Disconnections of Alkenes

In this section we shall closely inspect the retrosynthetic approach to simple alkenes, which includes disconnection of the C=C bond in two synthons, which have useful building blocks for synthetic equivalents. We shall not consider the formation of a double bond by p-elimination of two substituents on the vicinal carbon atoms, as for instance dehydration. More about these approaches is presented in the Sect. 4.3.1. 

Note Ylides are neutral, dipolar molecules that comprise a C atom with a formal negative charge directly bound to the positively charged heteroatom, usually nitrogen, phosphor or sulfur. They are characterized by separated charges in the betaine structure. Both vicinal atoms possess an octet of electrons and can be regarded as 1,2-dipolar compounds [17]. 

In the next example disconnection of an alkene reveals some typical pitfalls when proposing a synthetic route based on seemingly acceptable retrosynthetic analysis. 

Example 2.6 Propose the retrosynthetic analysis and synthesis of TM 2.6 without use of the Wittig reagent in the formation of the C=C bond. 

In the frame of the next example, we consider in more detail the mechanism and steric aspects of the Wittig reaction. 

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There are many other reactions that make C-C bonds using only one functional group. Among the most important involve alkynes by alkylation 73 (chapter 16), alkenes by the Wittig reaction 74 (chapter 15) and nitro compounds by alkylation 75 (chapter 22). Disconnections of alkenes outside the double bond 76 and especially disconnections of dienes between the double bonds 77 use palladium chemistry and are discussed extensively in Strategy and Control. 

Dicarbonyl disconnection of symmetrical (38) again reveals a suitable 1,6-dicarbonyl starting material (39) but reconnection gives an impossibly strained alkene (40). 

Besides the bond-pair cheletropic disconnection of oxiranes and aziridines to an alkene and "atomic oxygen" (from a carboxylic peracid) or a nitrene, respectively, and the hetero-Diels-Alder cycloreversion, of special interest are the 1,3-dipolar cycloeliminations of five-membered rings [-(34-2)] leading to 1,3-dipoles and an unsaturated acceptor or dipolarophile. So large is the number of different five-membered heterocyclic systems resulting from 1,3-dipolar... 

Abstract The main computational studies on the formation of (3-lactams through [2+2] cycloadditions published during 1992-2008 are reported with special emphasis on the mechanistic and selectivity aspects of these reactions. Disconnection of the N1-C2 and C3-C4 bonds of the azetidin-2-one ring leads to the reaction between ketenes and imines. Computational and experimental results point to a stepwise mechanism for this reaction. The first step consists of a nucleophilic attack of the iminic nitrogen on the sp-hybridized carbon atom of the ketene. The zwitterionic intermediate thus formed yields the corresponding (3-1 actant by means of a four-electron conrotatoty electrocyclization. The steroecontrol and the periselectivity of the reaction support this two-step mechanism. The [2+2] cycloaddition between isocyanates and alkenes takes place via a concerted (but asynchronous) mechanism that can be interpreted in terms of a [n2s + (n2s + n2s)] interaction between both reactants. Both the regio and the stereochemistry observed are compatible with this computational model. However, the combination of solvent and substituent effects can result in a stepwise mechanism. 

Metathesis reactions may be intramolecular and ring-closing diene metathesis (RCM, implicated in Scheme 1.13, see Chapter 12) allows disconnections in retro-synthetic analysis otherwise of little use. The normal disconnection of the macrocyclic amide in Scheme 1.13 would be at the amide but, because of the ready reduction of alkenes to alkanes, the alternative disconnection now becomes a viable option. And since any of the C—C linkages could be formed by RCM, such a disconnection allows far greater synthetic flexibility than the conventional disconnection at the functional group. 

With the advances in pro-catalyst design that have been witnessed over the last decade or so, the transition-metal-catalysed alkene metathesis reaction has now become a practical procedure that can be utilised by the chemist at the bench. Undeniably, this has added a new dimension to the repertoire of synthetic organic chemistry as it facilitates disconnections that, pre-metathesis, simply would not have been considered. Take, for example, a macro-cyclic amide where the normal disconnection would be at the amide. Now, with the ready reduction of alkenes to alkanes, a ring-closing diene metathesis (RCM), followed by hydrogenation, becomes an alternative disconnection. And, when one considers that any of the C—C linkages could be established in such a manner, the power of the RCM disconnection becomes obvious. 

An excellent application of the distinction between stabilised and unstabilised ylids is in the synthesis of leukotriene antagonists.10 The intermediate 39 (R is a saturated alkyl group of 6, 11 or 16 carbon atoms) was needed and disconnection of the Z-alkene with a normal Wittig reaction in mind followed by removal of the epoxide exposed a second alkene with the E configuration that could be made from the aldehyde 43 and the stabilised ylid 42. 

Having got the idea, you might not want to be bothered with the rehydration step as it is easy to see the hidden carbonyl group where the alkene is and the half of the molecule with the carbonyl group must be the enolate in real life. Most people just disconnect the alkene and write... 

The cyclisation methods we have used so far all depend on the simple disconnection 27a into a carbonyl group and an alkylating agent in the same molecule 28. But the same general class of molecule 27 can be made a very different way that is revealed by disconnection of two C-C bonds 27b to suggest an alkene 29 and a carbene 30. 

Disconnection of the bicyclic diketone 21 starts reasonably to reveal 22 but the two carbonyl groups are now 1,6-related suggesting a reconnection strategy (chapter 27). But this is impossible as the bridgehead alkene 23 is too strained to exist. However, if we extrude the carbon atom in the seven-membered ring between the ketone and the branchpoint 22a, we get a new ketoester 24 with a 1,5 relationship that can be made by conjugate addition (chapter 21). 

Disconnection of both C-N bonds of a pyridine 50 gives an ene-dione 51 but the alkene has to be cis for cyclisation to be possible and conjugated m-enones are rather unstable. It is usually easier to remove the double bond to reveal the saturated 1,5-diketone 52 that can be made by the methods of chapter 21. This usually means conjugate addition of an enolate to an enone. 

The disconnection of a four-membered ring is very simple—you just split in half and draw the two alkenes. There may be two ways to do this. 

Disconnection of an internal ( )- or (Z)-double bond or a side chain of an alkene suggests a Wittig-type reaction or an alkylation of a vinylcuprate, respectively. 

The Robinson annulation consists of a Michael addition followed by aldol cyclization with dehydration. In the retrosynthetic direction, disconnect the alkene formed in the aldol/dehydration, then disconnect the Michael addition to discover the reactants. 

The allylation of ketones is a simple reaction. Most of the specific enol equivalents described in chapters 2-6 react well with allylic halides. Disconnection of the y,5-unsaturated ketone 59 to the enolate 61 and the allylic halide 60 is trivial and the reaction of, say, an enamine will occur at the less hindered primary centre to give 59. However, supposing the target molecule is the isomeric ketone 63. The same disconnection gives the isomeric allylic bromide 62 which will almost certainly give the alternative product 59 by reaction at the less hindered end of the alkene. 

Since 227 has a 1,2-diX relationship, one way to make it would be to change the terminal OR into 1229 and use an iodine cyclisation of the alkene 230. That allows us to recognise a glycidol unit 231 by disconnection of the vinyl group. 

Both these products were used in the synthesis of epothilone A 173. The disconnection of the lactone is simple but the other is less obvious. The epoxide must come from a cis alkene and that can be made by a Suzuki coupling of a borane derived from 174 and the Z-vinyl iodide 175. As you will see, 174 was made from 169 and 175 from 172, unlikely as it seems. 

Disconnection at alkene a gives a fragment 130 with some functional group OR for the Wittig or Peterson reaction. There is a unique carbon atom between the nitrogen atom and alkene b so disconnection to an (unstable) iminium ion and a stereochemically controlled vinyl anion synthon 131 (chapter 16) was chosen by Overman,20 who rather specialises in this kind of iminium ion. 

When Zimmermann wished to study the photochemistry of a series of alkenes of general structure (3), he could have put the OH group at either end of the double bond. Putting OH at the branch point is better strategy as disconnection of the alcohol (4) then gives simpler starting materials. 

The first compound is an a,p-unsaturated carbonyl compound and this is one of the most important functional group combinations for you to recognize in planning syntheses. It is the product of an aldol reaction so simply disconnect the alkene and write a new carbonyl group at the far end of the old one. Don t lose any carbon atoms ... 

The ether is prepared via the corresponding halide. If the C-0 bond in 163 is disconnected, the logical bond polarization makes O 6- and a donor site Cj, and that of C2 is 6+, or (an acceptor site). In Chapter 25, Table 25.1 indicates that a synthetic equivalent for Cg is an alkyl halide. Therefore, a reasonable disconnection of 163 leads to 2-bromopentane (167) and the nucleophilic methoxide ion. This suggests a Williamson ether synthesis (Section 11.3.2). Can 167 be prepared directly from 1-pentene The answer is yes, by reaction of the alkene with HBr (Chapter 10, Section 10.2). Therefore, the retrosynthesis shown leads to the synthesis shown in which 1-pentene reacts with HBr to give 167, and a subsequent Sn2 reaction with... 

The new functional group exchange reactions presented in this chapter can be combined with reactions from previous chapters to expand the ability to synthesize molecules. Alkene 85 is synthesized from aldehyde 86, for example. The first task is to identify the four carbons of 86 in 85. It appears that the carbons marked in blue are the best candidates. Rather than disconnect the C-C=C unit marked in blue, first disconnect the ethyl group of 85 to give 87 and 88. This choice is made because no reaction has been presented that will allow direct incorporation of EtCHCH to X-C-CMea. Disconnection of the ethyl group takes advantage of the fact that an alkyne anion reacts with an alkyl halide. However, before this reaction can be used, the alkene unit in 87 needs to be changed to an alkyne unit in 89. 

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