Practical synthesis of anti-methicillin-resistant Staphylococcus aureus (MRSA) carbapenem L-742,728

Article abstract of DOI:10.1021/jo980381n

Anti-MRSA carbapenem, L-742,728, has been prepared in large quantity using the Suzuki-Miyaura cross-coupling as the key reaction. Three approaches have been examined by varying the coupling reaction between carbapenem nucleus A and side chains B, BC, and

Full text of DOI:10.1021/jo980381n

5438
J . Org. Chem. 1998, 63, 5438-5446
P r a ctica l Syn th esis of An ti-Meth icillin -Resista n t Sta ph ylococcu s
Au r eu s (MRSA) Ca r ba p en em L-742,728
Nobuyoshi Yasuda,* Mark A. Huffman,* Guo-J ie Ho, Lyndon C. Xavier, Chunhua Yang,
Khateeta M. Emerson, Fuh-Rong Tsay, Yulan Li, Michael H. Kress, Dale L. Rieger,
Sandor Karady, Paul Sohar, Newton L. Abramson, Ann E. DeCamp, David J . Mathre,
Alan W. Douglas, Ulf-H. Dolling, Edward J . J . Grabowski, and Paul J . Reider
Department of Process Research, Merck Research Laboratories, P.O. Box 2000,
Rahway, New J ersey 07065
Received March 2, 1998
Anti-MRSA carbapenem, L-742,728, has been prepared in large quantity using the Suzuki-Miyaura
cross-coupling as the key reaction. Three approaches have been examined by varying the coupling
reaction between carbapenem nucleus A and side chains B, BC, and BCD, wherein BCD represents
the fully elaborated side chain. The coupling of A with BCD offers the advantage of convergence
and requires fewer chemical steps after installation of the thermally unstable carbapenem skeleton.
This key reaction highlights the versatility and efficiency of the Suzuki-Miyaura reaction. This
approach offers a general method for the preparation of the 3-aryl carbapenems, which possess
strong antibacterial activity against resistant strains.
In tr od u ction
four sections: the â-methyl carbapenem skeleton (A), a
functionalized methylfluorenone (B), doubly quaternized
1,4-diazabicyclooctane (DABCO) (C), and acetamide (D)
(Scheme 1). The carbapenem skeleton derives from the
readily available diazo compound 2.7 The methylfluo-
renone can be prepared from 4-bromobenzonitrile (3) and
4-toluidine (4).
The ubiquitous use of antibiotics for the treatment of
infectious disease has resulted in many bacterial strains
acquiring resistance to multiple drugs. One of the most
serious resistant strains is the methicillin-resistant Sta-
phylococcus aureus (MRSA).1 First observed in Australia
in the 1980s,2 MRSA has become a worldwide problem,
especially in areas where potent antibiotics have been
heavily used. In such MRSA infections, vancomycin has
become the primary treatment despite its adverse side
effects. The search for alternative therapies is driven by
the expected emergence of vancomycin-resistant MRSA.3
Indeed the transfer of vancomycin resistance to S. aureus
from a resistant Enterococcus has been demonstrated in
the laboratory.4
The key step in the synthesis is the coupling between
the carbapenem core A and the side chain. Two aspects
(5) Previously, we reported this class of carbapenem as 2-aryl
carbapenem based on the traditional numbering system in â-lactam
chemistry. In this report, we use the IUPAC numbering system as
depicted in L-742,728 (1). (a) Greenlee, M. L.; Cama, L. D.; DiNinno,
F. P.; Heck, J . V. U.S. Pat. 5034384, 1991. (b) DiNinno, F.; Dykstra,
K. D.; Greenlee, M. L.; Rano, T. A.; Guthikonda, R. N.; Schmitt, S. M.;
Meurer, L. C.; Cama, L. D.; Sasor, M. F.; Laub, J . B.; Rouen, G. P.;
Lee, W.; Muthard, D. A.; Hammond, M. L.; Heck, J . V.; Salzmann, T.
N.; Kahan, J . S.; Huber, J . L.; Sundelof, J . G.; Dorso, K.; Kohler, J .;
Gerkens, L.; Pelak, B.; St. Rose, E.; J ackson, J . J .; Hajdu, R.; Kropp,
H.; Hammond, G. G.; Overbye, K. M.; Silver, L. L. The 4th Interna-
tional Conference on Chemical Synthesis of Antibiotics and Related
Microbial Products, Nashville, IN, September 1994. (c) Sasor, M. F.;
Cama, L. D.; Greenlee, M. L.; DiNinno, F.; Heck, J . V. The 34th
Interscience Conference on Antimicrobial Agents and Chemotherapy,
Paper #F 50, Orlando, FL, October 1994. (d) Huber, J . L.; Dorso, K.;
Gerckens, L.; St. Rose, E.; Kohler, J .; Dufresne, S.; Kahan, J .; Shungu,
D.; Kropp, H. The 34th Interscience Conference on Antimicrobial
Agents and Chemotherapy, Paper #F 54, Orlando, FL, October 1994.
(e) Rylander, M.; Rollof, J .; Norrby, S. R. The 34th Interscience
Conference on Antimicrobial Agents and Chemotherapy, Paper #F 56,
Orlando, FL, October 1994. (f) Dykstra, K. D.; DiNinno, F. The 6th
Symposium on the Latest Trends in Organic Synthesis, Blacksburg,
VA, October 1994. (g) Meurer, L. C.; Guthikonda, R. N.; Huber, J . L.;
DiNinno, F. BioMed. Chem. Lett. 1995, 5, 767. (h) DiNinno, F.;
Muthard, D. A.; Salzmann, T. N.; Huber J .; Kahan, J .; Kropp, H.
BioMed. Chem. Lett. 1995, 5, 945. (i) Laub, J . B.; Greenlee, M. L.;
DiNinno, F.; Huber, J . L.; Sundelof, J . G. The 210th National Meeting
of the American Chemical Society, Abstract #MEDI 210, Chicago, IL,
August 1995. (j) Chambers, H. F. Antimicrob. Agents Chemother. 1995,
39, 426. (k) Rylander, M.; Rollof, J .; J acobsson, K.; Norrby, S. R.
Antimicrob. Agents Chemother. 1995, 39, 1178. (l) Norrby, S. R.
Antimicrob. Therapy II 1995, 79, 745. (m) Yasuda, N. 1995 Interna-
tional Chemical Congress of Pacific Basin Societies, Honolulu, HI,
December 1995.
Recently, Merck scientists have reported anti-MRSA
activity in carbapenems bearing aromatic substituents
at the 3-position.5 The most recent candidate to emerge
from this program is L-742,728 (1),6 the large-scale
synthesis of which we report here.
Resu lts a n d Discu ssion
The antibacterial 1 is a cationic zwitterionic â-methyl
carbapenem which can be retrosynthetically divided into
(1) (a) Methicillin Resistant Staphylococcus aureus; University of
Tokyo Press: Tokyo, 1986. (b) Brumfitt, W.; Hamilton-Miller, J . N.
Eng. J . Med. 1989, 320, 1188.
(2) McDonald, O. J . Med. J . Australia 1982, 1, 445.
(3) Very recently, vancomycin resistant MRSA has been reported.
Michel, M.; Gutmann, L. Lancet 1997, 349, 1901.
(4) Noble, W. C.; Virani, Z.; Cree, R. G. A. FEMS Microb. Lett. 1992,
93, 195.
(6) (a) Greenlee, M. L.; DiNinno, F.; Hammond, M. L. U.S. Pat.
5,451,579, 1995. (b) Greenlee, M. L.; Laub, J . B.; Rouen, G. P.; DiNinno,
F.; Cama, L. D.; Hammond, M. L.; Huber, J . L.; Sundelof, J . G.;
Hammond, G. G. The 211th National Meeting of the American
Chemical Society, Abstract #MEDI0178, New Orleans, LA, March
1996.
S0022-3263(98)00381-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/15/1998

Practical Synthesis of Carbapenem L-742,728
J . Org. Chem., Vol. 63, No. 16, 1998 5439
Sch em e 1
Sch em e 2a
a
(a) BCl3, AlCl3, PhCl, 130-134 °C. (b) NaNO2, H3PO4, 80 °C.
Sch em e 3a
were considered: coupling convergence and method.
Three different approaches were explored, namely, A +
B; A + BC, and A + BCD. The coupling of A with the
simpler side-chain B was expected to be the easiest to
achieve. On the other hand, coupling with the more
complex, quaternized side chains (BC or BCD) would
minimize the number of steps involving unstable car-
bapenem intermediates.
a
(a) NBS, VAZO-52, AcOH, CH2Cl2. (b) NaOAc, DMF. (c)
NaOMe. (d) MeOH, 100 °C. (e) CH(OMe)3, concentrated H2SO4,
MeOH. (f) B(O-i-Pr)3, n-BuLi, THF/toluene/hexanes, <-70 °C. (g)
TFA. (h) NaOH, THF, H2O; then aqueous HCl.
Previously, introduction of the side chain has efficiently
been accomplished by a Stille cross-coupling reaction
yield (Scheme 2). Diazotization of 5, followed by Pschorr
cyclization under standard radical conditions, gave a ca.
1:1 mixture of 2-methyl- and 4-methylfluorenone, due to
a 1,5 hydrogen transfer.11 The hydrogen transfer was
successfully suppressed by carrying out the cyclization
under acidic conditions. Solid NaNO2 was slowly added
to the PhCl solution of 5 and superphosphoric acid12 at
80 °C to provide 6 without accumulation of a potentially
explosive diazonium intermediate. In this way, 6 was
prepared in two steps in an overall yield of 70%.
P r ep a r a tion of Sim p le Sid e-Ch a in Bor on ic Acid
B (14). In three steps, benzyl alcohol 9 was prepared
from common intermediate 6 (Scheme 3). All transmetal-
ation attempts on either 9 or O-protected versions failed
due to the reactivity of the carbonyl group. Protection
as the dimethylketal 11 was achieved by heating 9 with
a large excess of CH(OMe)3 in MeOH in the presence of
1 equiv of concentrated H2SO4. Benzyl methyl ether
formation is inevitable during the ketalization, so prepa-
ration of 11 was modified to a route via methyl ether 10
[6 f 7 f 10 f 11], reducing the number of chemical
steps.
between
a carbapenem enol triflate and an aryl
stannane.5b,g,8 We judged this method to be unsuitable
for large-scale pharmaceutical synthesis due to the
toxicity of the organotin byproducts and the difficulty in
removing them from coupled products. Recent reports
from these laboratories disclosed mild conditions in which
the Suzuki-Miyaura cross-coupling served as a success-
ful replacement for the Stille reaction in the cross-
coupling of a carbapenem enol triflate with simple boronic
acids.9 With this method, the byproduct boric acid is
easily removed by aqueous extraction and poses no
toxicological concern. For the present synthesis, we
sought to apply the Suzuki-Miyaura cross-coupling
method to this more complex side chain.
P r ep a r a tion of 2-Meth ylflu or en on e (6). All side-
chain coupling partners were prepared from 2-methyl-
fluorenone (6) as a common intermediate. Employing a
modified Sugasawa reaction,10 amino benzophenone 5
was obtained from 3 and 4 as a PhCl solution in excellent
Halo-transmetalation of 11 to boronic acid 12 was
accomplished by addition of n-BuLi to a solution of 11
and B(O-i-Pr)3 below -70 °C, followed by acidic hydroly-
sis. Solvolysis of the methyl ether of 11 with hot TFA,
followed by hydrolysis, gave the simple side-chain frag-
ment 14 in an overall yield of 45% in seven steps from 3.
P r ep a r a tion of Ela bor a ted Sid e-Ch a in s BC a n d
BCD (19, 20). To access further functionalized coupling
(7) Compound 2 is readily available from (2R)-[(3S,4S)-3-[(1R)-tert-
butyldimethylsilyloxyethyl]azetidinone-4-yl]propionic acid, which is
now commercially available from Kanegafuchi, J apan, Nippon Soda,
J apan, and Takasago, J apan. For recent preparation of the propionic
acid; see: J ones, D. K.; Liotta, D. C.; Choi, W.-B.; Volante, R. P.; Reider,
P. J .; Shinkai, I.; Churchill, H. R. O.; Lynch, J . E. J . Org. Chem. 1994,
59, 3749 and references therein.
(8) Rano, T. A.; Greenlee, M. L.; DiNinno, F. Tetrahedron Lett. 1990,
31, 2853 and references therein.
(9) (a) Yasuda, N.; Xavier, L.; Rieger, D. L.; Li, Y.; DeCamp, A. E.;
Dolling, U.-H. Tetrahedron Lett. 1993, 34, 3211. (b) Narukawa, Y.;
Nishi, K.; Onoue, H. Tetrahedron 1997, 53, 539 and references therein.
(10) Douglas, A. W.; Abramson, N. L.; Houpis, I. N.; Karady, S.;
Molina, A.; Xavier, L. C.; Yasuda, N. Tetrahedron Lett. 1994, 35, 6807
and references therein.
(11) Karady, S.; Abramson, N. L.; Dolling, U.-H.; Douglas, A. W.;
McManemin, G. J .; Marcune, B. J . Am. Chem. Soc. 1995, 117, 5425.
(12) Purchased from Aldrich Co. Ltd.

5440 J . Org. Chem., Vol. 63, No. 16, 1998
Yasuda et al.
Sch em e 4a
Sch em e 5a
a
(a) CH(OMe)3, concentrated H2SO4, MeOH; then TEA. (b) B(O-
a
(a) Rh2(C7H15CO2)4, ZnBr2, CH2Cl2. (b) Et3N, Tf2O, CH2Cl2,
-78 °C. (c) Et3N, TESOTf, CH2Cl2, -78 °C. (d) Imidazole, TESCl,
i-PrOAc/THF. (e) Et3N, i-Pr2NH, Tf2O, CH2Cl2, -40 °C.
i-Pr)3, n-BuLi, THF/toluene/hexanes. <-70 °C; then dilute H2SO4.
(c) Pinacol, PhCl, 133 °C. (d) Dibromodimethylhydantoin, VAZO-
52, 37-39 °C. (e) DABCO, t-BuOMe/MeOH. (f) 21, MeCN/MeOH,
28-30 °C.
secondary alcohol with the TES group provided the more
stable protected enol triflate 26, which was then used in
situ for cross-coupling.
partners 19 and 20, 2-bromomethyl-9-fluorenone-6-
boronic acid derivative 18 was considered an ideal
intermediate (Scheme 4). Methylfluorenoneboronic acid
16 was prepared from 6 in two steps under the previously
used ketalization/transmetalation conditions (vide supra)
in good yield. Direct bromination of 16 failed due to
solubility problems. Consequently, 16 was first converted
to its more soluble pinacol ester 17, allowing smooth
bromination to 18.
Mono-quaternized boronic acid pinacol ester 19 was
obtained in excellent yield from 18 and DABCO. Finally,
doubly quaternized boronic acid 20 was prepared by
reacting 18 with DABCO N-acetamide triflate salt 21,
prepared from DABCO and chloroacetamide, followed by
boronic ester hydrolysis. Crystallization of 20 in the
presence of triflate kept the amount of bromide counter-
anion below 0.6 equiv, a factor which affected the
subsequent Suzuki-Miyaura coupling reaction (vide
infra).
P r ep a r a tion of Ca r ba p en em En ol Tr ifla te (26).
The carbapenem coupling partner was the triethylsilyl
(TES) protected enol triflate 26. The TES protective
moiety was chosen to balance the stability of the pro-
tected carbapenem enol triflate with the need for mild
deprotection conditions.
In our initial approach to 1, enol triflate 26 was
prepared from diazo compound 2 according to the previ-
ously reported method (Scheme 5).6,8,9 Rhodium-cata-
lyzed cyclization of 2 gave the â-keto ester 22 which was
not isolated because it is not crystalline. A small amount
of ZnBr2 was added prior to cyclization to inhibit base-
catalyzed epimerization of the â-methyl substituent in
22.13 The unprotected enol triflate 23, generated from
22 by addition of Et3N and Tf2O, is extremely unstable
even at -78 °C. Immediate in situ protection of the
While efficient for multigram synthesis, this sequence
did not perform well on large scale. The exothermic
character of both the triflation and silylation steps
required very slow additions to maintain the temperature
below -70 °C, and during this time significant decom-
position of the unprotected enol triflate 23 occurred.
To bypass the most unstable intermediate 23, we opted
to silylate the secondary alcohol prior to cyclization.
While other bases gave mixtures of N- and O-silylated
products, selective O-silylation of 2 was achieved with
imidazole and TESCl to afford 24 as a crystalline solid.
Rhodium-catalyzed cyclization of 24 gave a solution of
â-keto ester 25 as a 97:3 mixture of â and R epimers at
C-2.
Triflation of 25 was not as straightforward as it was
with 23. The use of Et3N (or other 3° amines) as the base
gave 26 in only 82% HPLC assay yield. On the other
hand, diisopropylamine (or other 2° or 1° amines) gave
initially high yields but poor stability even at -78 °C.
Optimum results were achieved with a combination of 1
equiv of diisopropylamine and 0.35 equiv of Et3N. Under
these conditions, vinyl triflate 26 was formed in 98% yield
with good stability. The reaction can be carried out at
temperatures as high as -40 °C, and scales up without
difficulty.
Cr oss-Cou p lin g Rea ction s. Initial cross-coupling
efforts employed the simple fluorenone boronic acid 14
(Scheme 6). The previously developed conditions (Pd-
(dba)2 and aqueous KOH)9a were successful, with the only
modification being the substitution of DMF for THF
because of the low solubility of 14. The problem with
this method for scale-up is that the product (27) could
not be isolated as a crystalline solid without chromatog-
raphy.
In an attempt to increase its solubility, boronic acid
14 was reacted with 3 equiv of N,O-bis(trimethylsilyl)-
(13) Liu, T. M.-H.; Lynch, J . E.; Volante, R. P. U.S. Pat. 5,493,018,
1996.

Practical Synthesis of Carbapenem L-742,728
J . Org. Chem., Vol. 63, No. 16, 1998 5441
Sch em e 6a
Sch em e 7
Sch em e 8
appended in situ by treatment with bromoacetamide to
give the TBS/pNB-protected L-742,728 (34) in good yield.
Encouraged by the successful coupling of 19, we next
moved to the more ambitious goal of coupling vinyl
triflate 26 with the doubly quaternized boronic acid 20.
This approach initially proved fruitless, primarily due to
the difficult solubility properties of 20 and its borate salts.
As a result of the highly charged character of 20, a
solvent mixture of DMF and water was essential for the
reaction. The countercation of the base was also critical
for success. Lithium carbonate was found to be the best
base, with potassium and cesium carbonates being much
worse. This trend is the opposite of the usual cation
influence observed by us9 and others,15 and it correlates
with borate solubility.
a
(a) Pd2(dba)3‚CHCl3, aqueous KOH, CH2Cl2/DMF. (b) 14 +
BSA; Pd(dba)2, Et3N, H2O, CH2Cl2/THF. (c) pH 4.0, aqueous THF.
(d) n-PrSO2Cl, Et3N, CH2Cl2. (e) NaI, CH3CN. (f) pH 2.2-2.4,
aqueous THF; then pH 6.5, NaOTf, H2O.
acetamide (BSA) in THF.14 The resulting homogeneous
solution of fully silylated material was effective for cross-
coupling with vinyl triflate 26 in CH2Cl2/THF. The TMS-
containing product 28 crystallized well from methanol
and could be isolated without chromatography. However,
the usual cross-coupling conditions employing aqueous
inorganic base caused substantial desilylation of the
fluorenone hydroxymethyl position and so limited the
isolated yield. Milder conditions employing 2 equiv of
Et3N as base and only 2 equiv of water limited the
desilylation and allowed isolation of 28 without chroma-
tography in 80% yield. Subsequent desilylation of 28 at
pH 4.0 gave 27 in high yield.
The alcohol 27 was converted to the final intermediate,
p-nitrobenzyl (pNB)-protected L-742,728 (31), in three
steps via the n-propanesulfonate 29, in greater than 80%
yield. Isolation of intermediates 27 and 30 was difficult
because of poor crystallinity. In addition, this scheme
suffers from multiple steps involving the sensitive car-
bapenem unit.
A further critical factor turned out to be the quantity
of bromide ion; bromide typically constituted a portion
of the counterion to the boronic acid 20. The highest
coupling rate was observed with ca. 0.2 molar equiv of
bromide. Either larger or smaller quantities slowed the
reaction, and no coupling occurred in the absence of
halide.
(14) Silylation of the boronic acid 14 proved not to be a trivial task.
The slow addition of 14 to a solution of BSA in THF at 40 °C was
required to prevent formation of oligomeric boronic esters (a ), which
would give 27 after the coupling and workup.
O
O
To minimize post-coupling elaboration, we next inves-
tigated reaction of the mono-quaternized-DABCO-con-
taining side chain, as the pinacol boronate bromide salt
19 (Scheme 7). Model studies employed the tert-butyl-
dimethylsilyl (TBS)-protected enol triflate 32, which is
stable enough to isolate and need not be generated in
situ. The coupling of 32 and 19 proceeded smoothly in
DMF/CH2Cl2 to give 33. The acetamide moiety was
O
B
OTMS
(TMSO)2B
n
OTMS
a
(15) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.

5442 J . Org. Chem., Vol. 63, No. 16, 1998
Yasuda et al.
6-Br om o-2-m eth yl-9H-flu or en -9-on e (6). To a warm
(80-82 °C) two-phase mixture of a PhCl solution of 5 (29.0 g,
100 mmol, 200 mL) and superphosphoric acid (93 g, 996 mmol)
was added solid NaNO2 (10.3 g, 149 mmol) in 10 equal portions
every 15 min, keeping the reaction temperature at 80-82 °C
with vigorous stirring. After an additional 2 h at 80-82 °C,
the mixture was cooled to 60 °C and diluted with PhCl (55
mL). Water (150 mL) was added to the mixture over a 0.5 h
period, maintaining the temperature at 60 °C. The organic
layer was separated, washed with 5 w/v % aqueous Na2CO3
(150 mL) three times at 60 °C, concentrated in vacuo to a
volume of ca. 170 mL, and diluted with dry PhCl (80 mL) at
60-70 °C. To the hot solution was added 15 g of silica gel at
60-70 °C, and the mixture was stirred for 0.5 h at the same
temperature. The mixture was filtered, and the silica gel cake
was washed with hot (60 °C) PhCl (200 mL). The filtrate and
washings were combined, and the solvent was switched to
n-BuOH. From ca. 150 mL of n-BuOH solution, crystals were
precipitated at 0 °C, filtered, washed with cold n-BuOH (30
mL) followed by cold (0-5 °C) hexane (100 mL), and dried to
With the proper choice of solvents and base, high-
yielding coupling occurred at 30-35 °C. Because the
TES-containing product 30 was difficult to isolate (vide
supra), it was desirable to proceed directly into desilyl-
ation. To do so, it was necessary to change the solvent
to THF and remove the DMF to a level below 0.5%.
Higher amounts of DMF led to unacceptable levels of
â-lactam hydrolysis during desilylation. The CH2Cl2 was
first removed by vacuum distillation. Then THF was
added, and the solution was extracted thoroughly with
aqueous NaCl. Desilylation was carried out by addition
of water and acidifying to pH 2.3 with aqueous TfOH.
When desilylation was complete, 31 was crystallized by
neutralization, addition of NaOTf, and slow addition of
water. This sequence has been carried out on a multi-
kilogram scale, and 31 is typically isolated in a yield of
60% over the four steps from diazo compound 24.
P r ep a r a tion of L-742,728. Removal of the 4-nitro-
benzyl protective moiety from 31 was accomplished by
hydrogenolysis with Pt2O below 10 °C. Purification of
crude 1 was achieved by a chromatography on HP20s16
polystyrene resin. The aqueous eluent was treated with
NaCl followed by acetone, crystallizing 1 as the chloride
salt which was isolated in ca. 65% yield. The highly
crystalline sulfate salt was obtained by addition of
sodium sulfate to an aqueous solution of the chloride salt.
1
give 6 (19.9 g; 73%): mp 159-160 °C; H NMR (CDCl3, 250
MHz) δ 7.56 (d, J ) 1.3 Hz, 1H), 7.47-7.44 (m, 2H), 7.37 (dd,
J ) 7.9, 1.6 Hz, 1H), 7.33 (d, J ) 7.9 Hz, 1H), 7.27 (m, 1H),
2.38 (s, 3H); 13C NMR (CDCl3, 63 MHz) δ 192.9, 146.3, 140.5,
140.2, 135.3, 134.4, 132.9, 131.5, 129.6, 125.4, 125.2, 123.5,
120.4, 21.4; HRMS calcd for
C14H9BrO 271.9836, found
271.9832. Anal. Calcd for C14H9BrO: C, 61.57; H, 3.29.
Found: C, 61.53; H, 3.12.
6-Br om o-2-(br om om eth yl)-9H-flu or en -9-on e (7). To mix-
ture of 6 (50 g, 183 mmol), NBS (35.7 g, 200 mmol), and AcOH
(5.0 mL) in CH2Cl2 (500 mL) was added a solution of VAZO-
5217 (2.5 g; 10 mmol) in CH2Cl2 (100 mL) over a 1 h period,
maintaining reflux temperature. The reaction was completed
in 12 h at reflux. The mixture was heated to reflux for 1 h
with added THF (350 mL). The mixture was cooled to 0 °C.
The product was filtered, washed with a mixture of THF and
CH2Cl2 (1:1) and then THF, and dried to give 7 (57.8 g; 90%)
as yellowish crystals: mp 236-237 °C; 1H NMR (DMF-d7, 70
°C, 400 MHz) δ 8.08 (d, J ) 1.6 Hz, 1H), 7.89 (m, 1H), 7.77-
7.74 (m, 2H), 7.62 (dd, J ) 7.9, 1.6 Hz, 1H), 7.57 (dd, J ) 7.9,
0.6 Hz, 1H), 4.81 (s, 2H); 13C NMR (DMF-d7, 70 °C, 100 MHz)
δ 192.0, 146.6, 143.6, 141.5, 136.7, 135.2, 133.8, 133.1, 130.2,
126.1, 125.4, 125.3, 122.6, 33.7. Anal. Calcd for C14H8Br2O:
C, 47.77; H, 2.29. Found: C, 47.44; H, 2.34.
Con clu sion
The potent antibacterial L-742,728 was synthesized in
31-36% yield over six steps from the diazo intermediate
2. The centerpiece of the synthesis was the highly
complex Suzuki-Miyaura coupling of the dicationic bo-
ronic acid 20 with in situ prepared carbapenem vinyl
triflate 26, a convergent approach which minimized the
number of steps involving unstable carbapenem inter-
mediates.
Exp er im en ta l Section
2-[(Acetoxy)m eth yl]-6-br om o-9H-flu or en -9-on e (8). A
suspension of 7 (1.7 g, 4.8 mmol) and KOAc (580 mg; 5.8 mmol)
in DMF (25 mL) was stirred at 100 °C for 1 h. The reaction
mixture was diluted with EtOAc, washed four times with H2O
and twice with saturated aqueous NaCl, dried over MgSO4,
and chromatographed on a silica gel column to give 8 (1.04 g;
Gen er a l. Reactions were carried out under an atmosphere
of dry N2. Reagents and solvents were dried over 3- or 4-Å
molecular sieves. In many cases, the R-carbon of the boronic
acids could not be observed due to its long relaxation time.
(2-Am in o-5-m e t h ylp h e n yl)(4-b r om op h e n yl)m e t h a -
n on e (5). A precooled (-20 °C) solution of 4-toluidine (4; 19.5
g, 0.182 mol) in dry PhCl (50 mL) was added to precooled (-5
°C) BCl3 (26.0 g, 0.222 mol) in dry PhCl (75 mL) over 5 min,
maintaining the internal temperature below 25 °C. After 1 h
at room temperature, the toluidine-BCl3 complex slurry was
added to a solution of 4-bromobenzonitrile (3; 18.0 g, 99 mmol)
and AlCl3 (15.0 g, 113 mmol) in PhCl (95 mL) at reflux over a
2 h period. After an additional 2 h at 130-134 °C, the mixture
was cooled to 70 °C. The mixture was quenched into the
preheated H2O (300 mL) at 60 °C, rinsing with PhCl (30 mL).
After 1 h at 80-85 °C, the mixture was cooled to 60 °C. The
mixture was diluted with H2O (630 mL) and PhCl (180 mL)
and stirred at 60 °C for 0.5 h. The organic layer was separated
at 60 °C, cooled to 20-25 °C, washed with H2O (250 mL) and
5 w/v % aqueous NaHCO3 (250 mL), and then azeotropically
dried to give a solution of 5 (495 mL, 27.5 g; 96%). This
solution was used directly in the next reaction. Analytically
pure 5 was obtained by crystallization from EtOAc/hexane: mp
111-112 °C; 1H NMR (CDCl3, 250 MHz) δ 7.58 (m, 4H), 7.20-
7.11 (m, 2H), 6.69 (d, J ) 8 Hz, 1H), 2.19 (s, 3H); HRMS calcd
for C14H12BrNO 289.0140, found 289.0102. Anal. Calcd: C,
57.96; H, 4.13; N, 4.82. Found: C, 57.82; H, 4.06; N, 4.80.
1
66%): mp 148-149 °C; H NMR (CDCl3, 250 MHz) δ 7.68-
7.58 (m, 2H), 7.56-7.38 (m, 4H), 5.10 (s, 2H), 2.12 (s, 3H); 13
C
NMR (CDCl3, 63 MHz) δ 192.0, 170.7, 145.6, 142.8, 138.0,
134.5, 134.3, 132.8, 132.1, 129.8, 125.5, 124.0, 123.9, 120.6,
65.4, 20.9. Anal. Calcd for C16H11BrO3: C, 58.03; H, 3.35.
Found: C, 58.08; H, 3.34.
6-Br om o-2-(h yd r oxym eth yl)-9H-flu or en -9-on e (9). To
a suspension of 8 (1.18 g; 3.5 mmol) in a mixture of MeOH
(102 mL) and THF (23 mL) was added 0.054 M NaOMe in
MeOH (6.6 mL, 0.35 mmol) at room temperature. After 1.25
h, the mixture was neutralized with 0.2 M pH 7 phosphate
buffer and concentrated in vacuo. The residual was dissolved
in EtOAc, washed with H2O and saturated aqueous NaCl
successively, dried over MgSO4, and concentrated in vacuo to
1
give 9 (1.00 g; 100%): mp 191-192 °C; H NMR (DMSO-d6,
250 MHz) δ 7.90-7.33 (m, 6H), 5.38 (t, J ) 5.0 Hz, 1H), 4.51
(d, J ) 5.0 Hz, 2H); 13C NMR (DMSO-d6, 63 MHz) δ 191.9,
145.9, 145.1, 141.1, 133.4, 132.9, 132.3, 131.6, 129.2, 125.3,
124.1, 121.9, 121.4, 62.4. Anal. Calcd for C14H9BrO2: C, 58.16;
H, 3.14. Found: C, 57.79; H, 3.30.
6-Br om o-2-(m eth oxym eth yl)-9H-flu or en -9-on e (10). A
slurry of 7 (20 g, 57 mmol) in MeOH (200 mL) was heated in
(17) 2,2′-Azobis(2,4-dimethylvaleronitrile). Trademark of E. I. Du
Pont De Nemours & Co. Inc.
(16) Trademark of Mitsubishi Chemical Co. Ltd.

Practical Synthesis of Carbapenem L-742,728
J . Org. Chem., Vol. 63, No. 16, 1998 5443
the sealed tube at 100 °C for 24 h. The reaction mixture was
used in the next reaction without further purification. Ana-
lytically pure 10 was obtained by filtration of the resulting
slurry: mp 100 °C; 1H NMR (DMSO-d6, 250 MHz) δ 7.93 (d, J
) 1.5 Hz, 1H), 7.69 (d, J ) 7.5 Hz, 1H), 7.49-7.38 (m, 4H),
4.40 (s, 2H), 3.31 (s, 3H); 13C NMR (DMSO-d6, 63 MHz) δ 191.6,
145.6, 141.7, 140.7, 133.9, 133.4, 132.2, 131.8, 129.2, 125.3,
124.3, 122.7, 121.5, 72.8, 57.6. Anal. Calcd for C15H11BrO2:
C, 59.43; H, 3.66. Found: C, 59.27; H, 3.63.
mL toluene solution of 15 (58.4 g; 100%). The solution was
used in the next reaction without further purification. Ana-
lytically pure 15 was isolated by concentration of the solution,
followed by trituration with hexanes: mp 79-80 °C; 1H NMR
(CDCl3, 250 MHz) δ 7.67 (d, J ) 0.7 Hz, 1H), 7.43 (d, J ) 7.8
Hz, 1H), 7.38-7.36 (m, 2H), 7.33 (m, 1H), 7.19 (dd, J ) 7.8,
0.7 Hz, 1H), 3.30 (s, 6H), 2.40 (s, 3H); 13C NMR (CDCl3, 63
MHz) δ 142.3, 142.0, 140.2, 138.8, 135.9, 130.8, 130.0, 125.9,
125.3, 124.1, 123.2, 120.2, 107.4, 51.6, 21.7. Anal. Calcd for
6-Br om o-9,9-d im et h oxy-2-(m et h oxym et h yl)-9H -flu o-
r en e (11). To the slurry of 10 (57 mmol) in MeOH (200 mL)
were added concentrated H2SO4 (4.6 mL, 85.7 mmol) and
CH(OMe)3 (93.5 mL, 855 mmol) under ice-cooling. The
mixture was then heated to reflux (60 °C). The reaction was
completed in 1.5 h and cooled to 10 °C. After addition of Et3N
(47.7 mL; 340 mmol), the mixture was concentrated in vacuo,
diluted with toluene (400 mL), and washed with 1 M aqueous
NaOH (400 mL). The aqueous layer was extracted with
toluene (200 mL). The combined organic phases were washed
with H2O (200 mL) twice and azeotropically dried to give a
toluene solution of 11 (57 mL, 18.2 g; 92%). Analytically pure
11 was isolated as colorless crystals by silica gel column
chromatography in the presence of Et3N: mp 57 °C; 1H NMR
(CDCl3, 250 MHz) δ 7.72 (brs, 1H), 7.59-7.48 (m, 2H), 7.46-
7.33 (m, 3H), 4.51 (s, 2H), 3.42 (s, 3H), 3.33 (s, 6H); 13C NMR
(CDCl3, 63 MHz) δ 142.0, 141.8, 140.5, 139.0, 138.0, 130.4,
129.4, 125.9, 124.1, 123.9, 123.4, 120.3, 107.3, 74.4, 58.2, 51.6.
Anal. Calcd for C17H17BrO3: C, 58.47; H, 4.91. Found: C,
58.47; H, 4.57.
C
16H15BrO2: C, 60.21; H, 4.74. Found: C, 60.19; H, 4.79.
(2-Meth yl-9-oxo-9H-flu or en -6-yl)bor on ic Acid (16). To
the solution of 15 (58.4 g, 183 mmol) in toluene (150 mL) were
added B(O-i-Pr)3 (62 mL, 265 mmol) and dry THF (550 mL).
To this solution was slowly added n-BuLi solution in hexanes
(1.6 M, 160 mL, 256 mmol) over a 3-7 h period, maintaining
the temperature below -70 °C. The reaction was completed
in 0.5 h after completion of addition. The mixture was warmed
to 15 °C and slowly poured into aqueous 1 M KOH (600 mL)
at about 20 °C. The mixture was washed with t-BuOMe (200
mL) and filtered through a medium sintered glass funnel. To
the filtrate, diluted with i-PrOH (200 mL), was added 1 M
aqueous H2SO4 (ca. 550 mL), keeping the temperature at 55-
60 °C, until the pH became 3-4. After 2 h at 55-60 °C, the
resulting slurry was aged at 15-20 °C. Crystals were filtered,
washed with water, and dried to give 16 (43.0 g; 98%) as
yellowish crystals: mp >250 °C; 1H NMR (DMSO-d6, 250 MHz)
δ 8.37 (s, 2H), 8.02 (s, 1H), 7.74 (d, J ) 7.4 Hz, 1H), 7.61 (m,
1H), 7.52 (d, J ) 7.4 Hz, 1H), 7.42-7.35 (m, 2H), 2.32 (s, 3H);
13C NMR (DMSO-d6, 63 MHz) δ 193.7, 142.9, 141.8, 139.1,
135.8, 134.9, 134.7, 133.7, 125.8, 124.6, 122.8, 120.7, 20.9.
[2-(Meth oxym eth yl)-9-oxo-9H-flu or en -6-yl]bor on ic Acid
(12). Compound 12 was prepared from 11 by the method
described for 16 in typically 95-99% yield. Analytically pure
12 was obtained by recrystallization from hot aqueous DMF:
Anal. Calcd for
Found: C, 69.60; H, 4.89.
C14H11BO3‚0.25H2O: C, 69.33; H, 4.78.
2-(Br om om eth yl)-6-(4,4,5,5-tetr am eth yl-1,3,2-dioxabor o-
la n -2-yl)-9H-flu or en -9-on e (18). A suspension of 16 (23.8
g, 100 mmol) and pinacol (12.0 g, 101 mmol) in PhCl (560 mL)
was heated and distilled until the reaction temperature
increased to ca. 133 °C. The mixture was then heated at reflux
for a 1 h period to give a solution of pinacol ester 17. To the
resulting solution were added AcOH (1.05 g, 17 mmol),
dibromodimethylhydantoin (14.8 g, 52 mmol), and VAZO-52
(1 g, 4 mmol) at 20 °C. The mixture was heated at 37-39 °C.
The reaction was completed in 15-20 h. The mixture was
cooled to 0 °C and aged for 1 h. The precipitates were filtered
and washed with cold PhCl (50 mL). The filtrate and washings
were combined, concentrated to ca. 100 mL in vacuo, and
diluted with hexanes (500 mL). The slurry was stirred at 0-5
°C for 4 h. The precipitate was filtered, washed with hexanes
(100 mL), and dried in vacuo to give 18 (35.5 g; 89% based on
HPLC purity). This compound was a mixture of 2-methyl,
2-dibromomethyl, and 18. The typical purity of 18 was 90 wt
% and it was used in the next reaction without further
purification: mp 147-150 °C; 1H NMR (DMSO-d6, 250 MHz)
δ 7.98 (s, 1H), 7.87 (m, 1H), 7.68-7.63 (m, 3H), 7.57 (dd, J )
7.3, 0.6 Hz, 1H), 4.76 (s, 2H), 1.32 (s, 12H); 13C NMR (DMSO-
d6, 63 MHz) δ 192.6, 143.7, 142.6, 139.6, 136.3, 136.0, 135.8,
133.7, 126.5, 124.7, 123.2, 121.7, 84.2, 33.7, 24.7. Anal. Calcd
for C20H20BBrO3: C, 60.19; H, 5.05. Found: C, 60.57; H, 4.99.
1-[[9-Oxo-6-(4,4,5,5-t et r a m et h yl-1,3,2-d ioxa b or ola n -2-
yl)-9H-flu or en -2-yl]m eth yl]-4-a za -1-a zon ia bicyclo[2.2.2]-
octa n e Br om id e (19). To a slurry of 18 (2.0 g, 4.5 mmol, 90
wt %) in t-BuOMe (25 mL) was added a solution of DABCO
(0.60 g; 5.35 mmol) in MeOH (10 mL) at room temperature.
After 2 h at room temperature, the solid was filtered, washed
with t-BuOMe (10 mL) twice, and dried to give 19 (2.07 g; 92%)
as yellowish solid: mp >250 °C; 1H NMR (DMSO-d6, 250 MHz)
δ 8.14-8.03 (m, 2H), 7.83-7.74 (m, 2H), 7.73 (d, J ) 7.5 Hz,
1H), 7.64 (d, J ) 7.5 Hz, 1H), 4.69 (s, 2H), 3.51-3.27 (m, 6H),
3.15-2.91 (m, 6H), 1.33 (s, 12H); 13C NMR (DMSO-d6, 63 MHz)
δ 192.6, 145.4, 142.3, 140.5, 136.5, 135.7, 133.6, 128.6, 128.5,
126.8, 123.4, 122.0, 84.3, 65.4, 51.5, 44.7, 24.7.
1
mp 249-251 °C (dec); H NMR (DMSO-d6, 250 MHz) δ 8.41
(s, 2H, exchangeable with D2O), 8.05 (s, 1H), 7.76 (d, J ) 7.4
Hz, 1H), 7.66 (d, J ) 7.4 Hz, 1H), 7.54-7.47 (m, 3H), 4.39 (s,
2H), 3.28 (s, 3H); 13C NMR (DMSO-d6, 63 MHz) δ 193.3, 143.6,
142.6, 139.9, 135.2, 134.8, 134.3, 133.6, 126.1, 122.9, 122.8,
120.7, 72.9, 57.7. Anal. Calcd for C15H13BO4: C, 67.21; H,
4.89. Found: C, 67.01; H, 4.87.
[2-(Hydr oxym eth yl)-9-oxo-9H-flu or en -6-yl]bor on ic Acid
(14). A solution of 12 (70.8 g, 264 mmol) in TFA (710 mL)
was heated to reflux for 36 h to give a solution of trifluoro-
acetate 13. The solution was concentrated, diluted with H2O
(500 mL), and concentrated again. The residue was dissolved
in THF (1.5 L) and 1 M aqueous NaOH (1 L) and stirred at
room temperature for 1 h. Sodium salts were precipitated out
by addition of THF (1.85 L) followed by aging at 5 °C overnight.
The precipitates were filtered at 0 °C and washed with THF
(1.1 L). The resulting solid was dissolved in a mixture of
MeOH (550 mL) and H2O (2.2 L). Insoluble material was
filtered off. The filtrate was adjusted to pH 1.8 with 2 M
aqueous HCl at room temperature and stirred at 5 °C. The
precipitates were collected by filtration at 5 °C, washed with
H2O (1 L), and dried at 80 °C in vacuo to give 14 (60.3 g; 90.0%)
as a yellowish crystalline solid: mp > 250 °C; 1H NMR (DMSO-
d6, 250 MHz) δ 8.41 (s, 2H), 8.06 (s, 1H), 7.75 (d, J ) 7.7 Hz,
1H), 7.68 (d, J ) 7.7 Hz, 1H), 7.56-7.52 (m, 3H), 5.42 (t, J )
5.7 Hz, 1H), 4.52 (d, J ) 5.7 Hz, 2H); 13C NMR (DMSO-d6, 63
MHz) δ 193.5, 144.3, 142.9, 142.8, 135.1, 134.8, 133.5, 133.2,
125.9, 122.8, 122.0, 120.6, 62.3. Anal. Calcd for C14H11BO4:
C, 66.19, H, 4.36. Found: C, 65.95; H, 4.44.
6-Br om o-9,9-d im eth oxy-2-m eth yl-9H-flu or en e (15). To
a solution of 6 (50 g, 183 mmol) in MeOH (500 mL) were added
concentrated H2SO4 (15 mL, 274 mmol) and CH(OMe)3 (300
mL, 2.7 mol) sequentially at 0-5 °C. The mixture was heated
at reflux (56-58 °C) until the reaction was completed (typically
1.5-2.5 h). After the reaction mixture was cooled to 10 °C,
Et3N (153 mL, 1.1 mol) was added to the mixture, maintaining
the temperature below 20 °C. The solution was concentrated
in vacuo to ca. 225 mL. The mixture was diluted with toluene
(1 L), and 1 M aqueous NaOH (1 L) was added. The organic
layer was separated. The aqueous layer was extracted with
toluene (0.5 L). The combined organic solution was washed
with water (250 mL) and azeotropically dried to give a 150
1-(2-Am in o-2-oxoet h yl)-4-a za -1-a zon ia b icyclo[2.2.2]-
octa n e Tr iflu or om eth a n esu lfon a te (21). To a precooled
(5 °C) solution of DABCO (12.3 g, 0.11 mol) in MeCN (65 mL)
was added a solution of 2-chloroacetamide (9.35 g, 0.10 mol)

5444 J . Org. Chem., Vol. 63, No. 16, 1998
Yasuda et al.
in MeCN (210 mL) over a 0.5-2 h period, keeping the
temperature below 15 °C. The reaction was completed at 20-
25 °C in 8-10 h. The slurry was filtered, washed with MeCN
(100 mL), and dried to give the chloride salt (20.0 g; 97%): 1H
NMR (D2O, 250 MHz) δ 4.13 (s, 2H), 3.71 (t, J ) 7.4 Hz, 6H),
3.26 (t, J ) 7.4 Hz, 6H); 13C NMR (CD3OD, 63 MHz) δ 166.7,
63.5, 54.3, 46.0. The chloride salt (11.3 g, 55 mmol) was added
portionwise to a solution of NaOTf (9.9 g, 57 mmol) in MeCN
(180 mL) at 20 °C. After 2-4 h at 40-45 °C, the mixture was
filtered through Solka Floc, rinsing with MeCN (20 mL) at 40
°C. The filtrate and washings were combined to obtain a
solution of 21 (96-98%) in MeCN and used for the next
reactions. Analyticaly pure 21 was obtained by crystallization
from EtOH: mp 174-175 °C; 1H NMR (D2O, 250 MHz) δ 4.04
(s, 2H), 3.65 (t, J ) 7.5 Hz, 6H), 3.22 (t, J ) 7.5 Hz, 6H); 13C
NMR (CD3OD, 63 MHz) δ 166.6, 121.8 (q, J ) 319 Hz), 63.3,
54.3, 45.9. Anal. Calcd for C9H16F3N3O4S: C, 33.85; H, 5.05;
N, 13.16. Found: C, 34.00; H, 5.03; N, 13.15.
alcohol 2 (20.0 g, 51.2 mmol) in dry CH2Cl2 (200 mL) was
heated to reflux for 4 h in the presence of rhodium octanoate
(199 mg, 0.26 mmol) and ZnBr2 (118 mg, 0.52 mmol) and then
cooled to -78 °C. To this solution were added Et3N (6.82 mL,
48.9 mmol) and Tf2O (48.9 mmol) keeping the reaction tem-
perature below -73 °C. After 30 min at -78 °C, Et3N (7.85
mL, 56.4 mmol) and TESOTf (12.7 mL, 56.4 mmol) were
sequentially added, again below -73 °C to give a solution of
triflate 26. After the mixture was stirred an additional 1 h at
-78 °C, a solution of boronic acid 14 (13.0 g; 51.2 mmol) in
DMF (110 mL) was added to the cold mixture, followed by
Pd2(dba)3‚CHCl3 (1.08 g, 1.04 mmol) and 6 M aqueous KOH
(25.6 mL, 153.6 mmol). The reaction mixture was then
warmed to 30 °C. After 1 h at 30-35 °C, the mixture was
cooled and diluted with EtOAc (300 mL). The precipitate was
filtered, and the mixture was concentrated to ca. 200 mL. The
solution was diluted with EtOAc (300 mL) and washed with
H2O (300 mL). The aqueous layer was back extracted with
EtOAc (50 mL). The organic extracts were combined, dried
over MgSO4, and purified by silica gel column chromatography
(1.5 L; EtOAc:hexanes from 37:63 to 50:50) to give 27 (26.6 g,
containing 2.5 wt % EtOAc; 77%) as amorphous solid. Ana-
lytically pure 27 was obtained by crystallization from a
mixture of t-BuOMe and heptane: mp 85-87 °C; 1H NMR
(CDCl3, 250 MHz) δ 7.92 (m, 2H), 7.57-7.50 (m, 2H), 7.43-
7.24 (m, 5H), 7.15 (dd, J ) 7.5, 1.1 Hz, 1H), 5.19 (d, J ) 13.5
Hz, 1H), 5.08 (d, J ) 13.5 Hz, 1H), 4.63 (s, 2H), 4.40 (dd, J )
10.3, 3.0 Hz, 1H), 4.33-4.22 (m, 1H), 3.52-3.34 (m, 2H), 3.10
(br, 1H), 1.26 (d, J ) 6.1 Hz, 3H), 1.10 (d, J ) 7.3 Hz, 3H),
0.93 (t, J ) 7.2 Hz, 9H), 0.63-0.54 (m, 6H); 13C NMR (CDCl3,
63 MHz) δ 192.8, 175.1, 160.0, 148.7, 147.1, 143.7, 143.1, 142.5,
141.9, 139.7, 134.1, 133.9, 132.9, 128.8, 128.2, 127.2, 123.6,
123.2, 122.6, 121.0, 120.1, 65.5, 65.3, 64.0, 60.6, 55.5, 44.1, 22.3,
15.5, 6.6, 4.7. Anal. Calcd for C37H40N2O8Si: C, 66.45; H, 6.03;
N, 4.19. Found: C, 66.12; H, 6.18; N, 4.05.
1-(2-Am in o-2-oxoeth yl)-4-[(6-bor on o-9-oxo-9H-flu or en -
2-yl)m eth yl]-1,4-d ia zon ia bicyclo[2.2.2]octa n e Br om id e
Tr iflu or om eth a n esu lfon a te (20). A slurry of 21 (17.6 g, 55
mmol), 18 (20 g, 45 mmol; 90 wt %) in MeCN (200 mL), and
MeOH (200 mL) was stirred at 28-30 °C for 12-15 h. To the
mixture was added 0.5 M aqueous KOTf (200 mL, 100 mmol)
over 1 h at 20-25 °C. The mixture was concentrated in vacuo
to ca. 400 mL. After water (300 mL) was added, the mixture
was further concentrated to ca. 250 mL. The product was
precipitated out at 20 °C, filtered, washed with 0.2 M aqueous
LiOTf (50 mL, 100 mmol), and dried. A slurry of the crude
product in t-BuOMe (200 mL) was refluxed for 20 min and
cooled to 20 °C. The mixture was filtered, washed with
t-BuOMe (200 mL), and dried to give 20 (27.3 g; 95%): mp
1
>250 °C; H NMR (DMSO-d6 + D2O, 250 MHz) δ 8.13 (brs,
1H), 7.90 (d, J ) 8.2 Hz, 1H), 7.81 (dd, J ) 7.4, 1.2 Hz, 1H),
7.78-7.72 (m, 2H), 7.62 (d, J ) 7.4 Hz, 1H), 4.79 (s, 2H), 4.27
(s, 2H), 4.16-4.00 (m, 6H), 4.00-3.85 (m, 6H); 13C NMR
(DMSO-d6 + D2O, 63 MHz) δ 193.5, 164.8, 147.0, 143.2 (br),
142.5, 140.9, 136.8, 135.3, 134.6, 128.8, 127.4, 127.2, 123.9,
122.3, 121.0 (q, J ) 321 Hz), 67.0, 62.1, 52.1, 50.7. Anal. Calcd
for C23H26BBrF3N3O7S‚0.5H2O: C, 42.81; H, 4.22; N, 6.51; S,
4.97. Found: C, 42.67; H, 4.09; N, 6.26; S, 4.74. The bis
triflate salt was prepared by treatment with AgOTf followed
by crystallization from MeOH: mp >250 °C; 1H NMR (DMSO-
d6, 250 MHz) δ 8.44 (brs, 2H), 8.20 (s, 1H), 8.00 (brs, 1H), 7.95
(d, J ) 7.4 Hz, 1H), 7.89-7.79 (m, 2H), 7.78-7.68 (m, 2H),
7.64 (d, J ) 7.4 Hz, 1H), 4.79 (s, 2H), 4.29 (s, 2H), 4.07 (m,
6H), 3.91 (m, 6H); 13C NMR (DMSO-d6, 63 MHz) δ 192.8, 164.6,
146.4, 142.0, 140.3, 136.2, 134.8, 134.1, 128.3, 127.4, 126.9,
123.2, 121.7, 120.7 (q, J ) 319 Hz), 66.3, 61.5, 51.5, 50.2.
(4-Nitr op h en yl)m eth yl [2R-[2r(R*),3â(R*)]]-r-Dia zo-γ-
m et h yl-â,4-d ioxo-3-[1-[(t r iet h ylsilyl)oxy]et h yl]-2-a zet i-
d in ebu ta n oa te (24). To a vigorously stirred solution of
alcohol 2 (15.0 g, 38.4 mmol) and imidazole (4.7 g, 69.0 mmol)
in a mixture of i-PrOAc (90 mL) and THF (20 mL) was slowly
added TESCl (9.0 mL, 53.6 mmol), maintaining a temperature
of 18-22 °C. After being stirred for 2 h at 20 °C, the mixture
was poured into a mixture of heptane (30 mL) and 0.01 M
phosphate buffer (100 mL; pH 6.8) at room temperature. The
organic layer was separated and washed with 0.01 M phos-
phate buffer three times. The organic solution was concen-
trated and 24 was isolated from a mixture of heptane (ca. 97%)
and i-PrOAc (ca. 3%) at 0 °C as crystalline solid (18.0 g; 93%):
(4-Nitr op h en yl)m eth yl [4S-[4r,5â,6â(S*)]]-4-Meth yl-7-
oxo-3-[9-oxo-2-[[(tr im eth ylsilyl)oxy]m eth yl]-9H-flu or en -
6-yl]-6-[1-[(t r iet h ylsilyl)oxy]et h yl]-1-a za b icyclo[3.2.0]-
h ep t a n -2-ca r b oxyla t e (28). To
a solution of bis(tri-
methylsilyl)acetamide (BSA) (1.485 kg, 7.30 mol) in THF (15
L) was added 14 (996 g, 3.92 mol) in 10-20 portions over 2 h.
The resulting solution was stirred at 35 °C for 30 min and
then cooled to 0 °C. Simultaneously, a solution of 26 was
prepared from 2 (1.50 kg, 3.84 mol) by Rh(II)-catalyzed
cyclization (14.9 g of rhodium octanoate, 8.85 g of ZnCl2, 15 L
of CH2Cl2) followed by the sequential additions of Et3N (536
mL, 3.84 mol), Tf2O (646 mL, 3.84 mol), Et3N (669 mL, 4.80
mol), and TESOTf (956 mL, 4.23 mol) as described in the above
example. The THF solution of silylated 14 was added to the
-78 °C solution of 26. To the resulting -40 °C mixture were
added H2O (138 mL, 7.68 mol), Pd(dba)2 (66.3 g, 115 mmol),
and Et3N (1.02 L, 7.30 mol), and the solution was warmed to
30 °C. When the reaction was complete (2-3 h), the solution
was cooled to room temperature. The mixture was diluted
with hexanes (9 L) and washed with aqueous NaCl twice. The
solution was filtered through Solka Floc. The solvent was then
evaporated with concurrent addition of methanol (final volume
6 L), inducing crystallization. The crystals were filtered and
dried to give 28 (2.0 kg; 70%). On a smaller scale (20 g) this
procedure gave a somewhat higher yield of 81%: mp 142-
145 °C; 1H NMR (CDCl3, 250 MHz) δ 8.04 (m, 2H), 7.64-7.58
(m, 2H), 7.47-7.32 (m, 5H), 7.19 (dd, J ) 7.5, 1.3 Hz, 1H),
5.27 (d, J ) 13.6 Hz, 1H), 5.13 (d, J ) 13.6 Hz, 1H), 4.69 (s,
2H), 4.41 (dd, J ) 10.3, 3.1 Hz, 1H), 4.37-4.25 (m, 1H), 3.52-
3.40 (m, 1H), 3.37 (dd, J ) 5.8, 3.1 Hz, 1H), 1.29 (d, J ) 6.2
Hz, 3H), 1.12 (d, J ) 7.4 Hz, 3H), 0.96 (t, J ) 7.9 Hz, 9H),
0.67-0.56 (m, 6H), 0.17 (s, 9H); 13C NMR (CDCl3, 63 MHz) δ
192.9, 175.1, 160.1, 148.9, 147.5, 144.1, 143.1, 142.6, 142.2,
139.7, 134.4, 134.3, 132.6, 128.9, 128.3, 127.3, 123.9, 123.5,
122.5, 120.9, 120.2, 65.8, 65.4, 63.9, 60.9, 55.7, 44.3, 22.5, 15.7,
6.8, 4.9, -0.5. Anal. Calcd for C40H48N2O8Si2: C, 64.84; H,
6.53; N, 3.78. Found: C, 64.84; H, 6.59; N, 3.65.
1
mp 64 °C; H NMR (CDCl3, 250 MHz) δ 8.22 (d, J ) 8.6 Hz,
2H), 7.52 (d, J ) 8.6 Hz, 2H), 6.14 (s, 1H), 5.33 (s, 2H), 4.20-
4.07 (m, 1H), 3.94-3.81 (m, 2H), 2.92 (dd, J ) 4.9, 1.5 Hz,
1H), 1.18 (d, J ) 6.3 Hz, 3H), 1.14 (d, J ) 6.6 Hz, 3H), 0.90 (t,
J ) 7.9 Hz, 9H), 0.60-0.50 (m, 6H); 13C NMR (CDCl3, 63 MHz)
δ 194.1, 168.2, 160.6, 147.9, 141.9, 128.7, 123.9, 76.0, 65.5, 65.2,
61.2, 51.9, 43.3, 22.6, 12.3, 6.7, 4.8. Anal. Calcd for C23H32N4O7-
Si: C, 54.75; H, 6.39; N, 11.10. Found: C, 54.65; H, 6.32; N,
11.07.
(4-Nitr op h en yl)m eth yl [4S-[4r,5â,6â(S*)]]-4-Meth yl-7-
oxo-3-[2-(h ydr oxym eth yl)-9-oxo-9H-flu or en -6-yl]-6-[1-[(tr i-
eth ylsilyl)oxy]eth yl]-1-a za bicyclo[3.2.0]h ep ta n -2-ca r box-
yla te (27). Cou p lin g of 26 a n d 14. A solution of the diazo
Com p ou n d 27, fr om Desilyla tion of 28. A solution of
28 (3.45 kg, 4.66 mol) in a mixture of THF (55.2 L) and 0.05
M phthalic acid potassium acid salt aqueous solution (22.1 L;

Practical Synthesis of Carbapenem L-742,728
J . Org. Chem., Vol. 63, No. 16, 1998 5445
pH 4.0) was stirred at room temperature for 16 h. To the
solution was added solid NaCl (5.52 kg); the resulting organic
layer was separated and washed with saturated aqueous
NaHCO3 (22 L) followed by saturated aqueous NaCl (22 L).
The organic layer was concentrated in vacuo to about 4 L. The
solution was diluted with t-BuOMe (50 L) and washed with
2.5 wt % aqueous NaCl (22 L). Further concentration of the
organic layer gave a solution in t-BuOMe (20 L). Compound
27 was crystallized by the addition of heptane (60 L). Filtra-
tion and drying gave 2.90 kg, 93%.
(4-Nitr op h en yl)m eth yl [4S-[4r,5â,6â(S*)]]-4-Meth yl-7-
oxo-3-[9-oxo-2-[[(p r op ylsu lfon yl)oxy]m eth yl]-9H-flu or en -
6-yl]-6-[1-[(tr ieth ylsilyl)oxy]eth yl]-1-azabicyclo[3.2.0]h ept-
2-en e-2-ca r boxyla te (29). To a -20 °C solution of 27 (1.4
kg, 2.09 mol) in dry CH2Cl2 (14 L) were added Et3N (0.321 L,
2.30 mol) and n-PrSO2Cl (0.235 L, 2.09 mol). After 30 min at
-20 °C, the reaction solution was added to 0.25 M MOPS
buffer at pH 6.8 (14 L). The organic layer was separated, dried
over Na2SO4, and concentrated in vacuo to ca. 7 L. By addition
of MeCN and vacuum concentration, the mixture was con-
verted to a solution in 14 L of MeCN and used directly for the
next reaction. Alternatively, by evaporation of the CH2Cl2, 29
could be isolated as an amorphous solid: 1H NMR (CDCl3, 250
MHz) δ 7.95 (brd, J ) 8.6 Hz, 2H), 7.60-7.53 (m, 2H), 7.48-
7.32 (m, 5H), 7.21 (m, 1H), 5.22 (d, J ) 13.6 Hz, 1H), 5.15 (s,
2H), 5.08 (d, J ) 13.6 Hz, 1H), 4.40 (dd, J ) 10.3, 3.0 Hz, 1H),
4.27 (m, 1H), 3.47 (dq, J ) 10.3, 7.4 Hz, 1H), 3.37 (dd, J ) 5.5,
3.0 Hz, 1H), 3.12-3.02 (m, 2H), 1.84 (m, 2H), 1.25 (d, J ) 6.1
Hz, 3H), 1.10 (d, J ) 7.4 Hz, 3H), 0.99 (t, J ) 7.5 Hz, 3H),
0.92 (t, J ) 7.9 Hz, 9H), 0.64-0.51 (m, 6H); 13C NMR (CDCl3,
63 MHz) δ 191.8, 174.9, 159.9, 148.3, 147.1, 144.1, 143.1, 142.1,
139.9, 135.2, 134.7, 134.4, 133.8, 129.4, 128.1, 127.3, 124.0,
123.7, 123.2, 121.4, 120.5, 69.7, 65.5, 65.2, 60.7, 55.4, 52.4, 44.0,
[4S-[4r,5â,6â(S*)]]-1-(2-Am in o-2-oxoeth yl)-4-[[6-[4-m eth -
yl-2-[[[(4-n it r op h en yl)m et h yl]oxy]ca r b on yl]-7-oxo-6-[1-
[[1,1-dim eth yleth yl)dim eth ylsilyl]oxy]eth yl]-1-azabicyclo-
[3.2.0]h ep t-2-en -3-yl]-9-oxo-9H-flu or en -2-yl]m eth yl]-1,4-
d ia za n ia bicyclo[2.2.2]octa n e (34). To a solution of vinyl
triflate 32 (304 mg, 0.50 mmol), prepared from 2 by a method
similar to that described for the preparation of 26, and pinacol
boronate 19 (256 mg, 0.50 mmol) in a mixture of CH2Cl2 (2
mL) and DMF (1.1 mL) was added Pd(dba)2 (12 mg, 0.02 mmol)
and 3 M aqueous K2CO3 (0.333 mL, 1 mmol). The mixture
was stirred at 32 °C for 2.5 h to give a solution of DABCO salt
33. To this reaction mixture was added bromoacetamide (83
mg, 0.6 mmol), and the mixture was stirred at 32 °C for 1.5 h.
The mixture was then stirred at room temperature overnight
with additional bromoacetamide (24 mg, 0.17 mmol). The
reaction mixture was filtered and diluted with THF to 25 mL.
Analysis by HPLC indicated the presence of 34 (0.41 mmol,
82%). HPLC assay: Inertsil ODS 4.6 × 250 mm; MeCN:0.02
M HNEt3OAc buffer (pH 4.5); 50:50 for 0-5 min; 50:50 to 90:
10 over 5-15 min; 90:10 for 15-25 min; flow rate 1.0 mL/
min; UV detection at 254 nm; tR(32) ) 24 min; tR(33) ) 16.3
min; tR(34) ) 11.7 min. An authentic sample of 34 was
prepared as the propanesulfonate trifluoromethanesulfonate
salt from coupling 32 with 14, followed by conversion to 34 by
the same sequence used to make 30 from 27. Amorphous
solid: 1H NMR (acetone-d6 + D2O) δ 7.88 (d, J ) 8.6 Hz, 2H),
7.84-7.69 (m, 2H), 7.67-7.58 (m, 2H), 7.50-7.40 (m, 3H), 7.31
(d, J ) 7.7 Hz, 1H), 5.19 (d, J ) 7.7 Hz, 1H), 5.08 (d, J ) 7.7
Hz, 1H), 4.95 (brs, 2H), 4.50 (brs, 2H), 4.47-4.12 (m, 14H),
3.64-3.43 (m, 2H), 2.68 (m, 2H), 1.63 (m, 2H), 1.15 (d, J ) 6.0
Hz, 3H), 1.04 (d, J ) 7.0 Hz, 3H), 0.84 (t, J ) 7.5 Hz, 3H),
0.77 (s, 9H), 0.01 (s, 6H); 13C NMR (acetone-d6 + D2O) δ 193.0,
176.5, 165.3, 160.7, 149.0, 147.5, 146.4, 143.4, 143.3, 141.4,
141.0, 134.9, 133.8, 131.0, 129.0, 128.7, 127.7, 127.4, 124.3,
123.6, 123.0, 122.6, 120.8 (q, J ) 319 Hz), 68.0, 65.8, 65.5,
62.7, 61.0, 55.2, 53.6, 52.7, 51.3, 44.1, 25.8, 21.9, 18.6, 18.1,
22.2, 17.0, 15.5, 12.6, 6.6, 4.7. Anal. Calcd for C40H46N2O10
-
SSi: C, 62.00; H, 5.98, N, 3.61, S, 4.14. Found: C, 62.05; H,
6.03; N, 3.59; S, 4.30.
15.6, 13.2, -4.5, -5.2. Anal. Calcd for C45H55N5O8Si2+
‚
[4S-[4r,5â,6â(S*)]]-1-(2-Am in o-2-oxoeth yl)-4-[[6-[4-m eth -
yl-2-[[[(4-n it r op h en yl)m et h yl]oxy]ca r b on yl]-7-oxo-6-[1-
[(tr ieth ylsilyl)oxy]eth yl]-1-a za bicyclo[3.2.0]h ep t-2-en -3-
yl]-9-oxo-9H -flu or en -2-yl]m et h yl]-1,4-d ia za n ia b icyclo-
[2.2.2]oct a n e 1-P r op a n esu lfon a t e Tr iflu or om et h a n e-
su lfon a te (30). To a solution of 29 (containing 2.09 mol) in
MeCN (14 L) were added 21 (801 g, 2.51 mol) and NaI (16 g,
0.11 mol). The solution was stirred at 28-29 °C for 20 h in
the dark. To the resulting suspension was added t-BuOMe
(14 L). The solids were collected by filtration, washed with
t-BuOMe, and dried to give crude 30 (2.19 kg, 93%). This solid
was used for the next reaction without further purification:
1H NMR (acetone-d6 + D2O, 250 MHz) δ 8.00-7.57 (m, 6H),
7.57-7.28 (m, 4H), 5.18 (d, J ) 13.4 Hz, 1H), 5.08 (d, J ) 13.4
Hz, 1H), 4.95 (brs, 2H), 4.63-4.02 (m, 16H), 3.66-3.39 (m,
2H), 2.65 (m, 2H), 1.62 (m, 2H), 1.16 (d, J ) 6.4 Hz, 3H), 1.03
(d, J ) 7.1 Hz, 3H), 0.98-0.74 (m, 12H), 0.64-0.43 (m, 6H);
13C NMR (acetone-d6 + D2O, 63 MHz) δ 193.0, 176.3, 165.3,
160.7, 149.1, 147.5, 146.4, 143.4, 143.3, 141.4, 141.0, 134.9,
133.9, 131.1, 129.0, 128.7, 127.7, 127.4, 124.4, 123.6, 122.9,
122.6, 120.8 (q, J ) 319 Hz), 68.0, 65.8, 65.6, 62.7, 61.0, 55.4,
53.6, 52.7, 51.3, 44.2, 22.0, 18.6, 15.6, 13.2, 6.8, 5.0. Anal.
Calcd for C49H62F3N5O14S2Si: C, 53.78; H, 5.71; N, 6.40; S, 5.86.
Found: C, 53.62; H, 5.79; N, 6.31; S, 5.94.
1.3CF3O3S-‚0.7C3H7O3S-: C, 52.75; H, 5.48; N, 6.35; S, 5.82.
Found: C, 52.50; H, 5.24; N, 6.32; S, 5.70.
P r ep a r a tion of 31 fr om 24 a n d 20. A mixture of 24 (30.0
g; 59.5 mmol), rhodium octanoate (0.23 g; 0.30 mmol), and
ZnBr2 (0.13 g; 0.60 mmol) in CH2Cl2 (120 mL) was heated to
reflux under nitrogen for 90 min. The resulting solution of
25 was cooled to -50 °C, and to it was added a mixture of
diisopropylamine (7.79 mL, 59.5 mmol) and Et3N (2.90 mL,
20.8 mmol) dropwise. After 15 min, Tf2O (10.5 mL, 62.4 mmol)
was added, maintaining the reaction temperature below -40
°C, and the mixture was stirred at this temperature for 1 h to
give a solution of 26. Simultaneously, boronic acid 20 (33.9
g, 52.9 mmol) and Li2CO3 (6.26 g, 84.7 mmol) were suspended
in a mixture of DMF (184 mL) and H2O (74 mL) at 30 °C. To
this suspension was added the cold mixture containing 26,
rinsing with DMF (30 mL). The combined reaction mixture
was warmed to 30 °C after addition of Pd(dba)2 (1.30 g, 2.26
mmol). The reaction was typically complete in 8 h. The
CH2Cl2 was removed from the reaction mixture in vacuo. The
mixture was filtered through Solka Floc, rinsing with 1:1 DMF/
H2O (43 mL). After dilution with THF (300 mL), the solution
was washed three times with 20 wt % aqueous NaCl, with THF
being added before the second and third washing. The solution
was concentrated in vacuo to give 265 mL of 90:10 THF/water
containing 50.4 mmol of 30. After addition of water (96 mL),
the pH of the solution was adjusted to 2.4 with 1.0 M aqueous
TfOH at room temperature. After 1 h of stirring, the pH was
readjusted to 5 with 1.0 M. aqueous NaHCO3. Aqueous
NaOTf (45 mL of 2.0 M) was then added, and the pH was
adjusted to 6.5. Addition of water (554 mL) induced crystal-
lization. After 8 h of stirring at room temperature and 2 h at
5 °C, the mixture was filtered and the crystals were washed
with water followed by MeOH. Vacuum drying gave 31 (36.8
g; 94 wt %; 58% overall yield): 1H NMR (acetone-d6 + D2O,
250 MHz) δ 7.85-7.72 (m, 4H), 7.68 (d, J ) 7.7 Hz, 1H), 7.58
(brs, 1H), 7.50 (d, J ) 7.7 Hz, 1H), 7.32-7.24 (m, 3H), 5.11 (d,
J ) 13.1 Hz, 1H), 5.04 (d, J ) 13.1 Hz, 1H), 4.96 (brs, 2H),
4.49 (brs, 2H), 4.47-4.34 (m, 7H), 4.28-4.19 (m, 6H), 4.14 (q,
[4S-[4r,5â,6â(S*)]]-1-(2-Am in o-2-oxoet h yl)-4-[[6-[6-(1-
h yd r oxyeth yl)-4-m eth yl-2-[[[(4-n itr op h en yl)m eth yl]oxy]-
ca r bon yl]-7-oxo-1-a za bicyclo[3.2.0]h ep t-2-en -3-yl]-9-oxo-
9H -flu o r e n -2-y l]m e t h y l]-1,4-d ia za n ia b ic y c lo [2.2.2]-
octa n e 1-P r op a n esu lfon a te Tr iflu or om eth a n esu lfon a te
(31). A solution of 30 (2.19 kg, 1.95 mol) in a mixture of THF
(9.24 L) and H2O (4.62 L) was stirred at 23-25 °C, maintaining
a pH of 2.3-2.4 by addition of 1 M aqueous TfOH and
saturated aqueous NaHCO3. After 4 h, NaOTf (402 g, 2.34
mol) was added and the pH was adjusted to 6.4 with saturated
aqueous NaHCO3. Crystallization was induced by addition of
H2O (ca. 40 L). The crystals were isolated by filtration, washed
with 20 v/v % aqueous THF (5 L), and dried to give 31 (1.85
kg; 90% yield; typical purity was 92-95%; containing 0.3-1
-
equiv of PrSO3 residue).

5446 J . Org. Chem., Vol. 63, No. 16, 1998
Yasuda et al.
J ) 6.3 Hz, 1H), 3.56 (dq, J ) 10.1, 7.4 Hz, 1H), 3.45 (dd, J )
6.3, 3.1 Hz, 1H), 1.23 (d, J ) 6.3 Hz, 3H), 1.04 (d, J ) 7.4 Hz,
3H); 13C NMR (acetone-d6 + D2O) δ 193.0, 177.2, 165.2, 160.9,
150.1, 147.4, 146.6, 143.2, 143.0, 142.0, 141.0, 134.9, 133.8,
130.8, 129.6, 128.6, 127.8, 127.3, 124.4, 123.7, 123.0, 122.6,
120.8 (q, J ) 319 Hz), 68.2, 66.2, 65.3, 62.7, 60.4, 56.4, 52.7,
51.4, 44.7, 21.1, 15.3. Anal. Calcd for C41H41F6N5O14S2: C,
48.96; H, 4.11; N, 6.96. Found: C, 48.61; H, 4.21; N, 6.78.
[4S-[4r,5â,6â(S*)]]-1-(2-Am in o-2-oxoeth yl)-4-[[6-[2-ca r -
b oxy-6-(1-h yd r oxyet h yl)-4-m et h yl-7-oxo-1-a za b icyclo-
[3.2.0]h ep t-2-en -3-yl]-9-oxo-9H-flu or en -2-yl]m eth yl]-1,4-
d ia zon ia bicyclo[2.2.2]octa n e Hem isu lfa te (1; L-742,728
Hem isu lfa te). A suspension of 31 (206 g, 95 wt % pure; 195
mmol) in a mixture of 0.025 M MOPS buffer (pH 7.0; 6 L) and
i-PrOH (6 L) was hydrogenated at 5-10 °C under 100 psi of
hydrogen in the presence of PtO2 (6 g) for 5 h 45 min. The
reaction mixture was diluted with THF (5 L) and filtered
through a pad of Solka Floc, rinsing with 2 L of cold saturated
aqueous NaCl. After addition of solid NaCl (1.5 kg), the
combined solution was washed three times with wet i-AmOH
(12 L) at 5 °C. The aqueous solution contained 132 mmol of 1
in 6 L (68%). Chromatography on HP20s resin at 5 °C, eluting
with acetone/water, followed by addition of NaCl and acetone/
methyl ethyl ketone crystallized 1 as the chloride salt (76.2 g;
64%): 1H NMR (D2O; 400 MHz) δ 7.49 (d, J ) 7.8 Hz, 1H),
7.31-7.27 (m, 4H), 7.29 (d, J ) 7.8 Hz, 1H), 4.71 (d, J ) 13.3
Hz, 1H), 4.65 (d, J ) 13.3 Hz, 1H), 4.49 (s, 2H), 4.37-4.29 (m,
8H), 4.11 (m, 6H), 3.52 (dd, J ) 5.7, 2.7 Hz, 1H), 3.47 (dq, J )
9.0, 7.1 Hz, 1H), 1.36 (d, J ) 6.4 Hz, 3H), 1.09 (d, J ) 7.1 Hz,
3H); 13C NMR (D2O, 101 MHz) δ 194.5, 177.5, 169.4, 166.1,
146.8, 143.6, 142.4, 141.0, 136.4, 135.3, 135.1, 132.5, 130.6,
128.4, 126.7, 125.1, 122.8, 121.7, 68.4, 65.7, 63.2, 59.0, 56.9,
53.1, 51.5, 42.0, 21.0, 16.9. The chloride salt was converted
to the hemisulfate dihydrate by addition of K2SO4 solution to
+
the aqueous chloride salt. Anal. Calcd for C32H35N4O6
‚
0.5SO42-‚2H2O: C, 58.62; H, 5.99; N, 8.54; S, 2.44. Found:
C, 58.57, H, 5.90, N, 8.43, S, 2.56.
Ack n ow led gm en t. We thank Drs. M. J . Williams
and J . Brands, Mr. R. J obson, and Mr. G. Marchesini
for assistance in L-742,728 isolation. We also acknowl-
edge the late Mr. W. F. Benning, Mr. A. L Houck, and
Mr. C. Bazaral J r. for help in optimization of hydro-
genolysis conditions. Additionally we are grateful for
NMR support from Mr. R. A. Reamer and Ms. L. M.
DiMichele.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compounds 19 and 20 (4 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
J O980381N