Aminophosphine-oxazoline and phosphoramidite-oxazoline ligands and their application in asymmetric catalysis

Article abstract of DOI:10.1016/j.tetasy.2007.04.020

The synthesis of a novel series of aminophosphine-oxazoline and phosphoramidite-oxazoline is described. The efficacy of these aminophosphine-oxazoline ligands was investigated in the palladium catalysed asymmetric allylic alkylation of 1,3-diphenylprop-2-

Full text of DOI:10.1016/j.tetasy.2007.04.020

Tetrahedron: Asymmetry 18 (2007) 1094–1102
Aminophosphine–oxazoline and phosphoramidite–oxazoline ligands
and their application in asymmetric catalysis
Raymond P. J. Bronger and Patrick J. Guiry*
Centre for Synthesis and Chemical Biology, Conway Institute of Biomolecular and Biomedical Research,
School of Chemistry and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland
Received 19 March 2007; accepted 20 April 2007
Available online 1 June 2007
Abstract—The synthesis of a novel series of aminophosphine–oxazoline and phosphoramidite–oxazoline is described. The efficacy of
these aminophosphine–oxazoline ligands was investigated in the palladium catalysed asymmetric allylic alkylation of 1,3-diphenyl-
prop-2-enyl acetate leading to a maximum of 38% ee at 64% conversion. Phosphoramidite–oxazoline ligands, however, gave ees of
up to 87% at 71% conversion in the same reaction and also proved to be effective in the palladium catalysed asymmetric Suzuki coupling
between 2-methylnaphthylboronic acid and 1-bromonaphthalene, leading to a maximum of 46% ee in 54% isolated yield at room
temperature.
ꢀ 2007 Published by Elsevier Ltd.
1. Introduction
phosphinite–oxazoline ligands can be equally efficient in a
wide range of reactions, exhibiting excellent conversions
and enantioselection.9–20 Research on aminophosphine–
oxazoline21 and phosphoramidite–oxazoline ligands, how-
ever, has hardly been reported, while ligands containing
an aminophosphine22–25 or a phosphoramidite26 sub-unit
have been highly successful in many catalytic applications.
In recent years, it has been shown that sterically and elec-
tronically unsymmetrical ligands are very efficient in many
transition metal mediated asymmetric transformations.1,2
In particular, phosphine–oxazoline ligands represent a ver-
satile and successful class. For example, the PHOX-type
O
R2
N
R1
O
N
3
PPh2
O
PR2
O
P
R
N
O
O
PPh2 N
N
O
R2
R1
R
R1
R2
4
1
2
3
ligands 1, which were reported independently by Pfaltz,3
Helmchen4 and Williams,5 give excellent conversions and
enantioselection in allylic substitution reactions, intermo-
lecular Heck reaction, iridium catalysed hydrogenations
and enantioselective Diels–Alder reactions, among oth-
ers.6–8 Following the success of these phosphino-oxazoline
ligands, many groups have shown that phosphite– and
Interested by this relatively unexplored class of ligands, we
herein wish to report the synthesis of heterodonor amino-
phosphine–oxazoline and phosphoramidite–oxazoline
ligands of general formula 2 and the preliminary evaluation
of their corresponding palladium complexes as catalysts for
asymmetric allylic alkylation and Suzuki couplings. Com-
pared to the PHOX ligands 1, which form a 6-membered
chelate, and Claver’s phosphite–oxazoline ligands 3,27
which form a 7-membered chelate, PN-oxazoline ligands
2 form an 8-membered chelate, similar to Hayashi’s and
Ikeda’s binaphthyl-based oxazoline–phosphine ligands
*
Corresponding author. Tel.: +353 1 716 2309; fax: +353 1 716 2501;
e-mail: p.guiry@ucd.ie
0957-4166/$ - see front matter ꢀ 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2007.04.020

R. P. J. Bronger, P. J. Guiry / Tetrahedron: Asymmetry 18 (2007) 1094–1102
1095
ZnCl2 or ZnBr2
R1
H
X
N
OH
NH2
BnNH2
Br
N
N
O
O
PhCl, 140 °C
42 - 77%
66 - 88%
CN
R1
R1
5
7
6a: X = Br
6b: X = Cl
2
Et3N, ClPR2
16h
N
2
PR2
50 - 72%
N
O
R1
Ph
O
Ph
O
Ph
Ph
O
O
O
2
PR2
=
P
P
PPh2
O
O
Ph
O
Ph
Ph
Ph
8a: R1 = Me
8b: R1 = i-Pr
8c: R1 = Bn
9a: R1 = Me
9b: R1 = i-Pr
9c: R1 = Bn
10a: R1 = Me
10b: R1 = i-Pr
10c: R1 = Bn
Scheme 1. Synthesis of ligands 8–10.
4,28,29 which we hoped to be beneficial in obtaining high
enantioselectivities by creating a chiral pocket, that is,
more confined than ligands with a smaller chelate ring size.
The ligands were prepared in a modular way, which allows
facile independent structural variations at different parts of
the molecule during each step of synthesis.
ful way of assessing the ability of the ligand to induce
enantioselectivity.31,32 One of the most typically used sys-
tems involves nucleophilic attack of the dimethylmalonate
anion on 1,3-diphenylprop-2-enyl acetate 11. This reaction
has been used extensively by many groups for testing the
potential of new chiral ligands, because of its high synthetic
utility and a detailed understanding of its mechanism. Pal-
ladium complexes of homobidentate ligands have proven
to be successful in this transformation by creating a chiral
environment that influences the orientation of the reactants
sufficiently to cause one enantiomer of the product to pre-
dominate. Heterobidentate ligands, such as phosphine–
oxazolines 1, affect the stereochemical outcome of the bond
forming process by the desymmetrisation of the substrate
allyl through electronic effects. The incoming nucleophile
then reacts preferentially at the more electrophilic end of
the substrate, giving rise to the observed enantioselectiv-
ity.33–38
Thus, aminophosphine–oxazoline ligands 8 and phospho-
ramidite–oxazoline ligands 9 and 10 were readily prepared
starting from commercially available a-bromo-o-tolunitrile
and the appropriate enantiopure aminoalcohols in a ZnCl2
catalysed cyclocondensation (Scheme 1). During this reac-
tion we observed partial exchange of the a-bromo-group
for an a-chloro-group resulting in the formation of 6b.
To circumvent the formation of this side product, ZnBr2
instead of ZnCl2 can be used as catalyst, although this only
worked well for the formation of 6a (R = i-Pr, Bn). For
ligand 6a (R = Me), significant amounts of undetermined
side products were formed when ZnBr2 was used. Although
mixtures of 6a and 6b can be separated by column chroma-
tography on silica, the subsequent nucleophilic substitution
with benzylamine operates well with this mixture to yield
secondary amine 7. Subsequent reaction of 7 with chlorodi-
phenylphosphine or with in situ prepared TADDOL-
derived phosphorchloridites30 in the presence of Et3N gave
ligand classes 8 and 9–10, respectively. Although these
ligands are sensitive towards hydrolysis, especially the
members of ligand class 8, we found that they can be
purified by quick column chromatography on silica using
solvents as received without noticeable loss of yield.
The enantio-differentiating abilities of 8–10 were initially
assessed in the palladium catalysed allylic alkylation of
1,3-diphenylprop-2-enyl acetate using in situ generated
dimethylmalonate anion as the nucleophile. The results
obtained with ligands 8a–10c are summarised in Table 1.
During preliminary work we investigated a range of sol-
vents, including coordinating solvents such as diethyl ether
and tetrahydrofuran, but these afforded low levels of
enantioselectivities (in the range up to 25% ee). However,
dichloromethane proved to be our optimal solvent and of
the aminophosphine–oxazoline ligands 8 tested, ligand 8b
afforded the highest ee of 38% in a good yield of 64%.
Unfortunately, the levels of enantioselectivities observed
with ligand 8c were poor (up to 10% ee). The nature of
the base had a large impact on enantioselectivity; higher
1.1. Asymmetric allylic alkylation
The formation of asymmetric carbon–carbon linkages
catalysed by palladium complexes of chiral ligands is a use-

1096
R. P. J. Bronger, P. J. Guiry / Tetrahedron: Asymmetry 18 (2007) 1094–1102
Table 1. Pd-Catalysed allylic alkylation with 8a–10ca
[Pd(allyl)Cl]2, 2 eq. L
base, BSA,
dimethylmalonate
MeO2C CO2Me
MeO2C CO2Me
OAc
Ph
+
Ph
Ph
Ph
(S)-12
Ph
Ph
(R)-12
( )-11
Entry
Ligand
Base
Solvent
Conversionb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
8a
8b
KOAc
KOAcd
LiOAc
NaOAc
KOAc
Cs2CO3
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
59
11
30
76
68
64
87
22
86
68
71
46
41
25 (R)
38 (R)
6 (R)
17 (R)
29 (R)
38 (R)
4 (S)
64 (R)
73 (R)
78 (R)
87 (S)
81 (S)
88 (S)
8b
8b
8b
8b
8c
9a
9b
9c
10a
10b
10c
a Reaction conditions: [[Pd(allyl)(l-Cl)]2] = 2.5 mM in CH2Cl2, L/Pd = 1.1, substrate/Pd = 200, KOAc/Pd = 10, BSA/Pd = 300, dimethylmalonate/
Pd = 300, T = 20 ꢁC, t = 48 h.
b Conversion determined by 1H NMR.
c Ee determined by Chiral HPLC (Chiralcel OD column). Specific rotations were compared to literature values.
d KOAc/Pd = 1.
ees were obtained with softer bases, whereas conversions
were hardly affected (entries 3–6). Since KOAc is the most
commonly applied base for allylic alkylation, we used this
base for all our other experiments. However, we were
pleased to determine that improved results could be
obtained with TADDOL-based ligands 9 and 10 (entries
6–11). The configuration of the product was mainly deter-
mined by the configuration of the TADDOL-moiety: (+)-
TADDOL derived ligands 9a–c led to (R)-12, whereas
(ꢀ)-TADDOL derived ligands 10a–c resulted in (S)-12.
Consistently higher enantiopurities of 12 were obtained
using 10a–c compared to 9a–c, indicating that the (S)-con-
figurations of the oxazoline-unit and (ꢀ)-TADDOL-unit
are matched.
reaction.42,43 As a model reaction we studied the coupling
between 2-methylnaphthylboronic acid 15 with 1-bromo-
naphthalene 16 in DME/H2O (10/1)41,43 using various
bases (Table 2). We did not test ligand class 8 under these
reaction conditions in view of their potential instability
under these reaction conditions.
Ph2P
Fe
NMe2
NMe2
PCy2
14
13
1.2. Asymmetric Suzuki reaction
The nature of the base had a large impact both on conver-
sion and ee. The influence between the different ligands was
non-consistent, for example, for 9b the best conversion and
ee were obtained with Cs2CO3, while for 10b the use of
Cs2CO3 resulted in racemic product, whereas CsOH gave
the best combination of both conversion and ee. Similarly,
9a and 9c and 10a and 10c were tested using different bases.
While 9a gave no or low ees in all cases (yield = 30–63%,
ee = 0–17%), 10a showed some promising results with
Ba(OH)2 as base (yield = 57%, ee = 34%). 9c and 10c gave
low conversions independent of the applied base
(yield = 0–36%, ee = 0–34%). The role of the base is still
unclear although in the case of softer (larger) bases with
Cs, and to a lesser extent with Ba, the complex is clearly
less able to distinguish between different approaches of
the boronic acid species.
In recent years, much research has been devoted to the syn-
thesis of axially chiral biaryls. Many useful methods use
either chiral auxiliaries or start from chiral materials.39
The asymmetric Suzuki coupling is a powerful method
for the synthesis of axially chiral biaryls starting from
achiral materials and using mild methods, additionally
the Suzuki coupling shows high functional group tolerance.
Especially successful is the procedure by Buchwald, who
used phosphinamine binaphthyl ligands 13 for the prepara-
tion of functionalised biaryls in high conversion and with
high ees.40 Cammidge also reported an asymmetric Suzuki
protocol in a study that tested a range of chiral ligands,
with the ferrocene-derived P,N ligand 14, affording ees of
up to 64% in 44% yield.41 It is known that monodentate
phosphoramidite ligands can effect the Suzuki coupling at
room temperature in high yields and thus we became
interested in the application of ligands 9 and 10 in this
Surprisingly, for all ligands (R)-2-methyl-1,10-binaphthyl
was formed preferentially suggesting that in this reaction,

R. P. J. Bronger, P. J. Guiry / Tetrahedron: Asymmetry 18 (2007) 1094–1102
Table 2. Pd-Catalysed asymmetric Suzuki coupling using ligands 9b and 10ba
1097
Pd(dba)2, 2 eq. L,
DME/H2O, base,
+
B(OH)2
Br
+
T = 20 °C, t = 24h
(R)-17
(S)-17
15
16
Entry
Ligand
Base
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
9b
9b
KOH
30
25
16
19
54
31
45
43
61
49
25
38 (R)
36 (R)
37 (R)
40 (R)
46 (R)
43 (R)
35 (R)
34 (R)
33 (R)
0
NaOH
CsOH
CsF
Cs2CO3
Ba(OH)2
KOH
NaOH
CsOH
Cs2CO3
Ba(OH)2
9b
9b
9b
9b
10b
10b
10b
10b
10b
10
11
18 (R)
a Reaction conditions: [Pd(dba)2] = 5 mM in DME/H2O (10:1), L/Pd = 2, 1-bromonaphthalene/Pd = 250, 2-methyl-1-naphthaleneboronic acid/Pd = 300,
base/Pd = 500, T = 20 ꢁC, t = 24 h.
b Isolated yield after column chromatography on silica.
c ees determined by Chiral HPLC (Chiralcel OJ column), optical rotations were compared to literature values.
1
the configuration of the oxazoline-unit determined the
chirality of the product.
pled mode. TMS was used as the external standard for H
and 13C NMR and 85% H3PO4 in H2O as an external stan-
dard for 31P NMR. HPLC analysis was carried out on a
Shimadzu LC-10ATvp machine and Shimadzu LC-2010A
machine equipped with a UV–vis detector employing Chi-
ralcelꢂ OD and OJ columns from Diacel Chemical
Industries.
2. Conclusion
In conclusion, we have shown a facile synthesis of a new
class of modular P–N ligands. The results obtained with
phosphoramidite–oxazoline ligands 9 and 10 in asymmetric
allylic alkylation and asymmetric Suzuki coupling show the
potential of this type of ligands in asymmetric catalysis.
Work is currently underway in order to fine-tune the ligand
structure and its use in other asymmetric transformations
and the results of these investigations will be reported in
due time.
3.2. General synthesis of 2-(2-bromomethylphenyl)-(4S)-4-R-
4,5-dihydrooxazole (R = Me, i-Pr, Benzyl) 6a
To a mixture of 1.0 g of a-bromo-o-tolunitrile (5.2 mmol)
and the appropriate (S)-2-aminoalcohol (5.2 mmol) in
8 mL of chlorobenzene was added 0.22 mL of a 1 M solu-
tion of ZnCl2 in Et2O (0.22 mmol) at 50 ꢁC. Thereafter, the
mixture was heated at 134 ꢁC. After 24 h, the reaction mix-
ture was diluted with 30 mL of CH2Cl2 and washed with a
saturated solution of NaHCO3 in water (3 · 20 mL). The
organic layer was dried over Na2SO4 and subsequently
concentrated in vacuo to yield either a white solid
(R = Me, Bn) or a colourless oil (R = i-Pr) after purifica-
tion by column chromatography on silica (pentane:ethyl-
acetate 3:1). (Yield: 42–77%).
3. Experimental
3.1. General
All air- or water-sensitive reactions were performed using
standard Schlenk techniques under a nitrogen atmosphere.
THF and diethyl ether were distilled from sodium/benzo-
phenone, toluene and dichloromethane were distilled from
calcium hydride. Chlorodiphenylphosphine was distilled
prior to use. All other solvents were of reagent grade and
were used as received. Chemicals were purchased form Al-
drich Chemical Co. Melting points were determined using a
Gallenkamp melting point apparatus in open capillaries
and are uncorrected. Optical rotation values were mea-
sured on a Perkin–Elmer 343 polarimeter. 1H NMR
spectra were obtained on a 300 MHz Varian-Unity spec-
trometer and a 500 MHz Varian-Unity spectrometer.
1H–1H COSY spectra were recorded on a 300 MHz Varian
Unity spectrometer and a 500 MHz Varian-Unity spec-
3.3. 2-(2-Bromomethylphenyl)-(4S)-4-methyl-4,5-dihydro-
oxazole 6a (R = Me)
Yield: 42% as an off-white solid; mp: 83–84 ꢁC;
20
½aꢁD ¼ þ14:4 (c 0.39, CHCl3); 1H NMR (CDCl3):
d = 7.86 (d, 3J(H,H) = 7.2 Hz, 1H), 7.55 (m, 1H), 7.47
2
(m, 2H), 4.74 (m, 1H), 4.54 (d, J(H,H) = 16.7 Hz, 1H),
2
4.41 (d, J(H,H) = 16.6 Hz, 1H), 3.71–3.58 (m, 2H), 1.46
(d, 3J(H,H) = 6.9 Hz, 3H). 13C{1H} NMR (CDCl3):
d = 168.5 (s), 141.2 (s), 132.6 (s), 131.4 (s), 128.1 (s),
123.7 (s), 122.8 (s), 48.1 (s), 46.8 (s), 36.1 (s), 17.4 (s); IR
(NaCl): m = 3055, 2978, 2933, 2875, 1664, 1470, 1454,
1
trometer. 31P and 13C spectra were measured in H decou-

1098
R. P. J. Bronger, P. J. Guiry / Tetrahedron: Asymmetry 18 (2007) 1094–1102
1409 cmꢀ1; HRMS (ES-I) Calcd for C11H13NOBr (M+1)
254.0181. Found: 254.0192.
123.61 (s), 122.73 (s), 53.37 (s), 52.46 (s), 46.59 (s), 45.56
(s), 17.06 (s); IR (NaCl): m = 3273, 2975, 2937, 2877, 1662,
1470, 1452, 1414, 1215, 1026, 746 cmꢀ1; HRMS (ES-I)
Calcd for C18H21N2O (M+1) 281.1654. Found: 281.1664.
3.4. 2-(2-Bromomethylphenyl)-(4S)-4-isopropyl-4,5-dihydro-
oxazole 6a (R = i-Pr)
3.8. 2-(N-Benzyl-2-aminomethylphenyl)-(4S)-4-i-propyl-4,5-
dihydrooxazole 7 (R = i-Pr)
20
Yield: 77% as a colourless oil; ½aꢁD ¼ ꢀ13:0 (c 0.32,
CHCl3); 1H NMR (CDCl3): d = 7.83 (d, 3J(H,H) = 7.2 Hz,
1H), 7.54–7.46 (m, 1H), 7.46–7.38 (m, 2H), 4.56 (d,
(2J(H,H) = 17.1 Hz, 1H), 4.32 (d, 2J(H,H) = 16.8 Hz,
1H), 4.20 (td, 3J(H,H) = 9.0 Hz, 3J(H,H) = 3.6 Hz, 1H),
20
Yield: 87% as a pale yellow oil; ½aꢁD ¼ þ2:1 (c 0.54,
CHCl3); 1H NMR (CDCl3): d = 7.81 (d, 3J(H,H) = 7.5 Hz,
1H), 7.45–7.4 (m, 1H), 7.39–7.35 (m, 2H), 7.16–7.13
(m, 5H), 4.2–4.1 (m, 3H), 3.78 (d, 2J(H,H) = 13.5 Hz,
1H), 3.61 (d, 2J(H,H) = 13.5 Hz, 1H), 2.91 (dd,
2J(H,H) = 12.6 Hz, 3J(H,H) = 3.9 Hz, 1H), 2.73 (dd,
2J(H,H) = 12.3 Hz, 3J(H,H) = 10.5 Hz, 1H), 1.81 (m,
2
3
3.74 (dd, J(H,H) = 11.4 Hz, J(H,H) = 3.6 Hz, 1H), 3.67
2
3
(dd, J(H,H) = 11.1 Hz, J(H,H) = 8.7 Hz, 1H), 2.09 (m,
1H), 1.04 (d, 3J(H,H) = 6.6 Hz, 3H), 0.87 (d,
3J(H,H) = 6.6 Hz, 3H). 13C{1H} NMR (CDCl3):
d = 168.97 (s), 141.16 (s), 132.21 (s), 131.29 (s), 127.85
(s), 123.69 (s), 122.64 (s), 58.28 (s), 47.22 (s), 34.11 (s),
30.15 (s), 19.88 (s), 19.63 (s); IR (NaCl): m = 2966, 2873,
1686, 1470, 1452, 1410, 1223, 737 cmꢀ1; HRMS (ES-I)
calcd for C13H17NOBr (M+1) 282.0494. Found: 282.0498.
3
1H), 1.37 (br s, 1H), 0.95 (d, J(H,H) = 6.6 Hz, 3H), 0.78
(d, 3J(H,H) = 6.9 Hz, 3H). 13C{1H} NMR (CDCl3):
d = 169.54 (s), 141.52 (s), 140.33 (s), 132.82 (s), 131.11
(s), 128.24 (s), 128.07 (s), 127.82 (s), 126.83 (s), 123.62 (s),
122.77 (s), 57.05 (s), 53.32 (s), 48.78 (s), 46.33 (s), 29.87
(s), 20.08 (s), 20.02 (s); IR (NaCl): m = 3288, 2962, 2929,
2873, 1678, 1470, 1452, 1411, 1213, 737 cmꢀ1; HRMS
(ES-I) Calcd for C20H25N2O (M+1) 309.1967. Found:
309.1970.
3.5. 2-(2-Bromomethylphenyl)-(4S)-4-benzyl-4,5-dihydro-
oxazole 6a (R = Bn)
20
Yield: 73% as a white solid; mp: 78–79 ꢁC; ½aꢁD ¼ ꢀ45:8 (c
0.31, CHCl3); 1H NMR (CDCl3): d = 7.86 (d,
3J(H,H) = 7.2 Hz, 1H), 7.56–7.39 (m, 3H), 7.31–7.19 (m,
3.9. 2-(N-Benzyl-2-aminomethylphenyl)-(4S)-4-benzyl-4,5-
dihydrooxazole 7 (R = Bn)
2
5H), 4.72 (m, 1H), 4.41 (d, J(H,H) = 16.5 Hz, 1H), 4.35
20
2
2
(d, J(H,H) = 16.8 Hz, 1H), 3.78 (dd, J(H,H) = 10.8 Hz,
3J(H,H) = 7.2 Hz, 1H), 3.72 (dd, 2J(H,H) = 10.8 Hz,
3J(H,H) = 4.8 Hz, 1H), 3.22 (dd, 2J(H,H) = 14.1 Hz,
3J(H,H) = 8.1 Hz, H), 3.15 (dd, 2J(H,H) = 13.8 Hz,
3J(H,H) = 7.5 Hz, 1H). 13C{1H} NMR (CDCl3):
d = 168.28 (s), 140.863 (s), 136.48 (s), 132.04 (s), 130.95
(s), 128.36 (s), 128.27 (s), 127.50 (s), 126.43 (s), 123.19 (s),
122.22 (s), 54.51 (s), 48.10 (s), 37.03 (s), 33.80 (s); IR
(NaCl): m = 3058, 3026, 2926, 1680, 1470, 1452, 1408,
1365, 1213, 737, 700 cmꢀ1; HRMS (ES-I) Calcd for
C17H17NOBr (M+1) 330.0484. Found: 330.0482.
Yield: 88% as a pale yellow oil; ½aꢁD ¼ ꢀ17:2 (c 0.31,
CHCl3); 1H NMR (CDCl3): d = 7.83 (d, 3J(H,H) = 7.2 Hz,
1H), 7.52–7.43 (m, 2H), 7.39 (d, 3J(H,H) = 9 Hz, 1H),
7.35–7.14 (m, 10H), 4.79 (m, 1H), 4.20 (s, 2H), 3.84 (d,
2
2J(H,H) = 13.2 Hz, 1H), 3.72 (d, J(H,H) = 13.2 Hz, 1H),
3.03–2.88 (m, 4H), 1.62 (br s, 1H). 13C{1H} NMR
(CDCl3): d = 169.11 (s), 141.43 (s), 140.15 (s), 137.86 (s),
132.95 (s), 131.12 (s), 128.80 (s), 128.55 (s), 128.33 (s),
128.15 (s), 127.86 (s), 126.50 (s), 123.63 (s), 122.65 (s),
53.44 (s), 52.87 (s), 50.59 (s), 46.99 (s), 37.50 (s); IR (NaCl):
m = 3305, 3027, 2929, 2850, 1676, 1470, 1452, 1412, 1213,
735 cmꢀ1; HRMS (ES-I) Calcd for C24H25N2O (M+1)
357.1967. Found: 357.1964.
3.6. General synthesis of 2-(N-benzyl-2-aminomethylphenyl)-
(4S)-4-R-4,5-dihydrooxazole (R = Me, i-Pr, t-Bu, Benzyl) 7
3.10. General synthesis of 2-(N-Benzyl-N-diphenylphos-
phino-2-aminomethylphenyl)-(4S)-4-R-4,5-dihydrooxazole
(R = Me, i-Pr, t-Bu, Benzyl) 8
Compound 6a (8.5 mmol) was dissolved in 10 mL of benz-
ylamine (9.8 g, 92 mmol) and both reactants were allowed
to react for 16–96 h at 60 ꢁC until full conversion of 6a
was observed by TLC and GC–MS. Thereafter, the prod-
uct was purified by column chromatography on silica
(ethylacetate:triethylamine 7:1) to yield a pale yellow oil.
(Yield: 66–88%).
To 1.54 mmol of 7 in 15 mL of THF was added 0.26 mL of
Et3N (1.8 mmol, 1.2 equiv). Next 0.31 mL of chlorodiphen-
ylphosphine (1.7 mmol, 1.1 equiv) was added dropwise at
0 ꢁC, which immediately resulted in the formation of an
Et3NÆHCl precipitate. The reaction mixture was allowed
to react overnight. The salts were removed by filtration
of the reaction mixture over MgSO4, which was followed
by the removal of the organics in vacuo. After column
chromatography on silica (ethylacetate:pentane 1:3), the
product was isolated as a white solid. (Yield: 50–60%).
3.7. 2-(N-Benzyl-2-aminomethylphenyl)-(4S)-4-methyl-4,5-
dihydrooxazole 7 (R = Me)
20
Yield: 66% as a pale yellow oil; ½aꢁD ¼ þ17 (c 0.29, CHCl3);
1H NMR (CDCl3): d = 7.77 (d, 3J(H,H) = 7.5 Hz, 1H),
7.46–7.26 (m, 3H), 7.25–7.09 (m, 5H), 4.58 (m, 1H), 4.20
(s, 1H), 3.76 (d, 2J(H,H) = 13.5 Hz, 1H), 3.66 (d,
2J(H,H) = 13.2 Hz, 1H), 2.73–2.71 (m, 2H), 1.56 (br s,
1H), 1.18 (d, 3J(H,H) = 6.9 Hz, 3H). 13C{1H} NMR
(CDCl3): d = 168.78 (s), 141.41 (s), 140.25 (s), 133.11 (s),
131.11 (s), 128.32 (s), 128.11 (s), 127.92 (s), 126.91 (s),
3.11. 2-(N-Benzyl-N-diphenylphosphino-2-aminomethyl-
phenyl)-(4S)-4-methyl-4,5-dihydrooxazole 8a
20
Yield: 50% as a white solid; mp: 62–65 ꢁC; ½aꢁD ¼ þ88 (c
1
0.28, CHCl3); H NMR (CDCl3): d = 7.76 (m, 1H), 7.36

R. P. J. Bronger, P. J. Guiry / Tetrahedron: Asymmetry 18 (2007) 1094–1102
1099
(m, 2H), 7.32 (td, J = 7.0 Hz, J = 2.0 Hz, 2H), 7.23–7.17
(m, 4H), 7.11 (br t, J = 7.0 Hz, 2H), 7.07 (m, 1H), 7.01–
6.94 (m, 3H), 6.84–6.82 (m, 2H), 4.76 (m, 1H), 4.32 (dd,
J = 14.5 Hz, J = 5.0 Hz, 1H), 4.20 (dd, J = 15.0 Hz,
J = 5.0 Hz, 1H), 4.07 (s, 2H), 3.28 (m, 1H), 3.05 (ddd,
J = 14.5 Hz, J = 10.5 Hz, J = 4 Hz, 1H), 0.94 (d,
J = 6.5 Hz, 3H); 13C{1H} NMR (CDCl3): d = 168.7 (s),
141.5 (s), 140.3 (d, J = 13.9 Hz), 139.6 (d, J = 13.4 Hz),
137.9 (s), 133.2 (s), 132.9 (d, J = 21.3 Hz), 131.3 (d,
J = 20.5 Hz), 130.9 (s), 129.0 (s), 128.8 (s), 128.4 (d,
J = 6.2 Hz), 128.14 (s), 128.12 (s), 127.9 (d, J = 5.5 Hz),
127.7 (s), 126.9 (s), 123.5 (s), 122.7 (s), 55.3 (d,
J = 32.2 Hz), 52.8 (s), 45.1 (d, J = 6.2 Hz), 44.4 (d,
J = 3.8 Hz), 16.9 (s); 31P{1H} (CDCl3): d = 68.16; IR
(NaCl): m = 3057, 3003, 2970, 2929, 2852, 1678, 1470,
J = 6.0 Hz), 127.6 (s), 126.9 (s), 126.3 (s), 53.5 (d,
J = 30.1 Hz), 53.5 (s), 50.8 (br s), 46.4 (d, J = 5.1 Hz),
37.5 (s); (31P{1H} (CDCl3): d = 68.08; IR (NaCl):
m = 3060, 3026, 3002, 2920, 2854, 1680, 1470, 1452, 1433,
1410, 1215, 1093, 952, 744, 698 cmꢀ1; HRMS (ES-I) Calcd
for C36H34N2OP (M+1) 541.2409. Found: 541.2418. Anal.
Calcd for C36H33N2OP: C, 79.98; H, 6.15; N, 5.18. Found:
C, 79.45; H, 6.17; N, 4.97.
3.14. General synthesis of 2-(N-benzyl-N-(+)-TADDOL-2-
aminomethylphenyl)-(4S)-4-R-4,5-dihydrooxazole (R = Me,
i-Pr, Benzyl) (9)
To
a stirred solution of 0.233 g of (+)-TADDOL
(0.5 mmol) and 0.25 mL of Et3N (0.182 g, 1.8 mmol) in
2 mL of CH2Cl2 was added 42 lL of PCl3 at 0 ꢁC. Immedi-
ately a precipitate was formed and the reaction mixture was
allowed to react for 1 h. Next, a solution of 7 (0.5 mmol) in
2 mL of CH2Cl2 was added dropwise. The mixture was al-
lowed to react for 2 days at room temperature. The salts
were removed by filtration of the reaction mixture over
MgSO4, which was followed by the removal of the organics
in vacuo. After column chromatography on silica
(CH2Cl2), the product was isolated as a white solid. (Yield:
68–72%).
1452, 1433, 1412, 1215, 1147, 1092, 958, 742, 696 cmꢀ1
;
HRMS (ES-I) Calcd for C30H30N2OP (M+1) 465.2096.
Found: 465.2098; Anal. Calcd for C30H29N2OP: C, 77.57;
H, 6.22; N, 5.82. Found: C, 76.67; H, 6.22; N, 5.82.
3.12. 2-(N-Benzyl-N-diphenylphosphino-2-aminomethyl-
phenyl)-(4S)-4-i-propyl-4,5-dihydrooxazole 8b
20
Yield: 60% as a white solid; mp: 70–72 ꢁC; ½aꢁD ¼ þ114 (c
1
0.30, CHCl3); H NMR (CDCl3): d = 7.78 (m, 1H), 7.37–
7.34 (m, 4H), 7.25–7.21 (m, 3H), 7.15–7.12 (m, 1H), 7.06–
7.04 (m, 3H), 7.01 (br t, J = 7.0 Hz, 2H), 6.92 (br t,
J = 7.0 Hz), 6.84 (td, J = 8.0 Hz, J = 1.5 Hz), 2H), 6.78–
6.76 (m, 2H), 4.30 (m, 1H), 4.25 (dd, J = 14.5 Hz, J = 3.5
Hz, 1H), 4.23 (dd, J = 16.5 Hz, J = 3.5 Hz, 1H), 4.14 (dd,
J = 14.5 Hz, J = 3.0 Hz, 1H), 4.03 (d, J = 16.5 Hz, 1H),
3.33–3.24 (m, 2H), 1.57 (m, 1H), 0.65 (d, J = 6.5 Hz, 3H),
0.62 (d, J = 6.5 Hz, 3H); 13C{1H} NMR (CDCl3):
d = 169.6 (s), 141.5 (s), 140.7 (d, J = 14.3 Hz), 139.3 (d,
J = 11.5 Hz), 137.7 (s), 133.2 (d, J = 21.8 Hz), 133.0 (s),
130.87 (s), 130.85 (s), 130.7 (s), 129.2 (s), 129.0 (s), 128.5
(d, J = 6.5 Hz), 128.0 (s), 127.82 (s), 127.81 (s), 127.8 (s),
127.6 (s), 126.9 (s), 123.6 (s), 122.7 (s), 54.7 (s), 52.5 (d,
J = 38.9 Hz), 51.9 (d, J = 6.5 Hz), 46.1 (d, J = 7.9 Hz),
30.3 (s), 20.0 (s), 19.8 (s); 31P{1H} (CDCl3): d = 68.31; IR
(NaCl): m = 3058, 3002, 2964, 2929, 2872, 1678, 1470,
3.15. 2-(N-Benzyl-N-(+)-TADDOL-2-aminomethylphenyl)-
(4S)-4-methyl-4,5-dihydrooxazole 9a
20
Yield: 68% as a white solid; mp: 125–128 ꢁC; ½aꢁD ¼ þ97 (c
1
0.28, CHCl3); H NMR (CD2Cl2): d = 7.67 (m, 1H), 7.66–
7.63 (m, 2H), 7.50–7.47 (m, 2H), 7.38–7.31 (m, 9H), 7.24–
7.10 (m, 14H), 7.06 (d, J = 7.0 Hz, 1H), 5.14 (dd,
J = 8.5 Hz, J = 3.5 Hz, 1H), 4.75 (d, J = 8.5 Hz, 1H),
4.62 (m, 1H), 4.46 (dd, J = 15.5 Hz, J = 10.0 Hz, 1H),
4.27 (dd, J = 10.0 Hz, J = 15.0 Hz, 1H), 4.08 (d,
J = 16.5 Hz, 1H), 4.02 (d, J = 16.5 Hz, 1H), 3.20 (m,
1H), 3.10 (m, 1H), 1.32 (s, 3H), 1.15 (d, J = 7.0 Hz, 3H),
0.17 (s, 3H); 13C{1H} NMR (CD2Cl2): d = 168.2 (s),
147.3 (s), 146.6 (d, J = 2.5 Hz), 142.2 (d, J = 1.5 Hz),
142.0 (s), 141.9 (d, J = 1.6 Hz), 138.7 (2C or d), 133.5 (s),
131.3 (s), 129.6 (s), 129.2 (d, J = 4.6 Hz), 129.1 (s), 128.6
(s), 128.4 (s), 128.13 (s), 128.09 (s), 128.0 (s), 127.92 (s),
127.89 (s), 127.8 (s), 127.7 (s), 127.63 (s), 127.59 (s),
127.58 (s), 127.4 (s), 123.5 (s), 123.3 (s), 112.0 (s), 83.2 (d,
J = 3 Hz), 82.6 (d, J = 21.5 Hz), 82.3 (d, J = 8.2 Hz), 82.1
(d, J = 1.5 Hz), 49.3 (d, J = 19.0 Hz), 48.3 (d,
J = 22.6 Hz), 45.8 (s), 45.1 (d, J = 4.0 Hz), 27.7 (s), 25.3
(s), 17.0 (s); 31P{1H} NMR (CD2Cl2): d = 140.67; IR
(NaCl): m = 3089, 3059, 2991, 2929, 1680, 1495, 1448,
1382, 1371, 1303, 1215, 1163, 1032, 1009, 760, 736, 698;
HRMS (ES-I) Calcd for C49H48N2O5P (M+1) 775.3301.
Found 775.3337; Anal. Calcd for C49H47N2O5P: C, 75.95;
H, 6.11; N, 3.62. Found: C, 75.85; H, 6.34; N, 3.34.
1452, 1432, 1410, 1215, 1147, 1093, 947, 758, 698 cmꢀ1
;
HRMS (ES-I) Calcd for C32H34N2OP (M+1) 493.2409.
Found: 493.2433. Anal. Calcd for C32H33N2OP: C, 78.02;
H, 6.75; N, 5.69. Found: C, 77.65; H, 6.69; N, 5.65.
3.13. 2-(N-Benzyl-N-diphenylphosphino-2-aminomethyl-
phenyl)-(4S)-4-benzyl-4,5-dihydrooxazole 8c
20
Yield: 57% as a white solid; mp: 149–152 ꢁC; ½aꢁD ¼ þ51 (c
1
0.30, CHCl3); H NMR (CDCl3): d = 7.69 (m, 1H), 7.33–
7.24 (m, 4H), 7.21–7.18 (m, 3H), 7.13 (br t, J = 7.0 Hz,
3H), 7.06–6.97 (m, 9H), 6.90 (br d, J = 7.0 Hz, 2H), 6.75
(br d, J = 6.5 Hz, 2H), 4.78 (m, 1H), 4.24 (dd,
J = 14.5 Hz, J = 5.0 Hz, 1H), 4.15 (dd, J = 14.5 Hz,
J = 5.5 Hz, 1H), 3.99 (s, 2H), 3.40 (m, 1H), 3.19 (ddd,
J = 15.0 Hz, J = 11.0 Hz, J = 4.0 Hz, 1H), 2.65–2.61 (m,
2H); 13C{1H} NMR (CDCl3): d = 168.9 (s), 141.5 (s),
140.2 (d, J = 13.9 Hz), 139.4 (d, J = 13.4 Hz), 138.1 (d,
J = 1.0 Hz), 137.7 (s), 133.1 (s), 132.8 (d, J = 20.9 Hz),
1313.5 (d, J = 19.9 Hz), 128.9 (s), 128.8 (s), 128.6 (s),
128.4 (s), 128.39 (s), 128.35 (s), 128.2 (s), 127.8 (d,
3.16. 2-(N-Benzyl-N-(+)-TADDOL-2-aminomethylphenyl)-
(4S)-4-i-propyl-4,5-dihydrooxazole 9b
20
Yield: 67% as a white solid; mp: 130–134 ꢁC; ½aꢁD ¼ þ95 (c
1
0.29, CHCl3); H NMR (CD2Cl2) d = 7.69 (m, 1H), 7.57
(m, 2H), 7.39–7.05 (m, 23H), 6.99 (app. t, J = 7.5 Hz,
2H), 6.80 (br d, J = 8.0 Hz, 1H), 5.12 (dd, J = 8.5 Hz,

1100
R. P. J. Bronger, P. J. Guiry / Tetrahedron: Asymmetry 18 (2007) 1094–1102
J = 3.5 Hz, 1H), 4.76 (d, J = 8.5 Hz, 1H), 4.33 (dd,
J = 15.5 Hz, J = 10.5 Hz, 1H), 4.23 (dd, J = 15.0 Hz,
J = 13.5 Hz, 1H), 4.17 (m, 1H), 4.13 (d, J = 17.0 Hz,
1H), 3.84 (d, J = 17.0 Hz, 1H), 3.39 (m, 1H), 3.21 (m,
1H), 1.74 (m, 1H), 1.32 (s, 3H), 0.72 (d, J = 7.0 Hz, 3H),
0.64 (d, J = 7.0 Hz, 3H), 0.15 (s, 3H). 13C{1H} NMR
(CD2Cl2): d = 169.2 (s), 147.1 (s), 146.5 (d, J = 1.9 Hz),
142.2 (s), 142.1 (d, J = 2.0 Hz), 141.8 (d, J = 1.7 Hz),
138.4 (d, J = 1.9 Hz), 133.3 (s), 131.2 (s), 129.7 (s), 129.31
(s), 129.28 (d, J = 4.6 Hz), 128.5 (s), 128.3 (s), 128.1 (s),
128.03 (s), 128.0 (s), 127.9 (s), 127.8 (s), 127.62 (s), 127.59
(s), 127.5 (s), 127.3 (s), 123.7 (s), 123.3 (s), 111.9 (s), 82.3
(d, J = 7.8 Hz), 82.2 (d, J = 21.8 Hz), 82.1 (d,
J = 2.3 Hz), 55.3 (br s), 49.2 (d, J = 22.2 Hz), 46.8 (br s),
44.2 (d, J = 18.6 Hz), 30.7 (s), 27.8 (s), 25.3 (s), 20.3 (s),
20.0 (s); 31P{1H} NMR (CDCl3): d = 140.80; IR (NaCl):
m = 3090, 3065, 2915, 1678, 1495, 1446, 1382, 1371, 1217,
1084, 1049, 1032, 1012, 947, 877, 754, 698 cmꢀ1; HRMS
(ES-I) Calcd for C51H52N2O5P (M+1) 803.3614. Found:
803.3643; Anal. Calcd for C51H51N2O5P: C, 76.29; H,
6.40; N, 3.49. Found: C, 76.06; H, 6.38; N, 3.25.
mixture was allowed to react for 2 days at room tempera-
ture. The salts were removed by filtration of the reaction
mixture over MgSO4, which was followed by removal of
the organics in vacuo. After column chromatography on
silica (CH2Cl2), the product was isolated as a white solid.
(Yield: 64–71%).
3.19. 2-(N-Benzyl-N-(ꢀ)-TADDOL-2-aminomethylphenyl)-
(4S)-4-methyl-4,5-dihydrooxazole 10a
20
Yield: 71% as a white solid; mp: 126–129 ꢁC; ½aꢁD ¼ ꢀ121:2
1
(c 0.33, CHCl3); H NMR (CD2Cl2): 7.66–7.64 (m, 1H),
7.46–7.41 (m, 4H), 7.37–7.34 (m, 2H), 7.30–7.26 (m, 5H),
7.30–7.25 (m, 4H), 7.18–7.09 (m, 11H), 7.07–7.03 (m,
3H), 4.99 (dd, J = 8.5 Hz, J = 3.5 Hz, 1H), 4.74 (d,
J = 8.5 Hz, 1H), 4.65 (m, 1H), 4.47 (dd, J = 15.5 Hz,
J = 8.0 Hz, 1H), 4.35 (d, J = 16.5 Hz, 1H), 4.27 (dd,
J = 15.5 Hz, J = 5.0 Hz, 1H), 4.16 (d, J = 16.5 Hz, 1H),
3.27 (m, 1H), 2.89 (m, 1H), 1.17 (s, 3H), 1.03 (d,
J = 7.0 Hz, 3H), 0.20 (s, 3H); 13C{1H} NMR (CD2Cl2):
d = 168.3 (s), 147.3 (s), 146.6 (d, J = 1.5 Hz), 142.4 (s),
141.9 (s), 141.7 (d, J = 1.7 Hz), 138.7 (d, 1.7 Hz), 133.6
(s), 131.3 (s), 129.5 (s), 129.2 (s), 129.0 (d, J = 6.1 Hz),
128.7 (s), 128.5 (s), 128.1 (s), 128.0 (s), 127.8 (s), 127.7
(s), 127.53 (br s), 127.48 (s), 127.4 (s), 123.5 (s), 123.2 (s),
112.2 (s), 82.8 (s), 82.7 (d, J = 20.4 Hz), 82.3 (d,
J = 3.6 Hz), 82.1 (d, J = 9.3 Hz), 48.4 (d, J = 15.5 Hz),
48.2 (d, J = 28.5 Hz), 45.6 (d, J = 3.1 Hz), 44.2 (d,
J = 4.1 Hz), 27.6 (s), 25.5 (s), 16.9 (s); 31P{1H} NMR
(CD2Cl2): d = 140.85; IR (NaCl): m = 3089, 3056, 2989,
2933, 1680, 1495, 1470, 1448, 1304, 1265, 1213, 1162,
1088, 1036, 1007, 737, 698 cmꢀ1; HRMS (ES-I) Calcd for
C49H48N2O5P (M+1) 775.3301. Found: 775.3286; Anal.
Calcd for C49H47N2O5P: C, 75.95; H, 6.11; N, 3.62. Found:
C, 76.15; H, 6.40; N, 3.18.
3.17. 2-(N-Benzyl-N-(+)-TADDOL-2-aminomethylphenyl)-
(4S)-4-benzyl-4,5-dihydrooxazole 9c
20
Yield: 72% as a white solid; mp: 156–159 ꢁC; ½aꢁD ¼ þ55 (c
1
0.29, CHCl3); H NMR (CD2Cl2): d = 7.65–7.60 (m, 3H),
7.48–7.46 (m, 2H), 7.35–7.28 (m, 8H), 7.21–7.09 (m,
15H), 7.06–6.98 (m, 3H), 6.96–6.94 (m, 1H), 6.93–6.91
(m, 1H), 5.16 (dd, J = 8.5 Hz, J = 3.5 Hz, 1H), 4.77 (d,
J = 8.5 Hz, 1H), 4.64 (m, 1H), 4.40 (dd, J = 15.0 Hz,
J = 10.5 Hz, 1H), 4.29 (dd, J = 15.0 Hz, J = 10.5 Hz,
1H), 3.93 (s, 2H), 3.38 (m, 1H), 3.31 (m, 1H), 2.97 (dd,
J = 14.5 Hz, J = 5.0 Hz, 1H), 2.82 (dd, J = 14.5 Hz,
J = 10.5 Hz, 1H), 1.31 (s, 3H), 0.18 (s, 3H); 13C{1H}
NMR (CD2Cl2): d = 168.6 (s), 147.2 (s), 146.5 (d,
J = 1.9 Hz), 142.2 (d, J = 1.8 Hz), 142.0 (s), 141.9 (d,
J = 1.4 Hz), 138.9 (d, J = 2.1 Hz), 138.6 (d, J = 2.1 Hz),
133.4 (s), 131.3 (s), 129.23 (d, J = 4.9 Hz), 129.2 (s), 129.0
(s), 128.7 (s), 128.5 (s), 128.2 (s), 128.04 (s), 127.96 (s),
127.9 (s), 127.8 (s), 127.7 (s), 127.6 (s), 127.5 (s), 126.6
(s), 123.5 (s), 123.2 (s), 112.1 (s), 83.2 (d, J = 3.8 Hz),
82.5 (d, J = 21.3 Hz), 82.4 (d, J = 8.4 Hz), 82.3 (d,
J = 1.4 Hz), 52.2 (br s), 50.0 (d, J = 19.9 Hz), 47.4 (br s),
47.4 (d, J = 20.9 Hz), 37.1 (s), 27.8 (s), 25.3 (s); 31P{1H}
NMR (CDCl3): d = 141.06; IR (NaCl): m = 3087, 3062,
3006, 2912, 1680, 1495, 1448, 1383, 1372, 1215, 1162,
1084, 1049, 1032, 1011, 877, 755, 736, 698 cmꢀ1; HRMS
(ES-I) calcd for C55H52N2O5P (M+1) 851.3614. Found:
851.3649; Anal. Calcd for C55H52N2O5P: C, 77.63; H,
6.04; N, 3.29. Found: C, 77.38; H, 6.11; N, 3.24.
3.20. 2-(N-Benzyl-N-(ꢀ)-TADDOL-2-aminomethylphenyl)-
(4S)-4-i-propyl-4,5-dihydrooxazole 10b
20
Yield: 64% as a white solid; mp: 136–139 ꢁC; ½aꢁD ¼ ꢀ145
(c 0.31, CHCl3); 1H NMR (CD2Cl2): d = 7.68–7.66 (m,
1H), 7.48–7.44 (m, 2H), 7.36–7.24 (m, 4H), 7.24–7.20 (m,
7H), 7.17–7.01 (m, 12H), 7.00–6.98 (m, 2H), 6.95 (d,
J = 6.5 Hz, 1H), 4.93 (dd, J = 8.0 Hz, J = 3.5 Hz, 1H),
4.75 (d, J = 8.5 Hz, 1H), 4.50 (d, J = 16.0 Hz, 1H), 4.48
(dd, J = 16.0 Hz, J = 7.0 Hz, 1H), 4.16 (m, 1H), 4.09 (dd,
J = 15.5 Hz, J = 11.5 Hz, 1H), 4.06 (d, J = 17.0 Hz, 1H),
3.30 (m, 1H), 3.04 (m, 1H), 1.69 (m, 1H), 1.08 (s, 3H),
0.65 (d, J = 6.5 Hz, 6H), 0.23 (s, 3H); 13C{1H} NMR
(CD2Cl2): d = 169.2 (s), 147.3 (s), 146.8 (d, J = 1.4 Hz),
142.4 (d, J = 1.4 Hz), 142.0 (s), 141.7 (d, J = 1.8 Hz),
138.6 (br s), 129.5 (s), 129.4 (s), 129.0 (d, J = 11.7 Hz),
128.7 (s), 128.5 (s), 128.1 (s), 128.0 (s), 127.8 (s), 127.7
(s), 127.6 (s), 127.5–127.4 (multiple signals), 123.7 (s),
123.2 (s), 112.3 (s), 83.3 (d, J = 2.3 Hz), 82.7 (d,
J = 20.1 Hz), 82.1 (d, J = 8.8 Hz), 82.0 (d, J = 3.8 Hz),
54.5 (br s), 48.1 (d, J = 14.5 Hz), 46.7 (br s), 44.5 (d,
J = 29.4 Hz), 30.4 (s), 27.5 (s), 25.6 (s), 20.2 (s), 20.1 (s);
31P{1H} NMR (CDCl3): d = 141.43; IR (NaCl): m = 3087,
3060, 3005, 2966, 2935, 2873, 1680, 1495, 1470, 1448,
1412, 1371, 1248, 1217, 1165, 1086, 1051, 1011, 945, 883,
750, 698 cmꢀ1; HRMS (ES-I) Calcd for C51H52N2O5P
3.18. General synthesis of 2-(N-benzyl-N-(ꢀ)-TADDOL-2-
aminomethylphenyl)-(4S)-4-R-4,5-dihydrooxazole (R = Me,
i-Pr, Benzyl) 10
To
a
stirred solution of 0.233 g of (ꢀ)-TADDOL
(0.5 mmol) and 0.25 mL of Et3N (0.182 g, 1.8 mmol) in
2 mL of CH2Cl2 was added 42 lL of PCl3 at 0 ꢁC. Immedi-
ately, a precipitate was formed and the reaction mixture
was allowed to react for 1 h. Next, a solution of 7
(0.5 mmol) in 2 mL of CH2Cl2 was added dropwise. The

R. P. J. Bronger, P. J. Guiry / Tetrahedron: Asymmetry 18 (2007) 1094–1102
1101
(M+1) 803.3614. Found: 803.3608; Anal. Calcd for
C51H51N2O5P: C, 76.29; H, 6.40; N, 3.49. Found: C,
75.82; H, 6.36; N, 3.23.
Column chromatography on silica gave pure product 17
as a white crystalline solid. The enantiomeric excess was
determined by chiral HPLC (Chiralcel OJ, hexanes/etha-
nol/methanol = 1000/5/3.5, flow = 1.0 mL minꢀ1, tr(R) =
7.0 min, tr(S) = 10.6 min, k = 254 nm). Specific rotations
were compared to literature values. It is crucial to remove
all 1-bromonaphthalene starting material as this com-
pound overlaps with the (R)-enantiomer of the product
in HPLC.
3.21. 2-(N-Benzyl-N-(ꢀ)-TADDOL-2-aminomethylphenyl)-
(4S)-4-benzyl-4,5-dihydrooxazole 10c
20
Yield: 70% as a white solid; mp: 136–139 ꢁC; ½aꢁD ¼ ꢀ112
(c 0.28, CHCl3); 1H NMR (CD2Cl2): d = 7.60–7.58 (m,
1H), 7.45 (bd, J = 7.5 Hz, 2H), 7.35 (m, 4H), 7.30–7.00
(m, 24H), 6.98–6.96 (m, 1H), 6.94–6.92 (m, 2H), 4.99 (dd,
J = 8.5 Hz, J = 3.5 Hz, 1H), 4.78 (d, J = 8.5 Hz, 1H),
4.70 (m, 1H), 4.45 (dd, J = 15.0 Hz, J = 8.0 Hz, 1H),
4.25–4.20 (m, 2H), 4.04 (d, J = 16.5 Hz, 1H), 3.41 (m,
1H), 3.08 (m, 1H), 2.77–2.70 (m, 2H), 1.15 (s, 3H), 0.22
(s, 3H); 13C{1H} NMR (CD2Cl2): d = 168.7 (s), 147.3 (s),
146.7 (d, J = 1.9 Hz), 142.3 (d, J = 1.9 Hz), 141.9 (s),
141.7 (d, J = 1.9 Hz), 138.7 (d, J = 1.6 Hz), 138.4 (s),
131.3 (s), 129.6 (s), 129.3 (s), 129.1 (d, J = 6.1 Hz), 129.0
(s), 128.8 (s), 128.7 (s), 128.5 (s), 128.1 (s), 128.0 (s),
127.9 (s), 127.7 (s), 127.6 (multiple C’s), 127.4 (s), 126.6
(s), 123.6 (s), 123.1 (s), 112.3 (s), 83.1 (d, J = 0.9 Hz),
82.6 (d, J = 20.4 Hz), 82.3 (d, J = 3.8 Hz), 82.2 (d,
J = 8.8 Hz), 50.9 (br s), 49.0 (d, J = 15.9 Hz), 47.1 (d,
J = 26.5 Hz), 47.0 (br s), 37.3 (s), 27.6 (s), 25.5 (s);
31P{1H} NMR (CDCl3): d = 141.40; IR (NaCl): m = 3087,
3062, 3008, 2915, 1680, 1494, 1448, 1217, 1163, 1103,
1088, 947, 883, 756, 737, 700 cmꢀ1; HRMS (ES-I) calcd
for C55H52N2O5P (M+1) 851.3614. Found: 851.3623;
Anal. Calcd for C55H52N2O5P: C, 77.63; H, 6.04; N,
3.29. Found: C, 77.51; H, 6.31; N, 3.15.
Acknowledgements
We wish to thank Enterprise Ireland for a Basic and Stra-
tegic Research Scholarship (SC2003-341) to support
R.P.J.B. We also acknowledge the facilities of the Centre
for Synthesis and Chemical Biology (CSCB), which was
funded through the Higher Education Authority’s Pro-
gramme for Research in Third-Level Institutions (PRTLI).
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