A formal synthesis of (-)-cephalotaxine

Article abstract of DOI:10.1021/ol8010166

(Chemical Equation Presented) An enantioselective formal synthesis of the alkaloid (-)-cephalotaxine has been completed, using an alkylidene carbene 1,5-CH insertion reaction as a key step to construct the spiro[4.4]azanonane core D/E-ring system. A Heck-type cyclization was used to close the tetrahydroazepine C-ring and a selective epoxidation-rearrangement sequence was used to elaborate the E-ring.

Full text of DOI:10.1021/ol8010166

ORGANIC
LETTERS
2
008
A Formal Synthesis of (-)-Cephalotaxine
Vol. 10, No. 14
†
William R. Esmieu, Stephen M. Worden, David Catterick, Claire Wilson, and
†
‡
†
3045-3048
,†
Christopher J. Hayes*
School of Chemistry, UniVersity of Nottingham, UniVersity Park, Nottingham NG7
RD, U.K., and GlaxoSmithKline, Old Powder Mills, Tonbridge, Kent TN11 9AN, U.K.
2
chris.hayes@nottingham.ac.uk
Received May 2, 2008
ABSTRACT
An enantioselective formal synthesis of the alkaloid (-)-cephalotaxine has been completed, using an alkylidene carbene 1,5-CH insertion
reaction as a key step to construct the spiro[4.4]azanonane core D/E-ring system. A Heck-type cyclization was used to close the tetrahydroazepine
C-ring and a selective epoxidation-rearrangement sequence was used to elaborate the E-ring.
1
Since its isolation in 1963, the polycyclic alkaloid (-)-
cephalotaxine (1) has become an enduring target for total
2
,3
chemical synthesis (Figure 1). The continued interest in
this molecule is due to a combination of its fascinating
chemical structure and it being the parent of a larger family
of related alkaloid esters that show clinically useful anticancer
activity. Homoharringtonine (2), for example, is undergoing
4
clinical trials for use as an antileukemia drug.
†
University of Nottingham.
GlaxoSmithKline.
‡
Figure 1
2)
. Structures of cephalotaxine (1) and homoharringtonine
(
1) (a) Isolation: Paudler, W. W.; Kerley, G. I.; McKay, J. J. Org. Chem.
(
1
963, 28, 2194. (b) Structure elucidation: Abraham, D. J.; Rosenstein, R. D.;
McGandy, E. L. Tetrahedron Lett. 1969, 4085. (c) Arora, S. K.; Bates,
R. B.; Grady, R. A.; Powell, R. G. J. Org. Chem. 1974, 39, 1269.
2
3
(
2) (a) Racemic syntheses: Auerbach, J.; Weinreb, S. M. J. Am. Chem.
A number of racemic and enantioselective syntheses of
Soc. 1972, 94, 7172. (b) Semmelhack, M. F.; Chong, B. P.; Jones, L. D.
J. Am. Chem. Soc. 1972, 94, 8629. (c) Semmelhack, M. F.; Chong, B. P.;
Stauffer, R. D.; Rogerson, T. D.; Chong, A.; Jones, L. D. J. Am. Chem.
Soc. 1975, 97, 2507. (d) Weinreb, S. M.; Auerbach, J. J. Am. Chem. Soc.
cephalotaxine have been published to date, and the efficient
asymmetric construction of the embedded spiro[4.4]azanonane
ring system has proven to be a significant challenge. Our
1
975, 97, 2503. (e) Burkholder, T. P.; Fuchs, P. L. J. Am. Chem. Soc. 1988,
1
10, 2341. (f) Kuehne, M. E.; Bornmann, W. G.; Parsons, W. H.; Spitzer,
T. D.; Blount, J. F.; Zubieta, J. J. Org. Chem. 1988, 53, 3439. (g)
Burkholder, T. P.; Fuchs, P. L. J. Am. Chem. Soc. 1990, 112, 9601. (h)
Ishibashi, H.; Okano, M.; Tamaki, H.; Maruyama, K.; Yakura, T.; Ikeda,
M. J. Chem. Soc., Chem. Commun. 1990, 1436. (i) Ikeda, M.; Okano, M.;
Kosaka, K.; Kido, M.; Ishibashi, H. Chem. Pharm. Bull. 1993, 41, 276. (j)
Lin, X.; Kavash, R. W.; Mariano, P. S. J. Am. Chem. Soc. 1994, 116, 9791.
(3) (a) Enantioselective syntheses: Zhong, S.; Liu, W.; Ling, Y.; Li, R.
Zhongguo Yaowu Huaxue Zazhi 1994, 4, 84. (b) Isono, N.; Mori, M. J.
Org. Chem. 1995, 60, 115. (c) Nagasaka, T.; Sato, H.; Saeki, S.-I.
Tetrahedron: Asymmetry 1997, 8, 191. (d) Ikeda, M.; El Bialy, S. A. A.;
Hirose, K.-I.; Kotake, M.; Sato, T.; Bayomi, S. M. M.; Shehata, I. A.;
Abdelal, A. M.; Gad, L. M.; Yakura, T. Chem. Pharm. Bull. 1999, 47,
983. (e) Tietze, L. F.; Schirok, H. J. Am. Chem. Soc. 1999, 121, 10264. (f)
El Bialy, S. A. A.; Ismail, M. A.; Gad, L. M.; Abdelal, A. M. M. Med.
Chem. Res. 2002, 11, 293. (g) Planas, L.; Perard-Viret, J.; Royer, J. J. Org.
Chem. 2004, 69, 3087. (h) Eckelbarger, J. D.; Wilmot, J. T.; Gin, D. Y.
J. Am. Chem. Soc. 2006, 128, 10370. (i) Zhao, Z.; Mariano, P. S.
Tetrahedron 2006, 62, 7266. (j) Liu, Q.; Ferreira, E. M.; Stoltz, B. M. J.
Org. Chem. 2007, 72, 7352.
(
(
(
k) Lin, X.; Kavash, R. W.; Mariano, P. S. J. Org. Chem. 1996, 61, 7335.
l) Tietze, L. F.; Schirok, H. Angew. Chem., Int. Ed. Engl. 1997, 36, 1124.
m) Koseki, Y.; Sato, H.; Watanabe, Y.; Nagasaka, T. Org. Lett. 2002, 4,
8
85. (n) Li, W.-D. Z.; Wang, Y.-Q. Org. Lett. 2003, 5, 2931. (o) Li, W.-
D. Z.; Ma, B.-C. J. Org. Chem. 2005, 70, 3277. (p) Ma, B.-C.; Wang, Y.-
Q.; Li, W.-D. Z. J. Org. Chem. 2005, 70, 4528. (q) Li, W.-D. Z.; Wang,
X.-W. Org. Lett. 2007, 9, 1211
.
10.1021/ol8010166 CCC: $40.75
Published on Web 06/13/2008
 2008 American Chemical Society

previous model study in this area showed that this spirocycle
could be constructed using an alkylidene carbene 1,5-CH
insertion reaction, and we now wish to report the successful
5
Scheme 2. Synthesis of Pentacycle 5
application of this novel strategy to an enantioselective
formal total synthesis of 1. Weinreb first showed that 1 can
be synthesized from the related natural product demethyl-
2
a
cephalotaxinone (3) in two steps, and this dione therefore
became our interim target. We were aware of previous
synthetic work that had shown that ꢀ-amino ketones such
as 3 have to be handled with care as they can undergo
racemization of the nitrogen-bearing quaternary stereocenter
2
k,3b
via sequential elimination-Michael addition reactions.
In order to minimize our exposure to this racemization
problem, we decided to attempt installation of the R-dicar-
bonyls at a late stage in our synthesis from the cyclopentene
5
via oxidation to the enone 4 and subsequent oxidative
cleavage to provide 3 (Scheme 1).
Scheme 1. Retrosynthetic Analysis of Cephalotaxine (1)
the corresponding aldehyde, and this was homologated with
-triphenylphosphoranylidene-2-propanone to give the E-enone.
Catalytic hydrogenation (Pd(OH) /C, H ) then gave 10, and a
second Wittig reaction then afforded the vinyl chloride 11 (3:
, E:Z) in good overall yield. Deprotection (TFA, CH Cl ),
amide formation with the carboxylic acid 12 (EDCI, HOBt),
and reduction of the resulting amide (LiAlH ) then afforded
1
2
2
1
2
2
4
the desired alkylidene carbene precursor 13. The pivotal
Disconnection of 5 revealed the spiro[4.4]azanonane 7 as
an advanced precursor, with the tetrahydroazepine ring being
formed in the synthetic direction via a Heck-type cyclization
similar to that used by Tietze et al. (i.e., 7 f 5). We
envisaged that the aromatic iodide 7 could be accessed from
alkylidene carbene 1,5-CH insertion reaction was then effected
6
by teatment of 13 with KHMDS (2 equiv) at room temperature
to afford the desired spiro[4.4]azanonane 6 in good yield
3
e
(
I
2
7
65-79%). Regioselective iodination of the aromatic ring (TFA,
, CF CO Ag) then gave the key Heck-cyclization precursor
At this stage, an X-ray crystal structure of the iodide 7
3
2
6
, which itself could be constructed via a 1,5-CH insertion
3e
.
reaction of the pyrrolidine-substituted alkylidene carbene 8.
Our first synthetic task, therefore, was to prepare a suitable
precursor to the alkylidene carbene 8.
Our chosen carbene precursor was the vinyl chloride 13, and
this was easily prepared in seven steps from N-Boc-proline
methyl ester (9) (Scheme 2). Reduction of 9 with Dibal-H gave
7
was obtained (Figure 2). In addition to demonstrating spiro-
cycle formation, the presence of the iodine atom allowed us to
confirm the molecule’s absolute stereochemistry, thus demon-
strating that the 1,5-CH insertion reaction had proceeded with
retention of configuration as expected.
The Heck cyclization (7 f 5) proved to be much more
difficult than we had expected and required extensive
optimization (Scheme 2). Hermann and Beller’s palladacycle
(
4) (a) Levy, V.; Zohar, S.; Bardin, C.; Vekhoff, A.; Chaoui, D.; Rio,
B.; Legrand, O.; Sentenac, S.; Rousselot, P.; Raffoux, E.; Chast, F.; Chevret,
S.; Marie, J. P. Br. J. Cancer 2006, 95, 253. (b) Kantarjian, H. M.; Talpaz,
M.; Santini, V.; Murgo, A.; Cheson, B.; O’Brien, S. M. Cancer 2001, 92,
8
catalyst gave only low and capricious yields of 5, while
the use of more traditional conditions (Pd(OAc)
2 3
/Ph P/
1
591.
9
(
5) Worden, S. M.; Mapitse, R.; Hayes, C. J. Tetrahedron Lett. 2002,
K
2
CO ) gave the enamine 14 as the major product (84%)
3
4
3, 6011.
with the desired pentacycle 5 representing only a minor
(
6) (a) Taber, D. F.; Christos, T. E.; Neubert, T. D.; Batra, D. J. Org.
Chem. 1999, 64, 9673. (b) Taber, D. F.; Neubert, T. D. J. Org. Chem. 2001,
6, 143. (c) Taber, D. F.; Neubert, T. D.; Rheingold, A. L. J. Am. Chem.
Soc. 2002, 124, 12416. (d) Auty, J. M. A.; Churcher, I.; Hayes, C. J. Synlett
6
(7) The crystallographic data have been deposited with the Cambridge
Crystallographic Data Centre. CCDC 682009 contains the supplementary
crystallographic data for 7, and CCDC 682010 contains the supplementary
crystallographic data for 15. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
2
004, 1443. (e) Hayes, C. J.; Sherlock, A. E.; Selby, M. D. Org. Biol. Chem.
006, 4, 193. (f) Bradley, D. M.; Mapitse, R.; Thomson, N. M.; Hayes,
2
C. J. J. Org. Chem. 2002, 67, 7613. (g) Green, M. P.; Prodger, J. C.;
Sherlock, A. E.; Hayes, C. J. Org. Lett. 2001, 3, 3377.
3046
Org. Lett., Vol. 10, No. 14, 2008

1
1,12
BF
3
·OEt
2
(63-90%)
or m-CPBA/TFA (60%), and the
stereochemistry of the epoxide 15 was confirmed by X-ray
7
crystallography (Figure 3).
Figure 2. X-ray crystal structure of spirocycle 7.
component (14%). In contrast to these somewhat disappoint-
ing results, the desired cyclization could be effected in
acceptable yield (61%) by using a slightly modified version
Figure 3. X-ray crystal structure of epoxide 15.
t
of Fu’s conditions (Pd(OAc)
2 4 3 2 3
, BF H·P Bu , Cs CO , dioxane
1
0
reflux). Under these conditions, the enamine 14 was still
formed (30%), but it was easily separated from 5 via SiO
column chromatography. It was essential to use Pd(OAc)
2
Regioselective rearrangement of the epoxide 15 using
Yamamoto’s conditions then produced the allylic alcohol
6 in quantitative yield, and oxidation of 16 under Swern
conditions finally afforded the desired enone 4. Unfortu-
nately, we were not able to effect the desired oxidative
cleavage reaction of 4 to produce demethylcephalotaxinone
3) as the enone 4 proved to be quite unstable and
spontaneously dimerized in solution to afford the endo
2
13
as the palladium source in this reaction as the use of Pd(0)
precatalysts (e.g., Pd (dba) ) gave inferior results with the
1
2
3
reduced compound 6 (12%) being produced in addition to
the enamine 14 (23%) and the desired compound 5 (41%).
Having closed the C-ring of cephalotaxine, our next
challenge was elaboration of the E-ring (Scheme 3). Under
(
hetero-Diels-Alder adduct 17 in a regio- and stereoselective
1
4
manner (Scheme 3). As oxidative cleavage of 4 was not
possible, a modified strategy for the completion of the
synthesis was developed (Scheme 4).
a
Scheme 3. Elaboration of the E-Ring
a
Scheme 4. Completion of the Synthesis
a
Key: (a) BF3·OEt2, Et2O, -78 °C, then DMDO, CH2Cl2, 0 °C, 63-90%;
b) n-BuLi, TMP, AlEt2Cl, toluene, 0 °C, quant; (c) (COCl)2, DMSO, NEt3,
(
DCM, -60 °C, quant (to 4).
a
Key: (a) Ac2O, pyridine, 23 °C; (b) 5% aqueous HCl, reflux, 58%
(
three steps from 15); (c) (COCl)2, DMSO, NEt3, DCM, -60 °C, 53%; (d)
carefully optimized conditions the alkene was epoxidized in
the presence of the tertiary amine using either DMDO/
Rh(PPh ) Cl, toluene, reflux, 20-40%.
3
3
Org. Lett., Vol. 10, No. 14, 2008
3047

First, the secondary alcohol 16 was converted to the acetate
8, which was then exposed to 5% HCl(aq) to afford the
bonylated product 21 was recovered cleanly from this
reaction (100% mass recovery), although a significant amount
of material was lost during the final chromatographic
1
primary alcohol 19 (Scheme 4). Swern oxidation of 19 then
afforded aldehyde 20, which was then treated with Wilkin-
3b
purification on SiO
that 21 can be converted into 1, via demethylcephalotaxinone
3), we have successfully completed a novel formal synthesis
2
gel. Since Mori has shown previously
1
5
son’s catalyst in toluene at reflux. Pleasingly, the decar-
(
(
8) Herrmann, W. A.; Brossmer, C.; Reisinger, C.-P.; Riermeier, T. H.;
Oefele, K.; Beller, M. Chem. Eur. J. 1997, 3, 1357.
9) An enamine similar to 14 was observed in our previous model
of (-)-cephalotaxine (1) using an alkylidene carbene 1,5-
CH insertion as a key step.
(
study, and a mechanistic rationalization was proposed. See ref 5 for full
details.
Acknowledgment. We thank GlaxoSmithKline, Roche,
the EPSRC (DTA) and The University of Nottingham for
financial support of this work.
(
(
10) Littke, A. F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989.
11) Ferrer, M.; Sanchez-Baeza, F.; Messeguer, A.; Diez, A.; Rubiralta,
M. J. Chem. Soc., Chem. Commun. 1995, 293.
(
12) The yield of 15 was dependent upon the success of forming the
initial BF3·amine adduct, and the main byproduct observed was the
hydroxylamine 23. We believe that 23 is formed by fragmentation of the
N-oxide 22 and that 22 is formed by oxidation of the residual tertiary amine
Supporting Information Available: Detailed experimen-
tal procedures, spectroscopic data, and copies of H NMR
spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
1
5
that remains after incomplete BF3·amine adduct formation of 5.
OL8010166
(
14) Chrobok, A.; Goessinger, E.; Kalb, R.; Orglmeister, E.; Schwaiger,
(
13) Yasuda, A.; Tanaka, S.; Oshima, K.; Yamamoto, H.; Nozaki, H.
J. Tetrahedron 2007, 63, 8326.
J. Am. Chem. Soc. 1974, 96, 6513.
(15) Ohno, K.; Tsuji, J. J. Am. Chem. Soc. 1968, 90, 99.
3048
Org. Lett., Vol. 10, No. 14, 2008