J. Am. Chem. Soc. 2017, 139, 4282Presented by: Chuan Pin Chen

CEM 852 PresentationFebruary 9, 2019

Introduction• Palhinine-type alkaloids, as members of the

Lycopodium family

Figure 1. Lycopodiaceae Plant and Known palhinine-type Lycopodium Alkaloids.

2

NR

Skeleton of Palhinine-typeLycopodium Alkaloids

Palhinine D2013 by Yu et al.Fitoterapia 2013, 91,

74

N

O

HO

HHOHN

O

HO

HH

OMe

Palhinine A2010 by Long et al.Org. Lett.

2010, 12,

3922

+

Although no activity was observed in preliminary studies, scarcity in nature precludes extensive biological evaluations of these alkaloids.

https://en.wikipedia.org/wiki/Lycopodiaceae

Challenge

3Figure 2. Designed Strategies for Assembly of the Nine-Membered Azonane Ring Embedded in the Framework of Palhinine-type Alkaloids

NR

N

O

N N

N-substitution ring-closing metathesis This work[3+2] cycloadditionInevitably twisted and transannular strain

Retrosynthesis

4

tert-Butyldimethylsilyl

(TBS) Benzyl (Bn) Oxime

Si R R

NOH

N

O

HO

HH

OMe

N

O

HO

HHOH N

O

HO

HH

ROR'

OR' N

O

H

ROR'

OR'

O

N

O

H

ROR'

OR'

HO

H

O

HR'O OR'

NO

O

HR'O OR'

HNHOH

HOTBSO

OBnTBSO

OBnO

or

palhinine A palhinine D A B

C D E F-12

chemo- andstereoselective

reduction3

reductive cleavageof N-O bond key step

regio-and stereoselective

Nitrone-olefin 3+2 cycloaddition1,3 dipolar cycloaddition

3

3

Wittigreaction

oxime formationand reduction

G-4

Synthesis of 4

5

O

Op-TsOH (1.0 equiv)

98% yield

OBr

SH

84% yield

PhSO

52% yield

OS

BnO

m-CPBA (1.05 equiv)

−78 °C to 25 °C

75% yield

NBS (1.2 equiv)CH2Cl2

NaH (1.1 equiv)

THF

NaH (1.1 equiv)I(CH2)3OBn (1.2 equiv)

DMF

0 °C, 1 h

CH2Cl2

(1.1 equiv)

reflux, 4h0 °C, 30 min

0 °C to 25 °C, 1 h

overnight

Ph

25 °C, 1.5 h

4

BnO

1 2 3

p-Toluenesulfonic acid

(p-TsOH) N-Bromosuccinimide

(NBS) Benzyl

Bn meta-Chloroperoxybenzoic

acid (m-CPBA)

SO

O OH

OO NBr

O

OOHCl

Org. Lett. 2012, 14, 3696.

I O

I(CH2)3OBn

HO OH DMF

NaH (0.1 equiv)

Br

(0.1 equiv)

CH2Cl2

PPh3 (1.05 equiv)

imidazole (1.26 equiv)rt, 24 h

rt, 24 h

HO O

Org. Lett., 2008, 10,

5497

I2 (1.05 equiv)

Synthesis of 8

6

Benzyl (Bn)

Trimethylsilyl (TMS)

4-methylmorpholine 4-oxide (NMO)

tert-Butyldimethylsilyl

(TBS) imidazole

Si

N+

O

O

Si

NHN

O

BnO

4

TMS

TiCl4 (1.2 equiv)

CH2Cl2−78 °C, 1h

82% yield

(1.5 equiv)O

BnO

(±)−5(≈

1:1 dr)

(0.1 equiv)

NMO (5.0 equiv)

K2OsO4·2H2O

THF/H2O 83% yield

25 °C, 5h25 °C, 1h

1 h

NaIO4 (5.0 equiv)

O

BnO

O(±)−6

IOTBS

CrCl2 (3.0 equiv)

(2.0 equiv)

DMFNiCl2

(0.02 equiv)

0 °C to rt, 15 h

76% yield

O

BnO

(±)−7

TBSO

(≈

1:1 dr) (≈

1:1:1:1 dr)

TBSCl (1.5 equiv)imidazole (2.0 equiv)

DMF

0 °C to rt, 1 dOH

O

BnO

(±)−8

TBSOOTBS

84% yield

(≈

1:1:1:1 dr)

Org. Lett. 2012, 14, 3696.

tert-butyldimethylsilyl 2-iodoallyl ether

7

OHCH3CN

(CH3)3SiCl (1.2 equiv)

NaI (1.2 equiv)H2O (1.0 equiv)

[(CH3)3Si]2O NaCl

rt, 1h

57% yield

+ +

Synthesis 1988, 366

OHI

OHI

OTBSI

Cl Si

https://www.synarchive.com/protecting-group/Alcohol_tert-Butyldimethylsilyl_ether

Base

Solvent

Synthesis of 12

8

O

BnO

(±)−8

TBSOOTBS

TMSOTf (2.3 equiv)NEt3

(3.5 equiv)

CH2Cl2

0 °C, 1 h

OTMS

BnO

TBSOOTBS

(±)−9

Pd(OAc)2

CH3CN

25 °C, 10 h

O

BnO

TBSOOTBS

(±)−10

TMSCl (6.0 equiv)NEt3

(6.0 equiv)

DMF

90 °C, 4 d

(≈

1:1:1:1 dr) (≈

1:1:1:1 dr) (≈

1:1:1:1 dr)

OTMS

BnO

TBSOOTBS

(±)−11

(≈

1:1 dr)

12

(≈

1:1 dr)

180 °C, 2 d

p-xylene

65% yield(2 steps)

68% yield(2 steps)

HOTBSO

OBnTBSO OTMS

BnO

TBSOOTBS

(±)−11 12

HOTBSO

OBnTBSO

Benzyl (Bn)

tert-Butyldimethylsilyl

(TBS)

Trimethylsilyl trifluoromethanesulfonate

(TMSOTf)

Si

CF3S

O

OOSi

Palladium(II) acetate (Pd(OAc)2)

Trimethylsilyl (TMS) p-xylene

Pd2+O

O-

Si

Org. Lett. 2012, 14, 3696.

Synthesis of 16

9

tert-Butyldimethylsilyl

(TBS) Benzyl (Bn)

Pyridinium p-toluenesulfonate (PPTS)

Dess–Martin periodinane

(DMP)

Si NH+

SO

O O-

IO

O

O

OO

O

O

O

J. Am. Chem. Soc. 2017, 139, 4282

H2SiF6 (30% aq. 6.0 equiv)

CH3CN

0 °C to rt

95% yield12

(≈

1:1 dr)

HOTBSO

OBnTBSO

overnight 13

(≈

1:1 dr)

HOHO

OBnHO (CH2OH)2 (20.0 equiv)

PPTS (0.1 equiv)

rt to reflux, 5 h

63% yield

14

(≈

1:1 dr)

HHO

OBnHO

OO

Dess-Martinperiodonane(2.2equiv)

NaHCO3 (5.0 equiv)H2O (2.2 equiv)

CH2Cl20 °C to rt, 30 min

15

(≈

1:1 dr)

HO

OBnO

OO

H Pd(OH)2/C (20%)

MeOH

rt to 50 °C, 45 min

quant.

H2

MgSO4 (3.2 equiv)

H

O

OO

O

HO HO

OHO

OO

H

16a (minor) 16b (major)

Synthesis of 20

10

17

(≈

1:1 dr)

H

OHHO

OOH

O

OO

O

HO HO

OHO

OO

H

16a (minor) 16b (major)

n-BuLi (2.5 equiv)

[MePPh3]+Br

(2.2 equiv)

0 °C, 30 min

then −78 °C to rt, 30 min

64% yield

THF

Dess-Martinperiodonane(1.2equiv)

NaHCO3 (2.4 equiv)CH2Cl2

rt, 30 min81% yield

18

(≈

1:1 dr)

H

OHO

OO

19

(Z/E = 1:1)

H

NHO

OO

NaOAc (4.0 equiv)

NH2OH·HCl (2.0 equiv)

EtOH/H2O

(v/v = 5:2)

rt, 30 min

99% yield

NaBH3CN (2.5 equiv)

CF3CO2H (5.0 equiv)EtOH

−40 °C, 30 min

90% yield

OH

20

H

HN

HO

OO

OH

Triphenylphosphine (PPh3)

Dess–Martin periodinane

(DMP)

Sodium acetate

(NaOAc)

P

IO

O

O

OO

O

O

O

Na+O

O-

J. Am. Chem. Soc. 2017, 139, 4282

Synthesis of 22 Building Block

11

20

H

HN

O

OO

OH HCHO (aq.) (100 equiv)

CH2Cl2rt, 12 h

21

H

NO

OO

O

22

H

O

OOo-C6H4Cl2

150 °C, 1.5 h

microwave(300 W)

N

O

H

N

O

HO

HH

OMe

palhinine Afrom 22, 23...to 26

palhinine Dfrom 22, 27 to 31

N

O

HO

HHOH

21

H

NO

OO

O

22

H

O

OO

N

O

Hor

several and differentpathways

Nitrone-olefin 3+2 cycloaddition1,3 dipolar cycloaddition

J. Am. Chem. Soc. 2017, 139, 4282

Palhinine A (the Blue Pathway)

12

Dess–Martin periodinane

(DMP)

Lithium trisiamylborohydride

(L-Selectride)

IO

O

O

OO

O

O

O

BHi-Pr

H3C

i-Pr

CH3CH3i-Pr

Li

J. Am. Chem. Soc. 2017, 139, 4282

22

H

O

OO

N

O

H

rt, 12 h

23

H

O

OO

N

O

H

Me

I

Zn (10.0 equiv)

AcOH/THF/H2O

(v/v/v = 2:1:1)

81% yield

30 °C, 8 h

24

H

O

OO

NMe

HO

Dess-Martinperiodonane(2.0 equiv)

NaHCO3 (4.0 equiv)

CH2Cl2rt, 30 min96% yield

25

H

O

OO

NMe

O

L-selectride (5.0 equiv)

−78 °C to 0 °C, 2h

THF

92% yield

26

H

O

OO

NMe

HO

2N HCl (10.0 equiv)

80 °C, 2h

89% yield

MeI (102.0 equiv)

THF

MeOH N

O

HO

HH

OMe

palhinine A

Chemo- and Stereoselective Reduction

13

Lithium trisiamylborohydride (L-Selectride)

BHi-Pr

H3C

i-Pr

CH3CH3i-Pr

Li

25

H

O

OO

NMe

O

L-selectride (5.0 equiv)

−78 °C to 0 °C, 2h

THF

92% yield

26

H

O

OO

NMe

HOO

O

HH

HH

N

Me

O

HH

HHO 3

53

5

J. Am. Chem. Soc. 2017, 139, 4282

14

Synthesis of 31 (the Red Pathway)

Dess–Martin periodinane

(DMP)

Lithium trisiamylborohydride

(L-Selectride)

p-Toluenesulfonic acid

(p-TsOH)

IO

O

O

OO

O

O

O

BHi-Pr

H3C

i-Pr

CH3CH3i-Pr

Li

SO

O OH

22

H

O

OO

N

O

HBr

(184.9 equiv)

acetonert

overnight

27

H

O

OO

N

O

H

BrZn (10.0 equiv)

AcOH/THF/H2O

(v/v/v = 2:1:1)

88% yield

30 °C, 8 h

28

H

O

OO

N

HO

Dess-Martinperiodonane(2.0 equiv)

NaHCO3 (4.0 equiv)

CH2Cl2rt, 30 min

99% yield

29

H

O

OO

N

O

L-selectride (5.0 equiv) −

78 °C to 0 °CTHF

2 h

75% yield30

H

O

OO

N

HO

p-TsOH (2.0 equiv)

60 °C

acetone/H2O

(v/v = 10:1)

31

H

O

O

N

HO

4 h

95% yield

J. Am. Chem. Soc. 2017, 139, 4282

Palhinine D (the Red Pathway)

15

31

H

O

O

N

HO

palhinine D

N

O

HO

HHOH

RuCl3 (2.0 equiv)

CH3CN/H2O

(v:v = 5:1)

64% yield

90 °C, 10 h

H

O

O

N

HON

O

HO

HHOH

J. Am. Chem. Soc. 2017, 139, 4282

Conclusion• First report on total synthesis of palhinines A and D

16

Thank You For Listening

17https://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&ved=2ahUKEwiw6sGdk6vgAhUOUt8KHYC6DLkQjxx6BAgBEAI&url=https%3A%2F%2Fdepositphotos.com%2F41441791%2Fstock-illustration-cartoon-chemist.html&psig=AOvVaw21koLy1qu0x5EKHaDb_W1s&ust=1549677893534548

~~~• ~~~

18

Details About Deprotection of N-allylamines

19Chem. Commun. 2005, 4086

To promote C=C migrations in waterChem. Eur. J. 2007, 13, 6590

Tetrahedron Lett. 2003, 44, 8693

Palhinine Related Products

20

22

H

O

OO

N

O

H

Mo(CO)6 (5.0 equiv)

CH3CN/H2O

(v/v = 9:1)

85 °C75% yield

3-epi-palhinine D

N

O

HO

HHOH

24

H

O

OO

NMe

HO N

O

HO

HH

OMe

3-epi-palhinine A

p-TsOH (2.0 equiv)

acetone/H2O

(v/v = 10:1)

98% yield

p-Toluenesulfonic acid (p-TsOH)

SO

O OH