Seminar PSU 09.04.2013 - 10.04.2013 MiFIT, Arbuzov Vyacheslav
Room-Temperature Alternative to the Arbuzov Reaction: The ...ccc.chem.pitt.edu › wipf › Current...
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Room-Temperature Alternative to the Arbuzov Reaction: The Reductive Deoxygenation of Acyl Phosphonates Kedrowski, S. M. A.; Dougherty, D. A. Org. Lett. 2010 ASAP John Maciejewski Wipf Group - Current Literature 4 September 2010 R OH O 1. oxalyl chloride 2. P(OEt) 3 R P O OEt O OEt R P OEt O OEt 3. N 2 H 4 , BzOH 4. KOBu t John Maciejewski @ Wipf Group Page 1 of 12 9/27/2010
Transcript of Room-Temperature Alternative to the Arbuzov Reaction: The ...ccc.chem.pitt.edu › wipf › Current...
Room-Temperature Alternative to the Arbuzov Reaction: TheReductive Deoxygenation of Acyl Phosphonates
Kedrowski, S. M. A.; Dougherty, D. A. Org. Lett. 2010 ASAP
John MaciejewskiWipf Group - Current Literature
4 September 2010
R OH
O 1. oxalyl chloride
2. P(OEt)3 R P
O
OEt
OOEt
R POEt
OOEt
3. N2H4, BzOH
4. KOBut
John Maciejewski @ Wipf Group Page 1 of 12 9/27/2010
Michaelis-Arbuzov Reaction
Kurti, Laszlo, and Barbara Czako. Strategic Applications of Named Reactions in Organic Synthesis. Boston:Elsevier, 2005.Chem. Rev. 1981, 81, 415-430.
- Trialkylphosphite displaces alkyl halide to form phosphonate ester- Discovered by Michaelis in 1898, but the scope and limitations explored by Arbuzov- Ethyl halide produced considered a reactive byproduct; can undergo undesired side reactions
R
O
X R XR X
R
> >
R X
RR>>
Reactivity of alkyl halides toward phosphites decreases with branching
R X R POEt
OOEt
P(OEt)3
heatH3C X
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Michaelis-Arbuzov Reaction
Limitations include:- high temperatures may not be tolerated by sensitive substrates- phosphonate esters are usually purified by fractional distillation (multiple products)- phosphite reagent is often used as the solvent
Kurti, Laszlo, and Barbara Czako. Strategic Applications of Named Reactions in Organic Synthesis. Boston:Elsevier, 2005.Chem. Rev. 1981, 81, 415-430.
R X R POEt
OOEt
P(OEt)3
heatH3C X
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Preparation of Alkyl phosphonates
R
NaH2PO2, AIBN
H2SO4, EtOH, reflux RP
O
OH
R1OH, DCC
DMAP, THF, rt RP
O
OR1
37-41% 60-70%
NaIO4, dioxane
H2O, rt
66-91%R
P
O
OR1
OH
R = n-alkyl
Bioorg. Med. Chem. Lett. 1996, 6, 1951-1954.
Tetrahedron Lett. 2007, 48, 5755.5759.
J. Org. Chem. 1996, 56, 5556-5560.
HexH3PO2 (1-2 equiv.)
Pd2dba3 (2 mol%) OctP
O
H
OH
OctP
O
OH
OHair, base, heat
100%, 2 steps
3 step protocol to generate alkyl phosphonates
Tandem hydrophosphinylation/oxidation to produce phosphonic acid
Enolate trap with phosphonyl chloride provides alkyl phosphonate
OEt2O, LDA
ClP
O
OEt
OEt
O
P
O
OEt
OEt
79% yield
O
EtO
O
EtOP
O
OEt
OEt
Et2O, LDA
ClP
O
OEt
OEt
46% yield
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Horner-Wadsworth-Emmons (HWE) Reaction
Developed to improve the Wittig olefination by:- allows further functionalization of α-carbon to phosphonate- water soluble phosphate anions are easier to remove than phosphine oxides
HWE produces E-alkene as major isomer
Still-Gennari modification produces Z-alkene as major-R = CH2CF3- R’’/RL lies anti to phosphonate in transition state
RO P
O
RO
R'
R = aryl or alkylR' = aryl, alkeny, COR, CO2R, CN, SO2R
base R'H
HR''
O
HR''
O
RSRL
or
R'H
RSRL
or
Kurti, Laszlo, and Barbara Czako. Strategic Applications of Named Reactions in Organic Synthesis. Boston: Elsevier, 2005.Chem. Rev. 1974, 74, 87.
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Therapeutics and Agrochemicals
Small molecules with C-P bonds find applications in both pharmaceutical and agrochemical industries
Fosfomycin:- activity against methicillin- and vancomcin-resistant Staphylococcus aureus- deactivates essential enzyme (MurA) which is essential in the first step of cell wall biosynthesis
Dehydrophos:- isolated by Eli Lilly; shown to have broad antibiotic activity- structure confirmed by synthesis- mode of action of enamine not fully understood- hydrolysis of C-terminus of peptide may produce methyl acetophosphonate, a pyruvate mimic
Phosphinothricin:- widely used herbicide
Annu. Rev. Biochem. 2009, 78, 65-94.Annu. Rev. Biochem. 2007, 61, 379-400.
HOP
OHO
OH H
fosfomycin
antibiotics
H2N
HN
NH
P
O
O
OMe
OHO
dehydrophosH2N
OH
O
PH3C O
OH
phosphinothricin
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Therapeutics
Anti-malaria activity- small molecules containing phosphonic acid moiety show promising antimalarial activity
Phosphoserine mimic- used to study kinase signal transduction- C-P bonds are not hydrolyzed under physiological conditions
N O
O
TBS
HO
Tf2O, DCMN O
O
TBS
TfO
FP
Li
FOEt
O
OEt
THF, HMPA, -78 oC
38%, 2 stepsF
P
F
EtO
O
OEt
N
O
O
TBS
Chem. Biol. 2009, 16, 928
Annu. Rev. Biochem. 2009, 78, 65-94.Annu. Rev. Biochem. 2007, 61, 379-400.
P N CH3
O
HOHO
OH
O
FR-900098
P N H
O
HOHO
OH
Ofosmidomycin
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Wolff-Kishner Reduction
Standard conditions for Wolff-Kishner reduction are harshCram modification proceeds at rt; yields are variable on small scale
Recent example of Lewis acid catalyzed hydrazone formation proceeds in good yield
Kurti, Laszlo, and Barbara Czako. Strategic Applications of Named Reactions in Organic Synthesis. Boston: Elsevier, 2005.J. Am. Chem. Soc. 2004, 126, 5436.5445.
R
N
R
NH2KOH/heat
Kishner (1911)
RR
HH
R
N
R
HN
EtOH/NaOEt
180 oC
Wolff(1912)
O
NH2
R
N
R
NH2
DMSO, rtKOt-Bu/t-BuOH
PhOH
ON N
H
TBS H
TBS
cat. Sc(OTf)3
DMSO, 100 oC
92%, 2 steps
KOt-Bu/t-BuOH
PhO CH3
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Title Paper: Preparation of Acyl Phosphates
- Phosphine addition to acyl halide occurs under mild conditions over the traditional alkyl halide displacement- Hydrazones of acyl phosphonates can be isolated
- pH neutral and basic pH leads to decomposition to hydrazide and phosphite- “Moderately acidic” conditions worked the best, where low pH promoted no reaction
R P
O
OEt
OOEt R P
OEt
OOEt
HN OH
NH2 acid
base
R P
OEt
O
OEt
NH2N
R POEt
OOEt
NH
O
NH2 H
N2H4
R OH
O 1. oxalyl chloride
2. P(OEt)3 R P
O
OEt
OOEt
R POEt
OOEt
3. N2H4, BzOH
4. KOBut
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Title Paper: Deoxygenation of Acyl Phosphates
Hydrazones of acyl phosphonates can be deoxygenated via a Wolff-Kishner pathway
After hydrazone formation, all residual water was removed through lyophilization before adding baseStabilized carbanion α to phosphonate facilitates reaction under mild conditions
R OH
O 1. oxalyl chloride
2. P(OEt)3 R P
O
OEt
OOEt
R POEt
OOEt
3. N2H4, BzOH
4. KOBut
R P
O
OEt
OOEt R P
N
OEt
OOEt
H2N
-N2
R POEt
OOEt
1.05 equiv. N2H4
2.0 equiv. BzOH
3.0 equiv. of KOtBu
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Title Paper: Substrate Scope
Cl
O
Cl
O
Cl
O
Cl
O
AcO
OH
O
OH
O
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
AcO
P(O)(OEt)2
P(O)(OEt)2
entry starting material productyield (%)
(over 3 or 4 step sequence)
1
2
3
4
5
6
58
35
< 5
21
< 5
65
MeO MeO
R Cl/OH
O 1. oxalyl chloride
2. P(OEt)3 R P
O
OEt
OOEt
R POEt
OOEt
3. N2H4, BzOH
4. KOBut
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Conclusions
Uses two classical reactions to formulate a new methodology
Mild conditions offer attractive method to prepare alkyl phosphonates over classical methods
Methodology should be applied to sensitive molecules to demonstrate synthetic utility
R OH
O 1. oxalyl chloride
2. P(OEt)3 R P
O
OEt
OOEt
R POEt
OOEt
3. N2H4, BzOH
4. KOBut
John Maciejewski @ Wipf Group Page 12 of 12 9/27/2010
