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Purification by column chromatography allowed the separation of
both isomers.
4.9. (1S,5S,6S)-6-(Diisopropoxyphosphoryl)bicyclo[3.1.0]hexan-
2-one 12
4.8.2.1. (1R,5R,6S,SS) 1-(p-Tolylsulfinyl)-6-[5,5-dimethyl-2-oxo-
(1,3,2)dioxaphosphorinanyl] (p-tolylsulfinyl)bicyclo(3.1.0)hex-
an-2-one 10a. The major isomer (68 mg, 31% yield), white nee-
To a solution of the freshly prepared Grignard reagent from iso-
propyl chloride (1.97 g, 25 mmol) and magnesium (0.6 g, 25 mmol)
in dry diethyl ether (100 mL) sulfoxide 9 (1 g, 2.5 mmol) was added
at room temperature. The reaction mixture was stirred for 3 h and
quenched with an aqeous solution of ammonium chloride. The or-
ganic layer was separated and the water fraction was extracted
with CH2Cl2 (5 ꢃ 15 mL). The combined organic fractions were
dried and evaporated in vacuum. The crude product was purified
by column chromatography on silica gel using diethyl ether as an
dles (recrystallization from Et2O), mp = 153–154 °C; ½a D20
ꢄ
= +64.8
(c 3.2, acetone). 31P NMR (81 MHz, CDCl3): d 13.8. 1H NMR
(200 MHz, CDCl3): d 1.20 (s, 3H, CH3), 1.01 (s, 3H, CH3), 1.92 (dt,
1HD, J = 6.5, 13.0 Hz), 2.26–2.10 (m, 2H), 2.39 (s, 3H, C6H4CH3),
2.55–2.35 (m, 2H), 2.91–2.61 (m, 2H), 4.25–3.87 (m, 4H, OCH2),
7.30 and 7.47 (AA0BB0, 4H, C6H4CH3). 13C NMR (50 MHz, CDCl3): d
17.8 (d, J = 103 Hz), 19.4, 20.5, 21.3, 32.1, 35.7, 37.8, 58.8 (d,
J = 4 Hz), 124.8, 129.8, 139.3, 141.8, 207.4 (d, J = 3.2 Hz). Anal. Calcd
for C18H23O5PS: C, 56.64; H, 6.06; S, 8.38. Found: C, 56.62; H, 6.18;
S, 8.22.
eluent to give a yellow oil, 470 mg (72% yield). ½a D20
ꢄ
= +10.8 (c
2.3, acetone). 31P NMR (81 MHz, CDCl3):
d
22.3. 1H NMR
(200 MHz, CDCl3): d 1.27–1.35 (m, 12H, CH3), 1.34–1.52 (m, 1H),
2.09 ꢀ2.40 (m, 5H), 2.61–2.84 (m, 1H), 4.68 (dq, 2H, OCH, J = 6.5,
13.6 Hz). 13C NMR (50 MHz, CDCl3): d 20.4 (d, J = 5.1 Hz), 21.3 (d,
J = 196 Hz), 23.8, (d, J = 9.6 Hz), 28.2 (d, J = 2.8 Hz), 33.0 (d,
J = 3.2 Hz), 36.4, 70.6 (d, J = 6.1 Hz), 70.9 (d, J = 5.8 Hz), 213.5 (d,
J = 4.2 Hz). Anal. Calcd for C12H21O4P: C, 55.38; H, 8.13. Found: C,
55.62; H, 8.04.
4.8.2.2. (1S,5S,6R,SS) 1-(p-Tolylsulfinyl)-6-[5,5-dimethyl-2-oxo-2-
(1,3,2)dioxaphosphorinanyl]bicyclo[3.1.0]hexan-2-one 10b. The
minor isomer 7 mg, 3% yield, white needles (recrystallization from
C6H6), mp 141–142 °C. ½a D20
ꢄ
= 58 (c 2.2, acetone). 31P NMR (81 MHz,
CDCl3): d 14.3. 1H NMR (200 MHz, CDCl3): d 0.63 (s, 3H, CH3),1.01
(s, 3H, CH3), 2.13 (d, 1HD, J = 9.4 Hz), 2.69–2.10 (m, 3H), 2.38 (s, 3H,
C6H4CH3), 3.41–2.81 (m, 2H), 3.65–3.44 (m, 3H, OCH2), 3.95–3.81
(m, 1H, OCH2), 7.32 and 7.76 (AA0BB0, 4H, C6H4CH3). 13C NMR
(50 MHz, CDCl3): d 17.8 (d, J = 186 Hz), 19.3, 20.5, 21.3, 32.1 (d,
J = 7.5 Hz), 35.7 (d, J = 3.5 Hz), 37.9, 58.8 (d, J = 4.1 Hz), 75.9, 124.8,
129.8, 139.3, 141.8, 207.4 (d, J = 3.2 Hz). Anal. Calcd for C18H23O5PS:
C, 56.62; H, 6.06. Found: C, 56.78; H, 6.32.
4.10. 6-(Diisopropoxyphosphoryl)-2-spirohydantoinbicyclo-
[3.1.0]hexane 13
Sodium cyanide (130 mg, 0.2 mmol), ammonium carbonate
(240 g, 0.24 mmol) and ketone (12) (312 mg, 0.12 mmol) were dis-
solved in 10 mL of a mixture of ethanol and water in a ratio of 1:1.
The reaction mixture was heated at 35 °C for 3 days. The solvent
was evaporated and H2O (10 mL) was added. This solution was ex-
tracted with CH2Cl2 (5 ꢃ 10 mL). The extract was dried over MgSO4
and concentrated, giving a yellow oil. Purification by column chro-
matography on silica gel, hexane/acetone (10:1) gave 388 mg
4.8.3. 1-(p-Tolylsulfinyl)-6-(diisopropoxyphosphoryl)
bicyclo[3.1.0]hexan-2-one 11
To a mixture of (diisopropoxyphosphorylmethyl)dimethyl sul-
fonium perchlorate (2.5 g, 11 mmol) and K2CO3 (1.7 mg, 24 mmol)
in CH2Cl2 (50 mL) was added slowly (ꢀ)-(S)-3 (2.2 g, 10 mmol). The
reaction mixture was stirred for 12 h and then H2O (20 mL) added.
The organic layer was separated, dried over MgSO4 and concen-
trated in vacuum. The crude product was obtained as mixture of
two endo isomers in a 3:1 ratio (8.4 g 96% yield). Purification and
isomer separation were done by column chromatography using sil-
ica gel and diethyl ether/hexane, 3:1 as eluent.
(98%) of a colourless oil, ½a D20
ꢄ
= +92 (c 6.4, acetone). 31P NMR
(81 MHz, CDCl3): d 27.7. 1H NMR (200 MHz, CDCl3): d 1.01 (ddd,
1H, J = 4.2, 8.7, 8.7 Hz), 1.32 (d, 6H, CH3CHO, J = 6.1 Hz), 1.34 (d,
6H, CH3CHO, J = 6.1 Hz), 2.37–1.92 (m, 6H), 4.81–4.59 (m, 2H,
OCH), 7.23 (br s, 1H, N–H), 8.81 (br s, 1H, N–H). 13C NMR
(50 MHz, CDCl3):
d 16.2 (d, J = 194 Hz), 23.8, 24.7, 26.3 (d,
J = 5.5 Hz), 31.0 (d, J = 6.4 Hz), 31.1, 69.5 (d, J = 5.2 Hz), 70.6 (d,
J = 5.9 Hz), 71.2 (d, J = 7.1 Hz), 155.6, 177.8. Anal. HRMS: calcd for
C
14H23PN2O5 330.1345. Found 330.1344.
4.8.3.1. Major (1R,5R,6S,SS)-11a. 6.3 g (72%) of white needles
(recrystallization from pentane–ethanol, 15:1), mp 84–85 °C;
4.11. (1S,2R,5S,6S)-2-Amino-6-phosphonobicyclo[3.1.0]hexane-
2-carboxylic acid 2
½
a 2D0 = +49 (c 8.2, acetone). 31P NMR (81 MHz, CDCl3): d 17.7 1H
ꢄ
NMR (200 MHz, CDCl3): 1.34–1.28 (m, 12H, CH3CH), 1.97–1.62
(m, 2H), 2.41–2.03 (m, 2H), 2.36 (s, 3H, C6H4CH3), 2.80–2.45 (m,
2H), 4.77–4.58 (m, 2H, OCH), 7.24 and 7.44 (AA0BB0, 4H,
C6H4CH3). 13C NMR (50 MHz, CDCl3): d 20.1 (d, J = 169 Hz), 21.3,
23.7, 27.5, 29.4 (d, J = 3.4 Hz), 38.8, 60.4 (d, J = 3.0 Hz), 71.5 (d,
J = 6.4 Hz), 71.2 (d, J = 6.4 Hz), 124.5, 129.8, 138.8, 142.3, 208.3
(d, J = 3.2 Hz). Anal. Calcd for C19H27O5PS: C, 57.27; H, 6.83; P,
7.77. Found: C, 57.05; H, 6.74; P, 7.78.
Hydantoin 13 (200 mg, 0.7 mmol) was heated in 10 mL of 6 N
HCl at a temperature of 86 °C for 48 h. The acid was removed by
rotaevaporation and the remaining oil was diluted with H2O
(5 mL). The solution was chromatographed on a column by ion ex-
change resin of Dowex 50ꢃ8 (H+ form). The product was eluted
with water. The fractions were collected and evaporated to give
2 (87 mg 65%) as a colourless oil, ½a D20
ꢄ
= +82.5 (c 4.2, methanol).
31P NMR (81 MHz, CD3OD): d 26.6. 1H NMR (200 MHz, CD3OD): d
1.21 (ddd, 1H, J = 3.8, 8.7, 8.7 Hz), 2.12–1.92 (m, 4H), 2.36–2.12
(m, 2H). 13C NMR (50 MHz, CD3OD): d 17.3 (d, J = 188 Hz), 25.8
(d, J = 4.8 Hz), 26.9 (d, J = 4.8 Hz), 32.0 (d, J = 5.2 Hz), 32.2, 71. 1
(d, J = 5.5 Hz), 71.7 (d, J = 5.5 Hz, 180.3. Anal. Calcd for C7H12
NO5P: C, 38.02; H, 5.47. Found: C, 37.89; H, 5.61.
4.8.3.2. Minor (1S,5S,6R,SS)-11b. 2.1 g (24%), ½a D20
= ꢀ23 (c 2.2,
ꢄ
acetone). 31P NMR (81 MHz, CDCl3): d 19.0. 1H NMR (200 MHz,
CDCl3): d 0.88 (d, 3H, CH3CH, J = 6.1 Hz), 1.03 (d, 3H, CH3CH,
J = 6.1 Hz), 1.22 (d, 3H, CH3CH, J = 6.1 Hz), 1.24 (d, 3H, CH3CH,
J = 6.1 Hz), 2.10 (d, 1H, J = 9.5 Hz), 2.48–2.29 (m, 2H), 2.39 (s, 3H,
C6H4CH3), 2.70–2.52 (m, 1H), 3.02–2.80 (m, 2H), 4.23 (dq, 1H,
OCH, J = 6.5, 13.4 Hz), 4.56 (dq, 1H, OCH, J = 6.5, 13.4 Hz), 7.28
and 7.71 (AA0BB0, 4H, C6H4CH3). 13C NMR (50 MHz, CDCl3): d 20.0
(d, J = 175 Hz), 21.8, 23.7 (d, J = 5.1 Hz), 27.4, 29.4 (d, J = 3.5 Hz),
38.6, 60.4 (d, J = 2.9 Hz), 71.5 (d, J = 6.2 Hz), 71.1 (d, J = 6.1 Hz),
124.5, 129.8, 138.7, 142.3, 208.3 (d, J = 3.8 Hz). Anal. Calcd for
5. Crystallographic data
Intensity data for the crystals of (+)-10b and (+)-11a were col-
lected on a Bruker AXS Smart APEX CCD 3-circle diffractometer
with MonoCap capillary and monochromated Mo K
a radiation
C19H27O5PS: C, 57.27; H, 6.83. Found: C, 5.42; H, 6.69.