Diastereoselective zinc-catalyzed conjugate addition of alkynes

Article abstract of DOI:10.1021/ol0491585

The conjugate addition of in situ generated zinc alkynylides is reported. The use of chiral, ephedrine derived acceptors provides access to enantiomerically enriched β-alkynyl acids in good yields.

Full text of DOI:10.1021/ol0491585

ORGANIC
LETTERS
2004
Vol. 6, No. 13
2281-2283
Diastereoselective Zinc-Catalyzed
Conjugate Addition of Alkynes
Thomas F. Kno1pfel, Dean Boyall, and Erick M. Carreira*
Laboratorium fu¨r Organische Chemie, ETH-Ho¨nggerberg,
CH-8093 Zu¨rich, Switzerland
carreira@org.chem.ethz.ch
Received May 9, 2004
ABSTRACT
The conjugate addition of in situ generated zinc alkynylides is reported. The use of chiral, ephedrine derived acceptors provides access to
enantiomerically enriched â-alkynyl acids in good yields.
Conjugate addition reactions of organometallic species are
well-established approaches for the stereoselective formation
of carbon-carbon bonds.1 In such processes, the use of Cu-
(I) in stoichiometric or catalytic quantities has enjoyed wide
application with alkyl, alkenyl, and aryl carbanions. Until
recently, alkynes rarely have been used as nucleophiles for
this process, mainly due to the low tendency of the
corresponding copper alkynylides to undergo conjugate
addition.2 However, some exceptions have been docu-
mented.3,4 Other metal alkynylides can be used, such as those
of aluminum,5boron,5b,c,6,7 and zinc.8 In the only report
documenting the use of alkynylzinc reagents, these were
prepared upon mixing a lithium alkynylide with ZnBr2 and
prescribed the use of tBuMe2SiOTf as an activating agent
for the addition to R,â-unsaturated ketones.8 We have
recently described the Cu(I)-catalyzed conjugate addition
reaction of acetylenes to Meldrum’s acid-derived acceptors,
which provides access to racemic alkynyl acids.4 Given the
utility of these compounds as useful building blocks, it would
be advantageous to have available methodology that furnishes
them in enantiomerically enriched form. To the best of our
knowledge, neither diastereoselective nor enantioselective
approaches have been described for ester-derived acceptors
and alkynylzinc reagents. Herein we document an approach
that involves the in situ activation of terminal acetylenes by
Zn(II) and an amine base and their subsequent participation
in conjugate addition reactions to chiral oxazepanedione
acceptors derived from ephedrine and malonates.
(1) Kanai, M.; Shibasaki, M. In Catalytic Asymmetric Synthesis, 2nd ed.;
Ojima, I., Ed.; Wiley-VCH: New York, 2000; pp 569-592.
(2) Corey, E. J.; Beames, D. J. J. Am. Chem. Soc. 1972, 94, 7210-
7211.
(3) The addition of copper alkynylides to enones has been reported to
proceed in the presence of activating agents such as TMSI/LiI or
TBDMSOTf, see: (a) Bergdahl, M.; Eriksson, M.; Nilsson, M.; Olsson, T.
J. Org. Chem. 1993, 58, 7238-7244. (b) Kim S.; Park, J. H.; Jon, S. Y.
Bull. Korean Chem. Soc. 1995, 16, 783-786.
We have previously described the facile generation of zinc
alkynylides by treating terminal alkynes with Zn(OTf)2 and
an amine base.9-12 The in situ produced zinc alkynylides
have been shown to undergo addition to electrophiles
including nitrones,9 acyliminiums,10 and aldehydes.11 Because
(4) Kno¨pfel, T. F.; Carreira, E. M. J. Am. Chem. Soc. 2003, 125, 6054-
6055.
(5) (a) Hooz, J.; Layton, R. B. J. Am. Chem. Soc. 1971, 93, 7320-7322.
(b) Pappo, R.; Collins, P. W. Tetrahedron Lett. 1972, 13, 2627-2630. (c)
Bruhn, M.; Brown, C. H.; Collins, P. W.; Palmer, J. R.; Dajani, E. Z.; Pappo,
R. Tetrahedron Lett. 1976, 17, 235-238. (d) Schwartz, J.; Carr, D. B.;
Hansen, R. T.; Dayrit, F. M. J. Org. Chem. 1980, 45, 3053-3061.
(6) Sinclair, J. A.; Molander, G. A.; Brown, H. C. J. Am. Chem. Soc.
1977, 99, 954-956.
(7) Chong and co-workers have reported the use of alkynylboronates
prepared from 3,3′-diphenyl-BINOL in enantioselective additions to unsatur-
ated ketones: Chong, J. M.; Shen, L. X.; Taylor, N. J. J. Am. Chem. Soc.
2000, 122, 1822-1823.
(8) Kim, S.; Lee, J. M. Tetrahedron Lett. 1990, 31, 7627-7630.
(9) (a) Frantz, D. E.; Fa¨ssler, R.; Carreira, E. M. J. Am. Chem. Soc. 1999,
121, 11245-11246. (b) Aschwanden, P.; Frantz, D. E.; Carreira, E. M.
Org. Lett. 2000, 2, 2331-2333. (c) Fa¨ssler, R.; Frantz, D. E.; Oetiker, J.;
Carreira, E. M. Angew. Chem., Int. Ed. 2002, 41, 3054-3056.
(10) Fischer, C.; Carreira, E. M. Org. Lett. 2004, 6, 1497-1499.
10.1021/ol0491585 CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/03/2004

Scheme 1
Table 1. Zinc-Mediated Conjugate Addition of Alkynes to 1
acceptor
(R1)
compd
no.
alkyne
(R2)
time,
h
yield,
%
entry
1
2
3
4
5
6
Pr
1a
1b
1b
1b
1c
1d
Ph(CH2)2
Ph(CH2)2
Me3Si
Ph
Ph(CH2)2
Ph(CH2)2
2
2
1.5
3
2
88
89
86
85
87
90
â-alkynyl acids provided they were sufficiently electrophilic
toward an alkynylzinc (Scheme 1). They are accessed from
ephedrine and dimethylmalonate in useful yields.17 Conden-
sation of 3 with aldehydes is mediated by TiCl4 and
pyridine16c,18 and gives predominantly the (Z)-alkylidene
products (6-11:1, 72-97% yield);19 importantly, the minor
(E)-isomers can be conveniently removed by silica gel
chromatography. These acceptors 4 have been used in
asymmetric nickel-catalyzed conjugate additions of Grignard
reagents,16 hetero-Diels-Alder reactions,20 and trimethylen-
emethane cycloadditions.21 However, the use of alkynylmetal
nucleophiles was not examined in these studies.
We have found that the addition of zinc alkynylides to 4
proceeds to completion at 23 °C in CH2Cl2. Optimal results
were obtained by using 60 mol % of Zn(OTf)2 furnishing
the adducts 5a-e in 63-95% yield in 18 h as a mixture of
diastereomers, because the CR stereocenter produced upon
protonation of the enolate is formed nonselectively. The
selectivity at Câ was assayed by converting the adducts into
the corresponding â-alkynyl acids 6a-e and analyzing their
ee (Table 2). Thus, alkaline hydrolysis of 5a-e with KOH
in refluxing 1-propanol led to intermediate diacids, which
were decarboxylated in DMSO at 100 °C (Table 2) furnishing
6a-e in 84-92% yield over two steps.
We found that the addition is highly diastereoselective for
acceptors with branched substituents (95f98% ee, Table 2).
The adduct is formed with lower stereocontrol (82% ee) for
an acceptor bearing an unbranched alkyl chain. Additions
to acceptors with aromatic or unsaturated residues were not
observed to proceed. The high selectivities at room temper-
ature are noteworthy, as alkyl Grignard additions previously
reported were selective only at -78 °C with these acceptors.16c
The loading of Zn(II) could be lowered to 20 mol %, when
the reaction was conducted at 60 °C in toluene,11b although
the selectivities and isolated yields were somewhat lower
(Table 2). The stereoselectivity of addition is consistent with
iPr
iPr
iPr
tBu
Ph
1
the alkynylzinc reagents produced (RCtCsZnOTf)12 are
distinct from those that have been previously examined,
derived from transmetalation (RCtCsLi + ZnCl2) or
metalation (RCtCsH + Me2Zn or Et2Zn), we have been
interested in exploring their reactivity in a host of different
processes.
In initial investigations with the alkynylzinc reagent
derived from 4-phenyl-1-butyne and Zn(OTf)2/Et3N, we
observed that doubly activated Michael acceptors were
required for conjugate addition. In this respect, Meldrum’s
acid derived acceptors 14,13,14 (Table 1) are useful, since they
can be easily prepared by simply heating Meldrum’s acid
and aldehydes in water15 and, furthermore, the product of
conjugate addition can be easily hydrolyzed and decarboxy-
lated to yield the corresponding â-alkynyl acids by heating
in wet DMF.4
Under optimized conditions, the in situ generated zinc
alkynylides add to 1a-d to form adducts 2a-f in acetonitrile
at 60 °C in 1.5-3 h. The method allows addition of alkyl-,
aryl-, and silyl-alkynylides to acceptors substituted with
propyl, isopropyl, tert-butyl, and phenyl groups in 85-90%
isolated yield (Table 1). This unprecedented process with
Zn(II) is notable because of its ease of execution with short
reaction times.
We next decided to investigate chiral Michael acceptors
with Zn-alkynylides. We speculated that the optically active
oxazepanedione acceptors developed by Mukaiyama16 would
be useful reaction partners leading to optically active
(11) (a) Frantz, D. E.; Fa¨ssler, R.; Carreira, E. M. J. Am. Chem. Soc.
2000, 122, 1806-1807. (b) Anand, N. K.; Carreira, E. M. J. Am. Chem.
Soc. 2001, 123, 9687-9688. (c) El-Sayed, E.; Anand, N. K.; Carreira, E.
M. Org. Lett. 2001, 3, 3017-3020. (d) Sasaki, H.; Boyall, D.; Carreira, E.
M. HelV. Chim. Acta 2001, 84, 964-971. (e) Boyall, D.; Frantz, D. E.;
Carreira, E. M. Org. Lett. 2002, 4, 2605-2606. (f) Reber, S.; Kno¨pfel, T.
F.; Carreira, E. M. Tetrahedron 2003, 59, 6813-6817.
(12) Fa¨ssler, R.; Tomooka, C. S.; Frantz, D. E.; Carreira, E. M. Proc.
Natl. Acad. Sci. U.S.A. 2004, 101, 5843-5845.
(13) For enantioselective Et2Zn additions to Meldrum’s acid derived
acceptors see: Watanabe, T.; Kno¨pfel, T. F.; Carreira, E. M. Org. Lett.
2003, 5, 4557-4558.
(16) (a) Mukaiyama, T.; Takeda, T.; Osaki, M. Chem. Lett. 1977, 1165-
1168. (b) Mukaiyama, T.; Hirako, Y.; Takeda, T. Chem. Lett. 1978, 461-
464. (c) Mukaiyama, T.; Takeda, T.; Fujimoto, K. Bull. Chem. Soc. Jpn.
1978, 51, 3368-3372.
(17) For details see the Supporting Information.
(18) Lehnert, W. Tetrahedron Lett. 1970, 11, 4723-4724.
(19) Proved by the X-ray structure of 4d (R3 ) tBu), see Supporting
Information. The stereochemistry was initially missassigned (ref 15), but
later corrected (refs 19 and 20).
(20) (a) Tietze, L. F.; Brand, S.; Pfeiffer, T. Angew. Chem., Int. Ed. Engl.
1985, 24, 784-786. (b) Tietze, L. F.; Brand, S.; Pfeiffer, T.; Antel, J.;
Harms, K.; Sheldrick, G. M. J. Am. Chem. Soc. 1987, 109, 921-923.
(21) Trost, B. M.; Yang, B. W.; Miller, M. L. J. Am. Chem. Soc. 1989,
111, 6482-6484.
(14) Kruse, L. I.; Kaiser, W. E. D.; Chambers, P. A.; Goodhart, P. J.;
Ezekiel, M.; Ohlstein. J. Med. Chem. 1988, 31, 704-706.
(15) Bigi, F.; Carloni, S.; Ferrari, L.; Maggi, R.; Mazzacani, A.; Sartori,
G. Tetrahedron Lett. 2001, 42, 5203-5205.
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Org. Lett., Vol. 6, No. 13, 2004

Zn(II) loading. Thus, although the additions to Meldrum’s
acid acceptors (1 f 2) necessitate, at the current level of
development, the use of stoichiometric amounts of Zn(OTf)2
to observe full conversion, the additions to oxazepanedione
acceptors (4 f 5) can be carried out with substoichiometric
amounts of Zn(II). As a possible explanation for this
observation, it is important to note that in the course of
additions to 1, a precipitate is observed, whose structure by
1H NMR spectroscopy is consistent with that of a zinc-
enolate. By contrast, in the additions to the oxazepanediones
no such precipitation is observed. The phase separation that
occurs with the former can be speculated to obviate turnover.
In summary, we have shown for the first time that zinc
alkynylides generated in situ under mild conditions by the
action of Zn(OTf)2 and Et3N on terminal acetylenes undergo
conjugate addition to Meldrum’s acid derived acceptors in
good yields for a range of substrates. In the diastereoselective
addition to ephedrine-derived oxazepanedione acceptors, Zn-
(OTf)2 can be used in catalytic amounts and the adducts
obtained can be converted into enantiomerically enriched
â-alkynyl acids. These are a useful class of chiral building
blocks that are otherwise not easily accessed.24 In a broader
sense, the results described expand the scope of zinc
alkynylide reagents beyond the CdO and CdN additions
reported to date and thus provide new avenues for further
investigations with these reagents.
Table 2. Zinc-Catalyzed Conjugate Addition of Alkynes to 4
acceptor compd
alkyne
(R4)
mol % of yield of 6, ee of 6,
(R3)
no.
ZnII
%
%
d
Pr
4a
Ph(CH2)2
Ph(CH2)2
Et3Si
60a
20b
60a
20b
60a
20b
60a
20b
60a
82
75
76
75
79c
68c
83
63
55
82
68
>98
96
95
89
>98
84
>98
iPr
4b
4b
4c
4d
iPr
cC6H11
tBu
Ph(CH2)2
Ph(CH2)2
a Additions conducted in CH2Cl2 at 23 °C for 18 h. b Additions conducted
in toluene at 60 °C for 24 h. c The Et3Si- group was cleaved off during
treatment with KOH. d ee was determined either by 19F NMR analysis of
the Mosher ester of the corresponding alcohol or by chiral HPLC (see the
Supporting Information for details).
attack of the Zn-alkynylides from the convex face of the
oxazepane, namely syn to the substituents on the ring,22
which is in agreement with earlier mechanistic studies
involving cycloadditions and conjugate additions by Grignard
reagents.20b,23
Acknowledgment. We thank Dr. Schweizer for the X-ray
analysis of 4d and the Roche Research foundation for support
of T.F.K.
Supporting Information Available: Characterization
data for compounds 2, 4, and 6, X-ray structure of 4d, as
well as experimental procedures. This material is available
free of charge via the Internet at http://pubs.acs.org.
It is interesting to note the contrasting behavior between
the two acceptors that have been presented herein vis a vis
(22) Assigned by determination of the absolute stereochemistry of 6c
(R3 ) iPr, R4 ) H) by converting it into the corresponding alkane with H2,
PtO2 in EtOAc (quant.) and comparing the optical rotation with a reported
value: Enders, D.; Rendenbach, B. E. M Tetrahedron 1986, 42, 2235-
2242.
(23) Addition of 4-phenyl-1-butyne to (E)-4d with use of 60 mol % of
zinc and converting the adduct into the â-alkynyl acid gave ent-6d in 84%
yield and 95% ee (not shown).
OL0491585
(24) For a different approach to a related class of compounds possessing
CR and Câ substitution, see: (a) Schreiber, S. L.; Sammakia, T.; Crowe,
W. E. J. Am. Chem. Soc. 1986, 108, 3128-3130. (b) Schreiber, S. L.;
Klimas, M. T.; Sammakia, T. J. Am. Chem. Soc. 1987, 109, 5749-5759.
Org. Lett., Vol. 6, No. 13, 2004
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