2170
J. Org. Chem. 1989,54, 2170-2178
DDQ Oxidations in the Indole Area. Synthesis of 4-Alkoxy-@-carbolines Including the Natural Products Crenatine and 1-Methoxycanthin-6-one' Timothy J. Hagen, Krishnaswamy Narayanan, Jeffrey Names, and James M. Cook* Department of Chemistry, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53201
Received S e p t e m b e r 20, 1988
The seven-stepsynthesis of the cytotoxic, antileukemic alkaloid 1-methoxycanthin-&one(2b) is described. The pivotal steps are represented by the oxidation (DDQ, aqueous THF, room temperature) of 1-(methoxycarbonyl)-1,2,3,4-tetrahydro-~-carboline (10) to provide the 4-oxo-substituted derivative 14 in 78% yield, and conversion of the 4-OXO analogue 7 into 4-methoxy-l-alkyl-@-carboline (23) via a methoxylation-oxidationprocess [CH,OH, (CH,O),CH, pTSA, A]. This four-step, one-pot reaction has been shown to be general; 4-OXO1,2,3,4-tetrahydro-P-carboline (18) was converted into the corresponding 4-methoxy-, 4-ethoxy-, 4-(allyloxy)-, and 4-(benzyloxy)-@-carbolines(19a-d, respectively) on heating in the appropriate alcohol in the presence of pTSA and a trialkyl orthoformate (Table 11). The proposed mechanism for this intriguing transformation is outlined in Scheme IV. Execution of this process has also resulted in a four-steppreparation of crenatine (la), a 4-methoxy-l-ethyl-@-carboline alkaloid. Finally, steric and electronic parameters have also been successfully manipulated to direct the DDQ oxidation of 1,2,3,4-tetrahydro-P-carbolines to position 1,regiospecifically. The conversion of tetrahydro-@-carboline25 into 2-acylindole38 and benzamide 26 into 1-oxotetrahydro-@-carboline 27 (Table I), respectively, is in agreement with the proposed mechanism for this process. In recent years increasing numbers of P-carboline alkaloids that contain an oxygen substituent at position 4 have been isolated.%bv38-s The 4-methoxy-P-carbolines la-hh* and canthin-6-ones 2b, 2 ~ , 3 e p (Scheme ~ 1 ~ ~ ~I), as well as several b i s i n d o l e ~serve ~ ~ ~as~ representative ~*~ examples. The diindole, 4- (4,8-dimethoxy-SH-pyrido[ 3,4-b]indol-lyl)-l-(9H-pyrido[3,4-b]indol-l-yl)-l-butanone, exhibits inhibitory activity against cyclic AMP while some members of the canthin-6-one series have been shown to possess antileukemic activity."g6 Canthin-6-one (%a),1-methoxycanthin-6-one (2b),and l-hydroxycanthin-6-one (2c) (Figure 1)were isolated from Ailanthus u l t i ~ s i m u , ~while ~ , ~ 2a, , ~ ~11-hydroxycanthin-6-one ,~ (2d), and l,ll-dimethoxycanthin-6-one (2e) were obtained from Brucea antidysenterica." In addition, 2a, 2b, and 2e have recently been isolated from Soulameu p ~ n c h e r i .The ~~ alkaloid 1-methoxycanthin-6-one (2b) and its congeners have been shown to exhibit cytotoxic activity via their inhibitory effects on DNA synthesis in GPK epithelial cell^.^^,^ Oxygenation of the canthin-6-one skeleton at positions C-1 (C-4 in the P-carboline numbering system) and C-11 greatly enhances the cytotoxic, antileukemic activity of these alkaloids."i6 A versatile approach for the synthesis of 1-oxygen-substituted canthin-6-one alkaloids should provide facile entry into more potent antitumor agents of this class for biological evaluation. In this regard, a general method for the synthesis of 4-alkoxy-P-carbolines from 4-oxo-1,2,3,4-tetrahydro-~-carbolines has been de(1)A portion of this work was presented in preliminary form. Hagen, T. J.; Cook, J. M. Tetrahedron Lett. 1988,29,2421. (2)(a) For a list of structures of these alkaloids, see: Hagen, T. J., Ph.D. Thesis, University of Wisconsin-Milwaukee, WI, 1988;pp 164. (b) Sung, Y.-i.; Koike, K.; Nikaido, T.; Ohmoto, T.; Sankawa, U. Chem. Pharm. Bull. 1984,32,1872. (3)(a) Ohmoto, T.; Tankaka, R.; Nikado, T. Chem. Pharm. Bull. 1976, 24,1532. (b) Ohmoto, T.; Koike, K.; Sakamoto, Y. Chem. Pharm. Bull. 1981,29,390.(c) Ohmoto, T.; Koike, K. Chem. Pharm. Bull. 1983,31, 3198. (d) Ohmoto, T.; Koike, K. Chem. Pharm. Bull. 1984,32,3579.(e) Ohmoto, T.; Koike, K. Chem. Pharm. Bull. 1986.34, 2090. (4)(a) Awad, A. T.; Beal, J. L.; Talapatra, S. K.; Cave, M. P. J. Pharm. Sci. 1976,56,279.(b)Kahn, S.A.; Shamuasuddin, K. M. Phytochemistry 1986,20,2062.(c) Fukamiya, N.; Okano, M.; Aratani, T. J. Nat. Prod. 1986, 49, 428. (d) Viola, B. Thesis, Universite de Paris-Sud Centre d'Orsay, France, 1971. ( 5 ) Ohmoto, T.; Koike, K. Chem. Pharm. Bull. 1982,30,1204. (6)Anderson, L.A.; Harris, A.; Phillipson, J. D. J. Nat. Prod. 1983, 46,374.
Scheme I 0
Hu 8 , R = OCH,
6
7
veloped, which has resulted in an improved synthesis of crenatine (la)798and the first synthesis of l-methoxycanthin-6-one (2b).l Relatively few methods for the incorporation of oxygen functionality into position 4 of P-carbolines are available. Deceptively simple syntheses of 4-oxygenated P-carbolines would stem from a Pi~tet-Spengler~ or Bischler-Napieralski reaction of the corresponding substituted 3-acyltryptamine; however, both reactions take a different course2a (see also ref 1, 10, and 11 for details). Several methods, however, do exist that can be employed to prepare 4-oxo-1,2,3,4-tetrahydro-~-carbolines, and they are listed here: oxidation of 1,2,3,4-tetrahydro-P-carbolines with dichlorodicyanobenzoquinone (DDQ)7*12,13 or selenium dioxide (Se02),14J5as well as the intramolecular acylation of an appropriately substituted (position 2) i n d ~ l e . ~ J ~ J ~ DDQ is known to form a blue-colored charge-transfer complex (Bergman et al.)lS with the 2,3-double bond of (7)Cain, M.; Mantei, R.; Cook, J. M. J. Org. Chem. 1982,47,4933. Campus, 0.; DiPerro, M.; Cain, M.; Mantei, R.; Gawish, A.; Cook, J. M. Heterocycles 1980,14,975. (8)Murakami, Y.; Yokoyama, Y.; Aoke, C.; Miyagi, C.; Watanabe, T.; Ohmoto, T. Heterocycles 1987,26,875. (9)Ungemach, F.; Cook, J. M. Heterocycles 1978,9,1089. (10)Joshi, B. S.;Taylor, W. I.; Bhate, D. S. Tetrahedron 1963, 19, 1437. Oikawa, Y.; Yoshioka, J.; Mohri, K.; Yonemitsu, 0. Heterocycles 1979,12, 1457. Naidoo, B.; Smith, A. E.; Bailey, A. S.; Vandevala, (11)Jackaon, A. H.; M. H. J. Chem. SOC.,Chem. Commun. 1978,18,779. (12)Oikawa, Y.; Yonemitsu, 0. J. Org. Chem. 1977,42,1213. (13)Trudell, M. L.;Fukada, N.; Cook, J. M. J. Org. Chem. 1987,52, 4293. (14)Cain, M.; Campos, 0.; Guzman, F.; Cook, J. M. J.Am. Chem. SOC. 1983,105, 907. (15)Gata, F.; Misiti, D. J. J. Heterocycl. Chem. 1987,42,1213. (16)Rosenmund, P.; Trommer, W.; Corn-Zachertz, D.; Ewerdwalbesloh, U. Justus Liebigs Ann. Chem. 1979,1643. (17)Cain, M. Ph.D. Thesis, University of Wisconsin-Milwaukee, 1982, and references cited therein.
0022-3263/89/ 1954-2170$01.50/0 0 1989 American Chemical Society
J. Org. Chem., Vol. 54, No. 9, 1989
DDQ Oxidations in the Indole Area
2171
Table I. DDQ Oxidation of Substituted 1,2,3,4-Tetrahydro-&carbolines entry
substrate
solvent
reaction conditions
-78 "C
THF/H20
q
1
y
o
\
H
-
products
rt
e
0 II
% yield
ref
71
7
14
7
Ph
3
H
Ph
4 b
Ph
H
THF/H20
-78
qy0
O C
9
THF/H*O
3
H
R
-60 "C
-
rt
-
rt
5
no reaction
17
56
Ph
17
H
R
Ph
18, R = H
THF/H20
rt
HO
H
95
17
CH3
15, R = COPh
16
These 4-oxo-1,2,3,4-tetrahydro-fl-car~olines are also described as 3-acylindoles in the text. *These 2-acylindoles are formerly derived from oxidation at position 1 of a 1,2,3,4-tetrahydro-fl-carboline. w 3
Scheme I1
R
2
.
.
R2
RI
1 a , R1= CH2CH3, R2 = H l b , Ri=CH=CHz,Rz=H 1 c , R1= CHzCHzOH, RZ= H 1d , R1= CH(OH)CH20H, R2 = H 1e , R1= CH(OCH~)CHZOH,R2 = H If, R I = C O C H ~ , R ~ = H l g , R1= COOCH3, R2 = H 1h , Ri = CH=CHz, Rz = OCH3
0
2a, R l = R 2 = H 2 b . Ri=OCH3,Rz=H 2c, R1= OH, Rz = H 2d, Rl=H,Rz=OH 2 e , Rl=Rz=OCH3
Figure 1. Representative examples of 4-methoxy-substituted
P-carboline alkaloids.
ind01e;~J~J~ consequently, the regiochemistry of the oxidation can better be controlled than in the corresponding case with selenium dioxide.14 For this reason, a route toward 2b that centered on the use of DDQ was pursued. Recently, during work directed toward the synthesis of crenatine (la),7it was found that oxidation of amide 3 (Table I, entry 1) when performed at room temperature gave 4 (3-acylindole) and 5 (2-acylindole) in a ratio of 1:1, while this increased to 5:l at -78 "C. Disappointingly, treatment of the y-lactam 6 with DDQ (aqueous THF) (18)Walker, D.;Hiebert, J. D.Chem. Rev. 1967,67,153.Braude, E. A,; Jackman, L. M.; Linstead, R. P. J. Chem. SOC.1954,3548. Braude, E.A.;Jackman, L. M.; Linstead, R. P. J.Chem. SOC.1954,3564.Jackman, L. M. Adu. Org. Chem. 1960,2,329. Berg", J.; Carlsson, R.; Misztal, S. Acta Chem. Scand. ( B ) 1976,30, 853.
even at low temperature, according to the method of Cain,7J7 failed to produce the desired 3-acylindole 7. However, when the oxidation was carried out in methanol at -78 "C, the methyl ether 8 was obtained in 48% yield. In this case the DDQ oxidation has occurred at both positions 1 and 4 despite previous work which indicated that low temperature would favor oxidation at the desired carbon atom (position 4). In a related study (Table I, entry 2), the DDQ-mediated oxidation of the hexahydrocanthin-6-one9 was attempted. The hexahydrocanthin-6-one ring system was easily constructed via the reaction between Nb-benzyltryptamineand 2-ketoglutaric a ~ i d . ~I tJwas ~ hoped that oxidation of 9 would provide the desired 1-oxohexahydrocanthin-6-one. Unfortunately, on reaction of 9 with DDQ (see Table I) the necessary blue-colored charge-transfer complex was not observed, and the reaction returned only starting 9. Similarly, treatment of either 4 or 5 with DDQ, under the analogous conditions, provided no evidence to support formation of the charge transfer complex. The presence of electron-withdrawinggroups at position 1, 2, or 3 of the indole prevents the formation of the necessary chargetransfer complex7J2J7and limits the approaches to these 1-oxo-substituted systems.
2172
J. Org. Chem., Vol. 54, No. 9, 1989
Hagen et al.
Table 11. Synthesis of 4-Alkoxy-~-carbolines
qI$ OR"
0
Q-$) R
H
Yo R'
H
entry 1 2 3
added reagents MeOH, (Me0)3CH, pTSA EtOH, (Et0)3CH, pTSA
substrate 18, R = H, R' = P h 18 18
&"OH,
pTSP
-Ox0-,
4 5 6
18 4, R = CzH5, R' = Ph 22, R = C2H5, R' = CC13
Ph-OH
R
19
18
reaction 3 daw. 3 dais; 3 days,
conditions reflux reflux 75-80 "C
product 19a. R = H. R" = CH, 19b; R = H; R = C2H5 19c, R = H, R" = CH2CH=CH2
% yield
64 70 38
pTSA
pTSA
MeOH, (CH30)&H, pTSA MeOH, (CH30)3CH,HzS04
Results and Discussions With particular regard to the observations detailed above, a retrosynthetic analysis of 1-methoxycanthin-6-one (2b)is depicted in Scheme 11. It was decided to begin efforts toward the preparation of the 1-substituted (blocked) tetrahydro-@-carboline10 in order to direct the regiochemistry of the DDQ oxidation toward position 4, rather than to positions 1 and 4 (Scheme I). Hydrolysis of the labile ester function at C-lZ1would provide keto amide 7, which presumably could be hydrolyzed and oxidized to the phenolic (desmethyl) derivative of 11 (R = H).Formation of the aromatic @-carbolinenucleus would prevent facile relactamization to 7 and promote cyclization of 11 to the canthin-6-one skeleton. In this regard, the dimethyl ester of 2-ketoglutaric acid 13 was reacted with tryptamine hydrochloride 12 in refluxing methanol to provide the desired lactam 10 in 92% yield, as illustrated in Scheme 111. During this process a Pictet-Spengler cyclization had occurred and the ylactam 10 had formed in a one-pot reaction. The lactam 10 could also be obtained by heating the free base of tryptamine with 13 in refluxing benzene. The highly electrophilic nature of the iminium ion is responsible for the effective cyclization in nonacidic aprotic media.9J9 The y-lactam 10 contains the necessary carbon atoms for the synthesis of 2b;moreover, both the Nb-nitrogen atom and C-1 are protected from interaction with DDQ. In fact, when 10 was stirred with DDQ ( N 1:2) in aqueous THF at room temperature, the desired 3-acylindole (4-oxo-THBC) 14 was obtained in good yield. Under the conditions (2 equiv of DDQ, -70 "C) earlier reported by Cain," only the corresponding 4-hydroxy-1,2,3,4-tetrahydro-@-carboliie was obtained. It is believed that steric hindrance from the newly generated 4-hydroxyl group and the substituent at C-1 prevent (at low temperature) the formation of the second charge-transfer complex required for the conversion of the 4-hydroxy derivative of 10 into ketone 14. This is not without precedent (see 15 16,Table I and ref 17 for details). In order to remove the ester protecting group from C-1 and convert the y-lactam of 14 into the d-lactam present in 2b,ester 14 was heated in HCl/HOAc, according to the procedure of Hobson.20 This resulted in formation of 3-acylindole 7 in 88% yield; however, none of the 6-lactam
-
(19) Soerens, D.; Sandrin, J.; Ungemach, F.; Mokry, P.; Wu, G. S.; Yamanaka, E.; Hutchins, L.; DiPierro, M.; Cook, J. M. J. Org. Chem. 1979, 44, 535.
(20) Hobson, J. D.; Raines, J.; Whiteoak, R. J. Chem. SOC.1963,3495.
3 days, 75-80 "C
19d, R = H, R" = CHzPh
36
1 day, reflux 1 day, reflux
la, R = C2Hs, R" = CH3 la, R = CzH5, R" = CH3
42 48
Scheme I11 00
0
II
IIII
+
CH3OC.CCH2CH2 COCHj
13
I
HCI
H
12
wo t
78%
14
10
C02CH3
COzCHj
1 i) aq.NH,OH. MeOH ii) PTSA
o 2A d b
70%
ow 24
was observed. In agreement with the original plan the ester at C-1 had been easily removed on treatment with acid.21 The y-lactam of 7, however, proved to be resistant. to hydrolysis under a variety of conditions.% Moreover, the use of aqueous sodium peroxide,22which has been employed for amides found to be reluctant to hydrolysis, led only to decomposition products, many of which reflected the destruction of the indole system. In order to facilitate cleavage of the y-lactam to provide the &lactam, it was decided to form the enol ether of the 3-acylindole 7. This would provide a 1,2-dihydro-Pcarboline, congeners of which are known to readily undergo oxidation (02,air) or disproportionation to provide the (21) Hahn, G.; Hansel, A. Chem. Ber. 1938, 71,2163. Corsano, S.; Algieri, S. Ann. Chim. (Italy) 1960, 50, 75. (22) Vaughan, H. L.; Robbins, M. D. J. Org. Chem. 1975, 40, 1187.
J. Org. Chem., Vol. 54, No. 9, 1989
DDQ Oxidations in the Indole Area
2173
Scheme IV
IS,R'=H 4, R=CH*CH,
;1
Ph
20
H
+
P
21
H
R'
11p9,8 ,RR=' =CHzCH3, H , R = O CRH=gOCHg
Ph OR
fully aromatic & c a r b o l i n e ~ . ' ~ - ~The ~ acylpyridinium species generated in this process would be activated toward hydrolysis; moreover, the propionic acid function a t C-1 would be prohibited from recyclization to the y-lactam (see 11, Scheme 11). To examine this hypothesis 4-oxo-2benzoyl-1,2,3,4-tetrahydro-~-carboline (18) was chosen as a substrate (Table 11, entry 1). When 18 was heated with trimethyl orthoformate in methanol in the presence of p-toluenesulfonic acid (pTSA), a reasonable yield of 4methoxy-/3-carboline 19a was realized (Table 11, entry 1). Although the yield was only 64%, four steps had occurred in a one-pot reaction (see below). This alkoxylation-oxidation proved to be general for 18 and gave 3-ethoxy-Pcarboline (19b) in 70% yield when heated in ethanol [pTSA, (EtO),CH]; however, the yields decreased in the case of the allyloxy (19c) (Table 11, entry 3) and benzyloxy (19d) 8-carbolines. This is presumably due to carbocation-mediated side reactions in the cases of the allyl and benzyl alcohols. In the two reactions (Table 11, entries 1 and 2) examined closely, methyl and ethyl benzoate were isolated, respectively, which resulted from alcoholysis of the 2-benzoyl group of 18. The trialkyl orthoformate functions as a water scavenger for reaction of 18 with ethanol, and pTSA in the presence of trimethyl orthoformate gave 4-ethoxy-@-carboline(19d), accompanied by only trace amounts (
