Enantiospecific synthesis of the diacid side-chain of deoxyharringtonine and homodeoxyharringtonine

Article abstract of DOI:10.1139/cjc-2013-0066

The enantiospecific synthesis of the diacid side-chain of deoxyharringtonine (2) and homodeoxyharringtonine (3) was accomplished from (L)-N-Boc-α-amino alcohol 10 in high yield. A key feature of the synthesis is the construction of the chiral tertiary alcohol by a three-step sequence (i.e., Wittig reaction, Meisenheimer rearrangement, and catalytic hydrogenation).

Full text of DOI:10.1139/cjc-2013-0066

738
ARTICLE
Enantiospecific synthesis of the diacid side-chain of
deoxyharringtonine and homodeoxyharringtonine
Moran Sun, Yangla Xie, Jincan Gu, and Hua Yang
Abstract: The enantiospecific synthesis of the diacid side-chain of deoxyharringtonine (2) and homodeoxyharringtonine (3) was
accomplished from (L)-N-Boc-␣-amino alcohol 10 in high yield. A key feature of the synthesis is the construction of the chiral
tertiary alcohol by a three-step sequence (i.e., Wittig reaction, Meisenheimer rearrangement, and catalytic hydrogenation).
Key words: deoxyharringtonine, homodeoxyharringtonine, Meisenheimer rearrangement, tertiary alcohol.
Résumé : On a effectué la synthèse énantiospécifique de la chaîne latérale diacide de la désoxyharringtonine (2) et de
l’homodésoxyharringtonine (3) a` partir du (L)-N-Boc-␣-aminoalcool 10 avec un haut rendement. La caractéristique essentielle de
la synthèse est la construction de l’alcool tertiaire chiral selon une séquence en trois étapes (réaction de Wittig, réarrangement
de Meisenheimer et hydrogénation catalytique). [Traduit par la Rédaction]
Mots-clés : désoxyharringtonine, homodésoxyharringtonine, réarrangement de Meisenheimer, alcool tertiaire.
synthesis of 4 and 5 side-chain acid.7 The side-chain diacid of 2 and
3 appeared to us as attractive target molecules to which we could
apply our methodology, and herein, we report a concise asymmet-
ric synthesis of these two molecules.
Introduction
Biological evaluation showed that several alkaloids (Fig. 1) iso-
lated from the genus Cephalotaxus (evergreen conifers and shrubs
native to South-East Asia) exhibit significant antileukemic activi-
ties.1 In comparison of this family of antitumor alkaloids,
deoxyharringtonine (2) was the most potent one, demonstrating
acute toxicity towards various murine leukemia, murine lym-
phoma, and human epidermoid carcinoma cells. For instance, the
IC50 value of 2 against P-388 leukemia cells was 7.5 ng/mL, and it is
stronger than those of harringtonine (5) (32 ng/mL) and homohar-
ringtonine (4) (17 ng/mL).2 Since occurring naturally in extremely
small quantities, biological studies on 2 have not been carried out.
Indeed, 4 is currently in phase III of clinical trials in the United
States for the treatment of chronic myeloid leukaemia. Thus, ob-
taining large quantities of 2 and homodeoxyharringtonine (3)3
becomes an urgent concern. In view of the fact that cephalotaxine
(1) itself was found to be biologically inactive, the most practical
path for this task is semi-synthesis by coupling the carboxyl group
of an individual enantiopure side-chain acid to the C-3 hydroxyl
group of 1.
Results and discussion
The structural similarities between these compounds led us to
design a common retrosynthetic strategy (Scheme 1). In a most
interesting and productive retrosynthetic maneuver, diacid
6 could be traced in three steps (i.e., debenzylation, double-bond
saturation, and cleavage of the N−O bond tandem sequence in one
pot) to N-oxides 7. Although it may not be obvious, intermediate
7 could conceivably be fashioned from allylamine 8 by a [2,3]-
Meisenheimer rearrangement. A Wittig reaction could then per-
mit the formation of 8 by coupling the appropriate ylide with
amino aldehyde 9, which in turn is smoothly derived from inex-
pensive and readily available L-valine and L-leucine, respectively.
The starting material N-Boc-protected amino alcohols 10 was
prepared from (L)-␣-amino acid according to literature procedures
(Scheme 2).8 The subsequent oxidation of (L)-N-Boc-␣-amino alco-
9
hol 10 using commercially available or freshly prepared MnO2
The interesting activity of 2 combined with the challenge to
resulted in no detectable product formation. Initial attempts to
oxidize with Parikh−Doering oxidation (DMSO−Py·SO3 in dry
CH2Cl2)10 was unsuccessful, as only unreacted starting material
was recovered. Increasing Py·SO3 loading to largely excess or em-
ploying a dropwise fashion proved to be to no avail. After several
trials, good results were obtained by prior activation of Py·SO3 in
DMSO for at least 15 min and quickly adding to the solution of
substrates in one portion. This transformation was also studied by
Swern oxidation11 and the yields were about the same. To avoid
the undesired decomposition and racemization of aldehyde 11,
the obtained crude products were used immediately in the next
step.
selectively construct
a stereogenic quaternary carbon has
prompted several groups to address the total synthesis of the
side-chain acid of 2 and 3. These methods have one common
feature that the quaternary hydroxyl carbonyl moiety was incor-
porated into certain optically active starting materials, such as
D-malic acid,4 chiral citrate derivative,5 or a factionalized chiral
nonracemic epoxide,6 in advance. Then, the ester chain was intro-
duced by nucleophilic addition of organocurates and Grignard
reagent, respectively. Nevertheless, the troubles resulted from the
alkylation process. For instance, employment of expensive strong
base (LiHMDS), low temperature conditions (–60 to –78 °C), and
troublesome operation was an inconvenience for large-scale
production.
Exposure of aldehyde 11 to freshly prepared 1-butyrolactonyli-
dene triphenylphosphorane12 provided exclusively E-isomer
olefin 12, the configuration of which was assigned by comparing
We have recently discovered the formation of chiral tertiary
alcohol through a Wittig reaction/Meisenheimer rearrangement/
catalytic hydrogen sequence and exploited this in an asymmetric
1
the chemical shift (␦ 6.50 for 2 and ␦ 6.42 for 3) in the H NMR
Received 17 February 2013. Accepted 31 March 2013.
M. Sun, Y. Xie, J. Gu, and H. Yang. School of Pharmaceutical Science, Zhengzhou University, Zhengzhou 450001, China.
Corresponding author: Hua Yang (e-mail: yanghua@zzu.edu.cn).
Can. J. Chem. 91: 738–740 (2013) dx.doi.org/10.1139/cjc-2013-0066
Published at www.nrcresearchpress.com/cjc on 8 April 2013.

Sun et al.
739
Fig. 1. Structure of several Cephalotaxus alkaloids.
Me
O
O
3'
1'
2'
4'
N
5'
Me
O
HO
O
5
H
3
O
H
R
OMe
OMe
deoxyharringtonine
(2)
R=H cephalotaxine (1)
OH
1'
1'
6'
Me
6'
HO
Me
O
O
O
5'
Me
Me
Me
HO
O
HO
O
HO
O
Me
OMe
OMe
OMe
homoharringtonine
harringtonine
homodeoxyharringtonine
(4)
(5)
(3)
Scheme 1. Retrosynthesis analysis for diacid side-chain 6.
O
HO
1'
OH
OH
n
2'R
6
6–9
n
O
a
b
0(DHT)
1(HDHT)
Bn2N
O
O
O
H
O
OH
OH
1'
OH
OH
n
n
n
2'R
NBn2
NBn2
7
9
8
O
O
spectrum with 1H NMR data of related compounds (␦ 6.53 for
E-isomer and ␦ 5.80 for Z-isomer13).
proximately 40% recovery. After several trials, we observed that
the workup protocol had a crucial influence on the yield. Our
efforts to separate the reaction mixture were based on the re-
ported procedure but with a slight modification in which extract
manipulation was performed before and after acidification by
using ethyl acetate and chloroform, respectively. Thus, the ob-
tained crude product contains minor impurities and further re-
crystallization delivers 6 in excellent isolated yield. The physical
and spectroscopic properties of 6, prepared by current methodol-
ogy, match those reported in the literature.4a,6 It is important to
mention that the optical rotation of the obtained product was
nearly equal to that of the natural product, which confirms the R
absolute configuration of 6, and furthermore validates that the
[2,3]- Meisenheimer rearrangement of 13 proceeded with essen-
tially complete [1,3]-transfer of chirality.
After sequential cleavage of the Boc protective group of 12 with
TFA and doubly N-benzylation through the action of K2CO3 and
BnBr,14 the crucial N-oxide Meisenheimer rearrangement was ac-
complished uneventfully in the presence of m-CPBA, leading to 14
within 20 min in excellent yield. It should be pointed out that the
crude product 14 exhibited good stability in CH2Cl2 even after an
extended period of reaction time to 12 h, but with evidence of
complete decomposition in methanol after 5 h. Therefore, residue
14 without further purification was directly subjected to a flow of
hydrogen and 10% Pd/C catalyst in methanol at 5–20 °C. In one pot,
the reaction temperature was increased to 60 °C for cleaving the
N−O bond, furnishing lactone 15 and the minor side-product 16.
Although compounds 15 and 16 can be obtained in pure form,
careful purification at this stage was deemed unnecessary because
they can be converted into the same diacid 6. The initial conver-
sion of 15 to diacid side-chain 6 with KMnO4 was more trouble-
some, as the reaction mixture was extremely viscous and hard to
extract. Finally, oxidation of the mixture of 15 and 16 by the
TEMPO−NaClO−NaClO2 system15 was carried out. However, diacid
6 showed poor stability to chromatography on silica with an ap-
Conclusions
We report here on a method whereby (L)-␣-amino acid can be
converted into side-chain diacids 6a and 6b in the natural R con-
figuration in 52% and 60% overall yield, calculated from inexpen-
sive (L)-N-Boc-␣-amino alcohol 10 by a linear sequence of six
Published by NRC Research Press

740
Can. J. Chem. Vol. 91, 2013
Scheme 2. Synthesis of the chiral diacid 6 from (L)-N-Boc-␣-amino alcohol 10.
O
O
Ph3P
R
O
R
R
CHO
Boc
Swern oxidation
OH
O
HN
HN
11
CH2Cl2, rt
Boc
or Parikh-Doering
oxidation
HN
Boc
10
12
TFA, CH2Cl2, rt
BnBr, K2CO3
Bn
O
O
R
10–6
N Bn
O
R
m-CPBA
a
R
(CH3)2CH
O
N
O
CH2Cl2, rt
b
Bn
Bn
(CH3)2CHCH2
13
14
H2, Pd/C, CH3OH
O
HO
O
O
HO
R
R
HO
TEMPO
OH
OH
R
O
+
O
OH
6
15
O
16
Mori-Yasumoto, K.; Sekita, S.; Hirasawa, Y. Heterocycles 2010, 81 (1), 441.
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chemical operations. This three-step sequence (i.e., Wittig reac-
tion, Meisenheimer rearrangement, and catalytic hydrogenation)
serves as an exceptionally convenient method to access the chiral
tertiary alcohol. A particularly appealing feature of this approach
is that the stereogenic center ␣ to the carbonyl is controlled by the
chirality of the starting amino acid. More notably, the experimen-
tal operation of each step is convenient and able to be performed
in a 5–20 g scale in the laboratory and no expensive reagents are
required. Currently, we can prepare the enantiopure side-chain
diacid of 2 and 3 in 7–9 g quantities from 5 g of L-valine and
L-leucine, respectively, within 1 week.
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Acknowledgements
We thank the National Natural Science Foundation (20502023)
for financial support.
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