Synthesis of Thienamycin methyl ester from 2-deoxy-d-ribose via Kinugasa reaction

Article abstract of DOI:10.1038/ja.2015.108

A novel synthesis of thienamycin is described. The crucial step of the synthesis is based on Cu(I)-mediated Kinugasa cycloaddition/rearrangement cascade reaction between terminal acetylene derived from d-lactic acid and suitable, partially protected, five-membered cyclic nitrone obtained from 2-deoxy-d-ribose. The reaction was performed in the presence of tetramethylguanidine as a base to provide 5,6-trans substituted carbapenam as the main product. Thus obtained carbapenam 11 with (5R,6S) configuration at the azetidinone ring was subsequently subjected to oxidation/deprotection/oxidation reaction sequence to afford the β-keto ester 20, which was directly transformed into N,O-protected methyl ester of thienamycin.

Full text of DOI:10.1038/ja.2015.108

The Journal of Antibiotics (2015), 1–5
2015 Japan Antibiotics Research Association All rights reserved 0021-8820/15
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&
ORIGINAL ARTICLE
Synthesis of Thienamycin methyl ester from
2-deoxy-D-ribose via Kinugasa reaction
Magdalena Soluch, Barbara Grzeszczyk, Olga Staszewska-Krajewska, Marek Chmielewski and
Bartłomiej Furman
A novel synthesis of thienamycin is described. The crucial step of the synthesis is based on Cu(I)-mediated Kinugasa
cycloaddition/rearrangement cascade reaction between terminal acetylene derived from D-lactic acid and suitable, partially
protected, five-membered cyclic nitrone obtained from 2-deoxy-D-ribose. The reaction was performed in the presence of
tetramethylguanidine as a base to provide 5,6-trans substituted carbapenam as the main product. Thus obtained carbapenam 11
with (5R,6S) configuration at the azetidinone ring was subsequently subjected to oxidation/deprotection/oxidation reaction
sequence to afford the β-keto ester 20, which was directly transformed into N,O-protected methyl ester of thienamycin.
The Journal of Antibiotics advance online publication, 28 October 2015; doi:10.1038/ja.2015.108
INTRODUCTION
two regioisomers 11 and 12 (6:1), however, in a low yield (35%) only.
Carbapenems are important β-lactam antibiotics which, owing to high Higher pressure led to debenzylation of both groups to afford 13 in
antibacterial activity and resistance to β-lactamase, continually attract low yield. The same deprotection of both benzyl groups can be
the interest of industrial and academic laboratories.1–13 Recently we achieved by a reduction with sodium in liquid ammonia (Figure 1).22
have shown that the Kinugasa reaction between D-lactic acid-derived
This results prompted us to use partly deprotected nitrone 14 in the
acetylene 2 and five-membered cyclic nitrone 1 obtained from Kinugasa reaction with 8. Nitrone 14 was obtained from 1 by a
2-deoxy-D-ribose14–17 offers an attractive entry into carbapenems.18 modification of a known method,23,24 using the complex of BCl3 with
The main drawback of this strategy has been related to the undesired dimethyl sulfide. Under such milder conditions, only the primary
cis configuration of H-5 and H-6 protons in the major adducts 4 or 6 hydroxyl group was deprotected in 50% yield (Scheme 2).
(Scheme 1). We have demonstrated that the stereogenic center at C-6
The reaction of 14 with 8 gave a mixture of cis and trans
of the alcohol 4 can be epimerized in the presence of 2 equiv. KHMDS carbapenams 15 and 11 in a ratio of about 1:3 and with 54% overall
to provide the trans isomer 5 in 55% yield (Scheme 1). Epimerization yield. The trans adduct 11 was separated by chromatography. The
performed on compound with protected side-chain hydroxyl 6 caused primary hydroxyl group was oxidized to the aldehyde using Dess–
β-elimination to the exo double bond.
Martin periodinane25 in 91% yield and subsequently the crude
As effective cis/trans epimerization requires a free hydroxyl group product was oxidized with sodium chlorite under Pinnick–
in the side chain and seeing that Kinugasa reaction involving Lindgren26,27 conditions to afford the carboxylic acid function, which
commercially available alcohol 2 and its t-butyldiphenysilyl-protected was in turn methylated with diazomethane28 to afford ester 18
derivative 319 was low yielding, we decided to change the side-chain (Scheme 3).
hydroxyl group protection and reaction conditions. After conducting
The benzyl protecting group was then removed using palladium
several experiments we found that the protection of alcohol 2 as hydroxide on carbon to afford the alcohol 19 in 97% yield. The
t-butyldimethylsilyl derivative 820 and the use of 1,1,3,3-tetramethyl- structure and configuration of alcohol 19 was confirmed by X-ray
guanidine as the base offered better yield and higher content of the crystallography. Compound 19 was then oxidized to ketone 20 using
trans isomer 10 which allowed for its easy separation (Scheme 1). Dess–Martin reagent (Scheme 4). It’s important to know that the
This observation was important for the further synthesis of similar keto-p-nitrobenzyl ester 20a has already been transformed into
thienamycin because one of the structural features present in thienamycin by the Hannesian group.29
carbapenem antibiotics is the trans configuration in the four-
membered β-lactam ring.
The transformation of the ketone 20 into thienamycin derivative 21
according to a known procedure required the enolization of the
carbonyl group followed by phosphorylation of the enol hydroxyl and
subsequent addition of N-acetylcysteamine.29 The best result was
RESULTS AND DISCUSION
Selective debenzylation of the primary hydroxyl group21 in 10 by obtained for diethyl chlorophosphate as a phosphorylation agent. We
hydrogenolysis under the pressure of 6 bar H2 provided a mixture of also found that the enolization of ketone 20 required quite a long time.
Institute of Organic Chemistry of Polish Academy of Sciences, Warsaw, Poland
Correspondence: Professor B Furman, Institute of Organic Chemistry of Polish Academy of Sciences, Kasprzaka 44/52, Warsaw 01-224, Poland.
E-mail: bartlomiej.furman@icho.edu.pl
Received 13 June 2015; revised 2 September 2015; accepted 18 September 2015

Synthesis of Thienamycin methyl ester
M Soluch et al
2
RO
RO
RO
H
N
H
H
N
H
CuI, Et3N
OBn
N
+
+
OBn
OBn
MeCN
0 °C-RT
12h
OBn
OBn
O
OBn
O
O
1
2: R=H
3: R=TBDPS
30%,
45%,
4
6
(2:1)
(3:1)
5
7
CuI, TMG,
8: R=TBS
50%,
9
(1:3)
10
MeCN
0 °C-RT
12h
HO
HO
H H
H H
KHMDS (2 equiv.)
THF, -50oC
55%
4
2
6
5
3
OBn
OBn
OBn
OBn
N
N
O
O
4
5
Scheme 1 Synthesis of carbapenams via Kinugasa reaction with Et3N and 1,1,3,3-tetramethylguanidine as a base. Attempted epimerization at C-6.
TBSO
TBSO
TBSO
TBSO
H H
N
H H
N
H H
N
H H
N
OH
OH
OH
OBn
OBn
OBn
OH
O
O
O
O
OBn
10
11
12
13
Figure 1 Selective debenzylation of the primary hydroxyl group.
TBSO
TBSO
TBSO
H H
H H
N
8
OBn
OBn
.
BCl3 SMe2 (5equiv.)
N
OBn
OBn
OH
N
+
N
O
O
CH2Cl2, 0oC
CuI, TMG,
MeCN
cis/trans 1:3
54%
O
O
OBn
15 h, 50%
1
OH
OH
14
15
11
Scheme 2 Deprotection of nitrone 1 and Kinugasa reaction with alkyne 8.
TBSO
TBSO
TBSO
H
H
N
TBSO
H
H
N
H
H
H
H
N
NaClO2, NaH2PO4
2-methyl-2-butene
CH2N2
Et2O
DMP, NaHCO
OBn
OH
3
OBn
OBn
CO2H
OBn
CO2Me
N
t-BuOH, H2O, 0C
CH2Cl2
rt, 3 h
O
O
O
O
12 h
CHO
58%
17
16
11
91%
18
Scheme 3 Preparation of carbapenam 18.
Otherwise phosphorylation did not occur and compound 21 was not EXPERIMENTAL PROCEDURE
Melting points were determined using Köfler hot-stage apparatus with
microscope and were uncorrected. Proton and carbon NMR spectra were
recorded on a Varian VN MRS Spectrometer (Varian Inc., St Clara, CA, USA)
at 600 and 150 MHz, respectively, in CDCl3 or C6D6. IR spectra were obtained
on an FT-IR-1600 Perkin-Elmer spectrophotometer (Perkin Elmer, Waltham,
MA, USA). The optical rotations were measured with a JASCO J-2000 digital
polarimeter (Jasco Inc., Easton, MD, USA). High-resolution mass spectra were
recorded on ESI-TOF Mariner spectrometer (Perspective Biosystem, Framing-
ham, MA, USA). X-ray analysis were performed on Nonius MACH3
diffractometer (Bruker, Madison, WI, USA). The HPLC analysis were carried
out on Hitachi chromatograph (Hitaschi, Tokyo, Japan) with L-2130 pump and
L-2450 DAD detector (Brucker, Karlsruhe, Germany) equipped with LiChro-
spher Si60 analytical column (Merck, Darmstadt, Germany).
formed. Particularly when treating 20 with diphenyl chlorophosphate,
we observed the opening of the pyrrolidine ring via retro-Dieckmann
reaction and formation of thioester 22 (Scheme 5).
In conclusion, we have demonstrated that the cyclic five-membered
nitrone 1, easily available from 2-deoxy-D-ribose represents an
attractive substrate for the stereocontrolled synthesis of thienamycin
—an important natural carbapenem antibiotic. The configuration of
the stereogenic center next to the nitrogen atom has a decisive role in
the asymmetric induction at the C-5 carbon atom of the carbapenam
scaffold. The predominance of the isomer with anti configuration of
H-5 and H-6 protons was achieved by the use of tetramethylguanidine
as a base in the Kinugasa reaction.
The Journal of Antibiotics

Synthesis of Thienamycin methyl ester
M Soluch et al
3
TBSO
TBSO
H H
H H
N
TBSO
H H
DMP, NaHCO3
CH2Cl2, rt, 1 h, 48%
H2, Pd(OH)2/C
OH
OBn
CO2Me
O
N
N
EtOAc
rt, 3 h, 97%
O
O
O
CO2Me
CO2Me
18
19
20
TBSO
NHAc
TBSO
H H
H H
O
S
N
N
O
O
CO2Me
O
O
20a
21
X-ray structure of compound 19
O2N
Scheme 4 Synthesis of ketone 20. A full color version of this scheme is available at The Journal of Antibiotics journal online.
NHAc
TBSO
TBSO
H H
N
H H
N
1. (EtO)2POCl, (iPr)2NEt, DMAP
O
S
2. HSCH2CH2NHAc
44%
O
O
CO2Me
CO2Me
20
21
NHAc
TBSO
S
TBSO
TBSO
H H
NHAc
H H
N
H H
N
HS
S
O
NHAc
O
(PhO)2POCl,
(iPr)2NEt, DMAP
13%
N
O
O
O
O
CO2Me
OMe
22
OMe
O
O
20
Scheme 5 Synthesis of protected thienamycin 21 and side reactions in the phosphorylation-addition sequence.
Thin-layer chromatography (TLC) was performed on aluminum sheets silica 3/1 mixture of E/Z isomers) as an yellow oil. To a solution of mesylate (13.4 g,
gel 60 F254 from Merck. Column chromatography (CC) was carried out using
Merck silica gel (230–400 mesh) or Florisil (100–200 mesh). The TLC spots
were visualized in UV (254 nm) and by treatment with alcoholic solution of
ninhydrine, aqueous solution of KMnO4 or with ceric sulphate/phosphomo-
lybdic acid solution.
20.7 mmol) in THF (400 ml) placed at 0 °C under argon was added
tetrabutylammonium fluoride (24.2 ml, 1 M solution in THF, 24.2 mmol).
The reaction mixture was stirred for 5 min at 0 °C, and then the solvent was
removed under vacuum. The residue was dissolved in ethyl acetate, water was
added, and the aqueous layer was extracted three times with ethyl acetate. The
organic layers were washed with brine, dried over MgSO4, and concentrated
under vacuum to give a residue, which was use in the next step without further
purification.
Step 3: To a solution of crude oxime with previous step (6.2 g, 18.8 mmol) in
a 4:1 mixture of methanol and water (200 ml) were added NaHCO3 (8.5 g,
102.0 mmol) and hydroxylamine hydrochloride (6.7 g, 96.5 mmol). The reac-
tion mixture was heated overnight at reflux temperature. After concentration
under vacuum, the residue was dissolved in CH2Cl2, and water was added. The
aqueous layer was extracted three times with CH2Cl2, and the organic layers
were washed with brine, dried over MgSO4 and concentrated under vacuum to
give a residue, which upon column chromatography over silica gel (acetone/
DCM 1/9 then methanol/DCM 5/95) yielded the nitrone 1 (5.1 g, 87%) as an
olive syrup.
All solvents were dried and purified applying standard techniques.
(2S,3S)-3-(benzyloxy)-2-((benzyloxy)methyl)-3,4-dihydro-2H-
pyrrole-1-oxide (1) Compound 1 was prepared according to
literature methods
Step 1: To
a
solution of 3,5-di-O-benzyl-2-deoxy-D-ribofuranoside15
(8.91 g, 28.3 mmol)16 in dry toluene (70 ml) was added MgSO4 (10.3 g)
under argon. The suspension was stirred at reflux temperature for 5 min,
and then O-tert-butyldiphenylsilylhydroxylamine (8.6 g, 32 mmol) and pyridi-
nium p-toluenesulfonate (98 mg) were added. The reaction mixture was heated
at the same temperature for 30 min, and then it was filtered. The filtrate was
washed with a saturated aqueous solution of NaHCO3 and with brine and dried
over MgSO4 to give a residue, which was use in the next step without further
purification.
[α]D+23,7 (c 1, CHCl3), IR (film) ν: 737, 1113, 2866, 3062, 3239 cm− 1
1H NMR (600 MHz, CDCl3) δ: 2.74–2.78 (m, 1H, H-3), 2.79-2.85 (ddd
J = 2.6 Hz, 7,1 Hz, 17,9 Hz, 1H, H-3), 4.00–4.05 (m, 1H, H-5), 4.07–4.12
(m, 2H, CH2OBn), 4.45–4.50 (m, 1H, H-4), 4.54–4.62 (m, 2H, 2 × CH2Ph),
6.85–6.88 (m, 1H, H-2). 13C NMR (150 MHz, CDCl3) δ: 35.03, 64.86, 72.20,
73.63, 73.66, 74.32, 127.56, 127.60, 127.66, 127.94, 128.31, 128.50, 133.23,
Step 2: To a solution of oxime with previous step (12.0 g, 21.2 mmol) in
CH2Cl2 (70 ml) placed at 0 °C under argon atmosphere were added successively
triethylamine (4.5 ml, 32.8 mmol) and mesyl chloride (1.9 ml, 24.6 mmol). The
solution was stirred for 30 min, and then water (15 ml) was added. The
aqueous layer was extracted three times with CH2Cl2. The organic layers were
washed with brine, dried over MgSO4, and concentrated under vacuum to give 137.41, 137.99.
HR MS (ESI): m/z [M+Na]+calculated. for C19H21NO3Na: 334,1419; found:
a residue, which upon short column chromatography over silica gel (pentane/
AcOEt 9/1, 4/1, then 1/1) yielded the desired unstable mesylate (13.4 g, 97.6%: 334,1427
The Journal of Antibiotics

Synthesis of Thienamycin methyl ester
M Soluch et al
4
(2S,3S)-3-Benzyloxy-2-hydroxymethyl-3,4-dihydro-2H-pyrrole-N-
oxide (14)
To a solution of nitrone 1 (0.46 g, 1.50 mmol) in CH2Cl2 (30 ml), cooled to
0 °C, BCl3•Me2S complex (1 ml, 7.50 mmol) was added. The reaction mixture
was stirred at room temperature overnight. Subsequently the mixture was
mixture was stirred overnight at room temperature. NH4Cl was added and the
aqueous solution was extracted with ethyl acetate (3X). The combined extracts
were dried over MgSO4, filtered and evaporated. The crude acid 17 was
dissolved in Et2O (20 ml), cooled to 0 °C and treated with a solution of
diazomethane. After 5 min the mixture was treated with drop of acetic acid
evaporated, treated with methanol and evaporated again (4× 10 ml). The crude and evaporated. The product was purified on a silica gel column using
mixture was purified by silica gel chromatography to afford the nitrone 14
(0.17 g, 0.75 mmol) in 50% yield.
hexane-EtOAc, 6:4 v/v as an eluant to give 18 in 58% yield.
Colorless syrup; [α]D +121,1(c 1, CHCl3); IR (film) v: 1099, 1746, 1792,
2929, cm− 1; 1H NMR (500 MHz, CDCl3) δ: 0.08 (s, 6H, Si(CH3)2), 0,89 (s, 9H,
t-Bu), 1.24 (d, J = 6.0, 3H, CH3), 1.62-1.69 (m, 1H, H-4),2.32-2.38 (m, 1H,
H-4), 2.82 (dd, J = 2.1 Hz, 6,4 Hz, 1H, H-6), 3.70 (s, 3H, CO2CH3), 4.03-4.08
(m, 1H, H-5), 4.19-4.25 (m, 1H, CHOSi), 4.55 (s, 2H, OCH2Ph), 4.57-4.61
(m, 1H, H-3), 4.61-4.64 (m, 1H, H-2), 7.25-7.36 (m, 5H, Ar); 13C NMR
(150 MHz, CDCl3) δ: -4.21, 17.93, 22.62, 25.69, 36.02, 52.03, 55.28, 63.70,
65.34, 66.25, 72.61, 85.47, 127.54, 127.88, 128.42, 137.33, 168.59, 175.88.
HR MS(ESI) m/z [M+Na]+calculated. for C23H35NO5SiNa: 456.2182; found:
456.2185.
Colorless syrup; [α]D+23,7 (c 1, CHCl3), IR (film) ν: 1453, 2925, 3030,
3334 cm− 1
1H NMR (600 MHz, CDCl3) δ: 2.70-2.77 (m, 1H, H-4), 2.85–2.94 (m, 1H,
H-4), 4.01–4.07 (m, 1H, CHHOH), 4.09–4.15 (m, 2H, H-2, OH), 4.20-4.45
(m, 1H, CHHOH), 4.43-4.62 (m, 3H, CH2Ph, H-3), 6.89 (s, 1H, H-5),
7.24–7.40 (m, 5H, Ar). 13C NMR (150 MHz, CDCl3) δ: 34.93, 60.35, 71.78,
73.53, 76.79, 127.60, 128.26, 128.52, 128.68, 136.72.
HR MS (ESI): m/z [M+Na]+calculated for C12H15NO3Na: 244,1086; found:
244,1088
(2S,3S,5R,6S,1’R)-3-Benzyloxy-6-[1’-(tert-butyldimethylosiloxy)
ethyl]-2-(hydroxymethyl)-1-azabicyclo[3.2.0]heptan-7-one (15) and
(2S,3S,5R,6R,1’R)-3-benzyloxy-6-[1’-(tert-butyldimethylosiloxy)
ethyl]-2-(hydroxymethyl)-1-azabicyclo [3.2.0]heptan-7-one (11)
To a suspension of CuI (0.5 mmol, 95 mg) in dry, degassed MeCN (3 ml),
253 μl (2.0 mmol) of 1,1,3,3-tetramethylguanidine was added. After cooling to
0 °C a solution of acetylene 820 (92 mg, 0.5 mmol) in 1 ml of MeCN was added
and thus obtained mixture was stirred for 15 min. Then a solution of nitrone 14
(221 mg, 1.0 mmol) in MeCN (2 ml) was added slowly and the mixture was
kept at 0 °C for additional 15 min. After removal of the cooling bath, the
mixture was stirred at ambient temperature under an inert atmosphere for 24 h.
The progress of the reaction was monitored by TLC. Removal of the solvent
gave a residue, which was chromatographed on silica gel (hexane/AcOEt 4:6 v/
v) to afford a mixture of 15 and 11 in ratio 1:3 (110 mg, 54%, according to 1H
NMR of crude reaction mixture).
Compound 11; colorless syrup; [α]D +64,3 (c 1, CHCl3); IR (film) v: 1099,
1757, 2856, 3437 cm− 1; 1H NMR (600 MHz, CDCl3) δ: 0.06 (s, 6H, Si(CH3)2),
0,87 (s, 9H, t-Bu), 1.22 (d, J = 6.1 Hz, 3H, CH3), 1.68-1.73 (m, 1H, H-4),
2.31-2.36 (m, 1H, H-4), 2.80 (dd, J = 2.0 Hz, 6,0 Hz, 1H, H-6), 3.73
(d, J = 5.6 Hz, 2H,CH2OH), 3,86-3.89 (m, 1H, H-5), 4.00 (q,1H, J = 5.8 Hz,
H-2), 4,15-4.20 (m, 1H, CHOSi), 4.44-4.46 (m, 1H, H-3,), 4.45–4.64(m, 2H,
CH2Ph), 7.28–7.32 (m, 3H, Ar), 7.34-7.37 (m, 2H, Ar); 13C NMR (150 MHz,
CDCl3) δ: − 4.94, − 4.22, 17,95, 22,61, 25,68, 53.81, 61.28, 62.65, 65.23, 66.18,
72.33, 84.95, 127.57, 128.64, 137.33, 177.16; HR MS(ESI) m/z [M+Na]+
calculated for C22H35NO4SiNa: 428.2233; found: 428.2234.
(2R,3S,5R,6S,1’R)-6-[1’-(tert-Butyldimethylsiloxy)ethyl]-3-hydroxy-
2-methoxycarbonyl-1-azabicyclo[3.2.0]heptan-7-one (19)
Compound 18 (0.10 g, 0,30 mmol) in ethyl acetate (10 ml) was treated with Pd
(OH)2 (0.15 g) and hydrogenated under 1 atm H2 at room temp. for 3 h.
Subsequently the catalyst was filtered off through a short path of celite. The
solution was evaporated and purified on a silica gel column using hexane/
EtOAc 4:6 v/v as an eluent to give 19 (0.10 g, 0.29 mmol) in 97% yield.
Colorless crystals; [α]D +103, 8 (c 1, CHCl3); m.p. = 151–153 °C;
IR (film) v: 1718, 1735, 2927, 3337 cm− 1
;
1H NMR (500 MHz, CDCl3) δ: 0.09 (s, 6H, Si(CH3)2), 0,89 (s, 9H, t-Bu),
1.25 (d, J = 6.2 Hz, 3H, CH3), 1.69-1.70 (m, 1H, H-4), 2.34–2.36 (m, 1H, H-4),
2.69 (bs,1H, OH), 2.85 (dd, J = 1.8 Hz, 5,8 Hz, 1H, H-6), 3.77(s, 3H, CO2CH3),
4.09–4.10 (m, 1H, H-5), 4.24–4.26 (m, 1H, CHOSi), 4.5 (d, J = 4.8 Hz, 1H,
H-2), 4.94-4.95 (m, 1H, H-3);
13C NMR (150 MHz, CDCl3) δ: − 4.99, − 4.22, 17.94, 22.64, 25.67, 39.41,
52.45, 55.33, 64.56, 64.84, 66.00, 79.06, 169.91, 176.13.
HR MS(ESI) m/z [M+Na]+calculated for C16H29NO5SiNa: 366.1713; found:
366.1707.
Crystallographic data: C16H29NO5Si, MW= 343.49 Da, 0.40× 0.40× 0.05,
monoclinic, space group. P = 21, Z = 2, T = 100(2) K, a = 7.3250(2),
b = 7.5160(2), c = 17.4905(5) Å, V = 962.89(5) Å3, λ(Cu, Kα) = 1.54184 Å,
μ = 1.271 mm− 1.Intensity data were collected on SuperNova area detector
system. The structure was solved by direct mehods and refined by the full-
matrix least-squares on F2 (SHELXL-97). A total of 2389 reflections were
measured and 2345 were independent. Final R1= 0.0479, wR2 = 0.1325 (2389
references; I42σ(I), and GOF= 1.080 (for all data, R1 = 0.0483,
wR2 = 0.1333).
Compound 15: colorless syrup; [α]D +39,1 (c 1, CHCl3); IR (film) v: 1092,
1744, 2926, 3400 cm− 1; 1H NMR (600 MHz, CDCl3) δ: 0.06 (s, 6H, Si(CH3)2),
0,88 (s, 9H, t-Bu), 1.20 (d, J = 6.2 Hz, 3H, CH3), 1.82-1.87 (m, 1H, H-4),
2.15–2.20 (m, 1H, H-4), 3.39(dd, J = 5.7 Hz, 7,7 Hz, 1H, H-6), 3.71–3.3.78
(m, 2H, CH2OH), 3.90(q, J = 5.7 Hz, 1H, H-2), 3.91-3.95 (m, 1H, H-5),
4.00–4.05 (m, 1H, CHSi), 4.42–4.45(m, 1H, H-3), 4.46–4.63(m, 2H, CH2Ph),
7.35–7.37(m, 5H, Ar); 13C NMR (150 MHz, CDCl3) δ: − 4.55, − 4.33, 22.84,
(2R,5R,6S,4’R)-6-[1’-(tert-Butyldimethylosiloxy)ethyl]-2-
methoxycarbonyl-1-azabicyclo[3.2.0]heptan-3,7-di-one (20)
To a solution of compound 19 (84 mg, 0,24 mmol) in CH2Cl2 (10 ml),
25.81, 29.68, 32.08, 54.20, 58.12, 61.52, 61.94, 65.36, 72.27, 84.66, 126.97, NaHCO3 (81 mg, 0.96 mmol) and Dess–Martin periodinane (0.20 g, 0.48
127.64, 128.55, 140.87, 178.37; HR MS(ESI) m/z [M+Na]+calculated. for
mmol) were added. The reaction mixture was stirred at room temperature
C22H35NO4SiNa: 428.2233; found: 428.2227.
for 40 min. Subsequently, saturated aqueous solution of Na2S2O3 was added.
The aqueous phase was extracted with CH2Cl2 (3× ). The combined organic
extracts were washed with brine, dried over MgSO4 and evaporated. The
product was purified on a silica gel column with hexane–EtOAc, 4:6 (v/v) as the
eluent to afford 20 (40 mg, 0.11 mmol) in 48% yield.
(2R,3S,5R,6S,1’R)-3-Benzyloxy-6-[1’-(tert-butyldimethylsiloxy)
ethyl]-2-methoxycarbonyl-1-azabicyclo[3.2.0]heptan-7-one (18)
To a solution of 11 (166 mg, 0.4 mmol) in CH2Cl2 (15 ml) sodium bicarbonate
(134 mg, 1.6 mmol) and Dess–Martin periodinane (340 mg, 0.8 mmol) were
added. The reaction mixture was stirred at room temperature for 1 h.
Subsequently, a saturated solution of Na2S2O3 was added. The water phase
was extracted with CH2Cl2 (3×). The combined extracts were washed with
brine and dried over MgSO4. The solution was evaporated and the crude
aldehyde 16 was used in the next step without purification.
Colorless crystals m.p. 151–154 °C; [α]D +125,5 (c 1, CHCl3);
IR (film) v: 1256, 1770, 2856, 2929 cm− 1
;
1H NMR (600 MHz, CDCl3) δ: 0.08 (s, 6H, Si(CH3)2), 0,90 (s, 9H, t-Bu),
1.26 (d, J = 6.2 Hz, 3H, CH3), 2.40 (dd, J =7.7 Hz, 18,8 Hz, 1H, H-4), 2.86
(dd, J = 6.9 Hz, 18.8 Hz, 1H, H-4), 3.10 (dd, J = 2.0 Hz, 5,1 Hz, 1H, H-6), 3.75
(s, 3H, CO2CH3), 4.11-4.15 (m, 1H, H-5), 4.30 (dq, J =6.15 Hz, 1H, CHOSi),
4.64 (s, 1H, H-2);
The crude 16 was dissolved in t-BuOH (6 ml) and treated with 2-methyl-2-
butene (6 ml). Subsequently NaClO2 (0.21 g, 2.3 mmol) and a solution of
13C NMR (150 MHz, CDCl3) δ: -5.09, -4.25, 17.88, 22.59, 25.58, 27.14,
NaH2PO4 (0.26 g, 1.90 mmol) in water (11 ml) were added. The reaction 41.17, 46,87, 50.98, 53.02, 63.93, 65.35, 68.76, 165.46, 172.47, 207.32.
The Journal of Antibiotics

Synthesis of Thienamycin methyl ester
M Soluch et al
5
HR MS(ESI) m/z [M+Na]+calculated. for C16H27NO5SiNa: 364.1556; found:
364.1557
1
2
3
4
Coulton, S.
Luscombe D. K.) 99–145 (Elsevier, Cambridge, UK, 1996).
Hashizume, T. Morishima, H. Design and synthesis of new 1-beta-
methylcarbapenems. Drugs of the Future 25, 833–841 (2000).
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& Hunt, E. in Progress in Medicinal Chemistry (eds Ellis G. P. &
&
(5R,6S,1’R)-Methyl 3-[(2-acetamidoetyl)thio]-6-[1’-(tert-
butyldimethylsiloxy)ethyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-
carboxylate (21)
Bouffard, F. A. Thienamycin Total Synthesis. 1. Synthesis of azetidinone
precursors of
1130–1135 (1980).
( )-thienamycin and its stereoisomers. J. Org. Chem. 45,
Compound 20 (14 mg, 0.04 mmol) in acetonitrile (2 ml) was cooled to 0 °C
and treated with N,N-diisopropylethylamine (8 μl, 0.05 mmol), diethyl chlor-
ophosphate (7 μl, 0.05 mmol) and catalytic amount of DMAP. The mixture was
stirred for 1 h at room temperature. Subsequently it was cooled to 0 °C and
treated with a another portion of N,N-diisopropylethylamine (11 μl, 0.06
mmol) and N-acetylcysteamine (6,5 μl, 0.06 mmol). The mixture was stirred
overnight at room temperature. Subsequently it was evaporated under reduced
pressure and purified on a silica gel column using toluene-i-propanol, 4:1(v/v)
as an eluent to afford 21 (8 mg, 0.018 mmol) in 44% yield.
5
6
McCormick, J. P. & Thomason, T. Total synthesis of thienamycin. J. Am. Chem. Soc.
100, 313–315 (1978).
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syntheses of heterocyclic compounds. A formal total synthesis of ( )-thienamycin and a
(
)-decysteaminylthienamycin derivative. J. Am. Chem. Soc. 102, 2060–2065
(1980).
7
8
9
Schmitt, S. M., Johnston, D. B. R. & Christensen, B. G. Thienamycin total synthesis. 2.
Model studies-synthesis of a simple 2- (alkylthio) carbapen-2-em. J. Org. Chem. 45,
1135–1142 (1980).
Schmitt, S. M., Johnston, D. B. R. & Christensen, B. G. Thienamycin total synthesis. 3.
Total synthesis of ( )-thienamycin and ( )-8-epithienamycin. J. Org. Chem. 45,
1142–1148 (1980).
Wentrup, C. & Winter, H.-W. A stereocontrolled synthesis of (+)-thienamycin. J. Am.
Chem. Soc. 102, 6161–6163 (1980).
10 Shibasaki, M., Nishida, A. & Ikegami, S. A. Mild method for the conversion of propiolic
ester to β-keto esters. Application to the formal synthesis of
Tetrahedron Lett. 23, 2875–2878 (1982).
11 Shibasaki, M., Nishida, A.
phenylthioazetidin-2-one and an asymmetric Synthesis of (+)–thienamycin. J. Chem.
Soc. Chem. Commun. 1324–1325 (1982).
Easily solidifing syrup; [α]D+52,3 (c 0.69, CHCl3); IR (film) v: 1659, 1748,
1758, 2898, 2929, 2953 cm− 1
;
1H NMR (600 MHz, CDCl3 ) δ: 0.06 (s, 6H, Si(CH3)2), 0,90 (s, 9H, t-Bu),
1.24 (d, J = 6.1 Hz, 3H, CH3), 1.97 (s, 3H, CH3), 2.88-2.94 (m, 1H, SCHH),
2.99-3.06 (m, 2H, SCHH, H-4), 3.10 (dd, J = 2.7 Hz, 6,1 Hz,1H, H6), 3.22-3.29
(m, 1H, H-4), 3.39-3.49 (m, 2H, CHHNHAc), 3.81(s, 3H, CO2CH3), 4.14-4.21
(m, 2H, H5, CHOSi), 5.96 (bs, 1H, NHAc);
( )-thienamycin.
& Ikegami, S. A. A Simple preparation of (+) -4-
13C NMR (150 MHz, CDCl3) δ: -4.93, -4.26, 17.94, 22.51, 23.17, 25.62,
25.68, 31.87, 39.70, 40.10, 52.16, 52.64, 66.23, 67.38, 124.92, 145.93, 161.90,
170.44, 175.98.
HR MS(ESI) m/z [M+Na]+ calculated. for C20H34N2O5SNaSi: 465.1855;
found: 465.1858
12 Tatsuta, K., Takahashi, M., Tanaka, N. & Chikauchi, K. Novel synthesis of (+)-4-
acetoxy-3-hydroxyethyl-2-azetidinone from carbohydrate. Total synthesis of (+)-thiena-
mycin. J. Antibiot. 53, 1231–1234 (2000).
13 Chida, N.
& Sato, T. in Comprehensive Chirality Vol. 2 (eds Carreira E. M. &
Yamamoto H.) 207–239 (Elsevier, Amsterdam, 2012).
14 Khangarot, R. K. & Kaliappan, K. P. A stereoselective synthesis of sugar-derived chiral
β-lactams Eur. J. Org. Chem. 30, 6117–6127 (2011).
15 Desvergnes, S., Py, S.
based on SmI2-induced nitrone umpolung. J. Org. Chem. 70, 1459–1462
(2005).
& Valle´e, Y. Total synthesis of (+)-hyacinthacine A2
(3S,4R,1’R)-4-(2’’-acetamidoethyltiocarbonylmethyl)-3-[1’-(tert-
butylodimethylsiloxy) ethyl]-azetidin-2-one (22)
Compound 20 (45 mg, 0,13 mmol) in acetonitrile (2 ml) was cooled to 0 °C
and treated with N,N-diisopropylethylamine (25 μl, 0.14 mmol), diphenyl
chlorophosphate (30 μl, 0.14 mmol) and a catalytic amount of DMAP. After
1 h an another portion of N,N-diisopropylethyloamine (25 μl, 0.14 mmol) and
N-acetylcysteamine (15 μl, 0.14 mmol) were added. The mixture was stirred
overnight. Subsequently it was evaporated under reduced pressure and the
residue was purified by chromatography using hexane-acetone, 4:6 (v/v) as an
eluent to give 22 (8 mg, 0.017 mmol) in 13% yield.
16 Ludek, O. R. & Marquez, V. E. A greener enantioselective synthesis of the antiviral agent
Northmethanocarbathymidine (N-MCT) from 2-deoxy-D-ribose. Tetrahedron 65,
8461–8467 (2009).
17 Wang, W.-B. et al.
A practical synthesis of sugar-derived cyclic nitrones:
Powerful synthons for the synthesis of iminosugars. Synlett. 3, 488–492
(2010).
18 Maciejko, M. et al. An entry to carbapenem antibiotics scaffold via asymmetric
Kinugasa reaction. Synthesis 44, 2825–2839 (2012).
19 Yoshida, M., Ohsawa, Y. & Ihara, M. Palladium-catalyzed carbon dioxide elimination−
fixation reaction of 4-methoxycarbonyloxy-2-buten-1-ols. J. Org. Chem. 69,
1590–1597 (2004).
Syrup; [α]D +12,3 (c 0,6, CH2Cl2); IR (film) v: 1660, 1682, 1748 2930, 2954,
3202 cm− 1; 1H NMR (600 MHz, C6D6) δ: − 0.01 (s, 3H, Si(CH3)2), 0.08 (s, 3H,
Si(CH3)2), 0,88 (s, 9H, t-Bu), 1.07 (d, J = 6.1 Hz, 3H, CH3), 1.47(s, 3H, Ac),
2.56 (dd, J = 2.4 Hz, 6,1 Hz, 1H, H-3), 2.58–2.73 (m, 4H, SCH2, CH2COS),
3.03-3.12 (m, 2H, CH2NH), 3.19 (s, 3H, CO2CH3), 3.89 (m, 2H, NCH2CO2),
4.04–4.10 (m, 1H, CHOSi), 4.10-4.14 (m, 1H, H-4), 4.72 (bs, 1H, NH);
13C NMR (150 MHz, CDCl3) δ: − 5.22, − 4.63, 22.28, 22.30, 25.58, 28.60, 38.70,
42.20, 47.61, 51.32, 52.13, 63.71, 66.03, 128.05, 166.53, 168.53, 168.88, 197.08.
HR MS(ESI) m/z [M+Na]+ calculated for C20H36N2O6SiNaS: 483.1961;
found: 483.1958.
20 Santos, D., Ariza, X., Garcia, J. & Sάnchez, C. A new synthetic approach to the lactol
moiety of halichoblelide. Tetrahedron 67, 5184–5188 (2011).
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of specifically deuterated D-glucose, D-mannose, and 2-deoxy-D-glucose. Carbohydr.
Res. 368, 111–119 (2013).
22 Kovάč, P.
& Petríkovά, M. Alternative syntheses of methylated sugars. V. Methyl
furanosides of 6-O- and 2,6-Di-O-methyl-D-glucose. Chem. Zvesti. 26, 71–75
(1972).
23 Desvergnes, S., Vallée, Y.
& Py, S. Novel polyhydroxylated cyclic nitrones and
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(2008).
24 Holmes, A. B. et al. Selective cleavage of benzyl ether. Synlett. 663–664 (1993).
25 Dess, D. B. & Martin, J. C. Readily accessible 12-I-5 oxidant for the conversion of
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4155–4156 (1983).
CONFLICT OF INTEREST
The authors declare no conflict of interest.
26 Bal, B. S., Childers, W. E. Jr & Pinnick, H. W. Oxidation of α,β-unsaturated aldehydes.
Tetrahedron 37, 2091–2096 (1981).
27 Nagasawa, T., Nukada, T. & Kuwahara, S. Synthesis of aspergillide A via proline-
catalyzed trans-to-cis isomerization of a substituted tetrahydropyran. Tetrahedron 67,
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ACKNOWLEDGEMENTS
28 Arndt, F. in Organic Synthesis Coll Vol. II (ed. Blatt, A. H.) 165–167
(John Wiley & sons, New York, 1943).
29 Hanessian, S., Desilets, D. & Bennani, L. Y. A novel ring-closure strategy for the
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3098–3103 (1990).
Financial support by the European Union within European Regional
Development Fund, Project POIG.01.01.02.-14-102/09 is gratefully
acknowledged. MS thanks the National Science Centre for Preludium grant
UMO-2011/03/N/ST5/04435.
The Journal of Antibiotics