Practical access to axially chiral sulfonamides and biaryl amino phenols via organocatalytic atroposelective N-alkylation

The importance of axial chirality in enantioselective synthesis has been widely recognized for decades. The practical access to certain structures such as biaryl amino phenols known as NOBINs in enantiopure form, however, still remains a challenge. In drug delivery, the incorporation of axially chiral molecules in systematic screening has also received a great deal of interest in recent years, which calls for innovation and practical synthesis of structurally different axially chiral entities. Herein we present an operationally simple catalytic N-alkylation of sulfonamides using commercially available chiral amine catalysts to deliver two important classes of axially chiral compounds: structurally diverse NOBIN analogs as well as axially chiral N-aryl sulfonamides in excellent enantiopurity. Structurally related chiral sulfonamide has shown great potential in drug molecules but enantioselective synthesis of them has never been accomplished before. The practical catalytic procedures of our methods also bode well for their wide application in enantioselective synthesis.

The catalytic asymmetric synthesis of compounds possessing axially chiral Ar-N bond (e.g. axially chiral anilides) have been reported, however, the synthesis of analogue axially chiral N-aryl sulfonamides has not been reported. The second part of this manuscript reports the catalytic asymmetric synthesis of axially chiral N-aryl sulfonamides to address this issue.
Considering the importance of the products and the practicability of the method, this work might be suitable for publication in Nature Communications. However, the following issues should be addressed before acceptance of the manuscript. (1) The current study used acid-catalyzed reaction to prepare racemic NOBINs, which were then used for resolution. However, the chiral acid-catalyzed asymmetric synthesis of NOBINs has been reported (Tan, B. et al. Angew. Chem. Int. Ed. 2017, 56, 16308), which seems to be more practical and attractive. In this case,the authors may need to clearly state the advantages of the current method over that report. (2) The authors previously reported a kinetic resolution of NOBINs through NHC-catalyzed atroposelective acylation (Angew. Chem. Int. Ed. 2014, 53, 11041), and the strategy gave NOBINs with excellent enantioselectivities. The author mentioned they tried the previous conditions for the substrates in the current study, but no data was reported in the manuscript or in the SI. Is the previous strategy compatible with the current substrates? (3) In the abstract, the authors claimed the importance of axially chiral N-aryl sulfonamides in 'drug delivery', however, the example provided by the authors in the main text is used as a NMDA antagonist, which seems to be a drug, rather than used for drug delivery. (4) The structures of the amine catalysts in Table 1 are not in a consistent format. The authors should also check the stereocenters in the catalyst, e.g. the absolute configuration of chiral centers in (DHQD)2PHAL, (DHQD)2AQN, and (DHQD)2Pyr should be the same. (5) In Scheme 5, what is the ee of compound 12? There is an optical rotation data for chiral 12 in the supporting information, so the author should also report the ee value and add the HPLC chart.
The authors mentioned some of compounds 4 exist as a mixture of two isomers due to the presence of two axially chiral bonds. In this case, there should be four peaks for racemic 4 in the HPLC charts. However, there are only two peaks in all the HPLC charts of compounds 4. What's the reason?
Reviewer #3 (Remarks to the Author): Zhao, Kürti, and coworkers report in this paper an organocatalytic atropenantioselective N-alkylation of sulfonamides for the synthesis of chiral biaryls.
The first part dealt with the kinetic resolution of racemic biaryl using MBH carbonate as an electrophilic partner. The racemic starting materials were synthesized using the methodology developed by Kürti, while the kinetic resolution is the extension of Zhao's earlier work on the atropenanotioselective acylation of phenols. Although the selectivity factor remained moderate to good, the starting material could be recovered with excellent enantioselectivity at the expense of the yield. The second part concerned the catalytic enantioselective N-alkylation of sulfonamides. This unprecedented atropenanotioselective process provided the novel type of axially chiral tertiary N-aryl sulfonamides in excellent yields and enantioselectivities.
The work reported in this paper provided a new practical method for the synthesis of NOBIN derivatives and might help the future exploitation of this type of ligands, known for a while but still underexploited due to their inaccessibility. In view of the importance of sulfonamides in synthetic and medical chemistry, the easy access to axially chiral tertiary N-aryl sulfonamides would certainly attracted the attention of wide readerships of this journal. The transfer of axial to point chiral chirality described in the conversion of 9ba to 11 (scheme 5) by reductive Heck is of interests. In fact, highly catalytic enantioselective reductive Heck is still difficult to accomplish. For a recent example dealing with the synthesis of enantioenriched oxindole related to 11, see: ACIE, 2017, 56, 3987.
Although I found that the introduction on the axially chiral amino alcohol NOBIN is a bit too long, overall, the paper is well-written and the supporting information is also of high quality. I highly recommend its publication in Nat Commun.

Reviewer #1:
(1) The only minor change to be suggested is to provide the configuration of indoles 11 and 12.
Response: The absolute configuration of indoles 11 and 12 were assigned by the conversion of 11 to 13 followed by single crystal X-ray analysis. This was included in the updated Scheme 5 and in the SI.

Reviewer #2:
(1) The current study used acid-catalyzed reaction to prepare racemic NOBINs, which were then used for resolution. However, the chiral acid-catalyzed asymmetric synthesis of NOBINs has been reported (Tan, B. et al. Angew. Chem. Int. Ed. 2017, 56, 16308), which seems to be more practical and attractive. In this case, the authors may need to clearly state the advantages of the current method over that report.
Response: we appreciate the comment and certainly agree that work from the Tan group represents a significant breakthrough in enantioselective NOBIN synthesis. Nonetheless, we included in the discussion part that there is a limitation on the Tan method to require an aryl protecting group on the substrate to get high ee (>90%). The deprotection of that would be rather troublesome. Our method can produce analogous NOBIN derivatives with a practical procedure, despite the inherent limitation of kinetic resolution.
(2) The authors previously reported a kinetic resolution of NOBINs through NHC-catalyzed atroposelective acylation (Angew. Chem. Int. Ed. 2014, 53, 11041), and the strategy gave NOBINs with excellent enantioselectivities. The author mentioned they tried the previous conditions for the substrates in the current study, but no data was reported in the manuscript or in the SI. Is the previous strategy compatible with the current substrates?