Dirhodium(ii) Carboxamidate and Carboxylate Catalysis: a Study on Chemoselectivity
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FORBES, D.C.; BARRETT, E.J.; BRIGHT, D.H.; EZELL, (1999). Dirhodium(ii) Carboxamidate and Carboxylate Catalysis: a Study on Chemoselectivity. National Undergraduate Research Clearinghouse, 2. Available online at http://www.webclearinghouse.net/volume/. Retrieved December 17, 2017 .

Dirhodium(ii) Carboxamidate and Carboxylate Catalysis: a Study on Chemoselectivity
FORBES, D.C.; BARRETT, E.J.; BRIGHT, D.H.; EZELL, B.O.; STINSON, S.M.
UNIVERSITY OF SOUTH ALABAMA DEPARTMENT OF CHEMISTRY

Sponsored by: DAVID FORBES (dforbes@jaguar1.usouthal.edu)
ABSTRACT
The synthesis of C-1 substituted 3-oxa-2-oxobicyclo[3.1.0]hexyl systems is described. Reaction of 3-methyl-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 [Rh2(5R-MEPY)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.

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-, regio- and 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 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
1H NMR (300 MHz) and 13C 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 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-2-butenyl 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 2-oxopyrrolidine-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, 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 2-oxopyrrolidine-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 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 nor purified. 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. 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. 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.

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 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 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.

REFERENCES
Doyle, M. P.; Forbes, D. C. (1998) Recent Advances in Asymmetric Metal Carbene Transformations. Chem. Rev. 98: 911-936.

Doyle, M. P.; McKervey, M. A.; Ye, T. (1997) In Modern Catalytic Methods for Organic Synthesis with Diazo Compounds; John Wiley & Sons, Inc.: New York, 1997.

Doyle, M. P.; Winchester, W. R.; Hoorn, J. A. A.; Lynch, V.; Simonsen, S. H.; Ghosh, R. (1993) Dirhodium(II) Tetrakis(carboxamidates) with Chiral Ligands. Structure and Selectivity in Catalytic Metal-Carbene Transformations. J. Am. Chem. Soc. 115: 9968-9978.

Doyle, M. P.; Winchester, W. R.; Protopopova, M. N.; Kazala, A. P.; Westrum, L. J. (1996) (1R, 5S)-(-)-6,6-Dimethyl-3-oxabicyclo[3.1.0]hexan-2-one. Highly Enantioselective Intramolecular Cyclopropanation Catalyzed by Dirhodium(II) Tetrakis[Methyl 2-Pyrrolidone-5(R)-carboxylate]. Org. Synth. 73: 13-24.

Noyori, R. (1994) Asymmetric Catalysis in Organic Synthesis; John Wiley & Sons, Inc.: New York.

Ojima, I. (1993) Catalytic Asymmetric Synthesis; VCH Publishers, Inc.: New York.

Padwa, A.; Austin, D. J. (1994) Ligand Effects on the Chemoselectivity of Transition Metal Catalyzed Reactions of -Diazo Carbonyl Compounds. Angew. Chem., Int. Ed. Engl. 33: 1797-1815.

Pfaltz, A. (1993) Chiral Semicorrins and Related Nitrogen Heterocyclies as Ligands in Asymmetric Catalysis. Acc. Chem. Res. 26: 339-345.

Rogers, R. S. (1998) Sepracor: Skating on `Ice`. Chemical & Engineering News, November 30.

Stinson, S. C. (1997) Chiral Drug Market Shows Signs of Maturity. Chemical & Engineering News, October 20.


Scheme 1


Scheme 2


Scheme 3


Scheme 4

Submitted 6/10/99 11:21:01 AM
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