Paclitaxel synthetic studies. A Diels-Alder approach to the A-ring

Article abstract of DOI:10.1039/b005533f

Highly substituted cyclohexenes corresponding to the A-ring of the anti-cancer diterpene natural product paclitaxel are synthesised using a Diels-Alder reaction and decarboxylative elimination as the key steps.

Full text of DOI:10.1039/b005533f

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Paclitaxel synthetic studies. A Diels–Alder approach to the A-ring†
Santiago Carballares,a Donald Craig,*a Charlotte A. L. Lane,a A. Roderick MacKenzie,b William P. Mitchella
and Anthony Woodb
a Centre for Chemical Synthesis, Department of Chemistry, Imperial College of Science, Technology and Medicine,
London, UK SW7 2AY. E-mail: d.craig@ic.ac.uk
b Pfizer Central Research, Sandwich, Kent, UK CT13 9NJ
Received 11th July 2000, Accepted 4th August 2000
First published as an Advance Article on the web 29th August 2000
Highly substituted cyclohexenes corresponding to the A-ring
of the anti-cancer diterpene natural product paclitaxel are
synthesised using a Diels–Alder reaction and decarboxy-
lative elimination as the key steps.
The paclitaxel family of molecules, exemplified by the parent
paclitaxel (Taxol®) 11 has commanded the attention of a
significant number of organic chemistry research teams world-
wide.2 The strategies we are pursuing for the assembly of
paclitaxel involve late-stage formation of the eight-membered
B-ring by the joining together of C-9 and C-8 using radical- or
carbocation-mediated cyclisation of a substrate 2; in one of the
approaches we intend to form the C-ring in the same step using
a Lewis acid-induced carbocation-mediated cascade process
starting from 3 in which the C-3–C-4 bond is formed as well.
Both these sequences require a pre-formed A-ring fragment
such as 5, and this Communication reports the synthesis of key
precursor 4 (Scheme 1).
Scheme 2
diene and dienophile termini; subsequent selective decarbox-
ylation and oxidation of adduct 8 would deliver the required C-
11–C-12 unsaturation, as in 9 (Scheme 2).
The required diene was synthesised using the Julia procedure
for the olefination step.‡ Thus, mono-protection of diol 104
followed by oxidation using TPAP–NMO5 gave enal 11.
Combination of 11 with the lithio-anion of benzyloxy(phe-
nylsulfonyl)methane6 and in situ trapping with benzoyl chloride
In our synthetic plan for 4 we were keen to incorporate the
required C-13 oxygenation directly using the Diels–Alder
reaction rather than introducing it later by oxidation of C-13.2a
This choice posed a strategic problem concerning Diels–Alder
regiochemistry, in that [4+2] cycloaddition of 6 and a simple
alkyne-containing dienophile such as a but-2-ynoate ester was
likely to give a cycloadduct 7 bearing a C-12 rather than a C-11
ester substituent. Therefore it was decided to use citraconic
anhydride as the dienophile,3 since it was anticipated that the
regiochemical orientation of the Diels–Alder reaction would be
controlled by steric repulsion between the fully-substituted
gave a mixture of esters, which was exposed to samarium(II
)
iodide7 to provide the required differentially protected diene 12.
Diels–Alder reaction of 12 with citraconic anhydride gave
cycloadduct 13 as a single regio- and stereoisomer in 63% yield
based on 12 (Scheme 3). The endo stereochemistry of 13 was
inferred from the analogous reaction of 12 with maleic
anhydride,3 which had given a crystalline product amenable to
X-ray structure determination.
With Diels–Alder adduct 13 in hand it was necessary to
differentiate between the anhydride carbonyl groups. Treatment
of 13 with dimethylamine gave an unstable§ half-amide as a
Scheme 3 Reagents and conditions: i, NaH (1.01 eq.), THF (0.07 M), rt, 1
h, then TBDPSCl (1 eq.), rt, 15 h; ii, TPAP (2.4 mol%), NMO (1.6 eq.),
powdered 4 Å mol sieves, CH2Cl2 (0.5 M), rt, 1 h; iii, BnOCH2SO2Ph (1
eq.), LDA (1 eq.), THF (0.1 M), 278 °C, 10 min, then add 11, 278 °C, 10
min, then add BzCl (1 eq.), 278 °C?rt, 45 min; iv, SmI2 (5 eq.), DMPU (15
eq.), THF, (0.1 M), rt, 1 h; v, citraconic anhydride (2 eq.), PhMe (3.3 M),
150 °C, 24 h.
Scheme 1
† Experimental details for 4, 13, 16, 17, 19–21 are available as supplemen-
tary data. For direct electronic access see http://www.rsc.org/suppdata/cc/
b0/b005533f/
DOI: 10.1039/b005533f
Chem. Commun., 2000, 1767–1768
This journal is © The Royal Society of Chemistry 2000
1767

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neously undergo b-elimination with concerted loss of CO2 and
chloride ion.10 Amide 19 was converted in high yield by
desilylation and esterification into the 3,5-dinitrobenzoate 20,
which yielded crystals suitable for X-ray diffraction analysis.
Similar treatment of 4 gave the crystalline ester 21.††
In summary, we have demonstrated that a highly substituted
cyclohexa-1,4-diene may be accessed using a sequential Diels–
Alder–decarboxylative olefination approach to introduce the C-
11–C-12 unsaturation present in the paclitaxel A-ring. Ongoing
studies in our laboratory seek to identify a direct [4+2]
cycloaddition entry to 17, and to develop ways of making the
cycloaddition enantioselective. The results of these and related
studies will be reported in due course.
We thank the EPSRC and Pfizer Central Research (CASE
Studentships to C. A. L. L. and W. P. M.) and the Spanish
Ministerio de Educacion y Ciencia (Studentship to S. C.) for
financial support of this research.
Scheme 4 Reagents and conditions: i, Me2NH (5 eq.), THF (0.5 M), rt, 16
h; ii, i-BuOCOCl (1.1 eq.), Et3N (1.1 eq.), CH2Cl2 (0.1 M), 215 °C?rt; iii,
2-mercaptopyridine N-oxide (1 eq.), Et3N (1.1 eq.), CCl3 (0.03 M), 80 °C,
2 h; iv, pyrrolidine (5 eq.), THF (0.5 M), rt, 2 h; v, i-BuOCOCl (1.1 eq.),
Et3N (2.5 eq.), CH2Cl2 (0.2 M), rt, 1 h; vi, NCS (1 eq.), Et3N (2 eq.), H2O
(5 eq.), THF (0.1 M), rt, 2 h.
Notes and references
‡ All yields reported herein refer to isolated, pure materials which had 1H
and 13C NMR, IR and high-resolution MS characteristics in accord with the
proposed structures.
single regioisomer,¶ which was converted into the mixed
anhydride 14 by addition of isobutyl chloroformate. Treatment
of 14 with N–hydroxy-2-thiopyridone in CCl4 under reflux8
gave in low yield the product 15 of decarboxylation–chlorina-
tion. The stereochemistry of 15 was presumed on the basis of
expected attack by CCl4 on the less hindered face of the
intermediate radical.∑ All attempts to effect base-mediated
elimination of the elements of HCl from 15 resulted in the
formation of the b,g-unsaturated isomer 18. In a modified
approach, treatment of cycloadduct 13 with pyrrolidine gave a
half-amide adduct which was considerably more stable than the
dimethylamine-derived analogue. Surprisingly, subsequent ex-
posure of this adduct to the mixed anhydride-forming condi-
tions resulted in cyclodehydration, giving the cyclic O-
acylketaminal 16 in virtually quantitative yield.** The desired
oxidation at C-11 was now effected by treatment of 16 with
NCS–aqueous THF, giving a-chloro anhydride 17 in high yield
(Scheme 4). The difference in behaviour of the dimethylamino
and pyrrolidino analogues under the carbonic anhydride-
forming conditions is striking; the apparent greater nucleophi-
licity of the amide oxygen in the latter is consistent with greater
delocalisation of the amide nitrogen lone pair into the carbonyl
group, which in turn inhibits the reverse reaction during ring-
opening of 13 with the secondary amine nucleophile.
The final part of the synthesis involved decarboxylation and
introduction of the double bond, and again this depended on
initial regioselective ring-opening to give a b-chloro carboxylic
acid. In the event, treatment of 17 with a large excess of
pyrrolidine gave amide 19 as a single regioisomer (Scheme 5).
Interestingly, 19 existed in CDCl3 and d6-DMSO solutions as
mixtures of rotamers. In similar fashion, treatment of 17 with
benzyltrimethylammonium methoxide in large excess gave
methyl ester 4. Mechanistically, the presumed initial ring-
opened half-amide and -ester either might form b-lactone
intermediates which subsequently lose CO2,9 or might sponta-
§ The half-amide had a half-life in CDCl3 of approximately 14 h.
¶ Treatment of this half-amide with ethyl chloroformate gave a mixed
anhydride which was reduced using sodium borohydride to give a g-lactone.
The appearance of both lactone -CH2- protons as simple doublets confirmed
the absence of a vicinal proton, and therefore the complete regioselectivity
of ring-opening of 13.
∑ This assumption was later confirmed by single-crystal X-ray diffraction
analysis of the product of one-pot epoxidation–debenzylation mediated by
dimethyldioxirane.
** For other examples of cyclic ketaminal formation, see: A. E. Baydar and
G. V. Boyd, J. Chem. Soc., Perkin Trans. 1, 1978, 1360; I. Tapia, V.
Alcázar, J. R. Morán and M. Grande, Bull. Chem. Soc. Jpn., 1990, 63,
2408.
†† We thank Professor David Williams and Dr Andrew White of this
Department for these determinations.
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3 Maleic anhydride reacted quantitatively with 12, giving only the endo
cycloadduct: C. A. L. Lane, PhD Thesis, University of London, 1997.
For the related Diels–Alder reaction of citraconic anhydride with (E)-
1-ethoxy-4-methylpenta-1,3-diene, see: F. Kienzle, I. Mergelsberg, J.
Stadlwieser and W. Arnold, Helv. Chim. Acta, 1985, 68, 1133.
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Scheme 5 Reagents and conditions: i, pyrrolidine (50 eq.), DMSO–DMPU
(5:3; 0.14 M), rt , 2 h; ii, BnMe3N+OMe2 (50 eq.), MeCN–DMPU (0.14 M),
rt, 27 h; iii, TBAF (1.1 eq.), THF (0.2 M), rt, 15 min; iv, ArCOCl (1.1 eq.),
Et3N (1.5 eq.), DMAP (0.2 eq.), CH2Cl2 (0.2 M), rt.
9 For a review of b-lactone chemistry, see: A. Pommier and J.-M. Pons,
Synthesis, 1993, 441.
10 For analogous olefin-forming reactions from b-haloesters, see: J. L.
Belletire and D. R. Walley, Tetrahedron Lett., 1983, 24, 1475.
1768
Chem. Commun., 2000, 1767–1768