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
Communication
pubs.acs.org/JACS
© 2017 American Chemical Society 4282 DOI:
10.1021/jacs.6b13401J. Am. Chem. Soc. 2017, 139, 4282−4285
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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*[email protected] 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
Journal of the American Chemical Society Communication
DOI: 10.1021/jacs.6b13401J. Am. Chem. Soc. 2017, 139,
4282−4285
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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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