Hydroxylated pyrrolodines
J . Org. Chem., Vol. 67, No. 4, 2002 1317
reference to tetramethylsilane (TMS) as an internal standard.
Column chromatography was performed using EM Science
silica gel (230-400 mesh). Ozonolysis was done using a
Welsbach Model 816 ozone generator set at 90V, 2 L/min.
Elemental analyses were determined by the Microanalytical
Laboratories, and X-ray crystallography was carried out by
the CHEXRAY Facility, University of California, Berkeley.
(4S,5S)-5-(N-Ben zyloxym eth yl-N-ph en ylsu lfon yl)am in o-
4-a llyl-2,2-d im eth yl-1,3-d ioxa n e (9). Sulfonamide 7 (9.25 g,
0.03 mol) was dissolved in CH2Cl2 (200 mL) and cooled to 0
°C. To this solution were added N,N-diisopropylethylamine
(36.0 mL, 0.21 mol) and then benzyl-oxymethyl chloride (18.0
mL, 0.13 mol) dropwise via syringe under a stream of nitrogen.
The pale yellow mixture was removed from the cold bath and
stirred under nitrogen for 24 h, and the dark red mixture was
then evaporated to afford a gelatinous residue. Chromatogra-
phy (1/4, EtOAc/ hexanes) gave 9 (10.2 g, 80%) as a colorless
oil: [R]D +28.1° (c 5.0, CHCl3); H NMR δ 1.32 (s, 3Η), 1.38
(s, 3H), 2.25-2.33 (m, 2H), 3.52-3.58 (bs, 1H), 3.64 (dd, J )
12.7, 2.1, 1H), 3.86 (dd, J ) 12.7, 4.2, 1H), 4.03-4.07 (m, 1H),
4.49-4.62 (m, 2H), 4.97-5.04 (m, 1H), 5.05 (dd, J ) 17.2, 1.8,
1H), 5.19 (d, J ) 9.6, 1H), 5.35 (d, J ) 9.6, 1H), 5.78 (dddd, J
) 17.0, 10.3, 6.7, 3.2, 1H), 7.25-7.41 (m, 6H), 7.47-7.53 (m,
2H), 7.91-7.94 (m, 2H); 13C NMR δ 19.0, 28.8, 36.0, 52.0, 62.7,
70.2, 71.5, 77.2, 99.1, 116.8, 127.5, 127.8, 128.0, 128.3, 128.5,
132.6, 134.6, 138.0, 141.0. Anal. Calcd for C23H29NO5S: C, 64.0;
H, 6.7; N, 3.3. Found: C, 64.0; H, 6.8; N, 3.1.
The filter pad was washed copiously with EtOAc and evapo-
rated to provide R-methylaldehyde 12 as a colorless oil in
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quantitative yield: [R]D +110.4° (c 0.5, CHCl3); H NMR δ
1.04 (d, J ) 6.9, 3H), 1.28 (s, 3H), 1.39 (s, 3H), 2.90-2.97 (m,
1H), 3.58 (dd, J ) 12.9, 2.1, 1H), 3.70 (br s, 1H), 3.87 (dd, J )
12.9, 3.9, 1H), 4.17 (dd, J ) 9.6, 3.3, 1H), 4.51 (dd, J ) 11.7,
6.3, 2H), 5.21 (d, J ) 9.9, 1H), 5.37 (d, J ) 9.9, 1H), 7.21-7.54
(m, 8H), 7.89 (dd, J ) 8.4, 3.0, 2H), 9.66 (d, J ) 3.0, 1H); 13C
NMR δ 9.7, 18.5, 28.5, 46.4, 49.8, 62.9, 70.0, 73.2, 77.2, 99.2,
127.4, 127.8, 128.1, 128.5, 128.7, 132.7, 137.5, 140.4, 203.2.
(3S,4S,5S)-2,4-Dih yd r oxy-5-h yd r oxym eth yl-3-m eth yl-
1-(p h en ylsu lfon yl)p yr r olid in e Isop r op ylid en e Keta l (13).
Aldehyde 12 (3.0 g, 6.7 mmol) was dissolved in MeOH (100
mL), and H2O (1 mL) and 20% Pd(OH)2-C (3.0 g) were added.
The reaction mixture was hydrogenated (1 atm) with vigorous
stirring for 2 h and filtered through Celite, and the filter pad
was washed copiously with MeOH. To the combined filtrate
was added triethylamine (1.8 mL, 12.9 mmol), and the mixture
was stirred for 90 min and evaporated to an oily residue.
Chromatography (1/2, EtOAc/hexanes) gave 13 (1.9 g, 87%)
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as a foam: [R]D +38.2° (c 1.5, CHCl3); H NMR δ 1.01 (d, J
) 7.1, 3H), 1.30 (s, 3H), 1.33 (s, 3H), 1.70-1.80 (m, 1H), 3.46-
3.53 (m, 1H), 4.02-4.08 (m, 1H), 4.17-4.20 (m, 3H), 5.21-
5.30 (m, 1H), 7.41-7.55 (m, 3H), 7.84-7.91 (m, 2H); 13C NMR
δ 7.9, 19.5, 28.1, 42.2, 57.4, 61.1, 73.0, 87.6, 98.6, 126.8, 129.3,
132.8, 139.7. Anal. Calcd for C15H21NO5S: C, 55.0; H, 6.5; N,
4.3. Found: C, 54.8; H, 6.6; N, 4.0.
(4S,5S)-5-(N-Ben zyloxym eth yl-N-ph en ylsu lfon yl)am in o-
4-(2’-oxoeth yl)-2,2-d im eth yl-1,3-d ioxa n e (10). Amino olefin
9 (11.1 g, 25.8 mmol) was dissolved in CH2Cl2 (200 mL) and
cooled to -78 °C. Oxygen was bubbled through the solution
for 20 min at -78 °C, followed by ozone (2L/min, 90 V), until
a blue color persisted (ca. 30 min). Excess ozone was removed
by bubbling a stream of oxygen through the reaction mixture
until it became colorless. The mixture was removed from the
cold bath and triphenylphosphine (9.5 g, 36.4 mmol) was added
with stirring for 2 h as the mixture came to rt. The solvent
was then evaporated and the residue chromatographed (1/3,
EtOAc/hexanes) to give aldehyde 10 (8.0 g, 72%) as a foam:
[R]D +43.1° (c 1.0, CHCl3); H NMR δ 1.31 (s, 3H), 1.44 (s,
3H), 2.72 (dd, J ) 7.2, 1.2, 1H), 2.84 (dd, J ) 5.4, 0.6, 1H),
3.46 (br s, 1H), 3.68 (dd, J ) 12.9, 1.8, 1H), 3.94 (dd, J ) 12.9,
3.9, 1H), 4.57-4.59 (m, 2H), 4.68-4.72 (m, 1H), 5.19 (d, J )
9.6, 1H), 5.38 (d, J ) 9.6, 1H), 7.24-7.54 (m, 8H), 7.89-7.92
(m, 2H), 9.66 (s, 1H); 13C NMR δ 18.6, 29.0, 45.7, 51.1, 62.7,
66.4, 70.1, 77.0, 99.3, 127.4, 127.5, 127.9, 128.3, 128.8, 132.7,
137.7, 140.2, 199.5. Anal. Calcd for C22H27NO6S: C, 61.0; H,
6.3; N, 3.2. Found: C, 60.9; H, 6.3; N, 3.2.
(4S,5S)-5-(N-Ben zyloxym eth yl-N-ph en ylsu lfon yl)am in o-
4-(1′-m eth ylen e-2′-oxoeth yl)-2,2-dim eth yl-1,3-dioxan e (11).
Aldehyde 10 (5.8 g, 13.4 mmol) was dissolved in CH2Cl2 (100
mL), and added sequentially were N,N-dimethylmethylene-
ammonium chloride (3.10 g, 33.2 mmol) and triethylamine
(3.65 mL, 26.2 mmol) dropwise via syringe. After stirring for
24 h at rt under an N2 blanket, saturated NaHCO3 (50 mL)
was added, and the aqueous layer was extracted with CH2Cl2
(3 × 50 mL). The combined organic layer was dried over
MgSO4, filtered, and evaporated, leaving an off-white solid
residue which was recrystallized from hexanes/EtOAc to give
R,â-unsaturated aldehyde 11 (4.5 g, 74%): mp 147-149 °C;
[R]D22 +67.6° (c 0.6, CHCl3); 1H NMR δ 1.42 (s, 3H), 1.47 (3H),
3.61 (br s, 1H), 3.74 (d, J ) 12.6, 1H), 4.04 (dd, J ) 12.6, 3.7,
1H), 4.54-4.56 (m, 2H), 5.12 (d, J ) 3.7, 1H), 5.21 (d, J ) 9.7,
1H), 5.31 (d, J ) 9.6, 1H), 6.22 (s, 1H), 6.41 (s, 1H), 7.22-7.40
(m, 7H), 7.45-7.51 (m, 1H), 7.86-7.90 (m, 2H), 9.45 (s, 1H);
13C NMR δ 18.4, 29.3, 50.5, 62.4, 68.7, 70.0, 76.9, 99.5, 127.2,
127.4, 128.0, 128.2, 128.6, 132.5, 134.3, 137.9, 140.3, 146.4,
192.5. Anal. Calcd for C23H27NO6S: C, 62.0; H, 6.1; N, 3.1.
Found: C, 62.0; H, 6.3; N, 3.0.
(2S,3S,4S,5S)-4-Hyd r oxy-5-h yd r oxym eth yl-2-m eth oxy-
ca r b on ylm e t h yl-3-m e t h yl-1-(p h e n ylsu lfon yl)p yr r oli-
d in e Isop r op ylid en e Keta l (15). To a suspension of 95%
NaH (600 mg, 25 mmol) in THF (180 mL) at - 30 °C was added
trimethyl phosphonoacetate (4.1 mL, 25 mmol) dropwise via
syringe, and the reaction mixture was stirred for 1 h. To the
cloudy white mixture was added a THF solution (15 mL) of
aminal 13 (3.5 g, 10.7 mmol) dropwise via syringe, and the
mixture was stirred at -30 °C for 4 h and then allowed to
come to room temperature overnight. To the clear homoge-
neous solution was added 50 mL of phosphate buffer, pH 7.
After being stirred for 30 min, the aqueous phase was
extracted with EtOAc (4 × 50 mL), and the combined organic
layer was dried, (MgSO4), filtered, and evaporated to an oil.
Chromatography (1/2, EtOAc/hexanes) gave 15 (3.1 g, 75%)
as a thick, colorless oil: [R]D -4.6° (c 1.0, CHCl3); H NMR
δ 0.86 (d, J ) 7.1, 3H), 1.31 (s, 3H), 1.39 (s, 3H), 1.60-1.65
(m, 1H), 2.79 (dd, J ) 16.4, 5.2, 1H), 2.92 (dd, J ) 8.4, 1H),
3.57 (q, J ) 5.2, 1H), 3.68 (s, 3H), 3.91-4.00 (m, 2H), 4.09
(dd, J ) 12.4, 6.4, 1H), 4.20-4.24 (dd, J ) 13.2, 8.0, 1H), 7.50-
7.64 (m, 3H), 7.81-7.87 (m, 2H); 13C NMR δ 8.2, 21.1, 26.0,
38.3, 40.1, 51.5, 59.0, 60.8, 62.8, 72.7, 98.9, 127.3, 129.1, 132.9,
137.0, 172.1. Anal. Calcd for C18H25NO6S: C, 56.4; H, 6.6; N,
3.7. Found: C, 56.4; H, 6.7; N, 3.5.
(2S,3S,4S,5S)-4-Hyd r oxy-5-h yd r oxym eth yl-2-m eth oxy-
ca r b on ylm et h yl-3-m et h yl-1-p h en ylca r b a m oylp yr r oli-
d in e Isop r op ylid en e Keta l (16). An electrolysis cell was
filled with an CH3CN solution of Et4NBr (0.1 M), and argon
was bubbled through the solution for 1 h. The current was set
at 1.73 eV, and pre-electrolysis of Hg resulted in a stable
background reading of 0.1 mA after 15 min. 4-Phenylphenol
(754 mg, 4.44 mmol) was added to the cathode solution, and
argon was bubbled through the solution for 15 min. Pre-
electrolysis of the solution resulted in a background reading
of 1.6 mA in 2 h. A CH3CN solution of pyrrolidine 15 (680 mg,
1.77 mmol) was added, with an intial current reading of 25
mA. After 12 h of electrolysis, the current was 1.1 mA. The
cathode solution was decanted from the Hg which was washed
with CH2Cl2 (3 × 30 mL). The combined filtrates were
evaporated, the residue was dissolved in CH2Cl2 (100 mL) and
washed with freshly prepared 0.1 M KOH (3 × 100 mL) and
brine (50 mL), and the combined organic layer was dried
(MgSO4), filtered, and evaporated. Chromatography (9/1, CH2-
Cl2/MeOH) gave 300 mg (69%) of the secondary amine as a
colorless oil. To a -10 °C solution of this oil in CH2Cl2 (10 mL)
were added Et3N (0.072 mL, 0.66 mmol) and phenyl isocyanate
(0.080 mL, 0.66 mmol). After stirring the mixture for 2 h, H2O
(15 mL) was added. The aqueous layer was extracted with CH2-
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(4S,5S)-5-(N-Ben zyloxym eth yl-N-ph en ylsu lfon yl)am in o-
4-[(1′S)-1′-m et h yl-2′-oxoet h yl]-2,2-d im et h yl-1,3-d ioxa n e
(12). R,â-Unsaturated aldehyde 11 (3.4 g, 7.6 mmol) was
dissolved in EtOAc (50 mL) and 10% Pd-C (630 mg) added.
The reaction mixture was shaken with hydrogen in a Parr
apparatus at 60 psi for 2 h and then filtered through Celite.