Total Synthesis of Lycopodium Alkaloids Palhinine A and Palhinine DFang-Xin Wang,† Ji-Yuan Du,† Hui-Bin Wang,† Peng-Lin Zhang,† Guo-Biao Zhang,† Ke-Yin Yu,†

Xiang-Zhi Zhang,† Xian-Tao An,† Ye-Xing Cao,† and Chun-An Fan*,†,‡

†State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, 222Tianshui Nanlu, Lanzhou 730000, China‡Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, China

*S Supporting Information

ABSTRACT: The first total syntheses of Lycopodiumalkaloids palhinine A, palhinine D, and their C3-epimershave been divergently achieved through the use of aconnective transform to access a pivotal hexacyclicisoxazolidine precursor. A microwave-assisted regio- andstereoselective intramolecular nitrone−alkene cycloaddi-tion was tactically orchestrated as a key step to install thecrucial 10-oxa-1-azabicyclo[5.2.1]decane moiety embed-ded in the conformationally rigid isotwistane framework,demonstrating the feasibility of constructing the highlystrained medium-sized ring by introduction of an oxygenbridging linker to relieve the transannular strain in thepolycyclic scaffold. Subsequent N−O bond cleavageprovided the synthetically challenging nine-memberedazonane ring system bearing the requisite C3 hydroxylgroup. Late-stage transformations featuring a chemo- andstereoselective reduction of the pentacyclic β-diketonesecured the availability of our target molecules.

Palhinine-type alkaloids (Figure 1),1 as members of theLycopodium family, have a unique 5/6/6/9 tetracyclic or 5/6/6/6/7 pentacyclic ring system characterized with a denselyfunctionalized isotwistane nucleus. Since the isolation ofpalhinine A from the whole plant of Palhinhaea cernua L.(Lycopodiaceae) byWang and Long in 2010,1a isopalhinine A andpalhinines B−D have been reported successively by Zhao1b andYu1c,d in 2013. Although no activity was observed in preliminarystudies, scarcity in nature precludes extensive biologicalevaluations of these alkaloids.1a−c Hence, exploration of a generalapproach for total synthesis of these Lycopodium alkaloids,together with their structurally related analogues, is requisite notonly for pursuing the novel molecular architecture but also forinvestigating their potential bioactivities. To date, four reports onassembly of the functionalized isotwistane (tricyclo[4.3.1.03,7]-decane) core have been revealed by She,2a Maier,2c Rychnov-sky,2d and our group.2b Very recently, a sequential protocolinvolving oxidative dearomatization and tandem hydroxyloxidation/intramolecular Diels−Alder reaction was elegantlydeveloped by She to install the 6/6/9 tricyclic skeleton ofpalhinine A.2e However, total synthesis of palhinine-typealkaloids still remains a challenge in the synthetic community.Over the past five years, many attempts in our lab have been

made to establish the final azonane ring of palhinine A on thefunctionalized isotwistane framework previously reported.3

Direct ring construction strategy through either N-substitution(e.g., N-alkylation, Mitsunobu cyclization) (Scheme 1a) or ring-closing metathesis (Scheme 1b) unexpectedly failed to providethe nine-membered azonane ring of palhinine A4 despitesuccessful implementations in syntheses of related fawcettimineLycopodium alkaloids.5,6

Considering the inevitably twisted and transannular strainengendered by direct assembly of the azonane ring embedded inthe isotwistane framework, an indirect approach involvingauxiliary ring construction/deconstruction, which was strategi-cally initiated by a connective transform in the retrosyntheticdirection,7 might be an alternative choice. In view of thegenerality of connective transform in constructing the medium-

Received: December 31, 2016Published: March 2, 2017

Figure 1. Known palhinine-type Lycopodium alkaloids.

Scheme 1. Designed Strategies for Assembly of the Nine-Membered Azonane Ring Embedded in the IsotwistaneFramework of Palhinine-type Alkaloids

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sized ring,8 together with the requirement for the site-specificassembly of the requisite oxygenated functional group in theazonane ring, an auxiliary ring system bearing an oxa-azabicyclo[5.2.1]decane characterized with a unique isoxazoli-dine moiety in III (Scheme 1) could be conceived byreconnection of the N−O bond in the backbone of palhinineA, wherein introduction of an oxygen bridging linker in the nine-membered azonane ring would be expected to relieve thepotential transannular strain.9 Such an auxiliary ring systemmightbe temporarily installed by an intramolecular [3 + 2] cyclo-addition (Scheme 1c) and feasibly provides access to the targetedazonane ring by selective scission of the N−O bond.Interestingly, installation of the isoxazolidine moiety inLycojaponicumins A and B had led to a putative biosyntheticpathway involving 1,3-dipolar cycloaddition10 that was latersupported by quantum mechanical calculations.11 Herein, wewish to report our designed strategy for the divergent totalsynthesis of Lycopodium alkaloids palhinine A, palhinine D, andtheir C3-epimers.Retrosynthetically, as shown in Scheme 2, palhinines A and D

could be achieved through elaboration of formally unifiedsynthon A, which might be envisaged from a common synthonCby its C3-OH configuration inversion involving a chemo- andstereoselective reduction of B. Strategically, the key nine-membered azonane ring inC could be generated by the reductiveN−O cleavage inD, which would be logically envisioned from Evia a selective intramolecular nitrone−alkene cycloaddition as akey step.12,13 Chemically, the olefin moiety and hydroxylamineunit in E could be introduced by sequential transformationsincluding Wittig reaction and oxime formation/reduction fromfunctionalized isotwistane building block 2, which is accessiblefrom 1 on the basis of our early synthetic studies.2b

Synthesis of hydroxylamine 10 (Scheme 3) began from highlyfunctionalized tricyclic compound 2, which could be accessedfrom 1 through a previously reported eight-step protocolfeaturing a nickel-catalyzed Nozaki−Hiyama−Kishi reactionand a thermally promoted intramolecular Diels−Alder reac-tion.2b Following removal of the TBS groups, protection of thecarbonyl group in 3 as the ethylene ketal afforded 4 in 60% yieldfor 2 steps. Because of the bulky steric property of the TBS group,direct ethylene ketalization of 2 failed. Dess−Martin periodinane(DMP) oxidation of 4 provided tetracyclic aldehyde 5 in 90%yield. It should be noted that stoichiometric water is essential forthorough oxidation,14 as formation of the β-hydroxy ketone wasobserved under anhydrous conditions. In the presence of MgSO4as additive, hydrogenative debenzylation of 5 delivered a

tautomeric mixture of minor hemiacetal 6a and major hydroxyaldehyde 6b. SubsequentWittig reaction of 6 gave terminal olefin7 in 64% yield with the ketone moiety untouched. Then, DMPoxidation yielded aldehyde 8, which was transformed into theinseparable Z/E oxime isomers 9 in 99% yield. The reduction ofthe oxime group in 9 was achieved with NaBH3CN as thereductive reagent and trifluoroacetic acid as the activator at −40°C for 30min, providing hydroxylamine 10 in 90% yield.Notably,higher temperature or longer reaction time partially resulted inreductive cleavage of the ethylene ketal unit in 10.With functionalized isotwistane 10 in hand, as shown in

Scheme 4, two-phase condensation in the presence of 37%aqueous formaldehyde afforded nitrone 11 as a precursor for ourdesigned key nitrone−alkene cycloaddition. Because of itsinstability toward column chromatography, nitrone 11 formedin situ was directly subjected to the optimized microwaveconditions (300 W, o-C6H4Cl2, 150 °C, 1.5 h),

15,16 deliveringisoxazolidine-containing hexacyclic building block 12 in 52%yield. Its structure and stereochemistry were unambiguouslydetermined by X-ray crystallographic analysis.17 It should benoted that a simple thermal condition (150 °C) with more than10 h only gave cycloaddition product 12 in∼35% yield. With thepossibility of π-facial selective addition of both dipole anddipolarophile components, four presumable transition states(TS-1−TS-4) could be proposed to rationalize the positional andstereochemical aspects of this intramolecular cycloaddition.Compared with the unfavorable steric and electrostatic repulsionin TS-2−TS-4, the energetically favorable dipole−dipoleattraction as well as the minimal steric interaction in TS-1might be mostly responsible for the high level of regiocontrol

Scheme 2. Retrosynthetic Analysis Scheme 3. Assembly of the Functionalized IsotwistaneBuilding Block

Scheme 4. Construction of Azonane-Containing AuxiliaryRing Embedded in the Isotwistane Scaffold

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(TS-1 vs TS-2/TS-3) and stereodiscrimination (TS-1 vs TS-4)found in this key transformation.Having obtained key common building block 12 with the

auxiliary oxa-azabicyclo[5.2.1]decane ring system, as shown inScheme 5, we then focused our attention on construction of thetargeted nine-membered azonane ring in palhinine-typeLycopodium alkaloids. Initial attempts to cleave the isoxazolidineN−O bond in 12 proved to be ineffective by hydrogenolysis withPd/C18a or Pearlman’s catalyst18b or reduction with Zn/HOAc.18c For the driving force of its N−O reductive cleavageto be improved, N-methylation was first conducted to give thecorresponding quaternary ammonium iodide 13, which wasdirectly exposed to the acidic reductive cleavage condition,18d

providing azonane-containing building block 14 in 81% yield.Subsequent removal of the acid-labile protecting group gave 3-epi-palhinine A in 98% yield, and its structure was confirmed byX-ray crystallographic analysis.17 Notably, a distorted twist-chair-boat conformation19 indicated in X-ray structure of 3-epi-palhinine A implies the existence of n → π* interaction,20

which could be clearly reflected by the spatial orientation and thedistance (2.6 Å) between the nine-membered azonane nitrogenatom and the keto-carbonyl carbon atom.To further achieve the desired hydroxyl stereochemistry in

palhinine A, a combined sequence for the inversion of C3-OHconfiguration of 14was implemented. Following sequential DMPoxidation and L-selectride reduction, configurationally reversedalcohol 16 could be readily formed through β-diketone 15 in 88%yield over two steps. Notably, the steric hindrance of theisotwistane C5-keto group and the backside inaccessibility of theC3-keto group in the azonane ring could account for the observedchemo- and diastereoselectivity, respectively, in the reduction of15 to alcohol 16. After acidic removal of the ketal protectinggroup, total synthesis of palhinine A was furnished for the firsttime.Upon treating 12 with Mo(CO)6 in CH3CN/H2O at elevated

temperature,21 a one-pot N−O bond cleavage/hydrolyzation ofethylene ketone/aza-hemiketalization occurred, giving 3-epi-palhinine D in 75% yield. Analogously, its stereochemicalarchitecture was assigned by X-ray crystallographic analysis.17

For the desired configuration of C3-OH in palhinine D to beestablished, a four-step protocol involvingN-quaternization withallyl bromide, acidic zinc reduction, DMP oxidation, and L-selectride reduction afforded pentacyclic alcohol 20 in 65% yield.Following successive acidic deprotection of the ethylene ketal

group and RuCl3-promoted N-deallylation, a spontaneousintramolecular aza-ketalization accomplished the first totalsynthesis of palhinine D in 61% yield over two steps, which wasfurther structurally identified by X-ray crystallographic analysis.17

In summary, focusing on the construction of the syntheticallychallenging nine-membered azonane ring system embedded inthe unique isotwistane framework of palhinine-type Lycopodiumalkaloids, we describe the first report on total synthesis ofpalhinines A andD aswell as their C3-epimers. Our route featuresthe development of a combined strategy consisting ofmicrowave-assisted regio- and stereoselective intramolecular nitrone−alkenecycloaddit ion for the establ ishment of 10-oxa-1-azabicyclo[5.2.1]decane-containing auxiliary ring and late-stageN−O disconnection for the final release of the key azonane ring.The present synthesis not only chemically demonstrates theutility of 1,3-dipolar cycloaddition in the total synthesis ofcomplex natural products but also tactically illustrates theeffectiveness of the auxiliary ring construction/deconstructionapproach to assembling the medium-sized ring in someconformationally rigid and sterically congested polycyclic system.

■ ASSOCIATED CONTENT*S Supporting InformationThe Supporting Information is available free of charge on theACS Publications website at DOI: 10.1021/jacs.6b13401.

Experimental procedures and spectral data (PDF)X-ray data for compound 12 (CIF), 3-epi-palhinine A(CIF), synthetic palhinine D (CIF), 3-epi-palhinine D(CIF), and compound SI-2-5 (CIF)

■ AUTHOR INFORMATIONCorresponding Author*fanchunan@lzu.edu.cnORCIDChun-An Fan: 0000-0003-4837-3394NotesThe authors declare no competing financial interest.

■ ACKNOWLEDGMENTSWe are grateful for financial support from NSFC (21572083,21322201, 21290180), FRFCU (lzujbky-2015-48, lzujbky-2016-ct02, lzujbky-2016-ct07), PCSIRT (IRT_15R28), the 111

Scheme 5. Divergent Synthesis of Palhinine A, Palhinine D, and Their C3-Epimers

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Project of MOE (111-2-17), and Chang Jiang Scholars Program(C.-A.F.). We thank Prof. Shi-Shan Yu and Dr. Xiao-Jing Wang(Institute of Materia Medica, CAMS, and PUMC) for theirhelpful discussion on the spectral analysis of palhinine D, andProf. Ran Fang (Lanzhou University) for assistance incalculations. We also thank referees and Prof. Phil S. Baran(TSRI) for valuable comments and language polishing.

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