Intermolecular and intramolecular reactions of resolved 2-alkoxytetrahydrofuran-3-yl and 2-alkoxytetrahydropyran-3-yl radicals

Article abstract of DOI:10.1016/S0040-4020(00)00547-0

Diastereomeric trans-2-alkoxy-3-phenylselenenyltetrahydrofuranyl acetals and trans-2-alkoxy-3-phenyl-selenenyltetrahydropyranyl acetals were prepared from dihydrofuran, dihydropyran, phenylselenenyl bromide, and the alcohols (S)-methyl lactate, (S)-methyl hexahydromandelate, and (R)-pantolactone. The diastereomers were chromatographically separated and were subjected to intermolecular alkylation via generation and trapping of free radicals. Observed diastereoselectivity was higher for 2-alkoxytetrahydrofuran-3-yl radicals than for 2-alkoxytetrahydropyran-3-yl radicals, and highest for acetals involving (R)-pantolactone. Alcohol exchanges at the anomeric carbon were highly stereocontrolled, and permitted introduction of alkenes for intramolecular trapping of free radical intermediates. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00547-0

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 5793±5800
Intermolecular and Intramolecular Reactions of
Resolved 2-Alkoxytetrahydrofuran-3-yl and
2-Alkoxytetrahydropyran-3-yl Radicals1
*
Kalpana S. Nimkar and Eugene A. Mash
Department of Chemistry, The University of Arizona, Tucson, AZ 85721-0041, USA
Received 12 May 2000; accepted 13 June 2000
AbstractÐDiastereomeric trans-2-alkoxy-3-phenylselenenyltetrahydrofuranyl acetals and trans-2-alkoxy-3-phenyl-selenenyltetrahydro-
pyranyl acetals were prepared from dihydrofuran, dihydropyran, phenylselenenyl bromide, and the alcohols (S)-methyl lactate, (S)-methyl
hexahydromandelate, and (R)-pantolactone. The diastereomers were chromatographically separated and were subjected to intermolecular
alkylation via generation and trapping of free radicals. Observed diastereoselectivity was higher for 2-alkoxytetrahydrofuran-3-yl radicals
than for 2-alkoxytetrahydropyran-3-yl radicals, and highest for acetals involving (R)-pantolactone. Alcohol exchanges at the anomeric
carbon were highly stereocontrolled, and permitted introduction of alkenes for intramolecular trapping of free radical intermediates.
q 2000 Elsevier Science Ltd. All rights reserved.
The biological signi®cance of compounds that contain tetra-
hydrofuran (THF) and tetrahydropyran (THP) rings has
encouraged the development of methods for the synthesis
and functionalization of these heterocycles.2 Methods that
involve carbon-centered radicals are particularly compatible
with the chemistry of these rings, can exhibit signi®cant
regioselectivity and diastereoselectivity, and have been
widely employed.3,4
Table 1. Synthesis and separation of diastereomeric acetals 1±4
Diastereomers
n
RpOH
Yieldsa (%)
ab (solvent)c
1a
1b
1
(S)-methyl lactate
29
35
1.24 (20)
2a
2b
1
1
2
(S)-methyl hexahydromandelate
(R)-pantolactone
28
35
1.29 (15)
1.29 (20)
1.20 (20)
3a
3b
44
26
4a
4b
(R)-pantolactone
31
21
a Isolated yields of the less polar (a) and more polar (b) diastereomers, respectively.
b The separation factor, a, is the ratio of the Rf values for the diastereomers on 0.25-mm silica gel 60 plates.
c Solvent is given as the percent of ethyl acetate in hexanes.
Keywords: selenoacetals; resolution; radicals and radical reactions; diastereoselection.
* Corresponding author. Tel.: 11-520-621-6321; fax: 11-520-621-8407; e-mail: emash@u.arizona.edu
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00547-0

5794
K. S. Nimkar, E. A. Mash / Tetrahedron 56 (2000) 5793±5800
Scheme 1. Intermolecular radical trapping reactions of diastereomeric acetals 1±4.
We developed a general chromatographic separation of
furanoside and pyranoside acetals that incorporate enantio-
pure esters of a-hydroxycarboxylic acids as the alcohol
component.5 This diastereomer resolution compliments the
chiron approach2a to THF and THP derivatives in that both
enantiomers of a target can be prepared simultaneously. We
are exploring the utility of this method,6 and present herein a
short survey of intermolecular and intramolecular reactions
of resolved 2-alkoxytetrahydrofuran-3-yl and 2-alkoxy-
tetrahydropyran-3-yl radicals.
separable 15:1 mixture of less and more polar diastereomers
14a and 14b.14 Similarly, the use of trans-2-buten-1-ol gave
a chromatographically separable 15:1 mixture of less and
more polar diastereomers 16a and 16b in 94% yield.
Assignment of the trans stereochemistry to the major
products 14a and 16a is consistent with literature
precedent15 and participation by the 3-phenylselenenyl
group.
Acetals 14a and 16a were subjected to radical generation
(n-Bu3SnH, AIBN, benzene, re¯ux) and trapping using
acrylonitrile as the radical trapping agent (Scheme 2).
Bicyclic nitrile 15 was obtained as a single diastereomer
from 14a in 45% yield, while a chromatographically
inseparable 2:1 mixture of diastereomeric nitriles 17a and
17b was obtained in 78% yield from 16a. Product structures
were initially assigned based on literature precedent16 and
con®rmed for 15 by NOE difference spectroscopy.17
Preparation of Radical Precursors for Intermolecular
Reactions
Diastereomeric acetals 1±4 (Table 1) were prepared by reac-
tion of dihydrofuran or dihydropyran with phenylselenenyl
bromide in methylene chloride, followed by reaction of the
intermediate bromide with an enantiopure alcohol and
triethylamine. Separation of the diastereomer pairs was
effected by column chromatography on silica gel eluted
with ethyl acetate in hexanes. Yields were good and the
separations facile (Table 1). Structures were assigned
based on previous work in our laboratory.5±7
Discussion
In keeping with past observations on intermolecular
trapping in cyclic systems,3,10 anti attack relative to the
substituent b to the radical center was generally favored.
Diastereoselectivity is expected to depend on the steric bulk
of the b substituent attached at the anomeric carbon. In fact,
the most useful chiral auxiliary of the three alcohols
examined was (R)-pantolactone. In the THF series,
synthetically useful diastereoselectivities were obtained
for intermolecular trapping of the radicals derived from 3a
and 3b. However, diastereoselectivites were low in the THP
series, even for the radicals derived from 4a and 4b.9 These
results were unexpected given that comparable diastereo-
selectivities were reported for trapping of 2-methoxytetra-
Intermolecular Radical Trapping Reactions
Acetals 1a, 1b, 2b, 3a, 3b, 4a, and 4b were subjected to
radical generation (n-Bu3SnH, AIBN, benzene, re¯ux) and
trapping using acrylonitrile as the radical trapping agent
(Scheme 1 and Table 2). Isolated yields of the correspond-
ing acrylonitrile adducts ranged from 60 to 82%. Diastereo-
selectivities were lower for THF acetals 1a, 1b, and 2b that
incorporate the (S)-methyl lactate and (S)-methyl hexa-
hydromandelate auxiliaries than for acetals 3a and 3b that
incorporate the (R)-pantolactone auxiliary.8 The diastereo-
selectivities for THP acetals 4a and 4b that incorporate the
(R)-pantolactone auxiliary were low.9 In each case, the more
polar product was predominant and could be isolated from
the less polar product by column chromatography. Struc-
tures were initially assigned to the product diastereomers
based on literature precedent that the trans products
would predominate.10 These assignments were supported
by the chemical shifts for the proton at C2 and by the
coupling constants between this proton and the proton at
C3 (Table 3).10±12 Radicals derived from selenoacetals 3a
and 3b were also trapped using methyl acrylate. This
produced 9a and 11a in 47 and 49% yields, respectively,
as the only isolable monoalklyated products.13
hydrofuran-3-yl
and
2-methoxytetrahydropyran-3-yl
radicals with acrylonitrile and methyl acrylate.10
Intramolecular Radical Trapping Reactions
Treatment of acetal 1b with a catalytic amount of p-toluene-
sulfonic acid in dichloromethane containing 10 equiv. of
allyl alcohol gave, in 66% yield, a chromatographically
Scheme 2. Intramolecular Radical Trapping Reactions of Acetals 14a and
16a.

K. S. Nimkar, E. A. Mash / Tetrahedron 56 (2000) 5793±5800
Table 2. Intermolecular radical trapping reactions of acetals 1±4
5795
a Reaction conditions A, CH2vCHCN, n-Bu3SnH, AIBN, PhH, heat; B, CH2vCHCO2Me, n-Bu3SnH, AIBN, PhH, heat.
b Isolated yields of the more polar (a) and less polar (b) diastereomers, respectively.
c The separation factor, a, is the ratio of the Rf values for the diastereomers on 0.25-mm silica gel 60 plates.
d Solvent is given as the percent of ethyl acetate in hexanes.
The synthetic utility of radical-mediated cyclization onto
carbohydrate templates is well established.18 A link between
this strategy and the diastereomer resolution of simpler THF
and THP acetals5,6 was forged using 14a and 16a. These
trans acetals, prepared from 1b by acid-catalyzed alcohol
exchange, were predominant over the cis diastereomers
under the conditions employed.14,19 Following radical
generation, cyclization to the corresponding intermediate
bicyclic radicals occurred with the expected regio- and
stereochemistry. However, trapping of the bicyclic acetal
radical derived from 16a was not stereocontrolled, and led
to production of diastereomers 17a and 17b.

5796
K. S. Nimkar, E. A. Mash / Tetrahedron 56 (2000) 5793±5800
Table 3. Selected 1H NMR data for diastereomeric acetals 5±13
Diastereomer
R
ORp
d
H2 (ppm)
3JH ±H3 (Hz)
2
5a
5b
6a
6b
7a
7b
8a
8b
CH2CH2CN
CH2CH2CN
CH2CH2CN
CH2CH2CN
(S)-methyl lactate
(S)-methyl lactate
(S)-methyl hexahydromandelate
(R)-pantolactone
4.88
5.00
4.91
4.99
4.81
4.94
5.30
5.40
5.27
4.99
5.10
4.94
4.61
5.20
4.43
4.79
2.2
4.5
0.6
4.3
,2
4.3
2.3
4.4
1.5
1.0
4.1
,2
7.1
2.8
4.8
,2
9a
CH2CH2CO2Me
CH2CH2CN
(R)-pantolactone
(R)-pantolactone
10a
10b
11a
12a
12b
13a
13b
CH2CH2CO2Me
CH2CH2CN
(R)-pantolactone
(R)-pantolactone
CH2CH2CN
(R)-pantolactone
Experimental
magnesium sulfate, ®ltered, and concentrated in vacuo. The
residue was chromatographed on silica gel 60 (275 g) eluted
with 10% EtOAc/hexanes. The less polar diastereomer 4a
(1.36 g, 3.67 mmol, 31%) was obtained as colorless oil,
[a]2D6ˆ199.4 (c 5.0, EtOAc); Rf 0.24 (20% EtOAc/
All reactions were performed in ¯ame-dried glassware
under argon. Hygroscopic liquids and solutions of reactive
intermediates were transferred via syringe. Reaction
product solutions were concentrated using a rotary evapora-
tor at 30±40 mmHg. Dichloromethane and benzene were
distilled from CaH2. Diethyl ether and tetrahydrofuran
were distilled from sodium/benzophenone ketyl. Analytical
thin-layer chromatography was performed on Merck glass-
backed pre-coated plates (0.25 mm, silica gel 60, F-254).
Visualization of spots was effected by treatment of the
plate with a 2.5% solution of para-anisaldehyde in ethanol
containing 6% H2SO4 and 2% acetic acid followed by
charring on a hot plate. Gravity-driven column chromato-
graphy was performed on Merck silica gel 60 (70±230
mesh). Optical rotations were measured at 589 nm. NMR
spectra were recorded in CDCl3 solution unless otherwise
indicated. Proton and 13C magnetic resonance spectra were
recorded at 250.1 and 62.9 MHz, respectively, using tetra-
methylsilane (0 ppm) and the center line of the chloroform-
d triplet (77.0 ppm) as internal standards. Elemental
analyses were performed by Desert Analytics, Tucson, AZ.
1
hexanes); H NMR d 1.03 (3, s), 1.18 (3, s), 1.50±1.65 (1,
m), 1.70±2.00 (2, m), 2.20±2.31 (1, m), 3.38±3.48 (1, m),
3.55±3.65 (1, m), 3.85±4.00 (3, m), 4.15 (1, s), 5.20 (1, d,
Jˆ4.4 Hz), 7.20±7.30 (3, m), 7.55±7.65 (2, m); 13C NMR d
19.2, 23.1, 23.7, 26.4, 39.9, 43.4, 62.7, 76.2, 77.4, 100.1,
127.2, 128.9, 129.5, 134.0, 174.8. The more polar diastereo-
mer 4b (0.914 g, 2.47 mmol, 21%) was obtained as color-
less oil, [a]2D6ˆ250.2 (c 5.0, EtOAc); Rf 0.20 (20% EtOAc/
hexanes); IR (neat) 3053, 2960, 1787, 1735, 1576, 1465,
1436, 1400, 1371, 1332, 1298, 1241, 1201, 1072,
1
1059 cm21; H NMR d 1.02 (3, s), 1.11 (3, s), 1.50±1.65
(1, m), 1.75±2.00 (2, m), 2.29±2.40 (1, m), 3.45±3.65 (2,
m), 3.86 (1, d, Jˆ8.9 Hz), 3.93 (1, d, Jˆ8.9 Hz), 4.15±4.25
(1, m), 4.19 (1, s), 4.79 (1, d, Jˆ3.7 Hz), 7.20±7.30 (3, m),
7.50±7.60 (2, m); 13C NMR d 19.4, 23.0, 23.4, 25.8, 41.0,
43.3, 62.4, 75.6, 79.0, 101.6, 127.5, 129.1, 134.0, 174.5.
Anal. Calcd for C17H22O4Se: C, 55.29; H, 6.00. Found: C,
55.32; H, 6.06.
(S)-Methyl lactyl 3-phenylselenenyl-2,3,4,5-tetrahydro-
furan-2-yl ethers 1a and 1b. By a similar procedure,
diastereomeric acetals 1a and 1b were obtained as pale
yellow oils in 29 and 35% yields, respectively. For the
less polar diastereomer 1a: [a]2D5ˆ250.4 (c 5.0, EtOAc);
Rf 0.36 (20% EtOAc/hexanes); 1H NMR d 1.37 (3, d,
Jˆ7.0 Hz), 1.85±2.00 (1, m), 2.45±2.60 (1, m), 3.64 (3,
s), 3.80 (1, dd, Jˆ7.7 and 3.5 Hz), 3.90±4.05 (2, m), 4.31
(1, q, Jˆ7.0 Hz), 5.25 (1, s), 7.25±7.31 (3, m), 7.54±7.57 (2,
m); 13C NMR d 18.8, 30.5, 44.3, 51.8, 66.9, 70.1, 107.4,
127.2, 129.0, 130.0, 133.2, 174.0. For the more polar dia-
stereomer 1b: [a]2D5ˆ215.7 (c 6.1, EtOAc); Rf 0.29 (20%
EtOAc/hexanes); IR (neat) 2986, 1747, 1269 cm21 1H
;
(R)-Pantolactonyl 3-phenylselenenyl-3,4,5,6-tetrahydro-
2H-pyran-2-yl ethers 4a and 4b. To a well stirred solution
of Ph2Se2 (1.85 g, 5.94 mmol) in methylene chloride
(15 mL) at 58C was added Br2 (306 mL, 950 mg,
5.94 mmol) dropwise. This solution was maintained at 58C
and added dropwise to a well stirred solution of dihydro-
pyran (1.08 mL, 1.00 g, 11.9 mmol) in methylene chloride
(15 mL) at 2788C. After 30 min a solution of triethylamine
(1.82 mL, 1.32 g, 13.1 mmol) and (R)-(2)-pantolactone
(1.54 g, 11.9 mmol) was added rapidly. The reaction
mixture was allowed to attain room temperature and was
stirred for 24 h. The reaction mixture was then diluted with
methylene chloride (25 mL), washed with sat aq. NaHCO3
(2£25 mL) and sat aq NaCl (25 mL), dried over anhydrous
NMR d 1.30 (3, d, Jˆ6.9 Hz), 1.84±2.00 (1, m), 2.50±

K. S. Nimkar, E. A. Mash / Tetrahedron 56 (2000) 5793±5800
5797
2.68 (1, m), 3.70 (3, s), 3.75±3.84 (1, m), 3.94 (2, t,
Jˆ7.0 Hz), 4.05 (1, q, Jˆ6.9 Hz), 5.20 (1, s), 7.25±7.28
(3, m), 7.51±7.55 (2, m); 13C NMR d 18.2, 30.9, 44.3,
51.7, 67.2, 71.9, 108.7, 127.4, 128.0, 129.0, 133.3, 175.0.
Anal. Calcd for C14H18O4Se: C, 51.07; H, 5.51. Found: C,
50.80; H, 5.56.
EtOAc/hexanes); IR (neat) 3056, 2953, 2360, 2247,
1
1746 cm21; H NMR d 1.38 (3, d, Jˆ6.9 Hz), 1.45±1.95
(3, m), 2.20±2.45 (4, m), 3.75 (3, s), 3.85±3.95 (2, m), 4.10
(1, q, Jˆ6.9 Hz), 4.91 (1, d, Jˆ0.6 Hz); 13C NMR d 15.6,
18.2, 27.9, 29.8, 44.7, 51.7, 66.8, 72.3, 107.7, 119.0, 174.0.
(S)-Methyl lactyl 3-(2-cyano)ethyl-2,3,4,5-tetrahydro-
furan-2-yl ethers 5a and 5b. By a similar procedure, dia-
stereomeric acetals 5a and 5b were obtained from 1a in 53
and 15% yields, respectively. For the less polar isomer 5b:
[a]2D7ˆ2131.8 (c 0.81, CHCl3); Rf 0.12 (20% EtOAc/
(S)-Methyl hexahydromandelyl 3-phenylselenenyl-
2,3,4,5-tetrahydrofuran-2-yl ethers 2a and 2b. By a simi-
lar procedure, diastereomeric acetals 2a and 2b were
obtained as pale yellow oils in 28% and 35% yields, respec-
tively. For the less polar diastereomer 2a: [a]2D7ˆ257.5 (c
1
hexanes); H NMR d 1.37 (3, d, Jˆ7.0 Hz), 1.60±2.33 (5,
1
2.79, EtOAc); Rf 0.44 (15% EtOAc/hexanes); H NMR d
m), 2.60±2.65 (2, m), 3.73 (3, s), 3.84±4.02 (2, m), 4.35 (1,
q, Jˆ7.0 Hz), 5.00 (1, d, Jˆ4.5 Hz). For the more polar
isomer 5a: [a]2D7ˆ135.2 (c 2.9, EtOAc); Rf 0.07 (20%
EtOAc/hexanes); IR (neat) 3056, 2935, 2360, 2247, 1746,
1.00±1.30 (6, m), 1.50±1.80 (6, m), 1.88±2.00 (1, m), 2.46±
2.64 (1, m), 3.63 (3, s), 3.80±4.05 (3, m), 5.15 (1, s), 7.26±
7.29 (3, m), 7.53±7.55 (2, m); 13C NMR d 25.8, 25.9, 26.0,
27.8, 29.1, 30.5, 40.5, 44.4, 51.6, 66.9, 78.0, 106.7, 127.2,
129.1, 129.8, 133.2, 177.5. For the more polar diastereomer
2b: [a]2D7ˆ226.9 (c 0.91, EtOAc); Rf 0.34 (15% EtOAc/
hexanes); IR (neat) 3052, 2929, 2854, 1743, 1576, 1477,
1
1500, 1325, 1050 cm21; H NMR d 1.39 (3, d, Jˆ7.0 Hz),
1.55±1.61 (1, m), 1.70±1.90 (2, m), 2.15±2.35 (2, m), 2.50
(2, t, Jˆ7.5 Hz), 3.74 (3, s), 3.85±4.00 (2, m), 4.35 (1, q,
Jˆ7.0 Hz), 4.88 (1, d, Jˆ2.2 Hz); 13C NMR d 15.6, 18.8,
28.2, 30.5, 44.9, 51.8, 66.8, 70.2, 106.5, 119.0, 173.0. Anal.
Calcd for C11H17NO4: C, 58.14; H, 7.54; N, 6.16. Found: C,
58.44; H, 7.38; N, 6.41.
1
1448, 1436, 1264 cm21; H NMR d 0.80±2.10 (13, m),
2.50±2.65 (1, m), 3.60 (1, d, Jˆ6.9 Hz), 3.70 (3, s), 3.70±
3.95 (3, m), 5.12 (1, s), 7.25±7.29 (3, m), 7.52±756 (2, m);
13C NMR d 25.6, 25.7, 26.0, 28.3, 28.5, 31.0, 40.5, 44.1,
51.5, 67.2, 81.4, 110.8, 127.4, 129.1, 129.6, 133.2, 173.0.
(S)-Methyl hexahydromandelyl 3-(2-cyano)ethyl-2,3,4,5-
tetrahydrofuran-2-yl ethers 7a and 7b. By a similar
procedure, diastereomeric acetals 7a and 7b were obtained
from 2b in 47 and 13% yields, respectively. For the less
polar isomer 7b: [a]D27ˆ140.6 (c 1.96, EtOAc); Rf 0.16
(30% EtOAc/hexanes); 1H NMR d 0.83±1.30 (8, m),
1.45±2.30 (8, m), 2.40±2.46 (2, m), 3.62 (1, d, Jˆ7.2 Hz),
3.71 (3, s), 3.75±3.97 (2, m), 4.94 (1, d, Jˆ4.3 Hz). For the
more polar isomer 7a: [a]2D7ˆ133.9 (c 0.38, EtOAc); Rf
0.12 (30% EtOAc/hexanes); IR (neat) 3053, 2983, 2929,
(R)-Pantolactonyl 3-phenylselenenyl-2,3,4,5-tetrahydro-
furan-2-yl ethers 3a and 3b. By a similar procedure, dia-
stereomeric acetals 3a and 3b were obtained in 44 and 26%
yields, respectively. The less polar diastereomer 3a was
obtained as colorless crystals, mp 74±768C (hexanes);
[a]2D7ˆ164.1 (c 2.5, EtOAc); Rf 0.27 (20% EtOAc/
1
hexanes); H NMR d 1.05 (3, s), 1.15 (3, s), 1.90±2.05 (1,
m), 2.46±2.62 (1, m), 3.81±4.09 (6, m), 5.59 (1, s), 7.25±
7.35 (3, m), 7.55±7.62 (2, m); 13C NMR d 19.3, 23.2, 30.4,
40.2, 44.3, 67.5, 75.5, 78.1, 109.2, 127.6, 129.2, 129.5,
133.5, 173.0. The more polar diastereomer 3b was obtained
as a colorless oil, [a]D27ˆ11.4 (c 4.8, CHCl3); Rf 0.21 (20%
EtOAc/hexanes); IR (CH2Cl2) 3054, 2986, 1789,
1
2854, 2306, 1732, 1266 cm21; H NMR d 0.80±1.25 (5,
m), 1.45±1.92 (9, m), 2.20±2.43 (4, m), 3.63 (1, d,
Jˆ7.3 Hz), 3.71 (3, s), 3.84±3.91 (2, m), 4.81 (1, br s);
13C NMR d 15.8, 25.6, 25.7, 26.1, 28.0, 28.6, 28.7, 30.0,
40.5, 44.8, 51.5, 66.9, 82.0, 109.3, 119.2, 173.3. Anal. Calcd
for C16H25NO4: C, 65.06; H, 8.53; N, 4.74. Found: C, 65.36;
H, 8.54; N, 5.00.
1
1250 cm21; H NMR d 0.91 (3, s), 1.02 (3, s), 1.82±1.98
(1, m), 2.53±2.68 (1, m), 3.80±4.25 (6, m), 5.22 (1, s),
7.26±7.30 (3, m), 7.55±7.58 (2, m); 13C NMR d 19.3,
23.2, 30.4, 40.0, 44.3, 67.5, 75.5, 78.1, 109.2, 127.6,
129.2, 129.4, 133.5, 174.8. Anal. Calcd for C16H20O4Se:
C, 54.09; H, 5.67. Found: C, 54.04; H, 5.62.
(R)-Pantolactonyl 3-(2-cyano)ethyl-2,3,4,5-tetrahydro-
furan-2-yl ethers 8a and 8b. By a similar procedure, dia-
stereomeric acetals 8a and 8b were obtained from 3a in 56
and 10% yields, respectively. For the less polar isomer 8b:
[a]2D6ˆ1138.9 (c 0.42, EtOAc); Rf 0.20 (40% EtOAc/
(S)-Methyl lactyl 3-(2-cyano)ethyl-2,3,4,5-tetrahydro-
furan-2-yl ethers 6a and 6b. Ether 1b (200 mg,
0.60 mmol) was dissolved in dry benzene (10 mL) and
acrylonitrile (278 mL, 224 mg, 4.24 mmol) and AIBN
(30 mg, 0.18 mmol) were added. The reaction mixture
was stirred and heated to 70±758C and n-Bu3SnH
(484 mL, 520 mg, 1.80 mmol) in benzene (1.2 mL) was
added via a syringe pump over 5.5 h. Volatiles were
removed in vacuo and the residue was chromatographed
on silica gel 60 (75 g) eluted with 20% EtOAc/hexanes to
give products 6b (20 mg, 0.09 mmol, 15%) and 6a (77 mg,
0.34 mmol, 57%). For the less polar isomer 6b:
[a]2D7ˆ231.9 (c 0.85, EtOAc); Rf 0.15 (20% EtOAc/
1
hexanes); H NMR d 1.04 (3, s), 1.17 (3, s), 1.75±2.14 (4,
m), 2.30±2.40 (1, m), 2.55±2.62 (2, m), 3.93±4.04 (4, m),
4.12 (1, s), 5.40 (1, d, Jˆ4.4 Hz). For the more polar isomer
8a: [a]2D6ˆ1119.2 (c 1.46, EtOAc); Rf 0.18 (40% EtOAc/
hexanes); IR (neat) 3057, 2963, 2245, 1787, 1734,
1
1464 cm21; H NMR d 1.06 (3, s), 1.17 (3, s), 1.55±1.95
(3, m), 2.20±2.28 (1, m), 2.35±2.45 (1, m), 2.52 (2, t,
Jˆ7.3 Hz), 3.88±3.98 (4, m), 4.11 (1, s), 5.30 (1, d,
Jˆ2.3 Hz); 13C NMR d 15.7, 19.4, 22.8, 28.1, 30.5, 39.9,
44.7, 67.0, 76.3, 77.9, 106.8, 119.2, 174.8. Anal. Calcd for
C13H19NO4: C, 61.64; H, 7.56; N, 5.53. Found: C, 61.56; H,
7.40; N, 5.56.
1
hexanes); H NMR d 1.31 (3, d, Jˆ6.8 Hz), 1.70±2.25 (5,
m), 2.30±2.40 (2, m), 3.67 (3, s), 3.70±3.95 (2, m), 4.01 (1,
q, Jˆ6.8 Hz), 4.99 (1, d, Jˆ4.3 Hz). For the more polar
isomer 6a: [a]2D7ˆ2116.6 (c 2.1, EtOAc); Rf 0.10 (20%
(R)-Pantolactonyl 3-(3-methyl propanoyl)-2,3,4,5-tetra-
hydrofuran-2-yl ether 9a. By a similar procedure, acetal
9a was obtained from 3a in 47% yield; [a]2D7ˆ1151.8 (c

5798
K. S. Nimkar, E. A. Mash / Tetrahedron 56 (2000) 5793±5800
1
(35% EtOAc/hexanes); H NMR d 1.12 (3, s), 1.22 (3, s),
2.7, EtOAc); Rf 0.19 (30% EtOAc/hexanes); IR (neat)
1
3056, 2961, 1787, 1733, 1436, 1371, 1266 cm21; H NMR
1.20±1.85 (6, m), 1.95±2.10 (1, m), 2.44 (2, t, Jˆ7.4 Hz),
3.45±3.55 (1, m), 3.92 (1, d, Jˆ8.9 Hz), 3.99 (1, d,
Jˆ8.9 Hz), 4.05±4.25 (1, m), 4.25 (1, s), 4.43 (1, d,
Jˆ4.8 Hz); 13C NMR d 14.9, 19.4, 22.3, 23.4, 24.3, 26.2,
38.0, 40.4, 63.4, 75.5, 78.6, 102.8, 119.3, 174.3.
d 1.08 (3, s), 1.22 (3, s), 1.45±1.85 (3, m), 2.19±2.40 (4, m),
3.69 (3, s), 3.85±4.00 (4, m), 4.09 (1, s), 5.27 (1, d,
Jˆ1.5 Hz); 13C NMR d 19.4, 23.4, 27.4, 29.7, 32.3, 40.2,
44.9, 51.6, 67.1, 75.5, 78.1, 108.3, 173.5, 174.8. Anal.
Calcd for C14H22O6: C, 58.73; H, 7.74. Found: C, 58.71;
H, 7.87.
Allyl 3-phenylselenenyl-2,3,4,5-tetrahydrofuran-2-yl ethers
14a and 14b. To a well stirred solution of 1b (1.00 g,
3.03 mmol) and allyl alcohol (2.06 mL, 1.75 g,
30.3 mmol) in CH2Cl2 (10 mL) at room temperature was
added a catalytic amount of TsOH (58 mg, 0.30 mmol).
After 20 min the reaction mixture was diluted with
CH2Cl2 (10 mL), washed with sat aq NaHCO3 (2£20 mL)
and water (20 mL), dried over anhydrous MgSO4, and
®ltered. Concentration in vacuo gave a mixture of isomers.
Chromatography on silica gel 60 (100 g) eluted with 5%
EtOAc/hexanes afforded 528 mg (1.86 mmol, 62%) of the
trans isomer 14a as a colorless oil, Rf 0.49 (20% EtOAc/
hexanes); [a]2D6ˆ138.3 (c 6.5, EtOAc); IR (neat) 3070,
2977, 2891, 1644, 1578, 1448, 1435, 1358, 1104,
(R)-Pantolactonyl 3-(2-cyano)ethyl-2,3,4,5-tetrahydro-
furan-2-yl ethers 10a and 10b. By a similar procedure,
diastereomeric acetals 10a and 10b were obtained from
3b in 78 and 4% yields, respectively. For the more polar
isomer 10a: [a]2D7ˆ282.8 (c 2.8, EtOAc); Rf 0.16 (40%
1
EtOAc/hexanes); H NMR d 1.09 (3, s), 1.22 (3, s), 1.48±
1.95 (3, m), 2.25±2.45 (4, m), 3.88±4.10 (4, m), 4.14 (1, s),
4.99 (1, d, Jˆ1.0 Hz); 13C NMR d 15.7, 19.4, 23.4, 27.9,
29.4, 29.6, 40.2, 44.7, 67.0, 75.7, 78.2, 107.7, 119.0, 174.7.
The less polar isomer 10b, Rf 0.22 (40% EtOAc/hexanes),
was contaminated with .20% of 10a and was not charac-
terized.
1
1021 cm21; H NMR d 1.85±2.00 (1, m), 2.44±2.60 (1,
(R)-Pantolactonyl 3-(3-methyl propanoyl)-2,3,4,5-tetra-
hydrofuran-2-yl ether 11a. By a similar procedure, acetal
11a was obtained from 3b in 49% yield; [a]2D7ˆ277.1 (c
m), 3.70±3.75 (1, m), 3.85±4.02 (3, m), 4.06±4.16 (1, m),
5.15±5.25 (3, m), 5.75±5.90 (1, m), 7.25±7.30 (3, m), 7.52±
7.56 (2, m); 13C NMR d 30.9, 44.5, 66.8, 68.0, 108.0, 117.0,
127.4, 129.0, 129.5, 133.5, 134.2. Also obtained were 39 mg
(0.14 mmol, 4%) of 14b, Rf 0.45 (20% EtOAc/hexanes);
1
2.65, EtOAc); Rf 0.11 (20% EtOAc/hexanes); H NMR d
1.08 (3, s), 1.22 (3, s), 1.55±1.85 (3, m), 2.25±2.35 (2, m),
2.35±2.41 (2, m), 3.69 (3, s), 3.70±4.10 (3, m), 4.10±4.25
(2, m), 4.94 (1, br s); 13C NMR d 19.4, 23.4, 27.4, 29.7, 32.3,
40.2, 44.9, 51.6, 67.1, 75.5, 78.1, 108.3, 173.3.
1
[a]2D6ˆ241.5 (c 2.6, EtOAc); H NMR d 2.15±2.40 (2,
m), 3.43±3.55 (1, m), 3.75±3.85 (1, m), 3.89±4.05 (2, m),
4.08±4.20 (1, m), 5.05±5.15 (2, m), 5.26 (1, dm, Jˆ18 Hz),
5.75±5.95 (1, m), 7.15±7.25 (3, m), 7.45±7.52 (2, m); 13C
NMR d 37.7, 44.3, 66.8, 68.2, 102.8, 116.8, 127.2, 129.0,
130.4, 133.4, 134.3. Anal. Calcd for C13H16O2Se: C, 55.13;
H, 5.69. Found: C, 55.38; H, 5.74.
(R)-Pantolactonyl 3-(2-cyano)ethyl-3,4,5,6-tetrahydro-
pyran-2H-2-yl ethers 12a and 12b. By a similar procedure,
diastereomeric acetals 12a and 12b were obtained from 4a
in 43 and 19% yields, respectively. For the less polar isomer
12b: [a]2D7ˆ1225 (c 0.5, EtOAc); Rf 0.17 (35% EtOAc/
Crotyl 3-phenylselenenyl-2,3,4,5-tetrahydrofuran-2-yl
ethers 16a and 16b. By a similar procedure, acetals 16a
and 16b were obtained from trans-crotyl alcohol and 1b in
88 and 6% yields, respectively. For the less polar isomer
16a: [a]2D6ˆ233.3 (c 6.15, CHCl3); Rf 0.37 (10% EtOAc/
hexanes); IR (neat) 2936, 2887, 1735, 1671, 1577, 1476,
1
hexanes); H NMR d 1.09 (3, s), 1.20 (3, s), 1.45±2.00 (7,
m), 2.45±2.65 (2, m), 3.53±3.78 (2, m), 3.90 (1, d,
Jˆ8.9 Hz), 3.96 (1, d, Jˆ8.9 Hz), 4.15 (1, s), 5.20 (1, d,
Jˆ2.8 Hz); 13C NMR d 14.1, 19.5, 23.2, 23.9, 25.1, 27.4,
38.2, 40.3, 60.0, 76.0, 76.7, 96.3, 120.2, 175.4. For the more
polar isomer 12a: [a]D27ˆ1272 (c 1.3, EtOAc); Rf 0.13
(35% EtOAc/hexanes); IR (CH2Cl2) 3056, 2245, 1788,
1
1436 cm21; H NMR d 1.67 (3, m), 1.84±1.98 (1, m),
2.43±2.60 (1, m), 3.69±3.74 (1, m), 3.84±3.87 (1, m),
3.95±4.18 (3, m), 5.15 (1, s), 5.50±5.51 (1, m), 5.62±5.65
(1, m), 7.25±7.29 (3, m), 7.52±7.55 (2, m); 13C NMR d
17.8, 31.0, 44.5, 66.7, 67.9, 107.7, 126.9, 127.4, 129.1,
129.5, 129.9, 133.5. The more polar isomer 16b, Rf 0.31
(10% EtOAc/hexanes), was contaminated with .20% of
16a and was not characterized. Anal. Calcd for
C14H18O2Se: C, 56.57; H, 6.10. Found: C, 56.73; H, 6.13.
1
1733 cm21; H NMR d 1.11 (3, s), 1.21 (3, s), 1.20±1.40
(1, m), 1.50±1.75 (4, m), 1.85±2.05 (2, m), 2.39±2.68 (2,
m), 3.38±3.52 (1, m), 3.90±4.05 (1, m), 3.94 (1, d,
Jˆ8.9 Hz), 4.01 (1, d, Jˆ8.9 Hz), 4.22 (1, s), 4.61 (1, d,
Jˆ7.1 Hz); 13C NMR d 15.4, 19.5, 22.6, 24.4, 27.4, 27.6,
38.9, 40.0, 65.2, 76.2, 78.1, 103.4, 119.9, 175.4. Anal. Calcd
for C14H21NO4: C, 62.90; H, 7.92; N, 5.24. Found: C, 62.80;
H, 8.03; N, 5.16.
4-(3-Cyano)propyl-2,8-dioxabicyclo[3.3.0]octane
15.
(R)-Pantolactonyl 3-(2-cyano)ethyl-3,4,5,6-tetrahydro-
pyran-2H-2-yl ethers 13a and 13b. By a similar procedure,
diastereomeric acetals 13a and 13b were obtained from 4b
in 53 and 18% yields, respectively. For the less polar isomer
13b: [a]2D7ˆ271.2 (c 0.5, EtOAc); Rf 0.15 (35% EtOAc/
Selenoacetal 14a (200 mg, 0.70 mmol) was dissolved in
dry benzene (10 mL) and acrylonitrile (0.292 mL, 235 mg,
4.43 mmol) and AIBN (30 mg, 0.21 mmol) were added. The
reaction mixture was stirred and heated to 70±758C and n-
Bu3SnH (508 mL, 550 mg, 1.89 mmol) in benzene (1.2 mL)
was added via syringe pump over 4.5 h. Volatiles were then
removed in vacuo and the residue was chromatographed on
silica gel 60 (90 g) eluted with 40% EtOAc/hexanes to
afford 67 mg (0.30 mmol, 45%) of 15 as a colorless oil, Rf
0.05 (30% ether/hexanes); [a]2D5ˆ211.9 (c 3.39, EtOAc);
IR (neat) 3058, 2869, 2245, 1596, 1458, 1423, 1404,
1
hexanes); H NMR d 1.11 (3, s), 1.23 (3, s), 1.20±2.50 (8,
m), 2.60±2.70 (1, m), 3.55±3.57 (1, m), 3.92 (1, d,
Jˆ8.7 Hz), 3.98 (1, d, Jˆ8.7 Hz), 4.18±4.32 (1, m), 4.25
(1, s), 4.79 (1, br s); 13C NMR d 14.7, 19.7, 22.6, 23.7, 24.8,
27.4, 38.8, 40.6, 60.2, 75.5, 78.1, 99.7, 119.5. For the more
polar isomer 13a: [a]D27ˆ268.0 (c 2.9, EtOAc); Rf 0.11

K. S. Nimkar, E. A. Mash / Tetrahedron 56 (2000) 5793±5800
5799
1376 cm21; 1H NMR d 1.35±1.70 (4, m), 1.70±1.85 (2, m),
2.15±2.40 (3, m), 2.65±2.80 (1, m), 3.30±3.41 (1, m), 3.75±
3.90 (3, m), 5.73 (1, d, Jˆ4.9 Hz); 13C NMR d 17.2, 24.2,
24.6, 26.5, 41.4, 45.0, 68.9, 71.9, 109.5, 119.1. Anal. Calcd
for C10H15NO2: C, 66.27; H, 8.34; N, 7.73. Found: C, 66.46;
H, 8.44; N, 7.69.
to known tetrabenzoate ii; see Ref. 5. The structure of more polar
diastereomer iii was established by X-ray crystallography
(J. Fryling, unpublished results).
4-(3-Cyano-1-methyl)propyl-2,8-dioxabicyclo[3.3.0]octanes
17a and 17b. By a similar procedure, an inseparable 2:1
mixture of nitriles 17a and 17b was obtained from 16a and
acrylonitrile in 78% yield. Rf 0.07 (30% ether/hexanes); IR
1
(neat) 2955, 2243, 1730, 1637, 1451, 1425, 1391 cm21; H
NMR d 0.96±1.10 (3, m), 1.25±2.15 (6, m), 2.30±2.50 (2,
m), 2.80±2.90 (1, m), 3.50±3.61 (1, m), 3.82±4.13 (3, m),
5.69±5.74 (1, m); 13C NMR d 13.4, 14.4, 14.5, 17.2, 17.3,
24.4, 24.5, 30.7, 31.2, 31.5, 44.4, 44.8, 48.3, 48.6, 68.6,
68.7, 70.7, 71.2, 109.3, 109.6, 119.2, 119.3. Anal. Calcd
for C11H17NO2: C, 67.66; H, 8.78; N, 7.17. Found: C,
67.48; H, 8.71; N, 7.38.
8. Use of (S)-methyl mandelate as the chiral auxiliary gave
products derived from intramolecular abstraction of the benzylic
hydrogen.
9. Diastereomer ratios for product THP acetals having (S)-methyl
lactate or (S)-methyl hexahydromandelate as the chiral auxiliary
were approximately 1:1; see Ref. 1.
Acknowledgements
Partial support of this research by Research Corporation, by
the Elsa U. Pardee Foundation, by the E. I. DuPont de
Nemours Company, and by the University of Arizona
through the Materials Characterization Program and the
Of®ce of the Vice President for Research are gratefully
acknowledged.
10. Giese, B.; Heuck, K.; Lenhardt, H.; LuÈning, U. Chem. Ber.
1984, 117, 2132±2139.
Â
11. (a) Zezula, V.; Kratochvõl, M. Collect. Czech. Chem.
Commun. 1970, 35, 1745±1751. (b) Glaudemans, C. P. J.; Fletcher,
H. G., Jr. J. Am. Chem. Soc. 1965, 87, 4636±4641.
12. The proton at the anomeric carbon of the cis isomer should be
up®eld from this proton of the trans isomer and should exhibit a
larger coupling with the adjacent proton; see: Descotes, G.; Sinou,
D.; Martin, J.-C. Bull. Soc. Chim. Fr. 1970, 3730±3737.
13. Greater diastereoselectivity for the methyl acrylate trap is
consistent with the literature; see Ref. 10.
References
1. This work is taken from the PhD dissertation of K. S. Nimkar,
The University of Arizona, 1994.
14. The predominance of 14a over 14b re¯ects kinetic control of
this exchange reaction at short reaction times. Use of long reaction
times resulted in equilibration to approximately a 1:1 mixture of
14a and 14b.
2. (a) Hanessian S. Total Synthesis of Natural Products: The
`Chiron' Approach; Pergamon Press: Oxford, 1983. (b) Zamojski,
A.; Grynkiewicz, G. In The Total Synthesis of Natural Products;
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(d) Ley, S. V. New Methods Drug Res. 1989, 3, 1±11. (e) Lee, E.
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3. (a) Giese, B. Radicals in Organic Synthesis: Formation of
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D. P.; Porter, N. A.; Giese, B. Stereochemistry of Radical
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Tetrahedron Lett. 1986, 27, 3715±3718. (b) Hackmann, C.;
È
Schafer, H. J. Tetrahedron 1993, 49, 4559±4574. (c) Vaupel, A.;
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Prandi, J.; Bamhaoud, T.; Bakkas, S.; Guillou, O. Tetrahedron
1998, 54, 8753±8770.
17. For compound 15, irradiation of proton Ha increased the
intensities of protons Hb and Hc by 3.3 and 1.2%, respectively.
Irradiation of Hb increased the intensities of protons Ha and Hc
by 3.7 and 2.8%, respectively.
4. (a) Albrecht, U.; Wartchow, R.; Hoffmann, H. M. R. Angew.
Chem. Int. Ed. Engl. 1992, 31, 910±913. (b) Breithor, M.; Herden,
U.; Hoffmann, H. M. R. Tetrahedron 1997, 53, 8401±8420.
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Lett. 1989, 30, 7145±7148. (b) Mash, E. A.; Arterburn, J. B.;
Fryling, J. A.; Mitchell, S. H. J. Org. Chem. 1991, 56, 1088±1093.
6. (a) Mash, E. A.; Fryling, J. A.. J. Org. Chem. 1991, 56, 1094±
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7. We have assumed that all less polar THF and THP diastereo-
mers derived from a particular a-hydroxyester enantiomer have
related con®gurations at the acetal carbon, and all more polar
diastereomers have the opposite con®guration. Thus far this has
proved to be the case. The less polar diastereomer i was converted
18. (a) RajanBabu, T. V.; Fukunaga, T.; Reddy, G. S. J. Am.
Chem. Soc. 1989, 111, 1759±1769 and references cited therein.
(b) De Mesmaeker, A.; Hoffmann, P.; Ernst, B.; Hug, P.; Winkler,
T. Tetrahedron Lett. 1989, 30, 6311±6314 and references cited
therein.

5800
K. S. Nimkar, E. A. Mash / Tetrahedron 56 (2000) 5793±5800
19. Treatment of acetal 6a with TsOH in CH2Cl2 containing
10 equiv. of allyl alcohol gave, in 88% yield, a chromatographi-
cally inseparable 10:1 mixture of the corresponding diastereomeric
allyl pyranosides. Radical generation, cyclization, and trapping
with acrylonitrile afforded a 5:1 mixture of acetals iv and v (see
Ref. 1).