Base-induced enantioselective synthesis of sulfinyl dihydropyrans

Article abstract of DOI:10.1080/10426500590910819

2-Sulfinyl dienols undergo an efficient base-promoted cyclization to produce sulfinyl dihydropyrans with creation of two asymmetric centers. The configurational stability of the allylic sulfoxide in most cases is noteworthy. Simple manipulations lead to a

Full text of DOI:10.1080/10426500590910819

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Phosphorus, Sulfur, and Silicon
and the Related Elements
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Base-Induced Enantioselective
Synthesis of Sulfinyl
Dihydropyrans
Roberto Fernández de la Pradilla a & Mariola Tortosa
a
a Instituto de Química Orgánica, Consejo Superior de
Investigaciones Científicas , Madrid, Spain
Published online: 16 Aug 2006.
To cite this article: Roberto Fernández de la Pradilla & Mariola Tortosa (2005)
Base-Induced Enantioselective Synthesis of Sulfinyl Dihydropyrans, Phosphorus,
Sulfur, and Silicon and the Related Elements, 180:5-6, 1217-1222, DOI:
10.1080/10426500590910819
To link to this article: http://dx.doi.org/10.1080/10426500590910819
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Phosphorus, Sulfur, and Silicon, 180:1217–1222, 2005
Copyright © Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500590910819
Base-Induced Enantioselective Synthesis
of Sulfinyl Dihydropyrans
´
Roberto Fernandez de la Pradilla
Mariola Tortosa
Instituto de Qu´ımica Orga´nica, Consejo Superior de Investigaciones
Cient´ıficas, Madrid, Spain
2-Sulfinyl dienols undergo an efficient base-promoted cyclization to produce sulfinyl
dihydropyrans with creation of two asymmetric centers. The configurational stabil-
ity of the allylic sulfoxide in most cases is noteworthy. Simple manipulations lead
to a variety of functionalized tetrahydropyrans.
Keywords Allylic sulfoxides; asymmetric synthesis; dihydropyrans; tetrahydropyrans
INTRODUCTION
Substituted dihydro- and tetrahydropyrans are common structural el-
ements in natural products that possess important therapeutic prop-
erties, and this had led to the development of a number of synthetic
approaches to these targets. Cationic, anionic, and radical cyclizations,
hetero-Diels–Alder cycloaddition, ring-closing metathesis, and addition
of organometallic reagents to glycals are frequently used strategies for
the synthesis of these heterocycles.1 Although many of them allow for
the creation of the pyran skeleton in a stereocontrolled manner, a gen-
eral approach that includes a variety of substitution patterns is still a
challenge for organic chemists.
In recent years we have been engaged in the development of syn-
thetic procedures involving vinyl sulfoxides, especially those that al-
low for subsequent sulfur-based chirality transfer operations.2 In
connection with our involvement in the synthesis of functionalized
tetrahydrofurans,3 we envisioned that a base-promoted cyclization of
Received July 9, 2004; accepted October 5, 2004.
This research was supported by DGICYT (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.
Address correspondence to Roberto Ferna´ndez de la Pradilla, Instituto de Qu´ımica
Orga´nica, CSIC, Juan de la Cierva, 3, E-28006 Madrid, Spain. E-mail: iqofp19@iqog.
csic.es
1217

1218
R. F. de la Pradilla and M. Tortosa
hydroxy dienyl and vinyl sulfoxides would be a viable entry to dihydro-
and tetrahydropyrans (Scheme 1).
SCHEME 1 Proposed base-induced cyclization of hydroxy vinyl sulfoxides.
This approach would involve the stereocontrolled synthesis of com-
pounds of general structure A and D, easily accessible by methodolo-
gies previously reported in our group. Substrates A could be prepared
by sigmatropic rearrangement of sulfinyl acrylates C4 with subsequent
reduction and substrates D by Stille coupling of the corresponding iodo
alkenyl sulfoxides.5 Considering the scope of both methodologies, this
strategy, if successful, would be a general method for the synthesis of
dihydro- and tetrahydropyrans with a regio- and stereodefined substi-
tution pattern and a useful array of functionality for synthetic purposes
either at sulfoxide or sulfone states.6
RESULTS AND DISCUSSION
We chose substrates 1 and 4a as representative examples to test the
base-promoted cyclization (Scheme 2). The treatment of 1 with different
bases (LDA, NaH) in THF did not result in any cyclization and only
unreacted starting material was recovered. We thought that the low
reactivity of 1 was due to a coordination of the hydrogen of the hydroxyl
group and the sulfinylic oxygen. Indeed, when we changed to a more
polar solvent such as DMF, the cyclization took place but elimination
of the sulfinyl group could not be avoided under these conditions.
At this point we decided to examine the cyclization of dienol 4a,
hoping that the presence of a cis double bond would avoid the prob-
lems found with 1. To our delight, optimal results were obtained with
LDA to produce an excellent yield of allylic sulfoxide 5a as a single
isomer.7 To test the scope of the methodology, we synthesized dienols
4b–e with a different substitution pattern (Scheme 3). Diene 4b, with a
phenyl substituent, behaved similarly, affording dihydropyran 5b. Sub-
strates with an additional sterocenter were then examined and while 4c

Synthesis of Sulfinyl Dihydropyrans
1219
SCHEME 2 Base-promoted cyclization of hydroxy dienyl and vinyl sulfoxides.
underwent a smooth cyclization to yield 5c, along with a small amount
of an isomeric vinyl sulfoxide, diastereomer 4d gave a slightly lower
yield of the expected product 5d as practically a single isomer that un-
derwent 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 4e leading to an
excellent yield of 5e that isomerized at sulfur upon standing in solution.
SCHEME 3 Synthesis of sulfinyl dihydropyrans.
The influence of the geometry of the vinyl sulfoxide moiety was then
addressed with dienols 6a and 6b. In contrast with their Z isomers,
NaH or KH was needed and small amounts of 5a and 5b could be de-
1
tected in the H NMR of the crude reaction mixtures. This cyclization
presumably entails nucleophilic attack on the α face of dienols 4 and
6, followed by protonation of the intermediate metalated allylic sulfox-
ide with retention, in most cases. The 2,3-trans stereochemistry found
for 8b is tentatively attributed to steric hindrance between the bulky
phenyl group and sulfinyl substituents.
Scheme 4 illustrates some aspects of the reactivity of these allylic sul-
foxides that allowed us to establish the relative cis-trans stereochem-
istry at C-2 and C-3 in dyhydropyrans 5b and 8b from the sulfoxide-
sulfenate adduct 9b. The relative stereochemistry of this adduct was
established by synthesis of the acetate 10b and the corresponding
Mitsunobu-inversion product 11b and comparison of their spectral
features. The coupling constants between H3-H2eq and H3-H2ax es-
tablish a pseudoaxial arrangement for H3 in 10b (J
= 5.1 Hz,
3−2ax

1220
R. F. de la Pradilla and M. Tortosa
J
3−2eq = 4.4 Hz) and a pseudoequatorial arrangement for H3 in 11b
(J < 1 Hz).
= 2.6 Hz, J
3−2ax
3−2eq
SCHEME 4 Structural assignments: sigmatropic rearrangements.
At this stage we focused our efforts on carrying out exploratory exper-
iments on the reactivity of our sulfinyl dihydropyrans to gain insight on
the design of synthetic applications of the methodology (Scheme 5). The
oxidation of several substrates under standard conditions yielded enan-
tiopure allylic sulfones, versatile synthetic intermediates, and gave ad-
ditional support to the stereochemical assignments carried out at the
sulfoxide stage.
SCHEME 5 Synthetic applications.
Then we examined in detail the dihydroxylation of model substrate
5b that led to a good yield of diol 13 as a single isomer. Diol 13 was
transformed smoothly to hydroxy vinyl sulfone 14 that, under nu-
cleophilic epoxidation conditions, gave sulfonyl oxirane 15 as a sin-
gle isomer. The reaction of 15 with MgBr2 produced bromo pyranone
16 initially as a single isomer that underwent rapid epimerization
at the bromine-substituted center. Treatment of this mixture with

Synthesis of Sulfinyl Dihydropyrans
1221
Bu3SnH/AIBN unexpectedly resulted in not just removal of bromine
but also rapid and stereoselective carbonyl reduction to afford diol 17
as a single isomer in excellent yield. Finally the functionality in 14
allowed for straightforward formation of a carbamate that cyclized to
oxazolidinone 18 in excellent yield. It should be mentioned that, aside
from the sulfone-bearing center, the relative stereochemistry of 19 is
enantiomeric to that found in the neurotoxin Dysiherbaine.
In conclusion, a new approach to substituted dihydro- and tetrahy-
dropyrans has been described. The base-promoted intramolecular cy-
clization of 2-sulfinyl dienols affords sulfinyl dihydropyrans with the
creation of two asymmetric centers in an expedient manner. The config-
urational stability of the allylic sulfoxide in most cases is noteworthy. In
addition the base-promoted cyclization of 1-hydroxy-4-vinyl sulfoxides
has been outlined. We are currently exploring the scope, limitations,
and synthetic applications of both methodologies.
EXPERIMENTAL PROCEDURE
Synthesis of (−)-(2S,3R,RS)-2-n-butyl-3-( p-tolylsulfinyl)-3,6-dih-
ydro-2H-pyran, 5a
To a solution of the dienyl sulfoxide 4a (20 mg, 0.070 mmol) in THF
(10 mL/mmol of sulfoxide), at −78◦C, under an argon atmosphere, was
added 1.1 equiv of a freshly prepared 0.5 M LDA solution (0.15 mL,
0.077 mmol) in THF. The mixture was allowed to warm to room tem-
perature (rt), monitored by TLC until completion (4 h), and quenched
with a saturated solution of NH4Cl and water. The layers were sepa-
rated and the aqueous phase was extracted with EtOAc. The combined
organic extracts were washed with a saturated solution of NaCl, dried
over anhydrous MgSO4, and filtered. Purification by chromatography
(10–50% EtOAc-hexane) afforded 18 mg (0.066 mmol, 94%) of 5a as a
colorless oil.
Data for 5a: R f = 0.34 (50% EtOAc-hexane). [α]2D0 = −218.8 (c =
0.75). 1H NMR (300 MHz)-COSY δ 0.88 (t, 3 H, J = 7.1 Hz, Me-n-Bu),
1.25–1.54 (m, 5 H), 1.74 (m, 1 H), 2.39 (s, 3 H, Me-p-Tol), 3.07 (m, 1 H,
H-3), 4.09 (m, 2 H, H-6), 4.32 (dm, 1 H, J = 9.5 Hz, H-2), 5.14 (ddd, 1 H,
J = 10.2, 4.9, 2.5 Hz, H-4), 5.95 (dtd, 1 H, J = 10.2, 2.5, 1.0 Hz, H-5),
7.29 (d, 2 H, J = 7.8 Hz, p-Tol), 7.53 (d, 2 H, J = 8.3 Hz, p-Tol). 13C
NMR (50 MHz)-HSQC δ 14.0 (Me-n-Bu), 21.5 (Me-p-Tol), 22.5, 27.9,
30.7, 60.8 (C-6), 66.1 (C-3), 69.9 (C-2), 116.6 (C-4), 125.5 (2 C), 129.7
(2 C), 132.6 (C-5), 138.9, 142.0. IR (film): 3038, 2932, 2857, 1651, 1596,
1493, 1462, 1380, 1302, 1210, 1182, 1082, 1037, 1016, 812 cm−1. MS
(ES): 579 [2M + Na]+, 301 [M + Na]+, 279 [M + 1]+ (100%).

1222
R. F. de la Pradilla and M. Tortosa
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