A short synthesis of conformationally constrained unnatural bicyclic amino acids containing a nitrogen atom at the ring juncture: (9aR)- and (9aS)-octahydropyrido[1,2-a]pyrazine-(3S)-carboxylic acids (Opc)

Article abstract of DOI:10.1055/s-2008-1042762

A short and efficient route to conformationally constrained amino acid analogues, (9aR)- and (9aS)-octahydropyrido[1,2-a]pyrazine-(3S)-carboxylate (Opc) has been developed. The new bicyclic amino acid derivatives can be stored and utilized as a modular unit for the construction of unnatural oligopeptides using conventional peptide coupling methods. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1042762

702
LETTER
A Short Synthesis of Conformationally Constrained Unnatural Bicyclic Amino
Acids Containing a Nitrogen Atom at the Ring Juncture: (9aR)- and (9aS)-Oc-
tahydropyrido[1,2-a]pyrazine-(3S)-carboxylic Acids (Opc)
A
S
hort Synth
o
e
sis of
U
nna
o
tural Bicycli
n
A
mino Acids (O
p
M
c) og So, Chang-Eun Yeom, Seong Mi Cho, Soo Young Choi, Young Keun Chung, B. Moon Kim*
Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 151-747, Korea
Fax +82(2)8727505; E-mail: kimbm@snu.ac.kr
Received 15 November 2007
Abstract: A short and efficient route to conformationally con-
strained amino acid analogues, (9aR)- and (9aS)-octahydropyri-
do[1,2-a]pyrazine-(3S)-carboxylate (Opc) has been developed. The
new bicyclic amino acid derivatives can be stored and utilized as a
modular unit for the construction of unnatural oligopeptides using
conventional peptide coupling methods.
H
OH
H
H
N
N
O
HO
O
S
N
H
Key words: conformationally constrained, unnatural amino acid,
Ph
bicyclic, peptidomimetic, cyclic sulfamidate
nelfinavir
OH
O
O
O
O
Many conformationally constrained amino acid deriva-
tives have been utilized for the construction of biological-
ly active molecules due to their stability towards
proteolytic process and alteration of undesired peptidic
characteristics while preserving or enhancing desirable
biological activities.1
O
O
N
H
O
N
O
N
OH
HN
OH
O
Tetrahydro- and decahydroisoquinoline-2-carboxylic ac-
ids [Tic (1) and Dic (2), respectively, Figure 1] can be
viewed as a conformationally constrained phenylalanine
analogues and have often been incorporated in biological-
ly active peptidomimetic structures such as HIV protease
inhibitors,2 ras farnesyl protein transferase (FTase) inhib-
itors,3 anticonvulsants,4 bradykinin antagonists,5 throm-
moexiprilat
quinapril hydrochloride
O
H
bin
inhibitors,6
angiotensin-converting
enzyme
O
NH2 OH
H
N
H
inhibitors,7 renin inhibitors,8 and angiotensin-receptor an-
tagonists.9 Some representative examples of these Tic- or
Dic-containing biologically active molecules are shown
in Figure 2. Due to such wide use, effort has been focused
on the efficient synthesis of the two unnatural amino ac-
ids.10 From our continuing work in the development of
HIV protease inhibitors11 and ras FTase inhibitors,12 we
N
N
O
N
H
O
Ph
N
H
saquinavir
Figure 2 Examples of Tic- or Dic-containing drug molecules
have been interested in the preparation of conformational-
ly constrained bicyclic amino acids containing an extra ni-
trogen atom at the ring juncture such as
octahydropyrido[1,2-a]pyrazine-3-carboxylic acid (3 and
4, Figure 1). The additional nitrogen atom at the bicyclic
ring juncture in these structures may alter the physico-
chemical properties, such as aqueous solubility and bio-
availability, of the molecules containing these moieties.
H
H
N
N
HN
HN
HN
HN
CO2H
CO2H
CO2H
CO2H
1 (Tic)
3
4
2 (Dic)
Recently the synthetic utility of cyclic sulfamidate 5 de-
rived from serine as an effective ‘b-alanine cation’ syn-
thon has been amply demonstrated in the literature.13,14
We have also established that optically active 2,3-diami-
nopropanoic acid derivatives 6 can be efficiently prepared
from the cyclic sulfamidate 5 (R1 = benzyl, R2 = CO2Et)14
without racemization, whereas treatment of activated al-
Figure 1 Examples of conformationally constrained amino acid de-
rivatives
SYNLETT 2008, No. 5, pp 0702–0706
x
x.
x
x.
2
0
0
8
Advanced online publication: 12.02.2008
DOI: 10.1055/s-2008-1042762; Art ID: U12107ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
A Short Synthesis of Unnatural Bicyclic Amino Acids (Opc)
703
O
R1
R1
a
O
S
NH
R2R3NH
N
*
*
NR2R3
O
N
H
CH2OTBS
N
CH2OH
H
RO2C
RO2C
10
(R or S)
11
(R or S)
6
5
H
H
R22NH
N
N
R1
O
R1
OMs
d
Bn
b,c
O
S
N
CO2R
Bn NH
RO2C
N
CO2R
O
CH2OTBS
RO2C
8
7
12 R = Et
14 R = Me
15 R = Et
16 R = Me
64%
61%
77%
80%
Scheme 1 Reactivity difference between cyclic sulfamidate and se-
rine mesylate
cohol-containing serine ester derivatives, such as 7, di-
rectly with a secondary amine nucleophiles tend to evoke
elimination yielding undesired a,b-unsaturated esters 8 as
shown in Scheme 1.15 We envisioned that the optically ac-
tive bicyclic amino acids 3 and 4 could be constructed
from the cyclic sulfamidate 5 by taking advantage of the
methodology developed for the preparation of 2,3-diami-
nopropanoic acid derivatives 6.14 Herein we report on the
short synthesis of both diastereomers of (9aR)- and (9aS)-
octahydropyrido[1,2-a]pyrazine-(3S)-carboxylates.
H
N
Bn
e
N
Bn NH
RO2C
N
CH2OH
RO2C
13 R = Et
17 R = Me
18 R = Et
19 R = Me
77%
75%
Scheme 3 Synthesis of 18 and 19. Reagents and conditions: (a)
TBSCl, imidazole, CH2Cl2; (b) (R)-11, MeCN; (c) BF3·OEt2, n-pro-
panethiol, CH2Cl2; (d) TBAF, THF; (e) I2, Ph3P, imidazole, MeCN.
For an amine nucleophile equipped with a handle for the
bicyclic ring closure, (2R)- and (2S)-hydroxymethylpipe-
ridines [(R)-10 and (S)-10, respectively] were chosen as
appropriate nucleophiles to open the corresponding cyclic
sulfamidate 5. As shown in Scheme 2, optically active 2-
hydroxymethylpiperidine (10) was prepared starting from
racemic pipecolic acid through resolution using tartaric
acid according to a known procedure16 followed by reduc-
tion using lithium aluminum hydride. With optically ac-
tive hydroxymethylpiperidine (10) in hand, direct ring-
opening reaction of sulfamidate 12 was attempted to pre-
pare compound 13 (Scheme 2). However, ring opening of
12 with (2R)-hydroxymethylpiperidine [(R)-10] followed
by hydrolysis of the sulfamic acid intermediate14a provid-
ed the desired product 13 in a poor yield (23%).
date 12 with (2R)-(tert-butyldimethylsilyloxymethyl)-
piperidine [(R)-11] followed by hydrolysis of the interme-
diate sulfamic acid furnished the desired product 14 in a
much improved yield (64%). Since a successful intramo-
lecular cyclization to piperidine from an alcohol and a sul-
fonamide under Mitsunobu conditions was reported,17 we
have attempted direct intramolecular reaction of 13. How-
ever, the reaction of the desilylated alcohol 13 under Mit-
sunobu conditions was very sluggish. Activation of the
hydroxyl group using Ph3P, imidazole, and I2 in acetoni-
trile led to successful cyclization as shown in Scheme 3.18
Conversion of the primary alcohol moiety of 13 into the
corresponding iodide induced spontaneous intramolecular
cyclization to the desired bicyclic structure 18 in 77%
yield. In the same manner, starting from methyl ester 14,
bicyclic methyl ester derivative 19 was prepared in almost
the same yield in each step as shown in Scheme 3.
To increase the yield of the coupling reaction, (R)-10 was
protected with tert-butyldimethylsilyl group to provide
(R)-11 (Scheme 3) and the ring-opening reaction was car-
ried out as shown in Scheme 3. Opening of the sulfami-
A diastereomeric bicyclic amino acid derivative 21 hav-
ing an epimeric center at the ring carbon was also pre-
a
b
*
+
*
N
CO2H
N
CO2H
N
H
CH2OH
H
H2
( )-pipecolic acid
9
10
(R or S)
(R or S)
O
–
SO3
d
Bn
O
c
S
+
N
BnHN
EtO2C
N
Bn
N
N
O
CH2OH
CH2OH
EtO2C
RO2C
12
13
23%
Scheme 2 Coupling of 10 with cyclic sulfamidate 12. Reagents and conditions: (a) (+) or (–)-tartaric acid, boiling EtOH; (b) LAH, THF; (c)
(R)-10, MeCN; (d) BF3·OEt2, n-propanethiol, CH2Cl2.
Synlett 2008, No. 5, 702–706 © Thieme Stuttgart · New York

704
S. M. So et al.
LETTER
O
Bn
O
S
N
O
H
MeO2C
13
Bn
Bn NH
MeO2C
N
N
a
b
+
CH2OH
N
73%
MeO2C
76%
21
20
N
H
CH2OTBS
(S)-11
Scheme 4 Preparation of epimeric amino acid 21. Reagents and conditions: (a) i) (S)-11, THF; ii) concd H2SO4, H2O; (b) I2, PPh3, imidazole,
MeCN.
H
pared using the same strategy with a slightly different
H
Boc
a
Bn
b
tactic in the hydrolysis of intermediate sulfamic acid. The
sulfamidate 14 was treated with an antipodal piperidine
derivative (S)-11 and the ring-opened product was direct-
ly hydrolyzed using a catalytic amount of sulfuric acid.19
As shown in Scheme 4, the free amino alcohol 20 could be
obtained directly in 76% yield. Cyclization through simi-
lar iodide intermediate provided the desired diastereomer-
ic bicyclic amino acid derivative 21 in 73% yield.
N
N
90%
94%
N
N
MeO2C
MeO2C
22
19
H
N
H
N
Ac
c
Ac
N
N
85%
MeO2C
BnHNOC
It has been found that these 6,6-bicyclic unnatural amino
acid derivatives 19 and 21 are both chemically and stereo-
chemically stable upon storage at 0 °C in an inert atmo-
sphere for several months. To see if the bicyclic amino
acid derivatives can be used as a modular unit for oli-
gopeptide synthesis, a dipeptide analogue 24 and a tri-
peptide derivative 27 were synthesized using
conventional solution-phase peptide synthesis as shown
in Schemes 5 and 6. Removal of the N-benzyl group of 19
followed by in situ Boc protection provided compound 22
in 90% yield. This Boc ester derivative 22 was stable upon
23
24
Scheme 5 Deprotection and coupling of compound 19 to provide an
end-capped compound 24. Reagents and conditions: (a) Pd/C, H2 (1
atm), (Boc)2O, MeOH; (b) i) TFA, CH2Cl2; ii) Ac2O, Et3N, CH2Cl2;
(c) i) LiOH, MeOH–H2O; ii) BnNH2, EDC, HOBt, DIEA, CH2Cl2.
H
H
N
Bn
Cbz
a
N
N
b
N
95%
MeO2C
MeO2C
75%
1
storage in a refrigerator over several months. H NMR
19
25
spectrum indicated that compound 22 exists as a mixture
(ca. 1:1) of cis- and trans-amide rotamers. Removal of the
Boc group followed by acetylation of the subsequent sec-
ondary amine moiety provided compound 23 in 94% yield
again as a ca. 3.3:1 rotamer mixture. Hydrolysis of the es-
ter 23 using LiOH and subsequent amide formation using
benzylamine provided compound 24 in 85% overall yield
for two steps. Likewise, synthesis of a tripeptide
(BocAlaOpcPheOMe) 27 containing the bicyclic amino
acid was easily performed through a conventional solu-
tion-phase peptide-coupling strategy showing that the bi-
cyclic amino acid can be used as a modular unit for a
regular peptide synthesis (Scheme 6).
O
H
H
N
N
O
Boc
N
H
N
H
N
c
Boc
N
O
78%
NH
MeO2C
Bn
26
CO2Me
27
Scheme 6 Synthesis of a tripeptide derivative employing the Opc.
Reagents and conditions: (a) i) Pd/C, H2 (1 atm), MeOH; ii) CbzCl,
Et3N, CH2Cl2; (b) i) Pd/C, H2 (1 atm), MeOH; ii) Boc-L-Ala-OH,
EtOCOCl, NMM, THF, –20 °C; (c) i) LiOH, MeOH–H2O; ii) L-Phe-
OMe·HCl, EDC, HOBt, DIEA, DMF, r.t., 18 h.
To confirm the stereochemistry of the bicyclic compound,
the structure of (3S,9aR)-Boc-Opc-OMe (22) was deter-
mined through X-ray crystallography.20 The X-ray crystal
structure indicates that the bicyclic unit exhibits trans-
decalin conformation positioning the bulkier tert-butoxy-
carbonyl group at the pseudo-equatorial site (Figure 3).
no acid can be stored at 0 °C without losing its chemical
and stereochemical integrity. It could be used as a modu-
lar unit for a conventional peptide synthesis as exempli-
fied
in
the
preparation
of
a
tripeptide
In conclusion, we have devised a short synthetic route to
(9aR)- and (9aS)-octahydropyrido[1,2-a]pyrazine-(3S)-
carboxylic acid (Opc) derivatives as unnatural amino ac-
ids mimicking phenylalanine.21–26 The new bicyclic ami-
(BocAlaOpcPheOMe) containing the Opc unit. Employ-
ment of these unnatural amino acids in the context of en-
Synlett 2008, No. 5, 702–706 © Thieme Stuttgart · New York

LETTER
A Short Synthesis of Unnatural Bicyclic Amino Acids (Opc)
705
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Figure 3 X-ray crystal structure of (3S,9R)-Boc-Opc-OMe
zyme inhibitor design is currently in progress and will be
reported in due course.
Acknowledgment
This work was supported by the Korea Research Foundation Grant
funded by the Korean Government (MOEHRD; KRF-2006-312-
C00229).
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(20) CCDC #660993.
(21) Characterization Data for Compound 16
[a]D27 –15.0 (c 1.1, CHCl3). 1H NMR (300 MHz, CDCl3):
d = 0.03 (s, 6 H), 0.88 (s, 9 H), 1.28 (t, 3 H), 1.32–1.70 (m,
6 H), 2.23–2.45 (m, 1 H), 2.50–2.57 (m, 1 H), 2.64–2.76 (m,
3 H), 2.97–3.05 (m, 1 H), 3.38–3.51 (m, 2 H), 3.94 (ABq,
J = 13.3 Hz, 2 H), 3.96–3.88 (m, 1 H), 4.26–4.32 (m, 2 H),
7.21–7.32 (m, 5 H). 13C NMR (75 MHz, CDCl3): d = –5.47,
14.28, 18.21, 22.16, 25.39, 25.84, 28.20, 51.06, 52.14,
56.96, 59.58, 60.34, 62.17, 63.70, 126.86, 128.16, 128.22,
139.85, 174.46. HRMS (CI): m/z calcd for C23H41N2O3Si
[M + H]+: 421.2886; found: 421.2884.
Synlett 2008, No. 5, 702–706 © Thieme Stuttgart · New York

706
S. M. So et al.
LETTER
HRMS–FAB: m/z calcd for C15H27N2O4 [M + H]+:
(22) Characterization Data for Compound 17
[a]D28 –4.1 (c 1.1, CHCl3). 1H NMR (300 MHz, CDCl3): d =
1.29 (t, 3 H), 1.37–1.71 (m, 6 H), 2.27–2.45 (m, 2 H), 2.57–
2.64 (m, 1 H), 2.82–2.91 (m, 1 H), 2.98–3.05 (m, 1 H), 3.22
(br s, 2 H), 3.35–3.42 (m, 2 H), 3.67–3.76 (m, 1 H), 3.75
(ABq, J = 12.9, 2 H), 4.13–4.24 (m, 2 H), 7.22–7.32 (m, 5
H). 13C NMR (75 MHz, CDCl3): d = 14.25, 23.71, 23.86,
27.05, 52.47, 52.74, 54.38, 59.89, 60.92, 61.95, 63.07,
127.20, 128.35, 128.42, 139.03, 174.90. HRMS (CI): m/z
calcd for C18H29N2O3 [M + H]+: 321.2178; found: 321.2176.
(23) Characterization Data for Compound 19
299.1971; found: 299.1970.
(25) Characterization Data for Compound 23
[a]D11 +23.9 (c 1.00, CHCl3). 1H NMR (300 MHz, CDCl3):
d = 1.12–1.28 (m, 2 H), 1.51–1.61 (m, 3 H), 1.72–1.98 (m, 3
H), 2.03 (s, 0.7 H), 2.14 (s, 2.3 H), 2.24 (dd, 0.75 H), 2.33
(dd, 0.25 H), 2.49–2.61 (m, 0.25 H), 2.77–2.80 (m, 0.75 H),
3.09–3.18 (m, 0.9 H), 3.24–3.38 (m, 1.2 H), 3.43–3.54 (m,
0.9 H), 3.75 (s, 2.3 H), 3.79 (s, 0.7 H), 4.22–4.23 (m, 0.08 H),
4.27–4.28 (m, 0.08 H), 4.34–4.37 (m, 0.14 H), 5.17–5.19 (m,
0.7 H). 13C NMR (75 MHz, CDCl3): d = 21.52, 21.81, 23.98,
25.58, 25.67, 29.55, 29.62, 45.07, 49.88, 52.51, 52.76,
53.12, 55.72, 55.82, 56.04, 56.43, 57.57, 60.63, 60.98,
170.79, 171.01, 171.22. HRMS–FAB: m/z calcd for
C12H21N2O3 [M + H]+: 241.1552; found: 241.1558.
(26) Characterization Data for Compound 24
[a]D27 –10.5 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3):
d = 1.12–1.29 (m, 2 H), 1.27 (t, 3 H), 1.34–1.41 (m, 1 H),
1.56–1.59 (m, 2 H), 1.65–1.68 (m, 1 H), 1.87–1.96 (m, 2 H),
2.38–2.48 (m, 2 H), 2.70–2.74 (m, 1 H), 2.90–2.97 (m, 1 H),
3.04–3.08 (m, 1 H), 3.40 (s, 1 H), 3.90 (ABq, J = 13.7, 2 H),
4.14–4.24 (m, 2 H), 7.20–7.31 (m, 5 H). 13C NMR (75 MHz,
CDCl3): d = 14.78, 24.37, 25.96, 29.91, 53.41, 56.15, 58.27,
59.35, 60.25, 60.62, 61.85, 127.30, 128.65, 129.03, 139.75,
172.83. HRMS (CI): m/z calcd for C18H27N2O2 [M + H]+:
303.2072; found: 303.2073.
[a]D11 –59.2 (c 1.00, CHCl3). 1H NMR (300 MHz, CDCl3):
d = 1.03–1.31 (m, 2 H), 1.41–2.01 (m, 6 H), 2.12 (s, 1.2 H),
2.23 (m, 1.8 H), 2.34–2.52 (m, 2 H), 2.78–2.86 (m, 1 H),
3.03–3.15 (m, 1 H), 3.29–3.33 (m, 0.4 H), 3.44–3.48 (m, 0.4
H), 3.71–3.78 (m, 0.2 H), 4.32–4.55 (m, 2.6 H), 5.18–5.20
(m, 0.4 H), 7.05 (s, 0.4 H), 7.26–7.69 (m, 5 H), 8.46 (m, 0.6
H). 13C NMR (75 MHz, CDCl3): d = 21.89, 21.96, 23.81,
23.94, 25.62, 25.89, 29.62, 29.74, 43.78, 43.83, 44.07,
50.02, 52.95, 55.26, 55.52, 55.735, 55.89, 57.70, 60.75,
61.26, 126.29, 127.75, 127.88, 127.91, 128.22, 129.050,
129.14, 138.39, 138.70, 169.76, 170.05, 170.51, 170.91.
HRMS–FAB: m/z calcd for C18H26N3O2 [M + H]+:
316.2025; found: 316.2026.
(24) Characterization Data for Compound 22
[a]D11 –31.3 (c 1.00, CHCl3).1H NMR (300 MHz, CDCl3):
d = 1.11–1.96 (m, 17 H), 2.24–2.31 (m, 1 H), 2.70–2.88 (m,
2 H), 3.17–3.24 (m, 1 H), 3.62 (d, J = 3.2 Hz, 0.25 H), 3.66
(d, J = 3.2 Hz, 0.25 H), 3.74–3.80 (m, 3.5 H), 4.53 (d, J = 4
Hz, 0.5 H), 4.70 (d, J = 4 Hz, 0.5 H). 13C NMR (75 MHz,
CDCl3): d = 24.02, 24.07, 25.67, 28.64, 28.73, 29.54, 29.56,
46.87, 47.84, 52.58, 54.38, 55.65, 55.81, 55.93, 56.17,
60.70, 60.72, 80.55, 80.60, 155.54, 155.96, 171.68, 171.98.
Synlett 2008, No. 5, 702–706 © Thieme Stuttgart · New York

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