Comments on The Curious Wavefunction: Constancy of the discodermolide hairpin motif

Anon: Thanks. You are indeed right about the A 1,2...

2010-02-25T06:00:38.843-08:00

Anon: Thanks. You are indeed right about the A 1,2 and A 1,3 aspect. However the conformational behavior was still surprising because even with the avoidance of this strain you still expect a fair number of conformations in solution. Obviously the force fields are very good at modeling this strain, but we were more surprised to find a disproportionate percentage of the conformer in solution. In past studies we have found that even constraining elements nonetheless impart a fair degree of flexibility to such molecules.

And thanks, the figures were drawn with Pymol.

Ah, well, I did just read your J Med Chem ASAP man...

2009-12-28T09:55:28.809-08:00

Ah, well, I did just read your J Med Chem ASAP manuscript, wherein you mention all but the A1,2 portion of my argument. My apologies for "dis'ing" you (sp.?) before reading. Nice paper, BTW. Also, kudos to the person who drew the figures (and knew the appropriate way to orient the hatched triangular bonds for the substituents in the alpha orientation). Structure 2 is the only one in the manuscript that contains the commonly found error in this regard.

The result is not surprising, and it doesn't take ...

2009-12-28T09:20:30.372-08:00

The result is not surprising, and it doesn't take a force field or a computer to recognize the rigid nature of the molecule. Take a hard, conformation-analytical look at the middle (about C8 to C16) of discodermolide-- it is a textbook example of avoidance of syn-pentane interactions and A1,2 + A1,3 strain. The only major regions of flexibility in the molecule are regions flanking the middle (the delta-lactone region can spin a bit, and the diene has some rotational freedom). Add to that the distinct possibility of a hydrogen bond between the lactone hydroxyl and the carbamate nitrogen and, voila, rigid acyclic molecule.

Ashutosh, please drop me an e-mail to my institute...

2009-11-26T21:45:32.029-08:00

Ashutosh, please drop me an e-mail to my institute address tomasv@xxxxxxx.edu

I have a somewhat interesting second-hand information about an unpublished order-of-magnitude more potent Discodermolide-related natural compound (a closely-related macrocyclic analog) that seems to fit your NMR/modeling studies in the J Med Chem paper.

Thanx, Milkshake