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Total Synthesis and Structural Revision of the Piperarborenines via Sequen9al Cyclobutane CH Aryla9on Will R. Gutekunst and Phil S. Baran Presented by: Jared Hammill J. Am. Chem. Soc., 2011, 133 (47), pp 19076–19079 Jared Hamill @ Wipf Group Page 1 of 13 1/7/2012
Transcript of TotalSynthesisandStructuralRevisionof ...ccc.chem.pitt.edu/wipf/Current...
Total Synthesis and Structural Revision of
the Piperarborenines via Sequen9al Cyclobutane C-‐H Aryla9on
Will R. Gutekunst and Phil S. Baran
Presented by: Jared Hammill
J. Am. Chem. Soc., 2011, 133 (47), pp 19076–19079 Jared Hamill @ Wipf Group Page 1 of 13 1/7/2012
Poten9al for [2+2]
Unfortunately in the flask homodimeriza9on, orienta9on (head to head vs. head to tail), and E/Z isomeriza9on, lead to a vairety of structural and stereochemical outcomes
N
ON
MeO OMe
OMe
MeO
MeO
OO
Opiperarborenin B
N
ON
MeO OMe
OMe
MeO
MeO
OO
Opiperaborenine D
N
ON
MeO
MeO OMe
MeO
MeO
OO
O
[2+2]
[2+2] N
O
N
MeO
MeO OMe
MeO OMe
OO
O
Jared Hamill @ Wipf Group Page 2 of 13 1/7/2012
The Plan
N
ON
MeO OMe
OMe
MeO
MeO
OO
Opiperarborenine B
N
ON
MeO OMe
OMe
MeO
MeO
OO
Opiperaborenine D
R'
OR''
MeO OMe
OMeO HO
OOMe
O
R', R'' => Need to: - Promote Pd mediated C-H cleavage - Direct stereochemistry of arylation - Allow for selective epimerization - Mild installation and removal
Previously unknown
C-H arylation
Previously unknown
C-H arylation
Need new method to synthesize:
8 steps, 20% overall, nonstereocontrolled
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“If I have seen further it is by standing on the shoulders of giants”
Isaac Newton in a le_er to Robert Hooke (1676)
Jared Hamill @ Wipf Group Page 4 of 13 1/7/2012
The Precedence A New Synthesis
O
Oh! O
O
hygroscopicpyrophoric, and explosive
in air with mild "
Et2O quantitative
Corey, E. J.; Streith, J. J. Am. Chem. Soc. 1964, 86, 950–951.
Frebault, F.; Luparia, M.; Oliveira, M. T.; Goddard, R.; Maulide, N. Angew. Chem., Int. Ed. 2010, 49, 5672–5676.
Only a C-‐O and a C=C reduc9on away
from our desired SM
O
O
OMeO
h!O
O
Stable at rt
Et2Oquantitative
O
OMe
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The Precedence C-‐H Aryla9on
Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2005, 127, 13154.
Giri, R.; Maugel, N.; Li, J.-‐J.; Wang, D.-‐H.; Breazzano, S. P.; Saunders, L. B.; Yu, J.-‐Q. J. Am. Chem. Soc. 2007, 129, 3510–3511.
Zhang, M.-‐X.; Eaton, P. E. Angew. Chem., Int. Ed. 2002, 41, 2169–2171.
H3C
Oi-Pr2NBuMgNi-Pr2
H3C
Oi-Pr2N Mg1. CO2
2. CH2N2
H3C
Oi-Pr2N CO2Me
17%
NNH
O
Pd(OAc)2 (5 mol%)
AgOAc, 110 ºC NNH
O92%
OMe
I
OMe+
ROH
OAr-I+
Pd(OAc)2Ag2CO3, K2HPO4
NaOAc, t-BuOH130 ºC, 3 h
ROH
O
Ar
ROH
O
ArAr
+
70% (5:2)
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[2+2] Photocycloadditon
aJ. Org. Process Res. Dev. 2003, 7, 74–81
O
O
OMeO
h!CH2Cl2, 15 ºC
96 h
O
OOMe
O
Pt/C, H2
5 h
OHO
OMeO
NH2
SMe
EDC, 0-23 ºC,3 h
ONH
OMeO
MeS
1.1 g scale: 61%+ photopyrone decomp
OH
O
OH
O
Malic Acid2 Kg: $50
HO 1. Oleum, H2SO4, 75 ºC,
2. DIPEA, NMP, dimethylsulphate,
42% (2 steps)80 g scalea
1 g: $40
previously 8 step (20%)to nonstereocontrolled
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Cylcobutane C-‐H Aryla9on
I
OMeMeO
MeO(2 equiv)
Pd(OAc)2 (15 mol%), Ag2CO3 (1.5 equiv), PivOH (1.0 equiv), HFIP, 90 ºC, 36 h
ONH
OMeO
MeS
MeO OMe
OMe
830 mg scale: 52%
ONH
OMeO
MeS
ONH
OMeO
MeS
MeO OMe
OMe
LiOtBu (1.0 equiv)PhMe
I
MeO
MeO(2 equiv)
Pd(OAc)2 (15 mol%), Ag2CO3 (1.5 equiv),
t-BuOH (1 M), 75 ºC, 36 h
ONH
OMeO
MeS
MeO OMe
OMe
MeO
MeO
660 mg scale: 46%>10:1 dr1.3 g: 79%
50 ºC, 36 h
Jared Hamill @ Wipf Group Page 8 of 13 1/7/2012
Cylcobutane C-‐H Aryla9on
ONH
OMeO
MeS
MeO OMe
OMeKHMDS
(2.25 equiv)
I
MeO
MeO(2 equiv)
Pd(OAc)2 (10 mol%), Ag2CO3 (1 equiv),PivOH (1.0 equiv)
HFIP (0.2 M), 75 ºC, 24 h
ONH
OMeO
MeS
MeO OMe
OMe
MeO
MeO
100 mg: 81%
THF/Toluene-15 ºC, 3 min
ON
OMeO
MeS
MeO OMe
OMe
Confirmed by X-ray200 mg: 76%
ONH
OMeO
MeS
MeO OMe
OMe
K K
Jared Hamill @ Wipf Group Page 9 of 13 1/7/2012
Comple9on of Piperarborenine B & Proposed Structure of Piperarborenine D
ONH
OMeO
MeS
MeO OMe
OMe
MeO
MeO
1. Boc2O, DMAP MeCN, 2 g: 91%2. LiOH, H2O2, THF/H2O 50 ºC 24 h, 1 g: 83%
3. (COCl)2, DMF, THF, then, PhMe, 4 Å mol siev, 80 ºC
NHO
N
ON
MeO OMe
OMe
MeO
MeO
OO
O
piperarborenine B100 mg: 77%
ONH
OMeO
MeS
MeO OMe
OMe
MeO
MeO
1. EtOH, NaOH, µW, 120 ºC, 24 h, 86%2. (COCl)2, DMF, THF, then, PhMe 4 Å mol siev, 80 ºC
N
ON
MeO OMe
OMe
MeO
MeO
OO
O
piperaborenine D(proposed structure)
48 mg: 78%NH
O
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Structural Revision and Synthesis of Piperarborenine D
O
ClMeO
MeO
O
O-MeO
MeO
K+
acetone
O
O
OMeMeO
O
OMeOMe
h!
1.4 g: 98%
MeCN
then BnOH,EDC, DMAP
OBnO
MeO
MeO
OBnO
OMe
OMe
OMe
120 mg: 21%
1. Pd/C, H2, THF, 98%2. (COCl)2, DMF THF
NLiO
ON
MeO
MeO
NO
OMe
OMe
OMe
O O
Piperarborenine D4 mg: 32%
OMe MeO
Jared Hamill @ Wipf Group Page 11 of 13 1/7/2012
Conclusions
• Piperarborenine B was synthesized in 7 steps, 7% overall yield
• Proposed structure for piperarborenine D was synthesized in 6 steps, 12% overall yield
• 1st cataly9c transi9on metal mediated C-‐H ac9va9on of cyclobutane ring
• Use of divergent epimeriza9on and sequen9al Sp3 aryla9on strategy to arrive at two NP from a common SM
• Expedient synthesis of desired cyclobutane SM in a stereocontrolled fashion
• Structural revision and synthesis of piperarborenine D
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Ques9ons?
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![Acid Promoted Radical-Chain Difunctionalization of …4 Optimization of reaction conditions[a] Entry Oxidant Equiv. Acid Equiv. Additive T/ C Yield (%)[b] 1 BPO (1.5 equiv.) HCl (aq.,](https://static.fdocuments.in/doc/165x107/5f1cbe1099fd92028a750a29/acid-promoted-radical-chain-difunctionalization-of-4-optimization-of-reaction-conditionsa.jpg)
