Synthetic studies

Much synthetic work has been carried out on systems relating to the neocarzinostatin chromophore, some of it aimed toward the synthesis of the chromophore and other parts inspired by the mechanism of action of the chromophore resulting in novel systems and triggering devices. Some of the strategies successfully utilized toward these goals are described in this section. 

Another notable approach to the NCS chromophore nine-membered ring based upon an acetylide-aldehyde ring closure, although ultimately unsuccessful, comes from the labora- 

Sciieme 7-26 Neocarzinostatin chromophore related model studies by Hirama et al. Cydoaromatization of 102 under aerobic and anaerobic conditions. 

An alternative use was found for bis-propargylic sulfones by Nicolaou et al., who hypothesized that such systems may be DNA-cleaving agents through their ability to form 

Although most work relating to the neocarzinostatin chromophore has concentrated upon the dienediyne core of the molecule, a number of studies concerning the naphthoate moiety have also appeared [175-179]. 

Synthetic Studies. The formation of carbon deposits by hydrocarbon pyrolysis has been extensively studied. Baker et have described the results of a 

The broad spectrum of biological properties, especially the antileukemic activity, of the quassinoids as well as their highly oxygenated carbon backbone coupled with the stereochemical features have stimulated a great deal of synthetic activity. A number of approaches towards their synthesis have been described, but success at total synthesis has so far been limited to only two published accounts (vide infra). 

The efforts at quassinoid total synthesis can be summarized as follows  

The tetracyclic compound (134) was also converted into the D-deoxyquassinoid (136) possessing the same ABCD-ring fusion as that of klaineanone 21b). 

In an alternative approach, the Diels-Alder adduct (144), obtained from the enedione (143) with l-methoxy-3 [(trimethylsilyl)oxy]-1,3-butadiene, was further transformed into the a-iodo ester (145). Exposure of the latter to iodotrimethylsilane furnished the 8-lactone (146), an attractive ABCD ring precursor to the quassinoids (106). 

An Improved Synthesis of 13-Desoxydelphonine and Chasmanine.—Wiesner and co-workers40,41 have reported a more efficient synthesis of (102). This intermediate (102) has been used in the synthesis of 13-desoxydelphonine (103) 

Investigators observed that the azidopyrazine 51 was about 100-fold more cytotoxic than the symmetrical pyrazines 49 in in vitro testing against human cancer cell lines (38). 

Fuchs et al. have also synthesized the trisdecacyclic pyrazines (52-54) from commercially available 3/3,12/3-diacetoxy-5a-spirostan-ll-one in 13-24% overall yields (38). It is important to remember that all cephalostatins and ritterazines have a trisdecacyclic dimeric steroidal skeleton. The efforts of Fuchs et al. represent the first studies directed at the total synthesis of this bissteroidal skeleton (38). 

Synthesis of Unsymmetrical Bis-Steroidal Pyrazines Related to Cephalostatin 1 (11) 

In 1992 Heathcock and Smith developed efficient routes for the synthesis of symmetrical and unsymmetrical bis-steroidal pyrazines from readily available precursors such as 3-cholestanone and androstanone (40). In a later publication they synthesized the unsymmetrical bis-steroidal pyrazines by the reaction of appropriate a-acetoxy ketones with a-amino oximes. Heating either 2/3,17/3-dihydroxyandrostan-3-one diacetate or 2/3-17/3-dihydroxyhecogenin-3-one diacetate with 2-amino-3-methoxyimino-cholestane in toluene at 145°C gave the corresponding symmetrical pyrazine in moderate yields. 

Fuchs et al. in 1995 reported the first biomimetic synthesis of cephalosta-tins 7 (17) and 12 (22) and ritterazine K (36) (42). This synthesis is based 

Ayer et al. 104) in their approach to the synthesis of lycoiiodine have constructed the cis-trans hexahydrojulolidine system substituted at C-13 but have not yet realized its conversion to the lycopodine skeleton. 

The group at the University of New Brunswick have developed an ingenious approach to the synthesis of annotinine 105). The lactam 

In a series of publications by Kametani and coworkers (55—62) a number of routes to systems related to the pyridine C-ring of streptonigrin were described. Most of these routes wer based upon classical methods for pyridine or 2-pyridone ring formation. 

Condensation of nitrile (63) with 2-butanone gave pyridone (64). However, attempts to introduce an amino substituent into the 3-position of (64) by various electrophilic reactions gave only phenyl ring-substitution products (55, 58). This work clearly indicated the inherent difficulties associated with functionalization of pyridine C-ring precursor by electrophilic chemistry in the presence of a highly oxygenated D-ring. 

A far more successful sequence (62) which produced a fully substituted pyridone (66) involved ethoxide promoted condensation of (65) with cyanoacetamide. Similarly, (65) could be combined with (67) to give, after methylation, dihydropyridone (68) which on dehydrogenation yielded the fully substituted pyridone (69). 

After extensive preliminary studies (68, 69), Weinreb and coworkers completed the first total synthesis of streptonigrin in 1980 ref. (70). The central strategy in their approach involved the use of an imino Diels-Alder reaction for construction of the CD framework. The quinoline system was ultimately synthesized by a new modification of the Fried-lander condensation after complete elaboration of all of the necessary pyridine substituents. 

Readily available aldehyde (98) could be converted to a,p-unsaturated aldehyde (99) in three simple steps. This compound on treatment with ethylidene triphenylphosphorane at low temperature, followed by n-butyl 

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The first definitive studies of boron hydrides were carried out by Alfred Stock in Germany starting about 1912 (1). Through extensive and now classic synthetic studies, the field of boron hydride chemistry was founded with the isolation of a series of highly reactive, air-sensitive, and volatile compounds of general composition and This accomplishment required the development of basic vacuum line techniques for the... 

The basic research that led to these products was done at the Northern Regional Research Center of the USD A dimer acids research in the 1940s (1—3), C-21 dicarboxyhc acid work in 1957 (4), and carboxystearic acid synthetic studies (5,6) in the 1970s (see Dicarboxylic acids). 

Perfluoropyridine is often subjected to synthetic studies in comparison with perfluorotoluene. Both substrates react very well with replacement of the fluorine in position 4, but yields from perfluoropyridine are generally higher. Car-banions, enamines, and silanes react readily with perfluoropyridine [101, 102, 103] (equation 52). 

Evodiamine, the alkaloid from the Chinese drug plant Evodia rutaecarpa Benth. and Hook., has also been called rhetsine and its oxidation product rhetsinine, which is also found in nature, was shown to be the diamide (53). Recently a hypotensive red alkaloid isolated from the Brazilian plant Hortia arborea Engl, was given the name hortiamine. Degradation and synthetic studies have shown it to possess the structure (55). It was found together with another... 

Synthetic studies on alkaloid pumilliotoxin C using Pd-promoted cyclization 98YGK818. 

Synthetic studies on heteroanthracyclines, heteroanalogs of anthracycline antitumor antibiotics 97H(46)705. 

Synthetic study of 4-thiazoline derivative curacin A, a novel antimitotic agent isolated from cyanobacterium Lyngbya majuscula 99YGK552. 

Synthetic studies on sesquiterpenoids from D-glucose, total syntheses of (-H)-eremantholide A and (—)-verrucarol 98YGK1026. 

Synthetic studies on biological activities of marine-origin polycyclic bis-steroid systems with 0-heterocyclic and pyrazine fragments or spirooxazoline fragment 99PAC1095. 

Synthetic study on marine polycyclic ethers and total synthesis of hemibreve-toxin B 98YGK940. 

During synthetic studies toward pynrolo-fiised indoles, the polymeric species 218 has been suggested as aproduct from the diformylation of 219 under Vilsmeier-Amold-Haack conditions, followed by heating with 35% aqueous sulfuric acid (Scheme 33) (9171,5035). With the deeper knowledge of the reactions of 3-formylIndoles now available (99CHE561), this assignment should be reconsidered. 

V. Synthetic Studies towai d Novel Heterocyclic Compounds and Natural Pi oducts.. 138... 

Daikon and wasabi phytoalexins are weak fungicidal alkaloids having a stabilized 1-methoxyindole structure. Relying on the expectation that more potent substances can be found among their derivatives, synthetic studies are in progress according to the method developed in Scheme 22 in Section IV.G. 

The TMM [4-1-3] cycloaddition to pyrone has been employed in a synthetic study of a novel biologically active diterpene pseudolaric acid B (106), in which the formation of the bridged adduct (107) from the 2-pyrone (108) is the key step in the sequence (Scheme 2.29). A mixture of the other isomer (109) and the methylenecyclopentane (110) was also isolated from the reaction. It is important to point out that the presence of a tin co-catalyst is critical in effecting the reaction. This is the first example a "tin-effect observed in a [4-1-3] cycloaddition [40]. 

Scheme 2.29 TMM [4+3 cydoadditions in the synthetic study of pseudolaric acid B (106)...

Carboxylative TMM q cloaddition has also been realized with 3-methoxytropone and precursor (56) to produce an epimeric mixture of acids (122), which was employed in a synthetic study of the bicyclic diterpene sanadaol (123). The use of bi-dentate ligand tpdp (12) and high pressure did not improve the reaction. However, the addition of MesSnOAc as a co-catalyst did produce a better yield of (122) (Scheme 2.33) [16]. 

Scheme 2.33 Carboxylative TMM [4-r3] cycloadditions with tropone in the synthetic study of sanadaol (123)...

The imposing structure and potential medicinal importance of rapamycin provide a strong impetus for the development of an efficient path by which a total synthesis can be achieved. At present, the chemical literature is replete with interesting synthetic studies that focus on various features of the rapamycin molecule. These undertakings provide salient testimony to the excitement that this natural product has generated. Rapamycin has already succumbed to four distinct and instructive total syntheses 5 8 this chapter will... 

In numerous synthetic studies,9" 6 100 it has been demonstrated that porphyrins react at the chromophore periphery in cycloaddition reactions, rearrangements, conjugative additions and substitution reactions to yield interesting porphyrin derivatives. Thus, metal-free protoporphyrin IX dimethyl ester reacts in Diels-Alder reactions108a b with dienophilcs like ethenetetra-carbonitrile and acetylenedicarboxylates at the diene structural parts to yield, according to the reaction conditions, the corresponding monoadducts 2 and 3 (see also Section 1.2.) and bisadducts 1 (see also Section 1.4.), respectively. 

Sapphyrins were discovered serendipitously by Woodward33 during the course of synthetic studies directed towards the total synthesis of vitamin B, 2. The sapphyrins were the first example of expanded porphyrins in the literature. Due to sapphyrin exhibiting a deep-blue color in the crystalline state and intense green in solution. Woodward coined the expression sapphyrin with reference to the deep-blue color of sapphire stones. 

This experiment made clear that a [4 + 1] approach for the synthesis of sapphyrins is not very satisfactory. In further synthetic studies,33 Woodward demonstrated that sapphyrins could be obtained along different routes, but the yields of these methods were not at all satisfactory. 

In conclusion, it may be noted that the pioneering investigations by both the Mislow and Braverman groups have contributed to the elucidation of the mechanism of this concerted [2,3]-sigmatropic rearrangement, and have thus laid the ground for the following stereochemical and synthetic studies. 

Synthesis of hydrolytically stable siloxane-urethanes by the melt reaction of organo-hydroxy terminated siloxane oligomers with various diisocyanates have been reported i97,i98) -yhg polymers obtained by this route are reported to be soluble in cresol and displayed rubber-like properties. However the molecular weights obtained were not very high. A later report56) described the use of hydroxybutyl terminated disiloxanes in the synthesis of poly(urethane-siloxanes). No data on the characterization of the copolymers have been given. However, from our independent kinetic and synthetic studies on the same system 199), unfortunately, it is clear that these types of materials do not result in well defined multiphase copolymers. The use of low molecular weight hydroxypropyl-terminated siloxanes in the synthesis of siloxane-urethane type structures has also been reported 198). 

Keywords intramolecular Diels-Alder reaction, tether-controlled, synthetic studies direct toward various classes of natural products, alkadienes... 

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