Organocatalytic asymmetric direct α-alkynylation of cyclic β-ketoesters

Article abstract of DOI:10.1021/ja067289q

The first organocatalytic enantioselective direct α-alkynylation of β-ketoesters and 3-acyl oxindoles is described. It is demonstrated that activated β-halo-alkynes undergo nucleophilic acetylenic substitution catalyzed by chiral phase-transfer compounds to afford the alkynylated products in high yields and excellent enantioselectivities. The potential of the reaction is first demonstrated for various alkynylating reagents having chloride and bromide as the leaving groups and substituents such as allyl and alkyl esters, amides, ketones, and sulfones. These reactions proceed with 74-99% yield and 88-97% ee. Then the scope in nucleophile is demonstrated for a large number of cyclic β-ketoesters with various ring-sizes and for oxindoles as well. The corresponding optically active products are formed in high yields and with enantioselectivities up to 98% ee. The procedure allows for the stereocontrolled attachment of an ethynyl unit in the α-position to the carbonyl compound by facile removal of the activating group, and this has been demonstrated for a number of the optically active allyl esters. Furthermore, the synthesis of optically active 1,4-enynes is also shown. The isolation and characterization by X-ray analysis of the catalyst with p-nitrophenolate as the counterion allowed us to propose a model of the catalyst-substrate intermediate which might account for the observed enantioselectivity of the organocatalytic enantioselective α-alkynylation reaction. Furthermore, it is suggested that this intermediate is also the reactive species for a number of other electrophiles adding to β-ketoesters giving enantioselectivities in the range of 90-98% ee.

Full text of DOI:10.1021/ja067289q

Published on Web 12/22/2006
Organocatalytic Asymmetric Direct r-Alkynylation of Cyclic
â-Ketoesters
Thomas B. Poulsen, Luca Bernardi, Jose´ Alema´n, Jacob Overgaard, and
Karl Anker Jørgensen*
Contribution from the Department of Chemistry, Center for Catalysis, Danish National Research
Foundation, Aarhus UniVersity, DK-8000 Aarhus C, Denmark
Received October 11, 2006; E-mail: kaj@chem.au.dk
Abstract: The first organocatalytic enantioselective direct R-alkynylation of â-ketoesters and 3-acyl oxindoles
is described. It is demonstrated that activated â-halo-alkynes undergo nucleophilic acetylenic substitution
catalyzed by chiral phase-transfer compounds to afford the alkynylated products in high yields and excellent
enantioselectivities. The potential of the reaction is first demonstrated for various alkynylating reagents
having chloride and bromide as the leaving groups and substituents such as allyl and alkyl esters, amides,
ketones, and sulfones. These reactions proceed with 74-99% yield and 88-97% ee. Then the scope in
nucleophile is demonstrated for a large number of cyclic â-ketoesters with various ring-sizes and for oxindoles
as well. The corresponding optically active products are formed in high yields and with enantioselectivities
up to 98% ee. The procedure allows for the stereocontrolled attachment of an ethynyl unit in the R-position
to the carbonyl compound by facile removal of the activating group, and this has been demonstrated for a
number of the optically active allyl esters. Furthermore, the synthesis of optically active 1,4-enynes is also
shown. The isolation and characterization by X-ray analysis of the catalyst with p-nitrophenolate as the
counterion allowed us to propose a model of the catalyst-substrate intermediate which might account for
the observed enantioselectivity of the organocatalytic enantioselective R-alkynylation reaction. Furthermore,
it is suggested that this intermediate is also the reactive species for a number of other electrophiles adding
to â-ketoesters giving enantioselectivities in the range of 90-98% ee.
Introduction
Chiral molecules containing a carbon-carbon triple bond with
an adjacent stereogenic carbon-atom (propargylic stereocenter)
Since the discovery of ethyne by Edmund Davy in 1836 the
carbon-carbon triple bond has fascinated chemists. The linear
geometry and the electronic properties associated with the sp-
hybridized carbon atoms, give alkynes a unique chemical
reactivity that has been exploited for numerous transformations
in organic chemistry.1 In recent times, the interest in alkynes
has expanded beyond organic chemistry to also include, for
example, chemical biology, organometallic chemistry, material
science, and nanoscience. In the field of organic chemistry, a
recent example of a reaction involving the carbon-carbon triple
bond with applications in growing scientific areas such as
nanoscience and chemical biology2 is the copper-catalyzed
cycloaddition of azides to acetylenes pioneered by the groups
of Sharpless3a and Meldal.3b
have found great use both as optically active building blocks
in the synthesis of natural products4 and as bioactive compounds
possessing antiviral properties.5 Therefore, the efficient asym-
metric synthesis of propargylic stereocenters has attracted the
attention of many chemists, and within the past few years,
reaction protocols employing optically active catalysts have been
disclosed by several groups.6,7 Fundamental studies in this
(4) See, for example: (a) Denmark, S. E.; Yang, S.-M. J. Am. Chem. Soc.
2002, 124, 15196. (b) Bode, J. W.; Carreira, E. M. J. Am. Chem. Soc.
2001, 123, 3611.
(5) See, for example: (a) Jiang, B.; Si, Y.-G. Angew. Chem., Int. Ed. 2004,
43, 216. (b) Corbett, J. W.; Ko, S. S.; Rodgers, J. D.; Gearhart, L. A.;
Magnus, N. A.; Bacheler, L. T.; Diamond, S.; Jeffrey, S.; Klabe, R. M.;
Cordova, B. C.; Garber, S.; Logue, K.; Trainor, G. L.; Anderson, P. S.;
Erickson-Viitanen, S. K. J. Med. Chem. 2000, 43, 2019.
(6) For additions to aldehydes catalytic in metal see: (a) Anand, N. K.; Carreira,
E. M. J. Am. Chem. Soc. 2001, 123, 9687. (b) Jiang, B.; Chen, Z.; Tang,
X. Org. Lett. 2002, 4, 3451. (c) Takita, R.; Yakura, K.; Ohshima, T.;
Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 13760. (d) Chen, Z.; Xiong,
W.; Jiang, B. Chem. Commun. 2002, 2098. For procedures stoichiometric
in metal, see: (e) Frantz, D. E.; Fa¨ssler, R.; Carreira, E. M. J. Am. Chem.
Soc. 2000, 122, 1806. (f) Trost, B. M.; Weiss, A. H.; von Wangelin, A. J.
J. Am. Chem. Soc. 2006, 128, 8. (g) Lui, L.; Wang, R.; Kang, Y.-F.; Cai,
H.-Q.; Chen, C. Synlett 2006, 1245. For additions to imines catalytic in
metal see: (h) Wei, C; Li, C.-J. J. Am. Chem. Soc. 2002, 124, 5638. For
procedures stoichiometric in metal, see ref 5a. For catalytic conjugate alkyne
addition, see: (i) Kno¨pfel, T. F.; Zarotti, P.; Ichikawa, T.; Carreira, E. M.
J. Am. Chem. Soc. 2005, 127, 9682. (j) Frantz, D. E.; Fa¨ssler, R.; Tomooka,
C. S.; Carreira, E. M. Acc. Chem. Res. 2000, 33, 373. (k) Aschwanden, P.;
Carreira, E. M. in Acetylene Chemistry; Diederich, F., Stang, P. J.,
Tykwinski, R. R., Eds.; VCH: Weinheim, Germany, 2005, Chapter 3, pp
101-138.
(1) (a) The Chemistry of the Carbon-Carbon Triple Bond; Patai, S., Ed.; Wiley:
New York, 1978; Part 1-2. (b) Modern Acetylene Chemistry; Stang, P. J.;
Diederich, F., Eds.; VCH: Weinheim, Germany, 1995. (c) Acetylene
Chemistry; Diederich, F.; Stang, P. J.; Tykwinski, R. R., Eds.; VCH:
Weinheim, Germany, 2005.
(2) See, for example: (a) Speers, A. E.; Adam, G. C.; Cravatt, B. F. J. Am.
Chem. Soc. 2003, 125, 4686. (b) Prescher, J. A.; Bertozzi, C. R. Nat. Chem.
Biol. 2005, 1, 13. (c) Burley, G. A.; Gierlich, J.; Mofid, M. R.; Nir, H.;
Tal, S.; Eichen, Y.; Carell, T. J. Am. Chem. Soc. 2006, 128, 1398. (d)
Dichtel, W. R.; Miljanic´, O. Sˇ.; Spruell, J. M.; Heath, J. R.; Stoddart, J. F.
J. Am. Chem. Soc. 2006, 128, 10388.
(3) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew.
Chem., Int. Ed. 2002, 41, 2596. (b) Tornøe, C. W.; Christensen, C.; Meldal,
M. J. Org. Chem. 2002, 67, 3057.
9
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J. AM. CHEM. SOC. 2007, 129, 441-449
441

A R T I C L E S
Poulsen et al.
Scheme 1. Two Methods for the Construction of Propargylic Stereocenters with Concomitant Formation of the C-C Bonda
a (Left) Addition of metal-acetylides to prochiral electrophiles; (right) acetylenic substitution by prochiral nucleophiles.
respect have been carried out by the group of Carreira.6a,e,j
A
[3.3.1]nonane skeleton found in the polycyclic polyprenylated
acylphloroglucinols.12
common feature of the procedures published thus far is their
reliance on the catalytic formation of optically active metal-
acetylides which can add to a number of different prochiral
electrophiles (Scheme 1, left). This approach has been successful
in the addition of terminal alkynes to carbonyl compounds,6a-g
imines,6h,5a and more recently to R,â-unsaturated carbonyl
derivatives.6i Unfortunately, terminal alkynes equipped with
electron-withdrawing groups (e.g., propiolates and propynones)
have rarely been applied with success in these types of reactions
owing to self-addition of the activated alkynes under the basic
reaction conditions.8
An alternative approach to the formation of propargylic
stereocenters can be envisioned by inverting the reactivity of
the acetylenic system. For instance, triple bonds equipped with
potential leaving groups, such as halides, can under suitable
conditions substitute the leaving group for a carbanion nucleo-
phile via an addition-elimination mechanism (Scheme 1, right).
Such acetylenic substitutions have been reported for several
combinations of haloalkynes and both carbon- and heteroatom-
centered nucleophiles,9 and in the case of an enolate as the
nucleophile, this reaction results in the R-alkynylation (assuming
C-regioselectivity) of the corresponding carbonyl compound.
The R-alkynylation of enolates can also be realized through
the use of hypervalent alkynyl-main-group derivatives such
as alkynyl-iodonium salts,10 or alternatively using in situ
formed alkynyl-lead triacetate reagents.11 Mechanistically, the
former reaction has been shown to involve the formation of a
carbene intermediate eventually rearranging to the R-alkynylated
carbonyl compound, while the latter proceeds through formation
of an enolate alkynyl-lead intermediate which collapses to
afford the same product. It is worth mentioning, that enolate
alkynylations of the latter type were recently applied by the
group of Grossman in the racemic synthesis of the bicyclo-
Scheme 2. Catalytic Enantioselective Acetylenic Substitution
Despite the synthetic utility of such enolate alkynylations,
enantioselective variants of the different reactions outlined above
have remained unexplored.13 In this paper we wish to provide
a contribution toward this goal, namely the development of
organocatalytic enantioselective alkynylation of â-ketoesters
through phase-transfer-catalyzed14 acetylenic substitution (Scheme
2).
Results and Discussion
Electrophile Synthesis and Scope. It is important to mention
some considerations related to the choice of the acetylenic
electrophile. As shown below, it is possible to employ different
haloalkynes in the reaction. We were, however, especially
intrigued by the possibility of choosing one of the groups so
that it could be “exchanged” with hydrogen in one easy chemical
transformationsthereby enabling the attachment of an ethynyl
unit in an enantioselective manner.
It became apparent to us, that compounds such as 2a,b and
4 outlined in Figure 1 possessed these features. However, as
alkyne 4 is a suspected carcinogen15 and is known to form
explosive mixtures with air,13 we decided to focus our attention
on allyl 3-halopropiolates 2a,b.16
Traditionally, the synthesis of haloalkynes is performed
through formation of a metal-acetylide followed by reaction with
an electrophilic halogen-source. For instance, the reaction
between an alkyne and N-bromosuccinimide (NBS) in the
(7) Asymmetric synthesis of propargylic stereocenters can also be achieved
through the Nicholas reaction, for a review see: (a) Teobald, B. J.
Tetrahedron 2002, 58, 4133. By asymmetric reduction of ynones (prop-
argylic alcohols): (b) Helal, C. J.; Magriotis, P. A.; Corey, E. J. J. Am.
Chem. Soc. 1996, 118, 10938. By resolution of racemic propargylic
alcohols: (c) Birman, V. B. M.; Guo, L. Org. Lett. 2006, 8, 4859 and
references herein.
(8) For a discussion of this problem and an alternative solution, see: Tejedor,
D.; Garc´ıa-Tellado, F.; Marrero-Tellado, J. J.; de Armas, P. Chem.sEur.
J. 2003, 9, 3122.
(9) For a review see: (a) Miller, S. I.; Dickstein, J. I. Acc. Chem. Res. 1976,
9, 358. (b) Dickstein, J. I.; Miller, S. I. in The Chemistry of the Carbon-
Carbon Triple Bond; Patai, S., Ed.; Wiley: New York, 1978; Part 2
p 523.
(12) Ciochina, R.; Grossman, R. B. Org. Lett. 2003, 5, 4619.
(13) For racemic acetylenic substitutions involving enolates see: (a) Kende, A.
S.; Fludzinski, P.; Hill, J. H.; Swenson, W.; Clardy, J. J. Am. Chem. Soc.
1984, 106, 3551. (b) Jon´czyk, A.; Kulin´ski, T.; Czupryniak, M.; Balcerzak,
P. Synlett 1991, 639.
(14) For a review: (a) O’Donnell, M. J. In Catalytic Asymmetric Synthesis,
2nd ed.; Ojima I., Ed.; Wiley-VCH: Weinheim, Germany, 2000; p 727.
For recent examples of phase-transfer catalyzed asymmetric reactions,
see: (b) Ooi, T.; Uematsu, Y.; Maruoka, K. J. Am. Chem. Soc. 2006, 128,
2548. (c) Fini, F.; Sgarzani, V.; Pettersen, D.; Herrera, R. P.; Bernardi, L.;
Ricci, A. Angew. Chem., Int. Ed. 2005, 44, 7975. (d) Okada, A.; Shibuguchi,
T.; Ohshima, T.; Masu, H.; Yamaguchi, K.; Shibasaki, M. Angew. Chem.,
Int. Ed. 2005, 44, 4564. (e) Ooi, T.; Kameda, M.; Maruoka, K. J. Am.
Chem. Soc. 2003, 125, 5139. (f) Ooi, T.; Miki, T.; Taniguchi, M.; Shiraishi,
M.; Takeuchi, M.; Maruoka, K. Angew. Chem., Int. Ed. 2003, 42, 3981.
(g) Park, H.-g.; Jeong, B.-S.; Yoo, M.-S.; Lee, J.-H.; Park, M.-k.; Lee,
Y.-J.; Kim, M.-J.; Jew, S.-s. Angew. Chem., Int. Ed. 2002, 41, 3036. (h)
Kita, T.; Georgieva, A.; Hashimoto, Y.; Nakata, T.; Nagasawa, K. Angew.
Chem., Int. Ed. 2002, 41, 2832. (i) Palomo, C.; Oiarbide, M.; Laso, A.;
Lo´pez, R. J. Am. Chem. Soc. 2005, 127, 17622. (j) Fini, F.; Bernardi, L.;
Herrera, R. P.; Pettersen, D.; Ricci, A.; Sgarzani, V. AdV. Synth. Catal.
2006, 348, 2043.
(10) For reviews see: (a) Stang, P. J. J. Org. Chem. 2003, 68, 2997. (b) Stang,
P. J. In Modern Acetylene Chemistry; Stang, P. J., Diederich, F., Eds.; VCH:
Weinheim, Germany, 1995; Chapter 3, pp 67-98. (c) Stang, P. J. Angew.
Chem., Int. Ed. 1992, 31, 274. See also: (d) Kitamura, T.; Nagata, K.;
Taniguchi, H. Tetrahedron Lett. 1995, 36, 1081. (e) Bachi, M. D.;
Bar-Ner, N.; Stang, P. J.; Williamson, B. L. J. Org. Chem. 1993, 58,
7923.
(11) See, for example: Moloney, M. G.; Pinhey, J. T.; Roche, E. G. J. Chem.
Soc., Perkin Trans. 1 1989, 333.
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-Alkynylation of Cyclic
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-Ketoesters
A R T I C L E S
Scheme 3. Synthesis of Activated â-Haloalkynes 2a-ia
a For details, see Supporting Information.
presence of catalytic amounts of AgNO3 has been a popular
method for the introduction of bromine.17 To our surprise, this
method failed for the synthesis of 2a (Scheme 3, top).18
We therefore carried out the synthesis by dibutyltin(IV) oxide-
catalyzed transesterification with allylic alcohol of the corre-
sponding methyl ester (69% yield, Scheme 3, middle), which
was easily prepared by the AgNO3-catalyzed bromination
mentioned above. Using similar chemistry, several other acti-
vated â-bromoalkynes 2c-f,h having different activating groups
were also prepared, whereas the synthesis of chloro-derivatives
2b,g and 2i required the use of tert-butyl hypochlorite as the
halide-source and potassium tert-butoxide as the catalyst
(Scheme 3, bottom).19
Having synthesized the different activated â-haloalkynes 2,
we surveyed their ability to act as alkynylating agents in a model
reaction employing tert-butyl 1-oxo-2,3-dihydro-1H-indene-2-
carboxylate 1a as the nucleophile (eq 1, Table 1). The phase-
transfer-catalyst system employed was recently developed by
our group to effect enantioselective vinylic substitution reactions
of â-ketoesters.20 In this work, three parameters were identified
to be critical for obtaining high enantioselectivities: (i) the
â-ketoesters employed had to be equipped with bulky ester
groups (e.g., tert-butyl), (ii) the reactions should be carried out
in a liquid-liquid phase-transfer system, and (iii) the phase-
transfer-catalysts (based on N-anthracenemethyl dihydrocin-
chonine 5a or the quasienantiomer 5′a, see Figure 2) had to be
functionalized on the C9-hydroxyl group with sterically de-
manding substituents. This resulted in the preparation of the
corresponding 1-adamantoyl derivatives (5b and 5′b) which
were found to afford the highest enantioselectivities.20
As demonstrated in Table 1, this catalyst system was found
to be highly effective for the acetylenic substitution reaction.
Attempts to modify the catalyst structure and/or the solvent
system, resulted in lower enantioselectivities (see Supporting
Information). It is possible to employ alkynes equipped with
ester groups (entries 1, 2), amides (entry 3), ketones (entries 4,
5), and sulfones (entry 6), and in all cases we obtained the
alkynylated â-ketoesters 3a-f in good to high yields (62-99%)
and with excellent stereoselectivities (generally >95% ee; for
3f, 90% ee). The reactivity of the catalytic system was found
to be easily fine-tuned through the choice of the aqueous base
employed and the identity of the leaving group (Cl or Br). For
instance, in the case of â-haloalkyne 2d having an amide as
the activating group (entry 3), the reaction was found to be
sluggish when using aq K2CO3 (33%); however, the presence
of a more concentrated base solution (50% Cs2CO3) resulted in
complete consumption of the starting material within 24 h at
-20 °C. The choice of the leaving group serves two purposes
in this respect. Exchange of bromide for chloride generally
results in a more reactive electrophile;9b however, it also
effectively eliminates a possible side reaction of the system,
namely, the attack of the nucleophile on the halide resulting in
release of the terminal acetylene eventually resulting in ad-
ditional side reactions (e.g., addition on the triple bond by the
â-ketoester, see also mechanistic discussion later). Problems of
this kind were encountered in the case of highly electron-
deficient bromoalkynes 2f and 2h and in both cases the
preparation of the corresponding chloride compounds 2g and
2i restored the “normal” reactivity.
(15) Green, T. Hum. Ecol. Risk Assess. 2001, 7, 677.
(16) The allyloxycarbonyl (alloc) group can be removed from an alkyne by
palladium(0)-catalyzed deallylation-decarboxylation. See: (a) Greene, T.
W.; Wuts, P. G. M. In ProtectiVe Groups in Organic Synthesis, 3rd ed.;
Wiley: New York, 1999; p 409. (b) Okamoto, S.; Ono, N.; Tani, K.;
Yoshida, Y.; Sato, F. J. Chem. Soc., Chem. Commun. 1994, 279.
(17) Hofmeister, H.; Annen, K.; Laurent, H.; Wiechert, R. Angew. Chem., Int.
Ed. 1984, 23, 727.
(18) Upon addition of AgNO3 (10 mol%) to the reaction mixture in acetone we
observed the immediate formation of a greyish precipitate. This precipitate
is presumed to originate from a reaction between the silver(I) and allyl
propiolate resulting in irreversible removal of catalyst from the catalytic
cycle.
Nucleophile Synthesis and Scope. As stated above, a bulky
tert-butyl ester group in the â-dicarbonyl compounds was found
to be requisite for obtaining good enantioselectivities in the
substitution reactions catalyzed by the cinchonine and cinchoni-
dine catalysts 5b and 5′b. Although the importance of this bulky
ester moiety is in line with a number of different reports dealing
with enantioselective transformations of cyclic â-ketoesters,21
(19) Acheson, R. M.; Ansell, P. J.; Murray, J. R. J. Chem. Res., Synop. 1986,
378.
(20) Poulsen, T. B.; Bernadi, L.; Bell, M.; Jørgensen, K. A. Angew. Chem., Int.
Ed. 2006, 45, 6551.
9
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A R T I C L E S
Poulsen et al.
Figure 1. Two types of activated halo-alkynes enabling easy two-step attachment of an ethynyl unit by initial acetylenic substitution followed by removal
of the other group.
Figure 2. Structures of the dihydrocinchonine and dihydrocinchonidine derived catalysts 5 and 5′.
Table 1. Catalytic Enantioselective Acetylenic SubstitutionsScope
easy access to these compounds seems to be limited to indanone
derivatives like 1a-d, available through a transesterification
of Alkynylating Agents.a
reaction,22 and to unsubstituted, non-ring-fused compounds like
1g and 1h, obtainable through a Dieckmann condensation.23
However, we thought it would be of some interest to extend
our enantioselective reaction also to substituted cyclohexenone
derivatives, in light of the importance of these structures for
target-oriented synthesis.24 Considering the previously reported
possibility of a regioselective C-acylation of cyclohexenones
with methyl or allyl cyanoformate,25 we tested the acylation of
a few cyclohexenones with tert-butyl cyanoformate 626 under
similar conditions, giving the corresponding tert-butyl â-ke-
toesters 1i-k in reasonable yields and complete C-regioselec-
tivities (Scheme 4, top). The same reaction could also be used
for the preparation of the 1-tetralone and 1-benzosuberone
derivatives 1e and 1f (Scheme 4, bottom).
Although 1e and 1f were obtained only in rather low
(unoptimized) yields, the easy availability in multigram quanti-
ties of the tert-butyl cyanoformate 6 and the difficult obtainment
of 1e and 1f or structurally related tert-butyl â-ketoesters by
other procedures,27 render this approach useful for the prepara-
tion of these classes of compounds.
Having in our hands different tert-butyl â-ketoesters, we then
explored their reactivity and their behavior in the catalytic
enantioselective acetylenic substitution reaction. We focused on
(21) See for example: (a) Wu, F.; Li, H.; Hong, R.; Deng, L. Angew. Chem.,
Int. Ed. 2006, 45, 947. (b) Hamashima, Y.; Hotta, D.; Sodeoka, M. J. Am.
Chem. Soc. 2002, 124, 11240. (c) Hamashima, Y.; Yagi, K.; Takano, H.;
Tamas, L.; Sodeoka, M. J. Am. Chem. Soc. 2002, 124, 14530. (d) Sobhani,
S.; Fielenbach, D.; Marigo, M.; Wabnitz, T.; Jørgensen, K. A. Chem.-
Eur. J. 2005, 11, 5689. (e) Ooi, T.; Miki, T.; Taniguchi, M.; Shiraishi, M.;
Takeuchi, M.; Maruoka, K. Angew. Chem., Int. Ed. 2003, 42, 3796. (f)
Park, E. J.; Kim, M. H.; Kim, D. Y. J. Org. Chem. 2004, 69, 6897.
(22) (a) Otera, J.; Yano, T.; Kawabata, T.; Nozaki, H. Tetrahedron Lett. 1986,
27, 2383. (b) Nakajima, M.; Yamamoto, S.; Yamaguchi, Y.; Nakamura,
S.; Hashimoto, S. Tetrahedron 2003, 59, 7307.
(23) Bunnage, M. E.; Davies, S. G.; Parkin, R. M.; Roberts, P. M.; Smith, A.
D.; Withey, J. M. Org. Biomol. Chem. 2004, 2, 3337.
(24) For examples see: (a) Spassard, S. J.; Stoltz, B. M. Org. Lett. 2002, 4,
a Reaction performed with 0.20 mmol of 1a (0.15 M). b Isolated yield.
1943. (b) Ursuda, H.; Kanai, M.; Shibasaki, M. Org. Lett. 2002, 4, 8591.
c The enantiomeric excess was determined by HPLC using a chiral-stationary
(c) Miyashita, M.; Sasaki, M.; Hattori, I.; Sakai, M.; Tanino, K. Science
phase. d Reaction performed with the quasienantiomeric catalyst 5′b derived
from dihydrocinchonidine. e Reaction performed using Cs2CO3 (50%, aq)
as the base and with the amide as the limiting reagent; yield based on the
2004, 305, 495. (d) Ho, T.-L. EnantioselectiVe Synthesis: Natural Products
Synthesis from Chiral Terpenes; Wiley: New York, 1992. (e) Klunder, A.
J. H.; Zhu, J.; Zwanenburg, B. Chem. ReV. 1999, 99, 1163. See also ref
12.
f
amide. Absolute configuration determined by chemical correlation (see
(25) (a) Mander, L. N.; Sethi, S. P. Tetrahedron Lett. 1983, 24, 5425. (b) Mohr,
J. T.; Behenna, D. C.; Harned, A. M.; Stoltz, B. M. Angew. Chem., Int.
Ed. 2005, 44, 6924.
Supporting Information). g Reaction performed at 4 °C using chloroalkyne
2i; in brackets is shown the result obtained using bromoalkyne 2h at -20
°C.
(26) Carpino, L. A. J. Am. Chem. Soc. 1960, 82, 2725.
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444 J. AM. CHEM. SOC. VOL. 129, NO. 2, 2007

R
-Alkynylation of Cyclic
â
-Ketoesters
A R T I C L E S
Scheme 4. Preparation of tert-Butyl â-Ketoesters through Acylation with tert-Butyl Cyanoformate 6
the use of chloro and bromo alkynes 2a and 2b, since the
possible removal of the allyl ester moiety through a Pd(0)-
catalyzed deallylation-decarboxylation reaction (see below) can
provide an easy access to the corresponding derivatives bearing
a simple acetylenic unit, available for further chemical manipu-
lations. As shown in Table 2, the tuning of the base properties
of the aqueous phase, together with the use of the appropriate
leaving group on the alkyne, allowed the obtainment of a range
of products 3g-q derived from different cyclic tert-butyl
ketoesters 1b-k in good yields and generally good enantiose-
lectivities, using the dihydrocinchonine derived salt 5b as the
catalyst (entries 1-11). Two examples demonstrate the possible
access to the opposite enantiomer of the products, with nearly
similar results, using the quasienantiomeric catalyst 5′b derived
from dihydrocinchonidine (entries 4, 10).
K2HPO4 at -20 °C (entries 2, 3). In contrast, the reactions
employing the 1-tetralone and 1-benzosuberone derived â-ke-
toesters 1e and 1f proceeded only sluggishly when aq K2CO3
was used as the bulk base. However, as observed before (see
Table 1) the reaction rate could be dramatically increased by
simply employing a more basic aqueous solution (aq Cs2CO3),
allowing the isolation of the corresponding adducts 3j and 3k
in satisfactory yields (entries 4, 5), although 3k was obtained
with a rather low enantioselectivity.28 Similar reaction conditions
furnished with very good results compound 3l derived from the
cyclopentanone derived â-ketoester 1g (entry 6), which proved
to be a competent substrate also in the reaction with a
â-bromoalkynone such as 2e (entry 7). The cyclohexanone
derivative 1h was instead found to be rather reluctant in
undergoing this alkynylation reaction, as only a combination
of a stronger base such as aq K3PO4 with the use of the more
reactive â-chloroalkyne 2b as the electrophilic partner could
lead to a good isolated yield in the corresponding adduct 3n
(Table 2, entry 8). The excellent enantioinduction (97% ee)
observed for this substrate even at +4 °C demonstrates the high
efficiency of catalyst 5b for six-member ring substrates (see
also entry 4), confirmed by the results obtained with the
cyclohexenone derivatives 1i-k, all giving very high enanti-
oselectivities at the same temperature (entries 9-11). In the last
three examples, despite the inherently lower reactivity of the
parent â-ketoesters 1i-k, the corresponding products 3n-q
could be formed with satisfactory yields simply using a diluted
NaOH aqueous solution as the bulk base in the reaction.
Although the reaction time in these cases must be controlled to
some extent (see Supporting Information), the stability of these
adducts in the biphasic reaction conditions with diluted aq
NaOH, as well as the absence of decomposition for the
cyclopentanone and cyclohexanone derivatives 3l-n in the
presence of relatively strongly basic aqueous solutions, is worthy
of note, as the hydroxide promoted retro-Dieckmann reaction
for this kind of compounds is a known process, reported to occur
under mild conditions.29
As a first example, we investigated the reactivity of 1-in-
danone derivative 1b bearing the ubiquitous 6,7-dimethoxy
motif, which afforded the corresponding alkynylated product
3g in very good yield and enantioselectivity (Table 2, entry 1).
A clear evidence of the necessary tuning of the strength of the
bulk base in relation to the basicity and reactivity of the
â-ketoester employed, came from the catalytic alkynylation
reaction using the 6-chloroindan-1-one and the 2-indanone
derived â-ketoesters 1c,d. At first, we attempted to perform the
reaction under the conditions used successfully for their
corresponding 1-indanone derivatives 1a,b (aq K2CO3 33%, -20
°C), but obtained a disappointing result in terms of the
enantiomeric excess of the adducts 3h and 3i (64% and 18%
ee, respectively). We attributed these low values to the presence
of a background reaction, promoted by the inorganic base. Since
a further cooling of the reaction mixture turned out to be
unpractical, owing to the freezing of the aqueous phase, we
realized that a possible solution relied on the use of an
appropriate, milder inorganic base, and after considerable
experimentation (see Supporting Information, Tables S1-4) we
found that the R-alkynylated products 3h and 3i could be
obtained with a satisfactory level of enantioselectivity using aq
As a final test of the efficiency of the catalytic system we
synthesized triisopropylsilyl 2-ether indole 1l.30 It was antici-
(27) The only described synthesis of 1e proceeds through a Pd-catalyzed
carbonylation reaction from the corresponding bromo derivative: Raju, P.
V. K.; Adapa Srinivas, R. Indian J. Chem., Sect. B 1992, 31, 363. In our
hands, the transesterification from the methyl ester in the conditions used
for indanones 1a-d (ref 22) proceeded only sluggishly (conversion <50%
after several days), though providing the expected product.
(28) Apparently, the present catalytic system does not accommodate relatively
flexible substrates: for example, a noncyclic â-ketoester such as tert-butyl
2-methyl-3-oxo-3-phenylpropanoate could be alkynylated only with low
enantioselectivities (<20% ee).
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A R T I C L E S
Poulsen et al.
Table 2. Catalytic Enantioselective Acetylenic SubstitutionsScope of the Nucleophilea
a Reaction performed with 0.20 mmol of 1 (0.15 M). b Isolated yield. c The enantiomeric excess was determined by HPLC using a chiral stationary phase.
d 2a used as the electrophile. e 2b used as the electrophile. f Reaction performed with the quasienantiomeric catalyst 5′b derived from dihydrocinchonidine.
g 2e used as the electrophile. h Absolute configuration determined by chemical correlation (see Supporting Information). i A total of 2 equiv of 2b used as
the electrophile.
pated that a change of the aqueous base to KF (33%) would
facilitate in situ desilylation of the ether indole resulting in
release of the oxindole-enolate, which would then undergo the
acetylenic substitution guided by the chiral phase-transfer
catalyst. To the best of our knowledge, no previous examples
of the use of such nucleophiles in phase-transfer catalyzed
reactions have been reported. We were therefore very pleased
to observe that the reaction occurred smoothly at -20 °C
affording the 3-alkynylated quaternary 2-oxindole 3r in 95%
yield and 85% ee. This result is significant because of the
9
446 J. AM. CHEM. SOC. VOL. 129, NO. 2, 2007

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-Alkynylation of Cyclic
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-Ketoesters
A R T I C L E S
Table 3. Removal of the Alloc-Group by Pd(0)-Catalyzed
Deallylation-Decarboxylation
Scheme 5. Synthesis of 1,4-Enynes by Catalytic Decarboxylative
sp-sp3 Coupling
allyl-scavenger which results in the rupture of the cyclopen-
tanone ring by retro-Dieckmann reaction.29 It was found,
however, that sodium phenyl sulfinatesbeing less nucleophilic
than morpholinescould be used as an alternative allyl-scavenger
allowing the isolation of 7b in 58% yield.
Omitting the allyl scavenger from the reaction mixture allows
another important chemical transformation of the R-alkynylated
carbonyl compounds. As was recently demonstrated by Tunge
et al.33 the intermediate palladium-allyl-acetylide may undergo
reductive elimination resulting in the coupling of the alkyne
with the allyl fragment as exemplified for compound 3l (Scheme
5). The resulting 1,4-enyne 8 was obtained in 74% yield and
with unchanged optical purity confirmed by HPLC.
X-ray Crystal Structure and Mechanistic Considerations.
Historically, acetylenic substitution was the last type of nucleo-
philic substitution reaction to be realized in the laboratory34 and
in the years following, the reaction mechanism was heavily
debated by various investigators. Although SN1- and SN2-type
(concerted) substitution mechanisms have been considered, both
mechanisms were finally refuted - the former because of the
instability of the intermediate alkynyl-cation35 necessarily
involved and the latter because of unfavorable steric and
electronic factors. With compounds such as 2 there is now
increasing evidence that the mechanism involves carbanionic
intermediates, formed by initial addition of the nucleophile to
the electrophilic triple bond at C3, and that these interme-
diates undergo rapid elimination of the nucleofuge reform-
ing the acetylene.9 Using â-ketoester 1a as a model, the pro-
posed addition-elimination mechanism is presented in
Scheme 6.
Alkali-metal enolate 1aa, formed from 1a by deprotonation
by the bulk aqueous base, first undergoes cation exchange with
the chiral phase-transfer catalyst, which leads to organic soluble
ammonium enolate 1aA as a tight ion-pair. This enolate adds
to â-haloalkyne 2 in a highly enantioselective manner, owing
to the chiral environment provided by the ammonium salt,
forming initially ammonium allenolate 3aa. The allenolate might
undergo elimination of X directly resulting in the release of
alkynylated product 3a or get protonated to form trisubstituted
vinylic ester 3ab.36 Previous experiments revealed that â-halo
substituted enones, which are closely related to 3ab, do not
undergo elimination of HX to any appreciable extent in the
presence of aqueous bases such as K2CO3 or Cs2CO3.20 As we
have never observed the formation of products of type 3ab, it
seems most likely that elimination of the halide occurs from
allenoate 3aa in a comparatively fast process and that the
substrate is not released from the phase-transfer catalyst until
the elimination has taken place.
a Isolated yield. b PhSO2Na (1.2 equiv) was used as the allyl-scavenger.
abundance of oxindole containing natural products with an all-
carbon quaternary stereocenter in the 3-position of the hetero-
cycle.31 Fu et al. have previously devised a catalytic asymmetric
strategy toward these types of quaternary oxindoles based on
the use of chiral nucleophilic catalysts;32 however, no examples
of products bearing an alkynyl substituent were reported.
Product Elaborations. As mentioned above, we anticipated
that the allyloxycarbonyl moeity would undergo facile depro-
tection when subjected to catalytic amounts of Pd(0) and an
appropriate allyl-scavenger,16 and in Table 3 are shown some
representative results for this deprotection. In the presence of
10% Pd(PPh3)4 and 1.2 equiv of morpholine, all compounds
tested underwent the deprotection (easily monitored by TLC-
analysis) within minutes at 65 °C. After column chromatogra-
phy, the deprotected compounds 7a-d were obtained in good
yields (generally around 70%) and, as expected, with complete
fidelity of the enantiomeric excess. In the case of compound 3l
(entry 2) the conditions mentioned above should be avoided.
The five-membered ring present in this compound renders the
ketone reactive enough to undergo nucleophilic attack by the
(29) (a) Nagao, Y.; Kim, K.; Sano, S.; Kakegawa, H.; Lee, W. S.; Shimizu, H.;
Shiro, M.; Katunuma, N. Tetrahedron Lett. 1996, 37, 861. (b) Sano, S.;
Shimizu, H.; Nagao, Y. Tetrahedron Lett. 2005, 46, 2883.
(30) The parent 3-acyl oxindole was obtained by acylation of N-Me-oxindole
with tert-butyl cyanoformate 6. These compounds are inherently unstable
towards isolation by chromatography on silica gel. To facilitate isolation,
the 3-acyl oxindole was converted to the 2-silyl ether indole 1l (see
Supporting Information for details).
(31) For recent total syntheses of compounds possessing this structural feature,
see for example: (a) Reisman, S. E.; Ready, J. M.; Hasuoka, A.; Smith, C.
J.; Wood, J. L. J. Am. Chem. Soc. 2006, 128, 1448. (b) Madin, A.;
O’Donnell, C. J.; Oh, T.; Old, D. W.; Overman, L. E.; Sharp, M. J. J. Am.
Chem. Soc. 2005, 127, 18054. (c) Baran, P. S.; Richter, J. M. J. Am. Chem.
Soc. 2005, 127, 15395. (d) Marti, C.; Carreira, E. M. J. Am. Chem. Soc.
2005, 127, 11505. (e) Lin, H.; Danishefsky, S. J. Angew. Chem., Int. Ed.
2003, 42, 36.
(33) Tunge, J. A.; Rayabarapu, D. K. J. Am. Chem. Soc. 2005, 127, 13510.
(34) Ott, E.; Dittus, G. Chem. Ber. 1943, 76, 80.
(35) Angelini, G.; Hanack, M.; Vermehren, J.; Speranza, M. J. Am. Chem. Soc.
1988, 110, 1298.
(36) For a very nice study on the protonation of allenic enols and enolates, see:
Zimmerman, H. E.; Pushechnikov, A. Eur. J. Org. Chem. 2006, 3491.
(32) Hills, I. D.; Fu, G. C. Angew. Chem., Int. Ed. 2003, 42, 3921.
9
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A R T I C L E S
Poulsen et al.
Scheme 6. Mechanistic Proposal for the Acetylenic Substitution Reaction
As mentioned above, the â-haloalkynes 2 are polyphilic
electrophiles, and they might undergo nucleophilic additions also
at the halide (Scheme 6) and occasionally on C2.37 Attack at
the halide results in R-halogenation of the nucleophile with
concomitant formation of an ammonium acetylide 10, which
can result in a number of side reactions. Protonation of the
acetylide releases the free terminal alkynoate to solution and
this highly reactive electrophile will undergo nucleophilic
additions from residual non-halogenated nucleophile or eventu-
ally from another ammonium acetylide. Fortunately, nucleophilic
attack at C3 is so strongly favored under the conditions described
here that such complications rarely arise. In the few cases
mentioned above, an exchange of the halide from bromide to
chloride completely eliminated this side reaction. The reason
is probably that the more electronegative chlorine atom will be
more reluctant in accepting the electron pair from the attacking
enolate than the bigger and more polarizable bromine atom.9
In the present work and in our previous study on the vinylic
substitution reaction we have demonstrated the use of catalysts
5b and 5′b in two types of substitution reactions at unsaturated
carbon atoms employing 1,3-dicarbonyl compounds of type 1
as the nucleophiles. As these studies, to the best of our
knowledge, present the first examples of catalytic enantiose-
lective versions of these fundamental nucleophilic substitutions,
we have naturally been very interested in gaining insight into
the factors responsible for the high enantioselectivities observed.
Repeated attempts finally allowed to us to obtain a single-crystal
X-ray structure of catalyst 5b with p-nitrophenolate38 as the
counterion. The structure is shown in Figure 3a,b. When
inspecting the structure it should be noted that the asymmetric
unit cell contains two molecules of both the catalyst and the
counterion as well as several molecules of solvent (water and
acetonitrile). The two catalysts in the unit cell were found to
have very similar conformations as revealed by superposition
studies, and for clarity we have omitted one of them as well as
the solvent molecules.
Figure 3. X-ray crystal structure of 5b-p-NO2PhO-. The carbon atoms
of the p-nitrophenolate counterion are colored green for clarity.
with a distance of 4.5 Å between the negatively charged phenolic
oxygen atom and the quaternized nitrogen atom. Among the
X-ray structures previously published of 9-anthracenylmethyl
derived cinchona-based phase-transfer catalysts, only two have
the C9-hydroxy group protected, and in both cases the protecting
group is allyl.39 These structures were published by Corey et
al. in 1997.40 On the basis of the X-ray data, the authors
suggested that negatively charged species might bind the catalyst
in the groove between the quinoline and the anthracene ring-
systems, which in their case could explain the absolute stere-
ochemistry observed in the alkylation of glycine Schiff bases.
In our case, this part of the structure is to some extent blocked
by the sterically demanding 1-adamantoyl group.41 Despite the
speculative nature of an attempt to understand the behavior
observed in solution through the interpretation of solid-state data,
we propose the model shown in Scheme 7 to account for the
enantioselectivity and absolute stereochemistry of the alkyny-
lation, in which the p-nitrophenolate in the X-ray structure from
Figure 3 has been replaced with â-ketoester 1a.
Positioning the enolate in the space between the quinoline-
and quinuclidine rings with the tert-butyl ester oriented toward
a lipophilic part of the structure effectively blocks the back side
(Re-face) of the enolate and allows electrophiles to approach
from above (Si-face). Obviously, the presence of the electro-
phile must be considered in the transition state of the reaction.
However, as is also documented in Scheme 7, the identity of
The phenolate counterion was found to reside in a pocket of
the catalyst between the quinoline and the quinuclidine rings
(37) For the haloalkynes employed in this study, attack at C2 must be considered
unlikely because the electron withdrawing group strongly stabilizes the
incipient anion resulting from attack at C3. No such stabilization is possible
when C2 undergoes nucleophilic attack.
(38) Prepared by ion-exchange with potassium p-NO2-phenolate in MeOH for
2 h followed by aqueous work-up.
(39) By searching of the Cambridge Crystallographic Data Centre.
(40) Corey, E. J.; Feng, Xu.; Noe, M. C. J. Am. Chem. Soc. 1997, 119, 12414.
(41) It is worth noting that the overall conformation of our catalyst and the one
described by Corey et al. in ref 40 is to a very large extent the same in the
solid state (by comparison of the X-ray structures).
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-Alkynylation of Cyclic
â
-Ketoesters
A R T I C L E S
Scheme 7. Model of the Enolate-Catalyst Complex and Observed Enantioselectivities with Different Electrophiles
this species seems to matter very little. In fact, besides the
two substitution reactions we have documented in this paper
and in the previous one,20 catalyst 5b also performs the
conjugate addition to methyl vinyl ketone as well as the alipha-
tic nucleophilic substitution using benzyl bromide with excel-
lent enantioselectivities (95% and 98% ee, respectively)
and with the same absolute configuration at the stereocen-
ter formed. These results provide further evidence of the effi-
ciency of catalyst 5b for the asymmetric R-functionalization of
â-ketoesters.
the catalytic reaction are easily deprotected in the presence of
Pd(0). Finally, we have, on the basis of X-ray crystallographic
data, discussed a plausible catalyst-enolate complex to account
for the enantioselectivities and absolute stereochemistry ob-
served in the reaction. We believe that acetylenic substitution,
in its catalytic asymmetric variant, might be an important tool
for the construction of propargylic stereocenters and that this
reaction might be interesting to investigate also in other domains
of enantioselective catalysis as well as in asymmetric organic
synthesis.
Acknowledgment. This work was made possible by a grant
from the Danish National Research Foundation. J.A. thanks
Ministerio de Educacio´n y Ciencia of Spain for a postdoctoral
fellowship.
Conclusion
In this paper we have presented the first example of a catalytic
enantioselective acetylenic substitution reaction. The reaction
enables the R-alkynylation of â-ketoesters and 3-acyl oxindoles
with excellent enantioselectivities using a readily accessible
chiral phase-transfer catalyst under experimentally simple
conditions. Furthermore, we have presented that formal addition
of an ethynyl unit is possible, as the allyl alkynoates formed in
Supporting Information Available: Complete experimental
procedures and characterization. This material is available free
of charge via the Internet at http://pubs.acs.org.
JA067289Q
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