Total synthesis of (-)-normalindine via addition of metalated 4-methyl-3-cyanopyridine to an enantiopure sulfinimine

Article abstract of DOI:10.1021/jo061443+

A concise total asymmetric synthesis of the tetrahydronaphthyridine alkaloid (-)-normalindine has been accomplished via the addition of a laterally metalated 4-methyl-3-cyanopyridine to a sulfmimine (N-sulfmyl imine) as the key step.

Full text of DOI:10.1021/jo061443+

Total Synthesis of (-)-Normalindine via Addition of Metalated
4-Methyl-3-cyanopyridine to an Enantiopure Sulfinimine
Franklin A. Davis,* Jeffrey Y. Melamed, and Steven S. Sharik
Department of Chemistry, Temple UniVersity, Philadelphia, PennsylVania 19122
fdaVis@temple.edu
ReceiVed July 11, 2006
A concise total asymmetric synthesis of the tetrahydronaphthyridine alkaloid (-)-normalindine has been
accomplished via the addition of a laterally metalated 4-methyl-3-cyanopyridine to a sulfinimine (N-
sulfinyl imine) as the key step.
Enantiopure tetrahydroisoquinolines and tetrahydronaphthyri-
dines represent a large class of naturally occurring alkaloids
which possess a broad range of biological activities.1,2 Generally
the synthesis of these compounds involves an intramolecular
electrophilic aromatic cyclization step to form the nitrogen-con-
taining ring of the isoquinoline. Examples include the Bischler-
Napieralski,3 Pictet-Spengler,4 and Pomeranz-Fritch5 reactions.
Although these methods have been extensively exploited for
this purpose, the success of these procedures is greatly enhanced
when the aromatic ring is electron rich. Furthermore, these
procedures often require harsh reaction conditions and suffer
from unreliable regio- and stereoselectivity. Side reactions
involving the reactive nitrilium ion intermediates can also be
an issue. While some methods have been devised to circumvent
these limitations, these procedures are largely target specific.6
An attractive alternative to the Bischler-Napieralski and
Pictet-Spengler protocols is the addition of laterally lithiated
amides and nitriles 1 to imines, such as enantiopure sulfinimines
(N-sulfinyl imines) 2 (Scheme 1).7 Indeed, this methodology
has the promise of overcoming many of the problems of the
electrophilic cyclization processes and to provide isoquinolines
with substitution patterns not easily accessible by other means.
The nitrogen-containing ring is formed via a nucleophilic
cyclization step of the sulfinamide intermediate 3 with the
aromatic ring amide or nitrile substituent. The resulting isoqui-
nolone 4 and cyclic imine 5 can be readily elaborated to
tetrahydroisoquinolines. Using this methodology, we have
described highly stereoselective asymmetric syntheses of (2R,4S)-
(-)-6-methoxy-N-methyl-3-phenyl-1,2,3,4-tetrahydroisoquino-
line-4-ol (6),8 trans-(1R,3R)-(-)-6,8-dimethoxy-1,3-dimethyl-
1,2,3,4-tetrahydroisoquinoline (7),9 the isoquinoline segment of
the anti-HIV michellamines, and (-)-xylopinine (8), the pro-
totypical member of the protoberberine alkaloids.10 In these
studies, it was found that the addition of laterally lithiated nitriles
to enantiopure sulfinimines was preferred over laterally lithiated
(1) (a) Martin, S. F. In The Alkaloids; Brossi, A., Ed.; Academic Press:
New York, 1987; Vol. 30, p 252. (b) Bringman, G.; Pokorny, F. In The
Alkaloids; Cordell, G. A., Ed.; Academic Press: New York, 1995; Vol.
46, p 128. (c) Bhakuni, D. S.; Jain, S. In The Alkaloids; Brossi, A., Ed.;
Academic Press: New York, 1986; Vol. 28, p 95.
(2) (a) Massiot, G.; Thepenier, P.; Jacquier, M. J.; Men-Olivier, L. L.;
Verpoorte, R.; Delaude, C. Phytochemistry 1987, 26, 2839. (b) Jahangir;
Brook, M. A.; MacLean, D. B.; Holland, H. L. Tetrahedron 1987, 43, 5761.
(c) Phillipson, J. D.; Hemingway, S. R. Phytochemistry 1974, 13, 973. (d)
Erdelmeier, C. A.; Regenass, U.; Rali, T.; Sticher, O. Planta Med. 1992,
58, 43. (e) Abreu, P.; Pereira, A. Heterocycles 1998, 48, 885. (f) Arbain,
D.; Putra, D. P.; Sargent, M. V. Aust. J. Chem. 1993, 46, 977. (g) Caprasse,
M.; Tavernier, D.; Anteunis, M. J. O.; Angenot, L. Planta Med. 1984, 50,
27. (h) Arbain, D.; Lajis, N. H.; Putra, D. P.; Sargent, M. V.; Skelton, B.
W.; White, A. H. Aust. J. Chem. 1993, 46, 969. (i) Arbain, D.; Byrne, L.
T.; Dachriyanus; Sargent, M. V. Aust. J. Chem. 1997, 50, 1109.
(3) Whaley, W. M.; Govindachari, T. R. Org. React. 1951, 6, 74.
(4) Whaley, W. M.; Govindachari, T. R. Org. React. 1951, 6, 151.
(5) Gensler, W. J. Org. React. 1951, 6, 191.
(6) (a) Mendelson, W. L.; Spainhour, C. B., Jr.; Jones, S. S.; Lam, B.
L.; Wert, K. L. Tetrahedron Lett. 1980, 21, 1393. (b) Subimoto, A.; Shinba-
Tanaka, H.; Ishikawa, M. Synthesis 1995, 431. (c) Quallich, G. J.;
Makowski, T. W.; Sander, A. F.; Urban, F. J.; Vazquez, E. J. Org. Chem.
1998, 63, 4116.
(7) For reviews on lateral lithiation reactions, see: (a) Clark, R. D.;
Jahangir, A. Org. React. 1995, 47, 5. (b) Snieckus, V. Chem. ReV. 1990,
90, 879.
(8) Davis, F. A.; Andemichael, Y. W. J. Org. Chem. 1999, 64, 8627.
(9) Davis, F. A.; Mohanty, P. K.; Burns, D. M.; Andemichael, Y. W.
Org. Lett. 2000, 2, 3901.
(10) Davis, F. A.; Mohanty, P. K. J. Org. Chem. 2002, 67, 1290.
10.1021/jo061443+ CCC: $33.50 © 2006 American Chemical Society
Published on Web 10/18/2006
J. Org. Chem. 2006, 71, 8761-8766
8761

Davis et al.
SCHEME 1
SCHEME 2
TABLE 1. Addition of Metalated 11 to (S)-(+)-13 at -78 °C
entry
basea
solvent
14 % isolated yieldb (% de)c
1
2
3
4
5
6
7
LDA
LDA
LDA
LiHMDS
NaHMDS
NaHMDSd
KHMDS
THF
toluene
ether
THF
THF
THF
THF
56 (18)
no reaction
23 (16)
32 (16)
22 (60)
87 (58)
68 (34)
a Anion aged for 30 min before adding to 13. b Yields correspond to the
diastereomeric mixtures. c Determined by H NMR on the crude reaction
1
mixtures. c Anion aged for 2 min before adding to 13.
amides because the cyclic imine is formed in one pot.
Furthermore, the formation of atropisomers in the sulfinamide
derived from the laterally lithiated amides made it difficult to
determine the diastereoselectivity of the reaction.
3-bromo-4-methylpyridine (10) (Scheme 2).10 The laterally
metalated species were generated by the addition of 11 to a
solution of base in THF at -78 °C and resulted in an intense
orange colored solution of the anion. After 0.5 h, (S)-(+)-13
was added dropwise to the base solution. The reaction was
complete as determined by TLC of the solution (typically 15
min) and was quenched with a saturated aqueous NH4Cl
solution. Flash chromatography afforded the sulfinamide prod-
ucts 14 as an inseparable mixture of diastereomers. These results
are summarized in Table 1.
The results summarized in Table 1 reveal that LDA, the base
of choice for the generation of laterally lithiated o-tolunitriles,6b,c
gave poor diastereomeric excesses of the desired product with
11 (Table 1, entry 1). Diethyl ether gave lower yields, probably
due to the poor solubility of the laterally lithiated species in
this solvent (Table 1, entry 3). No improvement in the yield or
diastereomeric excess was noted with LiHMDS or KHMDS
(Table 1, entries 4 and 7). However, NaHMDS resulted in a
diastereomeric excess of 60%, but the yield was poor (Table 1,
entry 5). The isolated yield was dramatically improved when
the anion was formed and subsequently quenched with sulfin-
imine within 2 min. Apparently longer reaction times resulted
in product decomposition. Although results using NaHMDS as
the base were promising, the product diastereoisomers 14 proved
to be inseparable. However, an advantage of our synthetic
methodology is that modification of the sulfinimine often not
only improves the diastereoselectivity but also results in
chromatographically separable products.
(-)-Normalindine (9) is an unusual 1,3-cis-disubstituted
tetrahydronaphthyridine alkaloid which was isolated from the
root bark of Strychnos johnsonii.2a This alkaloid has been the
subject of several racemic syntheses11 but only one asymmetric
synthesis. In their preparation of (-)-9, Ohba and co-workers
employed an intramolecular oxazole-olefin Diels-Alder cy-
clization to form the key tetrahydronaphthyridine core.12 Al-
though their synthesis confirmed the absolute configuration of
the natural product, it required 16 steps with an overall yield
of less than 0.1%. Here we describe a highly efficient asymmet-
ric synthesis of (-)-9, requiring 8 steps with an overall yield of
14%, using our laterally lithiated nitrile sulfinimine technology.
In earlier work, we attributed the high diastereoselectivities
for the addition of laterally lithiated ortho-tolylnitriles to
sulfinimines based on the o-quinonedimethane structure which
was chelated through a lithium cation to the sulfinyl oxygen.9
On the basis of this hypothesis, one would predict that the
diastereoselectivity for sulfinimine addition could be poor
(Scheme 2) if in the o-quinonedimethane structure 12 generated
from 3-cyano-4-methylpyridine (11) the anion is localized at
the pyridine nitrogen. For this reason, we first carried out a
model study for the addition of 12 to sulfinimine (S)-(+)-13
before pursuing the synthesis (-)-normalindine (9).
3-Cyano-4-methylpyridine (11) was prepared in 80% yield
by the catalytic palladium(0) coupling of zinc cyanide with
(11) (a) Maiti, B. C.; Giri, V. S.; Pakrashi, S. C. Heterocycles 1990, 31,
847. (b) Rey, A. W.; Szarek, W. A.; MacLean, D. B. Heterocycles 1991,
32, 1143.
(12) (a) Ohba, M.; Kubo, H.; Fujii, T.; Ishibashi, H.; Sargent, M. V.;
Arbain, D. Tetrahedron Lett. 1997, 38, 6697. (b) Ohba, M.; Kubo, H.;
Ishibashi, H. Tetrahedron 2000, 56, 7751.
The synthesis of (-)-normalindine (9) begins with the
preparation of the requisite sulfinimines 20a-c as outlined in
Scheme 3. Commercially available tryptophol (15) was protected
with either a benzyl or p-methoxy benzyl (PMB) to give 16a
8762 J. Org. Chem., Vol. 71, No. 23, 2006

Total Synthesis of (-)-Normalindine
TABLE 2. Addition of the Anion of 11 to (+)-20 at -78 °C in
THF
SCHEME 3
sulfinamide (-)-21
(+)-20
R )
(+)-20
PG )
conditions,
base, timea
% isolated yieldb
(% de)c
entry
1
2
3
4
5
20a (p-tolyl)
20a (p-tolyl)
20a (p-tolyl)
20b (p-tolyl)
20c (t-Bu)
Bn
Bn
Bn
LiHMDS, 30 min
KHMDS, 30 min
NaHMDS, 2 min
27 (40)
50 (64)
68 (80)
81 (82)
PMB NaHMDS, 2 min
Bn NaHMDS, 2 min
no reaction
a Time for anion formation, before adding 20. b Isolated yield of major
1
diastereoisomer. c Determined by H NMR on the crude reaction mixture.
SCHEME 5
SCHEME 4
and 16b, respectively, in excellent yields. The Vilsmeier
formylation reaction of the protected indoles 16 with POCl3 in
DMF afforded the corresponding aldehydes 17a and 17b in
moderate to excellent yields.14 Apparently, in the course of this
reaction with 17b, some hydrolysis of the PMB group occurs,
resulting in the formation of alkyl chloride 18, which was
isolated in 23% yield (Scheme 3). The optimal conditions for
the Vilsmeier reaction proved to be 10 equiv of POCl3 in DMF
at 45 °C for 3 h. Sulfinimines 20a-c were prepared in 77-
80% yields in the usual manner by condensing the aldehydes
with either (S)-(+)-p-toluenesulfinamide (19a) or (S)-(-)-tert-
butanesulfinamide (19b) in the presence of Ti(OEt)4 in refluxing
CH2Cl2 for 24 h.15
Next, 3-cyano-4-methylpyridine (11) was treated with the
appropriate base at -78 °C in THF, affording the orange colored
solution of the anion (Scheme 4). Addition of the sulfinimines
20a-c to the anion solution quenched the color, producing the
diastereomeric sulfinamides 21a,b (Table 2). The results
revealed in Table 2 indicated that while LiHMDS and KHMDS
gave moderated diastereomeric excess values of 40 and 60%,
respectively, the yields were poor to modest (Table 2, entries 1
and 2). However, when NaHMDS was employed as the base,
the diastereomeric excesses were better than 80%. Furthermore,
the diastereoisomers were easily separated, affording the major
isomers (SS,S)-(-)-21a and (SS,S)-(-)-21b in 68 and 81%
isolated yields, respectively (Table 2, entries 3 and 4). Decom-
position occurred upon addition of the anion of 11 to the (S)-
(-)-tert-butanesulfinimine 20c (Table 2, entry 5). The major
diastereoisomer is predicted to have the (S)-configuration at the
newly created chiral center in sulfinamide 21, based on our
earlier proposed chelated transition state hypothesis.8,9 Indeed,
this was confirmed in the total synthesis of (-)-normalindine
(9).
Reaction of sulfinamides (-)-21 with MeLi, followed by
addition of aqueous HCl, accomplishes four operations in one
pot: (i) installation of the 1-methyl group, (ii) removal of the
sulfinyl auxiliary, (iii) hydrolysis of the resulting ketimine to
the methyl ketone, and (iv) formation of the cyclic imines 22
(Scheme 5). The resulting imines were unstable to silica gel
chromatography and therefore were immediately reduced with
sodium borohydride to give the corresponding disubstituted
tetrahydronaphthyridines (1S,3S)-(-)-23a and (1S,3S)-(-)-23b
in modest 60 and 63% de, respectively.16 Other reducing
reagents, such as Super-Hydride or LiBH4, failed to improve
the diastereoselectivity. Chromatographic separation of the
diastereoisomers afforded (-)-22a and (-)-22b in 46 and 65%
isolated yields, respectively, for the two-step reaction sequence
(Scheme 5).
Removal of the alcohol and indole benzyl protecting groups
from (-)-23a was explored next. Dissolving metal reduction
with sodium and liquid ammonia led to only trace amounts of
(-)-24. Catalytic hydrogenation with 10% Pd-C with or
without acetic acid at 350 psi in a Parr high-pressure reactor
(13) Tschaen, D. M.; Desmond, R.; King, A. O.; Fortin, M. C.; Pipik,
B.; King, S.; Verhoeven, T. R. Synth. Commun. 1994, 24, 887.
(14) Walkup, R. E.; Linder, J. Tetrahedron Lett. 1985, 26, 2155.
(15) Davis, F. A.; Zhang, Y.; Andemichael, Y.; Fang, T.; Fanelli, D. L.;
Zhang, H. J. Org. Chem. 1999, 64, 1403.
(16) Bringmann, G.; Weirich, R.; Reuscher, H.; Jansen, J. R.; Kinzinger,
L.; Ortmann, T. Liebigs Ann. Chem. 1993, 877.
J. Org. Chem, Vol. 71, No. 23, 2006 8763

Davis et al.
under an argon atmosphere were placed bromobenzene (13.26 g,
77.5 mmol) and NaH (1.48 g, 61.8 mmol) in DMF (250 mL) at 0
°C. Tryptophol (15) (20 mL, 15.5 M in DMF, 31.0 mmol) was
then added to the reaction mixture at 0 °C. The reaction mixture
was warmed to room temperature, stirred for 12 h, and quenched
with water (100 mL). The organic phase was extracted with Et2O
(3 × 50 mL), dried (Na2SO4), and concentrated. Purification by
flash chromatography (hexane/Et2O 10:1) gave 7.30 g (95%) of an
oil: 1H NMR (CDCl3) δ 7.71 (d, J ) 7.2 Hz, 1 H), 7.38 (m, 8 H),
7.22 (m, 4 H), 7.07 (s, 1 H), 5.34 (s, 2 H), 4.65 (s, 2 H), 3.89 (d,
J ) 7.5 Hz, 2 H), 3.20 (d, J ) 7.0 Hz, 2 H); 13C NMR (CDCl3) δ
138.6, 137.8, 136.6, 128.8, 128.4, 128.3, 127.8, 127.6, 126.9, 126.3,
121.8, 119.1, 119.0, 112.2, 109.7, 73.0, 70.8, 50.0, 25.9. HRMS
calcd for C24H23NO (M + H): 342.1893. Found: 342.1835.
1-(4-Methoxybenzyl)-3-(2-(4-methoxybenzyloxy)ethyl)-1H-in-
dole (16b). In a 250 mL, round-bottom flask equipped with a
stirring bar and rubber septa under an argon atmosphere were placed
p-methoxybenzyl chloride (2.43 g, 15.51 mmol) and NaH (0.37 g
77.5 mmol) in DMF (100 mL) at 0 °C. To the reaction mixture
was added dropwise tryptophol (15) (10 mL, 6.2 M in DMF, 6.2
mmol) at 0 °C, and the solution was warmed to room temperature
and stirred for 12 h. At this time, the reaction mixture was quenched
with water (30 mL), and the organic phase was extracted with Et2O
(3 × 25 mL), dried (Na2SO4), and concentrated. Purification by
flash chromatography (hexane/Et2O, 10:1) gave 2.18 g (95%) of
an oil: 1H NMR (CDCl3) δ 7.67 (d, J ) 8.4 Hz, 1 H), 7.35 (m, 4
H), 7.19 (m, 4 H), 7.03 (s, 1 H), 6.92 (m, 4 H), 5.28 (s, 2 H), 4.57
(s, 2 H), 3.88 (s, 2 H), 3.85 (s, 3 H), 3.83 (t, J ) 7.2 Hz, 2 H), 3.16
(t, J ) 7.1 Hz, 2 H); 13C NMR (CDCl3) δ 159.2, 159.1, 136.5,
130.7, 129.8, 129.4, 128.3, 128.3, 126.1, 121.7, 119.1, 118.9, 114.1,
113.8, 112.1, 109.7, 72.7, 70.5, 55.4, 55.3, 49.4, 25.9. HRMS calcd
for C26H27NO3 (M + H): 402.2064. Found: 402.2054.
1-Benzyl-3-(2-(benzyloxy)ethyl)-1H-indole-2-carbaldehyde (17a).
In a 250 mL, round-bottom flask equipped with a stirring bar and
rubber septum under an argon atmosphere were placed phosphoryl
chloride (53.9 g, 102.5 mmol) and 16a (7.30 g, 21.39 mmol) in
DMF (150 mL). The reaction mixture was heated to 60 °C and
stirred for 12 h, cooled to 0 °C, and 1 M NaOH (1 M, 250 mL)
was slowly added. The solution was warmed to room temperature,
stirred for 1 h, and saturated NH4Cl (100 mL) was added. The
organic phase was extracted with Et2O (3 × 70 mL), dried (Na2-
SO4), and concentrated. Purification by flash chromatography
(hexane/EtOAc 10:1) gave 7.84 g (95%) of a yellow oil: 1H NMR
(CDCl3) δ 10.25 (s, 1 H), 7.84 (d, J ) 6.1 Hz, 1 H), 7.31 (m, 13
H), 5.91 (s, 2 H), 4.60 (s, 2 H), 3.86 (t, J ) 7.1 Hz, 2 H), 3.52 (t,
J ) 6.8 Hz, 2 H); 13C NMR (CDCl3) δ 182.0, 138.1, 131.4, 128.7,
128.6, 128.5, 128.0, 127.7, 127.7, 127.6, 127.5, 127.4, 127.3, 126.7,
126.6, 126.5, 121.5, 121.1, 120.7, 111.2, 111.0, 73.2, 70.7, 47.9,
24.8. HRMS calcd for C25H23NO2 (M + H): 370.1802. Found:
370.1786.
1-(4-Methoxybenzyl)-3-(2-(4-methoxybenzyloxy)ethyl)-1H-in-
dole-2-carbaldehyde (17b). In a 50 mL, round-bottom flask
equipped with a stirring bar and rubber septum under an argon
atmosphere were placed phosphoryl chloride (0.95 g, 6.2 mmol)
and 16b (0.25 g, 0.62 mmol) in DMF (1.5 mL, 0.4 molar) at room
temperature. The reaction mixture was heated to 45 °C for 4.5 h.
At this time, the reaction mixture was cooled to 0 °C in an ice
bath, and NaOH (3 mL, 1 M) was added, and the solution was
stirred for 1 h at room temperature. At this time, saturated NH4Cl
(3 mL) was added, and the organic phase was extracted with Et2O
(3 × 15 mL), dried (Na2SO4), and concentrated. Purification by
flash chromatography (hexane:EtOAc, 10:1) gave 0.16 g (62%) of
a yellow oil: 1H NMR (CDCl3) δ 10.21 (s, 1 H), 7.78 (dd, J )
1.2, 8.1 Hz, 1 H), 7.46 (m, 2 H), 7.55 (m, 1 H), 7.25 (m, 3 H),
7.13 (d, J ) 8.1 Hz, 2 H), 6.87 (m, 4 H), 5.82 (s, 2 H), 4.51 (s, 2
H), 3.87 (m, 3 H), 3.81 (m, 6 H), 3.47 (t, J ) 6.6 Hz, 2 H); 13C
NMR (CDCl3) δ 182.0, 159.2, 158.8, 139.6, 131.3, 130.3, 130.2,
129.2, 128.0, 128.0, 127.4, 126.7, 121.4, 120.6, 114.0, 114.0, 113.8,
produced none of the desired product, and starting materials
were recovered. Aluminum chloride, anisole-mediated depro-
tection of the benzyl groups led to molecular destruction, again
with only trace amounts of 24 being detected.
Fortunately, we were able to remove the PMB protecting
group in (-)-23b using a modification of the procedure reported
by Forbes and co-workers.17 They reported that PMB depro-
tection of a protected indole could be accomplished in high yield
with trifluoroacetic acid (TFA) in the presence of concentrated
sulfuric acid and anisole. However, when 23b was submitted
to these reaction conditions, only low yields of the desired
product (-)-24 were obtained; ca. 15% and numerous other
impurities was observed. The elimination of sulfuric acid led
to cleaner conversion to 24. Here the TFA and 10 equiv of
anisole solution were cooled to 0 °C followed by addition of
23b. The reaction turned deep green and after 30 min was
complete, affording (-)-24 in 64% isolated yield. Monitoring
the reaction by TLC indicated that deprotection of the alcohol
occurred first followed by a slower removal of the protecting
group on the indole nitrogen. This represents the first simulta-
neous deprotection of an alcohol and indole protecting groups.
Cyclization was easily accomplished by reaction of (-)-24
with methanesulfonyl chloride, (dimethylamino)pyridine, and
Hunigs base, resulting in a 90% yield of (-)-normalindine (9).
This concise synthesis provided (-)-9 in 8 steps with an overall
yield of 14% from commercially available starting materials.
The spectral properties, specific rotation, and melting point of
(-)-normalindine (9) were in agreement with literature values.2f
Importantly, this methodology suggests that it will find applica-
tions in the asymmetric synthesis of other electron-deficient
tetrahydroisoquinolines and tetrahydronaphthyridines.
Experimental Section
(S)-(-)-N-(Benzylidene)-p-toluenesulfinamide (13) was prepared
as previously described.15
(SS,S)-(+)-N-[(1)-2-(3-Cyanopyridin-4-yl)-1-phenylethyl]-4-
methylbenzenesulfinamide (14). In a 100 mL, three-necked oven-
dried round-bottom flask equipped with a magnetic stirring bar and
rubber septum under argon were placed anhydrous THF (8 mL)
and NaHMDS (8.47 mL, 1.0 M in THF, 8.47 mmol). The solution
was cooled to -78 °C, and 4-methyl-3-cyanopyridine (11) (0.50
g, 4.2 mmol) in THF (3 mL) was added dropwise while keeping
the internal temperature less than -76 °C. To the yellow solution
was immediately added (S)-(+)-13 (1.04 g, 4.23 mmol) in THF (5
mL) dropwise. After stirring for 2 min, the reaction mixture was
quenched with aqueous NH4Cl (10 mL) at -78 °C, and the solution
was warmed to room temperature. After dilution with water (10
mL) and EtOAc (20 mL), the phases were separated, the aqueous
layer was extracted with EtOAc (20 mL), and the combined organic
phases were dried (Na2SO4), filtered, and concentrated. Flash
chromatography (CHCl3/MeOH, 98:2) afforded 1.1 g (87%) of a
mixture of diastereomers (79:21): [R]20 +9.5° (c 1.0, MeOH);
D
1H NMR of the major diastereomer (DMSO-d6) δ 8.78 (s, 1 H),
8.67 (d, J ) 5.2 Hz, 1 H), 7.49 (m, 2 H), 7.30 (d, J ) 5.2 Hz, 1
H), 7.27 (m, 5 H), 7.12 (m, 2 H), 4.75 (m, 1 H), 4.45 (d, J ) 5.8
Hz, 1 H), 3.59 (dd, J ) 7.2, 13.8 Hz, 1 H), 3.39 (dd, J ) 7.6, 13.7
Hz, 1 H), 2.42 (s, 3 H); 13C NMR (DMSO) δ 153.1, 151.1, 142.2,
140.9, 137.9, 129.1, 128.0, 127.1, 126.5, 125.5, 116.0, 110.3, 57.1,
42.3, 21.2. ES HRMS calcd for C21H19N3OS (M + H): 362.1319.
Found: 362.1321.
1-Benzyl-3-(2-(benzyloxy)ethyl)-1H-indole (16a). In a 500 mL,
round-bottom flask equipped with a stirring bar and rubber septum
(17) Forbes, I. T.; Johnson, C. N.; Thompson, M. J. Chem. Soc., Perkin
Trans. 1 1992, 275.
8764 J. Org. Chem., Vol. 71, No. 23, 2006

Total Synthesis of (-)-Normalindine
111.0, 72.8, 70.4, 55.3, 55.3, 47.3, 24.8. HRMS calcd for C27H27-
NO4 (M + Na): 452.1838. Found: 452.1829.
To the yellow solution was immediately added dropwise (S)-(+)-
20a (0.43 g, 0.85 mmol) in dry THF (3 mL). After stirring for 2
min, the reaction mixture was quenched with saturated NH4Cl (10
mL) at -78 °C, and the solution was warmed to room temperature.
After dilution with water (10 mL), EtOAc (20 mL) was added, the
organic phase was separated, and the aqueous phase was extracted
with EtOAc (2 × 20 mL). The combined organic phases were dried
(Na2SO4) and concentrated. Flash chromatography (10-40%
acetone/hexanes) afforded 0.36 g (68%) of the major diastereomer
1-(4-Methoxybenzyl)-3-(2-chloroethyl)-1H-indole-2-carbalde-
hyde (18). Purification by flash chromatography (hexane/EtOAc,
10:1) gave 0.63 g (24%) of a clear oil: 1H NMR (CDCl3) δ 10.25
(s, 1 H), 7.84 (d, J ) 6.1 Hz, 1 H), 7.31 (m, 13 H), 5.91 (s, 2 H),
4.60 (s, 2 H), 3.86 (t, J ) 7.1 Hz, 2 H), 3.52 (t, J ) 6.8 Hz, 2 H);
13C NMR (CDCl3) δ 182.0, 138.1, 131.4, 128.7, 128.6, 128.5, 128.0,
127.7, 127.7, 127.6, 127.5, 127.4, 127.3, 126.7, 126.6, 126.5, 121.5,
121.1, 120.7, 111.2, 111.0, 73.2, 70.7, 47.9, 24.8. HRMS calcd for
C19H18ClNO2 (M + H): 328.1099. Found: 328.1105.
(S)-(+)-N-((1E)-{1-Benzyl-3-[2-(benzyloxy)ethyl]-1H-indol-2-
yl}methylidene)-4-methylbenzenesulfinamide (20a). In a 250 mL,
oven-dried round-bottom flask equipped with a reflux condenser,
magnetic stirring bar, and rubber septum under argon was placed
17a (3.57 g, 9.66 mmol) in anhydrous CH2Cl2 (75 mL). To the
solution were added Ti(OEt)4 (22.0 g, 96.6 mmol) and p-
toluenesulfinamide (S)-(+)-19a (1.82 g, 11.60 mmol). The solution
was refluxed for 20 h, cooled to room temperature, and was slowly
poured into a 1 L beaker containing ice water (200 mL) and CH2-
Cl2 (100 mL) with vigorous stirring. The resulting white solids were
collected by vacuum filtration, and the organic and aqueous phases
were added to a separatory funnel. The aqueous phase was extracted
with CH2Cl2 (200 mL), and the combined organic layers were dried
(Na2SO4) and concentrated. Purification by flash chromatography
as a white solid: mp 49-51 °C; [R]20 -44.0° (c 0.43, CHCl3);
D
1H NMR (CDCl3) δ 8.59 (s, 1 H), 8.38 (d, J ) 5.2 Hz, 1 H), 7.53
(d, J ) 8 Hz, 1 H), 7.37 (d, J ) 8 Hz, 2 H), 7.29-7.13 (m, 14 H),
6.71 (d, J ) 7.2 Hz, 2 H), 6.60 (br s, 1 H), 5.25-5.20 (m, 1 H),
4.81-4.70 (m, 2 H), 4.26 (d, J ) 12 Hz, 1 H), 4.23 (d, J ) 11.6
Hz, 1 H), 3.89-3.86 (m, 1 H), 3.70 (t, J ) 8 Hz, 1 H), 3.65-3.60
(m, 1 H), 3.24-3.19 (m, 3 H), 2.36 (s, 3 H); 13C NMR (CDCl3) δ
153.0, 152.6, 150.6, 141.8, 141.3, 138.3, 137.8, 137.3, 130.0, 129.4,
128.8, 128.4, 128.2, 127.9, 127.9, 126.2, 126.2, 125.0, 123.1, 120.1,
119.0, 116.4, 111.9, 111.8, 110.2, 73.1, 70.0, 50.3, 46.3, 41.1, 25.9,
21.3. HRMS calcd for C39H36N4O2S (M + H): 625.2632. Found:
625.2659.
(SS,S)-(-)-N-[(1S)-2-(3-Cyanopyridin-4-yl)-1-(1-(4-methoxy-
benzyl)-3-{2-[(4-methoxybenzyl)oxy]ethyl}-1H-indol-2-yl)ethyl]-
4-methylbenzenesulfinamide (21b). In a 1000 mL, three-necked
oven-dried round-bottom flask equipped with a magnetic stirring
bar and rubber septum under argon were placed THF (250 mL)
and NaHMDS (21.2 mL, 1.0 M in THF, 21.2 mmol). The solution
was cooled to -78 °C, and 11 (1.38 g, 11.7 mmol) in THF (10
mL) was added dropwise while keeping the internal temperature
less than -76 °C. To the yellow solution was immediately added
dropwise (S)-(+)-20b (6.0 g, 10.6 mmol) in THF (25 mL). After
stirring for 5 min, the reaction mixture was quenched with aqueous
NH4Cl (200 mL) at -78 °C and the solution was warmed to room
temperature. After dilution with water (100 mL), EtOAc (200 mL)
was added, and the phases were separated. The aqueous phase was
extracted with EtOAc (2 × 200 mL), and the combined organic
phases were dried (Na2SO4) and concentrated. Flash chromatog-
(hexane:EtOAc, 10:1) gave 3.75 g (76%) as a light yellow oil:
1
[R]20 28.2° (c 2.2, CHCl3); H NMR (CDCl3) δ 9.19 (s, 1 H),
D
7.86 (d, J ) 8.0 Hz, 1 H), 7.52 (d, J ) 8.0 Hz, 2 H), 7.42-7.29
(m, 13 H), 7.09 (d, J ) 6.2 Hz, 2 H), 6.06 (d, J ) 17.2 Hz, 1 H),
5.87 (d, J ) 16 Hz, 1 H), 4.65 (s, 2 H), 3.86 (m, 2 H), 3.53 (m, 2
H), 2.50 (s, 3 H); 13C NMR (CDCl3) δ 150.0, 142.6, 141.4, 140.0,
138.5, 138.3, 130.0, 129.9, 128.6, 128.5, 127.6, 127.6, 127.2, 127.1,
126.5, 126.4, 124.8, 124.8, 121.0, 120.6, 110.6, 73.1, 70.6, 48.2,
25.3, 21.6. HRMS calcd for C32H30N2O2S (M + H): 507.2101.
Found: 507.2076.
(SS)-(E)-N-((1-(4-Methoxybenzyl)-3-(2-(4-methoxybenzyloxy)-
ethyl)-1H-indol-2-yl)methylene)-4-methylbenzenesulfinamide
(20b). Prepared from 1-(4-Methoxybenzyl)-3-(2-(4-methoxy-
benzyloxy)ethyl)-1H-indole-2-carbaldehyde (17b). Purification by
flash chromatography (hexane/EtOAc, 10:3) gave 0.14 g (80%) of
a light oil: [R]20D 137.8° (c 1.0, CHCl3); 1H NMR (CDCl3) δ 9.01
(s, 1 H), 7.28 (m, 15 H), 6.75 (d, J ) 6.9 Hz, 1 H), 5.44 (s, 2 H),
4.53 (s, 2 H), 3.86 (m, 8 H), 3.34 (t, J ) 6.9 Hz, 2 H), 2.50 (s, 3
H); 13C NMR (CDCl3) δ 159.4, 159.2, 137.6, 135.5, 130.4, 130.3,
130.2, 129.8, 129.3, 129.2, 128.4, 127.6, 126.4, 126.2, 125.5, 124.4,
121.1, 121.0, 120.9, 120.3, 114.3, 113.8, 113.8, 110.8, 109.0, 72.7,
69.5, 55.3, 55.2, 48.5, 26.1, 21.5. HRMS calcd for C34H34N2O4 (M
+ H): 567.2312. Found: 567.2308.
(SS)-(E)-N-((1-Benzyl-3-(2-(benzyloxy)ethyl)-1H-indol-2-yl)-
methylene)-2-methylpropane-2-sulfinamide (20c). Prepared from
tert-Butylsulfinamide (S)-(-)-19b and 1-Benzyl-3-(2-(benzyloxy)-
ethyl)-1H-indole-2-carbaldehyde (17a). Purification by flash
chromatography (hexane/EtOAc 10:2) gave 0.95 g (80%) of a
yellow oil: mp 147-150 °C; [R]20D 35.6° (c 2.1, CHCl3); 1H NMR
(CDCl3) δ 8.91 (s, 1 H), 7.79 (d, J ) 8.1 Hz, 1 H), 7.36-7.18 (m,
11 H), 6.12 (d, J ) 16.9 Hz, 1 H), 5.75 (d, J ) 16.8 Hz, 1 H), 4.57
(s, 2 H), 3.81 (m, 2 H), 3.47 (m, 2 H), 1.097 (s, 9 H); 13C NMR
(CDCl3) δ 152.3, 140.0, 138.7, 138.4, 130.3, 128.9, 128.6, 127.8,
127.7, 127.5, 127.3, 126.5, 126.0, 124.4, 121.2, 120.7, 110.6, 73.2,
70.9, 57.6, 48.3, 25.5, 22.5. HRMS calcd for C29H32N2O2S (M +
H): 473.2257. Found: 473.2232
raphy (12.5-40% acetone:hexanes) afforded 5.9 g (81%) as a white
1
solid: mp 55-58 °C; [R]20 -47.3° (c 1.35, CHCl3); H NMR
D
(CDCl3) δ 8.55 (s, 1 H), 8.35 (d, J ) 4.8 Hz, 1 H), 7.48 (d, J )
8.0 Hz, 1 H), 7.36 (d, J ) 7.6 Hz, 2 H), 7.20 (m, 4 H), 7.12 (m,
1 H), 7.03 (d, 2 H), 6.77-6.66 (m, 5 H), 6.57 (d, J ) 8.4 Hz, 2 H),
5.14 (br m, 1 H), 4.71 (br s, 2 H), 4.19 (d, J ) 11.6 Hz, 1 H), 4.16
(d, J ) 11.6 Hz, 1 H), 3.81 (m, 1 H), 3.77 (s, 3 H), 3.73 (s, 3 H),
3.65-3.55 (m, 2 H), 3.25-3.11 (m, 3 H), 2.39 (s, 3 H); 13C NMR
(CDCl3) δ 159.7, 159.3, 152.9, 152.5, 150.6, 141.7, 141.4, 137.2,
135.3, 130.1, 130.0, 129.9, 127.7, 127.4, 126.2, 125.7, 125.0, 123.0,
119.9, 118.9, 116.3, 114.7, 114.1, 111.9, 111.7, 110.1, 73.1, 70.1,
55.7, 55.6, 50.5, 46.2, 41.4, 26.3, 21.7. ES HRMS calcd for
C41H40N4O4S (M + H): 685.2843. Found: 685.2835. Anal. Calcd
for C41H40N4O4S: C, 71.91; H, 5.89; N, 8.18. Found: C, 71.56;
H, 5.65; N, 8.04.
(1S,3S)-(-)-3-{1-Benzyl-3-[2-(benzyloxy)ethyl]-1H-indol-2-
yl}-1-methyl-1,2,3,4-tetrahydro-2,7-naphthyridine (23a). In a 250
mL, oven-dried round-bottom flask equipped with a magnetic
stirring bar and rubber septum was placed (-)-21a (1.0 g, 1.6 mmol)
in toluene (30 mL). The solution was cooled to -18 °C, and MeLi
(9.97 mL, 1.6 M in ether, 15.95 mmol) was added. After 2 h, the
reaction mixture was quenched with 1 N HCl (27 mL), and stirring
was continued for 1.5 h at 0 °C. At this time, saturated bicarbonate
solution (50 mL) was added to neutralize the acid (pH 7.0). After
dilution with water (50 mL), the solution was extracted with EtOAc
(2 × 50 mL), and the combined organic phases were dried (Na2-
SO4) and concentrated to afford a yellow solid of 22a. Since this
material was unstable to chromatography and slowly air oxidized,
it was immediately taken to the reduction step.
(SS,S)-(-)-N-[(1S)-1-{1-Benzyl-3-[2-(benzyloxy)ethyl]-1H-in-
dol-2-yl}-2-(3-cyanopyridin-4-yl)ethyl]-4-methylbenzenesulfina-
mide (21a). In a 100 mL, three-necked oven-dried round-bottom
flask equipped with a magnetic stirring bar and rubber septum under
argon was placed NaHMDS (1.69 mL, 1.0 M in THF, 1.69 mmol)
in THF (10 mL). The solution was cooled to -78 °C, and 4-methyl-
3-cyanopyridine (11) (0.10 g, 0.85 mmol) in THF (1 mL) was added
dropwise while keeping the internal temperature less than -76 °C.
In a separate 100 mL, oven-dried round-bottom flask equipped
with a magnetic stirring bar and rubber septum were placed
anhydrous MeOH (25 mL), crude imine (S)-22a (0.70 g, 1.44
J. Org. Chem, Vol. 71, No. 23, 2006 8765

Davis et al.
mmol), and NaBH4 (0.11 g, 2.88 mmol) at -78 °C. After 2 h, the
reaction mixture was quenched with aqueous NH4Cl (30 mL), and
EtOAc (75 mL) was added. At this time, the solution was extracted
with EtOAc (2 × 50 mL), and the combined organic phases were
dried (Na2SO4) and concentrated. Flash chromatography (hexanes:
2-{2-[(1S,3S)-1-Methyl-1,2,3,4-tetrahydro-2,7-naphthyridin-
3-yl]-1H-indol-3-yl}ethanol (24). In a 50 mL, oven-dried round-
bottom flask equipped with a magnetic stirring bar and rubber septa
was placed 23b (0.28 g, 0.51 mmol), and cold TFA (9 mL) was
added followed by anisole (0.28 mL, 2.53 mmol). After 0.5 h, the
green solution was slowly poured into ice cold saturated sodium
bicarbonate solution (50 mL), and EtOAc (50 mL) was added. The
solution was extracted with EtOAc (2 × 50 mL), and the combined
organic phases were dried (Na2SO4) and concentrated. Flash
chromatography (MeOH:CHCl3, 2-8%) afforded 0.99 g (64%) of
acetone, 70:30) afforded 0.32 g (46%) over two steps of a yellow
1
solid: mp 55-58 °C; [R]20 -47.3° (c 1.35, CHCl3); H NMR
D
(CDCl3) δ 8.44 (s, 1 H), 8.31 (d, J ) 4.8 Hz, 1 H), 7.65 (m, 1 H),
7.29-7.24 (m, 8 H), 7.18-7.15 (m, 3 H), 6.93 (d, J ) 6.4 Hz, 2
H), 6.78 (d, J ) 5.0 Hz, 1 H), 5.92 (d, J ) 17.2 Hz, 1 H), 5.59 (d,
J ) 17.2 Hz, 1 H), 4.51 (m, 2 H), 4.06 (q, J ) 6 Hz, 1 H), 3.78 (t,
J ) 6.8 Hz, 2 H), 3.60 (t, J ) 6.8 Hz, 2 H), 3.20-3.13 (dd, J )
11.6, 17.2 Hz, 1 H), 2.69-2.64 (dd, J ) 3.4, 17.0 Hz, 1 H), 1.34
(d, J ) 6.4 Hz, 3 H); 13C NMR (CDCl3) δ 147.6, 147.2, 144.1,
139.1, 138.8, 137.7, 137.5, 135.9, 129.1, 128.7, 128.1, 128.0, 127.4,
126.1, 123.9, 122.4, 119.8, 119.0, 110.7, 110.4, 73.6, 71.4, 52.0,
51.2, 48.3, 35.6, 25.7, 22.0. ES HRMS calcd for C33H33N3O (M +
H): 488.2697. Found: 488.2716.
a white powder: mp 203-205 °C; [R]20 -13.0° (c 1.0, CHCl3);
D
1H NMR (CD3OD) δ 8.66 (s, 1 H), 8.47 (d, J ) 5.1 Hz, 1 H), 7.69
(d, J ) 7.8 Hz, 1 H), 7.51 (d, J ) 8.1 Hz, 1 H), 7.41 (d, J ) 5.4
Hz, 1 H), 7.27 (t, J ) 6.9 Hz, 1 H), 7.09 (t, J ) 6.9 Hz, 1 H), 4.63
(dd, J ) 3.0, 11.7 Hz, 1 H), 4.58-4.52 (q, J ) 6.3 Hz, 1 H), 3.96
(t, J ) 6.6 Hz, 2 H), 3.54 (m, 1 H), 3.23-3.14 (m, 3 H), 1.75 (d,
J ) 6.9 Hz, 3 H); 13C NMR (CD3OD) δ 146.2, 146.0, 145.4, 136.2,
136.0, 135.6, 127.9, 124.1, 121.3, 118.5, 117.9, 110.7, 109.0, 62.1,
51.2, 49.4, 34.3, 27.3, 19.8. ES HRMS calcd for C19H21N3O (M +
H): 308.1758. Found: 308.1729.
(1S,3S)-(-)-3-(1-(4-Methoxybenzyl)-3-{2-[(4-methoxybenzyl)-
oxy]ethyl}-1H-indol-2-yl)-1-methyl-1,2,3,4-tetrahydro-2,7-naph-
thyridine (23b). In a 500 mL, oven-dried three-necked round-
bottom flask equipped with a magnetic stirring bar and rubber septa
was placed 21b (2.47 g, 3.60 mmol) in ether (100 mL). The solution
was cooled to -18 °C (salt water ice bath), and MeLi (22.5 mL,
1.6 M in ether, 36.0 mmol) was added dropwise. Upon addition of
MeLi, the solution became heterogeneous and turned yellow. After
1 h, the reaction mixture was quenched with 1 N HCl (72 mL),
stirring was continued for 1.5 h at 0 °C, and saturated bicarbonate
solution (200 mL) was added. At this time, the solution was
extracted with EtOAc (2 × 200 mL), and the combined organic
phases were dried (Na2SO4) and concentrated to give crude imine
(S)-22b.
In a separate 100 mL, oven-dried round-bottom flask equipped
with a magnetic stirring bar and rubber septa were placed crude
imine (S)-22b (0.92 g, 1.69 mmol) and sodium borohydride (0.128
g, 3.37 mmol) in anhydrous MeOH (25 mL) at -78 °C. After
stirring for 1 h, the reaction mixture was quenched with saturated
aqueous NH4Cl (30 mL), and EtOAc (75 mL) was added. The
solution was extracted with EtOAc (2 × 50 mL), and the combined
organic layers were dried (Na2SO4) and concentrated. Flash
chromatography (CH2Cl2/MeOH, 98:2) afforded 0.60 g (65%) and
an orange solid: mp 66-70 °C; [R]20D -43.3° (c 1.0, CHCl3); 1H
NMR (CDCl3) δ 8.41 (s, 1 H), 8.27 (d, J ) 5.1 Hz, 1 H), 7.59 (m,
1 H), 7.17-7.09 (m, 5 H), 6.85-6.75 (m, 7 H), 5.80 (d, J ) 17.1
Hz, 1 H), 5.47 (d, J ) 17.4 Hz, 1 H), 4.50-4.45 (dd, J ) 3.6, 11.4
Hz, 1 H), 4.40 (m, 2 H), 4.03 (q, J ) 6.9 Hz, 1 H), 3.78 (s, 3 H),
3.75 (s, 3 H), 3.71 (t, J ) 6.6 Hz, 2 H), 3.20 (t, J ) 6.6 Hz, 2 H),
3.13 (m, 1 H), 2.63 (dd J ) 3.6, 16.9 Hz, 1 H), 1.90 (br s, 1 H),
1.33 (d, J ) 6.3 Hz, 3 H); 13C NMR (CDCl3) δ 159.5, 159.0, 147.6,
147.2, 144.2, 137.6, 137.5, 136.0, 131.1, 130.9, 129.7, 128.2, 127.2,
123.9, 122.4, 119.7, 119.0, 114.4, 114.1, 110.7, 110.4, 73.2, 71.1,
55.6, 55.6, 52.0, 51.2, 47.7, 35.6, 25.7, 22.1. ES HRMS calcd for
C35H37N3O3 (M + H): 548.2913. Found: 548.2901.
(-)-Normalindine (9). In an oven-dried 11 dram vial equipped
with a magnetic stirring bar and rubber septum was added 24 (0.02
g, 0.065 mmol) in a 1:1 CH2Cl2/DMF (2 mL) mixture. Mesyl
chloride (5 L, 0.065 mmol) and DMAP (0.002 g, 0.02 mmol) were
added, and the reaction mixture was stirred at 0 °C for 1.5 h. At
this time, water (5 mL) and EtOAc (5 mL) were added, and the
solution was extracted with EtOAc (5 × 5 mL). The combined
organic phases were dried (Na2SO4) and concentrated. Flash
chromatography (MeOH:CH2Cl2, 4%) afforded 0.010 g (90%) of
a light yellow solid: mp 120-124 °C [lit.2f 131-136 °C]; [R]20
D
-204.0° (c 0.4, CHCl3) [lit.2f [R]20 -210° (c 0.1, CHCl3)]; H
1
D
NMR (CHCl3) δ 8.52 (s, 1 H), 8.37 (d, J ) 5.1 Hz, 1 H), 7.94 (br
s, 1 H), 7.52 (d, J ) 7.2 Hz, 1 H), 7.33 (d, J ) 7.5 Hz, 1 H),
7.20-7.07 (m, 3 H), 3.82 (m, 2 H), 3.60 (ddd, J ) 1.8, 5.3, 11.4
Hz, 1 H), 3.09-2.94 (m, 3 H), 2.84 (m, 1 H), 2.58 (td, J ) 3.7,
11.4 Hz, 1 H), 1.64 (d, J ) 6.3 Hz, 3 H); 13C NMR (CDCl3) δ
148.7, 146.6, 142.6, 136.5, 136.0, 134.3, 127.1, 123.1, 121.8, 119.6,
118.4, 110.9, 109.2, 57.3, 55.1, 48.8, 34.8, 22.4, 22.1. ES HRMS
calcd for C19H19N3 (M + H): 290.1652. Found: 290.1656.
Acknowledgment. This work was supported by a grant from
the National Institutes of Health (GM51982), Merck through a
fellowship to J.Y.M., and support in part to S.S.S. by the
Howard Hughes Medicinal Institute Grant to the Undergraduate
Biological Sciences Education Program at Temple University.
Mass spectra were provided by Charles Ross and Joan Murphy
at Merck.
Supporting Information Available: 1H and 13C NMR spectra
for all new compounds and (-)-9. This material is available free
of charge via the Internet http://pubs.acs.org.
JO061443+
8766 J. Org. Chem., Vol. 71, No. 23, 2006