Stereocontrol and ring formation

Stereocontrol in acyclic systems

Reactions of acyclic molecules can generate diastereomers and the term controlling
stereochemistry usually refers to an attempt to generate one diastereomer in preference to
another as the mayor product of a reaction. The types of situations where attempts to control
stereochemistry are important include:
1. Regioselectivity (Markovnikov/anti-Markovnikov)
2. Retention versus inversion of configuration
3. Cis-Trans selectivity
4. Syn-Anti selectivity
5. Hereroatom chelation effects
Regioselectivity
A typical reaction that illustrates Markovnikov addition is the reaction of HBr with 2-methyl-2butene to give 2-bromo-2methylbutane. This reaction proceeds by formation of the more stable
carbocation, which reacts with the nucleophilic bromide ion. If the anti-Markovnikov bromide is
desired, a different mechanistic pathway must be followed. A typical anti-Markovnikov addition
reaction is addition of borane to the alkene, giving primary alcohol (2) after oxidation of the
intermediate alkylborane. This alcohol can be converted to the anti-Markovnikov bromide 3, by
treatment with PBr3.

Retention versus inversion of configuration.

A classical example of controlling the configuration of a stereocenter is conversion of a chiral
secondary alcohol to the corresponding secondary chloride with thionyl chloride, and it is also
another example of changing stereochemistry by modifying the mechanism of the reaction. Both
retention of configuration (neat SOCl2) and inversion (SOCl2 + pyridine) are possible. Thionyl
chloride reacts with (S)-2-pentanol to produce a chlorosulfinate ester (5). The HCl byproduct
escapes from the reaction medium and an intramolecular delivery of chloride in what is called a
SN1 mechanism, with concomitant loss of sulfur dioxide (SO2) gives (S)-2-chloropentane (6). The
synfacial delivery of chlorine generates the chloride with retention of configuration of the original
hydroxyl moiety.

If pyridine (or another basic tertiary amine) is added, then the HCl byproduct is trapped as the
pyridinium hydrochloride salt and nucleophilic chloride ion is in the medium. Displacement of the
chlorosulfinate ester by chloride in an SN2 reaction gives chloride 8 with net inversion of
configuration. The presence or absence of a nucleophilic chloride ion allows one to control the
stereochemistry of the reaction.

Cis-trans selectivity.
Control of cis-trans geometry is well illustred by catalytic hydrogenation of alkali metal reduction
of alkynes. The Lindlar catalyst allows selective reduction of alkynes to the cis-alkene, as in the
conversion of 23 to 24 in Kaiser s synthesis of niphatoxin B. This contrasts sharply with treatment
of an alkyne with alkali metals to give the trans alkene, as in the conversion of 25 to 26. Once

again, a fundamental understanding of the difference in these two reaction mechanisms allowed
control of the cis-trans geometry of the final product.

Syn-anti selectivity
There are many reactions that generate a mixture of syn and anti diastereomers, and if the
reaction is diastereoselective, one predominates. An example is the conversion of alkenes to 1,2diols. Reactions of alkenes with aqueous permanganate or osmium tetroxide lead exclusively to a
cis diol via the syn hydroxylation mechanism. It is a diastereospecific reaction. Sharpless
developed a protocol for high asymmetric induction by adding quinidine (33), with either Nmethylmorpholine oxide (NMO) or tert-butylhydroperoxide with osmium tetroxide (OsO4). As
seen in the hydroxylation of trans-stilbene, the syn-diol 34 is the major product.

Heteroatom chelation.
One major way to control diastereoselectivity is to take advantage of the chelating effect of
neighboring hereroatom groups (neighboring group effects) with certain reagents, wich can be
illustrated by reaction of chiral allylic alcohol 37 with a peroxyacid. Coordination with the oxygen
and delivery of the electrophilic oxygen from that side gave epoxy alcohol 39 as the major
diastereomer, which means that coordination directs the stereochemical course of the reaction.
The Sharpless asymmetric epoxidation esploits this chelation effect because its selectivity arises
from coordination of the allylic alcohol to a titanium complex in the presence of a chiral agent. The

most effective additive was a tartaric acid ester (tartrate), and its presence led to high
enantioselectivity in the epoxidation.

Stereocontrol in cyclic systems

Many of the problems encountered in acyclic systems also arise in cyclic systems. The methods for
controlling Markovnikov and anti-Markovnivkov regiochemistry and retention or inversion of the
configuration are essentially the same as in acyclic systems. It is difficult to separate regiochemical
(mode of addition) effects and retention versus inversion effects from cis-trans isomerism in cyclic
molecules. Addition to a substituted bond leads to geometrical isomers, and in most cyclic
systems control of the absolute configuration of a stereogenic center is associated with cis-trans
isomers and/or with diastereomer formation. The terms syn and anti have no meaning in cyclic
systems, and only three discussions fundamental to cyclic molecules will be presented: control of
diastereoselectivity, inversion of configuration of a sterogenic center, and the chelating effects of
heteroatoms. An important and differentiating feature of cyclic systems is the relatively rigid
conformations assumed by these molecules. These effects provide the tools to control selectivity.
Regioselectivity
The problems associated with regioselective addition to cyclic molecules are essentially the same
as those noted in acyclic molecules.
Bredt s rule.
As we have just seen in the formation of 53 or 54, regioselectivity is important in the formation of
double bonds in elimination reactions. Regiocontrol in the elimination was achieved by binding the
base to the molecule (an internal base for anti-elimination). Treatment of a halide such as 55 with
potassium tert-butoxide in tert-butanol led to anti elimination and formation of the more
substituted alkene (56), which is due to the late transition state of the reaction, invoking the
Hammond postulate, and the electronic requirements that position the leaving group anti to the
hydrogen being removed, effectively locking the conformation in that transition state. The same

effect is observed in cyclic halides such as cis-2-bromo-1-methylcyclopentane (57), which gives

methylcyclopentene (58) upon treatment with base. The major difference, of course, is the
inability of the ring to rotate about the carbon-carbon bonds. Nonetheless, the more highly
substituted (more stable) alkene is also produced. For both syn and anti-elimination, the betahydrogen and the leaving group are fixed by the regiochemistry of the halide. Syn-elimination
involves intramolecular attack of base, dictating removal of the beta-hydrogen that is syn to the
leaving group.

Kobrich established three guidelines that govern the application of Bredt s rule.
1. For homologs with different S values, the ring strain varies inversely with S.
2. For a given S, the ring strain varies inversely with the size of the larger of the two rings
with respect to which the bridgehead bond is endocyclic.
3. For a given bicyclic ring skeleton, the ring strain varies inversely with the size of the bridge
containing the bridgehead double bond.
Retention versus inversion (diastereocontrol)
Las mentioned previously, reactions of cyclic molecules that involve formation of sterogenic
centers are similar to those of acyclic systems in that they can proceed with clean retention or
inversion of configuration, or a mixture of the two. Reaction of sodium azide (NaN3) and cis-4-tertbutyl-1-bromocyclohexane gives trans-4-tert-butylazidocyclohexane with complete inversion of
configuration via an SN2 pathway. A synthetic example of a reaction that proceeds with inversion
in the Mitsunobu reaction that featured chiral alcohol 75. The presence of an acid or acid salt
(such as potassium benzoate) in the reaction medium leads to nucleophilic displacement with
clean inversion to generate an ester. Subsequent treatment with methanolic potassium carbonate
liberated alcohol 76 with the inverted hydroxyl, in Mori s synthetic work toward poitediol.

Diastereoselectivity
If one stereoisomer can be produced when more than one is possible (a diastereoselective
reaction), this is desirable and obviously related to the concepts discussed in previous sections in
the context of acyclic systems. In cyclic systems, the conformation of the ring, conformational
preferences in the transition state, and stability of the final product are critically important for
predicting and controlling stereochemistry.

Neighboring group effects and chelation effects

The influence of heteroatom substituents in directing reactions to one face or another has been
noted in this as well as several preceding chapters. Peroxyacid epoxidation of 117 proceeded via
coordination of the peroxyacid to the alcohol (118), delivering the electrophilic oxygen from that
face to give 119, which contrasts with epoxidation of allylic acetate 120, which gave primarily 121
via delivery from the less sterically hindered face. The acetate group inhibits coordination with the
peroxyacid, and delivery of the nucleophilic oxygen is from the less sterically hindered face so the
epoxide unit is on the opposite side of the ring.

Acyclic stereocontrol via cyclic precursors

It is apparent from preceding sections that stereocontrol in cyclic systems is much easier than in
acyclic systems, which is due, of course, to the conformational bias inherent in cyclic systems.
Synthetic chemists have exploited this fact for many years. A cyclic system can be used to position
functional groups, often with control of regio- and stereochemistry. The ring is then opened to
give an acyclic system and the regiochemistry and stereochemistry of the substituents has been
fixed. There are many examples.

The utility of the process is demonstrated by the ozonolysis of 1.5-cyclooctadiene to give diol 146
in 85% yield. Conversion to the dibromide and two copper assisted displacements followed by
epoxidation led to the racemic sex pheromone of the female face fly, 148. An excess of the
organocruprate reagent was required for reasonable yields of the coupling products due to
decomposition and disproportionation of the copper reagents. Examining the overall sequence
shows that the requisite functional groups at the -and -positions were inserted by the
sequential alkylation reactions, first to 146 giving 147 and then to 147 to give the alkene precursor
to 148.
Ring-forming reactions
Baldwin s rules.
From the preceding discussion, it is clear that cyclic compounds play an important role in organic
synthesis. The desired compound is not always commercially available, however, and must often
be prepared by cyclization reactions from acyclic precursors, which is particularly true for large
ring (macrocyclic) compounds and poly-cyclic molecules. In the latter case, a cyclic molecule acts
as a template and the other rings are built onto the template (this is called annulation). This
section will discuss the salient features of ring forming reactions commonly encountered in
synthesis.

An introduction to cyclization reactions is best begun with a discussion of Baldwin rules for ring
closure or simply Baldwin s rules. Baldwin studied many nucleophilic, hemolytic, and cationic ringclosing processes and found a predictable pattern of reactivity. This approach is based on the
stereochemical requirements of both reagent and substrate as well as the angles of approach that
are allowable when two reactive centers come together. To form a ring, the two reactive centers
are connected by a tether of atoms (usually carbon atoms but not always) and this imposes
constraints on angles from which they can approach one another, and on the stereochemistry of
the product. If the length and nature of the chain (tether) linking terminal atoms X and Y allows
this geometry to be attained, ring formation is possible (favored) and we make the predication
that the reaction will succeed. If the proper geometry cannot be attained, ring formation is
difficult (disfavored). In this latter case, alternative but competitive processes usually dominate.
Baldwin classified ring closing reactions in two categories: exo (the electron flow of the reaction is
external to the ring being formed [158 from 157] and endo [the electron flow is within the ring
being formed (160 from 159)]. Baldwin further classified reactions according to the hybridization
of the atoms accepting the atom in the ring closing process. If the atom being attacked is sp3
hybridized, as in 161, the reaction is termed tet and an exo-tet reaction will generate a ring such as
162. Attack at an sp2 atom (157) is termed trig (forming the ring 158 or 160). Attack at an sp
hybridized atom (163) is dig, and exo-dig reaction will generate ring 164.
Ring closures categorized by Baldwin s rules.
When two reactive ends of a molecule come together, they can approach each other only from
certain trajectories, called the angle of attack. Before discussing Baldwin s rules, it is first
necessary to establish what angles of attack are possible. Elliot and Graham-Richards described a
method for predicting the preferred approach angles based only on the substrate. Displacement at
a sp3 carbon generally requires backside attack (165) and the incoming group (X) must approach
the Y-bearing carbon at an angle close to 180. For exo processes, this is usually easy but for endo
processes it can be difficult. Reactions at double bonds (trig) are controlled by the planar nature of
alkenes, imines, and carbonyls. The bond angles are 120, but upon reaction the sp2 atom is
converted to a sp3 atom. Since sp3 atoms are tetrahedral (with bond angles of 109), the best
trajectory for attack of a sp2 atom (a carbonyl, for example) is about 109.

Macrocycles
Macrocyclic ring closures.
Baldwin s rules explain most of the cyclization reactions for small and medium-sized rings
encountered in previous chapters and those that are seen in succeeding chapters. An exception is
the formation of large rings. Formation of carbocyclic rings will be discussed in later chapters in
connection with the appropriate carbon-carbon bond-forming reactions. Macrolactonization,
however, is a functional group exchange process, and large lactone rings are also an important
feature of many natural products. The principles discussed here for preparing large ring lactones
are applicable to most other macrocyclizations. Illuminati and Mandolini described the ring-closing
reactions of bifunctional chain molecules. In the 1920s and 1930s Ruzicka and Ziegler studied
macrocyclic reactions. Macrocyclic ring formation requires an intramolecular cyclization reaction
of a bifunctional molecule such as 213, where cyclization gives the monocyclic product, 214. In this
model, X and Y are reactive functional groups that generate a new group, Z (which may contain X,
Y, or both).

An important reaction that competes with cyclization is the intermolecular reaction where initial
coupling generates the dimeric 215. Repeated intermolecular reactions give the oligomers or
polymers (216). Ruggli discovered that high substrate concentrations favor polymerization while
low concentrations favor cyclization. The rate of cyclization is a function of the structure of the

open-chain precursor and that of the product-like transition state. The activation energy for ring
closure is largely determined by the strain energy of the final ring.

The relative preference of a reaction is given by the effective molarity (EM)= Kintra/Kinter. The EM
is supposed to be the first-order rate constant for ring closure times the second order rate
constant for reaction between chain ends (if they were not connected) but EM for five and sixmembered rings exceeds the real concentration. Two parameters similar to EM are useful for
predicting conditions under which a ring can be synthesized, free of significant polymerized
byproducts. The first is the parameter C/Mo, where Kr is the rate of ring formation of cyclic
monomer and Kp is the rate of formation of cyclic dimer. If the initial concentration is less than
unity ( < 1), the yield is not less than 55%. For medium rings, Kr/Kp should be < 0.1 M.

Synthetic approaches to macrocyclic lactones.

There are many examples of biologically important, naturally occurring lactones. A variety of
cyclization techniques have been developed, but all are based on the idea that the carbonyl end of
a -substituted acid is activated to facilitate attack by or at the other functionalized end.
Trifluoroacetic anhydride, for example, was used to convert 220 to 222 in 31% yield. The initially
formed mixed anhydride (221) activated the carbonyl to attack by the hydroxyl moiety, leading to
222 in the Taub synthesis of zcaralenone. An alternative synthetic route required a
macrocyclization reaction but it involved Friedel-Crafts acylation. Cyclization has also been
observed using a mixture of trifluoroacetic acid and trifluoroacetic anhydride.

Conclusion.
In addition, many of the principles used in the important chapters dealing with making carboncarbon bonds have been discussed. If there is a theme to this chapter, it is that organic chemists
can exercise a significant amount of control over synthetic reactions, which is possible by
understanding the mechanism of the transformations and the various interactions of heteroatoms
and reagents. A thorough understanding of the conformational aspects of reactivity is essential.
With knowledge of these principles a useful plan can be assembled for the synthesis of even
complex molecules. Without this understanding, syntheses beyond a very few simple steps will be
doomed to failure.
One last piece of information is required for synthesis in order to manipulate functional groups. In
those cases where a heteroatom functional group interferes with a transformation and cannot be
removed, modified, or inserted earlier or later in a synthesis, methods are available to temporarily
block it.