Concise formal synthesis of (+)-englerin A and total synthesis of (-)-orientalol F: Establishment of the stereochemistry of the organocatalytic [4+3]-cycloaddition reaction

Article abstract of DOI:10.1055/s-0031-1290090

The enantioselective formal synthesis of (+)-englerin A and the total synthesis of (-)-orientalol F were successfully accomplished via a triene. The success enabled establishment of the relative as well as absolute stereochemistry of the organocatalytic [4+3]-cycloaddition reaction. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0031-1290090

LETTER
263
Concise Formal Synthesis of (+)-Englerin A and Total Synthesis of (–)-
Orientalol F: Establishment of the Stereochemistry of the Organocatalytic
[4+3]-Cycloaddition Reaction
S
ynthesis of (+)-E
h
nglerin A ao-Lei Wang,a,b Bing-Feng Sun,*a Shu-Guang Chen,a,c Rui Ding,a Guo-Qiang Lin,*a Jin-Yi Xu,*b Yong-Jia Shangc
a
b
c
CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, CAS,
345 Lingling Road, Shanghai 200032, P. R. of China
Fax +86(21)54925081; E-mail: bfsun@sioc.ac.cn; E-mail: lingq@sioc.ac.cn.
Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University,
24 Tongjiaxiang, Nanjing 210009, P. R. of China
E-mail: jinyixu@china.com
College of Chemistry and Materials Science, Anhui Normal University, Beijing East Road No. 1, Wuhu 241000, P. R. of China
Received 11 October 2011
tive biological activity, englerin A has become one of the
most studied targets in the past couple of years among the
synthetic community.6 Additionally, orientalol F (2) and
orientalol E (3) from a Chinese herbal medicine, the rhi-
zome of Alisma orientalis,7 and pubinernoid B (4) from
the leaves and stems of Schisandra pubescens var. pubin-
ervis,8,9 are structurally closely related to englerin A.
Thus, a unified synthetic strategy that allows ready access
to these natural products is highly desirable.9
Abstract: The enantioselective formal synthesis of (+)-englerin A
and the total synthesis of (–)-orientalol F were successfully accom-
plished via a triene. The success enabled establishment of the rela-
tive as well as absolute stereochemistry of the organocatalytic
[4+3]-cycloaddition reaction.
Key words: asymmetric synthesis, chemoselectivity, regioselectiv-
ity, natural product, cycloaddition
The past decade has witnessed the renaissance of organo-
catalysis. A myriad of organocatalytic reactions, primari-
ly asymmetric ones, has been developed and added to an
arsenal of organic synthesis.1 As a consequence, exploit-
ing these organocatalytic reactions for natural product
synthesis has increasingly gained attention from the syn-
thetic community.2 In 2003, Harmata and co-workers re-
ported an elegant organocatalytic [4+3]-cycloaddition
reaction between symmetrical dialkyl furan and 4-(trime-
thylsilyloxy)penta-2,4-dienal under the catalysis of Mac-
Millan’s amine, providing a rapid approach to 1,5-homo-
dialkyl-3-oxo-8-oxabicyclo[3.2.1]octene in an enantiose-
lective manner.3 However, the assignments of the relative
stereochemistry of the product, which were based on anal-
ogy with Eguchi’s results,4 along with the absolute stereo-
chemistry, were not yet confirmed, which probably
constituted part of the reason behind the fact that the orga-
nocatalytic [4+3]-cycloaddition reaction aroused little in-
terest in the arena of natural product synthesis.
HO
O
O
O
H
HO
O
O
O
Ph
H
H
(–)-englerin A (1)
(+)-orientalol F (2)
HO
H
O
O
HO
H
HO
H
orientalol E (3)
pubinernoid B (4)
Figure 1 Selected oxo-bridged guaiane sesquiterpenoids
In our previous paper,6f the organocatalytic [4+3]-cy-
cloaddition reaction of furan 5 and dienal 6 had been real-
ized under the catalysis of (S,S)-7 through modified
Harmata’s conditions to generate 8a/8b, thus extending
the reaction scope to bulkier unsymmetrical furan
(Scheme 1). The major product 8a was successfully ad-
vanced to 9 and 10 both endowed with the guaiane skele-
ton. However, no solid proof had been obtained for the
relative as well as absolute stereochemistry of both 9 and
10. In this paper, we delineate our elaboration of 10 into
(+)-englerin A and (–)-orientalol F, which would finally
clarify the stereochemical issue of this reaction.
7,10-Epoxy-guaianoids comprise a small group of exquis-
ite natural products, among which englerin A (1, Figure 1)
is the newest and the most prominent member. Isolated by
Beutler and co-workers in 2009 from the root and bark of
Phyllanthus engleri, a tree indigenous to East Africa, en-
glerin A was identified to be a potent and selective inhib-
itor of renal cancer cell lines with GI50 levels being 1–2
orders of magnitude lower than that obtained with taxol.5
Owing to its intriguing molecular architecture and attrac-
Our synthetic plan for englerin A and orientalol F is de-
picted in Scheme 2. As a proven precursor for the synthe-
sis of englerin A,6b diol 11 was selected as the target of our
SYNLETT 2012, 23, 263–266
Advanced online publication: 05.12.2011
DOI: 10.1055/s-0031-1290090; Art ID: W54411ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
1
1

264
C.-L. Wang et al.
LETTER
O
that the trisubstituted double bond in 10 is the most elec-
tron-rich one, a selective epoxidation was attempted. To
our delight, when 10 was treated with MCPBA at ambient
temperature, the substrate was consumed within several
minutes, generating 13 as the major product based on 1H
NMR spectroscopic analysis of the crude reaction mix-
ture. The stoichiometry of MCPBA should be controlled
since excess amount of MCPBA led to further oxidation
of the terminal double bond. Decreasing the reaction tem-
perature to –20 °C improved the selectivity significantly
by nearly complete suppression of the side reactions. The
stereochemistry of the epoxide was assigned as depicted
in 13 according to the rationale that the a face of the dou-
ble bond is less sterically hindered and thus more accessi-
ble to the oxidant. Although crude 13 was sufficiently
stable for NMR studies, it decomposed rapidly on silica
gel during column purification, probably due to the exces-
sive sensitivity of the vinyl epoxide towards even such
weakly acidic conditions. Use of Et3N-treated silica gel
was not helpful. These difficulties hampered the procure-
ment of a pure sample for fully characterization of 13.
Nonetheless, direct SN2¢-type reductive opening of the vi-
nylepoxide was successfully realized by exposure of
N
O
N
H
TFA
(S,S)-7
5
O
O
O
+
O
+
MeNO2
63%
8a/8b = 2.4:1
OTMS
OHC
OHC
8a
67% ee
8b
82% ee
CHO
6
3 steps
5 steps
O
O
H
H
O
9
10
stereochemistry not established
Scheme 1 Summary of our previous results reported in the
literature6f
formal synthesis of (+)-englerin A. We envisioned that the crude 13 to DIBAL-H to produce allylic alcohol 12. Actu-
hydroxy group at C-9 in 11 could trace its way back to the ally, when crude 10 obtained from the Heck reaction6f was
C-8–C-9 bridging double bond in 12. As a versatile inter- used, 12 could be obtained in 52% yield over three steps
mediate, compound 12 could also serve as a precursor from the substrate for the Heck reaction. Other hydride re-
leading to (–)-orientalol F. Toward that end, an oxidation– agents were also examined for comparison. While NaBH4
reduction protocol taking advantage of the steric bias be- only gave a messy and incomplete reaction, LiBH4 deliv-
tween the two faces of the [5.3.0] bicyclic framework was ered the product in 37% yield. As an advanced versatile
envisaged to invert the stereochemistry of the C-6 hy- intermediate, 12 could serve as the precursor for natural
droxy group in 12, while a hydrogenation reaction was en- products, such as englerin A, orientalol E, and orientalol
visioned to selectively saturate the bridging double bond. F.
Given the potential difficulty of reducing the carbonyl in
9 into the methylene group, triene 10 was selected as the
starting point of our synthesis.
HO
MCPBA
DIBAL-H
O
O
O
O
OH
O
52% over 3
steps (see text)
O
8
H
H
H
6
HO
O
H
9
ref. 6b
10
13
12
O
O
OH
O
1
Ph
5
15
4
MCPBA
DIBAL-H
H
H
(+)-englerin A
11
O
O
O
O
OH
Al
"O"
i-Bu
i-Bu
H
HO
HO
O
O
O
H
Scheme 3 Synthesis of the key intermediate 6
H
H
(–)-orientalol F
12
10
With an efficient protocol established for the synthesis of
the key intermediate 12, we turned our attention to realiz-
ing a formal synthesis of englerin A (Scheme 4). Consid-
ering that the a face of C-9 in allylic alcohol 12 is the least
sterically hindered among the eight potential reactive sites
around C-4, C-5, C-8, and C-9, the regio- as well as stereo-
selective formal hydration of the bridging double bond
Scheme 2 Retrosynthetic analysis of englerin A and orientalol F
The major challenge of our synthesis lies in the transfor-
mation of triene 10 into allylic alcohol 12 which entails
chemoselective as well as regioselective elaborations of
the olefinic double bonds (Scheme 3). In view of the fact
Synlett 2012, 23, 263–266
© Thieme Stuttgart · New York

LETTER
Synthesis of (+)-Englerin A
265
might be realized via a simple hydroboration–oxidation
procedure. The bulky 9-BBN was first investigated. Prob-
ably due to severe steric hindrance, no reaction occurred
at ambient temperature. Delightfully, when the concen-
trated reaction mixture (0.5 M) was heated at 70 °C over-
night followed by oxidative workup, diol 11 was isolated
as a single isomer, albeit in a meager yield of 14%. Other
boranes such as BH3 and Cy2BH were also tested, but
messy reactions were observed with none producing 11 in
a comparable yield.
O
Me
(S)
(S)
N
N
H
RL
O
RS
O
TFA
OR
7
CHO
O
RS
O
(R)
(R)
RS
RL
A
OHC
OHC
O
P1
P2
RL
B
To improve the synthesis of 11, another strategy based on
oxymercuration–reduction protocol was subsequently ex-
plored (Scheme 4). While initial treatment of 12 with
Hg(OAc)2 was unsuccessful due to sluggish reaction,
switching the reagent to Hg(OTFA)2 led to improved re-
activity with 12 being consumed within 24 hours at ambi-
ent temperature. To our disappointment, subsequent
reductive demercuration afforded 11 as a single isomer in
38% yield.
C
N
N
N
O
O
N
O
N
N
B
RS
RL
O
endo addition
RO
RO
RO
O
RL
RS
9-BBN, H2O2
14%
(more favored)
(less favored)
HO
HO
Scheme 5 Stereochemical course of Harmata’s [4+3]-cycloaddition
reaction
ref. 6b
O
O
OH
or
(+)-englerin A
(1)
7 steps
H
H
Hg(OTFA)2
NaBH4
38%
The total synthesis of orientalol F was next investigated
(Scheme 6). Although initial trials with MnO2 or Swern
oxidation gave no reaction, oxidation of 12 by employing
Ley’s conditions underwent smoothly to furnish ketone
14 in 70% yield. Subsequent reduction of the carbonyl
group with NaBH4 proceeded uneventfully to give alcohol
15 in a quantitative yield. Finally, a Pd/C-catalyzed hy-
drogenation selectively saturated the less hindered bridg-
ing double bond to deliver 2 in 85% yield. Interestingly, if
crude 14, obtained by Ley oxidation, was exposed to
NaBH4, 2 could be obtained directly in 40% yield. Al-
though such a one-pot procedure gave a comparatively di-
minished overall yield from 12, it eliminated the necessity
of performing a separate step of hydrogenation. It was
speculated that the remaining ruthenium species from Ley
oxidation was catalyzing the transfer hydrogenation in the
presence of NaBH4. Finally, the comparison of the optical
rotation of 2 with literature data9 confirmed 2 to be the an-
tipode of the natural (+)-orientalol F, as depicted in
Scheme 6, which is in accord with the absolute stereo-
chemical outcome shown in Scheme 5. This work consti-
tutes the second total synthesis of orientalol F based on a
new strategy with around 10 steps overall.
12
11
Scheme 4 Formal synthesis of (+)-englerin A (1)
Although the yield of 11 is far from being satisfactory,
probably as a result of the labile nature of 12 under these
reaction conditions, the selectivity observed in the above-
mentioned oxymercuration was intriguing. The oxymer-
curation proceeded preferentially through an exo-syn ad-
dition due to steric factors, which is consistent with that
observed with other bicyclic alkenes in literature prece-
dents.10 The regioselectivity could be ascribed to the syn-
ergy of steric and electronic factors. Both the more
sterically demanding isopropyl group and the electron-
withdrawing OH group at C-6 favored the introduction of
the incoming hydroxy group to the distal C-9 position.11
The comparison of the optical rotation of 11 with litera-
ture data6e confirmed its absolute stereochemistry as
shown in Scheme 4. Although considerable room remains
for improvement in the efficiency of converting 12 to 11,
the enantioselective synthesis of 11 constitutes a formal
synthesis of the antipode of the natural (–)-englerin A
with 16 overall steps starting from the initial [4+3]-cy-
cloaddition reaction.
In conclusion, the enantioselective formal synthesis of
(+)-englerin A and the total synthesis of (–)-orientalol F
were successfully accomplished in 16 and 10 steps, re-
spectively. More importantly, the success obtained en-
abled the establishment of the relative as well as absolute
stereochemistry of the organocatalytic [4+3]-cycloaddi-
tion reaction. It also demonstrated for the first time that
the organocatalytic [4+3]-cycloaddition reaction could be
a powerful tool for natural product synthesis. The current-
In light of the above-mentioned results, the absolute stereo-
chemical course of the [4+3]-cycloaddition reaction could
finally be established (Scheme 5). Thus, the chiral (S,S)-7
catalyzes the endo addition reaction of dienal A and furan
B to furnish 2-{(2R)-3-oxo-8-oxabicyclo[3.2.1]oct-6-en-
2-yl} acetaldehyde P1 and P2. When the substituent RL is
sterically more demanding than RS, P1 is preferred over
P2.
© Thieme Stuttgart · New York
Synlett 2012, 23, 263–266

266
C.-L. Wang et al.
LETTER
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O
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O
H
"H"
NaBH4
O
HO
HO
TPAP
NMO
NaBH4
99%
O
O
O
70%
H
H
H
12
14
15
H2
Pd/C
85%
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HO
TPAP, NMO; then NaBH4
40%
O
H
(–)-orientalol F (2)
Scheme 6 Total synthesis of (–)-orientalol F (2)
ly moderate enantioselectivity of the [4+3]-cycloaddition
reaction needs to be enhanced, which entails the develop-
ment of more efficient catalysts. The currently low effi-
ciency of the transformation of 12 to 11 involved in the
formal synthesis of englerin A also presses us for new
strategies to circumvent the difficulties. Endeavors along
these lines are currently being actively pursued in our lab-
oratory and will be reported in due course.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
(8) Huang, S.-X.; Yang, J.; Xiao, W.-L.; Zhu, Y.-L.; Li, R.-T.;
Li, L.-M.; Pu, J.-X.; Li, X.; Li, S.-H.; Sun, H.-D. Helv. Chim.
Acta 2006, 89, 1169.
(9) For the synthesis of orientalol F and pubinernoid B using the
gold-catalyzed cycloaddition of functionalized ketoenynes,
see: Jiménez-Núñez, E.; Molawi, K.; Echavarren, A. M.
Chem. Commun. 2009, 7327.
Acknowledgment
Financial support from National Natural Science Foundation of
China (grant No. 20902101, No. 21172246), and National Basic Re-
search Program of China (973 Program, grant No. 2010CB833206)
are gratefully appreciated.
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Synlett 2012, 23, 263–266
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