Synthesis of novel enantiopure biphenyl P,N-ligands and application in palladium-catalyzed asymmetric addition of arylboronic acids to N-benzylisatin

Article abstract of DOI:10.1021/jo802036m

(Chemical Equation Presented) Enantiopure tetra-ortho-substituted biphenyl phosphinoimine ligands (R_a,S)-3 and (S_a,S)-3 were synthesized via multistep reactions. The first asymmetric addition reactions of arylboronic acids to N-benzy

Full text of DOI:10.1021/jo802036m

Synthesis of Novel Enantiopure Biphenyl P,N-Ligands and
Application in Palladium-Catalyzed Asymmetric Addition of
Arylboronic Acids to N-Benzylisatin
Hongshan Lai,† Zhiyan Huang,† Qiong Wu, and Yong Qin*
Department of Chemistry of Medicinal Natural Products, Key Laboratory of Drug Targeting and NoVel
DeliVery System of Ministry of Education, West China School of Pharmacy, and State Key Laboratory of
Biotherapy, Sichuan UniVersity, Chengdu 610041, P. R. China
yongqin@scu.edu.cn
ReceiVed September 22, 2008
Enantiopure tetra-ortho-substituted biphenyl phosphinoimine ligands (Ra,S)-3 and (Sa,S)-3 were synthesized
via multistep reactions. The first asymmetric addition reactions of arylboronic acids to N-benzylisatin
catalyzed by Pd(OAc)2 and (Ra,S)-3 were studied to provide 3-aryl-3-hydroxyoxindoles in moderate yields
and enantioselectivities.
Introduction
15 (PHOX, Figure 1), showed very promising regio- and
enantioselectivities in Pd-catalyzed allylic substitution compared
to C2-symmetric ligands.6 In that reaction, the mixed P,N-ligand
1 provided an effective electronic and steric discrimination on
the coordinated allylic substrate.
Chiral ligands have been considered one of the most
interesting topics in organic synthesis over the last two decades
owing to their fruitful applications to asymmetric synthesis.1
Among the thousands of chiral ligands prepared, C2-symmetric
P,P- and N,N-ligands represented a major structural class and
were well-documented in the literature,2 while unsymmetric
ligands with an axial chirality were paid less attention and
remained underdeveloped.3,4 Recent progress by Pfaltz dem-
onstrated that the unsymmetric P,N-ligand, phosphinooxazoline
Besides chiral oxazoline and simple amine, chiral sulfinyl
imine is also a potential transition-metal coordination unit. This
concept has been well practiced by Ellman in the design of the
sulfinyl imine P,N-ligand 2 (Figure 1).7 Inspired by Ellman’s
successful ligand design and the fact that a variety of ligands
with an axially chiral biaryl framework are widely observed to
produce excellent performance in asymmetric catalysis,8 we
envisioned that novel biphenyl sulfinyl imine P,N-ligands with
both sulfur chirality and axial chirality should provide a more
rigid asymmetric environment for the enantioselective discrimi-
nation on a prochiral substrate. Furthermore, axially chiral
resolution of such biphenyl sulfinyl imine P,N-ligands would
be easily achieved by incorporation of an aldehyde precursor
with chiral tert-butylsulfinamide (TBSA). In this paper, we
* To whom correspondence should be addressed. Tel/fax: +86 28 85503842.
† These authors contributed equally to this work.
(1) (a) Yoon, T. P.; Jacobsen, E. N. Science 2003, 299, 1691. (b) Catalytic
Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York, 2000.
(c) ComprehensiVe Asymmetric Catalysis; Jacobsen, E. J., Pfaltz, A., Yamamoto,
H., Ed.; Springer: New York, 1999.
(2) For leading reviews on C2-symmetric P,P- and N,N-ligands, see: (a) Li,
Y.-M.; Kwong, F.-Y.; Yu, W.-Y.; Chan, A. S. C. Coord. Chem. ReV. 2007,
251, 2119. (b) Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325. (c)
Ghosh, A. K.; Mathivanan, P.; Cappiello, J. Tetrahedron: Asymmetry 1998, 9,
1.
(3) (a) Kim, K. H.; Jeong, Ch.-K.; Kim, D.-H.; Ha, D.-Ch. Tetrahedron:
Asymmetry 2006, 17, 1688. (b) Kocovsky, P.; Vyskocil, S.; Cisarova, I.; Sejbal,
J.; Tislerova, I.; Smrcina, M.; Lloyd-Jones, G. C.; Stephen, S. C.; Butts, C. P.;
Murray, M.; Langer, V. J. Am. Chem. Soc. 1999, 121, 7714. (c) Vyskocil, S.;
Smrcina, M.; Hanus, V.; Polasek, M.; Kocovsky, P. J. Org. Chem. 1998, 63,
7738. (d) Ogasawara, M.; Yoshida, K.; Kamei, H.; Kato, K.; Uozumi, Y.;
Hayashi, T. Tetrahedron: Asymmetry 1998, 9, 1779. (e) Imai, Y.; Zhang, W.;
Kida, T.; Nakatsuji, Y.; Ikeda, I. Tetrahedron Lett. 1998, 39, 4343.
(4) (a) Wang, Y.; Li, X.; Sun, J.; Ding, K. Organometallics 2003, 22, 1856.
(b) Wang, Y.; Li, X.; Ding, K. Tetrahedron Lett. 2002, 43, 159. (c) Wang, Y.;
Guo, H.; Ding, K. Tetrahedron: Asymmetry 2000, 11, 4153.
(5) The synthesis and application of PHOX, see: (a) Williams, J. M. J. Synlett
1996, 705. (b) Koch, G.; Lloyd-Jones, G. C.; Loiseleur, O.; Pfaltz, A.; Pretot,
R.; Schaffner, S.; Schnider, P.; von Matt, P. Recl. TraV. Chim. Pays-Bas 1995,
114, 206. (c) Helmchen, G.; Kudis, S.; Sennhenn, P.; Steinhagen, H. Pure Appl.
Chem. 1997, 69, 513.
(6) (a) Pfaltz, A.; Drury, W. J., III. Proc. Natl. Acad. Sci., U.S.A. 2004, 101,
5723. (b) Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336.
(7) Schenkel, L. B.; Ellman, J. A. Org. Lett. 2003, 5, 545.
(8) A recent review on axially chiral ligands, see: McCarthy, M.; Guiry, P. J.
Tetrahedron 2001, 57, 3809.
10.1021/jo802036m CCC: $40.75
Published on Web 11/17/2008
2009 American Chemical Society
J. Org. Chem. 2009, 74, 283–288 283

Lai et al.
SCHEME 1. Synthesis of Chiral Ligand 3a
FIGURE 1. Unsymmetric P,N-ligands 1-4.
report the synthesis of enantiopure tetra-ortho-substituted bi-
phenyl phosphinoimine ligands 3, phosphinonitrile ligands 4,
and application in the palladium-catalyzed asymmetric addition
of arylboronic acids to N-benzylisatin (Figure 1).
Results and Discussion
The synthesis of chiral ligand 3 was initiated from 6,6′-
dimethylbiphenyl-2,2′-dibromine 59 (Scheme 1). Bromine-lithium
exchange by treatment of dibromine 5 with 1.1 equiv of n-BuLi
at -78 °C and subsequent addition of dry DMF afforded
formaldehyde 6 in an 86% yield. Unfortunately, initial attempts
to direct conversion of 6 to diphenylphosphine 8 via cross-
coupling reaction of 6 with diphenylphosphine by employing
Pd(PPh3)4 as a catalyst were unsuccessful under various condi-
tions.10 After conversion of aryl bromide 6 to aryl iodide 7 in
a three-step reaction of protection, halogen exchange, and
deprotection, we were able to isolate diphenylphosphine 8 in a
51% yield via a cross-coupling reaction of 7 with diphenylphos-
phine under microwave-assisted conditions within 1 h in DMF.
Microwave heating greatly promoted the reaction, while at least
4 days were needed to complete the cross-coupling reaction
under classical conditions in DMF or toluene. As anticipated
and pioneered by Lin and Xu,11 axially chiral resolution of
sulfinyl imine (Ra,S)-3a and (Sa,S)-3a was readily achieved in
high yield by the condensation of aldehyde 8 with (S)-TBSA
using Cs2CO3 as a condensation reagent.12 Diastereomers (Ra,S)-
3a and (Sa,S)-3a were easily separated by silical gel chroma-
tography (Rf 0.40 for (Ra,S)-3a, Rf 0.36 for (Sa,S)-3a, eluted with
ethyl acetate/petroleum (1:8)).
diastereomer (Ra,S)-3a with [Pd(allyl)Cl]2, followed by coun-
terion exchange of Cl- with SbF6 (Scheme 1). The X-ray
-
crystallographic analysis of (Ra,S)-913 unambiguously confirms
the absolute configuration of the less polar diastereomer (Ra,S)-
3a with R axial chirality.
A methoxy group is the most frequently used electron-
donating substituent in studies of the electronic effect of biaryl
ligands on asymmetric catalysis.14 Having accomplished the
enantiopure 3a, we then explored the synthesis of methoxy-
substituted biphenyl phosphinoimine 3b from the easily prepared
6,6′-dimethoxybiphenyl 2,2′-diiodide 1015 (Scheme 2). Direct
introduction of a formaldehyde group on the phenyl ring of 10
to form aldehyde 13 by iodide-lithium exchange and DMF
addition encountered with an extremely low yield (<8%) due
to the unsuccessful first step of iodide-lithium exchange. A
large amount of 10 remained unchanged after the reaction.
Alternative transformation of iodide in 10 to cyanide or
carbonamide by transition-metal-catalyzed cyanization16 and
aminocarbonylation17 also failed. The reason for this unsuc-
cessful reaction was probably ascribed to the electron-rich
characteristics of the phenyl ring with stronger electron-donating
methoxy groups. Theoretically, localized dispersion of the
electronic density in the phenyl ring of 11 by forming lithium
In order to elucidate the absolute configuration of axial
chirality in (Ra,S)-3a, an eight-membered P,N-chelate palladium
complex (Ra,S)-9 was prepared by reaction of the less polar
(13) A yellow crystal of (Ra,S)-9 (C34H37F6NOPPdSSb, mp 147-149 °C)
for X-ray analysis was obtained by recrystallization from a mixture of CHCl3
and Et2O. For the ORTEP diagram of (Ra,S)-9 and the crystallographic data, see
the Supporting Information. The crystallographic data have been deposited with
the Cambridge Crystallographic Data Centre, CCDC 683001.
(14) Shimizu, H.; Nagasaki, I.; Saito, T. Tetrahedron 2005, 61, 5405.
(15) Peng, H.-Y.; Lam, Ch.-K.; Mak, T. C. W.; Cai, Z.; Ma, W.-T; Li, Y.-
X.; Wong, H. N. C. J. Am. Chem. Soc. 2005, 127, 9603.
(9) (a) Liang, Y.; G, Sh.; Wan, H.; Wang, J.; Chen, H.; Zheng, Z.; Hu, X.
Tetrahedron: Asymmetry 2003, 14, 1267. (b) Miyashita, A.; Karino, H.;
Shimamura, J.; Chiba, T.; Nagano, K.; Nohira, H.; Takaya, H. Chem. Lett. 1989,
10, 1849.
(10) Vignolle, J.; Donnadieu, B.; Bourissou, D.; Soleilhavoup, M.; Bertrand,
G. J. Am. Chem. Soc. 2006, 128, 14810.
(11) Zhu, Ch.; Shi, Y.; Xu, M.-H.; Lin, G.-Q. Org. Lett. 2008, 10, 1243.
(12) Higashibayashi, S.; Tohmiya, H.; Mori, T.; Hashimoto, K.; Nakata, M.
Synlett 2004, 457.
(16) (a) Anderson, B. A.; Bell, E. C.; Ginah, F. O.; Harn, N. K.; Pagh, L. M.;
Wepsiec, J. P. J. Org. Chem. 1998, 63, 8224. (b) Chatani, N.; Hanafusa, T. J.
Org. Chem. 1986, 51, 4714.
(17) (a) Ju, J.; Jeong, M.; Moon, J.; Jung, H. M.; Lee, S. Org. Lett. 2007, 9,
4615. (b) Hosoi, K.; Nozaki, K.; Hiyama, T. Org. Lett. 2002, 4, 2849.
284 J. Org. Chem. Vol. 74, No. 1, 2009

Asymmetric Addition of Arylboronic Acids to N-Benzylisatin
SCHEME 2. Synthesis of Formaldehyde 13
SCHEME 4. Synthesis of Chiral Phosphinonitrile 4
SCHEME 3. Synthesis of Chiral Ligand 3b
by refluxing in xylene under nitrogen atmosphere (Scheme 4).19
Gratifyingly, as demonstrated by (Ra,S)-3a and (Ra,S)-3b, the
reactions proceeded smoothly to give the desired (Ra)-4a and
(Ra)-4b20 at high yields without racemization (>98% ee).21
Interestingly, unlike the sulfinyl imine (Ra,S)-3b, the phosphino-
nitrile (Ra)-4b was stable under chromatographic isolation.
3-Substituted 3-hydroxyoxindoles are widespread in natural
products with important biological activities.22 However, only
two cases were reported to prepare this substructure in an
asymmetric version by using chiral rhodium complex as a
catalyst. Feringa described the first phosphoramidite-rhodium
catalyzed addition of arylboronic acids to isatins with 55% ee.23
Hayashi achieved a 93% ee in the asymmetric addition of
arylboronic acids to isatins by using Rh/(R)-MeO-mop complex
as a catalyst.24 To the best of our knowledge, the palladium/
ligand-catalyzed asymmetric addition of arylboronic acids to
isatins has not been reported. To extend our studies on indole
alkiloids,25 the synthesized chiral ligands 3 and 4 were evaluated
in the palladium-catalyzed asymmetric addition of arylboronic
acids to N-benzyl isatin 15.
phenol salts should be beneficial to the subsequent iodide-lithium
exchange. This consideration was proved to be reasonable by
selective demethylation of 10, followed by treatment of the
resulting phenol 11 with 1.8 equiv of n-BuLi and DMF at -78
°C for 12 h to afford formaldehyde 12 in an acceptable yield
(40%). Reprotection of the hydroxy group in 12 with a methyl
group provided 13 in an excellent yield.
Conversion of 13 to 3b is depicted in Scheme 3. Coupling
of formaldehyde 13 with HPPh2 in the presence of 5 mol % of
Pd(PPh3)4 in toluene under N2 for 16 h afforded phosphine 14.
Again, phosphine 14 was condensed with (S)-TBSA to give a
mixture of two diastereomers (Sa,S)-3b and (Ra,S)-3b in a 90%
isolated yield and a 1:1 ratio by flash chromatography under
nitrogen atmosphere. It was noteworthy that (Sa,S)-3b and (Ra,S)-
3b were less stable than the corresponding methyl ligands (Ra,S)-
3a and (Sa,S)-3a. Separation of diastereomers (Sa,S)-3b and
(Ra,S)-3b from each other by chromatography was more difficult
than the separation of (Ra,S)-3a and (Sa,S)-3a (Rf 0.10 for (Sa,S)-
3b, Rf 0.12 for (Ra,S)-3b, eluted with degassed ethyl acetate/
petroleum (1:6)).
About 25% of 3b was oxidized to the corresponding
phosphine oxide when exposed to air during preparative TLC
purification. Therefore, separation of (Sa,S)-3b and (Ra,S)-3b
should be carried out with caution under nitrogen atmosphere.
The absolute configuration of the axial chirality of (Sa,S)-3b
and (Ra,S)-3b was determined by comparison of CD spectra of
(Ra)-4b and (Sa)-4b with that of (Ra)-4a and (Sa)-4a after
converting the sulfinyl imine group in 3 to a nitrile group in 4
(see Scheme 4 and the next paragraph).
As shown in Table 1, initial experiments gave very disap-
pointing results in that a strong background addition of
phenylboronic acid to 15 was observed when 5 mol % of either
Rh(CH3CN)(cod)BF4 or Rh2(OAc)4 was used in the presence
t
of 0.5 equiv of BuOK in THF (Table 1, entries 1, 2, and 4).
The rhodium-catalyzed addition reaction did not occur in the
presence of 10 mol % of (Ra,S)-3a once the background reaction
was completely suppressed by lowering the reaction temperature
(Table 1, entries 3 and 5); these results indicated that
Rh(CH3CN)(cod)BF4 and Rh2(OAc)4 might not efficiently
(18) (a) Głuszynska, A.; Rozwadowska, M. D. Tetrahedron: Asymmetry 2004,
15, 3289. (b) Selvakumar, K.; Valentini, M.; Woerle, M.; Pregosin, P. S.; Albinati,
A. Organometallics 1999, 18, 1207. (c) Schumacher, D. P.; Clark, J. E.; Murphy,
B. L.; Fischer, P. A. J. Org. Chem. 1990, 55, 5291.
(19) Mukade, T.; Dragoli, D. R.; Ellman, J. A. J. Comb. Chem. 2003, 5,
590.
(20) (Ra)-4a and (Ra)-4b gave a positive first Cotton effect at 280-330 nm
in the CD spectra, while (Sa)-4a and (Sa)-4b were observed to give a negative
first Cotton effect at 280-330 nm; see the Supporting Information.
(21) The enantiomeric excess of 4a and 4b was determined by HPLC analysis
on a Chiralpak AD-H column (see the Supporting Information).
(22) (a) Nicolaou, K. C.; Hao, J.; Reddy, M. V.; Rao, P.; Rassias, G.; Synder,
S. A.; Huang, X.; Chen, D. Y.-K.; Brenzovich, W. E.; Giuseppone, N.;
Giannakakou, P.; O’Brate, A. J. Am. Chem. Soc. 2004, 126, 15316. (b) Marti,
C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 2209.
(23) Toullec, P. Y.; Jagt, R. B. C.; de Vries, J. G.; Feringa, B. L.; Minnaard,
A. J. Org. Lett. 2006, 8, 2715.
Chiral biaryl phosphinonitriles are potential ligands for
asymmetric catalysis and are useful precursors for preparation
of biaryl phosphino-oxazoline ligands.18 Conversion of the
sulfinyl imine moiety in 3a and 3b to nitrile was easily realized
(24) Shintani, R.; Inoue, M.; Hayashi, T. Angew. Chem., Int. Ed. 2006, 45,
3353.
(25) (a) Yang, J.; Wu, H. X.; Shen, L. Q.; Qin, Y. J. Am. Chem. Soc. 2007,
129, 13794. (b) Shen, L. Q.; Zhang, M.; Wu, Y.; Qin, Y. Angew. Chem., Int.
Ed. 2008, 47, 3618.
J. Org. Chem. Vol. 74, No. 1, 2009 285

Lai et al.
TABLE 1. Condition Screening for the Asymmetric Addition of Phenylboronic Acid to 15a
entry
M
solvent
T (°C)
additive (equiv)
yieldb (%)
eec (%) (config)d
1e
2e
3
Rh(CH3CN)(cod)BF4
Rh(CH3CN)(cod)BF4
Rh(CH3CN)(cod)BF4
Rh2(OAc)4
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
25
-40
-78
50
25
50
50
50
50
50
50
50
50
25
25
0
80
10
0
75
0
0
0
6
5
0
0
0
0
4e
5
Rh2(OAc)4
6
7
8
9
[Pd(allyl)Cl]2
Pd(PPh3)2(OAc)2
Pd2(dba)3
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
13 (S)
17 (S)
90 (S)
64 (S)
62 (S)
60 (S)
67 (S)
-
10
11
12
13
14
15f
16
17
18
19
20
21
4
BF3 ·Et2O(1)
BF3 ·Et2O(2)
BF3 ·Et2O(4)
BF3 ·Et2O(4)
BF3 ·Et2O(4)
BF3 ·Et2O(4)
BF3 ·Et2O(4)
BF3 ·Et2O(4)
BF3 ·Et2O(4)
BF3 ·Et2O(4)
BF3 ·Et2O(4)
35
60
65
63
10
trace
20
0
-
CH2Cl2
dioxane
DME
MeCN
toluene
25
25
25
25
25
40 (S)
-
0
0
5
trace
0
12
a
5 mol % of M, 10 mol % of (Ra,S)-3a, 0.5 equiv of BuOK. b Isolated yield. c ee values were determined by HPLC on a chiralcel OD-H column
t
with hexane/2-propanol. d The absolute configuration of adduct was determined by comparing the optical rotation of its methyl-protected derivative with
that of the known compound.26 e Without addition of 3a. f 5 mol % of Pd(OAc)2 and 5 mol % of 3a were used.
TABLE 2. Asymmetric Addition of Arylboronic Acids to 15
coordinate with (Ra,S)-3a. Encouraged by our previous experi-
mental result that [Pd(allyl)Cl]2 readily coordinated with (Ra,S)-
3a, we then screened a variety of palladium salts (5 mol %)
including [Pd(allyl)Cl]2, Pd(PPh3)2(OAc)2, Pd2(dba)3, Pd(PPh3)4,
and Pd(OAc)2 in the addition reaction of phenylboronic acid to
15 in the presence of 10 mol % of (Ra,S)-3a and 0.5 equiv of
tBuOK at 50 °C. Although the yield was very low (4%),
Pd(OAc)2 provided the adduct 16a with a very promising ee
value (90%) (Table 1, entries 6-10). A background reaction
was not observed by using these palladium salts alone. In order
to enhance the reactivity of the ketone group in 15, a number
of Lewis acids such as Ti(OiPr)4, ZnCl2, MgCl2, Et3B, and
BF3 ·Et2O were individually tested as an additive (1 equiv). To
our delight, among the tested additives, BF3 ·Et2O was found
to efficiently promote the addition reaction at 50 and 25 °C
(Table 1, entries 11-14). Changing the ratio of (Ra,S)-3a to
Pd(OAc)2 from 2:1 to 1:1 and further lowering reaction
temperature to 0 °C resulted in a dramatic loss of yield (Table
1, entries 15 and 16). Under the best conditions of 4 equiv of
BF3 ·Et2O, 5 mol % of Pd(OAc)2, and 10 mol % of (Ra,S)-3a,
the addition reaction of phenylboronic acid to 15 proceeded
smoothly at room temperature for 48 h to afford (S)-16a in 63%
yield and 67% ee. Variation of solvents did not improve the
yield and ee value of the addition reaction at room temperature
(Table 1, entries 17-21).
Catalyzed by Ligands 1-4a
yieldb
(%)
eec (%)
entry
ligand
1a
2
adduct 16 (Ar)
(config)d
1
2
3
4
5
6
7
8
16a (Ar ) Ph)
0
0
0
16a (Ar ) Ph)
(Ra)-4a
(Ra)-4b
(Ra,S)-3a
(Sa,S)-3a
(Ra,S)-3b
(Sa,S)-3b
(Ra,S)-3a
(Ra,S)-3a
(Sa,S)-3a
16a (Ar ) Ph)
16a (Ar ) Ph)
0
(-)-16a (Ar ) Ph)
(+)-16a (Ar ) Ph)
(-)-16a (Ar ) Ph)
(+)-16a (Ar ) Ph)
(+)-16b (Ar ) 4-MeO-Ph)
(-)-16c (Ar ) 3-MeO-Ph)
(+)-16d (Ar ) 4-F-Ph)
63
48
40
30
78
51
36
67 (S)
62 (R)
60 (S)
57 (R)
38 (S)
73 (S)
65 (S)
9
10
11
a 5 mol % of M, 10 mol % of (Ra,S)-3a, 0.5 equiv of tBuOK.
b Isolated yield. c ee values were determined by HPLC on a Chiralcel
OD-H or AD-H column with hexane/2-propanol. d The absolute
configuration of adduct was determined by comparing the optical
rotation of it’s methyl-protected derivative with that of the known
compound.26
slightly less active compared with (Ra,S)-3a and provided similar
enantioselectivities (Table 2, entries 5-8), which showed that
the absolute configuration of adduct was controlled by the
ligand’s axial chirality rather than the sulfur chirality. The fact
that (S)-2 with the same coordinating units of imine and
phosphine was incapable of catalyzing the addition reaction had
demonstrated the importance of an axial chirality in 3a and 3b.
Furthermore, the performance of ligand (Ra,S)-3a was further
examined in the asymmetric additions of a variety of arylboronic
acids to 15. Under the best conditions, additions of 4-methoxy-
Under the best conditions, the performance of the known P,N-
ligands (S)-1a and (S)-2 as well as the synthesized ligands (Ra,S)-
3a, (Sa,S)-3a, (Ra,S)-3b, (Sa,S)-3b, (Ra)-4a, and (Ra)-4b were
comparatively tested in the addition reaction of phenylboronic
acid to 15. As shown in Table 2, ligands (S)-1a, (S)-2, (Ra)-4a,
and (Ra)-4b did not catalyze the addition reaction at all (Table
2, entries 1-4). Ligands (Sa,S)-3a, (Ra,S)-3b, and (Sa,S)-3b were
(26) Jia, Y.-X.; Hillgren, J. M.; Watson, E. L.; Marsden, S. P.; Kundig, E. P.
Chem. Commun. 2008, 4040.
286 J. Org. Chem. Vol. 74, No. 1, 2009

Asymmetric Addition of Arylboronic Acids to N-Benzylisatin
yield) and (Sa,S)-3b (206 mg, 36% yield). The de values of (Ra,S)-
3b and (Sa,S)-3b were determined to be >98% by chiral HPLC
analysis [Daicel chiralcel OD-H column, 80:20 hexanes/IPA, 1.0
mL/min, 254 nm; (Ra,S)-3b, tR ) 9.4 min, (Sa,S)-3b, tR ) 4.4 min].
(Ra,S)-3b: Rf 0.12 eluted with EtOAc/petroleum 1:6; mp 78-80
°C; [R]20D +115.9 (c 1.01, CHCl3); 1H NMR (400 MHz, CDCl3) δ
1.15 (s, 9H) 3.25 (s, 3H), 3.67 (s, 3H), 6.72 (dd, J ) 7.6, 3.2 Hz,
1H), 6.84 (d, J ) 8.0 Hz, 1H), 6.95 (d, J ) 8.0 Hz, 1H), 7.06-7.09
(m, 2H), 7.17-7.20 (m, 5H), 7.26-7.31 (m, 4H), 7.38 (t, J ) 8.0
Hz, 1H), 7.69 (d, J ) 7.6 Hz, 1H), 8.25 (s, 1H); 13C NMR (100
MHz, CDCl3) δ 22.6 (3C), 55.0, 55.7, 57.5, 111.4, 113.4, 119.8,
126.2, 128.0 (3C), 128.2, 128.3 (2C), 128.6, 128.7, 128.8, 129.2,
129.6, 133.2, 133.4, 134.0, 134.2, 136.6 (d, Jcp ) 12 Hz), 137.6
(d, Jcp ) 12 Hz), 139.5 (d, Jcp ) 11 Hz), 157.2 (d, Jcp ) 9 Hz),
phenylboronic acid, 3-methoxyphenylboronic acid, and 4-fluoro-
phenylboronic acid to 15 provided the corresponding tertiary
alcohols (S)-16b, (S)-16c, and (S)-16d with acceptable enantio-
selectivities and yields (Table 2, entries 9-11).
Conclusion
In summary, we have developed a concise synthetic route to
enantiopure tetra-ortho-substituted phosphinoimine ligand 3 with
a biphenyl backbone. The first asymmetric additions of aryl-
boronic acids to N-benzylisatin catalyzed by Pd(OAc)2 and
(Ra,S)-3a were realized to provide 3-aryl-3-hydroxyoxindoles
16 in moderate yields and enantioselectivities. Further applica-
tion of these novel ligands in asymmetric catalysis is under
investigation.
157.5, 162.2; 31P NMR (161 MHz) δ -13.1; IR (KBr) 1080.8 cm-1
;
HRMS-ESI calcd for C31H32NNaO3PS (M + Na)+ 552.1733, found
552.1735.
(Sa,S)-3b: Rf 0.10 eluted with EtOAc/petroleum 1:6; mp 150-152
°C; [R]20D +193.0 (c 0.76, CHCl3); 1H NMR (400 MHz, CDCl3) δ
1.14 (s, 9H) 3.58 (s, 3H), 3.65 (s, 3H), 6.70 (dd, J ) 7.6, 3.2 Hz,
1H), 6.96-7.05 (m, 4H), 7.17-7.23 (m, 5H), 7.26-7.35 (m, 4H),
7.39 (t, J ) 8.0 Hz, 1H), 7.59 (d, J ) 8.0 Hz,1H), 7.83 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 22.5 (3C), 55.6, 55.7, 57.2, 111.4,
113.7, 118.9, 125.7, 128.1, 128.2 (2C), 128.3, 128.4, 128.6, 128.7,
128.8, 128.9, 129.5, 133.6, 133.7, 133.8, 134.0, 134.2, 136.0 (d,
Jcp ) 11 Hz), 137.1 (d, Jcp ) 13 Hz), 139.9 (d, Jcp ) 10 Hz), 157.1
(d, Jcp ) 9 Hz), 157.2, 161.7; 31P NMR (161 MHz) δ -12.1; IR
(KBr) 1082.4 cm-1; HRMS-ESI calcd for C31H32NNaO3PS (M +
Na)+ 552.1733, found 552.1738.
Experimental Section
General Procedure for the Synthesis of Ligands 3a and
3b. (Ra,S)-3a and (Sa,S)-3a. To a stirred solution of (S)-tert-
butanesulfinamide (154 mg, 1.27 mmol) in dry toluene (10 mL) at
50 °C were added anhydrous Cs2CO3 (414 mg, 1.27 mmol) and 8
(500 mg, 1.27 mmol). After 18 h, the reaction mixture was filtered
through a pad of Celite, concentrated, and purified by column
chromatography (ethyl acetate/petroleum 1/8) under N2 atmosphere
to afford two diastereomers of ligand (Ra,S)-3a (284 mg, 45% yield)
and (Sa,S)-3a (297 mg, 47% yield) as white powder. The absolute
configuration of the first eluted diastereomer was confirmed with
R axial chirality by X-ray crystallographic analysis of its palladium
complex.13 The diastereomeric purities of (Ra,S)-3a and (Sa,S)-3a
were determined to be >99% de by chiral HPLC analysis [Daicel
chiralcel OD-H column, 90:10 hexanes/IPA, 1.0 mL/min, 254 nm;
(Ra,S)-3a, tR ) 8.0 min, (Sa,S)-3a, tR ) 3.9 min].
Synthesis of Complex (Ra,S)-9. A solution of (Ra,S)-3a (61 mg,
0.12 mmol) and [Pd(allyl)Cl]2 (20 mg, 0.06 mmol) in 3 mL of dry
CH2Cl2 was prepared and degassed (three freeze-pump-thaw
cycles). After this solution was stirred at room temperature for 2 h,
the resulting mixture was added to the solution of AgSbF6 (42 mg,
0.12 mmol) in 3.0 mL of THF by syringe. The resulting hetero-
geneous mixture was stirred for 15 min and then filtered through a
pad of Celite. The filter cake was washed with CH2Cl2, and the
filtrate was concentrated to give 106 mg of a yellow solid (99%
crude yield). Single yellow crystals of (Ra,S)-9 suitable for X-ray
diffraction were obtained by vapor diffusion of Et2O into a solution
of (Ra,S)-9 in CHCl3: mp 147-149 °C; 1H NMR (400 MHz, CDCl3)
δ 0.94 (s, 9H), 1.07 (s, 9H), 1.18 (s, 3H), 1.24 (s, 3H), 1.87 (s,
3H), 1.88 (s, 3H), 2.32 (d, J ) 12.8 Hz, 1H), 3.05 (d, J ) 5.2 Hz,
1H), 3.09 (d, J ) 12.0 Hz, 1H), 3.62 (d, J ) 4.8 Hz, 1H), 3.90-3.99
(m, 2H), 4.95 (td, J ) 6.4, 2.0 Hz, 1H), 5.08 (t, J ) 6.0 Hz, 1H),
5.73-5.83 (m, 2H), 6.75 (d, J ) 7.6 Hz, 1H), 6.82 (d, J ) 7.2 Hz,
1H), 7.05-7.10 (m, 3H), 7.17-7.21 (m, 2H), 7.26-7.39 (m, 12H),
7.48-7.56 (m, 12H), 8.99 (s, 1H), 9.04 (s, 1H); 13C NMR (100
MHz, CDCl3) δ 19.7 (3C), 19.9, 22.0 (3C), 22.1 (3C), 59.3, 59.5,
60.2, 60.4, 82.2 (2C), 82.5 (2C), 120.8, 120.9, 121.0, 121.1, 124.8,
125.0, 126.2, 126.7, 127.2, 128.6, 128.9, 129.0, 129.1 (2C), 129.2
(2C), 129.3, 129.5, 129.6 (3C), 129.7 (2C), 129.9, 130.0 (2C), 131.5,
131.7, 132.0, 132.4, 132.5, 133.0, 133.1, 133.3 (2C), 133.4, 133.5,
135.0 (2C), 135.1, 135.2, 138.3, 138.4, 139.0 (2C), 141.3 (dd, Jcp
) 15, 10 Hz), 174.1 (2C); 31P NMR (161 MHz) δ 25.0, 25.4; IR
(KBr) 658.8, 1102.0, 1605.3 cm-1; MS-ESI 644.3 (M-SbF6).
General Procedure for the Synthesis of 4a and 4b. (Ra)-4a.
Under N2, (Ra,S)-3a (50 mg, 0.10 mmol) was dissolved in dry
xylene (2 mL), and the solution was heated to reflux for 2 h. The
reaction solution was cooled to rt, and the most of the solvent was
removed under vacuum to give a colorless residue. The residue
was purified by flash column chromatography (hexane/ethyl acetate
50/1) under N2 atmosphere to afford (Ra)-4a (37 mg, 95%) as a
white solid. The ee value was determined to be >99% by chiral
HPLC analysis [Daicel chiralcel AD column, 99:1 hexanes/IPA,
(Ra,S)-3a: Rf 0.40 eluted with EtOAc/petroleum 1:8; mp 60-62
°C; [R]20 +13.4 (c 0.98, CHCl3); H NMR (400 MHz, CDCl3) δ
1
D
1.10 (s, 9H), 1.58 (s, 3H), 1.87 (s, 3H), 7.05-7.08 (m, 1H),
7.10-7.14 (m, 2H), 7.15-7.17 (m, 2H), 7.18-7.31 (m, 9H), 7.37
(t, J ) 7.6 Hz, 1H), 7.86 (d, J ) 7.6 Hz, 1H), 8.13 (s, 1H); 13C
NMR (100 MHz, CDCl3) δ 19.5, 20.3, 22.6 (3C), 57.4, 126.4, 127.8,
127.9, 128.1, 128.2, 128.3 (3C), 128.8, 130.9, 131.7, 132.2 (d, Jcp
) 4 Hz), 133.1, 133.4, 133.6, 134.4, 134.6, 136.3 (d, Jcp ) 12
Hz), 136.5 (d, Jcp ) 6 Hz), 137.1 (dd, Jcp ) 24, 11 Hz), 137.8,
141.6 (d, Jcp ) 8 Hz), 143.2, 143.5, 162.2; 31P NMR (161 MHz) δ
-14.2; IR (KBr) 1083.6 cm-1
;
HRMS-ESI calcd for
C31H32NNaOPS (M + Na)+ 520.1834, found 520.1837.
(Sa,S)-3a: Rf 0.36 eluted with EtOAc/petroleum 1:8; mp 145-147
°C; [R]20D +389.6 (c 1.06, CHCl3); 1H NMR (400 MHz, CDCl3) δ
1.10 (s, 9H), 1.84 (s, 3H), 2.03 (s, 3H), 6.95-6.98 (m, 1H),
7.04-7.09 (m, 2H), 7.14-7.18 (m, 2H), 7.24-7.29 (m, 8H), 7.34
(t, J ) 8.0 Hz, 1H), 7.42 (d, J ) 7.2 Hz, 1H), 7.55 (s, 1H), 7.79
(d, J ) 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 19.1, 19.2,
21.4 (3C), 56.1, 123.4, 126.9, 127.2, 127.3 (4C), 127.4, 128.0,
129.9, 130.2, 131.4, 132.4, 132.6 (2C), 133.4, 133.5, 133.6, 135.1
(d, Jcp ) 6 Hz), 135.9, 136.0, 136.4 (d, Jcp ) 10 Hz), 141.0, 141.3
(d, Jcp ) 5 Hz), 159.8; 31P NMR (161 MHz) δ -12.6; IR (KBr)
1089.5 cm-1; HRMS-ESI calcd for C31H32NNaOPS (M + Na)+
520.1834, found 520.1830.
(Ra,S)-3b and (Sa,S)-3b. Under N2, to a stirred solution of (Ss)-
tert-butanesulfinamide (145 mg, 1.20 mmol) in dry toluene (10 mL)
at 50 °C were added anhydrous Cs2CO3 (391 mg, 1.20 mmol) and
14 (512 mg, 1.20 mmol). After being stirred for 18 h, the reaction
mixture was filtered, concentrated, and purified by column chro-
matography (EtOAc/petroleum 1:6) under N2 atmosphere to afford
a mixture of the two diastereomers (Ra,S)-3b and (Sa,S)-3b (572
mg, 90% overall yield) as a white powder. Separation of (Ra,S)-3b
and (Sa,S)-3b from each other was realized by consecutive prepared
TLC chromatography eluted with degassed EtOAc/petroleum (1:
6) under nitrogen atmosphere to afford (Ra,S)-3b (224 mg, 39%
1.0 mL/min, 254 nm; (Ra)-4a, tR ) 12.1 min, (Sa)-4a, tR ) 7.5
1
min]: mp 139- 141 °C; [R]20 -29.9 (c 0.77, CHCl3); H NMR
D
(400 MHz, CDCl3) δ 1.81 (s, 3H), 1.97 (s, 3H), 7.04 (dd, J ) 6.8,
2.8 Hz, 1H), 7.18-7.34 (m, 13H), 7.40 (d, J ) 7.6 Hz, 1H), 7.47
J. Org. Chem. Vol. 74, No. 1, 2009 287

Lai et al.
(d, J ) 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 19.8, 19.9,
114.1, 118.1, 127.9, 128.2, 128.4 (2C), 128.5, 128.6, 128.7, 129.0,
130.3, 131.1, 131.9, 133.6, 133.8, 134.0, 134.1, 134.2, 136.2 (t, Jcp
) 5 Hz), 136.3 (t, Jcp ) 6 Hz), 137.3 (d, Jcp ) 11 Hz), 138.3 (d,
Jcp ) 3 Hz), 142.7, 143.0, 143.7; 31P NMR (161 MHz) δ -14.0;
IR (KBr) 2224.7 cm-1; HRMS-ESI calcd for C27H22NNaP (M +
Na)+ 414.1382, found 414.1370.
min]: white solid; mp 141-142 °C; [R]20 -6.4 (c 0.46, acetone)
D
1
with 67% ee; H NMR (400 MHz, CDCl3) δ 3.25 (s, 1H), 4.97
(dd, J ) 83.2, 16.0 Hz, 2H), 6.80 (d, J ) 8.0 Hz, 1H), 7.05 (td, J
) 8.0, 0.8 Hz, 1H), 7.22 (dd, J ) 8.0, 1.6 Hz, 1H), 7.27-7.43 (m,
11H); 13C NMR (50 MHz, CDCl3) δ 44.0, 77.9, 109.7, 123.5, 124.9,
125.3 (2C), 127.2 (2C), 127.7, 128.2 (2C), 128.5 (2C), 128.8, 129.8,
131.7, 135.4, 140.1, 142.5, 177.6. IR (KBr) 3370.9, 1705.5, 1613.9,
1493.2, 1468.2, 1377.5, 1172.9, 749.3 cm-1; HRMS-ESI calcd for
C21H18NO2 (M + H)+ 316.1338, found 316.1329.
(+)-(S)-16b. The ee value was determined to be 38% by chiral
HPLC analysis [Daicel chiralcel AD column, 70:30 hexanes/IPA,
1.0 mL/min, 227 nm; (S)-16b, tR ) 19.3 min, (R)-16b, tR ) 13.8
min]: white solid; mp 152-153 °C; [R]20D +11.3 (c 0.80, acetone)
with 38% ee; 1H NMR (400 MHz, CDCl3) δ 3.21 (s, 1H), 3.79 (s,
3H), 4.97 (dd, J ) 67.2, 15.6 Hz, 2H), 6.82 (d, J ) 8.0 Hz, 1H),
6.88 (d, J ) 8.8 Hz, 1H), 7.06 (t, J ) 7.2 Hz, 1H), 7.23 (t, J ) 8.0
Hz, 1H), 7.27-7.36 (m, 9H); 13C NMR (50 MHz, CDCl3) δ 43.9,
55.2, 77.6, 109.4, 113.9, 123.4, 124.9, 126.6 (2C), 127.2 (2C),
127.6, 128.7 (2C), 129.5, 131.7, 132.2, 135.4, 142.5, 159.5, 177.6;
IR (KBr) 3363.7, 1707.7, 1612.9, 1512.8, 1375.1, 1257.1, 748.7
cm-1; HRMS-ESI calcd for C22H20NO3 (M + H)+ 346.1443, found
346.1445.
Similar to the synthesis of (Ra)-4a, (Sa)-4a was prepared from
(Sa,S)-3a as a white solid (95% yield): (Sa)-4a: mp 140-141 °C;
[R]20D +29.5 (c 0.80, CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.81
(s, 3H), 1.98 (s, 3H), 7.04 (dd, J ) 6.4, 3.6 Hz, 1H), 7.17-7.34
(m, 13H), 7.40 (d, J ) 7.6 Hz, 1H), 7.46 (d, J ) 7.6 Hz, 1H); 13
C
NMR (100 MHz, CDCl3) δ 19.8, 19.9, 114.1, 118.1, 127.9, 128.2,
128.4 (2C), 128.5, 128.6, 128.7, 129.0, 130.3, 131.1, 131.9, 133.6,
133.8, 134.0, 134.1, 134.2, 136.2 (t, Jcp ) 5 Hz), 136.3 (t, Jcp ) 6
Hz), 137.3 (d, Jcp ) 11 Hz), 138.3 (d, Jcp ) 3 Hz), 142.7, 143.0,
143.7; 31P NMR (161 MHz) δ -13.9; HRMS-ESI calcd for
C27H22NNaP (M + Na)+ 414.1382, found 414.1375.
Similar to the synthesis of (Ra)-4a, (Ra)-4b and (Sa)-4b were
prepared from (Ra,S)-3b and (Sa,S)-3b as a white solid (93-95%
yield), respectively. The ee values of (Ra)-4b and (Sa)-4b were
determined to be >98% by chiral HPLC analysis [Daicel chiralcel
AD column, 95:5 hexanes/IPA, 1.0 mL/min, 254 nm; (Ra)-4b, tR
(-)-(S)-16c. The ee value was determined to be 73% by chiral
HPLC analysis [Daicel chiralcel AD column, 70:30 hexanes/IPA,
1.0 mL/min, 227 nm; (S)-16c, tR ) 20.3 min, (R)-16c, tR ) 22.2
min]: white solid; mp 147-148 °C; [R]20D -16.0 (c 0.46, acetone)
with 73% ee; 1H NMR (400 MHz, CDCl3) δ 3.32 (s, 1H), 3.77 (s,
3H), 4.97 (dd, J ) 90.8, 15.6 Hz, 2H), 6.80 (d, J ) 8.0 Hz, 1H),
6.85 (dd, J ) 8.4, 2.0 Hz, 1H), 6.93 (d, J ) 8.0 Hz, 1H), 7.02-7.06
(m, 2H), 7.21-7.34 (m, 8H); 13C NMR (50 MHz, CDCl3) δ 44.0,
55.1, 77.9, 109.6, 110.9, 113.9, 117.5, 123.5, 124.9, 127.2 (2C),
127.7, 128.8 (2C), 129.6, 129.7, 131.6, 135.4, 141.7, 142.5, 159.8,
) 11.9 min, (Sa)-4b, tR ) 9.4 min].
1
(Ra)-4b: mp 158-160 °C; [R]20 +48.2 (c 0.83, CHCl3); H
D
NMR (400 MHz, CDCl3) δ 3.37 (s, 3H), 3.76 (s, 3H), 6.73 (dd, J
) 7.6, 3.2 Hz, 1H), 7.01 (dd, J ) 8.4, 4.8 Hz, 2H), 7.12-7.16 (m,
2H), 7.21-7.37 (m, 11H); 13C NMR (100 MHz, CDCl3) δ 55.2,
56.0, 111.9, 114.7, 115.5, 118.0, 124.2, 126.3, 128.1, 128.2, 128.3,
128.4 (3C), 129.3, 129.7, 129.8, 130.6 (d, Jcp ) 8 Hz), 133.3, 133.5,
133.7, 133.9, 136.6 (d, Jcp ) 12 Hz), 137.0 (d, Jcp ) 11 Hz), 139.2
(d, Jcp ) 12 Hz), 156.9 (d, Jcp ) 9 Hz), 157.5; 31P NMR (161
MHz) δ -13.1; IR (KBr) 2225.0 cm-1; HRMS-ESI calcd for
C27H22NNaO2P (M + Na)+ 446.1280, found 446.1269.
177.5;IR (KBr) 3298.1, 1696.3, 1610.1, 1375.3, 1158.8, 749.2 cm-1
;
HRMS-ESI calcd for C22H20NO3 (M + H)+ 346.1443, found
346.1456.
(Sa)-4b: mp 159-161 °C; [R]20D -48.0 (c 0.85, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 3.38 (s, 3H), 3.76 (s, 3H), 6.73 (dd, J ) 7.6,
3.2 Hz, 1H), 7.01 (dd, J ) 8.4, 4.8 Hz, 2H), 7.11-7.16 (m, 2H),
7.21-7.37 (m, 11H); 13C NMR (100 MHz, CDCl3) δ 55.2, 56.0,
111.9, 114.7, 115.5, 118.0, 124.2, 126.3, 128.1, 128.2, 128.3, 128.4
(3C), 129.3, 129.7, 129.8, 130.6 (d, Jcp ) 8 Hz), 133.3, 133.5, 133.7,
133.9, 136.6 (d, Jcp ) 12 Hz), 137.0 (d, Jcp ) 11 Hz), 139.2 (d,
Jcp ) 12 Hz), 156.9 (d, Jcp ) 9 Hz), 157.5; 31P NMR (161 MHz)
δ -13.0; HRMS-ESI calcd for C27H22NNaO2P (M + Na)+
446.1280, found 446.1274.
General Procedure for the Asymmetric Addition of
Arylboronic Acids to N-Benzylisatin 15. Under nitrogen, a
solution of Pd(OAc)2 (0.5 mg, 0.0025 mmol) and (Ra,S)-3a (2.5
mg, 0.005 mmol) in THF (0.5 mL) was stirred for 30 min at room
temperature. Meanwhile, another solution of BF3 ·Et2O (0.2 mL,
0.2 mmol) and N-benzylisatin 15 (12.2 mg, 0.05 mmol) in THF
(0.5 mL) was stirred for 30 min. The solution of Pd/(Ra,S)-3a was
then transferred into the solution containing PhB(OH)2 (12.2 mg,
0.1 mmol), followed by addition of the activated N-benzylisatin
solution. After being stirred for 48 h at rt, the mixture was then
directly passed through a pad of silica gel eluted with EtOAc. The
solvent was removed under vacuum, and the residue was purified
by preparative thin layer chromatography (EtOAc/CHCl3 1:20) to
afford adduct (S)-16a.
(+)-(S)-16d. The ee value was determined to be 65% by chiral
HPLC analysis [Daicel chiralcel AD column, 80:20 hexanes/IPA,
1.0 mL/min, 227 nm; (S)-16d, tR ) 14.4 min, (R)-16d, tR ) 11.5
min]: white solid; mp 149-150 °C; [R]20D +15.0 (c 0.27, acetone)
1
with 65% ee; H NMR (400 MHz, CDCl3) δ 3.32 (s, 1H), 4.95
(dd, J ) 76.0, 15.6 Hz, 2H), 6.81 (d, J ) 8.0 Hz, 1H), 7.01-7.08
(m, 3H), 7.23-7.41 (m, 9H); 13C NMR (50 MHz, CDCl3) δ 44.0,
77.6, 109.8, 115.2, 115.7, 123.6, 124.9, 127.2 (2C), 127.4, 127.8,
128.8 (2C), 129.9, 131.3, 135.2, 135.8, 142.5, 160.2, 165.1, 177.3;
IR (KBr) 3369.5, 1703.7, 1614.7, 1508.9, 1383.2, 830.8 cm-1
;
HRMS-ESI calcd for C21H17FNO2 (M + H)+ 334.1243, found
334.1236.
Acknowledgment. This work was supported by NSFC (Nos.
20572072, 20632030, and 20825207). We thank the Analytic
and Testing Center of Sichuan University for recording spec-
troscopic data.
Supporting Information Available: Experimental proce-
dures, analytical data for compounds 6-8 and compounds
11-14, X-ray crystallography of compound 9, CD spectra of
compound 4, HPLC spectra of chiral compounds, and NMR
spectra of new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
(-)-(S)-16a. The ee value was determined to be 67% by chiral
HPLC analysis [Daicel chiralcel OD column, 80:20 hexanes/IPA,
0.5 mL/min, 227 nm; (S)-16a, tR ) 14.2 min, (R)-16a, tR ) 15.5
JO802036M
288 J. Org. Chem. Vol. 74, No. 1, 2009