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
Sooty Blotch = Leptodontium elastius
-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.
Family of Zaragozic Acids
.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
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
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.
Synthesis of the C1 Akyl Side Chain
>95:5
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.
Synthesis of the C1 Akyl Side Chain
Recrystallisation for
cyclohexane to give 95% ee
8% overall yield in 10 steps from 4 (allylic alcohol)
C1 Alkyl 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.
Synthesis of C6 O-Acyl Side Chain
92% de
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.
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.
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.
1st Assymetric Dihydroxylation
β-face
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.
α-face
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 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.
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.
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.
Dithiane Addition – 1st Attempt
Undesired Product
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.
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.
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.
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.
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.
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.
Completion of the Total Synthesis
Zaragozic Acid A
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 Total Synthesis Summary
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
Addition of C6 side chain
Ketalisation
Addition of C1 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.
Synthesis of the C1 Akyl 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.
Synthesis of the C1 akyl chain
C1 Akyl 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.
Synthesis of C6 O-Acyl Side Chain
>95% ee
60:40 mixture
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 C6 O-Acyl Side Chain
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
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.
Addition of the C1 Alkyl 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.
Functionalization
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.
Ketalizaton
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
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
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.
1st 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.
1st Method Cont’d
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.
1st Method Cont’d
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.
2nd Method Cont’d
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
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
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
(+)-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.
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)
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.
Evans’s Retrosynthesis
Esterification
Zaragozic Acid C
Ketalisation
Addition
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
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
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
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
>10:1
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.
Functionalization
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
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.
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.
Evan’s Total Synthesis Summary
- Efficient Total Synthesis:
.Convergent
.Late coupling of the 2 side chains
- Complete control exerted over each newly formed chiral center
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.
Total Synthesis Summary
Carreira (Carbonyladdition Strategy)
Nicolaou (Dihydroxylation Strategy)
Evans (Tartrate-Derived Aldol Strategy)
Retrosynthetic Analysis