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Total Synthesis of (−)-Nahuoic Acid Ci (Bii)
Qi Liu, Yifan Deng, Amos B. Smith, III.*University of
Philadelphia, Pennsylvania
March 9, 2019
Presented by Chris Peruzzi
J. Am. Chem. Soc. 2017, 139, 13668
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Background
Me
HHO
HOOH
MeCO2H
MeMe
OH OH OHMe
MeMe
Me
• Isolated from tropical marine sediment
• Nahuoic acid derivatives inhibit SETD8 enzyme, which is the
epigenetic regulator of cell cycle progression
• Contain 8 contiguous stereocenters in a cis-decalin
framework
https://3c1703fe8d.site.internapcdn.net/newman/csz/news/800/2014/ancientreefs.jpg
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Synthetic Plan
(+)-19
Me
HHO
HOOH
MeCO2H
MeMe
Me RMicalizioCoupling Me
HMOMO
Me
Me
OO
Me MOMO O O
Me
Me
Me
OTBSO
MOMO
MeH
Me
Common intermediate
MOMO
MeH
MeO
O
OMe
AsymmetricDiels-Alder Reaction
Me
MOMO O
OMe
OMe
O S SMe
Me
OTMS
Me
TMSS S
H
O
Me
OCl
Li
bifunctional linchpin
Type II AnionRelay Chemistry
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Synthesis of Side Chain (+)-19
Synlett. 2005, 4, 655-657Chem. Eur. J. 2009, 15, 2874.
2 equiv n-BuLi2 equiv TMSClTHF, 0 C to rt, 2 hthen,1N HCl, rt,
30 min
81%
OHMe
3 equiv SO3•py5 equiv Me2SO5 equiv Et3NCH2Cl2, 0 C, 1.5 h
88%SS
TMSH OTr
Me
O
2 equiv HS(CH2)3SH2 equiv BF3•OEt2CH2Cl2, 0 °C to rt, 18 h
99% (2 steps)
OHMe
SS
2 equiv HMPAEt2O,
−50 ºC to rt
Me
SS
Li
OTMSMe
Me
OCl
1.5 equiv
Et2O, −50 ºC to rt,
3 h (3 steps)
Me
SS OTMS
O
76% d.r. > 20:1
Me
Me
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Synthesis of Side Chain (+)-19
1.1 equiv Et2BOMe2 equiv NaBH4THF/MeOH,
−78 °C, 3 h
75% d.r. = 98:2
Me
OTMSMe
Me
OHO
2 equiv 2-methoxypropene0.1 equiv PPTS
CH2Cl2, 0 °C, 2 h82%
Me
OMe
Me
OO
Li1.45 equiv1.55 equiv BF3•THF
THF, -78 °C, 2 h92%
Me
OMe
Me
OOHMe
3 equiv MOMCl3 equiv DIPEA0.1 equiv TBAICH2Cl2, rt, 12 h
86%
Me
OMe
Me
OMOMOMe
(+)-19
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Diels-Alder Synthons
OMOM
Me
OMOM
2 equiv n-BuLi
2 equiv HN(iPr)2THF, -78 C to 0 C, 2.5 h
50%
Me
OMOM
°
OMeOH
CHO2 equiv H2NNH2•H2OTEG, 110 °C, 10 min
8 equiv KOH150 °C, 12 h
95%OMe
OH
CH3 O24 mol% salcomineDMF, rt, 18 h
83%
O
O
OMeMe
N
ON
O
Cu
salcomine
OH2 equiv n-BuLiTHF,
−78 °C, 1 h
H
O1 equiv
THF, −78 °C to rt,
overnight
2.2 equiv MOMClTHF, 0 °C to rt,
2 h, 71%Me
OMOM
OMOM
J. Org. Chem. 1987, 52, 4817Org. Lett. 2015, 17, 2030
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Asymmetric Diels-AlderO
O
OMeMeOMOM
Me1 equiv 1.2 equiv
20 mol% (−)-catalyst
OMOMO
Me
OMeMe
HO
4Å MS, toluene,−78 °C, 6 h,
then, −40 °C, 36 h
95%, 88% ee
Conditions Results
Toluene/CH2Cl2, 120 °C, 48 h 74%, racemic
1 eq. catalyst, CH2Cl2, –40 °C, 24 h 71%, 73% ee
20 mol% catalyst, CH2Cl2, 0 °C to rt, 24 h 25%, 55% ee
20 mol% catalyst, CH2Cl2, –60 °C, 12 h 80%, 71% ee
20 mol% catalyst, toluene, –78 to –40 °C, 42 h 95%, 88% ee
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OMOMO
Me
OMeMe
HO
2.1 equiv LiAlH4Et2O, 0 °C, 5 hthen 1N HCl
61%
MOMO
Me
OMe
H
OH1.1 equiv TBSOTf3.3 equiv 2,6-lutidineCH2Cl2, 0 °C to rt, 2.5
h
82%
MOMO
Me
OMe
H
OTBS
MOMO
Me
OMe
H
OTBS 5 mol% OsO41.5 equiv MeSO2NH21.5 equiv NMOTHF/H2O (4:1),
rt,
92%
MOMO
Me
OMe
H
OTBSHO
HO
excess 2,2-dimethoxypropane8 mol% PPTS
CH2Cl2, rt94%
1.2 equiv TMSCl1.2 equiv LiHMDSTHF, 0 °C, 30 min
0.2 equiv Pd(OAc)2O2
(balloon)
Me2SO, rt, 12 h85%
MOMO
Me
OMe
H
OTBS
O
O HMPA, THF/DMS, −78 °C to
−30 °C, 1.5 h
62%
MgBr2 equiv6 equiv CuBr2•DMS
MOMO
Me
OMe
H
OTBS
O
O
Functionalization of Diels–Alder Adduct
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Functionalization of Diels–Alder Adduct
MOMO
Me
OMe
H
OTBS
O
O
1.5 equiv LiHMDSEt2O, rt, 5 h
1.5 equiv Tf2OEt2O, rt, 1 h
90% (2 steps)
MOMO
Me
OTfMe
H
OTBS
O
O
10 mol% Fe(acac)35 mol% Pd(dppf)Cl2•CH2Cl24 equiv MeMgBr
THF/NMP, rt, 2 h95%
MOMO
Me
MeMe
H
OTBS
O
O2 equiv TBAFTHF, 60 °C, 3 h
89%
MOMO
Me
MeMe
H
OH
O
O
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Micalizio CouplingMOMO
Me
MeMe
H
OH
O
O
Me
OMe
Me
OMOMOMe
1.2 equiv n-BuLitoluene,
−78 °C to 0 °C,
20 min
MOMO
Me
MeMe
H
OLi
O
O
2.2 equiv TiCl(OiPr)3
4.4 equivMgCl
toluene, −41 °C, 1.5 h
Me
OMe
Me
OMOMO
Me
TiiPrO
iPrO
Me
H
OH
H
Ti
iPrO
Me
−41 °C to rt
65%
MOMO
Me
Me
Me
HO
O
MeOR O O
Me
MeMe
R = MOM
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Micalizio Alkene–Alkyne Coupling
General Reaction
R1
R2
R3
R4
MLn M
R3R4
HR1 H
R2
Ln carbometalation MLn
RR
R R
H+ R1/2R1/2
R3/4
R3/4
Me
H
OH
H
Ti
iPrO
Meformal [3,3] type rearrangement
Me
Me
H H
Ti
Me
OiPrO
H+Me
Me
H H
Me
H
Angew. Chem., Int. Ed. 2007, 46, 1440J. Am. Chem. Soc. 2007,
129, 15112.Angew. Chem., Int. Ed. 2012, 51, 5152.
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Nahuoic Acid Ci16 Steps
Endgame Strategy for Nahuoic Acid Ci
Total Synthesis of �(−)-Nahuoic Acid Ci
(Bii)�BackgroundSynthetic PlanSynthesis of Side Chain
(+)-19Synthesis of Side Chain (+)-19Diels-Alder SynthonsAsymmetric
Diels-AlderSlide Number 8Functionalization of Diels–Alder
AdductMicalizio CouplingMicalizio Alkene–Alkyne CouplingEndgame
Strategy for Nahuoic Acid Ci
