A R T I C L E S
Viswanathan et al.
We first targeted protected indoline R-amino acid (13a),23
Table 5. Reductive 5-Exo Aryl Radical Cyclizations to Ketimines
a
(eq 8)a
constrained form of the endogenous alkaloids phenyl alanine
and proline. In the latter capacity, it was used in the development
of the ACE inhibitor Pentopril.24 cyclo-Dopa,25 the constrained
form of L-Dopa, occurs naturally in betanidin, a member of the
betalain natural products. Additionally, reduction and depro-
tection of 13a furnish an amino alcohol that has been used in
asymmetric synthesis, an application that requires the availability
of both enantiomers to access both product antipodes (Table
6).26-28
The requirement of an azomethine is common to the
aminations described here and the immediate products of phase
transfer-catalyzed alkylation (PTCA) of glycinyl imines pio-
neered by O’Donnell.29 Recent advances in enantioselective
variants of PTCA suggested a high probability of success.30
The ortho-bromobenzyl bromides required for the alkylation
step were prepared by radical bromination of commercially
available ortho-bromotoluene derivatives. Using the Corey
protocol for alkylation, we found that the cinchonidinium salt
(A, Table 4) provided the resulting (S)-phenyl alanine derivatives
in uniformly good yield and high enantiomeric excess. In our
hands, catalysts A and B obtained by large-scale synthesis
provided products of higher ee if the ammonium salt was first
chromatographed (silica gel, 2% MeOH/CH2Cl2).
1
2
3
entry
R /Y
R
R
8/9
9:3b
yield (%)c
1
2
3
4
5
6
7
8
CH3O/CH
CH3O/CH
CH3O/CH
CH3O/CH
CH3O/CH
H/N
Ph
Ph
Ph
CH3
CF3
Ph
CH3
Ph
Ph
CH3
CH3
a
b
c
d
e
f
g
h
9:1
9:1
12:1
nd
5:1
4:1
83
89
64
52
47
60
76
55
o-MeOPh
p-MeOPh
Ph
p-CF3Ph
p-MeOPh
H/N
H/N
5.5:1
5:1
a All reactions were carried out in C6H6 (0.01 M in substrate, 80 °C)
and proceeded to complete conversion. b Relative amount of direct aryl
radical reduction measured by 400 MHz 1H NMR of the untreated reaction
mixture. c Isolated yield (two steps) after chromatography.
dolines 9f-h in uniformly good yield (Table 5, entries 6-8).
In these examples, the cyclization efficiency differed at most
by a factor of 3.
To determine the viability of the present method for acid- or
base-sensitive substrates, we targeted indoline 12 for synthesis
(Scheme 1). The ketimine precursor was synthesized from ortho-
bromobenzaldehyde through a sequence of cyanohydrin forma-
tion, reduction, and Boc protection to 10 followed by O-me-
thylation, Boc deprotection, and transimination to arrive at the
requisite benzophenone ketimine 11. In the event, the radical-
mediated amination proceeded cleanly to the 3-methoxy indoline
12. Spectroscopic ananlysis (1H NMR) of the crude reaction
mixture did not reveal the presence of any N-diphenylmethyl
indole. The desired indoline was purified by chromatography
on neutral alumina, providing 12 in 70% yield. Complete
conversion of 12 to N-diphenylmethyl indole occurred upon
standing when exposed to air overnight.
Exposure of the aryl halides to tri-n-butyltin hydride in the
presence of AIBN furnished the products of cyclization in good
n
yield without the need for slow addition of Bu3SnH. Despite
the possibility for direct aryl radical reduction by stannane, no
evidence for this product was detected by GC/MS. It is not until
an 8-fold excess of stannane is used that intermolecular aryl
radical reduction becomes significant (5:1 cyclized:reduced).
(21) Asymmetric Heck cyclizations are generally limited to cyclic or 1,1-
disubstituted olefins, although exceptions exist: (a) Sato, Y.; Sodeoka, M.;
Shibasaki, M. J. Org. Chem. 1989, 54, 4738. (b) Carpenter, N. E.; Kucera,
D. J.; Overman, L. E. J. Org. Chem. 1989, 54, 5846. (c) Review: Donde,
Y.; Overman, L. E. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I.,
Ed.; Wiley: New York, 2000; Chapter 8G.
(22) Representative examples: (a) Overman, L. E.; Paone, D. V.; Stearns, B.
A. J. Am. Chem. Soc. 1999, 121, 7702. (b) Matsuura, T.; Overman, L. E.;
Poon, D. J. J. Am. Chem. Soc. 1998, 120, 6500. (c) Nukui, S.; Sodeoka,
M.; Sasai, H.; Shibasaki, M. J. Org. Chem. 1995, 60, 398. (d) Takemoto,
T.; Sodeoka, M.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1993, 115,
8477. (e) Ashimori, A.; Matsuura, T.; Overman, L. E.; Poon, D. J. J. Org.
Chem. 1993, 58, 6949.
(23) Two syntheses of 13 congeners were reported recently, both involving
asymmetric hydrogenation (functionalization): (a) Wagaw, S.; Rennels,
R. A.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 8451. (b) Kuwano,
R.; Sato, K.; Kurokawa, T.; Karube, D.; Ito, Y. J. Am. Chem. Soc. 2000,
122, 7614. For recent interest in Captopril-inspired ACE inhibitors, see:
(c) wa Mutahi, M.; Nittoli, T.; Guo, L.; Sieburth, S. McN. J. Am. Chem.
Soc. 2002, 124, 7363.
(24) Gruenfeld, N.; Stanton, J. L.; Yuan, A. M.; Ebetino, F. H.; Browne, J. J.;
Gude, C.; Huebner, C. F. J. Med. Chem. 1983, 26, 1277.
(25) There are no asymmetric syntheses of cyclo-Dopa; however, its synthesis
from 3,4-dihydroxy phenylalanine has been reported: (a) Buchi, G.; Fliri,
H.; Shapiro, R. J. Org. Chem. 1978, 43, 4765. (b) Hermann, K.; Dreiding,
A. S. HelV. Chim. Acta 1975, 58, 1805.
(26) CBS-type catalysts and their derivatives: (a) Martens, J.; Danelsberg, C.;
Behnen, W.; Wallbaum, S. Tetrahedron: Asymmetry 1992, 3, 347. (b)
Jones, G. B.; Heaton, S. B.; Chapman, B. J.; Guzel, M. Tetrahedron:
Asymmetry 1997, 8, 3625. (S)-Indoline R-amino acid has been used further
in asymmetric synthesis after transformation to the derived amino alcohol:
(c) hydrogenation - Pasquier, C.; Naili, S.; Mortreux, A.; Agbossou, F.;
Pelinski, L.; Brocard, J.; Eilers, J.; Reiners, I.; Peper, V.; Martens, J.
Organomet. Chem. 2000, 19, 5723. (d) Asymmetric additions to alde-
hydes: Asami, M.; Watanabe, H.; Honda, K.; Inoue, S. Tetrahedron:
Asymmetry 1998, 9, 4165.
Enantioselective Synthesis of Indoline r-Amino Acids.
Indoline alkaloids have long been the target of total synthesis
due to their prevalence in nature and their associated diverse
biological activity.20 This interest has driven the development
of methods to construct or, more commonly, functionalize the
indoline backbone. The importance of, and continuing need for,
enantioselective indoline annulation protocols is clear from the
impact that enantioselective Heck cyclizations21 have recently
had on alkaloid total synthesis.22 To fill this void and demon-
strate the utility of free radical-mediated aryl amination, we
developed a new indoline annulation protocol that can be
rendered stereoselective and utilizes nonaniline precursors (eq
9).
(27) Given the unavailability of ent-13, its octahydroindoline derivative is
necessarily used to generate the enantiomeric products: Kim, Y. H. Acc.
Chem. Res. 2001, 34, 955.
(28) Acquisition of ent-10 and related derivatives has relied solely on resolution
techniques.
(29) O’Donnell, M. J. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I.,
Ed.; Wiley-VCH: New York, 2000; Chapter 10.
(30) Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119, 12414.
(20) The Alkaloids: Chemistry and Biology; Cordell, G. A., Ed.; Academic:
San Diego, 1998; Vol. 50.
9
166 J. AM. CHEM. SOC. VOL. 125, NO. 1, 2003