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1. TESCl2. Ac2O3. side chain4. HF
Yuzuru Kanda Baran lab Group Meeting5/13/17Classics in Semisynthesis
Semi(-)synthesis is;A synthesis which uses complex natural products (isolated or cultured) as the starting material to synthesize other target molecules.
Other GMs to be referedsemisynthesis (Green, 2012), Vindoline (Mitsos, 2004), Delphinine (Ambhaikar, 2004), Shikimic acid (Ambhaikar, 2005), Classic terpene syntheses (Maimone, 2005), Tetracycline (Lin, 2005), Morphine/ Codeine (Li, 2005) , Limonoids (Renata, 2011),Creativity from the Chiral Pool: Carvone (Rosen, 2012), Pentacyclic Triterpenes (Michaudel, 2013), Creativity from the Chiral Pool: Sugar Edition (Martinez, 2014), Steroids (See, 2014),Highlights in Peptide and Protein Synthesis (Malins, 2016), Creativity from the Chiral Pool: Amino acids (deGruyter, 2017)
MeMe
Me Me
HHO
OO
AcO
OAc
O OH
OBz
O
OH
NHBz
PhMeMe
Me Me
HHO
OHO
HO
OAc
O OH
OBz
Good semisynthesis- least redox manipulation- least stereocenter inversion- least C-C bond formation/cleavage- other criterias for good syntheses (least step counts, high yield, high ee, atom economy etc...)
* no penalty for esterifications, heteroatom alkylations, PG manipulations * nothing to do with complexity change, mass change, atom incorporation ratio
Borderline between total/semi syntheses are very vague and arbitral
(Total) syntheses cannot clearly be classified to total/semi synthesis but we can "score" the synthesis by how "semisynthetic" it is.
Baccatin III Taxol
This is semisynthesis
O
OMe
Me
OHHO
Me
MeO O
O
MeOMe
MeOHO
NMe2
Me
Me
OMe
MeOH
ClarithromycinJ. Antibiot. 1984, 37, 187.
Erythromycin
O
OMe
NO
Me
MeO O
O
MeOMe
MeOHO
NMe2
Me
O
NN
NNH2
FMe
SolithromycinCN 104650166
Nature 2016, 533, 338.
Ti(III)-Promoted Radical Cyclization of Epoxy Enones. Total Synthesis of (+)-Paeonisuffrone. (JOC. 2009, 74, 1798.)
opinions of semisynthesis
- cheating!!!- step inefficient (PG, redox)- chemistry is limited by the SM
Total synthesis
semisynthesis
?
OMe
Me PaeonisuffroneCarvone
advantages of semisynthesis
- buying chiral centers- buying oxidations states- less C-C/X bond formations
steps1–
(Redox) C-C bondformation/cleavage
Non spontaneousstereo inversion+ +
Is this semisynthesis?
X (overall yield)
Good semisyntheses are not necessarily good and interesting total synthesis
Taxol
Paeonisuffrone
Redox C-C Inv step yield score0 0 0 4 80% 80
1. NH2OH2. 2-MeOpropene3. Me2SO44. H+, Na2S2O4
Clarithromycin 0 0 0 4 58% 586 1 0 10 6.7% 2.0
Cyclopamine
CyclopamineACIE. 2009, 48, 7911.
0 20 1%7 5 0.4
MeO
HMe
HOH H
HN MeMe H
OMe
O
OHOH
little lot
Me
MeO
O
Me
O OJolkinolide B
Synthesis. 2014, 46, 2574
Jolkinolide B 0 11 10%8 2 0.9
HN
NH2
OH
O
O
BF3•Et2O,TMSketene, KF
NO
OH
OMeO
OO
Me
TBSO
Me
NO
OH
OMeO
OMe
TBSO
Me
OH
OHO
NO
OH
OMeO
OMe
HO
Me
OHhomoharringtonineCN 102304132.TL. 1999, 40, 2931.
1. NaOMe2. Et3N•3HF
NO
OH
OMeHO
Cephalotaxine
OMe
MeCOOH
COOMe
20th century
1. ClCOAr
2. HBr
21st century
ClCOAr
Me
OTBSMe
Yuzuru Kanda Baran lab Group Meeting5/13/17Classics in Semisynthesis
OHO
O
OHOHHN
OMe
Me
OMe
MeO
MeHO
Me
OH
Me
Me
O
Me
Rifamycin SV; R = H CHO
R
NMeN
H2N
1.
2. RifampicinOL. 2004, 6, 3921.
NN
MeN
OH
MeOHOH
O
O Me
NEt2
OH OH
NN
O
O
Me
O
OHO
Me
NN
O
HO O
OHO
Mebutylaldehyde,FeSO4, H2O2/H2SO4
R
Camptothecin; R = H Et
N
O
NIrinotecanUS 6723849CN 101481377US 8546573
Cl NR2
O
HN
NH
NH
OK252c
MeN
NN
O
ONMe2
OMsMsO
OOTf
LY333531OPRD. 2002, 6, 471.
HN
NN
O
O
MeOMeN
Me
Staurosporine; R = HMidostaurin; R= BzCl
HN
NN
O
O
MeOMeN
Me
1. thioCDI2. MeI
N
S
NMe
TFA
NH
NH3
O
HN
NN
O
O
MeOMeN
Me
N
SNH
fradcarbazole ATet. 2015, 71, 7990.
R BzClMeOOC
Yuzuru Kanda Baran lab Group Meeting5/13/17Classics in Semisynthesis
OOMe
H
Me
O O
MeH H
O
ArtemisininOPRD. 2014, 18, 417.
OOMe
H
Me
O O
MeH H
OMe
ArtemetherOPRD. 2012, 16, 764.OPRD. 2007, 11, 336.
OOMe
H
Me
O O
MeH H
1. H2O2. Et3N, succinic anhydride
OOMe
H
Me
O O
MeH H
O
O
O
HOArtesunateUS 6677463
Me
Me
HOOC
H
H
Artemisinic acid
RuCl2[(R)-DRBM-Segphos](DMF)2H2, MeOH, Et3N
Me
Me
HOOC
H
H
Me
MeH
MeO
O
EtO
O
1. EtOCOCl2. TPP, air, hν, TFA
H H
H
Me
HOO
MeH
MeO
O
EtO
O
H
O
MeHO
KBH4, CaCl2, MeOH
OOMe
H
Me
O O
MeH H
OMe
HClMeOH
MeH
MeH
HOO
O
O
O
EtO
OHC
O
Me
cyanosafracin B
NNMe
O
O
Me
MeO
HOOMe
Me
NH
OMe
NH2
CNH
HH
NNMe
OMe
MOMOOMe
Me
NH2CN
H
HH
OO NaNO2,
H2OOH
NNMe
OMe
MOMOOMe
Me
OCN
H
HH
OO
OH
O
SFm
NHTroc
NNMe
AcOMe
MOMOOMe
Me
CNH
HH
OO
SO
O
NHTroc
Tf2O, DMSO; iPr2EtN; tBuOH; (CH3N)2C=NtBu;Ac2O
NNMe
AcOMe
HOOMe
Me
OHH
HH
OO
SO
ONH
HO
MeO
7 stepsPG
NNMe
OHMe
MOMOOMe
Me
NH
OMe
NHBoc
CNH
HH
OO
NNMe
OHMe
MOMOOMe
Me
NH
OMe
NHBoc
CNH
HH
OO
5 stepsPG
4 stepPG manipulation
Pt-650
2/3 stepsPG
ET-743OL. 2000, 2, 2545.
Jorumycin synthesis fromSafracin BEur. J. Org. Chem. 2017, 975.
Yuzuru Kanda Baran lab Group Meeting5/13/17Classics in Semisynthesis
N
O
OH
H
N
strychnine
N
O
H
N
R2
N
O
OH
H
N
1. DBU2. TBSCl
1. H2O22.TFAA; KOH
OTBS
MeO1. LDA; BF3•Et2O2. HF•py3. Cs2CO3
N
O
H
N
N
O
OH
H
NOH
HN
O
MeH
N
N
O
MeHH
NH
1. DBU2. Ac2O3. HBr4. NaBH3CN
Strychnogucine BSungucineChem. Eur. J. 2016, 22, 11593.
NH
NMe
COOMe
H
1. HNO32. Zn
NAc
NMe
COOMe
HMeO1. Ac2O2. NBS
3. BuONO4. CuI, NaOMe
R
Tabersonine R = H NH2
NMe
NMe
COOMe
H OAc
HOVindorosine
NMe
NMe
COOMe
H OAc
HO
MeO
Vindoline
JACS. 2009, 131, 4904.J. Chem. Soc. Perkin trans. I. 1987, 155.
J. Chem. Soc. Chem. Commun. 1984, 909.
Catharanthine
VinblastineLeurosidine
VincristineCatharanthine
O O
O
O
H2NHO
H2N
NH2
HO OH
OH
NH2
OH
OH
NH2
Bekanamycin
MeO OMe
1. (4'', 6'' protect)2. TsCl (N protect)3. Zn, NaI (deOxy)
Dibekacin
Chem. Phar. Bull. 1987, 35, 2136.CN 101575354
O O
O
O
H2NHO
H2N
NH2
HO OH
OH
NH2
NH2
ArbekacinCN 101575354
O O
O
O
H2NHO
NH
NH2
HO OH
OH
NH2
NH2
O
HO
NH2
O O
O
O
BocHNHO
H2N
NHBoc
HO OH
OH
NHBoc
NHBoc
O O
O
O
TsHNO
TsHN
NHTs
O OH
OH
NHTs
NHTs
1. AcOH2. Na, NH33. PtO2, H2
OH
COOH
PhthN
1. 2. TFA3. N2H44. Pt2O, H2
1. AcOH2. Na, NH33. Boc2O
Yuzuru Kanda Baran lab Group Meeting5/13/17Classics in Semisynthesis
HO
OH
OBn
OBn
BnO
BnO
O
O
O
O
OH
OH
HO
HO
O
O
Ellagic acid
1. BnCl, NaI, K2CO32. BnCl, NaI, KOH3. KOH
Bn-HHDP (rac); no epimerization AcOH reflux or even NEET
OO
OPhOH
OO
HOOH
OH
HO
HOOH
O
O1. sugar, DCC2. H2, Pd/C
1:1 atropisomer
5-O-desgalloylepipunicacorteinJ. Org. Chem. 1998. 63, 24.
Chem. Eur. J. 2012, 18, 9063.Chem. Commun. 2011, 47, 1628.
OO
OPhOH
OO
HOOH
OH
O
O CuCl2,nBuNH2
singleatropisomer!
O
OOH
OHOH
O
O
OH
HOOH
OH
HO
OH
HO1. phosphate buffer2. H2, Pd/C
1. DCC2. H2, Pd/C
OO
O
OHOO
HOOH
OH
HO
HOOH
O
O
OHHO
HO
O
OHO
HO
HOHO
HOOH
OHO OHOHO
HO
+Bn-HDDP (rac) Pedunculagin
Eur. J. Org. Chem. 2003, 2128
singleatropisomer!
O
H
NMe
OMeO
H
NR'
OMe
OMe
OHMe R
H
1.2. H2
3. RMgXMeO MeO
1. BrCN2. KOH
R' = Me H
O
H
N
OMeOH
Me RH
HO
1. RBr2. KOtBu, C5H11SH
R = tBu; BuprenorphineUS 8981097OPRD. 2015, 19, 957
Thebaine
R =ThienorphineSyn. Commun. 2005, 35, 701.
S
N
O
O
O
OCl 1. LAH
2. Me2SO4
N
O
O
O
O
MeSO4-
Me
N
O
O
O
O
Me
O
1. KOH2. mCPBA
MeN
O
O
OO
H
H
1. NaBH42. H2SO4/AcOH
MeN
O
O
OO
H
HOH
R
1. HCO3H2. KOH
Chelamidine R = OHChelidonine R = HCL. 1986, 739.
Coptisine chloride
O2N
BF3•Et2O,Et3SiH
Yuzuru Kanda Baran lab Group Meeting5/13/17Classics in Semisynthesis
Condelphine
N
Me
MeO
OMe
OMeOMe
HOMe
1. NaOH2. MeI
3. KMnO4
ON
Me
MeO
OH
OHOMe
H
HOAc
NeofinaconitineJACS. 2013, 135, 14313.
N
Me
HOOMe
OHOMe
HOMe
O
1. BBr3•SMe22. CrO3, H2SO43. H2SO4
N
Me
OOMe
OHOMe
HOMe
OONH2
O
OO
HO
Me H
Me
H
H
Me Me
H
HHecogenin
1. H+
2. [O]
3. Ac2O4. NaBH4
O
OOH
AcO
Me H
Me
H
H
Me Me
H
H
OH
OH
AcO
Me H
Me
H
H
MeO
AcO
Me H
H
MeR
Me
TsCl, py
air
Pb(OAc)4
1. KCN,2. NaH, DMSO
H2N COOtBu
Me
Me
N
H2N
MeH
COOtBu
Bz
HO
Me H
MeMe HNH
H2N
Me
H
HVeratramine
TL. 1964, 33, 2281.JACS. 1967, 89, 4521.
1. Me3SI, NaH2. BF3•Et2O
R = O CHO
COOH
HOOH
OH
COOEt
ONHAc
NH2
Me
Me
O
Me
Me O
AcHNNO2
NH
PhPh
OSiPh2MeHCOOH
PhCl
OO
Me
MeAcHN
NO2
COOEtPO
EtOEtO
COOEt
ONHAc
NO2
Me
Me
COOEtOAcHN
Me Me
O2N STol
Chem. Eur. J., 52, 17789-17800 (2013)
COOEt
ONHAc
NH2
Me
TolSMe Zn,TMSClNH3;
K2CO3
Roche process
Cs2CO3;EtOH
TolSH
Oseltamivir
Oseltamivir
One-potNo evaporation
No solvent exchange36%
Shikimic acid
R'O
Me H
Me
H
O
Me
HNR
H
Me
H+
R, R' = H; cyclopamineR = Cbz, R' = Piv
CbzCl;PivCl
H
PivO
Me H
H H
Me O
Me
H
HNCbz
Me
Et2Zn,(ArO)2P(O)OH,CH2I2; MsOH
Me H
H H
Me O
Me
H
HNH2
Me
Cl
NH
SMe
O O
IPI-926
Yuzuru Kanda Baran lab Group Meeting5/13/17Classics in Semisynthesis
Me Me
HO
Me Me H COOH
MeMe
Me Me
HO
Me Me H
MeMe
O
O
O
BnO OBn
OAc
PPh3AuOTf, DBU,BF3•Et2O
OOBn
BnOOAc
O
O
nBu
Me Me
O
Me Me H
MeMe
O
O
OHO
HO
OOHO
HOHOO
O
OHOH
OH
OOH
OHMeO
OO
O
Chem. Eur. J. 2010, 16, 1871.
Oleanolic acid
1. BnBr2. Jones3. NH2OH•HCl
N
Me
Me
AcOMe Me
HO
Me Me H COOH
Me
MeBnO
OBn
N
Me
MeMe
HO
Me Me
O
Me Me H
Me
O
O
OHO
HO
OOHO
HOHOO
O
OHOH
OH
OOH
OMeO
OO
O
JACS. 2008,130, 5872.
OH
HO
HO Me
O OH
OHOHOH
Lobatoside E
N
Me
Me
AcO
AcO
ClPd
1. Na2PdCl4, NaOAc, AcOH2. Ac2O
3. py; Pb(OAc)4; NaBH472% (3 steps)
O
Me H
H
Me O
OHCMeOOC
H
H
Me O
OMe
NaBH4;NaIO4;TsOHHO
Me
O
HOH
OHO
H
Mehydrocortisone
1. mCPBA2. TMSOTf; mCPBA3. NaIO4; CH2N2
MeOOC
H
H
Me O
OMe
H
H
Me O
OMeO
I
O
I2
MeOOC
H
H
Me
OMeO
H
OBz
O
O
H
H
Me
MeO
OBz
1. NaOMe2. LiAlH(OtBu)3; BzCl
CSA1. mCPBA; HCl2. Me4NBH(OAc)3; DDQ3. MeI4. MsCl
O
O
H
OBz
H
Me
OMeMeO
O
O
H
OBz
H
Me
OMeMeO
OO
1. OsO42. (MeO)2CMe23. DBU, Me2NCH(OMe)2; HCl; PCC
1. Et2NH2. DBN; HCl
3. Et2NH; K2CO3, MeOH; HCl4. Ac2O5. PCC
WortmanninTL. 1996, 37, 6141.
O
O
O
H
MeAcO
MeMeO
OO
