A concise stereoselective total synthesis of (2R,2′R)-threo-(+)- methyl-phenidate via a ring-closing metathesis protocol

Article abstract of DOI:10.1055/s-2007-982577

In the synthesis of (2R,2′R)-threo-(+)-methylphenidate, a ring-closing metathesis approach was adopted to construct the piperidine ring, while Sharpless asymmetric epoxidation was used for the efficient generation of two contiguous stereocenters. Georg Th

Full text of DOI:10.1055/s-2007-982577

1742
LETTER
A Concise Stereoselective Total Synthesis of (2R,2¢R)-threo-(+)-Methyl-
phenidate via a Ring-Closing Metathesis Protocol1
C
oncise Stereo
a
selective
T
l
otal Sy
a
nthesis of
(
k
2
R
,2
¢
R
)-thre
o
o
-(+)-Methy
d
lphenidate ety Radha Krishna,* Krishnarao Lopinti
D-206/B, Discovery Laboratory, Organic Chemistry Division III, Indian Institute of Chemical Technology, Hyderabad 500007, India
E-mail: prkgenius@iict.res.in
Received 12 February 2007
O
Ph
Abstract: In the synthesis of (2R,2¢R)-threo-(+)-methylphenidate,
H.HCl
NH
Ph
2'
N
2'
a ring-closing metathesis approach was adopted to construct the
piperidine ring, while Sharpless asymmetric epoxidation was used
for the efficient generation of two contiguous stereocenters.
2
COOMe
2
OTBDPS
1
2
4
Key words: (2R,2¢R)-threo-(+)-methylphenidate, ritalin, attention
deficit hyperactivity disorder (ADHD), cis-allylic alcohol,
Sharpless asymmetric epoxidation, bisolefin, ring-closing metathe-
sis (RCM)
O
OH
OH
3
Scheme 1
( )-threo-Methylphenidate hydrochloride, commonly
called ritalin on the market, is used mainly for the treat-
ment of attention deficit hyperactivity disorder (ADHD)
in children in the USA.2 This medication is also used to
treat patients with Narcolepsy (or disorder of sleep regu-
lation). Methylphenidate is a mild stimulant that works by
affecting the levels of neurotransmitters in the nervous
system. It has been marketed as racemate although the
(2R,2¢R)-threo-(+)-methylphenidate hydrochloride (1) is
ca. 13 times more active than the corresponding (2S,2¢S)-
threo-(–)-methylphenidate hydrochloride.3 Various syn-
thetic approaches for the preparation of the active isomer
have been reported including resolution,4 catalyst-mediat-
ed synthesis5 and few stereoselective syntheses.6
Amongst the reported syntheses, the enantioselective syn-
thesis by Winkler et al.5a using Doyle’s rhodium-cata-
lyzed C–H insertion reaction is the shortest. A recent
pared from Sharpless asymmetric epoxidation of allylic
alcohol obtained by the selective reduction of allylated
propargyl alcohol, which in turn could be prepared from
the commercially available propargyl alcohol (4).
a
b
c
OH
OH
OH
5
4
6
O
d
OH
OH
+
OH
Ph
OH
HO
Ph
7b
3
7a
Scheme 2 Reagents and conditions: (a) allyl bromide, CuI, TBAI,
K2CO3, DMF, r.t., 85%; (b) Ni(OAc)2·4H2O, ethylenediamine,
NaBH4, H2 atmosphere, EtOH, r.t., 90%; (c) (–)-DIPT, Ti(Oi-Pr)4,
review encompassing all the previous syntheses is worth cumene hydroperoxide, CH2Cl2, –20 °C, 83%; (d) (i) PhLi, CuI, Et2O,
noting.5b Recently we have introduced chiral 2,3-epoxy
–40 °C to 0 °C; (ii) NaIO4, MeOH, 73% over two steps.
aldehydes as electrophiles in the diastereoselective
Baylis–Hillman reaction7 and in the Passerini reaction.8 In
Thus, propargylic alcohol (4; Scheme 2), upon coupling
continuation of our interest in the use of chiral epoxides,
herein we have invoked Sharpless asymmetric epoxida-
tion for generating two contiguous stereocenters and
Grubbs’ ring-closing metathesis protocol as the key steps
towards the total synthesis of methylphenidate 1
(Scheme 1).
with allyl bromide in the presence of CuI–K2CO3–tetra-
butylammonium iodide (TBAI) in DMF at room tem-
perature, gave 5 in 85% yield.9 The triple bond present in
5 was partially reduced in the presence of nickel acetate
and catalytic amount of sodium borohydride to afford 6
(90%).10 Later, 6 on Sharpless asymmetric epoxidation11
with cumene hydroperoxide in the presence of (–)-diiso-
propyl D-tartrate and titanium(IV) isopropoxide afforded
3 (83%). The enantiomeric excess of epoxide 3 was
calculated to be 92% by correlating with the literature
values.12 Later, chelation-assisted regioselective nucleo-
philic ring-opening reaction13 of epoxide 3 with PhLi in
the presence of CuI gave the requisite 1,3-diol 7a (73%)
as the major product, while the minor product 1,2-diol 7b
(8%; 7a/7b = 9:1) was removed by oxidative cleavage
(NaIO4–MeOH–r.t.).
Accordingly, chiral piperidine present in 1 was built
through the ring-closing metathesis of bisolefin 2. The
amino functional group was introduced by SN2 mode of
the diol which in turn was obtained by the regioselective
ring-opening reaction of epoxide 3 by Ph2CuLi. The
appropriate stereoselective epoxide 3 was efficiently pre-
SYNLETT 2007, No. 11, pp 1742–1744
0
3
.0
7
.2
0
0
7
Advanced online publication: 25.06.2007
DOI: 10.1055/s-2007-982577; Art ID: G05307ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Concise Stereoselective Total Synthesis of (2R,2¢R)-threo-(+)-Methylphenidate
1743
OMs
OH
c
b
a
OTBDPS
O
7a
OTBDPS
Ph
Ph
9
8
O
N3
d, e
NH
NH
f
OTBDPS
OTBDPS
OTBDPS
Ph
10
11
2
Ph
Ph
O
h
NH
NBoc
g
NH
i
OTBDPS
ref . 6b
OTBDPS
OTBDPS
13
12
Ph
14
Ph
Ph
j
NBoc
k, l
NBoc
1
COOH
OH
Ph
Ph
16
15
PCy3
Ru
Ph
Cl
Cl
H
PCy3
I
Scheme 3 Reagents and conditions: (a) TBDPSCl, imidazole, CH2Cl2, r.t., 95%; (b) MsCl, Et3N, CH2Cl2, 0 °C to r.t., 87%; (c) NaN3, DMF,
80 °C, 73%; (d) PPh3, MeOH, r.t.; (e) acryloyl chloride, Et3N, CH2Cl2, 0 °C to r.t., 62% over two steps; (f) Grubbs’ catalyst (I; 15 mol%),
CH2Cl2, reflux, 75%; (g) Pd/C, H2 atmosphere, r.t., 86%; (h) (i) BH3·DMS, THF, 0 °C to r.t.; (ii) EtOH, reflux, 82%; (i) (Boc)2O, Et3N, THF,
0 °C to r.t., 85%; (j) HF·Py, THF, r.t., 80%; (k) Dess–Martin periodinane, NaHCO3, CH2Cl2, 0 °C; (l) NaClO2, NaH2PO4·2H2O, t-BuOH–2-
methyl-2-butene (2:1), 0 °C to r.t., 12 h, 89% over two steps.
The diol 7a (Scheme 3) was selectively protected as its olefin functionality was saturated in the presence of Pd/C
TPS ether 8 with TBDPS chloride and the secondary alco- in H2 atmosphere at room temperature and later the amide
hol was then conveniently transformed into amine by a functionality was efficiently reduced with BH3·DMS16 to
three-step process. Firstly, the secondary alcohol was yield the requisite amine 13 in a very good yield (82%).
mesylated (MsCl–Et3N–CH2Cl2, r.t.) which was then con-
verted into the corresponding azide (NaN3–DMF, 80 °C)
Next, amine 13 was protected as its carbamate 14 {85%,
(Boc)2O–Et3N–THF, r.t.} and the silyl group was depro-
via SN2 pathway. Later, azide 10 was reduced to amine
tected with HF·Py at room temperature without any race-
under Staudinger reaction conditions.14 Initially, a more
mization to produce the alcohol 15 (80%).6b The required
prudent strategy for constructing the azacyclic part of
the molecule was conceived through the reduction of the
acid 16 was obtained in two consecutive steps. The alco-
hol was first oxidized to an aldehyde in the presence of
azide functionality to amine, its conversion into Boc car-
Dess–Martin periodinane17 under basic conditions. The
bamate (Boc2O–Et3N–THF, r.t.), allylation of the carba-
crude aldehyde thus obtained was then oxidized to the
acid 16 (89% over two steps) under sodium chlorite
oxidation (NaClO2–NaH2PO4·2H2O–t-BuOH–2-methyl-
2-butene) conditions. Treatment of the acid 16 with meth-
anolic HCl at 50 °C yielded the desired (2R,2¢R)-threo-
(+)-methylphenidate hydrochloride (1) in 70% yield. All
the spectral and analytical data of 1 were identical to those
mate as an allyl amide (allyl bromide–NaH–DMF or THF)
followed by the ring-closing metathesis reaction. Howev-
er, it was observed that the highly acidic benzylic proton
was easily deprotonated under several allylation reaction
conditions resulting in a racemic allylated product. Con-
sequently milder reaction conditions were adopted for the
ring construction. The crude amine thus obtained was
reported previously.4
acryloylated (acryloyl chloride–Et3N–DMAP–CH2Cl2,
In conclusion, we have described a concise total synthesis
r.t.) to afford the bisolefin 2 in 62% yield. Ring-closing re-
of (2R,2¢R)-threo-(+)-methylphenidate hydrochloride
action of 2 was effected using Grubbs’ first-generation
(1),18 the active isomer of ritalin in high optical purity.
catalyst (I, 15 mol%) in CH2Cl2 at reflux temperature to
Herein, we have used Sharpless asymmetric epoxidation
for the generation of two contiguous stereocenters and
Grubbs’ ring-closing metathesis as the key step to con-
struct the piperidine ring. The strategy reported herein is
suitable for synthesizing all possible isomers of meth-
ylphenidate in enantiopure form or analogues thereof. The
present synthesis avoids the use of chiral auxiliary or
resolution, thus making it more adoptable.
give lactam 11 (75%).15 Next, in order to transform the
a,b-unsaturated lactam into piperidine ring, we tried to re-
duce both olefin and amide functionalities in a single step
with LiAlH4 but observed that the racemization was more
facile, and no 1,2- or 1,4-addition products were observed.
Hence it was decided to opt for a mild and stepwise reduc-
tion of a,b-unsaturated lactam ring. Consequently, the
Synlett 2007, No. 11, 1742–1744 © Thieme Stuttgart · New York

1744
P. Radha Krishna, K. Lopinti
LETTER
allylic). 13C NMR (75 MHz, CDCl3): d = 138.44, 134.72,
129.37, 128.57, 127.19, 118.13, 71.52, 64.53, 52.55, 39.49.
IR (KBr): 3386, 3077, 3028, 2929, 1453, 1037, 915, 703
cm–1. LC–MS: m/z (%) = 215 (17) [M + 23]. Anal. Calcd for
C12H16O2: C, 74.97; H, 8.39. Found: C, 74.95; H, 8.40.
Compound 10: [a]D –26.70 (c = 0.75, CHCl3). 1H NMR (200
MHz, CDCl3): d = 7.60–7.70 (m, 5 H, ArH), 7.37–7.34 (m,
6 H, ArH), 7.14–7.25 (m, 4 H, ArH), 5.71–5.91 (m, 1 H,
olefin), 5.04–5.15 (m, 2 H, olefin), 3.97–4.15 (m, 2 H,
CHN3, CH), 3.74 (dd, J = 4.92, 9.85 Hz, 1 H, CH), 2.80–2.89
(m, 1 H, CH), 2.18 (t, J = 6.44 Hz, 2 H, allylic), 1.05 (br s, 9
H, t-Bu). IR (KBr): 3069, 2931, 2858, 2102, 1427, 1109,
701, 503 cm–1. LC–MS: m/z (%) = 456 (30) [M + 1]. Anal.
Calcd for C28H33N3OSi: C, 73.80; H, 7.30. Found: C, 73.74;
H, 7.28. Compound 11: [a]D +25.80 (c = 0.55, CH 2Cl2). 1H
NMR (300 MHz, CDCl3): d = 7.53–7.62 (m, 4 H, ArH),
7.30–7.41 (m, 6 H, ArH), 7.19–7.25 (m, 3 H, ArH), 7.12 (br
s, 1 H, NH), 6.97–7.00 (m, 2 H, ArH), 6.41 (td, J = 4.53, 8.69
Hz, 1 H, olefin), 5.86 (d, J = 9.82 Hz, 1 H, olefin), 3.96–4.07
(m, 2 H, OCH, NCH), 3.85 (dd, J = 3.78, 10.58 Hz, 1 H,
OCH), 2.84–2.91 (m, 1 H, CH), 1.93–2.00 (m, 2 H, allylic),
1.09 (br s, 9 H, t-Bu). 13C NMR (75 MHz, CDCl3): d =
166.03, 140.24, 135.64, 135.56, 132.62, 129.97, 129.86,
128.79, 128.05, 127.88, 127.8, 127.34, 124.65, 67.67, 54.78,
51.88, 28.89, 26.9, 19.07. IR (KBr): 3370, 2924, 2854, 1675,
1611, 1109, 702 cm–1. LC–MS: m/z (%) = 456 (34) [M + 1].
Anal. Calcd for C29H33NO2Si: C, 76.44; H, 7.30. Found: C,
76.41; H, 7.28. Compound 13: [a]D +21.32 (c = 0.75,
CHCl3). 1H NMR (300 MHz, CDCl3): d = 7.51–7.57 (m, 3
H, ArH), 7.29–7.38 (m, 6 H, ArH), 7.11–7.25 (m, 6 H, ArH),
3.98 (dd, J = 6.04, 10.20 Hz, 1 H, OCH2), 3.89 (dd, J = 5.67,
10.58 Hz, 1 H, OCH2), 2.89–3.06 (m, 2 H, CH2NH), 2.74–
2.81 (m, 1 H, CHNH), 2.60 (td, J = 2.64, 11.71 Hz, 1 H,
CHPh), 2.19–2.24 (m, 1 H, NH), 1.61 (dd, J = 12.84, 43.81
Hz, 2 H, CH2), 1.17–1.44 (m, 4 H, 2 × CH2), 1.01 (br s, 9 H,
t-Bu). 13C NMR (75 MHz, CDCl3): d = 139.30, 135.60,
135.30, 134.80, 129.60, 128.80, 128.20, 127.60, 127.13,
67.40, 62.30, 59.20, 50.90, 45.80, 30.16, 29.60, 26.80,
26.50, 25.60, 24.70, 24.50, 23.40, 22.70, 18.90. IR (KBr):
3356, 2930, 2855, 1427, 1109, 702 cm–1. LC–MS: m/z (%) =
444 (35) [M + 1]. Anal. Calcd for C29H37NOSi: C, 78.50; H,
8.41. Found: C, 78.49; H, 8.44. Compound 15: white solid;
mp 78–80 °C; [a]D +12.70 (c = 0.50, CH2Cl2). 1H NMR (300
MHz, CDCl3): d = 7.19–7.37 (m, 5 H, ArH), 4.60 (d, J =
12.08 Hz, 1 H), 4.00 (d, J = 12.84 Hz, 1 H), 3.66–3.70 (m, 1
H), 3.47–3.55 (m, 2 H), 3.01 (d, J = 12.08 Hz, 1 H), 2.84 (d,
J = 10.8 Hz, 1 H), 1.62–1.66 (m, 2 H), 1.50 (br s, 9 H, t-Bu),
1.32–1.43 (m, 4 H). 13C NMR (50 MHz, CDCl3): d = 156.40,
141.20, 128.80, 128.50, 126.70, 80.40, 63.50, 50.20, 45.80,
39.80, 28.40, 26.03, 25.36, 18.80. IR (KBr): 3448, 2928,
2840, 1681, 1598, 1258, 1158 cm–1. LC–MS: m/z (%): 328
(26) [M + Na]. Anal. Calcd for C18H27NO3: C, 70.79; H,
8.91. Found: C, 70.77; H, 8.93. Compound 16: white solid;
mp 115–120 °C; [a]D = –40.66 (c = 0.80, CH2Cl2). 1H NMR
(300 MHz, CDCl3): d = 7.25–7.46 (m, 5 H, ArH), 4.73–5.03
(m, 1 H, NCH), 4.10 (d, J = 11.7 Hz, 1 H, CHPh), 3.88–4.00
(m, 1 H, NCH), 2.85–3.14 (m, 1 H, NCH), 1.72–1.88 (m, 6
H, 3 × CH2), 1.42 (br s, 9 H, t-Bu). 13C NMR (75 MHz,
CDCl3): d = 176.90, 154.8, 135.88, 128.80, 128.70, 127.80,
79.88, 54.02, 53.04, 51.17, 39.80, 38.30, 29.67, 28.23,
25.20, 18.80. IR (KBr): 3447, 2924, 2854, 1631, 1260, 760
cm–1. LC–MS: m/z (%) = 342 (22) [M + 23]. Anal. Calcd for
C18H25NO4: C, 67.69; H, 7.89. Found: C, 67.66; H, 7.85.
Acknowledgment
One of the authors (K.L.) thanks the CSIR, New Delhi for the finan-
cial support in the form of a fellowship.
References and Notes
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white solid; mp 49–52 °C; [a]D –10.30 (c = 0.55, CHCl3). 1H
NMR (200 MHz, CDCl3): d = 7.23–7.35 (m, 5 H, ArH),
5.69–5.89 (m, 1 H, olefin), 5.03–5.12 (m, 2 H, olefin), 3.88–
4.12 (m, 3 H, OCH, OCH2), 2.88 (td, J = 4.50, 6.73 Hz, 1 H,
CHPh), 2.15–2.27 (m, 1 H, allylic), 1.95–2.09 (m, 1 H,
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