Total Synthesis of Lycopodium Alkaloids Palhinine A and Palhinine D

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Total Synthesis of Lycopodium Alkaloids Palhinine A and Palhinine D Fang-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 J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b13401 • Publication Date (Web): 02 Mar 2017 Downloaded from http://pubs.acs.org on March 2, 2017

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Total Synthesis of Lycopodium Alkaloids Palhinine A and Palhinine D Fang-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, 222 Tianshui Nanlu, Lanzhou 730000 (China) ‡ Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071 (China) Supporting Information Placeholder ABSTRACT: The first total syntheses of Lycopodium alkaloids palhinine A, palhinine D and their C3-epimers have been divergently achieved through the use of a connective transform to access a pivotal hexacyclic isoxazolidine precursor. A microwave-assisted regio- and stereoselective intramolecular nitrone–alkene cycloaddition was tactically orchestrated as a key step to install the crucial 10-oxa-1azabicyclo[5.2.1]decane moiety embedded in the conformationally rigid isotwistane framework, demonstrating the feasibility of constructing the highly strained medium-sized ring by introduction of an oxygen bridging linker to relieve the transannular strain in the polycyclic scaffold. Subsequent N−O bond cleavage provided the synthetically challenging nine-membered azonane ring system bearing requisite C3 hydroxyl group. Late-stage transformations featuring a chemo- and stereoselective reduction of the pentacyclic β-diketone secured the availability of our target molecules.

molecular architecture but also for investigating their potential bioactivities. To date, four reports on assembly of the functionalized isotwistane (tricyclo[4.3.1.03,7]decane) core have been revealed by She,2a Maier,2c Rychnovsky2d and our group.2b Very recently, a sequential protocol involving oxidative dearomatization and tandem hydroxyl oxidation/intramolecular Diels-Alder reaction was elegantly developed by She to install the 6/6/9 tricyclic skeleton of palhinine A.2e However, total synthesis of palhinine-type alkaloids 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 the functionalized 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) Scheme 1. Designed Strategies for Assembly of the Ninemembered Azonane Ring Embedded in the Isotwistane Framework of Palhinine-type Alkaloids

Palhinine-type alkaloids (Figure 1),1 as members of the Lycopodium family, have a unique 5/6/6/9 tetracyclic or 5/6/6/6/7 pentacyclic ring system characterized with densely functionalized isotwistane nucleus. Since the isolation of palhinine A from the whole plant of Palhinhaea cernua L. (Lycopodiaceae) by Wang and Long in 2010,1a isopalhinine A and palhinines B–D have been reported successively by Zhao1b and Yu1c,1d in 2013. While no activity was observed in preliminary studies, scarcity in nature precludes extensive biological evaluations of these alkaloids.1a-c Hence, exploration of a general approach for total synthesis of these Lycopodium alkaloids, together with their structurally related analogs, is requisite not only for pursuing the novel

Me N

H O

H

O

N Me

N

O

H

HO

3 OH

O H

H O

palhinine A

O connective transform

O–N

I

N

II

N

III

O

N

3

a

Previous attempts

N-substitution

Figure 1. Known palhinine-type Lycopodium alkaloids.

Me O

b

ring-closing metathesis

c

This work

[3+2] cycloaddition

unexpectedly failed to provide the nine-membered azonane ring of palhinine A,4 despite successful implementations in syntheses of related fawcettimine Lycopodium alkaloids.5,6 Considering the inevitably twisted and transannular strain engendered by direct assembly of the azonane ring embedded in the isotwistane framework, an indirect approach involving auxiliary ring construction/deconstruction, which was strategically initiated by a connective transform in retrosynthetic direction,7 might be an alternative choice. In view of the generality of connective transform in constructing the medium-sized ring,8 together with the requirement for the site-

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specific assembly of the requisite oxygenated functional group in azonane ring, an auxiliary ring system bearing an oxaazabicyclo[5.2.1]decane characterized with a unique isoxazolidine moiety in III (Scheme 1) could be conceived by reconnection of NO bond in the backbone of palhinine A, wherein introduction of an oxygen bridging linker in the nine-membered azonane ring would be expected to relieve the potential transannular strain.9 Such auxiliary ring system might be temporarily installed by an intramolecular [3+2] cycloaddition (Scheme 1c), and feasibly provides access to the targeted azonane ring by selective scission of the N−O bond. Interestingly, installation of the isoxazolidine moiety in Lycojaponicumins A and B had led to a putative biosynthetic pathway involving 1,3-dipolar cycloaddition10 that was later supported by quantum mechanical calculation.11 Herein, we wish to report our designed strategy for the divergent total synthesis of Lycopodium alkaloids palhinine A, palhinine D and their C3-epimers.

Scheme 3. Assembly of Functionalized Isotwistane Building Block BnO

O

H

O

N Me

H O

palhinine A

HO

3 NO R R'

chemo- and stereoselective reduction OBn

O

H OR'

1

HO

palhinine D

O

HO O NO R' R

1

N

A

3

O

H OH

H OR'

H

3 NO R' R

B

H OR'

C reductive cleavage of N-O bond

ref. 2b oxime formation and reduction OBn

TBSO

H TBSO

H

O

R'O

O Wittig reaction 2

E

N O

NHOH key step

H OR'

O

H

regioand stereoselective 1,3-dipolar cycloaddition

R'O

H OR'

D

Retrosynthetically, as shown in Scheme 2, palhinines A and D could be achieved through elaboration of a formally unified synthon A, which might be envisaged from a common synthon C by its C3-OH configuration inversion involving a chemo- and stereoselective reduction of B. Strategically, the key nine-membered azonane ring in C could be generated by the reductive NO cleavage in D, which would be logically envisioned from E via a selective intramolecular nitrone–alkene cycloaddition as a key step.12,13 Chemically, the olefin moiety and hydroxylamine unit in E could be introduced by sequential transformations including Wittig reaction and oxime formation/reduction from the functionalized isotwistane building block 2, which is accessible from 1 on the basis of our early synthetic studies.2b Synthesis of hydroxylamine 10, shown in Scheme 3, began from the highly functionalized tricyclic compound 2, which could be accessed from 1 through a previously reported eight-step protocol featuring a nickel-catalyzed Nozaki–Hiyama–Kishi reaction and a thermally promoted intramolecular Diels–Alder reaction.2b Following removal of the TBS groups, protection of the carbonyl group in 3 as the ethylene ketal afforded 4 in 60% yield for 2 steps. Due to the bulky steric property of the TBS group, direct ethylene ketalization of 2 failed. Dess-Martin periodinane (DMP) oxidation of 4 provided the tetracyclic aldehydeketone 5 in 90% yield. It should be noted that stoichiometric water is essential for thorough oxidation,14 as formation of the β-hydroxy

O

TBSO

HO

rt to reflux

O

O

H O

O

HO

6a (minor)

O

8

H O

H O

NaOAc NH2OH•HCl

H

EtOH/H2O rt, 0.5 h

O

99% yield

H O

O

O

Pd(OH)2/C H2 , MgSO4 MeOH rt to 50 o C quant.

5

n-BuLi, THF [MePPh3 ]+Br–

H

OH Dess-Martin periodinane

O

N O

H O

9 (Z/E = 1:1)

H O

O

0 oC to 78 oC, then 78 oC to rt 64% yield

O

3 OBn

NaBH3CN CF3 CO2H EtOH 40 oC, 0.5 h 90% yield

NaHCO3 CH2Cl2, rt 81% yield

7

OH H

H O

90% yield

O

6b (major)

Dess-Martin periodinane

( )3

OBn

HO

CH3CN 0 oC to rt

NaHCO 3, H 2O CH2Cl2 , 0 oC to rt

4 O

OH

O

H O

O

63% yield (84% yield brsm)

H

OBn

HO

95% yield

2

2

HO

(CH2OH)2 PPTS, toluene

O

H

R = allyl

H H 2SiF6 (aq.)

TBSO

H

O

H

R = Me

OBn

TBSO

TBSO

OBn

O

HO

O

8 steps (ref. 2b)

O

Scheme 2. Retrosynthetic Analysis

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OH H

NH

O

O

H O

10

ketone was observed under anhydrous conditions. In the presence of MgSO4 as additive, hydrogenative debenzylation of 5 delivered a tautomeric mixture of the minor hemiacetal 6a and the major hydroxy aldehyde 6b. Subsequent Wittig reaction of 6 gave the terminal olefin 7 in 64% yield with the ketone moiety untouched. Then, DMP oxidation yielded the aldehyde 8, which was transformed into the inseparable Z/E oxime isomers 9 in 99% yield. The reduction of the oxime group in 9 was achieved with NaBH3CN as the reductive reagent and trifluoroacetic acid as the activator at −40 oC for 30 min, providing the hydroxylamine 10 in 90% yield. Notably, higher temperature or longer reaction time partially resulted in reductive cleavage of the ethylene ketal unit in 10. Scheme 4. Construction of Azonane-Containing Auxiliary Ring Embedded in the Isotwistane Scaffold

With the functionalized isotwistane 10 in hand, as shown in Scheme 4, two-phase condensation in the presence of 37% aqueous formaldehyde afforded the nitrone 11 as a precursor for our designed key nitrone-alkene cycloaddition. Due to its instability toward column chromatography, the nitrone 11 formed in situ was directly subjected to the optimized microwave conditions (300 W, o-C6H4Cl2, 150 oC, 1.5 h),15,16 delivering the isoxazolidine-containing hexacyclic building block 12 in 52% yield. Its structure and stereochemistry were

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

Br

O

H O

H

acetone rt

O

H O

THF rt

O

O

AcOH/THF/H 2O HO (v/v/v = 2:1:1)

O

81% yield 17 Zn, 30 oC AcOH/THF/H 2O (v/v/v = 2:1:1)

88% yield allyl N

HO

O

HO O 18 99% yield allyl N

HO N

O O

H O

THF

H

O

3 O

O H

H

H

H

15 p-TsOH, 60 oC acetone/H2O (v/v = 10:1)

92% yield

N Me

H O

allyl

N

n

3

*

2.6 Å

O

HO O

75% yield 20

H O

2) RuCl3, 90 oC CH3CN/H2O (v/v = 5:1) 61% yield (2 steps)

H

N

palhinine D

unambiguously determined by X-ray crystallographic analysis.17 It should be noted that simple thermal condition (150 oC) with more than 10 hours only gave the cycloaddition product 12 in about 35% yield. With the possibility of π-facial selective addition of both dipole and dipolarophile components, four presumable transition states (TS1–TS-4) could be proposed to rationalize the positional and stereochemical aspects of this intramolecular cycloaddition. Compared with the unfavorable steric and electrostatic repulsion in TS-2, TS-3 and TS-4, the energetically favorable dipole-dipole attraction as well as the minimal steric interaction in TS-1 might be mostly responsible for a high level of regiocontrol (TS-1 vs TS-2/TS-3) and stereodiscrimination (TS-1 vs TS-4) found in this key transformation. Having obtained the key common building block 12 with the auxiliary oxa-azabicyclo[5.2.1]decane ring system, as shown in Scheme 5, we then focused our attention on construction of the targeted ninemembered azonane ring in palhinine-type Lycopodium alkaloids. The initial attempts to cleave the isoxazolidine N−O bond in 12 proved to be ineffective by hydrogenolysis with Pd/C18a or Pearlman's catalyst18b or reduction with Zn/HOAc.18c To improve the driving force for its N−O reductive cleavage, N-methylation was first conducted to give the corresponding quaternary ammonium iodide 13, which was directly exposed to the acidic reductive cleavage condition,18d providing the 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 by X-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 the distance (2.6 Å) between the nine-membered azonane nitrogen atom and the keto-carbonyl carbon atom. To further achieve the desired hydroxyl stereochemistry in palhinine A, a combined sequence for the inversion of C3-OH configuration of 14 was implemented. Following sequential DMP oxidation and Lselectride reduction, the configurationally reversed alcohol 16 could be readily formed through β-diketone 15 in 88% yield over two steps. Notably, the steric hindrance of the isotwistane C5-keto group and the backside inaccessibility of C3-keto group in the azonane ring, respectively, could account for the observed chemo- and diastereoselectivity

H O

O 16

X-ray of 3-epi-palhinine A

2N HCl MeOH 80 oC

H O

O

HO

O

HO

N 1) p-TsOH, 60 oC acetone/H2O (v/v = 10:1)

L-selectride –78 oC to 0 o C, THF

Me

O

3

3-epi-palhinine A

X-ray of 3-epi-palhinine D

H O

5

89% yield

L-selectride –78 oC to 0 oC

O

19

H OH

3-epi-palhinine D Dess-Martin periodinane NaHCO3, CH2Cl2, rt

98% yield

O

3

H

H O

Mo(CO)6, 85 oC CH3CN/H2O (v/v = 9:1)

75% yield

O

14

H O

O

96% yield

13

12

H

H O 5

3

H NaHCO3 O CH2Cl2, rt

N

H

Dess-Martin periodinane O

3

H O

Me

N

Zn, 30 oC

O

H

Me N

I

MeI

O

O

H

N

O

allyl bromide

O

Me

Me

N

N

H OH

HO

X-ray of palhinine D

N Me

H O

palhinine A

in the reduction of 15 to alcohol 16. After acidic removal of the ketal protecting group, total synthesis of palhinine A was furnished for the first time. When 12 was treated with Mo(CO)6 in CH3CN/H2O at elevated temperature,21 a one-pot N−O bond cleavage/hydrolyzation of the ethylene ketone/aza-hemiketalization occurred, giving 3-epi-palhinine D in 75% yield. Analogously, its stereochemical architecture was assigned by X-ray crystallographic analysis.17 In order to establish the desired configuration of C3-OH in palhinine D, a four-step protocol involving N-quaternization with allyl bromide, acidic zinc reduction, DMP oxidation and L-selectride reduction afforded the pentacyclic alcohol 20 in 65% yield. Following successive acidic deprotection of the ethylene ketal group and RuCl3-promoted N-deallylation, a spontaneous intramolecular aza-ketalization accomplished the first total synthesis of palhinine D in 61% yield over two steps, which was further structurally identified by X-ray crystallographic analysis.17 In summary, focusing on the construction of the synthetically challenging nine-membered azonane ring system embedded in the unique isotwistane framework of palhinine-type Lycopodium alkaloids, we describe the first report on total synthesis of palhinine A, palhinine D as well as their C3-epimers. Our route features the development of the combined strategy consisting of a microwave-assisted regio- and stereoselective intramolecular nitrone–alkene cycloaddition for the establishment of 10-oxa-1-azabicyclo[5.2.1]decane-containing auxiliary ring and a late-stage N−O disconnection for the final release of the key azonane ring. The present synthesis not only chemically demonstrates the utility of 1,3-dipolar cycloaddition in the total synthesis of complex natural products, but also tactically illustrates effectiveness of the auxiliary ring construction/deconstruction approach to assembling the medium-sized ring in some conformationally rigid and sterically congested polycyclic system.

ASSOCIATED CONTENT Supporting Information Experimental procedures and spectral data. X-ray data for the compound 12, 3-epi-palhinine A, the synthetic palhinine D and 3-epi-

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palhinine D (CIF). This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author *[email protected]

Notes The authors declare no competing financial interests.

ACKNOWLEDGMENT We are grateful for financial support from NSFC (21572083, 21322201, 21290180), FRFCU (lzujbky-2015-48, lzujbky-2016-ct07), PCSIRT (IRT_15R28), the 111 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 their helpful discussion on the spectral analysis of palhinine D, and Prof. Ran Fang (Lanzhou University) for assistance in calculations. We also thank referees and Prof. Phil S. Baran (TSRI) for valuable comments and language polishing.

REFERENCES (1) For the isolation of palhinine-type Lycopodium alkaloids, see: (a) Zhao, F.-W.; Sun, Q.-Y.; Yang, F.-M.; Hu, G.-W.; Luo, J.-F.; Tang, G.-H.; Wang, Y.-H.; Long, C.-L. Org. Lett. 2010, 12, 3922. (b) Dong, L.-B.; Gao, X.; Liu, F.; He, J.; Wu, X.-D.; Li, Y.; Zhao, Q.-S. Org. Lett. 2013, 15, 3570. (c) Wang, X.-J.; Li, L.; Yu, S.-S.; Ma, S.-G.; Qu, J.; Liu, Y.-B.; Li, Y.; Wang, Y.; Tang, W. Fitoterapia 2013, 91, 74. For a terminology revision of compound 5 in ref.[1c] from palhinine B to palhinine D, see: (d) Wang, X.-J.; Li, L.; Yu, S.-S.; Ma, S.-G.; Qu, J.; Liu, Y.-B.; Li, Y.; Wang, Y.; Tang, W. Fitoterapia 2016, 114, 194. (2) For previous reports on constructing the functionalized isotwistane core in the palhinine-type Lycopodium alkaloids, see: (a) Zhao, C.; Zheng, H.; Jing, P.; Fang, B.; Xie, X.; She, X. Org. Lett. 2012, 14, 2293. (b) Zhang, G.-B.; Wang, F.X.; Du, J.-Y.; Qu, H.; Ma, X.-Y.; Wei, M.-X.; Wang, C.-T.; Li, Q.; Fan, C.-A. Org. Lett. 2012, 14, 3696. (c) Gaugele, D.; Maier, M. E. Synlett 2013, 24, 955. (d) Sizemore, N.; Rychnovsky, S. D. Org. Lett. 2014, 16, 688. For the assembly of 9/6/6 tricyclic skeleton of palhinine A, see: (e) Duan, S.; Long, D.; Zhao, C.; Zhao, G.; Yuan, Z.; Xie, X.; Fang, J.; She. X. Org. Chem. Front. 2016, 3, 1137. (3) For our previous attempts to construct the nine-membered azonane ring system on the functionalized isotwistane core, see: (a) Zhang, G.-B. Synthetic Studies towards the Lycopodium Alkaloid Palhinine A. Ph. D. Dissertation. Lanzhou: Lanzhou University, 2013. (b) Wang, F.-X.; Zhang, P.-L.; Wang, H.-B.; Zhang, G.-B.; Fan, C.-A. Sci. China Chem. 2016, 59, 1188. (4) For details on our attempts to the direct azonane ring construction, see the Supporting Information. (5) For selected examples on the direct construction of the nine-membered azonane ring system via N-alkylation or Mitsunobu cyclization in the total synthesis of fawcettimine-related Lycopodium alkaloids, see: (a) Heathcock, C. H.; Blumenkopf, T. A.; Smith, K. M. J. Org. Chem. 1989, 54, 1548. (b) Linghu, X.; Kennedy-Smith, J. J.; Toste, F. D. Angew. Chem., Int. Ed. 2007, 46, 7671. (c) Nakayama, A.; Kogure, N.; Kitajima, M.; Takayama, H. Org. Lett. 2009, 11, 5554. (d) Otsuka, Y.; Inagaki, F.; Mukai, C. J. Org. Chem. 2010, 75, 3420. (e) Yang, Y.-R.; Lai, Z.-W.; Shen, L.; Huang, J.-Z.; Wu, X.-D.; Yin, J.-L.; Wei, K. Org. Lett. 2010, 12, 3430. (f) Yang, Y.-R.; Shen, L.; Huang, J.-Z.; Xu, T.; Wei, K. J. Org. Chem. 2011, 76, 3684. (g) Nakayama, A.; Kogure, N.; Kitajima, M.; Takayama, H. Angew. Chem., Int. Ed. 2011, 50, 8025. (h) Pan, G.; Williams, R. M. J. Org. Chem. 2012, 77, 4801. (i) Shimada, N.; Abe, Y.; Yokoshima, S.; Fukuyama, T. Angew. Chem., Int. Ed. 2012, 51, 11824. (j) Itoh, N.; Iwata, T.; Sugihara, H.; Inagaki, F.; Mukai, C. Chem. Eur. J. 2013, 19, 8665. (k) Zaimoku, H.; Nishide, H.; Nishibata, A.; Goto, N.; Taniguchi, T.; Ishibashi, H. Org. Lett. 2013, 15, 2140. (6) For one example on the direct construction of the nine-membered azonane ring system via ring-closing metathesis in the total synthesis of fawcettimine-related alkaloid lycoflexine, see: Ramharter, J.; Weinstabl, H.; Mulzer, J. J. Am. Chem. Soc. 2010, 132, 14338.

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(7) For comprehensive description on the connective transform in retrosynthetic analysis, see: Corey, E. J.; Cheng, X.-M. in The Logic of Chemical Synthesis, Wiley, New York, 1989, chapter 5, pp 71‒75. (8) For selected examples by connective transform application to construct the medium-sized ring in natural product total synthesis, see: (a) Corey, E. J.; Hortmann, A. G. J. Am. Chem. Soc. 1963, 85, 4033. (b) Moricz, A.; Gassman, E.; Bienz, S.; Hesse, M. Helv. Chim. Acta 1995, 78, 663. (c) Limanto, J.; Snapper, M. L. J. Am. Chem. Soc. 2000, 122, 8071. (d) Paquette, L. A.; Yang, J.; Long, Y. O. J. Am. Chem. Soc. 2002, 124, 6542. (e) Maimone, T. J.; Shi, J.; Ashida, S.; Baran, P. S. J. Am. Chem. Soc. 2009, 131, 17066. (9) As was known, the existence of severe non-bonding interaction in [10]annulene renders its non-planar structure with non-aromaticity. To relieve such transannular strain, a thought-provoking work for the design and synthesis of 1,6-methano[10]annulene through replacing 1,6-internal hydrogen atoms in [10]annulene by a bridging methylene linker was pioneered by Vogel in 1964, giving one classical example of aromaticity driven by the release of transannular strain. For the synthesis of 1,6-methano[10]annulene, see: Vogel, E.; Roth, H. D. Angew. Chem., Int. Ed. 1964, 3, 228. (10) Wang, X.-J.; Zhang, G.-J.; Zhuang, P.-Y.; Zhang, Y.; Yu, S.-S.; Bao, X.-Q.; Zhang, D.; Yuan, Y.-H.; Chen, N.-H.; Ma, S.-g.; Qu, J.; Li, Y. Org. Lett. 2012, 14, 2614. (11) Krenske, E. H.; Patel, A.; Houk, K. N. J. Am. Chem. Soc. 2013, 135, 17638. (12) For recent elegant examples on the application of intramolecular nitrone-alkene cycloaddition in natural product synthesis, see: (a) Ideue, E.; Shimokawa, J.; Fukuyama, T. Org. Lett. 2015, 17, 4964. (b) Higo, T.; Ukegawa, T.; Yokoshima, S.; Fukuyama, T. Angew. Chem., Int. Ed. 2015, 54, 7367. (c) Yokoyama, T.; Fukami, Y.; Sato, T.; Chida, N. Chem.‒Asian J. 2016, 11, 470. (13) For leading reviews on nitrone-alkene cycloaddition, see: (a) Confalone, P. N.; Huie, E. M. Org. React. 1988, 36, 1. (b) Frederickson, M. Tetrahedron 1997, 53, 403. (c) Gothelf, K. V.; Jørgensen, K. A. Chem. Commun. 2000, 1449. (d) Koumbis, A. E.; Gallos, J. K. Curr. Org. Chem. 2003, 7, 585. (e) Nguyen, T. B.; Martel, A.; Gaulon, C.; Dhal, R.; Dujardin, G. Org. Prep. Proced. Int. 2010, 42, 387. (f) Nguyen, T. B.; Martel, A.; Gaulon-Nourry, C.; Dhal, R.; Dujardin, G. Org. Prep. Proced. Int. 2012, 44, 1. (14) For the role of water in the Dess-Martin Periodinane oxidation, see: Meyer, S. D.; Schreiber, S. L. J. Org. Chem. 1994, 59, 7549. (15) For some leading reviews on microwave-assisted 1,3-dipolar cycloaddition, see: (a) Appukkuttan, P.; Mehta, V. P.; Eycken, E. V. V. d. Chem. Soc. Rev. 2010, 39, 1467. (b) Bougrin, K.; Benhida, R. Microwave Assisted Cycloaddition Reactions. In Microwaves in Organic Synthesis; Hoz, A. d. l.; Loupy, A. Ed.; Wiley-VCH, Weinheim, 2012, Vol. 1, Chapter 17, pp 737–809. (16) For details on the condition optimization of the nitrone-alkene cycloaddition, see the Supporting Information. (17) The relative configuration was determined by X-ray crystallographic analysis. CCDC 1523463 (12), CCDC 1523464 (3-epi-palhinine A), CCDC 1523465 (3-epi-palhinine D), and CCDC 1523466 (the synthetic palhinine D) contain the crystallographic data for this paper. The data can be obtained free of charge via the Internet at www.ccdc.cam.ac.uk/data_request/cif. (18) For selected examples on cleavage of the N−O bond via hydrogenation with palladium on carbon, see: (a) Bailey, J. T.; Berger, I.; Friary, R.; Puar, M. S. J. Org. Chem. 1982, 47, 857. For hydrogenation with Pearlman’s catalyst, see: (b) DeShong, P.; Dicken, C. M.; Leginus, J. M.; Whittle, R. R. J. Am. Chem. Soc. 1984, 106, 5598. For reduction with zinc in aqueous acetic acid, see: (c) Aschwanden, P.; Kværnø, L.; Geisser, R. W.; Kleinbeck, F.; Carreira, E. M. Org. Lett. 2005, 7, 5741. (d) Kong, K.; Enquist, J. A.; McCallum, M. E.; Smith, G. M.; Matsumaru, T.; Menhaji-Klotz, E.; Wood, J. L. J. Am. Chem. Soc. 2013, 135, 10890. (19) (a) Bryan, R. F.; Dunitz, J. D. Helv. Chim. Acta 1960, 43, 3. (b) Anet, F. A. L.; Krane, J. Isr. J. Chem. 1980, 20, 72. (c) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of Organic Compounds; Wiley: New York, 1994, pp 766–767. (20) For reviews, see: (a) Leonard, N. J. Acc. Chem. Res. 1979, 12, 423. (b) Rademacher, P. Chem. Soc. Rev. 1995, 24, 143. For selected examples, see: (c) Leonard, N. J.; Fox, R. C.; Oki, M.; Chiavarelli, S. J. Am. Chem. Soc. 1954, 76, 630. (d) Leonard, N. J.; Morrow, D. F.; Rogers, M. T. J. Am. Chem. Soc. 1957, 79, 5476. (e) Bürgi, H. B.; Dunitz, J. D.; Shefter, E. J. Am. Chem. Soc. 1973, 95, 5065. (f) Breton, G. W.; Crasto, C. J. J. Org. Chem. 2015, 80, 7375. (21) Gioia, C.; Fini, F.; Mazzanti, A.; Bernardi, L.; Ricci, A. J. Am. Chem. Soc. 2009, 131, 9614.

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