Synthesis of the Isodityrosine Moiety of Seongsanamide A–D and Its Derivatives

Round 1

Reviewer 1 Report

The manuscript presents an interesting and flexible approach to a useful structural core. The work is generally well-presented and the scope of the method is well-explored. There are some minor points for attention, which are listed below. 

It is noted that the Ar-O-Ar moiety is described mainly as biaryl ether throughout the manuscript, but as both biaryl ether and diaryl ether (DE) in the Introduction and conclusion, a reason for the variation in nomenclature is not explained, this seems to lack consistency. 

Section 2 has a number of minor errors throughout, including missing spaces. Errors include: Line 67, italics needed for  N-phthaloylalanine; Line 70; italics for O-methylhydroxyamine; Line 75, superscript needed for C(sp³)-H; Line 98, space needed after end of sentence;  Line 116, needs "the" or "an" before "aryl iodide"; Line 168, the compound number 1 should be in bold and requires a space before the following word. I would suggest proof-reading throughout this section in particular.

Line 129, suggest "steric" is replaced with "sterically-hindered".

Scheme 3: the structures are rather crowded with overlap of the Phth and N-H labels (also 3a in Scheme 4), can this be improved? The last two lines of structures in Scheme 3 also seem very close together.

Section 3.1 "most of the chemicals" were from commercial sources - if not all from commercial sources, from where were the remainder obtained?

Section 3.4 Some errors in subscripts of chemical formulae in lines 422-424.

The standard of English is good, a few minor errors as described in the main comments to the authors.

Author Response

Thank you for your advice.

“biaryl ether” has been corrected to “diaryl ether”

Some errors in Section 2, Section 3.1, and Section 3.4, have been corrected.

Scheme 3: The ortho-groups of diaryl ether, such as methyl, methoxy, may modulate the physicochemical, pharmacodynamic, and pharmacokinetic properties by ortho effect, inductive effect, and conformational effect. The introduction of methyl group has be applied as a very useful structural modification in the rational drug design, including imatinib, nilotinib, dasatinib. Although we know that sterically-hindered immediately adjacent to the iodide may decrease reactivity, we still tried to synthesize 3r-v, which may be used as useful building blocks for further drug development efforts. 

Author Response File: Author Response.docx

Reviewer 2 Report

Dear Authors,

The manuscript is in general clear and well written.

I found, however, that the following should be corrected and modified to improve readibility.

Scheme 1: IMHO, there is no need to specify compound substituents groups but instead remark the retrosynthetic strategy.  Please, consider to make a simpler version focused in the disconnections!

Scheme 2: compound numbering is confusing. There is absolutely no reference in the main text to compound 3 prime, 3ab or 3ac. The font used in the formula captions is not always the same.

Table 1: captions are confusing, and several typos are present. Please check and correct. Why the table title says "optimization of conditions" I can only see that you tried or tested several reaction conditions, but optimization would require a different approach. Perhaps something lik "typical conditions used"? Please consider.

 

Page 5, 2nd paragraph: several typos are present (like derivative1, dioxone, yieids, etc.) Please check the whole document!

Page 7, line 212: the HRMS calcd and found look a bit off, especially when compared to all the other ones. Could you please check and correct if needed?

 

The manuscript is well written and enjoyable to read.
Some compound captions are a bit confusing, and there are some minor typos in the text, and I would recommend to check and correct them before final acceptance.

Author Response

Thank you for your advice.

Scheme 1: “the retrosynthetic strategy” has been corrected.

Scheme 2: compound numbering has been corrected.

Table 1: captions has been corrected to “Palladium-catalyzed arylation of 4a-c with 5a”

Some errors in Table 1, Page 5 and Page 7, have been corrected.

Author Response File: Author Response.docx