Chapter 4

Functional Group Transformations: Oxidation and Reduction

Oxidation states (numbers)

Less E.N. than C = -1

More E.N. than C = +1
C=0

C OH

4.8 Terminology for Reduction of Carbonyl Compounds

Chemoselective reagent reacts selectively with one FG in the presence of others

Ranu, B. C. Synlett. 1993, 885-892

Regioselective reaction reagent adds at only one of several regions (places)

Kar, A.; Argade, N. P. Synthesis 2005, 2284-2286

4.8 Terminology for Reduction of Carbonyl Compounds

Stereoselective reaction one stereoisomer is formed preferably over other(s)

Chang, et. al. Tetrahedron Lett. 2001, 42, 7019-7023

Stereospecific reaction one isomer of the SM gives only one product isomer

Decicco, C. P.; Grover, P. Synlett. 1997, 529-530

4.8 Terminology for Reduction of Carbonyl Compounds

Prochiral Center sp2 hybridized C, which may become chiral upon addition

Stereogenic Carbon general term for chiral atom, asymmetric atom, etc.

Careful molecules without stereogenic carbon may still be chiral (i.e. asymmetric)

4.8 Terminology for Reduction of Carbonyl Compounds

Stereoisomers molecules with the same formula but different spatial arrangements
Enantiomers molecules that are related as non-superimposable mirror images
Diastereomers stereoisomers not related as mirror images
Asymmetric Induction preferential formation of one stereoisomer (enantiomer or
diastereomer over another. Controlled by another chiral entity in either the substrate,
the reagent, a catalyst, or even solvent
Enantioselective Reaction preferential formation of one of two enantiomers when
an achiral starting material is used
Enantiomeric Excess a measure of the ratios of the two possible enantiomers
formed in an enantioselective reaction (%ee)
Diastereomeric Excess [% major diastereomer - % minor diastereomer] (%de)
Racemate racemic mixture, i.e. equal amounts of two enantiomers ([a]D = 0)
Homochiral same sense of chirality as a related molecule

4.9 Nucleophilic Reducing Agents

4.9 Nucleophilic Reducing Agents

4 LiH + AlCl3 LiAlH4 + 3 LiCl
Powerful reducing agent - ust use aprotic solvent,
not chemoselective

4.9 Nucleophilic Reducing Agents

Nicolaou, et. al. J. Org. Chem. 1985, 50, 1440

Woodward, et. al. Pure Appl. Chem. 1971, 25, 283

Kishi, et. al. J. Am. Chem. Soc. 1979, 101, 262

4.9 Nucleophilic Reducing Agents

4.9 Nucleophilic Reducing Agents - Selective

Ketone to alcohol

Nicolaou, et. al. Chem. Eur. J. 2000, 6, 3095

Nitrile to aldehyde

Brown, H. C.; Gang, C. P. J. Am. Chem. Soc. 1964, 86, 1085-1089

4.9 Nucleophilic Reducing Agents - Selective

Acid chloride to aldehyde

Brown, H. C.; Krishnamurthy, S. Tetrahedron 1979, 35, 567

Na(t-BuO)3AlH

4.9 Nucleophilic Reducing Agents - Selective

Amide to aldehyde

Brown, H. C.; Tsukamoto, A. J. Am. Chem. Soc. 1964, 86, 1089-1095

4.9 Nucleophilic Reducing Agents Red-Al

Sodium Bis(2-methoxyethoxy)aluminum hydride Red-Al

Tietze, et. al. Chem. Eur. J. 2000, 6, 2801-2808

4.9 Nucleophilic Reducing Agents - Red-Al

Amide survives, acid gets reduced

Koodziejczyk, A. S, et. al. Lett. Pept. Sci. 2003, 10, 79-82

4.9 Nucleophilic Reducing Agents NaBH4

B(OCH3)3 + 4 NaH NaBH4 + 3 NaOCH3

Ianni, A.; Waldvogel, S. R. Synthesis 2006, 2103-2112

Van Brabandt, W.; Vanwalleghem, M.; D'hooghe, M.; De Kimpe, N.

J. Org. Chem., 2006, 71, 7083-7086

4.9 Nucleophilic Reducing Agents - NaBH4

4.9 Nucleophilic Reducing Agents - NaBH4

Fexofenadine
(antihistamine)

Okaramine N
synthesis

Ianni, A.; Waldvogel, S. R. Synthesis 2006, 2103-2112

4.9 Nucleophilic Reducing Agents - NaBH4

Luche reduction

4.9 Nucleophilic Reducing Agents - LiBH4

4.9 Nucleophilic Reducing Agents - Borohydrides

ZnBH4

Less basic than NaBH4 but short shelf-life

Nakata, T.; Tani, Y.; Hatozaki, M.; Oishi,T.

Chem. Pharm. Bull. 1984, 32, 1411

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4.9 Nucleophilic Reducing Agents - Selectrides

4.9 Nucleophilic Reducing Agents NaBH3CN

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4.9 Nucleophilic Reducing Agents NaBH3CN

4.9 Nucleophilic Reducing Agents NaBH3CN

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4.9 Nucleophilic Reducing Agents NaBH3CN

4.9 Nucleophilic Reducing Agents NaBH3CN

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4.9 Nucleophilic Reducing Agents NaBH3CN

4.10 Electrophilic Reducing Agents

DIBAL-H reacts slowly with electron poor compounds, and more quickly with electron rich
compounds. In short it is an electrophilic reducing agent. While the mechanism by which
LiAlH4 reacts is complex, LiAlH4 can be thought of as a nucleophilic reducing agent.

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4.10 Electrophilic Reducing Agents

4.10 Electrophilic Reducing Agents

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4.10 Electrophilic Reducing Agents

4.10 Electrophilic Reducing Agents

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4.10 Electrophilic Reducing Agents

4.11 Regio- and Chemoselective Reductions

Ranu, B. C. Synlett. 1993, 885-892

Ianni, A.; Waldvogel, S. R. Synthesis 2006, 2103-2112

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4.11 Regio- and Chemoselective Reductions

Attack from underneath favoured?

Mat Maust (Schering-Plough)

4.12 Diastereoselective Reductions of Cyclic Ketones

Conditions

cis (%)

trans (%)

Al(Oi-Pr)3, i-PrOH

70

30

LiAlH4, THF

76

24

LiAlH(Ot-Bu)3, THF

90

10

NaBH4, MeOH

77

23

LiBH(sec-Bu)3, THF

95

Li-trisiamylborohydride

<1

>99

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4.12 Diastereoselective Reductions of Cyclic Ketones

4.13 Inversion of Secondary Alcohol Configuration

Mitsunobu reaction

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4.14 Diastereofacial Selectivity in Acyclic Systems

[Link]

4.14 Diastereofacial Selectivity in Acyclic Systems

Enantiotopic faces of the carbonyl

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4.14 Diastereofacial Selectivity in Acyclic Systems

4.14 Diastereofacial Selectivity in Acyclic Systems

the behavior of conformationally mobile acyclic compounds

is more difficult to rationalize (than for cyclic systems)

Example: enantioselective reduction i.e asymmetric induction

Singaram, B., et. al. Eur. J. Org. Chem. 2005, 24, 5289.

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4.14 Diastereofacial Selectivity in Acyclic Systems

The reductions so far (except the MPV reaction) have been concerned with
kinetically controlled reactions (i.e. irreversible) that involve the formation
of tetrahedral (sp3) carbon atoms within a molecular framework.
Because of the conformational mobility of acyclic compounds, it is important
to recognize an important precept known as The Curtin Hammett Principle:
The ratio of products obtained from a group of equilibrating conformers
is determined by transition state energies, not conformer
concentrations

4.14 Diastereofacial Selectivity in Acyclic Systems

Enantiomers are equal in energy, therefore enantiomeric transition states

are also equal in energy. It is impossible to achieve any selectivity (without
the addition of a chiral reagent), and a racemic mixture is formed.
If there is a chiral centre in the substrate we form diastereomers, then the
transition state energies need not be equal and we should observe some
selectivity. This forms the basis for all diastereoselectivity (and also for all
enantioselectivity except that the chirality is not in the substrate).
[Link]

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4.14 Diastereotopicity Asymmetric Induction

1st example: 1,2-diastereoselectivity ; the chiral center at C-2

influences the outcome of the reduction asymmetric induction
2nd example: chiral center too far away to have any influence
1,3-diastereoselectivity also possible (later)

4.14 Models for Predicting Mode of Asymmetric Induction

the substituents on the chiral center adjacent to the carbonyl group are labeled L
(large), M (medium) and S (small), reflecting their approximate size
Each model predicts the correct configuration of the favored diastereomer
from LiAlH4 reduction of 3-phenyl-2-butanone. Original Cram model (1952)
updated by Karabatsos and then Felkin and Ahn.
[Link]

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4.14 Models for Predicting Mode of Asymmetric Induction

Felkin-Ahn model takes into account:

1. The Brgi-Dunitz trajectory of the nucleophile (107-109o)
2. Conformational (torsional) issues in both reactant and the transition state
3. Stereoelectronic considerations (C-L donation into C=O *)

4.14 Models for Predicting Mode of Asymmetric Induction

Felkin-Ahn model to explain observed diastereoselectivity

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4.14 Chelation-controlled Addition Reactions

1. A heteroatom with lone pairs available for coordination to a metal ion.

2. A metal ion that favours coordination to both C=O and the heteroatom. E.g.:
Mg2+, Zn2+, Al3+, Ce3+ and Ti4+ are excellent
Li+ is sometimes okay
Na+ and K+ are bad

4.14 Chelation-controlled Addition Reactions

When to Use Which Model?

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4.14 Examples of Cram/Felkin-Ahn vs. Chelation

Single diastereomer

Rationale using chelation model (Zn2+)

Hanessian, S.; Machaalani, R. Tetrahedron Lett. 2003, 44, 8321-8323.

4.14 Examples of Cram/Felkin-Ahn vs. Chelation

ds = > 20 : 1

Rationale using Felkin-Ahn model

Hanessian, S.; Machaalani, R. Tetrahedron Lett. 2003, 44, 8321-8323.

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4.14 Examples of Cram/Felkin-Ahn vs. Chelation

Ford, M.J.; Ley, S.V. Synlett. 1990, 771-772.

4.14 Hydroxyl-directed Reduction of -Hydroxy Ketones

Chelate formed at low temperature in the first step

External nucleophile then added (NaBH4)
Nucleophile attack from underneath to avoid CH3
Syn stereochemistry achieved from remote location

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4.14 Hydroxyl-directed Reduction of -Hydroxy Ketones

Reagent chelates to hydroxyl to form complex

Internal nucleophile then adds in an intramolecular sense
Nucleophile attack directed by 6-membered transition state
Anti stereochemistry achieved from remote location

4.15 Enantioselective Reductions

Alpine-Borane

Diastereomeric TS#

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4.15 Enantioselective Reductions

Corey-Bakshi-Shibata Reduction

E. J. Corey, S. Shibata, R. K. Bakshi, J. Org, Chem., 1988, 53, 2861-2863.

W. M. Clark, A. M. Tickner-Eldridge, G. K. Huang, L. N. Pridgen, M. A. Olsen, R. J. Mills, I.

Lantos, N. H. Baine, J. Am. Chem. Soc., 1998, 120, 4550-4551.

4.15 Enantioselective Reductions

Y. Kawanami, S. Murao, T. Ohga, N. Kobayashi, Tetrahedron, 2003, 59, 8411-8414.

In situ formation of the Oxazaborolidine catalyst

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4.15 Enantioselective Reductions

Y. Kawanami, S. Murao, T. Ohga, N. Kobayashi, Tetrahedron, 2003, 59, 8411-8414.

4.15 Enantioselective Reductions

Proposed catalytic cycle

[Link]

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