Racemization-free synthesis of (S)-(+)-tylophorine from l -proline by radical cyclization

Article abstract of DOI:10.1021/ol100652b

Figure presented The phenanthroindolizidine alkaloid (S)-(+)-tylophorine was synthesized from l-proline in nine linear steps including a double bromination and a free-radical cyclization of an N-aziridinylimine as the key steps. The phenanthrene moiety was prepared from homoveratric acid and veratraldehyde and permits the variation of each oxygen-substituted ring.

Full text of DOI:10.1021/ol100652b

ORGANIC
LETTERS
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010
Vol. 12, No. 9
140-2141
Racemization-Free Synthesis of
2
(S)-(+)-Tylophorine from L-Proline by
Radical Cyclization
Alexander Stoye and Till Opatz*
Department of Chemistry, UniVersity of Hamburg, Martin-Luther-King-Platz 6,
D-20146 Hamburg, Germany
opatz@chemie.uni-hamburg.de
Received March 19, 2010
ABSTRACT
The phenanthroindolizidine alkaloid (S)-(+)-tylophorine was synthesized from L-proline in nine linear steps including a double bromination
and a free-radical cyclization of an N-aziridinylimine as the key steps. The phenanthrene moiety was prepared from homoveratric acid and
veratraldehyde and permits the variation of each oxygen-substituted ring.
7
Phenanthroindolizidine and phenanthroquinolizidine alkaloids
represent a group of pentacyclic natural products isolated
mainly from the Cynanchum, Pergularia, and Tylophora
downregulation of cyclin A2 expression, while (R)-antofine
exerts its cytotoxic effects via cell cycle arrest in the G2/M
phase. The naturally occurring tylophorine is the levorota-
tory (R)-enantiomer, although its optical antipode surprisingly
was found to be an even more potent inhibitor of cancer
cell growth. Consequently, numerous synthetic approaches
to the phenanthroindolizidines and the phenanthroquinoliz-
8
1
,2
species. Today, more than 60 members of this class are
known. Because of their potent biological and pharmacologi-
cal activities, they are of significant interest for medical
9
3,4
research. For example, some of these compounds suppress
5
6
10
protein biosynthesis and exhibit antiinflammatory effects.
Tylophorine (1) arrests carcinoma cells in the G1 phase by
idines have been developed.
Herein, we report a short racemization- and protecting-
group-free synthesis of (S)-(+)-tylophorine from L-proline,
veratraldehyde, and homoveratric acid (2). Condensation of
the latter two starting materials in a mixture of triethylamine
and acetic anhydride, followed by esterification of the free
acid with acetyl chloride in methanol, afforded methyl ester
(
1) Ratnagiriswaran, A. N.; Venkatachalam, K. Indian. J. Med. Res.
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10.1021/ol100652b  2010 American Chemical Society
Published on Web 04/08/2010

1
2
18
3
.
This compound undergoes oxidative cyclization upon
of Kim, leading to the direct formation of the pentacyclic
treatment with [bis(trifluoroacetoxy)iodo]benzene in com-
bination with boron trifluoride etherate to furnish the
phenanthrene carboxylate. After treatment with lithium
alkaloid in 61% yield.
1
3
aluminum hydride in THF, the corresponding alcohol 4 was
obtained (Scheme 1).
Scheme 2
1
0c,e,g
Scheme 1
3
The use of AIBN/Bu SnH in boiling benzene or in toluene
at 90 °C led to significant debromination of the starting
material, and the reactions furnished only small amounts
(20% and 35%, respectively) of tylophorine while the use
Subsequently, alcohol 4 was treated with 1.1 equiv of
bromine in dichloromethane, resulting in the formation of
14
the double-brominated compound 5, which cleanly effects
of the Et
Me Si) SiH did not afford the desired product. The best
results were obtained by using AIBN and Ph SnH in toluene
3 2 3
B/O system in combination with Bu SnH or
the N-alkylation of L-proline methyl ester in 92% yield
Scheme 2). Reduction of the obtained ester 6 with an excess
of diisobutyl aluminum hydride in toluene at -78 °C turned
out to be the method of choice for obtaining the unstable
(
3
3
(
3
at 80 °C, where (S)-(+)-tylophorine (1) was obtained in 61%
yield with an enantiomeric excess of more than 99% (HPLC,
ChiralPak AD-H, see the Supporting Information). The
4
aminoaldehyde. Interestingly, reduction of 6 with LiAlH in
THF at room temperature resulted in quantitative debromi-
nation of the phenanthrene moiety. The crude aminoaldehyde
was immediately transformed to the hydrazone 8 in 79%
yield which was obtained as a mixture of diastereomers. The
amino aziridine used as the nucleophile (7) was prepared in
2
2
optical rotation ([R]
D
3
) +78.9 (c ) 0.5, CHCl )) is slightly
1
0d,e
higher than the values reported in the literature.
In summary, a very short and efficient synthesis of (S)-
+)-tylophorine of high optical purity has been described.
(
1
5
16
It requires only nine steps in the longest linear sequence,
provides the target compound in an overall yield of 31%
from readily available starting materials, and is devoid of
any protecting group manipulations.
two steps from styrene glycol. To achieve the 6-exo-trig
ring closure, the bromo-substituted N-aziridinylimine 8 was
17
subjected to a free-radical reaction according to the method
(
10) (a) Bradsher, C. K.; Berger, H. J. Am. Chem. Soc. 1957, 79, 3287–
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(
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OL100652B
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