Asymmetric Total Synthesis of (-)-Englerin A through Catalytic Diastereo- and Enantioselective Carbonyl Ylide Cycloaddition

Article abstract of DOI:10.1002/chem.201502009

An asymmetric total synthesis of the guaiane sesquiterpene (-)-englerin A, a potent and selective inhibitor of the growth of renal cancer cell lines, was accomplished. The basis of the approach is a highly diastereo- and enantioselective carbonyl ylide cycloaddition with an ethyl vinyl ether dipolarophile under catalysis by dirhodium(II) tetrakis[N-tetrachlorophthaloyl-(S)-tert-leucinate], [Rh₂(S-TCPTTL)₄], to construct the oxabicyclo[3.2.1]octane framework with concomitant introduction of the oxygen substituent at C9 on the exo-face. Another notable feature of the synthesis is ruthenium tetraoxide-catalyzed chemoselective oxidative conversion of C9 ethyl ether to C9 acetate.

Full text of DOI:10.1002/chem.201502009

DOI: 10.1002/chem.201502009
Communication
&
Natural Products |Hot Paper|
Asymmetric Total Synthesis of (À)-Englerin A through Catalytic
Diastereo- and Enantioselective Carbonyl Ylide Cycloaddition
Taiki Hanari, Naoyuki Shimada, Yasunobu Kurosaki, Neetipalli Thrimurtulu, Hisanori Nambu,
Masahiro Anada,* and Shunichi Hashimoto*[a]
Structurally, this molecule features an oxygen-bridged 5-6-5 tri-
Abstract: An asymmetric total synthesis of the guaiane
cyclic system with seven contiguous stereogenic centers con-
sesquiterpene (À)-englerin A, a potent and selective inhib-
taining a cinnamate side chain at C6 and a glycolate fragment
itor of the growth of renal cancer cell lines, was accom-
at C9 (englerin numbering). Not surprisingly, its great potential
plished. The basis of the approach is a highly diastereo-
as a new drug lead in renal cancer chemotherapy coupled
and enantioselective carbonyl ylide cycloaddition with an
with a substantial structural challenge has rendered englerin A
(1) a highly attractive target for synthetic investigations.[4] In
ethyl vinyl ether dipolarophile under catalysis by dirhodiu-
m(II)
tetrakis[N-tetrachlorophthaloyl-(S)-tert-leucinate],
2009, Christmann et al. accomplished the first total synthesis of
(+)-englerin A from (+)-trans,cis-nepetalactone utilizing an ep-
oxylactone rearrangement, a stereoselective Barbier-type allyla-
tion, a ring-closing metathesis, and a transannular epoxide
opening as the key steps, thereby establishing the previously
unknown absolute configuration of natural (À)-englerin A as
shown in 1.[5] Since then, eight total syntheses,[6] three formal
syntheses,[7] and several synthetic studies,[8] which are all based
on innovative strategies and tactics, as well as results of struc-
ture-activity relationship studies[5b,6c,7c,9] have been reported.
The dirhodium(II) complex-catalyzed tandem cyclic carbonyl
ylide formation/1,3-dipolar cycloaddition reaction of a-diazo-
carbonyl compounds, which has been extensively studied by
Padwa’s group, represents one of the most powerful methods
for the rapid assembly of complex oxapolycyclic systems con-
taining embedded di- or tetrahydrofuran rings,[10–12] and an
enantioselective version of this sequence employing chiral RhII
complexes has also been realized.[13,14] Capitalizing on the car-
bonyl ylide cycloaddition strategy, Maier et al. reported a con-
cise chiral pool approach toward the oxygen-bridged guaiane-
type core structure of 1 starting from inexpensive, commercial-
ly available (R)-(À)-carvone (Scheme 1).[8a] However, contrary to
what they expected, cycloaddition of the bicyclic carbonyl
ylide 4 generated from Rh2(OAc)4-catalyzed dinitrogen extru-
sion of a-diazo-b-ketoester 2 with allyl propiolate (3) occurred
[Rh2(S-TCPTTL)4], to construct the oxabicyclo[3.2.1]octane
framework with concomitant introduction of the oxygen
substituent at C9 on the exo-face. Another notable feature
of the synthesis is ruthenium tetraoxide-catalyzed chemo-
selective oxidative conversion of C9 ethyl ether to C9 ace-
tate.
(À)-Englerin A (1) (Figure 1), a guaiane sesquiterpene isolated
from the stem bark of the East African plant Phyllanthus engleri
by Beutler et al., was found to possess very potent growth in-
hibitory (GI) activity (GI50 <20 nm) against four of eight renal
cancer cell lines with approximately 1000-fold selectivity over
most other cancer cell lines in the NCI-60 panel.[1] While the
mechanism of action of englerin A remains to be elucidated,[2]
it has very recently been disclosed that 1 activates transient re-
ceptor potential canonical channels 4 and 5 (TRPC4/5) in renal
cancer cells to induce cell death caused by Ca2+ overload.[3]
Figure 1. Structure of (À)-englerin A (1).
[a] Dr. T. Hanari, Dr. N. Shimada, Dr. Y. Kurosaki, Dr. N. Thrimurtulu,
Dr. H. Nambu, Dr. M. Anada, Prof. Dr. S. Hashimoto
Faculty of Pharmaceutical Sciences
Hokkaido University
Sapporo 060–0812 (Japan)
Fax: (+81)11-706-981
E-mail: anada@pharm.hokudai.ac.jp
hsmt@pharm.hokudai.ac.jp
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201502009.
Scheme 1. RhII-catalyzed carbonyl ylide formation/cycloaddition approach by
Maier et al.[8a] TES=triethylsilyl.
Chem. Eur. J. 2015, 21, 11671 – 11676
11671
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
exclusively with undesired facial selectivity, wherein the dipo-
larophile approached the carbonyl ylide 4 syn to the C4
methyl group. In this context, we have reported catalytic enan-
tioselective intermolecular cycloadditions of six-membered car-
bonyl ylides derived from a-diazo-b-ketoesters with electron-
rich arylacetylene and styrene dipolarophiles using dirhodiu-
m(II) tetrakis[N-tetrachlorophthaloyl-(S)-tert-leucinate], [Rh2(S-
TCPTTL)4] (8),[15] that provide 8-oxabicyclo[3.2.1]octane deriva-
tives with high levels of enantioselectivity (up to 99% ee) and
perfect exo-diastereoselectivity for styrenes.[16,17] Intrigued by
the oxabicyclo[3.2.1]octane framework carrying the oxygen
substitutent at C9 on the exo-face found in (À)-englerin A (1),
we report herein an alternative approach to 1 highlighting
[Rh2(S-TCPTTL)4]-catalyzed exo-diastereoselective and enantio-
selective carbonyl ylide cycloaddition with a vinyl ether dipo-
larophile as the key step.
Scheme 3. Preparation of a-diazo-b-ketoester 12. Reagents and conditions:
a) ethyl 2-bromoisobutyrate, Zn-Cu, DMF, 658C, 2 h; b) hydrochloric acid
(18%) 1008C, 1 h; c) CDI, THF, 1 h; d) tBuO2CCH2CO2H, iPrMgBr, THF, 8 h;
e) MsN3, Et3N, MeCN, 14 h.
cycloadduct has become a major challenge in carbonyl ylide
cycloaddition with a vinyl ether dipolarophile.
Our synthesis commenced with the preparation of the cyclic
carbonyl ylide precursor 12 from succinic anhydride (14) as de-
picted in Scheme 3. Following the procedure of Schick and
Ludwig,[21] Reformatsky reaction of 14 with ethyl 2-bromoiso-
butyrate in DMF and subsequent decarboxylation provided g-
keto acid 15 in 67% yield. Treatment of 11 with 1,1’-carbonyl-
diimidazole (CDI) followed by reaction with the dianion de-
rived from tert-butyl hydrogen malonate gave b-ketoester
16[22] in 83% yield, which, upon diazo transfer with methane-
sulfonyl azide (MsN3),[23] produced a-diazo-b-ketoester 12 in
96% yield.
Our synthetic strategy for 1 based on the enantioselective
carbonyl ylide cycloaddition is outlined retrosynthetically in
Scheme 2.[18] Following the precedents,[5,6] (À)-englerin A (1)
Patterned after our original work,[16a] we initially evaluated
the reaction of a-diazo-b-ketoester 12 with methyl vinyl ether
(13a) (3 equiv) using 1 mol% of [Rh2(S-TCPTTL)4] (8). The reac-
tion in a,a,a-trifluorotoluene at room temperature proceeded
smoothly to give a 62:38 mixture of cycloadducts 11 a and
17a (Table 1, entry 1). These diastereomers could be separated
by column chromatography on silica gel, affording exo-cyclo-
Table 1. Enantioselective carbonyl ylide cycloaddition of a-diazo-b-ke-
toester 12 with vinyl ethers 13 catalyzed by [Rh2(S-TCPTTL)4] (8).
Scheme 2. Retrosynthetic analysis of (À)-englerin A (1).
would be accessible from tricyclic alcohol 9 bearing all of the
stereogenic centers of 1. It was anticipated that 9 would be
formed from diketone 10 by intramolecular aldol condensation
and stereoselective reduction, which in turn could be elaborat-
ed from bicyclic b-ketoester 11. On the basis of our previous
work,[16] we envisioned that [Rh2(S-TCPTTL)4]-catalyzed reaction
of 2-diazo-3,6-diketoester 12 with vinyl ether derivative 13
would preferentially provide the desired exo-cycloadduct
11.[19,20] In this regard, Koyama et al.[19a] reported that
Rh2(OAc)4-catalyzed cycloadditions of carbonyl ylides derived
from 2-diazo-3,6-diketoesters with vinyloxytrimethylsilane or
benzyl vinyl ether proceeded in a regio- and stereoselective
manner to give endo-cycloadducts, wherein the dominant in-
teraction was found to be between the LUMO of the carbonyl
ylide and the HOMO of the dipolarophile.[19] Consequently,
apart from enantiocontrol, diastereocontrol in favor of the exo-
Entry Dipolarophile
11:17[b] exo-Cycloadduct
endo-Cycloadduct
17
13
11
R
Yield ee
[%][c] [%][d]
Yield ee
[%][c] [%][d]
1
2
3
4
5
6
7[e]
13a
13b
13c
13d
13e
13 f
13e
Me
Bn
TMS
MOM
Et
62:38 11 a 53
54:46 11 b 34
41:59 11 c 22
23:77 11 d 20
87:13 11 e 76
90:10 11 f 60
86:14 11 e 75
92
85
78
89
95
92
95
17a 27
17b 31
17c 14
17d 60
17e 11
88
33
5
89
77
27
77
nPr
Et
17 f
7
17e 10
[a] All reactions were carried out as follows: a solution of 12 (107 mg,
0.4 mmol) and dipolarophile 13 (2 equiv) in CF3C6H5 (2 mL) was added
over 1 h to a solution of [Rh2(S-TCPTTL)4]·2EtOAc (8) (7.9 mg, 0.004 mmol,
1 mol%) in CF3C6H5 (2 mL) at rt. [b] Determined by 1H NMR spectroscopy
of the crude product. [c] Isolated yield. [d] Determined by HPLC analysis.
[e] The reaction was conducted on 16 mmol scale and 85% of the cata-
lyst was recovered with sufficient purity for reuse.
Chem. Eur. J. 2015, 21, 11671 – 11676
www.chemeurj.org
11672
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
adduct 11 a in 53% yield with 92% ee and endo-cycloadduct
17a in 27% yield with 88% ee. Stereochemical assignments of
1
11 a and 17a were obtained from H NOE experiments.[24] En-
couraged by the observed enantioselectivity, we next exam-
ined the reaction of 12 with vinyl ethers 13b–d bearing easily
removable protecting groups. Cycloaddition with benzyl- and
trimethylsilyl (TMS)-protected vinyl ethers 13b and 13c result-
ed in a marked drop in exo-selectivity as well as enantioselec-
tivity for exo cycloadducts 11 b and 11 c (entries 2 and 3), while
the use of methoxymethyl (MOM) vinyl ether (13d) provided
endo-cycloadduct 17d as a major isomer with 89% ee (exo/
endo=23:77, entry 4). Thus, we were pleased to find that the
reaction with ethyl vinyl ether (13e) greatly improved the exo-
diastereoselectivity (exo/endo=87:13) to give exo-cycloadduct
11 e in 76% yield and 95% ee (entry 5). Switching the dipolaro-
phile to propyl vinyl ether (13 f) resulted in similar levels of dia-
stereo- and enantioselectivities as those with 13e, but product
yield was drastically diminished (entry 6). Clearly, ethyl vinyl
ether (13e) proved to be the dipolarophile of choice for this
cycloaddition in terms of exo-diastereoselectivity and enantio-
selectivity as well as product yield,[25] though the reason is not
clear at present. However, the use of 13e might pose a serious
problem of unmasking of the hydroxy group since harsh con-
ditions would be required to cleave the ether bond after cyclo-
addition. Thus, we were gratified to find that ruthenium tetra-
oxide-catalyzed oxidation of 11 e under Sharpless conditions[26]
proceeded in a fully chemoselective manner to give the C9
acetate 18 as a sole product in 88% yield, with the oxa-bicyclic
system remaining intact (Scheme 4). From a practical stand-
Scheme 5. Determination of the absolute configuration of 11 e. Reagents
and conditions: a) recrystallization from EtOAc-hexane; b) NaBH4, EtOH, 08C,
1 h; c) (R)-a-methylbenzyl isocyanate, 4-(dimethylamino)pyridine (DMAP),
toluene, reflux, 48 h.
Scheme 4. Chemoselective oxidative conversion of the C9 ethyl ether into
the C9 acetate.
point, it is important to note that the cycloaddition reaction
could be conducted on a large scale (16 mmol) with no ero-
sion in yield or selectivity as well as with good recovery of
[Rh2(S-TCPTTL)4] (entry 7), though catalyst loading (1 mol%)
could not be decreased. Furthermore, a single recrystallization
of 11 e from ethyl acetate-hexane produced enantiomerically
Scheme 6. Synthesis of the tricyclic alcohol 30. Reagents and conditions:
a) NaHMDS, THF, À788C, 30 min then Me3SiCl, À788C ! 08C; b) Pd(OAc)2,
MeCN; c) 22, tBuLi, THF/HMPA (5:1), À788C; d) PCC, NaOAc, 4 Š-MS, CH2Cl2;
e) H2, Pd/C, EtOH; f) Red-Al, toluene, 18 h; g) TsCl, DMAP, Et3N, CH2Cl2, 23 h;
h) PCC, NaOAc, 4 Š-MS, CH2Cl2, 26 h; i) H2, Pd/C, EtOAc, 1 h; j) 5% hydrochlo-
ric acid, acetone, 3 h; k) NaOMe, CH2Cl2, 46 h; l) NaBH4, CeCl3·7H2O, MeOH,
08C; m) H2 (80 atm), Pd/C, EtOH, 48 h.
pure material [m.p. 157.0–159.08C, ½aŠ23 = À32.5 (c=1.04,
D
CHCl3)] in 84% yield (Scheme 5). The preferred absolute config-
uration of 11 e was assigned as (7R,9R,10R) by single-crystal X-
ray analysis of carbamate 20 derived from alcohol 19b, which
was consistent with that of 1.[27]
With enantiomerically pure exo-cycloadduct 11 e in hand, we
then focused on elaboration of the tricyclic core structure of
(À)-englerin A. Treatment of ketone 11 e with sodium bis(tri-
methylsilyl)amide (NaHMDS) at À788C followed by addition of
TMSCl and subsequent Ito–Saegusa oxidation[28] of the resul-
tant silyl enol ether furnished a,b-enone 21 in 96% yield
(Scheme 6). Addition of 2-(2-methyl-1,3-dioxolan-2-yl)ethyllithi-
um generated from alkyl iodide 22[29] and tBuLi[30] to enone 21
in THF at À788C led to the formation of a diastereomeric mix-
ture of alcohols 23a and 23b in 39% and 37% yields, respec-
Chem. Eur. J. 2015, 21, 11671 – 11676
www.chemeurj.org
11673
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
tively. Although the oxidation of cyclic tertiary allylic alcohol
23a with pyridinium chlorochromate (PCC)[31] afforded a,b-
enone 24 in good yield, all attempts at oxidative rearrange-
ment of 23b met with failure presumably due to steric hin-
drance around the C1 position of the epimeric tertiary alcohol.
In an effort to improve the stereoselectivity, it was found that
the reaction in THF/hexamethylphosphoric triamide (HMPA)
(5:1) at À788C provided 23a in 61% yield along with 15% of
23b.[32] In the next step, we anticipated that catalytic hydroge-
nation of enone 24 should occur from the less hindered exo
face to give the desired ketone 25a. Unfortunately, hydrogena-
tion of 24 over Pd/C gave the undesired C1 epimer 25b as
a major product. Molecular mechanics calculations revealed
that the O-C10-C15=O fragment of 24 adopts an antiperiplanar
conformation and that the exo face of the C1ÀC5 double bond
is shielded by the bulky tert-butyl ester. Thus, we reasoned
that the stereoselectivity of hydrogenation of this alkene
would be reversed by decreasing the steric hindrance of the
ester moiety. Toward this end, allyl alcohol 23a was trans-
formed into a,b-enone 27 in 73% yield by reduction with
sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al)[33] and
subsequent tosylation of the primary alcohol followed by oxi-
dative rearrangement.[34] Indeed, hydrogenation of 27 over Pd/
C produced the desired ketone 28 as a single diastereomer in
virtually quantitative yield. Removal of the ketal protection in
28 was followed by an intramolecular aldol condensation
using sodium methoxide in CH2Cl2 and stereoselective reduc-
tion under Luche conditions[35] to afford allylic alcohol 29 as
a sole product in 82% yield. Hydroxy group-directed hydroge-
nation[6a–c,f] of 29 with Pd/C at room temperature and under
80 atm of H2 provided alcohol 30 as a single diastereomer in
67% yield, along with a small amount (6%) of ketone 31. The
nium tetraoxide-catalyzed oxidation in an actual system un-
eventfully provided the C9 acetate 32 in 81% yield. Sequential
reductive removal of acetyl and tosylate groups in 32 with lith-
ium triethylborohydride[38] furnished alcohol 33 in 91% yield,
which was acylated with 2-(4-methoxybenzyloxy)acetic acid
(34)[39] and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hy-
drochloride (EDCI) to give glycolate ester 35 in 98% yield. De-
protection of the TES ether with tetrabutylammonium fluoride
(TBAF) followed by esterification with cinnamic acid under Ya-
maguchi conditions[5,40] provided diester 36 in 93% yield. Final-
ly, removal of the 4-methoxybenzyl (PMB) group in 36 with
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)[41] completed
the synthesis of (À)-englerin A (1). Synthetic material 1 was
spectroscopically (1H and 13C NMR, IR and HRMS) identical to
natural 1 and also had an optical rotation, ½aŠ20 =À58.6 (c=
D
0.51, MeOH), in good agreement with the literature value[1]
[a]D À63 (c=0.13, MeOH)].
In conclusion, we have accomplished the asymmetric total
synthesis of (À)-englerin A in 25 steps and 5.2% overall yield
from succinic anhydride. In this synthesis, we have developed
a diastereo- and enantioselective carbonyl ylide cycloaddition
of 2-diazo-3,6-diketoester with ethyl vinyl ether under catalysis
by [Rh2(S-TCPTTL)4] as the key step to construct the oxabicy-
clo[3.2.1]octane framework with concomitant introduction of
the oxygen substitutent at C9 on the exo-face, wherein good
diastereoselectivity (exo/endo=87:13) and high enantioselec-
tivity of 95% ee for the exo-cycloadduct were achieved. To the
best of our knowledge, this is the first example of chiral RhII
complex-catalyzed enantioselective carbonyl ylide cycloaddi-
tion with a vinyl ether dipolarophile.[42] Other features of the
synthesis include a hydroxy group-directed hydrogenation of
tetrasubstituted allylic alcohol with Pd/C under high pressure
to give trans ring fusion and a ruthenium tetraoxide-catalyzed
chemoselective oxidative conversion of the C9 ethyl ether into
the C9 acetate. Exploitation of the present strategy for the
asymmetric synthesis of englerin A analogues with modifica-
tion of the core structure is currently in progress.
1
stereochemistry of 30 was verified by H NOE experiments.[24]
The unexpected side product 31 could arise from palladium-
catalyzed isomerization of the double bond of 29 on the exo
face followed by tautomerization of the resultant enol.[34] It
should be noted that high hydrogen pressure is essential to
minimize the formation of 31.[37]
With a highly controlled elaboration of the tricyclic core
structure achieved, the stage was now set for completion of
the total synthesis as depicted in Scheme 7. Protection of the
C6 hydroxy group in 30 as its TES ether and subsequent ruthe-
Experimental Section
Procedure for enantioselective carbonyl ylide cycloaddition
of 2-diazo-3,6-diketoester 12 with ethyl vinyl ether (13e)
(Table 1, entry 7)
A solution of a-diazo-b-ketoester 12 (4.29 g, 16.0 mmol) and ethyl
vinyl ether (13e) (3.46 g, 48.0 mmol) in a,a,a-trifluorotoluene
(80 mL) was added dropwise over 1 h to a solution of [Rh2(S-
TCPTTL)4] · 2EtOAc (8) (316 mg, 0.16 mmol, 1 mol%) in a,a,a-tri-
fluorotoluene (80 mL) at 238C. The reaction mixture was concen-
trated in vacuo, and the residue was purified by column chroma-
tography (silica gel, 6:1 hexane/EtOAc) to provide 11 e (3.73 g,
75%) as a white solid and 17e (524 mg, 10%) as a colorless oil,
and 95% of [Rh2(S-TCPTTL)4]·2EtOAc (8) (302 mg) was recovered. A
single recrystallization of the recovered 8 (302 mg) from EtOAc/
hexane gave a first crop (222 mg), and the mother liquor was con-
centrated and the residue was recrystallized from EtOAc/hexane to
give a second crop (47 mg). Both crops were of sufficient purity for
reuse.
Scheme 7. Completion of the total synthesis of 1. Reagents and conditions
a) TESOTf, 2,6-lutidine, CH2Cl2, 08C, 0.5 h; b) RuCl3 (10 mol%), NaIO4, CCl4/
MeCN/pH 7.0 phosphate buffer (2:2:3), 6.5 h; c) LiBEt3H, THF, 1.5 h;
d) PMBOCH2CO2H (34), EDCI, CH2Cl2, 08C, 0.5 h; e) TBAF, THF, 08C, 0.5 h;
f) cinnamic acid, 2,4,6-Cl3C6H2COCl, DMAP, Et3N, toluene, 08C, 1 h; g) DDQ,
CH2Cl2, 7 h.
Chem. Eur. J. 2015, 21, 11671 – 11676
www.chemeurj.org
11674
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
8843; c) B.-F. Sun, C.-L. Wang, R. Ding, J.-Y. Xu, G.-Q. Lin, Tetrahedron
Lett. 2011, 52, 2155–2158.
Acknowledgements
[9] For synthesis and biological evaluation of englerin A analogues, see:
a) K. P. Chan, D. Y.-K. Chen, ChemMedChem 2011, 6, 420–423; b) D. B.
Ushakov, V. Navickas, M. Strçbele, C. Maichle-Mçssmer, F. Sasse, M. E.
Maier, Org. Lett. 2011, 13, 2090–2093; c) L. Dong, X.-Z. Jiao, X.-Y. Liu, C.-
S. Tian, X.-Y. Li, Y.-Y. Yao, P. Xie, J. Asian. Nat. Prod. Res. 2014, 16, 629–
639.
[10] For books and reviews on 1,3-dipolar cycloadditions of carbonyl ylides,
see: a) A. Padwa, M. D. Weingarten, Chem. Rev. 1996, 96, 223–269;
b) M. P. Doyle, M. A. McKervey, T. Ye, Modern Catalytic Methods for Or-
ganic Synthesis with Diazo Compounds, Wiley-Interscience, New York,
1998, chap. 7; c) D. M. Hodgson, F. Y. T. M. Pierard, P. A. Stupple, Chem.
Soc. Rev. 2001, 30, 50–61; d) G. Mehta, S. Muthusamy, Tetrahedron
2002, 58, 9477–9504; e) D. M. Hodgson, A. H. Labande, S. Muthusamy,
Org. React. 2013, 80, 133–496.
[11] For a book and reviews on the syntheses of natural products by a car-
bonyl ylide cycloaddition strategy, see: a) M. C. McMills, D. Wright, in
Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Het-
erocycles and Natural Products, (Eds.: A. Padwa, W. H. Pearson), Wiley,
Hoboken, 2003, chap. 4; b) A. Padwa, Helv. Chim. Acta 2005, 88, 1357–
1374; c) V. Nair, T. D. Suja, Tetrahedron 2007, 63, 12247–12275; d) V.
Singh, U. M. Krishna, Vikrant, G. K. Trivedi, Tetrahedron 2008, 64, 3405–
3428; e) A. Padwa, Chem. Soc. Rev. 2009, 38, 3072–3081; f) A. Padwa,
Tetrahedron 2011, 67, 8057–8072.
This research was supported, in part, by a Grant-in-Aid for Sci-
entific Research from the Japan Society for the Promotion of
Science (JSPS) and also by a Grant-in-Aid for Scientific Research
on Innovative Areas “Organic Synthesis Based on Reaction Inte-
gration” (No. 2105) from the Ministry of Education, Culture,
Sports, Science and Technology, Japan. T.H. is grateful to the
JSPS for a graduate fellowship. We thank S. Oka, M. Kiuchi, and
T. Hirose of the Center for Instrumental Analysis at Hokkaido
University for mass measurements and elemental analysis.
Keywords: (À)-englerin
A
·
1,3-dipolar cycloaddition
·
asymmetric synthesis
·
carbonyl ylide dirhodium(II)
·
complexes · total synthesis
[1] a) R. Ratnayake, D. Covell, T. T. Ransom, K. R. Gustafson, J. A. Beutler,
Org. Lett. 2009, 11, 57–60; b) J. A. Beutler, R. Ratnayake, D. Covell, T. R.
Johnson, WO 2009/088854; c) R. K. Akee, T. Ransom, R. Ratnayake, J. B.
McMahon, J. A. Beutler, J. Nat. Prod. 2012, 75, 459–463.
[12] For more recent works, see: a) D. M. Hodgson, F. L. Strat, T. D. Avery,
A. C. Donohue, T. Brück, J. Org. Chem. 2004, 69, 8796–8803; b) T. Graen-
ing, V. Bette, J. Neudçrfl, J. Lex, H.-G. Schmalz, Org. Lett. 2005, 7, 4317–
4320; c) Z. Geng, B. Chen, P. Chiu, Angew. Chem. Int. Ed. 2006, 45, 6197–
6201; Angew. Chem. 2006, 118, 6343–6347; d) Y. Hirata, S. Nakamura, N.
Watanabe, O. Kataoka, T. Kurosaki, M. Anada, S. Kitagaki, M. Shiro, S. Ha-
shimoto, Chem. Eur. J. 2006, 12, 8898–8925; e) S. Nakamura, Y. Sugano,
F. Kikuchi, S. Hashimoto, Angew. Chem. Int. Ed. 2006, 45, 6532–6535;
Angew. Chem. 2006, 118, 6682–6685; f) D. B. England, A. Padwa, Org.
Lett. 2007, 9, 3249–3252; g) D. B. England, A. Padwa, J. Org. Chem.
2008, 73, 2792–2802; h) S. K. Lam, P. Chiu, Chem. Eur. J. 2007, 13,
9589–9599; i) C. H. Kim, K. P. Jang, S. Y. Choi, Y. K. Chung, E. Lee, Angew.
Chem. Int. Ed. 2008, 47, 4009–4011; Angew. Chem. 2008, 120, 4073–
4075; j) Y. Sugano, F. Kikuchi, A. Toita, S. Nakamura, S. Hashimoto, Chem.
Eur. J. 2012, 18, 9682–9690; k) L. T. Leung, P. Chiu, Chem. Asian J. 2015,
10, 1042–1049.
[13] a) D. M. Hodgson, P. A. Stupple, C. Johnstone, Tetrahedron Lett. 1997, 38,
6471–6472; b) D. M. Hodgson, P. A. Stupple, F. Y. T. M. Pierard, A. H. Lab-
ande, C. Johnstone, Chem. Eur. J. 2001, 7, 4465–4476; c) D. M. Hodgson,
R. Glen, G. H. Grant, A. J. Redgrave, J. Org. Chem. 2003, 68, 581–586;
d) D. M. Hodgson, T. Brückl, R. Glen, A. H. Labande, D. A. Selden, A. G.
Dossetter, A. J. Redgrave, Proc. Natl. Acad. Sci. USA 2004, 101, 5450–
5454.
[2] For biological studies of englerin A, see: a) F. J. Sulzmaier, Z. Li, M. L. Na-
kashige, D. M. Fash, W. J. Chain, J. W. Ramos, PLoS One 2012, 7, e48032;
b) C. Sourbier, B. T. Scroggins, R. Ratnayake, T. L. Prince, S. Lee, M.-J. Lee,
P. L. Nagy, Y. H. Lee, J. B. Trepel, J. A. Beutler, W. M. Linehan, L. Neckers,
Cancer Cell 2013, 23, 228–237; c) R. T. Williams, A. L. Yu, M. B. Diccianni,
E. A. Theodorakis, A. Batova, J. Exp. Clin. Cancer Res. 2013, 32, 57.
[3] Y. Akbulut, H. J. Gaunt, K. Muraki, M. J. Ludlow, M. S. Amer, A. Burns,
N. S. Vasudev, L. Radtke, M. Willot, S. Hahn, T. Seitz, S. Ziegler, M. Chrsit-
mann, D. J. Beech, H. Waldmann, Angew. Chem. Int. Ed. 2015, 54, 3787–
3791; Angew. Chem. 2015, 127, 3858–3862.
[4] For reviews, see a) M. Willot, M. Christmann, Nat. Chem. 2010, 2, 519–
520; b) W. J. Chain, Synlett 2011, 2605–2608; c) M. Szostak, D. J. Procter,
Angew. Chem. Int. Ed. 2011, 50, 7737–7739; Angew. Chem. 2011, 123,
7881–7883; d) R. H. Pouwer, J.-A. Richard, C.-C. Tseng, D. Y.-K. Chen,
Chem. Asian J. 2012, 7, 22–35.
[5] a) M. Willot, L. Radtke, D. Kçnning, R. Frçhlich, V. H. Gessner, C. Stroh-
mann, M. Christmann, Angew. Chem. Int. Ed. 2009, 48, 9105–9108;
Angew. Chem. 2009, 121, 9269–9272. Christmann et al. subsequently
achieved the total synthesis of (À)-englerin A (1) by using (+)-citronellal
as a starting material, see: b) L. Radtke, M. Willot, H. Sun, S. Ziegler, S.
Sauerland, C. Strohmann, R. Frçhlich, P. Habenberger, H. Waldmann, M.
Christmann, Angew. Chem. Int. Ed. 2011, 50, 3998–4002; Angew. Chem.
2011, 123, 4084–4088.
[14] a) S. Kitagaki, M. Anada, O. Kataoka, K. Matsuno, C. Umeda, N. Wata-
nabe, S. Hashimoto, J. Am. Chem. Soc. 1999, 121, 1417–1418; b) S. Kita-
gaki, M. Yasugahira, M. Anada, M. Nakajima, S. Hashimoto, Tetrahedron
Lett. 2000, 41, 5931–5935; c) H. Tsutsui, N. Shimada, T. Abe, M. Anada,
M. Nakajima, S. Nakamura, H. Nambu, S. Hashimoto, Adv. Synth. Catal.
2007, 349, 521–526.
[15] a) M. Yamawaki, H. Tsutsui, S. Kitagaki, M. Anada, S. Hashimoto, Tetrahe-
dron Lett. 2002, 43, 9561–9564; b) V. N. G. Lindsay, W. Lin, A. B. Char-
ette, J. Am. Chem. Soc. 2009, 131, 16383–16385.
[16] a) N. Shimada, M. Anada, S. Nakamura, H. Nambu, H. Tsutsui, S. Hashi-
moto, Org. Lett. 2008, 10, 3603–3606; b) N. Shimada, T. Hanari, Y. Kuro-
saki, K. Takeda, M. Anada, H. Nambu, M. Shiro, S. Hashimoto, J. Org.
Chem. 2010, 75, 6039–6042; c) N. Shimada, T. Hanari, Y. Kurosaki, M.
Anada, H. Nambu, S. Hashimoto, Tetrahedron Lett. 2010, 51, 6572–
6575; d) K. Takeda, T. Oohara, N. Shimada, H. Nambu, S. Hashimoto,
Chem. Eur. J. 2011, 17, 13992–13998.
[17] For the effective use of [Rh2(S-TCPTTL)4] in enantioselective carbonyl
ylide cycloadditions with N-methylindole, arylallene, and tropone dipo-
larophiles, see: a) N. Shimada, T. Oohara, J. Krishnamurthi, H. Nambu, S.
Hashimoto, Org. Lett. 2011, 13, 6284–6287; b) J. Krishnamurthi, H.
Nambu, K. Takeda, M. Anada, A. Yamano, S. Hashimoto, Org. Biomol.
Chem. 2013, 11, 5374–5382; c) S. Murarka, Z.-J. Jia, C. Merteb, C.-G.
[6] For total synthesis of englerin A, see: a) Q. Zhou, X. Chen, D. Ma,
Angew. Chem. Int. Ed. 2010, 49, 3513–3516; Angew. Chem. 2010, 122,
3591–3594; b) K. Molawi, N. Delpont, A. M. Echavarren, Angew. Chem.
Int. Ed. 2010, 49, 3517–3519; Angew. Chem. 2010, 122, 3595–3597;
c) K. C. Nicolaou, Q. Kang, S. Y. Ng, D. Y.-K. Chen, J. Am. Chem. Soc. 2010,
132, 8219–8222; d) Z. Li, M. Nakashige, W. J. Chain, J. Am. Chem. Soc.
2011, 133, 6553–6556; e) K. Takahashi, K. Komine, Y. Yokoi, J. Ishihara, S.
Hatakeyama, J. Org. Chem. 2012, 77, 7364–7370; f) J. Wang, S.-G. Chen,
B.-F. Sun, G.-Q. Lin, Y.-J. Shang, Chem. Eur. J. 2013, 19, 2539–2547; g) M.
Zahel, A. Keßberg, P. Metz, Angew. Chem. Int. Ed. 2013, 52, 5390–5392;
Angew. Chem. 2013, 125, 5500–5502; h) J. Zhang, S. Zheng, W. Peng, Z.
Shen, Tetrahedron Lett. 2014, 55, 1339–1341.
[7] For formal synthesis of englerin A, see: a) J. Xu, E. J. E. Caro-Diaz, E. A.
Theodorakis, Org. Lett. 2010, 12, 3708–3711; b) C.-L. Wang, B.-F. Sun, S.-
G. Chen, R. Ding, G.-Q. Lin, J.-Y. Xu, Y.-J. Shang, Synlett 2012, 263–266;
c) J. Xu, E. J. E. Caro-Diaz, A. Batova, S. D. E. Sullivan, E. A. Theodorakis,
Chem. Asian J. 2012, 7, 1052–1060; d) J. Lee, K. A. Parker, Org. Lett.
2012, 14, 2682–2685; e) P. Gao, S. P. Cook, Org. Lett. 2012, 14, 3340–
3343.
[8] For synthetic studies of englerin A, see: a) V. Navickas, D. B. Ushakov,
M. E. Maier, M. Strçbele, H.-J. Meyer, Org. Lett. 2010, 12, 3418–3421;
b) K. Ishida, H. Kusama, N. Iwasawa, J. Am. Chem. Soc. 2010, 132, 8842–
Chem. Eur. J. 2015, 21, 11671 – 11676
www.chemeurj.org
11675
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
Daniliuc, A. P. Antonchick, H. Waldmann, Angew. Chem. Int. Ed. 2015, 54,
7653–7656; Angew. Chem. 2015, 127, 7763–7766.
[28] Y. Ito, T. Hirao, T. Saegusa, J. Org. Chem. 1978, 43, 1011–1013.
[29] G. L. Larson, R. Klesse, J. Org. Chem. 1985, 50, 3627.
[30] a) W. F. Bailey, E. R. Punzalan, J. Org. Chem. 1990, 55, 5404–5406; b) E.
Negishi, D. R. Swanson, C. J. Rousset, J. Org. Chem. 1990, 55, 5406–
5409.
[31] W. G. Dauben, D. M. Michno, J. Org. Chem. 1977, 42, 682–685.
[32] The reaction of enone 21 with 2-(2-methyl-1,3-dioxolan-2-yl)ethylmag-
nesium bromide in THF exclusively provided 23b in 65% yield.
[18] A synthetic strategy involving construction of an oxabicyclo[3.2.1]oc-
tane framework followed by cyclopentane annulation was originally de-
veloped by Nicolaou, Chen et al. employing a [5+2] cycloaddition of
oxidopyrylium species with acrylate. Thereafter, conceptually similar ap-
proaches were reported by Theodorakis et al.[7a,c] and Sun, Lin
et al.[6f,7b,8c] utilizing a RhII-catalyzed [4+3] cycloaddition of a chiral enol-
diazoacetate with 2-isopropyl-5-methylfuran and an enantioselective or-
ganocatalytic [4++3] cycloaddition between 4-siloxydienal and the same
furan, respectively.
[19] For RhII-catalyzed cycloaddition of carbonyl ylides with vinyl ethers, see:
a) H. Koyama, R. G. Ball, G. D. Berger, Tetrahedron Lett. 1994, 35, 9185–
9188; b) A. Padwa, G. E. Fryxell, L. Zhi, J. Am. Chem. Soc. 1990, 112,
3100–3109.
[20] For enantioselective cycloaddition of 2-benzopyrylium-4-olates or car-
bonyl ylides generated from a Rh2(OAc)4-catalyzed nitrogen extrusion
of diazoacetophenones or a-diazoketones with vinyl ethers using chiral
Lewis acid catalysts, see: a) H. Suga, D. Ishimoto, S. Higuchi, M. Ohtsuka,
T. Arikawa, T. Tsuchida, A. Kakehi, T. Baba, Org. Lett. 2007, 9, 4359–4362;
b) H. Suga, S. Higuchi, M. Ohtsuka, D. Ishimoto, T. Arikawa, Y. Hashimo-
to, S. Misawa, T. Tsuchida, A. Kakehi, T. Baba, Tetrahedron 2010, 66,
3070–3089.
ˇ
ˇ
[33] V. Bazˇant, M. Capka, M. Cerny´, V. Chvalovsky´, K. Kochloefl, M. Kraus, J.
Mµlek, Tetrahedron Lett. 1968, 9, 3303–3306.
[34] Since reductive removal of the C15 tosylate in 26 with LiAlH4 or LiBEt3H
did not take place, we decided to keep the tosylate until a later stage
of the synthesis.
[35] a) J.-L. Luche, J. Am. Chem. Soc. 1978, 100, 2226–2227; b) A. L. Gemal,
J.-L. Luche, J. Am. Chem. Soc. 1981, 103, 5454–5459.
[36] a) M. Kraus, Coll. Czech. Chem. Commun. 1972, 37, 460–465; for reviews
on isomerization of allylic alcohols, see: b) R. Uma, C. CrØvisy, R. GrØe,
Chem. Rev. 2003, 103, 27–51; c) J. Muzart, Tetrahedron 2005, 61, 9423–
9463.
[37] Hydrogenation of 29 over Pd/C at 1 atm gave 30 and 31 in 48% and
21% yields, respectively.
[38] S. Krishnamurthy, H. C. Brown, J. Org. Chem. 1976, 41, 3064–3066.
[39] N. P. Probst, A. Haudrechy, K. PlØ, J. Org. Chem. 2008, 73, 4338–4341.
[40] J. Inanaga, K. Hirata, H. Saeki, T. Katsuki, M. Yamaguchi, Bull. Chem. Soc.
Jpn. 1979, 52, 1989–1993.
[21] H. Schick, R. Ludwig, Synthesis 1992, 369–370.
[22] a) D. W. Brooks, L. D.-L. Lu, S. Masamune, Angew. Chem. Int. Ed. Engl.
1979, 18, 72–74; Angew. Chem. 1979, 91, 76–77; b) M. P. Moyer, P. L.
Feldman, H. Rapoport, J. Org. Chem. 1985, 50, 5223–5230.
[23] D. F. Taber, R. E. Ruckle, Jr., M. J. Hennessy, J. Org. Chem. 1986, 51,
4077–4078.
[24] See the Supporting Information for details.
[25] As reported by Koyama et al. the reaction of 12 with vinyl acetate led
to a complex mixture of products.
[41] Y. Oikawa, T. Yoshioka, O. Yonemitsu, Tetrahedron Lett. 1982, 23, 885–
888.
[42] For a catalytic asymmetric synthesis of 8-oxabicyclo[3.2.1]octane deriva-
tives through highly diastereo- and enantioselective [3+2]-cycloaddi-
tion of platinum-containing carbonyl ylides with vinyl ethers, see
Ref. [8b].
[26] a) P. H. J. Carlsen, T. Katsuki, V. S. Martin, K. B. Sharpless, J. Org. Chem.
1981, 46, 3936–3938; b) M. Drees, T. Strassner, J. Org. Chem. 2006, 71,
1755–1760, and references therein.
[27] CCDC 1011865 (for 20) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre.
Received: May 22, 2015
Published online on July 14, 2015
Chem. Eur. J. 2015, 21, 11671 – 11676
www.chemeurj.org
11676
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim