D. S. Coffey et al. / Tetrahedron Letters 46 (2005) 7299–7302
Table 1. Conversion of 1 ! 7 via Scheme 2
7301
Entry
Silylation conditions
%Yield 7
1
2
3
4
5
BSU (2.5–5.0 equiv), DMAC, 60 °C
BSA (5.0 equiv), CH2Cl2, rt
TMS–Cl (3.0 equiv), Et3N (5.0 equiv), CH2Cl2, rt
TMS-Cl (5.0 equiv), CH2Cl2, reflux, 3.5 h; cool to rt, add NMM (6.0 equiv), reflux 1 h; cool to rt
HMDS (5.0 equiv), reflux
45
76
45
80
82
TMS–Cl = chlorotrimethylsilane, BSU = 1,3-bis(trimethylsilyl)urea, BSA = N,O-bis(trimethylsilyl)acetamide, HMDS = 1,1,1,3,3,3-hexamethyl-
disilazane.
Ala to afford 7 after work-up. This initial result was very
encouraging and warranted further optimization.
hydrolysis of trimethylsilyl esters to enable an efficient
peptide coupling sequence. While the overall yields of
the syntheses of LY544344ÆHCl via methyl esters and
trimethylsilyl esters are approximately equivalent, the
trimethylsilyl ester route is more streamlined and effi-
cient. Results from the application of this methodology
on pilot plant scale will be reported in due course.
In short order, we confirmed that 1 could be esterified by
treatment with 5 vol12 of HMDS at reflux. Upon com-
pletion of the silylation, CH2Cl2 (5 vol) was added,
and this resulting solution was added to the correspond-
ing isobutyl mixed anhydride at ꢀ10 °C. Addition of
CH2Cl2 to the HMDS solution mixture prior to addition
to the mixed anhydride aided in transfer and increased
the yield of the peptide coupling. Other solvents such
as THF and toluene were examined, but CH2Cl2 proved
optimal at this stage. The mixture was then allowed to
warm to rt. Upon completion of the reaction, 5.0 M
NaOH was added resulting in hydrolysis of the trimeth-
ylsilyl esters. A simple layer separation was effective in
removing the silyl related impurities with the organic
layer leaving biscarboxylate of 7 in the aqueous layer.
Following acidification of the aqueous layer, the mono-
hydrate of 7 was isolated in 82–85% yield (Scheme 3).13
Acknowledgements
The authors would like to thank Drs. Eric Moher and
Jared Fennell for helpful discussions. We would also like
to thank Steve Bandy, Paul Dodson, and Brian Scherer
for analytical assay support.
References and notes
1. Linder, A.-M.; Greene, S. J.; Bergeron, M.; Schoepp, D.
D. Neuropsychoparmacology 2004, 29, 502–513.
2. Pedregal, C. Peptide Prodrug Design for Improving Oral
Absorption; Abstracts of Papers, 228th American Chemi-
cal Society National Meeting, Philadelphia, PA; August
22–26, 2004.
Completion of the synthesis was accomplished by treat-
ing the monohydrate of 7 with aqueous HCl in acetone
to afford technical grade 2.8 Subsequent recrystallization
afforded LY544344ÆHCl in 90–94% yield and >99.8%
purity.15
´
3. Bueno, A. B.; Collado, I.; de Dios, A.; Domınguez, C.;
´
´
´
Martın, J. A.; Martın, L. M.; Martınez-Grau, M. A.;
Montero, C.; Pedregal, C.; Catlow, J.; Coffey, D. S.; Clay,
M. P.; Dantzig, A. H.; Lindstrom, T.; Monn, J. A.; Jiang,
H.; Schoepp, D. D.; Stratford, R. E.; Tabas, L. B.;
Tizzano, J. P.; Wright, R. A.; Herin, M. F. J. Med. Chem.
2005, 48, 5305–5320.
In conclusion, we have demonstrated a very efficient
synthesis of LY544344ÆHCl from LY354740 that high-
lights the use of in situ formation and subsequent
4. Monn, J. A.; Valli, M. J.; Massey, S. M.; Wright, R. A.;
Salhoff, C. R.; Johnson, B. G.; Howe, T.; Alt, C. A.;
Rhodes, G. A.; Robey, R. L.; Griffey, K. R.; Tizzano, J.
P.; Kallman, M. J.; Helton, D. R.; Schoepp, D. D. J. Med.
Chem. 1997, 40, 528–537.
5. For experimental procedures described in Scheme 1 and
the corresponding characterization data, see: Bueno Mel-
endo, A. B.; Coffey, D. S.; Dantzig, A. H.; De Dios, A.;
Dominguez-Fernadez, C.; Herin, M.; Hillgren, K. M.;
Martin, J. A.; Martin-Cabrejas, L. M.; Martinez-Grau, M.
A.; Massey, S. M.; Moher, E. D.; Monn, J. A.; Montero
Salgado, C.; Pedersen, S. W.; Pedregal-Tercero, C.;
Sweetana, S. A.; Valli, M. J. Preparation of Prodrugs of
Excitatory Amino Acids; WO 0255481.
H
Me3SiO2C
a
b
(1)
H
H2N CO2SiMe3
8
(not isolated)
H
H
HO2C
Me
HO2C
·H2O
CO2H
H
H
c, d
HN CO2H
HN
Me
O
O
6. Sontag, N. O. V. Chem. Rev. 1953, 52, 272–273.
7. Levine, S. J. Am. Chem. Soc. 1954, 76, 1382.
NH2·HCl
LY544344·HCl (2)
BocHN
8. The physical properties of 2 also limited the number of
benign N-protecting groups that could be used. The Boc
group proved ideal. See: Coffey, D. S.; Hawk, M. K. N.;
Ghera, S. J.; Marler, P. G.; Dodson, P. D.; Lytle, M. L.
Org. Process Res. Dev. 2004, 8, 945–947.
7 (monohydrate)
Scheme 3. Reagents and conditions: (a) HMDS, reflux; (b) (i) Boc-L-
Ala, isobutyl chloroformate, N-methylmorpholine, CH2Cl2, ꢀ10 °C,
(ii) 82–85% for two steps; (c) HCl(aq), acetone; (d) acetone, H2O
recrystallization, 90–94% for two steps.
9. Kato, T.; Kurauchi, M. U.S. Patent 5,032,675, 1991.