Asymmetric Retro-Claisen Reaction by Chiral Primary Amine Catalysis

Article abstract of DOI:10.1021/jacs.6b00627

The communication describes an enamine-based asymmetric retro-Claisen reaction of β-diketones by primary amine catalysis. The reaction proceeds via a sequence of stereoselective C-C formation, C-C cleavage, and a highly stereospecific enamine protonation to afford chiral α-alkylated ketones or macrolides with high yields and enantioselectivities. A detailed mechanism was explored on the basis of experimental evidence and computational studies to account for the observed stereocontrol.

Full text of DOI:10.1021/jacs.6b00627

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Communication
Asymmetric Retro-Claisen Reaction by Chiral Primary Amine Catalysis
Yunbo Zhu, Long Zhang, and Sanzhong Luo
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b00627 • Publication Date (Web): 18 Mar 2016
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Asymmetric Retro-Claisen Reaction by Chiral Primary Amine
Catalysis
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Yunbo Zhu, Long Zhang, Sanzhong Luo*
Beijing National Laboratory for Molecule Sciences (BNLMS), CAS Key Laboratory for Molecular Recognition and
Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
Collaborative Innovation Center of Chemical Science and Engineering, Tianjin 300071, China
Supporting Information Placeholder
literature to date. β-Diketones are versatile synthons widely
ABSTRACT: The communication describes an enamine-
based asymmetric retro-Claisen reaction of β-diketones by
primary amine catalysis. The reaction proceeds via
sequence of stereoselective C-C formation, C-C cleavage and
a highly stereospecific enamine protonation to afford chiral
α-alkylated ketones or macrolides with high yields and
enantioselectivities. A detailed mechanism was explored on
the basis of experimental evidence and computational
studies to account for the observed stereocontrol.
employed in synthetic chemistry. 4 In our pursuit of asym-
metric catalysis with 1,3-diketones, we have investigated the
reaction with in-situ generated ortho-quinone methide by
chiral primary amine catalysis.5 Unexpectedly, the reaction
delivered a deacylated product with good regioselectivity and
a
Scheme 1. Catalytic Asymmetric Retro-Claisen Reac-
tion
Mimicking the enzyme-catalyzed biochemical transfor-
mations is an attractive and powerful strategy in synthetic
methodology development.1 The enzyme-catalyzed retro-
Claisen reaction，distributing widely in human metabolism,
biodegradation and other biocatalysis, provides a prototype
for strategic C-C bond cleavage in organic synthesis.2
number of these C-C bond hydrolases, such as or β-
A
α
diketone hydrolase, MCP hydrolase and Friedel-Crafts hydro-
lase, have been discovered, which catalytically cleave C-C
bonds of diketones via varied mechanisms. Recently, stere-
oselective retro-Claisen type enzymes with synthetic poten-
tial have also been identified. 6-Oxo camphor hydrolase
(OCH) from Rhodococcus as well as its orthologue Anabaena
β-diketone hydrolase (ABDH) from the cyanobacterium An-
abaena has been found to catalyze an enantioselective trans-
formation of 6-oxocamphor along with the formation of an
interesting chiral cyclopentanone (Scheme 1, I).3 Base acti-
vated water molecule as well as a well-defined enolate oxyan-
ion hole are the key factors contributing in the effective and
stereoselective catalysis in these enzymes. Given the funda-
mental importance of this process in organic synthesis, an
asymmetrically chemical mimic for such a retro-Claisen reac-
tion remains surprisingly unknown.
moderate enantioselectivity (Scheme 1, II). Mechanistically,
this reaction features a unique sequential enamine-based C-
C bond formation and cleavage, formulating an unprece-
dented stereoselective retro-Claisen process based on the
electrophilic nature of o-QM in C-C formation6 as well as the
nucleophilic ability of the resulted phenoxide anion to ini-
tialize C-C cleavage (Scheme 1, II). The observed decent re-
gio- and stereocontrol promoted us to further develop this
reaction. The difficulties for such an enamine-based process
are multifold: 1) both enzymatic and chemical retro-Claisen
processes are enol/enolated-based, enamine-based retro-
Claisen reaction is unknown; 2) as a prerequisite, the driving
force of regioseleclive C-C cleavage and chiral control re-
quired a successful enamine/o-QMs coupling avoiding the
Retro-Claisen reaction is distinguished by the C-C bond
cleavage of β-carbonyl to generate an ester and an enolate-
carbanion, serving as a versatile precursor in late-stage syn-
thesis.4 Unfortunately, the current methods are limited in
their applications owing to the use of strong Lewis acid or
dependence on stoichiometric strong base. Consequently,
the stereocontrol in these processes is extremely challenging.
As far as we are aware, asymmetric retro-Claisen reactions
with C-C bond activation have not been described in the
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background reaction of stabilized enolic form of β-diketones
carboxylic acids were found to favor enantioselective control
and side reaction of the fleeting o-QMs;7 3) moreover, ma-
nipulating a proton to enamine intermediate is also a chal-
lenge differing from protonation of enol in enzyme-catalyzed
process (Scheme 1, II).8 In this context, we demonstrated the
first example of an asymmetric retro-Claisen reaction via C-C
bond activation by primary amine catalysis and Lewis base
(Table 1, entries 5, 6 and 11), and monoacids, with varied acid-
ity and loadings, led to poor enantioselectivity (Table 1, en-
tries 7-10). Both adipic acid and m-phthalic acid were identi-
fied as the optimal additive (entry 11). In the latter case, even
the geometry of the diacids has a significant influence on
reactivity and stereoselectivity (entries 11-13) and the mono-
protected m-phthalic acid was also ineffective (entry 10),
highlighting the critical diacid effect. Further optimization
also revealed noted solvent effect (Table 1, entries 14-16). No
reaction occurred when using dichloromethane as reaction
media (entry 15), and the reaction worked more effectively in
the dilute solution of acetonitrile with higher enantioselec-
tivity (entry 16).
1
2
3
4
5
6
7
8
activation, providing access to chiral
α-tertiary alkylated
ketones that are difficult to reach using other methods.
Table 1. Screening and Optimizationa
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With the optimized conditions in hand, we then examined
the scope of the reaction. Asymmetric β-ketoacetones
worked well to give the expected reto-Claisen products in
good yields and excellent enantioselectivities (Table 2, en-
tries 2-4). The C-C cleavage occurred exclusively on the more
bulky keto moiety and no other regioisomer was observed,
highlighting the capability of primary amine to differentiat-
ing the two keto groups and selectively forming enamine on
the smaller aceto side (Scheme 1, II). Acetoacetones bearing
entry variation from standard condi- yield
ee (%)c
tions
(%)b
1
none
83
93
95
92
2
1b
76
81
3
1c
different α-substituents such as ethyl (4e), allyl (4f), propar-
gyl (4g), benzyl (4h) and carboxylate-containing alkyl (4i)
could also be incorporated to give desymmetric alkylation
products in 40-84% yields and 92-97% ee (Table 2, entries 5-
4
no aminocatalyst
succinic acid
malonic acid
n-valeric acid
n-valeric acid (1.0 eq.)
1b + no acid
no
64
63
55
5
91
6
90
40
49
4
9).
not a workable substrate in this reaction (not shown). The
reaction also worked equally well with -heteroatom substi-
tuted acetoacetones such as -methoxyl (4j)- or acetoxyl
α-Phenylacetoacetone, dominantly in its enol form, was
7
α
8
59
27
α
9
(4k)- acetoacetones (Table 2, entries 10 and 11) and quantita-
tive conversion to the expected adduct could be achieved in
the case of 4k with 98% yield and 94% ee (entry 11). α-
Fluoroacetoactone also worked, albeit with low enantioselec-
tivity (60% ee, entry 12). A large ethyl ketone has also been
examined, giving 96% ee, but low yield (30% yield, entry 13).
10
11
12
13
14
15
16
1b + m-MeO2CPhCO2H (1.0 eq.) 64
63
95
85
79
80
1b + m-phthalic acid
1b + p-phthalic acid
1b+ o-phthalic acid
THF
86
80
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30
β-Diketones are mainly to exist as enols, particularly with
cyclic diketones. The dominant enol forms might pose prob-
lems in exploring the enamine-catalysis with cyclic β-
diketones. Indeed, when we examined the reactions with 2-
acetylcyclopentanone or 2-acetylcyclohexanone, only race-
mic product (Table 2, entry 26) or complicated mixture (for
cyclohexanone, not shown) was obtained. In contrast, 2-
acetylcycloheptanone worked smoothly to afford retro-
Claisen type products (Table 2, entry 14). In this case, both
keto moieties were amenable to the enamine activation (veri-
fied by NMR, SI) and hence two C-C cleavage adducts, 4n
and 4n’, corresponding to the deactylation pathway and ring-
enlarged pathway, were isolated with 95% ee and 98% ee,
respectively. Notably, the latter adduct 4n’ is an 11-membered
lactone that was notoriously challenging to synthesize. A
benzocycloheptanone was also employed in the reaction to
afford interestingly a single deacetyled adduct macrolide 4o
in 85 yield and 96% ee (Table 2, entry 15). Cyclooctanone has
also been examined, showing lower activity. In this case, the
use of chiral primary amine 1b led to a sole product of mac-
rolide 4p in 24% yield and 98% ee (Table 2, entry 16). The
scope of o-QM precursors with both electron-withdrawing
and electron-donating groups were tolerated to furnish the
target retro- Claisen products in moderate to good yields
CH2Cl2
trace
86
CH3CN (0.7 mL)
95
aReactions were performed at room temperature in 0.3 mL
CH3CN, with 2a (0.1 mmol), 3a (0.11 mmol), 1a (20 mol %), KF
(0.11 mmol) and adipic acid (50 mol %), 40 h. bYield of isolat-
ed product. cDetermined by HPLC analysis.
We explored this asymmetric retro-Claisen process using 3-
methy-2,4-pentanedione 2a and the o-QM precursor 3a as
the coupling partners by our developed chiral primary amine
catalyst 1. Delightfully, the desired C-C bond cleavage prod-
uct 4a was acquired in 83% yield and 93% ee under the opti-
mized conditions with primary amine 1a (Table 1, entry 1).
Other diamine catalysts 1 derived from different amino acids
all performed equally well with comparable yields and enan-
tioselectivities for the retro-Claisen reaction (Table 1, entries
2 and 3). No desired reaction was observed in the absence of
aminocatalyst, highlighting the aminocatalytic nature (Table
1, entry 4).9 KF was identified as the optimal Lewis base and
other fluoride additives such as NaF, LiF and KHF2 led to
lower yield. The use of acidic additive was essential for effec-
tive stereocontrol, to note that the reaction in absence of
weak acid was virtually non-selective (Table 1, entry 9). Di-
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Table 2. Scope of
β
-Diketones and o-QMs of Retro-Claisen Reactions via C-C Bond Cleavagea
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2
3
4
5
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9
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aAll reactions were performed at room temperature in 0.7 mL CH3CN, with 2 (0.1 mmol), 3 (0.11 mmol), 1a (20 mol %), KF (0.11
mmol) and adipic acid (50 mol %), 40 h. Yield of isolated product. Determined by HPLC analysis. bReactions performed with 1b
(20 mol %), 3 (0.15 mmol) and KF (0.15 mmol). cWith 3 (0.15 mmol) and KF (0.15 mmol).
tions of this catalytic multi-step process using Gaussian 09
and high enantioselectivities (entries 17-25).
(Scheme 2 and see SI for the full scheme). 10 It was found that
the irreversible nucleophilic addition of the enamine inter-
A number of experimental and theoretical studies were car-
mediate to the in-situ formed o-QM was quite facile, leading
to a much stable ketal intermediate (int3). Next, the
enamine-based reversible retro-Claisen step occurred with
16.3 kcal/mol of activation energy (TS3). Unlike the classic
retro-Claisen process, the tertiary amine embedded in the
catalyst could facilitate the proton transfer of ketal O-H,
ried out to understand the mechanistic details. The reaction
mixture was in-situ examined by ESI-MS and key aminocata-
lytic intermediates (e.g. enamine and catalyst-product ad-
duct, a and e in Scheme 1) could be identified. In addition,
alkylation of aminocatalyst with ortho-quinone methide and
other side products were also clearly noted in the absence of
which made the C-C bond cleavage much more facile. It
weak acid additive (See SI), suggesting one role of the weak
should be noted that the reversible retro-Claisen step also
proceeded in a highly stereospecific manner and only E-
enamine was formed (int5). Our subsequent exploration on
acid additive is to suppress side reactions leading to catalyst
poison or background reactions.
Scheme 2. The Reaction Energy Profile
the stereogenic enamine protonation revealed a highly stere-
ospecific shuttled proton transfer leading to only S-product,
irrespective of the involving additive (Scheme 2, TS 5-7). Sim-
ilar proton shuttle was previously verified in a conjugate ad-
dition-enamine protonation reaction.8h After careful exami-
nation, we found that a competing reaction pathway was
existed for the stable ketal intermediate, where direct hy-
drolysis of the iminium moiety could occur with activation
energy of 22.1 kcal/mol (TS4). The so-formed β-ketone-ketals
would then undergo enol type retro-Claisen/protonation
process, resulting in racemic product. Our calculation re-
vealed that the presence of weak acid additive would favor
the enamine-protonation pathway over that of the iminium-
hydrolysis pathway (Table 1, entries 9-13; Scheme 2, TS4 vs
TS 5-7), thus facilitating high stereoinduction.
To further look into the acid effect, we separately prepared
and characterized the enamine intermediate 7 using our pre-
vious procedure (SI).5b When 7/TfOH was employed in react-
ing with ortho-quinone precursor 3a under otherwise identi-
cal acidic conditions, the coupling proceeded quickly to
To determine the origin of stereo-induction as well as the
dicarboxylic acid effect, we performed detailed DFT calcula-
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completion in less than 3 hrs and there seemed no obvious
Experimental details, characterization of new compounds
1
2
3
4
5
6
7
8
diacid effect at this stage. The resulted mixture was then
treated with either water or sat. NH4Cl aqueous solution, and
in both case, notable stereoeffect was observed with the di-
carboxylic acid showing significantly better enantioselectivity
than mono acid and only 9% ee in the absence of weak acid,
consistent with those observed under catalytic conditions
(Scheme 3, eq. 1).11 In addition, no enantio-enrichment or
deracemization was observed when rac-4a or (S)-4a was sub-
jected to the catalytic conditions (Scheme 3, eq. 2). Taken
together, these results verified that enamine-protonation was
the stereogenerating step in the reaction sequence and that
weak acid was directly involved in this key step. The plausi-
ble mode of weak acid participation is a proton shuttle as
illustrated in TS 5-7 (Scheme 2).8h Besides providing a favor-
able acid/base buffer media to suppress side reactions, the
stereocontrol effect of dicarboxylic acid might also be under-
stood by considering the known recognition effect between
diamine and diacid.12 The observed geometry effect of diacid
is in line with this notion (Table 1, entries 11-13).
and computational studies. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
Luosz@iccas.ac.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The project was supported by Ministry of Science and Tech-
nology (2012CB821600), the Natural Science Foundation of
China (NSFC 21390400, 21572232 and 21521002), and the Chi-
nese Academy of Sciences.
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(7) For selected reviews on o-QMs, see: (a) Singh, M. S.; Nagaraju, A.;
Anand, N.; Chowdhury, S. RSC Adv. 2014, 4, 55924. (b) Bai, W.-J.;
David, J. G.; Feng, Z.-G.; Weaver, M. G.; Wu, K.-L.; Pettus, T. R. R.
Acc. Chem. Res. 2014, 47, 3655. (c) Pathak, T. P.; Sigman, M. S. J. Org.
To further demonstrate the utility of this new asymmetric
retro-Claisen reaction of β-diketones, 4a was subjected to a
Baeyer-Villiger oxidation reaction followed by hydrolysis
using KOH to generate diol 5.13 Then intramolecular
Mitsunobu reaction gave the dihydrobenzofuran 6 (Scheme
4), a class of heterocycles presented in many natural prod-
ucts and biologically active compounds.14
Scheme 4. Synthetic Transformations
Chem. 2011, 76, 9210. (d) Willis, N. J.; Bray, C. D. Chem.―Eur. J. 2012,
18, 9160.
OH
O
OAc
PPh3, DIAD
HO
1) m-CPBA, DCM
(8) For reviews, see: (a) Oudeyer, S.; Brière, J.-F.; Levacher, V. Eur. J.
Org. Chem. 2014, 2014, 6103. For selected examples, see: (b) Mohr, J.
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6178. (g) Guin, J.; Varseev, G.; List, B. J. Am. Chem. Soc. 2013, 135, 2100.
THF, 0 oC–rt
O
2) KOH, MeOH
5 92% yield
6 60%, 94% ee
4a 95% ee
In summary, we have developed an enamine strategy for
asymmetric retro-Claisen C-C bond cleavage of β-diketones
by merging chiral primary amine catalysis and Lewis base
activation. The salient features include the highly stereose-
lective C-C coupling between enamine and ortho-quinone
methide, as well as the enamine-mediated C-C cleavage and
the highly stereospecific enamine protonation. This retro-
Claisen protocol provides accesses to chiral α-tertiary ke-
tones and chiral macrolides that are difficult to synthesize
otherwise. Further development of enamine-based Claisen
reactions is underway in our laboratory.
(h) Fu, N.; Zhang, L.; Luo, S.; Cheng, J.-P. Chem.―Eur. J. 2013, 19,
15669. (i) Wang, M. H.; Cohen, D. T.; Schwamb, C. B.; Mishra, R. K.;
Scheidt, K. A. J. Am. Chem. Soc. 2015, 137, 5891.
(9) Most acetoacetone (>75%) was recovered.
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Wallingford, CT, 2009. (See SI for full citations).
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iminium hydrolysis under stoichiometric conditions. Efforts to char-
acterize the in-situ generated intermediates (e.g. int3, int5, Scheme
2) have been in vain due to the heterogeneous nature of the reaction.
(12) Periasamy, M.; Sivakumar, S.; Reddy, M. N.; Padmaja, M. Org.
Lett. 2004, 6, 265.
ASSOCIATED CONTENT
Supporting Information
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(13) Zhang, L.; Zhang, W.; Liu, J.; Hu, J. J. Org. Chem. 2009, 74, 2850.
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Graphic abstract
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H
R
N
OTf
NH2
O
O
O
OCOR3
G
Br
(20 mol%)
G
+
R1
R3
R1
OTBS
R2
KF/adipic acid, rt
R2
H
9
up to 99%, 98% ee
regioselective C-C bond formation/cleavage
stereoselective protonation
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asymmetric -alkylation of ketones
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