The Nicolaou Taxol total synthesis, published by K. C. Nicolaou and his group in 1994 concerns the total synthesis of taxol.[1] Taxol is an important drug in the treatment of cancer but also expensive because the compound is harvested from a scarce resource, namely the pacific yew.
The Nicolaou synthesis is an example of convergent synthesis because the molecule is assembled from three 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.[3][4][5][6]
Retrosynthesis
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 acetal 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.
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.
Stereochemistry of addition to 4.2. The Re face was preferred.
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).
The acetyl group in 6.1 (Scheme 6) was removed to give primary alcohol 6.2. The Taxol ring (D) was added by an intramolecularnucleophilic substitution involving this hydroxyl group to give oxetane6.3. After acetylation, 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 D2 synthesis Scheme 6
Scheme 6
Tail addition
As shown in Scheme 7, Ojima lactam7.1 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 Scheme 7
Scheme 7
Precursor synthesis
Synthesis of the Diels-Alder dienophile for Ring C
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.
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.
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. Later, opening of the carbonate ester ring gives alcohol 6.5.
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.
TBS (tert-butyldimethylsilyl) [1]
tert-Butyldimethylsilyl triflate, lutidine, 4-(dimethylamino)pyridine, and dichloromethane
^K. C. Nicolaou; P. G. Nantermet; H. Ueno; R. K. Guy; E. A. Couladouros & E. J. Sorensen (1995). "Total Synthesis of Taxol. 1. Retrosynthesis, Degradation, and Reconstitution". J. Am. Chem. Soc. 117 (2): 624–633. doi:10.1021/ja00107a006. S2CID30357150.
^K. C. Nicolaou; J.-J. Liu; Z. Yang; H. Ueno; E. J. Sorensen; C. F. Claiborne; R. K. Guy; C.-K. Hwang; M. Nakada & 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. doi:10.1021/ja00107a007.
^
K. C. Nicolaou; Z. Yang; J.-J. Liu; P. G. Nantermet; C. F. Claiborne; J. Renaud; R. K. Guy & K. Shibayama (1995). "Total Synthesis of Taxol. 3. Formation of Taxol's ABC Ring Skeleton". J. Am. Chem. Soc. 117 (2): 645–652. doi:10.1021/ja00107a008.
^K. C. Nicolaou; H. Ueno; J.-J. Liu; P. G. Nantermet; Z. Yang; J. Renaud; K. Paulvannan & R. Chadha (1995). "Total Synthesis of Taxol. 4. The Final Stages and Completion of the Synthesis". J. Am. Chem. Soc. 117 (2): 653–659. doi:10.1021/ja00107a009.
