selected as our target. Retrosynthetic analysis of 1 gives two
strategies involving an aldehyde and a homoallylic alcohol
(Scheme 1). The first, pathway A, involves reaction of the
Scheme 2. Synthesis of Homoallylic Alcohol 5
Scheme 1. Retrosynthetic Analysis of Tetrahydropyran 1
example, oxonia-Cope rearrangements are favored in the
reaction of aldehydes with benzylic homoallylic alcohols
possessing an electron- rich aromatic ring due to the inherent
stabilization via conjugation with the aromatic ring.13 How-
ever, as shown in Scheme 2, neither substituent would give
this extra stabilizisation to promote an oxonia-Cope rear-
rangement, and so the driving force must be the substitution
of the alkene as it is converted from a terminal position to
a 1,2-disubstituted double bond.
To investigate the effect of alkene substitution on the
reaction, alcohol 5 (with a 1,2-disubstituted alkene) was
treated with propanal and TFA. In this case, the reaction
proceeded cleanly to give tetrahydropyran 8 in 84% yield
with the creation of three new asymmetric centers with
complete stereocontrol (Scheme 3). It was evident that all
substituted homoallylic alcohol 2 with protected 3-hydrox-
ypropanal. 3-tert-Butyldiphenylsilyloxypropanal was readily
prepared in 94% yield from propane-1,3-diol (by a standard
monoprotection followed by oxidation under Swern condi-
tions7), and then crotonylation employing Brown’s condi-
tions8 gave the known alcohol 4 in 89% yield (Scheme 2).9
Interestingly, reaction of 4 with aldehydes, e.g., dihydrocin-
namaldehyde in the presence of TFA, gave, as the major
product, homoallylic alcohol 5, [R]D +13.6 (c 1.7, CHCl3)
[lit.10 +15.2 (c 1.0, CHCl3)]. Formation of 5 can be
rationalized by an oxonia-Cope rearrangement of the initially
formed oxycarbenium ion 6 to 7 followed by fragmentation.
The mechanism of the Prins cyclizations is not simple,
and there is good evidence for the participation of oxonia-
Cope rearrangements11 and allyl transfer processes.12 For
Scheme 3. Synthesis of Tetrahydropyran 8
(5) Examples of Prins cyclizations include: (a) Cloninger, M. J.;
Overman, L. E. J. Am. Chem. Soc. 1999, 121, 1092. (b) Rychnovsky, S.
D.; Hu, Y.; Ellsworth, B. Tetrahedron Lett. 1998, 39, 7271. (c) Al-Mutairi,
E. H.; Crosby, S. R.; Darzi, J.; Harding, J. R.; Hughes, R. A.; King, C. D.;
Simpson, T. J.; Smith, R. W.; Willis, C. L. Chem. Commun. 2001, 835. (d)
Dixon, D. J.; Ley, S. V.; Tate, E. W. J. Chem. Soc., Perkin Trans. 1 2000,
1829. (e) Hart, D. J.; Bennet, C. E. Org. Lett. 2003, 5, 1499. (f) Marumoto,
S.; Jaber, J. J.; Vitale, J. P.; Rychnovsky, S. D. Org. Lett. 2002, 4, 3919.
(g) Winstead, R.; Simpson, T. H.; Loch, G.; Schiavelli, M. D.; Thompson,
D. W. J. Org Chem. 1986, 51, 275.
(6) For examples of cyclizations to introduce an oxygen-containing
substituent at C-4, see: (a) Zhang, W.-C.; Li, C.-J. Tetrahedron 2000, 56,
2403. (b) Rychnovsky, S. D.; Thomas, C. R. Org. Lett. 2000, 2, 1217. (c)
Kozmin, S. A. Org. Lett. 2001, 3, 755. (d) Nishizawa, M.; Shigaraki, T.;
Takao, H.; Imagawa, H. T. Tetrahedron Lett. 1999, 40, 1153. (e) Petasis,
N. A.; Lu, S.-P. Tetrahedron Lett. 1996, 37, 141.
the substituents were located in an equatorial position in 8
from the characteristic vicinal coupling constants in the H
1
(10) Nokami, J.; Ohga, M.; Nakamoto, H.; Matsubara, T.; Hussain, I.;
Kataoka, K. J. Am. Chem. Soc. 2002, 123, 9169.
(11) Examples of oxonia-Cope rearrangements include: (a) Rychnovsky,
S. D.; Marumoto, S.; Jaber, J. J. Org. Lett. 2001, 3, 3815. (b) Roush, W.
R.; Dilley, Synlett. 2001, 955. (c) Gasparki, C. M.; Herrinton, P. M.;
Overman, L. E.; Wolfe, J. P. Tetrahedron Lett. 2000, 41, 9431. (d) Loh,
T.-P.; Hu, Q.-Y.; Ma, L.-T. J. Am. Chem. Soc. 2001, 123, 2450. (e) Semeyn,
C.; Blaauw, R. H.;. Hiemstra, H.; Speckamp, W. N. J. Org. Chem. 1997,
62, 3426. (f) Huang, H. B.; Panek, J. S. J. Am. Chem. Soc. 2000, 122,
9836.
(7) (a) Jenmalm, A.; Berts, W.; Li, Y.-L.; Luthman, K.; Csoeregh, I.;
Haksill, U. J. Org. Chem. 1994, 59, 1139. (b) Omura, K.; Swern, D.
Tetrahedron 1978, 34, 1651.
(8) (a) Brown, H. C.; Bhat, K. S.; Randad, R. S. J. Org. Chem. 1989,
54, 1570. (b) Brown, H. C.; Bhat, J. Am. Chem. Soc. 1986, 108, 293 and
5919.
(9) Nicolaou, K. C.; Piscopio, A. D.; Bertinato, P.; Chakraborty, T. K.;
Minowa, N.; Koide, K. Chem. Eur. J. 1995, 1, 318.
(12) Examples of allyl transfer reactions include: Nokami, J.; Yoshizane,
K.; Matsuura, H.; Sumida, S.-I. J. Am. Chem. Soc. 1998, 120, 6609. (b)
Loh, T.-P.; Hu, Q.-Y.; Ma, L.-T. J. Am. Chem. Soc. 2001, 123, 2450. (c)
Loh, T.-P.; Tan, K.-T.; Hu, Q.-Y. Angew. Chem., Int. Ed. 2001, 40, 2021.
(d) Nokami, J.; Anthony, L.; Sumida, S.-I. Chem. Eur. J. 2000, 6, 2909.
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