References and Notes
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<A NAME="RG37408ST-4A">4a</A>
Endo A.
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<A NAME="RG37408ST-5">5</A> FDA approved in 1996, also known
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Kuroda M.
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<A NAME="RG37408ST-6">6</A> Also known as velostatin, with a
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For selected literature, see:
Hoffman WF.
Alberts AW.
Anderson PS.
Chen JS.
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Willard AK.
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<A NAME="RG37408ST-7">7</A> FDA approved in 1996, with a brand
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For selected literature, see:
Roth
BD.
Blankley CJ.
Chucholowski AW.
Ferguson E.
Hoefle ML.
Ortwine DF.
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<A NAME="RG37408ST-8">8</A> FDA approved in 2003, with a brand
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Watanabe M.
Koike H.
Ishiba T.
Okada T.
Sea S.
Hirai K.
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<A NAME="RG37408ST-9">9</A> FDA approved in 1993, with a brand
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Fuenfschilling PC.
Pascale H.
Mutz J.-P.
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<A NAME="RG37408ST-10">10</A> For selected literature, see:
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Fujikawa Y.
Kitahara M.
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<A NAME="RG37408ST-19">19</A>
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<A NAME="RG37408ST-21B">21b</A> For recent review on hypervalent
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<A NAME="RG37408ST-22">22</A>
Synthesis of (4
R
,6
S
)-4-(
tert
-Butyldimethylsilyloxy)-6-(dihydroxymethyl)tetrahydro-2
H
-pyran-2-one
(4)
A mixture of 2
¹5 (500
mg, 1.92 mmol) and DMP (896 mg, 2.11 mmol) in CH2Cl2 (50
mL) was stirred at 26 ˚C for 30 min. The mixture
was diluted with MTBE (35 mL) and washed with sat. NaHCO3 (45
mL). The organic phase was separated. The water phase was additionally
extracted with MTBE (3 × 25 mL). Combined
organic layers were washed with sat. aq Na2S2O3 (2 × 25
mL), sat. NaHCO3 (2 × 25 mL), H2O
(70 mL), dried (MgSO4), and concentrated under reduced
pressure to give pure hydrate 4 (498 mg,
94%) as a white crystalline powder; mp 73-75 ˚C. ¹H
NMR (300 MHz, THF-d
8): δ = 0.10
(s, 6 H, CH3Si), 0.91 (s, 9 H, CH3C), 1.80-2.00
(m, 2 H, H-5), 2.39 (dd, J = 17.1,
3.9 Hz, 1 H, H-3), 2.58 (dd, J = 17.1,
4.2 Hz, 1 H, H-3), 4.35-4.45 (m, 2 H, H-4, H-6), 4.83-4.91 [m,
1 H, CH(OH)], 5.14 (d, J = 6.0
Hz, 1 H, OH), 5.22 (d, J = 6.0
Hz, 1 H, OH). ¹³C NMR (75 MHz, THF-d
8): δ = -4.79
(CH3Si), -4.74 (CH3Si), 18.7 (CCH3),
26.2 (CH3C), 31.0 (C-5), 40.4 (C-3), 65.1 (C-4), 79.1
(C-6), 91.7 [CH(OH)], 168.8 (C-2). IR (KBr): ν = 1697
cm-¹. MS (ES+): m/z (%) = 851.6
(10) [3 M + Na]+, 575.4
(58) [2 M + Na]+,
570.4 (13) [2 M + NH4]+,
299.2 (35) [M + Na]+,
294.2 (100) [M + NH4]+,
277.2 (88) [M + 1]+, 259.2
(73), 145.1 (8). Anal. Calcd (%) for C12H24O5Si:
C, 52.14; H, 8.75. Found: C, 52.45; H, 9.18.
<A NAME="RG37408ST-23">23</A>
Kralj B.
igon D.
Košmrlj J.
Polanc S.
Rapid Commun. Mass Spectrom.
1997,
11:
335
<A NAME="RG37408ST-24A">24a</A>
Wu J.
Serianni AS.
Carbohydr.
Res.
1991,
210:
51
<A NAME="RG37408ST-24B">24b</A>
McAlpine JM.
Riggs NV.
Aust.
J. Chem.
1975,
28:
211
<A NAME="RG37408ST-25">25</A>
(4
R
,6
S
)-4-(
tert
-Butyldimethylsilyloxy)-6,7-dihydroxy-oxepan-2-one
(5)
Hydrate 4 (50 mg, 0.18
mmol) was dissolved in MeOH (2 mL) and left to stand at r.t. for
2.5 d. The solvent was evaporated to dryness to give 5 (50
mg, 100%) as a colorless solid. ¹H
NMR (300 MHz, CD3OD): δ = 0.14
(s, 6 H, CH3Si), 0.94 (s, 9 H, CH3C), 1.87-2.06
(m, 2 H, H-5), 2.52 (ddd, J = 17.5,
2.9, 2.0 Hz, 1 H, H-3), 2.72 (dd, J = 17.5,
3.8 Hz, 1 H, H-3), 4.42-4.52 (m, 1 H, H-4), 4.56-4.70
(m, 2 H, H-6, H-7). ¹³C NMR (75 MHz,
CD3OD): δ = -4.82
(CH3Si), -4.76 (CH3Si), 18.9 (CH3C),
26.2 (CH3C), 30.7 (C-5), 31.0 (C-5), 40.5 (C-3), 64.9
(C-4), 79.0, 79.5, 98.6, 98.8, 172.58 (C-2), 172.60 (C-2). Two sets
of ¹³C resonances are observed in the
intensity ratio of 1:1. HRMS (ES+): m/z calcd for C12H24O5SiNa+ [M + Na]+:
299.1291; found: 299.1299. Anal. Calcd (%) for C12H24O5Si:
C, 52.14; H, 8.75. Found: C, 52.35; H, 8.97.
<A NAME="RG37408ST-26">26</A>
(4
R
,6
S
)-4-(
tert
-Butyldimethylsilyloxy)-6-formyltetra-hydro-2
H
-pyran-2-one
(1)
A solution of hydrate 4 (500
mg, 1.81 mmol) in CH2Cl2 (30 mL) was left
to stand for 1 d. The solvent was evaporated to afford quantitatively
aldehyde 1 as a colorless oil. ¹H
NMR (300 MHz, CDCl3): δ = 0.11
(s, 6 H, CH3Si), 0.90 (s, 9 H, CH3C), 1.80-1.91
(m, 1 H, H-5), 2.13 (ddd, J = 14.0,
4.2, 4.2 Hz, 1 H, H-5), 2.55-2.70 (m, 2 H, H-3), 4.37 (m,
1 H, H-4), 5.07 (dd, J = 11.3,
3.9 Hz, 1 H, H-6), 9.83 (s, 1 H, CHO). ¹³C NMR
(75 MHz, CDCl3): δ = -4.9
(CH3Si), 17.9 (CCH3), 25.6 (CH3C),
31.4, 39.6, 63.0, 79.2, 167.9 (C-2), 199.3 (CHO). IR (NaCl): ν = 1739,
1697 cm-¹. [α]D
²0 -12.2
(c 1, CHCl3). MS (ES+): m/z (%) = 517.3 (20) [2 M + H]+,
259.1 (100) [M + 1]+,
246.1 (11), 233.1 (15), 221.1 (31), 205.1 (34), 183.1 (9), 169.1
(16), 153.1 (14), 129.1 (33), 127.0(27). HRMS (TOFMS+): m/z calcd for C12H22O4Si+ [M + H]+: 259.1366;
found: 259.1366.
<A NAME="RG37408ST-27">27</A>
β-Substituted δ-lactone
ring is unstable and readily undergoes elimination to unsaturated
compounds. For example, see ref. 13, 18.
<A NAME="RG37408ST-28">28</A>
Sabitha G.
Sudhakar K.
Srinivas C.
Yadav JS.
Synthesis
2007,
705
<A NAME="RG37408ST-29">29</A>
(4
R
,6
S
)-4-(
tert
-Butyldimethylsilyloxy)-6-styryltetra-hydro-2
H
-pyran-2-one
(7)
Benzyltriphenylphosphonium bromide (0.130 g, 3.00
mmol) was dissolved in dry toluene (70 mL) and NaHDMS (5.25 mL,
3.15 mmol, 0.6 M in toluene) was added at r.t. The reaction mixture
was stirred at r.t. for 2.25 h to give ylide 6. Then
the solution of ylide 6 was warmed up to
65 ˚C within 10 min. At this temperature a solution
of pre-dried aldehyde 1 (853 mg, 3.30 mmol)
in toluene (25 mL), prepared from hydrate 4 (913
mg, 3.30 mmol) and toluene, was added. The resulting reaction mixture
was stirred at 65 ˚C for 5 min quenched with EtOH
and allowed to cool down to r.t. The solvent was evaporated, and
the residue was subjected to flash chromatography with ARMEN INSTRUMENT
Spot® apparatus on SiO2 [gradient
elution; EtOAc-hexane (3:97) over 10 min; from 3:97 to
5:95 over 15 min, from 5:95 to 15:85 over 10 min, and from 15:85
to 100:0 over 5 min; flow rate 60 mL/min] to obtain
a mixture of (E)-7/(Z)-7 in the ratio
of 63:37 (740 mg, 74%). For analysis, the isomers were separated
by the second flash chromatography under the same conditions as
described above.
Data for Compound
(
E
)-7
White
solid; mp 57.5 ˚C (DSC onset). ¹H
NMR (400 MHz, CDCl3): δ = 0.00
(s, 6 H, CH3Si), 0.81 (s, 9 H, CH3C), 1.73-1.82
(m, 1 H), 1.87-1.95 (m, 1 H), 2.48-2.61 (m, 2
H), 4.22-4.29 (m, 1 H), 5.21-5.28 (m, 1 H), 6.12
(dd, J = 6.4,
15.9 Hz, 1 H), 6.59 (d, J = 15.9
Hz, 1 H, CHPh), 7.14-7.32 (m, 5 H, Ph). ¹³C
NMR (100 MHz, CDCl3): δ = -5.0
(CH3Si), -4.9 (CH3Si), 17.9, 25.6,
36.9, 39.3, 63.4, 76.1, 126.6, 126.8, 128.1, 128.6, 132.0, 135.9,
169.8. IR (NaCl): ν = 2927, 1727,
1348, 1233, 1165, 1090, 1072, 693 cm-¹.
HRMS (CI+): m/z calcd
for C15H19O3Si+ [M - C4H9]+:
275.1104; found: 275.1110.
Data for
Compound (
Z
)-7
White
solid; mp 65.8 ˚C (DSC onset). ¹H
NMR (400 MHz, CDCl3): δ = 0.05
(s, 6 H, CH3Si), 0.81 (s, 9 H, CH3C), 1.80-2.00
(m, 2 H), 2.52-2.69 (m, 2 H), 4.29-4.35 (m, 1
H), 5.64-5.76 (m, 2 H), 6.67 (d, J = 10.5
Hz, 1 H, CHPh), 7.22-7.36 (m, 5 H, Ph). ¹³C
NMR (100 MHz, CDCl3): δ = -5.1 (CH3Si), -5.0
(CH3Si), 17.8, 25.5, 36.6, 39.2, 63.6, 72.4, 127.6, 128.4,
128.5, 129.0, 133.0, 135.7, 169.8. IR (NaCl): ν = 2927,
1737, 1359, 1239, 1160, 1084, 1065, 697 cm-¹. HRMS
(CI+): m/z calcd
for C15H19O3Si+ [M - C4H9]+: 275.1104;
found: 275.1110.