Highly efficient, enantioselective syntheses of (S)-(+)- and (R)-(-)-dapoxetine starting with 3-phenyl-1-propanol

Article abstract of DOI:10.1021/jo902176s

(Chemical Equation Presented) A highly efficient, enantioselective sequence has been developed for the synthesis of (S)- and (R)-dapoxetine. The pathways involve the intermediacy of the 6-membered-ring sulfamate esters 4, which were generated by Du Bois asymmetric C-Hamination reactions of the prochiral sulfamate 3, catalyzed by the chiral dirhodium(II) complexes. During the course of our research, the absolute configuration of the enantiomer of 4-pheny[1,2,3]oxathiazinane 2,2-dioxide (4r), prepared by the Du Bois asymmetric C-H amination reaction of 3 and the Rh₂(S-nap)4 catalyst, is determined to be R and not S as was originally reported.

Full text of DOI:10.1021/jo902176s

pubs.acs.org/joc
threatening condition, along with erectile dysfunction it is one
Highly Efficient, Enantioselective Syntheses of
(S )-(þ)- and (R)-(-)-Dapoxetine Starting with
3-Phenyl-1-propanol
of the most common male sexual disorders, which could cause
elevated levels of anxiety and have a negative impact on the
quality of an individual’s life and that of their partner. (S)-(þ)-
Dapoxetine hydrochloride (1; (S)-(þ)-N,N-dimethyl-[3-(naph-
thalen-1-yloxy)-1-phenylpropyl]amine; Priligy),3
a potent
Soyeong Kang and Hyeon-Kyu Lee*
SSRI with a short half-life, has been developed specifically
for the treatment of PE. This substance was first launched in
2009 in Europe where it is used for the oral, on-demand
treatment of PE in men between 18 and 64 years of age.
Drug Discovery Division, Korea Research Institute of
Chemical Technology, P.O. Box 107, Yuseong, Daejeon
305-600, Korea, and Medicinal and Pharmaceutical
Chemistry Major, University of Science and Technology,
113 Gwahango, Yuseong, Daejeon 305-333, Korea
leehk@krict.re.kr
Received October 9, 2009
A highly efficient, enantioselective sequence has been devel-
oped for the synthesis of (S)- and (R)-dapoxetine. The
pathways involve the intermediacy of the 6-membered-ring
sulfamate esters 4, which were generated by Du Bois asym-
metric C-H amination reactions of the prochiral sulfamate
3, catalyzed by the chiral dirhodium(II) complexes. During
the course of our research, the absolute configuration of the
enantiomer of 4-pheny[1,2,3]oxathiazinane 2,2-dioxide (4r),
prepared by the Du Bois asymmetric C-H amination
reaction of 3 and the Rh2(S-nap)4 catalyst, is determined
to be R and not S as was originally reported.
FIGURE 1. Examples of selective serotonin reuptake inhibitors
(SSRIs).
In the context of drug development, selective syntheses of
individual enantiomers of targets are extremely important since
the antipodes usually display different pharmacological and/or
physiological properties.4 For example, (S)-dapoxetine is 3.5
times more potent as an SSRI than is (R)-dapoxetine.5 Pre-
viously (S)-dapoxetine was produced from a racemic mixture
of dapoxetine by means of tartaric acid promoted chiral
resolution of a racemic mixture. An alternative synthesis of
(S)-dapoxetine, starting from (R)-1-phenyl-1,3-propandiol and
selective displacement of the secondary alcohol moiety with
dimethylamine, was described.6 Another route for the prepara-
tion of (S)-(þ)-dapoxetine, beginning with chiral 1,3-amino
alcohols that are obtained by enzyme-catalyzed resolution of
racemic 1,3-amino alcohols, has also been reported.7 However,
each of the reported methods for the synthesis of (S)-(þ)-
dapoxetine have the intrinsic disadvantage that the undesired
(R)-enantiomer is discarded or recycled after racemization.
Consequently, the development of an efficient and enantiose-
lective synthesis of (S)-dapoxetine is highly desirable.
Selective serotonin reuptake inhibitors (SSRIs) are a class of
compounds typically used for the treatment of depression and
anxiety disorder.1 Among these substances, Fluoxetine
(Prozac),1c,1d Paroxetine (Paxil),1e and Sertraline (Zoloft)1f
are widely prescribed for depression and other psychiatric
disorders, such as bulimia and anxiety (Figure 1). Recently,
it has been suggested that premature ejaculation (PE) might be
associated with perturbation of serotonergic 5-hydroxytrypta-
mine (5-HT) neurotransmission.2 Although PE is a non-life-
Only a few strategies are currently available for the
asymmetric synthesis of (S)-(þ)-dapoxetine. The first
(1) (a) Katzman, M. A. CNS Drug 2009, 23, 103. (b) Preskorn, S. H.; Ross,
R.; Stanga, C. Y. In Selective serotonin reuptake inhibitor. Antidepressants:
Past, Present, and Future; Preskorn, S. H., Ross, R., Stanga, C. Y., Feighner, J. P.,
Eds.; Springer-Velarg: Berlin, Germany, 2004, 242. (c) Wong, D. T.; Perry, K. W.;
Bymaster, F. P. Nat. Rev. Drug Discovery 2005, 4, 764. (d) Wong, D. T.;
Bymaster, F. P.; Engleman, E. A. Life Sci. 1995, 57, 411. (e) Anderson, I. M.
J. Affective Disord. 2000, 58, 19. (f ) Cipriani, A.; Furukawa, T. A.; Salanti, G.;
Geddes, J. R.; Higgins, J. P. T.; Churchill, R.; Watanabe, N.; Nakagawa, A.;
Omori, I. M.; McGuire, H.; Tansella, M.; Barbui, C. Lancet 2009, 373, 746.
(2) Kendirci, M.; Salem, E.; Hellstrom, W. J. G. Ther. Clin. Risk Manag.
2007, 3, 277.
(3) Hellstrom, W. J. G. Neuropsychiatr. Dis. Treat. 2009, 5, 37.
(4) Agranat, I.; Caner, H.; Caldwell, J. Nat. Rev. Drug Discovery 2002, 1,
753.
(5) Robertson, D. W.; Wong, D. T.; Thompson, D. C. U.S. Patent
5 135 947, 1992.
(6) Sorbera, L. A.; Castaner, J.; Castaner, R. M. Drugs Future 2004, 29,
1201.
(7) (a) Torre, O.; Gotor-Fernadez, V.; Gotor, V. Tetrahedron: Asymmetry
2006, 17, 860. (b) Fadnavis, N. W.; Radhika, K. R.; Vedamayee Devi, A.
Tetrahedron: Asymmetry 2006, 17, 240.
DOI: 10.1021/jo902176s
r
Published on Web 12/03/2009
J. Org. Chem. 2010, 75, 237–240 237
2009 American Chemical Society

Kang and Lee
JOCNote
asymmetric synthesis of (S)-(þ)-dapoxetine hydrochloride
and its 14C-isotopomer, beginning with (R)-N-Boc-phenyl-
glycine, was described by a research group at Lilly.8 Re-
cently, stereoselective syntheses of (S)-(þ)-dapoxetine from
trans-methyl cinnamate9 and cinnamyl alcohol,10 employ-
ing respective Sharpless asymmetric dihydroxylation and
epoxidation processes in key steps, were developed. Unfor-
tunately, both of these routes are long (9 to 10 steps) and they
require a radical deoxygenation step to remove the undesired
hydroxyl group and a non-atom-economic Mitsunobu reac-
tion to introduce the 1-naphthol moiety. A formal synthe-
sis of (S)-(þ)-dapoxetine from enantiopure 3-hydroxy-
azetidine-2-one was described in a recent paper.11 However,
this route also required radical deoxygenation and Mit-
sunobu reaction steps.
With the cyclic sulfamate ester 4r in hand, completion of
the route to dapoxetine (1r) was straightforward (Scheme 1).
Methylation of the supposed (S)-sulfamate ester 4r with
CH3I affords the cyclic N-methyl-sulfamate ester 5r (83%
yield, 91.1% ee). Subsequent reaction of 5r with 1-naphthol
in the presence of base smoothly produced N-methyl-
[3-(naphthalen-1-yloxy)-1-phenylpropyl]amine (6r) in good
yield (87% yield, 92.5% ee). Finally, reductive amination of
6r, under Eschweiler-Clarke conditions9 with formaldehyde
and formic acid as the hydrogen source, gave dapoxetine (1r)
in good yield (79%) and a 91.2% ee (determined by using
chiral HPLC). 1H and 13C NMR spectroscopic and HRMS
data for the synthetic dapoxetine matched those previously
reported for this substance. However, surprisingly the sign
of the optical rotation of the synthetic dapoxetine ([R]28
D
As part of ongoing studies aimed at the synthesis
of antidepressant SSRIs, we have uncovered a highly effi-
cient and enantioselective syntheses of the (S)-(þ)- and
(R)-(-)-enantiomers of dapoxetine starting with the readily
available 3-phenyl-1-propanol (2). The routes, described
below, involve intermediate 6-membered-ring sulfamate
esters 4, which were prepared by chiral dirhodium(II) com-
plex catalyzed Du Bois asymmetric C-H amination reac-
tions of a prochiral sulfamate (3).12a
-67.0 (c 0.3, CHCl3)) was opposite to the reported value
([R]25D þ64.2 (c 0.3, CHCl3),9 þ61.7 (c 0.3, CHCl3),10 þ62.5
(c 0.3, CHCl3)7a). Consequently, we concluded that we had
prepared (R)-(-)-dapoxetine rather than its (S)-(þ)-enan-
tiomer. Since it was virtually impossible that the configura-
tion of the chiral carbon atom bearing the amine moiety had
changed during the execution of the sequence shown in
Scheme 1, we doubted the assignment of absolute configura-
tion to the cyclic sulfamate ester 4r, which was proposed
to have the S-configuration when prepared with the Rh2-
(S-nap)4 Du Bois catalyst.12a
Recently, Du Bois and his co-workers described a novel
method for the enantioselctive synthesis of the cyclic sul-
famate ester 4 by using an asymmetric C-H amination
reaction of the prochiral sulfamate ester 3, catalyzed by a
chiral valerolactam-derived, dirhodium(II) complex.12a The
6-membered-ring oxathiazinanes 4, possessing both a chiral
carbon that bears an amine moiety and cyclic sulfamidate
group, which is reactive with various nucleophiles, are
extremely valuable precursors of 1,3-functionalized amine
derivatives including 1,3-amino alcohols and dapoxetine
derivatives. Consequently, we employed the Du Bois methodo-
logy to prepare the requisite sulfamate ester 4 by using the
Rh2(S-nap)4-catalyzed C-H amination reaction of 3. This
process produced the alleged (S)-sulfamate ester 4r in a 80%
yield and 92.6% ee. However, contrary to the original
To make the correct absolute configuration assignment to 4r,
we prepared both enantiomers 4s and 4r starting with 3 and the
enantiomeric Rh2(S-nap)4 and Rh2(R-nap)4 catalysts and em-
ploying essentially the same reaction conditions described by
Du Bois and his co-workers.12a The unknown Rh2(R-nap)4
catalyst was generated by reaction between Rh2(OAc)4 and
(R)-3-tosylaminovalerolactam, which was obtained from un-
natural D-(-)-ornithine hydrochloride in a manner that is
similar to the procedure employed for the preparation of
Rh2(S-nap)4 catalyst from L-(þ)-ornithine hydrochloride by
Du Bois and his co-workers.12a,15 The synthesized Rh2(R-nap)4
1
catalyst has essentially the same H NMR spectroscopic and
optical properties of Rh2(S-nap)4 except for the sign of the
optical rotation ([R]29D -70.5 (c 0.2, CHCl3) for Rh2(R-nap)4
and [R]27D þ71.5 (c 0.2, CHCl3) for Rh2(S-nap)4). Treatment
of the prochiral sulfamate ester 3 with PhIdOandRh2(R-nap)4
catalyst smoothly afforded the antipodal cyclic sulfamate ester
proposal,12a the absolute configuration of 4r ([R]27 þ6.14
D
(c 1.0, CHCl3)) was shown by us to be R (vide infra).
SCHEME 1. Synthetic Process to Dapoxetine (1) from
3-Phenyl-1-propanol (2)a
4s ([R]27 -6.0 (c 1.0, CHCl3), 85% yield, 91.7% ee). The
D
physical data of 4s, generated from 3 by using the Rh2(R-nap)4
catalyst, are essentially the same as those of 4r. However, the
sign of the optical rotation and the chiral HPLC column
(Chiralcel OD-H, 8% isopropanol/hexane) eluting order of
(8) Wheeler, W. J.; O’Bannon, D. D. J. Labelled Compd. Radiopharm.
1992, XXXI, 305.
(9) Siddiqui, S. A.; Srinivasan, K. V. Tetrahedron: Asymmetry 2007, 18,
2099.
(10) Venkatesan, K.; Srinivasan, K. V. ARKIVOC 2008, xvi, 302.
(11) Chincholkar, P. M.; Kale, A. S.; Gumaste, V. K.; Deshmukh,
A. R. A. S. Tetrahedron 2009, 65, 2605.
(12) (a) Zalatan, D. N.; Du Bois, J. J. Am. Chem. Soc. 2008, 130, 9220. (b)
Espino, C. G.; Wehn, P. M.; Chow, J.; Du Bois, J. J. Am. Chem. Soc. 2001,
123, 6935.
(13) (S)-3-Amino-3-phenylpropan-1-ol (98% ee, 95%) was purchased
from Acros Organics (http://www.acros.com), Catalog No. 36217.
(14) Tse, M. K.; Bhor, S.; Klawonn, M.; Anilkumar, G.; Jiao, H.; Dobler,
C.; Spannenberg, A.; Magerlein, W.; Hugl, H.; Beller, M. Chem.;Eur. J.
2006, 12, 1855.
aReagents and conditinos: (a) ClSO2NH2, DMA, 0 °C to rt; (b) 2 mol %
Rh2(S-nap)4 or Rh2(R-nap)4, PhIdO, 4 A MS, CH2Cl2, rt; (c) CH3I,
K2CO3, cat. TBAI, DMF, 0 °C to rt; (d) NaH, 1-naphthol, DMF then
5 M HCl, rt; (e) HCO2H, HCOH, reflux.
˚
(15) Maguire, M. P.; Feldman, P. L.; Rapoport, H. J. Org. Chem. 1990,
55, 948.
238 J. Org. Chem. Vol. 75, No. 1, 2010

Kang and Lee
JOCNote
the 4s and 4r are opposite each other. Therefore, 4s and 4r
prepared from 3 by using the respective Rh2(R-nap)4 and
Rh2(S-nap)4 catalysts are enantiomers.
The absolute configuration of the enantiomer of 4s synthe-
sized with Rh2(R-nap)4 was determined by converting it to
commercially available (S)-3-amino-3-phenylpropan-1-ol
(9)13 by the route shown in Scheme 2.
this substance. The overall sequence for the synthesis of
(S)-(þ)-dapoxetine (1s) is highly efficient taking place in a
greater than 33% overall yield over five synthetic steps beginning
with readily available 3-phenyl-1-propanol (2).
In conclusion, a highly efficient (33% and 34% overall
yields and 5 steps) and enantioselective strategy has been
developed for the synthesis of (S)-(þ)- and (R)-(-)-dapoxe-
tine starting from 3-phenyl-1-propanol (2). The routes
proceeded through the intermediacy of 6-membered-ring
sulfamate esters 4s and 4r, which were prepared by Du Bois
asymmetric C-H amination reactions of prochiral sulfa-
mate 3 catalyzed by the respective chiral valerolactam-
derived dirhodium(II) complexes, Rh2(R-nap)4 or Rh2-
(S-nap)4. Subsequent N-methylation reactions of 4s and
4r, followed by nucleophilic substitution reactions of
the resulting cyclic sulfamate esters 5 with 1-naphthol and
final N-methylations of 6, smoothly afforded (S)-(þ)- or
(R)-(-)-dapoxetine, respectively.
During the course of our research, the absolute configura-
tion of the enantiomer of 4-pheny[1,2,3]oxathiazinane
2,2-dioxide (4r), prepared by Du Bois asymmetric C-H
amination reaction of the sulfamate ester 3 and the Rh2-
(S-nap)4 catalyst, was determined to be R and not S as was
originally reported. The correct absolute configuration
assignment was made by comparing the optical properties
of 3-amino-3-phenylpropan-1-ol (9), prepared from 4s, with
those of the commercially available substance. In addition,
the absolute configuration of 4r was determined by using
X-ray crystallographic analysis.
SCHEME 2. Conversion of 4s to the Known 1,3-Amino Alcohol 9a
aReagents and conditions: (a) NaOtBu, Cbz-Cl, DME; (b) CH3CN/H2O,
75 °C then 1 N HCl, rt; (c) H2/Pd-C, EtOAc.
As expected, the optical and spectroscopic properties of 9
([R]28D -20.4 (c 0.44, CHCl3), 93% ee), generated from this
enantiomer of 4s, are essentially identical with those of
commercial (S)-913 ([R]27 -22.0 (c 0.40, CHCl3), 98% ee)
D
as well as those reported originally14 for the latter substance
([R]27 -22.5 (c 0.5, CH2Cl2), 100% ee). These findings
D
enable us to assign the S configuration to the major enantio-
mer of 4s produced by C-H amination catalyzed by Rh2-
(R-nap)4 and the R configuration to the antipode 4r pro-
duced by using the Rh2(S-nap)4 catalyst (Scheme 3).
SCHEME 3. (R)-4 and (S)-4 from Du Bois Asymmetric C-H
Amination Reaction of 3 with Respective Rh2(S-nap)4 and
Rh2(R-nap)4 Catalysts
Experimental Section
(S)-4-Phenyl[1,2,3]oxathiazinane 2,2-Dioxide: (S)-4. A mix-
ture of sulfamate 3 (200 mg, 0.9 mmol), Rh2(R-nap)4 (24 mg,
˚
0.02 mmol), and powdered 4 A molecular sieves (500 mg) was
suspended in dry dichloromethane (2.0 mL). A single portion of
PhIdO (240 mg, 1.1 mmol) was then added and the reaction
mixture was stirred at room temperature for 2 h. The reaction
mixture was loaded directly onto silica gel and purified by flash
chromatography (n-hexane:ethyl acetate = 4:1) to afford the
desired product (168 mg, 85%) as a white crystal: 91.7% ee
(Chiralcel OD-H, 8% isopropanol/hexanes, 1.0 mL/min,
The absolute configuration of 4-phenyl[1,2,3]oxathiazinane
2,2-dioxide (4r) was confirmed to be R by X-ray crystallo-
graphic analysis16 (see the Supporting Information).
210 nm, tr(major) = 27.9 min, tr(minor) = 33.9 min); [R]36
D
These findings demonstrate that the cyclic (S)-sulfamate ester
4s was required for an (S)-(þ)-dapoxetine synthesis following
the plan described in Scheme 1. With the (S)-sulfamate ester 4s,
which was obtained from the prochiral sulfamate ester 3 with
PhIdO and Rh2(R-nap)4 catalyst, the route to (S)-dapoxetine
(1s) was straightforward. Methylation of 4s with CH3I afforded
the N-methyl cyclic sulfamate ester 5s (81% yield, 92.0% ee) and
subsequent reaction with 1-naphthol in the presence of NaH in
DMF smoothly generated N-methyl-[3-(naphthalen-1-yloxy)-
1-phenylpropyl]amine (6s) (84% yield, 91.2% ee). Finally,
reductive amination of 6s under Eschweiler-Clarke conditions
gave (S)-dapoxetine 1s (75% yield, 91.8% ee). Reductive amina-
tion of 6s with Na(CN)BH3 and formaldehyde also led to
efficient production of 1s. 1H and 13C NMR spectroscopic data
of synthetic 1s, including the magnitude and sign of the optical
rotation ([R]28D þ63.2 (c 0.3, CHCl3), lit. [R]25D þ64.2 (c 0.3,
CHCl3),9 þ61.7 (c 0.3, CHCl3),10 þ62.5 (c 0.3, CHCl3)7a), were
in perfect agreement with those previously reported for
-6.0 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.33-7.44
(m, 5H), 4.82-4.90 (m, 2H), 4.62-4.68 (m, 1H), 4.40 (br d, 1H,
J = 9.2 Hz), 2.18-2.33 (m, 1H), 1.98-2.05 (m, 1H); 13C NMR
(75 MHz, CDCl3) δ 138.0, 129.2, 128.9, 126.3, 71.9, 59.0, 30.2;
HRMS (EI) m/z calcd for C9H11NO3S 213.0460, found
213.0462.
(S)-3-Methyl-4-phenyl[1,2,3]oxathiazinane 2,2-Dioxide: (S)-5.
To a solution of (S)-4 (154 mg, 0.72 mmol) in DMF (3 mL) were
added CH3I (93 μL, 1.5 mmol), K2CO3 (122 mg, 0.88 mmol), and a
catalytic amount of n-Bu4NI at 0 °C and the mixture was stirred at
rt for 6 h. The reaction mixture was diluted with ethyl acetate (30
mL) and H2O (15 mL). The biphasic solution was extracted with
ethyl acetate (3 times). The combined organic layer was washed
successively with water and brine, dried over anhydrous MgSO4,
and concentrated in vacuo to give a residue that was subjected to
flash chromatography on silica gel (n-hexane:ethyl acetate = 10:1)
to afford the desired product (81%) as a white crystal: 92.0%
ee (Chiralcel OD-H, 10% isopropanol/hexanes, 1.2 mL/min,
210 nm, tr(major) = 18.5 min, tr(minor) = 15.6 min); [R]28
D
1
-3.0 (c 0.3, CHCl3); H NMR (500 MHz, CDCl3) δ 7.35-7.41
(m, 5H), 4.76-4.85 (m, 2H), 4.55-4.58 (m, 1H), 2.46-2.55 (m,
(16) (a) Thompson, A. L.; Watkin, D. J. Tetrahedron: Asymmetry 2009,
20, 712. (b) Flack, H. D.; Bernardinelli, G. Chirality 2008, 20, 681.
1H),2.49(s, 3H),1.88-1.91 (m, 1H); 13C NMR (125 MHz, CDCl3)
J. Org. Chem. Vol. 75, No. 1, 2010 239

Kang and Lee
JOCNote
δ 137.5, 129.3, 129.0, 127.6, 71.7, 64.3, 32.6, 28.1; HRMS (EI) m/z
calcd for C10H13NO3S 227.0616, found 227.0611.
(100 μL, 1.0 mmol) and the reaction mixture was refluxed for 8 h.
After this time the solution was acidified with concd HCl until pH 1
and basified with 4 N NaOH. The reaction mixture was diluted with
ethyl acetate and washed with aqueous NaHCO3 solution. The
organic phase was separated and dried over MgSO4. After evapora-
tion of solvent the crude residue was purified by flash chromato-
graphy (n-hexane:ethyl acetate = 1:3) to afford the desired product
(42.5 mg, 75%) as a colorless oil: 91.8% ee (Chiralcel OD-H, 2%
isopropanol/hexanes, 0.7 mL/min, 210 nm, tr(major) = 10.1 min,
tr(minor) = 8.9 min); [R]28D þ63.2 (c 0.3, CHCl3); 1H NMR (500
MHz, CDCl3) δ 8.26-8.28 (m, 1H), 7.79-7.81 (m, 1H), 7.28-7.52
(m,10H), 6.67 (d, 1H, J = 7.5 Hz), 4.07-4.12 (m, 1H), 3.91-3.95
(m, 1H), 3.62-3.65 (m, 1H), 2.63-2.70 (m, 1H), 2.26-2.34 (m, 1H),
2.28 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 154.8, 139.7, 134.7,
128.8, 128.4, 127.6, 127.5, 126.5, 126.1, 125.9, 125.3, 122.2, 120.2,
(S)-Methyl[3-(naphthalen-1-yloxy)-1-phenylpropyl]amine: (S)-6.
The mixture of 1-naphtol (140 mg, 0.97 mmol) and NaH (42 mg,
0.97 mmol) in DMF (1 mL) was stirred at rt for 10 min. A solution
of (S)-5 (111 mg, 0.49 mmol) in DMF (1 mL) was added to a
reaction mixture and stirred at rt for 1 h. HCl (1 M, 1.5 mL,
5 equiv) was added and the mixture was stirred at rt for 2 h, then
basified with 2 M NaOH. The reaction mixture was diluted with
ethyl acetate (10 mL) and H2O (5 mL). The biphasic solution was
extracted with ethyl acetate (3 times). The combined organic layer
was washed successively with water and brine, and dried over
anhydrous MgSO4, and concentrated in vacuo to give a residue
that was subjected to flash chromatography on silica gel
(dichloromethane:methanol = 10:1) to afford the desired product
(120 mg, 84%) as an orange oil: 91.2% ee (Chiralcel OD-H, 2%
isopropanol/hexanes, 1.2 mL/min, 210 nm, tr(major) = 12.6 min,
0
104.8, 67.9 (1C, C3), 65.8 (1C, C1), 43.0 (2C, C4 þ C4 ), 33.2(1C, C2);
HRMS (EI) m/z calcd for C21H23NO 305.1780, found 305.1765.
1
tr(minor) = 10.0 min); [R]28 þ60.3 (c 0.3, CHCl3); H NMR
(500 MHz, CDCl3) δ 8.24-D8.26 (m, 1H), 7.78-7.80 (m, 1H),
7.46-7.51 (m, 2H), 7.39-7.41 (m, 1H), 7.25-7.34 (m, 7H), 6.70
(d, 1H, J = 7.5 Hz), 4.13-4.17 (m, 1H), 3.97-4.02 (m, 1H),
3.90-3.92 (m, 1H), 2.41-2.47 (m, 1H), 2.33 (s, 3H), 2.17-2.2 3
(m, 1H); 13C NMR (125 MHz, CDCl3) δ 154.6, 134.6, 128.8,
127.59, 127.55, 127.5, 126.5, 126.1, 126.0, 125.8, 125.3, 122.1, 120.3,
104.7, 65.5, 62.8, 37.2, 34.4; HRMS (EI) m/z calcd for C20H21NO
291.1623, found 291.1622.
Acknowledgment. We thank the Center for Biological
Modulators of the 21st Century Frontier R&D program
(CBM31-A1200-01-00-00) and the Korea Research Institute
of Chemical Technology for financial support.
Supporting Information Available: Characterization data
for all new compounds including copies of 1H, 13C NMR spectra
and chromatograms for the determination of enantiomeric
excess of all chiral compounds on chiral HPLC, and X-ray
crystallography data of 4r with a cif file. This material is
available free of charge via the Internet at http://pubs.acs.org.
(S)-Dimethyl[3-(naphthalen-1-yloxy)-1-phenylpropyl]amine: (S)-1.
To a solution of (S)-6 (54 mg, 0.19 mmol) in formic acid (38 μL,
1.0 mmol) was added a 30% aqueous solution of formaldehyde
240 J. Org. Chem. Vol. 75, No. 1, 2010