synthesis of sidechain of docetaxel?

Answer 1

In J. Org. Chem. , 59(6), 1239, an asymmetric Mannich reaction was used.

Mannich reaction:
enolate + imine = b-amino carbonly compound. This is the same as an Aldol reaction, with the imine replacing the aldehyde/ketone component.

Boc-amine reacted with benzaldehyde to form the protected imine.

The enolate component was prepared by reacting benzyloxyacetyl chloride (PhCH2OCH2-COCl) with a chiral auxiliary (specifically camphorsultam).

Lithium bis(trimethylsilyl)amide was used as a base to carry out the Mannich reaction. The chiral sulfonamide was cleaved, giving the protected sidechain).


If I had to come up with another way, I might prepare the cis-cinnamic acid, form the epoxide and do an aminohydroxylation.

Answer 2

Docetaxel is a semi-synthetic antineoplastic agent obtained from the Taxus baccata. It is an analugue of paclitaxel, modified for better solubility in water by -OH group addition. It is a mitotic inhibitor because of its effect on the cell during mitosis. It is used to treat breast, lung, and prostate cancers, and may be used for other cancers as well. It is a white to off-white crystalline powder; insoluble in water; soluble in ethanol and acetone; melting point 190 C. The chemical designation is (2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-12b- (acetyloxy)- 12- (benzoyloxy)- 2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-4,6,11-trihydroxy-4a,8,13,13- tetramethyl-5-oxo-7,11-methano-1H-cyclodeca[3,4]benz[1,2-b]oxet-9-yl ester.
Paclitaxel, containing oxetane ring nucleus, is one of the most medicinally valuable diterpenes in which phyto and vitamin A1 are classified. It is an antineoplastic agent that acts by promoting and stabilizing the polymerization of microtubules. It is semi-synthetic or originally obtained from the Pacific yew tree (Taxus brevifolia). It is a white to off-white crystalline powder; insoluble in water; soluble in ethanol and acetone; melting point 216 - 217 C. The chemical designation is 5-beta,20-epoxy-1,2-alpha, 4,7-beta,10-beta,13-alpha- hexahydroxy-tax- 11-en-9-one 4,10-diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenyl Isoserine. Paclitaxel is commonly referred to Taxol, by the trade name. Paclitaxel is a representative compound belong to the family of compounds called taxanes. It binds to the N-terminal region of b-tubulin and promotes the formation of highly stable microtubules that resist depolymerization, and thus inhibits cell replication. It is used to treat cancers of ovaries, breast, head, neck and certain types of lung cancer, as well as cancers of skin and mucous membrane more commonly found in patients suffered from AIDS (acquired immunodeficiency syndrome). Other related taxanes modified by substitution of functional side chains including N-acyl groups, -OH group addition and stereochemistry for better solubility in water, oral bioavailability and cytotoxic activity include followings:

10-Deacetyl-7-epibaccatin III
10-Deacetyl-7-epipaclitaxel
10-Deacetyl-7-xylosylpaclitaxel C
10-Deacetyl-7-xylosylpaclitaxel ( CAS #: 90332-65-3)
10-Deacetylbaccatin III ( CAS #: 32981-86-5)
10-Deacetylcephalomannine
10-Deacetyl-N-Debenzoylpaclitaxel
10-Deacetylpaclitaxel
10-Deaceyl-7-xylosylpaclitaxel
13-Acetyl-9-dihydrobaccatin III ( CAS #: 142203-65-4)
2',3'-Dihydrocephalomannine (Paclitaxel E)
2-Debenzoylpaclitaxel
7-Epi-10-Deacetylcephalomannine
7-Epicephalomannine
7-Epipaclitaxel ( CAS #: 105454-04-4)
7-Xylosylpactlitaxel C
7-Xylosylpactlitaxel
Baccatin III ( CAS #: 27548-93-2, (the form that side chains are removed)
Cephalomannine (( CAS #: 71610-00-9, Paclitaxel B)
Docetaxel ( CAS #: 114977-28-5)
Isocephalomannine (2-Debenzoylpaclitaxel-2-Pentenoate)
N-Benzoyl-(2R, 3S)-3-phenylisoserine ( CAS #: 132201-33-3, side chain in paclitaxel)
N-Benzoyl-(2R, 3S)-3-phenylisoserine esters (side chain in paclitaxels)
N-Debenzoylpaclitaxel
N-Methylpaclitaxel C
N-Methylpaclitaxel
Paclitaxel C
Paclitaxel D
Paclitaxel F
Paclitaxel