synthetic approaches to the pepluanol natural products

Synthetic Approaches to the Pepluanol Natural Products

Nicholas A. FalconeLiterature Group Meeting

November 19th, 2021

OMe Me

OHO OH

MeOH OHO

Me OMe

Kiyota, H. et al. Chem. Rev. 2008, 108, 4295.Vasas, A.; Hohmann, J. Chem. Rev. 2014, 114, 8579.

Euphorbia Diterpenes: Featured Classes

lathyrane jatrophane

daphnane tigliane ingenane

> 750 members across more than 2000 species

Zhou, M.; Qiu, M.-H. et al. Org. Lett. 2016, 18, 2166.Zhou, M.; Qiu, M.-H. et al. Org. Lett. 2018, 20, 3074.

Pepluanol Natural Products

OHO OH

MeOH OHO

Me OMe

pepluanol A pepluanol B pepluanol C pepluanol D pepluacetal

tigliane ingenane

OHO OH

MeOH OHO

Me OMe

鏃�Unprecedented polycyclic ring systems

鏃 Inhibit voltage-gated potassium channel Kv1.3

鏃�Potential application as immunosuppressants

OHO OH

MeOH OHO

Me OMe

Pepluanol A:Xuan, J.; Lio, Z.; Zhu, A.; Rao, P.; Yu, L.; Ding, H.

Zhejiang UniversityAngew. Chem. Int. Ed. 2017, 56, 8898–8901.

Yuan, P.; Gerlinger, C. K. G.; Herberger, J.; Gaich, T. University of Konstanz

J. Am. Chem. Soc. 2021, 143, 11934–11938.

Pepluanol B:Zhang, J.; Liu, M.; Wu, C.; Zhao, G.; Chen, P.; Zhou, L.; Xie, X.; Fang, R.; Li, H.; She, X.

Lanzhou UniversityAngew. Chem. Int. Ed. 2020, 59, 3966–3970.

OHO OH

MeOH OHO

Me OMe

J. Am. Chem. Soc. 2021, 143, 11934–11938.

OHO OH

MeOH OHO

Me OMe

Molander, G. A.; Shakya, S. R. J. Org. Chem. 1996, 61, 5885.Aurrecoechea, J. M.; Iztueta, E. Tetrahedron Lett. 1995, 36, 7129.Ding, H. et al. Angew. Chem. Int. Ed. 2017, 56, 8898.

Ding’s Reductive Annulation Strategy

pepluanol A

Reductive

annulation

pepluanol A

Reductive

annulation

pepluanol A

Reductive

annulation

SmI2–HMPA

n = 1 (76%, > 200:1 dr)n = 2 (78%, > 200:1 dr)

Molander (1996):

pepluanol A

Reductive

annulation

SmI2–HMPA

THF, -40 ˚C70%

Aurrecoechea (1995):

HOCp2TiCl2 (0.2 eq.), Zn (4.0 eq.)

2,4,6-collidine･HCl (1.0 eq.)THF, rt

95%, 1.5:1 d.r.

Other conditions: SmI2–HMPA; n-Bu3SnH/AIBN; n-Bu3SnH/Et3B/O2;Pd(PPh3)4/SmI2, CrCl2/LiI; SnCl2/n-Bu4NBr; LiDBB

9 examples73–93%, up to 8:1 dr

HOCp2TiCl2 (0.2 eq.), Zn (4.0 eq.)

2,4,6-collidine･HCl (1.0 eq.)THF, rt

95%, 1.5:1 d.r.

Other conditions: SmI2–HMPA; n-Bu3SnH/AIBN; n-Bu3SnH/Et3B/O2;Pd(PPh3)4/SmI2, CrCl2/LiI; SnCl2/n-Bu4NBr; LiDBB

9 examples73–93%, up to 8:1 dr

Reductive

Annulation

Pearson, A. J.; Bansal, H. S. Tetrahedron Lett. 1986, 27, 283.Danishefsky, S. J. et al. J. Am. Chem. Soc. 2008, 130, 13765.Rawal, V. H. et al. Angew. Chem. Int. Ed. 2008, 47, 4373.Ding, H. et al. Angew. Chem. Int. Ed. 2017, 56, 8898.

Assembling the [5.4.0]-Ring System

MeOBz4 steps TMSN3, I2

pyridine, CH2Cl2

0 ˚C to rt88%

pyridine, CH2Cl2

0 ˚C to rt88%

Pd(dba)2 (cat.)P(2-furyl)3

DMF, rt74%

neat, 40 ˚C

then 2.0 M HClTHF, –25 ˚C to rt

pyridine, CH2Cl2

0 ˚C to rt88%

Pd(dba)2 (cat.)P(2-furyl)3

DMF, rt74%

neat, 40 ˚C

then 2.0 M HClTHF, –25 ˚C to rt

H1) KHMDS; PhNTf2 THF, , –78 ˚C to rt

2) CuI (cat.), MeMgBr THF, 0 ˚C

72% (2 steps)

MeOBzH

Jin, Z. et al. Org. Lett. 2004, 6, 2417.Ding, H. et al. Angew. Chem. Int. Ed. 2017, 56, 8898.

Advancing to the Reductive Annulation

1) NaOMe, MeOH, 65 ˚C

2) Oxone, NaHCO3 acetone/H2O (4:1)

PPh3, THF, 60 ˚C67%

MeOBzH

58% (2 steps)

OO N N

CO2EtMe H

O(DEAD)

Jin, Z. et al. Org. Lett. 2004, 6, 2417.Ding, H. et al. Angew. Chem. Int. Ed. 2017, 56, 8898.

Advancing to the Reductive Annulation

1) NaOMe, MeOH, 65 ˚C

2) Oxone, NaHCO3 acetone/H2O (4:1)

PPh3, THF, 60 ˚C67%

MeOBzH

58% (2 steps)

OO N N

CO2EtMe H

O(DEAD)

OsO4 (cat.), NaIO42,6-lutidine

1,4-dioxane/H2O (3:1)70%

Cp2TiCl2 (cat.), Zn

2,4,6-collidine･HClTHF

91%, 1:1 d.r.

Winkler, J. D. et al. J. Am. Chem. Soc. 2002, 124, 9726.Einhorn, J. et al. J. Org. Chem. 1996, 61, 7452.Ding, H. et al. Angew. Chem. Int. Ed. 2017, 56, 8898.

Completing the Synthesis of Pepluanol A

1) BnEt3NCl (cat.) NaOH/CHBr3

2) Me2Cu(SCN)Li2 HMPA, Et2O then MeI –78 ˚C to –20 ˚C

44% (2 steps)

TEMPO (cat.), Et4NClNCS, NaHCO3

CH2Cl2/H2O (1:1)95%

44% (2 steps)

CH2Cl2/H2O (1:1)95%

1) TMSOTf, Et3N CH2Cl2, 0 ˚C

2) Pd(OAc)2, MeCN

86% (2 steps)

44% (2 steps)

CH2Cl2/H2O (1:1)95%

1) TMSOTf, Et3N CH2Cl2, 0 ˚C

2) Pd(OAc)2, MeCN

86% (2 steps)

MeMgBr

PhMe, 0 ˚C5:1 d.r.Me

PCC, NaOAcSiO2, CH2Cl2

then HCl59% (2 steps)

pepluanol A

Ding, H. et al. Angew. Chem. Int. Ed. 2017, 56, 8898.

H Diels-Alder constructs6-membered ring

Ding, H. et al. Angew. Chem. Int. Ed. 2017, 56, 8898.

pepluanol A

H Diels-Alder constructs6-membered ring

Reductive annulationestablishes 1,5-diol

Maimone, T. J. et al. Chem. Rev. 2017, 117, 11753.Gaich, T. et al. J. Am. Chem. Soc. 2021, 143, 11934.

Gaich’s IMDA Strategy

pepluanol A

Late Stage

Functionalization

pepluanol A

Diels-Alder

Late Stage

Functionalization

pepluanol A

Diels-Alder

Late Stage

Functionalization

HMeMeMe

(+)-3-carene$16/gram

Baran, P. S. et al. J. Am. Chem. Soc. 2014, 136, 5799.Gaich, T. et al. J. Am. Chem. Soc. 2021, 143, 11934.

Accessing a Functionalized Cycloheptenone

HMeMeMe

HOMeMe

Me3 steps H

HTBSOMeMe

MeKHMDS, TBSOTf

THF, –78 ˚C90%

HMeMeMe

HOMeMe

Me3 steps H

HTBSOMeMe

MeKHMDS, TBSOTf

THF, –78 ˚C90%

CHBr3, t-BuOK,pet. ether, –20 ˚C

then Ag2O, HBF4,EtOH 0 ˚C to rt

HMeMeMe

HOMeMe

Me3 steps H

HTBSOMeMe

MeKHMDS, TBSOTf

THF, –78 ˚C90%

NiCl2 (cat.), CrCl2DMF, 50 ˚CO

42%21%

HMeMeMe

HOMeMe

Me3 steps H

HTBSOMeMe

MeKHMDS, TBSOTf

THF, –78 ˚C90%

NiCl2 (cat.), CrCl2DMF, 50 ˚CO

42%21%

Desired configuration

Gaich, T. et al. J. Am. Chem. Soc. 2021, 143, 11934.

Diels-Alder Attempts with the C-13 Epimers

*various Lewis Acids

& thermal conditions

o-xylene, 150 ˚C

Only the minor isomer shows reactivity under various conditions

*o-xylene, 150 ˚C

o-xylene, 150 ˚C

Only the minor isomer shows reactivity under thermal conditionsDFT studies suggest the possibility of a Curtin–Hammett-driven stereoconvergent IMDA

*DBU, o-xylene, 150 ˚C

R = TES

LDA, THF, –78 ˚Cthen AcOH, Bu4NF

quant.

*DBU, o-xylene, 150 ˚C

R = TES

LDA, THF, –78 ˚Cthen AcOH, Bu4NF

quant.

TESCl, DBU, o-xylene, rt;then 150 ˚C, overnight;then LDA, –78 ˚Cthen AcOH, Bu4NF

48%one pot!!

Tsuji, J. et al. Tetrahedron, 1986, 42, 2971.Gaich, T. et al. J. Am. Chem. Soc. 2021, 143, 11934.

Completing the Synthesis of (+)-Pepluanol A

PCC, basic Al2O3

CH2Cl277%

PCC, basic Al2O3

CH2Cl277%

LiTMP, TMSCl, THFthen Pd2(dba)3

allylmethylcarbonateMeCN, rt96%

PCC, basic Al2O3

CH2Cl277%

allylmethylcarbonateMeCN, rt

SeO2 1,4-dioxane, 60 ˚C

37% (52% brsm)+ 34% undesiredoxidized species

pepluanol A

PCC, basic Al2O3

CH2Cl277%

allylmethylcarbonateMeCN, rt

SeO2 1,4-dioxane, 60 ˚C

37% (52% brsm)+ 34% undesiredoxidized species

18% 1˚ alcohol

16% ketone

pepluanol A

HMeMeMe

Ring Enlargementto cycloheptenone

HMeMeMe

(+)-3-carene$16/gram Convergent NHK coupling

pepluanol A

HMeMeMe

pepluanol A

HMeMeMe

StereoconvergentIMDA constructs6-membered ring

pepluanol A

HMeMeMe

Saegusa-ItoOxidation

pepluanol A

HMeMeMe

Saegusa-ItoOxidation

Allylic [O]

J. Am. Chem. Soc. 2021, 143, 11934–11938.

OHO OH

MeOH OHO

Me OMe

J. Am. Chem. Soc. 2021, 143, 11934–11938.

OHO OH

MeOH OHO

Me OMe

She, X. et al. Angew. Chem. Int. Ed. 2020, 59, 3966.

Synthesis of (–)-Pepluanol B

pepluanol B

Late Stage

Functionalization

pepluanol B

PGO OH

Late Stage

Functionalization

RCM &cyclopropanation

pepluanol B

PGO OH

Late Stage

Functionalization

RCM &cyclopropanation

1) Pd(OAc)2 (cat.) Pb(OAc)4, AcOH

2) Dowex 1x8, MeOHHO H

75% (2 steps)

1) NaH, PMBCl, Bu4NI THF, 0 ˚C to 66 ˚C

2) (COCl)2, DMSO, Et3N CH2Cl2, –78 ˚C to rt

80% (2 steps)PMBO H

Henry, P. J. et al. J. Chem. Soc., Chem. Commun. 1974, 112–113.Disanayaka, B. W.; Weedon, A. C. Synthesis 1983, 952.She, X. et al. Angew. Chem. Int. Ed. 2020, 59, 3966.

Assembling a Functionalized [3.3.0] System

1) Pd(OAc)2 (cat.) Pb(OAc)4, AcOH

2) Dowex 1x8, MeOHHO H

75% (2 steps)

1) NaH, PMBCl, Bu4NI THF, 0 ˚C to 66 ˚C

2) (COCl)2, DMSO, Et3N CH2Cl2, –78 ˚C to rt

80% (2 steps)PMBO H

1) LDA, TMSCl, THF –78 ˚C to 0 ˚C2) (Me2NCH2)+I-, CH2Cl23) MeI, basic Al2O3

Henry, P. J. et al. J. Chem. Soc., Chem. Commun. 1974, 112–113.Disanayaka, B. W.; Weedon, A. C. Synthesis 1983, 952.She, X. et al. Angew. Chem. Int. Ed. 2020, 59, 3966.

Assembling a Functionalized [3.3.0] System

66% (3 steps)

PMBO H

OHRhCl3ꙓ3H2O (cat.)

EtOH/pH 7 buffer (19:1)110˚C, sealed tube

PMBO H

1) LDA, THF, –78 ˚C then

78% (2 steps)3:2 dr

(epimeric at C14)

Winkler, J. D. et al. J. Am. Chem. Soc. 2002, 124, 9726.She, X. et al. Angew. Chem. Int. Ed. 2020, 59, 3966.

Constructing the Eight-Membered Ring

PMBO H

2) TMSOTf, Et3N CH2C2, 0 ˚C

PMBO H

TMSO 14 CeCl3, allylMgBr

THF, –78 ˚C to rt72%

PMBO H

TMSO OH

78% (2 steps)3:2 dr

(epimeric at C14)Grubbs II (cat.)CH2Cl2, 40 ˚C

PMBO H

TMSO OH

TMSO OHBnEt3NCl, CHBr3

NaOH (aq.)/CH2Cl278%

TMSO OH

78% (2 steps)3:2 dr

PMBO H

TMSO OH

Exclusive regio- anddiastereoselectivity

78% (2 steps)3:2 dr

PMBO H

TMSO OH

1) Me3CuLi2 then MeI Et2O, –45 ˚C to rt

2) n-Bu4NF, THF3) n-Pr4N+RuO4

-, NMO CH2Cl2, 4 Å MS

75% (3 steps)PMBO

TMSO OH

Exclusive regio- anddiastereoselectivity

A Conformational Conundrum

13C NMR shift = 223.1 ppm(209.1 ppm in natural product)

Me 1) TMSOTf, pyridine CH2Cl2, 0 ˚C

2) LDA then MeI THF, –78 ˚C

78% (2 steps)

Undesired C13 epimer

pepluanol B

13-epi-pepluanol B

C13 epimerizationattempts were unsuccessful

Me 1) TMSOTf, pyridine CH2Cl2, 0 ˚C

2) LDA then MeI THF, –78 ˚C

78% (2 steps)

pepluanol B

13-epi-pepluanol B

Cyclooctanone conformation determines spatial orientation of Z-enolate

NBS, pyridine

then DMPCH2Cl295%

LDA then MeI

THF, –78 ˚C72%

NBS, pyridine

then DMPCH2Cl295%

LDA then MeI

THF, –78 ˚C72%

Desired C13 epimer

NBS, pyridine

then DMPCH2Cl295%

LDA then MeI

THF, –78 ˚C72%

Desired C13 epimer

New enolate conformation

NBS, pyridine

then DMPCH2Cl2

LDA then MeI

THF, –78 ˚C72%

1) DDQ, CH2Cl2/pH 7 buffer2) n-Pr4N+RuO4

-, NMO CH2Cl2, 4 Å MS

48% (2 steps)

Desired C13 epimer

New enolate conformation

Zn-Cu, EtOH

sat. aq. NH4Cl93%

Completing Pepluanol B

Zn-Cu, EtOH

sat. aq. NH4Cl93%

Me2N NMe2Ac2O, DMF, 95 ˚C

pepluanol B

RhCl3ꙓ3H2O (cat.)

EtOH/pH 7 buffer (4:1)95 ˚C, sealed tube40% (60% brsm)

Undesired C13 epimer Desired C13 epimer

synthetic approaches to the pepluanol natural products

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