A Carbene Catalysis Strategy for the Synthesis of Protoilludane Natural Products

Article abstract of DOI:10.1002/anie.201705308

The Armillaria and Lactarius genera of fungi produce the antimicrobial and cytotoxic mellolide, protoilludane, and marasmane sesquiterpenoids. We report a unified synthetic strategy to access the protoilludane, mellolide, and marasmane families of natural products. The key features of these syntheses are 1) the organocatalytic, enantioselective construction of key chiral intermediates from a simple achiral precursor, 2) the utility of a key 1,2-cyclobutanediol intermediate to serve as a precursor to each natural product class, and 3) a direct chemical conversion of a protoilludane to a marasmane through serendipitous ring contraction, which provides experimental support for their proposed biosynthetic relationships.

Full text of DOI:10.1002/anie.201705308

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: A Carbene Catalysis Strategy for the Synthesis of Protoilludane
Natural Products
Authors: Karl Scheidt, Todd Hovey, Daniel Cohen, Daniel Walden, and
Paul Cheong
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201705308
Angew. Chem. 10.1002/ange.201705308
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10.1002/anie.201705308
Angewandte Chemie International Edition
COMMUNICATION
A Carbene Catalysis Strategy for the Synthesis of
Protoilludane Natural Products**
M. Todd Hovey,[a] Daniel T. Cohen,[a] Daniel M. Walden,[b] Paul H-Y. Cheong, [b] and Karl A.
Scheidt*[a]
Dedicated to Prof. Dr. W. Robert Scheidt on the occasion of his 75th birthday
Abstract: The Armillaria and Lactarius genera of fungi produce
antimicrobial and cytotoxic mellolide, protoilludane, and marasmane
sesquiterpenoids. Herein, we report a unified synthetic strategy to
access the protoilludane, mellolide, and marasmane families of
natural products. The significance of these syntheses lies in a) the
organocatalytic, enantioselective construction of key chiral
intermediates from a simple achiral precursor, b) the utility of a key
1,2-butanediol intermediate to serve as a progenitor to each natural
product class, and c) a direct chemical conversion of a protoilludane
asymmetric catalysis has not been successfully utilized to
generate either the mellolides or protoilludanes.[4]
Structural Challenges
• densely functionalized
O
Me
Cl
O
H
O
H
O
H
• 5 contiguous stereocenters
• cis-fused A,B ring
H
OH
O
• [4.6.5]+[3.6.5] tricyclic core
MeO
H
H
HO
H
R2
OH
Me
Me
Me
Me
H
Me
R1
Me
to
a marasmane via serendipitous ring contraction, providing
H
isovelleral (4)
armillaridin (1)
(cytotoxic & antimicrobial)
HO
experimental support for their proposed biosynthetic relationships.
(antimicrobial)
Me
Me
Me
echinocidin B (2); R1, R2 = H, OH
echinocidin D (3); R1, R2 = OH, H
(endophytic growth modulator)
The rise in bacterial resistance to current treatments is a
critical threat to society.[1] Since the discovery of penicillin, global
research activity has taken inspiration from natural products to
drive the development of new antimicrobial therapeutics.[2] The
antimicrobial protoilludane and marasmane sesquiterpenoids
were isolated in the 1960s from the Armillaria mellea and
Lactarius vellereus species of parasitic basidiomycetes fungi
(Scheme 1, 1-4).[3] These compounds gained attention for their
R
sequential
alkylations
OPG
H
H
reductive
coupling
OPG
H
H
O
O
HO
H
H
H
HO
OHC
Me
Me
Me
Me
Me
7
6
5
Me
Me
Me
annulation
O
structurally
unique
and
densely
functionalized
NHC
catalysis
O
H
H
H
H
perhydrocyclobuta[e]indene and related frameworks.[4] Recently,
the mellolide armillaridin (1) has gained considerable attention
NHC
O
Me
Me
H
H
O
Me
Me
Me
Me
O
R
O
for possessing apoptotic and radiosensitizing activity towards
H
R
several cancer cell lines.[3a-c,
The biosynthetically related
3e]
9
2 stereocenters
3 bonds
8
R
marasmanes (including isovelleral, 4), exhibit broad-spectrum
antimicrobial and anti-feedant activity.[3g,
These tricyclic
5]
Scheme 1. Overall Synthesis Plan.
sesquiterpenoids have five contiguous stereocenters, a cis-
fused cyclohexyl/cyclopentyl ring system, at least one
quaternary carbon, a vicinal cyclobutane-diol, as well as an α,β-
unsaturated aldehyde. An asymmetric catalytic strategy that
could efficiently address these architectural challenges would
add to the body of work dedicated to synthesizing complex
natural products through catalysis. Notably, Banwell has
reported a chemoenzymatic route to access members of the
mellolide family as single antipodes.[6] However, abiotic
Biological systems frequently employ linear substrates to
quickly prepare complex molecules. In this regard, we sought to
utilize our previously developed N-heterocyclic carbene (NHC)-
catalyzed asymmetric annulation reaction to construct the
difficult cis-fused octahydro-1H-indene ring systems found in the
mellolides and protoilludanes from a linear precursor (i.e., 9).[7]
In contrast, the trans-fused [5.6] carbocyclic system can be
prepared by enolate annulations, compelling us to examine our
methodology in the context of these specific targets.[8] Moreover,
developing a unified approach to this core would provide
opportunities to prepare several members of each family and
analogs to further translational/chemical biology investigations.
[a]
M. T. Hovey, D. T. Cohen, K. A. Scheidt*
Department of Chemistry, Department of Phamacology, Center for
Molecular Innovation and Drug Discovery, Northwestern University
2145 Sheridan Rd, Evanston IL 60208 (USA)
E-mail: scheidt@northwestern.edu
Two major disconnections anchor our retrosynthetic
approach. We initially identified the late stage intermediate triol 5
as the key divergence point (Scheme 1). We envisioned the
vicinal cyclobutane-diol functional group arising from a pinacol-
type reductive coupling.[9] To the best of our knowledge, this
approach toward cyclobutane-diols has not been utilized in
complex total synthesis.
[b]
D. M. Walden, P. H-Y. Cheong
Department of Chemistry
Oregon State University
153 Gilbert Hall, Corvallis OR, 97331 (USA)
**
We thank Prof. Dirk Hoffmeister (Liebniz Institute for Natural Product
Research and Infection Biology) for providing authentic samples and
spectral data of armillaridin. We thank David B. Elmets
(Northwestern) for experimental assistance. Support for this work
was provided by NIGMS R01-GM073072. DTC was supported in
part by an ACS Division of Organic Chemistry Fellowship.
Supporting information for this article is given via a link at the end of
the document
This article is protected by copyright. All rights reserved.

10.1002/anie.201705308
Angewandte Chemie International Edition
COMMUNICATION
O
N
Et
BF4
N
N
O
O
O
O
O
O
O
H
Me
Me
Et
O
O
P
Me
Me
Me
Me
H
Me
c) DIBAL-H
d) DMP
14
(5 mol %)
a) O3
then DMS
H
EtO
EtO
Me
Me
EtO
OEt
OEt
Me
O
Me
O
i-Pr2EtN
66%
(2 steps)
95%
b) LiCl,
i-Pr2NEt
70%
Me
H
H
10
from i-PrCHO
(3 steps)
99:1 er
>20:1 dr
avg 60–70%
11
15
12
13
Me
Me
H
H
Ar
Ar
N
N
O
f) DIBAL
g) PPA
reagents
N
O
Me
Me
H
N
17 : 18 : 19
15
O
N
H
O
Me
Me
N
H
O
Me
Me
Me
Michael
addition
16
Me
O
Me
H
O
O
H
H
H
OH
H
Ar
Major-TS-(Si,Re)
ΔΔG = 0.0
H
Ent-TS-(Re,Si)
ΔΔG = 3.3
Me
Me
Me
Me
O
N
Me
Me
H
N
Me
Me
N
O
H
O
R
H
O
R
O
Me
H
17
cis - minor
18
trans - major
19
Me
entry
conditions
17 : 18 : 19
1
DBU (1.0 equiv)
0 : 0 : 1
2 : 4 : 1
2
3
4
5
6
KOH, Bu4OH (0.1 equiv)
LiHMDS (1.1 equiv)
H3PO4 (0.1 equiv)
decomposition
1 : 9.5 : 0
Sc(OTf)2 (0.2 equiv)
(L)-proline (0.3 equiv)
decomposition
1.8 : 4 : 1
Scheme 2. Exploration of NHC-catalyzed annulation strategy. See Supporting Information for more details.
The pinacol-coupling substrate, enone 6, would be prepared
from cis-fused carbocycle 7. This intermediate could arise from
bicyclic lactone 8 leading back to the second key strategic
disconnection, affording annulation linear precursor 9. In the
forward sense, we anticipated that an asymmetric intramolecular
NHC annulation we previously developed could yield the desired
lactone 8, serving as the key enantioselective step by selectively
installing the two key cis-stereocenters.[10] Our synthesis
commenced with 1,5-dienoate 10, prepared in large quantities
(>100 g) over three steps from isobutyraldehyde (Scheme 2).[11]
entries 1–6). Calculations of the ground state energies of 16 and
19 identified a 1.7 kcal preference for trans-epimer 19, which
explains the appearance of trans-enone 18 as the major
annulation product (see SI, Fig. S2). We surmised that an
intramolecular Horner-Wadsworth-Emmons olefination strategy
utilizing α−ketophosphonate 20 as an acylic substrate (Scheme
3) could circumvent the need for epimerically labile
intermediates like keto-aldehyde 16.
Consequently, ketophosphonate 20 was prepared by
α−iodination of ketone 12,[13] an Arbuzov reaction to yield the
corresponding α−ketophosophonate, followed by global DIBAL-
A
large-scale (>60 g) ozonolysis of enoate 10 furnished
aldehyde 11 in excellent yield. A Masamune-Roush modified
H
reduction and subsequent manganese dioxide double
Horner-Wadsworth-Emmons (HWE) olefination afforded enone
oxidation to afford enal 20, carried out on a large scale (> 10 g).
Employing our NHC annulation yielded lactone 21 on decagram
12 in good yield.[12]
A careful diisobutylalumnium hydride
(DIBAL-H) reduction followed by Dess-Martin oxidation yielded
the desired enal substrate 13 in gram quantity. The exposure of
acyclic enals to NHC pre-catalyst 14 in the presence of amine
bases affords vinyl lactone products.[10a] The conversion of enal
13 to lactone 15 was achieved in 61% isolated yield and 99:1 er
with low catalyst loading (5 mol %). To gain insight on the
stereoselection aspects of this annulation, we employed
Gaussian calculations to probe the transition state energies.
These efforts revealed a unique mode of stabilization in which
the formal step-wise [4+2] annulation more closely resembles a
[4+3] type process (see SI, Fig. S1). The electron deficient
nature of the NHC carbon (Major-TS) appears to interact
favorably with the forming alkoxide of the enone oxygen through
electrostatic attraction, which affords improved stability of the
transition state leading to the cis-fused product 15. The
annulation was followed by reduction of lactone 15 to a lactol,
which upon treatment with acid yielded keto-aldehyde 16.
Unfortunately, further elaboration of this key intermediate to the
desired bicyclic cis-enone 17 was complicated by the generation
of the isomeric trans-enone 18 and the epimeric keto-aldehyde
19, prompting revision of our synthetic strategy (Scheme 2,
scale,
exhibiting
superlative
enantioselectivity
and
diastereoselectivity. Of particular note, an NHC annulation on
this scale is rare, underscoring the robust nature of the highly
selective process.
Our attention turned toward investigating lactone 21 as the
precursor to the required cis-fused enone 7. Our initial studies
on the reduction of lactone 21 to intermediary lactol IV
unexpectedly yielded small quantities of phosphonate-enone 22.
An evaluation of hydride reagents identified the sterically
hindered lithium tri-tert-butoxyaluminium hydride as optimal for
yielding enone 22. The required hydroxy-methylene functional
group was installed through hydrogenation, olefination, and
regioselective hydrobromination to yield bromohydrin 23.
Silylation of the primary alcohol of 23 followed by addition of
lithium carbonate promoted elimination of the bromide to yield
enone 24 in good yield on gram scale. Attempts to alkylate or
allylate the a’-position of enone 24 using common enolization
conditions initially yielded only recovered starting material, O-
alkylation products, or oxidation to the phenol (not shown). We
determined that formation of the desired α-ketoester 25
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10.1002/anie.201705308
Angewandte Chemie International Edition
COMMUNICATION
depended on a precise temperature profile during preparation of
the lithium enolate. Methylation of α-ketoester 25 (>10:1 dr)
followed by palladium-catalyzed diastereoselective Tsuji-Trost-
Stoltz decarboxylative allylation (>20:1 dr) afforded the desired
diastereomer of alkylated enone 26.[14] Oxidative cleavage of the
olefin delivered the desired aldehyde 27 with the necessary
aldehyde functional group installed.
of cylcobutane-diol 28 had been synthesized.[3i] Our attempts to
convert the cis-diol 28 directly to orsellinate 32 using orsellinic
acid derivative 31 under Mitsunobu reaction conditions yielded
no desired product. Interestingly, when using para-nitrobenzoic
acid we observed an unexpected semi-pinacol ring contraction
to yield cyclopropane 29. While the general idea that
protoilludanes and marasmanes are biogenetically related
through carbon skeleton rearrangement was advanced by
Nozoe[17], this particular transformationhas not been explored or
experimentally validated until our serendipitous discovery of 28
undergoing conversion to 29, albeit under non-biological
O
O
H
Me
Me
H
a) CuO, I2
b) P(OEt)3
H
Me
Me
e) 5 mol % 14
O
conditions.[18] From cyclopropane 29,
a deprotection using
12
c) DIBAL-H
d) MnO2
99:1 er,
>20:1 dr
10 g scale
tetrabutylammonium fluoride (TBAF) buffered with acetic acid
followed by oxidation using 4-NHAc-TEMPO under acidic
conditions produced isovelleral (4) in good yield.[6] The spectral
data (1H and 13C NMR, IR, α[D]) of synthetic isovelleral (4)
matched the reported spectral data, which confirms our
structural assignment of the unusual ring-contraction
cyclopropane product 29.
H
O
PO(OEt)2
60% (4 steps)
avg. 80 %
20
PO(OEt)2
21
f) LiAl(Ot-Bu)3H
84%
OEt
OEt
O
OH
P
H
H
H
g) H2, Pd/C
h) (CH2O)n
O
O
Me
Me
O
H
H
H
PO(OEt)2
Me
Me
Br
Me
Me
22
IV
OTBDPS
OTBDPS
OTBDPS
a) VCl3•(THF)3
Zn(0),HMPA
85%
c) DEAD
PPh3
ArCO2H
H
H
H
j) TBDPSCl
k) Li2CO3
O
O
l) LDA
Et2O
O
H
H
i) TsNBr2
H
H
O
HO
H
H
27
45%
(3 steps)
3 : 1 rs
HO
HO
76%
(2 steps)
61%
H
Me
Me
NC
OAllyl
Me
Me
b) TASF
87%
Me
Me
Me
Me
Me
29
23
24
Me
OTBDPS
OTBDPS
H
OTBDPS
H
28
d) TBAF,
e) TEMPO
60%
(2 steps)
f) DMS, NCS
g) NaHB(OAc)3
61% (2 steps)
H
OH
H
O
H
O
O
H
o) OsO4
m) MeI
H
H
AllylO2C
H
O
H
HO
O
H
H
p) NaIO4
75%
(2 steps)
n) Pd2(dba)3
68% (3 steps)
Me
HO
Me
Me
Me
H
O
H
OTBDPS
Me
OH
Me
Me
Me
Me
H
H
Me
Me
27
26
25
Me
Me
H
H
echinocidin D (3)
Me
HO
Scheme 3. Synthesis of reductive coupling susbstrate. See Supporting
Information for more details.
31
isovelleral (4)
HO2C
OH
Me
Me
Me
Me
h) TASF
85%
30
Our attention turned toward synthesizing key intermediate
cis-cyclobutane-diol 28 using an intramolecular pinacol reductive
coupling strategy (Scheme 4). A report by Pedersen in 1991
highlighted a single example of a cyclobutane-diol (cis or trans)
being prepared from 4-oxo-butanals using an in situ prepared
Cl
OMe
OH
OH
HO
ArCO2 OTBDPS
H
H
i) EDCI
DMAP
71%
H
H
H
H
HO
Me
Me
Me
Me
32
O
Me
Me
Me
vanadium(II)/ zinc(II) bimetallic complex.[9b] In contrast,
a
echinocidin B (2)
Cl
MeO
O
O
H
j) TBAF,
k) TEMPO
70%
(2 steps)
H
majority of intramolecular pinacol-type reductive couplings utilize
titanium(III) species.[9a] Fortunately, the desired cis-cyclobutane-
diol 28 was generated under modified Pedersen conditions (pH
7 buffer quench), which avoided decomposition under standard
work up conditions (Scheme 4). To the best of our knowledge,
this step serves as the first example of producing a cyclobutane
diol from an enone/aldehyde in complex total synthesis.[15]
Intermediate 28 serves as the key divergence point in order to
complete the unified total synthesis of the protoilludane,
mellolide and marasmane natural products.
OH
H
HO
Me
Me
armillaridin (1)
Me
Scheme 4. Synthesis of armillaridin (1), echinocidin B&D (2&3), and
isovelleral (4). See Supporting Information for more details.
To access mellolide armillaridin (1), the inversion of the
secondary alcohol of cis-diol 28 to the trans configuration was
compulsory and an oxidation/directed reduction sequence was
explored.
A
Corey-Kim oxidation afforded the desired
directed reduction with sodium
intermediate ketone.[19]
A
The final phase of our synthetic route commenced with the
desilylation of cis-diol 28 by exposure to anhydrous TAS-F,
affording the protoilludane echinocidin D (3) cleanly and in high
yield, constituting the first total synthesis of this protoilludane
triol (Scheme 4).[3i, 16] Spectroscopic characterization of synthetic
echinocidin D (1H and 13C NMR, IR, [α]D, HRMS) matched all
data reported for the natural compound, while simultaneously
confirming the absolute stereochemistry established in our
enantioselective NHC annulation and the correct diastereomer
triacetoxyborohydride yielded the desired trans-diol 30 (12:1 dr)
and subsequent desilylation with TAS-F yielded protoilludane
echinocidin B (2), which possessed spectroscopic data in
agreement with published data.[3h] The synthesis of echinocidin
B (2) confirms the trans-diol stereochemistry of the penultimate
intermediate 30 as well as represents the first total synthesis of
this protoilludane triol. The esterification of trans-diol 30 with
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10.1002/anie.201705308
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COMMUNICATION
[13] Z. H. Wang, G. D. Yin, J. Qin, M. Gao, L. P. Cao, A. X. Wu, Synthesis
2008, 3675-3681.
[14] a) B. M. Trost, T. J. Fullerton, J. Am. Chem. Soc. 1973, 95, 292–294; b)
J. Tsuji, H. Takahashi, M. Morikawa, Tetrahedron Lett. 1965, 6, 4387–
4388; c) D. C. Behenna, B. M. Stoltz, J. Am. Chem. Soc. 2004, 126,
15044-15045.
orsellinic acid derivative 31 using EDCI afforded orsellinate ester
32.[20] The exposure of orsellinate 32 to TBAF buffered with
acetic acid gave facile (<15 min) deprotection to the allylic
alcohol, which was then oxidized using a 4-NHAc-TEMPO/para-
toluensulfonic acid combination to yield armillaridin (1). The
spectral data of synthetic armillaridin (1) matched all reported
data on the natural material, thus completing the first total
synthesis of this natural product.[3a, 3d]
[15] For an example of
a pinacol coupling applied in natural products
synthesis, see: a) J. S. Kingsbury, E. J. Corey, J. Am. Chem. Soc. 2005,
127, 13813-13815; For an example of a pinacol coupling to prepare
cyclohexanediols, see: b) M. Kang, J. Park, A. W. Konradi, S. F.
Pedersen, J. Org. Chem. 1996, 61, 5528-5531. For cyclopentanediols
see reference 9a.
[16] K. a. Scheidt, H. Chen, B. C. Follows, S. R. Chemler, D. S. Coffey, W. R.
In total, the unified total syntheses of the protoilludanes,
mellolides, and marasmane have been achieved through a key
organocatalytic enantioselective annulation. The elaboration of
key bicyclic lactone 21 is the molecular springboard from which
the first enantioselective total syntheses of protoilludanes
echinocidin B (2), echinocidin D (3) and mellolide armillaridin (1)
as well as the synthesis of the marasmane isovelleral (4) are
accomplished. The vanadium(II)/zinc(II) reductive coupling
yielded the final ring of the densely functionalized cis-fused
carbocyclic core. Lastly, the unexpected semi-Pinacol-type ring
contraction to establish cyclopropyl aldehyde 29 from the
cyclobutane-diol 28 is potentially biomimetic in origin. With a
succinct and unified route to these classes of biologically active
compounds further investigations into their biology and
therapeutic potential are now ongoing.
Roush, J. Org. Chem. 1998, 63, 6436-6437.
[17] S. Nozoe, H. Kobayashi, S. Urano, J. Furukawa, Tetrahedron Lett. 1977,
18, 1381-1384.
[18] J. M. Conia, J. P. Barnier, Tetrahedron Lett. 1971, 12, 4981–4984.
[19] E. J. Corey, C. U. Kim, J. Am. Chem. Soc. 1972, 94, 7586-7587.
[20] C. Pulgarin, J. Gunzinger, R. Tabacchi, Helv. Chim. Acta 1985, 68, 945-
948.
Keywords: Total Synthesis • NHC • Armillaridin • Protoilludane •
Marasmane
[1] J. M. A. Blair, M. A. Webber, A. J. Baylay, D. O. Ogbolu, L. J. V. Piddock,
Nat Rev Micro 2015, 13, 42–51.
[2] a) A. L. Harvey, R. Edrada-Ebel, R. J. Quinn, Nat Rev Drug Discov 2015,
14, 111–129; b) D. J. Newman, G. M. Cragg, J. Nat. Prod. 2007, 70,
461-477.
[3] a) Y. Junshan, C. Yuwu, F. Xiaozhang, Y. Dequan, L. Xiaotian, Planta
Med. 1984, 50, 288–290; b) M. Bohnert, S. Miethbauer, H.-M. Dahse, J.
Ziemen, M. Nett, D. Hoffmeister, Bioorg. Med. Chem. Lett. 2011, 21,
2003–2006; c) C.-W. Chi, C.-C. Chen, Y.-J. Chen, Evid. Based.
Complement. Alternat. Med. 2013, 2013, 459271–459278; d) Z. Li, Y.
Wang, B. Jiang, W. Li, L. Zheng, X. Yang, Y. Bao, L. Sun, Y. Huang, Y.
Li, J. Ethnopharmacol. 2016, 184, 119–127; e) S. L. Midland, R. R. Izac,
R. M. Wing, A. I. Zaki, D. E. Munnecke, J. J. Sims, Tetrahedron Lett.
1982, 23, 2515–2518; f) T. C. Mcmorris, M. Anchel, J. Am. Chem. Soc.
1965, 87, 1594–1600; g) P. H. List, H. Hackenberg, Arch. Pharm. 1969,
302, 125-143; h) Y. Shiono, T. Seto, M. Kamata, C. Takita, S. Suzuki, T.
Murayama, M. Ikeda, Z. Naturforsch. B 2004, 59, 925–929; i) Y. Shiono,
S. Suzuki, T. Murayama, M. Ikeda, Y. Abe, Z. Naturforsch. B 2005, 60,
449–452.
[4] P. Siengalewicz, J. Mulzer, U. Rinner, Eur. J. Org. Chem. 2011, 7041-
7055.
[5] a) R. Bergman, T. Hansson, O. Sterner, B. Wickberg, J. Chem. Soc.,
Chem. Commun. 1990, 865–867; b) S. K. Thompson, C. H. Heathcock,
J. Org. Chem. 1990, 55, 3004–3005; c) S. K. Thompson, C. H.
Heathcock, J. Org. Chem. 1992, 57, 5979-5989; d) R. P. L. Bell, J. B. P.
A. Wijnberg, A. de Groot, J. Org. Chem. 2001, 66, 2350-2357.
[6] B. D. Schwartz, E. Matousova, R. White, M. G. Banwell, A. C. Willis, Org.
Lett. 2013, 15, 1934–1937.
[7] J. Izquierdo, G. E. Hutson, D. T. Cohen, K. A. Scheidt, Angew. Chem. Int.
Ed. 2012, 51, 11686-11698.
[8] M. T. Hechavarria Fonseca, B. List, Angew. Chem. Int. Ed. 2004, 43,
3958–3960.
[9] a) E. J. Corey, R. L. Danheiser, S. Chandrasekaran, J. Org. Chem. 1976,
41, 260–265; b) A. S. Raw, S. F. Pedersen, J. Org. Chem. 1991, 56,
830-833.
[10] a) E. M. Phillips, M. Wadamoto, A. Chan, K. A. Scheidt, Angew. Chem.
Int. Ed. 2007, 46, 3107-3110; b) D. M. Flanigan, F. Romanov-Michailidis,
N. A. White, T. Rovis, Chem. Rev. 2015, 115, 9307-9387; c) M. N.
Hopkinson, C. Richter, M. Schedler, F. Glorius, Nature 2014, 510, 485-
496.
[11] M. Noack, R. Göttlich, Eur. J. Org. Chem. 2002, 3171–3178.
[12] M. A. Blanchette, W. Choy, J. T. Davis, A. P. Essenfeld, S. Masamune,
W. R. Roush, T. Sakai, Tetrahedron Lett. 1984, 25, 2183-2186.
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10.1002/anie.201705308
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
M. Todd Hovey, Daniel T. Cohen,
Daniel. M. Walden, Paul H-Y. Cheong,
Karl A. Scheidt*
Page No. – Page No.
The first total syntheses of the protoilludanes armillaridin and echinochidins B/D are
reported. Notable features of the unified synthesis include: i. A large-scale
enantioselective NHC-catalyzed annulation to establish the critical cis-cyclopentane
core of the products’ [5.6] fused backbones; ii. A late-stage vanadium(II)/zinc(II)-
promoted reductive pinacol coupling to give an advanced cis-cyclobutane-diol
intermediate; iii. A serendipitous and potentially biomimetic ring-contraction of the
protoilludane skeleton to give the marasmane core, which was verified by total
synthesis of the related marasmane natural product isovelleral.
A Carbene Catalysis Strategy for the
Synthesis of Protoilludane Natural
Products
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