The first enantioselective synthesis of (2R,2'R)-threo-(+)- methylphenidate hydrochloride

Full text of DOI:10.1021/jo9821473

1750
J . Org. Chem. 1999, 64, 1750-1753
Sch em e 1
Th e F ir st En a n tioselective Syn th esis of
(2R,2′R)-th r eo-(+)-Meth ylp h en id a te
Hyd r och lor id e
Mahavir Prashad,* Hong-Yong Kim, Yansong Lu,
Yugang Liu, Denis Har, Oljan Repic,
Thomas J . Blacklock, and Peter Giannousis
Process Research & Development, Chemical & Analytical
Development, Novartis Institute for Biomedical Research,
59 Route 10, East Hanover, New J ersey 07936
Received October 26, 1998
(()-threo-Methylphenidate hydrochloride (Ritalin hy-
drochloride) is a mild nervous system stimulant mar-
keted for the treatment of children with attention deficit
hyperactivity disorder (ADHD). (2R,2′R)-(+)-threo-Me-
thylphenidate hydrochloride (1) has been reported to be
5 times1 to 38 times2 more active than the corresponding
(2S,2′S)-(-)-threo-methylphenidate hydrochloride. The
clinical relevance of this difference to the use of racemate
versus the pure eutomer is yet to be determined. We were
therefore interested in developing a process that is
suitable for manufacturing the active (2R,2′R)-enanti-
omer 1. In the event that a ready supply of (()-threo-
methylphenidate hydrochloride is available, one must
contrast the obvious choice of classical resolution to a
total synthesis. We recently reported the resolution of
(()-threo-methylphenidate by an enzymatic hydrolysis,3
which was followed by other patent literature.4,5 Several
classical resolution methods have been reported for the
resolution of (()-threo-methylphenidate free base or (()-
activation of the hydroxyl groups, as in A. The methyl
ester functionality would be introduced by the displace-
ment of the chiral auxiliary with methoxide. One possible
method for accessing compounds such as B enantiose-
lectively would be the asymmetric aldol condensation of
an aldehyde (C) with the (Z)-boron enolate derived from
N-phenylacetyl-(R)-4-substituted-2-oxazolidinone (D). The
erythro-selective syn aldol addition of aldehydes with (Z)-
boron enolates is well-known.11
threo-ritalinic acid toward the preparation of 1.1,6-9
A
synthesis of 1 has also been reported recently10 that
utilizes an enantiopure amino acid (D-pipecolic acid) as
the starting material, which in turn was prepared by the
resolution of (()-pipecolic acid using tartaric acid, making
this route unattractive for a scale-up in comparison to
the direct resolution of (()-threo-methylphenidate itself.
Our goal was to develop an enantioselective synthesis of
1 that is suitable for manufacturing of this drug sub-
stance on a commercial scale. In this paper we report the
first enantioselective synthesis of (2R,2′R)-threo-(+)-
methylphenidate hydrochloride (1).
We opted to use (R)-4-phenyl-N-phenylacetyl-2-oxazo-
lidinone (3) and 5-chlorovaleraldehyde (4) as the starting
materials for the key aldol reaction (Scheme 2). Com-
pound 3 was easily prepared by the new method devel-
oped in our laboratories,12 a direct coupling of phenyl-
acetic acid (2, 1.14 equiv) with the cheap and readily
available (R)-4-phenyl-2-oxazolidinone in the presence of
pivaloyl chloride and triethylamine, in 78% yield. The
aldehyde 4 was prepared by the oxidation of commercially
available 5-chloropentanol with NaOCl and TEMPO,
using a known method.13 The key aldol condensation of
3 with 4 was performed under known conditions,11 which
afforded the desired single diastereomer 5, as confirmed
Our synthetic strategy toward 1 is depicted in Scheme
1. We rationalized that the piperidine ring system would
be furnished by the cyclization of the stereoselectively
substituted 1,5-diol such as B with an amine, after
(1) Rometsch, R. U.S. Patent 2,957,880, October 25, 1960.
(2) Maxwell, R. A.; Chaplin, E.; Eckhardt, S. B.; Soares, J . R.; Hite,
G. J . Pharmacol. Exp. Ther. 1970, 173, 158-165.
(3) Prashad, M.; Har, D.; Repic, O.; Blacklock, T. J .; Giannousis, P.
Tetrahedron: Asymmetry 1998, 9, 2133-2136.
(4) Zeitlin, A. L.; Stirling, D. I. United States Patent No. 5,733,756,
March 31, 1998.
(5) Faulconbridge, S.; Zavareh, H. S.; Evans, G. R.; Langston, M.
World Patent Application No. WO 98/25902, J une 18, 1998.
(6) Patrick, K. S.; Caldwell, R. W.; Ferris, R. M.; Breese, G. R. J .
Pharmacol. Exp. Ther. 1987, 241, 152-158.
(7) Harris, M. C. J .; Zavareh, H. S. World Patent Application No.
WO 97/27176, J uly 31, 1997.
1
by H NMR, in 78% yield as an oil. 1H NMR of the crude
5 did not indicate the presence of the undesired diastre-
omer. Similar results were obtained using either CH2-
Cl2 or toluene as the solvent. These results suggested that
cheaper (R)-4-phenyl-2-oxazolidinone, which is not a
(8) Zavareh, H. S. World Patent Application No. WO 97/32851,
September 12, 1997.
(9) Zavareh, H. S. Potter, G. A. World Patent Application No. WO
98/31668, J uly 23, 1998.
(10) Thai, D. L.; Sapko, M. T.; Reiter, C. T.; Bierer, D. E.; Perel, J .
M. J . Med. Chem. 1998, 41, 591-601.
(11) Evans, D. A.; Bartoli, J .; Shih, T. L. J . Am. Chem. Soc. 1981,
103, 2127-2129.
(12) Prashad, M.; Kim, H. Y.; Har, D.; Repic, O.; Blacklock, T. J .
Tetrahedron Lett. 1998, 39, 9369-9372.
(13) Leanna, M. R.; Sowin, T. J .; Morton, H. E. Tetrahedron Lett.
1992, 33, 5029-5032.
10.1021/jo9821473 CCC: $18.00 © 1999 American Chemical Society
Published on Web 01/28/1999

Notes
J . Org. Chem., Vol. 64, No. 5, 1999 1751
Sch em e 2
commonly used auxiliary, is a suitable chiral auxiliary
for the aldol reaction. Use of (R)-4-benzyl-2-oxazolidinone
also gave the same diastereoselectivity in the aldol
reaction. Mesylation of 5 with either methanesulfonic
anhydride and pyridine in dichloromethane or methane-
sulfonyl chloride and triethylamine in toluene yielded the
mesylate 6 in 92% yield. With 6 in hand, we were ready
to construct the piperidine ring. We decided to use
benzylamine, also used by Masamune to prepare a
pyrrolidine ring,14 to construct the piperidine ring. Reac-
tion of 6 with benzylamine at 85 °C gave a complicated
mixture, and no desired product 12 could be obtained.
We postulated that the undesired ring opening of the
2-oxazolidinone by benzylamine and the steric bulk of
this chiral auxiliary may be responsible for the unex-
pected outcome. To overcome this problem, we decided
to replace the chiral auxiliary with the desired methyl
ester functionality prior to the cyclization. The reaction
of 6 with lithium methoxide15 in methanol at 0 °C yielded
the expected methyl ester 13. Treatment of 13 with
benzylamine yielded the cyclic product; however, it was
characterized to be (()-erythro-methylphenidate (14).
These results could be explained based on the elimination
of the mesylate, which destroyed both stereogenic centers;
the R,â-unsaturated ester intermediate then underwent
a Michael addition with benzylamine, followed by cy-
clization. To circumvent the elimination problem, we
decided to replace the methyl ester group with the
corresponding alcohol function prior to the cyclization
step and oxidize it back to the desired carboxylic ester
functionality afterward. The desired alcohol 7 was di-
rectly prepared from 6 in 91% yield by the reductive
removal of the chiral auxiliary with sodium borohydride
in THF and water16 followed by a silica gel chromatog-
raphy. This reductive removal was highly selective and
no reduction of the chloride or the mesylate functional-
ities was observed. Treatment of alcohol 7 with benzyl-
amine (10 equiv) at 85 °C and purification by a silica gel
chromatography afforded the desired piperidine inter-
mediate 8 in 60% yield. The optical purity of 8 was
ascertained by a chiral HPLC method. No (2S,2′S)-
enantiomer could be detected in 8.
Having secured the two stereogenic centers and the
piperidine ring in 8, our next objective was to cleave the
benzyl group and convert the alcohol group to the methyl
ester. Oxidation of 8 with H5IO6 in the presence of
catalytic amounts of CrO3 in wet acetonitrile17 yielded
the corresponding acid in ∼35% yield. These poor yields
may be due to side reactions such as N-benzylic oxidation
and the oxidation of the tertiary amine in 8. To circum-
vent this problem, we decided to replace the N-benzyl
group with another protecting group which is stable
(14) Short, R. P.; Kennedy, R. M.; Masamune, S. J . Org. Chem. 1989,
54, 1755-1756.
(15) Evans, D. A.; Ennis, M. D.; Mathre, D. J . J . Am. Chem. Soc.
1982, 104, 1737-1739.
(16) Prashad, M.; Har, D.; Kim, H. Y.; Repic, O. Tetrahedron Lett.
1998, 39, 7067-7070.
(17) Zhao, M.; Song, Z.; Desmond, R.; Tschaen, D. M.; Grabowski,
E. J . J .; Reider, P. J . Tetrahedron Lett. 1998, 39, 5323-5326.

1752 J . Org. Chem., Vol. 64, No. 5, 1999
Notes
Calcd for C22H24NO4Cl: C, 65.75; H, 6.02; N, 3.49; Cl, 8.82.
under oxidative conditions. tert-Butyloxycarbonyl (BOC)
group was our first choice. Thus, hydrogenation of 8 in
the presence of Pd-C (10%) in ethanol yielded the amino
alcohol 9 (92% yield), which was acylated with di-tert-
butyl dicarbonate to afford N-BOC-protected alcohol 10
in 82% yield. Oxidation of 10 with NaIO4 and RuCl3
under reported conditions18 furnished the acid 11 in 80%
yield. Treatment of the acid 11 with methanol in the
presence of HCl gas at 50 °C yielded the desired (2R,2′R)-
threo-(+)-methylphenidate hydrochloride (1) in 70% yield.
Optical purity of crude as well as crystalline 1 was >99%
as determined by a chiral HPLC method. All of the
spectral and analytical data of 1 were identical to those
of an authentic sample.3
In summary, we have described a novel and the first
enantioselective synthesis of (2R,2′R)-threo-(+)-meth-
ylphenidate hydrochloride with >99% optical purity in
a total of nine steps and 13.0% overall yield starting from
phenylacetic acid. The key steps in the sequence are
Evans’s asymmetric aldol reaction, our own selective
reductive removal of the 2-oxazolidinone chiral auxiliary,
an extension of Masamune’s method to piperidine ring
formation, and Sharpless’s oxidation of a primary alcohol
to the carboxylic acid. This strategy would allow access
to analogues of 1 and the corresponding (2S,2′S)-enan-
tiomer by using (S)-4-phenyl-2-oxazolidinone as the chiral
auxiliary.
Found: C, 65.49; H, 6.34; N, 3.15; Cl, 8.68. [R]25 +11.80 (c )
D
0.61, MeOH); IR (neat, cm-1) 1780, 1697, 1601.
3-[7-Ch lor o-3-(S)-(m eth ylsu lfon yl)oxy-2-(R)-p h en ylh ep -
ta n oyl]-4-(R)-p h en yl-2-oxa zolid in on e (6). Meth od A. To a
stirred solution of 5 (19.0 g, 47.3 mmol) in toluene (150 mL) was
added methanesulfonyl chloride (8.9 g, 77.7 mmol). Triethyl-
amine (8.7 g, 86.0 mmol) was then added over 20 min while
maintaining an internal temperature at 0 °C. After stirring at
0 °C for 2 h, the reaction mixture was quenched by addition of
1 N HCl (20 mL), water (100 mL), and brine (50 mL). The
mixture was extracted with EtOAc (2 × 125 mL), and combined
organic layers were washed sequentially with 0.1 N HCl (100
mL), brine (100 mL), saturated NaHCO3 solution (2 × 100 mL),
and brine (100 mL) and then dried (MgSO4). The solution was
concentrated in vacuo to give the crude product, which was
purified by column chromatography on SiO2 (EtOAc/hexanes,
1:4) to give 6 (21.1 g, 93%) as an oil.
Meth od B. To a stirred solution of 5 (3 g, 7.7 mmol) in 30
mL of CH2Cl2 were added methanesulfonic anhydride (1.6 g, 9.2
mmol) and pyridine (0.91 g, 11.6 mmol) at 0 °C. After 3 h at 0
°C, the reaction mixture was quenched by addition of 1 N HCl
(20 mL). The mixture was extracted with CH2Cl2 (2 × 30 mL),
and the combined organic layers were washed with saturated
NaHCO3 solution (30 mL), H2O (30 mL), and brine (30 mL) and
then dried (MgSO4). The solution was concentrated in vacuo to
give the crude product, which was purified by column chroma-
tography on SiO2 (EtOAc/hexanes, 1:4) to give 6 (3.39 g, 92%)
as an oil: 1H NMR (300 MHz, CDCl3) δ 7.34-7.15 (m, 8 H), 6.93
(d, 2 H, J ) 7.7 Hz), 5.50 (dd, 1 H, J ) 8.9, 4.7 Hz), 5.37 (d, 1 H,
J ) 9.5 Hz), 5.35-5.20 (m, 1 H), 4.73 (t, 1 H, J ) 8.9 Hz), 4.16
(dd, 1 H, J ) 8.9, 4.7 Hz), 3.59 (t, 2 H, J ) 6.5 Hz), 2.09 (s, 3 H),
1.95-1.60 (m, 6 H); 13C NMR (125 MHz, CDCl3) δ 170.3, 153.3,
138.1, 134.3, 130.6, 130.5, 129.3, 129.1, 128.9, 126.1, 84.1, 70.1,
Exp er im en ta l Section
58.1, 53.7, 44.9, 37.8, 33.8, 32.3, 22.2. Anal. Calcd for C23H26
-
3-[7-Ch lor o-3-(S)-h yd r oxy-2-(R)-p h en ylh ep ta n oyl]-4-(R)-
p h en yl-2-oxa zolid in on e (5). To a stirred solution of 319 (8.5
g, 30.2 mmol) in 100 mL of CH2Cl2 (or toluene) was added di-
n-butylboryl trifluoromethanesulfonate (33 mL, 1 M in CH2Cl2)
dropwise to maintain the internal temperature at 0 °C. After
stirring for 5 min at 0 °C, diisopropylethylamine (4.6 g, 35.6
mmol) was added dropwise, while maintaining the internal
temperature at 0 °C. The solution turned from dark orange to
light yellow after this addition. The reaction mixture was stirred
for 30 min at 0 °C and then cooled to -20 °C. Aldehyde 420 (4.02
g, 33.2 mmol) in 4 mL of CH2Cl2 was added at -20 °C. The
reaction mixture was stirred at this temperature for 2 h and
then allowed to warm to 22 °C. After stirring at 22 °C for 3 h,
the reaction was quenched by addition of phosphate buffer (pH
) 7.2, 20 mL). The mixture was extracted with CH2Cl2 (2 × 30
mL), and the combined organic layers were washed with
saturated NaHCO3 solution (40 mL), H2O (40 mL), and brine
(40 mL). The organic layer was concentrated in vacuo. The crude
oil was dissolved in MeOH (90 mL) and cooled to an internal
temperature at 0 °C, and 30% H2O2 (30 mL) was added. The
reaction mixture was stirred at 0 °C for 1 h and then allowed to
warm to 22 °C. After 1 h at room temperature, the reaction was
quenched by addition of H2O (120 mL). The mixture was
extracted with EtOAc (2 × 200 mL), and the combined organic
layers were washed with saturated NaHCO3 solution (50 mL),
H2O (50 mL), and brine (50 mL) and then dried (MgSO4). The
solution was concentrated in vacuo to give the crude aldol
product, which was purified by column chromatography on SiO2
(EtOAc/hexanes, 1:4) to give 5 (9.1 g, 78%) as an oil: 1H NMR
(270 MHz, CDCl3) δ 7.34-6.91 (m, 10 H), 5.47 (dd, 1 H, J ) 9.0,
5.0 Hz), 5.0 (d, 1 H, J ) 5.0 Hz), 4.66 (t, 1 H, J ) 9.0 Hz), 4.22-
4.14 (m, 1 H), 4.09 (dd, 1 H, J ) 9.0, 5.0 Hz), 3.50 (t, 2 H, J )
6.6 Hz), 2.66 (bs, 1 H), 1.82-1.36 (m, 6 H); 13C NMR (125 MHz,
CDCl3) δ 173.3, 152.7, 137.8, 132.8, 130.2, 129.0, 128.7, 128.3,
127.8, 125.7, 71.3, 69.6, 57.6, 54.4, 44.8, 33.5, 32.3, 23.1. Anal.
NSO6Cl: C, 57.55; H, 5.46; N, 2.92; S, 6.68; Cl, 7.38. Found: C,
57.28; H, 5.78; N, 3.15; S, 6.35; Cl, 6.65. [R]25 +9.83 (c ) 0.84,
D
MeOH); IR (neat, cm-1) 1780, 1699.
r-(S)-(4-Ch lor obu tyl)-â-(S)-(h yd r oxym eth yl)ben zen eeth -
a n ol Meth a n esu lfon a te (7). To a stirred solution of 6 (1.45 g,
3.1 mmol) in 25 mL of THF was added a solution of NaBH4 (0.45
g, 11.8 mmol) in 4.5 mL of H2O at 0 °C. The reaction mixture
was stirred at 0 °C for 5 min and allowed to warm to 22 °C.
After stirring at 22 °C for 1 h, the reaction was quenched by
addition of 2 N HCl solution (7 mL). The mixture was extracted
with EtOAc (2 × 30 mL), and the combined organic layers were
washed with saturated NaHCO3 solution (20 mL), H2O (20 mL),
and brine (20 mL) and then dried (MgSO4). The solution was
concentrated in vacuo to give the crude product, which was
purified by column chromatography on SiO2 (EtOAc/hexanes,
1:2) to give 7 (0.9 g, 91%) as an oil: 1H NMR (300 MHz, CDCl3)
δ 7.50-7.38 (m, 5 H), 5.34-5.32 (m, 1 H), 4.15 (dd, 1 H, J )
11.5, 9.3 Hz), 3.94 (dd, 1 H, J ) 11.5, 5.9 Hz), 3.64 (t, 2 H, J )
6.4 Hz), 3.23-3.19 (m, 1 H), 3.05 (s, 3 H), 1.92-1.68 (m, 6 H);
13C NMR (125 MHz, CDCl3) δ 136.8, 129.3, 128.7, 127.7, 82.1,
62.8, 51.6, 44.5, 38.3, 32.4, 31.9, 22.6. Anal. Calcd for C14H21
-
ClO4S: C, 52.41; H, 6.6; S, 9.99; Cl, 11.05. Found: C, 52.47; H,
6.50; S, 9.69; Cl, 11.27. [R]25D +9.59 (c ) 0.86, MeOH); IR (neat,
cm-1) 1495, 1454.
â-(R)-P h e n yl-1-(p h e n ylm e t h yl)-2-(R)-p ip e r id in e e t h a -
n ol (8). A solution of 7 (10 g, 31.3 mmol) in benzylamine (34 g,
317 mmol) was stirred at 85 °C for 3 h. The reaction mixture
was allowed to cool to 22 °C, and EtOAc (200 mL) was added.
The mixture was washed with saturated NaHCO3 solution (100
mL), H2O (100 mL), and brine (100 mL) and then dried (MgSO4).
The solution was concentrated in vacuo to give the crude product,
which was purified by column chromatography on SiO2 (EtOAc/
hexanes, 1:1) to give 8 (5.5 g, 60%) as an oil: 1H NMR (300 MHz,
CDCl3) δ 7.38-6.89 (m, 10 H), 3.98 (s, 2 H), 3.81 (t, 1 H, J )
10.3 Hz), 3.67 (dd, 1 H, J ) 10.7, 3.5 Hz), 3.46 (td, 1 H, J )
10.7, 3.3 Hz), 3.31-3.16 (m, 2 H), 2.72 (bd, 1 H, J ) 14.9 Hz),
1.80-0.88 (m, 6 H); 13C NMR (125 MHz, CDCl3) δ 140.8, 138.5,
129.1, 128.6, 127.8, 127.4, 126.7, 70.0, 63.0, 57.2, 45.2, 44.9, 20.5,
20.0, 18.9. Anal. Calcd for C20H25NO: C, 81.31; H, 8.53; N, 4.74.
(18) Carlsen, P. H. J .; Katsuki, T.; Martin, V. S.; Sharpless, K. B.
J . Org. Chem. 1981, 46, 3936-3938.
(19) Kise, N.; Tokioka, K.; Aoyama, Y. J . Org. Chem. 1995, 60,
1100-1101.
Found: C, 81.11; H, 8.82; N, 4.41. [R]25 -51.83° (c ) 0.54,
D
(20) Kuehne, M. E.; Matsko, T. H.; Bohnert, J . C.; Motyka, L.; Oliver-
Smith, D. J . Org. Chem. 1981, 46, 2002-2009.
MeOH).

Notes
The optical purity of 8 was determined by a chiral HPLC
method on a Rainin Dynamax system using a Daicel Chiralpak
AD column (4.6 × 250 mm) and a mixture of hexane/2-propanol/
TFA (88:12:0.1 mL) as the mobile phase (isocratic at a flow rate
of 1.0 mL/min and UV detector at 254 nm). The retention time
of 8 was 15.8 min, and that of its corresponding (2S,2′S)-
enantiomer was 19.7 min. No (2S,2′S)-enantiomer of 8 could be
detected.
J . Org. Chem., Vol. 64, No. 5, 1999 1753
layers were washed with H2O (50 mL) and brine (50 mL) and
then dried (MgSO4). The solution was concentrated in vacuo to
give the crude product, which was purified by column chroma-
tography on SiO2 (EtOAc/hexanes, 1:2) to give 11 (520 mg, 80%)
as a white solid, mp 117-119 °C: 1H NMR (300 MHz, CD3OD)
δ 7.46-7.25 (m, 5 H), 5.03-4.80 (bm, 1 H), 4.16 (d, 1 H, J )
11.8 Hz), 4.12-3.92 (bm, 1 H), 3.25-3.01 (bm, 1 H), 1.75-1.12
(m, 6 H), 1.50 (s, 9 H); 13C NMR (125 MHz, CD3OD) δ 176.0,
156.9, 138.6, 130.3, 130.2, 129.2, 81.7, 56.1, 54.9, 52.7, 41.6, 40.1,
29.0, 26.8, 20.1. Anal. Calcd for C18H25NO4: C, 67.69; H, 7.89;
â-(R)-P h en yl-2-(R)-p ip er id in eeth a n ol (9). To a solution of
8 (220 mg, 0.74 mmol) in ethanol (7 mL) in a Parr bottle was
added 10% Pd/C (20 mg). The Parr bottle was flushed three times
with H2 (50 psi) and then vibrated at room temperature with
N, 4.39. Found: C, 67.54; H, 7.97; N, 4.41. [R]25 -40.9 (c )
D
1.09, CH2Cl2).
H
2 (50 psi) for 4 h. The catalyst was filtered over a pad of Celite
(2R,2′R)-th r eo-(+)-Meth ylp h en id a te Hyd r och lor id e (1).
Into a solution of 11 (230 mg, 0.75 mmol) in MeOH (10 mL) was
bubbled HCl gas, and the solution was stirred at 50 °C for 15 h.
The reaction mixture was concentrated in vacuo to give a
residue. The residue was treated with tert-butyl methyl ether
(10 mL), and the resulting solid was collected by filtration and
dried to give 1 (142 mg, 70%), mp 222-224 °C.3
The optical purity of crude as well as crystalline 1 was
determined to be >99% (no other diastereomers could be
detected) by a chiral HPLC method on a Rainin Dynamax system
using a Daicel Chiralpak AD column (4.6 × 250 mm) and a
mixture of hexane/ethanol/methanol/TFA (96:2:2:0.1 mL) as the
mobile phase (isocratic at a flow rate of 0.8 mL/min and UV
detector at 230 nm). The retention time of 1 was 15 min, and
that of its corresponding (2S,2′S)-enantiomer was 13 min. The
retention times of (2′S,2R)- and (2′R,2S)-erythro-methylpheni-
dates were 13.5 and 16.5 min, respectively.
and washed with ethanol (2 × 5 mL). The filtrate was concen-
trated in vacuo to give crude 9 (140 mg, 92%), which was used
in the next step without purification: 1H NMR (300 MHz, CDCl3)
δ 7.35-7.16 (m, 5 H), 4.03 (dd, 1 H, J ) 11.0, 8.5 Hz), 3.86 (dd,
1 H, J ) 11.0, 4.0 Hz), 3.7-3.3 (bs, 2 H), 3.12 (dd, 1 H, J ) 13.3,
2.7 Hz), 3.01 (td, 1 H, J ) 10.0, 2.4 Hz), 2.73 (td, 1 H, J ) 8.7,
4.0 Hz), 2.63 (td, 1 H, J ) 12.3, 3.1 Hz), 1.74-1.0 (m, 6 H); 13C
NMR (125 MHz, CDCl3) δ 140.4, 128.6, 128.1, 126.8, 68.3, 62.8,
51.8, 46.4, 31.7, 26.7, 24.2.
1-(t er t -Bu t yloxyca r b on yl)-â-(R )-p h e n yl-2-(R )-p ip e r i-
d in eeth a n ol (10). To a solution of 9 (130 mg, 0.63 mmol) in
THF (5 mL) were added (BOC)2O (0.28 g, 1.26 mmol) and
triethylamine (0.1 mL, 0.72 mmol). The solution was stirred at
22 °C for 19 h. The reaction mixture was concentrated in vacuo.
The residue was purified by chromatography on SiO2, to yield
10 (160 mg, 82%) as a white solid, mp 79-80 °C.10
1-(t er t -Bu t yloxyca r b on yl)-r-(R )-p h e n yl-2-(R )-p ip e r i-
d in ea cetic Acid (11). To a stirred solution of 10 (630 mg, 2.06
mmol) in a mixed solvent (CCl4/CH3CN/H2O ) 8:8:12 mL) were
added NaIO4 (1.75 g, 8.2 mmol) and RuCl3‚H2O (10 mg, 0.05
mmol) at 22 °C. After stirring at 22 °C for 2 h, the mixture was
extracted with EtOAc (2 × 50 mL), and the combined organic
Ack n ow led gm en t. We thank Dr. Bin Hu for pre-
paring an authentic sample of (()-8.
J O9821473