Chem 242b Chemical Synthesis - chemistry.caltech.educhemistry.caltech.edu/courses/ch242/l8.pdf ·...
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Chem 242b Chemical Synthesis Scott Virgil, California Institute of Technology, Jan. 22, 2018 Lecture 8 [2+2] Cycloaddition Strategies in Synthesis 8A. Ginkgolide B (Corey JACS 1988, 110, 649) Corey’s retrosynthetic strategy for of Ginkgolide B initially sought to clear ring A which could be envisaged as arising from an ester enolate addition to the α,β-epoxyketone shown. Further simplification suggested the α,β-epoxyketone shown could be formed from the simple B-ring cyclopentene. This enables the application of the ketene [2+2] – Baeyer-Villiger “tactical combination” (TC) which utilizes the steric hindrance of Ginkgolide’s natural tert-butyl group for control of relative stereochemistry. O H HO O Me H HO O O O H O H O HO Gingkolide B O O O H O H O O O O H O OMe H OMe O H O H ~ ~ Enamine aldol with glyoxal dimethyl acetal followed by acid-catalyzed isomerization afforded the cyclopentenone which was reacted with tert-butyl cyanocuprate with TMS chloride trapping. Subsequent aldol reaction with formaldehyde trimer (s-trioxane) proceeded from the less hindered top face to afford the spiro acetal. The enol triflate was then coupled to OBO ester containing alkyne, reduced to the Z- olefin and hydrolyzed to the acid. Ketene generation from the acid chloride in refluxing toluene led to the cyclobutanone formed from top face attack. The Baeyer-Villiger oxidation required delicate choice of reagent (trityl hydroperoxide) and temperature to obtain regiocontrol in the lactone formation. N O 1. 2. H 3 O + (75%) O H OMe OMe O Et 2 O -78 to -45 °C then TMSCl TMSO t BuLi, CuCN t Bu TiCl 4 , CH 2 Cl 2 -78 °C O O O OMe OMe OMe OMe O t Bu O MeO LDA PhN(Tf) 2 TfO t Bu O MeO 1. Pd(PPh 3 ) 4 , CuI BnNH 2 , 16 °C (76 - 84%) 2. Cy 2 BH, THF then HOAc O O O H t Bu O MeO CO 2 H 1. H + (pH 3) 2. NaOH 2. Bu 3 N, toluene, Δ (80%) 1. (COCl) 2 benzene, cat. DMF O H O H 1M NaOH acetone, -30 °C (86%) Ph 3 C-OOH O O H O H 13 steps in
Transcript of Chem 242b Chemical Synthesis - chemistry.caltech.educhemistry.caltech.edu/courses/ch242/l8.pdf ·...
Chem 242b Chemical Synthesis Scott Virgil, California Institute of Technology, Jan. 22, 2018
Lecture 8 [2+2] Cycloaddition Strategies in Synthesis 8A. Ginkgolide B (Corey JACS 1988, 110, 649) Corey’s retrosynthetic strategy for of Ginkgolide B initially sought to clear ring A which could be envisaged as arising from an ester enolate addition to the α,β-epoxyketone shown. Further simplification suggested the α,β-epoxyketone shown could be formed from the simple B-ring cyclopentene. This enables the application of the ketene [2+2] – Baeyer-Villiger “tactical combination” (TC) which utilizes the steric hindrance of Ginkgolide’s natural tert-butyl group for control of relative stereochemistry.
O
HHO
O
Me
HHO
O
OO H
O
H
OHO
Gingkolide B
O
OO H
O
H
O
OOO H
O
OMeH
OMe
O H
OH
~ ~
Enamine aldol with glyoxal dimethyl acetal followed by acid-catalyzed isomerization afforded the cyclopentenone which was reacted with tert-butyl cyanocuprate with TMS chloride trapping. Subsequent aldol reaction with formaldehyde trimer (s-trioxane) proceeded from the less hindered top face to afford the spiro acetal. The enol triflate was then coupled to OBO ester containing alkyne, reduced to the Z- olefin and hydrolyzed to the acid. Ketene generation from the acid chloride in refluxing toluene led to the cyclobutanone formed from top face attack. The Baeyer-Villiger oxidation required delicate choice of reagent (trityl hydroperoxide) and temperature to obtain regiocontrol in the lactone formation.
NO 1.
2. H3O+
(75%)
O
H
OMe
OMe
O Et2O-78 to -45 °Cthen TMSCl
TMSO
tBuLi, CuCN
tBu TiCl4, CH2Cl2-78 °C
O
O
OOMe
OMe
OMe
OMe
O tBu
OMeO LDA
PhN(Tf)2TfO tBu
OMeO
1. Pd(PPh3)4, CuIBnNH2, 16 °C (76 - 84%)2. Cy2BH, THF then HOAc
O
OO
H
tBu
OMeO
CO2H
1. H+ (pH 3)2. NaOH
2. Bu3N, toluene, Δ (80%)
1. (COCl)2 benzene, cat. DMF
O H
OH 1M NaOH
acetone, -30 °C(86%)
Ph3C-OOH
OO H
OH
13 steps in
Chem 242b Chemical Synthesis Scott Virgil, California Institute of Technology, Jan. 22, 2018
8A. Ginkgolide B (cont.) Two stages of the synthesis remained to complete Ginkgolide B. After a little surgery on the oxidation level of the spiro acetal ring, the oxa- bridge was installed by α-hydroxylation of the lactone and acid-catalyzed acetal exchange. The oxygenation of the cyclopentene ring to the enone was more vexing with standard conditions for allylic chromium (VI) oxidation failing completely. A complicated radical bromination strategy involving individual processing of the three brominated products was adopted to squeak by with a 50% yield of the enone. After nucleophilic epoxidation, the A-ring was assembled and the final oxidation of the dihydrofuran afforded Ginkgolide B.
Build oxa- bridge :
2. PDC oxid.
1. HS(CH2)3SHTiCl4, CH2Cl2
CHOS
S
2. H+
MeOH
1. HIO4MeOH
O
OMe
OMe LiNEt2
OO H
O
OMeOH
OMe
NO
Ph
PhSO2
CSA
CH2Cl2
O
OO H
O
H
OMe
Convert to epoxy ketone:
2. AgNO33. separate:(1-nitro,3-nitro,enone)nitrate cleavage, oxid.
1. NBS, hν, CCl4(1-Br, 3-Br, 3,3-Br2)
enone2. Ph3C-OOHBnNMe3
+ iPrO-
THF
O
OO H
O
H
O
O then oxid'n(6 steps)
A-ringannulation
1. pyH+TsO-
C6H5Cl, 135 °C OtBu
OLiMe
8B. Photo [2+2] Cycloadditions – an overview 1. Alkene-Alkene: often need hν < 280 nM may be catalyzed by metals (Org. Synth. Coll. Vol. 7, 177)
hνH
HHO
Me
HO H
Me
hν (Pyrex)
CuOTf, Et2O(64%)
2. Alkene-aldehyde (Paterno-Büchi), Alkene-ketone: see Classics Vol. 1, Ch. 20 Asteltoxin (Schreiber) “Photochemical Key Steps in Organic Synthesis Matthay, J.; Griesbeck, A., Ed. VCH 1994. (all 3 examples) O Me
Hhν (280 nM)
Et2O(92%) O
Me
H
Actually, all three examples above constitute experimental procedures that would be considered quite hazardous due to the use of “Hanovia” 450W lamps with highly flammable materials. Without going into extensive detail on experimental set-ups, one should appreciate that a great deal of heat comes off these lamps and the temperature needs to be controlled and monitored carefully.
Chem 242b Chemical Synthesis Scott Virgil, California Institute of Technology, Jan. 28, 2013
8B. Photochemical [2+2] (cont.) 3. Alkene-enone, allene-enone by far the most useful and dependable in synthesis Enones are easily excited by λ = 300 – 320 nM so the [2+2] cycloaddition can be performed on advanced synthetic intermediates that might have other functional groups High yields frequently obtained.
O
Me
AcO
O
Me
hν (290 nM)
(82%)
O
hν (290 nM)
(55%)
OH
HH In some cases, one may obtain trans- fusion: TL 1972, 28, 2195, 2211. Corey Caryophyllene synthesis (JACS 1963, 85, 362) More recently, Antheliolide was made by a ketene-olefin route (JACS 2006, 128, 14050-14052)
O
Me
O
O
Me
H H
H
H
H
Antheliolide
Me
H
H
Caryophyllene
Me
O
Me
O
hν,
(95%)H
hν,O O H
H
O H
+
H
NaOH, H2O
-40 °C4:1 trans:cis
Allene may also be reliably photocyclized onto an enone allowing one to achieve a sort of “conjugate acetate enolate addition” in hindered systems.
1. O3hν
O • O O
CO2Me2. NaOMe
8C. Isocomene (Pirrung, Classics Vol. 1, Ch 14) The synthesis of isocomene by Pirrung represents an exceedingly short synthesis of this terpene using photo [2+2] cycloaddition followed by acid-catalyzed rearrangement. The regiochemistry is predictable by considering the diradical nature of the triplet excited state and the subsequent diradical intermediate.
OMeMe
Me
O
Me
hν (350 nM)
hexane(77%)
*Me
Me
triplet excited stateof enone has diradicalcharacter
O
Me
Me
Me
predictableregiochemistry
O
Me
Me
Me
Ph3P=CH2CH2
Me
Me
Me
TsOHMe
Me
Me
Me
+Me
Me Me
Isocomene
