Diastereoselective Allylation of Carbonyl Compounds and Imines:
Application to the Synthesis of Natural Products
Miguel Yus,* Jose
C. Gonza
lez-Go
mez, and Francisco Foubelo*
Departamento de Química Orga
nica, Facultad de Ciencias and Instituto de Síntesis Orga
nica (ISO), Universidad de Alicante, Apdo.
99, 03080 Alicante, Spain
CONTENTS
1. Introduction 5595
2. Substrate Control 5597
2.1. Chiral Carbonyl Compounds 5597
2.1.1. Allyl Stannanes 5597
2.1.2. Allyl Silanes and Boranes 5599
2.2. Chiral Imines and Imine Derivatives 5600
2.2.1. Imines and Imine Derivatives from
Chiral Carbonyl Compounds 5600
2.2.2. Imines and Imine Derivatives with a
Chiral Framework A ttached to the
Nitrogen 5602
2.3. Carbonyl Compounds with Chiral Auxiliaries
Attached to the Oxygen Atom 5612
3. Reagent Control 5614
3.1. Chiral Nucleophiles with Stereogenic Cen-
ters in the Transferred Hydrocarbon Back-
bone 5614
3.1.1. α-Substituted Allyl Boranes 5614
3.1.2. Cyclic α-Substituted Allyl Boronates 5615
3.1.3. Acyclic α-Substituted Allyl Boronates 5617
3.1.4. α-Substituted Allyl Stannanes 5620
3.1.5. Allyl Zinc Reagents 5620
3.2. Chiral Nucleophiles with Stereogenic Cen-
ters in Nontransferred Ligands Bonded to
the Metal Center 5622
3.2.1. Allyl Boron Reagents 5622
3.2.2. Allyl Silanes 5629
3.2.3. Allyl Titanium Reagents 5637
3.3. Double Stereoselection 5637
3.4. Chiral Donors in Allyl-Transfer Reactions 5638
3.4.1. Chiral Homoallyl Alcohols 5638
3.4.2. Chiral Homoallyl Amines 5641
4. Propargylation and Allenylation Reactions 5643
4.1. Propargylation Reactions 5643
4.1.1. Substrate Control 5643
4.1.2. Reagent Control 5647
4.2. Allenylation Reactions 5651
4.2.1. Substrate Control 5651
4.2.2. Reagent Control 5652
5. Synthesis of Natural Products 5655
5.1. Substrate Control 5655
5.1.1. Chiral Carbonyl Compounds 5655
5.1.2. Chiral Imines and Imine Derivatives 5662
5.1.3. Carbonyl Compounds with Chiral Auxil-
iaries Attached to the Oxygen Atom 5664
5.2. Reagent Control 5667
5.2.1. Chiral Nucleophiles wi th Stereogenic
Centers in the Transferred Hydrocarbon
Backbone 5667
5.2.2. Chiral Nucleophiles wi th Stereogenic
Centers in Nontransferred Ligands
Bonded to the Metal Center 5669
5.2.3. Double Allylation under Reagent Con-
trol 5687
5.2.4. Allyl Transfer from a Chiral Homoallyl
Amine 5688
5.3. Propargylation and Allenylation Reactions 5688
5.3.1. Propargylation Reactions 5688
5.3.2. Allenylation Reactions 5691
6. Conclusions and Outlook 5691
Author Information 5691
Corresponding Author 5691
Notes 5691
Biographies 5691
Acknowledgments 5692
Abbreviations 5692
References 5693
1. INTRODUCTION
The addition of an allylic organometallic compound to a
carbonyl compound or an imine is of great synthetic interest
because in this reaction together with a new functionality
(hydroxyl or amino group, respectively), a carbon−carbon
bond is formed. In addition, the double bond of the allylic
moiety can participate in a number of further synthetically
useful transformations: cycloaddition, dihydroxylation, epox-
idation, hydroboration, hydroformylation, hydrogenation, hy-
dration, olefin metathesis, ozonolysis, etc.
1
Importantly, if the
allylations are carried out in a stereoselective fashion,
enantioenriched homoallylic alcohols and amines would be
produced, which are valuable building blocks.
2
Among the
stereoselective methodologies, the catalytic enantioselective
Received: January 10, 2013
Published: March 29, 2013
Review
pubs.acs.org/CR
© 2013 American Chemical Society 5595 dx.doi.org/10.1021/cr400008h | Chem. Rev. 2013, 113, 5595−5698
allylations
3
rely on the use of both chiral Lewis acids,
4
which
bind to the electrophile activating it toward nucleophilic attack,
and chiral Lewis bases.
5
Double activation could be also
achieved by using chiral bifunctional catalysts.
6
In this case, the
simultaneous activation of both electrophilic and nucleophilic
reaction partners occurs ideally through a cooperative action of
different functionalities of the ligand. Although the develop-
ment of catalytic enantioselective allylation reactions is a very
attractive growing field, it is not always straightforward to find
an efficient and practical protocol for any synthetic application.
Some challenges that still limit the applicability of catalytic
enantioselective allylation are as follows: (a) some of the
reported catalytic methods make use of large excess of reagents
to ensure the turnover of the catalyst, which are not always
cheap and green; (b) when the activation mode does not
significantly increase the reaction speed, the noncatalytic
allylation causes a lower enantioselection; (c) the “plausible
mechanisms” reported for the existing catalytic methods do not
always allow good predictions of the stereochemical results of
new substrates; (d) in the construction of complex molecules,
the allylation step is often performed on chiral substrates (chiral
pool or advanced intermediates) that can override the chiral
induction of the catalyst. Some of these reasons are behind of
the fact that in the synthesis of complex organic molecules,
including natural products, the stereoselective allylations are
more commonly performed with stoichiometric amounts of
chiral reagents. In these reactions, the stereochemical
information can be transferred by substrate diastereocontrol
(substrate control), including chiral auxiliaries, or through the
use of chiral reagents (reagent control). Sometimes a double
induction could be involved in the process, a match/mismatch
effect being possible (Scheme 1).
In addition to the face selectivity under the influence of a
chiral substrate or reagent, substituted allyl organometallics
display high levels of diastereoselection because they react
usually at the γ -position through an ordered acyclic or cyclic
transition state, depending mainly on the metal of the allylic
organometallic nucleophile. For Si and Sn derivatives, the
addition is commonly explained using acyclic models where the
major approach ( antiperiplanar or synclinal) takes place
Scheme 1
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through the conformation where destabilizing gauche inter-
actions are minimized. In contrast, for Mg, Ti, B, and In allylic
derivatives, a cyclic six-membered Zimmerman−Traxler
7
type
transition state is usually invoked. In the cyclic model, it is
generally proposed that aldehydes locate the H (R
2
= H) in the
axial position, while aldimines with E-configuration place the H
(R
2
= H) in the equatorial position (Scheme 1),
8
consequently,
opposite relative configurations (anti/syn)aregenerally
observed in the reaction of aldehydes and aldimines with the
same γ-substituted allyl organometallic.
The goal of this review is to highlight diastereoselective
allylations involving the use of chiral reagents, emphasizing
recent developments of synthetic interest. The review is
organized according to the source of stereocontrol: first
substrate control and after that reagent control allylations will
be studied [stereogenic center(s) could be in the allyl unit or in
a ligand bonded to the metal atom]. The last section of this
review will be dedicated to related propargylation/allenylation
processes, and to the application of these methodologies to
some selected synthesis of natural products. Diastereoselective
allylations leading to racemic products will not be considered in
this review. The present work will comprehensively cover the
most pertinent contributions to this important research area
from 2003 to the end of 2011. We regret in advance that some
contributions are excluded in order to maintain a concise
format, especially concerning the natural product synthesis
section.
2. SUBSTRATE CONTROL
Nucleophilic addition to chiral carbonyl compounds and imines
is governed by steric and electronic factor s and occurs
predominantly to the less hindered face of the prostereogenic
unit. Efficiency, regarding the stereoselectivity, depends
strongly on the bulkiness of the reactants and the nature of
the nucleophilic species. Felkin−Anh and Cram-chelate
models
9
have been recurrently used in order to explain the
stereochemical outcomes of these processes, and in many cases,
the configuration of the newly created stereogenic center could
be successfully predicted.
2.1. Chiral Carbonyl Compounds
2.1.1. Allyl Stannanes. Allylic stannanes are not reactive
enough to add to aldehydes, and for that reason the allylation of
carbonyl compounds with these nucleophiles must be
performed in the presence of a Lewis or a Brønsted acid in
order to increase the reactivity of the electrophile.
Marko
and co-workers found that the reacti on of α-
benzyloxyaldehydes with the functionalized stannane 1 in the
presence of SnCl
4
proceeded with remarkable levels of
stereocontrol producing syn−anti and syn−syn configured triol
units in almost enantiomerically pure form.
10
The reactions
were performed in dichloromethane at −78 °C. Importantly,
the stoichiometry of the Lewis acid determined the relative
configuration of the three stereogenic centers. Thus, when 1
equiv of SnCl
4
was used syn−anti triols were obtained (Table 1,
entries 1 and 2). However, the allylation in the presence of 2
equiv of the Lewis acid afforded syn−syn triols (Table 1, entries
3 and 4) in good to excellent yields and with high
diastereoselectivities in all cases. It was also observed that
under these reaction conditions racemization at the chiral
aldehyde did not take place.
Two different transition states have been proposed in order
to rationalize the observed diastereoselectivities. A bicyclic
transition state, which is formed after transmetalation, operates
when 1 equiv of SnCl
4
is used. The tin atom would be chelated
to the benzyl ether and to the carbonyl oxygen of the aldehyde,
and the carbamate would thus adopt a pseudoaxial orientation
in order to interact with the tin. The syn−anti triols would be
produced after allyl transfer through this transition state (Figure
1). On the other hand, an open transition state would operate
when the reaction is performed in the presence of 2 equiv of
SnCl
4
: 1 equiv reacts with the aldehyde to form the chelate and
the second one transmetallates the allylating agent, generating a
more reactive nucleophile. The allyl transfer in this open
transition state leads to the syn−syn triols (Figure 1).
High levels of stereoselection were also achieved in the
reaction of functionalized 2-propenylstannane 2 with different
chiral α-substituted aldehydes. The allylation reagent 2 was
prepared by distannylation of the corresponding allene.
Williams and Fultz found that optimal results were obtained
working in dichloromethane as solvent at −78 °C in the
presence of 2 equiv of MgBr
2
·etherate.
11
Destannylation is
prevented working at low temperature, otherwise acid-catalyzed
Table 1. Allylation of α -Benzyloxyaldehydes with Stannane 1
in the Presence of SnCl
4
Figure 1. Hypothetical transition state structures for the allylation of
α-benzyloxyaldehydes with 1 in the presence of SnCl
4
.
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decomposition of compound 2 could occur. The allylation of
chiral α-alkoxyaldehyd es u nder these reaction conditions
provided excellent yields with high stereoselectivity, a single
diastereomer being observed in many cases by NMR analyses
of the crude reaction product (Table 2, entries 1−3 and 5).
Regarding the relative configuration of the created stereogenic
centers, the 3,4-anti -4,5-syn-relationship was always found. This
stereochemical outcome could be rationalized by considering a
S
E
2′ reaction in an open chelated transition state as depicted in
Table 2.
Allylation of carbonyl compounds with allylic stannanes
could also be promoted using carboxylic acids. Li and Zhao
demonstrated that the reaction of a wide range of aldehydes
with allyltributyltin in different solvents, in the presence of 1
equiv of a carboxylic acid at room temperature, provided the
homopropargyl alcohol.
12
They also studied the allylation of
chiral (R)-N-Boc-2-amino-3-phenylpropanal in acetonitrile
under the influence of different carboxylic acids. In all cases,
the allylation gave high to quantitative yields with moderate
diastereoselectivity, the anti diastereomer being always the
major product (Table 3).
Diastereoselective Lewis acid promoted allylation of ketones
with allylic stannanes has also been studied. In this way,
optically enriched quarternary α-hydroxy amides 4 and 5 were
prepared from chiral α-ketoamides bearing a camphorpyrazo-
lidinone unit 3. Allylation did not take place in the absence of a
Lewis acid. Taking phenylketoamide 3 (R = Ph) as the model
compound, Chen and co-workers found that the allylation
using 1 equiv of Eu(OTf)
3
in acetonitrile at room temperature
provided the allylated products in 50% yield and moderate
diastereoselectivity (Table 4, entry 1).
13
Both, chemical yield
and diastereoselectivity were signifi cantly improved when
Zn(OTf)
2
was used (Table 4, entry 2). However, the allylation
proceeded in a totally stereoselective fashion in almost
quantitative yield using Sn(OTf)
2
in acetonitrile, after 4 min
at room temperature (Table 4, entry 3). This result was not
improved by using other solvents under the same reaction
conditions. Similar results in terms of yield and stereoselectivity
were obtained in the case of other α-ketoamides 3 (Table 4,
entries 4−6).
The stereochemical outcome of this study was rationalized by
considering the conformational preference of α-ketoamides 3 in
the transition state. The pseudoplanar s-trans conformation of
the α-dicarbonyl group in 3 is electronically favored over its s-
cis conformer due to the dipole repulsion of the two carbonyl
functionalities. However, in the presence of a Lewis acid, the
coordination of the metal ion to the dicarbonyl oxygen atoms
resulted in the formation of the preferred s-cis conformation.
The equilibrium of different conformational states is highly
dependent upon the type and amount of Lewis acid used in the
reaction. Strong Lewis acids, such as Sn(OTf)
2
, would favor the
s-cis over the s-trans conformer making predominant the Si-face
attack of the allylic nucleophile leading to compounds 4 (Figure
2).
Table 2. Allylation of α-Substituted Aldehydes with Stannane 2 in the Presence of MgBr
2
·Etherate
Table 3. Diastereoselective Allylation of (R)-N-Boc-2-
Amino-3-phenylpropanal with Allyltributyltin Promoted by
Carboxylic Acids
entry carboxylic acid t (h) syn/anti
a
yield (%)
b
1 4-NO
2
C
6
H
4
CO
2
H 4.5 27/73 98
2 maleic acid 0.25 27/73 88
3 1,2-(CO
2
H)
2
C
6
H
4
4 27/73 100
4 salicylic acid 4 15/75 89
a
Determined by
1
H NMR.
b
Combined isolated yield.
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2.1.2. Allyl Silanes and Boranes. Similarly to allylic
stannanes, the allylation of carbonyl compounds with allylic
silanes must be carried out in the presence of an activating
reagent. A diastereoselective synthesis of 2,3,4-trisubstituted
tetrahydrofurans has been reported by Cox and co-workers. In
these processes, an allyl silane and a carbonyl group of an
aldehyde are involved in an intramolecular allylation promoted
by a Brønsted acid. When the optimized reaction conditions
were applied to the polyfunctionalized enantiomerically pure
aldehyde 6, derived from (S)-ethyl mandelate, a trisubstituted
tetrahydrofuran was produced with good 1,2-stereoinduction
(Scheme 2).
14
Allylic acetates have been also used as allylating reagents for
carbonyl compounds under Pd catalysis.
15
The character of the
initially formed palladium allyl complex can be reversed from
electrophilic to nucleophilic in the presence, for instance, of
trialkylboron species. Kirschning and co-workers described a
stereocontrolled palladium-catalyzed umpolung allylation of
aldehydes with allyl acetates in the presence of bis(pinacolato)-
diboron. The reactions were performed in DMSO at 40 °C
(Table 5).
16
They found that higher yields and levels of
stereocontrol were achieved when chiral aldehydes (substrate
control) were used instead of chiral allyl boronates (reagent
control). The reactions of different chiral α-substituted
aldehydes with cinnamyl acetate or racemic 1-methylallyl
acetate, under the optimized reaction conditions depicted in
Table 5, proceeded with moderate to good yields and with
remarkably high 3,4-anti-4,5-syn selectivities. Importantly, the
here observed 4,5-syn selectivity in these palladium-catalyzed
reactions of chiral α-substituted aldehydes with (E)-crotylbor-
onates, which are the reaction intermediates, is unprecedented.
Hoffmann and Roush previously noted that α-alkoxy-
substituted aldehydes show a moderate 4,5-anti selectivity in
the reaction with (E)-crotylboronates.
17
Hall studied also the allylation and crotylation of O-TBS-
protected (S)-2-methyl-3-hydroxypropanal with allyl- and
Table 4. Diastereoselective Allylation of Camphorpyrazolidinone Derived α-Ketoamides 3 with Allyltributyltin
entry R solvent Lewis acid t yield (%)
a
dr (4:5)
b
1 Ph MeCN Eu(OTf)
3
72 h 50 72:28
2 Ph MeCN Zn(OTf)
2
40 min 93 96:4
3 Ph MeCN Sn(OTf)
2
5 min 95 99:1
4 Me MeCN Sn(OTf)
2
5 min 89 77:23
5 Et MeCN Sn(OTf)
2
5 min 91 83:17
6 2-thienyl MeCN Sn(OTf)
2
5 min 92 99:1
a
Total isolated yield (4 + 5).
b
Determined by
1
H NMR and chiral HPLC.
Figure 2. Proposed conformational structures of reacting α-
ketoamides 3 with allyltributyltin in the presence of a Lewis acid.
Scheme 2
Table 5. Pd-Catalyzed Stereoselective Allylation of Chiral
Aldehydes with Allylic Acetates in the Presence of
Bis(pinacolato)diboron
a
Isolated yield.
b
Determined by
1
H NMR.
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