In the course of our studies in the area of phosphine
organocatalysis,5-9 we explored intramolecular variants of
Lu’s phosphine-catalyzed [3 + 2] cycloaddition reported in
1995.5a,10-12 Whereas the intermolecular cycloaddition
generally provides mixtures of regio- and stereoisomeric
adducts, the intramolecular cycloaddition delivers diquinanes
in structurally homogeneous form. As a regio- and stereo-
controlled intermolecular cycloaddition of this type would
be of great utility, we explored dipolarophiles possessing
γ-heteroatom substitution, as in the case of enones 3, which
are prepared conveniently through the Achmatowicz reaction
of furfuryl alcohol.13 It was postulated that such γ-heteroatom
substitution should (a) activate the dipolarophile toward
cycloaddition, (b) reinforce the inherent regiochemical bias,
and (c) direct the diastereofacial selectivity of cycloaddition.
Here, we report that “Achmatowicz enones” 3 engage in
regio- and stereocontrolled intermolecular [3 + 2] cycload-
dition, thus providing direct access to the iridoid ring system
4. This methodology was applied to the synthesis of the
iridoid glycoside (+)-geniposide 1,14 which displays anti-
tumor15 and anti-inflammatory16 activity. The total asym-
metric synthesis of (+)-geniposide 1 constitutes a formal
synthesis of its aglycone (+)-genipin 2,17,18 which recently
has garnered attention as an effective treatment for type II
diabetes (Scheme 1).19
Scheme 2. Kinetic Resolution of rac-3b Using
Palladium-Catalyzed Allylic Substitution
a Theoretical yields are based on a maximum 50% isolated yield.
analysis of the 4,5-dichlorophthalimide adduct of (S)-3b
using the anomalous dispersion method and is consistent with
the stereochemical models developed by Trost for related
kinetic resolutions.21
With (S)-3b in hand, the phosphine-catalyzed [3 + 2]
cycloaddition was attempted using ethyl-2,3-butadienoate.
Gratifyingly, using triphenylphosphine as catalyst (10 mol
%) in toluene (0.2 M) at 110 °C, the desired cycloadduct 4
was obtained in 63% isolated yield after 30 min as a single
regio- and stereoisomer, as confirmed by single-crystal X-ray
diffraction analysis. Note that while 2 equiv of (S)-3b is used
in the cycloaddition, unreacted (S)-3b was recovered in 96%
isolated yield (Scheme 3).
Scheme 1
.
Retrosynthetic Analysis of (+)-Geniposide 1 and
(+)-Genipin 2
Installation of the R,ꢀ-unsaturated methyl ester was
accomplished in a stepwise fashion. Cycloadduct 4 was
converted to the cyanohydrin, which upon elimination
furnished the R,ꢀ-unsaturated nitrile 5 in 60% isolated yield
over two steps. Chemoselective reduction of the R,ꢀ-
(12) For related phosphine-catalyzed cycloadditions, see: (a) Xu, Z.; Lu,
X. Tetrahedron Lett. 1997, 38, 3461. (b) Xu, Z.; Lu, X. J. Org. Chem.
1998, 63, 5031. (c) Zhu, X.-F.; Lan, J.; Kwon, O. J. Am. Chem. Soc. 2003,
125, 4716. (d) Zhu, X.-F.; Schaffner, A.-P.; Li, R. C.; Kwon, O. Org. Lett.
2005, 7, 2977. (e) Tran, Y. S.; Kwon, O. J. Am. Chem. Soc. 2007, 129,
12632. (f) Henry, C. E.; Kwon, O. Org. Lett. 2007, 9, 3069. (g) Creech,
G. S.; Kwon, O. Org. Lett. 2008, 10, 429.
Exposure of commercially available furfuryl alcohol to
m-CPBA in dichloromethane delivered lactol rac-3a in 78%
yield,13 which was converted to the pivalate rac-3b in 80%
yield. Kinetic resolution of rac-3b was attempted under the
conditions of palladium-catalyzed allylic substitution em-
ploying p-nitrobenzyl alcohol as the nucleophile.20 After
careful optimization, it was found that chirally modified
palladium catalysts arising from the combination of [(η3-
C3H5)PdCl]2 (1.0 mol %) and the parent Trost ligand (3 mol
%) enable recovery of the allylic pivalate (S)-3b in 92% ee
in a satisfactory 70% theoretical isolated yield (Scheme 2).
Optically pure (S)-3b is readily obtained upon recrystalli-
zation from pentane. The byproduct (R)-3c was isolated in
96% theoretical isolated yield in 68% ee. Absolute stereo-
chemistry was determined by single-crystal X-ray diffraction
(13) (a) Achmatowicz, O., Jr.; Bukowski, P.; Szechner, B.; Zwi-
erzchowska, Z.; Zamojski, A. Tetrahedron 1971, 27, 1973. (b) Lefebvre,
Y. Tetrahedron Lett. 1972, 2, 133.
(14) For the isolation of (+)-geniposide, see: Inouye, H.; Saito, S.
Tetrahedron Lett. 1969, 28, 2347.
(15) (a) Ueda, S.; Iwahashi, Y.; Tokuda, H. J. Nat. Prod. 1991, 54,
1677. (b) Lee, M.-J.; Hsu, J.-D.; Wang, C.-J. Anticancer Res. 1995, 15,
411.
(16) Koo, H.-J.; Lim, K.-H.; Jung, H.-J.; Park, E.-H. J. Ethnopharmacol.
2006, 103, 496.
(17) For the isolation of (+)-genipin, see: Djerassi, C.; Gray, J. D.; Kincl,
F. A. J. Org. Chem. 1960, 25, 2174.
(18) For the conversion of (+)-geniposide to its aglycone (+)-genipin,
see: (a) Endo, T.; Taguchi, H. Chem. Pharm. Bull. 1973, 21, 2684. (b)
Tanaka, M.; Kigawa, M.; Mitsuhashi, H.; Wakamatsu, T. Heterocycles 1991,
32, 1451.
(19) Zhang, C.-Y; Parton, L. E.; Ye, C. P.; Krauss, S.; Shen, R.; Lin,
C.-T; Porco, J. A.; Lowell, B. B. Cell Metab. 2006, 3, 417.
(20) For related allylic alkylations, see: (a) van der Deen, H.; van
Oeveren, A.; Kellogg, R. M.; Feringa, B. L. Tetrahedron Lett. 1999, 40,
1755. (b) Comely, A. C.; Eelkema, R.; Minnaard, A. J.; Feringa, B. L.
J. Am. Chem. Soc. 2003, 125, 8714. (c) Babu, R. S.; O’Doherty, G. A.
J. Am. Chem. Soc. 2003, 125, 12406. (d) Babu, R. S.; Zhou, M.; O’Doherty,
G. A. J. Am. Chem. Soc. 2004, 126, 3428. (e) Trost, B. M.; Toste, F. D.
J. Am. Chem. Soc. 2003, 125, 3090.
(11) For the seminal phosphine-catalyzed [3 + 2] cycloaddition reported
by Lu, see: (a) Zhang, C.; Lu, X. J. Org. Chem. 1995, 60, 2906. (b) Xu,
Z.; Lu, X. Tetrahedron Lett. 1997, 38, 3461. (c) Xu, Z.; Lu, X. Tetrahedron
Lett. 1999, 40, 549. (d) Xu, Z.; Lu, X. J. Org. Chem. 1998, 63, 5031. (e)
(21) Trost, B. M.; Machacek, M. R.; Aponick, A. Acc. Chem. Res. 2006,
39, 747.
Du, Y.; Lu, X.; Yu, Y. J. Org. Chem. 2002, 67, 8901
.
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