Improved Synthesis and Determination of the Biologically Active Diastereomer of YK11
, Taichi Kusakabe, Nao Saito, Shoko Kikkawa, Keisuke Takahashi, Isao Azumaya, Kiyomitsu Nemoto * and Keisuke Kato *
Round 1
Reviewer 1 Report
This manuscript reports the synthesis by means of the asymmetric cyclization carbonylation of propargyl acetate using a Pd catalyst of the biologically active diastereomer of the synthetic steroid YK11. Authors get improve the yield and enantioselectivity with respect above methods. The crystal structure of YK11 was determined by X-ray monocristal diffraction. The biological properties were measured by means of a AR luciferase study. In my opinion the work seems competently carried out and the work could be attractive to Molbank readers. However, in my opinion, some minor changes should be accomplished before acceptance:
1) Crystal structure study is well-done. Author applied the SQUEEZE program to solve the problem with disordered molecules of solvent. They explain how in supplementary material but they did not include SQUEEZE data in .cif file. In this link (https://www.platonsoft.nl/platon/pl000303.html) it is explained how to use .sqf with the results in CIF format and then be appended to the final CIF file. I think that authors should include it in CIF file.
2) In Table 1, the L1 and L2 ligand schemes are not diasteroisomers. I think the L1 is badly drawn and has an extra phenyl group.
3) Perhaps my greatest doubts with respect to the manuscript come from the methodology followed when it is compared the yields of different catalysts in the synthesis of YK11. The yields of L1 and L3 are compared without being made at the same temperature, 0 and 25 ºC, respectively, when it is subsequently found that temperature is an important factor in yield. Likewise, solvent is changed later. In my opinion, reactions with L3 at 0 ºC should be carried out and mixtures of MeOH/DMSO 10:1 solvent should be used to make the comparison adequate. Can the authors explain why they have not made these experiments?
Author Response
1) Crystal structure study is well-done. Author applied the SQUEEZE program to solve the problem with disordered molecules of solvent. They explain how in supplementary material but they did not include SQUEEZE data in .cif file. In this link (https://www.platonsoft.nl/platon/pl000303.html) it is explained how to use .sqf with the results in CIF format and then be appended to the final CIF file. I think that authors should include it in CIF file.
⇒ Revised files will be uploaded.
2) In Table 1, the L1 and L2 ligand schemes are not diasteroisomers. I think the L1 is badly drawn and has an extra phenyl group.
⇒ The drawn structure is correct. The sentence will be revised to [Pd(tfa)2 / L2 catalyst gave a complex mixture (Table 1, entry 2).].
3) Perhaps my greatest doubts with respect to the manuscript come from the methodology followed when it is compared the yields of different catalysts in the synthesis of YK11. The yields of L1 and L3 are compared without being made at the same temperature, 0 and 25 ºC, respectively, when it is subsequently found that temperature is an important factor in yield. Likewise, solvent is changed later. In my opinion, reactions with L3 at 0 ºC should be carried out and mixtures of MeOH/DMSO 10:1 solvent should be used to make the comparison adequate. Can the authors explain why they have not made these experiments?
⇒ The use of L3 at 0 ºC, the reaction did not proceed.
Reviewer 2 Report
This manuscript presents interesting results on the synthesis, isolation, structure characterization and biological activity of YK11. The aim of authors was to explore the unequivocal identification of Active Diastereomer of YK11. The work has been then directed to isolate and elucidate this compound.
In my opinion, the manuscript presents a detailed discussion both on the synthesis and Isolation of the compound, and in elucidation by MNR and X-ray crystallographic analysis. The quality of the experimental procedures is, in general, satisfactory, and the interpretations and conclusions reached are reasonable. The layout and presentation of the manuscript is satisfactory. The experimental section presents consistent data concordant with the discussion previously carried out. In general, the distribution of content is appropriate.
Thus, I recommend to consider this manuscript for publication after minor revision:
- Line 40 and similarly below: please, put the reference to the table entry (parentheses) before the end point of the sentence; It is very ambiguous as currently appears.
Author Response
- Line 40 and similarly below: please, put the reference to the table entry (parentheses) before the end point of the sentence; It is very ambiguous as currently appears.
⇒ They will be revised.
