Enantioselective synthesis of the ester side chain of homoharringtonine

Article abstract of DOI:10.1016/S0040-4039(01)00086-7

The Michael adduct 6 was converted in ten steps with an overall yield of 5.7% into the methyl ester derivative of the side chain of homoharringtonine, (R)-17.

Full text of DOI:10.1016/S0040-4039(01)00086-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1911–1913
Enantioselective synthesis of the ester side chain of
homoharringtonine
Laurent Keller, Franc¸oise Dumas* and Jean d’Angelo*
Unite´ Associe´e au CNRS, Centre d’Etudes Pharmaceutiques, Universite´ de Paris Sud, 5, rue J.-B. Cle´ment,
92296 Chaˆtenay-Malabry, France
Received 3 November 2000; accepted 13 January 2001
Abstract—The Michael adduct 6 was converted in ten steps with an overall yield of 5.7% into the methyl ester derivative of the
side chain of homoharringtonine, (R)-17. © 2001 Elsevier Science Ltd. All rights reserved.
Homoharringtonine (HHT, 1a), accompanied by sev-
eral congener alkaloids, was isolated from the plumyew
Cephalotaxus
harringtonia
(Cephalotaxaceae,
Coniferae), an evergreen tree native of the southern
provinces of China.1 Research efforts have focused on
HHT, since it is the main natural ester of cephalotaxine
(1b) in the tree, and the most potent in this family of
antitumor drugs. Several teams have investigated the
mechanism by which HHT and related alkaloids exert
their antineoplastic effects; all have concluded that
these drugs inhibit protein biosynthesis in the cell. The
effects of HHT and congeners on protein synthesis are
the breakdown of polyribosomes to monosomes, the
release of completed globin chains, and delayed inhibi-
tion of initiation of protein synthesis without affecting
chain elongation. HHT has been clinically tested in
advanced breast cancer, acute myelogenous leukemia
and myelodysplastic syndrome (MDS), and MDS
evolving to acute myeloid leukemia.2 This drug is now
widely used in China as the front-line chemotherapy for
acute myeloid leukemias, particularly in acute promye-
locytic leukemia. In the US, the efficiency of HHT in
the treatment of chronic myeloid leukemia is being
evaluated in a large scale study.3
(1b), although more abundant in C. harringtonia than
HHT and congener esters, per se is devoid of biological
activity; thus, the presence of an ester side chain at C-3
appears to be critical to the antitumor potency of HHT
(and analogs). As a result of nearly 30 years of intensive
research, numerous strategies for the elaboration of the
side chain of HHT, or its cyclic equivalents, have been
developed.4 However, there is a marked stereorequire-
ment of the structure of the side chains for both their
antitumor activity and toxicity; thus epi-HHT, which
only differs from HHT in the configuration of the
stereogenic center at C-2%, exhibited no significant anti-
neoplastic activity.1
Reported herein is a highly stereoselective approach to
the methyl ester derivative of the HHT side chain, in
the natural R configuration, exploiting our general
methodology for the enantioselective construction of
quaternary carbon centers.5 The key tactical element in
this synthesis was the enantiopure Michael adduct
(2R,1%R)-6 which resulted from the addition of imine 4,
derived from racemic 2-benzyloxycyclohexanone (2)
and (R)-1-phenylethylamine (3), to 2-acetoxyacryloni-
trile (5)6 (Scheme 1).
The structure–activity relationships for Cephalotaxus
alkaloids have been defined. In this respect, it has been
established that the tetracyclic alcohol cephalotaxine
Keywords: antitumor compounds; asymmetric synthesis; cyanohy-
drins; ozonolysis; ring transformations.
* Corresponding authors. E-mail: francoise.dumas@cep.u-psud.fr;
jean.dangelo@cep.u-psud.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00086-7

1912
L. Keller et al. / Tetrahedron Letters 42 (2001) 1911–1913
yield;9 10 to 11: CH2N2, quantitative yield), or more
directly by treating 9 with MnO2 in MeOH in the
presence of NaCN (72 h at 20°C, 60% yield).10
Removal of the acetal protecting group (CeCl3·7H2O,
NaI, MeCN, 18 h at 80°C)11 delivered finally the cor-
nerstone ketone (R)-1212 with a 85% yield (Scheme 3).
Scheme 1.
The conversion of compound 6 into the HHT side
chain would require, in no particular order, three essen-
tial chemical operations, namely the transformation of
the a-acetoxypropionitrile appendage into an acetate
moiety, the regioselective oxidative cleavage of the
cyclohexane ring at the less substituted a-side of the
carbonyl function, and the introduction of two gemi-
nate methyl groups to complete the carbinol termini.
Scheme 3.
The oxidative cleavage of the cyclohexane ring of 12
was next undertaken. For this purpose, ketone 12 was
first converted into silyl enol ether 13 (TMSCl, Et3N,
MeCN, 20 h at 20°C),13 which was ozonolyzed (i: O3,
CH2Cl2/EtOH, −78°C; ii: Me2S) into sensitive aldehyde
14 (not characterized). Slow addition (30 min) of
methyl Grignard reagent to crude 14 (1.95 equiv. of
MeMgBr, THF, −40°C), followed by esterification with
CH2N2 afforded an equimolar mixture of epimeric alco-
hols 15 with an overall yield of 35%, calculated from
ketone 12 (Scheme 4).
Regeneration of the masked aldehyde function at C-2
was examined first. While basic treatments of adduct 6
furnished invariably undefined compounds, the hemiac-
etal (2R,1aS,3aR)-7 was formed under acidic condi-
tions. The conversion of 7 into lactone (1aS,3aR)-8 has
recently been accomplished;6 however, the overall yield
for the process was found to be unsatisfactory (ca.
25%). This troublesome hemiacetalization side-reaction
was circumvented by protecting first ketone 6 as the
acetal 97 (TMSOCH2CH2OTMS, TMSOTf, −78 to
20°C, 80% yield)8 (Scheme 2).
Scheme 4. (a) TMSCl, Et3N; (b) i: O3; ii: Me2S; (c) i:
MeMgBr; ii: H3O+; iii: CH2N2.
Scheme 2.
At this juncture, we stood ready to complete the syn-
thesis of the methyl ester derivative of the HHT side
chain. In the event, sequential exposure of alcohol 15 to
pyridinium chlorochromate (CH2Cl2, 16 h at 20°C) and
1 equiv. of MeMgBr (slow addition at −30°C) produced
with a 40% yield carbinol (R)-16, which was finally
transformed by hydrogenolysis of the benzyloxy group
(1 bar of H2, Pd/C, EtOH, 24 h at 20°C, quantitative
Transformation of the protected cyanohydrin moiety of
acetal 9 into a carbomethoxy group now proceeded
straightforwardly, either by basic treatment followed by
the in situ oxidation of the intermediary aldehyde and
esterification of the resulting acid 10 (9 to 10: i: 2.1
equiv. LiOH, THF, 1 h at 20°C; ii: NaO2Cl, NaH2PO4,
2-methyl-2-butene, t-BuOH/H2O, 16 h at 20°C, 75%

L. Keller et al. / Tetrahedron Letters 42 (2001) 1911–1913
1913
5. For recent references, see: (a) Thominiaux, C.; Rousse´,
S.; Desmae¨le, D.; d’Angelo, J.; Riche, C. Tetrahedron:
Asymmetry 1999, 10, 2015–2021; (b) Nour, M.; Tan, K.;
Cave´, C.; Villeneuve, D.; Desmae¨le, D.; d’Angelo, J.;
Riche, C. Tetrahedron: Asymmetry 2000, 11, 995–1002;
(c) Gassama, A.; d’Angelo, J.; Cave´, C.; Mahuteau, J.;
Riche, C. Eur. J. Org. Chem. 2000, 3165–3169.
6. Keller, L.; Camara, C.; Pinheiro, A.; Dumas, F.; d’An-
gelo, J. Tetrahedron Lett. 2001, 42, 381–383; d’Angelo, J.;
Dumas, F.; Keller, L. Patent application FR 0017281.
7. 9: colorless solid; mp 138°C (EtOH); [h]2D0 +106 (c=2.1,
CHCl3); IR (KBr): 2250, 1743 cm−1 1H NMR (CDCl3,
;
400 MHz): 1.41–1.73 (m, 6H), 1.88 (m, 1H), 1.95 (s+m,
4H), 2.16 (dd, J=5.2, 15.9 Hz, 1H), 2.65 (dd, J=5.2, 15.9
Hz, 1H), 4.01 (m, 3H), 4.18 (m, 1H), 4.49 (d, J=11.4 Hz,
1H), 4.55 (d, J=11.4 Hz, 1H), 5.72 (t, J=5.2 Hz, 1H),
7.34 (m, 5H) ppm; 13C NMR (50 MHz, CDCl3): 20.1
(CH3), 20.4 (CH2), 22.5 (CH2), 29.8 (CH2), 32.2 (CH2),
34.8 (CH2), 58.1 (CH), 63.7 (CH2), 64.1 (CH2), 64.4
(CH2), 78.6 (C), 110.3 (C), 118.3 (C), 126.8 (2 CH), 127.2
(CH), 128.3 (2CH), 138.4 (C), 168.9 (C) ppm. Anal.
calcd: C, 66.83: H, 7.01: N, 3.89. Found: C, 66.89: H,
7.14: N, 3.92.
Scheme 5.
yield) into our goal (R)-methyl 3-carbomethoxy-3,7-
dihydroxy-7-methyloctanoate (17),14 identical in all
respects with the ester deriving from the methanolysis
of natural HHT15 (Scheme 5).
Thus, an highly stereoselective synthesis of the methyl
ester derivative of the HHT side chain 17 in the natural
R configuration, has been completed in 5.7% overall
yield from Michael adduct 6 by a linear sequence of ten
chemical operations (mean yield per step: 75%). Studies
directed towards the elaboration of a sterically less
hindered, cyclic form of 17,16 suitable for coupling with
cephalotaxine (1b) to produce enantiopure HHT (1a),
are currently under investigation in our laboratory.
8. Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett.
1980, 21, 1357–1358.
9. Kraus, G. A.; Taschner, M. J. J. Org. Chem. 1980, 45,
1175–1176.
10. Busato, S.; Scheffold, R. Helv. Chim. Acta 1994, 77,
92–99.
11. Marcantoni, E.; Nobili, F.; Bartoli, G.; Bosco, M.; Sam-
bri, L. J. Org. Chem 1997, 62, 4183–4184.
12. 12: colorless oil; [h]2D0 +131 (c=0.7, CHCl3); IR (neat):
1
1735, 1715 cm−1; H NMR (CDCl3, 200 MHz): 1.41–2.08
(m, 5H), 2.16–2.44 (m, 2H), 2.49–2.74 (m, 2H), 2.92 (d,
J=14.9 Hz, 1H), 3.57 (s, 3H), 4.02 (d, J=10.8 Hz, 1H),
4.57 (d, J=10.8 Hz, 1H), 7.15–7.38 (m, 5H) ppm; 13C
NMR (50 MHz, CDCl3): 20.3 (CH2), 27.6 (CH2), 36.7
(CH2), 38.2 (CH2), 39.1 (CH2), 51.5 (CH3), 65.7 (CH2),
81.2 (C), 127.4 (2 CH), 127.5 (CH), 128.3 (2 CH), 137.7
(C), 170.8 (C), 210.4 (C) ppm.
Acknowledgements
We are grateful to Dr. Jacqueline Mahuteau for the
valuable assistance with NMR studies and Mrs. Sophie
Mairesse-Lebrun for performing the elemental analyses
(Centre
Malabry).
d’Etudes
Pharmaceutiques,
Chaˆtenay-
13. Cazeau, P.; Moulines, F.; Laporte, O.; Duboudin, F. J.
Organometal. Chem. 1980, 201, C9–C13.
14. 17: colorless solid; mp 34°C (pentane); [h]2D0 −14 (c=0.7,
CHCl3); IR (neat): 3501, 1733 cm−1 1H NMR (CDCl3,
;
References
200 MHz): 1.19 (s, 6H+OH), 1.34–1.75 (m, 6H), 2.70 (d,
J=16.3 Hz, 1H), 2.92 (d, J=16.3 Hz, 1H), 3.67 (s, 3H),
3.72 (s, 1H, OH), 3.80 (s, 3H) ppm; 13C NMR (50 MHz,
CDCl3): 18.0 (CH2), 29.0 (CH3), 29.2 (CH3), 39.5 (CH2),
43.3 (CH2), 43.5 (CH2), 51.7 (CH3), 52.8 (CH3), 70.6 (C),
75.2 (C), 171.2 (C), 175.5 (C) ppm. Anal. calcd: C, 54.94:
H, 8.45. Found: C, 54.97: H, 8.55.
1. In Chinese Drugs of Plant Origin, Chemistry, Pharmacol-
ogy, and Use in Traditional and Modern Medicine; Tang,
W.; Eisenbrand, G., Eds.; Cephalotaxus spp. Springer:
Berlin, 1992; pp. 281–306.
2. Zhou, D.-C.; Zittoun, R.; Marie, J.-P. Bull. Cancer 1995,
82, 987–995.
15. Powell, R. G.; Weisleder, D.; Smith, Jr., C. R. J. Pharm.
Sci. 1972, 61, 1227–1230.
16. Kelly, T. R.; McNutt, Jr., R. W.; Montury, M.; Tosches,
N. P.; Mikolajczak, K. L.; Smith, Jr., C. R.; Weisleder,
D. J. Org. Chem. 1979, 44, 63–67.
3. Zhou, D.-C.; Ramond, S.; Viguie, F.; Faussat, A.-M.;
Zittoun, R.; Marie, J.-P. Int. J. Cancer 1996, 65, 365–371.
4. Robin, J.-P.; Dhal, R.; Dujardin, G.; Girodier, L.; Mevel-
lec, L.; Poutot, S. Tetrahedron Lett. 1999, 40, 2931–2934
and references cited therein.
.
.