Iodoetherification of conformationally restricted dienyl alcohols: Unexpected formation of oxocenes by 8-endo-mode oxacyclizations

Article abstract of DOI:10.3987/COM-13-S(S)54

Iodine-promoted oxacyclizations of a family of conformationally restricted dienyl alcohols consistently afford oxocenes, arising from 8-endo-mode cyclizations.

Full text of DOI:10.3987/COM-13-S(S)54

SUPPORTING INFORMATION for
IODOETHERIFICATION OF CONFORMATIONALLY RESTRICTED DIENYL ALCOHOLS:
UNEXPECTED FORMATION OF OXOCENES BY 8-ENDO-MODE CYCLIZATIONS
Kristen L. Stoltz, Andrea-Nekane R. Alba, Frank E. McDonald,*
Marika B. Wieliczko, and John Bacsa
Experimental details and tabulated data for new compounds:
General experimental
compound 6
2
2
compound 7
3
compound 9
3
compound 11
compound 13
compound 14
compound 15
compound 16
compound 17
compound 18
compound 19
compound 20
compound 21
compound 22
compound 23
compound 24
compound 25
References
4
5
5
5
5
6
7
8
9
9
10
10
11
11
12
1
13
H and C NMR spectra for new compounds:
compound 6
compound 7
compound 9
compound 11
compound 13
compound 14
compound 15
compound 16
compound 17
compound 18
compound 19
compound 20
compound 21
compound 22
compound 23
compound 24
compound 25
13
14
15
16
17
18
19
20
21
22
23
25
27
28
29
30
31
Crystal structure data:
compound 18
33
38
compound 19
S-1

1
13
General experimental: H NMR and C NMR spectra were recorded on Varian INOVA 600,
Unity 600 and INOVA 400 spectrometers. NMR spectra were recorded in solutions of deuterated
1
13
chloroform (CDCl ) with the residual chloroform (7.27 ppm for H NMR and 77.23 ppm for C
3
NMR) taken as the internal standard, deuterated methanol (CD OD) with residual methanol (3.31
3
1
13
ppm for H NMR and 49.3 ppm for C NMR) taken as the internal standard, or deuterated
1
13
benzene with residual benzene (7.16 ppm for H NMR and 128.23 ppm for C NMR) taken as
the internal standard, and were reported in parts per million (ppm). Abbreviations for signal
coupling are as follows: s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublet; ddd,
doublet of doublet of doublet; dt, doublet of triplet; app d, apparent doublet; app t, apparent
triplet; m, multiplet. IR spectra were collected on a Mattson Genesis II FT-IR spectrometer as
neat films on sodium chloride discs. Mass spectra (high resolution ESI, APCI and NSI) were
recorded on a Finnigan LTQ FTMS Mass spectrometer. Optical rotations were measured using a
Perkin-Elmer 341 polarimeter (concentration in g/100mL). Thin Layer Chromatography (TLC)
was performed on precoated glass backed plates purchased from Whatman (silica gel 60F ; 0.25
2
54
mm thickness). Flash column chromatography was carried out with silica gel 60 (230-400 mesh
ASTM) from EM Science. All reactions were carried out with anhydrous solvents in oven dried
or flame dried and argon-charged glassware. All anhydrous solvents were dried with 4Å
molecular sieves purchased from Sigma-Aldrich and tested for trace water content with
Coulometric KF titrator from Denver instruments. All solvents used in extraction procedures and
chromatography were used as received from commercial suppliers without prior purification.
Compounds 5, 8, 10, and 12 were prepared as described in the literature, and the spectroscopic
1
data matched that reported. The preparations of compounds 6 and 7 were described in the patent
2
literature, but spectroscopic data was not provided for those compounds.
(
(
3aR,4S,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbaldehyde
1
6): The ribose-derived primary alcohol 5 (22.73 g, 111 mmol) was dissolved in MeCN (330
mL), and IBX (51.77 g, 202 mmol) was added in one portion at room temperature. The
suspension was refluxed for 3 h and stirred at room temperature overnight. The cloudy white
reaction mixture was filtered, rinsed with EtOAc, and concentrated under reduced pressure to
obtain aldehyde 6 as a white crystalline solid that melted at room temperature (22.74 g, 99%
1
yield). H NMR (400 MHz, CDCl ) δ 9.57 (s, 1H), 5.08 (s, 1H), 5.04 (d, J = 5.9 Hz, 1H), 4.49
3
S-2

1
3
(
d, J = 5.9 Hz, 1H), 4.47 (s, 1H), 3.44 (s, 3H), 1.48 (s, 3H), 1.32 (s, 3H). C NMR (100 MHz,
CDCl ) δ 200.9, 112.8, 109.3, 89.6, 84.1, 80.9, 55.9, 26.3, 25.0. HRMS (APCI): m/z calcd.
3
+
-1
C H O (M+H ) 203.09140, found 203.09143. FT-IR (neat, cm ): 2857, 1730, 1376, 1274,
9
15
5
2
5
1
200, 1162, 1090, 1038, 941, 868. [α]D = -151 (c = 1.00, CHCl3).
(
S)-1-((3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-
yl)ethanol (7): Aldehyde 6 (22.73 g, 111 mmol) was dissolved in THF (448 mL), the solution
was cooled to -50 ˚C, and MeMgBr (70 mL, 191 mmol) was added dropwise at -50 ˚C,
maintaining the temperature with the addition of dry ice as needed. The reaction was stirred at
-
40 ˚C for 2 h before slowly warming to 0 ˚C. The reaction was quenched by the slow addition
of sat. aq. NH Cl (250 mL). The aqueous phase was extracted with EtOAc (3 x 100 mL), and the
4
combined organic layers were washed with brine, dried over MgSO , filtered, and concentrated
4
under reduced pressure to obtain secondary alcohol 7 as a 7:1 mixture of diastereomers as a clear,
yellow oil (22.35 g, 91% yield). We have not independently confirmed the stereochemical
assignment of reference 2 for the secondary alcohol, as this was inconsequential for the
1
preparation of compounds 15 and 16. H NMR (600 MHz, CDCl ) δ 4.97 (s, 1H), 4.86 (d, J =
3
6
1
.0 Hz, 1H), 4.58 (d, J = 6.1 Hz, 1H), 4.19 (d, J = 1.8 Hz, 1H), 3.89 (q, J = 6.7 Hz, 1H), 3.66 (s,
1
3
H), 3.44 (s, 3H), 1.49 (s, 3H), 1.33 (s, 3H), 1.23 (d, J = 6.5 Hz, 3H). C NMR (100 MHz,
CDCl ) δ 112.1, 110.1, 110.0, 92.6, 92.6, 85.9, 79.6, 68.3, 55.7, 55.6, 26.4, 24.7, 18.7. HRMS
3
+
-1
(
NSI): m/z calcd. C H O Na (M+Na ) 241.10464, found 241.10479. FT-IR (neat, cm ): 3458,
10 18 5
2
5
2
973, 1374, 1209, 1087, 1056, 1025, 864, 754. [α]D = -56.6 (c = 1.00, CHCl ).
3
(
3aS,4S,6R,6aR)-4-((R)-1-iodoethyl)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-
d][1,3]dioxole (9): The secondary alcohol 7 (22.35 g, 102 mmol) was dissolved in THF (500
mL), and PPh (53.51 g, 204 mmol), imidazole (20.83 g, 306 mmol) and I (38.83 g, 153 mmol)
3
2
were added to form a dark brown suspension that turned to a clear, yellow solution after 1 min at
room temperature. The reaction mixture was refluxed for 4 h. After cooling to room
temperature, the yellow solution was diluted with sat. aq. Na S O (300 mL) and EtOAc (200
2
2
3
mL). The aqueous and organic layers were separated, and the organic layer was washed with
Na S O (200 mL), H O (2 x 125 mL) and brine (125 mL). The organic layer was dried with
2
2
3
2
MgSO , filtered, and concentrated under reduced pressure. The crude material was purified by
4
S-3

flash column chromatography (3-5% EtOAc in hexanes) to obtain the iodide 9 as a clear,
1
colorless oil (17.50 g, 52% yield). H NMR (400 MHz, CDCl ) δ 4.97 (s, 1H), 4.62 – 4.58 (m,
3
1
3
2
H), 4.23 – 4.10 (m, 2H), 3.45 (s, 3H), 1.91 (d, J = 6.5 Hz, 3H), 1.46 (s, 3H), 1.29 (s, 3H). C
NMR (100 MHz, CDCl ) δ 113.0, 109.4, 93.0, 85.9, 80.0, 56.6, 29.4, 26.7, 25.4, 24.5. HRMS
3
+
-1
(
NSI): m/z calcd. 329.02443 (M+H ), found 329.02425. FT-IR (neat, cm ): 2985, 2933, 1374,
2
5
1
271, 1209, 1158, 1090, 1056, 1037, 864. [α]D = 1.5 (c = 1.00, CHCl3).
(
2Z)-methyl 3-((4S,5R)-2,2-dimethyl-5-(prop-1-en-1-yl)-1,3-dioxolan-4-yl)acrylate (11): The
secondary iodide 9 (14.83 g, 45.20 mmol) was diluted with MeOH (450 mL), and activated zinc
dust (<10 µm, 20.67 g, 316.4 mmol) was added in one portion, followed by AcOH (1.45 mL).
The reaction mixture was refluxed for 4 h. The reaction mixture was cooled to room
temperature, and filtered through a pad of silica gel to remove excess Zn˚ and Zn salts, collecting
the filtrate directly into a 250 mL round-bottom flask, containing a solution of (4R,5R)-2,2-
dimethyl-5-(prop-1-en-1-yl)-1,3-dioxolane-4-carbaldehyde (mixture of E and Z-alkene isomers),
which was not further purified. This aldehyde solution in methanol was cooled to 0 ˚C, and
methyl(triphenylphosphoranylidene) acetate (18.14 g, 54.20 mmol) was added in one portion.
The reaction mixture was stirred overnight at room temperature and the solvent was removed
under reduced pressure. The residue was partitioned between sat. aq. NH Cl and EtOAc. The
4
aqueous layer was extracted with EtOAc (2x), and the combined organic layers were washed with
brine, dried over MgSO , filtered, and concentrated under reduced pressure. The residue was
4
diluted with Et O and the solids were removed by gravity filtration (2x). The crude was purified
2
by flash column chromatography (93:7 to 9:1 hexanes: EtOAc). Although the alkene isomers of
1
1 (1 : 1.3 ratio, arising from the elimination stage) could not be separated from each other, the
Z-unsaturated ester (from the Wittig olefination stage) was obtained a clear, colorless oil (5.47 g,
4% yield). A small quantity of the E-unsaturated ester 13 was isolated from more polar
5
chromatography fractions, as a clear, colorless oil (734 mg, 14% yield).
1
Data for 11: H NMR (400 MHz, CDCl ) δ 6.22 (ddd, J = 11.7, 7.8, 3.9 Hz, 1H), 6.21 (ddd, J =
3
1
1.4, 7.6, 3.6 Hz, 1H), 5.89 (m, 2H), 5.81 – 5.54 (m, 4H), 5.39 – 5.21 (m, 3H), 4.80 (t, J = 7.6
Hz, 1H), 3.71 (s, 3H), 3.70 (s, 3H), 1.67 (dd, J = 6.9, 1.9 Hz, 3H), 1.63 (dd, J = 6.4, 1.6 Hz, 3H),
1
3
1
1
.54 (s, 3H), 1.53, (s, 3H), 1.42 (s, 3H), 1.40 (s, 3H). C NMR (100 MHz, CDCl ) δ 166.1,
3
66.1, 146.8, 146.7, 130.7, 129.4, 126.7, 126.3, 121.1, 120.9, 109.15, 109.0, 79.9, 75.6, 74.5,
S-4

+
5
2
9
1.6, 51.6, 28.3, 28.1, 25.5, 25.4, 17.9, 13.3. HRMS (APCI): m/z calcd. C H O (M+H )
12 19 4
-1
27.12779, found 227.12762. FT-IR (neat, cm ): 3415, 2986, 2935, 1374, 1214, 1163, 1029,
2
5
65, 872. [α]D = +120.2 (c = 1.00, CHCl3).
Data for (2E)-methyl 3-((4S,5R)-2,2-dimethyl-5-(prop-1-en-1-yl)-1,3-dioxolan-4-yl)acrylate
1
(
13): H NMR (600 MHz, CDCl ) δ 6.81 (ddd, J = 16.2, 11.1, 5.7 Hz, 1H), 6.12 – 6.02 (m, 1H),
3
5
.83 (dq, J = 15.0, 6.5 Hz, 1H), 5.78 – 5.71 (m, 1H), 5.35 (ddt, J = 13.1, 9.4, 1.9 Hz, 1H), 5.10
(
dd, J = 8.8, 6.9 Hz, 1H), 4.78 – 4.70 (m, 1H), 4.69 – 4.65 (m, 1H), 3.75 (s, 3H), 1.72 (td, J = 7.2,
1
3
1
1
7
.7 Hz, 3H), 1.54 (s, 3H), 1.41 (s, 3H). C NMR (100 MHz, CDCl ) δ 166.68, 166.63, 144.63,
3
44.54, 132.40, 129.96, 126.15, 125.75, 122.25, 109.46, 109.35, 79.92, 77.66, 77.42, 77.30,
4.12, 51.88, 28.05, 27.99, 25.61, 25.57, 18.06, 13.77. HRMS (NSI) m/z calcd. 227.12779
+
-1
(
M+H ), found 227.1770. FT-IR (neat, cm ): 2989, 2949, 1723, 1662, 1436, 1373, 1307, 1253,
2
5
1
214, 1161, 1041, 968, 873, 755. [α]D = -88.3 (c = 1.00, CHCl ).
3
(
Z)-3-((4S,5R)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl)prop-2-en-1-ol (14): The Z-unsaturated
1
ester 10 (450 mg, 2.12 mmol, 1 equiv.) was dissolved in anhydrous dichloromethane (12 mL),
cooled to 0 ºC, and DIBAL-H (1.0 M in dichloromethane, 4.24 mL, 4.24 mmol, 2 equiv.) was
added. The reaction mixture was allowed to warm to room temperature over 2 hours. Solid
NH Cl (155 mg) and methanol (1 drop) were added, and the mixture was filtered through a short
4
pad of silica gel, which was subsequently rinsed with 5% MeOH in EtOAc. The filtrate was
concentrated by rotary evaporation, and the residue was chromatographed (9:1 to 85:15
hexanes:EtOAc as eluent) to afford hydroxydiene 14 (250 mg, 64% yield) as a colorless oil. The
1
3
1
H NMR spectrum matched that reported in the literature, generated by a different route.
H
1
NMR H NMR (400 MHz, CDCl ) δ 5.89 – 5.62 (m, 2H), 5.53 (ddt, J = 11.4, 8.5, 1.5 Hz, 1H),
3
5
.31 (dt, J = 17.1, 1.3 Hz, 1H), 5.27 – 5.19 (m, 1H), 4.98 (ddd, J = 8.0, 6.5, 1.3 Hz, 1H), 4.59 (t, J
7.0 Hz, 1H), 4.27 (ddd, J = 13.3, 7.1, 1.3 Hz, 1H), 4.14 (ddd, J = 13.3, 5.9, 1.6 Hz, 1H), 1.87 (s,
H), 1.52 (s, 3H), 1.40 (s, 3H).
=
1
(
2Z)-3-((4S,5R)-2,2-dimethyl-5-(prop-1-en-1-yl)-1,3-dioxolan-4-yl)prop-2-en-1-ol (mixture of
1
5 and 16): The dienyl ester 11 (5.20 g, 22.98 mmol; 1 : 1.3 cis : trans) was dissolved in CH Cl2
2
o
(
130 mL), cooled to 0 C, and DIBAL-H (72 mL, 72 mmol) was added along the sides of the
flask. The reaction mixture warmed to room temperature over 3 hours. Solid NH Cl (2.0 g) and
4
S-5

MeOH (2 mL) were added. After bubbling ceased, the cloudy reaction mixture was filtered
through a short pad of silica gel. The filter cake was rinsed with 5 % MeOH in EtOAc, and the
solvents were removed under reduced pressure. The crude material was purified by flash column
chromatography (2:1 to 3:2 hexanes:EtOAc) to obtain the mixture of dienyl alcohols 15 and 16 as
a clear, colorless oil (1.68 g, 53% yield). A portion of the product was subjected to flash column
chromatography on 25% AgNO silica gel (2:1 hexanes:EtOAc) to obtain the cis,trans-dienyl
3
alcohol 16 (197 mg) as a clear, colorless oil, followed by elution of the cis,cis-isomer 15 as a
clear, colorless oil (154 mg).
1
Data for 15: H NMR (600 MHz, CDCl ) δ 5.85 – 5.77 (m, 1H), 5.72 (dq, J = 11.1, 6.9 Hz, 1H),
3
5
1
3
1
2
1
.60 – 5.52 (m, 1H), 5.42 (ddq, J = 10.8, 8.8, 1.9 Hz, 1H), 5.04 – 4.87 (m, 2H), 4.26 (dd, J =
3.3, 7.2 Hz, 1H), 4.12 (ddd, J = 13.3, 6.0, 1.6 Hz, 1H), 1.91 (bs, 1H), 1.68 (dd, J = 7.0, 1.8 Hz,
13
H), 1.51 (s, 3H), 1.40 (s, 3H). C NMR (100 MHz, CDCl ) δ 132.6, 129.4, 128.6, 126.4,
3
+
08.9, 74.4, 74.2, 58.9, 28.4, 25.8, 13.5. HRMS (NSI): m/z calcd. C H O Na (M+Na )
1
1
18
3
-1
21.11482, found 221.11467. FT-IR (neat, cm ): 3127, 3039, 2923, 2852, 1644, 1401, 1185,
2
5
049, 879, 716. [α]D = -12.7 (c = 1.00, CHCl3).
1
Data for 16: H NMR (400 MHz, CDCl ) δ 5.89 – 5.68 (m, 2H), 5.56 (ddt, J = 11.2, 8.5, 1.4 Hz,
3
1
6
1
1
H), 5.43 (ddq, J = 15.3, 8.6, 1.7 Hz, 1H), 4.92 (ddd, J = 8.1, 6.4, 1.3 Hz, 1H), 4.56 (dd, J = 8.5,
.4 Hz, 1H), 4.33 – 4.20 (m, 1H), 4.20 – 4.08 (m, 1H), 1.72 (dd, J = 6.6, 1.7 Hz, 3H), 1.7 (bs,
13
H), 1.51 (s, 3H), 1.39 (s, 3H). C NMR (100 MHz, CDCl ) δ 132.60, 131.42, 128.55, 126.94,
3
08.82, 80.05, 77.42, 76.98, 74.48, 58.90, 28.33, 25.75, 18.06. HRMS (NSI): m/z calcd.
+
-1
C H O Na (M+Na ) 221.11482, found 221.11471. FT-IR (neat, cm ): 3415, 2986, 2935, 1451,
1
1
18
3
2
5
1
374, 1214, 1163, 1029, 965, 872, 766. [α]D = +34.2 (c = 1.00, CHCl ).
3
3
-((4S,5R)-2,2-dimethyl-5-(prop-1-en-1-yl)-1,3-dioxolan-4-yl)propan-1-ol (17, mixture of
alkene isomers): The unsaturated ester 13 (1.01 g, 4.46 mmol, recovered from multiple batches)
was dissolved in MeOH (74 ml) and cooled to -78 °C. Copper(I) chloride (0.340 g, 3.44 mmol)
and cyclohexene (1.74 ml, 17.2 mmol) were added, followed by NaBH (0.811 g, 21.4 mmol).
4
The reaction mixture turned dark brown over the course of 2 h at -78 °C. The mixture was then
concentrated while the solvent was still cold. The residue was partitioned between aq. NH Cl
4
and Et O, and the aqueous layer was extracted with Et O. The combined organic layers were
2
2
dried over MgSO , filtered, and concentrated by rotary evaporation to provide the saturated ester
4
S-6

1
(
798 mg, 78% yield). H NMR (400 MHz, CDCl ) δ 5.88 – 5.66 (m, 2H), 5.56 – 5.40 (m, 2H),
3
4
4
1
.95 (ddd, J = 9.0, 6.1, 1.2 Hz, 1H), 4.51 (dd, J = 8.5, 6.2 Hz, 1H), 4.11 (dddd, J = 17.1, 9.1, 6.1,
.5 Hz, 2H), 3.68 (s, 3H), 3.68 (s, 3H), 2.49 (ddt, J = 16.4, 8.8, 5.7 Hz, 2H), 2.44 – 2.30 (m, 2H),
.76 – 1.72 (m, 3H), 1.70 (dd, J = 7.0, 1.8 Hz, 3H), 1.47 (s, 3H), 1.46 (s, 3H), 1.37 (s, 3H), 1.35
1
3
(
s, 3H). C NMR (100 MHz, CDCl ) δ 174.05, 131.38, 129.26, 126.63, 126.24, 108.29, 108.24,
3
7
9.63, 77.31, 73.80, 51.81, 30.84, 28.50, 26.39, 26.22, 25.84, 18.11, 13.59. HRMS (ESI): m/z
+
-1
calcd. C H O Na (M+Na ) 251.12538, found 251.12522. FT-IR (neat, cm ) 3691, 3619, 3189,
1
2
20
4
2
5
2
986, 2930, 1738. [α]D = -38.6 (c = 0.67, CHCl ). A portion of this intermediate (398 mg, 1.74
3
mmol) was dissolved in CH Cl (11.6 ml) at 0 °C. DIBAL-H (3.7 ml, 3.66 mmol) was added
2
2
dropwise to the solution. The reaction slowly warmed to room temperature over 2 h, was diluted
with Et O, and was quenched by the sequential addition of H O (0.1 mL), 15% aqueous NaOH
2
2
(
0.1 mL), and H O (0.22 mL). The cloudy reaction mixture stirred at room temperature for 15
2
min, and MgSO was added. After 15 min, the solids were removed by filtration and the solvents
4
removed by rotary evaporation.
The crude material was purified by flash column
chromatography (2:1 hexanes:EtOAc) to obtain compound 17 as a clear, colorless oil (185 mg,
1
5
3% yield). No additional attempt was made to separate the alkene isomers. H NMR (600
MHz, CDCl ) δ 5.78 – 5.68 (m, 2H), 5.51 – 5.41 (m, 2H), 4.94 (ddd, J = 8.4, 6.2, 1.6 Hz, 1H),
3
4
.48 (ddd, J = 8.2, 6.1, 1.8 Hz, 1H), 4.18 – 4.09 (m, 2H), 3.71 – 3.63 (bs, 4H), 2.06 (bs, 1H), 2.03
(
bs, 1H), 1.73 (dt, J = 6.5, 1.8 Hz, 3H), 1.70 (dt, J = 6.9, 2.0 Hz, 3H), 1.72 – 1.61 (m, 4H), 1.57 –
1
3
1
1
2
.51 (m, 4H), 1.48 (s, 6H), 1.38 (s, 3H), 1.36 (s, 3H). C NMR (100 MHz, CDCl ) δ 130.99,
3
28.91, 127.17, 126.60, 108.20, 108.11, 80.02, 78.50, 78.35, 73.93, 62.92 (2), 29.99, 29.94,
8.54, 28.46, 27.68, 27.46, 25.92, 25.82, 18.08, 13.46. HRMS (NSI): m/z calcd. C H O Na
11
20
3
+
-1
(
M+Na ) 223.13047, found 223.13059. FT-IR (neat, cm ): 3414, 2986, 2936, 2870, 1450, 1370,
2
5
1
242, 1215, 1164, 1059, 1022, 969, 877, 753. [α]D = -20.4 (c = 1.00, CHCl3).
(
3aS,4S,9aS,Z)-4-Iodo-2,2-dimethyl-4,5,7,9a-tetrahydro-3aH-[1,3]dioxolo[4,5-d]oxocine (18):
The dienyl alcohol 14 (165 mg, 0.89 mmol, 1 equiv.) was dissolved in anhydrous THF (8.9 mL),
NaHCO (223 mg, 2.69 mmol, 3 equiv.) was added and the reaction mixture was cooled to 0 ˚C.
3
At this temperature, I (682 mg, 2.69 mmol, 3 equiv.) was added. The reaction mixture was left
2
to warm to room temperature, and stirred for 1 day. As unreacted compound 14 was still present
by TLC analysis, an extra portion of I (682 mg, 2.69 mmol, 3 equiv.) was then added at once.
2
S-7

The reaction mixture was stirred for 3 more days. An aqueous saturated solution of Na S O was
2
2
3
added. The aqueous phase was extracted three times with ethyl acetate. The combined organic
layers were washed with brine, dried over MgSO , filtered, concentrated under reduced pressure
4
and purified by column chromatography (hexane/ethyl acetate 90:10, to 75:25), to give
1
iodooxocene 18 (63 mg, 23% yield) as a white solid, mp 65-67 ˚C. H NMR (CDCl , 600 MHz)
3
δ 5.58-5.64 (H , m, 1H), 5.34-5.39 (H , H , m, 2H), 4.47-4.52 (H , m, 1H), 4.45 (H , ddd, J =5.0
a
b
c
d
e
1
Hz, J =10.5 Hz, J =12.5 Hz, 1H), 4.25 (H , dd, J = 5.8 Hz, J =10.5 Hz, 1H), 4.03 (H , t, J=12.5
2
3
f
1
2
g
Hz, 1H), 3.84-3.89 (H , m, 1H), 3.75 (H , dd, J =5.0 Hz, J =12.5 Hz, 1H), 1.50 (s, 3H), 1.41 (s,
h
i
1
2
1
3
3
H). C NMR (CDCl , 150 MHz) δ 129.9, 129.8, 107.4, 81.9, 76.9, 76.5, 71.9, 28.1, 26.7, 26.2.
3
+
HRMS Calcd for C H O I (M+H) : 311.01387, found 311.01466. FT-IR (neat from a CH Cl
1
0
16 3 1
2
2
-
1
solution, the compound solidified upon standing, cm ): 2986, 2918, 1380, 1368, 1262, 1248,
-1
25
1
222, 1164, 1106, 1081, 1055, 872, 738, 705 cm . [α] = +17.9 (c = 0.6, CHCl ). Deposition
D 3
number CCDC-946585 for compound 18.
(
3aS,4S,5R,9aS,Z)-4-iodo-2,2,5-trimethyl-4,5,7,9a-tetrahydro-3aH-[1,3]dioxolo[4,5-
d]oxocine (19): The dienyl alcohol 15 (82 mg, 0.41 mmol) was dissolved in THF (4.1 mL), the
solution was cooled to 0 ˚C, and solid NaHCO (265 mg, 3.2 mmol) was added, followed by I2
3
(
624 mg, 2.5 mmol). The reaction mixture slowly warmed to room temperature over 19 h and
was quenched with saturated aqueous Na S O (30 mL). The aqueous layer was extracted with
2
2
3
EtOAc (3 x 15 mL), and the combined organic layers were dried over MgSO , filtered, and
4
concentrated under reduced pressure. The crude yellow material was purified by flash column
chromatography (9:1 hexanes:EtOAc) to obtain iodooxocene 19 as a clear, colorless oil that
o
1
solidified over time (77 mg, 58% yield). mp 82 - 84 C; H NMR (600 MHz, CDCl ) δ 5.54
3
(
ddd, J = 12.0, 5.4, 4.2 Hz, 1H), 5.36 (ddd, J = 12.0, 6.0, 4.8 Hz, 1H), 5.28 (ddd, J = 6.0, 5.4, 2.4
Hz, 1H), 4.55 (dd, J = 11.1, 4.5 Hz, 1H), 4.46 (ddd, J = 18.6, 4.8, 4.2 Hz, 1H), 4.29 (dd, J = 11.1,
1
5
.2 Hz, 1H), 3.91 – 3.85 (m, 2H), 1.53 (d, J = 6.5 Hz, 3H), 1.48 (s, 3H), 1.39 (s, 3H); H NMR
(
600 MHz, C D ) δ 5.39 (m, 2H), 4.97 (ddd, J = 13.2, 6.0, 2.4 Hz, 1H), 4.48 (dd, J = 11.1, 4.8
6 6
Hz, 1H), 4.36 (dd, J = 11.1, 6.0 Hz, 1H), 3.93 (ddd, J = 18.6, 4.8, 2.4 Hz, 1H), 3.53 (qd, J = 6.6,
4
.6 Hz, 1H), 3.04 (ddd, 18.6, 4.8, 2.4 Hz, 1H), 1.45 (s, 3H), 1.41 (d, J = 6.6 Hz, 3H), 1.33 (s, 3H).
1
3
C NMR (101 MHz, CDCl ) δ 129.9 (2 carbons), 107.1, 80.5, 77.9, 76.1, 71.2, 29.3, 28.3, 26.6,
3
+
1
8.5. HRMS (APCI): m/z calcd. C H O I (M+H ) 325.02951, found 325.02930. FT-IR (neat,
1
1
18
3
S-8

-
1
cm ): 2990, 2932, 2889, 1454, 1434, 1368, 1268, 1246, 1222, 1158, 1101, 1077, 1059, 1028,
2
5
9
35, 879, 711, 652. [α]D = +24.0 (c = 1.00, CHCl ). Deposition number CCDC-946586 for
3
compound 19.
(
(
3aS,4S,5S,9aS,Z)-4-iodo-2,2,5-trimethyl-4,5,7,9a-tetrahydro-3aH-[1,3]dioxolo[4,5-d]oxocine
20): Dienyl alcohol 16 (113 mg, 0.57 mmol) was dissolved in THF (5.7 mL), the solution was
cooled to 0 ˚C, and solid NaHCO (369 mg, 4.4 mmol) was added, followed by I (868 mg, 3.4
3
2
mmol). The reaction slowly warmed to room temperature over 19 h and was quenched with
saturated aqueous Na S O (40 mL). The aqueous layer was extracted with EtOAc (3 x 15 mL),
2
2
3
and the combined organic layers were dried over MgSO , filtered, and concentrated under
4
reduced pressure. The crude yellow material was purified by flash column chromatography (9:1
1
hexanes:EtOAc) to obtain iodooxocene 20 as a clear, colorless oil (108 mg, 59% yield).
H
NMR (600 MHz, CDCl ) δ 5.61 (ddd, J = 11.8, 4.2, 2.7 Hz, 1H), 5.41 (ddd, J = 11.8, 2.6, 1.6 Hz,
3
1
1
3
H), 5.33 (ddd, J = 6.3, 4.8, 2.4 Hz, 1H), 4.44 – 4.32 (m, 1H), 4.25 – 4.20 (m, 2H), 4.18 (ddd, J =
8.0, 3.4, 1.9 Hz, 1H), 4.12 (ddd, J = 18.1, 4.8, 2.6 Hz, 1H), 1.59 (d, J = 4.9 Hz, 3H), 1.48 (s,
1
H), 1.40 (s, 3H); H NMR (600 MHz, C D ) δ 5.47 – 5.36 (m, 2H), 5.04 (ddd, J = 13.2, 3.6, 2.4
6
6
Hz, 1H), 4.32 (dd, J = 10.2, 2.0 Hz, 1H), 4.14 – 4.05 (m, 2H), 3.68 (ddd, J = 18.0, 4.8, 2.4 Hz,
1
H), 3.54 (ddd, J = 18.0, 4.8, 1.8 Hz, 1H), 1.46 (s, 3H), 1.32 (s, 3H), 1.26 (d, J = 6.1 Hz, 3H).
1
3
C NMR (101 MHz, CDCl ) δ 131.4, 130.0, 107.3, 83.2, 77.5, 76.7, 62.0, 35.4, 28.3, 26.2, 17.7.
3
-
1
FT-IR (neat, cm ): 2984, 283, 1376, 1247, 1218, 1165, 1080, 1048, 910, 866, 732, 694, 650.
2
5
[
α]D = +14.8 (c = 1.94, CHCl ).
3
(
3aS,4S,9aS)-4-iodo-2,2,5-trimethylhexahydro-5H-[1,3]dioxolo[4,5-d]oxocine (21), mixture of
diastereomers at C5: Alkenyl alcohol 17 (174 mg, 0.87 mmol) was dissolved in THF (8.6 ml).
NaHCO (569 mg, 6.8 mmol) was added, followed by I (1.32 g, 5.2 mmol). The reaction was
stirred for 14 h, at whch time additional NaHCO (292 mg) and I (662 mg) were added. After 9
3
2
3
2
h, the reaction mixture was diluted with saturated aqueous sodium thiosulfate (10 mL). The
aqueous layer was extracted with EtOAc (3 x 15 mL), and the combined organic layers were
4
dried over MgSO , filtered, and concentrated. The crude material was purified by flash column
chromatography (92:8 hexanes:EtOAc) to obtain iodooxocine 21 as an inseparable mixture of
diastereomers (1:1.3), as a clear, colorless oil (134 mg, 47% yield).
S-9

1
H NMR (600 MHz, CDCl ) δ 4.61 (dd, J = 11.4, 4.8 Hz, 1H), 4.35 – 4.22 (m, 6H), 4.04 (ddd, J
3
=
13.8, 7.2, 6.6 Hz, 1H), 3.93 – 3.84 (m, 2H), 3.56 (ddd, J = 11.4, 4.5, 2.7 Hz, 1H), 3.32 (td, J =
1.6, 2.4 Hz, 1H), 3.26 (t, J = 12.2 Hz, 1H), 1.93 – 1.82 (m, 1H), 1.80 – 1.69 (m, 3H), 1.69 – 1.61
m, 4H), 1.60 (d, J = 6.5 Hz, 3H), 1.52 (d, J = 6.2 Hz, 3H), 1.43 (s, 6H), 1.36 (s, 3H), 1.36 (s,
1
(
1
3
3
6
H). C NMR (150 MHz, C D ) δ 105.83, 105.71, 83.02, 80.18, 79.67, 77.71, 77.45, 76.01,
6 6
8.48, 62.14, 34.85, 31.57, 30.58, 29.43, 29.17, 28.74, 26.52, 26.26 (2), 19.27, 18.63. HRMS
+
-1
(
NSI): m/z calcd. C H IO (M+H ) 325.02951, found 325.02928. IR (neat, cm ): 2984, 2932,
11 20 3
2
5
2
0
877, 1451, 1369, 1220, 1168, 1080, 1037, 961, 939, 866, 826, 753, 706. [α]D = +10.8 (c =
.80, CHCl ).
3
(
3aR,9aS,Z)-2,2-Dimethyl-4,5,7,9a-tetrahydro-3aH-[1,3]dioxolo[4,5-d]oxocine (22):
The
iodooxocene 18 (35 mg, 0.11 mmol, 1 equiv.) and AIBN (4 mg, 0.02 mmol, 0.2 equiv.) were
dissolved in toluene (1.6 mL), and tributyltin hydride (0.06 mL, 0.23 mmol, 2 equiv) was added.
The reaction mixture was warmed to 90 ˚C and stirred at this temperature for 4.5 h. The reaction
mixture was allowed to cool to room temperature and diluted with diethyl ether and washed with
a saturated aqueous solution of KF. The aqueous phase was extracted with diethyl ether (x3) and
the combined organic layers dried over MgSO , filtered, concentrated in vacuo and purified by
4
column chromatography (pentane/diethyl ether 3:1 to 2:1) to afford oxocene 22 (12 mg, 59%
1
yield). H NMR (CDCl , 400 MHz) δ 5.54 (apparent dq, J =2.4 Hz, J =12.1 Hz, 1H) 5.25-5.31
3
1
2
(
m, 1H), 5.32-5.40 (m, 1H), 4.46 (apparent dq, J =2.4 Hz, J =18.2 Hz, 1H), 4.29 (ddd, J =3.6 Hz,
1 2 1
J =6.1 Hz, J =11.2 Hz, 1H), 3.81-3.90 (m, 1H), 3.81-3.90 (m, 1H), 3.78 (apparent dq, J =2.5 Hz,
2
3
1
J =18.2 Hz, 1H), 3.57 (ddd, J =1.1 Hz, J =5.1 Hz, J =12.2 Hz, 1H), 2.19-2.31 (m, 1H), 1.93
2
1
2
3
1
3
(
apparent dt, J =3.1 Hz, J =13.9 Hz, 1H), 1.47 (s, 3H), 1.38 (s, 3H). C NMR (CDCl , 100
1 2 3
-
1
MHz) δ 129.9, 129.7, 107.4, 77.8, 77.4, 71.5, 69.5, 29.8, 28.1, 26.1. FT-IR (neat, cm ): 2985,
25
2
0
933, 2866, 1378, 1367, 1253, 1241, 1218, 1168, 1123, 1090, 1062, 1040, 867. [α]D = -5.7 (c =
.6, CHCl ).
3
(
3aR,5R,9aS,Z)-2,2,5-trimethyl-4,5,7,9a-tetrahydro-3aH-[1,3]dioxolo[4,5-d]oxocine
(23):
Iodooxocene 19 (73 mg, 0.23 mmol) was dissolved in toluene (3.8 mL) and AIBN (8 mg, 0.05
mmol) was added to the flask, immediately followed by Bu SnH (0.12 mL, 0.46 mmol). The
3
reaction mixture was heated to 87 ˚C for 1.5 h, then was cooled to room temperature. The
S-10

reaction was diluted with Et O (5 mL) and saturated aqueous KF (5 mL). The aqueous layer was
2
washed with Et O (2 x 5 mL) and the combined organic layers were dried over MgSO , filtered,
2
4
and concentrated by rotary evaporation. The crude material was purified by flash column
chromatography (5-10% Et O in pentane as eluent) to afford oxocene 23 as a clear colorless oil
2
1
(
7.4 mg, 15% yield). H NMR (600 MHz, CDCl ) δ 5.55 – 5.49 (ddd, J = 12, 2.4, 2.4 Hz, 1H),
3
5
.36 (ddd, J = 12.2, 2.8, 2.8 Hz, 1H), 5.27 (m, 1H), 4.48 (ddd, J = 18.3, 2.5, 2.5 Hz, 1H), 4.42
ddd, J = 11.7, 5.8, 3.7 Hz, 1H), 3.87 (ddd, J = 18.2, 3.0, 2.5 Hz, 1H), 3.75 (app. p, J = 6.4 Hz,
H), 2.31 (ddd, J = 13.6, 11.9, 5.7 Hz, 1H), 1.90 (dd, J = 13.8, 3.6 Hz, 1H), 1.47 (s, 3H), 1.40 (s,
(
1
3
7
1
1
1
3
H), 1.30 (d, J = 6.6 Hz, 3H). C NMR (100 MHz, CDCl ) δ 129.75, 129.71, 107.38, 77.68,
3
+
5.66, 74.01, 71.30, 34.12, 28.38, 26.50, 21.27. HRMS (APCI): m/z calcd. C H O (M+H )
1
1
19
3
-1
99.13287, found 199.13291. FT-IR (neat, cm ): 3023, 2978, 2889, 2845, 1456, 1366, 1246,
25
212, 1063, 1030, 880, 860, 659, 644. [α]D = -18.5 (c = 0.61, CHCl3).
(
3aR,5S,9aS,Z)-2,2,5-trimethyl-4,5,7,9a-tetrahydro-3aH-[1,3]dioxolo[4,5-d]oxocine
(24):
Iodooxocene 20 (146 mg, 0.45 mmol) was dissolved in toluene (7.7 mL) and AIBN (15 mg, 0.09
mmol) was added to the flask, immediately followed by Bu SnH (0.25 mL, 0.93 mmol). The
3
reaction mixture was heated to 87 ˚C for 1.5 h, and then was cooled to room temperature. The
reaction was diluted with Et O (5 mL) and saturated aqueous KF (5 mL). The aqueous layer was
2
washed with Et O (2 x 5 mL) and the combined organic layers were dried over MgSO , filtered,
2
4
and concentrated by rotary evaporation. The crude material was purified by flash column
chromatography (5-10% Et O in pentane as eluent) to afford oxocene 24 as a clear colorless oil
2
1
(
(
17 mg, 19% yield). H NMR (600 MHz, CDCl ) δ 5.53 (ddd, J = 12.2, 3.0, 2.8 Hz, 1H), 5.39
3
ddd, J = 12.4, 2.9, 1.8 Hz, 1H), 5.27 (m, 1H), 4.33 (ddd, J = 10.6, 5.9, 3.6 Hz, 1H), 4.16 (ddd, J
=
18.6, 2.7, 2.7 Hz, 1H), 4.12 – 4.03 (m, 2H), 2.04 (app. dd, J = 13.7, 11.7 Hz, 1H), 1.91 (dt, J =
1
3
1
3.9, 3.3 Hz, 1H), 1.47 (s, 3H), 1.37 (s, 3H), 1.28 (d, J = 6.7 Hz, 3H). C NMR (100 MHz,
CDCl ) δ 130.27 130.14 78.56 77.68 71.63 61.70 35.73 28.24 26.38, 18.57. HRMS (APCI): m/z
3
+
-1
calcd. C H O (M+H ) 199.13287, found 199.13298. FT-IR (neat, cm ): 2982, 2934, 1459,
1
1
19
3
2
5
1
377, 1215, 1173, 1130, 1043, 879, 861, 644. [α]D = -26.3 (c = 1.00, CHCl3).
(
3aR,9aS)-2,2,5-trimethylhexahydro-3aH-[1,3]dioxolo[4,5-d]oxocine
(25),
mixture
of
diastereomers at C5: Iodooxocane 21 (125 mg, 0.38 mmol) was dissolved in benzene (6.4 ml),
S-11

and AIBN (1 crystal) and tributyltin hydride (0.16 ml, 0.58 mmol) were added at room
temperature. The reaction mixture was heated to reflux for 1 h. and cooled to room temperature.
The solvent was removed by rotary evaporation and the residue diluted with Et O and saturated
2
aqueous KF. The aqueous layer was extracted with Et O (3 x 8 mL) and the combined organic
2
layers were washed with saturated aqueous KF (2 x 5 mL), brine (5 mL), dried over MgSO4,
filtered, and concentrated by rotary evaporation. The crude material was purified by flash
column chromatography (8-10% Et O in pentane), which allowed separation and independent
2
1
characterization of diastereomers. Data for the diastereomer eluting first (16 mg, 21% yield): H
NMR (600 MHz, CDCl ) δ 4.38 (ddd, J = 11.8, 5.7, 3.2 Hz, 1H), 4.27 (dd, J = 10.7, 5.8 Hz, 1H),
3
3
1
1
.93 (ddd, J = 13.2, 5.1, 4.2 Hz, 1H), 3.73 (app. p, J = 6.4 Hz, 1H), 3.20 (td, J = 12.3, 2.1 Hz,
H), 2.31 (ddd, J = 14.4, 11.8, 5.4 Hz, 1H), 1.90 – 1.81 (m, 1H), 1.78 (dd, J = 14.5, 3.2 Hz, 1H),
1
3
.75 – 1.60 (m, 3H), 1.41 (s, 3H), 1.34 (s, 3H), 1.27 (d, J = 6.6 Hz, 3H). C NMR (150 MHz,
CDCl ) δ 105.79, 80.37, 72.77, 72.74, 69.29, 32.89, 30.76, 29.33, 28.50, 25.75, 20.51. HRMS
3
+
-1
(
NSI): m/z calcd. C H O (M+H ) 201.14852, found 201.14849. FT-IR (neat, cm ): 2980,
11 21 3
2
5
2
0
931, 2872, 1456, 1376, 1243, 1217, 1172, 1092, 1044, 1024, 892, 870, 754. [α]D = -23 (c =
1
.26, CHCl ). Data for the diastereomer eluting subsequently (24 mg, 31%): H NMR (600
3
MHz, CDCl ) δ 4.30 (ddd, J = 11.3, 5.9, 2.6 Hz, 1H), 4.22 (ddd, J = 11.1, 5.9, 1.8 Hz, 1H), 3.80
3
(
dqd, J = 13.1, 6.5, 2.2 Hz, 1H), 3.62 (ddd, J = 12.1, 8.4, 3.6 Hz, 1H), 3.32 (ddd, J = 12.4, 6.4,
.9 Hz, 1H), 2.00 (dt, J = 14.6, 11.4 Hz, 1H), 1.89 (tdd, J = 13.6, 11.0, 3.0 Hz, 1H), 1.78 – 1.67
3
1
3
(
m, 3H), 1.59 – 1.51 (m, 1H), 1.41 (s, 3H), 1.33 (s, 3H), 1.21 (d, J = 6.4 Hz, 3H). C NMR (150
MHz, CDCl ) δ 105.94, 79.44, 77.73, 72.97, 63.72, 37.11, 28.52, 28.32, 28.13, 25.46, 20.78.
3
+
-1
HRMS (NSI): m/z calcd. C H O (M+H ) 201.14852, found 201.14859. FT-IR (neat, cm ):
1
1
21
3
2
5
2
931, 2874, 1454, 1375, 1242, 1216, 1175, 1108, 1069, 1036, 896, 755. [α]D = -11.9 (c = 0.54,
CHCl ).
3
References:
1
) L. J. Baird, M. S. M. Timmer, P. H. Teesdale-Spittle, and J. E. Harvey, J. Org. Chem., 2009,
4, 2271.
7
2
3
) L. Beigelman, L. Blatt, and G. Wang, US Patent 2010/0249068 A1.
) M. B. S. Ferjani, Z. Zhou, and S. M. Bennett, Tetrahedron, 2004, 60, 8113.
S-12

1
13
H and C NMR spectra for compound 6:
S-13

1
13
H and C NMR spectra for compound 7:
S-14

1
13
H and C NMR spectra for compound 9:
S-15

1
13
H and C NMR spectra for compound 11 (1 : 1.3 mixture of cis : trans):
S-16

1
13
H and C NMR spectra for compound 13:
S-17

1
13
H and C NMR spectra for compound 14:
S-18

1
13
H and C NMR spectra for compound 15:
S-19

1
13
H and C NMR spectra for compound 16:
S-20

1
13
H and C NMR spectra for compound 17 (1 : 1.2 mixture of diastereomers):
S-21

1
13
H and C NMR spectra for compound 18:
S-22

1
3
H NMR spectra for compound 19 (CDCl ):
1
6 6
H NMR spectra for compound 19 (C D ):
S-23

13
C NMR spectra for compound 19:
S-24

1
3
H NMR spectra for compound 20 (CDCl ):
1
6 6
H NMR spectra for compound 20 (C D ):
S-25

13
C NMR for compound 20:
S-26

1
13
H and C NMR spectra for compound 21 (1 : 1.3 mixture of diastereomers):
S-27

1
13
H and C NMR spectra for compound 22:
S-28

1
13
H and C NMR spectra for compound 23:
S-29

1
13
H and C NMR spectra for compound 24:
S-30