Total Syntheses of Rhodomolleins XX and XXII: A Reductive Epoxide-Opening/Beckwith–Dowd Approach

Article abstract of DOI:10.1002/anie.201903349

A new Ti^III-mediated reductive epoxide-opening/ Beckwith–Dowd rearrangement process efficiently assembles the bicyclo[3.2.1]octane framework of highly oxidized grayanane diterpenoids. By incorporation of a Cu(tbs)₂-catalyzed (tbs=N-tert-butylsalicylaldiminato) intramolecular cyclopropanation, a diastereoselective oxidative dearomatization-induced Diels–Alder cycloaddition and a MeReO₃-catalyzed Rubottom oxidation, this approach has enabled the first total syntheses of rhodomolleins XX and XXII in 23 and 22 steps, respectively.

Full text of DOI:10.1002/anie.201903349

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Accepted Article
Title: Total Syntheses of Rhodomolleins XX and XXII: A Reductive
Epoxide-Opening/Beckwith-Dowd Approach
Authors: Kuan Yu, Zhen-Ning Yang, Chun-Hui Liu, Shao-Qi Wu, Xin
Hong, Xiao-Li Zhao, and Hanfeng Ding
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Total Syntheses of Rhodomolleins XX and XXII: A Reductive
Epoxide-Opening/Beckwith–Dowd Approach
Kuan Yu, Zhen-Ning Yang, Chun-Hui Liu, Shao-Qi Wu, Xin Hong, Xiao-Li Zhao, and Hanfeng Ding*
Abstract:
A
new Ti(III)-mediated reductive epoxide-opening/
santonin rearrangement (>39 steps, <0.0005% overall yield).[3a,b]
In 1994, Shirahama and coworkers achieved an enantioselective
total synthesis of (‒)-grayanotoxin III (2) in 38 steps and 0.05%
Beckwith–Dowd rearrangement process efficiently assembles the
bicyclo[3.2.1]octane framework of highly oxidized grayanane
diterpenoids. By incorporation of a Cu(tbs)
cyclopropanation, a diastereoselective ODI-Diels–Alder cycloaddition
and a MeReO -catalyzed Rubottom oxidation, this apporach has
2
-catalyzed intramolecular
2
overall yield, featuring a series of SmI -mediated stereoselective
cyclizations.[3c] Despite these impressive developments, more
efficient and general strategies for assembling grayanoids remain
in urgent demand to accelerate the process of their syntheses and
biological investigation.
3
enabled the first total syntheses of rhodomolleins XX and XXII in 23
and 22 steps, respectively.
On the other hand, apart from few examples of cascade
strategies,[4] the construction of the [3.2.1] bicyclic skeletons in
total syntheses of tetracyclic diterpenoids required multistep
reaction sequences,[5] which inevitably maximized functional
group manipulations and resulted in lengthier synthetic routes.
Prompted by this problem, we sought to develop versatile
protocols by establishing the [3.2.1] bicyclic motif in a more
straightforward manner. Recently, inspired by the oxidative
dearomatization-induced (ODI) cycloaddition/ring distortion
approaches toward the syntheses of diterpenoid alkaloids, we
reported an ODI-[5+2] cycloaddition/pinacol-type 1,2-acyl
migration cascade reaction, leading to the concise total syntheses
of several highly oxidized ent-kauranoids.[7] In continuation of our
interest in this area, we herein describe the first total syntheses of
rhodomolleins XX (5) and XXII (6), two congeners of the
grayanoid family that isolated from Rhododendron molle G. Don
(Ericaceae),[8] through a new titanium(III)-mediated reductive
epoxide-opening/Beckwith–Dowd rearrangement process.
The Ericaceae species have a long history of being used in
traditional herbal folk medicines to treat a variety of diseases due
to their curative ability. To date, over 150 grayanane diterpenoids
have been isolated from this genus.[1] Besides high toxicities,
grayanoids are well known for their broad range of bioactivities,
such as sodium channel modulating, analgesic, sedative,
insecticidal, and antifeedant activities. The structures of the vast
majority of grayanoids feature an unusual [5,7,6,5] tetracyclic
carbon framework decorated with 7–10 stereogenic centers, as
well as the dense arrangement of hydroxy groups (e.g., 1‒6,
Figure 1). Biosynthetically, these molecules are assumed to
originate from a common ent-kaurane skeleton, which contains a
characteristic bicyclo[3.2.1]octane (C/D) ring system.[2] The above
distinct features rendered grayanoids attractive targets for
[
6]
[3]
synthetic studies. However, only two total syntheses have been
disclosed, presumably ascribed to the challenges in construction
of their highly functionalized tetracyclic skeletons. More than forty
years ago, the group of Matsumoto reported a relay total
synthesis of grayanotoxin II (1) based on a key biomimetic photo-
Our retrosynthetic analysis toward rhodomolleins XX (5) and
Figure 1. Structures of grayanane diterpenoids 1–6.
[*]
K. Yu, Z.-N. Yang, C.-H. Liu, S.-Q. Wu, Prof. Dr. X. Hong,
Prof. Dr. H. Ding
Department of Chemistry
Zhejiang University, Hangzhou 310058 (China)
E-mail: hfding@zju.edu.cn
Prof. Dr. X.-L. Zhao
Shanghai Key Laboratory of Green Chemistry and Chemical
Processes, Department of Chemistry
East China Normal University, Shanghai 200062 (China)
Supporting information for this article is given via a link at the end of
the document.
Scheme 1. Retrosynthetic analysis of rhodomolleins XX (5) and XXII (6).
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XXII (6) is depicted in Scheme 1. Initially, we assumed that the
bicyclo[3.2.1]octane carbon frameworks of 5 and 6 could be built
up from vinylphenol 8 according to our previously developed ODI-
vinyl ether[17] followed by Roskamp homologation of the resultant
aldehyde in the presence of catalytic SnCl and ethyl diazoacetate
2
to give β-keto ester 16 in 72% yield over two steps. After being
converted to the corresponding diazo compound, different metal
catalysts were screened for the following intramolecular
cyclopropanation to forge the A ring. Pleasingly, by treatment with
[
5+2] cascade (path a).[7] However, attempts to access the
cycloheptane-fused cycloadduct 7 were met with disappointing
results (for details, see the Supporting Information). Based on the
elegant works of Baran[9a] and Mori,[9b] an alternative strategy
relying on the regioselective fragmentation of an excessively
functionalized intermediate[10] was proposed (path b). Therefore,
we rationalized that both 5 and 6 could be synthesized from
tetracycle 7 through a late-stage core modification. For the
construction of 9, an unprecedented ring distortion cascade was
devised. Accordingly, a titanium(III)-mediated reductive ring-
opening of [2.2.2] bicyclic keto-epoxide 12 generates 11,[11] which
would undergo successive Beckwith–Dowd rearrangement[12]
through the intermediacy of cyclopropoxy radical 10 to forge the
desired bicyclo[3.2.1]octane ring of the molecules. The realization
of this cascade would require a preferential cleavage of the C12-
C16 bond over the C13-C16 bond in 10. Although control of such
a fragmentation was estimated to be challenging since these two
bonds appear to be nearly indistinguishable,[13] we envisioned that
the β-titanoxy group in 11 might be capable of retarding the rate
of radical quenching at C-13, thus allowing for reversible
formation of the exocyclic β-keto radical leading to 9.[14] Finally,
the preparation of 12 could be traced back to vinylphenol 13 by
Cu(tbs)
2
(17, 5 mol%),[18] the expected 5,3-fused bicycle 18 was
generated in 87% yield over two steps. To our disappointment,
initial attempts on the direct introduction of the hydroxy group at
C6 through oxy-homo-Michael additions of various oxygen
nucleophiles[19] to 18 proved futile. As an alternative, the ring-
opening of the cyclopropane accompanied by acetal protection of
the ketone at C2 was achieved upon exposure to TMSOTf/
(CH
2
OTMS)
2
, affording 19 in 70% yield. A substrate-controlled
6,7
epoxidation of the Δ olefin exclusively gave the β-isomer, which
underwent further hydrogenative ring-opening of the epoxide at
benzylic position to provide 20 in 65% yield over two steps.
Subsequently, a tandem β-keto phosphonate formation/Horner–
Wadsworth–Emmons olefination took place smoothly in the
presence of excess LDA and afforded enone 21 in 82% yield.
Desilylation of 21 produced intermediate vinylphenol 13, which
was then engaged in an intramolecular ODI-Diels–Alder
cycloaddition upon exposure to PhI(OAc)
a 2.8:1 mixture of 22a and 22b (ORTEP drawing, Scheme 2) in
95% combined yield.[21,22] After SmI
demethoxylation of 22a to gave 23, the epoxidation of the Δ1
olefin proceeded from the convex face of the bicyclo[2.2.2]octane
framework and provided 12 as a single diastereomer in 83% yield
over two steps.
2
in methanol, delivering
[20]
2
-mediated reductive
3,14
taking advantage of
cycloaddition.[15]
a
diastereoselective ODI-Diels–Alder
Our synthesis commenced with construction of the keto-
epoxide 12 (Scheme 2). The 1,2-addition of Grignard reagent 14,
prepared in four steps from commercially available 3-hydroxy-2-
methoxybenzaldehyde (for details, see the Supporting
Information),[ to 3-methylbut-2-enal afforded alcohol 15 in 88%
yield. The latter underwent a Claisen rearrangement with n-butyl
Having secured 12, we turned our attention to investigating
the proposed reductive epoxide-opening/Beckwith–Dowd
rearrangement reaction (Scheme 3). After extensive optimization,
we were pleased to find that by subjection of 12 to catalytic
16]
Scheme 2. Construction of keto-epoxide 12. DMDO = dimethyldioxirane, LDA= lithium diisopropylamide, NBS = N-bromosuccinimide, TBAF = tetra-n-
butylammonium fluoride, tbs = N-tert-butylsalicylaldiminato, THF = tetrahydrofuran, TiPS = triisopropylsilyl, TMSOTf = trimethylsilyl trifluoromethanesulfonate,Ts =
4-toluenesulfonyl.
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Scheme 3. Late-stage syntheses of rhodomolleins XX (5) and XXII (6). acac = acetylacetonate, collidine = trimethylpyridine, Cp = cyclopentadiene, DCE = 1,2-
dichloroethane, DMAP= N,N’-dimethylaminopyridine. NMO = N-methylmorpholine N-oxide, PPTS = pyridinium 4-toluenesulfonate, Py = pyridine, TBSOTf = tert-
butyldimethylsilyl trifluoromethanesulfonate.
Cp
2
TiCl
2
, Mn and 2,4,6-collidine•HCl in DCE at 50 oC over a
hand, the α-hydroxylation at C3 of 31 proved to be problematic
(Table S1). Although Rubottom oxidation with DMDO provided a
promising diastereoselectivity (2.5:1 at C3), an unsatisfactory
yield (ca. 20%) was observed. However, replacement with other
oxidants such as m-CPBA, Davis’ oxaziridine and Cu/TBHP
caused desilylation of the enol ether, and the dihydroxylation of
31 afforded 32 and its C3-epimer in 81% yield as a 1:4 mixture.
Probably due to steric hindrance around A ring, the attempted
[4+2] cycloaddition between the silyl dienol ether moiety and in
situ generated singlet oxygen from triphenyl phosphite ozonide
(TPPO)[26] led only to the recovery of 31. Fortunately, with the aid
period of 12 h, the desired bicyclo[3.2.1]octane 9 could be formed
in 61% yield on gram scale, accompanied by the generation of 24
in 15% yield.[23] The structure of 9 was verified by X-ray
crystallographic analysis of its corresponding diacetate 25
(
ORTEP drawing, Scheme 3).[20] Of note, the nonpolar solvent
was pivotal to the success of this cascade, and the free alcohol at
C6 of 12 was found to play an important role in regioselective
control of the reductive epoxide-opening step.[24] With suitable
quantities of 9 in hand, we next focused on the late-stage
syntheses of rhodomolleins XX (5) and XXII (6). Regioselective
methylenation of the ketone at C16 was achieved using Petasis
reagent. By following a deacetalization in one pot, enol 27 was
formed in 67% yield (ORTEP drawing, Scheme 3).[20] Surprisingly,
through treatment of 27 with PhSeCl and pyridine for a prolonged
reaction time, a slow but spontaneous elimination of the resultant
selenide was observed to forge the desired Δ1,5 double bond,
providing 28 in 93% yield. The above outcome indicates the
involvement of an exclusive α-facial selenation,[25] which could
also be supported by the fact that addition of extraneous oxidants
3 2 2
of catalytic MeReO , H O
and pyridine,[27] 32 was formed with
excellent d.r. (>20:1). Further deprotection in the presence of
PPTS furnished rhodomollein XX (5) in 64% yield over three steps.
1
13
Synthetic 5 and 6 exhibited H and C NMR spectra identical in
all respects to those reported for the natural products.[8]
To further extend the generality of this reductive epoxide-
opening/Beckwith–Dowd rearrangement process, the regio-
selective fragmentation of cyclopropanol 33, which could be
prepared from 12 in 75% yield following Fernández-Mateos’
(
2 2 4
m-CPBA, H O , NaIO , etc.) to accelerate the elimination through
procedure,[ was also conducted (Scheme 4). On the basis of
seminal works by DePuy, Saegusa and Narasaka,[ it was found
that the cleavage of C13-C16 bond could be significantly inhibited
28]
[29]
selenoxide intermediate led to messy reaction mixtures. As
expected, Mukaiyama hydration of the more reactive Δ15,16 olefin
occurred from the convex face of the bicyclo[3.2.1]octane
skeleton and delivered triol 29 in 65% yield as a single
diastereomer. After tentative protection of the ketone at C2 as a
silyl dienol ether (30), the Grignard addition to the C10-ketone,
which was presumably directed by the pseudo-axial C6-OH, gave
30]
3 3
in the presence of Fe(NO )
and 1,4-cyclohexadiene in DMF,[31]
affording a 5.4:1 mixture of 9 and 24 in 83% yield (cond. a). More
importantly, triol 9’, a viable advanced intermediate enroute to the
C12-oxygenated grayanane diterpenoids of biological importance
(
such as grayanotoxin XI and rhodomollein XXVIII),[32] was
obtained as well in an even higher yield upon treatment of 33 with
catalytic VO(acac)
under oxygen atmosphere (cond. b).[33] The
structures of 33 and 9’ were unambiguously determined by X-ray
31 as the solely detectable isomer. Without isolation, the latter
was further transformed into rhodomollein XXII (6) via an acid-
promoted desilylation in 77% yield over two steps. On the other
3
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crystallographic analysis of their corresponding triacetates 34 and
3
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5]
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[
For selected examples toward the syntheses of diterpenoid alkaloids,
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Scheme 4. Regioselective fragmentation of cyclopropanol 33. CHD
cyclohexadiene, DMF = N,N-dimethylformamide.
=
2
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In summary, we have developed a new titanium(III)-mediated
reductive epoxide-opening/Beckwith–Dowd rearrangement
process, in an either cascade or stepwise fashion for the
construction of functionalized bicyclo[3.2.1]octane core structures
Doering, B. X. Li, G. M. Gallego, T. P. Lebold, R. Sarpong, J. Am. Chem.
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of grayanane diterpenoids. Taken together with a Cu(tbs)
catalyzed intramolecular cyclopropanation, a diastereoselective
ODI-Diels–Alder cycloaddition and MeReO -catalyzed
2
-
a
3
[
7]
8]
Rubottom oxidation, the employment of this efficient approach for
assembling highly oxidized grayanoids is demonstrated by the
first total syntheses of rhodomolleins XX and XXII in 23 and 22
steps, respectively. Moreover, the asymmetric syntheses could
also be realized through the enantioselective preparation of (‒)-
[
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to the total syntheses of other members of grayanoids as well as
other related diterpenoids and alkaloids, and allow further
exploration of their biological properties.
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Acknowledgements
[
[
Financial support from Zhejiang Natural Science Fund for
Distinguished Young Scholars (LR16B020001) and National
Natural Science Foundation of China (21871230, 21622205 for
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Keywords: cyclopropanation • Diels–Alder • radical reactions •
terpenoids • total synthesis
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COMMUNICATION
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[
[
[
22] DFT calculations were performed to support the observed
diastereoselectivity; see the Supporting Information for details.
23] Recycle of 24 was realized by conversion to 23 through a Chugaev
elimination in 73% yield over two steps.
[31] K. I. Booker-Milburn, A. Barker, W. Brailsford, B. Cox, T. E. Mansley,
Tetrahedron 1998, 54, 15321.
[32] a) H. Hikino, T. Ohta, S. Koriyama, Y. Hikino, T. Takemoto, Chem. Pharm.
Bull. 1971, 19, 1289; b) Y. Li, Y.-B. Liu, J.-J. Zhang, Y. Liu, S.-G. Ma, J.
Qu, H.-N. Lv, S.-S. Yu, J. Nat. Prod. 2015, 78, 2887.
24] As a comparison, the corresponding acetate C6-OAc-12 afforded C6-
OAc-9, C6-OAc-24 and 26 in 32%, 9% and 38% yield, respectively.
[
33] a) M. Kirihara, M. Ichinose, S. Takizawa, T. Momose, Chem. Commun.
998, 1691; b) M. Kirihara, H. Kakuda, M. Ichinose, Y. Ochiai, S.
Takizawa, A. Mokuya, K. Okubo, A. Hatanoa, M. Shiro, Tetrahedron
005, 61, 4831.
1
2
[
25] a) M. R. Roberts, R. H. Schlessinger, J. Am. Chem. Soc. 1981, 103, 724;
b) D. Liotta, C. Barnum, R. Puleo, G. Zima, C. Bayer, H. S. Kezar, III., J.
Org. Chem. 1981, 46, 2920.
[34] The optically active (–)-17 was obtained through a diastereoselective
cyclopropanation under chiral bisoxazoline-Cu(I) catalysis (ca. 17:1 d.r.,
93% ee); see the Supporting Information for details.
[26] C. Iwata, Y. Takemoto, A. Nakamura, T. Imanishi, Tetrahedron Lett. 1985,
26, 3227.
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Angewandte Chemie International Edition
10.1002/anie.201903349
COMMUNICATION
COMMUNICATION
K. Yu, Z.-N. Yang, C.-H. Liu, S.-Q. Wu,
X. Hong, X.-L. Zhao, H. Ding*
Page No. – Page No.
Total Syntheses of Rhodomolleins XX
and XXII: A Reductive Epoxide-
Opening/Beckwith–Dowd Approach
A new Ti(III)-mediated reductive epoxide-opening/Beckwith–Dowd rearrangement
process efficiently assembles the bicyclo[3.2.1]octane framework of highly oxidized
grayanane diterpenoids. By incorporation of a Cu(tbs)
cyclopropanation, diastereoselective ODI-Diels–Alder cycloaddition and
MeReO -catalyzed Rubottom oxidation, this apporach has enabled the first total
syntheses of rhodomolleins XX and XXII in 23 and 22 steps, respectively.
2
-catalyzed intramolecular
a
a
3
This article is protected by copyright. All rights reserved.