Total synthesis of (S)-(+)-tylophorine via enantioselective intramolecular alkene carboamination

Article abstract of DOI:10.1021/jo801024h

(Chemical Equation Presented) The enantioselective synthesis of (S)-(+)-tylophorine, a potent cancer cell growth inhibitor, has been accomplished in eight steps from commercially available 3,4-dimethoxybenzyl alcohol. A copper (II)-catalyzed enantioselective intramolecular alkene carboanimation was employed as the key step to construct the chiral indolizidine ring.

Full text of DOI:10.1021/jo801024h

vitro and in vivo)1b,4 and anti-inflammatory activity2,5 to anti-
ameobicidal6 and anti-viral7 activity. Structure-activity relation-
ship studies focusing on the anticancer activity of these
counpounds have drawn particular interest as many of them are
low nanomolar inhibitors of cancer cell growth, including multi-
drug-resistant cell lines. Notably, based upon the NCI’s COM-
PARE8 analysis,4d their mode of action appears to be different
from other known anticancer compounds.
Total Synthesis of (S)-(+)-Tylophorine Via
Enantioselective Intramolecular Alkene
Carboamination
Wei Zeng and Sherry R. Chemler*
Department of Chemistry, The UniVersity at Buffalo, The
State UniVersity of New York, Buffalo, New York 14260
schemler@buffalo.edu
ReceiVed May 13, 2008
FIGURE 1. Phenanthroindolizidine natural products.
The structures of two particularly potent cancer cell growth
inhibitors in vitro, (S)-tylophorine (1) and (R)-antofine (2), are
illustrated in Figure 1. Although (S)-tylophorine is the unnatural
enantiomer, it is a more potent inhibitor of cancer cell growth
than (R)-tylophorine.4c,d Further investigations into the antican-
cer activity of (S)-tylophorine and (R)-antofine as well as
tylophorinidine, a C(14) hydroxylated, C(2)-desmethoxy analog
of tylophorine, revealed that they are only moderately potent
tumor growth inhibitors in vivo, possibly because of suboptimal
pharmakokinetics.4d,e,g Therefore, the development of a highly
convergent synthesis useful for the discovery of more potent
analogs is desirable.
The enantioselective synthesis of (S)-(+)-tylophorine, a
potent cancer cell growth inhibitor, has been accomplished
in eight steps from commercially available 3,4-dimethoxy-
benzyl alcohol. A copper (II)-catalyzed enantioselective
intramolecular alkene carboamination was employed as the
key step to construct the chiral indolizidine ring.
It is noteworthy that a decrease in molecular complexity via
removal of the indolizidine ring, dubbed the “limiting synthetic
factor” by some researchers, led to substantial reduction of
cancer cell growth inhibitory activity.9 Thus, an efficient route
to analogs with intact indolizidine rings is necessary.
A number of racemic synthetic routes to tylophorine and
antofine have been published, some of them quite concise.1,4g
Both the (R)- and (S)-tylophorine enantiomers have been
synthesized selectively using the chiron approach, starting with
either proline,10 glutamic acid,11 or pyroglutamate,12 as well as
the chiral auxiliary approach manifested in diastereoselective
Grignard additions13 and double Michael reactions,14 respec-
The phenanthroindolizidine and phenanthroquinolizidine al-
kaloids have attracted human interest for centuries.1 As early
as the 1800s, the leaves of one of the plants, Tylophora indica,
from which these compounds are isolated, was recommended
in a medical text as an herbal remedy for conditions such as
bronchitis, rheumatism, and dysentery in India.2 Since the
isolation of the major alkaloid, (R)-tylophorine, in 1935,3 from
Tylophora indica, over 60 compounds in this class have been
isolated from the Asclepiadaceae and Moraceae plant families,
found primarily in India and Japan.1 The biological properties
of these alkaloids range from cancer cell growth inhibition (in
(5) Gopalakrishnan, C.; Shankaranarayanan, D.; Nazimudeen, S. K.; Ka-
meswaran, L. Indian J. Med. Res 1980, 71, 940.
(1) (a) Gellert, E. J. Nat. Prod. 1982, 45, 50. (b) Li, Z.; Jin, Z.; Huang, R.
Synthesis 2001, 2365. (c) Bhakuni, D. S. J. Indian Chem. Soc. 2002, 79, 203.
(2) Gopalakrishnan, C.; Shankaranarayan, D.; Kameswaran, L.; Natarajan,
S. Indian J. Med. Res. 1979, 69, 513.
(6) Bhutani, K. K.; Sharma, G. L.; Ali, M. Planta Med. 1987, 53, 532.
(7) (a) Xi, Z.; Zhang, R.; Yu, Z.; Ouyang, D. Bioorg. Med. Chem. Lett. 2006,
16, 4300. (b) Li, H.; Hu, T.; Wang, K.; Liu, Y.; Fan, Z.; Huang, R.; Wang, Q.
Lett. Org. Chem. 2006, 3, 806.
(3) Rathnagiriswaran, A. N.; Venkatachalam, K. Indian J. Med. Res. 1935,
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Res. Commun. 1968, 31, 104. (b) Ali, M.; Ansari, S. H.; Grever, M. R. Pharmazie
2001, 56, 188. (c) Staerk, D.; Christensen, J.; Lemmich, E.; Duus, J. O.; Olsen,
C. E.; Jaroszewski, J. W. J. Nat. Prod. 2000, 63, 1584. (d) Gao, W.; Lam, W.;
Zhong, S.; Kaczmarek, C.; Baker, D. C.; Geng, Y.-C. Cancer Res. 2004, 64,
678. (e) Gao, W.; Busson, S.; Grill, S. P.; Gullen, E. A.; Hu, U.-C.; Huang, X.;
Zhong, S.; Kaczmarek, C.; Gutierrez, J.; Francis, S.; Baker, D. C.; Yu, S.; Cheng,
Y.-C. Bioorg. Med. Chem. Lett. 2007, 17, 4338. (f) Shiah, H.-S.; Gao, W.; Baker,
D. C.; Cheng, Y.-C. Mol. Cancer Ther. 2006, 5, 2482. (g) Fu, Y.; Lee, S. K.;
Min, H.-Y.; Lee, T.; Lee, J.; Cheng, M.; Kim, S. Bioorg. Med. Chem. Lett. 2007,
17, 97.
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Shi, Q.; Lee, K.-H. Bioorg. Med. Chem. 2006, 14, 6560.
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Fu¨rstner, A.; Kennedy, W. J. Chem. Eur. J. 2006, 12, 7398.
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10.1021/jo801024h CCC: $40.75
Published on Web 06/28/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 6045–6047 6045

SCHEME 1. Retrosynthetic Analysis
SCHEME 2. Phenanthrene Synthesis
SCHEME 3. Completion of (S)-Tylophorine
tively. Reported enantioselective syntheses of antofine make use
of either the chiral pool (proline,10b,7b pyroglutamate,15 methyl
lactate16) or asymmetric catalysis (phase transfer alkylation).17
In the former case,7b however, epimerization of the indolizidine
stereocenter is sometimes observed, while in the latter case the
synthesis is somewhat lengthy.17 Although a considerable
amount of synthetic effort has been exerted toward these targets,
we believed we could contribute uniquely to this area of
research. We sought to develop a concise, convergent, and
enantioselective route to these compounds that would be
amenable to the synthesis of substituted indolizidine analogs
where both the relative and absolute stereochemistry could be
predictably installed. Herein is described our enantioselective
synthesis of (S)-tylophorine, which uses a catalytic asymmetric
carboamination reaction to install the required indolizidine
stereocenter.
We have recently reported the use of copper(II) complexes
in the efficient intramolecular carboamination of terminal
alkenes.18 These reactions result in the formation of polycyclic
aromatic nitrogen heterocycles and can be performed both
diastereoselectively18b and enantioselectively.18c We saw the
carboamination disconnection in tylophorine, wherein sulfona-
mide 4 could undergo enantioselective carboamination to
provide sultam 3, which could be processed in short order to
tylophorine (1) (Scheme 1). The sulfonamide serves a dual
purpose in this reaction, both in increased reactivity (compared
to the corresponding amide) and as a handle for enantioinduction
(we have not been able to render the carboamination reactions
of γ-alkenyl amides asymmetric yet).
Sulfonamide 4 is convergently synthesized from commercially
available 3,4-dimethoxybenzyl alcohol. Conversion of 3,4-
dimethoxybenzyl alcohol (6) to the bromide 7 followed by
radical-induced dimerization19 provided dimer 8 (Scheme 2).
Oxidative cyclization and aromatization with phenyliodine(II-
I)bis(trifluoroacetate) (PIFA) provided the known phenanthrene
9.20 Monosulfonylation with chlorosulfonic acid provided the
necessary arylsulfonyl chloride 5.21 Careful control of the
reaction temperature and equivalents of chlorosulfonic acid was
necessary to avoid disulfonylation.
Coupling of 3-pentenyl amine (10) with arylsulfonyl chloride
5 provided sulfonamide 4 (Scheme 3). Enantioselective car-
boamination, promoted by substoichiometric (0.4 equiv) cop-
per(II)-(R)-Ph-Box 11, provided sultam 3 in 64% yield. Because
of the poor solubility properties of this compound in the HPLC
solvents hexanes/isopropanol, the enantiomeric excess was not
measured at this point. Removal of sulfur dioxide under
dissolving metal conditions (Li/NH3/DMSO) provided the
known10a pyrrolidine 12. The yield of this step is modest because
removal of aryl methoxy groups also occurred under these
conditions.22 A range of reduction conditions were explored as
alternative (Raney nickel, Ni(acac)2/i-Pr2Mg,23 Mg/MeOH,24
Na/NH3), but no superior conditions were identified. Pictet-
Spengler reaction with formaldehyde closed the indolizidine
(15) Faber, L.; Wiegrebe, W. HelV. Chim. Acta 1976, 59, 2201.
(16) Kim, S.; Lee, T.; Lee, E.; Lee, J.; Fan, G.-j.; Lee, S. K.; Kim, D. J.
Org. Chem. 2004, 69, 3144.
(20) (a) Moreno, I.; Tellitu, I.; San Martin, R.; Dominguez, E. Synthesis 2001,
1161. (b) Moreno, I.; Tellitu, I.; Dominguez, E.; San Martin, R. Eur. J. Org.
Chem. 2002, 2126.
(17) Kim, S. H.; Lee, J.; Lee, T.; Park, H.-G.; Kim, D. Org. Lett. 2003, 5,
2703.
(18) (a) Sherman, E. S.; Chemler, S. R.; Tan, T. B.; Gerlits, O. Org. Lett.
2004, 6, 1573. (b) Sherman, E. S.; Fuller, P. H.; Kasi, D.; Chemler, S. R. J.
Org. Chem. 2007, 72, 3896. (c) Zeng, W.; Chemler, S. R. J. Am. Chem. Soc.
2007, 129, 12948. (d) Fuller, P. H.; Chemler, S. R. Org. Lett. 2007, 9, 5477.
(19) Barrero, A. F.; Herrador, M. M.; Quilez Del Moral, J. F.; Arteaga, P.;
Akssira, M.; Hanbali, F. E.; Arteaga, J. F.; Dieguez, H. R.; Sanchez, E. M. J.
Org. Chem. 2007, 72, 2251.
(21) Kanehara, M.; Oumi, Y.; Sano, T.; Teranishi, T. Bull. Chem. Soc. Jpn.
2004, 77, 1589.
(22) This side reaction has been previously observed: Evans, P.; McCabe,
T.; Morgan, B. S.; Reau, S. Org. Lett. 2005, 7, 43.
(23) Milburn, R. R.; Snieckus, V. Angew. Chem., Int. Ed. 2004, 43, 888.
(24) Yokoyama, Y.; Matsumoto, T.; Murakami, Y. J. Org. Chem. 1995, 60,
1486.
6046 J. Org. Chem. Vol. 73, No. 15, 2008

ring,10a thereby providing synthetic (S)-tylophorine (1). The
enantiomeric excess was measured to be 81% on chiral HPLC
(Chiralcel AD-H). The NMR spectra of synthetic tylophorine
matched the reported values,10 and the optical rotation of (S)-
per 5 min was added). After the mixture was stirred at -78 °C
under Ar for 30 min, solid NH4Cl (1.0 g) was added, and the
solution was warmed to room temperature and allowed to evaporate
overnight. EtOAc (10 mL) and aqueous KOH (20%, 10 mL) were
added to the resulting residue. The aqueous layer was extracted
with EtOAc (3 × 15 mL), and the combined organic layers were
dried over Na2SO4. The solvents were removed in vacuo, and flash
chromatography of the resulting crude oil on SiO2 using CH3OH/
aqueous 37% NH4OH (3: 0.1) as eluent afforded 8.5 mg (44%) of
(S)-2-(2,3,6,7-tetramethoxyphenanthren-9-ylmethyl)-pyrrolidine (12)
as a light yellow oil, whose NMR spectrum was identical to that
previously reported for 12.10a [R]23D ) +3.5° (c 0.94, CH2Cl2). 1H
NMR (500 MHz, CDCl3): δ 7.84 (s, 1 H), 7.77 (s, 1 H), 7.48 (s,
1 H), 7.44 (s, 1 H), 7.19 (s, 1 H), 4.12 (s, 3 H), 4.11 (s, 3 H), 4.05
(s, 3 H), 4.03 (s, 3 H), 3.60-3.50 (m, 1 H), 3.19 (d, 2 H, J ) 6.8
Hz), 3.18-3.08 (m, 1 H), 2.90-2.80 (m, 1 H), 1.91-1.88 (m, 2
H), 1.78-1.73 (m, 2 H), 1.60-1.50 (m, 1 H). 13C NMR (75 MHz,
CDCl3): δ 149.4, 149.1, 132.4, 126.9, 126.1, 125.5, 125.2, 124.2,
108.6, 105.5, 104.0, 103.4, 59.2, 56.7, 56.6, 56.5, 56.4, 46.8, 40.8,
32.3, 25.5.
(+)-1, [R]23 ) +62.1° (c 1.0, CHCl3) is in agreement with
D
that reported previously, [R]21 ) +73.0° (c 0.7, CHCl3).10a
D
In summary, we have described a concise and convergent
enantioselective synthesis of (S)-tylophorine. This route is
amenable to the synthesis of either enantiomer of tylophorine
from a common advanced intermediate and is also applicable
to the synthesis of substituted indolizidine analogs via coupling
of arylsulfonyl chloride 5 with a number of functionalized
terminal γ-alkenyl amines. Structure-activity relationship stud-
ies of indolizidine-substituted analogs of tylophorine are in
progress and will be reported in due course.
Experimental Section
Procedure for the Carboamination. (S)-2,3,6,7-Tetramethoxy-
11,12,12a,13-tetrahydro-10H-9-thia-9a-aza-cyclopenta[b]triphenylene-
9,9-dioxide (3). Cu(OTf)2 (10.0 mg, 0.028 mmol, 0.4 equiv), 2,2-
bis[(4R)-4-phenyl-2-oxazolin-2-yl]-propane (9.2 mg, 0.028 mmol,
0.4 equiv), and 2.5 mL of PhCF3 were combined in a pressure tube
equipped with a stir bar under Ar, and the mixture was stirred at
45-50 °C for 1 h to make the Cu(II) salt coordinate with the ligand
completely. This mixture was then treated with K2CO3 (9.5 mg,
0.069 mmol, 1 equiv), MnO2 (18.0 mg, 0.206 mmol, 3 equiv), and
2,3,6,7-tetramethoxyphenanthrene-9-sulfonic acid pent-4-enylamide
(4) (30.6 mg, 0.069 mmol, 1 equiv), and then the tube was refreshed
with Ar for 5 min, sealed, and heated at 120 °C in an oil bath for
24 h. Upon cooling to room temperature, the mixture was diluted
with CHCl3 (2.0 mL) and stirred for about 5 min. Filtration of the
cooled solution and removal of the solvent in vacuo afforded a
crude residue. Successive chromatography on SiO2 (EtOAc/hexane,
3:1; CHCl3/EtOAc, 20:1) afforded purified sultam 3 (20.0 mg, 64%)
as a light yellow solid. This reaction was performed on 0.344 mmol
(S)-(+)-Tylophorine (1). The Pictet-Spengler reaction was
performed by a modification of the procedure as reported by
Njoroge.10a To a solution of amine 12 (7.3 mg, 0.02 mmol) in EtOH
(0.50 mL) were added 37% formaldehyde (0.11 mL) and concen-
trated HCl (11.0 µL). The reaction mixture was refluxed for 2 days
in the dark and then concentrated to dryness under reduced pressure.
The residue was treated with 20% KOH (1 mL), the aqueous layer
was extracted with CH2Cl2 (2 × 3 mL), and the combined organic
layers were washed with water and brine and dried over Na2SO4.
Filtration and concentration in vacuo afforded the crude oil, which
was purified by flash column chromatography on silica gel (CH2Cl2/
MeOH, 20:1) to afford (S)-tylophorine (1) (6.7 mg, 89%) as light
yellow solid. Mp 283-285 °C (lit. mp 282-284 °C,11 284-286
°C10a). [R]23D ) +62.1° (c 1.0 in CHCl3). Lit.10 [R]21D ) +73° (c
0.7 in CHCl3), ee ) 81%, determined by HPLC analysis [Chiralcel
AD-H, 15% IPA/hexane, 0.70 mL/min, λ ) 254 nm, tR (major) )
22.50 min, tR (minor) ) 34.54 min]. 1H NMR (400 MHz, CDCl3):
δ 7.81 (s, 2 H), 7.29 (s, 1 H), 7.14 (s, 1 H), 4.61 (d, 1 H, J ) 16
Hz), 4.11 (s, 6 H), 4.05 (s, 6 H), 3.66 (d, 1 H, J ) 14.4 Hz),
3.51-3.41 (m, 1 H), 3.34 (d, 1 H, J ) 17.2 Hz), 2.90 (t, 1 H, J )
11.2 Hz), 2.48-2.46 (m, 2 H), 2.31-2.20 (m, 1 H), 2.10-2.00
(m, 1 H), 2.00-1.80 (m, 1 H), 1.80-1.70 (m, 1 H). 13C NMR (75
MHz, CDCl3): δ 147.7, 147.5, 147.4, 125.3, 124.8, 123.3, 122.6,
122.4, 103.0, 102.5, 102.3, 102.1, 59.2, 55.0, 54.9, 54.1, 52.9, 32.7,
30.2, 20.6. IR (neat): 2957, 1717, 1602, 1535, 1515, 1472, 1441,
(0.153 g) of 4 as well, and a 61% yield was obtained. Mp 289-291
1
°C (decomposed); [R]23 ) +47.1 ° (c 2 in CH2Cl2). H NMR
D
(400 MHz, CDCl3): δ 8.32 (s, 1 H), 7.79 (s, 1 H), 7.77 (s, 1 H),
7.30 (s, 1 H), 4.40-4.25 (m, 1 H), 4.14 (s, 3 H), 4.12 (s, 3 H),
4.10 (s, 3 H), 4.06 (s, 3 H), 3.80-3.70 (m, 1 H), 3.51-3.39 (m, 2
H), 3.20 (dd, J ) 16.0, 8.0 Hz, 1 H), 2.52-2.40 (m, 1 H),
2.13-2.08 (m, 2 H), 2.00-1.90 (m, 1 H). 13C NMR (75 MHz,
CDCl3): δ 151.3, 150.0, 149.8, 149.7, 130.1, 129.6, 127.0, 125.0,
123.9, 120.9, 107.0, 105.3, 103.7, 103.4, 56.9, 56.5, 46.6, 33.2,
31.3, 23.0. IR (neat): 2959, 2938, 2253, 1619, 1533, 1515, 1476,
1466, 1421, 1278, 1264, 1247, 1213, 1199, 1147, 1044, 1005, 728,
607 cm-1. HRMS (EI) calcd for [M]+ C23H25NO6S 443.1397, found
443.1407.
1425, 1416, 1262, 1249, 1213, 1195, 1150, 1016, 840, 770 cm-1
.
HRMS (EI) calcd for [M]+ C24H27NO4 393.1935, found 393.1933.
These data were in agreement with those reported.10–13
Acknowledgment. The National Institutes of Health (NIGMS)
GM078383 is gratefully acknowledged for financial support of
this work.
Sulfonamide Reduction. (S)-2-(2,3,6,7-Tetramethoxyphenan-
thren-9-ylmethyl)-pyrrolidine (12). The desulfonylation was per-
formed by modification of the procedure reported by Evans.22
Ammonia (10.0 mL) was condensed in a volume-marked two-neck
flask containing sultam 3 (22.5 mg, 0.051 mmol) and dry THF/
DMSO (1.0 mL, 1: 2) at -78 °C under Ar. Lithium metal (3.0 mg,
0.43 mmol, 8.4 equiv) was added over 15 min (1.0 mg of lithium
Supporting Information Available: Procedures and char-
acterization data and NMR spectra for all products. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO801024H
J. Org. Chem. Vol. 73, No. 15, 2008 6047