Catalytic amide allylation of α-ketoesters: Extremely high enantioselective synthesis of ester functionalised α-methylene-γ-butyrolactones

Article abstract of DOI:10.1039/c4ob01508h

This communication reports a significant breakthrough on the novel catalytic amide allylation to the acyclic α-ketoester systems, achieving satisfactorily high yields and extremely high levels of the asymmetric induction to allow for highly enantioselective synthesis of ester functionalised α-methylene-γ-butyrolactones.

Full text of DOI:10.1039/c4ob01508h

Organic &
Biomolecular Chemistry
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Catalytic amide allylation of α-ketoesters:
extremely high enantioselective synthesis of ester
Cite this: Org. Biomol. Chem., 2014,
12, 7686
functionalised α-methylene-γ-butyrolactones†
Masaki Takahashi,a Yusuke Murata,b Masahiro Ishida,a Fumitoshi Yagishita,c
Masami Sakamoto,c Tetsuya Sengokua and Hidemi Yoda*a,b
Received 17th July 2014,
Accepted 12th August 2014
DOI: 10.1039/c4ob01508h
www.rsc.org/obc
This communication reports a significant breakthrough on the 1,2-dicarbonyl backbone structures may serve as prospective can-
novel catalytic amide allylation to the acyclic α-ketoester systems, didates for enantioselective catalysis of the amide allylations.
achieving satisfactorily high yields and extremely high levels of the Nevertheless, many previous reports have underscored the
asymmetric induction to allow for highly enantioselective synthesis inherent difficulty of obtaining notable success in the catalytic
of ester functionalised α-methylene-γ-butyrolactones.
asymmetric addition to the α-ketoester systems. The most suc-
cessful systems for this type of reaction have limited the
reagents to have only structurally simple substituents, as exem-
plified by unfunctionalised alkylating agents, yet a promising
way to achieve exceedingly high levels of enantioselectivity
remains firmly out of reach. Thus, the realization of the strat-
egy for enantioselective catalytic transformation of α-ketoesters
capable of overcoming these drawbacks continues to be a
highly challenging endeavour for synthetic organic chemists.7
In this communication, we disclose a significant breakthrough
on the catalytic amide allylation on the acyclic α-ketoester
systems represented by structure 1 (Scheme 1), achieving satis-
factorily high yields and extremely high levels of the asym-
metric induction to allow for enantioselective synthesis of
ester functionalised α-methylene-γ-butyrolactones.
The previous results on the amide allylation of isatins have
highlighted the potential use of N-(p-tolyl)-β-amido allyltributyl-
stannane 2a and a chiral catalyst, prepared from In(OTf)3
and (S,S)-phenyl-pybox ligand,8 in exerting the highest level of
enantiocontrol.4,5 Thus, the initial attempt was made to apply
these reaction conditions to methyl benzoylformate 1a. When
this substrate (c 0.5 mol L−1) was subjected to react with 2a
(1.2 equiv.) in anhydrous MeCN in the presence of the catalyst
(10 mol%) and MS3 Å (0.5 g mmol−1) at r.t., the amide allyla-
Carbonyl allylation with β-amido-functionalised allylstan-
nanes,1 which we call an “amide allylation”,2 has emerged as a
powerful method that can facilitate high-yielding synthesis of
amido-appended homoallylic alcohols with very high levels
of enantiocontrol under the influence of chiral indium
catalysts.3–5 The synthetic appeal of this method lies in ready
accessibility to enantiomerically enriched or pure forms of
pharmaceutically meaningful α-methylene-γ-butyrolactones6
via acid-promoted lactonisation of the allylated products. Our
research group has recently developed a fully mechanistic
understanding of the origin of the enantioselectivity for the
amide allylation of isatin substrates, and also succeeded in
demonstrating the broad utility of this approach to deliver a
variety of optically active spiro-fused 2-oxindole/α-methylene-
γ-butyrolactones.4,5 As part of our continuing program to
develop this catalytic system, we directed our efforts to extend
our investigations toward applying the methodology to acyclic
substrates, instead of the heterocyclic isatins. To address this
challenge, a rational design of practical reaction systems can
be derived from the lessons acquired from the earlier work
that ketoamide structural motifs of isatins play a key role in
enhancing the catalytic performance.5 In light of this knowl-
edge, it is suggested that α-ketoesters sharing the common
aDepartment of Applied Chemistry, Graduate School of Engineering, Shizuoka
University, 3-5-1 Johoku, Naka-ku, Hamamatsu 432-8561, Japan.
E-mail: tchyoda@ipc.shizuoka.ac.jp; Fax: +81 53 478 1150; Tel: +81 53 478 1150
bGraduate School of Science and Technology, Shizuoka University, 3-5-1 Johoku,
Naka-ku, Hamamatsu 432-8561, Japan
cDepartment of Applied Chemistry and Biotechnology, Graduate School of
Engineering, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
†Electronic supplementary information (ESI) available: Experimental details and
characterization data. CCDC 1003520. For ESI and crystallographic data in CIF
or other electronic format see DOI: 10.1039/c4ob01508h
Scheme 1 Synthetic route for α-methylene-γ-butyrolactones.
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Table 1 Scope of amide allylationa and lactonisationb
Yield of 3e [%]
Abs
Yield of 4e [%]
Entry
R, R′ (1)c
R″ (2)c
td [h]
3c
(eef [%])
tg [h]
4c
config.h
(eef [%])
1
2
3
4
5
6
7
8
Ph, Me (1a)
Ph, Me (1a)
Ph, Me (1a)
Ph, Me (1a)
Ph, Me (1a)
Ph, Me (1a)
Ph, Me (1a)
Ph, Me (1a)
Ph, Bn (1b)
Ph, iPr (1c)
Me, Me (1d)
p-tolyl (2a)
Ph (2b)
p-anis (2c)
p-tBuPh (2d)
1-naph (2e)
nC5H11 (2f)
tBu (2g)
p-ClPh (2h)
p-anis (2c)
p-anis (2c)
p-anis (2c)
18
24
15
16
24
15
18
24
13
13
66i
3a
3b
3c
3d
3e
3f
3g
3h
3i
99 (99)
99 (98)
99 (99)
98 (98)
99 (93)
98 (96)
98 (96)
98 (97)
97 (98)
96 (97)
72 (99)
9
12
11
8
10
26
49
11
11
11
11
4a
4a
4a
4a
4a
4a
4a
4a
4b
4c
4d
S
S
S
S
S
S
S
S
S
S
R
84 (98)
85 (97)
98 (99)
97 (96)
82 (93)
77 (96)
68 (94)
97 (95)
99 (98)
97 (97)
86 (99)
9
10
11
3j
3k
a The amide allylations of 1 were carried out with 2 (1.2 equiv.) in anhydrous MeCN in the presence of the chiral catalyst (10 mol%) and MS3 Å
(0.5 g mmol−1) at r.t. under an argon atmosphere. b The lactonisations of 3 were carried out with PTSA (1.1 equiv.) in DCE at 50 °C (60 and 80 °C
for 3f and 3g, respectively). c Structures of 1–4, which indicate R, R′ and R′′ substituents, can be found in Scheme 1. d Reaction times required for
amide allylation under the standard conditions until complete consumption of starting materials (incomplete consumption of the starting
material was observed in the case of entry 11). e Isolated product yields. f The ee values were determined by HPLC analysis with Daicel Chiralpaks
IA (for 3d), IC (for 3e, 3f, 3i and 3j), IE (for 4a–d) and IF (for 3a–c, 3g, 3h and 3k). g Reaction times required for lactonisation under the standard
conditions until complete consumption of starting materials. h Absolute configurations of both the lactones 4 and their homoallylic precursors 3.
i High catalyst loading (20 mol%) was employed.
tion proceeded quantitatively to afford the allylated product 3a
over a time period of 18 h. To our delight, HPLC analysis on a
chiral stationary phase column (Daicel Chiralpak IF) showed
that this product was obtained with an excellent ee value of
99% (Table 1, entry 1). The results obtained here suggest that
a mechanistic scenario similar to the previously proposed one
may apply to the series of α-ketoester systems.5 We next investi-
gated the reaction scope of 1a with regard to variation of the
substituents on the stannylated reagents. Indeed, a number of
reagents containing diverse amide groups 2b–h reacted in
the same way, regardless of whether the aromatic or alkyl
groups were incorporated, to lead similarly to excellent yields
Fig. 1 ORTEP diagram for the absolute configuration of (S)-3h with
50% thermal ellipsoid probability.
(98–99%) and enantioselectivities (93–99% ee) of the corres-
ponding homoallylic alcohols 3b–h, respectively, thus showing
the potential generality of the reaction (Table 1, entries 2–8).
From these results, we found that the N-(p-anis) analogue 2c
gave the highest yield and enantioselectivity (99%, 99% ee) for methodology will have far more general applicability of the
a slightly shorter reaction period (15 h) and would be a more α-ketoesters, tolerating a variety of structural modifications
preferable reagent than 2a (Table 1, entry 3). Encouraged by without a loss of high catalytic performance.
the preceding results, we then investigated further applicability
Next, our focus turned to stereochemical assignment for
of the catalytic amide allylation to the other α-ketoesters predominant isomers of the obtained products. In order to
to encompass a broader substrate scope. To this end, three probe this issue, single crystal X-ray diffraction analysis was
additional entries of the substrates 1b–d were tested as undertaken on the chloro-functionalised homoallylic alcohol
α-ketoester alternatives. Upon subjection of 1b and 1c to the 3h, which was expected to have larger anomalous dispersion
amide allylation conditions involving the use of 2c, clean and effects due to the presence of the heavy atom element.10 This
smooth reactions again took place to afford the expected pro- analytical technique allowed unequivocal determination of its
ducts 3i and 3j in very high yields (97 and 96%) with excellent absolute stereochemistry on the basis of the satisfactory Flack
levels of enantioselectivity (98 and 97% ee), respectively parameter value, revealing S configuration at the newly formed
(Table 1, entries 9 and 10). On the other hand, methyl pyruvate stereogenic centre (Fig. 1).11 With this information in hand,
1d reacted sluggishly under the standard conditions,9 but per- the absolute configurations of 3a–h could be established by
forming the same reaction with a catalyst loading of 20 mol% converting them into structurally uniform α-methylene-γ-butyro-
yielded the product 3k in a considerably improved yield with lactones and by correlating their chiral HPLC profiles with
the maximum ee value of 99%. Considering the fact that this that for the authentic standard prepared by the same method
substrate, the smallest member of the series, shows the excel- from (S)-3h. For this conversion, an approach with p-toluene-
lent asymmetric induction, it is intuitive to expect that this sulfonic acid (PTSA) proved effective on heating in 1,2-dichloro-
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In conclusion, we have developed the first catalytic enantio-
selective amide allylation of acyclic α-ketoesters, which
achieved excellent reaction performance while exemplifying
the wide substrate and reagent generality to provide ready
access to a variety of the ester functionalised enantiopure
α-methylene-γ-butyrolactones. Future studies will explore the
full synthetic potential of these reaction systems and drive
expansion of the amide allylation method to be of more
general utility.
Scheme 2 Transformations for absolute configuration determinations.
Acknowledgements
This work was supported in part by a Grant-in-Aid for Scienti-
fic Research from the Ministry of Education, Culture, Sports,
Science and Technology, Japan.
ethane (DCE) at 50 °C,4,5 and could be used to furnish the
common lactones, denoted as 4a, without noticeable degra-
dation of the stereochemical qualities for all cases (Table 1,
entries 1–8). The comparative analysis of the HPLC results
showed remarkable consistency of the stereochemical prefer-
ences, providing clear evidence that all the homoallylic precur-
sors analysed here include the S absolute configurations
resulting mechanistically from Re-face additions of 2 onto the
prochiral carbonyl centres of 1.5
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11 Crystal data for 3h (recrystallized from chloroform–hexane
solution): orthorhombic, space group P212121 (no. 19), a =
6.6270(3) Å, b = 7.9739(3) Å, c = 32.9949(14) Å, α = β = γ =
90°, V = 1743.55(13) Å3, Z = 4, ρ = 1.371 Mg m−3, μ(CuKα) =
methyl levulinate, representing β- and γ-ketoesters, respecti-
vely, failed to undergo the amide allylation under the stan-
dard reaction conditions, resulting in complete recovery of
the starting materials. This fact strongly suggests that the
α-dicarbonyl functionalities of the substrates meet the
necessary structural requirements for the effective catalysis
of the enantioselective amide allylation.
This journal is © The Royal Society of Chemistry 2014
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