Page 16 - Advanced Organic Chemistry Part B - Reactions & Synthesis

synthetic interest are now within the range of computational analysis. Intermediates xvii
and transition structures on competing or alternative reaction pathways can be modeled
and compared on the basis of MO and/or DFT calculations. Such computations can Introduction
provide intricate structural details and may lead to mechanistic insight. A number of
such studies are discussed in the course of the text.
A key skill in the practice of organic synthesis is the ability to recognize important
aspects of molecular structure. Recognition of all aspects of stereochemistry, including
conformation, ring geometry, and configuration are crucial to understanding reactivity
and applying reactions to synthesis. We consider the stereochemical aspects of each
reaction. For most reactions, good information is available on the structure of key
intermediates and the transition structure. Students should make a particular effort to
understand the consequences of intermediates and transition structures for reactivity.
Applying the range of reactions to synthesis involves planning and foreseeing the
outcome of a particular sequence of reactions. Planning is best done on the basis of
retrosynthetic analysis, the identification of key subunits of the target molecule that
can be assembled by feasible reactions. The structure of the molecule is studied to
identify bonds that are amenable to formation. For example, a molecule containing
a carbon-carbon double bond might be disconnected at that bond, since there are
numerous ways to form a double bond from two separate components. -Hydroxy
carbonyl units suggest the application of the aldol addition reaction, which assembles
this functionality from two separate carbonyl compounds.

O R 2
base or
2
1
R CH O + R CH CR 3 R 1 R 3
2
acid
electrophilic nucleophilic OH O
reactant reactant
The construction of the overall molecular skeleton, that is, the carbon-carbon and
other bonds that constitute the framework of the molecule, is the primary challenge.
Molecules also typically contain a number of functional groups and they must be
compatible with the projected reactivity at each step in the synthesis. This means that
it may be necessary to modify or protect functional groups at certain points. Generally
speaking, the protection and interconversion of functional groups is a less fundamental
challenge than construction of the molecular framework because there are numerous
methods for functional group interconversion.
As the reactions discussed in Chapters 1 to 12 illustrate, the methodology of
organic synthesis is highly developed. There are many possible means for introduction
and interconversion of functional groups and for carbon-carbon bond formation, but
putting them together in a multistep synthesis requires more than knowledge of the
reactions. A plan that orchestrates the sequence of reactions toward the final goal is
necessary.
In Chapter 13, we discuss some of the generalizations of multistep synthesis.
Retrosynthetic analysis identifies bonds that can be broken and key intermediates.
Various methods of stereochemical control, including intramolecular interactions.
Chiral auxiliaries, and enantioselective catalysts, can be used. Protective groups can
be utilized to prevent functional group interferences. Ingenuity in synthetic planning
can lead to efficient construction of molecules. We take a retrospective look at the
synthesis of six molecules of differing complexity. Juvabione is an oxidized terpene