Synthesis of 4-(R)-naphthalene-2-yloxy-1-(1-phenyl-(S)-ethyl)-pyrrolidin-3- (R)-ol and 4-(S)-naphthalen-2-yloxy-1-(1-phenyl-(S)-ethyl)-pyrrolidin-3-(S)-ol: Versatile chiral intermediates for synthesis

Article abstract of DOI:10.1081/SCC-200039498

A convenient and rapid synthesis of 4-(R)-(naphthalene-2-yloxy)-1-(1- phenyl-(S)-ethyl)-pyrrolidin-3-(R)-ol and 4-(S)-(naphthalen-2-yloxy)-1-(1- phenyl-(S)-ethyl)-pyrrolidin-3-(S)-ol is disclosed. The reaction scheme is highlighted by the meso-epoxidation

Full text of DOI:10.1081/SCC-200039498

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Synthesis of
4‐(R)‐Naphthalene‐2‐yloxy‐1‐(1‐Ph
and
4‐(S)‐Naphthalen‐2‐yloxy‐1‐(1‐Phe
Versatile Chiral Intermediates
for Synthesis
Daniel D. Holsworth a , Michael Stier a , Wei
Wang b , Jeremy J. Edmunds a , Tingsheng Li c &
Samarendra N. Maiti c
a Department of Chemistry , Pfizer Global
Research and Development , Bldg. 28‐3, 2800
Plymouth Rd., Ann Arbor, MI, 48105, USA
b Discovery Technologies , Pfizer Global Research
and Development , Ann Arbor, Michigan, USA
c Department of Chemistry , Naeja
Pharmaceutical, Inc. , Edmonton, Alberta, Canada
Published online: 12 Jan 2011.
To cite this article: Daniel D. Holsworth , Michael Stier , Wei Wang ,
Jeremy J. Edmunds , Tingsheng Li & Samarendra N. Maiti (2004) Synthesis
of 4‐(R)‐Naphthalene‐2‐yloxy‐1‐(1‐Phenyl‐(S)‐Ethyl)‐Pyrrolidin‐3‐(R)‐ol and
4‐(S)‐Naphthalen‐2‐yloxy‐1‐(1‐Phenyl‐(S)‐Ethyl)‐Pyrrolidin‐3‐(S)‐ol: Versatile Chiral
Intermediates for Synthesis, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 34:23, 4421-4430, DOI:
10.1081/SCC-200039498

To link to this article: http://dx.doi.org/10.1081/SCC-200039498
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 23, pp. 4421–4430, 2004
Synthesis of 4-(R)-Naphthalene-2-yloxy-
1-(1-Phenyl-(S)-Ethyl)-Pyrrolidin-3-(R)-ol
and 4-(S)-Naphthalen-2-yloxy-1-(1-Phenyl-
(S)-Ethyl)-Pyrrolidin-3-(S)-ol: Versatile
Chiral Intermediates for Synthesis
1
2
Daniel D. Holsworth,1, Michael Stier, Wei Wang,
Jeremy J. Edmunds,1 Tingsheng Li,3 and
Samarendra N. Maiti3
*
2
1Department of Chemistry and Discovery Technologies, Pfizer Global
Research and Development, Ann Arbor, Michigan, USA
2Department of Chemistry, Naeja Pharmaceutical, Inc., Edmonton,
Alberta, Canada
ABSTRACT
A
convenient and rapid synthesis of 4-(R)-(naphthalen-2-yloxy)-
1-(1-phenyl-(S)-ethyl)-pyrrolidin-3-(R)-ol and 4-(S)-(naphthalen-2-yloxy)-
1-(1-phenyl-(S)-ethyl)-pyrrolidin-3-(S)-ol is disclosed. The reaction
*
Correspondence: Daniel D. Holsworth, Department of Chemistry, Pfizer Global
Research and Development, Bldg. 28-3, 2800 Plymouth Rd., Ann Arbor, MI 48105,
USA; Tel.: 734-622-1344; Fax: 734-622-3909; E-mail: daniel.holsworth@pfizer.com.
4421
DOI: 10.1081/SCC-200039498
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

4422
Holsworth et al.
scheme is highlighted by the meso-epoxidation of 1-(1-phenyl-(S)-ethyl)-
2,5-dihydro-1H-pyrrole followed by addition of 2-naphthol alkoxide to
provide both expected diastereoisomers. Separation of the diastereoi-
somers by crystallization provided access to both diastereoisomers in
modest yield without the employment of expensive chiral catalysts.
X-ray analysis of one of the diastereoisomers led to the unambiguous
assignment of each diastereoisomer. These chiral pyrrolidine analogues
should be useful as intermediates in natural product, combinatorial/
parallel synthesis, and medicinal chemistry.
Key Words: Chiral 3,4-disubstituted pyrrolidines; Meso-epoxide ring
opening; Pyrrolidine analogs.
INTRODUCTION
The presentation of substituents in both the 3- and 4-positions of the pyr-
rolidine scaffold combined with the stereochemical configuration present in
molecules 1 and 2, provide useful intermediates for natural product synthesis,
combinatorial/parallel synthesis, and medicinal chemistry.[1] However, proto-
cols for the preparation of chiral 3,4-disubstituted pyrrolidines are relatively
sparse.[1c] Methods have involved chiral starting materials, such as hydroxy-
citric acid lactones,[1d] D- and L-tetronic acids,[1g] tartaric acid,[1h] and chiral
oxazolidinones (used for 1,3-dipolar cycloadditions).[2a,2b] Disclosed herein,
we wish to report a convenient and rapid synthesis of 4-(R)-(naphthalen-2-
yloxy)-1-(1-phenyl-(S)-ethyl)-pyrrolidin-3-(R)-ol (1) and 4-(S)-(naphthalen-
2-yloxy)-1-(1-phenyl-(S)-ethyl)-pyrrolidin-3-(S)-ol (2) from inexpensive
racemic starting materials (Scheme 1).
Construction of the pyrrolidine core (A) began with a condensation
reaction between cis-1,4-dichloro-2-butene and S-(-)-a-methylbenzylamine,
an amine that served as a chiral auxillary for the generation of diastereoi-
somers. Epoxidation of A with meta-chloroperoxybenzoic acid produced
compound B in good yield.a
Epoxide ring opening with 2-naphthol in the presence of cesium carbo-
nate gave two diastereoisomers (1 and 2) in 41% yield in approximately a
1 : 1 ratio. The products were crystallized from a mixture of dichloromethane
and hexanes to provide compound 1 (56% from mixture/12% overall yield)
as a single diastereoisomer. The stereochemistry of compound 1 was
1
aCompound B was characterized by H NMR, COSY, HSQC, and NOESY (data not
shown).

Versatile Chiral Intermediates for Synthesis
4423

4424
Holsworth et al.
unambiguously assigned by x-ray[3],b and by high-resolution NMR techniques
(1H NMR, COSY, HSQC, NOESY) (Fig. 1). Compound 2 remained in the
mother liquor and was accessed by evaporation of solvent in vacuo, followed
bCrystallographic Experimental Details:
A. Crystal Data
Formula
C22H23NO2
333.41
Formula weight
Crystal dimensions (mm)
Crystal system
0.46 ꢀ 0.36 ꢀ 0.23
Monoclinic
I2 (an alternate setting of C2 [No. 5])
Space group
Unit cell parameters1
˚
a(A)
18.3026 (18)
6.8814 (7)
14.7614 (15)
103.926 (2)
1804.5 (3)
4
˚
b(A)
˚
c(A)
b(deg)
3
˚
V(A )
Z
r calcd. (g cm23
m (mm21
B. Data Collection and Refinement Conditions
)
1.227
0.078
)
Diffractometer
˚
Radiation (l[A])
Temperature (8C)
Scan type
Bruker PLATFORM/SMART 1000 CCD2
Graphite-monochromated Mo Ka (0.71073)
280
v scans (0.28) (25s exposures)
52.76
Data collection 2u limit (deg)
Total data collected
4609 (220 ꢁ h ꢁ 22, 28 ꢁ k ꢁ 8,
212 ꢁ l ꢁ 18)
Independent reflections
Number of observed
reflections (NO)
3481 (Rint ¼ 0.0241)
3140 [F2o ꢂ 2s (F2o)]
Structure solution method
Refinement method
Direct methods (SHELXS-86[3a]
Full-matrix least-squares on F2
)
(SHELXL-93[3b],3
)
Absorption correction method
Range of transmission factors
Data/restraints/parameters
Flack absolute structure
parameter[3c],4
Multi-scan (SADABS)
0.9823–0.9650
3481 [F2o ꢂ 23s(F2o)]/0/227
0.3 (11)
Goodness-of-fit (S)5
1.038 [F2o ꢂ 23s(F2o)]
Final R indices6
R1 [F2o ꢂ 2s(F2o)]
0.0356
0.0878
0.189 and 20.123 e A
wR2[F2o ꢂ 23s(F2o)]
23
˚
Largest difference peak and hole

Versatile Chiral Intermediates for Synthesis
4425
by flash column chromatography. Compound 2 was isolated in 50% yield from
the mixture and in 11% overall yield.
In summary, a practical synthesis of 4-(R)-(naphthalen-2-yloxy)-1-(1-phenyl-
(S)-ethyl)-pyrrolidin-3-(R)-ol (1) and 4-(S)-(naphthalen-2-yloxy)-1-(1-phenyl-(S)-
ethyl)-pyrrolidin-3-(S)-ol (2) from inexpensive racemic starting materials is
described. Separation of diastereoisomers by crystallization provided access to
both diastereoisomers in good yield without the employment of expensive
chiral catalysts.[4] Compounds 1 and 2 can serve as useful chiral intermediates
in natural product, combinatorial/parallel synthesis, and medicinal chemistry.
EXPERIMENTAL
All reagents were purchased from Aldrich and used without further
purification. Solvents used were of high-performance liquid chromatography
(HPLC) grade and used without further purification. Nuclear magnetic
resonance (NMR) spectra were recorded on a Varian 400 MHz spectrometer
and referenced to solvent. Melting point values are uncorrected.
1-(1-Phenyl-(S)-Ethyl)-2,5-Dihydro-1H-pyrrole (A)
To a solution of cis-1,4-dichloro-2-butene (5.0g, 40mmol) in ethyl
acetate (200mL) was added a mixture of S-(-)-a-methylbenzylamine (4.85 g,
1Obtained from least-squares refinement of 3039 reflections with 5.698 , 2u ,
52.528.
2Programs for diffractometer operation, data collection, data reduction, and
absorption correction were those supplied by Bruker.
3Refinement on Fo2 for all reflections [all of these having Fo2 ꢂ 23s(F2o)].
Weighted R-factors wR2 and all goodnesses of fit S are based on F2o; conventional
R-factors R1 are based on Fo, with Fo set to zero for negative F2o. The observed criterion
of F2o . 2s(F2o) is used only for calculating R1, and is not relevant to the choice of
reflections for refinement. R-factors based on F2o are statistically about twice as large
as those based on Fo, and R-factors based on all data will be even larger.
4The Flack parameter will refine to a value near zero if the structure is in the
correct configuration and will refine to a value near one for the inverted configuration.
In this case, the absolute structure cannot be reliably determined from the x-ray data,
but can be assigned based upon the known stereochemistry of the precursor pyrrolidin-
3,4-diol.
5S ¼ [Sw(Fo2 2 Fc2)2/(n 2 p)]1/2 (n ¼ number of data; p ¼ number of parameters
varied; w ¼ [s2(Fo2) þ (0.0387P)2 þ 0.4245P]21, where P ¼ [Max(Fo2, 0) þ 2F2c]/3).
6R1 ¼ SkFoj 2 jFck/SjFoj; wR2 ¼ [Sw(Fo2 2 F2c)2/Sw(Fo4)]1/2
.

4426
Holsworth et al.
Figure 1. X-ray of compound 1.
40mmol) and triethylamine (12 g, 120 mmol) in ethyl acetate (50 mL) at room
temperature. The resulting mixture was stirred at room temperature overnight,
and the crystallized solid was removed by filtration. After the solvent was
evaporated in vacuo, the residue was subjected to flash column chromatography
on silica gel eluting with ethyl acetate and hexanes (1 : 2) to give 4.0 g of
1-(1-phenyl-(S)-ethyl)-2,5-dihydro-1H-pyrrole (A) in 58% yield. 1H NMR
(400 MHz, CDCl3) d: 7.38–7.22 (m, 5H), 5.80 (s, 2H), 3.58–3.32 (m, 5H),
1.43–1.41 (d, J ¼ 6.0 Hz, 3H). 13C NMR (100MHz, CDCl3) d: 145.90,
128.62, 128.04, 127.44, 127.13, 65.40, 58.77, 23.84. MS: m/z 173.9 [M þ 1].
3-(1-Phenyl-(S)-Ethyl)-6-oxa-3-aza-Bicyclo[3.1.0]Hexane (B)
To a solution of compound A (4.0 g, 23 mmol) in a mixture of H2SO4
(2.5 g, 27.8 mmol), H2O (3 mL), and acetone (50 mL) was added m-CPBA
portion-wise at 08C with stirring. After addition, the resulting mixture was
stirred at room temperature overnight, and then the solvent was removed
under reduced pressure. The residue was treated with 1N NaOH and
extracted with dichloromethane. The organic layer was dried over Na2SO4

Versatile Chiral Intermediates for Synthesis
4427
and evaporated in vacuo. The residue was subjected to flash column chromato-
graphy on silica gel eluting with ethyl acetate and hexanes (1 : 3) to give 2.5 g
of 3-(1-phenyl-(S)-ethyl)-6-oxa-3-aza-bicyclo[3.1.0]hexane (B) in 57% yield.
HPLC: 90.2%. 1H NMR (400 MHz, CDCl3) d: 7.32–7.20 (m, 5H), 3.60–3.59
(m, 1H), 3.50–3.49 (m, 1H), 3.41–3.35 (m, 2H), 2.98 (d, J ¼ 11.7 Hz, 1H),
2.46 (dd, J ¼ 1.0 Hz, J ¼ 11.2 Hz, 1H), 2.21 (dd, J ¼ 1.5 Hz, J ¼ 11.7 Hz,
1H), 1.37–1.36 (d, J ¼ 6.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) d:
144.74, 128.57, 127.52, 127.33, 64.92, 55.83, 52.73, 22.96. MS: m/z 190.1
[M þ 1]. [a]24.7 ¼ 222.78 (c ¼ 0.5, CH3OH).
4-(R)-(Naphthalen-2-yloxy)-1-(1-Phenyl-(S)-Ethyl)-
Pyrrolidin-3-(R)-ol (1) and 4-(S)-(Naphthalen-2-yloxy)-1-
(1-Phenyl-(S)-Ethyl)-Pyrrolidin-3-(S)-ol (2)
A mixture of compound B (2.5 g, 13 mmol), 2-naphthol (3.8 g, 26 mmol),
Cs2CO3 (10.8 g, 33 mmol), and 18-crown-6 (25 mg) in ethanol were refluxed
overnight. The solvent was removed under reduced pressure. The residue was
dissolved in ethyl acetate, washed with 1N NaOH, brine, and H2O. The
organic layer was dried over Na2SO4 and concentrated in vacuo. The residue
was subjected to flash column chromatography on silica gel eluting with
ethyl acetate and hexanes (1 : 3) to give 1.8 g of compounds 1 (Chiral HPLC:
44.89%, Rt ¼ 7.291 min) and 2 (Chiral HPLC: 54.84%, Rt ¼ 6.8 min) as a
mixture in 41% yield. HPLC: 99.93%. (Chiral HPLC method: isopropyl
alcohol/hexanes (20 : 80): Chiral PAK AD 0.46cmu ꢀ 25cm).
4-(R)-(Naphthalen-2-yloxy)-1-(1-Phenyl-(S)-Ethyl)-
Pyrrolidin-3-(R)-ol (1)
1.8 g of compounds 1 and 2 were dissolved in dichloromethane (ꢀ2 mL)
and added to hexanes (200 mL). The resulting solution was allowed to stand
at room temperature for 2 days. Compound 1 (0.45 g) crystallized out prefer-
entially [56% of 0.81 g (calcd.)]. (Chiral HPLC: 93%, Rt ¼ 7.326 min)
Mp ¼ 157–1588C; 1H NMR (400 MHz, CDCl3) d 7.77–7.73 (m, 3H),
7.46–7.12 (m, 9H), 4.79–4.76 (m, 1H), 4.28 (br s, 1H), 3.58 (dd, J ¼ 6.8 Hz,
J ¼ 10.7Hz, 1H), 3.39 (q, J ¼ 6.8 Hz, 1H), 2.72 (dd, J ¼ 4.9 Hz, J ¼
10.2Hz, 1H), 2.70–2.59 (m, 1H), 2.53 (dd, J ¼ 3.9 Hz, J ¼ 10.7Hz, 1H),
2.35 (s, 1H), 1.43–1.42 (d, J ¼ 6.3 Hz, 3H). 13C NMR (100MHz, CDCl3)
d 155.65, 144.60, 134.67, 129.81, 129.22, 128.74, 127.82, 127.43, 127.35,
127.14, 126.64, 124.01, 119.36, 108.19, 83.33, 75.59, 65.05, 59.35, 57.37,
22.79. MS: m/z 334.1 [M þ 1]. [a]20.1 ¼ 268.58 (c ¼ 0.1, CH3OH). Anal.

4428
Holsworth et al.
calcd. for C22H23NO2 (%): C, 79.25; H, 6.95; N, 4.20. Found: C, 78.58; H, 6.82;
N, 4.13.
4-(S)-(Naphthalen-2-yloxy)-1-(1-Phenyl-(S)-Ethyl)-
Pyrrolidin-3-(S)-ol (2)
The mother liquor was evaporated in vacuo and subjected to flash
column chromatography [ethyl acetate/hexanes (1 : 10 to 1 : 5)] to afford
1
0.5 g of compound 2 [50% of 1 g (calcd.)]. Mp ¼ 111–1128C; H NMR
(400 MHz, CDCl3) d 7.74–7.70 (m, 3H), 7.43–7.25 (m, 7H), 7.14–7.09 (m,
2H), 4.69 (t, J ¼ 4.9 Hz, 1H), 4.33 (br s, 1H), 3.38 (q, J ¼ 7.2 Hz, 1H), 3.20
(dd, J ¼ 6.8 Hz, J ¼ 10.7 Hz, 1H), 2.91 (d, J ¼ 9.6 Hz, 1H), 2.77 (dd,
J ¼ 4.9 Hz, J ¼ 9.8 Hz, 2H), 2.52 (dd, J ¼ 3.9 Hz, J ¼ 10.7 Hz, 1H), 1.40
(d, J ¼ 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) d 155.65, 144.50, 134.68,
129.79, 129.23, 128.67, 127.80, 127.47, 127.39, 127.13, 126.62, 124.00,
119.32, 108.26, 83.23, 75.74, 65.06, 58.86, 57.89, 22.72. MS: m/z 334.1
[M þ 1]. [a]25.1 ¼ þ21.28 (c ¼ 0.5, CH3OH). Anal. calcd. for C22H23NO2
(%): C, 79.25; H, 6.95; N, 4.20. Found: C, 78.77; H, 7.06; N, 4.18.
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Received in the USA August 4, 2004