Photochemical Reactions in Natural Product Synthesis By P. G. Sammes DEPARTMENT OF CHEMISTRY IMPERIAL COLLEGE LONDON S.W.7 1 Introduction One of the most rewarding areas for synthetic innovations in recent years has been in the field of organic photochemistry. In general absorption of light by a molecule can produce three types of activated molecule not accessible by normal thermal means. These are the electronically excited singlet and triplet states and often a vibrationally ‘hot’ ground state. Each of these excited states may undergo different chemical reactions in proceeding back to the ground state. The triplet excited state which generally has a relatively long lifetime is frequently encoun- tered in photochemical reactions. The potential complexity of photochemical reactions has deterred many chemists from exploiting them in syntheses.However with the increased under- standing of the nature of photochemical processes the chemist is now often able to quench undesirable reaction paths and to sensitise the required course of reaction. Furthermore because excited states possess potential energy levels above that of the ground state photochemical reactions often lead to products with strained structures. The controlled release of such strain energy can provide a suitable driving force for subsequent reactions as illustrated below in the synthesis of caryophyllene alcohol (p. 48). Although related reviews1 have been written and several excellent textbooks2 have appeared the present review is intended to illustrate recent examples of the scope and preparative significance of photochemical reactions as applied to the synthesis of natural products.As a consequence many important photo- chemical reactions such as halogenation nitrosationag and alkylati~n,~ have been omitted. However because of the importance of protecting groups in any synthetic work a final brief section on photosensitive protecting groups has been included. (a) K. Schaffner Fortschr. Chern. otg. Nu?ws?ofe 1964 22 1 ; (b) P. de Mayo and S. T. Reid Quart. Rev. 1961,15,393; (c) P. de Mayo Adv. Org. Chem. 1960’2,367. * (a) A. Schonberg ‘Preparative Organic Photochemistry’ Springer Verlag Berlin 1968; (b) J. G. Calvert and J. N. Pitts ‘Photochemistry’ J. Wiley New York 1965; (c) R. 0. Kan ‘Organic Photochemistry’ McGraw-Hill Book Co. New York 1966; (d) D. C. Neckers ‘Mechanistic Organic Photochemistry’ Reinhold Publishing Corp.New York 1967; (c) ‘Organic Photochemistry’ ed. 0. L. Chapman Marcel Dekker Inc. New York 1967; (f) ‘Advances in Organic Photochemistry’ eds. W. A. Noyes G. S. Hammond and J. N. Pitts Interscience New York 1963; G. Sosnovsky ‘Free Radicals in Preparative Organic Chemistry’ Macmillan Co. New York 1964. a D. Elad Forrschr. Chem. Forsch. 1967.7 528. 37 Photochemical Reactions in Natural Product Synthesis 2 cis-trans Isomerisation The light induced isomerisation of cis and trans olefins is well do~umented.~ For example irradiation readily establishes an equilibrium between maleic (75 %) and fumaric acid (25 %).s Similarly photolysis effects isomerisation ( 1 ) (2) between cis- and trans-cinnamic acids6 and between tiglic (1) and angelic (2) acids.? cis-trans Isomerisation is of extreme importance in the visual processes associated with vitamin A8 and in carotenoid chemistry.3b The conversion of HO (3) (4) trans-vitaminD (3) into the active cis-isomer (4) proved crucial in the total synthesis of the vitamin.B The mechanism of cis-trans isomerisation has been investigated in detail.3,10 In the excited triplet state of simple olefins the lowest energy conformation is produced by rotation of 90" about the carbon-bon bond.ll It is believed that collapse to the ground state occurs from this orthogonally disposed excited ' ( a ) G.M. Wyman Chem. Rev. 1955 55 625; (b) L. Zechmeister 'Cis-tram Isomeric Carotenoids Vitamins A and Arylpolyenes' Academic Press New York 1962. bA. R. Olsen and R. F. Hudson J. Amer. Chem.SOC. 1933,55 1410. ' S. W. Pelletier and W. L. McLeish J. Amer. Chem. SOC. 1952,74,6292. * (a) H. H. Inhoffen G. Quinkert H. J. Hess and H. Hirschfield Chem. Ber. 1957,90,2544; (b) H. H. Inhoffen H. Burchardt and G. Quinkert Chem. Ber. 1959 92 1564; (c) I. T. Harrison and B. Lythgoe J. Chem. Soc. 1958 837; ( d ) I. T. Harrison R. A. A. Hurst B. Lythgoe and D. H. Williams J. Chem. Soc. 1960 5176. lo (a) R. B. Cundall and P. A. Griffiths J. Amer. Chem. Soc. 1963,85,1211; (b) G. S. Ham- mond N. J. Turro and P. S. Leermakers J. Phys. Chem. 1962,66 1144. l1 R. S . Mulliken and C. C. J. Roothan Chem. Rev. 1947,41,219. R. Stoermer Ber. 1909,42,4865 and 1911,44,637. M. Mousseron Adv. Photochem. 1966,4 195. 38 Sammes state to form either the cis- or the trans-isomer. The isomerisation is often sensitised since direct photolysis to the excited singlet state is often difficult to achieve the energy required lying in the far ultraviolet region and because intersystem crossing to give the required triplet level is inefficient.In sensitised reactions the triplet level can be reached directly by energy transfer from an excited triplet dOnor.la For stilbene Hammond‘s group found that high energy donors those capable of transferring energy in excess of that required to promote either the cis- or tram-olefin to its triplet level all afforded the same equilibrium ratio of cis- to trans-stilbene as expected for diffusion controlled energy transfer.l2U As lower energy sensitisers were used different ratios of the two isomers formed since the excitation energy required by either the cis- or the trans-stilbene differ with the consequence that the sensitiser preferentially excites one of the two isomers in this case the trans-isomer so that the ratio of the cis-isomer in the equilibrium mixture increases.Isomerisation even occurred when the sensitiser energy was below that required to attain the usual triplet excited state of either of the starting olefins. This effect was explained by postulat- ing that non-Franck-Condon processes occur in which excitation occurs with T1 (trans) &’ So (trans) S (cis) 0 trans 90 180 cis Figure 1 Schematic representation of cis-trans isomerisation a. Sensitised excitation. b. “on-vertical’ excitation. c. Internal conversion to the ground state. T. Triplet state. S. Singlet state. 8. Angle of twist ‘*(a) G. S. Hammond J.Saltiel A. A. Lamola N. J. Turro J. S. Bradshaw D. 0. Cowan R. C. Counsell V. Vogt and C. Dalton J. Amer. Chem. SOC. 1964,86,3197; (b) P. J. Wagner and G. S. Hammond Adv. Photochem. 1968 5 21. 39 Photochemical Reactions in Natural Product Synthesis rotation about the olefin carbon-carbon bond to give the so-called ‘phantom’ triplet state i.e. the orthogonally oriented triplet (see Figure 1). For sensitisers of very low energy no isomerisation is possible. 3 Photolytic Electrocyclic Reactions Conjugated olefinic systems can often undergo direct photocatalysed electro- cyclic processes recently reviewed.13 Such reactions are extremely useful in natural product synthesis because they generally proceed along well defined stereochemical paths. An example is in the synthesis of vitamin D2 from ergo- sterol (5).14 The cyclic diene is isomerised photolytically into the acyclic triene previtamin D2 (6) by cleavage of the 9,lO-carbon-carbon bond.The latter compound can undergo photocatalysed recyclisation to give back either starting material or lumisterol (7) in both of which the cyclisation has occurred in a conrotatory mode as well as cis-trans isomerisation to (8). On heating pre- vitamin D2 establishes an equilibrium with pyrocalciferol (9) and isopyro- calciferol (lo) the thermal cyclisations occurring in a disrotatory manner. At the same time a thermal sigmatropic rearrangement occurs to give vitamin D2 (11). The photoisomerisation of a cyclic diene into a triene has also been used in an elegant synthesis of dihydrocostunolide (1 2).16 Photolysis of the bicyclic lactone diene (14) derived from a-santonin (13) gives an equilibrium mixture with the medium ring triene (15) again by a conrotatory process.Because of strain in the medium ring triene conjugation is restricted and selective reduction of the central cis-disubstituted bond with Raney nickel is readily effected to yield dihydrocostunolide (12). A simple extension of this reaction has allowed the conversion of the trans-fused bicyclic precursor (1 6) into the cis-fused compound occidentalol (17).l6 Cyclisation of the intermediate triene occurs thermally by a disrotatory process. Since the hexatriene-cyclohexadiene isomerisation is reversible suitable trienes are readily cy~1ised.l~ For example cis-stilbene is cyclised on photolysis to 9,lO-dihydrophenanthrene the trans-isomer forming.Mild oxidation of the latter with air iodine,l* or cupric chloride,lg produces phenanthrene. This very useful reaction has been applied to the synthesis of aporphine alkaloids.20 For example the substituted stilbene (18) on photolysis can lead to (&)-nu& ferine (19).21 The reaction is general and other triene systems will also cyclise. Thus the anil (20) cyclises upon irradiation provided the nitrogen atom is l3 G. B. Gill Quart. Rev. 1968 22 338. l4 (a) B. Lythgoe Proc. Chem. Soc. 1959 141; (b) H. H. Inhoffen Angew. Chem. 1960,72 875; (c) E. Havinga and J. L. M. A. Schlatmann Tetrahedron 1961 16 146. l5 E. J. Corey and A. G. Hortmann J. Amer. Chem. SOC. 1963,85,4033. l6 A. 0. Hortmann Tetrahedron Letters 1968 5785. l7 F. R. Stermitz ‘Organic Photochemistry’ ed.0. L. Chapman Marcel Dekker Inc. New York vol. 1 1967 p. 247. ln D. J. Collins and J. J. Hobbs Chem. and Znd. 1965 1725. 2o N. C. Yang G. R. Lenz and A. Shani Tetrahedron Letters 1966 2941. 21 M. P. Cava S. C. Havlicek A. Lindert and R. J. Spangler Tetrahedron Letters 1966,2937. C. S . Wood and F. B. Mallory J. Org. Chem. 1964,29 3373. 40 t- * c n W h 2 r- e h 2 W n E. 41 Photochemical Reactions in Natural Product Synthesis I g e 1 4 I I g n 2 W 0 ,o h 2 W n M - W 0 42 Sammes Reduction M e 0 Meo3YMe (19) protonated to give calycanine (21),22 a degradation product of the alkaloid ~alycanthine.~~ Under acidic conditions amides such as (22) can also be cyclised by irradiation. Presumably the acid protonates the amide group to give the immonium alcohol (23) which has increased carbon to nitrogen double bond character so that it behaves as a hexatriene system.The cyclised isomer can re-aromatise by loss of water. Borohydride reduction of the salt (24) yields the protoberberine alkaloid /3-coryaldine (25).24 The observed mode of cyclisation is of interest in that little of the competing reaction leading to the aporphine skeleton was obtained. It appeared therefore that cyclisations were preferred which aromatise without the need of oxidation. Using this argument Kupchan considered that a more efficient way of effecting similar conversions was to replace one of the hydrogen atoms normally removed by oxidation by a good leaving group. The iodo- 22 V. M. Clark and A. Cox Tetrahedron 1966,22 3421. and N. Sheppard Proc. Chem. SOC. 1960,76.24 G. R. Lenz and N. C. Yang Chem. Comm. 1967 1136. R. B. Woodward N. C. Yang T. J. Katz V. M. Clark J. Harley-Mason R. F. J. Ingleby 43 Photachemical Reactions in Natural Product Synthesis n m tf. n N N W 44 Sarnmes group was found to be useful for this Thus the iodostilbene (26) cyclised to give aristolochic acid (27) whereas classical methods for its synthesis had failed. In a detailed study of the mechanism of this reaction however it was concluded that the reaction does not proceed via a dihydrophenanthrene type of intermediate but instead by prior homolysis of the carbon to iodine bond.2s Nevertheless this alternative method of cyclisation is of general syn- thetic application. It has been used in an alternative synthesis of (&)- nuciferine (19) via photolysis of the precursor (28) as its hydrochloride sa1t.l' Further ramifications of the photocyclisation reactions have been exploited in syntheses.Brockmann has studied the cyclisation of bianthrone derivatives,28 the work culminating in the synthesis of hypericine (30) from protohypericine (29).29 This process is believed to be involved in the biosynthetic route to hypericine. Diphenylamine and its derivatives form the corresponding carbazoles on irradiati~n.~~ The presence of a mild oxidising agent is beneficial but does not appear to be essentiaL31 The alkaloid glycozoline (32) was readily prepared from the amine (31).32 25 S. M. Kupchan and H. C. Wormser Tetrahedron Letters 1965 359. 2e S. M. Kupchan and H. C. Wormser J . Org. Chem. 1965,30 3792. a7 S. M. Kupchan and R. M. Kanojia Tetrahedron Letters 1966 5353.28 H. Brockmann R. Neef and E. Miihlmann Chem. Ber. 1950,83,467. 28 H. Brockmann and H. Eggers Angew. Chem. 1965 67 706. 'l E. J. Bowen and J. H. D. Eland Proc. Chem. SOC. 1963,202. 32 W. Carruthers Chem. Comm. 1966,272. C. A. Parker and W. J. Barnes Analyst 1957 82 606. 45 Photochemical Reactions in Natural Product Synthesis OH 0 OH OH 0 OH OH 0 Oil hv Me0 Me0 OMe According to theory the electrocyclic process hexatriene to cyclohexadiene is one of a series of reactions.13 Conjugated butadienes should also photoisomerise to the corresponding cyclobutenes by a concerted disrotatory process.33 Such 38 R. Srinivasan Adv. Photochem. 1966 4 113. 46 Sammes a reaction is realised in the conversion of colchicine (33) by sunlight to P-lumi- colchicine (34) and its y-isomer (35).34 The #komer is further converted by light to give the dimer a-lumicolchicine (36).36 These processes have been achieved in ~ i t r o .~ ~ 4 Cycloaddition Reactions The addition of an olefin to another double bond can be catalysed by light.37 However simple olefins absorb in the far ultraviolet region which is difficult to reach experimentally particularly for preparative work. This problem can be overcome by either using sensitisers in which case reactions can proceed via the triplet manifold,12 or by using suitable derivatives of olefins which absorb at longer wavelengths i.e. either by conjugation or suitable intramolecular interaction. Thus germacrene D (37) in which there is a strong transannular effect has )cmsx at 259nm ( E 4500). Direct photolysis gives mainly (-)$- bourbonene (38).38 (37) A similar example is the photolysis of myrcene (39) which gave besides the more favoured cyclobutene derivative (41) some /3-pinene (40).a@ Better yields of the latter would be expected at higher temperatures where the cycIobutene could thermdly reform starting diene.In contrast the sensitised photolysis gives neither (40) nor (41) but instead the bicyclobutane (43).40 The sensitised cyclisation proceeds via a triplet excited state. This state behaves as a diradical and the two bond forming steps occur consec~tively.~~ Primary bond formation has a choice as to where it will occur. In such cases the preferred initial reaction will tend to form a five-membered ring where possible in preference to a smaller or bigger size.42 This empirical guide is known as the 'rule of five'.43 34 F.Santavy Coll. Czech. Chem. Comm. 1950,15 552. 85 0. L. Chapman H. G. Smith and R. W. King J. Amer. Chem. SOC. 1963 85 806. 36 (a) E. J. Forbes J. Chem. SOC. 1955 3864; (b) P. D. Gardner R. L. Brandon and 0. R. Haynes J. Amer. Chem. SOC. 1957,79 6334. s7 J. S. Swenton J . Chem. Educ. 1969 46 7. s8 K. Yoshihara Y. Ohta T. Sakai and Y. Hirose Tetrahedron Letters 1969 2263. 38 K. J. Crowley Proc. Chem. SOC. 1962 245. 40 R. S. H. Liu and G. S. Hammond J. Amer. Chem. SOC. 1967 89,4936. 48 (a) R. C. Lamb P. W. Ayers and K. M. Toney J . Amer. Chem. SOC. 1963 85 3483; (b) N. 0. Brace J. Amer. Chem. Soc. 1964 86 523; (c) C. Walling and M. S. Pearson J. Amer. Chem. SOC. 1964 86 2262. 48 R. Srinivasan and K. H. Carlough J. Amer. Chem. SOC.1967 89,4932. Cf. P. S. Skell and R. C. Woodworth J. Amer. Chem. SOC. 1960 82 3217. 47 Photochemical Reactions in Natural Product Synthesis For myrcene the primary step probably yields the most stable diradical (42) followed by cyclisation to the bicyclobutane (43). Sensitised Itv \ -1 (42) (43) On irradiation conjugated ketones can add to olefhs to give a cyclobutane deri~ative.~~ One of the first reported examples of this extremely important reaction was the intramolecular photocyclisation of carvone (44) to carvone- camphor (45).46 Corey was the first to realise that intermolecular applications of this reaction could be useful for the synthesis of natural products.4s In an elegant demonstration of its potential 4,4-dimethylcyclopentene (46) and 3- methylcyclohex-Zenone (47) were photolysed to give a mixture of cis- and trans-fused strained tricyclic ketones.The main isomer was the cis-anti-cis form (48). Addition of methyllithium gave the corresponding tertiary alcohol (49). Treatment of the alcohol with acid catalysed loss of water to give a carbonium ion followed by 1,Zbond rearrangement to relieve strain from the cyclobutane moiety. Quenching of the rearranged carbonium ion with water afforded directly a-caryophyllene alcohol (50). 44(u) P. E. Eaton J. Arner. Chern. SOC. 1962 84 2344 and 2454; (b) R. Criegee and H. Furrer Chern. Ber. 1964 97 2949. 46(u) G. Ciamician and P. Silber Ber. 1908 41 1928; (b) G. Biichi and I. M. Goldman J. Amer. Chem. SOC. 1957 79 4741. 46 E. J. Corey and S. Nozoe J. Amer. Chern. SOC. 1964 86 1652. 48 Sammes H+ (47) (48) )+ ! (49) H I L H+ In a related isobutene was added to cyclohexenone to give a mixture of (4,2,0)-bicycloketones.Mild base yielded mainly the &isomer (51) which was used as starting material in a synthesis of (j-)-caryophyllene (52) and (&)-isocaryophyllene (53). Y 4- Q 0 -3 4 The addition of substituted olehs to cyclohexenones is often stereoselective. The direction of addition is that expected for a stepwise reaction with formation of an intermediate diradical. A probable explanation for the stereoselectivity involves initial excitation of the enone by an n -+ m* transition to give a triplet state which is polarised (e.g. 54).48 An approaching olefin (e.g. 55) would also be polarised to give an oriented complex possibly even a charge transfer com- E. J. Corey R.B. Mitra and H. Uda J. Amer. Chem. SOC. 1964,86,485. '' E. J. Corey J. D. Bass R. LeMahieu and R. B. Mitra J. Amer. Chem. SOC. 1964,86,5570. 49 Photochemical Reactions in Natural Product Synthesis plex followed by bonding at the 2-position of the enone with the nucleophilic end of the olefin and final collapse to the observed product (56). Several approaches to the synthesis of the bourbonenes have been reported. In photolysis of a mixture of 2-cyclopentenone and the cyclopentene (57) gave a 1 :1 mixture of cis-anti-cis head to tail (58) and head to head (59) adduct s. Treatment of the latter ketone with methylenetriphenylphosphorane yielded p-bourbonene (38) which could be equilibrated with acid to give a- bourbonene (60). An alternative route started with the bis-enone (61) which was irradiated to give the diketone (62) that could be condensed and converted into a-bourbonene.60 ** J.D. White and D. N. Gupta J. Amer. Chem. SOC. 1968 90 6171. M. Brown J . Org. Chem. 1968,33 162. 50 Sarnrnes In a related studys1 the cyclodecadienone (63) was photolysed to give sub- stantial amounts of the ketone (a) an effective precursor of copaene (65)51 and the ketone (59). In contrast germacrene D (37) gave only small amounts of (64 x = 0) (65 X = CHa copaene on photolysis (see above). It is probable that the cyclisation of germ- acrene D proceeds by a singlet excited state in a concerted manner. Sensitised photolysis of germacrene would be expected to give more copaene. The synthetic utility of such photocycloaddition reactions has been con- siderably extended by de may^.^^ Irradiation of cyclic 1,3-diones or their en01 acetate esters with olefins gives a strained cyclobutane of the p-hydroxyketone type.These may spontaneously deketolise to give the ring expanded cyclic system by the addition of two carbon atoms. The reaction is exemplified by the synthesis of y-tr~polone.~~ Dichloroethylene and the en01 acetate of 173-cyclo- pentadione (66) were photolysed and the reaction product immediately hydro- lysed with methanolic base to give directly y-tropolone (67). c1 c*j +Jj AcO hv ‘*’’ “d AcO OH’- - 0 Cycloaddition of the enol acetate (66) to dimethyl chloromaleate (68) gave a mixture of isomeric adducts (69) which could be brominated with pyridinium perbromide followed by treatment with silver oxide and oxidation with sodium bismuthate to give the bicyclic dione (70).Mild acid hydrolysis removed the acetate group and the resulting #%hydroxyketone spontaneously deketolised 61 C. H. Heathcock and R. M. Badger Chem. Comm. 1968 1510. (a) V. H. Kapadia B. A. Nagsampagi V. 0. Naik and S. Dev Tetrahedron 1965,21,607; (b) P. de Mayo R. E. Williams G. Buchi and S. H. Feairheller Tetrahedron 1965 21 619. 68 P. de Mayo Pure Appl. Chem. 1964,9 597. “H. Hikino and P. de Mayo J. Amer. Chem. SOC. 1964 86 3582. 51 Photochemical Reactions in Natural Product Synthesis to give the naturally occurring tropolone stipitatonic acid (71) a synthesis that would be difficult to achieve by classical means.6s By the use of the appropriate precursors fused bicyclic systems containing a seven membered ring can also be synthesised.Thus /3-himachalene (76) has been prepared from the en01 acetate (72) and the acetal (73). Photolysis gave a good yield of the required adduct (74) but as an alternative to dealdolisation the ketone moiety was reduced to the alcohol followed by formation of the mesylate 0 9 u (73) H AcO’ OAc 0 m 0 P (74) + Q=@ O w 0 OAc (77) 65 0. L. Lange and P. de Mayo Chem. Comrn. 1967,704. 52 Sammes ester and then hydrolysis. Fragmentation to the keto-olefin (75) occurred which was eventually converted into the desired hydrocarbon.66 A study of the factors affecting the initial photocyclisation in the latter case showed that for non-polar solvents addition was highly stereoselective giving mainly (74) but as solvent polarity increased this preference decreased and more of the isomer (77) formed.This result again points to the importance of dipolar interactions between reactants.s7 That these reactions may also be sensitised indicates operation of a triplet mechanism.68 Various ramifications of these additions to enones have recently been applied to synthetic work. A route to the prostanoic acids e.g. (81) started from the cyclopentenone (78) and the chloro-olefin (79).69 This approach takes advantage of the fact that strained 1,4-diketones such as the adduct (80) are readily reduced by zinc dust with opening of the cyclobutane ring to give the diketone (81). de Mayo has recently discovered that enol esters of cyclopenta-1,2-diones &YR* Zn > & R l + c1 k hv > c1 R2 H 0 178) (79) (SO) (81) R ' = (CH2)6<:02CHj R2 =(CHz )4CH3 also add to olefins. Thus the acetate (82) adds to the cyclopentene (83) to give an adduct (84).This particular cyclopentene was chosen because of its ready 0 ( 8 5 ) I OH (87) B. D. Challand G. Kornis G. L. Lange and P. de Mayo Chem. Comm. 1967 704. 67 B. D. Challand and P. de Mayo Chem. Comm. 1968,982. 58 H. Nozaki M. Kurita T. Mori and R. Noyori Tetrahedron 1968,24 1821. 5D J. F. Bagli and T. Bogri Tetrahedron Letters 1969 1639. 53 Photochemical Reactions in Natural Product Synthesis availability and because the cyclopropane ring in the adduct is readily hydro- genated to the required dimethyl derivative. Subsequent oxidation gave the cyclopentenone (85) which rearranged on hydrolysis with mild base to relieve strain in the fused cyclobutane ring. The ring expanded product (85) was used in an approach to the synthesis of methyl isomarasmate (87).s0 The usefulness of these cycloaddition reactions is further clearly demon- strated by the synthesis of the steroid skeleton (89) in good yield from the p-diketone (88) and cyclopentene.6s 0 (92) (93) (94) 6o P.de Mayo D. Helmlinger R. B. Yates and L. Westfelt Abstracts International Sym- posium on ‘Synthetic Methods and Rearrangements in Alicyclic Chemistry’ Oxford July 1969 The Chemical Society London p. 32. 54 The addition of allene to the a/?-unsaturated ketone (90) has been used in the synthesis of the diterpenic alkaloids atisineB1 and veatchine,Ba via the inter- mediate (91). Similarly vinylogous amides also add to allene and this has been made the basis of an approach to the lycopodium alkaloidsBs For example reaction of the amide (92) with allene gives the cyclobutene (93) further con- verted into the known degradation product annatonine (94).s4 5 Photolysis of Carbonyl Groups General trends in the reactivity of carbonyl groups have been well established.os Saturated ketones react principally either by a-cleavage (e.g.95 to 96) the Norrish Type I process or by y-hydrogen abstraction (e.g. 97 to 98) often followed by further fragmentation as in the Norrish Type I1 process (98 to 99). Both reactions are believed to take place via an excited rz -+ ?T* triplet state.B6 B (95) hv ~ (97) 1 a R. W. Guthrie 2. Valenta and K. Wiesner Tetrahedron Letters 1966,4645. K. Wiesner S. Uyeo A. Philipp and 2. Valenta Tetrahedron Letters 1968 6279. K. Wiesner V. Musil and K. J. Wiesner Tetrahedron Letters 1968 5643.64 K. Wiesner I. Jirkovsky M. Fishman and C. A. J. Williams Tetrahedron Letters 1967 1523. *t5 J. S. Swenton J. Chem. Educ. 1969,46,217. 66 R. Srinivasan Adv. Photochem. 1963,1,83. 55 Photochemical Reactions in Natural Product Synthesis A. Cyclic Ketones.-These very often do not possess an available hydrogen atom and therefore a-cleavage is often favoured. The diradical (e.g. 96) cau collapse to either an aldehydo-olefin (100) or a keten (101).67 In the presence of oxygen an olefin-carboxylic acid can result formed by addition of oxygen to the excited carbonyl group (e.g. 95 to 102). In this way Quinkert has been able to synthesise nyctanthic acid (105) from b-amyrone (103) and roburic acid (106) from a-amyrone (104).68 (103 R1 = H Ra = Me) (104 Ra = Me Ra = H) (105 R1 = H Ra =Me) (106 R1 = Me Ro = H) Loss of carbon monoxide from the diradical formed during a-cleavage (e.g.96) only occurs in solution if the resulting diradical is stabilised.gB Thus the sugar pyranosidulose (107) collapses to the diradical (108) by extrusion of carbon monoxide since both the radicals are stabilised by a-oxygen substituents; recombination leads to the furanoid pentoses (109).70 Suitably a-substituted cyclic ketones which possess an available y-hydrogen atom also collapse by the Norrish Type I1 process.71 Thus colupulone (110) Po ohle > M e y - I I \ I \ I \ O x 0 O x 0 O x 0 67 G. Quinkert Angew. Chem. Internal. Edn. 1962,1 166. 6Q (a) G. Quinkert Pure Appl. Chem. 1964,9 607; (b) M. P. Cava and D. Mangold Tetru- he&on Letters 1964 1751; (c) K. Mislow and A.J. Gordon J. Amer. Chem. SOC. 1963 85 3521. ?O(u) P. M. Collins Chem. Comm. 1968 403; (6) For a review on the photochemistry of carbohydrates see G. 0. Phillips Adv. Carbohydrate Chem. 1963,18,9. 71 J. E. Gano Tetrahedron Letters 1969 2549. G. Quinkert and H.-G. Heine Tetrahedron Letters 1963 1659. 56 Sarnrnes which is very sterically crowded about the ring carbonyl function gives a good yield of 4-deoxycohumulone (1 1 l).7a Similar reactions of quinones are well documented. Jz v Y AT HO B. Conjugated Cyclic Ketones.-In the absence of a suitable addend so that cycloaddition reactions (see above) are not observed conjugated cyclic ketones tend to react so that the absorbing chromophore is lost.'* A simple case is the rearrangement of verbenone (1 12) to the unconjugated chrysanthenone (1 13).76 Similarly umbelhlone (1 14) rearranges to the phenol thymol (1 15).76 More complex are the transformations of the cross-conjugated ketones such as a-santonin (116) which has long been known to be sensitive towards light.?? The mechanisms of the photochemical transformations of santonin have been W.M. Fernandez Chem. Comm. 1967 1212. 73 CJ J. E. Baldwin and J. E. Brown Chem. Comm. 1969 167. K. Schaffner Adv. Photochem. 1966,4 81. 75 J. J. Hunt and 0. H. Whitham Proc. Chem. SOC. 1959 160. 76 J. W. Wheeler and R. H. Eastman J. Amer. Chem. SOC. 1959,81,236. 77 Kahler Arch. Pharm. 1830,34 318. 57 Photochemical React ions in Natural Product Synthesis 0 Jq-*oqy*0 0 0 0 0 (116 R = H) (121 R = OAC) ’0 A (120,R = H) / (122 R = OAC) / / O a 0 ( 1 23) OAc ‘ the subject of much study.’* They are best rationalised in terms of Zimmerman’s explanati~n.~~ An initial n + w* transition produces a diradical (117) which isomerises to (118) followed by collapse to a dipolar species (119).In aqueous acetic acid the anion is protonated and the resulting carbonium ion rearranges to isophotosantonic acid lactone (120) which has a guaianolide skeleton. This rearrangement has been shown to be generalso and consequently it has been used in the synthesis of several perhydroazulenes of the guaianolide series. For example 8-epi-artemisin acetate (121) on photolysis afTorded 8-epi-isophoto- artemisic acid lactone acetate (122). Dehydration and reduction followed by (a) P. 3. Kropp ‘Organic Photochemistry’ ed. 0. L. Chapman Marcel Dekker Inc. New York 1967 vol.1 p. 1; (b) D. H. R. Barton P. de Mayo and M. Shafiq Proc. Chem. Soc. 1957,205; (c) D. H. R. Barton P. de Mayo and M. Shafiq J . Chem. SOC. 1958,140; (d)D. Arigoni H. Bosshard H. Bruderer G. Buchi 0. Jeger and L. J. Krebaum Helv. Chim. Ada 1957,40 1732; (e) 0. L. Chapman and L. F. Englert J. Amer. Chem. SOC. 1963,85 3028; ( f ) M. H. Fisch and J. H. Richards J. Amer. Chem. SOC. 1963 85 3029. (a) H. E. Zimmerman Pure Appl. Chem. 1964 9 493; (b) H. E. Zimmerman and D. I. Schuster J. Amer. Chem. SOC. 1962 84,4527. D. H. R. Barton J. E. D. Levisalles and J. T. Pinhey J. Chem. SOC. 1962 3472. 58 Sammes chromous chloride reduction of the lactone gave an isomeric lactone 1 l-epi-de- oxygeigerin which with mild base was isomerised to deoxygeigerin (1 23). Oxidation with lead tetra-acetate eventually produced geigerin acetate (1 24).*l Related syntheses include an approach to aromadendrene (127),8a via the dienone (125) and its isophoto-derivative (126). Also synthesised in this manner have been cx-bulnesene (128)s3 and desacetoxymatricarine (129).84 Q eq 0 In an approach to the spirovetivane sesquiterpenoids Marshall has also used the rearrangement of the dienone (130).s5 In aprotic solvents the dipolar inter- mediate (e.g. 119) immediately collapses to the lumi-isomer (131) since no protons are available to quench the anion. Compound (131) was readily trans- formed into the spiro-compound (1 32) itself eventually converted into vetivone (133). C. Vinyl Esters.-Upon photolysis vinyl esters (e.g. 134) are often cleaved to give two radical species which can recombine via resonance forms to give a 81 D.H. R. Barton J. T. Pinhey and R. J. Wells J . Chem. SOC. 1964,2518. 82 J. Streith and A. Blind Bull. SOC. chim. France 1968,2133. 83 E. Piers and K. F. Cheng Chem. Comm. 1969 562. 84 E. H. White S. Eguchi and J. N. Marx Tetrahedron 1969 25 2099. J. A. Marshall and P. C. Johnson Chem. Comm. 1968 391. 59 Photochemical Reactions in Natural Product Synthesis p-diketone (135).86 Phenolic esters are similarly cleaved by irradiation to give eventually ortho- or para-acylated phenols a photochemical type of Fries rearra~~gement.~’ This reaction can therefore be used when the ester bears P (134) ( 1 3 5 ) functional groups that are sensitive to Lewis acid catalysts. Use of this reaction has been made in a synthesis of racemic griseofulvin (138).88 The substituted aromatic ester (136) was rearranged by photolysis to the ketone (137) a pre- cursor of griseofulvin.* * M e 0 0 OMe Me0 M e 0 OH OH c1 (137) - M e 0 fJpo 6 Photosensitised Addition of Oxygen An important method of oxidation invoIves the photosensitised addition of oxygen to olefins.8s Although alternative mechanisms are available the sensitis- ing dye generally acts as a catalyst in the conversion of oxygen from its ground triplet state to either of its metastable singIet states (Figure 2). In most cases it is the lower excited state ldg that appears to be responsible for the autoxida- tion~.~O The chemistry of the upper excited state l&+ has not been well studied although it does appear to have a different reactivity from that of the lAg state.@l O6 CJ A.Yogev M. Gorodetsky and Y. Mazur J. Amer. Chem. SOC. 1964,86,5208 D. Bellus and P. Hrdlovic Chem. Rev. 1967 67 599. D. Taub C. H. KUO H. L. Slates and N. L. Wendler Tetrahedron 1963,19 1. *@ C. S. Foote Science 1968 162 963. so C. S. Foote S. Wexler R. Higgins and W. Ando J. Amer. Chern. SOC. 1968,90,975. O1 (a) D. R. Kearns R. A. Hollins A. U. Khan R. W. Chambers and P. Radlick J. Amer. Chem. SOC. 1967 89 5455; (b) D. R. Kearns R. A. Hollins A. U. Khan and P. Radlick J. Amer. Chem. SOC. 1967 89 5456. 60 State 1Cg+ Highest occupied orbitals -3- -4- Sammes Energy 37 kcal. - 22 kcal. ?-+ 0 (Ground state) 9- 4- Figure 2 Energy levels of molecular oxygen Two modes of addition to olefinic systems may be recognised. Isolated double bonds react by addition with allylic migration of the double bond in a highly specific manner (139) to Thus p-pinene (141) can be readily and specifically converted into myrtenol (142).93 Conjugated dienes prefer to react by normal Diels-Alder type of cycloaddition as in the conversion of a-terpenene (143) into the anthelmintic ascaridole (14Qg4 An interesting variant of the latter reaction lead to the synthesis of the powerful vesicant cantharidin (146) from the anhydride (145).96 iB; hv ~ '*& - reduction '& O2 ISens. A. Nickon and J. F. Bagli J . Amer. Cltem. SOC. 1961 83 1498; (b) A. Nickon and W. L. Mendelson J. Amer. Chem. Soc. 1963,85 1894; (c) cf. K. Alder and H. von Brachel Annulen 1962 651 141. st G. 0. Schenck H. Eggert and W. Denk Annalen 1953,584 176. K. Ziegler and G. 0. Schenck Naturwiss. 1944,32 157.s6 G. 0. Schenck and R. Wurtz Naturwiss. 1953,40,581. 61 Photochemical Reactions in Nutural Product Synthesis Similarities between photosensitised oxygenations and certain biological oxidations have often been noted,g6 for example in the biosynthesis of abscisin-I1 (147).D7 The diene precursor (148) was oxidised in vitvo with oxygen to give the cyclic peroxide (149) which gave abscisin after treatment with dilute b a ~ e . ~ ' * ~ * *o ____) hv Go ____) Reduction &o \ I 0 2 /Sens. 0 I I C0,H ' 0 ' 0 i) HBr (145) / ii) OH- ' 0 (147) (a) See refs. 90 and 92a; (6) W. Waters and E. McKeown J. Chem. SOC. (B) 1966 1040; (c) J. E. Baldwin H. H. Basson and H. Krauss Chem. Comm. 1968,984. 97 J. W. Cornforth B. V. Milborrow and G. Ryback Nature 1965 206 715. (a) M. Mousseron-Canet J.C. Mani J. L. Olive and J. P. Dalle Compt. rend. 1966 262 C 1397; (b) cf. R. LeMahieu M. Carson and R. W. Kierstead J. Org. Chem. 1968 33 3660. 62 Sammes Oxidation of quercetin tetramethyl ether (150) gave the depside (152) via the peroxide (151) by a process analogous with that occurring nat~rally.~@ Singlet oxygen is also often involved in the oxidation of fatty acids,loO carotenoids,lO1 and naturaIly occurring heterocyclic systems. 89 7 Intramolecular Hydrogen Abstraction Several very specific photoreactions are known which involve intramolecular chemical attack at a carbon atom some distance removed from a functional group. A short list with leading references is given in the Table. These reactions proceed by intramolecular formation of a carbon radical which can then be quenched by such reagents as nitric oxide iodine etc.For example nitrite esters (e.g. 153) react with preferential abstraction of a y-hydrogen atom via a six- membered transition state to give an oximino-alcohol (154).lo2 Many applica- NOH ss T. Matsuura H. Matsushima and H. Sakamoto J. Amer. Chem. SOC. 1967 89 6370. loo (a) H. R. Rawls and P. J. von Santen Tetrahedron Letters 1968,1675; (b) cf. S. Bergstrom Science 1967 157 382. l01 (a) M. Mousseron-Canet J. P. Dalle and J. C. Mani Photochem. and Photobiol. 1969 9,91; (6) S. Isoe S. B. Hyeon H. Ichikawa S. Katsumura and T. Sakan Tetrahedron Letters 1968 5561. 1°*D. H. R. Barton J. M. Beaton L. E. Gellcr and M. M. Pechet J. Arner. Chem. SOC. 1961,83,4076. 63 3 Photochemical Reactions in Natural Product Synthesis Table Photolytic intramolecular hydrogen abstraction reactions Functional group Alcohol Amine Amide Nitrile Carboxylic acid Derivative Princbal products Nitrite y-Oximino-alcohol Hypochlorite y-Chloro-alcohol Hypoiodite y-Iodo-alcohol or tetrahydrofuran N-Chloro- y-Chloro-amine or amine pyrrolidine N-Iodoamide y-Lactone N-Bromo-t- y-Lactone or butylamide imino-ether N-Nitroso- y-Oximino- acetamide acetamide N-Chloro-amide y-Chloro-amide Nitrile oxide 7 Acyl azide ) 'y- and &lactams J Sulphonamide N-Chloro- y- and s-chloro- sulphonamide sulphonamides a b d e f g h C 1 j k 1 1 Comments Reference a Alkoxy radical b formed RO.c d Hofmann-Loeffler- e Freytag reaction. Photolysed with acid present Via C-iodide f g h i l j mixtures if possible A. L. Nussbaum and C. H. Robinson Tetrahedron 1961 17 35.M. Akhtar and D. H. R. Barton J. Amer. Chem. SOC. 1961 83,2213. M. Akhtar Adv. Photochem. 1964. 2 263. K. Heusler and J. Kalvoda Angew. Chem. Znternat. Ed. 1964 3 525. M. Wolff Chem. Rev. 1963 63 55. D. H. R. Barton A. L. J. Beckwith and A. Goosen J. Chem. Soc. 1965 181. R. S. Neale N. L. Marcus and R. G. Schepers J . Amer. Chem. SOC. 1966 88 3051. Y. L. Chow and A. C. H. Lee Chem. and Znd. 1967 827. R. C. Petterson and A. Wambsgans J. Amer. Chern. SOC. 1964 86 1648. G. Just and W. Zehetner Tetrahedron Letters 1967 3389. J. W. ApSimon and 0. E. Edwards Canad. J. Chem. 1962,40 896. M. Okahara T. Ohashi and S. Kanai Tetrahedron Letters 1967 1629. tions of these reactions to the synthesis of natural products have been reported and only a few are presented here to illustrate their usefulness.The readily available corticosterone acetate was converted into its nitrite ester (155) before photolysis in benzene solution. Nitrous acid treatment of the derived oxime (156) gave the important hormone aldosterone acetate (157) in overall 15 % yield.lo3 N-Chloroamines are very sensitive t o lightlo4 and under acidic conditions the 108 D. H. R. Barton and J. M. Beaton J. Arner. Chem. Soc. 1961,83,4083. M. Wolff Chem. Rev. 1963,63,55. 64 Sammes 0’ d ’ 0 & OH r O A c OAc 0 chloro-mine (158) gives the 7-chloroammonium salt (159). Mild base treat- ment affords the pyrrolidine (1 60) the steroidal alkaloid dihydroconnessine.lo6 C1 (158) ( 1 59) ( 1 60) Io5 E. J. Corey and W. R. Hertler J. Amer. Cheni. Soc. 1960 82 1657. 65 Photochemical Reactions in Natural Product Synthesis Most intramolecular hydrogen abstraction reactions proceed via the favoured 6-membered transition state leading to 7-substituted products.A notable excep- tion is for the acyl nitrenes generated from either the acyl azide or nitrile oxide which prefer to abstract hydrogen from the 8-position.lo6 For example the acyI azide (161) affords mainly the 8-lactam (162) as well as a minor amount of y-lactams. The major product was converted into the phenol (163) a degrada- OMe OMe \ OH I (1 61) ( 1 62) (163) tion product of the alkaloid atisine.lo7 An explanation for the required larger transition state is that singlet nitrene is responsible which inserts in a concerted manner into the 8-carbon-hydrogen bond (e.g. 161A) with carbon to nitrogen H bond formation in the transition state that is again via a formally 6-membered intermediate.lo8 Isocyanates are also formed during this photolysis and again involve singlet excited species probably of the excited azide.loD Sensitised photolysis inhibits the rearrangement to isocyanate but also retards lactam format ion.l0 8 Photosensitive Protecting Groups Protecting groups employed in synthetic work are usually removed chemically for example by acid or base or by hydrogenolysis.llo Problems often arise when the substrate itself is also sensitive under the conditions required to regenerate the protected group.The use of protecting groups which may be Io6 (a) W. L. Meyer and A. S . Levington J. Org. Chem. 1963 28,2859; (&) R. F. C. Brown Austral. J. Chem. 1964 17 47. lo' J. W. ApSimon and 0. E. Edwards Canad.J. Chem. 1962,40 896. l08 I. Brown and 0. E. Edwards Canad. J. Chem. 1967,45,2599. 109 (a) W. Lwowski Angew. Chem. Internat. Edn. 1967 6 897; (&) G. T. Tissue S. Linke and W. Lwowski J . Amer. Chem. SOC. 1967,89 6303 6308. J. F. W. McOmie Adv. Org. Chem. 1963 3 191. 66 Sammes removed by irradiation avoiding the need for chemical treatment of the sub- strate is an attractive alternative. Two approaches to the design of such photosensitive protecting groups have been developed. In the first the internal redox reaction of substituted o-nitro- toluenes has been used.lll Brief irradiation of o-nitrodiphenylmethyl esters (e.g. 164) gives the corresponding o-nitrosohemiacetal (1 65) which collapses spon- taneously into o-nitrosobenzophenone (166) and the free acid.Amines can also be protected with this group. 01 I G O - OC'OK I'll In an alternative approach use is made of the greater reactivity of excited aromatic compounds compared to that of their ground states.l12 Thus m-nitro- phenyl esters are photosensitive and in protic solvents the acid is di~p1aced.l~~ Similarly 3,5-dimethoxybenzyl esters react with liberation of the protected g r 0 ~ p . l ~ ~ Related to the latter reaction is the observed photolytic decarboxylation of the 3,5-dimethoxybenzene derivative (167).llS This probably reacts via the 0- ll1 J. A. Barltrop P. J. Plant and P. Schofield Chem. Comm. 1966 822. For a recent summary see (a) E. Havinga and M. E. Kronenberg Pure Appl. Chem. 1968 16 137; (b) E. Havinga R. 0. de Jongh and M. E. Kronenberg Helv. Chim. Acfa 1967 50 2550.113 T. Wieland and C. Lamperstorfer Mukromol. Chem. 1966 31 1658. 114 J. W. Chamberlain J. Org. Chem. 1966,31 1658. 115 J. D. White and J. B. Bremner Abstracts 155th meeting of the American Chemical Society San Francisco 1968 170th abstract. 67 Photochemical Reactions in Natural Product Synthesis excited species (168) which eventually collapses to the ketone (169) used in a synthetic approach to mitorubrin.ll6 Other photosensitive protecting groups have been described including the benzyloxycarbonyl moiety,l17 desyl derivatives,lls and 2,4-dinitrobenzene- sulphenyl esters.lls It should be emphasised that many organic photochemical reactions have been reported which could be adapted for use in removing photo- sensitive protecting groups. An example is with the biphenylurethane (170) which is smoothly transformed by photolysis to phenanthridone (171) with liberation of the alcoho1.lZ0 116 G. Buchi J. D. White and G. N. Wogan J. Amer. Chem. SOC. 1965 87 3484. 11' J. A. Barltrop and P. Schofield J. Chem. SOC. 1965 4758. 118 J. C. Sheehan and R. M. Wilson J . Amer. Chem. SOC. 1964 86 5277. llS D. H. R. Barton Y. L. Chow A. Cox and G. W. Kirby J . Chem. SOC. 1965 3571. 120 N. C. Yang A. Shani and G. R. Lenz J . Amer. Chem. SOC. 1966,88,5369. 68