Baran Lab Group Meeting

Maximilian Palkowitz Total Synthesis of the Daphniphyllum Alkaloids

4/20/2020
Hanessian, et. al. Chem. Rev. 2017, 117, 4104

O O O
O O
O N
N
N N

O O Bukittinggine Daphnezomine F N
Yuzurimine Yuzurine
O Daphnicyclidin
O
N HN N N N
H N
Daphniphylline Secodaphniphylline Daphnilactone A Daphnilactone B Daphnezomine A
Daphnezomine L N O
O
N N
O Daphnicyclidin J

N
N N
Daphmanidin A, E, F Daphniglaucin A N N O
Daphniglaucin C
O Calyciphylline A Calyciphylline D O
Calyciphylline B Daphnicyclidin K
N O
N

N
O N N N
Macropodumine D Macropodumine E Daphenylline Daphhimalenine A Daphlongeranine B
Daphnimacropodine A

Quick Facts Early Synthetic Studies: Orban & Turner's DA approach towards secodaphniphylline (1983)
- The Daphniphyllum Alkaloids consist of > 300 members with OTBS
CO Me 1) allylBr, TBAF
rich structural diversity OH O O 2
5 steps 2) O3; Zn, AcOH
- Squalene derived CO2Me
H 3) TBAF
Topic for today: Me
- Early synthetic studies Me Me 160 oC
- Heathcock's Campaign 20% OTBS CO Me
O 2
- Modern syntheses & synthetic studies
Turner, et. al. Tetrahedron Me R
Resources: Me H
Letters 1983, 24, 2697 Me
Biosynthesis: Kubota, et. al. Natural Product Reports 2009, 26, 936 Me HN O
Bioactivity: Xu, et. al. Planta Med 2013, 79, 1589 OH
 Baran Lab Group Meeting
Maximilian Palkowitz Total Synthesis of the Daphniphyllum Alkaloids 4/20/2020
Heathcock's first synthesis of methyl homodaphniphyllate (1986)
OBn OBn
Guiding logic:
OBn Me
CO2Me Br Corey's Network
H + Analysis
Me O
Intramolecular +
H Annulation
Michael Addn Me HO2C
Me
Me S N
O O Me
+ O
Me O
N H N
O H2N
O O
O
methyl homodaphniphyllate
OBn OBn OBn
OH 1) LDA;
1) Me2CuLi;
Li0 MeCHO Me
(EtO)2POCl
H2, Pd(OH)2 >99% H
EtNH2 Me 82% Me
>99% Me Me Me
Me Me 2) H2SO4 O
Me 64% (EtO) OPO N 2) LDA, HMPA; O N
N 2
acetone H N
(EtO)2POCl O
69%
73%
OPO(OEt)2 O O
OH
OH OH CO2Me
Shortcomings:
Me 1) CrO3 H - Removal of [O] necessary for
Me H Me
Me Me H2SO4 key bond forming steps
Me
Me Me Me + Me - Hydrogenation gives epimeric
Me
N H Me N
N 2) 6M HCl, mixture of PDTs.
N
MeOH [19 steps]
1:1
undesired desired
Heathcock, et. al. JACS 1986, 108, 5650

Biomimetic Retrosynthesis
New synthetic strategy?

R R R R R
H via
O -NH3 [4+2]
Aza-prins H
Me Me Me Me Me
O Me
Me Me Me Me
Me N Me N Me HN Me
NH
Me Secodaphniphyllin skeleton
 Baran Lab Group Meeting
Maximilian Palkowitz
Total Synthesis of the Daphniphyllum Alkaloids 4/20/2020

Heathcock's Biomimetic Approaches

Heathcock, et. al. JACS 1988, 110, 8734 OBn OBn
O OBn N H 1) DIBAL O H

LDA Me Me 2) NaOH, H2O LiAlH4

N O Me Me
CO2Me EtOH, 95oC O
MeO2C
87% 96%
Me Me 80%
I Me Me
Me OBn
OBn HO H
CO2Me 1) (COCl)2, DMSO
1) H2, Pd/C, HCl
Et3N, DCM Me Me
1) H2SO4 2) CrO3, H2SO4 HO
Me Me
2) O3, -78oC
Me 2) NH3; AcOH
Me 3) MeOH, H2SO4
Me HN HN 77% over 2 steps Me
3) CrO3 85% over 3 steps
4) MeOH, H2SO4 [9 steps from iodide] OBn
(rac)-Methyl
67% 1) (COCl)2, DMSO
Homosecodaphniphyllate
[Mechanism?] Et3N, DCM
Me
Me 2) MeNH2
Me 3) AcOH, NH4OAc
Me Me Me
Me Me HN 85oC
Me via:
Me 75% over 3 steps
Me
Me HN H
Me
A happy accident Heathcock, et. al. ACIE 1992, 31, 665
O Me
(PPh3)3RhCl Access to (Z) through: Me
Me
H2 OH O
TMS Me
88% Me Me
Me Ot-Bu
Me
Me then Peterson olefination
I
1) KOH, TBA(HSO4) (E/Z = 3:7)
Me O
2) NH3, NH4OAc Br OLi
Me (E) or (Z) MeO
DMSO, 80oC
Me MeO Ot-Bu
Me O t-BuO
HN o
3) HOAc, 80 C Me - H2O
O
50% over 3 steps
Proto-Daphniphylline Me Me Me

[10 steps] Works equally well with Me Me

other geometric isomer
Heathcock, et. al. Science 1990, 248, 1532
 Baran Lab Group Meeting
Maximilian Palkowitz Total Synthesis of the Daphniphyllum Alkaloids 4/20/2020

Heathcock's Biomimetic Approach Cont: Key strategy: Grob Fragmentation

MeO2C
Skeletal Converions Me OH Me
Me
Addressing the original synthetic question: Me H+; [O] Me
Me NH N
R Me O
R
Me ? Me Me Homodaphniphyllate
Me Me CH2O; [O] O O
HN
Me Me
Me HN N OH O
Me Me
Homosecodaphniphyllate
Me Me
Homosecodaphniphyllate Homodaphniphyllate Me N
Me N
Daphnilactone

Total Synthesis of Daphnilactone & Homodaphniphyllate

Me Me Br
I 1) LDA, R-I H
Me [Mechanism?] O O H
2) LiAlH4 Br HO O 1) (COCl)2, DMSO
OEt O O Zn; HMPA
O 3) R-Br LiAlH4 Et3N, DCM
O
O HO
EtO 81% 90% Me 90%
Me 2) NH3; HOAc
Me
47%
O Me
Me Me
Br
Br
Me
Br Me Me
Me O

Me
HN
Me OCONPH
1) HCO2H
Me O Me OH Me O AlHR2H 1) H2, Pt
2) KOH Me PhNCO
N 2) DIBAL
Me Me Me
94% over 3 steps Me NH R2Al N
NH
Ph 60%
OH [13 steps] CO2Me

1) CrO3 Daphnilactone O
Me 1) CrO3
Me 2) MeOH, HCl Me [11 steps]
Me 2) CH2O, H2O Me O Heathcock, et. al.
Me Me
N 73% N Me JACS 1989, 111, 1530
Methyl- 50% Me N
Heathcock, et. al.
Homodaphniphyllate
JOC 1990, 55, 3714
 Baran Lab Group Meeting
Maximilian Palkowitz Total Synthesis of the Daphniphyllum Alkaloids 4/20/2020

Heathcock's synthesis of (rac)-Bukittinggine

1) (COCl)2, DMSO OBn OBn

OBn
Et3N, DCM 1) BH3; NaBO3
HO H
2) NH3 (CF3CO2)2Pd
2) TsCl
3) NH4OAc, HOAc Me Benzoquinone, PPh3
OBn OBn 3) LiEt3BH
HO
76% HN MeCN, r.t. N 70%
BnO 70%

I
, Me OBn

Me BnO [20 steps] 1) Na/NH3

[12 steps] O 2) Ag2CO3 on Celite
, Me Me O Me OBn

N 74% N
Me
Heathcock, et. al. JOC 1992, 57, 2575 [8 steps]
(rac)-Bukittinggine
15:1 d.r.

Heathcock's asymmetric synthesis of (-)-secodaphniphylline (+)-Codapnhiphylline synthesized

Me CO2Me through an analogous strategy
Me
O OBn OBn
H Cl O 1) LDA
N N
Me Me 2) NaCN, DMSO
LDA Me Me + Me O
Me O Me O Me
MeO2C Me HN 43%
MeO2C 64% 99.6 ee
92% ee
Me Me Me 90% ee after rcrys.
11:1 d.r. 1) RuCl3, NaIO4 Me
I
Me 2) CH2N2 O
3) separate O
43%
4) KOH O
1) MeONHMe 1) LiAlH4, 5) (COCl)2 Me
Me Li
O 2) Me Me Me OH
O Darvon alcohol O
Me Me HgSO4
Me 93% Me Me
O H2SO4 O
HO2C O O Me O Me Me
Me 79% 2) KAPA Me
Me Me HN
O OH 95%
1,3-diaminopropane
Heathcock, et. al. JOC 1992, 57, 2566 87% 92% ee 5:1 d.r. (-)-secodaphniphylline
 Baran Lab Group Meeting
Maximilian Palkowitz Total Synthesis of the Daphniphyllum Alkaloids 4/20/2020
PGO OH
PGHN CO2Me CO2Me
N N
EtO2C O O H Me O Me O
O Me O
Carreira Me Smith
Me O
HO HO O O
PGO R Me Si Si
O CO2Et OAc Me Me
Me Me Me Me
5 steps X (+)-daphmanidin E (-)-calyciphylline N
1) KHMDS, AllylOTs, 89% Me
O 1) 9-BBn; NaBO3, 60% Me O
2) Xylenes, 165oC, 86% 1) LDA; MeCHO
Me O O 10 steps
O 3) KHMDS, AllylBr, 83% O 2) Ac2O; TBAF, 86% 2) DMP, 91%
4) Xylenes, 165oC, 40% 3) 2-NO2-C6H4SeCN 3) AllylOAc, NaH O
Me Me O Si Me
O O PBu3; H2O2, 94% Pd(PPh3)4, 95% Si Me
Me O Me Me CO2Et
BzO MOMO 4) CeCl3,(CO2H)2, 98% 4) p-TsOH, 92% Me Me
Me Si Me OTBS
TBDPSO O 5) TMS, imidazol; MOMCl, 90%Me Me [4 steps]
Me I 5) I 2, PPh3 , 97%
OAc BzO 6) DMP, 99% [Diels-Alder]
TBDPSO
O2N t-Bu H O 7) MeNO2, NH4OAc, 77% LDA 1) 9-BBN; H2O2, 71% PhthN
O N
N NEt 2 77% 2) TBSCl, Imid. 94% O OTBS
PPh
O OAc
2
Me Me O 3) 4-MeOPhLi, 95% Sn
ZnMe2, OBn O2N OTf
H OMOM O Me 4
[Cu(OTf)]2 PhMe O 4) Phth, PPh3, Pd(PPh3)4
MOMO DEAD, 99% ArMe2Si LiCl, CO
BzO H OMOM O 5) KHMDS, PhNTf2, 73% Me
90%, 5:1 d.r. Si 97%
1) Zn, NH4Cl; MOMO Me O
Me Me
Boc2O, 85% PhthN
SnPh3 BzO PhthN
2) O3, PPh3; O H O 1) HBF4 OEt2, 82%
Me
N
O O O O OTBS
NaBH(OAc)3, 72% Me N
Co N
N
Me OAc 1) Bn2NH TFA, 69% 2) KF, m-CPBA, 74%
O
3) MsCl, Et3N; NaI, 76% H O
N
Me 2) AcOH, NaCN 3) TESCl, Imid., 83%
BocHN
4) DBU, 92% OAc O O MnO2, MeOH, 82% 4) MOMBr,
O MOMO Me iPr2NEt, 88%
BocHN [Co], i-Pr2NEt ArMe2Si Me
O Me 5) IBX, DMSO,
Blue LED
95% 1) N2H4
93% MOMO O
Me PhthN OMe 2) NH4Cl,
OBz O PhthN ETOH, 72 %
OBz H2 (900 psi) H CO2Me
MOMO O 1) K2CO3, MeOH O 3) Ph2BBr
Me [(cod)(py)(Pcy3)]IrBArF
I BocHN OMe H
77% 79%
O Me
2) PCC, 92% MOMO 84%, 4:1 d.r.
1) TFA; NH4Cl Me 3)Bn2NH TFA, Me
TGT 56% MOMO Me
4) NaCN, AcOH TGT
Same sequence
Carreira, et. al. ACIE 2) Ph2BBr MOMO MeOH, MnO2;
as Carriera
2011, 50, 11501 76% OAc K2CO3; Ac2O, 79% Smith, et. al. JACS 2014, 136, 870
 Baran Lab Group Meeting
Maximilian Palkowitz Total Synthesis of the Daphniphyllum Alkaloids 4/20/2020

Highlights of Synthetic Studies Towards Daphenylline Alkaloids O 1) Me3Alm HNMe(OMe)

nBuLi, CuI Me 2) TBSCl, Et3N
OTHP OTHP O BF3 OEt2
HG II I + 3) DIBAL, 85%
MeO MeO
Me 69% O
NsN 74% Me
NsN Me
O
O O Me
[Friedel Crafts] Me
H2NCH2SnBu3; TBSO
TfOH small scope TBSO nBuLi
1) PhSH, K2CO3 71% explored
Me
DMF Me
OMe 60% O
H 2) MsCl, Et3N [3+2] 1) HCl
OMe N
DMAP, 65% Me 2) PPh3, CBr4 Me
N H
N OH Et3N
O Me Me
She, et. al. JOC 3) NaH, 77% Ns
O Me H H
2012, 77, 8367 HN 40% N
TBSO
Me H
H She, et. al. Chem. - Asian. J. 2012, 77, 8367
OH N
NHTs
Daphenylline
O
FeCl3
Br [Aza-cope]
Br 1) (COCl)2,
91% DMSO H
TsN TBSO Et2AlCl
OH H Et3N
2) n-BuLi 80%

OTBS
1) NaBH4
72% O
Br 2) (PhS)2, PBu3 Br
OH 3) DMP, 74%
Br
O OH
83% over 2 steps TsN
TsN H
SPh [Diels-Alder] O
TsN
Bu3SnH, TBSO
[Radical Cylization]
AIBN 76% [Friedel Crafts]
OEt 1) LiOH H DDQ
2) SOCl2; O H
4 steps
H H O AlCl3, 69% TBSO
H H >99%
O
H
TsN H Cao, et. al. Chem. HN She, et. al. Chem. - Asian. J.
TsN Asian. J. 2015, 10, 377 2019, 9, 1274
 Baran Lab Group Meeting
Maximilian Palkowitz Total Synthesis of the Daphniphyllum Alkaloids 4/20/2020

Suzuki Yokoshima
Li Me
Me Fukuyama Me
O O 6 [3+2]
Me H
Me H
H N H X H
N N
NH Me
Me 1,4 OPG
O Daphenylline R 1) NaBH4, 99%
1) TBDPSOTf, 2) PCl3
o-Ns O 1) TFAA, TFA; 3) NiBr2(dme)
N 2,6-lutidine
O O Na2CO3, 81% (S)-Pybox, Alkyl-ZnBr
H 2) Au(PPh3)Cl,
AgOTf 2) BBr3, quant
PPh3, DIAD MeO
3) MeMgBr; 4) NaOH, EtOH MeO
Me O
Me 70% N Me MgBr2, TsOH 45% over 3 steps
86% N HO2C
o-Ns 68%
OH o-Ns
1) Tf2O, 73% 1) nBu vinyl ether
1,4 Inspired by: Dixon, et. al. O
Me O 1) K2CO3, ArSH 2) Propargyl-OH OH Hg(OAc)2, 74%
Org. Lett. 2012, 14, 1016
2) HOBt, EDC PdCl2(dppf), pyrrol. 2) iBu3Al
K2CO3, HO H
R-CO2H TBAI, 86% 90%, 5.9 :1 d.r.
100 oC N Me H
N Me 3) H2, Lindlar,
CO2Me
O 72% quinoline, 98% Me
CO2Me OTBS 86%
O
OTBS 1) TBSCl, Imid. 96%
1) KHMDS, H
PhN(Tf)2 O H 2) 9-BBN; H2O2,
O H
2) Pd(PPh3)4, 1) h 71% Me H NaOH, quant.
O HO
K2CO3 Me 2) DBU, air, 67% O 3) AZADOL, PIDA
Me
Me 4) TFA
(pin)B CO Me 1) LDA, MeI, HMPA, 67% 63% over 2 steps
N 2
R CO2Me
73% N 2) LiAlH4, 99%
OTBS
O 3) TIPSCl, Imid. 64%
OTBS
O 1) TMSOTf, Et3N 4) RNHNs, DEAD,
2) Pd(OAc)2, 81% PPh3, 85%
3) HF py 5) PhSH, K2CO3 92% Me
1) H2, Crabtree's cat.
4) I2, PPh3, 93% 6) TBAF; Boc2O, 83%
2) LiCl H2O, 86% Me H
7) DMP, 93%
3) Pd/C, MeOH Me Me MeO2C NaOAc, BHT H
Me N
4) LiAlH4, 66% O (TMS)3SiH, O
H microwave, 200 oC
AIBN BocN
TGT H MeO2C 1) NH3, 79%
N H N CO2Me 53%
O 2) Burgess,
98% Me
Li, et. al. Nat. Chem. CO2Me I Fukuyama, et. al. ACIE TGT 94%
O O
2013, 5, 679 2016, 55, 6067 3) NaBH4, 36%
 Baran Lab Group Meeting
Maximilian Palkowitz Total Synthesis of the Daphniphyllum Alkaloids 4/20/2020
Divergent Syntheses Intercepting Daphenylline (details on further slides)
Friedel Crafts/ Dehydrative Nazarov
Me
Me Me O Me N Me
Robinson Qui Me
Me O O
Me
H O Me Me H Me O N N
N O O H
N H H H
H N N OH
N
O 72%
O Daphenylline Et3SiH, TFA
O3; SN2';
1) SO2Cl2; 81%
D.A. Li, et. al. ACIE
NaN3 80% TGT
Me OH 2018, 57, 952
2) VinylMgBr; Mg(ClO4)2
PPh3 75% Via:
H 85%
N Me Me
O N
Me OH Me Me OH - H2O
3) AcryloylCl, O
88% 6 Me Aldol
Me O O BHT, xylene O
Me
1) H2, Crabtree's cat. O O Me
COMe 200 oC, 85% H N H
Me 88% N PDT
Me O 2) O3; Py, Me
TMS
LDA; KOH H Me2S, 92%
N O
95% 3) (TMSOCH 2)2, H Me O
N [Mechanism?] Me
O O TMSOTf, 98% O
p-TsOH Me O
Me O
O 1) NaOMe, O
Me N H H
Me MeOH, 65% 85% N Me
Me 2) NaH, MeI; OMe Me
Me O Me O
p-TsOH, 88% 1) K2CO3; Tf2O O
H CO2H 2) VinylBF3K, PCC
N 3) NaClO2, 93% N
O Me O quant.
Pd(dppf)Cl2
H
O O Me O 1) (COCl)2; Me 3) PdCl2, CuCl2, Me
AlCl3, 83% Me
NaBH4, MeOH; O H2O/DMF OAc
N H Me
p-TsOH, 82% Me O
2) Tf2O
O
H 3) VinylBF3K 80% N H
N
Pd(dppf)Cl2, O
Me NaOH
O 95% O
76%
Me
Me 1) Pd/C, H2
N H H O 2) LiAlH4 TGT
Me
1) H2, Pd/C, 99%
O 2) Lawesson's Rgnt. Qui, et. al. ACIE H
TGT N 58% over 2 steps Zhai, et. al. ACIE
3) Raney Ni 2019, 58, 5754
2018, 57, 947
78% over 2 steps O
 Baran Lab Group Meeting
Maximilian Palkowitz Total Synthesis of the Daphniphyllum Alkaloids 4/20/2020

Prior synthetic study: Hanessian, et. al. JOC 2010, 75, 2577 OH
O Lactonization OTBS
[O]; Lactonization
O
O Me RCM CO2Me
O Aldol O
Hanessian Sarpong
CO2Et CO2Et H H Me
H H H Ph N
H H [M] N H
N H H O
N H Br
O NBoc H
H H Radical
1,4 Me Pauson Khand
1)K2CO3; Me cyclization
Me Me
AllylBr Me Daphlongamine H Prior strategies: Sarpong, et. al. JOC, 2019, 141, 8431
2) Baker's yeast Me Isodaphlongamine H O
O
1) (COCl)2, DMSO, 1) NaBH4, CeCl3,43% 1) HCl, MeOH LDA O
CO Et 2) Br O
Et3N, 96% 2 2) DIBAL, 69%
Me
2) NaHMDS, 3) MsCl, py, DMAP, 92% Br Ph NH 82%, ~ 1:1 d.r. O
CO2Et O 77% H undesired recycled
41% TfO CO2Me 4) Bu4NN3, 83% S
S
Me H 3) TBSCl tBu O Ph N tBu
OH
CO2Me 4) Ac 2O, 85% OTBS OTBS
O
CO Me 1) HG II 1) Bu3SnH, Et3B O2
O 1) PPh3, NaOH; 2
O 2) LiHMDS 2) H2, Pd(OH)2, 79%
Boc2O, 91% CO2Et Me
HCO2H, NaI; >20:1
K2CO3, MeOH H 2) DIBAL, 75% Ph N N O
H OMs H 74% over 2 steps H d.r.
3) DMP, 91% Br O Br
N NBoc Me H
80% H 4) EthynylMgBr
H OTBS
5) DMP, 85% N3 OH O
Me TMSOTf O
Me over 2 steps 1) NaH,
Vinyl-I, nBuLi; O OTBS O MgBr 4-iodobutene, 72% H
CuBr2 Me 2S, 1) CSA, 91% HCl, 79% H 2) [IrCl(CO)(PPh3)2]
BF3 OEt2, 92% 2) PCC, 65% 3.6:1 d.r. N O
H H N TMDS, 73%
3) TBD, 90%
Vinyl-I: N N
I H H 4) p-TsOH, 70% H H OH Me H
O
H Me H
1) LiAlH4
Me Me OTFA 2) NaCNBH3, BF3 OEt2
OTBS H
O 3) CrO3, H2SO4
OH 1) L-Selectride N H
Me H 4) Cl N Cl
1) 9-BBN; 60%
H H
NaOH, H2O2 2) MeLi, 85%
H H Me H 1) MeLi 2) Co2(CO)8 N N N
Isodaphlongamine H 13% over
2) PCC, 55% over 2 steps H
N 4 steps
Hanessian, et. al. ACIE 65% over 2 steps H H Cl
Me H O
2016, 55, 2577 3) TFAA; SOCl2 Daphlongamine H
Me
4) CF3CO3H, 25% over 2 steps
Sarpong, et. al. JACS 2019, 141, 8431
 Baran Lab Group Meeting
Maximilian Palkowitz Total Synthesis of the Daphniphyllum Alkaloids 4/20/2020

Highlights of Synthetic Studies Towards Longeracinphyllin A and Calyciphyline A Alkaloids

1) Et3N, acrolein, 85%
O 1) DIBAL 2) K2CO3, EtOH
Me 1) NCS
Me 2) propargylamine, H O 1) CeCl3, NaBH4
O OH 2) DMP O O
MgSO4; NaBH4 96% over 2 steps PO(OMe)2 78%
Me O O
HN EtO 2) MsCl, py, 72%
86% over 2 steps Me N2 85%
Me EtO
[3 steps from carvone]
Me
H
[Double Radical Cylization] O HO O O [Pauson Khand]
1) AIBN, O2
O AIBN, Bu3SnH tBuOOH Co2(CO)8, NMO
Me N H EtO2C
Cl Me EtO2C H
Me
N 74% 2) SnCl2 58%
EtO2C
34% over 2 steps 4:1 d.r.

Me
Stockdill, et. al. Org. Lett. 2014, 16, 1072 Dixon, et. al. Org. Lett. 2012, 14, 1684
Me
N

O H Me
O TMS H [2+2]
TMS H
1) AcCl, Et3N Me
BHT, 140 oC CHBr3, TEBA H H OAc
Me 2) h
O
Me Me
Me
HN [Diels-Alder] H O N 47% over 2 steps O
BnN
O O N O
O OMe
MeO MeO2C
HO 1) NaBH4
TEBA O TMS
NEt3 H MeO 2) MsCl, py
Br DMAP
Zhai, et. al. Chem. - Asian. J. Cl Me Wang, et. al. JOC,
[Grob Fragmentation] 3) K2CO3
2015, 10, 865 Br 2012, 77, 6307
78% over
BnN H
3 steps
O O O Me Me O
H O H H
HCO2H, Bu3N H2, PtO2
Me Me Me
[Pd(PPh3)2Cl2] Br HCO2H Me
N 94% O
85% BnN H 67%
BnN H N
O O MeO MeO2C
 Baran Lab Group Meeting
Maximilian Palkowitz Total Synthesis of the Daphniphyllum Alkaloids 4/20/2020

O O O
OH O radical Stetter OH
D.A. Dixon Me OTES
cyclization O Xu Me H
Nazarov Heck Br
Me Me
H Me ZnBr N Me
N N Me
N Me X Negishi coupling H H
N H O H
(-)-Himalensine A
H
O O Van Leusen;
1) CH(OMe)3
Ph
1) Oxone, 1,4-addn.
PPh3 p-TsOH, 82%
Ph N NaHCO3, 61%
O NH OH O MeO 2) tBuOK, O
O 2) TESOTf
O TFA; TosMIC, 61%
3) BQ, Pd(OAc)2
F3C CF3 Pd(OH)2 H Me 73% over 2 steps Me [Mechanism for 2?]
Me 5 mol % H2 Me
O Me HO CN O
O HN H
86% 63% O Cu(OAc)2 O OTES TsNHNH2;
O BocN H O
N 92:8 d.r., 90% ee HONEt2, DBU HB(cat). 91%
Boc O 1) NaHMDS Me
HN
propargylBr, 63% Me 81% [Mechanism?]
[7 steps] CN H
2) LiAlH4; MeOH, Br O
Br
HCl, 86% O N H
OTES OTES H N OTES
H H
O Br H H OTIPS 1) TIPSOTf Br
NBS NaH
lutidine, 86% H Me Me HN Me Me
N HN
Me H N Me 2) Bu3SnH, AIBN 82%
N 82% H
3) CSA H H O H
N O
H H Pd(OAc)2 OTES
O O 78% over 2 steps O 1) H2, Wilkinson's cat;
PPh3, Et3N OTf
Py, p-TsOH 4) Crabtree's cat. AZADOL,
55% Me Me
O2 H2/Ar (1:2), 92% N PIDA, 82%
1) NaHMDS; PhNTf2, 58% N Me
65% > 20:1 d.r. 2) KHMDS,
OH H
2) Pd2(dba)3, DTBPF, 96% Me O PhNTf2, 96%
O H
O O ZnBr S O O O
Me O Cl
Me BnN Sn
O O Me
Me SnCl4 Me 4
N Me Et3N, EtOH Pd(PPh3)4
3) HCl, 87% N N Me
75% N Me CO, LiCl, 86%
H 75%
O H H
O O O O H
O O O
[Ir(CO)(PPh3)2Cl]
TGT Me m-CPBA; TMDS
TMDS; HCO2H Me TGT
BF3 Et2O [IrCl(CO)(PPh3)2];
Dixon, et. al. JACS N Me N Me
54%
2017, 139, 17755 67% TFA, EtSiH3 Xu, et. al. ACIE
H H 57%
O O 2019, 58, 7390
 , ,
Baran Lab Group Meeting
Maximilian Palkowitz Total Synthesis of the Daphniphyllum Alkaloids 4/20/2020
Divergent Syntheses
1) p-thiocresol Li O Li, et. al. Chem.
1) HF py
Me O HO2C 2) Commun. 2014,
2) I2, PPh3, imid.
OTBS 50, 5294
85% over 2 steps Me O OH
CO2Me N Me Li, et. al. ACIE
3) Zn, CuI, 90% Me
N CO2Me o-Ns 2018, 57, 952
4) [Rh(cod)Cl]2, PPh3, EDC, HOBt, Et3N
AgBF4, H2, 98% Common Intermediate N OH
O 3) DBU (CH2O)n [3 steps]
TBSO 1) CrO3, H2SO4,
Me O 69% over 3 steps H
1) LiCl, 96% Me 90% Himalenine D
O
Me 2) PBu3 CO2tBu 2) SOCl2, PhSeH,
4 steps Me py, 90%
N Me 83%
CO2Me 3) h , 46% NaBH4, CeCl3
N
CO2Me 3) Crabtree's cat. 72%, 3:1 d.r.
O
H2; HCO2H, 91% O
1) KHMDS, PhSeBr TBSO Me
1) m-CPBA, DCC Me O O O
2) m-CPBA, Me H O
O 2) PCC, 79% Me O Me
75% over 2 steps O Me O
3) K2CO3; DMP
3) DABCO, air, Me OH
OH 4) p-TsOH, 71% Me N N
91% N
Me O N H
CO2Me
O Dapnipaxianine A
H H 1) dppf, COMe
Me O O O
OHCO
N 1) EtNO2, DBU, 81% 2) LiI, H2O
52%
2) PdCl2, CuCl2 MeCN, DMSO
CO2Me Me
O DMF, H2O, 87%
Me 1) NaOH, 80%
H 8 steps Me O
1) dppf, CO2Me 2) LiAlH4 Me1) IrCl(CO)(PPh3)2
H (see Daphenylline slide) O Me O
N 3) DMP, 61% TMDS;
Me O
45%
Me O O NaBH(OAc)3 81%
2) LiCH2PO(OMe)2 (-)-Daphenylline Zhai, et. al. ACIE N H 2) DBU, LiCl, 79%
86% 2018, 57, 947 Me N
(MeO)2OP O
1) Pd/C, H2 H
Me H Me H O
O 2) TBD, 91% Me O Me
O O
3) LiCl, H2O
Me OO Me Me
MeCN, 95% Me O 3 H
N 4) Lawesson N H
N steps N
reagent, 67% H
CO2Me H
O 5) Raney Ni, 90% see (-)-Daphenylline
Longeracinphyllin A (-)-Daphnilongeranin B
daphenylline
Li, et. al. JACS 2017, 139, 14893 slides
Zhai, et. al. ACIE 2018, 57, 947 Li, et. al. ACIE 2018, 57, 952
 Baran Lab Group Meeting
Maximilian Palkowitz Total Synthesis of the Daphniphyllum Alkaloids 4/20/2020

Divergent Syntheses Cont.

1) LiCl, H2O, 76% Me Me O 1) Cy2BH; H2O2, NaOH, 92%

Me O O
2) KHMDS, PhSeCl 1) KHMDS, AllylBr, 92% 2) (COCl)2, DMSO, Et3N
Me 3) m-CPBA, 94% Me 2) 80oC, 94% Me 3) t-BuOK, O
N N H P
N OMe
OMe
CO2Me H H N2
[10 steps] O O 71%
O

1) Lawesson reagent, 75%

Dienophile Me O
Me H Me O H 2) Co2(CO)8
MgSO4, BHT, O NaBH4, CeCl3
3) K2CO3, 63% over 2 steps Me
160oC 99% Me
Me
24% desired OH O N
N N
plus 37% isomers
H
H H O
S S
Me Dienophile Raney Ni
O
81%
Me OAc
OAc
H
N O OAc Me H Me O OH
O O
H H t-BuOK, O2
S O O O Me Me
OAc O P(OEt)3 O
N N
OAc 61%
H H
[10 steps from (+)-genipin]
Daphnilongeranin B Daphniyunnine E

OAc TFA
OAc p-TsOH
H OH
O OAc OH 79%
H
O
H O OH
O O O 1) Raney Ni, 75% O
OAc H Me O
H 2) Et3N, MeOH, O O O
O OH
H OAc H2O, 86% H Me
O
O
H OH N
Me Me
Me Me H
Li, et. al. JACS 2019,
N 140, 4227 Dehydrodaphnilongeranin B
S N Hybridaphniphylline B
 Baran Lab Group Meeting
Maximilian Palkowitz Total Synthesis of the Daphniphyllum Alkaloids 4/20/2020

"If progress in important fields such as medicine, biochemistry, and materials sceince is to continue, it is
essential that we be able to synthesize literally any structure that the imagination can conceive....
Our textbooks are filled with hundreds of synthetic methods, all of which have limitations that will never
be discovered unless the methods are tested in the challenging arena of [synthesis]. Although our
approaches to problems have matured, we need even more mature strategies of synthesis. There is no
reason that organic chemists should not be able to surpass nature's virtuosity in the synthesis of complex
organic structures. In fact, we are still very far from this goal in most cases."

- Clayton Heathcock
ACIE 1992, 31, 665

Total syntheses not covered:

O OH
O
CO2Me OH
Me Me Me
Me Me
OH
N N
Me
Me N H
(-)-Caldaphnidine O (-)-Himalensine A
Dapholdhamine B
Xu. et. al. JACS 2019, 141, 13043 Xu, et. al. JACS 2019, 141, 11713 Gau, et. al. Org. Lett. 2019, 21, 3741