THE DISCONNECTION PROTOCOL

Finally, a recently reported copper catalyzed carbon-nitrogen bond forming process utilises reagents with polarity opposite to the common disconnection protocols. An electrophilic nitrogen, in most cases an (9-acyl hydroxylamine derivative, was successfully coupled with diarylzinc reagents in the presence of copper triflate or copper chloride. Di(2 -pyridyl)zinc and TV-benzoyloxy-morpholine were reacted at ambient temperature in the presence of 1% copper(I) triflate to give 2-morpholinopyridine in 71% yield (7.81.), Under these mild conditions the reaction was over in less than one hour.103... 

The SASAPOS protocol has been applied to a small variety of pentafluoro benzene derivatives C6F5-E [E = -C(0)H, —C(N—Ph) H, — PCI2/—P(L+)2, —H] yielding the ion clusters C6(L+)s-E (F3CS03-)5.15 The reaction conditions required to observe a heteropolar C-C or C-P disconnection, with a highly stabilized pentakisonio-substituted phenyl anion (10) as the key intermediate have been specified. 

The radicals may dimerize, participate in mixed coupling between two different radicals, or undergo cyclization. Each of these avenues is illustrated by the examples discussed next. Simple dimerization allows retrosynthetic disconnections to be made at any symmetrical carbon-carbon bond in a target molecule, and has been used in, for example, the synthesis of onocerin (13) [5], a- and )6-oconceradiene (14 and 15) [6], and pentacyclosqualene (16) [6,7]. The use of a mixed Kolbe oxidation allows disconnections to be made at nonsymmetrically substituted sites. A host of natural products have been generated using the latter protocol including, for example, brevicomin (21) [8], looplure (29) [9], and disparlure (35) [10] [note Scheme 2, Eq. (6), and Scheme 3]. 

In particular, the disconnection between vincorine (18) and indoline 118 comprises the seemingly simple formation of a carbon—carbon bond, reminiscent of work performed by Rawal to install the ethyhdene moiety into Strychnos alkaloids. Unfortunately, multiple attempts including various reductive Heck coupHng protocols, Michael conditions, and radical... 

Application of this donor/acceptor protocol to 13 leads to a problem, however. The carbon that was part of the disconnected bond, marked with a may be either a donor or an acceptor. If that carbon is designated as a donor in 13d°n° , then the analogous carbon in must be an acceptor. Conversely,... 

An alternative disconnection of homopropargylic alcohols substrates for intramolecular hydrosilylation is the opening of an epoxide with an alkynyl anion. This strategy was employed in a total synthesis of the macrolide RK-397 (Scheme 20). Epoxide ring opening serves to establish homopropargylic alcohol C with the appropriate stereochemistry. A hydrosilylation/oxidation protocol affords the diol E after liberation of the terminal alkyne. The... 

If this protocol is applied to disconnect fragments 20 - 23, either carbon at the point of disconnection can be assigned as a donor (d) or an acceptor (a), giving four different possibilities. Disconnect products 20 and 21, for example, become 25 or 26 and 27 or 28, respectively. Fragments 25 - 28 are still not real molecules, and another step is required before the best donor-acceptor pair can be chosen each fragment must be correlated with a synthetic equivalent. Table 1.2 provides a list of common synthetic equivalents, leading to a modified definition of synthetic equivalent, which is a molecular fragment that is equivalent to a real molecule... 

These final examples illustrate the power of hydroamination as a disconnection strategy in the assembly of complex natural products. Most importantly, these examples show that efforts in catalyst development have realized catalytic protocols that can be compatible with heavily functionalized substrates and can also be transferred to more specialized hydroguanidation reactions. 

Fragments 2 and 3 are not real because each carbon (marked in red) has only three bonds. As noted before, there must be a protocol that converts these fragments into real molecules. Disconnection of the indicated bond in 4 can be correlated with two real molecules 5 and 6. A reaction in Chapter 18 prepared the indicated bond of an alkyne-alcohol (4) from fragments 5 and 6 (Section 18.3.2). Note the similarity of 5 to 2 and of 6 to 3. In terms of a disconnection, this simply means that the bond in 4 is disconnected because that bond can be formed in a synthesis by an acyl addition of the anion of 5 to 6. Acyl addition... 

There is a simple test for this protocol. Is it possible to make molecule 1 by the reaction of the anion derived from 7 and acetone The answer is yes The lesson is to correlate disconnect fragments with real molecules. This often means recognizing the chemical relationships of the functional groups involved and adding appropriate functional group transformations. 

What is the first bond in 9 to be disconnected Either bond a or bond b may be chosen, based on the previous analysis. Before making a choice, a protocol will be developed to assist in the choice. Ml or nearly all reactions presented in this book involve formal ionic intermediates (cations or anions) or they involve the reactions of molecules with positive or negative polarized atoms. Exceptions are those reactions that involve a pericychc mechanism (see Chapter 24). Reactions used to construct new carbon-carbon bonds usually involve carbocation intermediates, carbanion intermediates, compormds containing a nucleophilic (6-) carbon, or those with an electrophUic ( f) carbon atom. It can therefore be said that most of the organic chemistry presented in this book involves ionic chemistry of one sort or another. 

C-C P is an epoxide. Given these synthetic equivalents and the need to disconnect carbon-carbon bonds near the functional group, a real example will illustrate the protocol. 

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