Synthetic Methods Developed

in the Romo Group (1993-2006, reverse chronology)

 

 

19) "Synthesis, Structure, and Reactivity of Unexpectedly Stable Spiroepoxy-b-Lactones Obtained by Epoxidation of 4-Alkylidene-2-Oxetanones"  Duffy, R. J.; Morris, K. A. and Romo, D.  J. Am. Chem. Soc. 2005, 127, 16754-16755.

 


This paper describes the first synthesis of spiroepoxy-b-lactones obtained via epoxidation of ketene dimers.  These compounds display unexpected stability that may be due to a double anomeric effect garnered from analysis of bond lengths by x-ray crystallography of one spirocycle in comparison to calculated bond lengths of related structures.  These new strained intermediates display interesting reactivity leading to a butenolide, an a-hydroxyketone, a triol, an a-chloroketone and an a-azidoketone.

 

 

18) "Radical Reactions and a-Silylations of Optically Active 4-Trichloromethyl-b-Lactone" Mitchell, T. A. and Romo, D. Hetereocycles 2005, 66, 627-637.

 

 

Radical alkylations and a-silylations of optically active (R)-4-trichloromethyl-2-oxetanone are described that maintain the integrity of the b-lactone.  Alternate methods for selective dechlorinations of both the b-lactone and the derived Weinreb amide are described.

 

17) "Asymmetric Synthesis of Bicyclic b-Lactones via the Intramolecular, Nucleophile-Catalyzed Aldol-Lactonization (NCAL): Improved Efficiency and Expanded Scope" Oh, S. H.; cortez, G. S. and Romo, D. J. Org. Chem.  2005, 70, 2835-2838.

 

 


 

This paper described a major improvement in efficiency to our previously described intramolecular NCAL process.  A key finding was that the reactivity, stability, and counterion of the Mukaiyama reagent used to activate the acid is critical in obtaining good yields.  New bicyclic-b-lactones prepared by this method are also described.

 

 

16) "Nucleophilic Openings of Bicyclic b-Lactones via Acyl C-O and Alkyl C-O Cleavage:  Catalytic, Asymmetric Synthesis of a Versatile, Carbocyclic Nucleoside Precursor and Protected Transpentacin" Yokota, Y.; Cortez, G. S. and Romo, D. Tetrahedron, 2002, 58, 7075-7080.

 

 

This paper describes the ring cleavage of bicyclic b-lactones under mild conditions via both acyl C-O and alkyl C-O bond cleavage.  The utility of these transformations was demonstrated by the synthesis of protected (1S, 2S)-transpentacin and a versatile diol for carbocyclic nucleoside synthesis

 

 

15) "Mechanism and Origin of Stereoselectivity in Lewis Acid-Catalyzed [2 + 2] Cycloadditions of Ketenes with Aldehydes" Singleton, D. A.; Wang, Y.; Yang, H. W. and Romo. D. Angew. Chem. Int. Ed. 2002, 41, 1572-1575.

 

 

The Lewis acid-catalyzed [2 + 2] cycloaddition of ketenes with aldehydes was studied employing natural abundance kinetic isotope effects. The data suggest divergent rate-limiting steps for the formation of cis-and trans-b-lactone diastereomers and are supported by calculations.  These results rationalize the differing enantioselectivity of these diastereomeric products (see #7 above) and suggest the importance of considering divergent rate-determining steps in the development of catalytic asymmetric processes that lead to diastereomeric products.

 

 

14) "A b-Lactone Route to Chiral g-Substituted a-Amino Acids: Application to the Concise Synthesis of (S)-a-Azidobutyrolactone and a Natural Amino Acid." Tennyson, R. L.; Cortez, G. S.; Galicia, H. J.; Kreiman, C. R.; Thompson, C. M. and Romo, D. Org. Lett 2002, 4, 533-536.

 

 

 

This paper describes the utility of  (R) and (S)-4-trichloromethyl-b-lactone for the preparation of a variety of amino acid synthons, in particular g-substituted a-amino acids. A concise synthesis of a protected homoserine equivalent, a-azidobutyro lactone, and a naturally occurring amino acid were synthesized to demonstrate the utility of this methodology.

 

13) "Bicyclic b-Lactones via Intramolecular NCAL Reactions with Cinchona Alkaloids: Effect of the C9-Substituent on Enantioselectivity and Catalyst Conformation" Cortez, G. S.; Oh, S. H. and Romo, D. Synthesis 2001, 1731-1736.

 

 

This paper describes studies of various C9-acylated cinchona alkaloids utilized to promote the intramolecular nucleophile catalyzed aldol-lactonization reaction(NCAL) process leading to bicyclic b-lactones. A mechanistic proposal to rationalize the enantioselectivity is proposed for this catalytic, asymmetric process (which should be revised based on subsequent data).

 

 

12) "Intramolecular, Nucleophile-Catalyzed Aldol-Lactonization (NCAL) Reactions: Catalytic Asymmetric Synthesis of Bicyclic b-Lactones" Cortez, G. S.; Tennyson, R. L. and Romo, D. J. Am. Chem. Soc. 2001, 123, 7945-7946.

 

 

This paper describes the first nucleophile catalyzed aldol-lactonization (NCAL) reaction of unactivated aldehydes leading to novel bicyclic b-lactones. This process effectively merges catalytic, asymmetric b-lactone and carbocycle synthesis utilizing cincona alkaloids as catalysts, the bicyclic b-lactones can be obtained  in moderate yield and good enantioselectivity.

 

 

11) "Use of In Situ Generated Ketene in the Wynberg b-lactone Synthesis: New Transformations of the Dichlorinated b-lactone Products" Tennyson, R. and Romo, D. J. Org. Chem. 2000, 65, 7248-7252.

 

This paper described an extension of  Wynberg's method for the asymmetric synthesis of b-lactones by using in situ generated ketene with several a,a-dichloroaldehydes.  This extension increases the utility and practicality of the original Wynberg method.  New transformations of the resulting chlorinated b-lactones leading to several optically active functional arrays including chloro epoxides, a-azido ketones, vinyl chlorides, and propargylic benzyl ethers are described.

 

 

10) "A Stereocomplementary Approach to b-Lactones: Highly Diastereoselective Synthesis of cis-b-Lactones, a b-Chloroacid, and a Tetrahydrofuran" Wang, Y.; Zhao, C. and Romo, D. Org. Lett. 1999, 1, 1197-1199.

 

 

A SnCl4-mediated reaction between aldehydes and a thiopyridyl ketene acetal has been discovered that provides a highly diastereoselective entry to cis-1,2-disubstituted-b-lactones. This process is stereocomplimentary to the Zn(II) promoted TMAL process.  By raising the reaction temperature and using TBS- rather than TES-ketene acetals, a subsequent in situ reaction ensues leading to b-chloro carboxylic acids. In addition, the use of a silyl ether substituted aldehyde substrate led to the formation of a tetrahydrofuran product.

 

 

9) "A Single-Pot, Mild Conversion of b-Lactones to b-Lactams" Yang, H. W. and Romo, D. J. Org. Chem. 1999, 64, 7657-7660.

 

 

This paper describes an expedient, single-pot conversion of b-lactones to b-lactams involving ring opening with benzyloxy amine followed by Miller Mitsunobu reaction. By utilizing this method, a variety of optically active b-lacams were prepared.

 

8) "Simultaneous Deprotection and Purification of BOC-amines Based on Ionic Resin Capture" Liu, Y.-S.; Zhao, C.; Bergbreiter, D. E. and Romo, D. J. Org. Chem. 1998, 63, 3471-3473.

 

 

This paper described an effective deprotection, purification and isolation of BOC-protected amine containing compounds. A sulfonic acid resin (Amberlyst) simultaneously deprotects and then forms a retained salt of the resulting amine.  Following washing of the resin to remove any non-amine containing  impurities, free-basing with ammonia leads to amines in high purity.  This method tolerates a wide variety of substrates and can be used for solution-phase parallel synthesis.

 

 

7) "Studies of the Asymmetric [2+2] Cycloaddition of Silylketenes and Aldehydes Employing Ti-TADDOL Catalysts" Yang, H. W. and Romo, D. Tetrahedron Lett, 1998, 39, 2877-2880.

 

 

This paper describes a Ti-TADDOL catalyzed  asymmetric [2+2] cycloaddition of silyl ketenes and aldehydes with moderate enantioselectivity. The effects of potential bidentate chelation of benzyloxy substituted aldehydes and of the steric size of the ketene silyl group were studied.

 

6) "Practical, One-Step Synthesis of Optically Active b-Lactones via the Tandem Mukaiyama Aldol-Lactonization (TMAL) Reaction." Yang, H. W. and Romo, D. J. Org. Chem. 1998, 63, 1344-1347.

 

 

 

This paper describes a concise, diastereoselective route to optically active b-lactones from various chiral aldehydes under mild conditions via the tandem Mukaiyama aldol-lactonization process.  Less than 2% racemization of a-chiral aldehyde substrates was observed and high internal stereoselection was obtained.

 

 

5) "A Highly Diastereoselective, Tandem Mukaiyama Aldol-Lactonization Route to b-Lactones: Application to a concise Synthesis of the Potent Pancreatic Lipase Inhibitor,    (-)-Panclicin D." Yang, H. W. and Romo, D. J. Org. Chem. 1997, 62, 4-5.

 

 

This paper describes a ZnCl2-mediated tandem aldol-lactonization reaction of aldehydes and readily available ketene thiopyridylacetals. This reaction provides an expedient, mild and highly stereoselective route to b-lactones. The first total synthesis of (-)-panclicin D was accoumplished by utilizing this method.

 

 

4) "A b-Lactone-Based Route to Cyclopentanes via Intramolecular Allylsilane Additions. An Unexpected Friedel-Crafts Alkylation."Zhao, C. and Romo, D. Tetrahedron Lett. 1997, 38, 6537-6540.

 

 

This paper describes a Lewis acid promoted intramolecular additions of allylsilanes to b-lactones proceed smoothly to give variously substituted cyclopentanes.  A proposed transition state arrangement for this reaction guided our efforts to improve the stereoselectivity.  A novel Friedel-Crafts alkylation of a b-lactone is also described.

 

 

3) "Tandem Transacylation/Debenzylation of b-Lactones Mediated by FeCl3 Leading to g and d-Lactones: Application to the Synthesis of (-)-Grandinolide." Zemribo, R.; Champ, M. S. and Romo, D. Synlett, 1996, 278-280.

 

 

This paper describes a FeCl3 mediated tandem debenzylation/transacylation reaction of b-lactones bearing a pendant benzyloxy group one or two carbons removed from the b-lactone. A concise synthesis of (-)-grandinolide was accomplished utilizing this methodology.

 

 

2) "A New Route to 2-Substituted D­­2-Thiazolines: Stille Cross-Couplings of Bromo- D2-Thiazolines"  Schmitz, W.D. and Romo, D. Tetrahedron Lett. 1996, 37, 4857-4860.

 

 

This paper describes a new route to various 2-substituted thiazolines involving transition metal catalyzed cross couplings between bromothiazolines and various tributylstannanes. This method provides a potentially general and mild route to thiazoline containing natural products.

1) "Highly Diastereoselective [2+2] Cycloadditions via Chelation Control: Asymmetric synthesis of b-Lactones" Zemribo, R. and Romo, D. Tetrahedron Letters, 1995, 36, 4159-4162.

 

 

This paper described a MgBr2.OEt2 mediated, [2+2] cycloaddition of ketenes to aldehydes bearing a- or b- benzyloxy groups with high diastereoselectivities. This method provided a facile access to optically active, functionalized b-lactones.