Synthesis of dirhodium(II) tetrakis[methyl 1-(3-phenylpropanoyl)-2- oxaimidazolidine-4(S)-carboxylate], Rh2(4S-MPPIM)4

Article abstract of DOI:10.1016/j.tetasy.2003.08.035

The large-scale synthesis with greatly improved yields of methyl 1-(3-phenylpropanoyl)-2-oxaimidazolidine-4(S)-carboxylate and the chiral dirhodium(II) carboxamidate derived from it, Rh₂(4S-MPPIM) ₄, is described. The key step in the

Full text of DOI:10.1016/j.tetasy.2003.08.035

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3601–3604
Synthesis of dirhodium(II) tetrakis[methyl
1-(3-phenylpropanoyl)-2-oxaimidazolidine-4(S)-carboxylate],
Rh2(4S-MPPIM)4
Michael P. Doyle* and John T. Colyer
Department of Chemistry, University of Arizona, Tucson, AZ 85721, USA
Received 23 June 2003; accepted 7 August 2003
Abstract—The large-scale synthesis with greatly improved yields of methyl 1-(3-phenylpropanoyl)-2-oxaimidazolidine-4(S)-car-
boxylate and the chiral dirhodium(II) carboxamidate derived from it, Rh2(4S-MPPIM)4, is described. The key step in the overall
synthesis is the Hofmann rearrangement of Boc-protected
near quantitative yield.
L
-asparagine, the procedure for which has been modified to achieve
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
2-Oxaimidazolines, as cyclic ureas, have attracted con-
siderable attention because of their applicability as HIV
protease inhibitors,1 5HT3 receptor antagonists,2
amongst others.3 They are also useful chiral auxiliaries
in a variety of highly diastereoselective reactions.4 Vari-
ous methods for their synthesis have been reported,5
but those derived from amino acids remain important.6
Our interest in 2-oxaimidazolines stems from their use
as chiral ligands for dirhodium(II)7 with the resulting
chiral imidazolidinone-ligated catalysts 1 proven to be
exceptionally valuable for asymmetric catalytic cyclo-
propanation,8 carbon–hydrogen insertion,9 and hetero-
Diels–Alder reactions.10 The most convenient access to
2. Results and discussion
Although the synthesis of Rh2(4S-MPPIM)4 on a 0.3
the ligands of these catalysts employs Boc-protected-L-
mmol scale has previously been reported,14 several steps
in its synthesis proved to be problematic when scaling
up. The first step of the synthesis, the Hofmann cycliza-
asparagine whose conversion to 2 via the Hofmann
rearrangement has until now remained problematic.
Even with the ‘improved procedure’11 in which a 65%
yield was reported, 2 could not be obtained in higher
than the reported 81%12 or 83% yield,13 with often low
yields of this product produced. To resolve this prob-
lem we have modified the Hofmann procedure so that
we can routinely prepare 2 on a 60 g scale in nearly
quantitative yield. This synthesis and its application to
the preparation of 1b is reported herein.
tion of carbobenzyloxy- -asparagines, 3 (Eq. (1)), was
L
particularly troublesome, as impurities or incomplete
conversion made crystallization of the desired product
difficult. The most important discovery for this step
was that excess bromine should not be used, as the
resultant impurities made the product difficult to iso-
late. The optimal conditions to minimize the formation
of impurities proved was the use of a slight molar
excess of bromine (0.05 equiv.) to allow for evaporation
that occurs during addition, along with a three-fold
molar excess of sodium hydroxide, which was required
to generate sodium hypobromite. If there was a stoi-
chiometric match between the sodium hypobromite in
* Corresponding author. E-mail: mdoyle@u.arizona.edu
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.08.035

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M. P. Doyle, J. T. Colyer / Tetrahedron: Asymmetry 14 (2003) 3601–3604
solution and carbobenzyloxy-
L
-asparagine, the solution
The procedure for imidazolidinone ligand exchange
with rhodium(II) acetate (Eq. (2)) is well documented,14
although a large-scale synthesis of an imidazolidinone-
based dirhodium(II) carboxamidate catalyst has not
been reported.16 This reaction was performed on a 2.0
gram scale of rhodium(II) acetate. After chromatogra-
phy and recrystallization, 4 g of (2,2-cis)-Rh2(4S-
MPPIM)4 (CH3CN)2, 1b, was obtained as red crystals
(65% yield). Excess unreacted ligand was recovered in
90% yield through column chromatography without
loss of enantiomeric excess. Large scale reactions per-
formed using 4 g of the aforementioned catalyst 1b
could be expected to produce nearly one-third mole of
product at 1.0 mol% catalyst loading.9 If the amount of
catalyst were dropped to 0.1 mol%, then up to three
moles of product could be expected.10
became colorless upon completion of the addition. If
the solution retained a yellow color after addition or
became colorless before all of 3 was added, then 2 was
generally difficult to isolate in high yield and/or purity.
After optimization as described, the reaction was per-
formed conveniently on 60 g-scale resulting in 99%
isolated yields of 3 as a white powder.
(1)
The Fischer esterification of 2 also proceeded smoothly
on a large scale (Scheme 1). In this reaction, thionyl
chloride was the source of anhydrous hydrogen chlo-
ride. However, when more than a slight molar excess of
bicarbonate solution was used to quench the acid, a
lower yield of 4 was obtained. Purification of 4 by
column chromatography was not required. Yields were
high (95%) and, while the desired product was a white
powder, a slight yellow color was shown to be accept-
able. A prior report of the same chemistry described the
formation of 4 in 81% yield.15
(2)
The imidazolidinone series of carboxamidate-ligated
dirhodium compounds is unique in the formation of
isomeric dirhodium(II) compounds (Scheme 2)—those
in which three nitrogens and one oxygen (or three
oxygens and one nitrogen) are bound to rhodium [the
(3,1)-isomer]14 or four nitrogens (or four oxygens) are
bound [the (4,0)-isomer].17 As previously documented
on smaller scale reactions, these isomers are in equi-
librium with one another under the reaction conditions
and, over time, the (4,0)-isomer will convert to a mix-
ture of the (cis-2,2)- and (3,1)-isomers. However, the
(3,1)-isomer and (cis-2,2)-isomer constitute a 1:5 equi-
librium mixture. Fortunately, chromatographic separa-
tion is easily achieved, and further ligand exchange
under equilibrium conditions will convert the (3,1)-iso-
mer to the equilibrium mixture.
Attachment of the N-acyl group to 4 was accomplished
in 98% isolated yield with 1.1 molar equiv. of hydrocin-
namoyl chloride, rather than the 2.0 equiv. used in the
prior report.14 Purification of 5 by column chromatog-
raphy on silica gel removed any impurities that would
adversely affect the subsequent deprotection step.
The deprotection of 5 proceeded well with 5% palla-
dium on carbon in methanol with the catalyst loading
at 0.1% in Pd; the rate can be greatly increased with the
use of palladium black at atmospheric pressure. This
reaction afforded a white solid in 93% yield, whereas a
colorless oil has been reported in the past.14 Recogniz-
ing that the formation of oil might be due to the
presence of ethyl acetate trapped in 6 from column
chromatography, addition of diethyl ether to the chro-
matographed sample and concentration under reduced
pressure produced the white solid.
3. Conclusions
The process described here reports the four-step synthe-
sis of imidazolidinone 6 on an initial 60 g scale in 87%
overall yield, which represents a nearly 20% improve-
ment over that previously reported.14 An increase in the
yield of the derivative chiral dirhodium(II) carboxami-
date catalyst 16 from the earlier 0.23 g scale reaction14
has also been achieved.
Scheme 2.
Scheme 1.

M. P. Doyle, J. T. Colyer / Tetrahedron: Asymmetry 14 (2003) 3601–3604
3603
4. Experimental
solution washed with cold 1 M HCl (2×75 mL), satu-
rated NaHCO3 (1×100 mL), and brine (1×100 mL). The
organic solution was dried over anhydrous MgSO4,
filtered and concentrated to afford a yellow oil. Purifi-
cation by column chromatography on silica gel (ethyl
acetate:hexanes, 1:2) yielded 21.7 g of 6 (52.8 mmol,
98% yield) as a white solid.14
4.1. General
All compounds have been previously synthesized, and
references to physical and spectroscopic data refer to
the original publications.11–17 Compounds reported
were analyzed for purity by comparison with published
data. Solvents were dried by conventional methods.
-asparagine and rhodium(II) acetate
were obtained commercially.
4.5. Methyl 1-(3-phenylpropanoyl)-2-oxaimidazolidine-
4(S)-carboxylate 6
Carbobenzyloxy-
L
Hydrogenolysis of a solution containing 5 (15.0 g,
36.5), methanol (150 mL), and 5% Pd/C (75 mg, 0.1%
Pd) with H2 (40 psi) was performed with a Parr hydro-
genator for 12 h. Dichloromethane (40 mL) was added
and the mixture filtered through Celite. The resulting
colorless solution was concentrated under reduced pres-
sure to afford an oil which was subsequently purified
via column chromatography on silica gel (ethyl ace-
tate:hexanes 1:1). A small amount of 5 was isolated
(0.59 g, 1.4 mmol, 3.9%). The title compound 7 was
obtained as a colorless oil after evaporation of the
solvent, at which time diethyl ether was added and
removed under reduced pressure, giving 7 (9.34 g, 33.9
mmol) as a white solid in 93% yield, mp 82–83°C,
[h]2D3=+27.8 (c 1.82 in CHCl3); lit.14 [h]2D3=+26.0 at the
same concentration in CHCl3.
4.2. 3-Benzyloxycarbonyl-2-oxaimidazolidinone-4(S)-
carboxylic acid 3
A 1.0 L round bottom flask was charged with sodium
hydroxide (29.8 g, 744 mmol) and 600 mL of distilled
water and then cooled to 0°C. Bromine (11.7 mL, 243
mmol) was placed in an addition funnel, protected from
evaporation with a layer of distilled water, and then
added slowly over 30 min to the sodium hydroxide in
water to yield a clear yellow solution. Dry carbobenzyl-
oxy-L-asparagine (60.0 g, 225 mmol) was added as a
solid through a funnel over a period of 2 min. The
resulting clear, colorless solution was then heated at
55°C for 3 h. After cooling, the reaction mixture was
washed with diethyl ether (2×50 mL), then acidified to
pH 1 with 6 M HCl which precipitated a white solid.
After cooling overnight in a refrigerator, the solution
was filtered and the white solid dried under vacuum to
afford 58.9 g of 3 (737 mmol, 99% yield). The physical
and spectral data correspond to those previously
published.11–13
4.6. Dirhodium(II) tetrakis[methyl 1-(3-phenyl-
propanoyl)-2-oxaimidazolidine-4(S)-carboxylate],
Rh2(4S-MPPIM)4 1b
A 100 mL two neck round bottom flask equipped with
a Soxhlet extractor and reflux condenser was assembled
while still warm (from being flame-dried) under a flow
of argon. A drying thimble filled with an oven-dried
mixture of sodium carbonate and sand (2:1) and capped
with glass wool was placed in the Soxhlet extractor
during assembly. Dirhodium(II) acetate (2.0 g, 4.52
mmol), methyl 1-(3-phenylpropanoyl)-2-oxaimidazo-
lidine-4(S)-carboxylate 7 (10.0 g, 36.2 mmol) and
chlorobenzene (65 mL) were added to the flask through
the open neck. The neck was then closed with a septum,
and the solution heated at a vigorous reflux for 16
hours. Progress of the exchange reaction was monitored
by HPLC using a 3.9×150 mm reverse-phase-CN resin
column. As the ligand band (2.6 min) became smaller, a
major band appeared at 9.6 min (the 2,2-cis isomer),
followed by two smaller bands at 15 and 19 min,
respectively. When no further change was observed by
HPLC, the reaction mixture was concentrated and
purified via column chromatography on a reverse phase
Bakerbond® CN resin (100% methanol to 99:1
methanol:acetonitrile). The first band, light brown in
color, was excess ligand, while the following pink band
was the desired (2,2-cis)-1b isomer. The (3,1) and (4,0)
isomers remained at the top of the column and were
eluted together using acetonitrile. After concentrating
the (2,2-cis) fraction, a purple powder resulted. To this
residue was added methanol (100 mL), and acetonitrile
was added dropwise with gentle heating until the solid
was completely dissolved (approx. 10 mL). The result-
ing red solution was placed in a refrigerator at 10°C
4.3. Methyl 3-benzyloxycarbonyl-2-oxaimidazolidinone-
4(S)-carboxylate 4
To a stirred solution of 3-benzyloxycarbonyl-2-oxaimi-
dazolidine-4(S)-carboxylic acid 2 (30.0 g, 114 mmol) in
methanol (400 mL), (6.75 g, 56.8 mmol) was added
thionyl chloride (6.75 g, 56.8 mmol) dropwise at room
temperature. The solution was allowed to stir for 24 h,
at which time methanol was removed under reduced
pressure to yield a white powder. This solid was dis-
solved in dichloromethane (300 mL), washed with 5%
NaHCO3 (100 mL), dried over anhydrous MgSO4,
filtered, and concentrated to afford 30.0 g of 4 (108
mmol, 95% yield).12,15
4.4. Methyl 1-(3-phenylpropanoyl)-3-benzyloxycarbonyl-
2-oxaimidazolidine-4(S)-carboxylate 5
To a 250 mL round bottom flask fitted with a reflux
condenser was added 4 (15.0 g, 53.9 mmol), 4-dimethyl-
aminopyridine (0.66 g, 5.39 mmol) and 150 mL of
distilled dichloromethane, then pyridine (8.70 mL, 108
mmol). The flask was flushed with nitrogen, cooled to
0°C at which point hydrocinnamoyl chloride (8.30 mL,
59.3 mmol) was added dropwise over 30 min via syringe
pump. After stirring at 0°C for an additional 30 min,
the reaction mixture was heated at reflux overnight to
afford a brown solution. After cooling to room temper-
ature, 150 mL of dichloromethane was added, and the

3604
M. P. Doyle, J. T. Colyer / Tetrahedron: Asymmetry 14 (2003) 3601–3604
where red crystals slowly formed over the next 6 days.
The crystals were removed by filtration, washed with a
minimal amount of cold methanol, and dried under
John Wiley & Sons: New York, 1987.
7. (a) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern
Catalytic Methods for Organic Synthesis with Diazo Com-
pounds: From Cyclopropanes to Ylides; John Wiley &
Sons: New York, 1998; Chapter 2; (b) Doyle, M. P. In
Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.;
John Wiley & Sons: New York, 2000; Chapter 5.
8. Doyle, M. P.; Zhou, Q.-L.; Dyatkin, A. B.; Ruppar, D.
A. Tetrahedron Lett. 1995, 36, 7579.
vacuum to give 4.08
g
of (2,2-cis)-Rh2(4S-
MPPIM)4(CH3CN)2 1 (2.94 mmol, 65% yield). The
purity of the crystals was determined to be greater than
99.5% by HPLC and [h]D23 was the same (−310) as that
previously reported.14 The recovered ligand was
purified via column chromatography (SiO2; ethyl ace-
tate) to afford 4.48 g of a white solid that was spectro-
scopically identical to 6, mp 81–82°C, without loss of
enantiomeric purity [h]2D3=+27.7 (c1.82, CHCl3).
9. (a) Doyle, M. P.; Hu, W.; Valenzuela, M. V. J. Org.
Chem. 2002, 67, 2954; (b) Doyle, M. P.; Catino, A. J.
Tetrahedron: Asymmetry 2003, 14, 925.
10. Doyle, M. P.; Phillips, I. M.; Hu, W. J. Am. Chem. Soc.
2001, 123, 5366.
11. (a) Shiba, T.; Koda, A.; Kusomoto, S.; Kaneko, T. Bull.
Chem. Soc. Jpn. 1968, 41, 2748; (b) Schneider, F. Liebigs
Ann. Chem. 1937, 529, 1.
12. Doyle, M. P.; Austin, R. E.; Bailey, A. S.; Dwyer, M. P.;
Dyatkin, A. B.; Kalinin, A. V.; Kwan, M. M. Y.; Liras,
S.; Oalmann, C. J.; Pieters, R. J.; Protopopova, M. N.;
Raab, C. E.; Roos, G. H. P.; Zhou, Q.-L.; Martin, S. F.
J. Am. Chem. Soc. 1995, 117, 5763.
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