Cycloadditions quaternary centers

A synthetic approach to hyperevolutin A 421, prenylated bicyclo[3.3.1] nonanone derivative, with an acylated phloroglucinol-type fragment, has been described (464). Intramolecular allene-nitrile oxide cycloaddition of 422 has been used to construct the bicyclic framework and the vicinal quaternary centers in cycloadduct 423. 

With this revision in our original plans, both alkenes and allenes were found to undergo efficient cycloadditions to produce cyclooctenone products in a new [6+2] cycloaddition process. This novel cycloaddition has been shown to proceed efficiently with alkenes tethered with sulfonamide, ether, or geminal diester Hnkers (Tab. 13.15, see page 294). Isomerization of the olefin, a potential competing reaction in this process, is not observed. Methyl substitution of either alkene in the substrate is well tolerated, resulting in the facile construction of quaternary centers. Of mechanistic importance, in some cases cycloheptene byproducts were isolated from [6+2] cycloaddition reactions in addition to the expected cyclooctenone products (that is, entries 3 and 4). 

Synthesis of 16,16,16-trifluororetinal requires the constmction of a quaternary center bearing a CF3 group. For this, a Diels-Alder cycloaddition (cf. trifluoromethyl steroids) between a trifluoromethacrylate and a functionahzed diene has been conducted. The obtained adduct has been transformed further into the trifluoromethyl analogue of jS-cyclocitral (Figure 4.26). ... 

The synthesis of (+)-estrone methyl ether (36) illustrates the enantioselective construction of a polycyclic target by the use of chiral auxiliary control to establish the first cyclic stereogenic center [14], In this case, the specific design of the naphthyldiazoester 32 directed Rh-mediated intramolecular C-H insertion selectively toward one of the two diastereotopic C-H bonds on the target methylene. The new ternary center so created then biased the formation of the adjacent quaternary center in the course of the alkylation. The chiral skew in the product cyclo-pentanone (35) controlled the relative and absolute course of the intramolecular cycloaddition, to give the steroid (+)-estrone methyl ether (36). 

Heathcock used as concerted cycloaddition intramolecular photochemical (2 + 2) addition to create the quaternary center in his projected synthesis. A cationic rearrangement Wagner-Meerwein rearrangement) was intended as further key step but failed (162). 

The utility of such cycloadditions has been demonstrated by the elaboration of the cycloadducts to complex natural products [60]. For example, the adduct derived from a cyclopentadiene having a 2-bromoallyl sidechain has been converted to an intermediate employed in a previous (racemic) synthesis of gibberel-lic acid. As illustrated in Scheme 12, an exceptionally efficient synthesis of cassi-ol is realized by the successful execution of a rather difficult endo-selective Diels-Alder reaction using a slightly modified oxazaborolidine (11). The high catalyst loading is balanced by the fact that all the carbons and the quaternary center of the natural product are introduced in a single step. 

Intramolecular alkene cycloadditions are also important, not only for generation of quaternary centers but also for construction of bigbly bridged molecules. We saw an example of this in tbe photocyclization of 356... 

The cycloaddition proceeds efficiently even with methyl substitution of the double bond of the vinylcyclopropane. Although angular alkyl substituents are commonly encountered in natural products and designed targets However, the introduction of such a group has remained a considerable synthetic challenge. Given this situation, it is noteworthy that these new reactions proceed well even when a quaternary center is developed. Cycloaddition of yne-vinylcyclo-... 

Substrates 46 (E Z =5.5 1) and 48 were selected for study because of the number of naturally occurring bicyclo[5.3.0]decanes bearing an angular methyl group and because of the general difficulties associated with quaternary center formation. These methyl-substituted substrates (46 and 48) react rapidly (reaction times 1 h) and with high efficiency (>90%) to afford exclusively the cw-fused products 47 and 49, respectively (Eqs. 59 and 60). In these cases, silver triflate is required for clean conversion. In its absence, decomposition occurs more rapidly than cycloaddition. At higher substrate concentration and... 

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-... 

In the case of 1,1,2,2-tetramethylenecyclobutane made optically active by virtue of labeling frani-methyls with deuterium, pyrolytic retro 2 + 2 cycloaddition is much faster than either double or single rotation. This must represent the difficulty of reclosure of any biradical to generate two contiguous quaternary centers relative to cleavage. 

An equally enticing interpretation for the formation of colombiasin A (1), first advanced by the Nicolaou group in 2001, relies instead upon dehydration of the hydroxy group at C-9 in 2 with concurrent isomerization leading to the diene system 5. Due to the proximal nature of the putative diene and dienophile units in 5, a productive Diels—Alder cycloaddition would then lead directly to 1 with concomitant formation of the adjacent and daunting quaternary centers. In this chapter, we shall focus our attention... 

During a synthesis of ( )-albene 133, an orthoester rearrangement allowed the control in the formation of a stereogenic quaternary center in a bicyclo[2.2.1]hep-tane alcohol derivative. In this synthesis [31], Srikishna prepared the aUyUc alcohol 134 by a Diels-Alder cycloaddition followed by several transformations. Alcohol 134 afforded by rearrangement the ester 135 via a sterically preferred exo transition state (Scheme 6.19). 

Phosphine-Catalyzed Reactions Phosphine-catalyzed [3+2] dipolar cycloaddition has been applied in an intramolecular manner, whereby three contiguous stereogenic centers, including a quaternary center, are created in a single operation (Scheme 6.27). It may be noted that the intramolecular cycloaddition is stereospecific. When the E-isomer is used as the starting material, the quaternary center formed possesses the stereochemistry consistent with the structural features of hirsutene [31]. 

As mentioned in the Introduction, the group 3 biomimetic approach (see Scheme 1) has been the most popular route to the trichothecene skeleton. Two different moieties have served as the electrophilic site for biomimetic cyclization. When the cyclization proceeds via an allylic carbonium ion (127) (Path A, Scheme 9), the desired trisubstituted olefin (126) is obtained directly. On the other hand, the Michael acceptor (128) (PathB) yields, upon cyclization, a ketone (129) which must then be transformed into the olefin (126), a process which shows good but not complete regioselectivity. Hence, Path A, which can also be entered from the enone (128), is the superior route. Further analysis of Scheme 9 reveals that the primary stereochemical challenge of the biomimetic approach is to control the relative stereochemistry at the two quaternary centers C-5 and C-6. Within the context of trichothecene synthesis, a number of useful protocols have been devised for this purpose and include photocyclization (99), selective ring contraction (134), Diels-Alder cycloaddition (117,125) conjugate addition (27,120), and interconversion of dienyl iron complexes (114). 

Vollhardt s total synthesis of strychnine successfully demonstrated the power of the cobalt-mediated [2+2+2]cycloaddition (111) for the construction of complex polycyclic molecules (Scheme 11). This key reaction was originally developed by his group in the 1970s, and widely utilized for the syntheses of complex natural and unnatural products (112-116). Here, this reaction was used for the simultaneous closure of the E and G rings with formation of the C7 quaternary center (117-119). To accomplish total synthesis, five synthetic approaches were investigated, but only the successful one is shown here. 

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