Supporting Information © Wiley-VCH 2005

69451 Weinheim, Germany

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Total Synthesis of Caprazol, a Core Structure of the

Anti-tuberculosis Antibiotics, Caprazamycins**

Shinpei Hirano, Satoshi Ichikawa, and Akira Matsuda*

Graduate School of Pharmaceutical Sciences, Hokkaido

University, Sapporo 060-0812, Japan

Methyl (E)-1-(3’-Benzyloxymethyluracil-1’-yl)-5,6-

dideoxy-2,3-O-isopentylidene-β-D-ribo-5-ene-heptofranuronat

e(4). A solution of 2’,3’-O-isopropylideneuridine (3, 10.0 g,

41.0 mmol) in MeCN (400 mL) was treated with IBX (28.6 g, 103

mmol), and the mixture was heated at 80 °C for 1 hour. The

reaction mixture was cooled in ice bath, then the white

precipitates were filtered off. The filtrate was concentrated

in vacuo. The residue was dissoloved in CH2Cl2 (400 mL), and

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the solution was cooled to –20 °C, to which the solution of

Ph3P=CHCO2Me (16.4 g, 49.2 mmol) in CH2Cl2 (100 mL) was added

dropwise. The reaction mixture was stirred at –20 °C for 1 hour

before the saturated oxalic acid in methanol (20 mL) was added.

The mixture was diluted with EtOAt (800 mL), washed with H2O

(800 mL) and saturated aqueous NaCl (800 mL). The organic phase

was dried (Na2SO4), filtered, and concentrated in vacuo. The

residue was dissoloved in CH2Cl2 (300 mL) and treated with BOMCl

(8.5 mL, 61.5 mmol), Bu4NI (756 mg, 2.05 mmol), and Na2CO3 (17.4

g, 164 mmol) in H2O (200 mL). The resulting biphasic layers were

vigorously stirred at room temperature for 12 hours. The organic

phase was diluted with EtOAt (500 mL), washed with H2O (500 mL)

and saturated aqueous NaCl (500 mL). The organic phase was dried

(Na2SO4), filtered, and concentrated in vacuo. The residue was

purified by silica gel column chromatography (15×20 cm, 25–45%

EtOAc–hexane eluent) to afford 4 (12.4 g, 66%) as a colorless

syrup: [α]22D +52.0 (c 1.66, CHCl3); 1H NMR (CDCl3, 500 MHz) δ

7.32 (m, 5H, H-Ar), 7.13 (d, 1H, H-6, J6,5 = 8.1 Hz), 7.02 (dd,

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1H, H-5’, J5’,6’ = 15.6 , J5’,4’ = 5.6 Hz), 6.04 (dd, 1H, H-6’,

J6’,5’ = 15.6, J6’,4’ = 1.5 Hz), 5.76 (d, 1H, H-5, J5,6 = 8.1 Hz),

5.57 (d, 1H, H-1’, J1’,2’ = 1.3 Hz), 5.48 (d, 1H, NCH2OBn, J =

9.8 Hz), 5.43 (d, 1H, NCH2OBn, J = 9.8 Hz), 5.04 (dd, 1H, H-2’,

J2’,1’ = 1.3, J2’,3’ = 6.4 Hz), 4.87 (dd, 1H, H-3’, J3’,2’ = 6.4,

J3’,4’ = 1.1 Hz), 4.70 (s, 2H, NCH2OCH2Ph), 4.66 (ddd, 1H, H-4’,

J4’,3’ = 1.1, J4’,5’ = 5.6, J4’,6’ = 1.5 Hz), 3.70 (s, 3H, COCH3),

1.58 (s, 3H, acetonide), 1.36 (s, 3H, acetonide); 13C NMR (CDCl3,

125 MHz) δ 166.07, 162.35, 150.60, 143.68, 141.09, 137.86,

128.27, 127.67, 127.61, 122.32, 114.70, 102.39, 95.98, 86.92,

84.56, 84.04, 72.33, 70.34, 51.70, 27.10, 25.29; FABMS-LR m/z

459 (MH+); FABMS-HR (NBA) calcd for C23H27N2O8 459.1767, found

459.1756.

Metyl06-Benzyloxycarbonylamino-1-(3’-benzyloxymethyl

uracil-1’-yl)-6-deoxy-2,3-O-isopropylidene-β-D-glycelo-L-ta

lo-heptofuranuronate0(5a)0and0Metyl06-Benzyloxycarbonylamin

o-1-(3’-benzyloxymethyluracil-1’-yl)-6-deoxy-2,3-O-isopropy

lidene-α-L-glycelo-D-allo-heptofuranuronate (5b). t-Butyl

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hypochlorite (1.13 mL, 10.0 mmol) was added to a solution of

benzyl carbamate (1.49 g, 9.87 mmol) in 0.6 M aqueous NaOH (14

mL) and PrOH (16.5 mL) at 15 °C, and the mixture was stirred

for 15 min, which was then allowed to room temperature. A

solution of [DHQD]2AQN (422 mg, 0.49 mmol) in PrOH (8.3 mL),

a solution of 4 (1.50 g, 3.28 mmol) in PrOH (8.3 mL) and a solution

of K2[Os2(OH)4] (180 mg, 0.498 mmol) were sequentially added to

the mixture. The resulting whole mixture was stirred at room

temperature for 2 hours. After saturated aqueous Na2S2O3 (100

mL) was added, the reaction mixture was extracted with EtOAc

(100 mL × 3). The combined organic phase was washed with

saturated aqueous NaCl (400 mL), dried (Na2SO4), filtered, and

concentrated in vacuo. The residue was purified by flash silica

gel column chromatography (6×15 cm, 40–45% EtOAc–hexane eluent)

to afford 5a (1.08 g, 52%) as a white foam and 5b (175 mg, 0.28

mmol, 8.5%) as a white foam: data for 5a; [α]22D +34.4 (c 1.03,

CHCl3); 1H NMR (CDCl3, 500 MHz) δ 7.33-7.24 (m, 10H, H-Ar), 7.15

(d, 1H, H-6, J6,5 = 8.1 Hz), 5.72 (d, 1H, H-5, J5,6 = 8.1 Hz),

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5.59 (br s, 1H, NH), 5.46-5.41 (m, 3H, NCH2OBn, H-1’), 5.12 (d,

1H, CO2CH2Ph, J = 11.1 Hz), 5.06 (d, 1H, CO2CH2Ph, J = 11.1 Hz),

4.95 (m, 2H, H-2’, H-3’), 4.68 (m, 2H, NCH2OCH2Ph), 4.53 (m,

1H, H-6’), 4.26 (m, 2H, H-4’, H-5’), 3.72 (s, 3H, COCH3), 3.72

(br s, 1H, OH), 1.54 (s, 3H, acetonide), 1.34 (s, 3H, acetonide);

13C NMR (CDCl3, 125 MHz) δ 170.67, 162.12, 141.55, 151.16, 141.55,

137.69, 136.13, 128.50, 128.32, 128.20, 128.13, 127.75, 127.59,

114.79, 102.49, 97.00, 86.20, 82.83, 81.36, 72.43, 71.51, 70.37,

67.51, 56.48, 52.69, 27.18, 25.27, 12.00; FABMS-LR m/z 626

(MH+); FABMS-HR (NBA) calcd for C31H36N3O11 626.2356, found

626.2340; data for 5b; [α]22D +24.9 (c 1.74, CHCl3); 1H NMR (CDCl3,

500 MHz) δ 7.36-7.25 (m, 10H, H-Ar), 7.12 (d, 1H, H-6, J6,5 =

7.7 Hz), 5.74 (d, 1H, H-5, J5,6 = 7.7 Hz), 5.58 (d, 1H, NH, JNH,6’

= 8.6 Hz), 5.47 (d, 1H, NCH2OBn, J = 9.9 Hz), 5.40 (d, 1H, NCH2OBn,

J = 9.9 Hz), 5.35 (s, 1H, H-1’), 5.13 (m, 3H, H-3’, CO2CH2Ph),

5.08 (dd, 1H, H-2’, J2’,1’ = 1.6, J2’,3’ = 6.7 Hz), 4.66 (m, 2H,

NCH2OCH2Ph), 4.58 (d, 1H, H-4’, J4’,5’ = 9.2 Hz), 4.42 (m, 1H,

H-5’), 4.15 (m, 1H, H-6’), 3.71 (s, 3H, COCH3), 3.26 (br s, 1H,

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OH), 1.53 (s, 3H, acetonide), 1.31 (s, 3H, acetonide); 13C NMR

(CDCl3, 125 MHz) δ 171.17, 162.31, 157.00, 150.97, 142.16,

137.74, 136.15, 128.49, 128.32, 128.15, 127.98, 127.76, 127.61,

114.25, 102.34, 97.84, 87.82, 83.99, 81.16, 72.44, 71.48, 70.37,

67.21, 55.60, 52.68, 27.05, 25.11, 11.43; FABMS-LR m/z 626

(MH+); FABMS-HR (NBA) calcd for C31H36N3O11 626.2350, found

626.2368.

Methyl05-O-[5’’-Azido-5’’-deoxy-2’’,3’’-O-(3’’’-penty

lidene)-β-D-ribofuranosyl]-6-benzyloxycarbonylamino-1-(3’-b

enzyloxymethyluracil-1’-yl)-6-deoxy-2,3-O-isopropylidene-β-

D-glycelo-L-talo-heptofuranuronate0(7a)0and0Methyl05-O-[5’’

-Azido-5’’-deoxy-2’’,3’’-O-(3’’’-pentylidene)-α-D-ribofuran

osyl]-6-benzyloxycarbonylamino-1-(3’-benzyloxymethyluracil-

1’-yl)-6-deoxy-2,3-O-isopropylidene-β-D-glycelo-L-talo-hept

ofuranuronate (7b). A mixture of 5a (20.0 mg, 0.032 mmol), 6b

(11.8 mg, 0.048 mmol), and MS4A (100 mg) in CH2Cl2 (1 mL) was

stirred at –30 °C for 15 min. BF·OEt2 (1.2 µL, 0.01 mmol) was

added five times at each hour. The reaction mixture was stirred

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for totally 5 hours. The saturate aqueous NaHCO3 (5 mL) was added,

and the mixture was extracted with EtOAc (5 mL). The organic

phase was washed with saturate aqueous NaCl (5 mL), dried

(Na2SO4), filtered, and concentrated in vacuo. The residue was

purified by silica gel column chromatography (6×15 cm, 33%

EtOAc–hexane eluent) to afford 7a (20.9 mg, 77%) as a white foam

and 7b (0.8 mg, 0.94 µmol, 3%) as a white foam: data for 7a;

[α]22D +20.2 (c 1.36, CHCl3); 1H NMR (CDCl3, 500 MHz) δ 7.38-7.28

(m, 11H, H-Ar, H-6), 5.79 (d, 1H, NH, JNH,6’ = 9.7 Hz), 5.71 (d,

1H, H-5, J5,6 = 8.1 Hz), 5.61 (s, 1H, H-1’), 5.48 (d, 1H, NCH2OBn,

J = 9.7 Hz), 5.43 (d, 1H, NCH2OBn, J = 9.7 Hz), 5.22 (d, 1H,

CO2CH2Ph, J = 12.1 Hz), 5.12 (s, 1H, H-1”), 5.05 (d, 1H, CO2CH2Ph,

J = 12.1 Hz), 4.81 (m, 2H, H-2’, H-3’), 4.70 (s, 2H, NCH2OCH2Ph),

4.65 (d, 1H, H-6’, J6’,NH = 9.7 Hz), 4.56 (m, 2H, H-2”, H-3”),

4.46 (d, 1H, H-5’, J5’,4’ = 7.0 Hz), 4.22 (m, 2H, H-4’, H-4”),

3.74 (s, 3H, COCH3), 3.38 (dd, 1H, H-5”a, J5”a,5”b = 12.7, J5”a,4”

= 5.6 Hz), 3.32 (dd, 1H, H-5”b, J5”b,5”a = 12.7, J5”b,4” = 7.9 Hz),

1.59 (m, 2H, CH2CH3), 1.48 (m, 5H, CH2CH3, acetonide), 1.32 (s,

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3H, acetonide), 0.83 (m, 6H, CH2CH3×2) ; 13C NMR (CDCl3, 125 MHz)

δ 170.45, 162.42, 156.26, 150.85, 140.67, 137.88, 136.31,

128.50, 128.33, 128.24, 127.72, 117.30, 114.91, 113.38, 102.20,

94.62, 86.77, 86.03, 85.38, 83.92, 81.90, 80.80, 78.78, 72.41,

70.39, 67.24, 54.62, 53.20, 52.84, 29.34, 28.90, 27.13, 25.42,

8.36, 7.38; FABMS-LR m/z 851 (MH+); FABMS-HR (NBA) calcd for

C41H51N6O14 851.3463, found 851.3447; data for 7b; [α]22D +14.9

(c 1.13, CHCl3); 1H NMR (CDCl3, 500 MHz) δ 7.66 (d, 1H, H-6, J6,5

= 7.9 Hz), 7.37-7.24 (m, 10H, H-Ar), 5.97 (s, 1H, H-1’), 5.87

(d, 1H, NH, JNH,6’ = 8.0 Hz) , 5.73 (d, 1H, H-5, J5,6 = 7.9 Hz),

5.48 (d, 1H, NCH2OBn, J = 9.7 Hz), 5.44 (d, 1H,NCH2OBn, J = 9.7

Hz), 5.17 (d, 1, CO2CH2Ph, J = 12.3 Hz), 5.14 (br s, 1H, H-1”),

5.07 (d, 1H, CO2CH2Ph, J = 12.3 Hz), 4.87 (dd, 1H, H-3’, J3’,2’

= 6.2, J3’,4’ = 3.7 Hz), 4.70 (s, 2H, NCH2OCH2Ph), 4.63 (d, 1H,

H-6’, J6’,NH = 8.0 Hz), 4.59 (m, 2H, H-2’, H-2”), 4.53 (dd, 1H,

H-3”, J3”,2” = 6.8, J3”,4” = 3.0 Hz), 4.44 (m, 1H, H-4’), 4.32 (m,

1H, H-5’), 4.22 (m, 1H, H-4”), 3.73 (s, 3H, COCH3), 3.46 (m,

1H, H-5”a), 3.35 (m, 1H, H-5”b), 1.56 (s, 3H, acetonide), 1.49

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(s, 3H, acetonide), 1.33 (s, 3H, acetonide), 1.32 (s, 3H,

acetonide); 13C NMR (CDCl3, 125 MHz) δ 170.71, 162.49, 156.03,

150.93, 139.94, 137.92, 136.18, 128.47, 128.26 128.22, 127.97,

127.68, 127.68, 127.61, 115.47, 114.73, 103.22, 102.41, 91.56,

84.77, 83.56, 80.94, 80.75, 80.60, 80.21, 77.99, 77.25, 72.25,

70.42, 67.15, 54.62, 52.82, 52.46, 29.65, 27.23, 26.17, 25.38,

25.27; FABMS-LR m/z 823 (MH+); FABMS-HR (NBA) calcd for

C39H47N6O14 823.3150, found 823.3167.

Methyl05-O-[5’’-t-Butyloxycarbonylamino-5’’-deoxy-2’’,

3’’-O-(3’’’-pentylidene)-β-D-ribofuranosyl]-6-deoxy-6-benzy

loxycarbonylamino-1-(3’-benzyloxymethyluracil-1’-yl)-2,3-O-

isopropylidene-β-D-glycelo-L-talo-heptofuranuronate (9). A

solution of 7a (712 mg, 0.839 mmol) in benzene–THF (1:1, 8 mL)

was treated with Ph3P (660 mg, 2.52 mmol) and H2O (755 µL, 41.1

mmol), and the resulting mixture was heated at 50 °C for 12 hours.

The reaction mixture was allowed to room temperature, to which

(Boc)2O (389 µL, 1.68 mmol) and NaHCO3 (141 mg, 1.68 mmol). The

resulting mixture was stirred at room temperature for an hour

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and partitioned between EtOAc (30 mL) and H2O (30 mL). The

organic phase was washed with saturated aqueous NaCl (30 mL),

dried (Na2SO4), filtered, and concentrated in vacuo. The residue

was purified by silica gel column chromatography (5×20 cm,

37–40% EtOAc–hexane eluent) to afford 8 (736 mg, 2 steps 95%)

as a white foam: [α]23D +31.2 (c 0.63, CHCl3); 1H NMR (CDCl3, 500

MHz) δ 7.38-7.27 (m, 10H, H-Ar), 7.22 (d, 1H, H-6, J6,5 = 8.0

Hz), 5.73 (d, 1H, H-5, J5,6 = 8.0 Hz), 5.56 (d, 1H, NCH2OBn, J

= 9.8 Hz), 5.18 (m, 1H, NH), 5.12 (d, 1H, CO2CH2Ph, J = 12.3

Hz), 5.06 (s, 1H, H-1”), 5.02 (d, 1H, CO2CH2Ph, J = 12.3 Hz),

4.97 (d, 1H, H-2’, J2’,3’ = 6.3 Hz), 4.84 (dd, 1H, H-3’, J3’,2’

= 6.3, J3’,4’ = 4.4 Hz), 4.70 (s, 2H, NCH2OCH2Ph), 4.67 (m, 1H,

H-6’), 4.52 (m, 2H, H-2”, H-3”), 4.42 (d, 1H, H-5’, J5’,4’ = 8.2

Hz), 4.21 (m, 2H, H-4’, H-4”), 3.77 (s, 3H, COCH3), 3.20 (m,

1H, H-5”a), 3.07 (m, 1H, H-5”b), 1.57-1.44 (m, 4H, CH2CH3×2),

1.48 (s, 3H, acetonide), 1,41 (s, 9H, t-butyl), 1.33 (s, 3H,

acetonide), 0.79-0.73 (m, 6H, CH2CH3×2); 13C NMR (CDCl3, 125 MHz)

δ 171.06, 162.36, 156.10, 155.96, 150.81, 141.41, 137.75,

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136.10, 128.44, 128.26, 128.16, 127.69, 116.48, 114.71, 112.46,

102.22, 96.12, 86.99, 86.157, 84,14, 82.02, 81.14, 79.82, 79.33,

72.34, 70.29, 67.22, 54.86, 52.98, 43.32, 29.34, 28.76, 28.33,

27.01, 25.29, 8.32, 7.21; FABMS-LR m/z 925 (MH+); FABMS-HR (NBA)

calcd for C46H61N4O16 925.4083, found 925.4064.

N-[(1’’R,2’’S)-2’’-Benzyloxy-1’’-t-butyldiphenylsilyl

oxymethyl-3-butenyl]-N-methyl-6-benzyloxycarbonylamino-1-(3

’-benzyloxymethyluracil-1’-yl)-6-deoxy-2,3-O-isopropylidene

-β-D-glycelo-L-talo-heptofuranuronamide (11). Barium

hydroxide octahydrates (260 mg, 0.824 mmol) was added to a

solution of 8 (692 mg, 0.749 mmol) in THF–H2O (4:1, 10 mL) at

room temperature, and the resulting reaction mixture was

stirred at room temperature for 10 hours. The reaction mixture

was poured onto 1 M aqueous HCl (30 mL) and extracted with CHCl3

(30 mL). The organic phase was dried (Na2SO4), filtered, and

concentrated in vacuo. The residue was purified by short silica

gel column chromatography (5×13 cm, 33% MeOH–CHCl3 eluent) to

afford crude carboxylic acid 9 (319 mg, 47%) as colorless syrup.

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A solution of the carboxylic acid 9 and 10 (254 mg, 0.527 mmol)

in THF (3.5 mL) was treated sequentially with NaHCO3 and DEPBT

(420 mg, 1.40 mmol) at 0 °C. The mixture was stirred at 0 °C

for an hour, then at room temperature for additional 28 hours.

The reaction mixture was partitioned between EtOAc (10 mL) and

saturated aqueous NaHCO3 (10 mL). The organic phase was washed

with 1 M aqueous HCl (10 mL) and saturated aqueous NaCl (10 mL),

dried (Na2SO4), filtered, and concentrated in vacuo. The residue

was purified by flash silica gel column chromatography (8×10

cm, 17–33% EtOAc–hexane eluent) to afford 11 (315 mg, 65%) as

a white foam: [α]23D –9.78 (c 0.45, CHCl3); 1H NMR (CDCl3, 500

MHz, 3:1 mixture of rotamers) δ 7.69-7.56 (m, 5.2H, H-Ar),

7.45-7.23 (m, 22.1H, H-Ar, H-6), 6.22 (m, 0.3H), 5.98 (m, 1.0H),

5.92-5.80 (m, 3.0H), 5.48-5.44 (m, 2.0H, CO2CH2Ph), 5.38 (d,

1.0H, CO2CH2Ph, J = 9.6 Hz), 5.28 (m, 0.6H), 5.18-5.09 (m, 3.6H),

5.05-4.98 (m, 3.9H), 4.82-4.76 (m, 1.9H), 4.71-4.68 (m, 4.0H),

4.51 (m, 1.8H), 4.23 (m, 1.0H), 4.32-4.22 (m, 4.0H), 4.16-4.09

(m, 2.6H), 4.09-3.90 (m, 2.7H), 3.62 (t, 0.3H, J = 10.2 Hz),

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3.28 (m, 1.3H), 3.10 (m, 4.0H, include CONCH3), 2.79 (s, 0.9H,

include CONCH3), 1.71-1.42 (m, 20.8H, t-butyl, acetonide,

CH2CH3), 1.30 (s, 3H, acetonide), 1.29 (s, 3H, acetonide), 1.03

(s, 9H, t-butyl), 0.98 (s, 3H, t-butyl), 0.82 (m, 7.8H, CH2CH3),

0.73 (s, 9H, t-butyl), 0.72 (s, 3H, t-butyl), −0.12 (m, 3.9H,

SiCH3), −0.15 (m, 3.9H, SiCH3); 13C NMR (CDCl3, 125 MHz) δ 171.15,

170.52, 162.40, 162.40, 162.38, 156.20, 156.18, 150.98, 150.96,

139.93, 139.74, 138.74, 138.09, 137.94, 137.88, 136.21, 135.71,

135.51, 135.48, 136.21, 133.12, 132.67, 132.61, 129.87, 129.76,

129.76, 129.69, 128.45, 128.41, 128.35, 128.26, 127.78, 127.72,

127.70, 127.62, 127.57, 117.47, 117.10, 116.68, 116.33, 115.22,

114.76, 112.03, 11.05, 102.56, 102.41, 92.69, 86.69, 86.20,

85.79, 84.75, 84.01, 83.50, 81.99, 81.75, 80.57, 79.22, 78.85,

78.31, 73.31, 73.04, 72.24, 70.45, 70.32, 67.14, 63.20, 60.79,

60.54, 50.94, 43.38, 43.19, 29.65, 29.45, 29.33, 28.95, 28.43,

27.23, 27.18, 26.86, 26.73, 25.69, 25.56, 25.50, 25.29, 19.03,

18.80, 17.82, 17.76, 8.33, 7.50, 7.38, −4.00, −4.23, −5.18,

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−5.32; FABMS-LR m/z 1376 (MH+); FABMS-HR (NBA) calcd for

C73H102N5O17Si2 1376.6807, found 1376.6800.

N-[(1’’’R,2’’’S)-2’’’-t-Butyldimethylsilyloxy-1’’’-t-

butyldiphenylsilyloxymethyl-3-oxo-propyl]-N-methyl-6-benzyl

oxycarbonylamino-1-(3’-benzyloxymethyluracil-1’-yl)-5-O-[5’

’-t-butyloxycarbonylamino-5’’-deoxy-2’’,3’’-O-(3’’’-pentyli

dene)-β-D-ribofuranosyl]-6-deoxy-2,3-O-isopropylidene-β-D-g

lycelo-L-talo-heptofuranuronamide (12). A solution of 11 (310

mg, 0.225 mmol) and NMO (121 mg, 0.563 mmol) in acetone–H2O (4:1,

2.5 mL) was treated with OsO4 (5.0 mg/mL t-BuOH solution, 500

µL), and the resulting reaction mixture was stirred at room

temperature for 24 hours. After saturated aqueous Na2S2O3 (10

mL) was added, the mixture was extracted with EtOAc (10 mL).

The organic phase was washed with saturated aqueous NaCl (10

mL), dried (Na2SO4), filtered, and concentrated in vacuo. The

residue was purified by short silica gel column chromatography

(3×5 cm, 33% EtOAc–hexane, then 2% MeOH, 50% EtOAc–hexane

eluent), and fractions containing the diol were collected and

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concentrated in vacuo. A solution of the diol in

acetone–phosphate buffer (4:1, pH 7.5, 3 mL) was treated with

NaIO4 (123 mg, 0.609 mmol), and the resulting reaction mixture

was stirred at room temperature for 12 hours. After saturated

aqueous Na2S2O3 (10 mL) was added, the mixture was extracted with

EtOAc (10 mL). The organic phase was washed with saturated

aqueous NaCl (10 mL), dried (Na2SO4), filtered, and concentrated

in vacuo. The residue was purified by silica gel column

chromatography (3×10 cm, 3% acetone–CHCl3 eluent) to afford 12

(189 mg, 61%) as a white foam: [α]21D –19.8 (c 0.34, CHCl3); 1H

NMR (CDCl3, 500 MHz, 4:1 mixture of rotamers) δ 9.70 (s, 0.3H,

H-1’’’), 9.56 (s, 1.0H, H-1’’’), 7.64-7.59 (m, 5.0H, H-Ar),

7.42-7.20 (m, 21.3H), 6.07 (br s, 1.0H), 5.89 (br s, 0.3H, H-1’),

5.76 (m, 1.3H), 5.68-5.66 (m, 1.9H), 5.48 (d, 0.3H, NCH2OBn,

J = 9.7 Hz), 5.44 (d, 0.3H, NCH2OBn, J = 9.7 Hz), 5.37 (d, 1.0H,

NCH2OBn, J = 9.6 Hz), 5.28 (d, 1.0H, NCH2OBn, J = 9.6 Hz), 5.19

(m, 1.3H), 5.12 (m, 0.3H), 4.96-4.92 (m, 2.5H), 4.90-4.75 (m,

2.2H), 4.70-4.35 (m, 7.6H), 4.32-4.18 (m, 2.0H), 4.14-4.08 (m,

S16

2.3H), 4.01-3.98 (m, 1.3H), 3.85 (m, 1.0H), 3.67 (m, 0.3H),

3.25-3.16 (m, 1.3H), 3.10 (m, 4.0H, CONCH3), 2.86 (s, 0.7H,

CONCH3), 1.60-1.40 (m, 20H), 1.31 (m, 5.0H), 1.00 (t-butyl),

0.98 (s, 3.0H), 0.93 (s, 3.0H), 0.87 (s. 9.0H, t-butyl),

0.85-0.78 (m, 8H), 0.10 (s, 0.7H, SiCH3), 0.07 (s, 0.7H, SiCH3),

0.03 (s, 3.0H, SiCH3), −0.05 (s, 3.0H, SiCH3); 13C NMR (CDCl3,

125 MHz) δ 199.94, 162.32, 156.19, 150.93, 140.65, 137.78,

136.23, 135.45, 135.35, 132.67, 132.51, 129.84, 128.42, 128.24,

128.07, 127.87, 127.80, 127.63, 127.57, 116.67, 114.61, 112.73,

102.43, 86.84, 85.93, 84.26, 81.95, 80.76, 79.73, 79.13, 72.17,

70.38, 70.12, 67.16, 59.99, 51.50, 43.20, 29.31, 28.84, 28.40,

27.20, 27.08, 26.64, 26.48, 25.81, 25.67, 25.31, 18.96, 17.95,

17.90, 8.36, 7.33, 7.19, −4.24, −4.62, −5.27, −5.39; FABMS-LR

m/z 1378 (MH+); FABMS-HR (NBA) calcd for C72H100N5O18Si2 1378.6602

found 1378.6580.

Diazepanone (13). A mixture of 12 (78.3 mg, 0.054 mmol)

and Pd black (150 mg) in i-PrOH (10 mL) was vigorously stirred

under H2 atmosphere at room temperature for 12 hours. The

S17

catalyst was filtered off through Celite pad, and the filtrate

was concentrated in vacuo. The residue in EtOAc (4 mL) was

treated with AcOH (40 µL) and NaBH(OAc)3 (45.4 mg, 0.216 mmol),

and the reaction mixture was stirred at room temperature for

12 hours. The mixture was partitioned between EtOAc (5 mL) and

saturated aqueous NaHCO3 (5 mL). The organic phase was washed

with saturated aqueous NaCl (5 mL), dried (Na2SO4), filtered,

and concentrated in vacuo. The residue was purified by neutral

silica gel column chromatography (1.5×13, 33–50% EtOAc–hexane

eluent) to afford 13 (eluted at 40% EtOAc–hexane eluent , 20.0

mg, 0.018 mmol, 2 steps 34%) as a white solid and 14 (eluted

at 50% EtOAc–hexane eluent , 14.4 mg, 2 steps 24%) as a white

solid: data for 13; [α]21D +19.8 (c 0.34, CHCl3); 1H NMR (CDCl3,

500 MHz) δ 7.71 (br s, 1H, H-3), 7.67-7.38 (m, 10H, H-Ar), 7.21

(d, 1H, H-6, J6,5 = 8.3 Hz), 6.22 (m, 1H, NHBoc), 5.65 (d, 1H,

H-5, J5,6 = 8.3 Hz), 5.45 (s, 1H, H-1’), 5.33 (s, 1H, H-1”), 4.84

(d, 1H, H-2’, J2’,3’ = 6.1 Hz), 4.63 (d, 1H, H-2”, J2”,3” = 5.9

Hz), 4.54 (dd, 1H, H-3’, J3’,2’ = 6.1, J3’,4’ = 6.1 Hz), 4.49 (d,

S18

1H, H-5’, J5’,4’ = 7.7 Hz), 4.44 (d, 1H, H-3”, J3”,2” = 5.9 Hz),

4.25 (dd, 1H, H-4”, J4”,5”a = 8.9, J4”,5”b = 5.2 Hz), 4.23 (dd, 1H,

H-4’, J4’,3 = 6.1, J4’,5’ = 7.7 Hz), 3.95 (m, 1H, H-6”’), 3.80 (m,

2H, H-8”’a, H-8”’b), 3.49 (m, 1H, H-7”’, H-5”a), 3.15 (s, 1H,

H-3”’), 3.09 (s, 3H, CONCH3), 2.98 (dd, 1H, H-5”’a, J5”’a,5”’b =

14.7, J5”’a,6”’ = 3.2 Hz), 2.77 (d, 1H, H-5”’b, J5”’b,”’a = 14.7 Hz),

2.72 (m, 1H, H-5”b), 1.59 (m, 2H, CH2CH3), 1.45 (m, 2H, CH2CH3),

1.40 (s, 9H, t-butyl), 1.26 (s, 3H, acetonide), 1.23 (s, 3H,

acetonide), 1.05 (s, 9H, t-butyl), 0.86(s, 9H, t-butyl), 0.81

(m, 6H, CH2CH3×2), 0.09 (s, 3H, SiCH3), 0.05 (s, 3H, SiCH3); 13C

NMR (CDCl3, 125 MHz) δ 173.33, 162.26, 156.10, 149.30, 142.38,

135.50, 135.41, 132.83, 132.68, 130.14, 130.11, 128.03, 128.00,

116.32, 114.79, 110.48, 102.32, 93.83, 87.04, 86.58, 86.36,

84.21, 82.09, 80.09, 80.28, 78.44, 68.53, 66.82, 62.59, 59.85,

50.73, 43.69, 40.29, 29.81, 29.02, 28.48, 27.32, 26.74, 25.65,

25.57, 19.05, 17.82, 8.27, 7.29, −4.84, −4.94; FABMS-LR m/z 1108

(MH+); FABMS-HR (NBA) calcd for C56H86N5O14Si2 1108.5711, found

1108.5700; data for 14; [α]21D –17.6 (c 0.67, CHCl3); 1H NMR (CDCl3,

S19

500 MHz) δ 9.06 (br s, 1H, H-3), 7.66-7.30 (m, 11H, H-Ar, H-6),

6.67 (m, 1H, NHBoc), 5.59 (m, 2H, H-5, H-1’), 5.26 (s, 1H, H-1’’),

4.68 (m, 2H, H-2’, H-3’), 4.56 (m, 2H, H-2’’, H-3’’), 4.33 (d,

1H, H-5’, J5’,6’ = 7.3 Hz), 4.24-4.14 (m, 2H, H-4’, H-4’’), 4.01

(m, 1H, H-6’’’), 3.92 (dd, 1H, H-8’’’a, J8’’’a,8’’’b = 10.4, J8’’’a,

7’’’ = 7.5 Hz), 3.86 (dd, 1H, H-8’’’b, J8’’’b, 8’’’a = 10.4, J8’’’b,

7’’’ = 6.9 Hz), 3.52-3.48 (m, 2H, H-7’’’, H-3’’’), 3.20 (m, 1H,

H-5’’a), 3.12 (m, 1H, H-5’’b), 3.07 (d, 1H, H-5’’’a, J5’’’a, 5’’’b

= 14.6 Hz), 2.98 (s, 3H, CONCH3), 2.87 (d, 1H, H-5’’’b, J5’’’b,

5’’’a = 14.6 Hz), 2.41 (s, 3H, NCH3), 1.62 (m, 2H, CH2CH3), 1.52

(m, 2H, CH2CH3), 1.48 (s, 3H, acetonide), 1.35 (s, 9H, t-butyl),

1.26 (s, 3H, acetonide ), 0.99 (s, 9H, t-butyl), 0.88 (s, 9H,

t-butyl), 0.86-0.79 (m, 6H, CH2CH3×2), 0.07 (s, 3H, SiCH3), 0.06

(s, 3H, SiCH3); 13C NMR (CDCl3, 125 MHz) δ 170.33, 162.43, 156.44,

149.30, 139.90, 135.34, 135.31, 132.75, 132.59, 130.15, 127.87,

116.75, 114.82, 112.08, 102.35, 89.81, 87.40, 86.69, 85.93,

84.29, 82.66, 79.59, 78.94, 75.78, 69.25, 63.80, 63.20, 59.67,

43.18, 38.97, 37.71, 29.67, 29.39, 28.00, 28.56, 27.29, 26.71,

S20

25.68, 25.6, 19.01, 17.81, 8.35, 7.47, −4.87, −5.03; FABMS-LR

m/z 1122 (MH+); FABMS-HR (NBA) calcd for C57H88N5O14Si2 1122.5866,

found 1122.5820.1

Alcohol (15). A solution of 14 (10.0 mg, 7.8 µmol) in MeOH

(1 mL) was treated with NH4F (50 mg), and the resulting reaction

mixture was stirred at room temperature for 48 hours and

concentrated in vacuo. The residue was purified by preparative

TLC (33% EtOAc–hexane eluant) to afford 15 (5.7 mg, 72%) as a

white solid: [α]21D –17.6 (c 0.67, CHCl3); 1H NMR (CD3CN, 500 MHz,

10:1 mixtures of conformers) δ 9.00 (br s, 1.0 H, NH-3), 7.56

(d, 1H, H-6, J6,5 = 8.2 Hz), 6.82 (br s, 1H, NHBoc), 5.81 (s,

1H, H-1’), 5.64 (d, 1H, H-5, J5,6 = 8.2 Hz), 5.27 (s, 1H, H-1’’),

4.80 (m, 2H, H-2’, H-3’), 4.59 (m, 2H, H-2’’, H-3’’), 4.34 (m,

1H, H-5’), 4.26 (m, 2H, H-4’, H-4’’), 4.00 (m, 1H, H-6’’), 3.69

(m, 3H, H-3’’’, H-8’’’a, H-8’’’b), 3.42 (m ,1H, H-7’’’), 3.18

(m, 3H, H-5’’a, H-5’’b, H-5’’’a), 3.04 (s, 3H, CONCH3), 3.02

(br s, 1H, OH), 2.83 (m, 1H, H-5’’’b), 2.41 (s, 3H, NCH3), 1.63

(m, 2H, CH2CH3), 1.52 (m, 5H, CH2CH3, acetonide), 1.39 (s, 9H,

S21

t-butyl), 1.31 (s, 3H, acetonide), 0.89 (s, 9H, t-butyl), 0.83

(m, 6H, CH2CH3×2), 0.09 (s, 6H, SiCH3×2); 13C NMR (CD3CN, 125

MHz) δ 163.69, 157.17, 151.12, 142.00, 141.99, 117.06, 115.19,

112.97, 103.05, 90.93, 87.79, 87.47, 87.02, 84.90, 83.22, 80.77,

79.18, 77.79, 70.91, 70.33, 63.81, 62.11, 60.45, 43.88, 38.29,

30.10, 29.60, 28.69, 27.53, 26.10, 25.59, 18.37, 14.25, 11.27,

8.65, 7.70, −4.69, −4.94; FABMS-LR m/z 884 (MH+); FABMS-HR (NBA)

calcd for C41H70N5O14Si 884.4689, found 884.4678.

Carboxylic acid (16). A solution of 15 (6.5 mg, 7.8 µmol)

in CH2Cl2 (0.5 mL) was treated with Dess-Martin periodinane

(11.4 mg, 26.5 µmol), and the resulting reaction mixture was

stirred at 0 °C for 40 min. Saturated aqueous NaHCO3–saturated

aqueous Na2S2O3 (2:1, 2 mL) and EtOAc (2 mL) were added, and the

resulting biphasic layers were vigorously stirred at room

temperature for 10 min. The organic phase was washed with

saturated aqueous NaCl (2 mL), dried (Na2SO4), filtered, and

concentrated in vacuo. The residue was dissolved in t-BuOH–H2O

(3:1, 0.5 mL) and treated sequentially with 2-methyl-2-butene

S22

(3.7 µL, 35.1 µmol), NaH2PO4·2H2O (1.2 mg, 7.8 µmol), and NaClO2

(3.1 mg, 27.3 µmol). The resulting reaction mixture was stirred

at room temperature for 10 min. After phosphate buffer (pH 7.5,

2 mL) was added, the mixture was extracted with CHCl3 (2 mL).

The organic phase was washed with saturated aqueous NaCl (2 mL),

dried (Na2SO4), filtered, and concentrated in vacuo. The residue

was purified by preparative TLC (17% MeOH–CHCl3 eluant) to

afford 16 (3.9 mg, 2 steps 56%) as a white solid: [α]21D –27.5

(c 0.39, CHCl3); 1H NMR (CD3OD, 500 MHz) δ 7.90 (d, 1H, H-6, J6,5

= 7.9 Hz), 5.82 (d, 1H, H-1’, J1’, 2’ = 2.7 Hz), 5.65 (d, 1H, H-5,

J5,6 = 7.9 Hz), 5.25 (s, 1H, H-1’’), 4.90-4.80 (m, 2H, H-2’, H-3’),

4.60 (m, 2H, H-2’’, H-3’’), 4.51 (br, 1H, H- 3’’’), 4.43 (m,

1H, H-5’), 4.31 (m, 1H, H-4’, ), 4.27 (dd, 1H, H-4’’, J4’’, 5’’a

= 5.6, J4’’, 5’’b = 4.8 Hz), 4.14 (d, 1H, H-6’, J6’, 5’ = 4.1 Hz),

3.85 (d, 1H, H-2’’’,J2’’’, 3’’’ = 8.0 Hz), 3.37 (d, 1H, H-4’’’a,

J4’’’a, 4’’’b = 14.0 Hz), 3.33 (m, 1H, H-5’’a), 3.14 (m, 1H, H-5’’b),

3.11 (s, 3H, CONCH3), 2.98 (d, 1H, H-4’’’b, J4’’’b, 4’’’a = 14.0

Hz ), 2.51 (s, 3H, NCH3), 1.64 (m, 2H, CH2CH3), 1.53 (m, 5H, CH2CH3,

S23

acetonide), 1.43 (s, 9H, t-butyl), 1.35 (S, 3H, acetonide), 0.93

(, s, 9H, t-butyl), 0.87 (m, 3H, CH2CH3), 0.84 (m, 3H, CH2CH3),

0.15 (s, 3H, SiCH3), 0.14 (s, 3H, SiCH3); 13C NMR (CD3OD, 100

MHz) δ 173.63, 166.08, 158.36, 151.82, 144.00, 143.87, 117.45,

115.80, 112.74, 102.64, 92.23, 88.28, 87.88, 86.73, 85.26,

83.67, 81.85, 81.58, 80.35, 71.44, 71.18, 64.15, 61.19, 44.27,

39.57, 38.93, 30.77, 30.49, 29.97, 28.98, 27.69, 27.64, 26.35,

25.84, 18.79, 8.79, 7.85, -4.75, -4.93 ; FABMS-LR m/z 898 (MH+);

FABMS-HR (NBA) calcd for C41H68N5O15Si 898.4481, found 898.4475.

Synthetic caprazol (2). A solution of 16 (7.4 mg, 8.25 µmol)

in CH3CN (1.0 mL) was treated with 40% aqueous HF (100 µL), and

the resulting mixture was stirred at room temperature for 18

h. After the mixture was neutralized with saturated aqueous

NaHCO3 and evaporated in vacuo, the residue was purified by C18

reverse phase HPLC (20×250 mm, 100% H2O eluent) to afford

synthetic 2 (2.4 mg, 50%) as a white solid. [α]25D + 23.8°(c 0.24,

DMSO); 1H NMR (D2O, 500 MHz) δ 7.77 (d, 1H, H-6, J6,5 = 8.1 Hz),

5.81 (d, 1H, H-5, J6,5 = 8.1 Hz), 5.59 (s, 1H, H-1’), 5.16 (s,

S24

1H, H-1’’), 4.43 (m, 1H, H-3’’’), 4.38 (d, 1H, H-5’, J5’, 6’’’

= 9.5 Hz), 4.30 (d, 1H, H-2’, J2’, 3’ = 5.1 Hz), 4.24 (m, 1H, H-3’’),

4.21-4.18 (m, 2H, H-4’’, H-2’’’), 4.13-4.11 (m, 2H, H-4’, H-2’’),

4.07 (dd, 1H, H-3’, J3’, 2’ = 5.2, J3’,4’ = 7.8 Hz), 3.84 (d, 1H,

H-6’’’, J6’’’, 5’ = 9.5 Hz), 3.32 (dd, 1H, H-5’’a, J5’’a,5’’b = 14.0,

J5’’a,4’’ = 3.3 Hz), 3.19 (dd, 1H, H-5’’b, J5’’b,5’’a = 14.0, J5’’b,4’’

= 4.4 Hz), 3.12 (d, 1H, H-4’’’a, J4’’’a,4’’’b = 14.7 Hz), 3.06 (s,

3H, CONCH3), 3.00 (d, 1H, H-4’’’b, J4’’’b, 4’’’a = 14.7 Hz), 2.42

(s, 3H, NCH3); 13C NMR (D2O, 100 MHz) δ 174.10, 172.69, 167.01,

151.75, 142.97, 111.21, 101.69, 91.91, 82.47, 79.03, 77.66,

75.51, 74.16, 70.64, 70.10, 69.37, 63.57, 59.22, 40.22, 39.37,

37.0; ESIMS-LR (negative) m/z 574 (M-H)-; ESIMS-HR (NBA) calcd

for C22H32N5O13 574.1997, found 574.2012.

S25

O

O O

NNBOM

O

O

OH

MeO2C

CbzHN

O

O O

OHHO

HO

NHBoc

OTBDPS

O

O O

N3 OH

NHBoc

TBSO OTBDPS

O

O O

N3 F

NHMe

TBSO OTBDPS

O

O O

NNBOM

O

OH3CO2C H

MTPHNH OH

H

H

aReagents and Conditions: (a) 3pentanone, H2SO4, DMF, room temperature (54%); (b) TsCl, pyridine, 0

°C–room temperature; (c) NaN3, DMF, 50 °C (80%, 2 steps); (d) DAST, CH2Cl2, 0 °C (99%, α/β = 30/70)

aReagents and Conditions: (a) HCl, aq. MeOH, room temperature; (b) TBDPSCl, imidazole, DMF (89%, 2 steps); (c) TBSCl, imidazole, DMF, room temperature (89%); (d) MeI, NaH, DMF, room temperature; (e) HCl/AcOEt (83%, 2 steps)

D-ribose

Scheme S1a

Scheme S2a

a b,c d

c d,e

Scheme S3

1) H2, Pd/C, MeOH2) (S)- or (R)-MTPA EDCI, HOBt, CH2Cl2

S5a: (S)-MTP amide (89%, 2 steps)S5b: (R)-MTP amide (78%, 2 steps)

–0.040

–0.205–0.402

+0.022

–0.140–0.190+0.006

+0.251

S1 S2 6

S3 10

5a

O

N

OH

Boca,b

S4

2,3-O-(3’-Pentylidene)-D-ribofranose (S1)

A solution of D-ribose (10.0 g, 66.7 mmol) in DMF (100 mL) was

treated with 3-pentanone (350 mL) and conc. H2SO4 (3 mL), and

the mixture was stirred at room temperature for 45 hours. The

reaction mixture was quenched by the addition of ammonia gas

for 10 minutes, and the precipitates were filtered off. The

filtrate was concentrated in vacuo. After H2O (200 mL) was added,

S26

the resulting mixture was extracted with EtOAc (200 mL×3). The

combined organic phase was dried (Na2SO4), filtered, and

concentrated in vacuo. The residue was purified by flash silica

gel column chromatography (10×15 cm, 40-45% EtOAc-hexane

eluent) to afford S1 (7.82 g, 54%) as a colorless syrup: [α]D24

−6.78 (c 1.00, CHCl3); 1H NMR (CDCl3, 500 MHz, β-dominant

anomeric mixture) δ5.47 (d, 1H, H-1, J1,OH = 5.0 Hz), 4.66 (d,

1H, H-2, J2,3 = 6.1 Hz), 4.64 (d, 1H, H-3, J3,2 = 6.1 Hz), 4.36

(t, 1H, H-4, J4,5a = 6.4, J4,5b = 6.4 Hz), 3.57 (m, 1H, H-5a),

3.40 (m, 1H, H-5b), 3.10 (br s, 1H, OH-1), 1.70 (m, 2H, CH2CH3),

1.58 (m, 2H, CH2CH3), 0.89 (m, 6H, CH2CH3×2); 13C NMR (CDCl3, 125

MHz) δ 117.10, 103.64, 86.44, 85.79, 82.48, 54.04, 29.38, 28.92,

8.34, 7.37; FABMS-LR m/z 244 (MH+); FABMS-HR (NBA) calcd for

C10H1804N3 244.1297, found 244.1304.

5-Azido-5-deoxy-2,3-O-(3’-pentylidene)-D-ribofranose (S2)

A solution of S1 (4.32 g, 19.8 mmol) in pyridine (200 mL) was

treated with TsCl (5.67g, 29.7 mmol) at 0 °C, and the mixture

was stirred for 24 hours, which was then allowed to room

S27

temperature and stirred for additional 24 hours. The mixture

was diluted with EtOAc (600 mL), washed with 1 M aqueous HCl

(600 mL×2) and saturated aqueous NaCl (600 mL). The organic

phase was dried (Na2SO4), filtered, and concentrated in vacuo.

The residue was dissolved in DMF (200 mL). The solution was

treated with sodium azide (2.58 g, 39.7 mmol) at 50 °C for 16

hours. The reaction mixture was diluted with EtOAc (600 mL),

washed with H2O (600 mL×3) and saturated aqueous NaCl (600 mL),

dried (Na2SO4), filtered, and concentrated in vacuo. The residue

was purified by silica gel column chromatography (15×13 cm,

10-20% EtOAc-hexane eluent) to afford S2 (3.85 g, 2 steps 80%)

as a yellow syrup: [α]D24 −6.78 (c 1.00, CHCl3); 1H NMR (CDCl3,

500 MHz, β-dominant anomeric mixture) δ 5.47 (d, 1H, H-1, J1,OH

= 5.0 Hz), 4.66 (d, 1H, H-2, J2,3 = 6.1 Hz), 4.64 (d, 1H, H-3,

J3,2 = 6.1 Hz), 4.36 (t, 1H, H-4, J4,5a = 6.4, J4,5b = 6.4 Hz),

3.57 (m, 1H, H-5a), 3.40 (m, 1H, H-5b), 3.10 (br s, 1H, OH-1),

1.70 (m, 2H, CH2CH3), 1.58 (m, 2H, CH2CH3), 0.89 (m, 6H, CH2CH3×2);

13C NMR (CDCl3, 125 MHz) δ 117.10103.64, 86.44, 85.79, 82.48,

S28

54.04, 29.38, 28.92, 8.34, 7.37; FABMS-LR m/z 244 (MH+);

FABMS-HR (NBA) calcd for C10H1804N3 244.1297, found 244.1304.

5-Azido-5-deoxy-2,3-O-(3’-pentylidene)-β-D-ribofranosyl

fluoride and05-Azido-5-deoxy-2,3-O-(3’-pentylidene)-α-D-

ribofranosyl fluoride (6).

A solution of S2(2.50 g, 10.3 mmol) in CH2Cl2 (100 mL) was treated

with dietylaminosulfur trifluoride (1.63 mL, 12.4 mmol) at

–30 °C for 10 mimutes. The reaction was quenched by the addition

of saturated aqueous NaHCO3 (10 mL), and then the organic phase

was washed with H2O (100 mL) and saturated aqueous NaCl (100

mL), dried (Na2SO4), filtered, and concentrated in vacuo. The

residue was purified by flash silica gel column chromatography

(7×15 cm, 5% EtOAc-hexane eluent) to afford 6 (β-anomer, 1.78

g, 7.26 mmol, 71%) and (α-anomer, 2.88 mmol, 28%) each as a

yellow syrup. β-anomer: [α]D21 +16.5 (c 0.98, CHCl3); 1H NMR (CDCl3,

500 MHz) δ 5.80 (d, 1H, H-1, J1,F = 61.5 Hz), 4.82 (dd, 1H, H-2,

J2,F = 6.0, J2,3 = 5.8 Hz) , 4.67 (d, 1H, H-3, J3,2 = 5.8 Hz), 4.47

S29

(ddd, 1H, H-4, J4,3 = 3.4, J4,5a = 7.7, J4,5b = 6.6 Hz), 3.50 (dd,

1H, H-5a, J5a,4 = 7.7, J5a,5b = 12.9 Hz), 3.23 (dd, 1H, H-5b, J5b,4

= 6.6, J5b,5a = 12.9 Hz), 1.69 (m, 2H, CH2CH3), 1.58 (m, 2H, CH2CH3),

0.89 (m, 6H, CH2CH3); 13C NMR(CDCl3, 125 MHz) δ 117.63116.41,

114.64, 87.62, 85.30, 84.97, 81.34, 53.19, 29.42, 28.78, 8.32,

7.24; FABMS-LR m/z 246 (MH+); FABMS-HR (NBA) calcd for C10H1703N3F

246.1254, found 246.1266. α-anomer: [α]D21 +100.3 (c 1.54,

CHCl3); 1H NMR (CDCl3, 500 MHz) δ 5.69 (dd, 1H, H-1, J1,F = 63.6,

J1,2 = 3.6 Hz), 4.75 (ddd, 1H, H-2, J2,F = 11.0, J2,3 = 7.3, J2,1

= 3.6 Hz), 4.62 (dd, 1H, H-3, J3,2 = 7.3, J3,4 = 3.1 Hz), 4.50

(m, 1H, H-4), 3.64 (dd, 1H, H-5a, J5a,4 = 3.5, J5a,5b = 13.3 Hz),

3.42 (dd, 1H, H-5b, J5b,4 = 3.8, J5b,5a = 13.3 Hz), 1.83 (m, 2H,

CH2CH3), 1.65 (m, 2H, CH2CH3), 0.96 (t, 3H, CH2CH3, J = 7.5 Hz),

0.89 (t, 3H, CH2CH3, J = 7.4 Hz); 13C NMR (CDCl3, 125 MHz) δ 121.06,

109.11, 107.23, 82.85, 81.43, 79.93, 52.09, 28.80, 28.70, 8.37,

8.17; FABMS-LR m/z 246 (MH+); FABMS-HR (NBA) calcd for C10H17O3N3F

246.1254, found 246.1245.

S30

(2R,3S)-1-O-t-Butyldiphenylsilyl-2-t-butyloxycarbonylamino-

4-pentene-1,3-diol (S3).

A solution (2R, 3S)-2-amino-1,2-O,N-isopropylidene-4-

pentene-1,3-diol[1] (1.04 g, 4.03 mmol) in aqueous 1 M HCl-MeOH

(1:1, 40 mL) was stirred at room temperature for 2 hours. The

mixture was partitioned between EtOAc (100 mL) and saturated

aqueous NaHCO3 (100 mL), and the organic phase was dried (Na2SO4),

filterd and evaporated in vacuo. A solution of the residue in

DMF was treated with imidazole (823 mg, 12.1 mmol) and TBDPSCl

(1.05 mL, 4.03 mmol) at room temperature for 3 hours. The

reaction was quenched by the addition of MeOH (3 mL), and the

mixture was partitioned between EtOAc (150 mL) and H2O (150 mL).

The organic phase was washed with saturated aqueous NaCl (150

mL), dried (Na2SO4), filtered, and concentrated in vacuo. The

residue was purified by silica gel column chromatography (7×10

cm, 5-20% EtOAc-hexane eluent) to afford S3 (1.63 g, 2 steps

89%) as a colorless syrup: [α]D22 –18.1 (c 1.20, CHCl3); 1H NMR

S31

(CDCl3, 500 MHz) δ 7.65-7.63 (m, 4H, H-Ar), 7.45-7.38 (m, 6H,

H-Ar), 5.90 (ddd, 1H, H-4, J4,3 = 5.0, J4,5b = 10.6, J4,5a = 15.6

Hz), 5.41 (dd, 1H, H-5a, J5a,5b = 1.5, J5a,4 = 15.6 Hz), 5.24 (br

s, 1H, NH), 5.24 (d, 1H, H-5b, J5b,4 = 10.6 Hz), 4.31 (m, 1H,

H-3), 3.90 (dd, 1H, H-1a, J1a,1b = 10.6, J1a,2 = 3.7 Hz), 3.76 (d,

1H, H-1b, J1b,1a = 10.6 Hz), 3.70 (br s, 1H, OH), 3.29 (m, 1H,

H-2), 1.45 (s, 9H, t-butyl), 1.07 (s, 9H, t-butyl); 13C NMR (CDCl3,

125 MHz) δ 155.87, 137.66, 135.51, 132.50, 132.46, 129.98,

129.96, 127.85, 116.06, 79.58, 76.75, 74.50, 64.06, 54.79,

28.38, 26.84, 19.14; FABMS-LR m/z 456 (MH+); FABMS-HR (NBA)

calcd for C26H38O4NSi 457.2570, found 456.2576.

(2R,3S)-3-O-t-Butyldimethylsilyl-1-O-t-butyldiphenylsilyl

-2-t-butyloxycarbonylamino-4-pentene-1,3-diol (S4).

A solution of S3 (1.63 g, 3.57 mmol) in DMF (30 mL) was imidazole

(875 mg, 12.9 mmol) and TBSCl (647 mg, 4.31 mmol) at room

temperature for 12 hours. The reaction was quenched by the

addition of MeOH (1 mL), and the mixture was partitioned between

EtOAc (150 mL) and H2O (150 mL). The organic phase was washed

S32

with saturated aqueous NaCl (150 mL), dried (Na2SO4), filtered,

and concentrated in vacuo. The residue was purified by silica

gel column chromatography (7×10 cm, 5-10% EtOAc-hexane eluent)

to afford S4 (1.86 g, 91%) as a colorless syrup: [α]D21 –7.34

(c 0.83, CHCl3); 1H NMR (CDCl3, 500 MHz) δ 7.67-7.63 (m, 4H, H-Ar),

7.44-7.36 (m, 6H, H-Ar), 5.73 (m, 1H, H-4), 5.20 (m, 1H, H-5a),

5.08 (m, 1H, H-5b), 4.54 (m, 1H, HNBoc), 4.35 (m, 1H, H-3), 3.72

(m, 3H, H-1a, H-1b, H-2), 1.42 (s, 9H, t-butyl), 1.06 (s, 9H,

t-butyl), 0.83 (s, 9H, t-butyl), 0.03 (s, 3H, SiCH3), 0.00 (s,

3H, SiCH3); 13C NMR (CDCl3, 125 MHz) δ 155.53, 137.89, 135.64,

135.63, 133.43, 133.36, 129.70, 127.70, 127.68, 115.96, 78.88,

73.39, 62.07, 56.60, 28.40, 26.88, 25.78, 19.22, 18.08, −4.49,

−5.09; FABMS-LR m/z 570 (MH+); FABMS-HR (NBA) calcd for

C32H5204NSi2 570.3435, found 570.3452.

(2R,3S)-3-O-t-Butyldimethylsilyl-1-O-t-butyldiphenyls

ilyl-2-methylamino-4-pentene-1,3-diol (10).

S33

A solution of S4 (512 mg, 0.901 mmol) in DMF (20 mL) was treated

with MeI (140 µL, 2.25 mmol) and NaH (28.1 mg, 1.80 mmol, 60%

purity) at room temperature for 10 hours. After AcOH (50 µL)

was added to the solution, the mixture was diluted with EtOAc

(100 mL), washed with H2O (100 mL×3) and saturated aqueous NaCl

(100 mL). The organic phase was dried (Na2SO4), filtered, and

concentrated in vacuo. The residue was treated 4 M HCl in EtOAc

(10 mL) at 0 °C for 5 minutes. The reaction mixture was

neutralized with saturated aqueous NaHCO3 (40 mL), and then the

organic phase was washed with saturated aqueous NaCl (40 mL),

dried (Na2SO4), filtered, and concentrated in vacuo. The residue

was dissolved in DMF (5 mL) and the solution was imidazole (550

mg, 8.10 mmol) and TBSCl (405 mg, 2.70 mmol) at room temperature

for 12 hours. The reaction was quenched by the addition of MeOH

(1 mL), and the mixture was partitioned between EtOAc (50 mL)

and H2O (50 mL). The organic phase was washed with saturated

aqueous NaCl (50 mL), dried (Na2SO4), filtered, and concentrated

in vacuo. The residue was purified by silica gel column

S34

chromatography (3×10 cm, 10-20% EtOAc-hexane eluent) to afford

10 (361 mg, 3 steps 83%) as a colorless syrup: [α]D20 –22.17 (c

0.43, CHCl3); 1H NMR (CDCl3, 500 MHz) δ 7.67-7.65 (m, 4H, H-Ar),

7.43-7.37 (m, 6H, H-Ar), 5.81 (ddd, 1H, H-4, J4,5a = 17.1, J4,5b

= 10.5, J4,3 = 5.9 Hz), 5.20 (d, 1H, H-5a, J5a,4 = 17.1 Hz), 5.12

(d, 1H, H-5b, J5b,4 = 10.5 Hz), 4.43 (dd, 1H, H-3, J3,4 = 5.9 Hz,

J3,2 = 4.5 Hz), 3.69 (dd, 1H, H-1a, J1a,1b = 10.4, J1a,2 = 5.6 Hz),

3.57 (dd, 1H, H-1b, J1b,1a = 10.4, J1b,2 = 7.6 Hz), 2.66 (ddd, 1H,

H-2, J2,1b = 5.6, J2,1b = 7.6, J2,3 = 4.5 Hz), 2.33 (s, 3H, NCH3),

1.57 (br s, 1H, NH), 1.07 (s, 9H, t-butyl), 0.88 (s, 9H, t-butyl),

0.05 (s, 3H, SiCH3), 0.04 (s, 3H, SiCH3); 13C NMR (CDCl3, 125

MHz) δ 137.49, 135.60, 135.58, 133.58, 133.53, 129.66, 127.67,

127.66, 115.82, 73.68, 66.93, 63.29, 35.77, 26.88, 25.84, 19.21,

18.18, −4.48, −4.97; FABMS-LR m/z 484 (MH+); FABMS-HR (NBA)

calcd for C28H46O2NSi2 484.3067, found 484.3064.

(S)-MTPA amide (S5a). A mixture of 5a (12.8 mg, 0.02 mmol)

and Pd(OH)2/C (5 mg) in MeOH (3 mL) was vigorously stirred under

H2 atmosphere at room temperature for 30 min. The catalyst was

S35

filtered off through Celite pad, and the filtrate was

concentrated in vacuo. The residue in CH2Cl2 (300 µL) was treated

with (S)-MTPA (4.7 mg, 0.02 mmol), HOBt (8.1 mg, 0.06 mmol),

and EDCI (11.7 mg, 0.06 mmol) at 0 °C for 5 hours. The reaction

mixture was concentrated in vacuo. The residue was purified by

preparative TLC (17% MeOH–CHCl3 eluent) to afford S5a (12.6 mg,

2 steps, 89%) as a white foam: [α]22D +14.5 (c 1.08, CHCl3); 1H

NMR (CDCl3, 500 MHz) δ 7.5529 (m, 2H, H-Ar), 7.2938 (d, 1H, NH,

JNH,6’ = 8.3 Hz), 7.3670-7.2565 (m, 8H, H-Ar), 7.0214 (d, 1H,

H-6, J6,5 = 8.1 Hz), 5.7189 (d, 1H, H-5, J5,6 = 8.1 Hz), 5.4494

(d, 1H, NHCH2OBn, J = 9.8 Hz), 5.3851 (d, 1H, NHCH2OBn, J = 9.8

Hz), 5.2269 (d, 1H, H-1’, J1’,2’ = 1.3 Hz), 4.9279 (m, 2H, H-2’,

H-3’), 4.7946 (dd, 1H, H-6’, J6’,NH = 8.3 , J6’,5’ = 3.8 Hz), 4.6709

(s, 2H, NHCH2OCH2Ph), 4.3997 (m, 1H, H-5’), 4.0820 (t, 1H, H-4’,

J4’,5’ = 3.1, J4’,3’ = 3.1 Hz), 3.7604 (s, 3H, COCH3), 3.6441 (d,

1H, OH, JOH,5’ = 5.8 Hz), 3.5042 (s, 3H, OCH3), 1.5370 (s, 3H,

acetonide), 1.3360 (s, 3H, acetonide); 13C NMR (CDCl3, 125 MHz)

δ 169.95, 166.64, 162.03, 151.14, 141.54, 137.61, 132.72,

S36

129.40, 128.36, 128.30, 127.81, 127.61, 114.87, 102.53, 97.33,

86.81, 82.91, 81.30, 72.48, 71.06, 70.34, 55.25, 54.83, 52.87,

27.19, 25.19; FABMS-LR m/z 708 (MH+); FABMS-HR (NBA) calcd for

C33H37N3O11F3 708.2380, found 708.2371.

(R)-MTPA amide (S5b). A mixture of 5a (12.8 mg, 0.02 mmol)

and Pd(OH)2/C (5 mg) in MeOH (3 mL) was vigorously stirred under

H2 atmosphere at room temperature for 30 min. The catalyst was

filtered off through Celite pad, and the filtrate was

concentrated in vacuo. The residue in CH2Cl2 (300 µL) was treated

with (R)-MTPA (4.7 mg, 0.02 mmol), HOBt (8.1 mg, 0.06 mmol),

and EDCI (11.7 mg, 0.06 mmol) at 0 °C for 5 hours. The reaction

mixture was concentrated in vacuo. The reaction mixture was

concentrated in vacuo. The residue was purified by preparative

TLC (17% MeOH–CHCl3 eluent) to afford S5b (11.0 mg, 2 steps,

78%) as a white foam: [α]22D +33.7 (c 0.63, CHCl3); 1H NMR (CDCl3,

500 MHz) δ 7.6957 (d, 1H, NH, JNH,6’ = 8.2 Hz), 7.5362 (m, 2H,

H-Ar), 7.4089-7.2634 (m, 8H, H-Ar), 7.1632 (d, 1H, H-6, J6,5 =

8.1 Hz), 5.7901 (d, 1H, H-5, J5,6 = 8.1 Hz), 5.4955 (d, 1H,

S37

NHCH2OBn, J = 9.8 Hz), 5.4480 (d, 1H, NHCH2OBn, J = 9.8 Hz),

5.3670 (d, 1H, H-1’, J1’,2’ = 2.4 Hz), 5.0688 (dd, 1H, H-2’, J2’,1’

= 2.4, J2’,3’ = 6.7 Hz), 5.0216 (dd, 1H, H-3’, J3’,2’ = 6.7, J3’4’

= 4.2 Hz), 4.7724 (dd, 1H, H-6’, J6’,NH = 8.2, J6’,5’ = 2.8 Hz),

4.6990 (s, 2H, NCH2OCH2Ph), 4.4395 (m, 1H, H-5’), 4.2723 (t,

1H, H-4’, J4’,5’ = 3.2, J4’,3’ = 3.2 Hz), 3.8494 (d, 1H, OH, JOH,5’

= 7.0 Hz), 3.7547 (s, 3H, COCH3), 3.2530 (s, 3H, OCH3), 1.5477

(s, 3H, acetonide), 1.3525 (s, 3H, acetonide); 13C NMR (CDCl3,

125 MHz) δ 170.00, 166.29, 162.06, 151.32, 142.28, 137.65,

131.76, 129.53, 128.57, 128.37, 127.98, 127.82, 127.62, 115.05,

102.52, 98.34, 87.17, 82.71, 81.26, 72.44, 71.24, 70.30, 54.99,

54.50, 52.84, 27.09, 25.24; FABMS-LR m/z 708 (MH+); FABMS-HR

(NBA) calcd for C33H37N3O11F3 708.2380, found 708.2371.

Reference

[1] P. Garner, J. M. Park, J. Org. Chem., 1988, 53, 2979-2984.