Stereoselective Synthesis of Functionalized Carbocycles and Heterocycles via an Ester Enolate Claisen/Ring-Closing Metathesis Manifold

Full text of DOI:10.1021/jo980118m

3158
J . Org. Chem. 1998, 63, 3158-3159
Sch em e 1
Ster eoselective Syn th esis of F u n ction a lized
Ca r bocycles a n d Heter ocycles via a n Ester
En ola te Cla isen /Rin g-Closin g Meta th esis
Ma n ifold †,‡
J ohn F. Miller, Andreas Termin, Kevin Koch, and
Anthony D. Piscopio*
Department of Chemistry, Amgen Inc., Boulder, Colorado 80301
Received J anuary 26, 1998
The Ireland ester enolate Claisen rearrangement1 and
variants thereof2 are well-established protocol for stereose-
lective carbon-carbon bond formation. A more contempo-
rary but equally powerful carbon-carbon bond-forming
process involves ring-closing metathesis of R,ω dienes3 as
catalyzed by the transition-metal carbene complexes I4 and
II.5-7 Our interest in obtaining diverse carbocyclic and
heterocyclic scaffolds for solid-phase combinatorial synthesis
prompted us to explore the possibility of utilizing these
reactions as consecutive key steps according to Scheme 1.8
For the purpose of this study, all of the starting esters
were derived from primary allylic alcohols and ω-unsatur-
ated carboxylic acids.9 Rearrangements were carried out
using one of several silyl ketene acetal-forming conditions
depending on the nature of the starting ester (Table 1). As
Sch em e 2a
* To whom correspondence should be addressed.
† Dedicated to the memory of Dr. Charles William (Bill) Murtishaw.
‡ Reported in part: Book of Abstracts, 213th ACS National Meeting, San
Francisco, April 13-17, 1997; American Chemical Society: Washington,
D.C., 1997; ORGN-064.
a
Key: (a) LDA (2 equiv), ZnCl2 (1 equiv), THF, -78 °C to rt. See
ref 2f. (b) KHMDS (2 equiv), allyl iodide, THF-DMF, -78 °C; (c)
Me3SiCHN2, MeOH, rt; (d) catalyst I (2 mol%), CH2Cl2, rt, 12 h.
(1) (a) Ireland, R. E.; Mueller, R. H.; Willard, A. K. J . Am. Chem. Soc.
1976, 98, 2868-2877. (b) Ireland, R. E.; Mueller, R. H. Ibid. 1972, 94, 5897-
5898.
anticipated, with glycolate-derived substrates (entries 1-8),
chelation-assisted enolate formation provided a high degree
of stereochemical control.2a-e Thus, relative stereochemical
preferences were altered by adjusting the olefin geometry
of the starting allylic alcohols. With esters derived from
5-hexenoic acid (entries 13 and 14), stereochemical toggling
was conveniently achieved through manipulation of enolate
geometry.10,11 With the exception of entry 15, ring-closing
metathesis substrates bearing geminal olefin substitution
required the use of the more reactive molybdenum catalyst
I (entries 6-10). In fact, substrates bearing relatively large
alkene substituents (Ph or Me3Si; entries 9 and 10, respec-
tively) required more than the usual amount of catalyst to
obtain useful quantities of desired products. Catalyst I was
also required for the efficient cyclization of allytin-12 and
sulfur-containing13,14 substrates (entries 4 and 11, respec-
tively). It is notable that, in addition to fused bicyclic
systems (entry 15), spirocyclic olefins are easily prepared
via this method (entry 16).
(2) (a) Bartlett P. A.; Barstow, J . F. J . Org. Chem. 1982, 47, 3933-3941.
(b) Bartlett, P. A.; Tanzella, D. J .; Barstow, J . F. Ibid. 1982, 47, 3941-
3945. (c) Sato, T.; Tajima, K.; Fujisawa, T. Tetrahedron Lett. 1983, 24, 729-
732. (d) Burke, S. D.; Fobare, W. F.; Pacofsky, G. J . J . Org. Chem. 1983,
48, 5221-5228. (e) Kallmerten, J .; Gould, T. J . Tetrahedron Lett. 1983, 24,
5177-5180. (f) Kazmaier, U. Angew. Chem., Int. Ed. Engl. 1994, 33, 998-
999. (g) Kazmaier, U.; Krebs, A. Angew. Chem., Int. Ed. Engl. 1995, 34,
2012-2014.
(3) For early examples of ring-closing metathesis see: (a) Grubbs, R.;
Miller, S. J .; Fu, G. C. Acc. Chem. Res. 1995, 28, 446-452. (b) Warel, S.;
Bachem, H.; Deckers, N.; Doring, N.; Katker, H.; Rose, E. Seifen, Oele, Fette,
Wachse 1989, 115, 538-545 and references therein. (c) Calderon, N. Acc.
Chem. Res. 1972, 5, 127-132.
(4) (a) Fu, G. C.; Grubbs, R. H. J . Am. Chem. Soc. 1992, 114, 7324-
7325. (b) Fu, G. C.; Grubbs, R. H. J . Am. Chem. Soc. 1993, 115, 3800-
3801. (c) Grubbs R. H.; Miller, S. J .; Fu, G. C. Acc. Chem. Res. 1995, 28,
446-452 and references therein. (d) Schmalz, H.-G. Angew. Chem., Int. Ed.
Engl. 1995, 107, 1981-1984 and references therein. (e) Schrock, R. R.;
Murdzek, J . S.; Bazan, G. C.; Robbins, J .; DiMare, M.; O’Reagan, M. J . Am.
Chem. Soc. 1990, 112, 3875-3886. (f) Bazan, G. C.; Schrock, R. R.; Cho,
H.-N.; Gibson, V. C. Macromolecules 1991, 24, 4495-4502.
(5) (a) Schwab, P.; Grubbs, R. H.; Ziller, J . W. J . Am. Chem. Soc. 1996,
118, 100-110.
(6) For recent applications of I and II in natural products synthesis see:
(a) Xu, Z.; J ohannes, C. W.; Salman, S. S.; Hoveyada, A. H. J . Am. Chem.
Soc. 1996, 118, 10926-10927. (b) Fu¨rstner, A.; Kindler, N. Tetrahedron
Lett. 1996, 37, 7005-7008. (c) Crimmins, M. T.; King, B. W. J . Org. Chem.
1996, 61, 4192-4193. (d) Houri, A. F.; Xu, Z.; Cogan, D. A.; Hoveyada, A.
J . Am. Chem. Soc. 1995, 117, 2943-2944. (e) Martin, S. F.; Liao, Y.; Chen,
H.-J .; Patzel, M.; Ramser, M. N. Tetrahedron Lett. 1994, 35, 6005-6008.
(f) Nicolaou, K. C.; Winnsinger; N.; Pastor, J .; Ninkovic, S.; Sarabia, F.;
He, Y.; Vourloumis, D.; Yang, Z.; Li, T.; Giannakakou, P.; Hamel, E. Nature
1997, 387, 268-262 and references therein.
As shown in Scheme 2, 3-substituted pipecolinic acids
were accessed using a slightly modified sequence. Thus,
(10) (a) Ireland, R. E.; Wipf, P.; Armstrong, J . D., III. J . Org. Chem. 1991,
56, 650-657. (b) Ireland, R. E.; Willard, A. K. Tetrahedron Lett. 1975, 46,
3975-3978.
(7) For
a
clever application of olefin metathesis to the synthesis of
(11) The method described herein complements the lactonic variant of
the Ireland-Claisen rearrangement in that trans, vicinally substituted
carbocyclic and heterocyclic products are unavailable using the latter
method. See: (a) Danishefsky, S.; Funk, R. L.; Kerwin, J . F. J r., J . Am.
Chem. Soc. 1980, 102, 6889-6891. (b) Burke, S. D.; Armistead, D. M.;
Shoenen, F. J .; Fevig, J . M. Tetrahedron 1986, 42, 2787-2801. (c) Angle,
S. R.; Breitenbucher, J . G.; Arniaz, D. O. J . Org. Chem. 1992, 57, 5947-
5955.
complex polycyclic frameworks using a titanium-based reagent see: Nico-
laou, K. C.; Postema, M. H. D.; Claiborne, C. F. J . Am. Chem. Soc. 1996,
118, 1565-1566.
(8) (a) Piscopio, A. D.; Miller, J . F, Koch, K. Book of Abstracts, 213th
ACS National Meeting, San Francisco, April 13-17, 1997; American
Chemical Society: Washington, D.C., 1997; ORGN-064. (b) Ng, R. A.;
Morrison, J . A.; Burke, S. D. Book of Abstracts, 213th ACS National Meeting,
San Francisco, April 13-17, 1997, ORGN-431. American Chemical Society,
Washington, D. C.; (c) J . Org. Chem. 1998, 63, 3160-3161.
(9) Studies using chiral, nonracemic secondary allylic alcohols are in
progress.
(12) Catalyst II gave small amounts of cyclization product.
(13) No product was oberved using catalyst II.
(14) (a) Lee, R. T.; Shon, Y.-S. Tetrahedron Lett. 1997, 38, 1283-1286.
(b) Armstrong, S.; Christie, B. A. Tetrahedron Lett. 1996, 37, 9373-9376.
S0022-3263(98)00118-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/22/1998

Communications
J . Org. Chem., Vol. 63, No. 10, 1998 3159
Ta ble 1
a
(A) LiHMDS, TMSCl (in situ), THF, -95 °C to rt; (B) LDA, TMSCl, THF, -78 °C to rt; (C) LDA, TMSCl, THF-DMPU, -78 °C to rt;
b
(D) TBDMSCl, Et3N, CH2Cl2, 0 °C to rt. Esterification conditions: ROH, EDCI, DMAP (cat.), CH2Cl2, rt or Me3SiCHN2, MeOH, rt.
c Ratios were determined through integration of characteristic resonances using 1H NMR at 400 MHz. Refers to combined diastereomer
d
mass following esterification. e (E) 2.5 mol % II, CH2Cl2, rt, 1-16 h. (F) 2.5 mol % II, 1,2-dichloroethane, 80 °C, 16 h. (G) 5 mol % I,
benzene, rt, 1 h. (H) 50 mol % I, benzene, rt, 6 h. (I) 100 mol % I, benzene, rt, 6 h. f Major diastereomer from [3,3]. Stereochemical
g
assignments were made based on diagnostic 1H NMR coupling constants and through comparison with known compounds. Refers to
h
i
combined diastereomer mass. Product contained small amounts of catalyst derived impurity (2,6-diisopropylaniline) following chroma-
tography. Oxidized to the corresponding sulfone (PhSeSePh, H2O2, CH2Cl2, Et2O, rt) prior to cyclization. The silyl ketene acetal was
heated at 65 °C for 2 h. Isolated and characterized as a mixture of diastereomers after chromatography.
j
k
l
diastereoselective Kazmier-Claisen rearrangement2f,g of 4a
and 4b gave acids 5a and 5b, respectively, again as a result
of a chelation-controlled enolization process. N-Allylation15
followed by esterification and ring-closing metathesis gave
the desired pipecolinates 6a and 6b in good overall yields.
In conclusion, we have demonstrated that the ester
enolate Claisen/ring-closing metathesis manifold is a power-
ful reaction tandem for the stereoselective synthesis of
functionalized carbocycles and heterocycles. Additional
work in this area, including application to the synthesis of
natural products, will be reported in due course.
Ack n ow led gm en t. We would like to thank Dr. Leszek
Poppe and Mr. Stephan Gro¨ger for their NMR assistance
and Ms. Bhavana Shah and Ms. Anjali Bhide for their mass
spectroscopy assistance.
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures and copies of spectra are included (22 pages).
(15) No detectable epimerization was observed.
J O980118M