Synthesis of optically active monoacid side-chains of Cephalotaxus alkaloids

Article abstract of DOI:10.1002/ejoc.200800935

The general preparation of enantiopure monoacid side-chains of several esters of cephalotaxine is described. The strategy, similar to Weinreb's approach to the synthesis of deoxyharringtonine, used as key intermediate the chiral nonracemic epoxide 11a pre

Full text of DOI:10.1002/ejoc.200800935

FULL PAPER
DOI: 10.1002/ejoc.200800935
Synthesis of Optically Active Monoacid Side-Chains of Cephalotaxus
Alkaloids
Farouk Berhal,[a] Sébastien Tardy,[a] Joëlle Pérard-Viret,[a] and Jacques Royer*[a]
Keywords: Alkaloids / Esters / Epoxides / Ring-opening / Chirality
The general preparation of enantiopure monoacid side-
chains of several esters of cephalotaxine is described. The
strategy, similar to Weinreb’s approach to the synthesis of de-
cuprate nucleophiles. Hydrogenolysis as the final step gave
the monacid side-chains of the corresponding esters of ce-
phalotaxine in moderate to good overall yields from epoxide
oxyharringtonine, used as key intermediate the chiral nonra- 11a.
cemic epoxide 11a prepared from the commercially available
monomethyl itaconate (8). The key step of the strategy was
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
the ring-opening of the epoxide 11a by using different organo- Germany, 2009)
Introduction
Several alkaloids isolated from the genus Cephalotaxus
(evergreen conifers and shrubs) have been shown to exhibit
interesting antileukemic activities.[1] Among them harring-
tonine (1), deoxyharringtonine (2), homodeoxyharrington-
ine (3), neoharringtonine (4), anhydroharringtonine (5),
and homoharringtonine (6) have been studied extensively.[2]
Homoharringtonine is the most potent in this family of an-
titumor alkaloids. Indeed, it is currently in phase II–III of
clinical trials in the United States for the treatment of
chronic myeloid leukaemia.[3] The limited availability of
these alkaloids has led to the development of a number of
strategies for their synthesis. The products are all esters of
cephalotaxine (7), the most abundant alkaloid extracted
Figure 1. Structures of some natural esters of Cephalotaxus.
from Cephalotaxus, and could be used as the starting mate-
rial for their hemisynthesis (Figure 1). Cephalotaxine itself
does not exhibit any interesting antitumor activity.[4]
based upon Seebach’s procedure for the alkylation of -
malic acid with self-regeneration of the stereogenic centers.
Herein we wish to report a general procedure for the
preparation of some enantiomerically enriched monoacid
side-chains based upon the approach of Weinreb and co-
workers developed for the racemic synthesis of the deoxy-
harringtonine side-chain.[6c] Our strategy (Scheme 1) uses a
functionalized chiral nonracemic epoxide as the key inter-
mediate of the synthesis, which was prepared in good yield
and optical purity. A general epoxide ring-opening pro-
cedure using organocuprates as nucleophiles led to various
side-chains.
It thus appears that the bioactivity of the natural esters
is closely related to the acid side-chains. Moreover, these
types of α-alkyl malates are an important part of many
other bioactive compounds[5] and, as for the cephalotaxine
esters, their biological activity is linked to the nature of the
side-chains. Several methods have been reported for the
synthesis of the individual side-chains.[6] One of the chal-
lenges in the synthesis of the side-chains of esters of cephal-
otaxine is to obtain a general and enantioselective pro-
cedure by using the same intermediate for all chains. Up to
now the only general strategy had been reported recently
by Tietze and co-workers,[7] who prepared the side-chains
of 1–6 from a unique intermediate. Their approach was
[a] UMR 8638 CNRS – Université Paris Descartes, Faculté des
Sciences Pharmaceutiques et Biologiques,
4 avenue de l’Observatoire, 75270 Paris Cedex 06, France
E-mail: jacques.royer@univ-paris5.fr
Scheme 1. Retrosynthetic scheme.
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F. Berhal, S. Tardy, J. Pérard-Viret, J. Royer
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96% yield. The alkene diester 10 was epoxidized by using
2 equiv. of enriched m-CPBA[8] (Ͼ95% purity) and 2,4,6-
tri-tert-butylphenol as radical inhibitor. This reaction was
also carried out with commercially available m-CPBA (ca.
70% purity) and gave a similar yield, but in this case the
peracid had to be used in large excess (6 equiv.). The epox-
ide was obtained in 72% optimized yield as a 1:1 mixture
of two diastereomers. No chiral induction was observed in
this epoxidation; the asymmetric carbon atom of the man-
delic ester was probably too distant to induce any facial
stereoselectivity during the reaction. Fortunately, the two
diastereomers were separated by flash chromatography, and
the desired compound 11a with the (S,S) configuration was
isolated in 96% de (Scheme 2).
Results and Discussion
One of the main difficulties in our approach is the con-
trol of the asymmetric carbon atom in the side-chains. We
envisaged introducing asymmetry through a chiral nonrace-
mic functionalized epoxide, the quaternary center of which
had the desired absolute configuration. The side-chains
would then be obtained by epoxide ring-opening with ap-
propriate nucleophiles.
The two main criteria we defined for this key chiral epox-
ide intermediate were the following: (1) Easy preparation
on a large scale (laboratory scale) and (2) orthogonal pro-
tection of the two ester groups, which allows the prepara-
tion of the monoacid derivative before or after the epoxide
ring-opening.
Having secured the absolute configuration of the quater-
nary carbon atom in 11a, various side-chains could be in-
troduced through chemoselective ring-opening of the epox-
ide with appropriate nucleophiles. Organocuprate reagents
are often used for this type of reaction.[9] First, we tried
to apply this strategy to the synthesis of the deoxy- and
homodeoxyharringtonine side-chains. The lower-order Gil-
man organocuprates were prepared as reported in the litera-
ture from the corresponding lithium derivatives: Isobutyl-
or isopentyllithium (prepared from the corresponding bro-
mide reagents in diethyl ether at 0 °C) (2 equiv.) and CuI in
diethyl ether as solvent.[10]
These criteria dictated the use of epoxide 11 (Scheme 2).
It appeared to be easily available from methyl itaconate (8),
which could be esterified with methyl mandelate (9) before
epoxidation of the double bond. The presence of the man-
delate ester as a chiral appendage would permit the intro-
duction of chirality and easy deprotection under hydro-
genolysis conditions.
Epoxide 11a readily reacted with isobutyl- and isopentyl-
cuprates in diethyl ether at –78 °C to give the deoxy- and
homodeoxyharringtonine side-chain diesters 12 and 13 in
65 and 73% yields, respectively (Scheme 3).
The monoacid side-chains were then prepared by selec-
tive cleavage of the mandelic ester by hydrogenolysis using
palladium on charcoal as catalyst in ethyl acetate and under
hydrogen at room temperature and atmospheric pressure.[11]
The monoacid side-chains of deoxy- and homodeoxyhar-
ringtonines 14 and 15 were obtained in 95 and 92% yields,
respectively (62 and 67% overall yields from epoxide 11a).
According to the same sequence starting from the reac-
tion of phenylcuprate with epoxide 11a and then hydro-
genolysis of the mandelic ester, the monoacid side-chain 17
of neoharringtonine was prepared in 43% overall yield.
Scheme 2. Synthesis of epoxide 11a. Reagents and conditions: (a)
DCC, DMAP, DCM, room temperature, 5 h (96%); (b) m-CPBA
(Ͼ95% purity), radical inhibitor, DCE, reflux, 16 h (72%); (c) flash
chromatography.
Esterification of commercially available monomethyl ita-
conate (8) with enantiopure methyl mandelate (9) in the However, and surprisingly, hydrogenolysis of the mandelic
presence of DCC and DMAP furnished the diester 10 in ester under the conditions described above did not afford
Scheme 3. Synthesis of monoacid side-chains of deoxyharringtonine, homodeoxyharringtonine, neoharringtonine, and a non-natural side-
chain from epoxide 11a. Reagents and conditions: (a) Et2O, –78 °C to –60 °C, 2 h; (b) H2, Pd/C, AcOEt, room temperature, 5 h or
Pd(OH)2, AcOEt, room temperature, 5 bar, 5 h.
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Monoacid Side-Chains of Cephalotaxus Alkaloids
the monoacid product, and the starting material was reco-
vered unchanged. After several trials, hydrogenolysis was
achieved by using palladium hydroxide as the catalyst in
ethyl acetate under 5 bar of hydrogen for 5 h. The monoacid
side-chain of the neoharringtonine 17 was obtained in a
good 85% yield.
We eventually applied this strategy to the synthesis of a
non-natural monoacid side-chain, the structure of which is
similar to the homodeoxyharringtonine. The organocuprate
was prepared from commercially available n-butyllithium.
The monoacid side-chain 19 was synthesized in 59% overall
yield from the key intermediate epoxide 11a by using the
same procedure (Scheme 3). Thus, we have shown that the
aliphatic side-chains can be synthesized in good yields by
using this simple and efficient procedure.
The addition of 2-methylpropen-1-ylcuprate to 11a al-
lowed the preparation of the side-chain of anhydroharring-
tonine 5. The tertiary alcohol intermediate 20 was obtained
in a moderate 55% yield by ring-opening of 11a with the
copper reagent. The furan ring was formed by hydroxymer-
curation followed by spontaneous cyclization[12] to give 21
in 76% yield (Scheme 4).
Scheme 5. Hydrogenolysis of epoxide 11a. Reagents and condi-
tions: (a) H2, Pd(OH)2, THF, room temperature, 2 h (70%).
al.,[14] we anticipated that this esterification could be
achieved with compound 23, which possesses a smaller ste-
ric effect. It would give an epoxycephalotaxine intermedi-
ate, which could be opened with nucleophiles to give natural
esters of cephalotaxine. This strategy is under investigation
in our laboratory.
Conclusions
The side-chains of esters of cephalotaxine are very im-
portant because they are responsible for the bioactivity and
particularly the antileukemic activity of Cephalotaxus alka-
loids. Several methods have been reported for the individual
synthesis of these compounds, but only a few of them are
general and enantioselective. In this paper we have de-
scribed a straightforward and effective synthesis of mono-
acid side-chains of different natural esters of this family by
the ring-opening of the chiral nonracemic functionalized
epoxide 11a with different organocuprates as nucleophiles.
This epoxide, which represents the key intermediate in our
procedure, was easily prepared from commercially available
monomethyl itaconate (8). Unfortunately, the side-chains of
harringtonine and homoharringtonine have not so far been
obtained by this methodology, but efforts are being made
to synthesize them.
Scheme 4. Synthesis of anhydroharringtonine monoacid side-chain
from epoxide 11a. Reagents and conditions: (a) Et2O, –78 to
–60 °C, 2 h (55%); (b) Hg(OAc)2, NaBH4, THF/H2O, 0 °C to room
temperature, 2.5 h (76%); (c) H2, Pd/C, AcOEt, room temperature,
5 h (90%).
Experimental Section
General: Reagents were commercially obtained at the highest com-
mercial quality and used without further purification. All reactions
were carried out under anhydrous conditions under argon or nitro-
gen in dry, freshly distilled solvents. Reactions were monitored by
thin-layer chromatography on Merck 60F-254 precoated silica
(0.2 mm) on aluminium. Flash chromatography was performed
with SDS silica gel 60 (35–70 µm). Melting points were determined
with a Kofler apparatus and are uncorrected. Specific rotations
were measured at 25 °C with a Perkin-Elmer 341 polarimeter with
a sodium (589 nm) lamp. IR spectra were recorded with a Nicolet
205 spectrometer and NaCl pellets. Only noteworthy IR absorp-
tions are listed. 1H and 13C NMR spectra were recorded with a
Bruker Avance-300 apparatus operating at 300 and 75 MHz,
respectively. Chemical shifts (δ) are reported in ppm.
Finally, the target acid 22 was obtained in 90% yield af-
ter hydrogenolysis under the previously described condi-
tions. This side-chain corresponding to anhydroharrington-
ine was synthesized in three steps from epoxide 11a in 42%
overall yield. The harringtonine monoacid side-chain could
probably be synthesized by this method with prior protec-
tion of the free hydroxy group followed by hydroxymercura-
tion of the double bond.
We also showed that it was possible to hydrogenolyze the
epoxide 11a to generate the corresponding monoacid. The
hydrogenolysis was carried out in THF by using a catalytic
amount of palladium hydroxide at room temperature and
atmospheric pressure for 2 h. The monoacid epoxide 23 was
obtained in 70% yield (Scheme 5).
1-[(1S)-2-Methoxy-2-oxo-1-phenylethyl] 4-Methyl 2-Methylidene-
butanedioate (10): DCC (4.99 g, 24.2 mmol) and DMAP (2.96 g,
24.2 mmol) were added to a solution of methyl (S)-mandelate (9;
2.01 g, 12.1 mmol) and monomethyl itaconate (8) (2.62 g,
18.1 mmol) in anhydrous CH2Cl2 (40 mL). The mixture was stirred
It has been reported that direct esterification of a side-
chain with cephalotaxine was not possible because of steric
hindrance.[13] By comparison with the work of Robin et at room temperature for 5 h. The reaction mixture was then filtered
Eur. J. Org. Chem. 2009, 437–443
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F. Berhal, S. Tardy, J. Pérard-Viret, J. Royer
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through a Celite® pad. The filtrate was washed (3ϫ) with a satu-
rated solution of NH4Cl. The aqueous layer was extracted with
CH2Cl2. The combined organic phases were washed (2ϫ) with
brine, dried with MgSO4, filtered, and concentrated in vacuo. The
crude residue was purified by silica gel column chromatography
(cyclohexane/AcOEt, 4:1) to afford the alkene 10 (3.394 g, 96%
slowly added. After 2 h of stirring at –78 °C, saturated ammonium
chloride solution was added to the reaction mixture. At room tem-
perature the resulting aqueous and organic layers were diluted with
water and CH2Cl2 and then separated. The aqueous phase was ex-
tracted with CH2Cl2 (3ϫ). The combined organic extracts were
washed with brine, dried with MgSO4, filtered, and concentrated
in vacuo. The crude product was purified by silica gel column
chromatography to give the ring-opened compound.
yield) as a colorless oil. [α]2D5 = +118 (c = 1.0, CHCl ). IR (film): ν
˜
3
= 2954 (CH), 1743 (C=O), 1642 (C=C), 1498, 1455, 1436 (Ar)
1
cm–1. H NMR (CDCl3, 300 MHz): δ = 3.40 (t, J = 1.2 Hz, 2 H,
1-[(1S)-2-Methoxy-2-oxo-1-phenylethyl] 4-Methyl (2R)-2-Hydroxy-
2-(3-methylbutyl)butanedioate (12): Obtained from a 0.85  solu-
tion of 2-methylpropyllithium (3.16 mL, 2.68 mmol) in Et2O (pre-
pared from 1-bromo-2-methylpropane and lithium at 0 °C), a sus-
pension of CuI (256 mg, 1.34 mmol) in Et2O (9 mL), and epoxide
11a (276 mg, 0.895 mmol) dissolved in Et2O (2 mL). Chromatog-
raphy (cyclohexane/AcOEt, 4:1) afforded the ring-opened product
12 (212 mg, 65% yield) as a colorless oil. [α]2D5 = +82.8 (c = 0.75,
3-H), 3.65 (s, 3 H, OMe), 3.72 (s, 3 H, OMe), 5.83 (td, J = 0.8,
1.2 Hz, 1 H, 5a-H), 5.99 (s, 1 H, 6-H), 6.49 (d, J = 0.8 Hz, 1 H,
5b-H), 7.36–7.43 (m, 3 H, Ar-H), 7.44–7.50 (m, 2 H, Ar-H) ppm.
13C NMR (CDCl3, 75 MHz): δ = 37.5 (C-3), 52.1 (OMe), 52.7
(OMe), 74.9 (C-6), 127.6 (C-o), 128.8 (C-m), 129.3 (C-p), 130.1 (C-
5), 132.9 (C-2), 133.7 (C-i), 165.3 (C-1), 169.0 (C-4), 170.8 (C-7)
ppm. HRMS (ESI): calcd. for C15H16O6 [M + Na]+ 315.0845;
found 315.0838.
CHCl ). IR (film): ν = 3521 (OH), 2956 (CH), 1747 (C=O), 1498,
˜
3
1456, 1438 (Ar) cm–1. H NMR (CDCl3, 300 MHz): δ = 0.90 (d, J
1
(1S)-2-Methoxy-2-oxo-1-phenylethyl (2S)- and (2R)-2-(2-Methoxy-
2-oxoethyl)oxirane-2-carboxylate (11a and 11b): 2,4,6-Tri-tert-bu-
tylphenol (44 mg, 2% w/w of m-CPBA) and m-CPBA (2.21 g,
12.8 mmol, Ͼ95% purity[8]) were successively added to a solution
of the alkene 10 (1.872 g, 6.4 mmol) in 1,2-dichloroethane (32 mL).
The mixture was stirred at 85 °C for 16 h. After cooling, the reac-
tion mixture was diluted with CH2Cl2 and poured into a saturated
and well-stirred solution of Na2SO3. Then powdered NaHCO3 was
added in portions until the release of gas had ceased. The organic
and aqueous layers were separated. The aqueous phase was ex-
tracted with CH2Cl2 (3ϫ30 mL). The combined organic extracts
were washed with a saturated solution of NaHCO3 (3ϫ100 mL)
and brine, dried with MgSO4, filtered, and concentrated in vacuo.
The crude residue was purified by silica gel column chromatog-
raphy (cyclohexane/AcOEt, 7:3) to give the epoxides 11a and 11b
(1.414 g, 72% global yield) as an equimolar mixture. The dia-
stereomers were isolated as colorless oils after a second silica gel
column chromatography (pentane/Et2O, 3:1).
= 6.6 Hz, 3 H, 8-H), 0.91 (d, J = 6.6 Hz, 3 H, 9-H), 1.16–1.31 (m,
1 H, 7-H), 1.32–1.47 (m, 1 H, 6a-H), 1.47–1.63 (m, 1 H, 6b-H),
1.67–1.94 (m, 2 H, 5a-H, 5b-H), 2.71 (d, J = 16.3 Hz, 1 H, 3a-H),
2.92 (d, J = 16.3 Hz, 1 H, 3b-H), 3.53 (s, 3 H, OMe), 3.72 (s, 3 H,
OMe), 3.73 (s, 1 H, OH), 5.99 (s, 1 H, 10-H), 7.30–7.45 (m, 5 H,
Ar-H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 22.5, 22.6 (C-8 and
C-9), 28.2 (C-7), 31.5 (C-6), 37.2 (C-5), 43.3 (C-3), 51.8 (OMe),
52.6 (OMe), 75.2 (C-2), 75.3 (C-10), 127.6 (C-o), 128.8 (C-m), 129.4
(C-p), 133.5 (C-i), 168.7 (C-4), 171.1 (C-11), 174.6 (C-1) ppm.
HRMS (ESI): calcd. for C19H26O7 [M + Na]+ 389.1576; found
389.1587.
1-[(1S)-2-Methoxy-2-oxo-1-phenylethyl] 4-Methyl (2R)-2-Hydroxy-
2-(4-methylpentyl)butanedioate (13): Obtained from a 0.89  solu-
tion of 3-methylbutyllithium (3.28 mL, 2.92 mmol) in Et2O (pre-
pared from 1-bromo-3-methylbutane and lithium at 0 °C), a sus-
pension of CuI (278 mg, 1.46 mmol) in Et2O (9.5 mL), and epoxide
11a (300 mg, 0.973 mmol) dissolved in Et2O (2 mL). Chromatog-
raphy (cyclohexane/AcOEt, 4:1) afforded the ring-opened product
13 (269 mg, 73% yield) as a colorless oil. [α]2D5 = +70.9 (c = 0.38,
Diastereomer 11a: 30% yield. [α]2D5 = +95.5 (c = 1.1, CHCl3). IR
(film): ν = 2956 (CH), 1747 (C=O), 1497, 1455, 1438 (Ar) cm–1.
˜
1H NMR (CDCl3, 300 MHz): δ = 2.82 (d, J = 16.9 Hz, 1 H, 4a-
H), 2.95 (d, J = 5.8 Hz, 1 H, 3a-H), 3.07 (d, J = 16.9 Hz, 1 H, 4b-
H), 3.24 (d, J = 5.8 Hz, 1 H, 3b-H), 3.64 (s, 3 H, OMe), 3.72 (s, 3
H, OMe), 6.00 (s, 1 H, 7-H), 7.36–7.46 (m, 5 H, Ar-H) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 37.4 (C-4), 52.3 (C-3), 52.9 (OMe),
53.6 (C-2), 75.5 (C-7), 127.7 (C-o), 129.0 (C-m), 129.6 (C-p), 133.2
(C-i), 168.5 (C-5), 168.8 (C-8), 169.6 (C-6) ppm. HRMS (ESI):
calcd. for C15H16O7 [M + Na]+ 331.0794; found 331.0809.
CHCl ). IR (film): ν = 3516 (OH), 2954 (CH), 1748 (C=O), 1498,
˜
3
1456, 1438 (Ar) cm–1. H NMR (CDCl3, 300 MHz): δ = 0.87 (d, J
1
= 6.6 Hz, 6 H, 9-H, 10-H), 1.14–1.26 (m, 2 H, 7-H), 1.26–1.44 (m,
1 H, 8-H), 1.44–1.63 (m, 2 H, 6-H), 1.66–1.91 (m, 2 H, 5-H), 2.71
(d, J = 16.3 Hz, 1 H, 3a-H), 2.92 (d, J = 16.3 Hz, 1 H, 3b-H), 3.54
(s, 3 H, OMe), 3.71 (s, 1 H, OH), 3.72 (s, 3 H, OMe), 5.99 (s, 1 H,
11-H), 7.35–7.45 (m, 5 H, Ar-H) ppm. 13C NMR (CDCl3,
75 MHz): δ = 20.7 (C-6), 22.6, 22.7 (C-9 and C-10), 27.9 (C-8),
39.0 (C-5), 39.6 (C-7), 43.2 (C-3), 51.8 (OMe), 52.7 (OMe), 75.2
(C-2), 75.4 (C-11), 127.7 (C-o), 128.9 (C-m), 129.4 (C-p), 133.5 (C-
i), 168.7 (C-4), 171.2 (C-12), 174.7 (C-1) ppm. HRMS (ESI): calcd.
for C20H28O7 [M + Na]+ 403.1733; found 403.1734.
Diastereomer 11b: 35% yield. [α]2D5 = +113.0 (c = 1.0, CHCl3). IR
(film): ν = 2956 (CH), 1747 (C=O), 1498, 1456, 1438 (Ar) cm–1.
˜
1H NMR (CDCl3, 300 MHz): δ = 2.80 (d, J = 16.9 Hz, 1 H, 4a-
H), 2.97 (d, J = 5.9 Hz, 1 H, 3a-H), 3.12 (d, J = 16.9 Hz, 1 H, 4b-
H), 3.36 (d, J = 5.9 Hz, 1 H, 3b-H), 3.69 (s, 3 H, OMe), 3.72 (s, 3
H, OMe), 5.99 (s, 1 H, 7-H), 7.35–7.47 (m, 5 H, Ar-H) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 37.1 (C-4), 52.0 (C-3), 52.2 (OMe),
52.8 (OMe), 53.6 (C-2), 75.2 (C-7), 127.6 (C-o), 128.9 (C-m), 129.5
(C-p), 133.0 (C-i), 168.6 (C-5), 169.1 (C-8), 169.6 (C-6) ppm.
HRMS (ESI): calcd. for C15H16O7 [M + Na]+ 331.0794; found
331.0798.
1-[(1S)-2-Methoxy-2-oxo-1-phenylethyl] 4-Methyl (2R)-2-Benzyl-2-
hydroxybutanedioate (16): Obtained from a 1.18  commercial
solution of phenyllithium (2.29 mL, 2.72 mmol) in dibutyl ether, a
suspension of CuI (253 mg, 1.33 mmol) in Et2O (7 mL), and epox-
ide 11a (205 mg, 0.665 mmol) dissolved in Et2O (2 mL). The cupr-
ate formed after 30 min of stirring at 0 °C. After addition of the
epoxide, the temperature was increased from –78 to –40 °C.
Chromatography (cyclohexane/AcOEt, 4:1) afforded the ring-
General Procedure for the Epoxide Ring-Opening with Organocup-
rates: A solution of the relevant lithium compound (3 equiv.) in
opened product 16 (127 mg, 50% yield) as a colorless oil. [α]2D5
=
Et2O was added dropwise to
a
cooled suspension of CuI
+61.0 (c = 0.4, CHCl ). IR (film): ν = 3535 (OH), 3020, 2956 (CH),
˜
3
(1.5 equiv.) in Et2O at –78 °C. The temperature was progressively
increased to –60 °C for 1.5 h. Then the black solution was recooled
to –78 °C, and the epoxide 11a (1 equiv.) dissolved in Et2O was
1747 (C=O), 1497, 1456, 1439 (Ar) cm–1. 1H NMR (CDCl3,
300 MHz): δ = 2.66 (d, J = 16.4 Hz, 1 H, 3a-H), 3.01 (d, J =
16.4 Hz, 1 H, 3b-H), 3.06 (d, J = 13.7 Hz, 1 H, 5a-H), 3.19 (d, J
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Monoacid Side-Chains of Cephalotaxus Alkaloids
= 13.7 Hz, 1 H, 5b-H), 3.51 (s, 3 H, OMe), 3.75 (s, 4 H, OMe,
OH), 6.01 (s, 1 H, 6-H), 7.23–7.33 (m, 5 H, Ar-H), 7.36–7.47 (m,
5 H, Ar-H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 42.4 (C-3), 45.0
CHCl ). IR (film): ν = 2956, 2926 (CH), 1747 (C=O), 1498, 1455,
˜
3
1435 (Ar) cm–1. 1H NMR (CDCl3, 300 MHz): δ = 1.25 (s, 3 H, 11-
H), 1.36 (s, 3 H, 12-H), 1.76–1.98 (m, 2 H, 4-H), 2.26 (ddd, J =
(C-5), 51.9 (OMe), 52.8 (OMe), 75.4 (C-6), 75.5 (C-2), 127.2 (C- 7.8, 8.8, 13.1 Hz, 1 H, 3a-H), 2.63 (ddd, J = 5.1, 7.4, 13.1 Hz, 1 H,
pЈ), 127.8 (C-o), 128.3 (C-mЈ), 128.9 (C-m), 129.5 (C-p), 130.8 (C-
oЈ), 133.5 (C-i), 134.6 (C-iЈ), 168.8 (C-4), 171.1 (C-7), 174.0 (C-1)
3b-H), 2.78 (d, J = 15.5 Hz, 1 H, 6a-H), 2.97 (d, J = 15.5 Hz, 1 H,
6b-H), 3.55 (s; 3 H, OMe), 3.70 (s, 1 H, OMe), 5.96 (s, 1 H, 9-H),
ppm. HRMS (ESI): calcd. for C21H22O7 [M + Na]+ 409.1263; 7.30–7.49 (m, 5 H, Ar-H) ppm. 13C NMR (CDCl3, 75 MHz): δ =
found 409.1261.
28.3 (C-11), 29.0 (C-12), 35.6 (C-3), 37.6 (C-4), 43.7 (C-6), 51.8
(OMe), 52.7 (OMe), 74.8 (C-9), 83.7 (C-5), 84.5 (C-2), 127.7 (C-o),
128.8 (C-m), 129.3 (C-p), 133.7 (C-i), 169.2 (C-7), 170.3 (C-10),
172.9 (C-8) ppm. HRMS (ESI): calcd. for C19H24O7 [M + Na]+
387.1420; found 387.1427.
1-[(1S)-2-Methoxy-2-oxo-1-phenylethyl] 4-Methyl (2R)-2-Hydroxy-
2-pentylbutanedioate (18): Obtained from a 2.15  commercial
solution of butyllithium (0.996 mL, 2.14 mmol) in hexane, a sus-
pension of CuI (204 mg, 1.07 mmol) in Et2O (7.5 mL), and epoxide
11a (220 mg, 0.714 mmol) dissolved in Et2O (2 mL). Chromatog-
raphy (cyclohexane/AcOEt, 4:1) afforded the ring-opened product
18 (166 mg, 64% yield) as a colorless oil. [α]2D5 = +73.7 (c = 0.51,
General Procedure for the Hydrogenolysis of the Chiral Auxiliary:
Under nitrogen, the substrate was dissolved in AcOEt (c =
0.035 ). Then 10% palladium on charcoal was added (mass of
substrate/mass of catalyst = 1.8). The reaction was conditioned un-
der hydrogen with stirring at room temperature for 4–5 h. Then it
was filtered though a Celite® pad. The filtrate was concentrated
under reduced pressure. The crude product was purified by silica
gel column chromatography to yield the acid compound.
CHCl ). IR (film): ν = 3521 (OH), 2955 (CH), 1747 (C=O), 1498,
˜
3
1456, 1438 (Ar) cm–1. H NMR (CDCl3, 300 MHz): δ = 0.91 (t, J
1
= 6.7 Hz, 3 H, 9-H), 1.26–1.44 (m, 5 H, 8-H, 7-H, 6a-H), 1.44–
1.61 (m, 1 H, 6b-H), 1.70–1.95 (m, 2 H, 5-H), 2.73 (d, J = 16.3 Hz,
1 H, 3a-H), 2.94 (d, J = 16.3 Hz, 1 H, 3b-H), 3.55 (s, 3 H, OMe),
3.74 (s, 4 H, OMe, OH), 6.01 (s, 1 H, 10-H), 7.35–7.48 (m, 5 H,
Ar-H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 14.0 (C-9), 22.5 (C-
6), 22.5 (C-8), 31.9 (C-7), 39.3 (C-5), 43.2 (C-3), 51.8 (OMe), 52.7
(OMe), 75.2 (C-2), 75.3 (C-10), 127.6 (C-o), 128.9 (C-m), 129.4 (C-
p), 133.5 (C-i), 168.7 (C-4), 171.2 (C-11), 174.6 (C-1) ppm. HRMS
(ESI): calcd. for C19H26O7 [M + Na]+ 389.1576; found 389.1564.
(2R)-2-Hydroxy-2-(2-methoxy-2-oxoethyl)-6-methylheptanoic Acid
(14): Obtained from the ester 12 (504 mg, 1.375 mmol) in AcOEt
(40 mL) with 10% Pd/C (280 mg). Silica gel column chromatog-
raphy (CH2Cl2 then CH2Cl2/MeOH, 95:5) afforded the acid com-
pound 14 (296 mg, 95% yield) as a colorless oil. [α]2D5 = –22.3 (c =
0.73, CHCl ). IR (film): ν = 3600–2300, 3500 (COOH, OH), 2956
˜
3
(CH), 1739 (C=O) cm–1. 1H NMR (CDCl3, 300 MHz): δ = 0.85 (d,
J = 6.6 Hz, 3 H, 8-H), 0.85 (d, J = 6.6 Hz, 3 H, 9-H), 1.00–1.16
(m, 1 H, 7-H), 1.28–1.42 (m, 1 H, 6a-H), 1.42–1.56 (m, 1 H, 6b-
H), 1.61–1.80 (m, 2 H, 5a-H, 5b-H), 2.72 (d, J = 16.5 Hz, 1 H, 3a-
H), 2.96 (d, J = 16.5 Hz, 1 H, 3b-H), 3.67 (s, 3 H, OMe), 7.28 (br.
s, 2 H, OH, COOH) ppm. 13C NMR (CDCl3, 75 MHz): δ = 22.4,
22.5 (C-8 and C-9), 28.1 (C-7), 31.8 (C-6), 37.1 (C-5), 43.0 (C-3),
52.1 (OMe), 75.2 (C-2), 171.8 (C-4), 179.4 (C-1) ppm. HRMS
(ESI): calcd. for C10H18O5 [M + Na]+ 241.1052; found 241.1051.
1-[(1S)-2-Methoxy-2-oxo-1-phenylethyl] 4-Methyl (2R)-2-Hydroxy-
2-(3-methylbut-2-en-1-yl)butanedioate (20): Obtained from a 0.18 
solution of 2-methylprop-1enyllithium (11.0 mL, 1.95 mmol) in
Et2O (prepared from 1-bromo-2-methylpropene and tert-butyllith-
ium at –78 °C), a suspension of CuI (185 mg, 0.973 mmol) in Et2O
(3.5 mL), and epoxide 11a (200 mg, 0.649 mmol) dissolved in Et2O
(2 mL). Chromatography (cyclohexane/AcOEt, 4:1) afforded the
ring-opened product 20 (130 mg, 55% yield) as a colorless oil. [α]
25 = +65.3 (c = 0.86, CHCl ). IR (film): ν = 3508 (OH), 2955 (CH),
˜
D
3
1747 (C=O), 1497, 1462, 1438 (Ar), 1352 (C=C) cm–1. 1H NMR
(CDCl3, 300 MHz): δ = 1.63 (s, 3 H, 8-H), 1.73 (s, 3 H, 9-H), 2.54
(d, J = 7.5 Hz, 2 H, 5-H), 2.72 (d, J = 16.4 Hz, 1 H, 3a-H), 2.94
(d, J = 16.4 Hz, 1 H, 3b-H), 3.53 (s, 3 H, OMe), 3.69 (s, 1 H, OH),
3.72 (s, 1 H, OMe), 5.24 (t, J = 7.5 Hz, 1 H, 6-H), 5.99 (s, 1 H, 10-
H), 7.34–7.47 (m, 5 H, Ar-H) ppm. 13C NMR (CDCl3, 75 MHz):
δ = 18.1 (C-8), 26.1 (C-9), 38.0 (C-5), 42.2 (C-3), 51.8 (OMe), 52.7
(OMe), 75.3 (C-10), 75.4 (C-2), 116.7 (C-6), 127.7 (C-o), 128.9 (C-
m), 129.4 (C-p), 133.5 (C-i), 136.8 (C-7), 168.7 (C-4), 171.2 (C-11),
174.3 (C-1) ppm. HRMS (ESI): calcd. for C19H24O7 [M + Na]+
387.1432; found 387.1420.
(2R)-2-Hydroxy-2-(2-methoxy-2-oxoethyl)-6-methylheptanoic Acid
(15): Obtained from the ester 13 (491 mg, 1.29 mmol) in AcOEt
(40 mL) with 10% Pd/C (275 mg). Silica gel column chromatog-
raphy (CH2Cl2 then CH2Cl2/MeOH, 95:5) afforded the acid com-
pound 15 (276 mg, 92% yield) as a white solid. [α]2D5 = –15.8 (c =
0.57, CHCl ). M.p. Ͻ50 °C. IR (film): ν = 3600–2400, 3494
˜
3
(COOH, OH), 2956 (CH), 1738 (C=O) cm–1. 1H NMR (CDCl3,
300 MHz): δ = 0.85 (d, J = 6.6 Hz, 6 H, 9-H, 10-H), 1.10–1.20 (m,
2 H, 7-H), 1.20–1.32 (m, 1 H, 8-H), 1.42–1.60 (m, 2 H, 6-H), 1.60–
1.80 (m, 2 H, 5-H), 2.73 (d, J = 16.6 Hz, 1 H, 3a-H), 2.98 (d, J =
16.6 Hz, 1 H, 3b-H), 3.70 (s, 3 H, OMe), 8.15 (br. s, 2 H, OH,
COOH) ppm. 13C NMR (CDCl3, 75 MHz): δ = 21.0 (C-6), 22.6,
22.7 (C-9 and C-10), 27.9 (C-8), 38.8 (C-5), 39.3 (C-7), 42.8 (C-3),
52.2 (OMe), 75.3 (C-2), 172.0 (C-4), 179.4 (C-1) ppm. HRMS
(ESI): calcd. for C11H20O5 [M + Na]+ 255.1208; found 255.1205.
(1S)-2-Methoxy-2-oxo-1-phenylethyl
(2R)-2-(2-Methoxy-2-oxo-
ethyl)-5,5-dimethyltetrahydrofuran-2-carboxylate (21): Mercury di-
acetate [Hg(OAc)2; 116 mg, 0.364 mmol] was added to a solution
of compound 20 (102 mg, 0.28 mmol) in a 1:1 mixture of THF/
H2O (1.4 mL) cooled to 0 °C. The mixture was warmed to room (2R)-2-Hydroxy-2-(2-methoxy-2-oxoethyl)heptanoic Acid (19): Ob-
temperature and stirred for 2.5 h. Then NaBH4 (21 mg,
0.570 mmol) dissolved in a 1  NaOH solution (0.310 mL) was
added dropwise. Following the release of gas and precipitation of
mercury, the organic layer was diluted with THF. A saturated solu-
tion of NaCl was introduced, and the layers were separated. The
aqueous phase was neutralized with a 1  HCl solution and then
extracted with AcOEt (3ϫ). The combined extracts were washed
with brine, dried with MgSO4, filtered, and concentrated in vacuo.
The crude residue was purified by silica gel column chromatog-
raphy (cyclohexane/AcOEt, 4:1) to give the tetrahydrofuran 21
(78 mg, 76% yield) as a colorless oil. [α]2D5 = +50.0 (c = 1.15,
tained from the ester 18 (161 mg, 0.439 mmol) in AcOEt (12.5 mL)
with 10% Pd/C (89 mg). Silica gel column chromatography
(CH2Cl2 then CH2Cl2/MeOH, 95:5) gave the acid compound 19
(88 mg, 92% yield) as a colorless oil. [α]2D5 = –8.7 (c = 0.64, CHCl3).
IR (film): ν = 3700–2300, 3500 (COOH, OH), 2956, 2931 (CH),
˜
1736 (C=O) cm–1. 1H NMR (CDCl3, 300 MHz): δ = 0.86 (t, J =
6.7 Hz, 3 H, 9-H), 1.14–1.36 (m, 5 H, 8-H, 7-H, 6a-H), 1.39–1.56
(m, 1 H, 6b-H), 1.60–1.80 (m, 2 H, 5-H), 2.72 (d, J = 16.6 Hz, 1
H, 3a-H), 2.97 (d, J = 16.6 Hz, 1 H, 3b-H), 3.68 (s, 3 H, OMe)
ppm. 13C NMR (CDCl3, 75 MHz): δ = 14.0 (C-9), 22.5 (C-6), 22.8
(C-8), 31.8 (C-7), 39.1 (C-5), 42.9 (C-3), 52.1 (OMe), 75.3 (C-2),
Eur. J. Org. Chem. 2009, 437–443
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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441

F. Berhal, S. Tardy, J. Pérard-Viret, J. Royer
FULL PAPER
171.9 (C-4), 179.3 (C-1) ppm. HRMS (ESI): calcd. for C10H18O5
[M + Na]+ 241.1052; found 241.1047.
[1]
a) H. Itokawa, X. Wang, K.-H. Lee, in Anticancer Agents from
Natural Products (Eds.: G. H. Cragg, D. G. I. Kingston, D. J.
Newman), CRC Press, Boca Raton, FL, 2005, pp. 47–70; b)
J. L. Grem, B. D. Cheson, S. A. King, B. Leyland-Jones, M.
Suffness, J. Natl. Cancer Inst. 1988, 80, 1095–1103; c) W. Tang,
G. Eisenbrand (Eds.), “Cephalotaxus spp.” in Chinese Drugs
of Plant Origin, Chemistry, Pharmacology, and Use in Tradi-
tional and Modern Medecine, Springer, Berlin, 1992, pp. 281–
306.
a) R. G. Powell, D. Weisleder, C. R. Smith Jr, W. K.
Rohwedder, Tetrahedron Lett. 1970, 11, 815–818; b) for a re-
view, see: M. A. Jilal Miah, T. Hudlicky, J. W. Reed in The Al-
kaloids (Ed.: G. A. Cordell), Academic Press, San Diego, 1998,
vol. 51, pp. 199–264.
For recent papers on clinical trials of homoharringtonine, see:
a) H. M. Kantarjian, M. Talpaz, V. Santini, A. Murgo, B. Che-
son, S. M. O’Brien, Cancer 2001, 92, 1591–1605; b) S. M.
O’Brien, M. Talpaz, J. Cortes, J. Shan, F. J. Giles, S. Faderl, D.
Thomas, G. Garcia-Manero, S. Mallard, M. B. Rios, C. Koller,
S. Kornblau, M. Andreeff, A. Murgo, M. Keating, H. M. Kan-
tarjian, Cancer 2002, 94, 2024–2032; c) B. Scappini, F. Onida,
H. M. Kantarjian, L. Dong, S. Verstovsek, M. J. Keating, M.
Beran, Cancer 2002, 94, 2653–2662; d) E. Hitt, Lancet Oncol.
2002, 3, 259; e) A. Quintas-Cardama, J. Cortes, Expert Opin.
Pharmacother. 2008, 9, 1029–1037; f) W. G. Zhang, F. X. Wang,
Y. X. Chen, X. M. Cao, A. L. He, J. Liu, X. R. Ma, W. H.
Zhao, S. H. Liu, J. L. Wang, Am. J. Hematol. 2008, 83, 185–
188.
(2R)-2-(2-Methoxy-2-oxoethyl)-5,5-dimethyltetrahydrofuran-2-carb-
oxylic Acid (22): Obtained from the ester 21 (117 mg, 0.321 mmol)
in AcOEt (9 mL) with 10% Pd/C (65 mg). Silica gel column
chromatography (CH2Cl2 then CH2Cl2/MeOH, 95:5) afforded the
acid compound 22 (62 mg, 90% yield) as a white solid. [α]2D5 = –23.0
(c = 0.45, CHCl ). M.p. 83 °C. IR (film): ν = 3600–2700, 3475
˜
3
(COOH, OH), 2982 (CH), 1747, 1731 (C=O) cm–1. 1H NMR
(CDCl3, 300 MHz): δ = 1.29 (s, 3 H, 9-H), 1.37 (s, 3 H, 10-H), 1.86
(t, J = 7.2 Hz, 2 H, 4a-H, 4b-H), 2.20 (ddd, J = 7.4, 7.6, 13.3 Hz,
1 H, 3a-H), 2.42 (ddd, J = 6.9, 7.1, 13.3 Hz, 1 H, 3b-H), 2.67 (d,
J = 15.8 Hz, 1 H, 6a-H), 3.10 (d, J = 15.8 Hz, 1 H, 6b-H), 3.67 (s;
3 H, OMe), 8.21 (br. s, 1 H, COOH) ppm. 13C NMR (CDCl3,
75 MHz): δ = 28.5 (C-9), 28.7 (C-10), 36.1 (C-3), 37.6 (C-4), 43.7
(C-6), 52.1 (OMe), 84.1 (C-5), 85.7 (C-2), 170.2 (C-7), 176.5 (C-8)
ppm. HRMS (ESI): calcd. for C10H16O5 [M + Na]+ 239.0895;
found 239.0899.
[2]
[3]
(2R)-2-Benzyl-2-hydroxy-4-methoxy-4-oxobutanoic Acid (17): Ob-
tained after 24 h from the ester 16 (32 mg, 0.083 mmol) in AcOEt
(5 mL; c = 0.017 ) with 20% palladium hydroxide [Pd(OH)2;
47 mg] and under 5 bar of hydrogen in a Parr apparatus. Silica
gel column chromatography (CH2Cl2 then CH2Cl2/MeOH, 95:5)
provided the acid compound 17 (16 mg, 85% yield) as a colorless
oil. [α]2D5 = –20.3 (c = 0.58, CHCl ). IR (film): ν = 3600–2500, 3480
˜
3
[4] a) W. W. Paudler, G. I. Kerley, J. McKay, J. Org. Chem. 1963,
28, 2194–2197; b) R. G. Powell, D. Weisleder, C. R. Smith Jr,
I. A. Wolff, Tetrahedron Lett. 1969, 10, 4081–4084; c) D. J.
Abraham, R. D. Rosenstein, E. L. McGandy, Tetrahedron Lett.
1969, 10, 4085–4086; d) S. K. Arora, R. B. Bates, R. A. Grady,
R. G. Powell, J. Org. Chem. 1974, 39, 1269–1271; e) S. K.
Arora, R. B. Bates, R. A. Grady, G. Germain, J. P. Declercq,
R. G. Powell, J. Org. Chem. 1976, 41, 551–554.
(COOH, OH), 2957, 2927 (CH), 1743, 1732 (C=O) cm–1. 1H NMR
(CDCl3, 300 MHz): δ = 2.70 (d, J = 16.6 Hz, 1 H, 3a-H), 2.96 (d,
J = 13.5 Hz, 1 H, 5a-H), 3.05 (d, J = 16.6 Hz, 1 H, 3b-H), 3.08 (d,
J = 13.5 Hz, 1 H, 5b-H), 3.66 (s, 3 H, OMe), 5.65 (br. s, 2 H,
OH, COOH), 7.19–7.33 (m, 5 H, Ar-H) ppm. 13C NMR (CDCl3,
75 MHz): δ = 42.2 (C-3), 45.0 (C-5), 52.3 (OMe), 75.8 (C-2), 127.4
(C-p), 128.4 (C-m), 130.6 (C-o), 134.6 (C-i), 172.0 (C-4), 178.2 (C-
1) ppm. HRMS (ESI): calcd. for C12H14O5 [M + Na]+ 261.0729;
found 261.0739.
[5]
a) S. Brandange, S. Josephson, S. Vallen, Acta Chem. Scand.
1974, 28, 153–156; b) S. Brandange, S. Josephson, S. Vallen,
Acta Chem. Scand. 1973, 27, 3668–3672; c) S. Brandange, I.
Granelli, B. Luning, C. Moberg, E. Sjostrand, Acta Chem.
Scand. 1972, 26, 2558–2560; d) S. Brandange, B. Luning, Acta
Chem. Scand. 1969, 23, 1151–1154; e) B. Luning, H. Trankner,
S. Brandange, Acta Chem. Scand. 1966, 20, 2011; f) H. Kizu,
E. Kaneko, T. Tomimori, Chem. Pharm. Bull. 1999, 47, 1618–
1625.
(2S)-2-(2-Methoxy-2-oxoethyl)oxirane-2-carboxylic
Acid
(23):
Pd(OH)2 (0.030 g) in anhydrous THF (10 mL) was placed in a two-
necked round-bottomed flask under nitrogen. The reaction was
conditioned under hydrogen. Then epoxide 11a (0.100 g,
0.325 mmol) dissolved in anhydrous THF (2 mL) was added, and
the solution was stirred at room temperature and atmospheric pres-
sure for 2 h. The reaction mixture was then filtered though a Ce-
lite® pad. The filtrate was concentrated under reduced pressure.
The crude product was washed with saturated aqueous NaHCO3,
the aqueous layer was then acidified with 0.1  aqueous hydrochlo-
ric acid, and extracted with ethyl acetate. The combined organic
extracts were dried with MgSO4, filtered, and concentrated under
reduced pressure. This treatment afforded the epoxide 23 (0.036 g,
[6]
a) T. R. Kelly, J. C. McKenna, P. A. Christenson, Tetrahedron
Lett. 1973, 14, 3501–3504; b) L. Keller, F. Dumas, J. d’Angelo,
Eur. J. Org. Chem. 2003, 2488–2497; c) J. Auerbach, T.
Ipaktchi, S. M. Weinreb, Tetrahedron Lett. 1973, 14, 4561–
4564; d) R. A. Ancliff, A. T. Russell, A. J. Sanderson, Chem.
Commun. 2006, 3243–3245.
[7]
[8]
[9]
S. A. A. El Bialy, H. Braun, L. F. Tietze, Eur. J. Org. Chem.
2005, 2965–2972.
D. D. Perrin, W. L. F. Armarego in Purification of Laboratory
Chemicals, 3rd ed., Pergamon Press, Oxford, 1988, p. 123.
a) C. R. Johnson, R. W. Herr, D. M. Wieland, J. Org. Chem.
1973, 38, 4263–4268; b) H. M. Sirat, E. J. Thomas, J. D. Wallis,
J. Chem. Soc. Perkin Trans. 1 1982, 2885–2896.
70% yield) as a colorless oil. IR (film): ν = 3486, (COOH), 2957
˜
(CH3), 2856 (CH2), 1743 (C=O) cm–1. 1H NMR (CDCl3,
300 MHz): δ = 2.75 (d, J = 17.16 Hz, 1 H, 4a-H), 3.00 (d, J =
5.51 Hz, 1 H, 3a-H), 3.15 (d, J = 17.17 Hz, 1 H, 4b-H), 3.25 (d, J
= 5.49 Hz, 1 H, 3b-H), 3.77 (s, 3 H, OMe), 6.9 (br. s, 1 H, COOH)
ppm. 13C NMR (CDCl3, 75 MHz): δ = 36.83 (C-4), 52.06 (C-3),
52.34 (OMe), 53.58 (C-2), 169.80 (C-5), 173.85 (C-6) ppm. HRMS
(ESI): calcd. for C6H8O5 [M + Na]+ 183.0263; found 183.0269.
[10]
a) H. Gilman, R. G. Jones, L. A. Woods, J. Org. Chem. 1952,
17, 1630–1634; b) B. H. Lipshutz, J. A. Kozlowski, R. S.
Wilhelm, J. Org. Chem. 1983, 48, 546–550; c) N. R. Schmuff,
B. M. Trost, J. Org. Chem. 1983, 48, 1404–1412.
[11]
[12]
a) M. Ohtani, T. Matsuura, F. Watanabe, M. Narisada, J. Org.
Chem. 1991, 56, 4120–4123; b) J. L. Charlton, K. Koh, J. Org.
Chem. 1992, 57, 1514–1516.
a) The same cyclization procedure was recently reported by Gin
and co-workers in the preparation of anhydroharringtonine:
J. D. Eckelbarger, J. T. Wilmot, M. T. Epperson, C. S. Thakur,
D. Shum, C. Antczak, L. Tarassishin, H. Djaballah, D. Y. Gin,
Acknowledgments
The CNRS and the French Ministry of Education and Research
are acknowledged for funding.
442
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 437–443

Monoacid Side-Chains of Cephalotaxus Alkaloids
Chem. Eur. J. 2008, 14, 4293–4306; b) hazards in handling mer-
curic acetate can be found in P. Kocovský, J. Hofferberth,
“Mercury(II) acetate” in Encyclopedia of Reagents for Organic
Synthesis (Ed.: L. A. Paquette), Wiley, Chichester, 1995, p.
3242.
Mikolajczak, C. R. Smith Jr, D. Weisleder, J. Org. Chem. 1979,
44, 63–67.
[14] J.-P. Robin, R. Dhal, G. Dujardin, L. Girodier, L. Mevellec, S.
Poutot, Tetrahedron Lett. 1999, 40, 2931–2934.
Received: September 24, 2008
[13] T. R. Kelly, R. W. McNutt Jr, M. Montury, N. P. Tosches, K. L.
Published Online: December 2, 2008
Eur. J. Org. Chem. 2009, 437–443
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
443