Asymmetric syntheses of pharmaceuticals containing a cyclopropane moiety using catalytic asymmetric Simmons-Smith reactions of allylalcohols: Syntheses of optically active tranylcypromine and milnacipran

Article abstract of DOI:10.1246/cl.130498

Asymmetric synthesis of tranylcypromine was achieved using an enantioselective Simmons-Smith cyclopropanation catalyzed by a simple disulfonamide derived from an -amino acid. The optically active milnacipran was also synthesized by porcine pancreas lipase-catalyzed selective monoacylation of the C4-hydroxy group in (Z)-2-phenylbut-2-ene-1,4-diol and the enantioselective Simmons-Smith cyclopropanation as the key steps.

Full text of DOI:10.1246/cl.130498

doi:10.1246/cl.130498
Published on the web July 10, 2013
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Asymmetric Syntheses of Pharmaceuticals Containing a Cyclopropane Moiety
Using Catalytic Asymmetric Simmons-Smith Reactions of Allylalcohols:
Syntheses of Optically Active Tranylcypromine and Milnacipran
Yuki Ishizuka,1 Hirohisa Fujimori,1 Takuya Noguchi,1,2 Masashi Kawasaki,3 Mari Kishida,1
Takuya Nagai,2 Nobuyuki Imai,2 and Masayuki Kirihara*1
1Department of Materials and Life Science, Shizuoka Institute of Science and Technology,
2200-2 Toyosawa, Fukuroi, Shizuoka 437-8555
2Faculty of Parmacy, Chiba Institute of Science, 15-8 Shiomi-cho, Choshi, Chiba 288-0025
3Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Imizu, Toyama 939-0398
(Received May 29, 2013; CL-130498; E-mail: kirihara@ms.sist.ac.jp)
Asymmetric synthesis of tranylcypromine was achieved
using an enantioselective Simmons-Smith cyclopropanation
catalyzed by a simple disulfonamide derived from an ¡-amino
acid. The optically active milnacipran was also synthesized by
porcine pancreas lipase-catalyzed selective monoacylation of the
C4-hydroxy group in (Z)-2-phenylbut-2-ene-1,4-diol and the
enantioselective Simmons-Smith cyclopropanation as the key
steps.
Ph
H
Ph
H
H
Et2N
NH2
Milnacipran (2)
NH2
O
Tranylcypromine (1)
Scheme 1. Pharmaceutical amines containing a cyclopropane
moiety.
Ph
10 mol%
Ar
Ar
4
MsHN
NHTs
Ar
Ar
H
OH
5 (76-51% ee)
Et2Zn, CH2I2, CH2Cl2
OH
Amines containing cyclopropane moieties are important
compounds in medicinal chemistry and biochemistry because
they sometimes exhibit several biological activities.1-5 More-
over, some of them are used as pharmaceuticals, such as
tranylcypromine (1)1 and milnacipran (2) (Scheme 1).2
3
Scheme 2. The chiral disulfonamide 4 catalyzed asymmetric
Simmons-Smith reaction of allyl alcohols 3.
Tranylcypromine (1) is a strong monoamineoxidase (MAO)
inhibitor, and it has been used as an antidepressant and
anxiolytic agent in the clinical treatment of mood and anxiety
disorders, respectively.1 Several analogs of 1 bearing a trans-2-
arylcyclopropylamine moiety have been studied by medicinal
chemists because of their variety of interesting biological
activities.3 Milnacipran (2) is a serotonin-noradrenaline reuptake
inhibitor (SNRI), and it has also been used as an antidepres-
sant.2,4 The racemic forms of 1 and 2 are used as clinical
medicines; however, it is important to develop asymmetric
syntheses for these compounds because their stereospecific
analogs show more effective pharmaceutical activities.5
Although several asymmetric syntheses of optically active
amines containing a cyclopropane moiety, including 1 and 2,
have been developed,3c,3e-3g,4a,4d,4f-4i,6 enantioselective catalytic
Simmons-Smith cyclopropanations7,8 have not been used for
these syntheses. We developed a catalytic enantioselective
Simmons-Smith cyclopropanation using simple disulfonamides
derived from an ¡-amino acid (Scheme 2).8
In this report, we describe the syntheses of optically active 1
and 2 by the aforementioned asymmetric reaction, as described in
Scheme 2. Retrosyntheses of 1 and 2 are depicted in Scheme 3.
The amino group of 1 might be introduced by oxidation
of the hydroxymethyl group of 5a and the subsequent Curtius
rearrangement. The optically active cyclopropane 5a can be
prepared by the enantioselective Simmons-Smith cyclopropa-
nation of trans-cinnamyl alcohol 3a. The aminomethyl group
and amide group of 2 might be derived from the hydroxymethyl
groups of 5b, which can be prepared by an asymmetric
Simmons-Smith reaction of allylic alcohol 3b.
Ph
Ph
H
H
Ph
H
H
OH
NH2
OH
3a
Ph
1
5a
Ph
H
Ph
H
Et2N
NH2
RO
OH
RO
OH
3b
5b
2
O
Scheme 3. Retrosyntheses of 1 and 2.
Asymmetric synthesis of 1 was achieved as described
in Scheme 4. The optically active 5a was prepared by an
asymmetric Simmons-Smith reaction of 3a in the presence of
a catalytic amount of the asymmetric sulfonamide 4, as we
reported previously.8,9 Alcohol 5a was oxidized to the corre-
sponding carboxylic acid by the Jones reagent, followed by
Shioiri’s method10 using diphenylphosphoryl azide, t-butanol,
and triethylamine to afford carbamate 6. Deprotection of the
t-butoxycarbonyl group using chlorotrimethylsilane in methanol
provided the desired (+)-tranylcypromine [(+)-1] in 34% yield
with 74% ee11 (22% yield from 3a).
Asymmetric synthesis of milnacipran was attempted next.
Initially, 3b was synthesized from commercially available but-
2-yne-1,4-diol 7, as shown in Scheme 5. According to the
literature procedure,12 7 was converted to (Z)-2-phenylbut-2-
ene-1,4-diol (8) by a Pd(0)-catalyzed reaction with phenylboric
acid. The C4-hydroxy group of 8 was regioselectively protected
by porcine pancreas lipase (PPL)-catalyzed monoacetylation that
we had developed13 to afford 9.
Protection of the C1-hydroxy of 9 with a t-butyldimethyl-
silyl group and subsequent alkaline hydrolysis of the C4-acetoxy
Chem. Lett. 2013, 42, 1311-1313
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1312
Ph
the result of the recrystallization of (¹)-2¢HCl from ethanol-
diethyl ether.
10 mol%
MsHN
NHTs
Ph
H
H
Ph
4
In conclusion, asymmetric syntheses of tranylcypromine (1)
and milnacipran (2) were achieved by catalytic enantioselective
Simmons-Smith cyclopropanations using the simple disulfon-
amides derived from an ¡-amino acid. Synthesis studies of
several derivatives of 1 and 2 are in progress.
OH
OH
Et2Zn (2.0 equiv), CH2I2 (3.0 equiv)
5a
3a
CH2Cl2, 0 °C, 24 h
(87%, 84% ee)
1) Jones Reagent (3.8 equiv)
Ph
H
H
acetone, 0 °C, 6 h
NHBoc
2) Ph2PON3 (1.1 equiv),
Et3N (1.1 equiv)
References and Notes
6
(85% in two steps)
1
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t-BuOH, reflux, 9 h
Ph
H
H
TMSCl (40 equiv)
(+)-Tranylcypromine
MeOH, 0 °C, 3 h
NH2
2
(+)-1 (34%, 74% ee)
Scheme 4. Asymmetric synthesis of (+)-tranylcypromine
[(+)-1].
3
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3 mol% [Pd(PPh3)4]
15 mol% AcOH
lipase (PPL)
vinyl acetate
Ph
H
HO
OH
HO
HO
OH
PhB(OH)2 (1.2 equiv)
7
8 (69%)
1,4-dioxane, 80 °C, 21 h
1) TBSOTf (3 equiv), Et3N (4 equiv),
CH2Cl2, rt, 30 min (91%)
Ph
H
H
Ph
H
TBSO
TBSO
OH
OH
OAc
2) K2CO3 (1.1 equiv), MeOH
H2O, rt, 1 h (89%)
3b
5b
9 (91%)
Ph
Ph
10 mol%
4
NHTs
MsHN
Et2Zn (2.0 equiv), CH2I2 (3.0 equiv), CH2Cl2, 0 °C, 24 h
(87%, 59% ee)
1) NaN3 (20 equiv), PPh3 (6 equiv)
CBr4 (3 equiv), DMF, rt, 1.5 h.
2) n-Bu4NF (1.2 equiv), THF,
Ph
H
1) (COCl2)2 (29 equiv),
CH2Cl2, DMF, rt, 2 h
rt, 2.5 h
HO
N3
4
O
2) Et2NH (32 equiv),
CH2Cl2, rt, 1 h
10
[72% (in 3 steps)]
3) Jones Reagent (2.7 equiv)
acetone, 0 °C, 1 h
1) H2 (balloon),
Ph
H
Ph
H
10%Pd/C, MeOH
rt, 1 h
Et2N
NH3Cl
Et2N
N3
O
.
(-)-2 HCl
O
11
2) HCl (g),
1,4-dioxane,
rt, 1 h
(-)-Milnacipran hydrochloride
[56% (in 2 steps), 72% ee]
[80% (in 2 steps)]
Scheme 5. Asymmetric synthesis of (¹)-milnacipran [(¹)-2]
hydrochloride.
group provided 3b, which was treated with diiodomethane and
diethylzinc in the presence of 10 mol % of 4 to produce 5b in
87% yield and 59% ee.14 The primary hydroxy group of 5b
was converted to an azide; the t-butyldimethylsilyl group was
removed using fluoride ions, and the resulting primary alcohol
was oxidized using the Jones reagent to afford carboxylic acid
10. The carboxy group of 10 was converted to an amide 11, and
hydrogenation of the azide group of 11 and subsequent reaction
with hydrogen chloride afforded the desired optically active
(¹)-milnacipran hydrochloride (2¢HCl) with 72% ee15 (14%
yield from 7). The improvement in the optical purity might be
Chem. Lett. 2013, 42, 1311-1313
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1313
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9
The enantiomeric excess was determined using HPLC-
analysis [chiralcel OD hexane:2-PrOH = 95:5 (flow rate
1.0 mL min¹1)].
10 T. Shioiri, K. Ninomiya, S. Yamada, J. Am. Chem. Soc.
1972, 94, 6203.
23
11 (+)-Tranylcypromine [(+)-1]: pale yellow oil; ½¡ꢀD
+100.0° (c 0.09, CHCl3) [(¹)-1: lit.1d ¹135.4° (c 0.81,
CHCl3)]; IR (neat) cm¹1: 3340, 2869, 2364, 1604, 1497,
5
6
1
1020, 754, 697, 472; H NMR (CDCl3): ¤ 0.97-1.13 (2H,
m), 1.72 (2H, br), 1.84-1.88 (1H, m), 2.55 (1H, m), 7.01-
7.26 (5H, m); 13C NMR(CDCl3): ¤ 18.43, 28.40, 58.47,
126.01, 126.45, 128.31, 140.71; MS (m/z): 133 (M+). These
spectral data are consistent with those of the literature.1d The
enantiomeric excess was caluculated from the value of
specific rotation of (+)-1 in the literature.1d
12 C. H. Oh, H. H. Jung, K. S. Kim, N. Kim, Angew. Chem.,
Int. Ed. 2003, 42, 805.
13 N. Koyata, T. Nagai, M. Kawasaki, T. Noguchi, M. Kirihara,
N. Imai, Chem. Lett. 2009, 38, 892.
14 The enantiomeric excess was determined using HPLC-
analysis [chiralcel OD hexane:2-PrOH = 95:5 (flow rate
1.0 mL min¹1)].
7
15 (¹)-Milnacipran hydrochloride [(¹)-2¢HCl]: colorless crys-
tals; mp 177-179 °C (ethanol-diethyl ether) (lit4m 179-
23
181 °C); ½¡ꢀD ¹57.1° (c 0.105, MeOH) [(+)-2¢HC: lit.4n
+72.8° (c 0.95, CHCl3)]; IR (KBr) cm¹1: 3465, 2973, 1617,
1445; 1H NMR (D2O): ¤ 0.72-0.81 (3H, m), 1.03-1.09 (3H,
m), 1.27-1.39 (2H, m), 1.89-1.93 (1H, m), 2.68-2.74 (1H,
m), 3.21-3.31 (9H, m), 7.20-7.31 (5H, m); 13C NMR (D2O):
¤ 11.56, 11.95, 18.83, 24.21, 34.65, 40.10, 41.64, 42.83,
125.82, 127.45, 129.21, 138.88, 171.36. These spectral data
are consistent with those of the literature.4l The enantiomeric
excess of the free amine 2, which was prepared from the
recrystallized (¹)-2¢HCl by treatment with aqueous 0.1 M
NaOH, extraction with chloroform, and evaporation,
was determined using HPLC-analysis [chiralcel OJ
hexane:EtOH = 90:10 (flow rate 1.0 mL min¹1)].
8
Chem. Lett. 2013, 42, 1311-1313
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/