pubs.acs.

org/JACS Communication

Enantioselective Total Synthesis of (+)-Alterbrassicicene C

Noah J. Sims, Weston C. Bonnet, Danielle M. Lawson, and John L. Wood*
Cite This: J. Am. Chem. Soc. 2023, 145, 37−40 Read Online

ACCESS Metrics & More Article Recommendations *

sı Supporting Information

ABSTRACT: Herein, the first total synthesis of (+)-alterbrassicicene C (2) is described. Key features of the synthesis include an
oxiranium mediated ether ring expansion, an oxa-Michael/retro-oxa-Michael cascade, and installation of a vinyl methoxy ether
See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

moiety via Stille coupling.

Downloaded via IISER THIRUVANANTHAPURAM on January 16, 2023 at 06:17:51 (UTC).

A recent report from Zhang and co-workers described the

isolation of seven novel fusicoccane diterpenoids from the
fungal plant pathogen Alternaria brassicicola.1 The most
Scheme 1. Retrosynthetic Analysis

complex of the isolated congeners, alterbrassicicenes B and C

(1 and 2, respectively), were found to possess unprecedented
tetracyclic oxa-bridged ring systems (Figure 1). Although

Figure 1. Isolates from Alternaria brassicola (1, 2) and a previously

prepared fusicoccane diterpenoid (3).

several fusicoccane diterpenoids possess important biological

activity and have been the focus of numerous synthetic efforts
(e.g., 3),2−5 there are no reports directed toward 1 and 2.
Intrigued by the densely packed ring system of 2 and
challenges associated with assembling the core structure, we
began developing a total synthesis. Herein we report these In implementing our planned approach (Scheme 2A), we
recent efforts which have culminated in the successful synthesis began by employing a yeast mediated reductive desymmetriza-
of 2. tion to convert dione 10 to known ketone 9 in 98 ee and >20:1
As illustrated retrosynthetically in Scheme 1, (+)-alter- dr.6,7 Alkylation of 9 with 2-iodopropane afforded the
brassiciciene C (2) was seen as arising from oxa-bicycle 4 via a isopropyl ketone 11 as an inconsequential mixture of
series of reactions, central to which would be a retro-oxa- diastereomers. Migration of the terminal olefin in 11
Michael/oxa-Michael cascade that would deliver the core (Grubbs-II) to the internal position was followed directly by
bicycle. Additionally, we hoped to leverage the conformational reductive ozonolysis to provide aldehyde 12 in good yield.8
preferences of intermediate 6 in facilitating the stereoselective Treatment of 12 with lithium hexamethyldisilazide (LiHMDS)
transannular migration of oxygen (red) from C1 to C8 (cf., 6 followed by phenyl triflimide furnished the corresponding vinyl
and 2), a sequence envisioned as proceeding via the
intermediacy of 5 and 4, which would respectively arise from
halo-etherification and Lewis acid promoted 1,2-migration Received: November 21, 2022
reactions. This strategic transfer of stereochemistry would then Published: December 23, 2022
be predicated upon effectively setting the C1 hydroxyl
stereochemistry in 6 via diastereoselective coupling of 7 and
8. The electrophilic component of this latter coupling,
aldehyde 8, would arise from the known cyclopentanone 9.
© 2022 The Authors. Published by
American Chemical Society https://doi.org/10.1021/jacs.2c12275
37 J. Am. Chem. Soc. 2023, 145, 37−40
Journal of the American Chemical Society pubs.acs.org/JACS Communication

Scheme 2. (A) Synthesis of Substituted Cyclopentene 8, (B) Scheme 3. Unexpected Formation of a Bis-oxa-bicycle
Synthesis of Bromo-cyclopentene 7

triflate, which was further advanced via Stille cross-coupling to

give skipped-diene 8 in 55% yield over the two steps.
Our point of departure for the preparation of vinyl bromide
7 (Scheme 2 B) was known bromo-vinylogous ester 139 which,
upon exposure to Corey’s modified Danheiser−Stork con-
ditions, furnished dienone 14 in 67% yield.10 Protection of the
derived ketone with ethylene glycol under Dean−Stark
conditions then gave the desired dioxolane 7.
Having prepared both 7 and 8, we turned next to their
coupling (Scheme 3). To this end, we found that exposure of 7
to tBuLi in Et2O as solvent, followed by addition of aldehyde 8, chemistry. This notion was thwarted by the discovery that,
produced a single diastereomer of intermediate alcohol 15 upon bromide abstraction (AgTFA) and presumed oxiranium
which, without purification, could be advanced to 6 via formation, 5a rapidly undergoes intramolecular SN2′ addition
Grubbs-II-promoted ring-closing metathesis and in situ of the pendant secondary alcohol and furnishes bis-oxa-bicycle
exposure to 2 M HCl (54% yield, two steps). Although high 16 in excellent yield. This unexpected outcome was
diastereoselectivity has been observed upon nucleophilic subsequently confirmed by single crystal X-ray analysis.
additions to α-methyl cyclopentene-carbaldehydes containing Although we had rapidly assembled the carbocyclic core of 2
substituents capable of chelation, we were hesitant to base a and successfully initiated the transannular migration of
structural assignment on these precedents given that siloxy hydroxyl from C1 to C8, the unanticipated formation of 16
ether 8 would be less prone to chelation.11 Fortunately, 6 derailed not only our planned approach to controlling the
proved to be a crystalline solid and thus single crystal X-ray functionality at C7 and C8 but also our intention of employing
analysis was employed to unambiguously assign the illustrated a late-stage oxa-Michael to construct the core ring system. To
stereochemistry of the newly formed and critical C1-hydroxyl. prevent formation of 16, we explored masking the hydroxyl in
To our delight, this analysis revealed that the highly 5 with a variety of protecting groups. However, these latter
diastereoselective coupling of 7 and 8 had furnished the C1- efforts proved unsuccessful, and we thus began considering
stereochemistry required for the planned synthesis. In addition, methods whereby we might reverse the undesired SN2′
it appeared that, at least in the solid state, the cyclooctadiene addition. To this latter end, we screened the reactivity of 16
moiety adopted a conformation poised for the planned toward a variety of Lewis acids (Scheme 4) and were delighted
transannular haloetherification. In practice, exposure of 6 to to discover that BCl3 rapidly promotes diastereoselective
N-bromosuccinimide smoothly induced the latter reaction as opening of the tetrahydrofuran in SN2′ fashion where chloride
well as concomitant removal of the TBS-group to furnish oxa- now serves as the nucleophile. Based on crystallographic data
bicycle 5. Next, we began exploring conditions for advancing 5 obtained on subsequent intermediates, the derived product
via 1,2-migration of the newly formed oxygen bridge. Based on (17) arises from exoaddition of the chloride anion to the oxa-
the pioneering work of Bartlett,12 we hoped that exposure of 5 bicycle thus delivering the illustrated diastereomer. Having
to a suitable halophile would induce formation of an reintroduced the enone moiety, we began preparing for oxa-
intermediate oxiranium ion (5a) which, upon capture by an Michael addition by subjecting 17 to hydroxyl-directed
external nucleophile (e.g., hydride), would generate 4 (Scheme epoxidation with m-CPBA and subsequent oxidation with the
1), thereby setting both the C7-methyl and C8-oxo stereo- Dess-Martin Periodinane. Exposure of the resultant keto-
38 https://doi.org/10.1021/jacs.2c12275
J. Am. Chem. Soc. 2023, 145, 37−40
Journal of the American Chemical Society pubs.acs.org/JACS Communication

Scheme 4. Novel Oxa-Michael Cascade Comins’s reagent. Interestingly, subjecting 21 to the Stille
conditions resulted in not only the desired coupling but also
the formation of a new tetrahydrofuran ring (cf. 21 and 23).
Given that the epoxide had proved stable during the
conversion of 20 to 21, we surmised that the ring forming
event leading to 23 was not the result of simple nucleophilic
epoxide opening but instead involved the likely intermediacy of
a π-allyl-palladium species (21a) that forms from the initial
Stille product.16,17
Unfortunately, efforts to advance 23 toward the natural
product proved fruitless. Thus, it became necessary to prevent
the deleterious ring formation by masking the nucleophilic
hydroxyl moiety of 21. As illustrated in Scheme 6, this was

Scheme 6. Completetion of (+)-Alterbrassicicene C

epoxide 18 to DBU in methanol initiates a cascade that

involves β-eliminative epoxide opening (18a), trans-annular
oxa-Michael addition (18b), and completion of the C1 to C8
oxygen transfer by β-eliminative opening of bis-oxa-adaman-
tane intermediate 18c to furnish 19, which possesses the core
5/6/6/5 ring system of 2.13 Interestingly, a total of six C−C
and C−O bonds are either broken or formed in the course of
this oxa-Micahel/retro-oxa-Michael cascade.
With the core oxa-bicycle in place, efforts turned toward
introducing the remaining two oxygen atoms (Scheme 5). The
first was by way of a hydroxyl-directed nucleophilic
epoxidation of 19, which furnished 20.14 The remaining
oxygen resides in a pendent methoxy methyl moiety which we
found could be introduced via Stille-coupling of known stannyl
ether 22 with vinyl triflate 21,15 which was, in turn, readily
produced from ketone 20 using a combination of KHMDS and

Scheme 5. Unexpected Alkyl-Stille Byproduct accomplished by exposure of 21 to TESOTf in the presence of

2,6-lutidine to furnish the corresponding triethylsilyl ether 24.
Subjecting 24 to the previously employed Stille coupling
afforded the expected vinyl methoxy methyl ether 25 in 88%
yield. Introduction of the final carbonyl and TES deprotection
were next accomplished by treatment of 25 with BF3·Et2O,
followed by TBAF. Monitoring by NMR indicated that this
sequence proceeds by an initial Meinwald rearrangement
(epoxide ring opening and 1,2-hydride shift) and concomitant
double bond migration.18 This was followed by desilylation to
enone 26. Finally, exposure of 26 to radical dehalogenation
with AIBN and (Bu)3SnH afforded (+)-alterbrassicicene C
(2).
In conclusion, the enantioselective total synthesis of
(+)-alterbrassicicene C (2) has been achieved from known
ketone 9. The synthetic strategy leverages the conformational
preferences of the carbocyclic core structure to control the
stereochemistry in a series of transannular carbon−oxygen
bond forming reactions that culminate in an oxa-Michael/
retro-oxa-Michael cascade reaction of epoxide 18, which
delivers the requisite oxa-bicyclic core. In addition to providing
enantioselective access to the natural product our synthetic
efforts have produced numerous advanced intermediates that
39 https://doi.org/10.1021/jacs.2c12275
J. Am. Chem. Soc. 2023, 145, 37−40
Journal of the American Chemical Society pubs.acs.org/JACS Communication

can be used to access additional congeners and, given the (4) Huffman, T. R.; Kuroo, A.; Sato, R.; Shenvi, R. A. Concise
potent activity of many related fusicoccanes, assayed for Synthesis of (−)-Cotylenol, a 14-3-3 PPI Molecular Glue ChemRxiv
biological activity. Preprint, 2022-08-28. DOI: 10.26434/chemrxiv-2022-dcbd8 (Ac-
cessed 2022-08-28).

■ ASSOCIATED CONTENT
* Supporting Information
sı
(5) Chen, B.; Wu, Q.; Xu, D.; Zhang, X.; Ding, Y.; Bao, S.; Zhang,
X.; Wang, L.; Chen, Y. A Two-Phase Approach to Fusicoccane
Synthesis to Uncover a Compound that Reduces Tumourigensis in
The Supporting Information is available free of charge at Pancreatic Cancer Cells. Angew. Chem., Int. Ed. 2022, 61, 19.
https://pubs.acs.org/doi/10.1021/jacs.2c12275. (6) Brooks, D. W.; Grothaus, P. G.; Irwin, W. L. Chiral
Cyclopentanoid Synthetic Intermediates via Asymmetric Microbial
Experimental procedures, analytical data, spectra, and Reduction of Prochiral 2,2-Disubstituted Cyclopentanediones. J. Org.
crystallographic data for C25H40O3Si (6) and C19H24O3 Chem. 1982, 47, 2820−2821.
(16) (PDF) (7) The desired diastereomer (10:1 dr) could be separated from the
undesired diastereomer via flash column chromatography (see
Accession Codes Supporting Information).
CCDC 2222737−2222738 contain the supplementary crys- (8) Hanessian, S.; Giroux, S.; Larsson, A. Efficient Allyl to Propenyl
tallographic data for this paper. These data can be obtained Isomerization in Functionally Diverse Compounds with a Thermally
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by Modified Grubbs Second-Generation Catalyst. Org. Lett. 2006, 8,
emailing data_request@ccdc.cam.ac.uk, or by contacting The 5481−5484.
Cambridge Crystallographic Data Centre, 12 Union Road, (9) Kruger, A. C.; Kati, W. M.; Carroll, W. A.; Pratt, J. K.;
Cambridge CB2 1EZ, UK; fax: +44 1223 336033. Hutchinson, D. K. Anti-Viral Compounds U.S. Patent WO
2012083170, June 21, 2012.

■ AUTHOR INFORMATION
Corresponding Author
(10) He, F.; Bo, Y.; Altom, J. D.; Corey, E. J. Enantioselective Total
Synthesis of Aspidophytine. J. Am. Chem. Soc. 1999, 121, 6771−6772.
(11) Jacobi, P. A.; Selnick, H. G. Total Synthesis of (±)-Gnididione
John L. Wood − Department of Chemistry and Biochemistry, and (±)-Isognididione. J. Org. Chem. 1990, 55, 202−209.
Baylor University, Waco, Texas 76798, United States; (12) Bartlett, P. A.; Mori, I.; Bose, J. A. A Subtotal Synthesis of
orcid.org/0000-0002-9066-5588; Methynolide via an Electrophilic Spirocyclization Reaction. J. Org.
Email: John_L_Wood@baylor.edu Chem. 1989, 54, 3236−3239.
(13) Under modified conditions we were able to isolate the bis-oxa-
Authors adamantane intermediate (18c) as a minor product.
Noah J. Sims − Department of Chemistry and Biochemistry, (14) Stereochemistry was corroborated by low-quality X-ray crystal
Baylor University, Waco, Texas 76798, United States (see Supporting Information).
(15) Blaszczak, L. C.; Brown, R. F.; Cook, G. K.; Hornback, W. J.;
Weston C. Bonnet − Department of Chemistry and
Indelicato, J. M.; Jordan, C. L.; Katner, A. S.; Kinnick, M. D.;
Biochemistry, Baylor University, Waco, Texas 76798, United Mcdonald, J. H. Comparative Reactivity of 1-Carba-1-dethiacephalo-
States sporins with Cephalosporins. J. Med. Chem. 1990, 33, 1656−1662.
Danielle M. Lawson − Department of Chemistry and (16) Liang, X. T.; You, L.; Li, Y. H.; Yu, H. X.; Chen, J. H.; Yang, Z.
Biochemistry, Baylor University, Waco, Texas 76798, United Asymmetric Total Synthesis of Propindilactone G, Part 3: The Final
States Phase and Completion of the Synthesis. Chem. Asian J. 2016, 11,
1425−1435.
Complete contact information is available at:
(17) This route was initially explored with racemic material (see
https://pubs.acs.org/10.1021/jacs.2c12275 Supporting Information).
(18) Nagumo, S.; Miura, T.; Mizukami, M.; Miyoshi, I.; Imai, M.;
Notes Kawahara, N.; Akita, H. Intramolecular Friedel-Crafts type reaction of
The authors declare no competing financial interest. vinyloxiranes linked to an ester group. Tetrahedron 2009, 65, 9884−

■ ACKNOWLEDGMENTS
The authors thank Amy Jackson, Joey Tuccinardi, and Kevin
9896.

Klausmeyer for their assistance in obtaining and analyzing X-

ray crystallographic data. The authors also acknowledge
financial support from the Welch Foundation (Chair, AA-
006), then Cancer Prevention and Research Institute of Texas
(CPRIT, R1309), NIGMS-NIH (R01GM136759), and the
NSF (CHE-1764240).

■ REFERENCES
(1) Li, F.; Lin, S.; Zhang, S.; Pan, L.; Chai, C.; Su, J.-C.; Yang, B.;
Liu, J.; Wang, J.; Hu, Z.; Zhang, Y. Modified Fusicoccane-Type
Diterpenoids from Alternaria Brassicicola. J. Nat. Prod. 2020, 83,
1931−1938.
(2) Uwamori, M.; Osada, R.; Sugiyama, R.; Nagatani, K.; Nakada,
M. Enantioselective Total Synthesis of Cotylenin A. J. Am. Chem. Soc.
2020, 142, 5556−5561.
(3) Williams, D. R.; Robinson, L. A.; Nevill, R.; Reddy, J. P.
Strategies for the Synthesis of Fusicoccanes by Nazarov Reactions of
Dolabellaidenones: Total Synthesis of (+)-Fusicoauritone. Angew.
Chem., Int. Ed. 2007, 46, 915−918.

40 https://doi.org/10.1021/jacs.2c12275
J. Am. Chem. Soc. 2023, 145, 37−40