1Terpene Cyclization insidesupramolecular capsule catalyst
2017 8/26
M2 Kei Ito2

1. Introduction

2. Today`s contents~tail-to-head terpene (THT)
cyclization in capsule catalyst~
3. Summary

3Terpenes, Terpenoids

IUPAC GOLD BOOK

Category of terpene, terpenoid

4

David W. Chem. Rev, 2006, 106, 3412-3442

Diversity of terpene, terpenoid5

Simple Mono-Terpene
has structurally diversity
David W. Chem. Rev, 2006, 106, 3412-3442

HTT and THT cyclization

6

HTT (Head-to-Tail Terpene)

・Reproducible inbulk solvent
・ Mainly yieldingdecaline framework

THT (Tail-to-Head Terpene)・Lacking example in bulk
solvent (Man-made catalyst)
・Produce a diverse varietyof frameworks
Surgey V. et. al, Nat. Chem, 2012, 4, 915

7HTT cyclization(1)Stork-Eschenmoser`s hypothesis (1950`s)

W. S. Johnson, Acc. Chem. Res, 1968, 1, 1
G. Stork. et. al, J. Am. Chem. Soc, 1955, 77, 5068
A. Eschenmoser. et. al, ibid, 1955, 38, 1890

8

HTT cyclization(2)Biomimetic synthesis of steroids

William. S. Johnson. et. al, J. Am. Chem. Soc, 1977, 99, 8341Corey. E. J. et. al, J. Am. Chem. Soc, 1996, 118, 8765

9HTT cyclization(3)Enantioselective biomimetic cyclization
First example of enantioselective cyclization

Yamamoto. H. et. al, J. Am. Chem. Soc, 1999, 121, 4906
Yamamoto. H. et. al, J. Am. Chem. Soc, 2002, 124, 3647

Difficulty of THT cyclization(1)10

D. D. Syrdal. et.al, Tetrahedron. Lett, 1972, 24, 2455

Difficulty of THT cyclization(2)11Hirose. Y. et.al, Chem. Lett, 1972, 263

Yamamoto. H. et.al, J. Am. Chem. Soc, 1983, 105, 6154

What makes THT cyclization difficult?(1)12Norman. L. Allinger. et. al, J. Am. Chem. Soc, 1975, 97, 752

David W. Chem. Rev, 2006, 106, 3412-3442

What makes THT cyclization difficult?(2)In bulk solvent
Stabilization of cationicintermediate is absent
Surgey V. et. al, Nat. Chem, 2012, 4, 915
Rudolf. K. Allemann, et. al, Bioorganic & Medicinal Chemistry, 2017, ASAP

13

What makes THT cyclization difficult?(3)14Joseph. P. Noel. et. al, Science, 1997, 277, 1815

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1. Introduction

2. Today`s contents~tail-to-head terpene (THT)
cyclization in capsule catalyst~
3. Summary

16

Today`s topic
Konard Tiefenbacher

University of Basel Department of chemistry
ETH Zürich Department of Biosystems Science and Engineeringhttps://nanocat.chemie.unibas.ch/en/welcome/konrad/

Konard. Tiefenbacher. et. al, J. Am. Chem. Soc, 2017, ASAP

Supramolecular capsule17

・Octahedral capsule (6* Resorcinarene +8*H2O )・ Self-assembly by 60 H-bonds
intermolecular O-H・・・O
intramolecular O-H・・・O
intramolecular (with H2O) O-H・・・O{K. Tiefenbacher et. al, Nat. chem, 2015, 7, 197

Leonard. R. MacGillvray. et.al, Nature, 1997, 389, 469

Capsule stabilizing cationic guest

18

Cation-π interaction
stabilize cationic guest
in cavity

Shivanyuk. A .et.al, Proc. Natl. Acad. Sci, 2001, 98, 7662

Merits of using capsule catalyst

19

Potential of capsule catalyst for THT(1)20Capsule works as a brønsted acid

Estimated pKa: 5.5~6.0
Konard. Tiefenbacher. et. al, J. Am. Chem. Soc, 2013, 135, 16213

Potential of capsule catalyst for THT(2)21

Potential for activation of acyclic terpene by protonation
Konard. Tiefenbacher. et. al, J. Am. Chem. Soc, 2013, 135, 16213

Results of THT cyclization(1)K. Tiefenbacher et. al, Nat. chem, 2015, 7, 197

22

Results of THT cyclization(2)K. Tiefenbacher et. al, Nat. chem, 2015, 7, 197

23

Results of THT cyclization(3)K. Tiefenbacher et. al, Nat. chem, 2015, 7, 197

24

Reaction condition (Effect of acid)(1)25

Different cyclization yield depending on supplier of CDCl3

NMR spectrum of catalyst in CDCl3

NMR spectrum of catalyst in CDCl3(treat with Al2O3)

Broadening of OH and H2O is observedwith CDCl3 without stabilizer (Fast protonexchange)

Removal of DCl gives sharp peaksof OH and H2OTrace DCl causes protonation of capsule
Konard. Tiefenbacher. et. al, J. Am. Chem. Soc, 2017, ASAP

Reaction condition (Effect of acid)(2)26

Cyclization with different amount of DCl

0 mol% DCl

No conversion

・Removal of capsule (3 mol% DCl)
No conversion
Combination of capsule andacid is necessary for cyclization
Konard. Tiefenbacher. et. al, J. Am. Chem. Soc, 2017, ASAP

Reaction inside the capsule

27

Reaction inside the capsule

Reaction inside the capsuleis necessary for cyclization
Konard. Tiefenbacher. et. al, J. Am. Chem. Soc, 2017, ASAP

Remarkable point of capsule catalyst

28

E.J. Leὰo Lana. et. al, J. Mol. Catal, 2006, 259, 99

Tristan. H. Lambert, et. al, Org. Lett, 2009, 11, 1381

Mechanism analysis (Eucalyptol)

29

1. Protonation steprCS= recombinant 1,8-cineol synthase

Similar protonation
to cyclase enzyme

Rodney. Croteau, et. al, J. Am. Chem. Soc, 2002, 124, 8546
Konard. Tiefenbacher. et. al, J. Am. Chem. Soc, 2017, ASAP

Mechanism analysis (Isotope-labeling)30

Konard. Tiefenbacher. et. al, J. Am. Chem. Soc, 2017, ASAP

Results of THT cyclization (other LGs)(1)31

・H2O (leaving group) causes quenching of cationic intermediate

Other leaving group (weak nucleophilicity) shows other selectivity?

Konard. Tiefenbacher. et. al, J. Am. Chem. Soc, 2017, ASAP

Results of THT cyclization (other LGs)(2)32

Konard. Tiefenbacher. et. al, J. Am. Chem. Soc, 2017, ASAP

Cyclization in SN1 or SN2 type manner(1)33

Konard. Tiefenbacher. et. al, J. Am. Chem. Soc, 2017, ASAP

Cyclization in SN1 or SN2 type manner(2)34Proposed mechanism of different selectivity

Konard. Tiefenbacher. et. al, J. Am. Chem. Soc, 2017, ASAP

Results of THT cyclization (other LGs)(3)35

Konard. Tiefenbacher. et. al, J. Am. Chem. Soc, 2017, ASAP

Results of THT cyclization (other LGs)(4)36

Konard. Tiefenbacher. et. al, J. Am. Chem. Soc, 2017, ASAP

Affinity and reaction selectivity(1)37Encapsulation ratio of substrates with different LGs (Affinity)

Lower affinity
Lower selectivity(SN2 (+ SN1))

Higher affinity
Higher selectivity(SN1)
Konard. Tiefenbacher. et. al, J. Am. Chem. Soc, 2017, ASAP

Affinity and reaction selectivity(2)38Kinetic investigations(1)1st order on capsuleⅠ39

1st order consumption of SM

𝑣 =𝑘𝑜𝑏𝑠 [GOAc][Ⅰ]Konard. Tiefenbacher. et. al, J. Am. Chem. Soc, 2017, ASAP

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Kinetic investigations(2)Eyring equation𝒌 ∆𝑯≠ 𝟏∆𝑺≠𝒌𝑩
ln =++ln𝑻𝑹 𝑻𝑹𝒉∆𝐻≠ = −(−13568) × 8.31/4.2 ≈27.0 (kcal・mol−1 )∆𝑆 ≠ = (29.3 − 23.76) × 8.31/4.2 ≈ 11.0(cal・mol−1 )𝒌※ln 𝒉𝑩=23.76∆𝑆 ≠ > 0 ⇒ Disordered state = Rate determining step

Cleavage of LG=Rate determining step
Konard. Tiefenbacher. et. al, J. Am. Chem. Soc, 2017, ASAP

Kinetic investigations(3)41Konard. Tiefenbacher. et. al, J. Am. Chem. Soc, 2017, ASAP

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Kinetic investigations(4)Proposed mechanism for cyclization of GOAc

𝑘2 [𝐒@𝐈𝐇 + ]=(𝑘−2 +𝑘3 ) 𝐒𝐇 + @𝐈
[𝐒@𝐈𝐇 + ] [𝐒@𝐈𝐇 + ]𝐾1 =≈+𝐈𝐇 [𝐒]𝐈 [𝐒]𝑣 = 𝑘3 [𝐒𝐇 + @𝐈]
𝐾 𝑘 𝑘= 1 2 3 [ 𝐈 [𝐒]
𝑘−2 +𝑘3≒ Steady-state

Konard. Tiefenbacher. et. al, J. Am. Chem. Soc, 2017, ASAP

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1. Introduction

2. Today`s contents~tail-to-head terpene (THT)
cyclization in capsule catalyst~
3. Summary

Summary
・ Self assembly capsule can catalyze THT cyclization
・ Selectivity of the reaction is changed by44