REVIEW IN FUNCTIONAL AND PROTECTING GROUPS · Review in Functional and Protecting Groups The...
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REVIEW IN FUNCTIONAL AND PROTECTING GROUPS
NAGHAM MAHMOOD ALJAMALI
Organic Chemistry, Chemistry Department, College of Education, Iraq
ABSTRACT
In organic chemistry, many preparations of delicate organic compounds, some specific parts of their molecules
cannot survive the required reagents or chemical environments. Then, these parts, or groups, must be protected. For
example, lithium aluminum hydride is a highly reactive but useful reagent capable of reducing esters to alcohols. It will
always react with carbonyl groups, and this cannot be discouraged by any means. When a reduction of an ester is required
in the presence of a carbonyl, the attack of the hydride on the carbonyl has to be prevented.
KEYWORDS : Protecting, Function, Carbonyl Protected, Amine Protected
INTRODUCTION
Protecting groups are more commonly used in small-scale laboratory work and initial development than in
industrial production processes because their use adds additional steps and material costs to the process, it is introduced
into a molecule by chemical modification of a functional group to obtain chemoselectivity in a subsequent chemical
reaction. It plays an important role in multistep organic synthesis.
Protecting Groups
• Protecting groups are used in synthesis to temporarily mask the characteristic chemistry of a functional
group because it interferes with another reaction.
• A good protecting group should be easy to put on, easy to remove and in high yielding reactions, and
inert to the conditions of the reaction required.
• For example, consider the following scenario: How can you perform the following reaction?
Figure: 1 The overall transformation required is ester to primary alcohol. This is a reduction of the ester, which requires
LiAlH 4, but that will reduce the ketone as well which we don't want. We can avoid this problem if we "change" the ketone
to a different functional group first. Conceptually, this is like being able to put a cover (shown below) over the ketone
while we do the reduction, then remove the cover.
Journal of Applied, Physical and Bio-ChemistryResearch (JAPBR) Vol. 1, Issue 2, Dec 2015, 75-86 © TJPRC Pvt. Ltd.
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BOC glycine. The tert-Butyloxycarbonyl group is protecting group.
One of the purposes in protecting groups in organic synthesis
the major problems in organic synthesis is the suppression of
accompanied by reaction at other parts of the molecule, especially when more than one functional group is present.
Functional groups usually are the most
one functional group from a reaction occurring at another. Therefore any proposed synthesis must be evaluated at each step
for possible side reactions that may degrade o
an understanding of how variations in structure affect chemical reactivity. Such understanding is acquired through
experience and knowledge of reaction mechanism and reaction ste
To illustrate the purpose and practice of
of cis-2-octene, which we outlined in BUILDING THE CARBON SKELETON
octyn-l-ol. We could write the following:
However, the synthesis as written would fail because the
alkynide anion would react much more rapidly with
from carbon:
The hydroxyl group of 4-bromo
alkynide salt. There are a number of ways to protect hy
on the fact that unsaturated ethers of the type
readily adds to the double bond of such an ether in the presence of an acid catalyst:
Figure: 2 Butyloxycarbonyl group is protecting group.
protecting groups in organic synthesis is to eliminate unwanted side reactions. One of
organic synthesis is the suppression of unwanted side reactions. Frequently the desired reaction is
accompanied by reaction at other parts of the molecule, especially when more than one functional group is present.
Functional groups usually are the most reactive sites in the molecule, and it may be difficult or even impossible to insulate
one functional group from a reaction occurring at another. Therefore any proposed synthesis must be evaluated at each step
for possible side reactions that may degrade or otherwise modify the structure in an undesired way. To do this will require
an understanding of how variations in structure affect chemical reactivity. Such understanding is acquired through
experience and knowledge of reaction mechanism and reaction stereochemistry.
To illustrate the purpose and practice of protecting groups in organic synthesis, let us suppose that the synthesis
BUILDING THE CARBON SKELETON, has to be adapted for the synthesis of 5
ol. We could write the following: Stop Wearing Lame Shirts!
Figure: 3
However, the synthesis as written would fail because the alkyne is a weaker acid
alkynide anion would react much more rapidly with the acidic proton of the alcohol than it would displace bromide ion
Figure: 4 bromo-l-butanol therefore must be protected before it is allowed to react with the
alkynide salt. There are a number of ways to protect hydroxyl groups, but one method, which is simple and effective, relies
on the fact that unsaturated ethers of the type are very reactive in electrophilic addition reactions
readily adds to the double bond of such an ether in the presence of an acid catalyst:
Figure:5
Nagham Mahmood Aljamali
is to eliminate unwanted side reactions. One of
unwanted side reactions. Frequently the desired reaction is
accompanied by reaction at other parts of the molecule, especially when more than one functional group is present.
reactive sites in the molecule, and it may be difficult or even impossible to insulate
one functional group from a reaction occurring at another. Therefore any proposed synthesis must be evaluated at each step
r otherwise modify the structure in an undesired way. To do this will require
an understanding of how variations in structure affect chemical reactivity. Such understanding is acquired through
, let us suppose that the synthesis
, has to be adapted for the synthesis of 5-
alkyne is a weaker acid than the alcohol, and the
the acidic proton of the alcohol than it would displace bromide ion
butanol therefore must be protected before it is allowed to react with the
droxyl groups, but one method, which is simple and effective, relies
electrophilic addition reactions. An alcohol
Review in Functional and Protecting Groups
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The protected compound is a much weaker acid than the alkyne, and the displacement reaction can
with the alkynide salt without difficulty. To obtain the final product, the protecting group must be removed, and this can be
done in dilute aqueous acid solution by an
Protection of amines:
• Carbobenzyloxy (Cbz) group
• p-Methoxybenzyl carbonyl
• tert-Butyloxycarbonyl
concentrated strong acid (such as HCl or CF
• 9-Fluorenylmethyloxycarbonyl (
by base, such as piperidine
• Acetyl (Ac) group is common in
in adenine nucleic bases and is removed by treatment with a base, most often, with
gaseous ammonia or methylamine. Ac is too stable to be readily removed from aliphatic amides.
• Benzoyl (Bz) group is common in
in adenine nucleic bases and is removed by treatment with a base, most often with
methylamine. Bz is too stable to be readily removed from aliphatic amides.
• Benzyl (Bn) group – Removed by
• Carbamate group – Removed by acid and mild heating.
• p-Methoxybenzyl (PMB)
• 3,4-Dimethoxybenzyl
• p-methoxyphenyl (PMP) group
The protected compound is a much weaker acid than the alkyne, and the displacement reaction can
with the alkynide salt without difficulty. To obtain the final product, the protecting group must be removed, and this can be
done in dilute aqueous acid solution by an SN1 type of substitution:
Figure:6 (Cbz) group – Removed by hydrogenolysis
Methoxybenzyl carbonyl (Moz or MeOZ) group – Removed by hydrogenolysis
Butyloxycarbonyl (BOC) group (common in solid phase peptide synthesis
concentrated strong acid (such as HCl or CF3COOH), or by heating to >80 °C.
Fluorenylmethyloxycarbonyl (FMOC) group (Common in solid phase peptide synthesis
group is common in oligonucleotide synthesis for protection of N4 in
nucleic bases and is removed by treatment with a base, most often, with
. Ac is too stable to be readily removed from aliphatic amides.
group is common in oligonucleotide synthesis for protection of N4 in
nucleic bases and is removed by treatment with a base, most often with aqueous or gaseous ammonia or
methylamine. Bz is too stable to be readily removed from aliphatic amides.
Removed by hydrogenolysis
Removed by acid and mild heating.
(PMB) – Removed by hydrogenolysis, more labile than benzyl
Dimethoxybenzyl (DMPM) – Removed by hydrogenolysis, more labile than p
(PMP) group – Removed by ammonium cerium(IV) nitrate
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The protected compound is a much weaker acid than the alkyne, and the displacement reaction can be carried out
with the alkynide salt without difficulty. To obtain the final product, the protecting group must be removed, and this can be
hydrogenolysis, more labile than Cbz
solid phase peptide synthesis) – Removed by
solid phase peptide synthesis) – Removed
for protection of N4 in cytosine and N6
nucleic bases and is removed by treatment with a base, most often, with aqueous or
. Ac is too stable to be readily removed from aliphatic amides.
for protection of N4 in cytosine and N6
aqueous or gaseous ammonia or
, more labile than benzyl
, more labile than p-methoxybenzyl
ammonium cerium(IV) nitrate (CAN)
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• Tosyl (Ts) group – Removed by concentrated acid (HBr, H
liquid ammonia or sodium naphthalenide
• Other Sulfonamides (Nosyl & Nps) groups
CARBONYL PROTECTING GROUPS
Protection of Carbonyl Groups:
• Acetals and Ketals – Removed by acid. Normally, the cleavage of acyclic acetals is easier than of cyclic
acetals.
• Acylals – Removed by
• Dithianes – Removed by metal salts or oxi
CARBOXYLIC ACID PROTECTING GROUPS
Protection of Carboxylic Acids
• Methyl esters – Removed by acid or base.
• Benzyl esters – Removed by hydrogenolysis.
• tert-Butyl esters – Removed by acid, base and some
• Esters of 2,6-disubstituted phenols (e.g.
butylphenol) – Removed at room temperature by
• Silyl esters – Removed by acid, base and
• Orthoesters – Removed by mild aqueous acid to form ester, which is removed according to ester
properties.
• Oxazoline – Removed by strong hot acid (pH < 1, T > 100
e.g. LiAlH4, organolithium reagents or Grignard (organomagnesium)
Phosphate Protecting Groups:
• 2-cyanoethyl – removed by mild base. The group is widely used in
• Methyl (Me) – removed by strong nucleophiles
Removed by concentrated acid (HBr, H2SO4) & strong reducing agents (
sodium naphthalenide)
(Nosyl & Nps) groups – Removed by samarium iodide,
CARBONYL PROTECTING GROUPS :
Figure: 7 Removed by acid. Normally, the cleavage of acyclic acetals is easier than of cyclic
Removed by Lewis acids.
Removed by metal salts or oxidizing agents.
CARBOXYLIC ACID PROTECTING GROUPS :
Figure: 8 Removed by acid or base.
Removed by hydrogenolysis.
Removed by acid, base and some reductants.
disubstituted phenols (e.g. 2,6-dimethylphenol, 2,6-
Removed at room temperature by DBU-catalyzed methanolysis under high-pressure conditions.
Removed by acid, base and organometallic reagents.
Removed by mild aqueous acid to form ester, which is removed according to ester
Removed by strong hot acid (pH < 1, T > 100 °C) or alkali (pH > 12, T > 100
Grignard (organomagnesium) reagents.
removed by mild base. The group is widely used in oligonucleotide synthesis
removed by strong nucleophiles e.c. thiophenole/TEA.
Nagham Mahmood Aljamali
) & strong reducing agents (sodium in
Removed by samarium iodide, tributyltin hydride[2]
Removed by acid. Normally, the cleavage of acyclic acetals is easier than of cyclic
-diisopropylphenol, 2,6-di-tert-
pressure conditions.[3]
Removed by mild aqueous acid to form ester, which is removed according to ester
°C) or alkali (pH > 12, T > 100 °C), but not
oligonucleotide synthesis.
Review in Functional and Protecting Groups
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Terminal Alkyne Protecting Groups:
• propargyl alcohols in the
• silyl groups, especially in protection of the
ALCOHOL PROTECTING GROUPS
Protection of Alcohols
• Acetyl (Ac) – Removed by acid or base (see
• Benzoyl (Bz) – Removed by acid or base, more stable than Ac group.
• Benzyl (Bn, Bnl) –
chemistry.
• β-Methoxyethoxymethyl ether
• Dimethoxytrityl, [bis-
widely used for protection of 5'-hydroxy group in nucleosides, particularly in
• Methoxymethyl ether
• Methoxytrityl [(4-methoxyphenyl)diphenylmethyl, MMT)
• p-Methoxybenzyl ether
• Methylthiomethyl ether
• Pivaloyl (Piv) – Removed by acid, base or reductant agents. It is substantially more stable than other acyl
protecting groups.
• Tetrahydropyranyl (THP)
• Tetrahydrofuran (THF)
• Trityl (triphenylmethyl, Tr)
• Silyl ether (most popular ones include
propylsilyloxymethyl (TOM), and triisopropylsilyl (TIPS) ethers)
(Tetra-n-butylammonium fluoride, HF-
function in nucleosides, particularly in oligonucleotide synthesis
• Methyl Ethers – Cleavage is by TMSI in DCM or MeCN or Chlorofo
methyl ethers is BBr3 in DCM
alcohols in the Favorskii reaction,
silyl groups, especially in protection of the acetylene itself.[4]
ALCOHOL PROTECTING GROUPS
Figure: 9
Removed by acid or base (see Acetoxy group).
Removed by acid or base, more stable than Ac group.
Removed by hydrogenolysis. Bn group is widely used in sugar and nucleoside
Methoxyethoxymethyl ether (MEM) – Removed by acid.
-(4-methoxyphenyl)phenylmethyl] (DMT) – Removed by weak acid. DMT group is
hydroxy group in nucleosides, particularly in oligonucleotide synthesis
Methoxymethyl ether (MOM) – Removed by acid.
methoxyphenyl)diphenylmethyl, MMT) – Removed by acid and hydrogenolysis.
Methoxybenzyl ether (PMB) – Removed by acid, hydrogenolysis, or oxidation.
Methylthiomethyl ether – Removed by acid.
Removed by acid, base or reductant agents. It is substantially more stable than other acyl
(THP) – Removed by acid.
(THF) - Removed by acid.
(triphenylmethyl, Tr) – Removed by acid and hydrogenolysis.
(most popular ones include trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS),
propylsilyloxymethyl (TOM), and triisopropylsilyl (TIPS) ethers) – Removed by acid or fluoride
-Py, or HF-NEt3)). TBDMS and TOM groups are used for
oligonucleotide synthesis.
Cleavage is by TMSI in DCM or MeCN or Chloroform. An alternative method to cleave
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. Bn group is widely used in sugar and nucleoside
Removed by weak acid. DMT group is
oligonucleotide synthesis.
ed by acid and hydrogenolysis.
Removed by acid, hydrogenolysis, or oxidation.
Removed by acid, base or reductant agents. It is substantially more stable than other acyl
butyldimethylsilyl (TBDMS), tri-iso-
fluoride ion. (such as NaF, TBAF
)). TBDMS and TOM groups are used for protection of 2'-hydroxy
rm. An alternative method to cleave
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• Ethoxyethyl ethers (EE)
BRIEFLY
Protecting of Alcohol :
• Trimethylsilyl ether (TMS)
• Triethylsilyl ether (TES)
• Triisopropylsilyl ether (TI
• tert-Butyldimethylsilyl ether (TBS, TBDMS)
• tert-Butyldiphenylsilyl ether (TBDPS)
• Acetate (Ac)
• Benzoate (Bz)
• Benzyl ether (Bn)
• 4-Methoxybenzyl ether (PMB)
• 2-Naphthylmethyl ether (Nap)
• Methoxymethyl acetal (MOM)
• 2-Methoxyethoxymethyl ether (MEM)
• Ethoxyethyl acetal (EE)
• Methoxypropyl acetal (MOP)
• Benzyloxymethyl acetal (BOM)
• Tetrahydropyranyl acetal (THP)
• 2,2,2-Trichloroethyl carbonate (Troc)
• Methyl ether
Protecting of Phenol
• Triisopropylsilyl ether (TIPS)
Ethoxyethyl ethers (EE) – Cleavage more trivial than simple ethers e.g. 1N
Figure:10
Trimethylsilyl ether (TMS)
Triethylsilyl ether (TES)
Triisopropylsilyl ether (TIPS)
Butyldimethylsilyl ether (TBS, TBDMS)
Butyldiphenylsilyl ether (TBDPS)
Methoxybenzyl ether (PMB)
Naphthylmethyl ether (Nap)
Methoxymethyl acetal (MOM)
Methoxyethoxymethyl ether (MEM)
al (EE)
Methoxypropyl acetal (MOP)
Benzyloxymethyl acetal (BOM)
pyranyl acetal (THP)
Trichloroethyl carbonate (Troc)
Triisopropylsilyl ether (TIPS)
Nagham Mahmood Aljamali
Hydrochloric acid[1]
Review in Functional and Protecting Groups 81
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• tert-Butyldimethylsilyl ether (TBS, TBDMS)
• Methyl ether
• Benzyl ether (Bn)
• Methoxymethyl acetal (MOM)
• [2-(Trimethylsilyl)ethoxy]methyl acetal (SEM)
Protecting of Amine
• Trifluoroacetamide
• tert-Butoxy carbamate (Boc)
• Benzyloxy carbamate (CBz)
• Acetamide (Ac)
• Formamide
• Methyl carbamate
• 4-Methoxybenzenesulfonamide
• Benzylamine (Bn)
Protecting of Carboxylic Acid
• Methyl ester
• Benzyl ester
Protecting of Aldehyde and Ketone
• Dimethyl acetal
• Ethylene glycol acetal
• Neopentyl glycol acetal
• Trimethylsilyl cyanohydrin
• 1,3-Dithiane
• Diethyl acetal
• 1,3-Dithiolane
Protecting of Sulfonamide
• tert-Butoxy carbamate (Boc)
Protecting of 1,2-Diol
• Acetonide
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• Benzaldehyde acetal
• Carbonate
Protecting of Acetylene
• Trimethylsilane (TMS)
Protecting of Indole
• tert-Butoxy carbamate (Boc)
• N-(4-Methoxybenzyl)indole (PMB)
• Methoxymethyl aminal (MOM)
General Characteristics
Carbonyl groups are generally protected
basic, nucleophilic, and oxidizing (nonacidic) conditions.
Reaction Mechanism
Acetalization is naturally reversible. Use of the alcohols in excess and/or efficient removal of water
system become important to push the reactions to completion.
The order of reactivity for carbonyl compounds is roughly as follows.
Examples
The total synthesis of saxitoxin
Lewis acids or Brønsted acids than sulfurs, the O
Trimethylsilane (TMS)
Butoxy carbamate (Boc)
oxybenzyl)indole (PMB)
Methoxymethyl aminal (MOM)
Carbonyl groups are generally protected as acetals under acidic conditions. Acetals are stable under reductive,
basic, nucleophilic, and oxidizing (nonacidic) conditions.
Acetalization is naturally reversible. Use of the alcohols in excess and/or efficient removal of water
system become important to push the reactions to completion.
Figure: 11
The order of reactivity for carbonyl compounds is roughly as follows.
Figure:12
The total synthesis of saxitoxin[1]: Taking advantage of the fact that oxygens are more easily activated by hard
Lewis acids or Brønsted acids than sulfurs, the O-acetal was directly converted into the S-acetal.
Figure: 13
Nagham Mahmood Aljamali
as acetals under acidic conditions. Acetals are stable under reductive,
Acetalization is naturally reversible. Use of the alcohols in excess and/or efficient removal of water from the
more easily activated by hard
acetal.
Review in Functional and Protecting Groups
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The Noyori conditions[2]: Acetals or ketals can be synthesized in high yield using the bis
catalytic TMSOTf. This reaction works even at cryogenic temperatures. The disiloxane (TMSOTMS) byproduct is stable
and unreactive that the reverse reaction does not occur, allowing for kinetically
The Otera catalyst[3]: Otera’s distannoxane catalyst mediates acetalization
proposed that the catalyst forms a nucleophilic tin alkoxide as well as acting as a mild Lewis acid. This reaction does not
require any dehydration apparatus.
Ketone-selective acetalization in the presence of aldehyde
dimethylsulfide and TMSOTf, followed by the Noyori conditions.
The protection of cyclohexanone with ethylene glycol.
The most popular acetal protecting groups are shown below. The hydrolysis of six
than that of five-membered ring acetals.
: Acetals or ketals can be synthesized in high yield using the bis
TMSOTf. This reaction works even at cryogenic temperatures. The disiloxane (TMSOTMS) byproduct is stable
and unreactive that the reverse reaction does not occur, allowing for kinetically-controlled protection.
Figure: 14 Otera’s distannoxane catalyst mediates acetalization of acid
proposed that the catalyst forms a nucleophilic tin alkoxide as well as acting as a mild Lewis acid. This reaction does not
Figure: 15 selective acetalization in the presence of aldehyde[4]: The example shown here uses treatment with
dimethylsulfide and TMSOTf, followed by the Noyori conditions.
Figure:16 The protection of cyclohexanone with ethylene glycol.[5]
Figure: 17 The most popular acetal protecting groups are shown below. The hydrolysis of six-membered ring acetals is faster
membered ring acetals.
Figure: 18
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: Acetals or ketals can be synthesized in high yield using the bis-TMS ether reagent and
TMSOTf. This reaction works even at cryogenic temperatures. The disiloxane (TMSOTMS) byproduct is stable
controlled protection.
of acid-sensitive compounds. It is
proposed that the catalyst forms a nucleophilic tin alkoxide as well as acting as a mild Lewis acid. This reaction does not
: The example shown here uses treatment with
membered ring acetals is faster
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Thioacetals are Deprotected Mainly by
• Methylation then hydrolysis.
• Oxidation (e.g. by hyp
• Hydrolysis using Hg(II).
are Deprotected Mainly by
Methylation then hydrolysis.
Oxidation (e.g. by hypervalent iodine) then hydrolysis.
Hydrolysis using Hg(II).
Nagham Mahmood Aljamali
Review in Functional and Protecting Groups
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REFERENCES
1. Kamaya, Yasushi; T Higuchi (2006). "Metabolism of 3,4
versicolor". FEMS Microbiology Letters
2. Moussa, Ziad; D. Romo (2006). "Mild deprotection of primary N
Kamaya, Yasushi; T Higuchi (2006). "Metabolism of 3,4-dimethoxycinnamyl alcohol and derivatives by Coriolus
FEMS Microbiology Letters 24 (2–3): 225–229. .
Moussa, Ziad; D. Romo (2006). "Mild deprotection of primary N-(p-toluenesufonyl) amides with SmI
85
dimethoxycinnamyl alcohol and derivatives by Coriolus
toluenesufonyl) amides with SmI2 following
86 Nagham Mahmood Aljamali
www.tjprc.org [email protected]
trifluoroacetylation". Synlett 2006 (19): 3294–3298. .
3. Romanski, J.; Nowak, P.; Kosinski, K.; Jurczak, J. (Sep 2012). "High-pressure transesterification of sterically
hindered esters". Tetrahedron Lett. 53 (39): 5287–5289..
4. Clayden, Jonathan; Greeves, Nick; Warren, Stuart; Wothers, Peter (2000). Organic Chemistry. Oxford University
Press. p. 1291. .
5. Chan, Weng C.; White, Peter D. (2004). Fmoc Solid Phase Peptide Synthesis. Oxford University Press.
6. Weng C. Chan, Peter D. White: Fmoc Solid Phase Peptide Synthesis, S. 10–12.
7. Merrifield, R. B.; Barany, G.; Cosand, W. L.; Engelhard, M.; Mojsov, S. (1977). "Proceedings of the 5th
American Peptide Symposium". Biochemical Education 7 (4): 93–94.
8. Blanc, Aurélien; Bochet, Christian G. (2007). "Isotope Effects in Photochemistry: Application to Chromatic
Orthogonality". Org. Lett. 9 (14): 2649–2651.
9. Baran, Phil S.; Maimone, Thomas J.; Richter, Jeremy M. (22 March 2007). "Total synthesis of marine natural
products without using protecting groups". Nature (446): 404–408.
10. Daignault, R. A.; Eliel, E. L. Org. Synth. 1973, 5, 303.
11. Tanino, H.; Nakata, T.; Kaneko, T.; Kishi, Y. J. Am. Chem. Soc. 1977, 99, 2818.
12. Noyori, R.; Murata, S.; Suzuki, M. Tetrahedron 1981, 37, 3899.
13. Nozaki, H. Tetrahedron 1992, 48, 1449.
14. Kim, S.; Kim, Y. G.; Kim, D. Tetrahedron Lett. 1992, 33, 2565.