Practical Short Synthesis of 1β-Methylcarbapenem Utilizing a New Dehydration Type Ti-Dieckmann Condensation

Article abstract of DOI:10.1002/adsc.200303065

An efficient, practical, and stereocontrolled synthesis of 1β-methylcarbapenems has been performed utilizing a new dehydration type of Ti-Dieckmann (intramolecular Ti-Claisen) condensation. This cyclization reaction has the advantage of direct incorporati

Full text of DOI:10.1002/adsc.200303065

COMMUNICATIONS
Practical Short Synthesis of 1b-Methylcarbapenem Utilizing a
New Dehydration Type Ti-Dieckmann Condensation
Yoo Tanabe,a,* Naoki Manta,a Ryohei Nagase,a Tomoniri Misaki,a Yoshinori
b
Nishii,a Makoto Sunagawa,b Akira Sasaki
a
Department of Chemistry, School of Science andTechnology, Kwansei Gakuin University, 2 1 Gakuen, Sanda, Hyogo
669 1337, Japan
Fax: ( ‡ 81)-795-65-9077, e-mail: tanabe@kwansei.ac.jp
b
Sumitomo Pharmaceutical Research Division, Sumitomo Pharmaceutical Co. Ltd., 3-1-98, Kasugade-naka, Konohana-ku,
Osaka 554 0022, Japan
Received: April 7, 2003; Accepted: May 14, 2003
was synthesizedfrom commercially available 1-acetoxy-
Abstract: An efficient, practical, andstereocontrol-
ledsynthesis of 1 b-methylcarbapenems has been
performed utilizing a new dehydration type of Ti-
Dieckmann (intramolecular Ti-Claisen) condensa-
tion. This cyclization reaction has the advantage of
direct incorporation of the thiol moiety into the
target 1b-methylcarbapenem, comparedwith the
traditional basic Dieckmann condensation. Another
advantage is the use of environmentally benign (low
toxicity andsafe) reagents (TiCl 4 andEt 3N or Bu3N).
2-azetidinone 1 by coupling with propionic acidderiv-
atives (Scheme 2). Some effective methods for stereo-
selective synthesis of the key 1b-methyl synthon 2 have
been developed, however there remains a strong need
for practical methods for the subsequent construction of
bicyclic framework of 1b-methylcarbapenem 6. Basic
Dieckmann condensation,[4] Rh-carbene insertion,[5]
[6]
andintramolecular Wittig-type reaction,
are repre-
sentative methodologies.[7] Among them the Die-
ckmann condensation protocol seems to be the most
efficient to date for the practical synthesis of a series of
1b-methylcarbapenems. This methodinvolves three
reaction sequences; cyclization of 3 to give 4, successive
formation of enolphosphate 5, andfinal substitution
with thiolate to give 6 (Scheme 2).
Keywords: cyclization; Dieckmann condensation; 1b-
methylcarbapenem; titanium; Ti-Claisen condensa-
tion
The Ti- andZr-Claisen andDieckmann condensations
À
exhibit powerful reactivity andare able to realize C C
bondformations between various carboxylic esters
The discovery of 1b-methylcarbapenem (e.g., merope- under mild reaction conditions.[8] These characteristic
nem[1] andbiapenem [2]), which has potent andbroad
antibacterial activity as well as enhancedmetabolic and
chemical stability, has promptedmany synthetic organic
chemists to develop efficient methods for the stereo-
selective synthesis of the key carbapenem skeleton
(Scheme 1). Recent reviews describe the impressive
progress in this area.[3]
features wouldbe ideal for application of the reaction
Among many synthetic methods, 1b-methylcarbox-
ylic acid 2 with four contiguous stereogenic centers is
regarded as the most advantageous intermediate, which
Scheme 2. Synthetic route to 1b-methylcarbapenem 6 utiliz-
ing basic Dieckmann condensation.
Scheme 1. 1b-Methylcarbapenem.
Adv. Synth. Catal. 2003, 345, 967 970
DOI: 10.1002/adsc.200303065
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
967

Yoo Tanabe et al.
COMMUNICATIONS
Scheme 3. Dehydration type Ti-Dieckmann condensation of
thioester 7a d.
Scheme 4. Proposed mechanism of the dehydration type Ti-
Dieckmann condensation.
for the construction of the 1b-methylcarbapenem skel- new methodology for the synthesis of 1b-methylcarba-
eton. We present a short andefficient cyclization
reaction between the a-position of allyl esters and
carbonyl position of thioesters in 7a d, which did not
yield basic reagent mediated Dieckmann-products 4
with the elimination of thiols, but yielded vinyl sulfides
6a d through a novel dehydration type Ti-Dieckmann
condensation (Scheme 3).
penems.
Experimental Section
Scheme 3 lists four successful results, including the
precursor of meropenem, which is one of the most
representative 1b-methylcarbapenem antibiotics. Pre-
cursor 6d couldbe transformedinto meropenem by the
known method, which involves desilylation followed by
Pd-catalyzed deprotection of the allyl moiety in the
ester.[1] Optimization of the conditions revealed that 3.0
(3S,4S)-1-(Allyloxycarbonylmethyl)-3-[(1R)-1-(tert-
butyldimethylsilyloxy)ethyl]-4-[(1R)-1-
benzylthiocarbonylethyl]-2-azetidinone (7a)[4c]
To a stirredsolution of (3 S,4S)-1-(allyloxycarbonylmethyl)-3-
[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-carboxy-
ethyl]-2-azetidinone[4c] (200 mg, 0.5 mmol) in benzene (4.0 ml)
was added N,N'-dicyclohexylcarbodiimide (206 mg, 1.0 mmol)
and 4-dimethylaminopyridine (12 mg, 0.1 mmol) at 20 258C
under an Ar atmosphere, and the mixture was stirred for
30 min at that temperature. Benzyl mercaptan (248 mg,
2.0 mmol) was added to that mixture, followed by being stirred
for 12 h. After Celite filtration, the mixture was concentrated
to give the crude product, which was purified by silica-gel
column chromatography (hexane : EtOAc ˆ 5:1) to give the
desired product 3a as a pale yellow oil; yield: 335 mg (66%).
Spectroscopic data matched with the literature.
equiv. of TiCl4 and3.3 equiv. of Bu N were required.
3
When 1.0 equiv. of TiCl4 was used, the desired carbape-
nem 6 resultedin low yield( ꢀ 20%). It shouldbe noted
that no epimerization of the 1b-position was observed;
that is, the four contiguous stereogenic centers were
successfully retained, although the 1a-diastereomer of
enolate 4 was more thermodynamically stable than the
1b one. In addition, the elimination of dummy benze-
nethiol anddiphenyl chlorophosphate is more atom-
economical.
As a proposedmechanism, this unexpectedreaction
comprises the following steps (Scheme 4); (i) regiose-
lective formation of titanium allyl ester enolates inter-
mediate 8, (ii) cyclization to form the Ti-intermediate 9
with an sp3 tetrahedral carbon adjacent to a chiral
methyl group, and(iii) elimination of Ti( O)Cl2 and
HCl (net process is dehydration of 7) to give the desired colorless oil; [a]D
vinyl sulfides 6. In general, the thiol function of
thioesters is regarded as a more easily displaced moiety,
however this unusual behavior is considered to be due to
the greater affinity of TiCl4 towardoxygen than that of
sulfur. Mukaiyama andhis coworkers reporteda related
condensation reaction in which ketones were trans-
(3S,4S)-1-(Allyloxycarbonylmethyl)-3-[(1R)-1-(tert-
butyldimethylsilyloxy)ethyl]-4-[(1R)-1-
octylthiocarbonylethyl]-2-azetidinone (7b)
A similar procedure as for the preparation of 7a using
ˆ
octanethiol in the place of benzyl mercaptan; yield: 98%;
23
:
À 31.8 (c 0.32, CHCl3). 1H NMR
(400 MHz, CDCl3): d ˆ 0.079 (3H, s), 0.084 (3H, s), 0.87 (9H,
s), 1.21 1.37 (17H, m), 1.51 1.58 (2H, m), 2.85 (2H, t, J ˆ
7.4 Hz), 2.99 3.05 (2H, m), 3.90 (1H, d, J ˆ 18.0 Hz), 4.07 (1H,
dd, J ˆ 2.8 and2.8 Hz), 4.13 4.19 (1H, m), 4.25 (1H, d, J ˆ
18.0 Hz), 4.62 4.64 (2H, m), 5.24 5.37 (2H, m), 5.86 5.96
(1H, m); 13C NMR (100 MHz, CDCl3): d ˆÀ 4.86, À 4.40,
12.24, 13.94, 17.74, 22.48, 22.55, 25.68, 28.66, 28.90, 28.94, 28.99,
29.25, 31.64, 42.50, 49.46, 57.33, 61.08, 65.67, 66.47, 118.68,
131.48, 167.84, 167.88, 201.45; IR (neat): n ˆ 1770, 1684, 1460,
formedinto vinyl sulfides with thiols using TiCl and
4
Et3N.[9]
1412, 1375 cmÀ1; HRMS (FAB): calcd. for C27H49NO5SSi (M ):
‡
The present straightforwardmethodis more conven-
ient than the basic Dieckmann methodandprovides a
‡
527.3101; found(M ‡ 1): 528.3218.
968
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2003, 345, 967 970

Practical Short Synthesis of 1b-Methylcarbapenem
COMMUNICATIONS
added to the mixture, which was extracted with ether. The
organic phase was washedwith water, brine, dried(Na 2SO4),
and concentrated. The obtained crude product was purified by
silica gel column chromatography (hexane:EtOAc ˆ 40:1) to
give the desired product 6a as a pale yellow oil; yield: 71 mg
(72%). Spectroscopic data matched with the literature.
(3S,4S)-1-(Allyloxycarbonylmethyl)-3-[(1R)-1-(tert-
butyldimethylsilyloxy)ethyl]-4-[(1R)-1-
cyclohexylthiocarbonylethyl]-2-azetidinone (7c)
A similar procedure as for the preparation of 7a using
cyclohexanethiol in the place of benzyl mercaptan; yield:
82%; pale yellow oil; [a]D23: À 33.9 (c 0.23, CHCl3). 1H NMR
(300 MHz, CDCl3): d ˆ 0.082 (3H, s), 0.085 (3H, s), 0.88 (9H, s),
1.20 1.48 (11H, m), 1.53 1.76 (3H, m), 1.81 1.94 (2H, m),
2.95 3.02 (2H, m), 3.40 3.54 (1H, m), 3.90 (1H, d, J ˆ
18.0 Hz), 4.07 (1H, dd, J ˆ 2.8 and2.8 Hz), 4.12 4.19 (1H,
m), 4.26 (1H, d, J ˆ 18.0 Hz), 4.62 4.64 (2H, m), 5.24 5.37
(2H, m), 5.86 5.96 (1H, m); 13C NMR (75 MHz, CDCl3): d ˆ
À 4.85, À 4.41, 12.14, 17.76, 22.58, 25.35, 25.70, 32.64, 32.81,
42.43, 42.48, 49.37, 57.38, 61.01, 65.68, 66.50, 118.70, 131.47,
167.84, 167.92, 201.21; IR (neat): n ˆ 1766, 1680, 1450, 1412,
Allyl (4R,5S,6S)-6-[(1R)-1-(tert-
Butyldimethylsilyloxy)ethyl]-4-methyl-3-octylthio-7-
oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (6b)
A similar procedure as for the preparation of 6a using 7b in the
place of 7a; yield: 65%; pale yellow oil; [a]D23: ‡ 54.0 (c 0.13,
1
CHCl3). H NMR (400 MHz, CDCl3): d ˆ 0.079 (6H, s), 0.88
(9H, s), 1.22 1.46 (19H, m), 1.61 1.68 (2H, m), 2.75 2.88
(2H, m), 3.18 (1H, dd, J ˆ 6.6 and2.4 Hz), 3.25 3.33 (1H, m),
4.12 4.14 (1H, dd, J ˆ 9.2 and2.6 Hz), 4.19 4.26 (1H, m),
4.66 4.81 (2H, m), 5.21 5.25 (1H, m), 5.42 5.47 (1H, m),
5.90 6.00 (1H, m); 13C NMR (75 MHz, CDCl3): d ˆÀ 5.02, À
4.28, 13.97, 16.82, 17.85, 22.52, 25.62, 28.68, 29.00, 29.59, 31.49,
31.66, 42.92, 55.98, 59.96, 65.33, 66.31, 117.95, 123.98, 131.68,
151.15, 160.71, 172.49; IR (neat): n ˆ 1718, 1655, 1462,
1375 cmÀ1; HRMS (FAB): calcd. for C25H43NO5SSi (M ):
‡
‡
498.2710; found(M ‡ 1): 498.2689.
(3S,4S)-1-(Allyloxycarbonylmethyl)-3-[(1R)-1-(tert-
butyldimethylsilyloxy)ethyl]-4-{(1R)-1-[(3S,5S)-1-
allyloxycarbonyl-5-dimethylaminocarbonylpyrrolidin-
3-yl]thiocarbonylethyl}-2-azetidinone (7d)[4c]
‡
1379 cmÀ1; HRMS (FAB): calcd. for C27H47NO5SSi (M ):
‡
509.2995; found(M ‡ 1): 510.2889.
To
a stirredsolution of [(3 S,5S)-1-allyloxycarabonyl-3-
benzoylthio-5-dimethylaminocarbonylpyrrolidine (435 mg,
1.2 mmol) in CH3CN (2.0 mL), NaOCH3 (28% in CH3OH,
243 mg, 1.26 mmol) was added at À 15 to À 108C under an Ar
atmosphere, andthe mixture was stirredfor 1 h at that
temperature. To the mixture, phosphoric acid(85%, 145 mg,
1.26 mmol) was added, and then dried (Na2SO4). After Celite
filtration themixturewas concentratedto a volume of ca. 2 mL,
which contained(3 S,5S)-1-allyloxycarbonyl-5-dimethylami-
nocarbonyl-3-mercaptopyrrolidine.
N,N'-Carbonyldiimidazole (195 mg, 1.20 mmol) was added
to a stirredsolution of (3 S,4S)-1-(allyloxycarbonylmethyl)-3-
[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-carboxy-
ethyl]-2-azetidinone[4c] (400 mg, 1.0 mmol) in CH3CN (8.0 ml)
at 20 258C under an Ar atmosphere, and the mixture was
stirredfor 1 h at that temperature. To the mixture, a solution of
(3S,5S)-1-allyloxycarbonyl-5-dimethylaminocarbonyl-3-mer-
captopyrrolidine in CH3CN (ca. 2.0 mL) preparedabove and
Et3N (121 mg, 1.20 mmol) in CH3CN (1.5 mL) were succes-
sively added, followed by stirring for 6 h. 1 M aqueous HCl
solution was added to the mixture, which was extracted by
EtOAc. The organic phase was washedwith water, brine,
dried (Na2SO4), andconcentrated. The obtainedcrude pro-
duct was purified by silica gel column chromatography
(hexane:EtOAc ˆ 1:2) to give the desired product 7d as a
colorless oil; yield: 515 mg (80%). Spectroscopic data matched
with the literature.
Allyl (4R,5S,6S)-6-[(1R)-1-(tert-
Butyldimethylsilyloxy)ethyl]-3-cyclohexylthio-4-
methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-
carboxylate (6c)
A similar procedure as for the preparation of 6a using 7c in the
place of 7a; yield: 81%; pale yellow oil; [a]D23: ‡ 85.0 (c 0.15,
CHCl3). 1H NMR (400 MHz, CDCl3): d ˆ 0.082 (3H, s), 0.087
(3H, s), 0,88 (9H, s), 1.19 1.52 (11H, m), 1.59 1.71 (1H, m),
1.76 1.86 (2H, m), 1.91 2.02 (2H, m), 3.03 3.11 (1H, m), 3.19
(1H, dd, J ˆ 5.6 and2.8 Hz), 3.24 3.32 (1H, m), 4.15 (1H, dd,
J ˆ 9.6 and2.4 Hz), 4.21 4.27 (1H, m), 4.65 4.82 (2H, m),
5.21 5.25 (1H, m), 5.42 5.47 (1H, m), 5.91 6.00 (1H, m);
13C NMR (75 MHz, CDCl3): d ˆÀ 5.02, À 4.32, 17.15, 17.89,
22.39, 25.33, 25.64, 26.04, 32.08, 35.94, 43.11, 43.84, 55.64, 60.11,
65.33, 65.98, 117.93, 125.11, 131.70, 149.39, 160.58, 172.66; IR
(neat): n ˆ 1718, 1464, 1450, 1381 cmÀ1; HRMS (FAB): calcd
‡
‡
for C25H41NO5SSi (M ): 527.2526; found(M ‡ 1): 528.2478.
Allyl (4R,5S,6S)-3-[1-Allyloxycarbonylpyrrolidin-
(3S,5S)-5-dimethylaminocarbonyl-3-ylthio]-6-[(1R)-1-
(tert-butyldimethylsilyloxy)ethyl]-4-methyl-7-oxo-1-
azabicyclo[3.2.0]hept-2-ene-2-carboxylate (6d)[4c]
A similar procedure as for the preparation of 6a using 7d in the
place of 7a; yield: 72%; pale yellow oil. Spectroscopic data
matchedwith the literature.
Allyl (4R,5S,6S)-3-Benzylthio-6-[(1R)-1-(tert-
butyldimethylsilyloxy)ethyl]-4-methyl-7-oxo-1-
azabicyclo[3.2.0]hept-2-ene-2-carboxylate (6a)[4c]
Acknowledgements
TiCl4 (1.0M solutionin CH2Cl2; 0.60 mL) was added to astirred
solution of 7a (101 mg, 0.2 mmol) andBu 3N (122 mg,
0.66 mmol) in CH2Cl2 (0.5 mL) at À 45 to À 408C under an
Ar atmosphere, andthe mixture was stirredfor 1 h. Water was
This research was partially supported by a Grant-in-Aid for
Scientific Research on Priority Areas (A) ™Exploitation of
Multi-Element Cyclic Molecules∫ and on Basic Areas (C) from
Adv. Synth. Catal. 2003, 345, 967 970
asc.wiley-vch.de
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
969

Yoo Tanabe et al.
COMMUNICATIONS
the Ministry ofEducation, Culture, Sports, Science and
Technology, Japan.
1997, 53, 1635; f) N. Yasuda, C. Yang, K. M. Wells, M. S.
Jensen, D. L. Hughes, Tetrahedron Lett. 1999, 40, 427.
[6] a) L. D. Cama, B. G. Christensen, J. Am. Chem. Soc. 1978,
100, 8006; b) A. J. G. Baxter, P. Davis, R. J. Ponsford, R.
Southgate, Tetrahedron Lett. 1980, 21, 5071; c) A. Yoshida,
Y. Tajima, N. Takeda, S. Oida, Tetrahedron Lett. 1984, 25,
2793; d) T. Sibata, Y. Sugimura, J. Antibiot. 1989, 42, 374;
e) K. Oda, A. Toshida, Chem. Pharm. Bull. 1997, 45, 1439;
f) X. E. Hu, T. P. Demuth, Jr., J. Org. Chem. 1998, 63,
1791; g) P. Bitha, Y. I. Lin, Synth. Commun. 2001, 31, 587;
h) M. Mori, S. Oida, Chem. Pharm. Bull. 2000, 48, 126.
[7] Other methods: a) O. Sakurai, H. Horikawa, Tetrahedron
Lett. 1996, 37, 7811; b) O. Sakurai, T. Ogiku, M. Takaha-
shi, M. Hayashi, T. Yamanaka, H. Horikawa, T. Iwasaki, J.
Org. Chem. 1997, 62, 7889; c) R. Hayakawa, I. Fuseya, T.
Konagaya, M. Shimizu, T. Fugisawa, Chem. Lett. 1998, 49;
d) J. C. Galland, S. Roland, J. Malpart, M. Savignac, J. P.
Genet, Eur. J. Org. Chem. 1999, 3, 621; e) M. Mori, S.
Oida, Chem. Pharm. Bull. 2000, 48, 126; f) Y. Kozawa, M.
Mori, Tetrahedron Lett. 2002, 43, 111.
[8] a) Y. Tanabe, Bull. Chem. Soc. Jpn. 1989, 62, 1917; b) Y.
Yoshida, R. Hayashi, H. Sumihara, Y. Tanabe, Tetrahe-
dron Lett. 1997, 38, 8727; c) Y. Yoshida, N. Matsumoto, R.
Hamasaki, Y. Tanabe, Tetrahedron Lett. 1999, 40, 4227;
d) R. Hamasaki, S. Funakoshi, T. Misaki, Y. Tanabe,
Tetrahedron 2000, 56, 7423; e) Y. Tanabe, R. Hamasaki, S.
Funakoshi Chem. Commun. 2001, 1674; f) Y. Tanabe, A.
Makita, S. Funakoshi, R. Hamasaki, T. Kawakusu, Adv.
Synth. Catal. 2002, 344, 507.
References
[1] a) M. Sunagawa, H. Matsumura, T. Inoue, M. Funasaka,
M. Kato, J. Antibiot. 1990, 43, 519; b) M. Sunagawa, A.
Sasaki, Heterocycles 2001, 54, 497.
[2] a) P. J. Petersen, N. V. Jacobus, W. J. Weiss, R. T. Testa,
Antimicrob. Agents Chemother. 1991, 35, 203; b) G. J.
Malonski, L. Collins, C. Wennerstein, R. C. Moellering,
G. M. Eliopoulos, Antimicrob. Agents Chemother. 1993,
37, 2009.
[3] a) A. H. Berks, Tetrahedron 1996, 52, 331; b) M. Sunaga-
wa, A. Sasaki, J. Synth. Org. Chem. Jpn. 1996, 54, 761.
[4] a) M. Sunagawa, A. Sasaki, H. Matsumura, K. Goda, K.
Tamoto, Chem. Pharm. Bull. 1994, 42, 1381; b) M. Seki, K.
Kondo, T. Iwasaki, J. Chem. Soc. Perkin Trans. 1 1996,
2851; c) K. Kondo, M. Seki, T. Kuroda, T. Yamanaka, T.
Iwasaki, J. Org. Chem. 1997, 62, 2877; d) D. K. Pyun, W. J.
Jeong, H. J. Jung, J. H. Kim, J. S. Lee, C. H. Lee, B. J. Kim,
Synlett 2001, 1950; e) M. Seki, T. Yamanaka, K. Kondo, J.
Org. Chem. 2000, 65, 572.
[5] a) R. W. Ratcliff, T. N. Salzmann, B. G. Christensen,
Tetrahedron Lett. 1980, 21, 31; b) D. H. Shih, F. Baker,
L. Cama, B. G. Christensen, Heterocycles 1984, 21, 29;
c) T. J. Sowin, A. I. Meyers, J. Org. Chem. 1988, 53, 4154;
d) M. A. Williams, M. J. Miller, Tetrahedron Lett. 1990, 31,
1807; e) M. Kume, H. Ooka, H. Ishitobi, Tetrahedron
[9] T. Mukaiyama, K. Saigo, Chem. Lett. 1973, 479.
970
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2003, 345, 967 970