Nature grows proteins N -> C so the biomimetic approach has a great appeal. From a practical perspective, many times you want to modify or play with the C terminus, and therefore it'd me much more flexible having the possibility of doing it without synthesizing the whole peptide chain each time. Personally I think that the holly graill is not N -> C synthesis, but regardless if the direction, doing it without protecting groups. Now, THAT would be really cool!! :-)

Agree with Eugenio. The biomimetic appeal of building a peptide from N to C is not that relevant from a pratical viewpoint. As far as I see it, the main advantage of being able to do so would be what Eugenio refers to: the ability to expand our options regarding chemical modifications at the peptide's C-terminus.

As regarding a cutting-edge evolution in peptide synthesis, besides that suggested by Eugenio, I would add the ability to carry out low-cost peptide synthesis in water.

Agree with the two previous answers. From a practical point of view, if you could attach the growing peptide by the side chain of an aminoacid, you could probably grow your peptide in both directions. That would increase the different options of SPPS and thus would allow for different synthetic strategies to avoid certain difficult couplings. Maybe it could also have some applications in the synthesis of cyclic peptides on resin

The advantage of an N>C synthesis would be that you can modify the C-terminus on resin whereas normally this is done after cleavage and often means that additional purification steps are necessary (a particular problem with low yield or long sequences). In addition, since N-terminus modification is easier, this is the norm and hence the different behaviours of C- or N-terminally labelled peptides habe not been explored.

I would also agree with the foregoing contributions, N to C directed peptide synthesis would directly mimic natural peptide synthesis and also open up a whole world of opportunities for C- terminal on-resin modification.

N -> C synthesis is also a valuable addition with respect to synthetic strategies for so-called difficult sequences.

I'd recommend looking at Bill Gutheil's work on C-terminal modifications. Look at:

1) J Comb Chem. 2004 Nov-Dec;6(6):911-5. General inverse solid-phase synthesis method for C-terminally modified peptide mimetics. Sasubilli R1, Gutheil WG.

2) J Pept Sci. 2005 Feb;11(2):69-73. A Dde resin based strategy for inverse solid-phase synthesis of amino terminated peptides, peptide mimetics and protected peptide intermediates. Rai A, Gutheil WG.

He has some rationale for the synthesis direction and its future use.

I feel sorry for disappointing the enthusiastic participants of this thread, but this still-born approach offers no advantages at all. It's because no one in this world can afford the 10-fold or even higher levels of racemization/epimerization which are inevitably observed when someone activates and couples N-acylaminoacids (not urethane-protected ones!). This trend was firmly established  during 1960-1980 already and to those in doubts I strongly recommend to read classical reviews on racemization by Kemp, Kovacs and Benoiton in The Peptides vols. 1,2 and 5, respectively, published in 1979-83 by Academic Press under editorship of Gross, E. and Meienehofer, J.