that allows for rapid access to substrates and requires mild
reaction conditions compatible with various functional
groups.
functional group at the C4 position that would increase the
1,3-diaxial interaction with the C6 allyl substituent (Figure
1). The unfavorable 1,3-diaxial interaction of the axially
Herein, we report the facile and efficient synthesis of
4-hydroxy-2,6-cis-tetrahydropyrans via a tandem CM/thermal
SN2′ reaction under mild reaction conditions and its application
to a protecting-group-free synthesis of (()-diospongin A.
To test the feasibility of the tandem reaction, we prepared
hydroxy alkene 16 by the addition of CH2dCH(CH2)3MgBr
to PhCHO (84%). Treatment of 1 with CH2dCHCH2Cl in
the presence of Grubbs’ second-generation catalyst (Grubbs
II, (IMesH2)(PCy3)(Cl)2RudCHPh)7 and subsequent in-
tramolecular SN2′ reaction8,9 of the corresponding allylic
chloride 2 under thermal conditions (tandem CM/thermal
SN2′ reaction, Table 1)10,11 provided a mixture of 4a and 4b
Figure 1. Introduction of 1,3-diaxial interactions to the tandem CM/
thermal SN2′ reaction.
Table 1. Initial Attempts for the Tandem CM/Thermal SN2′
Reaction
oriented C4 substituent and the C6 allyl substituent in
conformation 5B is larger than that of the hydrogen and the
C4 substituent in conformation 5A, thus preferentially
affording 2,6-cis-tetrahydropyran 6a. In addition, the C4
substituent could be transformed to other useful functional
groups. Since 4-hydroxy-2,6-cis-tetrahydropyrans and 2,6-
cis-tetrahydropyran-4-ones are abundant structural motifs in
biologically important natural products,3 we hypothesized
that a hydroxy group at the C4 position could satisfy these
requirements.
entry
1
conditions
yield (%)a
66
drb
2:1
CH2dCHCH2Cl, Grubbs II
(10 mol %), CH2Cl2
(0.1-0.02 M), reflux, 16 h
CH2dCHCH2Cl, Grubbs II
(10 mol %), CH2Cl2
(0.1 M), reflux, 3 h,
then toluene (0.02 M)
reflux, 12 h
CH2dCHCH2Br, Grubbs II
(10 mol %), CH2Cl2
(0.1 M), reflux, 2 h, then
toluene (0.02 M),
To test the hypothesis, we prepared hydroxy alkenes (7
and 10)13 and subjected them to the tandem reaction
(5) For recent examples of tetrahydropyran synthesis, see: (a) Minami,
T.; Moriyama, A.; Hanaoka, M. Synlett 1995, 663–665. (b) Matsukura, H.;
Morimoto, M.; Koshino, H.; Nakata, T. Tetrahedron Lett. 1997, 38, 5545–
5548. (c) Cloninger, M. J.; Overman, L. E. J. Am. Chem. Soc. 1999, 121,
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55, 14097–14110. (e) Wong, M.-K.; Chung, N.-W.; He, L.; Yang, D. J. Am.
Chem. Soc. 2003, 125, 158–162. (f) Clark, J. S.; Whitlock, G.; Jiang, S.;
Onyia, N. Chem. Commun. 2003, 2578–2579. (g) Hartung, J.; Gottwald,
T. Tetrahedron Lett. 2004, 45, 5619–5621. (h) Lee, E. Pure Appl. Chem.
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Lett. 2005, 7, 1113–1116. (j) Chan, K.-P.; Loh, T.-P. Org. Lett. 2005, 7,
4491–4494. (k) Alonso, D.; Pe´rez, M.; Go´mez, G.; Covelo, B.; Fall, Y.
Tetrahedron 2005, 61, 2021–2026. (l) Uenishi, J.; Ohmi, M.; Ueda, A.
Tetrahedron: Asymmetry 2005, 16, 1299–1303. (m) Kawai, N.; Lagrange,
J. M.; Ohmi, M.; Uenishi, J. J. Org. Chem. 2006, 71, 4530–4537. (n)
Uenishi, J.; Vikhe, Y. S.; Kawai, N. Chem. Asian J. 2008, 3, 473–484. (o)
Smith, A. B., III; Fox, R. J.; Razler, T. M. Acc. Chem. Res. 2008, 41, 675–
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H.-M.; Xiao, W.-J. Tetrahedron Lett. 2008, 49, 1631–1635. (r) Hiebel, M.-
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2
79
78
2:1
2:1
3
reflux, 10 h
a Combined yield of 4a and 4b. b Diastereomeric ratio (4a:4b)
1
determined by integration of the H NMR of the crude product.
in 66% yield but in poor stereoselectivity (4a:4b ) 2:1, entry
1).12 On the basis of the fact that we isolated the intermediate
2 in addition to 4a and 4b, we anticipated that a higher
reaction temperature would promote the SN2′ cyclization step.
After the completion of the CM reaction of 1 and
CH2dCHCH2Cl in CH2Cl2 as monitored by TLC, addition
of toluene to the reaction mixture increased the yield of the
reaction from 66% to 79% (entry 2). Use of CH2dCHCH2Br
instead of CH2dCHCH2Cl had no effect on yield, but slightly
shortened the reaction time (entry 3). We attributed the low
stereoselectivity to a less well-defined transition state of the
intramolecular SN2′ reaction.8
(6) Ashby, E. C.; DePriest, R. N.; Goel, A. B.; Wenderoth, B.; Pham,
T. N. J. Org. Chem. 1984, 49, 3545–3556.
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Stirling, C. J. M. Tetrahedron 1992, 48, 7383–7423.
To improve the low stereoselectivity of the tandem
reaction, we envisioned the introduction of an axially oriented
(9) For examples of intramolecular SN2′ reaction, see: (a) Kim, D.; Choi,
W. J.; Hong, J. Y.; Park, I. Y.; Kim, Y. B. Tetrahedron Lett. 1996, 37,
Org. Lett., Vol. 11, No. 22, 2009
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