Enantioselective total syntheses of nankakurines A and B: Confirmation of structure and establishment of absolute configuration

Article abstract of DOI:10.1021/ja804624u

Total syntheses of (+)-nankakurine A (2) and (+)-nankakurine B (3) were accomplished by a sequence that employs an intramolecular dipolar cycloaddition of an azomethine imine intermediate to form the azatricyclic moiety and establish the relative configur

Full text of DOI:10.1021/ja804624u

Published on Web 08/02/2008
Enantioselective Total Syntheses of Nankakurines A and B: Confirmation of
Structure and Establishment of Absolute Configuration
Bradley L. Nilsson,† Larry E. Overman,* Javier Read de Alaniz, and Jason M. Rohde‡
Department of Chemistry, UniVersity of California, IrVine, 1102 Natural Sciences II, IrVine, California 92697-2025
Received June 17, 2008; E-mail: leoverma@uci.edu
The Lycopodium alkaloids1 have attracted synthetic interest for
Scheme 1
many years, as a result of their diverse architectures and to a lesser
extent their biological activities. In 2004, Kobayashi and co-workers
reported the isolation of nankakurine A,2 a minor component of
the club moss Lycopodium hamiltonii. Utilizing NMR and mass
spectrometric analyses, structure 1 was proposed (Figure 1).2 The
relative configuration at the spiro stereocenter of nankakurine A
1
was assigned on the basis of H NMR NOE experiments and was
in accord with the structure of spirolucidine (4), whose relative
configuration had been secured by single-crystal X-ray analysis of
a derivative.3 Further purification of this club moss extract led to
the isolation of a related, slightly less abundant, alkaloid nankaku-
rine B, for which structure 3 was proposed.4 In this case, 1H NMR
NOE data were interpreted to support a configuration at the spiro
stereocenter opposite to that found in spirolucidine (4) and that
proposed originally for nankakurine A (1). Since nankakurine A
was converted to nankakurine B upon reductive methylation, the
structure of nankakurine A was revised to 2 in 2006.4
Preliminary biological studies of nankakurine A (2) suggested
its ability to induce secretion of neurotrophic factors and promote
neuronal differentiation of rat adrenal PC-12 cells.4 Neurotrophic
factors play an important role in mediating neuronal growth and
survival; consequently, they have long been recognized for their
potential in combating neurodegenerative disorders such as Alzhe-
imer’s and Parkinson’s diseases.5 Recently, there has been interest
in small molecules that exhibit neurotrophic effects6 because of
the poor pharmacokinetics of naturally occurring polypeptidyl
neurotrophic factors.7
The scarcity of the nankakurines (2 and 3 were isolated in 0.0003
and 0.0002%, respectively),4 contributed to the uncertainty regard-
ing their relative configuration, and has prevented further evaluation
of the purported neurotrophic properties of nankakurine A. We
report herein total syntheses of (+)-nankakurine A, (+)-nankakurine
B, and the originally purported structure 1 of nankakurine A, which
rigorously establish the relative and absolute configuration of these
rare alkaloids as 2 and 3, respectively.
Although nankakurines A and B might well be assembled from
luciduline (5), we were intrigued by the opportunity to evaluate an
amino-terminated aza-Prins cyclization for directly assembling the
diazatetracyclic ring system of structure 1 (Scheme 1, 7 f 6).
Although aza-Prins cyclizations are often used to assemble azacyclic
ring systems,8 few examples of terminating such cyclizations by
Figure 1. Nankakurines A and B and two structurally related Lycopodium
alkaloids.
tethered heteroatom nucleophiles have been described and none to
our knowledge wherein this nucleophile is nitrogen.9cis-Decalin
amine 8, the precursor of formaldiminium ion 7, would be available
by a Diels-Alder construction that draws direct precedent from
† Current address: Chemistry Department, University of Rochester, Rochester,
NY 14627.
the first total synthesis of (+)-luciduline (5) by Oppolzer and
‡ Current address: Ironwood Pharmaceuticals, Inc., 320 Bent Street, Cambridge,
MA 02141.
Petrzilka.10
9
10.1021/ja804624u CCC: $40.75
2008 American Chemical Society
J. AM. CHEM. SOC. 2008, 130, 11297–11299 11297

C O M M U N I C A T I O N S
Scheme 2
Scheme 3
a Reagents: (a) 2.5 mol % Grubbs’ second-generation catalyst, ethylene
(300 psi), CH2Cl2, 25 °C (90%); (b) 50 mol % of EtAlCl2, CH2Cl2, PhMe,
25 °C (74%, 1:1-1:3 cis:trans); (c) HONH2 ·HCl, MeOH, KOH, 25 °C
(56%); (d) MoO3, NaBH4, MeOH, 25 °C (98%); (e) ClCO2Me, Et3N,
CH2Cl2, 25 °C (56%); (f) (CH2O)n, TFA, CHCl3, 25 °C (20%); (g) Na,
NH3, THF, -78 °C (98%); (h) LiAlH4, THF, 25 °C (65%).
An unoptimized sequence that led to diazatetracycle 1, the
structure proposed originally for nankakurine A, is summarized in
Scheme 2. Enyne metathesis of N-tosylaminoalkyne 1111 and
ethylene in the presence of 2.5 mol % of Grubbs’ second-generation
catalyst12 provided 1,3-diene 12 in 90% yield.13 The Diels-Alder
reaction of diene 12 and racemic cyclohexenone rac-13 took place
at room temperature in the presence of 50 mol % of EtAlCl2 to
generate decalone 14 in 74% yield as a mixture of cis and trans
epimers. Conversion of the cis epimer to the oxime under conditions
designed to equilibrate the decalone epimers,10 and subsequent
reduction with NaBH4 and MoO314 provided cis-decalin amine 15
in 55% yield. Attempts to cyclize formaldiminium ions derived
from 15, or its N-Me congener, yielded only tricyclic aza-Prins
products. However, the desired nitrogen-terminated aza-Prins
biscyclization could be realized by reaction of the methyl carbamate
derived from amine 15 with 1 equiv of paraformaldehyde and 20
equiv of TFA at room temperature in CHCl3. Although the yield
of this conversion was low, it did provide sufficient amounts of
tetracyclic diamine 16 to allow rac-1 to be accessed in two
additional reductive steps. 1H and 13C NMR spectra of this product
are quite different from those reported for nankakurine A,2
confirming that the initial structural assignment for this alkaloid
was incorrect.
At this point, it seemed likely that nankakurine A was indeed
structure 24 having the relative configuration of the spiropiperidine
unit that orients both nitrogen atoms on the concave face of the
bridged tricyclic moiety. Connecting these atoms provides potential
precursor 9, which we hoped could be accessed by intramolecular
dipolar cycloaddition of azomethine imine intermediate 10 (Scheme
1).15
The successful asymmetric total syntheses of (+)-nankakurines
A (2) and B (3) commenced with the preparation of diene 18 in
90% yield by ruthenium-catalyzed cross metathesis of benzyloxy-
alkyne 1716 and ethylene (Scheme 3).12,13 To circumvent epimer-
ization of the cis-decalone product during the Diels-Alder reaction,
the cycloaddition of diene 18 and (R)-5-methylcyclohex-2-en-1-
one [(R)-13]17 was carried out at low temperature on multigram
a Reagents: (a) 5 mol % of Grubbs’ second-generation catalyst, ethylene
(300 psi), CH2Cl2, 25 °C (90%); (b) 10 mol % of TMSOTf, CH2Cl2, -78
°C (64%); (c) FeCl3/SiO2, acetone, 25 °C (99%); (d) i. H2NNHCOPh,
MeOH, ii. NaCNBH3, MeOH, HCl, 25 °C (80%); (e) (CH2O)n, 4 Å
molecular sieves powder, (i-Pr)2NEt, PhMe, 115 °C (82%); (f) i. SmI2, 9:1
THF-MeOH, ii. 37% aq formaldehyde, NaCNBH3, MeOH, HCl, 25 °C
(80%); (g) H2, 10 mol % of Pd(OH)2, HCl, MeOH, 25 °C (97%); (h) AlH3,
THF, 25 °C (74%); (i) MsCl, Et3N, CH2Cl2, -40 °C (96%); (j) H2, 10 mol
% of Pd/C, HCl, MeOH, 25 °C (99%); (k) 37% aq formaldehyde,
NaCNBH3, MeOH, HCl, 25 °C (80%).
scale by a modification of the method of Gassman.18 Allowing diene
18, cyclohexenone (R)-13, and 1,2-bis(trimethylsiloxy)ethane to
react in CH2Cl2 at -78 °C in the presence of 10 mol % of TMSOTf
provided cis-decalone acetal 19 in 64% yield, as a single stereo-
isomer. Cleavage of the dioxolane with FeCl3 adsorbed on silica
gel19 gave cis-decalone 20 in 99% yield. Condensation of this
product with benzoic hydrazide, followed by a stereoselective
reduction of the hydrazone intermediate with NaCNBH3 delivered
benzoic hydrazide 21 in 80% yield.
With hydrazide 21 in hand, we turned to the pivotal intramo-
lecular azomethine imine cycloaddition reaction. Early survey
experiments revealed that addition of base was required in order
to obtain tetracyclic pyrazolidine 22 in high yield; in the absence
of base, tricyclic aza-Prins products predominated.20,21 Under
optimized conditions, pyrazolidine 22 was isolated in 82% yield
when hydrazide 21 was heated with excess paraformaldehyde, 1
equiv of N,N-diisopropylethylamine, and powdered 4 Å molecular
sieves in toluene at 115 °C. Single-crystal X-ray analysis of product
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C O M M U N I C A T I O N S
2222 confirmed that the dipolar cycloaddition had taken place with
the expected regioselectivity.10,15
(4) Hirasawa, Y.; Kobayashi, J.; Obara, Y.; Nakahata, N.; Kawahara, N.; Goda,
Y.; Morita, H. Heterocycles 2006, 68, 2357–2364.
(5) (a) Dawbarn, D.; Allen, S. J. Neuropath. Appl. Neurobiol. 2003, 29, 211–
230. (b) Dauer, W. Science 2007, 411, 60–62.
The conversion of tetracyclic pyrazolidine 22 to (+)-nankaku-
rines A (2) and B (3) commenced with cleavage of the N-N bond
(6) (a) Hefti, F. Annu. ReV. Pharmacol. Toxicol. 1997, 37, 239–267. (b) Luu,
B.; Gonza´lez de Aguilar, J.-L.; Girlanda-Junges, C. Molecules 2000, 5,
1439–1460. (c) Water, S. P.; Tian, Y.; Li, Y.-M.; Danishefsky, S. J. J. Am.
Chem. Soc. 2005, 127, 13514–13515, and references therein.
(7) Kirik, D.; Georgievska, B.; Bjo¨rklund, A. Nat. Neurosci. 2004, 7, 105–
110.
(8) (a) For a review, see: Overman, L. E.; Ricca, D. J. In ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
1991; Vol. 2, pp 1007-1046. (b) An intramoleular Mannich reaction was
a key element of the first total synthesis of (()-luciduline; see: Scott, W. L.;
Evans, D. A. J. Am. Chem. Soc. 1972, 94, 4779–4780.
23
with SmI2 and selective in situ reductive methylation of the
secondary amine to generate diamine 23 in 80% yield. Hydro-
genolytic cleavage of the O-benzyl protecting group, followed by
reduction of the amide with AlH3,24 gave diamine alcohol 24 in
72% yield.25 Selective O-mesylation of this intermediate at -40
°C, followed by warming the primary mesylate to ambient
temperature to form the spiropiperidine ring, provided N-benzyl-
nankakurine A (25) in 96% yield. Hydrogenolysis of this intermedi-
ate in acidic methanol gave (+)-nankakurine A (2), [R]24D +13 (c
0.4, MeOH),26a in 99% yield. Standard reductive methylation of
(9) For examples of carboxylate-terminated aza-Prins biscyclization reactions,
see: (a) Heathcock, C. H.; Ruggeri, R. B.; McClure, K. F. J. Org. Chem.
1992, 57, 2585–2594. (b) Lo¨gers, M.; Overman, L. E.; Welmaker, G. S.
J. Am. Chem. Soc. 1995, 117, 9139–9150.
(10) (a) Oppolzer, W.; Petrzilka, M. J. Am. Chem. Soc. 1976, 98, 6722–6723.
(b) Oppolzer, W.; Petrzilka, M. HelV. Chim. Acta 1978, 61, 2755–2762.
(11) (a) Luo, F.-T.; Wang, R.-T. Tetrahedron Lett. 1992, 33, 6835–6838. (b)
See the Supporting Information for details.
nankakurine A (2) delivered (+)-nankakurine B (3), [R]24 +12
D
(c 1.5, MeOH),26b in 80% yield.27
(12) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953–
In summary, the first total syntheses of (+)-nankakurine A (2)
and (+)-nankakurine B (3) were accomplished, respectively, in 13
steps and 20% overall yield and 14 steps and 16% overall yield.
These syntheses, together with the synthesis of the originally
purported structure 1 of nankakurine A, rigorously establish the
relative and absolute configuration of (+)-nankakurines A (2) and
B (3). These enantioselective total syntheses are sufficiently concise
that gram quantities of (+)-nankakurine A (2) and (+)-nankakurine
B (3) will be available for further biological studies.
956.
(13) For selected examples of enyne metathesis, see: (a) Hansen, E. C.; Lee, D.
J. Am. Chem. Soc. 2004, 126, 15074–15080. (b) Smulik, J. A.; Diver, S. T.
Org. Lett. 2000, 2, 2271–2274.
(14) Ipaktschi, J. Chem. Ber. 1984, 117, 856–858.
(15) For a recent review, see: (a) Schantl, J. G. Azomethine Imines. In Science
of Synthesis; Georg Thieme Verlag: Stuttgart, 2004; Vol. 27, p 731. For
select examples, see: (b) Oppolzer, W. Tetrahedron Lett. 1970, 11, 3091–
3094. (c) Oppolzer, W. Tetrahedron Lett. 1972, 13, 1707–1710. (d)
Oppolzer, W. Angew. Chem., Int. Ed. Engl. 1977, 16, 10–23. (e) Jacobi,
P. A.; Martinelli, M. J.; Polanc, S. J. Am. Chem. Soc. 1984, 106, 5594–
5598. (f) Katz, J. D.; Overman, L. E. Tetrahedron 2004, 60, 9559–9568.
(g) Gergely, J.; Morgan, J. B.; Overman, L. E. J. Org. Chem. 2006, 71,
9144–9152.
Acknowledgment. This research was supported by the NIH
Neurological Disorders & Stroke Institute (NS-12389), and by
unrestricted grants from Amgen and Merck. J.R.A. thanks the
University of California President’s Postdoctoral Fellowship Pro-
gram for funding. NMR and mass spectra were obtained at UC
Irvine using instrumentation acquired with the assistance of NSF
and NIH Shared Instrumentation grants. We thank Dr. Hiroshi
Morita, Department of Pharmacognosy, Faculty of Pharmaceutical
Sciences, Hoshi University, Japan, for copies of 1H and 13C NMR
spectra of natural nankakurine B, and Dr. Joe Ziller, X-Ray
Crystallography Facility Director, UC Irvine, for X-ray analyses.
(16) Takami, K.; Mikami, S.; Yorimitsu, H.; Shinokubo, H.; Oshima, K. J. Org.
Chem. 2003, 68, 6627–6631.
(17) Fleming, I.; Maiti, P.; Ramarao, C. Org. Biomol. Chem. 2003, 1, 3989–
4004, and references therein.
(18) (a) Gassman, P. G.; Singleton, D. A.; Wilwerding, J. J.; Chavan, S. P.
J. Am. Chem. Soc. 1987, 109, 2182–2184. (b) Grieco, P. A.; Collins, J. L.;
Handy, S. T. Synlett 1995, 1155–1158.
(19) (a) Anderson, J. C.; Blake, A. J.; Graham, J. P.; Wilson, C. Org. Biomol.
Chem. 2003, 1, 2877–2885. (b) Kim, K. S.; Song, Y. H.; Lee, B. H.; Hahn,
C. S. J. Org. Chem. 1986, 51, 404–407.
(20) In the absence of base, cycloadduct 22 was produced in 25-50% yield,
with the remaining material being a mixture of tricyclic alkene isomers.
The use of triethylamine resulted in 80% yield of 22; however, the reaction
was much slower (24 vs 5 h, 50 mg scale).21
(21) Kanemasa, S.; Tomoshige, N.; Wada, E.; Tsuge, O. Bull. Chem. Soc. Jpn.
1989, 62, 3944–3949.
Supporting Information Available: Experimental details and copies
of 1H and 13C NMR spectra of new compounds; CIF file for compound
22. This material is available free of charge via the Internet at http://
pubs.acs.org.
(22) CCDC 690534. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
(23) Freshly prepared SmI2 was required to obtain reproducible yields for this
reaction; see the Supporting Information for details.
(24) Brown, H. C.; Yoon, N. M. J. Am. Chem. Soc. 1966, 88, 1464–1472.
(25) To facilitate monitoring reactions and purifying subsequent intermediates,
References
the N-benzyl protecting group was retained until the last step.
(26) Reported optical rotations for the natural products are: (a) nankakurine A:
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[R]21D +16 (c 0.4, MeOH).2 (b) nankakurine B: [R]19D +12 (c 1.0, MeOH)4
(27) Because they are strong bases and readily pick up protons (and potentially
also CO2), we could reproducibly obtain 1H and 13C NMR spectra of the
free-base forms of nankakurines A (2) and B (3) only in CD3OD containing
a trace amount of NaOCD3. These spectra were not identical to those
reported for natural 2 and 3 in CD3OD.2,4 However, by adding successive
amounts of CF3CO2H to samples of synthetic 2 and 3, 1H and 13C NMR
spectra identical to those of the natural products were obtained, consistent
with the notion that the natural samples contained an undetermined amount
of the conjugate acids. See the Supporting Information for details.
JA804624U
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