Highly enantioselective copper-phosphoramidite-catalyzed conjugate addition of dialkylzinc reagents to acyclic α,β-unsaturated imides

Article abstract of DOI:10.1002/adsc.200505309

A new and practical way to introduce an alkyl fragment in the β-position of aliphatic carboxylic acid derivatives with high enantioselectivities by the use of a commercially available chiral ligand is reported. N-Acylpyrrolidinones, as simple derivatives

Full text of DOI:10.1002/adsc.200505309

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DOI: 10.1002/adsc.200505309
Highly Enantioselective Copper-Phosphoramidite-Catalyzed
Conjugate Addition of Dialkylzinc Reagents to Acyclic
a,b-Unsaturated Imides
Mauro Pineschi,* Federica Del Moro, Valeria Di Bussolo, Franco Macchia
`
Dipartimento di Chimica Bioorganica e Biofarmacia, Universita di Pisa, Via Bonanno 33, 56126 Pisa, Italy
Fax: (þ39)-(0)50-221-9660, e-mail: pineschi@farm.unipi.it
Received: August 4, 2005; Accepted: November 28, 2005
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: A new and practical way to introduce an
alkyl fragment in the b-position of aliphatic carbox-
ylic acid derivatives with high enantioselectivities
by the use of a commercially available chiral ligand
is reported. N-Acylpyrrolidinones, as simple deriva-
tives of an a,b-unsaturated carboxylic acid, were
found to be the substrates of choice featuring good
reactivity and high enantioselectivities (up to >
99% ee).
to aliphatic bidentate substrates with chiral metal cata-
lysts, pointing to an apparent need for specialist ligands.[5]
We report here the development of a simple, practical
and highly enantioselective copper-catalyzed 1,4-addi-
tion of alkylmetals to acyclic a,b-unsaturated carboxylic
acid derivatives, based on the use of modular (biden-
tated) cyclic imides and the commercially available
phosphoramidite chiral ligand 1, developed by Feringa
et al.[6]
We recently reported a new copper-catalyzed ACA of
organometallic reagents to a,b-unsaturated lactams
bearing appropriate protecting-activating groups on
the nitrogen atom.[7] The use of carbonyl protecting
groups on the endocyclic nitrogen of g- and d-lactams
was essential to attain their reactivity and to reach
high ees of the corresponding conjugate adducts. In
À
Keywords: asymmetric catalysis; C C bond forma-
tion; conjugate addition; copper; phosphoramidite
ligands; zinc
The asymmetric conjugate addition (ACA) of organo- the search for a new carbonylic protecting-activating
metallic reagents to a,b-unsaturated carbonyl com- group for the nitrogen, we considered the 2-butenoyl
pounds has been the subject of intensive research activ- moiety. The copper-phosphoramidite (R,S,S)-1 cata-
ity in the past few years.[1] However, highly enantioselec- lyzed addition of Et2Zn to compounds 2a and b, each
tive catalytic procedures which make use of acyclicunsa- containing two conjugated double bonds of a different
turated carboxylic acid derivatives are rare.[2] The high nature, afforded a reaction mixture in which the addi-
conformational mobility of these species, together with tion occurred predominantly on the acyclic framework,
the presence of only feeble substrate-catalyst steric to give adducts 3 with a moderate to good enantioselec-
and electronic interactions, makes the design of effec- tivity (Scheme 1).
tive highly enantioselective systems a real challenge.
The use of imides 5a and b, which are devoid of the en-
Whereas chiral imides have been widely used to perform docyclic double bond, gave improved yields and enan-
efficient ACA in the context of a chiral auxiliary ap- tioselectivities with respect to compounds 2a and b (en-
proach,[3] the addition of alkylmetals to the enantiotopic tries 1 and 2, Table 1). It is interesting that the small ster-
faces of a,b-unsaturated imides remained problematic ic and electronic differences present in compounds 2a, b
until Hoveydaꢀs recent report on the asymmetric addi- and 5a–d have such an important effect on the enantio-
tion of dialkylzinc reagents to N-acyloxazolidinones selectivity. Imide 5c, containing a 2-azepanone, gave the
promoted by modular triamide phosphanes.[4] However, lowest ee (38%, entry 3) whereas the oxazolidinone
high enantioselectivities were reached only with b-alkyl moiety, successfully used by Hoveyda,[4] gave only a
derivatives whereas, for example, simple b-aryl deriva- 64% ee in our reaction conditions (entry 4), while the
tives proved to be only poorly reactive and b-vinyl deriv- highest ee (87%) was obtained with 2-pyrrolidinone as
atives were not considered. Moreover, it has been sug- the achiral template. The fact that a,b-unsaturated
gested that conventional chiral ligands developed for amides 5e and f were not reactive in our reaction condi-
enones were not suitable for the 1,4-addition of R2Zn tions (Table 1, entries 5 and 6), further confirmed ourex-
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301

Mauro Pineschi et al.
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der to obtain the corresponding adducts with apprecia-
ble yields and enantioselectivities.
Having identified the optimal achiral template, next
we examined the scope of our system in reactions with
several b-substituted a,b-unsaturated N-acyl-2-pyrroli-
dinones.[8] The results, summarized in Table 2, indicate
that different groups in the b-position participate suc-
cessfully in the enantioselective conjugate addition.
Our reaction protocol worked particularly well with
cinnamyl substrates, giving an efficient catalytic forma-
tion of benzylic carbon stereocenters (entries 4–13). In
p-substituted cinnamyl substrates 7d–g there is a major
electronic effect, with a clear relationship between the
electronic effects and the enantiomeric excesses of the
corresponding adducts, the stronger electron-withdraw-
ing substituents (p-CF3, p-Br) showing the higher enan-
Scheme 1. Catalytic enantioselective addition of Et2Zn to 2-
butenoyl a,b-unsaturated lactams 2a and b.
pectations that the presence of a carbonyl group on the tiomeric excesses (Table 2, entries 7 and 8). To the best
nitrogen, i.e., a bidentate substrate, was mandatory in or- of our knowledge, there appears to have been no system-
Table 1. Individuation of the optimal achiral template by copper-phosphoramidite catalyzed addition of Et2Zn to crotonic acid
derivatives.[a]
Entry
1
Substrate (Y¼ )
Conditions
Conversion [%][b] Product
ee [%][c]
56
6h, À78 to 08C
98 (56) 6a
5a
5b
2
3
2.5 h, À78 to À208C
6h, À78 to 08C
>98 (75) 6b
98 (65) 6c
87 (R)
38
5c
4
4 h, À78 to 08C
98 (60) 6d
64
5d
5e
5f
5
6
6h, 0 8C
6h, 0 8C
No reaction
No reaction
–
–
[a]
All reactions were carried out in accordance with the general procedure by the use of 1.5 equivs. of Et2Zn.
Conversions were determined by H NMR of the crude product. Yields of isolated product after chromatography on SiO2
are reported in parentheses.
Determined by HPCL on a Daicel Chiralpak AD-H or Daicel Chiralcel OD-H. Absolute configuration determined by cor-
relation with known compounds.
[b]
1
[c]
302
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Adv. Synth. Catal. 2006, 348, 301 – 304

Addition of Dialkylzinc Reagents to Acyclic a,b-Unsaturated Imides
Table 2. Copper-catalyzed addition of dialkylzincs to a,b-unsaturated N-acyl-2-pyrrolidinones.[a]
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Entry
R (7)
Alkyl
T [h]
Conversion [%][b] Product
ee [%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16(
17
(a) Pr
(5b) Me
(b) i-Pr
(c) Ph
(c) Ph
(c) Ph
(d) p-BrC6H4
(e) p-CF3C6H4
(f) p-OMeC6H4
(g) p-CH3C6H4
(h) m-CF3C6H4
(i) o-BrC6H4
(j) o-CH3C6H4
(k) (E)-CH3CH CH
(l) 1-cyclohexenyl
a) Pr
Et
i-Pr
Et
3
3
2
3
>98 (80)
>98 (78)
>98 (75) 10
>98 (78) 11
12
>98 (75) 13
>98 (82) 14
>98 (84) 15
>98 (74) 16
>98 (88) 17
92 (55) 18
>98 (78) 19
90 (44) 20
21
8
9
84
60
95
98 (S)
85
81
>99
>99
94
94
94
80
87
96
n.d.
36
Et
Bu
i-Pr
Et
Et
Et
Et
Et
Et
Et
2)
695 (6
4
3
2
4
4
4
4
4
¼
Et
)
1675 (16
1638 (7)
4
4
Et
22
Me[d]
Me[d]
>98 (70) 23
>98 (65) 24
(f) p-OMeC6H4
20
[a]
All reactions were carried out in accordance with the general procedure.
See corresponding notes of Table 1.
Reactions carried out with AlMe3 (1.5 equivs.)
[b], [c]
[d]
atic study of how purely substrate electronic effects in- use of the more reactive organoaluminum reagents.[7]
fluence the degree of asymmetric induction for a catalyt- Also with a,b-unsaturated N-acylpyrrolidinones 5b
ic ACA reaction. However, even if there was a qualita- and 7a, f, it was possible to transfer an Me group only
tive correlation between the substrateꢀs electronic prop- by the use of AlMe3, although the corresponding reac-
erties and the enantioselectivity of the corresponding tions proceeded only with modest ees (Table 2, entries
adducts, an exact correlation of Hammett sigma-p con- 16and 17). Interestingly, in a separate set of experi-
stants and enantioselectivity proved not to be linear.[9]
ments, we found that by the use of organoaluminum re-
While the addition of bulky Grignard reagents to a,b- agents rather than organozinc reagents (AlEt3 instead of
unsaturated esters exhibited a poor efficiency in terms Et2Zn), enantiomeric products were obtained using the
of conversion and enantioselectivity,[2] our enantioselec- same chiral catalyst (data not shown in Table 2). This is
tive CA was not limited to linear organozinc reagents, an indication that the structure of the active catalyst in-
and also (i-Pr)2Zn gave satisfactory results (Table 2, en- corporates a substrate binding pocket which depends on
tries 2 and 6). The addition of dialkylzincs to b-alkenyl the nature of the organometallic reagent.
a,b-unsaturated pyrrolidinones was also addressed.
Optically enriched b-alkyl-N-acyl-2-pyrrolidinones
The reaction of pyrrolidinone 7k, derived from sorbic may easily be converted into the corresponding b-substi-
acid, proved to be slower and the conversion was not tuted esters by simple treatment with a catalytic amount
complete even after a long reaction time, and an even of Er(OTf)3 in EtOH,[11] or hydrolyzed [12] to the corre-
lower reactivity was displayed by b-cyclohexenyl-susbti- sponding carboxylic acid (see Supporting Informa-
tuted substrate 7l (Table 2, entries 14 and 15). However, tion).[13]
one of the corresponding 1,4-adducts, 21, was obtained
Probably, the delocalization of the nitrogen lone pair
with a high ee, albeit with low yield (entry 14). It is worth in the endocyclic carbonyl reduces the donation to the
mentioning that it was not possibleto isolate anyadducts carbonyl adjacent to the a,b-unsaturation, and thus con-
deriving from a 1,6-addition pathway, even if their pres- tributes to an increase in the reactivity of the b-position.
ence in minor amounts in the relatively complex crude Moreover, it is reasonable to hypothesize a chelation by
mixture cannot be ruled out.[10]
the zinc ion of the two carbonyl oxygens, and the forma-
A limitation of our reaction protocol is the scarce re- tion of a highly organized cluster, which is in turn re-
activity of Me2Zn, which can be by-passed through the sponsible for the high enantioselectivity. The chelation
Adv. Synth. Catal. 2006, 348, 301 – 304
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asc.wiley-vch.de
303

Mauro Pineschi et al.
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[2] While this manuscript was being prepared, an impressive
highly enantioselective copper-catalyzed conjugate addi-
tion of Grignard reagents to a,b-unsaturated esters was
is able to enhance the electrophilicity of the b-carbon,
and ensures a good enantiofacial control by blocking
the substrate in a dominant reactive conformer, which
is most probably the s-cis one.[14]
To sum up, we have found a new and practical way to
introduce an alkyl fragment in the b-position of aliphatic
carboxylic acid derivatives with high enantioselectivi-
ties by the use of a commercially available chiral ligand.
`
reported, see: a) F. Lopez, S. R. Haratyunyan, A. Meet-
sma, A. J. Minnaard, B. L. Feringa, Angew. Chem. Int.
Ed. 2005, 44, 2752–2756; for a highly enantioselective
rhodium-catalyzed procedure, see: b) Y. Takaya, T. Sen-
da, H. Kurushima, M. Ogasawara, T. Hayashi, Tetrahe-
dron: Asymmetry 1999, 10, 4047–4056.
[3] For a recent example, see: J. Dambacher, R. Anness, P.
Pollock, M. Bergdahl, Tetrahedron 2004, 60, 2097–2110
and references cited therein.
Experimental Section
[4] A. W. Hird, A. H. Hoveyda, Angew. Chem. Int. Ed. 2003,
42, 1276–1279.
General Procedure for the Copper-Phosphoramidite
ACA
[5] S. Matsunaga, T. Kinoshita, S. Okada, S. Harada, M. Shi-
basaki, J. Am. Chem. Soc. 2004, 126, 7559–7570.
[6] B. L. Feringa, M. Pineschi, L. A. Arnold, R. Imbos,
A. H. M. de Vries, Angew. Chem. Int. Ed. 1997, 36,
2620–2623.
A flame-dried Schlenk flask was charged with Cu(OTf)2
(2.5 mg, 0.0069 mmol) and (R,S,S)-1 (7.5 mg, 0.00128 mmol)
in anhydrous toluene (1.0 ml) and the mixture was stirred at
room temperature for 40 min. The colorless solution was
cooled to À788C and subsequently, a solution of the N-acyl-
pyrrolidinone (0.46mmol, dissolved in the minimal amount
of toluene or CH2Cl2) and the organometallic reagent (0.69–
1.38 mmol), were added under an Ar atmosphere. The reaction
was monitored by TLC analysis, quenched with saturated
aqueous NH4Cl and extracted several times with Et2O. The
combined organic phases were dried (MgSO4) and evaporated
under reduced pressure to give a crude product that was puri-
fied by flash chromatography.
[7] M. Pineschi, F. Del Moro, F. Gini, A. J. Minnaard, B. L.
Feringa, Chem. Commun. 2004, 1244–1245.
[8] For the use of this achiral template with soft nucleo-
philes, see: a) D. J. Guerin, S. J. Miller, J. Am. Chem.
Soc. 2002, 124, 2134–2136; for an alternative approach
based on the use of asymmetric Lewis-acid mediated
free radical additions to unsaturated N-acyl-2-pyrrolidi-
nones, see: b) M. P. Sibi, G. Petrovic, J. Zimmerman, J.
Am. Chem. Soc. 2005, 127, 2390–2391 and references cit-
ed therein.
[9] See Supporting Information for further details.
[10] For a very recent rhodium-catalyzed asymmetrical 1,6-
addition of arylzinc reagents to dienones, see: T. Haya-
shi, S. Yamamoto, N. Tokunaga, N. Angew. Chem. Int.
Ed. 2005, 44, 4224–4227.
See Supporting Information for characterization data of all
new compounds, ee determinations, conversion to carboxylic
acid derivatives, determination of absolute configurations,
and Hammett plots.
[11] C. D. Vanderwal, E. N. Jacobsen, J. Am. Chem. Soc. 2004,
126, 14724–14725.
Acknowledgements
[12] K. Tomioka, T. Suenaga, K. Koga, Tetrahedron Lett.
1986, 27, 369–372.
This work was supported by the Ministero dellꢀ Istruzione, del-
`
lꢀUniversita e della Ricerca (M. I. U. R. Rome, P. R. I. N. 2004)
and by the University of Pisa.
[13] b-Substituted optically active esters and acids are impor-
tant chiral subunits; for an alternative approach to their
synthesis, see: a) B. H. Lipshutz, J. M. Servesko, B. R.
Taft, J. Am. Chem. Soc. 2004, 126, 8352–8353; b) G.
Hughes, M. Kimura, S. L. Buchwald, J. Am. Chem. Soc.
2003, 125, 11253–11258.
[14] a) V. A. Soloshonok, C. Cai, V. J. Hruby, J. Org. Chem.
2000, 65, 6688–6696; b) C. Bçrner, W. A. Kçnig, S.
Woodward, Tetrahedron Lett. 2001, 42, 327–329.
References and Notes
[1] For reviews, see: a) N. Krause, A. Hofmann-Rçder, Syn-
thesis 2001, 171–196; b) M. P. Sibi, S. Manyem, Tetrahe-
dron 2000, 56, 8033–8061; c) Catalytic Asymmetric Syn-
thesis, 2nd edn., (Ed.: I. Ojima), Wiley, New York, 2000,
Chapter 8D.
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