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Synthesis of Neurotrophic Seco-prezizaane Sesquiterpenes (1R,10S)-2-oxo-3,4-dehydroneomajucin, (2S)hydroxy-3,4-dehydroneomajucin, and (–)-jiadifenin Xiayun Cheng, and Glenn C. Micalizio J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b12694 • Publication Date (Web): 19 Jan 2016 Downloaded from http://pubs.acs.org on January 20, 2016
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Synthesis of Neurotrophic Seco-prezizaane Sesquiterpenes (1R,10S)2-oxo-3,4-dehydroneomajucin, (2S)-hydroxy-3,4-dehydroneomajucin, and (–)-jiadifenin Xiayun Cheng and Glenn C. Micalizio* Department of Chemistry, Burke Laboratory, Dartmouth College, Hanover, NH 03755. ABSTRACT: An asymmetric approach to the synthesis of neurotrophic seco-prezizaane sesquiterpenes is described that is based on strategic application of a hydroxyl-directed metallacyclemediated [2+2+2] annulation and an intramolecular radical cyclization cascade. Targets prepared are among the most potent members of the natural product class and include (1R,10S)-2-oxo3,4-dehydroneomajucin, (2S)-hydroxy-3,4-dehydroneomajucin and (–)-jiadifenin. In addition to representing the first application of the alkoxide-directed metallacycle-mediated hydrindaneforming annulation reaction in natural product synthesis and the first total synthesis of (2S)-hydroxy-3,4-dehydroneomajucin, these pursuits have resulted in the elucidation of a complex radical cascade process for installation of the C5 quaternary center common to the natural product class. The search for agents that promote regeneration and growth of neurons is of great current interest, as axon degeneration and neuronal atrophy accompany chronic neurodegenerative disease and acute spinal cord injury.1 While proteins that serve in this regard (neurotrophins) have been investigated as potential therapeutic agents, they suffer from a variety of suboptimal characteristics that negatively impact their potential utility in the clinic (i.e. low serum stability, poor oral bioavailability, and inefficient penetration into the central nervous system).1a, 2 As such, there has been growing interest in identifying small molecule neurotrophic agents that have a more favorable pharmacokinetic profile.3 While early investigations of the seeds of the Japanese star anise (IlliciA. Majucin-type skeleton. O 15
HO Me 1
2
3
O
9
8
4
=
7 5
Me 13
HO
O
11
10
14
OH O
6
O
15
9
Me
11 O 10 14 O 7 8
1
12
4
2
5
3
O 6
12
Me OH 13
B. Molecular structure of representative natural products from Illicium. HO H
O
O O
HO O
H Me
O
O
O
O
(2S)-hydroxy-3,4-dehydroneomajucin (2)
CO2Me
O
O
H Me
Me Me OH
O
(–)-jiadifenin (3)
H
HO O
O
O
5
Me
C5-stereocenter by radical cyclization
O
O Me
O OH
9
H H
Me OH
O
5
Me
RO
1
SePh
OH
4
O
O
O
Me
OH O
anisatin
Figure 1. Introduction to majucin-type sesquiterpenes from Illicium.
O TMS
9
Me
HO OH
O
9
O
H
O
O
H H
(1R,10S )-2-oxo-3,4dehydroneomajucin (1)
O
Synthesis was initiated by regioselective addition of the organometallic reagent derived from 9 to chiral epoxide 810 (Figure 3A).11 Conversion of the resulting homoallylic alcohol to enyne 6 was then accomplished by a sequence of desilylation (TBAF,
Me OH H
HO
Our pursuits began by targeting the synthesis of 1 by Bu3SnHmediated intramolecular 5-exo trig cyclization of the phenylseleno-substituted radical precursor 4 (Figure 2). Synthesis of this substrate was planned from hydrindane 5 and would require differential functionalization of the TMS- and Bu3Sn-substituted alkene. Finally, hydrindane 5 was expected to be accessible from union of enyne 6 with alkyne 7 by application of a recently developed regio- and stereoselective hydroxyl-directed titaniummediated annulation reaction.
HO
H HO
Me OH
O
Me
um anisatum, L.) delivered anisatin,4 a neurotoxic noncompetitive GABA antagonist,5 more recent studies of Illicium terrestrial plants (evergreen shrubs/trees) have delivered a collection of complex carbocyclic natural products that have been shown to possess potent neurotrophic properties (Figure 1).3 Perhaps not surprisingly, molecules in this class have emerged as attractive targets for chemical synthesis due to the combination of their potential therapeutically relevant biological activity and their interesting carbocyclic structures.3,6 In 1990 Kouno and coworkers described the isolation of (1R, 10S)-2-oxo-3,4-dehydroneomajucin (1) and (2S)-hydroxy-3,4-dehydroneomajucin (2) in 0.0006 and 0.007% yield, respectively, from the dried fruit of the Chinese Illicium majus.7,8 These natural products, while structurally related to anisatin, did not exhibit convulsive toxicity in mice. Fourteen years later, in efforts targeting the synthesis of (+/–)jiadifenin, Danishefsky reported that 1 is a highly active neurotrophic agent in vitro: 184% vs. control at 300 nM6c, 6e – an activity that was later supported by structure–activity relationships reported by Theodorakis.6n Here, we report the first of our studies aimed at establishing an asymmetric synthesis of neurotrophic seco-prezizaane natural products and demonstrate the first application of an alkoxide-directed metallacycle-mediated annulative coupling reaction in natural product synthesis.9 In addition, a powerful intramolecular radical cascade reaction has been found to be useful for installing the sterically congested C5 quaternary center common to the natural product class.
C9-stereocenter and hydrindane core
+ by metallacycleSnBu 3 centered annulation
HO 5
6
Me
H H
TMS 9 5
HO
7
Figure 2. Retrosynthetic strategy for 1.
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O Me
5
SnBu 3 Me
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O O
O
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
O
Me
9
O
Br
Me
O
Mg, CuI, THF 59%
OTBS
1) TBAF, THF (81%) 2) TsCl, Et 3N, DMAP CH2Cl (92%) 3) NaH, THF (76%) 4) propynyl lithium BF 3•OEt 2 (91%)
HO OTBS
8 OEt
H 5
13
O
TBDPSO
H 5
Me
O
(~1:1)
OH OH
+
SnBu 3
O
HO
O O
O
TBDPSO
12
SnBu 3
2) TBDPSCl, imid. CH2Cl2 (96%)
Me
5 ds ≥ 20:1; rs ≥20:1
Me OH
Me
3) MeLi, THF then CO2
O
OsO4
OH O
PhH, 80 °C 80%
1) TBAF, DMSO (65%)
O
Me
Bu 3SnH AIBN
TMS
9
O O
OH
Me
Ti(Oi-Pr)4, n-BuLi PhMe, –78 to 50 °C then PhCHO 73%
HO
6 Me
Me OH
Me
TMS
O
O
7
Me
10
Me TBDPSO
O O
TBDPSO
O
pyridine/THF 85%
O
Me
11
4) PhSeCH 2Cl i-Pr2NEt, NaI, DME (50% over two steps)
O
4 SePh
SePh
Figure 3. Establishment of the carbocyclic skeleton of the seco-prezizaane sesquiterpenes. O
THF), epoxide formation (TsCl, Et3N, DMAP, then NaH, THF), and nucleophilic addition of propynyl lithium. In accord with our earlier observations regarding the regio- and stereosleective coupling of 4-hydroxy-1,6-enynes with TMS-alkynes,9, 12 exposure of stannyl-substituted TMS-acetylene 7 to the combination of Ti(OiPr)4 and n-BuLi (–78 to 50 °C), followed by addition of the Lialkoxide of enyne 6 (–78 °C to rt) generated hydrindane 5 in 73% yield (rs ≥ 20:1), where the C9 quaternary center was established with high levels of stereoselectivity (ds ≥ 20:1).
O O Me H TBDPSO
With the goal of influencing the course of this radical cascade reaction, we anticipated that slowing the rate of intermolecular reduction of II would result in the production of a greater quantity of ester 13. While simply decreasing the concentration of Bu3SnH would be anticipated to have such an effect, slow addition by syringe pump (over 3 h) did little to effect selectivity. Use of Bu3SnD was hypothesized as an alternative means to slow the rate of reduction of II through exploiting the primary deuterium isotope effect,17 yet this modification resulted in only a minor shift in selectivity favoring the formation of 13(D) (1.4 : 1; Figure 4B). Satisfyingly, use of TMS3SiH instead of Bu3SnH in this radical cascade reaction resulted in a more substantial change in ratio to favor the ethyl ester-containing product 13 (4.7 : 1). As illustrated in Figure 5, both products of the radical cyclization were converted to the tetracyclic bis-lactone 14 by a sequence of straightforward functional group manipulations. Desilylation of 14 with TBAF and sequential oxidation (IBX, then Saegusa) then
Me OH
12 Bu 3SnH O
O O • O Me
Treatment of hydrindane 5 with TBAF resulted in removal of the TMS-group and was followed by silylation of the secondary alcohol (TBDPSCl, imid., CH2Cl2). Subsequently, tin-lithium exchange was followed by carboxylation,13 and esterification with PhSeCH2Cl – a sequence that ultimeatley delivered the selenophenyl methyl ester 4.14 Site- and stereoselective dihydroxylation15 then generated 11 in 85% yield as a single observable stereoisomer. We next turned our attention to the radical cyclization process that was anticipated to establish the sterically congested C5 quaternary center. Heating selenophenyl methyl ester 11 in the presence of Bu3SnH and AIBN resulted in the formation of two cyclized products 12 and 13 in 80% combined yield (notably, each of these products possessed the desired C5-quaternary center). While the formation of 12 was expected, observation of the ethyl ester-containing product 13 was unanticipated and, on further consideration, warmly welcomed. We speculate that this latter compound is produced from the sequence summarized in Figure 4, where formation of radical I is followed by stereoselective 5exo trig cyclization16 en route to II. While intermolecular quenching of this tertiary radical with Bu3SnH results in the expected product 12, intramolecular hydrogen atom transfer from the acetal carbon (II → III), fragmentation (III → IV), and reduction delivers the ethyl ester-containing carbocycle 13.
O OH
H
H
Me
O
O OH
H
O O O H
•
Me OH
H
TBDPSO
RO
13
O
O O H
O OH
Me OH
RO
II
O
O Bu SnH 3 Me OH
•
H
Me OH
O O
H
Me
=
RO
I
H
•
H
RO
Me
H
Me
OH OH
O O O
• O O
O OH
Me H
Me OH
H
Me OH
RO
IV
O OH
III
B. Identification of reaction conditions that result in selective formation of 13. R O
conditions
O O
11
Me H TBDPSO
R
O O OH
Me OH
+
O O Me H
H
O OH
Me OH
TBDPSO
conditions
12
13
ratio (12:13):
Bu 3SnD, AIBN PhMe, 80 °C
R =D
R =D
1 : 1.4
TMS3SiH, AIBN PhMe, 80 °C
R =H
R =H
1 : 4.7
Figure 4. Proposed mechanism for the radical cascade reaction.
delivered enone 15. Finally, removal of the tertiary TMS-ether that was generated during the Saegusa oxidation, and αhydroxylation18 delivered (1S,10R)-2-oxo-3,4-dehydroneomajucin (1) through a process that was accompanied by epimerization at C1. As reported by Danishefsky, oxidation and methanolysis of 1 was successful for producing synthetic (–)-jiadifenin (3).6c, 6i, 6k The complex tetracyclic intermediate 15 also served as a precursor to one of the most active neurotrophic agents in this natural product family, (2S)-hydroxy-3,4-dehydroneomajucin (2).7b First, stereoselective reduction of the enone and α-hydroxylation of the lactone delivered 17. Subsequent Mitsunobu reaction with pnitrobenzoic acid, followed by a sequence of oxidation to the αketo-lactone (Dess Martin periodinane), stereoselective reduction (NaBH4), hydrolysis of the p-nitrobenzoate and deprotection of the TMS ether (K2CO3, MeOH) furnished the first synthetic sample of (2S)-3,4-dehydroneomajucin 2.
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CO2Et O Me H
H
O OH
Me OH
TBDPSO
HO H
1) Swern oxid. (80%) 2) NaBH 4, MeOH (97%)
1) TBAF, THF (70%)
3) TsOH, PhMe (86%)
2) NaHMDS THF, then 16 (54%) O
O O
O
Me H
H
TBDPSO O O O Me H
1) Swern oxid. (71%) 2) HCl, THF (85%) 3) NaClO 2, 2-methyl-2O butene, NaH 2PO 4
Me OH
14
O
PhO 2S
1) TBAF, THF (87%) 2) IBX, DMSO (79%)
O Me
3) LDA, TMSCl then Pd(OAc) 2 (83%)
H
O
N
16
Me OH
TBDPSO
12
O
H
then MeOH
Me O
1
Me
Me OH
O
1 (1R ,10S )-2-oxo-3,4-dehydroneomajucin
Ph
Jones oxidation
O
O
O
Me OH
(ref. 6c, 6i, 6k)
3 (–)-jiadifenin
MeOTMS
O
15 O
1) NaBH 4, CeCl 3•7H 2O MeOH (92%) 2) NaHMDS, THF then 16 (50%)
t-BuOH/H2O 4) NaBH 4, then TsOH, PhMe (70% over 3 steps)
HO O
O
OH
H
CO2Me O
H
O
13
O
HO
O
Me H H
O
1) PPh 3, DIAD p-NO2-benzoic acid O 2) DMP
MeOTMS 3) NaBH 4 4) K 2CO 3, MeOH 14%
HO
17
O HO
O
O
Me H HO
O
Me OH H
2 (2S)-hydroxy-3,4-dehydroneomajucin
Figure 5. Total syntheses of (1R,10S)-2-oxo-3,4-dehydroneomajucin, (–)-jiadifenin, and (2S)-3,4-dehydroneomajucin.
Overall, we report an enantioselective pathway for the synthesis of several neurotrophic seco-prezizaanes by way of an alkoxide-directed metallacycle-mediated [2+2+2] annulation and intramolecular radical cyclization. This marks the first demonstration of such a metallacycle-centered annulation reaction in natural product synthesis and demonstrates the utility of a selenophenylmethyl ester-based radical cyclization cascade to generate the congested quaternary center at C5 of this natural product family. We look forward to further developing chemistry capable of producing neurotrophic agents inspired by the seco-prezizaanes and to exploring the broad utility of alkoxide-directed metallacyclecentered annulative cross-coupling reactions in natural product synthesis. ACKNOWLEDGMENT: We gratefully acknowledge financial support of this work by the National Institutes of Health –NIGMS (GM080266). The authors also thank Dr. Haruki Mizoguchi and Dr. Christopher amEnde for helpful discussions, and Professor Yoshiyasu Fukuyama for NMR spectra of 2. AUTHOR INFORMATION
Corresponding Author *
[email protected] SUPPORTING INFORMATION PARAGRAPH: Experimental procedures and tabulated spectroscopic data for new compounds (PDF) are available free of charge via the Internet at http://pubs.acs.org/page/jacsat/submission/authors.html. REFERENCES: (1) (a) Price, R. D.; Milne, S. A.; Sharkey, J.; Matsuoka, N. Pharmacol. Therapeut. 2007, 115, 292-306. (b) Dakas, P.-Y.; Parga, J. A.; Höing, S.; Schöler, H. R.; Sterneckert, J.; Kumar, K.; Waldmann, H. Angew. Chem. Int. Ed. 2013, 52, 9576-9581. (c) Burch, P.; Binaghi, M.; Scherer, M.; Wentzel, C.; Bossert, D.; Eberhardt, L.; Neuburger, M.; Scheiffele, P.; Gademann, K. Chem. Eur. J. 2013, 19, 2589-2591. (2) Skaper, D. S.; Walsh, F. S. Mol. Cell. Neurosci. 1998, 12, 179193. (3) Xu, J.; Lacoske, M. H. Theodorakis, E. A. Angew. Chem. Int. Ed. 2014, 53, 956-987. (4) (a) Lane, J. F.; Kock W. T.; Leeds, N. S.; Gorin, G. J. Am. Chem. Soc. 1952, 74, 3211-3215. (b) Yamada, K.; Takada, S.; Nakamura, S.; Hirata, Y. Tetrahedron 1968, 24, 199-229. (5) Kudo, Y.; Oka, J.-I.; Yamada, K. Neurosci. Lett. 1981, 25, 83-88. (6) (a) Birman, V. B.; Danishefsky, S. J. J. Am. Chem. Soc. 2002, 124, 2080-2081. (b) Inoue, M.; Sato, T.; Hirama, M. J. Am. Chem. Soc. 2003, 125, 10772-10773. (c) Cho, Y. S.; Carcache, D. A.; Tian, Y.; Li, Y.-M.; Danishefsky, S. J. J. Am. Chem. Soc. 2004, 126, 14358-14359. (d) Meng, Z.; Danishefsky, S. J. Angew. Chem. Int. Ed. 2005, 44, 1511-1513. (e) Carcache, D. A.; Cho, Y. S.; Hua, Z.; Tian, Y.; Li, Y.-M.; Danishefsky, S. J. J. Am. Chem. Soc. 2006, 128, 1016-1022. (f) Inoue, M.; Sato, T.; Hirama, M. Angew. Chem. Int. Ed. 2006, 45, 4843-4848. (g) Mehta, G.; Singh, S. R.
Angew. Chem. Int. Ed. 2006, 45, 953-955. (h) Mehta, G.; Shinde, H. M. Tetrahedron Lett. 2007, 48, 8297-8300. (i) Trzoss, L.; Xu, J.; Lacoske, M. H.; Mobley, W. C.; Theodorakis, E. A. Org. Lett. 2011, 13, 4554-4557. (j) Xu, J.; Trzoss, L.; Chang, W. K.; Theodorakis, E. A. Angew. Chem. Int. Ed. 2011, 50, 3672-3676. (k) Yang, Y.; Fu, X.; Chen, J.; Zhai, H. Angew. Chem. Int. Ed. 2012, 51, 9825-9828. (l) Mehta, G.; Shinde, H. M. J. Org. Chem. 2012, 77, 8056-8070. (m) Chen, J.; Gao, P.; Yu, F.; Yang, Y.; Zhu, S.; Zhai, H. Angew. Chem. Int. Ed. 2012, 51, 5897-5899. (n) Trzoss, L.; Xu, J.; Lacoske, M. H.; Mobley, W. C.; Theodorakis, E. A. Chem. Eur. J. 2013, 19, 6398-6408. (o) Paterson, I.; Xuan, M.; Dalby, S. M. Angew. Chem. Int. Ed. 2014, 53, 7286-7289. (p) Siler, D. A.; Mighion, J. D.; Sorensen, E. J. Angew. Chem. Int. Ed. 2014, 53, 5332-5335. (q) Lu, H.-H.; Martinez, M. D.; Shenvi, R. A. Nat. Chem. 2015, 7, 604-607. For recent reviews, see: (r) Wilson, R. M.; Danishefsky, S. J. Acc. Chem. Res. 2006, 39, 539549. (s) Urabe, D.; Inoue, M. Tetrahedron 2009, 65, 6271-6289, and ref. 3. (7) Kouno, I.; Baba, N.; Hashimoto, M.; Kawano, N.; Takahashi, M.; Kaneto, H.; Yang, C.-S. Chem. Pharm. Bull. 1990, 38, 422-425. (8) (2S)-hydroxy-3,4-dehydroneomajucin has also recently been isolated from Illicium jiadifengpi, along with a collection of related seco-prezizaane-type sesquiterpenes, see: (a) Yokoyama, R.; Huang, J.-M.; Yang, C.-S.; Fukuyama, Y. J. Nat. Prod. 2002, 65, 527-531. (b) Liu, J.-F.; Li, Y.-C.; Wang, L.; Wang, Y.-F.; Jia, L.; Bi, Y.-F.; Zhang, Y.-B. Tetrahedron Lett. 2014, 55, 2942-2944. (9) (a) Greszler, S. N.; Reichard, H. A.; Micalizio, G. C. J. Am. Chem. Soc. 2012, 134, 2766-2774. (b) Jeso, V.; Aquino, C.; Cheng, X.; Mizoguchi, H.; Nakashige, M.; Micalizio, G. C. J. Am. Chem. Soc. 2014, 136, 8209-8212. (c) Cheng, X.; Micalizio, G. C. Org. Lett. 2014, 16, 5144-5147. (10) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765-5780. (11) For a similar regioselective addition reaction, see: Baker, R.; Castro, J. L. J. Chem. Soc., Chem. Commun. 1989, 378-381. (12) Mizoguchi, H.; Micalizio, G. C. J. Am. Chem. Soc. 2015, 137, 6624-6628. (13) (a) Boeckman, R. K.; Wrobleski, S. T. J. Org. Chem. 1996, 61, 7238-7239. (b) Lander, P. A.; Hegedus, L. S. J. Am. Chem. Soc. 1994, 116, 8126-8132. (c) Fleming, I.; Taddei, M. Synthesis 1985, 898. (14) (a) Beckwith, A. L. J.; Pigou, P. E. Aust. J. Chem. 1986, 39, 7787. (b) Singh, R.; Singh, G. C.; Ghosh, S. K. Eur. J. Org. Chem. 2007, 5376-5385. (c) Kumamoto, H.; Takahashi, N.; Shimamura, T.; Tanaka, H.; Nakamura, K. T.; Hamasaki, T.; Baba, M.; Abe, H.; Yano, M.; Kato, N. Tetrahedron 2008, 64, 1494-1505. (15) (a) Yaji, K.; Shindo, M. Tetrahedron 2010, 66, 9808-9813. (b) Ohyoshi, T.; Funakubo, S.; Miyazawa, Y.; Niida, K.; Hayakawa, I.; Kigoshi, H. Angew. Chem. Int. Ed. 2012, 51, 4972-4975. (c) Caldwell, J. J.; Colman, R.; Kerr, W. J.; Magennis, E. J. Synlett 2001, 1428-1430. (16) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734-736. (17) For examples of the use of isotope effects in synthesis, see: (a) Clive, D. L. J.; Cantin, C.; Khodabocus, A.; Kong, X.; Tao, Y. Tetrahedron 1993, 49, 7917-1930. (b) Vedejs, E.; Little, J. J. Am. Chem. Soc. 2002, 124, 748-749. (c) Dudley, G. B.; Danishefsky, S. J.; Sukenick, G. Tetrahedron Lett. 2002, 43, 5605-5606. (d) Miyashita, M.; Sasaki, M.; Hattori, I.; Sakai, M.; Tanino, K. Science 2004, 305, 495-499. (18) (a) Davis, F. A.; Nadir, Upender, K.; Kluger, E. W. J. Chem. Soc., Chem. Commun. 1977, 25-26. (b) Davis, F. A.; Lamendola, J.; Nadir, U.; Kluger, E. W.; Sedergran, T. C.; Panunto, T. W.; Billmers, R.; Jenkins, R.; Turchi, I. J.; Watson, W. H.; Chen, J. S.; Kimura, M. J. Am. Chem. Soc. 1980, 102, 2000-2005.
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TOC Figure: O
HO H
H O
10
O
H 1
Me O
2
4 3
5
Me OH
HO O
O
CO2Me O
O
Me
HO
O
O
O
H
H HO
Me OH H
(1R,10S )-2-oxo-3,4-dehydro- (2S)-hydroxy-3,4-dehydroneomajucin neomajucin
Me
O
Me OH
O
(–)-jiadifenin
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