Chiral dirhodium(II) carboxamidate-catalyzed [2 + 2]-cycloaddition of TMS-ketene and ethyl glyoxylate

Article abstract of DOI:10.1002/adsc.200404245

The [2 + 2]-cycloaddition reaction between ethyl glyoxylate and trimethylsilylketene is reported. Enantiomeric excesses up to 83% have been achieved with the use of only 1.0 mol % of a previously unreported chiral imidazolidinone-ligated dirhodium(II) carboxamidate catalyst. An extensive survey of chiral catalysts has shown that enantiocontrol for cycloaddition increases as the steric bulk of the ligand is increased. However, enantioselectivity is increased to 99% ee by the addition of 10 mol % of quinine as a co-catalyst with a chiral dirhodium(II) azetidinone-ligated catalyst, and there is a significant decrease in reaction time.

Full text of DOI:10.1002/adsc.200404245

FULL PAPERS
Chiral Dirhodium(II) Carboxamidate-Catalyzed
[2þ2]-Cycloaddition of TMS-Ketene and Ethyl Glyoxylate
Raymond E. Forslund,a James Cain,b John Colyer,b Michael P. Doylea,*
a
University of Maryland, Department of Chemistry and Biochemistry, College Park Maryland 20742, USA
Fax: (þ1)-301-414-9121, e-mail: mdoyle3@umd.edu
b
University of Arizona, Department of Chemistry, Tucson, Arizona 85721, USA
Received: August 4, 2004; Accepted: November 9, 2004
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: The [2 þ2]-cycloaddition reaction between 99% ee by the addition of 10 mol % of quinine as a
ethyl glyoxylate and trimethylsilylketene is reported. co-catalyst with a chiral dirhodium(II) azetidinone-li-
Enantiomeric excesses up to 83% have been achieved gated catalyst, and there is a significant decrease in
with the use of only 1.0 mol % of a previously unre- reaction time.
ported chiral imidazolidinone-ligated dirhodium(II)
carboxamidate catalyst. An extensive survey of chiral
catalysts has shown that enantiocontrol for cycloaddi- Keywords: [2þ2]-cycloaddition; dirhodium(II) car-
tion increases as the steric bulk of the ligand is in- boxamidates; ethyl glyoxylate; Lewis acid catalysis;
creased. However, enantioselectivity is increased to trimethylsilylketene
Introduction
with TON greater than 100 and selectivities up to 83%
ee in reactions that occur at room temperature.
Studies from this laboratory have shown that chiral di-
rhodium(II) carboxamidates are weak Lewis acids that
can be used as asymmetric catalysts for the hetero-
Diels–Alder reaction,[1] and recent results from Hashi-
moto have complimented this development.[2] High
enantioselectivities (>90%) have been obtained in re-
actions of aromatic aldehydes with Danishefskyꢀs diene,
and these reactions occur with turnover numbers (TON)
that exceed 10,000. The mechanism is reported to occur
through a concerted [4þ2]-cycloaddition, rather than
by a Mukiyama aldol pathway.[3] In our efforts to broad-
en the applicability of these catalysts in Lewis acid-cat-
alyzed reactions we have investigated the [2þ2]-cyclo-
addition reaction between ethyl glyoxylate (2) and tri-
methylsilylketene (1) [Eq. (1)] that was recently shown
ð1Þ
by Evans to be effectively promoted with high selectivity Results and Discussion
through catalysis by copper(II) triflate ligated to chiral
bis-oxazoline.[4]
Our study began with the investigation of the Lewis
Unlike the copper(II) catalysts that are capable of bi- acid-catalyzed [2þ2]-cycloaddition between trimethyl-
dentate coordination with substrate,[5] however, dirho- silylketene and ethyl glyoxylate utilizing a broad selec-
dium(II) catalysts possess only one available coordina- tion of chiral dirhodium(II) carboxamidate catalysts
tion site per rhodium.[6] This was thought to be a control- (5–8) as the Lewis acid. These catalysts were selected
ling factor in reactions with glyoxylates and that, with to be representative of the four classes of carboxamidate
chiral dirhodium(II) catalysis, use of these substrates ligated dirhodium(II) compounds that we have devel-
could yield product with low enantiocontrol. We report, oped – those with 2-oxapyrrolidine-5-carboxylate
however, that dirhodium(II) carboxamidates are effec- (4),[7] 2-oxaoxazolidine-4-carboxylate (5),[8] 2-oxaazeti-
tive catalysts for this cycloaddition reaction, operating dine-4-carboxylate[9] (6), and 2-oxaimidazolidine-4-car-
Adv. Synth. Catal. 2005, 347, 87–92
DOI: 10.1002/adsc.200404245
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tiocontrol was observed, likely the result of a mismatch
between chiral centers in the ligand that frustrates asym-
metric induction in the cycloaddition process. In the case
of the imidizolidinone catalyst system (entry 7!8),
however, only a modest increase (13!18% ee) was ob-
served by use of the N-(3-phenylpropanoyl) group in
place of the much smaller acetyl group. Based on these
observations we have incorporated a (ꢀ)-l-menthyl
group into the ester side chain of an imidizolidinone cat-
alyst in hope of increasing enantiocontrol of the [2þ2]-
cycloaddition reaction.
The synthesis of compound 12 began with the previ-
ously reported 4(S)-imidazolidinonecarboxylic acid 8,
which was esterified with (ꢀ)-l-menthol through a
DCC coupling to generate 9 as a white powder in 60%
yield (Scheme 1).[8] The N-acyl chain was then attached
using acetyl chloride in the presence of DMAP and pyr-
idine to afford 10 in an 84% yield. The carbobenzyloxy-
protected ligand was subjected to hydrogenolysis with
palladium black in ethyl acetate to afford ligand 11 in
78% yield after recrystallization. Catalyst 12 was suc-
boxylate[10] (7) ligands – but, as seen in Table 1, very low cessfully generated through standard ligand exchange
selectivity was achieved.
reaction with rhodium acetate in refluxing chloroben-
All reactions were slow at room temperature, taking zene[10] to yield a dark red powder that was subsequently
up to 3 days to reach completion; but in most cases recrystallized from boiling acetonitrile to afford com-
good to excellent product yields were achieved. The cis: pound 12 as red crystals in 40% yield. The crystals
trans ratio of the cycloaddition product 9 was deter- were of sufficient quality for an X-ray crystallographic
mined by integration of the 1H NMR resonance of H-4 structural determination. Table 2 reports selected
prior to desilylation [cis (4.95 ppm, d, J¼7.2 Hz); trans bond lengths and bond angles of 12.
(4.57 ppm, d, J¼4.5 Hz)].
With ethyl glyoxylate and TMS-ketene under the
Since electronic differences in these dirhodium(II) same conditions as reported for the reactions in Table 1,
catalysts[11] do not have a significant influence on enan- use of this catalyst formed b-lactone 3 in 90% yield after
tiocontrol (entries 2–4 and 6 and7), we looked to steric three days at room temperature. While Rh2(S,R-MAN-
influences from ligand attachments to increase selectiv- ICM)4 (12) possesses a rhodium-rhodium bond length
ity. Thus, when the pendant methyl ester of the 2-oxa- (2.46 ꢂ) and bond angles similar to catalyst 7 [Rh2(4S-
azetidine-4-carboxylate ligand was replaced by the MPPIM)4], it displayed much improved enantiocontrol
much bulkier l-menthyl ester, 4!5, a nearly five-fold (83% ee). We believe that the steric crowding of the
increase in enantioselectivity was observed. However, menthyl esters around the active rhodium site plays an
when the d-menthyl ester derivative was used, no enan- important role in enhancing enantiocontrol.[12]
Table 1. Dirhodium(II) catalyst screening for [2þ2]-cycloaddition in Eq. (1).[a]
Entry
Catalyst
cis:trans[b]
Yield [%][c]
ee [%][d]
[e]
1
2
3
4
5
6
7
8
Rh2(OAc)4
13: 1
10: 1
62: 1
24: 1
22: 1
19: 1
99: 1
22: 1
90
16
90
79
74
65
99
40
NA
Rh2(5S-MEPY)4 (4)
4 (R)
24 (R)
5 (S)
28 (S)
0
Rh2(4S-MEOX)4 (5)
Rh2(4S-MEAZ)4 (6a)
Rh2(S,R-MenthAz)4 (6b)
Rh2(S,S-MenthAz)4 (6b)
Rh2(4S-MACIM)4 (7a)
Rh2(4S-MPPIM)4 (7b)
13 (R)
18 (R)
[a]
All reactions were performed with 0.498 mmol of ethyl glyoxylate.
The diastereomer ratio was determined by H NMR spectroscopy.
Yield [%]was determined by integration of H-4 and comparison of naphthalene internal standard.
Enantiomeric excess was determined by capillary GLC using a Cyclodex b column.
Reaction was complete in 20 h.
[b]
[c]
[d]
[e]
1
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[2þ2]-Cycloaddition of TMS-Ketene and Ethyl Glyoxylate
FULL PAPERS
Table 3. Effect of catalyst loading and temperature on yield
and selectivity.[a]
Entry
Catalyst
[mol %]
Temperature
[ 8C ]
Yield
[%][b]
ee [%]
1
2
3
4
5
1.0
0.5
0.1
1.0
1.0
24
24
24
4
90
77
39
57
99
83 (R)
73 (R)
50 (R)
82 (R)
59 (R)
35d
[a]
Reactions were performed as previously described using
Rh2(S,R-MANICM)4.
Yield determined by integration of H-4 and comparison of
naphthalene internal standard.
Enantiomeric excess was determined by capillary GLC
using a Cyclodex B-DM column.
Reaction was complete in 26 h.
[b]
[c]
[d]
With this application we investigated the effect of cat-
alyst loading of Rh2(S,R-MANICM)4 and of reaction
temperature on the outcome of the reaction (Table 3).
Lowering the amount of catalyst from 1.0 mol % to
0.5 mol % lowered product yield and reaction selectivi-
ty (entry 2), and a further decrease in yield and selectiv-
ity was observed when only 0.1 mol % of catalyst was
used (entry 3). Similar effects on selectivity and/or yield
were observed when the reaction temperature was var-
ied. Product yield diminished (57%) upon lowering the
temperature to 48C (entry 4) due to incomplete conver-
sion of starting material. On the other hand, increasing
the temperature to 358C reduced the reaction time to
26 h, while increasing product yield, but decreased
enantioselectivity to 59% ee (entry 5). Efforts to extend
this methodology beyond the use of ethyl glyoxylate, to
aromatic aldehydes and cinnamaldehyde, were unsuc-
cessful; cycloaddition was not observed.
Scheme 1.
Table 2. Selected bond lengths [ꢂ] and angles [8] for dirho-
dium(II) carboxamidate 12.
The specificity of this cycloaddition reaction for glyox-
ylate, and the low response from the catalysts reported
in Table 1, suggested a more complex process than had
been anticipated. In an effort to further optimize the re-
action conditions, we investigated the use of co-cata-
lysts. Confident that the chiral dirhodium(II) carboxa-
midate was activating the aldehyde based on previous
work on the hetero-Diels–Alder reaction,[1b] we be-
lieved that if activation of the ketene could be achieved
a decrease in reaction time would be observed. We chose
the Lewis base quinine as a co-catalyst due to its known
activation of ketenes[13] in an effort to shorten the reac-
tion time and possibly increase enantiocontrol. We hy-
ꢀ
ꢀ
ꢀ
Rh1 Rh2
2.459(4)
2.005(3)
2.073(3
O4 Rh2 Rh1
89.29(8)
176.54(9
91.66(13)
91.36(13)
175.57(12)
89.46(12)
ꢀ
ꢀ
ꢀ
Rh1 N2
N20 Rh1 Rh2
ꢀ
ꢀ
ꢀ
Rh2 O4
N2 Rh1 O14
ꢀ
ꢀ
ꢀ
Rh1 N20
2.214(4)
1.305(5)
1.444(5)
1.262(5)
1.411(5)
1.463(5)
1.545(6)
1.362(5)
1.233(5)
85.45(9)
N2 Rh1 N4
ꢀ
ꢀ
ꢀ
N2 C13
N2 Rh1 O11
ꢀ
ꢀ
ꢀ
N2 C12
O100 Rh2 O4
ꢀ
ꢀ
ꢀ
O4 C13
N2 Rh1 N20
97.97(13) pothesized that added steric bulk associated with the pu-
ꢀ
ꢀ
ꢀ
N1 C13
O4 Rh2 N2
92.42(12)
121.3(3)
126.4(3)
115.1(3))
111.2(3)
109.2(3)
tative ammonium ketene enolate would be beneficial in
increasing the selectivity of the reaction. One major con-
cern was whether or not the Cinchona alkaloid would in-
hibit the activity of the dirhodium(II) catalyst through
coordination of either the hindered tertiary amine or
the quinoline nitrogen. To test the compatibility of the
ꢀ
ꢀ
ꢀ
N1 C8
C13 N2 Rh1
ꢀ
ꢀ
ꢀ
C12 C8
C12 N2 Rh1
ꢀ
ꢀ
ꢀ
N1 C11
C13 O4 Rh2
ꢀ
ꢀ
ꢀ
O1 C11
N2 C13 N1
ꢀ
ꢀ
ꢀ
ꢀ
N2 Rh1 Rh2
C13 N1 C8
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Raymond E. Forslund et al.
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Table 4. Screening of dirhodium(II) catalysts with quinine for selectivity.
Entry
Catalyst
cis:trans[a]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
Rh2(OAc)4
none
1: 99
68
NR
34
84
87
85
88
85
33
36
90 (R)
Rh2(5S-MEPY)4 (4)
Rh2(4S-MEOX)4 (5)
Rh2(4S-MEAZ)4 (6a)
Rh2(4S-MACIM)4 (7a)
Rh2(4S-MPPIM)4 (7b)
Rh2(4S-MANICM)4 (12)
Rh2(5R-MEPY)4 (ent-4)
1: 99
1: 99
1: 99
1: 99
1: 99
1: 99
1: 99
1: 99
12 (R)
52 (R)
99 (R)
60 (R)
30 (R)
59 (R)
11 (R)
12 (S)
[d]
10
Rh2(5S-MEPY)4 (4)
[a]
1
Diastereomeric ratio determined by H NMR spectroscopy.
[b]
[c]
[d]
Yield determined by integration of H-4 and comparison of naphthalene internal standard.
Enantiomeric excess was determined by capillary GC using a Chiraldex b column.
Quinidine (10 mol %) used in place of quinine.
two catalysts, the reaction was performed under stand- (OAc)4 reaction solution, indicating nitrogen coordina-
ard conditions utilizing 1 mol % of Rh2(OAc)4 as the tion to the axial coordination site.[14] Preliminary results
Lewis acid and 10 mol % of quinine. The desired b-lac- in our laboratory lead us to believe that coordination
tone was obtained in 68% yield and 90% ee in 20 h at with Rh2(OAc)4 is to the quinoline nitrogen, and further
room temperature (Table 4, entry 1). To rule out the pos- investigation is currently underway to evaluate the val-
sibility that the reactivity and selectivity of this reaction idity of this claim.
were completely controlled by quinine, we performed
Since addition of Cinchona alkaloids proved fruitful in
the reaction under identical conditions in the absence increasing the enantiocontrol of the [2þ2] reaction, oth-
of Rh2(OAc)4 and observed no background reaction er tertiary chiral nitrogen sources were also investigated,
(entry 2). Confident that there was a synergistic effect including N-methyl-L-proline, 2,2’-isopropylidene-
between the two catalysts, we screened chiral dirhodi- bis[4(S)-4-tert-butyl-2-oxazoline] and 2,2’-isopropylid-
um(II) carboxamidate catalysts for the best possible inebis[4(S)-4-isopropyl-2-oxazoline].[15] In all cases mod-
match. The results from this investigation are summar- erate yieldsofb-lactonewereobtained (55–78%) inreac-
ized in Table 4.
tions ofTMS-keteneandethylglyoxylateperformedwith
In all cases an increase in enantioselectivity and a sig- rhodium acetate, but only with 4(S)-isopropyl-2-oxazo-
nificant decrease in reaction time were observed with line was any enantioselectivity (14% ee) observed. This
the most dramatic outcome being that with Rh2(4S- result suggests that in Evansꢀ bis-oxazoline-catalyzed
MEAZ)4 which gave a single enantiomer in high yield [2þ2]-cycloaddition reaction an excess of ligand is not
(entry 5). Interestingly, no change in enantioselectivity a contributor to reaction selectivity through independent
was observed in quinine-catalyzed reactions when the activation of the ketene for cycloaddition.
5R-MEPY was used in place of 5S-MEPY (entries 3
and 9); however, when quinidine was used in place of
quinine with 5S-MEPY (entry 10), a reversal of enantio- Conclusion
selectivity was observed. Since quinine and the dirho-
dium(II) catalysts both influence enantiocontrol of the We report the first example of the intermolecular [2þ
reaction, even though the influence of quinine is domi- 2]-cycloaddition reaction between ethyl glyoxylate and
nant, the change in % ee from the chiral catalyst trimethylsilylketene catalyzed by dirhodium(II). The
suggests that bifunctional catalysis is operative. The successful development and application of Rh2(S,R-
low yield of product with rhodium acetate and MNACIM)4 and other dirhodium(II) carboxamidate
Rh2(MEPY)4 (entries 1, 3, 9 and 10 ) may be a conse- catalysts[2] specifically for use as a Lewis acids opens
quence of rhodium catalyst inhibition due to association the door for further catalyst development in this arena.
of quinine at the axial coordination site of dirhodiu- The use of quinine as a co-catalyst with Rh2(4S-MEAZ)4
m(II). This rationale is substantiated by the observation suggests a novel bifunctional catalysis capable of excep-
of a red color upon addition of quinine to the green Rh2 tional enantiocontrol and enhanced reactivity.
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[2þ2]-Cycloaddition of TMS-Ketene and Ethyl Glyoxylate
FULL PAPERS
gas chromatography using a 30-m Chiraldex B-DM chiral col-
umn operated isothermally at 1008C. Typical values for the re-
tention times of the S and R enantiomers were 20.3 min and
22.1 min, respectively.
Experimental Section
Preparation of Trimethylsilylketene
To a stirred solution of 5.00 g (40% by wt. in hexanes,
28.0 mmol) of ethyl ethynyl ether in THF (100 mL) at 08C
was added 16.0 mL (2 M in THF, 32 mmol) of ethylmagnesium
chloride. The solution was stirred for 3 h with warming to room
temperature. After cooling to 08C, 4.0 mL (32.0 mmol) of
chlorotrimethylsilane were added, and the reaction was stirred
overnight (15 h) at room temperature. After concentration to
one-third of the original volume on a rotary evaporator,
100 mL of pentanes were added, and the resulting slurry was
decanted and filtered through Celite. Concentration under
vacuum was followed by distillation (408C/8 mm Hg) of trime-
Typical Procedure for Ketene/Aldehyde
Cycloadditions with Quinine
To a 0.5-dram vial containing 5 mmol of catalyst in 300 mL of an-
hydrous CH2Cl2 was added 16.0 mg (0.05 mmol) of quinine and
50.9 mg (0.50 mmol) of ethyl glyoxylate solution in 400 mL of
CH2Cl2. Next a solution of 70 mL (0.50 mmol) of trimethylsilyl-
ketene in 400 mL of CH2Cl2 was added. Finally, a solution of
50 mg of naphthalene in 200 mL of CH2Cl2 was introduced,
and the vial was sealed. The reaction was allowed to proceed
for three days before filtering the resulting reaction solution
through a plug of silica. After solvent evaporation, the crude
reaction mixture was analyzed by 1H NMR to obtain the yield
and the cis/trans ratio. The yield was determined by compari-
son of the integrated areas of the product and naphthalene.
The diastereomeric ratio was assessed using the integrations
of H-4 in the cis (4.95 ppm, d, J¼7.2 Hz) and trans
(4.57 ppm, d, J¼4.5 Hz) configured products.
thylsilylethoxyacetylene as
a
colorless oil. 1H NMR
(500 MHz): d¼0.01 (s, 9H), 1.26 (t, J¼7.0 Hz, 3H), 4.00 (q,
J¼7 Hz, 2H).
Thermolysis and distillation at 1208C and atmospheric pres-
sure gave trimethylsilylketene; yield: 1.14 g (35% overall);
1H NMR: d¼0.18 (s, 9H), 1.79 (s, 1H).
Distillation of Ethyl Glyoxylate
The silylated intermediate was dissolved in 2 mL of acetoni-
trile, followed by addition of 60 mg (1.0 mmol) of KF, and this
solution was stirred at room temperature for 20 min. Purifica-
tion was achieved by column chromatography on silica gel,
eluting with 30% diethyl ether in hexanes. Analyses were per-
formed as previously described.
Commercial ethyl glyoxylate/toluene solution (12–13 mL)
was added to an oven-dried 25-mL round-bottom flask, to
which a short path distillation apparatus was subsequently at-
tached. Heating at 140–1508C removed the majority of the tol-
uene, and raising the temperature of the oil bath to 160–1708C
allowed collection of the remaining ethyl glyoxylate/toluene
solution. The ratio of these components was determined by
1H NMR, and a 4:1 solution of ethyl glyoxylate to toluene
was typical.
Supporting Information
For the synthesis of imidazolidinones 9–11 and catalyst 12, and
for the crystallographic study of 12, see Supporting Informa-
tion.
Typical Procedure for Ketene/Aldehyde
Cycloadditions
To a 0.5-dram vial containing 5 mmol of catalyst in 300 mL of an-
hydrous CH2Cl2 was added 50.9 mg (0.50 mmol) of ethyl glyox-
ylate solution in 400 mL of CH2Cl2. Next a solution of 70 mL
(0.50 mmol) of trimethylsilylketene in 400 mL of CH2Cl2 was
added. Finally, a solution of 50.0 mg of naphthalene in
200 mL of CH2Cl2 was introduced, and the vial was sealed.
The reaction was allowed to proceed for three days before fil-
tering the resulting solution through a plug of silica. After sol-
vent evaporation, the crude reaction mixture was analyzed by
1H NMR to determine the yield and the cis/trans ratio. Product
yield was found by comparing the integrated areas of the prod-
uct and naphthalene. The diastereomeric ratio was assessed us-
ing the integrations of H-4 in the cis (4.95 ppm, d, J¼7.2 Hz)
and trans (4.57 ppm, d, J¼4.5 Hz) configured products.
Acknowledgements
We are grateful to the National Science Foundation and the Na-
tional Institutes of Health (GM-46503) for their support of this
research.
References and Notes
[1] a) M. P. Doyle, I. M. Phillips, W. H. Hu, J. Am. Chem.
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P. L. Huang, Proc. Natl. Acad. Sci. USA 2004, 101, 5391.
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Chem. Int. Ed. 2000, 39, 3558.
The silylated intermediate was dissolved in 2.0 mL of aceto-
nitrile, followed by addition of 60.0 mg (1.0 mmol) of KF with
stirring at room temperature for 20 min. Purification was ach-
ieved by column chromatography on silica gel, eluting with
1
30% diethyl ether in hexanes. H NMR (600 MHz): d¼1.34
(t, J¼7.2 Hz, 3H), 3.61 (dd, J¼4.8 Hz, 16.8 Hz, 1H), 3.79
(dd, J¼6.6 Hz, 16.8 Hz, 1H), 4.31 (m, 2H), 4.85 (dd, J¼
4.2 Hz, 6.6 Hz, 1H); 13C NMR (150 MHz): d¼14.0, 43.4, 62.4,
65.2, 165.7, 168.0. Enantiomeric excess was determined by
[4] D. Evans, J. M. Janey, Org. Lett. 2001, 3, 2125.
[5] J. S. Johnson, D. A. Evans, Acc. Chem. Res. 2000, 33, 325.
[6] M. P. Doyle, T. Ren, Prog Inorg Chem. 2001, 49, 113.
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[8] M. P. Doyle, A. B. Dyatkin, M. N. Protopopova, C. L.
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[12] The other diastereomer of the catalyst was also synthe-
sized and tested but provided no enantiocontrol.
[13] H. Wynberg, E. G. J. Staring, J. Am. Chem. Soc. 1982,
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[15] Reactions were performed under identical conditions as
previously described for the addition of quinine.
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ꢁ 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2005, 347, 87–92