Total Syntheses of (-)-Englerins A/B, (+)-Orientalols E/F, and (-)-Oxyphyllol

Article abstract of DOI:10.1021/acs.orglett.8b00552

(-)-Englerin A was synthesized in 20 steps from the commercially available material (R)-(+)-limonene. In addition, (-)-englerin B, (+)-orientalol E/F and (-)-oxyphyllol were obtained from the intermediate in the route. The key steps include a hydroxyl-directing stereoselective and regioselective intramolecular cyclopropanation and a multi-gram-scale stereoselective formal intramolecular [3 + 2] cross cycloaddition ([3 + 2]-IMCC) of a cyclopropane 1,1-diester with a carbonyl. A precursor of 7,10-diastereoisomer of englerins was also obtained.

Full text of DOI:10.1021/acs.orglett.8b00552

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Total Syntheses of (−)-Englerins A/B, (+)-Orientalols E/F, and
(−)-Oxyphyllol
Pengcai Liu, Yutao Cui, Kang Chen, Xinyue Zhou, Wenyan Pan, Jun Ren, and Zhongwen Wang*
State Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic Chemistry, College of Chemistry, Collaborative
Innovation Center of Chemical Science and Engineering, Nankai University, 94 Weijin Road, Tianjin 300071, PR China
S
* Supporting Information
ABSTRACT: (−)-Englerin A was synthesized in 20 steps
from the commercially available material (R)-(+)-limonene. In
addition, (−)-englerin B, (+)-orientalol E/F and (−)-oxy-
phyllol were obtained from the intermediate in the route. The
key steps include a hydroxyl-directing stereoselective and
regioselective intramolecular cyclopropanation and a multi-
gram-scale stereoselective formal intramolecular [3 + 2] cross
cycloaddition ([3 + 2]-IMCC) of a cyclopropane 1,1-diester
with a carbonyl. A precursor of 7,10-diastereoisomer of englerins was also obtained.
(−)-Englerin A (1) and B (2) were isolated by Beutler and co-
workers in 2008 from stem/root bark of Phyllanthus engleri,1
and it was proven that 1 was an excellent selective inhibitor of
renal cancer (Figure 1). Orientalols E/F2 and oxyphyllol3 are
mates) have been reported. The key strategies include ring-
closing metathesis (Christmann et al.,9,10 Parker et al.,11
Hatakeyama et al.,12 Metz et al.,13−15 Shen et al.16), gold-
catalyzed [2 + 2 + 2] cycloaddition (Echavarren et al.,17,18 Ma
et al.19), 1,3-dipolar [3 + 2] cycloaddition (Nicolaou/Chen et
al.,20 Hashimoto/Anada et al.,21 Iwasawa et al.22), [4 + 3]
cycloaddition (Theodorakis et al.,23,24 Sun/Lin/Xu et al.,25,26
Mascarenas/Lopez et al.27), intramolecular cross-coupling
(Cook et al.28), Michael-addition/radical cyclization (Chain et
al.29), ring contraction (Maier et al.30) and Nazarov cyclization
(Iwabuchi et al.31).
We herein report the total syntheses of (−)-englerins A/B,
(+)-orientalols E/F and (−)-oxyphyllol via a formal IMCC
(intramolecular cross cycloaddition) strategy of cyclopropanes.
This formal IMCC strategy, which we have recently developed
on the basis of intermolecular formal cycloadditions of donor−
acceptor cyclopropanes,32 can provide a general and highly
efficient construction of bridged skletons.33−44
(−)-Englerin A was selected as an example for the
retrosynthetic analysis (Scheme 1). Our retrosynthesis of
(−)-englerin A started from the cleavage of the two ester
groups to diol 6. Diol 6 could be prepared either from
compound 7 or 11. Compound 7 or 11 can be obtained via the
key formal [3 + 2]-IMCC of 8 or 12 respectively. Compound 8
or 12 can be prepared from the same intermediate 9 through
northern cyclopropanation of carbon−carbon double bond a or
southern cyclopropanation of carbon−carbon double bond b
respectively. Trienol 9 can be prepared from a known
compound 10, which has been obtained from commercially
available (R)-(+)-limonene in two steps.45
Figure 1. Englerin A and selected structurally related natural products.
three structurally related natural products, the biological
activities of which were not well studied due to their extremely
low content in nature. These five natural products belong to a
family of guianolide sesquiterpenes, which is characterized by a
bicyclo[5.3.0]decane (hydroazulene) skeleton and an embed-
ded oxa-[3.2.1]octane skeleton. In view of their biological
activities and novel structures, englerins have been attracting
attention from the synthetic and medicinal communities since
their isolations.4−8
Our initial attempts to the northern cyclopropanation of
carbon−carbon double bond a failed and no cyclopropanations
So far, since the first total synthesis of (+)-englerin A by
Christmann et al. in 2009,9 over 20 (formal) total syntheses of
this englerin family (including their enantiomers and race-
Received: February 14, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00552
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Scheme 1. Retrosynthetic Analysis of (−)-Englerin A
Scheme 2. Intermolecular Cyclopropanation of Double Bond b
were observed (see Supporting Information SI). However, we
successfully carried out the southern cyclopropanation of
carbon−carbon double bond b via both intermolecular and
intramolecular pathways.
while 8a gave a complex result. Krapcho decarboxylation of 7b
afforded 16b/16b′ (16b:16b′ = 10:1), a single crystal X-ray
analysis of the minor diastereoisomer 16b′ showed that the
stereochemistries of C7 and C10 were opposite from those of
the natural products. This result implies an SN2-like mechanism
of the formal [3 + 2]-IMCC, which is in accordance with our
previously reported results.33
As the intrinsic stereoselectivity of the southern intermo-
lecular cyclopropanation preferred the Re face, we considerd an
intramolecular cyclopropanation strategy as a rational one to
match the desired stereochemistry (Scheme 3). In this strategy,
benefiting from its suitable stereochemistry, the hydroxyl group
could be considered as a stereochemistry-directing group. Thus,
we planned to connect the Rh-carbene moiety to the hydroxyl
group. After a three-step isolation-free sequence composed of a
Mukaiyama esterification,47 a Regitz diazotization48 and a
Aldehyde 10 was converted into alcohol 9 by a Shapiro
reaction46 in 96% yield (dr = 10:1). Protection of the hydroxyl
group in 9 afforded 13a or 13b (Scheme 2). The southern
intermolecular cyclopropanation of 13a or 13b afforded 15a or
15b respectively. The steric hindrance probably played a key
role for the chemoselective cyclopropanation. A single-crystal
X-ray analysis of 15a confirmed the absolute stereochemistry of
the quaternary carbon in cyclopropane as R configuration (see
SI). This result implies that the Rh-carbene attacked the Re face
of the double bond b. After ozonolysis of double bond a,
Yb(OTf)3/CuI-catalyzed formal [3 + 2]-IMCC of the obtained
8b was successfully carried out to afford cycloadduct 7b (85%),
B
DOI: 10.1021/acs.orglett.8b00552
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Scheme 3. Intramolecular Cyclopropanation of Double Bond b and Formal [3 + 2]-IMCC
Scheme 4. Completion of the Total Syntheses of (−)-Englerins A and B
chemoselective intramolecular cyclopropanation of double
bond b, 9 was successfully converted to lactone 14 in 58%
overall yield. Treatment of lactone 14 with sodium methoxide
led to transesterification product 15 in 87% yield. We have tried
several protecting groups for protection of the hydroxyl group
in compound 15. However, in most of the subsquent [3 + 2]-
IMCC, instead of the desired [3 + 2] cycloadducts, the
deprotected product was recovered. To our delight, a
chloroacetyl group was proven to be a successful one. After
several attempts, chloroacetyl chloride was selected for the
protection of hydroxyl group. Subsequent ozonolysis of the
double bond a, the formal [3 + 2]-IMCC precursor 8c was
obtained in 75% yield over two steps. The Lewis acid-catalyzed
formal [3 + 2]-IMCC of 8c proceeded smoothly in most cases
(see SI). Under the catalysis of 0.05 equiv of Sc(OTf)3, with
DCE as a solvent at 50 °C, the cycloadduct 7c was obtained in
C
DOI: 10.1021/acs.orglett.8b00552
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Scheme 5. Completion of Total Syntheses of (+)-Orientalols E/F and (−)-Oxyphyllol
79% yield. This reaction was run on a 6.2 g (14.4 mmol) scale
in 72% yield. To our great delight, a single-crystal X-ray analysis
of 7c unambiguously confirmed its absolute configuration,
which is in accordance with that of the natural products.
With 7c in hand, we then started to carry out the subsequent
decorations (Scheme 4). Krapcho decarboxylation of 7c
afforded monoester 16c in 93% yield and with a 3:1 dr.
Following the reduction of the two ester groups in 16c with
DIBAL-H, diol 17 was obtained as a single diastereoisomer.
Without purification, aldehyde 18 was obtained (76%, 2 steps)
under the global oxidation of 17 with Dess−Martin period-
inane. An enamine Saegusa oxidation49 was adopted to give
α,β-unsaturated aldehyde 19 (75%), and a Tsuji−Wilkinson
decarbonylation of which afforded 20 (81%). The intermediate
20 was the enantiomer of the intermediate in total synthesis of
ent-englerin A by Sun/Lin et al.25 Hydroboration−oxidation of
20 gave the diol 21 in 84% yield and with dr > 20:1. The
absolute configuration of 21 was determined by X-ray
crystallographic analysis.50 After a dozen of failed attempts
(e.g., Raney Ni19,22 and IrI-based catalyst20,25), the hydroxyl-
directing Pd/C-hydrogenation21 of 21 was finally accomplished,
and 6 was obtained in 84% yield and with 3.3:1 dr. After the
double esterifications and desilylation, we finally achieved
(−)-englerin A (1) in 70% yield (3 steps). Under a mild
saponification condition, (−)-englerin B (2) was obtained in
92% yield.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00552.
■
S
Detailed experimental procedures and characterization
data (PDF)
Accession Codes
CCDC 1485699, 1564694, 1812332, and 1812334 contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: wzwrj@nankai.edu.cn.
ORCID
Zhongwen Wang: 0000-0003-1029-7904
Notes
The authors declare no competing financial interest.
From the intermediate 18, we also synthesized (+)-orientalol
F (3), (−)-oxyphyllol (4) and (+)-orientalol E (5) (Scheme 5).
After a Tsuji-Wilkinson decarbonylation and Luche reduction,
(+)-orientalol F (3) was obtained in 80% yield over two steps.
Pd/C-hydrogenation of 3 afforded (−)-oxyphyllol (4) (65%
yield, dr 4:1). Using a protocol similar to that reported by Sun/
Lin et al.,25 we obtained (+)-orientalol E (5) (48% over 3
steps). All the data of the synthesized products were in
accordance with those reported in the literature.
In conclusion, we achieved the total syntheses of
(−)-englerin A, (−)-englerin B, (+)-orientalol F and (−)-oxy-
phyllol, as well as the first total synthesis of (+)-orientalol E,
from the commercially available and inexpensive (R)-
(+)-linonene. The key steps include the hydroxyl-directing
stereoselective and regioselective intramolecular cyclopropana-
tion, and the multi-gram-scale stereoselective formal [3 + 2]-
IMCC of a cyclopropane 1,1-diester with a carbonyl for
construction of a core oxa-[3.2.1]octane bicyclic skeleton. A
precursor of 7,10-diastereoisomer of englerins was also
obtained. Additionally, benefiting from the broad structural
diversities being provided by the IMCC, we strongly believe
that this synthetic strategy will also show its potential
applications to drug discovery in the future. Further research
includes construction of structurally diverse libraries via this
synthetic strategy and study of their biological activities.
ACKNOWLEDGMENTS
We thank the NSFC (Nos 21372126, 21572103 and
21421062) for financial support.
■
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