Stereoselective Michael additions on α-aminoacrylates as the key step to an l-Oic analogue bearing a quaternary stereocenter

Article abstract of DOI:10.1039/c9ob02084e

A novel, highly stereoselective route for pharmaceutically relevant octahydroindole-2-carboxylates bearing a quaternary stereocenter has been developed. The key chiral intermediates 3 have been prepared in good yields and enantiomeric excesses up to 98%. A broad substrate range has been tolerated under the reaction conditions.

Full text of DOI:10.1039/c9ob02084e

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Stereoselective Michael additions on
α-aminoacrylates as the key step to an L-Oic
analogue bearing a quaternary stereocenter†
Cite this: DOI: 10.1039/c9ob02084e
Federico Maria Cecchinelli,a Giuseppe Celentano,a Alessandra Puglisi b and
a
Nicoletta Gaggero
*
Received 25th September 2019,
Accepted 13th December 2019
A novel, highly stereoselective route for pharmaceutically relevant octahydroindole-2-carboxylates
bearing a quaternary stereocenter has been developed. The key chiral intermediates 3 have been prepared
in good yields and enantiomeric excesses up to 98%. A broad substrate range has been tolerated under
the reaction conditions.
DOI: 10.1039/c9ob02084e
rsc.li/obc
Peptides present high potentiality for the development of new mational rigidity and increased lipophilicity as compared with
drugs.1,2 However, the major disadvantages of practical appli- proline.4 The most studied stereoisomer of Oic is the one with
cation in medicine of bioactive peptides are low bioavailability, (2S,3aS,7aS) absolute configuration, known as L-Oic (Fig. 1),
poor metabolic stability and intrinsic flexibility. Thus, the which is also the only commercially available stereoisomer.
active sequence must be constrained in a defined confor- The methodologies for the preparation of enantiopure L-Oic
mation, in order to achieve the desired activity and selectivity. take advantage both from stereoselective synthesis and chemi-
Proline residues, due to their unique conformational pro- cal, chromatographic and enzymatic resolutions.5 Derivatives
perties and limited ability to establish hydrogen bonds, do not containing the L-Oic scaffold have numerous pharmacological
occur in regular α-helices or β-sheet structures. Rather, they proprieties. Among the more relevant applications, it has been
play a specific structural role as N-terminal caps to α-helices, used in several bradykinin B2 receptor antagonists and prolyl
as helix termination signals, or as corner residues in β-turn oligopeptidase (POP) inhibitors. L-Oic is also a key intermedi-
sequences. Most notably, however, prolines are key players in ate in the synthesis of angiotensin-converting enzyme (ACE)
many biologically essential processes, such as protein folding, inhibitors for the treatment of hypertension, e.g. Perindopril.
signal transduction, protein–protein recognition, or receptor–
The lack of synthetic procedures for the synthesis of the
ligand binding of Pro-containing peptides.3 The peculiar con- other Oic stereoisomers has hampered the investigations on
formational features of proline have made it a major target for their pharmacological properties to date.
potential molecular engineering modifications, since its inner
Another method to reduce conformational flexibility aims
constitutional restrictions aid limiting low energy accessible at building quaternary centers to afford C-branched derivatives
conformations, helping biasing the conformational freedom of featuring an additional substituent.6 Molecules containing
the peptide in which this residue is included. In the search for quaternary stereocenters play a key role and many biologically
more potent and selective drugs, the design of constrained active molecules occurring in nature share this structural
analogues of chemical leads has been a classical approach. To feature. The construction of quaternary stereocenters via
reach this goal a first method consists in introducing a second chemical synthesis is extremely challenging. Until now, within
cycle on the parent structure to reduce its conformational the top 200 drug in US only 12 contain a tetrasubstituted
mobility and adjust the substituent’s orientation. A particu- stereocenter (6%) and none of them has been built by chemi-
larly attractive proline analogue is octahydroindole-2-carboxylic
acid (Oic). The fused bicyclic structure of Oic secures confor-
aDipartimento di Scienze Farmaceutiche, Sezione di Chimica Generale e Organica “A.
Marchesini”, Università degli Studi di Milano, via Venezian 21, 20133-Milano, Italy.
E-mail: nicoletta.gaggero@unimi.it
bDipartimento di Chimica, Università degli Studi di Milano, via Golgi 19-20133,
Milano
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c9ob02084e
Fig. 1 (L)-Oic and (L)-Oic scaffold containing Perindopril.
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Table 1 Michael addition between chiral imines 1a–1e and methyl
2-benzamido acrylate 2a
Scheme 1 Retrosynthetic strategy.
cal synthesis but results from derivatization of natural sub-
strates already bearing the tetrasubstituted stereocenter in the
correct absolute configuration.7 Cativiela has reported the syn-
thesis of an Oic analogue bearing a quaternary stereocenter in
the α-position to the carboxylic group.8 Recently, a stereo-
selective Lewis base (LB)-catalyzed dual umpolung domino
Michael reaction between cyclohexadienones and alkynyl
esters has been developed. Triphenylphosphine (PPh3), as a LB
catalyst, afforded the hydroindole-2-carboxylate scaffold as a
single diastereoisomer in moderate yield. The intermediate
could be easily transformed to a (2R,3aS,7aS)-methyl 7a-
methyloctahydroindole-2-carboxylate.9
The aim of our work has been the synthesis of a proline
derivative which contains both the octahydroindolic con-
strained bicyclic scaffold and a quaternary stereocenter at the 3a
position of the fused bicyclic skeleton. We envisaged the possi-
bility of stereoselectively access highly functionalized propano-
ates 3 as the key intermediates of our synthetic route. The fol-
lowing deprotection of the amino functionality, its intra-
molecular cyclization to the corresponding imine, followed by
hydrogenation of the CvN bond would lead to an Oic derivative
bearing a quaternary stereocenter in 3a position (Scheme 1).
The synthesis of the enantiomerically enriched N-protected
3-(1-substituted-2-oxocyclohexyl)-2-amino propanoates 3 was
performed via the stereoselective alkylation of racemic 2-mono-
substituted cycloalkanones, first reported by d’Angelo et al.10
This methodology has emerged as a powerful tool for the
stereoselective construction of quaternary carbon atoms with
excellent enantiomeric excesses. It involves a Michael-type
addition of electrophilic olefins and chiral ketimines derived
from enantiopure α-phenylethylamine reacting in their second-
ary enamine tautomeric forms at the most substituted
α-carbon atom. When α-substituted Michael acceptors are
used, a largely prevailing diastereoisomer is obtained, thereby
allowing the simultaneous, complete stereo-control of both
new stereocenters formed.11–15 Notheworthy, a patent by
Sanofi-Aventis reported an application of the d’Angelo strategy
to prepare another ACE inhibitor known as Ramipril.16
Entry Ketimine Michael adduct
Yielda (%) drb
eec (%)
1
1a
90
>98 : 2 95
2
1b
90
95 : 5
98
3
4
5
1c
1d
1e
95
93
80
>98 : 2 98
>98 : 2 98
85 : 15 96
a Isolated yield after chromatographic purification. b Determined by
1H-NMR on the crude. c Determined by HPLC on chiral stationary
phase.
mido acrylate17 2a for 72 h in THF at 66 °C in presence of
hydroquinone (few mg) to prevent acrylate§ polymerization
under the reaction conditions (scheme in Table 1).
(S)-Methyl-3-((R)-1-methyl-2-oxocyclohexyl)-2-benzamido
propanoate 3a has been obtained as a single diastereoisomer
after hydrolysis in 20% acetic acid (1 h, rt),¶ extraction with
ethyl acetate and flash chromatography purification in 90%
chemical yield and 96% enantiomeric excess.∥ We assigned
the absolute configurations of the two stereocenters based on
the mechanism proposed by d’Angelo et al.11–15
With this optimal result in our hands, the reaction scope
has been investigated on a series of 2-substituted cyclanones
with five or six carbon atoms (Table 1, entries 1–5). The reac-
The first attempt has been performed at neutral conditions
between the crude ketimine (S)-1a obtained by the conden-
sation of 2-methylcyclohexanone and (S)-α-phenylethylamine‡
with the potentially competent electrophile, methyl 2-benza-
§Acrylates can be stored at −18° C without degradation for about one month.
¶It was possible to quantitatively recover the optically pure (S)-
α-phenylethylamine after neutralization of the aqueous medium and extraction
after hydrolysis of crude Michael adduct.
‡The condensation of the cyclanones with optically pure or racemic
α-phenylethylamine was typically performed in refluxing toluene for 24 h in the
presence of 4 Å molecular sieves. The conversion was evaluated by 1H-NMR and
the imine was used without further purification.
∥The attempt to carry out the Michael reaction under organocatalytic conditions
according to the procedure of Carter et al.19 gave poor yield and incomplete dia-
stereoselection probably due to the presence of two groups with similar steric
and electronic features in the α position of acrylate.
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tion proved to be very efficient, leading to high yields and appears as a significant improvement if compared with 2a,
enantiomeric excess over a broad substrate range. Sulfur func- allowing to carry out the reactions at room temperature for a
tionalized 2-methyltetrahydrothiophen-3-one afforded the shorter time, affording the corresponding products in high
corresponding adduct in excellent yield and ee (Table 1, entry yields and enantiomeric excesses. Hence, a new set of experi-
4). 3-Allylcyclohexanone led to the corresponding product in ments was explored employing 2b with the ketimines derived
80% yield and 96% ee (Table 1, entry 5). In the examined from different 2-substituted cyclanones (Table 2, entries 2–5).
cases, one single diastereoisomer was detected, except with Also in this new series of experiments the length of the alkyl
2-ethylcyclohexanone (Table 1, entry 2) and 2-allylcyclohexa- chain in α position to the carbonyl group of five or six mem-
none (Table 1, entry 5) where measurable amounts of a second bered cyclanones did not modify the outcome of the reaction
diastereoisomer were detected.
(Table 2, entries 1, 5 and 2, 3). The more sterically demanding
We then examined the reaction’s tolerance to the acrylate methylthio substituent was well tolerated (Table 2, entry 4).
coupling partner in view of further synthetic elaboration of the Moreover, under these milder conditions, in all cases only one
product. N-Boc and N-Cbz protected methyl 2-aminoacrylates diastereoisomer was obtained. At last, benzyl 2-(2,2,2-trifluor-
were unreactive with the ketimine of 2-methyl cyclohexanone oacetamido) acrylate 2c was synthesized and tested using (S)-
(S)-1a, under the usual experimental conditions, also for 1a as nucleophilic partner according to the new conditions,
longer reaction times.
affording 3k in 90% yield and 96% ee (Table 2, entry 6).
On the other hand, methyl 2-(2,2,2-trifluoroacetamido) acry-
Having demonstrated the feasibility of the methodology for
late 2b smoothly reacted with (R)-1f affording the Michael the stereoselective synthesis of propanoates 3, we attempted to
adduct 3f in 80% yield and 94% ee after 30 h in toluene at synthesize an Oic analogue by further modification of adduct
room temperature (Table 2, entry 1). Indeed, the use of 2b 3f. The overall synthesis is illustrated in Scheme 2. Michael
adduct 3f was subjected to acidic hydrolysis (stoichiometric
p-toluenesulfonic acid, PTSA, 65 °C, methanol, 24 h) followed
Table 2 Michael reactions using 2-(2,2,2-trifluoroacetamido) acrylates
2b–2c
by hydrogenation reaction. We preferred acidic removal of tri-
fluoroacetyl group with respect to basic hydrolysis to prevent
the possibility of racemization of the stereocenter in a position
to the protected amino group. Moreover, this methodology pre-
served the methylester. The deprotection step directly afforded
imine 4 after intramolecular in situ condensation of the free
amino group with the carbonyl functionality. Hydrogenation
of the crude reaction mixture using 10% palladium–carbon as
a catalyst, at 40 °C, for 24 hours, under 15 bar of H2 in a Parr®
system quantitatively afforded bicycle 5 as p-toluene sulfonate
salt. A first attempt of performing hydrogenolysis of com-
pound 4 at room temperature and atmospheric pressure
required much longer reaction time (72 h).
In order to evaluate the enantiomeric excess of the final
product we converted amine 5 into its 2-bromo-benzenesulfo-
nic amide 6. HPLC on chiral stationary phase revealed an
enantiomeric excess ≥98%.
It is worth mentioning that the use of para-toluenesulfonic
acid and methanol as the solvent in the deprotection step is
more convenient if compared to the aqueous hydrolysis with
hydrochloric acid at 100 °C necessary for the benzamide func-
Entry Ketimine Acrylate Michael adduct
Yielda (%) eeb (%)
1
1f
2b
80
94
2
1g
2b
68
97
3
4
5
1h
1i
2b
2b
2b
52
80
75
94
97
97
1j
6c
1a
2c
90
96
a Isolated yield after chromatographic purification. b Determined by
HPLC on chiral stationary phase. c (S)-Phenylethylamine was used.
Scheme 2 Synthetic sequence for the preparation of 2(R),3a(S),7a(S)-5.
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prepare both the enantiomers of the final product, since both
(R) and (S) α-phenylethylamine are commercially available at
modest price.
Fig. 2 Some selected NOE correlations for 5.
Conflicts of interest
There are no conflicts to declare.
tionality hydrolysis of 3a.** It allowed milder reaction con-
ditions and the possibility of performing the hydrogenation
step on a crude material in methanol avoiding a partial hydro-
lysis of the ester moiety, which affords a mixture of 5 and the
product with the free carboxylic acid. Moreover, the presence
of para-toluenesulfonic acid in the crude mixture, allowed to
isolate compound 5 as its sulfonate salt by precipitation after
concentrating the solution. Compound 5 was obtained after a
4-step reaction sequence with one chromatography purifi-
cation only, in 40% yield.
The relative stereochemistry of 5 was determined by ana-
lysis of NOESY spectroscopic data, assuming the absolute con-
figuration of 3f as determined by d’Angelo experiments
(Fig. 2).11–15 A nOe correlation between methyl 3a and H-7a
and a nOe correlation between methyl 3a and H-3b are sugges-
tive of their close spatial proximity, indicating that they are
located on the same side of the ring. The spectrum shows the
absence of a measurable nOe correlation between methyl 3a
and protons H-3a and H-2.
Notes and references
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We also observed other nOe correlations: between H-2 and
H-3a, between H-3b and H-7a and between O–CH3 and H-3b.
These correlations confirmed the trans relationship between
H-2 and methyl 7a on the octahydroindole skeleton.18
10 M. Pfau, G. Revial, A. Guingant and J. d’Angelo, J. Am.
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Conclusions
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commercially available, optically pure PEA needs to be used in J. Org. Chem., 2008, 73, 7807–7810.
stoichiometric amount, it can be recovered and recycled in 18 For proton assignement see ESI.†
subsequent reactions. With this methodology it is possible to 19 J. Y. Kang and R. G. Carter, Org. Lett., 2012, 14, 3178–3181.
**The hydrolysis/cyclization reaction of 3a has been performed in HCl 6N, at
100 °C for 24 h.
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