Synthesis of pseudo-geminal-, pseudoo-ortho-, and ortho-phosphinyl- oxazolinyl-[2.2]paracyclophanes for use as ligands in asymmetric catalysis

Article abstract of DOI:10.1021/jo060668h

Syntheses of three regioisomers of aromatic-substituted phosphinyl-oxazolinyl-[2.2]paracyclophanes, pseudo-geminal, pseudo-ortho, and ortho, have been carried out or, in the latter two cases, newly developed. It has, therefore, been demonstrated that all

Full text of DOI:10.1021/jo060668h

Synthesis of Pseudo-geminal-, Pseudo-ortho-, and
ortho-Phosphinyl-oxazolinyl-[2.2]paracyclophanes for Use as Ligands
in Asymmetric Catalysis
Daniel K. Whelligan and Carsten Bolm*
Institut f u¨ r Organische Chemie der RWTH Aachen, Landoltweg 1, D-52074 Aachen, Germany
carsten.bolm@oc.rwth-aachen.de
ReceiVed March 28, 2006
Syntheses of three regioisomers of aromatic-substituted phosphinyl-oxazolinyl-[2.2]paracyclophanes,
pseudo-geminal, pseudo-ortho, and ortho, have been carried out or, in the latter two cases, newly developed.
It has, therefore, been demonstrated that all aromatic-substituted isomers relevant for use as chelating
ligands for asymmetric catalysis are accessible. These P,N-ligands, along with their diastereoisomers,
were shown to exhibit widely differing activity and enantioselectivity (up to 89% ee) in the Pd-catalyzed
asymmetric allylic alkylation reaction.
Introduction
for asymmetric catalysts. Despite this, all studies to date have
concentrated on the development and use of ligands based on
only one of these patterns. The closest exception involves the
Planar chiral-substituted [2.2]paracyclophanes have often been
used as ligands in asymmetric catalysis.1,2 Perhaps the most
famous example is PHANEPHOS, a planar chiral equivalent
of BINAP, which, among other applications,3 exhibited a
higher activity and enantioselectivity than BINAP in the Rh-
catalyzed hydrogenation of the tetrahydropyrazine precursor to
synthesis of iso-FHPC, the pseudogeminal analogue of 5-formyl-
9-13
4
-hydroxy[2.2]paracyclophane (FHPC).
FHPC is an estab-
-7
14,15
lished precursor to [2.2]paracyclophane Schiff bases, salens,
which have been used in asymmetric
additions of diorganozincs to aldehydes and imines,
16,17
and hydroxy-amines,
18,19
sul-
8
the HIV protease inhibitor Crixivan (86 vs 56% ee).
There are three aromatic disubstitution patterns available to
2.2]paracyclophane that give compounds geometrically capable
of chelating a metal and, therefore, applicable as chiral ligands
(
9) Rozenberg, V.; Kharitonov, V.; Antonov, D.; Sergeeva, E.; Aleshkin,
A.; Ikonnikov, N.; Orlova, S.; Belokon, Y. Angew. Chem., Int. Ed. Engl.
994, 33, 91.
[
1
(10) Hopf, H.; Barrett, D. G. Liebigs Ann. 1995, 449.
(
11) Antonov, D. Y.; Belokon, Y. N.; Ikonnikov, N. S.; Orlova, S. A.;
(
1) Rozenberg, V.; Sergeeva, E.; Hopf, H. In Modern Cyclophane
Pisarevsky, A. P.; Raevski, N. I.; Rozenberg, V. I.; Sergeeva, E. V.;
Struchkov, Y. T.; Tararov, V. I.; Vorontsov, E. V. J. Chem. Soc., Perkin
Trans. 1 1995, 1873.
(12) Pamperin, D.; Schulz, C.; Hopf, H.; Syldatk, C.; Pietzsch, M. Eur.
J. Org. Chem. 1998, 1441.
Chemistry; Gleiter, R., Hopf, H., Eds.; Wiley-VCH: New York, 2004; p
4
1
35.
(2) Review: Gibson, S. E.; Knight, J. D. Org. Biomol. Chem. 2003, 1,
256.
(
3) Dyer, P. W.; Dyson, P. J.; James, S. L.; Martin, C. M.; Suman, P.
Organometallics 1998, 17, 4344.
4) Pye, P. J.; Rossen, K.; Reamer, R. A.; Volante, R. P.; Reider, P. J.
Tetrahedron Lett. 1998, 39, 4441.
5) (a) Rossen, K.; Pye, P. J.; Maliakal, A.; Volante, R. P. J. Org. Chem.
1
9
(13) Rozenberg, V. I.; Antanov, D. Y.; Sergeeva, E. V.; Vorontsov, E.
V.; Starikova, Z. A.; Fedyanin, I. V.; Schulz, C.; Hopf, H. Eur. J. Org.
Chem. 2003, 2056.
(14) Danilova, T. I.; Rozenberg, V. I.; Vorontsov, E. V.; Starikova, Z.
A.; Hopf, H. Tetrahedron: Asymmetry 2003, 14, 1375.
(15) Issberner, J.; B o¨ hme, M.; Grimme, S.; Nieger, M.; Paulus, W.;
V o¨ gtle, F. Tetrahedron: Asymmetry 1996, 7, 2223.
(
(
997, 62, 6462. (b) Pye, P. J.; Rossen, K.; Volante, R. P. PCT Appl. WO
7/47632, 1997.
(
6) Burk, M. J.; Hems, W.; Herzberg, D.; Malan, C.; Zanotti-Gerosa, A.
Org. Lett. 2000, 2, 4173.
7) Dominguez, B.; Zanotti-Gerosa, A.; Hems, W. Org. Lett. 2004, 6,
927.
8) Pye, P. J.; Rossen, K.; Reamer, R. A.; Tsou, N. N.; Volante, R. P.;
Reider, P. J. J. Am. Chem. Soc. 1997, 119, 6207.
(16) (a) Rozenberg, V. I.; Danilova, T. I.; Sergeeva, E. V.; Shouklov, I.
A.; Starikova, Z. A.; Hopf, H.; K u¨ hlein, K. Eur. J. Org. Chem. 2003, 432.
(b) For similar use of ketimine derivatives, see: Rozenberg, V. I.; Danilova,
T. I.; Sergeeva, E. V.; Vorontsov, E.; Starikova, Z.; Lysenko, K.; Belokon,
Y. Eur. J. Org. Chem. 2000, 3295.
(
1
(
(17) Dahmen, S.; Br a¨ se, S. Tetrahedron: Asymmetry 2001, 12, 2845.
1
0.1021/jo060668h CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/18/2006
J. Org. Chem. 2006, 71, 4609-4618
4609

Whelligan and Bolm
foxidations,20 and the trimethylsilylcyanation of benzaldehyde.21
However, to the best of our knowledge, the conversion of iso-
FHPC into similar ligands and their use in asymmetric catalysis
has not yet been published. We, therefore, decided to address
this general absence by demonstrating that all three aromatic-
disubstituted [2.2]paracyclophane isomers can be synthesized
using established [2.2]paracyclophane chemistry and that they
are all effective as ligands in asymmetric catalysis. The
compounds chosen were the oxazolinyl-phosphinyl-[2.2]para-
2
2,23
cyclophanes, P,N-ligands
designed by Pelter et al. and Hou
et al.2 Hou showed that the use of the pseudogeminal isomers
4,25
gave up to 90% ee in the Pd-catalyzed allylic alkylation
26
reaction. This paper will describe the syntheses of the pseudo-
geminal, pseudo-ortho, and ortho analogues of these compounds
(Figure 1) and compare their effectiveness as ligands in the same
allylic alkylation reaction.
Results and Discussion
By taking advantage of literature-described directing effects,
we were able to synthesize both diastereoisomers of each of
the three desired aryl-substituted regioisomers of phosphinyl-
oxazolinyl-[2.2]paracyclophane 1-3. iso-Propyl was chosen as
the substituent on the oxazoline ring on account of the inexpense
of the amino alcohol required (valinol) and its effectiveness as
a sterically demanding group that is not so bulky as to inhibit
reactions.
FIGURE 1. All isomers of the aromatic-substituted [2.2]paracyclo-
phane for use as P,N-ligands.
Synthesis of Pseudo-geminal Isomers. Following previously
SCHEME 1. Synthesis of Pseudo-geminal-phosphinyl-
oxazolinyl-[2.2]paracyclophanes
described syntheses of 1 and similar derivatives,2
4,25,27,28
racemic
carboxylic acid 4 was converted to the acid chloride, reacted
2
9
with L-valinol and cyclized under Bryce’s conditions to give
an inseparable mixture of diastereoisomers 5 (Scheme 1). The
pseudogeminal substitution pattern was attained by exploiting
a directing effect, which occurs during iron-catalyzed bromi-
nation.30 The resulting bromides 6a and 6b were separable by
(18) (a) Danilova, T. I.; Rozenberg, V. I.; Sergeeva, E. V.; Starikova, Z.
A.; Br a¨ se, S. Tetrahedron: Asymmetry 2003, 14, 2013. (b) Danilova, T. I.;
Rozenberg, V. I.; Starikova, Z. A.; Br a¨ se, S. Tetrahedron: Asymmetry 2004,
1
5, 223. (c) Br a¨ se, S.; Dahmen, S.; H o¨ fener, S.; Lauterwasser, F.; Kreis,
M.; Ziegert R. E. Synlett 2004, 2647. For a similar use of ketimine
derivatives, see: (d) Lauterwasser, F.; Nieger, M.; Mansikkam a¨ ki, H.;
N a¨ ttinen, K.; Br a¨ se, S. Chem.sEur. J. 2005, 11, 4509. (e) Dahmen, S.;
Br a¨ se, S. Chem. Commun. 2002, 26. (f) H o¨ fener, S.; Lauterwasser, F.; Br a¨ se,
S. AdV. Synth. Catal. 2004, 346, 755.
(
19) Hermanns, N.; Dahmen, S.; Bolm, C.; Br a¨ se, S. Angew. Chem., Int.
Ed. 2002, 41, 3692.
20) (a) Vetter, A. H.; Berkessel, A. Tetrahedron Lett. 1998, 39, 1741.
(
For the use of other [2.2]paracyclophane-derived ligands in asymmetric
sulfoxidations, see: (b) Bolm, C.; K u¨ hn, T. Synlett 2000, 899. (c) Bolm,
C.; K u¨ hn, T. Isr. J. Chem. 2001, 41, 263. (d) Bolm, C.; Beckmann, O.;
K u¨ hn, T.; Palazzi, C.; Adam, W.; Bheema Rao, P.; Saha-M o¨ ller, C. R.
Tetrahedron: Asymmetry 2001, 12, 2441.
(
21) Belokon, Y.; Moscalenko, M.; Ikonnikov, N.; Yashkina, L.; An-
tonov, D.; Vorontsov, E.; Rozenberg, V. Tetrahedron: Asymmetry 1997,
, 3245.
8
(
(
(
22) Guiry, P. J.; Saunders, C. P. AdV. Synth. Catal. 2004, 346, 497.
23) McManus, H. A.; Guiry, P. J. Chem. ReV. 2004, 104, 4151.
24) Marchand, A.; Maxwell, A.; Mootoo, B.; Pelter, A.; Reid, A.
column chromatography. However, this reaction rarely pro-
ceeded to completion, even if commercial FeBr2 or FeBr3 was
used as catalyst, and bromide 6a often had to be used in the
next step as an inseparable mixture with 5. The bromides 6 were
converted to the target compounds 1 by bromo-lithium
exchange using t-BuLi followed by reaction with ClPPh2.
Interestingly, it was found that the diastereomeric phosphines
1a and 1b could be far more easily separated from the
Tetrahedron 2000, 56, 7331.
25) Wu, X.-W.; Yuan, K.; Sun, W.; Zhang, M.-J.; Hou, X.-L. Tetra-
hedron: Asymmetry 2003, 14, 107.
26) Reviews: (a) Trost, B. M. J. Org. Chem. 2004, 69, 5813. (b) Trost,
B. M.; Crawley, M. L. Chem. ReV. 2003, 103, 2921. (c) Helmchen, G. J.
Organomet. Chem. 1999, 576, 203. (d) Trost, B. M. Acc. Chem. Res. 1996,
(
(
2
9, 355. (e) Trost, B. M.; Vranken, D. L. V. Chem. ReV. 1996, 96, 395.
27) Wu, X.-W.; Hou, X.-L.; Dai, L.-X.; Tao, J.; Cao, B.-X.; Sun, J.
Tetrahedron: Asymmetry 2001, 12, 529.
(
(28) Bolm, C.; Wenz, K.; Raabe, G. J. Organomet. Chem. 2002, 662,
2
3.
(
29) Chesney, A.; Bryce, M. R. Tetrahedron: Asymmetry 1996, 7, 3247.
(30) Reich, H. J.; Cram, D. J. J. Am. Chem. Soc. 1969, 91, 3505.
4610 J. Org. Chem., Vol. 71, No. 12, 2006

Phosphinyl-oxazolinyl-[2.2]paracyclophanes
SCHEME 2. Access to Pseudo-ortho-Substituted
tives, a novel workup procedure was developed, and the yields
improved to 34 and 32%. This procedure is described later in
the “Asymmetric Catalysis” section.
[2.2]Paracyclophanes
The absolute configurations of 2a and 2b were determined
by the synthesis of 2b from enantiopure dibromide (+)-(SP)-8.
This was obtained by resolution of the racemate by preparative
chiral HPLC (see Experimental Section).
Synthesis of ortho Isomers. ortho-Substituted phosphinyl-
oxazolinyl-[2.2]paracyclophanes similar to 3 (Figure 1) have
been previously synthesized in our group by a metal-phosphine
SCHEME 3. Synthesis of
Pseudo-ortho-phosphinyl-oxazolinyl-[2.2]paracyclophanes
2
8
exchange of ortho-oxazolinyl-palladacycles. Although ef-
ficient, the use of stoichiometric (1.1 equiv) palladium acetate
is expensive, so an alternative procedure was sought. Attempted
ortho-directed lithiations proved problematic due to the com-
petitive 1,2-addition of the alkyllithium to the oxazoline and
the 1,4-addition to the [2.2]paracyclophane backbone.28 Hou,
however, showed that ortho-lithiation of the diastereotopic
mixture of oxazolinyl[2.2]paracyclophanes 5, using n-BuLi with
TMEDA in Et2O, was successful and that after quenching with
PhSSPh or PhSeSePh, a mixture of the desired ortho products,
as well as those resulting from lithiation at the benzylic position,
3
4,35
were obtained.
An attempt by us to synthesize phosphines
3
by carrying out Hou’s lithiation and then adding ClPPh2 led
to a mixture of products (including 17% starting material), none
of which could be identified as the desired phosphines 3.
oxazolinyl[2.2]paracyclophane byproducts (resulting from pro-
tonation of the lithium intermediates) by column chromatog-
raphy if a three-component solvent system (pentane/DCM/
EtOAc [20:4:1]) was used instead of the more usual two-
component system (pentane/EtOAc).
Hence, the ortho-substitution pattern was obtained by ortho-
lithiation of the carbamate 11 (Scheme 4), a reaction which has
been shown to proceed readily and highly regioselectively when
1
0,36,37
s-BuLi is used in the presence of TMEDA.
According to
The absolute configurations of 1 were checked by preparation
of 6a, in the same manner, from enantiopure carboxylic acid
the literature, lithiation of 11 followed by reaction with DMF
and an acidic workup leads to the ortho-hydroxy-aldehyde
FHPC (see Introduction), in 64% yield, as a result of the facile
hydrolysis of the carbamate during workup. We desired the
carboxylic acid rather than the aldehyde, so gaseous CO2 was
used as the electrophile in place of DMF. Interestingly, the yield
was higher and the carbamate was left intact. In view of our
synthetic plan, this was actually a useful result, as it acted as a
protecting group during subsequent amidation of the carboxylic
acid to give separable diastereoisomers 13. The absolute
configurations of 13 were determined by the synthesis of 13b
from enantiopure (-)-(RP)-11, which itself was obtained in two
steps from enantiopure bromo[2.2]paracyclophane. The latter
compound was synthesized by monolithiation and protonation
of enantiopure dibromide 8. Unfortunately, removal of the
carbamate from 13 was impossible under acidic conditions, and
forcing basic conditions (NaOH, MeOH, reflux, 20 h), although
successful, gave 15 in low yields along with the carbamate-
migrated byproducts 14. The carbamates 14 could only be
hydrolyzed under yet harsher conditions (KOH, i-PrOH, reflux,
3
1
(-)-(RP)-4.
Synthesis of Pseudo-Ortho Isomers. The pseudo-ortho
substitution pattern was set up early on in the synthesis by
starting from dibromide 8, prepared according to the procedure
3
2a
8
by Reich and Cram with the improvements of Pye and et al.
and Braddock et al.32b (Scheme 2). Its synthesis involves
dibromination of [2.2]paracyclophane to give a mixture of
isomers from which the highly insoluble pseudo-para dibromide
7
can be crystallized. Thermal isomerization of 7 leaves the
pure pseudo-ortho-dibromide 8 alone in solution after cooling.
Dibromide 8 was converted to the monocarboxylic acid 9,
as previously described.33 This was then converted to the
diastereotopic bromo-oxazolinyl [2.2]paracyclophanes 10 (Scheme
3
) in the same manner as for the pseudo-geminal compounds
described above. Oxazolines 10a and 10b were inseparable at
this stage, but the corresponding phosphines 2, synthesized by
lithiation and reaction with ClPPh2, had different Rf values on
silica, so could be separated by chromatography. Using the
standard technique, yields of only 9 and 11% of 2a and 2b,
respectively, were obtained and this was attributed to phosphine
oxidation during workup and lengthy chromatographic separa-
tion. This was despite degassing of the solvents prior to use by
bubbling argon through them while under sonication. However,
during later research with 4-methoxyphenylphosphine deriva-
5
1 h). The overall calculated yields of 15a and 15b, from 13a
(34) Hou, X.-L.; Wu, X.-W.; Dai, L.-X.; Cao, B.-X.; Sun, J. Chem.
Commun. 2000, 1195.
35) Hou, X. L.; You, S. L.; Tu, T.; Deng, W. P.; Wu, X. W.; Li, M.;
Yuan, K.; Zhang, T. Z.; Dai, L.-X. Top. Catal. 2005, 35, 87.
36) See also: Pelter, A.; Mootoo, B.; Maxwell, A.; Reid, A. Tetrahedron
(
(
(
31) Rozenberg, V.; Dubrovina, N.; Sergeeva, E.; Antonov, D.; Beloko n´ ,
Y. Tetrahedron: Asymmetry 1998, 9, 653.
32) (a) Reich, H. J.; Cram, D. J. J. Am. Chem. Soc. 1969, 91, 3527. (b)
Braddock, D. C.; MacGilp, I. D.; Perry, B. G. J. Org. Chem. 2002, 67,
Lett. 2001, 42, 8391.
(37) (a) Diisopropylcarbamate is equally ortho directing. See: Focken,
T.; Hopf, H.; Snieckus, V.; Dix, I.; Jones, P. G. Eur. J. Org. Chem. 2001,
2221. For reviews on directed metalations, see: (b) Snieckus, V. Chem.
ReV. 1990, 90, 879. (c) Anctil, E. J.-G.; Snieckus, V. J. Organomet. Chem.
2002, 653, 150. (d) Hartung, C. G.; Snieckus, V. In Modern Arene
Chemistry; Astruc, D., Ed.; Wiley-VCH: New York, 2002; p 330.
(
8
679.
(33) Bolm, C.; Focken, T.; Raabe, G. Tetrahedron: Asymmetry 2003,
1
4, 1733.
J. Org. Chem, Vol. 71, No. 12, 2006 4611

Whelligan and Bolm
SCHEME 4. Synthesis of ortho-Phosphinyl-oxazolinyl-[2.2]paracyclophanes, Part 1
SCHEME 5. Synthesis of ortho-Phosphinyl-oxazolinyl-
2.2]paracyclophanes, Part 2
TABLE 1. Palladium-Catalyzed Asymmetric Allylic Alkylation
[
time
(h)
yield
(%)
ee
(%)
entry
ligand
substitution
abs. config.
1
2
3
4
5
6
7
8
9
1a
1b
2a
2b
3a
3b
19a
19b
pseudogem.
pseudogem.
pseudo-ortho
pseudo-ortho
ortho
6
8
10
10
8
7
5
20
5
20
>98
96
56a
30
82
28
23
47
89
63
89
62
(S)
(S)
(S)
(R)
(S)
(S)
(S)
(R)
(R)
(S)
>98
>98
>98
>98
>98
>98
>98
>98
ortho
pseudo-ortho
pseudo-ortho
pseudo-ortho
pseudo-ortho
b
22a
1
0
22bb
a
Hou et al. obtained 62% ee (ref 25). b Pseudoenantiomer of 2 (see text).
and 13b, over these two steps are 69 and 56%, respectively.
Strangely, when these same conditions were applied to the
starting carbamates 13 directly, a reduced overall yield of 15a,
but increased yield of 15b, was observed (hydrolysis of 13a,
the compounds’ conformations. The chemical shift of the CH
proton in the oxazoline ring (identified by COSY, DEPT, and
HETCOR NMR experiments) is 3.33 ppm for 3a and 2.99 ppm
for 3b. The increased shielding occurring in 3b is attributed to
delocalization of electron density from the P lone pair, through
the π-system, onto the N atom of the oxazoline ring. Cor-
34% of product, 8% of SM; hydrolysis of 13b, 60% of product,
0
% of SM). An attempt was also made to carry out carbamate
hydrolysis after formation of the oxazoline 16a, but this was
unsuccessful and only the ring-opened product 13a (actually
the precursor of 16a) could be isolated in 10% yield.
On treatment with Tf2O, the hydroxy-amides 15 underwent
simultaneous cyclization and triflation38 of the phenol group to
give oxazolinyl-triflates 18 (Scheme 5). Subsequent nucleophilic
aromatic substitution of the triflate with Ph2PK gave the desired
ortho-phosphinyl-oxazolines 3. Inspection of the NMR spectra
of 3a and 3b is very interesting and reveals information about
31
respondingly, P NMR of 3b shows the P atom to be more
deshielded (1.48 ppm) than that of 3a (0.20 ppm). In conclusion,
3b must have the oxazoline, P lone pair and [2.2]paracyclophane
aromatic ring in conjugation, whereas 3a does not.
Asymmetric Catalysis. Asymmetric allylic alkylation was
chosen as a test reaction for the new ligands to make a good
comparison with the work with compounds 1 of Hou et al.25
As hoped, a different positional isomer of the same ligand gave
a much higher ee; pseudo-ortho-2a gave 82% ee, where the
original pseudo-geminal derivative gave 56% ee (Table 1).
(
38) Ortner, B.; H u¨ bner, H.; Gmeiner, P. Tetrahedron: Asymmetry 2001,
1
2, 3205.
4612 J. Org. Chem., Vol. 71, No. 12, 2006

Phosphinyl-oxazolinyl-[2.2]paracyclophanes
SCHEME 6. Ligand Optimization: Synthesis of
Phenyl-oxazolines
FIGURE 2. Cartoons of speculative Pd complexes with pseudogeminal
and pseudo-ortho ligands.
FIGURE 3. Ligand optimization: 4-methoxyphenylphosphines.
Rather than simply being an effect of the bite angle at the
metal in the active catalyst, this result must arise from the chiral
environment being entirely different to that of the complex
formed with 1a. As shown in Figure 2, in 1a, half of the [2.2]-
paracyclophane backbone shields one side of the active site,
whereas 2a could form a pseudo-C2-symmetric-type complex.
This argument is especially relevant when one considers that
the opposite diastereoisomers of the pseudo-ortho ligands gave
opposite enantiomers of the product (entries 3 and 4), whereas
the pseudo-geminal and -ortho ligands gave the same enantiomer
(entries 1, 2, 5, and 6). The latter selectivities must depend more
strongly on the stereochemistry of the oxazoline substituent than
that of the [2.2]paracyclophane backbone, and the conformations
shown in Figure 2 are in accord with this.
Although these arguments account for the selectivity differ-
ences stemming from the various ligand types, they cannot fully
explain the observed selectivity values, because the complete
mechanistic scenario must also consider the exo/endo isomerism
of the substrate allyl fragment. However, no information is
available on that aspect at the present time.
Hou showed that the allylic alkylation could be optimized
by using derivatives of the pseudo-geminal compounds with a
di(4-methoxyphenyl)phosphinyl group in place of the diphe-
nylphosphinyl group. We, therefore, synthesized such derivatives
6
) possessing phenyl-substituted oxazoline units. (It should be
noted that the Ph-substituted products 22 were pseudoenanti-
omers of the i-Pr-analogues 2 because D-phenylglycinol was
used. Accordingly, the products from the allylic alkylation
reaction were the opposite enantiomers.) It was also found that
the diastereoisomers could be separated at the amide stage.
Cyclization to the oxazolines 21 required harsher conditions than
the i-Pr analogues; an extra equivalent of each reagent was
added, and the mixture was heated at 50 °C for an additional 4
h. Heating was necessary as a result of the lower solubility of
the starting amides 20. Once again, the absolute configurations
of 21 were assigned by the synthesis of 21a from enantiopure
1
9 of the pseudo-ortho compounds (Figure 3), using the same
technique as for 2, but using (MeOC6H4)2PCl instead of Ph2-
PCl. These electron-rich phosphines were found to be more
susceptible to oxidation, and the oxides could not be reduced
8
by the usual method using HSiCl3. However, the yields could
(+)-(Sp)-9.
be improved from 9 and 6% (of 19a and 19b, respectively) to
Three different procedures for the metalation of 21b were
3
2 and 31% by modifying the workup. Hence, in place of the
tested, including using n-BuLi, t-BuLi (both at -78 °C), and
s-Bu2Mg‚LiCl at room temperature, a reagent recently described
by Knochel et al. as highly effective for the metalation of aryl
addition of degassed aq NH4Cl and the extraction with degassed
DCM, 2 equiv of Et3N were added (to quench HCl formed later)
along with Et2O, and the mixture was suspended directly onto
silica. After drying, this was placed atop a silica column, and
chromatography was carried out as quickly as possible to give
the separated diastereoisomers.
Use of compounds 19 as ligands in the allylic alkylation
reaction gave improved enantioselectivities of 89 and 63% ee,
respectively (Table 1, entries 7 and 8). Further attempted ligand
optimization involved the synthesis of compounds 22 (Scheme
39
bromides. The reaction of the organometallics, generated in
these ways, with the chlorophosphine gave 70, 33, and 0% of
the desired product 22b, respectively. The reaction starting with
t-BuLi gave an unidentified byproduct that was difficult to
separate from the product and that, starting with Knochel’s
(39) Krasovskiy, A.; Straub, B. F.; Knochel, P. Angew. Chem., Int. Ed.
1996, 45, 159.
J. Org. Chem, Vol. 71, No. 12, 2006 4613

Whelligan and Bolm
reagent, gave 29% starting material and 33% oxazolinyl[2.2]-
paracyclophane, resulting from quenching of the unreacted
paracyclophanylmetallic during workup. Hence, for the meta-
lation of the opposite diastereoisomer 21a, n-BuLi became the
reagent of choice, but strangely, in this case, the procedure was
completely unsuccessful. Instead, lithiation at -78 °C gave a
mixture of products (including one with m/z ) 487/489,
corresponding to the addition of a butyl group to the starting
material). It was hypothesized that problems were arising as a
result of either deprotonation of the oxazoline at the benzylic
position or migration of the anion resulting from bromo-lithium
exchange. To avoid this, the reaction was carried out at -95
(500 mL) was then added, and the solution was washed with aq
NaHCO
The organic phase was dried over MgSO
and dried in vacuo to give the crude amide. PPh
mmol), MeCN (859 mL), CCl (6.9 mL, 71.6 mmol), and Et
10.1 mL, 71.6 mmol) were added, and the mixture stirred for 18
h. DCM (850 mL) was then added, and the solution was washed
with brine (2 × 850 mL), dried over MgSO , filtered, and
concentrated. Flash column chromatography, gradient elution
pentane/EtOAc (19:1),(9:1)] gave an inseparable mixture of the
3
solution (3.5% w/v, 2 × 600 mL) and brine (600 mL).
, filtered, concentrated,
(18.78 g, 71.59
4
3
4
3
N
(
4
[
title compounds as a pale yellow solid (11.63 g, 89%): Rf
(petroleum ether/EtOAc ) 8:2) 0.52.
A pure sample of (-)-(S,4R
P
)-5a was prepared in the same
manner as that described above, but on a smaller scale, from
°C using a diethyl ether/liquid nitrogen bath. The desired product
31
20
enantiopure (-)-(4R
170 (c 0.88, CHCl
.7 Hz, H-5), 6.61-6.46 (6H, m, H-7, 8, 12, 13, 15, 16), 4.40 (1H,
P
)-carboxylic acid 4. Colorless oil; [R]
3
D
2
2a was now formed and isolated in 57% yield. Its use as a
1
-
1
); H NMR (400 MHz) δ 7.04 (1H, d, J )
ligand in allylic alkylation, however, gave the same ee (89%)
as the i-Pr-oxazoline 19a. Similarly, the diastereoisomer 22b
acted with almost the equivalent selectivity as 19b. This is
understandable because the phenyl group is only “longer” than
the i-Pr group and the steric bulk is in fact less (A values (-∆G
of interconversion between equatorial and axial substituents on
dd, J ) 9.3, 7.7 Hz, OCHH), 4.20-4.08 (3H, m, OCHH, NCH,
H-2a), 3.19-2.97 (6H, m, H-1a, 1b, 9a, 9b, 10a, 10b), 2.85 (1H,
ddd, J ) 12.6, 10.2, 6.6 Hz, H-2b), 1.93 (1H, oct, J ) 6.7 Hz,
CH(CH
3
)
2
), 1.11 (3H, d, J ) 6.7 Hz, CH ), 1.01 (3H, d, J ) 6.7
3
Hz, CH3); 13C NMR (100 MHz) δ 163.4, 140.7, 139.8, 139.4, 139.2,
-
1 40
a cyclohexane ring): Ph ) 2.9 and i-Pr ) 2.15 kcal mol ).
135.6, 134.6, 134.2, 132.8, 132.6, 132.2, 131.1, 128.4, 72.9, 69.3,
-
1
3
5.9, 35.3, 35.1, 34.9, 32.9, 19.2, 18.2; IR (neat, cm ) νmax 1640
+
+
(
2
1
CdN); MS (EI, m/z) 320 (14), 319 (M , 57), 276 (M - i-Pr, 9),
Conclusion
+
16 (15), 215 (CH
04 (14); HRMS calcd for C22
A pure sample of (+)-(S,4S
2 6 3 2
C H (oxazoline)CH , 100), 159 (11), 147 (11),
H25NO, 319.1936; found, 319.1936.
We have devised synthetic routes to all aromatic-substituted
regioisomers of phosphinyl-oxazolinyl-[2.2]paracyclophanes that
are relevant for use as chelating ligands in asymmetic catalysis.
In the allylic alkylation reaction, use of the pseudo-ortho version
of a previously reported pseudo-geminal i-Pr-substituted com-
pound gave higher enantioselectivity. However, the Ph-
substituted pseudo-ortho-phosphinyl-oxazolinyl-[2.2]paracyclo-
phane was less selective than the published pseudo-geminal
analogue, which shows that the conformation of the active
catalyst with the pseudo-ortho ligand forms a chiral environment
that obeys different rules for selectivity.
P
)-5b was obtained as a byproduct
from the synthesis of 1b as a pale yellow solid; mp 93.5-95.0 °C;
20
1
[R]
D
3
+26 (c 1.20, CHCl ); H NMR (400 MHz) δ 7.04 (1H, d,
J ) 1.9 Hz, H-5), 6.58 (1H, dd, J ) 8.0, 1.9 Hz, H-7), 6.57-6.48
(5H, m, H-8, 12, 13, 15, 16), 4.37-4.30 (2H, m, OCHH, H-2a),
4
9
1
.17-4.08 (2H, m, OCHH, NCH), 3.20-2.98 (6H, m, H-1a, 1b,
a, 9b, 10a, 10b), 2.87 (1H, ddd, J ) 12.9, 10.2, 6.9 Hz, H-2b),
.95 (1H, oct, J ) 6.7 Hz, CH(CH
3
)
2
3
), 1.17 (3H, d, J ) 6.7 Hz,
1
CH ), 1.05 (3H, d, J ) 6.7 Hz, CH ); C NMR (100 MHz) δ 162.9,
140.9, 139.8, 139.3, 139.2, 135.7, 134.6, 134.1, 132.8, 132.6, 132.2,
131.2, 128.3, 73.0, 69.2, 35.8, 35.3, 34.9, 34.7, 33.4, 19.3, 18.7;
3
3
-
1
IR (KBr, cm ) νmax 1637 (CdN); MS (EI, m/z) 320 (14), 319
+
+
(
M , 56), 276 (M - i-Pr, 8), 216 (16), 215 (CH
C H
2 6 3
(oxazoline)-
, 100), 159 (10), 147 (10), 104 (13); HRMS calcd for C22
NO, 319.1936; found, 319.1938.
Experimental Section
+
CH
2
25
H -
General. For instrumental details, see Supporting Information.
2
4
(-)-(S,4S ,13R )-4-Bromo-13-(4-iso-propyloxazolin-2-yl)[2.2]-
Starting materials: (()-[2.2]Paracyclophane-4-carboxylic acid (4),
p
p
3
2
paracyclophane (6a).27 The diastereomeric mixture of oxazolines
(
()-4,12-dibromo[2.2]paracyclophane (7), (()-4-bromo[2.2]-
33
paracyclophane-12-carboxylic acid (9) (and its enantiopure forms),
5 (0.13 g, 0.40 mmol) was dissolved in dry DCM (11 mL). Iron
powder (3 mg, 0.05 mmol) was added, followed by bromine (0.03
mL, 0.48 mmol), and the mixture was heated at reflux for 16 h
10
(
()-O-(4-[2.2]paracyclophanyl) diethylcarbamate (11), and 1,3-
diphenyl-2-propenyl acetate were prepared according to literature
41
procedures. Acid 4 was resolved according to the procedure of
[Note: On larger scales, a solution of bromine should be added
Rozenberg et al.31 and dibromide 7 was resolved by preparative
dropwise, according to the literature procedure.24] The reaction
chiral HPLC (OD column, 55 mm ID, n-hexane/i-PrOH ) 95:5,
mixture was washed with saturated NaHCO
and brine (10 mL). The organic phase was dried over MgSO ,
3
solution (2 × 10 mL)
-
1
flow rate ) 30 mL min , 2 bar, t(R)-(-) ) 17 min, t(S)-(+) ) 23
min); HPLC analysis (Chiralcel OD column, n-hexane/i-PrOH )
4
filtered, and concentrated. Flash column chromatography with
gradient elution [petroleum ether/EtOAc (9:1), (8:2)] gave the title
compound as a white solid (0.07 g, 42%); R (petroleum ether/
f
-
1
9
5:5, flow rate ) 1 mL min , t(R)-(-) ) 5.9 min, t(S)-(+) ) 7.5
min).
2
0
EtOAc ) 8:2) 0.58; mp 131.0-133.0 °C; [R]
2
D
-5 (c 1.00, CH
); H NMR (500 MHz) δ 7.19 (1H, br s, H-12), 6.64 (1H, d, J
1.5 Hz, H-5), 6.62 (1H, dd, J ) 7.8, 2.0 Hz, H-16), 6.58 (1H, d,
2
-
P P
(-)-(S,4R )- and (+)-(S,4S )-4-(4-iso-Propyloxazolin-2-yl)[2.2]-
1
Cl
paracyclophane (5a and 5b). Thionyl chloride (16.8 mL, 230.3
mmol) was added to carboxylic acid 4 (10.31 g, 40.91 mmol), and
the resulting mixture was heated at 60 °C for 4 h. The excess thionyl
chloride was removed by evaporation, and the final traces were
removed by azeotropic distillation with toluene. The resulting crude
acid chloride was dissolved in DCM (67 mL) and cooled to 0 °C.
)
J ) 7.8 Hz, H-15), 6.55 (1H, d, J ) 7.8 Hz, H-8), 6.53 (1H, dd, J
)
4
8
7.8, 1.5 Hz, H-7), 4.56 (1H, ddd, J ) 13.7, 10.4, 4.1 Hz, H-1a),
.40 (1H, dd, J ) 9.4, 8.2 Hz, OCHH), 4.11 (1H, ddd, J ) 9.4,
.2, 6.6 Hz, NCH), 4.04 (1H, t, J ) 8.2 Hz, OCHH), 3.56 (1H,
ddd, J ) 12.9, 10.4, 4.1 Hz, H-2a), 3.06 (2H, m, H-10a, 10b), 3.01
A solution of l-valinol (8.36 g, 81.00 mmol) and Et
1.00 mmol) in DCM (10 mL) was added, and the reaction mixture
was allowed to warm to room temperature and stir for 24 h. DCM
3
N (11.4 mL,
(
3H, m, H-9a, 9b, 1b), 2.93 (1H, ddd, J ) 12.9, 10.4, 4.1 Hz, H-2b),
8
1
.89 (1H, oct, J ) 6.6 Hz, CH(CH ), 1.05 (3H, d, J ) 6.6 Hz,
3 2
)
1
3
CH
41.1, 141.0, 139.2, 138.6, 136.6, 136.0 (C-15), 135.9 (C-5), 134.9
2C, s, C-8, 16), 132.9 (C-12), 131.6 (C-7), 126.3, 73.2 (NCH),
3
), 0.89 (3H, d, J ) 6.6 Hz, CH
3
); C NMR (75 MHz) δ 163.0,
1
(
40) March, J. AdVanced Organic Chemistry, 3rd ed.; Wiley-Inter-
science: New York, 1985.
41) Leung, W.; Cosway, S.; Jones, R. H. V.; McCann, H.; Wills, M. J.
Chem. Soc., Perkin Trans. 1 2001, 2588.
(
6
8.7 (OCH
2
), 35.1 (C-2), 34.9 (C-10), 34.5 (C-9), 33.6 (C-1), 32.5
(
-
1
(CH(CH
)
3 2
3 3
), 19.6 (CH ), 18.1 (CH ); IR (KBr, cm ) νmax 1637
4614 J. Org. Chem., Vol. 71, No. 12, 2006

Phosphinyl-oxazolinyl-[2.2]paracyclophanes
(
C
CdN); MS (CI, methane, m/z) 428 (M + C
2
H
5
+, 22), 426 (M +
, 21), 401 (24), 400 (M + H , 100), 399 (46), 398 (M +
oct, J ) 6.8 Hz, CH(CH
3
)
2
), 1.19 (3H, d, J ) 6.8 Hz, CH
3
), 1.02
+
+
13
2
+
H
5
(3H, d, J ) 6.8 Hz, CH
3
); C NMR (75 MHz) δ 163.5 (CdN),
+
H , 98), 397 (24), 215 (CH
-)-(S,4R ,13S )-4-Bromo-13-(4-iso-propyloxazolin-2-yl)[2.2]-
paracyclophane (6b). Further elution gave the title compound
as a white solid (0.08 g, 49%); R (petroleum ether/EtOAc ) 8:2)
.47; mp 147.5-149.0 °C; [R]20
500 MHz) δ 7.24 (1H, br s, H-12), 6.66 (1H, br s, H-5), 6.61 (1H,
dd, J ) 7.9, 1.8 Hz, H-16), 6.56 (1H, br s, H-7, 8), 6.55 (1H, d, J
7.9 Hz, H-15), 4.53 (1H, ddd, J ) 13.1, 10.0, 4.3 Hz, H-1a),
2
C
6
3
H (oxazoline)CH
2
, 7).
143.7 (d, JC-P ) 17.2 Hz, C-4), 141.1, 139.2 (d, JC-P ) 14.3 Hz),
138.9, 138.0 (d, JC-P ) 10.7 Hz), 137.2 (d, JC-P ) 13.7 Hz), 136.1,
135.1, 134.8, 134.5, 133.7, 133.6, 133.4 (2C, s), 133.2 (d, JC-P
(
p
p
27
)
4.2 Hz), 128.6, 128.52, 128.48, 128.38, 128.2, 128.1, 127.0, 73.1
(NCH), 69.9 (OCH ), 35.7, 34.9, 34.8, 34.1 (d, JC-P ) 15.5 Hz,
C-2), 32.9 (CH(CH
MHz) δ -5.46; IR (KBr, cm ) νmax 1624 (CdN); MS (EI, m/z)
f
1
0
(
D
-104 (c 1.00, CH
2
Cl
2
); H NMR
2
31
3 2 3 3
) ), 20.0 (CH ), 19.1 (CH ); P NMR (162
-
1
+
+
+
)
4
504 (38), 503 (M , 100), 502 (67), 488 (M - Me, 19) 460 (M
+
.42 (1H, dd, J ) 9.5, 8.4 Hz, OCHH), 4.13 (1H, t, J ) 8.4 Hz,
2 6 3 2 2
- i-Pr, 27), 434 (16), 289 (20), 288 (CH C H (PPh )CH , 58),
OCHH), 4.00 (1H, m, NCH), 3.54 (1H, ddd, J ) 13.2, 10.0, 4.0
Hz, H-2a), 3.09 (3H, m, H-10a, 10b, 1b), 3.02 (2H, m, H-9a, 9b),
287 (33), 208 (31), 198 (27), 178 (18). Data agrees with that
published.25
2
6
.93 (1H, ddd, J ) 13.2, 10.4, 4.3 Hz, H-2b), 1.96 (1H, oct, J )
(()-O-[4-(5-Carboxy-[2.2]paracyclophanyl)]diethylcarbam-
ate (12). s-BuLi [1.2 M solution in cyclohexane/hexane (92:8), 99.3
mL, 119.2 mmol] was added to a solution of carbamate 11 (32.6
g, 101.0 mmol) and TMEDA (18.2 mL, 121.2 mmol) in THF (1.5
L) at 0 °C. The resulting orange solution was stirred for 1.25 h.
.9 Hz, CH(CH
6.9 Hz, CH
3
)
2
3
3
), 1.16 (3H, d, J ) 6.9 Hz, CH ), 0.97 (3H, d, J
); 1 C NMR (75 MHz) δ 164.2 (CdN), 141.2, 140.6,
10
)
3
1
39.0, 138.6, 136.1, 136.0, 135.1, 134.7, 132.7 (C-12), 131.5, 126.9,
26.6, 73.0 (NCH), 69.8 (OCH ), 35.4 (C-2), 34.8 (C-10), 34.5
), 19.8 (CH ), 18.9 (CH ); IR
1
(
2
C-9), 33.2 (C-1), 33.1 (CH(CH
)
3 2
3
3
CO
mixture was allowed to warm to room temperature and stirred for
18 h with slow bubbling of CO . The mixture was extracted twice
2
gas was then bubbled through the solution for 2 h. The reaction
-
1
(
KBr, cm ) νmax 1643 (CdN); MS (CI, methane, m/z) 428 (M +
+
+
+
C
2
H
5
, 20), 426 (M + C
2
H
5
, 21), 401 (21), 400 (M + H , 88),
(oxazoline)-
24BrNO: C, 66.34; H, 6.07; N, 3.52.
Found: C, 66.08; H, 5.94; N, 3.26.
+)-(S,4S ,13R )-4-Diphenylphosphinyl-13-(4-iso-propylox-
2
+
3
99 (45), 398 (M + H , 100), 397 (25), 215 (CH
C H
2 6 3
with water (1 L, 500 mL) and then aq NaOH solution (6 M, 50
mL). The combined aq layers were washed with DCM (500 mL)
+
2
CH , 7); Anal. Calcd for C22H
and Et
2
O (2 × 500 mL). The aq layer was acidified to pH 1 with
(
p
p
aq HCl (6 M) to give a white precipitate. The mixture was then
25
azolin-2-yl)[2.2]paracyclophane (1a). t-BuLi (15% w/v solution
in n-pentane, 2.3 mL, 4.2 mmol) was added dropwise to a solution
of bromide 6a (0.80 g, 2.00 mmol) in THF (20 mL) at -78 °C to
extracted with DCM (3 × 500 mL), and the combined organic
2 4
layers were dried over Na SO , filtered, concentrated, and dried in
vacuo to give the title compound as a white solid (33.4 g, 90%):
1
give an orange solution. After stirring for 1.5 h, ClPPh
2
(0.75 mL,
f
R (DCM/EtOAc ) 8:2) 0.07; mp 125.0-127.0 °C; H NMR (300
4.20 mmol) was added dropwise. The resulting pale yellow solution
MHz) δ 6.82 (1H, dd, J ) 7.9, 1.7 Hz), 6.70 (1H, dd, J ) 7.9, 1.7
Hz), 6.67 (1H, d, J ) 8.2 Hz), 6.62 (1H, dd, J ) 7.9, 1.7 Hz), 6.53
(1H, dd, J ) 7.9, 1.7 Hz), 6.50 (1H, d, J ) 7.9 Hz), 3.59 (2H, m,
was allowed to warm to room temperature and stirred for 18 h. A
degassed (by argon bubbling under sonication), saturated aq solution
of NH
was separated and extracted with degassed DCM (2 × 14 mL).
The combined organic layers were dried over Na SO , filtered, and
concentrated. Flash column chromatography (degassed pentane/
DCM/EtOAc ) 20:4:1) gave the title compound as a white solid
4
Cl (10 mL) was added and shaken vigorously. The aq layer
CH
) 12.6, 10.6, 4.9 Hz), 3.16-3.04 (4H, m), 2.88 (1H, ddd, J )
12.6, 10.4, 5.2 Hz), 2.79 (1H, m), 1.42 (3H, t, J ) 6.9 Hz, CH CH ),
); C NMR (75 MHz) δ 170.2,
153.8, 148.1, 142.8, 139.4, 139.3, 137.8, 133.2, 132.9, 132.7, 132.2,
131.0, 129.2, 125.4, 42.3 (CH CH ), 42.0 (CH CH ), 34.7, 34.3
(2C, s), 30.6, 14.2 (CH ), 13.2 (CH ); IR (KBr, cm ) νmax 3433
(OsH), 1723 (Et NCdO), 1678 (CdOOH); MS (EI, m/z) 368 (17),
2 3 2 3
CH ), 3.50 (1H, m), 3.39 (2H, m, CH CH ), 3.25 (1H, ddd, J
2
4
2
3
13
2 3
1.21 (3H, t, J ) 7.2 Hz, CH CH
(
0.63 g, 62%): R
37.0 °C; [R]20
4H, m, P-C
f
(petroleum ether/EtOAc ) 8:2) 0.64; mp 134.0-
2
3
2
3
-1
1
1
D
+4 (c 0.44, CHCl
), 7.24 (6H, m, P-C
.64 (2H, br s, H-15, 16), 6.50 (2H, m, H-7, 8), 5.84 (1H, dd, JH-P
7.9 Hz, J ) 1.5 Hz, H-5), 4.61 (2H, m, OCHH, H-1a), 4.20
1H, td, J ) 9.2, 7.0 Hz, NCH), 4.10 (1H, dd, J ) 9.2, 7.2 Hz,
OCHH), 3.49 (1H, m, H-2a), 3.07 (1H, m, H-10a), 2.85 (5H, m,
H-1b, 2b, 9a, 9b, 10b), 1.92 (1H, oct, J ) 7.0 Hz, CH(CH ),
3
); H NMR (300 MHz) δ 7.33
3
3
(
6
)
(
6
H
5
6 5
H ), 7.06 (1H, br s, H-12),
2
+
+
367 (M , 72), 251 (17), 250 (ParacyclophanylCHO , 90), 104
+
(CH
2 6 4 2 4
C H CH , 58), 100 (100); HRMS calcd for C22H25NO ,
367.1784; found, 367.1784.
P P
Enantiopure (+)-(4R ,5S )-12 was prepared from enantiopure
carbamate 111 (see Results and Discussion). White solid: mp
6a
3 2
)
13
20
1
.13 (3H, d, J ) 7.0 Hz, CH
NMR (75 MHz) δ 162.7 (CdN), 144.0 (d, JC-P ) 17.3 Hz, C-4),
41.6, 138.83 (d, JC-P ) 14.3 Hz), 138.80, 138.6, 138.0 (d, JC-P
10.7 Hz), 137.5 (d, JC-P ) 13.7 Hz), 136.1, 135.0, 134.8, 134.2,
3
), 0.92 (3H, d, J ) 7.0 Hz, CH
3
);
C
140.0-142.0 °C; [R]
D
3
+53 (c 0.70, CHCl ).
(-)-(S,4S ,5R )-O-[4-(5-(1-Hydroxymethyl-2-methyl-propyl-
P
P
1
)
1
2
7
carbamoyl)-[2.2]paracyclophanyl)]diethylcarbamate (13a). Thio-
nyl chloride (2.0 mL, 27.8 mmol) was added to (()-carboxylic acid
12 (1.81 g, 4.94 mmol), and the resulting mixture was heated at 60
°C for 4 h. The excess thionyl chloride was removed by evaporation,
and the final traces were removed by azeotropic distillation with
toluene. The resulting crude acid chloride was dissolved in DCM
(8 mL) and cooled to 0 °C. A solution of L-valinol (1.01 g, 9.78
33.7, 133.6 (d, JC-P ) 2.4 Hz), 133.4 (2C, s), 133.3 (d, JC-P
)
.9 Hz), 133.2, 128.52, 128.49, 128.40, 128.3, 128.2, 128.1, 127.0,
3.8 (NCH), 69.1 (OCH2), 36.3, 34.9, 34.8, 33.6 (d, JC-P ) 14.9
31
3 2 3 3
Hz, C-2), 32.7 (CH(CH ) ), 20.0 (CH ), 18.5 (CH ); P NMR (121
-
1
MHz) δ -4.12; IR (KBr, cm ) νmax 1637 (CdN); MS (EI, m/z)
+
+
+
5
-
2
04 (26), 503 (M , 100), 502 (58), 488 (M - Me, 18) 460 (M
mmol) and Et N (1.37 mL, 9.78 mmol) in DCM (1 mL) was added,
3
+
i-Pr, 18), 434 (19), 289 (11), 288 (CH
2
C
6
3
H (PPh
2
)CH
2
, 38),
and the reaction mixture was allowed to warm to room temperature
and stirred for 24 h. DCM (120 mL) was then added, and the
87 (18), 208 (16), 198 (19), 178 (11). Data agrees with that
25
published.
solution was washed with aq NaHCO solution (3.5% w/v, 2 ×
3
(
-)-(S,4R
p
,13S
p
)-4-Diphenylphosphinyl-13-(4-iso-propylox-
120 mL) and brine (120 mL). The organic phase was dried over
25
azolin-2-yl)[2.2]paracyclophane (1b). Treatment of bromide 6b,
according to the procedure for the synthesis of 1a, gave the title
compound as a white solid (0.46 g, 46%): R
EtOAc ) 8:2) 0.67; mp 159.0-161.0 °C; [R]
CHCl
Na
gradient elution (pentane/DCM/EtOAc ) 6:2:2 f 5:2:3 f 4:2:4)
gave the title compound as a white solid (0.85 g, 38%): R (DCM/
EtOAc ) 8:2) 0.21; mp 61.5-63.0 °C; [R] -23 (c 0.90, CHCl );
1
2 4
SO , filtered, and concentrated. Flash column chromatography,
f
(petroleum ether/
f
20
20
D
-80 (c 0.39,
), 7.23 (6H,
5
H ), 7.15 (1H, br s, H-12), 6.62 (2H, br s), 6.51 (2H, m,
D
3
1
3
); H NMR (300 MHz) δ 7.35 (4H, m, P-C
6
H
5
H NMR (300 MHz) δ 7.10 (1H, dd, J ) 7.9, 1.7 Hz), 6.72 (1H,
dd, J ) 7.9, 1.7 Hz), 6.58 (1H, dd, J ) 7.9, 1.7 Hz), 6.54 (1H, d,
J ) 7.9 Hz), 6.52 (1H, dd, J ) 7.9, 1.7 Hz), 6.44 (1H, d, J ) 7.9
Hz), 5.78 (1H, br d, J ) 8.9 Hz, NH), 3.81 (1H, dddd, J ) 8.9,
m, P-C
6
H-7, 8), 5.83 (1H, dd, JH-P ) 8.2 Hz, J ) 1.7 Hz, H-5), 4.55 (1H,
dd, J ) 9.9, 8.1 Hz, OCHH), 4.51 (1H, m, H-1a), 4.31 (1H, t, J )
8.1 Hz, OCHH), 4.10 (1H, m, NCH), 3.43 (1H, m, H-2a), 3.06
2 2 3
7.2, 5.4, 3.5 Hz, NCH), 3.59 (3H, m, CH OH, CH CH ), 3.44 (1H,
(1H, m, H-10a), 2.87 (5H, m, H-1b, 2b, 9a, 9b, 10b), 2.19 (1H,
m, CHHCH ), 3.28 (1H, m, CHHCH ), 3.23 (2H, m), 3.19-2.98
3
3
J. Org. Chem, Vol. 71, No. 12, 2006 4615

Whelligan and Bolm
(
1
5H, m), 2.74 (1H, m), 1.81 (1H, oct, J ) 6.7 Hz, CH(CH
.43 (3H, t, J ) 7.2 Hz, CH CH ), 1.20 (3H, t, J ) 7.2 Hz,
CH CH ), 0.95 (3H, d, J ) 6.7 Hz, CH(CH )CH ), 0.91 (3H, d, J
6.7 Hz, CH(CH ); C NMR (75 MHz) δ 167.1, 154.7,
46.0, 140.0, 139.2, 138.9, 136.1, 132.8, 132.5, 132.0 (2C, s), 131.6,
29.6, 129.5, 63.3 (CH OH), 57.3 (NCH), 42.12 (CH CH ), 42.08
CH ), 35.1, 34.5, 33.4, 30.4, 28.9 (CH(CH ), 19.5 (CH(CH )-
), 18.8 (CH(CH )CH ), 14.0 (CH CH ), 13.2 (CH CH ); IR
, cm ) νmax 3411 (br, OsH and NsH), 1699 (Et NCdO),
657 (CdOONH); MS (EI, m/z) 453 (21), 452 (M , 78), 350 (9),
3
)
2
),
(0.27 g, 4.8 mmol) were dissolved in i-PrOH (10 mL). The reaction
mixture was then heated at reflux for 51 h. Aqueous HCl (3 M, 7
2
3
2
3
3
3
mL, 21 mmol) was added, and the mixture was extracted with Et
(2 × 22 mL) and DCM (22 mL). The combined organic layers
were washed with NaHCO (30 mL) to remove any [2.2]paracy-
2
O
1
3
)
1
1
3 3
)CH
3
2
2
3
clophane carboxylic acid byproduct, and the aq layer was extracted
with DCM (22 mL). All organic layers were combined, dried over
Na SO , filtered, and concentrated. Flash column chromatography
2 4
with gradient elution (pentane/EtOAc ) 9:1 f 8:2 f 7:3) first
gave unreacted starting material 14a (0.04 g, 16%) and then the
(CH
2
3
)
3 2
3
CH
(
1
3
(
3
3
3
2
3
2
3
-
1
CHCl
3
2
+
+
48 (M - CH
sC sCH
52.2675; found, 452.2675.
+)-(S,4R ,5S )-O-[4-(5-(1-Hydroxymethyl-2-methyl-propyl-
2
C
2
6
H
4
CH
2
, 7), 335 (12), 248 (14), 231 (60), 104
f
title compound as a white solid (0.10 g, 59%): R (petroleum ether/
+
20
CH
2
H
6 4
, 23), 100 (100); HRMS calcd for C27
36 2 4
H N O ,
EtOAc ) 1:1) 0.50; mp 43.0-48.0 °C; [R]
D
-148 (c 1.30,
1
4
CHCl ); H NMR (400 MHz) δ 11.52 (1H, s, OH), 7.05 (1H, dd,
3
(
P
P
J ) 8.0, 1.9 Hz), 6.59 (1H, dd, J ) 8.0, 1.9 Hz), 6.51 (1H, dd, J
) 8.0, 1.9 Hz), 6.48 (1H, d, J ) 7.7 Hz), 6.45 (1H, dd, J ) 8.0,
1.9 Hz), 6.25 (1H, d, J ) 7.7 Hz), 6.08 (1H, br d, J ) 8.7 Hz,
NH), 3.95 (1H, tdd, J ) 8.7, 6.8, 4.1 Hz, NCH), 3.68 (2H, m,
carbamoyl)-[2.2]paracyclophanyl)]diethylcarbamate (13b). Fur-
ther elution gave the title compound as a white solid (0.58 g,
2
+
7
1
6
2
0
6%): R
20.7 (c 1.09, CHCl
f
(DCM/EtOAc ) 8:2) 0.10; mp 136.5-137.0 °C; [R]
D
1
); H NMR (300 MHz) δ 7.13 (1H, dd, J )
2
CH OH), 3.53 (1H, m, H-9a), 3.48 (1H, q, J ) 7.0 Hz), 3.41 (1H,
3
.9, 1.7 Hz), 6.67 (1H, dd, J ) 7.9, 2.0 Hz), 6.59 (1H, dd, J ) 7.7,
.7 Hz), 6.53 (1H, d, J ) 7.8 Hz), 6.52 (1H, dd, J ) 7.7, 2.0 Hz),
.43 (1H, d, J ) 7.8 Hz), 6.08 (1H, br d, J ) 7.9 Hz, NH), 3.71
ddd, J ) 12.9, 10.2, 2.8 Hz), 3.17 (1H, ddd, J ) 12.9, 10.4, 5.2
Hz), 3.11 (1H, m), 3.02 (1H, ddd, J ) 12.9, 10.7, 2.8 Hz), 2.96-
2.82 (2H, m), 2.55 (1H, ddd, J ) 13.2, 10.7, 5.2 Hz, H-2b), 2.05
(
3
1H, m, NCH), 3.64 (1H, m, CHHCH ), 3.52 (3H, m, CHHCH
3
,
(1H, oct, J ) 6.8 Hz, CH(CH
3
)
2
3
), 1.10 (3H, d, J ) 6.8 Hz, CH ),
1
3
CH
2
OH), 3.37 (1H, m, CHHCH
3
), 3.33-3.17 (3H, m), 3.06-2.91
1.09 (3H, d, J ) 6.8 Hz, CH
3
); C NMR (75 MHz) δ 171.0, 159.4,
(
4H, m), 2.86 (1H, m), 2.76 (1H, m), 1.83 (1H, oct, J ) 6.8 Hz,
CH(CH ), 1.40 (3H, t, J ) 7.2 Hz, CH CH ), 1.18 (3H, t, J )
.2 Hz, CH CH ), 0.89 (3H, d, J ) 6.8 Hz, CH(CH )CH ), 0.88
3H, d, J ) 6.8 Hz, CH(CH ); C NMR (75 MHz) δ 167.6,
54.5, 146.0, 140.6, 139.6, 138.8, 136.1, 132.7, 132.5, 132.3, 132.1,
32.0, 129.3, 128.8, 63.7 (NCH), 57.9 (CH
140.1, 137.9, 137.7, 137.3, 133.0, 131.8, 131.4, 129.2, 127.7, 127.1,
117.9, 63.1 (CH OH), 56.8 (NCH), 36.1, 35.0, 33.8, 30.2, 29.4 (CH-
(CH ), 19.8 (CH
OsH and NsH), 1622 (CdOONH); MS (EI, m/z) 354 (24), 353
3
)
2
2
3
2
-
1
7
(
2
3
3
3
3
)
2
3 3
), 19.2 (CH ); IR (KBr, cm ) νmax 3419 (br,
13
3 3
)CH
+
+
+
1
1
CH
CH
(
(M , 100), 322 (M - CH
2
OH, 13), 310 (M - i-Pr, 21), 268
(34), 250 (33), 249 (M - CH CH , 52), 248 (12), 218 (62),
2 6 4
206 (22), 164 (15), 163 (15), 147 (21), 146 (17), 104 (CH C H -
+
OH), 42.0 (2C, s, 2 ×
), 35.1, 34.4, 33.4, 30.3, 28.8 (CH(CH ), 19.1 (CH(CH )-
), 19.0 (CH(CH )CH ), 14.2 (CH CH ), 13.2 (CH CH ); IR
NCd
O), 1661 (CdOONH); MS (EI, m/z) 453 (25), 452 (M , 90), 350
2
C
H
6 4
2
2
2
CH
3
)
3 2
3
+
CH
2
, 74), 102 (22); HRMS calcd for C22
H
3
27NO , 353.1991; found,
3
3
3
2
3
2
3
-
1
KBr, cm ) νmax 3493 (br, OsH), 3259 (NsH), 1719 (Et
2
353.1990..
+
(+)-(S,4R ,5S )-O-[2-(5-(4-Hydroxy[2.2]-paracyclophanyl))-
P P
+
(
1
4
10), 348 (M - CH
2
C
6
H
4
CH
, 24), 100 (100); HRMS calcd for C27
52.2675; found, 452.2676.
-)-(S,4S ,5R )-O-[2-(5-(4-Hydroxy[2.2]-paracyclophanyl))-
2
, 7), 335 (14), 248 (14), 231 (60),
3-methylbutyl] Diethylcarbamate (14b). Treatment of carbamate
13b (0.58 g, 1.29 mmol) according to the procedure for the synthesis
of 14a gave the title compound as a pale yellow solid (0.31 g,
+
04 (CH
2
C
6
H
4
CH
2
36 2 4
H N O ,
(
P
P
54%): R
f
(petroleum ether/EtOAc ) 1:1) 0.68; mp 111.0-113.0
°C; [R]20
1
3
1
-methylbutyl] Diethylcarbamate (14a). Carbamate 13a (0.85 g,
D
3
+74 (c 0.76, CHCl ); H NMR (400 MHz) δ 11.42 (1H,
.89 mmol) was dissolved in a mixture of MeOH (53 mL) and aq
s, OH), 7.04 (1H, dd, J ) 7.9, 1.9 Hz), 6.57 (1H, dd, J ) 7.9, 1.9
Hz), 6.49 (1H, dd, J ) 7.9, 1.9 Hz), 6.48 (1H, d, J ) 7.7 Hz), 6.44
(1H, dd, J ) 7.9, 1.9 Hz), 6.26 (1H, d, J ) 7.7 Hz), 6.02 (1H, br
d, J ) 9.1 Hz, NH), 4.40 (1H, dd, J ) 11.5, 5.8 Hz, CHHO), 4.27
(1H, dd, J ) 11.5, 3.3 Hz, CHHO), 4.19 (1H, m, NCH), 3.47 (1H,
ddd, J ) 13.6, 9.3, 2.7 Hz, H-9a), 3.44-3.30 (5H, m, H-2a, 2 ×
NaOH (6 M, 19.8 mL, 118.9 mmol). The reaction mixture was
then heated at reflux for 20 h. Aqueous HCl (3 M, 45 mL, 135
mmol) was added, and the mixture was extracted with EtOAc (4
×
2 4
50 mL). The combined organic layers were dried over Na SO ,
filtered, and concentrated. Flash column chromatography, gradient
elution (pentane/EtOAc ) 19:1 f 9:1 f 8:2 f 7:3) gave the title
2 3
CH CH ), 3.17 (1H, ddd, J ) 12.9, 10.2, 5.2 Hz, H-1a), 3.04 (2H,
compound as a colorless oil (0.26 g, 31%): R
f
(petroleum ether/
-117 (c 0.95, CHCl ); H NMR (300
3
m, H-1b, 10a), 2.88 (1H, ddd, J ) 13.6, 9.3, 6.7 Hz, H-9b), 2.78
(1H, ddd, J ) 12.6, 9.3, 6.7 Hz, H-10b), 2.54 (1H, ddd, J ) 13.2,
EtOAc ) 1:1) 0.71; [R]20
1
D
MHz) δ 11.65 (1H, s, OH), 7.04 (1H, dd, J ) 7.9, 1.7 Hz), 6.58
10.7, 5.2 Hz, H-2b), 1.88 (1H, oct, J ) 6.8 Hz, CH(CH
(6H, t, J ) 7.1 Hz, 2 × CH CH
(CH )CH ), 0.92 (3H, d, J ) 6.8 Hz, CH(CH
(100 MHz) δ 170.0, 159.1, 155.4, 139.9, 137.7, 137.5, 137.2, 132.7,
131.6, 131.2, 128.9, 127.5, 126.9, 118.0, 65.1 (CH OH), 54.0
(NCH), 41.9 (CH CH ), 41.3 (CH CH ), 35.9, 35.0, 33.8, 30.2, 29.7
(CH(CH ), 19.2 (CH(CH )CH ), 18.8 (CH(CH )CH ), 14.2
(CH CH ), 13.5 (CH CH ); IR (KBr, cm ) νmax 3308 (OsH and
NsH), 1682 (Et NCdO), 1622 (CdOONH); MS (EI, m/z) 453
3
)
2
), 1.18
(
(
1H, dd, J ) 7.9, 1.7 Hz), 6.48 (1H, dd, J ) 7.7, 1.7 Hz), 6.44
1H, d, J ) 7.7 Hz), 6.43 (1H, dd, J ) 7.7, 1.7 Hz), 6.25 (1H, d,
2
3
), 0.97 (3H, d, J ) 6.8 Hz, CH-
1
3
3
3
3 3
)CH ); C NMR
J ) 7.7 Hz), 4.25 (2H, m, NCH, CHHO), 4.06 (1H, dd, J ) 15.6,
8
2
CH
.3 Hz, CHHO), 3.57 (1H, m, H-9a), 3.39 (1H, ddd, J ) 12.7, 9.9,
.7 Hz, H-2a), 3.20-2.80 (9H, m, H-10a, 10b, 9b, 1a, 1b, 2 ×
2
2
3
2
3
CH
3
), 2.53 (1H, ddd, J ) 12.7, 10.6, 5.2 Hz, H-2b), 1.99 (1H,
3
)
2
3
3
3
3
2
-
1
m, CH(CH
3
)
2
), 1.12 (6H, d, J ) 6.9 Hz, CH(CH
3
)
2
), 0.93 (6H, m,
); C NMR (75 MHz) δ 170.9, 159.5, 155.9, 140.1,
37.8, 137.5, 137.4, 133.0, 131.8, 131.3, 129.0, 127.7, 127.1, 117.9,
4.6 (CH OH), 54.3 (NCH), 42.0 (CH CH ), 41.4 (CH CH ), 36.1,
5.0, 33.8, 30.2 (2C, s, CH(CH , C-2), 19.6 (CH(CH )CH ), 18.9
)CH ), 13.9 (CH CH ), 13.1 (CH CH ); IR (CHCl
NCdO), 1624 (CdOONH);
2
3
2
3
13
2
1
6
3
× CH
2
CH
3
2
+
+
(29), 452 (M , 100), 348 (M - CH
2
C
6
H
4
CH
2
, 33), 347 (38), 335
+
(M - HOC(O)NEt
2
, 13), 232 (13), 231 (69), 230 (13), 146 (8),
2
2
3
2
3
+
)
3 2
3
3
104 (CH
2 6 4 2 36 2 4
C H CH , 21), 100 (15); HRMS calcd for C27H N O ,
-
1
(CH(CH
3
3
2
3
2
3
3
, cm )
452.2675; found, 452.2674.
ν
max 3309 (OsH and NsH), 1686 (Et
2
(+)-(S,4R ,5S )-4-Hydroxy-[2.2]paracyclophane-5-carboxyl-
P
P
+
+
MS (EI, m/z) 453 (30), 452 (M , 100), 348 (M - CH
2
C
6
H
4
CH
2
,
ic Acid (1-Hydroxymethyl-2-methyl-propyl)-amide (15b). (i)
Further elution gave the title compound (0.11 g, 25%).
+
3
2
0), 347 (33), 335 (M - HOC(O)NEt
30 (15), 146 (10), 104 (CH sC sCH
, 452.2675; found, 452.2675.
)-4-Hydroxy-[2.2]paracyclophane-5-carboxyl-
2
, 15), 232 (14), 231 (71),
+
2
H
6 4
2
, 27), 100 (16); HRMS
(ii) Alternatively, treatment of carbamate 14b (0.29 g, 0.64 mmol)
according to procedure (ii) for the synthesis of 15a first gave the
starting material 14b (0.04 g, 12%) and then the title compound as
calcd for C27
36 2 4
H N O
(
-)-(S,4S ,5R
P P
ic Acid (1-Hydroxymethyl-2-methyl-propyl)-amide (15a). (i)
Further elution gave the title compound (0.34 g, 51%).
a white solid (0.13 g, 58%): R (petroleum ether/EtOAc ) 1:1)
f
0.50; mp 85.5-87.0 °C; [R]20 +58 (c 1.95, CHCl ); H NMR
1
D
3
(ii) Alternatively, carbamate 14a (0.22 g, 0.48 mmol) and KOH
(400 MHz) δ 11.46 (1H, s, OH), 7.05 (1H, dd, J ) 7.7, 1.7 Hz),
4616 J. Org. Chem., Vol. 71, No. 12, 2006

Phosphinyl-oxazolinyl-[2.2]paracyclophanes
6
6
.59 (1H, dd, J ) 8.0, 1.7 Hz), 6.54 (1H, dd, J ) 7.7, 1.9 Hz),
.49 (1H, d, J ) 7.7 Hz), 6.44 (1H, dd, J ) 8.0, 1.9 Hz), 6.28 (1H,
(1H, ddd, J ) 12.9, 9.9, 4.1 Hz), 3.07-2.96 (4H, m), 2.90 (1H,
ddd, J ) 13.5, 10.2, 4.1 Hz, H-2b), 2.00 (1H, oct, J ) 6.6 Hz,
d, J ) 7.7 Hz), 6.14 (1H, br d, J ) 8.5 Hz, NH), 3.97 (1H, m,
NCH), 3.88 (2H, m, CH
CH(CH
Hz, CH
139.2, 138.9, 137.2, 134.3, 132.7, 132.4, 132.3, 131.9, 130.2, 124.1,
3
)
2
), 1.13 (3H, d, J ) 6.6 Hz, CH
3
), 1.04 (3H, d, J ) 6.6
13
2
OH), 3.59 (1H, m, H-9a), 3.42 (1H, ddd,
3
); C NMR (100 MHz) δ 159.3 (CdN), 145.5, 143.5,
J ) 13.0, 10.3, 2.8 Hz, H-2a), 3.17 (1H, ddd, J ) 12.6, 10.3, 5.0
Hz, H-1a), 3.13 (1H, m, H-10a), 3.01 (1H, ddd, J ) 12.6, 10.7,
118.5 (q, JC-F ) 317.9, CF
3
), 73.5 (NCH), 69.6 (CH
2
O), 34.8, 34.4,
1
9
2
.8 Hz, H-1b), 2.88 (2H, m, H-9b, 10b), 2.55 (1H, ddd, J ) 13.0,
34.1, 32.6 (CH(CH ), 30.8 (C-2), 19.6 (CH
3
)
2
3
), 18.5 (CH
3
);
F
-
1
1
0.7, 5.0 Hz, H-2b), 1.91 (1H, oct, J ) 6.9 Hz, CH(CH
), 0.94 (3H, d, J ) 6.9 Hz, CH
NMR (100 MHz) δ 170.6, 159.2, 139.8, 137.9, 137.5, 137.4, 132.9,
31.6, 131.2, 129.0, 127.4, 127.2, 117.9, 63.6 (CH OH), 56.7
NCH), 36.3, 35.0, 33.8, 30.1 (C-2), 29.1 (CH(CH ), 19.5 (CH ),
3
)
2
), 0.98
NMR (376 MHz) δ -73.8 (3F, s); IR (neat, cm ) νmax 1659 (Cd
1
3
+
+
(3H, d, J ) 6.9 Hz, CH
3
3
);
C
N); MS (EI, m/z) 468 (13), 467 (M , 44), 424 (M - i-Pr, 2), 335
+
(29), 334 (M - Tf, 100), 249 (8), 248 (11), 231 (14), 230
+
+
1
(
2
(CH
calcd for C23
(-)-(S,4R ,5S )-Trifluoromethansulfonic Acid [4-(5-(4-iso-
2
C
6
H
2
(O)(oxazoline)CH
2
2 6 4 2
, 89), 104 (CH C H CH , 19); HRMS
3
)
2
3
3 4
H24SF NO , 467.1378; found, 467.1379.
-
1
1
9.0 (CH
3
); IR (CHCl
3
, cm ) νmax 3434 (br, OsH and NsH),
P
P
+
+
+
1619 (CdOONH); MS (EI, m/z) 354 (22), 353 (M , 100), 322 (M
Propyloxazolin-2-yl)-[2.2]paracyclophanyl)] Ester (18b). Treat-
ment of diol 15b (90 mg, 0.255 mmol), according to the procedure
for the synthesis of 18a, gave the title compound as a colorless
+
-
-
CH
CH
2
OH, 15), 310 (M - i-Pr, 25), 268 (38), 250 (28), 249 (M
CH
2
C
6
H
4
2
, 46), 248 (14), 218 (56), 206 (19), 164 (14), 163
+
20
(
13), 147 (13), 146 (11), 104 (CH
, 353.1991; found, 353.1991.
)-O-[4-(5-(4-iso-Propyloxazolin-2-yl)-[2.2]para-
cyclophanyl)]diethylcarbamate (16a). Carbamate 13a (65 mg,
2 6
C
H
4
CH
2
, 44), 102 (18); HRMS
oil: R (petroleum ether/EtOAc ) 8:2) 0.42; [R] -69 (c 0.66,
f
D
1
calcd for C22
H27NO
3
CHCl ); H NMR (300 MHz) δ 6.80 (1H, dd, J ) 7.9, 1.7 Hz),
6.75 (1H, dd, J ) 7.9, 1.7 Hz), 6.63 (1H, dd, J ) 7.9, 1.7 Hz),
3
(-)-(S,4S ,5R
P P
6.61 (2H, s, H-7, 8), 6.58 (1H, dd, J ) 7.9, 1.7 Hz), 4.50 (1H, dd,
J ) 9.9, 8.7 Hz, CHHO), 4.17 (1H, t, J ) 8.7 Hz, CHHO), 4.05
(1H, m, NCH), 3.70 (1H, ddd, J ) 12.1, 9.6, 4.0 Hz, H-9a), 3.36
(1H, ddd, J ) 13.4, 9.9, 3.7 Hz), 3.21 (1H, m), 3.12-2.84 (5H,
0
0
.143 mmol) was dissolved in MeCN (3.0 mL) and PPh
3
(65 mg,
4
N (35 µl, 0.250 mmol), and CCl (24 µl, 0.250
.250 mmol), Et
3
mmol) were added. The resulting solution was stirred for 23 h. It
was then diluted with DCM (3 mL), washed with brine (2 × 3
m), 1.92 (1H, oct, J ) 6.7 Hz, CH(CH
Hz, CH ), 1.05 (3H, d, J ) 6.7 Hz, CH
159.8 (CdN), 145.7, 143.7, 139.2, 139.1, 137.1, 134.6, 132.7, 132.5,
), 72.9 (NCH), 70.3
), 30.8, 19.4 (CH ), 19.0
3 2
) ), 1.17 (3H, d, J ) 6.7
13
mL), and dried over Na
2
SO
4
. The mixture was filtered and
3
3
); C NMR (75 MHz) δ
concentrated. Flash column chromatography with gradient elution
pentane/EtOAc ) 9:1 f 8:2 f 7:3) gave the title compound as a
colorless oil that became a white crystalline solid on standing (35
mg, 56%): R (petroleum ether/EtOAc ) 8:2) 0.12; mp 62.0-64.0
C; [R]20
-50 (c 0.79, CHCl
(
132.3, 130.1, 124.4 (q, JC-F ) 319.5, CF
3
(CH
(CH
2
O), 34.7, 34.3, 34.2, 33.3 (CH(CH
3
)
2
3
-1
19
3
); F NMR (376 MHz) δ -73.8 (3F, s); IR (neat, cm ) νmax
f
1
+
+
°
D
3
); H NMR (400 MHz) δ 6.98 (1H,
1654 (CdN); MS (EI, m/z) 468 (12), 467 (M , 39), 424 (M -
+
dd, J ) 7.7, 1.9 Hz), 6.71 (1H, dd, J ) 7.7, 1.9 Hz), 6.60 (1H, dd,
i-Pr, 2), 335 (26), 334 (M - Tf, 100), 249 (7), 248 (10), 231
+
+
J ) 8.0, 1.9 Hz), 6.58 (1H, d, J ) 8.0 Hz), 6.53 (1H, dd, J ) 8.0,
(13), 230 (CH
2
C
6
H
2
(O)(oxazoline)CH
2 2 6 4 2
, 85), 104 (CH C H CH ,
1
.9 Hz), 6.46 (1H, d, J ) 8.0 Hz), 4.25 (1H, dd, J ) 9.6, 8.0 Hz,
21); HRMS calcd for C23
H
24SF
3
NO , 467.1378; found, 467.1378.
4
CHHO), 4.08 (1H, ddd, J ) 9.6, 8.0, 6.6 Hz, NCH), 3.98 (1H, t,
(-)-(S,4S ,5R )-4-Diphenylphosphinyl-5-(4-iso-propyloxazo-
P
P
J ) 8.0 Hz, CHHO), 3.68 (1H, m, CHHCH
3
), 3.52 (1H, ddd, J )
), 3.30 (1H,
), 3.21 (1H, ddd, J ) 12.4, 10.6, 4.7 Hz, H-10a), 3.10
lin-2-yl)[2.2]paracyclophane (3a). Triflate 18a (1.05 g, 2.24 mmol)
1
2.6, 10.6, 2.5 Hz, H-9a), 3.44 (2H, m, 2 × CHHCH
3
was dissolved in THF (6.5 mL), and Ph PK (0.5 M w/v solution in
2
m, CHHCH
3
THF, 0.43 mL, 0.21 mmol) was added. The solution was stirred at
(
1
6
1H, m, H-2a), 3.04 (3H, m, H-1a, 1b, 10b), 2.87 (1H, ddd, J )
room temperature for 20 h. Degassed water (75 mL) and DCM
(45 mL) were added, and the mixture was shaken vigorously. The
aq layer was separated and extracted with DCM (45 mL). The
combined organic layers were dried over Na SO , filtered, and
2.6, 10.4, 4.7 Hz, H-9b), 2.75 (1H, m, H-2b), 1.82 (1H, oct, J )
.6 Hz, CH(CH ), 1.41 (3H, t, J ) 6.9 Hz, CH CH ), 1.18 (3H,
CH ), 1.09 (3H, d, J ) 6.6 Hz, CH(CH )CH ),
.98 (3H, d, J ) 6.6 Hz, CH(CH ); C NMR (100 MHz) δ
60.4, 153.3, 148.2, 142.2, 139.4, 139.2, 136.2, 132.8, 132.5, 132.3,
31.5, 131.1, 129.3, 123.1, 73.3 (NCH), 69.3 (CH O), 42.2 (CH
), 42.0 (CH CH ), 34.8, 34.4, 34.1, 33.2 (CH(CH ), 30.7 (C-
), 19.2 (CH(CH )CH ), 18.8 (CH(CH )CH ), 14.5 (CH CH ), 13.5
CH CH ); IR (CHCl NCdO), 1653 (Cd
3
)
2
2
3
t, J ) 7.1 Hz, CH
2
3
3
3
2
4
13
0
1
1
CH
2
3
)CH
3
concentrated. Flash column chromatography with gradient elution
(petroleum ether/DCM/EtOAc ) 32:7:1 f 31:7:2) gave the title
2
2
-
compound as a white crystalline solid (0.52 g, 46%): R (petroleum
f
2
0
3
2
3
3
)
2
ether/DCM/EtOAc ) 7:2:1) 0.55; mp 88.0-91.0 °C; [R] -12
D
1
3
3
3
3
3
2
3
(c 0.30, CHCl ); H NMR (300 MHz) δ 7.56 (2H, m), 7.34 (2H,
-
1
(
2
3
3
, cm ) νmax 1716 (Et
2
m), 7.15 (3H, m), 7.10 (3H, m), 6.87 (1H, br d, J ) 8.0 Hz), 6.77
(1H, br d, J ) 8.0 Hz), 6.55 (2H, m), 6.40 (1H, d, J ) 7.8 Hz,
+
+
N); MS (EI, m/z) 435 (28), 434 (M , 100), 391 (M - i-Pr, 3),
+
3
(
61 (8), 334 (M - CONEt
12), 230 (CH (O)(oxazoline)CH
, 434.2569; found, 434.2569.
)-Trifluoromethansulfonic Acid [4-(5-(4-iso-
2
, 28), 305 (6), 271 (8), 257 (6),243
H-7), 6.35 (1H, dd, J ) 7.8 Hz, J
H-P
) 3.7 Hz, H-8), 3.52 (1H, t,
+
2
C
6
H
2
2
, 40), 100 (60); HRMS
J ) 8.1 Hz, CHHO), 3.33 (1H, m, NCH), 3.16 (1H, dd, J ) 9.9,
8.1 Hz, CHHO), 3.09-2.80 (5H, m), 2.68 (2H, m), 2.41 (1H, m,
34 2 3
calcd for C27H N O
(
-)-(S,4S
P
,5R
P
H-2b), 1.65 (1H, oct, J ) 6.7 Hz, CH(CH
3 2
) ), 0.94 (3H, d, J ) 6.7
13
Propyloxazolin-2-yl)-[2.2]paracyclophanyl)] Ester (18a). A solu-
tion of diol 15a (0.19 g, 0.53 mmol) and pyridine (0.1 mL, 1.27
mmol) in DCM (1.5 mL) was added dropwise to a solution of Tf O
2
Hz, CH(CH )CH ), 0.83 (3H, d, J ) 6.7 Hz, CH(CH
3
3
3 3
)CH );
C
NMR (75 MHz) δ 163.2 (CdN), 145.5 (d, JC-P ) 8.9 Hz), 142.0
(d, JC-P ) 12.5 Hz), 140.1 (d, JC-P ) 9.5 Hz), 139.5, 138.8, 138.7,
138.3, 138.0, 135.5, 134.6, 133.3, 133.2, 133.0, 132.9, 131.7,
131.64, 131.57, 131.2, 128.5, 128.4, 128.3, 128.0 (2C, s), 127.9,
(0.19 mL, 1.11 mmol) in DCM (0.5 mL) at 0 °C. After stirring for
1
.5 h, the solution was warmed to room temperature and stirred
for an additional 2 h. Water (6 mL) was added, and the aq layer
72.7 (NCH), 68.5 (CH
33.5, 32.2 (CH(CH
MHz) δ 0.20; IR (CHCl
2
O), 36.4 (d, JC-P ) 6.5 Hz, C-2), 34.7, 34.6,
31
was separated and extracted with DCM (3 × 6 mL). The combined
3 2 3 3
) ), 19.7 (CH ), 18.2 (CH ); P NMR (121
-
1
organic layers were dried over Na
2
SO
4
, filtered, and concentrated.
3
, cm ) νmax 1653 (CdN); MS (EI, m/z)
+
+
Flash column chromatography with gradient elution (pentane/EtOAc
19:1 f 9:1) gave the title compound as a colorless oil (0.18 g,
3%): R
504 (37), 503 (M , 100), 502 (17), 488 (M - Me, 8) 461 (13),
+
)
7
460 (M - i-Pr, 39), 434 (17), 433 (36), 432 (45), 413 (9), 412
(petroleum ether/EtOAc ) 8:2) 0.52; [R]20
-26 (c 1.35,
); H NMR (400 MHz) δ 6.90 (1H, dd, J ) 7.7, 1.9 Hz),
(31), 358 (15), 357 (24), 356 (27), 330 (22), 329 (49), 328 (58),
f
1
D
+
CHCl
3
322 (14), 308 (20), 104 (CH
34PNO, 503.2378; found, 503.2379.
(-)-(S,4R ,5S )-4-Diphenylphosphinyl-5-(4-iso-propyloxazo-
2
C
6 4
H
CH
2
, 8); HRMS calcd for
6
6
.82 (1H, dd, J ) 7.7, 1.7 Hz), 6.63 (1H, dd, J ) 7.7, 1.7 Hz),
34
C H
.62 (1H, d, J ) 8.0 Hz), 6.60 (1H, dd, J ) 7.7, 1.9 Hz), 6.58 (1H,
P
P
d, J ) 8.0 Hz), 4.42 (1H, dd, J ) 9.1, 7.7 Hz, CHHO), 4.18 (1H,
td, J ) 9.1, 6.6 Hz, NCH), 4.10 (1H, dd, J ) 9.1, 7.7 Hz, CHHO),
3
lin-2-yl)[2.2]paracyclophane (3b). Treatment of triflate 18b (0.84
g, 1.81 mmol), according to the procedure for the synthesis of 3a,
gave the title compound as a white crystalline solid (0.59 g, 65%):
.43 (1H, m), 3.36 (1H, ddd, J ) 13.5, 9.9, 4.1 Hz, H-2a), 3.23
J. Org. Chem, Vol. 71, No. 12, 2006 4617

Whelligan and Bolm
)CH
+, 50), 347 (13),
R
°
f
(petroleum ether/DCM/EtOAc ) 7:2:1) 0.32; mp 170.0-172.0
(6), 349 (13), 348 (CH
2
C
6
H
3
(P(C
6
H
4
OMe)
2
2
C; [R]20
-242 (c 1.04, CHCl
); H NMR (400 MHz) δ 7.58 (2H,
1
282 (8), 240 (8), 239 (9), 215 (10), 178 (9); HRMS calcd for C36
D
3
38
H -
m), 7.45 (2H, m), 7.23-7.18 (6H, m), 6.81 (1H, dd, J ) 8.0, 1.7
Hz), 6.63 (3H, m), 6.53 (1H, d, J ) 7.7 Hz, H-7), 6.42 (1H, dd, J
PNO , 563.2589; found, 563.2588.
3
(-)-(S,4S ,12S )-4-Di(4-methoxyphenyl)phosphinyl-13-(4-iso-
propyloxazolin-2-yl)[2.2]paracyclophane (19b). Further elution
gave the title compound as a white crystalline solid (0.06 g, 31%):
p
p
)
7.7 Hz, JH-P ) 3.8 Hz, H-8), 3.79 (1H, t, J ) 8.6 Hz, CHHO),
3
.68 (1H, dd, J ) 9.9, 8.6 Hz, CHHO), 3.63 (1H, ddd, J ) 13.0,
2.4, 5.8 Hz, H-9a), 3.08 (1H, ddd, J ) 13.2, 9.6, 3.9 Hz), 2.99
2
0
1
R (petroleum ether/Et O ) 8:2) 0.08; mp 147.0-149.0 °C; [R]
f
2
1
D
(2H, m, NCH, CHHCH
2
), 2.93-2.84 (3H, m), 2.76 (1H, ddd, J )
-50 (c 0.87, CHCl ); H NMR (300 MHz) δ 7.69 (1H, d, J ) 1.5
3
1
1
0
1
3.0, 9.6, 4.7 Hz), 2.49 (1H, ddd, J ) 13.7, 9.9, 4.4 Hz, H-2b),
.65 (1H, m, CH(CH ), 1.01 (3H, d, J ) 6.6 Hz, CH(CH )CH ),
.88 (3H, d, J ) 6.9 Hz, CH(CH ); C NMR (100 MHz) δ
62.4 (CdN), 145.4 (d, JC-P ) 9.9 Hz), 142.0 (d, JC-P ) 11.4
Hz, H-13), 7.40 (2H, dd, J ) 8.7 Hz, J
OMe (ortho)), 7.24 (2H, br dd, J ) 8.7 Hz, J
H-P
) 8.2 Hz, P-C H -
H-P
) 7.2 Hz, P-C H -
6
4
3
)
2
3
3
6
4
13
3
)CH
3
OMe (ortho)), 6.85 (2H, br d, J ) 8.7 Hz, P-C H OMe (meta)),
6
4
6.76 (2H, br d, J ) 8.7 Hz, P-C H OMe (meta)), 6.63 (1H, dd, J
6
4
Hz), 139.4, 138.90, 138.95, 138.0 (d, JC-P ) 9.1 Hz), 137.0, 136.8,
) 7.7, 1.5 Hz, H-15), 6.59 (1H, d, J ) 7.7 Hz, H-16), 6.55 (1H,
dd, J ) 7.8, 1.7 Hz, H-7), 6.45 (1H, dd, J ) 7.8 Hz, J ) 5.7
135.3 (2C, s), 133.4, 133.2, 133.1, 132.9, 132.2, 132.1, 131.4, 130.9,
H-P
128.4, 128.34, 128.26, 128.2, 127.9, 127.8, 72.6 (NCH), 69.3
Hz, H-8), 5.89 (1H, dd, J
H-P
) 8.4 Hz, J ) 1.7 Hz, H-5), 4.32-
(
(
CH
CH
2
O), 36.5 (d, JC-P ) 9.1 Hz, C-2), 35.0, 34.8, 34.2, 33.1 (CH-
4.18 (2H, m, OCHH, H-10a), 4.00-3.90 (2H, m, NCH, OCHH),
31
3 2 3 3 3 3
) ), 19.6 (CH(CH )CH ), 19.2 (CH(CH )CH ); P NMR (162
3.79 (3H, s, OCH ), 3.74 (3H, s, OCH ), 3.45 (1H, ddd, J ) 12.9,
3
3
-
1
MHz) δ 1.48; IR (CHCl
3
, cm ) νmax 1651 (CdN); MS (EI, m/z)
9.7, 6.7 Hz, H-1a), 3.27 (1H, br dd, J ) 13.6, 9.7 Hz, H-2a), 3.05
(2H, m, H-1b, 9a), 2.81-2.62 (3H, m, H-9b, H-2b, 10b), 1.53 (1H,
oct, J ) 6.7 Hz, CH(CH ) ), 1.00 (3H, d, J ) 6.7 Hz, CH(CH )-
+
+
5
4
04 (37), 503 (M , 100), 502 (19), 488 (M - Me, 10) 461 (10),
+
60 (M - i-Pr, 28), 434 (25), 433 (57), 432 (63), 413 (19), 412
3
2
3
1
3
(64), 358 (13), 357 (24), 356 (36), 330 (39), 329 (75), 328 (93),
CH ), 0.88 (3H, d, J ) 6.7 Hz, CH(CH )CH ); C NMR (75 MHz)
3
3
3
+
3
C
22 (27), 308 (22), 104 (CH
34PNO, 503.2378; found, 503.2378.
+)-(S,4R ,12R )-4-Di(4-methoxyphenyl)phosphinyl-13-(4-iso-
2
C
6
H
4
CH
2
, 22); HRMS calcd for
δ 162.7 (CdN), 160.4 (MeOC), 159.9 (MeOC), 143.0 (d, J
C-P
)
34
H
17.9 Hz), 140.8, 139.7, 139.5, 138.7 (d, JC-P ) 10.7 Hz), 137.7,
(
p
p
137.3, 135.6, 134.9, 134.4, 134.3, 134.2, 134.1, 132.5, 131.6 (d,
propyloxazolin-2-yl)[2.2]paracyclophane (19a). n-BuLi (15% w/v
solution in n-hexane, 0.23 mL, 0.53 mmol) was added dropwise to
a solution of the diastereomeric mixture of bromides 10 (0.14 g,
JC-P ) 4.8 Hz), 130.5 (d, J
) 7.1 Hz), 127.8 (d, J
C-P
) 7.7
C-P
Hz), 127.6, 113.9 (2C, s), 113.8, 113.7, 73.1 (NCH), 69.1 (OCH ),
2
3
3
C-P
55.08 (OCH ), 55.05 (OCH ), 36.4 (C-10), 35.5 (d, J ) 9.5
0.35 mmol) in THF (3.5 mL) at -78 °C to give an orange solution.
3 2 3 3
Hz, C-2), 34.0, 33.5 (CH(CH ) ), 33.0, 19.4 (CH(CH )CH ), 18.9
31
-1
After stirring for 1.5 h, a solution of chlorodi(4-methoxyphenyl)-
phosphine (0.21 g, 0.74 mmol) in THF (0.5 mL) was added
dropwise to give a black solution that slowly became orange. After
(CH(CH )CH ); P NMR (121 MHz) δ -4.70; IR (CHCl , cm )
3
3
3
+
νmax 1638 (CdN); MS (EI, m/z) 564 (35), 563 (M , 100), 562 (18),
+
548 (M - Me, 4) 478 (5), 349 (12), 348 (CH C H (P(C H -
2
6
3
6
4
+
1
0 min, the cooling bath was removed, and the reaction mixture
was stirred for an additional 3 h. Ordinary “wet” Et N (0.1 mL,
.71 mmol) was added, followed by Et O (3 mL), and the resulting
OMe) )CH2 , 49), 347 (12), 282 (8), 240 (7), 239 (9), 215 (9);
2
3
HRMS calcd for C H PNO , 563.2589; found, 563.2590.
36
38
3
0
2
General Procedure for the Palladium-Catalyzed Allylic Alkyl-
ation of 1,3-Diphenyl-2-propenyl Acetate.25 [Pd(η -C H )Cl] (3.7
3
mixture was added to silica gel (1.4 g) and DCM (3 mL). The
solvent was evaporated to leave the crude product mixture
suspended on silica, which was added to the top of a column of
silica gel for flash chromatography with gradient elution (pentane/
3
5
2
mg, 0.01 mmol) and the appropriate ligand (0.03 mmol) were
dissolved in toluene (2.0 mL) and stirred for 1 h. A solution of
1,3-diphenyl-2-propenyl acetate41 (0.13 g, 0.50 mmol) in toluene
(1.0 mL) was added, and the solution was stirred for 0.5 h.
Dimethylmalonate (0.17 mL, 1.50 mmol), then N,O-bis(trimethyl-
silyl)acetamide (0.37 mL, 1.50 mmol), and LiOAc (1 mg, 0.015
mmol) were added. The reaction was monitored by TLC [starting
material, R (petroleum ether/EtOAc ) 9:1) 0.51; product, R 0.34]
Et
solid (0.06 g, 32%): R
9.0-81.0 °C; [R]20
+19 (c 0.96, CHCl
δ 7.61 (1H, br s, H-13), 7.32 (2H, br dd, JH-P ) 8.7 Hz, J ) 7.9
Hz, P-C OMe (ortho)), 7.23 (2H, br dd, JH-P ) 8.7 Hz, J )
.6 Hz, P-C OMe (ortho)), 6.85 (2H, br d, J ) 7.6 Hz, P-C
OMe (meta)), 6.77 (2H, br d, J ) 7.9 Hz, P-C OMe (meta)),
.62 (1H, dd, J ) 7.9, 1.7 Hz, H-15), 6.58 (1H, d, J ) 7.9 Hz,
2
O ) 9:1 f 8:2 f 7:3. This gave the title product as a white
f
(petroleum ether/Et O ) 8:2) 0.21; mp
2
1
7
D
3
); H NMR (300 MHz)
6
H
4
f
f
7
H
6 4
6 4
H -
until completion. DCM (15 mL) was then added, and the solution
H
6 4
was washed with aq saturated NH Cl solution (2 × 10 mL), dried
4
6
over MgSO , filtered, and concentrated. Flash column chromatog-
4
H-16), 6.54 (1H, dd, J ) 7.7, 1.8 Hz, H-7), 6.45 (1H, dd, J ) 7.7
Hz, JH-P ) 5.4 Hz, H-8), 5.88 (1H, dd, JH-P ) 8.4 Hz, J ) 1.8
Hz, H-5), 4.34 (1H, m, OCHH), 4.18 (1H, br dd, J ) 12.4, 9.3 Hz,
H-10a), 3.92 (2H, m, NCH, OCHH), 3.80 (3H, s, OCH
s, OCH
raphy (petroleum ether/EtOAc ) 9:1) gave the product as a clear
oil that slowly crystallized. The ee was determined by HPLC
analysis [(Chiralcel AD column, heptane/i-PrOH ) 95:5), flow rate
) 0.5 mL min , t ) 30.6 min, t ) 43.3 min].
-
1
3
), 3.74 (3H,
), 3.43 (1H, ddd, J ) 12.9, 9.9, 6.7 Hz, H-1a), 3.26 (1H,
R
S
3
br dd, J ) 13.6, 9.9 Hz, H-2a), 3.02 (2H, m, H-1b, 9a), 2.86 (1H,
ddd, J ) 12.6, 9.3, 7.4 Hz, H-9b), 2.78-2.61 (2H, m, H-2b, 10b),
Acknowledgment. This work was supported by the Fonds
der Chemischen Industrie, the Deutsche Forschungsgemeinschaft
DFG) within the Collaborative Research Center (SFB) 380
Asymmetric Synthesis by Chemical and Biological Methods”,
and DIP-G 7.1. D.W. is grateful to the Alexander-von-Humboldt
Stiftung for a postdoctoral fellowship.
1
CH
.74 (1H, oct, J ) 6.7 Hz, CH(CH ) ), 1.00 (3H, d, J ) 6.7 Hz,
3 2
(
“
13
3
), 0.88 (3H, d, J ) 6.7 Hz, CH
3
); C NMR (75 MHz) δ 161.9
(CdN), 160.4 (MeOC), 159.9 (MeOC), 142.9 (d, JC-P ) 17.9 Hz),
1
1
1
1
5
3
41.1, 140.1, 139.5, 138.8 (d, JC-P ) 12.0 Hz), 137.3, 137.0, 135.3,
34.8, 134.5, 134.2, 134.1, 133.9, 132.6, 130.9 (d, JC-P ) 4.7 Hz),
30.0 (d, JC-P ) 7.5 Hz), 127.9 (d, JC-P ) 8.3 Hz), 127.6, 113.9,
13.8 (2C, s), 113.7, 73.6 (NCH), 68.8 (OCH
5.06 (OCH ), 36.1 (C-10), 35.3 (d, JC-P ) 9.5 Hz, C-2), 33.8,
3.0 (2C, s), 19.3 (CH ); P NMR (121 MHz) δ -4.64;
Supporting Information Available: Detailed preparative de-
2 3
), 55.13 (OCH ),
1
13
scriptions for compounds 10a,b, 2a,b, and 20-22a,b. H and
C
3
NMR spectra of all new compounds (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
31
3
), 18.3 (CH
3
, cm ) νmax 1642 (CdN); MS (EI, m/z) 564 (33), 563
3
-
1
IR (CHCl
+
+
+
(M , 100), 562 (11), 548 (M - Me, 4), 460 (M - i-Pr, 9), 478
JO060668H
4618 J. Org. Chem., Vol. 71, No. 12, 2006