Abstract The purpose of this experiment is to find the proper conditions of a chlorocyclization of a phenol derivative to create a substrate that will be used in total synthesis of Napyradiomycin A1 (Fig. 1). To optimize the synthesis of the compound, temperature, reaction time, chlorine source, catalyst, solvent, and R-group on the phenol derivative were all modified to select for both high ee percentage and high yield.

Introduction •  Enantioselective halocyclizations are a relatively new field of

research that have been becoming more important recently •  Optimizing the synthesis of the compound with high yields and high

percent ee will allow it to be used as a substrate in total synthesis of natural products like Napyradiomycin A1 in an asymmetric fashion.

•  Napyradiomycin A1 has antibacterial properties and some anticancer properties

•  Enantioselective total synthesis of Napyradiomycin A1 has already been achieved, but use of the phenol derivative as a substrate will allow the synthesis to be approached in an entirely new manner.

Entry   Cl+  source  (eq)  

Cat  (eq)   Solvent  (M)   Temp   9me   Yield   ee%  

1   DCDMH  (1.1  eq)  

(DHQD)2PHAL    (0.1  eq)  

TFE:DCM  (1:1)  

(0.025  M)  

-­‐30  °C   30  min   98%   30%  

2   DCDPH  (1.2  eq)  

(DHQD)2PHAL    (0.1  eq)  

TFE  (0.025  M)  

-­‐30  °C   170  min   44%   39%  

2   DCDMH*  (1.2  eq)  

(DHQD)2PHAL    (0.1  eq)  

TFE  (0.05  M)  

-­‐30  °C   120  min   35%   64%  

4   DCDMH  (1.1  eq)  

(DHQD)2PHAL    (0.1  eq)  

TFE  (0.025  M)  

-­‐30  °C   30  min   82%   64%  

5   DCDMH  (1.2  eq)  

(DHQD)2PHAL    (0.1  eq)  

TFE  (0.025  M)  

-­‐30  °C   110  min   18%   66%  

6   Dich.T  (1.1  eq)  

(DHQD)2PHAL    (0.1  eq)  

TFE  (0.025  M)  

-­‐30  °C   30  min   68%   69%  

7   DCH    (1.2  eq)  

(DHQD)2PHAL    (0.1  eq)  

TFE  (0.025  M)  

-­‐30  °C   45  min   89%   70%  

*  Regular  DCDMH  from  the  boPle;  all  other  DCDMH  was  recrystallized  

Citations

•  Jiminez, Consuelo M, Miguel A Miranda, and Rosa Tormos. "Intramolecular excited-state interactions in phenol–styrene bicromophoric systems: a photochemical and photophysical study." Tetrahedron. 58.1 (2001) 115 – 120.

•  Panteleev, Jane, Richard Y. Huang, Erica K. J. Lui, and Mark

Lautens. "Addition of Arylboronic Acids to Arylpropargyl Alcohols en Route to Indenes and Quinolines." Organic Letters. 13.19 (2011) 5314 – 5317.

•  Whitehead, Daniel C., Roozbeh Yousefi, Arvind Jaganathan, and Babak Borhan. "An Organocatalytic Asymmetric Chlorolactonization." JACS. 132.10 (2010) 3298 – 3300.

Figure 1. Structure of Napyradiomycin A1

Table 1: Results of Chlorocyclization of substrate A

Figure 3. Synthesis of cinnamyl chloride from acetyl chloride

Figure 4. Synthesis of substrate A from para-methoxyphenol

Figure 2. Structures of catalyst and chorine sources used

Conclusions •  1.2 eq DCH, 0.1 eq (DHQD)2PHAL, and 0.025 TFE give the best

results. •  70% ee is not perfect, but it indicates that enantioselectivity is

possible; the relatively high % ee indicates good interaction between catalyst and substrate, and suggests promising future results

•  For further studies, Dichloramine T and DCH should be considered as a chlorine sources, different phenol derivatives should be pursued, and reaction times should be more closely monitored.

                         

Figure 5. Synthesis of substrate B from para-methoxyphenol

Dichloramine T

O

O

OH

HO

ClCl

SO

ONCl

Cl

OH

O

condition O

O Cl

(DHQD)2PHAL

NN

O

O

R'R'

Cl

Cl

DCDMHN

MeO

N OH

N N

H

N

OMe

NO H

H

R' = MeR' = Ph DCDPH

DCHR' = H

!

Figure 6. Crystal structure of final compound

Results & Discussion •  Using a 1:1 mixture of TFE and DCM as a solvent has a much

higher yield than TFE alone, but a much lower ee%. •  When concentration of (DHQD)2PHAL is lowered to ten mole

percent from 20 mole percent, ee % increases •  The smaller the R’-group on the chlorine source, the higher the

ee %; lower bulk decreases steric hindrance

A Catalytic Asymmetric Chlorocyclization of Phenol Compounds"Meghan Richardson, Nastaran Salehi Marzijarani, Arvind Jaganathan, Babak Borhan"

Department of Chemistry, Michigan State University, East Lansing, MI 48824!  

O Me

OClAcetyl chloride (0.8 equiv.)

Ethanol, rt, 30 min, 96% yield

OH

OCH3

OH

OCH3

Cinnamyl chloride (1.5 equiv.)Na (1.0 equiv.), benzene

5h, 80 °C, 16 % yield

OH

Br

OH

Br

1. NaH (1.0 equiv.), Et2O 1h, 80 °C2. Cinnamyl chloride (1.2 equiv.) 5h, 80 °C

Figure 6. Synthesis of substrate C from para-methoxyphenol

ClOH

SOCl2 ,Chloroformrt, 6h, 91% yield

OH

OCH3

OH

OCH3

Na (1.2 equiv.), benzene

Cl(1.5 equiv.)

5h, 80 °C