Baran Lab

Alkaloid Photochemistry

K. J. Eastman

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) I. Introduction: 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. The survey to follow will primarily features nitrogen as the key participant for both sensitized and direct photochemically induced reactions.

The following scheme represents a likely pathway for the observed products (see Santamaria, J. Pure & Appl. Chem., 1995, 67, 141-147).

-H
Py N Py N
+

[O]
Py N Py N

H2O 2

H2O 2

KCN

O2H Py N H O
+

CN Py N

Py

H2O2

O Py N Py N

CONH2

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/h /O2
N H N N N N H N O N H O N+

Hubert-Brierre and co-workers also investigated the irradiation of N-methylanabasine under a similar set of conditions.

sens/h /O2/KCN
Py N Py N H Py N CH2 CN Py N CH2CONH2

sens/h/O2/KCN
CONH2 H N H N CONH2

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.

CN N H N

H2O 2
H N

Baran Lab

Alkaloid Photochemistry

K. J. Eastman

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+

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). XR1 N+

h H 2O-KOH

H OH

1. h HNu 1 2. base

R1 H N H Nu1

1. h HNu1 2. base

NHR1 Nu2 R2 Nu1

R2

R2

Mariano (1983): ClO4- N+

CH2CH=C(CH3 )2 OCH3

IIa. -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).

h CH3OH

ClO4- N+

CH2CH=CH2

CH2CH=CH2

h CH3OH

HClO4 CH3OH

Bn N CN

Bn

OCH3

h or
EWG

N CN EWG

NHCH2 CH=CH2 H3CO OCH3

head-to-head adducts

Baran Lab

Alkaloid Photochemistry

K. J. Eastman

III. Isoquinoline Alkaloids: 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). h -CO2 10-20 %
R N

Direct photooxidation of glaucin gave O-methylatheroline (85 %) and corunnine (10 %) (Castedo, L.; Suau, R.; Mourino, A. An. Quim. 1977, 73, 290).

H3CO H3CO N H

H3 CO

H3CO N O H3CO N+ O H3CO OCH3

+ RCOOH

h /O 2

H3 CO

H3CO OCH3

H3 CO OCH3

85 %

10 %

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 H3CO H3CO H3CO H3 CO N H3CO H3CO N H3CO O H3CO CHO H3 CO N H3CO

HO N
+

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).
H3 CO H3 CO H3CO N

XN+ H

h /O2

NaBH4

h /ROH

H3CO

H3 CO OCH3

H3CO OCH3

Photosolvolysis of laudanosine methyliodide (Bremner, J. B.; Thuc, L. V. Chem. Ind. (London) 1976, 453).
H3 CO H3 CO H3 CO H3 CO N+ H3 CO 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 H3 CO N

h/ROH

H3 CO H3 CO R N

I-

h/ROH

H3 CO H3 CO H3 CO

Baran Lab

Alkaloid Photochemistry

K. J. Eastman

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 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). h

H3CO N O OCH3 OCH3 OCH3 H3 CO N H O O H3 CO N HO O OCH3 H3CO OCH3 OCH3 OH O N

+

h/O2

H3CO O O

N O

RCOOH

V. Tropane alkaloids:
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).
OHC N H N N

H3CO H3CO

NaBH4

sens/h /O2

OH

OH

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).
OCH3 OH O H O O H H OH N H

IV. Quinoline Alkaloids: Quinoline suffers dimerization upon irradiation in alcoholic solution (Pfordte, K.; Leuschner, G. Justus Liebigs Ann. Chem. 1061, 30, 646).

h/MeOH/no O2

OCH3

h
O N N N

Baran Lab

Alkaloid Photochemistry

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).
H3 CO
OCH3 OCH3

h, 366 nm
O N
H3CO
-

O N
H3 CO

O N OH R O

O OH CH2R

H3 CO

85 %

O N+

O N
OCH3 O N O OH R H OH N OCH3 OH R O

H3CO

H3 CO

H3CO
-

H3CO
-

O N

H3CO+ N H3CO+

VIII. Indole Alkaloids: 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).
ClN N H
+

reduction
H3CO HO H3CO HO

sens/h /O 2
N H O

H3CO OCH3

Baran Lab

Alkaloid Photochemistry
O ClN+

K. J. Eastman

sens/h /O2
N

N+

Cl-

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).
H3COC H3COC COCH3

N N O

ClN COCH3

h
N N H N H

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 N H3 CO

alkyl

h
N O

alkyl

20 %
N

unstable!

N H3 CO N H CO2CH3

sens/h
HO

N H

CO2 CH3 N NH2

H3 CO

NH

h 80 %
N

N H

CO2CH3

N O

N H3CO N H H

sens/h

H3 CO N N H H H N OH

Baran Lab

Alkaloid Photochemistry
X. Misc. Examples of Photochemical Alkaloid Chemistry:

K. J. Eastman

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 O N Ph CH2OBn Ph O O O N CH2OBn N Ph O CH2 OBn

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 N+ TMS

25 %

38 %
RO RO

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).

a) h b) SET
ClO4N TMS ClO4 N

N H

NH

HN

HN

I2
H N

-TMS
RO RO

67 %
N

IX. Steroidal Alkaloids: 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).
-

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).
O N N O H N O H H3 CO O O N O N N H

O N+

h 25 %
H3 CO OCH3

HO

HCl 28 %
OH OCH3 OCH3

H3CO

6%

18 %

7%

Baran Lab

Alkaloid Photochemistry

K. J. Eastman

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).

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).

H3CO N H3CO O StBu

C N

O C

C N

OH C

C N

H3 CO H3 CO tBuS OH

O C

* H C
N

O C

C N

OH C

C N

H3CO
-

O N O H StBu

H3 CO N HO H3 CO StBu

O N N CHO H H C C H N N H RO2 C OH CO2R HO H CO2R H H CO2R

H3CO

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).
OTMS O O O TMSO MeOOC N O O N

OH

h
O MeOOC O N O

O OHC

h
HO

?
HO

O COOMe O OTMS N H

O O