Table 1 Addition of Et Zn to 1b and 1e using ligands L1–5 in various
2
solvents
a
b
Substrate
Ligand
Solvent
ee (%)
1
1
1
1
1
1
1
1
1
1
a
b
b
b
b
b
e
e
e
e
e
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
Toluene
Hexane
92
66
55
5
13
94
33
—
20
23
Et
THF
CH Cl
2
O
2
2
Toluene
Toluene
Toluene
Toluene
Toluene
Scheme 3 Tandem 1,4-addition-allylation.
Concerning various N-protecting groups (substrates 1a–e, 3), it
can be concluded that the nature of this group does not affect
reactivity or enantioselectivity of the 1,4-addition significantly.
Similarly, only minor influence of the temperature was observed.
The fact that the primary products of conjugate additions of
dialkylzinc reagents are zinc enolates offers possibilities for further
Additions to 1b were performed using 2 mol% Cu(OTf)
2
at 225 uC
b
and to 1e with 5 mol% of Cu(OTf)
on a Chiraldex G-TA column or by HPLC on a Chiralpak AS
column.
2
at 220 uC. Determined by GC
1
5
12
functionalization. Indeed, the enolate formed from 1e and Et
2
Zn
reagents. We confirmed this by testing phosphoramidite ligands
L1–5 in the addition of Et Zn to enone 1e, and all ligands were
inferior to L1 (Table 1).
In order to obtain acceptable yields of products we increased the
was trapped in catalytic allylation using 8 mol% Pd(PPh ) and
3
4
2
allyl acetate. Allylated product 5 was obtained as a single (trans)
diastereomer in 84% ee (Scheme 3).
1
3
In conclusion, we have shown that simple alkyl groups (Me, Et,
iPr and Bu) can be introduced with up to 97% ee in copper/
phosphoramidite-catalyzed conjugate addition of dialkylzinc
reagents to N-protected-2,3-dehydro-4-piperidones, providing
valuable substrates for alkaloid synthesis. Preliminary results
indicate that the procedure is also open to tandem reactions which
enables construction of more complex heterocycles.
amount of catalyst to 5 mol%. Under these conditions, reactions
with diethyl- and diisopropylzinc usually went to completion in 8
to 28 h, depending on the temperature. The resulting products
were formed with excellent stereoselectivity, e.g. piperidones 4h
and 4k were obtained with 97 and 94% ee, respectively. Me
proved to be quite unreactive towards N-substituted-2,3-dehydro-
-piperidones, which is in agreement with our previous findings
2
Zn
4
3
Financial support from the Dutch Ministry of Economic
Affairs, the Netherlands Scientific Research Foundation (NWO-
CW) and the University of Groningen (Parel subsidy) is gratefully
acknowledged.
2
with Me Zn addition to a,b-unsaturated lactams. No methylated
14
2
product could be obtained with Me Zn at temperatures below
0 uC, but this does not constitute a problem as also at higher
temperatures, product 4j was obtained in 96% ee. Surprisingly, the
addition of Bu Zn was problematic, both in terms of chemical
2
ˇ
Radovan Sebesta, Maria Gabriella Pizzuti, Arnold J. Boersma,
Adriaan J. Minnaard* and Ben L. Feringa*
Department of Organic and Molecular Inorganic Chemistry, Stratingh
Institute, University of Groningen, Nijenborgh 4, 9747, AG Groningen,
The Netherlands. E-mail: B.L.Feringa@rug.nl
yield and enantioselectivity. Results obtained with the optimized
2
conditions (5 mol% of Cu(OTf) , 10 mol% of phosphoramidite L1
and toluene as solvent) for several substrates and zinc reagents are
given in Table 2.
Table 2 Addition of R Zn to N-protected-2,3-dehydro-4-piperidones
2
Notes and references
1a–e and 3 using 5 mol% of Cu(OTf) and 10 mol% of L1
2
1
2
(a) K. Tomioka and Y. Nagaoka, in Comprehensive Asymmetric
Catalysis, eds. E. N. Jacobsen, A. Pfaltz, H. Yamamoto, Springer-
Verlag, Berlin, 1999, vol. 3; ch. 31.1; (b) B. L. Feringa, R. Naasz,
R. Imbos and L. A. Arnold, in Modern Organocopper Chemistry, ed.
N. Krause, Wiley-VCH, Weinheim, 2002, ch. 7.
Time
(h)
Temperature
(uC)
Conversion/
Yield (%)
ee
(%)
a
b
Substrate
R
c
1a
1a
1b
1b
1b
1c
1d
1d
1d
1e
1e
1e
1e
1e
1e
3
a
Et
iPr
Et
iPr
Bu
Et
40
16
16
16
16
24
16
16
16
24
8
225
225
225
225
225
220
225
225
225
0 A r.t.
0
95/20
100/79
100/35
87
94
94
96
74
91
94
97
82
96
91
94
94
95
59
81
For reviews on the use of phosphoramidites in stereoselective conjugate
additions see: (a) N. Krause and A. Hoffmann-R o¨ der, Synthesis, 2001,
c
100/80
39/16
83/58
100/87
100/84
36/22
171; (b) B. L. Feringa, Acc. Chem. Res., 2000, 33, 346; (c) A. Alexakis
and C. Benjamin, Eur. J. Org. Chem., 2002, 3221.
M. Pineschi, F. Del Moro, F. Gini, A. J. Minnaard and B. L. Feringa,
Chem. Commun., 2004, 1244.
R. Shintani, N. Tokunaga, H. Doi and T. Hayashi, J. Am. Chem. Soc.,
2004, 126, 6240.
D. L. Comins, J. Heterocycl. Chem., 1999, 36, 1491.
3
4
Et
iPr
Bu
Me
Et
iPr
Et
iPr
Bu
Et
80/44
5
6
100/69
100/54
100/70
100/68
20/12
For a recent review on piperidones and piperidines see: P. M. Weintraub,
J. S. Sabol, J. M. Kane and D. R. Borcherding, Tetrahedron, 2003, 59,
8
0
28
24
48
24
220
220
0 A r.t.
220
1
2953.
d
7
8
D. L. Comins, G. Chung and M. A. Foley, Heterocycles, 1994, 37, 1121.
K. C. Nicolaou, T. Montagnon and P. S. Baran, Angew. Chem. Int. Ed.,
2002, 41, 993.
64/50
Conversions determined by H NMR examination of the crude
b
9 K. H. Yoo, H. S. Choi, D. C. Kim, K. J. Shin, D. J. Kim, Y. S. Song
and C. Jin, Arch. Pharm., 2003, 336, 208.
10 For preparation of phosphoramidites L1, L2 and L4 see: L. A. Arnold,
R. Imbos, A. Mandoli, A. H. M. de Vries, R. Naasz and B. L. Feringa,
Tetrahedron, 2000, 56, 2865; for L3 and L5: H. Bernsmann, M. van den
reaction mixture; isolated yield of pure piperidone. Determined by
GC on Chiraldex G-TA column or HPLC on Chiralpak AS or
Chiralcel OD columns. Low isolated yields due to difficult
c
d
purification. Addition of 1 equivalent of Zn(OTf)
2
.
1
712 | Chem. Commun., 2005, 1711–1713
This journal is ß The Royal Society of Chemistry 2005