A rapid construction of the ABC tricyclic skeleton of malabanone A

Article abstract of DOI:10.1039/C8OB02495B

The construction of the ABC tricyclic skeleton of malabanone A with the required 4 stereocenters was accomplished in a concise route starting from R-carvone. The synthesis featured an intramolecular [3 + 2] cycloaddition reaction to assemble its A ring and an intramolecular Diels-Alder reaction to construct its C ring.

Full text of DOI:10.1039/C8OB02495B

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A rapid construction of the ABC tricyclic skeleton
of malabanone A†
Cite this: Org. Biomol. Chem., 2018,
16, 8491
Tao Li, Guangmiao Wu, Shangbiao Feng, Zemin Wang, Xingang Xie * and
Xuegong She
Received 8th October 2018,
Accepted 24th October 2018
DOI: 10.1039/c8ob02495b
rsc.li/obc
The construction of the ABC tricyclic skeleton of malabanone A reports towards malabanone A. Continuing with our long-term
with the required 4 stereocenters was accomplished in a concise research interest in the synthesis of natural polycyclic terpe-
route starting from R-carvone. The synthesis featured an intra- noids,2 we recently initiated a program towards the total syn-
molecular [3 + 2] cycloaddition reaction to assemble its A ring and thesis of malabanone A.3 Herein, we reported a concise syn-
an intramolecular Diels–Alder reaction to construct its C ring.
thesis of its ABC tricyclic skeleton, a very common structure in
many triterpenoids,4with the required 4 stereocenters (C5, C7,
C8, C10) which featured an intramolecular [3 + 2] cyclo-
addition reaction to assemble the A ring and an intra-
molecular Diels–Alder reaction to construct its C ring.
Since the B ring of malabanone A has a similar carbon
skeleton to carvone (Scheme 1, red part of 1), commercially
available and inexpensive R-carvone was envisioned to be an
ideal starting point of our synthesis and our retrosynthetic
analysis is outlined in Scheme 1. The cyclopropane subunit
(E ring) of malabanone A could be assembled by an intra-
molecular SN2 substitution cyclization reaction from precursor
Malabanone A (Fig. 1, 1), a novel octanor-triterpenoid with the
[4.3.1.01,6]decane unit in its structure was isolated from
Ailanthus malabarica DC (Simaroubaceae) of India and Indo-
China by Koichi Takeya’s group in 2001.1 Its parent plant has
long been used by the local people for treatment of dysentery,
dyspepsia, febrifuge and bronchitis and a preliminary bioassay
indicated that malabanone A showed weak cytotoxic activity on
P-388 murine leukemia cells with an IC50 value of 16 μg mL−1
To our knowledge, there have been no previous synthetic
.
Fig. 1 Structures of chisosiamesin, gedunin, octanorsimaroubin A and
malabanone A.
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and
Chemical Engineering, Lanzhou University, 222 South Tianshui Road, Lanzhou,
730000, P. R. China. E-mail: xiexg@lzu.edu.cn
†Electronic supplementary information (ESI) available. CCDC 1868194, 1868195
and 1868145. For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c8ob02495b
Scheme 1 Retrosynthetic analysis.
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2 which might be obtained via the Nazarov cyclization reaction condition optimization was performed and the results are
of divinyl ketone 3. Compound 3 could be easily derived from shown in Table 1. Solvents were first screened. While product
diene 4 by vinyl Grignard addition on a weinreb amide deriva- formation did not occur in CH3CN or methanol, employing
tive. The C ring of compound 4 was envisioned to be con- DCM, toluene, or a mixture of toluene and THF gave a compar-
structed through an intramolecular Diels–Alder cycloaddition able yield of 30% (Table 1, entries 2–6). Chloroform proved to
reaction and the requisite precursor 5 was expected to be be the best choice, as the yield increased to 56% (Table 1, entry
obtained from conjugated dienone 6 which could be prepared 7). Different oxidants were tested, without success (Table 1,
by a two step process (vinyl Grignard reagent addition/PCC- entries 8–10). So the optimal conditions at present are perform-
induced oxidative rearrangement) from the known tricyclic ing the reaction in CHCl3 with 14.5% NaClO aqueous solution
cyclohexenone 7.5 And compound 7 could be prepared via an for 4 h. Under the above reaction conditions, this cycloaddition
intramolecular 1,3-dipolar cycloaddition reaction of the corres- reaction could be performed on a 1 g scale in 56% yield which
ponding derivatives of commercially available R-carvone.
Our synthesis started with dialkylation of C10 of R-carvone.
expediently fulfilled the requirement of our synthetic program.
With enough tricyclic cyclohexenone 7 in hand, we then
As Scheme 2 depicts, the two-step process afforded acetal 9 as turned our attention to its further transformations (Scheme 3).
a single diastereoisomer with the requisite C10 quaternary After vinyl Grignard reagent 1,2-addition7 and a subsequent
carbon stereocenter and could be performed on a 10 g scale in PCC promoted oxidative rearrangement reaction,8 conjugated
61% overall yield. The configuration of compound 9 was deter- dienone 6 was obtained in 65% yield. LAH reduction of com-
mined by analogy with the literature.6a Subsequent acid hydro- pound 6 gave the corresponding 7β secondary alcohol 11 in
lysis and condensation with hydroxyl amine hydrochloride 98% yield whose stereo-configuration was confirmed by X-ray
gave the [3 + 2] cycloaddition precursor 10.
single crystal diffraction experiment. However all attempts to
Following literature precedents,5 only 30% of desired 7 was invert the configuration of the secondary alcohol under
obtained in our first trial (Table 1, entry 1). The low yield could Mitsunobu conditions9 failed. Nucleophilic substitutions on
be attributed to the decomposition of reaction precursor 10 and
the formation of other unknown by-products. So the reaction
Scheme 2 Preparation of tricyclic cyclohexenone 7.
Scheme 3 Failed route towards compound 12.
Table 1 Optimization of the [3 + 2] dipolar cycloaddition reaction of 10 a
Entry
Solvent
Time (h)
T (°C)
Oxidantb
Yieldc (%)
1
2
3
4
5
6
7
8
9
CH2Cl2
CH2Cl2 : THF = 2 : 1
CH3CN
Toluene
CH3OH
CH2Cl2
CHCl3
EtOH
CHCl3 : THF = 2 : 1
CHCl3
4
4
4
4
25
25
25
25
25
75
25
25
25
0
NaClO
NaClO
NaClO
NaClO
NaClO
NaClO
NaClO
Tolamine
NaClO·5H2O
PhI(OAc)2
30
31
N.R
30
N.R
33
56
Complex
38
4
Overnight
4
4
4
4
10
Trace
a All the reactions were performed on a 0.2 mmol scale at 0.04 M concentration. b In entries 1–7, 14.5% NaClO aqueous solution was used as the
oxidant. c Isolated yield.
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Conflicts of interest
The authors declare no competing financial interest.
Acknowledgements
We wish to acknowledge the generous financial support by the
NSFC (21472079, 21572088) and the Fundamental Research
Funds for the Central Universities (lzujbky-2017-91).
Notes and references
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Scheme 4 Synthesis of 4.
the mesylate10 or tosylate derivatives of 11 did not afford
propargyl ether 12. The poor reactivity of alcohol 11 may be
attributed to the steric hindrance preventing the required
approach of a nucleophile from the α face.
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α-epoxide 13 as a single diastereoisomer with basic H2O2.11,13
The configuration of compound 13 was determined by analogy
with the literature.11 Then it was treated with the lithium
derivative of 14 followed by 1 N hydrochloric acid quenching
to obtain the secondary alcohol 16 with the requisite C-7
stereocenter in 57% overall yield.11 The configuration of 16
was also confirmed by X-ray single crystal diffraction experi-
ment. At this time, the corresponding propargyl ether was
obtained smoothly and the requisite Diels–Alder precursor 5
was obtained via a subsequent common propargyl ester assem-
bly.11 The Diels–Alder reaction11,14 proceeded smoothly in
toluene at 115 °C to give the desired adduct 4 in 89% yield and
its stereo configuration was also confirmed by X-ray single
crystal diffraction experiment analysis (Scheme 4).
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Conclusions
In summary, the construction of the ABC tricyclic skeleton of
malabanone A with the requisite 4 stereocenters (C5, C7, C8
and C10) was accomplished in a concise route starting from
R-carvone. Our synthesis featured two highly effective intra-
molecular cycloaddition reactions to assemble the required
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C. Giménez-Saiz, Tetrahedron, 2003, 59, 9523.
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8494 | Org. Biomol. Chem., 2018, 16, 8491–8494
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