An Introduction to Multistep Synthesis

The negatively charged acetylide ion (a nucleophile) is attracted to the partially positively charged carbon (an electrophile) of the alkyl halide. As the electrons of the acetylide ion approach the carbon to form the new C—C bond, they push out the bromine and its bonding electrons because carbon can bond to no more than four atoms at a time. 

The previous reaction is an example of an alkylation reaction. An alkylation reaction attaches an alkyl group to a species. The mechanism for this and similar reactions is discussed in greater detail in Chapter 9. Then you will understand why the reaction works best with primary alkyl halides and methyl halides. 

We can convert terminal alkynes into internal alkynes of any desired chain length, simply by choosing an alkyl halide with the appropriate structure. Just count the number of carbons in the terminal alkyne and the number of carbons in the product to see how many carbons are needed in the alkyl halide. 

A chemist wants to synthesize 3-heptyne but cannot find any 1-pentyne, the starting material used in the synthesis just described. How else can 3-heptyne be synthesized  

Solution The sp carbons of 3-heptyne are bonded to an ethyl group and to a propyl group. Therefore, to synthesize 3-heptyne, the acetylide ion of 1-pentyne can react with an ethyl halide or the acetylide ion of 1-butyne can react with a propyl halide. Since 1-pentyne is not available, the chemist should use 1-butyne and a propyl halide. 

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Section 6.11 Designing a Synthesis I An Introduction to Multistep Synthesis 255... 

CHAPTER 7 The Reactions of Alkynes An Introduction to Multistep Synthesis... 

An illustrative example of an alternative strategy (cf Fig. 11c) involving the use of a novel traceless linker is found in the multistep synthesis of 6-epi-dysidiolide (363) and several dysidiolide-derived phosphatase inhibitors by Waldmann and coworkers [153], outlined in Scheme 70. During the synthesis, the growing skeleton of 363 remained attached to a robust dienic linker. After completion of intermediate 362, the terminal olefin in 363 was liberated from the solid support by the final metathesis process with concomitant formation of a polymer-bound cyclopentene 364. Notably, during the synthesis it turned out that polymer-bound intermediate 365a, in contrast to soluble benzoate 365b, produced diene 367 only in low yield. After introduction of an additional linker (cf intermediate 366), diene 367 was released in distinctly improved yield by RCM. 

For an effective synthesis of trichodermol, there remain three points of concern. First, the formation of an equimolar mixture of diastereomers (97) leads to inefficiency, since realistically only half of the material can be used. Second, the ester group of complex (168) has to be reduced to methyl, a multistep operation which again is unattractive it would be better to attach to complex (30) an enolate having methyl in place of the ester. Third, the introduction of the trichodermol 4-hydroxy group must be accomplished in some manner. 

Modified microwave ovens. The accuracy and safety factor in microwave assisted organic synthesis can be increased by causing a slight variation in domestic microwave oven. The modified microwave oven differs from domestic microwave oven in having a hole on top of cavity. This allows the introduction of a tube (acting as an air cooler) surmounted by a water cooler to maintain reaction s solvent reflux or under inert atmosphere, or allowing the chemist to follow multistep procedures of chemical synthesis. 

Estradiol bis(trimethylsilyl) ether (235 Scheme 50) has been converted into a diasteromeric mixture of adducts (236) which were hydrolyzed by aqueous acetic acid to a mixture of the isomeric enones (237 36% yield) and (238 9% yield).This provides an especially direct route for the introduction of functionality at C-1, which would otherwise require a multistep sequence. Reductive silylation has also been used to convert anisole into enone (239)which, following a kinetic resolution, has been used in an en-antioselective synthesis of (-i-)-a-curcumene (240 Scheme 51). The silyl substituent was employed to control the stereochemical and regiochemical aspects of subsequent steps. 

The above example is very simple where the method of conventional organic synthesis did not need to be modified much. There are. however, other labeled s)mtheses where the organic synthesis method has to be modified profoimdly. One such example is the mthesis of DL-lysine labeled in the e-carbon atom. One interesting problem arises here. Since this synthesis is a multistep process, the isotope can be introduced either at an early step in the experiment, or in a later step. The latter option seems ro firom the point of view of conserving the radioactive isotope. However, it is experimentally found that introduction of isotope at a later step in the experiment does not yield the desired product. Therefore, even though the yield would be less, it is necessary that liie isotope be introduced at an early step in the mthesis. The reaction steps are givert low. 

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