Stereochemistry ylids

E) alkenes. One explanation for this is that the reaction of the ylid with the carbonyl compound is a 2-1-2 cycloaddition, which in order to be concerted must adopt the [rt2s+n2al pathway. As we have seen earlier (p. 1079), this pathway leads to the formation of the more sterically crowded product, in this case the (Z) alkene. If this explanation is correct, it is not easy to explain the predominant formation of ( ) products from stable ylids, but (E) compounds are of course generally thermodynamically more stable than the (Z) isomers, and the stereochemistry seems to depend on many factors. 

For many years15 activated acetylenes have been known to undergo Diels-Alder reactions, which take place8,9 by concerted processes. The stereochemistry of the pyrazoline 9, obtained as sole product from the cw-aziridine 7 by heating in the presence of DMAD, can only be accounted for if opening of the ring to the ylid 8 is followed by a concerted, or extremely rapid, combination with the acetylene.16... 

The conrotatory stereochemistry fits the Woodward-Hoffmann rule, illustrated 4.81 as [dashed lines could equally have been drawn to make it [02a+w2J. 

The relative rates and stereochemistry of epoxidation reactions of 5-substituted-adamantan-2-ones with two sulfur ylids (methylenedimethylsulfurane and its oxy-sulfurane analogue) have been studied in DMSO and in benzene.318... 

These reactions may show considerable selectivity. Corey and Chaykovsky19 give an example with the terpene carvone 80. The ylid 78 is made with NaH and reacts only with the enone and not with the unconjugated alkene. The product is one diastereoisomer 81 as the ylid has added to the opposite side of the ring to the only substituent. It also has retained the stereochemistry of the cis alkene but that is inevitable as 3/6 ring fusion must be cis. 

The female silkworm moth attracts mates by producing a pheromone known as stabilized and unstabilized ylids, respectively, to control the stereochemistry of bombykol. Bombykol is an E.Zdiene, and in this synthesis (dating from 1977) the product, two successive Wittig reactions exploit the stereoselectivity obtained with... 

Because the cycloaddition is stereospecific (suprafacial on both components), the stereochemistry of the products can tell us the stereochemistry of the intermediate ylid, and confirms that the ring opening is conrotatory (the ylid is a 471 electron system). 

You will recall from Chapter 31 that we divided phosphorus ylids into two categories, stabilized and un stabilized , in order to explain the stereochemistry of their alkene-forming reactions. Again, there is a similarity with sulfonium ylids the same sort of division is needed—this time to explain the different regioselectivities displayed by different sulfonium ylids. Firstly, an example. 

The second reaction is a simple Wittig process. It stereoselectively gives the cis (Z-) alkene as it is a non-stabilized ylid (pp. 814—18). The three-dimensional stereochemistry is entirely controlled by the starting material. If we want a single enantiomer of the product, we must start with a single enantiomer of the aldehyde-ester. Asymmetry must be introduced before this reaction sequence. 

It was only after Woodward and Hoffmann had predicted a conrotatory mode for the thermal cyclopropyl-allyl anion transformation in 1965 9) that new interest developed in this reaction 10). But it was first shown by Huisgen and coworkers U) by means of the iso-rc-electronic uncharged aziridine 1 which gives the azomethine ylids 2 and 3, respectively, that the stereochemistry of the thermal and the photochemical reactions agrees with the prediction. 

These ylids are classified as semi-stabilised or of intermediate reactivity, and their stereoselectivity may be poor.43 If the stereochemistry of the double bond in the ylid (from 167) is E, this is generally retained in the product, but if it is Z, as in the ylid derived from 170, low temperatures are needed to stop rotation at the allyl ylid stage. At -25 °C less than 5% -171 is formed in the synthesis of vitamin D metabolites.44 The stereochemistry of the new double bond is generally not well controlled, 1 1 ratios of E Z are not uncommon, but Vedejs finds that phosphonium salts such as 172 with two phenyl and two allyl groups give good yields of T-dicncs45 such as 173. 

Corey s method20 relies on metal exchange with the bromocyclopropane 69 prepared by carbene addition. The extra stabilisation of cyclopropyl anions (chapter 8) makes both this lithium derivative and the ylid 63 more easily handled. Addition to aldehydes or ketones gives mixtures of adducts 70 [it turns out that none of the stereochemistry of 69 or 70 matters] which fragment under Lewis acid catalysis to give the thioacetal 71. Careful hydrolysis releases the 3,4-enal -72, the product of a homoaldol reaction with an aldehyde homoenolate and RCHO and a difficult compound to make as the double bond moves into conjugation very easily. 

This procedure was used in the synthesis of the upper chain of a prostaglandin 82 (see chapter 6) where the stereochemistry is related to the biological activity.13 Note that the aldehyde is tied up as a hemiacetal in the starting material 81 (see chemoselectivity chapter) and that the salt-free ylid is actually a carboxylate anion made with sodium derivative of DMSO in DMSO. As you will see in the next section, not all Wittig reactions are cis selective - those of stabilised ylids are trans selective. 

In a Wittig reaction with a non-stabilised ylid, the carbon-carbon bond formation is essentially irreversible and so the product stereochemistry... 

A.ii. (ElZ) Isomers in Wittig Reactions. When a phosphorus ylid reacts with an aldehyde or ketone, the alkene that is formed is a mixture of ( ) and (Z) isomers. l Initial postulations suggested that the stereochemistry of the alkene products was controlled by the stereochemistry of the betaine, which rapidly collapsed to an oxaphosphetane. Subsequent fragmentation to the alkene occurred via a syn-elimination pathway An example of this postulate is shown by addition of ylid 524 to 2-butanone to generate betaine 525 and the anti-oxaphosphetane, 527. Syn elimination led to the (El-alkene, 529. The reaction mixture also contained betaine 526, the precursor to the syn oxaphosphetane (528) which led to the (Z) alkene, 530. 

The intermediacy of the betaines used in the mechanistic discussions of the Wittig reaction has been questioned and Vedejs has proposed an alternative explanation. The Wittig reaction is subject to solvent effects that indicate a nonpolar transition state for stabilized ylids.There appears to be no direct evidence for the presence of betaines, and none have been isolated. Alternatively, Vedejs and Snoble detected oxaphosphetanes as the only observable intermediates in several Wittig reactions of nonstabilized ylids, using 3Ip NMR. In more recent work, Vedejs devised a test for the betaine mechanism based on changes in phosphorus stereochemistry in the proposed intermediates (betaine vs. oxaphosphetane). The results of this test suggested that "the conventional betaine mechanism l can play at most a minor role in the Wittig reaction".Vedejs points out that the "stereochemical test does not necessarily disprove mechanisms via intermediates with lifetimes that are short compared to the time scale of bond rotation. "494... 

The ability to control the stereochemistry of a Wittig reaction is seen in Wu s synthesis of annonacin, in which aldehyde 546 was treatment ylid 547 to give an 81 % yield of 548. A trans specific reaction is shown as a contrast in Pan s synthesis of (-)-6,7-dehydroferruginyl methyl ether. Aldehyde 549 reacted with the ylid generated from phosphonium chloride 550 to give the trans alkene (551) in 60% yield. 

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