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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
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.
Synthesis 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.
(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
Synthesis 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.
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
Synthesis 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.
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
Synthesis 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.
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
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.
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
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.
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
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.
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
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.
(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
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.
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
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.
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
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.
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
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.
O
CO2Bn
O
O
O O
BnO2C OTMS
O
CO2Bn
O
OH
O O
BnO2CTMSO
OTPS
OTPS
S
S
+
a) 45, nBuLi (1.6 equiv),THF,-25oC, 1.5h
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
2% HCl in MeOH/CH2Cl2(1:3), rt, 5 min
95%
47
S S
Rearrangement Cascade
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.
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
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.
O
CO2Bn
O
O
O O
BnO2C OTMS
O
CO2Bn
O
OH
O O
BnO2CTMSO
ODTBMS
ODTBMS
S
S
+
a) 50, nBuLi (1.2 equiv),THF,-25oC, 1.5h
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
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
S S
Rearrangement Cascade
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.
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
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.
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
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.
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
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.
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
Synthesis of the C1 Akyl 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
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.
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.
Synthesis of C6 O-Acyl Side Chain
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
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.
>95% ee
60:40 mixture
Synthesis of C6 O-Acyl Side Chain
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
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.
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
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.
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
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.
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)
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.
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%
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.
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%
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.
(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
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.
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%)
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.
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%)
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.
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
ii) N-N'-diisopropyl-O-tert-butylisoureaCH2Cl2 (70-85%)
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
ii) N-N'-diisopropyl-O-tert-butylisoureaCH2Cl2 (70-85%)
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.
2nd Method
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.
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
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.
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
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.
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
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 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
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.
-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
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 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
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.
Mukaiyama Aldol Reaction
O
OtBuO2C OTBS
OtBu
O
OBn
Ph
OTBDMS
H
+
iPrOTiCl3, CH2Cl2, -78oC
76%O
OtBuO2C
PhTBDMSO
OBn
HO
CO2tBu
3
8
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.
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
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.
>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
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.
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%
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.
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
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.
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
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.
- 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