pubs.acs.

org/JACS Communication

Enantioselective Total Synthesis of (+)-Pedrolide

Marlene Fadel and Erick M. Carreira*
Cite This: J. Am. Chem. Soc. 2023, 145, 8332−8337 Read Online

ACCESS Metrics & More Article Recommendations *

sı Supporting Information

ABSTRACT: The first total synthesis of (+)-pedrolide, a tigliane-derived diterpenoid featuring an unprecedented 5−5−6−6−3
carbon skeleton, is reported. Key to the approach is the construction of the bicyclo[2.2.1]heptane core via an intramolecular
See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
Downloaded via INDIAN INST OF TECH HYDERABAD on February 6, 2024 at 08:52:22 (UTC).

cyclopentadiene-Diels−Alder cycloaddition. To this end, a norbornadiene serves as an effective surrogate for cyclopentadiene, which
is unmasked under mild conditions involving a complex Diels−Alder reaction cascade. In addition, the synthesis provides a novel
approach to a densely functionalized carane in an efficient and enantioselective manner.

P lants of the genus Euphorbia are a rich source of structurally

diverse diterpenoids, including tiglianes, ingenanes, daph-
nanes, jatrophanes, and lathyranes.1 These natural products
an intriguing target. Herein, we disclose the first total synthesis
of (+)-pedrolide (1). The salient features include an efficient
and stereoselective approach to a highly oxidized carane
exhibit a broad range of biological effects, such as pro- fragment that is also commonly found in a number of tigliane-
inflammatory, tumor-promoting, cytotoxic, anti-inflammatory, type natural products.4 Additionally, the bicyclo[2.2.1]heptane
and antiviral (anti-HIV) activities, earning them a privileged role is accessed via an intramolecular cyclopentadiene-Diels−Alder
as targets for natural product-based drug discovery.1,2 Isolated in cycloaddition, which relies on the use of norbornadiene as a
2021 from Euphorbia pedroi by Ferreira and co-workers,3 masked cyclopentadiene. Crucial to the success of the Diels−
(+)-pedrolide (1) is a noncytotoxic diterpenoid with P- Alder reaction are (A) efficient introduction of the norborna-
glycoprotein inhibitory properties (Scheme 1). Biosynthetically, diene via ketone addition and (B) mild unmasking of the
1 is proposed to derive from a tigliane precursor and features an norbornadiene, neither of which have previously been examined
unprecedented 5−5−6−6−3-fused pentacyclic carbon skeleton in the context of complex molecule total synthesis.
with an embedded bicyclo[2.2.1]heptane (pedrolane scaffold; Retrosynthetic analysis of (+)-pedrolide (1) (Scheme 2)
see SI for proposed biogenesis from tigliane precursor). The suggested olefin I as a precursor to the α-methyl ketone in the
complex nature of the highly congested skeleton in 1 renders it target. This functional group interconversion revealed the full
retron of an intramolecular Diels−Alder reaction for con-
Scheme 1. (+)-Pedrolide and Key Synthetic Steps struction of the bicyclo[2.2.1]heptene in I from 5-substituted
cyclopentadiene II. Opening the δ-lactone in II would lead to

Scheme 2. Retrosynthetic Analysis

Received: February 27, 2023

Published: April 4, 2023

© 2023 American Chemical Society https://doi.org/10.1021/jacs.3c02113

8332 J. Am. Chem. Soc. 2023, 145, 8332−8337
Journal of the American Chemical Society pubs.acs.org/JACS Communication

tertiary alcohol III, which was envisioned to be derived from 4). Oxidative dearomatization with PhI(OAc)2 in 74% yield,17
ketone IV. A key challenge of the illustrated retroanalysis is how followed by enantioselective copper-catalyzed conjugate
to manage the cyclopentadiene in III en route to II.
Despite their high reactivity in Diels−Alder reactions,5 5- Scheme 4. Synthesis of Ketone 9a
alkyl-substituted cyclopentadienes have found limited applica-
tion in total synthesis.6 Early examples such as Corey’s landmark
synthesis of prostaglandins F2α and E2 showcase that such
building blocks are usually prepared in situ or reacted
immediately after preparation.7 This is mainly attributed to
facile 1,5-sigmatropic hydrogen shifts,8 which result in isomer-
ization to the thermodynamically more stable isomers at a
significant rate at 25 °C.9,10 These and other potential issues,
such as the high dimerization tendency of cyclopentadienes,11,12
prompted us to search for an alternative that would serve as a
stable moiety over several steps and be unmasked to produce the
highly reactive 5-substituted cyclopentadiene at a predeter-
mined step late in the synthesis.
Multiple possibilities were considered for masked cyclo-
pentadienes, which would need to fulfill the following criteria
(Scheme 3, A): They would need to be competent nucleophiles

Scheme 3. Key Challenge

a
Reagents and conditions: (a) PhI(OAc)2, MeOH, 0 °C, 1 h, 74%;
(b) Cu(OTf)2 (2.6 mol %), SI-L1 (5.7 mol %), PhMe, rt, 1.5 h, then
3, Me2Zn, −25 °C, 15 h, 62%, >99% ee; (c) Me3SiOTf, Et3N, CH2Cl2,
−78 °C, 1.5 h, then m-CPBA, NaHCO3, −78 °C, 2.5 h, then n-
Bu4NF·3H2O, −78 to −20 °C, 1.5 h, 45%; (d) 6, THF, −78 to −20
°C, 1.5 h; (e) EtOAc, sat. aq. NH4Cl, rt, 1 h, 59% (two steps); (f)
Et3SiOTf, 2,6-lutidine, CH2Cl2, −78 °C, 2.5 h, 96%; (g) Fe(acac)3,
PhSiH3, EtOH, 60 °C, 20 min, 98%.

addition by use of (S,R,R)-phosphoramidite ligand SI-L1 and

Me2Zn in 62% and >99% ee according to Feringa and co-workers
provided ample quantities of known enone 4.18 The latter was
subjected to a one-pot reaction sequence consisting of silyl-enol
ether formation, Rubottom oxidation, and deprotection to give
α-hydroxy enone 5 in 45% yield.
Treatment of 5 with isopropenyl magnesium bromide (6)
furnished the corresponding diol, which partially hydrolyzed
upon work-up and was converted to enone 7 after complete ketal
deprotection with sat. aq. NH4Cl (59% yield over two steps).
for addition to ketone IV. Adduct V would then need to be stable The Grignard addition delivered a mixture of diastereomers at
over a number of steps. Finally, subjection to preferably mild C(13) in 5:1 dr (1H NMR analysis of unpurified reaction
conditions should release the substituted cyclopentadiene in II mixture) in favor of desired product 7, which could be isolated as
in situ for intramolecular cycloaddition. Of the potential a single isomer after chromatography on silica gel. The
candidates considered,13,14 we were particularly attracted to stereochemical assignment of the newly formed stereogenic
C(7)-metalated norbornadiene derivative VI.15 The lithiated center was determined by NOESY experiments. We speculate
species would readily be accessed and,15 additionally, recent that the vicinal C(12) hydroxy-group directs the addition of the
reports suggest mild ways of unmasking the cyclopentadiene, Grignard reagent, thereby installing the 1,2-anti diol motif
which we could examine in a complex setting.16 common to tigliane diterpenoids.4 Protection of the diol in 7 by
In a recent study aimed at accessing disubstituted cyclo- use of Et3SiOTf provided enone 8 in 96% yield. Treatment of 8
pentadienes it has been reported that 2,3-disubstituted with PhSiH3 and Fe(acac)3 resulted in conjugate addition to give
norbornadienes undergo inverse-electron-demand Diels− desired cyclopropyl ketone 9 in excellent yield (98%).19 This
Alder reactions with 1,2,4,5-tetrazines (Scheme 3, B).16a HAT-initiated cyclopropanation completes the synthetic
Following a sequence of reactions, the corresponding cyclo- sequence delivering the natural product’s fully functionalized
pentadienes are generated in situ and trapped with dimethyl carane fragment in a concise and enantioselective fashion.
acetylenedicarboxylate. Although the reaction has been used in With ketone 9 in hand, we set out to synthesize key Diels−
click coupling of polymers,16c,d it has not found application in Alder reaction precursor 17 (Scheme 5). Initial attempts at side-
the setting of complex molecule synthesis. chain installation by deprotonation of 9 with LiNi-Pr2 or
The synthesis of pedrolide (1) commenced with the rapid LiN(SiMe3)2, followed by addition of (S)-Roche ester derived
construction of ketone 9 from 4-methoxyphenol (2) (Scheme aldehyde 10, gave desired aldol product 11 in merely 20−30%
8333 https://doi.org/10.1021/jacs.3c02113
J. Am. Chem. Soc. 2023, 145, 8332−8337
Journal of the American Chemical Society pubs.acs.org/JACS Communication

Scheme 5. Synthesis of Enoate 17a Bu4NF provided triol 15 in 80% yield. The latter was subjected
to Piancatelli’s and Margarita’s TEMPO oxidation protocol
(PhI(OAc)2) giving lactone 16 in 76% yield.25 Finally,
treatment of 16 with MeSO2Cl furnished enoate 17 (60%),
setting the stage for the key Diels−Alder reaction cascade.
Preliminary studies on the conversion of 17 to bicyclo[2.2.1]-
heptene 19 through a sequence of inverse-electron-demand
Diels−Alder reaction (1, Scheme 6), nitrogen extrusion (2) and

Scheme 6. Diels−Alder Reaction Cascade of Enoate 17

a
Reagents and conditions: (a) LiNi-Pr2, THF, −78 °C, 1 h, then
Me3SiCl, −78 to −10 °C, 35 min; (b) MeLi, THF−Et2O, 0 °C, 20
min, then 10, −78 °C, 1.5 h, then Me3SiOTf, Et3N, −78 °C, 2 h, 11 +
12 78% (two steps); (c) Me3SiCl, imidazole, DMF, 0 °C to rt, 40
min, 86%; (d) 7-chloronorbornadiene, lithium 4,4′-di(tert-butyl)-
biphenyl, THF, −78 °C, 15 min, then 12, −78 °C, 2 h, 81%; (e) n-
Bu4NF, THF, −10 °C, 25 min, 80%; (f) TEMPO (30 mol %),
PhI(OAc)2, CH2Cl2, rt, 36 h, 76%; (g) MeSO2Cl, Et3N, DMAP,
CH2Cl2, 0 to 40 °C, 30 h, 60%.

yield with concomitant formation of a large amount of

unidentified side-products. Gratifyingly, conversion of 9 to its
Me3Si-enol ether proceeded smoothly. Subjection of the crude retro-Diels−Alder reaction (3), followed by intramolecular
enol ether to a reaction sequence consisting of lithium enolate Diels−Alder reaction (4) included treatment with 1.2 equiv of
generation (MeLi),20 aldol reaction with 10, and in situ 3,6-di-2-pyridyl-1,2,4,5-tetrazine (18) in CHCl3 at room
treatment with Me3SiOTf gave a mixture of aldol adduct as temperature.16a,c Although we were pleased to observe
alcohol 11 in 48% and silyl ether 12 in 30% yield from 9 and as formation of desired bicycloheptene 19, the reaction gave rise
single diastereomers (determined by 1H NMR spectroscopy).21 to a mixture of 19, unreacted starting material, and adducts such
Silylation of isolated 11 was effected using Me3SiCl (86%).22 as 20.26 These findings suggested that 17 undergoes the desired
At this stage we turned our attention to the introduction of the Diels−Alder reaction sequence producing 19, which in turn
pivotal norbornadienyl group. In 2003 Sutton and co-workers reacts readily with 18 in an inverse-electron-demand Diels−
reported the 1,2-addition of 7-lithio-norbornadiene (13)15 to Alder reaction giving rise to 20 after nitrogen extrusion, followed
trans-oct-2-enal in the course of a prostaglandin synthesis, by tautomerization. Accordingly, the competitive reaction of
wherein the adduct was subjected to oxidation and rearrange- tetrazine 18 with both 17 and 19 would initially lead to complex
ment to afford a trisubstituted cyclopentene.23 To the best of our reaction mixtures with high side-product ratios and low product
knowledge, no addition to ketones or more densely function- yields.
alized substrates is known. Despite of the hindered nature of the To harness the full potential of the Diels−Alder reaction
ketone in 12 and the presence of potentially epimerizable sites, cascade, we turned to the exploration of substoichiometric
treatment of 12 with 13 (obtained from 7-chloronorbornadiene tetrazine use with the aim of reisolating unreacted starting
by reduction with lithium 4,4′-di(tert-butyl)biphenyl24) fur- material 17. In addition, extensive optimization was performed
nished alcohol 14 in 81% yield as single diastereomer (1H NMR with regard to solvents, temperature, and additives (see SI for
analysis of unpurified reaction mixture). The stereochemical detailed experimental studies). While polar solvents (e.g.,
outcome of the ketone addition reaction was established by MeCN, DMF, MeOH) resulted in a better ratio of 19:17 and
NOESY experiments. Selective alcohol deprotection with n- side-products, less polar solvents (e.g., PhMe, 1-hexanol)
8334 https://doi.org/10.1021/jacs.3c02113
J. Am. Chem. Soc. 2023, 145, 8332−8337
Journal of the American Chemical Society pubs.acs.org/JACS Communication

performed worse. Decreasing the reaction temperature from Scheme 8. Completion of the Synthesisa
room temperature to 10 °C proved favorable for the reaction
outcome. Finally, we were able to identify optimized reaction
conditions (0.85 equiv 18, MeOH, 0 to 4 °C, 6 d, then
norbornadiene, rt, 36 h), which provided 19 in 56% yield with
34% reisolated 17 (85% brsm).
Successful access to bicycloheptene 19 allowed us to turn our
attention to the completion of the synthesis of 1. Diaster-
eoselective oxidation of 19 with m-CPBA furnished epoxide 21
in 80% yield (Scheme 7). Treatment of 21 with Me2CuLi

Scheme 7. Regioselective Epoxide Openinga

a
Reagents and conditions: (a) DMP, CH2Cl2, 0 °C to rt, 3 h, 83%;
(b) HF·pyridine, pyridine, THF, 0 °C to rt, 13 h; (c) i-PrCOCl, Et3N,
CH2Cl2, 0 to 50 °C, 4.5 h, 43% (two steps); (d) (PhCO)2O, pyridine,
DMAP, 0 to 40 °C, 60 h, 45%.

was constructed through a complex cascade, involving inverse-

electron-demand Diels−Alder → retro-Diels−Alder → retro-
Diels−Alder → intramolecular Diels−Alder reaction of enoate
17, introducing 7-substituted norbornadiene as a 5-cyclo-
pentadiene surrogate for complex molecule total synthesis.
The implementation of this powerful tool in natural product
synthesis broadens the scope of the Diels−Alder reaction for
highly congested and synthetically challenging structural motifs.

■
*
ASSOCIATED CONTENT
sı Supporting Information

a
The Supporting Information is available free of charge at
Reagents and conditions: (a) m-CPBA, NaHCO3, CH2Cl2, 0 °C to https://pubs.acs.org/doi/10.1021/jacs.3c02113.
rt, 12 h, 80%; (b) Me2CuLi, CH2(EtO)2, 0 to 50 °C, 30 h, 63% 22,
24% 21. Experimental procedures and characterization data for all
compounds and X-ray crystallographic data for 7 and 16
(PDF)
delivered alcohol 22 as a single regioisomer (1H NMR analysis
of unpurified reaction mixture) in 63% yield, allowing for Accession Codes
recovery of unreacted starting material 21 (24%). The excellent CCDC 2244481−2244482 contain the supplementary crystallo-
regioselectivity of this reaction can be understood by analysis of graphic data for this paper. These data can be obtained free of
transition states of the two potential products shown in Scheme charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
7. We suggest that the regioselectivity observed arises from ing [email protected], or by contacting The Cam-
consideration that the alternative attack would suffer from 1,3- bridge Crystallographic Data Centre, 12 Union Road, Cam-
diaxial Me ↔ Me noncovalent interactions. bridge CB2 1EZ, UK; fax: +44 1223 336033.
Alcohol 22 was readily converted to ketone 23 by Dess−
Martin oxidation (83%, Scheme 8). Global Et3Si-deprotection
(HF·pyridine), followed by acylation of the tertiary alcohol with
■ AUTHOR INFORMATION
Corresponding Author
i-PrCOCl, produced 24 in 43% yield over two steps. Erick M. Carreira − Department of Chemistry and Applied
Benzoylation of the secondary alcohol in 24 completed the Biosciences, Laboratory of Organic Chemistry, ETH Zürich,
total synthesis delivering (+)-pedrolide (1) in 45% yield. The 8093 Zürich, Switzerland; orcid.org/0000-0003-1472-
analytical data (1H NMR, 13C NMR, HRMS, IR, [α]25 D ) of 490X; Email: [email protected]
synthetic 1 is in agreement with the data reported for the isolated
material.3 Author
In conclusion, we have completed the first and enantiose- Marlene Fadel − Department of Chemistry and Applied
lective total synthesis of (+)-pedrolide (1) in 20 steps. The Biosciences, Laboratory of Organic Chemistry, ETH Zürich,
synthetic approach provides access to the unprecedented 8093 Zürich, Switzerland; orcid.org/0000-0002-2790-
pedrolane scaffold, a rearranged tigliane.3 A novel sequence 710X
comprising a diastereoselective isopropenyl Grignard addition Complete contact information is available at:
onto an α-hydroxy ketone and a HAT-initiated cyclopropana- https://pubs.acs.org/10.1021/jacs.3c02113
tion allows for efficient construction of the natural product’s
fully functionalized carane fragment. This constitutes a potential Funding
strategy for streamlined tigliane and tigliane derived natural We are grateful to the Swiss National Science Foundation
product synthesis. The embedded bicyclo[2.2.1]heptane in 1 (SNSF) and ETH Zurich for financial support.
8335 https://doi.org/10.1021/jacs.3c02113
J. Am. Chem. Soc. 2023, 145, 8332−8337
Journal of the American Chemical Society pubs.acs.org/JACS Communication

Notes (+)-Trehazolin. J. Org. Chem. 1998, 63, 3403−3410. (i) Ohkita, M.;
The authors declare no competing financial interest. Kawai, H.; Tsuji, T. Intramolecular Diels−Alder reaction of cyclopenta-
1,3-diene derivatives generated in situ from 4-(pent-4-enyl)cyclopent-
■ ACKNOWLEDGMENTS
We are grateful to Dr. Marc-Olivier Ebert, René Arnold, Rainer
2-enone ethylene ketals. J. Chem. Soc., Perkin Trans. 1 2002, 366−370.
(j) Hudon, J.; Cernak, T. A.; Ashenhurst, J. A.; Gleason, J. L. Stable 5-
Substituted Cyclopentadienes for the Diels−Alder Cycloaddition and
Frankenstein, and Stephan Burkhardt for NMR measurements their Application to the Synthesis of Palau’amine. Angew. Chem., Int. Ed.
and to Dr. Nils Trapp and Michael Solar for X-ray crystallo- 2008, 47, 8885−8888.
graphic analysis. (8) Woodward, R. B.; Hoffmann, R. Selection Rules for Sigmatropic
Reactions. J. Am. Chem. Soc. 1965, 87, 2511−2513.
■ REFERENCES
(1) (a) Shi, Q.-W.; Su, X.-H.; Kiyota, H. Chemical and
(9) According to kinetic studies by McLean and co-workers, the rate
constant for the rearrangement of 5-methylcyclopentadiene to 1-
methylcyclopentadiene is 1.8 · 10−4 s−1 at 25 °C.10d
Pharmacological Research of the Plants in Genus Euphorbia. Chem.
(10) (a) Mironov, V. A.; Sobolev, E. V.; Elizarova, A. N. Some General
Rev. 2008, 108, 4295−4327. (b) Vasas, A.; Hohmann, J. Euphorbia
Characteristic Properties of Substituted Cyclopentadienes. Tetrahedron
Diterpenes: Isolation, Structure, Biological Activity, and Synthesis
1963, 19, 1939−1958. (b) Mironov, V. A.; Sobolev, E. V.; Elizarova, A.
(2008−2012). Chem. Rev. 2014, 114, 8579−8612. (c) Zhan, Z.-j.; Li,
N. Substituted Cyclopentadienes and Related Compounds. Commu-
S.; Chu, W.; Yin, S. Euphorbia diterpenoids: isolation, structure,
nication 10. The Three Isomeric Methylcyclopentadienes. Bull. Acad.
bioactivity, biosynthesis, and synthesis (2013−2021). Nat. Prod. Rep.
Sci. USSR., Div. Chem. Sci. 1963, 12, 1467−1474. (c) McLean, S.;
2022, 39, 2132−2174.
Haynes, P. Hydrogen Migration in Cyclopentadienes. Tetrahedron
(2) Vasas, A.; Rédei, D.; Csupor, D.; Molnár, J.; Hohmann, J.
1965, 21, 2329−2342. (d) McLean, S.; Webster, C. J.; Rutherford, R. J.
Diterpenes from European Euphorbia Species Serving as Prototypes for
D. Kinetic isotope effect for the thermally-induced migration of
Natural-Product-Based Drug Discovery. Eur. J. Org. Chem. 2012, 2012,
hydrogen in cyclopentadienes. Can. J. Chem. 1969, 47, 1555−1559.
5115−5130.
(11) Sternbach, D. D.; Hobbs, S. H. Facile Synthesis of Alkoxyalkyl
(3) Ferreira, R. J.; Spengler, G.; Orthaber, A.; dos Santos, D. J. V. A.;
Cyclopentadienes. Synth. Commun. 1984, 14, 1305−1312.
Ferreira, M.-J. U. Pedrolane, a Polycyclic Diterpene Scaffold
(12) (a) Turnbull, A. G.; Hull, H. S. A Thermodynamic Study of the
Containing a Bicyclo[2.2.1]heptane System, from Euphorbia pedroi.
Dimerization of Cyclopentadiene. Aust. J. Chem. 1968, 21, 1789−1797.
Org. Lett. 2021, 23, 274−278.
(b) Krupka, J. Kinetics of Thermal Dimerization of Cyclopentadiene
(4) Wang, H.-B.; Wang, X.-Y.; Liu, L.-P.; Qin, G.-W.; Kang, T.-G.
and Methylcyclopentadienes and Their Codimerization. Pet. Coal
Tigliane Diterpenoids from the Euphorbiaceae and Thymelaeaceae
2010, 52, 290−306.
Families. Chem. Rev. 2015, 115, 2975−3011.
(13) More conventional ways of generating dienes in situ include
(5) Levandowski, B. J.; Raines, R. T. Click Chemistry with
elimination and retro-cyclization. For the considered surrogates for
Cyclopentadiene. Chem. Rev. 2021, 121, 6777−6801.
cyclopentadiene (e.g., see below), extensive literature research revealed
(6) For selected reviews on the Diels−Alder reaction, see: (a) Fallis, A.
G. The intramolecular Diels−Alder reaction: recent advances and their reported or likely instability, and none was found to fulfill the
synthetic applications. Can. J. Chem. 1984, 62, 183−234. (b) Nicolaou, mentioned requirements comparably to norbornadiene VI.14
K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis, G. The Diels−
Alder Reaction in Total Synthesis. Angew. Chem., Int. Ed. 2002, 41,
1668−1698. (c) Takao, K.-i.; Munakata, R.; Tadano, K.-i. Recent
Advances in Natural Product Synthesis by Using Intramolecular Diels−
Alder Reactions. Chem. Rev. 2005, 105, 4779−4807. (d) Juhl, M.;
Tanner, D. Recent applications of intramolecular Diels−Alder reactions
to natural product synthesis. Chem. Soc. Rev. 2009, 38, 2983−2992.
(e) Heasley, B. Stereocontrolled Preparation of Fully Substituted
Cyclopentanes: Relevance to Total Synthesis. Eur. J. Org. Chem. 2009, (14) (a) Blümel, J.; Köhler, F. H.; Müller, G.; Wilkinson, D. L.
2009, 1477−1489. (f) Heravi, M. M.; Vavsari, V. F. Recent applications Blocking of the Retro-Diels−Alder Reaction by Complex Formation:
of intramolecular Diels−Alder reaction in total synthesis of natural [(η5-Cyclopentadienyl)(η5-dicyclopentadienyl)iron]. Angew. Chem.,
products. RSC Adv. 2015, 5, 50890−50912. (g) Sara, A. A.; Um-e- Int. Ed. Engl. 1988, 27, 977−979. (b) Blümel, J.; Köhler, F. H. Direkte
Farwa, U.-e.-F.; Saeed, A.; Kalesse, M. Recent Applications of the und indirekte Metallierung von endo-Dicylopentadien. 119Sn- und 13C-
Diels−Alder Reaction in the Synthesis of Natural Products (2017− NMR Studie stannylierter Folgeprodukte. J. Organomet. Chem. 1988,
2020). Synthesis 2022, 54, 975−998. 340, 303−315. (c) Little, R. D.; Venegas, M. G. A New, Mild Method
(7) For selected examples of the application of 5-substituted for the Synthesis of Azo Compounds. J. Org. Chem. 1978, 43, 2921−
cyclopentadienes, see: (a) Corey, E. J.; Weinshenker, N. M.; Schaaf, 2923. (d) Little, R. D.; Carroll, G. L. Electrochemical Generation of the
T. K.; Huber, W. Stereo-Controlled Synthesis of Prostaglandins F2α and Azo Linkage. Synthesis of Bicyclic Azo Compounds, Precursors of 1,3-
E2 (dl). J. Am. Chem. Soc. 1969, 91, 5675−5677. (b) Brieger, G.; Diyls. J. Org. Chem. 1979, 44, 4720−4722. (e) Cohen, S. G.; Zand, R.;
Anderson, D. R. A New Route to Brex-4-ene. J. Org. Chem. 1971, 36, Steel, C. Preparation and Kinetics of Decomposition of a Bicyclic Azo
243−244. (c) Paquette, L. A.; Wyvratt, M. J. Domino Diels−Alder Compound. A Novel Reduction. J. Am. Chem. Soc. 1961, 83, 2895−
Reactions. I. Applications to the Rapid Construction of Polyfused 2900. (f) Stille, J. K.; Anyos, T. A Novel Diimide Reduction. J. Org.
Cyclopentanoid Systems. J. Am. Chem. Soc. 1974, 96, 4671−4673. Chem. 1962, 27, 3352−3353. (g) Wang, C.-X.; Sheridan, R. S. Synthesis
(d) Snowden, R. L. The Intramolecular [4 + 2]π Cycloadditions of (3- and Reaction of 2,3-Diazabicyclo[2.2.1]hept-5-ene. Tetrahedron Lett.
Alkenyl)cyclopentadienes. Tetrahedron Lett. 1981, 22, 97−100. 1993, 34, 5673−5676.
(e) Snowden, R. L. A Stereoselective Total Synthesis of (±)-Sativene. (15) Stapersma, J.; Klumpp, G. W. 7-Lithio-Norbornadiene.
Tetrahedron Lett. 1981, 22, 101−102. (f) Stille, J. R.; Grubbs, R. H. Tetrahedron 1981, 37, 187−189.
Intramolecular Diels−Alder Reaction of α,β-Unsaturated Ester (16) (a) Dalkılıç, E.; Daştan, A. Synthesis of cyclopentadiene
Dienophiles with Cyclopentadiene and the Dependence on Tether derivatives by retro-Diels−Alder reaction of norbornadiene derivatives.
Length. J. Org. Chem. 1989, 54, 434−444. (g) Goering, B. K.; Ganem, B. Tetrahedron 2015, 71, 1966−1970. (b) Pilgrim, B. S.; Roberts, D. A.;
Total Synthesis of (±)-Allosamizoline from a Symmetric Trisubstituted Lohr, T. G.; Ronson, T. K.; Nitschke, J. R. Signal transduction in a
Cyclopentene. Tetrahedron Lett. 1994, 35, 6997−7000. (h) Li, J.; Lang, covalent post-assembly modification cascade. Nat. Chem. 2017, 9,
F.; Ganem, B. Enantioselective Approaches to Aminocyclopentitols: A 1276−1281. (c) St. Amant, A. H.; Discekici, E. H.; Bailey, S. J.; Zayas,
Total Synthesis of (+)-6-Epitrehazolin and a Formal Total Synthesis of M. S.; Song, J.-A.; Shankel, S. L.; Nguyen, S. N.; Bates, M. W.;

8336 https://doi.org/10.1021/jacs.3c02113
J. Am. Chem. Soc. 2023, 145, 8332−8337
Journal of the American Chemical Society pubs.acs.org/JACS Communication

Anastasaki, A.; Hawker, C. J.; Read de Alaniz, J. Norbornadienes:

Robust and Scalable Building Blocks for Cascade “Click” Coupling of
High Molecular Weight Polymers. J. Am. Chem. Soc. 2019, 141, 13619−
13624. (d) Tran, T. M.; Read de Alaniz, J. Controlled Synthesis of a
Homopolymer Network Using a Well-Defined Single-Component
Diels−Alder Cyclopentadiene Monomer. J. Am. Chem. Soc. 2023, 145,
3462−3469.
(17) Meister, A. C.; Sauter, P. F.; Bräse, S. A Stereoselective Approach
to Functionalized Cyclohexenones. Eur. J. Org. Chem. 2013, 2013,
7110−7116.
(18) Imbos, R.; Brilman, M. H. G.; Pineschi, M.; Feringa, B. L. Highly
Enantioselective Catalytic Conjugate Additions to Cyclohexadienones.
Org. Lett. 1999, 1, 623−626.
(19) Lo, J. C.; Yabe, Y.; Baran, P. S. A Practical and Catalytic
Reductive Olefin Coupling. J. Am. Chem. Soc. 2014, 136, 1304−1307.
(20) Stork, G.; Hudrlik, P. F. Isolation of Ketone Enolates as
Trialkylsilyl Ethers. J. Am. Chem. Soc. 1968, 90, 4462−4464.
(21) The configuration at C(7) for 11 and 12 is seemingly
inconsequential, because the alcohol is subjected to an elimination
reaction later in the synthesis. The configuration shown for both
adducts at Cα-ketone was established by NOESY experiments. The
configuration at Cβ, or C(7), could not be determined at this stage of
the synthesis. However, on the basis of the X-ray crystal structure
obtained for 16 later in the route, we suggest the assignment as shown
for 11 and 12.
(22) It should be noted that in situ protection of 11 was desirable, as
signs of decomposition of the free alcohol were observed on several
occasions during work-up, purification, or drying of the product under
high vacuum.
(23) Bickley, J. F.; Jadhav, V.; Roberts, S. M.; Santoro, M. G.; Steiner,
A.; Sutton, P. W. Synthesis of Optically Active Prostaglandin-J2 and 15-
Deoxy-Δ12,14-prostaglandin-J2. Synlett 2003, 2003, 1170−1174.
(24) Freeman, P. K.; Hutchinson, L. L. Organolithium Reagents from
Alkyl Halides and Lithium Di-tert-Butylbiphenyl. Tetrahedron Lett.
1976, 17, 1849−1852.
(25) De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli,
G. A Versatile and Highly Selective Hypervalent Iodine (III)/2,2,6,6- Recommended by ACS
Tetramethyl-1-piperidinyloxyl-Mediated Oxidation of Alcohols to
Carbonyl Compounds. J. Org. Chem. 1997, 62, 6974−6977.
(26) 20 and other species were observed in the NMR spectrum of the Total Syntheses of Scabrolide A and Yonarolide
unpurified reaction mixture. 20 was isolated for structural assignment. Roberto Serrano, David Sarlah, et al.
The other species were tentatively assigned as isomers or derivatives of APRIL 17, 2023
20 by analogy (see SI for detailed experimental studies). JOURNAL OF THE AMERICAN CHEMICAL SOCIETY READ

Asymmetric Total Synthesis of the Rearranged Steroid

Phomarol Enabled by a Biomimetic SN2′ Cyclization
Xudong Wang, Jinghan Gui, et al.
APRIL 12, 2023
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY READ

Total Synthesis of Strempeliopidine and Non-Natural

Stereoisomers through a Convergent Petasis
Borono–Mannich Reaction
Alexander W. Rand, Brian M. Stoltz, et al.
MARCH 23, 2023
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY READ

Total Synthesis of Vilmoraconitine

Jiujian Ji, Yong Qin, et al.
FEBRUARY 13, 2023
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY READ

Get More Suggestions >

8337 https://doi.org/10.1021/jacs.3c02113
J. Am. Chem. Soc. 2023, 145, 8332−8337