A facile two synthon approach to the camptothecin skeleton

Tetrahedron Vol. 36. pp. 321 to 327

004D-4020/80/0 115-0321/$02.00/0

© Pergamon Press Ltd. 1980. Printed in Great Britain

A FACILE TWO SYNTHON APPROACH TO THE CAMPTOTHECIN SKELETON H. G. M.

WALRAVEN!

and U. K.

PANDIT*

Organic Chemistry Laboratory, University of Amsterdam, Nieuwe Achtergracht 129, Amsterdam. The Netherlands (Received in UK 9 May 1979) Abstrad-A synthesis of deethyldesoxycamptothecin via the reaction of two readily accessible synthons is described. One of the synthons constitutes the ABC ring system of camptothecin, while the second provides all the C atoms of the rings D and E. The synthetic approach is suited for the total synthesis of camptothecin analogues.

The initial reports 2a --c on the carcinostatic activity of camptothecin (1) stimulated intensive interest in the total synthesis of the alkaloid. 3a-g However, subsequent biological evaluation indicated that the compound was highly toxic and consequently unusable as a chemotherapeutic agent. 4 In view of this development, attention is now being concentrated on methodology which could provide a practical approach to the synthesis of camptothecin analogues. Such an approach would have to take into consideration the fact that the rings D and E of the natural alkaloid are essential structural elements for the expression of biological activity. An ideal general synthesis would, therefore, comprise an approach in which a potential DE (rings) precursor can react with suitably modified ABC systems, to form camptothecin like compounds. The principle of the approach has been illustrated by the synthesis of camptothecin and deethyldesoxycamptothecin described in a recent report by Corey 3e and in the preliminary communication from this laboratory,3 g respectively. We now present the details of the general synthesis of the camptothecin skeleton, via the two synthons approach. The strategy of the synthesis as applied to camptothecin (1) is shown in Scheme 1. Reaction

+

°tfC02Rl 0

between the tricyclic system 2 and the substituted lactone, such as 3, results in an amide which carries all the atoms of the camptothecin skeleton at a suitably functionalized level. Directed manipulation of these functions should allow, in a stepwise fashion, the formation of ring D (intermediate 4) and ring E (5). Compound 5 in the scheme is deethyldesoxycamptothecin, the elaboration of which to 1 has been reported in the literature. Since the dihydropyrroloquinoline 2 is readily available via the method of Zalkow,5 the first critical multistep transformation in the proposed synthetic scheme (Scheme 1) namely, the conversion of the tricycle to the tetracyclic system (2 -44), was investigated. A preliminary detailed study of the aminolysis of lactones by cyclic secondary amines 6a-d indicated that the rate of formation of the aminolysis product, that is the amide, besides being determined by the basicity of the amine and steric and electronic factors in the lactone, was very significantly influenced by the nature of the solvent. For the reaction of 2 with butyrolactone 6 (Scheme 2), the best results were obtained when the amine (2) was added to a large excess of 6 and the homogeneous mixture was allowed to stand at room temperature (3 days), where upon the amide 7 was obtained (78%) as a crystalline product. In

----

o

_" ',~X U

---Scheme 1 321

322

0 08

.£

H. G. M.

-

.£

+

O~COOEt OAe

HO

-

.£

O~ OAe 10

0""

2

COOEt

H

-

0 3D~ ....

12

?D~

N

PANDIT

N

2

8a

0

and U. K.

-

2D;1

.§.. 0

WALRAVEN

H

- ~

13

+

~

N

H.

~

~ ~,9

N COOEt

15

COOEt

- ~ - ~ N

11

""-

0

j§.

H

-

-

-

Scheme 2

an analogous manner, reaction of 2 with lacatone 8a (to be described in the sequel) yielded

13-

formylamide 9. Aminolysis of 10, leading to 11 (80%) was, however, attained by warming the reactants in toluene. The hydroxy amide 7 could be conveniently converted into the corresponding 13formyl amide 12 by a Collins oxidation. For the cyclization of l3-formyl amides of the dihydropyrroloquinoline system, the procedure described by Meyers et ai. 78 was utilized. Heating the amides 12, 9 and 11 in acetic anhydride in the presence of potassium acetate gave the ring-closure products 13, 14 + 15 and 16 respectively, in modest to good yields. The formation of 15 is a reflection of the ease oxidation of the dihydropyridone system in 14. It should be pointed out that 15 has been converted into dl-camptothecin, in three steps, by Danishefsky,8 consequently, its synthesis represents a formal total synthesis of camptothecin itself. Having shown the generality of annelation of 2, via its reaction with lactones; attention was directed to the synthesis of an appropiately functionalized lactone corresponding to structure 3 (described in Scheme 1). The target-synthon of choice was the lactone 17a,b (Scheme 3) which carried three masked carboxyl functions of different levels of reactivities. A practical route to 17a,b is described in Scheme 3. Starting with furfural (18), 5-ethoxy2(5H)-furanone (19) was obtained by photochemical oxidation. Michael addition of malonate ion to 19 and subsequent hydrolytic decarboxylation of the adduct 20, so formed, resulted in dilactone 21. NMR spectra of the latter products attested to the sterochemistry assigned to them in Scheme 3. Compound 21 serves as a common intermediate for a

variety of lactones of different orders of functionality. Treatment of 21 with acid, in ethanol, resulted in the formation of 8a, which has been mentioned earlier. Basic hydrolysis (KOH/HzO), on the other hand gave the di-potassium salt of formylmalonic acid (22). Reduction of the latter with sodiumborohydride yielded 23, which, without isolation was directly cyclized to 8b by acidification. The sequence 8b~8c~8d, provided the tertiary amide, required for further functionalization. An ester group was introduced at the 3-position of 8d, by reaction with dimethyl carbonate/sodium methoxide. While the reaction mixture contained both isomers 17a and 17b, one isomer constituted the predominant product. In view of the known stability of trans-2,3-disubstituted y-Iactones,98-c structure 17a is assigned to the major product. Besides 17a,b, a small amount of 24 was isolated from the reaction mixture. The formation of 24 can be rationalized by considering the deprotonation of 8d in the direction of anion 25, which, via two acylation steps (with excess dimethyl carbonate) results in the malonate derivative 26. Base-catalyzed fragmentation of 26, according to the mechanism shown in Scheme 3, gives the amide 24. With the desired (rings DE) synthon 17a in hand, the approach to pentacyclic system 5, outlined in Scheme 1, was undertaken. Reaction of 2 with 17a, in benzene, was found to be critically dependent upon the amount of the solvent which was employed. When the two reactants were dissolved in a minimum quantity of benzene and stirred at room temperature for three days, the hydroxy amide 27 crystallized out in 58% yield, as a pure product. From the filtrate a second (single) product could be isolated to which structure 28 (Scheme 4) has been

A facile two synthon approach to the camptothecin skeleton

-

323

~ -

lI~H

H-tJ

OEt

~

19

0

~

-

~3 0 ~X R .§.Q. 8e

R =X= OEt R =H ,X =OH R =H • X =CI

8d

R=H ,X= { )

80

M-

+

0

)(

-C-CH(COOMe)2

.H.

-

-

Scheme 3

assigned on the basis of the considerations to be discussed further. This lactone is presumably formed via an intramolecular loss of methanol from 27, rather than by direct aminolysis of the ester function in 17a, by amine 2, since the lactone function is much more reactive in such a bimolecular process. Analogous reactions of malonate lactones have been described in the literature. 1o It has not been possible to elucidate the sterochemistry of 27 and 28 from NMR spectral data, owing to their complexity. The lactone is assigned the trans configuration in view of the earlier mentioned thermodynamic stability factor. The hydroxy amide can, in principle, be represented by two diastereomeric structures, 27A and 27B, which are written as thermodynamically favoured rotamers. It is obvious that in addition to the aforementioned stability of the trans-2,3-disubstituted butyrolactone system, the transition state leading to lactonization will be energetically favoured for rotamer 27A. While the possibility that the ultimately iso-

lated trans-lactone 28 is formed from the corresponding cis-isomer by epimerization, cannot be excluded, it appears more likely that 28 arises by cyclization of 27A. As a corollary, the hydroxy amide obtained in the reaction can be assigned the diastereomeric structure 27B. This points to an epimerization of 17a during the reaction or to epimerization of 27A -+ 27b. For the synthetic scheme itself, the relative sterochemistry of the ester function is not of consequence since the chirality of the a -carbon in 27 is lost in the further stages of the synthesis. In connection with the sensitivity of the course of the reaction, to reactionconditions, it is pertinent to record that when 2 is allowed to react with 17a in large amounts of the solvent (benzene), only 28 could be isolated as a crystalline product. The hydroxy amide 27 is however a perfectly stable compound, which can be kept for months without any transformation into 28. To construct ring D intermediate 27, the OR

27A R = CHpH 29A R = CHO Scheme 4

278 R=CH20H 29B R=CHO

H. G. M. WALRAVEN and U. K. PANDIT

324

-

-

+

-

~~-{c ~'OH

N

N

32

0

Scheme 5

group was oxidized with Cr0 3 /pyridine to yield the aldehyde 29 (72%, Scheme 5). Heating of 29 with potassium acetate and acetic acid resulted in the formation of two cyclized products 30 and 31 in a total yield of 70%. The structural relationship between the two last mentioned products could be established by conversion of 30 into 31 by oxidation with DDQ. Like the hydroxy amide 27, the formyl amide 29 can also exist as two diastereomers, 29A and 29B (Scheme 4), and for analogous steric reasons, the cryclization of diastereomer 29A will be a favoured process. Since the starting hydroxy amide has been assigned the 27B stereochemistry, it would follow that an epimerization of the ester function must precede the cyclization step. Unfortunately, NMR signals of the C7 and Cs protons in 30 fall together, thus making an independent assignment of their relative sterochemistry impossible. For further elaboration of the skeleton, the ester function in 31 was reduced by lithium borohydride to give the corresponding alcohol 32, which, without purification, was treated with concentrated hydrochloric acid to give the deethyldesoxycamptothecin 5. Since the conversion of 5 to 1 has been reported in the literature, its preparation, as described, represents the formal total synthesis of camptothecin via two synthons. One of the synthons, namely the tricyclic system, can be modified to give suitably modified camptothecin analogues. EXPERIMENTAL All m.ps and b.ps are uncorrected. IR spectra were recorded on a Unicam SP 200 or a Perkin Elmer 257 spectrometer. The absorptions are given in cm- I . PMR spectra were run on Varian Associates Model A-60, A-60D, HA-I00 and XL-IOO instruments. The chemical shifts (8) are given in ppm, using TMS as an internal standard. For the resonance signals the following abbrevations are used s = singlet, d = doublet, t = triplet, q = quartet and m = multiplet. Spin-spin coupling constants (J) are given in ertz. UV spectra were recorded on a Cary-14 spectrophotometer. The maxima are given in nm and the corresponding molar extinction coefficients are placed between brackets.

Mass spectra were obtained with a Varian Mat-711 spectrometer. Analyses were carried out by Mr H. Pieters of the Microanalytical Department of this laboratory. When necessary, the reactions were carried out with dry reagents under a nitrogen atmosphere. 2,3-Dihydro-lJj-py"olo[3,4-b]quinoline (2). 5 Owing to its instability, this compound was stored as its dihydrobromide. s Prior to use, the latter was readily converted into the free base: the dihydrobromide (0.5 g) was stirred at room temp under a N z in a mixture of triethylamine (5ml) and water (0.5 m!) during 45 min. After the addition of excess water the mixture was extracted with CHzCl z. The organic layer was dried (MgS04), the solvent was evaporated and 2 was obtained as a solid. This material was used without further purification. 2,3- Dihydro -2-(4- hydroxybutyryl)-IJj- py"olo[3,4-b] quinoline (7). According to the procedure described, 2dihydrobromide (0.5 g) was converted into 2. This compound was dissolved in y-butyrolactone and the soln was stirred at room temp for 72 hr. The resulting crystalline material was filtered off and was washed with EtOAc and ether to give 7 (0.3 g, 78%), m.p. 187-189°, dec; IR(KBr): 3380, 3230 (OH), 1630 (C = 0, amide), 1600, 1570, 1500 (arom.); PMR (DMSO-d6): 1.77 (m, 2H, C3 , -Hz), 2.45 (m, 2H, C z, -Hz), 3.00 (m, 2H, C 4, -Hz), 4.51 (t, IH, OH), 4.91 and 4.96 (4S, 4H, C1-Hz, C 3Hz), 7.45-8.30 (m, 5H, aromatic protons). (Found:C, 70.16; H, 6.48; N, 10.93; 0, 12.58. Calc. for CIsHI6NzOz: C, 70.29; H, 6.29; N, 10.93; 0, 12.49%). Ethyl {3-formyl-2,3-dihydro-6-oxo-lJj-py"olo[3,4-b] quinoline-2-vaierate (9). Amine 2, prepared from its dihydrobromide (0.58) was dissolved in 8a (1.2 g) and the soln was stirred for 168 hr at room temp. The mixture was chromatographed on silica gel. Elution with EtOAc yielded a solid (185 mg. 36%) which was recrystallized from the same solvent, m.p. 128.5-131.5°; Ir(KBr): 1725 (C = 0, ester and aldehyde), 1625 (C = 0, amide); PMR(CDCI 3 : 1.27 (t, 3H, CH3 ), 2.80 (m, 4H, C,,-Hz, C.,,-Hz), 3.34 (m, IH, CIl-H), 4.17 (q, 2H, CHz), 4.98 (m, 4H, CI-Hz, C3 -Hz), 7.40-8.15 (m, 5H, aromatic protons), 9.87 (s, IH, CHO). (Found: C, 67.10; H, 5.87; N, 8.19. Calc. for C19HzoNz04; c, 67.04; H, 5.92 N, 8.23; 0,18.80%). 3-Acetoxyphthalide (10). Phthalaldehydic acid (1.00 g) was stirred in AczO in the presence of pyridine for 72 hr. The excess AczO was evaporated and the residue was chromatographed on silica gel. Elution with EtOAc gave the product (730 mg, 56%), m.p. 63-63,50; IR(KBr): 1785 (C = 0, lactone), 1765 (C = 0, ester); PMR

A facile two synthon approach to the camptothecin skeleton (CDCI 3): 2.15 (s, 3H, CH3), 7.40 (s, IH, C 3-H), 7.458.00 (m, 4H, aromatic protons). (Found: C, 62.54; H, 4.23; 0, 33.18 Calc. for C IOH g0 4: C, 62.50; H, 4.20; 0, 33.30%). 2-(2(Formylbenzoyl)-2,3-dihydro -1t1- pyrrolo[3,4-b] quinoline (11). Amine 2 liberated from its dihydrobromide (0.5 g) was dissolved in toluene (50 ml) and the pseudo-anhydride 10 (300 mg) and KOAc (155 mg) was added. This mixture was stirred at 80° for 1 hr. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel. Elution with EtOAc yielded 11 (190 mg, 41%) as crystalline material, m.p. 161-163°, dec.; IR(KBr): 1680 (C= 0, aldehyde); 1630 (C = 0, amide); PMR(CDCI 3): 4.65 and 5.23 (m and s, together 4H, C1-H z, C 3-H z), 7.30-8.20 (m, 9H, aromatic protons), 10.11 and 10.13 (2s, together IH, CHO). (Found: C, 75.37; H, 4.81; N, 9.24 Calc. for C19H14NzOz: C, 75.48; H, 4.67; N, 9.27; 0, 10.58%). 2-(3-Form ylbutyryl)-2,3-dihydro-lt1-pyrrolo [3,4-b] quinoline (12). To a mixture of dry pyridine (1.10 g) and CHzCl z (20 ml), Cr03 (700 mg) was added over H. after stirring for 15 min at room temp, a soln of 7 (500 mg) in CHzCl z was added. After stirring for another 15 min the ppt was filtered off and thoroughly extracted with EtOAc. The combined organic layers were dried (MgS04) and after evaporation of the solvent the residue was chromatographed on silica gel. Elution with EtOAcgave 12 (297 mg, 61%). m.p. 153-155°, dec.; IR(KBr): 1705 (C = 0, aldehyde), 1620 (C = 0, amide); PMR(CDCI 3): 2.75 and 2.95 (m, 4H, Cz, -Hz, C 3, -Hz 4.95 and 5.00 (s, 4H, C1-H z, C 3 -H z), 7.3-8.2 (m, 5H, aromatic protons), 9.89 (s, IH, CHO). (Found: C, 70.71; H, 5.62; N, 11.01. Calc. for ClsH14NzOz: C, 70.85; H, 5.55; N, 11.020,12.58%). 7,11- Dihydroindolizino[1,2-b]quinolin-9(8J:j)-one (13). A mixture of 12 (92 mg) and KOAc (5 mg) was refluxed in glacial AcOH (10 ml) for 2 hr. After evaporation of the acid the residue was chromatographed on silica gel. Elution with EtOAc yielded the product (25 mg, 30%). IR(KBr): 1650 (C = 0, amide), 1620 (C = C); PMR(CDCI 3): 2.15 (m, 4H, Cor-Hz, Cg-H z), 4.40 (s, 2H, C l1-H z), 6.17 (m, IH, C 6-H), 7.40-8.15 (m, 5H, aromatic protons). Ethyl 7,8,9,11- Tetrahydro-9-oxoindolizino[I,2-b ]quinolin-7-yl-acetate (14) and ethyl 9,11-dihydro-9oxoindolizino[I,2- b]quinolin-7-yl-acetate (15). A mixture of 9 (270 mg) and KOAc (80 mg) was refluxed in glacial AcOH (12 ml) for 2 hr. Evaporation of the solvent gave a residue which was chromatographed on silica gel. Elution with EtOH/EtOAc (1: 10) gave a fraction from which 14 could not be isolated as pure compound. However, its presence could be concluded from the PMR spectrum of the mixture 8 (CDC1 3): 6.18 (C6-H). From a later fraction 15 (59 mg, 23%) could be isolated, m.p. 215-21 r; IR(KBr): 1720 (C = 0, ester), 1655 (C = 0, pyridone), 1590 (C = C, pyridone); PMR (CDCI 3): 1.13 (t, 3H, CH 3), 3.49 (broad s, 2H, C",-H z ), 4.07 (q, 2H, CH z ), 5.04 (s, 2H, C l1 -Hz ), 6.42 and 7.10 (s, 2H, C6-H, Cg-H), 7.45-8.20 (m, 5H, aromatic protons); UV(CzHsOH): 365 (14400), 286 (4750), 253 (25300), 246 (4070, shoulder), 219 (32400); MS: m/e = 191 (13%), 217 (11), 218 (31), 219 (52), 220 (17), 247 (96), 248 (45), 292 (21), 320 (100)M+ 321 (22). Benz[6,7]indolizino[I,2- b ]chinolin-ll(13J:j)-one (16). A mixture of 11 (120 mg) and KOAc (1 equiv.) was stirred in glacial AcOH at 60° for 1 hr. Evaporation of the solvent gave a residue that was purified on silica gel. Elution with EtOAc yielded 16 (87 mg, 76%), m.p. 286°, dec; this material sublimes just below its m.p.; IR(KBr): 1660 (C = 0, pyridone), 1630 (C = C, pyridone), UV (CzHsOH): 378, 365, 282, 252, 220 (qualitative); MS: m/e = 114 (11 %), 128 (16), 227 (11), 225 (33), 283 (74), 284 (100)M+, 285 (21). (Found: C, 80.08; H, 4.41; N,

325

7.7. Calc. for C 19H 12N zO: C, 80.26; H, 4.25; N, 9.85; 0, 5.63%). 5-Ethoxy-2 (5tI)-furanon (19).0 In abs EtOH (1500 ml) and in the presence of eosin (1.5 g) freshly distilled furfural (50.0 g) was irradiated with the light of a 300 W lamp, while 0z was bubbled through the soln. After 33 hr another portion of eosin (1.5 g) was added. The reaction was followed with IR spectroscopy. The irradiation was ended after the disappearence of the aldehyde absorption. The solvent was evaporated in vacuo and the residue was distilled under reduced pressure to give 19 (35.29 g, 53%) as an oil, b.p. 90-96° (10 mm); 95° (12 mm)l1; IR(CHCI 3): 1790, 1760 (C = 0, lactone) PMR(CDCI 3): 1.30 (t, 3H, CH 3), 3.85 (m, 2H, CH z), 5.94 (t, J = 1, IH, Cs-H), 6.23 (2d, J 3.4 = 6, J 3,s = 1, IH, C 3-H), 7.23 (2d, J 3,4 = 6, J 4,5 = 1, IH, C4-H). trans Diethyl 2- Ethoxytetrahydro -5-oxo- 3- furanylmalonate (20). A NaH-dispersion in mineral oil (230 mg) was washed with petroleum ether 40-60° to give NaH (140 mg). Diethyl malonate (9.37 g) was added dropwise to this NaH. After cooling the mixture to 5°, the pseudoester 19 (7.5 g) was added, keeping the temp below 20°. To neutralize the mixture, glacial AcOH was added slowly. The mixture was divided between a water-ether system, The aqueous layer was saturated with NaCI and thoroughly extracted with ether. The combined ether layers were washed with a sat NaHC03 aq and dried (MgS04). After evaporation of the solvent, the residue was distilled under reduced pressure to yield 23 (10.7 g, 64%) as an oil, b.p. 160-170° (2 mm); IR(CHCI 3): 1790, 1740 (C = 0, lactone), 1730 (C = 0, ester); PMR(CDCI 3): 1.22 (t, 3H, CH 3), 1.27 (t, 6H, CH 3), 2.40 (2d, J 4.4 = 20, J4,3 = 9, IH, C4-H), 2.80 (2d, J 4,4 = 20, J 4,3 = 12, IH, C4-H), 2.95 (m. lH, C 3-H), 3.53 (d, J=7, IH, C",H), 3.80 (q, 2H, CH z), 4.22 (q, 4H, CH z ), 5.44 (d, JZ •3 = 2, IH, C z - H). (Found: C, 53.23; H, 7.02. Calc. for ClgHzo07: C, 54.16; H, 6.99; 38.85%). cis Dihydrofuro[2,3-b ]furan-2,5(3t1, 4t1)-dione (21). A mixture of 30% HBr in glacial AcOH (400 ml), in water (25 ml), and 23 (93.4 g) was refluxed for 72 hr. After evaporation of the solvent under reduced pressure the residue was crystallized with ether. The crystalline mass was filtered off and the filtrate was hydrolysed once again. The combined crystalline material was discoloured with active carbon in EtOAc and recrystallized from this solvent to give 21 (31.3 g, 68%), m.p. 140-145°; IR(KBr): 1780 (C = 0, lactone), PMR(CF3COzH): 2..75 (2d, J 3,3(4,4) = 19, J 3(4),3a = 5, 2H, C 3-H, C 4-H), 3.17 (2d, J 3,3(4,4) = 19, J 3,(4),3a = 9.5, 2H, C 3-H), 3,67 (m, IH, C 3a-H), 6.52 (d, J 6a 3a = 6, IH, C 6a-H). (Found: C, 50.72; H, 4.17; 0, 44.86%. Calc. for C 16H 60 4: C, 50.71; H, 4,26; 0, 45.04%). Ethyl 2-ethoxytetrahydro-5-oxo-3-furanyl acetate (8a). In EtOAc (40 ml), 21 (1.42 g), EtOH (1.0 g) and a catalytic quantity of p-TsOH.HzO were stirred for 18 hr. After the addition of some EtOH the mixture was stirred for another 72 hr, whereupon the solid material dissolved, The mixture was extracted with a sat NaHC0 3 aq and with water. The organic layer was dried (MgS04) and evaporation of the EtOAc gave a colourless oil that consisted of a mixture of the cis- and trans isomers 8a (1.38 g, 64%), IR(CHC1 3); 1770 (C=O, lactone), 1720 (C = 0, ester); PMR(CDCI3): 1.20 (m, 6H, CH3), 2.2-3,0 (m, 5H, C 3-H, C 4 -H z , C",-H z ), 3.70 (m, 2H, CH z ), 4,15 (2q, 2H, CH z ), 5,27 (d, JZ,3 = 1.5, 0.5 H, Cz-H, trans isomer), 5.54 (d, Jz 3= 5, 0.5 H, Cz-H, cis isomer). (Found: C, 55.48; H, 7.36; 0, 37.11. Calc. for CIOH1 60 S : C, 55.54; H, 7.46; 0, 37.00%). Tetrahydro-5-oxo-3-furanyl acetic acid (8b). The bilactone 21 (1.42 g) was heated in IN KOH (300 ml) till the solid was dissolved. The mixture was cooled and NaBH4 (9.2 g) was added carefully in small portions over a period of 10 min. The mixture was refluxed for 4 hr, After

326

H. G. M. WALRAVEN and U. K. PANDIT

cooling the mixture was acidified with conc HCl to pH = 1. The aqueous layer was saturated with NaCl and extracted with EtOAc. Evaporation of the solvent yielded crude material (15 g) that was recrystallized from EtOAc to give 8b (13.9 g, 96%), m.p. 86-88°; IR(CHCI 3): 25003500 (OH, acid), 1770 (C = 0, lactone) 1705 (C = 0, acid; PMR(CD 30D): 2.0-2.8 (m, 4H, C4-H z, C",-H z), 2.95 (m, IH, C 3-H), 4.06 (2d, J z z = 9.5, J z 3= 6, IH, Cz-H), 4.57 (2d, Jz,z=9.5, J Z,3·=7.5 IH: Cz-H). (Found: C, 50,07; H, 5.64; 0, 44.35. Calc. for C6 H g0 4: C, 50.00; H, 5.60; 0, 44.41%). 1-[Tetrahydro-510xo-3-furanylacetyl]pyrrolidine (8d). The acid 8b (13.91 g) was dissolved in freshly distilled SOCl z (47 ml). After addition of DMF (0.5 ml) the mixture was stirred at room temp for 2 hr. Finally, the mixture was refluxed for 5 min. The excess of SOCl z was evaporated under reduced pressure. Benzene (250 ml) was added to 8c and pyrrolidine (17.1 ml) was added dropwise. After a reaction time of 30 min the mixture was diluted with EtOAc, washed with dil HCI and water and dried (MgS04). After evaporation of the solvents the crude material was chromatographed on a silicia gel column, Elution with acetone gave an impure product (13.40 g). This was chromatographed once again. Elution with EtOAc yielded colourless crystalline product 8d (11.82 g, 62%). m.p. 97-100°; IR(CHCI 3): 1760 (C=O, lactone), 1620 (C = 0, amide); PMR(CDCI 3): 1.95 (m, 4H, C 3-Hz), 2.25 (2d, J 4. 4' = 17, J 4, 3' = 8, IH, C4~H), 2.50 (m, 2H, CHzCON), 2.75 (2d, J4'~' = 17, J4'3'= 7, IH, C4~H), 3.10 (m, IH, C3~H), 3.43 (m, 4H, Cz-H z, Cs-H z), 4.04 (2d, J z'z.=9.5, JZ'3,=5.5, IH, Cz~H), 4.58 (2d, J z'z,9.5, J2'3:=7, IH, Cz~H); MS: mle=32 (13%),39 (12),41 (22),43 (47), 55 (27), 56 (13), 70 (49), 71 (27), 83 (11), 85 (34), 98 (16), 113 (100), 197 (9) M+. (Found: C, 60.81; H, 7.57; N, 6.97. Calc. for C lO H 1S N0 3: C, 60.89; H, 7.67; N, 7.10; 0, 24.34%). trans and cis Methyl tetrahydro-2-oxo-4-[2-oxo-2-(1pyrrolidinyl)ethyl]-3-furancarboxylate (17.) and (17b) and diethyl(l-pyrrolidinylcarbonyl)malonate (24). A NaHdispersion in mineral oil (6.3 g) was washed with petroleum ether 40-60° to give NaH (3.78 g). To this dimethyl carbonate (130 ml), 8d (5.91 g) and MeOH (100 m!) were added to the mixture was refluxed for 5 hr, during which a voluminous ppt was formed. After cooling to room temp glacial AcOH was added slowly with stirring. After the addition of water the aqueous layer was extracted with EtOAc and CHCl 3. The combined organic layers were dried (MgS04) and concentrated in vacuo. The residue was chromatographed on a silica gel column. Elution with EtOAc afforded the isomers 17. and 17b as a mixture. Recrystallization from EtOAc gave the transisomer 17. (5,63 g, 73%), m.p. 106-108,50; IR(KBr): 1760 (C = 0, lactone), 1730 (C = 0, ester), 1630 (C = 0, amide), 1155, 1010; PMR(CDCI 3): 1.90 (M, 4H, CH zCHz-N), 2.55 (m, 2H, Cl~Hz), 3.40 (m, 6H, CHzN, C 3-H, C4-H), 3.80 (s, 3H, CH 3), 4.06 (m, IH, Cs-H), 4.74 (m, IH, Cs-H); PMR(C 6 D 6 ): 1.45 (m, 4H, CH zCHz-N), 2,06 (m, 2H, Cl~Hz), 2.76 (m, 2H, CHz-N), 3.33 (m, 4H, CHz-N, C 3-H, C 4-H), 3,60 (s, 3H, CH 3), 3.80 (m, IH, Cs-H), 4.60 (M, IH, Cs-H; MS = mle = 43/37%), 55 (26), 56 (13), 70 (56), 71 (24), 83 (12),85 (27), 98 (20), 113 (100), 224 (10), 255 (13) M+. (Found: C, 56.56; H, 6.60; N, 5.52. Calc. for C 12H 17 NOs: C, 56.46; H, 6.71; N, 5.49; 0, 31.34%). Besides 17. a small quantity of the cis-isomer 17b was obtained, m.p. 101-102,50; IR(KBr): 1770 (C=O, lactone), 1730 (C = 0, ester), 1625 (C = 0, amide), 1145, 1060, 1030. (Found: C, 56.56; H, 6.64; N, 5.42; 0, 31.44. Calc. for C 12H1 7 NO s : C, 56.46; H, 6.71; N, 5.49; 0, 31.34%). From the mixture compound 37 (550 mg, 8%) could be isolated by chromatography, m,p. 83-84°. IR(KBr): 1740, 1735 (C = 0, ester), 1635 (C = 0, amide); PMR (CDCI 3): 1.90 (m, 4H, C3~Hz' C4~Hz), 3.40 (m, 4H, Cz~Hz,

Cs~Hz), 3.79 (s, 6H, CH 3), 4.52 (s, IH, Cz-H). (Found: 52.37; H, 6.53; 0, 34.91. Calc. for ClOH1SNO s : C, 52.39; H, 6.60; 0, 34.90%). Methyl 2,3- Dihydro-a -[ 1-(hydroxymethyl)-3-oxo-3-( 1pyrrolidinyl)propyl]-13 - oxo -IB- pyrrolo[3,4- b ]quinoline- 2propionate (27). The diamine 2 obtained from dihydrobromide (0.5 g) was dissolved in benzene and some insoluble material was filtered off. To the filtratc-containing the amine (218 mg)-the lactone 17. (384 mg) was added. Then, a quantity of benzene was distilled off, which allowed the starting materials to remain in the soln. The viscous residue was-under Nz-stirred at room temp for 72 hr. The crystalline mass was filtered off and washed with EtOAc and ether to give 27 (316 mg, 58%), m.p. 175-177°, dec; IR(KBr): 3400 (OH) 1730 (ester), 1635) (C = 0, amide); PMR(CDCI 3): 1.90 (m, 4H, CB zCHz-N), 2.50-3.20 (m, 3H, Cl~H, Cz,-H z), 3.45 (t, CHz-N), 3,30-3.80 (CBz-OH) and 3.71 (s, CH 3) together 9H, 4.20-4.70 (OH) and 4,30 (m, C",-H) together 2H, 4.92-5.20 (s, 2H, and m, 2H, C1-Hz, C 3-H z), 7,30-8,20 (m, 5H, aromatic protons); MS: mle = 32 (11%),78 (11), 115 (16), 140 (13), 142 (15), 168 (16), 169 (100),170 (43), (Found: C, 65.13; H, 6,36; N, 9.75; 0, 18.72. Calc. for C 23 H 27 N 30 S: C, 64,92; H, 6.40; N, 9,98; 0, 18,80%). 2,3- Dihydro- 2- tetrah ydro -2-oxo -4-[2-oxo - 2-( 1- pyrrolidinyl )ethyl]-3- furanylcarbonyl]-IB - pyrrolo[3,4- b ]quinoline (28), The filtrate obtained after removal of 27 was concentrated in vacuo and the residue was chromatographed on a silica gel column. Elution with EtOAc/EtOH (5: 1) gave 28 (60 mg, 12%) as a foam, IR(KBr): 1760 (C = 0, lactone), 1630 (C = 0, amide): PMR(CDCl 3): 1.90 (m, 4H, CBz-CHz-N), 2,55 (broad d, J = 7, 2H, CHzCON), 3.40 (m, 4H, CHzN), 3.50-4,20 (m, 3H, C3~H, C4~H, C5~H), 4,60-5.40 (m, 5H, Cs~H, C1-H z, C3-H z), 7.40-8.20 (m, 5H, aromatic proton); MS = mle = 41 (12%), 43 (11), 44 (29), 55 (15), 70 (13), 98 (12), 113 (16), 168 (19), 169 (100), 170 (45), 224 (10), 393 (23)M+. Oxidation of 27 to 29, To a mixture of dry pyridine (2.52 g) and CHzCl z (48 ml), Cr0 3 (166 g), dried over PzOs was added. After stirring for 15 min at room temp, a soln of 27 (1.18 g) in CHzCl z was added, After stirring for another 15 min the ppt was filtered off and thoroughly extracted with EtOAc and CHzCl z, The combined organic layers were concentrated and the residue was chromatographed on a silica gel column. Elution with MeOH/EtOAc (1 :5) gave 29 (848 mg, 72%). IR(CHCI 3): 1750 (C = 0, ester), 1730 (C = 0, aldehyde), 1660, 1640 (C=O, amide); PMR(CDCl 3): 1.95 (m, 4H, CB zCHz-N), 2,50-3,20 (4m, 2H, Cz~Hz), 3.47 (m, 5H, CHzN, Cl~H), 3.81 (s, 3H, CH 3), 4.45-4.70 (m, IH, C",-H), 4,97-5,35 (m, 4H, C1-H z, C 3-Hz), 7.40-8.20 (m, 5H, aromatic protons), 9.90 (m, IH, CHO); MS: 43 (100%), 44 (16), 56 (13), 58 (15), 59 (70), 70 (14), 71 (10), 85 (45), 123 (15), 166 (14), 168 (15), 169 (50), 170 (18), 182 (11), 183 (31), 184 (43), 222 (13), 238 (10), 254 (11), 270 (12), 423 (16)M+, Methyl 7,8,9,II-tetrahydro-9-oxo-7-[2-oxo-(I-pyrrolodin yl)eth yl]- indolizino[ 1,2-b ]quinoline -8-carboxylate (30) and methyl 9,11-dihydro-9-oxo-7 -[2-oxo-2-pyrrolindinyl) ethyl]indolizino[I,2-b]quinolino-8-carboxylate (31), In glacial AcOH (20 ml) a mixture of KOAc (150 mg) and 29 (614 mg) was refluxed for 2 hr. After cooling of the mixture, the AcOH was distilled off in vacuo and the residue was chromatographed on a silica gel column. Elution with EtOAc/MeOH (5: 1) gave two products 30 and 31. The dihydropyridone 30 (320 mg, 58%), IR(KBr): 1725 (C = 0, ester), 1670 C = 0, lactam), 1630 (C = 0, amide; PMR(CDCI 3): 1.90 (m, 4H, CB zCHzN); 2.51 (d, 2H, Cl~Hz), 3.45 (m, 4H, CHzN), 3.60-4,20 and 3,75 (m and s, 5H, C7-H, Cg-H, CH 3), 5,04 (s, 2H, Cn-Hz), 6.33 (d, J = 4,5, IH, C 6 - H),

A facile two synthon approach to the camptothecin skeleton 7.40-8.20 (m, 5H, aromatic protons; UV(CzHsOH): 360 (4050), 320 (5500), 321 (4300), 307 (4950), 300 (5100), 293 (5300), 233 (33400); MS: m/e = 39 (2%), 41 (21),42 (15),43 (100), 44 (37), 55 (13), 70 (78), 85 (16), 113 (48), 151 (10), 177 (11), 203 (13), 204 (24), 205 (40), 206 (13), 234 (49), 235 (12), 261 (34), 292 (31), 346 (2) and pyridone 31 (142 mg, 25%), m.p. 240-245°, dec.; IR(KBr): 1700 (C = 0, ester), 1650 (C = 0, pyridone), 1630 (C = 0, amide), 1600 (C = C, pyridone); PMR(CDCL 3): 1.95 (m, 4H, CtIz-CHz-N), 3.51 (m, 4H, CHz-N), 3.79 (s, 2H, C 1,-Hz), 3.94 (s, 3H, CH 3), 5.10 (s, 2H, C l1 -H z), 7.25 (m, IH, C 6-H), 7.45-8.30 (m, 5H, aromatic protons); UV(CzHsOH): 372 (18300), 289 (5270), 256 (256 (26700), 215 (38600); MS: m/e = 40 (14%), 43 (17),44 (100), 55 (50), 56 (16), 70 (19), 98 (19),217 (14), 218 (15),219 (11), 248 (16), 274 (74),275 (21),301 (39),306 (72), 307 (14), 344 (14), 403 (13)M+. (Found: C, 68.40; H, 5.40; N, 10.36. Calc. for C 23 H z1 N,04: C, 68.47; H, 5.29; N, 10.42; 0, 15.86%). IH-Pyrano[3',4': 6,7]indolizino[I,2-b]chinoline-3,14(4tI,12B)-dione (deethyldeoxycamptothecine) 5. The ester 31 (162 mg) was dissolved in dimethoxyethane and LiBH 4 (70 mg) was added. The mixture was stirred at room temp for 18 hr. Then glacial AcOH (2 ml) and water (5 ml) were added and the stirring was continued for 1 hr. After evaporation of the solvents the residue was refiuxed for 30 min in conc HCL. After evaporation of the solvent the residue was chromatographied on silica gel. Elution with EtOAc and EtOAc/MeOH (4: 1) gave 5 (12 mg, 10%) as pale yellow crystals. Its solubility in most organic solvents is very low, m.p. > 250°; dec; 256-259°, dec. 7a ; >275°, dec. l1 ; 270°, dec. 1z ; 250°, dec. 13 ; > 300°14; IR(KBr): 1730 (C = 0, lactone); 1650 (C = 0, pyridone), 1590 (C = C, pyridone); 1745, 1660, 1605 7a ; 1740, 1660, 1610, 1565 1z ; 1747, 1640 11 ; 1745, 1660, 1600 14 ; PMR(DMSO-d 6) multi scan averaging; 3.85 (s, C4-H z), 5.27 and 5.34 (s, C 1-H z, C 12-H z), 7.25 (s, Cs-H), 7.50-8.50 (m, C7-C lO-H), 8.68 (s, C l1 -H), UV(CzHs-OH): 370-360, 288, 254 and 218, qualitative; 360-370 (20500-20100), 288 (6030), 254 (31400), 218 (42100); 367 (18200),290 (5900), 255 (27000), 220 (34000); MS m/e = 44/66%), 115 (11), 219 (13), 231 (21),232 (17), 247 (10),248 (93), 249 (17), 260 (22), 216 (11), 304 (100)M+, 305 (20). REFERENCES *To whom correspondence should be addressed. [Taken in part from the doctorate thesis of H. G. M. Walraven, University of Amsterdam (1978). ZaM. E. Wall, M. C. Wani, C. E. Cook, K. H. Palmer, A. T. McPhail and G. A. Sim, J. Arn. Chern. Soc. 88, 3888 (1966); bR. C. Gallo, J. Whang-Peng and R. H. Adam-

327

son, J. Nat. Cancer Inst. 46, 781 (1971); cJ. A. Gottlieb, A. M. Guarino, J. B. Call, V. T. Olivero and J. B. Block, Cancer Chernother. Rep. 54, 461 (1970). 3aA. G. Schultz, Chern. Rev. 73, 385 (1973); bM. Shamma and V. St. Georgier, J. Pharrn. Sci. 63, 163 (1974); cEo Winterfeldt, Recent Dev. Chem. Nat. Carbon Cornpounds 6, 9 (1975); dJ. E. Richmann, thesis, University of Rochester (1975). Diss. Abs., Int. B, 36, 243 (1975); cE. J. Corey, D. N. Crouse and J. E. Anderson, J. Org. Chern. 40, 2141 (1975); fJ. C. Bradley and G. Buechi, ibid. 41, 699 (1976); 5th Pharmaceutical Factory of Shanghai, 12th Pharmaceutical Factory of Shanghai, Institute for Pharmaceutical Industrial Research at Shanghai and Institute for Materia Medica at Shanghai. Sci. Sinica 21, 87 (1978); gH. G. M. Walraven and U.K. Pandit, Tetrahedron Letters 4507 (1975). 4C. G. Moertel, A. J. Schuit, R. J. Reitmeier and R. H. Hahn, Cancer Chernother. Rep. 56, 95 (1972). 5L. H. Zalkow, J. B. Nabors, K. French and S. C. Bisarya, J. Chern. Soc. (C), 3551 (1971). 6aRef. 1, pp. 77-89; bG. G. Schlessinger, Thesis p 35. University of Pennsylvania (1957); cS. L. Jung, J. G. Miller and A. R. Day, J. Am. Chern. Soc. 75, 4664 (1953); dR. A. Ferren, thesis, University of Pennsylvania (1956). 7A. I. Meyers, R. L. Nolen, E. W. Collington, T. A. Narwid and R. Strickland, J. Org. Chern. 38, 1974 (1973), aA. I. Meyers, R. L. Nolen, E. W. Collington, T. A. Narwid and R. Strickland, J. Org. Chem. 38,1974 (1973), bA. S. Kenke, T. J. Bentley, R. W. Draper, J. K. Jenkins, M. Joyeux and I. Kubo, Tetrahedron Letters 1307 (1973); cEo J. Corey, D. N. Crouse and J. E. Anderson, 1. Org. Chern. 40,2141 (1975), dJ. C. Bradley and G. Bucchi, Ibid. 41, 699 (1976). 8R. Volkmann, S. Danishefsky, J. Eggler and D. M. Solomon, J. Arn. Chem. Soc. 93, 5576 (1971). 9aS. A. M. Tayyab Hussain, W. D. Ollis, C. Smith and J. Fraser Stoddart, J. Chern. Soc. Perkin Trans. I, 1430 (1975); bJ. E. Batterbee, R. S. Burden, L. Crombie and D. A. Whithing, Ibid. (c) 2470 (1969); CF. M. Hauser and R. C. Huffmann, Tetrahedron Letters 905 (1974). lOp. L. Pacini and R. G. Ghirardelli, J. Org. Chern. 31, 4133 (1966). l1G. 0. Schenk, Liebigs Ann. 584, 156 (1953). 1ZT. Sugasawa, T. Toyoda and K. Sasakura. Tetrahedron Letters 5109 (1972). 13M. Boch, T. Kor, J. M. Nelke, D. Pike, H. Radunz and E. Winterfeldt, Chern. Ber. 105, 2126 (1972). 14M. Shamma, D. A. Smithers and V. St. Georgiev, Tetrahedron 29, 1949 (1973). ISShanghai Institute of Materia Medica et aI., Sci. Sinica 21, 87 (1978).