3,4-Methano-β-proline: A conformationally constrained β-amino acid

Article abstract of DOI:10.1055/s-0028-1087965

An enantiomerically pure, conformationally constrained β-proline derivative, 3,4-methano-β-proline, was synthesized starting with a readily available bicyclic lactone by using a straightforward synthetic route.

Full text of DOI:10.1055/s-0028-1087965

LETTER
921
3,4-Methano-b-Proline: A Conformationally Constrained b-Amino Acid
S
ynthesis of 3,4-M
m
ethano-
b
-Proline iya Kumar Medda, Hee-Seung Lee*
Department of Chemistry and School of Molecular Science (BK21), Korea Advanced Institute of Science and Technology (KAIST),
Daejeon 305-701, Korea
Fax +82(42)3502810; E-mail: hee-seung_lee@kaist.ac.kr
Received 29 November 2008
composed of d,d-disubstituted b-proline monomers can
preferentially form cis-amide conformations that display
different CD signals than those of poly-b-prolines.7
Abstract: An enantiomerically pure, conformationally constrained
b-proline derivative, 3,4-methano-b-proline, was synthesized start-
ing with a readily available bicyclic lactone by using a straightfor-
ward synthetic route.
These findings suggest that b-proline analogues with dif-
Key words: 3,4-methano-b-proline, conformationally constrained ferent substitution patterns could give rise to new fold-
b-amino acid, enantioselective synthesis
amer scaffolds with unique conformational properties.
Systematic conformational studies exploring this issue re-
quire the availability of b-proline monomers with diverse
substitution patterns. However, only a few reports exist
describing the synthesis of substituted b-prolines.8 In ad-
dition, b-proline has received a great deal of attention re-
cently owing to its role as an organocatalyst in
enantioselective C–C bond-forming reactions. For exam-
ple, b-proline and its derivatives have been used as ef-
fecient catalysts for anti-selective Mannich-type reactions
of aldehydes and ketones with imines.9 Consequently,
properly designed b-proline derivatives containing an ar-
ray of different substitution patterns could have unique
applications in the area of organocatalysis.
Conformationally constrained cyclic b-amino acids are
useful building blocks for the preparation of b-peptide fold-
amers.1 Secondary structures of b-peptide oligomers are
governed by conformational preferences of the compo-
nent monomers. For example, b-peptides that are com-
posed of five-membered-ring b-amino acids (ACPC2 or
APC,3 Figure 1) adopt 12-helical b-peptide structures,
whereas analogous oligomers arising from six-mem-
bered-ring b-amino acids (ACHC) display stable 14-heli-
cal structures.4
H2N
CO2H
H2N
CO2H
H2N
CO2H
Stimulated by the recent dual interest in b-proline deriva-
tives, we have designed a new, conformationally con-
strained, cyclic b-amino acid skeleton found in 3,4-
methano-b-proline, where the methano bridge is located
at Cb- and Cg-positions of the amino acid. The structure of
3,4-methano-b-proline resembles that of both b-proline
and NIP, but it is unique in that the pyrrrolidine-ring puck-
ering is highly restricted. Owing to this structural feature,
3,4-methano-b-proline should serve as useful substance to
explore the conformational space void that exists current-
ly in peptidomimetic studies. In addition, it is anticipated
that this substance will have unique organocatalytic prop-
erties that derive from the nucleophilicity and/or basicity
of the nitrogen and orientation of the carboxylic acid
group that differ from those of b-proline.10
N
H
ACPC
APC
ACHC
CO2H
CO2H
γ
β
CO2H
α
δ
N
N
H
N
H
H
NIP
β-proline
3,4-methano-β-proline
Figure 1 Structures of cyclic b-amino acids
b-Proline (pyrrolidine-3-carboxylic acid, PCA) and nipe-
cotic acid (NIP) are examples of types of cyclic b-amino
acids that are known to form oligomers with unique sec-
ondary structures.5 Due to the lack of hydrogen-bonding
donor sites in their backbones, oligomers arising from
these monomers possess nonhydrogen-bonded helical
structures that resemble natural polyproline helices. The
results of a theoretical study by Carson and coworkers
suggest that the nature of the substitution patterns of the
side chains of b-prolines should influence the conforma-
tional properties of the resulting oligomers.6 Indeed, Gell-
man and his coworkers have proven that the oligomers
Although a considerable effort has been given to the syn-
thesis of natural and unnatural methano-a-prolines,11 only
a few reports exist describing the preparation of methano-
b-prolines.12 Below we present the results of an investiga-
tion that has led to the development of a straightforward
route for the synthesis of the Boc-protected (3R,4R)-meth-
ano-b-proline (1, Figure 2) in enatiomerically pure form.
Importantly, we have found that the approach can be ap-
plied to the preparation of the Boc-b-proline (2).13
The retrosynthetic plan outlined in Scheme 1 suggests that
both Boc-(3R,4R)-methano-b-proline (1) and Boc-b-pro-
line (2) can be generated from the respective bicyclic lac-
tones (–)-3 and (+)-3. The starting, enantiomerically pure
SYNLETT 2009, No. 6, pp 0921–0924
Advanced online publication: 16.03.2009
DOI: 10.1055/s-0028-1087965; Art ID: U12308ST
x
x.
x
x.
2
0
0
9
© Georg Thieme Verlag Stuttgart · New York

922
A. K. Medda, H.-S. Lee
LETTER
CO2H
BH3·SMe2 was sluggish at room temperature and when
performed under refluxing THF conditions, the yield for
the desired bicyclic pyrrolidine was only 15% (alcohol 8
was obtained as a major product in 57% yield). Although
TLC analysis showed that amide reduction preceded ester
reduction under these conditions, ester reduction could
not be avoided. Therefore, complete reduction of both the
lactam and ester groups in 7 was accomplished by using
an excess of BH3·SMe2 in refluxing THF. This process
provided 8 in an 85% yield. Several methods were
screened to transform 8 to the target carboxylic acid 1.
Reactions of 8 with Jones reagent or PDC were not clean.
Although oxidation of 8 with RuCl3 and NaIO4 provided
the desired acid 1 when carried out on a milligram scale,16
the process was not efficient when performed on a gram
scale. A two-step oxidation process was more reliable.
CO2H
R
R
R
N
N
Boc
Boc
1
2
Figure 2 Structure of (3R,4R)-methano-b-proline (1) and b-proline (2)
A
H
CO2H
O
N
O
O
N
CO2Et
Boc
CO2Et
(–)-3
1
B
CO2H
H
O
O
O
N
O
O
N
CO2Et
N3
Boc
HO
(+)-3
2
Scheme 1 Retrosynthetic analysis
bicyclic lactones should be readily accessed on multigram
scales by using the known14 one-step synthetic protocol.
Importantly, the carbon skeleton and all of the sterogenic
centers of the target compound 1 already exist in the start-
ing bicyclic lactone (–)-3 (Scheme 1, A).
Figure 3 ORTEP plot of Boc-(3R,4R)-methano-b-proline (1) with
30% thermal ellipsoid probability.
R
As shown in Scheme 1 (B), the route to b-proline 2 begins
with the opposite enantiomer of the same bicyclic lactone
(+)-3 and employs selective manipulation of cyclopro-
pane ring. For conformational analysis of the oligomer
that is composed of the (3R,4R)-methano-b-proline
monomer, the b-proline with R-configuration is needed as
a reference, which will give the b-proline oligomer with
the same helical sense as that of (3R,4R)-methano-b-pro-
line. To synthesize b-proline with R-configuration, the bi-
cyclic lactone (+)-3, the opposite enantiomer of (–)-3, is
needed.
O
N
O
O
R
CO2Et
CO2Et
a
c
H
CO2Et
CO2Et
(–)-3
4, R = Br
5, R = N3
6, R = H
b
g
d
7, R = Boc
e
CO2H
Boc
N
Boc
N
f
N
The sequence used to prepare enantiomerically pure Boc-
(3R,4R)-methano-b-proline (1) is given in Scheme 2. The
bicyclic g-lactone ring in (–)-3 was opened by treatment
with TMSBr and ethanol to yield the bromide 4 (60%),
which was then reacted with NaN3 in DMF at 70 °C for 5
hours to generate the corresponding azide 5 (83%). Al-
though reduction of the azide 5 can be accomplished using
standard hydrogenation conditions (H2, 10% Pd/C), the
reaction is not reproducible on a large scale. As a result,
the azide reduction was carried out using Ph3P in THF–
H2O at reflux to furnish the desired g-lactam 6 in 80%
yield. The amide nitrogen was Boc-protected (forming 7)
prior to further manipulations. Initial attempts to
chemoselectively reduce the amide carbonyl group in 7
were not successful. For example, no reaction was ob-
served when 7 was treated 9-BBN, which is typically used
for selective reduction of an amide group in the presence
of an ester moiety.15 Moreover, reaction of 7 with
O
OH
Boc
1
9
8
Scheme 2 Reagents and conditions: (a) TMSBr (1.3 equiv), EtOH–
CH2Cl2 (1:10), 0 °C to r.t., 24 h, 60%; (b) NaN3 (8 equiv), 15-crown-
5, DMF, 70 °C, 5 h, 83%; (c) Ph3P (1.3 equiv), THF–H2O (8:1), r.t.,
3 h, and then 60 °C, 36 h, 80%; (d) (Boc)2O (2 equiv), Et3N, DMAP,
CH2Cl2, r.t., 2 h, 87%; (e) BH3·SMe2 (7.5 equiv), THF, 55 °C, 2 h,
85%; (f) IBX (2.5 equiv), DMSO, r.t., 6 h, 83%; (g) NaClO2,
KH2PO4, t-BuOH, 2-methylbut-2-ene, H2O, r.t., overnight, 70%.
Specifically, treatment of 8 with IBX proceeded smoothly
to form aldehyde 9 (83%),17 which was then converted
into Boc-(3R,4R)-methano-b-proline (1, 70%, white crys-
talline solid) by treatment with NaClO2. The methyl ester
of Boc-(3R,4R)-methano-b-proline was prepared in order
to determine the enantiomeric purity (>99%) by using
chiral HPLC analysis.18 Since the enantiomeric purity of
Synlett 2009, No. 6, 921–924 © Thieme Stuttgart · New York

LETTER
Synthesis of 3,4-Methano-b-Proline
923
starting (–)-3 is 99%, the configurations at all of the chiral 3,4-methano-b-proline 1 and the effects of conformation-
centers are completely retained in this sequence. The crys- al constraints on the secondary structure of the b-proline
tal structure of 1 is shown in Figure 3,19 and the absolute oligomer derived from 1 are currently being investigated.
configuration of 1 was confirmed by using the Flack
method.20
1
All compounds were characterized by analysis of their H NMR,
13C NMR, and HRMS properties.
OR2
O
O
O
Compound 1
O
a, b
c
White solid; mp 114–117 °C; [a]D25 –87.3 (c 1.03, CHCl3). 1H NMR
(400 MHz, CDCl3): d = 0.91 (t, J = 5.0 Hz, 3 H), 1.42 (s, 9 H), 1.64
O
N
CO2Et
R1
N3
(dd, J = 4.7, 8.2 Hz, 1 H), 2.10 (br, s, 1 H), 3.40–3.72 (m, 4 H). 13
C
(+)-3
10
11, R1 = R2 = H
NMR and DEPT (100 MHz, CDCl3): d = 19.01/19.2 (1 CH2), 27.7
(1 CH), 28.4 (3 CH3), 28.9/29.7 (C), 47.0/47.2 (1 CH2), 47.3/47.5 (1
CH2), 79.9/80.0 (C), 154.9 (C), 178.2 (C). ESI-HRMS: m/z calcd
for [M + K]+ C11H17NO4K: 266.0789; found: 266.0711.
d
12, R1 = R2 = Boc
e
Compound 2
White solid; mp 141–142 °C, [a]D23 –13.8 (c 1.00, CHCl3) { ref 13g:
mp 139–141 °C; [a]D22 –14.6 (c 1.00, CHCl3)}. 1H NMR (400 MHz,
CDCl3): d = 1.43 (s, 9 H), 2.13 (m, 2 H), 3.05 (m, 1 H), 3.34–3.57
(m, 4 H), 10.12 (br s, 1 H). 13C NMR and DEPT (100 MHz, CDCl3):
d = 28.1/28.7 (1 CH2), 28.4 (3 CH3), 42.2/43.0 (1 CH), 45.0/45.3 (1
CH2), 47.8 (1 CH2), 79.8 (C), 154.5 (C), 178.0 (C). HRMS (EI, pos.
mode): m/z calcd for [M]+ C10H17NO4: 215.1158; found: 215.1159.
CO2H
OR
g
N
N
Boc
Boc
2
13, R = Boc
14, R = H
f
Scheme 3 Reagents and conditions: (a) NaN3 (4 equiv), AcOH (0.1
equiv), Et3N (0.1 equiv), DMSO, 75 °C, 4 h; (b) 6 N HCl, 120 °C, 18
h, 58% (in 2 steps); (c) H2, 10% Pd/C, MeOH, r.t., overnight, 85%;
(d) (Boc)2O (2.5 equiv), Et3N, DMAP, CH2Cl2, r.t., 6 h, 74%; (e)
BH3·SMe2 (2.5 equiv), THF, 55 °C, 2 h, 98%; (f) KOH (4.5 equiv),
MeOH, r.t., 18 h, 98%; (g) RuCl3 (10 mol%), NaIO4 (4 equiv),
MeCN–CCl4–H2O (2:2:3), 0 °C to r.t., 2 h, 79%.
Acknowledgment
This work was supported by the Korea Research Foundation Grant
funded by the Korean Government (MOEHRD). We thank Mr.
Kang Mun Lee for obtaining the single crystal diffraction data.
References and Notes
The enantiomerically pure b-proline 2 was synthesized
starting with the bicyclic lactone (+)-3 (Scheme 3). Open-
ing of the cyclopropane ring in this substance was per-
formed by using sodium azide to obtain the lactone
intermediate which was then treated with 6 N HCl at 120
°C for 18 hours to produce the b-azidomethyl g-butyrolac-
tone (10) in 58% overall yield. After hydrogenolysis of
the azide group in 10 by using H2 and 10% Pd/C in
MeOH, and stirring the resulting mixture overnight, the
known g-lactam 11 was generated as a white solid in 85%
yield. Both the amide nitrogen and the primary alcohol of
11 were protected with Boc groups by treatment with
(Boc)2O and DMAP to give 12 as a white solid in 74%
yield. Reduction of lactam 12 with BH3·SMe2 in refluxing
THF efficiently provided 13 as an oil in 98% yield. Selec-
tive O-Boc deprotection 13 was performed by using meth-
anolic KOH to furnish alcohol 14 in a quantitative yield.
The RuCl3/NaIO4 oxidation of the alcohol moiety in 14
was successfully carried out to generate the desired Boc-
protected amino acid 2 as a white solid in 79% yield. The
enantiomeric purity of 2 was determined to be >99% by
using chiral-HPLC.21
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130, 875.
In summary, a new conformationally restricted b-proline
derivative, Boc-(3R,4R)-methano-b-proline (1), has been
synthesized in enantiomerically pure form in seven steps
and a 17% overall yield starting with the readily available
bicyclic lactone (–)-3. Boc-(R)-b-proline (2) was also pre-
pared from the enantiomerically pure bicyclic lactone (+)-3
in 28% overall yield. The organocatalytic properties of
Synlett 2009, No. 6, 921–924 © Thieme Stuttgart · New York

924
A. K. Medda, H.-S. Lee
LETTER
(10) Hanessian, S.; Shao, Z.; Warrier, J. S. Org. Lett. 2006, 8,
4787.
(15) Flaniken, J. M.; Collins, C. J.; Lanz, M.; Singaram, B. Org.
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Bessieres, B.; Corre, M. L. Tetrahedron: Asymmetry 1996,
7, 1267. (b) Tverezovsky, V. V.; Baird, M. S.; Bolesov, I. G.
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(17) Frigerio, M.; Santadostino, M.; Sputore, S.; Palmisano, G.
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(18) HPLC Data for Boc-(3R,4R)-Methano-b-proline Methyl
Ester
tR = 13.622 (min), area = 100%; OJ-H, IPA–n-hexane =
5:95; flow rate = 0.4 mL/min, 25 °C, l = 220 nm.
(19) Crystal Data for Compound 1
C11H17NO4, crystal size: 0.10 × 0.20 × 0.20 mm3,
Mr = 227.26 g mol–1, monoclinic, space group P21,
l = 0.71073 Å, a = 6.1437 (8) Å, b = 11.3449 (17) Å,
c = 9.3146 (13) Å, a = 90, b = 104.369 (10), g = 90,
V = 628. 92 (15) Å3, Z = 2, rcalcd = 1.200 g cm–3, m = 0.091
min–1, T = 293 (2) K, q range = 3.6–33.2°; reflections
collected: 10063, independent: 4247 (Rint = 0.037). The
structure was solved by direct methods and refined by full-
matrix least-squares on F2; R1 = 0.0432, wR2 = 0.1196 [ I >
2s (I)]; maximal residual electron density: 0.12 e Å–3.
CCDC 710057 contains the supplementary crystallographic
data for this structure. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
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(20) Flack, H. D. Acta Crystallogr., Sect. A: Fundam.
Crystallogr. 1983, 39, 876; the Flack parameter of the
crystal structure of 1 was 0.0(10), and that of ent-1 was
1.0(10).
(21) HPLC Data for Boc-(3R)-b-proline Methyl Ester
tR = 20.621 (min), area = 100%; racemic Boc-b-proline
methyl ester, tR = 15.985, 20.824 (min). OJ-H, IPA–n-
hexane = 5:95; flow rate = 0.4 mL/min, 25 °C, l = 220 nm.
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Synlett 2009, No. 6, 921–924 © Thieme Stuttgart · New York