Download Enol esters: Versatile substrates in synthesis of fine and specialty

Synthetic Organic Chemistry
Literature Research
Enol esters: Versatile substrates in synthesis of fine and
specialty chemicals
by
Consuela Cambridge
May 3rd, 2016
Student number
10316035
Research institute
Van´t Hoff Institute for Molecular Sciences
Research group
Synthetic Organic Chemistry
Supervisor
Prof. dr. Jan van Maarseveen
second supervisor
Drs. Linda Wijsman
Enol esters: versatile substrates in synthesis of fine and specialty chemicals
I.
Abbreviations
AH
AHF
AM
BDP
BINAP
ee
EVA
(iPr)3SiH
M
NBS
NCS
NHC
PHOX
P-OP
p-TsOH
PVCA
TBDMS ether
TBS ether
TBSOTf
THF
TIPS ether
TMS ether
TMSCl
TMSOTf
TOF
TON
VA
VAM
Asymmetric hydrogenation
Asymmetric hydroformylation
Anti-Markovnikov
Bis-3,4-diazaphospholane
2,2'-bis(diphenylphosphino)-1,1'-binaphthyl
Enantiomeric excess
Ethylene-vinyl acetate
Tri-isopropyl silane
Markovnikov
N-bromosuccinimide
N-chlorosuccinimide
N-heterocyclic carbene
Phosphinooxazolines
Phosphine-phosphite ligands
para-toluene sulfonic acid
Polyvinyl chloride acetate
tert-butyldimethylsilyl ether
tert-butyldimethylsilyl ether
Trimethylsilyl trifluoromethane sulfonate
Tetrahydrofuran
Tri-isopropylsilyl ether
Trimethylsilylether
Trimethylsilyl chloride
Trimethylsilyl trifluoromethanesulfonate
Turn over frequency
Turn over number
Vinyl acetate
Vinyl acetate monomer
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Enol esters: versatile substrates in synthesis of fine and specialty chemicals
II.
Abstract
Enol ester synthesis has gradually evolved from the mercury-catalysed transvinylation of
olefinic acetates with carboxylic acids, to asymmetric ruthenium-catalysed stereoselective
hydrocarboxylation of alkynes; obtaining enol esters via either Markovnikov or antiMarkovnikov addition. Optimised synthesis and ongoing research on stereo- and
regioselectivity, initiated an interest in applications of enol esters. This thesis therefore provides
an overview of enol and vinyl esters as substrates and intermediates, by exploring their
application on small and large scale.
The asymmetric hydroformylation/Wittig olefination tandem process of Z-enol acetates yields γhydroxy-α,β-unsaturated carbonyl motifs present in antifungal bioactive compounds. Z-enol
esters allow for asymmetric epoxidation yielding cis-epoxides, which can be converted to useful
α-acyloxy ketones and α-silyloxyaldehydes. Furthermore, vinyl acetates are an opportune
replacement for the synthesis of chiral alcohols when there are no suitable catalysts to
hydrogenate intricate carbonyl starting material, and also function as alternative acylating
agents. As for more complex applications, enol esters have been used in both substitution and
addition reactions leading to α-substituted carbonyl compounds and intricate molecular
scaffolds essential in synthesis of bioactive compounds. Scheme 1 provides a brief overview of
enol ester applications.
Scheme 1. A brief overview of the versatility of vinyl acetate in various reactions.
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Enol esters: versatile substrates in synthesis of fine and specialty chemicals
II. Table of contents
I.
Abbreviations ................................................................................................................................. 1
II.
Abstract .......................................................................................................................................... 2
II.
Table of contents ............................................................................................................................ 3
1.
Introduction ................................................................................................................................... 4
2. Asymmetric hydroformylation of enol esters ................................................................................. 6
2.2. AHF/ Wittig tandem process involving enol esters ................................................................. 7
3. Asymmetric epoxidation of (Z)-enol esters ..................................................................................... 8
3.1. Enol ester epoxide derivatives: α-Acyloxy ketones ................................................................. 9
3.2. Enol ester epoxide derivatives: α-Silyloxyaldehydes .............................................................. 9
3.3. Summary and partial conclusion I ........................................................................................... 10
4. Asymmetric hydrogenation of enol ester derivatives................................................................... 11
5. Acylation of alcohols: Transesterification using enol esters ........................................................ 12
6. Functionalisation of enol acetates at the α-position ..................................................................... 13
6.1. α-Alkyl substituted carbonyl compounds ............................................................................... 13
6.2. Michael addition of enol acetates to α,β-unsaturated ketones ............................................. 15
6.3. Heck olefination reactions ....................................................................................................... 16
6.3.1. Decarboxylative Heck olefination of enol esters ............................................................. 17
6.4. α-Arylation of enol acetates mediated by visible light........................................................... 18
6.5. Summary and partial conclusion II ......................................................................................... 19
7. Useful molecular scaffolds accessible via enol ester derivatives ................................................. 20
7.1. Oxetane synthesis: The Paternò-Büchi reaction involving enol esters ................................ 20
7.2. 4-Substituted Isocoumarins: The silver(I)-mediated annulation of enol esters ................. 21
7.3. Di-substituted cyclic ethers: The Aldol reaction of enol acetates and lactols ...................... 23
7.4. Quinolines and N-aryl lactams: Mannich-type Povarov reactions with vinyl acetates ....... 24
7.5. Synthesis of di-hydropyranones: The NHC-mediated pathway using α,β-unsaturated enol
esters................................................................................................................................................. 26
7.6. Summary and partial conclusions III ...................................................................................... 28
8. Polymers: The use of vinyl acetate in polymers ............................................................................ 29
8.1. Vinyl acetates in polymers ....................................................................................................... 29
9. Discussion and conclusion .............................................................................................................. 30
10. References ...................................................................................................................................... 32
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Enol esters: versatile substrates in synthesis of fine and specialty chemicals
1. Introduction
Enol esters and their derivatives are promising compounds with the potential to be utilised as
substrates and intermediates in organic and pharmaceutical chemistry.1,2 They can be converted
to bioactive compounds such as antibiotics, steroids, and are also promising substrates for
polymer synthesis and synthesis of various molecular scaffolds. Thus far, a broad variety of
reactions have been developed for the synthesis of enol esters.
Since 1940, the industry was provided with rare valuable vinyl esters via transvinylation of
olefinic acetates with carboxylic acids, in presence of mercury(II), ruthenium(II), rhodium(II),
platinum(II) and palladium(II) catalysts (eq. 1, Scheme 2). This method was coexistent with the
thermal decomposition of vinylmercury carboxylates (eq. 2).3,4 Soon after, the application of the
highly active mercury, and palladium catalysts was restricted due to toxicity of mercury and fast
palladium deactivation.
Between 1960 and 1995 alternative methods to obtain alk-1-en-2-yl esters were tested. In 1995,
Limat et al. isolated O-acylated enol esters in moderate to high yields when silyl enol ethers were
treated with acid chlorides, and copper(I) chloride catalysts (eq. 3).5 Enolate acylation was also
achieved by condensation of O-trimethylsilyl enethers with acylfluorides in presence of fluoride
sources (eq. 4).6 Hitherto, the vapour-phase oxyacylation of olefins with acetic acid involving
supported palladium(II) catalysts accounts for the industrial production of enol acetates (eq. 5).
2,3 Though, for researchers, a much preferred route is the hydrocarboxylation of alkynes and
alkenes (eq. 6a and eq. 6b respectively), a pathway facilitated by ruthenium(II), iridium(II),
rhodium(II) and palladium(II) catalyst precursors, under mild reaction conditions.2,3,7 With this
straightforward synthesis, the focus in enol ester preparation shifted towards influencing their
regioselectivity, by use of specific reagents and catalysts.
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Enol esters: versatile substrates in synthesis of fine and specialty chemicals
Scheme 2. Schematic representation of various pathways to synthesise enol ester
derivatives.
The majority of the aforementioned reactions facilitate the Markovnikov (M) addition of
carboxylic acids to terminal alkynes, while the anti-Markovnikov (AM) addition yields E- and Zenol ester isomers, which as masked aldehydes, are useful in synthetic chemistry. Doucet et al.
reported that ruthenium based catalysts with chelating phosphine and labile allylic ligands
favour the anti-Markovnikov addition via a stereoselective trans-addition reaction, with mostly
Z-enol ester products (eq.7, Scheme 3).3
In contrast, the stereoselective outcome of the acylation of silylenol ether is dependent on the
conjugation of the enolate anion, since merely pure Z-isomers are obtained when the double
bond is conjugated with the oxygen atom of the enolate anion, and E-isomers if the substrate has
a higher conjugation.5 Access to enantioselective synthesis of enol esters was provided by
Schaefer et al., when he demonstrated the catalytic asymmetric coupling of ketenes and
aldehydes yielding α-arylalkanoic acids (91% enantiomeric excess (ee)), in presence of a chiralplanar DMAP iron catalyst.7
Scheme 3. Stereoselective synthesis of Z-enol esters with asymmetric ruthenium
catalysts developed by Doucet et al.3
With optimised synthesis and ongoing research on stereo and regioselectivity, interest in
applications of enol esters is increasing. This thesis provides background information on enol
and vinyl esters as substrates and intermediates by exploring their application on large and
small scale. Currently, enol and vinyl esters are involved in multicomponent8, hydroformylation9,
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Enol esters: versatile substrates in synthesis of fine and specialty chemicals
epoxidation10 and acylation11,12 processes. Furthermore, variation in structural features make
them eligible substrates for bio-organic and pharmaceutical synthesis. When functionalisations
are made at the α-position, various α-alkylated/arylated carbonyl compounds, which are
essential in natural product synthesis, can be achieved.13,14 Enol esters derivatives also serve as
precursors for synthesis of molecular scaffolds such as oxetanes15, isocoumarins16, disubstituted cyclic ethers17, quinolines and N-aryl lactams. Finally, vinyl acetate derivatives, vinyl
haloacetates and vinylacetates are monomers applied for production of comonomers and
copolymers such as vinyl acetate/acrylic (VAA) copolymers and ethylene-vinyl acetates (EVA)
copolymers used in coatings, adhesives and emulsion paints amongst others.3,4
2. Asymmetric hydroformylation of enol esters
Asymmetric hydroformylation (AHF) of alkenes proceeds in one step via a one carbon
homologation reaction, and is a well-known process for obtaining either a branched or linear
aldehyde.9,18 This process requires an alkene substrate that is converted to an aldehyde in
presence of syngas and a metal catalyst. Depending on the ligand properties two regioisomers
can be obtained (see Scheme 4). The branched regioisomer contains an α-chiral centre and when
enantioenriched, is very versatile in subsequent applications.
Scheme 4. Asymmetric hydroformylation of a terminal alkene obtaining branched
and linear regioisomers.10
Experiments conducted by Risi and Landis et al. concluded that rhodium(I) complexes
comprising of (S,S,S)/(S,S,R) bis-3,4-diazaphospholane (BDP) ligands, depicted in Figure 1,
exhibit great performance on the AHF of olefins, which is expressed by the turnover number
(TON) (150.000:1) and turnover frequencies (TOF) averaging 19400.9,18 Hydroformylation of
vinyl acetate utilising rhodium(I) complexes with (S,S,S)-BDP ligands exhibited excellent regioand enantioselectivity (41:1 B: L with 92-96% ee) for the chiral product, 2-(S)acetyloxypropanal (Scheme 5).
Figure 1. Chemical structures of (S,S,S) and (S,S,R)-bis-3,4-diazaphospholane, (S,S,S)-BDP and
(S,S,R)-BDP (adapted from Risi et al.).9
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Enol esters: versatile substrates in synthesis of fine and specialty chemicals
Scheme 5. Asymmetric hydroformylation of vinylacetate with a rhodium catalyst
yielding branched and linear regioisomers.10
Asymmetric hydroformylation reactions have several benefits. They are atom efficient, have high
atom economy, are carried out under neutral pH, which suppresses isomerisation of the chiral
product, and the syngas mixture is easily vented from the reaction vessel. These benefits, added
to the inert catalyst, make AHF a convenient reaction for tandem processes. Tandem processes
involving AHF have led to the development of pathways including: AHF/crotylation19,20,
hydroformylation/ Sn1 alkylation21, AHF/ asymmetric aldol22, bidirectional
hydroformylation/tandem hydrogenation-reductive bis-amination23, AHF/Wittig
olefination9,24,25 and hydroformylation/asymmetric Mannich26 reactions. For the total synthesis
of natural products these ensure sufficient increase in the overall yield.
2.2. AHF/ Wittig tandem process involving enol esters
As far as known, the only tandem process involving enol ester derivatives is the asymmetric
hydroformylation of Z-enol acetates with rhodium(I) (S,S,S)-BDP catalysts yielding αacetoxcyaldehydes, which was first reported by both Roberto and Risi et al.9 They demonstrated
that α-acetoxcyaldehydes can be converted to γ-chiral α,β-unsaturated carbonyl compounds via
a stabilised ylide-mediated reaction, also known as the Wittig reaction (Scheme 6).24 Wittig
olefinations with carboethoxy-substituted ylides and carbobenzyloxy- substituted ylides were
both attempted and respective yields of 79% and 46% in 99 % ee were reported. Olefination
with carbobenzyloxy- substituted Wittig ylides was found to undergo another AHF/Wittig
olefination cycle, whereas allylic ylides yielded 1,4-dienes, which are susceptible to subsequent
hydroformylation. Depending on the Wittig reagent and repetition of the AHF/Wittig process
multiple stereocenters and functionalities can be introduced which have proven to be essential
in the synthesis of bioactive compounds. After the AHF/Wittig olefination strategy, Risi et al.
reported on a lipase-catalysed deacetylation providing a γ-hydroxy- α,β-unsaturated carbonyl
motif which is in (+)-patulolide C, (+)-decarestrictine L and (-)-pyrenophorol (Figure 2).9,25
These bioactive compounds often require multiple synthetic steps, which have decreased
significantly due to the AHF/Wittig olefination strategy starting from Z-enol ester
intermediates. As reported, the AHF/Wittig olefination is a fruitful process, especially in total
synthesis of complex compounds. Development of the aforementioned tandem processes with
enol ester derivatives as substrates will ease complex synthesis.
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Enol esters: versatile substrates in synthesis of fine and specialty chemicals
Scheme 6. Schematic representation of the AHF/Wittig olefination tandem process.9
Figure 2. Molecular structure of (+)-patulolide C, (+)-decarestrictine L and (-)pyrenophorol; bioactive compounds with γ-hydroxy- α,β-unsaturated moiety
(adapted from Risi et al.).9
3. Asymmetric epoxidation of (Z)-enol esters
The double bond adjacent to the ester moiety in enol esters is susceptible to asymmetric
epoxidation, yielding enantioenriched epoxides.10 These products can be transformed to
corresponding α-hydroxy carbonyl derivatives or rearrange to α-acyloxy ketones in a highly
stereoselective manner. Matsumoto et al. have proven that asymmetric epoxidation with
titanium(salalen)complexes and hydrogen peroxide, favoured the enantioselective conversion of
cis-alkenes. Experiments involving mixtures of E-and Z-enol esters, such as (E)- and (Z)-Oct-1enyl-benzoate, lead to high yields of cis-epoxide products, derived from the (Z)-enol ester, with
an enantioselectivity of 99% ee (Scheme 7).
Scheme 7. Asymmetric epoxidation of (E) and (Z)-oct-1-enyl-benzoate with cisepoxide as the major product (adapted from Matsumoto et al.).10
Other researchers utilised peroxides such as dimethyldioxiranes27 or fructose derived ketone
catalyst with oxone10 for the epoxidation of enol esters. However, both the yield and
enantiomeric excess are dependent on sterics and electronic effects of the para substituent on
the Z-enol ester.10 Enol esters can be converted to cis-epoxides via asymmetric epoxidation,
8
Enol esters: versatile substrates in synthesis of fine and specialty chemicals
however these epoxides can also function as a substrate for subsequent conversions. The
upcoming paragraphs provide an overview of several epoxide derivatives, which are accessible
via reduction in presence of an (asymmetric) Lewis acid catalysts, providing α-acyloxyketones
and α-silyloxyaldehydes.
3.1. Enol ester epoxide derivatives: α-Acyloxy ketones
Enol ester epoxides can be rearranged to α-acyloxy ketones, a transformation often integrated in
steroid synthesis.10,28 Enol ester epoxides can be transformed either thermally with
intermolecular migration of the acyloxy moiety, along with inversion of configuration, or under
acidic conditions with mostly retention of configuration. Both α-acyloxy ketones and their αhydroxy ketone derivatives, are essential in synthesis of alkaloids, sugars, antibiotics, terpenes
and pheromones, for they function as stereodirective groups or chiral synthons. Zhu et al.
practised the rearrangement of enol ester epoxides, (R,R)-1benzoxyloxy-1,2-epoxycyclohexane,
with protic and Lewis acids.29 With protic acids such as p-TsOH the ee slightly declined, while
with Lewis acids the ee varied drastically depending on the acids acidity constant. For example
when Yb(OTf)3 was used the R-enantiomer (4) was favoured, while the weaker acid, YbCl3,
yielded the S-enantiomer (6). A schematic representation exhibited in Scheme 8 suggests that
strong acids cause retention of configuration by complexation to the epoxide oxygen and
cleaving the C1-O bond (pathway a), obtaining carbocation intermediate 3 and subsequent acyl
rearrangement with retention of configuration yields acyloxy ketone 4. Contrary to strong acids,
weak acids labilise both epoxide bonds (5) and facilitate acyloxy rearrangement with inversion
of configuration yielding acyloxy ketone 6 (pathway b).
Scheme 8. Reduction of enol ester epoxides with a strong Lewis acid (pathway a) and
a weak Lewis acid (pathway b) (adapted from Zhu et al.).29
3.2. Enol ester epoxide derivatives: α-Silyloxyaldehydes
Generally, α-silyloxyaldehydes are synthesised following multistep processes, for instance
diazotisation and partial reduction of α-amino acid derivatives or multistep differential
protection and oxidation of 1,2-diols. α-Silyloxyaldehydes risk being oligomerised or
tautomerised to hydroxy ketones when not protected.27 In order to limit the aforementioned
setbacks, Friestad et al. designed a process which induces ring opening of Z-enol ester epoxides
through application of a silyl cation.27 This experiment was carried out at room temperature and
microwave irradiation, using trimethylsilyl trifluoromethanesulfonate (TBSOTf) and 2,6-lutidine
in dichloromethane. These alternatives reduce the reaction time and diminish degradation
pathways with yields ranging from 79% up to 97% compared to conventional methods. Though
the exact mechanism has not been investigated yet, Friestad et al. suspects 2,6-lutidine to have a
similar function in the silyl cation induced ring-opening of ether epoxides as in the Fujioka-Kita
9
Enol esters: versatile substrates in synthesis of fine and specialty chemicals
reaction involving acetals (Scheme 9).The oxycarbenium ion generated after ring opening of the
epoxide moiety is stabilised by 2,6-lutidine resulting in a pyridinium salt intermediate. Scheme 9
depicts both the Fujioka-Kita reaction and the silyl-cation induced ring opening concept devised
by Friestad et al. The asymmetric epoxidation of Z-enol esters eliminates the necessity of a
resolution step when a particular stereoisomer of the enol ester epoxide is desired.
Scheme 9. The Fujita-Kita mechanism and a mechanistic proposal of the silyl cationinduced ring opening reaction with 2,6-lutidine by Friestad et al.27
3.3. Summary and partial conclusion I
The asymmetric epoxidation of Z-enol esters results in α-acyloxy ketones and αsilyloxyaldehydes via reduction in presence of an (asymmetric) Lewis acid catalysts. Z-enol
esters are, due to their configuration, ideal substrates for asymmetric epoxidation yielding cisepoxides. And cis-epoxides can then be thermally reduced to α-acyloxy ketones by inversion of
configuration or under acidic conditions wherein the configuration is retained. That aside, the
acids acidity also contributes to inversion or retention of configuration. Though there is no
evident explanation, strong Lewis acids promote retention, while weaker Lewis acids favour
inversion.
Other cis-epoxide derivatives are α-silyloxyaldehydes which are obtained after TBSOTfmediated epoxide ring opening and formation of a 2,6-lutidine intermediate. Deacetylation and
release of 2,6-lutidine results in α-silyloxyaldehydes. However, this mechanistic proposal by
Friestad et al. has not been confirmed. Though, there are numerous conventional methods to
synthesise α-silyloxyaldehydes, this method reduces the amount of reaction steps, but also
functional group differentiation and protecting group interchanges are reduced. Furthermore,
enol ester epoxide/lutidine intermediates are easily converted to α-silyloxyaldehydes, as both
the acyl moiety and 2,6-lutidine, due to their stability, are considered good leaving groups.
To summarise, the configurational features of Z-enol esters allow for asymmetric epoxidation
yielding cis-epoxides, which can be readily converted to useful α-acyloxy ketones and αsilyloxyaldehydes under ambient conditions with reasonable yields. The asymmetric
epoxidation of Z-enol esters also eliminates the necessity of a resolution step when a particular
stereoisomer is desired.
10
Enol esters: versatile substrates in synthesis of fine and specialty chemicals
4. Asymmetric hydrogenation of enol ester derivatives
Asymmetric hydrogenation (AH) is a thoroughly studied process which has been crucial in the
synthesis of chiral amines, chiral amino acids, chiral alcohols and other essential chiral
derivatives.30 Asymmetric hydrogenation of enol esters is rather novel research and is seen as
an alternative pathway wherein acyl deprotection of esters (3) leads to chiral alcohols (2)
(pathway b).30,31 This is contrary to the conventional AH of carbonyl compounds (1) (pathway a;
Scheme 10).
Scheme 10. Hydrogenation pathways towards chiral esters (3) and chiral alcohols (2).32
Throughout the years rhodium(I) catalysts became the catalyst of choice for AH and several
monodentate phosphine ligands, such as phosphonites, phosphites and phosphoramidite
ligands, have been screened.32 Though AH of carbonyl compounds is facilitated by the
aforementioned catalysts, AH of complex carbonyl compounds using the same catalysts, may
cause a decrease in selectivity. Therefore, researchers such as Panella and Kleman et al.
continued research on vinyl acetates as substrates using suitable phosphine ligands. They
concluded that monodentate phosphine ligands, in most cases, are superior to bidentate
derivatives.31,32 The AH of aromatic enol acetates results in chiral products with high
enantioselectivity (98%) when rhodium complexes comprising of monodentate phosphinephosphite ligands (P-OP) and its octahydro-analogue where utilised. Furthermore, substrates
with alkyl moieties preferred phosphine ligands with ethane backbones and PPh2 fragments
(complex 2a, c and d), whereas bulkier groups such as tert-butyl groups had higher yields and
enantioselectivity when the backbone consisted of an aryl moiety (complex 1a and b, Figure 3.
Figure 3. Structures of phosphines-phosphite (PO-P) ligands and hydrogenated
products (Kleman et al.)33
Altogether, the substrate scope and corresponding suitable catalysts for the AH of vinyl esters is
comprehensive and AH of vinyl acetates is mainly regarded as an auspicious replacement for the
11
Enol esters: versatile substrates in synthesis of fine and specialty chemicals
synthesis of chiral alcohols when there are no suitable catalysts to hydrogenate (complex)
carbonyl starting materials.
5. Acylation of alcohols: Transesterification using enol
esters
Acylation of hydroxyl- or amine-groups is often applied in multistep organic synthesis and is
useful due to the resistance of the acyl moiety to a variety of reagents.11 (Acetic) anhydrides, 3acetylthiazolidine, hindered amines and acid halides are few of the generally applied acylating
agents. Acylation is often facilitated in the presence of protic or Lewis acids such as Sn(OTf)3,
TiCl4/AgClO4, CoCl2, Sc(NTf2)3, TMSCl, TMSOTf and Sc(OTf)3.11 In acylation with anhydrides, the
use of bases, such as pyridine, triethylamine and 4-(dimethylamino) pyridine, is recurrent
(Scheme 11). Moreover, a combination of Lewis acid/base systems (MgBr2/R3N) is also
considered in some cases.
For the past twenty years researchers have been exploring alternative methods in order to
replace aforesaid traditional systems, as these pose several inconveniences. For example, (basic)
catalysts can be air-sensitive and flammable. Also, in polyhydroxy natural product synthesis
some acylating agents lack selectivity for either primary or secondary hydroxyl groups.
Additionally, functional groups, namely dienes, epoxides, acetals and tert-butyldimetylsilyl
ethers (TBDMS ether) are susceptible to cleavage when acidic acylation catalysts are used. To
prevent these from occurring, transesterification with esters was attempted. This method
however had a high reversibility rate, urging scientists to consider enol esters. The advantage of
enol esters is that the enolate ion can interconvert to an aldehyde or ketone (Scheme 11).
Catalyst used in acylation reactions with enol esters/vinyl acetates include PdCl2/CuCl systems
34, Sm(Cp*)2(thf)2 or SmI2 in cross coupling reactions of aldehydes and vinyl acetates 12, and
iminophosphiranes11.
Scheme 11. An overview of enol acetates and anhydrides as acylating agents.
12
Enol esters: versatile substrates in synthesis of fine and specialty chemicals
As several conventional methods pose inconveniences ranging from stability to lack of
selectivity, vinyl acetates would provide a plausible solution, as upon release the enol moiety is
resonance stabilised and ceases the reverse reaction from occurring. Studies assessing vinyl
acetate selectivities between hydroxides and amine groups are limited, however insight on this
topic would promote utilisation of vinyl acetates as acylating agents.
6. Functionalisation of enol acetates at the α-position
Researchers are genuinely interested in enol acetates as these substrates fulfil an important role
in carbon-carbon bond formation. The catalytic arylation or alkylation of carbonyl compounds is
therefore a subject of interest. In the following paragraphs an overview of a variety of enol
acetates functionalisation is provided.
6.1. α-Alkyl substituted carbonyl compounds
Alkylation of carbonyl compounds at the α-position has been attempted several times.13
Previous attempts include a ruthenium catalysed reaction, coupling of 1-arylpropargylic alcohol
with an excess of ketone compounds, like acetone (eq. 14a), direct alkylation of 1,3-dicarbonyl
compounds (eq. 14b) and hydrogenation transfer method involving ketones and primary
alcohols (eq.14c), which require strong base for enolate generation (Scheme 12).13
Scheme 12. A brief overview of previously attempted α-alkylation reactions.
13
Enol esters: versatile substrates in synthesis of fine and specialty chemicals
Reactions with tosylates and mesylate alcohol derivatives, organometallic compounds, enolates
and enamines with electrophiles, and organic halides are conventional methods for C-C bond
formation. However, direct use of alcohols is preferred, mainly because they are readily
accessible. Unfortunately, their application still poses a problem due to poor leaving group
ability of the hydroxyl moiety and their tendency to decompose catalysts and active
intermediates.13,35 Intensive investigation by amongst others Nishimoto et al. provided novel
Lewis acid catalysts, namely InCl3, Hf(OTf)3, FeBr3, GaBr3 and La(OTf)3 for effective carboncarbon bond formation between diverse alcohols and enol acetates, with either ketone or
aldehyde products13(Scheme 13). The reaction requires Lewis acids with moderate oxophilicity
and proceeds under ambient conditions (83ᵒC, 1 atm).
Scheme 13. Schematic representation of carbon-carbon bond formation between
diverse alcohols and enol acetates, with either ketone or aldehyde products.
In 2011, Onishi et al. considered using silylethers to couple alkyl groups to enol acetates/enol
esters, while retaining the ketone/aldehyde functionality (Scheme 14).36 Their stability against
nucleophilic substitution makes them eligible coupling reagents. In synthesis of α-alkylated
carbonyl compounds, silyl ethers where coupled to enol acetates in presence of a combined
Lewis acid system, InCl3 and Me3SiBr. A variety of silylethers were tested, and secondary
benzylic ethers bearing electron-withdrawing and donating groups had yields up to 99%, while
high yields were also obtained when enol acetates derived from aromatic or aliphatic ketones
were used. Advantages to this pioneering method include the absence of deprotection steps and
the occurrence of the coupling reaction at room temperature within approximately two hours.
The best solvent for this synthesis is dichloromethane, which is neither a coordinating nor noncoordinating solvent.
Scheme 14. Synthesis of α-substituted ketones/aldehydes from silylethers and enol
acetates (adapted from Onishi et al.)36
The previously mentioned catalysts enable the reaction between alcohols and enol acetates, but
remain toxic and expensive alternatives. Their pyrophoric properties and the use of excessive
amounts of reagents urged scientists to explore for other catalysts. Umeda et al. discovered that
ReX(CO)5 complexes (X=Cl or Br), which are both less toxic and less expensive, also facilitate
14
Enol esters: versatile substrates in synthesis of fine and specialty chemicals
coupling of alcohols and enol acetates under ambient conditions with ketones or aldehydes as
products.35
6.2. Michael addition of enol acetates to α,β-unsaturated ketones
The synthesis of 1,5-dicarbonyl compounds is an essential preliminary step in preparation of
many natural products such as terpenoids.37 Extensive studies have provided several
conventional pathways of which the Michael addition of metal or ester enolates (metal =Li, Sn, K,
Si) to α-β-unsaturated ketones is most conventional (Scheme 15).38,39
Scheme 15. Reaction of a metal ester enolate with an α-β-unsaturated ketone
yielding a 1,5-dicarbonyl compound.
In 2012, Onishi et al. reported the Michael addition of enol acetates instead of metal enolates to
α,β-unsaturated carbonyl compounds.39 This method facilitates isolation and usage of enol-form
products, contrary to when metal enolates are used. They screened various Lewis acid catalysts
in a reaction between crotonophenone ((E)-1-phenyl-2-buten-1-one) and isopropenyl acetate,
and concluded that InBr3, InCl3, InI3 with additive, Me3SiCl, had consecutive yields of 53%, 69%
and 72% respectively (Scheme 16). Reactions were carried out in dichloromethane at room
temperature and took approximately five hours to complete. The yield increased when a fivefold amount of isopropenyl acetate was utilised. Enol acetates derived from aliphatic or aromatic
ketones along with enol acetates carrying a substituent at the olefinic moiety all had yields
ranging between 60% and 95%. In all isolated products the enol acetate moiety had the Zconfiguration.
Scheme 16. Reaction of crotonophenone and isopropenyl acetate, yielding the enol
form of 1,5-dicarbonyl compounds.
15
Enol esters: versatile substrates in synthesis of fine and specialty chemicals
Experiments with a variety of α-β-unsaturated ketones showed that increased substitution with
phenyl rings increases the overall yield. To further demonstrate the utility of stable enol-acetate
products, they were submitted for hydrogenation reactions, radical coupling reactions, nitrosoaldol reactions and transesterification reactions visible in Scheme 17 all which had moderate to
high yields.39
Scheme 17. Possible follow-up reactions with the enol form of 1,5-dicarbonyl
compounds (adapted from Onishi et al.)39
6.3. Heck olefination reactions
The Mizoroki-Heck reaction, also known as Heck-reaction, enables one to do reactions at the sp2hybridised carbon atoms.40,41 The most approachable Heck reactions involve triflates, diazonium
salts, and aryl, aroyl- and arylsulfonyl halides with an electron deficient alkene containing at
least one hydrogen atom. Formation of a carbon-carbon double bond is mediated in presence of
palladium acetates, preformed triarylphosphine palladium complexes or palladium chlorides;
other ligands include BINAP and PHOX.42 A special feature of this reaction is the high selectivity
for trans-products (Scheme 18).
Scheme 18. Schematic representation of a readily accessible Heck olefination
reaction.
16
Enol esters: versatile substrates in synthesis of fine and specialty chemicals
The mechanism depicted in Figure 4 reveals that the halide and hydrogen atom, released upon
β-hydrogen elimination, form a strong acid, therefore stoichiometric amounts of base, usually
potassium carbonate, and triethylamine and sodium acetate, are necessary for Pd0 regeneration
and neutralisation of acidic waste. The aforementioned is also the downside of the reaction,
because separation and disposal of precipitates are a subject of concern, especially in industrial
processes.
Figure 4. The Palladium-catalysed Heck olefination mechanism between an aryl
halide and activated alkene.
6.3.1. Decarboxylative Heck olefination of enol esters
In order to reduce the salt load, different approaches to the Heck olefination have been designed
by Gooßen and de Vries et al.41 Dams et al. suggested to upgrade previous attempts by Gooßen
and de Vries et al. which include utilising p-nitrophenyl esters and aryl carboxylic anhydrides,
regenerable nonhalogenated aryl substrates, by direct coupling of arenes to alkenes wherein the
palladium catalyst is reoxidised by oxygen (Scheme 19).40,43,44 Contrary to conventional methods,
this method proceeds under ambient conditions (90ᵒC, 0.8 MPa) and no solvent is required, no
halide promoter is needed, and instead of carbon monoxide, water is the only by-product.
Although these reactions allow for waste reduction, they remain small scale alternatives, as
isolation and recyclability of the by-products still pose difficulties.
17
Enol esters: versatile substrates in synthesis of fine and specialty chemicals
Scheme 19. Previous attempts by Gooßen and de Vries et al. to waste free Heck
olefination reactions.
Nevertheless, enol esters could offer a solution following a decarboxylative Heck olefination
pathway introduced by Lukas et al..41 They generated an enol ester intermediate by reacting
aromatic carboxylic acids with allenes or propynes. The enol ester intermediate is then left to
react with an olefinic compound to give vinyl arenes with carbon monoxide and acetone as byproducts, which can be burned to carbon dioxide and water. Unfortunately, the trail reaction
which involved the conversion of isopropenyl benzoate with styrene in order to obtain transstilbene, depicted in Scheme 20, had poor yield with conventional palladium catalysts, Pd(OAc)2
and (dba)3Pb2. Hence, a combination of palladium bromide and tetra-alkyl
phosphoniumbromides or tetra-alkylammonium, provided sufficient yields (<80%). This
reaction reduces waste and does not require stoichiometric amounts of base. However, catalyst
stabilizing agents, namely N-dodecyl-N-methylephedriniumbromide and tri n-butyl (2hydroxyethyl) ammonium bromide, are required.
Scheme 20. Decarboxylative Heck olefination of isopropenyl benzoate.
6.4. α-Arylation of enol acetates mediated by visible light
Arylation of (unsaturated) compounds has led to reactions involving aromatic haloethylation,
arylation of olefins, aromatic allylation and arylation of allylic alcohols.45 Many arylation
reactions have been developed and involved nickel, palladium, copper, iron or mercury
catalysts, palladium being the most frequently used. In 1968, Heck et al. first reported the
palladium-catalysed arylation of enol esters, unfortunately with poor selectivity.45 One of the
most recent developments in enol ester applications is the arylation of enol acetates with aryl
diazonium salts, mediated by visible light.14 The arylated species can be valuable in ibuprofen
and β-blocker atenolol synthesis. Heterocycles accessible via 1,2-diarylated ethanones are
essential in a broad spectrum of drugs including indoles, pyrazoles, oxazoles and diazepines. All
these substrates can be acquired starting from a procedure designed by Hering et al.14 Through
18
Enol esters: versatile substrates in synthesis of fine and specialty chemicals
photoinduced electron transfer, a reaction of aryl diazonium salt, p-nitrobenzenediazonium
tetrafluoroborate, with isopropenyl acetate irradiated with 440 nm light in presence of
[Ru(bpy)3]Cl2 or photocatalytic active organic dyes yielded α-arylated ketones (Scheme 21).14
The ruthenium catalysts had best results with yields ranging from 40% to 90% depending on
the reactants. The reaction was carried out at 20ᵒC in DMSO for two hours. Hering et al. proved
the reaction could be followed up by a reductive cyclisation reaction with iron powder and
acetic acid, obtaining substituted indoles (Scheme 22).
Scheme 21. Schematic representation of the photoinduced electron transfer reaction
of aryl diazonium tetrafluoroborate salt with enol acetate.
Scheme 22. Reductive cyclisation reaction of α-arylated product mediated by iron
powder and acetic acid, obtaining substituted indoles.
6.5. Summary and partial conclusion II
Conventional pathways to functionalise carbonyl compounds at the α-position often involve
reacting an excess of ketones with 1-arylpropargylic alcohol or primary alcohols. These
reactions require strong base for enolate generation, and are often catalysed by oxophilic
transition metal catalysts leading to fast catalyst deactivation. To reduce side reactions, Lewis
acids such as InCl3, Hf(OTf)3, FeBr3, GaBr3 and La(OTf)3 with moderate oxophilicity are applied in
reactions involving alcohols and vinyl acetate reagents. Additionally, combined Lewis acid
systems, such as InCl3 and Me3SiBr, exhibited great selectivity in synthesis of α-alkylated
carbonyl compounds in which silyl ethers where coupled to enol acetates.
The reaction of α,β-unsaturated ketones with enol acetates catalysed by InBr3, InCl3, InI3 with
additive, Me3SiCl, yielded the enolised form of 1,5-dicarbonyl compounds in the Z-configuration.
Increased substitution with phenyl rings at the α-β-unsaturated ketones showed an increase in
the overall yield ranging from 60% to 95%. The partly enolised 1,5-dicarbonyl product is
susceptible to subsequent hydrogenation, radical coupling, nitroso-aldol and transesterification
19
Enol esters: versatile substrates in synthesis of fine and specialty chemicals
reactions. Inspired by the Heck olefination reaction, researchers developed the decarboxylative
Heck olefination reaction with enol ester substrates. The enol ester reacts with an olefinic
compound to give vinyl arenes with carbon monoxide and acetone as by-products, which can be
burned to carbon dioxide and water. Palladium bromide and tetra-alkyl phosphoniumbromides
or tetra-alkylammonium, along with catalyst stabilizing agents, namely N-dodecyl-Nmethylephedriniumbromide and tri-n-butyl(2hydroxyethyl)ammonium provided sufficient
yields (<80%). This reaction reduces waste and does not require stoichiometric amounts of
base.
Probably the most recent development in enol ester applications, is the α-arylation of enol
acetates with aryl diazonium tetrafluoroborate salts mediated by light in presence of
[Ru(bpy)3]Cl2 or photocatalytic active organic dyes. This reaction yielded α-arylated ketones
with potential application in ibuprofen and β-blocker atenolol synthesis. With mediocre yields
depending on the substrate properties, optimisation is necessary. Nevertheless this method can
be followed up by a reductive cyclisation reaction with iron powder and acetic acid, obtaining
substituted indoles.
Though the reaction conditions for functionalisation of enol esters at the α-position are ambient,
an excess of reagents is often necessary, also most catalysts are toxic, pyrophoric, expensive or
require promoting additives for optimal activity. Vinyl acetates are, due to their nucleophilicity
at the β-carbon and easy release of the acyl group, ideal starting materials. As the application of
vinyl acetates in these reactions is novel, extensive research is necessary to enlarge substrate
scopes and develop optimal catalytic systems while enhancing yields.
7. Useful molecular scaffolds accessible via enol ester
derivatives
In many experiments simple vinyl acetates are either functionalised, used as a masked acylating
agent or masked carbonyl compound. Nonetheless, the enol ester scaffold can also be (partly)
incorporated in intricate molecular structures essential in bio-inspired synthetic pathways. In
the following paragraphs a brief overview is given on the incorporation of enol esters in
synthesis of oxetanes, 4-substituted isocoumarins, cyclic ether quinolines, N-aryl lactams and dihydropyranones.
7.1. Oxetane synthesis: The Paternò-Büchi reaction involving enol
esters
The Paternò-Büchi reaction involves a photochemical addition of an olefin to a carbonyl
compound with an oxetane as product.15,46 According to the Woodward-Hoffmann rules, the
reaction has to proceed photochemically and is valuable in stereoselective intermolecular [2+2]
photocycloaddition reactions, which are crucial reactions in synthesis of bio-inspired
compounds such as taxols (Figure 5).15 Taxols contain a 3-acetoxyoxetane-subunit which is
accessible via a Paternò-Büchi reaction of enol acetates and benzaldehydes.
20
Enol esters: versatile substrates in synthesis of fine and specialty chemicals
Figure 5. Taxol molecular structure with oxetane subunits.
Vasudevan et al. has executed these intermolecular photocycloadditions of enol acetates, by
reacting isopropenyl acetates, 1-acetoxycylododecenes or 4-tert-butyl-1-acetoxycyclohexenes
with various benzaldehydes at room temperature in benzene (Scheme 23).15 An excess of enol
acetate was used and the product consisted of 2-aryl-3-acetoxyoxetanes. Reaction times varied
from 20 up to 72 hours with increasing moderate yields (6%-28%) and the regio- and
stereochemistry of the reaction products mainly depend on the starting materials used.
Scheme 23. Schematic representation of the Paternò-Büchi reaction involving enol
acetates and benzaldehydes.
Oxetanes are also readily available via dehydration of 1,3-diols, cyclisation of aryl sulfonate
esters on polystyrene and PEG-polymeric supports, reactions with potassiumhydroxide and 3chloropropyl acetate or decarboxylation of cyclic six-membered carbonates.46 However, the
Paternò-Büchi reaction enables more stereo- and regioflexibility and preserves the acetoxysubunit essential in natural product synthesis. Furthermore, most of the reactions mentioned
above are multistep processes, which require high reaction temperatures and/or harsh
chemicals.
7.2. 4-Substituted Isocoumarins: The silver(I)-mediated
annulation of enol esters
Isocoumarins are often incorporated into pharmaceuticals with the purpose of treating
antifungal, anti-inflammatory, antiallergic, anticancer, inhibitory activities, antimicrobial and
anti-diabetic disorders.47 Due to their importance, their synthesis has been thoroughly
investigated and includes (for example) the ruthenium, rhodium and iridium-catalysed
annulation of carboxylic acids with alkynes. This Sonogashira type coupling of terminal alkynes
with halo-carboxylic acids, is mediated by transition metal catalysts.
More recent research resulted in the copper(I)-catalysed cross-coupling of various 2halobenzoic acids and 1,3-dicarbonyl compounds, and also the copper(I)-catalysed tandem CC/C-O coupling reactions involving 2-bromobenzoates with acyclic 1,3-diones succeeded by
annulation.47 However, in general these methods are less favourable, since they involve
multistep synthesis at high temperatures in order to obtain the required starting materials, and
require of highly toxic transition metal catalysts. The products of aforesaid procedures often
21
Enol esters: versatile substrates in synthesis of fine and specialty chemicals
yield 3- or 3,4-disubstituted isocoumarins, while procedures for 4-substituted isocoumarins are
scarce. Apart from the palladium-catalysed preparation of 4-alkyl/aryl-substituted
isocoumarins, more pathways need to be developed in order to synthesise equally important 4substituted isocoumarins. A short overview of reactions, developed to synthesise substituted
isocoumarins, is given in Scheme 24.
Scheme 24. Various synthetic pathways toward the synthesis of substituted
isocoumarins.
In 2015, Panda et al. explored the selective intramolecular silver(I)-mediated C-arylation
reaction yielding 4-substituted isocoumarins (Scheme 25).16 Their approach involved
intramolecular annulation of 2-(ethoxycarbonyl)-vinyl 2-iodobenzoate derivatives, a product of
alkyl propiolates and o-iodobenzoic acids. Several copper- and silver-catalysts were tested, and
yields of 95% and 79% were obtained using respectively AgOAc and Ag2O at room temperature.
22
Enol esters: versatile substrates in synthesis of fine and specialty chemicals
Optimal results were reported when promoting oxidants (K2S2O8), bases (preferably 4dimethylaminopyridine) and acetonitrile as solvent were used. The substrate scope of the
reaction is promising, albeit reaction conditions require adjustments. Moreover, deacetylation is
supressed resulting in higher product yields.
Scheme 25. Selective intramolecular silver(1)-mediated C-arylation of 2(ethoxycarbonyl)vinyl 2-iodobenzoate yielding 4-substituted isocoumarins.
Enol ester derivatives are often selected in reactions due to the ease of the acyl moiety. Contrary
to this, in the intramolecular silver(I)-mediated C-arylation reaction yielding 4-substituted
isocoumarins, the entire enol ester moiety is embedded. The 2-(ethoxycarbonyl)vinyl 2iodobenzoate derivatives are easily accessible via alkyne hydrocarboxylation, making the
approach developed by Panda et al. a promising contribution to existing methods for the
synthesis of 4-alkyl/aryl-substituted isocoumarins
7.3. Di-substituted cyclic ethers: The Aldol reaction of enol
acetates and lactols
Enol acetates have also proven to be promising substrates in aldol reactions with lactols
(hemiacetals) from which cyclic di-substituted ethers result.17 Enol acetates were applied in a
peculiar diastereoselective reaction reported by Masuyama et al.17 By combining 2-hydroxy-5pentyl-tetrahydrofuran and isopropenyl acetate with SnX2 (X= Cl, Br, F) and Nchlorosuccinimide (NCS) or N-bromosuccinimide (NBS) the product, 2-acetonyl-5-pentyltetrahydrofuran, was obtained with yields ranging from 80% to 88%, and a diastereomer ratio
of 60:40 (Scheme 26). Using SnCl2 and NCS in dichloromethane at -30-5ᵒC were found to be
optimal reaction conditions. The reaction is believed to proceed by primary formation of a tin
lactol alkoxide intermediate succeeded by cyclic tin oxy-carbenium ion formation that further
reacts with vinyl acetate. The Lewis acid facilitates the formation of the oxy-carbenium
intermediate. The preference for vinyl esters is due to the stability of the leaving group (acyl
moiety).
23
Enol esters: versatile substrates in synthesis of fine and specialty chemicals
Scheme 26. Formation of di-substituted cyclic ether by reacting a lactol with enol
acetate.
7.4. Quinolines and N-aryl lactams: Mannich-type Povarov
reactions with vinyl acetates
Carbon-carbon bond formation is facilitated according to several reactions, of which one is the
Mannich reaction (Scheme 27).48 The Mannich reaction is a multi-component reaction wherein a
carbonyl compound reacts with an iminium-compound. The iminium-compound is obtained via
a reaction of a primary or secondary amine with an aldehyde. The three components yield a βamino-carbonyl compound, also known as the Mannich-base, which upon variation of each
component provides access to various molecular scaffolds.
Scheme 27. Schematic representation of the Mannich reaction: A reaction between a
non-enolisable aldehyde, a primary or secondary amine and an enolisable carbonyl
compound.
On the other hand, the Povarov reaction requires an aniline, aldehyde and an activated olefin
which usually results in tetrahydroquinolines.48 Isambert et al. aspired to increase the synthetic
versatility of this multicomponent reaction by using (cyclic) enol esters as the necessary
activated alkene.8 Contrary to their expectations, the reaction of 2,4-dihydro-6-methyl-2Hpyran-2-one (1), p-toluidine (2) and ethyl glyoxalate (3) yielded not the desired lactone product
A, but an N-aryl lactam C (25%). In order to obtain N–aryl lactam C, the expected Friedel-Crafts
termination in the Povarov reaction should be less dominant than the heterocyclic ring
formation involving deacetylation, when the nucleophilic nitrogen reacts with the carbonyl
group as can be seen in Scheme 28. However, this can only be achieved if the three components
react according to the Mannich reaction resulting in intermediate B.
24
Enol esters: versatile substrates in synthesis of fine and specialty chemicals
Scheme 28. Proposed mechanism of the Mannich reaction of 2,4-dihydro-6-methyl2H-pyran-2-one (1), p-toluidine (2) and ethyl glyoxalate (3).
The synthesis was carried out at room temperature in acetonitrile with Sc(OTf)3 as catalyst. The
kinetic product, C, has a cis/trans ratio of 3:1 which after refluxing for 24 hours with
trifluoroacetic acid (20%) epimerised to a 1:9 cis/trans mixture, D. The highest yield reported
was 65%, however many additional catalysts and additives including Yb(OTf)3, TMSCl,
anhydrous Na2SO4, molecular sieves (4Å) and SOCl2 were used. The low yield of the reaction is
caused by hydrolysis of intermediate B with an acyclic amino acid byproduct. When isopropenyl
acetate was utilised, simple Mannich products were obtained while vinyl acetate substrates
yielded quinoline scaffolds (Scheme 29 and Scheme 30 respectively).
Scheme 29. The Mannich reaction with isopropenyl acetate yielding simple Mannich
products.
25
Enol esters: versatile substrates in synthesis of fine and specialty chemicals
Scheme 30. The Mannich reaction with vinyl acetate affording a quinoline product.
Most importantly, Isambert et al. succeeded in designing N-arylated lactams via a multicomponent reaction which has never been attempted. These lactams are important scaffolds for
herbicides, integrin antagonists and other bioactive derivatives.8,49 Though promising, the
aforementioned reactions still have meagre yields and need to be optimised.
7.5. Synthesis of di-hydropyranones: The NHC-mediated pathway
using α,β-unsaturated enol esters
Between 1950 and 1965, N-Heterocyclic carbenes (NHC) have been used in inorganic and
organometallic reactions.50 Nowadays, NHCs are known for their utility as organocatalysts and
are often derived from thiazoles, imidazolines, imidazoles and triazoles. Due to their
nucleophilicity, NHCs are often used in reactions requiring carbonyl coupling, including benzoin
and Stetter reactions.51 This organocatalysts is often combined with other molecular structures
gaining useful intermediates for organic synthesis. One of these intermediates is α,β-unsaturated
acyl azolium (4) which is created when an aldehyde or ketene is added via oxidation, redox or
addition mechanisms (Scheme 31).52,51 Because of their potential, Ryan et al. explored conjugate
addition reactions involving α,β-unsaturated acyl azolium.51 They discovered that when
choosing an α,β-unsaturated enol esters 2, an enolate ion 3 is released upon generation of α,βunsaturated carboxylate 4 under Lewis basic conditions. Recombination of 3 and 4 provides
enolate intermediate 5, which followed by proton transfer and acylation results in pyranone 7.
The NHC catalysts 1 is regenerated after every cycle. Tetra-methyl carbenes and carbenes with
both aromatic and aliphatic substituents resulted in the highest yields, 40% and 79-86%
respectively. The reaction was carried out under reflux or at low temperature (-78ᵒC) in toluene,
for approximately sixteen hours in presence of potassium tert-butoxide, which is responsible for
deprotonation of α,β-unsaturated acyl azolium prior to the cyclisation step yielding the dihydropyranone product.
26
Enol esters: versatile substrates in synthesis of fine and specialty chemicals
Scheme 31. The proposed catalytic pathway for formation of di-hydropyranones
adapted from Ryan et al.51
The importance of the aforementioned approach was illustrated by Candish et al., who
demonstrated the 18-step synthesis of bicyclic cyclopenta[c]pyran, the core structure of iridoids,
that belong to a class of monoterpenoids that exhibit medicinal activity.53 In general, the H5 of
the cyclopenta[c]pyran core 2, depicted in Scheme 32, is positioned cis to the H9.53 In this
diastereoselective synthesis, this orientation was achieved when the α,β-unsaturated enol ester
1, was reacted with diastereoselective NHC, A, in tetrahydrofuran (THF) at temperatures
ranging from -78ᵒC to room temperature. The yield was 83% with a d:r ratio of 3.4 to 1. Further
trails to optimise the process by use of different solvents, chiral carbenes and temperatures
were less successful. The final product, (-)-7-deoxyloganin 3, was isolated after β-glycosylation.
27
Enol esters: versatile substrates in synthesis of fine and specialty chemicals
Scheme 32. Synthesis of (-)-7-deoxyloganin involving the reaction of α-β-unsaturated
enol ester with diastereoselective NHC, adapted from Candish et al.53
7.6. Summary and partial conclusions III
In many experiments simple vinyl acetates are either functionalised, or used as a masked
acylating agent or masked carbonyl compound. Nonetheless, the enol ester scaffold can be
(partly) incorporated in intricate molecular structures essential in bio-inspired synthetic
pathways.
Some of these have been listed above and include the intermolecular photocycloaddition of enol
acetates with benzaldehydes forming oxetane units known to be present in taxols. In contrast to
conventional multistep synthesis that require high reaction temperatures and/or harsh
chemicals, the Paternò-Büchi reaction enables more stereo- and regioflexibility and preserves
the acetoxy-subunit essential in taxols.
Furthermore, the synthesis of 4-substituted isocoumarins involving intramolecular annulation
of enol ester containing scaffolds such as 2-(ethoxycarbonyl)vinyl 2-iodobenzoate derivatives (a
product of alkyl propiolates and o-iodobenzoic acids) was investigated. Silver catalysts, such as
AgOAc and Ag2O resulted in yields of 95% and 79% respectively at room temperature. Optimal
results were reported when promoting oxidant (K2S2O8) and base (4-dimethylaminopyridine)
were used.
Enol acetates have also proven to be promising substrates in aldol reactions with lactols
(hemiacetals) from which cyclic di-substituted ethers result. In this reaction the Lewis acid
catalyst facilitates the formation of the oxy-carbenium intermediate.
Contrary to oxetane and isocoumarin synthesis, vinyl acetate was chosen due to the stability of
the leaving group (acyl moiety). Enol ester derivatives were also applied in multicomponent
reactions in which their cyclic derivatives yielded N-aryl lactams while vinyl acetate substrates
yielded quinoline scaffolds. Simple Mannich products were acquired when isopropenyl acetate
was used as the activated alkene. This multicomponent Mannich-type Povarov reaction still
needs catalyst optimisation to increase yields. However, it gives insight on how the molecular
structure of enol esters affects the mechanism and therefore the reaction products.
Lastly, dihydropyranones are easily formed when substituted α,β-unsaturated enol esters were
combined with N-heterocyclic carbenes under basic conditions and low temperatures in
presence of a Lewis acid catalyst. In a mechanism involving addition, C-C bond formation, proton
transfer and acylation, dihydropyranones were formed in moderate yields.
28
Enol esters: versatile substrates in synthesis of fine and specialty chemicals
In conclusion, incorporation of enol ester scaffolds in the synthesis of the structures mentioned
above, results in valuable structures. Both the oxetane and 4-substituted isocoumarins units
incorporated all of the enol ester moiety, while the multicomponent Mannich-type Povarov
reaction excluded the acyl moiety via a deacetylation reaction. When N-heterocyclic carbenes
were applied, α,β-unsaturated enol esters would undergo recombination in order to facilitate
dihydropyranone formation. Although, enol esters have been utilised only upon recently, they
make good substrates for addition of carbonyl, aldehyde or olefin functional groups to molecular
structures. This is facilitated by the nucleophilicity at the β-carbon and facile release of the acyl
group.
8. Polymers: The use of vinyl acetate in polymers
Apart from utilisation in organic and pharmaceutical synthesis, enol esters have been
commercially exploited in the form of polymers.4 In 2007, the annual production of vinyl acetate
monomer (VAM) was estimated at 6,154,000 tonnes/annum. Vinyl acetate monomers find their
use in non-woven binders, paper coatings, textile sewing thread, paper coating, emulsion paints,
caulks and adhesives. They are often combined with other monomers forming copolymers such
as vinyl acetate/acrylic (VA/AA) copolymers, ethylene-vinyl acetate (EVA) copolymers, polyvinyl (butyral/formal) and polyvinyl chloride acetate (PVCA) copolymers.
8.1. Vinyl acetates in polymers
Polyvinyl acetate is the simplest polymer produced, however its poor hydrolytic stability
expressed by the acetate hydrolysis of ester moieties make it a less desired product for outdoor
use. Therefore higher vinyl ester monomers (RC(O)O-CH=CH2, R>CH3) are preferred.4,54 Higher
vinyl ester monomers are less susceptible to hydrolysis as aliphatic branches shield the ester
moieties from hydrolysis (Figure 6).
In the 60s, chemists from Shell in collaboration with Dr .H. Koch and the Max-Planck institute,
developed copolymers of vinyl esters of C9 or C10 versatic acid (commercially known as
VeoVA9™ and VeoVa10™) and vinyl acetate (Figure 7).54 VeoVA9™ monomers provide rigidity
and VeoVa10™ monomers flexibilize the copolymer.
Figure 6. Higher vinyl esters increase hydrophobicity of the polymer.
29
Enol esters: versatile substrates in synthesis of fine and specialty chemicals
Figure 7. Molecular structure of VeoVa9™ and VeoVa10™ monomer. R1 and R2 are
alkyl groups containing a total of six carbon atoms for VeoVa9™ and seven carbon
atoms for VeoVa10™.
In the early 1990s, R.E. Murray of Union Carbide applied the transvinylation method on vinyl
esters and numerous carboxylic acids in polymer synthesis to obtain new hard and soft
monomers such as vinyl pivalate and vinyl-2-ethylhexanoate, also known commercially as
Vynate™.4,54 All these monomers can be combined with a variety of vinyl acetates to form
comonomers necessary to produce polymers with high tensile strength, varying glass transition
temperatures, water resistance and other performance properties.
9. Discussion and conclusion
Over the years, enol esters have been applied in various chemical reactions. In this thesis many
have been discussed, starting with the asymmetric hydroformylation of Z-enol acetates, which
yields linear and branched α-acetoxcyaldehydes. Due to its efficiency and high atom economy,
asymmetric hydroformylation can be combined in several tandem processes of which the
asymmetric hydroformylation/Wittig olefination process has been explored in synthesis of γhydroxy-α,β-unsaturated carbonyl motifs present in bioactive compounds, such as (+)patulolide C, (+)-decarestrictine L and (-)-pyrenophorol.
Apart from asymmetric hydroformylation, Z-enol acetates are also asymmetrically epoxidised to
cis-epoxides, which can be readily converted to useful α-acyloxy ketones and αsilyloxyaldehydes under ambient conditions with reasonable yields. The asymmetric
epoxidation of Z-enol esters also eliminates the necessity of a resolution step when a particular
stereoisomer is desired.
Both asymmetric hydroformylation and epoxidation provide valuable compounds. However,
when it comes to the synthesis of chiral alcohols, asymmetric hydrogenation of vinyl esters is
regarded as an auspicious method. Especially when there are no suitable catalysts to
hydrogenate intricate carbonyl substrates. As several conventional acylating methods pose
inconveniences ranging from instability to lack of selectivity, vinyl acetates would provide a
plausible solution, as upon release, the enol moiety is stabilised by resonance, which ceases the
reverse reaction from occurring. Functionalisation of vinyl acetates in the α-position via
substitution, Michael additions, decarboxylative Heck olefinations and α-arylation mediated by
visible light gave rise to a variety of α-alkylated/arylated ketones and aldehydes. Additionally,
enol ester scaffolds can be incorporated in intricate molecular structures essential in bioinspired synthetic pathways of oxetanes and isocoumarins. In Mannich-type Povarov reactions,
parts of vinyl acetates are incorporated in N-aryl lactams and quinoline derivatives. When
combined with N-heterocyclic carbenes, α,β-unsaturated enol esters form di-hydropyranones
after a recombination step.
30
Enol esters: versatile substrates in synthesis of fine and specialty chemicals
In general, enol ester derivatives are versatile and therefore applicable in numerous reactions
ranging from simple acylation and asymmetric hydrogenation/hydroformylation reactions, to
more complex α-functionalisation reactions. Few researchers have also applied them in oxetane,
4-substituted isocoumarin, cyclic ether quinoline, N-aryl lactam and di-hydropyranone
synthesis.
Vinyl acetates are ideal starting materials due to their nucleophilicity at the β-carbon, and easy
release of the acyl group generating ketones and aldehydes. They have been utilised only upon
recently, and make good substrates for addition of carbonyl, aldehyde or olefin functional
groups to molecular structures. In most cases when conventional reagents were replaced by
vinyl acetates, reaction conditions remained ambient, however different catalysts had to be
tested.
Enol ester synthesis has gradually evolved and asymmetric ruthenium-catalysed stereoselective
hydrocarboxylation of alkynes and alkenes is currently the most accessible pathway in obtaining
enol esters via either Markovnikov or anti-Markovnikov addition. These reactions can be applied
in bio-organic and pharmaceutical chemistry for synthesis of a variety of scaffolds essential in
bioactive compounds, such as terpenes, alkaloids and steroids with antifungal, antiinflammatory, antiallergic, anticancer, inhibitory activities, antimicrobial and anti-diabetic
properties. Also vinyl acetate monomers combined with other monomers are used in
commercially available copolymers.
Further research is necessary in order to explore possible tandem processes which are initiated
with (asymmetric) hydroformylation. The asymmetric hydroformylation/Wittig olefination
tandem process is a predecessor while AHF/crotylation, hydroformylation/ SN1 alkylation, AHF/
asymmetric aldol, bidirectional hydroformylation/tandem hydrogenation-reductive bisamination, and hydroformylation/asymmetric Mannich reactions remain unexplored. In order
to optimise reactions concerning vinyl acetates as acylating agents, the selectivity between
amines and alcohols has to be tuned. As the application of vinyl acetates in functionalisation
reactions and bio-inspired organic synthesis is novel, extensive research is necessary to enlarge
substrate scopes and to develop optimal catalytic systems for enhancing yields and selectivity.
Nonetheless, enol esters and their derivatives remain promising substrates in chemical and
pharmaceutical chemistry.
31
Enol esters: versatile substrates in synthesis of fine and specialty chemicals
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