Total Synthesis of Huperzine R

Article abstract of DOI:10.1021/acs.orglett.7b03555

A total synthesis of huperzine R was accomplished. Intramolecular cycloaddition of a nitrile oxide and reductive cleavage of the resulting isoxazoline induced sequential cleavage of the C-C and C-O bonds to form the characteristic bicyclic lactam core with an enone moiety. Construction of the butenolide moiety from the enone afforded huperzine R.

Full text of DOI:10.1021/acs.orglett.7b03555

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Total Synthesis of Huperzine R
Toshimune Nomura, Satoshi Yokoshima,* and Tohru Fukuyama*
Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan
*
S Supporting Information
ABSTRACT: A total synthesis of huperzine R was accom-
plished. Intramolecular cycloaddition of a nitrile oxide and
reductive cleavage of the resulting isoxazoline induced
sequential cleavage of the C−C and C−O bonds to form
the characteristic bicyclic lactam core with an enone moiety.
Construction of the butenolide moiety from the enone
afforded huperzine R.
uperzine R (1), isolated from Lycopodium serratum by
ring (Scheme 1). Although the resulting tertiary amine moiety
in 7 could not be converted into the amide moiety, the
H
Zhu and co-workers in 2002, is characterized by a unique
1
bicyclic lactam core (Figure 1). Although huperzine R can be
Scheme 1. Synthetic Strategy toward Huperzine R
Figure 1. Fawcettimine-type Lycopodium alkaloids.
classified as a fawcettimine-type Lycopodium alkaloid on the2
basis of structural similarities, it lacks the C12−C13 bond.
Phlegmariurine-A (3) is a related natural product that has the
same bicyclic lactam moiety, and its biosynthetic pathway from
lycoposerramine-C (4) has been proposed by Takayama and
successful formation of the requisite ring system motivated us
to try the ring-enlargement strategy with other fused ring
systems. Thus, the connection between C12 and C13 in
huperzine R (1) led to hemiaminal 8 as a candidate for a fused
ring system, which is similar to that of fawcettimine (2) or
lycoposerramine-C (4). We envisioned that cleavage of the
shared C12−C13 bond could be achieved using a suitable
ketone (X = O) or imine (X = NR) through a retro-aldol-type
3
co-workers. The chemical transformation of lycoposerramine-
C into phlegmariurine-A has been reported, in which a
vinylogous retro-aldol reaction was induced by treatment with
3
,4
sodium methoxide or potassium tert-butoxide. While these
reports are the only successful synthetic approaches to this class
of alkaloids to date, we now disclose a total synthesis of
huperzine R.
8
reaction of the resulting β-hydroxy ketone or imine. The
hemiaminal moiety in 8 could in turn be formed from an amino
ketone via formation of the seven-membered ring. To
simultaneously install X and Y in 8, we employed the 1,3-
The lactam moiety in huperzine R contains two medium-
sized rings whose transannular strains make it difficult to
9
5
dipolar cycloaddition of a nitrile oxide to form isoxazoline 9.
construct. For the construction of medium-sized rings,
Our synthesis commenced with the preparation of the
precursor for the nitrile oxide (Scheme 2). Symmetrical alkyne
cleavage of a bond shared by two rings in a fused bicyclic
6
system to form a larger ring system is a reasonable solution. In
10
7
10 was subjected to a hydrozirconation/iodination process to
our previous synthetic studies toward huperzine R, we
prepared ammonium salt 6 via six-membered ring formation
from mesylate 5, and subsequent cleavage of the C−N bond
shared by the rings produced 7 containing an 11-membered
Received: November 16, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03555
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Preparation of Isoxazoline 18
Scheme 3. Construction of the Bicyclic Lactam Core
After construction of the bicyclic lactam core, the remaining
task toward the synthesis of huperzine R was to construct the
butenolide moiety (Scheme 4). Nucleophilic epoxidation
Scheme 4. Completion of the Synthesis
give iodide 11. After removal of the TBS groups, the resulting
diol was converted into bismesylate 12, which was then reacted
with nosylamide and cesium carbonate to furnish a cyclic amine
1
1
derivative. Replacement of the nosyl group with a Boc group
afforded 13. Halogen/lithium exchange in 13 generated an
alkenyllithium species, which upon addition of lactone 14
provided hydroxy ketone 15. Oxidation of 15 with Dess−
1
2
Martin periodinane followed by condensation with hydroxyl-
amine afforded oxime 16. Chlorination of the oxime with
sodium hypochlorite and subsequent treatment with sodium
hydroxide generated a nitrile oxide that underwent intra-
molecular cycloaddition with the olefin moiety to give
isoxazoline 17 in a diastereomeric ratio of 3.7:1. The
diastereomers could be separated after cleavage of the Boc
group with TFA to afford hemiaminal 18 in 56% yield.
toward the enone moiety in 23 afforded epoxy ketone 24,
which was subjected to a Wittig reaction with (methoxy-
methylene)(triphenyl)phosphorane to give, after acidic hydrol-
ysis, hydroxyaldehyde 25. Oxidation with Jones reagent
furnished ketocarboxylic acid 26, which was stereoselectively
reduced with lithium borohydride to give huperzine R (1).
In conclusion, we have accomplished a total synthesis of
huperzine R (1). Our synthesis features intramolecular 1,3-
dipolar cycloaddition of a nitrile oxide and reductive cleavage of
the resulting isoxazoline to induce a retro-aldol-type reaction,
forming the bicyclic lactam core. Further transformations of the
bicyclic lactam intermediate into natural and unnatural
analogues are currently underway and will be reported in due
course.
With the requisite isoxazoline in hand, we next focused on
the ring enlargement via cleavage of the C12−C13 bond
(Scheme 3). Treatment of 18 with a base did not induce the
C−C bond cleavage, resulting in recovery of the starting
material. Hence, liberation of the ketone function from
isoxazoline 18 was attempted by reduction with Raney nickel.
While cleavage of the N−O bond proceeded to generate imine
1
9, undesired cleavage of the C4−C12 bond occurred to give
13
β-amino-α,β-unsaturated ketone 20. After extensive inves-
tigation into the reductive conditions, much to our delight,
14
Kulinkovich’s conditions effected the desired transformation.
Thus, 18 was treated with a titanium(III) reagent, prepared by
15
ASSOCIATED CONTENT
Supporting Information
premixing Ti(OiPr) and EtMgBr, to give lactam 23. Under
■
4
*
S
these conditions, upon reductive cleavage of the N−O bond, a
retro-aldol-type reaction of 21 cleaved the C12−C13 bond to
generate 22, from which an elimination reaction proceeded to
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03555.
1
6
afford 23.
B
DOI: 10.1021/acs.orglett.7b03555
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Experimental procedures, spectroscopic data, and H and
Letter
1
Org. Chem. 2015, 2015, 5709. (f) Gros, G.; Hasserodt, J. Eur. J. Org.
13
́
Chem. 2015, 2015, 183. (g) Prado, G.; Veiga, A. X.; Fernandez-Nieto,
C NMR spectra (PDF)
F.; Paleo, M. R.; Sardina, F. J. Org. Lett. 2015, 17, 2054. (h) Tong, T.
M. T.; Soeta, T.; Suga, T.; Kawamoto, K.; Hayashi, Y.; Ukaji, Y. J. Org.
Chem. 2017, 82, 1969.
AUTHOR INFORMATION
Corresponding Authors
■
(7) Kumazaki, H.; Nakajima, R.; Bessho, Y.; Yokoshima, S.;
Fukuyama, T. Synlett 2015, 26, 2131.
(
*
E-mail: yokosima@ps.nagoya-u.ac.jp.
E-mail: fukuyama@ps.nagoya-u.ac.jp.
8) For selected examples of the related cleavage via retro-aldol-type
*
reaction, see: (a) Von Strandtmann, M.; Puchalski, C.; Shavel, J. J. J.
Org. Chem. 1968, 33, 4010. (b) Ohnuma, T.; Nagasaki, M.; Tabe, M.;
Ban, Y. Tetrahedron Lett. 1983, 24, 4253. (c) Crabb, T. A.; Roxburgh,
C. J.; Newton, R. F. J. Chem. Soc., Perkin Trans. 1 1989, 2431.
d) Moon, B.; Han, S.; Yoon, Y.; Kwon, H. Org. Lett. 2005, 7, 1031.
e) Roxburgh, C. J.; Banting, L. Aust. J. Chem. 2006, 59, 59. (f) Yeom,
ORCID
Satoshi Yokoshima: 0000-0003-4036-0062
Tohru Fukuyama: 0000-0001-9612-5665
Notes
(
(
H.-S.; Lee, Y.; Jeong, J.; So, E.; Hwang, S.; Lee, J.-E.; Lee, S. S.; Shin, S.
Angew. Chem., Int. Ed. 2010, 49, 1611. (g) Kitsiou, C.; Hindes, J. J.;
I’anson, P.; Jackson, P.; Wilson, T. C.; Daly, E. K.; Felstead, H. R.;
Hearnshaw, P.; Unsworth, W. P. Angew. Chem., Int. Ed. 2015, 54,
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by JSPS KAKENHI
1
5794.
(Grants 26713001, 16H01141, and 17H01523) and by the
(
9) (a) Curran, D. P. J. Am. Chem. Soc. 1982, 104, 4024.
Platform Project for Supporting Drug Discovery and Life
Science Research (Basis for Supporting Innovative Drug
Discovery and Life Science Research; BINDS) from the
Japan Agency for Medical Research and Development
(b) Kozikowski, A. P. Acc. Chem. Res. 1984, 17, 410. For recent
examples, see: (c) Maehara, T.; Motoyama, K.; Toma, T.; Yokoshima,
S.; Fukuyama, T. Angew. Chem., Int. Ed. 2017, 56, 1549. (d) Fischer, S.;
Huwyler, N.; Wolfrum, S.; Carreira, E. M. Angew. Chem., Int. Ed. 2016,
5
́ ́
5, 2555. (e) Hog, D. T.; Huber, F. M. E.; Jimenez-Oses, G.; Mayer,
(AMED).
P.; Houk, K. N.; Trauner, D. Chem. - Eur. J. 2015, 21, 13646. (f) Xuan,
J.; Pan, S.; Zhang, Y.; Ye, B.; Ding, H. Org. Biomol. Chem. 2015, 13,
REFERENCES
■
1
2
643. (g) Hartung, J.; Wright, B. J. D.; Danishefsky, S. J. Chem. - Eur. J.
014, 20, 8731. (h) Enev, V. S.; Felzmann, W.; Gromov, A.; Marchart,
(
1) Tan, C.-H.; Chen, G.-F.; Ma, X.-Q.; Jiang, S.-H.; Zhu, D.-Y. J.
Nat. Prod. 2002, 65, 1021.
2) For reviews of the Lycopodium alkaloids, see: (a) MacLean, D. B.
In The Alkaloids; Manske, R. H. F., Ed.; Academic Press: San Diego,
968; Vol. 10, p 305. (b) MacLean, D. B. In The Alkaloids; Manske, R.
H. F., Ed.; Academic Press: San Diego, 1973; Vol. 14, p 347.
c) MacLean, D. B. In The Alkaloids; Brossi, A., Ed.; Academic Press:
San Diego, 1985; Vol. 26, p 241. (d) Ayer, W. A.; Trifonov, L. S. In
The Alkaloids; Cordell, G. A., Brossi, A., Eds.; Academic Press: San
Diego, 1994; Vol. 45, p 233. (e) Ma, X.; Gang, D. R. Nat. Prod. Rep.
004, 21, 752. (f) Kobayashi, J.; Morita, H. In The Alkaloids; Cordell,
G. A., Ed.; Academic Press: San Diego, 2005; Vol. 61, p 1.
g) Hirasawa, Y.; Kobayashi, J.; Morita, H. Heterocycles 2009, 77,
79. (h) Kitajima, M.; Takayama, H. Top. Curr. Chem. 2011, 309, 1.
i) Nakayama, A.; Kitajima, M.; Takayama, H. Synlett 2012, 23, 2014.
j) Siengalewicz, P.; Mulzer, J.; Rinner, U. In The Alkaloids; Knolker,
H.-J., Ed.; Academic Press: San Diego, 2013; Vol. 72, p 1. (k) Wang,
X.; Li, H.; Lei, X. Synlett 2013, 24, 1032. (l) Murphy, R. A.; Sarpong,
R. Chem. - Eur. J. 2014, 20, 42. (m) Takayama, H. Yuki Gosei Kagaku
Kyokaishi 2015, 73, 1072.
S.; Mulzer, J. Chem. - Eur. J. 2012, 18, 9651.
10) Shimada, N.; Abe, Y.; Yokoshima, S.; Fukuyama, T. Angew.
Chem., Int. Ed. 2012, 51, 11824.
11) (a) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett.
(
(
1
(
1
995, 36, 6373. (b) Kan, T.; Kobayashi, H.; Fukuyama, T. Synlett
(
2
002, 2002, 697. (c) Kan, T.; Fukuyama, T. Yuki Gosei Kagaku
Kyokaishi 2001, 59, 779. (d) Kan, T.; Fukuyama, T. Chem. Commun.
004, 353.
2
(12) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
2
(13) Upon reduction of 17 with Raney nickel, undesired cleavage of
the C4−C12 bond also occurred. For details, see the Supporting
Information.
(
6
(
(
(
2
(
14) Churykau, D. H.; Zinovich, V. G.; Kulinkovich, O. G. Synlett
004, 2004, 1949.
15) Although the first trial of the reaction with aged Ti(Oi-Pr)4
̈
produced 23 in good yield, distillation of Ti(Oi-Pr) prior to use
4
lowered the yield of the reaction. We found that addition of 2-
propanol improved the reproducibility.
(16) Under the protic solvent (ethanol) conditions of the Raney Ni
(
3) Takayama, H.; Katakawa, K.; Kitajima, M.; Yamaguchi, K.; Aimi,
N. Tetrahedron Lett. 2002, 43, 8307.
4) Nakayama, A.; Kogure, N.; Kitajima, M.; Takayama, H. Org. Lett.
009, 11, 5554.
5) The attempted formation of the lactam from 27 proved to be
unsuccessful.
reaction, the hemiaminal and ketone were present in equilibrium, and
liberation of the ketone moiety could potentially facilitate the cleavage
of the C4−C12 bond via a retro-aldol reaction. On the other hand,
under Kulinkovich’s conditions, the hemiaminal moiety was present as
the corresponding anion in an aprotic solvent (THF), which may have
suppressed the cleavage of the C−N bond in the hemiaminal moiety.
(
2
(
(
6) For recent examples, see: (a) Punirun, T.; Peewasan, K.;
Kuhakarn, C.; Soorukram, D.; Tuchinda, P.; Reutrakul, V.;
Kongsaeree, P.; Prabpai, S.; Pohmakotr, M. Org. Lett. 2012, 14,
1
820. (b) Des
Boschetti, F.; Denat, F. Eur. J. Org. Chem. 2014, 2014, 7831.
c) Davies, S. G.; Fletcher, A. M.; Foster, E. M.; Houlsby, I. T. T.;
Roberts, P. M.; Schofield, T. M.; Thomson, J. E. Org. Biomol. Chem.
014, 12, 9223. (d) Yoshida, M.; Sassa, N.; Kato, T.; Fujinami, S.;
Soeta, T.; Inomata, K.; Ukaji, Y. Chem. - Eur. J. 2014, 20, 2058.
e) Roudier, M.; Constantieux, T.; Quintard, A.; Rodriguez, J. Eur. J.
́ ̀
ogere, P.; Rousselin, Y.; Poty, S.; Bernhard, C.; Goze, C.;
(
2
(
C
DOI: 10.1021/acs.orglett.7b03555
Org. Lett. XXXX, XXX, XXX−XXX