Enantioselective copper-catalyzed conjugate additions of in situ generated organozirconium reagents to N-heterocyclic Michael acceptors

Article abstract of DOI:10.1016/j.jorganchem.2017.12.042

Stereoselective conjugate additions of organometallic reagents provide access to many useful chiral compounds. In this work, we have studied the enantioselective Cu-catalyzed conjugate addition of organozirconium reagents, which were generated in situ by

Full text of DOI:10.1016/j.jorganchem.2017.12.042

Accepted Manuscript
Enantioselective copper-catalyzed conjugate additions of in situ generated
organozirconium reagents to N-heterocyclic Michael acceptors
Ivana Némethová, Stanislav Bilka, Radovan Šebesta
PII:
S0022-328X(17)30740-4
10.1016/j.jorganchem.2017.12.042
JOM 20237
DOI:
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 15 December 2017
Accepted Date: 31 December 2017
Please cite this article as: I. Némethová, S. Bilka, R. Šebesta, Enantioselective copper-catalyzed
conjugate additions of in situ generated organozirconium reagents to N-heterocyclic Michael acceptors,
Journal of Organometallic Chemistry (2018), doi: 10.1016/j.jorganchem.2017.12.042.
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ACCEPTED MANUSCRIPT
Enantioselective Copper-Catalyzed Conjugate Additions of
in situ Generated Organozirconium Reagents to N-
Heterocyclic Michael Acceptors
Ivana Némethová, Stanislav Bilka, and Radovan Šebesta*
Comenius University in Bratislava, Faculty of Natural Sciences, Department of Organic
Chemistry, Mlynská dolina, Ilkovičova 6, 842 15 Bratislava, Slovak Republic.
Corresponding author e-mail: radovan.sebesta@uniba.sk
Abstract
Stereoselective conjugate additions of organometallic reagents provide access to many useful
chiral compounds. In this work, we have studied the enantioselective Cu-catalyzed conjugate
addition of organozirconium reagents, which were generated in situ by hydrozirconation of
alkenes. We show that N-heterocyclic Michael acceptors, represented by unsaturated lactams
and 2,3-dihydropyridin-4(1H)-ones can be useful substrates for Cu-catalyzed conjugate
additions of organozirconium reagents. Phosphorus ligands screening identified Feringa´s
phosphoramidite as the most active and enantioselective ligand for this transformation, which
afforded corresponding conjugate addition products with an enantiomeric purity of up to 92:8
e.r. The absolute configuration of one of the conjugate addition products was established by
comparison of DFT calculated and experimental electronic CD spectra. The study also
showed that mildly reactive organozirconium reagents combined with relatively unreactive
Michael acceptors afford typically conjugate addition products in medium yields. DFT
calculations of LUMO maps also supported non-reactivity of heterocyclic Michael acceptors.
LUMO maps showed decreasing electrophilicity at the β-carbon due to donor substituents
present near unsaturated carbonyl scaffold.
Keywords
Conjugate addition, organozirconium regents, copper, N-heterocycles
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1. Introduction
Copper-catalyzed reactions belong among the most widely used C-C and C-heteroatom bond
building strategies in organic synthesis.[1, 2] Copper-complexes or in-situ formed
organocopper compounds can mediate cross-coupling reactions, allylic substitutions,[3, 4]
hydrometallations,[5, 6] 1,2-additions to ketones,[7] or conjugate additions. Arguably, Cu-
catalyzed conjugate additions of organometallic reagents to Michael acceptors represent the
most versatile and valuable facet of organocopper chemistry.[8-13] Conjugate additions of
organozinc, organoaluminium and Grignard reagents were developed and can now be
efficiently employed in synthesis. In several instances, the methodology was robust enough
for application in total syntheses of complex natural products.[14] One of the challenges in
the application of conjugate addition reactions is the availability of organometallic reagents.
Another problem is functional group compatibility with reactive metal organyls such Grignard
or trialkylaluminiums. This issue can be addressed by in situ performed hydrometallations of
alkenes or alkynes. In this way, obtained organoboranes or organozirconium reagents can
serve as mild organometallic donors for conjugate additions.[15] Fletcher and coworkers have
demonstrated the applicability of hydrozirconation in the conjugate additions to cyclic,[16-20]
and acyclic enones,[21, 22] as well as to unsaturated lactones,[23] and thioesters.[24] Despite
great progress in enantioselective conjugate additions of organozirconium species, there are
no reports on the additions to nitrogen-containing heterocyclic Michael acceptors. Pineschi,
and later Alexakis and coworkers have performed conjugate additions to unsaturated lactams
with organozinc and organoaluminium reagents.[25, 26] N-Substituted-2,3-dehydro-4-
piperidones are also amenable to the conjugate addition of dialkylzinc reagents,[27]
trialkylaluminiums.[28] N-Carbamoyl-4-pyridones underwent conjugate addition with
preformed cuprates and Grignard reagents.[29] In this context, we decided to investigate
conjugate additions of in situ formed organozirconium reagents to two prototypical nitrogen-
containing Michael acceptors, α,β-unsaturated N-protected lactams and piperidones.
2. Results and Discussion
To explore reactivity of N-heterocyclic Michael acceptor towards in-situ obtained
organozirconium compounds, we selected two benchmark substrates, based on 5,6-
dihydropyridin-2(1H)-one (1) and 2,3-dihydropyridin-4(1H)-one (2) (Figure 1).
Figure 1.
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Conjugate additions of organozirconium reagents to α,β-unsaturated lactams
At first, we have explored a racemic version of conjugate addition of organozirconium
reagents to lactam 1a. Organozirconium reagents were obtained by modified experimental
conditions of Wipf and co-workers.[30] Schwartz reagent [3, chloridobis(η5-
cyclopentadienyl)hydridozirconium] served as a hydrozirconation reagent to obtain
organozirconium reagents 5 from the corresponding alkenes 4a-d.[31, 32] A THF solution of
an organozirconium reagent 5a-d was then employed as a nucleophile donor in the copper-
catalyzed conjugate additions to lactam 1a. Using four different alkenes, corresponding
conjugate addition products 6a-d were obtained in medium yields (Scheme 1).
Scheme 1.
We have used the reaction of lactam 1a with alkene 4b as a benchmark reaction for evaluation
of chiral ligands and other experimental conditions for an enantioselective variant of
hydrozirconation conjugate addition to unsaturated lactams (Scheme 2). Screening of Cu(I)
sources showed that CuOTf was the most effective one; for details see supporting
information. Inspired by Fletcher´s work,[16] we started the chiral ligand screening with
binaphthyl-based phosphoramidite ligands.[33] We have tested binaphthyl-based ligands L1-
L7 with varying amine parts. When amine part was chiral as well, we have screened also
corresponding diastereomeric ligands. Ligands L3 and L4 were not yet described in the
literature. To explore different structural scaffolds, we also synthesized biphenyl-based
phosphoramidite L8, and phosphites derived from phenol and TADDOL L9-11. As carbene
and phosphane ligands were often successful in Cu-catalyzed conjugate additions, we have
also evaluated ligands L12 and L13. All ligands employed in this study are depicted in Figure
2.
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Scheme 2
Figure 2. Ligands used in this study.
Phosphoramidite ligand (S,R,R)-L1 afforded the product 6b in 81% yield and the highest
enantiomeric purity of 82:18 e.r. (Table 1, entry 1). Surprisingly, pre-made copper-complex
with ligand (S,R,R)-L1 was less effective in this reaction than an in-situ obtained catalyst.
Diastereomeric ligand (R,R,R)-L1 was less active and also the enantiomeric purity of
compound 6b was lower (e.r. 61:39). As can be expected, using (R,R,R)-L1 led to another
enantiomer of the product 6b (Table 1, cf. entries 1 and 4). Ligands L2-6 showed medium to
none chemical activity as well as enantioinduction (Table 1, entries 5-13). Promising results,
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both regarding chemical yield and enantioselectivity was achieved by ligand L7 (Table 1,
entry 14). Phosphite ligands L9-11 afforded product 6b in medium yields, but with little or no
enantioselectivity (Table 1, entries 15-18). Ferrocenyl carbene ligand L12 also displayed
medium chemical activity but small asymmetric induction (Table 1, entry 19). Ferrocenyl
diphosphane Josiphos (L13) was inactive in this reaction (Table 1, entry 20).
Table 1. Screening of chiral ligands in the reaction of lactam 1a with 3b.
Entry
1
Ligand
(S,R,R)-L1
(S,R,R)-L1
Cu-(S,R,R)-L1b
(R,R,R)-L1
(S,S)-L2
(R,S)-L2
(S,S)-L3
(R,S)-L3
(S,S)-L4
(R,S)-L4
(R)-L5
Yield (%)
e.r.
82:18 (S)
-
81
0a
33
47
42
23
-
2
3
77:23 (S)
61:39 (R)
60:40 (S)
53:47 (R)
-
4
5
6
7
8
-
-
9
47
42
75
71
-
63:37 (R)
54:46 (R)
50:50
50:50
-
10
11
12
13
14
15
16
17
18
19
20
rac-L5
(S)-L6
(R)-L7
Cu-L8b
60
-
71:29 (R)
-
44
33
40
30
-
62:38 (R)
50:50
50:50
53:47 (R)
-
L9
L10
L11
L12
L13
a BF3.Et2O (1 equiv.), TMSCl (3 equiv.); b pre-made Cu-complex.
We have employed the most efficient ligand (S,R,R)-L1, in the hydrozirconation reaction also
with other alkenes (Scheme 3). With allylcyclohexene, hexene, and 4-phenylbutene, the
reaction afforded corresponding products in medium yields and medium to low enantiomeric
purities. The reaction with styrene did not proceed.
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Scheme 3
Using 4-allyltoluene, we have also tried lactams 1 with other N-protecting groups, such as
Cbz and Bz, but corresponding addition products were rather unstable and not even
characterization data could have been obtained. Similarly, no products were isolated from N-
tosyl protected five and seven-membered lactams.
Conjugate additions of organozirconium reagents to 2,3-dihydropyridin-4(1H)-ones
In the second part of our work, we have evaluated several N-protected 2,3-dihydropyridin-
4(1H)-ones (2) as Michael acceptors in the conjugate addition of organozirconium reagents.
In an achiral conjugate addition, we have again used 30 mol% of copper bromide as catalyst
(Scheme 4). Corresponding conjugate addition products 7a-g were obtained in yields up to
60%, and they were usually accompanied by a considerable amount of unreacted starting
material (see Supporting information, Table S1 for more details).
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Scheme 4.
An enantioselective version of the conjugate addition was assessed on the reaction of tosyl
protected substrate 2a with hex-1-ene as pro-nucleophile (Scheme 5). As enantioselective
reaction uses lower catalyst loading, yields of corresponding products were lower. Using
Feringa´s phosphoramidite (S,R,R)-L1, the product 7c was isolated in 19% yield but with
appreciable enantiomeric purity of 92:8 e.r. (Table 4, entry 1). Many experimental conditions
(variations in reaction time, sequential addition of organozirconium reagents, various copper
sources, additives) were tested with the aim of improving the reaction parameters. In some
cases, it was possible to improve chemical yield, but at the expense of enantiomeric purity. In
contrast to reactions with lactam 1a, for substrates 2 it became necessary to use BF3.Et2O as
an additive to achieve an enantioselective reaction. For more information on experimental
conditions assessed, see Supporting information, Table S3.
With ligand (S,R,R)-L1, product (R)-7c was formed predominantly. Similarly to the reaction
with lactam 1a, diastereoisomeric phosphoramidite ligands afforded opposite (S)-enantiomer
(Table 4, entry 2). Useful results were also achieved with biphenyl phosphoramidite ligand L8
(Table 4, entry 12). Results of ligands screening are summarized in Table 4.
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Scheme 5.
Table 4. Screening of chiral ligands in the reaction of 2a with 5c.a
e.r.b
Entry
Ligand
Cu(I) salt
Recov.
SM (%)
Yield
(%)
1
2
(S,R,R)-L1
(CuOTf)2.C6H6
57
n.d.
88
19
9
92:8 (R)
53:47 (S)
83:17 (R)
71:29 (R)
72:28 (R)
60:40 (S)
-
(R,R,R)-L1
(S,S)-L2
(CuOTf)2.C6H6
(CuOTf)2.PhMe
3
8
4
(R,S)-L3
(CuOTf)2.PhMe
93
5
5
(S,S)-L3
(CuOTf)2.PhMe
n.d.
n.d.
n.d.
15
2
6
(R,S)-L4
(CuOTf)2.PhMe
20
0
7
(S,S)-L4
(CuOTf)2.PhMe
8
(R)-L5 (40 mol%)
(R)-L5 (10 mol%)
(S)-L6
CuBr.Me2S (40 mol%)
(CuOTf)2.C6H6
30
7
50:50
9
46
50:50
10
11
12
13
14
15
(CuOTf)2.C6H6
n.d.
n.d.
n.d.
n.d.
34
0
-
(R)-L7
CuCl, AgOTf (10 mol%)
6
60:40 (S)
79:21 (R)
-
CuCl-L8 (11 mol%), AgNTf2 (11 mol%)
20
0
(S)-L8
L9
(CuOTf)2.C6H6
(CuOTf)2.C6H6
(CuOTf)2.C6H6
34
49:51
52
15
49:51
L10
a Experimental conditions: Schwartz´s reagent (0.8 mmol), ligand (0.024 mmol), (CuOTf)2.PhMe
(0.012 mmol), substrate 2 (0.4 mmol), BF3.Et2O (0.4 mmol), TMSCl (2.0 mmol) in CH2Cl2 (1.2 mL)
and Et2O (1.8 mL).
The most efficient ligand (S,R,R)-L1 was used to prepare Michael adducts with different
alkenes and N-protecting groups (Scheme 6). Similarly, to reactions with compound 1a, yields
were rather low using Michael acceptors 2. Piperidine derivatives 7a-f were obtained in
reasonably high enantiomeric purities.
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Scheme 6.
Determination of absolute configuration
We have determined the absolute configuration of piperidinone derivative 7c as (R) by
comparison of its electronic CD spectra with calculated one. CD spectrum was calculated for
two most populated conformers at the M06/def2-TZVP level. CD spectra of derivatives 7e
and 7f had similar profiles (see Supporting information).
Figure 3. Comparison of calculated and measured ECD spectra for (R)-7c.
Reactivity of Michael acceptors
To understand differences in reactivity between unsaturated lactams and 2,3-dihydropyridin-
4(1H)-ones, we have calculated LUMO maps at the M06-2X/6-311+G**//ωB97X-D/6-31G*
level. LUMO maps show the most electrophilic site in the molecule, or in other words the
most likely site of the nucleophilic attack. DFT calculated LUMO maps of cyclohex-2-en-1-
one,
1-(methylsulfonyl)-5,6-dihydropyridin-2(1H)-one,
and
1-(methylsulfonyl)-2,3-
dihydropyridin-4(1H)-one are depicted on Fig. 4. It can be seen from these data that
electrophilicity at the C3-position decreases from cyclohex-2-en-1-one, 1-(methylsulfonyl)-
5,6-dihydropyridin-2(1H)-one, and 1-(methylsulfonyl)-2,3-dihydropyridin-4(1H)-one.
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Figure 4. LUMO maps of cyclohex-2-en-1-one, 1-(methylsulfonyl)-5,6-dihydropyridin-
2(1H)-one, and 1-(methylsulfonyl)-2,3-dihydropyridin-4(1H)-one calculated at M06-2X/6-
311+G**//ωB97X-D/6-31G* level.
3. Conclusions
We have evaluated N-heterocyclic Michael acceptors in the Cu-catalyzed conjugate additions
of in-situ formed organozirconium reagents. The reactivity of unsaturated lactams and 2,3-
dihydropyridin-4(1H)-ones is lower compared to typical enones as yields of conjugate
addition products with mildly reactive organozirconium regents were only medium.
Nevertheless, a series of substituted piperidinones was obtained. Screening of chiral
phosphorus ligands revealed that Feringa-type phosphoramidite ligands are the most suitable
ones. Corresponding piperidones were obtained in enantiomeric purities of up to 92:8 e.r. The
absolute configuration of products was determined by comparison of experimental and DFT
calculated electronic CD spectra. Calculated LUMO maps confirm the notion of lower
reactivity of N-heterocyclic Michael acceptors.
4. Experimental Section
All reactions were carried out under an inert atmosphere of Ar. Solvents were dried and
purified by standard methods before being used. NMR spectra were measured on Varian
1
13
NMR System 300 and 600 instruments (300 MHz for H, 75 MHz for C and 300 MHz for
19F; 600 MHz for 1H, 150 MHz for 13C and 240 MHz for 31P). Chemical shifts (δ) are given in
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ppm relative to tetramethylsilane for 1H NMR and 13C NMR. Chromatographic purification of
products was performed on Merck silica gel 60. Merck TLC-plates silica gel 60, F-254, were
used for thin-layer chromatography. High-resolution mass spectra were measured on Orbitrap
Elite Thermo Scientific Velos pro with HESI/heated electrospray ionization. Mass
spectroscopy was measured on Agilent Technologies 1200 series using ESI ionization. IR
spectra were measured on Agilent Technologies Cary 630 TFIR.
Starting materials: 1-tosyl-5,6-dihydropyridin-2(1H)-one (1a),[34]1-tosyl-2,3-dihydropyridin-
4(1H)-one (2a),[27] 1-benzoyl-2,3-dihydropyridin-4(1H)-one (2b),[27] 1-benzyl-2,3-
dihydropyridin-4(1H)-one (2c),[27] 1-Benzyloxycarbonyl-2,3-dehydro-4-piperidone (2d)[27]
were synthesized according to literature procedures.
Following chiral ligands were obtained according to literature procedures: (S,R,R)-L1,[35]
(R,R,R)-L1,[35] (S,S)-L2,[35] (S)-L5,[35] (S)-L6,[35] (R)-L7,[35] (R,R)-L8,[36] (Cu-(R,R)-
L8),[16] (R,R)-L9,[37] (R,R,R,R)-L10,[38] (S,S)-L11,[37] L12, L13 (CAS: 158923-11-6).
Characterization data for new chiral phosphoramidite ligands
New phosphoramidite ligands (R,S)-L2, L3, and L4 were synthesized using procedure
described in the literature for other phosphoramidite ligands using corresponding starting
materials.[35]
N-benzyl-N-((S)-1-phenylethyl)dinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepin-4-amine
((R,S)-L2)
Colorless solid; yield 61 %; M.p.: 95 °C. IR (ATR): 2926 (w, C-H); 1588 (w, C-C); 1228 (s,
C-O); 1202 (m, C-N); 1069 (m, C-N); 946 (s, P-OR); 818 (s, C-H); 744 (s, C-H); 694 (s, C-
H); 625 (s, C-H) cm-1. 1H NMR (300 MHz, CDCl3): δ = 8.00 (d, J = 8.8 Hz, 1H); 7.93 (d, J =
8.2 Hz, 1H); 7.82 (d, J = 8.1 Hz, 1H); 7.76 (d, J = 8.8 Hz, 1H); 7.62 (d, J = 8.7 Hz, 1H); 7.45-
7.15 (m, 17H); 4.68 (sx, J = 7.0 Hz, 1H); 3.97 (dd, J = 15.8, 4.4 Hz, 1H); 3.47 (dd, J = 15.8,
6.0 Hz, 1H). 13C NMR (150 MHz, CDCl3): δ = 149.9 (2x Cq), 149.4 (Cq), 141.8 (Cq), 140.5
(Cq), 132.8 (Cq), 132.5 (Cq), 131.4 (Cq), 130.5 (Cq), 130.2 (CH), 129.8 (CH), 128.3 (CH),
128.2 (CH), 128.1 (2x CH), 128.0 (CH), 127.3 (CH), 127.0 (2x CH), 126.8 (CH), 126.0 (2x
CH), 124.8 (CH), 124.5 (CH), 124.1 (Cq), 122.2 (CH), 121.7 (CH), 55.8 (CH), 47.0 (CH2),
20.9 (CH3). 31P NMR (240 MHz, CDCl3): δ = 152.6. [α]20 = 99 (c = 0.5, CHCl3). HRMS
589
(HESI): m/z [M+H]+ calcd for C35H29NO2P: 526.1938; found: 526.1933.
N-Isopropyl-N-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)dinaphtho[2,1-d:1',2'-
f][1,3,2]dioxaphosphepin-4-amine ((R,S)-L3)
Colorless solid; yield 55 %. M.p.: 114 °C. IR (ATR): 2924 (w, C-H); 1589 (w, C-C); 1230 (s,
C-O); 1154 (m, C-N); 1069 (w, C-N); 945 (s, P-OR); 819 (s, C-H); 788 (s, C-H); 746 (s, C-
1
H); 696 (s, C-H) cm-1. H NMR (300 MHz, CDCl3): δ = 7.95-6.94 (m, 16 H); 4.39-4.26 (m,
11

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1H); 3.33-3.19 (m, 1H); 2.85-2.70 (m, 1H); 2.66-2.53 (m, 1H); 2.24-2.12 (m, 1H); 2.05-1.85
13
(m, 2H); 1.44-1.21 (m, 7H). C NMR (150 MHz, CDCl3): δ = 150.1 (2x Cq), 149.8 (Cq),
138.2 (Cq), 132.7 (2x Cq), 131.3 (Cq), 130.4 (Cq), 130.1 (CH), 129.2 (CH), 128.8 (CH),128.5
(CH), 128.2 (CH), 128.0 (CH), 127.2 (CH), 127.0 (CH), 126.4 (CH), 125.9 (CH), 125.8 (CH),
125.6 (CH), 124.6 (CH), 124.3 (CH), 123.9 (Cq), 122.4 (CH), 122.2 (CH), 121.9 (Cq), 46.8
(CH), 34.7 (CH), 29.7 (CH3), 26.9 (CH2), 25.3 (CH2), 22.7 (CH2), 22.1 (CH3). 31P NMR (240
MHz, CDCl3): δ = 150.0. [α]20 589 = -53 (c = 0.5, CHCl3). HRMS (HESI): m/z [M+H]+ calcd
for C33H31NO2P: 504.2094; found: 504.2089.
(11bS)-N-isopropyl-N-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)dinaphtho[2,1-d:1',2'-
f][1,3,2]dioxaphosphepin-4-amine ((S,S)-L3)
Colorless solid; M.p.: 228 °C. IR (ATR): 2927 (w, C-H); 1588 (w, C-C); 1229 (s, C-O); 1200
(m, C-N); 1071 (m, C-N); 945 (s, P-OR); 815 (s, C-H); 789 (s, C-H); 746 (s, C-H); 692 (s, C-
H) cm-1. 1H NMR (300 MHz, CDCl3): δ = 7.97-6.99 (m, 16H); 4.45-4.31 (m, 1H); 3.35-3.20
(m, 1H); 2.88-2.57 (m, 2H); 2.23-2.10 (m, 1H); 2.03-1.81 (m, 2H); 1.58-1.44 (m, 1H); 1.38-
1.17 (m, 6H). 13C NMR (150 MHz, CDCl3): δ = 150.7 (2x Cq), 150.0 (Cq), 138.4 (Cq), 132.8
(Cq), 132.7 (Cq), 131.3 (Cq), 130.4 (Cq), 130.2 (CH), 129.5 (CH), 129.0 (CH), 128.6 (CH),
128.2 (CH), 128.1 (CH),127.2 (CH), 127.1 (CH), 126.5 (CH), 125.9 (CH), 125.8 (CH), 125.6
(CH), 124.6 (CH), 124.2 (CH), 124.1 (Cq), 122.4 (CH), 122.1 (CH), 121.3 (Cq), 46.7 (CH),
33.3 (CH), 29.7 (CH3), 26.9 (CH2), 26.1 (CH2), 23.6 (CH2), 22.4 (CH3). 31P NMR (240 MHz,
CDCl3): δ = 152.6. [α]20 = 19° (c = 0.5, CHCl3). HRMS (HESI): m/z [M+H]+ calcd for
589
C33H31NO2P: 504.2094; found: 504.2088.
N-cyclohexyl-N-((S)-1-(p-tolyl)ethyl)dinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepin-4-
amine ((R,S)-L4)
Colorless solid; yield 51%. M.p.: 205 °C. IR (ATR): 2922 (w, C-H); 1591 (w, C-C); 1233 (s,
C-O); 1205 (w, C-N); 1112 (w, C-N); 946 (s, P-OR); 819 (s, C-H); 800 (s, C-H); 756 (s, C-H)
cm-1. 1H NMR (300 MHz, CDCl3): δ = 8.01-7.88 (m, 4H); 7.57 (d, J = 8.7 Hz, 1H); 7.53 (d, J
= 8.8 Hz, 1H); 7.43-7.22 (m, 8H); 7.09 (d, J = 7.9 Hz, 2H); 4.53 (q, J = 7.1 Hz, 1H); 2.82-
13
2.71 (m, 1H); 2.32 (s, 3H); 2.15-2.06 (m, 1H); 1.81-1.70 (m, 3H); 1.58-1.40 (m, 9H). C
NMR (75 MHz, CDCl3): δ = 150.2 (2x Cq), 149.9 (Cq), 136.1 (Cq), 132.8 (Cq), 132.7 (Cq),
131.3 (Cq), 130.4 (Cq), 130.2 (CH), 129.3 (CH),128.6 (CH), 128.2 (CH), 128.1 (CH), 127.6
(CH), 127.1 (CH), 125.9 (CH), 125.8 (CH), 124.6 (CH), 124.3 (CH), 124.1 (CH), 124.0 (Cq),
122.4 (2x CH), 121.8 (Cq), 54.6 (CH), 51.5 (CH), 35.8 (CH2), 35.2 (CH2), 35.1 (CH2), 26.9
(CH3), 26.6 (CH2), 25.4 (CH2), 21.0 (CH3). 31P NMR (240 MHz, CDCl3): δ = 148.2. [α]20
589
= -60.9 (c = 1.0, CHCl3). HRMS (HESI): m/z [M+H]+ calcd for C35H35NO2P: 532.2407;
found: 532.2402.
12

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(11bS)-N-cyclohexyl-N-((S)-1-(p-tolyl)ethyl)dinaphtho[2,1-d:1',2'-
f][1,3,2]dioxaphosphepin-4-amine ((S,S)-L4)
Colorless solid; yield 43 %; M.p.: 106 °C. IR (ATR): 2922 (w, C-H); 1589 (w, C-C); 1508
(w, C-C); 1230 (s, C-O); 1202 (m, C-N); 1059 (w, C-N); 940 (s, P-OR); 818 (s, C-H); 788 (s,
C-H); 747 (s, C-H); 686 (m, C-H) cm-1. 1H NMR (300 MHz, CDCl3): δ = 7.97 (d, J = 8.8 Hz,
1H); 7.91 (d, J = 8.2 Hz, 1H); 7.85 (d, J = 8.1 Hz, 1H); 7.77 (d, J = 8.8 Hz, 1H); 7.53 (d, J =
8.7 Hz, 1H); 7.47 (d, J = 7.9 Hz, 2H); 7.42-7.18 (m, 9H); 4.50 (q, J = 6.9 Hz, 1H); 2.77-2.69
13
(m, 1H); 2.39 (s, 1H); 1.85-1.79 (m, 1H); 1.66 (d, J = 7.0 Hz, 3H); 1.60-1.25 (m, 9H). C
NMR (150 MHz, CDCl3): δ = 154.4 (2x Cq), 150.0 (Cq), 142.5 (Cq), 136.0 (Cq), 132.8 (Cq),
132.6 (Cq), 131.2 (Cq), 130.4 (Cq), 130.1 (CH), 129.4 (CH), 128.8 (CH), 128.2 (CH), 128.0
(CH), 127.0 (4x CH), 125.9 (CH), 125.8 (CH), 124.6 (CH), 124.3 (CH), 122.4 (CH), 122.0
(2xCH), 121.6 (Cq), 55.3 (CH), 53.4 (CH), 34.7 (CH2), 33.8 (CH2), 29.7 (CH2), 26.2 (CH2),
25.4 (CH2), 24.4 (CH3), 21.0 (CH3). 31P NMR (240 MHz, CDCl3): δ = 151.3. HRMS (HESI):
m/z [M+H]+ calcd for C35H35NO2P: 532.2407; found: 532.2403.
General procedure for racemic conjugate addition of alkylzirconium species
Schwartz´s reagent (0.799 mmol) was suspended in anhydrous THF (1.5 mL), and alkene
(0.981 mmol) was then added dropwise. The resulting white heterogenous mixture turned
clear yellow after 40 min of stirring, which indicated the formation of the alkylzirconium
compound. Michael acceptor 1 or 2 (0.399 mmol) was added to the mixture via syringe
followed by CuBr.Me2S (0.122 mmol). The reaction mixture was stirred over night (18-24
hours) and then quenched with 1 M NH4Cl (3 mL) and tBuOMe (3 mL), followed by
extraction with 5% NaHCO3 (16 mL)/tBuOMe (2x16 mL). Combined organic extracts were
dried over Na2SO4, filtered and concentrated. The resulting crude products were purified by
flash chromatography on silica using hexane/EtOAc (3:1) as the mobile phase.
General procedure for stereoselective conjugate addition of alkylzirconium species
General procedure for additions to lactam 1a
To a solution of Schwarz reagent (103 mg, 0.4 mmol) in anhydrous DCM (0.7 mL) was added
dropwise the corresponding alkene (0.5 mmol) The resulting mixture turned yellow after 30
min of stirring, which indicated formation of alkylzirconium reagent. In another flask,
(CuOTf)2.PhMe (0.02 mmol, 10.4 mg, 10 mol %) and the phosphoramidite ligand (0.02
mmol, 10 mol %) were disolved in anhydrous Et2O (1 mL) under an argon atmosphere and
allowed to stir for 45 min at room teperature. The resulting clear solution was transferred via
syringe to the stirred solution of the organozirconium compound. The resulting dark mixture
was left to stir for an additional 10 min before lactam 1a (0.2 mmol) was added. After another
10 min the TMSCl (108.6 mg, 127 µL, 1 mmol) was added dropwise and the reaction was
stirred overnight, then quenched with aq 1 M NH4Cl (2mL) and extracted with a mixture of
13

ACCEPTED MANUSCRIPT
with aq 5% NaHCO3 (8 mL)/tBuOMe (4 x 10 mL). The combined organic extracts were dried
(MgSO4), filtered and concentrated by rotary evaporation to give the desired product, which
was purified by column chromatography (silica gel, hexanes/EtOAc, 2:1).
General procedure for addition to piperidones 2; using (CuOTf)2.PhMe
Schwartz´s reagent (0.799 mmol) was suspended in anhydrous CH2Cl2 (1.2 mL), then alkene
(0.981 mmol) was added dropwise, and the mixture was stirred for 40 min until it turned clear
yellow, which indicated the formation of alkylzirconium species.
Catalytic copper-ligand complex (0.024 mmol) was prepared from phosphoramidite ligand L
(0.024 mmol) and (CuOTf)2.PhCH3 (0.012 mmol) by stirring in anhydrous Et2O (1.8 mL) for
40 min.
A clear yellow solution of alkylzirconium reagent was transferred to the solution of Cu-
complex via cannula. The combined black reaction mixture was stirred for 10 min, then
Michael acceptor 2 (0.399 mmol) and BF3.Et2O (0.399 mmol) was added as a solution in
anhydrous CH2Cl2, followed by TMSCl (1.995 mmol). Reaction mixture was stirred over
night (18 to 24 hours), then quenched with 1 M NH4Cl (3 mL) and tBuOMe (3 mL), followed
by extraction with 5% NaHCO3 (16 mL)/tBuOMe (2x16 mL). Combined organic extracts
were dried over Na2SO4, filtered and concentrated. The resulting crude products purified by
flash chromatography on silica using hexane/EtOAc (3:1) as the mobile phase.
General procedure for addition to piperidones 2; using CuCl and AgOTf (or AgNTf2)
Schwartz´s reagent (0.799 mmol) was suspended in anhydrous CH2Cl2 (1.2 mL), then alkene
(0.981 mmol) was added dropwise, and the mixture was stirred for 40 min until it turned clear
yellow, which was the indication of the formation of alkylzirconium species.
Catalytic copper-ligand complex (0.024 mmol) was prepared from phosphoramidite ligand L
(0.024 mmol) and CuCl (0.024 mmol) by stirring both reagents for 40 min in anhydrous Et2O
(1.8 mL). After that time, AgOTf (or AgNTf2) was added to the mixture followed by
formation of a white precipitate, and it was stirred for 15 min.
The reaction mixture containing Cu-complex was filtered to the mixture containing
alkylzirconium reagent under an inert atmosphere. The combined black reaction mixture was
stirred for 10 minutes, then Michael acceptor 2 (0.399 mmol) and BF3.Et2O (0.399 mmol) was
added as a solution in anhydrous CH2Cl2, followed by TMSCl (1.995 mmol). Reaction
mixture was stirred over night (18 to 24 h), then quenched with 1 M NH4Cl (3 mL) and
tBuOMe (3 mL), followed by extraction with 5% NaHCO3 (16 mL)/tBuOMe (2x16 mL).
Combined organic extracts were dried over Na2SO4, filtered and concentrated. The resulting
crude products purified by flash chromatography on silica using hexane/EtOAc (3:1) as the
mobile phase.
14

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Characterization data for Michael addition products
(S)-4-(3-Cyclohexylpropyl)-1-tosylpiperidin-2-one (6a)
Yellow oil; yield: 38%. IR (ATR): 2920 (m, C-H); 1687 (m, C=O); 1351 (m, C-H); 1165 (s,
C-C); 1088 (m, S=O); 686 (s, N-S); 539 (s, C-C) cm-1. 1H NMR (300 MHz, CDCl3): δ = 7.90
(d, J = 8.4 Hz, 2H); 7.30 (d, J = 8.2 Hz, 2H); 4.17 (dt, J = 12.2, 4.2 Hz, 1H); 3.63 (dt, J =
11.1, 4.3 Hz, 1H); 2.51 (ddd, J = 17.4, 5.2, 2.0 Hz, 1H); 2.42 (s, 3H); 2.07-1.97 (m, 2H);
13
1.88-1.51 (m, 8H); 1.31-1.06 (m, 11H). C NMR (150 MHz, CDCl3): δ = 170.1 (C=O),
144.7 (Cq), 136.0 (Cq), 129.3 (CH), 128.7 (CH), 46.0 (CH2), 40.5 (CH2), 37.5 (CH2), 37.3
(CH), 35.6 (CH2), 33.3 (CH2), 32.3 (CH), 29.3 (CH2), 26.6 (CH2), 26.3 (CH2), 23.6 (CH2),
21.6 (CH3). HRMS (HESI): m/z [M+H]+ calcd for C21H32NO3S: 378.2105; found: 378.2098.
HPLC: Chiralpak OD-H, hexane/i-PrOH 90:10, 231 nm, 0.5 mL/min; major: 18.3 min,
minor: 17.0 min; er 57:43.
(S)-4-(3-(p-Tolyl)propyl)-1-tosylpiperidin-2-one (6b)
Yellow oil; yield: 81%. IR (ATR): 2924 (w, C-H); 1735 (s, C=O); 1691 (m, C-C); 1352 (s, C-
1
H); 1166 (s, C-C); 1089 (m, S=O); 812 (m, C-H); 686 (s, S-N); 539 (s, C-C) cm-1. H NMR
(300 MHz, CDCl3): δ = 7.89 (d, J = 8.3 Hz, 2H); 7,30 (d, J = 8.2 Hz, 2H); 7.08 (d, J = 7.8 Hz,
2H); 7.02 (d, J = 7.9 Hz, 2H); 4.15 (dt, J = 11.6, 4.2 Hz, 1H); 3.61 (td, J = 11.2; 4.2 Hz, 1H);
2.54 (t, 7.6 Hz, 2H); 2.42 (s, 3H); 2.31 (s, 3H); 2,04-1,96 (m, 2H); 1.81-1.76 (m, 1H); 1.61-
1.55 (m, 3H); 1.51-1.44 (m, 1H); 1.33-1.27 (m, 2H). 13C NMR (150 MHz, CDCl3): δ = 170.1
(C=O), 144.9 (Cq), 138.9 (Cq), 136.2 (Cq), 135.5 (Cq), 129.4 (CH), 129.2 (CH), 128.8 (CH),
128.4 (CH), 46.1 (CH2), 40.6 (CH2), 35.4 (CH2), 35.0 (CH2), 32.5 (CH), 29.4 (CH2), 28.5
(CH2), 21.8 (CH3), 21.2 (CH3). HRMS (HESI): m/z [M+H]+ calcd for C22H28NO3S:
386,1791; found: 386.1787. [α]20
= 58 (c = 1.0, CHCl3). HPLC: Chiralpak OD-H,
589
hexane:i-PrOH = 90:10, 231 nm, 0.7ml/min; major: 28.1 min, minor: 30.3 min; er: 82:18.
(S)-4-Hexyl-1-tosylpiperidin-2-one (6c)
Yellow oil; yield: 33%. IR (ATR): 2923 (w, C-H); 1690 (m, C=O); 1351 (m, C-H); 1165 (s,
1
C-C); 1088 (m, S=O); 812 (m, C-H); 686 (s, N-S); 539 (s, C-C) cm-1. H NMR (300 MHz,
CDCl3): δ = 7.91 (d, J = 8.4 Hz, 2H); 7.30 (d, J = 8.0 Hz, 2H); 4.17 (dt, J = 12.2, 4.1 Hz, 1H);
3.64 (td, J = 11.0, 4.4 Hz, 1H); 2.51 (ddd, J = 17.4, 5.2, 2.0 Hz, 1H); 2.43 (s, 3H); 2.0 (m,
13
2H); 1.77 (m, 2H); 1.31-1.20 (m, 13H). C NMR (150 MHz, CDCl3): δ = 170.1 (C=O),
144.7 (Cq), 136.1 (Cq), 129.3 (CH), 128.7 (CH), 46.0 (CH2), 40.5 (CH2), 35.3 (CH2), 32.3
(CH), 31.7 (CH2), 29.3 (CH2), 29.2 (CH2), 26.4 (CH2), 22.6 (CH2), 21.6 (CH3), 14.0 (CH3).
HRMS (HESI): m/z [M+H]+ calcd for C18H28NO3S: 338.1793; found: 338.1784. HPLC:
15

ACCEPTED MANUSCRIPT
Chiralpak OD-H, hexane/i-PrOH 90:10, 231 nm, 0.5 mL/min; tR(major): 24.3 min, tR(minor):
23.1 min, er 65:35.
(S)-4-(4-Phenylbutyl)-1-tosylpiperidin-2-one (6d)
Yellow oil; yield: 47%. IR (ATR): 2921 (w, C-H); 1688 (s, C=O); 1348 (s, C-H); 1164 (s, C-
1
C); 1089 (m, S=O); 810 (m, C-H); 686 (s, N-S); 540 (s, C-C) cm-1. H NMR (300 MHz,
CDCl3): δ = 7.90 (d, J = 8.4 Hz, 2H); 7.34-7.10 (m, 7H); 4.16 (dt, J = 12.2, 4.9, 1H); 3.64 (td,
J = 11.1, 4.3 Hz, 1H); 2.58 (t, J = 7.5 H), 2H); 2.50 (ddd, J = 17.4, 5.2, 2.0 Hz, 1H); 2.42 (s,
3H); 2.07-1.96 (m, 2H); 1.86-1.68 (m, 1H); 1.64-1.51 (m, 3H); 1.34-1.22 (m, 4H). 13C NMR
(150 MHz, CDCl3): δ = 170.0 (C=O), 144.7 (Cq), 142.2 (Cq), 136.0 (Cq), 129.3 (CH), 128.7
(CH), 128.3 (2 x CH), 125.7 (CH), 46.0 (CH2), 40.5 (CH2), 35.7 (CH2), 35.2 (CH2), 32.3
(CH), 31.3 (CH2), 29.3 (CH2), 26.0 (CH2), 21.6 (CH3). HRMS (HESI): m/z [M+H]+ calcd for
C22H28NO3S: 386.1792; found: 386.1783. HPLC: Chiralpak OD-H, hexane/i-PrOH 90:10,
231 nm, 0.5 mL/min; tR(major): 18.4 min, tR(minor): 17.1 min; er 64:36.
(R)-1-Benzyloxycarbonyl-2-hexyl-4-piperidone (7a)
Colorless oil, yield: 22%. IR: 2924 (CH), 2859 (CH2), 1692 (C=O), 1420 (NH-(C=O)-O) cm-
1. 1H NMR (600 MHz, CDCl3): δ =7.44-7.28 (m, 5H), 5.18 (q, J = 11.7 Hz, AB system, 2H),
4.65 (br. s, 1H), 4.40 (br. s, 1H), 3.21 (t, J=11.8 Hz, 1H), 2.64 (dd, J = 14.3 Hz, J= 6.4 Hz,
1H), 2.47 (br. s, 1H), 2.31 (t, J= 12.9 Hz, 2H), 1.56-1.47 (m, 1H), 1.42 (br. s, 1H), 1.33-1.19
13
(m, 8H), 0.86 (t, J= 7.0 Hz, 3H) ppm. C NMR (150 MHz, CDCl3):δ =207.7 (C=O), 155.3
(N-C=O-O), 136.4 (Cq), 128.5 (2xCH), 128.2 (2xCH), 128.0 (1xCH), 67.6 (CH2), 52.4 (CH),
45.6 (CH2), 40.6 (CH2), 38.4 (CH2), 32.6 (CH2), 31.6 (CH2), 28.8 (CH2), 25.6 (CH2), 22.5
(CH2), 14.0 (CH3) ppm. HRMS (HESI): m/z [M+H]+calcd for C19H27NO3 = 318.2064,
found= 318.2063. HPLC: Chiralpak AS-H, hexane/i-PrOH = 95:5, 1 ml/min, 212 nm, tR
(major)= 12.2 min, tR(minor)= 13.6 min, er 76:24.
1-Benzyloxycarbonyl-2-(3-(p-tolyl)propyl)-4-piperidone (rac-7b)
Colorless oil, yield: 42%. IR: 2934 (CH), 2859 (CH2), 1692 (C=O), 1420 (NH-(C=O)-O) cm-
1. 1H NMR (600 MHz, CDCl3): δ = 7.41-7.31 (m, 3H), 7.13-6.96 (m, 6H), 5.24-5.13 (m, AB
system, 2H), 4.71 (m, 1H), 4.40 (m, 1H), 3.68 (t, J= 6.4 Hz, 1H), 2.71-2.65 (m, 2H), 2.65-
2.46 (m, 2H), 2.36-2.29 (m, 5H), 1.96-1.85 (m, 2H), 1.55-1.43 (m, 2H). 13C NMR (150 MHz,
CDCl3): δ = 207.6 (C=O), 155.3 (N-C=O-O), 138.7 (Cq), 135.32 (Cq), 135.28 (Cq), 129.1
(CH), 129.0 (2xCH), 128.6 (2xCH), 128.3 (CH), 128.22 (CH), 128.19 (CH), 128.0 (CH), 67.7
(CH2), 62.3 (CH2), 52.2 (CH), 38.4 (CH2), 34.7 (CH2), 34.3 (CH2), 31.6 (CH2), 27.4 (CH2),
21.0 (CH3). HRMS (HESI): m/z [M+H]+calcd for C23H27NO3 = 366.2064, found= 366.2064.
16

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(R)-2-hexyl-1-tosylpiperidin-4-one (7c)
1
Colorless oil, yield: 19%. IR: 2926 (CH), 2857 (CH2), 1717 (C=O), 1156 (S=O) cm-1. H
NMR (600 MHz, CDCl3): δ =7.76 (d, J= 8.2 Hz, 2H), 7.31 (d, J= 8.0 Hz, 2H), 4.35 (dd, J=
15.1 Hz, J= 8.9 Hz, 1H), 4.16-4.11 (m, 1H), 3.28 – 3.21 (m, 1H), 2.53 (dd, J= 14.3 Hz, J= 6.5
Hz; 1H), 2.42 (s, 3H), 2.41-2.36 (m, 1H) 2.22 (d, J= 14.3 Hz, 2H), 1.40-1.32 (m, 2H), 1.25-
13
1.12 (m, 8H), 0.84 (t, J= 7.2 Hz, 3H) ppm. C NMR (150 MHz, CDCl3): δ = 206.6 (C=O),
143.8 (Cq), 137.6 (Cq), 129.9 (2x CH), 127.0 (2xCH), 54.9 (CH), 45.4 (CH2), 40.4 (CH2), 40.0
(CH2), 32.1 (CH2), 31.6 (CH2), 28.6 (CH2), 25.8 (CH2), 22.5 (CH2), 21.5 (CH3), 14.0 (CH3)
ppm. [α]20589 = - 1.3° (c = 0.38, CHCl3). HRMS (HESI): m/z [M+H]+calcd for C18H27NO3S=
338.1790, found = 338.1785. HPLC: Chiralpak OD-H, hexane/i-PrOH = 90:10, 1 ml/min,
233 nm, tR (minor) = 10.3, tR(major)= 11.9 min, er 92:8.
(R)-2-(3-(p-tolyl)propyl)-1-tosylpiperidin-4-one (7d)
1
Colorless oil, yield: 9%. IR: 2923 (CH), 2859 (CH2), 1717 (C=O), 1153 (S=O) cm-1. H
NMR (600 MHz, CDCl3): δ =7.76 (d, J= 8.3 Hz, 2H), 7.29 (d, J= 8.1 Hz, 2H), 7.07 (d, J= 7.8
Hz, 2H), 6.97 (d, J= 7.9 Hz, 2H), 4.41 (dd, J= 15.2 Hz, J= 6.8 Hz; 1H), 4.16-4.10 (m, 1H),
3.24-3.16 (m, 1H), 2.56-2.44 (m, 3H), 2.42 (s, 3H), 2.39-2.33 (m, 1H), 2.32 (s, 3H), 2.23-2.18
(m, 2H), 1.56-1.46 (m, 2H), 1.46-1.36 (m, 2H) ppm. 13C NMR (150 MHz, CDCl3): δ = 206.6
(C=O), 143.8 (Cq), 138.4 (Cq), 137.6 (Cq), 135.3 (Cq), 129.9 (2x CH), 129.0 (2xCH), 128.2
(2xCH), 127.0 (2xCH), 54.5 (CH), 45.4 (CH2), 40.3 (CH2), 40.0 (CH2), 34.5 (CH2), 31.5
(CH2), 27.4 (CH2), 21.5 (CH3), 21.0 (CH3) ppm. [α]20 = 5.2° (c = 0. 42, CHCl3). HRMS
589
(HESI): m/z [M+H]+calcd for C22H27NO3S= 386.1790, found = 386.1786. HPLC: Chiralpak
IA, hexane/i-PrOH = 90:10, 1 mL/min, 237 nm, tR (major) = 13.8 min, tR(minor)= 15.9 min,
er 80:20.
(R)-2-(4-phenylbutyl)-1-tosylpiperidin-4-one (7e)
1
Colorless oil, yield: 8%. IR: 2930 (CH), 2858 (CH2), 1716 (C=O), 1153 (S=O) cm-1. H
NMR (600 MHz, CDCl3): δ = 7.76 (d, J= 8.3 Hz, 2H), 7.31 (d, J= 8.1 Hz, 2H), 7.29-7.24 (m,
2H), 7.19-7.16 (m, 1H), 7.13-7.10 (m, 2H), 4.36 (dd, J= 15.1 Hz, J= 6.9 Hz, 1H), 4.13 (dd, J=
14.3 Hz, J= 7.3 Hz, 1H), 3.24 (ddd, J= 15.1 Hz, J= 9.3 Hz, J= 3.1 Hz, 1H), 2.56-2.50 (m,
2H), 2.43 (s, 3H), 2.41-2.36 (m, 1H), 2.26-2.16 (m, 2H), 1.64-1.47 (m, 3H), 1.45-1.36 (m,
2H), 1.29-1.22(m, 2H) ppm. 13C NMR (150 MHz, CDCl3):δ =206.6 (C=O), 143.8 (Cq), 142.1
(Cq), 137.5 (Cq), 129.9 (2x CH), 128.3 (3xCH), 127.0 (2xCH), 125.8 (2xCH), 54.5 (CH) ,
45.4 (CH2), 40.3 (CH2), 40.0 (CH2), 35.6 (CH2), 32.1 (CH2), 30.7 (CH2), 25.5 (CH2), 21.5
(CH3) ppm. [α]20
= 11.6° (c = 0.53, CHCl3). HRMS (HESI): m/z [M+H]+calcd for
589
C22H27NO3S+ H+ = 386.1784 , found= 386.1785. HPLC: Chiralpak IA, hexane/i-PrOH =
90:10, 1 mL/min, 237 nm, tR (major)= 14.9 min, tR(minor) = 16.8 min, er 91:9.
17

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(R)-2-Hexyl-1-benzoylpiperidin-4-one (7f)
Colorless oil, yield: 14%. IR: 2926 (CH), 2856 (CH2), 1717 (C=O), 1629 (NH-C=O) cm-1. 1H
NMR (600 MHz, CDCl3): δ =7.50-7.37 (m, 5H), 5.22 (br. s, 1H), 4.49 (br. s, 1H), 3.45-3.00
(m, 2H), 2.79-2.57 (m, 1H), 2.47-2.22 (m, 2H), 1.82-1.63 (m, 1H), 1.50-1.10 (m, 9H), 0.85 (t,
J= 6.1 Hz, 3H) ppm. 13C NMR (150 MHz, CDCl3): δ = 207.1 (C=O), 171.1 (-N-C=O), 135.8
(Cq), 129.9 (1xCH), 128.7 (2xCH), 126.6 (2xCH), 55.8 (CH), 50.0 (CH2), 45.6 (CH2), 40.9
(CH2), 32.1 (CH2), 31.6 (CH2), 28.8 (CH2), 25.6 (CH2), 22.5 (CH2), 14.0 (CH3) ppm. [α]20
589
= –118 (c = 0.2, CHCl3). HRMS (HESI): m/z [M+H]+ calcd for C18H25NO2 = 288.1964,
found = 288.1957. HPLC: Chiralpak IA, hexane/i-PrOH = 90:10, 1 mL/min, 212 nm, tR
(minor) = 14.3 min, tR(major)= 17.0 min, er 91:9.
2-(3-(p-Tolyl)propyl)-1-benzoylpiperidin-4-one (rac-7g)
Colorless oil, yield: 15%. 1H NMR (600 MHz, CDCl3): δ = 7.63-7.36 (m, 5H), 7.13-6.96 (m,
4H), 4.27-4.08 (m, 1H), 2.79-2.46 (m, 4H), 2.31 (s, 3H), 1.71-1.44 (m, 5H), 1.37-1.13 (m,
13
3H) ppm. C NMR (150 MHz, CDCl3):δ = 207.2 (C=O), 171.4 (N-C=O), 143.7 (Cq), 135.9
(Cq), 135.6 (Cq), 130.2 (CH),129:3 (2xCH), 128.9 (2xCH), 128.4 (2xCH), 126.8 (2xCH), 45.9
(CH2), 42.0 (CH2), 41.2 (CH2), 34.9 (CH2), 31.3 (br, CH), 29.9 (CH2), 27.6 (CH2), 21.1 (CH3)
ppm. HRMS (HESI): m/z [M+H]+calcd for C22H25NO2 = 336.1958, found = 336.1957.
Acknowledgement
This work was supported by the Slovak Research and Development Agency under the
contract No. APVV-0321-12.
Supporting Information
Supporting information contain: details of conditions optimization experiments, pictures of 1H
and 13C NMR, pictures of HPLC chromatograms, details for computational studies and
absolute configuration determination.
References
[1] A. Alexakis, N. Krause, S. Woodward, Copper-Catalyzed Asymmetric Synthesis, Wiley-
VCH, Weinheim, 2014.
[2] N. Krause, Modern Organocopper Chemistry, Wiley-VCH, Weinheim, 2002.
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[3] A. Alexakis, J.E. Bäckvall, N. Krause, O. Pàmies, M. Diéguez, Enantioselective copper-
catalyzed conjugate addition and allylic substitution reactions, Chem. Rev., 108 (2008) 2796-
2823.
[4] S.R. Harutyunyan, T. den Hartog, K. Geurts, A.J. Minnaard, B.L. Feringa, Catalytic
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