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Nicolaou Taxol total synthesis

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Title: Nicolaou Taxol total synthesis  
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Subject: Shapiro reaction, Diels–Alder reaction, The Scripps Research Institute, McMurry reaction, Total synthesis
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Nicolaou Taxol total synthesis

Nicolaou Taxol total synthesis overview from raw material perspective.

The Nicolaou Taxol total synthesis, published by

  1. ^ Classics in Total Synthesis: Targets, Strategies, Methods K. C. Nicolaou, E. J. Sorensen ISBN 3-527-29231-4
  2. ^ Nicolaou, KC; Yang, Z; Liu, JJ; Ueno, H; Nantermet, PG; Guy, RK; Claiborne, CF; Renaud, J; et al. (February 1994). "Total synthesis of taxol". Nature 367 (6464): 630–4.  
  3. ^ K. C. Nicolaou, P. G. Nantermet, H. Ueno, R. K. Guy, E. A. Couladouros, and E. J. Sorensen (1995). "Total Synthesis of Taxol. 1. Retrosynthesis, Degradation, and Reconstitution". J. Am. Chem. Soc. 117 (2): 624–633.  
  4. ^ K. C. Nicolaou, J.-J. Liu, Z. Yang, H. Ueno, E. J. Sorensen, C. F. Claiborne, R. K. Guy, C.-K. Hwang, M. Nakada, and P. G. Nantermet (1995). "Total Synthesis of taxol. 2. Construction of A and C ring intermediates and initial attempts to construct the ABC ring system". J. Am. Chem. Soc. 117 (2): 634–644.  
  5. ^ K. C. Nicolaou, Z. Yang, J.-J. Liu, P. G. Nantermet, C. F. Claiborne, J. Renaud, R. K. Guy, and K. Shibayama (1995). "Total Synthesis of Taxol. 3. Formation of Taxol's ABC Ring Skeleton". J. Am. Chem. Soc. 117 (2): 645–652.  
  6. ^ K. C. Nicolaou, H. Ueno, J.-J. Liu, P. G. Nantermet, Z. Yang, J. Renaud, K. Paulvannan, and R. Chadha (1995). "Total Synthesis of Taxol. 4. The Final Stages and Completion of the Synthesis". J. Am. Chem. Soc. 117 (2): 653–659.  

References

  • Nicolaou Taxol Synthesis @ SynArchive.com
  • Taxol in dynamic 3D

External links

See also

Protected secondary alcohol in Ojima lactam 7.1 during reaction with alcohol 7.2 in the tail addition.

Deprotection: Hydrolysis using hydrofluoric acid and pyridine

Protection: See Ojima lactam.

TES (triethylsilyl) [2]

Protection of the secondary hydroxyl group in 5.7 was necessary for the final addition of the tail to alcohol 7.2.

Deprotection: Hydrolysis using hydrofluoric acid, pyridine and tetrahydrofuran.

Protection: Triethylsilyl chloride and pyridine.

TES (triethylsilyl) [1]

Protection of hydroxyl group in 3.4 allowed the ketone to undergo a Shapiro reaction to form the viyllithium compound 3.7.

Deprotection: Tetra-n-butylammonium fluoride

Protection: Dichloromethane, imidazole, and tert-butyldimethylsilyl chloride.

TBS (tert-butyldimethylsilyl) [3]

Protection of the tertiary hydroxyl group in 1.8 was necessary to allow selective protection of other hydroxyl groups on the C ring.

Deprotection: Camphorsulfonic acid

Protection: Tert-butyldimethylsilyl triflate, lutidine, 4-(dimethylamino)pyridine, and dichloromethane.

TBS (tert-butyldimethylsilyl) [2]

The secondary hydroxyl group in 1.8 was briefly protected during the protection of a tertiary hydroxyl group in the same compound.

Deprotection: Camphorsulfonic acid, dicholoromethane, and methanol.

Protection: Tert-butyldimethylsilyl triflate, lutidine, 4-(dimethylamino)pyridine, and dichloromethane.

TBS (tert-butyldimethylsilyl) [1]

Primary alcohol 2.1 was protected in preparation for lactone reduction in 2.3. The protecting group was removed to give diol 4.7 in preparation for the pinacol coupling reaction.

Deprotection: Tetra-n-butylammonium fluoride


Protection: Tert-butyldiphenylsilyl chloride, imidazole, and dimethylformamide.

Protection adds rigidity in ring structure for pinacol coupling reaction forming diol 4.9, and also prevents unwanted oxidation in the formation of dialdehyde 4.8.

Deprotection: Phenyllithium opens the carbonate ester ring to give alcohol 6.5.

Protection: Potassium hydride, phosgene

Carbonate Ester

Secondary alcohol 2.2 was protected as the benzyl ether so that the reduction of lactone 2.3 could occur. Protection was removed much later in the synthesis to form alcohol 5.7, which was reprotected as the triethylsilyl ether.

Deprotection: Hydrogen, Pd(OH)2/C

Protection: Potassium hydride, tetra-n-butylammonium iodide, and benzyl bromide.

Bn (benzyl)

Protection of the vicinal diol 2.4 allowed the remaining hydroxyl group in alcohol 2.5 to be selectively oxidized to give aldehyde 2.6. The acetonide was removed much later in the synthesis in preparation for the closure of ring D.

Deprotection: Hydrochloric acid, methanol, water, and ethyl ether

Protection: 2,2-dimethoxypropane and camphorsulfonic acid, and dichloromethane

Acetonide

Protection prevented mesylation of the primary oxygen in 5.8.

Deprotection: Potassium carbonate in methanol and water solvent

Protection: Acetic anhydride, pyridine, 4-(dimethylamino)pyridine, and dicholoromethane

Ac (acetyl)

Protecting groups

App II

Reduction and acylation gave diene 7 (Scheme 3, compound 1).

Synthesis of the Diels-Alder diene for Ring A

App I

The ethyl ester of propionic acid (1) was brominated and then converted to the Wittig reagent using triphenylphosphine. Aldehyde 6 was obtained from allyl alcohol (4) by protection as the tert-butyldiphenylsilyl ether (5) followed by ozonolysis. Wittig reagent 3 and aldehyde 6 reacted in a Wittig reaction to give unsaturated ester 7, which was deprotected to give dienophile 8 (Scheme 1, compound 1).

Synthesis of the Diels-Alder dienophile for Ring C

Precursor synthesis

Tail Addition Scheme 7
Scheme 7

As shown in Scheme 7, Ojima lactam 7.1 reacted with alcohol 7.2 with sodium bis(trimethylsilyl)amide as a base. This alcohol is the triethylsilyl ether of the naturally occurring compound baccatin III. The related compound, 10-deacetylbaccatin III, is found in Taxus baccata, also known as the European Yew, in concentrations of 1 gram per kilogram leaves. Removal of the triethylsilyl protecting group gave Taxol.

Tail addition

Ring D2 synthesis Scheme 6
Scheme 6

The phenyllithium was used to open the carbonate ester ring to give alcohol 6.5. Allylic oxidation with pyridinium chlorochromate, sodium acetate, and celite gave ketone 6.6, which was subsequently reduced using sodium borohydride to give secondary alcohol 6.7. This was the last compound before the addition of the amide tail.

Ring D1 synthesis Scheme 5
Scheme 5

The desired enantiomer from resolution, allylic alcohol 5.1 (Scheme 5) was acetylated with acetic anhydride and 4-(dimethylamino)pyridine in methylene chloride to yield monoacetate 5.2. It is noteworthy that this reaction was exclusive for the allylic alcohol, and the adjacent hydroxyl group was not acetylated. Alcohol 5.2 was oxidized with tetrapropylammonium perruthenate and N-methylmorpholine N-oxide to give ketone 5.3. Alkene 5.3 underwent hydroboration in tetrahydrofuran. Oxidation with basic hydrogen peroxide and sodium bicarbonate gave alcohol 5.4 in 35% yield, with 15% yield of a regioisomer. The acetonide was removed, giving triol 5.5. This alcohol was monoacetylated, to give acetate 5.6. The benzyl group was removed and replaced with a triethylsilyl group. Diol 5.7 was selectively activated using methanesulfonyl chloride and 4-(dimethylamino)pyridine to give mesylate 5.8, in 78% yield.

D Ring synthesis

resolution
Enantiomeric resolution of 4.9.

At this point in the synthesis of Taxol, the material was a racemic mixture. To obtain the desired enantiomer, allylic alcohol 4.9 was acylated with (1S)-(−)-camphanic chloride and dimethylaminopyridine, giving two diastereomers. These were then separated using standard column chromatography. The desired enantiomer was then isolated when one of the separated disatereomers was treated with potassium bicarbonate in methanol.

Resolution

Ring B synthesis Scheme 4
Scheme 4

A reduction with lithium aluminium hydride, gave diol 4.5. This diol was then protected as carbonate ester 4.6. The carbonate group also served to create rigidity in the ring structure for the imminent pinacol coupling reaction. The two silyl ether groups were removed, and diol 4.7 was then oxidized to give dialdehyde 4.8 using N-methylmorpholine N-oxide in the presence of a catalytic amount of tetrapropylammonium perruthenate. In the final step of the formation of Ring B, a pinacol coupling using conditions developed by McMurry (titanium(III) chloride and a zinc/copper alloy) gave diol 4.9.

The coupling of ring A and ring C created the 8 membered B ring. One connection was made via a nucleophilic addition of a vinyllithium compound to an aldehyde and the other connection through a pinacol coupling reaction of two aldehydes (Scheme 4).

Stereochemistry of addition to 4.2. The Re face was preferred.

B Ring synthesis

Ring A synthesis Scheme 3
Scheme 3

The A ring synthesis (Scheme 3) started with a Diels-Alder reaction of diene 3.1 with the commercially available dienophile 2-chloroacrylonitrile 3.2 to give cyclohexene 3.3 with complete regioselectivity. Hydrolysis of the cyanochloro group and simultaneous cleavage of the acetate group led to hydroxyketone 3.4. The hydroxyl group was protected as a tert-butyldimethylsilyl ether (3.5). In preparation for a Shapiro reaction, this ketone was converted to hydrazone 3.6.

A Ring synthesis

Ring C synthesis Scheme 2
Scheme 2

Lactone diol 2.1, after selective protection, was reduced with lithium aluminium hydride to give triol 2.4. This triol, after protection as the 5-membered ring acetonide, was selectively oxidized to the aldehyde using tetrapropylammonium perruthenate (TPAP) and N-methylmorpholine N-oxide. Aldehyde 2.6 served as a starting point for the construction of ring B (Scheme 4, compound 4.2).

Ring C synthesis Scheme 1
Scheme 1

As shown in Scheme 1, the ring synthesis of ring C began with a Diels-Alder reaction between diene 1.3 and dienophile 1.1 in the presence of phenylboronic acid (1.2), which, after addition of 2,2-dimethyl-1,3-propanediol, gave five-membered lactone 1.8 in 62% yield. Boron served as a molecular tether and aligned both diene and dienophile for this endo Diels-Alder cycloaddition. After protection of the hydroxyl groups as tert-butyldimethylsilyl ethers, reduction of the ester with lithium aluminium hydride and selective deprotection of the secondary hydroxyl group gave lactone diol 1.11. The unusual lactone hydrates 1.9 and 1.10 were isolated as synthetic intermediates in this process.

C Ring synthesis

Scheme 2 Nicolaou Retrosynthesis
Retrosynthesis Scheme 2

Retrosynthetic Scheme II indicates that both the aldehyde and the hydrazone used in the Shapiro coupling reaction were synthesized using Diels-Alder reactions.

Scheme 1 Nicolaou Taxol Retrosynthesis
Retrosynthesis Scheme 1

As illustrated in Retrosynthetic Scheme I, Taxol was derived from diol 7.2 by an ester bond formation, according to the Ojima-Holton method. This diol comes from carbonate 6.3 by the addition of phenyllithium. The oxetane ring in compound 6.3 was obtained via an SN2 reaction involving a mesylate derived from acetate 4.9. Ring B was closed via a McMurry reaction involving dialdehyde 4.8 which ultimately was derived from aldehyde 4.2 and hydrazone 3.6 using a Shapiro coupling reaction.

Retrosynthesis

Contents

  • Retrosynthesis 1
  • C Ring synthesis 2
  • A Ring synthesis 3
  • B Ring synthesis 4
  • Resolution 5
  • D Ring synthesis 6
  • Tail addition 7
  • Precursor synthesis 8
    • Synthesis of the Diels-Alder dienophile for Ring C 8.1
    • Synthesis of the Diels-Alder diene for Ring A 8.2
  • Protecting groups 9
    • Ac (acetyl) 9.1
    • Acetonide 9.2
    • Bn (benzyl) 9.3
    • Carbonate Ester 9.4
    • TBS (tert-butyldimethylsilyl) [1] 9.5
    • TBS (tert-butyldimethylsilyl) [2] 9.6
    • TBS (tert-butyldimethylsilyl) [3] 9.7
    • TES (triethylsilyl) [1] 9.8
    • TES (triethylsilyl) [2] 9.9
  • See also 10
  • External links 11
  • References 12

The Nicolaou synthesis is a good example of convergent synthesis because the molecule is assembled from 3 pre-assembled synthons. Two major parts are cyclohexene rings A and C that are connected by two short bridges creating an 8 membered ring in the middle (ring B). The third pre-assembled part is an amide tail. Ring D is an oxetane ring fused to ring C. Two key chemical transformations are the Shapiro reaction and the pinacol coupling reaction.[2] The overall synthesis was published in 1995 in a series of four papers in the Journal of the American Chemical Society.[3][4][5][6]

This synthetic route to Taxol is one of several; other groups have presented their own solutions, notably the group of Holton with a linear synthesis starting from borneol, the Samuel Danishefsky group starting from the Wieland-Miescher ketone and the Wender group from pinene.

. pacific yew but also expensive because the compound is harvested from a scarce resource, namely the cancer in the treatment of drug Taxol is an important [1]

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