First total synthesis

One reason for the poor yield in the last step is a side-reaction caused by the side-chain. By attack of the carboxyamide function of the phenoxyacetyl residue on the carboxy centre, which is activated as the isourea, an adactone is formed. 

In subsequent studies, Sheehan could show that in case of the synthesis of 6-ami-no-penicillanic add with carbodiimides and a trityl protecting group, lactami-sation works much better, because the formation of an adactone is excluded by steric hindrance. 

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Many notable examples of the synthesis of complex natural products from optically pure starting materials have been reported (70). One synthesis of considerable interest is that of taxol [33069-62-4] (74), a potent antitumor agent used clinically. The starting material (73) used ia the first total synthesis of taxol is produced ia enantiomericaHy pure form from inexpensive and readily available /-camphor [464-48-2] (72) (73). 

Cinnamyl—sesamol ethers, eg (35), are useful as insect chemosterilants (111). 3,4-Methylenedioxyphenyl-3-halo-2-propynyl ethers (36, X = halogen) are synergists for carbamate insecticides (112). HaloaLkyl or haloalkenyl ethers, eg (37), show acaricidal and insect juvenile hormone activity (113). The first total synthesis of gibbereUic acid was from 2-methoxy-6-aLkoxyethyl-l,4-benzoquinone, a derivative of hydroxyhydroquinone (114). 

Chemical degradation of erythromycin A yielded its aglycone, erythronoHde A (16, R = R = OH), whereas erythronoHde B (16, R = H, R = OH) was obtained from fermentation (63,64). Biosynthesis of erythromycin proceeds via 6-deoxyerythronoHde B (16, R = R = H) and then erythronoHde B (64,65). The first total synthesis of erythromycin-related compounds was erythronoHde B (66) syntheses of erythronoHde A and 6-deoxyerythronoHde B soon foUowed (67,68). 

The first total synthesis of erythronolide A was accomplished from iodide A and lactone B, the same intermediate which had been used for the synthesis of erythronolide B. The pronounced acid sensitivity of erythronolide A necessitated a digression of the final steps of the synthesis from those used for the earlier synthesis of erythronolide B. 

The first total synthesis of 87 was published in 1990 (90TL1523). 5-Hydroxyindole (88) was mesylated and then reduced with sodium cyanoborohydride to give an indoline which was brominated to afford the bromoindoline 89 in good yield (Scheme 33). Cross-coupling with ortho-formyl boronic acid under Suzuki conditions, followed by air oxidation of the resulting cyclized product, followed by reduction of the lactam formed with excess Red-Al gave the target compound 87. 

The Stille coupling of an aryl triflate normally calls for the addition of at least one equivalent of LiCl. Presumably, the transmetallation is facilitated by replacing triflate with CP at the palladium intermediate generated from oxidative addition. As Stille demonstrated in 1988, 4-quinolinyl triflate 100 was coupled with phenylstannane 101 in the presence of Pd(Ph3P)4 and LiCl in refluxing 1,4-dioxane to furnish biaryl 102, which was used as an intermediate for the first total synthesis of antibiotic amphimedine (88JA4051). 

A great advantage of catalyst 24b compared with other chiral Lewis acids is that it tolerates the presence of ester, amine, and thioether functionalities. Dienes substituted at the 1-position by alkyl, aryl, oxygen, nitrogen, or sulfur all participate effectively in the present asymmetric Diels-Alder reaction, giving adducts in over 90% ee. The reaction of l-acetoxy-3-methylbutadiene and acryloyloxazolidinone catalyzed by copper reagent 24b, affords the cycloadduct in 98% ee. The first total synthesis of ewt-J -tetrahydrocannabinol was achieved using the functionalized cycloadduct obtained [23, 33e] (Scheme 1.39). 

The first total synthesis of erythronolide B (1) by Corey stands as an event of great historical significance in synthetic chemistry it provides a powerful illustration of the utility of Corey s methods of macrolactonization and it demonstrates, in a particularly insightful way, the value of using readily accessible six-membered ring templates for the assembly of contiguous arrays of stereo-genic centers. 

In 1952, it was reported that a constituent of excretions from female American cockroaches of the species Periplaneta ameri-cana is an extraordinarily potent sex pheromone.1 Early attempts to isolate and characterize the active compounds were hampered because individual cockroaches store only minute amounts of the pheromone ( 1 pg), and a full 25 years elapsed before Persoons et al. reported the isolation of two extremely active compounds, periplanones A and B.2 The latter substance is present in larger relative measure and its germacranoid structure (1, without stereochemistry) was tentatively assigned on the basis of spectroscopic data. Thus, in 1976, the constitution of periplanone B was known but there remained a stereochemical problem of a rather serious nature. Roughly three years intervened between the report of the gross structure of periplanone B and the first total synthesis of this substance by W. C. Still at Columbia.3... 

Corey s solution to the intimidating structural and stereochemical complexities of ginkgolide B features an impressive collection of powerful bond-forming strategies. The first total synthesis of ginkgolide B by the Corey group is a major achievement of contemporary organic synthesis. 

Our general survey of palladium in organic synthesis must now come to an end. At the very least, we hope that our brief foray into this fascinating area conveys some of the vitality that characterizes research in this area. The remainder of this chapter will address the first total synthesis of rapamycin by the Nicolaou group. This work is predicated on a novel variant of the Stille reaction. 

Azinomycins A and B (64 and 65 Scheme 11.5) [115, 116] were isolated in 1986 from Streptomyces griseofuscus at the SS pharmaceutical company in Japan and were found to have potent in vitro cytotoxicities [117] and to display significant in vivo antitumor activity [118]. Since their discovery [117] and structure determination [119], their unusual molecular framework has attracted the attention of many chemists interested in their mode of action and in developing synthetic approaches to them [115,116]. The first total synthesis of azinomycin A was achieved in 2000 by Coleman et al. [120]. 

Scheme 1 RCM-based formation of a densely substituted cyclopentene in the first total synthesis of madindoline A (7) and ewf-madindoline B (8) [21]...

The first total synthesis of the marine dolabellane diterpene (+)-4,5-deoxy-neodolabelline (70) was accomplished by D. R. Williams et al. [58]. The trans-disubstituted dihydropyran moiety in key intermediate 69 was efficiently prepared from mixed acetal 66 by RCM with second-generation catalyst C and subsequent Lewis acid-catalyzed allylation of ethyl glycosides 67 with allylsi-lane 68 (Scheme 12) [59]. 

Scheme 13 RCM-based formation of the advanced dihydropyran fragment 72 in the first total synthesis of cacospongionolide B (74) [60]...

Scheme 17 RCM-based synthesis of octahydroindole 87 and pyrroline 90 in the first total synthesis of dynosin A (92) [66]...

Scheme 21 Threefold use of ruthenium catalysts in the first total synthesis of Stemona alkaloid tuberostemonine (113) [71]...

Nakadomarin A ((-)-145) is a marine natural product with a unique hexa-cyclic structure (Scheme 26). Recently, the first total synthesis of its enantiomer... 

In subsequent reports [87], the principle of asymmetric glycolate alkylation/ RCM sequence was applied to the first total synthesis of isolaurallene (172), that contains a densely functionalized A5-oxonene core (Scheme 32). Anticipating that the gearing effect created by two synergistic gauche effects at C6-C7 and... 

Migrastatin (192) (Scheme 37) is a novel macrolide natural product that displays an inhibitory effect on the migration of human tumor cells. After an RCM-based synthesis of the 14-membered macrolide core of 192 [94], Danishefsky also achieved the first total synthesis of the natural compound [95], using the fully functionalized tetraene 191 as the metathesis precursor. Under the conditions shown in Scheme 37, the ring-closing step proceeded (E)-selectively with exclusive participation of the two terminal double bonds in 191, delivering only the ( , ,Z)-trienyl arrangement present in 192. 

Another example of macrocyclic RCM with a diene-ene was disclosed in 2000 by Meyers and coworkers in the first total synthesis of griseoviridin (223) [ 107]. Griseoviridin is a highly complex member of the family of streptogramin antibiotics, featuring a 23-membered unsaturated bis-lactam core incorporat-... 

The first example of successful diene-diene RCM to construct a macrocyclic conjugated triene was disclosed by Wang and Porco in the first total synthesis of oximidine II (258) [121]. Oximidine II belongs to the family of salicylate en-... 

Roseophilin (273), a deeply red-colored pentacyclic compound isolated from the culture broth of Streptomyces griseoviridis, is a novel antitumor antibiotic. Compound 273 possesses a topologically unique pentacyclic skeleton, consisting of a 13-membered macrocycle incorporated in an ansa-bridged azafulvene, which in turn is linked to a conjugated heterocyclic ring system. The absolute stereochemistry of roseophilin, as depicted in Fig. 9, was unknown until the first total synthesis published by Tius and Harrington in 2001 [125]. All syn-... 

A stmple and general synthesis of 2,2,4,5-tetrasubstituted furan-3(2//)-ones from 4-hydroxyalk-2-ynones and alkyl halides via tandem CO, addition-elimination protocol is described <96S 1431>. Palladiuni-mediated intramolecular cyclization of substituted pentynoic adds offers a new route to y-arylidenebutyrolactones <96TL1429>. The first total synthesis of (-)-goniofupyrone 39 was reported. Constmction of the dioxabicyclo[4.3.0]nonenone skeleton was achieved by tosylation of an allylic hydroxy group, followed by exposure to TBAF-HF <96TL5389>. 

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