A Catalytic Asymmetric Chlorocyclization of Phenol...
Transcript of A Catalytic Asymmetric Chlorocyclization of Phenol...
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