Dirhodium(II) Carboxamidate and Carboxylate Catalysis:
A Study on Chemoselectivity
David C. Forbes,* Elvis J. Barrett, Daniel H. Bright, Brian O. Ezell and Shannon M. Stinson
Department of Chemistry, University of South Alabama, Mobile, Alabama 36608-0002 USA
E-mail: dforbes@jaguar1.usouthal.edu
Abstract The synthesis of C-1 substituted 3-oxa-2-oxobicyclo[3.1.0]hexyl systems is described. Reaction of 3methyl-2-butenyl diazoacetoacetate with dirhodium(II) tetraacetate resulted in complete conversion to the desired
acetyl bicyclic lactone derivative in one step. Upon switching to carboxamidate bridging ligands [Rh 2(5RMEPY)4] under identical reaction conditions (0.01 mol%), none of the desired product was observed. Cyclization
using dirhodium(II) carboxamidate catalysis was only observed when 3-methyl-2-butenyl diazoacetate was
employed.
Keywords: asymmetric catalysis, chemoselectivity, diazo carbonyl compound, intramolecular cyclization.
Introduction
Asymmetric catalysis is one of the most powerful and efficient methods for
stereoselective carbon-carbon bond formation (Noyori 1994; Ojima 1993).
This area of
chemistry continues to be a subject of considerable interest and intensive investigation. Under
appropriate reaction conditions, catalytic methodologies employing catalyst loading as low as
0.01 mol% can completely alter the reaction's outcome. That is, the enantio-, diastereo-, regioand chemodefining steps of a reaction can be modulated with the proper catalyst. Recent
advances in the area of improved chemical entities which highlight the pharmacological
properties of single isomers and not racemates state that changes in stereochemistry alone are
now considered impurities (Rogers 1998; Stinson 1997). This discovery reinforces the need to
understand existing methodologies while concurrently developing new and improved
methodologies in asymmetric catalysis.
Catalytic methods which enter the vast array of transformations that take place via metal
carbene intermediates are among the most versatile now available (Doyle et al. 1997).
Transformations encompassing catalytic diazocarbonyl decomposition include intra- and
intermolecular cyclopropanation, carbon-hydrogen insertion and ylide-type processes (Doyle
and Forbes 1998). Even though many transition metal complexes are relatively unselective,
when suitably modified with chiral, non-racemic ligands, extremely high levels of
stereoselectivity can result (Padwa and Austin 1994; Pfaltz 1993). Perhaps most notable are
intramolecular cyclopropanation reactions which afford compounds in high isolated yields of
greater than 95% enantiomeric excess as single diastereomers (Doyle et al. 1993).
The
catalysts employed in these reactions are unique because the transfer of chirality relies solely
on the ligated groups of the transition metals. Furthermore, each class within the realm of
diazocarbonyl chemistry has witnessed a level of substrate generality which has allowed for the
production of numerous compounds of both industrial and pharmaceutical importance (Doyle
et al. 1993).
The general framework for these cyclizations involves reaction of a diazocarbonyl
compound with a transition metal complex to form a metal carbene upon extrusion of
dinitrogen (Scheme 1).
This reactive intermediate i is suitably poised to undergo
intramolecular cyclization onto a pendant olefin affording a bicyclic lactone (1). Yet to be
Scheme 1
ML n
O
N2
O
N2
+
O
O
ML n
O
O
1
i
O
CH 3
ML n = Rh 2 L4 =
O
O
Rh
O
Rh
CH 3
O
O
Rh
3
H OCH
H
N
O
Rh
N
COOCH 3
dirhodium (II)
carboxylate
dirhodium (II)
carboxamidate
[Rh 2 (OAc)4 ]
[Rh 2 (5R-MEPY)4 ]
2
C-1
ML n
exploited in these processes are systems that afford C-1 substituted bicyclic templates.
Substitution on all other sites has been reported using dirhodium(II) carboxamidate catalysis.
We wish to now report on a highly chemoselective intramolecular cyclization yielding C-1
substituted bicyclic lactones using diazocarbonyl compounds in the presence of dirhodium(II)
carboxylate catalysis.
Materials and Methods
1
H NMR (300 MHz) and
13
C NMR (75 MHz) spectra were obtained as solutions in
CDCl3, and chemical shifts were reported in parts per million (ppm, ) downfield from internal
Me4Si (TMS).
Infrared spectra were recorded as a thin film on sodium chloride and
absorptions were reported in wavenumbers (cm-1). Anhydrous CH2Cl2 was dried over calcium
hydride for 24 h and then distilled prior to use.
Diketene and 3-methyl-2-buten-1-ol,
methanesulfonyl chloride were purchased from Aldrich and used without purification. Sodium
azide was purchased from Mallickrodt and used without purification. Methanesulfonyl azide
(mesyl azide) and dirhodium (II) catalyst Rh2(5R-MEPY)4 were prepared by standard methods
(Doyle et al. 1996); Rh2(OAc)4 was recrystallized from methanol prior to use.
Preparation of 3-methyl-2-butenyl diazoacetoacetate (2) To a cold solution (0C) consisting
of 3-methyl-2-buten-1-ol (5.2 ml, 51 mmol), triethylamine (TEA) (710 L, 5.1 mmol) and THF
(250 ml) was added dropwise via syringe diketene (7.8 ml, 101 mmol). The reaction mixture
was allowed to warm to room temperature and stir for an additional 18 h at which time mesyl
azide (7.4 g, 61 mmol) and TEA (8.6 ml, 61.7 mmol) were added. The mixture was allowed to
stir for an additional 12 h. The brown solution was then diluted with Et2O (250 mL) and
washed with water (3  50 mL) and brine (50 mL). The organic layer was next dried with
anhydrous MgSO4, filtered and concentrated under reduced pressure. The resulting brown
viscous oil was purified by silica gel column chromatography (hexanes/EtOAc (4/1)) to afford
3
91 g (91%) of diazoacetoacetate 2. Analytical data obtained were in agreement with that
previously reported (Doyle et al. 1996).
Preparation of 3-methyl-2-butenyl diazoacetate (3) To a solution consisting of 3-methyl-2butenyl diazoacetoacetate (2) (8.9 g, 51 mmol), THF (50 mL) and water (50 mL) was added an
aqueous lithium hydroxide (21 g, 500 mmol) solution (20 mL). The reaction mixture was
vigorously stirred at room temperature for 3.5 h at which time 200 mL of Et2O was added. The
resulting biphase was transferred to a separatory funnel and washed with water (3  20 mL) and
brine (20 mL).
The organic layer was then dried with anhydrous MgSO4, filtered and
concentrated under reduced pressure. The resulting yellow viscous oil was purified by silica
gel column chromatography (hexanes/EtOAc (4/1)) to afford 7.3 g (94%) of diazoacetate 3.
Analytical data obtained were in agreement with that previously reported (Doyle et al. 1996).
Reaction of 3-methyl-2-butenyl diazoacetoacetate with dirhodium(II) [tetrakis(methyl 2oxopyrrolidine-5R-carboxylate)]
To a solution of dirhodium(II) [tetrakis(methyl 2-
oxopyrrolidine-5R-carboxylate)] [Rh2(5R-MEPY)4] (15 mg, 0.017 mmol) in 20 ml of refluxing
anhydrous CH2Cl2 was added a solution of 3-methyl-2-butenyl diazoacetoacetate (2) (347 mg,
1.77 mmol) in 10 ml of CH2Cl2 at a rate of 1.0 ml/h. Upon completion of addition, the reaction
mixture was cooled to room temperature and filtered through a plug of silica gel (5 mm x 15
mm) using CH2Cl2 (100 mL). The mixture was concentrated under reduced pressure to afford
283 mg of unreacted 3-methyl-2-butenyl diazoacetoacetate (2) (81% recovery). Analysis of
infrared and 1H NMR data confirmed incomplete diazo decomposition of the starting
diazoacetoacetate as well as the absence of the desired product.
Reaction of 3-methyl-2-butenyl diazoacetoacetate with dirhodium(II) tetraacetate To a
solution of dirhodium (II) tetraacetate (Rh2(OAc)4) (4.5 mg, 0.010 mmol) in 20 ml of refluxing
anhydrous CH2Cl2 was added a solution of 3-methyl-2-butenyl diazoacetoacetate (2) (2.0 g,
4
0.01019 mol) in 10 ml of CH2Cl2 at a rate of 1.0 ml/h. Upon completion of addition, the
reaction mixture was cooled to room temperature and filtered through a plug of silica gel (5
mm x 15 mm) using CH2Cl2 (100 mL). The mixture was concentrated under reduced pressure
to afford 410 mg of 1-acetyl-6,6-dimethyl-3-oxabicyclo[3.1.0]hexan-2-one (4) (51% yield).
Due to the presence of the acetyl group at C-1, purification of the crude product was
unsuccessful. Purification via both bulb-to-bulb distillation (140C/0.10 torr) as well as silica
gel chromatography afforded the desired product as well as other species which were detected
via 1H NMR.
Analytical data obtained on the crude material confirmed the structural
assignment of the desired product.
Reaction of 3-methyl-2-butenyl diazoacetate with dirhodium(II) tetraacetate To a solution
of dirhodium(II) acetate [Rh2(OAc)4] (29 mg, 0.066 mmol) in 40 ml of refluxing anhydrous
CH2Cl2 was added a solution of 3-methyl-2-butenyl diazoacetate (3) (1.0 g , 6.5 mmol) in 10
ml of CH2Cl2 at a rate of 0.5 ml/h. Upon completion of addition, the reaction mixture was
cooled to room temperature and filtered through a plug of silica gel (5 mm x 15 mm) using
CH2Cl2 (100 mL). The mixture was concentrated under reduced pressure to afford 600 mg of
dimeric products.
Spectral analysis of the products obtained confirmed complete diazo
decomposition of the starting diazoacetate as well as the absence of any bicyclic material.
Reaction of 3-methyl-2-butenyl diazoacetate with dirhodium(II) [tetrakis(methyl 2oxopyrrolidine-5R-carboxylate)]
To a solution of dirhodium(II) [tetrakis(methyl 2-
oxopyrrolidine-5R-carboxylate)] [Rh2(5R-MEPY)4] (41 mg, 0.048 mmol) in 120 ml of
refluxing anhydrous CH2Cl2 was added a solution of 3-methyl-2-butenyl diazoacetate (3) (733
mg, 4.75 mmol) in 15 ml of CH2 Cl2 at a rate of 2.0 ml/h. Upon completion of addition, the
reaction mixture was cooled to room temperature and filtered through a plug of silica gel (5
mm x 15 mm) using CH2Cl2 (100 mL). The mixture was concentrated under reduced pressure
5
to afford 600 mg of 6,6-dimethyl-3-oxabicyclo[3.1.0]hexan-2-one (5) (quantitative yield).
Analytical data obtained were in agreement with that previously reported (Doyle et al. 1996).
Results
The synthesis of both 3-methyl-2-butenyl diazoacetoacetate (2) and 3-methyl-2-butenyl
diazoacetate (3) was performed using identical diazotization protocols (Doyle et al. 1996).
Commercially available 3-methyl-2-buten-1-ol was reacted with an excess of diketene while in
the presence of catalytic amounts of triethylamine (Scheme 2). The resulting acetoacetate was
neither isolated
Scheme 2
+
H3 C
O
O
OH
cat. TEA
MsN3
THF
TEA
THF
O
CH 3
O
O
H3 C
CH 3
N2
CH 3
2
O
O
O
H3 C
O
CH 3
N2
CH 3
LiOH
O
THF / H 2 O
H3 C
2
nor purified.
N2
CH 3
3
Formation of the diazoacetoacetate 2 was achieved via treatment of the
acetoacetate with mesyl azide (methanesulfonyl azide) and triethylamine. Diazoacetoacetate 2
was isolated and purified by silica gel column chromatography (91% yield). Completion of the
diazo ester 3 synthesis was carried out via deacetylation of diazoacetoacetate 2 using lithium
hydroxide in an aqueous THF solution. Diazoacetate 3 was isolated and purified by silica gel
chromatography to afford the desired compound in 94% yield.
6
Catalytic diazo decomposition studies were then performed using both diazocarbonyl
compounds 2 and 3 (Scheme 3). Starting with 3-methyl-2-butenyl diazoacetate (3), incomplete
cyclization onto the olefin was observed with dirhodium(II) carboxylate catalysis. Dimer
products formed via coupling of the starting diazo ester with a metal carbene intermediate were
observed. Upon switching to carboxamidate ligated complexes, complete cyclization was
observed, affording the desired bicyclic lactone 5.
Scheme 3
O
O
H3 C
O
N2
H3 C
dirhodium (II)
carboxylate
H3 C
CH 3
dirhodium (II)
carboxamidate
2
CH 3
no cyclization
O
R
O
4: R = COOCH 3
5: R = H
O
dirhodium (II)
carboxamidate
dirhodium (II)
carboxylate
O
N2
H3 C
CH 3
3
A complete reversal in chemoselectivity was observed when diazoacetoacetate 2 was
subjected to dirhodium(II) carboxamidate catalysis (Scheme 3).
Reaction of 3-methyl-2-
butenyl diazoacetoacetate with the dirhodium(II) carboxamidate catalyst Rh2(5R-MEPY)4
resulted in incomplete diazo decomposition. Interestingly, cyclization onto the substituted
olefin was observed when the bridging ligands were switched back to acetate derivatives, that
is, Rh2(OAc)4.
7
Discussion
Although not completely understood, a reversal in product selectivity solely based upon
catalyst choice has been reported (Doyle and Forbes 1998; Padwa and Austin 1994; Pfaltz
1993). The necessity of metal carbene formation, which is heavily dependent upon the ligated
groups of the transition metal complex, is unique with diazocarbonyl chemistry. Outlined in
Scheme 4 are the key steps involved with the catalytic cycle of decomposition of diazocarbonyl
compounds. Initiation begins upon association of a transition
Scheme 4
H3 C
CH 3
R
O
MLn
N2
O
2: R = COOCH 3
3: R = H
H3 C
MLn = Rh 2 L4
O
LnM
H3 C
CH 3
H3 C
H3 C
R
N2
O
CH 3
R
O
H
O
R
O
4: R = COOCH 3
5: R = H
MLn
O
ii
metal complex with a diazocarbonyl compound. Upon extrusion of dinitrogen, the metal
carbene intermediate (ii) can carry out a number of transformations. For example, diazoacetate
3 when subjected to dirhodium(II) carboxamidate catalysis resulted in complete cyclization
affording the desired bicyclic lactone 5 because of the suitably located olefin. Competitive
processes with the more reactive dirhodium(II) carboxylate catalyst were observed and none of
the desired material was formed. A complete reversal in product formation was seen when the
diazoacetoacetate 2 was treated with the carboxylate derived metal complex (24). Here, the
increased reactivity of the catalyst paired well with the less reactive diazocarbonyl compound
(Doyle et al. 1997). By simple ligand exchange at a load of 0.01 mol%, a quantitative reversal
8
in reactivity/selectivity was observed. Efforts to understand the subtle effects of catalyst
control in diazocarbonyl chemistry are underway and will be reported in due course.
Acknowledgments
The authors are grateful to the University of South Alabama Research Council and the
University of South Alabama Department of Chemistry for financial support.
Professor
Michael P. Doyle (University of Arizona) is thanked for generously providing both
dirhodium(II) complexes.
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