Asymmetric Total Syntheses of 8,9-Seco-ent-kaurane Diterpenoids Enabled by an Electrochemical ODI-[5+2] Cascade

Article abstract of DOI:10.1002/anie.202104410

An electrochemical ODI-[5+2] cascade reaction was developed which enables the rapid assembly of diversely functionalized bicyclo[3.2.1]octadienones from sensitive ethynylphenols. By combining a directed retro-aldol/aldol process, a [2,3]-sigmatropic rearr

Full text of DOI:10.1002/anie.202104410

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Accepted Article
Title: Asymmetric Total Syntheses of 8,9-Seco-ent-kaurane
Diterpenoids Enabled by An Electrochemical ODI-[5+2] Cascade
Authors: Bingnan Wang, Zhaobo Liu, Zhenzhong Tong, Beiling Gao,
and Hanfeng Ding
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Asymmetric Total Syntheses of 8,9-Seco-ent-kaurane
Diterpenoids Enabled by An Electrochemical ODI-[5+2] Cascade
Bingnan Wang,[a] Zhaobo Liu,[a] Zhenzhong Tong,[a] Beiling Gao,[a] and Hanfeng Ding*[a,b]
[a]
B. Wang,† Z. Liu,† Z. Tong, B. Gao, Prof. Dr. H. Ding
Department of Chemistry
Zhejiang University, Hangzhou 310058, China
E-mail: hfding@zju.edu.cn
[b]
Prof. Dr. H. Ding
State Key Laboratory of Elemento-Organic Chemistry
Nankai University, Tianjin 300071, China
These authors contributed equally to this work.
[†]
Supporting information for this article is given via a link at the end of the document.
Abstract: An electrochemical ODI-[5+2] cascade reaction was
developed, which enables the rapid assembly of diversely
functionalized bicyclo[3.2.1]octadienones from sensitive ethynyl-
phenols. Taken together with a directed retro-aldol/aldol process, a
[2,3]-sigmatropic rearrangement and an Al(O-iPr)3-promoted
reductive 1,3-transposition, the asymmetric total syntheses of five 8,9-
seco-ent-kauranoids, namely (−)-shikoccin, (−)-O-methylshikoccin,
(−)-epoxyshikoccin, (+)-O-methylepoxyshikoccin and (+)-rabdo-
hakusin have been achieved in a concise and efficient manner.
Guided by the biosynthetic hypothesis for 2−6, we planned to
establish a streamlined synthetic approach to (−)-shikoccidin (7;
Scheme 1b). Surprisingly, although substantial progress was
made toward the total syntheses of ent-kauranoids,[7-9] their C9-
oxygenated congeners have not been conquered. We conceived
that (−)-7 would be assembled from 8 through a [2,3]-sigmatropic
rearrangement of the corresponding allylic selenoxide[10] to forge
the tertiary alcohol at C9. The latter intermediate would be
accessible from bicyclo[3.2.1]octadienone 9 via a Schenck ene
reaction[11] for the introduction of the enone functionality at C15
and C16. Taking advantage of an oxidative dearomatization-
induced (ODI) [5+2] cycloaddition/pinacol rearrangement
cascade that recently developed by our group for the vinylphenol
variants,[12] the preparation of 9 was envisioned to be traced back
The 8,9-seco-ent-kaurane diterpenoids belong to a small sub-
family that mainly isolated from the genera Rabdosia (Labiatae)
and Croton (Euphorbiaceae).[1] Over the past decades, these
molecules are known for their intriguing biological properties. For
example, (−)-kongensin A (1) was recently discovered to be an
effective HSP90 inhibtor which has potential clinical applications
for necroptosis-related diseases (Scheme 1a).[2] In addition, (−)-
shikoccin (2),[3a] (−)-O-methylshikoccin (3) and their correspoding
epoxides (−)-4 and (+)-5[3b] exhibit potent inhibitory activities
against Hela, KB and FM 3A/B cells, P388 lymphocytic leukemia,
as well as Ehrlich ascites and Walker intramuscular carcinomas.[4]
Structurally,
the
8,9-seco-ent-kauranoids
possess
an
unprecedented
cyclohexyl-fused bicyclo[7.2.1]dodecane
framework decorated with 5−7 stereogenic centers. Although not
fully elucidated, 2−6 were proposed to be biogenetically
originated from (−)-shikoccidin (7) bearing a bicyclo[3.2.1]octane
skeleton (C/D rings) as the same precursor through either a retro-
aldol[3a] or a Grob-type fragmentation[5] process leading to the
cleavage of C8-C9 bond, followed by formation of the uncommon
bridgehead Δ8,14- and Δ7,8-alkene motifs, respectively.
The above distinct profiles rendered 1−6 attractive yet
challenging targets for synthetic studies. However, the only total
synthesis reported to date was by Paquette and coworkers,[6] who
accomplished (−)-O-methylshikoccin (3) and (+)-O-methylepoxy-
shikoccin (5) featuring a well-designed oxy-Cope rearrangement.
Despite their pioneering work, a systematic investigation toward
the total syntheses of 8,9-seco-ent-kauranoids remains highly
desirable, which would not only acquire these molecules in an
efficient manner but also provide more insights into the
biosynthetic origin of their unique skeletons. Herein, we describe
our recent efforts in this field culminating in the concise
asymmetric total syntheses of 2−6 based on an electrochemical
ODI-[5+2] cascade strategy.
Scheme 1. a) Structures and proposed biogenetic pathways of 8,9-seco-ent-
kauranoids 1−6; b) our retrosynthetic plan toward (−)-shikoccidin (7).
1
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directly to a sensitive ethynylphenol 11 through the intermediacy
of cycloadduct 10. By doing so, this strategy would obviate the
of 16a (64% yield, entry 1).[16] The formation of the latter side
product presumably arose from nucleophilic demethylation on the
C2-oxygen atom of phenoxonium ion 17 to generate an
unmasked ortho-benzoquinone 18, followed by intramolecular
Diels−Alder cycloaddition.[17] Therefore, bulky acids were then
employed to delay the demethylation process and modulate
reaction pathways. While 19A and 19B indeed provided 15a
predominantly, a significant decomposition was observed (entries
2 and 3). To further inhibit the generation of 16a and improve the
overall efficiency, we focused on scrutinizing an array of less
acidic nitrophenols (e.g., 19C−F) with weak nucleophilicities.
Eventually, 19F turned out to be superior, delivering 15a in 71%
yield on 0.5 mmol scale (entry 4). Moreover, other solvents such
as DCE led to a diminishing yield (entry 5).
challenges associated with a late-stage construction of the Δ9,11
-
alkene in complex systems. However, we were unaware of its
feasibility due to the potential incompatibility between both
benzylic alcohol and terminal alkyne moieties in 11 with the
established hypervalent iodine-mediated conditions for the ODI-
[5+2] cascade.
Our synthesis commenced with the practical preparation of
ethynylphenol 11 (Scheme 2). Ester 13 was prepared from
commercially available epoxide (−)-12 (98% ee) through a
sequence of Eschenmoser−Tanabe fragmentation and oxidative
esterification in 51% overall yield (Scheme S1). Ensuing photo-
Fries rearrangement[13] and stereoselective ketone reduction
afforded 11 and its C7-epimer in 85% yield (4:1 d.r.) on decagram
scale. To our disappointment, the crucial ODI-[5+2] cascade
reaction of 11 under the standard conditions (PIFA, HFIP, 0 oC)
caused rapid decomposition, probably owing to the acid liability of
the benzylic alcohol moiety.[12a,c] Subsequent survey of various
basic additives revealed that K4P2O7 was the best choice (Table
S2). However, the desired product 9 was obtained in only 16%
yield, impeding further elaboration to the target natural products.
Under the optimized conditions, the substrate scope of the
electrochemical ODI-[5+2] cascade reaction was explored (Figure
1). Among them, ethynylphenols with variable steric and
electronic parameters on the phenyl ring, involving 3-, 4-, and 5-
substituted, were transformed into the corresponding bicyclo-
[3.2.1]octadienones 15b−d and 15f−h with good to excellent
efficiency. In contrast, the strong electron-withdrawing nitro group
exclusively afforded the Diels−Alder adduct 16e. On the other
hand, substrates bearing different substitution on the side chain
were also found compatible, resulting in good yields and excellent
diastereoselectivities (69−74%, >20:1 dr; 15i−k). These
outcomes indicated that the single benzylic stereocenters in
ethynylphenols are critical for guiding fabrication of the
bicyclo[3.2.1]octane rings with desired stereochemistry.
Furthermore, other types of functionalities on the side chain
including conjugated and skipped enynes and internal alkynes are
tolerated as well, furnishing products 15l−p in satisfactory yields.
The electrochemical oxidation showed evident advantages over
the conventional chemical method not only with improved
efficiency and innate scalability (vide infra), but also by avoiding
the use of relatively expensive hypervalent iodine and HFIP.
Table 1. Optimization of the electrochemical ODI-[5+2] cascade reaction.[a]
Entry
1
Additive
AcOH
19A
Solvent
MeCN
MeCN
MeCN
MeCN
DCE
Products (Yield)[b]
15a (13%), 16a (64%)
15a (15%), 16a (<5%)
15a (21%), 16a (14%)
15a (71%), 16a (8%)
15a (50%), 16a (13%)
2
3
19B
4[c]
5[c]
19F
19F
Figure 1. Scope of the electrochemical ODI-[5+2] cascade reaction. Yields in
parenthesis refer to hypervalent iodine oxidation (PIFA, K4P2O7, HFIP, 0 oC).
[a] Reaction conditions: undivided cell, graphite anode, graphite cathode,
constant current = 5 mA, 14a (0.2 mmol), additive (3.0 equiv), nBu4BF4 (0.01
M), solvent (10 mL), rt, 4 h. [b] Isolated yields. [c] 0.5 mmol scale.
Encouraged by these results, the total syntheses of 8,9-seco-
ent-kauranoids 2−6 were then pursued (Scheme 2). Gratifyingly,
under the optimized conditions, the anodic oxidation of 11 could
be readily conducted on a commercial potentiostat equipped with
a carousel assembly to afford >800 mg of 9 every 10 h (65% yield;
for set-up see the Supporting Information), accompanied by an
unexpected tricycle 20 in 9% yield. The formation of the latter was
probably derived from the corresponding unstable Diels−Alder
Inspired by the seminal studies of Yamamura and
Nishiyama,[14] we turned to investigating the ODI-[5+2] cascade
reaction of ethynylphenols under electrochemical conditions for
an alternative solution (Table 1; for a detailed optimization see
Table S1).[15] Initial anodic oxidation of model substrate 14a (CCE:
5 mA, nBu4BF4, MeCN) in an undivided cell in the presence of
acetic acid afforded 15a in 13% yield, along with a large amount
2
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adduct through a photolytic double decarbonylation/aromatization
sequence.[18] Due to failed attempts to access the C14β-alcohol
in the ensuing stereoselective reduction of 9, we planned to
prepare β-hydroxyketone 21 in hopes of inverting the
stereochemistry at C14 via a retro-aldol/aldol transformation (path
a). However, this also proved to be troublesome from two aspects:
1) treating 9 with LiAl(O-tBu)3H followed by aqueous HBr-induced
hydrolytic removal of the MEM group gave triol 21 in 70% yield
together with the non-negligible generation of aldehyde 22
bearing a bannaringaolide skeleton,[19] implying that a vinylogous
retro-aldol process resulting in the fragmentation of C8-C14 bond
(path b) would be competitive under certain conditions; 2)
exposing 21 to pTsOH•H2O led to moderate epimerization
(21/C14-epi-21 1:1.1, 63% combined yield), in which the lack of
steric control is consistent with distant alignment between the
C14α-alcohol oxygen and the axial C20-Me (4.08 Å by X-ray).[16]
To address these problems, we envisaged that the equatorial
hydroxyl group at C7 might be able to direct the aldol cyclization
toward the required stereochemistry via a chelation-controlled
complex 23. Delightfully, upon extensive screening, LiHMDS was
found most effective. After a one-pot regioselective acetylation
and Jones oxidation, 24 was uneventfully obtained in 67%
yield.[20]
DIBAL-H and tBuOK. After transformed into the corresponding
acetonide, a Schenck ene reaction with singlet oxygen proceeded
smoothly to afford 25 in 45% yield over three steps. The one-pot
silylation of the hydroperoxide followed by iodination at C12 gave
a labile iodide, which should then undergo an immediate
selenation.[21] The following dehydration was performed at −78 oC
to avoid the premature reduction of the fragile peroxide anion by
the existing selenide, producing enone 8 in 51% yield over two
steps. At this point, the exo-Δ16,17-double bond needed to be
masked prior to modification of the more inert Δ11,12-alkene. In this
regard, 8 was converted to a thioether (3.7:1 dr at C16), which on
treatment with mCPBA to trigger both [2,3]-sigmatropic
rearrangement and sulfone formation, providing 29 in 64% yield.
An elevated temperature was required to prevent the undesired
[1,2]-sigmatropic rearrangement. Catalytic hydrogenation of the
Δ11,12-alkene was realized in the presence of Pd/C and H2 (400
psi). Direct subjection of the resulting mixture to pTsOH•H2O at
room temperature for 30 min to release the exo-Δ16,17-alkene
furnished (−)-shikoccidin (7) in 87% yield. On the other hand, by
performing the reaction at 35 oC for 3 h to facilitate an additional
retro-aldol/elimination process, (−)-shikoccin (2) was obtained
exclusively in 80% yield. Further advancement of (−)-2 through
methylation and stereocontrolled epoxidation granted efficient
access to (−)-O-methylshikoccin (3), (−)-epoxy-shikoccin (4) and
(+)-O-methylepoxyshikoccin (5), respectively.
With sufficient quantities of 24 in hand, the stereochemistry at
C7 and C12 was secured by global reduction in the presence of
Scheme 2. Asymmetric total syntheses of 8,9-seco-ent-kauranoids 2−6. AIBN = 2,2′-azobis(2-methylpropionitrile), DIBAL-H = diisobutylaluminium hydride, 4-DMAP
= 4-(dimethylamino)pyridine, HFIP = 1,1,1,3,3,3-hexafluoro-2-propanol, LiHMDS = lithium bis(trimethylsilyl)amide, mCPBA = 3-chloroperbenzoic acid, MEM = 2-
methoxyethoxymethyl, Ms = methanesulfonyl, NBS = N-bromosuccinimide, PIFA = phenyliodine(III) bis(trifluoroacetate), PPTS = pyridinium 4-toluenesulfonate,
TBAF = tetrabutylammonium fluoride, TES = triethylsilyl, TFAA = trifluoroacetic anhydride, UHP = urea-hydrogen peroxide complex.
3
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[6]
[7]
a) L. A. Paquette, D. Backhaus, R. Braun, J. Am. Chem. Soc. 1996, 118,
11990; b) L. A. Paquette, D. Backhaus, R. Braun, T. L. Underiner, K.
Fuchs, J. Am. Chem. Soc. 1997, 119, 9662.
Having secured (−)-2, its conversion to (+)-rabdohakusin (6)
was also investigated. The congested thionoester was prepared
in the presence of PhOC(S)Cl, Ag2O and KI, which underwent a
radical deoxygenation to cast 30 in a trace amount. However, the
Δ8,14-alkene was found reluctant to isomerize under either acidic,
basic or thermally induced conditions. Close inspection of the
structures between (−)-2 and (+)-6 led us to assume that the latter
skeleton might be forged from the former through a reductive 1,3-
transposition. While the treatment of corresponding allylic acetate
with various reductants [Cu(OAc)2/PMHS,[22a] NaBH4, LiBEt3H,
TiCl3/LiAlH4,[22b] etc.] caused complete decomposition, the
sigmatropic rearrangements of allylic diazene[23] or sulfenate[24]
also failed to be executed due to inaccessibility of the precursors.
Finally, we were surprised to find that by subjection of (−)-2 to
Al(O-iPr)3 in refluxing iPrOH, (+)-6 was formed directly in 76%
yield. The reaction presumably proceeded through the chelated
transition state 32 to achieve a regioselective reduction of the
Δ8,14-double bond, which was supported by decreased efficiency
observed for the reduction of (−)-3 under the same conditions.
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In conclusion, we have developed an ODI-[5+2] cascade
reaction of sensitive ethynylphenols under mild electrochemical
conditions, which led to the rapid construction of diversely
functionalized bicyclo[3.2.1]octadienones. This crucial step,
combined with a directed retro-aldol/aldol process, a [2,3]-
sigmatropic rearrangement and an Al(O-iPr)3-promoted reductive
1,3-transposition, have facilitated the asymmetric total syntheses
of five 8,9-seco-ent-kauranoids 2−6 in a concise and efficient
manner by traversing through (−)-shikoccidin (7). Among them,
(−)-2, (−)-4, and (+)-6 were accomplished for the first time.
Notably, our synthetic efforts offered new possibilities for the
biosynthetic relationship between the two different types of
skeletons found in 8,9-seco-ent-kauranoids, as exemplified by
(−)-2 and (+)-6. The described methodologies and strategies
would find broad application in the synthesis of other relevant
natural products.
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[12] a) C. He, J. Hu, Y. Wu, H. Ding, J. Am. Chem. Soc. 2017, 139, 6098; b)
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K. Xu, S. Wang, Y. Wu, C. He, H. Ding, J. Am. Chem. Soc. 2020, 142,
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Acknowledgements
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Financial support was provided by the National Natural Science
Foundation of China (21871230, 21622205) and the “National
Young Top-Notch Talent Support Program”.
[14] For a comprehensive review and references therein, see: S. Yamamura,
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Keywords: cascade reactions • electrochemistry • sigmatropic
rearrangement • terpenoids • total synthesis
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4
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[16] CCDC 2070181, 2070182 and 2070183 [16a, rac-20′, rac-21] contain the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre.
[17] A detailed mechanistic investigation was included in the Supporting
Information. For the Diels−Alder cycloaddition of unmasked ortho-
benzoquinones, see: a) V. Nair, R. S. Menon, A. T. Biju, K. G. Abhilash,
Chem. Soc. Rev. 2012, 41, 1050; b) L. Song, G. Zhu, Y. Liu, B. Liu, S.
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[20] The chelation-controlled induction model was further verified by
epimerization of 21′, which bears an ent-phyllocladane skeleton.
[21] The leaving group at C12 was critical to the success of selenation. By
comparison, the corresponding chloride 26 underwent a vinylogous Grob
fragmentation to cleave the C8-C15 bond and delivered 28 in 52% yield.
[22] a) R. T. H. Linstadt, C. A. Peterson, C. I. Jette, Z. V. Boskovic, B. H.
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[23] A. G. Myers, B. Zheng, Tetrahedron Lett. 1996, 37, 484.
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10.1002/anie.202104410
Angewandte Chemie International Edition
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An efficient ODI-[5+2] cascade reaction of sensitive ethynylphenols was achieved under mild electrochemical conditions, which led to
the rapid construction of a series of bicyclo[3.2.1]octadienone skeletons. By incorporation of a directed retro-aldol/aldol process, a [2,3]-
sigmatropic rearrangement and an Al(O-iPr)3-promoted reductive 1,3-transposition, the asymmetric total syntheses of five 8,9-seco-
ent-kauranoids have been accomplished.
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