Unprecedented copper-catalyzed asymmetric conjugate addition of organometallic reagents to α,β-unsaturated lactams

Article abstract of DOI:10.1039/b403793f

For the first time, an excellent enantioselectivity has been obtained in the conjugate addition of hard organometallic reagents to α,β-unsaturated lactams bearing appropriate protecting-activating groups on the nitrogen.

Full text of DOI:10.1039/b403793f

Unprecedented copper-catalyzed asymmetric conjugate addition of
organometallic reagents to a,b-unsaturated lactams†
Mauro Pineschi,*a Federica Del Moro,a Francesca Gini,ab Adriaan J. Minnaardb and Ben L. Feringab
a Dipartimento di Chimica Bioorganica e Biofarmacia, Università di Pisa, Via Bonanno 33, 56126 Pisa,
Italy. E-mail: pineschi@farm.unipi.it; Fax: +3905043321
b Department of Organic and Molecular Inorganic Chemistry, Stratingh Institute, University of Groningen,
Nijenborgh 4, 9747, AG Groningen, The Netherlands
Received (in Cambridge, UK) 11th March 2004, Accepted 6th April 2004
First published as an Advance Article on the web 28th April 2004
For the first time, an excellent enantioselectivity has been
obtained in the conjugate addition of hard organometallic
reagents to a,b-unsaturated lactams bearing appropriate pro-
tecting–activating groups on the nitrogen.
a very fast reaction occurred at 278 °C even in the absence of the
catalyst and invariably the racemic trans adduct 5 was obtained as
the major product. To minimize the uncatalyzed background
reaction, the sole use of a protecting–activating group for the
nitrogen proved to be sufficient (Table 1).
The asymmetric conjugate addition of organometallic reagents to
a,b-unsaturated carbonyl compounds is one of the most useful
methods to assemble carbon–carbon bonds in organic chemistry,
and several highly enantioselective processes have been devel-
oped.1 In the case of a,b-unsaturated lactams, Hayashi has recently
The Cu(II)/(R,S,S)-1 catalysed addition of Et2Zn to the N-benzoyl
lactam 2d gave 83% conversion in 4 h from 278 °C up to 0 °C and
4-ethyl-2-piperidinone 6 was obtained with 26% ee (entry 1, Table
1). The Cbz-protected lactam 2e underwent a clean addition
reaction, with a complete conversion in 3 h from 278 °C up to 0 °C,
to provide the corresponding b-ethyl substituted lactam 7 with 75%
ee (entry 2).
described a highly enantioselective Rh( )/BINAP catalyzed 1,4-ad-
I
dition of arylboronic reagents to cyclic 5,6-dihydro-2(1H)-pyr-
idinones.2 Using a different approach, Buchwald very recently
developed a catalytic enantioselective conjugate reduction of five-
and six-membered a,b-unsaturated lactams.3 However, the ster-
eoselective introduction of a carbon–carbon bond in the b-position
of a lactam is mostly based on the use of stoichiometric amounts of
chiral auxiliaries4 or reagents.5 Chiral copper complexes with non-
racemic BINOL-based phosphoramidites have proved to be
excellent catalysts for the conjugate addition of dialkylzinc
reagents to enones.6 To the best of our knowledge, the catalytic
enantioselective 1,4-addition of hard alkyl metals to a,b-un-
saturated lactams has not been described. Here we wish to report an
unprecedented enantioselective copper-phosphoramidite catalyzed
alkylation of a,b-unsaturated lactams with dialkylzincs and
trialkylaluminium reagents.
It is known that N-alkyl-a,b-unsaturated lactams without an
additional withdrawing group in the a-position possess an
inherently low reactivity.7 Consistent with this observation, we
found that N-methyl- and N-benzyl-5,6-dihydro-2(1H)-pyridinones
2a and 2b do not react with Et2Zn in the presence of catalytic
amounts of Cu(OTf)2/(R,S,S)-1 (Scheme 1).8
The contemporary introduction of a carbomethoxy group in the
a-position and a carbamate protecting group for the nitrogen, as in
compound 2c, was able to overcome this low reactivity. In this case
During the search for a more enantioselective reaction, the N-
carbophenoxy group was found to be superior to all the other
protecting–activating groups in terms of both reactivity and
enantioselectivity. Indeed substrate 2f gave the corresponding b-
ethyl substituted lactam 8a with 95% ee and complete conversion in
2 h (entry 3). Similarly, the reaction of 2f with Bu2Zn was
completed in 4 h from 278° to 0 °C and afforded the corresponding
b-butylated lactam 8b with a high ee (entry 4). Unfortunately, the
easily accessible N-Boc-dihydropyrrol-2-one10 3 gave a more
complex reaction mixture with dialkylzinc reagents and the
corresponding b-ethylated addition product 9 was found to be not
entirely stable under standard chromatographic purification on
SiO2 (entry 5).11 d-Lactams 2d–f and N-Boc-g-lactam 3 were not
alkylated by Me2Zn under our reaction protocol even using
prolonged reaction times and a large excess of the reagent (data not
shown in Table 1). Therefore, we decided to change the primary
organometallic reagent from the poorly reactive Me2Zn to Me3Al in
order to address the asymmetric formation of b-methylated
lactams.
Trialkylaluminiums are interesting organometallic reagents
because they are produced on an industrial scale and possess a high
chemoselectivity and a low toxicity.12 Only a few examples of
enantioselective conjugate additions using trialkylaluminium rea-
gents have been reported,13 and to the best of our knowledge,
Table 1 Enantioselective conjugate addition of organometallic reagents
a
(“RM”) to a,b-unsaturated lactams catalysed by (R,S,S)-1/Cu(OTf)2
Ee
(%)c
Entry
Lactam “RM”
Time/T
Conv.b
1
2
3
4
5
6
7
8
2d
2e
2f
2f
3
2f
2f
3
Et2Zn
Et2Zn
Et2Zn
Bu2Zn
Et2Zn
Me3Al
Et3Al
Et3Al
4 h/up to 0 °C
3 h/up to 0 °C
2 h/up to 250 °C
4 h/up to 0 °C
4 h/up to 0 °C
2 h/up to 0 °C
1 h/up to 230 °C
2 h/up to 0 °C
83 (50)
100 (70)
100 (65)
100 (52)
90 (15)
100 (78)
100 (88)
95 (25)e
26
75
95
> 90d
35
68
28
3
a Conditions: all reactions were run in accordance with the typical
procedure.9 b Conversions are determined by 1H NMR examination of the
crude reaction mixture. Isolated yields after chromatographic purification
(SiO2) are reported in parentheses. c Determined by HPLC on Daicel
Chiralcel OB-H or OD-H columns. d Determined after zinc enolate trapping
with acetaldehyde. e Isolated yield after transformation into the correspond-
ing N-benzyl derivative.11
Scheme 1
† Electronic supplementary information (ESI) available: experimental
procedures, enantioselectivity determinations and characterization data for
all new compounds. See http://www.rsc.org/suppdata/cc/b4/b403793f/
1244
C h e m . C o m m u n . , 2 0 0 4 , 1 2 4 4 – 1 2 4 5
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

unsaturated lactams have never been used as substrates for this
reaction. The Cu(OTf)2–1 catalysed addition of Me3Al to lactam 2f
proceeded very cleanly in 2 h to give the corresponding methylated
addition product 8c, with a good enantioselectivity of 68% (entry
6). When the reaction was carried out with Et3Al it was possible to
obtain compound 8a with a high yield, albeit with a modest 28% ee
(entry 7). Also with the g-lactam 3, the use of Et3Al proved to be
less enantioselective than Et2Zn (entry 8).
It is reasonable to assume that the different reactivity displayed
by N-alkyl- and N-carbonyl-d-lactams with dialkylzinc and orga-
noaluminium reagents is due to the greater electron withdrawing
ability of the latter protecting–activating group, which renders the
reactive b-carbon more electrophilic in nature. Furthermore, a
chelation by the metal ions of the two carbonyl oxygens, as shown
in A (Fig. 1), might be responsible for a further double bond
activation14 and for a beneficial reduction of the conformational
mobility of the substrate.
reagents. The reaction gives access to new b-alkyl-substituted d-
lactams in an enantioenriched form. Further findings established
that the reaction is also amenable to three-component processes to
give a,b-disubstituted lactams.
We gratefully acknowledge funding by M.I.U.R. (PRIN 2002)
and by the University of Pisa.
Notes and references
1 K. Tomioka and Y. Nagaoka, in Comprehensive Asymmetric Catalysis,
E. N. Jacobsen, A. Pfaltz, H. Yamamoto, Eds., Springer-Verlag, Berlin,
Heidelberg, 1999; Vol. 3; Chapter 31.1.
2 T. Senda, M. Ogasawara and T. Hayashi, J. Org. Chem., 2001, 66, 6852
and references therein.
3 G. Hughes, M. Kimura and S. L. Buchwald, J. Am. Chem. Soc., 2003,
125, 11253.
4 (a) A. I. Meyers and L. Snyder, J. Org. Chem., 1993, 58, 36; (b) M.
Amat, M. Pérez, N. Llor and J. Bosch, Org. Lett., 2002, 4, 2787; (c) J.
Cossy, O. Mirguet, D. Gomez Pardo and J.-R. Desmurs, Tetrahedron
Lett., 2001, 42, 7805.
5 (a) S. Hanessian, A. Gomtsyan and N. Malek, J. Org. Chem., 2000, 65,
5623; (b) S. H. Lim and P. Beak, Org. Lett., 2002, 4, 2657.
6 For overviews of phosphoramidites in catalytic asymmetric conjugate
additions, see: (a) B. L. Feringa, Acc. Chem. Res., 2000, 33, 346; (b) A.
Alexakis and C. Benhaim, Eur. J. Org. Chem., 2002, 3221.
7 M. Amat, N. Llor, J. Bosch and X. Solans, Tetrahedron, 1997, 53, 719
and references therein.
8 A useful conversion of compounds 2a can only be obtained by the use
of THF as the reaction solvent (see Supporting Information). However,
the corresponding adduct 4 was obtained as a racemate.
9 Typical procedure: a solution of Cu(OTf)2 (2.5 mg, 0.0069 mmol) and
(R,S,S)-1 (7.5 mg, 0.00138 mmol) in anhydrous toluene (1 ml) was
stirred at room temperature for 40 min. The colorless solution was
cooled to 278 °C and subsequently a solution of the lactam (0.46 mmol)
in the minimal amount of toluene (or CH2Cl2 for 2f) and 0.69 mmol of
R2Zn or R3Al (0.92 mmol) were added. The reaction was followed by
TLC analysis and quenched with saturated aqueous NH4Cl after the
times and at the temperatures indicated in Table 1.
10 G. Rassu, G. Casiraghi, P. Spanu, L. Pinna, G. Gasparri Fava, M.
Belicchi Ferrari and G. Pelosi, Tetrahedron: Asymmetry, 1992, 3,
1035.
11 For preparative and enantioselectivity determination, 9 was transformed
into the corresponding N-benzyl derivative.
Fig. 1 Plausible intermediate metal-chelated structure.
Conjugate addition to unsaturated ketones, followed by trapping
of the zinc enolate with an electrophile, is an efficient method to
build up more complex molecules.15 Here we report that also the
intermediate zinc enolate derived from the conjugate addition of
Et2Zn to unsaturated lactam 2f can be trapped with acetaldehyde at
250 °C to give the new trans-3,4-disubstituted 2-piperidinone
10a,b as an inseparable mixture of aldols with 94% ee (Scheme
2).16 Furthermore, the same intermediate can be trapped in a one-
pot procedure by allyl bromide or allyl acetate and 4 mol% of
Pd(PPh3)4 to deliver piperidinone 11 with 89% ee, albeit with
25–35% isolated yield.17 It should be noted that substituted six-
membered lactams can also serve as precursors to enantiomerically
enriched piperidines which are important structural motifs in
pharmaceuticals.18
12 J. Westermann and K. Nickisch, Angew. Chem., Int. Ed. Engl., 1993, 32,
1368.
13 (a) L. Su, X. Li, W. L. Chan, X. Jia and A. S. C. Chan, Tetrahedron Lett.,
2003, 14, 1865; (b) S. M. Bennett, S. M. Brown, J. P. Muxworthy and
S. Woodward, Tetrahedron Lett., 1999, 40, 1767; (c) M. Dieguez, S.
Deerenberg, O. Pamies, C. Claver, P. W. N. M. van Leeuwen and P.
Kamer, Tetrahedron: Asymmetry, 2000, 11, 3161.
In conclusion, we have reported the first catalytic asymmetric
alkylation of a,b-unsaturated lactams with hard organometallic
14 For a discussion of the acceleration of conjugate addition reactions by
Lewis acids, see: E. Nakamura, M. Yamanaka and S. Mori, J. Am.
Chem. Soc., 2000, 122, 1826 and references therein.
15 For examples, see: (a) B. L. Feringa, M. Pineschi, L. A. Arnold, R.
Imbos and A. H. M. de Vries, Angew. Chem., Int. Ed. Engl., 1997, 36,
2620; (b) O. Knopff and A. Alexakis, Org. Lett., 2002, 4, 3835.
16 The mixture of aldols was oxidized to the corresponding ketone (see
Supporting Information). Also N-Boc-dihydropyrrol-2-one can be used
in analogous three-component aldol reactions, although the yields are
lower.
17 For a tandem conjugate addition–allylation reaction of enones, see: R.
Naasz, L. A. Arnold, M. Pineschi, E. Keller and B. L. Feringa, J. Am.
Chem. Soc., 1999, 121, 1104.
18 For a recent review of methods for the stereoselective synthesis of
piperidines, see: S. Laschat and T. Dickner, Synthesis, 2000, 1781.
Scheme 2
C h e m . C o m m u n . , 2 0 0 4 , 1 2 4 4 – 1 2 4 5
1245
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