Photochemical reactions of chiral 2,3-dihydro-4(1H)-pyridones: Asymmetric synthesis of (-)-perhydrohistrionicotoxin

Article abstract of DOI:10.1039/a807448h

The first chiral auxiliary-mediated asymmetric synthesis of (-)-perhydrohistrionicotoxin is described.

Full text of DOI:10.1039/a807448h

Photochemical reactions of chiral 2,3-dihydro-4(1H)-pyridones: asymmetric
synthesis of (2)-perhydrohistrionicotoxin
Daniel L. Comins,* Yue-mei Zhang and Xiaoling Zheng
Department of Chemistry, North Carolina State University, Raleigh, North Carolina 27695-8204, USA.
E-mail: daniel_comins@ncsu.edu
Received (in Cambridge, UK) 24th September 1998, Accepted 12th October 1998
The first chiral auxiliary-mediated asymmetric synthesis of
(2)-perhydrohistrionicotoxin is described.
The acetal was hydrolyzed and the resulting alcohol was
converted to iodide 11 in high yield (84%). The C-4 carbonyl of
11 was protected as the triethylsily enol ether 12. The synthesis
In an effort to expand the utility of chiral 2,3-dihydro-4(1H)-
pyridones as synthetic building blocks,1 we are exploring their
annulation using intramolecular [2+2] photocycloaddition reac-
tions.2 As was first demonstrated by Neier,3 novel ring systems
can be prepared from dihydropyridones using this approach. We
were able to demonstrate through model studies that the
skeleton of perhydrohistrionicotoxin 1 was accessible using this
strategy.4 Histrionicotoxin 2 is one of the biologically active
alkaloids found in the skin secretions of the neotropical frog
Dendrobates histrionicus.5 Alkaloids 1 and 2 have been used in
OMe
OMe
TIPS
TIPS
i
Cl
N
N
3
CO2R*
4
ii,iii
O
O
N
4
5
6
3
2
OH
OH
TIPS
7
1
N
iv
8
N
H
11
10
9
N
H
H
CO2R*
2
1
6
5
perhydrohistrionicotoxin
histrionicotoxin
v, vi
studies of the mechanisms involved in transsynaptic transmis-
sion of neuromuscular impulses. The biological activity and
novel structure of these alkaloids have stimulated numerous
synthetic studies.6 Several racemic and two enantioselective
syntheses of 1 have been published. In addition, one asymmetric
route to histrionicotoxin 2 has been reported.6c The enantio-
selective routes used enantiopure intermediates prepared by
OTMS
O
EEO
vii
N
N
CO2Bn
CO2Bn
resolution7 or derived from -glutamic acid.6a Here we report a
L
7
9
novel asymmetric synthesis of 1 using a photochemical
conversion of an enantiopure 2,3-dihydro-4(1H)-pyridone as a
key step. The enantiopure dihydropyridone was prepared by an
efficient chiral auxiliary-mediated asymmetric synthesis.1 The
synthetic plan called for a stereoselective intramolecular [2+2]
cycloaddition of an enantiopure dihydropyridone to set the
stereochemistry at C-6 and C-7, and a subsequent cyclobutane
ring opening to provide the azaspiroundecane skeleton of 1.
Reaction of enantiopure 1-acylpyridinium salt 4, prepared in
situ from 4-methoxy-3-(triisopropylsilyl)pyridine 38 and the
chloroformate of (2)-(1R,2S,4R)-2-(a-cumyl)-4-isopropyl-
cyclohexanol (CPC),9 with n-pentylmagnesium bromide in
THF–toluene at 278 °C gave the crude dihydropyridone 5 in
95% yield and 90% de (Scheme 1). Purification by radial PLC
(silica gel, EtOAc–hexanes) afforded a 91% yield of pure 5 [mp
viii
O
O
N
EEO
I
ix, x
N
CO2Bn
CO2Bn
10
11
xi
23
OTES
75–78 °C; [a]D 248.1 (c 0.88, CDCl3)]. Treatment of 5 with
EEO
MgBr
NaOMe in MeOH followed by aqueous 10% HCl provided
dihydropyridone 6 [[a]D25 +353 (c 0.18, CHCl3)] in 84% yield,
and the chiral auxiliary [(2)-CPC] was recovered in 95% yield.
Acylation of 6 with BunLi and ClCO2Bn gave a 90% yield of
I
8
N
CO2Bn
12
23
enantiopure carbamate 7 [[a]D 283.7 (c 2.24, CHCl3)]. A side
chain was introduced at C-6 of 7 through a 1,4-addition and
oxidation sequence. In the presence of TMSCl, copper-
mediated conjugate addition of Grignard reagent 8 to 7 provided
silyl enol ether 9. Oxidation of crude 9 with Pd(OAc)2 gave
dihydropyridone 10 in 92% overall yield for the two steps.1c
Scheme 1 Reagents and conditions: i, ClCO2R*; ii, C5H11MgCl; iii, H3O+;
iv, NaOMe, MeOH, then 10% HCl, v, BunLi; vi, ClCO2Bn; vii, 8, CuBr,
TMSCl; viii, Pd(OAc)2, MeCN; ix, oxalic acid; x, NIS, PPh3; xi, NaHMDS,
TESCl.
Chem. Commun., 1998, 2509–2510
2509

was continued (Scheme 2) by treatment of crude 12 with the
anion of 13, prepared from the corresponding commercially
available aldehyde, to give enone 14 in 94% yield. Protection of
the ketone carbonyl using enantiopure bis-TMS ether 1510
provided ketal 16 (87%). Since the C-2 substituent of 16 is axial,
due to A1,3 strain,11 photocyclization was anticipated to be
highly stereoselective for the less hindered olefin face. On
photolysis in acetone (460 W Hanovia Hg lamp, 16 min, 5 °C),
16 gave a 79% yield of cycloadduct 17 as the sole isolated
product. The (R,R)-hydrobenzoin ketal of 16 is important for
high facial selectivity, for the corresponding ethylene ketal gave
only a 7:1 mixture of photoadducts. At this stage of the
synthesis, installation of three stereogenic centers with the
correct relative and absolute stereochemistry needed for the
construction of 1 had been achieved. Treatment of 17 with SmI2
in THF and DMPU effected cyclobutane ring opening to give
spirocyclic ketone 18 in 70% yield, which was converted to a
mixture of vinyl triflates 19 (90%) using LiHMDS and N-
(5-chloro-2-pyridyl)triflimide.12 Catalytic hydrogenation of
this mixture effected vinyl triflate reduction, cleavage of the
ketal, and removal of the Z group to provide the known amino
ketone 206a in 81% yield. The synthesis of (2)-perhydrohis-
trionicotoxin 1 was completed by reduction of 20 with
LiAl(OBut)3H according to the procedure of Winkler.6a Our
synthetic 1 exhibited spectral data in agreement with reported
data of authentic material.5,6 The optical rotation [[a]D 283.8 (c
0.2, CH2Cl2)] was also in agreement with literature values
22
22
[[a]D 284.1 (c 0.024, CH2Cl2); [a]D 283.1 (c 0.0067,
CH2Cl2)].6a
In summary, the first chiral auxiliary-mediated asymmetric
synthesis of (2)-perhydrohistrionicotoxin was accomplished in
15 steps (14% overall yield) with a high degree of ster-
eoselectivity. Key steps include a highly stereoselective intra-
molecular [2+2] photocyclization of dihydropyridone 16 and a
SmI2-promoted cyclobutane ring opening, which provide the
azaspiroundecane skeleton of the alkaloid.
We express appreciation to the National Institutes of Health
(Grant GM 34442) and the Petroleum Research Fund (ACS-
PRF #28394-AC) for financial support of this research.
O
i, ii
O
12
N
Notes and references
† Satisfactory IR, 1H and 13C NMR spectra, HRMS or microanalyses were
obtained for all compounds described.
CO2Bn
14
1 (a) D. L. Comins and S. P. Joseph, Advances in Nitrogen Heterocycles,
ed. C. J. Moody, JAI Press, Greenwich, CT, 1996; vol. 2, pp. 251–294;
(b) D. L. Comins, S. P. Joseph and X. Chen, Tetrahedron Lett., 1995, 36,
9141; (c) D. L. Comins, S. P. Joseph and D. D. Peters, Tetrahedron Lett.,
1995, 36, 9449; (d) D. L. Comins, S. P. Joseph and Y. Zhang,
Tetrahedron Lett., 1996, 37, 793; (e) D. L. Comins and L. Guerra-
Weltzien, Tetrahedron Lett., 1996, 37, 3807; (f) D. L. Comins, X. Chen
and S. P. Joseph, Tetrahedron Lett., 1996, 37, 9275; (g) D. L. Comins,
X. Chen and L. A. Morgan, J. Org. Chem., 1997, 62, 7435; (h) D. L.
Comins, D. H. LaMunyon and X. Chen, J. Org. Chem., 1997, 62,
8182.
iii
O
O
Ph
H
Ph
H
O
O
iv
Ph
N
O
N
O
Ph
CO2Bn
CO2Bn
2 D. L. Comins, Y. Lee and P. D. Boyle, Tetrahedron Lett., 1998, 39,
187.
3 P. Guerry and R. Neier, Chimia, 1987, 41, 341; P. Guerry and R. Neier,
J. Chem. Soc., Chem. Commun., 1989, 1727; P. Guerry, P. Blanco, H.
Brodbeck, O. Pasteris and R. Neier, Helv. Chem. Acta., 1991, 74,
163.
16
17
v
4 D. L. Comins and X. Zheng, J. Chem. Soc., Chem. Commun., 1994,
2681.
O
OTf
Ph
Ph
5 J. W. Daly and T. F. Spande, Alkaloids: Chemical and Biological
Perspectives, ed. S. W. Pelletier, Wiley, New York, 1986; vol. 4, ch. 1,
pp. 1–274; J. W. Daly, H. M. Garraffo and T. F. Spande, The Alkaloids,
ed. G. A. Cordell, Academic Press: San Diego, CA, 1993; vol. 43, pp.
185–288.
O
O
vi, vii
N
N
O
Ph
O
Ph
CO2Bn
CO2Bn
6 For recent synthetic work and leading references on the histrionicotox-
ins, see: (a) J. D. Winkler and P. M. Hershberger, J. Am. Chem. Soc.,
1989, 111, 4852; (b) J. J. Venit, M. DiPierro and P. Magnus, J. Org.
Chem., 1989, 54, 4298; (c) G. Stork and K. Zhao, J. Am. Chem. Soc.,
1990, 112, 5875; (d) J. Zhu, J. Royer, J.-C. Quirion and H.-P. Husson,
Tetrahedron Lett., 1991, 32, 2485; (e) C. M. Thompson, Heterocycles,
1992, 34, 979; (f) P. Compain, J. Gore and J-M. Vatele, Tetrahedron
Lett., 1995, 36, 4063; (g) R. W. Fitch and F. A. Luzzio, Ultrason.
Sonochem., 1997, 4, 99.
7 K. Takashashi, B. Witkop, A. Brossi, A. M. Maleque and E. X.
Albuquerque, Helv. Chim. Acta, 1982, 65, 252.
8 D. L. Comins, S. P. Joseph and R. R. Goehring, J. Am. Chem. Soc., 1994,
116, 4719.
19
18
viii
ix
O
1
N
H
(–)-perhydrohistrionicotoxin
20
9 D. L. Comins, L. Guerra-Weltzien and J. M. Salvador, Synlett, 1994,
972; D. L. Comins and L. Guerra-Weltzien, Tetrahedron Lett., 1996, 37,
3807.
10 C. N. Eid and J. P. Konopelski, Tetrahedron Lett., 1991, 32, 461.
11 For reviews on A1,3 strain, see: R. W. Hoffman, Chem. Rev., 1989, 89,
1841; F. Johnson, Chem. Rev., 1968, 68, 375.
12 D. L. Comins and A. Dehghani, Tetrahedron Lett., 1992, 33, 6299; D. L.
Comins, A. Dehghani, C. J. Foti and S. P. Joseph, Org. Synth. 1996, 74,
77.
Ph
Ph
OTMS
OTMS
NC
OTMS
H
13
15
Scheme 2 Reagents and conditions: i, 13, LHMDS, THF; ii, 10% HCl, then
NaOH; iii, 15, TMSOTf; iv, hn, acetone, 5 °C, 16 min; v, SmI2, THF,
2
M
DMPU; vi, LHMDS, THF; vii, N-(5-chloro-2-pyridyl)triflimide; viii, H2,
Pd(OH)2, Li2CO3, EtOH; ix, LiAl(OBut)3H.
Communication 8/07448H
2510
Chem Commun., 1998, 2509–2510