Synthesis of 2-(hydroxyymethyl)-1β-methylcarbapenem. Chemoselective organometallic addition to 3-substituted 4-[(R)-1-carboxyethyl]azetidin-2- one

Full text of DOI:10.1021/jo9716845

J . Org. Chem. 1998, 63, 1719-1723
1719
Sch em e 1
Syn th esis of
2-(Hyd r oxym eth yl)-1â-m eth ylca r ba p en em .
Ch em oselective Or ga n om eta llic Ad d ition
to 3-Su bstitu ted
4-[(R)-1-Ca r boxyeth yl]a zetid in -2-on e
X. Eric Hu* and Thomas P. Demuth, J r.
Procter and Gamble Pharmaceuticals, Mason, Ohio 45040
Received September 8, 1997
Thienamycin (1), an early carbapenem reported by the
Merck research group,1 exhibited an unusually broad
spectrum of antibacterial activity.2 Its discovery trig-
gered intense synthetic activity to explore carbapenem
congeners, such as 2, with enhanced or retained anti-
bacterial activity but with improved chemical and meta-
bolic stability.3 The structural characteristics of this
class of stable carbapenem antibiotics include 6-hydroxy-
ethyl and 1â-methyl substitutions. As richly documented
in the literature, chemical manipulation with 2-(alkyl-
thio) substitution around the basic skeleton of the car-
bapenem has continued to be the major subject of a
synthetic focus area.4 However, the discovery of carbam-
ate 3 of 2-(O-functionalized methyl) carbapenem, which
was among the most active and exceeded the activity of
thienamycin against most bacterial strains except for
P. aeruginosa,5 has led to the synthesis of several 2-alkyl-
1â-methylcarbapenems with pronounced antibacterial
activity.6
multifunctionalized molecule having an extremely high
level of ring strain was a major concern for the introduc-
tion of the 2-(hydroxymethyl) group to the carbapenem.
To date, only a limited number of methodologies for the
synthesis of 2-(hydroxymethyl)-1â-methylcarbapenems
have been published.6-8 One representative method,
developed at Merck,5,8 involved the introduction of the
hydroxy group R to the methyl ketone by oxidation of a
lithium enolate using MoOPH reagent followed by Wittig
cyclization (Scheme 1). Another method, reported by a
Shionogi group, described the construction of the hy-
droxymethyl ketone functionality from an azetidinone
epoxide derivative,9a or preferably from a protected allylic
alcohol by ozonolysis.9b Unfortunately, none of these
methods was suitable to meet our needs for large-scale
synthesis due either to low chemical yield and poor
reproducibility or to tedious separation of two diastere-
omers and lengthy synthetic sequences. These problems
2-(Hydroxymethyl)-1â-methylcarbapenem (4) has been
used as a versatile building template to prepare potent
carbapenem antibiotics.6,7 Chemical stability of such a
* To whom correspondence should be addressed. Tel.: (513) 622-
3859. Fax: (513) 622-0085. E-mail: HU/XE@PG.COM.
(1) (a) Ratcliffe, R. W.; Albers-Schonberg, G. The Chemistry of
Thienamycin and Other Carbapenem Antibiotics. In Chemistry and
Biology of â-Lactam Antibiotics; Morin, R. B., Gorman, M., Eds.;
Academic Press: New York, 1982 Vol. 2, p 227. (b) Kametani, T.;
Fukumoto, K.; Ihara, M. Heterocycles 1982, 17, 463.
(2) Kahan, J . S.; Kahan, F. M.; Goegelman, R.; Currie, S. A.;
J ackson, M.; Stapley, E. O.; Miller, T. W.; Miller, A. K.; Hendlin, D.;
Mochales, S.; Hernandez, S.; Woodruff, H. B.; Birnbaum, J . J . Antibiot.
1979, 32, 1.
(3) (a) Shih, D. H.; Baker, F.; Cama, L. D.; Christensen, B. G.
Heterocycles 1984, 21, 29. (b) Shih, D. H.; Fayter, J . A.; Cama, L. D.;
Christensen, B. G.; Hirshfield, J . Tetrahedron Lett. 1985, 26, 583. (c)
Shih, D. H.; Cama, L.; Christensen, B. G. Tetrahedron Lett. 1985, 26,
587.
(4) Salzmann, T. N.; DiNinno, F. P.; Greenlee, M. L.; Guthikonda,
R. N.; Quesada, M. L.; Schmitt, S. M.; Herrmann, J . J .; Woods, M. F.
Recent Advances in the Chemistry of Beta-Lactam Antibiotics; The
Chemical Society: London, 1989; Special Publication 70, p 170.
(5) Schmitt, S. M.; Salzmann, T. N.; Shih, D. H.; Christensen, B. G.
J . Antibiot. 1988, 41, 780.
(6) (a) Imuta, M.; Itani, H.; Ona, H.; Hamada, Y.; Uyeo, S.; Yoshida,
T. Chem. Pharm. Bull. 1991, 39, 663. (b) Imuta, M.; Itani, H.; Ona,
H.; Konoike, T.; Uyeo, S.; Kimura, Y.; Miwa, H.; Matsuura, S.; Yoshida,
T. Chem. Pharm. Bull. 1991, 39, 672. (c) Imuta, M.; Itani, H.; Nishi,
K.; Ona, H.; Uyeo, S.; Kimura, Y. Bioorg. Med. Chem. Lett. 1993, 3,
2199. (d) Arnould, J . C.; Landier, F.; Pasquel, M. J . Poster at Recent
Advances in the Chemistry of Anti-Infective Agents Cambridge, UK,
1992.
(7) (a) Corraz, A. J .; Dax, S. L.; Dunlap, N. K.; Georgopapadakou,
N. H.; Keith, D. D.; Pruess, D. L.; Rossman, P. L.; Then, R.; Unowsky,
J . Wei, C.-C. J . Med. Chem. 1992, 35, 1828.
(8) Christensen, B. G.; Salzmann, T. N.; Heck, J . V. U.S. Patent
4,680,292, 1987.
(9) (a) Imuta, M.; Itani, H.; Ona, H.; Hamada, Y.; Uyeo, S. and
Yoshida, T. Chem. Pharm. Bull. 1991, 39, 663. (b) Uyeo, S.; Itani, H.
Tetrahedron Lett. 1994, 35, 4377.
S0022-3263(97)01684-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 02/18/1998

1720 J . Org. Chem., Vol. 63, No. 5, 1998
Notes
Sch em e 2
were sufficient to warrant development of a new and
more convergent method for the synthesis of 2-(hy-
droxymethyl)-1â-methylcarbapenems. Our synthetic strat-
egy is based on the addition of a hydroxymethyl anion
equivalent to an azetidinone carboxyl at a very early
stage and in a relatively short synthetic sequence.
Addition of organometallic reagents to activated aze-
tidinone carboxylic acids is known in the literature to give
the corresponding ketones.7,10 We envisaged that if a
protected hydroxymethyl synthon (-CH2OR) could be
used as a nucleophile, the resulting oxygenated methyl
ketone would provide an intermediate with the desired
functionality. This approach would eliminate the need
for the oxidation of the enolate.5 Furthermore, since the
direct addition of nucleophiles to lithium salts of car-
boxylic acids is a well-known procedure,11 the application
of this method to the azetidinone carboxylic acid would
eliminate activation, protection, and deprotection steps
in the synthetic sequence. We therefore anticipated that
this approach would overall be more expeditious and
practical.
To develop a general method, we initially chose to use
MeLi (5a ) and n-BuLi (5b) as both base and nucleophile
to examine the feasibility of direct organometallic addi-
tion to the lithium salt of the azetidinone carboxylic acid.
In addition, we planned to incorporate such a suitable
protecting group into the oxygenated carbon nucleophile
so that it could be readily removed under mild conditions
in a late stage of the synthetic sequence. According to
literature procedures, lithium reagents MOMOCH2Li
(5c) and PMBOCH2Li (5d ) were derived from organome-
tallic exchange of tributyltin compounds MOMOCH2Sn-
(Bu-n)3 (6c)12 and PMBOCH2Sn(Bu-n)3 (6d ).13 These
lithium reagents were used immediately after their prep-
aration for the next addition reaction.
The 3-substituted 4-[(R)-1-carboxyethyl]azetidin-2-one
7,14 a useful carbapenem precursor having four contigu-
ous stereogenic centers and the requisite carboxylic acid,
was treated with slightly in excess of 2 equiv of an
organic base to form either dilithium 8 or dimagnesium
salt 9 below -60 °C (Scheme 2). The amount of the base
added for the deprotonation was critical, and therefore,
it was monitored by the color change of triphenylmethane
indicator in the reaction solution in order to achieve the
maximum deprotonation of both the acid and the â-lac-
tam nitrogen protons of 7. The use of excess base com-
plicated the reaction, since it could act as a nucleophile
to compete with the desired addition. The consequence
was difficulty in separation of the products and reduced
chemical yields. The formed dilithium salt (8) in turn
reacted in situ with lithium reagents 5a -d at -78 °C,
and then the temperature was slowly raised to 0 °C. In
Ta ble 1
nucleophile
entry
base
MeLi
n-BuLi
n-BuLi
n-BuLi/CeCl3
n-BuLi
MeMgBr
isolated yield
1
2
3
4
5
6
MeLi (5a )
n-BuLi (5b)
LiCH2OMOM (5c)
LiCH2OMOM (5c)
LiCH2OPMB (5d )
LiCH2OPMB (5d )
55
50
49
45
19
46
the case of 5a and 5b (entries 1 and 2 in Table 1), the
bases used for the deprotonation were the same as the
nucleophiles for the addition. In the case of 5c and 5d ,
n-BuLi was used for the deprotonation (entries 3 and 5,
Table 1). Reaction of 8 with 5c gave results consistent
with the previous findings. However, an unexpectedly
low chemical yield (19%) was obtained when the PMB
protected carbon anion (5d ) was added to the lithium salt
(8). Replacement of the dilithium salt 8 with its mag-
nesium counterpart (intermediate 9, prepared by treat-
ment of 8 with 2 equiv of MeMgBr) improved the yield
to 46% (entry 6, Table 1). The protected hydroxymethyl
ketones (10a -d ) were isolated by chromatography in
moderate yield, and the unreacted starting material was
recovered in 14-25% yield by a simple aqueous workup.15
In two cases, byproducts 11a and 11b were isolated in
less than 5% yield and characterized by NMR and MS
analyses as evidence of competing double addition via
ketone intermediates.11a During the course of this study,
the use of CeCl3 reagent in the addition of organometallic
reagents to less complex carboxylic acids appeared in the
literature, and improved chemical yields were reported.16
Therefore, we tried to use CeCl3 reagent in the addition
of 5c to carbapenem lithium salt 8 but found the reagent
was not effective in improving the chemical yield (entry
4, Table 1). Finally, it should be pointed out that under
our reported conditions17a the additions of vinyllithium,
ethynyllithium, and [[(tert-butyldimethylsilyl)oxy]meth-
yl]lithium to the azetidinone 8 were unsuccessful.17b
Subsequent application of the literature procedure for
cyclization to the carbapenem5,18 led to the successful
synthesis of the 2-(hydroxymethyl)-1â-methyl carbap-
enem (Scheme 3). The keto ylides 12a and 12b were
(10) (a) Guthikonda, R. N.; Cama, L. D.; Quesada, M.; Woods, M.
F.; Salzmann, T. N.; Christensen, B. G. J . Med. Chem. 1987, 30, 871.
(b) Prasad, J . S.; Liebeskind, L. S. Tetrahedron Lett. 1987, 28, 1857.
(11) (a) Knudsen, C. G.; Rapoport, H. J . Org. Chem. 1983, 48, 2260.
(b) Maurer, P. J .; Knudsen, C. G.; Palkowitz, A. D.; Rapoport, H. J .
Org. Chem. 1985, 50, 325.
(12) (a) J ohnson, C. R.; Medich, J . R. J . Org. Chem. 1988, 53, 4131.
(b) Compound 6c was purified by chromatography using EtOAc:
hexanes (0:1 f 1:10).
(13) (a) Hutchinson, D. K.; Fuchs, P. L. J . Am. Chem. Soc. 1987,
109, 4930. (b) For the preparation of (iodomethyl)tributyltin compound,
see: Ahman, J .; Somfai, P. Synth. Commun. 1994, 24, 1117. (c)
Compound 6d was purified by chromatography using EtOAc:hexanes
(0:1 f 1:10).
(14) (a) This compound was purchased from Kaneka Inc. (b) For the
preparation of this azetidinone, see a recent review: Berks, A. H.
Tetrahedron 1996, 52, 331.
(15) The azetidinone was collected as a white solid by filtration of
the acidified aqueous layer after extraction of the product. The material
was pure by 1H NMR analysis and recycled.
(16) Ahn, Y.; Cohen, T. Tetrahedron Lett. 1994, 35, 203.
(17) (a) n-BuLi was used as a base. (b) Presumably, â-lactam ring
opening occurred to give a water-soluble amino acid, because material
recovery was very poor.
(18) Baxter, A. J . G.; Dickinson, K. H.; Roberts, P. M.; Smale, T. C.;
Southgate, R. J . Chem. Soc., Chem. Commun. 1979, 236.

Notes
J . Org. Chem., Vol. 63, No. 5, 1998 1721
Sch em e 3a
12b prior to the cyclization also proceeded smoothly
under DDQ conditions to provide 12c, which cyclized in
refluxing toluene to afford 4.
In conclusion, the development of a method for the
addition of organometallic carbon nucleophiles directly
to the preformed dilithium or dimagnesium salt of an
azetidinone acid as a key step allows the introduction of
the hydroxymethyl functionality at the 2-position of the
carbapenem system at a very early stage. The advan-
tages of the chemistry described above include the
elimination of activation, protection, and deprotection
steps in the synthetic sequence. Thus, our method is
indeed more streamlined for the synthesis of 2-(hy-
droxymethyl)-1â-methyl carbapenems. It is noteworthy
that this method was reproducible in our laboratory from
a 0.5-g scale to a 50-g scale, and the overall yields were
between 12 and 19% for the five discrete steps.
Exp er im en ta l Section
Gen er a l Exp er im en ta l P r oced u r es. All reagents were
commercial grade and were used as received without further
purification, unless otherwise specified. Commercially available
anhydrous solvents were used for reactions conducted under an
inert atmosphere. Reagent-grade solvents were used in all other
cases, unless otherwise specified. Flash chromatography was
performed on E. Merck silica gel 60 (230-400 mesh). Thin-
layer chromatography was performed on E. Merck 60 F-254
precoated silica plates (250 µm layer thickness). 1H NMR
1
spectra were recorded at 300 MHz. Chemical shifts for H NMR
spectra are expressed in parts per million downfield from
tetramethylsilane. Splitting patterns are designated as fol-
lows: s, singlet; d, doublet; t, triplet; q, quartet; p, pentet; m,
multiplet; br, broad. Coupling constants are given in hertz (Hz).
The 13C NMR spectra were recorded at 75 MHz. Chemical shifts
for 13C NMR spectra are expressed in parts per million downfield
from chloroform. Mass spectra were obtained by electrospray
mass spectrometry using an electrospray ionization (ESI) inter-
face in flow injection analysis (FIA) mode equipped with an ESI
interface. Melting points were taken on a capillary melting point
apparatus. High-resolution mass spectra were obtained by fast
atom bombardment (FAB) with a p-nitrobenzyl alcohol matrix.
IR spectra were recorded using attenuated total reflectance
spectroscopy with a germanium internal reflection element.
Optical rotations were measured with the use of a 10-cm cell at
20 °C.
Rep r esen ta tive P r oced u r e for th e Ad d ition of Alk yl-
lith iu m Rea gen ts to 4-[(R)-1-Ca r boxyeth yl]a zetid in -2-on e.
Syn th esis of (3S,4R)-3-[(1′R)-1′-[(ter t-Bu tyld im eth ylsilyl)-
oxy]eth yl]-4-[(1′′R)-1′′-[[(m eth oxym eth oxy)m eth yl]ca r bo-
n yl]eth yl]a zetid in -2-on e (10c). To a solution of 10.0 g (33.2
mmol) of azetidinone 7 and 10 mg of triphenylmethane as an
indicator dissolved in 200 mL of anhydrous THF was added 41.5
mL (66.4 mmol) of 1.6 M n-BuLi solution in heptane below -60
°C under an argon atmosphere. After addition, an additional
1.5 mL of n-BuLi was added, the color of the solution changed
from pale yellow to pink, and then the mixture was stirred at
-75 °C for 30 min.
Meanwhile, a solution of [(methoxymethoxy)methyl]lithium
was prepared by addition of 34.2 mL (54.8 mmol) of 1.6 M n-BuLi
to a solution of 20 mL (54.8 mmol) of [(methoxymethoxy)methyl]-
tributylstannane in 100 mL of anhydrous THF at -75 °C under
an argon atmosphere and stirred for 15 min.
To the THF solution of azetidinone dilithium salt was added
the THF solution of [(methoxymethoxy)methyl]lithium imme-
diately through a double-tipped needle by applying a slight
vacuum pressure in the reaction flask at -78 °C. The addition
was finished as fast as possible. After addition, the mixture was
stirred for 3 h with a slow increase of reaction temperature to 0
°C. The mixture was quenched by addition of 200 mL of water
and extracted with ethyl acetate (200 mL m~ 2). The combined
extracts were dried over anhydrous MgSO4 and evaporated
under reduced pressure. The residue was chromatographed and
eluted with hexane:ethyl acetate (3:1, 250 mL; 1:1, 400 mL; 0:1,
a
Key: (a) OHCCO2-allyl, toluene, reflux; (b) SOCl2, 2,6-
lutidine, THF; (c) PPh3, 2,6-lutidine, DMF; (d) toluene, reflux; (e)
TMSBr, CH2Cl2, -35 °C, 15 min; (f) DDQ, CH2Cl2, H2O, rt, 2.5 h.
prepared via a three-step sequence: condensation of
azetidinones 10c and 10d , respectively with allyl gly-
oxylate, chlorination of the corresponding hemiaminals,
and then ylide formation. It was noticed that the
hemiaminals were stable enough to undergo purification
by flash chromatography, and the purified hemiaminals
proved to give higher overall yields in the three-step
sequence. Cyclization of the keto ylides in boiling toluene
afforded carbapenems 13a and 13b. Unexpectedly,
considerable difficulty was encountered in the removal
of the MOM protecting group in 13a , with most of the
conventional and mild MOM deprotection methods (in-
cluding HCl,19 TMSBr,20 Py‚TsOH,21 and LiBF4 ) prov-
22
ing ineffective. Therefore, an alternative route was
chosen in which the MOM group was removed prior to
the cyclization. Deblocking the hydroxy ketone 12a with
TMSBr produced hydroxymethyl ketone 12c, and the
intramolecular Wittig annulation of the ylide completed
the synthesis of 2-(hydroxymethyl)-1â-methylcarbapenem
(4) in 40% yield for the last two steps. In contrast,
carbapenem 13b underwent debenzylation under very
mild conditions using DDQ23 to give 2-(hydroxymethyl-
)penem 4 in good yield. Similarly, the debenzylation of
(19) Auerbach, J .; Weinreb, S. M. J . Chem. Soc., Chem. Commun.
1974, 298.
(20) Hanessian, S.; Delorme, D.; Dufresne, Y. Tetrahedron Lett.
1984, 25, 2515.
(21) Monti, H.; Leandri, G.; Klos-Ringquet, M.; Corriol, C. Synth.
Commun. 1983, 13, 1021.
(22) Ireland, R. E.; Varney, M. D. J . Org. Chem. 1986, 51, 635.
(23) Tanaka, T.; Yoshioka, T.; Oikawa, Y.; Hamada, T.; Yonemitsu,
O. Tetrahedron Lett. 1986, 27, 3651.

1722 J . Org. Chem., Vol. 63, No. 5, 1998
Notes
200 mL) (Rf ) 0.68, EtOAc) to give 5.78 g (16.1 mmol, 49%) of
10c as a white solid: mp 55-56 °C; IR (CHCl3) 3298, 2954, 2931,
mmol) of thionyl chloride dropwise under an argon atmosphere.
The mixture was stirred at -40 to -30 °C for 1 h, and the formed
salt solid was removed by immediate filtration. The filtrate was
dried in vacuo. The residue was dissolved in 150 mL of
molecular sieve-dried ethyl acetate, and the precipitate was
removed by filtration. The filtrate was dried in vacuo again.
The filtration should be performed as fast as possible under an
argon atmosphere to avoid exposure to moisture. The residue
was dissolved in 100 mL of DMF dried with molecular sieves,
and 7.082 g (27.0 mmol) of triphenylphosphine was added
followed by 3.14 mL (27.0 mmol) of 2,6-lutidine. The resulting
solution was stirred at room temperature for 15 h and then
partitioned between 200 mL of saturated aqueous NaCl solution
and 300 mL of ethyl acetate. The organic layer was separated,
and the aqueous layer was extracted with 200 mL of ethyl
acetate. The combined organic phase was dried over anhydrous
MgSO4 and evaporated under reduced pressure. The residue
was flash chromatographed using hexane:ethyl acetate (4:1, 500
mL; 1:1, 800 mL) (Rf ) 0.45, hexane:EtOAc 1:1) to give 6.772 g
(9.45 mmol, 70%) of ylide 12a as a light brown thick oil: 1H
NMR (300 MHz, CDCl3) δ 7.82-7.40 (m, 15H), 6.02-5.85 (m,
1H), 5.40-5.05 (m, 2H), 4.75-4.49 (m, 4H), 4.26-3.98 (m, 4H),
3.37 (s, 3H), 2.77-2.58 (m, 2H), 1.40-0.98 (m, 6H), 0.90-0.65
(m, 9H), +0.04 to -0.06 (m, 6H).
(3S,4R)-3-[(1′R)-1′-[(ter t-Bu t yld im et h ylsilyl)oxy]et h yl]-
1-[1-h yd r oxy-1-[(a llyloxy)ca r b on yl]m et h yl]-4-[(1′′R)-1′′-
[[(m e t h oxym e t h oxy)m e t h yl]ca r b on yl]e t h yl]a ze t id in -2-
on e (12b). According to the procedure described above, keto
azetidinone 10d (35.43 g, 81.45 mmol) was converted to the
hemiaminal intermediate (37.24 g, 70.0 mmol, 83%) as a thick
oil. The hemiaminal (2.29 g, 4.18 mmol) was then transferred
to the corresponding ylide 12b (2.714 g, 3.42 mmol, 82%) as a
foaming material: 1H NMR (300 MHz) in CDCl3 δ 7.82-6.83
(m, 19H), 6.02-5.85 (m, 1H), 5.40-5.03 (m, 2H), 4.64-4.33 (m,
4H), 4.32-3.72 (m, 4H), 3.81 (s, 3H), 2.75-2.60 (m, 2H), 1.51-
0.95 (m, 6H), 0.92-0.75 (m, 9H), 0.15 to -0.50 (m, 6H).
(3S ,4R )-1-[[(Allyloxy)ca r b on yl](t r ip h e n ylp h osp h or -
a n ylid en e)m et h yl]-3-[(1′R)-1′-[(ter t-b u t yld im et h ylsilyl)-
oxy]et h yl]-4-[(1′′R)-1′′-[(h yd r oxym et h yl)ca r b on yl]et h yl]-
a zetid in -2-on e (12c) fr om 12a . To a solution of 46 mg (0.064
mmol) of ylide 12a in 3 mL of dry CH2Cl2 was added 34 µL (0.258
mmol, 4 equiv) of trimethylsilyl bromide at -35 °C, and the
mixture was stirred at -35 to -30 °C. TLC analysis showed
no starting material in 15 min (Rf ) 0.40, hexane:EtOAc 1:1).
The mixture was washed with 5 mL of saturated aqueous
NaHCO3 solution. The organic layer was dried over anhydrous
MgSO4 and evaporated to afford 44 mg of the crude hydroxym-
ethyl ketone, which was used in the next step without further
purification.
1761, 1733; [R]27 -20.0° (c 0.20 in CHCl3); 1H NMR (300 MHz,
D
CDCl3) δ 6.02 (br, 1H), 4.70 (s, 2H), 4.23 (s, 2H), 4.20 (pentet, J
) 6.3 Hz), 3.90 (dd, J ) 2.4, 4.8 Hz), 3.41 (s, 3H), 3.08 (m, 1H),
2.93 (dd, J ) 2.4, 4.8 Hz, 1H), 1.21 (d, J ) 6.3 Hz, 3H), 1.20 (d,
J ) 7.2 Hz, 3H), 0.89 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 210.2, 168.4, 96.7, 71.8, 65.6, 61.8, 56.0, 51.2,
44.4, 25.9, 22.8, 18.1, 11.8, -4.1, -4.8. Anal. Calcd for C17H33
-
NO5Si: C, 56.79; H, 9.25; N, 3.90. Found: C, 56.82; H, 9.30; N,
3.89.
The aqueous layer after the extraction was acidified with
concentrated HCl to pH <1, and the precipitate was collected
by filtration, washed with water, and dried under reduced
pressure overnight to give 2.34 g of a white solid. 1H NMR
analysis confirmed the compound was the starting azetidinone
(recovered yield 63%).
(3S,4R)-3-[(1′R)-1′-[(ter t-Bu t yld im et h ylsilyl)oxy]et h yl]-
4-[(1′′R)-1′′-(m eth ylca r bon yl)eth yl]a zetid in -2-on e (10a ). Ac-
cording to the procedure described above, addition of MeLi to
the dilithium salt of azetidinone 8 (10.0 g, 0.033 mol) gave 5.48
g (0.018 mol, 55%) of 10a as a white solid: mp 108-110 °C (Rf
) 0.70, EtOAc); [R]20D -3.6° (c 2.0 in CHCl3); 1H NMR (300 MHz,
CDCl3) δ 5.90 (b, 1H), 4.17 (pentet, J ) 6.3 Hz, 1H), 3.89 (dd, J
) 2.7, 4.8 Hz, 1H), 2.85 (dd, J ) 1.8, 5.1 Hz, 1H), 2.80 (m, 1H),
2.20 (s, 3H), 1.18 (d, J ) 6.3 Hz, 3H), 1.17 (d, J ) 6.3 Hz, 3H),
0.86 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 210.4, 168.0, 65.4, 61.4, 50.9, 48.7, 29.2, 25.5, 22.3, 17.7, 11.1,
-4.5, -5.2; IR (NaCl)) 3298, 2954, 2931, 1761, 1733. Anal.
Calcd for C15H29NO3Si: C, 60.16; H, 9.76; N, 4.68. Found: C,
60.10; H, 9.56; N, 4.59.
(3S,4R)-3-[(1′R)-1′-[(ter t-Bu t yld im et h ylsilyl)oxy]et h yl]-
4-[(1′′R)-1′′-(1-bu tylca r bon yl)eth yl]a zetid in -2-on e (10b). Ac-
cording to the procedure described above, addition of n-BuLi to
the dilithium salt of azetidinone 8 (0.600 g 1.99 mmol) gave 0.341
g (1.00 mmol, 50%) of 10b as a white solid: mp 66-67 °C (Rf )
0.45, EtOAc:hexane 1:2); [R]20 -5.6° (c 3.7 in CHCl3); 1H NMR
D
(300 MHz, CDCl3) δ 5.98 (b, 1H), 4.16 (pentet, J ) 6.3 Hz, 1H),
3.86 (dd, J ) 2.4, 4.5 Hz, 1H), 2.85 (dd, J ) 2.4, 5.1 Hz, 1H),
2.81 (m, 1H), 2.48 (m, 2H), 1.55 (pentet, J ) 7.5 Hz, 2H), 1.32
(m, 2H), 1.19 (d, J ) 6.3 Hz, 3H), 1.18 (d, J ) 6.3 Hz, 3H), 0.91
(t, J ) 7.2 Hz, 3H), 0.86 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 212.9, 168.0, 65.4, 61.4, 50.1, 47.8, 41.8,
25.5, 25.3, 22.1, 22.3, 17.7, 13.6, 11.4, -4.4, -5.2; IR (NaCl) 3161,
2958, 2928, 1757, 1710. Anal. Calcd for C18H35NO3Si: C, 63.30;
H, 10.33; N, 4.10. Found: C, 63.30; H, 10.09; N, 4.02.
(3S,4R)-3-[(1′R)-1′-[(ter t-Bu t yld im et h ylsilyl)oxy]et h yl]-
4-[(1′′R)-1′′-[[[(p-m eth oxyben zyl)oxy]m eth yl]car bon yl]eth yl]-
a zet id in -2-on e (10d ). According to the procedure described
above, addition of [[(p-methoxybenzyl)oxy]methyl]lithium to the
dimagnesium salt of azetidinone 9 (51.0 g, 0.169 mol) gave 33.83
g (0.078 mol, 46%) of 10b as a colorless oil (Rf ) 0.68, EtOAc):
Allyl (1S,5R,6S)-2-(Hyd r oxym eth yl)-6-[(1′R)-1′-[(ter t-bu -
tyld im eth ylsilyl)oxy]eth yl]-1-m eth ylca r ba p en -2-em -3-ca r -
boxyla te (4) fr om 12c. A solution of 44 mg of hydroxymethyl
ketone ylide 12c in 2 mL of toluene was heated at reflux for 1
h, and the solvent was evaporated under reduced pressure to
give 45 mg of crude product, which was flash chromatographed
using hexane:ethyl acetate (4:1 and then 1:1) (Rf ) 0.80, hexane:
EtOAc 1:1) to afford 10 mg (0.025 mmol, 40% for two steps) of
carbapenem 4 as a colorless oil: IR (CHCl3) 3500, 2955, 2859,
[R]20 +28.0° (c 0.3.4 in CHCl3); 1H NMR (300 MHz, CDCl3) δ
D
7.29 (d, J ) 8.4 Hz, 2H), 6.92 (d, J ) 8.4 Hz, 2H), 5.85 (s, 1H),
4.54 (s, 2H), 4.23-4.11 (m, 1H), 4.08 (s, 2H), 3.86 (dd, J ) 2.1,
4.5 Hz, 1H), 3.84 (s, 3H), 3.14 (m, 1H), 2.91 (dd, J ) 1.8, 4.8 Hz,
1H), 1.19 (d, J ) 6.3 Hz, 3H), 1.18 (d, J ) 7.2 Hz, 3H), 0.89 (s,
9H), 0.09 (s, 3H), 0.08 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 210.9,
168.1, 159.5, 129.7, 128.8, 114.0, 74.0, 73.1, 65.3, 61.4, 55.3, 51.0,
43.9, 25.7, 22.5, 17.9, 11.4, -4.3, -5.1; IR (NaCl)) 3155, 2954,
2926, 1757, 1716. Anal. Calcd for C23H37NO5Si: C, 63.41; H,
8.56; N, 3.22. Found: C, 63.60; H, 8.39; N, 3.10.
1774, 1720, 1651, 1624; [R]27 +60.0° (c 0.2 in CHCl3); 1H NMR
D
(300 MHz, CDCl3) δ 5.85 (ddt, J ) 5.1, 10.8, 17.1 Hz, 1H), 5.52
(dq, J ) 1.5, 17.1 Hz, 1H), 5.15 (dq, J ) 1.5, 17.1 Hz, 1H), 4.72-
4.55 (m, 3H), 4.28-4.06 (m, 3H), 3.28-3.17 (m, 1H), 3.15 (dd, J
) 2.7, 5.7 Hz, 1H), 1.16 (d, 3H), 1.10 (d, 3H), 0.80 (s, 9H), 0.00
(s, 6H); 13C NMR (75 MHz, CDCl3) δ 175.0, 161.7, 152.6, 131.4,
127.2, 118.2, 66.2, 65.9, 60.1, 57.4, 56.4, 41.1, 25.8, 22.4, 18.0,
15.4, -4.1, -4.9. Anal. Calcd for C20H33NO5Si‚1/5H2O: C,
60.18; H, 8.43; N, 3.51. Found: C, 59.84; H, 8.19; N, 3.45.
Allyl (1S,5R,6S)-2-[(Met h oxym et h oxy)m et h yl]-6-[(1′R)-
1′-[(ter t-bu tyld im eth ylsilyl)oxy]eth yl]-1-m eth ylca r ba p en -
2-em -3-ca r boxyla te (13a ). The procedure used for the prepa-
ration of carbapenem 4 was employed to prepare carbapenem
13a as a white solid from the ylide in 71% after flash chroma-
tography using hexane:ethyl acetate (4:1 and then 1:1) (Rf )
(3S ,4R )-1-[[(Allyloxy)ca r b on yl](t r ip h e n ylp h osp h or -
a n ylid en e)m et h yl]-3-[(1′R)-1′-[(ter t-b u t yld im et h ylsilyl)-
oxy]eth yl]-4-[(1′′R)-1′′-[[(m eth oxym eth oxy)m eth yl]ca r bo-
n yl]eth yl]a zetid in -2-on e (12a ). A solution of 5.76 g (16.0
mmol) of keto azetidinone 10c and 3.67 g (32.0 mmol) of allyl
glyoxylate in 80 mL of toluene was heated at reflux for 16 h,
and the small amount of water was removed by azeotropic
distillation using a Dean-Stark trap. The solvent was evapo-
rated under reduced pressure, and the residue was chromato-
graphed using eluent hexane:ethyl acetate (4:1, 300 mL; 2:1, 300
mL; 1:1, 300 mL) to give 6.39 g (13.5 mmol, 84%) of the
hemiaminal as a thick oil.
0.70, hexane:ethyl acetate 4:1): mp 23-25 °C; MS (ion spray)
1
A solution of 6.38 g (13.5 mmol) of the hemiaminal intermedi-
ate and 4.72 mL (40.5 mmol) of 2,6-lutidine in 150 mL of dry
THF was cooled to -40 °C, and to it was added 2.95 mL (40.5
440 (M + 1); [R]20 +65.2° (c 1.2 in CHCl3) (c 2.8 in CHCl3); H
D
NMR (300 MHz, CDCl3) δ 5.87 (ddt, J ) 5.4, 10.5, 17.1 Hz, 1H),
5.35 (dq, J ) 1.5, 17.1 Hz, 1H), 5.18 (dq, J ) 1.5, 17.1 Hz,

Notes
J . Org. Chem., Vol. 63, No. 5, 1998 1723
1H), 4.86 (dd, J ) 0.6, 14.1 Hz, 1H), 4.66 (dtq, J ) 1.5, 5.4, 13.8
Hz, 2H), 4.57 (d, J ) 1.5 Hz, 2H), 4.17 (dd, J ) 1.2, 14.1 Hz,
1H), 4.16-4.06 (m, 1H), 3.31 (s, 3H), 3.34-3.23 (m, 1H), 3,14
(dd, J ) 3.0, 6.6 Hz, 1H), 1.18 (d, J ) 6.0, 3H), 1.12 (dd, J ) 7.2
Hz, 3H), 0.81 (s, 9H), 0.00 (s, 6H); 13C NMR (75 MHz, CDCl3) δ
174.8, 161.0, 148.4, 131.7, 127.6, 118.6, 96.6, 66.6, 65.9, 62.1,
60.4, 56.4, 55.7, 40.6, 25.9, 22.6, 18.1, 15.5, -4.0, -4.8. Anal.
Calcd for C22H37NO6Si: C, 60.11; H, 8.48; N, 3.19. Found: C,
59.75; H, 8.18; N, 3.02.
Allyl (1S,5R,6S)-2-[(p -m et h oxyb en zyl)oxy]-6-[(1′R)-1′-
[(ter t-bu tyld im eth ylsilyl)oxy]eth yl]-1-m eth ylca r ba p en -2-
em -3-ca r boxyla te (13b). The procedure used for the prepa-
ration of carbapenem 4 was employed to prepare carbapenem
13b as a colorless oil in 95% after flash chromatography using
hexane:ethyl acetate (8:1 and then 4:1) (Rf ) 0.45, hexane:ethyl
130.1, 129.7, 127.4, 118.6, 114.0, 72.9, 66.6, 65.8, 64.3, 60.4, 56.3,
55.5, 40.6, 25.9, 22.7, 18.2, 15.6, -4.0, -4.7. Anal. Calcd for
C
28H41NO6Si: C, 65.21; H, 8.01; N, 2.72. Found: C, 65.5; H,
7.61; N, 2.61.
Allyl (1S,5R,6S)-2-(Hyd r oxym eth yl)-6-[(1′R)-1′-[(ter t-bu -
tyld im eth ylsilyl)oxy]eth yl]-1-m eth ylca r ba p en -2-em -3-ca r -
boxyla te (4) fr om 13b. To a solution of 5.00 g (9.70 mmol) of
[[(p-methoxybenzyl)oxy]methyl]carbapenem 13b dissolved in 250
mL of CH2Cl2 was added 3.306 g (12.6 mmol) of 2,3-dichloro-
5,6-dicyano-1,4-benzoquinone (DDQ) followed by 25 mL of H2O,
and the mixture was stirred at room temperature for 2.5 h. The
solid was removed by filtration, and the filtrate was washed by
saturated NaHCO3. The organic phase was dried over anhy-
drous MgSO4 and evaporated. The residue was chromato-
graphed using hexane:ethyl acetate (8:1 f 2:1) to give 2.437 g
(6.09 mmol, 63%) of hydroxymethyl carbapenem 4 as a pale
yellow thick oil.
acetate 4:1): IR (NaCl) 2955, 2884, 1778, 1720 cm-1, [R]20
D
+62.0° (c 2.8 in CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.25 (d, J
) 12.0 Hz, 2H), 6.88 (d, J ) 12.0 Hz, 2H), 5.93 (m, 1H),5.42
(dtq, J ) 1.2, 5.4, 13.5 Hz, 2H), 4.50 (d, J ) 11.4 Hz, 1H), 4.40
(d, J ) 11.4 Hz, 1H), 4.24-4.12 (m, 3H), 3.807 (s, 3H), 3.35 (dq,
J ) 2.7, 7.2 Hz, 1H), 3.19 (dd, J ) 3.0, 6.6 Hz, 1H), 1.25 (d, J )
6.3 Hz, 3H), 1.13 (d, J ) 7.5 Hz, 3H), 0.88 (s, 9H), 0.07 (s, 6H);
13C NMR (75 MHz, CDCl3) δ 175.0, 161.2, 159.6, 149.2, 131.7,
Ack n ow led gm en t. We gratefully acknowledge Pro-
fessor Paul Helquist and Professor Andrew Kende for
helpful discussions.
J O9716845