In situ enzymatic screening (ISES) of P,N-ligands for Ni(0)-mediated asymmetric intramolecular allylic amination

Article abstract of DOI:10.1016/j.tetasy.2004.06.052

An in situ enzymatic screening (ISES) approach to rapid catalyst evaluation recently pointed to Ni(0) as a new candidate transition metal for intramolecular allylic amination. This led to further exploration of chiral bidentate phosphine ligands for such transformations. Herein, a variety of P,N-ligands are examined for this Ni(0)-chemistry, using a model reaction leading into the vinylglycinol scaffold. On the one hand, an N,N-bis(2-diphenylphosphinoethyl)alkylamine ('PNP') ligand proved to be the fastest ligand yet seen for this Ni(0)-transformation. On the other, phosphinooxazoline (PHOX) ligands of the Pfaltz-Helmchen-Williams variety gave the highest enantioselectivities (up to 51% ee) among P,N-ligands examined.

Full text of DOI:10.1016/j.tetasy.2004.06.052

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 2845–2851
In situ enzymatic screening (ISES) of P,N-ligands for
Ni(0)-mediated asymmetric intramolecular allylic amination
*
David B. Berkowitz, Weijun Shen and Gourhari Maiti
Department of Chemistry, University of Nebraska, Lincoln, NE 68588-0304, USA
Received 2 June 2004; accepted 28 June 2004
Abstract—An in situ enzymatic screening (ISES) approach to rapid catalyst evaluation recently pointed to Ni(0) as a new candidate
transition metal for intramolecular allylic amination. This led to further exploration of chiral bidentate phosphine ligands for such
transformations. Herein, a variety of P,N-ligands are examined for this Ni(0)-chemistry, using a model reaction leading into the
vinylglycinol scaffold. On the one hand, an N,N-bis(2-diphenylphosphinoethyl)alkylamine (ÔPNPÕ) ligand proved to be the fastest
ligand yet seen for this Ni(0)-transformation. On the other, phosphinooxazoline (PHOX) ligands of the Pfaltz–Helmchen–Williams
variety gave the highest enantioselectivities (upto 51% ee) among P,N-ligands examined.
Ó 2004 Elsevier Ltd. All rights reserved.
1
1
1
.Introduction
inversion (r-allyl metal) mechanism. Similar observa-
tions have been made by Martin et al. recently, for unli-
1
2
The surge of activity in combinatorial catalysis has led
1
gated Rh(I) in allylic alkylation chemistry.
to a keen interest in catalyst screening methods. We
have found that enzymes can be used to assist organic
chemists in this regard, using an approach that we term
An initial screen of late TMÕs for the transformation of
1!2 turned upNi(0) as a good candidate for further
2
,3
2a
in situ enzymatic screening (ISES). To demonstrate
proof of principle for ISES, we chose to study transition
metal (TM)-mediated intramolecular allylic amination.
Specifically, the transformation of 1!2 was chosen, as it
yields a protected vinylglycinol product, commensurate
with our interest in vinylic amino acids as PLP enzyme
development. Those studies also identified Ni(cod)
2
as useful catalyst precursor and relatively electron rich
and bidentate phosphines (i.e., dppb or dppf) as excel-
lent supporting ligands for this chemistry. The internal
carbamate nitrogen nucleophile was found to perform
4
0
best when outfitted with a PMP (4 -methoxyphenyl) or
0
5
,6
0
0
inhibitors.
TMP (3 ,4 ,5 -trimethoxyphenyl) protecting group and
when deprotonated with one equivalent of LiHMDS.
Clearly, the most well studied TM for allylic amination,
7
and particularly for asymmetric variants, is palladium.
These findings raised the interesting prospect that one
might be able to developthe first asymmetric allylic ami-
By contrast, there is remarkably little literature on the
use of other TMÕs for asymmetric allylic amination.
Notable exceptions are recent reports on the use
1
3
nation chemistry supported by Ni(0). Indeed, this
turns out to be the case, with members of the Josiphos
(Solvias) and BIPHEP (Roche) ligand families providing
eeÕs at the 75–82% level. This led to an enantioselective
synthesis of L-vinylglycine, based on this new Ni
8
of Ru(II) from Takahashi et al., and Ir(I) from
9
10
Hartwig et al., and Helmchen et al., in which impres-
sive levels of stereoinduction are achieved. Interestingly,
Evans has shown that, with the appropriate ligand
sphere, Rh(I)-complexes can be employed for allylic
amination with preservation of stereochemistry at a
pre-existing stereocenter, presumably via a strict double
2
b
chemistry.
Given these developments, it seemed a reasonable next
stepto screen bidentate ligands more broadly, for sup-
port of this chemistry. Herein, then, we report our find-
ings on ISES screening across a range of P,N-ligands,
followed by closer examination of the most promising
hits under typical RB-flask conditions.
*
Corresponding author. Tel.: +1 402 472 2738; fax: +1 402 472
402; e-mail: dbb@unlserve.unl.edu
9
0
957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.06.052

2846
D. B. Berkowitz et al. / Tetrahedron: Asymmetry 15 (2004) 2845–2851
2
.Results and discussion
Ph2P
Ph P
N(
PPh2
2
The set of P,N-ligands chosen for the initial ISES survey
is illustrated in Figures 1 and 2. This set is bracketed by
two ÔhomonuclearÕ bidentate reference ligands. The fast-
est P,P-ligand previously seen, DPPB 4, was included as
a bis-phosphine reference ligand. For the other Ôbook-
end,Õ we chose sparteine. Sparteine was seen as a reason-
able choice for a ÔrepresentativeÕ N,N-ligand as it
represents one of the earliest chiral ligands ever exam-
ined for asymmetric allylic alkylation with palladium
R)
Ph
PPh2
Me
DPPB 4
reference P,P-ligand
phenethyl-PNP 5
H
Me
NMe2
PPh2
(R)
Fe (Sp)
Cy2P
Me2N
1
4
in pioneering work by Trost and Dietsch. Later, Togni
et al. showed that sparteine indeed displays bidentate
(S )-α-[(R)-diphenylphosphino-
ferroceny]lethyldimethylamine = PPFA 6
2-Dicyclohexylphosphino-
2'-(N,N-dimethylamino)biphenyl 7
p
1
5
(
Hayashi-Kumada)
(Buchwald)
coordination in a p-allyl-Pd complex. Finally, the re-
cent successes with sparteine as a chiral element in the
Pd(II)-mediated oxidative kinetic resolution of second-
ary alcohols that have been registered by the groups of
Ph P
2
O
Ph2P
1
6
17
Me
Sigman et al. and Stoltz et al. suggest that renewed
attention should be paid to this chiral ligand for late
transition metal chemistry.
N
R)
N
(
Me
(R)-sulfinyl imine
P,N-ligand 9
S(R)
Me
Ph
O
(R)-Ph-PHOX 8a
(
Pfaltz-Helmchen-Williams)
(Ellman)
N,N-ligand
DPPB4
PNP5
PPFA 6
H
N
=
(R)
(S)
N
N
Buchwald ligand 7
N
H
(
R)-Ph-PHOX 8a
Abs340
Ellman ligand 9
Sparteine 10
sparteine 10
(Sigman-Stolz)
2
.5
1
Figure 2. Structures of the ligands in the initial screen.
The biphenyl ligand 7, developed in the Buchwald
group, has proved to be one of the most successful lig-
ands for Pd-mediated Suzuki couplings and aminations
1
(
Buchwald–Hartwig reaction) of aryl chlorides and
2
1
bromides. Ligand class 8 represents the most well-
studied phosphinooxazoline family, wherein the chiral-
ity usually resides in the oxazoline moiety, and often is
derived from an amino acid. These PHOX ligands
were developed concurrently in the laboratories of
2
2
2
3a
23b
23c
Pfaltz, Helmchen, and Williams, about a decade
ago, and have found quite widespread application in
late transition metal chemistry, including allylic substi-
tution chemistry. Finally, Schenkel and Ellman have re-
ported that substitution of the chiral oxazoline moiety
with a chiral tert-butylsulfinamide-based imine, leads
to a P,N-ligand 9 that also supports Pd(0)-based allylic
substitution with malonate upon 1,3-diphenylpropenyl
0
.5
0
2
4
6
8
10
time (min)
Figure 1. ISES data from the initial ligand screen.
2
4
The selected P,N-ligands themselves span a range of
hybridization states on nitrogen, from sp (amine nitro-
acetate.
3
2
gen; ligands 5 and 6), to intermediate between sp and
In the ISES assay (see Table 1 figure), turnover of sub-
strate 1 implies loss of an ethyl carbonate leaving group,
that following decarboxylation and protonation (per-
haps at the organic/aqueous interface), leads to release
of ethanol. The ethanol signal is diffusible and can be
detected by the tandem action of yeast alcohol dehydro-
genase and yeast aldehyde dehydrogenase in the
reporting aqueous layer. This results in the formation
of two molecules of NADH per EtOH detected. Cata-
lysts that turn over the carbonate substrate more rapidly
should lead to a greater rate of NADH formation in the
aqueous layer. Several catalysts can be screened in par-
allel, using a UV/vis-spectrophotometer with a multicell
changer. The method is sensitive, since even 0.1lmol of
3
2
sp (aniline nitrogen, ligand 7), to sp (oxazoline/imine
nitrogen, ligands 8 and 9). All, in principle, offer the pos-
sibility for five- or six-ring bidentate chelation to nickel.
Whereas, the PNP-ligand 5 has been relatively little
studied heretofore, the other amine-based ligand,
PPFA 6, was developed by Hayashi and Kumada in
the 1970Õs, and represents the first planar chiral P,N-
1
8
1
9
ligand developed. It has been widely studied and has
found early application in asymmetric Grignard cross-
1
9b
couplings with vinylic halides, mediated by nickel.
also served as the direct precursor to the Josiphos lig-
It
2
0
ands with which we have found some success in early
b
asymmetric versions of this nickel chemistry.
2

D. B. Berkowitz et al. / Tetrahedron: Asymmetry 15 (2004) 2845–2851
2847
Table 1. Surveying new ligand classes for intramolecular Ni(0)-
mediated allylic amination using in situ enzymatic screening (ISES)
Unfortunately, for this substrate, relatively slow rates
were seen by ISES with the other P,N-ligand classes
screened, including the ligands of Hayashi and Kumada
O
O
Me
6
, Buchwald 7 and Ellman 9, as well as sparteine. As can
O
O
O
Ni(cod)2 3
be seen from Table 1, a good correlation was seen be-
tween ISES rankings (10min window, biphasic condi-
tions) of the ligands screened and NMR conversions
for the same ligands under RB flask conditions (10min
window, THF solvent).
N
O
PMP
1
(Li salt)
O
NLi
P,N-ligand
2
PMP
CO2
YAlDH
YADH
O
Me
O
Me
O
Me
H
HO
H
H
H
The results for PNP-ligand 5 are striking, in terms of
both the dramatic ISES rate seen, and the nearly com-
plete conversion of 1 to 2 that is seen within 10min of
performing the reaction under standard conditions in
THF (Table 1). This ligand accelerates this Ni(0) chem-
istry more effectively than any other ligand yet studied.
Unfortunately, that catalytic power does not translate
into any significant enantiodiscrimination, as 2 is ob-
tained in essentially racemic form (chiral HPLC).
+
+
NADH
H
NAD
NADH
NAD
+
+
+
+
H
a
b
c
No
Ligand
DPPB 4
DO.D.340/time
%Conv.
70
90
d
1
2
3
4
5
6
7
180 ± 40
e
360
(R)-Phenethyl-PNP 5
PPFA 6
f
4 ± 1
20 ± 15
137 ± 22
18 ± 6
f
Buchwald ligand 7
(R)-Ph-PHOX 8a
Ellman ligand 9
(À)-Sparteine 10
38
f
Ligand 5 has been previously shown to support the
Pd(II)-mediated intramolecular hydroamination of 6-
f
21 ± 10
a
b
c
18a
Conditions for the biphasic ISES screen (YADH = yeast alcohol
dehydrogenase and YAlDH = yeast aldehyde dehydrogenase) as
described in Note 25.
aminohexyne to 2-methyl-1,2-dehydropiperidine. Tri-
dentate coordination to palladium was proposed in that
work, though a monomer–dimer equilibrium was also
postulated to rationalize the NMR data seen. Perhaps
À1
ObsÕd rates (10min) of NADH formation in units of DO.D.340 min
(Fig. 1). ISES slopes are reported as mean ± SD (duplicate runs)
unless otherwise indicated.
18b,c
more striking, Bianchini et al.
have found that lig-
and 5 promotes the Ir(I)-mediated enantioselective
transfer hydrogenation of a,b-unsaturated ketones, in
upto 54% ee. Interestingly, these workers succeeded in
crystallizing both the (cod)Ir(I)-hydride-5 complex and
an Ir(III)-5-dihydride complex. The former exhibits
bidentate P,P-coordination to the iridium(I) center,
whereas the latter clearly shows P,N,P-tridentate coordi-
nation to the Ir(III) center (Fig. 3).
2
Reaction conditions: 67mM 1, 10mol% Ni(cod) , 10mol% ligand,
LiHMDS (1equiv), THF, rt, 10min. Product:educt ratio estimated
by NMR following work-up.
Average of four runs.
d
e
This value is derived from extrapolation as the absorbance rises above
the detection limit over the course of the screen (Fig. 1).
Crude NMR shows 65% conversion to product.
f
NADH in approximately a 1mL volume gives rise to a
for
the 1,4-dihydronicotinamide chromophore of reduced
pyridine nucleotide co-factors. This then allows for an
approximate catalyst ranking, in terms of relative turn-
over rates.
Ph
Ph
Ni
significant absorbance (ꢀ0.6) at 340nm, the k
max
P
Ph
N
Me
P
Ph Ph
For reactions to which it applies, the ISES method has
the advantage of providing a rapid readout, as no ali-
quots need be drawn and no work-upis necessary, and
the readout is semi-continuous. Another important
advantage is that one need not modify the substrate
by installing a chromophore, for example. This avoids
the synthetic manipulation entailed in such approaches
and, more importantly, does not raise the spectre of
potentially altered reactivity associated with structural
modifications.
Figure 3. Potential tridentate Ni-coordination for ligand 5.
This latter observation raises the interesting possibility
that 5 may exhibit tridentate coordination to the nickel
center, either at the Ni(0) or Ni(II) oxidation state along
the reaction coordinate, for the conversion of 1 to 2.
Given the impressive rate seen here, future experiments
are warranted to assess whether rate acceleration corre-
lates well with this ÔtridentateÕ ligand motif, and to
establish whether alterations in the chiral scaffold within
this PNP class can lead to appreciable asymmetric
induction in this Ni(0) chemistry.
The actual UV/vis data obtained for P,N-ligands of
classes 4–9 are shown in Figure 1 and the reporting rates
are tabulated in Table 1. As noted, the DPPB ligand was
the most effective ligand previously found to promote
this Ni(0)-transformation (1!2), and so provides a use-
ful calibration point. One notices immediately that two
of the new P,N-ligand classes screened, namely the chi-
ral-PNP ligand 5, and the PHOX ligand 8a, give much
more significant ISES signals than the others.
Given the modular nature of the PHOX ligands, and the
potential for readily introducing a range of chiral direct-
ing groups into these ligands, we were particularly intri-
gued that the ISES screen identified 8a as one of the
better promoters of this Ni(0)-mediated intramolecular
amination chemistry. It was decided to expand upon this

2848
D. B. Berkowitz et al. / Tetrahedron: Asymmetry 15 (2004) 2845–2851
lead result. A family of PHOX ligands 8a–g was assem-
bled for a more focused screen, in a second round of ISES.
nucleophilic aromatic substitution upon the resulting
2
(2-fluoro)aryloxazoline.
7
It was found that O-ethyl 2-fluorobenzimidate tetra-
fluoroborate salt 11, a reagent introduced recently by
Busacca et al. for the synthesis of phosphinoimidazoline
ligands, provides an excellent nucleus for the assembly
of a focused array of PHOX ligands. The approach
taken is illustrated in Scheme 1, and involves initial con-
densation of a chiral amino alcohol with 11, followed by
introduction of the desired diarylphosphino group by
Five different chiral amino alcohols were chosen,
derived from D-phenylglycine (a), D-valine (b), L-phenyl-
alanine (c), L-tert-leucine (d) and (1R,2S)-1-amino-2-
indanol (e), respectively. The corresponding diphenyl-
phosphinooxazolines, 8a–e, all known ligands, were
examined for promotion of the title transformation by
ISES. The average reporting rates observed and actual
UV traces are presented in Table 2 and Figure 4,
respectively.
2
6
Step 1 - Amino alcohol introduction
NH2
NH2
NH2
OH
OH Ph
OH
,
,
,
(
R)-Ph-PHOX 8a
NH2
NH2
OH
(R)-i-Pr-PHOX 8b
(S)-Bn-PHOX 8c
OH or
2
.5
1
(
(
S)-t-Bu-PHOX 8d
3aR, 8aS)-8e
Abs340
(3aR, 8aS)-8g
(R)-Ellman ligand 9
F
Step 2 - Phosphino
group installation
1
BF4 H2N
OEt 11
K
P
Ar2P
,
Me
Me
N
Me
Me
O
Li
P
Li
P
8
a-g
or
0
.5
0
2
4
6
8
10
Me
Me
time (min)
Scheme 1. Synthesis of the PHOX ligand array.
Figure 4. ISES data from the PHOX ligand screen.
Table 2. An ISES examination of chiral PHOX ligands
O
O
O
Me
(R2)
Ar2P
N
O
O
O
R1
N
O
PMP
1
(Li salt)
O
NLi
2
Ni(cod)2
PMP
CO2
Yeast ADH/AlDH enzyme reporting layer
EtOH
a
No
b
c
Conv. (%)
L
Ar
R
1
(R
2
)
DO.D.340/t
d
1
2
3
4
5
6
7
(R)-8a
(R)-8b
Ph
Ph
Ph
137 ± 22
166 ± 29
38
36
41
16
53
33
<5
i-Pr
Bn
d
(S)-8c
(S)-8d
Ph
Ph
198 ± 15
77
t-Bu
e
Ind
(3aR,8aS)-8e
(3aR,8aS)-8g
(R)-9
Ph
3,5-Xyl
Ph
224 ± 18
100 ± 11
18 ± 6
e
Ind
f
a
b
c
Conditions for the biphasic ISES screen (YADH = yeast alcohol dehydrogenase and YAlDH = yeast aldehyde dehydrogenase) as described in Note
5.
2
À1
ObsÕd rates (10min) of NADH formation in units of DO.D.340 min (Fig. 4). ISES slopes are reported as mean ± SD (duplicate runs) unless
otherwise indicated.
2
Reaction conditions: 67mM 1, 10mol% Ni(cod) , 10mol% ligand, LiHMDS (1equiv), THF, rt, 10min. Product:educt ratio estimated by NMR
following work-up.
This slope is the average of four runs.
d
e
f
The chiral element here is the oxazoline derived from (1R,2S)-1-amino-2-indanol.
This is EllmanÕs ligand, bearing the (R)-t-butylsulfinyl imine chiral element.

D. B. Berkowitz et al. / Tetrahedron: Asymmetry 15 (2004) 2845–2851
Table 3. RB flask results: Ni(0)-PHOX-mediated cyclizations of 1 to 2
2849
a
No
b
Yield (%)
c
Ee
d
Ligand
Base
Config
1
2
3
4
5
6
7
8
9
(R)-8a
(R)-8b
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
NaHMDS
KHMDS
LiHMDS
LiHMDS
49
41(74)
0
28
24
36
30
38
34
4
e
(R)
(S)
(S)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(S)-8c
(S)-8d
49
27(46)
e
(3aR,8aS)-8e
(3aR,8aS)-8f
(3aR,8aS)-8f
(3aR,8aS)-8f
(3aR,8aS)-8g
(R)-9
57
66–82
f
61
60
37
14
48
23
43
38
13
35
<5
37
45
31
46
50
37
45
24
48
10
11
12
13
14
15
16
17
18
19
20
(3aR,8aS)-8f
(3aR,8aS)-8f
(3aR,8aS)-8f
(3aR,8aS)-8f
(R)-8a
NaH
g
2 3
Na CO
KO-t-Bu
g
K CO
2 3
h
None
None
None
None
None
None
h
h
h
h
(R)-8b
(S)-8c
ND
48
(S)-8d
(3aR,8aS)-8e
(3aR,8aS)-8f
(S)
(R)
(R)
e
40(69)
38
50
51
a
b
c
Reaction conditions: 67mM 1, 10mol% Ni(cod)
2
, 10mol% ligand, base (1equiv), THF, rt, overnight.
Yields reflect isolated pure product, following chromatography.
HPLC with a chiral stationary phase was used to determine ee [Chiralcel OD; hexane–i-PrOH (80/20)]. ND = Not determined.
Absolute configuration established by correlation of the second-eluting peak of 2 with L-vinylglycine (Ref. 2b).
d
e
The yields in parentheses reflect runs in which a second portion of Ni(cod)
Range for two runs.
2
and ligand were added at t = 2h.
f
g
h
Nominally, 3equiv base were employed here, though the base was not completely soluble.
These runs employed a Ni:L ratio of 1:2.
Given the impressive rate displayed by ligand 8e, bear-
ing the aminoindanol chiral scaffold, it was selected
for further modification. Thus, alteration of the phos-
phide nucleophile employed in the second module of
the synthesis (Scheme 1), permitted for the facile intro-
duction of either a bis(p-toluyl)phosphino group or a
bis(3,5-xylyl)phosphino group, to give the previously
3.Conclusions
Recently, the ISES approach to catalyst screened uncov-
ered conditions (model substrate 1, N-PMP protecting
group, LiHMDS base, Ni(cod) catalyst precursor) that
2
were particularly conducive to Ni(0)-mediated allylic
2
amination chemistry. The pattern of ligand perform-
2a
2
7
undescribed ligands 8f and 8g, respectively.
ance initially found set the stage for the identification
of the first asymmetric such transformation with chiral
bidentate phosphine ligands (1!2 in 88% yield and
While 8e and 8f showed comparable rates, 8g showed
somewhat attenuated reactivity for the model reaction.
Nonetheless, all of the PHOX ligands screened showed
respectable ISES rates and clearly supported this Ni(0)
chemistry better than even the closely related ligand 9
2
b
75% ee with MeO-BIPHEP). This prompted us to
screen other classes of bidentate ligands, such as the
P,N-array examined here. This has led to the discovery
of the ÔfastestÕ ligand yet uncovered for the title transfor-
mation; namely PNP-ligand 5. We also find that PHOX
ligands 8b and 8d–g promote this chemistry with eeÕs up
to 51%, though conversion remains an issue here.
(
Fig. 4). Given these observations, it was decided to
examine this ligand set further, under standard reaction
conditions, over more extended periods of time, with
purification of the product 2 and evaluation of its enan-
tiomeric purity by chiral HPLC. The results are col-
lected in Table 3.
2
6
Finally, we note that imidate salt 11 provides a very
convenient and modular vehicle into the PHOX ligand
class. This approach allowed for the efficient synthesis
of the parent 1-amino-2-indanol-based PHOX ligand,
Several trends are apparent. With few exceptions, the
inclusion of base improves both rate and yield. In some
cases (i.e., entries 5–8), yields in the 60–80% range are
attained. However, base generally leads to a lower ee
in the product than that observed in the, albeit incom-
plete, reactions carried out in the absence of base. In
the best cases, eeÕs in the 48–51% range are seen for
the i-Pr, t-Bu, and aminoindanol-based directing groups
2
7
8e, as well as two new congeners thereof, 8f and 8g.
Whereas ligand 8e remains incompletely studied,
though Wiese and Helmchen have examined allylic sub-
2
8
2
8c
stitutions with Pd here, ligands 8f and 8g are new. All
three ligands appear to have promise when compared to
the other PHOX ligands surveyed. Future studies will
exploit this modular ligand synthesis, as substrate and
catalyst structure are further varied.
(entries 16 and 18–20). One can drive these base-free
reactions to higher conversions, and maintain these
eeÕs, by adding a second portion of Ni(0) and ligand
In this light, it is perhaps useful to survey the lim-
ited but emerging landscape of catalytic, asymmetric
(
i.e., entry 19), if desired.

2850
D. B. Berkowitz et al. / Tetrahedron: Asymmetry 15 (2004) 2845–2851
Ni(0)-mediated C–C bond forming reactions, with an
eye toward PHOX ligand performance. Interestingly,
Chem. Soc. 2002, 124, 12–13, (A Pd(II) cycle is proposed
here); (b) Trost, B. M.; Bunt, R. C.; Lemoine, R. C.;
Calkins, T. L. J. Am. Chem. Soc. 2000, 122, 5968–5976; (c)
Larksarp, C.; Alper, H. J. Am. Chem. Soc. 1997, 119,
3709–3715; (d) Hayashi, T.; Yamamoto, A.; Ito, Y.
Tetrahedron Lett. 1988, 29, 99–102.
PHOX ligands (i) perform poorly in MoriÕs R Zn-initi-
2
2
9
ated carboxylative bis-diene cyclizations, (ii) provide
modest eeÕs in UemuraÕs allylic substitutions involving
hard RMgX or arylboronate-ate nucleophiles, and
3
0
8
9
. Matsushima, Y.; Onitsuka, K.; Kondo, T.; Mitsudo, T.;
Takahashi, S. J. Am. Chem. Soc. 2001, 123, 10406–10495.
. (a) Leitner, A.; Shu, C.; Hartwig, J. F. Proc. Natl. Acad.
Sci. U.S.A. 2004, 101, 5830–5833; (b) Kiener, C. A.; Shu,
C.; Incarvito, C.; Hartwig, J. F. J. Am. Chem. Soc. 2003,
125, 14272–14273; (c) Ohmura, T.; Hartwig, J. F. J. Am.
Chem. Soc. 2002, 124, 15164–15165.
0. (a) Welter, C.; Koch, O.; Lipowsky, G.; Helmchen, G.
Chem. Commun. 2004, 896–897; (b) Lipowsky, G.; Helm-
chen, G. Chem. Commun. 2004, 116–117; (c) Bartels, B.;
Garcia-Yebra, C.; Rominger, F.; Helmchen, G. Eur. J.
Inorg. Chem. 2002, 2569–2586.
(
iii) perform either brilliantly (high conversions and
eeÕs with dinaphthothiophenes) or not at all (with
dibenzothiophenes) in HayashiÕs Grignard-based fused
arylthiophene ring openings, depending on subtle nuan-
3
1
ces of substrate structure. This suggests that further
exploration of PHOX-based Ni(0)-allylic amination
chemistry across a greater expanse of substrate space
may reapdividends.
1
1
Acknowledgements
1. (a) Evans, P. A.; Robinson, J. E.; Moffett, K. K. Org. Lett.
2
001, 3, 3269–3271; (b) Evans, P. A.; Robinson, J. E. Org.
Lett. 1999, 1, 1929–1931; (c) Evans, P. A.; Robinson, J. E.;
Nelson, J. D. J. Am. Chem. Soc. 1999, 121, 6761–6762.
The authors thank the NSF (CHE-0317083) for sup-
port. D.B.B. acknowledges the Alfred P. Sloan Founda-
tion for a fellowship. This research was facilitated by
shared instrumentation grants for NMR (NIH SIG-1-
12. Ashfeld, B. L.; Miller, K. A.; Martin, S. F. Org. Lett.
004, 6, 1321–1324.
2
1
3. To our knowledge, there had not been a previous report of
asymmetric Ni(0)-mediated allylic amination, prior to our
recent findings (Ref. 2b). However, there were several
studies of non-stereocontrolled allylic aminations using
Ni(0): (a) Bricout, H.; Carpentier, J.-F.; Mortreux, A.
Tetrahedron 1998, 54, 1073–1084; (b) Bricout, H.; Car-
pentier, J.-F.; Mortreux, A. J. Chem. Soc., Chem. Com-
mun. 1995, 1863–1864; For evidence of p-allyl-nickel
intermediates, see: (c) Moberg, C. Tetrahedron Lett. 1980,
21, 4539–4542; (d) Yamamoto, T.; Ishizu, J.; Yamamoto,
A. J. Am. Chem. Soc. 1981, 103, 6863–6869; (e) Tolman,
C. A. J. Am. Chem. Soc. 1970, 92, 6785–6790; For
examples, of substrate-directed, regio- and stereoselective
Ni(0)-mediated substitutions of allylic ethers with Grig-
nard reagents, see: (f) Didiuk, M. T.; Morken, J. P.;
Hoveyda, A. H. Tetrahedron 1998, 54, 1117–1130; (g)
Farthing, C. N.; Kocovsky, P. J. Am. Chem. Soc. 1998,
120, 6661–6672.
14. Trost, B. M.; Dietsch, T. J. J. Am. Chem. Soc. 1973, 95,
8200–8201.
15. Togni, A.; Rihs, G.; Pregosin, P. S.; Ammann, C. Helv.
Chim. Acta 1990, 73, 723–732.
16. (a) Mandal, S. K.; Sigman, M. S. J. Org. Chem. 2003, 68,
7535–7537; (b) Mueller, J. A.; Sigman, M. S. J. Am. Chem.
Soc. 2003, 125, 7005–7013; (c) Mueller, J. A.; Jensen, D.
R.; Sigman, M. S. J. Am. Chem. Soc. 2002, 124,
8202–8203; (d) Jensen, D. R.; Pugsley, J. S.; Sigman, M.
S. J. Am. Chem. Soc. 2001, 123, 7475–7476.
17. (a) Bagdanoff, J. T.; Ferreira, E. M.; Stoltz, B. M. Org.
Lett. 2003, 5, 835–837; (b) Ferreira, E. M.; Stoltz, B. M. J.
Am. Chem. Soc. 2001, 123, 7725–7726.
18. (a) Mueller, T. E.; Berger, M.; Grosche, M.; Herdtweck,
E.; Schmidtchen, F. Organometallics 2001, 20, 4384–4393;
(b) Bianchini, C.; Glendenning, L.; Zanobini, F.; Farnetti,
E.; Graziani, M.; Nagy, E. J. Mol. Catal. A: Chem. 1998,
132, 13–19; (c) Bianchini, C.; Farnetti, E.; Glendenning,
L.; Graziani, M.; Nardin, G.; Peruzzini, M.; Rocchini, E.;
Zanobini, F. Organometallics 1995, 14, 1489–1502.
19. (a) Hayashi, T.; Yamamoto, K.; Kumada, M. Tetrahedron
Lett. 1974, 4405–4408; (b) Hayashi, T.; Tajika, M.;
Tamao, K.; Kumada, M. J. Am. Chem. Soc. 1976, 98,
3718–3719; (c) Fernandez-Galan, R.; Jalon, F. A.; Manz-
ano, B. R.; Rodriguez-de la Fuente, J.; Vrahami, M.;
Jedlicka, B.; Weissensteiner, W.; Jogl, G. Organometallics
1997, 16, 3758–3768; (d) Cammidge, A. N.; Crepy, K. V. L.
5
0
10-RR-06301, NSF CHE-0091975, NSF MRI-
079750) and GC/MS (NSF CHE-9300831),
respectively.
References
1
. Reviews: (a) Reetz, M. T. Compr. Coord. Chem. II 2004, 9,
09–548; (b) Stambuli, J. P.; Hartwig, J. F. Curr. Opin.
5
Chem. Biol. 2003, 7, 420–426; (c) Traverse, J. F.; Snapper,
M. L. Drug Discovery Today 2002, 7, 1002–1012; (d) Finn,
M. G. Chirality 2002, 14, 534–540; (e) Reetz, M. T. Angew.
Chem., Int. Ed. 2002, 41, 1335–1338; (f) Loch, J. A.;
Crabtree, R. H. Pure Appl. Chem. 2001, 73, 119–128.
. (a) Berkowitz, D. B.; Bose, M.; Choi, S. Angew. Chem.,
Int. Ed. 2002, 41, 1603–1607; (b) Berkowitz, D. B.; Maiti,
G. Org. Lett. 2004, 6, 2661–2664.
. For examples, of the use of enzymes to analyze chiral
reaction products, post work-up, see: (a) Abato, P.; Seto,
C. T. J. Am. Chem. Soc. 2001, 123, 9206–9207; (b) Onaran,
M. B.; Seto, C. T. J. Org. Chem. 2003, 68, 8136–8141; (c)
Li, Z.; Buetikofer, L.; Witholt, B. Angew. Chem., Int. Ed.
2
3
2004, 43, 1698–1702; For related approaches, using anti-
bodies, see: (d) Matsushita, M.; Yoshida, K.; Yamamoto,
N.; Wirsching, P.; Lerner, R. A.; Janda, K. D. Angew.
Chem., Int. Ed. 2003, 42, 5984–5987; (e) Taran, F.;
Gauchet, C.; Mohar, B.; Meunier, S.; Valleix, A.; Renard,
P.-Y.; Cr e´ minon, C.; Grassi, J.; Wagner, A.; Mioskowski,
C. Angew. Chem., Int. Ed. 2002, 41, 124–127.
4
. Reviews concerning allylic amination: (a) Johannsen, M.;
Jorgensen, K. A. Chem. Rev. 1998, 98, 1708–1869; (b)
Trost, B. M. Pure Appl. Chem. 1996, 68, 779–784.
. For references on PLP–enzyme inhibition with a-vinylic
amino acids, see: Berkowitz, D. B.; Jahng, W.-J.; Peder-
sen, M. L. Bioorg. Med. Chem. Lett. 1996, 6, 2151–2156,
and references cited therein.
5
6
7
. For leading references on the stereocontrolled synthesis of
a-vinylic amino acids, see: (a) Ma, D.; Zhu, W. J. Org.
Chem. 2001, 66, 348–350; (b) Berkowitz, D. B.; McFad-
den, J. M.; Chisowa, E.; Semerad, C. L. J. Am. Chem. Soc.
2000, 122, 11031–11032; (c) Berkowitz, D. B.; McFadden,
J. M.; Sloss, M. K. J. Org. Chem. 2000, 65, 2907–2918.
. For examples, of related asymmetric allylic aminations
with Pd, see: (a) Overman, L. O.; Remarchuk, T. P. J. Am.

D. B. Berkowitz et al. / Tetrahedron: Asymmetry 15 (2004) 2845–2851
2851
J. Chem. Soc., Chem. Commun. 2000, 1723–1724; (e)
Bringmann, G.; Hamm, A.; Schraut, M. Org. Lett. 2003,
solvent, SiO chromatography (10% EtOAc–hexanes),
2
1
provided the desired oxazoline (220mg, 65%): H NMR
5, 2805–2808.
(400MHz, CDCl ) d 3.35 (dd, J = 2, 18Hz, 1H), 3.48 (dd,
3
2
2
0. Togni, A.; Breutel, C.; Schnyder, A.; Spindler, F.; Land-
ert, H.; Tijanit, A. J. Am. Chem. Soc. 1994, 116,
J = 11, 18Hz, 1H), 5.45 (dt, J = 2, 7Hz, 1H), 5.76 (d,
J = 8Hz, 1H), 7.07 (dd, J = 9, 11Hz, 1H), 7.10 (t,
J = 8Hz, 1H), 7.24–7.28 (m, 3H), 7.34–7.40 (m, 1H),
4
062–4066.
1. (a) Harris, M. C.; Huang, X.; Buchwald, S. L. Org. Lett.
002, 4, 2885–2888; (b) Tomori, H.; Fox, J. M.; Buchwald,
7.57–7.59 (m, 1H), 7.83 (dt, J = 2, 8Hz, 1H); HRMS calcd
H
+
13NOF (M+H) 254.0981, found 254.0978. Step
2
for C16
S. L. J. Org. Chem. 2000, 65, 5334–5341; (c) Old, D. W.;
Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120,
2: Phosphine installation/synthesis of (3aR,8aS)-8f. To a
solution of lithium di-(p-tolyl)-phosphide (1.1mmol) in
THF (3mL) was added the oxazoline from Step1 (200mg,
0.8mmol) in THF (1.5mL) at rt. The reaction was
complete within 10min and the reaction mixture was
cannulated into a separatory funnel and partitioned
9
722–9723.
2
2
2. For reviews, see: (a) Helmchen, G.; Pfaltz, A. Acc. Chem.
Res. 2000, 33, 336–345; (b) Helmchen, G.; Kudis, S.;
Sennhenn, P.; Steinhagen, H. Pure. Appl. Chem. 1997, 69,
5
1
13–518; (c) Pfaltz, A. Acta Chem. Scand. B 1996, 50,
89–194; (d) Williams, J. M. J. Synlett 1996, 705–710.
between H
(Na SO ), filtered and evaporated. Flash column chroma-
2 2 2
O and CH Cl . The organic layer was dried
2
4
3. (a) von Matt, P.; Pfaltz, A. Angew. Chem., Int. Ed. 1993,
2, 566–568; (b) Sprinz, J.; Helmchen, G. Tetrahedron
tography under an Ar stream (10% EtOAc–hexanes;
degassed and satd with Ar before use) gave 8f (340mg,
3
2
D
5
1
Lett. 1993, 34, 1769–1772; (c) Dawson, G. J.; Frost, C. G.;
Williams, J. M. J.; Coote, S. J. Tetrahedron Lett. 1993, 34,
96%): ½aŠ ¼ þ145 (c 1.22, CHCl
3
); H NMR (500MHz,
3
CDCl ) d 2.29 (s, 3H), 2.30 (s, 3 H), 3.05 (d, J = 18Hz,
3
149–3150.
1H), 3.26 (dd, J = 7.18Hz, 1H), 5.19 (app dt, J = 1.4,
18Hz, 1H), 6.80–6.84 (m, 1H), 7.0–7.2 (m, 11H), 7.82–7.88
2
2
4. Schenkel, L. B.; Ellman, J. A. Org. Lett. 2003, 5, 545–548.
5. Typical ISES conditions: Assays were run in Ar purged,
septum-sealed 1cm-path length quartz cuvets that are
nominally 1mL in volume. The organic layer (500lL) was
layered upon a lower aqueous enzymatic ÔreportingÕ layer
3
(m, 1H); P NMR (162MHz, CDCl
1
3
) d 6.47; HRMS
H26NOP (M+H) 448.1830, found 448.1839.
+
calcd for C30
28. (a) Bernardi, L.; Gothelf, A. S.; Hazell, R. G.; Jorgensen,
K. A. J. Org. Chem. 2003, 68, 2583–2591; (b) Carmona,
D.; Lahoz, F. J.; Elipe, S.; Oro, L. A.; Lamata, M. P.;
Viguri, F.; S a´ nchez, F.; Mart ´ı nez, S.; Catviela, C.; L o´ pez-
Ram de V ´ı u, M. P. Organometallics 2002, 21, 5100–5114;
(c) Wiese, B.; Helmchen, G. Tetrahedron Lett. 1998, 39,
5727–5730; (d) Carmona, D.; Catviela, C.; Elipe, S.;
Lahoz, F. J.; Lamata, M. P.; L o´ pez-Ram de V ´ı u, M. P.;
Oro, L. A.; Vega, C.; Viguri, F. J. Chem. Soc., Chem.
Commun. 1997, 21, 2351–2352.
29. For a review on Ni(0)-mediated cyclizations leading to C–
C bond installation, see: (a) Montgomery, J. Acc. Chem.
Res. 2000, 33, 467–473; (b) Takimoto, M.; Nakamura, Y.;
Kimura, K.; Mori, M. J. Am. Chem. Soc. 2004, 126,
5956–5957.
(
900lL) such that the light beam of the UV/vis spectro-
meter would pass cleanly through the aqueous layer. This
permits for the ready monitoring of NADH formation in
the aqueous layer (see Figs. 1 and 3 for representative UV
traces). Aqueous layer composition: 7.2mM NAD , 1.3U
of YADH, 0.12U of YAlDH, 10mM KCl in 50mM
sodium pyrophosphate buffer pH8.6. Organic layer com-
+
position/preparation: To a solution of Ni(cod)
(
2
and ligand
10mol% each) in THF (300lL), under Ar was added
substrate 1 (100lmol) dissolved in toluene (100lL).
LiHMDS (1equiv) in hexane (100lL) was added, and
the vial briefly vortexed, followed by layering onto the
aqueous solution.
2
6. Busacca, C.; Grossbach, D.; So, R. C.; OÕBrien, E. M.;
Spinelli, E. M. Org. Lett. 2003, 5, 595–598.
30. (a) Chung, K.-G.; Miyake, Y.; Uemura, S. J. Chem. Soc.,
Perkin Trans. 1 2000, 2725–2729; (b) Chung, K.-G.;
Miyake, Y.; Uemura, S. J. Chem. Soc. Perkin Trans. 1
2000, 15–18.
31. (a) Cho, Y.-H.; Kina, A.; Shimada, T.; Hayashi, T. J. Org.
Chem. 2004, 69, 3811–3823; (b) Shimada, T.; Cho, Y.-H.;
Hayashi, T. J. Am. Chem. Soc. 2002, 124, 13396–
13397.
2
7. Representative PHOX ligand synthesis. Step 1: Oxazoline
installation via 11. A mixture of (1R,2S)-1-amino-2-
indanol (200mg, 1.34mmol) and O-ethyl-2-fluoro-benzim-
idate, tetrafluoroborate salt (11, 350mg, 1.37mmol) in dry
ethanol (10mL), under Ar, was stirred at rt for 1h, and
then heated at reflux for 2h. Following removal of the