N-isopropylsulfinylimines as useful intermediates in the synthesis of chiral amines: Expeditive asymmetric synthesis of the calcimimetic (+)-NPS R-568

Article abstract of DOI:10.1021/jo7018703

(Chemical Equation Presented) An efficient and high-yielding approach for the asymmetric synthesis of calcimimetic (+)-NPS R-568 (1) has been developed. The key step of the synthesis is the highly diastereoselective addition of methyl Grignard to the (S

Full text of DOI:10.1021/jo7018703

breakthroughs in this endeavor has been the development of
efficient methods for the synthesis of sulfinamides and the
corresponding sulfinylimines. Accordingly, the exceptional
behavior of the chiral sulfinyl group in sulfinylimines, as
activator, chiral controller, and finally as useful protective group,
makes the sulfinamides an extremely versatile chiral intermedi-
ate in the construction of chiral amines.3 Up to now, the most
widely used sulfinylimines are the p-toluenesulfinylimines I
pioneered by Davis4 and the tert-butylsulfinylimine II, devel-
oped by Ellman.5 While both synthons have been successfully
used in the synthesis of a large number of biologically significant
amine-containing compounds, the use of the p-toluenesulfinyl
group as an imine substituent presents some drawbacks.
Accordingly, of interest to this work, the addition of small
organometallic reagents such as methylmagnesium bromide
were reported to attack the sulfur atom, while stabilized
organometallic reagents, such as benzylmagnesium chloride,
were reported to add only with moderate selectivity.
N-Isopropylsulfinylimines as Useful Intermediates
in the Synthesis of Chiral Amines: Expeditive
Asymmetric Synthesis of the Calcimimetic
(+)-NPS R-568
Inmaculada Ferna´ndez,*,† Victoria Valdivia,‡ and
Noureddine Khiar*,‡
Departamento de Qu´ımica Orga´nica y Farmace´utica, Facultad
de Farmacia, UniVersidad de SeVilla, c/ Prof. Garcia
Gonzalez, 2, 41012 SeVilla, Spain, and Instituto de
InVestigaciones Qu´ımicas, CSIC-UniVersidad de SeVilla, c/
Ame´rico Vespucio, s/n, Isla de la Cartuja, 41092 SeVilla, Spain
inmaff@us.es
ReceiVed September 7, 2007
FIGURE 1. N-Sulfinylimines.
On the other hand, while the use of the most sterically
hindered tert-butylsulfinyl group as imine substituent solves
most of these drawbacks, there are cases where the reaction
became exceedingly slow if not inhibited (vide infra).6 We have
recently introduced the lower molecular weight, highly reactive
isopropylsulfinyl derivative III as a new imine substituent, with
improved diastereoselectivity and reactivity (Figure 1). Accord-
ingly, in a previous work we have shown that the isopropyl-
sulfinyl group do confer better enantiomeric discrimination than
the p-tolylsulfinyl group and higher chemical reactivity with
equal or even better enantiomeric discrimination than the most
popular tert-butylsulfinyl group in two important reactions, the
Corey-Chaykovsky reaction of chiral sulfinylimine and the
organocatalytic allylation of acyl hydrazones with ferrocenyl-
sulfinyl derivatives.7 In the present work, we report on a highly
diastereoselective addition of methylmagnesium bromide to
isopropylsulfinylimime. The synthetic value of this approxima-
tion is further demonstrated by the enantioselective synthesis
of the potent calcimimetic (R)-(+)-NPS R-568 (1).
An efficient and high-yielding approach for the asymmetric
synthesis of calcimimetic (+)-NPS R-568 (1) has been
developed. The key step of the synthesis is the highly
diastereoselective addition of methyl Grignard to the (SS,E)-
N-(3-methoxybenzylidene)-2-propanesulfinamide [5(S)], which
afforded a single diastereoisomer in high yield in short
reaction time
The so-called chiral market is in continuous increase as a
consequence of the significance of enantiopure compounds in
important areas such as agriculture, fragrance, and medicine.
As illustrative data, more than 50% of the drugs currently in
the market are enantiopure compounds, and the main biologi-
cally significant molecules needed for basic biomedical studies,
possesses at least one chiral center.1 Among the biologically
significant chiral compounds, those having an amine function
occupy a prominent place, as they actually account for 75% of
the total of drugs or drug candidates. It is thus not surprising
that the development of effective approximations for the
synthesis of amines with an R-chiral center has been a standing
area of interest in the last decades.2-6 One of the major
Calcimimetics are small organic molecules which activate
specifically the calcium-sensing receptor (CaSR), in the same
way as extracellular Ca2+, and as such have great potential as
innovative medical approach for the treatment of primary and
(3) For a recent review, see: Morton, D.; Stockman, R. A. Tetrahedron
2006, 62, 8869.
† Departamento de Qu´ımica Orga´nica y Farmace´utica.
‡ Instituto de Investigaciones Qu´ımicas.
(1) (a) Stinson, S. C. Chem. Eng. News 2001, 79, 34. (b) Rouhi, A. M.
(4) (a) Davis, F. A.; Zhou, P.; Chen, B. C. Chem. Soc. ReV. 1998, 27,
13. (b) Davis, F. A. J. Org. Chem. 2006, 71, 8993.
(5) (a) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002,
35, 984. (b) Ellman, J. A. Pure. Appl. Chem. 2003, 75, 39.
(6) Garc´ıa-Ruano, J. L.; Ferna´ndez, I.; del Prado Catalina, M.; Alcudia
Cruz, A. Tetrahedron: Asymmetry 1996, 7, 3407.
Chem. Eng. News 2004, 82, 37.
(2) (a) Bloch, R. Chem. ReV. 1998, 98, 1407. (b) Hermanns, N.; Dahman,
S.; Bolm, C.; Braese, S. Angew. Chem., Int. Ed. 2002, 41, 3692. (c)
Senanayake, C. H.; Krishnamurthy, D.; Lu, Z.-H.; Han, Z.; Gallou, I.
Aldrichim. Acta 2005, 38, 93.
(7) Ferna´ndez, I.; Valdivia, V.; Gori, B.; Alcudia, F.; AÄ lvarez, E.; Khiar,
N. Org. Lett. 2005, 7, 1307.
10.1021/jo7018703 CCC: $40.75 © 2008 American Chemical Society
Published on Web 12/23/2007
J. Org. Chem. 2008, 73, 745-748
745

SCHEME 2. Diastereodivergent Approach for the Synthesis
of 8(SS) and 8(RS) DCG Isopropyl Sulfinate Esters
FIGURE 2. Structural formulas of calcium-sensing receptor calcimi-
metics NPS R-568 (1) and cinacalcet (2).
SCHEME 1. Retrosynthetic Analysis of (R)-(+)-NPS R-568
(1)
SCHEME 3. Synthesis of N-Isopropylsulfinylimine 9(S)
secondary hyperparathyroidism.8 Indeed, cinacalcet (2, Figure
2), a compound with improved metabolic profile, has recently
been launched in several countries for the treatment of hyper-
parathyroidism in patients with chronic kidney disease who are
on dialysis and for the treatment of hypercalcemia in patients
with parathyroid carcinoma.
Clinical studies with the calcimimetic NPS R-568 (1) have
shown that its biological activity is intimately related with the
configuration of the chiral center. Accordingly, the (R)-(+)-
NPS R-568, which is the eutomer, is 10-100 times more potent
than the (S)-(-)-NPS distomer.9 A retrosynthetic analysis of
(R)-(+)-NPS R-568 (1), Scheme 1, shows that it can be easily
obtained from the commercially available 3-(2-chlorophenyl)-
2-propenyl chloride 4 and (R)-1-(3-methoxyphenyl)ethylamine
3. The preparation of enantiomerically pure amine with the R
absolute configuration at C1 can be done from (S)-isopropyl-
sulfinylimine 5 derived from (S)-isopropylsulfinamide 6.
The asymmetric synthesis of isopropylsulfinamide 6 can be
done in an enantiodivergent manner using as sulfinylating agents
sugar based sufinate esters 8(RS) and 8(SS), prepared using our
DAG methodology (Scheme 2).10 Noteworthy, in this case we
have found that the glucose-derived dicyclohexylidene-D-glucose
(DCG) 7, obtained in a single step from D-glucose, gave better
chemical yields and diastereoselectivity than the diacetone-D-
glucose. Accordingly, the condensation of 1 molar equiv of
secondary carbinol 7 with 1.8 molar equiv of racemic i-PrSOCl
in THF using pyridine as base afforded the isopropylsulfinate
ester 8(RS) in 97% chemical yield and 86% de (Scheme 2). As
expected, employing toluene as solvent, and using exactly the
same conditions than before, but changing the base from
pyridine to i-Pr2NEt, afforded diastereoselectively isopropyl
sulfinate ester 8(SS) in quantitative yield and 96% de (Scheme
2). Additionally, the DCG isopropylsulfinate esters 8 were
stable, as no decomposition of these sulfinates was detected after
months at 4 °C.
The preparation of N-sulfinylimine 5(S) has been done in
two different ways, Scheme 3. The action of LiHMDS on
sulfinate ester 8(SS) leading to the N,N-bis-trimethylsilylsulfi-
namide 9, followed by treatment with 3-methoxybenzaldehyde
(10) in THF, in the presence of a suspension of CsF, afforded,
after a single recrystallization, enantiomerically pure (as shown
by HPLC analysis) sulfinylimine 5(S) in good chemical yield.
Alternatively, the preparation of 5(S) can be done in two steps,
through isolation of isopropylsulfinamide 6(S), followed by
imination with 3-methoxybenzaldehyde 10 using CuSO4 as
dehydrating agent, although in lowest chemical yield.
It is worth of mention that the synthesis of N-sulfinylimine
5(S), using sulfinate ester 8(SS) as sulfinylating agent, takes
place efficiently under very smooth reaction conditions as
compared with the procedures reported for the synthesis of
p-toluenesulfinylimines I and the 2-methylpropane-2-sulfi-
nylimines II. Accordingly, the complete transformation of
sulfinate ester 8(SS) to the silylated sulfinamide derivative 9
takes place at 0 °C in only 5 min, and through the condensation
of 3-methoxybenzaldehyde, the final sulfinylimine 5(S) has been
obtained in high chemical yield after 1 h. As the addition of
methyl Grignard on sulfinylimine 5(S) constitutes the key step
of the approach, a systematic study was conducted using
different solvents (THF, toluene, CH2Cl2), temperatures (from
-78 °C to rt), as well as number of molar equivalents of the
Grignard reagent.
(8) (a) Nagano, N. Pharmacol. Ther. 2006, 109, 339. (b) Steddon, S. J.;
Cunningham, J. Lancet 2005, 365, 2237. (c) Nemeth, E. F. Curr. Pharm.
Des. 2002, 8, 2077. (d) Steffey, M. E.; Fox, J.; Van Wagenen, B. C.; Delmar,
E. G.; Balandrin, M. F.; Nemeth, E. F. J. Bone Miner. Res. 1993, 8, S175.
(e) Silverberg, S. J.; Bone, H. G.; Marriott, T. B., III; Locker, F. G.; Thys-
Jacobs, S.; Dziem, G.; Kaatz, S.; Sanguinetti, E. L.; Bilezikian, J. P. N.
Engl. J. Med. 1997, 337, 1506.
(9) Nemeth, E. F.; Steffey, M. E.; Hammerland, L. G.; Hung, B. C. P.;
Van Wagenen, B. C.; DelMar, E. G.; Balandrin, M. Proc. Natl. Acad. Sci.
U.S.A. 1998, 95, 4040.
(10) (a) Ferna´ndez, I.; Khiar, N.; Llera, J. M.; Alcudia, F. J. Org. Chem.
1992, 57, 6789. (b) Khiar, N.; Ferna´ndez, I.; Alcudia, F. Tetrahedron Lett.
1994, 35, 5719. (c) Khiar, N.; Alcudia, F.; Espartero, J. L.; Rodr´ıguez, L.;
Ferna´ndez, I. J. Am. Chem. Soc. 2000, 122, 7598. (d) Ferna´ndez, I.; Khiar,
N. Chem. ReV. 2003, 103, 3651.
From this study, it was found that using 2 molar equiv of
methyl Grignard in toluene at -78 °C afforded sulfinamide 11-
746 J. Org. Chem., Vol. 73, No. 2, 2008

SCHEME 5. Synthesis of Calcimimetic (R)-(+)-NPS R-568
FIGURE 3. Explanative model for the preferred formation of 11(SS,R).
SCHEME 4. Synthesis of
(R)-1-(3-Methoxyphenyl)ethylamine [3(R)]
Experimental Section
General methods and experimental details for the synthesis of
sulfinate ester 8(SS) and sulfinamide 6(S) can be found in the
Supporting Information.
(S)-N-(3-Methoxybenzylidene)isopropylsulfinamide, 5(S).
Method A. To a solution of sulfinate ester 8(SS) (6.7 g, 14.7 mmol)
in THF (20 mL) at 0 °C was added a 1 M LiHMDS solution in
THF (17.6 mL, 17.6 mmol). The reaction mixture was stirred for
5 min and transferred via cannula to a second flask containing
3-methoxybenzaldehyde (3.36 mL, 22.05 mmol) and CsF (2.7 g,
17.6 mmol) in THF (15 mL). After being stirred for 30 min at
room temperature, the reaction mixture was quenched with saturated
NH4Cl aqueous solution, and the aqueous layer was extracted with
AcOEt (4 × 40 mL). The organic layer was washed with saturated
NaHCO3 aqueous solution and with saturated NaCl aqueous solution
and dried over Na2SO4. The solvent was removed under reduced
pressure, and the residue was purified by flash chromatography
(AcOEt/Cl2CH2 1:30-1:20), to give 5(S) (2.7 g, 81% yield) as a
white solid in 90% ee. Enantiopure sulfinylimine was obtained after
crystallyzation from hexanes.
Method B. To a suspension of CuSO4 (10.8 g, 67.67 mmol) in
CH2Cl2 (30 mL) at room temperature was added a solution of (S)-
isopropanesulfinamide 6(S) (1.2 g, 11.22 mmol) in CH2Cl2 (15 mL)
and then 3-methoxybenzaldehyde (1.36 mL, 11.22 mmol). After
being stirred overnight, the reaction mixture was quenched with
saturated aqueous NH4Cl solution, and the aqueous layer was
extracted with AcOEt (4 × 40 mL). The organic layer was washed
with saturated aqueous NaHCO3 solution and brine and dried over
Na2SO4. The solvent was removed under reduced pressure, and the
residue was purified by flash chromatography (AcOEt/Cl2CH2
1:30-1:20), to give enantiopure 5(S) (1.6 g, 63.4% yield) as a white
solid: mp 54 °C; [R]20D +77 (c 0.65, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 8.58 (s, 1H), 7.49-7.43 (m, 3H), 7.11-7.09 (m, 1H),
3.89 (s, 3H), 3.00 (m, J ) 6.9 Hz, 1H), 1.35 (d, J ) 6.9 Hz, 3H),
1.25 (d, J ) 6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 162.6,
160.0, 135.3, 130.0, 122.6, 119.0, 113.0, 55.4, 53.9, 14.8, 13.5;
HRMS m/e calcd for C11H16NO2S (M + H)+ 226.0901, found
226.0895.
(SS,R) as a single diastereoisomer. This result indicates that the
nucleophilic attack of the small methyl Grignard takes place
on the iminic carbon and not on the sulfinyl sulfur, probably as
consequence of steric and electronic factors.11 Treatment of
compound 11(SS,R) with trifluoroacetic acid in methanol
provokes the desulfinylation of the sulfinamide and provides
the desired product as trifluoroacetate ammonium salt in
quantitative yield (Scheme 4). Purification of the product on
an ion-exchange column (SCX) afforded enantiomerically pure
(R)-1-(3-methoxyphenyl)ethylamine ([R]D ) +21.7 (c 0.3,
MeOH) (lit.12 +17.6 (c 0.2, MeOH)). Based on the absolute
configuration of the final amine, the stereoselectivity of the
addition step can be rationalized by invoking a coordinated
Zimmerman-Traxler like model, where the approximation of
the nucleophile takes place from the less hindered face of the
imine, Figure 3.
Condensation of (R)-1-(3-methoxyphenyl)ethylamine 3(R)
with 3-(2-chlorophenyl)-2-propenyl chloride 4 in the presence
of sodium carbonate afforded amide 12(R) in excellent yield.
Finally, reduction of the R,â-insaturated amide 12(R), followed
by treatment with DIBAL-H in THF, afforded the calcimimetic
(R)-(+)-NPS R-568 (1) in enantiopure form and in good
chemical yield, Scheme 5.
In conclusion, the results presented in this work show that
besides the advantage of lower molecular weight, the isopropyl
sulfinyl group does confer high chemical reactivity, better
enantiomeric discrimination than the p-tolylsulfinyl group, and
equal or even much better enantiomeric discrimination than the
most popular tert-butyl group. The usefulness of this new chiral
controller has been demonstrated by a highly enantioselective
synthesis of arylamines. The synthetic utility of the approach
has been demonstrated by an expeditive synthesis of the
calcimimetic drug (R)-(+)-NPS R-568 (1).
The enantiomeric ratio was determined by HPLC analysis using
chiralpack OJ column: flow rate 0.8 mL/min, i-PrOH/hexane 3:97,
30 °C, tS ) 15.0 min (5S) and tR ) 19.7 min (5R).
(SS,R)-N-[1-(3-Methoxyphenyl)ethyl]isopropylsulfinamide, 11-
(SS,R). To a solution of sulfinylimine 5(S) (1.0 g, 4.42 mmol) in
toluene (15 mL) at -78 °C was added a 1.4 M MeMgBr solution
(6.35 mL, 8.89 mmol) in THF. The reaction mixture was slowly
warmed to room temperature and stirred overnight. Then, the
reaction mixture was quenched with saturated aqueous NH4Cl
solution and the aqueous layer was extracted with AcOEt (3 × 40
mL). The organic layer was washed with saturated aqueous NaCl
solution and dried over Na2SO4. The solvent was removed under
reduced pressure, and the residue was purified by flash chroma-
tography (AcOEt/hexanes 1:1-1:20), to give enantiopure 11(SS,R)
(11) (a) Cogan, D. A.; Liu, G.; Kim, K.; Backes, B. J.; Ellman, J. A. J.
Am. Chem. Soc. 1998, 120, 8011. (b) Liu, G.; Cogan, D. A.; Ellman, J. A.
J. Am. Chem. Soc. 1997, 119, 9913.
(12) (a) Atobe, M.; Yamazaki, N.; Kibayashi, C. J. Org. Chem. 2004,
69, 5595. (b) Hansen, M. C.; Buchwald, S. L. Tetrahedron Lett. 1999, 40,
2033.
(760 mg, 71.7% yield) as a colorless oil: [R]20 +112.0 (c 0.7,
D
CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.29-7.26 (m, 1H), 6.96-
J. Org. Chem, Vol. 73, No. 2, 2008 747

6.92 (m, 2H), 6.85-6.83 (m, 1H), 4.60-4.57 (m, 1H), 3.81 (s,
3H), 3.61 (bs, 1H), 2.75 (m, J)6.9 Hz, 1H), 1.56 (d, J)6.8 Hz,
3H), 1.28 (d, J)6.9 Hz, 3H), 1.27 (d, J)6.9 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 160.0, 140.2, 129.9, 118.9, 114.6, 111.9, 55.3,
51.5, 50.6, 22.8, 21.0, 17.4; HRMS m/e calcd for C12H20NO2S (M
+ H)+ 242.1214, found 242.1203.
added Pd(C) cat. and stirred under hydrogen pressure for 3 h. The
reaction mixture was filtered over Celite with MeOH. The solvent
was removed under reduced pressure, and the residue was purified
by flash chromatography (AcOEt/hexanes 1:2) to give the amide
13(R) (80 mg, 80% yield) as a white solid: mp 96 °C; [R]20D +47
1
(c 1.0, CHCl3) [lit.12a [R]20 +45.6 (c 1.0, CHCl3); H NMR (500
D
(R)-1-(3-Methoxyphenyl)ethylamine, 3(R). To a solution of
sulfinamide 11(SS,R) (765 mg, 3.17 mmol) in MeOH (20 mL) at 0
°C was added CF3CO2H (1.82 mL, 23.77 mmol), and the reaction
mixture was slowly warmed to room temperature. After the mixture
was stirred overnight, the solvent was removed under reduced
pressure to give the corresponding ammonium salt in quantitative
yield. The residue was passed through a cation-exchange column
(Isolute SPE SCX-2) to give the amine 3(R) (453 mg, 95%) as a
MHz, CDCl3) δ 7.31-7.20 (m, 5H), 6.82-6.80 (m, 3H), 5.51 (bd,
J ) 7.0 Hz, 1H), 5.09 (m, J ) 7.0 Hz, 1H), 3.81 (s, 3H), 2.99 (t,
J ) 7.5 Hz, 2H), 2.50 (t, J ) 7.5 Hz, 2H), 1.42 (d, J ) 6.9 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 171.0, 159.8, 144.7, 140.8,
136.0, 134.4, 129.7, 128.5, 128.4, 126.2, 118.4, 112.5, 112.3, 55.2,
48.7, 38.6, 31.7, 21.6; HRMS m/e calcd for C18H21NO2 (M + H -
Cl)+ 283.1572, found 283.1570.
3-(2-Chlorophenyl)-N-[(R)-1-(3-methoxyphenyl)ethyl]-1-pro-
panamine, 1(R). To a stirred solution of amide 13(R) (80 mg, 0.25
mmol) in CH2Cl2 (2 mL) was added a 1 M DIBAL solution in
THF (0.96 mL, 0.96 mmol) at room temperature. After being stirred
overnight, the reaction was quenched by addition of saturated
aqueous NH4Cl solution (3 mL). The mixture was filtered through
a Celite pad, the filtrate was concentrated in vacuo, and the residue
was purified on a cation-exchange column (Isolute SPE SCX-2) to
colorless oil: [R]20 +21.7 (c 0.3, MeOH) (lit.12a +17.6 (c 0.2,
D
MeOH)); 1H NMR (500 MHz, CDCl3) δ 7.29-7.25 (m, 1H), 6.95-
6.93 (m, 1H), 6.81-6.79 (m, 1H), 4.11 (q, J ) 6.6 Hz, 1H), 3.84
(s, 3H), 1.69 (bs, 2H), 1.41 (d, J ) 6.6 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 159.8, 149.5, 129.5, 118.1, 112.1, 111.4, 55.2,
51.35, 25.57; HRMS m/e calcd for C9H14NO (M + H)+ 152.1075,
found 152.1069.
give 1(R) as a yellow oil (42.6 mg, 56%): [R]20 +39.1 (c 1.0,
3-(2-Chlorophenyl)-N-[(R)-1-(3-methoxyphenyl)ethyl]-2-pro-
penamide, 12(R). To a stirred solution of amine 3(R) (136 mg,
0.89 mmol) in CH2Cl2 (15 mL) were added 3-(2-chlorophenyl)-2-
propenyl chloride (180.8 mg, 0.89 mmol) and Na2CO3 (95.33 mg,
0.89 mmol) at room temperature. After the mixture was stirred
overnight, water (20 mL) was added and the solution extracted with
CH2Cl2 (4 × 20 mL). The organic phase was dried over anhydrous
Na2SO4 and the solvent removed under reduced pressure. The
residue was purified by flash chromatography (AcOEt/hexanes 1:5)
to give the amide 12(R) (244 mg, 87% yield) as an enantiopure
white solid: mp 145-146 °C; [R]20D +33 (c 0.5, CHCl3); 1H NMR
(500 MHz, CDCl3) δ 8.02 (d, J ) 15.6 Hz, 1H), 7.57 (dd, J ) 2.0
and 7.3 Hz, 1H), 7.43 (dd, J ) 1.7 and 7.5 Hz, 1H), 7.32-7.23
(m, 3H), 6.98 (d, J ) 7.6 Hz, 1H), 6.94-6.93 (m, 1H), 6.85 (dd,
J ) 2.5 and 8.2 Hz, 1H), 6.42 (d, J ) 15.6 Hz, 1H), 5.89 (br d, J
) 7.5 Hz, 1H), 5.27 (m, J ) 7.3 Hz, 1H), 3.84 (s, 3H), 1.59 (d, J
) 6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 164.4, 159.9, 144.7,
137.2, 134.8, 133.2, 130.4, 130.2, 129.8, 127.6, 126.9, 123.6, 118.5,
112.7, 112.4, 55.3, 49.1, 21.6; HRMS m/e calcd for C18H18ClNO2
(M)+ 315.1026, found 315.1030.
D
CHCl3) [lit.12a [R]20D +38.6 (c 1.1, CHCl3)]; 1H NMR (500 MHz,
CDCl3) δ 7.29-7.16 (m, 5H), 6.93-6.91 (m, 2H), 6.79 (ddd, J )
8.3, 2.4 and 0.9 Hz, 1H), 3.83 (s, 3H), 3.76 (q, J ) 6.5 Hz, 1H),
2.70-2.50 (m, 4H), 1.85-1.80 (m, 2H), 1.38 (d, J ) 6.6 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ 159.8, 147.0, 142.1, 129.4, 128.3,
128.2, 125.7, 119.0, 112.3, 112.1, 58.4, 55.2, 47.3, 33.6, 31.7, 24.1;
HRMS m/e calcd for C18H22NO (M - Cl)+ 268.1701, found
268.1697.
Acknowledgment. We thank the Direccio´n General de
Investigacio´n Cient´ıfica y Te´cnica (Grant No. CTQ2004-01057
and CTQ-2006-15515) and La Junta de Andaluc´ıa (Grant No.
P06-FQM-1852) for financial support. V.V. thanks the CSIC
for a I3P predoctoral grant.
Supporting Information Available: General methods and
experimental details for the synthesis of 8(SS) and 6(S) are
described. Copies of 1H NMR and 13C NMR spectra of compounds
1, 3, 5(S), 11(SS,R), 12(R), and 13(R) are included. This material
is available free of charge via the Internet at http://pubs.acs.org.
3-(2-Chlorophenyl)-N-[(R)-1-(3-methoxyphenyl)ethyl]propan-
amide, 13(R). To a stirred solution of enamide 12(R) (100 mg,
0.32 mmol) in a 1:1 AcOEt/MeOH solvent mixture (4 mL) was
JO7018703
748 J. Org. Chem., Vol. 73, No. 2, 2008