Highly enantioselective copper-catalyzed conjugate addition of diethylzinc to cyclic enones with spirocyclic phosphoramidite ligands

Article abstract of DOI:10.1016/j.tetlet.2005.06.162

A series of spirocyclic phosphoramidite ligands 6-9 with different substituents on the amine moiety were synthesized from the chiral spirocyclic diol (R)-5. These monodentate ligands have been applied in copper-catalyzed conjugate addition of diethylzinc

Full text of DOI:10.1016/j.tetlet.2005.06.162

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6087–6090
Highly enantioselective copper-catalyzed conjugate addition of
diethylzinc to cyclic enones with spirocyclic phosphoramidite ligands
Weicheng Zhang, Chun-Jiang Wang, Wenzhong Gao and Xumu Zhang*
Department of Chemistry, The Pennsylvania State University, University Park, PA 16802, USA
Received 13 June 2005; revised 29June 2005; accepted 30 June 2005
Available online 15 July 2005
Abstract—A series of spirocyclic phosphoramidite ligands 6–9 with different substituents on the amine moiety were synthesized from
the chiral spirocyclic diol (R)-5. These monodentate ligands have been applied in copper-catalyzed conjugate addition of diethylzinc
to cyclic enones. Excellent enantioselectivities (up to 99% ee) can be achieved by the use of ligand (R,S,S)-9 bearing stereochemically
matched structure derived from the C2-symmetric (S,S)-bis(a-methylbenzyl)amine.
Ó 2005 Published by Elsevier Ltd.
Enantioselective conjugate addition of organometallic
reagents to a,b-unsaturated compounds is an important
synthetic method for the construction of carbon–carbon
bonds bearing a new stereogenic center.1 Parallel to the
development of chiral auxiliaries and stoichiometric
reagents,2 the more challenging catalytic strategy for this
transformation has recently become an actively studied
area. Among the many catalytic systems reported so
far, chiral monodentate phosphoramidite ligands com-
bined with copper salts have shown excellent enantio-
selectivities in the conjugate addition of organozinc
reagents to enones,3 dienones,4 nitroolefins,5 lactams,6
malonates,7 and meldrumꢀs acid derived acceptors.8 A
common structural feature of these trivalent phospho-
rous ligands is the existence of a C2-symmetric diol-
based framework as well as a sterically demanding chiral
secondary amine moiety. Representative ligands include
the BINOL-based phosphoramidites 1,3a–f biphenol-
based 2,3g,5c 3,3h,5d and SPINOL-based 43i (Scheme 1).
Recently, we have designed and synthesized a new spiro-
cyclic diol—9,90-spirobixanthene-1,10-diol 5, which has
more rigid coordinating conformation than BINOL.
The monodentate phosphoramidite ligand (R)-6 derived
from (R)-5 has shown excellent enantioselectivities in
Rh-catalyzed asymmetric hydrogenation of a-dehydro-
amino acid derivatives and itaconic acid.9 In an effort
to extend the utility of this type of monodentate ligands
for other asymmetric catalytic reactions, we reported
herein the preparation of a series of new spirocyclic
phosphoramidites based on (R)-5 and their application
in copper-catalyzed conjugate addition of diethylzinc
to cyclic enones.
Several methods have been reported for the synthesis of
phosphoramidites.10 While (R)-6 and (R)-7 were
prepared routinely by refluxing (R)-5 with hexamethyl-
phosphorous triamide (HMPT) or hexaethylphosphorous
triamide (HEPT) in toluene, a different procedure11 was
R2
R2
R
R
R1
R1
R
R
R1
R1
O
O
O
O
O
O
O
O
N
P
N
N
P
P
P
N
R2
R2
1
2
3
4
Scheme 1. Representative chiral monodentate phosphoramidite ligands for copper-catalyzed enantioselective conjugate addition.
Keywords: Asymmetric catalysis; Conjugate addition; Enones; Spirocyclic compound.
*
Corresponding author. Tel.: +1 8148804373; fax: +1 8148653932; e-mail: xumu@chem.psu.edu
0040-4039/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.06.162

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W. Zhang et al. / Tetrahedron Letters 46 (2005) 6087–6090
optimized for the synthesis of (R)-8, (R,S,S)-9, and
(R,R,R)-9 with sterically hindered structure (Scheme
2). Thus reacting the starting amine sequentially with
equivalent amount of n-butyllithium, trichlorophos-
phine and then (R)-5 afforded the product in a moderate
yield.
These ligands were then tested in copper-catalyzed con-
jugate addition of diethylzinc to cyclohex-2-enone 10, a
benchmark substrate for the quick determination of
ligand efficiency. As shown in Table 1, the combination
of Cu(OTf)2 (3 mol%) and ligand (R)-6, (R)-7, or (R)-8
(6 mol%) led to only low enantioselectivities at 0 °C
O
OH
OH
a or b
O
O
O
O
R
R
(R)-6 (yield 47%)
(R)-7 (yield 27%)
P N
O
(R)-5
(R)-6 R = Me
(R)-7 R = Et
(R)-8 R,R = (CH2)5
Ph
Ph
N
(R)-8 (yield 55%)
(R,S,S)-9 (yield 68%)
(R,R,R)-9 (yield 52%)
R
O
O
O
O
O
O
R
R
d
c
P
N
P
Cl2P
N
HN
R
O
O
Ph
Ph
(R,S,S)-9
(R,R,R)-9
Scheme 2. Synthesis of spirocyclic phosphoramidite ligands. Reagents and conditions: (a) HMPT, toluene, reflux, 72 h; (b) HEPT, toluene, reflux,
72 h; (c) (1) n-BuLi (1 equiv), ꢀ78 °C; (2) PCl3 (1 equiv), ꢀ78 °C; (d) (R)-5 (1 equiv), NEt3, 0 °C to rt overnight, then 60 °C 24 h.
Table 1. Copper-catalyzed enantioselective conjugate addition of diethylzinc to cyclohex-2-enone 10 with spirocyclic phosphoramidite ligands 6–913,a
O
O
Cu (3 mol%), ligand (6 mol%)
ZnEt2 (1.5 equiv.), toluene, 3 h
11
10
Entry
Ligand
Cu catalyst
Solvent
T (°C)
Yieldb (%)
eec,d (%)
1
2
3
4
5
6
7
8
(R)-6
(R)-7
(R)-8
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
(CuOTf)2Ætoluene
CuOAc
Cu(OAc)2ÆH2O
Cu(MeCN)4ClO4
Cu(MeCN)4PF6
CuOAc
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CH2Cl2
Et2O
0
0
0
0
0
92
93
8941 (
90
86
91
92
91
87
92
90
899
90
94
93
77
92
75
57 (S)
53 (S)
S)
(R,S,S)-9
(R,R,R)-9
(R,S,S)-9
(R,S,S)-9
(R,S,S)-9
(R,S,S)-9
(R,S,S)-9
(R,S,S)-9
(R,S,S)-9
(R,S,S)-9
(R,S,S)-9
(R,S,S)-9
(R,S,S)-9
(R,S,S)-9
(R,S,S)-9
(R,S,S)-9
93 (S)
10 (S)
75 (S)
94 (S)
96 (S)
49( S)
99 (S)
98 (S)
S)
52 (S)
98 (S)
96 (S)
90 (S)
96 (S)
96 (S)
90 (S)
25
ꢀ20
ꢀ30
ꢀ20
ꢀ20
ꢀ20
ꢀ720(
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
9
10
11
12
13
14e
15f
16e
17e
18e
19e
CuOAc
CuOAc
CuOAc
CuOAc
THF
EtOAc
CuOAc
73
a Reaction conditions: cyclohex-2-enone (0.33 mmol), ZnEt2 (0.5 mmol), copper catalyst (0.01 mmol), ligand (0.02 mmol) in 6 mL solvent for 3 h.
b Isolated yield.
c Enantiomeric excesses (ee) were determined by chiral GC (Supelco c-dex 225 column, 70 °C, 120 min, t1 = 67.8 min, t2 = 71.2 min).
d Absolute configuration was determined by comparing with the literature values.
e CuOAc:(R,S,S)-9:10 = 1:2:100.
f CuOAc:(R,S,S)-9:10 = 1:2:1000.

W. Zhang et al. / Tetrahedron Letters 46 (2005) 6087–6090
6089
(entries 1–3). Under the same reaction condition, how-
ever, good enantioselectivity (Table 1, entry 4, 93% ee)
was achieved by the use of ligand (R,S,S)-9 bearing a
bulky chiral amine. In contrast, the use of its diastereo-
mer (R,R,R)-9 resulted in only 10% ee. These results
indicate that a stereochemically matched ligand struc-
ture is fundamental to induce high enantioselectivities.
Our investigation is in agreement with what were
reported in other copper/phosphoramidite catalytic
systems.1b,3b,i Having identified (R,S,S)-9 as the best
ligand, further enhancement of enantioselectivity can
be achieved by lowering the reaction temperature. When
the reaction was carried out at room temperature
(25 °C), the ee dropped dramatically to 75%. On the
other hand, at ꢀ20 °C and ꢀ30 °C, the enantioselectiv-
ity can be improved to 94% ee and 96% ee, respectively
(Table 1, entries 7 and 8). Another tunable factor is the
copper salt, which also plays an essential role accounting
for high catalytic activity and enantioselectivity.1b
Recent mechanistic studies via EPR experiments,12
provided unequivocal evidence in favor of the earlier
assumption3d,g that the real catalytic species is the in situ
reduced CuI complex. Therefore, both CuI and CuII
salts can be successful in this reaction. Although
(CuOTf)2Ætoluene led to much lower ee than its divalent
counterpart (compare Table 1, entries 7 and 9, 49% ee
vs 94% ee), copper carboxylate, both CuOAc and
Cu(OAc)2ÆH2O, gave excellent enantioselectivities
(Table 1, entries 10 and 11). High ee was also achieved
when Cu(MeCN)4ClO4 was used (Table 1, entry 12).
However, the use of Cu(MeCN)4PF6 is detrimental,
leading to only 52% ee (Table 1, entry 13). This dra-
matic influence of copper salt on enantioselectivity
demonstrated that although Cu(OTf)2 is the most
commonly used precursor, some other copper salts,
especially Cu carboxylates, can be more effective.1b,3g
It is noted that with reduced catalyst loading, no
remarkable decrease in ee was observed. For example,
when 1% and 0.1% CuOAc were used, the ee is 98%
and 96%, respectively (Table 1, entries 14 and 15). In
addition to toluene, some other solvents have been
tested in this catalytic reaction. Although ethereal
solvents such as ether and THF lead to slightly higher
eeꢀs than CH2Cl2 and EtOAc, toluene is still the best
solvent (Table 1, entries 16–19).
The other two cyclic enones 12 and 14 were also tested in
this catalytic system using ligand (R,S,S)-9. When 12
was used, 98% ee was achieved. However, side reac-
tions1a dominate in the case of 14, resulting in low yield
and enantioselectivity (Scheme 3).
In conclusion, new monodentate spirocyclic phosphor-
amidite ligands were prepared from chiral spirocyclic
diol (R)-5. Among them ligand (R,S,S)-9 with a C2-
symmetric chiral secondary amine moiety can lead to
up to 99% ee in copper-catalyzed conjugate addition
of diethylzinc to cyclic enones. Further application of
these rigid ligands for other asymmetric catalytic reac-
tions will be studied.
Acknowledgment
This work was supported by NIH-GM.
References and notes
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O
O
CuOAc (3 mol%), (R,S,S)-9 (6 mol%)
ZnEt2 (1.5 equiv), toluene, -20°C
13
12
Yield 94%, ee 98%
O
O
Cu(MeCN)4ClO4 (3 mol%),(R,S,S)-9 (6 mol%)
8. Watanabe, T.; Knopfel, T. F.; Carreira, E. M. Org. Lett.
2003, 5, 4557.
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ZnEt2 (1.5 equiv), toluene, -20°C
14
15
Yield 8%, ee 66%
Scheme 3. Copper-catalyzed enantioselective conjugate addition of
diethylzinc to cyclohept-2-enone 12 and cyclopent-2-enone 14 with
spirocyclic ligand (R,S,S)-9.
10. van den Berg, M.; Minnaard, A. J.; Haak, R. M.; Leeman,
M.; Schudde, E. P.; Meetsma, A.; Feringa, B. L.; de Vries,
A. H. M.; Maljaars, C. E. P.; Willans, C. E.; Hyett, D.;

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W. Zhang et al. / Tetrahedron Letters 46 (2005) 6087–6090
Boogers, J. A. F.; Henderickx, H. J. W.; de Vries, J. G.
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NMR (75 MHz, CD2Cl2) d 19.2, 25.0, 30.1, 43.7, 113.5,
113.8, 113.8, 116.9, 117.1, 118.9, 120.3, 120.4, 120.9, 121.0,
121.8, 124.0, 126.2, 127.1, 128.1, 128.5, 128.7, 129.6, 129.7,
149.2, 149.3, 150.2, 150.5, 152.0, 152.1, 155.3, 155.5; 31P
NMR (146 MHz, CD2Cl2) d 130.0 (s). HRMS (M+Na+)
calculated: 656.1961. Found: 656.1948.
11. Typical synthetic procedure ((R,S,S)-9): in a flame-dried
Schlenk flask, n-BuLi (2 mmol, 2.5 M in hexane) was
added into (S,S)-bis(a-methylbenzyl)amine (2 mmol) in
20 mL THF at ꢀ78 °C within 15 min. After stirring for
10 min, it was warmed to room temperature for 20 min.
Then the solution was transferred into PCl3 (2 mmol) in
10 mL THF at ꢀ78 °C. After stirring for 30 min, it was
warmed slowly to room temperature over 1 h. Then it was
cooled to 0 °C, (R)-5 (2 mmol) and NEt3 (6 mmol) in
10 mL THF were added, and stirred overnight. The
reaction mixture was stirred at 60 °C for 24 h. After the
solvent was evaporated, flash chromatography on silica gel
(EtOAc–hexane = 1:15) afforded the product as white
powder (856 mg, yield 68%). 1H NMR (360 MHz, CD2Cl2)
d 1.65 (s, 6H), 4.33 (s, 2H), 6.25 (d, J = 8.0 Hz, 1H), 6.44
(d, J = 7.9Hz, 1H), 6.79(d, J = 7.8 Hz, 1H), 6.86–7.30 (m,
12. Pfretzschner, T.; Kleemann, L.; Janza, B.; Harms, K.;
Schrader, T. Chem. Eur. J. 2004, 10, 6048.
13. Typical procedure for conjugate addition: a solution of
copper salt and ligand in toluene was stirred at room
temperature for 1 h under N2. After it was cooled to
ꢀ20 °C, cyclohex-2-enone and ZnEt2 were added sequen-
tially. The reaction was running for 3 h at this tempera-
ture, and then quenched with saturated aqueous NH4Cl
solution. The mixture was extracted twice with ether. The
combined organic phase was dried with anhydrous
Na2SO4 and concentrated. Chromatography on silica gel
(ether–pentane = 1:6) gave the desired product as colorless
oil.
19H), 7.40 (t, J = 8.0 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H); 13
C