Synthesis of dihydrooxepin models related to the antitumor antibiotic MPC1001

Article abstract of DOI:10.1021/ol071147z

4-Hydroxy-L-proline was converted into the tetrahydrooxepino[4,3-b]pyrrole ring system characteristic of the potent antitumor agent MPC1001. Key steps were regioselective formation of a vinylogous amide by use of Bredereck's reagent and acid-induced cyclization of an alcohol onto the carbon-carbon double bond of that amide by addition-elimination to generate the seven-membered oxacyclic subunit. American Chemical Society.

Full text of DOI:10.1021/ol071147z

SUPPORTING INFORMATION
Synthesis of dihydrooxepin models related to the antitumor antibiotic MPC1001
Jianbiao Peng and Derrick L. J. Clive*
Chemistry Department, University of Alberta, Edmonton, Alberta T6G 2G2, Canada
E-mail: derrick.clive@ualberta.ca
Experimental procedures
S2
NMR spectra of 8, precursor to 9, 9-15, 16a, 16b, 17, 18, 19a, 19b, 20, 21, 22a,
22b, 23a, 23b, 24
S17

S2
14
(2S,4R)-4-Hydroxypyrrolidine-2-carboxylic Acid Methyl Ester Hydrochloride (6).
OH
OH
+
N
Cl-
HO2C
MeO2C
N
H
H
H
5
6
SOCl (4 mL, 54.7 mmol) was added dropwise to a stirred and cooled (0 °C) solution of
2
trans-4-hydroxy-L-proline (6.0 g, 45.7 mmol) in MeOH (80 mL). After 30 min, the cold bath
was removed and stirring was continued for 6 h. Evaporation of the solvent gave ester
hydrochloride 6 as a white solid (8.3 g, 100%), which was used for next step without further
14b
purification. The material had: mp 165-167 °C (lit. 171-172 °C).
(2S,4R)-4-Hydroxypyrrolidine-1,2-dicarboxylic Acid 1-tert-Butyl Ester 2-Methyl
14
Ester (7).
OH
OH
+
N
Cl-
MeO2C
MeO2C
N
H
H
Boc
6
7
Boc O (12.0 g, 54.8 mmol) was added to a stirred and cooled (0 °C) solution of ester
2
hydrochloride 6 (8.3 g, 45.7 mmol) and Et N (14.0 mL, 100 mmol) in CH Cl (100 mL). After
3
2
2
20 min, the cold bath was removed and stirring was continued for 2 h. The reaction mixture was
diluted with CH Cl (100 mL) and washed with hydrochloric acid (1 M, 60 mL). The organic
2
2
extract was washed with water, saturated aqueous NaHCO , and brine, dried (MgSO ) and
3
4
evaporated to afford crude alcohol 7 (10.8 g, 96%), which was used directly in the next step:
-1 1
FTIR (CDCl , cast) 3438, 2978, 1750, 1701 cm ; H NMR (500 MHz, CDCl ) δ 1.32-1.42 (m,
3
3
9 H), 2.02-2.14 (m, 1 H), 2.22-2.40 (m, 2 H), 3.42-3.62 (m, 2 H), 3.76 (s, 3 H), 4.38-4.52 (m, 2
13
H); C NMR (125 MHz, CDCl ) δ 28.2 (q), 28.4 (q), 38.5 (t), 39.1 (t), 45.9 (t), 52.0 (q), 54.7
3
(t), 57.5 (d), 57.9 (d), 69.4 (d), 70.2 (d), 80.3 (s), 153.9 (s), 173.6 (s); exact mass (electrospray)
m/z calcd for C H NNaO (M + Na) 268.11554, found 268.11563.
11 19
5
(2S,4R)-4-[(Triisopropylsilyl)oxy]-1,2-pyrrolidinedicarboxylic Acid 1-tert-Butyl
15
Ester 2-Methyl Ester (8).

S3
OH
OSiPr-i3
MeO2C
MeO2C
N
N
Boc
Boc
7
8
i-Pr SiCl (8.4 mL, 39.2 mmol) was added to a stirred solution of alcohol 7 (8.0 g, 32.6
3
mmol) and imidazole (4.5 g, 65.3 mmol) in CH Cl (100 mL), and stirring was continued for 48
2
2
h. The mixture was diluted with CH Cl (50 mL) and washed with hydrochloric acid (1 M, 40
2
2
mL). The organic extract was washed with water, saturated aqueous NaHCO and brine, dried
3
(MgSO ) and evaporated. Flash chromatography of the residue over silica gel, using 1:10
4
EtOAc-hexane, gave silyl ether 8 (12.3 g, 94%) as an oil: FTIR (CDCl , cast) 2945, 2868, 1754,
3
-1 1
1707 cm ; H NMR (500 MHz, CDCl ) δ 1.02 (s, 21 H), 1.40-1.42 (m, 9 H), 2.00-2.08 (m, 1
3
H), 2.10-2.12 (m, 1 H), 3.38-3.42 (m, 1 H), 3.58-3.64 (m, 1 H), 3.78 (s, 3 H), 4.35-4.42 (m, 1 H),
13
4.52 (s, 1 H); C NMR (100 MHz, CDCl ) δ 12.0, 17.9, 28.3, 39.2, 40.1, 51.9, 52.1, 54.8, 55.2,
3
57.7, 58.1, 69.9, 70.7, 80.0, 153.8, 173.7; exact mass (electrospray) m/z calcd for C H NO Si
20 40
5
402.26703, found 402.26746.
(2S,4R)-2-Formyl-4-[(triisopropylsilyl)oxy]pyrrolidine-1-carboxylic Acid tert-Butyl
Ester (9).
(a) (2S,4R)-2-Hydroxymethyl-4-[(Triisopropylsilyl)oxy]pyrrolidine-1-carboxylic Acid tert-
Butyl Ester.
OSiPr-i3
OSiPr-i3
HO
MeO2C
N
N
Boc
Boc
8
-
NaBH (3.7 g, 109.7 mmol) was added to a stirred and cooled (0 °C) solution of ester 8
4
(22.0 g, 54.8 mmol) in 1:1 THF-EtOH (140 mL). Then CaCl (5.5 g, 54.8 mmol) was added.
2
The ice bath was left in place, but not recharged, and stirring was continued overnight. The
mixture was quenched with hydrochloric acid (1 M) and extracted with EtOAc. The organic
extract was washed with saturated aqueous NaHCO and brine, dried (MgSO ) and evaporated.
3
4
Flash chromatography of the residue over silica gel, using 1:10 to 1:4 EtOAc-hexane, gave
(2S,4R)-2-hydroxymethyl-4-[(triisopropylsilyl)oxy]pyrrolidine-1-carboxylic acid tert-butyl ester

S4
-1 1
(18.6 g, 91%) as an oil: FTIR (CDCl , cast) 3120, 2944, 2867, 1698, 1775 cm ; H NMR (400
3
MHz, CDCl ) δ 1.00-1.10 (m, 21 H), 1.42 (s, 9 H), 1.58-1.62 (m, 1 H), 1.98-2.02 (m, 1 H), 3.33
3
(dd, J = 11.5, 3.7 Hz, 1 H), 3.42-3.63 (m, 2 H)), 3.68 (t, J = 8.8 Hz, 1 H), 4.07-4.20 (m, 1 H),
13
4.36 (s, 1 H), 4.90 (d, J = 7.1 Hz, 1 H); C NMR (100 MHz, CDCl ) δ 12.2, 17.7, 28.4, 38.2,
3
56.3, 59.0, 67.2, 70.0, 80.3, 157.4; exact mass (electrospray) m/z calcd for C H NNaO Si (M
19 39
4
+ Na) 396.25406, found 396.25405.
(b) (2S,4R)-2-Formyl-4-[(triisopropylsilyl)oxy]pyrrolidine-1-carboxylic Acid tert-Butyl
Ester (9).
OSiPr-i3
OSiPr-i3
O
HO
N
N
Boc
Boc
-
9
DMSO (11.4 mL, 160 mmol) was added to a stirred and cooled (-78 °C) solution of
(COCl) (7.0 mL, 80.4 mmol) in CH Cl (450 mL). After 10 min, the above alcohol (20 g, 53.6
2
2
2
mmol) in CH Cl (50 mL) was added dropwise. Stirring was continued for 20 min and then
2
2
Et N (22.4 mL, 160 mmol) was added dropwise. Stirring at -78 °C was continued for 30 min,
3
the cold bath was removed and stirring was continued for 20 min. The mixture was quenched
with saturated aqueous KHSO and the organic extract was washed with water, saturated
4
aqueous NaHCO and brine, dried (MgSO ) and evaporated. Flash chromatography of the
3
4
residue over silica gel, using 1:4 EtOAc-hexane, gave aldehyde 9 (18.1 g, 91%) as an oil: FTIR
-1 1
(CDCl , cast) 2944, 2868, 1738, 1698 cm ; H NMR (400 MHz, CDCl ) δ 1.00-1.05 (m, 21 H),
3
3
1.42-1.50 (m, 9 H), 1.90-2.00 (m, 1 H), 2.02-2.17 (m, 1 H), 3.40-3.60 (m, 2 H), 4.20-4.28 (m, 0.6
13
H), 4.38-4.42 (m, 0.4 H), 4.50 (s, 1 H); C NMR (100 MHz, CDCl ) δ 12.1, 17.7, 28.2, 36.0,
3
37.1, 55.6, 63.5, 63.9, 70.0, 70.7, 80.5, 80.9, 154.2, 200.0, 200.4; exact mass (electrospray) m/z
calcd for C H NNaO Si (M + Na) 394.23842, found 394.23864.
19 37
4
(2S,4R)-2-[(2Z)-3-Ethoxy-1-hydroxyallyl]-4-[(triisopropylsilyl)oxy]pyrrolidine-1-
carboxylic Acid tert-Butyl Ester (10).
OSiPr-i3
OSiPr-i3
OEt
O
N
N
HO
Boc
Boc
9
10

S5
t-BuLi (1.7 M in pentane, 7.8 mL, 13.3 mmol) was added dropwise to a stirred and
cooled (-78 °C) solution of (Z)-2-bromo-1-ethoxyethene (0.7 mL, 6.6 mmol) in THF (40 mL).
Stirring was continued for 30 min and then aldehyde 9 (1.9 g, 5.1 mmol) in THF (10 mL) was
added dropwise to the resulting vinyllithium solution. After 2 h, the mixture was quenched with
saturated aqueous NH Cl and extracted with EtOAc. The organic extract was washed with
4
brine, dried (Na SO ) and evaporated. Flash chromatography of the residue over silica gel,
2
4
using 1:10 EtOAc-hexane, gave the isomeric alcohols 10 [(1.42 g, 63% or 87% corrected for
-1 1
recovered 9 (475 mg, 25%)] as an oil: FTIR (CDCl , cast) 2925, 2867, 1694, 1666 cm ; H
3
NMR (400 MHz, CDCl ) δ 1.00-1.12 (m, 21 H), 1.15-1.1.45 (m, 3 H), 1.40- 1.55 (m, 9 H), 1.75-
3
2.10 (m, 2 H), 3.22-3.41 (m, 1 H), 3.48-3.3.68 (m, 1 H), 3.75-3.85 (m, 2 H), 3.95- 4.05 (m, 1 H),
13
4.25-4.55 (m, 3 H), 4.65-4.75 (m, 0.4 H), 5.35-5.40 (m, 0.6 H), 6.08 (d, J = 6.4 Hz, 1 H);
C
NMR (100 MHz, CDCl ) δ 12.0, 15.2, 17.9, 28.3, 37.7, 38.1, 55.7, 56.7, 62.7, 63.0, 68.0, 70.1,
3
70.2, 80.2, 80.5, 105.3, 146.8, 150.6; exact mass (electrospray) m/z calcd for C H NNaO Si
23 45
5
(M + Na) 466.29592, found 466.29611.
(2S,4R)-2-[(2Z)-3-Ethoxy-1-[(2-methoxyethoxy)methoxy]allyl]-4-[(triisopropylsilyl)-
oxy]pyrrolidine-1-carboxylic Acid tert-Butyl Ester (11).
OSiPr-i3
OSiPr-i3
OEt
OEt
N
N
HO
MEMO
Boc
Boc
10
11
MEMCl (3.4 mL, 30.0 mmol) was added to a stirred solution of alcohols 10 (8.9 g, 20.1
mmol), i-Pr NEt (7.0 mL, 40.2 mmol) and Bu NI (7.4 g, 20.1 mmol) in THF (100 mL) and the
2
4
mixture was refluxed for 20 h and then cooled to room temperature. Water and EtOAc were
added and the organic phase was washed with brine, dried (Na SO ) and evaporated. Flash
2
4
chromatography of the residue over silica gel, using 1:8 EtOAc-hexane, gave the isomeric MEM
-1 1
ethers 11 (8.8 g, 83%) as an oil: FTIR (CDCl , cast) 2943, 2868, 1697, 1662 cm ; H NMR
3
(300 MHz, CDCl ) δ 0.97-1.10 (m, 21 H), 1.20-1.30 (m, 3 H), 1.48 (s, 9 H), 1.80-2.00 (m, 1 H),
3
2.05-2.20 (m, 1 H), 3.35-3.50 (m, 5 H), 3.50-3.65 (m, 7 H), 4.10-4.25 (m, 1 H), 4.50-4.80 (m, 3
H), 5.05 (d, J = 12 Hz, 1 H), 6.05 (apparent d, J = 6.5 Hz, 0.5 H), 6.14 (apparent d, J = 6.5 Hz,
13
0.5 H); C NMR (100 MHz, CDCl ) δ 12.1, 15.2, 17.9, 28.4, 35.6, 36.4, 55.0, 55.2, 58.90,
3
58.94, 59.2, 59.9, 66.7, 66.9, 68.0, 68.1, 70.3, 70.5, 71.7, 79.0, 102.2, 103.9, 147.7, 154.6; exact
mass (electrospray) m/z calcd for C H NNaO Si (M + Na) 554.34835 found 554.34831.
27 53
7

S6
(2S,4R)-2-[1-[(2-Methoxyethoxy)methoxy]-3-oxo-2-(phenylselanyl)propyl]-4-
[(triisopropylsilyl)oxy]pyrrolidine-1-carboxylic Acid tert-Butyl Ester (12).
O
OSiPr-i3
OSiPr-i3
OEt
PhSe
MEMO
N
N
MEMO
Boc
Boc
11
12
A solution of PhSeCl (0.76 g, 3.9 mmol) in EtOAc (3 mL) was added to a stirred solution
of the enol ethers 11 (1.93 g, 3.6 mmol) in a mixture of EtOAc (36 mL) and water (15 mL).
After 15 min, NaHCO (0.60 g, 7.2 mmol) was added and stirring was continued for 30 min.
3
The mixture was diluted with EtOAc and the organic phase was washed with brine, dried
(Na SO ) and evaporated. Flash chromatography of the residue over silica gel, using 1:5
2
4
EtOAc-hexane, gave the isomeric aldehydes 12 (2.3 g, 98%) as an oil: FTIR (CDCl , cast) 2943,
3
-1 1
2867, 1699 cm ; H NMR (400 MHz, CDCl ) δ 1.00-1.10 (m, 21 H), 1.40-1.60 (m, 9 H), 1.90-
3
2.10 (m, 2 H), 2.95-3.00 (m, 0.33 H), 3.20-3.30 (m, 0.67 H), 3.38-3.43 (m, 3 H), 3.50-3.62 (m, 3
H), 3.65-3.85 (m, 3 H), 4.40-4.60 (m, 2 H), 4.60-5.00 (m, 3 H), 7.22-7.36 (m, 3 H), 7.52-7.60 (m,
13
2 H), 8.98-9.02 (m, 0.3 H), 9.38-9.42 (m, 0.7 H); C NMR (100 MHz, CDCl ) δ 11.9, 17.8,
3
28.3, 35.8, 54.3, 55.9, 58.5, 58.9, 67.7, 70.2, 71.6, 74.9, 80.8, 97.2, 125.2, 127.6, 128.6, 129.4,
131.4, 135.4, 154.2, 187.1, 191.5; exact mass (electrospray) m/z calcd for C H NNaO SeSi (M
31 53
7
+ Na) 682.26487, found 682.26478.
(2S,4R)-2-[3-Hydroxy-1-[(2-methoxyethoxy)methoxy]-2-(phenylselanyl)propyl]-4-
[(triisopropylsilyl)oxy]pyrrolidine-1-carboxylic Acid tert-Butyl Ester (13).
HO
O
OSiPr-i3
OSiPr-i3
PhSe
MEMO
PhSe
MEMO
N
N
Boc
Boc
12
13
A solution of aldehydes 12 (2.35 g, 3.6 mmol) in Et O (6 mL) was added dropwise to a
2
stirred and cooled (0 °C) suspension of LiAlH (157 mg, 3.9 mmol) in Et O. Stirring was
4
2
continued for 20 min and the reaction was quenched at 0 °C by addition of Na SO ·10H O.
2
4
2
Stirring at 0 °C was continued for 15 min and the solids were filtered off through a pad (2 x 4

S7
cm) of Celite, using Et O. Evaporation of the solvent gave the isomeric alcohols 13 (2.31 g,
2
98%) as an oil, which was used without further purification: FTIR (CDCl , cast) 3454, 2942,
3
-1 1
2867, 1696 cm ; H NMR (400 MHz, CDCl ) δ 1.00-1.08 (m, 21 H), 1.42-1.58 (m, 9 H), 1.90-
3
2.20 (m, 2 H), 3.22-3.35 (m, 2 H), 3.40 (s, 3 H), 3.51-3.92 (m, 7 H), 4.04-4.08 (m, 1 H), 4.10-
13
4.18 (m, 2 H), 4.62-4.90 (m, 3 H), 7.21-7.33 (m, 3 H), 7.55-7.63 (m, 2 H); C NMR (100 MHz,
CDCl ) δ 11.9, 17.8, 28.3, 35.1, 49.6, 55.5, 58.7, 58.9, 63.5, 67.8, 70.8, 71.6, 78.3, 79.6, 97.2,
3
127.2, 128.3, 129.0, 129.1, 133.4, 134.5, 155.7; exact mass (electrospray) m/z calcd for
C H NNaO SeSi (M + Na) 684.28052, found 684.28027.
31 55
7
(2S,4R)-2-[3-Acetoxy-1-[(2-methoxyethoxy)methoxy]-2-(phenylselanyl)propyl]-4-
[(triisopropylsilyl)oxy]pyrrolidine-1-carboxylic Acid tert-Butyl Ester (14).
HO
AcO
OSiPr-i3
OSiPr-i3
PhSe
MEMO
PhSe
MEMO
N
N
Boc
Boc
13
14
Pyridine (0.58 mL, 7.0 mmol) was added to a stirred solution of alcohols 13 (2.31 g, 3.5
mmol), Ac O (0.67 mL, 7.0 mmol) and DMAP (22 mg, 0.18 mmol) in CH Cl (40 mL).
2
2
2
Stirring was continued for 3.5 h, and the mixture was then diluted with CH Cl and water. The
2
2
organic phase was washed with brine, dried (Na SO ), and evaporated. Flash chromatography
2
4
of the residue over silica gel, using 1:4 EtOAc-hexane, gave the isomeric acetates 14 (1.97 g,
-1 1
80%) as an oil: FTIR (CDCl , cast) 2943, 2867 cm ; H NMR (400 MHz, CDCl ) δ 1.00-1.10
3
3
(m, 21 H), 1.42-1.58 (m, 9 H), 2.00-2.12 (m, 4.5 H), 2.40-2.48 (m, 0.5 H), 3.38-3.41 (m, 4 H),
3.52-3.72 (m, 5 H), 3.80-3.85 (m, 1 H), 4.10-4.20 (m, 1 H), 4.20-4.58 (m, 4 H), 4.75-4.85 (m, 2
13
H), 7.20-7.32 (m, 3 H), 7.56-7.62 (m, 2 H); C NMR (100 MHz, CDCl ) δ 12.0, 18.0, 20.8,
3
28.6, 38.1, 47.2, 55.6, 58.7, 59.0, 60.6, 65.8, 68.1, 70.5, 71.6, 78.0, 79.9, 96.4, 97.4, 127.7, 129.2,
129.5, 134.8, 155.6, 171.7; exact mass (electrospray) m/z calcd for C H NNaO SeSi (M + Na)
33 57
8
726.29109, found 726.29079.
(2S,4R)-2-[3-Acetoxy-1-[(2-methoxyethoxy)methoxy]-2-(phenylselanyl)propyl]-4-
hydroxypyrrolidine-1-carboxylic Acid tert-Butyl Ester (15).

S8
AcO
AcO
OSiPr-i3
OH
PhSe
MEMO
PhSe
MEMO
N
N
Boc
Boc
14
15
Bu NF (1 M in THF, 5.6 mL, 5.6 mmol) was added dropwise to a stirred solution of the
4
silylated alcohols 14 (1.97 g, 2.8 mmol) and AcOH (0.16 mL, 2.8 mmol) in THF (30 mL).
Stirring was continued for 2 h. Brine was then added and the mixture was extracted with EtOAc.
The organic extract was dried (Na SO ) and evaporated. Flash chromatography of the residue
2
4
over silica gel, using EtOAc-hexane mixtures from 2:1 EtOAc-hexane to 100% EtOAc, gave the
isomeric alcohols 15 (1.46 g, 95%) as an oil: FTIR (CDCl , cast) 3455, 2976, 2932, 1742, 1692
3
-1 1
cm ; H NMR (500 MHz, CDCl ) δ 1.46 (s, 9 H), 1.90-2.10 (m, 5 H), 3.25-3.25 (m, 5 H), 3.45-
3
3.55 (m, 3 H), 3.65-3.70 (m, 2 H), 3.75-3.80 (m, 1 H), 4.24-4.30 (dd, J = 6.5 Hz, 1 H), 4.58 (d, J
= 6.3 Hz, 1 H), 4.80 (s, 1 H), 4.54 (q, J = 6.5 Hz, 1 H), 4.70-4.80 (m, 2 H), 7.20-7.24 (m, 3 H),
13
7.45-7.49 (m, 2 H); C NMR (125 MHz, CDCl ) δ 20.8, 28.6, 36.8, 44.2, 55.3, 58.3, 59.0, 64.6,
3
65.7, 67.8, 68.1, 70.1, 71.7, 80.2, 96.5, 127.5, 129.1, 129.2, 133.4, 134.8, 155.6, 170.7; exact
mass (electrospray) m/z calcd for C H NNaO Se (M + Na) 570.15766, found 570.15750.
24 37 8
(2S)-2-[(1R)-3-Acetoxy-1-[(2-methoxyethoxy)methoxy]-2-(phenylselanyl)propyl]-4-
oxopyrrolidine-1-carboxylic Acid tert-Butyl Ester (16a) and (2S)-2-[(1S)-3-Acetoxy-1-[(2-
methoxyethoxy)methoxy]-2-(phenylselanyl)propyl]-4-oxopyrrolidine-1-carboxylic Acid tert-
Butyl Ester (16b).
AcO
AcO
AcO
OH
O
O
+
PhSe
MEMO
PhSe
MEMO
PhSe
MEMO
N
N
N
H
H
Boc
Boc
Boc
15
16a
16b
DMSO (0.57 mL, 8.0 mmol) was added to a stirred and cooled (-78 °C) solution of
(COCl) (0.35 mL, 4.0 mmol) in CH Cl (17 mL). Stirring was continued for 10 min and then
2
2
2
alcohols 15 (1.46 g, 2.7 mmol) in CH Cl (10 mL) were added dropwise. Stirring was continued
2
2
for 20 min, and Et N (1.12 mL, 8.0 mmol) was then added. Stirring at -78 °C was continued for
3
1 h. Water was added and the organic phase was washed with brine, dried (Na SO ) and
4
2
evaporated. Flash chromatography of the residue over silica gel, using 1:3 to 1:1 EtOAc-hexane,

S9
gave the ketone as a less polar fraction (16b) (0.58 g, 40%) and a more polar fraction (16a) (0.56
g, 40%).
The more polar fraction (16a) had: FTIR (CDCl , cast) 2976, 2929, 1762, 1742, 1696
3
-1 1
cm ; H NMR (400 MHz, CDCl ) δ 1.36-1.55 (m, 9 H), 2.00 (s, 3 H), 2.62-2.78 (m, 2 H), 3.08-
3
3.20 (m, 1 H), 3.36-3.40 (m, 3 H), 3.50-3.70 (m, 5 H), 3.80-3.97 (m, 2 H), 4.10-4.12 (m, 1 H),
4.30-4.39 (m, 1 H), 4.42-4.50 (m, 1 H), 4.60-4.89 (m, 2 H), 7.20-7.28 (m, 3 H), 7.48-7.62 (m, 2
13
H); C NMR (100 MHz, CDCl ) δ 20.7, 28.3, 41.1, 44.5, 53.6, 56.7, 58.9, 64.2, 65.2, 68.3,
3
71.5, 79.9, 81.2, 96.7, 127.2,128.9, 129.1, 132.9, 153.3, 170.4, 211.7; exact mass (electrospray)
m/z calcd for C H NNaO Se (M + Na) 568.14202 found 568.14231.
8
24 35
-1 1
The less polar fraction (16b) had: FTIR (CDCl , cast) 2929, 1763, 1743, 1697 cm ; H
3
NMR (400 MHz, CDCl ) δ 1.42-1.58 (m, 9 H), 1.90-2.05 (m, 3 H), 2.20-2.70 (m, 2 H), 3.35-
3
3.38 (m, 3 H), 3.40-3.82 (m, 7 H), 4.00-4.12 (m, 1 H), 4.20-4.33 (m, 2 H), 3.45-3.55 (m, 1 H),
13
3.65-3.75 (m, 2 H), 7.20-7.30 (m, 3 H), 7.52 -7.62 (m, 2 H); C NMR (100 MHz, CDCl ) δ
3
20.7, 28.3, 38.2, 46.1, 52.9, 56.7, 58.9, 64.2, 65.2, 68.2, 68.4, 71.4, 71.5, 79.9, 81.8, 97.6, 127.7,
128.1, 128.9, 129.3, 133.9, 134.9, 153.2, 170.3, 210.2; exact mass (electrospray) m/z calcd for
C H NNaO Se (M + Na) 568.14201, found 568.14249.
24 35
8
In the case of both fractions we did not distinguish between the presence of more than
one isomer or more than one rotamer.
(2S)-2-[(1R)-3-Hydroxy-1-[(2-methoxyethoxy)methoxy]-2-(phenylselanyl)propyl]-4-
oxopyrrolidine-1-carboxylic Acid tert-Butyl Ester (17).
AcO
HO
O
O
PhSe
MEMO
PhSe
MEMO
N
N
H
H
Boc
Boc
16a
17
K CO (157 mg, 1.1 mmol) was added to a solution of the more polar ketone fraction
2
3
(16a) (563 mg, 1.0 mmol) in a mixture of MeOH (10 mL) and water (1 mL). Stirring was
continued for 30 min, water was added and the mixture was extracted with EtOAc. The organic
extract was washed with brine, dried (Na SO ) and evaporated. Flash chromatography of the
2
4
residue over silica gel, using 1:1 EtOAc-hexane, gave the alcohol 17 (323 mg, 62%) as an oil
(we did not distinguish between the presence of more than one isomer or more than one
-1 1
rotamer): FTIR (CDCl , cast) 3446, 2928, 1762, 1695 cm ; H NMR (400 MHz, CDCl ) δ
3
3
1.38-1.50 (m, 9 H), 2.42-2.51 (m, 2 H), 3.08 (br s, 1 H), 3.38 (s, 3 H), 3.42-3.86 (m, 8 H), 4.02-

S10
13
4.15 (m, 1 H), 4.60-4.67 (m, 1 H), 4.80 (br s, 1 H), 4.90-5.00 (m, 1 H); C NMR (100 MHz,
CDCl ) δ 28.4, 41.8, 49.6, 56.8, 59.0, 64.0, 68.8, 71.6, 81.9, 82.8, 126.2, 129.1, 130.2, 133.4,
3
155.5, 211.4; exact mass (electrospray) m/z calcd for C H NNaO Se 526.13144 (M + Na)
22 33
7
found 526.13163.
(2S)-3-Dimethylaminomethylene-2-[(1R)-3-hydroxy-1-[(2-methoxyethoxy)methoxy]-
2-(phenylselanyl)propyl]-4-oxopyrrolidine-1-carboxylic Acid tert-Butyl Ester (18).
NMe2
HO
HO
O
O
PhSe
MEMO
PhSe
MEMO
N
N
H
H
Boc
Boc
17
18
A mixture of alcohols 17 (27 mg, 0.05 mmol), and t-BuOCH(NMe ) (22 mg, 0.13
2 2
mmol) in THF (1 mL) was refluxed for 24 h. Evaporation of the solvent and flash
chromatography of the residue over silica gel, using 1:20 to 1:10 MeOH-EtOAc, gave the
product 18 (20 mg, 67%) as an oil, which was a mixture of isomers: FTIR (CDCl , cast) 3411,
3
-1 1
2975, 2929, 1685, 1587 cm ; H NMR (400 MHz, CDCl ) δ 1.40-1.58 (m, 9 H), 3.03-3.18 (m,
3
6 H), 3.40 (s, 3 H), 3.48-3.65 (m, 4 H), 3.70-4.00 (m, 6 H), 4.11 (s, 1 H), 4.68-4.78 (m, 2 H),
13
5.62-5.79 (m, 1 H), 7.20-7.28 (m, 4 H), 7.55-7.70 (m, 2 H); C NMR (125 MHz, CDCl ) δ
3
28.3, 36.4, 50.3, 54.6, 59.0, 60.3, 63.3, 68.3, 71.7, 80.4, 82.5, 97.4, 101.1, 127.2, 129.0, 129.6,
133.5, 146.0, 155.5, 197.6; exact mass (electrospray) m/z calcd for C H N O Se (M + H)
25 39 2 7
559.19170, found 559.19203.
(8R,8aS)-8-[(2-Methoxyethoxy)methoxy]-3-oxo-7-(phenylselanyl)-2,3,6,7,8,8a-hexa-
hydrooxepino[4,3-b]pyrrole-1-carboxylic Acid tert-Butyl Ester (19a,b).
NMe2
O
O
O
O
O
HO
+
PhSe
PhSe
MEMO
PhSe
MEMO
N
N
N
H
H
H
MEMO
Boc
Boc
Boc
18
19a
19b
CF CO H (0.11 mL, 1.38 mmol) was added to a stirred solution of the vinylogous
3
2

S11
amides 18 (700 mg, 1.25 mmol) in PhMe (28 mL). The mixture was stirred at 70 °C for 15 h (Ar
atmosphere), and then cooled and evaporated. Flash chromatography of the residue over silica
gel, using 1:3 EtOAc-hexane, gave the major (and less polar) product 19a (288 mg, 45%), the
minor (and more polar) product 19b (43 mg, 6.7%) and recovered 18 (94 mg, 13.4%); the total
yield corrected for recovered 18 was 60%.
-1 1
The major product 19a had: FTIR (CHCl , cast) 2975, 2929, 2889, 1705, 1618 cm ; H
3
NMR (400 MHz, CDCl ) δ 1.47 (s, 9 H), 3.39 (s, 3 H), 3.47-3.74 (m, 5 H), 3.85-3.94 (m, 2 H),
3
4.00-4.12 (m, 2 H), 4.86 (AB q, J = 7.2 Hz, Δν = 29.2 Hz, 2 H), 4.89 (s, 1 H), 5.52 (d, J = 7.5
AB
13
Hz, 1 H), 7.25-7.35 (m, 3 H), 7.38 (d, J = 1.7 Hz, 1 H), 7.60-7.65 (m, 2 H); C NMR (100 MHz,
CDCl ) δ 28.3, 49.6, 53.7, 59.1, 67.6, 68.9, 71.7, 81.0, 81.6, 95.2, 110.8, 128.0, 128.6, 129.5,
3
135.6, 155.3, 155.7, 197.1; exact mass (electrospray) m/z calcd for C H NNaO Se (M + Na)
23 31 7
536.11579, found 536.11740.
The minor isomer product 19b had: FTIR (CDCl , cast) 2976, 2928, 2890, 1761, 1723,
3
-1 1
1696, 1616 cm ; H NMR (400 MHz, CDCl ) δ 1.40-1.62 (m, 9 H), 3.34-3.40 (m, 3 H), 3.44-
3
4.20 (m, 8 H), 4.22-4.36 (m, 1 H), 4.40-4.80 (m, 3 H), 5.60 (br s, 1 H), 7.20-7.40 (m, 4 H), 7.58-
13
7.7.72 (m, 2 H); C NMR (100 MHz, CDCl ) δ 28.3, 45.5, 46.6, 53.9, 56.2, 59.0, 67.7, 68.4,
3
71.1, 71.6, 71.7, 71.9, 74.8, 78.4, 80.3, 80.9, 98.6, 114.5, 127.4, 128.4, 128.6, 129.4, 129.3,
133.5, 135.2, 152.7, 155.3, 197.8, 199.4; exact mass (electrospray) m/z calcd for
C H NNaO Se (M + Na) 536.11579, found 536.11532.
23 31 7
(8S,8aS)-8-[(2-Methoxyethoxy)methoxy]-3-oxo-7-(phenylselanyl)-2,3,8,8a-tetra-
hydrooxepino[4,3-b]pyrrole-1-carboxylic Acid tert-Butyl Ester (20).
O
O
O
O
PhSe
MEMO
N
N
Ha
MEMO
H
Hb
Boc
Boc
19a
20
NaIO (19 mg, 0.09 mmol) was added to a stirred solution of selenide 19a (19 mg, 0.04
4
mmol) in a mixture of THF (0.7 mL) and water (0.7 mL). Stirring was continued for 14 h and
the reaction mixture was then diluted with EtOAc and saturated aqueous NaHCO . The organic
3
extract was washed with brine, dried (Na SO ) and evaporated. Flash chromatography of the
2
4
residue over silica gel, using 1:3 to 1:2 EtOAc-hexane, gave the product 20 (9 mg, 68%) as an
-1 1
oil: FTIR (CDCl , cast) 2976, 2929, 1735, 1670, 1653, 1626 cm ; H NMR (500 MHz, CDCl )
3
3
δ 1.50 (s, 9 H), 3.39 (s, 3 H), 3.51-3.57 (m, 2 H), 3.70-3.76 (m, 3 H), 4.14 (d, J = 18.0 Hz, 1 H),

S12
4.20 (td, J = 7.8, 2.2 Hz, 1 H), 4.83 (AB q, J = 7.3 Hz, Δν = 15.3 Hz, 2 H), 4.94 (d, J = 6.1
AB
Hz, 1 H), 5.10 (dd, J = 8.3, 1.9 Hz, 1 H), 6.28 (dd, J = 8.4, 2.4 Hz, 1 H), 7.46(d, J = 2.3 Hz, 1 H);
13
C NMR (125 MHz, CDCl ) δ 28.3, 53.6, 59.0, 61.5, 67.0, 71.6, 74.7, 80.8, 94.7, 111.9, 113.9,
3
138.4, 149.4, 155.3, 197.9; exact mass (electrospray) m/z calcd for C H NNaO (M + Na)
17 25
7
378.15232, found 378.15251.
(8S,8aS)-8-[(2-Methoxyethoxy)methoxy]-3-oxo-7-(phenylselanyl)-2,3,8,8a-tetra-
hydrooxepino[4,3-b]pyrrole-1-carboxylic Acid tert-Butyl Ester (20).
O
O
O
O
PhSe
MEMO
N
N
Ha
MEMO
H
Hb
Boc
Boc
19b
20
NaIO (28 mg, 0.13 mmol) was added to a stirred solution of selenide 19b (33 mg, 0.06
4
mmol) in a mixture of THF (1 mL) and water (1 mL). Stirring was continued for 42 h and the
reaction mixture was then diluted with EtOAc and saturated aqueous NaHCO . The organic
3
extract was washed with brine, dried (Na SO ) and evaporated. Flash chromatography of the
2
4
residue over silica gel, using 1:3 to 1:2 EtOAc-hexane, gave the product 20 (11 mg, 48%) as an
oil, which was identical to material obtained from 19a.
(2S)-2-[(1S)-3-Hydroxy-1-[(2-methoxyethoxy)methoxy]-2-(phenylselanyl)propyl]-4-
oxopyrrolidine-1-carboxylic Acid tert-Butyl Ester (21).
HO
AcO
O
O
PhSe
MEMO
PhSe
MEMO
N
N
H
H
Boc
Boc
16b
21
K CO (160 mg, 1.1 mmol) was added to a solution of the less polar ketone fraction
2
3
(16b) (576 mg, 1.0 mmol) in a mixture of MeOH (10 mL) and water (1 mL). Stirring was
continued for 30 min, water was added and the mixture was extracted with EtOAc. The organic
extract was washed with brine, dried (Na SO ) and evaporated. Flash chromatography of the
2
4
residue over silica gel, using 1:1 EtOAc-hexane, gave alcohols 21 (340 mg, 64%) as an oil:

S13
-1 1
FTIR (CDCl , cast) 3470, 2975, 2929, 1763, 1670 cm ; H NMR (400 MHz, CDCl ) δ 1.40-
3
3
1.60 (m, 9 H), 2.10-2.40 (m, 1 H), 2.52-2.68 (m, 1 H), 2.98-3.22 (m, 1 H), 3.38 (s, 3 H), 3.40-
13
3.92 (m, 8 H), 4.12-4.42 (m, 2 H), 4.60-4.80 (m, 3 H), 3.82 (br s, 1 H); C NMR (100 MHz,
CDCl ) δ 28.4, 37.7, 50.8, 53.0, 56.2, 58.9, 62.1, 68.2, 71.5, 79.7, 81.0, 97.1, 127.7, 127.9,
3
128.8, 129.3, 129.4, 134.4, 134.7, 152.8, 210.1; exact mass (electrospray) m/z calcd for
C H NNaO Se 526.13144 (M + Na), found 526.13185.
22 33
7
(2S)-3-Dimethylaminomethylene-2-[(1S)-3-hydroxy-1-[(2-methoxyethoxy)methoxy]-
2-(phenylselanyl)propyl]-4-oxopyrrolidine-1-carboxylic Acid tert-Butyl Ester (22a) and
(22b).
NMe2
NMe2
HO
PhSe
HO
HO
O
O
O
+
PhSe
MEMO
PhSe
MEMO
N
N
N
H
H
H
MEMO
Boc
Boc
Boc
21
22a
22b
A mixture of alcohols 21 (20 mg, 0.04 mmol) and t-BuOCH(NMe ) (16 mg, 0.09 mmol)
2 2
in THF (1 mL) was refluxed for 24 h. Evaporation of the solvent and flash chromatography of
the residue over silica gel, using 1:20 to 1:10 MeOH-EtOAc, gave the major product 22a (11.8
mg, 53%) and the minor product 22b (2.4 mg, 11%) as oils. Both products were single isomers.
-1 1
Isomer 22a had: FTIR (CDCl , cast) 3426, 2975, 2928, 1685, 1593 cm ; H NMR (400
3
MHz, CDCl ) δ 1.46 (s, 9 H), 3.15 (s, 6 H), 3.28-3.38 (m, 1 H), 3.40 (s, 3 H), 3.49-3.77 (m, 5 H),
3
3.84-3.94 (m, 3 H), 4.06-4.14 (m, 2 H), 4.77 (AB, J = 6.5 Hz, Δν = 33.3 Hz, 2 H), 5.77 (d, J =
AB
13
8.5 Hz, 1 H), 7.21-7.32 (m, 4 H), 7.47-7.54 (m, 2 H); C NMR (125 MHz, CDCl ) δ 28.4, 47.0,
3
52.3, 59.0, 59.9, 63.0, 68.4, 71.7, 80.8, 83.5, 97.3, 101.2, 127.4, 129.2, 130.5, 133.5, 147.4,
155.0, 195.9; exact mass (electrospray) m/z calcd for C H N O Se (M + H) 559.19170, found
25 39 2 7
559.19303.
-1 1
Isomer 22b had: FTIR (CDCl , cast) 3419, 2975, 2929, 1687, 1592 cm ; H NMR (400
3
MHz, CDCl ) δ 1.32-1.52 (m , 9 H), 3.00-3.22 (m, 6 H), 3.30-3.40 (m, 4 H), 3.42-3.92 (m, 8 H),
3
4.00-4.12 (m, 1 H), 4.62 (AB, J = 7.4 Hz, Δν = 60.4, Hz, 2 H), 5.95 (d, J = 6.4 Hz, 1 H), 7.12-
AB
13
7.39 (m, 3 H), 7.62-7.80 (m, 2 H); C NMR (100 MHz, CDCl ) δ 28.3, 49.3, 52.9, 58.9, 59.1,
3
62.9, 67.5, 71.7, 78.2, 80.3, 96.4, 101.3, 127.2, 128.7, 128.8, 134.3, 147.3, 154.8, 197.5; exact
mass (electrospray) m/z calcd for C H N O Se (M + H) 559.19170 found 559.19092.
25 39 2 7

S14
(8S,8aS)-8-[(2-Methoxyethoxy)methoxy]-3-oxo-7-(phenylselanyl)-2,3,6,7,8,8a-hexa-
hydrooxepino[4,3-b]pyrrole-1-carboxylic Acid tert-Butyl Ester (23a).
NMe2
O
O
O
HO
PhSe
PhSe
MEMO
N
N
H
H
MEMO
Boc
Boc
22a
23a
CF CO H (0.55 mL, 0.72 mmol) was added to a stirred solution of enamine 22a (380
3
2
mg, 0.68 mmol) in PhMe (30 mL) and stirring was continued for 31 h. Evaporation of the
solvent and flash chromatography of the residue over silica gel, using 1:3 EtOAc-hexane, gave
the cyclized product 23a [212 mg, 61% or 71% corrected for recovered 22a ((53 mg, 14%)]:
-1 1
FTIR (CDCl , cast) 2976, 2930, 1727, 1697, 1627 cm ; H NMR (300 MHz, CDCl ) δ 1.44-
3
3
1.61 (m, 9 H), 3.39 (s, 3 H), 3.51-3.82 (m, 5 H), 3.84-3.88 (m, 2 H), 4.19 (dd, J = 12.4, 8.6 Hz, 1
H), 4.39 (dd, J = 26.7, 3.8 Hz, 1 H), 4.70-5.06 (m, 4 H), 7.28-7.36 (m, 3 H), 7.55 (d, J = 2.4 Hz,
13
1 H), 7.58-7.64 (m, 2 H); C NMR (100 MHz, CDCl ) δ 28.3, 47.5, 54.8, 59.0, 62.8, 68.2, 70.3,
3
71.6, 75.9, 81.0, 97.5, 115.4, 128.3, 128.5, 130.6, 134.9, 154.6, 156.2, 197.2; exact mass
(electrospray) m/z calcd for C H NNaO Se (M + Na) 536.11579, found 536.11629.
23 31
7
(8S,8aS)-8-[(2-Methoxyethoxy)methoxy]-3-oxo-7-(phenylselanyl)-2,3,6,7,8,8a-hexa-
hydrooxepino[4,3-b]pyrrole-1-carboxylic Acid tert-Butyl Ester (23b).
NMe2
O
O
O
HO
PhSe
PhSe
MEMO
N
N
H
H
MEMO
Boc
Boc
22b
23b
CF CO H (0.12 mL, 0.16 mmol) was added to a stirred solution of enamine 22b (80 mg,
3
2
0.15 mmol) in PhMe (7.5 mL) and stirring was continued for 42 h. Evaporation of the solvent
and flash chromatography of the residue over silica gel, using 1:3 EtOAc-hexane, gave the
cyclized product 23b [40 mg, 52% or 57% yield corrected for recovered 22b (8.3 mg, 9.9%)]:
-1 1
FTIR (CDCl , cast) 2927, 1726, 1699, 1622 cm ; H NMR (500 MHz, CDCl ) δ 1.45-1.60 (m,
3
3
9 H), 3.38 (s, 3 H), 3.48-3.95 (m, 7 H), 4.00-4.19 (m, 1 H), 4.54-4.64 (m, 1 H), 4.78 (AB q, J =

S15
24.5 Hz, Δν = 46.1 Hz, 2 H), 5.02 (AB q, J = 24.5 Hz, Δν = 87.1 Hz, 2 H), 7.24-7.38 (m, 3
AB
AB
13
H), 7.41 (d, J = 1.7 Hz, 1 H), 7.59-7.68 (m, 2 H); C NMR (100 MHz, CDCl ) δ 28.3, 44.5,
3
54.4, 58.9, 67.3, 71.5, 72.2, 79.9, 81.5, 95.3, 112.8, 127.5, 129.4, 134.3, 153.8, 155.8, 197.3;
exact mass (electrospray) m /z calcd for C H NNaO Se (M + Na) 536.11579, found
23 31
7
536.11615.
(8R,8aS)-8-[(2-Methoxyethoxy)methoxy]-3-oxo-7-(phenylselanyl)-2,3,8,8a-tetra-
hydrooxepino[4,3-b]pyrrole-1-carboxylic Acid tert-Butyl Ester (24).
O
O
O
O
PhSe
MEMO
N
N
Ha
MEMO
H
Hb
Boc
Boc
23a
24
NaIO (23 mg, 0.11 mmol) was added to a stirred solution of selenide 23a (28 mg, 0.05
4
mmol) in a mixture of THF (1 mL) and water (1 mL). Stirring was continued for 5 h and the
mixture was then extracted with CH Cl . The organic extract was washed with brine, dried
2
2
(Na SO ) and evaporated. The residue was dissolved in CH Cl and the solution was refluxed
2
4
2
2
for 12 h. Evaporation of the solvent and flash chromatography of the residue over silica gel,
using 1:3 to 1:2 EtOAc-hexane, gave the product 24 (13 mg, 67%) as an oil: FTIR (CDCl , cast)
3
-1 1
2976, 2931, 1735, 1670, 1655, 1626 cm ; H NMR (500 MHz, CDCl ) δ 1.51 (s, 9 H), 3.38 (s,
3
3 H), 3.48-3.55 (m, 2 H), 3.57-3.66 (m, 2 H), 3.81-4.07 (m, 2 H), 4.69 (d, J = 6.9 Hz, 1 H), 4.79
(s, 1 H), 4.86 (s, 1 H), 5.07 (d, J = 5.7 Hz, 1 H), 5.22-5.30 (m, 1 H), 6.43 (d, J = 7.5 Hz, 1 H),
13
7.42 (s, 1 H); C NMR (125 MHz, CDCl ) δ 28.4, 53.9, 54.2, 59.0, 61.4, 61.6, 66.7, 66.9, 70.9,
3
71.6, 72.1, 80.7, 80.9, 94.2, 108.4, 109.0, 113.8, 144.5, 144.7, 147.5, 147.7, 154.2, 198.1; exact
mass (electrospray) m/z calcd for C H NNaO (M + Na) 378.15232, found 378.15268.
17 25
7
(8R,8aS)-8-[(2-Methoxyethoxy)methoxy]-3-oxo-7-(phenylselanyl)-2,3,8,8a-tetra-
hydrooxepino[4,3-b]pyrrole-1-carboxylic Acid tert-Butyl Ester (24).
O
O
O
O
PhSe
MEMO
N
N
Ha
MEMO
H
Hb
Boc
Boc
23b
24

S16
NaIO (29 mg, 0.14 mmol) was added to a stirred solution of selenide 23b (35 mg, 0.07
4
mmol) in a mixture of THF (1 mL) and water (1 mL). Stirring was continued for 48 h and the
mixture was then extracted with CH Cl . The organic extract was washed with brine, dried
2
2
(Na SO ) and evaporated. The residue was dissolved in CH Cl and the solution was refluxed
2
4
2
2
for 12 h. Evaporation of the solvent and flash chromatography of the residue over silica gel,
using 1:3 to 1:2 EtOAc-hexane, gave the product 24 (8.7 mg, 36%) as an oil, which was identical
to material obtained from 23a.

S17

S18

S19

S20

S21

S22

S23

S24

S25

S26

S27

S28

S29

S30