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Total Syntheses of Heimiol A, Hopeahainol D, and Constrained
Analogues Sco; A. Snyder, Nathan E. Wright, Jason J. Pflueger, and Steve P.
Breazzano ACIE Early View
Presented by: Jared Hammill
Jared Hammill @ Wipf Group Page 1 of 12 8/7/2011
The Synder Group • Sco; A. Snyder
– Undergrad @ Williams college
– Grad school @ Scripps under K.C. Nicolaou • 18 papers, 2 book chapters, 1 Book: Classics II
– Post‐doc @ Harvard under E.J. Corey – Currently @ Columbia as an Associate Professor of chemistry, without tenure
• Research Focus: Target‐Driven Discovery – Halonium‐Induced polyene cyclizaVon
http://www.columbia.edu/cu/chemistry/groups/snyder/index2.htm
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Halonium Induced CyclizaVons
• Goal – Expand polyene caVon‐π cascades to include halogen iniVators
– Need be;er syntheVc variant of haloperoxidases – Current problems:
• Olefin selecVvity • Poor reacVvity with unacVvated aromaVc systems
• AromaVc halogenaVon Review of pi-cation cascades: Chem. Rev. 2005, 105, 4730
OH
O
H
HH
HCl(CH2)ClTFA, 0 ºC
then K2CO3,H2O/MeOH
O
OO
72%
(±)-progesterone
JACS, 1971, 93, 4332
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New & Simple Reagents
• Stable >1 yr @ -20 ºC • Air stable for weighing • Scalable >100 g
JACS, 2010, 132, 14303 Jared Hammill @ Wipf Group Page 4 of 12 8/7/2011
ApplicaVons
ACIE, 2009, 121, 7899 Tet, 2010, 66, 4796
JACS, 2010, 132, 14303 ACIE, 2010, 49, 5146
OMe
X
Me
H
OMe
Starting Material Product Time (min)Temp (ºC) yield
X
Me
H
Me
H
OMOM
MOMOBr
O
Br
Me
H
Me
OMOMBr
precursor to peyssonic acid A
42%-25 5
-25 5 X= Br (76%)X= I (60%)
25 5 X= Br (73%)X=I (90%)
O
O
X
MeOH
O
O
0 1X= Br (80%)X= I (45%)X= Cl (18%)
Cl
Me
H
-25 5 46% (1:1 mix)
Jared Hammill @ Wipf Group Page 5 of 12 8/7/2011
Title Paper
OMeMeO
OBn
Br
HO OH
O
HO
HO
OH OH
HO OH
OO
OHHO
BnO
Substrate controlled addition
epizerization
OMeMeOOMe
OMe
OBn
OHO
Friedel-Crafts andHalo-lactonization
OMeMeO
OH
OMe
OMe
OBn
ACIE, 2011, 50, early view
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Synthesis of Precursor
ACIE, 2011, 50, early view ACIE, 2007, 46, 8186
OMeMeO
OH
OMe
OMe
OBn
1. DMP, 99%2. Me3S+I, n-BuLi
3. ZnI2, 80% (2 steps)4. NaClO2, 85%
OMeMeOOMe
OMe
OBn
OHO
OMeMeO
OH
OMe
OMe
OBn
OMeMeO
OBn
Br 1. n-BuLi
O
OMe
OMe
71%
Jared Hammill @ Wipf Group Page 7 of 12 8/7/2011
Key Cascade
Kinetic facial selectivity
ACIE, 2011, 50, early view
ORROOR
OR
OBn
OHOI
ORROOR
OR
OBn
OOI
BnORO OR
OOOR
RO
ORROOR
OR
OBn
OHO
S IEt
EtCl
IS
Et
Et
SbCl6
RO OR
OO
ORRO
BnOMeCN, 25 ºC, 2 min
R= Me
R= H
BBr336%
(2 steps)
Jared Hammill @ Wipf Group Page 8 of 12 8/7/2011
Substrate Controlled End Game
1.79 kcal/mol lower in E
ACIE, 2011, 50, early view
1. BnBr, 89%Li
OBn
2.
1. BF3•OEt2,
HO OH
O
HO
HO
OH OH
O
BnO
BnO
BnO OBn
BnO
HO OBn
O
BnO
HO
HO OH
HO
O
most accessibleface
heimiol A
HO OH
OO
OHHO
BnO
BCl3, BF3•OEt2
HO OH
O
HO
HO
OHH
OHH
2. Pd/C, H279%
hopeahainol D
Et3SiH57% (2 steps)
99%
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5‐membered Cascade
OMeMeOOMe
OMe
OBn
OZnI2
OMeMeO
OMe
OMe
OR
OHZnI2
HOH
MeO
MeO
OMe
MeO
BnO
1. Swern, 80% HHO
MeO
MeO
OMe
MeO
BnO OMe
63%
2. 4-OMe PhMgBr, 83%
ACIE, 2011, 50, early view
Jared Hammill @ Wipf Group Page 10 of 12 8/7/2011
End Game
ACIE, 2011, 50, early view
HOH
MeO
MeO
OMe
MeO
BnO
H
HO
MeO
MeO
OMe
MeO
BnO OMe
1. Swern, 86%2. 2,4-(OMe)2PhMgBr, 99%
3. BF3OEt2, Et3SiH, 84%4. BBr3, 82%
1. BF3OEt2,
2. BBr3, 74%
H
HO
HO
OH
HO
HO
HO
H
HO
HO
OH
HO
HO
HO
OH
epi-gnetuhainin C analogue
Et3SiH, 99%
H
H
H
Jared Hammill @ Wipf Group Page 11 of 12 8/7/2011
Conclusions
• First total racemic synthesis of heimiol A and hopeinol D • heimiol A (11 steps, 8.6%, 0.5 mg) • hopeinol D(11 steps, 6.9%, 3.3 mg)
• Key iodolactonization/intramolecular Friedel-Crafts cascade utilizing their new reagent IDSI
• Successfully applied their Friedel-Crafts reaction to a 5-membered ring
Jared Hammill @ Wipf Group Page 12 of 12 8/7/2011
