35±
2.17 (6H, m), 2.44±2.53 (1H, m), 2.58±2.65 (1H, m), 2.68±
2.73 (1H, m), 3.62 (1H, dd, Jˆ9.7, 2.1 Hz), 3.77 (1H, dd,
Jˆ10.0, 6.8 Hz), 3.86 (1H, dd, Jˆ10.0, 7.2 Hz), 4.16 (1H,
dq, Jˆ6.0, 5.9 Hz), 6.02 (1H, br s). MS (FAB) m/z: 470
(M1H)1. Anal. Calcd for C24H47NO4Si2: C, 61.36, H,
10.08, N, 2.98. Found: C, 61.31, H, 9.96, N, 2.97. 7:
[a]2D5ˆ165.48 (c 0.895, CHCl3). Mp 128±1298C. IR
Allyl (4S,8S,9R,10S)-10-[(R)-1-(t-butyldimethylsilyloxy)-
ethyl]-4-t-butyldimethylsilyloxymethyl-11-oxo-azatri-
cyclo[7.2.0.03,8]undec-2-ene-2-carboxylate (11) via 9. To
a solution of 7 (6.0 g, 12.8 mmol) in CH2Cl2 (100 mL) was
added triethylamine (3.24 g, 32.0 mmol) and allyl
oxalylchloride (3.80 g, 25.6 mmol) at 08C. The mixture
was stirred for 2 h at the same temperature. After adding
2-propanol (768 mg, 12.8 mmol) to the mixture, the solution
was evaporated in vacuo. The residue was puri®ed by silica
gel column chromatography (hexane±EtOAc, 3:1) to afford
crude 9 (7.73 g). A solution of crude 9 and diethyl
ethylphosphonite (5.77 g, 38.4 mmol) in xylene (120 mL)
was re¯uxed for 2 h and the mixture was evaporated in
vacuo. The residue was puri®ed by silica gel column
chromatography (hexane±EtOAc, 3:1) to afford 11
(5.92 g, 84%) as an oil. [a]2D5ˆ196.08 (c 1.32, CHCl3). IR
1
(liquid ®lm) cm21 2932, 2859, 1771, 1715, 1259, 1102. H
NMR (270 MHz, CDCl3) d 0.04 (6H, s), 0.07 (6H, s), 0.87
(9H, s), 0.88 (9H, s) 1.24 (3H, d, Jˆ6.1 Hz), 1.21±2.04 (6H,
m), 2.94±3.08 (1H, m), 3.17 (1H, dd, Jˆ6.2, 3.2 Hz), 3.67±
3.85 (3H, m) 4.08 (1H, dd, Jˆ10.5, 3.2 Hz), 4.19 (1H, dq,
Jˆ6.3, 6.0 Hz), 4.67 (1H, dd, Jˆ13.7, 5.5 Hz), 4.78 (1H, dd,
Jˆ10.4, 5.5 Hz), 5.24 (1H, d, Jˆ10.3 Hz), 5.42 (1H, d,
Jˆ17.2 Hz), 5.89±6.06 (1H, m). MS (FAB) m/z: 550
(M1H)1. Anal. Calcd for C29H51NO5Si2: C, 63.34, H,
9.35, N, 2.55. Found: C, 63.18, H, 9.12, N, 2.44.
(KBr) cm21 3080, 2930, 1761, 1716, 1257, 836. H NMR
1
Ethyl 2-hydroxycyclohexanecarboxylate (13). To a solu-
tion of ethyl 2-cyclohexanonecarboxylate (12) (10.2 g,
59.9 mmol) in methanol (200 mL) was added sodium boro-
hydride (2.72 g, 71.9 mmol) at 2408C. The mixture was
stirred for 3 h at the same temperature. After the mixture
was neutralized with acetic acid, the solution was evapo-
rated in vacuo. The residue was extracted with EtOAc
(200 mL£4). The combined organic extracts were washed
with saturated aqueous NaHCO3, brine, and dried over
Na2SO4. The solvent was evaporated in vacuo and the resi-
due was puri®ed by silica gel column chromatography
(hexane±EtOAc, 3:2) to afford cis-13 (5.47 g, 53%) and
trans-13 (1.59 g, 15%) as an oil. cis-13: IR (liquid ®lm)
(400 MHz, CDCl3) d 0.04 (6H, s), 0.06 (3H, s), 0.07 (3H, s),
0.87 (9H, s), 0.89 (9H, s) 1.17 (3H, d, Jˆ6.1 Hz), 1.66±2.09
(6H, m), 2.57±2.62 (1H, m), 2.63±2.75 (1H, m), 2.87 (1H,
dd, Jˆ4.3, 2.4 Hz), 3.74 (1H, dd, Jˆ10.2, 7.0 Hz), 3.90 (1H,
dd, Jˆ10.2, 7.0 Hz), 4.09 (1H, dd, Jˆ5.4, 2.4 Hz), 4.21 (1H,
dq, Jˆ6.1, 4.3 Hz), 5.79 (1H, br s). MS (FAB) m/z: 470
(M1H)1. Anal. Calcd for C24H47NO4Si2: C, 61.36, H,
10.08, N, 2.98. Found: C, 61.20, H, 9.90, N, 2.96.
Allyl (4R,8R,9R,10S)-10-[(R)-1-(t-butyldimethylsilyl-
oxy)ethyl]-4-t-butyldimethylsilyloxymethyl-11-oxo-aza-
tricyclo[7.2.0.03,8]undec-2-ene-2-carboxylate (10) via 8.

5644
O. Kanno, I. Kawamoto / Tetrahedron 56 (2000) 5639±5648
cm21 3513, 2937, 1713, 1185, 1040, 976. 1H NMR
(270 MHz, CDCl3) d 1.28 (3H, t, Jˆ7.0 Hz), 1.24±1.98
(8H, m), 2.48 (1H, ddd, Jˆ11.3, 3.5, 2.8 Hz), 3.20 (1H, br
d, Jˆ2.6 Hz), 4.11±4.18 (1H, m), 4.17 (2H, q, Jˆ7.0 Hz).
MS (FAB) m/z: 172 (Mz1). Anal. Calcd for C9H16O3: C,
62.77, H, 9.37. Found: C, 62.54, H, 9.20. trans-13: IR
(liquid ®lm) cm21 3448, 2936, 1733, 1180. 1H NMR
(270 MHz, CDCl3) d 1.14±1.45 (4H, m), 1.28 (3H, t,
Jˆ7.2 Hz), 1.68±1.94 (2H, m), 1.95±2.09 (2H, m), 2.25
(1H, ddd, Jˆ12.1, 9.8, 3.7 Hz), 2.83 (1H, br s), 3.79±3.84
(1H, m), 4.17 (2H, q, Jˆ7.2 Hz). MS (FAB) m/z: 172 (Mz1).
Anal. Calcd for C9H16O3: C, 62.77, H, 9.37. Found: C,
62.58, H, 9.09.
(380 mg, 2.92 mmol) in CH2Cl2 (5 mL) was added 4-
dimethylaminopyridine (20 mg), triethylamine (369 mg,
3.65 mmol) and t-butyldimethylsilylchloride (506 mg,
3.36 mmol) at room temperature. The mixture was stirred
for 2 h at the same temperature. The mixture was diluted
with EtOAc (150 mL) and washed with saturated aqueous
NaHCO3 and brine. The organic layer was dried over
Na2SO4 and then evaporated in vacuo. The residue was
puri®ed by silica gel column chromatography (hexane±
EtOAc, 10:1) to afford (1R, 2R)-15 (610 mg, 86%) as an
oil. The optical purity of (1R, 2R)-15 determined by NMR
analysis of 17a was .98% ee. [a]2D5ˆ212.78 (c 0.76,
1
CHCl3). IR (liquid ®lm) cm21 3356, 2931, 2857, 1450. H
NMR (270 MHz, CDCl3) d 1.18±1.85 (9H, m), 2.24 (2H,
m), 3.76 (2H, d, Jˆ4.1 Hz), 4.13±4.19 (1H, m).
Ethyl (1R,2S)-2-hydroxycyclohexanecarboxylate ((1R,
2S)-13). To a solution of sucrose (50 g) in water (260 mL)
was added baker's yeast (20 g). After stirring the mixture for
1 h at 308C, 12 (3.40 g, 20.0 mmol) was added to the
mixture. The mixture was stirred for 3 days and then
®ltrated with Celite. The ®ltrate was extracted with EtOAc
(400 mL£3) and the organic layer was dried over Na2SO4.
The solution was evaporated in vacuo and the residue was
puri®ed by silica gel column chromatography (hexane±
EtOAc, 3:1) to afford (1R, 2S)-13 (2.67 g, 78%) as an oil.
The optical purity of this compound by HPLC analysis
(column: Chiralcel OJ-R (Daicel), eluent: acetonitrile/phos-
phate buffer (pH 7)ˆ3:7) was 90% ee. IR (liquid ®lm) cm21
(1S, 2S)-2-t-Butyldimethylsilyloxymethylcyclohexanol ((1S,
2S)-15). To a suspension of lithium aluminium hydride
(LAH) (573 mg, 15.1 mmol) in THF (10 mL) was added a
solution of (1R, 2S)-13 (2.6 g, 15.1 mmol) in THF (10 mL)
at 08C. The mixture was stirred for 1 h at the same tempera-
ture. After adding Na2SO4´10H2O to the mixture, the
suspension was ®ltrated with Celite and the ®ltrate was
evaporated in vacuo. The residue was puri®ed by silica
gel column chromatography (hexane±EtOAc, 1:1) to afford
(1S, 2S)-2-hydroxymethylcyclohexanol (1.22 g, 62%) as an
oil. [a]2D5ˆ128.88 (c 1.11, CHCl3). IR (liquid ®lm) cm21
1
1
3513, 2937, 1713, 1185, 1040, 976. H NMR (270 MHz,
3356, 2931, 2857, 1450. H NMR (270 MHz, CDCl3) d
CDCl3) d 1.28 (3H, t, Jˆ7.0 Hz), 1.24±1.98 (8H, m), 2.48
(1H, ddd, Jˆ11.3, 3.5, 2.8 Hz), 3.20 (1H, br d, Jˆ2.6 Hz),
4.11±4.18 (1H, m), 4.17 (2H, q, Jˆ7.0 Hz).
1.18±1.85 (9H, m), 2.24 (2H, m), 3.76 (2H, d, Jˆ4.1 Hz),
4.13±4.19 (1H, m). To a solution of (1S, 2S)-2-hydroxy-
methylcyclohexanol (1.0 g, 7.68 mmol) in CH2Cl2
(10 mL) was added 4-dimethylaminopyridine (50 mg),
triethylamine (933 mg, 9.22 mmol) and t-butyldimethyl-
silylchloride (1.33 g, 8.83 mmol) at room temperature and
the mixture was stirred for 19 h at the same temperature.
The mixture was diluted with EtOAc (300 mL) and washed
with saturated aqueous NaHCO3 and brine. The organic
layer was dried over Na2SO4 and then evaporated in
vacuo. The residue was puri®ed by silica gel column chro-
matography (hexane±EtOAc, 10:1) to afford (1S, 2S)-15
(1.71 g, 91%) as an oil. The enantiomeric excess of (1S,
2S)-15 determined by NMR analysis of 17b was 86% ee.
Ethyl (1S,2R)-2-acetoxycyclohexanecarboxylate ((1S,
2R)-14). To a solution of cis-13 (1.72 g, 9.99 mmol) in
THF (75 mL) and vinyl acetate (175 mL) was added
immobilized lipase (TOYOZEMEw LIP, 10 g). The mixture
was stirred for 9 h at 378C and then ®ltrated with Celite. The
®ltrate was evaporated in vacuo. The residue was puri®ed by
silica gel column chromatography (hexane±EtOAc, 4:1) to
afford (1R, 2S)-14 (710 mg, 33%) as an oil. [a]2D5ˆ210.78
(c 0.61, CHCl3). IR (liquid ®lm) cm21 1238, 1250, 1740,
1
2940. H NMR (270 MHz, CDCl3) d 1.19±1.38 (1H, m),
1
1.23 (3H, t, Jˆ7.2 Hz), 1.41±1.65 (3H, m), 1.72±1.88 (3H,
m), 1.92±2.11 (1H, m), 2.03 (3H, s), 2.43±2.59 (1H, m)
4.02±4.21 (2H,m), 5.35±5.42 (1H, m). MS (FAB) m/z:
215 (M1H1). Anal. Calcd for C11H18O4: C, 61.66, H,
8.47. Found: C, 61.35, H, 8.50.
IR (liquid ®lm) cm21 3356, 2931, 2857, 1450. H NMR
(270 MHz, CDCl3) d 1.18±1.85 (9H, m), 2.24 (2H, m),
3.76 (2H, d, Jˆ4.1 Hz), 4.13±4.19 (1H, m).
(1R, 2R)-2-t-Butyldimethylsilyloxymethyl-1-[(S)-a-meth-
oxy-a-(tri¯uoromethyl)phenylacetoxy]cyclohexane (17a).
To a solution of (1R, 2R)-15 (25 mg, 0.10 mmol) in CH2Cl2
(1 mL) was added 4-dimethylaminopyridine (37 mg,
0.31 mmol) and (R)-MTPA chloride (39 mg, 0.15 mmol)
at room temperature. The mixture was then stirred for
14 h at the same temperature. The mixture was diluted
with EtOAc and washed with saturated aqueous NaHCO3
and brine. The organic layer was dried over Na2SO4 and
then evaporated in vacuo. The residue was puri®ed by silica
gel column chromatography (hexane±EtOAc, 10:1) to
(1R, 2R)-2-t-Butyldimethylsilyloxymethylcyclohexanol ((1R,
2R)-15). To a suspension of lithium aluminium hydride
(LAH) (158 mg, 4.19 mmol) in THF (5 mL) was added a
solution of (1S, 2R)-14 (690 mg, 3.22 mmol) in THF (5 mL)
at 2708C. The mixture was allowed to warm to 08C and
stirred for 1 h at the same temperature. After adding
Na2SO4´10H2O to the mixture, the suspension was ®ltrated
with Celite and the ®ltrate was evaporated in vacuo. The
residue was puri®ed by silica gel column chromatography
(hexane±EtOAc, 1:1) to afford (1R, 2R)-2-hydroxymethyl-
cyclohexanol (395 mg, 94%) as an oil. [a]2D5ˆ232.68 (c
0.73, CHCl3). IR (liquid ®lm) cm21 3356, 2931, 2857,
1
afford 17a (47 mg, 100%) as an oil. H NMR (400 MHz,
CDCl3) d 20.02 (3H, s), 20.01 (3H, s), 0.87 (9H, s), 1.15±
1.65 (5H, m), 1.67±1.76 (2H, m), 2.02±2.12 (1H, m), 3.26
(1H, dd, Jˆ10.0, 6.9 Hz), 3.35 (1H, dd, Jˆ10.0, 8.0 Hz),
3,55 (3H, s), 5.45 (1H, d, Jˆ1.7 Hz), 7.36±7.44 (3H, m),
7.52±7.58 (2H, m).
1
1450. H NMR (270 MHz, CDCl3) d 1.18±1.85 (9H, m),
2.24 (2H, m), 3.76 (2H, d, Jˆ4.1 Hz), 4.13±4.19 (1H, m).
To a solution of (1R, 2R)-2-hydroxymethylcyclohexanol

O. Kanno, I. Kawamoto / Tetrahedron 56 (2000) 5639±5648
5645
(1S, 2S)-2-t-Butyldimethylsilyloxymethyl-1-[(S)-a-meth-
oxy-a-(tri¯uoromethyl)phenylacetoxy]cyclohexane (17b).
To a solution of (1S, 2S)-15 (50 mg, 0.21 mmol) in CH2Cl2
(2 mL) was added 4-dimethylaminopyridine (75 mg,
0.61 mmol) and (R)-MTPA chloride (78 mg, 0.31 mmol)
at room temperature. The mixture was then stirred for 7 h
at the same temperature. The mixture was diluted with
EtOAc and washed with saturated aqueous NaHCO3 and
brine. The organic layer was dried over Na2SO4 and then
evaporated in vacuo. The residue was puri®ed by silica gel
column chromatography (hexane±EtOAc, 10:1) to afford
(N±H proton of azetidinone 7:5.79 ppm, 18:6.05 ppm,
7:18ˆ9:1). The residue was puri®ed by silica gel column
chromatography (hexane±EtOAc, 3:1) to afford 7 (485 mg,
63%) as crystals. The isomer 18 could not be isolated
because 18 and unreacted 5 could not be separated from
each other by silica gel column chromatography.
(3S,4R)-3-[(R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-[(20R,
60R)-20-hydroxymethylcyclohexanone-60-yl]azetidin-2-
one (19). To a solution of 7 (10 g, 21.3 mmol) in dimethyl-
formamide (100 mL) was added ammonium hydrogen
¯uoride (1.34 g, 23.4 mmol) at room temperature. The
mixture was then stirred for 3 days at the same temperature.
After adding saturated aqueous NaHCO3 to the mixture, the
aqueous mixture was extracted with EtOAc (250 mL£3).
The organic layer was washed with brine and then dried
over Na2SO4. The solution was evaporated in vacuo and
the residue was puri®ed by silica gel column chromato-
graphy (hexane±EtOAc, 1:2) to afford 19 (5.61 g, 74%) as
crystals. [a]2D5ˆ148.98 (c 0.84, CHCl3). Mp 135±1368C. 1H
NMR (270 MHz, CDCl3) d 0.07 (6H, s), 0.88 (9H, s), 1.11
(3H, d, Jˆ6.2 Hz), 1.64±2.05 (6H, m), 2.42 (1H, br s),
2.56±2.66 (2H, m), 2.93 (1H, dd, Jˆ3.5, 2.1 Hz), 3.69
(1H, dd, Jˆ11.2, 4.6 Hz), 3.82 (1H, dd, Jˆ11.2, 7.8 Hz),
4.08 (1H, dd, Jˆ7.8, 2.1 Hz), 4.17±4.25 (1H. m), 6.28 (1H,
br s). MS (FAB) m/z: 356 (M1H1). Anal. Calcd for
C18H33NO4Si: C, 60.81, H, 9.36, N, 3.94. Found: C, 60.58,
H, 9.18, N, 4.03.
1
17b (94 mg, 100%) as an oil. H NMR (400 MHz, CDCl3)
d 0.02 (6H, s), 0.88 (9H, s), 1.13±1.38 (3H, m), 1.40±1.52
(3H, m), 1.56±1.78 (2H, m), 2.06±2.14 (1H, m), 3.38 (1H,
dd, Jˆ10.1, 6.6 Hz), 3.44 (1H, dd, Jˆ10.1, 8.8 Hz), 3,54
(3H, s), 5.42 (1H, d, Jˆ1.7 Hz), 7.36±7.44 (3H, m), 7.49±
7.57 (2H, m).
(R)-2-t-Butyldimethylsilyloxymethylcyclohexanone ((R)-
16). To a solution of (1R, 2R)-15 (550 mg, 2.25 mmol) in
CH2Cl2 (5 mL) was added pyridinium dichromate (PDC)
(931 mg, 2.47 mmol) and molecular sieves 4A (931 mg) at
room temperature. The mixture was stirred for 4.5 h at the
same temperature. After ®ltrating the mixture with Celite,
the ®ltrate was evaporated in vacuo. The residue was puri-
®ed by silica gel column chromatography (hexane±EtOAc,
20:1) to afford (R)-16 (480 mg, 88%) as an oil.
[a]2D5ˆ139.08 (c 0.58, CHCl3). 1H NMR (270 MHz,
CDCl3) d 0.05 (6H, s), 0.88 (9H, s), 1.31±1.48 (1H, m),
1.54±1.76 (2H, m), 1.84±1.97 (1H, m), 1.96±2.13 (1H,
m), 2.24±2.42(3H, m), 2.42±2.56 (1H, m), 3.56 (1H, dd,
Jˆ10.3, 8.0 Hz), 3.98 (1H, dd, Jˆ10.3, 4.7 Hz). MS
(FAB) m/z: 243 (M1H)1.
(3S,4R)-3-[(R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-[(20R,
60R)-20-(triethylsilyloxymethyl)cyclohexanone-60-yl]aze-
tidin-2-one (20). To a solution of 19 (4.20 g, 11.8 mmol) in
dimethylformamide (30 mL) was added triethylsilylchloride
(2.41 g, 14.2 mmol) and imidazole (1.21 g, 17.7 mmol) at
08C. The mixture was then stirred for 2.5 h at 08C. After
adding saturated aqueous NaHCO3 was added to the
mixture, the aqueous mixture was extracted with a mixed
solvent of ethyl acetate and hexane. The organic layer was
washed with water and brine and then dried over Na2SO4
and evaporated in vacuo. The residue was puri®ed by silica
gel column chromatography (hexane±EtOAc, 2:1) to give
20 (5.43 g, 98%) as crystals. Mp 124±1258C. IR (KBr)
cm21 3082, 2954, 1760, 1704. 1H NMR (270 MHz,
CDCl3) d 0.06 (3H, s), 0.07 (3H, s), 0.57 (6H, q,
Jˆ7.9 Hz), 0.87 (9H, s), 0.94 (9H, t, Jˆ7.9 Hz), 1.20 (3H,
d, Jˆ6.1 Hz), 1.66±2.09 (6H, m), 2.57±2.70 (2H, m), 2.88
(1H, dd, Jˆ4.2, 2.4 Hz), 3.73 (1H, dd, Jˆ10.3, 7.1 Hz), 3.90
(1H, dd, Jˆ10.3, 6.9 Hz), 4.10 (1H, dd, Jˆ5.3, 2.2 Hz),
4.16±4.25 (1H, m), 5.76 (1H, br s). Anal. Calcd for
C24H47NO4Si2: C, 61.36, H, 10.08, N, 2.98. Found: C,
61.06, H, 9.82, N, 2.99.
(R)-2-t-Butyldimethylsilyloxymethyl-1-trimethylsilyl-
oxycyclohexene ((R)-4). To
a
solution of 1.0 M
lithiumhexamethyldisilazide (1.82 mL, 1.82 mmol) in
THF was added a solution of (R)-16 (400 mg, 1.65 mmol)
in THF (2 mL) at 2788C. The mixture was then stirred for
1 h at the same temperature. After adding trimethylsilyl
chloride (269 mg, 2.48 mmol) to the mixture, the resulting
mixture was allowed to warm to room temperature and was
evaporated in vacuo. The residue was puri®ed by silica gel
column chromatography (hexane±EtOAc, 40:1) to afford
(R)-4 (520 mg, 100%) as an oil. 1H NMR (270 MHz,
CDCl3) d 0.04±0.0.6 (6H, m), 0.11±0.20 (9H, m), 1.35±
1.87 (4H, m), 1.92±2.08 (2H, m), 2.11±2.28(1H, m), 3.48
(1H, dd, Jˆ9.7, 9.4 Hz), 3.82 (1H, dd, Jˆ9.7, 3.6 Hz),
4.86±4.90 (1H, m).
(3S,4R)-3-[(R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-[(20R,
60R)-20-(t-butyldimethylsilyloxymethyl)cyclohexanone
260-yl]azetidin-2-one (7) from (R)-4 and 5. To a solution
of (R)-4 (520 mg, 1.65 mmol) and azetidinone 5 (653 mg,
1.82 mmol) in CH2Cl2 (6 mL) was added zinc chloride
(450 mg, 3.30 mmol) at room temperature. The mixture
was stirred for 3 h at the same temperature. After adding
saturated aqueous NaHCO3 to the mixture, the insoluble
material was removed by ®ltration. The ®ltrate was
extracted with EtOAc (50 mL£3) and the organic layer
was washed with brine. The solvent was dried over
Na2SO4 and evaporated in vacuo. The ratio of 7 and 18
was determined by NMR analysis of the crude mixture
Allyl (4S,8S,9R,10S)-10-[(R)-1-(t-butyldimethylsilyloxy)-
ethyl]-4-triethylsilyloxymethyl-11-oxo-azatricyclo[7.2.0.03,8]-
undec-2-ene-2-carboxylate (21). By a similar procedure as
that described for the preparation of 11 from 7, 21 (4.25 g,
74%) was prepared from 20 (5.00 g, 10.6 mmol).
[a]D25ˆ195.18 (c 1.20, CHCl3). IR (liquid ®lm) cm21
2954, 2877, 1782, 1720, 1282, 1146, 1101. 1H NMR
(270 MHz, CDCl3)
d 0.07 (6H, s), 0.59 (6H, q,
Jˆ7.9 Hz), 0.88 (9H, s), 0.94 (3H, t, Jˆ7.9 Hz), 1.24 (3H,
d, Jˆ6.1 Hz), 1.21±2.04 (6H, m), 2.94±3.08 (1H, m), 3.16
(1H, dd, Jˆ6.7, 3.2 Hz), 3.67±3.85 (2H, m), 4.08 (1H, dd,

5646
O. Kanno, I. Kawamoto / Tetrahedron 56 (2000) 5639±5648
Jˆ10.8, 3.5 Hz), 4.19 (1H, dq, Jˆ6.3, 6.0 Hz), 4.61±4.83
(2H, m), 5.20±5.28 (1H, m), 5.38±5.48 (1H, m), 5.89±6.06
(1H, m). HRMS (FAB) m/z: calcd for C29H52NO5Si2
550.3384 (M1H)1, Found: 550.3373. Anal. Calcd for
C29H51NO5Si2: C, 63.34, H, 9.35, N, 2.55. Found: C,
63.12, H, 9.06, N, 2.59.
with EtOAc (30 mL£2). The organic layer was washed with
saturated aqueous NaHCO3, brine and then dried over
Na2SO4. The solution was evaporated in vacuo and the
residue was puri®ed by silica gel column chromatography
(hexane±EtOAc, 2:3) to afford 23a (216 mg, 66%) as an oil.
1H NMR (270 MHz, CDCl3) d 1.21±1.95 (6H, m), 1.31
(3H, d, Jˆ6.5 Hz), 3.21 (1H, dd, Jˆ6.4, 3.2 Hz), 3.22±
3.36 (1H, m), 3.79 (1H, dd, Jˆ12.8, 4.1 Hz), 3.99±4.28
(4H, m), 4.53±4.80 (6H, m), 5.17±5.49 (6H, m), 5.81±
6.02 (3H, m). HRMS (FAB) m/z: calcd for C25H33N2O8
489.2237 (M1H)1, found: 489.2238.
Allyl (4S,8S,9R,10S)-10-[(R)-1-(t-butyldimethylsilyloxy)-
ethyl]-4-hydroxymethyl-11-oxo-azatricyclo[7.2.0.03,8]-
undec-2-ene-2-carboxylate (3). To a solution of 21
(500 mg, 0.91 mmol) in dimethylformamide (5 mL) was
added ammonium hydrogen ¯uoride (52 mg, 0.91 mmol)
at room temperature. The mixture was then stirred for
8.5 h at the same temperature. After adding saturated
aqueous NaHCO3 to the mixture, the aqueous mixture was
extracted with EtOAc (50 mL£3). The organic layer was
washed with brine and then dried over Na2SO4. The solution
was evaporated in vacuo and the residue was puri®ed by
silica gel column chromatography (hexane±EtOAc, 1:1) to
afford 3 (359 mg, 91%) as an oil. [a]2D5ˆ11338 (c 0.78,
(4S,8S,9R,10S)-4-Aminomethyl-10-[(R)-1-hydroxyethyl]-
11-oxo-azatricyclo[7.2.0.03,8]undec-2-ene-2-carboxylic
acid (24a). To a solution of 23a (210 mg, 0.43 mmol),
bis(triphenylphosphine)palladium
dichloride
(6 mg,
0.009 mmol) and water (39 mL) in dichloromethane
(2 mL) was added tributyltin hydride (626 mg, 2.15 mmol)
at 08C. The mixture was then stirred for 0.5 h at the same
temperature. After EtOAc (20 mL) was added to the
mixture, the mixture was extracted with water (20 mL£3).
The aqueous layer was evaporated in vacuo and the residue
was puri®ed by reverse phase column chromatography
(Cosmosil 75C18 PREP, CH3CN±H2O, 4:96). The desired
fraction was concentrated and then lyophilized to afford 24a
(89 mg, 74%) as a colorless powder. IR (KBr) cm21 3391,
1
CHCl3). IR (liquid ®lm) cm21 2933, 2859, 1771, 1720. H
NMR (270 MHz, CDCl3) d 0.08 (6H, s), 0.88 (9H, s), 1.16±
1.92 (6H, m), 1.23 (3H, d, Jˆ6.1 Hz), 2.97±3.10 (1H, m),
3.20 (1H, dd, Jˆ6.3, 3.4 Hz), 3.71±3.88 (3H, m), 4.16 (1H,
dd, Jˆ10.6, 3.4 Hz), 4.21 (1H, dq, Jˆ6.3, 6.1 Hz), 4.69 (1H,
dd, Jˆ13.6, 5.5 Hz), 4.77 (1H, dd, Jˆ13.6, 5.2 Hz), 5.26
(1H, dd, Jˆ10.6, 1.2 Hz), 5.42 (1H, d, Jˆ17.2, 1.2 Hz),
5.88±6.04 (1H, m). MS (FAB) m/z: 436 (M1H)1. Anal.
Calcd for C23H37NO5Si: C, 63.41, H, 8.56, N, 3.22.
Found: C, 63.15, H, 8.85, N, 2.98. By a similar procedure
as that described for the preparation of 3 from 21, 3 (2.22 g,
49%) was prepared from 11 (5.90 g, 10.7 mmol).
1
2931, 1759, 1580, 1392. H NMR (400 MHz, D2O) d 1.27
(3H, d, Jˆ6.1 Hz), 1.28±1.44 (1H, m), 1.52±1.97 (5H, m),
3.09±3.17 (1H, m), 3.20 (1H, dd, Jˆ12.9, 5.6 Hz), 3.32 (1H,
dd, Jˆ12.9, 10.9 Hz), 3.44 (1H, dd, Jˆ5.9, 3.0 Hz), 4.17
(1H, dd, Jˆ10.3, 3.1 Hz), 4.24 (1H, qd, Jˆ6.3, 6.2 Hz).
HRMS (FAB) m/z: calcd for C14H21N2O4 281.1451
(M1H)1,
found:
281.1499.
Anal.
Calcd
for
Allyl (4S,8S,9R,10S)-4-(N,N-bis(allyloxycarbonyl)amino-
methyl)-10-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-11-oxo-
azatricyclo[7.2.0.03,8]undec-2-ene-2-carboxylate (22a). To
a solution of 3 (60 mg, 0.14 mmol), 25a (38 mg, 0.21 mmol)
and triphenylphosphine (60 mg, 0.35 mmol) in tetrahydro-
furan (2 mL) was added diethyl azodicarboxylate (60 mg,
0.35 mmol) at room temperature. The mixture was then
stirred for 1 h at the same temperature. After adding phos-
phate buffer (pH 7) to the mixture, the aqueous mixture was
extracted with EtOAc (10 mL£2). The organic layer was
washed with brine and then dried over Na2SO4. The solution
was evaporated in vacuo and the residue was puri®ed by
silica gel column chromatography (hexane±EtOAc, 2:1) to
C14H20N2O4´2.5H2O: C, 51.68, H, 7.74, N, 8.61. Found: C,
51.94, H, 7.42, N, 8.73.
Allyl (4S,8S,9R,10S)-4-[[1,2-bis(allyloxycarbonyl)guani-
dino]methyl]-10-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-
11-oxo-azatricyclo[7.2.0.03,8]undec-2-ene-2-carboxylate
(22b). To a solution of 3 (150 mg, 0.34 mmol), 25b
(156 mg, 0.69 mmol) and triphenylphosphine (135 mg,
0.52 mmol) in toluene (3 mL) was added diisopropyl azo-
dicarboxylate (104 mg, 0.52 mmol) at room temperature.
The mixture was then stirred for 1.5 h at the same tempera-
ture. The mixture was evaporated in vacuo and the residue
was puri®ed by silica gel column chromatography (hexane±
EtOAc, 3:1) to afford 22b (155 mg, 70%) as an oil. IR (KBr)
cm21 2951, 1770, 1722, 1613. 1H NMR (270 MHz, CDCl3)
d 0.07 (6H, s), 0.88 (9H, s), 1.17±1.92 (6H, m), 1.21 (3H, d,
Jˆ6.1 Hz), 3.17 (1H, dd, Jˆ5.8, 3.5 Hz), 3.36±3.52 (1H,
m), 3.78±3.91 (1H, m), 3.92±4.03 (1H, m), 4.07 (1H, dd,
Jˆ10.7, 3.3 Hz), 4.19 (1H, qd, Jˆ6.1, 6.0 Hz), 4.49±4.85
(7H, m), 5.18±5.49 (6H, m), 5.82±6.09 (3H, m), 9.10±9.41
(2H, br). HRMS (FAB) m/z: calcd for C32H49N4O8Si
645.3320 (M1H)1, found: 645.3333.
1
afford 22a (63 mg, 76%) as an oil. H NMR (270 MHz,
CDCl3) d 0.07 (3H, s), 0.08 (3H, s), 0.89 (9H, s), 1.15±
1.91 (6H, m), 1.21 (3H, d, Jˆ6.1 Hz), 3.16 (1H, dd,
Jˆ5.8, 3.4 Hz), 3.14±3.29 (1H, m), 3.80 (1H, dd, Jˆ12.7,
3.9 Hz), 3.99±4.28 (4H, m), 4.59±4.80 (6H, m), 5.18±5.49
(6H, m), 5.85±6.05 (3H, m). HRMS (FAB) m/z: calcd for
C31H46N2O8SiNa 625.2921 (M1Na)1, found: 625.2919.
Allyl (4S,8S,9R,10S)-4-(N,N-bis(allyloxycarbonyl)amino-
methyl)-10-[(R)-1-hydroxyethyl]-11-oxo-azatricyclo-
[7.2.0.03,8]undec-2-ene-2-carboxylate (23a). To a solution
of 22a (400 mg, 0.66 mmol) in tetrahydrofuran (5 mL) was
added 1 M tetrabutylammonium ¯uoride in tetrahydrofuran
solution (3.3 mL) and acetic acid (239 mg, 3.98 mmol) at
room temperature. The mixture was then stirred for about
two weeks in a refrigerator. After adding phosphate buffer
(pH 7) to the mixture, the aqueous mixture was extracted
Allyl (4S,8S,9R,10S)-4-[[1,2-bis(allyloxycarbonyl)guani-
dino]methyl]-10-[(R)-1-hydroxyethyl]-11-oxo-azatricyclo-
[7.2.0.03,8]undec-2-ene-2-carboxylate (23b). By a similar
procedure as that described for the preparation of 23a from
22a, 23b (178 mg, 56%) was prepared from 22b (390 mg,
0.61 mmol). 1H NMR (270 MHz, CDCl3) d 1.27±1.92 (6H,
m), 1.31 (3H, d, Jˆ6.1 Hz), 3.22 (1H, dd, Jˆ6.0, 3.5 Hz),

O. Kanno, I. Kawamoto / Tetrahedron 56 (2000) 5639±5648
5647
3.34±3.52 (1H, m), 3.77±3.91 (1H, m), 3.92±4.03 (1H, m),
4.10 (1H, dd, Jˆ10.7, 3.3 Hz), 4.22 (1H, qd, Jˆ6.1, 6.0 Hz),
4.49±4.85 (7H, m), 5.18±5.49 (6H, m), 5.82±6.09 (3H, m),
9.13±9.44 (2H, br). HRMS (FAB) m/z: calcd for
C26H35N4O8 531.2455 (M1H)1, found: 531.2427.
that described for the preparation of 24a from 23a, 24c
(56 mg, 54%) was prepared from 23c (140 mg,
0.29 mmol). IR (KBr) cm21 3373, 3253, 2931, 1764,
1
1623, 1558, 1398. H NMR (400 MHz, D2O) d 1.05±1.28
(1H, m), 1.07 (3H, d, Jˆ6.2 Hz), 1.33±1.90 (5H, m), 2.98±
3.05 (1H, m), 3.24 (1H, dd, Jˆ5.9, 3.2 Hz), 3.37 (1H, dd,
Jˆ13.8, 5.9 Hz), 3.50 (1H, dd, Jˆ13.8, 10.5 Hz), 3.67±3.73
(1H, m), 3.96 (1H, dd, Jˆ10.5, 3.3 Hz), 4.03 (1H, qd,
Jˆ6.2, 6.2 Hz), 6.62 (1H, d, Jˆ4.4 Hz), 6.96 (1H, d,
Jˆ4.4 Hz). HRMS (FAB) m/z: calcd for C17H22N3O4S
364.1331 (M1H)1, found: 364.1335. Anal. Calcd for
C17H21N3O4´1.5H2O: C, 52.29, H, 6.20, N, 10.76. Found:
C, 52.04, H, 5.92, N, 11.04.
(4S,8S,9R,10S)-10-[(R)-1-Hydroxyethyl]-4-guanidino-
methyl-11-oxo-azatricyclo[7.2.0.03,8]undec-2-ene-2-car-
boxylic acid (24b). By a similar procedure as that described
for the preparation of 24a from 23a, 24b (55 mg, 52%) was
prepared from 23b (170 mg, 0.32 mmol). IR (KBr) cm21
3357, 2931, 1755, 1664, 1632, 1576, 1398. 1H NMR
(270 MHz, D2O) d 1.17±1.42 (1H, m), 1.24 (3H, d,
Jˆ6.5 Hz), 1.50±1.97 (1H, m), 3.17±3.19 (1H, m), 3.34
(3H, dd, Jˆ13.9, 6.3 Hz), 3.40±3.52 (3H, m), 3.69±3.82
(1H, m), 4.16 (1H, dd, Jˆ10.3, 3.2 Hz), 4.24 (1H, qd,
Jˆ6.2, 6.1 Hz). HRMS (FAB) m/z: calcd for C15H23N4O5
323.1719 (M1H)1, found: 531.2427. Anal. Calcd for
C15H22N4O5´H2O: C, 52.93, H, 6.92, N, 16.46. Found: C,
52.71, H, 6.63, N, 16.70.
Allyl (4S,8S,9R,10S)-4-[(benzothiazol-2-yl)thiomethyl]-
10-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-11-oxo-aza-
tricyclo[7.2.0.03,8]undec-2-ene-2-carboxylate (22d). By a
similar procedure as that described for the preparation of
22c from 3, the crude mixture (395 mg) of 22d, triphenyl-
phosphine and 2-mercaptobenzothiazole was prepared from
1
3 (250 mg, 0.57 mmol) and 25d (192 mg, 1.15 mmol). H
Allyl (4S,8S,9R,10S)-4-[N-allyloxycarbonyl-N-(2-thia-
zolyl)aminomethyl]-10-[(R)-1-(t-butyldimethylsilyloxy)-
ethyl]-11-oxo-azatricyclo[7.2.0.03,8]undec-2-ene-2-car-
boxylate (22c). To a solution of 3 (25 mg, 0.06 mmol), 25c
(32 mg, 0.17 mmol) and triphenylphosphine (75 mg,
0.29 mmol) in toluene (2 mL) was added diethyl azodi-
carboxylate (50 mg, 0.29 mmol) at room temperature. The
mixture was then stirred for 2.5 h at the same temperature.
After adding phosphate buffer (pH 7) to the mixture, the
aqueous mixture was extracted with EtOAc (10 mL£2).
The organic layer was washed with brine and then dried
over Na2SO4. The solution was evaporated in vacuo and
the residue was puri®ed by silica gel column chromato-
graphy (hexane±EtOAc, 3:1) to afford 22c (24 mg, 68%)
as an oil. IR (liquid ®lm) cm21 2931, 2858, 1780, 1716,
NMR (270 MHz, CDCl3) d 0.05 (3H, s), 0.06 (3H, s), 0.87
(9H, s), 1.18±2.07 (6H, m), 1.22 (3H, d, Jˆ6.2 Hz), 3.08±
3.22 (2H, m), 3.57 (1H, dd, Jˆ12.9, 6.7 Hz), 3.74 (1H, dd,
Jˆ12.9, 9.5 Hz), 3.99 (1H, dd, Jˆ10.5, 3.2 Hz), 4.02±4.21
(2H, m), 4.61±4.69 (2H, m), 5.21±5.39 (2H, m), 5.78±5.96
(4H, m), 7.24±7.45 (2H, m), 7.70±7.88(2H, m). HRMS
(FAB) m/z: calcd for C30H41N2O4S2Si 585.2277 (M1H)1,
found: 585.2272.
Allyl (4S,8S,9R,10S)-4-[(benzothiazol-2-yl)thiomethyl]-
10-[(R)-1-hydroxyethyl]-11-oxo-azatricyclo[7.2.0.03,8]-
undec-2-ene-2-carboxylate (23d). By a similar procedure
as that described for the preparation of 23a from 22a, 23d
(172 mg, 69% in two steps) was prepared from the crude
mixture (395 mg, 0.40 mmol) of 22d, triphenylphosphine
and 2-mercaptobenzothiazole. 1H NMR (270 MHz,
CDCl3) d 1.16±2.08 (6H, m), 1.30 (3H, d, Jˆ6.2 Hz),
3.12±3.39 (2H, m), 3.59 (1H, dd, Jˆ12.9, 6.8 Hz), 3.72
(1H, dd, Jˆ12.9, 9.4 Hz), 4.01±4.27 (3H, m), 4.54±4.74
(2H, m), 5.12±5.38 (2H, m), 5.78±5.97 (4H, m), 7.24±
7.47 (2H,m), 7.71±7.89(2H, m). HRMS (FAB) m/z: calcd
for C24H26N2O4S2Na 493.1232 (M1Na)1, found: 493.1213.
1
1207. H NMR (270 MHz, CDCl3) d 0.07 (6H, s), 0.89
(9H, s), 1.23 (3H, d, Jˆ6.0 Hz), 1.47±1.91(5H, m), 3.11
(1H, dd, Jˆ7.0, 3.2 Hz), 3.32±3.34 (1H, m), 3.91 (1H, dd,
Jˆ10.5, 3.2 Hz), 4.08±4.26 (3H, m), 4.48±4.64 (2H, m),
4.65±4.81 (1H, m), 4.79 (1H, d, Jˆ6.0 Hz), 5.14±5.47
(4H, m), 5.73±5.91 (1H,m), 5.96±6.12(1H, m), 6.93 (1H,
d, Jˆ3.5 Hz), 7.37 (1H, d, Jˆ3.5 Hz). HRMS (FAB) m/z:
calcd for C30H44N3O6SSi 602.2761 (M1H)1, found:
602.2773.
Potassium (4S,8S,9R,10S)-4-[(benzothiazol-2-yl)thio-
methyl]-10-[(R)-1-hydroxyethyl]-11-oxo-azatricyclo-
[7.2.0.03,8]undec-2-ene-2-carboxylate (24d). To a solution
of 23d (85 mg, 0.18 mmol), triphenylphosphine (10 mg)
and potassium 2-ethylhexanoate (33 mg, 0.18 mmol) in
dichloromethane (3 mL) and EtOAc (3 mL) was added
tetrakis(triphenylphosphine)palladium (7 mg, 0.004 mmol)
at room temperature. The mixture was then stirred for 1 h at
the same temperature. After adding EtOAc (10 mL) to the
mixture, the mixture was extracted with water (10 mL£3).
The aqueous layer was evaporated in vacuo and the residue
was puri®ed by reverse phase silica gel column chromato-
graphy (Cosmosil 75C18 PREP,CH3CN±H2O 2:8). The
desired fraction was concentrated and then lyophilized to
afford 24d (44 mg, 52%) as a colorless powder. IR (KBr)
Allyl (4S,8S,9R,10S)-4-[N-allyloxycarbonyl-N-(2-thia-
zolyl)aminomethyl]-10-[(R)-1-hydroxyethyl]-11-oxo-
azatricyclo[7.2.0.03,8]undec-2-ene-2-carboxylate (23c).
By a similar procedure as that described for the preparation
of 23a from 22a, 23c (144 mg, 74%) was prepared from 22c
(264 mg, 0.40 mmol). 1H NMR (270 MHz, CDCl3) d 1.15±
1.41 (1H, m), 1.29 (3H, d, Jˆ6.1 Hz), 1.41±2.08 (5H, m),
3.19 (1H, dd, Jˆ6.5, 3.2 Hz), 3.38±3.52 (1H, m), 4.00 (1H,
dd, Jˆ10.5, 3.1 Hz), 4.05±4.25 (3H, m), 4.45±4.64 (2H, m),
4.65±4.82 (1H, m), 4.79 (2H, d, Jˆ5.6 Hz), 5.12±5.45
(4H,m), 5.95±6.13 (1H, m), 6.94 (1H, d, Jˆ3.9 Hz), 7.39
(1H, d, Jˆ3.9 Hz). HRMS (FAB) m/z: calcd for
C24H30N3O6S 488.1855 (M1H)1, found: 488.1855.
1
cm21 3414, 2928, 1754, 1590, 1427, 1392, 996. H NMR
(4S,8S,9R,10S)-10-[(R)-1-Hydroxyethyl]-4-[N-(2-thia-
zolyl)aminomethyl]-11-oxo-azatricyclo[7.2.0.03,8]undec-
2-ene-2-carboxylic acid (24c). By a similar procedure as
(400 MHz, D2O) d 0.98 (3H, d, Jˆ6.4 Hz), 1.01±1.31(1H,
m), 1.42±1.60 (3H, m), 1.62±1.78 (2H, m),2.81±2.89 (1H,
m), 3.08 (1H, dd, Jˆ6.0, 3.0 Hz), 3.21 (1H, dd, Jˆ13.1,

5648
O. Kanno, I. Kawamoto / Tetrahedron 56 (2000) 5639±5648
6. (a) Ghiron, C.; Piga, E.; Rossi, T.; Tambrini, B.; Thomas, R. J.
Tetrahedron Lett. 1996, 37, 3891. (b) Kennedy, G.; Rossi, T.;
Tambrini, B. Tetrahedron Lett. 1996, 37, 7441. (c) Giacobbe,
S. A.; Rossi, T. Tetrahedron: Asymmetry 1996, 7, 3079. (d)
Matsumoto, T.; Murayama, T.; Mitsuhashi, S.; Miura, T.
Tetrahedron Lett. 1999, 40, 5043.
4.9 Hz), 3.61 (1H, dd, Jˆ13.1, 11.2 Hz), 3.67±3.77 (1H, m),
3.89 (1H, qd, Jˆ6.4, 6.0 Hz), 7.21±7.28 (1H, m), 7.33±7.39
(1H, m), 7.69 (1H, d, Jˆ8.0 Hz), 7.74 (1H, d, Jˆ8.0 Hz).
HRMS (FAB) m/z: calcd for C21H21N2O4S2KNa 491.0460
(M1Na)1, found: 491.0469. Anal. Calcd for C21H21N2O4S2-
K´H2O: C, 51.83, H, 4.76, N, 5.76. Found: C, 52.07, H, 4.98,
N, 5.82.
7. Padova, A.; Roberts, S. M.; Donati, D.; Marchioro, C.; Perboni,
A. J. Chem. Soc., Chem. Commun. 1995, 661.
8. Yoshida, A.; Tajima, Y.; Takeda, N.; Oida, S. Tetrahedron Lett.
1984, 25, 2793.
9. (a) Oida, S.; Mori, M. Jpn Kokai Tokkyo Koho, JP 96-59663,
Acknowledgements
The authors would like to thank the members of the NMR
analysis and biological assay groups for their assistance.
È
1996. (b) Budt, K.-H.; Fiscer, G.; Horlein, R.; Kirrstetter, R.;
Lattrell, R. Tetrahedron Lett. 1992, 33, 5331.
10. Panunzio, M.; Camerini, R.; Mazzoni, A.; Donati, D.;
Marchioro, C.; Pachera, R. Tetrahedron: Asymmetry 1997, 8, 15.
11. Tokuyama, S.; Yamano, T.; Aoki, I.; Takanohashi, K.;
Nakahama, K. Chem. Lett. 1993, 741.
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Â
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