Intermediates for the production of podophyllotoxin and related compounds and processes for the preparation and use thereof

There are disclosed intermediates which can be converted into podophyllotoxin and related compounds, which are known antineoplastic agents. There are also disclosed processes for the preparation of such intermediates, and processes for the conversion of the intermediates into known intermediates which are readily converted into podophyllotoxin and related compounds.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The present invention is directed to intermediates which can be converted 
into podophyllotoxin and related compounds, which are known antineoplastic 
agents. More specifically, this invention relates to an efficient total 
synthesis of podophyllotoxin. Additionally, the present invention provides 
processes for the preparation of such intermediates, and processes for the 
conversion of the intermediates into known intermediates which are readily 
converted into podophyllotoxin and related compounds. 
2. Description of the Prior Art 
Podophyllotoxin (I), a known lignan lactone isolated from several species 
of Podophyllum, is a potent cytotoxic agent. Numerous other related 
compounds having the characteristic aryltetralin ring structure, either 
naturally occurring or derived from some naturally occurring compounds are 
known. Some of these compounds possess antineoplastic activity while 
others are useful for conversion to compounds having such activity. 
Podophyllotoxin is an important intermediate for the production of the 
antitumor agent etoposide and its analogues. Podophyllotoxin has the 
structure shown below: 
##STR1## 
The key molecular features of podophyllotoxin are (1) presence of the C2-C3 
trans lactone, and (2), a cis relationship between the C1 and C2 
substituents. For the synthesis of etoposide, the C4 hydroxy group can be 
either in the .alpha. (podophyllotoxin) or the .beta. (epipodophyllotoxin) 
orientation because in the glycosidation step only the C4 .beta. glycoside 
is obtained. 
In J. Org. Chem., 31, 4004-4008 (1966), W. J. Gensler and C. D. Gatsonis 
describe the completion of the total synthesis of podophyllotoxin through 
the epimerization by enolate quenching of the O-tetrahydropyranyl 
derivative of picropodophyllin. However, this epimerization does not 
proceed to completion, and separation of an about 45:55 mixture of 
podophyllotoxin and picropodophyllin is required. Picropodophyllin which 
is the cis-lactone isomer of podophyllotoxin has the structure: 
##STR2## 
In J. Org. Chem., 46, 2826-2828 (1981), A. S. Kende et al. report on an 
improved total synthesis of podophyllotoxin in 12 steps with an overall 
yield of 4.5% from piperonal. However, the Kende synthesis requires the 
preparation and then the subsequent epimerization of picropodophyllin 
similar to the above-mentioned Gensler synthesis. 
In J. Am. Chem. Soc., 103, 6208-6209 (1981), D. Rajapaksa and R. Rodrigo 
report a new synthesis of podophyllotoxin which avoids the thermodynamic 
hurdle present in the conversion of picropodophyllin to podophyllotoxin as 
was previously described in the above-mentioned references of Gensler et 
al. and Kende et al. However, the synthesis requires the preparation of a 
bicyclic precursor and a satisfactory yield can be achieved only by 
recycling procedures. 
SUMMARY OF THE INVENTION 
The preparation of podophyllotoxin in accordance with the present invention 
also avoids the picropodophyllin intermediate and, in addition, provides a 
new and efficient stereospecific synthesis starting with Gensler ketone of 
the formula: 
##STR3## 
This invention is based on the realization that the cis Gensler ketone of 
the formula 
##STR4## 
has a finite stability. This stability permits the incorporation of a 
hydroxymethyl group at C3 without epimerization at C2. 
Previously, Kende et al, [J. Amer. Chem. Soc., 99, 7082-7083 (1977) and J. 
Org. Chem., 46, 2826-2828 (1981)] and Murphy et al [J. C. S. Perskins I, 
271-276 (1982)] have tried hydroxymethylation at C3 using a base and 
formaldehyde. This gave mainly the bisalkylation product and the yield was 
not high. The present invention avoids bisalkylation, and gives a product 
with the desired stereochemistry at C2. 
The synthesis of podophyllotoxin and related compounds in accordance with 
this invention is depicted in Scheme I: 
##STR5## 
wherein R.sup.1 and R.sup.2 each are independently hydrogen or 
(lower)alkoxy, or R.sup.1 and R.sup.2, taken together, is methylenedioxy; 
R.sup.3 is hydrogen or a carboxyl-protecting group; R.sup.4 and R.sup.6 
each are independently hydrogen or (lower)alkoxy; R.sup.5 is hydrogen or a 
phenol-protecting group; R.sup.7, R.sup.8 and R.sup.9 each are 
independently lower(alkyl) or phenyl; and R.sup.10 is hydrogen, 
lower(alkyl), lower(alkoxy) or nitro. 
Compounds V, VI, VII and VIII in Scheme I are novel intermediates. 
The terms "(lower)alkyl" and "(lower)alkoxy" as used herein and in the 
claims mean unbranched or branched chain alkyl or alkoxy groups containing 
from 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, 
isobutyl, t-butyl, amyl, hexyl, etc. Preferably, these groups contain from 
1 to 4 carbon atoms and, most preferably, they contain 1 or 2 carbon 
atoms. Unless otherwise specified in the particular instance, the term 
"halogen" as used herein and in the claims is intended to include 
chlorine, fluorine, bromine and iodine. 
Carboxyl-protecting groups which can be employed in the present invention 
to block or protect the carboxylic acid function are well-known to those 
skilled in the art and include moieties such as (lower)alkyl, 
phenyl(lower)alkyl, ring substituted phenyl(lower)alkyl, methoxymethyl, 
benzyloxymethyl, allyl, diphenylmethyl and the like. Phenolprotecting 
groups which can be employed in the present invention to block or protect 
the phenol function are also well-known to those skilled in the art and 
include moieties such as (lower)alkyl, phenyl(lower)alkyl, ring 
substituted phenyl(lower)alkyl, benzyloxycarbonyl, 
2,2,2-trichloroethoxycarbonyl, methoxymethyl, allyl and the like. Other 
suitable protecting groups are disclosed in "Protective Groups in Organic 
Synthesis", Theodora W. Greene (John Wiley & Sons, 1981), Chapter 3 for 
phenol and Chapter 5 for carboxyl, which are hereby incorporated by 
reference. 
DETAILED DESCRIPTION OF THE INVENTION 
The aryltetralone starting material, a compound of Formula III, wherein 
R.sup.1 and R.sup.2, taken together, is methylenedioxy, R.sup.3 is 
hydrogen, CH.sub.3 or C.sub.2 H.sub.5, R.sup.4 and R.sup.6 are methoxy, 
and R.sup.5 is methyl may be prepared by the general method described in 
J. Am. Chem. Soc., 82, 1714-1727 (1960), W. J. Gensler et al. Compounds of 
Formula III may also be prepared by an improved procedure described in J. 
C. S. Perkin I, 271-276 (1982), W. S. Murphy and S. Wattanasin, in which 
R.sup.1 is methoxy and R.sup.2 is hydrogen, or R.sup.1 and R.sup.2, taken 
together, is methylenedioxy, R.sup.3 is hydrogen or ethyl, R.sup.4 and 
R.sup.6 are hydrogen or R.sup.4 and R.sup.6 are methoxy, and R.sup.5 is 
methyl. 
A compound of Formula III, with the ester radical in the relative trans 
configuration, is epimerized to a cis aryltetralone of Formula IV at low 
temperatures, i.e., from about -80.degree. C. to -20.degree. C., and 
preferably at about -78.degree. C., by enol quenching utilizing a 
non-nucleophilic strong base such as lithium hexamethyldisilazide, sodium 
methylsulfinylmethide, lithium 1,1,6,6-tetramethylpiperide and lithium 
diisopropylamide in an inert organic solvent such as tetrahydrofuran 
(THF), dioxane, dimethoxymethane, hexamethylphosphoramide and 
tetramethylurea and then adding a mineral acid, for example, hydrochloric 
acid. This is reaction A of Scheme I. 
Reaction B of Scheme I illustrates the preparation of the enol silyl ether, 
a compound of Formula V, from a compound of Formula IV. This is 
accomplished by reacting a compound of Formula IV with a reagent having 
the formula: 
##STR6## 
wherein R.sup.7, R.sup.8, and R.sup.9 are as previously defined and X is a 
halogen atom or a trifluoromethanesulfonate group. The reaction is 
conducted at a temperature of from -78.degree. C. to 25.degree. C. in the 
presence of a non-nucleophilic base such as triethylamine or 
hexamethyldisilazane. To avoid epimerization at C2, the mildest possible 
conditions should be employed. The silyl reagent XI may be, for example, 
trimethylsilyl trifluoromethanesulfonate (TMSOTf), trimethylsilyl iodide, 
t-butyl-dimethylsilyl iodide or triethylsilyl iodide. 
A compound of Formula V may be converted to a compound of Formula VI, 
reaction C in Scheme I, without purification or isolation of a compound of 
Formula V. This is accomplished by reacting a compound of Formula V with a 
bisbenzyloxymethane having the formula: 
##STR7## 
or a benzyloxymethyl halide having the formula: 
##STR8## 
wherein R.sup.10 is the same as previously described and X is halogen. 
This reaction is conducted in the presence of a Lewis acid such as TMSOTf, 
ZnCl.sub.2, ZnBr.sub.2, and TiCl.sub.4. The reaction should be conducted 
at a temperature of from about -50.degree. C. to 20.degree. C. and 
preferably at about 0.degree. C. 
A compound of Formula VI is converted to a compound of Formula VIII by 
reduction of the C4 carbonyl group at a temperature of from -20.degree. C. 
to 20.degree. C. using a reducing agent such as LiBH.sub.4, NaBH.sub.4, 
NaBH.sub.3 CN, LiBHC.sub.2 H.sub.5, or Zn(BH.sub.4).sub.2. Compounds of 
Formula VII are obtained as a by-product of this reaction. 
Reaction F of Scheme I illustrates the debenzylation of a compound of 
Formula VIII to obtain a compound of Formula IX. Debenzylation can be 
carried out by standard hydrogenating conditions, i.e., by using catalysts 
such as Pt, Raney Ni, Rh and solvents such as THF, ethanol and ethyl 
acetate. This reaction is carried out at a temperature of from 0.degree. 
C. to 50.degree. C., preferably about 25.degree. C. 
A compound of Formula IX is converted to a compound of Formula X (Reaction 
G of Scheme I) by treatment with an aqueous base followed by treatment 
with a condensation reagent, e.g., dicyclohexylcarbodiimide, 
1-cyclohexyl-3-(2-morpholinoethyl)-carbodiimide metho-p-toluenesulfonate, 
isopropyl chloroformate, etc. This reaction is carried out at a 
temperature of from about 0.degree. C. to about 50.degree. C., preferably 
about 25.degree. C. 
In accordance with the process of this invention, the C2 anion will not 
epimerize because it is tied back as a lactone and once the lactone is 
opened up, the carboxylate salt will suppress deprotonation at C2.