Unified Asymmetric Total Syntheses of (?)-Alotaketals A–D and (?)-Phorbaketal A

Article abstract of DOI:10.1002/anie.201704628

The novel tricyclic spiroketal alotane-type sesterterpenoids showed strikingly different biological activities and potency with subtle structural alterations. Asymmetric total syntheses of the tricyclic sesterterpenoids (?)-alotaketals A–D and (?)-phorbaketal A were accomplished [29–31 steps from (?)-malic acid] in a collective way for the first time. The key features of the strategy included 1) a new cascade cyclization of vinyl epoxy δ-keto-alcohols to forge the common tricyclic spiroketal intermediate, 2) a late-stage allylic C?H oxidation, and 3) olefin cross-metathesis to install the different side chains.

Full text of DOI:10.1002/anie.201704628

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Unified Asymmetric Total Syntheses of Alotaketals A-D and
Phorbaketal A
Authors: Hang Cheng, Zhihong Zhang, Hongliang Yao, Wei Zhang,
Jingxun Yu, and Rongbiao Tong
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201704628
Angew. Chem. 10.1002/ange.201704628
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10.1002/anie.201704628
Angewandte Chemie International Edition
COMMUNICATION
Unified Asymmetric Total Syntheses of Alotaketals AD and
Phorbaketal A
Hang Cheng, Zhihong Zhang, Hongliang Yao, Wei Zhang, Jingxun Yu, and Rongbiao Tong*
Abstract: The novel tricyclic spiroketal alotane-type sesterterpenoids
showed strikingly different biological activities and potency with subtle
structural alterations. Asymmetric total syntheses of such tricyclic
protein kinase C (PKC) and able to activate latent HIV-1
reservoirs at a concentration substantially lower (ca. 30 folds)
than the positive control prostratin. The structurally related
sesterterpenoid alotaketals A-D and phorbaketal
A
were
alotane-type phorbaketals A-K exhibited mild cytotoxicity (IC50 ≥
accomplished (29-31 steps from ()-malic acid) in a collective way for
the first time. The key features of our strategy included (i) the new
cascade cyclization of vinyl epoxy δ-keto-alcohol (VEKA) to forge the
common tricyclic spiroketal intermediate, (ii) a late-stage allylic C-H
oxidation, and (iii) olefin cross metathesis to install the different side
chains.
4.9 μM), while phorbaketal A (5) was found to significantly
stimulate osteoblast differentiation and to considerably inhibit
adipogenic differentiation.5
The potent and wide array of biological activities of alotaketals
and phorbaketals have attracted considerable synthetic interest.
Yang6a,b and Dalby6c accomplished the elegant total synthesis of
alotaketal A by the similar strategy that was tactically orchestrated
for the late-stage C-ring construction through the Barbier-type
reaction and spiroketalization. Recently, Brimble7a and Bray7b
disclosed two efficient strategies for the tricyclic spiroketal core,
which unfortunately could not be elaborated to the natural
products. To date, it remains an unmet challenge to synthesize
two or more members of this family with the reported strategies
that could not address the structural variations at both the C ring
and the side chains. Herein, we report a new synthetic strategy
that leads to collective total syntheses of alotaketals A-D (1-4) and
phorbaketal A (5), featuring a new cascade cyclization of vinyl
epoxy δ-keto-alcohol (VEKA) to forge the common tricyclic
spiroketal core (Scheme 1).
Alotaketals A-D1 and phorbaketals A-K2 (Figure 1) were
biogenetically
related,
structurally
novel
spiroketal
sesterterpenoid natural products isolated recently from the marine
sponge Hamigera sp. and/or Phorbas sp. They showed strikingly
different biological activities and potency with only subtle
structural variations at the C ring and/or the side chain.
Figure 1. Selected Alotaketals and Phorbaketals
For example, alotaketals A-C (1-3) exhibited different potency in
activating the cAMP cell signaling pathway3 (EC50: 18 nM6.5 μM).
Notably, alotaketal A is 170 times more potent than the widely
used forskolin (EC50 = 3 μM) in cell biology.4 Recent study by
Andersen1c et al showed that alotaketal C was an agonist of
Scheme 1. Unified synthetic strategy for alotaketals A-D and phorbaketal A
[*]
Dr. H. Cheng, Z. Zhang, Dr. H. Yao, Dr. W. Zhang, J. Yu, Prof. Dr.
R. Tong*
Department of Chemistry
The Hong Kong University of Science and Technology
Clear Water Bay, Kowloon, HK (China)
E-mail: rtong@ust.hk
Retrosynthetically (Scheme 1), we planned to install the
different side chain at the final stage of synthesis via olefin cross
metathesis of the linear diene (6a or 6b) and the common tricyclic
spiroketal core 7, which might be derived from allylic C-H
oxidation8 of
unprecedented cascade cyclization9 of VEKA (9
Preparation of 9 could be achieved by a Barbier-type reaction of
8
with the double bond migration and an
8).10
→
Supporting information for this article is available on the WWW
under http:
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10.1002/anie.201704628
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COMMUNICATION
the allyl Grignard of 1110 and Weinreb amide 10 followed by
regioselective epoxidation. The two biggest challenges for
implementing this strategy are (i) the efficiency, regioselectivity,11
stereochemical outcome of the previously unknown cascade
reaction of VEKA and (ii) practicability of the chemoselective
allylic C-H oxidation (8 → 7) in the context of the complex tricyclic
substrates.
These two challenges were first addressed with our model
studies (Table 1 and Scheme 2). Compound 12 (see Supporting
Information for details on its synthesis) was used to examine the
key cascade cyclization. Epoxidation of 12 with freshly prepared
dimethyldioxirane (DMDO) provided the clean but unstable
epoxide 13 (see SI for NMR spectra of the crude product). This
was treated with p-TsOH. The molecular structure of both 14a and
14b was substantiated by X-ray crystallography of their benzoyl
derivatives (15a and 15b).
To address the second challenge, we employed 14b to explore
the allylic C-H oxidation. After some experimentations, we found
that Dess-Martin periodinane (DMP) oxidation of 14b produced
the enone that electronically differentiated the trisubstituted
alkenes in A and B rings and allowed successful chemoselective
allylic C-H chlorination12 at B ring. SN2 substitution with NaOAc
provided allyl acetate 16, which relative configuration was
confirmed by the X-ray diffraction analysis of its 4-nitrobenzoate
17.
Table 1. Selected conditions for the cascade cyclization of vinyl epoxy δ-keto-
alcohol (VEKA, 12).[a]
Scheme 2. Model study on the allylic C-H oxidation. DMP = Dess-Martin
periodinane. Thermal ellipsoids shown at 40% probability.30
Overcoming these two potential synthetic challenges with the
model studies convinced us to undertake our planned unified total
syntheses (Scheme 1) of alotaketals A-D and phorbaketal A,
which represent major structural variations at the C ring and the
side chains within the alotane family (Figure 1). As depicted in
Scheme 3, our synthesis began with the preparation of allylic
alcohol 20 from the known β-keto ester 1813 (four steps from ()-
malic acid in 51% yield) through TES protection, triflation, CuCN
reagent
(equiv)
yield[b] (%,
14a/14b)
entry
1
solvent
CH2Cl2
time
1 h
temp
BF3-Et2O
(1.0)
-78 oC
50 (1/0)
TESOTf
(0.1)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
1 h
1 h
-78 oC
0 oC→rt
0 oC
40 (1/0)
54 (1/0)
35 (1/0)
71 (0/1)
0
2
3
4
5
6
7
8
AgSbF6 (1.0)
Yb(OTf)3
(1.0)
1 h
PPTS (1.0)
TFA (1.0)
CSA (1.0)
TfOH (0.5)
2 h
rt
2 h
0 oC→rt
rt
5 min
2 h
20 (0/1)
80 (0/1)
0 oC
aConditions: 12 (17.4 mg, 0.005 mmol) in CH2Cl2 (0.5 mL) was treated with
the acidic promoter. byield was based on 1H-NMR of the crude mixture.
DMDO = dimethyl dioxirane, TES = triethylsilyl, TsOH = p-toluenesulfonic
acid, PPTS = pyridinium p-toluenesulfonate, TFA = trifluoroacetic acid, CSA
= camphorsulfonic acid, TfOH = triflic acid. Thermal ellipsoids shown at 40%
probability.30
epoxide 13 was then treated with a variety of promoters and Table
1 listed selected conditions from >50 different runs. Clearly, triflic
acid (TfOH) was superior to other acidic promoters for the
cascade reaction on scales ranging from 17 mg to 100 mg.
Interestingly, Lewis acid (entries 1-4) effected only the cyclization
to afford the tricyclic product 14a in moderate yields, while
Brønsted acids (entries 5-8) promoted both the cyclization and
double bond isomerization to provide the 14b as the only product
with better overall yields (2 steps). Notably, the alkene
isomerization occurred in a nearly quantitative yield when 14a
Scheme 3. Synthesis of the tricyclic Core 8. DIBAL-H = diisobutylaluminum
hydride, DIPT = diisopropyl tartrate, DMSO = dimethyl sulfoxide, NHC = N-
heterocyclic carbene, TMS = trimethylsilyl, TBDPS = tert-butyldiphenylsilyl,
DMDO = dimethyl dioxirane, TBAF = tetra-n-butylammonium fluoride, DMP =
Dess-Martin periodinane. Thermal ellipsoids shown at 40% probability.30
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10.1002/anie.201704628
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-mediated methylation14 of (Z)-enol triflate, and DIBAL-H
reduction. Sharpless asymmetric epoxidation of 20 followed by
Parikh-Doering oxidation provided epoxy aldehyde 21, which was
converted to Weinreb amide 22 through a 3-step sequence
involving NHC-catalyzed redox esterification,15 TMS protection
and amidation. Reaction of Weinreb amide 12 and the freshly-
prepared Grignard reagent of the allylic chloride 1110 gave the
ketone 23 in a reproducibly excellent yield on decagram scales.
The key cascade cyclization was carried out by sequential
treatments of 23 with HF-py (chemoselective removal of TMS and
TES), DMDO (stereoselective epoxidation) and TfOH (cascade
reaction of VEKA) to provide the desired tricyclic spiroketal 8 in
56% yield (4.5 g obtained!) as a mixture of 10/1 diastereomers at
C4. Interestingly, we did not observe the exo-methylene
isomerization, which was different from our model study. The
relative and absolute configuration of 8 was confirmed by X-ray
diffraction analysis of its 4-nitrobenzoate derivative 24.
Kocienski,24 and Horner-Wadsworth-Emmons failed, the terminal
alkene for olefin cross metathesis was successfully introduced on
26 in three steps: desilylation with TBAF, DMP oxidation in the
presence of pyridine (other classical oxidation procedures
including Swern, Parikh-Doering, TPAP/NMO, PCC, IBX gave
<40% yield) and Julia-Kocienski methylenation (26 → 7). Double
desilylation of 7 followed by regioselective protection of the
primary alcohol as tert-butyldiphenylsilyl (TBDPS) ether provided
the advanced common intermediate 27 for all alotane natural
products. We first targeted alotaketal A and phorbaketal A and
therefore tertiary acetate of 27 was removed by DIBAL-H
reduction (poor conversion by K2CO3/MeOH) for dehydration.
After DMP oxidation of the secondary alcohol to the enone 28,
dehydration of the tertiary alcohol of 28 with Burgess reagent25
gave a 1/2 mixture of 29a/29b favoring 29b in 61% combined yield,
while dehydration with Martin sulfurance26 produced exclusive
thermodynamically more stable 29b in 93% yield. Grubbs-II-
catalyzed olefin cross metathesis of 29a and 29b with 1,6-diene
6b27 and 1,5-diene 6a,28 respectively, followed by desilylation
completed the total syntheses of ()-alotaketal A (1) and ()-
phorbaketal A (5).28 Sc(OTf)3-promoted acylation29 of the tertiary
alcohol of 28 with isovaleric anhydride provided 30, which
underwent olefin cross metathesis with 1,6-diene 6b and
desilylation to furnish ()-alotaketal B (2). On the other hand, the
tertiary acetate of the common intermediate 7, corresponding to
With 4.5 grams of the key tricyclic spiroketal core 8 in hand, we
set out to undertake the collective total synthesis (Scheme 4).
After double InCl3-mediated acetylation16 of 8 (other procedures
gave poor yields), Riley (SeO2) oxidation17 that gave a very poor
yield for our model substrates 14a/b was found to proceed
effectively and provide the allylic alcohol 25a (48% yield) and
over-oxidation product 25b (18.5% yield). Other allylic C-H
oxidation
methods
such
as
Kharasch-Sosnovsky,18
alotaketals
C
and D, could retain while regioselective
NaOCl/CeCl3,12 Br2/FeCl319 and NBS20 resulted in decomposition
of 8. Fortunately, both of 25a and 25b could be readily and
efficiently converted to the allylic acetate 26 in 2 and 3 steps,
respectively, by using Wender’s procedure.21 Although direct
installation of the long side chain on 26 through various aldehyde
olefinations (with 8-carbon ylide22) including Wittig,23 Julia-
deacetylation, silylation and DMP oxidation (7 → 27). Cross
metathesis of 27 with 1,5-diene 6a to provide the crude 29a/b,
which was treated either with TBAF to complete the total
synthesis of alotaketal C in 41% yield over 2 steps or sequentially
with CeCl3/NaBH4, acetic anhydride and TBAF to furnish
alotaketal D
Scheme 4. Collective total syntheses of alotaketals A-D and phorbaketal A. KHMDS = Potassium bis(trimethylsilyl)amide, G-II = Grubbs catalyst 2nd generation,
TBAF = tetra-n-butylammonium fluoride, DMP = Dess-Martin periodinane, DIBAL-H = diisobutylaluminum hydride, MeSO2PT = methyl 1-phenyl-1H-tetrazol-5-yl
sulfone.
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2221. For selected examples of allylic C-H oxidation in synthesis
complex molecules, see: c) E. J. Horn, B. R. Rosen, Y. Chen, J. Tang,
K. Chen, M. D. Eastgate, P. S. Baran, Nature 2016, 533, 77-81. d) Y. Jin,
C.-H. Yeh, C. A. Kuttruff, L. Jørgensen, G. Dünstl, J. Felding, S. R.
Natarajan, P. S. Baran, Angew. Chem. Int. Ed. 2015, 54, 14044-14048.
e) C. Yuan, Y. Jin, N. C. Wilde, P. S. Baran, Angew. Chem. Int. Ed. 2016,
55, 8280-8284. f) H. Chu, J. M. Smith, J. Felding, P. S. Baran, ACS Cent.
Sci. 2017, 3, 47-51. g) K. J. Fraunhoffer, N. Prabagaran, L. E. Sirois, M.
C. White, J. Am. Chem. Soc. 2006, 128, 9032-9033. h) E. M. Stang, M.
C. White, Nat. Chem. 2009, 1, 547-551.
in 29% yield over 4 steps. All spectroscopic data of our synthetic
samples were in good agreement with those reported for the
corresponding natural products.28
In conclusion, we developed a new cascade cyclization of vinyl
epoxy δ-keto-alcohol (VEKA), which enabled us to achieve unified
asymmetric total syntheses of alotaketals A-D and phorbaketal A.
Notably, alotaketals B-D and phorbaketal
A were totally
synthesized for the first time. Additional key reactions employed
in this new strategy include (1) allylic C-H oxidation and alkene
isomerization on the complex tricyclic spiroketal substrates and
(2) olefin cross metathesis to install the different side chain.
Extension of this strategy to other members of alotane-type
sesterterpenoids (phorbaketals B-K) and biological activity study
are undergoing in our lab and will be reported in due course.
[9]
The only related process is the PIFA-mediated cyclization of 4-(7-
hydroxy-3-keto) phenols for the total synthesis of aculeatins. For a recent
review, see: a) L. Song, H. Yao, Y. Dai, M. Wu, R. Tong, Tetrahedron
Lett. 2016, 57, 4257-4263. For approaches using a ketone to open the
epoxide, see: b) R. L. Mulholland, Jr., A. R. Chamberlin, J. Org. Chem.
1988, 53, 1082-1085. c) C. H. Fotsch, A. R. Chamberlin, J. Org. Chem.
1991, 56, 4141-4147. d) S. D. Rychnovsky, V. H. Dahanukar,
Tetrahedron Lett. 1996, 37, 339-342. e) Y. Xie, P. E. Floreancig, Angew.
Chem. Int. Ed, 2013, 52, 625-628
Acknowledgements
[10] W. Zhang, H. Yao, J. Yu, Z. Zhang, R. Tong, Angew. Chem. Int. Ed. 2017,
56, 4787-4791.
This research was financially supported by Research Grant
Council of Hong Kong (GRF 605113, GRF 16305314, and GRF
16311716). We are very grateful to Prof. Ian Williams (HKUST)
and Dr. Herman Sung (HKUST) for single-crystal diffraction
analysis and Prof. Guang Zhu (HKUST) for providing assistance
in NMR data collection.
[11] Ring opening of vinyl epoxides with internal alcohol nucleophiles usually
proceeds in 1,2-addition manner (SN2), not favoring our designed 1,4-
addition (SN2′). J. He, J. Ling, P. Chiu, Chem. Rev. 2014, 114, 8037-8128.
[12] a) F. J. Moreno-Dorado, F. M. Guerra, F. L. Manzano, F. J. Aladro, Z. D.
Jorge, G. M. Massanet, Tetrahedron Lett. 2003, 44, 6691-6693. b) M.
Blair, C. M. Forsyth, K. L. Tuck, Tetrahedron Lett. 2010, 51, 4808-4811.
[13] Y. Su, Y. Xu, J. Han, J. Zheng, J. Qi, T. Jiang, X. Pan, X. She, J. Org.
Chem. 2009, 74, 2743-2749.
Keywords: sesterterpenoid • alotaketal • phorbaketal • cascade
cyclization• vinyl epoxide opening
[14] T. J. Zahn, C. Weinbaum, R. A. Gibbs, Bioorg. Med. Chem. Lett. 2000,
10, 1763-1766.
[15] K. Y.-K. Chow, J. W. Bode, J. Am. Chem. Soc. 2004, 126, 8126-8127.
[16] A. K. Chakraborti, R. Gulhane, Tetrahedron Lett. 2003, 44, 6749-6753.
[17] a) M. A. Umbreit, K. B. Sharpless, J. Am. Chem. Soc. 1977, 99, 5526-
5528. b) M. Furber, L. N. Mander, J. Am. Chem. Soc. 1987, 109, 6389-
6396. c) K. M. Peese, D. Y. Gin, J. Am. Chem. Soc. 2006, 128, 8734-
8735. For a recent review, see: d) J. Młochowski, H. Wójtowicz-
Młochowska, Molecules 2015, 20, 10205-10243.
[1]
[2]
a) R. Forestieri, C. E. Merchant, N. J. de Voogd, T. Matainaho, T. J.
Kieffer, R. J. Andersen, Org. Lett. 2009, 11, 5166-5169. b) J. Daoust, M.
Chen, M. Wang, D. Williams, M. Garcia Chavez, Y. Wang, C. Merchant,
A. Fontana, T. Kieffer, R. Andersen, J. Org. Chem. 2013, 78, 8267-8273.
c) M. Wang, I. Tietjen, M. Chen, D. E. Williams, J. Daoust, M. A.
Brockman, R. J. Andersen, J. Org. Chem. 2016, 81, 11324-11334.
a) J.-R. Rho, B. S. Hwang, C. J. Sim, S. Joung, H. Y. Lee, H.-J. Kim, Org.
Lett. 2009, 11, 5590-5593 . (b) W. Wang, B. Mun, Y. Lee, M. V. Reddy,
Y.Park, J. Lee, H. Kim, D. Hahn, J. Chin, M. Ekins, S.-J. Nam, H. Kang,
J. Nat. Prod. 2013, 76, 170-177. (c) Y. Lee, W. Wang, H. Kim, A. G. Giri,
D. H. Won, D. Hahn, K. R. Baek, J. Lee, I. Yang, H. Choi, S.-J. Nam, H.
Kang, Bioorg. Med. Chem. Lett. 2014, 24, 4095-4098.
[18] a) M. S. Kharasch, G. Sosnovsky, J. Am. Chem. Soc. 1958, 80, 756-756.
[19] M. E. Maier, A. Bayer, Eur. J. Org. Chem. 2006, 4034-4043.
[20] A. Abad, C. Agulló, A. C. Cuñat, D. Pardo, Tetrahedron Lett. 2003, 44,
1899-1902.
[21] P. A. Wender, C. D. Jesudason, H. Nakahira, N. Tamura, A. L. Tebbe, Y.
Ueno, J. Am. Chem. Soc. 1997, 119, 12976-12977.
[3]
[4]
J. A. Beavo, L. L. Brunton, Nat. Rev. Mol. Cell. Biol. 2002, 3, 710-718.
a) S. V. Bhat, B. S. Bajwa, H. Dornauer, N. J. de Souza, H. W. Fehlhaber,
Tetrahedron Lett. 1977, 1669-1672. b) K. B. Seamon, W. Padgett, J. W.
Daly, Proc. Natl. Acad. Sci. U.S.A. 1981, 78, 3363-3367.
[22] A. Fukuzawa, H. Sato, T. Masamune, Tetrahedron Lett. 1987, 28, 4303-
4306.
[23] S. A. Snyder, Z.-Y. Tang, R. Gupta, J. Am. Chem. Soc. 2009, 131, 5744-
5745.
[5]
[6]
a) M. R. Byun, A. R. Kim, J.-H. Hwang, M. K. Sung, Y. K. Lee, B. S.
Hwang, J.-R. Rho, E. S. Hwang, J.-H. Hong, FEBS Lett. 2012, 586, 1086-
1092. b) M. R. Byun, C. H. Lee, J.-H. Hwang, A. R. Kim, S. A. Moon, M.
K. Sung, J.-R. Roh, E. S. Hwang, J.-H. Hong, Eur. J. Pharmacol. 2013,
718, 181-187.
[24] H. Huang, J. S. Panek, Org. Lett. 2004, 6, 4383-4385.
[25] G. M. Atkins, E. M. Burgess, J. Am. Chem. Soc. 1968, 90, 4744-4745.
[26] J. C. Martin, R. J. Arhart, J. Am. Chem. Soc. 1971, 93, 4327-4329.
[27] W. F. Berkowitz, Y. Wu, J. Org. Chem. 1997, 62, 1536-1539.
[28] See Supporting Information.
a) J. Huang, J. R. Yang, J. Zhang, J. Yang, J. Am. Chem. Soc. 2012, 134,
8806-8809. b) J. Huang, J. R. Yang, J. Zhang, J. Yang, Org. Biomol.
Chem. 2013, 11, 3212-3222. c) M. Xuan, I. Paterson, S. M. Dalby, Org.
Lett. 2012, 14, 5492-5495.
[29] a) K. Ishihara, M. Kubota, H. Kurihara, H. Yamamoto, J. Am. Chem. Soc.
1995, 117, 4413-4414. b) K. Ishihara, M. Kubota, H. Kurihara, H.
Yamamoto, J. Org. Chem. 1996, 61, 4560-4567.
[30] CCDC 1544104 (15a), CCDC 1544105 (15b), CCDC 1544106 (17), and
CCDC 1544499 (24) contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre.
[7]
[8]
a) J. G. Hubert, D. P. Furkert, M. A. Brimble, J. Org. Chem. 2015, 80,
2715-2723. (b) H. J. Shirley, C. D. Bray, Eur. J. Org. Chem. 2016, 1504-
1507.
For selected reviews, see: a) A. Nakamura, M. Nakata, Synthesis 2013,
45, 1421-1451. b) V. Weidmann, W. Maison, Synthesis 2013, 45, 2201-
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Entry for the Table of Contents (Please choose one layout)
COMMUNICATION
Hang Cheng, Zhihong Zhang, Hongliang
Yao, Wei Zhang, Jingxun Yu, and
Rongbiao Tong*
Page No. – Page No.
Unified Asymmetric Total Syntheses
of Alotaketals AD and Phorbaketal A
All-in-one: Unified total syntheses of tricyclic sesterterpenoid alotaketals A-D and
phorbaketal A were accomplished (29-31 steps from ()-malic acid) in a collective
way for the first time, featuring a new cascade cyclization of vinyl epoxy δ-keto-
alcohol (VEKA), late-stage C-H oxidation, and olefin cross metathesis.
This article is protected by copyright. All rights reserved.