The combined solid/solution-phase synthesis of nitrosamines: The evolution of the "libraries from libraries" concept

Article abstract of DOI:10.1021/jo0204909

The generation of diverse chemical libraries using the "libraries from libraries" concept by combining solid-phase and solution-phase methods is described. The central features of the approaches presented are the use of solid-phase synthesis methods for the generation of a combinatorial polyamine library. Following cleavage from the resin with HF, the polyamine library was reacted with ethyl nitrite in the solution phase to yield the desired nitrosamine library in good yield and purity. The approaches described enable the efficient syntheses of individual nitrosamines as well as mixture-based nitrosamine libraries.

Full text of DOI:10.1021/jo0204909

Th e Com bin ed Solid /Solu tion -P h a se
Syn th esis of Nitr osa m in es: Th e Evolu tion
of th e “Libr a r ies fr om Libr a r ies” Con cep t†
SCHEME 1
Yongping Yu, J ohn M. Ostresh, and
Richard A. Houghten*
Torrey Pines Institute for Molecular Studies,
550 General Atomics Court, San Diego, California 92121
3
tions were studied to optimize the reaction. However, no
nitrosamine product was obtained following cleavage
from the resin with HF. It was found that the N-N bond
of nitrosamine 1 was cleaved by HF after 7 h at 0 °C to
yield the corresponding amine 2 (Scheme 1).To overcome
this problem, we modified our “libraries from libraries”
concept by first generating the triamines of interest from
their corresponding resin-bound dipeptides, and following
cleavage, we used solution-phase chemistry to generate
the nitrosamines. The synthetic strategy followed is
shown in Scheme 2. The parallel solid-phase synthesis
of triamines 8 was carried out as described in our
previous report using the “tea-bag” methodology. Start-
ing from p-methylbenzhydrylamine (MBHA) resin, a Boc-
L-amino acid was coupled to the resin. The Boc group was
removed using 55% trifluoroacetic acid (TFA) in dichlo-
romethane (DCM). The resulting amine salt was neutral-
ized with DIEA, and the resulting primary amine 4 was
then protected with triphenylmethyl chloride (TrtCl). The
secondary amide 4 was selectively methylated in the
presence of lithium tert-butoxide and methyl iodide to
yield 5. Since the alkylation of the amide nitrogen of the
resin linkage dramatically increases the acid lability of
the MBHA resin-bound peptide, the use of Boc-amino
acids was precluded for the second coupling. However,
significant amounts of the resin-bound alkylated amino
acid are cleaved during the trityl removal, resulting in
lower than desired yields based on the loading of the
MBHA resin. Therefore, Fmoc-amino acids were em-
ployed in the subsequent coupling. Following Fmoc
removal and N-acylation of the resin-bound dipeptide 6
to afford the resin-bound N-acyl dipeptide 7, exhaustive
reduction of the amide bonds using borane in tetrahy-
drofuran yielded the corresponding resin-bound poly-
amines 8. The desired triamine products 9 were obtained
following cleavage using HF for 7 h at 0 °C. Since the
rhoughten@tpims.org
Received J uly 25, 2002
Abstr a ct: The generation of diverse chemical libraries
using the “libraries from libraries” concept by combining
solid-phase and solution-phase methods is described. The
central features of the approaches presented are the use of
solid-phase synthesis methods for the generation of a com-
binatorial polyamine library. Following cleavage from the
resin with HF, the polyamine library was reacted with ethyl
nitrite in the solution phase to yield the desired nitrosamine
library in good yield and purity. The approaches described
enable the efficient syntheses of individual nitrosamines as
well as mixture-based nitrosamine libraries.
7
8
The rapid syntheses of large organic compound collec-
tions by combinatorial methods using solid-phase and
solution-phase approaches are promising strategies for
1
the discovery of new pharmaceutical lead compounds.
These approaches permit the rapid synthesis of large
numbers of individual compounds, as well as mixture-
based combinatorial libraries, and facilitate their use in
high-throughput screening.2 The focus of this field of
research, which initially involved the synthesis of pep-
tides and oligonucleotides, is now on the synthesis of
3
small organic molecules. Recently, a new and unexpected
role of nitric oxide (NO) has generated much interest,
both as a regulator of many important physiological
functions in vivo and as a possible pharmaceutical
4
delivery system. As part of our ongoing efforts directed
toward the solid-phase synthesis of small molecules and
the generation of combinatorial libraries of organic
5
compounds, we report here an efficient approach for the
combined solid/solution-phase synthesis of nitrosamines
by expansion of the “libraries from libraries” concept.
6
Initially, we attempted the synthesis of nitrosamines
directly from resin-bound triamines. A variety of condi-
(4) (a) For recent highlights, see the following special issue: Chem.
Rev. 2002, 102 (4). (b) Murad, F. Angew. Chem., Int. Ed. 1999, 38,
1
856. (c) Ignarro, L. J . Angew. Chem., Int. Ed. 1999, 38, 1882-1892.
(
d) Furchgott, R. F. Angew. Chem., Int. Ed. 1999, 38, 1870. (e) Pfeiffer,
*
Address correspondence to this author. Phone: 858-455-3803.
Dedicated to the memory of Professor Henry Rapoport.
S.; Mayer, B.; Hemmen, B. Angew. Chem., Int. Ed. 1999, 38, 1714. (f)
Stamler, J . S.; J araki, O.; Osborne, J .; Simon, D. I.; Keaney, J .; Vita,
J .; Singel, D.; Valeri, C. R.; Loscalzo, J . Proc. Natl. Acad. Sci. U.S.A.
1992, 89, 7674. (g) Stamler, J . S.; Singel, D. J .; Loscalzo, J . Science
1992, 258, 1898. (h) Loeppky, R. N.; Michejda, C. J ., Eds. Nitrosamines
and Related N-Nitroso Compounds: Chemistry and Biochemistry; ACS
Symp. Ser. 553; American Chemical Society: Washington, DC, 1994.
(5) (a) Yu, Y.; Ostresh, J . M.; Houghten, R. A. J . Org. Chem. 2002,
67, 3138. (b) Yu, Y.; Ostresh, J . M.; Houghten, R. A. J . Comb. Chem.
2001, 3, 521. (c) Yu, Y.; Ostresh, J . M.; Houghten, R. A. Org. Lett. 2001,
3, 2797.
(6) Ostresh, J . M.; Husar, G. M.; Blondelle, S. E.; D o¨ rner, B.; Weber,
P. A.; Houghten, R. A. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 11138.
(7) (a) Ostresh, J . M.; Schoner, C. C.; Hamashin, V. T.; Nefzi, A.;
Meyer, J .-P.; Houghten, R. A. J . Org. Chem. 1998, 63, 8622. (b) D o¨ rner,
B.; Husar, G. M.; Ostresh, J . M.; Houghten, R. A. Bioorg. Med. Chem.
1996, 4, 709.
†
(1) (a) Geysen, H. M.; Meloen, R. H.; Barteling, S. J . Proc. Natl.
Acad. Sci. U.S.A 1984, 81, 3998. (b) Houghten, R. A.; Pinilla, C.;
Blondelle, S. E.; Appel, J . R.; Dooley, C. T.; Cuervo, J . H. Nature 1991,
45, 8486. (c) Amstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown,
S. D.; Keating, T. A. Acc. Chem. Res. 1996, 29, 123. (d) Wilson, S. R.;
Czarnik, A. W., Eds. Combinatorial Chemistry, Synthesis and Applica-
tion; Wiley: New York, 1997. (e) Booth, R. J .; Hodges, J . C. Acc. Chem.
Res. 1999, 32, 18. (f) An, H.; Cook, P. D. Chem. Rev. 2000, 100, 3311.
3
(
2) Houghten, R. A.; Pinilla, C.; Appel, J . R.; Blondelle, S. E.; Dooley,
C. T.; Eichler, J .; Nefzi, A.; Ostresh, J . M. J . Med. Chem. 1999, 42,
743.
3) (a) Thompson, L. A.; Ellman, J . A. Chem. Rev. 1996, 96, 555. (b)
3
(
Fruchtel, J . S.; J ung, G. Angew. Chem., Int. Ed. Engl. 1996, 35, 17. (c)
Nefzi, A.; Ostresh, J . M.; Houghten, R. A. Chem. Rev. 1997, 97, 449.
d) Robert G. F. J . Comb. Chem. 2000, 2, 195. (e) Krch nˇ a´ k, V.; Holladay,
(
M. W. Chem. Rev. 2002, 102, 61.
(8) Houghten, R. A. Proc. Natl. Acad. Sci. U.S.A. 1985, 82, 5131.
1
0.1021/jo0204909 CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/19/2002
J . Org. Chem. 2003, 68, 183-186
183

TABLE 1. In d ivid u a l Nitr osa m in es 10
R1
R2
R3
yielda (%)
purity (%)
b
MW (found)c
entry
product
+
1
2
3
4
5
6
7
8
10a
10b
10c
10d
10e
10f
10g
10h
CH3
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
CH3)2CHCH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
(CH2)5CHCH2
(CH3)3C
48.2
51.3
46.5
49.2
56.2
52.6
48.9
44.3
90
88
94
92
89
81
83
82
435.4 ([M + Na] )
+
C6H5CH2
(CH3)2CHCH2
(CH3)2CH
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
488.6 ([M + Na] )
+
454.6 ([M + Na] )
+
440.5 ([M + Na] )
+
454.5 ([M + Na] )
+
494.6 ([M + Na] )
+
454.6 ([M + Na] )
+
(CH3)2CH
440.5 ([M + Na] )
a
b
Yields (in %) are based on the weight of crude material and are relative to the initial loading of the resin. The purity of the crude
material was estimated based on analytical RP-HPLC traces at λ ) 214 nm. c Confirmed by mass spectra (ESI).
SCHEME 2
primary nitrosoamine products are known to be un-
9
stable, it was necessary that resin-bound 4 be methy-
lated and that all amines of product 9 be secondary
amines
For the next step, the solution-phase synthesis of the
nitrosamine library was carried out. We used a large
excess of nitroso reagent to drive the reaction to comple-
tion and unreacted reagents were simply removed by
evaporation. Following optimization of the reaction, it
was found that triamine 9 was completely converted to
nitrosamine 10 by treatment of 9 with ethyl nitrite (60
equiv) in DCM at room temperature for 5 days. Excess
ethyl nitrite was evaporated under vacuum. The products
were characterized by electrospray LC-MS under ESI
conditions and HRMS. The results are summarized in
Table 1.Nitrosamines generally assume planar structures
due to the rotational barriers of the N-NO bond and are
F IGURE 1. The (E)-and (Z)-rotamers of the unsymmetrical
N-nitrosamines.
(Z)-rotamers due to the stereochemical nature of the
N-NdO moiety. Contributing resonance structures give
1
2
rise to the barrier of rotation (Figure 1).
1
The H NMR spectrum of 1 indicated that there were
two rotational isomers in a ratio of 3.1:1 due to the
restricted rotation of the N-N bond. There were four
1
0
1
of similar magnitude to those of amides and carbam-
rotamers of 10a seen in the H NMR spectrum and it
ates.11 Unsymmetrical N-nitrosamines exist as (E)- and
was difficult to specifically attribute the NMR data to
(
9) Loeppky, R. N.; Michejda, C. J ., Eds. Nitrosamines and Related
N-Nitroso Compounds: Chemistry and Biochemistry; ACS Symp. Ser.
53; American Chemical Society: Washington, DC, 1994.
(10) Perrin, C. L.; Thoburn, J . D.; Kresge, A. J . J . Am. Chem. Soc.
1992, 114, 8800.
(11) Stewart, W. E.; Sidall, T. H., III Chem. Rev. 1970, 70, 517.
5
1
84 J . Org. Chem., Vol. 68, No. 1, 2003

torial library. Amino acids that generated a reactive
functionality after reduction (for example, asparagine and
1
2
glutamine) were not included in the R and R position.
We selected nineteen different amino acids at the first
1
position (R ) of diversity, nineteen different amino acids
2
at the second position (R ), and thirty-six carboxylic acids
3
at the third position of diversity (R ) for synthesis of a
2
positional scanning combinatorial library (SCL). The
preparation of the mixture-based positional scanning
1
2
combinatorial library containing 12 996 (19 R × 19 R
3
×
36 R ) different nitrosamines and its screening in
different assays for the identification of highly active
compounds will be reported in due course.
In summary, the work presented is a continution of
our efforts directed toward the synthesis of acyclic and
heterocyclic compounds directly from amino acids and
short peptides. Using the concept of “libraries from
libraries”,we have, thus, been able to generate individual
nitrosoamines as well as a mixture-based nitrosamine
library from resin-bound N-acylated dipeptides.
Exp er im en ta l Section
F IGURE 2. X-ray structure of compound 10h .
Analytical RP-HPLC was performed on a Beckman System
Gold Instrument. Samples were analyzed using a Vydac 218TP54
C18 column (0.46 × 25 cm). LC-MS (ESI) was recorded on a
Finnigan Mat LCQ mass spectrophotometer at 214 nm using a
given rotamers. A suitable crystal of one of the nitro-
samines of 10h could be grown by slow diffusion of a CH
CN and CH OH solution of 10h at room temperature.
The molecular structure of 10h is represented in Figure
3
-
3
1
Betasil C18, 3 µm, 100 Å, 3 × 50 mm column. H NMR spectra
3
were recorded at 400 MHz using CDCl as solvent. Preparative
2
1
. The bond lengths of N2-O1, N4-O2, and N6-O3 are
RP-HPLC was performed on a Waters DeltaPrep preparative
.234(2), 1.215(6), and 1.232(3) Å, respectively, which are
HPLC (Millipore) using a Vydac 218TP1022 C18 column (2.2 ×
2
5 cm). X-ray structure determination was performed on a
consistent with their formal double bond. The bond
lengths of N1-N2, N3-N4, and N5-N6 are 1.319(3),
1
bond than a single bond. An average distance of the N-N
bond in N-nitrosamines is 1.31 Å.13 The bond angles
about N3, C10-N3-C9, N4-N3-C9, and N4-N3-C10
are 121.1(3)°, 114.7(3)°, and 124.1(4)°, respectively, are
closer to that expected for an sp hybridized nitrogen
rather than an sp hybridized nitrogen, suggesting that
Bruker SMRAT 1KCCD automated diffractometer at The Scripps
Research Institute X-ray Facility. Crystals of compound 10h
were obtained by crystallization from methanol and acetonitrile
by slow solvent evaporation.
.305(4), and 1.330(3) Å, respectively, closer to a double
Gen er a l P r oced u r e for th e Solid -P h a se Syn th esis of
Tr ia m in es 9.7 A 100-mg sample of MBHA resin (1 mequiv/g,
1
00-200 mesh) was contained in a polypropylene mesh packet.
2
Following neutralization with 5% DIEA in DCM, the resin was
washed with DCM. The first Boc amino acid (6 equiv, 0.1M) was
coupled using hydroxybenzotriazole (HOBt, 6 equiv, 0.1M) and
diisopropylcarbodiimide (DICI, 6 equiv, 0.1M) for 90 min. Upon
removal of the Boc group with 55% TFA in DCM (30 min), the
packet was washed and neutralized with a solution of 5% DIEA
in DCM. The resin-bound amine was reacted with trityl chloride
in DCM/DMF (9:1) in the presence of DIEA. N-Alkylation was
performed by treatment of the resin packet with lithium tert-
butoxide (20 equiv, 1 M) in THF. Excess base was removed by
3
the pair of electrons formally located on N3 are delocal-
ized as would be expected for N-nitrosamines.
1
2f,13
Following optimization of the synthetic steps, we
expanded the number of individual controls by separately
varying the substituent at each of these three variable
positions. Ninety-six individual controls were prepared
by fixing two positions of diversity while varying the
other position. Twenty-nine amino acids were examined
at the first position of diversity (R ), twenty-nine amino
acids at the second position of diversity (R ), and thirty-
eight carboxylic acids at the third position of diversity
3
cannulation, followed by addition of CH I in DMSO (60 equiv,
1
0.1 M). The solution was vigorously shaken overnight. Upon
removal of the trityl group with 2% TFA in DCM (2 times, 10
min), the packet was washed and neutralized and an Fmoc
amino acid was coupled. Following removal of the Fmoc group,
the dipeptide was acylated with a carboxylic acid (6 equiv, 0.1
M) in the presence of hydroxybenzotriazole (HOBt, 6 equiv, 0.1
M) and diisopropylcarbodiimide (DICI, 6 equiv, 0.1 M). The
exhaustive reduction of the resin-bound amides was carried out
in 50-mL glass conical tubes under nitrogen. To each tube was
added the resin packet and boric acid (12 equiv). Trimethyl
borate (12 equiv) was added followed by the slow addition of
borane-THF complex (40 equiv). After cessation of hydrogen
evolution, the capped tubes were heated at 65 °C for 72 h in a
heating block followed by decantation of the reaction solution
and quenching with MeOH. The resin packet was then washed
with DMF and MeOH. The resin was treated with piperidine at
65 °C for 20 h to disproportionate the borane complex. Following
decantation of the piperidine-borane solution, the resin packet
2
3
(R ). The building blocks that produced compounds
having purities more than 80% were considered for
inclusion in the synthesis of a mixture-based combina-
(12) (a) Galtress, C. L.; Morrow, P. R.; Nag, S.; Smalley, T. L.;
Tschantz, M. F.; Vaughn, J . S.; Wichems, D. N.; Ziglar, S. K.; Fishbein,
J . C. J . Am. Chem. Soc. 1992, 114, 1406. (b) Cooney, J . D.; Brownstein,
S. K.; Apsimon, J . W. Can. J . Chem. 1974, 52, 3028. (c) Forlani, L.;
Lunazzi, L.; Macciantelli, D.; Minguzzi, B. Tetrahedron Lett. 1979,
1
451. (d) Ohwada, T.; Miura, M.; Tanaka, H.; Sakamoto, S.; Yamagu-
chi, K.; Ikeda, H.; Inagaki, S. J . Am. Chem. Soc. 2001, 123, 10164. (e)
Hitchcock, S. R.; Nora, G. P.; Hedberg, C.; Casper, D. M.; Buchanan,
L. S.; Squire, M. D.; West, D. X. Tetrahedron 2000, 56, 8799.
(13) Rademacher, P.; Stolevik, R. Angew. Chem., Int. Ed. Engl. 1968,
7
, 806.
J . Org. Chem, Vol. 68, No. 1, 2003 185

was washed with DMF, DCM, and MeOH and dried. Following
cleavage of the resin with HF/anisole (95/5) for 7 h at 0 °C, the
desired product was extracted with acetic acid/water (95/5) and
lyophilized. The product was characterized by electrospray LC-
MS under ESI conditions.
(2-p h en yleth yl)h yd r a zin e (10e). HRMS (MALDI) m/z calcd
+
for C24
34 6 3
H N O Na (M + Na) 477.2584, found 477.2590.
1-((1S)-1-Ben zyl-2-{1-[(1R)-1-ben zyl-2-(1-m eth yl-2-oxoh y-
dr azin o)eth yl]-2-oxoh ydr azin o}eth yl)-1-(2-cycloh exyleth yl)-
2-oxoh ydr azin e (10f). HRMS (MALDI) m/z calcd for C H N O -
2
7
38
6
3
+
Gen er a l P r oced u r e for th e Solu tion -P h a se Syn th esis of
Nitr osa m in e 10. A 5.7-mL sample of ethyl nitrite (10 wt %
solution in ethyl alcohol, 60 equiv) was added to a solution of
triamine 9 (0.1 mmol) in DCM (5 mL) in a 25-mL vial. The
reaction mixture was kept at room temperature for 5 days and
the solvent was removed via rotary evaporation to yield the
corresponding nitrosamine 10. The product was characterized
by electrospray LC-MS under ESI conditions and MALDI-FTMS.
Na (M + Na) 517.2897, found 217.2910.
-((1S)-1-Ben zyl-2-{1-[(1R)-1-ben zyl-2-(1-m eth yl-2-oxoh y-
d r a zin o)eth yl]-2-oxoh yd r a zin o}eth yl)-1-n eop en tyl-2-oxo-
h yd r a zin e (10g). HRMS (MALDI) m/z calcd for C24 Na
1
34 6 3
H N O
+
(
M + Na) 477.2584, found 477.2579.
-((1S)-1-Ben zyl-2-{1-[(1R)-1-ben zyl-2-(1-m eth yl-2-oxoh y-
d r a zin o)eth yl]-2-oxoh yd r a zin o}eth yl)-1-isobu tyl-2-oxoh y-
d r a zin e (10h ). HRMS (MALDI) m/z calcd for C23 Na (M
1
32 6 3
H N O
1
N-Meth yl-N-n itr osoph en eth ylam in e 1. H NMR (400 MHz,
+
+
Na) 463.2428, found 463.2427.
X-r a y Sin gle-Cr ysta l Str u ctu r e Deter m in a tion of Com -
p ou n d 10h a t 296(2) K. Cr ysta l d a ta : C23 , M 440.55,
monoclinic, space group P2 /n, a ) 6.1740(6) Å, b ) 20.897(2)
CDCl ): δ 3.00 (3.57) (s, 3H), 3.05 (2.81) (t, J ) 7.2 Hz, 2H),
3
4
.40 (3.80) (t, J ) 7.2 Hz, 2H). The NMR spectrum showed that
H
32
N
6
O
3
r
there were two rotational isomers in a ratio of 3.1:1 due to
1
restricted rotation of the N-N bond. The signals of the minor
Å, c ) 9.8368(10) Å, R ) 90°, â ) 106.255(2)°, γ ) 90°, V )
1
4
one are shown in parentheses. Compound 1 was treated with
HF for 7 h at 0 °C to yield N-methylphenethylamine 2: MS (ESI)
3
3
1
(
218.4(2) Å , Z ) 2, Fcalcd 1.201 Mg/m , F000 ) 472, wavelength
-1
λ) ) 0.71073 Å, absorption coefficient (µ) ) 0.082 mm . Da ta
+
m/z 370.1 (M + H ).
collection a n d r ed u ction : crystal size ) 0.26 × 0.18 × 0.12
1
-((1S)-1-Ben zyl-2-{1-[(1R)-1-m et h yl-2-(1-m et h yl-2-oxo-
3
mm ; θ range, 1.95-28.06°; index ranges -7 e h e 8, -27 e k
h yd r a zin o)et h yl]-2-oxoh yd r a zin o}et h yl)-2-oxo-1-(2-p h e-
e 25, -12 e l e 12; reflection collected, 9998; independent
reflections, 4810 (Rint ) 0.0319); refinement method, full-matrix
n yleth yl)h yd r a zin e (10a ). HRMS (MALDI) m/z calcd for
+
C
21
H
1
28
N
6
O
3
Na (M + Na) 435.2115, found 435.2128.
2
least-squares on F ; date/restraints/parameters, 4810/1/292; final
-((1S)-1-Ben zyl-2-{1-[(1R)-1-b en zyl-2-(1-m et h yl-2-oxo-
2
R indices[I > 2ú(I)]: R1 ) 0.0537, wR2 ) 0.1304, GOF on F
.025, R indices (all data) R1) 0.1018, wR2 ) 0.1539, largest
)
h yd r a zin o)et h yl]-2-oxoh yd r a zin o}et h yl)-2-oxo-1-(2-p h e-
n yleth yl)h yd r a zin e (10b). HRMS (MALDI) m/z calcd for
1
-3
difference peak and hole, 0.270 and -0.117 e Å
.
+
C
27
H
1
32
N
6
O
3
Na (M + Na) 511.2428, found 511.2419.
-[(1S)-1-Ben zyl-2-(1-{(1R)-3-m eth yl-1-[(1-m eth yl-2-oxo-
h yd r a zin o)m et h yl]bu t yl}-2-oxoh yd r a zin o)et h yl]-2-oxo-1-
2-p h en yleth yl)h yd r a zin e (10c). HRMS (MALDI) m/z calcd
Ack n ow led gm en t. This work was supported by
National Cancer Institute Grant No. CA78040 (Hought-
en).
(
+
for C24
-[(1S)-1-Ben zyl-2-(1-{(1R)-2-m eth yl-1-[(1-m eth yl-2-oxo-
h yd r a zin o)m eth yl]p r op yl}-2-oxoh yd r a zin o)eth yl]-2-oxo-1-
2-p h en yleth yl)h yd r a zin e (10d ). HRMS (MALDI) m/z calcd
34 6 3
H N O Na (M + Na) 477.2584, found 477.2578.
1
Su p p or tin g In for m a tion Ava ila ble: Copies of LC-MS,
(
1
HRMS of compounds 10a -h ; H NMR of compounds 1, 10a ,
+
for C23
-[(1S)-1-Ben zyl-2-(1-{(1R)-2-m eth yl-1-[(1-m eth yl-2-oxo-
h yd r a zin o)m eth yl]p r op yl}-2-oxoh yd r a zin o)eth yl]-2-oxo-1-
32 6 3
H N O Na (M + Na) 463.2428, found 463.2423.
and 10b; tables of crystal data for 10h (crystal data and
structure refinement, atomic coordinates and equivalent iso-
tropic displacement parameters and bond lengths and angles).
This material is available free of charge via the Internet at
http://pubs.acs.org.
1
(
14) (a) Seebach D.; Enders D. Angew. Chem., Int. Ed. Engl. 1972,
1, 301. (b) Itoh, T.; Matsuya, Y.; Maeta, H.; Miyazaki, M.; Nagata,
K.; Ohsawa, A. Chem. Pharm. Bull. 1999, 47, 819.
1
J O0204909
1
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