1068 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 7
Natchus et al.
then dissolved in ethyl acetate, washed with 5% NaHCO3 (2×),
5% NH4Cl (2×), brine, dried with MgSO4, filtered and evapo-
rated to give a brown oil (2.42 g). The crude oil was purified
via column chromatography with Hex:EtOAc (3:1 to 4:6) to give
a yellow oil which solidified upon standing (850 mg, 37%): 1H
NMR (CDCl3, 300 MHz) δ 1.47 (s, 9H), 2.49-2.69 (m, 6H), 3.39
(br s, 6H), 3.58 (d, J ) 13.6 Hz, 1H), 3.78 (s, 3H), 3.89 (s, 3H),
4.84 (d, J ) 9.9 Hz, 1H), 7.03 (d, J ) 8.8 Hz, 2H), 7.57 (d, J )
8.8 Hz, 2H), 7.69 (d, J ) 7.3 Hz, 2H), 7.97 (d, J ) 8.1 Hz, 2H);
ESI+ MS m/z 572.2 (M + H)+.
150 mL of CH2Cl2 in the presence of 15 mL of Et3N and treated
dropwise with methanesulfonyl chloride (7.74 mL, 100 mmol).
The resulting solution was stirred at room temperature for
18 h and then partitioned between CH2Cl2 and 1 N HCl. The
organic layer was dried over MgSO4, filtered and evaporated.
The residue was adsorbed onto silica and eluted through a
column of flash silica with hexanes:EtOAc (2:1 to 1:3) to give
1
4.71 g (34%) of the desired material as a pale yellow oil: H
NMR (CDCl3, 300 MHz) δ 1.24 (s, 9H), 2.72 (dd, J ) 2.2, 2.2
Hz, 1H), 2.74 (dd, J ) 2.2, 2.2 Hz, 1H), 3.12 (s, 3H), 3.39 (s,
3H), 3.60 (dd, J ) 10.3, 6.6 Hz, 1H), 3.65 (dd, J ) 10.3, 4.4
Hz, 1H), 4.11 (dd, J ) 2.1 Hz, 2H), 4.75 (ddd, J ) 12.8, 6.4,
4.4 Hz, 1H); ESI+ MS m/z 296.1 (M + NH4)+.
1-H yd r oxy-(2S)-m et h a n esu lfon oxy-6-m et h oxyh ex-4-
yn e (14b). The substrate 14a (4.68 g, 16.8 mmol) was taken
in 100 mL of CH2Cl2 and treated dropwise with 10 mL of TFA.
The resulting mixture was stirred for 18 h and then evaporated
to dryness and triturated 2× with CHCl3 to give 3.3 g of
brownish syrup which was carried forward without purifica-
tion: 1H NMR (CDCl3, 300 MHz) δ 2.67-2.82 (m, 2H), 3.15 (s,
3H), 3.38 (s, 3H), 3.85 (dd, J ) 12.5, 6.2 Hz, 1H), 3.95 (dd, J
) 12.5, 3.3 Hz, 1H), 4.09 (dd, J ) 4.0, 4.0 Hz, 2H), 4.81 (ddd,
J ) 12.8, 6.4, 3.5 Hz, 1H); ESI+ MS m/z 240.1 (M + NH4)+,
223.1 (M + H)+.
2-{[4′-Met h oxy(1,1′-b ip h en yl)-4-yl]su lfon yl}a m in o-6-
[4N-(ter t-b u t oxyca r b on yl)p ip er a zin -1N-yl)-h ex-4-yn oic
Acid (66). Compound 11 (128 mg, 0.224 mmol) was dissolved
in a 1:1:1 H2O:methanol:THF solution (15 mL) and NaOH:
H2O 1:1 (1.5 mL) was added dropwise at room temperature.
The reaction stirred for 1.5 h until complete by TLC. The
solvent was removed in vacuo and the white residue was
dissolved in H2O and passed through a reverse phase silica
column (H2O-CH3CN:H2O 1:1) to yield a pure white solid (109
1
mg, 84%): H NMR (DMSO-d6, 300 MHz) δ 1.39 (s, 9H), 2.32
(br s, 4H), 3.17 (br s, 4H), 3.83 (s, 2H), 4.32-4.35 (m, 1H),
5.17 (s, 1H), 7.07 (d, J ) 8.8 Hz, 2H), 7.71 (d, J ) 8.8 Hz, 2H),
7.81 (d, J ) 8.4 Hz, 2H), 7.97 (d, J ) 8.4 Hz, 2H); ESI+ MS
m/z 558.2 (M + H)+, 580.2 (M + Na)+. Anal. (C29H30N3NaO5S‚
2NaOH) C, H, N.
(2R)-Azid o-6-m eth oxyh ex-4-yn -1-ol (15). The starting
crude mesylate 14b (3.3 g) was taken in 50 mL of DMF in the
presence of sodium azide (10.9 g, 168 mmol) and stirred at 60
°C for 42 h. The resulting mixture was then partitioned
between Et2O and water. The organic layer was washed 2×
with water and 1× with brine. The aqueous layer was back
extracted and the combined organic layers were dried over
MgSO4, filtered and evaporated to give a brown syrup which
was adsorbed onto silica and eluted through a column of flash
silica with hexanes:Et2O (8:1 to 1:2) to give 1.83 g (64% from
14a ) of the desired product as a pale tan syrup: 1H NMR
(CDCl3, 300 MHz) δ 2.55 (dd, J ) 3.3, 3.3 Hz, 1H), 2.57 (dd, J
) 2.1, 2.1 Hz, 1H), 3.35 (s, 3H), 3.60-3.72 (m, 2H), 3.72-3.82
(m, 1H), 4.71 (dd, J ) 2.0, 2.0 Hz, 2H); ESI+ MS m/z 170.1 (M
+ H)+.
Met h yl 2-{[4′-Met h oxy(1,1′-b ip h en yl)-4-yl]su lfon yl}-
a m in o-6-(4N-a cet ylp ip er a zin -1N-yl)h ex-4-yn oa t e (12).
Compound 11 (210 mg, 0.37 mmol) was dissolved in CH2Cl2
(10 mL) and TFA (4 mL) was added at room temperature. The
reaction stirred for 2 h and the solvent and TFA were stripped
off and the resultant residue dissolved in CH2Cl2 (5 mL) and
to this was added triethylamine (3 mL), and acetic anhydride
(38 µL, 0.4 mmol) at room temperature and this stirred 16 h
and was then partitioned between ethyl acetate and aqueous
5% NaHCO3. The organic layer was washed with brine, dried
with MgSO4, filtered and evaporated to a yellow oil which was
purified via column chromatography on silica gel (ethyl
acetate-5% methanol:ethyl acetate) to yield a pure white solid
(180 mg, 95%): 1H NMR (CDCl3, 300 MHz) δ 2.10 (s, 3H), 2.49-
2.68 (m, 5H), 3.45-3.71 (m, 6H), 3.79 (s, 3H), 3.89 (s, 3H), 4.83
(dd, J ) 9.9, 3.7 Hz, 1H), 7.03 (d, J ) 8.8 Hz, 2H), 7.57 (d, J
) 8.8 Hz, 2H), 7.70 (d, J ) 8.4 Hz, 2H), 7.94 (d, J ) 7.7 Hz,
2H); ESI+ MS m/z 514.1 (M + H)+.
(2R)-{[4′-Meth oxy(1,1′-bip h en yl)-4-yl]su lfon yl}a m in o-
6-m eth oxyh ex-4-yn -1-ol (16). The starting azide (800 mg,
4.73 mmol) was taken in 25 mL of THF and triphenylphos-
phene (2.50 g, 9.47 mmol) was added followed by dropwise
addition of 3 mL of water which caused mild effervescing. The
mixture was stirred for 1 h at which time the mixture was
diluted with 200 mL of hexanes:EtOAc (1:1) and extracted
twice with 1 N HCl. The organic layer was diluted with 50
mL of dioxane and neutralized with excess, solid sodium
carbonate. [4′-Methoxy(1,1′-biphenyl)-4-yl]sulfonyl chloride
(1.93 g, 7.10 mmol was added and the mixture allowed to stir
for 16 h. The mixture was then partitioned between 1 N HCl
and EtOAc. The organic layer was washed with brine, dried
over MgSO4, filtered and evaporated. The residue was then
chromatographed over flash silica with hexanes:EtOAc (1:1 to
2-{[4′-Met h oxy(1,1′-b ip h en yl)-4-yl]su lfon yl}a m in o-6-
(4N-a cetylp ip er a zin -1N-yl)h ex-4-yn oic Acid (68). The es-
ter 12 was saponified to give the title acid as described for
1
compound 66: H NMR (DMSO-d6, 300 MHz) δ 1.97 (s, 3H),
2.24-2.42 (m, 6H), 3.17-3.31 (m, 4H), 3.84 (s, 3H), 4.31 (d, J
) 9.3 Hz, 1H), 5.18 (s, 1H), 7.08 (d, J ) 9.0 Hz, 2H), 7.72 (d,
J ) 8.6 Hz, 2H), 7.82 (d, J ) 8.4 Hz, 2H), 7.98 (d, J ) 8.4 Hz,
2H); ESI+ MS m/z 522.1 (M + Na)+, 500.1 (M + H)+. Anal.
(C28H34N3NaO7S‚0.7NaOH) C, H, N.
Gen er al Meth od C. 1-ter t-Bu toxy-(2S)-h ydr oxy-6-m eth -
oxyh ex-4-yn e (14). The 1-methoxyprop-2-yne (17.5 mL, 207
mmol) was taken in 350 mL of THF under a N2 atmosphere
and cooled to -78 °C. A solution of n-butyllithium (91 mL,
227 mmol) was added slowly via syringe and the resulting
solution was allowed to stir for 10 min; afterwhich, borontri-
fluoride etherate (28.3 mL,227 mmol) was added via syringe
and the resulting solution was allowed to stir for 10 min. The
neat starting epoxide 13 (26.2 mL, 207 mmol) was added to
the solution slowly via syringe and the resulting solution was
allowed to stir for 1 h, slowly come to room temperature over
2 h, and then partitioned between hexanes:EtOAc (2:1) and
water. The organic layer was washed with brine, dried over
MgSO4, filtered and evaporated to give a dark red residue
which was adsorbed onto silica and eluted through a flash
silica column with hexanes:EtOAc (10:1 to 2:1) to give 15.3 g
1
1:4) to give 1.42 g (77%) of the desired sulfonamide: H NMR
(CDCl3, 300 MHz) δ 2.45 (dddd, J ) 16.9, 6.6, 2.0, 2.0 Hz, 1H),
2.53 (dddd, J ) 16.9, 5.1, 2.2, 2.2 Hz, 1H), 3.45-3.56 (m, 1H),
3.67 (dd, J ) 11.4, 4.8 Hz, 1H), 3.75 (dd, J ) 11.0, 5.1 Hz,
1H),3.88 (s, 3H), 4.00 (dd, J ) 2.0, 2.0 Hz, 2H), 5.38 (d, J )
7.7 Hz, 1H), 7.02 (ddd, J ) 8.8, 2.9, 2.2 Hz, 2H), 7.58 (ddd,
8.8, 2.9, 2.2 Hz, 2H), 7.70 (br d, J ) 8.1 Hz, 2H), 7.95 (br d, J
) 8.4 Hz, 2H); ESI+ MS m/z 407.2 (M + NH4)+, 390.1 (M +
H)+.
(2R)-{[4′-Meth oxy(1,1′-bip h en yl)-4-yl]su lfon yl}a m in o-
6-m eth oxyh ex-4-yn oic Acid (48). Alcohol 16 (1.15 g, 2.95
mmol) was dissolved in acetone and J one’s reagent (10 mL, 8
N) was added dropwise at room temperature. The reaction
stirred for 4 h and was then quenched with isoproanol. The
green precipitate was filtered off through Celite and the
solvent was then evaporated to a green residue which was
dissolved in 5% aqueous NaHCO3 and washed with EtOAc.
The aqueous layer was acidified with concentrated HCl and
the pure white precipitate filtered off and washed with water
1
(35%) of clear oil: H NMR (CDCl3, 300 MHz) δ 1.22 (s, 9H),
1.62-1.69 (br s, 1H), 2.47-2.53 (m, 2H), 3.37 (dd, J ) 9.0, 6.4
Hz, 1H), 3.51 (dd, J ) 9.0, 3.8 Hz, 1H), 3.82-3.91 (m, 1H),
4.11 (dd, J ) 2.1, 2.1 Hz, 2H); ESI+ MS m/z 211.1 (M + H)+.
1-ter t-Bu t oxy-(2S)-m et h a n esu lfon oxy-6-m et h oxyh ex-
4-yn e (14a ). The alcohol 14 (10.5 g, 50 mmol) was taken in
1
and dried to give 720 mg (61%) of a white powder: H NMR