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Total Synthesis of the Daphniphyllum AlkaloidsMaximilian PalkowitzBaran Lab Group Meeting

4/20/2020

N

O

O

Daphniphylline

N

Yuzurimine

N

O

O

Daphnilactone A

HN

O

O

Secodaphniphylline

N

O

Daphnilactone B

O

N

Yuzurine

ON

Bukittinggine

N

Daphnezomine A

N

Daphnezomine F

O

N

Daphnicyclidin

NH

Daphnezomine L ON

Daphnicyclidin J

ON

Daphnicyclidin K

N

Daphmanidin A, E, F

N

Daphniglaucin A N

Calyciphylline A

N

O

O

Calyciphylline B

N

Daphniglaucin C

N

Calyciphylline D

N

O

O

Daphnimacropodine A

N

Macropodumine D

N

Macropodumine E

N

O

O

Daphlongeranine B

N

Daphhimalenine A

N

Daphenylline

Hanessian, et. al. Chem. Rev. 2017, 117, 4104

Quick Facts

- The Daphniphyllum Alkaloids consist of > 300 members with

rich structural diversity

- Squalene derived

Topic for today:

- Early synthetic studies

- Heathcock's Campaign

- Modern syntheses & synthetic studies

Resources:

Biosynthesis: Kubota, et. al. Natural Product Reports 2009, 26, 936

Bioactivity: Xu, et. al. Planta Med 2013, 79, 1589

Early Synthetic Studies: Orban & Turner's DA approach towards secodaphniphylline (1983)

OH

Me

5 stepsO

Me

CO2Me

OTBS

160 oC

20% OTBS

H

OCO2Me

Me

1) allylBr, TBAF

2) O3; Zn, AcOH

3) TBAF

H

OCO2Me

Me

OHO

Me

Me HNMe

RTurner, et. al. Tetrahedron

Letters 1983, 24, 2697

Maximilian PalkowitzBaran Lab Group Meeting

4/20/2020

Heathcock's first synthesis of methyl homodaphniphyllate (1986)

Me

Me N

Me

methyl homodaphniphyllate

CO2Me

N

O

Me

H

OBn

Intramolecular

Michael AddnH

O

O

Annulation

N

OBn

H

O

OS

Me

O

Me+

HO2C

O +

H2N O

OMe

Guiding logic:

Corey's Network

Analysis

OBn

Br+

N

O

Me

H

OBn

H

O

O

1) LDA;

MeCHO

>99%

2) H2SO4

acetone

69%

Me

N

Me

O

O

1) Me2CuLi;

(EtO)2POCl

82%

2) LDA, HMPA;

(EtO)2POCl

73%

Me

N

Me

(EtO)2OPO

OPO(OEt)2

OBnOBn

Me

Li0

EtNH2

64%

Me

N

Me

OH

Me

H2, Pd(OH)2>99%

Me

N

Me

OH

Me

N

Me

OH

Me

N

Me

OH

Me+

HMe

Me H

1:1

undesired desired

1) CrO3

H2SO4

2) 6M HCl,

MeOH

Me

N

Me

CO2Me

Me

H

Shortcomings:

- Removal of [O] necessary for

key bond forming steps

- Hydrogenation gives epimeric

mixture of PDTs.

Heathcock, et. al. JACS 1986, 108, 5650

[19 steps]

Biomimetic Retrosynthesis

Me

NH

Me

R

Me

HMe

Me HNMe

R

Secodaphniphyllin skeleton

New synthetic strategy?

via

Me

Me NMe

R

Aza-prinsMe

Me NMe

R

[4+2]-NH3

R

O H

O

Me

Me Me

Total Synthesis of the Daphniphyllum Alkaloids


4/20/2020

Heathcock's Biomimetic Approaches

OBn

N H

MeO2C

Me

Me MeN

O OBn

CO2Me

Me

Me

Me

I

OLDA

87%

1) DIBAL

2) NaOH, H2O

EtOH, 95oC

80%

OBnH

Me

Me Me

O

OLiAlH4

96%

OBnH

Me

Me Me

HO

HO

1) (COCl)2, DMSO

Et3N, DCM

2) NH3; AcOH

77% over 2 steps

Me

HNMe

OBn

1) H2, Pd/C, HCl

2) CrO3, H2SO4

3) MeOH, H2SO4

85% over 3 steps

Me

Me HNMe

CO2Me

(rac)-Methyl

Homosecodaphniphyllate

[9 steps from iodide]

Heathcock, et. al. JACS 1988, 110, 8734

1) (COCl)2, DMSO

Et3N, DCM

2) MeNH2

3) AcOH, NH4OAc

85oC

75% over 3 steps

Me

Me HNMe

OBn

[Mechanism?]

A happy accident Heathcock, et. al. ACIE 1992, 31, 665

Me

Me HNMe

Me

1) H2SO4

2) O3, -78oC

3) CrO3

4) MeOH, H2SO4

67%

Me

Me

Me

HNMe

Me

Me

Me

(PPh3)3RhCl

H2

88%

Proto-Daphniphylline

Me

Me

Me

O

O

O

H

Me

Me

Me

OH

Me

Me

Mevia:

1) KOH, TBA(HSO4)

2) NH3, NH4OAc

DMSO, 80oC

3) HOAc, 80oC

50% over 3 stepsMe

Me

Me

Me

Me

Me

OLi

O

Me

Me

Me

I

Ot-Bu

Br

t-BuO

MeO

MeO

- H2O

Works equally well with

other geometric isomer Heathcock, et. al. Science 1990, 248, 1532

O

Ot-Bu

(E) or (Z)

Access to (Z) through:

then Peterson olefination

(E/Z = 3:7)

TMS

[10 steps]



4/20/2020

Heathcock's Biomimetic Approach Cont:

Skeletal Converions

Addressing the original synthetic question:

Me

Me HNMe

R

? Me

N

Me

R

Me

Homosecodaphniphyllate Homodaphniphyllate

Me

Me HNMe

O

Me

Me NHMe

OH

H+; [O]

Me

N

Me

MeO2C

Me

Homodaphniphyllate

Homosecodaphniphyllate

CH2O; [O]

Me

Me NMe

OH Me

Me NMe

O

Daphnilactone

Key strategy: Grob Fragmentation

O O

Total Synthesis of Daphnilactone & Homodaphniphyllate

OEt

EtO

O

I

Me

Me

Me

Br

O

Br

Br

1) LDA, R-I

2) LiAlH4

3) R-Br

81%

O

Me

Me

Me

O

OBr

Br

Zn; HMPA

90%

[Mechanism?]

O

OOH

Me

Me

Me

LiAlH4

90%

HO

OHOH

Me

Me

Me

1) (COCl)2, DMSO

Et3N, DCM

2) NH3; HOAc

47%

Me

HNMe

O

Me

MeN

Me

O 1) H2, Pt

2) DIBAL

60%R2Al

AlHR2HMe

Me NHMe

OH

1) CrO3

2) CH2O, H2O

50%

Me

Me NMe

O

ODaphnilactone

[11 steps]Heathcock, et. al.

JACS 1989, 111, 1530

PhNCO

Me

MeN

Me

OCONPH

O

NHPh

Me

N

MeMe

1) HCO2H

2) KOH

94% over 3 steps

1) CrO3

2) MeOH, HCl

73%

Me

N

MeMe

OH CO2Me[13 steps]

Methyl-

HomodaphniphyllateHeathcock, et. al.

JOC 1990, 55, 3714



4/20/2020

Heathcock's synthesis of (rac)-Bukittinggine

HO

HO

H

BnO

Me

Me

OBn1) (COCl)2, DMSO

Et3N, DCM

2) NH3

3) NH4OAc, HOAc

76%

,

Me

HN

OBn

OBn

(CF3CO2)2Pd

Benzoquinone, PPh3

MeCN, r.t.

70%N

OBn

OBn

1) BH3; NaBO3

2) TsCl

3) LiEt3BH

70%

Me

N

OBn

OBn

15:1 d.r.

1) Na/NH3

2) Ag2CO3 on Celite

74%

Me

N

OO

(rac)-Bukittinggine

[20 steps]

[12 steps]

BnO

Me

Me

,

[8 steps]

I

Heathcock, et. al. JOC 1992, 57, 2575

Heathcock's asymmetric synthesis of (-)-secodaphniphylline

N

Me

Me

O OBn

MeO2C

Me

Me Me

I

LDA

64%

OBn

N H

MeO2C

Me

Me MeO

Me

Me

11:1 d.r.

Me

Me HNMe

CO2Me

O

OMe

Me

HO2CMe

1) MeONHMe

2)

79%

Me

Li

O

OMe

Me

MeO

Me

90% ee

1) LiAlH4,

Darvon alcohol

93%

2) KAPA

1,3-diaminopropane

87%

O

OMeMe

MeOH

92% ee

HgSO4

H2SO4

95%

OOMe

OH

Me

5:1 d.r.

1) RuCl3, NaIO4

2) CH2N2

3) separate

4) KOH

5) (COCl)2

OOMe

O

Me+

92% ee

43%

Cl 1) LDA

2) NaCN, DMSO

43%

99.6 ee

after rcrys.

Me

Me HNMe

Me

O

OMe

O

(-)-secodaphniphyllineHeathcock, et. al. JOC 1992, 57, 2566

(+)-Codapnhiphylline synthesized

through an analogous strategy



4/20/2020

N

Me

HO

CO2Me

OAc

(+)-daphmanidin E

N

Me

HO

CO2Me

Me

H

(-)-calyciphylline N

PGHN

Me

PGO R

O

PGO

O

X

O

O CO2Et

EtO2C

O

TBDPSOBzO

O

O

MeMe

5 steps

O

TBDPSOBzO

O

O

MeMe

MOMO

1) KHMDS, AllylOTs, 89%

2) Xylenes, 165oC, 86%

3) KHMDS, AllylBr, 83%

4) Xylenes, 165oC, 40%

O

BzO

MOMOOMOMH

O2N

OAcO

BzO

MOMOOMOMH

O2N

OAc

ZnMe2,

[Cu(OTf)]2 PhMe

90%, 5:1 d.r.

PPh2

N

HN

O

NEt2

O

OBn

t-Bu

Me

O

I

OBzMOMO

BocHN

OAc

Me

O [Co], i-Pr2NEt

Blue LED

93%

O

MOMO

BocHN

OAc

Me

O

OBz

N

NN

N

OO

Me

MeMe

Me

OO

H

H

Co

SnPh3

N

BocHN

Me

MOMO

OAc

O

OOMe

1) TFA; NH4Cl

56%

2) Ph2BBr

76%Carreira, et. al. ACIE

2011, 50, 11501

Me

O O

OSi

Me

MeMe

OH

Me

O

OSi

Me

MeMe

O

MeO

Si

Me

MeMe CO2Et

[4 steps]

[Diels-Alder]

10 steps

MeO

Si

Me

MeMe OTBS

O1) LDA; MeCHO

2) DMP, 91%

3) AllylOAc, NaH

Pd(PPh3)4, 95%

4) p-TsOH, 92%

5) I2, PPh3, 97%Me

OSi

Me

MeMe I

O

Me

O

LDA

77%

Me

O

OSi

Me

MeMe

O

1) 9-BBN; H2O2, 71%

2) TBSCl, Imid. 94%

3) 4-MeOPhLi, 95%

4) Phth, PPh3,

DEAD, 99%

5) KHMDS, PhNTf2, 73% Me

O

ArMe2Si

OTf

OTBS

PhthN

Pd(PPh3)4LiCl, CO

97%

Sn4

Me

O

ArMe2Si

OTBS

PhthN

O1) HBF4 OEt2, 82%

2) KF, m-CPBA, 74%

3) TESCl, Imid., 83%

4) MOMBr,

iPr2NEt, 88%

5) IBX, DMSO,

95%

Me

O

MOMO

O

PhthNO

1) Bn2NH TFA, 69%

2) AcOH, NaCN

MnO2, MeOH, 82%

PhthN

Me

MOMOMe

OOMe

Same sequence

as Carriera

H2 (900 psi)

[(cod)(py)(Pcy3)]IrBArF

84%, 4:1 d.r.

PhthN

Me

MOMO Me

CO2MeO

OH

TGT

Smith, et. al. JACS 2014, 136, 870

H

TGT

1) 9-BBn; NaBO3, 60%

2) Ac2O; TBAF, 86%

3) 2-NO2-C6H4SeCN

PBu3; H2O2, 94%

4) CeCl3,(CO2H)2, 98%

5) TMS, imidazol; MOMCl, 90%

6) DMP, 99%

7) MeNO2, NH4OAc, 77%

1) Zn, NH4Cl;

Boc2O, 85%

2) O3, PPh3;

NaBH(OAc)3, 72%

3) MsCl, Et3N; NaI, 76%

4) DBU, 92%

1) K2CO3, MeOH

77%

2) PCC, 92%

3)Bn2NH TFA,

4) NaCN, AcOH

MeOH, MnO2;

K2CO3; Ac2O, 79%

1) N2H4

2) NH4Cl,

ETOH, 72 %

3) Ph2BBr

79%


Carreira Smith

Me


4/20/2020Total Synthesis of the Daphniphyllum Alkaloids

Highlights of Synthetic Studies Towards Daphenylline Alkaloids

N H

Me

Me

H

Daphenylline

MeO

NsN

OTHP

O

MeO

NsN

OTHP

O

HG II

74%

TfOH

71%

N

OMe

ONs

OH

1) PhSH, K2CO3

DMF

2) MsCl, Et3N

DMAP, 65%

3) NaH, 77%

N

OMe

O

H

H

She, et. al. JOC

2012, 77, 8367

Me

I +O

O

Me

nBuLi, CuI

BF3 OEt2

69% O

Me

O

Me

[Friedel Crafts]

1) Me3Alm HNMe(OMe)

2) TBSCl, Et3N

3) DIBAL, 85%

Me

O

Me

TBSOH2NCH2SnBu3;

nBuLi

60%

Me

N

Me

TBSO

HN H

Me

Me

TBSO

1) HCl

2) PPh3, CBr4Et3N

40% N H

Me

Me

She, et. al. Chem. - Asian. J. 2012, 77, 8367

[3+2]

Br

O

OH

NHTs

FeCl3

91%TsN

OH

Br

TsN

Br

OHBr

TsN

O

[Aza-cope]

1) NaBH4

2) (PhS)2, PBu3

83% over 2 steps

Br

TsNSPh

Bu3SnH,

AIBN 76%

TsN

H H

4 steps

TsN

H H

H

OEt

O

1) LiOH

2) SOCl2;

AlCl3, 69%

HN HO

H

[Radical Cylization]

[Friedel Crafts]

Cao, et. al. Chem.

Asian. J. 2015, 10, 377

OH

H

1) (COCl)2,

DMSO

Et3N

2) n-BuLi

72%

3) DMP, 74%

OTBS

O

HTBSO Et2AlCl

80%

H

TBSO

O

H

TBSO

O

She, et. al. Chem. - Asian. J.

2019, 9, 1274

[Diels-Alder]

DDQ

>99%

small scope

explored


4/20/2020

N H

Me

Me

H

Daphenylline

N H

Me

OPG

O

O

6

NH

O

Me

O

Me

OH

PPh3, DIAD

86%

NH

o-Ns O

Me

No-Ns

1) TBDPSOTf,

2,6-lutidine

2) Au(PPh3)Cl,

AgOTf

70% N

O

Meo-Ns

1) K2CO3, ArSH

2) HOBt, EDC

R-CO2H

72%

N

O

Me

OCO2Me

OTBS

K2CO3,

100 oC

86%

N

CO2Me

OMe

OTBSO

R(pin)B

1) KHMDS,

PhN(Tf)22) Pd(PPh3)4,

K2CO3

N CO2Me

Me

OTBSO

O

1) h 71%

2) DBU, air, 67%

N CO2Me

Me

OTBS

O

O

73%

1) TMSOTf, Et3N

2) Pd(OAc)2, 81%

3) HF py

4) I2, PPh3, 93%

N CO2Me

Me

I

O

O

(TMS)3SiH,

AIBN

98%N

CO2Me

MeO

O

1) H2, Crabtree's cat.

2) LiCl H2O, 86%

3) Pd/C, MeOH

4) LiAlH4, 66%

TGT

Li, et. al. Nat. Chem.

2013, 5, 679

[3+2]

LiYokoshima

Fukuyama

N

Me

Me

H

R

H

Me

X

MeOO

1) NaBH4, 99%

2) PCl33) NiBr2(dme)

(S)-Pybox, Alkyl-ZnBr

4) NaOH, EtOH

45% over 3 steps

MeO

HO2C

1) TFAA, TFA;

Na2CO3, 81%

2) BBr3, quant

3) MeMgBr;

MgBr2, TsOH

68%

H

Me

HO

1) Tf2O, 73%

2) Propargyl-OH

PdCl2(dppf), pyrrol.

TBAI, 86%

3) H2, Lindlar,

quinoline, 98%

H

Me

OH

1) nBu vinyl ether

Hg(OAc)2, 74%

2) iBu3Al

90%, 5.9 :1 d.r.

Me

H

HO

1) TBSCl, Imid. 96%

2) 9-BBN; H2O2,

NaOH, quant.

3) AZADOL, PIDA

4) TFA

63% over 2 steps

Me

H

O

O

1) LDA, MeI, HMPA, 67%

2) LiAlH4, 99%

3) TIPSCl, Imid. 64%

4) RNHNs, DEAD,

PPh3, 85%

5) PhSH, K2CO3 92%

6) TBAF; Boc2O, 83%

7) DMP, 93%

Me

H

O

BocN

MeMeO2C

HH

H

NaOAc, BHT

microwave, 200 oC

53%

N H

Me

Me

H

MeO2C 1) NH3, 79%

2) Burgess,

94%

3) NaBH4, 36%TGTFukuyama, et. al. ACIE

2016, 55, 6067


1,4 Inspired by: Dixon, et. al.

Org. Lett. 2012, 14, 1016

H

Suzuki

1,4


4/20/2020

N H

Me

Me

H

Daphenylline

N HO

Me

Me

O

N

O

H OMe

Me

O

O3; SN2';

D.A.

Robinson Qui

O

Me

Me

1) SO2Cl2;

NaN3 80%

2) VinylMgBr;

PPh3 75%

3) AcryloylCl,

88%

HN

O

Me

OH

N

O

Me

Mg(ClO4)285%

BHT, xylene

200 oC, 85%

N

O

Me

H

1) H2, Crabtree's cat.

88%

2) O3; Py,

Me2S, 92%

3) (TMSOCH2)2,

TMSOTf, 98%

N

O

Me

Me

H

O

COMe

TMSLDA; KOH

95%

N

O

Me

H

OMe

Me

O

O

1) NaOMe,

MeOH, 65%

2) NaH, MeI;

p-TsOH, 88%

3) NaClO2, 93% NCO2HH

Me

Me

O

OMe

1) (COCl)2;

AlCl3, 83%

2) Tf2O

3) VinylBF3K

Pd(dppf)Cl2,

95%

N H

Me

Me

O

O

O

O

O

NaBH4, MeOH;

p-TsOH, 82%

N H

Me

Me

O1) H2, Pd/C, 99%

2) Lawesson's Rgnt.

3) Raney Ni

78% over 2 steps

TGTQui, et. al. ACIE

2019, 58, 5754

Divergent Syntheses Intercepting Daphenylline (details on further slides)

N HO

O

Me

Me

O

Me

N

N

NH

72%

N H

Me

Me

OH

O

Et3SiH, TFA

81%

Via:

N HO

OH

Me

Me

O

Me

TGT

6

N HO

Me

Me OHO

Me

- H2O

Aldol

Li, et. al. ACIE

2018, 57, 952

N H

O

Me

MeO

O

O

Me

p-TsOH

85% N H

OMe

Me

Me

[Mechanism?]

PCC

quant.

N HO

Me

Me

OAc

1) K2CO3; Tf2O

2) VinylBF3K,

Pd(dppf)Cl23) PdCl2, CuCl2,

H2O/DMF

80%

N HO

Me

Me O

Me

NaOH

76%

N H

Me

Me

O

O

O

O

O

1) Pd/C, H2

2) LiAlH4

58% over 2 steps

TGT

Zhai, et. al. ACIE

2018, 57, 947

PDT


Friedel Crafts/ Dehydrative Nazarov

H

N

O

O

Me

H H

H

Me

H

H

Isodaphlongamine HDaphlongamine HMe

Me


4/20/2020

HanessianO

Me

O

H

HN

Aldol

[O]; Lactonization

[M]

1,4Me

H

H NBoc

CO2Et

O

CO2Et

1)K2CO3;

AllylBr

2) Baker's yeast

OH

CO2Et

1) (COCl)2, DMSO,

Et3N, 96%

2) NaHMDS,

41% TfO CO2Me

Me

O

CO2Et

CO2Me

Me H

1) NaBH4, CeCl3,43%

2) DIBAL, 69%

3) MsCl, py, DMAP, 92%

4) Bu4NN3, 83%

OMs

H

CO2Et

Me

N3

1) PPh3, NaOH;

Boc2O, 91%

2) DIBAL, 75%

3) DMP, 91%

4) EthynylMgBr

5) DMP, 85%

over 2 steps

O

H

H

Me

NBoc

HCO2H, NaI;

K2CO3, MeOH

80%

Me

O

H

HN

Vinyl-I, nBuLi;

CuBr2 Me2S,

BF3 OEt2, 92%

Me

O

H

HN

OTBS1) CSA, 91%

2) PCC, 65%

3) TBD, 90%

4) p-TsOH, 70%

Me

O

H

HN

H H

1) L-Selectride

60%

2) MeLi, 85%

Me

OH

H

HN

H

H

Me1) 9-BBN;

NaOH, H2O2

2) PCC,

65% over 2 steps

Isodaphlongamine H

Hanessian, et. al. ACIE2016, 55, 2577

OTBS

IVinyl-I:

Sarpong

N

O

OH

H

H

Me

H

H

Lactonization

Pauson Khand

NH

CO2Me

Ph

Br

OTBS

Me

O

RCM

Radical

cyclization

O

O

Ph NS

O

tBu

LDA

82%, ~ 1:1 d.r.

undesired recycledNH

HPh

S

O

O

tBu O

1) HCl, MeOH

2)

77%

3) TBSCl

4) Ac2O, 85%

Br

Br

NH

CO2Me

Ph

Br

OTBS

Me

O

1) HG II

2) LiHMDS

74% over 2 steps NH

Br

OTBSO

O

1) Bu3SnH, Et3B O2

2) H2, Pd(OH)2, 79%

>20:1

d.r.

N

OTBSO

O

Me H

H

1) NaH,

4-iodobutene, 72%

2) [IrCl(CO)(PPh3)2]

TMDS, 73%N

OHO

Me H

H

TMSOTf

HCl, 79%

3.6:1 d.r.

MgBr

N

OHO

Me H

H

H

H

1) MeLi 2) Co2(CO)855% over 2 steps

3) TFAA; SOCl24) CF3CO3H, 25% over 2 steps

N

OTFA

Me H

H

H

H

O

H

O

1) LiAlH4

2) NaCNBH3, BF3 OEt23) CrO3, H2SO4

4)

N N

NCl Cl

Cl

13% over

4 steps

Daphlongamine H

Sarpong, et. al. JACS 2019, 141, 8431


Prior synthetic study: Hanessian, et. al. JOC 2010, 75, 2577

Prior strategies: Sarpong, et. al. JOC, 2019, 141, 8431

N

H

Me

Me



Highlights of Synthetic Studies Towards Longeracinphyllin A and Calyciphyline A Alkaloids

O

O

Me

Me

[3 steps from carvone]

1) DIBAL

2) propargylamine,

MgSO4; NaBH4

86% over 2 steps

OH

MeHN

MeH

1) NCS

2) DMP

96% over 2 steps

O

MeN

MeH

Cl

AIBN, Bu3SnH

74%N

MeMe

Stockdill, et. al. Org. Lett. 2014, 16, 1072

O

O

Me

HN

O

TMS

BHT, 140 oC

BnN

O

H

OH

TMS

MeCHBr3, TEBA

BnN

O

H

OH

TMS

Me

Br

Br

HCO2H

67%BnN

O

H

O

Me BrHCO2H, Bu3N

[Pd(PPh3)2Cl2]

85%BnN

O

O

Me

TEBANEt3

ClZhai, et. al. Chem. - Asian. J.2015, 10, 865

[Double Radical Cylization]

[Diels-Alder]

O

EtO

O

1) Et3N, acrolein, 85%

2) K2CO3, EtOH

Me

O

PO(OMe)2

N285%

O

EtO

O

1) CeCl3, NaBH4

78%

2) MsCl, py, 72%

EtO2CCo2(CO)8, NMO

58%

4:1 d.r.

EtO2C

O

HH

[Pauson Khand]

Dixon, et. al. Org. Lett. 2012, 14, 1684

1) AIBN, O2

tBuOOH

2) SnCl234% over 2 steps

EtO2C

OHO

Me

HMe

O

MeO

N

OMe

O

O

HO

1) AcCl, Et3N

2) h

47% over 2 steps

HMe

O

MeO

O

OAcH

Me

N

MeO2C

[2+2]

1) NaBH4

2) MsCl, py

DMAP

3) K2CO3

78% over

3 steps

HMe

O

MeO

H

Me

NMeO2C

O

[Grob Fragmentation]

N

H

Me

MeH O

Wang, et. al. JOC,2012, 77, 6307

H2, PtO2

94%

N

MeOH

O

Me

H(-)-Himalensine A


4/20/2020

N

Me

O

Me

H

NazarovXu

Heck

N Me

H

OTES

O

HBr

O

OMe

1) CH(OMe)3p-TsOH, 82%

2) tBuOK,

TosMIC, 61%

MeO

MeCN

[Mechanism for 2?]

1) Oxone,

NaHCO3, 61%

2) TESOTf

3) BQ, Pd(OAc)273% over 2 steps

O

MeCN

HO

Cu(OAc)2HONEt2, DBU

81%HN Me

H

OTES

O

O TsNHNH2;

HB(cat). 91%

HN Me

H

OTES

O

HN

NH

HN Me

H

OTESH

O

NaH

BrBr

82%N Me

H

OTESHBr

Pd(OAc)2PPh3, Et3N

55% N

OTES

Me

HO

1) H2, Wilkinson's cat;

AZADOL,

PIDA, 82%

2) KHMDS,

PhNTf2, 96%

N Me

HO

MeOTf

Pd(PPh3)4CO, LiCl, 86%

Sn4

N Me

HO

Me

O

SnCl4

75%N Me

HO

Me

O

m-CPBA;

BF3 Et2O

54% N Me

HO

Me

OO

[IrCl(CO)(PPh3)2];TMDS

TFA, EtSiH357%

TGT

Xu, et. al. ACIE2019, 58, 7390

Dixon

N

MeO

Me

H

X

O

ZnBr

Negishi coupling

Stetter

O

N

O

Me

H

H

OH O radical

cyclizationD.A.

O

Me

N

O

Boc

O

[7 steps]

Van Leusen;

1,4-addn.

CF3F3C

O NH

Ph

Ph

NPPh3

5 mol %

86%

92:8 d.r., 90% eeBocN

O

Me

H

O

O

TFA;

Pd(OH)2H2

63%HN

O

Me

H

OOH

H

1) NaHMDS

propargylBr, 63%

2) LiAlH4; MeOH,

HCl, 86%

N

O

Me

H

O

H

1) TIPSOTf

lutidine, 86%

2) Bu3SnH, AIBN

3) CSA

78% over 2 steps

4) Crabtree's cat.

H2/Ar (1:2), 92%

> 20:1 d.r.

N

OTIPS

Me

HO

HNBS

82%N

O

Me

HO

Br

Py, p-TsOH

O2

65%

H

H

N

O

Me

HO

Me

O

1) NaHMDS; PhNTf2, 58%

2) Pd2(dba)3, DTBPF, 96%

3) HCl, 87%

ZnBrO

O

N

MeO

O

Me

HO

BnNS

MeOH

Cl

Et3N, EtOH

75%

N

MeO

O

Me

HO

[Ir(CO)(PPh3)2Cl]

TMDS; HCO2H

67%

TGT

Dixon, et. al. JACS2017, 139, 17755


[Mechanism?]

, ,


4/20/2020

Divergent Syntheses

N

O

Meo-Ns

Common Intermediate

[3 steps]

1) p-thiocresol

2)

EDC, HOBt, Et3N

3) DBU (CH2O)n69% over 3 steps

CO2Me

HO2COTBS

N CO2Me

OMe

O

1) HF py

2) I2, PPh3, imid.

85% over 2 steps

3) Zn, CuI, 90%

4) [Rh(cod)Cl]2, PPh3,

AgBF4, H2, 98%

Li

N

CO2Me

O

Me

Me

O

TBSO

1) KHMDS, PhSeBr

2) m-CPBA,

75% over 2 steps

3) DABCO, air,

91%

N

CO2Me

O

Me

Me

O

O

1) dppf,

2) LiCH2PO(OMe)286%

CO2Me

45%

N

CO2Me

O

Me

Me

O

O O

(MeO)2OP 1) Pd/C, H2

2) TBD, 91%

3) LiCl, H2O

MeCN, 95%

4) Lawesson

reagent, 67%

5) Raney Ni, 90%

N

H

O

Me

Me OH

Longeracinphyllin A

Li, et. al. JACS 2017, 139, 14893

Me

CO2tBu1) LiCl, 96%

2) PBu3

3) Crabtree's cat.

H2; HCO2H, 91%

83%

N

O

Me

Me

OOHCO

H

O

OH

H1) m-CPBA, DCC

2) PCC, 79%

3) K2CO3; DMP

4) p-TsOH, 71%N

H

O

Me

Me

O

O

1) EtNO2, DBU, 81%

2) PdCl2, CuCl2DMF, H2O, 87%

N H

O

Me

MeO

O

O

Me

8 steps

(see Daphenylline slide)N H

Me

Me

H

(-)-Daphenylline Zhai, et. al. ACIE2018, 57, 947

1) NaOH, 80%

2) LiAlH4

3) DMP, 61%

N

O

Me

Me

O

H

H(-)-Daphnilongeranin B

Zhai, et. al. ACIE 2018, 57, 947

4 steps

N CO2Me

O

Me

Me

OTBSO

1) CrO3, H2SO4,

90%

2) SOCl2, PhSeH,

py, 90%

3) h , 46%

N

CO2Me

O

Me

Me

O

O

1) dppf, COMe

52%2) LiI, H2O

MeCN, DMSO

N

H

O

Me

Me

O

O O

Me

3

steps N H

Me

Me

H

(-)-Daphenylline

Li, et. al. ACIE 2018, 57, 952

see

daphenylline

slides

1) IrCl(CO)(PPh3)2TMDS;

NaBH(OAc)3 81%

2) DBU, LiCl, 79%

N

H

OMe

Me O

OH

Dapnipaxianine A

NaBH4, CeCl372%, 3:1 d.r.

N

H

OMe

Me OH

OH

Himalenine D

Li, et. al. ACIE2018, 57, 952


Li, et. al. Chem.

Commun. 2014,

50, 5294


4/20/2020

Divergent Syntheses Cont.

N

CO2Me

O

Me

Me

O

1) LiCl, H2O, 76%

2) KHMDS, PhSeCl

3) m-CPBA, 94%

N

H

O

Me

Me

O

1) KHMDS, AllylBr, 92%

2) 80oC, 94%

N

H

O

Me

Me

O

1) Cy2BH; H2O2, NaOH, 92%

2) (COCl)2, DMSO, Et3N

3) t-BuOK,PH

N2

OMe

O

OMe71%

N

H

O

Me

Me

O

1) Lawesson reagent, 75%

2) Co2(CO)83) K2CO3, 63% over 2 steps

N

O

Me

Me

O

H

HS

Raney Ni

81%

N

O

Me

Me

O

H

H

Daphnilongeranin B

t-BuOK, O2

P(OEt)3

61%

N

O

Me

Me

O

OH

H

Daphniyunnine E

TFA

p-TsOH

79%

N

O

Me

Me

O

H

Dehydrodaphnilongeranin B

NaBH4, CeCl399%

N

O

Me

Me

OH

H

HS

Dienophile

MgSO4, BHT,

160oC

24% desired

plus 37% isomers

N

O

Me

Me

HS

N

S

O

Me

H

Me

O

H

OAc

O

O

H

H

O

O

OAc

OAc

OAc

OAc

1) Raney Ni, 75%

2) Et3N, MeOH,

H2O, 86%

N

O

Me

H

Me

O

H

OH

O

O

H

H

O

O

OH

OH

OH

OH

Hybridaphniphylline B

Li, et. al. JACS 2019,

140, 4227

Dienophile

O

OAc

O

O

H

H

O

O

OAc

OAc

OAc

OAc

[10 steps]

[10 steps from (+)-genipin]




"If progress in important fields such as medicine, biochemistry, and materials sceince is to continue, it isessential 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 neverbe discovered unless the methods are tested in the challenging arena of [synthesis]. Although ourapproaches to problems have matured, we need even more mature strategies of synthesis. There is noreason that organic chemists should not be able to surpass nature's virtuosity in the synthesis of complexorganic structures. In fact, we are still very far from this goal in most cases."

- Clayton HeathcockACIE 1992, 31, 665

Me

N

Me

(-)-Caldaphnidine O

CO2Me

Xu. et. al. JACS 2019, 141, 13043

Total syntheses not covered:

N

MeOH

O

Me

H(-)-Himalensine A

Gau, et. al. Org. Lett. 2019, 21, 3741

N

Me

Me

OH

Me

OHO

Xu, et. al. JACS 2019, 141, 11713

Dapholdhamine B

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