Synthetic Challenges

Phomactin A is the most challenging family member architecturally. The fragments that are most challenging are highlighted in Fig. 8.4. In Box-A, the highly sensitive hydrated furan is prone to dehydration under acidic or basic conditions, and any total synthesis almost certainly must save introduction of this fragment until the end game. Box-B relates to the strained and somewhat twisted electron-rich double bond. This trisubstituted olefin is extremely reactive toward electrophilic oxidants. 

Additionally, we believe that the olefin is not free to rotate and rotamer issues may arise in an attempted synthesis. In Box-C, the cis-methyl groups at C6 and C7 

In nearly two decades, challenging structured of phomactins coupled with the interesting biological activity has elicited an impressive amount of synthetic efforts [16-18]. (+)-Phomactin D was first synthesized by Yamada in 1996 [19], and Wulff [20] reported the synthesis of ( )-phomactin B2 in 2007. However, (+)-phomactin A has been the most popular target because of its unique topology. To date, two monumental total syntheses have been accomplished Pattenden s [21] racemic synthesis and Halcomb s [22] asymmetric synthesis in 2002 and 2003, respectively. Both syntheses are beautifully done but also mimicked Yamada s synthesis of D, thereby underscoring the remarkable influence of Yamada s earlier work on the phomactin chemistry. Upon completing their synthesis of ( )-phomactin A, Pattenden [23] completed ( )-phomactin G via a modified route used for A. 

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In the search for improved antibacterials not only has the effect produced by the variation of the C-7 amido side chain and the 3 substituent been studied, but so also has the more synthetically challenging question of the effect of changes in the cephem nucleus (194,197,198). Nuclear analogues have been studied since the early 1970s but only the oxacephem class has reached the marketplace. 

Scheme 6 shows representative members of these three groups. Other combinations are possible and the design of an appropriate bielectrophile for use as a versatile synthon presents a considerable synthetic challenge, as by virtue of the structural entities involved they are extremely reactive. 

The synthetic challenge is now reduced to the preparation of intermediates 2-4. Although intermediates 3 and 4 could potentially be derived in short order from very simple precursors (see Scheme 4), intermediate 2 is rather complex, particularly with respect to stereochemistry. Through a short sequence of conventional functional group manipulations, it is conceivable that aldehyde 2 could be derived from intermediate 9. Hydrolysis and keta-lization reactions could then permit the formation of 9 from intermediate 11, the cyclic hemiaminal of the highly stereo-defined acyclic molecule, intermediate 12. 

In contrast to the IJK system 86, compound 87 (Scheme 17a) poses a much steeper synthetic challenge it is during the course of the synthesis of 87 that the diabolical bis(oxepane) problem would have to be dealt with. At this phase of the project, we had benefited from a good deal of experience with the bis(oxepane) problem, and this experience provided the foundation for a conservative solution. Starting from FG ring system 105, it was hoped that rings E, D, C, B, and A could be annulated sequentially and in that order (Scheme 17c). 

Three decades ago the preparation of oxepin represented a considerable synthetic challenge. The theoretical impetus for these efforts was the consideration that oxepin can be regarded as an analog of cyclooctatetraene in the same sense that furan is an analog of benzene. The possibility of such an electronic relationship was supported by molecular orbital calculations suggesting that oxepin might possess a certain amount of aromatic character, despite the fact that it appears to violate the [4n + 2] requirement for aromaticity. By analogy with the closely related cycloheptatriene/norcaradiene system, it was also postulated that oxepin represents a valence tautomer of benzene oxide. Other isomers of oxepin are 7-oxanorbornadiene and 3-oxaquadricyclane.1 Both have been shown to isomerize to oxepin and benzene oxide, respectively (see Section 1.1.2.1.). 

Phospholes can readily be prepared on a large scale and are known with a vast range of substituants [6, 16b,c]. However, the synthesis of oligo(phosphole)s analogous to (C) (Fig. 1) is a real synthetic challenge since the low aromatic character of phosphole prevents the functionalisation of the P-Ca,a carbon atoms via electrophilic substitution and inhibits their preparation using electropolymerisation. As a consequence, no poly(phosphole)s have yet been reported, although bi- and tetra-phospholes have been prepared by stepwise routes (Scheme 2). 

The introduction of new synthetic techniques has led to the discoveries of many new electronic materials with improved properties [20-22]. However, similar progress has not been forthcoming in the area of heterogeneous catalysis, despite the accumulation of considerable information regarding structure-reactivity correlations for such catalysts [14-19]. The synthetic challenge in this area stems from the complex and metastable nature of the most desirable catalytic structures. Thus, in order to minimize phase separation and destruction of the most efficient catalytic centers, low-temperature methods and complicated synthetic procedures are often required [1-4]. Similar challenges are faced in many other aspects of materials research and, in general, more practical synthetic methods are required to achieve controlled, facile assembly of complex nanostructured materials [5-11]. 

The preparation and investigation of the thietane oxide system (5a) is largely associated with stereochemical and conformational studies . The investigation of the thietane dioxides (5b) is substantially related to the chemistry of sulfenes , the [2 -I- 2] cycloaddition of which with enamines is probably the method of choice for the synthesis of 5b . The study of the thiete dioxide system (6) evolved, at least in part, from the recognition that the unstable thiete system 183 can be uniquely stabilized when the sulfur in the system is transformed into the corresponding sulfone , and that the thiete dioxide system is very useful in cycloadditions and thermolytic reactions. The main interest in the dithietane oxides and dioxides (7) appears to lie in the synthetic challenge associated with their preparation, as well as in their unique structural features and chemical behavior under thermolytic conditions . ... 

Longifolene is a tricyclic sesquiterpene. It is a typical terpene hydrocarbon in terms of the structural complexity. The synthetic challenge lies in construction of the bicyclic ring system. Schemes 13.24 through 13.33 describe nine separate syntheses of longifolene. We wish to particularly emphasize the methods for carbon-carbon bond formation used in these syntheses. There are four stereogenic centers in longifolene,... 

The key synthetic challenges in the target molecule 1 were the chiral 2-arylpyrrolidine fragment, the densely functionalized benzimidazole ring, and the hindered biaryl ether linkage. 

Thioethers lack the capacity to neutralize positive charge and display weak donor properties. Consequently, they do not readily displace strong donor solvents (water) or strongly bonding anions (such as halides) from the coordination sphere. As a consequence, many thioether complex syntheses employ aprotic or alcoholic solvents and precursor complexes with weakly bound solvents (such as DMSO or acetone) or anions (such as C+3S03 ). Despite the synthetic challenges, a wide range of complexes has been reported, particularly with the cyclic poly-thioethers, where the macrocyclic effect overcomes many of the above difficulties. 

Dioxabicyclo[2.2.1]heptane naturally assumed the role of the principal target molecule. It represented a considerable synthetic challenge, for not only is it a strained bicyclic molecule containing the weak and labile 0—0 bond, but it is also a di(secondary-alkyl) peroxide which is the most difficult type to make by classical procedures 12). New synthetic methods of exceptional mildness were clearly needed to solve this problem. In the course of the development of such techniques and from a desire to establish their scope, a variety of saturated bicyclic peroxides have been obtained in addition to 2,3-dioxabicyclo[2.2.1]heptane. The question of how substitution patterns and ring sizes affect the reactivity of bicyclic peroxides has further served to broaden interest in the subject. 

We recognized at the outset of our studies that the synthetic challenge in achieving a direct synthesis of complanadine A would be to identify ways to exploit two molecules of lycodine or a closely related precursor. With appropriately positioned functional handles (at C2 and C3, respectively see 36 and 37, Scheme 11.5), the coupling of the pyridine moieties would yield the complanadine skeleton. 

Reviews of the syntheses of marine natural products, including marine isonitriles, have appeared recently [72]. After the early synthetic challenges of the tricyclic 9-isocyanopupukeanane (76) [73, 74] and 2-isocyanopupukeanane (78) [75] were met in 1979, additional syntheses of marine isonitriles were reported during 1986-1991. These were ( )-7,20-diisocyanoadociane (95) [63], ( )-axisonitrile-1 (1) and ( )-axamide-l (3) [76], the axisonitrile-4 triad (7-9) [78], and ( )-8,15-diisocyano-ll(20)-amphilectene (96) [79], and theonellin isocyanide (85) [80],... 

The ability to selectively direct chemistry at indole positions C4 to C7 remains a synthetic challenge. Takayama and co-workers have developed a procedure for masking the 2,3-Jt bond of indole as a bridged ethylene glycol system that allowed for functionalization of the... 

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