A convenient method for synthesis of optically active methylphenidate from N-methoxycarbonylpiperidine by utilizing electrochemical oxidation and Evans aldol-type reaction

Article abstract of DOI:10.1016/S0040-4020(00)00653-0

A new method to prepare optically active methylphenidate starting from piperidine is described. The method consists of a transformation of N-methoxycarbonylated piperidine to the corresponding α-methoxylated carbamate utilizing electrochemical oxidation f

Full text of DOI:10.1016/S0040-4020(00)00653-0

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 7411–7422
A Convenient Method for Synthesis of Optically Active
Methylphenidate from N-Methoxycarbonylpiperidine by Utilizing
Electrochemical Oxidation and Evans Aldol-type Reaction
*
Yoshihiro Matsumura, Yasuhisa Kanda, Kimihiro Shirai, Osamu Onomura and Toshihide Maki
Faculty of Pharmaceutical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
Received 23 June 2000; accepted 27 July 2000
Abstract—A new method to prepare optically active methylphenidate starting from piperidine is described. The method consists of a
transformation of N-methoxycarbonylated piperidine to the corresponding a-methoxylated carbamate utilizing electrochemical oxidation
followed by the coupling reaction with optically active Evans imides to produce optically active methylphenidate derivatives with high
stereoselectivity (erythro/threoˆ5.3/94.7, the threo isomer; 99.6%ee). ᭧ 2000 Elsevier Science Ltd. All rights reserved.
Methylphenidate (methyl 2-phenyl-2-(20-piperidyl)acetate
(1), Fig. 1) has four stereoisomers since it possesses two
asymmetric carbons. Among them, the threo-methylpheni-
date hydrochloride salt (threo-1-HCl, Ritalin᭨) has been
used mainly for the treatment of attention deficit hyper-
activity disorder (ADHD) in children in the USA,1 and
administered to patients as the racemic form. However,
the most active enantiomer is the d-threo-isomer,2 while
d- and l-erythro-1 were shown to possess very little thera-
peutic effect and the toxic hypertensive effects.3 Accord-
ingly, a development of efficient methods selectively
producing the d-threo isomer is worthwhile.
1 from N-methoxycarbonylpiperidine (2) utilizing an elec-
trochemical oxidation and the Evans aldol-type reaction
(Scheme 1), and reported the preliminary result.10 This
paper describes the scope of the method.
Results and Discussion
The C–C bond forming reaction between a-methoxy-
carbamates 3 and Evans Imides 4a–c
Scheme 2 illustrates our general method for synthesis of 1
Existing practical methods for the preparation of dl-threo-1
consist of the attack of phenylacetonitrile on 2-halopyridine,
the hydrogenation of the 2-alkylated pyridine ring, and a
separation of threo precursor from the mixture of diastereo-
mers.4 Recently, there has been reported a new method for
the synthesis of dl-threo-1 through a b-lactam intermediate,
which leads to a 6/1 threo/erythro selectivity.5 There had
been only one report of an asymmetric synthesis of d-threo-
1 before our study has been started. It used an expensive
optically active pipecolinic acid as the starting compound
together with the use of an excess of (ϩ)-IPC·BH2 at the key
step of multistage reactions (8 steps).6 More recently, there
have appeared enantioselective syntheses of d-threo-17,8
which are based on the Evans aldol reaction9 and a Rh-
catalyzed insertion reaction of carbenoids into the a-C–H
bond of N-Boc-piperidine.8 We also developed a convenient
method for the stereoselective synthesis of d-threo isomer of
Figure 1. Methylphenidate (methyl 2-phenyl-2-(20-piperidyl)acetate (1)).
Keywords: asymmetric synthesis; electrochemical reactions; piperidines;
diastereoselection.
* Corresponding author. Tel./fax: ϩ81-95-843-2442;
e-mail: matumura@net.nagasaki-u.ac.jp
Scheme 1.
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00653-0

7412
Y. Matsumura et al. / Tetrahedron 56 (2000) 7411–7422
Scheme 4.
9b,d (3-(2S,3R)-isomer) either in a direct route (TiCl4,
DIPEA, i-PrCHO)9b or in an indirect route through boron
enolate 10b.9a,15
With this background, we first examined the reaction
between 3 and a simple Evans imide 11 to see whether
the C–C bond forming reaction efficiently takes place to
afford the coupling product 12 and also to explore the
reaction conditions to obtain a stereochemical outcome
suitable to our purpose (Scheme 4). The results, shown in
Table 1, show that the coupling reaction proceeds smoothly
under appropriate conditions. Although the diastereoselec-
tivity for the coupling reaction was clarified at the stage of
12, the absolute configuration of the 20-position of 12 was
difficult to determine. Thus, 12 was converted to amino
alcohol 13, which was compared with the authentic sample.
Scheme 2.
which consists of only five steps, (step 1) an electrochemical
a-methoxylation of 2 to afford a-methoxypiperidine 3,
(step 2) a C–C bond formation at the a-position of 3 with
Evans imides 4a–c, (steps 3 and 4) a removal of the chiral
auxiliary from the products 5 followed by the esterification
of an acid 6, and (step 5) the deprotection of N-methoxy-
carbonyl group of the resulting ester 7 to give 1. A highly
stereoselective synthesis of d-threo-1 was achieved by using
N-(phenylacetyl)-(4S)-isopropyl-2-oxazolidinone (4b) as
the Evans imide.
The efficiency for the C–C bond formation was found to be
dependent on the kind of Lewis acid and amine. Lewis acids
other than TiCl4 resulted in a recovery of most of 3 (entries
1–5, Table 1), suggesting that iminium ion 2ء (Fig. 2)
requisite for the C–C bond forming reaction might not be
generated under the reaction conditions without using TiCl4.
Since the first step in Scheme 2 has well been established by
us as a promising method for introducing nucleophiles to the
a-position of carbamates,11 the key step in the scheme is
step 2. While the Ti-promoted C–C bond forming reaction
of Evans imides with carbonyl compounds9 and O,O-
acetals12 has been reported, step 2 is a hitherto unknown
coupling13 between Evans imides and N,O-acetals such as
3.14
A
combination of TiCl4 and diisopropylethylamine
(DIPEA) gave the best result (entry 6) among the conditions
examined, though it gave an unsatisfactory diastereoselec-
tivity. Since the use of excess DIPEA also gave 12 in a good
yield (entry 7), the titanium enolate generated from 11
might be responsible for the formation of iminium ion 2ء
from 3. The temperature-dependent results (entries 8 and 9)
suggest that the titanium enolate generated from 11 was
unstable at room temperature and the C–C bond forming
reaction was slow at Ϫ78ЊC. Furthermore, it was found that
the kind of amines affected the diastereoselectivities, though
the reason was not clear (entries 10 and 11).
In general, the Evans aldol reaction between N-acyl-4-
substituted-2-oxazolidinone and an aldehyde has been
known to take place with high stereo- selectivity according
to a general rule exemplified by the reaction of N-propionyl-
(4S)-alkyl-2-oxazolidinone 8b,d with isobutyraldehyde
(Scheme 3). That is, 8b,d gives a syn (erythro) adduct
The major point in this coupling reaction is that the stereo-
chemistry at the 20-position of the major stereoisomer of 12
was opposite to that desired.
Next, we investigated the effect of an N-phenylthioacetyl
group upon the stereochemistry of the C–C bond forming
reaction (Scheme 5). It proved easy to determine the effect
since the phenylthio group of the coupling product 15 was
easily removed to afford 12. The result was as expected.
That is, the overall yield of 12 was 54% under the reaction
conditions similar to that in entry 6 of Table 1, and the ratio
of R/S at the 20-position of 12 was 77/23, the R-isomer being
major.
Scheme 3.

Y. Matsumura et al. / Tetrahedron 56 (2000) 7411–7422
7413
Table 1. Reaction of 3-acetyl-2-oxazolidinone 11 with a-methoxycarbamate 3 (the amount of 3 was 1.2 equiv. to 11)
Entry
Lewis acida
Amine
DIPEAd
(Equiv. to 11)
Reaction temp (ЊC)b
Isolated yields (%) of 12
(R/S)c
1
2
3
4
5
6
7
8
ZnCl2
SnCl4
SnCl4
Bu2B(OTf)
Bu2B(OTf)
TiCl4
TiCl4
TiCl4
1.2
1.2
5.0
1.2
5.0
1.2
5.0
1.2
1.2
1.2
1.2
Ϫ78ЊC to rt
Ϫ78ЊC to rt
Ϫ78ЊC to rt
Ϫ78ЊC to rt
Ϫ78ЊC to rt
Ϫ78ЊC to rt
Ϫ78ЊC to rt
Ϫ78ЊC to rte
Ϫ78ЊC
0
0
0
–
–
–
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
Et3N
12
12
81
78
0
47
50
75
(31/69)
(30/70)
(30/70)
(30/70)
–
(30/70)
(43/57)
(44/56)
9
10
11
TiCl4
TiCl4
TiCl4
Ϫ78ЊC to rt
Ϫ78ЊC to rt
N-Et-piperidine
a The amount of Lewis acid was 1.1 equiv. to 11.
b After an addition of amine to a solution of Lewis acid and 11 in CH2Cl2 at Ϫ78ЊC and stirring for 1.5 h at the temperature, a solution of 3 in CH2Cl2 was
added to the resulting solution, and then the solution was warmed to rt, if otherwise was not noted.
c The ratio of diastereomers; R and S show the absolute configuration of a-position of piperidine ring.
d Diisopropylethylamine.
e The solution containing titanium enolate was warmed to rt followed by the addition of 3 at rt.
Table 2. Reaction of a-methoxycarbamate 3 with 3-(phenylacetyl)-2-
oxazolidinones (4a–c)
Entry 4a–c Yield (%) of 7a erythro/threo threo-7 % eeb Main 7c
1
2
3
4a
4b
4c
48
54
40
6.9/93.1
5.3/94.7
1.6/98.4
–
99.6
81.8
–
(2R,20R)
(2S,20S)
Figure 2. Iminium ion 2ء from 3.
a Overall yield of 7 from 4a–c.
b The % ee was determined using CSP HPLC.
c The absolute configuration was determined by converting 7 to methyl-
phenidate 1 hydrochloride followed by comparison of the salts with the
authentic samples [Ref. 6].
With these results in hand, we tried the reaction between 3
and 4a–c (Scheme 2) with our expectation that the replace-
ment of the N-acetyl group of 11 with a more bulky N-
phenylacetyl group might bring about more remarkable
effect on the stereochemistry of the coupling reaction than
phenylthioacetyl group. Fortunately, the coupling reaction
proceeded smoothly to give the products 5a–c in 60–75%
yields as a mixture of the stereoisomers. They were
converted, without isolation, to N-methoxycarbonyl-
methylphenidate 7 since an analysis of the configuration
of 5a–c was difficult. The ratio of four stereoisomers of 7
was obtained using chiral HPLC; at this stage, the absolute
configuration of each stereoisomer of 7 was determined by
converting 7 to the stereoisomers of 1 followed by the
comparison with authentic samples. The overall yields of
7 from 4a–c were 40–54% and the stereoselectivity was
high. The results are summarized in Table 2.
of the threo isomer was 81.8%, indicating that the 4-iso-
propyl substituent of 2-oxiazolidinone ring was superior to
the 4-phenyl substituent. The product 7 obtained from the
reaction of 3 with 4c possessed an absolute configuration
(2S,20S) which was opposite to that (2R,20R) of 7 obtained
from the reaction of 3 with 4b.
Reaction mechanism
The observed stereochemical outcomes are explainable by
taking account of the reaction intermediates. For simplicity,
we discuss the cases of (4S)-isopropyl-2-oxazolidinone
derivatives 4b, 11 and 14. The titanium enolates generated
from 4b, 11 and 14 may exist as Z-forms 16–18 (Scheme 6)
since the formation of Z-enolates from Evans imides has
been established.9a,18 In addition, the re-face attack of an
iminium ion 2ء on an E-enolate, if it was generated,
produces a coupling product 19 as a main product which
possesses a 2S-configuration (Scheme 7).
Expectedly, the main diastereoisomer of 7 was threo and the
absolute configuration of the 20-position was found to be R.
The ratios of erythro to threo of 7 obtained in the reaction of
3 with 4a and 4b were 6.9/93.1 and 5.3/94.7, respectively,
and the ee of threo product (threo-7) from 4b was very high
(99.6%) (entries 1 and 2 in Table 2). The high diastereo-
selectivity was also observed in the reaction of 3 with 4c
(erythro/threoˆ1.6/98.4, entry 3 in Table 2), whereas the ee
With these considerations in mind, several plausible inter-
mediates must be examined depending upon the mode of
Scheme 5.

7414
Y. Matsumura et al. / Tetrahedron 56 (2000) 7411–7422
Scheme 6.
Scheme 9. Route (ii) via non-coordinated intermediates C and D involving
a chelated enolate.
Scheme 7.
attack of an iminium ion 2ء on Z-enolates 16–18. Schemes
8–10 show such intermediates A–F which are formed as (i)
a coordinated species involving a chelated enolate (Scheme
8), (ii) a non-coordinated intermediate involving a chelated
enolate (Scheme 9), or as (iii) a coordinated species
involving a non-chelated enolate (Scheme 10). Non-
chelated intermediates have been proposed to explain the
stereochemistry (syn) observed in the Evans aldol reaction
(Scheme 3).15
Scheme 10. Route (iii) via coordinated intermediates E and F involving a
non-chelated enolate.
Among those routes, route (iii) can be dismissed immedi-
ately since it affords coupling products possessing a 2S-
configuration. Thus, the reaction proceeds through routes
(i) or (ii). We prefer route (i) to route (ii) for the following
reasons; In the case where RˆPh, the severe repulsion
between it and the piperidinium ring may direct the reaction
to pass through A, which gives (20R)-isomer, rather than
through B (Scheme 8), while the same repulsion in route
(ii) may make the reaction to produce (20S)-isomer
through D rather than (20R)-isomer through C (Scheme 9).
The configuration of the main product obtained was 20R
as described above. Also, route (i) can explain the increase
in the amount of a coupling product possessing a
Scheme 8. Route (i) via coordinated intermediates A and B involving a chelated enolate.

Y. Matsumura et al. / Tetrahedron 56 (2000) 7411–7422
7415
Figure 3. Reactivity of imminium ion and aldehyde toward Evans Imide.
20S-configuration in proportion to the decrease of the
bulkiness of R group (PhϾPhSϾH).
Interestingly, the stereochemistry observed in our reaction
(threo isomer; (2R,20R)-isomer) was largely different from
that observed in the Evans aldol reaction which predomi-
nantly gives syn (erythro) products (Scheme 3). The differ-
ence may be explained in terms of the intervention of
chelated intermediates for iminium ions and non-chelated
intermediates for aldehydes. Accordingly, it may be
concluded that iminium ion behaves equivalent to aldehyde
in the C–C bond-forming reaction toward Evans imides but
it shows a stereochemical result completely different from
aldehydes (Fig. 3).
Scheme 12.
reduced the ee of threo isomer and the main stereoisomer
was threo-(2S,20S)-7 (entry 2 in Table 3). The formation of
(2S,20S)-7 cannot be explained in terms of intermediates
similar to A–D in routes (i) and (ii) since such intermediates
give (2R)-isomers. An intermediate similar to F may be
responsible for a formation of (2S,20S)-7.
Effect of the structure of iminium ions
The influence of the piperidine structure upon the C–C bond
forming reaction was then studied. Compounds 22 and 25
were prepared from 3 according to the routes shown in
Scheme 11.
Synthesis of p-substituted methylphenidate
Our method was applied to the preparation of racemic and
optically active p-substituted methylphenidates (Scheme
13). The reaction was carried out between 3 and 28a,b–
30a,b under the reaction conditions described above. The
C–C bond forming reaction proceeded successfully and the
stereoselectivity was also very high. Since the stereo-
chemistry of the initially formed C–C bond forming
products 31a,b–33a,b was ambiguous, their configurations
were determined at the stage of 34–36. Among p-substi-
tuted methylphenidate derivatives 34–36, the absolute
configuration of p-methoxy- and p-bromo-substituted
derivatives 34 and 35 were determined by their conversion
to 37 and 38, respectively, followed by comparison of 37
and 38 with authentic samples.6 The absolute configuration
of p-trifluoromethyl-substituted derivatives 36 was esti-
mated as depicted one on the basis of the stereochemical
results in the preparation of 7, 34 and 35. Those results are
summarized in Table 4.
The reaction of 22 and 25 with the titanium enolate derived
from 4b gave 26 and 27, respectively. After 27 was reduced
to 26 by tributyltin hydride, 26 was transformed to 7 through
5b. The stereochemistry of 7 was then clarified by use of the
CSP HPLC method (Scheme 12). The results are shown in
Table 3.
The result shows that the existence of a double bond at the
b,g-position of piperidine ring did not affect the stereo-
chemistry in the coupling reaction (entry 1 in Table 3).
Interestingly, however, a b-bromo-substituent largely
One of the advantages in our method is indicated by the high
stereoselectivity shown in Table 4. In addition, our method
can provide a route to prepare p-trifluoromethyl-substituted
methylphenidate 36 which could not be prepared by the
conventional method.4
Table 3. Reaction of a-methoxycarbamates 22 and 25 with 4b
Entry
22,25
Yield (%) of 7
7 erythro/threoa
threo-7 % eea,b
1
2
22
25
54
42
10.3/89.7
1.9/98.1
98.1 (2R,20R)
26.8 (2S.20S)
a The ratio was determined at the stage of 7.
b The configuration of main stereoisomer.
Scheme 11.

7416
Y. Matsumura et al. / Tetrahedron 56 (2000) 7411–7422
Scheme 13.
Table 4. Reaction of a-methoxycarbamate 3 with p-substituted phenylacetyl-2-oxazolidinones 28a,b–30a,b
Entry
Nucleophiles
For C–C bond formation
Yieldsb (%)
Ratioa of erythro/threo
threo-34–36
Stereochemistrya
Products
% eea
1
2
3
4
5
6
28a
28b
29a
29b
30a
30b
34
34
35
35
36
36
48
52
37
40
32
30
10.6/89.4
5.9/94.1
1.2/98.8
5.6/94.4
10.6/89.4
5.2/94.8
–
Ͼ99.9
–
97.6
–
–
(2R,20R)
–
(2R,20R)
–
Ͼ99.9
(2R,20R)c
a The ratio and absolute configuration were determined at the stage of 34–36 by CSP HPLC method.
b Overall yield from 28–30.
c Estimated configuration.
Scheme 14.
Scheme 15.
Table 5. Reaction of a-methoxycarbamates 39, 42 with phenylacetyl-2-oxazolidinones 4a,b
Entry
39,42
4a,b
For C–C bond formation
Yieldsb (%)
Ratioa of erythro/threo
threo-41,44 % eea
Products
1
2
3
4
39
39
42
42
4a
4b
4a
4b
41
41
44
44
62
52
61
59
7.0/93.0
12.0/88.0
3.5/96.5
15.1/84.9
–
93.0
–
96.4
a The ratio and absolute configuration were determined at the stage of 41, 44 by CSP HPLC method.
b Overall yield from 39,42.

Y. Matsumura et al. / Tetrahedron 56 (2000) 7411–7422
7417
Application to synthesis of five- and seven-membered
analogues of methylphenidate
Preparation of 3-phenylacetyl-2-oxazolidinones (4a–c),
3-acetyl-2-oxazolidinone (11), and 3-phenylthioacetyl-2-
oxazolidinone (14)
Our method was also applicable to the preparation of
five- and seven-membered amino esters 41 and 44,
analogues of methylphenidate derivative 7 (Schemes 14
and 15).
3-Acetyl-2-oxazolidinone (11) is commercially available.
The other compounds were prepared according to the
Evans method.9 The typical procedure was exemplified by
the preparation of 11. Into a solution of (4S)-(Ϫ)-4-iso-
propyl-2-oxazolidinone (100 mmol) in anhydrous THF
(200 mL) cooled by ice water was added NaH
(150 mmol), and the solution was stirred for 2 h. Then,
acetyl chloride (155 mmol) was added. After stirring for
3 h, the solution was poured into a saturated aqueous
solution of NH4Cl, and the organic portion was extracted
with CH2Cl2 three times. The extracts were dried on
MgSO4, and 11 was isolated by column chromatography.
In those reactions, high stereoselectivity was observed as
shown in Table 5. Although the configuration of products
41 and 44 could not be identified, that of the main
stereoisomer of 41 and 44 was estimated to be (2R,20R)
on the basis of the proposed reaction mechanism described
above.
3-Phenylacetyl-2-oxazolidinone (4a). Colorless solid; mp
64–65ЊC; IR (neat) 1771, 1698, 1497, 1476, 1456, 1387,
Experimental
General
1
1109, 1037 cmϪ1; H NMR (300 MHz) (CDCl3) d 4.03 (t,
Jˆ8.4 Hz, 2H), 4.29 (s, 2H), 4.41 (t, Jˆ8.4 Hz, 2H), 7.27–
7.38 (m, 5H). Anal. Calcd for C11H11NO3: C, 64.38; H, 5.40;
N, 6.83. Found: C, 64.35; H, 5.45; N, 6.77.
Electrochemical reactions were carried out by using DC
Power Supply (GP 050-2) of Takasago Seisakusho, Inc.
HPLC analyses were achieved by using a LC-10AT VP
and a SPD-10A VP of Shimadzu Seisakusho Inc. Specific
(4S)-3-Phenylacetyl-4-isopropyl-2-oxazolidinone (4b).
68% Yield; colorless oil; [a]2D0ˆϩ77.6Њ (cˆ2.05, CHCl3);
IR (neat) 1765, 1690 cmϪ1; 1H NMR (300 MHz) (CDCl3) d
0.78 (d, Jˆ6.9 Hz, 3H), 0.87 (d, Jˆ7.0 Hz, 3H), 2.23–2.37
(m, 1H), 4.11–4.38 (m, 5H), 7.20–7.38 (m, 5H). Anal.
Calcd for C14H17NO3: C, 68.00; H, 6.93; N, 5.66. Found:
C, 68.02; H, 6.89; N, 5.59.
1
rotations were measured with Jasco DIP-1000. H NMR
spectra were measured on a Varian Gemini 300 spectro-
meter with TMS as an internal standard. IR spectra were
obtained on a Shimadzu FTIR-8100A. Elemental analyses
were carried out in Center for Instrumental Analysis,
Nagasaki University. Mass spectra were obtained on a
JEOL JMS-DX 303 instrument.
(4R)-3-Phenylacetyl-4-phenyl-2-oxazolidinone (4c). 59%
Yield; colorless solid; mp 70–71ЊC; [a]2D4ˆϪ87.0Њ (cˆ1.0,
MeOH); IR (neat) 1779, 1705, 1613, 1512, 1387, 1329,
Preparation of a-methoxycarbamates 3, 22, 25, 39 and
42
1
1248, 1200, 1179, 1105, 1042 cmϪ1; H NMR (300 MHz)
(CDCl3) d 4.23–4.30 (m, 1H), 4.29 (s, 2H), 4.69 (t,
Jˆ8.9 Hz, 1H), 5.42 (dd, Jˆ3.9, 8.8 Hz, 1H), 7.18–7.40
(m, 10H); Anal. Calcd for C17H15NO3: C, 72.58; H, 5.37;
N, 4.98. Found: C, 72.55; H, 5.45; N, 4.87.
Electrochemical oxidation of N-methoxycarbonylpiperidine
(2), N-methoxycarbonylpyrroridine, and N-methoxycar-
bonylhexamethyleneimine in methanol has been reported
to give 3,11a,b 39,11a,b and 42,19 respectively, in good yields
(80–89%). a-Methoxycarbamates 22 and 25 were prepared
according to the reported method.20
(4S)-3-Phenylthioacetyl-4-isopropyl-2-oxazolidinone (14).
48% Yield; yellow oil: [a]2D4ˆϩ167.1Њ (cˆ1.00, MeOH);
IR (neat) 1784, 1700, 1483, 1389, 1368, 1323, 1210,
1171 cmϪ1 1H NMR (300 MHz) (CDCl3) d 0.88 (dd,
;
3,4-Didehydro-N-methoxycarbonyl-2-methoxypiperidine
(22). Colorless oil; IR (neat) 1701, 1445, 1402, 1304, 1266,
Jˆ3.8, 6.9 Hz, 6H), 2.22–2.42 (m, 1H), 4.09–4.47 (m,
5H), 7.18–7.35 (m, 3H), 7.39–7.48 (m, 2H); HRMS calcd
for C14H17NO3S: 279.0929. found: 279.0952. Anal. Calcd
for C14H17NO3S: C, 60.19; H, 6.13; N, 5.01; S, 11.48.
Found: C, 59.84; H, 5.92; N, 4.72; S, 11.32.
1
1238, 1190, 1082 cmϪ1; H NMR (300 MHz) (CDCl3) d
1.90–2.38 (m, 2H), 2.88–3.21 (m, 1H), 3.4 (br s, 3H),
3.75 (s, 3H), 3.90–4.24 (m, 1H), 5.30–5.53 (m, 1H),
5.70–5.84 (m, 1H), 5.95–6.10 (m, 1H); HRMS calcd for
C8H13NO3: 171.0895. found: 171.0891. Anal. Calcd for
C8H13NO3: C, 56.13; H, 7.65; N, 8.18. Found: C, 56.34;
H, 7.90; N, 8.21.
Coupling reaction of 3 with 11
A solution of 1.0 M TiCl4 in CH2Cl2 (1.1 mL, 1.1 mmol)
was added into a solution of 11 (1.0 mmol) in CH2Cl2
(5 mL) at Ϫ78ЊC under a nitrogen atmosphere; DIPEA
(0.21 mL, 1.2 mmol) was also added to the solution. After
1.5 h, a solution of 3 (1.2 mmol) in CH2Cl2 (1 mL) was
added, and the resulting solution was allowed to be stirred
at rt overnight. The reaction mixture was poured into
aqueous ammonium chloride. The organic portion was
extracted CH2Cl2 to afford a crude 12, which was subjected
on silica gel chromatography to afford a pure sample of 12.
3-Bromo-3,4-didehydro-N-methoxycarbonyl-2-methoxy-
piperidine (25). Colorless oil; IR (neat) 1725, 1649, 1410,
1
1335, 1256, 1117, 1092, 1059 cmϪ1; H NMR (300 MHz)
(CDCl3) d 1.98–2.40 (m, 2H), 3.02–3.31 (m, 1H), 3.4 (br s,
3H), 3.77 (s, 3H), 3.90–4.20 (m, 1H), 5.39 (br s, 0.5H), 5.54
(br s, 0.5H), 6.28 (br s, 1H); HRMS calcd for C8H12BrNO3:
249.0000. found: 249.0039. Anal. Calcd for C8H12BrNO3:
C, 38.42; H, 4.84; N, 5.60. Found: C, 38.45; H, 4.88; N,
5.62.

7418
Y. Matsumura et al. / Tetrahedron 56 (2000) 7411–7422
The yield of 12 was 81%, consisting of stereoisomers (30/
70). The ratio of (20S)-12 to (20R)-12 was determined by
DAICEL Chiralcel OD (4.6 mmл, 25 cm) [hexane/ethanol
(20/1)(v/v), 1.0 mL/min, detection at 210 nm]; 9 min for
(20R)-12, 16 min for (20S)-12. The main isomer was sepa-
rated by column chromatography and was found to possess a
(20S)-configuration after it was converted to 13, whose
stereochemistry is known.
(lit.21 [a]2D7ˆϪ43.8Њ (cˆ1.0, EtOH)); IR (neat) 3360,
1
1445, 1374, 1264, 1271, 1055 cmϪ1; H NMR (300 MHz)
(CDCl3) d 1.23–1.82 (m, 6H), 1.94–2.14 (m, 2H), 2.19–
2.31 (m, 1H), 2.36 (s, 3H), 2.84–2.96 (m, 1H), 3.35 (br s,
1H), 3.64–3.89 (m, 2H), 3.89–4.03 (m, 1H); HRMS calcd
for C8H17NO: 143.1310. Found: 143.1309.
Coupling reaction of 3 with 14
(20S,4S)-3-(N0-Methoxycarbonyl-20-piperidyl)acetyl-4-
isopropyl-2-oxazolidinone ((20S)-12). Colorless oil:
[a]1D5ˆϩ41.1Њ (cˆ0.88, MeOH); IR (neat) 1786, 1709,
According to a procedure similar to the coupling reaction of
3 with 11, the reaction of 3 with 14 was carried out to give
15, which was treated with Raney Ni without purification.
The Raney Ni reduction was achieved under hydrogen gas
atmosphere using MeOH as a solvent suspended with a
catalytic amount of Raney-Ni overnight. The overall yield
of 12 from 14 was 54%. The ratio of (20R)-12/(20S)-12 was
77/23.
1451, 1408, 1389, 1316, 1269, 1210 cmϪ1 1H NMR
;
(300 MHz) (CDCl3) d 0.90 (dd, Jˆ3.9, 7.0 Hz, 6H),
1.35–1.75 (m, 5H), 2.20–2.45 (m, 1H), 2.39–3.03 (m,
1H), 3.11 (dd, Jˆ16.4, 7.9 Hz, 6H), 3.66 (s, 3H), 3.94–
4.15 (m, 1H), 4.20–4.35 (m, 2H), 4.38–4.48 (m, 1H),
4.80–4.93 (m, 1H); HRMS calcd for C15H24N2O5:
312.1685. found: 312.1699. Anal. Calcd for C15H24N2O5:
C, 57.68; H, 7.74; N, 8.97. Found: C, 57.38; H, 7.40; N,
8.59.
Preparation of methyl (2-phenyl-2-(n-methoxycarbonyl-
20-piperidyl)acetate (7). Preparation of 7 by the reaction
of 3 with 4a
(20R,4S)-3-(N0-Methoxycarbonyl-20-piperidyl)acetyl-4-
isopropyl-2-oxazolidinone ((20R)-12). Colorless oil:
[a]1D5ˆϩ53.4Њ (cˆ1.75, MeOH); IR (neat) 1784, 1705,
A solution of 1.0 M TiCl4 (1.1 mL, 1.1 mmol) in CH2Cl2
was added into a solution of 4a (1 mmol) in CH2Cl2
(5 mL) at Ϫ78ЊC under a nitrogen atmosphere, and
DIPEA (1.2 mmol) was added to the solution. After 1.5 h,
a solution of 3 (1.2 mmol) in CH2Cl2 (1 mL) was added, and
the resulting solution was allowed to be stirred at rt over-
night. The reaction mixture was poured into aqueous
ammonium chloride. The organic portion was extracted
CH2Cl2 to afford a crude 5a, which was subjected without
isolation to further hydrolysis. That is, H2O (1 mL), LiOH
(4 mmol), and 35%H2O2 (1 mL) were successively added to
5a dissolved in THF (4 mL). The solution was stirred at rt
overnight, and quenched with 1.5 M NaHSO3. Then an
aqueous 5% NaOH solution was added and the organic
portion was extracted with CH2Cl2. The aqueous solution
was acidified with 5%HCl and the extraction with CH2Cl2
gave a crude carboxylic acid 6, which was subjected with
diazomethane in ether to give 7. The yield of 7 from 4a was
48%. The overall yield of 7 from 4a was 32% in a case that
esterification was carried out by 1 M HCl–MeOH method
(at rt, overnight). The threo-7 was separable from erythro-7
by column chromatography (silica gel, AcOEt/hexaneˆ
1/3). The ratio of erythro-7/threo-7 was 6.9/93.1.
1449, 1408, 1387, 1339, 1269, 1211 cmϪ1 1H NMR
;
(300 MHz) (CDCl3) d 0.89 (t, Jˆ7.1 Hz, 6H), 1.30–1.75
(m, 5H), 2.25–2.45 (m, 1H), 2.87–3.20 (m, 2H), 3.28–
3.45 (m, 1H), 3.65 (s, 3H), 3.90–4.39 (m, 4H), 4.75–4.90
(m, 1H); HRMS calcd for C15H24N2O5: 312.1685. found:
312.1647. Anal. Calcd for C15H24N2O5: C, 57.68; H, 7.74;
N, 8.97. Found: C, 57.30; H, 7.50; N, 8.67.
Transformation of (20S)-12 to (2S)-N-methyl-2-piperi-
dineethanol ((2S)-13). Water (1.5 mL), LiOH (6 mmol),
and 35%H2O2 (1.5 mL) were successively added to a
solution of (20S)-12 (486 mg, 1.6 mmol) in THF (6 mL),
and the resulting solution was stirred at rt overnight and
quenched with an aqueous 1.5 M NaHSO3 solution. Then
an aqueous 5%NaOH solution was added and the organic
portion was extracted with CH2Cl2. The aqueous solution
was acidified with 5%HCl and the extraction with CH2Cl2
gave a crude carboxylic acid, which was subjected
to column chromatography to afford (2S)-N-methoxycarbo-
nyl-2-piperidineacetic acid. 76% yield; colorless solid: mp
94–95ЊC: [a]2D3ˆϪ9.7Њ (cˆ3.1, MeOH); IR (neat) 3450,
1
3200, 1447, 1408, 1370, 1264, 1193, 1173 cmϪ1; H NMR
Preparation of 7 by the reaction of 3 with 4b and 4c
(300 MHz) (CDCl3) d 1.25–1.75 (m, 6H), 2.63 (d,
Jˆ7.7 Hz, 2H), 2.75–2.95 (m, 1H), 3.69 (s, 3H), 3.92–
4.10 (m, 1H), 4.68–4.81 (m, 1H), 6.5 (br s, 1H); HRMS
calcd for C9H15NO4: 201.1002. found: 201.1001. Anal.
Calcd for C9H15NO4: C, 53.72; H, 7.51; N, 6.96. Found:
C, 53.53; H, 7.49; N, 6.72.
According to a similar procedure described above, 7 was
obtained by the reactions of 3 with 4b, and 4c. The yields of
7 obtained in these reactions were 54 and 40%, respectively,
using diazomethane. The ratios of erythro-7/threo-7 were
5.3/94.7 in the reaction of 3 with 4b and 1.6/98.4 in the
reaction of 3 with 4c. The ee was obtained by DAICEL
Chiralpak AD (4.6 mmл, 25 cm) [hexane/isopropanol/
methanol (150:4:0.5) (v/v/v), 0.8 mL/min, detection at
210 nm, 17 min for (2R, 20R)-7, 22 min for (2S, 20S)-7,
25 min for (2R, 20S)-7, 28 min for (2S,20R)-7. The ratios
of (2R,20R)-7/(2S,20S)-7 were 99.8/0.2 in the reaction of 3
with 4b and 90.9/9.1 in the reaction of 3 with 4c.
Into a solution of (2S)-N-methoxycarbonyl-2-piperidine-
acetic acid (63 mg, 0.31 mmol) in THF (10 mL), LiAlH4
(35 mg, 0.93 mmol) was added, and the solution was
refluxed for 4 h. After water was added, the solution was
acidified with dilute HCl and extracted with CH2Cl2. The
aqueous solution was treated with an aqueous NaOH, and
extracted with CH2Cl2. The conventional procedures for the
extract gave (2S)-N-methyl-2-piperidineethanol ((2S)-13).
43% yield; colorless oil: [a]2D3ˆϪ42.1Њ (cˆ0.4, EtOH)
Methyl threo-(2-phenyl-2-(N-methoxycarbonyl-20-piperi-
dyl)acetate (threo-7). Colorless oil; IR (neat) 1736, 1698,

Y. Matsumura et al. / Tetrahedron 56 (2000) 7411–7422
7419
1447, 1271, 1248, 1192 cmϪ1; 1H NMR (300 MHz) (CDCl3)
Coupling reaction of 25 with 4b
d 1.18–1.78 (m, 6H), 2.96–3.20 (m, 1H), 3.61 (s, 3H), 3.74
(br s, 3H), 3.86–4.28 (m, 2H), 4.80–5.10 (m, 1H), 7.22–
7.50 (m, 4H); HRMS calcd for C16H21NO4: 291.1470.
found: 291.1485. Anal. Calcd for C16H21NO4: C, 65.96; H,
7.26; N, 4.81. Found: C, 66.13; H, 7.22; N, 4.71.
According to a similar procedure to the reaction of 3 with
4a, the coupling reaction of 25 with 4b was carried out
to yield 27, which was reduced without purification
(n-Bu3SnH (2.5 mmol), AIBN (0.25 mmol) in benzene
solvent (5 mL), refluxing for 4 h, then, washed with 10%
KF, extracted with benzene). The resulting compound 26
was converted to 7 via 5b by procedures described above.
The overall yield of 7 from 4b was 42%. The ratio of
erythro-7/threo-7 was 1.9/98.1, and the ratio of (2R,20R)-
7/(2S,20S)-7 was 36.6/63.4.
Methyl
piperidyl)acetate (erythro-7). Colorless oil; IR (neat)
1734, 1698, 1447, 1266, 1250, 1172 cmϪ1 1H NMR
erythro-(2-phenyl-2-(N-methoxycarbonyl-20-
;
(300 MHz) (CDCl3) d 1.18–1.83 (m, 6H), 2.65–2.83 (m,
1H), 3.67 (s, 3H), 3.77 (s, 3H), 3.87–4.20 (m, 2H), 4.77–
5.03 (m, 1H), 7.15–7.49 (m, 4H); HRMS calcd for
C16H21NO4: 291.1470. found: 291.1466. Anal. Calcd for
C16H21NO4: C, 65.96; H, 7.26; N, 4.81. Found: C, 66.20;
H, 7.21; N, 4.65.
Preparation of 3-(p-substituted phenylacetyl)-2-
oxazolidinones 28a,b–30a,b
Those compounds were prepared according to a procedure
of the preparation of 4a–c.
Synthesis of hydrochloride salt of methylphenidate (1)
from 7
3-(p-Methoxyphenyl)acetyl-2-oxazolidinone (28a). 79%
Yield; colorless solid; mp 112–115ЊC; IR (neat) 1786,
1705, 1612, 1514, 1478, 1391, 1368, 1267, 1181, 1113,
Each stereo isomer of the compound 7 derived from the
coupling product 5b in the reaction of 3 with 4b was isolated
by column chromatography (silica gel, hexane/AcOEt), and
they were subjected to deprotection procedures described
below. That is, a solution of Me3SiI (526 mg, 2.7 mmol)
in CH2Cl2 (5 mL) was dropwise added at rt into a solution
of the main diastereoisomer (polar isomer) of 7 (307 mg,
1.1 mmol) in CH2Cl2 (2 mL), and the solution was stirred at
rt. After 12 h, MeOH(2 mL) was added, and the solvents
were evaporated in vacuo to give a residue, which was
then dissolved in ether. The ethereal solution was washed
with an aqueous 5% HCl solution three times. The
combined aqueous solution was made alkaline by adding
a 5% NaOH solution, and then organic portion was
extracted with ether. The removal of ether in vacuo gave a
yellow residue, which was dissolved 1 M HCl–MeOH.
Evaporation of MeOH from the solution gave a white
solid, which was recrystallized from EtOH/ether to give
hydrochloride salt of threo-1: 60% yield from threo-7;
[a]D27ˆϩ83.0Њ (cˆ1.0, MeOH). [lit.6 (2R,20R)-1; [a]2D0ˆ
ϩ82.6Њ (cˆ1.09, MeOH)]. On the bases of this result, the
main stereoisomer in the reaction of 3 with 4b was found to
have a (2R,20R)-configuration.
1
1036 cmϪ1; H NMR (300 MHz) (CDCl3) d 3.79 (s, 3H),
4.01 (t, Jˆ7.5 Hz, 2H), 4.22 (s, 2H), 4.40 (t, Jˆ8.1 Hz, 2H),
6.68 (d, Jˆ8.8 Hz, 2H), 7.74 (d, Jˆ8.5 Hz, 2H); Anal. Calcd
for C12H13NO4: C, 61.27; H, 5.57; N, 5.95. Found: C, 61.14;
H, 5.57; N, 5.78.
3-(p-Methoxyphenyl)acetyl-(4S)-isopropyl-2-oxazolidi-
none (28b). 60% Yield; colorless solid; mp 89–90ЊC;
[a]2D4ˆϩ73.7Њ (cˆ0.6, MeOH); IR (neat) 1792, 1709,
1613, 1586, 1518, 1466, 1393, 1375, 1302, 1256, 1213,
1
1183, 1121, 1034 cmϪ1; H NMR (300 MHz) (CDCl3) d
0.79 (d, Jˆ6.9 Hz, 3H), 0.88 (d, Jˆ7.0 Hz, 3H), 2.22–
2.35 (m, 1H), 3.79 (s, 3H), 4.07–4.38 (m, 2H), 4.38–4.49
(m, 1H), 6.83–6.90 (m, 2H), 7.20–7.29 (m, 2H); Anal.
Calcd for C15H19NO4: C, 64.97; H, 6.91; N, 5.05. Found:
C, 65.17; H, 6.90; N, 4.93.
3-(p-Bromophenyl)acetyl-2-oxazolidinone (29a). 50%
Yield; colorless solid; mp 119–121ЊC; IR (neat) 1763,
1698, 1476, 1404, 1389, 1370, 1273, 1238, 1113,
1
1009 cmϪ1; H NMR (300 MHz) (CDCl3) d 4.03 (t, Jˆ
7.9 Hz, 2H), 4.24 (s, 2H), 4.43 (t, Jˆ8.1 Hz, 2H), 7.15–
7.24 (m, 2H), 7.42–7.50 (m, 2H); Anal. Calcd for
C11H10BrNO3: C, 46.50; H, 3.55; N, 4.93. Found: C,
46.50; H, 3.50; N, 4.85.
Also, according to the method described above, hydro-
chloride salt of erythro-1 was obtained from minor stereo-
isomer (less polar isomer) of 7; [a]2D0ˆϩ106.6Њ (cˆ0.7,
MeOH). [lit.6 (2R,20S)-1; [a]2D0ˆϩ92.3Њ (cˆ1.11,
MeOH)]. On the basis of this result, the minor stereoisomer
in the reaction of 3 with 4b was determined to have a
(2R,20S)-configuration.
3-(p-Bromophenyl)acetyl-(4S)-isopropyl-2-oxazolidinone
(29b). 49% Yield; colorless solid; mp 70–74ЊC; [a]2D3ˆ
ϩ56.3Њ (cˆ0.6, MeOH); IR (neat) 1790, 1701, 1489,
1389, 1374, 1306, 1254, 1211, 1121, 1013 cmϪ1; H NMR
1
(300 MHz) (CDCl3) d 0.84 (dd, Jˆ7.0, 17.0 Hz, 6H), 2.23–
2.43 (m, 1H), 4.12–4.39 (m, 4H), 4.40–4.49 (m, 1H), 7.19
(d, Jˆ8.1 Hz, 2H), 7.45 (d, Jˆ8.4 Hz, 2H); HRMS calcd for
C14H16BrNO: 325.0313. found: 325.0324. Anal. Calcd for
C14H16BrNO: C, 51.55; H, 4.94; N, 4.29. Found: C, 51.19;
H, 4.76; N, 3.99.
Coupling reaction of 22 with 4b
According to a similar procedure to the reaction of 3 with
4a, the coupling reaction of 22 with 4b was carried out to
yield 26, which was hydrogenated without purification (an
atmospheric pressure of hydrogen gas in MeOH with Pd/C
catalyst). Further, the crude product 5b was converted to 7
by procedures described above. The overall yield of 7 from
4b was 54%. The ratio of erythro-7/threo-7 was 10.3/89.7,
and the ratio of (2R,20R)-7/(2S,20S)-7 was 99.1/0.9.
3-(p-Trifluoromethylphenyl)acetyl-2-oxazolidinone (30a).
43% Yield; colorless solid; mp 144–146ЊC; IR (neat) 1761,
1694, 1477, 1414, 1333, 1279, 1240, 1111, 1017,
1071 cmϪ1 1H NMR (300 MHz) (CDCl3) d 4.04 (t,
;

7420
Y. Matsumura et al. / Tetrahedron 56 (2000) 7411–7422
Jˆ8.1 Hz, 2H), 4.35 (s, 2H), 4.44 (t, Jˆ8.2 Hz, 2H), 7.43 (d,
Jˆ8.1 Hz, 2H), 7.59 (d, Jˆ8.1 Hz, 2H); HRMS calcd for
C12H10F3NO: 273.0613. found: 273.0605. Anal. Calcd for
C12H10FNO: C, 52.75; H, 3.69; N, 5.13. Found: C, 53.10; H,
3.64; N, 5.43.
1744, 1701, 1611, 1514, 1449, 1408, 1260, 1173, 1088,
1034 cmϪ1 1H NMR (300 MHz) (CDCl3) d 1.19–1.75
;
(m, 6H), 2.95–3.18 (m, 1H), 3.61 (s, 3H), 3.73 (s, 3H),
3.80 (s, 3H), 3.90–4.25 (m, 2H), 4.74–5.03 (m, 1H),
6.80–6.91 (m, 2H), 7.30–7.41 (m, 2H); HRMS calcd for
C17H23NO5: 321.1576. found: 321.1561. Anal. Calcd for
C17H23NO5: C, 63.54; H, 7.21; N, 4.36. Found: C, 63.41;
H, 7.29; N, 4.27.
3-(p-Trifluoromethylphenyl)acetyl-(4S)-isopropyl-2-oxazo-
lidinone (30b). 35% Yield; colorless solid; mp 73–75ЊC;
[a]1D9ˆϩ44.7Њ (cˆ1.6, MeOH); IR (neat) 1779, 1701, 1619,
1
1323, 1165, 1119, 1067, 1021 cmϪ1; H NMR (300 MHz)
Methyl
erythro-2-(p-methoxyphenyl)-2-(N0-methoxy-
(CDCl3) d 0.85 (dd, Jˆ5.3, 14.9 Hz, 6H), 2.27–2.45 (m,
1H), 4.19–4.50 (m, 5H), 7.43 (d, Jˆ8.1 Hz, 2H), 7.59 (d,
Jˆ8.5 Hz, 2H); HRMS calcd for C15H16F3NO: 315.1082.
found: 315.1079. Anal. Calcd for C15H16F3NO: C, 57.14;
H, 5.11; N, 4.44. Found: C, 57.35; H, 4.86; N, 4.12.
carbonyl-20-piperidyl)-acetate (erythro-34). Colorless
oil; IR (neat) 1738, 1698, 1613, 1512, 1447, 1410, 1250,
1
1177, 1086, 1032 cmϪ1; H NMR (300 MHz) (CDCl3) d
1.19–1.75 (m, 6H), 2.30–3.49 (m, 1H), 3.67 (s, 3H), 3.76
(s, 3H), 3.81 (s, 3H), 3.90–4.17 (m, 2H), 4.80–4.50 (m, 1H),
6.78–6.88 (m, 2H), 7.30–7.41 (m, 2H); HRMS calcd for
C17H23NO5: 321.1576. found: 321.1587. Anal. Calcd for
C17H23NO5: C, 63.54; H, 7.21; N, 4.36. Found: C, 63.45;
H, 7.24; N, 4.18.
Reaction of 3 with 28a,b–30a,b
In a similar way to the preparation of 7 by the reaction of 3
with 4a–c and to the transformation of the coupling
products 5a–c to 7, p-substituted methylphenidate deriva-
tives 34–36 were obtained from 28a,b–30a,b. The yields of
34–36 were calculated based on the amount of 28a,b–
30a,b. The diastereo- and enantiostereo-selectivities at the
stage of the reaction of 3 with 28a,b–30a,b were deter-
mined by the analysis of the stereochemistry of 34–36
using CSP HPLC. The absolute configuration of main
stereoisomers of 34 and 35 was determined by their trans-
formation to p-MeO- and p-bromo-substituted methyl-
phenidates followed by the comparison with authentic
samples.6 That of 36 was estimated on the basis of the
proposed mechanism.
The ratio of threo-35 to erythro-35 was determined by
DAICEL Chiralpak AS (4.6 mmл, 25 cm) [hexane/iso-
propanol/methanol (150:11:0.8 (v/v/v). 0.4 mL/min, detec-
tion at 210 nm]; 18 min for (2S, 20R)- or (2R, 20S)-35,
20 min for (2S, 20S)-35, 21.5 min for (2R, 20R)-35, 23 min
for (2R, 20S)- or (2S, 20R)-35.
Methyl threo-2-(p-bromophenyl)-2-(N0-methoxycarbo-
nyl-20-piperidyl)acetate (threo-35). IR (neat) 1748, 1709,
1451, 1408, 1370, 1314, 1275, 1246, 1173, 1075,
1013 cmϪ1 1H NMR (300 MHz) (CDCl3) d 1.18–1.75
;
(m, 6H), 2.95–3.17 (m, 1H), 3.62 (s, 3H), 3.73 (s, 3H),
3.95–4.28 (m, 2H), 4.75–5.03 (m, 1H), 7.30–7.40 (m,
2H), 7.45–7.53 (m, 2H); HRMS calcd for C16H20BrNO4:
369.0575. found: 369.0574. Anal. Calcd for C16H20BrNO4:
C, 51.91; H, 5.44; N, 3.78. Found: C, 51.53; H, 5.11; N, 4.01.
The yield of 34 from the reaction of 3 with 28a; 48%;
erythro/threoˆ10.6/89.4.
The yield of 34 from the reaction of 3 with 28b; 52%;
erythro/threoˆ5.9/94.1; the %ee of the main stereoisomer
of threo is Ͼ99.9.
Methyl erythro-2-(p-bromophenyl)-2-(N0-methoxycarbo-
nyl-20-piperidyl)acetate (erythro-35). IR (neat) 1736,
1698, 1449, 1408, 1368, 1312, 1277, 1266, 1175, 1075,
1013 cmϪ1 1H NMR (300 MHz) (CDCl3) d 1.18–1.80
;
The yield of 35 from the reaction of 3 with 29a; 37%;
erythro/threoˆ1.2/98.8.
(m, 6H), 2.59–2.75 (m, 1H), 3.67 (s, 3H), 3.77 (s, 3H),
3.95–4.15 (m, 2H), 4.85–4.95 (m, 1H), 7.30–7.45 (m,
4H); HRMS calcd for C16H20BrNO4: 369.0575. found:
369.0575. Anal. Calcd for C16H20BrNO4: C, 51.91; H,
5.44; N, 3.78. Found: C, 51.89; H, 5.48; N, 3.89.
The yield of 35 from the reaction of 3 with 29b; 40%;
erythro/threoˆ5.6/94.4; the %ee of the main stereoisomer
of threo is 97.6.
The ratio of threo-36 to erythro-36 was determined by
DAICEL Chiralpak AD (4.6 mmл, 25 cm) [hexane/iso-
propanol (15:1 (v/v)), 0.5 mL/min, detection at 210 nm];
18 min for (2R, 20R)-36, 24 min for (2S, 20R)- or (2R,
20S)-36, 27 min for (2R, 20S)- or (2S, 20R)-36, 34 min for
(2S, 20S)-36.
The yield of 36 from the reaction of 3 with 30a; 32%;
erythro/threoˆ10.6/89.4.
The yield of 36 from the reaction of 3 with 30b; 30%;
erythro/threoˆ5.2/94.8; the %ee of the main stereoisomer
of threo is Ͼ99.9.
Methyl threo-2-(p-trifluoromethyl)-2-(N0-methoxycarbo-
nyl-20-piperidyl)acetate (threo-36). IR (neat) 1744, 1701,
The ratio of threo-34 to erythro-34 was determined by
DAICEL Chiralpak AD (4.6 mmл, 25 cm) [hexane/iso-
propanol (11:1 (v/v)), 0.5 mL/min, detection at 210 nm];
23 min for (2R, 20R)-34, 30 min for (2S, 20R)- or (2R,
20S)-34, 32 min for (2R, 20S) or (2S, 20R)-26, 35 min for
(2S, 20S)-34.
1
1449, 1410, 1327, 1260, 1167, 1127, 1069, 1021 cmϪ1; H
NMR (300 MHz) (CDCl3) d 1.14–1.80 (m, 6H), 2.95–3.20
(m, 1H), 3.63 (s, 3H), 3.74 (br s, 3H), 3.95–4.30 (m, 2H),
4.79–5.10 (m, 1H), 7.61 (br s, 4H); HRMS calcd for
C17H20F3NO4: 359.1344. found: 359.1263. Anal. Calcd for
C17H20F3NO4: C, 56.82; H, 5.61; N, 3.90. Found: C, 56.43;
H, 5.55; N, 4.23.
Methyl threo-2-(p-methoxyphenyl)-2-(N0-methoxycarbo-
nyl-20-piperidyl)acetate (threo-34). Colorless oil; IR (neat)

Y. Matsumura et al. / Tetrahedron 56 (2000) 7411–7422
7421
Methyl
erythro-2-(p-trifluoromethyl)-2-(N0-methoxy-
Methyl threo-(2-phenyl-2-(N0-methoxycarbonyl-20-hexa-
methyleneiminyl)acetate (threo-44). Colorless oil;
[a]2D3ˆϩ15.5Њ (cˆ1.5, MeOH) for a sample with 96.4%
ee; IR (neat) 1734, 1700, 1455, 1437, 1406, 1208, 1167,
carbonyl-20-piperidyl)-acetate (erythro-36). IR (neat)
1736, 1701, 1449, 1410, 1325, 1266, 1163, 1122, 1069,
1021 cmϪ1 1H NMR (300 MHz) (CDCl3) d 1.19–1.98
;
(m, 6H), 3.30–3.45 (m, 1H), 3.63 (s, 3H), 3.69 (s, 3H),
3.95–4.30 (m, 2H), 4.88–5.25 (m, 1H), 7.41–7.68 (m,
4H); HRMS calcd for C17H20F3NO4: 359.1344. found:
359.1313. Anal. Calcd for C17H20F3NO4: C, 56.82; H,
5.61; N, 3.90. Found: C, 56.48; H, 5.60; N, 4.21.
1105 cmϪ1 1H NMR (300 MHz) (CDCl3) d 1.05–1.90
;
(m, 8H), 2.58–2.78 (m, 1H), 3.45–3.92 (m, 2H), 3.64 (s,
3H), 3.73 (s, 1.5H), 3.76 (s, 1.5H), 4.49–4.74 (m, 1H),
7.23–7.44 (m, 5H); HRMS calcd for C17H23NO4:
305.1627. found: 274.1420. Anal. Calcd for C17H23NO4:
C, 66.86; H, 7.59; N, 4.59. Found: C, 67.06; H, 7.61; N,
4.27.
Hydrochloride salt of methyl (2R,20R)-2-(p-methoxy-
phenyl)-2-(20-piperidyl)acetate (37). After diastereomers
of 34 were separated by column chromatography, the
main stereoisomer was converted in 41% yield to the hydro-
chloride salt of the corresponding amine in a similar way to
the procedure for the conversion of 7 to the salt of 1. Hydro-
chloride salt of methyl (2R,20R)-2-(p-methoxyphenyl)-2-
(20-piperidyl)acetate (37): [a]2D2ˆϩ87.4Њ (cˆ1.0, MeOH).
[lit.6 [a]2D0ˆϩ86.6Њ (cˆ1.98, MeOH)].
Acknowledgements
One of authors (Y. M.) thanks a Grant-in-Aid for Scientific
Research on Priority Area (No. 236) from the Ministry of
Education, Science, Sports and Culture, Japan.
Hydrochloride salt of methyl (2R,20R)-2-(p-bromo-
phenyl)-2-(20-piperidyl)acetate (38). This salt was
obtained from 35 in a 34% yield. [a]2D2ˆϩ83.5Њ (cˆ1.0,
CH2Cl2)[lit.6 [a]D20ˆϩ69.1Њ (cˆ3.09, CH2Cl2)].
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1
1734, 1705, 1453, 1385, 1200, 1163, 1121 cmϪ1; H NMR
(300 MHz) (CDCl3) d 0.83–1.30 (m, 1H), 1.43–1.70 (m,
1H), 1.75–2.07 (m, 2H), 2.88–3.13 (m, 1H), 3.13–3.50 (m,
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13. After submitting our preliminary result,10 there has appeared
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¨
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7422
Y. Matsumura et al. / Tetrahedron 56 (2000) 7411–7422
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