Cyclisation of 1,2-dioxines containing tethered hydroxyl and carboxylic acid functionality: synthesis of tetrahydrofurans and dihydrofuran-2(3H)-ones

Article abstract of DOI:10.1016/j.tet.2009.11.068

Herein we outline cyclisations of tethered hydroxyl and carboxylic acid moieties onto the olefinic motif of 1,2-dioxines to generate tetrahydrofurans and dihydrofuran-2(3H)-ones, whilst maintaining the peroxide linkage intact. This work demonstrates the first examples of intramolecular cyclisation of tethered hydroxyl groupings onto 1,2-dioxines generating functionalised THFs in a highly stereoselective manner and includes improved methods for previously reported carboxylic acid tether cyclisations. Additionally, improved methods for the oxidation of 1,2-dioxines containing tethered alcohols to furnish tethered carboxylic acids are also detailed. Subsequent reduction of the peroxide linkage enables the generation of functionalised tetrahydrofurans and dihydrofuran-2(3H)-ones, which are useful building blocks for the construction of natural products.

Full text of DOI:10.1016/j.tet.2009.11.068

Tetrahedron 66 (2010) 1007–1013
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Cyclisation of 1,2-dioxines containing tethered hydroxyl and carboxylic acid
functionality: synthesis of tetrahydrofurans and dihydrofuran-2(3H)-ones
,
c
Ondrej Zvarec b, Thomas D. Avery b, Dennis K. Taylor a , Edward R.T. Tiekink
*
a Discipline of Wine and Horticulture, The University of Adelaide, South Australia 5005, Australia
b Discipline of Chemistry, The University of Adelaide, South Australia 5005, Australia
c Department of Chemistry, University of Malaya, Kuala Lumpur 50603, Malaysia
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein we outline cyclisations of tethered hydroxyl and carboxylic acid moieties onto the olefinic motif of
1,2-dioxines to generate tetrahydrofurans and dihydrofuran-2(3H)-ones, whilst maintaining the peroxide
linkage intact. This work demonstrates the first examples of intramolecular cyclisation of tethered hy-
droxyl groupings onto 1,2-dioxines generating functionalised THFs in a highly stereoselective manner
and includes improved methods for previously reported carboxylic acid tether cyclisations. Additionally,
improved methods for the oxidation of 1,2-dioxines containing tethered alcohols to furnish tethered
carboxylic acids are also detailed. Subsequent reduction of the peroxide linkage enables the generation of
functionalised tetrahydrofurans and dihydrofuran-2(3H)-ones, which are useful building blocks for the
construction of natural products.
Received 20 August 2009
Received in revised form
22 October 2009
Accepted 12 November 2009
Available online 18 November 2009
Keywords:
1,2-Dioxine
Tetrahydrofurans
Dihydrofuran-2(3H)-ones
Cyclisation
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
4 steps
Ph(H2C)10
Ph(H2C)10
O
O
The peroxide linkage of six-membered cyclic peroxides is mis-
takenly viewed as a very sensitive moiety with the general con-
sensus being that installation should be conducted late in any
synthetic sequence. This sensitivity is primarily due to the fact that
metal-based reagents may induce fragmentation of the peroxide
bond,1 whilst ring opening occurs when the reaction medium is
basic.2 There are only a few reports where the peroxide linkage is
installed early in the sequence prior to further chemical manipu-
lation. For example, the recent synthesis of marine natural product
6-epiplakortolide E 13 maintains the peroxide linkage intact
throughout four subsequent synthetic steps, including oxidation
with Jones Reagent, Figure 1. This example and our own experience
in cyclic peroxide chemistry lead us to conclude that it is worthy to
extend further the chemical manipulations of organics containing
the peroxide moiety, whilst maintaining the peroxide linkage in-
tact, particularly as there are an ever growing number of bi-
ologically active peroxide containing natural products.4
O
O
OTBDMS
O
O
H
H
2
6-epiplakortolide E 1
Figure 1. Synthetic approach used to synthesise 6-epiplakortolide E.
It was envisaged that intramolecular cyclisation of 3 in the pres-
enceofelectrophilicreagents (NBS, NIS, PhSeCl)wouldleadtobicyclic
fused peroxide furans or dihydrofuranones 4 (Scheme 1). The relative
stereochemistry of the bicyclic system should be predictable due to
the stereochemistry built into the precursor 1,2-dioxines upon their
synthesis. Clearance of X within 4 would furnish bicyclic fused per-
oxide furans fused dihydrofuran-2(3H)-ones of type 5. Such bicyclic
furans and furanones are key intermediates in the synthesis of
Hagen’s gland lactones and form the cores of the natural products
(þ)-bassianolone and cephalosporolides E and F vide infra.5
Finally, reduction of the peroxide linkage within 5 should afford
furans and lactones of type 6 in which the stereochemistry is well
defined. Such furans and lactones are at the cores of numerous
natural products.5,6
The Taylor group2 and Jung et al.3 have previously demonstrated
that cyclisations onto rings containing the peroxide bond are
plausible for the synthesis of tetrahydropyrans although both
studies were limited in scope.
2. Results and discussion
The requisite 1,2-dioxines for this study were synthesised in
a similar fashion to that outlined previously and proceeded in
* Corresponding author. Tel.: þ61 8 8303 5494.
E-mail address: dennis.taylor@adelaide.edu.au (D.K. Taylor).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.11.068

1008
O. Zvarec et al. / Tetrahedron 66 (2010) 1007–1013
R1
OH OH
O O
O O
O O
H2
n-Bu3SnH
NXS or
PhSeCl
R
R
R
R
OH
Pd/C (5%)
H
AIBN
R1
R1
O
R1
O
O
X
R = alkyl, aryl
X = SePh, I, Br
4
5
6
R
1 = O, H2
3
Scheme 1.
moderate to good overall yields (Scheme 2).2 To evaluate the ef-
fectiveness of tethered hydroxyl cyclisations we chose to in-
vestigate both aryl 10b and alkyl 10c substituted 1,2-dioxines;
noting that aryl substituted 1,2-dioxines can behave very differ-
ently under basic conditions to those of alkyl substitution due to
the increased acidity of the proton adjacent the peroxide bond.2b
The stereochemical variation of X was assigned utilising both 1D 1H
NMR and 2D 1H NMR techniques with typically small couplings of
Jz3.6 Hz between Ha and Hb and between Hb and Hc observed.
Additionally ROESY 2D 1H NMR of the obtained cis fused furans 11
showed interactions between the proton
a to the X group and the
methyl or phenyl functional groupings. The stereochemical orien-
X
n-BuLi
OR1
O
R
R
Ph3P
OR1
9a: R = Me, R1 = TBDMS, 31%
9b: R = Ph, R1 = H, 37%
7a: R = Me
7b: R = Ph
8a: R1 = H, X = Cl
8b: R1 = TBDMS, X = I
Rose Bengal bis
(triethylammonium salt),
O2, hv
O O
R
OR1
10a: R = Me, R1 = TBDMS, 39%
10b: R = Ph, R1 = H, 52%
10c: R = Me, R1 = H, 76%
MeOH,
conc.HCl
(cat.)
Scheme 2.
NBS or
NIS or
PhSeCl
With the precursor 1,2-dioxines in hand we first examined the
possibility of bicyclic furan formation employing NBS, NIS and
PhSeCl to initiate cyclisation. This one-pot cyclisation proceeded
well to afford bicyclic peroxide furans 11 in moderate to excellent
yields (Table 1). The assisting halogen or phenylselenyl group was
then removed to furnish peroxide furans 12a,b through reduction
with AIBN and tri-n-butyltin hydride (Scheme 3, Table 1). Treat-
ment of 1,2-dioxines 10b,c with NBS, NIS and phenylselenyl chlo-
ride gave cyclic peroxide furans 11 with varying stereochemistry
about the X group. Based on the 1D 1H NMR and 2D 1H NMR
analyses, the varying stereochemistry of the two isomers was seen
about the group assisting cyclisation and formation of the new
furan ring was always found to form in a cis fashion as expected.
O O Hd
O O
O O
Ha
R
H
n-Bu3SnH
R
R
OH
AIBN
b X
O
O
Hc
10b: R = Ph
10c: R = Me
12a: R = Me
12b: R = Ph
11a: R = Me, X = Br
11b: R = Me, X = I
11c: R = Me, X = SePh
11d: R = Ph, X = Br
11e: R = Ph, X = I
11f: R = Ph, X = SePh
Scheme 3.
tation of the X group resulting in minor amounts of the cis isomers
is believed to be a result of an SN1 process. This variation about X
was, however, irrelevant as reduction of 11 resulted in formation of
a single product 12a or 12b.
Table 1
Cyclisation and concomitant assisting group reduction of 1,2-dioxines 10b and 10c
With approaches to bicyclic peroxide furans of type 12 now
addressed we next turned our attention to developing methodol-
ogy for the synthesis of bicyclic peroxide lactones of type 14. Oxi-
dation of alcohols 10b and 10c to the requisite carboxylic acids was
accomplished with BAIB/TEMPO and proceeded in excellent yields
(Scheme 4).
Entrya
1,2-Dioxine
Reagent
11a–f (% Yield)
ratio cis:trans
12a,b (% Yield)
1
2
3
4
5
6
10b
10b
10b
10c
10c
10c
NBS
11d (51)
0:1
11e (71)
Trace:1
11f (38)
1:5
11a (64)
Trace:1
11b (62)
1:4
11c (85)
Trace:1
d
NIS
12b (67)
12b (55)
12a (66)
12a (89)
12a (46)
PhSeCl
NBS
O
BAIB,
O O
O O
TEMPO
R
R
OH
OH
NIS
MeCN/H2O
10b: R= Ph
10c: R= Me
13a: R= Me, 84% yield
13b: R= Ph, 81% yield
PhSeCl
a
Reagent (2 equiv), CH2Cl2. Ambient temp.
Scheme 4.

O. Zvarec et al. / Tetrahedron 66 (2010) 1007–1013
1009
Employing the same cyclisation process as for the construction
of bicyclic furans proved successful for all examples and provided
the bicyclic peroxide lactones 14a–f in moderate to good yields
(Scheme 5, Table 2). Further reduction with tri-n-butyltin hydride
furnished the desired furanones 15a,b.
Hd indicating a syn relationship. Interestingly 1D 1H NMR of the
bicyclic lactones 14 showed small couplings of Jz2.4–3.6 Hz be-
tween Ha and Hb as well as between Hb and Hc suggesting a cis
relationship. However, ROESY 2D 1H NMR showed interactions
between the proton
a to the X group and the methyl or phenyl
functional groupings indicating a trans relationship.
NBS or
X-ray crystallography of 14b supported the stereochemical as-
signments made by both 1D and 2D 1H NMR showing the X group
trans to both the methyl group and lactone ring (Fig. 2).
O
NIS or
O
O
Hd
Ha
R
H
O
O
O O
n-Bu3SnH
PhSeCl
R
R
OH
AIBN
b X
O
O
O
O
Hc
13a: R = Me
13b: R = Ph
15a: R = Me
15b: R = Ph
14a: R = Me, X = Br
14b: R = Me, X = I
14c: R = Me, X = SePh
14d: R = Ph, X = Br
14e: R = Ph, X = I
14f: R = Ph, X = SePh
Scheme 5.
Table 2
Cyclisation and concomitant assisting group reduction of 1,2-dioxines 13a and 13b
Figure 2. Molecular structure and crystallographic numbering scheme for 14b.
Entrya
1,2-Dioxine
Reagent
14a–f (% Yield)
ratio cis:trans
15a,b (% Yield)
Finally, the peroxide bonds of 12a and 15a were reduced to give
diols 16a and 17a in 69% and 45% yields, respectively (Schemes 6).
1
2
3
4
5
6
13a
13a
13a
13b
13b
13b
NBS
14a (69)
1:1
14b (76)
0:1
14c (57)
0:1
14d (56)
0:1
14e (56)
0:1
14f (55)
0:1
15a (60)
15a (81)
15a (68)
15b (73)
15b (62)
15b (45)
NIS
O
O
OH OH
Pd/C (5%)
PhSeCl
NBS
H2
69%
H
H
O
O
O
16a
12a
NIS
OH OH
O
O
Pd/C (5%)
H2
PhSeCl
O
O
O
a
62%
Reagent (2 equiv), CH2Cl2. Ambient temp.
17a
15a
In all cases cyclisation proceeded to furnish cis fused lactones
with a trans relationship to X as expected except for 13a (Table 2,
entry 1) where a 1:1 mixture of isomers about the X stereocentre
was observed. This was irrelevant as reduction of the mixture 14a
resulted in a single product 15a. 1D 1H NMR and 2D 1H NMR
analyses confirmed the orientation of the newly formed lactone
ring with typically small couplings of Jz3.0–4.2 Hz between Hc and
Scheme 6.
The methodology employed to yield diols 16a and 17a demonstrates
a useful means towards exotic furans and lactones that could be used
for the short simple construction of analogues of Hagen’s lactones
206 or as building blocks towards natural products (þ)-bassianolone
22,5 and cephalosporolides E 23 and F 24 (Schemes 7).5
HO
(ref 5)
O O
R
O
OH
R1
R
R
H
O
O
O
O
20a: R = n-C4H9, R1 = H
20b: R = n-C6H13, R1 = H
20c: R = H, R1 = n-C4H9
20d: R = H, R1 = n-C6H13
18
19
H
O
H
O
O
O
H
HO
O
O O
(ref 6)
cephalosporolide E 23
HO
HO
+
O
O
O
O
H
O
O
H
21
(+)-bassianolone 22
O
O
H
cephalosporolide F 24
Scheme 7.

1010
O. Zvarec et al. / Tetrahedron 66 (2010) 1007–1013
3. Conclusion
chromatography using 1:19 ethyl acetate/hexanes as eluent to yield
pure 1,2-dioxine 10a,b.
In conclusion, we have shown the versatility of cyclic peroxides
with tethered functionality to afford novel tetrahydrofurans and
dihydrofuran-2(3H)-ones whilst maintaining the peroxide linkage
intact. Subsequent removal of the assisting halogen or phenyl-
selenyl group afforded bicyclic peroxide furans or peroxide fur-
anones, which are at the cores of numerous natural products.
Reduction of the peroxide linkage to diols of type 16 and 17 has
allowed for the generation of a simple methodology towards the
synthesis of Hagen’s lactones6 and natural products (þ)-bassiano-
lone,5 and cephalosporolides E and F.5
4.3.1. (ꢂ) tert-Butyl-dimethyl-[2-((3S,6R)-6-methyl-3,6-dihydro-[1,2]-
dioxin-3-yl)ethoxy]-silane (10a). Yield: 4.04 g, 39% colourless oil; Rf
0.37 (1:19 ethyl acetate/hexane); vmax (film)/cmꢃ1 2957, 1471, 1255,
1096, 777; dH (300 MHz; CDCl3) 0.07 (6H, s), 0.89 (9H, s), 1.23 (3H, d,
J¼6.6 Hz), 1.69–1.79 (1H, m), 1.85–1.95 (1H, m), 3.71–3.81 (2H, m),
4.53–4.58 (1H, m), 4.64–4.71 (1H, m), 5.83–5.91 (2H, m); dC (75 MHz;
CDCl3) 128.9, 127.7, 75.1, 74.3, 59.1, 36.1, 25.91, 18.3, 18.0, ꢃ5.4; HRMS
(ESI) C13H26O3SiþNa requires 258.1651, found 258.1656.
4.3.2. (ꢂ) 2-((3S,6S)-6-Phenyl-3,6-dihydro-[1,2]dioxin-3-yl)-ethanol
(10b). Yield: 1.27 g, 52% as a colourless oil; Rf 0.40 (2:3 ethyl ace-
tate/hexane); vmax (film)/cmꢃ1 3120–3610, 1676, 1602; dH
(300 MHz; CDCl3) 1.89–2.31 (2H, m), 2.34 (1H, br s), 3.75–3.89 (2H,
m), 4.76–4.79 (1H, m), 5.59 (1H, d, J¼1.5), 6.08–6.16 (2H, m), 7.29–
7.48 (5H, m); dC (75 MHz; CDCl3) 136.9, 129.0, 128.6 (ꢀ2), 128.2,
126.9, 80.4, 76.6, 59.5, 35.7; m/z (EI) (Mþ 206, 6%),174(100),143(73),
105(41), 77(56); HRMS (ESI) C12H14O3þNa requires 229.0841, found
229.0837.
4. Experimental
4.1. General methods
Solvents were dried and purified where needed and according
to literature methods. Thin Layer Chromatography (TLC) using Sil-
ica gel F254 (30 mmꢀ60 mm) from Merck and visualised under
254 nm light or developed in vanillin or permanganate dip. Flash
chromatography was conducted using Merck Silica gel 60 of par-
ticle size 0.040–0.063 mm. 1H NMR and 13C NMR spectra were
conducted in deuterated chloroform on the 300 MHz Brucker ACP-
30 or on the 600 MHz Varian INOVA. TMS (0.00 ppm) and CDCl3
(77.00 ppm) were used as internal standards for 1H NMR and 13C
NMR analysis. Melting points were taken on a Reichert Thermovar
Kofler apparatus and are uncorrected. Infrared spectra were
recorded on an ATI Mattson Genesis Series FTIR spectrophotometer
as either Nujol mulls or neat as denoted. All yields reported are
isolated yields judged to be homogeneous by TLC and NMR
spectroscopy.
4.4. General procedure for deprotection of 1,2-dioxines:
synthesis of 1,2-dioxines 10c
To a solution of 1,2-dioxine (1 equiv) in methanol (10 mL/1 g of
1,2-dioxine) was added concentrated HCl (four drops/1 g of 1,2-
dioxine) and stirred until complete via TLC. The volatiles were re-
moved in vacuo and the crude residue was purified by column
chromatography to give the desired 1,2-dioxines 10c.
4.4.1. (ꢂ) 2-((3S,6R)-6-Methyl-3,6-dihydro-[1,2]dioxin-3-yl)-ethanol
(10c). Yield: 1.71 g, 76% as a colourless oil; Rf 0.51 (2:3 ethyl ac-
etate/hexane); vmax (film)/cmꢃ1 3100–3580, 3043, 2932, 2876,
1657; dH (300 MHz; CDCl3) 1.25 (3H, d, J¼6.6 Hz), 1.82–2.09 (3H,
m), 3.79–3.86 (2H, m), 4.61–4.65 (1H, m), 4.68–4.75 (1H, m),
5.86–5.89 (2H, m); dC (75 MHz; CDCl3) 129.3, 127.0, 76.5, 74.4,
59.5, 35.7, 17.9; m/z (EI) (MþHþ 145, 9%), 112(100), 95(13), 81(58),
71(7), 55(4); HRMS (ESI) C7H12O3þNa requires 167.0684, found
167.0680.
4.2. General procedure for Witting reaction: synthesis of 9a,b
To a stirred solution of the appropriate phosphonium salt
(1.1 equiv) in dry THF (4 mL/1 g of salt) under a stream of nitrogen
at 0 ꢁC was added dropwise n-BuLi (1.1 equiv). After 30 min a so-
lution of the respective aldehyde (1 equiv) in THF (5 mL/1 g of al-
dehydes) was added dropwise to the solution and stirred for 16 h.
Volatiles were removed in vacuo and the crude residue was filtered
through a pad of silica. Volatiles were removed in vacuo and the
crude residue purified via column chromatography to give the 1,3-
butadienes 9a,b as a mixture of E/E and E/Z isomers. 1,3-Butadiene
9b,7,8 has previously been reported.
4.5. General procedure for formation of 1,2-dioxines 13a,b
To a solution of 1,2-dioxine (1 equiv) in acetonitrile/water (1:1,
20 mL/1 g of 1,2-dioxine) was added BAIB (2.2 equiv) and TEMPO
(0.2 equiv) in a single portion, protected from light and stirred until
complete via TLC. The mixture was extracted using ethyl acetate
(4ꢀ30 mL) followed by 5% NaHCO3 (4ꢀ30 mL). The aqueous solu-
tion was acidified using concentrated HCl and extracted using ethyl
acetate (4ꢀ30 mL). The organic layer was then dried (MgSO4), fil-
tered and the volatiles were removed in vacuo. The crude residue
was purified by column chromatography to give the desired 1,2-
dioxines 13a,b.
4.2.1. (ꢂ)
tert-Butyl-[((E)-hepta-3,5-dienyl)oxy]-dimethyl-silane
(9a). Yield: 9.5 g, 31% as a yellow oil; Rf 0.40 (1:99 ethyl acetate/
hexane); vmax (film)/cmꢃ1 2897, 1610, 1463, 1256, 1104; dH
(300 MHz; CDCl3) 0.06 (12H, s), 0.89 (18H, s), 1.73 (3H, d,
J¼6.68 Hz), 1.77 (3H, d, J¼6.72 Hz), 2.33–2.43 (4H, m), 3.56–3.70
(4H, t, J¼6.9 Hz), 5.30 (1H, q, J¼7.8 Hz), 5.48–5.77 (3H, m), 5.94–6.1
(3H, m), 6.24–6.42 (1H, m); dC (75 MHz; CDCl3) 132.2, 131.6, 130.3,
129.5, 127.9, 127.3, 127.1, 125.3, 63.1, 62.9, 36.3, 31.5, 25.9, 18.4, 18.2,
17.9, ꢃ5.3. *Could not obtain m/z nor HRMS due to rapid de-
composition of compound 9a.
4.5.1. (ꢂ) ((3S,6R)-6-Methyl-3,6-dihydro-[1,2]dioxin-3-yl)-acetic acid
(13a). Yield: 689 mg as a colourless oil, 84%; Rf 0.19 (2:3 ethyl ac-
etate/hexane); vmax (film)/cmꢃ1 3441, 2360, 1715, 1274, 1043; dH
(300 MHz; CDCl3) 1.21(3H, d, J¼6.9 Hz), 2.69 (1H, dd, J¼5.1, 17.7 Hz),
2.94 (1H, dd, J¼7.8, 16.2 Hz), 4.60–5.00 (2H, m), 5.89–6.00 (2H, m);
dC (75 MHz; CDCl3) 176.6, 130.4, 125.6, 74.3, 74.2, 38.3, 17.5; m/z (EI)
(Mþ 158, 1%),143(56), 117(59), 87(100), 71(100), 45(50); HRMS (ESI)
C7H10O4þNa requires 181.0477, found 181.0480.
4.3. General procedure for the synthesis of 1,2-dioxines 10a,b
A solution of appropriate 1,3-butadiene (1 equiv) in anhydrous
dichloromethane (25 mL/1 g of 1,3-butadiene) was irradiated with
light from 3ꢀ500 W tungsten–halogen lamps at 0 ꢁC in the pres-
ence of rose bengal bis(triethylammonium) salt (0.01 equiv) with
oxygen bubbled through the solution for 6 h. The solution was
concentrated and the resulting residue purified by flash column
4.5.2. (ꢂ) ((3S,6S)-6-Phenyl-3,6-dihydro-[1,2]dioxin-3-yl)-acetic acid
(13b). Yield: 291 mg, 81% as a colourless oil; Rf 0.21 (2:3 ethyl ac-
etate/hexane); vmax (film)/cmꢃ1 3064, 1731, 1694, 1453, 1285; dH

O. Zvarec et al. / Tetrahedron 66 (2010) 1007–1013
1011
(300 MHz; CDCl3) 2.79 (1H, dd, J¼5.7, 16.4 Hz), 3.03 (1H, dd, J¼7.5,
16.4 Hz), 4.93–5.00 (1H, m), 5.65–5.67 (1H, m), 6.10–6.22 (2H, m),
7.33–7.38 (5H, m); dC (75 MHz; CDCl3) 176.1, 136.0, 129.2, 128.7,
128.7, 128.3, 126.7, 80.6, 74.5, 38.3; m/z (EI) (Mþ 220, 1%), 176(12),
161(27),133(15),105(100), 77(46); HRMS (ESI) C12H12O4ꢃH requires
219.0657, found 219.0658.
J¼8.4 Hz), 4.25 (1H, pentet, J¼6.3, 6.6 Hz), 4.59 (1H, dd, J¼3.6,
5.7 Hz), 4.86 (1H, dd, J¼1.8, 5.4 Hz); dC (75 MHz; CDCl3) 82.3, 78.2,
76.6, 65.9, 31.9, 23.6, 16.6; m/z (EI) (Mþ 270, 9%), 254(40), 170(47),
143(100), 127(18), 57(33); HRMS (ESI) C7H11O4IþNa requires
292.9651, found 292.9656.
4.6.3. (ꢂ) (3R,4S,4aR,7aS)-3-Methyl-4-phenylselanyl-hexahydro-furo-
[3,2-c][1,2]dioxine (11c). Yield: 199 mg, 85% as a yellow oil; Rf 0.53
(dichloromethane); vmax (film)/cmꢃ1 2976, 2934, 2884, 1579, 1060;
dH (600 MHz; CDCl3) 1.52 (3H, d, J¼6.6 Hz), 1.97–2.04 (1H, m), 2.11–
2.17 (1H, m), 3.47 (1H, t, J¼3.0 Hz), 3.82 (1H, ddd, J¼4.8, 8.4, 8.4 Hz),
4.00 (1H, t, J¼3.6 Hz), 4.04 (1H, q, J¼7.8 Hz), 4.37 (1H, dq, J¼3,
6.6 Hz), 4.92 (1H, dt, J¼3.0, 6.0 Hz), 7.25–7.31 (3H, m), 7.55–7.58 (2H,
m); dC (75 MHz; CDCl3) 134.1, 129.4, 129.4, 127.9, 79.5, 78.6, 77.6,
66.4, 43.1, 30.6, 19.5; m/z (EI) (Mþ 300, 55%), 214(30), 157(68),
83(100), 55(30); HRMS (ESI) C13H16O3SeþH requires 301.0343,
found 301.0340. *Trace amounts of the minor isomer were observed
by 1D 1H NMR however the isomer could not be isolated since
formed on a small scale.
4.6. General procedure for cyclisation: synthesis of 11a–f and
14a–f
Method 1: to
a solution of 1,2-dioxine (1 equiv) in dry
dichloromethane (10 mL/1 g 1,2-dioxine) was added N-iodosucci-
nimide (2 equiv) in one portion and stirred until product formation
was complete by TLC. The solution was washed with saturated
NaHCO3 (2ꢀ30 mL) followed by saturated Na2S2O3 (2ꢀ30 mL) and
water (2ꢀ30 mL). The organic layer was then dried (MgSO4), fil-
tered and the volatiles were removed in vacuo. The crude residue
was purified by column chromatography to give the desired 1,2-
dioxines 11b,e and 14b,e.
Method 2: to
a solution of 1,2-dioxine (1 equiv) in dry
dichloromethane (10 mL/1 g 1,2-dioxine) was added N-bromo-
succinimide (2 equiv) in one portion and stirred until product
formation was complete by TLC. The solution was washed with
saturated NaHCO3 (2ꢀ30 mL) followed by water (2ꢀ30 mL). The
organic layer was then dried (MgSO4), filtered and the volatiles
were removed in vacuo. The crude residue was purified by col-
umn chromatography to give the desired 1,2-dioxines 11a,d and
14a,d.
4.6.4. (ꢂ) (3R,4S,4aR,7aS)-4-Bromo-3-phenyl-hexahydro-furo[3,2-
c][1,2]dioxine (11d). Yield: 79 mg, 51% as a yellow oil; Rf 0.77
(dichloromethane); vmax (film)/cmꢃ1 2954, 2883, 1723, 1688, 1068;
dH (600 MHz; CDCl3) 2.20–2.24 (2H, m), 3.92 (1H, ddd, J¼6.6, 7.8,
7.8 Hz), 3.95 (1H, ddd, J¼7.8 Hz), 4.44 (1H, t, J¼5.4 Hz), 4.52 (1H, t,
J¼5.4 Hz), 5.05 (1H, q, J¼5.4 Hz), 5.36 (1H, d, J¼5.4 Hz), 7.33–7.50
(5H, m); dC (75 MHz; CDCl3) 29.8, 48.1, 66.6, 78.9, 81.3, 85.6, 127.5,
128.7, 128.8, 136.6; m/z (EI) (Mþ 285, 1%), 205(33), 105(100), 77(33),
51(8); HRMS (ESI) C12H13O3þNa requires 306.9946, found
306.9941.
Method 3: to
a solution of 1,2-dioxine (1 equiv) in dry
dichloromethane (10 mL/1 g 1,2-dioxine) was added phenylselenyl
chloride (2 equiv) in one portion and stirred until product forma-
tion was complete by TLC. The volatiles were removed in vacuo and
the crude residue was purified by column chromatography to give
the desired 1,2-dioxines 11c,f and 14c,f.
4.6.5. (ꢂ) (3R,4S,4aR,7aS)-4-Iodo-3-phenyl-hexahydro-furo[3,2-c]-
[1,2]dioxine (11e). Yield: 231 mg, 71% as a colourless oil; Rf 0.76
(dichloromethane); vmax (film)/cmꢃ1 2953, 2888, 1713, 1578,
1063; dH (600 MHz; CDCl3) 2.15–2.36 (2H, m), 3.90–3.94 (1H,
ddd, J¼6.0, 8.4, 8.4 Hz), 3.99–4.04 (1H, ddd, J¼6.6, 8.1, 8.1 Hz),
4.54–4.56 (1H, t, J¼6.0 Hz), 4.58–4.61 (1H, t, J¼6.0 Hz), 4.99–5.02
(1H, m), 5.40 (1H, d, J¼6.0 Hz), 7.33–7.45 (5H, m); dC (75 MHz;
CDCl3) 136.9, 128.9, 128.5, 127.6, 86.8, 81.7, 80.2, 66.4, 29.2, 27.4;
m/z (EI) (Mþ 332, 1%), 147 (31), 119 (23), 91(100), 77(15); HRMS
(ESI) C12H13O3þNa requires 354.9807, found 354.9802. *Trace
amounts of the minor isomer were observed by 1D 1H NMR
however the isomer could not be isolated since formed on
a small scale.
4.6.1. (ꢂ) (3R,4S,4aR,7aS)-4-Bromo-3-methyl-hexahydro-furo[3,2-
c][1,2]dioxine (11a). Yield: 109 mg, 64% as a yellow oil; Rf 0.51 (2:3
ethyl acetate/hexane); vmax (film)/cmꢃ1 2980, 2360, 1438, 1142,
1067; dH (600 MHz; CDCl3) 1.51 (3H, d, J¼6.6 Hz), 2.02–2.11 (1H,
m), 2.13–2.23 (1H, m), 3.91 (1H, ddd, J¼4.8, 9.0, 9.0 Hz), 4.05 (1H,
q, J¼9.0 Hz), 4.11 (1H, t, J¼3.0 Hz), 4.14 (1H, t, J¼3.0 Hz), 4.44 (1H,
dq, J¼3.0, 6.6 Hz), 4.97 (1H, d quin, J¼3.0, 12.0 Hz); dC (75 MHz;
CDCl3) 79.8, 79.2, 78.5, 66.7, 47.8, 29.9, 18.2; m/z (EI) (Mþ 223, 1%),
179(20), 143(70), 120(60), 101(68), 83(100), 69(30), 55(27); HRMS
(ESI) C7H11O4BrþK requires 260.9529, found 260.9568. *Trace
amounts of the minor isomer were observed by 1D 1H NMR
however the isomer could not be isolated since formed on a small
scale.
4.6.6. (ꢂ) (3R,4S,4aR,7aS)-3-Phenyl-4-phenylselanyl-hexahydro-furo-
[3,2-c][1,2]dioxine/(ꢂ)
(3R,4R,4aR,7aS)-3-phenyl-4-phenylselanyl-
hexahydro-furo[3,2-c][1,2]dioxine (11f). Yield: 173 mg, 38%; ratio
5:1. (ꢂ) (3R,4S,4aR,7aS)-3-Phenyl-4-phenylselanyl-hexahydro-furo-
[3,2-c][1,2]dioxine (11f): yield: 140 mg as a yellow oil; Rf 0.41 (1:5
ethyl acetate/hexane); vmax (film)/cmꢃ1 3059, 2953, 2887, 1712,
1063, 739; dH (600 MHz; CDCl3) 2.04–2.23 (2H, m), 3.82 (1H, ddd,
J¼4.8, 8.1, 8.1 Hz), 3.89 (1H, dd, J¼4.8 Hz), 3.94 (1H, ddd, J¼7.8 Hz),
4.28 (1H, t, J¼4.8 Hz), 5.00 (1H, ddd, J¼3.3, 4.8, 6.6 Hz), 5.25 (1H, d,
J¼4.8 Hz), 7.25–7.35 (6H, m), 7.40–7.50 (4H, m); dC (75 MHz; CDCl3)
138.3, 134.9, 129.3, 128.3, 128.3, 128.3, 128.2, 127.8, 84.6, 81.1, 77.4,
66.5, 43.3, 30.9; m/z (EI) (Mþ 362, 11%), 256(18), 157(22), 99(100),
77(47); HRMS (ESI) C18H18O3SeþNa requires 385.0319, found
385.0355. (ꢂ) (3R,4R,4aR,7aS)-3-Phenyl-4-phenylselanyl-hexahydro-
furo[3,2-c][1,2]dioxine (11f): yield: 33 mg as white needles; Mp
150–152 ꢁC; Rf 0.35 (1:5 ethyl acetate/hexane); vmax (Nujol)/cmꢃ1
1718, 1131, 1056, 742; dH (600 MHz; CDCl3) 1.95–2.04 (1H, ddd, J¼3.9,
7.95, 14.33 Hz), 2.18–2.30 (1H, m), 3.61 (1H, dd, J¼3.6, 11.1 Hz), 3.90
(1H, ddd, J¼4.2, 8.4, 9.6 Hz), 4.2 (1H, q, J¼8.4 Hz), 4.30 (1H, dd, J¼1.8,
3.6 Hz), 4.90 (1H, dd, J¼1.8, 4.8 Hz), 5.35 (1H, d, J¼11.1 Hz), 6.91–7.04
(4H, m), 7.07–7.34 (6H, m); dC (75 MHz; CDCl3) 135.2, 135.0, 129.3,
4.6.2. (ꢂ) (3R,4S,4aR,7aS)-4-Iodo-3-methyl-hexahydro-furo[3,2-c]-
[1,2]dioxine/(ꢂ)
(3R,4R,4aR,7aS)-4-iodo-3-methyl-hexahydro-furo-
[3,2-c][1,2]dioxine (11b). Yield: 233 mg, 62%; ratio 4:1. (ꢂ)
(3R,4S,4aR,7aS)-4-Iodo-3-methyl-hexahydro-furo[3,2-c][1,2]dioxine
(11b): yield: 186 mg as a colourless oil; vmax (film)/cmꢃ1 2935,
2886, 1439, 1372; Rf 0.42 (dichloromethane); dH (300 MHz;
CDCl3) 1.51 (3H, d, J¼6.6 Hz), 2.03–2.22 (2H, m), 3.91 (1H, ddd,
J¼5.1, 8.4, 8.4 Hz), 4.07 (1H, q, J¼8.4 Hz), 4.23 (1H, t, J¼3.6 Hz),
4.29 (1H, t, J¼3.6 Hz), 4.48 (1H, dq, J¼6.6, 3.6 Hz), 4.99 (1H, dt,
J¼3.0, 6.0 Hz); dC (75 MHz; CDCl3) 80.9, 79.9, 79.4, 66.7, 29.5, 27.4,
19.2; m/z (EI) (Mþ 270, 9%), 254(40), 170(47), 143(100), 127(18),
57(33); HRMS (ESI) C7H11O4IþNa requires 292.9651, found
292.9656. (ꢂ) (3R,4R,4aR,7aS)-4-Iodo-3-methyl-hexahydro-furo[3,2-c]-
[1,2]dioxine (11b): yield: 47 mg as colourless crystals; Rf 0.40
(dichloromethane); Mp 99–101 ꢁC; vmax (Nujol)/cmꢃ1 2935, 2886,
1439, 1372; dH (600 MHz; CDCl3) 1.77 (3H, d, J¼6.6 Hz), 2.02–2.05
(1H, m), 2.19–2.21 (1H, m), 3.89–3.93 (2H, m), 4.12 (1H, q,

1012
O. Zvarec et al. / Tetrahedron 66 (2010) 1007–1013
129.0, 128.5, 128.4, 128.2, 127.5, 84.4, 82.4, 78.5, 66.8, 47.3, 31.2; m/z
(EI) (Mþ 362, 1%), 157(33), 105(100), 77(75), 51(22); HRMS (ESI)
C18H18O3SeþNa requires 385.0319, found 385.0317.
4.6.11. (ꢂ) (3R,4S,4aR,7aS)-4-Bromo-3-phenyl-tetrahydro-furo[3,2-
c][1,2]dioxin-6-one (14d). Yield 76 mg, 56% as colourless needles; Rf
0.47 (dichloromethane); Mp 124–126 ꢁC; vmax (Nujol)/cmꢃ1 1792,
1164,1124, 1079,1033; dH (300 MHz; CDCl3) 2.85–3.00 (2H, m), 4.62
(1H, t, J¼4.5 Hz), 5.07 (1H, dd, J¼4.5, 6.0 Hz), 5.21 (1H, ddd, J¼3.9,
6.3, 6.3 Hz), 5.63 (1H, d, J¼4.5 Hz), 7.35–7.42 (5H, m); dC (75 MHz;
CDCl3) 172.9, 135.1, 129.6, 128.9, 127.7, 87.6, 78.7, 76.3, 44.6, 33.7; m/z
(EI) (Mþ 297, 1%), 280(75), 235(100), 128(75), 77(25); HRMS (ESI)
C12H11O4BrþNa requires 320.9738, found 320.9736.
4.6.7. (ꢂ) (3R,4R,4aR,7aS)-4-Bromo-3-methyl-tetrahydro-furo[3,2-
c][1,2]dioxin-6-one/(ꢂ) (3R,4S,4aR,7aS)-4-bromo-3-methyl-tetrahy-
dro-furo[3,2-c][1,2]dioxin-6-one (14a). Yield: 201 mg, 69% as
a colourless oil; ratio 1:1; Rf 0.57 (2:3 ethyl acetate/hexane). (ꢂ)
3R,4R,4aR,7aS)-4-bromo-3-methyl-tetrahydro-furo[3,2-c][1,2]dioxin-6
-one (14a): vmax (film)/cmꢃ1 1789, 1149, 1023, 849; dH (600 MHz;
CDCl3) 1.46 (3H, d, J¼6.6 Hz), 2.54 (2H, dd, J¼2.4, 13.2 Hz), 4.22 (1H,
dd, J¼3.6 Hz), 4.62 (1H, dq, J¼2.74, 6.6 Hz), 4.82 (1H, dd, J¼3 Hz), 5.12
(1H, m); dC (150 MHz; CDCl3) 172.8, 80.7, 77.9, 75.4, 44.7, 33.7, 18.4;
m/z (EI) (Mþ 237, 1%), 195(15), 139(17), 115 (50), 71(100), 55 (20);
HRMS (ESI) C7H9O4BrþNa requires 258.9582, found 258.9568. (ꢂ)
(3R,4S,4aR,7aS)-4-Bromo-3-methyl-tetrahydro-furo[3,2-c][1,2]dioxin
-6-one (14a): vmax (film)/cmꢃ1 1789, 1149, 1023, 849; dH (600 MHz;
CDCl3) 1.45 (3H, d, J¼6.6 Hz), 2.81 (2H, dd, J¼6.6,18 Hz), 4.18 (1H, dd,
J¼3.0 Hz), 4.49 (1H, dq, J¼3.0, 6.6 Hz), 4.69 (1H, dd, J¼3.6 Hz), 5.12
(1H, dd, J¼4.2, 6.0 Hz); dC (150 MHz; CDCl3) 172.8, 80.6, 77.6, 75.2,
54.0, 33.7, 17.7; m/z (EI) (Mþ 237, 1%), 195(15), 139(17), 115 (50),
71(100), 55 (20); HRMS (ESI) C7H9O4BrþNa requires 258.9582, found
258.9568.
4.6.12. (ꢂ)
(3R,4S,4aR,7aS)-4-Iodo-3-phenyl-tetrahydro-furo[3,2-
c][1,2]dioxin-6-one (14e). Yield: 88 mg, 56% as colourless needles;
Rf 0.38 (dichloromethane); Mp 154–155 ꢁC; vmax (Nujol)/cmꢃ11789,
1165, 1073, 1022; dH (300 MHz; CDCl3) 2.92–2.99 (1H, m), 3.09 (1H,
dd, J¼18, 3.0 Hz), 4.71 (1H, dd, J¼3.3, 5.4 Hz), 5.21–5.28 (2H, m),
5.81 (1H, d, J¼5.4 Hz), 7.41–7.46 (5H, m); dC (75 MHz; CDCl3) 172.9,
135.6, 129.7, 128.9, 127.7, 88.8, 80.6, 77.2, 33.6, 21.6; m/z (EI) (Mþ
346, 1%), 220(64), 158(73), 107(100), 91(55), 70(37); HRMS (ESI)
C12H11O4IþNa requires 368.9599, found 368.9594.
4.6.13. (ꢂ)
(3R,4S,4aR,7aS)-3-Phenyl-4-phenylselanyl-tetrahydro-
furo[3,2-c][1,2]dioxin-6-one (14f). Yield: 93 mg, 55% as a yellow oil;
Rf 0.50 (dichloromethane); vmax (film)/cmꢃ1 3060, 2995, 1789, 1578,
1154, 1022; dH (600 MHz; CDCl3) 2.87–2.95 (2H, m), 4.02 (1H, t,
J¼3.6 Hz), 4.98 (1H, dd, J¼3.6, 6.0 Hz), 5.21 (1H, ddd, J¼3.0, 6.9,
6.9 Hz), 5.51 (1H, d, J¼3.6 Hz), 7.28–7.40 (8H, m), 7.54–7.57 (2H, m);
dC (75 MHz; CDCl3) 173.8, 136.7, 134.8, 129.6, 129.2, 128.9, 128.9,
128.8, 127.9, 86.6, 78.6, 76.4, 41.9, 34.7; m/z (EI) (Mþ 375, 1%),
282(6), 203(100), 157(63), 105(50), 77(38); HRMS (ESI)
C18H16O4SeþNa requires 399.0112, found 399.0118.
4.6.8. (ꢂ) (3R,4S,4aR,7aS)-4-Iodo-3-methyl-tetrahydro-furo[3,2-c]
[1,2]dioxin-6-one (14b). Yield: 137 mg, 76% as a colourless solid;
Rf 0.51 (2:3 ethyl acetate/hexane); Mp 105–107 ꢁC, vmax (Nujol)/
cmꢃ1 1780, 1198, 1166, 1005, 925; dH (600 MHz; CDCl3) 1.44 (3H,
d, J¼6.6 Hz), 2.80 (2H, dd, J¼5.3, 4.2 Hz), 4.33 (1H, dd, J¼3.6 Hz),
4.71 (1H, dq, J¼3.6, 6.6 Hz), 4.93 (1H, t, J¼4.2 Hz) 5.15 (1H, q,
J¼4.2 Hz); dC (150 MHz; CDCl3) 173.1, 81.9, 79.8, 75.5, 33.9, 22.2,
19.44; m/z (EI) (Mþ 284, 14%), 254(22), 157(70), 128,(26)
71(100); HRMS (ESI) C7H9O4IþNa requires 306.9443, found
306.9446.
4.7. General procedure for the synthesis of 1,2-dioxines
12a,b and 15a,b
The crystallographic data (excluding structure factors) for 14b
has been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication nos. CCDC 689285. Copies of
the data can be obtained free of charge, on application to CCDC,12
Union Road, Cambridge CB2, 1EZ, UK (fax: +44 1223 336033 or
email: deposit@ccdc.ac.uk).
To a solution of 1,2-dioxines (1 equiv) in dry benzene (10 mL/
100 mg 1,2-dioxine) was added AIBN (2 equiv) and tri-n-BuSnH
(3 equiv) at room temperature. The mixture was then heated under
reflux for 2 h, following this potassium fluoride (3.3 equiv) in ace-
tonitrile (10 mL) was added to the mixture and stirring continued
overnight. The volatiles were removed in vacuo and the crude
residue was purified by column chromatography to give the desired
1,2-dioxines 12a,b and 15a,b.
4.6.9. Crystallographic data for 14b. M¼284.04, T¼173(2) K, tri-
clinic, P-1, a¼5.5421(13), b¼8.731(2), c¼9.3074(14) Å, ¼77.610(12),
a
b
¼82.565(15),
g
¼87.999(15)ꢁ, V¼436.16(16) Å3, Z¼2, Dx¼
4.7.1. (ꢂ) (3R,4aS,7aS)-3-Methyl-hexahydro-furo[3,2-c][1,2]dioxine
(12a). Yield: 38 mg, 66% as a colourless oil; Rf 0.55 (dichloro-
methane); vmax (film)/cmꢃ1 2930, 2873, 1464, 1377, 1064; dH
(600 MHz; CDCl3) 1.46 (3H, d, J¼6.6 Hz), 1.90 (1H, ddd, J¼2.4, 2.4,
14.4 Hz), 1.93–1.96(1H, m), 2.11–2.15 (1H, m), 2.18 (1H, ddd, J¼4.8,
6.6, 14.4 Hz), 3.77 (1H, ddd, J¼4.8, 8.4, 8.4 Hz), 3.83 (1H, dt, J¼3,
4.8 Hz), 4.03 (1H, ddd, J¼8.4 Hz), 4.23 (1H, ddq, J¼1.8, 6.6, 6.6 Hz),
4.67 (1H, ddd, J¼1.2, 3, 6 Hz); dC (75 MHz; CDCl3) 80.8, 73.3, 72.9,
65.8, 30.9, 29.9, 19.6; m/z (EI) (Mþ 167, 1%),143(38), 95(100), 87(46),
71(28), 55(15); HRMS (ESI) C7H12O3þNa requires 167.0684, found
167.0680.
2.163 g cmꢃ3, F(000)¼272,
m
¼3.644 mmꢃ1, no. of unique data
(AFC12
k/SATURN724 using Mo
K
a
radiation so that qmax
¼
25.0ꢁ)¼1454, no. of parameters¼109,
R (1440 data with
Iꢄ2 (I))¼0.029, wR (all data)¼0.075. The structure was solved by
s
direct-methods (SHELXS-97) and refined (anisotropic displacement
parameters, H atoms in the riding model approximation and
a
weighting scheme w¼1/[
s
2(Fo2)þ0.046P2þ0.053P] where
P¼(Fo2þ2F2c)/3) with SHELXL-97 on F2. The maximum residual
electron density peak of 1.17 e Åꢃ3 was located 0.94 Å from the I
atom. CCDC deposition number: 689285.
4.6.10. (ꢂ)
(3R,4S,4aR,7aS)-3-Methyl-4-phenylselanyl-tetrahydro-
4.7.2. (ꢂ) (3S,4aS,7aS)-3-Phenyl-hexahydro-furo[3,2-c][1,2]dioxine
(12b). Yield: 40 mg, 67% as colourless oil; Rf 0.44 (dichloro-
methane); vmax (film)/cmꢃ1 2936, 2881, 1731, 1456, 1071, 1024; dH
(600 MHz; CDCl3) 1.96–2.01 (1H, m), 2.13–2.19 (1H, sextet,
J¼6.9 Hz), 2.40–2.47 (2H, m), 3.75 (1H, ddd, J¼5.4, 8.4, 8.4 Hz), 3.84
(1H, q, J¼8.4 Hz), 4.15 (1H, q, J¼4.8 Hz), 4.85 (1H, ddd, J¼3.0, 4.5,
6.9 Hz), 5.17 (1H, dd, J¼6 Hz), 7.27–7.37 (3H, m), 7.5–7.52 (2H, m); dC
(75 MHz; CDCl3) 140.2, 128.2, 127.7, 127.2, 81.8, 78.4, 72.9, 65.8, 30.7,
29.4; m/z (EI) (Mþ 206, 1%), 188(14), 157(32), 105(100), 77(64),
55(21); HRMS (ESI) C12H14O3þNa requires 229.0841, found
229.0838.
furo[3,2-c][1,2]dioxin-6-one (14c). Yield: 167 mg, 57% as a yellow
oil; Rf 0.29 (dichloromethane); vmax (film)/cmꢃ1 1789, 1478, 1156,
1020, 692; dH (600 MHz; CDCl3) 1.47 (3H, d, J¼6.6 Hz), 2.75 (1H, dd,
J¼1.8, 18.6 Hz), 2.80 (1H, dd, J¼6.6, 18.6 Hz), 3.59 (1H, dd, J¼3 Hz),
4.62 (1H, dq, J¼2.4, 6.6 Hz) 4.75 (1H, dd, J¼3.0, 4.2 Hz), 5.13 (1H, dt,
J¼3.3, 6.6 Hz), 7.24–7.28 (1H, m), 7.32–7.37 (2H, m), 7.58–7.62 (2H,
m); dC (75 MHz; CDCl3) 173.9, 134.4, 129.7, 129.2, 128.7, 79.9, 78.3,
75.7, 41.6, 34.6, 19.8; m/z (EI) (Mþ 314, 100%), 234(24), 157(90), 77
(61), 51(11); HRMS (ESI) C13H14O4SeþNa requires 336.9954, found
336.9951.

O. Zvarec et al. / Tetrahedron 66 (2010) 1007–1013
1013
4.7.3. (ꢂ) (3R,4aS,7aS)-3-Methyl-tetrahydro-furo[3,2-c][1,2]dioxin-
6-one (15a). Yield: 21 mg, 81% as colourless oil; Rf 0.19 (dichloro-
methane); vmax (film)/cmꢃ1 2937, 1779, 1159, 1025; dH (300 MHz;
CDCl3) 1.58 (3H, d, J¼6.6 Hz), 2.11 (1H, ddd, J¼15.0, 2.4 Hz), 2.26
(1H, ddd, J¼15.0, 7.2, 4.2 Hz), 2.69 (1H, dd, J¼18.3, 1.2 Hz), 2.8 (1H,
dd, J¼18.3, 6.6 Hz), 4.47 (1H, ddq, J¼13.6, 2.4, 6.9 Hz), 4.72 (1H, ddd,
J¼3.0, 4.2, 4.2 Hz), 4.85 (1H, ddd, J¼1.2, 4.8, 4.8 Hz); dC (75 MHz;
CDCl3) 98.8, 86.5, 85.2, 80.9, 79.3, 66.4, 65.8, 56.7, 52.5, 28.6, 28.2,
17.9, 13.4; m/z (EI) (Mþ 158, 9%), 143(7), 95(7), 87(12), 71(100),
45(9); HRMS (ESI) C7H10O4þNa requires 181.0477, found 181.0471.
acetate); vmax (film)/cmꢃ1 3401, 2932, 1769, 1168, 1054; dH
(600 MHz; CDCl3) 1.34 (3H, d, J¼6.0 Hz), 2.04 (2H, m), 2.55 (1H, d,
J¼18.0 Hz), 2.67 (2H, br s), 2.78 (1H, dd, J¼6.0, 18.0 Hz), 4.05 (1H,
sextet, J¼6.0 Hz), 4.51 (1H, ddd, J¼3.6, 7.2, 7.2 Hz), 4.54 (1H, dd,
J¼3.6, 6 Hz); dC (75 MHz; CDCl3) 175.7, 83.6, 68.7, 65.3, 37.9, 36.4,
25.1; m/z (EI) (Mþ 160, 1%), 127(8), 98(66), 89(92), 71(83), 45(100);
HRMS (ESI) C7H12O4þNa requires 183.06332, found 183.0630.
Acknowledgements
D.K.T. and T.D.A. would like to thank the Australian Research
Council for funding. O.Z. would like to thank the School of Chem-
istry and Physics and the Faculty of Science for a Postgraduate
Scholarship.
4.7.4. (ꢂ) (3S,4aS,7aS)-3-Phenyl-tetrahydro-furo[3,2-c][1,2]dioxin-
6-one (15b). Yield: 34 mg, 73% as colourless oil; Rf 0.29 (dichloro-
methane); vmax (film)/cmꢃ1 3064, 2941, 1789, 1179, 1039; dH
(600 MHz; CDCl3) 2.56 (1H, ddd, J¼4.8, 7.8, 15 Hz), 2.64 (1H, ddd,
J¼4.2, 4.2, 15 Hz), 2.79 (1H, dd, J¼3.0, 18.6 Hz), 2.86 (1H, dd, J¼6.6,
18.6 Hz), 4.92–4.95 (1H, m), 4.99–5.01 (1H, m), 5.44 (1H, dd, J¼4.2,
7.8 Hz), 7.31–7.44 (5H, m); dC (75 MHz; CDCl3) 174.1, 137.9, 128.7,
128.7, 127.6, 79.3, 77.1, 74.6, 34.1, 29.1; m/z (EI) (Mþ 220, 1%),
176(33), 133(28), 105(100), 77(33), 51(14); HRMS (ESI)
C12H12O4þNa requires 243.0633, found 243.0639.
Supplementary data
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2009.11.068.
4.8. General procedure for the synthesis of 1,4-diols
16a and 17a
References and notes
1. Greatrex, B. W.; Taylor, D. K. J. Org. Chem. 2005, 70, 470–476.
2. (a) Avery, T. D.; Haselgrove, T. D.; Rathbone, T. J.; Taylor, D. K.; Tiekink, E. R. T.
Chem. Commun. 1998, 333–334; (b) Avery, T. D.; Taylor, D. K.; Tiekink, E. R. T. J.
Org. Chem. 2000, 65, 5531–5546; (c) Avery, T. D.; Caiazza, D.; Culbert, J. A.; Taylor,
D. K.; Tiekink, E. R. T. J. Org. Chem. 2005, 70, 8344–8351.
To a solution of 1,2-dioxine (1 equiv) in methanol (5 mL/500 mg
of 1,2-dioxine) was added 5% Pd/C (10% by weight) under a hydro-
gen atmosphere and stirred until complete by TLC. The volatiles
were removed in vacuo and crude residue was purified by column
chromatography to give the desired 1,4-diols 16a and 17a.
3. Jung, M.; Ham, J.; Song, J. Org. Lett. 2002, 4, 2763–2765.
4. (a) Saito, I.; Nattala, S. The Chemistry of Peroxides; Wiley: New York, NY, 1983; (b)
Casteel, D. A. Nat. Prod. Rep. 1992, 9, 289–312; (c) Horton, P. A.; Longley, R. E.;
Kelly-Borges, M.; McConnell, O. J. J. Nat. Prod. 1994, 57, 1374–1381; (d) Varoglu,
M.; Peters, B. M.; Crews, P. J. Nat. Prod. 1995, 58, 27–36; (e) Dussault, P. Synlett
1995, 997–1003; (f) Qureshi, A.; Salva, J.; Harper, M. K.; Faulkner, D. J. J. Nat. Prod.
1998, 61, 1539–1542; (g) Casteel, D. A. Nat. Prod. Rep. 1999, 16, 55–73; (h) Perry,
T. L.; Dickerson, A.; Khan, A. A.; Kondru, R. K.; Beratan, D. N.; Wipf, P.; Kelly, M.;
Hamann, M. T. Tetrahedron 2001, 57, 1483–1487; (i) Chen, Y.; Killday, K. B.;
MaCarthy, P. J.; Shimoler, R.; Chilson, K.; Selitrennikoff, C.; Pomponi, S. A.;
Wright, A. E. J. Nat. Prod. 2001, 64, 262–264; (j) Rudi, A.; Afanii, R.; Gravalos, L. G.;
Aknin, M.; Gaydou, E.; Vacelet, J.; Kashman, Y. J. Nat. Prod. 2003, 66, 682–685; (k)
Holzwarth, M.; Trendel, J.-M.; Albrecht, P.; Maier, A.; Michaelis, W. J. Nat. Prod.
2005, 68, 759–761.
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3204.
4.8.1. (ꢂ)
(2S,3S)-2-((R)-2-Hydroxy-propyl)-tetrahydrofuran-3-ol
(16a). Yield: 40 mg, 69% as colourless oil; Rf 0.14 (ethyl acetate);
vmax (film)/cmꢃ1 3400, 2967, 1374, 1119, 1061; dH (600 MHz; CDCl3)
1.28 (3H, d, J¼6.6 Hz), 1.81–1.90 (2H, m), 1.95–1.99 (1H, m), 2.16–
2.23 (1H, m), 2.48 (2H, br s), 3.71 (1H, ddd, J¼4.8, 8.4, 8.4 Hz), 3.80
(1H, ddd, J¼4.1, 6, 8.1 Hz), 3.99–4.09 (2H, m), 4.34 (1H, ddd, J¼1.8,
3.6, 5.7 Hz); dC (75 MHz; CDCl3) 81.7, 72.4, 65.9, 65.9, 37.4, 34.9,
24.8; m/z (EI) (Mþ 146, 1%),128(16), 89(53), 71(68), 57(100), 45(68);
HRMS (ESI) C7H14O3þNa requires 169.0841, found 169.0836.
4.8.2. (ꢂ) (4S,5S)-4-Hydroxy-5-((R)-2-hydroxy-propyl)-dihydrofu-
ran-2-one (17a). Yield: 21 mg, 62% as colourless oil; Rf 0.49 (ethyl