Synthetic Strategies Developed and Total Syntheses Completed in the Romo Group (1993-2005, reverse chronology)

 

1) "Studies toward a Marine Toxin Immunogen: Enantioselective Synthesis of the Spirocyclic Imine of (-)-Gymnodimine" Kong, K.; Moussa, Z.; Romo, D.  Org. Lett. 2005, 7,  5127-5130.

 

This paper describes an enantioselective Diels-Alder reaction catalyzed by an EvansÕ copper-bis(oxazoline) complex.  This cycloaddition was utilized to construct a highly functionalized spirolactam, a key intermediate in our projected total synthesis of the marine toxin, gymnodimine.

 

2) "Highly Regioselective Diels-Alder Reactions toward Oroidin Alkaloids: Use of a Tosylvinyl Moiety as a Nitrogen Masking Group with Adjustable Electronics" Dransfield, P. J.; Wang, S.; Dilley, A.; Romo, D. Org. Lett. 2005, 7, 1679-1682.

 

 

The use of the p-toluenesulfonyl (Ts) and tosylvinyl (Tsv) groups as nitrogen masking groups imparted high regioselectivity in Diels-Alder reactions directed towards palauÕamine and axinellamine. The Tsv group was utilized as an electronically adjustable, nitrogen-protecting group as subsequent hydrogenation provided the more electron rich tosylethyl (Tse) group. 

 

3) "Enantioselective Total Synthesis of (+)-Dibromophakellstatin" Poullenec, K.; Romo, D. J. Am. Chem. Soc. 2003, 125, 6344-6345.

 

 

The first enantioselective total synthesis of (+)-phakellstatin and (+)-dibromophakellstatin was achieved. Key steps in the synthesis were a desymmetrization of the diketopiperazine (S, S)-cyclo (Pro, Pro) via a diastereoselective acylation, an intramolecular Mitsunobu reaction to introduce the C6 aminal, and a tandem Hofmann rearrangement/cyclization to simultaneously introduce the C10 quaternary aminal center and deliver the cyclic urea.

 


4) "Concise Total Synthesis of (+)-Brefeldin A: A Combined b-Lactone/Cross-Metathesis-Based Strategy" Wang, Y.; Romo, D. Org. Lett. 2002, 4, 3231-3234.


A highly convergent total synthesis of (+)-brefeldin A (1) that relies on a diastereoselective, b-lactone-based cyclopentane synthesis combined with complex cross-metathesis reactions is described.

 

5) "Highly Diastereoselective Desymmetrizations of Cyclo (Pro-Pro): An Enantioselective Strategy toward Phakellstatin and Phakellin" Poullennec, K. G.; Kelly, A. T.; Romo, D. Org. Lett. 2002, 4, 2645-2648.

 

 

Mono-enolates of C­2-symmetric, proline-derived piperazine-2,5-diones were generated and trapped with a variety of electrophiles to produce, in a highly diastereoselective fashion, functionalized diketopiperazines (DKPs). These reactions provide the basis for an asymmetric, desymmetrization strategy toward the marine alkaloids phakellstatin and phakellin.

 

6) "Enantioselective Strategy to the Spirocyclic Core of Palau'amine and Related Bis-guanidine Marine Alkaloids" Dilley, A. S.; Romo, D. Org. Lett. 2001, 3, 1535-1538.


An enantioselective strategy to the spirocyclic core found in the oroidin-derived family of bisguanidine marine alkaloids has been devised, premised on a biosynthetic proposal. In this paper, we describe the successful implementation of this strategy, which entails a Diels-Alder reaction and a chlorination/ring contraction sequence that delivers the fully functionalized spirocyclic core.

 

7) "Studies Toward Gymnodimine: Development of a Single-Pot Hua Reaction for the Synthesis of Highly Hindered Cyclic Imines" Ahn, Y.; Cardenas, G. I.; Yang, J.; Romo, D. Org. Lett. 2001, 3, 751-754

 

In studies directed towards gymnodimine and related marine toxins, a single-pot variation of the Hua cyclic imine synthesis has been developed.  The reaction involves generation of N-trimethylsilyl lactams in situ followed by alkyllithium addition leading directly to cyclic imines.  Importantly, this reaction proceeds efficiently with highly hindered a,a-dialkyl lactams, provided 1,2-dimethoxyethane (DME) is used as the solvent, leading to stable cyclic imines.

 

8) "Studies Toward (-)-Gymnodimine: Concise Routes to the Spirocyclic and Tetrahydrofuran Moieties" Yang, J.; Cohn S. T.; Romo D, Org. Lett. 2000, 2, 763-767


 

(-)-Gymnodimine is a member of a unique class of potent marine toxins possessing imines within a spirocylic array.  This paper descibed the synthesis of the tetrahydrofuran fragment and a strategy towards the spirocyclic imine fragment of this family of toxins.  Key reactions include an asymmetric anti-aldol reaction to set the stereochemistry of the tetrahydrofuran and a formal, intermolecular Diels-Alder reaction involving an 4-methylene-d-lactam dienophile and a dienyne.

 

9) "Total Synthesis and Immunosuppressive Activity of (-)-Pateamine A and Related Compounds:  Implementation of a b-Lactam-Based Macrocyclization" Romo, D.; Rzasa, R. M.; Shea, H. A.; Park, K.; Langenhan, J. M.; Sun, L.; Akhiezer, A.; Liu, J. O.  J. Am. Chem. Soc.  1998, 120,  12237-12254.





This papers provides a full account of our enantioselective synthesis of the potent immunosuppressive agent (-)-pateamine A isolated from the marine sponge Mycale sp.  A key strategy employed in the synthesis was a b-lactam based macrocyclization to form the 19-membered dilactone macrolide.  Initial biological testing of PatA derivatives was conducted using the IL-2 reporter gene assay in collaboration with Prof. Jun Liu (Johns Hopkins).

 

10) "Total Synthesis of the Novel, Immunosuppressive Agent (-)-Pateamine A from Mycale sp. Employing a b-Lactam-Based Macrocyclization" Rzasa, R. M.; Shea, H. A.; Romo, D.  J. Am. Chem. Soc.  1998,  120,  591-592.

 

 

 

This paper described the first total synthesis of the potent immunosuppressive agent, (-)-pateamine A from (E)-3-bromo but-2-enal. Key features of the convergent synthesis include a novel b-lactam based macrocyclization, the use of SmI2 for N-O bond reduction of a N-benzyloxy-b-lactam, and the ability to perform a Stille coupling reaction in the presence of an allylic and triallylic acetate.

 

11) "A b-Lactone-Based Strategy Applied to the Total Synthesis of (8S, 21S, 22S, 23R) and (8R, 21S, 22S, 23R)-Okinonellin B" Schmitz, W. D.; Messerschmidt, N. B.; Romo, D.  J. Org. Chem. 1998,  63,  2058-2059.

 

 

 

This paper described the application of a b-lactone-based strategy to the first total syntheses of (8S, 21S, 22S, 23R)-okinonellin B  and (8R, 21S, 22S, 23R)-okinonellin B.  The present synthesis demonstrates the utility of b-lactones as intermediates in the synthesis of natural products and specifically, in the concise synthesis of all syn-trisubstituted butyrolactones.  The synthesis employed the tandem Mukaiyama aldol-lactonization to construct b-lactone  and the tandem transacylation debenzylation of this b-lactone to provide butyrolactone  as key steps.

 

12) "A Novel 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.; Romo, D. Synlett. 1996, 278-280.

 

 

The one step conversion of b-lactones bearing a pendant benzyloxy group to g- and d-lactones via a transacylation /debenzylation process is effected using FeCl3. This procedure in conjunction with a previously reported diastereoselective [2+2] cycloaddition was applied to an asymmetric synthesis of (-)-grandinolide.