The Configuration of Distaminolyne A is S: Quantitative Evaluation of Exciton Coupling Circular Dichroism of N,O- Bis-arenoyl-1-amino-2-alkanols

Abstract

The 2S configuration of the marine natural product distaminolyne A was recently disputed based upon total synthesis, yet paradoxically supported by a second independent total synthesis from a different research group. We now verify the 2S configuration of distaminolyne A by extensive chiroptical studies and support the veracity of the EC ECD method originally used to prove it. The origin of the apparent paradox appears to lie in the limits of precision of polarimetry in the context of weakly rotatory molecules, which strikes a cautionary note on the reliability of “reassignment” of natural product configurations based solely on specific rotation.

Enantiomeric Variability of Distaminolyne A. Refinement of ECD and NMR Methods for Determining Optical Purity of 1-Amino-2-Alkanols

“…For example, benzoylation of 1a (Figure 1b; Method A: BzCl, 4 equiv, DMAP, pyridine, 50 °C, 64 h), gave 1b in only 8%, but a larger amount (16%) of the mono-acylated N -benzamide, even with excess equivalencies of reagents [7]. Similar yields were obtained for model compounds ( S )- 3a and ( R )- 3b , giving ( S )- 4a (15%) and ( R )- 4b (25%; [12]). From earlier work, alternative conditions for benzoylation ( N -benzoylimidazole, DBU, CH 3 CN, 60 °C [13]) applied to (2 S ,3 R )-2-amin ododecan-3-ol, from Clavelina oblonga [14] or sphingolipids [15], were also less than satisfactory.…”

“…In order to test this hypothesis, benzoylation of ( R )- 3b was carried out under the milder conditions ( Method B ; see below). Gratifyingly, the product ( R )- 4b showed an essentially identical specific rotation ([α]normalD23 −24.1 ( c 1.48, MeOH)) to that of ( R )- 4b produced by Method A ([α]normalD23 −26.1 ( c 1.78, MeOH); [12]) eliminating the possibility of inversion at C-2 under the latter conditions.…”

“…on a ~1–3 mg scale and suppressed acylation byproducts. For example, our earlier low yielding N , O - bis -(2-naphthoylation) of ( S )- 3b to ( R )- 13b (9%; [12]) was greatly improved by applying Method B with replacement of 2-naphthoic acid for benzoic acid: The 1-AA ( S )- 3a was smoothly converted to ( S )- 13a in 46% yield.…”

“…The ECD spectra of the ( R )- N , O -bis-(2-naphthoyl) derivatives of C 6 and C 12 1-AAs displayed ECD spectra of the same form (negative split CE), with only slight differences in magnitudes (Figure 3a,b). Compared to the longer C 10 chain compound ( R )- 13b ( A = 172, A is defined as the difference of ∆ ε measured from trough to crest in the split-CE [8], MeOH [12], Figure 3b), the C 6 homolog ( R )- 9b was about 30% less intense when measured in 2,2,2-trifluoroethanol (TFE, A = 119; Figure 3a), but essentially within the expected range.…”

“…Upon revisiting the original assignment, we found the assignment of AC of ( S )- 1a was upheld by careful re-examination of the ECD data, and new comparisons to model 1-AAs, ( S )- 3a , and ( R )- 3b prepared by rational asymmetric synthesis, and converted to dibenzoyl derivatives 4a , b [12]: The ECD spectrum of ( S )- 1b was essentially the same as that of ( S )- 4a . An elementary lesson in chiroptical analysis, reprised here, is that reassignment of natural products based solely on comparisons of [α] D of weakly rotatory compounds is tenuous, at best, and unsupportable in light of stronger counter-evidence; for example, assignments based on the non-empirical interpretation of EC ECD [8].…”