Preparation and Diels-Alder cycloaddition of 2-acyloxyacroleins. Facile synthesis of functionalized taxol A-ring synthons

Full text of DOI:10.1021/jo960340w

2598
J . Org. Chem. 1996, 61, 2598-2599
be stereoselectively attached at C-2 in a chelation-
P r ep a r a tion a n d Diels-Ald er
Cycloa d d ition of 2-Acyloxya cr olein s.
F a cile Syn th esis of F u n ction a lized Ta xol
A-Rin g Syn th on s
controlled process,6 ideally with the carbamate (R )
NEt2) or carbonate (R ) O-i-Pr) derivatives of 2. The
most straightforward approach to aldehyde 2 is an
intermolecular cycloaddition of diene 3 with a 2-(acyloxy)-
acrolein 4. However, 2-(acyloxy)acroleins 4 had not been
Raymond L. Funk and Kenneth J . Yost, III
Department of Chemistry, The Pennsylvania State
University, University Park, Pennsylvania 16802
Received February 20, 1996
The antimitotic agent taxol has been heralded as a new
and exciting lead for the chemotherapeutic treatment of
cancer.1 Indeed, clinical trials for the treatment of breast,
melanoma, and lung cancers have been highly encourag-
ing, and taxol has recently been approved for the treat-
ment of ovarian and breast cancer.1g Consequently, an
enormous amount of effort has been directed toward the
total synthesis of taxol.1d-g Given the complexity of the
molecule, it is unlikely that a synthetic source will be
competitive with either the natural one or a semisyn-
thetic source from baccatin III (13-deacyltaxol). Fur-
thermore, the sensitive functionality has permited only
minor structural modifications of the natural material
to date and, hence, only limited access to structure-
activity information.1b,c,e,g However, simplified analogs
that can only be obtained via total synthesis can provide
further insight into the structure-activity relationships
which underlie taxol’s therapeutic activity. These efforts
may facilitate the discovery of a structurally simplified,
synthetically accessible taxol analog which possesses a
comparable or superior biological profile.
Critical to the realization of these goals is the discovery
of a concise, stereoselective synthesis of a suitably
functionalized taxane carbocyclic framework. Several
groups have recognized the benefits of initiating the
synthesis with a functionalized A-ring, attaching a C-
ring, and then completing the taxane ring system 1 by
bond closure at C-10, C-11 (e.g., Heck2 or Kishi-Nozaki3
reactions) or C-9, C-10 (e.g., pinacol4 or vinylogous aldol5
reactions). In order to investigate our own B-ring anne-
lation strategies, we sought a short synthesis of aldehyde
2 to which functionality appropriate for ring closure could
previously employed in Diels-Alder cycloaddition reac-
tions, due to the fact that a mild and versatile synthesis
of these valuable dienophiles was lacking.7 Conse-
quently, as our first goal we planned to investigate the
preparation and thermolysis of 5-(acyloxy)-4H-1,3-dioxins
5 based upon our previous discovery that the analogous
4-alkyl-4H-1,3-dioxins undergo facile retrocycloaddition
reactions to provide 3-alkylacroleins and formaldehyde.8
We describe herein the preparation of 2-(acyloxy)-
acroleins by this route and their cycloaddition reactions
which constitute an exceptionally brief synthesis of taxol
A-ring synthons.9
The (acyloxy)dioxins 5 could be readily prepared by
O-acylation of ketone 610 with a variety of anhydrides
(5a ,b,c,e: 1.3 equiv of RCO2COR, 2 equiv of NEt3, 0.2
equiv DMAP, CH2Cl2, reflux) or chloroformate/carbamoyl
halides (5d ,f,g: 1.3 equiv of RCOCl, 2 equiv of NEt3, 1.3
equiv of DMAP, rt). The outstanding reactivity of ketone
6 is noteworthy (cyclohexanone does not undergo O-
acylation with acetic anhydride under these conditions)11
(6) We, vide infra, and others have found that these addition
reactions can be highly stereoselective, see refs 2b and 5c.
(7) Only one example of this class of compounds, 2-acetoxyacrolein
(4a , R ) Me), has been reported and was prepared in low yield (10%),
accompanied by several byproducts and polymer, by treating (ac-
etoxymercurio)pyruvaldehyde diethyl acetal with acetyl chloride; see:
(a) Keiko, N. A.; Musorina, T. N.; Kalikhman, I. D.; Voronkov, M. G.
Zh. Org. Khim. 1979, 49, 170. 2-Alkoxyacroleins are known but were
anticipated to be inferior dienophiles based on the relative reactivity
of 3-alkoxy- vs 3-(acyloxy)-3-buten-2-ones; see: (b) Vogel, P.; Tamariz,
J . Helv. Chim. Acta 1981, 64, 188. For a general preparation of
2-alkoxyacroleins, see: (c) Williams, D. R.; Gaston, R. D.; Hoover, J .
F. Synthesis 1987, 909. For the SnCl4-catalyzed [4 + 3] cycloaddition
of 2-((trimethylsilyl)oxy)acrolein with butadiene, see: (d) Sasaki, T.;
Ishibashi, Y.; Ohno, M. Tetrahedron Lett. 1982, 23, 1693. For a review
of 2-substituted acrolein derivatives, see: (e) Keiko, N. A.; Voronkov,
M. G. Russ. Chem. Rev. 1993, 62, 751.
(8) Funk, R. L.; Bolton, G. L. J . Am. Chem. Soc. 1988, 110, 1290.
(9) For recent syntheses of taxane A-ring synthons, see: (a) Kishi,
Y.; Kress, M. H. Tetrahedron Lett. 1995, 36, 4583. (b) Winkler, J . D.;
Bhattacharya, S. K.; Liotta, F.; Batey, R. A.; Heffernan, G. D.;
Cladingboel, D. E.; Kelly, R. C. Ibid. 1995, 36, 2211. (c) Tjepkema, M.
W.; Wilson, P. D.; Wong, T.; Romero, M. A.; Audrain, H.; Fallis, A. G.
Ibid. 1995, 36, 6039. (d) Koskinen, A. M. P.; Karvinen, E. K.
Tetrahedron 1995, 51, 7555. (e) Wender, P. A.; Wessjohann, L. A.;
Peschke, B.; Rawlins, D. B. Tetrahedron Lett. 1995, 36, 7181. (f) Taber,
D. F.; Sahli, A.; Yu, H.; Meagley, R. P. J . Org. Chem. 1995, 60, 6571.
(10) This was prepared in two steps from tris(hydroxymethyl)-
aminomethane hydrochloride; see: Hoppe, D.; Schmincke, H.; Klee-
mann, H.-W. Tetrahedron 1989, 45, 687.
(1) For selected reviews, see: (a) Horwitz, S. B.; Manfredi, J . J .
Pharmac. Ther. 1984, 25, 83. (b) Kingston, D. G. I.; Samaranayake,
G.; Ivey, C. A. J . Nat. Prod. 1990, 53, 1. (c) Kingston, D. G. I. Pharmac.
Ther. 1991, 52, 1. (d) Swindell, C. S. Org. Prep. Proc. Int. 1992, 23,
465. (e) Nicolaou, K. C.; Dai, W.-M.; Guy, R. K. Angew. Chem., Int.
Ed. Engl. 1994, 33, 15. (f) Boa, A. N.; J enkins, P. R.; Lawrence, N. J .
Contemp. Org. Synth. 1994, 47. (g) Taxane Anticancer Agents; Georg,
G. I., Chen, T. T., Ojima, I., Vyas, D. M., Eds.; ACS Symposium Series
583: Washington, D.C., 1995.
(2) (a) Danishefsky, S. J .; Bornmann, W. G.; J ung, D. K.; Masters,
J . J .; de Gala, S. Tetrahedron Lett. 1993, 34, 7253. (b) Danishefsky,
S. J .; Young, W. B.; Masters, J . J . J . Am. Chem. Soc. 1995, 117, 5228.
(c) Danishefsky, S. J .; Masters, J . J .; J ung, D. K.; Snyder, L. B.; Park,
T. K.; Isaacs, R. C.; Alaimo, C. A.; Young, W. B. Angew. Chem., Int.
Ed. Engl. 1995, 34, 452.
(3) (a) Kishi, Y.; Miller, W. H.; Ruel, R.; Kress, M. H. Tetrahedron
Lett. 1993, 34, 5999. (b) Kishi, Y.; Miller, W. H.; Ruel, R.; Kress, M.
H. Ibid. 1993, 34, 6003.
(4) (a) Kende, A. S.; J ohnson, S.; Sanfilippo, P.; Hodges, J . C.;
J ungheim, L. N. J . Am. Chem. Soc. 1986, 108, 3513. (b) Nicolaou, K.
C.; Yang, A.; Sorensen, E. J .; Nakada, N. J . Chem. Soc., Chem.
Commun. 1993, 1024. (c) Nicolaou, K. C.; Claiborne, C. F.; Nantermet,
P. G.; Couladouros, E. A.; Sorensen, E. J . J . Am. Chem. Soc. 1994,
116, 1591. (d) Nicolaou, K. C.; Yang, A.; Liu, J . J .; Ueno, H.;
Nantermet, P. G.; Guy, R. K.; Claiborne, C. F.; Renaud, J .; Couladouros,
E. A.; Paulvannan, K.; Sorensen, E. J . Nature 1994, 367, 630.
(5) (a) Kuwajima, I.; Furukawa, T.; Horiguchi, Y. J . Am. Chem. Soc.
1989, 111, 8277. (b) Kuwajima, I.; Horiguchi, Y.; Morihira, K.; Seto,
M. J . Org. Chem. 1994, 59, 3165. (c) Kuwajima, I.; Horiguchi, Y.;
Tsuruta, K.; Waizumi, N.; Nakamura, T. Synlett 1994, 584.
(11) However, aldehydes can be converted to the corresponding enol
acetates using these conditions, see: Secrist, J . A., III; Cook, S. L.;
Cousineau, T. J . Synth. Commun. 1979, 9, 157.
0022-3263/96/1961-2598$12.00/0 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 8, 1996 2599
Ta ble 1. Cycloa d d ition s of 2-Acyloxya cr olein s
and may reflect a more favorable equilibrium with the
enol tautomer and/or a more nucleophilic enol tautomer
due to a vinylogous alpha effect.
We were gratified to discover that all of the 5-(acyloxy)-
dioxins 5 underwent smooth retrocycloaddition reactions
in the presence of 1% hydroquinone upon warming (100
°C) in toluene under an argon atmosphere, or in meth-
ylene chloride in a sealed tube, and were complete after
12-24 h as noted by TLC or 1H NMR spectroscopy
(toluene-d8). The resulting 2-(acyloxy)acroleins are rea-
sonably stable compounds and can be purified, if neces-
sary, by column chromatography. However, these com-
pounds polymerize upon standing at room temperature
and are best stored at low temperatures (-20 °C).
2-(Acyloxy)acroleins 4 were found to be excellent
substrates for Diels-Alder reactions as illustrated by the
examples shown in Table 1. Entries a and b demonstrate
that these transformations can be conveniently ac-
complished by generating the dienophile in situ from the
corresponding acyloxydioxin 5. Moreover, the stereo-
selectivity for the reaction of 4b with cyclopentadiene
(entry a) is similar to that observed with methacrolein
wherein the methyl group has been found to prefer the
endo position (76:24, 100 °C).12 The regioselectivity of
the cycloaddition with isoprene is moderate (entry b) but
is complete with the silyloxy-substituted dienes shown
in entries c and d. The example shown in entry e
signifies that (acyloxy)acroleins can also serve as com-
petent heterodienes in cycloadditions with electron rich
alkenes under the influence of lanthanide catalysis.13
Most importantly, optimized conditions for cyclizations
with the tetrasubstituted dienes shown in entries f and
g were eventually discovered and provide access to highly
functionalized taxol A-ring synthons in excellent yields.
These cycloadditions were unsuccessful in the absence
of Lewis acids at temperatures up to 150 °C. Tin
tetrachloride was the most effective of the various Lewis
acids examined (e.g., TiCl4, EtAlCl2, BF3, MgBr2), pro-
vided that the presumed bidentate complex generated
from the acyloxyacrolein and SnCl4 was soluble at -78
°C. Hence, the more hydrocarbon-rich (acyloxy)acroleins
4c and 4d were preferred. Varying amounts (10-15%)
of a product derived from heterocycloaddition with the
aldehyde moiety of the acycloxyacroleins was observed
when CH2Cl2 was the solvent, although this side product
could be largely suppressed when toluene was employed
as a cosolvent.
a
b
Dienophile generated in situ. Prepared in one-pot from
3-bromo-2,4-dimethyl-1,3-pentadiene:14 (1) 2 equiv of t-BuLi, -78
°C; (2) 1.1 equiv of thienyl-Cu(CN)Li; (3) 0.95 equiv of methyl
4-iodobutyrate, -78 to 0 °C; 88%. c Prepared from 3-bromo-2,4-
dimethyl-1,3-pentadiene:14 (1) 2 equiv of t-BuLi, -78 °C; 5 equiv
of oxirane; 90%; (2) NEt3, DMAP, (C5H11CO)2O; 96%.
mented the utility of these valuable reactants in Diels-
Alder cycloaddition reactions. Functionalized taxol A-
rings are now directly accessible and, moreover, can be
further modified by stereoselective addition reactions
with organometallic reagents (see the supporting infor-
mation). Thus, this methodology facilitates the prepara-
tion of compounds suitable for the elaboration of the
complete taxane framework and related taxol analogs.
These possibilities are under active investigation.
Ack n ow led gm en t. We appreciate the financial sup-
port provided by the National Institutes of Health
(GM28553).
In summation, we have developed the first general and
efficient synthesis of 2-(acyloxy)acroleins and have docu-
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic data
and experimental details for the preparation of compounds
4a -g, 5a -g, the cycloadducts in Table 1, and the product
obtained from treatment of cycloadduct g with PhMgBr (10
pages).
(12) Kobuke, Y.; Fueno, T.; Furukawa J . Am. Chem. Soc. 1970, 92,
6548.
(13) Danishefsky, S.; Bednarski, M. Tetrahedron Lett. 1985, 26,
2507.
(14) Sandler, S. R. Ph.D. Thesis, The Pennsylvania State University,
University Park, PA, 1960.
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