A borane-mediated palladium-catalyzed reductive allylic alkylation of α,β-unsaturated carbonyl compounds

Article abstract of DOI:10.1039/c9sc05970a

The development of the palladium-catalyzed allylic alkylation of in situ generated boron enolates via tandem 1,4-hydroboration is reported. Investigation of the reaction revealed insights into specific catalyst electronic features as well as a profound leaving group effect that proved crucial for achieving efficient allylic alkylation of ester enolates at room temperature and ultimately a highly preparatively useful synthesis of notoriously challenging acyclic all-carbon quaternary stereocenters. The method demonstrates boron enolates as viable pro-nucleophiles in transition-metal catalyzed allylic alkylation, potentially opening up further transformations outside their traditional use.

Full text of DOI:10.1039/c9sc05970a

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DOI: 10.1039/C9SC05970A
ARTICLE
A Borane-Mediated Palladium-Catalyzed Reductive Allylic
Alkylation of α,β-Unsaturated Carbonyl Compounds†
Received 00th January 20xx,
Accepted 00th January 20xx
‡
‡
Barry M. Trost,* Zhijun Zuo, Johnathan E. Schultz, Nagaraju Anugula and Katherine A. Carr
DOI: 10.1039/x0xx00000x
The development of the palladium-catalyzed allylic alkylation of in cyclohexanone, when treated with triethylborane, undergoes
situ generated boron enolates via tandem 1,4-hydroboration is clean alkylation, although it is unclear if it is the boron “ate”
reported. Investigation of the reaction revealed insights into complex, or the potassium enolate that is undergoing
8
specific catalyst electronic features as well as a profound leaving alkylation. More recently, Saegusa oxidation protocols have
group effect that proved crucial for achieving efficient allylic been developed using enol boranes in analogy to silicon
9
alkylation of ester enolates at room temperature and ultimately a enolates. Additionally, a dual chiral catalytic rearrangement
highly preparatively useful synthesis of notoriously challenging of allyl esters has been achieved using boron ester enolates
1
0
acyclic all-carbon quaternary stereocenters. The method and palladium catalysis.
demonstrates boron enolates as viable pro-nucleophiles in
transition-metal catalyzed allylic alkylation, potentially opening up AAA reactions (Scheme 1b),
Following our long standing interests in enantioselective Pd-
1
1
we became interested in
further transformations outside their traditional use.
incorporating neutral enol boranes as pronucleophiles in
transition metal catalysis, as means of overcoming
limitations imposed by decarboxylative AAA methods.
a
1
2
In
Introduction
Boron enolates have been shown to be of great utility in
organic synthesis.1 Most noteworthy is the enantio- and
diastereoselective aldol reaction. Synthesis of either geometric
isomer has been shown to be achievable by judicious choice of
base and borane.2 A less common method of their generation
particular, the formation of geometrically-controlled
tetrasubstituted enol carbonates has remained challenging.
Work by Marek and Stoltz has shown that geometrically-
selective synthesis of tetrasubstituted amide enolates is
1
3
achievable by elaboration of ynamides. However, in these
methods, asymmetric α-allylation reactions require the prior
synthesis of enol carbonates or enol silyl ethers. It would be
advantageous to remove this step to allow for a more direct
method of alkylation. Additionally, decarboxylative allylic
alkylation of unactivated esters remains a challenge, and
asymmetric methods have relied on achiral auxiliaries at the
involves 1,4-hydroboration of α,β-unsaturated carbonyl
compounds. First reports of this method using chiral boranes
showed low enantioselectivities in subsequent aldol
3
reactions. Recently, Roush and coworkers have accomplished
impressive enantio- and diastereoselectivities in the synthesis
1
4
ester oxidation state.
of tertiary and quaternary α-carbon centers in aldol reactions
4
when using chiral boranes.
a) the aldol reaction of -unsaturated ketones via 1,4 hydroboration. [Ref.3-4]
Beyond the aldol reaction, few reactions of boron enolates
are routinely employed. Alkylation of boron enolates has
R2B
O
OH
R''
O
R2B
H
O
H
aldol reaction
5
R1
R1
R2
R''CHO
R2
R1
R2
been achieved by formation of the “ate” complex followed by
b) traditional Pd-AAA reaction manifold
0
6
treatment with alkyl halides. In palladium catalysis, a few
NuH
+
[Pd ]/Ln*
-HX
0
-
[Pd Ln*]
examples involve forming boron enolates by protonolysis of
Nu
X
Nu Pd Ln*
II
7
triethylborane by acidic aldehydes or specific aryl ketones.
c) the enantioselective Pd-AAA reaction of -unsaturated carbonylic compounds via 1,4 hydroboration
Negishi has shown that the potassium enolate of
R2B
O
O
H
[Pd0]/L*
R2B
H
R3
R3
R4
R4
X
R
X
O
Departmentof Chemistry, Stanford University, Stanford, CA 94305-5080 (USA),
E-mail: bmtrost@stanford.edu
B
R3
alkylation reaction
R
R3
O
H

PdLn*
work-up
2
†
Footnotes relating to the title and/or authors should appear here.
R4
R4
-R BX
H
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
Scheme 1. Research plan for regio- and enatioselective reductive allylic alkylation
‡
These authors contributed equally to this work
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ARTICLE
Journal Name
The regioselective allylic alkylation of ketones has only been reactivity (Table 1). It was observed that TVrieowstArticlilegOannldines
achieved for ketones differentiated by a bulky substituent. We performed with little conversion, possiblDyOdIu: 1e0.t1o03t9h/eC9pSrCe0s5e9n70cAe
wished to explore a reactivity strategy that allowed for the of acidic amide hydrogen atoms. The efficiency of this process
direct formation of neutral enol boranes, and to demonstrate appeared to be highly dependent on ligand structure and
their potential for achieving regio- and stereoselectivity for electronics. Ligands L11 and L12 bearing electron-deficient
otherwise difficult substrates (Scheme 1c).
phosphines proved to be differential in reactivity, as the
In this scenario, 1,4-hydroboration would allow for product was formed in higher than 95% conversion for both
regioselective generation of enolates that would be ligands. Unfortunately, low enantioselectivity was observed for
inaccessible by acid/base chemistry. Additionally, the thermal this process.
1
,4-hydroboration of aliphatic enones is known to give
O
excellent regioselectivity. When employing 1,4-hydroboration,
solutions of pure boron enolates could be produced in the
absence of ammonium salts produced when reacting
O
OAc i. (+)-(Ipc)BH, THF
ii. [(3-cinnamyl)PdCp] (2.5 mol%)
Ligand (3.0 mol%), r.t.
+
Me

Me
Ph
H
Ph
PPh2
Ar
3a
1
a
2a
dialkylboron chlorides or triflates with ketones in the presence
of amine bases.15 Certain issues could be anticipated when
P
Fe
Ar
W001
>95% yield, 15% ee
Me
ent-W001
>95% yield, -15% ee
Ar = 3,5-CF3-C6H3
employing boron enolates in a Pd-catalyzed process. Off-cycle
events such as transmetallation of the alkyl group to palladium
are possible. Additionally, from the balanced reaction, it can
be seen that upon reaction with an activated allyl source, a
Lewis-acidic by-product is formed. If activation of the boron
enolate by the leaving group is required for reactivity, then the
build-up of a Lewis-acid by-product could cause product
inhibition, particularly if the by-product is more Lewis-acidic
than the starting boron enolate.
W001
Scheme 2. Absence of matched/mis-matched effect with chiral borane
It was postulated that if the boron atom is involved in the
enantio-determining step of this reaction, then the use of a
chiral borane could aid in inducing enantioselectivity. When
2
BH and employing both enantiomers of L11
W001), neither a matched nor mismatched effect was
using (+)-Ipc
(
observed, and the stereoselectivity was determined entirely by
the chirality of the ligand (Scheme 2).
Results and discussion
O
O
O
O
i. Cy2BH, THF
ii. Pd(PPh3)4 (5.0 mol%)
THF, r.t.
NMe2
Me

R =
O
Me
Me
Ph
At the outset, we commenced our efforts by examining the
coupling of α,β-unsaturated ketone 1a and allyl acetate 2a. A
comprehensive ligand screening was undertaken to determine
important structural and electronic properties required for
H
Ph
2b
91% yield
2c
61% yield
1
a
3a
OR (2.0 eq)
(
86% yield)[a]
2
Me2N
O
[Pd0]
CO2
O
B
Cy O
+
1
a + 2b
Cy
Me

-
H
Me
N
PdLn*
Me
Table 1 Ligand screening for reductive allylic alkylation of enones[a]
H
Ph
Me
Ph
Cy2B
3a
Int I
O
O
[a] yield for 10.0 mmol scale
O
OAc i. Cy2BH (1.01 eq), THF
+
Me

Scheme 3. Effect of leaving group on efficiency of ketone alkylation
Me
Ph
ii. [( -cinnamyl)PdCp] (5.0 mol%)
3
1.0 eq
2.0 eq
L* (6.0 mol%)
H
Ph
60 °C (1.0 M)
1
a
2a
3a
Although enantioselectivity proved elusive in this process, the
reactivity remained intriguing, as neutral boron enolates have
been used in only a limited way in transition-metal catalyzed
enolate allylation. Interestingly, Pd(PPh3)4 was an active
catalyst in the reaction. The reaction was found to display
limited conversion when using allyl acetate. It was postulated
that the boron Lewis acid could be a source of inhibition in the
reaction. Inspired by the work of Hooz employing lithium N,N-
dimethylethanolamine alkoxide in ionic alkylations of boron
Ph
N
O
O
Ph
Ph
N
O
O
N
P
PPh2
PPh2
NH HN
P
O
O
P
N
N
O
Ph
Ph
PPh2 Ph2P
O
Ar = 2-naphthyl
L2
60% conversion
8% yield, 25% ee
Ar
L1
L3
L4
0
% conversion
46% conversion
0% ee
74% conversion
71% yield, 9% ee
5
H
PCy2
PPh2
O
O
PPh2
PPh2
PCy2
Me
Me
PPh2
Me
Ph2P Fe
PCy2
Fe
6a
Me
Fe
enolates, we synthesized a specialized pro-electrophile 2b,
H
Me2N
with the aim of sequestering boron (Scheme 3). Gratifyingly,
this resulted in excellent yield (91%) in the model reaction
comparing with allyl acetate, which presumably is due to the
enhanced nucleophilicity of Int I. The established reaction
proved as a useful starting point for accomplishing high
reactivity of ester enolates at room temperature and a
preparatively useful method for synthesizing acyclic all-carbon
quaternary stereocenters (see below).
L5
2% conversion
9% yield, 8% ee
L6
L7
<10% conversion
L8
6
5
26% conversion
-6% ee
59% conversion
54% yield, 3% ee
PPh2
PPh2
PPh2
Ar
Ar
Cy2P
Me
PCy2
PPh2
Fe
P
P
Fe
Ar
Me2N
Fe
Ar
Fe
Me
Me
Ar = 3,5-CF3-C6H3
L11
>95% conversion
94% yield, -17% ee
Ar = 3,5-CF3-C6H3
L12
>95% conversion
92% yield, 35% ee
L9
6% conversion
2% yield, -17% ee
L10
5
84% conversion
80% yield, -6% ee
5
Allylic alkylation of unactivated esters remains a major
challenge in Pd-AAA chemistry. In the first demonstration of
ester enolate alkylation by Tsuji in 1984, silyl ketene acetals
[
a] reactions were conducted on 0.20 mmol scale.
2
| J. Name., 2012, 00, 1-3
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ARTICLE
were reacted with allylic carbonates in the presence of Pd(0) envisioned that upon 1,4-hydroboration of a tiglic acid-derived
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1
6a
DOI: 10.1039/C9SC05970A
substrate, high diastereoselectivity could be effected by
and diphenylphosphinoethane (dppe) in refluxing dioxane.
Following this work, room temperature reactivity was auxiliary-based control. The model system was chosen to
established when using diphenylphospinoferrocene (dppf) as demonstrate alkylation at a carbon bearing two sterically
ligand.1 More recently, Ito and Tunge have demonstrated similar substitutents.
6b
17
18
21
The stereospecificity of the 1,4-
the methods for the decarboxylative allylic alkylation of allyl hydroboration should prove useful in this context, since the
malonates. Interestingly, the identity of the leaving group also facial differentiation should be controlled by the chiral
has a strong influence on the conversion of this reaction, with auxiliary. Our initial screening was with the phenyl alaninol
the tert-butyl carbonate and the N,N-dimethylethanolamine derived auxiliary, giving good yield and modest
groups affording the product in highest yield (Scheme 4). In diastereoselectivity for allylation (Scheme 5).
the case of the N,N-dimethylethanolamine leaving group, the
O
O
Lewis-acidic leaving group is sequestered in the process.
Additionally, the higher basicity of the tert-butyl carbonate
leaving group may account for higher reactivity and diminished
by-product inhibition. It was discovered in this process that
boryl ketene acetals react rapidly at room temperature under
the previously discovered reaction conditions.
i. Cy BH, THF
O
O
2
Me
O
O
N
Me
+
O
NMe2
ii. Pd(PPh3)4 (2.5 mol%)
rt
N
Me
O
O

Bn
H
Me
Bn
7
a
2b
1.0 eq
8a 76%
77.5 : 22.5 d.r.
1.5 eq
Scheme 5. Initial results for chiral auxiliary-controlled diastereoselective allylic
alkylation of boryl-ketene aminals
Because of the 1,3-allylic strain between the α-methyl
substitutent and the auxiliary, the population of the S-cis
conformer is likely dependent on the identity of the auxiliary.
This potentially explains the lower reactivity for other
substrates. Gratifyingly, simply increasing the steric bulk local
to the auxiliary by employing phenyl glycinol-derived auxiliary
afforded the product in high diastereoselectivity, and this
auxiliary was chosen for further studies.
O
O
i. Cy BH (1.5 eq) THF (0.5 M)
2
tBuO
tBuO
ii. Pd(PPh ) , r.t.
3 4
H
H
OMe
RO
H
4a
6
a
1
.5 eq
OMe
5
1.0 eq
O
O
O
O
NMe2
t
R =
Me
OMe
5b
31% yield
O Bu
O
5
a
5c
78% yield
5d
80% yield
3
7% yield
Scheme 4. Effect of leaving group on efficiency of reductive allylic alkylation of
boryl ketene acetals
O
O
Me
O
O
i. Cy2BH, THF
N
O

N
Me ii. [(3-cinnamyl)PdCp] (2.5 mol%)
O
Me
Ligand, r.t
BnH
8a
Invariably, other ester alkylations require aryl esters or
electron-withdrawing α-substitutents for reactivity to be
observed (Table 2). To the best of our knowledge, this is the
only case of unactivated ester allylation proceed rapidly at
room temperature. In all cases observed, the reaction is
complete within minutes.
Me
Bn
O
O
NMe2
7a
O
2
b
Me Me
O
Ar
PCy2
PPh2
PPh2
t
P( Bu)2
P
Fe
2
Ph P
PPh2
Ar
Fe
Ph
38% NMR yield
Me
PPh2
PPh2
67:33 d.r.
76:24 d.r.
<10% NMR yield
Ar = 3,5-CF3-C6H3
80:20 d.r.
6
1% NMR yield
58% NMR yield
Table 2. A borane-mediated reductive allylic alkylation of acrylates[a]
74% NMR yield
Scheme 6. Screening of ligands in auxiliary-controlled allylation
Me Me O
Me Me O
+
R'
O
O
i. Cy2BH (1.5 eq) THF (0.5 M)
ii. Pd(PPh3)4 (5.0 mol%), r.t.
NMe2
R
O
O
R
O
R
Although our initial results were with the chiral Walphos
ligand, the absence of a pronounced match/mismatch effect
led us to reason that the selectivity was solely a result of the
auxiliary control. Therefore, a screen of achiral ligands was
pursued. Interestingly, achiral ligands afforded the product in
diminished reactivities and diastereoselectivities in
comparison with chiral Walphos ligand (Scheme 6). Therefore,
the chiral Walphos ligand was employed in subsequent
studies.
H
H
H
6
4
2a or 5
1.0 eq
1
.5 eq
O
O
O
O
tBuO
tBuO
OMe H
tBuO
tBuO
Me
H
H
H
NO2
H
H
H
H
H
H
H
H
6
a 80% yield
6b 50% yield
6c 95% yield
6d 81% yield
Me Me O
Bn
Me Me O
O
O
O
O
Et
Et
O
Bn
O
N
N
Ph
O
O
H
H
H
H
H
H
H
H
H
H
H
H
6
e 73% yield
6f 82% yield
6g 63% yield
6h 78% yield[b]
O
O
O
i. Cy2BH, THF
O
Me
[
a] reactions were conducted on a range of scales and details see SI. [b]using the tert-
ii. [(3-cinnamyl)PdCp] (2.5 mol%)
L11 (3.0 mol%), r.t.
N
N
Me
O
butyl carbonate as leaving group.
O
Me
H
Me
Ph
O
OR
Ph
8b
7
b
O
We became interested in applying this method for the
challenging synthesis of acyclic quaternary stereocenters.
Within allylic alkylation methodology, this has been
accomplished for a variety of systems, although alkylation of
esters has remained limited. A chiral auxiliary approach was
chosen due to the limitations in catalyst-controlled asymmetric
induction in the previously described systems. It was
2
1
9
O
O
O
R =
t
NMe2
O Bu
Me
O
2
0
2d
2c
82:18 d.r.
81% NMR yield
2b
92:8 d.r.
80% NMR yield
4:6 d.r.
1% yield (-20 C)
6
1:39 d.r.
Quant. NMR Yield
9
7
Scheme 7. Effect of the leaving group on diastereoselectivity
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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ARTICLE
Journal Name
stereochemical outcome is based on alkylation of an enolate
species with the rotamer maximizing dipole cancellation.
O
O
View Article Online
DOI: 10.1039/C9SC05970A
O
O
Me
i. Cy2BH, THF
N

Ph
N
Me ii. [( -cinnamyl)PdCp] (2.5 mol%)
O
O
3
Me
Ligand (3.0 mol%), -20°C to r.t.
H
Me
Ph
Ph
Ph
O
O
O
NMe2
O
O
LiOH / H2O2
THF / H2O
7b
8c
L11
O
g
HO
5
N
O
then
2
Me
Ph Me
8b
Me
Me
9
6
7% yield, 86:14 d.r.
Na SO3
ent-L11
89% yield, 85:15 d.r.
96% yield
Scheme 8. Absence of match/mismatch effect in stereoselectivity of
cinnamylation
9: []D23 = -7.66 (c = 1.00, CHCl3) for 88% ee.
Lit: []D23 = -5.64 (c = 1.00, CHCl3) for 82% ee.
O
O
O
O
Ph
O
O
O
O
The identity of the leaving group had a substantial effect on
diastereoselectivity, with the N,N-dimethylethanolamine
carbonate affording the product in the highest
diastereoselectivity (Scheme 7). If the reaction proceeds via a
boron–ate complex, then the dependence of the leaving group
on diastereoselectivity would explain these results. The
reactions were observed to proceed rapidly, with carbon
dioxide extrusion and precipitation of the boron/ethanolamine
adduct occurring upon addition of electrophile to the reaction.
It was reasoned that beginning the reaction at -20⁰C could
potentially control any possible exotherm, these observation
extended to cinnamylation as shown in Scheme 8.
allylation
allylation
N
O
N
Me
N
Me
N
O
O
Me
Ph
Me
Me
Me
Ph Me
Me
Ph
O
8b
8b
7b
major
minor
Scheme 9. Cleavage of auxiliary and determination of absolute stereochemistry
The reaction could proceed from the boron “ate” complex
that results from leaving group abstraction. In contrast,
transmetallation to palladium could conceivably occur prior to
alkylation; however, the effect of the leaving group is difficult
to rationalize for this reaction pathway, as the boron Lewis
acid is not expected to be involved in the diastereo-
determining step.
The Lewis acidity of boron enolates explains the higher
reactivity in comparison to their silyl counterparts. Abstraction
of leaving group upon ionization would be predicted to be
much more favorable, leading to a high pre-equilibrium
concentration of activated enol borane. The reductive
elimination is much more rapid in comparison to reactions of
other metal enolate species due to the high effective
concentrations afforded by ion-pairing of the active
nucleophile and the π-allyl species. Electron-deficient ligands
should have a two-fold effect on rate-acceration: they increase
The substrate scope revealed efficient 1,4-hydroboration and
alkylation for substrates bearing a methylene group at the γ-
1
position (Table 3). Branched substitution at this position (R =
i
Ph, Cy, Pr) proved unreactive in the 1,4-hydroboration
process. The sensitivity of the substrate to these structural
1
features can be explained by considering that R engages with
the α-methyl substitutent with a considerable amount of
strain. This likely causes substitutents such as a benzene ring
to turn out of conjugation with the π-system, effectively
hindering the 1,4-hydroboration event.
Table 3. Scope of auxiliary-controlled diastereoselective reductive allylic alkylation for the electrophilicity of the π-allyl species and are less prone to
the synthesis of acyclic quaternary stereocenters[a]
poisioning by the Lewis acidic by-product. This is better
O
understood when recognizing that σ-donation is diminished
O
O
O
Me
i. Cy2BH, THF
3
R2
R1
N
(ability to act as a Lewis base with boron) and π-back donating
ability is increased (i.e. higher affinity for palladium in
comparison to boron). The effect of leaving group on
conversion of ester enolates strongly suggests that the by-
product has an inhibitory effect on reaction conversion.
N
O
O
ii. [( -cinnamyl)PdCp] (2.5 mol%)
Me
Me
R1
L11 (3.0 mol%), -20°C to r.t.
H
Ph
2
Ph
R
O
O
NMe2
8
7
O
or 5
2
O
O
O
O
H
O
O
H
Me
Me
N
N
Ph
N
O
O
O
Me
H
Me
Me
Ph
Ph
Ph
8
b, 71% yield
8
c, 59% yield[b]
8d, 65% yield
95:5 d.r.
94:6 d.r.
91:9 d.r.
Conclusions
O
O
O
O
O
O
Me
Me
Me
N
N
N
The reactivity of neutral enol boranes was studied in Pd-allylic
alkylation. Important ligand and leaving group effects were
discovered that proved important in the development of room
temperature ester alkylation, and a preparatively useful
diastereoselective alkylation for the synthesis of acyclic
quaternary stereocenters bearing sterically similar α-
substituents. It is hoped that this work lays the groundwork for
understanding the utility of boron enolates in other transition-
metal catalyzed processes.
O
O
O
iPr
OBn
H
H
H
Me
Ph
Ph
Ph
8
e, 51% yield
8f, 33% yield
>95:5 d.r.
8g, 63% yield
95:5 d.r.
90:10 d.r.
O
O
O
O
O
O
Me
Me
Me
N
N
N
O
O
O
Boc
H
N
H
OBn
H
Ph
Ph
Ph
Ph
Bn
8
h, 52% yield
9
8i, 63% yield
>95:5 d.r.
8j, 65% yield
92:8 d.r.
1:9 d.r.
[
a] reactions were conducted on a range of scales and details see SI. [b] Using Pd(PPh
3 4
)
as catalyst
The product of the model reaction was converted to
corresponding acid, and the absolute stereochemistry was
determined by comparison to the optical rotation of the
Conflicts of interest
The authors declare no competing financial interests.
2
2
known compound 9 (Scheme 9). The model for the
4
| J. Name., 2012, 00, 1-3
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PleaseC dh oe mn oi ct a al dS cj ui es nt cme argins
Journal Name
ARTICLE
1
5 See reference 2 for the synthesis of boron eVnieowlaAtrteicsle Ofrnolimne
Acknowledgements
ketones and electrophilic borylating reagents.
DOI: 10.1039/C9SC05970A
We thank the Tamaki Foundation for their generous partial 16 a.) J. Tsuji, K. Takahashi, I. Minami and I. Shimizu,
Tetrahedron Lett. 1985, 25, 4783. b.) Carfagna, C.; Mariani, L;
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funding support for our program.
1
Notes and references
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652.
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0 T. Fujita, T. Yamamoto, Y. Morita, H. Chen,; Shimizu, Y.;
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1
1
4 a) B. M. Trost, K. Lehr, D. J. Michaelis, J. Xu, A. K. Buckl, J. Am.
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PleaseC dh oe mn oi ct a al dS cj ui es nt cme argins
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ARTICLE
Journal Name
R2B
H
O
H
R
X
View Article Online
DOI: 10.1039/C9SC05970A
R3
LG
O
B
R1
R3
via
R
O
H

R1
R2
[Pd ]/L*
alkylation reaction
0
PdLn*
R2
R1
R4
A palladium-catalyzed allylation of ester-derived boron enolates, which is prepared through 1,4-reduction of α,β-unsaturated ester
analogues.
6
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