by HPLC analysis (3 h). LiOH‚H2O (539 g, 12.8 mol, 4.8 equiv)
was added portionwise over ∼5 min, and the mixture was stirred
for 2 h. Acetic acid (770 g, 12.8 mol) was added, and the reaction
mixture was heated to 60 °C for 16 h to effect the decarboxylation.
The resulting slurry was diluted with water (10 L), maintaining an
internal temperature of 50 °C. The suspension was cooled to room
temperature over 3 h and then filtered. The filter cake was washed
with a 1:1 mixture of EtOH/H2O (5.0 L) and heptane (5.0 L) and
then dried under vacuum at 55 °C with a N2 bleed. The desired
product was obtained as a white crystalline solid (1.130 kg, 88.9:
11.1 3R/3S isomers). The product was suspended in 1:1 MeCN/
H2O (22.6 L) and heated to 75 °C for 1 h. The slurry was cooled
to 35 °C over 5 h and filtered. The filter cake was washed with 1:1
MeCN/H2O (4.5 L), heptane (4.5 L), and dried under vacuum at
55 °C with a N2 bleed for 1.5 days. The desired product was
obtained as a white solid (1.060 kg, 97.5:2.5 3R/3S isomers, 84%).
The dr was determined by normal-phase HPLC analysis: YMC-
Pack, silica, 250 × 4.6 mm, 5 µm particle size, observing at 215
nm, 10 µm injection volume. Mobile phase: 10% IPA/hexane,
isocratic method, 7 min run time. (3R)-Isomer elutes at 5.25 min;
layer was extracted with MTBE (150 mL), and the combined
organic layers were then washed with H2O (3 × 150 mL). The
organic layer was chase distilled with MeCN (3 × 100 mL),
redissolved in 200 mL of MeCN, and used in the next step without
further purification. An HPLC assay of the MeCN product solution
showed the product was formed in 95.3% yield (42.97 g) in a 94.1:
5.9 dr (HPLC area % at 220 nm). Analytically pure material was
obtained by column chromatography for use as an external standard
(50% EtOAc/hexane with 1% v/v NEt3, Rf ) 0.25): 1H NMR (400
MHz, CDCl3) δ 0.64-0.70 (m, 6 H), 0.95-1.03 (m, 9 H), 1.28 (s,
1 H), 1.37 (s, 8 H), 1.64 (ddd, J ) 13.41, 10.33, 3.57 Hz, 1 H),
1.88-1.97 (m, 1 H), 2.45-2.56 (m, 1 H), 2.65-2.90 (m, 4 H),
3.73 (dd, J ) 10.09, 3.77 Hz, 1 H), 3.86-3.94 (m, 1 H), 4.79-
4.95 (m, 3 H), 7.11-7.27 (m, 8 H), 7.64-7.76 (m, 2 H), 7.86 (d,
J ) 8.10 Hz, 2 H), 8.65 (ddd, J ) 4.84, 1.68, 0.89 Hz, 1 H); 13C
NMR (100 MHz, CDCl3) δ 5.6, 7.4, 28.6, 37.7, 39.6, 40.1, 44.9,
54.0, 70.5, 79.2, 120.0, 121.6, 126.0, 126.7, 128.0, 128.9, 129.0,
136.3, 137.2, 138.4, 139.8, 149.2, 155.5, 156.8, 175.5; [R]25
)
D
+9.12 (c 0.97, CHCl3). Anal. Calcd for C35H49N3O4Si: C, 69.61;
H, 8.18; N, 6.96. Found: C, 69.26; H, 8.28; N, 6.86.
1
(3S)-isomer elutes at 6.05 min: mp 157 °C; H NMR (400 MHz,
[(1S,2S,4S)-4-Amino-1-benzyl-2-hydroxy-5-(4-pyridin-2-yl-
phenyl)pentyl]carbamic Acid tert-Butyl Ester (1). The crude
MeCN solution of 11 was diluted to 0.16 M with additional MeCN
(152 mL). N,N-Dibromo-5,5-dimethylhydantoin (12) (9.6 g, 33.7
mmol, 0.6 equiv) was added; the suspension was stirred until it
became homogeneous. A 1 M NaOH solution (339 mL, 339 mmol,
6.0 equiv) was then added, and the resulting biphasic solution was
stirred at ambient temperature until the reaction was complete as
determined by HPLC analysis (30 min). The reaction was then
adjusted to pH 2-3 with HCl (37 wt % in H2O, 31.7 mL, 392.7
mmol, 7.0 equiv) and stirred until the TES-deprotection was
complete (4 h). The crude reaction mixture was extracted with
MTBE (150 mL) to remove the silyl byproducts. EtOAc (300 mL)
was added to the aqueous layer, followed by 2 M NaOH (84 mL,
168 mmol, 3.0 equiv) to achieve a pH of 9-10. The layers were
separated, and the aqueous layer was extracted with EtOAc (150
mL). The combined organic layers were washed with a 10 wt %
NaCl solution (3 × 150 mL). The organic solution was chase
distilled with EtOH (300 mL) and then dissolved in EtOH (130
mL). A HPLC assay of the EtOH solution vs an external standard
shows a 91.2% crude assay yield (22.1 g of 1,3-trans product 1,
1.53 g of 1,3-cis product, 93.5:6.5 dr). The EtOH solution was
heated to 70 °C and H2O (195 mL, 1.5:1 H2O/EtOH) was added
dropwise, during which time the crystallization nucleated. The
suspension was held at 70 °C for 2 h and then cooled to ambient
temperature at 10 °C/h. The product was then filtered and dried at
50 °C, 20 mmHg. The desired product was obtained in 87.8% yield
CDCl3) δ 1.37 (s, 9H), 1.77-1.90 (m, 1H), 2.11 (ddd, J ) 12.97,
8.64, 5.97 Hz, 1 H), 2.73 (dd, J ) 13.86-9.88 Hz, 1 H), 2.79-
3.02 (m, 3H), 3.32 (dd, J ) 13.86, 3.84 Hz, 1 H), 3.95 (q, J )
8.42, 1H), 4.32 (ddd, J ) 10.15, 5.97, 1.58, 1H), 4.61 (d, J ) 9.74
Hz, 1H), 7.15-7.3 (m, 8H), 7.64-7.75 (m, 2H), 7.90 (ddd, J )
8.37, 2.06, 1.97 Hz, 2H), 8.85 (ddd, J ) 4.77, 1.75, 1.03 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 28.4, 30.8, 36.2, 39.5, 42.6, 53.3,
77.7, 79.8, 120.0, 121.7, 126.4, 126.9, 128.3, 128.8, 129.0, 136.3,
136.8, 137.5, 138.9, 149.2, 155.3, 156.5, 177.2; MS-ESI 473 (M
+ 1); [R]25 ) +75.44 (c 0.98, CHCl3).
D
[(1S,2S,4S)-1-Benzyl-4-carbamoyl-2-hydroxy-5-(4-pyridin-2-
ylphenyl)pentyl]carbamic Acid tert-Butyl Ester (10). A stainless
steel bomb was charged with lactone 5 (38 g, 80.4 mmol, 1.0 equiv),
DME (380 mL, 0.2 M), and ammonia (380 mL, 133 psi) and stirred
at ambient temperature for 48 h. The reaction vessel was carefully
vented; the desired product was obtained as a slurry in DME. The
product solution was dissolved in NMP (380 mL, 0.2 M), and the
residual ammonia and DME were removed by distillation. An
HPLC assay of the crude reaction mixture vs an external standard
showed the product was formed in 95.4% yield (37.55 g) in a 94.6:
5.4 dr (HPLC area % at 220 nm), with 4.7 mol % residual starting
material (5). The crude product mixture was used in the next step
without further purification. Crystalline 10 was obtained by filtration
of the DME slurry and drying the resulting wet cake at 50 °C, 20
mmHg (76% isolated yield, 19% loss to DME liquors): mp 163
°C; 1H NMR (400 MHz, DMSO-d6, rotamers) δ 1.30 (br s, 1.0 H),
1.27 (br s, 1.1 H), 1.29 (br s, 6.9 H), 1.41-1.52 (m, 1 H), 1.64
(ddd, J ) 13.86, 7.34, 7.07 Hz, 1 H), 2.58-2.81 (m, 5 H), 3.49-
3.57 (m, 1 H), 3.74 (ddd, J ) 14.41, 9.19, 2.33 Hz, 1 H), 4.58 (d,
J ) 6.31 Hz, 1 H), 5.81 (d, J ) 9.74 Hz, 0.1 H), 6.31-6.39 (m,
0.9 H), 6.60-6.77 (m, 1 H), 7.10-7.28 (m, 7 H), 7.30 (ddd, J )
7.20, 4.87, 1.10 Hz, 1 H), 7.80-7.99 (m, 4 H), 8.60-8.65 (m, 1H);
13C NMR (100 MHz, DMSO-d6) δ 28.2, 36.2, 36.7, 37.6, 43.6,
55.0, 68.9, 77.2, 119.4, 121.9, 125.2, 125.6, 127.4, 128.6, 128.7,
1
(24.06 g, 97:3 dr): mp 153 °C; H NMR (400 MHz, CDCl3) δ
1.34-1.60 (m, 11 h), 2.46 (dd, J ) 13.52 Hz, 1H), 2.79-2.92 (m,
3 H), 3.00-3.11 (br s, 1 H), 3.49 (m, 1 H), 3.66 (q, J ) 8.05 Hz,
1 H), 3.79 (d, J ) 10.43 Hz, 1 H), 4.89 (br s, 1 H), 5.08 (d, J )
9.47 Hz, 1 H), 7.12-7.23 (m, 4 H), 7.24-7.31 (m, 4 H), 7.65-
7.76 (m, 2 H), 7.84-7.94 (m, 2 H), 8.66 (ddd, J ) 4.77, 1.68, 0.96
Hz, 1H); 13C NMR (400 MHz, CDCl3) δ 28.7, 39.0, 39.5, 47.2,
54.1, 56.4, 71.4, 78.9, 120.1, 121.8, 125.8, 126.8, 128.0, 129.3,
135.7, 136.5, 139.0, 140.6, 148.8, 154.7, 154.8, 155.3, 175.7; [R]25
129.4, 136.4, 137.5, 138.4(8), 138.5(4), 149.3, 155.5, 156.6; [R]25
D
D
) -30.44 (c 1.0, CHCl3). Anal. Calcd for C29H35N3O4: C, 71.14;
) +4.96 (c 0.99, CHCl3). Anal. Calcd for C28H35N3O3: C, 72.86;
H, 7.21; N, 8.58. Found: C, 70.98; H, 6.99; N, 8.53.
H, 7.64; N, 9.10. Found: C, 72.70; H, 7.96; N, 9.11.
[(1S,2S,4S)-1-Benzyl-4-carbamoyl-5-(4-pyridin-2-ylphenyl)-
2-triethylsilanyloxypentyl]carbamic Acid tert-Butyl Ester (11).
Imidazole (22.5 g, 331.0 mmol, 5.0 equiv) was added to the crude
NMP solution of 10 (32.4 g, 66.2 mmol, 1.0 equiv), triethylsilyl
chloride was added (27.8 mL, 165.5 mmol, 2.5 equiv), and the
reaction solution was stirred at ambient temperature until 10 was
consumed, as determined by HPLC analysis (1 h). H2O (150 mL)
was added, and the solution was allowed to stir for an additional
15 min. An addition 150 mL of H2O was added, and then the crude
reaction mixture was extracted with MTBE (300 mL). The aqueous
Acknowledgment. We gratefully acknowledge Drs. Larry
Klein and David DeGoey for the initial procedures. We thank
Tim Grieme for preparation of the 2-(R-bromotolyl)pyridine.
Supporting Information Available: Analytical methods, ex-
perimental procedures for the preparation of 3, and 2D NMR data
for 5. This material is available free of charge via the Internet at
JO060737S
5372 J. Org. Chem., Vol. 71, No. 14, 2006