Synthesis of an anti-methicillin-resistant Staphylococcus aureus (MRSA) carbapenem via stannatrane-mediated Stille coupling.

Article abstract of DOI:10.1021/ol005641d

[formula: see text] A short synthesis of carbapenem 1 is described. They key step involves the cross-coupling of an enol triflate with an amino-substituted sp3 carbon. This cross-couping, which allows the introduction of the complete side chain in one ste

Full text of DOI:10.1021/ol005641d

ORGANIC
LETTERS
2
000
Vol. 2, No. 8
081-1084
Synthesis of an
1
Anti-Methicillin-Resistant
Staphylococcus aureus (MRSA)
Carbapenem via Stannatrane-Mediated
Stille Coupling
Mark S. Jensen,* Chunhua Yang, Yi Hsiao, Nelo Rivera, Kenneth M. Wells,
John Y. L. Chung, Nobuyoshi Yasuda, David L. Hughes, and Paul J. Reider
Department of Process Research, Merck Research Laboratories, P.O. Box 2000,
Rahway, New Jersey 07065
mark•jensen@merck.com
Received February 9, 2000
ABSTRACT
A short synthesis of carbapenem 1 is described. The key step involves the cross-coupling of an enol triflate with an amino-substituted sp3
carbon. This cross-couping, which allows the introduction of the complete side chain in one step, utilizes a stannatrane as the heteroalkyl
transfer reagent.
Recently, â-lactam 1 was identified as a clinical candidate
for the treatment of serious bacterial infections, including
those caused by strains resistant to current therapeutic
1
protocols. Here we report a short synthesis of 1 that utilizes
an unprecedented cross-coupling of an enol triflate with an
amino-substituted methylene to join the two fragments of
the molecule. This cross-coupling was mediated by a
stannatrane as the heteroalkyl transfer agent.
While 1 can be disconnected in several ways, among the
most convergent disconnects is the C-C bond between the
carbapenem core A and the side chain B, as shown in
structure 1. While several cross-coupling reactions using
(
1) (a) Rosen, H.; Hajdu, R.; Silver, L.; Kropp, H.; Dorso, K.; Kohler,
Stille or Suzuki conditions with similar carbapenems have
J.; Sundelof, J. G.; Huber, J.; Hammond, G. G.; Jackson, J. J.; Gill, C. J.;
Thompson, R.; Pelak, B. A.; Epstein-Toney, J. H.; Lankas, G.; Wilkening,
R. R.; Wildonger, K. J.; Blizzard, T. A.; DiNinno, F. P.; Ratcliffe, R. W.;
Heck, J. V.; Kozarich, J. W.; Hammond, M. L. Science 1999, 283, 703. (b)
Ratcliffe, R. W.; Wilkening, R. R.; Wildonger, K. J.; Waddell, S. T.;
Santorelli, G. M.; Parker, D. L., Jr.; Morgan, J. D.; Blizzard, T. A.;
Hammond, M. L.; Heck, J. V.; Huber, J.; Kohler, J.; Dorso, K. L.; St. Rose,
E.; Sundelof, J. G.; May, W. J.; Hammond, G. G. Bioorg. Med. Chem.
Lett. 1999, 9, 679. (c) Wilkening, R. R.; Ratcliffe, R. W.; Wildonger, K.
J.; Cama, L. D.; Dykstra, K. D.; DiNinno, F. P.; Blizzard, T. A.; Hammond,
M. L.; Heck, J. V.; Dorso, K. L.; St. Rose, E.; Kohler, J.; Hammond, G. G.
Bioorg. Med. Chem. Lett. 1999, 9, 673.
2,3
been reported in recent years, that required for construction
of 1 would involve the cross-coupling of enol triflate 3 with
(2) Yasuda, N.; Huffman, M. A.; Ho, G.-J.; Xavier, L. C.; Yang, C.;
Emerson, K. M.; Tsay, F.-R.; Li, Y.; Kress, M. H.; Rieger, D. L.; Karady,
S.; Sohar, P.; Abramson, N. L.; DeCamp, A. E.; Mathre, D. J.; Douglas,
A. W.; Dolling, U.-H.; Grabowski, E. J. J.; Reider, P. J. J. Org. Chem.
1998, 63, 5438.
(3) Yasuda, N.; Yang, C.; Wells, K. M.; Jensen, M. S.; Hughes, D. L.
Tetrahedron Lett. 1999, 40, 427.
1
0.1021/ol005641d CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/30/2000

3
9
an amino-substituted sp carbon, a coupling for which we
3 2
transfer of CH and CH OMOM to aryl halides; however,
could find no precedence. This Letter discloses a route to 1
that makes this key bond connection and yields 1 in protected
form in one step from 3.4
no other reports of cross-coupling using this type of
organostannane have appeared.
Scheme 1 depicts the preparation of the enol triflate
Scheme 1. Enol Triflate Preparation
Preliminary cross-coupling studies of enol triflate 3,
protected with TBS, with the methylstannatrane 4 indicated
that the desired C-C bond could be made under mild
conditions. This provided impetus to investigate the coupling
of the entire side chain with the enol triflate using stannatrane
1
1. Using this highly convergent approach, the sensitive
carbapenem core would be required to survive relatively few
steps, as 1, in protected form, would be prepared in a single
reaction from 3. Scheme 2 outlines the synthesis of the fully
coupling partner. Protection of the alcohol function of 25
was required for the successful preparation and isolation of
3. Thus, O-silylation was favored over N-silylation when
imidazole was used as base with TESCl. TES-protected 2
was isolated in crystalline form from IPAC and heptane.
Reaction of this compound with 0.5 mol % of rhodium
octanoate and 1 mol % of zinc chloride in refluxing
methylene chloride gave quantitative conversion to the â-keto
ester. The crude solution was treated at -70 °C with 0.35
equiv of triethylamine and 1.0 equiv of diisopropylamine
followed by 1.05 equiv of trifluoromethanesulfonic anhy-
dride. Enol triflate 3 was then isolated as a crystalline
compound after passing through a short plug of silica gel,
eluting with methylene chloride and then switching the
solvent to heptane.
Scheme 2. Preparation of the Stannatrane Coupling Partner
Palladium-catalyzed cross-coupling of 3 with Bu
3
SnCH
OH was successful; however, attempts at attaching any
CH NRR′ to the carbapenem using either a typical Suzuki
2
-
3
2
or Stille approach failed. The transmetalation step of the
6
catalytic cycle was viewed as the problem in this case. If
this is true, a potential solution for the Stille approach would
be lengthening the Sn-CH bond. Long Sn-C bonds were
2
reported by Tzschach when he disclosed the preparation and
7
properties of methylstannatrane 4. In fact, this critical bond
distance is 2.214 Å which is about 0.1 Å longer than that in
8
the typical alkylstannane. Vedejs capitalized on this char-
acteristic when he demonstrated the palladium-catalyzed
(
4) An elegant synthesis of 1 that starts from a commercially available
elaborated stannatrane coupling partner 11.
acetoxyazetidinone was recently disclosed by colleagues in these labora-
tories. Humphrey, G. R.; Miller, R. A.; Pye, P. J.; Rossen, K.; Reamer, R.
A.; Maliakal, A.; Ceglia, S. S.; Grabowski, E. J. J.; Volante, R. P.; Reider,
P. J. J. Am. Chem. Soc. 1999, 121, 11261.
Stannatrane chloride 7 was treated with the zinc reagent
prepared by combining 1 equiv of diethylzinc and 2 equiv
of diiodomethane to provide iodomethylstannatrane 8 in
(5) Compound 2 is available from Kanegafuchi, Nippon Soda, and
Takasago.
10
11
quantitative yield. Treatment of 8 with 5 in the presence
(6) For a thorough discussion of the mechanism of the Stille cross-
coupling, see: Casado, A. L.; Espinet, P. J. Am. Chem. Soc. 1998, 120,
8
978 and references therein.
7) (a) Jurkschat, K.; Tzschach, A. J. Organomet. Chem. 1984, 272, C13.
b) Jurkschat, K.; Tzschach, A.; Meunier-Piret, J. J. Organomet. Chem.
986, 315, 45.
8) (a) Ross, J.; Wardell, J. L.; Ferguson, G.; Low, J. N. Acta Crystallogr.,
(9) Vedejs, E.; Haight, A. R.; Moss, W. O. J. Am. Chem. Soc. 1992,
114, 6556.
(
(
1
(10) This preparation of the organozinc reagent is a modification of
Knochel’s procedure (Rozema, M. J.; Sidduri, A.; Knochel, P. J. Org. Chem.
1992, 57, 1956) by J. C. McWilliams, unpublished results. To THF (33
mL) under nitrogen at -60 °C were added diethylzinc (2.56 mL, 25.0 mmol)
and then diiodomethane (4.02 mL, 50.0 mmol), maintaining an internal
temperature below -55 °C. After 1 h at -40 °C, stannatrane chloride (7,
(
C 1994, 50, 1703. (b) Belanger-Gariepy, F.; Leger, R.; Hanessian, S. Acta
Crystallogr., C 1992, 48, 1309. (c) Cox, P. J.; Wardell, J. L. Acta
Crystallogr., C 1995, 51, 2037.
1082
Org. Lett., Vol. 2, No. 8, 2000

of potassium carbonate and DMF provided 9, which was
isolated as a crystalline solid from EtOAc. The alcohol was
activated by conversion to triflate 10 using standard condi-
This was added to a solution of coupling partners 3, 11,
diisopropylethylamine, and NMP. The tertiary amine was
required to maintain basic conditions during the reaction.
Decomposition was observed when the mixture was allowed
to become acidic during the course of this cross-coupling.
After 3 h at 60 °C, the assay yield was 98% (HPLC).13
2
tions. When 10 was treated with 6 at ambient temperature
in acetonitrile, 11 was produced in high yield. This compound
was isolated as an amorphous ditriflate salt by precipitation
with ether.
A workup procedure was devised that allowed the
quantitative recovery of the stannatrane as chloride 7 as well
as the isolation of 12 as a crystalline solid in high yield.
The transmetalation step of the Stille coupling catalytic cycle
returns the stannatrane as its triflate. This compound was
converted to chloride 7 by diluting the crude reaction mixture
with THF and washing with 20% aqueous NaCl. A solvent
switch from THF to acetonitrile provided a slurry which,
when filtered, gave 61% of the stannatrane as crystalline 7
and a clear mother liquor. When 2-propanol was added
dropwise to this mother liquor, 12 crystallized and was
isolated in 98% yield by filtration. This mother liquor was
concentrated to dryness and the residue triturated with
methanol to return the remaining 39% of stannatrane chloride
Alternatively 11 could be prepared as a different salt form
by simply changing the order of reactions. First combining
the triflate of 5 with 6, followed by coupling with 8, provided
11 as the monoiodide monotriflate salt.
With the coupling partners 3 and 11 in hand, the key cross-
coupling reaction was explored (Scheme 3). The use of
Scheme 3. Coupling and Deprotection Sequence
7
.
To complete the preparation of drug candidate 1, all that
remained was the removal of the triethylsilyl and 4-nitroben-
zyl blocking groups from 12. This was accomplished using
a procedure that avoided any intermediate isolation. Treat-
ment of 12 with 0.06 M HCl removed the triethylsilyl moiety.
The pH was then adjusted to 7.0 using a 4-morpholinepro-
panesulfonic acid/NaOH buffer system. The mixture was
hydrogenated at 40 psi using 5% Pd/C as catalyst to remove
the 4-nitrobenzyl group. Carbapenem 1 was isolated in pure
form as the chloride salt using Amberchrome CG-161m resin
followed by lyophilization.
With this work we have demonstrated a brief and efficient
route to 1 that highlights the versatility of the stannatrane in
palladium-catalyzed cross-coupling reactions. The stan-
natrane was quantitatively recovered leaving residual tin in
HMPA as solvent or cosolvent with DMPU, which was
3
3 2
required for the cross-coupling of 3 with Bu SnCH OH, is
not needed in this case. In fact, NMP was found to give
superior yields. When the cross-coupling was attempted
between the monoiodide monotriflate salt of 11 and 3, no
reaction occurred. The technique of adding silver triflate or
silver nitrate to the reaction mixture to sequester the halide
also failed. The reaction of 3 with the ditriflate salt 11,
however, performed well.
(
12) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585.
(13) A suspension of Pd2(dba)3‚CHCl3 (31.6 mg, 0.031 mmol), tri-2-
furylphosphine (35.4 mg, 0.153 mmol), and NMP (2 mL) was degassed
and then warmed to 60 °C for 30 min. The catalyst solution was added to
a degassed solution of 3 (743 mg, 1.22 mmol), 11 (972 mg, 1.00 mmol),
diisopropylethylamine (47 mg, 0.37 mmol), and NMP (10 mL) at 60 °C.
The mixture was stirred for 3 h at 60 °C (98% assay yield). The crude
reaction was diluted with THF (50 mL) and washed with 20% aqueous
NaCl (3 × 50 mL). The THF was removed in vacuo, and the residue was
diluted with acetonitrile (5 mL). The resulting crystalline solids (7, 179
mg, 0.61 mmol) were collected on a frit. 2-Propanol (20 mL) was added
dropwise to the mother liquor, and the resulting crystalline solid was
collected by filtration to provide 12 (1.243 g) as a crystalline solid. The
mother liquor was concentrated to dryness and then triturated with methanol
The preferred catalyst was prepared by the combination
12
of Pd
2
(dba)
3
3
‚CHCl and tri-2-furylphosphine in warm NMP.
1
2
.94 g, 10.0 mmol) was added in one portion and the resulting suspension
(2 mL) to provide the remaining 7 (116 mg, 0.39 mmol). 12: H NMR
was stirred at 0 °C for 3 h and then rt for 0.5 h. The solution was poured
onto heptanes (100 mL) and water (33 mL) and then 2 M aqueous HCl (18
mL) was added (pH now 2.5); both phases were clear. The layers were
partitioned, and the organic phase was washed with water (2 × 30 mL)
and then brine (30 mL) and dried (MgSO4). The solvent was removed in
vacuo to provide 8 (3.98 g, 100%) as colorless crystals. An analytical
(CD3CN, 250 MHz) δ 8.19 (dt, J ) 8.8, 1.9 Hz, 2H), 8.06 (d, J ) 7.5 Hz,
1H), 7.80 (d, J ) 7.5 Hz, 1H), 7.73 (dt, J ) 8.8, 1.9 Hz, 2H), 7.76-7.57
(m, 2H), 6.94 (bs, 1H), 6.87 (dd, J ) 6.0, 2.1 Hz, 1H), 6.44 (bs, 1H), 5.52
(d, J ) 13.9 Hz, 1H), 5.37 (d, J ) 13.9 Hz, 1H), 5.31 (d, J ) 17.0 Hz,
1H), 4.68 (d, J ) 17.0 Hz, 1H), 4.28 (m, 1H), 4.27 (s, 2H), 4.23 (m, 1H),
4.21 (m, 6H), 4.17 (m, 6H), 3.82 (m, 2H), 3.63 (m, 2H), 3.39 (m, 1H),
3.34 (m, 1H), 1.23 (d, J ) 7.0 Hz, 3H), 1.15 (d, J ) 6.2 Hz, 3H), 0.90 (t,
J ) 8.0 Hz, 9H), 0.56 (q, J ) 8.0 Hz, 6H); C NMR (CD3CN, 62.9 MHz)
δ 175.9, 164.9, 162.0, 148.7, 147.2, 144.2, 138.2, 138.1, 131.3, 130.5, 130.4,
130.3, 130.1, 129.4, 124.5, 122.0 (q, J ) 320 Hz), 121.0, 120.1, 116.3,
105.6, 66.5, 66.1, 65.0, 63.0, 61.2, 56.0, 52.9, 52.1, 41.5, 39.1, 25.4, 22.3,
15.9, 7.1, 5.5. Anal. Calcd for C46H58N6O15F6S3Si‚0.5IPA: C, 47.41; H,
5.19; F, 9.47; N, 6.98. Found: C, 47.20; H, 5.30; F, 9.16; N, 6.69.
1
standard was prepared by recrystallization from methanol: mp 40-55 °C; H
13
NMR (CDCl3, 250 MHz) δ 2.37 (m, 6H), 1.67 (m, 6H), 1.66 (s, 2H), 0.82,
1
3
(
m, 6H); C NMR (CDCl3, 62.9 MHz) δ 54.6, 23.3, 7.2, -13.5. Anal.
Calcd for C10H20INSn: C, 30.04; H, 5.04; I, 31.75; N, 3.50. Found: C,
0.20; H, 4.88; I, 31.45; N, 3.41.
11) Miller, R. A.; Humphrey, G. R.; Lieberman, D. R.; Ceglia, S. S.;
3
(
Grabowski, E. J. J. J. Org. Chem. 2000, 65, 1399.
Org. Lett., Vol. 2, No. 8, 2000
1083

the drug substance at acceptable levels. Iodomethylstan-
natrane 8 should be viewed as a versatile reagent for the
preparation of numerous Sn-CH X compounds that will
2
function well in currently difficult cross-coupling reactions.
This promising approach using the stannatrane in Stille cross-
coupling reactions adds versatility to this already powerful
reaction.
Acknowledgment. We thank Drs. G. R. Humphrey and
R. A. Miller for a generous supply of naphthosultam 5. We
acknowledge Dr. E. J. J. Grabowski for helpful discussions
and Mr. R. A. Reamer and Ms. L. M. DiMichele for NMR
support. Expert hydrogenation assistance was provided by
Mr. C. Bazaral, Mr. A. L. Houck, and Mr. A. Newell.
OL005641D
1084
Org. Lett., Vol. 2, No. 8, 2000