Alkaloid Photochemistry
Baran Lab
ALKALOID PHOTOCHEMISTRY
(for a nice review of photochemistry of alkaloids prior to 1980 see Singh, A.
P.; Stenberg, V. I.; Parmar, S. S. Chem. Rev. 1980, 80, 269-282)
K. J. Eastman
The following scheme represents a likely pathway for the observed products
(see Santamaria, J. Pure & Appl. Chem., 1995, 67, 141-147).
I. Introduction:
[O]
-H
The photochemistry of alkaloids represents a field rich in diversity including
oxidation, reduction, dimerization, addition, hydrogen abstraction,
dealkylation, epimerization, isomerization and degradation. Yet 60 years after
Weil's1 observation of the photochemical oxidation of nicotine, much remains
to be discovered in this field.
Alkaloid photochemistry includes a wide variety of chromophoric substrates
including: pyrrolidine, piperdine, pyridine, quinoline, isoquinoline, and indole,
and come from a various alkaloid classes, colchicine, isocolchicine, tropane,
opium, ergot, strychnose, steriod and others.
N
Py
+
N
Py
H2O 2
H2O 2
N
Py
KCN
CN
O2H
Py
N
H
+
Py
O
N
Py
∆
The survey to follow will primarily features nitrogen as the key participant for
both sensitized and direct photochemically induced reactions.
N
H2O2
CONH2
O
Py
N
Py
N
Py
N
II. Pyrrolidine, Piperdine, and Pyridine Alkaloids:
Upon irradiation of a methanolic solution of nicotine in the presence of O 2 and
methylene blue, Hubert-Brierre and co-workers observed the formation of
nicotyrine, cotinine, and nicotine N-oxide (Hubert-Brierre, Y.; Herlem, D.;
Khuong-Huu, F. Tetrahedron 1975, 31, 3049-3054).
sens/hν
ν /O2
H
H
N
N+
N
N
H
O
N
N
N
sens/hν
ν/O2/KCN
CN
N
CONH2
H2O 2
N
H
N
N
Py
N
H
Py
N
CH2 CN
Py
N
CH2CONH2
The observation of the N-demethy lated compound, an aminonitrile and
a carboxamide lead to the conclusion that the oxidation with the six
membered ring is exocyclic vs. the five membered ring which was endocyclic.
H
H
N
H
N
sens/h ν/O2/KCN
Py
O
N
Hubert-Brierre and co-workers also investigated the irradiation of N-methylanabasine under a similar set of conditions.
H
CONH2
N
1
Alkaloid Photochemistry
Baran Lab
Photohydration of Pyridinium ions first observed by Kaplan and Wilzbach
(Kaplan, L.; Pavlik, J. W.; Wilzbach, K. E. J. Am. Chem. Soc. 1972, 94, 32833284) went nearly unnoticed for 10 years before Mariano and co-workers
described their observations of the divergent photochemical behavior of
N-allylpyridinium perchlorates (Yoon, U. C.; Quillen, S. L.; Mariano, P. S.;
Swanson, R.; Stavinoha, J. L.; Bay, E. J. Am. Chem. Soc. 1983, 105, 12041218).
Kaplan (1972):
Cl - N+
N
hν
H
N
H 2O-KOH
H
K. J. Eastman
Thirteen years after thier first observations with the pyridinium salt
photocyclization process, Mariano and co-workers returned to this area and have
subsequently reported on several occasions their investigations into the potential
synthetic power of a tandem sequences involving:
(1) photoinduced cyclization of pyridinium cations
(2) stereocontrolled nucleophile addition to produce bicyclic aziridines, and
(3) stereocontrolled nucleophilic cleavage of the bicyclic aziridine to produce
highly functionalized aminocyclopentenes.
(Ling, R.; Yoshida, M.; Mariano, P. S. J. Org. Chem. 1996, 61, 4439-4449, Song, L.;
Duesler, E. D.; Mariano, P. S. J. Org. Chem. 2004, 69, 7284-7293).
X-
R1
1. hν
ν
HNu 1
N+
OH
R1
H
N
H
2. base
R2
Nu1
R2
NHR1
1. hν
HNu1
Nu2
2. base
R2
Mariano (1983):
OCH3
CH2CH=C(CH3 )2
ClO4- N+
hν
CH2CH=CH2
IIa. β -aziridinylacrylonitriles and acrylates:
It has been well established that heating or irradiating aziridines, usually
bearing an adjacent electron-withdrawing group, results in the formation of
azomethane ylides. The 1,3-dipolar cycloaddition of azomethane ylides with
alkenes plays an important role in the synthesis of nitrogen containing fivemembered rings (see Ishii, K. et. al. Tetrahedron 2004, 60, 10887-10898 and
references within for some examples).
N
CH3OH
ClO4- N+
Nu1
CH2CH=CH2
hν
H
N
CH3OH
H
OCH3
HClO4
CH3OH
Bn
Bn
h ν or ∆
N
CN
CN
NHCH2 CH=CH2
H3CO
N
EWG
EWG
head-to-head adducts
OCH3
2
Alkaloid Photochemistry
Baran Lab
III. Isoquinoline Alkaloids:
Direct photooxidation of glaucin gave O-methylatheroline (85 %) and corunnine
(10 %) (Castedo, L.; Suau, R.; Mourino, A. An. Quim. 1977, 73, 290).
Noyori and co-workers observed that Irradiation of equimolar quantities of
isoquinoline and the appropriate carboxylic acids in benzene resulted in the
formation of the corresponding 1-alkylisoquinolines in poor yield (Noyori, R.;
Lato, M.; Kawanisi, M.; Nozaki, H. Tetrahedron 1969, 25, 1125-1169).
N
+ RCOOH
H3CO
H3 CO
N
H3CO
hν
-CO2
K. J. Eastman
H
H3CO
N
H3 CO
hν /O 2
N
O
10-20 %
R
H3CO
Bick and co-workers reported the photo-oxidative cleavage of some benzylisoquinoline-based alkaloids (Bick, I. R. C.; Bremner, J. B.; Wiriyachitra, P.
Tet. Lett. 1971, 50, 4795-4797).
laudanosine:
H3CO
H3CO
N
H3CO
hν /O2
H3CO
HO -
H3CO
CHO
NaBH4
N
H3 CO
H3 CO
H3 CO
H3 CO
N+
I-
hν
ν/ROH
H3 CO
H3 CO
OCH3
Photoinduced elimination products were obtained in moderate to high yield
upon irradiation of a methanolic solution of the quaternary salt of glaucine
(Bremner, J. B.; Winzenberg, K. N.; Aust. J. Chem. 1978, 31, 313).
H3CO
N
XN+
H3 CO
H
hν
ν /ROH
H3CO
H3CO
H3 CO
OCH3
OCH3
Photosolvolysis of laudanosine methyliodide (Bremner, J. B.; Thuc, L. V.
Chem. Ind. (London) 1976, 453).
H3 CO
10 %
H3CO
H3 CO
H3CO
H3CO
O
OCH3
N
O
H3CO
OCH3
+
H3CO
85 %
H3 CO
H3 CO
N
H3CO
N+
H3CO
N
OR
Stermitz and co-workers made the following observation of the irradiation of
alcoholic solutions of papaverine (Stermitz, F. R.; Seiber, R. P.; Nicodem, D. E.;
J. Org. Chem. 1968, 33, 1136-1140).
H3 CO
H3 CO
H3 CO
N
hν
ν/ROH
H3 CO
N
H3 CO
R
H3 CO
H3 CO
H3 CO
3
Alkaloid Photochemistry
Baran Lab
Many have observed the biogenetic conversion protoberberine-type alkaloids
into phthalideisoquinoline alkaloids (see Kondo, Y.; Imai, J.; Nozoe, S. J. Chem.
Soc. Perkin Trans. I 1980, 919-923).
H3 CO
Noyori and co-workers observed that Irradiation of equimolar quantities of
quinoline and equimolar quantities of the appropriate carboxylic acids in benzene
resulted in the formation of the corresponding 2-alkylquinolines in low yield
(Noyori, R.; Lato, M.; Kawanisi, M.; Nozaki, H. Tetrahedron 1969, 25, 1125-1169).
H3CO
N
H3 CO
hν
+
hν
ν/O2
N
H3CO
O
O
-
O
RCOOH
N
OCH3
OCH3
The irradiation of a methanolic solution of tropanol in the presence of a sensitizer
gave formamido, demethylated and N-oxytropanol products (Herlem, D.; HubertBrierre, Y.; Khuong-Huu, F.; Goutarel, R. Tetrahedron 1973, 29, 2195-2202).
H3 CO
OHC
N
O
H
NaBH4
O
N
H3 CO
R
V. Tropane alkaloids:
OCH3
H3CO
N
O
OCH3
H3CO
K. J. Eastman
N
O
H
N
N
N
O
sens/hν
ν /O2
HO
O
OCH3
H3CO
OH
OH
OCH3
OH
VI. Amaryllidaceae Alkaloids:
The photolysis of crinamine in MeOH under N2 gave the following result (Tsuda, Y.;
Kanede, M.; Takagi, S.; Yamaki, M.; Iitaka, Y. Tet. Lett. 1978,19, 1199-1200).
IV. Quinoline Alkaloids:
Quinoline suffers dimerization upon irradiation in alcoholic solution (Pfordte,
K.; Leuschner, G. Justus Liebigs Ann. Chem. 1061, 30, 646).
OCH3
OH
O
H
hν
O
N
OH
OCH3
N
N
hν
ν/MeOH/no O2
H
H
O
O
OCH3
OH
H
N
H
N
4
Alkaloid Photochemistry
Baran Lab
K. J. Eastman
VII. Opium Alkaloids:
Lotfy and co-workers have recently disclosed thier observations of the
irradiation of variably substituted codeinones and morphinones (Lotfy, H. R.;
Theuns and co-workers reported the biomimetic synthesis of neodihydrothebaine Schultz, A. G.; Metwally, M. A.; Russ. J. Org. Chem. 2003, 39, 1261-1263).
and bractazonine via simple irradiation of thebaine and subsequent reduction
(Theuns, H. B.; Vos, G. F.; ten Noever de Braw, M. C.; Salemink, C. A.; Tet. Lett.
1984, 25, 4161-4162).
OCH3
H3 CO
OCH3
hν, 366 nm
-
hν
O
H3 CO
OCH3
OCH3
O
OH
R
O
N
H3CO
-
O
O
N
H
OH
OH
R
-
85 %
O
N
H3CO
OH
-
N+
H3CO
R
O
N
CH2R
OH
H3 CO
H3 CO
O
N
N
H3CO
O
O
O
O
H3CO+
VIII. Indole Alkaloids:
N
N
Nakagawa and co-workers reported the results of irradiation of indoloquinolizide
chloride and its 1-methyl derivative in the presence of a sensitizer (Nakagawa,
M.; Okajima, Y.; Kobayashi, K.; Asaka, T.; Hino, T. Heterocycles 1975, 3, 799-803).
H3CO+
reduction
H3CO
Cl-
H3CO
HO
N
HO
N
N
N
H
+
sens/hν /O 2
N
N
O
H
H3CO
OCH3
5
Alkaloid Photochemistry
Baran Lab
Enamide photochemistry is well known and its useful application has been
thoroughly investigated. Simple enamides generally undergo a [1,3]-acyl radical
shift to afford vinylogous amides. Below are examples of the photorearrangement
of 1-acylindoles to 3 acylindolenines (Ban, Y.; Yoshida, K.; Goto, J.; Oishi, T. J. Am.
Chem. Soc. 1981, 103, 6990-6992).
O
ClN+
sens/hν /O2
Cl-
N+
N
N
K. J. Eastman
H3COC
COCH3
H3COC
O
+
Cl-
hν
N
N
N
N
O
N
H
COCH3
An interesting observation was made by Guise, Ritchie and Taylor regarding
the difference in irradiation products of voacangine and ibogaine (Giuse, G. B.;
Ritchie, E.; Taylor, W. C.; Aust. J. Chem. Soc. 1965, 18, 279-286).
O
alkyl
hν
ν
20 %
N
N
H3 CO
O
N
N
H
sens/hν
ν
H3 CO
N
H
CO2CH3
H3 CO
H
alkyl
O
N
N
unstable!
CO2 CH3
N
HO
NH2
N
H
CO2CH3
N
NH
O
hν
ν
80 %
N
O
O
N
sens/hν
ν
H3CO
H3 CO
N
N
H
H
N
H
H
N
OH
H
N
6
Alkaloid Photochemistry
Baran Lab
Sinibaldi and co-workers have demonstrated the the feasibility for a photochemical approach to 3,3-spiro indolines (Ibrahim-Ouali, M.; Sinibaldi, M. E.;
Troin, Y., Cuer, A.; Dauphin, G.; Gramain, J-C. Heterocycles 1995, 41, 1939-1950).
O
hν
N
CH2OBn
Ph
X. Misc. Examples of Photochemical Alkaloid Chemistry:
Electron-transfer photochemistry of allylsilane-iminium salt systems have been
shown to serve as a viable carbon-carbon forming methodology (Chiu, F-T.;
Ullrich,
J. T.; Mariano, P. S. J. - Org. Chem. 1984, 49, 228-236).
ClO4
O
O
N
Ph
O
O
O
N
CH2OBn
25 %
N+
hν
ν
NH
hν
H
H
RO
RO
a) h ν
b) SET
ClO4 -
ClO4N
HN
N
TMS
-TMS
I2
67 %
H
N
RO
RO
N
Coyle and co-workers have shown the irradiaton of Mannich bases obtained from
phthalimides, formaldehyde and 1,2,3,4-tetrahydroisoquinolines carrying methoxy
substituents gives pentacyclic photoproducts (Coyle, J. D.; Bryant, L. R. B.; Cragg,
J. E. J. Chem. Soc. Perkin Tans. I 1985, 1177-1180).
IX. Steroidal Alkaloids:
O
Irradiation of the steroidal alkaloid nitrone in acetonitrile gave the following
result (Parello, J.; Beugelmans, R.; Millient et Xavier Lusinchi, P. Tet. Lett.
1968, 10, 5087-5092).
-
N
38 %
Ph
HN
TMS
CH2 OBn
Cryptosanguinolentine was prepared by Mohan and co-workers as part of their
program of syntheis of heteroannelated acridines, below is the formation of the
tetracyclic system of cryptosanguinolentine (Nandha Kumar, R.; Suresh,
T.; Mohan, P. S. Tet. Lett. 2002, 43, 3327-2228).
N
K. J. Eastman
O
N
N
N
O
H
N
O
hν
ν
O
6%
18 %
OCH3
HCl
28 %
OH
OCH3
OCH3
H3 CO
H3 CO
N
N
H
25 %
H
O
HO
hν
O
N+
O
H3CO
7%
7
Alkaloid Photochemistry
Baran Lab
In their investigation of elusive intramolecular hydrogen transfer reactions, Kessar
and co-workers investigated the intramolecular photoreactions of 2-formyl
benzamides and 2-formylbanzylamines (Kessar, S. V.; Singh Mankotia, A. K.;
Agnihotri, K. R. J. Chem. Soc. Chem. Commun. 1993, 598-599).
A similar transformation described by Kanaoka (Sato, Y.; Nakai, H.; Misogucho,
T.; Hatanaka, Y.; Kanaoka, Y. J. Am. Chem. Soc. 1976, 98, 2349-2350) has been
employed by Mazzocchi in the synthesis of the functionalized ring system of
Chilinene, a berberine alkaloid (Mazzocchi, P. H.; King, C. R.; Ammon, H. L.; Tet.
Lett. 1987, 28, 2473-2476).
O
O
H3CO
hν
ν
N
H3CO
H3 CO
H
C
O
StBu
tBuS
O
H3CO
H3CO
*
OH
N
C
O
* H C
O
C
N
C
H
C
OH
C
N
C
N
N
C
OH
C
C
N
StBu
OTMS
hν
N
O
X
N
N H
RO2 C
hν
H3 CO
O
H
N
HO
OH
CHO
CO2R
H
H
CO2R
CO2R
HO H
H
Tsuda and co-workers have employed a simple [2+2] cycloaddition of an activated
butadiene to a dioxopyrroloisoquinoline followed by a 1,3-anionic rearrangement
to fashion the core of erythrin alkaloids (Tsuda, Y.; Oshima, T.; Hosoi, S.; Kaneuchi,
S.; Kiuchi, F.; Toda, J.; Sano, T. Chem. Pharm. Bull 1996, 44, 500-508, for a review
of light induced [2+2] cycloadditions see Crimmins, M. T. Chem. Rev. 1988, 88,
1453-1473).
O
N
N
O
H
MeOOC
O
O
H3 CO
StBu
O
C
H3 CO
O
-
K. J. Eastman
H
C
N
C
H
OH
O
O
N
O
O
N
TMSO
MeOOC
∆
O
N
O
O
N
hν
ν
OHC
HO
O
COOMe
O
N
OTMS
hν
ν
O
N
?
O
HO
H
O
O
8