The "Aqueous" Prins Reaction

Article abstract of DOI:10.1021/ol0359259

(Equation presented) In this communication we demonstrate that Prins cyclization reactions occur under very mild conditions when cyclic α,β-unsaturated acetals are employed as oxocarbenium ion progenitors and allylsilanes are used as nucleophiles. Cycliza

Full text of DOI:10.1021/ol0359259

ORGANIC
LETTERS
2003
Vol. 5, No. 23
4521-4523
The “Aqueous” Prins Reaction
Danielle L. Aubele, Christopher A. Lee, and Paul E. Floreancig*
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
florean@pitt.edu
Received October 1, 2003
ABSTRACT
In this communication we demonstrate that Prins cyclization reactions occur under very mild conditions when cyclic r,â-unsaturated acetals
are employed as oxocarbenium ion progenitors and allylsilanes are used as nucleophiles. Cyclizations proceed efficiently inside Lewis acidic
micelles in water, demonstrating that colloidal suspensions can protect highly electrophilic intermediates from hydrolysis. Reactions are
experimentally facile and useful in the preparation of a variety of vinyl- and aryl-substituted tetrahydropyrans with excellent stereocontrol.
Although water is inexpensive, nontoxic, and nonflammable,
it is not routinely1 used as a solvent for organic reactions.
In addition to the limited aqueous solubilities of most organic
compounds, a significant drawback to using water as a
solvent is its ability to act as both a nucleophile and as an
acid, making it incompatible with highly electrophilic and
basic species. Solubility and reactivity problems can, in
principle, be circumvented by encapsulating reactions in the
hydrophobic interiors of micelles, whereby the practical
benefits of aqueous chemistry can be realized while the
familiar reactivity patterns conferred by organic microsol-
vation are maintained.2 A stringent test of the extent to which
micelles protect sensitive species from water would be
provided by their use in reactions that proceed through
hydrolytically labile intermediates. In this communication
we report that acetals ionize in Lewis acidic micelles under
very mild conditions and that the intermediate oxocarbenium
ions undergo efficient and stereoselective Prins reactions in
preference to hydrolysis.
Relative to Prins reactions that proceed through direct
dehydrative conditions,4 sequestering two hydroxyl groups
into an acetal allows a convergent condensation of func-
tionalized segments without recourse to selective protecting
group manipulations. In accord with our objective of
conducting these reactions at advanced stages in complex
molecule synthesis, cyclization substrates should be designed
to react at ambient temperature with mild Lewis acids that
tolerate other acid-sensitive functional groups. We postulated
that this could be accomplished by employing R,â-unsatur-
ated acetals to facilitate the initial ionization step and using
electron-rich olefins to expedite the cyclization step (Figure
1). Proceeding through relatively stable conjugated oxocar-
benium ions is also expected to hinder oxonia-Cope rear-
rangements, which have been shown to cause partial
racemization and other side reactions in this process.5
As an initial test of our design, we exposed allylsilane6 1
to anhydrous CeCl3 in CH3CN at room temperature and
observed the formation of 2 as a single diastereomer in 57%
Initiating Prins cyclization reactions by activating cyclic
acetals under strongly acidic conditions3 has proved to be a
powerful method for accessing the 2,4,6-trisubstituted tet-
rahydropyran nucleus found in numerous natural products.
(3) (a) Kay, I. T.; Bartholomew, D. Tetrahedron Lett. 1984, 25, 2035.
(b) Hu, Y.; Skalitzky, D. J.; Rychnovsky, S. D. Tetrahedron Lett. 1996,
37, 8679. (c) Rychnovsky, S. D.; Yang, G.; Hu, Y. Q.; Khire, U. R. J. Org.
Chem. 1997, 62, 3022. (d) Wilson, T. M.; Kociensky, P.; Jarowicki, K.;
Isaac, K.; Hitchcock, P. M.; Faller, A.; Campbell, S. F. Tetrahedron 1990,
46, 1767. (e) Corminboeuf, O.; Overman, L. E.; Pennington, L. D. J. Am.
Chem. Soc. 2003, 125, 6650.
(4) For recent examples, see: (a) Miranda, P. O.; Diaz, D. D.; Padron,
J. I.; Bermejo, J.; Martin, V. S. Org. Lett. 2003, 5, 1979. (b) Crosby, S. R.;
Harding, J. R.; King, C. D.; Parker, G. D.; Willis, C. D. Org. Lett. 2002,
4, 3407. (c) Loh, T.-P.; Hu, Q.-Y.; Tan, K.-T.; Cheng, H.-S. Org. Lett.
2001, 3, 2669. (d) Cloninger, M. J.; Overman, L. E. J. Am. Chem. Soc.
1999, 121, 1092.
(1) (a) Organic Synthesis in Water; Grieco, P. A., Ed.; Blake Academic
and Professional: London, 1998. (b) Li, C.-J.; Chan, T.-H. Organic
Reactions in Aqueous Media; John Wiley and Sons: New York, 1997.
(2) (a) Reactions and Synthesis in Surfactant Systems; Texter, J., Ed.;
Marcel Dekker: New York, 2001. (b) Structure and ReactiVity in Aqueous
Solution; Cramer, C. J., Truhlar, D. G., Eds.; American Chemical Society:
Washington, DC, 1994. (c) Kobayashi, S.; Manabe, K. Acc. Chem. Res.
2002, 35, 209. (d) Tascioglu, S. Tetrahedron 1996, 52, 11113.
10.1021/ol0359259 CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/18/2003

Figure 2. Prins cyclizations with mild Lewis acids.
Figure 1. Reactivity enhancement in intramolecular Prins cycliza-
tions.
the scope of the reaction (Table 1).13 Increasing the length
of the hydrocarbon chain of the acetal and, therefore, the
hydrophobicity of the substrate, has a negligible effect on
reaction efficiency (entry 1). Initiating the reaction through
coordination to a secondary ether group does not inhibit the
process or lead to competitive oxecane formation (entry 2).
yield along with 3, the product of substrate desilylation, in
22% yield. In consideration of the correlation between the
rate of silyl group loss and the nucleophilicity of the
counterion on the Lewis acid, we examined scandium
dodecyl sulfate in water,7 Kobayashi’s micellar Lewis acid
catalyst, as a potential solution to this problem. While these
conditions have been employed to activate carbonyl groups
toward reactions with various nucleophiles,8 they had not
been shown to effect reactions in which the intermediate
electrophilic species would be irreversibly consumed when
exposed to water.9 Therefore, we were pleased to observe
that a colloidal mixture of 1 and scandium dodecyl sulfate
(10 mol %, prepared in situ by adding ScCl3 to a suspension
of 1 and sodium dodecyl sulfate (SDS) in water) at ambient
temperature provided a 71% yield of 2 as a single diastere-
omer with no formation of 3. To make the process more
cost-effective, we examined other Lewis acids that have been
predicted to be compatible with water on the basis of their
rate constants for hydrolysis and exchange of inner-sphere
water ligands.10 We found that micelles formed from
inexpensive Ce(NO3)3‚6H2O11 and SDS, although somewhat
less reactive than ScCl3-based micelles, effected the cycliza-
tion in 76% yield, providing an attractive alternative to our
original conditions.12 A range of substrates were prepared
and subjected to cyclization conditions in order to examine
Table 1. Reaction Scope
(5) (a) Crosby, S. R.; Harding, J. R.; King, C. D.; Parker, G. D.; Willis,
C. D. Org. Lett. 2002, 4, 577. (b) Rychnovsky, S. D.; Marumoto, S.; Jaber,
J. J. Org. Lett. 2001, 3, 3815. The advantage of employing conjugated
oxocarbenium ions for Prins cyclizations has recently been reported. See:
Barry, C. St. J.; Crosby, S. R.; Harding, J. R.; Hughes, R. A.; King, C. D.;
Parker, G. D.; Willis, C. L. Org. Lett. 2003, 5, 2429.
(6) For recent examples of allylsilanes in Prins cyclizations, see: (a)
Leroy, B.; Marko, I. E. J. Org. Chem. 2002, 67, 8744. (b) Keck, G. E.;
Covel, J. A.; Schiff, T.; Yu, T. Org. Lett. 2002, 4, 1189. (c) Chen, C.;
Mariano, P. S. J. Org. Chem. 2000, 65, 3252. (d) Roush, W. R.; Dilley, G.
J. Synlett 2001, 955. (e) Huang, H.; Panek, J. S. J. Am. Chem. Soc. 2000,
122, 9836.
(7) Manabe, K.; Mori, Y.; Wakabayashi, T.; Nagayama, T.; Kobayashi,
S. J. Am. Chem. Soc. 2000, 122, 7202.
(8) Manabe, K.; Iimura, S.; Sun, X.-M.; Kobayashi, S. J. Am. Chem.
Soc. 2002, 124, 11971.
(9) For dehydrative Prins reactions conducted in mixtures of water and
ionic liquids, see: Keh, C. C. K.; Namboodiri, V. V.; Varma, R. S.; Li,
C.-J. Tetrahedron Lett. 2002, 43, 4993.
(10) Kobayashi, S.; Nagayama, S.; Busujima, T. J. Am. Chem. Soc. 1998,
120, 8287.
(11) While 1 mmol of ScCl3 costs $12.41 (Sigma-Aldrich), 1 mmol of
Ce(NO3)3‚6H2O costs $0.09.
b
a See Supporting Information for substrate syntheses. Product stereo-
chemistry was determined by observing NOE enhancements between the
hydrogens on C2 and C6. c A: 10 mol % ScCl3‚nH2O, 30-60 mol % SDS,
0.5 M substrate in water. d B: 10 mol % Ce(NO3)3‚6H2O, 30-60 mol %
SDS, 0.5 M substrate in water. e Isolated yields of purified products.
f Performed with 100 mol% SDS.
4522
Org. Lett., Vol. 5, No. 23, 2003

Compatibility of these conditions with other acid-sensitive
functional groups has been demonstrated through the cy-
clization of methoxymethyl ether 8 (entry 3). The alkenyl
group of the acetal can be replaced by electron-rich arenes,
but the reactivity is diminished. For example, the cyclization
of p-methoxybenzylidine acetal 10 (entry 4) requires the
more reactive ScCl3-based micelles, and the corresponding
benzylidine acetal is unreactive. Control reactions established
that the allylsilane is necessary for cyclization, that acetal
hydrolysis does not occur to a significant extent in the
absence of a good nucleophile, that unsaturation is required
for oxocarbenium ion stabilization, and that SDS is necessary
for reactivity. Interestingly, enolsilane analogues of 1 were
inert toward Ce(NO3)3-based micelles and provided only a
poor yield with ScCl3-based micelles (data not shown),
indicating mechanistic subtleties that transcend simple π-nu-
cleophilicity analyses.14
Cyclizations can also be initiated by ionizing 1,3-diox-
olanes, with reactions being significantly faster than those
of 1,3-dioxanes. While both Ce(NO3)3- and ScCl3-based
micelles effect this transformation, the scandium system
provided superior yields of the desired products. The major
byproduct in these reactions contains a tertiary alcohol rather
than an exocyclic olefin in the tetrahydropyran. On the basis
of our isolation of desilylated starting material in the
cyclization of 14 and our inability to hydrate the exocyclic
olefin of 15 by resubjecting it to the reaction conditions, we
propose that this process occurs through substrate desilylation
followed by cyclization of the nonactivated olefin and
trapping the intermediate cation with either water or dodecyl
sulfate. This demonstrates that enhancing acetal reactivity
allows less nucleophilic olefins to participate in these
reactions. Of further note is that cyclizing an enantioenriched
sample of 14 (80% ee) provides 15 with no detectable
racemization.
We have demonstrated that Prins cyclization reactions can
be conducted under very mild conditions when initiated by
ionizing R,â-unsaturated acetals in the presence of electron-
rich olefins. These reactions proceed efficiently and without
racemization with Lewis acidic surfactant catalysts at room
temperature in water to provide a variety of 2,4,6-trisubsti-
tuted tetrahydropyrans, demonstrating that the interiors of
micelles are sufficiently anhydrous to protect oxocarbenium
ions from hydrolysis. The stability of acetals toward these
conditions demonstrates that acid-sensitive functional groups
are tolerated in cyclization substrates. These operationally
simple and environmentally benign conditions should be
applicable to other systems in which facile Lewis acid-
initiated ionizations are followed by rapid and thermo-
dynamically favorable steps. Further studies of metal/
surfactant combinations are expected to result in an expanded
role for these conditions in organic synthesis.
Acknowledgment. This work was supported by generous
funding from the National Institutes of Health (GM-62924),
the Research Corporation (Research Innovation Award), and
the donors of the Petroleum Research Fund, administered
by the American Chemical Society. We thank Professor Scott
Nelson and his group for the use of their HPLC.
(12) For another example of the use of Sc(III) to initiate dehydrative
Prins reactions, see: Zhang, W.-C.; Visiwanathan, G. S.; Li, C.-J. Chem.
Commun. 1999, 291
Supporting Information Available: Synthetic schemes
for all cyclization substrates and experimental procedures
and characterization for all cyclization reactions. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(13) All new compounds have been characterized by 1H NMR, 13C NMR,
IR, and HRMS.
(14) (a) Mayr, H.; Bug, T.; Gotta, M. F.; Hering, N.; Irrgang, B.; Janker,
B.; Kempf, B.; Loos, R.; Ofial, A. R.; Remennikov, G.; Schimmel, H. J.
Am. Chem. Soc. 2001, 123, 9500. (b) Mayr, H.; Kempf, B.; Ofial, A. R.
Acc. Chem. Res. 2003, 36, 66.
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