23

J. Phofochem. Photobiol. B: BioZ., 14 (1992) 23-46

Synthesis of psoralens

and analogues

Emile Bisagni URA 1387 CNRS, Institut Curie, Section de Biologic, BMment 110, 15 rue Georges CUmenceau, 91405 Orsay (France)

(Received November 18, 1991; accepted February 3, 1992)

Abstract

This review presents briefly the various classical syntheses of psoralens and angelicins which generally start from preformed suitably substituted coumarin or benzofuran derivatives. However, the discovery of the photocyclo-C-4 addition of psoralens to pyrimidine bases prompted new developments in this area. In particular, improved synthesis of psoralens and substituted angelicins, and synthesis of new analogues such as furochromenes, pyridopsoralens, pyrano benzopyrandiones, dioxinocoumarins and aza-psoralens were described recently. This review focuses on the chemical syntheses of these various compounds.

Keywords: Psoralens and derivatives, angelicin, furochromenes, pyridopsoralens, aza-psoralens.

dioxino[2,3-g] coumarins,

1. Introduction

Furocoumarins are widespread umbelliferon-derived compounds found in plants, mostly among members of the Leguminosae, Umbelliferae and Rutaceae families. Owing to their remarkable photoinducecl melanizing properties, they have proved active in the treatment of vitiligo and of such skin diseases as psoriasis, eczema and mycosis fungoides. A full account of the chemistry of naturally occurring furocoumarins and of their derivatives would be beyond the scope of the present paper. For a review on this matter we refer to other authors: Splth [l], Dean [2] and Mustafa [3]. Rather we shall focus here on the chemistry of new furocoumarin congeners whose synthesis was prompted by the discovery of the process of photocyclo-&addition of psoralens to pyrimidine bases. Some of these new compounds have shown improved therapeutic index in various biological studies.

2. Natural

and synthetic

pathways

to linear

and angular

fbrocoumarins

The biosynthetic route to psoralen and other natural furocoumarins has been elucidated to near completion by Brown et al. [4], Caporale and coworkers [5-g], Dall’Acqua et al. [9] and Innocenti et al. [lo]. It starts with isoprenylation of umbelliferon 1 leading to 6-dimethylallyl umbelliferon 2, which is subsequently transformed into

loll-1344/92/$5.ocl

0 1992 - Elsevler Sequoia. All rights reserved

I

OH

A -

6

7

Scheme

1. Proposed

b

pathway for tie biosynthesis

8

of 0-alkyd linear furocoumarins.

0

;d I

I>

I

I

6

15 9i

13

20%

Scheme 2. Psoralens: 7H-furo[3,2-g] [l] benzopyran-7-ones. Total synthesis from umbelliferon and umbelliferon derivatives: a, CICHzCO-RI, K&4; b, EtONa; c, O,, Hz; d, H+.

25

k3

18

Scheme 3. Synthesis of various substituted Smethylpsoralens according to Pardanani and Trivedi [17]: a, Br4XITCH=CH,, K&O,; b, Claisen transposition; c, HzS04; d, Pd/C, 245 “C, e, Oj, H,; f, H,PO,. the epoxide 3 and its dihydroxy derivative 4 ending in marmesin 5 after dehydration. Marmesin is thought to be the key intermediate in the biosynthesis of psoralen 6, as well as of the 5- and S-methoxypsoralens 7 and 8 via hydroxylation and methylation (Scheme 1). Total syntheses of psoralens have been performed following two general routes. The first starts either from the umbelliferon 1, from the substituted 7-hydroxycoumarins 9 and 14, or from the umbelliferon derivative 2 [ll-151 in the same way as in the biogenic pathway. In strongly basic medium acetonyl and phenacyl derivatives 10 undergo regiospecific ring closure at the 6-position of the coumarin ring as shown by Ray et al. [14] and Caporale and Antonello [IS]. In contrast, 4-chloro-1,3-dioxolan2-one led directly to a mixture of psoralen 6 (15%) and angelicin 13 upon reaction with umbelliferon 1 [16]. To date this reaction developed by Reisch and Mester [16] forms the more direct route to compounds 6 and 13 (Scheme 2).

23

24

a

0

‘/

-

a4

26

(---_-~--). 27

28

Scheme 4. Synthesis of some psoralen derivatives from 6-hydroxy-2,3_dihydrobenzofurans: malic acid, H2S04; b, Pd/C, 245 “C; c, R-CO-CH&OOEt, H+.

23

a,

29

I

b

32 A

b

I

30

31

Scheme 5. Synthesis of psoralens from 6-acetoxy-2,3-dihydrobenzofuran acrylonitrile: a, CH,=CH-CN, ZnClz, HCI; b, Pd/C, 245 “C.

or 4-ally1 resorcinol

and

27

I-Q-oH-~~

q.

OH 8

33 R-H

-R-C+

34

35

HoJ$Lo~J$Li~~o c

36

37

3s

Scheme 6. Synthesis of S-methoxypsoralen: a, malic acid, H$O,+; b, Pd/C, 245 “C, c, (CH&N4, AcOH, d, KzC09, BrCH,COOOEt.AqO, AcONa.

OMe

O-C.0 Me 48 46

Scheme 7. Synthesis of Bergapten: a, Hz, Pd; b, 43=NaOCHCHCOOGHS; c, cH,N,; d, 0,, HZ; e, BrCH,COO~HS; f, KOH, CH,OH, g, AGO, AcONa; h, ClCH,CN, ZnClz; i, AcOK, j, AGO, Pyr; k, KOH, H,O; 1, malic acid, H$O,: m, Pd/C, 245 “C.

d

Scheme 8. Synthesis of Angelicin: 5H-furo[2,3-h] coumarin or SH-furo[2,3-h] [l] benzopyran-5one. Various routes for its preparation from coumarin derivatives: a, CH,ONa; b, BrCH$ZH(O~H5),; c, heat; d, (CH,)&, AcOH, e, 0s and Hz, Pd/C, f, HaPOd; g, JCH,COOGH5; h, KOH; i, H+; j, Ac*O, AcONa; k, BrCH(COO~H5)2; 1, hydrolysis and decarboxylation.

In contrast, the presence of an g-methyl group on 7-hydroxy substituted coumarins results in the specific synthesis of linear polysubstituted furocoumarins [17] (Scheme 3). The use of 2,3-dihydro-6-hydroxy benzofuran derivatives as starting building blocks underlies the second general method for total psoralen synthesis. For example, psoralen 6 has been obtained by Spslth and coworkers [18, 191 from 2,3-dihydro-6-hydroxy benzofuran 21 and malic acid, via its dihydro derivative 22 and subsequent dehydrogenation over palladium on charcoal. Accordingly, 4-substituted psoralens 25 were prepared by Horning and Reisner [20] and Esse and Christensen [21] from 6-acetoxy2,3_dihydrobenzofuran 23 and 3-substituted psoralens 28 have been obtained by Foster etal. [22] from S-formyl-2,3-dihydro-6-hydroxybenzofuran 26 as starting material (Scheme 4).

29 Reimer-Ticman

58

50

a3 \

a3

P \'

3

0

0

59

Scheme 9. Preparation of angelicin from 4-hydroxy benzofuran different biologically interesting methylangelicins [33-381.

[32] and general

formula

of

In a similar approach to linear furocoumarins Chatterjee and Sen [23] obtained tetrahydropsoralen 29 from compound 23 and acrylonitrile and the parent intermediate 30 was also prepared in a one pot reaction by starting from 4-allylresorcinol 31 [24] (Scheme 5). 8-Methoxypsoralen (g-MOP, Xanthotoxin, 8) and S-methoxypsoralen (Bergapten, 7), both used in human phototherapy, have been obtained from suitably substituted benzofurans by Spath and coworkers [18, 19, 251 and Caporale [26] and from 6-formyl7-hydroxy coumarin derivatives by Howell and Robertson [27], Rodighiero and Antonello [28] and Antonello [29] (Schemes 6 and 7). The Spith and coworkers synthesis of bergapten 7 from phloroglucinol derivative 39 led to a mixture of linear (41) and angular (42) furocoumarins [25]. However, compound 7 has been obtained by Howell and Robertson in pure form using xanthoxyletin 44 as starting material [27]. The method of Caporale [26] appears to be the key to the synthesis of bergapten from methyl-2,6-dihydroxy-4-methoxy benzoate 46 (Scheme 7). In fact, both general routes to psoralens can be applied to the production of the angular furocoumarin angelicin 50 and derivatives. Scheme 8 summarizes those which start from preformed coumarins [13, 18, 30, 311. Methods using benzofuran synthons such as karanjol derivative 58 in order to yield angelicin are of more limited value [32] (Scheme 9). Various important mono-, di- and trimethyl angelicins corresponding to the general formula 59, have thus generally been prepared from the coumarin series.

3. Psoralen derivatives

of interest in mode of action studies

Psoralens have been recognized as photochemotherapeutic agents for the treatment of skin diseases (PUVA therapy) for a long time. Attempts at finding new drugs derived from furocoumarins have been very active in many countries and have been described in numerous reports. Most molecules that have shown a potential in mode of action studies will be discussed in the following.

28% overall yield 6 3

62

Scheme 10. Synthesis of trioxalen [39] and 4,5’-dimethyl-S-methoxypsoralen [29]: a, heat; b, Ac,O, AcONa; c, Br,; d, KOH, e, (CHJ&, AcOH; f, Br-CH(CH,)XOO,H,; g, KOH, H+.

8-Methoxypsoralen 8 (8-MOP) and 4,5’,8-trimethylpsoralen 63 (trioxsalen) are the best known of the psoralens that have proved active in daily clinical use. Trioxsalen was first prepared by Kaufman [39] from 7-allyloxy-4,8-dimethyl coumarin 60, giving in succession the 6-allyl-4,8-dimethyl-7-hydroxy coumarin 61 by Claisen transposition, the dibromo derivative 62 under usual conditions, and compound 63 by sodium ethoxidedependent ring ,closure. Surprisingly enough, 8-methoxy-4,5-dimethyl psoralen 68, a compound closely related to both 8 and 63, did not attract attention even though it was synthesized by Antonello [29] before trioxsalen, via aldehyde 66 and coumaryloxy acetic acid derivative 67 as intermediates (Scheme 10).

31

a3 69a

R=CHz-C=M

6 9b

R==C+c(Q)XH~

R=H

-

a-r3 Intractable ,I.

-

R=NHz -

R=-N

Scheme 11. Improved synthesis of trioxalen [40]: a, 70% H,SO,, room temperature; NH,OAr(NO&; c, GH,OH, Cl&COCH,, HCl; d, HsPO.,, AcOH, 60 “C.

k

L3 71c

b, Na,

71b

Scheme 12. Synthesis of 4’-aminomethyl-4,5’,8-trimethylpsoralen b, MeOH, c, H,O; d, K-phtalimide; e, NH&E&.

1411: a, ClCH,OCHs,

AcOH,

32

8

OMe

OMe

OMc

77

19

Scheme 13. 8-Dialkylamino alkyloxy psoralens and 5-dialkylamino alkyloxymethyl-S-methoxypsoralen derivatives: a, MgI,; b, Br-CH&H&HTBr; c, NH(CHJ,; d, ClCHZOCH3; e, OH-CH&H,OH, f, Ar,P, CBr.,; g, NaBT,; h, SOCl*.

Improved methods for furano ring formation of psoralen were described later by Bender et al. [40] and applied to the synthesis of trioxsalen 63. The most useful pathway at the present time makes use of P-chloro ally1 ether 69b as starting material (Scheme 11). Moreover, the synthesis of various trioxsalen derivatives, of 4’-aminomethyl trioxsalen 71 in particular, was carried out by Isaacs et al. [41] with the aim of obtaining psoralen derivatives with increased aqueous solubility and binding affinity for nucleic acids. Such compounds actually proved a higher photoreactivity with DNA and RNA. They were prepared from trioxsalen 63, by chloromethylation to 71a, derivatization into phthalimido compound 71b and hydrazinolysis, giving the expected If-aminomethyltrioxsalen 71c (Scheme 12). Other water-soluble psoralen derivatives with improved therapeutic potential and lesser side effects, have been prepared from 8-methoxypsoralen 8 by Antonello et al. [42], Hansen and Buchardt [43] and Hansen et al. [44]. 5-Dimethylaminomethyl-8methoxy psoralen 73 8-(3-dimethylaminopropyloxy)psoralen 75 and 5-(3-dimethylaminopropyloxymethyl)-8-methoxypsoralen 77 were obtained as summarized in Scheme 13. By using 5-formyl-8-methoxypsoralen 78 and its tritium derivative 79, several tritium labelled compounds were also synthesized by this route (Scheme 13). Also, 3-hydroxy and 3-amino-substituted 4’-methyl psoralens 83 and 85, bearing basic dialkylaminoalkyl groups, were prepared from 7-hydroxy-3-amino-coumarin 80 by Antonello et al. [45], as shown in Scheme 14.

33

R=H -

81

R=CH2CIXH3 80

b

84

82

J

cod. e

83

85

R=CH3 R = KHzh

WOz

Scheme 14. 3-Dialkylaminoalkyloxy a, KOH, EtOH, b, H+; c, CH,N,;

and 3-dialkylaminoacetamido-4’-methylpsoralen d, Br-(CH,),Br; e, NH(Et)2; f, ClCOCH,CI.

derivatives:

In order to obtain monofunctional DNA-binding compounds, psoralen derivatives with bulky groups at one of their photoactivable sites, or at both,, were designed and synthesized in the mid-1970s [46]. 3-Carbethoxy psoralen 88 (R = H), already described by Worden et al. [47], and 3,5’-dicarbethoxy-8-methylpsoralen 90 (R= CH-,), were then prepared from the substituted benzofurans 86 (Scheme 15). Further monofunctional psoralens were obtained with the pyridopsoralens 93, 94 and 95 by Moron et al. [48] and Blais et al. [49] (Scheme 16) and showed still higher specificity for photoinduced single-stranded DNA binding. Marked differences may appear between these compounds, depending on their structure. In this respect, some properties of 1,2,3,4-tetrahydro-8H-pyrano [3’,2’:5,6] benzofuro[3,2-c] pyridine-8-one 97 are similar to those of aminomethyltrioxsalen 71. The synthesis of the former, however, is considerably more straightforward.

4. Synthesis

of various

oxygen-related

compounds

Two kinds of linear benzodipyrones are related to psoralens: 2H, 8H-benzo[l,2b:5,4-b’] dipyrano-2,&dione 101 and its isomer 102. Whereas compound 101 was prepared from resorcinol in a two-step sequence by Das Gupta et al. [50], the synthesis

89

90

Scheme 15. Synthesis of 3-carbethoxypsoralens and 3,5’-dicarbethoxy-8-methylpsoralen AICI,; b, CH,(COO&H&; c, GH,OH.

[46]: a,

of compound 102 proceeded via the intermediates 103 and proved more tedious [51] (Scheme 17). Linear and angular furochromenes 104 and 105 correspond to another type of psoralen and angelicin analogues. They have been synthesized by Royer and coworkers [52-571 from suitably substituted chromenes and benzofurans 106 and 107, as summarized in Scheme 18. Based on the same strategy, various linear and angular isomers of functionalized furochromene 110 were synthesized from furo-fused salicylaldehydes 103, 111, 112, 113, 114 and 115, and difuro benzenes of type 116 and 117 as well [S2-571. The last two types of oxygen-containing heterocycles which retained our attention as psoralen-related compounds, are pyranocoumarins 120 and dioxinocoumarins 125. Pyranocoumarins 120, also referred to as homopsoralens, resulted from Claisen transposition of propargyl ethers 118 to functionalized chromenes 119 and subsequent pyrone ring formation by conventional methods [58, 591 (Scheme 19). Dioxinocoumarin 125 has been prepared by Guillaumet et al. [60] from dioxin0 benzaldehyde 122, by the sequence shown in Scheme 20.

5. Sulphur

and nitrogen

analogues

It was of interest to compare the biological properties of the thieno isoster of trioxsalen with those of its parent compound. This isoster has been prepared by Wellman [61] from 7-hydroxy-4,8-dimethyl coumarin dimethyl thiocarbamate 126, which thermally rearranged to 7-mercapto-4,8-dimethyl coumarin dimethyl carbamate 127. Potassium hydroxide hydrolysis then provided the key intermediate 7-mercapto-4,8dimethyl coumarin 128, easily transformed into its bromo ally1 thioether 129. This undergoes a slow thioclaisen rearrangement leading in good yield (78%) to 4,7,9trimethyl-2H-thieno[3,2-g] [l]-benzopyran-Zone 130 (Scheme 21). Two distinct routes have been developed for the synthesis of pyrrolo isosters of furocoumarins. That using indolines 134 shows a striking similarity to psoralen synthesis

35

R=HandCHx

“ok@

pJzRQOMe R=N&

a3

a3 R-NH2 R=N2+ (Cydization) Demechylation

a I

I

a3 95

a3 R=CHO 99

R=H

c=

Scheme 16. Synthesis of various pyridopsoralens: a, Pd/C, b, HCl, AcOH; c, (CH,),N,, CF,COOH. through dihydrobenzofuran derivatives (Scheme 22). I’-Azapsoralens 136 (RI = H, CH,) have been synthesized in this way by Quanten et al. [62]. Polysubstituted azapsoralens and aza-angelicines 140 and 141 were prepared by Rodighiero et al. [63] using another route from 7-amino coumarin 137, according to Scheme 23, a replica of psoralen synthesis from coumarin building blocks. As expected from the fact that coumarinhydrazones 139 were unsubstituted at their 8-position, a mixture of linear and angular pyrrolo coumarins 140 and 141 resulted upon Fischer indolization (Scheme 23). Another type of azapsoralen which remained unknown until recently corresponds to the general formula 148. Compared with psoralens, the coumarin ring has been replaced by a substituted quinolone, the synthesis of which was performed starting from 2,6-diamino toluene 142, which gave, successively, 7-amino-4,8-dimethyl-lHquinolin-Zones 143 and 7-hydroxy-4,8-dimethyl-lH-quinolin-2-ones 144. 4, 8 5’-Tri-

/--

R=CH3.X=

H

R=CH3,X-

cqa

R=CH3,X=

CHzOAc

OR

103

L 102

Scheme 17. Pycano[3,2-g] [l] benzopyran-2,8-dione and pyrano[2,3-g] a, Cl&l, HCI, CH,=CH-COOMe; b, Pd/C, 245 “C.

[l] benzopyran-2,7-dione:

methyl-l-azapsoralens 148 were then prepared by Guiotto et al. [64] from 144 via the Scheme 24 pathway, i.e. by the same method already used in the first synthesis of trioxsalen (Scheme 24). Among the various azapsoralen isosters that could be obtained, the synthesis of the 8-azapsoralen heterocycle proved to be particularly difficult. Van Sickle and Rapoport [65] have, however, recently prepared its 5,5’-dimethyl derivative 154, using the artful six-step sequence summarized in Scheme 25. In this method, the fully substituted pyridone 149 was cyclized in boiling trifluoroacetic acid to give furo[3,2-blpyridone 150 whose benzyloxy derivative 151 has been obtained in good yield, either by direct benzylation with benzylchloride in dimethyl formamide and triethylamine, or in a twostep procedure including chlorination and subsequent substitution by potassium benzyloxide. 5,5’-Dimethyl-8-azapsoralen 154 was then formed from reduction of the nitrile function to aldehyde 152, formation of the corresponding acrylic acid 153, and final ring closure with acetyl bromide at reflux temperature (Scheme 25). Bearing all the afore-mentioned data in mind, it could be concluded that virtually all known syntheses of psoralen, psoralen derivatives and closely related compounds are performed from resorcinol, resorcinol derivatives, or substituted 3-hydroqanilines in the case of aza-analogues. At least two recently reported furocoumarin syntheses do not conform to this scheme, however. This case deserves special mention. Here phenylsulphoxide 155 was specifically built up by Hayakawa et al. [66] from ethylacetylacetate and propargyl bromide, via the resulting ‘y-propargyl fi-ketoester, corresponding ketal, ester reduction, conversion to phenylsulphide and oxidation. The acid catalysed (TsOH) reaction of 155 with furan (10 eq) proceeded at room temperature to provide 156 in 78% yield. Only its ketal 157 underwent thermal cyclization in the presence of 10% palladium on charcoal giving the ketone 158 after hydrolysis of the ketal-protecting group (Scheme 26). Following this bicycloannulation by intramolecular Die&Alder reaction, the ketone 158 was easily transformed either into psoralen 6 by Baeyer-Villiger oxidation and aromatization, or into l-azapsoralen 160 via the

37

106

104 8

Scheme 18. Linear and angular furochromenes and difuro benzenes.

&=a3.-3

Scheme 19. Synthesis of homopsoralens;

Rl = COO&COOK

H.

38

=0I

’ \

I

OH

“b

.

OH 122

121

1

c.d

124

a, BrCH2CHZBr, NaOH, H,O; b, Scheme 20. Synthesis of dioxino[2,3-g] [l] b enzopyran-S-one: Br,, AcOH; c, MeONa, CuC12, DMF; d, AU,, CH&&; e, Ph,=CH-COOEt, Tol. rh, f, 240 “C; g, NBS, CC&, (C&I&0),0,; h, NaI, acetone.

130

Scheme 21. Pathway for preparation

129

of trioxsalen thioisoster:

a, heat; b, KOH, c, CHH,=C(Br)CHzBr.

39

,30)3LN”=-30QL~q-&o I

131

R1

132

RI

133

pJo

qJ&

-y-J--i-

RI

RI

RI

136

135

134

R1

Scheme 22. Synthesis of l’-azapsoralens 136 [62]: a, AGO, AcOH; B, LiAlH4; c, ClCH,COC~ d, AlC&; e, NaBH,; f, CH&OCH,COO~H&nCl~; g, Pd/C.

P a2 \ /F-N--, k3

(I' Da I H

0 139

y&o&--....o 140

R

141

Scheme 23. Linear and angular pyrrolo coumarins, synthesis from 7-arnhxxoumarin: a, NaN4, HCl, HzO, -5 “C, 0 “C, b, SnCl, HCl, H,O, c, CH&OCH& d, CH,COCHs; e, ZnC&.

40

a3 142

147

a3

H

a3

H

143

146

a3

145

H

148

Scheme 24. Preparation of I-azapsoralen derivatives from 2,6-diamino toluene: a, CH,COCH~COOC;H5; b, H,O, H,SO,; c, BrCH,CHCH,; d, heat; e, AGO, AcONa; f, Br,; g, KOH. Beckman rearrangement of the oxime 159 and subsequent dehydrogenation. In another method, dimethoxy cyclobutene dione 161 was reacted by Reed and Moore [67] with trimethylsilylethynil lithium togive 3-methoxy-4-[2-(trimethyl silyl)-l-ethynyl] cyclobuten1,Zdione 162. This was condensed with 2-lithiofuran to provide compound 163 which resulted from regioselective addition of lithiofuran to the more electron-deficient carbonyl group of 162. Thermolysis of 163 in refluxing toluene, led directly to hydroquinone 165 (R = H) via electrocyclic ring closure of the transient conjugated ketene 164. The synthesis of 5,6-dimethoxy angelicine (pimpinellin) 169 was further achieved by conventional methods, as summarized in Scheme 27. Finally, various routes to the synthesis of naturally occuring furocoumarins and derivatives were already well known before 1960. At that time, however, psoralens were studied empirically as possible photosensitizing agents, without sound knowledge of their mode of action at the molecular level. The discovery of photocyclo C-Caddition to pyrimidine bases, which appeared during the 1960s at Padua University by Musajo and Dall’Acqua and coworkers [6&71], prompted many studies aiming at increasing the therapeutic index of furocoumarin derivatives, i.e. at improving their therapeutic effectiveness together with lesser side effects. Investigations on the mode of action at the molecular level, in particular those concerning the processes of DNA monoadduct formation and DNA interstrand crosslinking and their genetic and epigenetic consequences, have flourished since then.

41

Scheme 25. Synthesis C6HsCH2Cl, (GH&N,

of 5,5’-dimethyl 8-azapsoralen: a, CsHt,N, rfx, b, CF,COOH, DMF; d, iBu&H, e, H3P04; f, CHz(COOH),; g, CHaCOBr.

155

157

156

rfx, c,

v-

b.a I

WIJ I>

I

IS9

If.g

T

N-OH

0

158

I

c. d

6

Scheme 26. First synthesis of psoralen starting from furan derivative via a bicycle annulation by an intramolecular Die&Alder reaction: a, TsOH (Cat); b, Pd/C, xylene, 200 “C; c, 30% H,OZ, excess, AczO, H2S04, 20 “C, d, Pd/C, 245 “C, e, NHzOH, HCl, AcONa, EtOH, e f, MsCl, NEt,, CHrClz, 0 “C; g, EtzAlCl, -70 “C, CHzClr, 5% NaOH.

42

cH,d

161

162

163

R=fl) 164

OR

167

OR

0

168

R=CH3

165

166

OR R=H -

RsCH3 (Pimpinellin) 169

Scheme 27. Synthesis of pimpinellin via electrocyclic ring closure of a conjugated ketene: a, TM!&C=C-Li; b, toluene, &, c, AgNO,, H,O, EtOH, KCN; d, n-BuLi, ClCOOMe; e, CAN, MeCN; f, HP

As can be seen from the numerous references from the Padua group cited in this review, a great part of the studies performed on the chemical synthesis of psoralens, psoralen derivatives and analogues, has been carried out at Padua University. Professor Rodighiero’s contribution in this field is among the most important with regard to both the biological and chemical aspects of the furocoumarin family.

43

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