Maytansins

Review Problem 3 Tliis odd-looking molecule (TM 34) was used by Corey as an intermediate in the synthesis of maytansine, an antitumour compound. 

Several semisynthetic maytansinoids have been prepared by acylating the C-3 hydroxyl group of maytansinol. Some of these derivatives have antiprotozoal and antitumor activity similat to maytansine (104) and ansamitocin P-3 (127) (52,254). 3-Epimaytansinoids have been synthesized and were not biologically active (255). 

The antitumor activity of geldanamycin and its derivatives appears to result from inhibition of DNA synthesis whereas RNA synthesis is not affected (261). The antitumor activity of the maytansinoids also appears to result from the inhibition of DNA synthesis. The mechanism of action of maytansine (104) has been hypothesized to be the acid catalyzed loss of water from the C-9 hydroxyl group of the carbinolamide to form a reactive acyl imine intermediate, which reacts rapidly with nucleophiles on the bases of DNA (262). 

The synthesis of (+)-N-methylmaysenine, a preliminary for the later synthesis of the antitumor agent maytansine, was accomplished by the joining of fragments A and B, chain extension and macrolactam closure using a mixed carboxylic-sulfonic acid anhydride. 

The first synthesis of the potent antitumor agent maytansine was carried out by the elaboration of aldehyde D, an intermediate in the enantioselective synthesis of (-)-A/-methylmaysenine (Ref. 1,2), using enantioselective and diastereoselective steps. 

Reaction of optically active a-sulphinyl acetate 298a with prochiral carbonyl compounds proceeds with a high asymmetric induction - , the degree of which depends on the nature of substituents at the carbonyl group (equation 252 Table 22) . The jS-hydroxy sulphoxides 422 formed may be transformed to optically active p-hydroxycarboxylic esters 423 (equation 253) and optically active long-chain lactones 424 99 (equation 254). Corey and coworkers have used this method to introduce a chiral centre at C-3 in their synthesis of maytansin °°, and Papageorgiou and Benezra for the synthesis of chiral a-hydroxyalkyl acrylates 425 ° (equation 255). 

Structure 1 vinblastine, 2 vincristine, 3 maytansine, 4 rhizoxin and 5 paclitaxel (Taxol)... 

Catharanthus roseus) [9]. Maytansine (3) is an ansa macrolyde isolated from Maytenus ovatus [10], and rhizoxin (4) is an antitumor macrolide isolated from the fungus Rhizopus chinensis [11]. Another very important tubulin interactive anti-cancer agent is colchicine (6), and this compound binds to a different binding site of tubulin but is also used in anti-cancer therapy. 

Maytansine 588 is a macrocyclic tetrahydro-l,3-oxazin-2-one derivative isolated from higher plants, mosses, and an actinomycete, kctinosynnema pretiosum. Despite the extraordinary antitumor activity found for many maytansine derivatives, the Phase II clinical trials with maytansine turned out to be disappointing. The chemistry and biology of maytansinoids have recently been reviewed <2004CPB1>. 

Maytenus diversifolia Hou. M. confertiflorus Luo Chen. Ci Luo Shi (leaf, bark) Dulcitol, maytansine, succinic acid, syringic acid, 3-oxykojie acid, loliolide.50 Antitumor, bark is used for cancer of the liver and stomach. 

Maytenus serrata (Hochst. ex A. Rich) Wilcz. M. hookeri Loes. Mei Deng Mu (fruit, bark, rhizome) Maytansine, maytanprine, maytanbutine, maytanvahne, maytanacine, maytansinol.33 Treat lung cancer, breast and ovarian cancer, acute lymphocytic leukemia, colon carcinoma, kidney carcinoma. 

Maytansine Maytenus diversifolia, M. confertifbrus, M. hookeri, M. serrata... 

This reaction was used to introduce the final two skeletal carbons in a total synthesis of maytansine (4).2 The reaction of the 2,/ -unsaturated aldehyde (2) with I (R = C6H5) gives the desired 4,5-unsaturated 3-hydroxy ester 3 in 80% yield. The ratio of the desired (S)-alcohol to the epimer is 93 7. The resulting amino acid was cyclized to the lactam in 80% yield with mesitylenesulfonyl chloride (8, 318-319). Epoxidation by the Sharpless procedure (9, 78 79) was also highly stereoselective, giving the desired epoxide and the undesired epimer in the ratio > 200 1. 

Isolation and Structure Proof. The maytansinoids were (lie first ansamacrolides to be found in plants. The term maytansinoids refers to those ansamacrolides related to maytansinc, whereas the term maytansides refers to maytansinoids lacking the ester side chain at C-3 as well as the corresponding elimination products. Maytansine was first isolated from the alcoholic extract of Maytenus ovatus Loes. Several other maytansinoids and maytansides have been isolated from this species. The structure of niaytan-sine was established by x-ray crystallographic analysis, and the structures of the other maytansinoids and maytansides were arrived at by comparative nmr studies using maytansine. The absolute configuration of maytansine is 3(5), 4(5), 5(5), 6(R), 7(5), 10(5), and 2 (5). 

Oxazinomycin (l)5 is a 1,3-oxazine antibiotic. There are five other antileukemic antibiotic macrolides of known tetrahydro-l,3-oxazine-2-one structures. Maytansine, Maytanprine, and Maytanbutine were found by Kupchan et a/.278,278 in Maytenus ovatus and Maytenus buchananii, and in Maytenus serrata by Meyers et al.,277 and Calubrinol... 

Corey and Bock280 designed a synthetic route to Maytansine, and obtained a fragment of the molecule containing the 1,3-oxazine ring. 

Confalone and Ko have reported formation of the macrocyclic INOC product (104) in 30% yield from cyclization of an aryl-bridged nitrotriene containing a 17-atom intervening bridge.48 Cyclization to the conjugated diene system did not occur, presumably because of geometric constraints and the fact that the more accessible double bond is trisubstituted. Isoxazoline (104) is a potential maytansine precursor. 

Semisynthetic Maytansine Analogues for the Targeted Treatment of Cancer. J Med Chem 49 4392... 

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