Cycloadditions Taxol

Preparation and Diels-Alder cycloaddition of 2-acyloxyacroleins. Facile synthesis of functionalized taxol A-ring synthons [144]... 

Oxetanes are present in several biologically active natural compounds as, for example, the taxol ring skeleton. An interesting method used to obtain this particular ring is the thermal [2 -i- 2] cycloaddition reaction. Longchar and co-workers reported a novel [2-1-2] cycloaddition of /1-formil enamides 5, often used in other cycloaddition and condensation processes, with acetylenic dienophiles 6 under microwave irradiation (in a domestic oven) to afford ox-etenes 7 in 80% yields [29]. This reaction was directed towards the synthesis of D-ring annelated heterosteroids (Scheme 2). 

The cycloaddition of ketone 54 could be effected in a sealed glass tube in a modified microwave oven to afford the tricyclic system stereoselectively. This major adduct arose via the preferred transition state, in which the nonbonded interactions were minimized, because of the alignment of the dienophile beneath the triene unit furthest from the MOM substituent. This pattern of n-facial selectivity implies that, with the natural C2 stereoselectivity, the preferred geometry should provide the relative stereochemistry required for taxol itself. 

Magnus and co-workers (158-162) used the power of the oxidopyrylium cycloaddition to prepare a taxol precursor 288, generating a synthon for the taxol... 

The intramolecular nitrile oxide-alkene cycloaddition sequence has been used for the assembly of a great variety of natural products. A target that has received special attention is that of taxol (156), undoubtedly due to its unique structural features, its potent anticancer activity, and its hmited availability from natural sources (318,319). In 1984 Kozikowski et al. found that the treatment of nitro dienone 158 (obtained from the p-benzoquinone derivative 157) with p-chlorophe-nyl isocyanate under Mukaiyama conditions afforded the unexpected eight-mem-bered ring 159, which is related to ring B of taxol (156) (Scheme 6.79). 

In later work, Mioskowski and co-workers (320) used cyclohexenone 160 to prepare oxime 161 as part of a twofold nitrile oxide strategy to synthesize the basic taxol ring system. Cycloaddition of 161 was effected by means of sodium hypochlorite and gave tricyclic isoxazoline 162, which feamres rings A and C of taxol (320) (Scheme 6.79). Nagaoka and co-worker tried to apply a related intramolecular cycloaddition toward the synthesis of the taxane A/B ring but this approach failed, producing only the oxime derivative (248) (see Scheme 6.44, Section 6.3.1). 

The 1,3-dipolar cycloaddition of the carbonyl ylide (31) to the aldimine (32) produces the adduct (33), which has been used to synthesize the taxol C(13) side-chain (34), which is known to be required for the antitumour activity of taxol (Scheme 9).35 The dirhodium tetraacetate-catalysed decomposition of l-diazo-5-phenylpentane-2,5-dione (35) yields the carbonyl ylide (36), which cycloadds to methylenecyclopropanes (37) to produce spirocyclopropanated 8-oxabicyclo[3.2.1]octan-2-ones [(38)-(40)] in 6-75% yields (Scheme 10).36 The 1,3-dipolar cycloadditions of aliphatic or alicyclic thiocarbonyl ylides with thiobenzophenone produce both regioisomeric 1,3-dithiolanes as expected. However, in the case of highly sterically hindered thiocarbonyl ylides, methylene transfer leads to the formation of 4,4,5,5-tetraphenyl-l,3-dithiolane.37,38... 

A similar approach was employed en route to a synthesis of taxol precursors, as shown in Scheme 14 <1996T14081>. In this case, a [5+2] cycloaddition reaction of 133 yielded diastereoisomers 134a and 134b. 

N-Acylimines which may react as l-oxa-3-aza-l,3-butadienes represent a class of heterodienes which exhibit a close relationship to l-thia-3-aza-l,3-butadienes [13]. A very impressive application of such an l-oxa-3-aza-l,3-butadiene has been worked out by Swindell et al.[445]. The asymmetric hetero Diels-Alder reaction described therein opens a very elegant approach to the A-ring side chain of taxol. This synthesis takes advantage of the bulky chiral auxiliary attached to the dienophile 6-5 which upon cycloaddition with the l-oxa-3-aza-1,3-butadiene 6-4 yielded the 1,3-oxazine derivative 6-6. Subsequent hydrolysis, hydrogenolysis and transesterification gave the methyl ester of the taxol A-ring side chain 6-7 in good endo and excellent zr-facial selectivity (Fig. 6-2). 

This method provides the basis for a general and efficient route to alkyl-substituted and heterofunctionalized bicyclo[6.4.0]dodecanes and to bicyclo[5.3.1]undecanes. In several model studies, the nickel-catalyzed intramolecular [4 + 4] cycloaddition of bis-dienes has been applied to the construction of diterpene systems, such as taxol (7), crispolide, and vulgarolide13 1S. Thus, in the case of taxol. both AB- and BC-ring fusion is achieved with high yield and high diastereoselectivity13. 

ABSTRACT In this chapter we describe the development and application of the intramolecular diyl trapping reaction (cycloaddition) to the total synthesis of hirsutene, capnellene, coriolin, and hypnophilin, as well as its application toward the synthesis of aphidicolin and an analog of taxol . 

Scheme 6. Diyl cycloaddition route to analog taxol 92.

Thus, Sieburth et al. have come pretty close to taxol (20) and fusicoccin (1) in an elegant way. Their results have provided vital new impetus for the total synthesis of naturally occurring cyclooctanoids, many of them exhibiting mitotic inhibition that is so typical for this class of compounds. It should always be attempted, by means of stereoselective cycloaddition, to save steps in a total synthesis. 

Scheme 10-21 Nicolaou et al. used a boron-tethered cycloaddition to construct the C-ring of taxol.

Tandem cyclization cycloaddition of diazoketones in the synthesis of sesquiterpenes, possessing 7-oxabicyclo [2.2.1]heptane fragment 97F303. Terpenoids with heterocycHc fragments as bioactive taxoids from Japanese yew Taxsus cuspidata and taxol bios5mthesis 98H(47)1 111. 

Another recent application of this methodology to synthesis is the diastereoselective [4+2] cycloaddition of pyrone 59 to (/ )-t-butylben-zyl vinyl ether in the presence of dimethylaluminum chloride which yields bicyclic lactone 60 in modest diastereomeric excess. The major isomer is subsequently elaborated to aC-ring fragment of taxol. 

Photosubstrate 69 was an intriguing and optimistic approach with all but two carbons of the tetracyclic taxol target. Unfortunately, this bis-2-pyridone did not photocyclize to 70 but only slowly decomposed photochemically. We speculated that the obstacle to this cycloaddition was the requirement that four fiilly substituted sp carbons be created in a single step. Molecular modeling reinforced this view. ... 

As described in Figures 18 and 24, cycloaddition of 52 yields a single photoproduct 53 that has both quaternary centers of taxol. The lone stereogenic center in 52 controls formation of the adjacent stereogenic center and the associated amide nitrogen. Then the trans-... 

Figure 24. Cycloaddition route to taxol and elaboration of the photo-product. ...

Intermolecular cycloaddition of n-butyl-2-pyridone and 4-methoxy-2-pyridone gives 17 in 51% yield (Figure 1)P This has provided a platform to explore the reactivity of the photoproducts. A combination of the n-butyl substituent and an absence of symmetry results in good solubility properties for 17 compared with many simple pyridone photodimers. Some initial transformations of 17 are shown in Figure 31. In all cases the yields exceed 70% and in most cases are nearly quantitative. The simplest reaction is hydrogenation. The close analogy of 17 to the core of taxol intermediate 53 (Figures 18... 

The enone 6.3.16 derived from baccatin III underwent a 2 + 2 cycloaddition reaction to give the hexacyclic product 6.3.17. This product was converted to the two taxol analogs 6.3.18 (epimeric at C-... 

Since the last review in this series in 1993 (10) and the publication of Ojima s paper summarizing his approach to the / -lactam (237), a number of new approaches for the asymmetric synthesis of the / -lactam taxol side chain have emerged. For example, chiral sulfonamide esters have been used as chiral auxiliaries to achieve diastereoselective cycloaddition with N-TMS-imine, to give lactam 7.1.1 in 94% yield. Benzoylation of 7.1.1 yielded the ready-to-couple lactam 7.1.2 in 96% yield (238). 

The approaches to the taxol side chain described so far have used either a cycloaddition reaction to form a / -lactam, or have installed functional groups on a preexisting carbon skeleton. Another possible approach is to couple two halves of the side chain in some sort of stereo-controlled coupling reaction, and several examples of this chemistry have been published. 

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