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.
1 Isolation: W. C. Wani, H. L. Taylor, M. E. Wall, P. Coggon and A. T.
McPhail, J. Am. Chem. Soc., 1971, 93, 2325.
2 Total synthesis: (a) K. C. Nicolaou, H. Ueno, J.-J. Liu, P. G. Nantermet,
Z. Yang, J. Rebaud, K. Paulvannan and R. Chadha, J. Am. Chem. Soc.,
1995, 117, 653, and preceding papers; (b) R. A. Holton, H. B. Kim, C.
Somoza, F. Liang, R. J. Biediger, P. D. Boatman, M. Shindo, C. C.
Smith, S. C. Kim, H. Nadizadeh, Y. Suzuki, C. L. Tao, P. Vu, S. H.
Tang, P. S. Zhang, K. K. Murthi, L. N. Gentile and J. H. Liu, J. Am.
Chem. Soc., 1994, 116, 1599, and preceding paper; (c) J. J. Masters, J. T.
Link, L. B. Snyder, W. B. Young and S. J. Danishefsky, Angew. Chem.,
Int. Ed. Engl., 1995, 34, 1723; (d) P. A. Wender, N. F. Badham, S. P.
Conway, P. E. Floreancig, T. E. Glass, J. B. Houze, N. E. Krauss, D. S.
Lee, D. G. Marquess, P. L. McGrane, W. Meng, M. G. Natchus, A. J.
Shuker, J. C. Sutton and R. E. Taylor, J. Am. Chem. Soc., 1997, 119,
2757; (e) K. Morihira, R. Hara, S. Kawahara, T. Nishimori, N.
Nakamura, H. Kusama and I. Kuwajima, J. Am. Chem. Soc., 1998, 118,
12980; (f) T. Mukaiyama, I. Shiina, H. Iwadare, M. Saitoh, T.
Nishimura, N. Ohkawa, H. Sakoh, K. Nishimura, Y. Tani, M.
Hasegawa, K. Yamada and K. Saitoh, Chem. Eur. J., 1999, 5, 121.
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.
4 J. A. Marshall and T. M. Warne, J. Org. Chem., 1971, 36, 178; R.
Gleiter, R. Merger and B. Nuber, J. Am. Chem. Soc., 1992, 114,
8921.
5 S. V. Ley, J. Norman, W. P. Griffith and S. P. Marsden, Synthesis, 1994,
639.
6 H. Finch, A. M. M. Mjalli, J. G. Montana, S. M. Roberts and R. J. K.
Taylor, Tetrahedron, 1990, 46, 4925.
7 G. E. Keck, K. A. Savin and M. A. Weglarz, J. Org. Chem., 1995, 60,
3194.
8 D. H. R. Barton, D. Crich, Y. Hervé, P. Potier and J. Thierry,
Tetrahedron, 1985, 41, 4347.
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