Investigation of the importance of nitrogen substituents in a N-P chiral ligand for enantioselective allylic alkylation

Article abstract of DOI:10.1016/S0957-4166(01)00137-9

The synthesis of three chiral chelate nitrogen-phosphorus (S)-valine derived ligands with the potential for stereogenic nitrogen donation is described. In palladium catalysed allylic substitution reactions the ligands induced varying enantioselectivities ranging from 92% e.e. of the (R)-enantiomer to 83% e.e. of the (S)-enantiomer. Structural and spectroscopic investigations into the origin of this effect were conducted, but were inconclusive. However, the importance of the consideration of N-substituents in such systems is highlighted.

Full text of DOI:10.1016/S0957-4166(01)00137-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 923–935
Investigation of the importance of nitrogen substituents in a N–P
chiral ligand for enantioselective allylic alkylation
James C. Anderson,a,* Rachel J. Cubbona and John D. Harlingb
aSchool of Chemistry, University of Nottingham, Nottingham NG7 2RD, UK
bGlaxoSmithKline Pharmaceuticals, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK
Received 7 March 2001; accepted 19 March 2001
Abstract—The synthesis of three chiral chelate nitrogen–phosphorus (S)-valine derived ligands with the potential for stereogenic
nitrogen donation is described. In palladium catalysed allylic substitution reactions the ligands induced varying enantioselectivities
ranging from 92% e.e. of the (R)-enantiomer to 83% e.e. of the (S)-enantiomer. Structural and spectroscopic investigations into
the origin of this effect were conducted, but were inconclusive. However, the importance of the consideration of N-substituents
in such systems is highlighted. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
these ligands and further studies into the origin of this
pronounced selectivity effect.
We have reported that allowing the nitrogen donor in
simple nitrogen–sulfur chelate ligands to become
configurationally fixed and stereogenic (1, Fig. 1) gave
higher enantioselectivities in the asymmetric addition of
diethylzinc to aromatic aldehydes when compared to
achiral nitrogen donors of the same ligand system.1
While the corresponding sulfide ligands 2 were ineffec-
tive for the asymmetric palladium catalysed allylic sub-
stitution reaction,2 the corresponding imine-sulfides 3
were shown to be excellent as chiral ligands in this
reaction3 and the mechanism of chirality transfer was
deduced.4 As nitrogen–phosphorus chelate ligands are
amongst the most successful in the palladium catalysed
asymmetric allylic substitution reaction,5 we investi-
gated the diphenylphosphine analogues 4 of our amino
sulfide ligands 2 and found a dramatic reversal in the
sense of enantioselection by simply altering the nitrogen
substitution pattern.6 Ligands 4 are essentially chiral N
versions of valphos 5. Herein, we detail the synthesis of
2. Design and synthesis of ligands
An essential feature of the molecular architecture of
these ligands is the potential for the transmission of
chirality inherent to the backbone of the ligand to the
stereogenic nitrogen atom. This should place an asym-
metric environment close to the reaction sphere. We
were interested in synthesising three sterically and elec-
tronically different ligands 6–8 (Scheme 1) for our
studies. To create a suitably large disymmetric environ-
ment around the nitrogen donor of 4 we chose the
methyl and phenyl substitutents (A values: Me=1.7;7
Ph=3.08) to give ligand 6. In order to try and assess
whether the donor ability of the nitrogen lone pair and
the three-dimensional shape of the amine could be
compromised by the delocalising effect of the phenyl
substituent, we decided to synthesise ligand 7. The
Figure 1.
* Corresponding author. Tel.: +44(0)115 951 4194; fax: +44(0)115 951 3564; e-mail: j.anderson@nottingham.ac.uk
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00137-9

924
J. C. Anderson et al. / Tetrahedron: Asymmetry 12 (2001) 923–935
Scheme 1.
N-iso-propyl substituent removes the possibility of any
delocalisation effect with only a small compromise in
size differential between the iso-propyl and methyl sub-
stituents (A values: Me=1.7;7 iPr=2.77). The two
phenyl substituents of ligand 8 give a nitrogen donor
possessing different orientations of its aromatic rings.
The rotational freedom of the b-phenyl ring will be
restricted by the proximity of the backbone chiral cen-
tre. The orientation of this phenyl ring will affect that
of the a-phenyl ring and render the nitrogen atom
stereogenic.9
ands 6–8 did not give the desired nitrogen–phosphine
chelates upon sequential treatment with HCl; SOCl2;
KPPh2.10
The synthesis of ligand 6 was achieved by using an
N-formyl group as a latent methyl group. Reaction of
(S)-N-phenyl-2-amino-3-methylbutan-1-ol1b with in situ
generated formic–acetic anhydride11 at ambient temper-
ature led to the N-formyl derivative 11 (94%, Scheme
2). Subsequent introduction of the diphenylphosphine
group by the literature method proceeded in good
overall yield to give 12 (67%, two steps). Failure of
DIBAL to effect the desired reduction of 12 to the
N-methyl derivative led us to use borane–dimethyl-
sulfide (BMS) complex, which served a dual purpose.
Reduction with this reagent proceeded in 89% yield and
gave the protected phosphine-borane complex 13 of
ligand 6; the reported sensitive nature of phosphines led
us to use 13 for storage purposes and, when required,
Our retrosynthetic analysis for the target ligands 4 is
outlined in Scheme 1. It was decided to introduce the
phosphine group late in the synthetic scheme in order
to minimise problems associated with oxidation. We
planned to achieve this by displacement of a suitable
leaving group X on precursor 9 using a phosphine
anion. This precursor was seen to be accessible via
functional group interconversions of amino acid 10. A
flexible synthetic route to ligands 4 was required to
permit access to a variety of structural and electronic
analogues. We chose to base our ligands on valinol and
although this retrosynthesis treats the ligands as being
similar to 2, their synthesis proved to be notably more
difficult. We were aware that internal displacement of
leaving groups by the nucleophilic nitrogen atom could
potentially lead to other products and loss of stereo-
chemical integrity via the formation of aziridinium
ions.1b In the synthesis of valphos10 this is avoided by
generating the hydrochloride salt of N,N-dimethyl vali-
nol before conversion of the hydroxyl function to a
chloride leaving group for displacement with potassium
diphenylphosphine. In analogous syntheses of our lig-
ands the prerequisite N,N-disubstituted valinols of lig-
ligand
6 was formed cleanly by treatment with
DABCO.12
Based on NMR evidence we believe the borane in 13 is
coordinated to phosphorus in preference to the possible
amino-borane intermediate. The 31P NMR spectrum of
13 exhibited a broad signal at 15.6 ppm, characteristic
of phosphine-boranes.13 The phosphorus resonance in 6
1
appears at −20.8 ppm. Also in the H NMR spectrum
the protons adjacent to phosphorus in 13 [2.47 (1H,
ddd) and 2.68–2.86 (1H, m)] exhibit an upfield shift in
decomplexed 6 [2.27 (1H, ddd) and 2.46–2.55 (1H, m)].
As the Kumada type synthesis10 of ligand 7 from
N-iso-propyl-N-methylvalinol was unsuccessful, we
attempted to carry the methyl substituent through as a
Scheme 2.

J. C. Anderson et al. / Tetrahedron: Asymmetry 12 (2001) 923–935
925
Scheme 3.
formyl group by a similar strategy to that used for
ligand 6 (Scheme 2). The N-iso-propyl group was intro-
duced by reductive alkylation of the (S)-valine methyl
ester to give 14 in a 97% yield (Scheme 3). Reduction to
the corresponding amino alcohol with LiAlH4 (94%)
was followed by selective formylation to give 15 in
moderate yield (50%). Alcohol 15 was seemingly inert
to thionyl chloride.
desired 19, which is protected at both ends of the
chelate structure. It would have been desirable to retain
the borane protection throughout the remainder of the
synthesis to prevent possible oxidation to the phosphine
oxide, but initial attempts to remove the N-Boc group
with trifluoroacetic acid (TFA) led to a mixture of
compounds, one of which showed loss of phosphine
complexed borane. In order to avoid such complica-
tions it was decided to remove the borane prior to
further manipulations. Treatment with DABCO in
warm toluene gave the free phosphine (97%), which was
further deprotected by treatment with TFA to afford 20
in 93% yield. Chiral amino-phosphines based on an
amino acid template may be interesting as chiral lig-
ands for other metal catalysed reactions. Their synthe-
sis has proved unsuccessful to date15 and this synthetic
route will enable these materials to be prepared
efficiently.
At this stage an attempt to protect the nitrogen of 15 as
its phthalimide derivative and displacement of tosylate
by a phosphinyl anion was attempted (Scheme 4). This
led to the rearranged product 16 which has literature
precedence;14 its congener was observed in an
attempted synthesis of a phenylalanine derived primary
amino phosphane ligand.15
A successful strategy we have used for the synthesis of
analogous amino sulfide ligands involved protection of
the primary amine function of valinol with a Boc
group.4 Treatment of 1716 with potassium diphenyl-
phosphine at low temperature resulted only in the
isolation of aziridine 18 in 40% yield (Scheme 5). All
attempts to alter the course of this reaction by varying
solvent, temperature and counterion failed.17 It has
been reported that anions of phosphine-boranes are less
basic than those of free phosphines.12 Treatment of 17
with lithium diphenylphosphine–borane complex under
optimised reaction conditions gave a 71% yield of the
Introduction of the iso-propyl substituent required a
two-step procedure whereby the isolated acetone-imine
was reduced with LiAlH4 to give the secondary amine
21 in 69% yield over two steps (Scheme 6). The N-
methyl substituent was similarly introduced as before to
give the required ligand 7 in 80% yield over two steps.
The N,N-diphenylated ligand 8 was easily synthesised
in the light of the experiences above. Mesylation of
Scheme 4.
Scheme 5.

Table 1. Allylic alkylation of 22 with CH2(CO2Me)2 catalysed by Pd–chiral ligand complexes
Entry
T (°C)
Conditions
Ligand (L*)
/
6 (-NPhMe)
7 (-NiPrMe)
8 (-NPh2)
Yieldb 23
Valphos (-NMe2)
ta
Yieldb 23
e.e. (%)c
ta
Yieldb 23
e.e. (%)c
ta
e.e. (%)c
ta
Yieldb 23
e.e. (%)c
(%)
(%)
(%)
(%)
1
2
3
4
5
6
7
8
9
rt
rt
0
A
B
A
B
B
A
B
B
A
1 m
98
89
98
85
85
91
93
89
94
50 (S)
33 (S)
50 (S)
45 (S)
47 (S)
73 (S)
65 (S)
73 (S)
83 (S)
–
–
–
1 h
–
–
–
24 h
–
–
–
–
82
–
–
–
89
–
–
–
–
15 m
15 m
5 h
50 m
4.5 h
12 h
12 h
3 d
97
89
91
83
90
93
94
94
96
20 (R)
54 (R)
32 (R)
68 (R)
80 (R)
70 (R)
85 (R)
92 (R)
80 (R)
–
–
–
15 m
1.5 h
14 m
12 h
12 h
2.5 d
4 d
15 m
10 m
15 m
12 h
12 h
2.5 d
4 d
90
97
91
91
97
95
91
93
54 (R)
61 (R)
54 (R)
69 (R)
54 (R)
59 (R)
62 (R)
60 (R)
1
0
11 (R)
–
–
–
56 (S)
–
−20
−30
−35
−50
−65
(
923
4 d
2 d
2.5 d
935
a m=minute, h=hour, d=day.
b Isolated yield.
c Determined by 1H NMR using chiral shift reagent Eu(hfc)3.

J. C. Anderson et al. / Tetrahedron: Asymmetry 12 (2001) 923–935
927
Scheme 6.
(S)-N,N-diphenylvalinol1b gave a stable derivative in
60% yield, which was treated with potassium diphenyl-
phosphine to give the ligand 8 in 69% yield (Eq. (1)).
can lead to enhanced enantioselectivity. Ligand 7 was
assayed to determine whether N-lone pair delocalisa-
tion into an N-phenyl substituent had any detrimental
effect. At room temperature ligand 7 exhibited very
poor (R)-selectivity of 11%, but at lower temperatures
gave a product with a greatly improved e.e. of 56% for
the (R)-enantiomer and 62% for the (S)-enantiomer.
This is comparable with the results obtained using
valphos.
(1)
From the limited examples we have it would seem that
a nitrogen donor in this ligand system with two identi-
cal substituents selects for the (R)-enantiomer of 23,
whereas a nitrogen donor with two unlike substituents
selects for the (S)-enantiomer. Based upon our charac-
terisation of a structurally similar imine-sulfide chelate
ligand in the same reaction,4 we offered a hypothesis
involving the conformation of the possible p-allyl palla-
dium intermediates in this reaction.6 The result from
use of ligand 7 fits this proposed model. Enantioselec-
tion by heterobidentate nitrogen–phosphorus chiral lig-
ands has been reported to be a result of the difference
in electronic character of the two donor atoms, which
may exert a stereoelectronic bias upon intermediate
p-allyl complexes.3,18 The palladiumꢀallyl terminus
bond opposite the more powerful acceptor atom (phos-
phorus) will be longer and hence more susceptible to
cleavage as a result of nucleophilic attack.19 Such char-
acteristics have been verified by NMR and X-ray stud-
ies and are claimed to control enantioselection.18c,20,21
To explain the sense of enantioselection with ligands
6–8 and valphos, assuming the ligands chelate the
reactive intermediate responsible for enantioselection
and that the conformation of the phosphorus phenyl
substituents are constant for each ligand system, we
arrived at the intermediates in Fig. 2. Ligands 6 and 7
with two different sized N-substituents should orientate
the allyl group in the ‘W’ conformation 24 due to the
avoidance of a destabilising steric interaction between
N–RL and the allyl phenyl group, which would arise if
the allyl group were orientated in the ‘M’ conformation
25 (Fig. 2). We propose for ligands 8 and valphos,
which possess two identical N-substituents, that the
3. Asymmetric alkylation
The effectiveness of these ligands for chirality transfer
was then investigated using the standard palladium
catalysed substitution of 1,3-diphenyl-2-propenyl ace-
tate 22 with dimethyl malonate. As a reference our
ligands were surveyed against valphos,10 which does not
have the potential for a stereogenic nitrogen atom when
chelated. Two common procedures were used which
involved either the generation of the nucleophile in situ,
using dimethyl malonate (3 equiv.) and N,O-
bis(trimethylsilyl)acetamide (BSA, 3 equiv.) with cata-
lytic potassium acetate (3 mol%) in dichloromethane or
the use of a preformed nucleophile, sodium dimethyl
malonate (1.5 equiv.) in THF. The palladium catalyst
(5 mol%) was formed by mixing the allyl palladium
chloride dimer with 2 molar equivalents of the chiral
ligand in the reaction solvent for 15 minutes at room
temperature. The results of the reactions carried out at
progressively lower temperatures, in terms of yield and
enantioselectivity for the substituted product 23, are
summarised in Table 1. Ligand 7, which was the most
difficult to synthesise, was only used in two cases and
showed no results to justify the synthesis and testing of
further quantities.
The most intriguing aspect of these results is the rever-
sal of selectivity exhibited by ligand 6 compared to
ligand 8, when both possess identical backbone chiral-
ity. They both perform substantially better than
valphos (compare entries 8 and 9), which supports our
hypothesis that a potentially stereogenic nitrogen donor
Figure 2.

928
J. C. Anderson et al. / Tetrahedron: Asymmetry 12 (2001) 923–935
intermediate 26 may be responsible for enantioselection.
For this intermediate to be more stable we must assume
that the backbone chirality pushes the N-b-substituent
into the reaction sphere making it more sterically
demanding than the N-a-substituent. Intermediate 26
would lead to the opposite (R)-enantiomeric product to
that which would arise from 24.
broad peaks at 24.1 and 30.6 ppm, which are typical
values for chelating phosphines in five-membered ring
environments.24 These latter signals could arise from the
exo and endo conformations of the desired allyl complex
28 in flux. Low temperature NMR studies on this
complex did not lead to any usable information. The
FAB mass spectrum revealed a 100% abundance mass
peak at 772, which corresponds to the cationic fragment
of 29. A mass signal for a ligand:palladium ratio of 2:1
was not observed. Attempts to obtain crystals of suit-
able quality for X-ray analysis were unsuccessful. It
would appear that for both complexes the mass spectral
data are in direct contradiction of the tentative NMR
data. It is clear that there is no single distinct p-allyl
intermediate present in solution and an explanation of
enantioselection is much more complex than in our
previous systems.4
4. Structural studies of p-allyl intermediates
As a starting point we assumed that the major
diastereoisomer of the intermediate p-allyl complex
would lead to the major enantiomer observed for the
product.22 Analogously to previous studies4,22 we
attempted to form a complex between chiral ligands 6
and 8 and the trans-1,3-diphenylpropenyl palladium
chloride dimer 2723 in an attempt to obtain a crystalline
sample of the p-allyl intermediate (Eq. (2)). The yellow–
orange solid 28 obtained with ligand 6 gave broad
A number of studies have reported differing results
when using different sources of palladium for standard
allylic substitution reactions.26 In general the presence
of chloride ions, commonly arising from the catalyst
precursor [Pd(h3-C2H5)Cl]2, had positive effects on
enantioselectivity (Reference 25b is an exception) when
compared to reactions performed using a non-chloride
containing source of palladium(0) [commonly Pd(dba)2
or Pd2(dba)3·CHCl3]. In order to investigate this effect
we repeated the sodiomalonate (procedure B) reactions
at −20°C, an intermediate temperature that gave moder-
ate enantioselectivities and good yields. The non-chlo-
ride source of catalyst Pd(dba)2 was used with all
ligands 6–8 and valphos. An extended reaction time of
up to 4 days was allowed, but only the valphos ligand
led to considerable product formation. In 12 hours
valphos gave a 78% yield of (R)-23 with 63% e.e. [Table
1: entry 5, 12 h, 91% yield, 69% e.e. (R)-enantiomer]. It
would appear that valphos is little affected by the
presence of chloride ions, but ligands 6–8 require chlo-
ride ions to act efficiently.
1
signals in its H NMR spectrum (CD2Cl2, rt), which
indicates fluctionality, but it could be seen that there
were two distinct sets of doublets for the iso-propyl
group. Originally it was thought that these signals arose
from two possible conformations of the allyl-palladium–
ligand complex. The 31P NMR spectrum in deuterochlo-
roform at room temperature revealed eight signals. Two
(lP=26.0 and 35.0) were significantly more intense than
the others, did not show phosphorus–phosphorus cou-
pling, and are in the typical range of phosphorus
chelates in five-membered rings.24 These could arise
from two different conformations of the p-allyl com-
plex. However, FAB mass spectroscopy failed to reveal
a mass peak for such a p-allyl complex, instead a signal
was detected corresponding to two ligands and one
palladium. If a ligand dimer did exist in solution there
would have to be two symmetrical complexes to account
for the lack of phosphorus–phosphorus coupling.25 The
NMR studies proved inconclusive and attempts to
obtain crystals suitable for X-ray analysis failed.
We were also interested in the binding mode of these
ligands. The structural studies had suggested the exis-
tence of complexes possessing a ligand:palladium ratio
of 2:1 and that the ligands were acting as non-chelating
monophosphine donors. Our experiments to date had
all involved the use of two equivalents of ligand to
palladium in order to ensure complete cyclisation. Con-
trol reactions were performed using the two sources of
palladium catalyst [[Pd(h3-C2H5)Cl]2 and Pd(dba)2] and
only one equivalent of ligand:palladium, again at
−20°C, using the sodiomalonate nucleophile (procedure
B) with extended reaction times. None of the ligands
gave good conversion with Pd(dba)2. Only 8 and
valphos gave any appreciable conversion with the allyl-
palladium chloride dimer [ligand 8, 91% yield, 83% e.e.
(R); valphos, 84% yield, 73% e.e. (R)-enantiomer] and
the results were similar to those obtained in the original
assay with two equivalents of ligand to palladium. These
results suggest that ligands 6 and 7 may be monodentate
in the active catalytic complex. Potentially ligand 8 may
be acting as a chelate ligand, but only in the presence of
chloride ions. Valphos also may act as a bidentate
ligand, but requires chloride ions to do so efficiently
with only one equivalent of ligand.
(2)
The formation of an allyl-palladium–ligand complex
with 8 was performed as before. The orange–red solid
29 gave broad signals in its 1H NMR spectrum in
CD2Cl2 at room temperature, suggesting that more than
one species were in dynamic equilibrium. Two sets of
iso-propyl signals could be identified, but these were
much broader than before. The 31P NMR spectrum
proved more revealing. The major signals were those of
2
an AB spin system (lA=15.9, lB=18.4, JP-P=57 Hz),
indicating a palladium species bound by two phospho-
rus atoms that were in chemically different environ-
ments. The chemical shifts suggest that the ligands are
non-chelating monophosphine donor ligands.24 The
other weaker signals present in the spectrum were two

J. C. Anderson et al. / Tetrahedron: Asymmetry 12 (2001) 923–935
929
5. Conclusions
(12 mL) at 0°C was added thionyl chloride (0.44 mL, 6
mmol) dropwise. The mixture was allowed to stir at
room temperature for 1 h before pouring onto pH 7
buffer (50 mL). The layers were separated and the
aqueous layer extracted with dichloromethane (3×20
mL). The combined organics were washed with brine (20
mL), dried over magnesium sulfate and concentrated in
vacuo to yield the crude product (1.23 g, 91%), which
was used crude in the next step. A small sample was
purified by flash column chromatography on silica to
yield the amino chloride as a clear oil; [h]2D1=−36.0 (c
0.75, CH2Cl2); wmax (film)/cm−1 3063, 2967, 2874, 1681,
1595m; lH (250 MHz, CDCl3) [rotamers] 1.01, 1.06 and
1.18 [4.5:4.5:1] (6H, 3d, J 6.7 CH(CH3)2), 1.84–1.96 and
2.15 [1:8] (1H, m and dsept, J 10.4, 6.7, CH(CH3)2),
3.35–3.54 and 3.52–3.85 [1:8] (2H, 2m, CH2Cl), 4.14–
4.27 (1H, m, NCH), 7.27–7.46 (5H, m, ArH), 8.31
and 8.39 [8:1] (1H, 2s, NCHO); lC (63 MHz, CDCl3)
[rotamers] 19.7, 20.3, 20.8 and 20.9 (CH(CH3)2), 30.1
(CH(CH3)2), 43.3 and 43.9 (CH2Cl), 62.3 and 68.7
(NCH), 127.0–129.5 (Ar), 163.7 and 168.3 (NCHO);
m/z (EI+) 225.0919 (M+, 30%, C12H16ON35Cl requires
225.0920), 182 (M+−43, i-Pr, 90%), 176 (M+−
49CH2Cl, 30%), 154 (M+−71i-Pr and CHO, 100%), 121
(50%).
Three new enantiomerically pure N–P ligands have been
synthesised with the specific design element of creating a
disymmetric environment around the nitrogen atom.
Ligands 6 and 8, which possess phenyl, methyl and
diphenyl nitrogen substituents, respectively, both per-
form substantially better than valphos in the palladium
catalysed allylic substitution reaction between dimethyl
malonate and trans-1,3-diphenylpropenyl acetate. The
most intriguing aspect of these results is that ligand 6,
with two unlike N-substituents, selects for the (S)-enan-
tiomer of the product 23, whereas ligand 8, with two
identical N-substituents, selects for the (R)-enantiomer.
This is despite both ligands possessing identical back-
bone chirality. Spectroscopic studies suggested that there
is a dynamic mixture of chelate and monophosphine
donor complexes. Chloride ion effects did not reveal any
firm evidence for a single catalytically active complex.
These results, though interesting by virtue of their non-
conformity, do not allow us to proceed with a rational
design strategy for new ligand systems. It is clear that
nitrogen substitution patterns in these ligand systems are
important to the observed enantioselectivity, but the
mechanism of the selection is unclear at this time.
To a suspension of potassium tert-butoxide (1.97 g, 17.6
mmol) in tetrahydrofuran (40 mL) was added
diphenylphosphine (2.0 mL, 11.7 mmol). This mixture
was stirred at room temperature for 20 min. Following
addition of the crude amino chloride from above (2.64 g,
11.7 mmol) the reaction was allowed to stir for 12 h (or
until the red colour had completely faded to colourless).
The reaction mixture was poured onto water (100 mL)
and the aqueous layer was extracted with ethyl acetate
(3×50 mL). The combined organic extract was washed
with brine (100 mL), dried over magnesium sulfate and
concentrated in vacuo to yield the crude product. Purifi-
cation by flash column chromatography on silica (20%
ethyl acetate/light petroleum) gave 12 (3.30 g, 74%) as a
colourless oil; [h]2D1=−42.0 (c 1.2, CH2Cl2); wmax (film)/
cm−1 3054, 2963, 2872, 1681, 1594; lH (250 MHz,
CDCl3) [rotamers] 0.90–0.94 (3H, m, CH(CH3)2), 1.00–
1.05 (3H, m, CH(CH3)2), 1.89–2.56 (3H, m, CH(CH3)2
and CHCH2PPh2), 3.05–3.18 and 3.8–3.95 [1:5] (1H, 2br-
m, NCH), 7.24–7.46 (15H, m, ArH), 8.08 and 8.39 [1:5]
(1H, 2s, NCHO); lP not recorded; lC (63 MHz, CDCl3)
20.5 (CH(CH3)2), 20.6 (CH(CH3)2), 30.1 (d, JC-P 13.0,
CH2PPh2), 32.7 (d, JC-P 6.8, (CH(CH3)2), 61.3 (d, JC-P
6.2 NCH), 61.9 (CH2PPh2), 124.7–141.0 (Ar), 163.5,
(NCHO); m/z (EI+) 375.1740 (M+, 5%, C24H26ONP
requires 375.1752), 332 (M+−43i-Pr, 15%), 255 (M+−
120PhNCHO, 85%), 202 (100%).
6. Experimental
Our general experimental details have been reported.27
6.1. (S)-N-Formyl-N-phenyl-2-amino-3-methylbutan-1-ol
11
Formic acid (98%, 340 mL, 8.9 mmol) was added drop-
wise to acetic anhydride (680 mL, 7.3 mmol) at 0°C.
When the addition was complete the mixture was heated
at 60°C for 2 h then allowed to cool to room tempera-
ture. Tetrahydrofuran (10 mL) was added and the solu-
tion cooled to 0°C before addition of a solution of
(S)-N-phenyl-2-amino-3-methylbutan-1-ol1b (500 mg,
2.8 mmol) in tetrahydrofuran (10 mL). The reaction mix-
ture was stirred at room temperature for 4 h before the
volatiles were removed in vacuo. Toluene (2×10 mL) was
added and removed in vacuo to yield a yellow oil which
was purified by flash column chromatography on silica
(30% ethyl acetate/light petroleum) affording 11 (545
mg, 94%); [h]2D1=−37.0 (c 1, CH2Cl2); wmax (film)/cm−1
3418, 3063, 2965, 2967, 1661, 1594; lH (250 MHz,
CDCl3) 1.00 (6H, pseudo-t, J 6.5, CH(CH3)2), 2.34 (1H,
dsept, J 10.1, 6.5, CH(CH3)2), 3.75–4.04 (3H, m, NCH
and CHCH2OH), 7.20–7.55 (5H, m, ArH), 8.3 (1H, s,
NCHO); lC (63 MHz, CDCl3) 19.9 (CH(CH3)2), 20.7
(CH(CH3)2), 27.3 (CH(CH3)2), 61.9 (CH2OH), 67.5
(NCH), 126.4 (Ar), 125.5 (Ar), 141.2 (Ar), 164.6
(NCHO); m/z (EI+) 207.1263 (M+, 15%, C12H17O2N
requires 207.1259), 176 (M+−31CH2OH, 99%), 150 (M+−
43i-Pr, 33%), 118 (20%).
6.3. (S)-N-Phenyl-N-methyl-2-amino-3-methylbutyl-1-
diphenylphosphine-borane 13
Borane–dimethylsulfide complex (1.67 mL, 17.6 mmol)
was added dropwise to a solution of 12 (3.31 g, 8.8
mmol) in tetrahydrofuran (40 mL) at 0°C and the reac-
tion was allowed to stir at room temperature for 12 h.
The reaction was quenched by slow addition of ethereal
hydrogen chloride (1 M, 3 mL) and the volatiles
6.2. (S)-N-Formyl-N-phenyl-2-amino-3-methylbutyl-1-
diphenylphosphine 12
To a solution of 11 (1.24 g, 6 mmol) in dichloromethane

930
J. C. Anderson et al. / Tetrahedron: Asymmetry 12 (2001) 923–935
removed in vacuo. The residue was taken up in
methanol (2×20 mL) and this was removed in vacuo.
The resulting oil was partitioned between diethyl ether
(20 mL) and sodium hydroxide solution (1 M, 20 mL)
and the aqueous layer was extracted with diethyl ether
(3×10 mL). The combined organics were washed with
brine (20 mL), dried over magnesium sulfate and con-
centrated in vacuo. The crude product was purified by
column chromatography on silica (10% ethyl acetate/
light petroleum) to give 13 as a white solid (2.97 g,
89%); mp 100–102°C; (found: C, 76.87; H, 8.17; N,
3.70; C24H31NPB requires: C, 76.81; H, 8.33; N, 3.73%);
[h]2D1=−110.0 (c 1, CH2Cl2); wmax (film)/cm−1 3048,
2960, 2924, 2404, 2364, 2334, 1598, 1505, 1435; lH (250
MHz, CDCl3) 0.74 (3H, d, J 6.5, (CH(CH3)2), 1.05 (3H,
d, J 6.5, (CH(CH3)2), 1.97 (1H, dsept, J 6.5, 9.2,
CH(CH3)2), 2.31 (3H, s, NCH3), 2.47 (1H, ddd, J 14.6,
10.0 (1H–31P), 2.7, CHCHhHbPPh2), 2.68–2.85 (1H, m,
CHCHaHiPPh2), 4.01 (1H, qd, J 10.4, 2.6, NCH),
6.57 (1H, t, J 7.3, p-NArH), 6.66 (2H, d, J 8.6,
o-NArH), 7.04 (2H, dd, J 8.6, 7.3, m-NArH), 7.00–
7.68 (10H, m, PArH); lP (101 MHz, CDCl3) 15.5 br; lC
(63 MHz, CDCl3) 20.0 (CH(CH3)2), 20.8 (CH(CH3)2),
27.8 (d, JC-P 36.8, CH2PPh2), 32.2 (NCH3), 33.7 (d, JC-P
10.7, ((CH(CH3)2), 59.4 (NCH), 112.3 (Ar), 115.8 (Ar),
128.1–132.6 (Ar), 148.9 (Ar); m/z (EI+) 375.2390 (M+,
10%, C24H31NPB requires 375.2402), 361 (M+−14BH3,
8%), 332 (M+−43i-Pr, 50%), 318 (M+−57BH3 and i-Pr,
60%), 185 (PPh2, 100%).
6.5. Methyl (S)-N-iso-propyl-2-amino-3-methyl-
butanoate 14
To a solution of (S)-valine methyl ester (5.88 g, 45
mmol) in methanol (75 mL) was added acetone (5.0
mL, 67 mmol) and sodium cyanoborohydride (11.30 g,
180 mmol). The reaction was allowed to stir
overnight at room temperature. Volatiles were
removed in vacuo and the residue partitioned between
water (75 mL) and dichloromethane (50 mL). The
aqueous layer was extracted with dichloromethane
(3×30 mL). The combined organics were washed with
brine (75 mL), dried over magnesium sulfate and the
solvent was removed in vacuo. The product was
purified by passing through a short column of silica
gel (20% ethyl acetate/light petroleum) to yield 14 as a
clear oil (7.53 g, 97%); [h]2D1=−76.5 (c 1, CH2Cl2);
wmax (film)/cm−1 2964, 2873, 1736; lH (250 MHz,
CDCl3) 0.90 (3H, d, J 6.4, CCH(CH3)2), 0.93 (3H, d,
J 6.7, CCH(CH3)2), 0.97 (3H, d, J 6.2, NCH(CH3)2),
1.03 (3H, d, J 6.4, NCH(CH3)2), 1.75–1.95 (1H, m,
CCH(CH3)2), 2.63 (1H, sept, J 6.2, NCH(CH3)2), 3.05
(1H, d, J 5.8, NCHCO2Me), 3.70 (3H, s, CO2CH3); lC
(63 MHz, CDCl3) 18.8 (CCH(CH3)2), 19.6
(CCH(CH3)2),
22.1
(NCH(CH3)2),
23.91
(NCH(CH3)2), 31.8 (CCH(CH3)2), 47.4 (NCH(CH3)2),
51.4 (CO2CH3), 64.8 (NCHCO2Me), 176.3 (CꢁO);
m/z (EI+) 174.1798 (MH+, 70%, C9H20O2N requires
174.1494), 130 (M+−44i-PrH, 30%), 114 (M+−
60CO2CH3H, 100%), 72 (CHNH-i-Pr, 70%).
6.4. (S)-N-Phenyl-N-methyl-2-amino-3-methylbutyl-1-
diphenylphosphine 6
6.6. (S)-N-Formyl-N-iso-propyl-2-amino-3-methyl-1-
butanol 15
A solution of 13 (640 mg, 1.79 mmol) in toluene (2 mL)
was warmed to 40°C in the presence of 1,4-diaza-
bicyclo-[2.2.2]-octane (210 mg, 1.87 mmol) for 12 h.
After removal of the solvent in vacuo the resulting
white solid residue was washed with light petroleum
(3×5 mL) and removed by filtration and concentration
of the organics in vacuo gave the crude product. This
was purified by flash column chromatography on silica
(5% ethyl acetate/light petroleum) to afford the product
6 as a white solid (540 mg, 87%); mp 132–134°C;
(found: C, 79.63; H, 7.98; N, 3.92; C24H28NP requires:
C, 79.75; H, 7.81; N, 3.87%); [h]2D1=+13.5 (c 2,
CH2Cl2); wmax (film)/cm−1 3054, 2957, 2808, 1597, 1504,
1433; lH (250 MHz, CDCl3) 0.67 (3H, d, J 7.0,
(CH(CH3)2), 0.92 (3H, d, J 7.0, (CH(CH3)2), 1.85 (1H,
dsept, J 9.1, 7.0, CH(CH3)2), 2.27 (1H, ddd, J 14.0,
11.0 (1H–31P), 3.4 CHCHhHbPPh2), 2.46–2.55 (1H, m,
CHCHaHiPPh2), 2.49 (3H, s, NCH3), 3.37–3.51 (1H,
m, NCH), 6.41 (2H, d, J 8.2, o-NArH), 6.53 (1H, t, J
7.3, p-NArH), 7.03 (2H, dd, J 8.2, 7.3 m-NArH),
7.16–7.30 (10H, m, PArH); lP (101 MHz, CDCl3)
−20.8; lC (63 MHz, CDCl3) 20.7 (CH(CH3)2), 20.9
(CH(CH3)2), 30.8 (NCH3), 31.9 (d, JC-P 12.7,
CH2PPh2), 33.5 (d, JC-P 7.0, (CH(CH3)2), 62.0 (d, JC-P
11.7, NCH), 112.6 (Ar), 115.8 (Ar), 128.1–133.7 (Ar),
138.1–140.1 (Ar), 150.8 (Ar); m/z (EI+) 361.1960 (M+,
15%, C24H28NP requires 361.1959), 318 (M+−43i-Pr,
100%), 183 (45%), 162 (M+−199CH2PPh2, 95%).
To a suspension of lithium aluminium hydride (132
mg, 3.50 mmol) in anhydrous tetrahydrofuran (8 mL)
at 0°C was added a solution of 14 (300 mg, 1.73
mmol) in tetrahydrofuran (4 mL). The reaction mix-
ture was allowed to stir at room temperature for 1 h
and quenched at 0°C by careful addition of water
(0.1 mL), aqueous sodium hydroxide (15% w/v, 0.1
mL) and water (0.3 mL). The resulting white precipi-
tate was removed by filtration and the residue was
washed with tetrahydrofuran (2×10 mL). The organics
were dried over magnesium sulfate and concentrated
in vacuo to yield the crude amino alcohol (100 mg,
94%), as a colourless oil, which was used without
further purification; [h]2D1=+32.1 (c 2, CH2Cl2); wmax
(film)/cm−1 3382, 2961, 2872; lH (250 MHz, CDCl3)
0.88 (3H, d, J 6.8, CCH(CH3)2), 0.94 (3H, d, J 6.8,
CCH(CH3)2), 1.01 (3H, d, J 6.2, NCH(CH3)2), 1.06
(3H, d, J 6.2, NCH(CH3)2), 1.75 (1H, pseudo-oct, J
6.8, CCH(CH3)2), 2.45 (1H, ddd, J 7.3, 6.8, 4.5,
NCHCH2OH) 3.03 (1H, sept, J 6.2 NCH(CH3)2), 3.20
(1H, dd, J 10.4, 7.3, CHCHhHb), 3.53 (1H, dd, J
10.4, 4.5, CHCHaHi); lC (63 MHz, CDCl3) 18.3
(CCH(CH3)2), 19.6 (CCH(CH3)2), 23.5 (NCH(CH3)2),
23.8
(NCH(CH3)2),
29.7
(CCH(CH3)2),
46.5
(NCH(CH3)2), 60.8 (NCHCH2OH), 61.2 (CH2OH);
m/z (EI+) 146.1545 (MH+, 5%, C8H20ON requires
146.1545), 114 (MH+−32CH2OH2, 100%), 102 (MH+−
44i-PrH, 60%).

J. C. Anderson et al. / Tetrahedron: Asymmetry 12 (2001) 923–935
931
Formic acid (98%, 52 mL, 1.4 mmol) was added drop-
wise to acetic anhydride (130 mL, 1.4 mmol) at 0°C.
When the addition was complete the mixture was
heated at 60°C for 2 h and then allowed to cool to
room temperature. Tetrahydrofuran (5 mL) was added
and the solution was cooled to 0°C before the addition
of a solution of the crude amino alcohol from above
(200 mg, 1.4 mmol) in tetrahydrofuran (5 mL). The
reaction was allowed to warm slowly to room tempera-
ture and stirred for 2 h before the volatiles were
removed in vacuo. Toluene (2×5 mL) was added and
removed in vacuo to yield the crude product, which was
purified by flash column chromatography on silica
(20% light petroleum/ethyl acetate) to afford 15 (118
mg, 50%) as a clear oil; [h]2D1=+91.6 (c 1.2, CH2Cl2);
wmax (film)/cm−1 3386, 2963, 2925, 2878, 1648; lH (250
MHz, CDCl3) [rotamers] 0.89–1.04 (6H, m,
CCH(CH3)2), 1.24–1.32 (6H, m, NCH(CH3)2), 1.70–
2.66 (2H, br-m, OH and CCH(CH3)2), 2.89–2.98 (1H,
m, NCH(CH3)2), 3.55–4.21 (3H, m, NCH(CH3)2 and
CHCH2OH), 8.10 and 8.22 [1:3] (1H, 2s, NCHO); lC
(63 MHz, CDCl3) [rotamers] 19.9–22.8 CCH(CH3)2 and
NCH(CH3)2), 25.2 and 28.2 (CCH(CH3)2), 45.1 and
51.4 (NCH(CH3)2), 62.0 and 64.4 (CH2OH), 65.0
(NCHCH2OCHO), 163.8 (NCHO); m/z (EI+) 174.1492
(MH+, 100%, C9H20O2N requires 174.1494), 142
(MH+−32CH2OH, 30%) 100 (7%), 88 (7%), 72 (7%).
3064, 2968, 2932, 2875, 1775, 1713 1612, 1598; lH (250
MHz, CDCl3) 0.97 (3H, d, J 6.7, CH(CH3)2), 0.97 (3H,
d, J 6.7, CH(CH3)2), 2.24–2.40 (1H, m, CH(CH3)2),
2.33 (2H, s, ArCH3), 3.90 (1H, td, J 10.4, 4.0, NCH),
4.35 (1H, dd, J 10.7, 4.0, CHCHhHbOH), 4.68 (1H,
pseudo-t, J 10.4, CHCHaHiOH), 7.14 (2H, d, J 8.4,
tosyl o-ArH), 7.66 (2H, d, J 8.4, tosyl m-ArH), 7.68–
7.77 (4H, m, phthalimide ArH); lC (63 MHz, CDCl3)
16.9 (CH(CH3)2), 17.7 (CH(CH3)2), 19.6 (CH(CH3)2),
25.5 (ArCH3), 54.5 (NCH), 68.9 (CH2OTs), 121.2–
132.0 (ArCH), 142.7 (ArCSO2R), 166.0 (CꢁO); m/z
(EI+) 387.1139 (MH+, 10%, C20H21O5NS requires
387.1140), 347 (30%), 304 (50%), 202 (100%), 148
(98%).
To a suspension of potassium hydride (86 mg, 2.16
mmol) in tetrahydrofuran (10 mL) was added
diphenylphosphine (354 mL, 2.06 mmol) and the mix-
ture was stirred at room temperature for 30 min. To the
resulting red mixture was added a solution of the
tosylate from above (800 mg, 2.06 mmol) in tetra-
hydrofuran (5 mL), and the reaction was stirred at
room temperature for 36 h before being poured into
water (10 mL). Extraction of the aqueous layer with
diethyl ether (3×20 mL) and combination of the organic
extracts was followed by washing with brine (30 mL)
and drying over magnesium sulfate. Removal of the
solvent in vacuo gave the crude product which was
purified by flash column chromatography on silica
(40% ethyl acetate/light petroleum), and after exposure
to air for 3 days characterised as the oxide 16, a white
solid (362 mg, 42%); mp 209–211°C; [h]2D1=+8.3 (c 1.2,
CH2Cl2); wmax (film)/cm−1 3057, 2963, 2900, 2870, 1719,
1611, 1591; lH (250 MHz, CDCl3) 0.87 (3H, d, J 6.7,
CH(CH3)2), 1.02 (3H, d, J 6.7, CH(CH3)2), 2.46 (1H,
dsept, J 10.7, 6.7, CH(CH3)2), 3.59–3.70 (1H, m,
NCH), 4.68 (1H, t, J 7.9, CHCHhHbO), 4.98 (1H, t, J
7.3, CHCHaHiOH), 6.62 (1H, d, J 7.6, ArH), 7.11–
8.05 (13H, m, ArH); lP (101 MHz, CDCl3) 32.0; lC (63
MHz, CDCl3) 19.6 (CH(CH3)2), 21.6 (CH(CH3)2), 32.6
(CH(CH3)2), 64.0 (NCHCH2), 79.1 (CHCH2O), 103.4
(ArNCPO), 123.6–143.0 (ArH), 173.7 (CꢁO); m/z (CI+)
418.1577 (MH+, 35%, C25H24O3NP requires 418.1572),
342 (M+−77Ph, 25), 293 (MH+−125P(O)Ph, 35%) 218
(MH+−200P(O)Ph2, 50%), 203 (100%).
6.7. [(3S)-3,5-Dihydro-3-iso-propyl-5-oxooxazolo[2,3-
a]iso-indol-9b(2H)-yl]phosphine oxide 16
A mixture of (S)-valinol (2.08 g, 20 mmol) and phthalic
anhydride (2.96 g, 20 mmol) in xylene (60 mL) was
heated to reflux under Dean–Stark conditions for 2 h.
After cooling, removal of solvent in vacuo produced
the crude product which was purified by flash column
chromatography on silica (20% ethyl acetate/light
petroleum) to give the phthalimide derivative (2.75 g,
60%) as a white solid; mp not recorded; [h]2D1=+8.1 (c
2.0, CH2Cl2) {lit.13 [h]D20=+8.33 (c 2.9, EtOH)}; lH (250
MHz, CDCl3) 0.80 (3H, d, J 6.7, CH(CH3)2), 1.05 (3H,
d, J 6.7, CH(CH3)2), 2.50 (1H, dsept, J 10.4, 6.7,
CH(CH3)2), 2.98 (H, dd, J 9.5, 2.7, OH), 3.87–4.03
(2H, m, CHCH2OH), 4.08–4.20 (1H, m, NCH), 7.68–
7.77 (2H, m, ArH), 7.80–7.90 (2H, m, ArH); lC (63
MHz, CDCl3) 19.9 (CH(CH3)2), 20.0 (CH(CH3)2), 27.0
(CH(CH3)2), 60.0 (NCH), 62.3 (CH2OH), 123.4
(ArCH), 131.7 (ArC), 134.2 (ArCH), 169.4 (CꢁO); m/z
(EI+) 234 (MH+, 100%), 216 (MH+−18OH2, 25%).
6.8. (S)-N-tert-Butoxycarbonyl-2-iso-propylaziridine 18
To a suspension of potassium hydride (87 mg, 2.18
mmol) in dimethylformamide (15 mL) was added
diphenylphosphine (375 mL, 2.18 mmol) and the reac-
tion was stirred at room temperature for 20 min. The
mixture was cooled to −35°C and stirred for a further
20 min before a solution of 1715 (778 mg, 2.18 mmol) in
dimethylformamide (5 mL) was added dropwise. The
reaction was allowed to stir at this temperature for 2 h
before warming to room temperature prior to addition
of diethyl ether (30 mL). The organics were washed
with water (4×20 mL), then brine (30 mL) and dried
over magnesium sulfate. Removal of the solvent in
vacuo gave the crude product, which was purified by
flash column chromatography on silica (2% ethyl ace-
tate/light petroleum) to yield 18 as a white solid (250
mg, 40%); mp 193–194°C; [h]2D1 not recorded; wmax
To a stirred solution of the phthalimide derivative (1.0
g, 4.27 mmol) in dichloromethane (1 mL) and pyridine
(1 mL) was added p-toluenesulfonyl chloride (0.90 g,
4.31 mmol). The mixture was allowed to stir for 12 h
before addition of 10% hydrochloric acid (10 mL),
followed by extraction with dichloromethane (3×10
mL). The combined organics were washed with satu-
rated aqueous copper(II) sulfate solution (3×20 mL),
saturated sodium bicarbonate solution (3×10 mL) and
brine (20 mL) before drying over magnesium sulfate.
Removal of solvent in vacuo gave the crude tosylate
(1.63 g, 98%) as a white solid; mp 44–45.5°C (lit.13
45–47°C); [h]D21=+10.0 (c 2.0, CH2Cl2); wmax (film)/cm−1

932
J. C. Anderson et al. / Tetrahedron: Asymmetry 12 (2001) 923–935
(film)/cm−1 3060, 2969, 1719; lH (250 MHz, CDCl3)
0.95 (3H, d, J 6.7, CCH(CH3)2), 1.05 (3H, d, J 6.7,
CCH(CH3)2), 1.35–1.44 (10H, m, C(CH3)3 and
CCH(CH3)2), 1.93 (1H, d, J 4.0, CHCHhHbN), 2.12
(1H, ddd, J 7.0, 6.1, 3.7, NCHCH2), 2.22 (1H, d, J 6.1,
CHCHaHiN); lC (63 MHz, CDCl3) 18.3 (CH(CH3)2),
18.9 (CH(CH3)2), 27.1 (CH(CH3)2), 29.8 (NCH2CH),
30.1 (NCH2CH), 79.9 (C(CH3)3), 162.1 (NCOt-Bu);
m/z (EI+) 358.1670 (M+, 0%, C17H28O5NS requires
358.1688), 319 (MH+−56C(CH3)3, 100%), 204 (M+−
171OSO2C6H4Me, 45%), 165 (35%), 147 (95%).
clear gum (0.94 g, 97%); [h]2D1=+16.6 (c 1.2, CH2Cl2);
wmax (film)/cm−1 3420, 3349, 3053, 2963, 2873, 1698,
1586, 1503, 1434; lH (250 MHz, CDCl3) 0.85 (3H, d, J
6.7, CH(CH3)2), 0.87 (3H, d, J 6.7, CH(CH3)2), 1.41
(9H, s, C(CH3)3), 1.75–1.98 (1H, br-m, CH(CH3)2),
2.05–2.35 (2H, br-m, CH2PPh2), 3.40–3.68 (1H, br-m,
NCH), 4.41 (1H, br-d, J 9.2, NH), 7.25–7.50 (10H, m,
ArH); lP (101 MHz, CDCl3) −22.3; lC (63 MHz,
CDCl3) 17.5 (CH(CH3)2), 18.9 (CH(CH3)2), 28.4
(C(CH3)3), 32.3 (d, JP-C 13.0, CH2PPh2), 32.7 (d, JP-C
8.0, CH(CH3)2), 53.6 (d, JP-C 14.0, NCH), 78.9
(OC(CH3)3), 128.4–133.2 (ArC), 138.8 (d, JP-C 13.0,
ArCP), 155.3 (NCO); m/z (FAB) 371.2007 (M+, 5%,
C22H30O2NP requires 371.2014), 314 (M+−56C(CH3)3,
80%), 244 (100%), 199 (CH2PPh2, 75%), 183 (40%).
6.9. (S)-N-tert-Butoxycarbonyl-2-amino-3-methylbutyl-
1-diphenylphosphine-borane 19
To a suspension of triphenylphosphine-borane (3.50 g,
12.6 mmol) in tetrahydrofuran (8.5 mL) was added
finely cut strips of lithium metal freshly washed with
methanol, then tetrahydrofuran. The mixture was
allowed to stir for 12 h at room temperature before the
addition of tert-butyl chloride (1.40 mL, 12.6 mmol),
followed by cooling to −78°C (30 min). This was trans-
ferred slowly, via cannula, over a 30 min period, to a
solution of 1715 (0.30 g, 8.4 mmol) in tetrahydrofuran
(40 mL), also at −78°C. The mixture was stirred at this
temperature for a further 2 h, then slowly warmed to
room temperature and stirred for 12 h prior to pouring
onto water (100 mL). The aqueous layer was extracted
with diethyl ether (3×50 mL) followed by combination
of the organics, washing with brine (80 mL) and drying
over magnesium sulfate. Removal of the solvent in
vacuo gave the crude product which was purified by
flash column chromatography on silica (8% ethyl ace-
tate/light petroleum) to yield 19 as a white solid (2.28 g,
71%); (found: C, 68.10; H, 8.50; N, 3.94; C22H33O2NPB
requires: C, 68.58; H, 8.63; N, 3.64%); mp 114–117°C;
[h]2D1=−110.0 (c 1, CH2Cl2); wmax (film)/cm−1 3444,
2967, 2932, 2370, 2343, 2248, 1706, 1438; lH (250 MHz,
CDCl3) 0.79–0.87 (6H, br-m, CH(CH3)2), 1.32 (9H, s,
C(CH3)3), 1.92–2.2 (1H, br-m, CH(CH3)2), 2.35–2.55
(2H, br-m, CH2PPh2BH3), 3.58–3.78 (1H, br-m, NCH),
4.52 (1H, br-s, NH), 7.37–7.50 (6H, m, ArH), 7.62–7.75
(4H, m, ArH); lP (101 MHz, CDCl3) 13.8 br; lC (63
MHz, CDCl3) 17.8 (CH(CH3)2), 18.8 (CH(CH3)2), 28.3
(C(CH3)3), 28.4 (d, JP-C 36, CH2PPh2BH3), 32.8
(CH(CH3)2), 52.3 (NCH), 79.0 (OC(CH3)3), 128.8–
132.3 (ArC), 154.8 (NCO); m/z (FAB) 402.719 (NH4−
M+, 15%, C22H37N2O2PB requires 402.2722), 384 (M+,
45%) 328 (M+−56C(CH3)3, 70%), 202 (50%), 284 (M+−
100CO2t-Bu, 35%), 187 (HPPh2, 100%).
To a solution of the free phosphine prepared above
(2.50 g, 6.74 mmol) in dichloromethane (20 mL) was
added trifluoroacetic acid (6.75 mL, 8.76 mmol) drop-
wise and the mixture was allowed to stir at room
temperature for 2 h. The reaction was poured carefully
onto ice cold aqueous sodium hydroxide solution (1 M,
30 mL) and washed with further sodium hydroxide
(2×30 mL) before washing with brine (50 mL). The
organic layer was dried over magnesium sulfate and
evaporated to give the crude product. This was passed
through a short column of silica to yield 20 as a clear
oil (1.69 g, 93%); (found: C, 75.08; H, 8.27; N, 5.20;
C17H22NP requires: C, 75.25; H, 8.17; N, 5.16%);
[h]2D1=+73.0 (c 1.5, CH2Cl2); wmax (film)/cm−1 3052,
2956, 2874, 1585, 1503, 1433; lH (250 MHz, CDCl3)
0.88 (6H, t, J 6.4, CH(CH3)2), 1.70 (1H, septd, J 6.7,
4.6, CH(CH3)2), 1.93 (1H, ddd, J 13.3, 10.0 (1H–31P),
2.7, CHhHbPPh2), 2.32 (1H, dt,
J
13.3, 2.7,
CHaHiPPh2), 2.55–2.69 (1H, m, NCH), 7.30–7.50
(10H, m, ArH); lP (101 MHz, CDCl3) −20.9; lC (63
MHz, CDCl3) 17.2 (CH(CH3)2), 18.9 (CH(CH3)2), 34.5
(d, JP-C 7.0, CH(CH3)2), 34.8 (d, JP-C 11.0, CH2PPh2),
54.1 (d, JP-C 13.0, NCH), 128.3–133.3 (ArC); m/z (EI+)
271.1488 (M+, 20%, C17H22NP requires 271.1490), 254
(M+−17NH3, 25%) 228 (M+−43i-Pr, 20%) 200
(CH2PPh2, 100%), 185 (PPh2, 60%).
6.11. (S)-N-iso-Propyl-2-amino-3-methylbutyl-1-
diphenylphosphine 21
To a suspension of basic alumina (163 mg) in acetone
(500 mL) was added a solution of 20 (100 mg, 0.37
mmol) in acetone (500 mL) and the mixture was stirred
at room temperature for 12 h. The reaction mixture was
filtered and the residue washed with acetone (1 mL).
Removal of solvent in vacuo gave the crude imine as a
colourless oil (113 mg, 99%); [h]2D1=+33.3 (c 0.12,
CH2Cl2); wmax (film)/cm−1 3071, 2958, 2871, 1586, 1434;
lH (250 MHz, CDCl3) 0.80 (3H, d, J 6.7, CH(CH3)2),
0.90 (3H, d, J 6.7, CH(CH3)2), 1.57 (3H, s, NC(CH3)2),
1.75–1.85 (1H, m, CH(CH3)2), 1.86 (3H, s, NC(CH3)2),
2.29 (1H, dd, J 13.4, 9.3, CHhHbPPh2), 2.45 (1H, dt, J
13.4, 2.9, CHaHiPPh2), 3.11–3.25 (1H, m,
NCHCH2PPh2), 7.22–7.48 (10H, m, ArH); lP (101
MHz, CDCl3) −19.3; lC (63 MHz, CDCl3) 18.7
(CH(CH3)2), 19.5 (CH(CH3)2), 29.0 (NC(CH3)2), 29.3
(NC(CH3)2), 33.4 (d, JP-C 12, CH2PPh2), 34.3 (d, JP-C 9,
CH(CH3)2), 63.3 (d, JP-C 13, NCHCH2PPh2), 128.1−
6.10. (S)-2-Amino-3-methylbutyl-1-diphenylphosphine 20
To a stirred solution of 19 (1.0 g, 2.6 mmol) in toluene
(20 mL) was added 1,4-diazabicyclo-[2.2.2]-octane (0.35
g, 3.1 mmol) and the mixture was warmed to 40°C for
12 h. The solvent was removed in vacuo and the
resulting residue was taken up in light petroleum, the
white solid was removed by filtration and washed with
light petroleum (3×5 mL). Removal of the solvent in
vacuo gave the crude product which was purified by
flash column chromatography on silica (8% ethyl ace-
tate/light petroleum) to yield the free phosphine as a

J. C. Anderson et al. / Tetrahedron: Asymmetry 12 (2001) 923–935
933
133.3 (ArC), 165.5 (NC(CH3)2); m/z (EI+) 312.1880
(MH+, 15%, C20H27NP requires 312.1881), 272 (60%),
202 (CH2PPh2H, 25%), 187 (PPh2H, 100%).
[rotamers] −21.6 and −22.4; lC (63 MHz, CDCl3)
[rotamers] 20.0, 20.2, 20.5 and 20.6 (CCH(CH3)2), 24.3
and 24.7 (NCH(CH3)2), 30.1 and 30.5 (2d, JP-C 15.0 and
18.0, CH2PPh2), 32.0 and 32.2 (2d, JP-C 7.0 and 6.0,
CCH(CH3)2), 47.0 (NCH(CH3)2), 62.8 (d, JP-C 13.0,
NCHCH2PPh2), 128.5–133.89 (ArC) 162.3 and 163.7
(NCHO); m/z (EI+) 341.1898 (M+, 15%, C21H28ONP
requires 341.1908), 298 (M+−43i-Pr, 95%) 271 (60%),
186 (CH2PPh2H+, 60%).
To a suspension of lithium aluminium hydride (126 mg,
3.31 mmol) in anhydrous tetrahydrofuran (3 mL) at 0°C
was added a solution of the crude imine from above
(344 mg, 1.10 mmol) in tetrahydrofuran (2 mL). The
reaction mixture was heated under reflux for 12 h and
then quenched at 0°C by careful addition of water (0.1
mL), aqueous sodium hydroxide (15% w/v, 0.1 mL) and
water (0.3 mL). The resulting white precipitate was
removed by filtration and the residue washed with tetra-
hydrofuran (2×10 mL). The organics were dried over
magnesium sulfate and concentrated in vacuo to yield
the crude product, which was purified by flash column
chromatography on silica (1% triethylamine/10% ethyl
acetate/light petroleum) to give 21 as a colourless oil
(100 mg, 94%); [h]D21=+60.0 (c 1.0, CH2Cl2); wmax (film)/
cm−1 3053, 2957, 2663, 1603, 1586, 1434; lH (250 MHz,
CDCl3) 0.80 (3H, d, J 7.0, CH(CH3)2), 0.87 (3H, d, J
7.0, CH(CH3)2), 0.89 (3H, d, J 6.2, NCH(CH3)2), 0.91
To a suspension of lithium aluminium hydride (79 mg,
2.08 mmol) in tetrahydrofuran (2 mL) at 0°C was added
a solution of the N-formyl derivative from above (236
mg, 0.69 mmol) in tetrahydrofuran (1.5 mL). The reac-
tion mixture was stirred at room temperature for 12 h
then quenched at 0°C by careful addition of water (0.1
mL), aqueous sodium hydroxide (15% w/v, 0.1 mL) and
water (0.3 mL). The resulting white precipitate was
removed by filtration and the residue was washed with
tetrahydrofuran (2×5 mL). The organics were dried over
magnesium sulfate and concentrated in vacuo to yield
the crude product, which was purified by flash column
chromatography on silica (0.5% triethylamine/10% ethyl
acetate/light petroleum) to give 7 as a colourless oil (184
mg, 81%); (found: C, 76.81; H, 9.09; N, 4.19; C21H30NP
requires: C, 77.03; H, 9.23; N, 4.28%); [h]2D1=+15.8 (c
1.9, CH2Cl2); wmax (film)/cm−1 3070, 2960, 2782, 1664,
1586, 1433; lH (250 MHz, CDCl3) 0.83–0.91 (12H,
m, CH(CH3)2 and NCH(CH3)2), 1.91 (1H, septd, J 6.7,
5.2, CH(CH3)2), 2.12–2.18 (4H, m, NCH3 and
CHhHbPPh2), 2.24 (1H, dd, J 13.7, 7.0, CHaHiPPh2),
2.42–2.57 (1H, m, NCHCH2PPh2), 2.73 (1H, sept, J 6.4,
NCH(CH3)2), 7.27–7.50 (10H, m, ArH); lP (101 MHz,
CDCl3) −18.0; lC (63 MHz, CDCl3) 20.3 (CH(CH3)2),
(3H, d,
J 6.2, NCH(CH3)2), 1.87–2.01 (2H, m,
CCH(CH3)2 and CHhHbPPh2), 2.20 (1H, ddd, J 13.4,
4.9 (1H–31P), 9.3, CHaHiPPh2), 2.39–2.51 (1H, m,
NCHCH2PPh2), 2.75 (1H, sept, J 6.2, NCH(CH3)2),
7.28–7.50 (10H, m, ArH); lP (101 MHz, CDCl3) −21.0;
lC (63 MHz, CDCl3) 17.3 (CH(CH3)2), 18.2
(CH(CH3)2), 23.2 (NCH(CH3)2), 23.8 (NCH(CH3)2),
30.7 (CCH(CH3)2), 31.0 (d, JP-C 13.0, CH2PPh2), 46.0
(NCH(CH3)2), 57.0 (d, JP-C 13, NCHCH2PPh2), 128.3–
133.4 (ArC); m/z (EI+) 313.1957 (M+, 5%, C20H28NP
requires 313.1959), 270 (M+−43iPr, 50%), 200
(CH2PPh2, 50%), 185 (PPh2, 40%) 114 (M+−
199CH2PPh2, 100%).
20.4
(CH(CH3)2),
20.5
(NCH(CH3)2),
21.0
(NCH(CH3)2), 28.7 (d, JP-C 13.0, CH2PPh2), 31.6
(CH(CH3)2), 32.0 (NCH3), 52.9 (NCH(CH3)2), 62.2 (d,
JP-C 12.0, NCHCH2PPh2), 128.2–133.43 (ArC); m/z
(EI+) 327.2117 (M+, 25%, C21H30NP requires 327.2116),
284 (M+−43iPr, 100%), 185 (PPh2, 40%) 128 (M+−
199CH2PPh2, 50%).
6.12. (S)-N-iso-Propyl-N-methyl-2-amino-3-methyl-
butyl-1-diphenylphosphine 7
Formic acid (98%, 82 mL, 2.18 mmol) was added drop-
wise to acetic anhydride (167 mL, 1.77 mmol) at 0°C.
When the addition was complete the mixture was heated
at 60°C for 2 h and then allowed to cool to room tem-
perature. Tetrahydrofuran (1 mL) was added and the
solution cooled to 0°C before addition of a solution of
21 (213 mg, 0.68 mmol) in tetrahydrofuran (2 mL). The
reaction was allowed to warm slowly to room tempera-
ture and stirred for 12 h before the volatiles were
removed in vacuo. Toluene (2×5 mL) was added and
removed in vacuo to yield the crude product, which was
purified by flash column chromatography on silica (1%
triethylamine/20% ethyl acetate/light petroleum) to
afford the N-formyl derivative as a clear oil (231 mg,
99%); [h]2D1=+80.0 (c 1.0, CH2Cl2); wmax (film)/cm−1
3052, 2971, 2873, 1668, 1585, 1434; lH (250 MHz,
CDCl3) [rotamers] 0.85–0.95 (6H, m, CCH(CH3)2),
1.31–1.50 (6H, m, NCH(CH3)2), 1.91 (1H, pseudo-oct, J
6.7, CCH(CH3)2), 2.19 (1H, ddd, J 14.6, 10.0 (1H–31P),
6.13. (S)-N,N-Diphenyl-2-amino-3-methylbutyl-1-
diphenylphosphine 8
To a solution of (S)-N,N-diphenylvalinol1b (1.75 g, 6.9
mmol) in dichloromethane (70 mL) at 0°C was added
triethylamine (1.9 mL, 13.7 mmol). Methanesulfonyl
chloride (0.74 mL, 9.6 mmol) was added dropwise and
the mixture was stirred at this temperature for 1 h. The
reaction mixture was poured onto ice-cold sodium
hydroxide (1 M, 80 mL) and the aqueous layer was
extracted with dichloromethane (3×50 mL). The organ-
ics were washed with brine (80 mL) and dried over mag-
nesium sulfate. The crude product was purified by flash
column chromatography on silica (10% ethyl
acetate/light petroleum) to give the product mesylate
(1.46 g, 60%) as a white solid, mp 94–95°C (found: C,
64.66; H, 6.98; N, 4.15; C18H23O3NS requires: C, 64.84;
H, 6.96; N, 4.20%); [h]2D1=−114.0 (c 1, CH2Cl2); wmax
(film)/cm−1 3039, 2968, 2875, 1590, 1496; lH (250 MHz,
CDCl3) 1.00 (3H, d, J 6.7, CH(CH3)2), 1.18 (3H, d, J
6.7, CH(CH3)2), 1.95–2.10 (1H, m, CH(CH3)2), 2.70
5.2, CHhHbPPh2), 2.51 (1H, dt,
J
14.6, 3.4,
CHaHiPPh2), 2.72–2.87 and 3.50 [1:1] (1H, m and
overlap, NCHCH2PPh2), 3.45 and 3.58 [1:1] (1H, 2sept,
J 7.0, 6.7, NCH(CH3)2), 7.20–7.50 (10H, m, ArH), 7.80
and 8.39 [1:1] (1H, 2s, NCHO); lP (101 MHz, CDCl3)

934
J. C. Anderson et al. / Tetrahedron: Asymmetry 12 (2001) 923–935
(3H, s, SO2CH3), 4.09 (1H, td, J 9.3, 4.1NCH), 4.31 (1H,
pseudo-t, J 9.3, CHCHhHb), 4.51 (1H, dd, J 10.5, 4.1,
CHCHaHi), 6.96–7.01 (6H, m, ArH), 7.23–7.29 (4H,
m, ArH); lC (63 MHz, CDCl3) 20.4 (CH(CH3)2), 20.9
(CH(CH3)2), 31.0 (CH(CH3)2), 37.2 (CH2SO2CH3), 65.0
(NCH), 67.8 (CH2SO2CH3), 122.1 (Ar), 123.1 (Ar),
129.4 (Ar), 147.4 (Ar); m/z (EI+) 333.1395 (M+, 20%,
C18H23O3NS requires 333.1399), 290 (M+−43i-Pr, 40%),
182 (M+−31CH2OSO2CH3, 100%), 77 (Ph, 20%).
ligand (0.08 mmol) in tetrahydrofuran (1.0 mL) was
stirred at room temperature for 15 min, then cooled to
the appropriate temperature (15 min). In a separate ves-
sel, sodium hydride in mineral oil (48 mg, 1.19 mmol)
was washed with hexane (3×1 mL) and dried under high
vacuum. Tetrahydrofuran (1.5 mL) was added, followed
by dropwise addition of dimethyl malonate (136 mL, 1.19
mmol). This solution was cooled to the appropriate tem-
perature (15 min) before the other solution was added
rapidly via cannula (0.5 mL wash). The reaction was
monitored by TLC and on completion diluted with
diethyl ether (15 mL) before washing with ice-cold satu-
rated aqueous ammonium chloride (3×20 mL), brine (30
mL), dried over magnesium sulfate and concentrated in
vacuo. Purification by flash column chromatography
(7% ethyl acetate/light petroleum) gave 23 as a colourless
oil.
To a suspension of potassium tert-butoxide (149 mg, 1.3
mmol) in tetrahydrofuran (10 mL) was added
diphenylphosphine (114 mL, 0.6 mmol) and this was
stirred at room temperature for 20 min. Following the
addition of the mesylate from above (222 mg, 0.7 mmol)
the reaction was allowed to stir overnight (or until the
red colour had completely faded to colourless). The reac-
tion mixture was poured onto water (20 mL) and the
aqueous layer was extracted with ethyl acetate (2×10
mL). The combined organics were washed with brine (20
mL), dried over magnesium sulfate and concentrated in
vacuo to yield the crude product. Purification by column
chromatography on basic alumina (1% ethyl acetate/
light petroleum) gave 8 (178 mg, 69%) as an amorphous
waxy white solid; mp 82.5–85°C; [h]2D1=−22.5 (c 2,
CH2Cl2); wmax (film)/cm−1 3054, 2958, 2871, 1588, 1495;
lH (250 MHz, CDCl3) 0.95 (6H, pseudo-t, J 6.7,
(CH(CH3)2), 2.11 (1H, dsept, J 9.2, 6.7, CH(CH3)2), 2.29
(1H, ddd, J 14.0, 10.7 (1H–31P), 4.6, CHCHhHbPPh2),
2.52 (1H, dt, J 14.0, 4.6, CHCHaHiPPh2), 3.70 (1H, qd,
J 9.2, 3.4, NCH), 6.85–7.00 (6H, m, ArH), 7.08–7.58
(14H, m, ArH); lP (101 MHz, CDCl3) −20.3; lC (63
MHz, CDCl3) 21.1 (CH(CH3)2), 21.2 (CH(CH3)2), 27.4
(d, JC-P 13.9, CH2PPh2), 35.1 (d, JC-P 6.3, (CH(CH3)2),
63.2 (d, JC-P 12.8, NCH), 121.3 (Ar), 123.3 (Ar), 127.8–
140.1 (Ar), 149.0 (Ar); m/z (EI+) 423.2106 (M+, 35%,
C29H30NP requires 423.2116), 380 (M+−43i-Pr, 100%),
224 (M+−199CH2PPh2, 75%), 185 (PPh2, 45%).
6.14.2. Procedure for chloride ion effect study. Method B
for the standard procedure above was employed, at −
20°C. The allyl-palladium chloride dimer (0.02 mmol)
was replaced with bis(benzylideneacetone)-palladium
(23 mg, 0.04 mmol) and 2 equivalents of ligand (0.08
mmol) were used.
6.14.3. Procedure for 1:1 ligand:palladium stoichiometry
study. Method B for the standard procedure above was
employed, at −20°C. The amount of ligand used was 0.04
mmol (1 equiv.) and employed with either allyl-pal-
ladium chloride dimer (0.02 mmol) or bis(benzylidene-
acetone)-palladium (23 mg, 0.04 mol).
Acknowledgements
This work is part of the PhD Thesis of R.J.C., University
of Sheffield, 1999. We would like to thank the EPSRC,
GlaxoSmithKline and the University of Sheffield, for
financial support, Mr. A. Jones and Ms. J. Stanbra for
measuring microanalytical data and Mr. S. Thorpe and
Mr. N. Lewus for providing mass spectra.
6.14. Allylic substitution procedures: trans-(R)-methyl
2-carbomethoxy-3,5-diphenylpent-4-enoate 23
6.14.1. Standard procedures for temperature study.
Method A: A solution of acetate 22 (200 mg, 0.8 mmol),
allyl-palladium chloride dimer (7.3 mg, 0.02 mmol) and
ligand (0.08 mmol) in dichloromethane (3.0 mL) was
stirred at room temperature for 15 min, then cooled to
the appropriate temperature (15 min). To this was added
a solution of dimethyl malonate (273 mL, 2.4 mmol) and
N,O-bis(trimethylsilyl)acetamide (583 mL, 2.4 mmol)
dropwise, followed by potassium acetate (2 mg, 0.03
mmol). The reaction was monitored by TLC and on
completion the volatiles were removed in vacuo and
purification by flash column chromatography (7% ethyl
acetate/light petroleum) gave 23 as a colourless oil; lH
(250 MHz, CDCl3), 3.53 (3H, s, CO2CH3), 3.70 (3H, s,
CO2CH3), 3.95 (1H, d, J 10.9, CH(CO2CH3)2), 4.27 (1H,
dd, J 10.9, 8.2, CHCH(CO2CH3)2), 6.32 (1H, dd, J 15.0,
8.2, PhCHꢁCH), 6.48 (41H, d, J 15.0, PhCHꢁCH), 7.51–
7.44 (10H, m, ArH).
References
1. (a) Anderson, J. C.; Harding, M. Chem. Commun. 1998,
393; (b) Anderson, J. C.; Cubbon, R.; Harding, M.; James,
D. S. Tetrahedron: Asymmetry 1998, 9, 3461.
2. This is not a general phenomenon. See: Rassias, G. A.;
Page, P. C. B.; Reignier, S.; Christie, S. D. R. Synlett 2000,
379–381.
3. Anderson, J. C.; James, D. S.; Mathias, J. P. Tetrahedron:
Asymmetry 1998, 9, 753.
4. Adams, H.; Anderson, J. C.; Cubbon, R.; James, D. S.;
Mathias, J. P. J. Org. Chem. 1999, 64, 8256.
5. (a) Sprinz, J.; Helmchen, G. Tetrahedron Lett. 1993, 34,
1769–1772; (b) von Matt, P.; Pfaltz, A. Angew. Chem., Int.
Ed. Engl. 1993, 32, 566–568; (c) Dawson, G. J.; Frost, C.
G.; Williams, J. M. J.; Coote, S. J. Tetrahedron Lett. 1993,
34, 3149–3150.
Method B: A solution of acetate 22 (200 mg, 0.8 mmol),
allyl-palladium chloride dimer (7.3 mg, 0.02 mmol) and
6. Anderson, J. C.; Cubbon, R.; Harling, J. D. Tetrahedron:
Asymmetry 1999, 10, 2829.

J. C. Anderson et al. / Tetrahedron: Asymmetry 12 (2001) 923–935
935
,
7. Booth, H.; Everett, J. R. J. Chem. Soc., Perkin Trans. 2
1980, 255.
8. Eliel, E. L.; Manoharan, M. J. Org. Chem. 1981, 46,
1959.
679–682; (b) Akermark, B.; Hansson, S.; Vitagliano, A. J.
,
Am. Chem. Soc. 1990, 112, 4587–4588; (c) Akermark, B.;
Krakenberger, B.; Hansson, S.; Vitagliano, A.
Organometallics 1987, 6, 620–628.
9. A similar transmission of chirality occurs with the suc-
cessful chiral diphosphine ligand chiraphos in various
asymmetric palladium catalysed reactions. Bosnichn, B.;
Fryzuch, M. D. In Topics in Stereochemistry; Geoffroy,
G. L., Ed.; John Wiley & Sons, 1981; Vol. 12, p. 119 (see
pp. 121–125).
10. Hayashi, T.; Konishi, M.; Fukushima, M.; Kanehira, K.;
Hioki, T.; Kumada, M. J. Org. Chem. 1983, 48, 2195.
11. Krishnamurthy, S. Tetrahedron Lett. 1982, 33, 3315.
12. Brisset, H.; Gourdel, Y.; Pellon, P.; Le Corre, M. Tetra-
hedron Lett. 1993, 34, 4523.
20. (a) Sprinz, J.; Kiefer, M.; Helmchen, G.; Reggelin, M.;
Huttner, G.; Walter, O.; Zsolnai, L. Tetrahedron Lett.
1994, 35, 1523–1526; (b) von Matt, P.; Lloyd-Jones, G.
C.; Minidis, A. B. E.; Pfaltz, A.; Macko, L.; Neuburger,
M.; Zehnder, M.; Ru¨egger, H.; Pregosin, P. S. Helv.
Chim. Acta 1995, 78, 265–284; (c) Togni, A.; Burckhardt,
U.; Gramlich, V.; Pregosin, P. S.; Salzmann, R. J. Am.
Chem. Soc. 1996, 118, 1031–1037.
21. Steinhagen, H.; Reggelin, M.; Helmchen, G. Angew.
Chem., Int. Ed. Engl. 1997, 36, 2108.
22. (a) Auburn, P. R.; Mackenzie, P. B.; Bosnich, B. J. Am.
Chem. Soc. 1985, 107, 2033; (b) Mackenzie, P. B.; Whe-
lan, J.; Bosnich, B. J. Am. Chem. Soc. 1985, 107, 2046.
23. Hayashi, T.; Yamamoto, A.; Ito, Y.; Nishioka, E.;
Miura, H.; Yanagi, K. J. Am. Chem. Soc. 1989, 111,
6301.
24. Garrou, P. E. Chem. Rev. 1981, 81, 229.
25. Alcock, N. W.; Platt, A. W. G.; Pringle, P. J. Chem. Soc.,
Dalton Trans. 1987, 2273.
26. (a) Graf, C.-D.; Malan, C. M.; Harms, K.; Knochel, P. J.
Am. Chem. Soc. 1999, 64, 5581; (b) Chen, Z.; Jiang, Q.;
Zhu, G.; Xiao, D.; Cao, P.; Guo, C.; Zhang, X. J. Org.
Chem. 1997, 62, 4521; (c) Bovens, M.; Togni, A.;
Venanzi, L. M. J. Organomet. Chem. 1993, 451, C28; (d)
Bolm, C.; Kaufmann, D.; Gessler, S.; Harms, K. J.
Organomet. Chem. 1995, 502, 47.
13. Mohr, B.; Lynn, D. M.; Grubbs, R. H. Organometallics
1996, 15, 4317.
14. Neidlein, R.; Greulich, P.; Kramer, W. Helv. Chim. Acta
1993, 76, 2407.
15. Christoffers, J. Helv. Chim. Acta 1998, 81, 845.
16. Sakuraba, S.; Okada, T.; Morimoto, T.; Achiwa, K.
Chem. Pharm. Bull. 1995, 43, 927.
17. Similar observations have been reported. See Ref. 14.
18. (a) Yang, H.; Khan, M. A.; Nicholas, K. M.
Organometallics 1993, 12, 3485–3494; (b) von Matt, P.;
Loiseleur, O.; Koch, G.; Pfaltz, A.; Lefeber, C.; Fuecht,
T.; Helmchen, G. Tetrahedron: Asymmetry 1994, 5, 573–
584; (c) Brown, J. M.; Hulmes, D. I.; Guiry, P. J.
Tetrahedron 1994, 50, 4493–4506; (d) Burckhardt, U.;
Hintermann, L.; Schnyder, A.; Togni, A. Organometallics
1995, 14, 5415–5425.
,
27. Anderson, J. C.; Siddons, D. C.; Smith, S. C.; Swarbrick,
M. E. J. Org. Chem. 1996, 61, 4820.
19. (a) Akermark, B.; Hansson, S.; Krakenberger, B.;
Vitagliano, A.; Zetterberg, K. Organometallics 1984, 3,
.