Asymmetric Assembly of All-Carbon Tertiary/Quaternary Nonadjacent Stereocenters through Organocatalytic Conjugate Addition of α-Cyanoacetates to a Methacrylate Equivalent

Article abstract of DOI:10.1002/chem.201603082

An efficient, highly diastereo- and enantioselective assembly of acyclic carbonyl fragments possessing nonadjacent all-carbon tertiary/quaternary stereoarrays is reported based on a Br?nsted base catalyzed Michael addition/α-protonation sequence involving α-cyanoacetates and 2,4-dimethyl-4-hydroxypenten-3-one as novel methacrylate equivalent.

Full text of DOI:10.1002/chem.201603082

DOI: 10.1002/chem.201603082
Full Paper
&
Asymmetric Organocatalysis
Asymmetric Assembly of All-Carbon Tertiary/Quaternary
Nonadjacent Stereocenters through Organocatalytic Conjugate
Addition of a-Cyanoacetates to a Methacrylate Equivalent
Igor Iriarte,[a] Silvia Vera,[a] Eider Badiola,[a] Antonia Mielgo,[a] Mikel Oiarbide,*[a]
Jesffls M. García,[b] JosØ M. Odriozola,[b] and Claudio Palomo*[a]
Abstract: An efficient, highly diastereo- and enantioselective
assembly of acyclic carbonyl fragments possessing nonadja-
cent all-carbon tertiary/quaternary stereoarrays is reported
based on a Brønsted base catalyzed Michael addition/a-pro-
tonation sequence involving a-cyanoacetates and 2,4-di-
methyl-4-hydroxypenten-3-one as novel methacrylate equiv-
alent.
Introduction
a Ca(BOX)2-catalyzed (BOX=bis(oxazolidine)) conjugate addi-
tion of glycine Schiff bases to a-substituted acrylate deriva-
tives, albeit no example involving generation of a quaternary
center was gathered. More recently Pihko has described[7]
enantioselective Mukaiyama–Michael addition reactions of
methacrolein through iminium activation; however, this reac-
tion led to an approximately 1:1 mixture of the two possible
diastereomers. To the best of our knowledge, highly enantiose-
Acyclic carbonyl compounds possessing multiple stereocenters
are important building blocks for the construction of complex
natural products and bioactive molecules. Huge advances have
been made in the stereoselective synthesis of these stereoar-
rays, particularly carbonyl compounds with contiguous stereo-
centers at a,b- or b,g-positions (A and B, Figure 1). In contrast,
direct asymmetric entries to the a,g-branched analogues C,
bearing two nonadjacent stereocenters, are less common,[1]
and rarely involve construction of a quaternary stereocenter as
in D.[2,3] Among the few precedents, Deng reported a Brønsted
base catalyzed Michael/a-protonation reaction cascade, which
implies a-chloroacrylonitrile as the Michael acceptor,[4] and
later on the group of Chen and Xiao described[5] a similar
tandem reaction involving ethyl 2-phthalimidoacrylate or ethyl
a-phosphonoacrylates as the doubly activated Michael accept-
or (Figure 2). However, the extension of this methodology to
inherently less reactive a-alkyl-substituted Michael acceptors,
that is, methacrylates, remains challenging, despite the fact
that the resulting a-alkyl- and more specifically a-methylcar-
bonyl units are present in a number of natural products and
bioactive targets. In that respect, Kobayashi has reported[6]
Figure 1. Acyclic carbonyl compounds with different stereoarrays.
[a] I. Iriarte, Dr. S. Vera, E. Badiola, Dr. A. Mielgo, Prof. M. Oiarbide,
Prof. C. Palomo
Departamento de Quꢀmica Orgꢁnica I
Universidad del Paꢀs Vasco UPV/EHU
Manuel Lardizabal 3, 20018 San Sebastiꢁn (Spain)
Fax: (+34)943015270
E-mail: claudio.palomo@ehu.es
[b] Prof. J. M. Garcꢀa, Dr. J. M. Odriozola
Departamento de Quꢀmica Aplicada
Universidad Pfflblica de Navarra
31006 Pamplona (Spain)
Supporting information and the ORCID identification number(s) for the au-
thor(s) of this article can be found under http://dx.doi.org/10.1002/
chem.201603082.
Figure 2. Advances in tandem addition/protonation approaches for the
asymmetric assembly of a,g-nonadjacent stereocenters.
Chem. Eur. J. 2016, 22, 1 – 8
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lective Michael reactions with methacrylates or equivalents to
provide carbonyl compounds with all-carbon tertiary/quaterna-
ry nonadjacent stereocenters have not been realized yet. Here
we present an effective asymmetric direct entry to such stereo-
arrays that is founded upon the development of a newly de-
signed methacrylate equivalent in combination with Brønsted
base catalysis.
after 90 h at 508C. Finally, methacrolein was more reactive, but
led to unselective reaction.[7]
Recently we have introduced a-unsubstituted a’-hydroxy
enones as efficient acrylate equivalents in Brønsted base cata-
lyzed enantioselective conjugate additions.[10] Both the remark-
able reaction acceleration and the high level of asymmetric in-
duction observed in these reactions were rationalized by as-
suming hydrogen-bond-mediated effective substrate–catalyst
complexation, with the ketol moiety of substrate forming tight
1,4-proton chelates. Now we hypothesize that by using the
parent a-substituted a’-hydroxy enones, the unique capacity
of these type of bidentate substrates[11] to act as both hydro-
gen-bond donor and acceptor, in cooperation with a proper
Brønsted base catalyst, may also be translated to the a-stereo-
center-determining step 2. If so, a shortcut to the challenging
construction of acyclic carbonyl adducts with nonadjacent ste-
reocenters would be provided. Specifically, it is predicted that
the evolved enolate from step 1 would preferentially adopt a Z
configuration because of unfavorable A1,3 strain in the chelated
E form (Figure 3b), thus overcoming the problem of ill-defined
enolate geometry in asymmetric a-protonations.[12,13] Eventual-
ly, the prevalence of such dynamic hydrogen-bond networks
may also help during proton transfer (shuttle). To achieve high
overall selectivity, however, both chiral units, namely the cata-
lyst and the newly generated stereocenter at g, have to work
in concert in step 2, an inherent difficult of the process that at
the outset remained unclear. In this respect, as far as we know,
a-substituted a’-hydroxy enones have never been employed in
catalytic asymmetric conjugate additions.[14]
Results and Discussion
Hypothesis and working plan
The challenge posed by a-alkyl-substituted Michael acceptors
is not only associated to their attenuated reactivity against
neutral C-pronucleophiles, but also concerns stereocontrol
during the key CÀC bond formation (step 1, Figure 3a) and the
subsequent a-protonation (step 2).[8]
Catalysts screening and reaction optimization
The investigation was started by studying the reaction of the
newly prepared a’-hydroxy enone 1[15] with a-substituted cya-
noacetate 2a in the presence of several bifunctional Brønsted
bases (Scheme 2).[16] Among the catalysts examined, that is, hy-
Figure 3. Construction of nonadjacent tertiary/quaternary stereocenters and
working hypothesis for designed methacrylate equivalent.
Preliminary studies involving the reaction of 2-phenyl a-cya-
noacetate 2a[9] and some elementary a-substituted Michael ac-
ceptors revealed these difficulties. For instance attempts to
react 2a with methyl methacrylate in the presence of several
mono- and bifunctional Brønsted base catalysts all led to re-
covery of unreacted material (Scheme 1). Under similar condi-
tions, 3-methylbutenone resulted essentially unreactive at am-
bient temperature; 60% conversion was hardly achieved only
droquinidine-2,5-diphenyl-4,6-pyrimidinediyl
diether
((DHQD)2PYR; C1), quinine (C2), the thiourea-aminoquinine
C3[17] and the squaramides C4,[18] C5,[19] and C6,[20] the last
proved to be superior as shown in Table 1. Using this catalyst,
the reaction between 2-phenyl a-cyanoacetate 2a and 1 at
ambient temperature afforded adduct 5a with essentially per-
fect enantio- and diastereocontrol (d.r.>99:1, 99% ee; entry 6).
This result indicates that not only the initial addition that ren-
ders the g-stereocenter, but also the subsequent a-protona-
tion, both proceeded with remarkable face selectivity. Interest-
ingly, this almost perfect chirality transfer was reproduced
(entry 7) when the reaction was run at 508C, which allowed at-
taining full reaction conversion at shorter time (24 h).
Under these conditions (10 mol% C6 in 1,2-DCE at 508C) the
reaction of 1 worked equally well with an array of 2-aryl a-cya-
noacetates 2 to afford the corresponding adducts 5 as essen-
tially single diastereomer in yields within the range from 62%
to 95% and ee values greater than 95% in most cases. As
Table 2 shows, these results seem to be independent upon the
meta/para substitution pattern of the aromatic ring or their
electron donating/withdrawing character. Entry 6 was an ex-
Scheme 1. Difficulties in the addition of a-cyanoester 2a to a-methyl a,b-
unsaturated ester, ketone or aldehyde under best reaction conditions.
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Table 2. Scope of the conjugate addition of a-cyanoacetates to 1.[a]
R1
Product
t
[h]
Yield
[%][b]
d.r.
ee
[%][c]
1
2
3
4
5b
5c
5d
5e
24
24
40
40
69
95
70
67
98:2
98
96
98:2
>98:2
98:2
>98
>98
5
6
7
5 f
40
40
16
83
>98:2
–
97
–
5g
5h
NR[d]
62
Scheme 2. Reaction of 1 with a-cyanoacetates catalyzed by chiral Brønsted
bases.
97:3
96
8
9
5i
20
24
24
72
76
88
96:4
97
92
91
Table 1. Catalyst screening for the reaction of 1 with 2a (R1 =Ph).[a]
6e
7b
90:10
88:12
Catalyst
t [h]
Conv [%]
Yield [%][b]
d.r.
ee [%][c]
1
2
3
4
C1
C2
C3
C4
C5
C6
C6
72
72
72
72
40
96
24
100
65
70
72
49
46
n.d.[e]
75
70:30
75:25
80:20
30
16
68
10
[a] Reactions conducted on a 0.2 mmol scale in 1,2-DCE (0.4 mL) at 508C
(molar ratio of 1/cyanoester/C6 1:1.5:0.1). [b] Yields of isolated product
after column chromatography. [c] Determined by chiral HPLC analysis.
[d] NR: no reaction.
23
n.d.
n.d.
À12
99
5
100
n.d.
100
75:25
>99:1
>99:1
6[d]
7
40
81
98
[a] Reactions conducted on a 0.2 mmol scale in 1,2-DCE (0.4 mL) at 508C
(molar ratio of 1/2a/catalyst 1:1.5:0.1). [b] Yields of isolated product after
column chromatography. [c] Determined by chiral HPLC analysis. [d] Reac-
tion carried out at room temperature. [e] n.d.: not determined.
the cases studied (entries 2, 3, 6, 9 and 10), with remarkable
diastereoselectivity (RSS/RRS/others up to 91:9:0). Catalyst C7
led to no reaction (entry 4), and C8 and C9 led to poor selec-
tivity (entries 5 and 7). It is worth noting that in the above re-
actions O-silylated enones 10/11 behaved in a more superior
fashion than hydroxy enones 8/9 as the results in entries 2/3
(d.r. of 67:32 and 89:11, respectively) and 8/9 (d.r. of 71:29 and
91:9, respectively) show.[25]
ception probably because of steric constraints imposed by the
ortho substituent. Using the less sterically demanding benzyl
and ethyl cyano esters 3 and 4, a slight loss of stereoselection
was produced (entries 9 and 10), albeit it was still acceptable.
The configuration of adduct 5e was established by a single-
crystal X-ray analysis[21] and that of the remaining adducts by
assuming a uniform reaction mechanism.
At this point it remained unclear whether the above sub-
strate/catalyst combinations correspond to a matched stereo-
chemical relationship. To answer that question, the reaction
between 2a and the (S)-configured ent-10 was carried out in
the presence of catalyst C6. As the data in Scheme 3 show,
a 69:12:12:7 mixture of diastereomers was obtained, with
(S,S,S)-16 as the major product. By comparison with data in
entry 3 of Table 3, it seems clear that the pair 10/C6, with the
configurations (R)-substrate/(S,S)-catalyst, corresponds to the
matched combination. Experiments using bifunctional Brønst-
ed base catalysts derived from other chiral 1,2-primary/tertiary
diamines also revealed (R)-substrate/(S,S)-catalyst as the best
combination to induce formation of adducts of RSS configura-
tion.[26]
Double asymmetric induction
Given the paucity of methods for the construction of tertiary/
quaternary nonadjacent stereocenters, this organocatalytic Mi-
chael/protonation cascade was next extended to chiral a’-oxy
enones 8/9 and 10/11,[22] a type of substrate that, as far as we
know, have neither been previously investigated within the
realm of organocatalysis.[23,24] As the results in Table 3 show,
the stereochemical outcome of the reactions varies notably de-
pending on the catalysts used. With Et3N as the only promoter
(entries 1 and 8), adducts 12 and 14 were produced with mod-
erate diastereoselectivity (ratio of RSS/other isomers 60:40 and
71:29, respectively). Again, the best catalyst was C6, which af-
forded only two out of the four possible diastereomers in all
Given these observations and the absence of studies con-
cerning double asymmetric induction in this field, we next ex-
amined briefly the reaction of chiral a’-hydroxy enones without
substituents at Ca position. Under optimized conditions it was
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almost perfect asymmetric induction with catalyst C6 for both
a-substituted and unsubstituted enones.
Table 3. Michael addition/protonation cascade involving chiral enones
(double asymmetric induction).[a]
Adduct elaboration and proposed reaction models
The results obtained are of special interest in that treatment of
adducts 5a and 5c with NaIO4 in MeOH/H2O provides the car-
boxylic acids 20 and 21 in 86% and 88% yield, respectively,
along with acetone as the only organic side product formed
(Scheme 5).
Enone
Cat
t [h]
Product
Yield [%]
RSS:RRS:others
1
2
3
4
5
6
7
8
9
8
8
Et3N
C6
C6
C7
C8
C6
C9
Et3N
C6
C6
24
24
60
24
64
72
72
24
72
72
12
12
12
12
12
13
13
14
14
15
75[b]
70[b]
73
60:23:17:0
67:32:0:0
89:11:0:0
–
49:41:10:0
83:17:0:0
22:21:57:0
71:29:0:0
91:9:0:0
90:10:0:0
10
10
10
10
10
9
NR[e]
70
75[c]
65[c,d]
83[b]
90[c]
80[c]
11
11
10
[a] Reactions conducted on a 0.2 mmol scale in 0.4 mL CH2Cl2 using
3 equiv a-cyanoester 2a–c. [b] Yield of isolated product (mixture of iso-
mers). [c] Yield of isolated product (mixture of isomers) after desilylation
with HF/MeOH. [d] Configuration of major isomer unknown. [e] NR: no re-
action.
Scheme 3. Reaction involving substrate/catalyst mismatchaed combination.
TMS: trimethylsilyl.
Scheme 5. Elaboration of adducts: a) conversion of ketol into carboxy and
aldehyde functions; b) stereoselective 1,2-diol formation.
found that reaction of 17 with either 2b or 2c produced the
corresponding adducts 18 and 19, respectively, essentially as
single diastereomers (Scheme 4). This result thus confirms that
generation of the quaternary stereocenter proceeds with
Acid 21 was transformed into its methyl ester 22 for compa-
rative purposes, vide infra. Alternatively, reduction of the car-
bonyl group of 5a followed by diol cleavage as above fur-
nished the aldehyde 23 in 76% yield over the two steps. Thus,
the lack of reactivity and selectivity associated with methacry-
late esters and methacrolein (vide supra) may now be remedi-
ated with this new methacrylate equivalent. Finally, to confirm
the stereochemical assignment of reactions involving double
asymmetric induction (Table 3), adduct 15 (90:10 diastereo-
meric mixture) was subjected to the oxidative cleavage condi-
tions to afford the same product 22 to that obtained from 5c,
along with the minor isomer 24. Similarly, 18 upon oxidative
cleavage of the ketol moiety as above and subsequent esterifi-
cation of the resulting carboxylic acid provided the methyl
Scheme 4. Generation of a quaternary g-stereocenter in chiral a-unsubstitut-
ed a’-hydroxy ketones. TES: triethylsilyl.
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ester 25. The absolute configuration of both 24 and 25 was es-
tablished by chemical correlation.[26] In addition to the above
transformations, stereoarrays bearing up to four stereogenic
centers may also be produced from this approach. Thus, diols
26 and 27 were obtained as essentially single anti-diol isomer
through reduction of the respective a’-hydroxy ketone 13 and
18 with Zn(BH4)2.[27]
carboxylic acids, aldehydes, and 1,2-diols with up to four con-
figurationally-defined stereocenters. We believe this new family
of enoate equivalents will rapidly find further applications in
organocatalysis.
Experimental Section
The high fidelity with which chirality is transferred from the
catalyst to the reaction products could be explained by the
stereomodels depicted in Figure 4. By analogy to previously
calculated TS geometries for the related conjugate addition of
cyanoesters to a-unsubstituted enone analog to 1,[10] ternary
complex A would account for the conjugate addition step,
which would proceed with the catalyst interacting with both
reaction components through several hydrogen bonds. Once
the addition adduct is formed, the local negative charge
would no longer be located in the cyano esther moiety, but in
the enolate site. This will weaken the hydrogen bond between
the protonated quinuclidine and the cyano esther carbonyl. Fi-
nally, proton transfer, either directly from the protonated cata-
lyst to the enolate or alternatively mediated by some proton–
shuttle mechanism, would preferentially occur through the
enolate Re face, as depicted in proposed model B.
Selected experimental procedures
All experimental details can be found in the Supporting Informa-
tion. The material includes compound characterization, stereo-
chemical determinations and copies of spectra of new compounds.
4-Hydroxy-2,4-dimethylpent-1-en-3-one (1): To a solution of com-
mercial methyl 2-hydroxy-2-methylpropanoate (15 mmol, 1.77 g)
and N,O-dimethylhydroxylamine hydrochloride (22.5 mmol, 2.14 g,
1.5 equiv) in THF (50 mL), a 2m solution of iPrMgCl in THF
(60 mmol, 4 equiv) was added at À208C. Once the reaction mixture
was stirred for 1.5 h at room temperature, it was quenched with
an aqueous saturated solution of NH4Cl (30 mL) and extracted with
CH2Cl2 (2”30 mL). The combined organic phases were dried over
MgSO4. After filtration the solvent was evaporated under reduced
pressure and the crude material was purified by flash column chro-
matography (eluent hexane/ethyl acetate 80:20) to obtain the de-
sired Weinreb amide product. Yield: 1.99 g (90%), colorless oil. To
a solution of this material (10 mmol, 1.85 g) in Et2O (20 mL) at
À208C, a solution of isopropenyl magnesium bromide (0.5m in
THF, 60 mL, 3 equiv) was added, and the resulting mixture was
stirred at 08C for 16 h. The reaction was quenched with an aque-
ous saturated solution of NH4Cl (50 mL) and extracted with Et2O
(2”50 mL). The combined organic phases were dried over MgSO4
and filtered, and the solvent was evaporated under reduced pres-
sure. The crude product was purified by flash column chromatog-
raphy (pentane/Et2O 95:5) to obtain compound 1. Yield: 833 mg
1
(65%), colorless oil; H and 13C NMR spectra were identical to those
reported in the literature.[28]
Preparation of chiral a’-hydroxy enones 8/9: To a solution of
methyl 2-hydroxy-3-phenylpropanoate or methyl 2-hydroxy-4-
methylpentanoate (10 mmol) and N,O-dimethylhydroxylamine hy-
drochloride (15 mmol, 1.5 equiv) in THF (35 mL), at À208C a 2m
solution of iPrMgCl in THF (40 mmol, 20 mL, 4 equiv) was added.
The reaction mixture was stirred for 1.5 h at 08C. The reaction was
then quenched with an aqueous saturated solution of NH4Cl
(30 mL) and extracted with CH2Cl2 (2”30 mL). The combined or-
ganic phases were dried over MgSO4. After filtration the solvent
was evaporated under reduced pressure and the crude product
was purified by flash column chromatography (eluent hexane/ethyl
acetate 80:20) to obtain the corresponding Weinreb amide. To a so-
lution of 2-bromopropene (9 mmol, 0.79 mL, 3 equiv) in Et2O
(5 mL) at À788C, a solution of tert-butyllithium (1.6m in pentane,
6.75 mL, 3.6 equiv) was added, and the resulting mixture was
stirred at the same temperature for 1 h. Subsequently, a solution of
the corresponding Weinreb amide (3 mmol) in Et2O (10 mL) was
added and the reaction mixture was stirred at À608C for 16 h. The
reaction was quenched with an aqueous saturated solution of
NH4Cl (50 mL) and extracted with CH2Cl2 (50 mL). The organic
phase was dried over MgSO4 and filtered, and the solvent was
evaporated under reduced pressure. The crude product was puri-
fied by flash column chromatography (eluent hexane/ethyl acetate
95:5).
Figure 4. Proposed approaching models for the addition and protonation
steps, respectively.
Conclusion
Direct approaches to the construction of acyclic carbonyl com-
pounds with nonadjacent all carbon tertiary/quaternary stereo-
centers that proceed with high diastereo- and enantioselectivi-
ty are lacking. Here an effective solution to this longstanding
problem is reported based on a bifunctional Brønsted base
catalyzed Michael/a-protonation cascade that involves 2,4-di-
methyl-4-hydroxypenten-3-one as design methacrylate equiva-
lent. A key feature of this template is the ability to act as
either hydrogen-bond donor or/and acceptor, a distinguishing
feature among known bidentate enoate equivalents employed
in organocatalysis.[11] Control experiments with other elementa-
ry Michael acceptors lacking such ambivalent character led to
inferior reactivity and/or selectivity. This design element also
demonstrated successful in Michael/protonation cascades in-
volving chiral a’-oxyenones. In this latter case, double asym-
metric induction occurs with substrate/catalyst matched com-
bination providing adducts in up to>98:2 d.r. The obtained
adducts are easily transformed into the corresponding acyclic
Preparation of chiral a’-silyloxy enones 10/11: To a solution of
the corresponding a’-hydroxy enone 8/9 (2 mmol) in CH2Cl2
(20 mL) at À208C, were added successively 2,6-lutidine (0.55 mL,
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4.8 mmol, 2.4 equiv) and TMSOTf (0.72 mL, 4 mmol, 2 equiv), and
the mixture was stirred at the same temperature for 3 h. EtOAc
(40 mL) was then added, and the organic phase was washed with
saturated aqueous solutions of NaHCO3 (40 mL), CuSO4 (3”40 mL),
NaHCO3 (2”40 mL) and NaCl (40 mL). The organic phase was dried
over MgSO4 and filtered, and the solvent was evaporated under re-
duced pressure. The resulting crude material was purified by flash
column chromatography (eluent hexane/ethyl acetate 99:1) to
obtain pure compounds 10/11.
temperature for 30 min. The solvents were removed under reduced
pressure and the residue thus obtained was subjected to oxidative
scission by treatment with NaIO4, as above. The crude material was
purified by flash column chromatography on silica gel (eluting
with hexanes/EtOAc 95:5) to give compound 23 (44 mg, 76%
yield, oil).
Acknowledgements
General procedure for the catalytic conjugate addition of a-cya-
noacetates to 1: To a solution of the corresponding a-cyanoace-
tate 2 (0.3 mmol, 1.5 equiv) and a’-hydroxy enone 1 (26 mg,
0.2 mmol) in 1,2-DCE (0.4 mL), catalyst C6 (13 mg, 0.02 mmol) was
added, and the resulting mixture was stirred at 508C until con-
Support was provided by the University of the Basque Country
UPV/EHU (UFI 11/22), Gobierno Vasco (GV, Grant No IT-628-13),
and Ministerio de Economía y Competitividad (MEC, Grant
CTQ2013-47925-C2), Spain. E. B. thanks MEC and I. I. thanks GV
for Fellowships. We also thank SGIker (UPV/EHU) for providing
NMR, HRMS, and X-ray resources.
1
sumption of enone 1 (monitored by H NMR spectroscopy). Then
the reaction was quenched with HCl 1n and the mixture was ex-
tracted with CH2Cl2 (3”2 mL). The combined organic phases were
dried over MgSO4 and the solvent was removed under reduced
pressure to give the corresponding addition/a-protonation adduct,
which was purified by flash column chromatography (eluent
hexane/ethyl acetate 95:5).
Keywords: asymmetric organocatalysis · Brønsted bases ·
Michael reactions · quaternary stereocenters · stereoselective
protonation
Catalytic conjugate addition of a-cyanoacetates 2 to chiral a’-
oxy enones: To a solution of the corresponding tert-butyl cyanoa-
cetate 2 (0.6 mmol) and the corresponding a’-oxy enone 8–11
(0.2 mmol, 1 equiv) in CH2Cl2 (0.4 mL), the catalyst (0.02 mmol) was
added and the resulting mixture was stirred at 208C until con-
[1] a) K. L. Kimmel, J. D. Weaver, M. Lee, J. A. Ellman, J. Am. Chem. Soc.
2012, 134, 9058–9061; b) B. Zheng, H. Wang, Y. Han, C. Liu, Y. Peng,
Chem. Commun. 2013, 49, 4561–4563; c) N. V. G. Moorthy, R. Dyapa,
S. V. Pansare, Org. Lett. 2015, 17, 5312–5315.
1
sumption of the a’-oxy enone (monitored by H NMR spectrosco-
py; see Table 3 for reaction times). The reaction mixture was
quenched with HCl 1N (5 mL) and the solution was extracted with
CH2Cl2 (5 mL). The combined organic phases were dried over
MgSO4 and filtered, and the solvent was evaporated under reduced
pressure.
[2] For classic examples of multistep approaches to a,g-substituted carbon-
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Reactions from a’-hydroxy enone 8/9: The residue was submitted to
purification by flash column chromatography (eluent hexane/ethyl
acetate 95:5).
Reactions from a’-silyloxy enone 10/11: The residue was dissolved in
MeOH (0.5 mL) and a solution of concentrated fluorhydric acid in
MeOH (10 mmol, 0.2 mL) was added. The resulting mixture was
stirred at 208C for 2 h. Then the solvent was evaporated and the
resulting residue was basified to pH 7 with a saturated solution of
NaHCO3. The mixture was extracted with CH2Cl2 (2”4 mL), dried
over MgSO4, and filtered, and the solvent was evaporated under
reduced pressure. The oily product was submitted to purification
by flash column chromatography (eluent hexane/ethyl acetate
95:5.)
Conversion of adduct 5a into carboxylic acid 20: A suspension of
sodium periodate NaIO4 (342 mg, 1.6 mmol) in water (0.8 mL) was
added to a solution of a-hydroxy ketone 5a (69 mg, 0.2 mmol) in
methanol (1 mL). The mixture was stirred at room temperature
until the reaction was complete (monitored by TCL, 24 h). Then
the solvent was removed under reduced pressure. Water (4.5 mL)
was added to the residue and the resulting mixture was extracted
with Et2O (3”6 mL). The combined organic extracts were dried
over MgSO4 and filtered, and the solvent was evaporated. The
product was purified by flash column chromatography (hexanes/
EtOAc 80:20) to afford carboxylic acid 20 (52 mg, 86% yield, color-
less oil).
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of Et3N, C6 or DBU. Partial epimerization of product 13 appeared only
upon prolonged exposure to DBU. See the Supporting Information for
details.
[26] See the Supporting Information for details.
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Received: June 28, 2016
Published online on && &&, 0000
Chem. Eur. J. 2016, 22, 1 – 8
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These are not the final page numbers! ÞÞ

Full Paper
FULL PAPER
&
Asymmetric Organocatalysis
I. Iriarte, S. Vera, E. Badiola, A. Mielgo,
M. Oiarbide,* J. M. Garcꢀa,
J. M. Odriozola, C. Palomo*
&& – &&
Michael does it again! 2,4-Dimethyl-4-
hydroxypenten-3-one has been intro-
duced as new methacrylate equivalent
for the asymmetric construction of non-
adjacent all carbon tertiary/quaternary
stereocenters through the organocata-
lytic addition of a-cyanoacetates (see
scheme). Direct assembly of such ster-
eoarrays with high enantio- and diaste-
reoselectivity has remained elusive to
date.
Asymmetric Assembly of All-Carbon
Tertiary/Quaternary Nonadjacent
Stereocenters through Organocatalytic
Conjugate Addition of a-
Cyanoacetates to a Methacrylate
Equivalent
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Chem. Eur. J. 2016, 22, 1 – 8
www.chemeurj.org
8
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!