Zaragozic Acids:

Zaragozic Acids:

Synthesis of Core, Side Chains and Total Synthesis of the Zaragozic Acid

A and C

Literature Meeting

Presented by Kimberly-Ann Laberge

April 17, 2007

Zaragozic Acids

-Characterized by a 4,6,7-trihydroxy-2,8-dioxabicyclo[3,2,1]octane-3,4,5-tricarboxylic acid core with an array of six stereogenic centers including contiguous quaterny ones, with various C1 alkyl and the C6 O-acyl side chains.

-Zaragozic Acid A was extracted from an unidentified sterile fungal culture, Sporormiella intermedia, and Zaragozic Acid B and C from a fungal strain, Leptodontium elatius.

-Class of Natural Products that have been shown to be potent inhibitor of both squalene synthase, an enzyme found in the cholestrol biosynthetic pathway, and farnesyl-protein transferase(FPTase), a potential target enzyme in the treatment of cancer.

OO

OHR1O

R2HO2CHO2C

OHCO2H

6 7

5 1

3

Zaragozic Acid Sooty Blotch = Leptodontium elastius

O OH

Ph

OAc

Ph

O

O OAc

Ph

O OAc

Ph

Ph

O

Ph

O

Ph

OAc

O OAc

PhA

B

C

D

D2

E

F

R1 R2

Family of Zaragozic Acids

OO

OHR1O

R2HO2CHO2C

OHCO2H

6 7

5 1

3

Zaragozic Acid

.Nicolaou(Dihydroxylation

Strategy)

.Carreira(Carbonyladdition

Strategy)

.Evans(Tartrate-Derived Aldol Strategy)

Outline

- Total Synthesis of Zaragozic Acid:

.A: Nicolaou

-Synthesis of the Side Chains

.C. Carreira

-Synthesis of the Side Chains

.C: Evans

Nicolaou’s Retrosynthesis

OO

OH

HO2CHO2C

HO2C

OAc

OH

O

O

OO

OH

HO2CHO2C

HO2C

OAc

OH

HO

O

OH

+

O

CO2Bn

O

OH

O O

BnO2C OTMS

ODTBMSS

S

+

PMBO

PMBOOH

MeO2C OH

OSEM

Addition of the C6 O-Acyl Side Chain

Addition of the C1 Akyl Side Chain

Yue, E. W.; La Greca, S.; Nadin, A.; Yang, Z.; Leresche, J. E.; Tsuri, T.; Naniwa, Y.; De Riccardis, F.; Nicolaou, K.C. Chem. Eur. J. 1995, 1, 467-494.Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem . Int. Ed. Engl. 1996, 35, 1622-1656.

Nicolaou’s Retrosynthesis

PMBO

PMBOOH

MeO2C OH

OSEM

PMBO

PMBO

CO2Me

OSEM

SnBu3PMBO

PMBO

OSEM

I

CO2Me

+

OH

OH

OH

Dihydroxylation

Stille Coupling


Synthesis of the C1 Akyl Side Chain


(OH2CF3C)2P

CO2Me

O

O

H

1 2(1.0 equiv) (1.0 equiv)

+

KHMDS (1.0 equiv)18-crown-6 (5.0 equiv)

THF, -78oC, 30 min

87%

CO2Me

3

Dibal-H (4.4 equiv)CH2Cl2, -78oC, 15 min

99%

4

HO

PPh3Br

TBSO

H O

+

5 (1.0 equiv) 6 (1.0 equiv)

NaHMDS (1.0 equiv)

CH2Cl2/THF (1:1.2)-78oC to rt, 1h

99% 7

TBAF (1.05 equiv)THF, 0oC, 30 min

90%

TBSO



Al(CH3)3 (2.0 equiv)BuLi (0.3 equiv)

toluene, -20oC, 20h

89%

10

OH

PMBO

O

O

MeO

12

OPMB

HO

11

DDQ (1.3 equiv)CH2Cl2, 4A M.S.

rt, 5h

53%

Dibal-H (1.2 equiv)CH2Cl2, -78oC to rt, 2h

81%

4 8

tBuOOH (2.0 equiv)Ti(OiPr)4 (0.1 equiv)

diiopropyl D-tartrate (0.14 equiv)

4A M.S., CH2Cl2, -20oC, 20h

83%, 81% ee

O

H

H

9

O

H

H

PMBCl (1.25 equiv)NaH (1.2 equiv)

nBu4N+I- (0.04 equiv)

THF, reflux, 30 min.

73%

HO HO PMBO

>95:5



12

OPMB

HO

13

OPMB

O

(COCl)2 (1.5 equiv), DMSO (2.0 equiv)Et3N (40 equiv)

CH2Cl2, -78oC, 2h

98%H

14

OPMB

OH

BrMg O

O

(3.0 equiv)

THF, 35oC, 6h

O

O

73%, 1:1 mixture of dia

Dess-Martin periodinane (1.2 equiv)

CH2Cl2, rt, 20 min

92%15

OPMB

O

O

O



15

OPMB

O

O

O

16

OPMB

O

O

Tebbe Reagent (1.4 equiv)

THF, rt, 1h

85%

17

OPMB

O

O

Dibal-H (3.2 equiv)

HS SH

(1.6 equiv)Benzene, rt, 20h

64%

C1 Alkyl Side Chain

8% overall yield in 10 steps from 4 (allylic alcohol)

Recrystallisation for cyclohexane to give 95% ee

Synthesis of C6 O-Acyl Side Chain


N

H

N

OMe

N

H

N

OMe

i) iPr2NH (1.1 equiv), nBuLi (1.05 equiv)THF, 0oC, 15min

ii) 18 (1.0 equiv), 0oC, 4h

iii) nBuLi (1.05 equiv), -20oC, 2h

iv) (1.2 equiv)

-100oC to -50oC, 1.25h

I

18 19

C6 O-Acyl Side Chain

O

H

O3, CH2Cl2-78oC, 30s

MeO

O

H

PPh3

(1.2 equiv)

CH2Cl2, rt, 3h

30% 20

OMe

O

OH

O

2122

LiOH.H2O (3.0 equiv)

MeOH/H2O (2:1), rt, 3h

90%

92% de

Stille Coupling

Organostannate

R-Halide


OH

OH

1. PMBCl (2.5 equiv), NaH (25 equiv),nBu4Ni (0.4 equiv), DMF, rt, 8h (94%)

2. Bu3SnH (1.1 equiv),Pd(PPh3)2Cl2 (0.015 equiv),

THF, rt, 17h (94%)

88%

SnBu3PMBO

PMBO

23 24

PPh3

CO2Me

I

OSEM

HO C6H6, rt, 24h

78%(30:1 Z/E isomers)

OSEM

I

CO2Me

OH 1. SEMCl (1.1 equiv), iPr2NEt (2.2 equiv),CH2Cl2, rt, 2h (98%)

2. O3, CH2Cl2/MeOH (10:1),Me2S (6 equiv), -78oC, 20 min (98%)

96%25 26 27

(0.8 equiv)

Stille Coupling


Pd(CH3CN)2Cl2 (0.15 equiv),DMF degassed, 3d, rt

70%

SnBu3PMBO

OSEM

I

CO2Me

+

PMBO

PMBO

PMBO

CO2Me

OSEM24

27

28

H

OSEM

OPMB

H

PMBO

OMe

O

NW NE

SESW

1st Assymetric Dihydroxylation

β-face

α-faceYue, E. W.; La Greca, S.; Nadin, A.; Yang, Z.; Leresche, J. E.; Tsuri, T.; Naniwa, Y.; De Riccardis, F.; Nicolaou, K.C. Chem. Eur. J. 1995, 1, 467-494.Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem . Int. Ed. Engl. 1996, 35, 1622-1656.

PMBO

PMBO

CO2Me

OSEM

PMBO

PMBOOH

MeO2C OH

OSEM

30%, 83 %ee

28 29

''super'' AD-mixß: K2OsO2(OH)4 (0.1 equiv), K3Fe(CN)6 (3.0 equiv),

(DHQD)2PHAL (0.1 equiv),

K2CO3 (3.0 equiv), CH3SO2NH2 (2.0-3.0 equiv),t-BuOH/H2O (1:1)

24-72h, 0oC

2nd Assymetric Dihydroxylation


(5.0 equiv)PPTS (0.2 equiv),

CH2Cl2, 12h, 0oC

88%

MeO

O

OSEM

O O

PMBO

PMBO

DDQ (3.0 equiv),

CHCl3/H2O (20:1), 12h, rt

86%

O

O

OSEM

O O

HO

PMBO

PMBOOH

MeO2C OH

OSEM

29

OMe

30 31

OsO4 (0.05 equiv),NMO (3.0 equiv)

THF/tBuOH/H2O (1:1:1)18h, 0oC

83%

O

O

OSEM

O O

HO OH OH

O

O

OSEM

O O

HO

32

OH

OH

3334

TBDPSCl (1.3 equiv),imidazole (2.0 equiv),

DMAP (0.05 equiv)

DMF, rt, 12h

89%

O

O

OSEM

O O

TBDPSO OH OH

Functionalization


O

O

OSEM

O O

TBDPSO OH OH

1. Dess-Martin periodinane (3.0 equiv) CH2Cl2, rt (89%)

2. NaClO2 (3.0 equiv), NaH2PO4 (1.05 equiv)(H3C)C=CHCH3 (4.2 equiv)

tBuOH/H2O (4:1), rt, 3h

3. O-benzyl-N,N'-dicyclohexylisourea (1.5 equiv), toluene, 100oC, 1h (96% over 2 steps)

O

CO2Bn

O

OSEM

O O

TBDPSO OH

34 35

O

CO2Bn

O

OSEM

O O

HO OH

TBAF (1.2 equiv),AcOH (2.0 equiv),

THF, 2h, 0oC

96%

36

O

CO2Bn

O

OSEM

O O

TMSO OTMS

37

CH3N(TMS)COCF3 (3.5 equiv)100oC, 2hO

CO2Bn

O

OSEM

O O

HO OTMS

38

PPTS (0.014 equiv)

CH2Cl2/MeOH (10:1), rt, 5 min

Functionalization


O

CO2Bn

O

OSEM

O O

HO OTMS

1. Dess-Martin periodinane (1.2 equiv) CH2Cl2, rt (97% over 3 steps)

2. NaClO2 (3.0 equiv), NaH2PO4 (1.05 equiv)(H3C)C=CHCH3 (4.2 equiv)

tBuOH/H2O (4:1), rt, 3h

3. O-benzyl-N,N'-dicyclohexylisourea (1.5 equiv), toluene, 60oC, 1h

3860% over 2 steps 3916% over 2 steps 40

O

CO2Bn

O

OSEM

O O

BnO2C OTMS

39

O

CO2Bn

O

OH

O O

BnO2C OH

TFA (50 equiv),CH2Cl2/MeOH (10:1),

0oC, 2h

88%

40

O

CO2Bn

O

O

O O

BnO2C OTMS1. CH3N(TMS)COCF3, 80oC, 1h

2. PPTS (0.15 equiv), CH2Cl2/MeOH (10:1), 5 min, rt

3. Dess-Martin periodinane (2.1 equiv)CH2Cl2, rt, 30 min

93% over 3 steps41

S S

O

CO2Bn

O

OH

O O

BnO2CHO

ODTBMS

2% HCl in MeOH/CH2Cl2(2:3), rt, 5 min

99%

Hg(ClO4)2 (1.2 equiv), CaCO3 (1.3 equiv)THF/H2O (5:1), rt, 2h

83%

52

O

ODTBMSOH

OMe

OO

O

O

BnO2C CO2Bn

53

Dithiane Addition – 1st Attempt


Undesired Product

O

CO2Bn

O

O

O O

BnO2C OTMS

OPMBS

S

+

41

17

(1.0 equiv)

(5.0 equiv)

O

CO2Bn

O

OH

O O

BnO2CTMSO

OPMB

a) 17, nBuLi (1.6 equiv),THF,-25oC, 1.5h

b) 41, -78oC, 5 min, THF

(29% 42, 21% epi-42)

42

SS

Dithiane Addition – 2nd Attempt


O

CO2Bn

O

O

O O

BnO2C OTMS

O

CO2Bn

O

OH

O O

BnO2CTMSO

OTPS

OTPS

S

S

+


b) -78oC, 5 min, THF

41

45

(29% 46, 23% epi-46)

46

(1.0 equiv)

(1.7 equiv)

S S

O

CO2Bn

O

OH

O O

BnO2CHO

OTPS


95%

47

S S

Rearrangement Cascade


2% HCl in MeOH,78oC, 21h

X

OO

OHHO

MeO2CBnO2C

BnO2C

OTPS

OH

49

OOO

O

HO

MeO2COH

CO2BnOH

50

OTPSOH

OH

OO

O

O

BnO2C CO2BnHg(ClO4)2 (1.6 equiv), CaCO3 (1.7 equiv)THF/H2O (5:1), rt, 2h

80%

48

O

CO2Bn

O

OH

O O

BnO2CHO

OTPS

47

S S

Dithiane Addition – 3rd Attempt


O

CO2Bn

O

O

O O

BnO2C OTMS

O

CO2Bn

O

OH

O O

BnO2CTMSO

ODTBMS

ODTBMS

S

S

+


b) -78oC, THF, 5 min

41

50

51

72%

(1.25:1)(40% 25, epi-25 32%)

7

(1.0 equiv)

(1.2 equiv)

S S

O

CO2Bn

O

OH

O O

BnO2CHO

ODTBMS


99%

Hg(ClO4)2 (1.2 equiv), CaCO3 (1.3 equiv)THF/H2O (5:1), rt, 2h

83%

52

O

ODTBMSOH

OMe

OO

O

O

BnO2C CO2Bn

53

S S

Rearrangement Cascade


O

ODTBMSOH

OH

OO

O

O

BnO2C CO2Bn1.8% HCl in MeOH,

78oC, 21h

45%

O

ODTBMSOH

OMe

OO

O

O

BnO2C CO2Bn

53 54

O

ODTBMSOH

OO

BnO2C

MeO2C

O

MeO2C

55

OO

OHHO

MeO2CBnO2C

BnO2C

ODTBMS

OH

56

Coupling of the Side Chain


OO

OHHO

MeO2CBnO2C

BnO2C

ODTBMS

OH

OO

OHHO

BnO2CBnO2C

BnO2C

OH

OH

1. 49% aq. HF/MeNO2 (1:1), 0oC, 24h (30%)

2. LiOH:H2O (10 equiv), THF/H2O(2:1), rt, 1h

3. O-benzyl-N,N'-dicyclohexylisourea (4.8 equiv),THF, 55oC, 1.5h (68%)

22%56 57

OO

OHHO

BnO2CBnO2C

BnO2C

OPMB

OH

CSA (0.1 equiv), CH2Cl2, rt, 45 min

21%+ 36% SM

O

OH

LiOH (15 equiv), THF/MeOH/H2O (2:1:1), rt, 4h

ii) EDC (1.2 equiv), DMAP (0.6 equiv), CH2Cl2, 22oC, 10.5h47%

OO

OH

BnO2CBnO2C

BnO2C

OPMB

OH

O

O

NH

Cl3C OPMB

58

22

59 28% C6, 19% C7, 20% 58

6 7

I)

(3:2 mixture of acyl 6 and acyl 70

(1.0 equiv)

(1.0 equiv)

Completion of the Total Synthesis


OO

OH

BnO2CBnO2C

BnO2C

OPMB

OH

O

O

OO

OTES

BnO2CBnO2C

BnO2C

OH

OH

O

O

1. TESOTf (1.1 equiv), Py (1.5 equiv), CH2Cl2, 22oC, 20 min (79%)

2. DDQ (1.2 equiv), CH2Cl2/H2O(20:1), 22oC, 1h (98%)

77%

59 60

OO

OH

BnO2CBnO2C

BnO2C

OAc

OH

O

O

1. Ac2O (2.5 equiv), Py (3.0 equiv),DMAP (0.1 equiv), CH2Cl2,

22oC, 4h

2. TBAF, THF,0oC, 15 min

84%

OO

OH

HO2CHO2C

HO2C

OAc

OH

O

O

10% Pd/C (1.0 wt equiv)1,4-cyclohexadiene

1,4-dioxane,110oC, 2h

50%

6162

Zaragozic Acid A

Nicolaou’s Total Synthesis Summary

OH

Zaragozic Acic A/Squalestin S135 steps

0.003% overall


Carreira’s Retrosythesis

OO

OH

HO2C

CO2H

Ph

OAc

OH

HO2C

Ph

Me

O

O

OO

OPivPivO

Ph

OPivTBSO

OTBSO

O

O

Et Et

OBn

OH

OH

Ph

Me

OPivOOH

OH

O

O

Et Et

OBn

OTMS

H

OTBS

ONMe2

OO

Et Et

OBn

OHO

HO

Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1994, 116, 10825-10826. , Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, 8106-8125.Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem . Int. Ed. Engl. 1996, 35, 1622-1656.

Addition of C6 side chain

Ketalisation

Addition of C1 side chain


NO

O O

Et

Bn

+

H

O

OBn

i) 9-BBN-OTf, iPr2NEt

ii) H2O/MeOH

84%

NO

O O

Bn

OH

Me

OBn

O OH

Me

OBnHOLiOH, H2O2, aq. THF

1

2

3 4

OH

Me

OBnHO

LiAlH4, THF

92%

OH

Me

OBnTsOTsCl, C5H5N, 0oC

89%

56


Synthesis of the C1 akyl chain

OH

Me

OBnTsOMe

OBn

O

PhLi, BF3.OEt2

91%

OH

Me

OBnPh

6 7 8

1) tBuCOCl, 4-DMAPCH2Cl2 (90%)

2) H2,Pd/C, EtOAc(99%)

OPiv

Me

OHPh

OPiv

Me

OPh

(COCl)2, DMSO, Et3N,

CH2Cl2, -78oC

96%

H

910

C1 Akyl ChainDu Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1994, 116, 10825-10826. , Du Bois, J.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, 8106-8125.Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem . Int. Ed. Engl. 1996, 35, 1622-1656.


Ph

H

PhOH1) nBuLi, (CH2O)n, THF (92%)

2)LiAlH4, Et2O (79%)Ph

OHOtBuOOH, Ti(OiPr)4, L-(+)-DIPT

4 A mol. sieves, CH2Cl2

98%

12 13

Ph

Me

O

HPh

Me

OH

1) Me3Al

2) NaIO4, aq. THF

vinyl MgBr, THF

62% over three steps

15 14


>95% ee

60:40 mixture


Ph

Me

OH

O

NaOH, H2O/THF

100%

Ph

Me

Cl

O

(COCl)2, cat. DMF, CH2Cl2

1718

Ph

Me

OEt

O

Ph

Me

OH

(EtO)3CH3, H+

89%

15 16

C6 O-Acyl Side Chain


Carbonyl Addition

TMS MgBr

THF, -78oC

84%

O

O

Et Et

OBn

OEt

OH

TMS

O3, CH2Cl2/EtOH, -78oCO

O

Et Et

OBn

O OEt

OH

TMS84%

O

CH2OHO

Et Et

OBn

OH

TMS

NaBH4, MeOH

222324

20:1


O

OHO

HO

ONMe2

OO

Et Et

OBn

1. Me2NH, MeOH,0oC (97%)

2. (MeO)2CEt2, TsOH cat. (90%)

3. NaH, BnBr,THF (96%)

86%

, THFO

OO

Et Et

OBn OEt

OEt

19 20 21

tBuLi,

Addition of the C1 Alkyl Chain

O

CH2OHO

Et Et

OBn

OH

TMS

24

O

CH2OHO

Et Et

OBn

OH

H

25

K2CO3, MeOH

78% in two steps

O

O

Et Et

OBn

OTMS

H

26

i) tBuMe2SiCl, Et3N, 4-DMAP

ii) Me3SiCl, Et3N, CH2Cl2

88%

OTBS


O

O

Et Et

OBn

OTMS

27

1) nBuLi, THF, -45oC

2)

LiBr, THF (93%)

Ph

H

O

Me

OPiv

Ph

Me

OPivOH

O

O

Et Et

OBn

OTMS

28

Ph

Me

OPivO

OTBS

Dess-Martin, CH2Cl2

93%

OTBS

10

Functionalization

O

O

Et Et

OBn

OH

30

OH

Ph

Me

OPivO

nBu4NF, THF

93%

O

O

Et Et

OBn

OH

31

OH

Ph

Me

OPivOOH

OHOsO4/NMO

MeSO2NH2, (DHQD)2PHAL

acetone/tBuOH/H2O(1.7:1 dr)


O

O

Et Et

OBn

OTMS

28

Ph

Me

OPivO

OTBS

O

O

Et Et

OBn

OTMS

29

OTBS[Cr(OAc)2.H2O]2,

THF/H2O

60%

Ph

Me

OPivO

Ketalizaton

O

O

Et Et

OBn

OH

32

OH

Ph

Me

OPivOOH

OH

OO

OHHO

BnO

H

Ph

OPiv

33

HO

OH

HCl/MeOH

85%

OO

OHHO

BnO

H

Ph

OPiv

34

TBSO

OTBS

TBSCl, 4-DMAP,Et3N, CH2Cl2

74%

OO

OPivPivO

BnO

H

Ph

OPiv

35

TBSO

OTBS

tBuCOCl, 4-DMAP,CH2Cl2

97%


Functionalization

OO

OPivPivO

BnO

H

Ph

OPiv

35

TBSO

OTBS OO

OPivPivO

HO

H

Ph

OPiv

36

TBSO

OTBS

H2 (1 atm), Pd(OH)2-C,Pd-CaCO3, EtOH

99%


(COCl)2, DMSO, Et3N,CH2Cl2

96%

OO

OPivPivO

Ph

OPiv

37

TBSO

OTBSOO

O

OPivPivO

Ph

OPiv

38

TBSO

OTBS

TMSC=CLi, Et2O/Et3N

OH

TMS(6.1:1 dr)

Towards Zaragozic Acid C


38

OO

OPivPivO

Ph

OPivTBSO

OTBSOH

TMS

46

OO

OAcAcO

tBuO2C

CO2tBu

Ph

OAc

OH

tBuO2C

1st Method

40

OO

OAcAcO

Ph

OAcTBSO

OTBSOH

H

1) Dibal-H,CH2Cl2/Toluene (84%)

2) Ac2O, 4-DMAPCH2Cl2 (94%)

41

OO

OAcAcO

Ph

OAcTBSO

OHOH

1) Cl2CHCO2H, MeOH (90%)

2) H2, Pd/C, C5H5N (99%)


38

AgNO3, 2,6-lutidine

OO

OPivPivO

Ph

OPivTBSO

OTBSOH

TMS

90%

39

OO

OPivPivO

Ph

OPivTBSO

OTBSOH

H

1st Method Cont’d

41

OO

OAcAcO

Ph

OAcTBSO

OHOH

42

OO

OAcAcO

CO2tBu

Ph

OAcTBSO

OH

1) Dess-Martin, CH2Cl2 (80-95%)

2) i) NaClO2, NaH2PO4, B-isoamylene, THF

ii) N-N'-diisopropyl-O-tert-butylisoureaCH2Cl2 (70-85%)


43

OO

OAcAcO

CO2tBu

Ph

OAcHO

OH

HF, pyr. THF/pyridine

90%

44

OO

OAcAcO

CO2tBu

Ph

OActBuO2C

OH

1) Dess-Martin, CH2Cl2 (80-95%)

2) i) NaClO2, NaH2PO4, B-isoamylene, THF


1st Method Cont’d

44

OO

OAcAcO

CO2tBu

Ph

OActBuO2C

OH

O3, CH2Cl2/MeOH

97%

45

OO

OAcAcO

CO2tBu

Ph

OActBuO2C

OHO

46

OO

OAcAcO

CO2tBu

Ph

OActBuO2C

OH

tBuO2C

i) NaClO2, NaH2PO4, B-isoamylene, THF



2nd Method


38

OO

OAcAcO

Ph

OAcTBSO

OTBSOH

TMS

47

OO

OAcAcO

Ph

OAcHO

OHOH

1) H2, Pd-C, C5H5N

2) HF.pyr, THF/C5H5N

64%

48

OO

OAcAcO

Ph

OAcO

OOH

Dess-Martin periodinane,CH2Cl2/pyridine

93%

49

OO

OAcAcO

Ph

OAcO

OOH

O

i) O3, CH2Cl2/MeOH, -78oC

ii) PPh3

2nd Method Cont’d

49

OO

OAcAcO

Ph

OAcO

OOH

O

1) NaClO2, NaH2PO4, B-isoamylene, THF

2) N-N'-diisopropyl-O-tert-butylisoureaCH2Cl2

72% in three steps46

OO

OAcAcO

tBuO2C

CO2tBu

Ph

OAc

OH

tBuO2C


Towards Zaragozic Acid C

OO

OBocHO

tBuO2C

CO2tBu

Ph

OAc

OH

tBuO2C

51

(Boc)2O,

4-pyrrolidinopyridine,CH2Cl2

82%

>20:1; 3:1 with DMAP

N N


0.2 % K2CO3, MeOH, 0.5h

90% OO

OHHO

tBuO2C

CO2tBu

Ph

OAc

OH

tBuO2C

46

OO

OAcAcO

tBuO2C

CO2tBu

Ph

OAc

OH

tBuO2C

50


Addition of the C6 O-Acyl Side Chain

OO

OH

HO2C

CO2H

Ph

OAc

OH

HO2C

53

Ph

Me

O

O

TFA, CH2Cl2

100%

(+)-Zaragozic Acid C

OO

OBocHO

tBuO2C

CO2tBu

Ph

OAc

OH

tBuO2C

51

DCC, 4-DMAP, CH2Cl2

78%

OO

OBoc

tBuO2C

CO2tBu

Ph

OAc

OH

tBuO2C

52

Ph

Me

Cl

O

18

Ph

Me

O

O

If coupling of the C6 side chain was done on 50, the hydroxyl groups free at C6 and C7 position, a 1:3 mixture of C6:C7

Carreira’s Total Synthesis Summary


-Highly diastereoselective addition of the Grignard to an unsaturated ketone: + effect of Cosolvant and additive

-Use of [Cr(OAc)2.H2O]2 for stereoselective reduction

-Regiselective protection of the C7 carbinol vs the C6 OH

-Installation of 3 aldehydes simultaneously (more efficient)

O

OHO

HO

(+)-Zaragozic Acid C32 steps

0.73% overall

Evans’s Retrosynthesis

OO

OTBDMS

tBuO2CtBuO2C

OHCO2tBu

Ph

OAc

Ph

O

O

OO

OTBDMS

tBuO2CtBuO2C

OHCO2tBu

Ph

OAcHO

Ph O

OH

+

BnO

O

OtBuO2C

OtBuO2C

OTBDMSCO2tBu

Ph

OAcOH

BnO

O

OtBuO2C

OtBuO2CO

OTBDMSCO2tBu

I

Ph

OPMB

+

Esterification

Ketalisation

Addition

Zaragozic Acid C

Barrow, J. C.; Leighton, J. L.; Robichaud, A. J.; Sefkow, M.; Evans, D. A. J. Am. Chem. Soc. 1994, 116, 12111-12112 .Koert, U. Angew. Chem. Int. Ed. Engli. 1995, 34, 773-778., Nadin, A.; Nicolaou, K.C. Angew. Chem . Int. Ed. Engl. 1996, 35, 1622-1656.

Evans’s Retrosynthesis

BnO

O

OtBuO2C

OtBuO2CO

OTBDMSCO2tBu

O

OtBuO2C

PhTBDMSO

OBn

O

CO2tBu

O

OtBuO2C OTBS

OtBu

O

OBn

Ph

OH

H

+

O

H PhO N

O

Ph

O

BnO+

tBuO2CCO2tBu

OH

OH

5

Mukaiyama Aldol Reaction

Evan’s Aldol Reaction


Evans Aldol Reaction

O

O

CO2tBu

tBuO2C

LiHMDS, TMSCl, THF-78oC, 30 min

0oC,30min

97%O

OtBuO2C OTBS

OtButBuO2CCO2tBu

OH

OH

OMe

OMe 3 equiv.

TsOH, C6H6, 65oC, 200 Torr, 12h

85%1 2 3

O

H Ph

O N

O

Ph

O

BnO

+

Bu2BOTf,Et3N, CH2Cl2,

-78oC, 1h-40oC, 1.5h

96%

O N

O

Ph

O

BnO

Ph

OH

1. TBDMSOTf, 2,6-lutidine, CH2Cl2, 0oC, 1h

2. LiBH4, MeOH, THF, 0oC, 3.5h

3. (COCl)2, DMSO, Et3N, CH2Cl2, -78oC - 0oC

92%

O

OBn

Ph

OTBDMS

H

4

5

5

5 75 7

6 7


Mukaiyama Aldol Reaction

O

OtBuO2C OTBS

OtBu

O

OBn

Ph

OTBDMS

H

+

iPrOTiCl3, CH2Cl2, -78oC

76%O

OtBuO2C

PhTBDMSO

OBn

HO

CO2tBu

3

8


Functionalization

O

OtBuO2C

Dess-Martin,Py, CH2Cl2, 8h

94%

PhTBDMSO

OBn

HO

O

OtBuO2C

PhTBDMSO

OBn

O

20 equiv. CH2=CHMgBrCH2Cl2/THF (6:1)

78oC, 10h

76%O

OtBuO2C

PhTBDMSO

OBn

HO

CO2tBu CO2tBu CO2tBu

8 9 10

O

OtBuO2C

O Bn

R

O

CO2tBu

M

O

OtBuO2C

O Bn

R

HO

CO2tBu

Nu

Nu

Si face

Correct C5 Dia


>10:1

Functionalization

BnO

O

OtBuO2C1. OsO4, NMO, tBuOH/THF/H2O, 40 min

2. Pb(OAc)4, C6H6, 20 min

3. [nPr4N][RuO4]NMO, Molecular Sieves 4A,CH2Cl2, 5h

84%

O O

OTBDMSCO2tBu

11

O

OtBuO2C

PhTBDMSO

OBn

HO

CO2tBu

10

BnO

O

OtBuO2C

OtBuO2CO

OTBDMSCO2tBu

i) O3, Py, CH2Cl2, -78oC

ii) Me2S, -78oC to rt, 2h

BnO

O

OtBuO2C

O O

OTBDMSCO2tBu

O

NaClO2, NaH2PO4, tBuOH, 3.5h

2. O-tert-butyl-N,N'-diisopropylisourea,CH2Cl2, 24h

1.

91% over 3 steps1213


Coupling of the Side Chain

BnO

O

OtBuO2C

OtBuO2CO

OTBDMSCO2tBu

I

Ph

OPMB

+

i) 1.7 equiv 143.4 equiv.tBuLi

Hexane/Et2O (1:1)-78oC, 5 min

ii) 13, -78oC, 15 min

BnO

O

OtBuO2C

OtBuO2C

OTBDMSCO2tBu

Ph

OPMBOH

13

14

1573%


BnO

O

OtBuO2C

OtBuO2C

OTBDMSCO2tBu

Ph

OAc

1. DDQ,CH2Cl2, H2O, 1h

2. Ac2O, DMAP,Py/C6H6 (1:4), 1h

90%

OH1. CH2Cl2/TFA,/H2O (20:10:1),

14h, 23oC

2. 7 eq. O-tert-butyl-N,N'-diisopropylisourea, CH2Cl2, 24h

52%

OO

OTBDMSBnO

tBuO2CtBuO2C

OBnCO2tBu

Ph

OAc

16

17

Completion of the Total Synthesis

(+)-Zaragozic Acid C


OO

OH

HO2CHO2C

OHCO2H

Ph

OAc

Ph

O

O

1. TBAF, THF,0oC, 15 min

2. TFA, CH2Cl2,24h

20

98%

OO

OTBDMSBnO

tBuO2CtBuO2C

OBnCO2tBu

Ph

OAc

Ph

OH

O

+

1) H2, 750psi, 10% Pd/C,AcOH, MeOH, 20h

2) 18, DCC, DMAP,CH2Cl2, 36h O

O

OTBDMS

tBuO2CtBuO2C

OHCO2tBu

Ph

OAc

Ph

O

O

79%

17

18

19

Evan’s Total Synthesis Summary

O N

O

Ph

O

OBn 22 steps

10% overall

Zaragozic Acid C


- Efficient Total Synthesis: .Convergent.Late coupling of the 2 side chains

- Complete control exerted over each newly formed chiral center

Total Synthesis Summary

O N

O

Ph

O

OBn 22 steps

10% overall

Zaragozic Acid C

Carreira (Carbonyladdition Strategy)

Nicolaou (Dihydroxylation Strategy)

Evans (Tartrate-Derived Aldol Strategy)

OH

Zaragozic Acic A/Squalestin S135 steps

0.003% overall

O

OHO

HO

(+)-Zaragozic Acid C32 steps

0.73% overall

Retrosynthetic Analysis

O

RO2COH

CO2H

HOO

C1-SK

HO

OH

O

RO2COR

CO2R

RORO

O

H

S S

LiC1-SK

+

NICOLAOU

OO

OHO

C1-SK

OSK-C6

HO2CHO2C

OHCO2H

OO

ORHO

C1-SKRO2C

RO2C

ORCO2R

CO2R

HORO CO2R

O C1-SK

OR

RO2C RO

OH

CO2R

HORO CO2R

OR

RO2C OLi

C1-SK+

EVANS

OO

OHHO

C1-SK

RO

HO

OH

HO

OH

OH

OH

OH

OH

O

C1-SK

OH

RO

OR

OR

OR

O

C1-SKOR

Li

H+

CARREIRA

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