Enantioselective synthesis of a (1 R,5 R,9 R)-2-azabicyclo[33.1]nonane-9- carboxylic acid with an embedded morphan motif: A multipurpose product

Article abstract of DOI:10.1055/s-0032-1317950

A convenient asymmetric synthesis of (1R,5R,9R)-2-azabicyclo[3.3.1]nonane- 9-carboxylic acid is described, starting from (2E,7E)-dimethyl nonadienedioate. The route involves a stereoselective domino Michael-Dieckman process that furnishes a 1,2,3-trisubst

Full text of DOI:10.1055/s-0032-1317950

LETTER
▌169
letter
Enantioselective Synthesis of a (1R,5R,9R)-2-Azabicyclo[3.3.1]nonane-9-carb-
oxylic Acid with an Embedded Morphan Motif: A Multipurpose Product
(1R,5R,9R)-2-Azabicyclo[3.3.1]nonane-9-carboxylic Acid
Narciso M. Garrido,* Carlos T. Nieto, David Díez
Departamento de Química Orgánica, Universidad de Salamanca, Plaza de los Caídos s/n, 37008 Salamanca, Spain
Fax +34(923)294574; E-mail: nmg@usal.es
Received: 26.10.2012; Accepted after revision: 05.12.2012
several goals, such as restricting the flexibility of
Abstract: A convenient asymmetric synthesis of (1R,5R,9R)-2-aza-
peptides2 or stabilizing the helical secondary structure and
bicyclo[3.3.1]nonane-9-carboxylic acid is described, starting from
helix-bundle quaternary structures that organize helical
(2E,7E)-dimethyl nonadienedioate. The route involves a stereo-
selective domino Michael–Dieckman process that furnishes a 1,2,3-
folding by replacing flexible β3-residues with their cyclic
trisubstituted cyclohexane derivative bearing three adjacent stereo- analogues.2b
centers with full stereochemical control. A subsequent chemoselec-
The 2-azabicyclo[3.3.1]nonane skeleton is present in sev-
tive transformation of one of the side-chain ester groups allows an
eral important narcotic analgesics like (–)-morphine3 (1,
effective second cyclization leading to the morphan motif. The ver-
Figure 1) and its derivatives; in (+)-aspernomine (2), an
insecticide, antifungal, and cytotoxic natural product;4 the
madangamines5 (3), a family of marine alkaloids from
Xestospongia ingens, and the novel aeroginusin family of
serine protease inhibitors headed by (+)-suomilide6 (4). In
the literature, this bicyclic system has been synthesized
employing nonstereoselective radical7 and Mannich8
reactions; organocatalytic9 approaches have also been
employed, with moderate enantioselection.
Our research group has experience10 in the asymmetric
addition of chiral lithium (α-methylbenzyl)benzylamide
[(R)-6 or (S)-6] to binary Michael systems 5. Using
(2E,6E)-octadienedioate, (2E,7E)-nonadienedioate, and
(2E,8E)-decadienedioate as either symmetric diesters or
orthogonal acceptors, a collection of cyclic (7, 9, 10) or
linear (8, 11, 12) derivatives has been assembled, with
total stereochemical control in all cases (Scheme 1).
satility of this novel amino acid for the generation of molecular
complexity was tested by elaborating a tripeptide in homogeneous
phase.
Key words: β-amino acids, asymmetric synthesis, Michael addi-
tion, morphan, GABA uptake inhibitors
Amino acids are one of the most widespread and biologi-
cally relevant families of substances. Within this group, β-
amino acids are gaining importance, as a result of their
multiple advantages (higher resistance to enzyme degra-
dation, higher conformational freedom) over their natural
homologues, leading to a wide variety of interesting appli-
cations.1 Nowadays, great efforts are being directed at
finding ways to introduce new scaffolds and additional
functionalities in these compounds, allowing their use as
building blocks for the construction of peptidomimetics.
The inclusion of bridged bicyclic backbones is a striking
example. This transformation restricts the conformational
space of the molecule, which can be exploited to reach
The E stereochemistry of the double bonds in the sub-
strates has a key role in avoiding the potential competition
between addition and γ-deprotonation.10 Thus, when the
HO
O
NH
n-C5H11
n-C5H11
O
HO
OH
N
O
OH
O
O
H
O
OH
O
(+)-aspernomine (2)
HO
(–)-morphine (1)
O
O
–O3SO
O
N
OMe
N
H
O
O
+H2N
H2N
N
HN
N
(+)-suomilide (4)
(+)-madangamine A (3)
Figure 1 Structures with a morphan core
SYNLETT 2013, 24, 0169–0172
Advanced online publication: 04.01.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317950; Art ID: ST-2012-D0921-L
© Georg Thieme Verlag Stuttgart · New York

170
N. M. Garrido et al.
LETTER
Bn
R1 = Me,
R2 = H
N
Bn
Ph
R1 = R2 = Me
n = 1, 2
CO2R1
CO2R2
Ph
N
CO2Me
CO2R1
CO2R2
Bn
n = 1, 2
n
n
Ph
N
Li
(R)-6
n
CO2Me
5
7
(R)-6
8
R1 = R2 = Me
n = 3
R1 = R2 = Me
R1 = R2 = Me
n = 1, 2, 3
n = 1, 2, 3
R1 = Me, R2 = t-Bu
(S)-6
n = 1
Bn
Bn
Bn
Ph
Ph
N
N
Bn
N
Ph
N
N
N
Ph
Ph
CO2R1
CO2R2
CO2R1
CO2R2
n
CO2t-Bu
CO2Me
n
+
CO2Me
CO2t-Bu
Ph
Bn
Bn
12
3 : 1
9
10
cyclic
linear
11
Scheme 1 Spectrum of the adducts of (R)-6 and (S)-6 over binary Michael acceptors
E,Z counterpart or the acid ester (5, R1 =Me, R2 =H) was complicates the reaction steps towards the cyclization to
used, the monoaddition adduct was obtained.10a,g Interest- the morphan core.13 In the next step, we transformed se-
ingly, these monoaddition products can be used to give the lectively the ester group in the C-6 side chain of 15 into a
diaddition derivatives by a second addition of the suitable mesylate.
chiral R- or S-amide (Scheme 1), increasing the stereo-
chemical range of the method.10g
Herein we report the enantioselective synthesis of several
β-amino acids and esters containing a 2-azabicyc-
lo[3.3.1]nonane (morphan) motif embedded in their struc-
tures. Scheme 2 shows the retrosynthetic route from the
morphan backbone to the starting material, (2E,7E)-di-
methyl nonadienedioate, which is readily available from
azelaic acid in two steps.11 In essence, the procedure has
three keys stages: 1) asymmetric conjugate addition of the
chiral amine12 (R)-6 to the binary Michael acceptor
(2E,7E)-dimethyl nonadienedioate, achieving the assem-
bly of the cyclohexane ring with the desired absolute and
relative stereochemistry; 2) protecting-group exchange
from the dibenzyl amine to the Boc amine, which leads to
better yields in subsequent functional-group transforma-
tions, and 3) cyclization to the final morphan structure.
The generation of the morphan framework late in the
sequence was dictated by the reluctance of the centers
involved in the morphan core to undergo forward transfor-
mations.13
The route starts with the previously discussed reaction be-
tween the lithium (α-methylbenzyl)benzylamide (R)-6
Scheme 2 Retrosynthetic scheme of the 9-substituted morphan core
and substrate 13 that furnished 14 in 72% yield (de >
95%)10c,d,g via a domino sequence comprising an asym-
Selective hydrolysis of the desired ester using LiOH·H2O
metric Michael addition and a 6-exo-trig cyclization that
generated one ring and three contiguous stereocenters in a
fully controlled fashion (Scheme 3).14
in MeOH–THF–H2O (3:1:1) was possible, presumably as
a consequence of the shielding of the ester in position 1 by
the carbamate group. BH3·THF reduction10a,15 of the re-
sulting acid led to the corresponding alcohol in quantita-
tive yield. A final esterification of 17 with MsCl/pyridine
catalyzed by DMAP in CH2Cl2 afforded mesylate 18 in
high yield.
The next stage, aiming at protecting-group interconver-
sion, involved releasing the free primary amine by hydro-
genation in the presence of Pd(OH)2/C at 3.5 bar and
reprotecting it as a Boc carbamate with Boc2O in one pot.
In our experience, the presence of the tertiary amine in 14
Synlett 2013, 24, 169–172
© Georg Thieme Verlag Stuttgart · New York

LETTER
(1R,5R,9R)-2-Azabicyclo[3.3.1]nonane-9-carboxylic Acid
171
Ph
NHBoc
CO2Me
a
Ph
N
CO2Me
CO2Me
b
CO2Me
CO2Me
81%
72%
15
CO2Me
13
14
c
84%
NHBoc
NHBoc
NHBoc
CO2Me
CO2Me
e
CO2Me
d
96%
100%
CO2H
OH
OMs
17
16
18
Scheme 3 Reagents and conditions: (a) lithium (R)-N-benzyl-N-α-methylbenzylamide [(R)-6; 1.6 equiv], THF, –78 °C; (b) Pd(OH)2/C, H2 (3.5
bar), Boc2O, EtOAc, 3 d; (c) LiOH·H2O, MeOH–THF–H2O (3:1:1), 4 h; (d) BH3·THF, THF, 20 °C, 60 min; (e) MsCl, pyridine, DMAP,
CH2Cl2, 2 h.
Finally, we undertook the cyclization of 18 to generate the
morphan core. Taking into account the presence of the
Boc carbamate, two approaches were conceived (Scheme
NHBoc
NHBoc
CO2Me
CO2Me
a
N
Boc
4). First, we carried out the cyclization on the Boc carba-
mate under basic conditions with 1,1,3,3-tetramethylgua-
nidine (TMG) in toluene.16 However, competition
between the nucleophilic and base nature of TMG led to
14% yield of the morphan-derived protected amino acid
19 and the TMG substitution product of the mesylate 20
in a 44% yield. Alternatively, deprotection of the carba-
mate 18 under acidic conditions with TFA followed by
treatment with Et3N to promote cyclization17 of the free
amine gave amino ester 21 in 84% yield.18 Hydrolysis of
the ester with LiOH·H2O quantitatively afforded the cor-
responding amino acid 22, isolated in its neutral form by
ion-exchange chromatography followed by freeze-drying.
+
CO2Me
19, 14%
N
OMs
18
Me2N
NMe2
20, 44%
b
84%
NHBoc
d
NH
N
CO2Me
86%
O
CO2Me
23
21
In order to examine the application of these compounds in
peptide chemistry, the synthesis of tripeptide 24 was en-
visaged (Scheme 4). Homogeneous-phase coupling of 21
with N-(tert-butoxycarbonyl)glycine in the presence of
EDCI and 1-hydroxybenzotriazole led to dipeptide 23 in
86% yield {[α]D20 –32.4 (c 1.54, CHCl3)}. Hydrolysis of
the ester with LiOH·H2O and subsequent coupling with L-
alanine methyl ester hydrochloride in the same conditions
afforded tripeptide 24 {[α]D20 –7.6 (c 0.41, CHCl3)}.19
c, e 53%
c
100%
NHBoc
N
NH
NH
O
CO2H
O
22
CO2Me
24
In conclusion, we have developed a methodology that al-
lows the easy preparation in seven steps of 22, an enantio-
merically enriched 9-substituted morphan-type amino
acid, with a global yield of 40%. All three stereocenters
are defined in a tandem asymmetric Michael addition–
Dieckman cyclization, and hence use of the S-amine
would make the other enantiomer accessible. Moreover,
the versatility of this amino acid was demonstrated cou-
pling it with two common amino acids, evidencing the ac-
cessibility of the amino and carboxylic acid functions.
These amino acids may be valuable products in the search
of bridged constrained amino acids, in the development of
new turns and hairpins in peptide structures. Their resem-
Scheme 4 Reagents and conditions: (a) tetramethylguanidine, tolu-
ene, 100 °C, 12 h; (b) TFA, CH2Cl2, 2 h, then Et3N, EtOH, 12 h; (c)
LiOH·H2O, MeOH–THF–H2O (3:1:1), 2 h; (d) N-(tert-butoxycarbon-
yl)glycine, EDCI, 1-hydroxybenzotriazole, DMF, r.t., 12 h; (e) L-ala-
nine methyl ester hydrochloride, EDCI, 1-hydroxybenzotriazole,
DIPEA, DMF, r.t., 12 h.
guvacine or isoguvacine may make them interesting in the
study of GABA uptake inhibition processes.20
Acknowledgment
blance to morphine make them suitable to explore their The authors are grateful for financial support from the Spanish MI-
CINN (EUI2008-00173), MEC (CTQ2009-11172/BQU), the FSE
and Junta de Castilla y León (SA162A12-1) and excellence GR-
potential as narcotic analgesics, and their similarity with
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 169–172

172
N. M. Garrido et al.
LETTER
178. The authors also thank Dr. A. M. Lithgow for work on the
NMR spectra and Dr. César Raposo for the mass spectra. C.T.N.
thanks Junta de Castilla y León for a FPI doctoral fellowship.
M.; Díez, D.; Domínguez, S. H.; Davies, S. G. Tetrahedron:
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updates the scope and applications of the conjugate addition
of enantiomerically pure lithium amides published in:
(b) Davies, S. G.; Smith, A. D.; Price, P. D. Tetrahedron:
Asymmetry 2005, 16, 2833.
(13) Nieto, C. T. PhD Dissertation, in progress.
(14) The stereochemistry of this compound has been
demonstrated in references 10d,g,c; the latter reports that
(R)-6-methylcyclohex-1-ene carboxylate was obtained from
an analogue of the enantiomer of 14.
(15) Yoon, N. M.; Chwang, S. P.; Krishnamurthy, S.; Stocky, T.
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References and Notes
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Chem. 1987, 52, 473.
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(5) (a) Kong, F.; Andersen, R. J.; Allen, T. M. J. Am. Chem. Soc.
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2010, 587. (b) Garrido, N. M.; Díez, D.; Domínguez, S. H.;
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(18) Typical Procedure
Mesylate 18 (18 mg, 0.047 mmol) was dissolved in CH2Cl2–
TFA 1:1 (5 mL) and stirred 2 h at r.t. Solvent was
evaporated, and the crude was further dissolved in EtOH–
Et3N 1:1 (5 mL). The mixture was refluxed at 80 °C for 20
h. The solvent was again evaporated and the crude dissolved
in EtOAc (30 mL) and extracted with HCl (0.5 M, 30 mL).
The aqueous phase was basified to pH 8 with NaOH (1 M)
and extracted with EtOAc. The organic phase was dried over
Na2SO4, filtered, and the solvent was removed at reduced
pressure. Purification of the crude product by flash
chromatography (CHCl3–MeOH, 9:1) provided 21 (7.1 mg,
84%) as an oil. [α]D20 = –4.01 (c 0.71, CHCl3). 1H NMR (400
MHz, CDCl3): δ = 1.65–2.24 (m, 8 H, H-4, H-6, H-7, H-8),
2.52 (s, 1 H, H-5), 3.06 (s, 1 H, H-9), 3.27 (dd, J = 13.5, 7.3
Hz, 1 H, H-3eq), 3.44 (dt, J = 13.5, 8.0 Hz, 1 H, H-3ax), 3.73
(s, 3 H, OCH3), 3.91 (br s, 1 H, H-1), 5.51 (br s, 1 H, NH).
IR (neat): 3396, 2931, 2858, 1733, 1426, 1384, 1287, 1203,
1124, 1405, 1023 cm–1. 13C NMR (50 MHz, CDCl3): δ =
19.8, 23.4, 25.5, 26.9, 28.9, 40.1, 43.6, 47.7, 52.7, 171.3.
HRMS: m/z calcd for C10H18NO2 [M + H]: 184.1332; found:
184.1313.
(19) All the obtained products have been fully characterized
including high-resolution mass spectrometry.
(20) Kulig, K.; Szwaczkiewicz, M. Mini-Rev. Med. Chem. 2008,
8, 1214.
Synlett 2013, 24, 169–172
© Georg Thieme Verlag Stuttgart · New York