A Symmetry-Based Synthesis of the Heterobicyclic Core of the Zaragozic Acids
COMMUNICATIONS
1H NMR (500 MHz, CDCl3): d=0.96 (s, 9H), 1.04 (s, 9H),
2.56 (d, J=2.6 Hz, 1H), 3.49 (s, 1H), 3.58 (d, J=11.6 Hz,
1H), 3.66 (d, J=10.1 Hz, 1H), 3.85 (d, J=11.6 Hz, 1H),
3.86 (d, J=10.1 Hz, 1H), 3.87 (d, J=11.7 Hz, 1H), 3.93 (d,
J=8.3 Hz, 1H), 4.06 (d, J=11.7 Hz, 1H), 4.53 (apparent t
with J=2.7 Hz, 1H), 4.60 (d, J=11.9 Hz, 1H), 4.69 (d, J=
11.9 Hz, 1H), 4.71 (d, J=0.8 Hz, 1H), 4.86 (dd, J=2.9 Hz,
J=8.3 Hz, 1H), 7.28–7.44 (m, 17H), 7.56–7.58 (m, 4H),
7.60–7.62 (m, 2H), 7.66–7.68 (m, 2H), 9.54 (d, J=0.8 Hz,
1H, CHO); 13C NMR (125.8 MHz, CDCl3): d=19.07 (s),
26.69 (q), 26.74 (q), 62.39 (t), 62.85 (t), 72.29 (t), 73.18 (s,
C4), 74.03 (t), 77.69 (d), 79.13 (d), 84.38 (d), 87.21 (s),
103.00 (s), 127.74 (d), 127.84 (d), 127.86 (d), 128.05 (d),
128.58 (d), 130.03 (d), 130.12 (d), 131.63 (s), 131.72 (s),
131.92 (s), 132.21 (s), 135.49 (d), 135.66 (d), 135.74 (d),
135.81 (d), 137.27 (s), 199.20 (d); MS (ESI): m/z=864.4
Preparation of Aldehyde 25 from Diketone 22 via
Selective Cyclization, Resilylation, Reduction and
Oxidative Cleavage
A solution of diketone 22 (2.95 g, 2.57 mmol) in CH2Cl2
(52 mL) cooled to 08C was treated with water (0.463 g,
25.72 mmol) and TFA (2.932 g, 25.72 mmol). After stirring
for 1 h at 08C and 24 h at room temperature, the reaction
was quenched by addition of saturated NaHCO3 solution
(36 mL). The layers were separated, the aqueous layer was
extracted with CH2Cl2 (3ꢂ60 mL), and the solvent was re-
moved under vacuum. Purification by flash chromatography
on silica gel (diethyl ether/CH2Cl2, 1:6) gave hemi-acetal 23
(yield: 1.17 g, 46%) and partially desilylated material (yield:
0.724 g, 37%) as white solids. The latter material was dis-
solved in dry CH2Cl2 (19 mL) and treated with triethylamine
(241 mg, 2.31 mmol), DMAP (5.8 mg, 0.05 mmol) and
TBDPSCl (315.5 mg, 1.15 mmol). After stirring for 50 h at
room temperature, the mixture was filtered through a pad
of silica gel (diethyl ether). Concentration under vacuum
and purification by flash chromatography on silica gel (di-
+
+
[M+NH4 ], 896.4 [M+MeOH+NH4 ], 901.4 [M+
MeOH+Na+]; anal. calcd. for C49H58O9Si2: C 69.47, H 6.90;
found: C 69.55, H 6.80.
ethyl ether/CH2Cl2, 1:6) gave additional (520 mg) 23 as a Preparation of Tri-tert-butyl Ester 30 from Triol 29
white solid; total yield from 22: 1.69 g (66%). Rf =0.26 (di-
A solution of dry DMSO (135 mg, 1.726 mmol) in dry
ethyl ether/CH2Cl2, 1:6); IR (ATR): n=3452 (br., w), 3070
CH2Cl2 (1 mL) was added dropwise to a solution of oxalyl
(w), 2931 (w), 2857 (w), 1469 (m), 1457 (m), 1427 (m), 1391
dichloride (109.6 mg, 0.863 mmol) in dry CH2Cl2 (4 mL)
(w), 1363 (w), 1184 (w), 1106 (s), 1072 (s), 1043 (s), 1000
cooled to À788C under argon. After stirring for 10 min, a
(m), 939 (m), 820 (m), 793 (m), 738 (s), 783 (m), 697 (s), 609
solution of triol 29 (216 mg, 0.332 mmol) in dry CH2Cl2
+
(m) cmÀ1; MS (ESI): m/z=1014.5 [M+NH4 ], 1019.4 [M+
(3.4 mL) was added dropwise, and stirring was continued at
Na+], 1035.4 [M+K+].
À788C for 45 min. Dry triethylamine (262 mg, 2.59 mmol)
A solution of hemi-acetal 23 (1.061 g, 1.064 mmol) in dry
was added, and the mixture was stirred for 30 min at
THF (32 mL) was treated with triethylamine (129 mg,
À788C. The reaction was quenched by addition of 1M
1.277 mmol). After stirring for 30 min at room temperature,
KH2PO4 (3.4 mL). The mixture was extracted with CH2Cl2
the mixture was cooled to 08C, lithium borohydride
(81.44 mg, 3.724 mmol) was added, and stirring at 08C was
continued for 4 h. The reaction was quenched by dropwise
addition of 2N NaOH (10 mL) followed by stirring for
30 min. Extraction with ethyl acetate (3ꢂ20 mL), drying of
the organic layer with Na2SO4 and removal of the solvent
under vacuum left a residue, which was purified by flash
chromatography on silica gel (diethyl ether/CH2Cl2, 1:6) to
(3ꢂ10 mL), and the combined organic layers were dried
with Na2SO4. The crude dialdehyde obtained after removal
of the solvent under vacuum was dissolved in a mixture of t-
BuOH (31 mL) and isoprene (7.7 mL). The resultant solu-
tion was cooled to 08C, and a 1M solution of NaClO2 in 1M
KH2PO4 (3.3 mL, 3.3 mmol) was added dropwise. After stir-
ring the reaction mixture for 1 h at 08C and 4 h at room
temperature, another portion of the 1M solution of NaClO2
give pentaol 24 as a white solid; yield: 1.002 g (94%). Rf =
0.23 (diethyl ether/CH2Cl2, 1:6); IR (ATR): n=3410 (br.,
in 1M KH2PO4 (3.3 mL, 3.3 mmol) was added dropwise, and
stirring was continued for further 19 h. The mixture was
w), 3071 (w), 2931 (w), 2858 (w), 1457 (m), 1427 (m), 1363
treated with brine (5 mL) and a pH 2 KH2PO4 buffer
(w), 1108 (s), 1072 (s), 936 (w), 821 (m), 783 (m), 698 (s),
(5 mL) followed by extraction with ethyl acetate (5ꢂ
15 mL). The combined organic layers were dried with
Na2SO4, and the solvent was removed under vacuum to give
610 (m) cmÀ1; MS (ESI): m/z=1016.5 [M+NH4 ], 1021.4
+
[M+Na+]; anal. calcd. for C58H70O11Si2: C 69.71, H 7.06;
found: C 69.85, H 6.96.
a crude diacid, which was dissolved in dry CH2Cl2 (15 mL)
and treated with N,N’-diisopropyl-O-tert-butylisourea
(664 mg, 3.32 mmol) under argon. After stirring for 24 h at
room temperature, another portion of N,N’-diisopropyl-O-
tert-butylisourea (664 mg, 3.32 mmol) was added, and stir-
ring was continued for further 24 h. The white precipitate
formed was filtered off, and the solvent was removed under
vacuum. Purification of the residue by flash chromatography
on silica gel (diethyl ether/CH2Cl2, 1:20) furnished tri-tert-
butylester 30 as a white foam; yield: 131 mg (50%). Rf =
0.20 (diethyl ether/CH2Cl2, 1:20); [a]2D2: +68.01 (c 1.31,
CH2Cl2); IR (ATR): n=3447 (br., w), 2981 (w), 2935 (w),
2876 (w), 1727 (s), 1454 (m), 1369 (m), 1315 (m), 1252 (s),
1150 (s), 1108 (s), 1063 (s), 1026 (m), 998 (m), 968 (w), 911
A solution of sodium periodate (343.5 mg, 1.61 mmol) in
water (4 mL) was added dropwise to a solution of pentaol
24 (802 mg, 0.803 mmol) and pyridine (190 mg, 2.41 mmol)
in methanol (28 mL). After stirring for 20 h at room temper-
ature, additional sodium periodate (86 mg, 0.402 mmol) in a
mixture of water (0.5 mL) and methanol (3 mL) was added,
and stirring was continued for 6 h. Dilution with ethyl ace-
tate, drying with Na2SO4, and removal of the solvent under
vacuum left a residue, which was purified by flash chroma-
tography on silica gel (diethyl ether/CH2Cl2, 1:15) to give al-
dehyde 25 as a white solid; yield: 786 mg (93%). Rf =0.24
(CH2Cl2/ethyl acetate, 15:1); mp 57.5–58.68C; [a]2D2: +6.63
(c 1.19, CH2Cl2); IR (ATR): n=3436 (br., w), 3068 (w),
2931 (m), 2858 (m), 1739 (m), 1457 (m), 1427 (m), 1390 (w),
(w), 838 (m), 708 (s), 602 (m) cmÀ1
;
1H NMR (500 MHz,
1108 (s), 1073 (s), 820 (m), 739 (m), 699 (s), 610 (m) cmÀ1
;
CDCl3): d=1.29 (s, 9H), 1.47 (s, 9H), 1.62 (s, 9H), 3.97 (d,
Adv. Synth. Catal. 2009, 351, 2075 – 2080
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2079