Enantioselective Synthesis of (?)-Halenaquinone

Article abstract of DOI:10.1002/anie.201805370

The efficient, 12–14 step (LLS) total synthesis of (?)-halenaquinone has been achieved. Key steps in the synthetic sequence include: (a) proline sulfonamide-catalyzed, Yamada–Otani reaction to establish the C6 all-carbon quaternary stereocenter, (b) multi

Full text of DOI:10.1002/anie.201805370

Angewandte
Communications
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International Edition: DOI: 10.1002/anie.201805370
German Edition: DOI: 10.1002/ange.201805370
Organocatalysis
Enantioselective Synthesis of (À)-Halenaquinone
Subir Goswami, Kenichi Harada, Mohamed F. El-Mansy, Rajinikanth Lingampally, and
Rich G. Carter*
Abstract: The efficient, 12–14 step (LLS) total synthesis of
(À)-halenaquinone has been achieved. Key steps in the
synthetic sequence include: (a) proline sulfonamide-catalyzed,
Yamada–Otani reaction to establish the C6 all-carbon quater-
nary stereocenter, (b) multiple, novel palladium-mediated
oxidative cyclizations to introduce the furan moiety, and
(c) oxidative Bergman cyclization to form the final quinone
ring.
related members of this family have been subsequently
reported.[10] This pentacyclic natural product has attracted
considerable synthetic attention[11] including total syntheses
by Harada,[3a] Shibasaki,[3b–c] Rodrigo,[3d] and Trauner.[3e] Two
of the major synthetic challenges present within halenaqui-
none (1) are the construction of the C6 all-carbon quaternary
stereocenter and the all-fused tricyclic ABC core with
a reactive furan ring. Our laboratory has recently developed
a proline sulfonamide-based method for the enantioselective
construction of all-carbon quaternary stereocenters embed-
ded within functionalized cyclohexenone ring systems.[12]
Herein, we disclose the application of this proline sulfona-
mide technology to a scalable, enantioselective total synthesis
of (À)-halenaquinone (1).
Steroidal furans represent an important class of natural
products due to their combination of intriguing chemical
structure and potent biological activity (Figure 1).[1] Central
Our initial retrosynthetic strategy for the synthesis of 1 is
shown below (Scheme 1). We envisioned a late-stage, regio-
selective Friedel–Crafts acylation to construct the C ring. The
furan moiety could arise from a palladium-catalyzed, Wacker-
type cyclization. Diol 5 should be accessible from the
cyclohexenone 6, which would in turn be available through
our proline-sulfonamide catalyzed protocol[12] using known
aldehyde 7[13] and enone 8.[14]
Figure 1. Select steroidal furan natural products.
to their reactivity is the presence of a naphtha[1,8b,c]furan core,
which has been attributed to impart much of the biological
activity due to the presumed strain present in the ring
system[1] and the pendant electron withdrawing groups. Three
prototypical members of this family are (+)-halenaquinone
(1),[2,3] viridin (2),[4–6] and wortmannin (3).[7–9] Continued
interest in this family of natural products can be seen in the
recent syntheses of viridin and wortmannin.[6,9]
(+)-Halenaquinone (1) was isolated by Scheuer and
Clardy in 1983[2a] from the marine sponge Xestospongia
exigua and showed antibiotic activity against both Staph-
ylococcus aureus and Bacillus subtilis. Multiple structurally
[*] S. Goswami, Prof. Dr. K. Harada, Prof. Dr. M. F. El-Mansy,
Dr. R. Lingampally, Prof. Dr. R. G. Carter
Department of Chemistry, Oregon State University
Corvallis, OR 97331 (USA)
Scheme 1. Retrosynthetic analysis.
E-mail: rich.carter@oregonstate.edu
Prof. Dr. K. Harada
Faculty of Pharmaceutical Sciences, Tokushima Bunri University
Tokushima (Japan)
Enantioselective synthesis of the key cyclohexenone ring
system is shown in Scheme 2. Starting from the enone 8 and
aldehyde 7, proline sulfonamide-catalyzed Yamada–Otani
reaction using commercially available (R)-Hua Cat 9[15]
provided the desired cyclohexenone 6 in excellent stereose-
lectivity and chemical yield (74% yield, > 20:1 dr, 93% ee).
Oxidation of the resultant sulfide 6 using m-CPBA cleanly
provided the corresponding sulfoxide. Next, syn-elimination
of the sulfoxide was best accomplished using microwave
Prof. Dr. M. F. El-Mansy
Department of Organometallic and Organometalloid Chemistry
National Research Center
Cairo (Egypt)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201805370.
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further increased by use of Pd(OAc)2 (Entry c). This trans-
formation likely proceeds via Wacker-type addition of the C1
alcohol across the C8,9 alkene followed by dehydration,
palladation, and oxidation at C9 to ultimately produce
aldehyde 14.[18]
Preliminary exploration into C ring formation via a Frie-
del–Crafts acylation is shown in Scheme 3. Pinnick oxidation
of the aldehyde to the corresponding carboxylic acid was
Scheme 2. Synthesis of furan precursor.
heating (1408C) in p-xylene. Use of more polar aprotic
solvents (e.g., DMSO) led to inferior chemical yields.
Methylenation at C1 using conditions developed by Connell
and co-workers[16] smoothly provided the exo-cyclic enone 12.
We had initially hypothesized that dihydroxylation of the
triene 12 would proceed on the C8-C9 monosubstituted
alkene. Instead, we observed clean dihydroxylation of the C1-
C2 exo-cyclic alkene to provide the diol 5 as a single
stereoisomer, which was established by X-ray crystallogra-
phy.[17] Oxidation of the C8,9 alkene is likely disfavored due to
the considerable steric bulk imparted by the neighboring all-
carbon quaternary stereocenter at C6.
Scheme 3. First generation Friedel–Crafts acylation approach to access
the pentacyclic core.
With key diol in hand, we next explored the construction
of the furan A ring (Table 1). Treatment of the diol under
Wacker-type conditions (Entry a) provided the furan 13 in
modest yield. Interestingly, addition of sodium acetate
(10 equiv.) induced formation of the furanyl aldehyde 14
(Entry b). This unexpected product was fortuitous as oxida-
tion at C9 is essential for our endgame strategy. We are
unaware of a related palladium-mediated process that has
been reported previously. The yield for aldehyde 14 can be
accomplished under standard conditions. Subsequent conver-
sion to corresponding acid chloride 16 was best performed
using SOCl2. 2-Susbsituted naphthalenes are typically
expected to react preferentially in the a-position.[19,20] Not
surprisingly, Friedel–Crafts acylation of compound 17 pro-
vided the undesired regioisomer as the major product in 45%
yield. We hypothesized that electronic modifications to the
naphthalene ring, coupled with steric requirements of com-
pound 16, might reverse that inherent selectivity to favor the
g-position. Our hypothesis was supported by preliminary
DFT calculations of a model naphthalene ring system.[21] The
selective oxidation of the naphthalene 14 to its corresponding
naphthylquinone moiety (2:1 regioisomeric ratio) followed by
a one-pot reduction/acylation provided 18 in an unoptimized,
15% yield (over 2 steps). Unfortunately, subsequent acylation
to form the crucial C8,9 bond proved unsuccessful giving
complex mixtures. Based on these results, it became clear that
the quinone had to be installed after formation of the ABCD
ring system.
Table 1: Optimization of palladium-catalyzed furanyl aldehyde forma-
tion.
Entry Conditions
% yield (13) % yield (14)
a
b
c
PdCl2 (1 equiv.)
PdCl2 (1 equiv.), NaOAc (10 equiv.) 15
Pd(OAc)2 (1 equiv.)
48
0
32
65
Given our setback with the endgame using the naphthyl
moiety, we identified that a 3,4-dibromophenyl derivative
0
2
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could serve as our naphthaquinone precursor. This approach
would necessitate a late-stage use of an oxidative Bergman
cyclization involving the formation of a diradical intermediate
to incorporate the final E ring. The Bergman cyclization was
discovered in the late 1960s by exploring the reactivity of
enediynes.[22] Interest in this area dramatically accelerated
with the discovery of the enediyne series of natural products,
which contain this highly unusual functionality and their
biological activity was directly linked to the use of this radical
process to cleave DNA.[23] The oxidative Bergman cyclization
was first reported by Grissom and Gunawardena over
20 years ago,[24] but we are unaware of any applications in
total synthesis.
The successful total synthesis of (À)-halenaquinone (1) is
shown in Scheme 4. Starting from methyl ketone 20, olefina-
tion followed by acid-catalyzed deprotection revealed the
benzylic aldehyde 22. Yamada–Otani reaction under
improved conditions provided the desired cyclohexenone in
excellent diastereo- and enantioselectivity. The previously
unreported addition of DMSO (1 equiv.) to this process led to
a dramatic increase in the reaction rate, improvement in
chemical yield and the reduction in the catalyst loading. While
the Yamada–Otani product can be isolated (90.5:9.5 er,
> 20:1 dr), we found that we could telescope the subsequent
sulfide oxidation to the sulfoxide in the same reaction vessel
using H2O2 and HFIP to yield the sulfoxide 23. Thermal
elimination under microwave heating in the presence of
CaCO3 to neutralize the PhSOH produced cleanly the desired
alkene in 57% yield over two steps. Formylation[25] of the
cyclohexenone using LiHMDS and the benztriazole formal-
dehyde surrogate 24 gave the 18 alcohol 25 in excellent yield
and stereoselectivity. For the key furanyl aldehyde synthesis,
we found that oxidative cyclization using catalytic amounts of
Pd(OTFA)2 followed by IBX-mediated benzylic oxidation of
the resulting methyl-furan intermediate cleanly provided
a reproducible process for accessing aldehyde 26.[18] We
have also developed an unprecedented, 1-step oxidation
cascade to synthesize the aldehyde 26 directly from alcohol
25.[18] Use of molecular sieves was essential for this trans-
formation. It should be noted, however, that both the methyl
furan and its corresponding aldehyde 26 proved unstable to
purification (including silica gel, Florisilꢀ, or basic alumina).
Consequently, the aldehyde 26 was carried forward crude.
Pinnick oxidation followed by selective hydrogenation of the
cyclohexenone alkene using Pd/C and H2 in AcOH[26]
produced the product 27. The selective reduction of the
alkene in the presence of the two carbon-bromine bonds was
crucial for the subsequent cyclization. Gram scale (1.96 g)
conversion of alcohol 25 to carboxylic acid 27 was smoothly
accomplished in 48% overall yield over four steps (82%
average yield)—pointing to the scalability of this synthetic
route. Friedel–Crafts acylation proceeded smoothly and with
complete regioselectivity favoring the desired isomer 29. The
regioselectivity of Friedel–Crafts acylations using polyhalo-
genic aromatic systems has not been heavily explored and this
example provides encouraging support for the potential
utility of this process. Next, Sonogashira cross coupling[27]
with TIPS-acetylene followed by TBAF/AcOH deprotec-
tion[3b–c] yielded the critical oxidative Bergman precursor 30.
Scheme 4. Total synthesis of (À)-halenaquinone (1).
Fortunately, thermolysis of this substrate in the presence of
TEMPO resulted in the Bergman cyclization followed by in
situ oxidation to yield (À)-halenaquinone (1). Unfortunately,
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followed by oxidative Bergman cyclization and DMP oxida-
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1
(1). Comparison (including H, 13C NMR)[29] of the synthetic
material with literature values[2] confirmed the identity of the
synthetic material as (À)-1 (observed [a]D: À19.7 as com-
pared to literature (+)-1[2a] [a]D: + 22.2). We attribute the
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In summary, a scalable, enantioselective total synthesis of
(À)-halenaquinone (1) has been reported. Key steps in the
sequence include: (a) construction of B ring via the first
reported total synthesis using an enantioselective Yamada–
Otani reaction, (b) multiple novel, Pd-catalyzed oxidative
cyclizations to construct the furan A ring, (c) a regioselective
Friedel–Crafts acylation to introduce the C ring of the highly
strained tricyclic core and (d) a late-stage oxidative Bergman
cyclization to construct the quinone moiety. This enantiomer
(À)-1 has only been synthesized once previously by Trauner
and co-workers and no biological activity was reported.[3e]
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Acknowledgements
Financial support provided by the National Science Founda-
tion (CHE-1363105 & CHE-1665246) and Oregon State
University (OSU). Tokushima Bunri University is acknowl-
edged for their fellowship for Dr. K. Harada. The authors are
grateful for assistance with mass spectrometry [Prof. Claudia
Maier (OSU) and Jeff Morrꢁ (OSU)], X-ray crystallography
[Lev Zakharov (U of O)] and lyophilization [Sandra Loesgen
(OSU)]. Finally, the authors acknowledge Paul Ha-Yeon
Cheong (OSU), Roger Hanselmann (Akebia Therapeutics),
Xin Li (OSU) and Partha Sarathi Sheet (OSU) for their
helpful discussions.
Conflict of interest
The authors declare no conflict of interest.
Keywords: asymmetric synthesis · organocatalysis · palladium ·
radical reactions · total synthesis
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Manuscript received: May 8, 2018
Version of record online: && &&, &&&&
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Communications
Organocatalysis
Key steps in the sequence of the scalable,
14 step enantioselective total synthesis of
(À)-halenaquinone include: (a) multiple
novel, Pd-mediated oxidative cyclizations
to construct the furan A ring, (b) a regio-
selective Friedel–Crafts acylation to
introduce the C ring of the highly strained
tricyclic core, and (c) a late-stage oxida-
tive Bergman cyclization to construct the
quinone moiety.
S. Goswami, K. Harada, M. F. El-Mansy,
R. Lingampally,
R. G. Carter*
&&&& — &&&&
Enantioselective Synthesis of (À)-
Halenaquinone
6
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