Winter Fragmentation

Guzman-Perez, Angew. Chem. 1998, 110, 405 15 Angew. Chem. Int Ed. Engl 1998, 37, 388. 

By application of the Corey-Winter reaction,vicinal diols 1 can be converted into olefins 3. The key step is the cleavage of cyclic thionocarbonates 2 (1,3-dioxolanyl-2-thiones) upon treatment with trivalent phosphorus compounds. The required cyclic thionocarbonate 2 can be prepared from a 1,2-diol 1 and thio-phosgene 4 in the presence of 4-dimethylaminopyridine (DMtVP)  

In addition there are certain other methods for the preparation such compounds. Upon heating of the thionocarbonate 2 with a trivalent phosphorus compound e.g. trimethyl phosphite, a -elimination reaction takes place to yield the olefin 3. A nucleophilic addition of the phosphorus to sulfur leads to the zwitterionic species 6, which is likely to react to the phosphorus ylide 7 via cyclization and subsequent desulfurization. An alternative pathway for the formation of 7 via a 2-carbena-l,3-dioxolane 8 has been formulated. From the ylide 7 the olefin 3 is formed stereospecifically by a concerted 1,3-dipolar cycloreversion (see 1,3-dipolar cycloaddition), together with the unstable phosphorus compound 9, which decomposes into carbon dioxide and R3P. The latter is finally obtained as R3PS  

The Corey-Winter reaction provides a useful method for the preparation of olefins that are not accessible by other routes. For instance it may be used for the synthesis of sterically crowded targets, since the initial attack of phosphorus at the sulfur takes place quite distantly from sterically demanding groups that might be present in the substrate molecule. Moreover the required vicinal diols are easily accessible, e.g. by the carbon-carbon bond forming acyloin ester condensation followed by a reductive step. By such a route the twistene 10 has been synthesized  

Furthermore highly strained compounds such as bicyclo[3.2.1]oct-l-ene 11, containing a double bond to a bridgehead carbon atom, have been prepared however this strained olefin could be identified only as its Diels-Alder product from subsequent reaction with an added diene.  

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As expected, the yields of catenanes by this approach are low, which is why improved methods for the preparation of such compounds have been developed. The acyloins are often only intermediate products in a multistep synthesis. For example they can be further transformed into olefins by application of the Corey-Winter fragmentation. 

In contrast to the case of uridine derivatives noted above, attempts to carry out a Corey-Winter fragmentation of N, 5 - protected cytidine 2 ,3 -thionocarbonates caused isomerisation to 2 -deoxy-2 -thiocytldine-2, 3 -carbonates (69). 121 The 3 -thiomethyl-, methylsulphinyl-, and methylsulphonyl derivatives of 3 -deoxythymidine have been prepared by treatment of the 5 -0-trltyl derivative of (63) with methanethiolate ion, followed by oxidation at sulphur and deprotection as appropriate. 122... 

Hollinger, P., Prospero, T., and Winter, G. (1993). "Diahodies" Small bivalent and bispecific antibody fragments. Proc. Natl. Acad. Sci. USA 90, 6444-6448. 

The winter flounder antifreeze protein (AFP), characterized by Sicheri and Yang [42], consists of 37 residues of eight amino acids in an a-helix configuration. The AFP protein was synthesized by the conjoining of the Aa residues determined in the glycine mold, with the exception of the two residues at each of the termini, FIOOC-Asp Thr and Ala Arg-NP and the synthesized protein fragment is left with open amidic surfaces on the... 

Fig. 7.6 The 33-residue fragment of the winter flounder antifreeze protein (AFP), constructed by the conjoining of the Aa amino acid residues defined within the glycine mold , pictured in terms of its 0.001 au isodensity envelope, its van der Waals envelope. This is a view showing the ice-binding motif. It is believed that the AFP strand binds... 

ACC 71 synthase, i. e. (S)-adenosylmethionine methylthioadenosine lyase (EC 4.4.1.14), has been purified from several plant tissues [116]. Recently, ACC synthase cDNA clones have been isolated and sequenced from wounded fruit tissues of tomato, winter squash, zucchini, ripening apple and tomato fruit. Using the polymerase chain reaction (PCR), four different ACC synthase gene fragments were obtained by amplification of cDNA derived from mRNA of tomato... 

Clackson, T., Hoogenboom, H. R., Griffiths, A D., and Winter, G. (1991) Making antibody fragments using phage display libraries. Nature 352, 624-628... 

Nen, D., Petrul, H., Winter, G., Light, Y, Marais, R, Britton, K E., and Creighton, A M. (1996) Radioactive labeling of recombinant antibody fragments by phosphorylation using casein kinase II and [y-32P]-ATP Nature Biotechnol. 114,485-490. 

Winters and Kiser have reported appearance potentials and cracking patterns for Ni(CO)4 (243), Fe(CO)5 (243), and the Group VI hexacar-bonyls (244). These carbonyls fragment by a series of consecutive uni-molecular reactions with loss of neutral CO groups. Support for this scheme came from an investigation of the metastable transitions in the spectrum of Fe(CO)5 (242), which were observed for the following processes ... 

Appearance potentials of molecular ions and fragment ions have been reported for some compounds (Section VII) and an estimation of heats of formation and of bond strengths has been attempted in several cases, notably by Winters and Kiser (199). These results must be treated cautiously, however, because the appearance potentials may include excess energy due to contributions from excited states. 

A different approach by Winters and Kiser 199) involves the calculation of heats of formation of fragment ions (discussed below). Using the appropriate thermochemical values, All (reaction) gives the bond strength Z)[R— M ] for the reaction... 

A more sophisticated approach has been used by Winters and Kiser (199) to calculate the heats of formation of the cyclopentadienylmetal carbonyls C5H5V(CO)4, C5H5Mn(CO)3, and C5H5Co(CO)2 as well as the heats of formation of some of the fragment ions. The heats of formation were calculated for the process... 

Hodits, R. A., Nimpf, J., Pfistermueller, D. M., Hiesberger, T., Schneider, W. J., Vaughan, T.J., Johnson, K. S., Haumer, M., Kuechler, E., Winter, G., etal. (1995). An antibody fragment from a phage display library competes for ligand binding to the low density lipoprotein receptor family and inhibits rhinovirus infection. J. Biol. Chem., 270(41), 24078-24085. 

Examples of such protein-protein interaction selection systems are phage display (Smith, 1985 Winter et al., 1994), display on other viruses (Kasahara et al., 1994), bacterial surface display (Georgiou et al., 1993 Daugherty et al., 1999), yeast display (Kieke et al., 1997 Boder and Wittrup, 1997), the yeast two hybrid system (Fields and Song, 1989 Chein et al., 1991), and protein-fragment complementation assays (Pelletier et al., 1998). These methods all contain a necessary in vivo step, which has a number of disadvantages that will be discussed in the following sections. 

Neri D, Carnemolla B, Nissim A, Leprini A, Querze G, Balza E, Pini A, Tarli L, Elalin C, Neri P, Zandi L, Winter G, Targeting by affinity-matured recombinant antibody fragments of an angiogenesis associated fibronectin isoform, Nat. Biotechnol., 15 1271-1275, 1997. 

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