A critical outlook and comparison of enantioselective oxidation methodologies of olefins

Full text of DOI:10.1016/S0040-4020(02)00440-4

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 4981±5021
Tetrahedron report number 610
A critical outlook and comparison of enantioselective oxidation
methodologies of ole®ns
Carlo Boninia,p and Giuliana Righib
a
Á
Dipartimento di Chimica, Universita della Basilicata, Via N. Sauro 85, 85100 Potenza, Italy
b
Á
Istituto di Chimica Biomolecolare-Sezione di RomaÐc/o Dipartimento di Chimica, Universita `La Sapienza', P.le A.Moro, 2,
00185 Roma, Italy
Received 27 March 2002
Contents
1. Introduction
4982
4983
4983
4984
4985
4986
4988
4988
4992
4994
4994
4995
4996
4997
2. Aim, scope and limitations of the most recent enantioselective oxidative methodologies
2.1. Asymmetric epoxidation (AE) of allylic alcohols
2.2. Asymmetric epoxidation of simple ole®ns
2.2.1. Jacobsen±Katsuki epoxidation approach (Salen-AE)
2.2.2. Recent asymmetric epoxidation by chiral dioxirane derivatives
2.2.3. Recent asymmetric epoxidation of enones
2.3. Asymmetric dihydroxylation (AD) of ole®ns
2.4. Asymmetric aminohydroxylation (AA) of ole®ns
3. Comparison of the most used asymmetric oxidative methodologies
3.1. Preparation, availability and cost of the ligands
3.2. Catalysis in the enantioselective oxidation
3.3. Availability and restrictions in the utilisation of the starting ole®ns
3.4. Experimental conditions
4. Manipulation and transformation of the chiral compounds obtained by asymmetric oxidative
methodologies: complementary stereochemical aspects
4.1. Transformation and utilisation of 1-epoxyalcohols
4.1.1. Reactions at C-1 and subsequent transformations
4.1.2. Regioselective substitution at C-1 by Payne rearrangement sequence
4.1.3. Oxirane ring opening at C-2 or C-3 of epoxyalcohols and derivatives and subsequent
transformations
4997
4997
4998
4998
4999
5000
5000
5001
4.2. Transformation and utilisation of 1,2-diols
4.2.1. Differentiation and transformation of terminal 1,2-diols
4.2.2. Differentiation and transformation of unsymmetrically substituted 1,2-diols
4.2.3. Differentiation and transformation of substituted 1,2-diols via cyclic sul®tes and sulfates 5002
4.3. Transformation and utilisation of simple epoxides obtained by the Salen-AE 5002
5. How to make the right choice: a comparison of selected examples of different routes to the same target 5003
5.1. Chiral epoxides
5.1.1. (1)-Disparlure and related natural epoxides
5.2. Chiral alcohols, diols and polyols
5.2.1. (2S,3S)-Octanediol
5.2.2. (R,R)-Muricatacin
5004
5005
5005
5007
5007
5007
5008
5.2.3. (5R,6S)-5-Acetoxy-hexadecanolide
5.2.4. (4R)-Dodecanolide
Keywords: enantioselective oxidation; ole®ns.
Corresponding author. Tel.: 139-971-202254; fax: 139-971-474223; e-mail: bonini@unibas.it
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00440-4

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5.3. Chiral b-aminoalcohols
5.3.1. Taxol side chain
5.3.2. (2R,3S)-3-Hydroxyleucine
5.3.3. Cyclohexylnorstatin
6. Conclusions
5009
5010
5012
5013
5015
1. Introduction
the petroleum industry or by simple and well developed
synthetic methodologies. In addition the resultant 1,2-
oxidised compounds such as epoxides, alcohols and diols,
halohydrins or amino derivatives can be further transformed
into other classes of compounds with control eventually of
the relative stereochemistry of the ®nal compounds
(Scheme 1).
The importance of asymmetric synthesis as a tool for obtain-
ing enantiomerically pure compounds has grown dramati-
cally in the last two decades not only in synthetic organic
chemistry as well as medicinal and agricultural chemistry,
but also in the pharmaceutical and agricultural industries.
This has been mainly due to the market situation for chiral
drugs where the use of racemic compounds, especially for
the pharmaceutical industry, has been severely cut by
national agencies such as the FDA (Food and Drug
Administration) in the USA.
As the need for enantioselective processes was increasing in
the early 1980s, chemists looked to the known oxidative
reactions of ole®ns and tried to make them enantioselective
processes. Although before the 1980s some enantioselective
oxidation reactions of ole®ns had already been developed,
the discovery of the Sharpless±Katsuki asymmetric epoxi-
dation (AE) in 19802 represents a major breakthrough, not
only in the enantioselective oxidation of ole®ns but in asym-
metric synthesis in general.
Although several methodologies to obtain enantiomerically
pure compounds are available (such as optical resolution of
racemates via separation of diastereoisomers, chiral chro-
matographic separations and biocatalytic or chemical
kinetic resolution), asymmetric synthesis appears increas-
ingly to be the future method for the production of pure
chiral compounds, and also for industrial use. The aim of
this chemistry requires the transformation of a known
reaction into an enantioselective process with the use of
simple reagents and chiral auxiliaries or, better still, in a
catalytic enantioselective process, as normally used by
enzymes.
Other major advances in asymmetric oxidation of ole®ns
followed: the Sharpless asymmetric dihydroxylation (AD)
in 1988,3 the Jacobsen and Katsuki Salen-asymmetric
epoxidation (Salen-AE) of unfunctionalised ole®ns in
1990,4 and later the Sharpless asymmetric aminohydroxyl-
ation (AA) in 19965 (Scheme 2). Very recently novel
methodologies have enabled the enantioselective epoxida-
tion of unfunctionalised ole®ns4f,6 and enones.7 While these
preliminary results appear to be a promising new achieve-
ment in this area, they have clearly yet to involve the wide-
spread use of the AE and the AD reactions.
The oxidation of carbon±carbon double bonds into a variety
of functionalised compounds is undoubtedly one of the most
useful transformations in synthetic organic chemistry.1 First
of all, the ole®n substrates can be regarded as probably the
most important synthetic organic intermediates because of
their inexpensive nature and ready availability, either from
It is worthy of note that oxidation of the carbon±carbon
double bond leads to functionalised compounds that can
frequently be obtained by different routes. None of the
known methods, however, provides for a general asym-
metric oxidation protocol. For this reason, a chemist
planning a short or lengthy synthesis, i.e. of natural
products, frequently has numerous options for the introduc-
tion of the correct chirality in a synthon to be elaborated. A
complete picture and comparison of the available method-
ologies, with consideration of their applicability, limits,
enantioselectivity, chemical yields and availability of the
starting materials, would facilitate a synthetic design.
The number of reviews in journals or books (see Refs. 1±6)
concerning the individual methodologies is large as newer
and more advanced enantioselective oxidative methods
appear in the literature. Critical analysis and comparison
of the various asymmetric oxidation methodologies are
however not ready available. Consequently, the scope of
this report has been directed toward such a critical analysis
and comparison between the different methodologies, with
particular emphasis on catalysis, chiral ligand and support
choice, and transformations of different functional groups.
The review is organised to compare all the different aspects
Scheme 1.

C. Bonini, G. Righi / Tetrahedron 58 (2002) 4981±5021
4983
Scheme 2.
of the methodologies in a manner so as to make such a
comparative analysis more straightforward and easier for
the reader.
almost be considered as ordinary synthetic chemistry, in
particular the AE of allylic alcohols and the AD of unfunc-
tionalised ole®ns. Other newer processes such as the Salen-
AE or dioxirane oxidation of unfunctionalised ole®ns as
well as the asymmetric aminohydroxylation AA, promise
to be as competitive as the other methodologies, although
more work is still needed to extend their scope and applic-
ability. The complementarities of these and other recent
methodologies are evident and their utilisation will now
be illustrated.
After a short description of the older and newer oxidative
methodologies (Section 2), a critical comparison of the
availability of the starting ole®ns and of the experimental
conditions (Section 3) will be given, followed by a con-
sideration of the importance and complementarity of func-
tional groups obtained directly or by different reactions
starting from the chiral functionalised compounds (Section
4). Finally, in order to rationalise the different possibilities
when planning a synthesis, Section 5 will directly compare
the different methodologies using selected examples from
the literature.
2.1. Asymmetric epoxidation (AE) of allylic alcohols
The Sharpless±Katsuki asymmetric epoxidation (AE) of
allylic alcohols represents a special example of the scienti®c
progress. The story of its discovery is legendary and came as
a thunderclap, since previous attempts were not as promis-
ing. The chemical community was struck by the novelty of
the growing area of asymmetric synthesis and the AE pro-
cedure started to be applied immediately. In spite of later
attempts, the original reagent combination still appears
today to be quite adequate in providing the best results,
and its discovery in 1980,2a does represent indeed the start
of a new era in asymmetric synthesis.
It must be noted that, with the aim of obtaining chiral func-
tionalised compounds such as epoxides, alcohols and
polyols, aminoalcohols and their derivatives, other methods
than the enantioselective oxidation of an ole®n, are being
increasing discovered and becoming available. Among
these methods, mention must be made of to: (a) biocatalytic
procedures8 such as direct epoxidation and dihydroxylation
as well as indirect preparation of epoxides, 1,2-diols and
halohydrins and (b) chemical kinetic resolution and desym-
metrisation of epoxides.9 The results obtained with these
procedures are, for some examples, highly remarkable, but
they will be not considered in this report which is dedicated
to oxidative enantioselective procedures.
The asymmetric epoxidation of allylic alcohols and the
related kinetic resolution of secondary allylic alcohols
have been reviewed2b±e also, with a detailed discussion of
the mechanism and synthetic utility. For primary achiral
allylic alcohols (Scheme 3), a combination of Ti(OiPr)4, a
dialkyl tartrate and TBHP is able to distinguish between
the two enantiofaces of the substrate, in accord with the
Additionally, other oxidation reactions of ole®ns, such as
double bonds breaking, hydration, hydrohalogenation, or
halogenations and other heteroatom addition, will not be
considered here, and the reader should refer to earlier
reviews10 where these reactions have been considered.
2. Aim, scope and limitations of the most recent
enantioselective oxidative methodologies
Although asymmetric processes of ole®ns oxidation are still
a challenging and primary research activity, synthetic
organic chemists have at their disposal a series of processes
to date, developed in the last 20 years, which have been
tested in hundreds of experiments and which could now
Scheme 3.

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C. Bonini, G. Righi / Tetrahedron 58 (2002) 4981±5021
empirical rule depicted. The chirality of the tartrate used
(typically dimethyl (DMT), diethyl (DET) or diisopropyl
(DIPT) tartrates) induces the sense of the oxygen
delivery from the top or bottom of the ole®n. Normally,
there is no exception to the empirical rule depicted in
Scheme 3, and it has therefore been frequently used for
the assignment of the absolute con®guration of the resulting
epoxides.
A wide range of allylic alcohols have been shown to be good
substrates for the reaction, as demonstrated by the hundreds
of applications2c reported over 20 years. The reaction
usually proceeds with good chemical yields and high enan-
tioselectivity, often .90% ee. The (E)-allylic alcohols, with
few exceptions, have been shown to be the best substrates
for high enantioselectivity, and are easily available by
standard methodologies (see the following Section for a
more detailed discussion of the availability of the
substrates). Although (Z)-allylic alcohols have been shown
in many cases to be good substrates, the enantioselectivity is
signi®cantly in¯uenced by the nature and size of the R3
substituent. In conclusion, the large number of applications
of the AE on a wide variety of primary allylic alcohols can
easily allow a correct prediction, in many examples, of the
range of enantioselectivity to be expected.
Scheme 5.
appears as the one with the R5 substituent at C-1 and inter-
feres with the delivery of the oxygen atom, thus resulting in
a preference for obtaining the opposite erythro epoxide.
Good results, especially with E substrates and with ole®ns
without Z substituents (R3ˆH) are generally expected,
although bulky Z (R3) substituents normally give poor selec-
tivity. Many examples have been suf®ciently exploited in
order to provide a rational explanation for the results of the
kinetic resolution.
In the presence of a stereogenic centre in the C1 position of
the allylic alcohols (Scheme 4), both diastereo- and enantio-
selectivity must be considered, in order to predict and
rationalise the kinetic resolution (KR) of the enantiomeric
couple. The ®rst results of the AE/KR were reported
in1981.11 As shown in Scheme 4 the epoxidation of one
enantiomer at a much faster rate than the other is dictated
by the con®guration of the (C-1) R substituent, which
hindered the approach of the oxygen from one side of the
ole®n. The success of the resolution depends on the differ-
ence in the epoxidation rates affording the erythro isomer
only (see Scheme 4). The ratio between the kfast/kslow rate of
the two enantiomers has normally been de®ned as krel, which
bears a mathematical relationship to the enantiomeric
excess of the epoxy alcohol and the remaining allylic
alcohol. A range of krel 50±100 is considered to be suf®cient
to afford products of .90% ee (for a related discussion, see
Refs. 2b,d).
The clear implication of the size of the substituent in the
success of the reaction also highlights that the ef®ciency of
the secondary alcohol epoxidation depends upon the reagent
used, in contrast to the epoxidation of the primary allylic
alcohols. DIPT is therefore generally used as the chiral
auxiliary, with a major preference over DMT or DET.2c
Additionally a large size of the alkoxy substituents in the
Ti species was found to be deleterious for the successful
kinetic resolution.12
Some particularly interesting results have shown how the
chiral catalyst in the AE could overcome the pre-existing
chirality in a primary chiral allylic alcohol. The starting
chiral isomer can couple with the catalyst (1 or 2 tartrate)
in a matched or mismatched pair, as shown for one impor-
tant example in Scheme 5.2b,c,13 This can be utilised
(although with some restrictions) to obtain the desired
diastereoisomer with good to excellent diastereomeric
excess by simply choosing the appropriate chiral catalyst.
The model shown in Scheme 4 clearly accounts for the
general stereochemical course of the kinetic resolution,
with a high predictability: the slow-reacting enantiomer
2.2. Asymmetric epoxidation of simple ole®ns
The major limitation of the Sharpless±Katsuki asymmetric
epoxidation is the need for the ole®ns to be functionalised as
allylic alcohols, although this condition could be con-
sidered, in some cases, as an advantage (see Section 4 for
the reactions and applications of epoxyalcohols). The
discovery and the limitations of the AE therefore
prompted chemists to seek reactions which could lead to
unfunctionalised epoxides.
Scheme 4.

C. Bonini, G. Righi / Tetrahedron 58 (2002) 4981±5021
4985
have also been employed.4d In addition the use of an axial
ligand on the active oxomanganese species was found to be
helpful in optimising of the chemical and optical yields,
when amine or isoquinoline N-oxides were used.15 The
importance of an axially coordinating N ligand, has been
elegantly con®rmed by the use of a chiral amine16a,b or
bipyridine N,N-dioxide16c with an achiral manganese
complex, which afforded the optically active epoxides
with ees up to 73 and 86%, respectively. The temperature
was, in some cases, also found to affect both the enantio-
selectivity and the chemical yields, these generally increas-
ing by lowering the reaction temperature to 2788C.17
Figure 1.
2.2.1. Jacobsen±Katsuki epoxidation approach (Salen-
AE). Ten years after the discovery of the AE of allylic
alcohols, the Jacobsen4a and Katsuki4b groups reported,
almost simultaneously, the asymmetric epoxidation of
unfunctionalised ole®ns (Salen-AE), with the use of chiral
Mn-salen catalysts. This discovery represents the asym-
metric version of the achiral ole®n epoxidation catalysed
by the salen±metal(III) complexes 1 (Fig. 1), which was
The choice of the starting ole®ns appeared to be crucial to
the success of the reaction, and after extensive studies on
different substrates, a general picture of the substrate
dependence can now be predicted.
described in
a
fundamental study by Kochi and
As a general trend, conjugated alkenes are always better
substrates than simple unconjugated ole®ns. The (Z)-di-
substituted alkenes are the best substrates for the catalysts
and the conditions used, with nearly complete enantio-
selectivity. Simple alkyl-substituted ole®ns give lower
enantioselectivity, although attention must be paid to the
conjugation and electronic pattern of the substitutions.
Some conjugated (Z)-disubstituted ole®ns exhibit isomeri-
sation during the epoxidation reaction, affording trans and
cis epoxides in different ratios18,19 and can thus be manipu-
lated advantageously. The analogous trans (E)-disubstituted
ole®ns are less suitable substrates, with the results varying
with the catalysts and the temperature, although the Katsuki
catalysts gave a generally superior performance. With
respect to the porphyrin-based catalysts, the monosubsti-
tuted ole®ns provide an unusually low selectivity under
the normal experimental conditions, with extensive isomer-
isation of the ®nal epoxide. This problem could be solved,
for styrene epoxidation, by the use of mCPBA in dichloro-
methane at 2788C, with the formation of enantiopure
styrene oxide.20 In contrast to this result, a considerable
number of ole®ns with tri- and tetra-substituted double
bonds have been successfully epoxidised,21 with enantio-
meric excesses up to 90%.
co-workers.14 It is important to note the structural correla-
tion between the salen-complexes 1 and the porphyrin±
metal complexes 2, well known as deoxidising reagents in
natural and synthetic processes.4c Among the different
catalysts proposed (see Ref. 4d for a list of the catalysts
used) the compounds 3±6, (see Fig. 2) were employed
and successively optimised by Jacobsen,4c while the
catalysts 7,8 were developed by Katsuki4d in later work.
The main differences between the two systems lie in the
presence of four different stereocenters (in the Katsuki
complexes) and in the replacements (in the Jacobsen
complexes) of the stereogenic centres at C-3 and C-30
with bulky t-butyl groups. The epoxidation was best carried
out in acetonitrile or dichloromethane, with NaOCl or
iodosylbenzene as the oxygen source but other oxidants
Some recent applications have extended the Jacobsen
version (catalyst 3, referred to as Jacobsen's catalyst) of
Salen-AE to substrates such as cyclic dienyl sulphones22a
with moderate to high enantioselectivity (see entries 1 and
2 in Table 1). The same authors also used Jacobsen's
catalyst22c on a dienyl tri¯ate (see entry 3), which was subse-
quently elaborated to cyclic and acyclic synthons.
A chromium complex version, utilising the different unsym-
metrical salen complexes, was recently tested.23 The ee
reported in the most recent developments23c for (E)-methyl-
styrene was found to be superior to the previous attempts on
(E)-ole®ns, with some interesting considerations on the
proposed mechanism for the metal-oxo side-on approach
model for the (Z)-ole®ns.24
A novel (NO)ruthenium-salen was recently proposed by
Katsuki,25a (see Fig. 2) which seems irrespective of the
substitution pattern for conjugated ole®ns (E or Z), and
affords the corresponding epoxides with ees often superior
Figure 2.

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C. Bonini, G. Righi / Tetrahedron 58 (2002) 4981±5021
Table 1. Salen-AE of particular substrates
Entry
Diene
Product
Yield (%)
75
ee (%)
Reference
22a
1
.99
2
3
80
65
.99
22a
22c
91
to 80±85%. The reaction is preferably carried out in
benzene under light irradiation, with 2,6-dichloropyridine
N-oxide as the terminal oxidant. A similar catalyst has
also been employed25b for the aerobic oxidation/KR of
sec-alcohols, with promising results.
which demonstrated its ability to act as a powerful catalyst27
for the dioxirane epoxidation of unfunctionalised trans-
ole®ns. The chiral catalyst can be prepared in both enantio-
meric forms: from d-fructose in a two-step synthesis and
from l-fructose (ent-9a), prepared from l-sorbose (®ve step
synthesis). Both catalysts are quite ef®cient (Table 2) in
stoichiometric or catalytic (0.3 equiv.) amounts, with the
need for careful pH control26 due to the catalyst decomposi-
tion by Baeyer±Villiger reaction, and with the oxone as the
oxidant, although, recently, H2O2 has also been used.28
In conclusion, although with some limitations on the
substrate choice and with mechanism of the reaction still
being debated,24 the results obtained with the Jacobsen±
Katsuki Salen-AE appear to be of great importance,
especially for their use in the preparation of enantiopure
epoxides. The major limitation of the Salen-AE, due to
the instability of the most common catalysts (e.g. 3), in
prolonged oxidative conditions, has prompted several
studies to incorporate the salen ligand into a matrix or
support as a means of recycling the chiral catalyst, as will
described in Section 3.1.
A high level (ee.90%) of enantioselectivity for trans-
ole®ns was reported (Table 2) and these results were
successively extended to different substrates.
Conjugated dienes29a (entries 6 and 7) and enynes29b,c
(entries 4 and 5), enol ethers and esters29d (entries 8±10)
and 2,2-disubstituted vinylsilanes29e (entries 11, 12), can be
regio-, chemo- and enantioselectively epoxidised, giving
rise to functionalised epoxides with good to high enantio-
meric excess. A recent report29f shows, however, that
terminal ole®ns are fair substrates for this procedure with
epoxides obtained with ees in the range 71±85%.
2.2.2. Recent asymmetric epoxidation by chiral dioxir-
ane derivatives. The major limitation of the Jacobsen±
Katsuki Salen-AE due to the lack of broad applicability
for the trans (E)-ole®ns appears to be circumvented in
most recent methodologies employing the generated chiral
dioxirane derivatives as the catalytic oxidants.
While the reaction was initially performed on trans substi-
tuted ole®ns, a very recent development by the same group
in late 2000,30 showed highly promising preliminary results
on the cis substituted ole®ns (entries 13±15 for selected
examples), by the use of the related nitrogen-derived chiral
catalyst 9b (Fig. 2), with excellent ees. The reaction
appears, so far, to be limited only to aromatic conjugated
ole®ns, with the use of 15% molar catalyst (to be prepared in
several steps).
The most promising catalytic system was developed starting
from a report in 1996 by Shi and co-workers,6,26 with the
construction of a d-fructose chiral ketone 9a (Scheme 6),
Although the reaction appears to be of great interest,
especially if it could be performed on all classes of ole®ns,
it has been applied only recently by other groups31 and
therefore its broad utilisation should be demonstrated in
the near future. Its potential applicability has recently,
however, been shown in a spectacular multi-epoxidation
with catalyst 9a, reported by Corey,32 with the concomitant
epoxidation of four and ®ve trisubstituted double bonds with
.80% estimated diastereomeric purity.
Other groups have achieved interesting results utilising
Scheme 6.

C. Bonini, G. Righi / Tetrahedron 58 (2002) 4981±5021
Table 2. Chiral dioxirane mediated AE of ole®ns
4987
Entry
Ole®n
Product
Catalyst
Yield (%)
75
ee (%)
97
1
2
9a
9a
XˆOH
XˆCl
XˆOTBS
60
61
74
84
93
93
3
4
9a
66
59
93
96
9a
5
6
9a
88
90
9a
9a
41
77
96
97
7
8
9a
nˆ1
nˆ2
nˆ3
nˆ4
79
82
87
82
80
93
91
95
9
9a
9a
9a
9a
9b
9b
9b
80
66
74
67
87
88
82
90
91
94
92
91
84
91
10
11
12
13
14
15

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C. Bonini, G. Righi / Tetrahedron 58 (2002) 4981±5021
different chiral ketone/oxone systems in order to achieve
trans-ole®n epoxidation, the most successful results being
reported by the Denmark,33 yang34 and Amstrong35 groups,
with different ketones. The reported chemical and optical
yields, however appear to be generally below the results
reported by the Shi group.
The mechanism of the proposed asymmetric epoxidation
with chiral ketone/oxone systems appears to be of great
importance for the design and developments of different
catalysts and for predicting the stereochemical outcome. A
general overview of the subject with the different proposed
mechanisms has recently been published.6b
Scheme 7.
2.2.3. Recent asymmetric epoxidation of enones. The
direct asymmetric epoxidation of enones to keto epoxides
was extensively explored in the early 1980s with variable
results. More recently, some new methodologies have been
discovered7 with the aim of complementing the results
obtained in the cases of the AE of allylic alcohols and of
the Jacobsen±Katsuki Salen-AE.
Scheme 8.
DET, afford diaryl epoxy ketones (Scheme 8) from chalcone
derivatives with good enantioselection.42
The ®rst of these methodologies, the Julia±Colonna AE36,37
using polyleucine as a catalyst, is still attracting interest for
providing further improvements. Among the more recent
results, a remarkable diastereoselective epoxidation was
performed by the Roberts group on different aryl unsatu-
rated keto and ketoesters,38a as well as g-heterosubstituted
a,b-unsaturated ketones.38b The same group has very
recently reported38c the ®rst soluble version of the Julia±
Colonna catalyst on a triblock PEG-bound poly-l-leucine
which, where employed in the epoxidation of enones,
afforded the chiral compounds with excellent ees.
Mild phase transfer-catalysed conditions have also been
used successfully with different quaternary chiral
ammonium salts, starting with the pioneering work by
Wynberg.43 Recently promising results have been reported
with the use of cinchona alkaloids,44 with superior enantio-
selectivity as previously reported by Wynberg.
Amongst the most recent methodologies,
a novel
asymmetric epoxidation of a,b-enones by optically active
hydroperoxide (S-(2)-(1-phenyl)ethyl hydroperoxide)
appeared45a as a signi®cant extension of the previously
reported Ti(IV)-catalysed asymmetric epoxidation of
sulphides and allylic alcohols.45b The good enantio-
selectivity observed was rationalised by a metal coordina-
tion between the enone system and the hydroperoxide.
The lanthanide-BINOL-derived catalysts such as 10 and 11
(Fig. 3) have been successfully employed39 for the catalytic
enantioselective preparation of trans and cis enones with
TBHP as oxidant. The results appear to be quite satisfactory
and could be improved with the addition of water39c or
triphenylphosphine oxide.40
In conclusion, although the improvements in the asym-
metric epoxidation of this particular class of ole®ns are
often impressive, some work is still required to achieve a
full and broad applicability of these reactions, as well as
their utilisation for synthetic purposes.
2.3. Asymmetric dihydroxylation (AD) of ole®ns
Eight years after the discovery of the Sharpless±Katsuki AE
of allylic alcohols, another breakthrough came from the
Sharpless group in 1988,3a the catalytic asymmetric
dihydroxylation (AD) of ole®ns. Since its discovery, this
reaction has been extensively optimised in both alkaloid
ligands as well as in the co-oxidant and solvent systems,
and has been performed on hundreds of different ole®ns
(functionalised or unfunctionalised). A large part of the
ole®n can now be dihydroxylated with good to excellent
enantioselectivity, by a proper choice of the reagent and
reaction conditions.46 With regard to the actual state of the
art, the AD process could probably be considered as the
most general oxidation asymmetric reaction of ole®ns,
with virtually no need for particular functionalisation or
conjugation of the reacting double bond.
Figure 3.
Chiral a,b-epoxyketones have also been prepared with the
use of (R,R)-N-methylpseudoephedrine as a catalyst and
with an O2/Et2Zn oxidant system41 with varying ees but
superior des (Scheme 7); the reaction is postulated to
proceed through a chiral alkoxy(ethylperoxy)zinc complex
from the si-face of the s±cis conformation of the (E) enones
in an oxa-Michael addition fashion.
Li and Mg t-butyl peroxides, chirally modi®ed with (1)
The reaction has been the subject of several reviews on both

C. Bonini, G. Righi / Tetrahedron 58 (2002) 4981±5021
4989
In an exhaustive study more than 400 alkaloids were tested
and a list of the most useful AD ligands can subsequently be
drawn (Fig. 4).47 These long-term studies revealed the
cinchona alkaloids to be perfect molecules for the AD,
and for the ligand acceleration effect (LAE), and they can
exhibit asymmetric induction at a very high level. While
modi®cations of the cinchona core were revealed to be
irrelevant, the major improvements were achieved in the
modi®cation of the O(9) substituent. As shown in Fig. 4,
the presence of at least an aromatic group proved to be
decisive for the discovery of the most effective derivatives.
The main differences between the ®rst and second genera-
tion ligands are in their monomeric or dimeric combination
with the core of the alkaloid.
Without doubt, the second generation ligands clearly show a
wider scope and application than the earlier ligands. In
Table 3, the recommended ligands for each class of ole®n
are reported, according to Sharpless's suggestions. Among
these the PHAL (phthalazine) ligands are the most widely
used in the AD owing to their large substrate applicability
and are currently employed in the AD-mix formulations (see
below). For certain ole®ns, the more recent AQN,48 DPP
and DP-PHAL ligands49 are preferred.
Although the catalytic system based on osmium-based
potassium ferrocyanide and potassium carbonate oxidation
is the most utilised, recent reports have appeared50 to be
particularly promising on the use of different oxidant
systems. The use of air under irradiation with visible
light,50a or of molecular oxygen, as the co-oxidant50b,c in
the AD of ole®ns, gave good results, although only
preliminary experiments have been carried out. The
development of such mild and environmentally friendly
reagents would enhance the potency of the AD of
prochiral ole®ns, and its extension to industrial applica-
tions.
AD of monosubstituted ole®ns appeared to be in¯uenced by
the substituent (alkyl or aryl), with long and bulky side
chains giving the best results, as well as aromatic substituted
ole®ns. Aryl and allyl ethers, highly important as starting
materials for chiral synthons, also appear to be good
substrates. Independent studies51a,b on vinyl furans (Table
4, entry 1), have also shown that such compounds afford in
high enantioselectivity and chemical yields chiral furfuryl
diols, which may then utilised for the synthesis of natural
products.51c±e
Figure 4.
the mechanistic and synthetic aspects, 3b±e and, therefore,
the general aspects of the reaction will be emphasised here
and, in the following sections, its most recent applications
and a comparison with the other synthetic asymmetric
oxidative methodologies.
Table 3. Recommended ligands for the AD of different classes of ole®ns
Ole®n class
Rˆaromatic
Rˆaromatic
Rˆaromatic
DPP, PHAL
DPP, PHAL
Acyclic
IND
DPP, PHAL
Preferred
ligand
Rˆaliphatic
Rˆaliphatic
Rˆaliphatic
PHAL,
DPP, AQN
PYR,
PHAL
AQN
AQN
Cyclic
PYR,
DPP, AQN
AQN
Rˆbranched
PYR
30±97%
Rˆbranched
PYR
70±97%
ee range
20±80%
90±99.8%
90±99%
20±97%

4990
C. Bonini, G. Righi / Tetrahedron 58 (2002) 4981±5021
Sharpless55a and Corey55b were, however, able to demon-
Table 4. AD of particular substrates
strate that suitable protecting groups of the hydroxyl func-
tion (4-substituted phenyl esters) in the allylic alcohol (entry
6) could overcome this limitation. More recently,55c the
unsubstituted allyl N-phenylcarbamate was found to be an
excellent substrate for the AD to give the corresponding 1,2-
diols.
Entry
1
Ole®n
ee (%)
92
Best ligand
(DHQD)2PHAL
2
.99 (DHQD)2AQN
98
(DHQD)2AQN
The asymmetric induction for cis (Z)-ole®ns has never
exceeded a fair ee of the corresponding anti 1,2-diol.
Manipulation strategies of the syn 1,2-diol (easily obtained
on the trans ole®ns) for obtaining the anti 1,2-diol have
therefore been developed (see Section 4).
3
4
91
(DHQ)2PHAL
One of the most impressive extensions of the AD process
was achieved on polyunsaturated conjugated or unconju-
gated alicyclic or cyclic polyenes. Generally the control of
the regio-, enantio- and diastereoselectivity is excellent,
leading to highly functionalised compounds useful as chiral
building blocks.56
84
(DHQ)2PHAL
5
6
.99 (DHQ)2PHAL
The proper choice of the ligands is crucial for the control of
the regio- and diastereoselectivity. The reaction is highly
regioselective with trans polyenes, both alicyclic and cyclic,
while the AD reaction on enynes gave unsatisfactory ees
only for the terminal ole®n. The regioselectivity of the
monodihydroxylation is normally determined by steric and
electronic factors. Isolated trans di- or trisubstituted double
bonds usually react much faster than cis or terminal ole®ns.
Electron-rich ole®ns react better than electron-poor ole®ns
and steric factors are the origin of the observed regio-
selectivity for the cyclic ole®ns.
97±99 (DHQD)2PYDZ
General reaction conditions employing AD-mix for 1 mmol of ole®n: 5 l of
tert-BuOH, 5 ml of H2O, 1.4 g of AD-mix-a or AD-mix-b; 1 kg of AD-
mix contains: K3Fe(CN)6, 699.6 g; K2CO3, 293.9 g; (DHQD)2- or (DHQ)2-
PHAL, 5.52 g; K2OsO2(OH)4, 1.04 g.
Better results are generally obtained for 1,1 disubstituted
ole®ns, although the aliphatic chains are not suitable for
an ef®cient AD. Very recently, 1-aryl-1-pyridylalkenes
(entry 2) have been reported52 to afford the corresponding
1,2-diols in high chemical and optical yields, depending on
the substituent effects and electronic nature of the hetero-
cyclic ring.
The double diastereoselective asymmetric dihydroxylation
of chiral ole®ns proved to be a valuable tool for the
introduction of the 1,2-diol system in many highly-
functionalised compounds. The AD was shown to be
powerful in several important syntheses: the high level of
enantioselectivity was re¯ected in a high level of diastereo-
selectivity, in the matched or mismatched pair (Scheme 9),
where a chiral proximate centre to the double bond is
present. The reaction worked particularly well for di- and
trisubstituted ole®ns, while with monosubstituted ole®ns,
the level of diastereoselectivity was never particularly high.
1,2-trans-(E)-Disubstituted ole®ns appear to be the best
substrates for AD with ees normally .90%. The length
and nature (aliphatic or aromatic) of the double bond sub-
stituent have little or no in¯uence on the enantioselectivity.
The in¯uence of allylic or homoallylic alkoxy groups on the
diastereoselectivity of the AD has been extensively
studied,57 with interesting observations on the reverse dia-
stereoselectivity58 with the use of the AD procedure
(Scheme 10, compound 12).
Good to excellent results are also obtained for trisubstituted
ole®ns and enol ethers, which are particularly attractive
substrates, since they afford a-hydroxyketones.
Electro-de®cient ole®ns provide ®nal chiral diols with
excellent ees (.93%) for the amides, and still good for
the enones, of sulphur-containing ole®ns, and, more
recently, of trans-alkenylphosphonates53 (entries 3 and 4).
Very recent useful results have been obtained in the AD of
unprecedented substrates such as differently-substituted
thiophenes (entry 5). Where a careful choice of conditions
led to good yields of valuable chiral diols.54
A study by Reetz59 (Scheme 10, compounds 13 and 14) has
The major serious limitation of the AD of ole®ns appears to
be the reactions of cis disubstituted ole®ns, including
aliphatic, aromatic, cyclic or electron-de®cient ole®ns as
well as allylic or homoallylic alcohols.
Scheme 9.

C. Bonini, G. Righi / Tetrahedron 58 (2002) 4981±5021
4991
Scheme 10.
shown that the protective group tuning (N-Boc- or
Bn-protected a,b-unsaturated esters) leads to optimal
diastereoselection in the AD of chiral amino derivatives,
with the appropriate choice of the chiral ligand.
Scheme 11.
The establishment of two hydroxyl stereogenic centres in
advanced intermediates for the synthesis of important
products appears to be one of the most signi®cant applica-
tions of the AD. Some of the more recent investigations are
shown in Scheme 11, where the intermediate compounds
15±21 are important examples60±66 of the powerfulness of
the AD reaction in order to introduce the appropriate 1,2-
diol moiety at an advanced stage for the synthesis of natural
products.
mechanism of the stereospeci®c transfer of the two OH
groups on the double bond still retains some uncertainty,
and a systematic study of all the possible explanations and
mechanistic models is beyond the scope of this review. The
most recent studies and models for the explanation of the
AD (mainly the concerted 312 or stepwise hypothesis)
were reviewed3d in 1998.
Nevertheless, the reliability of the AD process has led to
empirical rules, which are able to predict the face
Quite unexpectedly, the application of the AD to the kinetic
resolution of chiral racemic ole®ns has often given dis-
appointing results. A remarkable exception to this trend
has appeared, with the preparation of the C76 enantiomers
(Scheme 12) by AD kinetic resolution:67 the asymmetric
process was able to discriminate between 30 different
types of double bonds, where the osmylation occurred
preferentially at one of two possible sites.
Despite the strenuous efforts by several groups, the
Scheme 12.

4992
C. Bonini, G. Righi / Tetrahedron 58 (2002) 4981±5021
Scheme 13.
selectivity. In Scheme 13, a recent model3d for predicting
the face selectivity can be found, where the plane of the
ole®n is divided into four quadrants with the substituents
placed according to a simple set of rules. The SW quadrant
appears to be of particular importance since it must be
occupied by the most sterically demanding substituent,
especially aromatic groups. The mnemonic device can be
applied for each class of ligand (i.e. PHAL or PYR ligands).
Although the predictability of the rules is easily followed,
this is not always the case and exceptions have been found,
especially with terminal ole®ns.
nitrogen sources, leading to differently protected amino
alcohols (the main dif®culty to overcome appears to be
the deprotection of nitrogen, which in many examples can
be a serious problem). Table 5 summarises the current state
of the art in developing different methods for carrying out
the AA, although different nitrogen sources are con-
tinuously being developed and employed. In two procedures
the use of adenine-adenosine bases,68i or nitrogen-hetero-
cyclic bases,68k with variable results in terms of regio-
selectivity, can be considered as a useful entry in to
different classes of important pharmaceutical products.
Each of the different procedures has been tested on different
types of alkenes, and a careful choice of the alkaloid ligands
and the nitrogen substituent must be undertaken, in order to
optimise regio- and enantioselectivity and chemical yields.
The most successful ligands appear to be the (DHQ)2PHAL
or (DHQ)2AQN, where DHQ- and DHQD-derived ligands
produce opposite enantiomers as was found for the AD.
2.4. Asymmetric aminohydroxylation (AA) of ole®ns
Interest in the preparation of the b-aminoalcohol function-
ality in an optically active form has increased recently,
because of the discovery of an increasing number of natural
biologically active compounds possessing these subunits in
different stereochemical relationships. Since the ®rst report
in 1996 by the Sharpless group,5a,68 the asymmetric amino-
hydroxylation (AA) of ole®ns has rapidly became a useful
process and its applicability to the synthesis of biologically
active compounds has increased of late, promising to
become as popular as the other asymmetric oxidative
methodologies of ole®ns.
Unsaturated compounds such as cinnamates have proved to
be the most suitable substrates for a successful reaction
(Table 6, entries 1±16), which was also found to be depen-
dent on the substituents on the substrates and on the nitrogen
It must be emphasised that the contemporary addition, in
enantioselective fashion, of two different groups to a
carbon±carbon double bond, faces a major problem of
regioselectivity, in addition to the other stereochemical
problems inherent in an enantio- and stereoselective
reaction.
The AA is strictly correlated to the parent asymmetric
dihydroxylation reaction, since it utilizes the same alkaloid-
derived ligands (Fig. 5).
The main variation, with respect to the AD reaction, is
represented by the nitrogen source; after the initially utilised
chloramine-T trihydrate, yielding the corresponding
N-protected (p-toluenesulphonyl, Ts) alcohol, several
improvements have been made with the use of different
Figure 5.

C. Bonini, G. Righi / Tetrahedron 58 (2002) 4981±5021
4993
Table 5. N Sources for the AA of ole®ns
N source (equiv.)
Solvent
Temperature (8C)
(DHQ)2PHAL (mol%)
Reference
TsNClNa (3.5)
MsNClNa (3)
CbzNClNa (3)
BocNClNa (3)
TeoCNClNa (3)
AcNBrLi (1)
Adenine-NClNa(3)
Heterocycle-NClNa (3)
ClAcNBrLi (1)
tBuOH/H2O (1:1)
nPrOH/H2O (1:1)
nPrOH/H2O (1:1)
nPrOH/H2O (2:1)
nPrOH/H2O (1:1)
nPrOH/H2O (1:1.5)
EtOH/H2O (1:1)
EtOH/H2O (2:1)
tBuOH/ H2O (2:3)
rt
rt
rt
0
rt
4
50
rt
rt
5
5
5
6
5
5
6
5
4
5a
68b
68c
68f,69
68g
68d
68i
68k
68j
sources (compare entries 1±3 and 4±6). A recent applica-
tion of the AA on trans-cinnamates, leads to the short
synthesis of trans- and cis-oxazoline-5-carboxylates69 as
powerful intermediates as synthetic equivalents of
a-cations.
8:2). The main problem of regioselectivity control in the AA
has recently been explored in two different contemporary
approaches. In one report,72 it has been elegantly shown
how the reverse regioisomer B can be obtained for non-
cinnamyl aryl ester substrates (entries 11±13 in Table 6):
a careful choice of the aryl moiety with suitable substituents
on the ring (mainly halogens) allows the corresponding
b-hydroxy-a-amino acids to be obtained with good regio-
selectivity and reasonably good ee values. In the second
report,73 the assumed catalyst Ac-N-OsO3-(DHQD)2PHAL,
leads to a complex control of the steric, electronic and
substrate effects: the combination of all these factors, in
the same sense, can greatly enhance the regio control of
the reaction, as for entries 14±16 in Table 6.
As for the AD, the best substrates are trans ole®ns, which
lead to the 1,2-syn-aminoalcohols. Terminal ole®ns of aryl
derivatives70 (entries 7±9) gave variable results also
depending on nitrogen sources. In all of these examples
the regioselectivity favours the regioisomer A, with the
nitrogen on the alkyl or aryl side of the double bond. Very
recently, a modi®ed AA procedure (with the use of 1,3-
dichloro-5,5-dimethyl hydantoin as the co-oxidant)71 was
applied to several b-substituted styrene derivatives,
followed by a base-mediated ring closure to give the
corresponding chiral oxazolidin-2-ones. Although the
results are still to be improved in terms of regio- and
enantioselectivity, the procedure has been successfully
applied on a large scale.
The AA has also been applied recently to non-standard
substrates such as b-substituted vinylphosphonates,74 silyl
enol ethers75 and different heterocyclic conjugated
ole®ns75,76 (Scheme 14), with the variable regio- and
enantioselectivity mainly in¯uenced by the nitrogen source
used.
The reverse regioselectivity was ®rst achieved with the use
of the anthraquinone ligands such as (DHQ)2AQN and
(DHQD)2AQN instead of the PHAL analogues on trans
cinnamates68h (entry 10) although with a minor ratio (6:4±
The AA reaction is already a highly valuable method for the
introduction of the 1,2 aminoalcohol subunit, although
further work still needs to be done to make this reaction
Table 6. Selected examples of AA of ole®ns
Entry
R1
R2
COOMe
COOiPr
COOiPr
COOtBu
COOMe
COOMe
H
X
Ligand
Major product
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Me
Ts
Ms or CBz
Ac
(DHQ)2PHAL
(DHQ)2PHAL
(DHQ)2PHAL
(DHQ)2PHAL
(DHQ)2PHAL
(DHQ)2PHAL
(DHQ)2PHAL
(DHQ)2PHAL
(DHQ)2PHAL
(DHQ)2AQN
(DHQ)2AQN
(DHQ)2AQN
(DHQ)2AQN
(DHQD)2PHAL
(DHQD)2PHAL
(DHQD)2PHAL
A
A
A
A
A
A
A
60
65
81
63
76
89
70
40
70
58
60
58
59
79
63
83
82
94
99
89
95
84
98
93
88
95
87
89
96
95
92
95
CBz
Ms
COOMe
H
Naphthyl
Ph
(p-Ph)Ph
CBz
Boc
CBz
CBz
CBz
CBz
CBz
CBz
Ac
H
H
A (55:45)
A (91:9)
B
B (7:1)
B (5:1)
B (3:1)
A (20:1)
B (17:1)
B (20:1)
9
10
11
12
13
14
15
16
Ph
iPr
iPr
iPr
COOMe
COOpBrPh
COOpClPh
COOpFPh
COOEt
CH2-OBz-pOMe
CH2-OTBDPS
CH2-OTBDPS
COO-2-naphtyl
CH2-O-2-naphtoyl
Ac
Ac

4994
C. Bonini, G. Righi / Tetrahedron 58 (2002) 4981±5021
Scheme 15.
proper choice of an oxidation asymmetric methodology as
has been summarized in Scheme 15.
3.1. Preparation, availability and cost of the ligands
The discovery of novel ligands for the enantioselective
induction has been one of the major achievements in organic
synthesis in the last decades. From a practical point of view,
the ligands must be successful in the asymmetric induction,
but their availability (possibly as natural products or
derivatives) or preparation in standard conditions on a
large scale is also required; some of the most useful ligands
can now be found in chemical catalogues and therefore the
cost of a ligand becomes an important factor for their use in
organic synthesis. Fortunately many of the oxidative reac-
tions described above can also be performed in a catalytic
version, allowing a reduction in the cost of the ligands,
which are generally expensive. Another possibility to
explore is the use of supported ligand catalysts, which
allow a better, cleaner and recyclable use of the catalysts,
while the performance of the reaction remains compara-
tively the same. All these factors are of great importance
in the decision whether to use one or another route to the
same ®nal chiral molecule especially on a large scale.
Scheme 14.
of broader applicability and reliability as for other oxidative
procedures and more experiments and results are therefore
expected in the near future.
3. Comparison of the most used asymmetric oxidative
methodologies
Some of the earliest discovered asymmetric oxidative
methodologies of ole®ns have become very popular in
organic synthesis such as the AE of allylic alcohols and
the AD. The Salen-AE of unfunctionalised ole®ns has also
been used to prepare optically active epoxides, although not
as extensively as the AE of allylic alcohols and the AD. The
promising and latest AA of ole®ns, has been applied very
recently to the preparation of 1,2-aminoalcohols, which is a
known important functionality present in several natural
biologically active compounds. A comparison of the most
used methodologies, of their utilisation, restriction and
transformation to other functionalised compounds follows
in this section. This comparison would be helpful for the
The availability of the starting ole®ns will also be of great
importance for the ®nal decision (see discussion in Section
3.3).
In Table 7, a list of all the ligands available in a particular
chemical catalogue, with their comparative cost, is shown.
The discovery and optimization of the different ligands
already described, makes the tartaric esters some of the
more easily available in both enantiomeric forms for the

C. Bonini, G. Righi / Tetrahedron 58 (2002) 4981±5021
Table 7. Commercially available ligands with average costs
4995
catalysts 3 and ent-3 (see Fig. 2) were shown to be the
optimum catalysts in terms of availability, cost and broad
application to the enantioselective oxidation of many
unfunctionalised ole®ns. They are now commercially avail-
able as chiral ligands (Table 7, entries 13±14) and also as
their Mn(III) and Co(II) complexes (entries 15±18) for use
in different reactions. Alternatively, the synthesis of the
required enantiomerically pure salen ligands can be carried
out with optically active diamines and substituted salicyl-
aldehydes.78
Entry
Catalyst
Quantity
Cost (US $)a
1
2
3
4
5
6
7
8
(DHQ)2AQN
500 mg
500 mg
500 mg
1 g
250 mg
250 mg
10 g
10 g
5 g
25 g
10 g
25 g
1 g
1 g
1 g
33
33
31
49
25
25
13
13
14
9
40
14
27
26
35
39
28
28
(DHQD)2AQN
(DHQ)2PHAL
(DHQD)2PHAL
(DHQ)2PYR
(DHQD)2PYR
AD-mix-a
AD-mix-b
d(2)-DET
l(1)-DET
d(2)-DIPT
l(1)-DIPT
(R,R)-Salen
(S,S)-Salen
(R,R)-Co(II)Salen-ent55
(S,S)-Co(II)Salen-55
(R,R)-Mn(III)Salen-ent16
(S,S)-Mn(III)Salen-16
9
10
11
12
13
14
15
16
17
18
Improved results are also expected in the use of the ligands
on both soluble and insoluble supports.79 There have been
many attempts to optimise conditions in the polymer-
supported oxidative methodologies. While only little
progress has been made for the supported AE of allylic
alcohols,80 more promising results have appeared recently
for the AD81 and related AA82 processes. Interesting results
have also been reported for the Salen-AE,79d,83 although
catalyst decomposition is still the major limitation of this
solid-phase application. The developments in the area are
continuously growing and appropriate references can be
found as cited above.
1 g
1 g
1 g
a
From the Aldrich chemical catalogue 2000-2001.
AE of allylic alcohols, although the D(2) enantiomer is
more expensive than the l(1) enantiomer (see entries
9±12), but both have reasonably low prices. Additionally
the discovery of the AE with the use of the tartaric ligands
did not require improvements in the ligand design, since
they proved to be the perfect ligand of choice for most of
the AE reactions: without particular restrictions due to the
ligands used. The limitation, at the beginning, of the use of
the tartaric ligands in stoichiometric quantities has now
been overcome with their use in catalytic amounts (see the
discussion in Section 3.2).
3.2. Catalysis in the enantioselective oxidation
The need for catalytic processes in organic reactions has
become even more important than in previous work, given
the higher cost of the new complex reagents, as well as the
associated environmental problems, especially with the use
of toxic and polluting reagents on a large scale. The
catalytic version of an asymmetric oxidation of ole®ns
therefore appears to be particularly desirable and efforts
have been made in all the processes to make these reactions
truly catalytic. While the ®rst AE procedure in 1980 was
performed in a stoichiometric quantity, the other more
recent oxidative processes (the AD, Salen-AE and the last
AA, as well as the oxone-catalysed oxidation) were all
designed and realised in a catalytic version, in order to
make them immediately of high appeal for large-scale
reactions.
On the contrary, the discovery of, and improvements in
ligands used for the AD, and especially for the successive
AA, are still continuing, and, since the early attempts with
the cinchona alkaloids, many others have been prepared and
tested. In Table 7, the costs of the most successful and
available ligands are reported, both for the AD and for the
AA (entries 1±6). It should be pointed out that the complete
set of AD reagents, the AD mix formulation, is now
commercially available (see entries 7±8). The cost of this
complete set appears to be high compared to the prices of
the single reagents, and the routine use of this AD-mix
reagent must therefore be replaced by that of the standard
ligands and conditions. Due to the high cost of the ligands
(as well as the toxicity and cost of osmium sources),77 major
interest has been reported in their ef®cient utilisation on
supports and the facile recovery of the catalysts (see the
following discussion). The ligands have been now
optimised and almost all classes of ole®ns can be
dihydroxylated with good to excellent enantioselectivity
by carefully choosing the appropriate ligands. The recom-
mended ligands for each ole®n class presented in Table 3,
must therefore be compared with their availability and cost
as listed in Table 7. This variable use of different ligands,
often to be tested in the AD of particular ole®ns, represents a
limitation of the methodology, since there is no general and
widespread use of a single ligand for every class of ole®ns.
Since its discovery, the stoichiometric version of the AE of
allylic alcohols has often encountered some dif®culties,
especially in the isolation/puri®cation of unstable and/or
water-soluble epoxyalcohols, probably due to the mild
acidity of the Ti(OiPr)4 and to the tedious aqueous work-
up. In 1986, it was ®rst reported84 that the addition of
molecular sieves was able to reduce the use of the Ti±
tartrate complex to only 5±10%, for the complete achieve-
ment of the epoxidation reaction. The most recommended
catalytic procedure85 utilised is reported in Scheme 16. The
The discovery and optimisation for the Salen-AE ligands
required a testing period in order to obtain the most ef®cient
and versatile of the different ligands. The two Jacobsen
Scheme 16.

4996
C. Bonini, G. Righi / Tetrahedron 58 (2002) 4981±5021
Table 8. Estimate cost for asymmetric oxidation of 1 mmol of ole®n
be taken, however, with the purity of di-, tri- or tetrasubsti-
tuted ole®ns where the E/Z ratio is not always acceptable
and must be checked before use. From a typical catalogue,
hundreds of terminal ole®ns, as well as substituted ole®ns,
may be found. More complex ole®ns can also be easily
prepared by a large variety of standard reactions developed
for their stereospecifc preparation.1
Procedure
Cost (US $)
AE (asymmetric epoxidation)
AD (asymmetric
dihydroxylation)
0.4
1.9
AA (asymmetric
5.7
1.6
aminohydroxylation)
Salen-AE (salen asymmetric
epoxidation)
In Scheme 17, the most important types of ole®ns which can
be oxidised by the AD or the Salen-AE are listed, together
with the expected ®nal product. The scheme highlights
that the AD appears to be particularly favourable in the
dihydroxylation of trans (E)-ole®ns, while, for the Salen-
AE, trans (E)-substrates do not appear to be as good as the
cis (Z)-substrates (also electron-de®cient ole®ns), and that,
for best performance, the ole®n must be part of a conjugated
system.
amount of the Ti±tartrate complex cannot be ,5%, while
the amount of tartrate to be used must be carefully
controlled, since a large excess will decrease the reaction
rate, and contrarily, minor amounts will result in a lower
enantioselectivity. This procedure has the following advan-
tages: (a) the total cost of the reaction, already reasonable,
can be signi®cantly cut; (b) the procedure has been applied
to the preparation of unstable water-soluble compounds,
with advantages in separation and puri®cation procedures;
and (c) the substrate concentration can be substantially
higher (0.5±1.0 M) than the corresponding stoichiometric
version (0.1±0.3 M).
The availability of simple allylic alcohols as suitable
substrates for the AE is more limited and, so far, no more
than 100 of these alcohols are available from commercial
sources, although several suitable precursor aldehydes may
be purchased. Care must also be taken here with the stereo-
chemical purity of E/Z allylic alcohols as well as the optical
purity of allylic alcohols, which are eventually used for the
AE/KR. Due to the increasing use of allylic alcohols as
starting materials for the AE, many routes have been
developed to various classes of these compounds (Scheme
18), the most used sequence for their preparation being:
The other asymmetric oxidative procedures were developed
in a catalytic version, thus allowing a more economical use
of the often expensive ligands and regents.
In Table 8 a comparison is presented of the estimated costs
of the most utilised catalytic oxidation procedures, on the
basis of the catalogue prices for the ligands, the oxidant, the
solvent and all the other reagents required for a standard
`1 mmol ole®n' oxidation reaction. The total estimated
cost does not, however, consider the availability of the start-
ing ole®ns, which is not the same for every process and
often requires a synthetic preparation. The estimated costs
reported must therefore also be evaluated with other con-
siderations such as substrate, time-consuming reactions,
number of steps etc.
(1) the Horner±Emmons reaction of dialkyl carboalkoxy-
methylene phosphonates with aldehydes to produce
trans86a or cis86b a,b-unsaturated esters which, in turn,
can be reduced to alcohols, (Eq. (1)) and
(2) the use of propargylic alcohols, prepared by different
3.3. Availability and restrictions in the utilisation of the
starting ole®ns
The commercial availability of simple ole®ns, being
inexpensive products from the petroleum industry, is par-
ticularly widespread today: for the AD (and the more recent
AA) and the Salen-AE, of simple ole®ns the choice of the
starting material is therefore particularly broad. Care must
Scheme 17.
Scheme 18.

C. Bonini, G. Righi / Tetrahedron 58 (2002) 4981±5021
4997
4. Manipulation and transformation of the chiral
compounds obtained by asymmetric oxidative
methodologies: complementary stereochemical aspects
The great success of the most popular asymmetric oxidation
of ole®ns is due not only to the possibility of directly obtain-
ing important chiral products (i.e. epoxides or diols), but
also to the manipulation and transformation of the initially
obtained compounds into a large variety of related func-
tional groups. A ¯ood of methods for such a transformation
has therefore appeared and these are still in progress with
the major emphasis being on the chemo-, regio- and stereo-
control of the transformation. Comparing the chiral products
obtained by the AE, AD and the Salen-AE, the potential for
transformation of these compounds seems to be linked to the
possible sites of attack by the reagents. Fig. 6 summarises
the possible and studied sites of transformation of the chiral
starting compounds.
Scheme 19.
Exhaustive lists of transformations of epoxyalcohols (see
Refs. 2b±d), 1,2-diols (see Refs. 3b±d) and simple epoxides
Ref. 4c) have also been recently reviewed, and therefore in
this section a summary of the most important transforma-
tions will only be reported where the appropriate references
can readily be found in the previously cited reviews. A
major emphasis will be given to some of the most recent
methodologies (in the last 3±4 years). The aim of this
section is to provide a clear perspective on the different
possibilities of obtaining the same class of compounds,
with special attention being paid to the stereochemical
aspects of the ®nal products. A more detailed insight into
the competition of the different routes to the same
compounds will be given in Section 5, where some selected
examples will be reported and compared.
routes, as precursors of both cis87a or trans87b allylic
alcohols, by stereoselective reduction of the triple bond
(Eq. (2)).
The preparation of the substrate for the AE/KR (the
1-substituted allylic alcohols) has frequently been achieved
by simple addition of the appropriate alkenyl or alkynyl
organometallic reagent to the carbonyl compound, followed
by manipulation of the chiral allylic alcohol (Eq. (3)).
Some restrictions on the starting allylic alcohols must also
be considered and, in Scheme 19), a range of different
substrates are listed with an indication of their ability to
act as a good substrate for the standard AE.
4.1. Transformation and utilisation of 1-epoxyalcohols
3.4. Experimental conditions
The epoxyalcohol possesses three reactive sites for its trans-
formation (Fig. 6), namely in the carbon proximate to the
hydroxyl group (C-1), and in the two carbons of the oxirane
ring (C-2 and C-3), regio- and stereocontrolled reactions
being essential to completely explore the potential utility
of the compound. The main transformations can be
catalogued as follows:91 (a) direct substitution and/or trans-
formation of the hydroxyl group at C-1; (b) rearrangement
The simplicity and reproducibility of the reaction conditions
have always been carefully considered by organic chemists.
The main reaction conditions for the AE, the AD88 and the
Salen-AE are comparable with respect to reaction time,
temperature (2208C to rt), and concentration. The need
for pure organic solvent in the AE is less stringent for the
AD, the Salen-AE and the AA, where aqueous conditions
can be used. No doubt, the mild oxidant for the Salen-AE
(PhIO or NaOCl) appears to be superior for safety and
toxicity reasons to the TBHP (AE) or to the more toxic
OsO4 (AD and AA). The quenching and work up for the
AE is more tedious, although the catalytic version makes
tartrate elimination easier; generally, the separation of the
various components can easily be handled in a normal
laboratory apparatus for all the procedures, but the Salen-
AE still appears to be superior for a large-scale reaction.
The chemoselectivity represents a major advantage of the
reactions. Some care must be taken, when using the AE, in
the location of particular functional groups which can limit
the epoxidation or lead to epoxy ring opening.89 Noteworthy
is the chemoselectivity of the AD process, and also with
sulphur-containing compounds,90 where the catalytic AD
displays an interesting chemoselectivity with respect to
other stoichiometric oxidative processes.
Figure 6.

4998
C. Bonini, G. Righi / Tetrahedron 58 (2002) 4981±5021
of 2,3-epoxy alcohols into 1,2-epoxyalcohols (Payne
rearrangement) and subsequent regioselective substitution
at C-l; and (c) oxirane ring opening at C-2 or C-3. From a
synthetic point of view, the large range of possibilities for
the three active sites, which could eventually lead to three
stereogenic consecutive centres, makes the epoxyalcohols
the most versatile compounds obtained by the oxidative
ole®n methodologies. Some limitations could occur in the
¯exibility of the stereochemical products, since the starting
chiral epoxy alcohols are normally obtained by the AE of
E-ole®ns.
4.1.1. Reactions at C-1 and subsequent transformations.
For 2,3-epoxyalcohols, the free primary hydroxyl group can
be utilised for a series of transformations. The most straight-
forward transformation is the activation of the primary
hydroxyl group as shown in Scheme 20, and involves:
(1) transformation of the primary hydroxyl group into a
leaving group and its displacement by a variety of nucleo-
philes leading to different non-symmetrically-disubsti-
tuted chiral epoxides. The reaction sequence is an
alternative methodology to other direct epoxidations of
ole®ns: the success of this approach is strictly related to
the starting allylic alcohol availability and to the relative
stereochemistry of the desired epoxides (path a) and
(2) activation of the primary hydroxyl group (normally as
a halide) followed by rearrangement or transformation
into allylic alcohols or secondary alcohols (path b) as
an alternative to the direct preparation by reduction of
carbonyl compounds or asymmetric addition to alde-
hydes. In recent work, particular epoxy mesylates (path
c) were transformed into the corresponding a-alkoxy-
ketones by a variety of sodium alkoxides.92 An interesting
complementary reaction (path d), affording 2,3-syn-diol
phenylboronic esters sul®des93a or alkynyl hydroxy sul-
®des,93b has appeared via a double inversion of con®gura-
tion at C-2, through a probable episulfonium ion, with
high chemical and stereospeci®c control. In a recent
report,93c by the same authors, the intramolecular substi-
tution reaction of 1-silyloxy-2,3-epoxyalcohols, effects
the C-2 opening of the oxirane, leading to a ®nal cyclic
allenylsilane, with the results variable in terms of regio-
selectivity and chemical yields.
Scheme 20.
particular epoxyaldehydes have been treated with the
anion of t-butyl acetate to afford the corresponding
g,d,-epoxy-b-hydroxy esters with high anti diastereo-
selectivity.94a The use of particular experimental
conditions (e.g. chelating agents) has very recently94b
allowed the induction of a good level of anti selectivity
in the addition of different Grignard reagents to standard
epoxyaldehydes.
4.1.2. Regioselective substitution at C-1 by Payne
rearrangement sequence. The well-known Payne
rearrangement of 2,3-epoxyalcohols (Scheme 22) has
become an alternative to the C-1 substitution of the epoxy-
alcohols, since it was possible to shift the equilibrium by
introducing a proper nucleophile on the rearranged 1,2-
epoxyalcohol. The sequence, which was originally
developed by the Sharpless group,13,95 leads preferentially
to the 1,2-anti-diols with different nucleophiles (path a),
The primary hydroxyl group can also be oxidised to the
corresponding carbonyl compounds, without apparent
epimerisation, with standard methodologies, which have
been particularly studied for such sensitive compounds.2c
The corresponding, aldehydes (Scheme 21) can be further
transformed into a series of useful chiral compounds as
follows:
(1) a Wittig type ole®nation (path a) can lead to a variety
of vinyl epoxides which can undergo a series of other
useful transformations towards the synthesis of saturated
epoxides, allylic or homoallylic alcohols and then to the
®nal skipped 1,3-polyols and
(2) the addition reaction (path b) to the carbonyl group,
(although the high sensitivity of the epoxyaldehydes did
not allow extensive use of this important functionality)
could lead to the introduction of a further asymmetric
centre with fair to good results. More recently (path c)
Scheme 21.

C. Bonini, G. Righi / Tetrahedron 58 (2002) 4981±5021
4999
Scheme 22.
Scheme 23.
although an alternative pathway with inversion at the C-2
position has been developed, with the isolation of the inter-
mediate 1,2-epoxyalcohols (path b).
opening sequence (path a), the 1-iodo-2,3-syn-diols can
also be obtained, and eventually coupled with carbon
nucleophiles to yield unsymmetrical syn-1,2-diols (path b).
4.1.3. Oxirane ring opening at C-2 or C-3 of epoxy-
alcohols and derivatives and subsequent transforma-
tions. The regio- and stereocontrol of chiral primary and
secondary 2,3-epoxyalcohols has been extensively explored
in recent years and a large variety of C-2 or C-3 substi-
tutions of the oxirane ring can now be performed with
high stereochemical control. Apart from eventual steric
hindrance, the C-3 substitution by nucleophiles for 2,3-
epoxyalcohols often appears to be more favourable for
electronic effects (the presence of the C-1 hydroxyl
group). The possible formation of a chelate between the
hydroxyl group and the oxirane oxygen was found, after
the preliminary account by Sharpless,96 to be the most
effective in enhancing the C-3 selectivity. In Scheme 23
the most useful sequences in order to obtain synthetically
useful compounds are reported.
The most useful approach to the C-2 substitution can been
achieved via intramolecular nucleophilic opening, by
anchoring the nucleophile to the primary hydroxyl group.
In this way, useful compounds such as carbamates,
xanthates and carbonates can be prepared (path c), as
precursors of anti-2-amino-, sul®de- or hydroxy-substituted
diols. Recently, a highly regioselective azide opening to the
C-2 position was effected (path d, Scheme 24),101 leading to
the anti-2-azido-1,3-diols, with good applicability to several
substrates.
Stereode®ned 1,2-diols (path a) have also been obtained
very recently by several different reducing agents.97 In addi-
tion, the corresponding 3-substituted alkyl 1,2-diols have
been regio- and stereoselectively obtained with different
organometallic reagents; in more recent work, the sequence
affords a-silylaldehydes98 as the ®nal compounds. Espe-
cially important are the nitrogen nucleophilic substitutions
(path b) leading to the very important anti-3-amino-l,2-diol
moiety present in many natural products. Halogen nucleo-
philes can also regioselectively open the oxirane ring,99
affording the corresponding 3-halohydrins (path c), which
may be eventually transformed to the syn-3-amino-l,2-diols.
More recently, a new procedure was developed100 (path d),
improving the previous results,96 to selectively introduce the
CN function at the C-3.
The C-2 nucleophilic substitution (Scheme 24) can now be
effected with good regio- and stereocontrol. In this way,
stereode®ned 1,3- and 2-alkyl-1,3-diols can be obtained,
while, via a stereocontrolled inter- and intramolecular
Scheme 24.

5000
C. Bonini, G. Righi / Tetrahedron 58 (2002) 4981±5021
The regioselective opening by nucleophiles has also been
extensively performed on different 2,3-epoxyalcohol
derivatives. The easily obtained epoxy esters, can therefore
be opened (Scheme 25) at the C-2 (path b) or C-3 position
(path a and path c) by some nucleophiles, leading to the
important classes of hydroxy acids, halo hydroxy acids, or
hydroxy amino acids, with de®ned stereochemistry. More
recently, epoxy aldehydes have been opened by halogens
and then reacted with organometallic reagents (path d)
affording, in a highly stereochemical fashion, 3-bromo-
1,2-syn-diols, useful synthons for further transformations.102
Along with these transformation, very recent ®ndings103
allow the regioselective C-2 or C-3 opening of epoxyacids
with halogens (NaBr and NaI) and azide (NaN3), but in
water: careful pH control is needed in order to obtain the
best overall yields, together with the use of water-tolerant
Lewis acids,103b responsible for the C-3 regioselectivity.
The transformation of 2,3-epoxyalcohols to the correspond-
ing 2,3-aziridino alcohols104 or esters,105 has opened the way
to useful transformations of these interesting synthons
(Scheme 26). Following the behaviour of the corresponding
epoxy alcohols or esters, the aziridino alcohols have been
Scheme 26.
chiral epoxy alcohols obtained by AE (mainly on E-allylic
alcohols) has led to the preparation of a series of particularly
attractive compounds with different functionality and
de®ned stereochemistry.
opened at the C-3 position (path a) by hydrides and
106
cuprates105 and, more recently, via H2
or metal hali-
des.99b,107a On the other hand, aziridino esters (path b)
initially opened with alkyl and heteroatom nucleophiles at
C-3106 can now be regioselectively opened at C-2 or C-3 by
metal halides.99b,107b In conclusion, the manipulation of the
4.2. Transformation and utilisation of 1,2-diols
The 1,2-diol subunits are often the ®nal product of a
synthetic sequence, especially in the ®eld of carbohydrates
or polyols, the syntheses of which have taken on the major
advantages from the AD methodology. From a strategic
point of view, the 1,2-diol system can be introduced in the
latest steps of the synthesis, because of the high reagent
stereocontrol shown by the AD (examples of this powerful
application will be reported in Section 5). This makes the
AD an incomparable methodology to obtain syn-l,2-dios,
over other possible methodologies and transformations.
If the syn-1,2-diol is not the ®nal functionality required,
manipulation of the starting chiral compound can be
performed and, for this reason, the chemical transformation
and manipulation of diols prepared by the AD have been the
subject of several studies.
Several applications of the manipulation and transformation
of 1,2-diols have been the subject of exhaustive reviews3c,f
and, therefore, a general summary will be presented here,
with the major emphasis on the ®nal products with the
proper stereochemistry and the more recently introduced
methodologies.
4.2.1. Differentiation and transformation of terminal 1,2-
diols. The strategy for the transformation of the 1,2-diol
system requires the selective manipulation of one of the
two OH groups.3c This clearly occurs, more easily in the
presence of either a primary and secondary hydroxyl
group or a secondary and tertiary hydroxyl group. As
shown in Scheme 27, the easy functionalisation of the
primary hydroxyl group with a good leaving group can be
utilised for the preparation of chiral 1,2-epoxides (path a), a
strategy which has also been utilised for the preparation of
disubstituted epoxides (see below). Care must be taken,
Scheme 25.

C. Bonini, G. Righi / Tetrahedron 58 (2002) 4981±5021
5001
Scheme 27.
however, since a possible partial racemisation can occur. A
`one-pot' procedure for conversion of diols directly to epox-
ides (path b) has been also proposed, with the formation of a
cyclic orthoester intermediate, its opening and subsequent
base-mediated cyclisation to the epoxide ring in one reac-
tion vessel.
Scheme 28.
sulphonyl derivative, with one stereocenter inversion (path
c). The epoxides obtained can be manipulated by regio-
selective opening and substitution to give other important
compounds such as aminoalcohols.
The use of the intermediate halohydrins or acetoxy
bromides (with AcBr and subsequent alkaline treatment),
affords the chiral 1,2 epoxides by cyclodehydration of the
diols (path d) via 1,3,2l5-dioxaphospholanes (path c),
although racemisation can occur. It is noteworthy that the
same intermediate derivatives can be functionalised to the
secondary carbon, leading to chiral 1-alkanols (path e).
If a speci®c halohydrin is required, the regioselective
manipulation of the diols becomes decisive, but this can
be performed only for a well-de®ned electronic differentia-
tion of the two carbons of the 1,2-diols, i.e. when aromatic
groups are present or when EWG, such as carboxylic
derivatives, are proximate to one of the two hydroxyl groups
(path a).
The preparation of these 1,2-epoxides can be followed by
nucleophilic opening of the epoxy ring (path f), which
ultimately leads to chiral 2-alkanols, if organometallic
reagents are used. The overall sequence (which can be
An elegant differentiation of the hydroxyl groups can be
performed3c by intramolecular cyclisation directed by an
appropriate proximal reacting group. By this approach
(Scheme 29), g-lactones and carbamates have been
prepared, leading to important intermediates for the
synthesis of natural products, further demonstrated in a
short synthesis of (1)-laurediol.109
conveniently performed in
a
two-step procedure)108
represents the transformation of an ole®n into a variety of
enantiomerically pure carbinols.
4.2.2. Differentiation and transformation of unsym-
metrically substituted 1,2-diols. If the ®nal desired
compound is an epoxide, the selective manipulation of the
two substituted hydroxyl groups is not relevant.3c This
occurs for the formation of epoxides through an inter-
mediate halohydrin or acetoxy bromide, which arise from
a cyclic intermediate (Scheme 28, path a), prepared as an
unstable or stable 1,3-dioxolan-2-ylium cation. Given some
limitation in the direct enantioselective epoxidation of
ole®ns with an E geometry (see Salen-AE utilisation), the
overall sequence from the starting ole®ns, which can be
performed in one pot (path b), represents a straightforward
way to obtain important chiral compunds (i.e. trans glycidic
esters), by two stereocenters inversions.
Similarly, cis glycidic esters can be obtained3c by mono
activation of the diol, via the tosyl or p-nitrobenzene-
Scheme 29.

5002
C. Bonini, G. Righi / Tetrahedron 58 (2002) 4981±5021
cyclic sul®tes and sulfates depends strictly on the unsym-
metrical substitution pattern of the 1,2-diols. Many
examples of the reaction have therefore been performed
on symmetrically disubstituted diol derivatives, or by intra-
molecular nucleophilic cyclisation; the presence of a
proximate electron-effecting group to one of the two
carbons can help in a regioselective opening of the cyclic
derivative. A recent example of a regioselective azide open-
ing of sul®te derivative (path d), demonstrates the applic-
ability and the limit of this transformation.111 A new general
three-step procedure112 (path c) allows the preparation of a
large variety of glycidic esters starting from the chiral
dihydroxy esters, via cyclic sulfate and Br-opening followed
by cyclisation to the epoxide.
Scheme 30.
4.2.3. Differentiation and transformation of substituted
1,2-diols via cyclic sul®tes and sulfates. One of the most
useful transformation of the 1,2-diol moiety leads to cyclic
sul®tes and sulfates, which can be considered as epoxide
equivalents110 and are even more reactive. Different
preparations have been studied and developed: most of
them required the initial preparation of the sul®tes (less
utilised due to the liability at the sulfur centre and to the
minor reactivity), eventually followed by the oxidation to
cyclic sulfates (normally more utilised) by a variety of
oxidising reagents and conditions, also depending on the
acid-sensitive groups present in the molecule (Scheme 30).
To overcome this limitation, an irreversible Payne
rearrangement (as described in Scheme 32, path a) has
been elegantly proposed113 for the preparation of anti-1,2-
diols, which was utilised for the synthesis of polyhydroxyl-
ated,113a as well as for cis epoxides-containing, natural
compounds.113b Another two related rearrangement
reactions of cyclic thionocarbamates and iminocarbamates
have been successively proposed by the same authors (path
b), yielding syn b-hydroxythiol114 and syn-b-hydroxy-a-
amino115a or a-hydroxy-b-amino compounds,115b with
variable yields and regioselectivity which were better with
an aromatic substituent) still to be improved after consider-
ing the ®nal deprotection step of the cyclic products.
The cyclic sulfur derivatives obtained can be conveniently
opened, as oxiranes, by nucleophilic reagents (Scheme 31)
to a sulfate monoester which now possesses an anti relation-
ship between the OH and the incoming nucleophile (path a);
this monosulfate ester can be subjected to a further more
dif®cult second displacement (path b), with a ®nal double
inversion of con®guration with respect to the starting 1,2-
diol. Care must, however, be taken in the ®nal hydrolysis of
the sulfate monoester, since acidic conditions are normally
used.
The exhaustive work in the transformation and manipula-
tion of the enantiomericallly pure 1,2-diols obtained by the
AD, makes it now possible to obtain almost all varieties of
proximate functional groups.
4.3. Transformation and utilisation of simple epoxides
obtained by the Salen-AE
It should be noted that the regioselective opening of the
Without doubt the chiral epoxyalcohols and the 1,2-diols,
described above, have demonstrated their usefulness by the
number of transformations to which they have been
subjected. The possible transformations of the enantio-
Scheme 31.
Scheme 32.

C. Bonini, G. Righi / Tetrahedron 58 (2002) 4981±5021
5003
Scheme 35.
chiral compound 27 (Scheme 34) for the synthesis of a
tachykinin receptor antagonist.117 The indene analogue 25,
subjected to the Salen-AE with the Jacobsen catalyst 3,
afforded the epoxide 26 (ees up to 93%) which was then
regioselectively reduced to the alcohol 27 with 86% yield.
Scheme 33.
A remarkable example of the application of the Jacobsen
catalyst for Salen-AE and successive selective manipulation
is represented by the Merck approach to the cis 1S,2R-
aminoindanol 28, which constitutes a key intermediate for
the synthesis118 of the potent HIV protease inhibitor,
crixivan.119 Scheme 35 summarises the developed sequence
as reported,120 where the inexpensive starting indene can be
epoxidised on a 600 kg scale; subsequent treatment with
oleum and CH3CN afforded in a regioselective and stereo-
selective fashion the cis oxazoline, probably through a
Ritter-type mechanism. The ®nal production of the hydro-
lysed compound 28 represents one of the most important
examples of the practical application on an industrial scale
of a developed oxidative asymmetric methodology for
ole®ns.
merically pure epoxides obtained by the Jacobsen±Katsuki
Salen-AE protocol or by the most recent Shi procedure with
chiral dioxirane derivatives have been less studied but some
general considerations can be discussed.
The simple epoxides obtained directly by an enantio-
selective reaction, also possess two reactive sites for the
opening and the manipulation of the oxirane ring (Fig. 6).
In spite of these two possible reactive sites, the reactivity of
the oxirane ring, if not normally located in the proximity of
functional groups, appears to be more limited for regio-
selective reactions. So far the Salen-AE has therefore
successfully been applied to the preparation of particular
epoxides, with minor emphasis on the subsequent
transformation.
In some particular but important examples, however, a
regio- and stereoselective transformation of the epoxide
has been performed on other functional groups.
5. How to make the right choice: a comparison of
selected examples of different routes to the same target
The remarkably high enantioselectivc epoxidation,
performed via the Jacobsen catalyst, on a dimethyl chro-
mene derivative to compound 22 (Scheme 33) was followed
by regioselective opening with nitrogen and oxygen nucleo-
philes, leading to the ef®cient synthesis116 of the anti-
hypertensive agent cromakalim 23 and the related
compound 24.
A survey of the most reliable asymmetric oxidative pro-
cedures of ole®ns establishes that all the described
procedures give access to a wide variety of oxidative
products with reasonable to good chemical yields and, in
general, high enantioselectivity (ee.90%). Since many of
the primary oxidative products can be transformed into
functionalised compounds by selective manipulation
(Section 4), an organic synthetic chemist, when planning a
synthesis of target chiral compounds, could be faced with
alternative routes to the ®nal products. As described below,
alternative routes have been developed to different classes
of functionalised compounds, where the advantages and the
disadvantages are comparable.
A more recent report has described the preparation of a key
Apart from the direct end products such as epoxides or 1,2-
diols, very important considerations must be made in order
to transform the products, directly obtained in the oxidative
procedure, into the ®nal compounds, by a series of trans-
formations which must be chemo-, regio- and stereo-
selective and high yielding. Hydroxyesters, aminoalcohols
and aminoesters etc, which could in principle be obtained in
different ways, can therefore offer an interesting case study
as proof of the general improvements made in the ®eld of
asymmetric synthesis.
Scheme 34.

5004
C. Bonini, G. Righi / Tetrahedron 58 (2002) 4981±5021
Scheme 36.
5.1. Chiral epoxides
Chiral epoxides have been regarded as versatile products for
their easy stereospeci®c ring opening reactions to form
functionalised compounds (chiral building blocks).
Although the epoxides are involved in the metabolism of
many aliphatic and aromatic compounds in plants and living
organisms, examples of epoxides as end products are rare.
The most important chiral epoxides encountered are as sex
attractants of Lepidopteran pests,121 in leukotrienes122 and
as self-defensive substances against blast disease.123
Scheme 37.
cyclic lactone isolated from a South African tree and found
to show PS cell line activity (p-388).124 The structure shown
in Scheme 38 possesses two chiral centers on an oxirane
ring conjugated to an aromatic ring. The target compound
appeared easily obtainable by the Jacobsen-catalysed Salen-
AE of the corresponding natural analogue combretastatin
D-2. This direct approach, however, when initially
attempted,125 afforded the desired epoxide in a modest
35% ee, although the cis double bond and the conjugation
with an aromatic ring were found, in many cases, to be
A chiral 1,2-epoxide can be obtained by three different
methods as illustrated in Scheme 36. While the most direct
Salen-AE of monosubstituted ole®ns does not generally
afford terminal epoxides with high ee, the AD route
normally does proceed with high ee, although it requires a
two-step sequence. In addition the AE of allylic alcohols can
be followed by easy manipulation to yield terminal
epoxides.
Chiral disubstituted epoxides appear to be more easily
prepared (Scheme 37) and the three main possibilities are
outlined. Interestingly, the Salen-AE and the AD appear
complementary (cis or trans epoxides, respectively),
although with the known limitation for the Salen-AE (the
double bond must be conjugated), or a longer reaction
sequence for the AD-mediated preparation of trans or cis
(see Section 3).
The AE of allylic alcohols offers an alternative to trans or
cis disubstituted epoxides starting from (Z) allylic alcohols.
In this longer sequence, the choice of the starting epoxy
alcohol, and of the second chain introduced is crucial for
a competitive comparison with the other two approaches.
The different choices for the synthesis of epoxides must be
carefully examined when planning a synthesis, because an
apparently shorter route does not always prove to be
practical. An interesting example can be examined in the
synthesis of (1)-combretastatin D-l, a 15-membered macro-
Scheme 38.

C. Bonini, G. Righi / Tetrahedron 58 (2002) 4981±5021
5005
utilised for the industrial preparation132 of the ®nal
compound with a short sequence (as illustrated in Scheme
39) based on the ®rst report by Sharpless group.130a
Other unsaturated epoxides have recently been prepared by
the AE approaches133 but the number of steps and the over-
all yield do not appear to be competitive.
The AD methodology requires the selective manipulation of
the obtained 1,2-diol (Scheme 40), which was achieved in
two different ways by the Sharpless group (path a)131 and by
Ko et al. (path b).113b An alternative diol manipulation has
recently been applied for the synthesis of related unsaturated
epoxides.134
Scheme 39.
By comparison of the different routes, it appears that the ®rst
approach via the AE of the appropriate allylic alcohol, is
still the most straightforward process to the title compound.
The apparently more direct route by the AD approach
suffers from the need to manipulate the syn-l,2-diol to
yield the desired cis epoxide. On the other hand the direct
Salen-AE or the oxone-based AE of an appropriate ole®n
have not yet been reported.
suitable for a high enantioselective epoxidation. Much
better results, in terms of enantioselectivity (ee 96%),
were obtained by the use of the AD methodology on the
described ole®n (Scheme 38), despite the subsequent
tedious elaboration to the ®nal compound.126
The same AD-based strategy for the installation of the
epoxide moiety has very recently been successfully applied
to the synthesis of cryptophycin 52,127 and the eicosanoid,
(11R,12S)-oxidoarachinonic acid.128
5.2. Chiral alcohols, diols and polyols
The 1,2-diol and polyol subunits, due to their presence in the
structure of several biologically important compounds
(natural or synthetic), have been the subject of intensive
research activity for their preparation in optically active
form.135
5.1.1. (1)-Disparlure and related natural epoxides. One
of the most important epoxides found in nature is the sex
attractant pheromone of the female gypsy moth (Lymantria
dispar L)129 (Scheme 39) which has become and still is a
popular target of several asymmetric syntheses. Many of the
approaches are based on the asymmetric epoxidation of an
appropriate ole®n, with the use of the AE of allylic
alcohols130 and of the AD113b,131 of simple ole®ns.
In principle, these subunits can be prepared (directly or via
transformation) by the known asymmetric methodologies.
Sometimes the 1,2- or 1,3-diols are the ®nal target
compounds, but often the subunit is part of a large molecule,
where the introduction of the stereochemically appropriate
diol system can also be achieved at a certain step of the
synthetic sequence (diastereoselective reaction) instead of
at the beginning of the sequence (enantioselective reaction).
As already stated in Section 3, the AD has revealed its
enormous utility in the preparation of such 1,2-diol frame-
works with a preference for (E) ole®ns to yield syn-(threo)
diols.
It must be emphasised that the AE approach has been
The most simple terminal 1,2-diol can be prepared directly
from a monosubstituted ole®n via the AD methodology
(Scheme 41). This represents a very powerful strategy,
which, apparently, surpasses the other known approaches.
The aliphatic chain length of a terminal ole®n can, however,
in¯uence the AD enantioselectivity and good ees can be
obtained more easily for alkenes with at least a C-5 or
bulky chain.
This is illustrated in Scheme 42 for the preparation of the
compound 29 (a chiral synthon for the synthesis of complex
natural products)135 where the more straightforward
sequence (path a via AD) afforded the desired diol in ee
of 65%.136 On the other hand, by using the AE strategy
(path b) the ®nal diol could be obtained in ee.98%,
although with a longer sequence which involves a devel-
oped137 high-yielding regio- and chemoselective ring
Scheme 40.

5006
C. Bonini, G. Righi / Tetrahedron 58 (2002) 4981±5021
Scheme 41.
opening-reduction sequence with LiI/Amberlyst 15 and
radical reduction.
Scheme 43.
The disubstituted 1,2-diol system presents an additional
problem of the relative stereochemistry (syn or anti) of the
two hydroxyl groups and, in this case, the most direct way to
prepare the 1,2-diol utilises (Scheme 43) the AD strategy.
The longer sequence via the AE strategy may sometimes
represent an alternative route, depending on the availability
of the starting ole®n. In this second approach the second
substituent is introduced subsequent to the rearrangement
reaction.
isolation (about 300 compounds), structure elucidation and
synthesis of this class of compounds,138 because of their
remarkable activity as cytotoxic, antitumour, antimalarial,
immunosuppressive, pesticidal and antifeedant agents. They
are structurally characterised by the presence of one to three
tetrahydrofuran rings at the centre of two hydrocarbon
chains with one chain possessing a ®nal butenolide moiety
(Fig. 7). The stereocontrolled construction of the THF units,
with both anti or syn ring junctions, still represents the
major challenge in the total synthesis of this class of
substance.
A direct ef®cient synthesis of the anti diols is not yet avail-
able and therefore the choice is between the AE and the AD
strategy and relies on the Payne rearrangements (reversible
or irreversible, respectively). In these two different
approaches, the second R substituent is introduced in the
®nal steps and the proper choice may be strongly in¯uenced
by the availability of the starting ole®ns as well as the
enantioselectivity observed in the two asymmetric
procedures.
The required 1,2-diol subunits needed to construct the THF
rings, can be prepared in different ways, but the AD has
revealed its strategic importance in this ®eld.139
Interestingly, the AE of allylic alcohols has been often used
as a complement to the AD and, in several approaches, the
AE and the AD were successfully utilised for the introduc-
tion of the correct chirality in the core centres of these
interesting compounds.140
Among the hundreds of complex molecule which have been
prepared utilising the AE or the AD methodologies for the
introduction of the proper diol chirality, of particular note is
the most recent case of the Annonaceous acetogenins. In
past years, there has been an explosion of activity in the
This simultaneous utilisation of the AE and AD141 can be
considered a further con®rmation of the con®dence that
synthetic organic chemists have in these standard method-
ologies.
Scheme 42.
Figure 7.

C. Bonini, G. Righi / Tetrahedron 58 (2002) 4981±5021
5007
Scheme 44.
5.2.1. (2S,3S)-Octanediol. (2S,3S)-Octanediol, a well
known pheromone of the grape bore Xylotrechus
pyrrhoderus,142 can be considered an interesting example
of the apparently more simple and direct route. Application
of the AD on the commercially available oct-2-ene,
(Scheme 44) would be expected to directly afford the 2,3-
diol, with the superior optical purity normally observed for
the AD of (E)-disubstituted ole®ns, but the attempts only
yielded the desired compound in a 55% yield (together with
a signi®cant amount of a-hydroxy ketone) and with an ee of
62%.143
Scheme 45.
AD149 for the introduction of the 1,2-diol unit has received
much attention since the discovery of this natural product.
Some of the different routes are compared in Scheme 45.
The AD approach by the Sharpless group,149a as a general
approach to g-lactones, immediately appears to be as the
most straightforward route to this compound. A more
recent, similar approach by AD149b does not favourably
compete with the route.
Although the synthesis was more lengthy, much better
results, in terms of enantioselectivity, were obtained via
the AE/KR of a secondary allylic alcohol,144 but the fair
overall yield mirrored the resolution step. The use of the
AE on primary allylic alcohols proved to be quite useful,
coupled with the developed145 ring-opening rearrangement
of allylic alcohols with LiI to the 2,3-syn-diols, followed by
in situ reduction. In this way, optically pure (2S,2S)-octane-
diol could be obtained,146 starting from the commercially
available 3-octenal, in a three-step high-yielding route.
Some of the other most competitive approaches (Scheme
45) utilising the AE of allylic alcohols146 or the AE/
KR,148a do not exceed a 25±28% overall yield in ®ve steps.
In contrast to the preparation of 2,3,-octanediol, the synth-
esis of the acetogenin precursor, muricatacin, possessing the
1,2-diol syn con®guration, clearly establishes the superior
advantage of the AD methodology.
5.2.3. (5R,6S)-5-Acetoxy-hexadecanolide.
A
popular
synthetic target possessing an 1,2-diol unit with a relative
anti (erythro) con®guration is represented by (5R,6S)-5-
acetoxy-hexadecanolide (Scheme 46), a mosquito ovi-
position attractant pheromone isolated from the apical
droplet of eggs of the mosquito, Culex pipiens fatigans.150
5.2.2. (R,R)-Muricatacin. Another example of a syn (threo)
diol as a natural compound is that of (R,R)- or (S,S)-muri-
catacin,147 a simple acetogenin derivative (Scheme 45)
isolated from the seeds of Annona muricata in both
enantiomeric forms, the synthesis of which has attracted
the attention of many groups. Among the different
approaches to its synthesis, the use of the AE146,148 and
In comparison with the syntheses discussed in Sections
5.2.1 and 5.2.2, the direct asymmetric introduction of the

5008
C. Bonini, G. Righi / Tetrahedron 58 (2002) 4981±5021
Scheme 47.
A more recent AD approach,149b coupled with an interesting
lactonisation which allows the inversion of the con®gura-
tion to the desired anti diol (Scheme 48) only slightly
improved the overall yield to the target compound with a
comparable number of steps (nine) with respect to the AE
approaches.
In conclusion, this case study reveals that when direct
methodology for obtaining the 1,2-diol subunit is not avail-
able, both the AE and the AD gave similar and comparable
results and therefore the choice of the shortest route to the
same target is largely in¯uenced by the general strategy
followed in the synthesis, and less so by the asymmetric
methodology applied.
5.2.4. (4R)-Dodecanolide. The sacri®ce of a chiral centre
may be necessary for the synthesis of a particular
compound, since the introduction of the proper chirality
may use asymmetric methodologies with the introduction
of more chiral centres than required. This was the case for
Scheme 46.
syn-1,2-diol subunit cannot be straightforward, and there-
fore a longer sequence is required, although the molecule
appears simple. Some of the more direct approaches to the
synthesis of the target compound require the AE/KR151 or
the AE152 of allylic alcohols and, more recently,149b the AD
of the appropriate ole®n.
As shown in Scheme 46, the AE/KR was performed on
different racemic allylic alcohols (to be prepared) with
excellent enantioselectivity for all reactions.151 The number
of steps (six to ten) and the ®nal overall yields were,
however, not completely satisfactory, due to the key step
of the racemic resolution.
The AE on the appropriate allylic alcohol152 (Scheme 47)
does not appear to signi®cantly improve the process with
respect to the AE/KR approaches.
Scheme 48.

C. Bonini, G. Righi / Tetrahedron 58 (2002) 4981±5021
5009
Figure 8.
attracted the attention of synthetic chemists and several
approaches to the synthesis of these units have now been
developed157
The appropriate relative and absolute stereochemistry,
which may be present in many substrates (Fig. 8), requires
total stereocontrol for obtaining such subunits in optically
active form. This can be performed from a suitable ole®n
with the asymmetric methodologies reviewed in this article,
with eventual manipulation and transformation of the oxida-
tive products as has been summarised in Scheme 50.
Scheme 49.
(4R)-dodecanolide, a defensive secretion of rove beetles.153
The stereostructure (Scheme 49) reveals the presence of one
chiral centre of a g-lactone, but the AE and the AD
approaches can be conveniently utilised, on comparable
routes.
The recently developed AA of ole®ns5 is the most straight-
forward route to obtain the chiral b-aminoalcohol moiety
(Scheme 51): there are, however, still some limitations in
the use of this methodology, especially in the regio-
selectivity of the reaction as well as in the starting ole®n,
where the substrate of choice is often limited to trans-
conjugated disubstituted ole®ns. Care must be taken in the
deprotection of the nitrogen group, where the choice of the P
group can in¯uence the enantioselectivity of the reaction.
Good results can be obtained, in some cases, as illustrated
by some examples of recent applications to amino
As shown in Scheme 49, the AE approach146 utilises the
opening137 of the known epoxy tosylate, prepared in one
pot from commercial decen-2-ol in 89% yield. Regio-
selective LiI opening was followed by radical elimination
of the iodine (which could be eventually performed in one
step via DIBAL),154 and then by standard conversion to the
®nal dodecanolide.
The more recent AD approach,155 as part of a more general
route to butenolides and g-lactones, employs a highly
enantioselective AD on an unsaturated ester, followed by
the elimination of hydroxyl group and reduction of the
double bond, ®nally leading to the target compound in
49% overall yield and ®ve steps starting from decanal.
In the present example, where both the AE and the AD
approaches gave similar results, it must be emphasised
that the target compound appears not to be clearly related
to structures obtained by the two asymmetric method-
ologies, thus implying a profound modi®cation of the
starting epoxy alcohol and 1,2-diol.
5.3. Chiral b-aminoalcohols
The b-amino alcohol subunits, since their discovery in
many biologically active compounds especially as
a-amino. b-hydroxy or a-hydroxy, b-amino acids,156 have
Scheme 50.

5010
C. Bonini, G. Righi / Tetrahedron 58 (2002) 4981±5021
Scheme 51.
cyclitols,158 amino acids of the vancomycin skeleton159 and
2,3-diaminobutanoic acids,160 where syn(threo) aminodiols
are easily obtained in high ee and reasonable chemical
yields.
The Salen-AE (Scheme 52) followed by nitrogen opening of
the epoxide, also appears to be suitable for this purpose. In
this methodology, however, the limitations in the ole®nic
substrate (cis conjugated ole®ns) and in the regioselective
opening of the epoxide with nitrogen nucleophiles still
con®ne the approach to a small number of substrates. In
this example, as for the AA, the syn (threo) b-aminoalcohol
subunits are obtained.
The older AE of allylic alcohols has been widely utilised for
the introduction of the b-aminoalcohol moiety (Scheme 52).
In spite of the number of steps required for the transforma-
tion of the starting chiral epoxyalcohols to the ®nal amino-
alcohols, this approach frequently gives access to a large
variety of possible regio- and diastereoisomers, with more
¯exibility than the direct AA and Salen-AE. The introduc-
tion of the nitrogen substituents (i.e. azido), if carried out on
different 2,3-epoxyalcohols, normally gives rise to anti 3-
azido-l,2-diols,161 with high levels of regio-and stereo-
selectivity or, in a few cases to anti 2-azido-l,3-diols.101,162
On the contrary, the regioselective opening with metal
halides163 and subsequent replacement of the halogen by
azide could give access to syn 3-azido-1,2-diols.
Starting from the corresponding 2,3-epoxy esters, regio-
selective opening directly affords the anti 3-azido-2-
hydroxy esters,162 while regioselective opening with
halides, followed by stereoselective replacement by azide,
affords the syn 3-azido-2-hydroxy esters163 and the syn
2-azido-3-hydroxy esters164 with virtually all types of R
substituents. Very recently, the C-3 BF3±OEt2 catalysed
regioselective opening of non-aromatic glycidic esters or
amides, has been reported165 to afford the corresponding
2-oxazolines in mild conditions and good yields, which
can be hydrolysed into the b-amino, a-hydroxy esters or
amides.
Scheme 52.
ester or the anti 3-amino-2-hydroxy ester: the corresponding
syn 2-amino-3-hydroxy ester can be produced by a more
recent procedure114 using an internal process which allows
the conversion of the starting syn diol to the ®nal syn amino
hydroxy ester, although the regioselectivity of the
rearrangement is strongly dependent on the substituents.
As clearly demonstrated the b-aminoalcohol unit represents
a unique case of complementarity and competition of the
most common asymmetric oxidative methodologies, and
their applications in many signi®cant examples of bio-
logically active compounds will be illustrated below.
The appropriate choice of the starting substrate, as well as
the reaction conditions, can be therefore quite helpful for a
correct strategy to achieve the synthetic goal, utilising the
2,3-epoxyalcohols as chiral synthons.
5.3.1. Taxol side chain. Since the discovery of the essential
importance of the C-13 side chain of the taxol family for the
antitumour activity,166 the synthesis of the (2R,3S)-3-
phenylisoserine (Fig. 9) has become of great interest not
only for academic research but also for industrial-scale
production.167 All of the asymmetric oxidative method-
ologies of ole®ns described in this review have been
The AD approach also requires several steps to yield
hydroxy amino subunits. The obtained syn 2,3-diol ester
can ®rstly be transformed (Scheme 53) to the cyclic sulfate
and then conveniently opened by N3 with high regio-
selectivity for aromatic R groups and lower for alkyl R
moiety to afford, ®nally,3c,110 the anti 2-amino-3-hydroxy