Highly Enantioselective Formation of α-Allyl-α-Arylcyclopentanones via Pd-Catalysed Decarboxylative Asymmetric Allylic Alkylation

Article abstract of DOI:10.1002/chem.201602250

A highly enantioselective Pd-catalysed decarboxylative asymmetric allylic alkylation of cyclopentanone derived α-aryl-β-keto esters employing the (R,R)-ANDEN-phenyl Trost ligand has been developed. The product (S)-α-allyl-α-arylcyclopentanones were obtained in excellent yields and enantioselectivities (up to >99.9 % ee). This represents one of the most highly enantioselective formations of an all-carbon quaternary stereogenic center reported to date. This reaction was demonstrated on a 4.0 mmol scale without any deterioration of enantioselectivity and was exploited as the key enantioselective transformation in an asymmetric formal synthesis of the natural product (+)-tanikolide.

Full text of DOI:10.1002/chem.201602250

DOI: 10.1002/chem.201602250
Communication
&
Asymmetric Catalysis
Highly Enantioselective Formation of a-Allyl-a-
Arylcyclopentanones via Pd-Catalysed Decarboxylative
Asymmetric Allylic Alkylation
Ramulu Akula, Robert Doran, and Patrick J. Guiry*[a]
a considerable problem with the regioselective preparation of
these substrates. If poor selectivity is observed for the desired
enol ether formation this will be translated into a mixture of al-
lylated products. To circumvent this problem, Stoltz, inspired
by the earlier work of Tsuji and Saegusa, looked toward b-keto
allyl esters as possible substrates.
Abstract: A highly enantioselective Pd-catalysed decar-
boxylative asymmetric allylic alkylation of cyclopentanone
derived a-aryl-b-keto esters employing the (R,R)-ANDEN-
phenyl Trost ligand has been developed. The product (S)-
a-allyl-a-arylcyclopentanones were obtained in excellent
yields and enantioselectivities (up to >99.9% ee). This
represents one of the most highly enantioselective forma-
tions of an all-carbon quaternary stereogenic center re-
ported to date. This reaction was demonstrated on
a 4.0 mmol scale without any deterioration of enantiose-
lectivity and was exploited as the key enantioselective
transformation in an asymmetric formal synthesis of the
natural product (+)-tanikolide.
Not only is the in situ enolate generation regiospecific but
the substrates are relatively simple to prepare and quaternary
b-keto esters are bench-stable compounds. These substrates
were successfully applied in the DAAA reaction in excellent
yields and enantioselectivities.[9]
The substrate scope of the DAAA has been expanded great-
ly since it was first reported and has been used as a key step
in the total synthesis of a number of complex natural pro-
ducts.[8b] Typically, the reaction is carried out on cyclic sub-
strates, with and without a fused aromatic ring, for the synthe-
sis of all-carbon quaternary centers. Variation of the allyl frag-
ment can be achieved with a wide variety of substituents toler-
ated whilst still giving high levels of enantioselectivity. The
final a-substituent of the quaternary center is, in the majority
of cases, a methyl or substituted methyl group. To date, the
variation of this substituent has been limited and we wished
to expand this to a variety of aryl groups, which would gener-
ate quaternary a-aryl ketones in an enantioenriched manner.
The application of the DAAA to the synthesis of quaternary
a-aryl ketones has been surprisingly limited. The potential rea-
sons for this are twofold; firstly, the difficulty in the preparation
of a-aryl-b-keto esters or their enol carbonate equivalents and,
secondly, the increased steric bulk of the aryl group, which can
have a detrimental effect on reactivity and enantioselectivity.
Previously, Taylor reported the DAAA of oxindoles in which
phenyl, ortho- and para-methoxyphenyl and ortho-nitrophenyl
examples were reported with ee values ranging from 78–
95%.[10] Stoltz has shown an a-phenyl-a-allyl cyclohexanone
example, albeit in 50% ee, from allyl enol carbonates using an
electron-deficient phosphinooxazoline (PHOX) ligand [Eq. (1),
Scheme 1].[11] Trost has had more success with a-phenyl as the
substituent using his P,P ligand ((R,R)-ANDEN-Trost) forming a-
phenyl-a-allyl cyclohexanone in 90.5% ee [Eq. (2), Scheme 1].[8h]
Cyclopentanones have also been shown to be challenging sub-
strates to obtain high ee in the DAAA until a very recent report
by Stoltz for the preparation of a-alkyl/benzyl cyclopentanones
in up to 94% ee [Eq. (3), Scheme 1].[12]
The catalytic asymmetric generation of quaternary carbon cen-
ters continues to be a significant challenge in synthetic organic
chemistry. In particular, the enantioselective formation of qua-
ternary centers bearing an aryl group next to a carbonyl has
seen particular interest in the past decade. Since the seminal
report by Buchwald in 1998,[1] a number of approaches have
been developed whereby the aryl group is introduced during
the enantiodetermining step, in most cases.[2]
The Pd-catalysed asymmetric decarboxylative allylic alkyla-
tion reaction (DAAA) has become a key transformation in the
toolkit of modern catalytic asymmetric reactions. In 1980, Tsuji
and Saegusa independently reported the first examples of de-
carboxylative allylation of b-keto allyl esters, using Pd catalysis,
to form allylated ketones.[3] Subsequently, Tsuji expanded the
precursors for this transformation to allyl enol carbonates,[4]
silyl enol ethers[5] and enol acetates.[6] Surprisingly, the first
enantioselective example was only reported as recently as
2004, by Stoltz, from allyl enol carbonates and silyl enol
ethers.[7] The contributions to this methodology by the groups
of Trost and Stoltz have pioneered the field.[8]
Although both the use of allyl enol carbonates and silyl enol
ethers have proved successful in the DAAA reaction, there is
[a] Dr. R. Akula, Dr. R. Doran, Prof. P. J. Guiry
Centre for Synthesis and Chemical Biology
School of Chemistry, University College Dublin
Belfield, Dublin 4 (Ireland)
We have previously developed the catalytic asymmetric syn-
thesis of a range of tertiary a-aryl ketones by a Pd-catalysed
decarboxylative asymmetric protonation.[13] In these reports we
E-mail: patrick.guiry@ucd.ie
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201602250.
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Table 1. Optimisation of decarboxylative asymmetric allylic alkylation
using 1a.
Entry[a]
Ligand
Solvent
Time [h]
Conv. [%][b]
ee [%][c]
Scheme 1. Transition-metal-catalysed enantioselective decarboxylative allylic
alkylation.
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
Toluene
2-Me-THF
MTBE
DME
10
10
10
10
24
24
24
24
24
24
5
100 (86)
100 (89)
100 (90)
100 (92)
57 (50)
48 (40)
65 (59)
50 (43)
70 (63)
76 (69)
100 (92)
60 (54)
58 (51)
100 (91)
100 (93)
25
31
86
>99.9
96
overcame the difficulty in the preparation of sterically hindered
a-aryl-b-keto esters by the use of aryllead triacetates, which
have been shown to be a privileged reagent in the arylation of
b-keto esters.[14] Here, we wish to report the catalytic asymmet-
ric synthesis of a-allyl-a-aryl ketones via the DAAA of the cor-
responding a-aryl-b-keto esters with very high levels of enan-
tioselectivity [Eq. (4), Scheme 1].
98
97
98.6
99.8
99.4
99.8
99.8
99.6
>99.9
99.8
9
THF
THF
10
11
12
13
14
15
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
24
24
10
10
We began by using cyclopentanone a-aryl-b-keto allyl ester
(1a) bearing a 2,4,6-trimethoxyphenyl group as a model sub-
strate to optimise DAAA reaction conditions (Table 1). Previous-
ly, a number of P,N and P,P ligands were successfully utilised in
DAAA reactions and are well documented in the literature.[8]
We also chose two PHOX ligands (S)-L1, (S)-L2 and two Trost li-
gands (R,R)-L3, (R,R)-L4 to examine the feasibility of the enan-
tioselective transformation. We began by screening each
ligand (12.5 mol%) with Pd2(dba)3·CHCl3 (5.0 mol%) in 1,4-diox-
ane (0.06m) as the solvent at 258C. All of the reactions went
to complete conversion and gave very good isolated yields
(86–92%, entries 1–4, Table 1). The level of enantioselectivity
obtained when using both of the PHOX ligands was low at 25
and 31% ee, respectively (entries 1 and 2, Table 1). The (R,R)-
DACH-phenyl Trost ligand L3 provided a much more encour-
aging result with a good level of enantioselectivity (86% ee,
entry 3, Table 1). To our delight, the use of (R,R)-ANDEN-Trost
ligand L4 gave effectively a single enantiomer of the allylated
product (>99.9% ee, entry 4, Table 1) in a 92% isolated yield.
We then decided to test the tolerance of the reaction using
a variety of different solvents. In general, high levels of of
enantioselectivity were obtained (>96% ee) using toluene, 2-
Me-THF, methyl tert-butyl ether (MTBE) and THF (entries 5–7, 9
and 10, Table 1). However, the conversions obtained were sig-
nificantly lower compared to 1,4-dioxane. For example, toluene
[a] Entries 1–11 were carried out with Pd2(dba)3·CHCl3 (5.0 mol%), ligand
(12.5 mol%); entries 12 and 13 with Pd2(dba)3·CHCl3 (2.5 mol%), ligand
(6.25 mol%); entries 1–9 and 13–15 at 258C; entries 10–12 at 408C; en-
tries 1–13 at 0.06m concentration; entry 14 at 0.03m; entry 15 at 0.09m.
[b] Determined by 1H NMR spectroscopy of the crude reaction mixture.
Isolated yields in parentheses. [c] Determined by chiral supercritical fluid
chromatography (SFC).
and THF gave conversion of 57 and 70%, respectively with
THF giving rise to 99.8% ee (entries 5 and 9, Table 1). In the
case of THF, when the reaction temperature was increased to
408C the conversion improved slightly to 76%, maintaining
the very high level of enantioselectivity (entry 10, Table 1). We
also found that the reaction in 1,4-dioxane at 408C gave a com-
parable result to the reaction at 258C, albeit in a reduced reac-
tion time of 5 h (Entry 11, Table 1). Knowing this, we then in-
vestigated the effect of lowering the catalyst and ligand load-
ings. We found that reducing the Pd loading to 2.5 mol% and
the ligand to 6.25 mol% led to a significant reduction in con-
version to 60% at 408C, maintaining the high ee (entry 12,
Table 1). Lowering the temperature to 258C gave a similar
result (entry 13, Table 1).
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The effect of the reaction concentration was then examined.
Increasing the concentration to 0.09m led to a very slight re-
duction in ee (entry 15, Table 1); however, diluting the reaction
concentration to 0.03m had no effect on the ee and conver-
sion (entry 14, Table 1). Pre-complex formation prior to sub-
strate addition did not have any effect on the reaction.[15]
With the optimised reaction conditions in hand (Entry 4,
Table 1) we then explored the substrate scope through varia-
tion of the a-aryl group (Scheme 2). In general, all of the sub-
strates tested gave excellent yields (85–97%). With di-ortho
methoxy-substitued aryl groups (1b, 2b and 3b), excellent
levels of enantioselectivity (>99.9% ee) were achieved. Other
di-substituted aryl groups (4b, 5b and 6b) also gave excellent
enantioselectivity (>99.4% ee). Two similar mono-ortho-substi-
tuted aryl groups gave large differences in enantioselectivity.
The 2,4-dimethoxyphenyl example (7b) gave a high ee of
96.9%, whereas, to our surprise, the 2,3,4-trimethoxyphenyl ex-
ample (8b) gave a much reduced ee of 87.6%. Testing sub-
strates possessing other aryl groups lacking an ortho-substitu-
ent (9b–12b) led to a reduction in ee to 83–84%. It is clear
that di-ortho-substitution is necessary to obtain excellent levels
of enantioselectivity in this transformation.
We also investigated the electronic effects of the aryl sub-
stituent and found that electron-rich (9b and 10b), neutral
(12b) and electron-deficient (11 b) aryl groups had no effect
on the enantioselectivity. The reaction was also tolerant of
steric hindrance at the b-position as the gem-dimethyl-substi-
tuted compound (13b) was formed with excellent enantiose-
lectivity (99.3%). We also demonstrated that the reaction per-
formed equally well on a larger scale (4.0 mmol) using sub-
strate 1a.[15]
The absolute sense of stereoinduction was confirmed as (S)
by obtaining an X-ray crystal structure of product 1b.[16] Al-
though the traditional ‘wall and flap’ model can predict the
outcome of Pd-catalysed reactions with Trost-type ligands,
Lloyd-Jones, Norrby and co-workers conclusively showed that
this model does not reflect the true structure of the cationic
[allyl-Pd-DACH] complex.[17]
Their NMR and DFT studies indicated a structure in which
the allyl unit sits in a fairly open upper-hemisphere above Pd,
with the ligand structure (including all four phenyl groups)
well away from the allyl, and even further away from the in-
coming nucleophile for an outer-sphere mechanism.
Using the NÀH to guide the enolate carbon above the allyl
by hydrogen bonding leads to two possible approaches, path-
way A or B (Figure 1). In pathway A, the enolate is oriented
such that the aryl group is pointing away from the ligand
backbone allowing pro-S attack on the allyl group on Pd. In
pathway B, the aryl group experiences a large steric clash with
the ligand backbone, as the ANDEN framework provides a sub-
stantial steric bulk, so this approach is disfavoured. The [allyl-
Pd-ANDEN] complex can undergo a conformational inversion,
which locates the NÀH further away from the allyl group and
Scheme 2. Scope and enantioselectivity of a-allyl-a-arylcyclopentanone syn-
thesis.
Figure 1. Proposed pathways during enantiodeterming enolate addition.
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does not permit an enolate approach free from a steric clash
with the ligand backbone (not shown). Rotation of the sub-
strate aryl group becomes degenerate when it is 2,6-disubsti-
tuted, leading to very high ee values for such substrates.
ee). We demonstrated that this reaction was reproducible on
a 4.0 mmol scale without any deterioration of enantioselectivi-
ty. Finally, we illustrated the application of this asymmetric
methodology as the key enantioselective step in the asymmet-
ric formal synthesis of the natural product (+)-tanikolide. We
are currently exploiting the DAAA of a range of other a-aryl-
containing substrates and the reports of these investigations
will be the subject of future reports from these laboratories.
With a highly enantioselective synthesis of a-allyl- a-aryl cy-
clopentanones at hand, we carried out a concise asymmetric
formal synthesis of (+)-tanikolide from 1b (Scheme 3). Taniko-
lide is a brine shrimp toxin and antifungal marine natural prod-
uct isolated from blue green algae cyanobacterium Lyngbya
Acknowledgements
R.A. acknowledges post-doctoral funding from the Synthesis
and Solid State Pharmaceutical Centre (SSPC) under grant no.
12\RC\2275. R.D. is grateful for the award of an Irish Research
Council (IRC) EMBARK Initiative PhD Scholarship. We acknowl-
edge facilities provided by the Centre for Synthesis and Chemi-
cal Biology (CSCB), funded by the Higher Education Authority’s
PRTLI. We would like to thank Dr. Helge Mꢁller-Bunz for X-ray
crystal structure analysis and Dr. Yannick Ortin for help with
the NMR spectroscopic studies. We thank one of the manu-
script reviewers for key insights and suggestions on the model
to rationalise the asymmetric induction observed.
Keywords: allylic alkylation
·
asymmetric catalysis
·
decarboxylation · natural products · palladium
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ii) Pd/C, H2 (1 atm), EtOAc, RT, 18 h, quant. iii) LiAlH4 (1m in Et2O, 1.0 equiv),
Et2O, reflux, 3 h, 88%. iv) Ac2O (1.2 equiv), Et3N (1.2 equiv), DMAP (0.2 equiv),
CH2Cl2, RT, 92%. v) NaIO4 (15 equiv), RuCl3 (0.1 equiv), CCl4, MeCN and H2O
(1:1:1.5, VVÀ1), RT, 36 h. vi) LiAlH4 (1m in Et2O, 0.5 equiv), Et2O, reflux, 3 h vii)
NaOCl (13 wt%), AcOH, 108C, 30 min, 50% over three steps.
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of a-aryl-b-keto esters has been developed employing the
(R,R)-ANDEN-phenyl Trost ligand L4. Under these conditions,
substrates containing di-ortho-substituted aryl groups gave ex-
cellent enantioselectivities (>99.9% ee) of the (S)-a-allyl-a-aryl-
cyclopentanone products. Mono-ortho-substituted aryl groups
gave good to very high levels of enantioinduction (88 to 97%
ee). The absence of an ortho-substituent afforded the corre-
sponding products with good enantioselectivities (83 to 84%
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[16] CCDC 1457351 (1b) contains the supplementary crystallographic data
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ˇ
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[15] Complex formed at 408C for 30 min and cooled to 258C prior to sub-
strate addition.
Received: May 12, 2016
Published online on && &&, 0000
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COMMUNICATION
&
Asymmetric Catalysis
R. Akula, R. Doran, P. J. Guiry*
&& – &&
Highly Enantioselective Formation of
a-Allyl-a-Arylcyclopentanones via Pd-
Catalysed Decarboxylative
Grand Slam! All-Carbon 48 Centres: A
highly enantioselective Pd-catalysed de-
carboxylative asymmetric allylic alkyla-
tion of cyclopentanone derived a-aryl-b-
keto esters employing the (R,R)-ANDEN-
phenyl Trost ligand has been devel-
oped. The product (S)-a-allyl-a-arylcy-
clopentanones were obtained in excel-
lent yields and enantioselectivities (up
to >99.9% ee). This represents one of
the most highly enantioselective forma-
tions of an all-carbon quaternary stereo-
genic center reported to date.
Asymmetric Allylic Alkylation
&
&
Chem. Eur. J. 2016, 22, 1 – 6
www.chemeurj.org
6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!