New intramolecular alkylation and Michael addition reactions of hydroxysulfone derivatives - Stereoselective preparation of functionalized cyclic ethers

Article abstract of DOI:10.1016/S0040-4039(00)01770-6

A number of bromoacetal derivatives of γ and δ hydroxysulfones have been prepared and shown to undergo intramolecular alkylation reactions in good yields to give highly functionalized oxacyclic ring systems. Tetrahydrofuranyl and tetrahydropyranyl ring systems have also been prepared using the Michael addition reactions of the acrylate derivatives of hydroxysulfones. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01770-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9753–9757
New intramolecular alkylation and Michael addition
reactions of hydroxysulfone derivatives—stereoselective
preparation of functionalized cyclic ethers
Chunyang Jin, Hollie K. Jacobs and Aravamudan S. Gopalan*
Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, NM 88003-8001, USA
Received 17 August 2000; accepted 18 September 2000
Abstract
A number of bromoacetal derivatives of g and d hydroxysulfones have been prepared and shown to
undergo intramolecular alkylation reactions in good yields to give highly functionalized oxacyclic ring
systems. Tetrahydrofuranyl and tetrahydropyranyl ring systems have also been prepared using the
Michael addition reactions of the acrylate derivatives of hydroxysulfones. © 2000 Elsevier Science Ltd.
All rights reserved.
The intramolecular cyclization reactions of a-sulfonylcarbanions involving a variety of
electrophiles have been a valuable approach for the preparation of carbocyclic and heterocyclic
ring systems.1,2 Some time ago we disclosed that the intramolecular cyclization reactions of g
and d acyloxysulfones of the type 1a provided a convenient route for the preparation of a
number of functionalized chiral non-racemic dihydrofurans and dihydropyrans.3 Similarly,
cyclization reactions of the corresponding carbonate derivatives 1b were shown to be a useful
tool for the preparation of a variety of lactones and bicyclic lactones in good yields.4 Another
reaction of recent interest has been the intramolecular conjugate addition of nucleophiles to
functionalized vinylsulfones. These reactions have been used to synthesize a number of oxacyclic
and other heteroring systems.5
In this communication, we would like to report on the intramolecular alkylation and Michael
addition reactions of derivatives of hydroxysulfones of the types 2 and 3, respectively. These
reactions provide a new and convenient stereoselective route to a variety of functionalized five-,
six- or seven-membered oxacyclic ring systems, further enhancing the synthetic utility of
hydroxysulfones.
* Corresponding author. Tel: +1 505 646 2589; fax: +1 505 646 2394; e-mail: agopalan@nmsu.edu
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01770-6

9754
The bromoacetals required for this study were conveniently prepared by reaction of the
corresponding hydroxysulfones with N-bromosuccinimide and ethyl vinyl ether in good yields
(61–70%).6,7 Treatment of the bromoacetal 2a with lithium hexamethyldisilazane (LHMDS, 1.1
equiv.) in THF at −78°C gave the corresponding a-sulfonyl carbanion, which underwent ready
intramolecular alkylation upon warming to room temperature (Scheme 1). Surprisingly, only
two diastereomers of the cyclization product 4a (1:1) were obtained in high yield after careful
silica gel chromatography of the product mixture.8 The relative stereochemistry of each of these
1
diastereomers was determined by analysis of their H NMR spectra and the two products were
found to be epimers differing in the configuration at C-2. Since 2a is a 1:1 diastereomeric
mixture of acetals, we propose that the alkylation of the sulfonyl carbanion occurs with a high
degree of stereoselectivity through a chair-like transition state in which both the alkyl and
phenylsulfonyl groups prefer to be pseudoequatorial.
OEt
OEt
Br
1.1 eq. LHMDS,
THF, -78 oC → rt,
98%
Br
SO2Ph
O
2
O
O
_
..
SO2Ph
H3C
H3C
SO2Ph
OEt
H3C
2a
4a
H
Scheme 1.
The stereochemistry of the products 4a could be readily confirmed by their acid-catalyzed
exchange reactions. When a 1:1 diastereomeric mixture of 4a was treated with p-TsOH in
ethanol for 4 days, the major isomer that was isolated was the anomer with the ethoxy group
in the axial position (approximately 4:1 ratio of the two anomers, Eq. (1)). It is possible that this
thermodynamic preference is due to the anomeric effect of the ethoxy group in oxacyclic
systems. The equilibration studies have also been repeated with pure samples of each of the two
diastereomers of 4a with both ethanol and methanol giving similar results.
H
H
EtO
H
H+ / EtOH
H
H
H
EtO
(1)
SO2Ph
SO2Ph
O
H3C
O
H3C
The results of the intramolecular cyclization reactions of the bromoacetals investigated so far
are shown in Table 1. As can be seen from the table, the chloromethyl derivative 2c undergoes
cyclization in excellent yield to give 4c. The cyclization can also be readily extended to prepare
seven-membered oxacyclic ring systems such as 4d.9
The lactol ethers, 4a–d, are useful intermediates in organic synthesis. For example, the
diastereomeric mixture of ethyl lactol ethers 4a was readily converted to the corresponding

9755
Table 1
Intramolecular cyclization reactions of bromoacetals
glycal derivative 5 in high yields by a three-step procedure (Eq. (2)).10 The synthetic utility of
such glycal derivatives has recently received much interest, particularly in the area of polysac-
charide synthesis.11,12
1. p-TsOH, MeOH
OEt
2. NaI, TMSCl, CH3CN
3. [(CH3)3Si]2NH, 80%
O
O
(2)
SO2Ph
SO2Ph
4a
5
CO2Et
O
OH
Ethyl propiolate,
PBu3, THF, rt
CO2Et
SO2Ph
2 eq. LHMDS
THF, -78 οC
O
R
( )n
..
-
R
SO2Ph
( )n
R
SO2Ph
( )n
3a n=1, R=CH3, 87%
3b n=1, R=Ph, 87%
3c n=2, R=CH3, 78%
3d n=2, R=Ph, 94%
OH
SO2Ph
-
( )n
CO2Et
O
R
CO2Et
7a n=1, R=CH3, 98%
7b n=1, R=Ph, 72%
7c n=2, R=CH3, 92%
7d n=2, R=Ph, 94%
( )n
6
R
SO2Ph
CO2Et
SO2Ph
CO2Et
O
DBU/CH2Cl2
DBU/CH2Cl2
7a
7b
7c
7d
O
2
2 eq. LHMDS
THF, -78 οC
R
SO2Ph
2 eq. LHMDS
THF, -78 οC
R
8a R=CH3, 80%
8b R=Ph, 87%
8c R=CH3, 90%
8d R=Ph , 71%
Scheme 2.

9756
Highly functionalized oxacyclic ring systems are also accessible by the intramolecular cycliza-
tion reactions of the acrylate derivatives of hydroxysulfones using a conjugate addition strategy.
The acrylate adducts 3a–d were easily prepared by the reaction of the corresponding hydroxysul-
fones with ethyl propiolate.13 When sulfone 3a was treated with 2.0 equiv. of LHMDS at −78°C
and the reaction quenched after 1 h, the desired cyclic product 8a (Scheme 2) was not isolated.
Instead the product that was obtained after chromatography as an inseparable mixture of
diastereomers was the predominantly trans-hydroxy a,b-unsaturated ester 7a in 98% yield.
However, the isomeric mixture of esters 7a could be cyclized by treatment with DBU at room
temperature to give a separable diastereomeric mixture (2:1) of tetrahydrofuran 8a in 80% yield.
It is interesting to note that treatment of 8a with 2 equiv. of LHMDS at −78°C leads to rapid
ring opening to give back 7a. In view of these results, we propose that the initially formed
sulfonyl carbanion from the acrylate derivative 3a undergoes a Michael addition to give
intermediate 6. However, 6 is not stable under the reaction conditions and undergoes rapid ring
opening.
Similar treatment of acrylate derivatives 3b–d with LHMDS led to the isolation of products
7b–d, which could be recyclized with DBU to get 8b–d (in each case a mixture of two
diastereomers). The two diastereomers of 8c (2:1) obtained from the cyclization could be
separated by column chromatography and the products were found to differ only at the
stereochemistry at C-2 by 1H NMR analysis.14 The relative stereochemistry of the two
diastereomers of 8d could also be assigned by spectral analysis, while that of the diastereomers
of 8a and 8b are under investigation.
In conclusion, the intramolecular alkylation of bromoacetal derivatives of hydroxysulfones
can be achieved in synthetically useful yields to give a variety of functionalized six- and
seven-membered oxacyclic ring systems with stereochemical control. The acrylate derivatives of
hydroxysulfones also show useful reactivity and can be used to access substituted tetra-
hydrofuranyl or pyranyl ring systems. Given the current interest in the synthesis of cyclic ether
containing natural products15 and the availability of the starting hydroxysulfones in high optical
purities,16,4a these intramolecular cyclization strategies should provide valuable intermediates for
synthetic applications.
References
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2. (a) Marco, J. L.; Ingate, S. T.; Jaime, C.; Bea´, I. Tetrahedron 2000, 56, 2523. (b) Carretero, J. C.; Go´mez Arraya´s,
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9757
6. Ihara, M.; Katsumata, A.; Setsu, F.; Tokunaga, Y.; Fukumoto, K. J. Org. Chem. 1996, 61, 677.
7. Spectroscopic and elemental analysis of all compounds are in agreement with the assigned structures.
8. 4a diastereomer 1: 1H NMR (200 MHz, CDCl3) l 7.95–7.50 (m, 5H), 4.94 (d, J=2.5 Hz, 1H), 3.83 (ddq, J=12.4,
2.1, 6.2 Hz, 1H), 3.72–3.33 (m, 3H), 2.05–1.69 (m, 3H), 1.54–1.35 (m, 1H), 1.30–1.05 (m, 6H); anal. calcd for
1
C14H20SO4: C, 59.13%; H, 7.09%. Found: C, 58.77%; H, 6.95%. 4a diastereomer 2: H NMR (200 MHz, CDCl3)
l 7.95–7.50 (m, 5H), 4.38 (dd, J=9.4, 1.8 Hz, 1H), 4.00–3.82 (m, 1H), 3.60–3.43 (m, 2H), 3.23 (dddd, J=12.7,
12.7, 3.8, 3.8 Hz, 1H), 2.14–1.94 (m, 2H) 1.58–1.36 (m, 2H), 1.30–1.05 (m, 6H); anal. calcd for C14H20SO4: C,
59.13%; H, 7.09%. Found: C, 59.06%; H, 7.17%.
9. The relative stereochemistry of 4d has been assigned based on the precedence observed for the six-membered ring
system. Acid-catalyzed exchange studies on the two diastereomers of 4d show that they differ in the stereochem-
istry at the anomeric carbon. Assignment of the stereochemistry is currently under investigation.
10. Paquette, L. A.; Oplinger, J. A. J. Org. Chem. 1988, 53, 2953.
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1
14. 8c major diastereomer: H NMR (200 MHz, CDCl3) l 8.00–7.50 (m, 5H), 4.79 (ddd, J=10.7, 4.6, 4.5 Hz, 1H),
4.26–4.06 (m, 2H), 3.88 (ddq, J=11.9, 2.1, 6.0 Hz, 1H), 3.41 (ddd, J=12.3, 4.5, 4.4 Hz 1H), 3.20–2.90 (m, 2H),
2.15–1.70 (m, 3H), 1.35–1.15 (m, 1H), 1.26 (t, J=7.1 Hz, 3H), 1.07 (d, J=6.0 Hz, 3H); anal. calcd for C16H22SO5:
C, 58.88%; H, 6.79%. Found: C, 58.68%; H, 6.65%.
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.