Total Synthesis of Isomalabaricane Triterpenoids | Journal of the

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The Total Synthesis of Isomalabaricane Triterpenoids Yaroslav D Boyko, Christopher J. Huck, and David Sarlah J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b08487 • Publication Date (Web): 26 Aug 2019 Downloaded from pubs.acs.org on August 26, 2019

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Journal of the American Chemical Society

The Total Synthesis of Isomalabaricane Triterpenoids Yaroslav D. Boyko‡, Christopher J. Huck‡, David Sarlah* Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, IL 61801, United States.

Supporting Information Placeholder

ABSTRACT: The first total syntheses of (±)‑rhabdastrellic acid A and (±)-stelletin E, highly cytotoxic isomalabaricane triterpenoids, have been accomplished in a linear sequence of 14 steps from commercial geranylacetone. The exceptionally strained trans-syntrans-perhydrobenz[e]indene core characteristic of the isomalabaricanes is efficiently accessed in a selective manner through a rapid, complexity-generating sequence. This process features a reductive radical polyene cyclization, an unprecedented oxidative Rautenstrauch cycloisomerization, and umpolung 𝛼-substitution of a p-toluenesulfonylhydrazone with in situ reductive transposition. A late-stage cross-coupling in concert with a modular approach to polyunsaturated side chains renders this a general strategy for the synthesis of numerous family members of these synthetically challenging and hitherto inaccessible marine triterpenoids.

Me

O

H

Me

O

13

14

H Me Me

Me

Δ13(14) = E, rhabdastrellic acid A (1)

Me

IC50 = 1.46 µM (HL-60)

Δ13(14) = Z, stelletin E (2)

IC50 = 3.9 nM (HCT-116)

Me HO

O Me

O

H

Δ13(14) = E, stelletin A (3)

O

Me

ED50 = 2.16 nM (P388)

13

H

Me

Me

Δ13(14) = Z, stelletin B (4)

14

Me

O Me

Me

AcO Me H

Me

H

Me

Me

O Me

O OH

OH

stelliferin riboside (5) IC50 = 0.22 nM (L5178Y)

H Me

Rhabdastrellic acid A (1) and stelletin E (2) are among the flagship members of the isomalabaricane triterpenoids, a rare family of marine natural products that continue to attract attention for their remarkably specific antitumor properties (Figure 1).1 These selective apoptosis inducers boast nanomolar mean GI50 concentrations against the NCI-60 Human Tumor Cell Lines panel, but with a range that spans three orders of magnitude.2 The stelletins (2-4) have been heralded as promising lead compounds for targeted therapy,1c with stelletin E (2) exhibiting a 117-fold increase in potency against p21deficient HCT-116 human colon cancer cell lines when compared with the wildtype.3 Stelliferin riboside (5), an unusual glycosylated isomalabaricane, was found to be extremely toxic to the L5178Y mouse lymphoma cell line, with an IC50 value of 0.22 nM.4 Rhabdastrellic acid A (1) and the stelletins (2-4) induce apoptosis at nanomolar concentrations in human colon, leukemia, glioblastoma, and non-small cell lung cancer cell lines, and they have been shown to interfere with PI3K/Akt/mTOR growth factor signaling and induce G1 arrest and autophagic cell death—all while demonstrating minimal

IC50 = 0.010 µM (SF295)

Me IC50 = 0.022 µM (A549) HO

O

IC50 = 0.043 µM (HCT-116)

O

Me

Figure 1. Selected isomalabaricane triterpenoids

toxicity within healthy tissues.5 Despite these exciting preliminary reports, the isomalabaricane scaffold remains largely unexplored as an anticancer lead.1 To date, no complete apoptotic mechanism of action has been proposed, no specific molecular targets have been confirmed, no pharmacophore has been elucidated for this molecular framework, and detailed studies have been precluded by the scarcity of these compounds. The need for foundational biochemical investigations, bolstered by the possibility for analogue synthesis and drug development, lends a distinct urgency to the creation of an efficient and modular strategy to synthesize the isomalabaricane triterpenoids. Nonetheless, and despite several impressive efforts, the isomalabaricanes have yet to succumb to total synthesis in the 38 years since their first isolation.6 This is perhaps due to the complexity of their trans-syn-trans perhydrobenz[e]indene core, whose imposing strain and unorthodox boat-boat conformation stymies many of the traditional synthetic techniques for constructing polycyclic terpene systems. This singular motif has never been

1 ACS Paragon Plus Environment

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Me

O

a)

A

Me

Rautenstrauch Cycloisomerization

H B C

Me Me

O

Me

PivO H Me Me

TIPSO

Me

H

8

11

H

Me

Me

[14 steps]

Me

Me

H

6

Me

O

Me

Me

Me

O Me

TIPSO Me geranylacetone (10) $0.76/g

PivO H Me

TIPSO Me

Me

O

Zincke Reaction

rhabdastrellic acid A (1) stelletin E (2)

b)

Me

TIPSO

Stille Coupling

Me HO

O

H Me Me

Me

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Me

Me

[Au]

TIPSO Me

H

Me

O

Me

O

Me Radical Polyene Cyclization

Me

+ OPiv H3O

TIPSO

t-Bu

Me

6

H

Me

7

H

Me

9

Me 8

TIPSO Me

H

O

Me

8

Figure 2. (a) Retrosynthetic approach to the isomalabaricanes. (b) Mechanism of the Rautenstrauch rearrangement.

prepared in a selective fashion through chemical synthesis.7 With a keen interest in furthering the biological evaluation of the isomalabaricanes, we set out to provide a general solution to this tenacious problem in terpene synthesis. Herein we report a novel annulation strategy that enables the synthesis of the trans-syn-trans core of the isomalabaricane triterpenoids in only eight steps from commercial geranylacetone, as well as the first total syntheses of (±)-rhabdastrellic acid A (1) and (±)stelletin E (2). In the early stages of strategic design, we endeavored to develop a general blueprint for isomalabaricane triterpenoid synthesis that was amenable to diversification and analogue generation. To provide access to the myriad isomalabaricanes that differ only in the structure of their pendent side chain, we planned for a late-stage cross-coupling with an electrophile on the tricyclic core, after the key stereochemistry had been established at the BC-ring junction. The strained boat conformation in the B-ring severely circumscribes the methods available for its construction, and it has been well documented that conventional polyene cyclizations in bulk solution do not provide this stereochemical outcome.7a Instead, we opted for a stepwise process involving a cyclopentannulation of a much simpler bicyclic framework. We envisioned that this could be achieved through a stereospecific cycloisomerization (Rautenstrauch rearrangement) of enyne 6 to build the C-ring and set the quaternary center at C-8,8 after which a stereocontrolled reduction of enone 7 could set the requisite core stereochemistry (Figure 2a). The Rautenstrauch rearrangement has been shown to proceed through a helical transition state that transfers stereogenicity from the propargylic carbon, in this case C-11, to the newly formed stereocenter, C-8 (Figure 2b).8b Enyne 6 can be readily traced back to the bicyclic framework 9, a common derivative of the Wieland–Miescher ketone, which we speculated could be more swiftly synthesized from commercially available

geranylacetone (10) through a polyene cyclization (Figure 2a). The synthesis begins with two chemoselective modifications of this simple linear terpene to activate it for cyclization (Figure 3a). Commencing with geranylacetone (10), epoxynitrile 11 was synthesized by a modified van Leusen reductive cyanation of the ketone,9 followed by selective epoxidation of the terminal olefin.10 With all requisite carbons and reactive handles in place, construction of the bicyclic ketone 9 was accomplished with a Ti(III)-mediated reductive radical polyene cyclization11 and subsequent silylation of the resultant C-3 alcohol, generating an inconsequential 5:1 mixture of epimers on the C-8 position. Homologation of the ketone to an 𝛼,β– unsaturated aldehyde was achieved in 80% yield using dichloromethyllithium as a carbon source.12 A diastereoselective addition of lithium acetylide followed by in situ pivalate protection completed the synthesis of key cycloisomerization precursor 6 in 82% yield. We were pleased to find that, in one pass, this six-step sequence could produce more than five grams of enyne 6 as a single diastereomer, providing rapid entry into our studies on the stereocontrolled construction of the C-ring. Anticipating difficult regioselection during enolization of the saturated core, we planned to intercept enol pivalate 7 (Figure 2b)—the putative intermediate of the Rautenstrauch rearrangement—with an electrophile to selectively install a


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Journal of the American Chemical Society a) Me

Me 1. TosMIC, t-BuOK 94% 2. NBS, THF/H2O Me then K2CO3 geranylacetone (10) 82%, d.r. = 1:1 Me

O Me

O

Me

Me Me

Me Me

H 15 gram scale synthesis

Me

Me

H 9

F

H

12

5. LDA, CH2Cl2 then LiClO4 80%

TIPSO 6. C2H2, n-BuLi, Me then PivCl 82%, d.r. > 20:1

Me

Me

O

TIPSO Me

10. BH3,TfOH then H2O2 11. IBX 80% over 2 steps

H

H

16

Me

Me

H

PivO H Me Me H

6

[single crystal X-ray structure of 6, TIPS group omitted for clarity]

64% 9. Cp2ZrCl2, n-BuLi, then CuOAc, AcCl Me

Me

7. [Au(PPh3)Cl] AgOTf, Selectfluor® then NH2NHTs 81%, d.r. > 20:1

NHTs N

TIPSO

Me

O

TIPSO

4. TIPSOTf 95%

8. MeOH, Et3N then CatBH, CsOAc 58%, d.r. > 20:1

Me

Me

11

OMe

Me

H

Me 3. Cp2TiCl2, Zn 70%, d.r. = 5:1

Me

H

TIPSO

Me NC

O

Me

H O

Me

O Me H

17

Me

12. (COBr)2, DMF

H

O

Me

O Me Me H

Me

[single crystal X-ray structure of 17] Me

O

H

15. ℎ𝜈, 400 nm

O

Me H

Me

Me

Me

(±)-stelletin E (2)

b) Me

N Ts N

Me

TIPSO

Me

Me

Me

H

13

Me

Me

HN

H

14

Me

OMe H

13. Pd2(dba)3 Ph3As, 20 45%

O

[3 steps]

Bu3Sn

O Me

21 LHMDS

18

O (EtO)2P

69%

O

O OMe 21

Br

(±)-rhabdastrellic acid A (1)

3-picoline (19)

N

22

Me

Ref. 17

N

TIPSO

Me

HO

OH

Me

H Me Me

Me

O

14. Me3SnOH 98%, d.r. = 8:1 or 14. LiOH 96%, d.r. = 1.9:1

O

Me

Me

c)

H

Me

33%, 63% recovered 1 (53% 2 after two cycles)

Me

Me

O

H

Me

Bu3Sn

Me

OMe Me

Me 20

Figure 3. (a) The total synthesis of (±)-rhabdastrellic acid A (1) and (±)-stelletin E (2). Reagents and conditions: 1. 10, TosMIC, t‑BuOK, Et2O, EtOH, 0 °C to 25 °C, 94%; 2. NBS, THF/H2O 2:1, 0 °C; K2CO3, MeOH, 25 °C, 82% (d.r. = 1:1); 3. Cp2TiCl2, Zn, THF, 25 °C; NaH2PO4, 70% (d.r. = 5:1); 4. TIPSOTf, 2,6-lutidine, DCM, 0 °C to 25 °C, 95%; 5. LDA, DCM, THF, –100 °C to 60 °C; LiClO4, CaCO3, DMPU, 140 °C 80%; 6. n-BuLi, C2H2, THF, –78 °C to –40 °C; PivCl, 25 °C, 82% (d.r. > 20:1); 7. Selectfluor®, Au(PPh3)Cl (2.5 mol%), AgOTf (2.5 mol%), DCM/MeCN, 25 °C; TsNHNH2 , 40 °C, 81% (d.r. > 20:1); 8. Et3N, CHCl3/MeOH, 24 °C; CatBH, 0 °C; CsOAc, 65 °C, 58% (d.r. > 20:1); 9. Cp2ZrCl2, n-BuLi, THF, 0 °C to 25 °C; CuOAc (20 mol%), AcCl, 55 °C, 64%; 10-11. BH3•DMS, THF, –78 °C to 25 °C; TfOH, 0 °C to 25 °C; H2O2, NaOH; IBX, EtOAc, 75 °C, 80%; 12-13. (COBr)2, DMF, DCM, 0 °C to 25 °C; Pd2(dba)3 (10 mol%), Ph3As (30 mol%), 20, NMP, 70 °C, 45% (d.r. = 8:1); 14. Me3SnOH, DCE, 75 °C, 98%; or LiOH, THF/H2O/MeOH, 50 °C, 96% (1:2 = 1.9:1); 15. ℎ𝜈, 400 nm, MeCN, 24 °C, 34%. (b) Relevant intermediates during reductive transposition. (c) Synthesis of 20: LHMDS, 21, THF, –10 °C; HMPA, –60 °C; 18, –78 °C to 25 °C, 69%.

The kinetic and thermodynamic obstacles to reduce 12 with the desired facial selectivity were substantial, requiring hydrogen delivery at a bis(neopentyl) carbon within a trisubstituted, electronically-deactivated olefin, from the concave face of the tricyclic system. After experimentation, we found that the proper stereochemistry could only be established through a reductive transposition, using the Kabalka modification of the Caglioti reaction.14 Upon treatment of 12 with catecholborane, exploration of the effect of 𝛼–substitution on the transposition process revealed simple alkyl and silyl ethers to be optimal for an efficient and selective sequence. With no

functional handle on the desired side of the resultant enone 8.8,13 Instead of the conventional protic additives used for the hydrolysis of enol ester 7,13 we investigated the use of electrophilic halogenating agents. We were delighted to find that, upon treatment of 6 with a cationic gold(I) catalyst in the presence of Selectfluor®, the envisaged annulation and functionalization proceeded in high efficiency to construct the C-ring 𝛼–fluoro enone as a single diastereomer. In situ formation of the corresponding p–toluenesulfonylhydrazone allowed for the isolation of 𝛼–fluoro hydrazone 12 in 81% yield on gram scale.



for triflation; thus, we shifted our attention towards halogenation protocols that did not require the use of base. Fortunately, bromination with the Vilsmeier reagent proved uniquely capable of delivering electrophile 22 as a single constitutional and geometrical isomer.19 We propose that this interesting selectivity derives from syn-pentane-like steric interactions during the βelimination of DMF (A more detailed discussion is provided in the Supporting Information). Stille coupling20 of this vinyl bromide with tetraenylstannane 20 assembled the methyl ester of rhabdastrellic acid A in 45% overall yield from triketone 17, in an 8:1 ratio with the isomeric methyl ester of stelletin E. Saponification of the former with trimethyltin hydroxide21 quantitatively delivered (±)-rhabdastrellic acid A (1), spectroscopically identical to the reported isolate.22 Alternatively, hydrolysis of this ester with aqueous lithium hydroxide yielded a separable 1:1.9 mixture of (±)-stelletin E (2) and (±)-rhabdastrellic acid A (1) in 96%. The isomalabaricanes have been widely reported to undergo facile C-13–C-14 olefin isomerization (i.e., 1 ⇌ 2) upon exposure to visible light.1,2 Thus, larger quantities of 2 could be obtained from 1 after irradiation with light and chromatographic separation, providing 2 in 33% yield. The remaining 1 could be easily recovered in 63% yield and resubjected to these equilibration conditions, affording 2 in 53% overall yield after two cycles. The syntheses of (±)-rhabdastrellic acid A (1) and (±)stelletin E (2) were accomplished in a linear sequence of 14 steps. This work presents the first total syntheses of isomalabaricane triterpenoids as well as the only highly selective chemical approach for the preparation of the exceptionally strained trans-syn-transperhydrobenz[e]indene core.7 Highlights of this strategy include the implementation of a rapid and scalable sequence to access synthetically useful Wieland–Miescher ketone derivatives, as well as the development of two unusual tandem reactions that dramatically improve step economy. The protocol for the construction of the side chain polyenylstannanes via Zincke aldehyde 18 is highly general, and should render the future synthesis of numerous isomalabaricane family members a straightforward endeavor. We believe this unconventional approach to the tricyclic core in concert with a versatile route for the side chains will serve as a universal strategy for the synthesis of the isomalabaricane triterpenoids, providing material for comprehensive biological mode-of-action studies that has hitherto been near-inaccessible.

synthetically useful electrophilic alkoxylating agents available to produce the requisite ether during the Rautenstrauch rearrangement, we opted to build this motif through an umpolung 𝛼–substitution of 12 during the reductive transposition.15 Gratifyingly, exposure of 12 to triethylamine in methanol promoted conjugate addition of the solvent into transiently generated azoalkene 13 (Figure 3b), followed by stereospecific addition of hydrogen to the desired face through retro-ene rearrangement of allylic diazene 14 under the standard conditions. This unconventional complexity-building annulation sequence from 6 to 15 constructs the C-ring, forges three contiguous stereocenters, including both challenging ring-fusion points entrenched within the tricyclic core, and establishes an allylic electrophile for subsequent elaboration in just two steps. Notably, the key trans-syntrans intermediate 15 could be obtained on gram scale in a single pass from geranylacetone (10) in only eight steps. With the nature of the allylic electrophile restricted by the demands of the reductive transposition, we required a suitable method to activate the relatively unreactive methyl ether for substitution. We found that the desired transformation could be achieved through reductive zirconation and copper-catalyzed cross-coupling with acetyl chloride.16 After sufficient optimization of this somewhat rare transformation, we were able to forge the desired C–C bond of deconjugated enone 16 in 64% yield. Relay hydroboration of this olefin from the ketone, followed by in situ deprotection of the silyl group with triflic acid and two-fold global oxidation furnished triketone 17 as a single constitutional isomer, whose structure was confirmed by single crystal X-ray diffraction analysis. Remarkably, the IBX oxidation delivered 17 almost exclusively in the tautomeric form shown in Figure 3. With the fully oxidized core of the isomalabaricanes in hand, the stage was set for the synthesis of the polyene side chain and the final cross-coupling. We identified stannanedienal 18, which could be prepared from 3picoline (19) in three steps according to literature precedent,17 as an ideal point of divergence for the synthesis of numerous side chain coupling partners through simple olefination or prenylation (Figure 3c). Following this strategy, we obtained the requisite coupling partner 20 through a Horner-Wadsworth-Emmons olefination with phosphonate 21.18 As we initiated studies into the formation of a suitable vinyl electrophile for crosscoupling, we found that the triketone 17 exhibited a strong bias against the selectivity we required. Chemoselective functionalization of nonsymmetric 1,3-diketones seems to be a largely unaddressed problem in organic synthesis. Although we isolated 17 almost completely in the exocyclic enol form, triflation under a wide variety of conditions delivered only the undesired endocyclic constitutional isomer. This is likely the result of basecatalyzed tautomerization under the conditions required

ASSOCIATED CONTENT Supporting Information.


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The Supporting Information is available free of charge on the ACS Publications website.

lettin B, a Triterpene from Marine Sponge Jaspis stellifera, on Human Glioblastoma Cancer SF295 Cells. Mar. Drugs 2014, 12, 4200–4213. (c) Wang, R.; Zhang, Q.; Peng, X.; Zhou, C.; Zhong, Y.; Chen, X.; Qiu, Y.; Jin, M.; Gong, M.; Kong, D. Stellettin B Induces G1 Arrest, Apoptosis and Autophagy in Human Non-small Cell Lung Cancer A549 Cells via Blocking PI3K/Akt/ mTOR Pathway. Scientific Reports 2016, 6, 27071. (6) First isolation: (a) Ravi, B.N.; Wells, R.J.; Croft, K. D. Malabaricane Triterpenes from a Fijian Collection of the Sponge Jaspis stellifera. J. Org. Chem 1981, 46, 1998-2001. Structural revision to trans-syn-trans: (b) McCabe, T.; Clardy, J.; Minale, L.; Pizza, C.; Zollo, F.; Riccio, R. A Triterpenoid Pigment with the Isomalabaricane Skeleton from the Marine Sponge Stelleta sp. Tetrahedron Lett. 1982, 23, 3307-3310. Prior work: (c) Rosner, K. E. Approaches to the Synthesis of Stelliferin, a Marine Isomalabaricane Triterpene. PhD Dissertation, MIT, 1996. (d) Raeppel, F.; Weibel, J-M.; Heissler, D. Synthesis of the trans-syn-trans perhydrobenz[e]indene moiety of the stellettins and of the stelliferins. Tetrahedron Letters 1999, 40, 6377– 6381. (e) Raeppel, F.; Heissler, D. Conversion of a trans–syn–trans to a cis–syn–trans perhydrobenz[e]indenone triggered by intramolecular 1,5-hydrogen transfer. Tetrahedron Letters 2003, 44, 3487–3488. (7) To the best of our knowledge, the trans-syn-trans perhydrobenz[e]indene has been accessed by three non-enzymatic chemical strategies prior to our work: (a) as a very minor component of a mixture of products via polyene cyclization, see Fish, V. P.; Sudhakar, A. R.; Johnson, W. S. Epoxide-Initiated Cationic Polyene Cyclizations. Tetrahedron Letters 1993, 34, 7849. (b) as a component of a 1.4:1 mixture of four tricyclic products formed via transannular Diels– Alder reaction of 13-membered macrocycles, see Bérubé, G. Deslongchamps, P. Synthesis and transannular diels-alder reaction of a 13-membered macrocyclic triene having a tetrasubstituted enol ether as a dienophile. Tetrahedron Letters 1987, 28, 5255-5258. (c) as one component of a 3:2 mixture of 5- and 6-membered rings obtained by cyclopropane ring opening of a substrate obtained through total synthesis, see ref 6d. (8) (a) Shi, X.; Gorin, D. J.; Toste, D. F. Synthesis of 2Cyclopentenones by Gold(I)-Catalyzed Rautenstrauch Rearrangement. J. Am. Chem. Soc. 2005, 127, 5802–5803. (b) Faza, O. N., López, C. S., Álvarez, R., & de Lera, A. R. Mechanism of the Gold(I)-Catalyzed Rautenstrauch Rearrangement: A Center-to-Helixto-Center Chirality Transfer. J. Am. Chem. Soc. 2006, 128, 2434– 2437. For an elegant example in total synthesis, see: (c) Huang, Y.W.; Kong, K.; Wood, J. L. Total Synthesis of (+)- and (±)-Hosieine A. Angew. Chem. Int. Ed. 2018, 57, 7664-7667. (9) Oldenziel, O. H.; Van Leusen, D.; Van Leusen, A. M. Chemistry of sulfonylmethyl isocyanides. 13. A general one-step synthesis of nitriles from ketones using tosylmethyl isocyanide. Introduction of a one-carbon unit. J. Org. Chem. 1977, 42, 3114–3118. (10) (a) Ting, C. P.; Xu, G.; Zeng, X.; Maimone, T. J. Annulative Methods Enable a Total Synthesis of the Complex Meroterpene Berkeleyone A. J. Am. Chem. Soc. 2016, 138, 14868–14871. (b) van Tamelen, E. E.; Curphey, T. J. The Selective In Vitro Oxidation of the Terminal Double Bonds in Squalene. Tetrahedron Letters 1962, 3, 121-124. (11) Fernández-Mateos, A.; Teijón, H. P.; Clemente, R. R.; González, R. R.; González, F. S. Stereoselective Radical Cascade Cyclizations of Unsaturated Epoxynitriles: Quadruple Radical Cyclization Terminated by a 4-exo Process onto Nitrile. Synlett 2007, 17, 2718– 2722. (12) (a) Taguchi, H.; Tanaka, S.; Yamamoto, H.; Nozaki, H. A new synthesis of α,β-unsaturated aldehydes including (e)2-methyl-2alkenal. Tetrahedron Lett. 1973, 14, 2465–2468. (b) Dethe, D. H.; Sau, S. K.; Mahapatra, S. Biomimetic Enantioselective Total Synthesis of (−)-Mycoleptodiscin A. Org. Lett. 2016, 18, 6392–6395. (13) Bürki, C.; Whyte, A.; Arndt, S.; Hashmi, A. S. K.; Lautens, M. Expanding the Scope of the Gold(I)-Catalyzed Rautenstrauch Rearrangement: Protic Additives. Org. Lett., 2016, 18, 5058–5061. (14) Initial reaction discovery: (a) Hutchins, R. O.; Milewski, C. A.; Maryanoff, B. E. Selective Deoxygenation of Ketones and Aldehydes Including Hindered Systems with Sodium Cyanoborohydride. J. Am. Chem. Soc. 1973, 95, 3662-3668. Conditions used in this work:

Detailed experimental procedures, spectroscopic data, and 1H and 13C NMR spectra (PDF) Crystallographic data for 6 (CIF) and 17 (CIF)

AUTHOR INFORMATION Corresponding Author

*[email protected] Author Contributions

‡These authors contributed equally. Notes

The authors declare no competing financial interest.

ACKNOWLEDGMENTS Financial support for this work was provided by the University of Illinois. D.S. is an Alfred P. Sloan Fellow and acknowledges unrestricted support from Bristol-Myers Squibb. C.J.H. would like to acknowledge support from a National Science Foundation Graduate Research Fellowship as well as a Robert C. and Carolyn J. Springborn Fellowship. We thank the SCS NMR Lab, Dr. D. Olson, and Dr. L. Zhu for technical support and NMR spectroscopic assistance. The Bruker 500-MHz NMR spectrometer was obtained with the financial support of the Roy J. Carver Charitable Trust, Muscatine, Iowa, USA. We also thank Alexander Shved, Dr. D. L. Gray, and Dr. T. Woods for Xray crystallographic analysis assistance, and F. Sun for mass spectrometric assistance.

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Radical Polyene O Cyclization

Me

Interrupted Rautenstrauch Cycloisomerization

H O

Me Me

H Me Me

Me

Me

Me O

Me

14 steps Me geranylacetone

Zincke Reaction

Me HO O

(±)-rhabdastrellic acid A

ACS Paragon Plus Environment

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Total Synthesis of Isomalabaricane Triterpenoids | Journal of the

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