N -Isopropylsulfinylimines vs. N-tert -butylsulfinylimines in the stereoselective synthesis of sterically hindered amines: An improved synthesis of enantiopure (R)- And (S)-rimantadine and the trifluoromethylated analogues

Article abstract of DOI:10.1039/c9ob02241d

An improved fully stereoselective synthesis of both enantiomers of rimantadine and its trifluoromethylated analogues has been developed, using N-isopropylsulfinylimines as a starting chiral material, proving the superiority of the isopropyl group as a chiral inducer over the tert-butyl group in the case of hindered N-sulfinylimines.

Full text of DOI:10.1039/c9ob02241d

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N-Isopropylsulfinylimines vs. N-tert-
butylsulfinylimines in the stereoselective synthesis
of sterically hindered amines: an improved
synthesis of enantiopure (R)- and (S)-rimantadine
and the trifluoromethylated analogues†
a
Cite this: Org. Biomol. Chem., 2019,
17, 9854
Received 16th October 2019,
Accepted 3rd November 2019
Nazaret Moreno, ‡a Rocío Recio, ‡a Victoria Valdivia,
‡
DOI: 10.1039/c9ob02241d
a
rsc.li/obc
Noureddine Khiar *b and Inmaculada Fernández
*
An improved fully stereoselective synthesis of both enantiomers of sively developed by Ellman one year later.5 The development of
rimantadine and its trifluoromethylated analogues has been devel- highly efficient methods for the synthesis of the starting N-tert-
oped, using N-isopropylsulfinylimines as a starting chiral material, butanesulfinamide, currently commercially available in both
proving the superiority of the isopropyl group as a chiral inducer enantiomeric forms, and known as Ellman’s reagent, contribu-
over the tert-butyl group in the case of hindered N-sulfinylimines.
ted to the great success of the approach, as evidenced by its
innumerable applications described in the literature.2 More
recently, we introduced N-isopropylsulfinylimines as an
alternative intermediate to both tert-butyl and p-tolylsulfinyli-
mines. The advantage of this chiral controller is based on its
ability to induce a greater chiral discrimination than the
p-tolylsulfinyl group and higher reactivity than the tert-butyl-
sulfinyl group, while maintaining or even exceeding the chiral
induction of the process. The usefulness of the isopropyl-
sulfinyl group was demonstrated as a chiral organocatalyst in
the allylsilylation of hydrazones6 and as a chiral inducer in the
enantioselective synthesis of various trifluoromethyl aryl
amines including the trifluoromethyl analogue of the calcimi-
metic drug R-(+)-NPS R-568.7 The isosteric substitution of
hydrogen by fluoride is of special interest in the design of new
drugs, with a critical role and impact in drug potency, often
significantly improving their pharmacological properties.8
Guided by our interest in the synthesis of trifluoromethylated
derivatives of biological relevance,6–9 we became interested in
rimantadine. Rimantadine, 1-(1′-adamantyl)ethylamine, an
antiviral used in the treatment of type A influenza by inhibit-
ing proton conductance of the M2 ion channel of the virus,10
is also used as an antiparkinsonian drug thanks to its NMDA
antagonistic properties.11 Rimantadine was approved by the
Food and Drug Administration (FDA) in 1994 and commercia-
lized as a racemic mixture. Currently, rimantadine is no longer
clinically used due to the loss of its therapeutic efficacy, as a
consequence of the preponderance of resistant viral strains.
Surprisingly, although the antiviral effect of rimantadine and
its analogues has been known for more than four decades, the
study of the relative activity of the two enantiomers at the
molecular level was only conducted in 2016. Although it is
Enantiomerically pure amines are of interest as chiral building
blocks for numerous biologically active compounds, as inter-
mediates in the synthesis of pharmaceutical drugs, and as
ligands in organic and organometallic catalysis.1 The stereo-
selective 1,2-addition of organometallics to imines constitutes
one of the most direct approaches for the synthesis of chiral
amines. Interestingly, in contrast to the main chiral transform-
ations, where a catalytic approach is always preferred to a stoi-
chiometric one, the synthesis of chiral amines is an exception
owing to the particularity of chiral N-sulfinylimines. Indeed, in
the last two decades chiral N-sulfinylimines have proven to be
ideal substrates for the synthesis of structurally diverse enan-
tiopure amines, not only for laboratory experiments but also
for industrial scale production.2
The pioneering work of the Davis group in the mid-1990s,
using p-tolylsulfinylimine, demonstrated the great potential of
the sulfinylimine approach where the sulfinyl group plays the
triple role of a chiral auxiliary, an activator of the CN bond,
and an easily removable protective group of amines.3 However,
the real breakthrough in the field came with the use of the
bulkier N-tert-butylsulfinylimines, synthesized for the first
time by García-Ruano, Fernández and col. in 1996 4 and exten-
aDepartamento de Química Orgánica y Farmacéutica, Facultad de Farmacia,
Universidad de Sevilla, C/Profesor García González, 2, 41012 Sevilla, Spain.
E-mail: inmaff@us.es
bInstituto de Investigaciones Químicas, CSIC-Universidad de Sevilla, Avda. Américo
Vespucio, 49, 41092 Sevilla, Spain. E-mail: khiar@iiq.csic.es
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c9ob02241d
‡These authors contributed equally.
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known that in vivo both enantiomers of rimantadine have the
same therapeutic efficacy, the reported in vitro results are con-
troversial. Solid state NMR and molecular dynamics studies
conducted very recently, and for the first time, suggest that the
(R)-rimantadine enantiomer binds more strongly than the (S)
enantiomer to the M2 channel.12 However, functional assays
supported by theoretical and ITC studies showed, on the con-
trary, that both enantiomers have the same affinity for the M2
channel.13
Based on these premises and due to the structural simpli-
city of rimantadine and its interesting mode of action at the
molecular level, there is continuing interest in developing ana-
logues of rimantadine to combat the threat that influenza con-
tinues to present.14 Recently, various procedures have been
developed to access both enantiopure (R)- and (S)-rimantadine,
such as the optical resolution of the commercially available
racemic rimantadine,15 or the application of enzymatic
Scheme 2 Nucleophilic additions to N-tert-butylsulfinylaldimine 5(R).
methods for the reductive amination of methyl adamantyl aldimines, 5(R) and 5(S), respectively, by condensation with
ketone.16 However, until now there is only one approach, 1-adamantyl carboxaldehyde 4, Scheme 2. Thus, the oxidation
recently reported, for the stereoselective synthesis of deute- of 1-(adamantyl)methanol to the corresponding aldehyde, fol-
rated rimantadine enantiomers.12 In this paper we present our lowed by condensation with (R)-tert-butanesulfinamide 3(R),
methodology for the enantioselective synthesis of both enan- produced (R)-N-(adamantan-1-ylmethylidene) tert-butylsulfinyl-
tiomers of rimantadine, 1(R) and 1(S), as well as their corres- aldimine 5(R). This aldimine was treated with the methyl
ponding trifluoromethylated analogues, 2(R) and 2(S).
Grignard reagent at −78 °C and the reaction temperature was
A retrosynthetic analysis of enantiopure (R)- or (S)-rimanta- allowed to rise to r.t., to obtain the addition product as a
dine shows that both enantiomers (R2 = Me, Scheme 1) could mixture of both diastereomers 6(RS,SC) and 6(RS,RC) with a
be prepared by nucleophilic addition of the methyl Grignard moderate chemical yield (60%) and diastereomeric ratio
reagent to the adequate N-sulfinylaldimine
I (route a, (80 : 20 dr) (Scheme 2). This result can be rationalized by
Scheme 1), or by stereoselective reduction of the C–N double invoking the steric hindrance of the tert-butyl and adamantyl
bond of N-sulfinylketimine II (route b, Scheme 1). Taking into groups, which causes on the one hand the temperature to rise
account our interest in developing a methodology that allows so that the reaction takes place and on the other hand, the pro-
the preparation of not only enantiopure rimantadine but also motion of the formation of N-(adamant-1-ylmethyl) tert-
its trifluoromethyl analogues, route (a) seemed to be the most butanesulfinamide via competitive reduction of the imine.17
A
appropriate.
similar behaviour was observed in the addition of Ruppert–
Commercially available Ellman’s sulfinamides, (R)- and (S)- Prakash’s reagent to tert-butylsulfinylaldimine 5(R), yielding
tert-butylsulfinamide (3(R), R1 = tBu, Scheme 1), provide a fast the corresponding trifluoromethylated diastereomers 7(RS,RC)
and direct access to the corresponding enantiomeric sulfinyl- and 7(RS,SC), with a low chemical yield (50%) and only moder-
ate diastereoselectivity (82 : 18 dr) (Scheme 2).
In light of these results we decided to contrast the behavior
of N-isopropylsulfinylimines in the synthesis of the challen-
ging rimantadine enantiomers as a representative of sterically
hindered amines. (R)- and (S)-N-(adamantan-1-ylmethylidene)
isopropylsulfinylaldimine, 10(R) and 10(S), were prepared in a
two-step one-pot procedure by the reaction of LHMDS with the
corresponding isopropylsulfinate 9(S) and 9(R), respectively,
followed by condensation with 1-adamantylcarboxaldehyde 4
in THF, in the presence of CsF. The isopropylsulfinylating
agents 9(S) and 9(R) were prepared as previously described,
from dicyclohexylidene-D-glucose (DCGOH) and isopropyl-
sulfinyl chloride 8 as starting materials by the diastereodi-
vergent “DAG methodology” (Scheme 3).18
Starting with the trifluoromethylated analogues, the con-
densation of Ruppert–Prakash’s reagent with N-isopropyl-
sulfinylimines 10(S) was accomplished in toluene and the
1
temperature was maintained at −50 °C. H and 19F NMR ana-
Scheme 1 Retrosynthetic scheme of enantiopure (R) or (S)-rimantadine
and its analogs.
lysis of the crude mixture shows that the reaction takes place
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Scheme 5 Reaction products by treating N-sulfinylimine 10(R) with
Grignard reagents.
(R = Me or Et) did not yield the expected addition products to
the double bond. Instead, a mixture of products was obtained
as a result of the reduction of the imine, together with the
nucleophilic attack of the Grignard17 reagent on the sulfinyl
sulfur atom4 (Scheme 5). Unfortunately, the addition of a Lewis
acid (BF3·OEt2) as an additive did not improve the result.19
At this point, we, therefore, decided to evaluate route (b)
(Scheme 1) for the synthesis of both enantiomers of rimanta-
dine, using N-isopropylsulfinylketimines as starting intermedi-
ates. The advantage of this approach lies in the possibility of
obtaining the desired enantiomer of rimantadine through
the appropriate choice of the reducing agent, through a dia-
stereodivergent process. Both tert-butyl and isopropyl-
sulfinylketimines 12(R) and 14(R) were prepared as indicated
in Scheme 6, by condensation of the methyl adamantyl ketone
with the corresponding alkylsulfinamide, in the presence of
titanium tetraethoxide.
The reduction of N-tert-butylsulfinylketimine 12(R) with
L-selectride yielded the sulfinamide 6(RS,SC) as the major dia-
stereomer with a high chemical yield and 80% de. When
DIBAL was used as the reducing agent, sulfinamide 6(RS,RC)
was obtained with 92% chemical yield and 74% de. In both
cases, chromatographic separation was necessary to obtain
the diastereomerically pure sulfinamides (Table 1).
Interestingly, when N-isopropylsulfinylketimine 14(R) was
tested as the starting material, the stereoselectivity of the
process was improved significantly. Despite the lower steric
Scheme 3 Diastereodivergent synthesis of N-isopropylsulfinylaldi-
mines 10(S) and 10(R).
with 50% conversion and total diastereoselection in favor of
the trifluoromethylated sulfinamide 11(SS,RC) (Scheme 4).
Fortunately, the trifluoromethylated sulfinamide obtained was
easily purified by flash chromatography and the unreacted sul-
finylimine was recovered and reused. Raising the temperature
has a beneficial effect on the reaction conversion (100%), in
detriment of the diastereoselection. As it has been stated with
other similar substrates, the stereochemical outcome of the
addition of the trifluoromethyl group can be rationalized by
using a non-chelated Cram model with the approach of the
nucleophile on the less hindered si face of the C–N double
bond. Desulfinylation of N-sulfinamide 11(SS,RC) with 4 N HCl
in methanol at 0 °C provided the corresponding trifluoro-
methylated rimantadine hydrochloride analogue 2(R).
Following a similar route, starting from the N-sulfinylimine 11
(RS,SC), the enantiomeric trifluoromethylated analogue of (S)-
rimantadine hydrochloride was also obtained (Scheme 4).
In the case of rimantadine and its homologues, the reaction
of N-isopropylsulfinylimine 10(R) with the Grignard reagent
Scheme 4 Synthesis of enantiopure trifluoromethylated rimantadine
analogues 2(R) and 2(S).
Scheme 6 Synthesis of N-sulfinylketimines 12(R) and 14(R).
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Table 1 Diastereodivergent reduction of N-tert-butyl- and N-isopropyl-sulfinylketimines, 12(R) and 14(R)
Entry
R
Imine
[Red.]
Temperature
Sulfinamide
dr (%) (RS,SC) : (RS,RC)
Yield (%)
1
2
3
4
tBu
tBu
iPr
12(R)
12(R)
14(R)
14(R)
L-Selectride
DIBAL
L-Selectride
DIBAL
−78 °C to −40 °C
−78 °C
−78 °C to −40 °C
−78 °C
6(RS,SC)
6(RS,RC)
15(RS,SC)
15(RS,RC)
90 : 10
13 : 87
100 : 0
0 : 100
93
92
70
90
iPr
volume of the isopropyl group compared to the tert-butyl
group, the reduction of N-isopropylsulfinylimine with
Conflicts of interest
L-selectride or DIBAL took place in a completely stereo- There are no conflicts to declare.
selective manner, yielding sulfinamides 15(RS,SC) and 15(RS,
RC), respectively, as unique diastereomers, with good chemi-
cal yields (Table 1).
Acknowledgements
Thus, both enantiomers of rimantadine, 1(R) and 1(S),
We are grateful to the Spanish Ministerio de Economía y
Competitividad (MEC) for financial support (grant number
CTQ2016-78580-C2-2R). We gratefully thank CITIUS for the
NMR facilities. Nazaret Moreno thanks the Ministerio de
Ciencia, Innovación y Universidades for the Ph.D. grant.
were easily obtained as the corresponding hydrochloride
salt, in enantiopure forms, by desulfinylation of isopropyl-
sulfinamides 15(RS,SC) and 15(RS,RC), respectively, with 4 N
HCl (Scheme 7). Thereby, we have developed an improved
totally stereoselective synthesis for both enantiomers of
rimantadine and for their trifluoromethyl analogues using
N-isopropylsulfinylimines as chiral starting materials.
In summary, we have reported in this work a comparative
study on the stereoselective synthesis of sterically
challenging rimantadine and its analogues using
N-isopropylsulfinylimines and tert-butylsulfinylimines as
chiral intermediates. The N-isopropylsulfinyl group has
demonstrated its preeminence over the tert-butylsulfinyl
group both in the nucleophilic addition of trifluoromethyl
anions on the sulfinylaldimines, and in the diastereo-
selective hydrogenation of the corresponding sulfinyl keti-
mines. These N-isopropylsulfinylimines can be easily pre-
pared in a diastereodivergent manner using the “DAG meth-
odology”. The present work represents an improved fully
stereoselective synthesis of both enantiomers of rimantadine
and its trifluoromethylated analogues. Further application of
the protocol in the preparation of pharmacologically and syn-
thetically relevant enantiopure sterically hindered amines is
underway.
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Scheme 7 Synthesis of enantiopure (R)- and (S)-rimantadine, 1(R)
and 1(S).
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