Sulfoxide-directed enantioselective synthesis of functionalized dihydropyrans

Article abstract of DOI:10.1021/ol049393n

The highly selective base-promoted cyclization of enantiopure sulfinyl dienols affords allylic sulfinyl dihydropyrans.

Full text of DOI:10.1021/ol049393n

ORGANIC
LETTERS
2004
Vol. 6, No. 13
2157-2160
Sulfoxide-Directed Enantioselective
Synthesis of Functionalized
Dihydropyrans
Roberto Ferna´ndez de la Pradilla* and Mariola Tortosa
Instituto de Qu´ımica Orga´nica, CSIC, Juan de la CierVa, 3, 28006 Madrid, Spain
iqofp19@iqog.csic.es
Received April 2, 2004
ABSTRACT
The highly selective base-promoted cyclization of enantiopure sulfinyl dienols affords allylic sulfinyl dihydropyrans.
Functionalized dihydro- and tetrahydropyrans are common
constituents of bioactive natural products,1 and this has led
to the development of a number of synthetic approaches to
these targets.2 Several years ago we observed that vinyl
oxiranes A (Scheme 1) displayed an undesired SN2′ reactivity
with complex secondary alcohols present in the reaction
media to produce adducts B with high selectivity.3 In
connection with our interest in the design of sulfoxide-based
synthetic procedures, especially those that allow for multiple
chirality-transfer operations,4 and with our involvement in
the synthesis of functionalized tetrahydrofurans,5 we envi-
sioned that an intramolecular variant of this process entailing
the cyclization of cis-hydroxy oxiranes D to hydroxy dihy-
dropyrans F could be a viable process. If successful, we
perceived that dihydropyrans F had a useful array of func-
tionality for synthetic purposes either at sulfoxide or sulfone
oxidation states.6
Alternatively, dienyl sulfoxides C were also identified as
suitable precursors of dihydropyrans E with a stereochemi-
cally labile allylic sulfoxide functionality, upon treatment
with base.7,8 Dienols C are available by Stille couplings
(4) (a) Viso, A.; Ferna´ndez de la Pradilla, R.; Lo´pez-Rodr´ıguez, M. L.;
Garc´ıa, A.; Flores, A.; Alonso, M. J. Org. Chem. 2004, 69, 1542-1547.
(b) Ferna´ndez de la Pradilla, R.; Baile, R.; Tortosa, M. Chem. Commun.
2003, 2476-2477. (c) Ferna´ndez de la Pradilla, R.; Buergo, M. V.;
Manzano, P.; Montero, C.; Priego, J.; Viso, A.; Cano, F. H.; Mart´ınez-
Alca´zar, M. P. J. Org. Chem. 2003, 68, 4797-4805. (d) Viso, A.; Ferna´ndez
de la Pradilla, R.; Garc´ıa, A.; Guerrero-Strachan, C.; Alonso, M.; Tortosa,
M.; Flores, A.; Mart´ınez-Ripoll, M.; Fonseca, I.; Andre´, I.; Rodr´ıguez, A.
Chem. Eur. J. 2003, 9, 2867-2876.
(5) (a) Ferna´ndez de la Pradilla, R.; Montero, C.; Priego, J.; Mart´ınez-
Cruz, L. A. J. Org. Chem. 1998, 63, 9612-9613. (b) Ferna´ndez de la
Pradilla, R.; Viso, A. Recent Res. DeV. Org. Bioorg. Chem. 2001, 4, 123-
132. (c) Ferna´ndez de la Pradilla, R.; Manzano, P.; Montero, C.; Priego, J.;
Mart´ınez-Ripoll, M.; Mart´ınez-Cruz, L. A. J. Org. Chem. 2003, 68, 7755-
7767.
(6) For recent reviews on sulfoxide chemistry, see: (a) Ferna´ndez, I.;
Khiar, N. Chem. ReV. 2003, 103, 3651-3705. (b) Hanquet, G.; Colobert,
F.; Lanners, S.; Solladie´, G. ArkiVoc 2003, Vii, 328-401. (c) Wang, C.-C.;
Huang, H.-C.; Reitz, D. B. Org. Prep. Proc. Int. 2002, 34, 271-319. (d)
Prilezhaeva, E. N. Russ. Chem. ReV. 2001, 70, 897-920. (e) Procter, D. J.
J. Chem. Soc., Perkin Trans. 1 2001, 335-354. (f) Garc´ıa Ruano, J. L.;
Cid de la Plata, M. B. Top. Curr. Chem. 1999, 204, 1-126. (g) Carren˜o,
M. C. Chem. ReV. 1995, 95, 1717-1760. For recent reviews on sulfones,
see: (h) Chemla, F. J. Chem. Soc., Perkin Trans. 1 2002, 275-299. (i)
Procter, D. J. J. Chem. Soc., Perkin Trans. 1 2001, 335-354. (j) Back, T.
G. Tetrahedron 2001, 57, 5263-5301.
(1) For reviews, see: (a) Elliott, M. C. J. Chem. Soc., Perkin Trans. 1
2002, 2301-2323. (b) Faul, M. M.; Huff, B. E. Chem. ReV. 2000, 100,
2407-2473. (c) AÄ lvarez, E.; Candenas, M. L.; Pe´rez, R.; Ravelo, J. L.;
Mart´ın, J. D. Chem. ReV. 1995, 95, 1953-1980. (d) Shimizu, Y. M. Chem.
ReV. 1993, 93, 1685-1698. (e) Yasumoto, T.; Murata, M. Chem. ReV. 1993,
93, 1897-1909. (f) Perron, F.; Albizati, K. M. Chem. ReV. 1989, 89, 1617-
1661.
(2) For leading references on the construction of dihydro- and tetrahy-
dropyrans, see: (a) Trost, B. M.; Rhee, Y. H. J. Am. Chem. Soc. 2003,
125, 7482-7483. (b) Carren˜o, M. C.; Des Mazery, R.; Urbano, A.; Colobert,
F.; Solladie´, G. J. Org. Chem. 2003, 68, 7779-7787. (c) Betancort, J. M.;
Mar´ın, T.; Palazo´n, J. M.; Mart´ın, V. S. J. Org. Chem. 2003, 68, 3216-
3224. (d) Leroy, B.; Marko´, I. E. J. Org. Chem. 2002, 67, 8744-8752. (e)
Keck, G. E.; Covel, J. A.; Schiff, T.; Yu, T. Org. Lett. 2002, 4, 1189-
1192. (f) Cheung, A. K.; Snapper, M. L. J. Am. Chem. Soc. 2002, 124,
11584-11585. (g) Yu, C.-M.; Lee, J.-Y.; So, B.; Hong, J. Angew. Chem.,
Int. Ed. 2002, 41, 161-163.
(3) (a) Marino, J. P.; Anna, L. J.; Ferna´ndez de la Pradilla, R.; Mart´ınez,
M. V.; Montero, C.; Viso, A. Tetrahedron Lett. 1996, 37, 8031-8034. (b)
Ferna´ndez de la Pradilla, R.; Mart´ınez, M. V.; Montero, C.; Viso, A.
Tetrahedron Lett. 1997, 38, 7773-7776. (c) Marino, J. P.; Anna, L. J.;
Ferna´ndez de la Pradilla, R.; Mart´ınez, M. V.; Montero, C.; Viso, A. J.
Org. Chem. 2000, 65, 6462-6473. (d) Ferna´ndez de la Pradilla, R.; Buergo,
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10.1021/ol049393n CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/25/2004

between vinyl stannanes and stereodefined iodo alkenyl
sulfoxides G, which are prepared from alkynyl sulfoxides
H by stereocontrolled hydrostannylation and tin-halogen
exchange.9 In this report we describe our preliminary studies
on the efficient base-induced cyclization of hydroxy dienyl
sulfoxides C to produce good to excellent yields of allylic
sulfoxides E. In addition, we have outlined a simple protocol
for producing enantiopure sulfones related to F from
intermediates E and we have sketched some exploratory
experiments on the reactivity of these compounds.
Scheme 2. Base-Induced Synthesis of Sulfinyl Dihydropyrans
Scheme 2 gathers our preliminary results on this chemistry.
Substrate 1a was chosen as a representative example to
Scheme 1. Proposed Sulfinyl-Mediated Synthesis of
Dihydropyrans
b
a An additional 17% vinyl sulfoxide was obtained. Diastereo-
merization at sulfur took place upon standing in solution (70:30
and 50:50 mixture for 2d and 2e, respectively). cAn additional 12%
vinyl sulfoxide was obtained.
1a. Optimal results were obtained with LDA to produce an
excellent yield of allylic sulfoxide 2a as a single isomer.9
Phenyl-substituted diene 1b behaved similarly, affording
dihydropyran 2b. The influence of an additional stereocenter
in the dienol was then addressed, and while 1c underwent a
smooth cyclization to yield 2c, along with a small amount
of an isomeric vinyl sulfoxide, diastereomer 1d gave a
slightly lower yield of the expected product 2d as practically
a single isomer that underwent diastereomerization at sulfur
upon standing in solution. This protocol was also found to
be compatible with additional substitution on the double bond
with methyl-substituted substrate 1e leading to an excellent
yield of 2e that isomerized at sulfur upon standing in solution.
In contrast with the above results, E,Z substrates 3a and
3b were found to be less reactive and slightly less selective.
Thus, optimal conditions involved the use of NaH for 3a
and KH for 3b and small amounts of 2a and 2b could be
pursue the monoepoxidation to produce the desired vinyl
oxirane related to D. After considerable experimentation with
fruitless results, we chose to examine the cyclization of dienol
1
detected in the H NMR of the crude reaction mixtures. In
(7) For synthetic applications of allylic sulfoxides, see: (a) Hua, D. H.;
Venkataraman, S.; Chan-Yu-King, R.; Paukstelis, J. V. J. Am. Chem. Soc.
1988, 110, 4741-4748 and previous papers by this group. (b) Haynes, R.
K.; Katsifis, A. G.; Vonwiller, S. C.; Hambley, T. W. J. Am. Chem. Soc.
1988, 110, 5423-5433 and previous papers by this group. (c) Evans, D.
A.; Andrews, G. C. Acc. Chem. Res. 1974, 7, 147-155.
addition, the main products in these cases, 4a and 5b, had
different stereochemistry at C-2 and C-3. Indeed, while 4a
was a 2,3-cis isomer, 5b was a 2,3-trans isomer.10
Scheme 3 gathers a range of results that illustrate some
aspects of the reactivity of these allylic sulfoxides, namely,
their sigmatropic rearrangements to allylic alcohols and their
oxidation to produce enantiopure allylic sulfones, versatile
synthetic intermediates.11 It should be noted that diastereo-
meric sulfoxides 2b and 5b displayed remarkable differences
in the rate and yield of their sigmatropic rearrangements,
(8) (a) Solladie, G.; Moine, G. J. Am. Chem. Soc 1984, 106, 6097-
6098. (b) Iwata, C.; Maezaki, N.; Hattori, K.; Fujita, M.; Moritani, Y.;
Takemoto, Y.; Tanaka, T.; Imanishi, T. Chem. Pharm. Bull. 1993, 41, 339-
345. (c) Iwata, C.; Maezaki, N.; Hattori, K.; Fujita, M.; Moritani, Y.;
Takemoto, Y.; Tanaka, T.; Imanishi, T. Chem. Pharm. Bull. 1993, 41, 946-
950 and previous papers by this group. (d) Mandai, T.; Ueda, M.; Kashiwagi,
K.; Kawada, M. Tsuji, J. Tetrahedron Lett. 1993, 34, 111-114. (e) Mukai,
C.; Yamashita, H.; Hanaoka, M. Org. Lett. 2001, 3, 3385-3387.
(9) All new products were fully characterized by standard techniques.
The optical purity and absolute stereochemistry of the final products were
established by detailed 1H NMR analysis of the methoxy phenyl acetate of
hydroxy oxirane 16. The stereochemistry of dihydropyranyl sulfoxides and
sulfones was established by detailed 1H NMR analysis (see Supporting
Information). For the synthesis of dienols, see: Paley, R. S.; de Dios, A.;
Estroff, L. A.; Lafontaine, J. A.; Montero, C.; McCulley, D. J.; Rubio, M.
B.; Ventura, M. P.; Weers, H. L.; Ferna´ndez de la Pradilla, R.; Castro, S.;
Dorado, R.; Morente, M. J. Org. Chem. 1997, 62, 6326-6343. The Z vinyl
stannanes were prepared from the appropriate propargyl alcohols in one
step as described in: Havranek, M.; Dvorak, D. Synthesis 1998, 1264-
1268.
(10) This cyclization presumably entails nucleophilic attack on the R
face of dienols 1 and 3, consistent with literature knowledge (ref 8), followed
by protonation of the intermediate metalated allylic sulfoxide with retention,
in most cases. The 2,3-trans stereochemistry found for 5b is tentatively
attributed to steric hindrance between the bulky phenyl and sulfinyl
substituents.
(11) For reviews, see: (a) Trost, B. M. Bull. Chem. Soc. Jpn. 1988, 61,
107-124. (b) Pyne, S. In StereoselectiVe Synthesis (Houben-Weyl); Helm-
chen, G., Hoffmann, R. W., Mulzer, J., Schaumann, E., Eds.; Thieme:
Stuttgart, 1995; Vol. E21b, p 2068.
2158
Org. Lett., Vol. 6, No. 13, 2004

ments carried out at the sulfoxide stage. Thus, while 2a and
4a gave diastereomeric allylic sulfones 9a and 10a, respec-
tively, 2b and 5b led to enantiomeric products. Finally,
oxidation of diastereomeric mixtures of 2d and 2e gave single
isomers of sulfones 9d and 9e, respectively.
Scheme 3. Structural Assignments: Sigmatropic
Rearrangements and Oxidations
At this stage we focused our efforts on carrying out ex-
ploratory experiments on the reactivity of our sulfinyl dihy-
dropyrans to gain insight on the design of synthetic applica-
tions of the methodology. The dihydroxylation of diastereo-
meric mixtures of sulfoxides 2e gave an excellent yield of
sulfonyl diol 11 (Scheme 4).
Scheme 4. Survey of Synthetic Applications of Sulfinyl
Dihydropyrans
Encouraged by this result, we examined in detail the
dihydroxylation of model substrate 2b that led to a good
yield of diol 12 as a single isomer,14 that was transformed
smoothly to hydroxy vinyl sulfone 13, structurally related
to our initial objective F (Scheme 1).15 The functionality in
13 allowed for straightforward formation of carbamate 14,
which cyclized to oxazolidinone 15 in excellent yield.16 It
giving rise to allylic alcohols 6b and ent-6b.12 The spectral
features of 6b did not allow for a conclusive stereochemical
assignment, and therefore a comparison was made for ace-
tates 7b, obtained by acetylation of ent-6b, and 8b, derived
from Mitsunobu inversion of ent-6b.13
(13) For reviews, see: (a) Hughes, D. L. Org. React. 1992, 42, 335-
668. (b) Hughes, D. L. Org. Prep. Proc. Int. 1996, 28, 127-164.
(14) All attempts to obtain the related sulfinyl diol using OsO4 under
controlled conditions led to mixtures of starting material, allylic sulfone,
sulfinyl diol, and sulfonyl diol 12.
(15) Rayner, C. M.; Westwell, A. D.; Thornton-Pett, M. J. Chem. Soc.,
Perkin Trans. 1 1995, 847-859.
(16) Hirama, M.; Hioki, H.; Ito, S.; Kabuto, C. Tetrahedron Lett. 1988,
29, 3121-3124.
The oxidation of several substrates under standard condi-
tions gave additional support to the stereochemical assign-
(12) For alternative routes to related compounds, see: (a) Ramnauth, J.;
Poulin, O.; Rakhit, S.; Maddaford, S. P. Org. Lett. 2001, 3, 2013-2015.
(b) Steinhuebel, D. P.; Fleming, J. J.; Du Bois, J. Org. Lett. 2002, 4, 293-
295. (c) Di Bussolo, V.; Caselli, M.; Pineschi, M.; Crotti, P. Org. Lett.
2003, 5, 2173-2176.
Org. Lett., Vol. 6, No. 13, 2004
2159

should be mentioned that, aside from the sulfone-bearing
center, the relative stereochemistry of 15 is enantiomeric to
that found in the neurotoxin Dysiherbaine.17 Finally, the
nucleophilic epoxidation of 13 gave sulfonyl oxirane 16 as
a single isomer that underwent oxirane cleavage, with
MgBr2,18 to produce bromo pyranone 17 initially as a single
isomer that underwent rapid epimerization at the bromine-
substituted center. Treatment of this mixture with Bu3SnH/
AIBN unexpectedly resulted in not just removal of bromine
but also rapid and stereoselective carbonyl reduction to afford
diol 18 as a single isomer in excellent yield.
finyl dihydropyrans have been described. This strategy allows
for creation of two asymmetric centers within a synthetically
useful dihydropyran framework in an expedient manner.19
The configurational stability of the allylic sulfoxide in most
cases is noteworthy. We are currently exploring the scope,
limitations, and synthetic applications of the methodology.
Acknowledgment. This research was supported by DGI-
CYT (BQU2001-0582 and BQU2003-02921) and CAM
(08.5/0028/2003 2). We thank Janssen-Cilag for generous
additional support. We thank MEC for a doctoral fellowship
to M.T.
In conclusion, the first examples of the base-promoted
intramolecular cyclization of 2-sulfinyl dienols to afford sul-
Supporting Information Available: Experimental pro-
cedures and characterization for selected compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(17) Isolation: (a) Sakai, R.; Kamiya, H.; Murata, M.; Shimamoto, K.
J. Am. Chem. Soc. 1997, 119, 4112-4116. Syntheses: (b) Snider, B. B.;
Hawryluk, N. A. Org. Lett. 2000, 2, 635-638. (c) Masaki, H.; Maeyama,
J.; Kamada, K.; Esumi, T.; Iwabuchi, Y.; Hatakeyama, S. J. Am. Chem.
Soc. 2000, 122, 5216-5217. (d) Sasaki, M.; Koike, T.; Sakai, R.; Tachibana,
K. Tetrahedron Lett. 2000, 41, 3923-3926. (e) Phillips, D.; Chamberlin,
A. R. J. Org. Chem. 2002, 67, 3194-3201. (f) Kang, S. H.; Lee, Y. M.
Synlett 2003, 993-994.
OL049393N
(19) Enantiopure propargyl alcohols, precursors to the required stannanes
(ref 9), are readily available. See: El-Sayed, E.; Anand, N. K.; Carreira, E.
M. Org. Lett. 2001, 3, 3017-3020 and previous papers by this group. This
suggests that our methodology should be broadly applicable.
(18) de Reinach-Hirtzbach, F.; Durst, T. Tetrahedron Lett. 1976, 3677-
3680. For a recent application, see: Mori, Y.; Hayashi, H. Tetrahedron
2002, 58, 1789-1797.
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