First asymmetric total synthesis of (-)-antofine by using an enantioselective catalytic phase transfer alkylation

Article abstract of DOI:10.1021/ol0349007

(Matrix presented) The first asymmetric total synthesis of a potential antitumor phenanthroindolizidine alkaloid, (-)-antofine, is described. An important feature of this synthesis is the creation of a stereogenic center by using enantioselective catalyti

Full text of DOI:10.1021/ol0349007

ORGANIC
LETTERS
2003
Vol. 5, No. 15
2703-2706
First Asymmetric Total Synthesis of
(−)-Antofine by Using an
Enantioselective Catalytic Phase
Transfer Alkylation
Sanghee Kim,*,†,‡ Jaekwang Lee,‡ Taeho Lee,‡ Hyeung-geun Park,† and
Deukjoon Kim†
College of Pharmacy, Seoul National UniVersity, San 56-1, Shilim, Kwanak,
Seoul 151-742, Korea, and Natural Products Research Institute, College of Pharmacy,
Seoul National UniVersity, 28 Yungun, Jongro, Seoul 110-460, Korea
pennkim@snu.ac.kr
Received May 21, 2003
ABSTRACT
The first asymmetric total synthesis of a potential antitumor phenanthroindolizidine alkaloid, (−)-antofine, is described. An important feature
of this synthesis is the creation of a stereogenic center by using enantioselective catalytic phase transfer alkylation, affording an unnatural
r-amino acid derivative, together with a ring closing metathesis for pyrrolidine ring construction.
Phenanthroindolizidine alkaloids are a small group of
alkaloids isolated mainly from Cynanchum, Pergularia,
tylophora, and some genera of the Asclepiadaceae family.1,2
These pentacyclic natural products are known for their
profound cytotoxic activity through the inhibition of protein
and nucleic acid syntheses.2,3 Due to their interesting
bioactivity and unusual architecture, many unique and
interesting methodologies have been designed for their
synthesis.2,4
inhibition of cancer cell growth. Antofine has IC50 values in
the low nanomolar range, comparable to that of clinically
employed cytotoxic drugs.2,3,5 It is cytotoxic to drug-sensitive
and multidrug-resistant cells.3 Recent mechanism studies by
Among these alkaloids, (-)-antofine (1, Figure 1) has
recently attracted attention because of its extremely potent
† College of Pharmacy, Seoul National University.
‡ Natural Products Research Institute, Seoul National University.
(1) Gellert, E. In Alkaloids: Chemical and Biological PerspectiVes;
Pelletier, S. W., Ed.; Academic Press: New York, 1987; pp 55-132.
(2) Suffness, M.; Cordell, G. A. In The Alkaloids, Chemistry and
Pharmacology; Brossi, A., Ed.; Academic Press: New York, 1985; Vol.
25, pp 3-355.
(3) Stærk, D.; Lykkeberg, A. K.; Christensen, J.; Budnik, B. A.; Abe,
F.; Jaroszewski, J. W. J. Nat. Prod. 2002, 65, 1299-1302 and references
therein.
Figure 1. Chemical structures of compounds 1 and 2.
10.1021/ol0349007 CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/03/2003

Lee et al. indicated that antofine exhibits an inhibitory activity
on cell proliferation by arresting the G2/M phase of the cell
cycle.5
acid 8 and p-anisaldehyde 9 via the conventional four-step
sequence, according to the previously reported procedure of
Weinreb and co-workers (Scheme 2).9 Treatment of alcohol
10 with CBr4 and PPh3 provided bromide 7 in 98% yield.10
To further investigate the biochemical and pharmaceutical
effects of (-)-antofine, we needed to synthesize this alkaloid
in large quantities, due to its low natural abundance. A variety
of syntheses of antofine and other phenanthroindolizidine
alkaloids, e.g. tylophorine (2, Figure 1), in both racemic and
optically active forms have been reported.2,4,6,7 However, the
selective asymmetric synthesis of naturally occurring (-)-
antofine has not been achieved yet. Thus far, the synthesis
of the optical antipode of natural antofine has only once been
carried out, using an (S)-amino acid derivative, (S)-5-
(toluene-4-sulfonyloxymethyl)pyrrolidin-2-one, as the chiral
precursor.7 In this context, we describe an enantioselective
synthetic approach to (-)-antofine, which is unique as
compared to other previous phenanthroindolizidine alkaloid
syntheses. In our synthesis, the chirality was introduced by
employing the enantioselective catalytic phase transfer alky-
lation reaction, thus affording an unnatural R-amino acid
derivative.
Scheme 2a
The strategy of our synthesis is presented in Scheme 1.
The D ring of the phenanthroindolizidine skeleton could be
constructed at the last stage of the synthesis by employing
the reported Pictet-Spengler annulation of the amine 3,4a,7
which has been previously synthesized via a different
synthetic route. We envisioned the pyrrolidine ring of the
cyclization precursor 3 coming from the bis-allylated amine
4, via sequential ring-closing metathesis8 and hydrogenation.
The requisite amine 4 could be synthesized from the chiral
R-amino ester 5, which would be accessed by the enanti-
oselective catalytic phase transfer alkylation of the protected
glycine derivative 6 with phenanthryl bromide 7.
a Reagents and conditions: (a) CBr4, PPh3, CH3CN, 0 °C, 1 h,
98%; (b) 6, 11 (2 mol %), 50% aq NaOH, PhCH3/CHCl3 (7:3), 0
°C, 3 days, 97%, 96% ee.
There are a number of methodologies in the literature
concerning the enantioselective synthesis of unnatural R-ami-
Scheme 1. Retrosynthetic Analysis of Antofine
(5) Lee, S. K.; Nam, K.-A.; Heo, Y.-H. Plant Med. 2003, 69, 21-25.
(6) For a synthesis of racemic antofine, see: (a) Govindachari, T. R.;
Ragade, I. S.; Viswanathan, N. J. Chem. Soc. 1962, 1357-1360. (b)
Chauncy, B.; Gellert, E. Aust. J. Chem. 1970, 23, 2503-2516. (c) Iwao,
M.; Mahalanabis, K. K.; Watanabe, M.; De Silva, S. O.; Snieckus, V.
Tetrahedron 1983, 39, 1955-1962. (d) Iwao, M.; Watanabe, M.; De Silva,
S. O.; Snieckus, V. Tetrahedron Lett. 1981, 22, 2349-2352. (e) Bhakuni,
D. S.; Gupta, P. K. Indian J. Chem., Sect. B 1982, 21B, 393-395. See also
refs 4a and 4b.
(7) For a synthesis of the antipodal isomer of antofine, see: (a) Faber,
L.; Wiegrebe, W. HelV. Chim. Acta 1976, 59, 2201-2212. (b) Faber, L.;
Wiegrebe, W. HelV. Chim. Acta 1973, 56, 2882-2884.
(8) For the application of the ring-closing metathesis reaction to the
synthesis of 2,5-dihydropyrroles from dienes, see: (a) Huwe, C. M.; Velder,
J.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1996, 35, 2376-2378. (b)
Fu¨rstner, A.; Picquet, M.; Bruneau, C.; Dixneuf, P. H. Chem Commun. 1998,
1315-1316. (c) Cerezo, S.; Cortes, J.; Moreno-Manas, M.; Pleixats, R.;
Roglans, A. Tetrahedron 1998, 54, 14869-14884. (d) Fu¨rstner, A.;
Ackermann, L. Chem. Commun. 1999, 95-96. (e) Bujard, M.; Briot, A.;
Gouverneur, V.; Mioskowski, C. Tetrahedron Lett. 1999, 40, 8795-8788.
(f) Fu¨rstner, A.; Liebl, M.; Hill, A. F.; Wilton-Ely, J. D. E. T. Chem.
Commun. 1999, 601-602. (g) Ackermann, L.; Fu¨rstner, A.; Weskamp, T.;
Kohl, F. J.; Hermann, W. A. Tetrahedron Lett. 1999, 40, 4787-4790. (h)
Ahmed, M.; Barrett, A. G. M.; Braddock, D. C.; Cramp, S. M.; Procopiou,
P. A. Tetrahedron Lett. 1999, 40, 8657-8662. (i) Evans, P. A.; Robinson,
J. E. Org. Lett. 1999, 1, 1929-1931. (j) Hunt, J. C. A.; Laurent, P.; Moody,
C. J. Chem. Commun. 2000, 1771-1772. (k) Lindsay, K. B.; Pyne, S. G.
J. Org. Chem. 2002, 67, 7774-7780.
The synthesis began by preparing the known phenanthryl
alcohol 10 from the commercially available homoveratric
(4) For a good review with citations to recent work, see: (a) Lebrun, S.;
Couture, A.; Deniau, E.; Grandclaudon, P. Tetrahedron 1999, 55, 2659-
2670. (b) Ciufolini, M. A.; Roschangar, F. J. Am. Chem. Soc. 1996, 118,
12082-12089. (c) Pearson, W. H.; Walavalkar, R. Tetrahedron 1994, 50,
12293-12304.
(9) Bremmer, M. L.; Khatri, N. A.; Weinreb, S. M. J. Org. Chem. 1983,
48, 3661-3666.
2704
Org. Lett., Vol. 5, No. 15, 2003

no acids by the alkylation of an alkyl or aryl halide.11,12
Among those, we adapted the catalytic phase transfer
alkylation reaction13 for its practical operation and efficiency.
The carbon-carbon bond formation between the aryl bro-
mide 7 and the tert-butyl glycinate-benzophenone Schiff base
6 was investigated by using the phase transfer catalyst 11
that was recently developed by one of us.13a To our delight,
the enantioselective catalytic phase transfer alkylation reac-
tion to the synthesis of R-amino ester 12, bearing a bulky
substituent on the R-carbon, by using a catalyst 11 was
successfully achieved under the slightly modified reaction
conditions.14 Treatment of aryl bromide 7 with a slight excess
of 6 (1.2 equiv) in the presence of 50% aqueous NaOH and
11 (2 mol %) in PhCH3/CHCl3 (7:3) at 0 °C led to the
formation of the desired R-amino ester 12 with excellent
enantioselectivity (96% ee) and yield (97%).15 We believe
that such successful synthetic application would broaden the
utility of this catalytic phase transfer alkylation in natural
product synthesis.
yield. Swern oxidation of alcohol 13, followed by Wittig
reaction of the resulting unstable aldehyde with methylidene
triphenylphosphorane, provided the corresponding olefin 14
in 68% overall yield with no racemization problems.16 The
electrophilic allylation of the secondary amine 14 with allyl
bromide and K2CO3 at 60 °C in DMF led to the formation
of the bis-allylamine 15 in high yield (86%).17 The crucial
ring-closing metathesis of 15 was successfully performed
with Grubbs’s phosphorylidine catalyst18 [RuCl2(dCHPh)-
(PCy3)2] in CH2Cl2 at room temperature, to produce the
desired 2,5-dihydropyrrole derivative 16 in 92% yield.
Simultaneous reduction of the double bond and deprotection
of the diphenylmethyl protecting group by catalytic hydro-
genation afforded the previously known pyrrolidine 34a in
82% yield. Finally, the Pictet-Spengler cyclomethylenation
of amine 3, using the previously reported reaction con-
ditions4a,19 (formaldehyde, HCl, EtOH, reflux), afforded (-)-
antofine (1) in 64% yield. The spectroscopic data (1H and
13C NMR) for 1 were identical with those of the natural
antofine. The optical rotation measured for the synthetic 1
With multigram quantities of 12 in hand, we began the
second stage of our synthesis of antofine by converting the
R-amino ester functional group to a pyrrolidine ring (Scheme
3). Treatment of 12 with LAH effected the reduction of
{[R]22 -108.2 (c 0.71, CHCl3)} is between the values
D
reported for the natural antofine.20
In conclusion, we have accomplished the first asymmetric
total synthesis of (-)-antofine. An important feature of this
synthesis is the creation of a stereogenic center by using the
enantioselective catalytic phase transfer alkylation together
Scheme 3a
(10) This compound appeared to be sensitive to silica gel chromatog-
raphy. It was very important to minimize the residency time of this
compound on the chromatography column to obtain this product in high
yield.
(11) Williams, R. M. Synthesis of Optically Active R-Amino Acids. Vol.
7 of Organic Chemistry Series; Baldwin, J. E., Magnus, P. D., Eds.;
Pergamon Press: Oxford, UK, 1989.
(12) (a) Duthaler, R. O. Tetrahedron 1994, 50, 1539-1650. (b)
Chakraborty, T. K.; Ghosh, A. Tetrahedron Lett. 2002, 43, 9691-9693
and references therein.
(13) For a good review with citations, see: (a) Park, H.-g.; Jeong, B.-
S.; Yoo, M.-S.; Lee, J.-H.; Park, M.-k.; Lee, Y.-J.; Kim, M.-J.; Jew, S.-s.
Angew. Chem., Int. Ed. 2002, 41, 3036-3038. (b) Lygo, B.; Crosby, J.;
Lowdon, T. R.; Peterson, J. A.; Wainwright, P. G. Tetrahedron 2001, 57,
2403-2409. (c) O’Donnell, M. J. Aldrichim. Acta 2001, 34, 3-15. (d)
O’Donnell, M. J. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; Wiley-
VCH: New York, 2000; Chapter 10.
(14) For the previous asymmetric phase transfer alkylation involving
bulky electrophiles, see ref 13a and: Lygo, B.; Andrews, B. I.; Crosby, J.;
Peterson J. A. Tetrahedron Lett. 2002, 43, 8015-8018.
(15) The absolute configuration of 12 was reconfirmed by transformation
to the authentic natural compound (-)-1. The enantiomeric excess of 12
was determined by chiral stationary phase HPLC analysis (CHIRALCEL
OD-H, hexane/2-propanol (9:1, v/v), flow rate 0.5 mL/min, retention
time 25.52 min (S)-isomer and 30.33 min (R)-isomer, detected at
254 nm).
(16) Albeck, A.; Persky, R. J. Org. Chem. 1994, 59, 653-657.
(17) Lorthiois, E.; Marek, I.; Normant, J. F. J. Org. Chem. 1998, 63,
566-574.
(18) (a) Schwab, P.; Grubbs, R. M.; Ziller, J. W. J. Am. Chem. Soc.
1996, 118, 100-110. (b) Dias, E. L.; Nguyen, S. T.; Grubbs, R. H. J. Am.
Chem. Soc. 1997, 119, 3887-3897.
a Reagents and conditions: (a) LiAlH4, THF, 0 °C to rt, 1 h,
81%; (b) DMSO, oxalyl chloride, Et3N, CH2Cl2, -78 °C to rt, 30
min; (c) CH3PPh3+I-, n-BuLi, THF, 0 °C, 30 min, 68% from 13;
(d) allyl bromide, K2CO3, DMF, 60 °C, 2 days, 86%; (e) Grubbs’s
catalyst (2 mol %), CH2Cl2, rt, 1 day, 92%; (f) H2, 10% Pd/C, EtOH,
16 h, 82%; (g) HCHO, HCl, EtOH, reflux, 21 h, 64%, in the dark.
(19) Nordlander, J. E.; Njoroge, F. G. J. Org. Chem. 1987, 52, 1627-
1630.
(20) The optical rotation values of natural antofine range from -32° to
-165°. see: (a) Cave´, A.; Leboeuf, M.; Moskowitz, H.; Ranaivo, A.; Bick,
I. R. C.; Sinchai, W.; Nieto, M.; Sevenet, T.; Cabalion, P. Aust. J. Chem.
1989, 42, 2243-2263. (b) Baumgartner, B.; Erdelmeier, C. A. J.; Wright,
A. D.; Rali, T.; Sticher, O. Phytochemistry 1990, 29, 3327-3330. (c) Li,
X.; Peng, J.; Onda, M. Heterocycles 1989, 29, 1797-1808. (d) Herbert, R.
B.; Moody, C. J. Phytochemistry 1972, 11, 1184-1184. (e) Capo, M.; Saa,
J. M. J. Nat. Prod. 1989, 52, 389-390. (f) Wiegrebe, W.; Faber, L.;
Brockmann, H., Jr.; Budzikiewicz, H.; Krueger, U. Liebigs Ann. Chem.
1969, 721, 154-162. See also refs 3 and 7.
benzophenonimine and the concomitant reduction of the tert-
butyl ester to afford the desired amino alcohol 13 in 81%
Org. Lett., Vol. 5, No. 15, 2003
2705

with a ring-closing metathesis for pyrrolidine ring construc-
tion. We believe that this synthesis is efficient enough to
allow the asymmetric preparation of other naturally occurring
phenanthroindolizidine and phenanthroquinolizidine alka-
loids, as well as other modified analogues.
ref 15, the retention times for the (R)- and (S)-isomers were
transposed. These errors were also present in the Supporting
Information. The corrected version and new Supporting
Information were posted on July 9, 2003.
Supporting Information Available: Full experimental
1
Acknowledgment. This study was supported by a grant
from the Korea Health 21 R&D Project, Ministry of Health
& Welfare, Republic of Korea (01-PJ2-PG6-01NA01-0002).
procedures and analytical data of compounds; copies of H
NMR and 13C NMR spectra of compounds 1, 3, 12, and 15;
HPLC data of compound 12. This material is available free
of charge via the Internet at http://pubs.acs.org.
Note Added after ASAP Posting. There were errors in
compound 11 of Scheme 2 in the version posted on July 3,
2003; the corrected version was posted on July 8, 2003. In
OL0349007
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