Enantioselective Addition of Alkynyl Ketones to Nitroolefins Assisted by Br?nsted Base/H-Bonding Catalysis

Article abstract of DOI:10.1002/chem.201805542

Various sets of enolizable alkynyl ketones (including methyl ynones with α-aryl, α-alkenyl, and α-alkoxy groups) were able to react smoothly with nitroolefins with the assistance of bifunctional Br?nsted base/H-bond catalysts to provide adducts with two consecutive tertiary stereocenters in a highly diastereo- and enantioselective fashion. Further transformation of the obtained adducts into optically active acyclic and polycyclic molecules, including some with intricate carbon skeletons, was also demonstrated.

Full text of DOI:10.1002/chem.201805542

A Journal of
Accepted Article
Title: Enantioselective Addition of Alkynyl Ketones to Nitroolefins
Assisted by Brønsted Base/H-Bonding Catalysis
Authors: Teresa E. Campano, Igor Iriarte, Olatz Olaizola, Julen Etxabe,
Antonia Mielgo, Iñaki Ganboa, José Manuel Odriozola, Jesús
M. García, Mikel Oiarbide, and Claudio Palomo
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To be cited as: Chem. Eur. J. 10.1002/chem.201805542
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Enantioselective Addition of Alkynyl Ketones to Nitroolefins
Assisted by Brønsted Base/H-Bonding Catalysis
Teresa E. Campano,[a] Igor Iriarte,[a] Olatz Olaizola,[a] Julen Etxabe,[a] Antonia Mielgo,[a] Iñaki Ganboa,[a]
José M. Odriozola,[b] Jesús M. García,[b] Mikel Oiarbide*[a] and Claudio Palomo*[a]
Abstract: Various sets of enolizable alkynyl ketones (including methyl
ynones with -aryl, -alkenyl and -alkoxy groups) are able to react
smoothly with nitroolefins under the assistance of bifunctional
Brønsted base/H-bond catalysts to provide adducts with two
ideal atom economy and usually broad functional group
tolerance.[8] However, a general problem with this type of
activation is the functional pKa barrier of most catalysts that
compromises their efficiency with less acidic carbon
pronucleophiles.[9] To our knowledge there is a single report on
asymmetric Brønsted base-catalyzed -additions of enolizable
ynones, by Peng, Wang and Shao (Scheme 1a, top).[10] Ynone
substrates bearing an ester group at C are used, requiring a final
decarboxylation by acid treatment at 110 ºC in toluene.
consecutive tertiary stereocenters in
a highly diastereo- and
enantioselective fashion. Further transformation of the obtained
adducts into optically active acyclic and polycyclic molecules,
including some with intricate carbon skeletons, is also demonstrated.
Introduction
Given the rich chemistry of both the carbon-carbon triple bond[1]
and the carbonyl function,[2] alkynyl ketones (-ynones) are
excellent building-blocks for organic synthesis.[3] Therefore, the
development of catalytic methods for the proliferation of simple
ynones through new C–C bond forming processes into
configurationally defined, structurally and functionally more
complex, ynone molecules is highly desirable. One logical
approach would rely on the -functionalization of enolizable
ynones with electrophiles, but the implementation of catalytic
asymmetric methodologies progresses very slowly. One problem
relies on the tendency of -ynones to act as Michael acceptors
rather than donors.[4] In addition, useful methods would require
exquisite control of the intervening ketone enolate geometry as
well as the stereochemistry of the subsequent C–C bond forming
reaction. Some direct asymmetric aldol[5] and Mannich[6] reactions
of enolizable ynones acting as donor components promoted by
6]
bifunctional metal catalysts[5a-e, or enamine activation[5f-h] are
known. In some instances, the enamine activation approach
cannot stop at the acyclic addition adduct which undergoes
intramolecular cyclization,[7] hence exemplifying the tendency of
-ynones to act as Michael acceptors.
Scheme 1. Progress on bifunctional Brønsted base assisted direct Michael
reactions of alkynyl ketones.
During recent studies on the catalyst-controlled reactivity of
transiently generated vinylogous ketone enolates,[11] we found
that alkynyl allyl ketones are a suitable subset of allyl ketones for
their reaction with nitroolefins in the presence of bifunctional
Brønsted base/H-bond catalysts like C2[12] (Scheme 1a down).
Interestingly, these reactions proceeded with nearly perfect
enantio- and /-selectivity, but, unfortunately, the C=C double
bond in adducts isomerizes spontaneously to the most stable -
position with loss of a stereocenter.[11] Therefore, both the above
Brønsted base catalyzed methods afford products with a single
new stereocenter. In the present investigation we demonstrate
that the Brønsted base activation of enolizable -ynones can be
applied beyond the above constrains and thus becomes a
practical approach to synthetically useful building-blocks.
Specifically, ynones bearing an arylmethyl, alkoxymethyl or -
alkenyl sidearm all resulted suitable substrates for direct,
As a complement to metal- and aminocatalytic activation
strategies, Brønsted base catalysis bears great interest
considering it proceeds under proton transfer conditions, with
[a]
[b]
Prof. C. Palomo, Prof. M. Oiarbide, Prof. I. Ganboa, Prof. A. Mielgo,
T. E. Campano, I. Iriarte, O. Olaizola, Dr. J. Etxabe
Departamento de Química Orgánica I
Universidad del País Vasco UPV/EHU
Manuel Lardizabal 3, 20018 San Sebastián, Spain
E-mail: claudio.palomo@ehu.es
Prof. J. M. García, Prof. J. M. Odriozola
Departamento de Química Aplicada
Institute for Advanced Materials (INAMAT)
Universidad Pública de Navarra
31006-Pamplona, Spain
Supporting information for this article is given via a link at the end of
the document.
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Brønsted base-catalyzed Michael reactions producing adducts
with two contiguous stereogenic centers in high selectivity
(Scheme 1b). Details of the substrate scope, catalyst
requirements and the utility of thus obtained adducts for
accessing stereochemically complex carbon skeletons, are
shown.
was also very selective with the -alkyl substituted nitroolefin 4i,
although, as expected, progressed more slowly (44% conversion
Table 1. Catalyst screening for the reaction of 3A with 4a to give 5Aa[a] and
catalysts described in these manuscript.
Entry Cat
Product
Yield [%][b]
d.r.[c]
ee [%][d]
1
2
3
4
5
6
C2
C3
C4
C5
C6
C7
80
80
77
1.5:1
10:1
4:1
1:1
19:1
5.7:1
98
80
92
40
94
59
Results and Discussion
70[e]
82
Alkenyl alkynyl ynones. Background and reaction generality.
In our preliminary study allyl alkynyl ketones 1 were found to react
with nitroolefins in the presence of catalyst C2 to afford the Morita-
Baylis-Hillmann type products 2.[11] These observations indicate
that the initially formed adduct isomerizes spontaneously, with
one of the newly created stereocenters being ultimately loosed
(Scheme 1a). Our first task was to check whether this
isomerization bias is general for other allylic systems. The
experiments involving 1,1-(gem)-disubstituted allylic ynone 3A
and nitrostyrene 4a in the presence of several bifunctional
Brønsted base catalysts[13] (Scheme 2 and Table 1) showed that,
indeed, the -unsaturated adduct 5Aa resists isomerization
regardless the catalyst employed. For instance, after 3 h of stirring
at room temperature with 10 mol% catalyst C2, adduct 5Aa was
obtained in 80% isolated yield and an excellent 98% ee, although
a nearly equimolar mixture of diastereomers was produced (entry
1). With the N-benzyl analog C3[14] diastereoselectivity was
improved at the expense of enantioselectivity (80% ee, entry 2),
while the related cyclohexyldiamine-derived squaramide catalyst
C4[15] afforded product 5Aa with high ee, but yet suboptimal
diastereoselectivity (dr 4:1, 92% ee, entry 3). After additional
screening that showed thiourea catalysts inferior in reactivity and
selectivity (e.g. C5, entry 4), we finally found that the reaction in
the presence of newly developed catalyst C6[16] afforded the
desired product 5Aa in 82% yield, a remarkable 19:1 dr and 94%
ee (entry 5). While the superior behavior of catalyst C6 correlates
well with previous observations,[16] it seems that its origin cannot
be explained by steric congestion merely as the bulky neopentyl-
derived catalyst C7 was comparatively inferior (entry 6).
90[f]
[a] Reactions run at 0.2 mmol scale in 0.2 mL CH2Cl2; mol ratio of 3A/4a/cat
2:1:0.1. [b] Combined yield of diastereomers after chromatography. [c]
Determined by chiral HPLC after filtration through a short path of SiO2. [d] Ee
of major diastereomer determined by chiral HPLC. [e] Reaction conversion. [f]
Conversion after 3 h reaction; 73% isolated yield.
Table 2. C6-catalyzed conjugate addition of alkenyl ynones 3 to nitroolefins
4.[a]
Scheme 2. Catalytic addition of alkenyl ynones 3 to nitroolefins and catalysts
employed in this study.
[a] Reactions run at 0.2 mmol scale in 0.2 mL CH2Cl2; mol ratio of 3/4/catalyst
2:1:0.1. Variable amounts of isomerized starting material were observed in most
entries; yield of major diastereomer after chromatography, except for 5Db
(combined yield). Dr and ee determined by chiral HPLC analysis.
As data in Table 2 show, the catalytic addition of 3A to aromatic
nitroolefins 4b and 4e worked equally well and adducts 5Ab and
5Ae were obtained in good yield and high selectivity. The reaction
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after 3 h). Ynone substrates with other aromatic substituents at
the alkynyl moiety (adducts 5Ba, 5Ca) or even alkyl substituents
(5Db) were well tolerated too. These results constitute the first
evidence of Brønsted base catalyzed Michael additions of -
ynones that generate two adjacent tertiary stereocenters in highly
enantio- and diastereoselective manner. One feature of these
reactions is that whilst isomerization of the double bond on the
newly formed adducts was not observed, the starting allyl ynones
3 isomerized to the respective vinyl ynones to some extent.
However, the impact of this process on the reaction yield was
negligible upon the use of two equivalents of the starting ynone.
Some control experiments to assess the stability of products
towards epimerization or double bond isomerization under the
reaction conditions employed were carried out. For instance,
when a solution of each adduct 5 was stirred at room temperature
overnight in the presence of 10 mol% C4 or C6, no change in the
configurational integrity of adducts, nor appreciable isomerization,
were observed.
after stirring a solution of the adduct in the presence of 10 mol%
C6 at room temperature overnight) demonstrated their stability
towards double bond isomerization or epimerization. Two general
conclusions can be brought from these and the previous[11] results
involving vinylogous alkynyl ketone enolates: (i) Brønsted base
catalyzed additions of allyl alkynyl ketones proceed in all cases
tested with high C selectively, and (ii) the tendency of the allylic
ynone products towards double bond isomerization depends
primarily on the alkene substitution pattern, but also the catalyst
employed. Isomerization can be totally cancelled by choosing the
right Brønsted base catalyst, e.g. C6, providing adducts with two
contiguous stereocenters in very high enantioselectivity and
diastereomeric ratios from moderate to excellent.
Benzylic alkynyl ketones as nucleophiles. Although the above
results were encouraging, the question of whether this method is
suitable for a broader range of ynone compounds remained
unanswered so far. Particularly, simple alkyl ynones, such as
methyl ynones, had been previously shown unable to react with
nitrostyrene in the presence of typical Brønsted base catalysts.[10]
However, recent work by our own group revealed some
particularly active benzylic ketones to be amenable substrates for
Brønsted base-assisted activation.[15] Accordingly, benzylic
ynones were envisioned as candidates for the evaluation of the
method generality. A range of benzylic ynones 9–14 were easily
accessible for the reaction screening which was initiated with
ynone 9A and -aryl substituted nitroolefin 4b in the presence of
We next studied the reaction outcome involving allyl ynones with
a 1,2-disubstitution pattern on the olefin, which turned out to be
strongly catalyst-dependent. Thus, as Table 3 shows, the reaction
of 6A with nitrostyrene 4a in the presence of catalyst C4 at room
temperature overnight led to a mixture of adduct 7Aa and its
isomer 8Aa in a 66:34 ratio (entry 1). In contrast, the same
reaction promoted by catalyst C6 cleanly led to 7Aa as the only
isolated product, which was obtained as
a mixture of
diastereomers each in very high enantioselectivity (entry 2). A
similar trend was observed in the reactions of ynone 6A with
nitroolefins 4c and 4f, and of ynone 6E with 4a. Thus, exclusive
formation of the -addition products 7Ac, 7Af and 7Ea was
observed using catalyst C6 (entries 4, 6 and 7), whereas with
catalyst C4 mixtures of products 7 and 8 were obtained in ratios
of 83:17 and 81:19, respectively (entries 3 and 5). As before,
control experiments with adducts 7 (unaltered material recovered
Table 3. Reaction of -alkenyl ketones 6: no isomerization with catalyst
C6.[a]
Scheme 3. Catalytic reaction of benzylic ynones 9–14 and nitroolefins 4.
Table 4. Catalyst screening for the reaction of ynone 9A and nitroolefin 4b
to yield adduct 15Ab.[a]
Entry Cat
t [h]
Yield [%][b]
d.r.[c]
ee [%][c]
Entry R1
R2
Cat Ratio[b] Yield of 7 d.r.[b]
ee [%][d]
[%][c]
1
2
3
4
5
C2
C3
C4
C6
C7
2.5
2.5
4.5
6
95
96
99
97
90
1:1
2.8:1
3.3:1
5.7:1
1.5:1
ND
7/8
82 (92)
91 (97)
96 (99)
--
1
2
3
4
5
6
7
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
C4
C6
66:34
>95:5
83:17
>95:5
81:19
>95:5
>95:5
38
56
47
62
46
47
58
1.3:1
1:1
1.2:1
1.4:1
1.2:1
1:1
88 / 90
94 / >98
91 / 89
95 / 85
96 / 93
95 / 83
94 / 79
6
4-MeC6H4 C4
4-MeC6H4 C6
2-ClC6H4
2-ClC6H4
[a] Reactions run at 0.1 mmol scale in 0.3 mL CH2Cl2; mol ratio of 9A/4b/cat
1:1.2:0.1. [b] Combined yield of diastereomers after chromatography. [c]
Determined by chiral HPLC before chromatography. In parentheses the ee
of minor isomer.
C4
C6
C6
4-MeC6H4 Ph
1.4:1
[a] Reactions run at 0.2 mmol scale in 0.6 mL CH2Cl2; mol ratio of 6/4/cat
2:1:0.1. [b] Determined by 1H NMR. [c] Yield of pure 7 after chromatography.
[d] Ee of each diastereomer determined by chiral HPLC.
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Table 5. Scope of the catalytic, enantioselective addition of alkynyl ketones
9–14 to nitroolefins 4.[a]
[a] Reactions run at 0.1 mmol scale in 0.3 mL CH2Cl2; mol ratio of 9–14/4/cat
1:1.2:0.1. Combined yield of diastereomers after chromatography; dr and ee
determined by chiral HPLC. In parentheses the ee of minor isomer. [b]
Conversion of 84%. [c] Conversion of 74%.
several bifunctional squaramide catalysts.[13] As data in Scheme
3 and Table 4 show, the reaction in the presence of C2 took place
in a few hours to give product 15Ab in good yield, albeit no
diastereocontrol at all (entry 1). Diastereoselectivity was improved
using catalyst C3 (entry 2) and even more with C4 (entry 3) that
afforded product 15Ab in 3.3:1 dr and 91% and 97% ee,
respectively, for each isomer. Further screening showed catalyst
C6 the most selective once more (5.7:1 dr, 96% and 99% ee,
entry 4), whilst its bis-O-trimethylsilyl analog (see the supporting
information) led to slightly lower diastereoselectivity (3.2:1 dr,
98% and 99% ee). For comparative purposes, the reaction with
catalyst C7, bearing a bulky neopentyl group at the squaramide
terminus, was carried out, but again led to an almost equimolar
mixture of diastereomers. These results support the initial
assumption that steric effects alone may not suffice to explain the
salient performance of C6. This trend in catalyst behavior was
confirmed along the exploration of the reaction scope with regard
to the nitroolefin. As shown in Table 5, when the reaction of 9A
with 4a and 4e was promoted by catalysts C4 and C6 similar
results were produced albeit the latter provided somewhat better
diastereoselectivity. -Alkyl substituted nitroolefins as well as a
variety of electron-poor, and rich, -aryl substituted nitroolefins
participate well in the reaction of alkynylketones 9-14 to afford
adducts 15-20 in very high yield, good diastereoselectivity and
nearly perfect enantioselectivity for most cases, independently of
the substitution pattern of each reaction component. The absolute
configuration of adduct 15Ab was established by single crystal X-
ray structure analysis[17] and for the remaining adducts was
assumed by analogy on the bases of a uniform reaction
mechanism.
Benzyloxymethyl alkynyl ketones as nucleophiles. In view of
the successful reactivity of both benzyl and allyl ynones, the
behavior of ynones with an alkoxymethyl sidechain was explored
next. The heteroatom-substituted sidechain would not only render
synthetically appealing adducts, but also increased acidity to
substrates for Brønsted base catalyst activation. Concordant with
our expectations, it was found that ynones 21, bearing a
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benzyloxymethyl side-arm, are indeed competent for the
catalyzed reaction with nitroolefins. Among the catalysts
examined for these reactions,[13] C3 resulted superior. For
example, as data in Table 6 show, the reactions of 21A with
nitrostyrenes 4a-g in the presence of 10 mol% C3 afforded
adducts 22Aa-g in excellent diastereomeric ratio (typically greater
than 10:1) and ee’s up to 99% for the major diastereomer. The
reaction with the -heteroaromatic nitroolefin 4h, or the most
challenging alkyl nitroolefin 4j, also provided the corresponding
adducts 22Ah, 22Aj in very good yields, diastereomeric ratios of
10:1 and 6.7:1, and enantioselectivities of 99% and 96%,
respectively. Similarly, the alkyl substituted ynone 21D reacted
smoothly with either aromatic or aliphatic nitroolefins giving
access to adducts 22Da, 22Dj in nearly perfect stereoselectivity.
Absolute configuration of adduct 22Ae was established by single
crystal X-Ray structure analysis[17] and for the remaining adducts
22 was assumed by analogy on the bases of a uniform reaction
mechanism.
alkyl alkyl ketone products with two tertiary stereocenters at  and
 positions. For instance, catalytic hydrogenation of 15Ab
afforded 23 in 97% yield (Scheme 4), the -branched ketone
product formally derived from the yet unrealized site- and
stereoselective -alkyltion of the corresponding phenethyl ketone.
Scheme 4. Reduction of adducts to -branched alkyl alkyl ketones.
Alternatively, substrate-controlled stereoselective reduction of the
ketone carbonyl to carbinol was feasible according to two
stereodivergent pathways (Scheme 5). On the one hand,
reduction of 22Ab with K-Selectride proceeded via a Felkin-Anh
model[18] to afford syn alcohol 25 exclusively, while chelation
controlled reduction with NaBH4 afforded the complementary anti
alcohol[19] 27, in both cases with good isolated yields. The nitro
group in these molecules is amenable for efficient transformation
into a carboxylic acid function upon oxidation according to
Mioskowski[20] conditions, as illustrated by the conversion of 23 to
acid 24 (86%) (Scheme 4), 25 to 26 (77%) and 27 to 28 (84%),
respectively, Scheme 5.
Table 6. Catalytic, enantioselective reaction of benzyloxy ynones 21 with
nitroolefins 4.[a]
Scheme 5. Diastereodivergent reduction of the ketone carbonyl to syn and anti-
diol units.
[a] Reactions run at 0.2 mmol scale in 0.2 mL CH2Cl2; mol ratio of 21/4/catalyst
1:2:0.1. Yields of isolated product after chromatography; ee determined by
chiral HPLC before chromatography. [b] 80% conversion after 72 h. [c]
Reaction run at 0.2 mmol scale in 0.2 mL 1,2-DCE using 3 equiv. of nitroolefin.
[d] 65% conversion after 48 h.
Further synthetic interest of the present catalytic addition
reactions is derivable from intramolecular carbofunctionalizations
of the alkynyl moiety in adducts. As shown in Scheme 6, Larock’s
ipso-halocyclisation[21] of adduct 18Aa furnished spirocycle 29 in
86% yield, while heating adduct 18Ga at 65 °C in the presence of
Cu(II), according to the method of Taylor and Unsworth,[22] led to
the spirocycle 31. These spirocyclic quinones are easily
converted into compounds 30 and 32, respectively, which display
a tricyclic carbon core similar to that present in homodimericin
A,[23] a structurally intricate compound whose enantioselective
chemical synthesis is still pending.[24]
Elaboration of adducts. An interesting aspect of the above
catalytic reactions is that adducts can be transformed into
polyfunctionalized structures with two or more contiguous tertiary
stereocenters using simple chemical protocols. For instance,
reduction of the alkynyl moiety in adducts provides dissymmetric
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Compound 18Aa: Prepared from 1-(4-methoxyphenyl)-4-phenylbut-3-yn-
2-one (12A) (25.0 mg, 0.1 mmol) according to the general procedure with
cat C6, affording a 4.1:1 mixture of diastereomers. Yield: 38.34 mg, 96 %.
Crystallized from Et2O. White solid. [α]D25= –55.5° (c = 0.3, 96% ee,
1
CH2Cl2). m.p. 134–136 ºC. H NMR (300 MHz, CDCl3), δ: 7.52–7.26 (m,
14H), 6.99 (d, J= 8.7 Hz, 2H), 4.53–4.32 (m, 4H), 3.85 (s, 3H).13C NMR
(75 MHz, CDCl3) δ: 182.7, 158.8, 136.1, 131.8, 129.7, 128.9, 127.8, 127.4,
127.0, 126.9, 124.6, 118.4, 113.9, 92.0, 86.3, 78.0, 61.5, 54.1, 44.3.
UPLC-DAD-QTOF: C25H22NO4 [M+H]+ calcd.: 400.1549, found:400.1551.
Compound 18Ga: Prepared from 1,4-bis(4-methoxyphenyl)but-3-yn-2-
one (12G) (28.0 mg, 0.1 mmol) according to the general procedure with
cat C6, affording a 8.1:1 mixture of diastereomers. Yield: 41.2 mg, 96 %.
Crystallized from Et2O. White solid. [α]D25= –1.4° (c = 0.2, 98% ee, CH2Cl2).
m.p. 142–144 ºC. 1H NMR (300 MHz, CDCl3), δ: 7.44 (d, J= 9.0 Hz, 2H),
7.40 (d, J= 8.7 Hz, 2H), 7.38–7.29 (m, 5H), 6.98 (d, J= 8.8 Hz, 2H), 6.88
(d, J= 8.9 Hz, 2H), 4.51–4.30 (m, 4H), 3.85 (s, 3H), 3.85 (s, 3H). 13C NMR
(75 MHz, CDCl3) δ: 184.6, 160.6, 138.1, 135.8, 131.7, 130.7, 129.6, 128.8,
128.7, 128.2, 126.7, 115.7, 115.0, 110.7, 95.0, 88.3, 79.6, 63.3, 56.0, 46.3
UPLC-DAD-QTOF: C26H24NO5 [M+H]+ calcd.: 430.1654, found: 430.1658.
UPLC-DAD-QTOF:
found:452.1470.
C26H23NO5Na
[M+Na]+
calcd.:
452.1474,
Scheme 6. Elaboration of adducts into carbocycles of intricate structure.
Compound 22Ab: Prepared starting from ynone 21A (50 mg, 0.2 mmol)
according to the general procedure with cat C3. Orange oil, yield: 56 mg
(65 %). [α]D25 = 26.1° (c= 1, >99% ee, CH2Cl2). 1H NMR (300 MHz, CDCl3)
δ 7.63–7.28 (m, 11H), 7.25–7.18 (m, 2H), 6.90–6.82 (m, 2H), 4.95–4.68
(m, 4H), 4.46 (d, J= 11.3 Hz, 1H), 4.15 (ddd, J= 9.3, 7.0, 4.9 Hz, 1H), 3.78
(s, 3H). 13C NMR (75 MHz, CDCl3) δ 187.5, 160.6, 137.5, 134.5, 132.4,
131.4, 130.5, 129.8, 129.7, 129.4, 129.3, 128.2, 120.4, 115.5, 87.4, 87.2,
77.7, 74.2, 56.3, 46.6. UPLC-DAD-QTOF: C26H24NO5 [M+H]+ calcd.:
430.1654, found: 430.1654.
Conclusions
In conclusion, conjugate additions of enolizable -ynones to
nitroolefins is feasible in a highly selective fashion in the presence
of tertiary amine/squaramide bifunctional catalysts, affording an
atom economic route to densely functionalized building-blocks.
For the new C–C bond forming reaction not only allyl ynones, but
also benzylic ynones and alkoxymethyl ynones are suitable
ketone donors, thus complementing the few existing direct
approaches for the -functionalization of alkynyl ketones.
Elaboration of the -branched ynone adducts through simple
protocols allows an access to stereochemically complex
structures, both acyclic and intricate tricyclic carbon skeletons, in
optically pure form.
Syn selective reduction of 22Ab: To a solution of 22Ab (0.2 mmol, 86
mg) in dry THF (0.5 mL) at −78 °C a solution of K-selectride in THF (1M, 3
equiv., 0.6 mmol, 0.6 mL) was added and the mixture was stirred at that
temperature for 2 hours. Then water (0.2 mL) and EtOH (0.4 mL) were
successively added, and after 5 min of stirring H2O2 (30%, 0.4 mL) was
added. The reaction mixture was allowed to rise to room temperature and
the mixture was stirred for an additional 10 min. Then, it was diluted with
EtOAc (5 mL) and water (5 mL). The aqueous phase was extracted with
EtOAc (3 × 5 mL), the organic layers were combined, and dried with
MgSO4, filtered and the solvent was evaporated under reduced pressure.
The resulting crude material was purified by flash column chromatography
(eluent hexane/ethyl acetate 80:20) to afford compound 25 as a yellow oil
(dr: >95:5). Yield: 70 mg (84%). [α]D25 = 3.4° (c= 0.1, CH2Cl2, from adduct
of >99 % ee). 1H NMR (300 MHz, CDCl3) δ 7.46–7.26 (m, 10H), 7.20–7.15
(m, 2H), 6.92–6.87 (m, 2H), 5.13 (d, J= 10.9 Hz, 1H), 4.91–4.84 (m, 1H),
4.84–4.79 (m, 1H), 4.62–4.49 (m, 1H), 4.39 (d, J= 1.4 Hz, 1H), 4.00–3.93
(m, 2H), 3.81 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 160.5, 150.8, 138.1,
132.7, 131.2, 130.4, 129.9, 129.8, 129.6, 129.6, 129.5, 115.8, 89.6, 84.1,
78.8, 76.5, 63.1, 56.4, 46.4, 30.8. DAD-QTOF: C26H26NO5 [M+H]+ calcd.:
432.1811, found: 432.1814.
Experimental Section
General Procedure for the Michael reaction: To a solution of the
corresponding ynone (0.1 mmol, 1 eq.) and nitroalkene (0.12 mmol, 1.2
eq.) in dichloromethane (0.3 mL) at room temperature the catalyst (0.01
mmol, 10 mol %) was added and the resulting mixture was stirred at the
same temperature for the time indicated in the tables. Then the mixture
was directly submitted to
hexane/ethyl acetate).
a flash column chromatography (eluent
Anti selective reduction of 22Ab: NaBH4 (16 mg, 0.4 mmol, 2 equiv.)
was added to a stirred mixture of compound 22Ab (0.2 mmol, 86 mg) in
EtOH (1 mL) at room temperature. After 2 h the mixture was poured into
saturated aqueous NaHCO3 and extracted with Et2O (3 × 5 mL). The
combined organic extracts were washed with H2O (5 mL) and brine (5 mL),
and dried with MgSO4, filtered and the solvent was evaporated under
reduced pressure. The resulting crude material was purified by flash
Compound 15Ab: The title compound was prepared from 1,4-
diphenylbut-3-yn-2-one (9A) (22.0 mg, 0.1 mmol) according to the general
procedure with cat C6, affording a 5.7:1 mixture of diastereomers. Yield:
38.6 mg, 97%. Crystallized from Et2O. White solid. [α]D25= –62.9° (c= 0.53,
96% ee, CH2Cl2). m.p. 156–158 ºC. 1H NMR (300 MHz, CDCl3), δ: 7.59–
7.29 (m, 12H), 6.89 (d, J= 8.7 Hz, 2H), 4.56–4.28 (m, 4H), 3.79 (s, 3H).13
C
NMR (75 MHz, CDCl3) δ: 184.6, 160.0, 134.8, 133.7, 131.6, 130.3, 129.9,
129.6, 129.5, 129.3, 120.2, 115.1, 110.7, 94.0, 88.1, 79.6, 64.5, 55.9, 45.5.
UPLC-DAD-QTOF: C25H22NO4 [M+H]+ calcd.: 400.1549, found: 400.1550.
column chromatography (eluent hexane/ethyl acetate 80:20) to afford
25
compound 27 as a colourless oil (dr: >95:5). Yield: 74 mg (86 %). [α]D
=
18.3° (c= 0.3, CH2Cl2, from adduct of >99% ee). 1H NMR (400 MHz,
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CDCl3), δ: 7.50–7.25 (m, 10H), 7.24–7.20 (m, 2H), 6.89–6.84 (m, 2H), 5.02
(dd, J= 12.9, 5.0 Hz, 1H), 4.88 (d, J= 11.4 Hz, 1H), 4.73–4.62 (m, 2H), 4.59
(d, J= 3.5 Hz, 1H), 4.03 (ddd, J= 9.8, 7.5, 5.1 Hz, 1H), 3.93 (dd, J= 7.5, 3.5
Hz, 1H), 3.84–3.82 (m, 1H), 3.80 (s, 3H). 13C NMR (101 MHz, CDCl3), δ:
159.2, 137.4, 131.8, 129.2, 129.0, 128.8, 128.7, 128.3, 128.2, 128.1, 122.0,
114.4, 83.3, 74.7, 64.7, 55.2, 45.2, 29.7. DAD-QTOF: C26H26NO5 [M+H]+
calcd.: 432.1811, found: 432.1810.
QTOF: C24H19INO4 [M+H]+ calcd.: 512.0359, found: 512.0362. UPLC-
DAD-QTOF: C24H18NO4INa [M+Na]+ calcd.: 534.0178, found:534.0184.
Preparation of spirocycle 31: To a solution of adduct 18Ga (1 eq., 0.13
mmol, 55 mg) in 1,2-DCE (1mL) was added Cu(OTf)2 (1 eq., 0.13 mmol,
47 mg). The reaction mixture was stirred at 65 ºC for 3 h. Then the mixture
was filtered, rinsed with CH2Cl2 and concentrated in vacuo to afford a
brown foam. [α]D25= –9.5º (c= 1.5, CH2Cl2, from adduct of 98% ee). Yield:
44 mg (81%). 1H NMR (300 MHz, CDCl3), δ: 7.41 (d, J= 8.7 Hz, 3H), 6.93
(d, J= 8.1 Hz, 1H), 6.82 (d, J= 8.8 Hz, 2H), 6.65 (s, 1H), 6.56 (d, J= 10.1
Hz, 1H), 6.34–6.12 (m, 2H), 5.24 (dd, J= 13.2, 7.5 Hz, 1H), 5.02–4.84 (m,
Procedure for the Nef oxidation of adducts 23, 25 and 27: (Mioskowski
conditions) A solution of the corresponding diol (1 equiv.), sodium nitrite (3
equiv.) and acetic acid (10 equiv.) in DMSO (0.5 mL/0.2 mmol) was stirred
at 35 or 50 °C for 24 h. After this period, the reaction mixture was quenched
with HCl 1N (5 mL) and the mixture was extracted with Et2O (4 × 5 mL).
The combined organic phases were dried with MgSO4, filtered and the
solvent was evaporated under reduced pressure. The resulting crude
material was purified by flash column chromatography.
1H), 3.81 (s, 3H), 3.65 (td, J= 7.2, 3.5 Hz, 1H), 3.32 (d, J= 3.4 Hz, 1H). 13
C
NMR (75 MHz, CDCl3), δ: 204.2, 185.4, 173.1, 163.3, 151.4, 151.1, 137.4,
131.0, 130.1, 129.6, 128.9, 127.7, 125.6, 115.1, 94.1, 79.4, 73.8, 56.3,
56.1, 43.1, 30.3. UPLC-DAD-QTOF: C25H22NO5 [M+H]+ calcd.: 416.1498,
found: 416.1501. UPLC-DAD-QTOF: C25H21NO5Na [M+Na]+ calcd.:
438.1317, found:438.1314.
Compound 24: Prepared from compound 23 (65 mg, 0.16 mmol)
according to the general procedure. White solid, yield 53.8 mg (86%).
[α]D25= –129.6° (c= 0.1, CH2Cl2, from adduct of 96% ee). m.p. 144–146 ºC.
1H NMR (300 MHz, CDCl3), δ: 7.40–6.80 (m, 14H), 4.53–4.33 (m, 2H),
3.82 (s, 3H), 2.77–2.32 (m, 4H). 13C NMR (75 MHz, CDCl3), δ: 207.6, 177.6,
160.3, 141.6, 136.5, 133.4, 130.7, 130.0, 129.8, 129.4, 129.1, 129.0, 127,0,
115.3, 62.3, 56.3, 54.1, 45.4, 30.1. UPLC-DAD-QTOF: C25H24O4Na
[M+Na]+ calcd.: 411.1572, found:411.1570.
Preparation of tricycles 30 and 32: To a solution of the corresponding
spirocyclic compound 29 or 31 (1 eq., 0.1 mmol) in dichloromethane (0.6
mL) was added Et3N (20 eq., 2 mmol) and the reaction mixture was stirred
at room temperature for 2 h. The reaction mixture was directly submitted
to a non-acidic silica gel column chromatography (eluent hexane/AcOEt
95:5→ 90:10).
Compound 30: Prepared from compound 29 (51.1 mg, 0.1 mmol)
according to the general procedure. Brown foam, yield: 36.8 mg (72%).
[α]D25= –35.1º (c= 0.3, CH2Cl2, from adduct of 96% ee). Decomp. 135 ºC.
1H NMR (300 MHz, CDCl3), δ: 7.63–7.23 (m, 10H), 6.81 (dd, J= 10.2, 1.6
Hz, 1H), 6.36 (dd, J= 10.2, 0.7 Hz, 1H), 5.00 (t, J= 11.2 Hz, 1H), 3.96–3.84
(m, 1H), 3.24 (d, J= 9.1 Hz, 1H), 3.21–3.11 (m, 1H), 2.37 (d, J= 17.7 Hz,
1H), 1.94 (dd, J= 17.8, 6.4 Hz, 1H). 13C NMR (75 MHz, CDCl3), δ: 199.9,
194.2, 176.7, 147.7, 136.8, 134.8, 131.3, 131.2, 130.1, 129.8, 129.2, 128.0,
127.6, 105.5, 94.7, 60.3, 50.7, 47.3, 35.7. UPLC-DAD-QTOF:
C24H18NO4INa [M+Na]+ calcd.: 534.0175, found:534.0184.
Compound 26: Prepared from compound 25 (86 mg, 0.2 mmol) according
to the general procedure. Colourless oil, yield 64 mg (77%). [α]D25 = 13.5°
(c= 0.3, CH2Cl2, from adduct of 99% ee). IR (/ cm–1): 3356 (O–H), 1716
1
(C=O). H NMR (300 MHz, CDCl3), δ: 8.00–7.91 (m, 2H), 7.55–7.43 (m,
3H), 7.34–7.24 (m, 3H), 7.23–7.14 (m, 2H), 7.12–7.03 (m, 2H), 6.95–6.86
(m, 2H), 5.36 (d, J= 4.2 Hz, 1H), 4.77 (d, J= 6.6 Hz, 1H), 4.54 (dd, J= 6.6,
4.3 Hz, 1H), 4.48 (q, J= 11.7 Hz, 1H), 3.83 (s, 3H). 13C NMR (126 MHz,
CDCl3), δ: 171.9, 164.4, 159.1, 137.6, 130.6, 130.5, 129.2, 128.6, 128.2,
128.1, 127.7, 127.4, 127.1, 117.9, 114.2, 94.1, 72.8, 72.7, 55.6, 53.7, 45.3,
29.9. DAD-QTOF: C26H25NO5 [M+H]+ calcd.: 417.1702, found: 417.1702.
Compound 32: Prepared from compound 31 (41.5 mg, 0.1 mmol)
according to the general procedure. Brown solid, yield: 28.7 mg (69%).
[α]D25= –9.0º (c= 0.4, CH2Cl2, from adduct of 98% ee). Decomp. 130 ºC.
1H NMR (300 MHz, CDCl3), δ: 7.62 (d, J= 8.9 Hz, 2H), 7.46–7.24 (m, 5H),
7.05–6.90 (m, 3H), 6.45 (d, J= 10.2 Hz, 1H), 6.34 (s, 1H), 4.99 (t, J= 11.1
Hz, 1H), 3.89 (s, 3H), 3.84 (d, J= 10.9 Hz, 1H), 3.21–3.12 (m, 1H), 3.10 (d,
J= 9.5 Hz, 1H), 2.61–2.56 (m, 2H). 13C NMR (75 MHz, CDCl3), δ: 203.9,
195.0, 174.9, 163.0, 150.7, 137.0, 130.3, 129.1, 128.2, 128.1, 126.7, 115.4,
96.0, 63.9, 56.2, 51.2, 46.7, 36.8. UPLC-DAD-QTOF: C25H22NO5 [M+H]+
calcd.: 416.1498, found:416.1500.
Compound 28: Prepared from compound 27 (86 mg, 0.2 mmol) according
to the general procedure. Yield: 70 mg (84%). [α]D = 27.5° (c= 0.4,
25
CH2Cl2, from adduct of 99% ee). IR (/ cm–1): 3500 (O–H), 1731 (C=O). 1H
NMR (300 MHz, CDCl3), δ: 8.06–7.94 (m, 2H), 7.58–7.40 (m, 2H), 7.37 (d,
J= 8.6 Hz, 5H), 7.32–7.25 (m, 2H), 7.12–7.06 (m, 1H), 6.93 (d, J= 8.7 Hz,
2H), 5.27 (dd, J= 7.5, 5.1 Hz, 1H), 4.66 (dd, J= 5.9, 5.1 Hz, 1H), 4.52 (d,
J= 5.9 Hz, 1H), 4.35–4.21 (m, 2H), 3.85 (s, 3H), 3.13 (d, J= 7.6 Hz, 1H).
13C NMR (75 MHz, CDCl3), δ: 172.3, 165.1, 159.8, 137.4, 131.4, 130.9,
129.6, 129.2, 128.9, 128.9, 128.0, 128.0, 127.5, 120.2, 114.6, 88.9, 77.9,
74.6, 68.3, 56.0, 47.0, 30.4. DAD-QTOF: C26H25NO5 [M+H]+ calcd.:
417.1702, found: 417.1698.
Acknowledgements
Preparation of spirocycle 29: To a solution of adduct 18Aa (1 eq., 0.1
mmol, 40 mg.) in CH3CN (0.3 mL) at room temperature was added I2 (3
eq., 0.3 mmol, 76 mg) and NaHCO3 (2 eq., 0.2 mmol, 17 mg). The reaction
mixture was stirred at room temperature overnight, then it was diluted with
Et2O and washed with H2O. The organic layer was dried over MgSO4 and
filtered. The solvent was evaporated under reduced pressure, and the
resulting product was crashed with hexane to afford a brown foam. Yield:
44 mg (86%). [α]D25= –11.8º (c= 1.0, CH2Cl2, from adduct of 96% ee). 1H
NMR (300 MHz, CDCl3) δ: 7.46–7.21 (m, 9H), 7.13 (d, J= 7.9 Hz, 2H), 6.79
(dd, J= 10.0, 2.6 Hz, 1H), 6.39 (dd, J= 10.0, 1.4 Hz, 1H), 6.27–6.16 (m,
2H), 5.22 (dd, J= 13.4, 7.5 Hz, 1H), 4.89 (dd, J= 13.4, 7.6 Hz, 1H), 3.90–
3.64 (m, 2H), 3.54 (d, J= 4.6 Hz, 1H). 13C NMR (75 MHz, CDCl3), δ: 200.1,
184.9, 175.8, 148.5, 147.7, 136.9, 134.4, 132.6, 132.5, 131.2, 130.6, 129.8,
129.3, 129.2, 127.5, 106.1, 78.8, 59.4, 57.31, 43.5, 30.5. UPLC-DAD-
Finantial support was provided by the University of the Basque
Country UPV/EHU (UFI QOSYC 11/22), Basque Government
(BG Grant No IT-628-13), and Ministerio de Economía y
Competitividad (MINECO, Grant CTQ2016-78487-C2), Spain, T.
C. thanks MINECO and I. I. and O. O. thank BG for fellowships.
We also thank SGiker (UPV/EHU) for providing NMR, HRMS, and
X-Ray resources.
Keywords: asymmetric catalysis • Brønsted bases • Michael
reaction • organocatalysis • alkynyl ketones
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Entry for the Table of Contents (Please choose one layout)
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T. E. Campano, I. Iriarte, O. Olaizola, J.
Etxabe, A. Mielgo, I. Ganboa, J. M.
Odriozola, J. M. García, M. Oiarbide*, C.
Palomo*
Page No. – Page No.
Enantioselective Addition of Alkynyl
Ketones to Nitroolefins Assisted by
Brønsted Base/H-Bonding Catalysis.
Donor ynones: under very mild conditions linear ynones with no additional EWG at
C get activated by tertiary amine/squaramide chiral catalysts and react with
nitroolefins in a highly diastereo- and enantioselective fashion. This way, an easy
entry to branched alkyl alkynyl ketones with two contiguous stereocenters and
derivatives thereof is provided.
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