Cephalotaxine esters synthesis

The synthesis of cephalotaxine esters has been motivated by the recognition of the antitumor properties associated with some of these compounds, most notably homoharringtonine. Most, if not all, of their syntheses focus on the efficient preparation of the side chains and methods of esterification of the intact cephalotaxine nucleus, usually obtained from natural sources, where it is far more abundant than any of the corresponding esters. Because of the hindered nature of the cephalotaxyl alcohol, many approaches rely on partial esterification and further functionalization of the side chains. 

Padwa etal. utilized the ammonium ylide [1,2]-shift in the synthesis of tetrahydroisoquinoline and benzazepine fused with a five-membered ring, a structure found in a cephalotaxine family. When diazo ester 172 is treated with a catalytic amount of Cu(acac)2 in refluxing toluene, 5,7-fused compound 174 is isolated in 73% (Equation (25)). Again, use of Rh2(OAc)4 results in slow reaction and eventually gives a complex mixture of the products after a prolonged reaction time. 

Although cephalotaxine itself exhibits no significant antileukemic activity, a number of naturally occurring esters of the alkaloid, the harringtonines (107-110), are active against LI 210 and P388 leukemias in mice (89,100, 108), and so some attention has been devoted to the synthesis of the dicar-boxylic acid side chains (see also Section IV,A). 

Chinese workers have continued their pharmacological exploration of esters of cephalotaxine (3a) and have reported the transformation of this alkaloid into harringtonine (26a)12 and 0-(2-oxo-5-methylhexanoyl)cephalotaxine (26b).13 The latter compound is an intermediate in the synthesis of the antineoplastic alkaloid deoxyharringtonine (26c). The overall conversion of cephalotaxine into deoxyhar-ringtonine (26c) via (26b) has been patented.14 Of twenty-two esters of (-)-... 

Even though synthetic activity has waned somewhat since the 1980s, this chapter still covers the earlier syntheses of the parent alkaloid, its esters, and the model studies directed toward total synthesis. The readership will be better served by having all published activity in this area placed in context with new developments therefore, the syntheses already discussed in the 1987 review are included in this chapter as well, along with the appropriate updates in the three major areas synthesis of the title alkaloid, preparation of its esters, and new approaches to the skeleton and unnatural derivatives of cephalotaxine that may have been designed from the point of view of medicinal chemists. 

The second synthesis of cephalotaxine was reported by Semmelhack and co-workers (24), also in 1972. Their convergent strategy involved the alkylation of spirocycle 49, prepared in several steps from p)nTolidone 45, with p-nitrobenzenesulfonate ester 50, prepared from piperonal in 45-55% overall yield as shown in Scheme 2. The resulting key intermediate, 51a (X = Cl), was converted to ( )-cephalotaxinone (22), initially through an aryne intermediate. Route I, Scheme 3, in 15% yield. Cephalotaxinone was then converted to ( )-cephalotaxine (1) upon reduction with diisobutyl-aluminum hydride. The Semmelhack group expended considerable effort studying the conditions of the nucleophilic aromatic substitution (i.e., 51a-c... 

These two milestone syntheses were soon followed by others, and activity in this field continued to be driven by interest in the biologically active esters of cephalotaxine. In 1986, Hanaoka et al. (27) reported the stereoselective synthesis of ( )-cephalotaxine and its analog, as shown in Scheme 4. The amide acid 52, prepared by condensation of ethyl prolinate with 3,4-dimethoxyphenylacetyl chloride, followed by hydrolysis of the ethyl ester, was cyclized to the pyrrolobenzazepine 53 by treatment with polyphos-phoric acid, followed by selective O-alkylation with 2,3-dichloropropene (54) in the presence of sodium hydride. The resulting enol ether 55 underwent Claisen rearrangement on heating to provide C-allylated compound 56, whose reduction with sodium borohydride yielded the alcohol, which on treatment with 90% sulfuric acid underwent cationic cyclization to give the tetracyclic ketone 57. Presumably, this sequence represents the intramolecular version of the Wichterle reaction. On treatment with boron tribromide, ketone 57 afforded the free catechol, which was reacted with dibromometh-ane and potassium fluoride to give methylenedioxy derivative 58, suited for the final transformations to cephalotaxine. Oxidation of ketone 58... 

In 1988 and 1990, Fuchs reported a new approach to the synthesis of the Cephalotaxus alkaloids ( )-cephalotaxine (1) (30,31), ( )-ll-hydroxyceph-alotaxine (26) (31), and ( )-drupacine (28) (31), which was based on the exploitation of vinyl sulfones as convenient multifunctional synthons (Schemes 7 and 8). The synthesis of cephalotaxine (Scheme 7) began with the ortho ester 77, obtained from piperonyl alcohol in five steps, which was... 

Another synthesis of homoharringtonine was reported by Wang et al. 49-51) in 1980 (Scheme 21). Treatment of the sodium salt 154 of the protected keto acid with oxalyl chloride, followed by cephalotaxine, gave the cephalotaxyl ester 155, which, under Reformatsky conditions, reacted with methyl bromoacetate to furnish the expected diastereomeric mixture of ketals 156. Hydrolysis of 156 yielded an equilibrium mixture of ketone 157 and its cychc hemiketal 158. Treatment of this mixture with methyl-magnesium iodide yielded homoharringtonine (3) and its epimer. 

In the follow-up detailed report, Hudlicky s group (53) also described the synthesis of homoharringtonine from the unsaturated keto acid 151 (Scheme 23). Acid 151 was treated with formic acid in the presence of perchloric acid to provide the intermediate formylated derivative 163, which, on treatment with aqueous sodium hydroxide, produced hydroxy acid 164. Esterification of 164 with cephalotaxine yielded the cephalotaxyl ester 165, which underwent the Reformatsky reaction with methyl bro-... 

Danishefsky et al. (33) reported a method of one-carbon chain incorporation necessary for the elaboration to the five-membered D-ring of cephalo-taxine (Scheme 39). (See also Scheme 9, Section III, for the formal total synthesis of cephalotaxine by this method.) Reaction of dihydroisoquinoline 219 with acid chlorides 220 or 221 followed by the addition of aqueous sodium bicarbonate gave carbinolamides 222 or 223, respectively, which, on treatment with 1,3-propanedithiol and boron trifluoride etherate, yielded the ring-opened dithiane 224 or 225. These dithianes were converted by treatment with sodium hydride or potassium rert-butoxide to 226 or 227, respectively. Removal of the dithiane moiety in 226 or 227 by iV-bromosuc-cinimide gave the a-keto esters 228 or 229, which on treatment with Lawes-... 

In 1987, Hill and co-workers (75) reported a clever synthesis of the pentacyclic cephalotaxine analog 246 starting from the nitrostyrene derivative 98 (Scheme 42). The Diels-Alder adduct 244, obtained by the reaction of butadiene sulfone with 98, was treated with methyl acrylate to give a single stereoisomer of the nitro ester, which was reduced with zinc in etha-nolic HCl to yield the lactam 245 and further reduced by Red-AI to the corresponding pyrrolidine. Pictet-Spengler cyclization with formaldehyde gave the pentacyclic amine 246. Alternatively, the reduced pyrrolidine obtained from 245 could be formylated, cyclized to the iminium salt by a Bischler-Napieralski protocol, and finally reduced with sodium borohy-dride to 246. Nearly identical sequences have also been reported by Bryce... 

The evolution of synthetic organic chemistry, since the first preparation of cephalotaxine 25 years ago, places more specific demands on the practitioner today. A sequence of 15 or more steps to assemble a relatively simple molecule is not acceptable as the discipline enters the 21st century. The reader is referred to a recent review that summarizes the requirements for proper synthetic strategies for the present and certainly for the future (90). In conclusion, the synthesis of cephalotaxine and, more important, its esters remains a wide-open field that awaits the next good idea. 

Aluminum iminoxides. Nucleophilic amides are formed upon condensation of esters with amines, which are liable to undergo conjugate addition to enones when catalyzed by Sn(OTf)2. The reaction has found an application in the synthesis of (-)-cephalotaxine. 

Several years later, Liu and coworkers reported another synthesis of cephalotaxine 172 that relied on a distinct [2,3]-Stevens rearrangement fScheme 1 S.4QL ° Proline derivative 173 was transformed into ammonium ylide 174 in the presence of allyl bromide and K2CO3. This zwitterion rearranged to a-allyl aminoester 175. Hydration of the olefin and reduction of the ester furnished diol 176, which was converted to aminoketone 177 via oxidation and aldol condensation. The assembly of this spirocyclic intermediate represented a formal synthesis of cephalotaxine 172. ... 

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