• 10.1021/jo0263115
  • The Journal of Organic Chemistry
  • Volume 67
  • November 2002
  • pp 8958-8961

Efficient and reproducible method to obtain Amino-CBIs


Topic Area
Synthetic chemistry (non-biological)
Article Type
Primary Research

Logic / Design


Point of Paper
Very clear
Main Conclusions
Supported by evidence presented

Reproducibility


Key Procedures
Able to reproduce most
# Procedures Attempted
7 or more
Of Attempted, # Reproduced
Most

Improvements


Replicated Methods Exactly:
Exactly
Reviewer Improvements
Significant improvements made

Versatility


Applicability to Other Fields
Probably
Use in Own Work
Did not attempt

Clarity


Overall Clarity
Very good

Impact


Impact
Signifcantly advances the field

Transparency


Funding Sources
Clearly disclosed
Conflicts of Interest
Not aware of any

Other


Safety Concerns
None or clearly mentioned
Reagents
All commercially available

Details


The presented route provides an efficient and highly reproducible method to obtain penultimate allyl-protected intermediates of 3-Substituted 5-Amino-1-(chloromethyl)-1,2-dihydro-3H-benzo[e]indoles (amino-CBIs).  De-allylation utilizing Grubbs carbene proved challenging as the authors note in the manuscript and gave poor yields of the desired final compounds in my hands. I found a modified approach utilizing catalytic Pd(PPh3)4 with1-2 equivalents of p-TolSO2Na and CSA in DCM as described in DOI:10.1021/jo971194c significantly improved upon the reported conditions generating high yields (>90%) of the desired amino-CBI products within 30 minutes at room temperature. 

The end products tended to be poorly soluble and labile to hydrolysis in solution, DMSO stocks should be stored carefully in single use aliquots at -78 C.  Care should also be taken during solubilization as they readily decompose under even mild heating.  When handled carefully these products are highly potent DNA alkylators with sub-nanomolar activities against many mammalian cells.  Poor solubility and general toxicity limit their applications beyond tool compounds.

Overall the chemistry presented in this paper was robust, well-described, and highly reproducible.  Everything worked as described outside of the final step which was accurately noted to be challenging and give low yields. Modifying the final deprotection conditions can thus significantly improve the overall yields and ease of synthesis for these compounds.



Comments

Love the detail

Thanks for the review, Ben! Love the -80C storage / hydrolysis details. Super useful for anyone who wants to try this themselves :)

Leave a Comment