cns chapter 7 2016 - uni-muenchen.de · regio- and stereoselective favorskii rearrangement via the...
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Chemical Neuroscience a course for synthetic chemists
Calcium in Neuroscience
7
Calcium is complicated
sarcoplasmatic or endoplasmatic reticulum
cell membrane
cytosol
Ca2+ can come from the extracellular space and from intracellular “stores”
extracellular space
ORAI
ST IM
SM
SMOC
L
ROC
ryanodinereceptor
IP3
IP3 receptor
VOC
Ca2+
Ca2+
SR/ER membrane
VOC = voltage-operated ion channel, SMOC = second messenger-operated in channel,ROC = receptor-operated ion channels; STIM/ORAI = “store-operated ion channel”
Calcium is pumped out of the cytosolby NCX and SERCA
1 Ca2+
3 Na+
ATP ADP + Pi
Ca2+lumen of the SR/ER
cell membrane
cytosol
extracellular space
SR/ER membrane
sodium/calcium exchanger (NCX)
sarcoplasmic/endoplasmicreticulum calcium ATPase (SERCA)
The Sodium Calcium Exchanger (NCX)
extracellular
cytoplasm
pdb 3V5S
1 Ca2+
3 Na+
NCX is an electrogenic antiporter.
OSW-1 inhibits NCX
Me
Me
HO
H
H H
OOH
OMe
O
OHAcO
OOHOHO
OOMe
O
Hui synthesis: J. Org. Chem. 1999, 64, 202
Guo synthesis: J. Org. Chem. 2008, 73, 157
Review: Chem Rev. 2013, 113, 5480
The sarco/endoplasmatic reticulum Ca2+-ATPase (SERCA)
ATP ADP + Pi
Ca2+
cytoplasm
lumen
ATP binding site
pdb 2B4Y
Thapsigargin and cyclopiazonic acid inhibit SERCA
These probes are used to distinguish Ca2+ from intracellular stores from extracellular Ca2+.
O
HOAcMe
OOH
MeOH
O
O
O O
O
O H
NH
H
cyclopiazonic acid
N HOH
H
O
O
thapsigargin
O
HOAcMe
OOH
MeOH
O
O
O O
O
O H
NH
H
cyclopiazonic acid
N HOH
H
O
O
thapsigargin
The thapsigargin binding site
cytoplasm
lumen
pdb 2B4Y
Chem. Eur. J. 2007, 13, 5688
A relatively long but elegant synthesis of a challenging target and the only one to date.
The Ley synthesis of thapsigargin
O
Br
OEt
MeOH PO
OEtOEtHOOC
O
OO
HOAcMe
O OC3H7
OO
O
C7H15
OH
O
OOHMeO
H OAcMe
O OHMe
O
OO HO
O O
C3H7
O
C7H15 O
1,2
3
1) H2O2, NaOH, MeOH → LiCl, CF3COOH2) dihydropyran, PPTS
3) NaOMe, MeOH
Scheffer-Weitz epoxidation → in situ epoxide opening with by LiCl,protection of the alcohol
O(S)-carvone
MeO
THPO
Cl
regio- and stereoselective Favorskii rearrangementvia the following intermediate:
MeOMe
O
Me
THPOCOOMe
4,5
Me
TBDPSO
O
4) PPTS → TBPDSCl, im5) LiAlH4 → NaH, PMBCl → OsO4, NMO → NaIO4
change of alcohol protecting group,reduction → alcohol protection → dihydroxylation → diol cleavage
OPMB
Me
TBDPSO
O
OPMB
6 6) AllylMgBr
Me
TBDPSO OPMB
OHMe
major diastereomerd.r. = 8 :1
H
7-9 7) MOMCl, DIPEA, DMAP8) DDQ9) TPAP, NMO
allylation
protection of the tertiary alcohol,deprotection of the primary alcohol,Ley oxidation
Me
TBDPSO
OMOMMeH
H
10, 11 10) t-BuLi, CH2=CHOEt11) TESCl, im
addition of lithiated vinyl ether to aldehyde,protection of secondary alcohol
OTES
EtO
Me
TBDPSO
OMOMMeH
O
H
H OAcMe
O OHMe
O
OO HO
O O
C3H7
O
C7H15 O
12 key step: ring-closing metathesis12) Grubbs II
Me
TBDPSO
H
HTESO
OEt
OMOMMe
Me
TBDPSO
H
HTESO
O
OMOMMe
Me
TBDPSO
OMOMMeH
HOTES
EtO
OH
13 dihydroxylation13) K2OsO2(OH)4, K3Fe(CN)6, NaHCO3, MeSO2NH2
major diastereomerd.r. = 16 :1
H OAcMe
O OHMe
O
OO HO
O O
C3H7
O
C7H15 O
Me
TBDPSO
H
HTESO
OMOMMe
14 ester formation
Me
TBDPSO
H
HTESO
O
OMOMMe
OH
14) , EDCI
Me
TBDPSO
H
HTESO
OMOMMe
OH
16 reduction16) LiBH4
OH
O
O
15
Me
TBDPSO
H
HTESO
O
OMOMMe
O O
P O
15) NaH, Δ intramolecular HWE olefination
HO
OP(OEt)2
O
EtO OEt
H OAcMe
O OHMe
O
OO HO
O O
C3H7
O
C7H15 O
Me
TBDPSO
H
HTESO
OMOMMe
OH
OH
17 acetylation → MOM protection17) Ac2O, DMAP, 2,6-lutidine → MOMCl, DIPEA, DMAP
Me
TBDPSO
H
HTESO
OMOMMe
OMOM
OAc
18
Me
TBDPSO
H
HTESO
OMOMMe
OMOM
dihydroxylation18) K2OsO2(OH)2, K3Fe(CN)6, quinuclidine, K2CO3, MeSO2NH2
HO
OAcHO Me
NN
quinuclidine
H OAcMe
O OHMe
O
OO HO
O O
C3H7
O
C7H15 O
19-21 saponification,Ley oxidation,deprotection, reprotection
19) K2CO3, MeOH20) TPAP, NMO21) Amerlyst-15,
22 deprotection → Dess-Martin oxidation22) TBAF → DMP, NaHCO3
Me
H
H
OHMe
O
HOO
MeO
O
Me
TBDPSO
H
H
OHMe
O
HO
OMe
O
O
O
Me
TBDPSO
H
HTESO
OMOMMe
OMOMHO
OAcHO Me
OMeMeO
H OAcMe
O OHMe
O
OO HO
O O
C3H7
O
C7H15 O
Me
H
H
OHMe
O
HO
OMe
O
OO
23 protection, silyl enol ether formation23) TMSCl
Me
H
H
OTMSMe
OOMe
O
OTMSO RO
R = TMS24 24) DMDO, Me2CO
Me
H
H
OTMSMe
OOMe
O
OO RO
R = TMS
HO
OO
dimethyldioxirane (DMDO)
Rubottom oxidation
H OAcMe
O OHMe
O
OO HO
O O
C3H7
O
C7H15 O
Me
H
H
OTMSMe
OOMe
O
OO RO
R = TMS
HO
25-27 25) SEMCl26) LiHMDS → PhSeCl27) O3
H OTMSMe
OOMe
O
OO RO
R = TMS
SEMO
H OHMe
OO
MeO
OO HO
OSEMO
28) Zn(BH4)2 → TBAF29) Cl
Cl Cl
O
O O28,29
protection,ɑ-selenation,enone formation
HO
O
angelic acid
enone reduction,ester formation via mixed anhydride
Cl O Si
SEMCl
H OAcMe
O OHMe
O
OO HO
O O
C3H7
O
C7H15 O
Me
H
H
OTMSMe
OOMe
O
OO RO
R = TMS
HO
25-27 25) SEMCl26) LiHMDS → PhSeCl27) O3
H OTMSMe
OOMe
O
OO RO
R = TMS
SEMO
H OHMe
OO
MeO
OO HO
OSEMO
28) Zn(BH4)2 → TBAF29) Cl
Cl Cl
O
O O28,29
protection,ɑ-selenation,enone formation
HO
O
angelic acid
enone reduction,ester formation via the mixed anhydride
Cl O Si
SEMCl
H OAcMe
O OHMe
O
OO HO
O O
C3H7
O
C7H15 O
H OAcMe
O OHMe
O
OO HO
O O
C3H7
thapsigargin
O
C7H15 O
H OAcMe
OOMe
O
OO HO
O O
C7H15 O
32) HCl33) butyric anhydride
H OHMe
OOMe
O
OO HO
OSEMO
29) n-BuSH, MgBr2⋅Et2O30) octanoic anhydride31) isopropenyl acetate, p-TsOH
29-31
32,33
SEM removal,acylation,acetylation under acidic conditions
OAc
ACS Cent. Sci. 2017, 3, 47
A very short synthesis that exemplifies Baran’s cyclase-oxidation phase approach. A study in orchestration of oxidation events that took some key insights from previous approaches towards
similar guaianolides. Many transformations are carried out in a one-pot fashion.
The Baran synthesis of thapsigargin
O
HOAcMe
O OC3H7
OO
O
C7H15
OH
O
OOHMeO
HO
O
OH
O
C7H15
OH
O
C3H7
O
H OAcMe
O OHMe
O
OO HO
O O
C3H7
O
C7H15 O
1
2
1) KOH, → O2
2) TMSOTf, Et3N→ NBS→ DBU
key step: Robinson annulation → allylic oxidation
O(+)-dihydrocarvone
silyl enol ether formation → bromination→ elimination
3 3) → AD-mix-ɑ elimination using Burgess’ reagent →enantioselective Sharpless dihydroxylation
O
OOH
Me
OOH
Me
MeOOC N S NEt3O O
MeO
Me
OHOH
H OAcMe
O OHMe
O
OO HO
O O
C3H7
O
C7H15 O
4 4) TBSCl, im → SeO2, NaHCO3 TBS protection → allylic oxidation
MeO
Me
OHOH
MeO
Me
OHOTBS
OH
5 5) DEAD, PBu3, PrCOOH Mitsunobu reaction
MeO
Me
OHOTBS
O
O C3H7
5 6) hv, AcOH
HOAcMe
O
OHMe
OTBS
OC3H7
O
H OAcMe
O OHMe
O
OO HO
O O
C3H7
O
C7H15 O
7 key step: ɑ-oxidation and carboxylation7) KMnO4, C7H15COOH, (C7H15CO)2O
8 dihydroxylation and partial TBS deprotection8) OsO4, NMO, citric acid
HOAcMe
O
OHMe
OTBS
OC3H7
O
HOAcMe
O
OHMe
OTBS
OC3H7
OO
O
C7H15
HOAcMe
O
OHMe
OH
OC3H7
OO
O
C7H15
HO
HO
H OAcMe
O OHMe
O
OO HO
O O
C3H7
O
C7H15 O
HOAcMe
O
OHMe
OH
OC3H7
OO
O
C7H15
HO
HO
9,10 Swern oxidation → lactol formation→ oxidation to the lactone,enone reduction,esterification via the mixed anhydride
9) DMSO, SO3⋅py, py, DIPEA
10) ZnBH411) PhCOCl, Et3N,
HOAcMe
O OC3H7
OO
O
C7H15
OH
O
OOHMe
HO
O
O
thapsigargin
Chem. Commun. 2005, 3162
An efficient albeit racemic synthesis of an attractive indole target that hinges on a cationic cyclization.
The Knight synthesis of cyclopiazonic acid
O
O
MgBr
SO2N3
COOMeO2N
Me2N
OMe
OMe
COOEt(EtO)2PO
N H
O
N
N
H
HO
O OH
H
H
N
NH
H
HO
O OH
H
1 1) , → Fe, HOAc
2,3 2) Red-Al3) TBDPSCl, im
key step: Leimgruber-Batcho indole synthesis via:
ester reduction,alcohol protection
4-6 4) POCl3, DMF5) TsCl, NaH6) DBN, LiCl,
formylation,N-tosylation,Horner-Wadsworth-Emmons reaction underMasamune-Roush conditions
COOMeO2N
Me2N
OMe
OMeNH
NH
COOMe
COOMeO2N
N
COOMe
H2N
N
NH
TBDPSO
COOEt(EtO)2PO
NTs
TBDPSO COOEt
N
NH
H
HO
O OH
H
7,8 7) PhSCu,8) KHMDS, trisyl azide
organocuprate addition,α-azidation
9,10 9) PPh310) p-NsCl, py, DMAP
Staudinger reduction,amine nosylation
NTs
TBDPSO COOEt
MgBr
SO2N3
trisyl azideNTs
TBDPSO COOEt
N3
NTs
TBDPSO COOEt
NHp-Ns
O2N
SO2Cl
p-NsCl
An inconsequential mixture of diastereomers is formed.
12,13 12) LiSCH2COOLi
13) KOt-Bu,
double deprotection,
N-acylation → Dieckmann condensation via:
NTs
TBDPSO COOEt
NHp-Ns
11 11) TfOH key step: deprotection → cationic cylization via:
NH
H2O NHp-Ns
COOEtNp-Ns
N
H
HCOOEt
N
N
H
HO
O OH
H
cyclopiazonic acid
O
O
N
N
H
H COOEt
O O
Ts
H
H
The carboethoxy group epimerizes to reside inthe thermodynamically more favorable position.
Important Ca2+ channels
Voltage-gated:
L-Type channels (muscle cells incl. cardiac myocytes, dendrites of cortical neurons, photoreceptor cells, auditory hair cells)
P/Q-Type (axon terminals, crucial for synaptic vesicle release)
Ligand-gated:
IP3 receptors (endoplasmatic reticulum)
ryanodine receptors (sarco/endoplasmatic reticulum)
Neurons talk to muscles
neuromuscular endplate
L-Type Ca2+ channels and muscle contraction
Source: Phil Schatz
Excitation-contraction coupling in skeletal muscle
Source: Phil Schatz
Excitation-contraction coupling in skeletal muscle
Source: Phil Schatz
Structure of the actin-tropomyosin complex
pdb 3J8A
Structure of the actin-tropomyosin-myosin complex
pdb 4A7F
Ryanodine receptors are giant channelsgated by calcium or mechanical forces
27 nm
extracellular view
pdb 3J8E
cryo-EM structure:
Ryanodine receptors are inhibited by ryanodine
OHMeMe
OH
HO
HO
Me
HO
O
ONH
ryanodine
HO O
Ryania spetiosa
ryanodol
O
OHHO
OHHO
OHOH
OH
The Deslongchamps synthesis of ryanodol
On of the greatest (and most under-appreciated) achievements in synthesis. The culmination of an effort spanning ten years and a true classic. The final publication featured no less than 20 students.
Can. J. Chem. 1979, 57, 3348
MeO
MeO
MeO Cl
Cl
OLi
MeIO
HOHO
OHHO
OHOH
O
1,2
3,4
1)TiCl4,
2) BBr3
3) , py4) Na2CO3
5,65) N2H4, KOH → p-TsOH6) NaOH, NBS
MeO
MeO
HO
HOCHO
CHO
O
O
O
OO
O
O Cl
Cl
Br Br
O
O
O
OBr
OO
Wolff-Kishner reductionNBS-promoted oxidative dearomatization via:
Lewis acid promoted formylation using dichloromethyl methyl ether,demethylation
acylation,alkylation
fragment A
‡
O
HOHO
OHHO
OHOH
OH
O
HOHO
OHHO
OHOH
OH
O
7,8 7) Pt, H28) O3 → Pd-C, H2
exo-alkene hydrogenation,ozonolysis
Carvone is a cheap chiral pool building block.
HO
O
O
H
9, 10 9) (CH2OH)2, p-TsOH → NaOH, MeI10) LiH,
acetal formationmethyl ester formationvinyl additionLi
O
O
O
fragment B
(+)-carvone
O
HOHO
OHHO
OHOH
OH
12 12) NaOH, H2O key step: hydrolysis, epimerization (*) followed by intramolecular aldol reaction via:
11) fragment B, PhH, Δ11
OO
O
OO
O
O
O
mixture of isomers
O
O
O
OO
HO
O
O
O
O
OO
O
key step: intermolecular Diels-Alder reaction
*
O
HO
O
O
O+HH
*
O
HOHO
OHHO
OHOH
OH
13,14 13) AcOH14) NaOH
acetal hydrolysiskey step: epimerization followed byiintramolecular aldol addition
15,16 15) COCl2, py16) (Me3O)3CH, p-TsOH
O
OO
O
O
HOHO
H
carbonate formation,acetal formation
MeOOMe
HO
H
O
HO
O
O
OO
HO
O
O
O+HH
O
HOHO
OHHO
OHOH
OH
17,18 17) CH3CO3H, CH3CO2Na18) WCl6, n-BuLi
19 19) O3, DMS → p-TsOH
O
OO
O
OO
OOHO
O
O
O
O
OO
H
OO
OOO
OO
OH
OO
HOOO
O
OH
OO
key step: ozonolysis followed by transannular aldol addition
Baeyer-Villiger oxidation and epoxidation,deoxygenation of the epoxide to reform the alkene
O
OO
O
MeOOMe
H
MeOOMe
MeOOMe
MeOMeO
MeOMeO
MeOMeO
≡
O
20,21 20) LDA, BEt3 → MeI21) NaBH4
22,23 22) NaH, MOMCl23) LiAlH4
OO
OHOO
O O
HOHO
OO
O
O O
OO
OOHO
O
OMeOMeO
α-methylation via the boron enolate,carbonyl reduction
ortho-carbonate formation,lactone reduction
MeO
MeO
MeO
MeO
H
H
MeO
O
HOHO
OHHO
OHOH
OH
O
HOHO
OHHO
OHOH
OH
24, 25 24) CrO3•2py25) MsCl
26) n-BuLi, DMSO
O
OO
O
O O
OH
26key step: Grob fragmentation
Collins oxidation → hemiacetal formation,mesylate formation
O(H3CO)2HC
OO
O
OMsO
O
HOHO
OO
O
O OMeO
MeO
MeO
MeO
H
Ms
MeO
MeO
OO
O
O
OO
MeO
MeO
MeOMeO
27,28 27) HBF428) CF3CO3H, Na2HPO4
OO
O
O
OO
MeO
MeO
O
O
O
OO
OH
orthocarbonate hydrolysis,epoxidation
O
O
O
OBzp-NO2
OHOH
OO
29,30 29) NaOH30) p-NO2BzCl
p-NO2BzCl =O2N
O
Cl
MeO
MeO
OMe
MeO
ester hydrolysis and epoxide opening,alcohol benzoylation
O
MeO
O
HOHO
OHHO
OHOH
OH
O
HOHO
OHHO
OHOH
OH
O
O
O
OBzp-NO2
OH
OO
31) CrO3•2py32) LiBH433) Ac2O
31-33
O
34) p-TsOH34
O
O
O
OBzp-NO2
OHOH
OO
OMe
MeO
Collins oxidation,stereoselective reduction to the equatorial alcohol,acetylation
MeO
OMe
MeOH elimination
O
O
O
OBzp-NO2
OH
OO
O
MeO
Ac
Ac
O
HOHO
OHHO
OHOH
OH
O
O
O OH
O
O
OO
35) O3 → Me2S36) Ac2O, NaOAc
35,36
3737) DBN, Δ
DBN =
elimination of p-nitrobenzoate to form an exocyclic alkene which tautomerizes to the enone upon acetate deprotection
N
N
O
O
O
OBzp-NO2
OH
OO
O
MeO
O
O
O
OBzp-NO2
OH
OO
R
ozonolysis,enol acetate formation
AcO
O
O
O OH
OO
R
AcO
Ac
Ac
38-40 38) NaBH439) NaOH40) CF3CO3H, Na2HPO4
ryanodol
O
O
O OH
O
O
OO
enone reduction,acetate hydrolysisepoxidation
41 41) Li, NH3 key step: reductive epoxide opening
O
HOHO
OHHO
OHOH
O
O
HOHO
OH
OH
OO
O
Ac
H
H
The reverse sequence (from ryanodol)via Grob fragmentation had been establisedpreviously.
Pierre Deslongchamps
He wrote the book on stereoelectronic effects.
The Inoue synthesis of ryanodol
35 years after Deslongchamps, a second synthesis of ryanodol. Inoue's approach beautifully exploits symmetry to elaborate the central 5,5-ring system featuring the two quaternary stereocenters. Recently, a slightly modified strategy enabled the first total synthesis of ryanodine itself.
J. Am. Chem. Soc. 2014, 136, 5916Chem. Eur. J. 2016, 22, 230
LiLi
SnBu3
SO
I
OH
OH
OO
O
O
HOHO
OHHO
OHOH
OH
O
HOHO
OHHO
OHOH
OH
1
2
1) maleic anhydride, 210 °C
2) H2O → py, Et3N, Pt(+)/Pt(-)
Diels-Alder cycloaddition, followed by enol-to-ketone tautomerisation
hydrolysis to the diacid A, →electrolytic removal of both acids
OH
OH
O
O
OO
O
O
O
OO
O
O
O
HOOCHOOC
A
The product is C2-symmetric.
O
HOHO
OHHO
OHOH
OH
4
5) NaNO2, AcOH
3 3) NaH, stereoselective double epoxide formation via Corey-Chaykovsky reaction
O
O
O
O
OH
HO
5
NH2H2N
O
O
4) NH3 (aq) epoxide opening
twofold ring expansion via twoTiffeneau–Demjanov rearrangements
SO
I
HO O NN
HO
– N2
SO
O O SO
– DMSO
O
NH2
O
HOHO
OHHO
OHOH
OH
O
8
6) TMSOTf, Et3N7) DMDO
6,7
OTMS
O
TMSO
O
O
HO OHO
OH
9
OH
O
HO O
8) TfOH (1 mol%)
9) TfOH (3 mol%), 65 °C
TfOH = SO
OOHF3C
DMDO=OO
silyl enol ether formation,Rubottom oxidation
acidic cleavage to give α-hydroxy ketones
key step: transannular aldol addition
HO
O OHOH
OTMS OTMS
O
OOH
H2O[O]
The C2-symmetry is broken.
O
HOHO
OHHO
OHOH
OH
10,11
12
HO OHO
OH
13
O
O
TBSO
OTBS
10) dimethoxypropane, PPTS11) DMP
12) LDA, TBSOTf
13) m-CPBA Rubottom oxidation
silyl enol ether formation
protection of 1,2-diol,Dess-Martin oxidation
The C2-symmetry is restored.
OO
O
HO OHO
OO
OO
O
HOOH OH
HO
OHHO
HO
14,15
16
14) NaH, MOMCl15) O2, Co(acac)2, Et3SiH, t-BuOOH
16) NfF, DBU → SiO2 column
protection,key step: Et3Si-peroxide formation desymmetrizes and oxidizes key intermediate
key step: elimination, lactol formation
C4F9SO
OFNfF =
OO
O
O
OMOMMOMO
ONfO
O OO
O
OMOMMOMO
O
H
H2O
via:
O
OO
OHO
MOMO OMOMOH
OO
O
MOMO OMOMO
OTESO
OO
O
HO OHO
O
HOHO
OHHO
OHOH
OH
17,18
19
17) BnOH, SiO218) KH, B
19) AIBN,
NPhO
S
NCl
B
SnBu3
N NAIBN = N
N
protection,thiocarbonate formation
key step: radical transfer allylation
O
O O
O
OMOMH
MOMO
H
BnO
•
via:
O
OO
OBnO
MOMO OMOM
O
OO
OBnO
MOMO OMOMO
S OPh
O
OO
OHO
MOMO OMOMOH
O
HOHO
OHHO
OHOH
OH
20-23
24
20) BF3•OEt2, Me2S21) DMP22) Pd(MeCN)2Cl223) BF3•OEt2, Me2S
24) Li
selective MOM deprotection,Dess-Martin oxidation,alkene isomerization to the internal alkene,MOM deprotection
regio- and stereoselective nucleophilic addition(sterically shielding groups highlighted)
O
O O
O
OHO
H
BnO Li
O
OO
OBnO
HO O
O
OO
OH
OBnO
HO
O
OO
OBnO
MOMO OMOM
O
HOHO
OHHO
OHOH
OH
25
26-28
25) Hoveyda-Grubbs second generation catalyst
26) TMSOTf, py27) BH3•THF → NaBO328) TMSOTf, py → HCl
key step: ring-closing metathesis
double protection,hydroboration → oxidation,reprotection of the secondary alcohol
O
OO O
OBn
O
O
TMSH
TMSO
O
OO
HO
OBnO
HO
O
OO
OH
OBnO
HO
O
HOHO
OHHO
OHOH
OH
29-31
32,33
29) , Sc(OTf)3 → NaOH30) DMP
31) , CeCl3
32) TASF33) HCl
BnO
NPh
CF3
Li
protection → deprotection of secondary silyl ether,
Dess-Martin oxidation,
CeIII-mediated stereoselective nucleophilic addition
silyl ether deprotection,acetonide deprotection
O
HOHO
OHHO
OBn
O
O
O
OO OHO
OBn
O
O
TMSBn
Bn
O
OO O
OBn
O
O
TMSH
TMSO
N S N
NSiF
F
TASF
34
35
34) NaBH(OAc)3 →KHF2
35) H2, Pd-C hydrogenation, hydrogenolysis
stereoselective reduction, borate ester hydrolysis
ryanodol
O
HOHO
OHHO
OHOH
O
O
HOHO
OHHO
OHOBn
O
O
HOHO
OHHO
OBn
O
O
H
Bn
Bn
The Reisman synthesis of ryanodol
A very short synthesis that relies on a powerful Pauson-Khand reaction to furnish the central cyclopentane as well as a late-stage Riley oxidation. The resulting synthesis cuts the total step count in half.
Science 2016, 353, 912
O
HOHO
OHHO
OHOH
OH SnBu3
O
COBrMg
EtO MgBr
Me MgBr
O
HOHO
OHHO
OHOH
OH
1,2
3,4
1) KHMDS → Davis’ oxaziridine
2) , DIPEA TBAI
double α-hydroxylation
protection of the 1,3-diol
OH
OO
OBnOBn
O
3)4) O3/O2 → PPh3
Me MgBr
OO
OBnOBn
O
BnO Cl
O
Davis’ oxaziridine =NO SO2PhPh
alkynylation,ozonolysis
(S)-Pulegone is the enantiomer of the widely available (R)-pulegone.
O
HOHO
OHHO
OHOH
OH
5,6
7
5)6) AgOTf
7) , CuIBrMg
O
OO
O
OBnOBn
O
OO
O
OBnOBn
OH
OO
OBnOBn
O
EtO MgBr alkynylation,Ag-catalyzed lactonization via:
OHOEt
OHR
R2R3
Ag+
OH
OHR
R2R3
Ag
OEt
O
OHR
R2R3
Ag
OEt OR2
R3
Ag
OEt
R
H2O
OR2
R3
Ag
OEt
R
OH H+ OR2
R3
R
O
-Ag+
-EtOH
O
HOHO
OHHO
OHOH
OH
8
9
8) [RhCl(CO)2]2, CO
9) SeO2, 4 Å MS, 110 °C
key step: Pauson-Khand reaction
key step: Riley oxidation to selectively introduce three hydroxy groups
O
HOHO
O
O
O
O
OBnOBn
HO
O
HO
O
O
OBnOBn
O
O
OO
O
OBnOBn
O
HOHO
OHHO
OHOH
OH
10, 11
12,13 12) LiBH4 → KHF2/MeOH13) H2, Pd(OH)2-C
SnBu3
reduction → boronate removal,deprotection
O
HOHO
O
O
O
O
OBn
O
HOHO
OH
HO
O
O
H
OBn
enol triflation
Stille coupling
O
HOHO
O
O
O
O
OBnOBn
HO
10) , DIPEA
11) Pd(PPh3)2Cl2, LiCl,
N
Cl
Tf2N
O
HOHO
OHHO
OHOH
OH
14
15
14) CF3CO3H, H3PO4, urea hydrogen peroxide
15) Li, NH3/THF key step: reductive epoxide opening
epoxidation
ryanodol
O
HOHO
OH
OHOH
O
O
HOHO
OH
OH
OO
O
O
HOHO
OH
HO
O
O
H
H
H
HO
The synapse
http://en.wikipedia.org/wiki/Synapse
neurotransmitterrelease
synaptic vesicle
AP triggersCa2+ influx
Ca2+ triggersvesicle fusion
Ca2+
synaptic cleft
ca. 20 nm
vesicle fusion is mediatedby SNARE proteins
P/Q typeCa2+ channels
Synaptic vesicle release is driven by SNARE proteins
source: Wikipedia
Tetanus toxin cleaves SNARE proteins at inhibitory synapses
It proteolytically cleaves primarily synaptobrevin. This results in overstimulation and muscle spasms typical of tetanus (AKA lock jaw).
Charles Bell (1809)
Botulinum toxins (“Botox”) cleave SNARE proteins at excitatory synapses
This results in muscle relaxation.
Molecules that target P/Q-type Ca2+ channels
ω-agatoxin(blocker)
Aglenopsis aperta (funnel web spider)
COOH
NH2
pregabalin
COOHH2N
gabapentin
Richard Silverman
Gabapentin and pregabalin, both initially developed to target GABA receptors, bind to the α2δ subunit of voltage-gated Ca2+ channels and promote the trafficking of these channels away from the plasma membrane. They have anticonvulsant and analgesic effects.
Drugs that block L-type calcium channels
N
S
O
OMe
OAc
N diltiazem
N
NCMeO
MeO
OMe
OMe
verapamil
NH
NO2COOMeMeOOC
NH
ClCOOMeEtOOC
Cl
nifedipin (Adalat) felodipin
NH
MeOOC E
O2N
≡
The Jacobsen-Tanabe synthesis of diltiazem
An asymmetric version of the industrial route using Jacobsen’s signature reaction.
Tetrahedron 1994, 50, 4323
N
S
O
OAc
OMe
NH
Cl
OMe
OHCSH
NO2
ClCOOi-Pr
CBr4
ClCH2CH2NMe2
Ac2O
N
S
O
OAc
OMe
NH
Cl
1-3
4
1) CBr4, PPh32) n-BuLi → ClCOOi-Pr3) H2, Lindlar catalyst
4) (R,R)-Jacbosen catalyst 4-picoline-N-oxide, NaOCl
Corey-Fuchs homologation,addition of isopropyl chloroformate,semihydrogenation
OMe
OHC
N N
O O
t-Bu t-Bu
t-But-Bu
HH
Mn
Cl
(R,R)-Jacobsen catalyst
Gylcidates are a motif common to most syntheses of diltiazem.
ee = 96%cis/trans = 10:1
OMei-PrOOC
O
OMei-PrOOC
Jacobsen epoxidation
N
S
O
OAc
OMe
NH
Cl
5 5) NaHCO3
OMe
SH
NO2
The epoxide opening occursmostly via a SN2 mechanism. (threo/erythro = 6.7:1)
nucleophilic epoxide opening
NH
S
O
OH
OMe
NO2
SOH
OMe
COOi-Pr
6-8 6) FeSO4, NH4OH7) NaOH8) xylenes, Δ
Béchamp reduction,ester hydrolysis,amide formation
i-PrOOC
O
9-11 9) ClCH2CH2NMe2⋅HCl, NaH10) Ac2O11) HCl in EtOH
Steps 9 to 11 were carried out according to Tanabe Pharma.
NH
S
O
OH
OMe
cis-(+)-diltiazem hydrochloride
N
S
O
OAc
OMe
NH
Cl
N-alkylation,acylation of the alcohol,salt formation
A not-so-small molecule that activates Ca2+-permeant channels
OO
OO
OO
OO
O
O
O
OO
OO
O
OO
OHO
Me
OHHO
H
Me
MeH
OH
Me
H
H
HMe
H
H
OOHO
HOO
O
O
Me
H
HH
O
O
OO
OO
O O
OH
HO
HO
OHMe
Me
MeMe
Me
MeMe
Me
Me
HH
HH
HH
H
H
H
OH
HO OH
HOOSO3Na
H
HH
H
H
HH
H
HO
OHHO
H
H H
H
OH
OHMe
MeH
H
HH
H
H
H
H
OHHO
OHH
H Me
OH
Me
NaO3SO
OH
Me OH
OH
H
HO
H
HH H
H
Nicolaou approaches:J. Am. Chem. Soc. 1996, 118, 10335Angew. Chem. Int. Ed. 2007, 46, 8875J. Am. Chem. Soc. 2008, 130, 7466J. Am. Chem. Soc. 2010, 132, 6855J. Am. Chem. Soc. 2010, 132, 9900J. Am. Chem. Soc. 2011, 133, 214J. Am. Chem. Soc. 2011, 133, 220
Nakata approaches:Chem. Pharm. Bull. 1996, 44, 627Heterocycles 1997, 44, 105Org. Lett. 2001, 3, 2749Heterocycles 2007, 74, 259Org. Lett. 2008, 10, 1675Org. Lett. 2008, 10, 1679Org. Lett. 2008, 10, 1683
maitotoxin
Fluorescent sensors of [Ca2+]
O O
N NO O
O OO O
OO
Ca2+O O
N
N
OOC COO
COOOOC Ca2+
BAPTA
Fluorescent sensors of [Ca2+]
O O
O
NO
OOO
O
N
CH3
N
OO
O
O
O
O
O
O
O
O
O
O
O O
O
O
Fura2-AMλex = 340 nmλem = 390/510 nm
O O
N
N
O
O
O
O
O
O
O
O
O
O O
O
O
Fluo2-AMλex = 488 nmλem = 515 nm
O
O
O
O
OO
O
O
Acetoxymethyl (AM) esters make the dyes cell permeant and are enzymatically cleaved intracellularly.
Fluorescent sensors of [Ca2+]
OO
N
NO
O
O
O
O
O
O
O
O O
O
O
X-Rhod1-AMλex = 580 nmλem = 602 nm
ON
NO
O
OO
OO
N
N
O
O
O
O
O
O
O
O
O
O O
O
Oregon Green 488 BAPTA1λex = 494 nmλem = 523 nm
NHO
O
O
O
O
O OO
O
O
FFCOO
Acetoxymethyl (AM) esters make the dyes cell permeant and are enzymatically cleaved intracellularly.
GCaMP is a genetically encoded sensor of [Ca2+]
pdb 3SG3
Ca2+-binding domain
fluorescent domain
N
N
OH
HN
OH
OO
O
R
NHR'G
T
Y
fluorophore
Roger Tsien
2008 Nobel Prize in Chemistry
The in vivo visualization of neuronal activity with Ca2+-sensitive dyes
courtesy of Arthur Konnerth