synthetic approaches to the pepluanol natural products
TRANSCRIPT
Synthetic Approaches to the Pepluanol Natural Products
Nicholas A. FalconeLiterature Group Meeting
November 19th, 2021
OMe
MeMeH
HO
H
HOH
MeO
MeMe
H
OMe Me
MeH
HOH
Me
OH
OHO OH
Me
H
MeMeH
HH
Me
MeMe
OMe
MeOH OHO
O
Me
Me
Me
O
Me OMe
OMe
MeHH
MeMeH
HO
Me
H
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
OMe
MeMeH
HO
H
HOH
MeO
MeMe
H
OMe
OH
Me
OH
OHO OH
Me
H
MeMeH
HH
Me
MeMe
OMe
MeOH OHO
O
Me
Me
Me
O
Me OMe
OMe
MeHH
MeMeH
HO
Me
pepluanol A pepluanol B pepluanol C pepluanol D pepluacetal
H
MeMe
HH
tigliane ingenane
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
OMe
MeMeH
HO
H
HOH
MeO
MeMe
H
OMe
OH
Me
OH
OHO OH
Me
H
MeMeH
HH
Me
MeMe
OMe
MeOH OHO
O
Me
Me
Me
O
Me OMe
OMe
MeHH
MeMeH
HO
Me
pepluanol A pepluanol B pepluanol C pepluanol D pepluacetal
H
MeMe
HH
鏃�Unprecedented polycyclic ring systems
鏃 Inhibit voltage-gated potassium channel Kv1.3
鏃�Potential application as immunosuppressants
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
OMe
MeMeH
HO
H
HOH
MeO
MeMe
H
OMe
OH
Me
OH
OHO OH
Me
H
MeMeH
HH
Me
MeMe
OMe
MeOH OHO
O
Me
Me
Me
O
Me OMe
OMe
MeHH
MeMeH
HO
Me
pepluanol A pepluanol B pepluanol C pepluanol D pepluacetal
H
MeMe
HH
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.
Pepluanol Natural Products
OMe
MeMeH
HO
H
HOH
MeO
MeMe
H
OMe
OH
Me
OH
OHO OH
Me
H
MeMeH
HH
Me
MeMe
OMe
MeOH OHO
O
Me
Me
Me
O
Me OMe
OMe
MeHH
MeMeH
HO
Me
pepluanol A pepluanol B pepluanol C pepluanol D pepluacetal
H
MeMe
HH
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.
Pepluanol Natural Products
OMe
MeMeH
HO
H
HOH
MeO
MeMe
H
OMe
OH
Me
OH
OHO OH
Me
H
MeMeH
HH
Me
MeMe
OMe
MeOH OHO
O
Me
Me
Me
O
Me OMe
OMe
MeHH
MeMeH
HO
Me
pepluanol A pepluanol B pepluanol C pepluanol D pepluacetal
H
MeMe
HH
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
OMe
MeMeH
HO
H
HOH
MeMe
pepluanol A
O
Me H
MeO
O
H
OMe
H
HOH
MeHO
Reductive
annulation
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
OMe
MeMeH
HO
H
HOH
MeMe
pepluanol A
O
Me H
MeO
O
H
OMe
H
HOH
MeHO
Reductive
annulation
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
OMe
MeMeH
HO
H
HOH
MeMe
pepluanol A
O
Me H
MeO
O
H
OMe
H
HOH
MeHO
Reductive
annulation
n
OO
OH
OH
Hn
SmI2–HMPA
THF
n = 1 (76%, > 200:1 dr)n = 2 (78%, > 200:1 dr)
Molander (1996):
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
OMe
MeMeH
HO
H
HOH
MeMe
pepluanol A
O
Me H
MeO
O
H
OMe
H
HOH
MeHO
Reductive
annulation
SmI2–HMPA
THF, -40 ˚C70%
Aurrecoechea (1995):
OMe
O
Ph+
HO OH
Me
Ph
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
O
H
O
OH
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
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
O
H
O
OH
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
O
Me H
MeO
O
H
OMe
H
HOH
MeHO
OMe
MeMeH
HO
H
HOH
MeMe
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
O
MeOBz
O
MeOBz4 steps TMSN3, I2
pyridine, CH2Cl2
0 ˚C to rt88%
I
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
O
MeOBz
O
MeOBz4 steps TMSN3, I2
pyridine, CH2Cl2
0 ˚C to rt88%
I
ZnBr
Pd(dba)2 (cat.)P(2-furyl)3
DMF, rt74%
O
MeOBz
OTBS
NMe2
neat, 40 ˚C
then 2.0 M HClTHF, –25 ˚C to rt
83%
O
MeOBz
O
H
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
O
MeOBz
O
MeOBz4 steps TMSN3, I2
pyridine, CH2Cl2
0 ˚C to rt88%
I
ZnBr
Pd(dba)2 (cat.)P(2-furyl)3
DMF, rt74%
O
MeOBz
OTBS
NMe2
neat, 40 ˚C
then 2.0 M HClTHF, –25 ˚C to rt
83%
O
MeOBz
O
H1) KHMDS; PhNTf2 THF, , –78 ˚C to rt
2) CuI (cat.), MeMgBr THF, 0 ˚C
72% (2 steps)
O
MeOBzH
Me
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%
O
MeOBzH
Me
58% (2 steps)
HO
Me H
Me
13
OO N N
EtO2C
CO2EtMe H
MeO
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%
O
MeOBzH
Me
58% (2 steps)
HO
Me H
Me
13
OO N N
EtO2C
CO2EtMe H
MeO
O(DEAD)
OsO4 (cat.), NaIO42,6-lutidine
1,4-dioxane/H2O (3:1)70%
Me
O
H
MeO
O
H
Cp2TiCl2 (cat.), Zn
2,4,6-collidine･HClTHF
91%, 1:1 d.r.
OMe
H
HOH
MeHO
3
OMe
H
HOH
MeHO
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)
OMe
H
HOH
MeHO
H
HMe
Me
TEMPO (cat.), Et4NClNCS, NaHCO3
CH2Cl2/H2O (1:1)95%
OMe
H
HOH
MeO
H
HMe
Me
OMe
H
HOH
MeHO
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)
OMe
H
HOH
MeHO
H
HMe
Me
TEMPO (cat.), Et4NClNCS, NaHCO3
CH2Cl2/H2O (1:1)95%
OMe
H
HOH
MeO
H
HMe
Me
1) TMSOTf, Et3N CH2Cl2, 0 ˚C
2) Pd(OAc)2, MeCN
86% (2 steps)
OMe
H
HOTMS
MeO
H
HMe
Me
OMe
H
HOH
MeHO
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)
OMe
H
HOH
MeHO
H
HMe
Me
TEMPO (cat.), Et4NClNCS, NaHCO3
CH2Cl2/H2O (1:1)95%
OMe
H
HOH
MeO
H
HMe
Me
1) TMSOTf, Et3N CH2Cl2, 0 ˚C
2) Pd(OAc)2, MeCN
86% (2 steps)
OMe
H
HOTMS
MeO
H
HMe
Me
OMe
H
HOTMS
Me
H
HMe
Me
MeMgBr
PhMe, 0 ˚C5:1 d.r.Me
HO
PCC, NaOAcSiO2, CH2Cl2
then HCl59% (2 steps)
OMe
H
HOH
Me
H
HMe
Me
O
Me
pepluanol A
Ding, H. et al. Angew. Chem. Int. Ed. 2017, 56, 8898.
Completing the Synthesis of Pepluanol A
O
MeOBz
Me
O
H
MeO
O
H Diels-Alder constructs6-membered ring
Ding, H. et al. Angew. Chem. Int. Ed. 2017, 56, 8898.
Completing the Synthesis of Pepluanol A
OMe
H
HOH
Me
H
HMe
Me
O
Me
pepluanol A
O
MeOBz
Me
O
H
MeO
O
H Diels-Alder constructs6-membered ring
OMe
H
HOH
MeHO
H
HMe
Me
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
OMe
H
HOH
Me
H
HMe
Me
O
Me
pepluanol A
OMe
H
H
Me
H
HMe
Me
HO
Me
Late Stage
Functionalization
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
OMe
H
HOH
Me
H
HMe
Me
O
Me
pepluanol A
Diels-Alder
OMe
H
H
Me
H
HMe
Me
HO
Me
Late Stage
Functionalization
O
HO
Me
Me
Me
MeMeH
H
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
OMe
H
HOH
Me
H
HMe
Me
O
Me
pepluanol A
Diels-Alder
OMe
H
H
Me
H
HMe
Me
HO
Me
Late Stage
Functionalization
O
HO
Me
Me
Me
MeMeH
HH
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
H
HMeMeMe
(+)-3-carene$16/gram
H
HOMeMe
Me3 steps H
HTBSOMeMe
MeKHMDS, TBSOTf
THF, –78 ˚C90%
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
H
HMeMeMe
(+)-3-carene$16/gram
H
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
82%
O
Me
MeMeH
H
Br
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
H
HMeMeMe
(+)-3-carene$16/gram
H
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
82%
O
Me
MeMeH
H
Br
O
H
Me
Me
NiCl2 (cat.), CrCl2DMF, 50 ˚CO
HO
Me
Me
Me
MeMeH
H
O
HO
Me
Me
Me
MeMeH
H+
42%21%
*
* *
*
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
H
HMeMeMe
(+)-3-carene$16/gram
H
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
82%
O
Me
MeMeH
H
Br
O
H
Me
Me
NiCl2 (cat.), CrCl2DMF, 50 ˚CO
HO
Me
Me
Me
MeMeH
H
O
HO
Me
Me
Me
MeMeH
H+
42%21%
*
* *
*
Desired configuration
Gaich, T. et al. J. Am. Chem. Soc. 2021, 143, 11934.
Diels-Alder Attempts with the C-13 Epimers
O
HO
Me
Me
Me
MeMeH
H
O
HO
Me
Me
Me
MeMeH
H*
*
*
*
Minor
Major
Gaich, T. et al. J. Am. Chem. Soc. 2021, 143, 11934.
Diels-Alder Attempts with the C-13 Epimers
O
HO
Me
Me
Me
MeMeH
H
O
HO
Me
Me
Me
MeMeH
H*
*
*
*various Lewis Acids
& thermal conditions
o-xylene, 150 ˚C
17%
OMe
H
H
Me
H
HMe
Me
HO
Me
OMe
H
H
Me
H
HMe
Me
HO
Me
Only the minor isomer shows reactivity under various conditions
Minor
Major
Gaich, T. et al. J. Am. Chem. Soc. 2021, 143, 11934.
Diels-Alder Attempts with the C-13 Epimers
O
TESO
Me
Me
Me
MeMeH
H
O
TESO
Me
Me
Me
MeMeH
H*
*
*
*
Minor
Major
Gaich, T. et al. J. Am. Chem. Soc. 2021, 143, 11934.
Diels-Alder Attempts with the C-13 Epimers
O
TESO
Me
Me
Me
MeMeH
H
O
TESO
Me
Me
Me
MeMeH
H*
*
*
*o-xylene, 150 ˚C
o-xylene, 150 ˚C
90%
OMe
H
H
Me
H
HMe
Me
TESO
Me
OMe
H
H
Me
H
HMe
Me
TESO
Me
Only the minor isomer shows reactivity under thermal conditionsDFT studies suggest the possibility of a Curtin–Hammett-driven stereoconvergent IMDA
Minor
Major
O
RO
Me
Me
Me
MeMeH
H
O
RO
Me
Me
Me
MeMeH
H+
21
*
* *
*DBU, o-xylene, 150 ˚C
88%
R = TES
:
OMe
H
H
Me
H
HMe
Me
TESO
Me
LDA, THF, –78 ˚Cthen AcOH, Bu4NF
quant.
OMe
H
H
Me
H
HMe
Me
HO
Me
Gaich, T. et al. J. Am. Chem. Soc. 2021, 143, 11934.
Diels-Alder Attempts with the C-13 Epimers
O
RO
Me
Me
Me
MeMeH
H
O
RO
Me
Me
Me
MeMeH
H+
21
*
* *
*DBU, o-xylene, 150 ˚C
88%
R = TES
:
OMe
H
H
Me
H
HMe
Me
TESO
Me
LDA, THF, –78 ˚Cthen AcOH, Bu4NF
quant.
OMe
H
H
Me
H
HMe
Me
HO
Me
TESCl, DBU, o-xylene, rt;then 150 ˚C, overnight;then LDA, –78 ˚Cthen AcOH, Bu4NF
Gaich, T. et al. J. Am. Chem. Soc. 2021, 143, 11934.
Diels-Alder Attempts with the C-13 Epimers
48%one pot!!
R = H
OMe
H
H
Me
H
HMe
Me
HO
Me
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%
OMe
H
H
Me
H
HMe
Me
O
Me
OMe
H
H
Me
H
HMe
Me
HO
Me
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%
OMe
H
H
Me
H
HMe
Me
O
Me
LiTMP, TMSCl, THFthen Pd2(dba)3
allylmethylcarbonateMeCN, rt96%
OMe
H
H
Me
H
HMe
Me
O
Me
OMe
H
H
Me
H
HMe
Me
HO
Me
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%
OMe
H
H
Me
H
HMe
Me
O
Me
LiTMP, TMSCl, THFthen Pd2(dba)3
allylmethylcarbonateMeCN, rt
96%
OMe
H
H
Me
H
HMe
Me
O
Me
SeO2 1,4-dioxane, 60 ˚C
37% (52% brsm)+ 34% undesiredoxidized species
OMe
H
H
Me
H
HMe
Me
O
Me
OH
pepluanol A
OMe
H
H
Me
H
HMe
Me
HO
Me
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%
OMe
H
H
Me
H
HMe
Me
O
Me
LiTMP, TMSCl, THFthen Pd2(dba)3
allylmethylcarbonateMeCN, rt
96%
OMe
H
H
Me
H
HMe
Me
O
Me
SeO2 1,4-dioxane, 60 ˚C
37% (52% brsm)+ 34% undesiredoxidized species
OMe
H
H
Me
H
HMe
Me
O
Me
OH
18% 1˚ alcohol
16% ketone
pepluanol A
Completing the Synthesis of (+)-Pepluanol A
O
HO
Me
Me
Me
MeMeH
HH
HMeMeMe
(+)-3-carene$16/gram
Completing the Synthesis of (+)-Pepluanol A
O
HO
Me
Me
Me
MeMeH
HH
HMeMeMe
(+)-3-carene$16/gram
Ring Enlargementto cycloheptenone
Completing the Synthesis of (+)-Pepluanol A
O
HO
Me
Me
Me
MeMeH
HH
HMeMeMe
(+)-3-carene$16/gram Convergent NHK coupling
Ring Enlargementto cycloheptenone
Completing the Synthesis of (+)-Pepluanol A
OMe
H
H
Me
H
HMe
Me
O
Me
OH
pepluanol A
O
HO
Me
Me
Me
MeMeH
HH
HMeMeMe
(+)-3-carene$16/gram Convergent NHK coupling
Ring Enlargementto cycloheptenone
Completing the Synthesis of (+)-Pepluanol A
OMe
H
H
Me
H
HMe
Me
O
Me
OH
pepluanol A
O
HO
Me
Me
Me
MeMeH
HH
HMeMeMe
(+)-3-carene$16/gram Convergent NHK coupling
StereoconvergentIMDA constructs6-membered ring
Ring Enlargementto cycloheptenone
Completing the Synthesis of (+)-Pepluanol A
OMe
H
H
Me
H
HMe
Me
O
Me
OH
pepluanol A
O
HO
Me
Me
Me
MeMeH
HH
HMeMeMe
(+)-3-carene$16/gram Convergent NHK coupling
Saegusa-ItoOxidation
StereoconvergentIMDA constructs6-membered ring
Ring Enlargementto cycloheptenone
Completing the Synthesis of (+)-Pepluanol A
OMe
H
H
Me
H
HMe
Me
O
Me
OH
pepluanol A
O
HO
Me
Me
Me
MeMeH
HH
HMeMeMe
(+)-3-carene$16/gram Convergent NHK coupling
Saegusa-ItoOxidation
Allylic [O]
StereoconvergentIMDA constructs6-membered ring
Ring Enlargementto cycloheptenone
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.
Pepluanol Natural Products
OMe
MeMeH
HO
H
HOH
MeO
MeMe
H
OMe
OH
Me
OH
OHO OH
Me
H
MeMeH
HH
Me
MeMe
OMe
MeOH OHO
O
Me
Me
Me
O
Me OMe
OMe
MeHH
MeMeH
HO
Me
pepluanol A pepluanol B pepluanol C pepluanol D pepluacetal
H
MeMe
HH
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.
Pepluanol Natural Products
OMe
MeMeH
HO
H
HOH
MeO
MeMe
H
OMe
OH
Me
OH
OHO OH
Me
H
MeMeH
HH
Me
MeMe
OMe
MeOH OHO
O
Me
Me
Me
O
Me OMe
OMe
MeHH
MeMeH
HO
Me
pepluanol A pepluanol B pepluanol C pepluanol D pepluacetal
H
MeMe
HH
She, X. et al. Angew. Chem. Int. Ed. 2020, 59, 3966.
Synthesis of (–)-Pepluanol B
O
MeMe
H
OMe
OH
pepluanol B
MeMe
HH
PMBO
Me
H
OHOH
MeMe
HH
Late Stage
Functionalization
She, X. et al. Angew. Chem. Int. Ed. 2020, 59, 3966.
Synthesis of (–)-Pepluanol B
O
MeMe
H
OMe
OH
pepluanol B
MeMe
HH
PMBO
Me
H
OHOH
MeMe
HH
PGO
Me
H
PGO OH
Late Stage
Functionalization
RCM &cyclopropanation
She, X. et al. Angew. Chem. Int. Ed. 2020, 59, 3966.
Synthesis of (–)-Pepluanol B
O
MeMe
H
OMe
OH
pepluanol B
MeMe
HH
PMBO
Me
H
OHOH
MeMe
HH
PGO
Me
H
PGO OH
HO H
OHH
Late Stage
Functionalization
RCM &cyclopropanation
1) Pd(OAc)2 (cat.) Pb(OAc)4, AcOH
2) Dowex 1x8, MeOHHO H
OHH
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
OH
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
OHH
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
OH
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
86%
PMBO H
OH
Me
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
OH
Me
2) TMSOTf, Et3N CH2C2, 0 ˚C
OHC
PMBO H
O
Me
TMSO 14 CeCl3, allylMgBr
THF, –78 ˚C to rt72%
PMBO H
Me
TMSO OH
1) LDA, THF, –78 ˚C then
78% (2 steps)3:2 dr
(epimeric at C14)Grubbs II (cat.)CH2Cl2, 40 ˚C
88%
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
OH
Me
2) TMSOTf, Et3N CH2C2, 0 ˚C
OHC
PMBO H
O
Me
TMSO 14 CeCl3, allylMgBr
THF, –78 ˚C to rt72%
PMBO H
Me
TMSO OH
PMBO
Me
H
TMSO OHBnEt3NCl, CHBr3
NaOH (aq.)/CH2Cl278%
PMBO
Me
H
TMSO OH
BrBr
HH
1) LDA, THF, –78 ˚C then
78% (2 steps)3:2 dr
(epimeric at C14)Grubbs II (cat.)CH2Cl2, 40 ˚C
88%
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
OH
Me
2) TMSOTf, Et3N CH2C2, 0 ˚C
OHC
PMBO H
O
Me
TMSO 14 CeCl3, allylMgBr
THF, –78 ˚C to rt72%
PMBO H
Me
TMSO OH
PMBO
Me
H
TMSO OHBnEt3NCl, CHBr3
NaOH (aq.)/CH2Cl278%
PMBO
Me
H
TMSO OH
BrBr
HH
Exclusive regio- anddiastereoselectivity
1) LDA, THF, –78 ˚C then
78% (2 steps)3:2 dr
(epimeric at C14)Grubbs II (cat.)CH2Cl2, 40 ˚C
88%
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
OH
Me
2) TMSOTf, Et3N CH2C2, 0 ˚C
OHC
PMBO H
O
Me
TMSO 14 CeCl3, allylMgBr
THF, –78 ˚C to rt72%
PMBO H
Me
TMSO OH
PMBO
Me
H
TMSO OHBnEt3NCl, CHBr3
NaOH (aq.)/CH2Cl278%
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
Me
H
TMSO OH
BrBr
HH
PMBO
Me
H
OOH
MeMe
HH
Exclusive regio- anddiastereoselectivity
She, X. et al. Angew. Chem. Int. Ed. 2020, 59, 3966.
A Conformational Conundrum
PMBO
Me
H
OOH
MeMe
HH
MeHH
HPMBO
HO
O
Me
Me
She, X. et al. Angew. Chem. Int. Ed. 2020, 59, 3966.
A Conformational Conundrum
PMBO
Me
H
OOH
MeMe
HH
MeHH
HPMBO
HO
O
Me
Me
13C NMR shift = 223.1 ppm(209.1 ppm in natural product)
She, X. et al. Angew. Chem. Int. Ed. 2020, 59, 3966.
A Conformational Conundrum
PMBO
Me
H
OOH
MeMe
HH
MeH
H
HPMBO
HO
O
Me
Me 1) TMSOTf, pyridine CH2Cl2, 0 ˚C
2) LDA then MeI THF, –78 ˚C
78% (2 steps)
MeH
H
HPMBO
TMSO
O
Me
Me
H
Me
Undesired C13 epimer
HH
TMSOO
Me
Me
H
MeI
13C NMR shift = 223.1 ppm(209.1 ppm in natural product)
MeH
H
HO
HO Me
Me
MeO
MeH
H
HO
TMSO
O
Me
Me
H
Me
Me
pepluanol B
13-epi-pepluanol B
C13 epimerizationattempts were unsuccessful
HMe
She, X. et al. Angew. Chem. Int. Ed. 2020, 59, 3966.
A Conformational Conundrum
PMBO
Me
H
OOH
MeMe
HH
MeH
H
HPMBO
HO
O
Me
Me 1) TMSOTf, pyridine CH2Cl2, 0 ˚C
2) LDA then MeI THF, –78 ˚C
78% (2 steps)
MeH
H
HPMBO
TMSO
O
Me
Me
H
Me
Undesired C13 epimer
HH
TMSOO
Me
Me
H
MeI
13C NMR shift = 223.1 ppm(209.1 ppm in natural product)
MeH
H
HO
HO Me
Me
MeO
MeH
H
HO
TMSO
O
Me
Me
H
Me
Me
pepluanol B
13-epi-pepluanol B
HMe
Cyclooctanone conformation determines spatial orientation of Z-enolate
MeHH
HPMBO
HO
HO
Me
Me
NBS, pyridine
then DMPCH2Cl295%
LDA then MeI
THF, –78 ˚C72%
MeHH
HPMBO
Me
Me
OO
Br
MeHH
HPMBO
Me
Me
OO
Br
Me H
She, X. et al. Angew. Chem. Int. Ed. 2020, 59, 3966.
A Conformational Conundrum
MeHH
HPMBO
HO
HO
Me
Me
NBS, pyridine
then DMPCH2Cl295%
LDA then MeI
THF, –78 ˚C72%
MeHH
HPMBO
Me
Me
OO
Br
MeHH
HPMBO
Me
Me
OO
Br
Me H
She, X. et al. Angew. Chem. Int. Ed. 2020, 59, 3966.
A Conformational Conundrum
Desired C13 epimer
MeHH
HPMBO
HO
HO
Me
Me
NBS, pyridine
then DMPCH2Cl295%
LDA then MeI
THF, –78 ˚C72%
MeHH
HPMBO
Me
Me
OO
Br
MeHH
HPMBO
Me
Me
OO
Br
Me H
HH
Me
Me
O
HMeI
She, X. et al. Angew. Chem. Int. Ed. 2020, 59, 3966.
A Conformational Conundrum
Desired C13 epimer
New enolate conformation
MeH
H
HPMBO
HO
HO
Me
Me
NBS, pyridine
then DMPCH2Cl2
95%
LDA then MeI
THF, –78 ˚C72%
MeH
H
HPMBO
Me
Me
OO
Br
MeH
H
HPMBO
Me
Me
OO
Br
Me H
HH
Me
Me
O
HMeI
MeH
H
HO
Me
Me
OO
Br
Me H
1) DDQ, CH2Cl2/pH 7 buffer2) n-Pr4N+RuO4
-, NMO CH2Cl2, 4 Å MS
48% (2 steps)
She, X. et al. Angew. Chem. Int. Ed. 2020, 59, 3966.
A Conformational Conundrum
Desired C13 epimer
New enolate conformation
MeHH
HO
Me
Me
OHO
Me H
MeHH
HO
Me
Me
OO
Br
Me H
Zn-Cu, EtOH
sat. aq. NH4Cl93%
She, X. et al. Angew. Chem. Int. Ed. 2020, 59, 3966.
Completing Pepluanol B
MeH
H
HO
Me
Me
OHO
Me H
MeH
H
HO
Me
Me
OO
Br
Me H
Zn-Cu, EtOH
sat. aq. NH4Cl93%
Me2N NMe2Ac2O, DMF, 95 ˚C
96%
MeH
H
HO
Me
Me
OHO
Me H
MeH
H
HO
HO Me
Me
MeO
pepluanol B
RhCl3ꙓ3H2O (cat.)
EtOH/pH 7 buffer (4:1)95 ˚C, sealed tube40% (60% brsm)
She, X. et al. Angew. Chem. Int. Ed. 2020, 59, 3966.
Completing Pepluanol B
HMe
HH
TMSOO
Me
Me
H
MeI
MeHH
HPMBO
TMSO
O
Me
Me
MeHH
HPMBO
TMSO
O
Me
Me
H
Me
Undesired C13 epimer
She, X. et al. Angew. Chem. Int. Ed. 2020, 59, 3966.
Completing Pepluanol B
HH
Me
Me
O
HMeI
HH
TMSOO
Me
Me
H
MeI
MeHH
HPMBO
TMSO
O
Me
Me
MeHH
HPMBO
Me
Me
OO
Br
MeHH
HPMBO
Me
Me
OO
Br
Me H
MeHH
HPMBO
TMSO
O
Me
Me
H
Me
Undesired C13 epimer Desired C13 epimer
She, X. et al. Angew. Chem. Int. Ed. 2020, 59, 3966.
Completing Pepluanol B