Asymmetric Synthesis of Differentially Protected 2,7-Diaminosuberic Acid, a Ring-Closure Metathesis Approach

Article abstract of DOI:10.1021/jo971575q

An efficient and versatile method has been developed for the synthesis of a selectively protected 2,7-diaminosuberic acid derivative. A Grubbs ring-closure olefin metathesis reaction was used as a key step on an allylglycine-derived template.

Full text of DOI:10.1021/jo971575q

2130
J . Org. Chem. 1998, 63, 2130-2132
Asym m etr ic Syn th esis of Differ en tia lly P r otected
2,7-Dia m in osu ber ic Acid , a Rin g-Closu r e Meta th esis Ap p r oa ch
Robert M. Williams* and J iwen Liu
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523
Received August 25, 1997
An efficient and versatile method has been developed for the synthesis of a selectively protected
2,7-diaminosuberic acid derivative. A Grubbs ring-closure olefin metathesis reaction was used as
a key step on an allylglycine-derived template.
The disulfide bonds of cystine-containing peptides (1)
preparation of the related 2,6-diaminopimelic acid de-
rivatives in differentially protected form. Recently,
Grubbs and co-workers10 reported the elegant use of ring-
closing olefin metathesis on allylglycine-containing pep-
tides to construct rigidified amino acids and peptide
systems. Since the specific sequence and attendant
conformation of linear peptide substrates can often have
a profound effect on the efficiency of macrocyclization,
there still exists a need for alternative methods and
building blocks for making 2,7-diaminosuberic acid-
containing cyclic peptides. In this paper, we report an
alternative method for the synthesis of selectively pro-
tected 2,7-diaminosuberic acid with defined stereochem-
istry. The methodology, which is based on the Grubbs
approach,10 is readily applicable to synthesizing other
stereoisomers and could, in principle, be expanded to
include homologues with additional methylene units
spanning the glycyl substructures.
As shown in Scheme 1, N-(tert-butyloxycarbonyl)al-
lylglycine was synthesized via enolate alkylation of 4
(95% yield of 5 as a single diastereomer) followed by
dissolving metal reduction.11 Condensation of the acid
with 1,2-benzenedimethanol (7) afforded the benzyl ester
8 (85%). Activation with p-nitrophenyl carbonate gave
9, which was condensed with the TFA salt of allylglycine
phenyl ester (10, prepared from 6 in 75% yield by
formation of the phenyl ester (PhOH, DCC) and TFA
removal of the BOC group) to afford 11 in 86% yield.
Ring-closure olefin metathesis according to Grubbs10
furnished the macrocycle 12 in >80% yield. Finally,
catalytic hydrogenation of 12 concomitantly saturated the
olefin and cleaved both of the benzyl ester linkages,
providing the differentially protected 2,7-diaminosuberic
acid derivative 13 in high yield.
constitute an important determinant of peptide hormone
secondary structure and protein secondary and tertiary
structure. However, the disulfide linkage is chemically
and metabolically labile to reducing environments and
nucleophilic and basic agents. Thus, isosteric dicarba
analogues of cystine peptides (2), where the sulfur atoms
have been replaced by methylene groups, have been
synthesized and utilized to improve the chemical stability
of biologically active peptides such as analogues of
calcitonin,1 oxytocin,2-4 and somatostatin.5-7
The constituent amino acid of these dicarba cystine
analogues is (2S,7S)-2,7-diaminosuberic acid (3, Figure
1). Despite the simplicity of this structure, the two amino
and carboxyl groups must be differentially protected for
convenient manipulation during solution- and/or solid-
phase peptide synthesis. Previously described syntheses
of 2,7-diaminosuberic acid typically involve Kolbe dimer-
ization of two glutamic acid units. This approach is
useful for the synthesis of symmetrical compounds,
although it has also been used to prepare differentially
protected 2,7-diaminosuberic acid8 by the dimerization
of two differently protected glutamic acids. As expected,
this procedure yields a statistical mixture of two undes-
ired symmetric dimers and one desired unsymmetrical
dimer, which must separated.
It would be quite useful for additional applications of
this cystine replacement, if there were more flexible
methods for the unambiguous preparation of this build-
ing block that would also be amenable to the preparation
of the R,R, S,R, and R,S-diastereomers. We have previ-
ously reported9 such a solution to this problem for the
(1) Sakakibara, S. In Peptides, Proceedings of the Fifth American
Peptide Symposium; Goodman and Meienhofer, Eds.; Wiley: New York,
1977; p 436.
(2) Rudinger, J .; J ost, K. Experientia 1964, 20, 570.
(3) J ost, K.; Rudinger, J . J . Collect. Czech. Chem. Commun. 1967,
32, 1229.
(4) Walker, R.; Yamanaka, T.; Sakakibara, S. Proc. Natl. Acad. Sci.
U.S.A. 1974, 71, 1901.
(5) Veber, D. F.; Strachan, R. G.; Bergstrand, S. J .; Holly, F. W.;
Homnick, C. F.; Hirschmann. R.; Torchiana, M. L.; Saperstein, R. J .
Am. Chem. Soc. 1976, 98, 2367.
(6) Emura, J .; Morikawa, T.; Takaya, T.; Sakakibara, S. In Proceed-
ings of the 14th Symposium on Peptide Chemistry; Nakajima, T., Ed.;
Protein Research Foundation: Osaka, J apan, 1977; p 36.
(7) Veber, D. F.; Holly, F. W.; Nutt, R. F.; Bergstrand, S. J .; Brady,
R. F.; Hirschmann. R.; Glitzer, M. S.; Saperstein, R. Nature (London)
1979, 280, 512.
Some related observations on similar approaches that
we examined are worthy of note. Initially, we examined
the ring-closure olefin metathesis of the t-BOC-(S)-
allylgly-(S)-allylgly-OPh substrate 14. Unfortunately, no
cyclization products were observed (Scheme 2). This is
presumably due to the preference for the amide linkage
to adopt the more thermodynamically stable s-trans
conformation. We also examined the cyclization of the
corresponding 1,3-benzenedimethanol substrate (16) and
the 1,4-benzenedimethanol substrate (18). Compound 16
cyclized to provide the desired macrocycle 17, in similar
(8) Nutt, R. F.; Strachan, R. G.; Veber, D. F.; Holly, F. W. J . Org.
Chem. 1980, 45, 3078.
(9) (a) Williams, R. M.; Yuan, C. J . Org. Chem. 1994, 59, 6190. (b)
Williams, R. M.; Yuan, C. J . Org. Chem. 1992, 57, 6519.
(10) Miller, S. J .; Blackwell, H. E.; Grubbs, R. H. J . Am. Chem. Soc.
1996, 118, 9606.
(11) Williams, R. M.; Im, M. N. J . Am. Chem. Soc. 1991, 113, 9276.
S0022-3263(97)01575-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/12/1998

Synthesis of Protected 2,7-Diaminosuberic Acid
J . Org. Chem., Vol. 63, No. 7, 1998 2131
F igu r e 1.
Sch em e 1
Sch em e 2
C-C bond-coupling reactions besides olefin metathesis
are under examination via the general strategy employed
herein. Efforts to extend this methodology are being
pursued in this laboratory and will be reported in due
course.
Exp er im en ta l Section
Gen er a l Meth od s. For general experimental consider-
ations and conditions, please refer to ref 11. Compound 6 was
prepared according to ref 11. The purity of all new compounds
reported was >95% as ascertained by homogeneity on TLC
1
and by H NMR (see the Supporting Information).
Allylglycin e P h en yl Ester (10). To a stirred solution of
6 (402 mg, 1.87 mmol), phenol (176 mg, 1.87 mmol), and
pyridine (0.15 mL, 1.87 mmol) in THF (8 mL) at -20 °C was
added DCC (386 mg, 1.87 mmol). The mixture was stirred at
room temperature overnight. A few drops of AcOH was added,
and 0.5 h later, the precipitate was removed by filtration. The
filtrate was washed with 3% citric acid, 5% sodium bicarbon-
ate, and brine. The organic solution was dried and concen-
trated to give N-(tert-butyloxycarbonyl)allylglycine phenyl
ester (520 mg, 95%) as a colorless oil; this substance was used
directly without further purification for the next step. To a
solution of this compound (520 mg, 1.8 mmol) in CH2Cl2 (5
mL) at 0 °C was added trifluoroacetic acid (5 mL). The mixture
was stirred at 0 °C for 2.5 h. The mixture was concentrated
under reduced pressure at 0 °C to an oil. Ether was added to
the oil, and the mixture was concentrated again. The residue
was triturated with 1:1 ether/petroleum ether at -30 °C,
filtered, and washed with 1:1 ether/petroleum ether to give
10 (430 mg, 79%) as white solid: 1H NMR (300 MHz, DMSO-
d6, vs TMS) δ 2.75 (2H, apparent t, J ) 6.2 Hz), 4.46 (1H, t, J
yield (82%) to that obtained with 11. The 1,4-disubsti-
tuted substrate 18 failed to give any detectable cycliza-
tion product. It is thus clear from these observations and
related ones from the literature that the conformational
space accessible to the olefin metathesis substrate is a
critical aspect for a successful cyclization.
In summary, selectively protected 2,7-diaminosuberic
acid derivative 13 of high optical purity has been
prepared efficiently from N-(tert-butyloxycarbonyl)-(S)-
allylglycine.12 The protecting groups of 13 can be readily
manipulated and should prove useful for both solution-
phase and solid-phase cyclic peptide synthesis. Other
(12) After completion of this work, we learned that Prof. J ohn C.
Vederas (University of Alberta) and co-workers have independently
developed an olefin metathesis route to the selectively protected 2,7-
diaminosuberic acid system. We thank Prof. Vederas for sharing his
data with us prior to publication. J . Org. Chem. 1998, 63, 2133.

2132 J . Org. Chem., Vol. 63, No. 7, 1998
Williams and Liu
) 6.2 Hz), 5.20-5.40 (2H, m), 5.80-6.00 (1H, m), 7.10-7.50
(5H, m), 8.60 (3H, bs); 13C NMR (75 MHz, DMSO-d6) δ 34.43,
51.72, 120.3, 121.3, 126.5, 129.8, 131.1, 149.6, 167.9; IR (KBr
86%) as a colorless oil: 1H NMR (300 MHz, DMSO-d6, vs TMS)
δ 1.42 (9H, s), 2.40-2.62 (2H, m), 2.65-2.72 (2H, m), 4.35-
4.48 (1H, dd, J ) 7.8, 6 Hz), 4.60-4.72 (1H, dd, J ) 7.6, 6.3
Hz), 5.00-5.10 (3H, m), 5.15-5.30 (6H, m), 5.58-5.90 (3H,
m), 7.00-7.45 (9H, m); 13C NMR (75 MHz, CDCl3) δ 28.46,
36.80, 36.83, 53.10, 53.77, 64.75, 64.77, 80.14, 119.4, 119.9,
121.5, 126.3, 128.9, 129.1, 129.7, 130.2, 130.3, 132.1, 132.4,
134.2, 135.1, 150.6, 155.4, 155.8, 170.6, 172.0; IR (NaCl, neat)
pellet) 2927, 1762, 1667 cm-1; [R]25 +4.6° (c 2.4, CH2Cl2);
D
HRMS calcd for C11H14NO2 (M + H+) 192.1024, found 192.1017.
Com p ou n d 8. EDCI (240 mg, 1.25 mmol) was added to
solution of N-(tert-butyloxycarbonyl)allylglycine (6)12 (200 mg,
0.93 mmol), 1,2-benzenedimethanol (500 mg, 3.63 mmol), and
DMAP (14.7 mg, 0.12 mmol) in CH2Cl2 (16 mL) at 0 °C. The
solution was stirred at 0 °C for 3 h and at room temperature
overnight. The mixture was concentrated, and the residue was
purified by column chromatography (silica gel, 1:1 hexanes/
EtOAc then EtOAc) to give 8 (230 mg, 74%) as colorless oil
(400 mg of 1,2-benzenedimethanol was also recovered): 1H
NMR (300 MHz, DMSO-d6, vs TMS) δ 1.41 (9H, s), 2.22 (1H,
bs), 2.40-2.62 (2H, m), 4.30-4.42 (1H, dd, J ) 7.7, 6 Hz), 4.75
(2H, ABq, J ) 12.5 Hz), 4.95-5.20 (3H, m), 5.29 (2H, ABq, J
) 12.5 Hz), 5.55-5.70 (1H, m), 7.30-7.50 (4H, m); 13C NMR
(75 MHz, CDCl3) δ 28.38, 36.58, 53.16, 62.68, 64.92, 80.23,
119.4, 128.1, 128.9, 129.1, 129.9, 132.3, 133.3, 139.6, 155.5,
172.1; IR (NaCl, neat) 3375, 3080, 2978, 1698 cm-1; [R]25D -8.0°
(c 4.8, CH2Cl2); HRMS calcd for C18H26NO5 (M + H+) 336.1811,
found 336.1802.
3346, 3076, 2979, 1716 cm-1; [R]25 -3.5° (c 5.2, CH2Cl2);
D
HRMS calcd for
553.2581.
C
30H37N2O8 (M + H+) 553.2550, found
Com p ou n d 12. The Ru catalyst10 RuCl2(dCHPh)(PCy3)2
(81 mg, 0.1 mmol) in CH2Cl2 (2 mL) was added via gastight
syringe to a solution of 11 (135 mg, 0.24 mmol) in CH2Cl2 (70
mL, degassed and dried). The solution was stirred at 43 °C
for 66 h. The resulting mixture was concentrated, and the
residue was purified by column chromatography (silica gel, 3:1
hexanes/EtOAc) to give 12 (106 mg, 83%) as an off-white solid
(13 mg of 11 was recovered). 1H NMR revealed two geo-
metrical isomers exist in 1:1 ratio; these isomers were not
separated but used directly for the next step as a mixture (the
NMR data is included in the Supporting Information): IR
(KBr, pellet) 3340, 2977, 1718, 1506 cm-1; [R]25 -29° (c 1.36,
D
Com p ou n d 9. To a solution of 8 (220 mg, 0.66 mmol) and
bis(4-nitrophenyl) carbonate (500 mg, 1.64 mmol) in DMF (8
mL) was added diisopropylethylamine (128 mg, 0.99 mmol).
The yellow solution was stirred overnight and poured into
EtOAc (40 mL). The organic layer was washed with 0.01 N
KOH until the aqueous layer was no longer yellow, and the
organic layer was then washed with brine twice, dried, and
concentrated under reduced pressure. The residue was puri-
fied by column chromatography (silica gel, 3:1 hexanes/EtOAc)
to give 9 (300 mg, 90%) as a colorless oil: 1H NMR (300 MHz,
CDCl3) δ 1.42 (9H, s), 2.40-2.55 (2H, m), 4.38-4.48 (1H, dd,
J ) 7.7, 6 Hz), 5.00-5.15 (3H, m), 5.33 (2H, ABq, J ) 12.5
Hz), 5.42 (2H, s), 5.58-5.75 (1H, m), 7.30-7.50 (6H, m), 8.25-
8.30 (2H, m); 13C NMR (300 MHz, CDCl3) δ 28.46, 36.82, 53.14,
64.53, 68.53, 80.19, 119.5, 121.9, 125.5, 129.3, 129.8, 130.5,
130.5, 132.3, 133.1, 134.6, 145.6, 152.5, 155.7, 172.0; IR (NaCl,
CH2Cl2); HRMS calcd for C28H33N2O8 (M + H+) 525.2237, found
525.2254.
Com p ou n d 13. A mixture of 12 (15 mg, 0.029 mmol),
p-TsOH (5.7 mg, 0.03 mmol), and Pd/C (10%) (4 mg) in
2-propanol (2 mL) and THF (0.1 mL) was stirred at room
temperature under 1 atm of H2 for 2.5 h. The mixture was
filtered, and the filtrate was concentrated under reduced
pressure to give 13 (15 mg 95%) as an off-white solid: 1H NMR
(300 MHz, methanol-d4) δ 1.44 (9H, s), 1.45-2.15 (8H, m), 2.37
(3H, s), 4.05-4.15 (1H, m), 4.30-4.40 (1H, m), 7.10-7.50 (7H,
m), 7.71 (2H, d, J ) 8.2 Hz); 13C NMR (75 MHz, methanol-d4)
δ 21.45, 25.56, 26.51, 28.88, 31.56, 32.75, 54.25, 122.5, 127.1,
127.9, 130.0, 130.9, 141.8, 143.7, 151.7, 169.7; IR (KBr) 3422,
2977, 1718 cm-1; [R]25D +17.5° (c 1, methanol-d4); HRMS calcd
for C19H29N2O6 (M + H+) 381.2026, found 381.2040.
neat) 3400, 3081, 2978, 1766, 1716, 1525, 1348 cm-1; [R]25
D
Ack n ow led gm en t. This work was supported by the
National Science Foundation (CHE 9320010) and Ex-
cyte Therapies, Inc.
-6.9° (c 5.8, CH2Cl2); HRMS calcd for C25H29N2O99 (M + H+)
501.1873, found 501.1858.
Com p ou n d 11. To a solution of 9 (200 mg, 0.4 mmol) and
compound 10 (134 mg, 0.44 mmol) in DMF (3 mL) was added
diisopropylethylamine (0.175 mL, 0.99 mmol). The yellow
solution was stirred overnight and poured into EtOAc (40 mL).
The organic layer was washed twice with 3% citric acid and
with 0.01 N KOH until the aqueous phase was no longer
yellow. The mixture was then washed with brine twice, dried
over anhydrous Na2SO4, and concentrated to give 11 (190 mg,
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
compounds 8-13 (6 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 O971575Q