Synthesis of the ester side chains of homoharringtonine and harringtonine using lactones as building blocks

Article abstract of DOI:10.1080/00397911.2020.1829643

The efficient synthesis of the ester side chains of homoharringtonine and harringtonine using lactones as building blocks has been developed. The synthesis used classic reactions from readily available starting materials. Reactions of the lactone bearing

Full text of DOI:10.1080/00397911.2020.1829643

Synthetic Communications
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Synthesis of the ester side chains of
homoharringtonine and harringtonine using
lactones as building blocks
Fang-Fang Dang , Cui-Cui Wang , Feng Han & Zhi-Wei Zhang
To cite this article: Fang-Fang Dang , Cui-Cui Wang , Feng Han & Zhi-Wei Zhang (2020):
Synthesis of the ester side chains of homoharringtonine and harringtonine using lactones as
building blocks, Synthetic Communications, DOI: 10.1080/00397911.2020.1829643
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https://doi.org/10.1080/00397911.2020.1829643
Synthesis of the ester side chains of homoharringtonine
and harringtonine using lactones as building blocks
Fang-Fang Danga, Cui-Cui Wangb, Feng Hanc, and Zhi-Wei Zhangb
aSchool of Chemistry and Chemical Engineering, Xi’an University of Architecture and Technology, Xi’an,
b
P. R. China; College of Chemical and Pharmaceutical Engineering, Hebei University of Science and
c
Technology, Shijiazhuang, P. R. China; CSPC Innovation Pharmaceutical Co., Ltd, Shijiazhuang,
P. R. China
ABSTRACT
ARTICLE HISTORY
Received 24 April 2020
The efficient synthesis of the ester side chains of homoharringtonine
and harringtonine using lactones as building blocks has been devel-
oped. The synthesis used classic reactions from readily available
starting materials. Reactions of the lactone bearing an oxo-contain-
ing a-tetrasubstituted center with MeOH and cephalotaxine, respect-
ively, proceeded smoothly to give the corresponding ring-opening
products in 80% and 65% yield.
KEYWORDS
Alkaloid; classic reactions;
efficient synthesis; ester
side chain;
homoharringtonine
GRAPHICAL ABSTRACT
Introduction
Homoharringtonine (1c) and harringtonine (1b) are minor alkaloids (Scheme 1)[1] iso-
lated from the leaves and stems of Cephalotaxus harringtonia, an evergreen tree native
of the southern provinces of China. As the most potent antileukemia compound among
the family, homoharringtonine was approved by FDA as an adult orphan-drug for the
treatment of chronic myeloid leukemia in 2012.[2] Structurally, it has a pentacyclic diter-
penoid skeleton (cephalotaxine, 1a) that bears an a-tetrasubstituted ester side chain. The
unique structure and the important biological activities rendered Cephalotaxus alkaloids
attractive synthetic targets.[1,3] The side chain is closely related to the biological activity
since cephalotaxine itself does not exhibit any interesting antitumor activity.
The esterification of cephalotaxine 1a with a side chain intermediate for synthesis of
homoharringtonine is extremely challenging because of the formidable steric hindrance
of both of the reactants. Direct reaction of 1a with a-tertiary alcohol side chain proved
to be unsuccessful.[4] To address this issue, a-keto acid side chains[4,5] (Scheme 2a) have
CONTACT Zhi-Wei Zhang
zhangzw@hebust.edu.cn
College of Chemical and Pharmaceutical Engineering, Hebei
University of Science and Technology, Yuxiang Rd. 26, Shijiazhuang 050018, P. R. China.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

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F.-F. DANG ET AL.
Scheme 1. Cephalotaxus alkaloids.
Scheme 2. Cephalotaxine esterification with various side chain intermediates. (a) a-Keto acid. (b)
Tetrahydropyran acid. (c) Four-membered lactone acid. (d) This work: six or seven-membered lactone.
been successfully designed and used to synthesize 1c from 1a. However, the followed
Reformatsky reaction for construction of the tertiary alcohol gave low diastereoselectiv-
ity in most cases. In 2017, Chen’s group[6] reported a highly diastereoselective

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3
Scheme 3. Synthesis of the ester side chains of homoharringtonine and harringtonine from lactones.
Mukaiyama aldol reaction of the (Z)-a-chloro ketene silyl acetal, enabling an efficient
hemisynthesis of a series of natural and unnatural products. Additionally, cyclic side
chains such as tetrahydropyran-2-carboxylic acid (Scheme 2b) reported by Robin
group[7] and Russell group[8], and four-membered lactone intermediate (Scheme 2c)
reported by Gin group[9] also reacted with 1a to afford the desired products, respect-
ively. However, despite tremendous efforts to develop more efficient strategies, draw-
backs, such as expensive starting materials, harsh reaction conditions and long reaction
steps, are also obvious. A general and more efficient synthesis employing classic trans-
formations from readily available compounds remains highly desirable. As a continu-
ation of our study toward synthesis of Cephalotaxus alkaloids,[10] we report herein a
four-step synthesis of the six or seven-membered lactone as the side chain building
block (Scheme 2d), which was accomplished from readily available 2,2-dimethyl cyclo-
hexanone as starting materials. Treatment of the lactone with NaOMe led to an efficient

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synthesis of the ester side chains of homoharringtonine and harringtonine in six steps
with 37.8% overall yield. Reaction of cephalotaxine 1a with the seven-membered lactone
also proceeded smoothly to give the product in 65% yield.
Results and discussion
Our synthesis commenced with a Baeyer–Villiger oxidation of 2,2-dimethyl cyclohex-
anone 2 (Scheme 3).[11] The lactone 3 was obtained in 78% yield. A Claisen
condensation of 3 with allyl chloroformate provided the 1,3-diester 4 in 91% yield.
Base-induced a-benzoyloxylation[12] of 4 using benzoyl peroxide was employed to
introduce the oxygen atom, affording the a-tetrasubstituted ester 5 in almost quanti-
tative yield. Pd-catalyzed decarboxylative allylation of 5 gave the lactone 6 in
92% yield.
With the seven-membered lactone 6 in hand, we initially conducted a reaction of 6
with NaOMe to test the feasibility for the individual synthesis of the ester side chain of
homoharringtonine. The individual synthesis of the side chains bearing an oxygen-con-
taining tetrasubstituted stereogenic center has also attracted extensive research interest.
Dumas and coworkers[13] reached a 4.3% total yield of the ester side chain in 12 steps.
Tietze’s group[14] reported the synthesis of an acid side chain in 32% overall yield based
on Seebach’s procedure. However, they used a stoichiometric amount of SeO2 as oxi-
dant. Yang’s group[15] developed an efficient synthesis of the ester side chain via
Grignard reaction, Wittig condensation and [2,3]-Meisenheimer rearrangement as the
key transformations. Two cyclic side chain compounds are also synthesized by
Russell,[8] Tietze,[14] Yang,[15] and Royer,[16] respectively.
In our synthesis, the reaction of compound 6 with NaOMe gave the deprotected and
ring-opening ester 7 in 80% yield at 55 ꢀC for 6 h (Scheme 3). Finally, RuCl3-catalyzed
oxidative cleavage[17] of the double bond in 7 was performed with NaIO4 as oxidant to
give a crude acid intermediate, which was used directly for the next esterification with-
out further purification. The ester side chain (8) of homoharringtonine was obtained in
73% yield for the two steps. Encouraged by this result, esterification of cephalotaxine 1a
with lactone 6 using NaH as base in THF was performed to give the coupling product
9 as an inseparable diastereoisomers (65% yield). The ester side chain (8a) of harringto-
nine was also analogously synthesized from 2,2-dimethyl cyclopentanone 2a (Scheme 3).
The synthetic products
reported data.[15]
8
and 8a are identical spectroscopically with the
Conclusion
In conclusion, we have developed a general and efficient method for the synthesis of
the ester side chains of homoharringtonine and harringtonine in six steps from readily
available cyclic ketones in 37.8% overall yield. The seven-membered lactone can be used
for the esterification of cephalotaxine. Further studies on the synthesis of homoharing-
tonine and harringtonine and development of an asymmetric synthesis using catalytic
enantioselective allylation of the unprecedented seven-membered lactone 5 bearing a
protected a-tertiary alcohol are underway.

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Experimental
Procedure for the synthesis of the ester side chains of homoharingtonine and
harringtonine
Compound 7a/7 (0.17 mmol, 1.0 equiv.) was diluted in H2O (2.34 mL, 0.11 M), aceto-
nitrile (1.5 mL, 0.16 M), and EtOAc (1.5 mL, 0.16 M). Sodium periodate (NaIO4, 233 mg,
1.09 mmol, 6.4 equiv.) and ruthenium(III) trichloride (RuCl3, 3.2 mL, 0.1 M solution in
H2O, 0.019 equiv.) were added in single portion. The reaction was allowed to stir at
ambient temperature (ca. 23 ꢀC) for 5 h, at which time consumption of starting material
was completed (as determined by TLC analysis). Crude reaction mixture was filtered
through a celite plug and extracted with ethyl acetate. The extracts were washed with
brine, dried over Na2SO4, filtered and concentrated in vacuo to give the crude acid
products, which were carried on to the next step with no further purification. To the
crude acid (0.128 mmol, 1.0 equiv.) in dry MeOH (1.2 mL) was added 2, 2-dimethoxy-
propane (287 mL, 2.34 mmol, 18.24 equiv.) and TMSCl (4.5 mL, 0.036 mmol, 0.28 equiv.).
The mixture was stirred at room temperature for 12 h. After the reaction was complete,
the solvent was removed under reduced pressure. The residue was purified by chroma-
[15]
tography on silica gel (petroleum ether/EtOAc) to afford the ester side chains 8a/8.
Spectra data of dimethyl 2-hydroxy-2-(3-hydroxy-3-methylbutyl)succinate (8a)
White solid (23 mg, 0.09 mmol, 73% yield); mp. 20.6–21.5; Rf ¼ 0.42 (petroleum ether/
EtOAc ¼ 1:1); 1H NMR (500 MHz, CDCl3) d 3.81 (s, 3H), 3.68 (s, 3H), 2.94 (d,
J ¼ 16.2 Hz, 1H), 2.73 (d, J ¼ 16.3 Hz, 1H), 1.84–1.80 (m, 2H), 1.65–1.59 (m, 1H),
1.38–1.32 (m, 1H), 1.21 (d, J ¼ 3.4 Hz, 6H) ppm; 13C NMR (125 MHz, CDCl3) d 175.68,
171.43, 75.23, 70.43, 53.10, 52.04, 43.62, 36.94, 33.99, 29.61, 29.31 ppm; HRMS (ESI) m/
z: [M þ H]þ found for 249.1331, calcd for C11H21O6 249.1333.
Spectra data of dimethyl 2-hydroxy-2-(4-hydroxy-4-methylpentyl)succinate (8)
White solid (24 mg, 0.09 mmol, 73% yield); mp. 32.3–33.1; Rf ¼ 0.4 (petroleum ether/
1
EtOAc ¼ 1:1); H NMR (500 MHz, CDCl3) d 3.81 (s, 3H), 3.72 (br, 1H), 3.68 (s, 3H),
2.93 (d, J ¼ 16.3 Hz, 1H), 2.70 (d, J ¼ 16.3 Hz, 1H), 1.74–1.64 (m, 2H), 1.61 (br, 1H),
1.56–1.49 (m, 1H), 1.45–1.42 (m, 2H), 1.26–1.22 (m, 1H), 1.19 (d, J ¼ 2.1 Hz, 6H) ppm;
13C NMR (125 MHz, CDCl3) d 175.73, 171.47, 75.39, 70.99, 53.08, 52.01, 43.72, 43.55,
39.77, 29.52, 29.30, 18.24 ppm; HRMS (ESI) m/z: [M þ Na]þ found for 285.1304, calcd
for C12H22O6Na 285.1309.
1
Full experimental details, characterization data and copies of H and 13C NMR spec-
tra. This material can be found via the “Supplementary Content” section of this
article’s webpage.
Funding
We are grateful for financial support from Hebei Province Natural Science Foundation of China
[B2016208124] and Hebei University of Science and Technology.

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F.-F. DANG ET AL.
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