Total Synthesis of (±)-Phomoidride D

Article abstract of DOI:10.1002/anie.201712369

Described herein is a synthetic strategy for the total synthesis of (±)-phomoidride D. This highly efficient and stereoselective approach provides rapid assembly of the carbocyclic core by way of a tandem phenolic oxidation/intramolecular Diels–Alder cycloaddition. A subsequent SmI₂-mediated cyclization cascade delivers an isotwistane intermediate poised for a Wharton fragmentation that unveils the requisite bicyclo[4.3.1]decene skeleton and sets the stage for synthesis completion.

Full text of DOI:10.1002/anie.201712369

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Accepted Article
Title: Total Synthesis of (±)-Phomoidride D
Authors: Joyce C. Leung, Aaron A. Bedermann, Jón T. Njardarson,
David A. Spiegel, Graham K. Murphy, Naoto Hama, Barry M.
Twenter, Ping Dong, Tatsuya Shirahata, Ivar M. McDonald,
Munenori Inoue, Nobuaki Taniguchi, Travis C. McMahon,
Christopher M. Schneider, Nancy Tao, Brian M. Stoltz, and
John Wood
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201712369
Angew. Chem. 10.1002/ange.201712369
Link to VoR: http://dx.doi.org/10.1002/anie.201712369
http://dx.doi.org/10.1002/ange.201712369

Angewandte Chemie International Edition
10.1002/anie.201712369
COMMUNICATION
Total Synthesis of (±)-Phomoidride D
Joyce C. Leung, Aaron A. Bedermann, Jón T. Njardarson, David A. Spiegel, Graham K. Murphy, Naoto
Hama, Barry M. Twenter, Ping Dong, Tatsuya Shirahata, Ivar M. McDonald, Munenori Inoue, Nobuaki
Taniguchi, Travis C. McMahon, Christopher M. Schneider, Nancy Tao, Brian M. Stoltz, and John L.
Wood*
Dedicated to Professor Amos B. Smith, III in appreciation of his mentorship.
Abstract: Described herein is a synthetic strategy for the total
synthesis of phomoidride D. This highly efficient and stereoselective
approach provides rapid assembly of the carbocyclic core by way of
architecture inherent to the phomoidrides has served as the
primary inspiration to what has proven to be a variety of
2, 3
markedly creative approaches,
and four completed total
4
a tandem phenolic oxidation/intramolecular Diels-Alder cycloaddition. syntheses. Studies toward these targets also led to discovery
subsequent SmI mediated cyclization cascade delivers an of two other congeners, phomoidrides C and D (3 and 4,
A
2
4
f,
5
isotwistane intermediate poised for a Wharton fragmentation that
unveils the requisite bicyclo[4.3.1]decene skeleton and sets the
stage for synthesis completion.
respectively, Figure 1),
which differ in the relative
stereochemistry at C7. While previous synthetic efforts have
been primarily directed toward the densely functionalized
carbocyclic phomoidride core, biosynthetic work has focused on
6
biogenesis and congener interconversion. Herein we describe
Since the isolation and structural elucidation of the two fungal
a novel synthetic strategy that employs two cascade sequences
secondary metabolites, phomoidride A (1, CP-225,917) and
7
en route to a successful synthesis of (±)-phomoidride D (4).
phomoidride B (2, CP-263, 114) (Figure 1), by researchers at
1
Pfizer,
numerous groups have devoted efforts toward
As illustrated retrosynthetically in Scheme 1, our plan for
accessing 4 called for late stage introduction of the maleic
anhydride moiety, an endgame akin to those reported by
developing new synthetic strategies to construct these natural
2
products.
While the cholesterol-lowering and anticancer
properties displayed by 1 and 2 certainly motivated synthetic
8
3a
Fukuyama and Shair . In contrast to the latter efforts, our
strategy employs a regioisomeric b-ketoester that derives from
ketone 5, which was seen as arising from Wharton
fragmentation of isotwistane 6. Although increasing structural
complexity in a retrosynthesis appears counterintuitive from a
strategic planning perspective, we envisioned accessing 6 via a
ketyl-initiated cascade cylclization wherein an exomethylene
lactone serves as a lynchpin and bromide as the nucleofuge.
The cyclization cascade precursor (7) would arise from [2.2.2]
efforts, there is little doubt that the unique and complex
O
O
O
O
O
O
O
O
OH
OH
4
O
4
O
O
O
OH
7
OH
7
O
O
O
Phomoidride A (1)
Phomoidride B (2)
CP-225,917
CP-263, 114
O
O
O
O
O
O
O
S
O
O
O
HO
O
4
O
4
O
OH
OH
OH
S
4
O
4
O
O
O
O
O
4
O
O
O
O
O
OH
OH
7
O
O
O
O
O
S
O
O
OEt
7
O
S
O
Phomoidride C (3)
Phomoidride D (4)
(±)-Phomoidride D (4)
5
6
O
ONs
Figure 1. The Phomoidride Family.
Radical
Phenolic
O
4
4
O
OH
Cascade
Cyclization
O
Oxidation
IMDA
O O
O
O
O
Br
OEt
O
O
7
8
NsO
OH
O
*
Dr. J. C. Leung, Dr. A. B. Bedermann, Prof. J. T. Njardarson, Prof.
D. A. Spiegel, Prof. G. K. Murphy, Dr. N. Hama, Dr. B. M. Twenter,
Dr. P. Dong, Prof. T. Shirahata, Dr. I. M. McDonald, Dr. M. Inoue,
Dr. N. Taniguchi, Dr. T. C. McMahon, Dr. C. M. Schneider, Dr. N.
Tao, Prof. B. M. Stoltz, Prof. J. L. Wood
HO
OH
O
O
4
Br
Br
10
O
O
1
2
11
Department of Chemistry and Biochemistry
9
Baylor University
One Bear Place 97348, Waco, Texas 76798, United States
E-mail: john_l_wood@baylor.edu
Scheme 1. Retrosynthetic Analysis of Phomoidride D.
Supporting information for this article is given via a link at the end of
the document
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Angewandte Chemie International Edition
10.1002/anie.201712369
COMMUNICATION
1
) NsCl, Acetone
Br
bicycle 8, the product of a tandem phenolic oxidation/inverse
2 3
1) Cs CO , 16
Acetone, reflux
HO
OH
NsO
O
1
7
electron-demand
intramolecular
Diels-Alder
(IMDA)
OH
HO
O
2
) mCPBA, DCM
then K2CO3, MeOH
OH
19
cycloaddition wherein phenol 9 serves as substrate. This highly
efficient combination of two cascade reactions allows for global
control of relative stereochemistry and introduces all but five
carbons present in phomoidride D. Phenol 9 would arise from
2
)
TMSCl, TMSOTf
DCE, 0 °C to reflux
1
0
(56% yield, 2 steps)
18
(61% yield, 2 steps)
ONs
ONs
NsO
O
O
O
4
e,7d,8,9
1) Pd(PPh3)4, NaBH4
EtOH, rt
the readily available precursors 10, 11 and 12.
O
O
4
4
OH
+
OH
2) i) Pb(OAc) , DCE, reflux
4
O
O
O
O
4
ii) Silica gel, DCM, rt
O
In accord with our synthetic plan, 1,5-dibromopentane (11) was
homologated to 13 by exposure to sodium acetylide followed by
monomethylation of the intermediate diyne (Scheme 2).
Deprotonation of 13 at the terminal alkyne allowed for selective
reduction to enyne 14. Subsequent hydroalumination/iodination
O
O
2
0
(56% yield, 2 steps, 1:3 dr)
8a
8b
Scheme 3. Tandem Phenolic Oxidation/Diels-Alder Cascade.
10
of 14 delivered vinyl iodide 15, which following conversion to
the corresponding cuprate was advanced via conjugate addition
Interestingly, treating the derived mixture with TMS-Cl followed
by the lithium enolate of methyl 3-(dimethylamino)propionate
results in conversion of only the major diastereomer (8b) to the
8
-9
to known α,β-unsaturated ketone 12.
Under the illustrated
11
TMSCl-accelerated conditions, this latter reaction furnishes an
intermediate silyl enol ether which, upon in situ exposure to N-
bromosuccinimide (NBS), delivers 16.
1
4
corresponding aldol product 22 (Scheme 4). Subsequent nosyl
deprotection, Cope elimination, and desilylation provides an
intermediate (24) containing an exo-methylene lactone poised to
serve as a lynchpin in the second cascade reaction. Effecting
this latter event begins by condensing tertiary alcohol 24 with
1
) HC CH
Na/NH3
NaNH2
Br
Br
4
4
2) CH3I, NaNH2
NH3, reflux
Na, NH3
15
dibromide 25 to afford Stork/Ueno bromoacetal 7. Exposure of
7
2
to freshly prepared SmI promotes a smooth 5-exo-trig/5-exo-
11
(36% yield, 2 steps)
13
(93% yield)
14
1
6
tet cyclization cascade that delivers the key isotwistane 6 in
excellent yield. Importantly, this sequential C-C bond forming
event sets stereochemistry at the imbedded quaternary center
and positions the core structure for fragmentation to the
bicyclo[4.3.1]decene. To this end, we first converted 6 to the
1
) t-BuLi, CuI, DMS
TMSCl, THF, -78 °C
O
DIBAL-H
I2, THF
I
4
O
4
Br
16
(66% yield)
15
12
2
) NBS, THF, 0 °C
(82% yield)
Scheme 2. Synthesis of α-bromoketone 16.
ONs
N
1) TMSCl, Et3N
2 3
1) PhSH, Cs CO
DCM, rt
MeCN, rt
8
a/8b
4
CO2Me
OTMS
2
) LDA
Et2O, -40 °C
2 3
2) m-CPBA, Al O
DCM, 0 °C to rt
OH
O
O
2
Me N
Having developed an efficient five-step sequence to α-
bromoketone 16, we next focused on the aromatic coupling
partner. It is worth noting that a considerable number of
experiments over many years indicated that the planned IMDA
would likely be successful if the diene component were
sufficiently electron poor. In efforts to satisfy this electronic
requirement the o-nitrobenzenesulfonyl (nosyl) moiety was
discovered to be sufficiently electron withdrawing and stable to
subsequent synthetic steps. Thus, as illustrated in Scheme 3,
commercially available 1,2-dihydroxybenzaldehyde (10) was
sequentially nosylated, allylated, and exposed to Dakin oxidation
conditions to furnish 18. Alkylation of 18 with 16 furnished an
intermediate ketone that was protected under modified Noyori
CO
2
Me
(60% yield, 2 steps)
2
1
O
Only Observed
Aldol Product
22
Br
Br
OEt 25
O
O
TBAF, AcOH
THF, 0 °C to rt
N,N-dimethylaniline
CO2Me
OTMS
OH
4
4
O
O
DCM, rt
O
O
O OH
O
(
81% yield)
O
O
2
3
24
1) Ac
2 4 2
O, Mg(ClO )
O
HO
DCM
2) 1,3-propanedithiol,
BF •OEt , DCM, 0 °C
SmI2
3
2
4
O
4
O
O
O
O
THF, rt
3) MsCl, Et
DCM
3
N, DMAP
O O
O
O
O
OEt
Br (60% yield, 2 steps)
OEt
(60% yield, 3 steps)
O
7
O
6
AcO
S
12
O
S
O
S
S
conditions. Exposure of the derived acetal (20) to palladium-
mediated allyl deprotection followed by a Pb(OAc) induced
S
S
4
4
O
OMs
O
KOH (1.0 M)
4
O
4
O
O
O
+
O
S
OH
tandem aryl oxidation cycloaddition sequence, provided the α-
THF/MeOH
OH
O
S
(
81% yield)
S
hydroxy ketones 8a and 8b as an inseparable 1:3 mixture of
S
S
S
13
2
6
diastereomers, respectively.
2
7
5
Structure Established
by X-Ray Analysis
3
NsCl, Et N, DCM, rt
(67% yield)
Scheme 4. Synthesis of the [4.3.1]-Bicyclic Core via Radical Cyclization
Cascade and a Wharton Fragmentation.
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Angewandte Chemie International Edition
10.1002/anie.201712369
COMMUNICATION
corresponding acetate and then unveiled the latent tertiary
alcohol
via
transacetalization
with
1,3-propanedithiol.
Introduction of the requisite nucleofuge was accomplished via
mesylation of the derived alcohol to provide fragmentation
substrate 26. To our delight, exposure of 26 to KOH in a
THF/MeOH solvent mixture, resulted in Wharton fragmentation
and installation of the bridgehead olefin to furnish 5.
Unsurprisingly, the conditions required for fragmentation also
resulted in varying amounts of a diol (27) derived from ring
opening of the spiroacetal, an unwanted side-reaction that could
be reversed by treating the reaction mixture with nosyl chloride
and triethylamine. The illustrated stereochemical outcome of the
two cascade sequences was firmly established via single crystal
X-ray analysis.
O
O
O
S
S
O
O
O
1) MeI, CaCO3
0% MeCN aq.
O
OH
8
4
4
O
O
O
O
2
) NaClO2, NaH2PO4•H2O
-Me-2-butene
t-BuOH/THF/H2O (3:1:1)
O
S
O
O
2
S
(65% yield, 2 steps)
32
Phomoidride D (4)
Scheme 6. Completion of the Phomoidride D Total Synthesis.
In conclusion, a total synthesis of phomoidride D has been
achieved by employing a novel strategy that requires 26-steps in
its longest linear sequence. From the outset, the primary
motivation for pursuing a synthesis of this intriguing molecule
was the challenge of developing a non-obvious yet efficient
approach, an endeavor that invariably advances the forefront of
strategies and tactics in the science of synthesis.
With ready access to the bicyclic carbon framework, we turned
attention to constructing the maleic anhydride moiety and began
exploring conditions for the regio- and chemoselective acylation
of 5. After some experimentation, we were gratified to discover
17
2
that Mander’s reagent (28), employed with Et O as solvent
under thermodynamic deprotonation conditions, not only
minimized O-acylation but led to predominately the desired
regioisomer 29 as a mixture of keto-enol tautomers, favoring the
18
latter. Subsequent transformation of 29 to the corresponding
19
enol triflate 31 using Comins’ reagent (30) enabled maleic Acknowledgements
anhydride installation via a palladium mediated carbonylation
(
Scheme 5). At this point, all that was required to complete
The authors gratefully acknowledge support of this work from
Bristol-Myers Squibb, Eli Lilly, Glaxo-Wellcome, Yamanouchi
phomoidride D was deprotection of 32 followed by oxidation of
the derived aldehyde.
(
now Astellas), AstraZeneca, and Amgen through their faculty
award programs and the Camille and Henry Dreyfus Foundation
for a Teacher Scholar Award to J.W. J.T.N. thanks the Helgu
and Jónsdóttur and Sigurliða Kristjánsson Memorial Foundation,
G.K.M thanks the NSERC of Canada, T.S. thanks Prof. Satoshi
Ōmura and the Kitasato Institute, and N.T. thanks Yamanouchi
(now Astellas). The authors thank Prof. Kevin Klausmeyer and
Ms. Sam Yruegas for obtaining and analyzing X-ray
crystallographic data. We also gratefully acknowledge financial
support from Baylor University, the Welch Foundation (Chair,
AA-006), and the Cancer Prevention and Research Institute of
Texas (CPRIT, R1309).
O
S
S
HO
S
S
LiHMDS, HMPA
O
MeO
4
2
C
NaH
NC OMe
28
THF, 0 °C to rt
4
O
O
O
O
O
S
Et2O, -40 °C to rt
O
S
Cl
(60% yield)
N
30
NTf
2
S
S
29
5
(73% yield)
O
TfO
C
S
S
O
S
2 3
Pd(OAc) , P(2-furyl)
MeO
4
2
2
i-Pr NEt, H
2
O
O
S
O
O
4
CO, DMF, 90 °C
73% yield)
O
O
O
S
(
O
S
S
S
3
1
32
Keywords: Phomoidride • Synthesis • Cascade • Diels-Alder •
Scheme 5. Preparation of the Maleic Anhydride via Palladium-Mediated
Aryl-Oxidation
Carbonylation.
[
1]
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In the latter events, numerous methods to remove the dithiane
moieties, including both alkylation and oxidation processes,
were attempted but often led to the formation of complex
mixtures instead of the desired keto-aldehyde. Eventually, we
found that exposing 32 to excess iodomethane (80 equiv) in the
[2]
[3]
[4]
presence of calcium carbonate (CaCO
conversion to an intermediate keto-aldehyde which, upon
Pinnick oxidation using sodium chlorite (NaClO ), sodium
dihydrogenphosphate monohydrate (NaH PO •H O) as buffer,
3
) resulted in clean
2
1
774; Angew. Chem. Int. Ed. 1999, 38, 1669; c) K. C. Nicolaou, P. S.
2
4
2
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and 2-methyl-2-butene as hypochlorous acid scavenger,
furnished phomoidride D (4) in excellent yield (Scheme 6).
1
829; e) N. Waizumi, T. Itoh, T. Fukuyama, T. J. Am. Chem. Soc. 2000,
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Angewandte Chemie International Edition
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COMMUNICATION
1
1
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[13]
[14]
A brief discussion of this diastereoselective IMDA is included in the
supporting information.
Compound 8a appears to undergo denosylation under these conditions
and thus no attempts were made to recover this material.
[
[
5]
6]
P. Spencer, F. Agnelli, G. A. Sulikowski, Org. Lett. 2001, 3, 1443.
R. Fujii, Y. Matsu, A. Minami, S. Nagamine, I. Takeuchi, K. Gomi, H.
Oikawa, Org. Lett. 2015, 17, 5658.
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strategy, see: a) J. T. Njardarson, J. L. Wood, Org. Lett. 2001, 3, 2431;
b) J. T. Njardarson, I. M. McDonald, D. A. Spiegel, M. Inoue, J. L.
Wood, Org. Lett. 2001, 3, 2435; c) I. Drutu, J. T. Njardarson, J. L.
Wood, Org. Lett. 2002, 4, 493; d) G. K. Murphy, T. Shirahata, N. Hama,
A. Bedermann, P. Dong, T. C. McMahon, B. M. Twenter, D. A. Spiegel,
I. M. McDonald, N. Taniguchi, M. Inoue, J. L. Wood, J. Org. Chem.
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cascade.
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R. Crabtree, W. L. A. Chu, L. N. Mander, Synlett 1990, 3, 169.
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[
7]
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University, Waco, TX 76798. Graduate student theses from the Wood
Group are available for download by navigating to the doctoral student
alumni page at www.johnwoodgroup.com and clicking on the
appropriate image.
2
013, 78, 477.
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COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Dr. J. C. Leung, Dr. A. B. Bedermann,
Prof. J. T. Njardarson, Prof. D. A.
Spiegel, Prof. G. K. Murphy, Dr. N.
Hama, Dr. B. M. Twenter, Dr. P. Dong,
Prof. T. Shirahata, Dr. I. M. McDonald,
Dr. M. Inoue, Dr. N. Taniguchi, Dr. T. C.
McMahon, Dr. C. M. Schneider, Dr. N.
Tao, Prof. B. M. Stoltz, Prof. J. L. Wood*
Text for Table of Contents
Page No. – Page No.
Total Synthesis of (±)-Phomoidride D
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