.
Angewandte
Communications
provided the corresponding amines in high yields and
enantioselectivity (entries 10–12). ortho Substitution proved
detrimental to both reactivity and selectivity, while meta,para
disubstitution led to good results with an e.r. of 97:3
(entries 13 and 14). Interestingly, N-methyl imine 1o, which
is derived from a-tetralone, was reduced in high yield with an
e.r. of 95.5:4.5 (entry 15). N-Methyl imine 1p, which is derived
from 1-indanone, gave less satisfactory results (entry 16). An
aliphatic imine can also be employed but gave poor enantio-
selectivity (entries 17 and 18). Propiophenone-derived imine
1s was reduced in 90% yield with an e.r. of 71:29 (entry 19).
An additional strength of our method is revealed upon
exploring longer and substituted N-alkyl groups. Gratifyingly,
the reduction of N-ethyl imine 6a proceeded in 83% yield
and with an e.r. of 97:3 (Table 3, entry 2). Remarkably, even
Table 3: Scope of the asymmetric reduction of N-alkyl imines.[a]
Scheme 1. Synthesis of (S)-Rivastigmine, NPS R-568 Hydrochloride,
and (R)-Fendiline.
Entry
1
Products
Yield [%]
97
e.r./d.r.[b]
95.5:4.5
5a
7a
7b
7c
7d
7e
7 f
To illustrate the synthetic utility of our method, several
marketed pharmaceuticals were prepared (Scheme 1). For
example, a short synthesis of (S)-Rivastigmine, which is
currently used for treating Alzheimerꢀs disease, was real-
ized.[14] Boc-protected N-methyl amine 5k (Table 2, entry 11)
was converted into N,N-dimethyl amine 8 in 93% yield upon
LiAlH4 reduction. This transformation illustrates an addi-
tional benefit of the Boc moiety, which not only enables
turnover in the asymmetric reduction but also introduces
a useful N-methyl precursor. Next, cleavage of the O-methyl
group using aqueous HBr provided (S)-3-(1-dimethylaminoe-
thyl)phenol 9 in 95% yield. A single recrystallization from
CH2Cl2/pentane gave product 9 in 76% yield with an e.r. of
99.6:0.4. Finally, carbamoylation of alcohol (S)-9 with com-
mercially available N-ethyl-N-methylcarbamoyl chloride 10
in the presence of sodium hydride furnished (S)-Rivastigmine
in 98% yield with an e.r. of 99.6:0.4.
Furthermore, the calcimimetic compound NPS R-568
hydrochloride, which has been shown to be effective against
both primary and secondary hyperparathyroidism, was syn-
thesized.[15] In this case, imine generation from commercially
available ketone 11 and amine 12, asymmetric reduction, and
Boc deprotection, were all performed in one pot, thereby
providing NPS R-568 in 82% yield with an e.r. of 97:3. A
single recrystallization of the corresponding HCl salt from
CH2Cl2/MTBE gave NPS R-568 hydrochloride in 82% yield
with an e.r. of 99.7:0.3.
2
83
90
82
77
94
83
94
97:3
3
97.5:2.5
97.5:2.5
95.5:4.5
97:3
4
5
6
7[c]
8
95.5:4.5
97.5:2.5
7g
9[c]
7h
75
79
93:7
10[c,d]
ent-7h
97.5:2.5
[a] Reactions were run on a 0.25 mmol scale. [b] Determined by HPLC
with a chiral stationary phase. [c] Reaction time 3 d. [d] The S-enantiomer
of disulfonimide 2i was used.
the N-n-propyl, N-n-butyl, N-allyl, N-2-phenylethyl, N-2-(3,4-
dimethoxy)-phenylethyl, and N-3-phenylpropyl imine sub-
strates (6b–6g) are well tolerated and reacted with excellent
enantioselectivity (entries 3–8). Interestingly, the reduction of
imine 6h, which is derived from methyl (tert-butoxycar-
bonyl)-l-lysinate, with (R)-DSI-2i resulted in a d.r. of 93:7,
while (S)-DSI-2i gave a d.r. of 97.5:2.5, which is indicative of
a matched combination (entries 9 and 10).
In a similar manner, an enantioselective synthesis of (R)-
Fendiline, an effective antianginal drug for the treatment of
coronary heart diseases, was achieved in 78% yield with an
e.r. of 97.5:2.5.[16]
In summary, we have developed a highly enantioselective
Brønsted acid catalyzed reduction of N-alkyl imines. The
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 11852 –11856