Concise Synthesis of 9,11-Secosteroids Pinnigorgiols B and e

Article abstract of DOI:10.1021/jacs.0c13426

Pinnigorgiols B and E are 9,11-secosteroids with a unique tricyclic γ-diketone framework. Herein, we report the first synthesis of these natural products from inexpensive, commercially available ergosterol. This synthesis features a semipinacol rearrangem

Full text of DOI:10.1021/jacs.0c13426

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Concise Synthesis of 9,11-Secosteroids Pinnigorgiols B and E
Xinghui Li,∥ Zeliang Zhang,∥ Huafang Fan, Yinlong Miao, Hailong Tian, Yucheng Gu, and Jinghan Gui*
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ABSTRACT: Pinnigorgiols B and E are 9,11-secosteroids with a unique tricyclic γ-diketone framework. Herein, we report the first
synthesis of these natural products from inexpensive, commercially available ergosterol. This synthesis features a semipinacol
rearrangement and an acyl radical cyclization/hemiketalization cascade; the latter efficiently assembled the tricyclic γ-diketone
skeleton, with two rings and three contiguous stereogenic centers being formed in a single step.
earranged steroid natural products, including secosteroids
(in which at least one ring is cleaved) and abeo-steroids
isolated by Kigoshi and co-workers from the sea hare Agplysia
kurodai. Importantly, pinnigorgiols have been shown to induce
apoptosis of hepatic stellate cells,29 and aplysiasecosterol A is
moderately cytotoxic to human myelocytic leukemia cells (HL-
60).27
R
(in which there is at least one migrated C−C bond within the
classic tetracyclic framework), have recently received consid-
erable attention from synthetic chemists owing to the
structural diversity and biological importance of these
compounds.1,2 Representative naturally occurring rearranged
steroids include cyclopamine,3 glaucogenins,4 cortistatins,5−13
nakiterpiosin,14 strophasterol A,15 cyclocitrinols,16−18 pleuro-
cins,19 swinhoeisterol,20 bufospirostenin A,21 dankasterones,
and periconiastone A.20,22 Two particularly challenging
examples of such natural products are the 9,11-secosteroids
pinnigorgiol B (1) and pinnigorgiol E (2) (Figure 1),23−25
The heavily rearranged scaffolds and intriguing biological
activities of these 9,11-secosteroids make them interesting
targets for chemical synthesis.30 In 2018, Li and co-workers
reported a remarkable convergent synthesis of 4,31 which
featured a series of impressive transformations, including a
desymmetrizing lactolization, an Aggarwal lithiation−boryla-
tion, and a hydrogen-atom-transfer-based radical cyclization.
From a synthetic perspective, the development of an efficient
semisynthetic approach to 1 and 2 presents a formidable
challenge because it requires the identification of an
inexpensive steroid precursor that can undergo selective
cleavage of the C9−C11 bond, as well as a controllable
skeletal rearrangement to transform the common decalin A/B
ring system to the tricyclic γ-diketone core framework. Herein,
we report the realization of a concise, radical cyclization
approach32 to pinnigorgiols B and E from inexpensive,
commercially available ergosterol.
Our synthetic strategy to pinnigorgiols was largely guided by
a biosynthetic pathway proposed by Kigoshi and Kita (Scheme
1A).27,28 They suggested that the tricyclic γ-diketone structure
of 2 might be derived from 3 by means of an α-ketol
rearrangement33 to generate 6, followed by a vinylogous α-
ketol rearrangement15,34,35 to generate 7. Protonation of 7 and
subsequent hemiketal formation would afford 2. The brevity of
this proposed biosynthetic pathway inspired us to attempt to
design a practical, efficient route to these unique 9,11-
secosteroids. Because the ketol intermediate structurally similar
to 6 was reported to undergo facile C10 migration from C6 to
C5,36 and achieving the desired vinylogous α-ketol rearrange-
Figure 1. Structures of 9,11-secosteroids.
which possess a unique tricyclo[5,2,1,1]decane framework with
an embedded γ-diketone moiety. These compounds were
isolated by Sung and co-workers from a Pinnigorgia coral
species in 2016, along with a biogenetic precursor, pinnisterol
E (3).26 Pinnisterol E is a typical secosteroid with one cleaved
C−C bond, whereas pinnigorgiol B is both a secosteroid (the
C9−C11 bond is cleaved) and an abeo-steroid (several bonds
of the A/B bicyclic skeleton are migrated) and is among the
most heavily rearranged steroid natural products reported so
far. Notably, aplysiasecosterol A (4) and aplysiasecosterol B
(5),27,28 which share the same core skeleton as 1 and 3, were
Received: December 29, 2020
Published: March 24, 2021
https://doi.org/10.1021/jacs.0c13426
J. Am. Chem. Soc. 2021, 143, 4886−4890
© 2021 American Chemical Society
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Scheme 1. (A) Proposed Biosynthetic, Polar Framework
Rearrangement and (B) Design of an Alternative, Radical
Cyclization Approach
Scheme 2. Regioselective-Hydrogenation-Enabled
Divergent Access to Regioisomeric Olefins
group and subsequent hydrogenation over PtO2 provided 25
exclusively. The structures of 23 and 25 were confirmed by X-
ray crystallographic analysis of their corresponding semipinacol
rearrangement products (see Supporting Information for
details). The development of conditions for efficient access
to these three regioisomeric olefins can be expected to greatly
facilitate the selective redox and C−C bond reorganization
reactions of the tetracyclic skeleton, and thus, these conditions
are likely to find utility for the synthesis of other steroid natural
products. For example, intermediates bearing a C8−C9 or
C8−C14 olefin might find potential application in the
synthesis of 8,9-secosteroid jereisterol A or 8,14-secosteroid
jereisterol B.42
Having established a reliable method for preparing 14, we
were poised to attempt the first bond migration within the
decalin A/B ring system to generate the 7,5-bicyclic scaffold by
means of the semipinacol rearrangement. Selective mesylation
of 14 afforded the desired C6 mesylate, which was heated in
DMF in the presence of CaCO3 and NEt3 to furnish ketone 15
in 92% yield (Scheme 3).43 The stereochemistry at C6 for 15
was determined through X-ray crystallographic analysis of the
semipinacol rearrangement products of structurally similar
olefins 23 and 25 (see the Supporting Information for details).
Notably, this stereochemical result was in good agreement with
Newhouse’s recent elegant study of a cationic rearrangement
to access the triterpenoid justicioside E aglycone.44 Ozonolysis
of 15 and subsequent reduction with NaBH4 gave a 5,11-diol
intermediate, which was converted to 16 by selective
acetylation and in situ Dess−Martin oxidation. The conditions
for oxidative cleavage of the C5−C6 bond of 16 and
introduction of the C7−C8 double bond to produce acid 18
were investigated next. First, regioselective formation of a C5−
C6 silyl enol ether by reaction with trimethylsilyl iodide45 and
subsequent ozonolysis delivered the C5 carboxylic acid 17.
Dehydrogenation of the resulting 1,3-cyclopentanedione of 17
was achieved through bromination of the C6−C7 silyl enol
ether, which gave rise to 18 in 58% yield over four steps.
ment was challenging, we opted to design an alternative,
stepwise strategy for accessing 2 (Scheme 1B). We envisaged
that diol 8 would undergo a semipinacol rearrangement37 to
afford ketone 9, which would likely be much more stable than
6 and could thus be isolated. In contrast to the vinylogous α-
ketol rearrangement of 6, which involved tandem C5−C6
bond cleavage and C5−C7 bond formation, we speculated that
oxidative cleavage of 9 would break the C5−C6 bond to afford
10, and the pivotal C5−C7 bond formation reaction to access
7 could be accomplished by means of an acyl radical
cyclization.38,39
As depicted in Scheme 3, our work on the synthesis of 1 and
2 commenced with the preparation of the known compound
dehydroergosterol (12) from ergosterol.40 Protection of the
C3 hydroxyl group of 12 as a tert-butyldimethylsilyl ether,
followed by asymmetric dihydroxylation41 of the C5−C6 olefin
generated triene 13. Hydrogenation of the C7−C8 and C22−
C23 double bonds of 13 regioselectively over the C9−C11
double bond proved to be nontrivial and necessitated extensive
experimentation. Intriguingly, we were able to identify three
sets of optimal conditions for divergently accessing regioiso-
meric olefins 14, 23, and 25, which have C9−C11, C8−C9,
and C8−C14 double bonds, respectively (Scheme 2).
Treatment of 13 with 10% Rh/C in ethyl acetate enabled
selective hydrogenation of the C22−C23 olefin, providing
diene 21 in 96% yield. Li/NH3 reduction of 21 gave rise to
desired olefin 14 as the major product, along with the C7−C8
olefin (22) and 23 as minor products. Alternatively, hydro-
genation of 13 over 10% Pd/C in MeOH furnished 23 in 71%
yield. Interestingly, acetylation of the C6 hydroxyl group of 13
enabled regioselective epoxidation of the C9−C11 double
bond, giving rise to epoxide 24. Removal of the C6 acetyl
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a
Scheme 3. Acyl Radical Cyclization Approach to Pinnigorgiols B and E
a
Abbreviations: TBS, t-butyldimethylsilyl; Ms, mesyl; DMP, Dess−Martin periodinane; TMS, trimethylsilyl; HMDS, 1,1,1,3,3,3-hexamethyl-
disilazane; NBS, N-bromosuccinimide; DCC, dicyclohexylcarbodiimide; DMAP, N,N-4-dimethylaminopyridine; AIBN, 2,2′-azobis(isobutyro-
nitrile).
All that remained to complete the synthesis of 2 was
connection of the pivotal C5−C7 bond, which we envisioned
could be accomplished through an intramolecular acyl radical
cyclization approach.46−49 However, because this approach
would involve an 8-exo-trig cyclization to generate a
bicyclo[5.2.1] bridged ring system, the transformation
presented a considerable challenge.30 Therefore, we decided
to search for a suitable acyl radical precursor to investigate the
feasibility of the approach. Attempted preparation of the
corresponding acyl telluride39 of carboxylic acid 18 were
unsuccessful. Conversion of the carboxyl group of 18 to the
corresponding phenyl selenoester by reaction with (PhSe)2
and n-Bu3P in DMF proceeded smoothly.50 However,
treatment of the selenoester with azobis(isobutyronitrile)
(AIBN) and Bu3SnH led to a mixture of unidentified products,
and formation of the desired C5−C7 bond was not observed.
We speculated that the bulky tert-butyldimethylsilyl (TBS)
group at C3 was detrimental because its proximity to the acyl
radical at C5 hampered the approach of C5 to C7, thus
hindering formation of the desired bond. Attempts to remove
the TBS group from the phenyl selenoester intermediate
resulted in a complex mixture, possibly because of the
instability of the phenyl selenoester. Inspired by the generation
of an acyl radical from a thiolester by Crich et al.,51 we
prepared thiolester 20 by a coupling reaction between 18 and
thiol 19 followed by removal of the TBS group with HF. We
were pleased to find that treating 20 with a solution of Bu3SnH
and AIBN in benzene at 100 °C afforded 2 in 55% yield.51
This process, which likely involved an acyl radical cyclization/
hemiketalization cascade, efficiently forged the tricyclic γ-
diketone framework, with two rings and three contiguous
stereogenic centers being formed in a single step. Hydrolysis of
2 furnished 1 uneventfully, and the spectroscopic data for 1
and 2 were in good agreement with those of the isolated
samples.23−25
In conclusion, we have achieved the first synthesis of the
9,11-secosteroids pinnigorgiols B and E from inexpensive
ergosterol. Our synthesis of the pinnigorgiols features a
semipinacol rearrangement and an acyl radical cyclization/
hemiketalization cascade, which converts a biogenetic tandem
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Communication
polar rearrangement into a stepwise hybrid combination of
polar and radical reactions.52 Our work also demonstrates how
inspiration from a putative biosynthesis pathway can be
strategically used to develop a practical synthetic approach.
ACKNOWLEDGMENTS
■
Financial support was provided by the National Natural
Science Foundation of China (grant nos. 21871289 and
21672245), the Strategic Priority Research Program of the
Chinese Academy of Sciences (grant no. XDB20000000), the
SIOC and the Syngenta Ph.D. Studentship (Z.Z.). We thank
Prof. Ping-Jyun Sung (National Museum of Marine Biology
and Aquarium) for providing the NMR spectra of isolated 2
and Prof. Phil S. Baran (Scripps Research) and Prof. Ang Li
(SIOC) for insightful comments.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c13426.
Experimental procedures and H NMR and 13C NMR
1
spectra for all compounds (PDF)
Accession Codes
REFERENCES
■
CCDC 2058214−2058215 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
(1) Duecker, F. L.; Reuß, F.; Heretsch, P. Rearranged ergostane-type
natural products: Chemistry, biology, and medicinal aspects. Org.
Biomol. Chem. 2019, 17, 1624.
(2) Noack, F.; Heinze, R. C.; Heretsch, P. Contemporary Synthetic
Strategies towards Secosteroids, abeo-Steroids, and Related Triter-
penes. Synthesis 2019, 51, 2039.
(3) Giannis, A.; Heretsch, P.; Sarli, V.; Stößel, A. Synthesis of
Cyclopamine Using a Biomimetic and Diastereoselective Approach.
Angew. Chem., Int. Ed. 2009, 48, 7911.
(4) Gui, J.; Wang, D.; Tian, W. Biomimetic Synthesis of 5,6-dihydro-
glaucogenin C: Construction of the Disecopregnane Skeleton by
Iron(II)-Promoted Fragmentation of an α-Alkoxy Hydroperoxide.
Angew. Chem., Int. Ed. 2011, 50, 7093.
AUTHOR INFORMATION
Corresponding Author
■
Jinghan Gui − CAS Key Laboratory of Synthetic Chemistry of
Natural Substances, Center for Excellence in Molecular
Synthesis, Shanghai Institute of Organic Chemistry,
University of Chinese Academy of Sciences, Chinese Academy
of Sciences, Shanghai 200032, China; orcid.org/0000-
0002-4786-5779; Email: guijh@sioc.ac.cn
(5) Shenvi, R. A.; Guerrero, C. A.; Shi, J.; Li, C.-C.; Baran, P. S.
Synthesis of (+)-Cortistatin A. J. Am. Chem. Soc. 2008, 130, 7241.
(6) Nicolaou, K. C.; Sun, Y.-P.; Peng, X.-S.; Polet, D.; Chen, D. Y.-K.
Total Synthesis of (+)-Cortistatin A. Angew. Chem., Int. Ed. 2008, 47,
7310.
Authors
Xinghui Li − CAS Key Laboratory of Synthetic Chemistry of
Natural Substances, Center for Excellence in Molecular
Synthesis, Shanghai Institute of Organic Chemistry,
University of Chinese Academy of Sciences, Chinese Academy
of Sciences, Shanghai 200032, China
Zeliang Zhang − CAS Key Laboratory of Synthetic Chemistry
of Natural Substances, Center for Excellence in Molecular
Synthesis, Shanghai Institute of Organic Chemistry,
University of Chinese Academy of Sciences, Chinese Academy
of Sciences, Shanghai 200032, China
Huafang Fan − Shaanxi Key Laboratory of Natural Products
& Chemical Biology, College of Chemistry & Pharmacy,
Northwest A&F University, Yangling 712100, Shaanxi,
China
Yinlong Miao − Shaanxi Key Laboratory of Natural Products
& Chemical Biology, College of Chemistry & Pharmacy,
Northwest A&F University, Yangling 712100, Shaanxi,
China
Hailong Tian − CAS Key Laboratory of Synthetic Chemistry
of Natural Substances, Center for Excellence in Molecular
Synthesis, Shanghai Institute of Organic Chemistry,
University of Chinese Academy of Sciences, Chinese Academy
of Sciences, Shanghai 200032, China
Yucheng Gu − Syngenta, Jealott’s Hill International Research
Centre, Bracknell, Berkshire RG42 6EY, United Kingdom;
orcid.org/0000-0002-6400-6167
(7) Lee, H. M.; Nieto-Oberhuber, C.; Shair, M. D. Enantioselective
Synthesis of (+)-Cortistatin A, a Potent and Selective Inhibitor of
Endothelial Cell Proliferation. J. Am. Chem. Soc. 2008, 130, 16864.
(8) Flyer, A. N.; Si, C.; Myers, A. G. Synthesis of cortistatins A, J, K
and L. Nat. Chem. 2010, 2, 886.
(9) Simmons, E. M.; Hardin-Narayan, A. R.; Guo, X.; Sarpong, R.
Formal total synthesis of ( )-cortistatin A. Tetrahedron 2010, 66,
4696.
(10) Fang, L.; Chen, Y.; Huang, J.; Liu, L.; Quan, J.; Li, C.-C.; Yang,
Z. Formal Synthesis of Cortistatins. J. Org. Chem. 2011, 76, 2479.
(11) Nilson, M. G.; Funk, R. L. Total Synthesis of ( )-Cortistatin J
from Furan. J. Am. Chem. Soc. 2011, 133, 12451.
(12) Yamashita, S.; Iso, K.; Kitajima, K.; Himuro, M.; Hirama, M.
Total Synthesis of Cortistatins A and J. J. Org. Chem. 2011, 76, 2408.
(13) Kuang, L.; Liu, L. L.; Chiu, P. Formal Total Synthesis of
(+)-Cortistatins A and J. Chem. Eur. J. 2015, 21, 14287.
(14) Gao, S.; Wang, Q.; Chen, C. Synthesis and Structure Revision
of Nakiterpiosin. J. Am. Chem. Soc. 2009, 131, 1410.
(15) Heinze, R. C.; Lentz, D.; Heretsch, P. Synthesis of
Strophasterol A Guided by a Proposed Biosynthesis and Innate
Reactivity. Angew. Chem., Int. Ed. 2016, 55, 11656.
(16) Liu, J.; Wu, J.; Fan, J.-H.; Yan, X.; Mei, G.; Li, C.-C.
Asymmetric Total Synthesis of Cyclocitrinol. J. Am. Chem. Soc. 2018,
140, 5365.
(17) Wang, Y.; Ju, W.; Tian, H.; Tian, W.; Gui, J. Scalable Synthesis
of Cyclocitrinol. J. Am. Chem. Soc. 2018, 140, 9413.
(18) Wang, Y.; Ju, W.; Tian, H.; Sun, S.; Li, X.; Tian, W.; Gui, J.
Facile Access to Bridged Ring Systems via Point-to-Planar Chirality
Transfer: Unified Synthesis of Ten Cyclocitrinols. J. Am. Chem. Soc.
2019, 141, 5021.
(19) Heinze, R. C.; Heretsch, P. Translation of a Polar Biogenesis
Proposal into a Radical Synthetic Approach: Synthesis of Pleurocin
A/Matsutakone and Pleurocin B. J. Am. Chem. Soc. 2019, 141, 1222.
(20) Duecker, F. L.; Heinze, R. C.; Heretsch, P. Synthesis of
Swinhoeisterol A, Dankasterone A and B, and Periconiastone A by
Radical Framework Reconstruction. J. Am. Chem. Soc. 2020, 142, 104.
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c13426
Author Contributions
∥X.L. and Z.Z. contributed equally.
Notes
The authors declare no competing financial interest.
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(21) Cheng, M.-J.; Zhong, L.-P.; Gu, C.-C.; Zhu, X.-J.; Chen, B.; Liu,
J.-S.; Wang, L.; Ye, W.-C.; Li, C.-C. Asymmetric Total Synthesis of
Bufospirostenin A. J. Am. Chem. Soc. 2020, 142, 12602.
(22) Chen, P.; Wang, C.; Yang, R.; Xu, H.; Wu, J.; Jiang, H.; Chen,
K.; Ma, Z. Asymmetric Total Synthesis of Dankasterones A and B and
Periconiastone A Through Radical Cyclization. Angew. Chem., Int. Ed.
2021, 60, 5512.
(23) Chang, Y.-C.; Kuo, L.-M.; Su, J.-H.; Hwang, T.-L.; Kuo, Y.-H.;
Lin, C.-S.; Wu, Y.-C.; Sheu, J.-H.; Sung, P.-J. Pinnigorgiols A−C, 9,11-
secosterols with a rare ring arrangement from a gorgonian coral
Pinnigorgia sp. Tetrahedron 2016, 72, 999.
(24) Chang, Y.-C.; Hwang, T.-L.; Sheu, J.-H.; Wu, Y.-C.; Sung, P.-J.
New anti-inflammatory 9,11-secosterols with a rare tricyclo[5,2,1,1]-
decane ring from a formosan gorgonian Pinnigorgia sp. Mar. Drugs
2016, 14, 218.
(25) Chang, Y.-C. Ph.D. Thesis. Chemical Constituents and Their
Bioactivities from a Formosan Gorgonian Coral Pinnigorgia sp.
National Sun Yat-sen University, 2016.
(26) Chang, Y.-C.; Hwang, T.-L.; Kuo, L.-M.; Sung, P.-J. Pinnisterols
D-J, new 11-acetoxy-9,11-secosterols with a 1,4-quinone moiety from
formosan gorgonian coral Pinnigorgia sp. (Gorgoniidae). Mar. Drugs
2017, 15, 11.
(27) Kawamura, A.; Kita, M.; Kigoshi, H. Aplysiasecosterol A: A
9,11-Secosteroid with an Unprecedented Tricyclic γ-Diketone
Structure from the Sea Hare Aplysia kurodai. Angew. Chem., Int. Ed.
2015, 54, 7073.
(28) Kita, M.; Kawamura, A.; Kigoshi, H. Aplysiasecosterols B and
C: Two new 9,11-secosteroids with a cis-fused 1,4-quinone structure
from the sea hare Aplysia kurodai. Tetrahedron Lett. 2016, 57, 858.
(29) Kuo, L.-M.; Chen, P.-J.; Sung, P.-J.; Chang, Y.-C.; Ho, C.-T.;
Wu, Y.-H.; Hwang, T.-L. The Bioactive Extract of Pinnigorgia sp.
Induces Apoptosis of Hepatic Stellate Cells via ROS-ERK/JNK-
Caspase-3 Signaling. Mar. Drugs 2018, 16, 19.
(42) D’Auria, M. V.; Paloma, L. G.; Minale, L.; Riccio, R.; Debitus,
C. Jereisterol A and B: Two 3β-methoxy-secosteroids from the pacific
sponge Jereicopsis graphidiophora. Tetrahedron Lett. 1991, 32, 2149.
(43) Nussim, M.; Mazur, Y. Synthesis and conformational analysis of
A-homo-B-nor and A-nor-B-homo steroids. Tetrahedron 1968, 24,
5337.
(44) Elkin, M.; Scruse, A. C.; Turlik, A.; Newhouse, T. R.
Computational and Synthetic Investigation of Cationic Rearrange-
ment in the Putative Biosynthesis of Justicane Triterpenoids. Angew.
Chem., Int. Ed. 2019, 58, 1025.
(45) Miller, R. D.; McKean, D. R. The Facile Silylation of Aldehydes
and Ketones using Trimethylsilyl Iodide: An Exceptionally Simple
Procedure for the Generation of Thermodynamically Equilibrated
Trimethylsilylenol Ethers. Synthesis 1979, 1979, 730.
(46) Boger, D. L.; Mathvink, R. J. Acyl radicals: functionalized free
radicals for intramolecular cyclization reactions. J. Org. Chem. 1988,
53, 3377.
(47) Boger, D. L.; Mathvink, R. J. Acyl radicals: intermolecular and
intramolecular alkene addition reactions. J. Org. Chem. 1992, 57,
1429.
(48) Crich, D.; Fortt, S. M. Some studies on 6, 7-unsaturated
carbonyl radical cyclizations. Tetrahedron Lett. 1988, 29, 2585.
(49) Crich, D.; Angeline Eustace, K.; Fortt, S. M.; Ritchie, T. J. Acyl
radical cyclizations in synthesis. part 2 further substituent effects on
the mode and efficiency of cyclizaion of 6-heptenoyl radicals.
Tetrahedron 1990, 46, 2135.
(50) Singh, U.; Ghosh, S. K.; Chadha, M. S.; Mamdapur, V. R. A
new convenient approach to peptide synthesis using a diselenide and
a phosphine. Tetrahedron Lett. 1991, 32, 255.
(51) Crich, D.; Yao, Q. Generation of Acyl Radicals from Thiolesters
by Intramolecular Homolytic Substitution at Sulfur. J. Org. Chem.
1996, 61, 3566.
(52) For a recent elegant example of the translation of a polar
biogenesis proposal into a radical synthetic approach, see ref 19.
(30) For a synthetic study using a 6-exo-trig radical cyclization, see:
Ohyoshi, T.; Tano, H.; Akemoto, K.; Kigoshi, H. Synthetic studies
toward aplysiasecosterol A: Construction of the novel tricyclic core.
Tetrahedron Lett. 2017, 58, 3327.
(31) Lu, Z.; Zhang, X.; Guo, Z.; Chen, Y.; Mu, T.; Li, A. Total
Synthesis of Aplysiasecosterol A. J. Am. Chem. Soc. 2018, 140, 9211.
(32) For an excellent summary on this topic, see: Smith, J. M.;
Harwood, S. J.; Baran, P. S. Radical Retrosynthesis. Acc. Chem. Res.
2018, 51, 1807.
(33) Paquette, L. A.; Hofferberth, J. E. The α-Hydroxy Ketone (α-
Ketol) and Related Rearrangements. Org. React. 2003, 62, 477.
(34) Zhang, E.; Fan, C.-A.; Tu, Y.-Q.; Zhang, F.-M.; Song, Y.-L.
Organocatalytic Asymmetric Vinylogous α-Ketol Rearrangement:
Enantioselective Construction of Chiral All-Carbon Quaternary
Stereocenters in Spirocyclic Diketones via Semipinacol-Type 1,2-
Carbon Migration. J. Am. Chem. Soc. 2009, 131, 14626.
(35) Yang, M.; Wang, L.; He, Z.-H.; Wang, S.-H.; Zhang, S.-Y.; Tu,
Y.-Q.; Zhang, F.-M. Tandem Semipinacol-Type 1,2-Carbon Migra-
tion/Aldol Reaction toward the Construction of [5−6−7] All-Carbon
Tricyclic Core of Calyciphylline A-Type Alkaloids. Org. Lett. 2012, 14,
5114.
(36) Mazur, Y.; Nussim, M. Base catalysed rearrangements of α-
ketols. Tetrahedron Lett. 1961, 2, 817.
(37) Song, Z.-L.; Fan, C.-A.; Tu, Y.-Q. Semipinacol Rearrangement
in Natural Product Synthesis. Chem. Rev. 2011, 111, 7523.
(38) Boger, D. L. Applications of Free Radicals in Organic Synthesis.
Isr. J. Chem. 1997, 37, 119.
(39) Chatgilialoglu, C.; Crich, D.; Komatsu, M.; Ryu, I. Chemistry of
Acyl Radicals. Chem. Rev. 1999, 99, 1991.
(40) Delseth, C.; Kashman, Y.; Djerassi, C. Ergosta-5,7,9(11), 22-
tetraen-3β-ol and its 24ξ-Ethyl Homolog, Two New Marine Sterols
from the Red Sea Sponge Biemna fortis. Helv. Chim. Acta 1979, 62,
2037.
(41) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Catalytic
Asymmetric Dihydroxylation. Chem. Rev. 1994, 94, 2483.
4890
https://doi.org/10.1021/jacs.0c13426
J. Am. Chem. Soc. 2021, 143, 4886−4890