Reductive cyclization cascades of lactones using SmI2-H 2O

Article abstract of DOI:10.1021/ja1114908

Lactones bearing two alkenes or an alkene and an alkyne undergo reductive cyclization cascades upon treatment with SmI₂-H₂O, giving decorated azulene motifs in excellent yields with good diastereocontrol.

Full text of DOI:10.1021/ja1114908

Reductive cyclization cascades of lactones using SmI -H O
2
2
a
Dixit Parmar, Malcolm Spain, Kieran Price, Hiroshi Matsubara, Paul A. Bradley, David J. Procter *
a
a
b
c
a
a
School of Chemistry, University of Manchester, Oxford Road, Manchester, M13 9PL, UK.
b
Department of Chemistry, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka
5
99-8531, Japan.
c
Discovery Chemistry, Pfizer Global R & D, Ramsgate Road, Sandwich, Kent,
CT13 9NJ, UK
Email. david.j.procter@manchester.ac.uk.
Contents
S2 General Experimental
S3 Preparation of Samarium Iodide
S4-S1 Experimental
S72 X-ray crystal structure of 9l: CCDC = 804694
S73 X-ray crystal structure of 9j: CCDC = 804695
S74 X-ray crystal structure of 12: CCDC = 804696
1 13
S75 H and C NMR spectra of new compounds
S126-S139 Details of calculations and additional discussion
S1

General experimental
All experiments were performed under an atmosphere of nitrogen, using anhydrous
solvents, unless stated otherwise. THF was obtained from a solvent purification
system, and when used in conjunction with SmI
pump-thaw. Dichloromethane was distilled from CaH
being deoxygenated by bubbling with N
2
, deoxygenated by using freeze-
2
. Water was distilled before
2
.
1
13
H NMR and C NMR were recorded using 300, 400 and 500 MHz spectrometers,
with chemical shift values being reported in ppm relative to residual chloroform (δ
.27 or δ = 77.2) as internal standards. All coupling constants (J) are reported in
Hertz (Hz).
H
=
7
C
Mass spectra were obtained using positive and negative electrospray (ES±) or gas
chromatography (GC) methodology. Infra-red spectra were recorded as evaporated
films or neat using a FT/IR spectrometer.
Column chromatography was carried out using 35 – 70 µ, 60A silica gel. Routine
TLC analysis was carried out on aluminium sheets coated with silica gel 60 F254, 0.2
mm thickness. Plates were viewed using a 254 nm ultraviolet lamp and dipped in
aqueous potassium permanganate, p-anisaldehyde or phosphomolybdic acid.
S2

2
Preparation of samarium diiodide (SmI )
Samarium diiodide was prepared by a modification of the procedure of Imamoto and
1
Ono.
Samarium powder (2.00 g, 13.3 mmol, 1.2 eq) was added to an oven dried round-
bottomed flask, the flask sealed, covered in aluminum foil and flushed with N
2
for 30
for 15
min. THF (110 ml) was added and the resulting suspension bubbled with N
2
min. Finally, iodine (2.80 g, 11.0 mmol, 1 eq) was added and the flask flushed again
with N for 10 min. The flask was heated at 60 ºC for 18 hours. The 0.1 M solution
2
was allowed to cool to room temperature and then used directly.
1
T. Imamoto, M. Ono, Chem. Lett. 1987, 501.
S3

Preparation of lactone substrates
2
2
-Allylcyclopentanone S1
3
η
2
To a stirred solution of [( -allyl)PdCl] (157 mg, 0.43 mmol, 0.025 eq) and Xantphos
(
498 mg, 0.86 mmol, 0.05 eq) in DMSO (23 mL) was added allyl alcohol (1.00 g, 17
mmol, 1 eq), cyclopentanone (4.35 g, 52 mmol, 3 eq) and (DL)-proline (594 mg, 5.16
mmol, 0.30 eq). The resultant solution was heated to 70 ˚C for 18 hours, after which
the reaction mixture was filtered through a pad of silica eluting with 20% EtOAc in
petroleum ether (40 – 60 °C). The solvent was removed in vacuo to yield the crude
product. Purification by column chromatography on silica gel eluting with 10%
EtOAc in petroleum ether (40 – 60 °C) gave the title compound (1.53 g, 12.3 mmol,
-1
7
3%) as a colourless oil; νmax (neat)/cm 3003, 2964, 2913, 1712 (C=O), 1432, 1364,
222, 1094; δ (500 MHz, CDCl ) 1.54-1.63 (1H, m, CH CH), 1.77-1.85 (1H, m,
C(O)), 1.99-2.04 (1H, m, CH CH C(O)), 2.05-2.08 (1H, m,
CH=CH ), 2.09-2.16 (2H, m, CH + 1H from CH C(O)), 2.17-2.24 (1H, m,
CH), 2.31-2.36 (1H, m, CH C(O)), 2.50-2.55 (1H, m, CH CH=CH ), 5.04
), 5.08 (1H, dd, J 17.0, 1.6, CH=CH ), 5.74-5.82
(75 MHz, CDCl ) 20.7 (CH ), 29.0 (CH ), 33.9 (CH CH=CH ),
C(O)), 48.6 (CH), 116.4 (CH=CH ), 135.9 (CH=CH ), 220.6 (C(O)); m/z
GC-MS) 124 (M, 40), 67 (100), 39 (57), 96 (49), 55 (37), 81 (26); (Found: (M),
1
H
3
a b
H
CH
CH
CH
a
a
a
H
b
H
b
H
b
CH
2
a
H
b
2
2
a b
H
a
H
b
a
H
b
2
(
(
1H, dd, J 10.1, 1.6, CH=CH
1H, m, CH=CH ); δ
8.2 (CH
a
H
b
a b
H
2
C
3
2
2
2
2
3
2
2
2
(
1
8
24.0882. C H12O requires M, 124.0883).
2
G. H. Posner, C. M. Lentz, J. Am. Chem. Soc. 1979, 101, 934.
S4

3
2
-Cinnamylcyclopentanone S2
3
η
To a stirred solution of [(
-allyl)PdCl]
2
(0.137 g, 0.38 mmol, 0.025 eq) and Xantphos
(
0.434 g, 0.75 mmol, 0.05 eq) in DMSO (20 mL) was added (E)-3-phenylprop-2-en-
1
-ol (2.01 g, 15 mmol, 1 eq), cyclopentanone (3.79 g, 45 mmol, 3 eq) and (DL)-
proline (0.518 g, 4.50 mmol, 0.30 eq). The resultant solution was heated to 70 ˚C for
8 hours, after which the reaction mixture was filtered through a pad of silica eluting
1
with 20% EtOAc in petroleum ether (40 – 60 °C). The solvent was removed in vacuo
to yield the crude product. Purification by column chromatography on silica gel
eluting with 10% EtOAc in petroleum ether (40 – 60 °C) gave the title compound
-
1
(
2.00 g, 10 mmol, 66%) as a colourless oil; νmax (neat)/cm 2956, 1734 (C=O), 1491,
1
448, 1152, 966, 692; δ
.88 (1H, m, CH CH
C(O)), 2.21-2.28 (3H, m, CH
ddt, J 18.4, 8.3, 1.3, CH C(O)), 2.66-2.71 (1H, m, CH
J 15.6, 7.1, CH=CHPh), 6.45 (1H, d, J 15.6, CH=CHPh), 7.21-7.38 (5H, m, Ar-H); δ
H
(400 MHz, CDCl
C(O)), 1.99-2.06 (1H, m, CH
CH=CHPh + CH + 1H from CH
CH=CHPh), 6.19 (1H, dt,
3
) 1.59-1.70 (1H, m, 1H from CH
CH C(O)), 2.07-2.19 (1H, m,
), 2.36 (1H,
2
), 1.77-
1
a
H
b
2
a
H
b
2
CH
a
H
b
a
H
b
2
a
H
b
a b
H
C
(
(
(
100 MHz, CDCl
CH C(O)), 49.1 (CH), 126.1 (Ar-CH), 127.2 (Ar-CH), 127.7 (CH=CHPh), 128.5
Ar-CH), 131.8 (CH=CHPh), 137.4 (Ar-C), 220.6 (C(O)); m/z (ES+ mode) 218 ((M +
), 100), 223 ((M + Na), 36); (Found: (M + Na), 223.1094. C14 16ONa requires M,
3 2 2 2 2
) 20.7 (CH CH C(O)), 29.0 (CH ), 33.1 (CH CH=CHPh), 38.2
2
NH
4
H
2
23.1099).
3
I. Usui, S. Schmidt, B. Breit, Org. Lett. 2009, 11, 1453.
S5

4
6
-Allyltetrahydro-2H-pyran-2-one S3
To a stirred solution of 2-allylcyclopentanone (883 mg, 7.12 mmol, 1 eq) in CH
2 2
Cl
(
16 mL) was added anhydrous NaHCO (1.20 g, 14.2 mmol, 2 eq) followed by
3
dropwise addition of 77 % m-CPBA (1.76 g, 7.83 mmol, 1.1 eq). The reaction was
stirred at room temperature for 18 hours. The reaction was quenched with saturated
NaHCO
organic layers were combined and washed with H
10 mL) before being dried (Na SO ) and concentrated in vacuo to yield the crude
3
solution (10 mL), before being extracted with Et
2
O (3 × 20 mL). The
2
O (10 mL), then saturated NaHCO
3
(
2
4
product. Purification by column chromatography on silica gel eluting with 30%
EtOAc in petroleum ether (40 – 60 °C) gave the title compound (647 mg, 4.62 mmol,
-
1
6
5%) as a colourless oil; νmax (neat)/cm 2936, 1734 (C=O), 1243, 1046, 920; δ
MHz, CDCl ) 1.50-1.59 (2H, m, CH ), 1.79-1.87 (1H, m, CH CH CH C(O)), 1.88-
.96 (1H, m, CH CH CH C(O)), 2.34-2.43 (1H, m, CH CH=CH ), 2.44-2.52 (2H,
m, CH C(O) + 1H from CH CH=CH ), 2.55-2.63 (1H, m, CH C(O)), 4.31-
.38 (1H, m, CH), 5.12-5.18 (2H, m, CH=CH ), 5.82 (1H, ddt, J 17.3, 10.2, 7.1,
H
(400
3
2
a
b
2
1
a
b
2
a
H
b
2
a
H
b
a
H
b
2
a b
H
4
2
CH=CH
2
); δ
CH=CH
GC mode) 158 (M + NH
C
(100 MHz, CDCl
), 79.8 (CH), 118.6 (CH=CH
), 99 (100), 71 (63), 55 (29); (Found: (M + NH
8 16 2
H O N requires M, 158.1176).
3
) 18.4 (CH
2
), 27.2 (CH
2
), 29.5 (CH
), 171.7 (C(O)); m/z
), 158.1175.
2
C(O)), 40.0
(
(
CH
2
2
2 2
), 132.6 (CH=CH
4
4
C
4
R. Zibuck, N. J. Liverton, A. B. Smith, J. Am. Chem. Soc. 1986, 108, 2451.
S6

6
-Cinnamyltetrahydro-2H-pyran-2-one 6a
To a stirred solution of 2-cinnamylcyclopentanone (1.04 g, 5.18 mmol, 1 eq) in
CH Cl (11 mL) was added anhydrous NaHCO (0.65 g, 7.76 mmol, 1.5 eq) followed
by dropwise addition of 77 % m-CPBA (1.28 g, 5.70 mmol, 2.2 M solution in CH Cl
.1 eq). The reaction was stirred at room temperature for 18 hours. The reaction was
2
2
3
2
2
,
1
quenched with saturated NaHCO
3
solution (10 mL), before being extracted with Et
O (10 mL), then
) and concentrated in vacuo to
2
O
(
3 × 20 mL). The organic layers were combined and washed with H
2
saturated NaHCO (10 mL) before being dried (Na SO
3
2
4
yield the crude product. Purification by column chromatography on silica gel eluting
with 30% EtOAc in petroleum ether (40 – 60 °C) gave the title compound (0.32 g,
1
2
.47 mmol, 29%) as a white solid; M.p. 87 ˚C recrystallised from pentane/Et O; νmax
-
1
(
neat)/cm 2924, 1733 (C=O), 1488, 1438, 1373, 1239, 1172, 1047, 962, 923; δ
MHz, CDCl ) 1.59-1.67 (1H, m, CHCH ), 1.83-1.91 (2H, m, CH ), 1.94-2.02 (1H,
m, CHCH ), 2.46-2.52 (1H, m, CH C(O)), 2.55-2.62 (2H, m, CH CH=CHPh
1H from CH C(O)), 2.64-2.70 (1H, m, CH CH=CHPh), 4.41-4.47 (1H, m,
CH), 6.26 (1H, dt, J 16.1, 7.3, CH=CHPh), 6.51 (1H, d, J 16.1, CH=CHPh), 7.24-7.39
H
(500
3
a
H
b
2
a
H
b
a
H
b
a b
H
+
a
H
b
a b
H
(
(
5H, m, Ar-H); δ
CH CH=CHPh), 80.1 (CH), 124.1 (CH=CHPh), 126.2 (Ar-CH), 127.5 (Ar-CH),
28.6 (Ar-CH), 133.6 (CH=CHPh), 137.0 (Ar-C), 171.7 (C(O)); m/z (ES+ mode) 239
(M + Na), 100) 455 (31); (Found: (M + Na), 239.1051. C14 Na requires M,
39.1043).
C 3 2 2 2
(125 MHz, CDCl ) 18.5 (CH ), 27.3 (CH ), 29.5 (CH C(O)), 39.3
2
1
(
16 2
H O
2
S7

6
-Allyl-3,3-dimethyltetrahydro-2H-pyran-2-one S4
O
O
S4
A solution of LDA was prepared by adding n-butyllithium (5.9 mL, 9.44 mmol, 1.2 eq,
.6 M solution in hexane) to diisopropylamine (955 mg, 9.44 mmol, 1.2 eq) in THF
25 mL) at -78 °C under N and the solution stirred for 1 hour. To this solution was
added 6-6-allyltetrahydro-2H-pyran-2-one (1.10 g, 7.87 mmol, 1 eq) dissolved in THF
10 mL) over 1 hour using a syringe pump and the resulting solution stirred for a
1
(
2
(
further 1 hour. At this point, MeI (1.39 g, 9.44 mmol, 1.2 eq) was added and the
reaction allowed to warm to room temperature over 18 hours. The reaction was
quenched by the addition of aqueous saturated NH
was separated and extracted with EtOAc (3 × 50 mL). The combined organic layers
were washed with brine (40 mL), dried (Na SO ) and concentrated in vacuo. The
4
Cl (40 mL) and the aqueous layer
2
4
crude product was subsequently dissolved in THF (10 mL) and added over 1 hour
using a syringe pump to a solution of LDA (8.23 mmol, 1.2 eq). MeI (1.17 g, 8.23
mmol, 1.2 eq) was subsequently added and the reaction allowed to warm to room
temperature over 18 hours. The reaction was quenched by the addition of aqueous
4
saturated NH Cl (40 mL) and worked up following the above procedure. Purification
by column chromatography on silica gel eluting with 30% EtOAc in petroleum ether
(
40 – 60 °C) gave the title compound (1.02 g, 6.10 mmol, 76%) as a colourless oil;
-
1
ν
max (neat)/cm 2936, 1728 (C=O), 1472, 1385, 1287, 1138, 996, 920; δ
) 1.21 (3H, s, CH ), 1.23 (3H, s, CH ), 1.55-1.76 (4H, m, 2 × CH
1H, m, CH CH CH=CH ), 2.37-2.44 (1H, m, CH CH CH=CH
H
(400 MHz,
CDCl
3
3
3
2
), 2.28-2.35
(
a
b
2
a
b
2
), 4.25-4.31 (1H, m,
S8

CH), 5.05-5.10 (2H, m, CH=CH
MHz, CDCl ) 25.3 (CH ), 27.7 (CH
), 80.7 (CH), 118.6 (CH=CH
ES+ mode) 191 ((M + Na), 100), 223 (25); (found: (M + Na), 191.1049. C10
2
), 5.75 (1H, ddt, J 17.1, 10.3, 7.0, CH=CH
), 27.8 (CH ), 34.4 (CH ), 38.0 (C), 40.3
), 132.6 (CH=CH ), 177.4 (C(O)); m/z
Na
2
); δ
C
(100
3
2
3
3
2
(
(
CH
2
CH=CH
2
2
2
16 2
H O
requires M, 191.1043).
6
-Cinnamyl-3,3-dimethyltetrahydro-2H-pyran-2-one 6b
O
O
Ph
H
6
b
A solution of LDA was prepared by adding n-butyllithium (0.21 mL, 0.49 mmol, 1.2
eq, 2.30 M solution in hexane) to diisopropylamine (51 mg, 0.49 mmol, 1.2 eq) in
2
THF (1 mL) at -78 °C under N and stirred for 1 hour. To this solution was added 6-
cinnamyltetrahydro-2H-pyran-2-one (90 mg, 0.42 mmol, 1 eq) dissolved in THF (1
mL) over 1 hour using a syringe pump and the resulting solution stirred for a further 1
hour. At this point, MeI (106 mg, 0.75 mmol, 1.5 eq) was added and the reaction
allowed to warm to room temperature over 18 hours. The reaction was quenched by
the addition of aqueous saturated NH
and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed
with brine (10 mL), dried (Na SO ) and concentrated in vacuo to yield the crude
4
Cl (10 mL) and the aqueous layer was separated
2
4
product. The crude product was subsequently dissolved in THF (1 mL) and added
over 1 hour using a syringe pump to a solution of LDA (0.23 mmol, 1.2 eq). MeI (51
mg, 0.36 mmol, 1.5 eq) was subsequently added and the reaction allowed to warm to
room temperature over 18 hours. The reaction was quenched by the addition of
4
aqueous saturated NH Cl (10 mL) and worked up following the same procedure to
S9

yield the crude product. Purification by column chromatography on silica gel eluting
with 30% EtOAc in petroleum ether (40 – 60 °C) gave the title compound (25 mg,
-
1
0
1
1
.10 mmol, 24%) as a colourless oil; νmax (neat)/cm 2928, 2843, 1724 (C=O), 1432,
375, 1276, 1029, 987; δ (400 MHz, CDCl ) 1.21 (3H, s, CH ), 1.23 (3H, s, CH ),
.59-1.83 (4H, m, 2 × CH ), 2.44-2.51 (1H, m, CH CH=CHAr), 2.53-2.60 (1H, m,
CH=CHAr), 4.32-4.39 (1H, m, CH), 6.16 (1H, dt, J 15.9, 7.3, CH=CHAr),
.42 (1H, d, J 15.9, CH=CHAr), 7.13-7.30 (5H, m, Ar-H); δ (100 MHz, CDCl ) 25.5
CH ), 27.7 (CH ), 27.8 (CH ), 34.4 (CH ), 38.1 (C), 39.6 (CH CH=CHAr), 81.0
H
3
3
3
2
a b
H
a b
CH H
6
C
3
(
(
(
(
2
3
3
2
2
CH), 124.1 (CH=CHAr), 126.2 (Ar-CH), 127.4 (Ar-CH), 128.6 (Ar-CH), 133.6
CH=CHAr), 137.1 (Ar-C), 177.5 (C(O)); m/z (ES+ mode) 267 ((M + Na), 100), 262
20 2 1
13), 245 (11); (Found: (M + Na), 267.1367. C16H O Na requires M, 267.1356).
S10

General procedure A: Olefin Cross Metathesis
(
E)-6-(3-(2-Chlorophenyl)allyl)-3,3-dimethyltetrahydro-2H-pyran-2-one 6c
2
An oven-dried 1 piece flask and condenser was thoroughly flushed with N before the
nd
addition of Grubbs 2 generation catalyst (17 mg, 0.02 mmol, 1 mol%). To this was
added 6-allyl-3,3-dimethyltetrahydro-2H-pyran-2-one (330 mg, 1.96 mmol, 1 eq)
2 2
dissolved in CH Cl (7 mL), followed by 1-chloro-2-vinylbenzene (545 mg, 3.93
mmol, 3 eq). The reaction mixture was refluxed at 40 °C for 24 hours, whilst
periodically maintaining the solvent level. Once complete, the solvent was removed in
vacuo to yield the crude product. Purification by flash chromatography on silica gel
eluting with 10% EtOAc in petroleum ether (40 – 60 °C) gave the title compound
(
2
240 mg, 0.86 mmol, 44%) as an off-white solid. The product was dissolved in Et O
with stirred with activated charcoal for 24 hours. The product was obtained was a
white solid following filtration through celite; M.p. 81 ˚C recrystallised from pentane;
-
1
ν
max (neat)/cm 2977, 1731 (C=O), 1640, 1453, 1381, 1242, 1053, 999, 927; δ
MHz, CDCl ) 1.22 (3H, s, CH ), 1.24 (3H, s, CH ), 1.64-1.85 (4H, m, 2 × CH ), 2.40-
.57 (2H, m, CH CH=CHAr), 4.32-4.38 (1H, m, CH), 6.16 (1H, dt, J 15.9, 7.2,
CH=CHAr), 6.39 (1H, d, J 15.9, CH=CHAr), 7.05-7.27 (4H, m, Ar-H); δ (100 MHz,
CDCl ) 25.5 (CH ), 27.7 (CH ), 27.8 (CH ), 34.4 (CH ), 38.1 (C), 39.6
CH CH=CHAr), 81.1 (CH), 125.7 (CH=CHAr), 126.5 (Ar-CH), 127.2 (Ar-CH),
H
(400
3
3
3
2
2
2
C
3
2
3
3
2
2
1
1
3
31.4 (Ar-CH), 132.1 (CH=CHAr), 132.9 (Ar-CH), 133.4 (Ar-CCl) 136.9 (Ar-C),
77.5 (C(O)); m/z (ES+ mode) 301 ((M + Na), 100), 191 (10); (found: (M + Na),
2
01.0970. C16H19ClO Na requires M, 301.0966).
S11

(
E)-3,3-Dimethyl-6-(3-(m-tolyl)allyl)tetrahydro-2H-pyran-2-one 6d
nd
As for general procedure A, reaction of Grubbs 2 generation catalyst (18 mg, 0.02
mmol, 1 mol%), 6-allyl-3,3-dimethyltetrahydro-2H-pyran-2-one (358 mg, 2.13 mmol,
1
eq), and 1-methyl-3-vinylbenzene (750 mg, 6.39 mmol, 3 eq), after workup and
purification by flash chromatography on silica gel eluting with 10 % EtOAc in
petroleum ether (40 – 60 °C), gave the title compound (205 mg, 0.79 mmol, 37%) as a
-
1
yellow oil; νmax (neat)/cm 2961, 1721 (C=O), 1602, 1471, 1385, 1286, 1154, 1017,
68, 775, 694; δ (400 MHz, CDCl ) 1.29 (3H, s, CH ), 1.31 (3H, s, CH ), 1.73-1.89
4H, m, 2 × CH ), 2.34 (3H, s, ArCH ), 2.49-2.68 (2H, m, CH CH=CHAr), 4.35-4.44
1H, m, CH), 6.24 (1H, dt, J 15.8, 7.2, CH=CHAr), 6.46 (1H, d, J 15.8, CH=CHAr),
.04-7.23 (4H, m, Ar-H); δ (100 MHz, CDCl ) 21.4 (Ar-CH ), 25.5 (CH ), 27.8
CH ), 27.8 (CH ), 34.4 (CH ), 38.0 (C), 39.6 (CH CH=CHAr), 81.1 (CH), 123.4
CH=CHAr), 126.9 (Ar-CH), 128.2 (Ar-CH), 128.5 (Ar-CH), 133.6 (CH=CHAr),
37.0 (Ar-C), 138.1 (2 × Ar-C), 177.4 (C(O)); m/z (ES+ mode) 281 ((M + Na), 100);
found: (M + Na), 281.1517. C17 Na requires M, 281.1512).
9
H
3
3
3
(
(
2
3
2
7
C
3
3
2
(
(
3
3
2
2
1
(
22 2
H O
(
E)-6-(3-(4-Bromophenyl)allyl)-3,3-dimethyltetrahydro-2H-pyran-2-one 6e
As for general procedure A, reaction of Grubbs 2nd generation catalyst (17 mg, 0.02
mmol, 1 mol%), 6-allyl-3,3-dimethyltetrahydro-2H-pyran-2-one (330 mg, 1.96 mmol,
1
eq), and 1-bromo-4-vinylbenzene (720 mg, 3.93 mmol, 3 eq), after workup and
S12

purification by flash chromatography on silica gel eluting with 10 % EtOAc in
petroleum ether (40 – 60 °C) gave the title compound (184 mg, 0.57 mmol, 29%) as a
-
1
yellow oil; νmax (neat)/cm 3461, 2076, 2977, 2956, 1732 (C=O), 1641, 1453, 1381,
242, 1140, 1053, 999, 927; δ (400 MHz, CDCl ) 1.20 (3H, s, CH ), 1.23 (3H, s,
CH ), 1.61-1.81 (4H, m, 2 × CH ), 2.40-2.59 (2H, m, CH CH=CHAr), 4.31-4.37 (1H,
m, CH), 6.15 (1H, dt, J 15.8, 7.2, CH=CHAr), 6.36 (1H, d, J 15.8, CH=CHAr), 7.12-
.36 (4H, m, Ar-H); δ (100 MHz, CDCl ) 25.5 (CH ), 27.7 (CH ), 27.8 (CH ), 34.4
CH ), 38.1 (C), 39.6 (CH CH=CHAr), 80.8 (CH), 121.4 (Ar-CBr), 125.1 (Ar-CH),
27.7 (CH=CHAr), 131.7 (CH=CHAr), 132.4 (Ar-CH), 136 (Ar-C), 177.3 (C(O));
1
H
3
3
3
2
2
7
C
3
2
3
3
(
2
2
1
m/z (ES+ mode) 345 ((M + Na), 60), 281 (25), 173 (100), 137 (55), 101 (70), 85 (25).
Compound was unstable to accurate mass analysis.
5
6
-Allyl-6-methyltetrahydro-2H-pyran-2-one 6f
To a flask, degassed with N
2
, was added NiI
2
(48 mg, 0.15 mmol, 2 mol%) and the
flask was cooled to 0 ˚C. SmI
2
(0.1 M in THF, 76 mL, 7.60 mmol, 4 eq) was added
and the solution stirred for 5 minutes. Methyl 5-oxohexanoate (300 mg, 1.90 mmol, 1
eq) was then added, followed immediately by the dropwise addition of allyl bromide
(
1.1 M in THF, 19 mL, 2.09 mmol, 1.1 eq) over 30 minutes. The reaction was
monitored by TLC and once complete the flask was opened to air till the reaction
mixture decolourized. This was followed by the addition of a saturated solution of
2
Rochelle salt (20 mL). The aqueous layer was separated and extracted with Et O (3 ×
5
M. Wada, M. Honna, Y. Kuramoto, N. Miyoshi, Bull. Chem. Soc. Jpn. 1997, 70, 2265.
S13

2
0 mL) and the combined organic layers were washed with brine (2 × 10 mL), dried
Na SO ) and concentrated in vacuo to yield the crude product. Purification by flash
chromatography on silica gel eluting with 30% EtOAc in petroleum ether (40 –
0 °C) gave the title compound (286 mg, 1.86 mmol, 98%) as a colourless oil; νmax
(
2
4
6
-
1
(
neat)/cm 3076, 2977, 2945, 1728 (C=O), 1640, 1453, 1380, 1359, 1328, 1298, 1242,
1
173, 1140, 1096, 1053, 999, 927, 852; δ
.65-1.71 (1H, m, 1H from CH ), 1.79-1.84 (1H, m, 1H from CH
CH C(O)), 22.44 (2H, d, J 7.3, CH CH=CH ), 2.47-2.58 (2H, m, CH
.13-5.19 (2H, m, CH=CH ), 5.82 (1H, ddd, J 14.6 10.1 7.3, CH=CH ); δ (100 MHz,
CDCl ) 16.5 (CH ), 26.3 (CH ), 29.3 (CH C(O)), 31.4 (CH ), 46.1 (CH CH=CH ),
3.6 (C), 119.4 (CH=CH ), 132.3 (CH=CH ), 171.2 (C(O)); m/z (ES+ mode) 155 ((M
H), 100), 309 (41), 177 ((M + Na), 5); (Found: (M + Na), 177.0878. C Na
H
(400 MHz, CDCl
3
) 1.39 (3H, s, CH
), 1.87-1.93 (2H, m,
C(O)),
3
),
1
2
2
CH
2
2
2
2
2
5
2
2
C
3
2
3
2
2
2
2
8
2
2
+
9 14 2
H O
requires M, 177.0886).
6
6
,6-Diallyltetrahydro-2H-pyran-2-one 6g
Glutaric anhydride (1.00 g, 8.76 mmol, 1 eq) was dissolved in dry THF (13 mL) and
cooled to 0 ˚C. Allyl magnesium chloride (8.80 mL, 8.80 mmol, 2 eq, 2 M solution in
THF) was added over 10 mins and the reaction was stirred for a further 2 hours. The
reaction was quenched with 1N HCl (20 mL) and heated to 40 ˚C for 30mins. The
aqueous layer was separated and extracted with Et
2
O (3 × 30 mL). The combined
organic layers were washed with H
2
O (10 mL), brine (10 mL), dried (Na SO ) and
2
4
6
J. Barluenga, J. R. Fernandez, J. Florez, M. Yus, Synthesis 1983, 736.
S14

concentrated in vacuo to yield the crude product. Purification by column
chromatography on silica gel eluting with 5% Et O in CHCl gave the title compound
0.14 g, 0.76 mmol, 9%) as a colourless oil; νmax (neat)/cm 2952, 1725 (C=O), 1640,
445, 1333, 1235, 1188, 1031, 996, 923; δ (400 MHz, CDCl ) 1.75 (2H, dt, J 6.6 3.8,
CH ), 1.84-1.91 (2H, m, CH ), 2.43 (4H, tt, J 7.1 1.3, 2 × CH CH=CH ) , 2.48 (2H, t,
J 6.8, CH C(O)), 5.12-5.20 (4H, m, 2 × CH=CH ), 5.81 (2H, dddd, J 17.7 10.3 7.3 7.3,
× CH=CH ); δ (100 MHz, CDCl ) 16.4 (CH ), 29.0 (CH ), 29.5 (CH C(O)), 43.5
2 × CH CH=CH ), 84.9 (C), 119.6 (2 × CH=CH ), 132.1 (2 × CH=CH ), 171.1
C(O)); m/z (ES+ mode) 203 ((M + Na), 100); (Found: (M + Na), 203.1041.
Na requires M, 203.1043).
2
3
-1
(
1
H
3
2
2
2
2
2
2
2
2
C
3
2
2
2
(
(
2
2
2
2
11 16 2
C H O
(
E)-6-Cinnamyl-6-methyltetrahydro-2H-pyran-2-one 6h
nd
As for general procedure A, reaction of Grubbs 2 generation catalyst (37 mg, 0.044
mmol, 1 mol%), 6-allyl-6-methyltetrahydro-2H-pyran-2-one (670 mg, 4.35 mmol, 1
eq), and styrene (1.36 g, 13.05 mmol, 3 eq), after workup and purification by flash
2 3
chromatography on silica gel eluting with 2% Et O in CHCl gave the title compound
-
1
(
602 mg, 2.62 mmol, 60%) as a yellow oil; νmax (neat)/cm 3476, 2958, 1724 (C=O),
1
496, 1450, 1379, 1325, 1233, 1090, 1052, 979, 923; δ
), 1.57-1.68 (2H, m, CH ), 1.75-1.86 (2H, m, CH
C(O)), 2.50 (2H, d, J 7.3, CH CH=CHPh), 6.13 (1H, dt, J 15.8 7.3, CH=CHPh),
.39 (1H, d, J 15.8, CH=CHPh), 7.09-7.30 (5H, m, Ar-H); δ (100 MHz, CDCl ) 16.6
), 45.4 (CH CH=CHAr), 84.1 (C),
H
(400 MHz, CDCl
3
) 1.34 (3H,
s, CH
3
2
2
CH C(O)), 2.35-2.46 (2H, m,
2
CH
2
2
6
C
3
(
CH
2
), 26.5 (CH
3
), 29.4 (CH
2
C(O)), 31.7 (CH
2
2
S15

1
23.8 (CH=CHAr), 126.2 (Ar-CBr), 127.5 (Ar-CH), 128.6 (Ar-CH), 134.3
CH=CHAr), 137.0 (Ar-C), 171.3 (C(O)); m/z (ES+ mode) 253 ((M + Na), 100), 483
44); (Found: (M + Na), 253.1211. C15 Na requires M, 253.1199).
(
(
18 2
H O
(
E)-6-Methyl-6-(3-(m-tolyl)allyl)tetrahydro-2H-pyran-2-one 6i
As for general procedure A, reaction of Grubbs 2nd generation catalyst (15 mg,
.0175 mmol, 1 mol%), 6-allyl-6-methyltetrahydro-2H-pyran-2-one (270 mg, 1.75
0
mmol, 1 eq), and 3-methyl-1-vinylbenzene (414 mg, 3.51 mmol, 4 eq), after workup
and purification by flash chromatography on silica gel eluting with 15% EtOAc in
petroleum ether (40 – 60 °C), gave the title compound (207 mg, 0.84 mmol, 48%) as a
-
1
colourless oil; νmax (neat)/cm 2950, 1723 (C=O), 1602, 1453, 1290, 1245, 1053; δ
H
(
400 MHz, CDCl
from CH + 2H from CH
2H, d, J 7.8, CH
3
) 1.33 (3H, s, CH
3
), 1.59-1.65 (1H, m, CH
2
), 1.73-1.85 (3H, m, 1H
2
2
), 2.26 (3H, s, ArCH
3
2
), 2.31-2.45 (2H, m, CH C(O)), 2.48
(
2
CH=CHAr), 6.11 (1H, dt, J 15.9, 7.8 CH=CHAr), 6.35 (1H, d, J
5.9, CH=CHAr), 6.97 (1H, d, J 7.31, Ar-H), 7.10 (3H, m, 3 × Ar-H); δ (100 MHz,
) 16.6 (CH ), 21.4 (Ar-CH ), 26.5 (CH ), 29.4 (CH ), 31.7 (CH ), 45.4
CH=CHAr), 84.1 (C), 123.5 (CH=CHAr), 126.8 (2 × Ar-CH), 128.3 (2 × Ar-
CH), 134.3 (CH=CHAr), 136.9 (Ar-C), 138.2 (Ar-C), 171.3 (C(O)); m/z (ES+ mode)
67 ((M + Na); (found: (M + Na), 267.1365. C16 Na requires M, 267.1356).
1
C
CDCl
3
2
3
3
2
2
(
CH
2
2
20 2
H O
(
E)-6-(3-(2,5-Dimethylphenyl)allyl)-6-methyltetrahydro-2H-pyran-2-one 6j
S16

nd
As for general procedure A, reaction of Grubbs 2 generation catalyst (17 mg, 0.02
mmol, 1 mol%), 6-allyl-6-methyltetrahydro-2H-pyran-2-one (310 mg, 2.01 mmol, 1
eq), and 1,4-dimethyl-2-vinylbenzene (664 mg, 5.03 mmol, 3 eq), after workup and
purification by flash chromatography on silica gel eluting with 30% EtOAc in
petroleum ether (40 – 60 °C), gave the title compound (194 mg, 0.74 mmol, 37%) as a
-
1
colourless oil; νmax (neat)/cm 2920, 2851, 1729 (C=O), 1455, 1378, 1239, 1132,
089, 1052, 971, 808; δ (400 MHz, CDCl ) 1.35 (3H, s, CH ), 1.62-1.68 (2H, m,
CH ), 1.76-1.88 (2H, m, CH CH C(O)), 2.22 (3H, s, Ar-CH ), 2.24 (3H, s, Ar-CH ),
.35-2.48 (2H, m, CH C(O)), 2.52 (2H, d, J 8.6, CH CH=CHAr), 5.98 (1H, dt, J 15.6
.6, CH=CHAr), 6.58 (1H, d, J 15.6, CH=CHAr), 6.89 (1H, d, J 8.9, Ar-H), 6.96 (1H,
(100 MHz, CDCl ) 16.6 (CH ), 19.4 (CH ),
C(O)), 31.7 (CH ), 45.7 (CH CH=CHAr), 84.1 (C),
1
H
3
3
2
2
2
3
3
2
7
2
2
d, J 7.8, Ar-H), 7.16 (1H, s, Ar-H); δ
C
3
2
3
2
1
1
1.0 (CH
3
), 26.5 (CH
3
), 29.4 (CH
2
2
2
24.9 (CH=CHAr), 126.2 (Ar-CH), 128.2 (Ar-CH), 130.0 (Ar-C), 130.2 (Ar-CH),
32.0 (CH=CHAr), 135.5 (Ar-C), 135.9 (Ar-C), 171.3 (C(O)); m/z (ES+ mode) 281
(
22 2
(M + Na), 100), 313 (28), 282 (19); (Found: (M + Na), 281.1512. C17H O Na
requires M, 281.1512).
(
E)-6-(3-(4-Methoxyphenyl)allyl)-6-methyltetrahydro-2H-pyran-2-one 6k
O
O
O
Me
6
k
nd
As for general procedure A, reaction of Grubbs 2 generation catalyst (5 mg, 0.0062
mmol, 1 mol%), 6-allyl-6-methyltetrahydro-2H-pyran-2-one (95 mg, 0.62 mmol, 1
eq), and 1-methoxy-4-vinylbenzene (248 mg, 1.85 mmol, 3 eq), after workup and
S17

purification by flash chromatography on silica gel eluting with 30% EtOAc in
petroleum ether (40 – 60 °C), gave the title compound (92 mg, 0.35 mmol, 57%) as a
-
1
colourless oil; νmax (neat)/cm 2925, 1733 (C=O), 1605, 1504, 1243, 1173, 1088, 1049,
1
028; δ
.82-1.94 (3H, m, 3H from CH
CH=CHAr), 2.56 (1H, d, J 7.6, CH
1H, dt, J 15.9 7.6, CH=CHAr), 6.41 (1H, d, J 15.9, CH=CHAr), 6.85 (2H, d, J 8.8,
Ar-H), 7.30 (2H, d, J 8.8, Ar-H); δ (100 MHz, CDCl ) 16.6 (CH ), 26.5 (CH ), 29.3
CH C(O)), 31.6 (CH ), 45.4 (CH CH=CHAr), 55.3 (OCH ), 84.1 (C), 113.9 (Ar-CH),
21.5 (CH=CHAr), 127.3 (Ar-CH), 129.8 (Ar-C), 133.6 (CH=CHAr), 159.1 (Ar-
COMe), 171.6 (C(O)); m/z (ES+ mode) 283 ((M + Na), 100), 543 (15), 299 (9);
H
(400 MHz, CDCl
3
) 1.41 (3H, s, CH
), 2.42-2.52 (2H, m, CH
CH=CHAr), 3.81 (3H, s, OCH
3
), 1.67-1.73 (1H, m, 1H from CH
C(O)), 2.55 (1H, d, J 7.6,
), 6.05
2
),
1
2
2
CH
a
H
b
a
H
b
3
(
C
3
2
3
(
2
2
2
3
1
(
20 3
Found: (M + Na), 283.1296. C16H O Na requires M, 283.1305).
(
E)-6-(3-(4-Bromophenyl)allyl)-6-methyltetrahydro-2H-pyran-2-one 6l
nd
As for general procedure A, reaction of Grubbs 2 generation catalyst (7 mg, 0.0085
mmol, 0.5 mol%), 6-allyl-6-methyltetrahydro-2H-pyran-2-one (261 mg, 1.69 mmol, 1
eq), and 1-bromo-4-vinylbenzene (950 mg, 5.19 mmol, 3 eq), after workup and
purification by flash chromatography on silica gel eluting with 5% Et
2
O in CHCl
3
,
-
gave the title compound (186 mg, 0.60 mmol, 36%) as a colourless oil; νmax (neat)/cm
1
2
935, 1726 (C=O), 1489, 1359, 1290, 1230, 1068, 1006; δ
3H, s, CH ), 1.69-1.75 (1H, m, CCH ), 1.81-1.85 (1H, m, CCH
m, CH ), 2.42-2.53 (2H, m, CH
H
(400 MHz, CDCl
), 1.86-1.95 (2H,
CH=CHAr), 6.21 (1H,
3
) 1.41
(
3
a
H
b
a b
H
2
2
C(O)), 2.55-2.61 (2H, m, CH
2
S18

dt, J 15.9 7.6, CH=CHAr), 6.41 (1H, d, J 15.9, CH=CHAr), 7.23 (2H, d, J 8.3, Ar-H),
.43 (2H, d, J 8.3, Ar-H); δ (100 MHz, CDCl ) 16.9 (CH ), 26.8 (CH ), 29.6
CH C(O)), 32.1 (CH ), 45.7 (CH CH=CHAr), 84.1 (C), 121.5 (Ar-CBr), 125.0
7
C
3
2
3
(
(
(
2
2
2
CH=CHAr), 128.0 (Ar-CH), 131.9 (Ar-CH), 133.4 (CH=CHAr), 136.2 (Ar-C), 171.4
C(O)); m/z (ES+ mode) 331 ((MBr79 + Na), 100), 333 ((MBr81 + Na), 100), 349 (16),
3
47 (13), 233 (13), 235 (9); (Found: (M + Na), 331.0302. C15
31.0304).
17 2
H O BrNa requires M,
3
(
E)-6-(3-(2-Chlorophenyl)allyl)-6-methyltetrahydro-2H-pyran-2-one 6m
nd
As for general procedure A, reaction of Grubbs 2 generation catalyst (9.6 mg,
0
.0113 mmol, 1 mol%), 6-allyl-6-methyltetrahydro-2H-pyran-2-one (174 mg, 1.13
mmol, 1 eq), and 1-chloro-2-vinylbenzene (313 mg, 2.23 mmol, 2 eq), after workup
and purification by flash chromatography on silica gel eluting with 30% EtOAc in
petroleum ether (40 – 60 °C), gave the title compound (216 mg, 0.82 mmol, 72%) as a
-
1
white powder; νmax (neat)/cm 2936, 2881, 1707 (C=O), 1587, 1467, 1384, 1325,
1
301, 1286, 1237, 1090, 967, 802, 689; δ
.72-1.78 (2H, m, CH ), 1.85-1.98 (2H, m, CH
C(O)), 2.64 (1H, d, J 8.8, CH CH=CHAr), 6.22 (1H, dt, J 15.9, 7.6, CH=CHAr),
.87 (1H, d, J 15.9 CH=CHAr), 7.37 (1H, dd, J 7.8 1.5, Ar-H), 7.53 (1H, dd, J 7.6 1.8,
Ar-H), 7.17-7.26 (2H, m, Ar-H); δ (100 MHz, CDCl ) 16.6 (CH ), 26.5 (CH ), 29.4
CH=CHAr), 83.9 (C), 126.9 (CH=CHAr), 127.0
H
(400 MHz, CDCl
3 3
) 1.45 (1H, s, CH ),
1
2
2
CH C(O)), 2.45-2.61 (2H, m,
2
CH
2
2
6
C
3
2
3
(
(
2 2 2
CH C(O)), 31.8 (CH ), 45.5 (CH
Ar-CH), 127.0 (Ar-CH), 128.5 (Ar-CH), 129.6 (Ar-CH), 130.5 (CH=CHAr), 132.7
S19

(
Ar-CCl) 135.2 (Ar-C), 171.1 (C(O)); m/z (ES+ mode) 287 (M + Na), 90), 196 (100),
2
89 (28), 204 (13), 194 (9); (Found: (M + Na), 287.0812. C15
87.0809).
17 2 1 1
H O Cl Na requires M,
2
(
E)-6-(4-Chlorobut-2-en-1-yl)-6-methyltetrahydro-2H-pyran-2-one S5
nd
As for general procedure A, reaction of Grubbs 2 generation catalyst (27 mg, 0.33
mmol, 5 mol%), 6-allyl-6-methyltetrahydro-2H-pyran-2-one (100 mg, 0.65 mmol, 1
eq) and allyl chloride (0.22 ml, 2.60 mmol, 4 eq), after workup and purification by
o
flash chromatography on silica gel with 20% EtOAc in petroleum ether (40 – 60 C),
gave the title compound (47 mg, 23.2 mmol, 36%) as a yellow oil and as a 6:1 E:Z
-
1
mixture of geometric isomers; νmax (neat)/cm 2923, 2360, 2340, 1725 (C=O), 1236,
1
1
1
092, 1053, 926, 668; δ
.40 (3H, s, CH from minor isomer), 1.65-1.83 (2H, m, CH
.95 (2H, m, CH CH C(O)), 2.39-2.47 (2H, m, CH CH=CHCH
C(O)), 4.06 (2H, d, J 6.3, CH Cl from major isomer), 4.10 (2H, d, J 8.1,
Cl from minor isomer), 5.74 (1H, dt, J 15.4, 6.3, CH=CHCH Cl), 5.80 (1H, dt, J
5.4, 6.8, CH=CHCH Cl); δ (100 MHz, CDCl ) 16.5 (CH CH C(O)), 26.3 (CH ),
9.3 (CH C(O)), 31.7 (CH CH CH C(O)), 44.3 (CH CH=CHCH Cl), 44.7 (CH Cl),
3.6 (C), 129.1 (CH=CHCH Cl), 130.6 (CH=CHCH Cl), 171.0 (C(O)); m/z (ES+
ClNa requires M,
H
(400 MHz, CDCl
3
) 1.38 (3H, s, CH
3
from major isomer),
CH CH C(O)), 1.84-
Cl ), 2.47-2.59 (2H,
3
2
2
2
2
2
2
2
m, CH
2
2
CH
2
2
1
2
8
2
C
3
2
2
3
2
2
2
2
2
2
2
2
2
mode) 225 ((M+Na), 100); (Found: (M + Na), 203.0828. C10
03.0833).
16 2
H O
2
S20

(
E)-6-Methyl-6-(4-(phenylthio)but-2-en-1-yl)tetrahydro-2H-pyran-2-one 6n
O
O
SPh
Me
6
n
To a stirred solution of (E)-6-(4-chlorobut-2-en-1-yl)-6-methyltetrahydro-2H-pyran-
-one (63 mg, 0.31 mmol, 1 eq) in acetone (2 ml) was added K CO (52 mg, 0.37
2
2
3
mmol, 1.2 eq), NaI (12 mg, 0.08 mmol, 25 mol%) and thiophenol (0.44 ml, 0.37
mmol, 1.2 eq). The reaction was stirred at room temperature for 18 hours. The crude
reaction mixture was concentrated in vacuo to yield the crude product as a 6:1 E:Z
mixture of geometric isomers. Purification by column chromatography on silica gel
o
with 30% EtOAc in petroleum ether (40 – 60 C), gave the title compound (56 mg,
0
ν
6
.20 mmol, 68 %) as a yellow oil and as a 13:1 E:Z mixture of geometric isomers;
-
1
max (neat)/cm 2922, 2360, 2340, 1719 (C=O), 1437, 1235, 1088, 1052, 969, 741,
90, 668; δ (400 MHz, CDCl ) 1.14 (3H, s, CH from major isomer), 1.25 (3H, s,
from minor isomer), 1.32-1.49 (2H, m, CH CH C(O)), 1.59-1.80 (2H, m, CH ),
.19-2.32 (1H, m, 1H from CH C(O)), 2.25 (2H, d, J 7.3, CH CH=CHCH SPh),
.39 (1H, dt, J 18.4, 6.6, 1H from CH C(O)), 3.46 (2H, d, J 6.8, CH SPh, from
SPh from minor isomer), 5.41 (1H, dt, J 15.1,
SPh from major isomer), 5.51 (1H, dt, J 15.4, 6.8, CH=CHCH SPh
from major isomer), 5.62-5.66 (1H, m, CH=CHCH SPh from minor isomer), 5.66-
SPh from minor isomer), 7.08-7.17 (1H, m, Ar-CH), 7.17-
.23 (2H, m, Ar-CH), 7.23-7.32 (2H, m, Ar-CH); δ (100 MHz, CDCl ) 16.5 (CH ),
6.2 (CH ), 29.2 (CH C(O)), 31.1 (CH CH C(O)), 31.6 (CH=CHCH SPh from minor
SPh from major isomer), 44.6 (CH CH=CHCH SPh), 83.7
H
3
3
CH
3
2
2
2
2
2
a
H
b
2
2
a
H
b
2
major isomer), 3.49 (2H, d, J 7.4, CH
2
7
.3, CH=CHCH
2
2
2
5
7
2
.71 (1H, m, CH=CHCH
2
C
3
2
3
2
2
2
2
isomer), 36.3 (CH=CHCH
2
2
2
(
C), 126.4 (Ar-CH), 127.4 (CH=CHCH
2
2
SPh), 128.9 (Ar-CH), 130.3 (CH=CHCH SPh
S21

from major isomer), 130.5 (Ar-CH), 135.5 (Ar-C), 171.2 (C(O)); m/z (ES+ mode) 299
M + Na), 100), (Found: (M 299.1079. C16 SNa requires M, 299.107880).
(
20 2
H O
S22

2 2
General procedure B: SmI -H O mediated cyclization
rac-(1R, 2R ,4S)-2-Benzylcycloheptane-1,4-diol 8a
To a stirred solution of SmI
room temperature was added distilled H
change from blue to red at which point a solution of 6-cinnamyltetrahydro-2H-pyran-
-one (66 mg, 0.31 mmol, 1 eq) in THF (4 mL) was added quickly and the flask was
sealed under N . The reaction was left to stir until decolourization had occurred. The
reaction was quenched by opening the flask to air and by adding aqueous saturated
sodium potassium tartrate (15 mL). The aqueous layer was extracted with Et O (3 ×
5 mL), and the organic extracts combined, dried (Na SO ) and concentrated in vacuo
2
(0.1 M in THF, 21 mL, 2.14 mmol, 7 eq) under N
2
at
2
O (5.30 mL). This resulted in a colour
2
2
2
1
2
4
to yield the crude product. Purification by column chromatography on silica gel
eluting with 60% EtOAc in petroleum ether (40 – 60 °C), gave the title compound (37
-
1
mg, 0.17 mmol, 55%) as a colourless oil; νmax (neat)/cm 3360 (OH), 2925, 2852,
1
491, 1453, 1320, 1026, 984, 747, 699; δ
.3, CHCH CHOH), 1.42-1.48 (1H, m, 1H from CH
), 1.81-1.92 (1H, m, CH CH CHOHCH
CHOH), 2.15-2.22 (1H, m, CH from major diastereoisomer),
.32-2.43 (1H, m, CH from minor diastereoisomer), 2.52 (1H, dd, J 13.6, 8.3,
Ar from major diastereoisomer), 2.70 (1H, dd, J 13.6, 7.3, CH Ar from
major diastereoisomer), 2.84 (1H, dd, J 13.4, 5.8, CH Ar from minor
diastereoisomer), 3.01 (1H, dd, J 13.4, 4.5, CH Ar from minor diastereoisomer),
.82 (1H, dt, J 4.8, 1.5, CHCHOH from major diastereoisomer), 3.86 (1H, dt, J 4.5,
H
(400 MHz, CDCl
3
) 1.31 (1H, br dd, J 15.1
CHOHCH ), 1.62-1.71
), 2.05 (1H, ddd, J
4
a
H
b
a
CH
b
2
(
4H, m, 4H from 2 × CH
2
a
b
2
1
a b
4.9, 5.6, 4.3, CHCH H
2
CH
a
H
b
a b
H
a
H
b
a b
H
3
S23

1
7
3
.3, CHCHOH from minor diastereoisomer), 3.95-4.00 (1H, m, CH
.24 (5H, m, Ar-H); δ (100 MHz, CDCl ) for major diastereoisomer: 18.3 (CH
4.5 (CH CHCHOH), 36.9 (CH ), 37.8 (CH ), 38.5 (CH), 40.2 (CH Ar), 69.3
2
CHOH), 7.11-
C
3
2
),
2
2
2
2
(
CHOH), 71.1 (CHOH), 126.0 (Ar-CH), 128.4 (Ar-CH), 129.2 (Ar-CH), 140.9 (Ar-
C); m/z (ES+ mode) 243 ((M + Na), 100), 238 (21); (Found: (M + Na), 243.1354.
Na requires M, 243.1356).
14 20 2
C H O
rac-(1S,2R,4S)-2-Benzyl-7,7-dimethylcycloheptane-1,4-diol 8b
As for general procedure B, reaction of 6-cinnamyl-3,3-dimethyltetrahydro-2H-pyran-
2
-one (25 mg, 0.10 mmol, 1 eq) with SmI
2
(0.1 M in THF, 8.2 mL, 0.82 mmol, 8 eq)
and H O (1.50 mL) after workup and purification by column chromatography on
2
silica gel eluting with 30% EtOAc in petroleum ether (40 – 60 °C) gave the title
compound (21 mg, 0.085 mmol, 83%) as a colourless oil and as a 9:2 mixture of
-
1
diastereoisomers; νmax (neat)/cm 3418 (OH), 2925, 2863, 1453, 1359, 1285, 1029,
87, 700; Major Diastereoisomer: δ (400 MHz, CDCl ) 0.74 (3H, s, CH ), 0.84 (3H,
s, CH ), 1.18 (1H, dd, J 14.4, 8.1, CCH ), 1.29 (1H, dt, J 14.9, 4.3, CHCH ),
.43 (1H, dd, J 14.4, 12.1, CCH ), 1.50-1.57 (1H, m, CH CHOH), 1.68-1.75 (1H,
m, CH CHOH), 2.09 (1H, ddd, J 14.9, 10.6, 5.8, CHCH ), 2.22-2.30 (1H, m,
CH), 2.59 (2H, d, J 7.6, CH Ar), 3.13 (1H, s, CHCHOH), 3.92-3.98 (1H, m,
CH CHOH), 7.10-7.23 (5H, m, Ar-H); δ (100 MHz, CDCl ) 25.6 (CH ), 28.9 (CH ),
1.2 (CH CHOH), 32.4 (CH C), 35.0 (CH), 36.3 (CHCH ), 37.5 (C), 42.1 (CH Ar),
0.6 (CHCHOH), 79.8 (CH
9
H
3
3
3
a
H
b
a b
H
1
a
H
b
a b
H
a
H
b
a b
H
2
2
C
3
3
3
3
7
2
2
2
2
2
CHOH), 126.0 (Ar-CH), 128.4 (Ar-CH), 129.1 (Ar-CH),
S24

1
40.9 (ArC); m/z (ES+ mode) 271 ((M + Na), 100), 269 (49); (Found: (M + H),
49.1850. C16 requires M, 249.1849).
2
25 2
H O
rac-(1S, 2R, 4S)-2-(2-Chlorobenzyl)-7,7-dimethylcycloheptane-1,4-diol 8c
As for general procedure B, reaction of (E)-6-(3-(2-chlorophenyl)allyl)-3,3-
dimethyltetrahydro-2H-pyran-2-one (29 mg, 0.105 mmol, 1 eq) with SmI
THF, 8.40 mL, 0.84 mmol, 8 eq) and H O (1.50 mL), after purification by column
chromatography on silica gel eluting with 5 % Et O in CHCl gave the title compound
24 mg, 0.086 mmol, 82%) as a colourless oil and as a 5:3 mixture of
2
(0.1 M in
2
2
3
(
-
1
diastereoisomers; νmax (neat)/cm 3393 (OH), 2928, 1474, 1388, 992, 943, 754, 680;
For major diastereoisomer: δ (400 MHz, CDCl ) 0.71 (3H, s, CH ), 0.85 (3H, s,
CH ), 1.14 (2H, m, CH CH CHOH), 1.29 (1H, dt, J 14.6, 4.5, CH CH CH CHOH),
.45 (1H, dd, J 14.6, 12.3, CH CH CH CHOH), 1.50- 1.56 (1H, m,
CHOHCH CH CH), 2.08 (1H, ddd, J 14.6, 10.6, 5.8, CHOHCH CH CH), 2.32-2.39
1H, m, CHCH Ar), 2.64 (1H, dd, J 13.4, 7.3, CH CH Ar), 2.75 (1H, dd, J 13.4, 7.8
CH CH Ar ), 3.11 (1H, s, CHCHOH), 3.93- 3.99 (1H, m, CH CHOH), 7.05-7.27 (4H,
m, Ar-H); δ (100 MHz, CDCl ) 25.5 (CH ), 28.9 (CH ), 31.2 (CH CHOH), 32.6
C), 33.6 (CH), 36.4 (CHCH ) 37.4 (C), 39.8 (CH Ar), 70.7 (CHCHOH), 80.2
CHOH), 126.6 (Ar-CH), 127.5 (Ar- CH), 129.6 (Ar-CH), 131.5 (Ar-CH), 134.4
H
3
3
3
2
2
2
a
b
1
2
a
b
a
b
a
b
(
2
a
b
a
b
2
C
3
3
3
2
(
(
(
(
CH
2
2
2
CH
2
Ar-CCl) 138.5 (Ar-C); m/z (ES+ mode) 305 ((M + Na), 90), 255 (40), 193 (50);
found: (M + Na), 305.1287. C16 requires M, 305.1279).
H23ClO
2
S25

rac-(1S, 2R, 4S)-7,7-Dimethyl-2-(3-methylbenzyl)cycloheptane-1,4-diol 8d
As for general procedure B, reaction of (E)-3,3-dimethyl-6-(3-(m-
tolyl)allyl)tetrahydro-2H-pyran-2-one (48 mg, 0.186 mmol, 1 eq) with SmI
THF, 14.80 mL, 1.49 mmol, 8 eq) and H O (2.65 mL), purification by column
chromatography on silica gel eluting with 5 % Et O in CHCl , gave the title
compound (33 mg, 0.129 mmol, 69%) as a colourless oil and as a 4:3 mixture of
2
(0.1 M in
2
2
3
-
1
diastereoisomers; νmax (neat)/cm 3428 (OH), 2959, 2868, 1704 (C=O), 1468, 1446,
1
384, 1083, 1049, 781, 702, 665; For major diastereoisomer: δ
.64 (3H, s, CH ), 0.96 (3H, s, CH ), 1.16-1.23 (2H, m, CH CH
CH CHOH), 1.45 (1H, apparent dt, J 14.8, 3.2, CHCH
1H, d, J 14.8, CHCH CH CHOH), 2.22 (Ar-CH ), 2.24-2.30 (1H, m, CH), 2.43 (1H,
CH Ar), 2.94 (1H, dd, J 13.4, 8.6, CH CH Ar), 3.44-3.53 (1H, m,
CHOH), 3.98-4.01 (1H, m, CHOH), 6.87-7.07 (4H, m, Ar-H); δ (100 MHz, CDCl
CHOH), 30.8 (CH CH CHOH),
CHOH), 43.6 (CHOH), 47.3 (C(CH ), 66.9
H
(400 MHz, CDCl
CHOH), 1.26-1.35
CH CHOH), 1.74
3
)
0
3
3
2
2
(
(
2H, m, CH
2
2
a
b
a
b
3
dd, J 13.4, 6.0, CH
a
b
a
b
C
3
)
2
1.4 (Ar-CH
3
), 22.8 (CH
3
), 26.4 (CH
3
), 29.6 (CH
2
2
2
3
7.5 (C), 38.0 (CH
2
Ar), 40.9 (CHCH
2
3 2
)
(
COH), 126.3 (Ar-CH), 126.8 (Ar-CH), 128.1 (Ar-CH), 130.1 (Ar-CH), 137.7 (Ar-C),
1
40.2 (Ar-C); m/z (ES+ mode) 285 ((M + Na), 30), 283 (100); (found: M + Na),
85.1821. C17 Na requires M, 285.1826).
2
26 2
H O
S26

rac-(1S,2R,4S)-2-(4-Bromobenzyl)-7,7-dimethylcycloheptane-1,4-diol 8e
As for general procedure B, reaction of (E)-6-(3-(4-bromophenyl)allyl)-3,3-
dimethyltetrahydro-2H-pyran-2-one (25 mg, 0.08 mmol, 1 eq) with SmI
THF, 6.10 mL, 0.62 mmol, 8 eq) and H O (1.10 mL), purification by column
chromatography on silica gel eluting with 5 % Et O in CHCl , gave the title
compound (19 mg, 0.059 mmol, 78%) as a colourless oil and as a 11:7 mixture of
2
(0.1 M in
2
2
3
-
1
diastereoisomers; νmax (neat)/cm 3379 (OH), 2930, 2852, 1700, 1558, 1485, 1454,
287, 1021; For major diastereoisomer: δ (400 MHz, CDCl ) 0.73 (3H, s, CH ), 0.84
3H, s, CH ), 1.25 (2H, m, CH ), 1.44 (1H, m, CHCH CH ), 1.49-1.54 (1H, m,
CHOH), 1.68-1.75 (1H, m, CH CH CHOH), 2.03-2.11 (1H, m, CHCH CH ),
Ar), 3.08 (1H, s, CHCHOH), 3.92-3.98 (1H,
CHOH), 6.99-7.32 (4H, m, Ar-H); δ (100 MHz, CDCl ) 25.5 (CH ), 28.3
), 31.1 (CH ), 32.2 (CH ), 34.8 (CH), 36.1 (CHCH ), 37.5 (C), 41.4 (CH Ar),
0.4 (CHCHOH), 79.6 (CH CHOH), 119.7 (Ar-CBr), 130.9 (Ar-CH), 131.4 (Ar-CH),
1
H
3
3
(
3
2
a
b
CH
a
H
b
a
b
a
b
2
.18-2.25 (1H, m, CH), 2.54 (2H, m, CH
m, CH
CH
2
2
C
3
3
(
3
2
2
2
2
7
1
2
39.9 (Ar-C); Mass spectra data could not be obtained for the molecular ion.
S27

General procedure C: SmI
2
-H
2
O mediated cyclization followed by DMP
oxidation
rac-(1R,5S)-5,7-Dimethyl-8-oxabicyclo[3.2.1]octan-1-ol 9f
To a stirred solution of SmI
2
(0.1 M in THF, 13.0 mL, 1.30 mmol, 8 eq) under N
2
at
room temperature was added distilled H
2
O (2.30 mL). This resulted in a colour
change from blue to red at which point a solution of 6-allyl-6-methyltetrahydro-2H-
pyran-2-one (25 mg, 0.16 mmol, 1 eq) in THF (2 mL) was added quickly and the
2
flask was sealed under N . The reaction was left to stir until decolourization had
occurred. The reaction was quenched by opening the flask to air and by adding
aqueous saturated sodium potassium tartrate (15 mL). The aqueous layer was
extracted with Et
and concentrated in vacuo to yield the crude diol. The crude diol was dissolved in dry
CH Cl (2 mL), cooled to 0 ˚C and Dess-Martin Periodinane (103 mg, 0.24 mmol, 1.5
2 2 4
O (3 × 15 mL), and the organic extracts combined, dried (Na SO )
2
2
eq) was added. The reaction was stirred for 3 hours whilst allowing to warm to room
temperature. The reaction was then quenched by the addition of a saturated solution of
Na
was extracted with Et
combined, dried (Na SO
Purification by column chromatography on silica gel eluting with 30% Et
gave the title compound (19 mg, 0.12 mmol, 75%) as a colourless oil and as a 1:1
2
S
2
O
3
(2 mL) and NaHCO
O (3 × 20 mL), washed with brine and the organic extracts
) and concentrated in vacuo to yield the crude product.
O in CHCl
3
(2 mL), whilst stirring for 30 min. The aqueous layer
2
2
4
2
3
-
1
mixture of diastereoisomers; νmax (neat)/cm 3397 (OH), 2961, 2873, 1450, 1376,
1
H 3
227, 1205, 1112, 1030, 952, 922, 872, 792; δ (400 MHz, CDCl ) 0.93 (3H, d, J 6.8,
S28

CHCH
.20-1.26 (1H, m, CH
diastereoisomer), 1.32 (3H, s, CH
CHCH from 1 diastereoisomer), 1.35-1.43 (1H, m, CH
diastereoisomer), 1.40-1.45 (2H, m, CHCH from 1 diastereoisomer and CHCH
from 1 diastereoisomer), 1.51-1.60 (1H, m, CHCH from 1 diastereoisomer), 1.63-
.69 (2H, m, CH COMe from 1 diastereoisomer), 1.72-1.76 (2H, m, CH ), 1.85-1.88
CH COMe from 1 diastereoisomer), 1.97-2.02 (1H, m, CH from 1 diastereoisomer),
.05-2.13 (2H, m, 1H from CH from 1 diastereoisomer + 1H from CH CO(OH)
CO(OH) from 1
from 1 diastereoisomer), 17.4
from 1 diastereoisomer), 18.8 (CH from
), 30.3 (CHCH from 1 diastereoisomer), 30.9
COMe from 1 diastereoisomer), 35.4 (CHCH from 1 diastereoisomer), 35.7
3
from 1 diastereoisomer), 1.03 (3H, d, J 7.1, CHCH
CO(OH) from 1 diastereoisomer), 1.29 (3H, s, CH
from 1 diastereoisomer), 1.34-1.35 (1H, m,
CO(OH) from 1
3
from 1 diastereoisomer),
1
a
H
b
3
from 1
3
a
H
b
a b
H
a
H
b
a b
H
a
H
b
1
2
2
(
2
2
a b
H
from 1 diastereoisomer), 2.12-2.19 (1H, m, 1H from CH
diastereoisomer); δ (100 MHz, CDCl ) 13.0 (CHCH
CHCH from 1 diastereoisomer), 18.7 (CH
diastereoisomer), 27.2 (CH
a b
H
C
3
3
(
3
2
2
1
3
2
(
(
(
(
(
(
(
CH
2
2
2
2
2
CH
CH
CH
COMe from 1 diastereoisomer), 38.5 (CH from 1 diastereoisomer), 41.5
CO(OH) from 1 diastereoisomer), 43.4 (CH from 1 diastereoisomer), 44.3
CO(OH) from 1 diastereoisomer), 65.8 (COMe from 1 diastereoisomer), 79.2
COMe from 1 diastereoisomer), 104.1 (CO(OH) from 1 diastereoisomer), 105.1
CO(OH) from 1 diastereoisomer); m/z (ES+ mode) 179 ((M + Na), 100), 195 (28);
9 16 2
Found: (M + Na), 179.1039. C H O Na requires M, 179.1043).
rac-(1R, 5R)-5-Allyl-7-methyl-8-oxabicyclo[3.2.1]octan-1-ol 9g
OH
O
9
g
S29

As for general procedure C, reaction of 6,6-diallyltetrahydro-2H-pyran-2-one (26 mg,
.14 mmol, 1 eq) with SmI (0.1 M in THF, 12.0 mL, 1.16 mmol, 8 eq) and H O (2.10
0
2
2
mL) after workup gave the crude diol. Following oxidation of the crude reaction
mixture using Dess-Martin Periodinane (89 mg, 0.21 mmol, 1.5 eq) gave after workup
and purification by column chromatography on silica gel eluting with 30% Et
2
O in
CHCl gave the title compound (24 mg, 0.13 mmol, 93%) as a colourless oil and as a
3
-1
1
:1 mixture of diastereoisomers; (neat)/cm 3391 (OH), 2943, 1640, 1446, 1356,
221, 1089, 1047, 975, 912; δ (400 MHz, CDCl ) 0.98 (3H, d, J 7.1, CH from 1
from 1 diastereoisomer), 1.28 (1H, dd, J
from 1 diastereoisomer), 1.32-1.37 (1H, m, CHCH from 1
diastereoisomer), 1.39-1.51 (2H, m, 2H from CH from both diastereoisomers), 1.58-
.69 (2H, m, 2H from CH from both diastereoisomers), 1.71-1.78 (2H, m, 2H from
CH from both diastereoisomers), 1.96 (1H, dd, J 12.9, 9.1, CHCH from 1
diastereoisomer), 2.04 (2H, m, 1H from CH from 1 diastereoisomer + 1H from
CHCH from 1 diastereoisomer), 2.09 (1H, m, CH from 1 diastereoisomer), 2.33
2H, dd, J 7.3, 3.3, CH CH=CH from 1 diastereoisomer), 2.36 (2H, dd, J 7.3, 4.0,
CH CH=CH from 1 diastereoisomer), 2.63 (1H, s, OH from 1 diastereoisomer), 2.74
1H, s, OH from 1 diastereoisomer), 5.05-5.12 (2H, m, CH=CH
diastereoisomers), 5.84 (1H, ddt, J 15.6, 10.9, 7.3, CH=CH
diastereoisomers); δ (100 MHz, CDCl ) 13.0 (CH
CH from 1 diastereoisomer), 18.4 (CH from 1 diastereoisomer), 18.6 (CH
1
H
3
3
diastereoisomer), 1.11 (3H, d, J 6.8, CH
3
1
2.9, 7.1, CHCH
a
H
b
a b
H
2
1
2
2
a b
H
a
H
b
(
2
2
2
2
(
2
from both
from both
2
C
3
3
from 1 diastereoisomer), 17.1
from 1
(
3
2
2
diastereoisomer), 31.2 (CH
2
2
from 1 diastereoisomer), 33.6 (CH
2
2
from 1
from 1
from 1
diastereoisomer), 33.7 (CH
from 1 diastereoisomer), 35.8 (CH
diastereoisomer), 38.0 (CH from 1 diastereoisomer), 39.1 (CHCH
2
diastereoisomer), 41.7 (CHCH
2
from 1 diastereoisomer), 43.1 (CH from 1
S30