Site-selective acylation of complex moleculesby 4-pyrrolidinopyridine catalyst
Literature seminar
M1 Yu Irie
2022/8/25 (Thu)Table of contents
1. Introduction
2. Site-selective acylation of monosaccharides
3. Site-selective acylation of complex molecules
4. Application to total syntheses
5. Summary2

Table of contents
1. Introduction
2. Site-selective acylation of monosaccharides
3. Site-selective acylation of complex molecules
4. Application to total syntheses
5. Summary3

Modification of carbohydrates: Challenges
The key issue: Site-selectivity(several OH groups in onemolecule)
Protecting-group strategies✓ Well developed✗ Requires multi-step syntheticsequences✗ May cause deactivation of theunprotected hydroxyl groups✓ Site-selective modification withminimally protected substrates

V. Dimakos, M. S. Taylor, Chem. Rev. 2018, 118, 11457–11517. 4

Modification of carbohydrates: Precedents
Sulfation
Formation of cyclic
adducts from diolmoieties

Phosphorylation

Silylation

Glycosylation

Acylation(Esterification)
Alkylation…and so on

V. Dimakos, M. S. Taylor, Chem. Rev. 2018, 118, 11457–11517. 5

Modification of carbohydrates: Precedents
Sulfation
Formation of cyclicadducts from diolmoieties

Phosphorylation

Silylation

Glycosylation

Acylation(Esterification)
Alkylation…and so on

V. Dimakos, M. S. Taylor, Chem. Rev. 2018, 118, 11457–11517. 6

Examples of selective acylation of OH groups• Carbodiimide / Uronium Salt-Mediated Coupling
OO

O

O

CO2H

BnO2C
OO
HOO

O

O

O

O
OO

DCC, DMAP
CH2Cl20 oC to rt

OO

O

OH

OO

O

OH

BnO2C
O
75% yield

S. Jana, S. Mondal, S. S. Kulkarni, Org. Lett. 2017, 19, 1784–1787.

• Complexation of OH groups
OPhB
PhOMeMeHOOHOOHN
H2BzCl(10 mol%)

iPr2NEt
MeCN, 23 oC

OMeMeHOOOPhBO

PhOMe
MeO
HOBzO
OH
92% yield+ iPr2NHEt

D. Lee, M. S. Taylor, J. Am. Chem. Soc. 2011, 133, 3724–3727.

• Organocatalyzed acylations (using DMAP catalyst)
7…and so on

Examples of selective acylation of OH groups• Carbodiimide- / Uronium Salt-Mediated Coupling
OO

O

O

CO2H

BnO2C
OO
HOO

O

O

OOOO

DCC, DMAP
CH2Cl20 oC to rt

OO

OOHOOOOH

BnO2CO
75% yield

S. Jana, S. Mondal, S. S. Kulkarni, Org. Lett. 2017, 19, 1784–1787.

• Complexation of OH groupsOPhB
Ph
OMe
MeHOO
HOOH

N
H2
BzCl(10 mol%)

iPr2NEt
MeCN, 23 oC

OMe
MeHOO
OPhBO

Ph

OMeMeO
HOBzO
OH
92% yield+ iPr2NHEt

D. Lee, M. S. Taylor, J. Am. Chem. Soc. 2011, 133, 3724–3727.

• Organocatalyzed acylations (using DMAP catalyst)
8…and so onSite-selective acylation using DMAP

Chemoselective acylation of a secondary hydroxyl group in thepresence of a primary hydroxyl group= Difficult because of the steric effects
OHHOHOOAc
OOHAcCl, DMAPO(CH2)7CH3

DCM, pyridine

HOHOO

O(CH2)7CH3

OH

85% site-selectivity
73% yield

E. Kattnig, M. Albert, Org. Lett. 2004, 6, 945–948.

9

Site-selective acylation of C(4)-OH• octyl α-D-glucopyranoside
OHHOHO

4O

53AcO
HO

K2CO3, CHCl323 oC, 1 h12OH

0.7 eq. Ac2O
0.05 eq. DMAP

6OH OC H

8 17O
OH OC H

8 17Octyl α-D-glucopyranoside
2 mmol/L

61% site-selectivity
98% conversion

T. Kurahashi, T. Mizutani, J. Yoshida, J. Chem. Soc. Perkin 1 1999, 465–474.

• octyl β-D-glucopyranoside
NOH
HOHOO
OH

OH

Ac2O
pentapeptide catalyst
OC8H17AcO
NaOAc
HOtoluene/CH2Cl2, 0 oC

OO

OC8H17

BocHN

NHOH

58% site-selectivity
100% conversion

NNBn
HN

O
NMe

MeO
N
HcHx

HNO

O
OMe
Ph

pentapeptide catalyst

K. S. Griswold, S. J. Miller, Tetrahedron 2003, 59, 8869–8875.

✗ Low selectivities

10Table of contents
1. Introduction
2. Site-selective acylation of monosaccharides
3. Site-selective acylation of complex molecules
4. Application to total syntheses
5. Summary

11

Catalytic site-selective single-step acylation✓ A newly developed catalyst ✓ High selectivity and high yield✓ An extremely short method
T. Kawabata, et al. J. Am. Chem. Soc. 2007, 129, 12890–12895. 12

Catalyst design: PPy as an active site
・ 4-pyrrolidinopyridine (PPy): Powerful catalysts for acylationof alcohols
Relative effects of the cataysts
PhPhOH

MeR

N
1.0
PPyN

R
NMe2

N

NMe2

NMe20.9

PhPhAc2O0.63

OAc

MeHMeN0.5

MeN

NMe20.3

DMAPE. F. V. Scriven, Chem. Soc. Rev. 1983, 12, 129–161.

• Reactive intermediate generated from PPy: acylpyridiniumions (such as in the reaction using DMAP).
G. Höfle, W. Steglich, H. Vorbrüggen, Angew. Chem. Int. Ed. Engl. 1978, 17, 569–583.
13

Proposed transition state••C(6)-OH: Preferentially form an H-bond with an acceptor (e.g. anamide carbonyl group) of the catalyst
C(2)-OH, C(3)-OH: Additional interactions to fix the conformationof carbohydrate→ Selective acylation at C(4)-OHT. Kawabata, et al. J. Am. Chem. Soc. 2007, 129, 12890–12895. 14

Catalyst design: Functional side chains
Indole substructure oftryptophan:
Suitable for H-bonding and CH-πinteraction with carbohydrates
Octyl esters:
Enhance the solubility of thecatalysts in nonpolar solvents
Catalysts 3 and 4:
Tyrosine instead oftryptophan

T. Kawabata, et al. J. Am. Chem. Soc. 2007, 129, 12890–12895. 15

Comparison of catalysts’ activity

The highest selectivity for 4-O-acylation was observed byusing catalyst 1.
T. Kawabata, et al. J. Am. Chem. Soc. 2007, 129, 12890–12895. 16

Solvent effects

H-bonding > CH-π interaction
T. Kawabata, et al. J. Am. Chem. Soc. 2007, 129, 12890–12895. 17

Temperature effects and catalyst loading✓ Low temperature and high catalyst loading

T. Kawabata, et al. J. Am. Chem. Soc. 2007, 129, 12890–12895. 18

Mechanistic studies: Use of 6-OMe derivative
Confirmation of the effects of H-bonding between C(6)-OH
and the catalyst to the regioselectivity→ Use 6-OMe derivative

Ø H-bonding between C(6)-OH and the catalyst is critical forthe regioselective reaction.

T. Kawabata, et al. J. Am. Chem. Soc. 2007, 129, 12890–12895. 19

Mechanistic studies: Competitive acylation

Ø Site-selective acylation proceeds in an accelerative
manner.

T. Kawabata, et al. J. Am. Chem. Soc. 2007, 129, 12890–12895. 20

Effects of catalyst structures

Indole substructure ofcatalyst 1:→ N-methylindole (entry 2)→ 2-naphthyl (entry 3)

Two amide carbonyl groups at
C(2’) and C(5’) are essential
for the selective acylation atC(4)-OH.

T. Kawabata, et al. J. Am. Chem. Soc. 2007, 129, 12890–12895. 21

C2-symmetric structure of the catalyst

With C2-symmetric structure,
approach of the carbohydrate
substrate from…
the face of the C(2’) side chain= the face of the C(5’) side chain
The low selectivity in entry 4 iscaused by the nonselective
acylation of carbohydrates
which approaches from the C(5’)
side chain.

T. Kawabata, et al. J. Am. Chem. Soc. 2007, 129, 12890–12895. 22

Proposed transition state model
1) The primary hydroxyl group atC(6) (most reactive) forms H-bondwith an amide carbonyl (strongestH-bond acceptor).

2) Indole NH locatednear C(3)-OH of thecarbohydrate forms Hbond.

3) Substrate is fixed at thisconformation via multiple H-bonding,and the acylation proceeds in an
accelerative manner at C(4)-OH.
T. Kawabata, et al. J. Am. Chem. Soc. 2007, 129, 12890–12895. 23

Substrate scopeO
C8H17O

H(S) N (S)

H
N (S)

(S)
N

O

O
OC8H17O
NH

HN

HO

HO(a)

O
R

HO

XC8H17(b)O

O
R

OC8H17HO

HO(c)

HOO

O

O

O

HO(RCO)2O
collidine, CHCl3

HOO

HO
R

1 (10 mol%)

O

HOO

NHOR

SC8H17HOHOXC8H17O

HOHOO

O
HO

OC8H17R = iPr : >99% regioselective
R = iPr : 97% regioselective
R = iPr : 54% regioselective
oo
98% yield (-50 C, 38 h)
92% yield (-60 C, 72 h)
75% yield (20 oC, 12 h)a
R = CH3 : 96% regioselective
R = CH3 : 95% regioselective
96% yield (-20 oC, 24 h)
99% yield (-60 oC, 41 h)
O(d)

OR

HO(e)

HOO

OH

O

OC8H17ROHOO

HO

OC8H17HO

R = iPr : 85% regioselective
61% yield (-50 oC, 120 h)
a1 mol% of 1 was used.

R = iPr : 91% regioselective
46% yield (20 oC, 12 h)T. Kawabata, et al. J. Am. Chem. Soc. 2007, 129, 12890–12895. 24

Explanation of the substrate scope results(c)

ORHOHOOOαHO

OC8H17R = iPr : 54% regioselective
75% yield (20 oC, 12 h)

Unfavorable interaction
between an α-octyloxy
substituent and theacylpyridinium ion

O(e)

ROHOO

HO

OC8H17HO

R = iPr : 91% regioselective
46% yield (20 oC, 12 h)

Axial hydroxy group atC(4)Ø C(6)-OH selective
reaction

T. Kawabata, et al. J. Am. Chem. Soc. 2007, 129, 12890–12895. 25

Short summaryü Organocatalytic site-selective acylation of monosaccharides
ü Up to >99% selectivity, 98% yieldü Reduction of synthetic steps toward carbohydrates
Ø Application to various molecules
T. Kawabata, et al. J. Am. Chem. Soc. 2007, 129, 12890–12895. 26

Table of contents
1. Introduction
2. Site-selective acylation of monosaccharides
3. Site-selective acylation of complex molecules
4. Application to total syntheses
5. Summary

27

Expansion of substrate scopeü Various acid anhydrides (derived from α-amino acids,cinnamic acid, and gallic acid)ü Disaccharides with seven free hydroxy groups
Ø High functional group tolerance was confirmed.
T. Kawabata, et al. J. Org. Chem. 2009, 74, 8802–8805. 28

Site-selective acylation of digitoxindigitoxinü Various acid anhydrides (R = Me, i-Pr, Ph and so on)ü High C(4’’’) selectivity
K. Yoshida, T. Furuta, T. Kawabata, Tetrahedron Lett. 2010, 51, 4830–4832. 29

Site-selective acylation of Lanatoside CO
C8H17O

OH
HO
3’’’’

O

6’’’’

OH

4’’’’

OH
MeMeHOMeMeO

OAcOOOO
HOMeOHOOHOH(S)NOOHN (S)OOC8H17ONH

HN

catalyst (10 mol%)(i-PrCO)2O (1.1 equiv.) HO

3’’’’

HH(S) N (S)collidine (1.5 equiv.)
CHCl3/THF = 9:1-60 oC, 96 h

N

OAc
6’’’’
4’’’’

HOH

1OHO
C8H17O

H(R) N (S)

(S)
N

O

H
N (R)

O
OC8H17O
NH

HN
N
1aentry

catalyst

monoacylate

regioselectivity (6’’’’-O:4’’’’-O:3’’’’-O:others)

1

DMAP

85%

0:3:97:0

C8H17O

2

175%

0:86:14:0

HN

3

1a77%

0:73:27:0

4

1b65%

7:13:80:0

5ent-162%

25:13:62:06587%

0:90:10:0O

H(S) N (R)NO

H(R) N (S)O
OC8H17O
NHN1bOO

H(S) N (S)

(S)
NO

H
N (S)OOO
NHHNN
5ü High C(4’’’’) selectivity with catalyst 5
ü Confirmed significance of the chirality at the pyrrolidine ring
Y. Ueda, K. Mishiro, K. Yoshida, T. Furuta, T. Kawabata, J. Org. Chem. 2012, 77, 7850–7857. 30

Site-selective acylation of 10-Deacetylbaccatin IIIO

H
N

C8H17ONOOHN

OC8H17ONHHNOHONOHORCOOOH(10 mol%)

HOH OBz OAc

HO(RCO)2O (1.1 equiv.)
collidine (1.5 equiv.)
CHCl3/THF (10/1)

OHOH
OH OBz OAc

Entry

RTemp.

Time (h)Monoacylate (%)

Site-selectivity (%)

1aiPr-20 oC

4895

62

2

iPr-40 oC

48

8995

3

Me-20 oC

1299

90

4

C11H23-20 oC

1207595

5C 6H 5-20 oC

16884

62

OaDMAP was used as a catalyst.

ü Substrate without saccharide moiety
T. Kawabata, Chem. Pharm. Bull. 2016, 64, 907–912. 31

Short summaryOHOHOHOOROX
ROROROO

HOHO

Site-selective acylation

Y

O

O(RCO)2O

X
RO
RO
ROOH
O

OH
ROMeO

HNY

HOO
OROAcOOHH
OH OBz OAc

MeO

NH
NO

OH

HOO

HN

AcO

HOH
NNO

O

HOO

OCOR

HOHOO

RCOO

O
HOO

OH

H
OH OBz OAcOü Site-selective acylation of complex molecules was achievedby using a similar PPy catalyst.
Ø Application to total synthesis

32

Table of contents
1. Introduction
2. Site-selective acylation of monosaccharides
3. Site-selective acylation of complex molecules
4. Application to total syntheses
5. Summary33

Total synthesis of Ellagitannins• Ellagitannins: A large class of plant polyphenols with a wide
variety of biological activities• Strictinin (1) and tellimagrandin II (2): anti HSV, antitumor,
anti-influenza virus, antiallergic activities

T. Kawabata, et al. Angew. Chem. Int. Ed. Engl. 2015, 54, 6177–6180. 34

Retrosynthetic analysis• Sequential and site-selective introduction of galloyl groups(G1~G3)
T. Kawabata, et al. Angew. Chem. Int. Ed. Engl. 2015, 54, 6177–6180. 35

Stereoselective glycosidation• Highly stereoselective glycosidation under Mitsunobu
conditions

T. Kawabata, et al. Angew. Chem. Int. Ed. Engl. 2015, 54, 6177–6180. 36

C(4)-OH selective acylation• The chirality at the pyrrolidine ring is important.
T. Kawabata, et al. Angew. Chem. Int. Ed. Engl. 2015, 54, 6177–6180. 37

Site-selective acylation of C(6)-OH• Site-selective introduction of a galloylgroup to C(6)-OH of 9 (C(4)-OHacylated product)• 14 is generated from anhydride 7 andcatalyst 11
Ø One-pot reaction

T. Kawabata, et al. Angew. Chem. Int. Ed. Engl. 2015, 54, 6177–6180. 38

One-pot site-selective diacylation

51% yield

1) Regioselective C(4)-Ogalloylation
2) Substrate-controlled C(6)-Ogalloylation

T. Kawabata, et al. Angew. Chem. Int. Ed. Engl. 2015, 54, 6177–6180. 39

Final steps of the total synthesis

Ø Total syntheses achieved without using protecting groups
for the glucose substrate
T. Kawabata, et al. Angew. Chem. Int. Ed. Engl. 2015, 54, 6177–6180. 40

Total Syntheses of Punicafolin and Macaranganinü Sequential site-selective introduction of the galloyl groups intounprotected D-glucose
ü Stereodivergent construction of the 3,6-HHDP bridge byoxidative phenol coupling
H. Shibayama, Y. Ueda, T. Tanaka, T. Kawabata, J. Am. Chem. Soc. 2021, 143, 1428–1434. 41

Site-selective acylation by PPy catalyst

ü Key step: (2)-OH selective acylation
H. Shibayama, Y. Ueda, T. Tanaka, T. Kawabata, J. Am. Chem. Soc. 2021, 143, 1428–1434. 42

Catalyst screening for the C(2)-OH acylation

ü A newly developed catalyst(C5) with a 3-benzothiophenylgroup instead of the 3-indolyl
group of C2
H. Shibayama, Y. Ueda, T. Tanaka, T. Kawabata, J. Am. Chem. Soc. 2021, 143, 1428–1434. 43

Sequential introduction of galloyl groups• 12 was synthesized through sequential, site-selective reactions.
• Condensation of 12 with 8’ gave an intermediate 15.
H. Shibayama, Y. Ueda, T. Tanaka, T. Kawabata, J. Am. Chem. Soc. 2021, 143, 1428–1434. 44

Construction of the 3,6-HHDP bridge• 3,6-HHDP bridge: A less stable axial-rich conformer of thepyranose ring (3 with 1C4 conformation) is required for theformation. = difficult to synthesizeH. Shibayama, Y. Ueda, T. Tanaka, T. Kawabata, J. Am. Chem. Soc. 2021, 143, 1428–1434. 45

Feasibility of using less stable intermediate• Conformational analysis of glucose (β-Glc) and theperbenzoylated derivative (β-PBG, a model for 3 (intermediate))• Stronger anomeric effect was suggested for β-PBG.
Ø Axial-rich conformations of 3 can exist to some extent via thering-flip process of the stable 4C1 conformer.

H. Shibayama, Y. Ueda, T. Tanaka, T. Kawabata, J. Am. Chem. Soc. 2021, 143, 1428–1434. 46

Final steps of the syntheses

ü Construction of HHDP
group: Oxidative phenol
coupling using chiral amine
catalyst
H. Shibayama, Y. Ueda, T. Tanaka, T. Kawabata, J. Am. Chem. Soc. 2021, 143, 1428–1434. 47

Short summary
OH
HOHO

OG
O
OH OH Site-selective sequential functionalizationO
C8H17O

H
NH
N

N
O

GO
HOO

OGOH

O
OC8H17oxidative
phenol coupling

O
X

X
N

Strictinin / tellimagrandin IIOG
GO
GO

oxidative
phenol coupling

OOG

Punicafolin / Macaranganin

OGü No protective groups used for glucose
ü Extremely short-step total syntheses
48

Table of contents
1. Introduction
2. Site-selective acylation of monosaccharides
3. Site-selective acylation of complex molecules
4. Application to total syntheses
5. Summary

49

Site-selective acylation of complex molecules
Site-selective acylation(R2CO)2OO
R1 OH・monosaccharides
・disaccharides

・other complex molecules

R 3O

HNH
N

NOOO
OR3

O

R1O

R2

NHHNN

✓ A newly developed PPy catalyst ✓ High site-selectivity✓ Minimally protected monosaccharides and complex molecules✓ Key steps of total synthesesØ This catalyst can also be used for challenging kinetic resolution(an example for rotaxanes was reported recently: Nat. Commun.
2021, 12, 404.).

50