Total synthesis of (+)-chloranthalactone F

Article abstract of DOI:10.1039/c2cc17882f

Sequential biomimetic elaborations, featured by CrO₃-mediated oxidative lactonization, and DDQ-involved oxidative enol-lactonization, ensured the concise total synthesis of (+)-chloranthalactone F.

Full text of DOI:10.1039/c2cc17882f

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COMMUNICATION
Total synthesis of (+)-chloranthalactone Fw
Shan Qian and Gang Zhao*
Received 17th December 2011, Accepted 10th February 2012
DOI: 10.1039/c2cc17882f
Sequential biomimetic elaborations, featured by CrO3-mediated oxi-
dative lactonization, and DDQ-involved oxidative enol-lactonization,
ensured the concise total synthesis of (+)-chloranthalactone F.
Since the first isolation of shizukaol A, a large number of
lindenane sesquiterpenoid dimers, with various biological
activities, have been isolated from the plants of chloranthaceae.1
Biogenetically, these unique dimers are supposed to be formed
through
a
[2+2] or [4+2] cycloaddition process,2 like
chloranthalactone F (1)1k,l and chlorahololide A (2),1m respec-
tively (Fig. 1). Efforts on this class and related monomer had
been reported.3
Chloranthalactone F was isolated from the leaves of chlor-
anthus glaber. The structure of chloranthalactone F (1, Fig. 1),
which was originally misassigned by Takeda and co-workers,1k
was revealed as a result of the pioneering studies of the group of
Nakatani.1l Structurally, chloranthalactone F features two
cyclopropane rings bearing two adjacent angular methyl
groups, a highly congested cyclobutane ring, two exocyclic
double bonds, and twelve contiguous stereogenic centers.
Although the structure of this compound was determined as
shown,1l its absolute configuration and biological activities have
not been reported thus far. Herein, we describe a concise and
enantioselective synthesis of chloranthalactone F (1).
Scheme 1 Retrosynthetic analysis of chloranthalactone F.
strategy was taken for its total synthesis (Scheme 1). [2+2]
photocycloaddition of enol lactone 3, known as chlorantha-
lactone A,1l,4 would provide chloranthalactone F. Further-
more, it was anticipated that enol lactone 3 could be
obtained through oxidative enol-lactonization from 4, named
shizukanolide.4a,b And lactone 4 would then be accessible by
stereocontrolled oxidative lactonization5 at C8 of precursor 5.
Overall, the proposed retrosynthetic strategy was designed,
with minimal protecting-group used and tandem reactions
included,6 to allow investigation into the potentially biosynthetic
interconnectivity between chloranthalactone F, 3 and 4.
Given the axial symmetry of chloranthalactone F (1) and
the biogenetical hypothesis on its formation, a biomimetic
Our synthesis began with the cyclopropanation of the allylic
alcohol 6 (Scheme 2), which was available with a scalable and
highly efficient synthetic route.3a Previous approaches for the
construction of the chiral cyclopropane unit include
Cu(acac)2-catalyzed intramolecular cyclopropanation reaction
taken by Baldwin and co-workers,3b and a chiral pool strategy
followed by Pd-catalyzed enyne cyclization adopted by Liu
and Nan,3e However, both methods gave products with the
newly formed cyclopropane anti to the C10-methyl group as
favored by sterics, which is opposite to the configuration
present in the natural product. Herein, it was presumed that
the well-documented directing effect7 of the hydroxyl group at
C4 of 6 in Simmons–Smith’s cyclopropanation would override
the stereocontrol of the C10 methyl group to deliver the
product with the correct configuration. Indeed, initial investi-
gation from our lab has disclosed that Simmons–Smith’s
reaction is an effective method for the construction of the
highly strained 3–5 bicyclic framework,3a whereas long reaction
Fig. 1 Representative molecular structures of lindenane sesquiterpenoid
dimers.
Key Laboratory of Synthetic Chemistry of Natural Substances,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032, China.
E-mail: zhaog@mail.sioc.ac.cn; Fax: 0086-21-64166128;
Tel: 0086-21-54925182
w Electronic supplementary information (ESI) available: Experimental
procedures, copies of spectral data, characterization data. CCDC
839420 and 839421. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c2cc17882f
c
3530 Chem. Commun., 2012, 48, 3530–3532
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Scheme 2 Preparation of ester 5.
time and tedious operation were included. To our delight,
further screening conditions revealed that treatment of 6 with
excess of ZnEt2 and CH2I2 in the presence of ZnI28 as additive
afforded the desired cyclopropane 7 in a nearly quantitative
yield as a single diastereoisomer in 12 h. As the excellent
diastereoselectivity was ascribed to the hydroxyl group acting
as the directing group to create an orderly transition state, we
hypothesized that the ZnI2 could be responsible for shortening
the reaction time due to the enhanced reaction rate via the
proximity effect (TS, Scheme 2). Subsequent oxidation of 7
with Dess–Martin periodinane9 together with NaHCO3 as
neutralizer was followed by methylenation using an improved
Julia reagent 810 to deliver the desired exocyclic methylene
adduct 9. Removal of the ketal in 9 with FeCl3ꢀSiO211 furnished
the tricyclic ketone 10 in an excellent yield (overall yield 93%
from 7) and its relative stereochemical structure was confirmed
by a nOe experiment. Also mentionable here is that the four
synthetic steps from 6 to 10 could be done with only one
chromatographic purification on silica gel. Treating ketone 10
with phosphite ester derivative 11 resulted in an inseparable
1.3 : 1.0 mixture of 5 in a quantitative yield favoring the
desired (E)-isomer, the stereochemistry of which was deter-
mined by extensive spectroscopic studies and a single crystal
X-ray diffraction analysis of the (Z)-isomer. Stereoselectivity
improvement was tried by the application of the Peterson
olefination and treatment with (RO)2POCH(Me)CO2Me
Scheme 3 Total synthesis of (+)-chloranthalactone F.
SeO2,13a Mn(OAc)3/tBuOOH,13b Pd(OH)2/tBuOOH,13c PCC,13d
and PDC,13e resulted in no reaction or numerous unidentified
impurities which probably originated from the release of the
severe ring-strain of cyclopropane and 5–6 bicycle. Gratifyingly,
it was found that employing ester 5, CrO3 and 3,5-dimethyl-
pyrazole (DMP)5 in a mole ratio of 1 : 2 : 4 in dried CH2Cl2 at
reflux for 12 h provided 4 in reproducibly respectable yields
(32%) for this complex system, with complete diastereo-
selectivity. As the moderate yield was imputed to the low
conversion, which was caused by ligand reorganization or
polymerization of the oxidant under reflux,5a the sole stereo-
selectivity was probably attributed to the unpreferred
b-hydrogen abstraction at C8 which was blocked due to the
1,3-diaxial interaction with the C10 methyl group. With a
reliable route to 4 secured, sequential biomimetic elaboration
was tried to obtain 3 and 1. Reduction of lactone 4 with
DIBAL-H in CH2Cl2 at ꢁ78 1C afforded hemiacetal 12,
which was subjected to DDQ14 in the presence of PPTS to
deliver 3 by way of furan derivate 13 in three steps (36%).
Further studies here show that enol lactone 3 could be
formed directly from lactol 12 in 80% yield by means of
DDQ. In view of the unfeasibility from lactone 4 to 3 in
the presence of DDQ (see the ESIw for details), two possible
pathways for DDQ-mediated oxidative enol-lactonization
were proposed (Scheme 3), in which furan derivate 13
and keto-aldehyde 15 were involved, respectively. At this
juncture, exposure of the enol lactone 3 in hexanes to a
high pressure Hg lamp (125 W) in quartz at rt1l furnished
(+)-chloranthalactone F (1) smoothly in 92% yield, the
absolute configuration of which was confirmed unequivocally
i
(R = Me or Pr), which resulted in no reaction or gave no
improvement on the ratio of E/Z (ca. 1.3 : 1.0), respectively.
To complete the total synthesis, we firstly turn our attention
to realize the activation of g-methylene at C8 of ester 5
(Scheme 3). Considering the innate structural character, com-
petitive reactions due to the discrepancy of chemoselectivity12
between the exocyclic methylene group and a,b-unsaturated
ester would make this pivotal transformation very challenging.
Incipient experimentations for oxidant screening, including
c
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by X-ray crystallography.z Besides, all spectral data ([a]D,
NMR, HRMS) of the synthetic materials were identical to
those reported.
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In summary, we have accomplished the asymmetric total
synthesis of chloranthalactone F (1) in 14 steps from
Hajos–Wiechert ketone15 using CrO3-mediated oxidative
lactonization, and DDQ-involved oxidative enol-lactonization
as key steps. Additionally, the present work, which disclosed
the potential biosynthetic interconnectivity between chlor-
anthalactone F, 3 and 4, paves a consulting synthetic strategy
to the other dimers. Efforts in this direction are being actively
pursued in our lab and the results will be reported in due course.
This work was financially supported by National Natural
Science Foundation of China (No. 20172064, 203900502,
21032006), 973 program (2010CB833204), Shanghai Natural
Science Council (11XD1406400), and Excellent Young
Scholars Foundation of National Natural Science Foundation
of China (No. 20525208).
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z Crystal data: CCDC 839420:
M = 246.34, orthorhombic,
P2(1)2(1)2(1), a = 7.0704(14), b = 9.5189(19), c = 20.411(4) A,
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3532 Chem. Commun., 2012, 48, 3530–3532
This journal is The Royal Society of Chemistry 2012