14.8, 9.3, 5.0 Hz, 1H), 4.94 (d, J ) 11.4 Hz, 1H), 4.87 (d, J )
10.9 Hz, 1H), 4.73 (d, J ) 10.9 Hz, 1H), 4.58 (d, J ) 11.4 Hz,
1H), 4.34 (d, J ) 7.6 Hz, 1H), 4.18–4.06 (m, 2H), 3.91 (ddd, J )
9.4, 6.7, 1.5 Hz, 1H), 3.65 (dd, J ) 10.0, 3.7 Hz, 1H), 3.58 (s,
3H), 3.54 (dd, J ) 10.0, 7.6 Hz, 1H), 2.59–2.16 (m, 8H); 13C NMR
(CDCl3) 100 MHz δ 173.5, 172.0, 138.8, 138.2, 132.0, 129.5, 128.5,
128.4 (2), 128.2, 127.8 (2), 104.7, 79.2, 78.8, 75.5, 72.7, 69.8, 66.2,
61.3, 57.3, 34.8, 33.7, 29.4, 27.6; EMS [M + Na]+ m/z calcd for
C29H34O8Na+ 533.2146, found 533.2144.
stereocontrol are primarily governed by substituents in close
proximity to the reactive site.20 For [13]-macro-dilactones 1–3,
the only stereocenters present are those from the fused carbo-
hydrate ring which are remote relative to the reactive alkene.
Our results clearly suggest that the observed stereoselectivity
in the epoxidation of these [13]-macro-dilactones is not influ-
enced by sterics near the reactive site but rather is entirely
attributed to the macro-dilactone ring conformation as governed
by the fused carbohydrate moiety. The switch in facial selectivity
observed for the DMDO epoxidation of 1 versus 2 depended
solely on the epimerization of the C4 stereochemistry. That is,
the anti-relationship of the stereocenters in 1 dictated presenta-
tion of one E-alkene diasteroface (pro-R,R), while the syn-
oriented stereocenters in 2 dictated presentation of the pro-S,S
face. The results reported here are among the rare examples of
highly diastereoselective macrocycle epoxidations at a site
delimited only by the adjacent methylene chains of the macro-
dilactone.21
Through the analysis of the spectroscopic data for 1–3,
inspection of the crystal structure of 2, and the assignment of
absolute configuration of the epoxides 14 and 15, a consistent
picture of the structure and reactivity of the novel carbohydrate-
fused [13]-macrolactones has emerged. Conformational control
of a modestly functionalized macrolactone was therefore
achieved by the incorporation of a fused sugar moiety. This
unique facial selectivity is directed by remote stereocenters that
influence the shape of the macrolactone rather than by stereo-
centers adjacent to the alkene. Further, we used a Shi epoxi-
dation as a key step in the determination of the absolute
stereochemistry of the macrolactones.
Methyl 2,3,4-tri-O-benzyl-5,7-O-(E-oct-4-ene-dioyl)-ꢀ-D-glycero-
D-guloseptanoside (3): Rf 0.72 (7:3, hexanes-EtOAc); [R]D +19.42
(c 0.94, CHCl3); IR (KBr) cm-1 3088, 3062, 3030, 1734, 1497,
1
1454, 1385, 1354, 1238, 1207, 1171, 1134, 1076, 1038; H NMR
(CDCl3) 400 MHz δ 7.38–7.17 (m, 15H), 5.58–5.51 (m, 1H), 5.37
(ddd, J ) 14.8, 9.0, 5.4 Hz, 1H), 5.25 (dd, J ) 10.0, 3.6 Hz, 1H),
4.79 (d, J ) 12.0 Hz, 1H), 4.70–4.56 (m, 6H), 4.40 (ddd, J ) 9.9,
3.1, 3.1 Hz, 1H), 4.31 (dd, J ) 12.1, 3.0 Hz, 1H), 4.06 (dd, J )
12.2, 3.0 Hz, 1H), 3.84 (d, J ) 6.2 Hz, 2H), 3.70 (dd, J ) 6.6, 3.4
Hz, 1H), 3.52 (s, 3H), 2.48–2.14 (m, 8H); 13C NMR (CDCl3) 100
MHz δ 174.2, 171.6, 138.8, 138.5, 138.4, 131.6, 129.3, 128.6, 128.5,
128.2, 128.1, 128.0, 127.8, 127.7, 105.9, 79.9, 79.8, 79.4, 74.0,
73.8, 73.3, 71.1, 65.7, 56.6, 35.0, 34.2, 29.2, 27.5; EMS [M + Na]+
m/z calcd for C37H42O9Na+ 653.2721, found 653.2722.
General Epoxidation Procedure. The macro-dilactone (0.1
mmol) was dried via azeotropic distillation from toluene (3 × 5
mL) and dissolved in dry CH2Cl2 (5 mL). The solution was cooled
to 0 °C and a DMDO (2.4 eq.) solution was added dropwise. The
mixture was stirred at 0 °C for 1 h and the solvent was removed
under reduced pressure. The residue was purified by column
chromatography (hexanes/EtOAc 7:3).
Methyl 2,3-di-O-benzyl-4,6-O-(4R,5R-epoxyoctanedioyl)-r-D-glu-
copyranoside (4): mp 128–130 °C; Rf 0.37 (7:3, hexanes-EtOAc);
[R]D –22.78 (c 1.07, CHCl3); IR (KBr) cm-1 3088, 3065, 3033,
2947, 2932, 2905, 2860, 1740, 1461, 1365, 1234, 1212, 1179, 1102,
882, 731, 697; 1H NMR (CDCl3) 400 MHz δ 7.39–7.21 (m, 10H),
5.21 (dd, J ) 10.1, 10.1 Hz, 1H), 5.00 (dd, J ) 13.0, 3.6 Hz, 1H),
4.91 (d, J ) 11.8 Hz, 1H), 4.84 (d, J ) 11.9 Hz, 1H), 4.67 (d, J )
12.1 Hz, 1H), 4.63 (d, J ) 11.8 Hz, 1H), 4.57 (d, J ) 3.8 Hz, 1H),
4.00 (dd, J ) 10.2, 2.8 Hz, 1H), 3.90 (d, J ) 9.5, 9.5 Hz, 1H),
3.73 (d, J ) 12.8 Hz, 1H), 3.67 (d, J ) 9.4, 3.8 Hz, 1H), 3.41 (s,
3H), 2.90 (ddd, J ) 10.0, 2.3, 2.3 Hz, 1H), 2.66 (ddd, J ) 10.0,
2.1, 2.1 Hz, 1H), 2.56–2.39 (m, 2H), 2.31–2.07 (m, 4H), 1.55–1.44
(m, 2H); 13C NMR (CDCl3) 100 MHz δ 172.9, 171.5, 138.7, 138.0,
128.8, 128.5 (2), 128.3, 128.1, 127.8, 99.2, 80.2, 79.6, 75.4, 74.0,
69.2, 67.6, 62.4, 59.4, 58.4, 55.8, 29.5, 29.2, 26.9, 26.4; EMS [M
+ Na]+ m/z calcd for C29H34O9Na+ 549.2095, found 549.2112.
Methyl 2,3-di-O-benzyl-4,6-O-(4S,5S-epoxy-octanedioyl)-ꢀ-D-ga-
lactopyranoside (5): mp 135–149 °C; Rf 0.24 (7:3, hexanes-EtOAc);
[R]D +55.72 (c. 0.90, CHCl3); IR (KBr) cm-1 3064, 3031, 2963,
2924, 2866, 1745, 1454, 1369, 1261, 1222, 1178, 1076, 1028, 878,
799, 736, 699; 1H NMR (CDCl3) 400 MHz δ 7.36–7.28 (m, 10H),
5.68 (d, J ) 2.2 Hz, 1H), 4.88 (d, J ) 10.9 Hz, 1H), 4.82 (d, J )
11.6 Hz, 1H), 4.76–4.71 (m, 2H), 4.56 (d, J ) 11.3 Hz, 1H), 4.35
(d, J ) 7.4 Hz, 1H), 3.88 (dd, J ) 10.6, 6.3 Hz, 1H), 4.03–3.98
(m, 1H), 3.65 (dd, J ) 9.8, 3.6 Hz, 1H), 3.59–3.53 (m, 4H), 2.89
(d, J ) 9.9 Hz, 1H), 2.70 (d, J ) 9.8 Hz, 1H), 2.65–2.46 (m, 4H),
2.29–2.13 (m, 2H), 1.62–1.49 (m, 2H); 13C NMR (CDCl3) 100 MHz
δ 172.4, 172.2 (2), 172.0, 138.7, 138.6, 138.3, 138.0, 128.5 (2),
128.4, 128.2 (2), 128.1, 127.9 (2), 127.8, 104.8, 99.4, 78.9, 78.8,
75.7, 75.6, 75.5, 73.9, 72.6 (2), 70.1, 67.2, 66.1, 65.8, 60.7, 60.4,
59.4, 59.3, 58.5, 57.4, 56.0, 29.6, 29.5, 29.1, 27.1 (2), 26.5 (2);
EMS [M + Na]+ m/z calcd for C29H34O9Na+ 549.2095, found
549.2093.
Experimental Section
General RCM Procedure. To a solution of diester in dry toluene
(0.1 mmol scale, final diene concentration ) 4 mM) was added
Grubbs II catalyst (5 mol %). The reaction mixture was heated to
reflux for 12–16 h and then concentrated under reduced pressure.
The mixture was purified by column chromatography (hexanes/
EtOAc 7:3).
Methyl 2,3-di-O-benzyl-4,6-O-(E-oct-4-enedioyl)-r-D-glucopy-
ranoside (1): Rf 0.57 (7:3, hexanes-EtOAc); [R]D –1.53 (c 2.74,
CHCl3); IR (KBr) cm-1 3088, 3063, 3031, 2925, 2856, 1735, 1454,
1355, 1260, 1237, 1170, 1138, 1101, 1043, 780, 739, 698; 1H NMR
(CDCl3) 400 MHz δ 7.36–7.28 (m, 10H), 5.60–5.52 (m, 1H), 5.36
(ddd, J ) 14.9, 9.0, 5.4 Hz, 1H), 5.11 (dd, J ) 9.9, 9.9 Hz, 1H),
4.89 (d, J ) 11.6 Hz, 1H), 4.83 (d, J ) 12.1 Hz, 1H), 4.68 (d, J )
2.2 Hz, 1H), 4.65 (d, J ) 2.8 Hz, 1H), 4.56 (d, J ) 3.6 Hz, 1H),
4.24 (dd, J ) 12.3, 2.5 Hz, 1H), 4.03 (dd, J ) 12.5, 3.0 Hz, 1H),
3.96 (ddd, J ) 10.0, 2.7, 2.7 Hz, 1H), 3.89 (dd, J ) 9.6, 9.6 Hz,
1H), 3.65 (dd, J ) 9.5, 3.7 Hz, 1H), 3.40 (s, 3H), 2.48–2.10 (m,
8H); 13C NMR (CDCl3) 100 MHz δ 173.9, 171.2, 138.7, 138.0,
131.9, 129.4, 128.7, 128.5, 128.4, 128.2, 128.0, 127.7, 98.9, 80.0,
79.6, 75.3, 73.9, 70.8, 67.0, 64.3, 55.7, 34.9, 29.0, 26.9; EMS [M
+ Na]+ m/z calcd for C29H34O8Na+ 533.2146, found 533.2149.
Methyl 2,3-di-O-benzyl-4,6-O-(E-oct-4-enedioyl)-ꢀ-D-galactopy-
ranoside (2): mp 148–151 °C; Rf 0.41 (7:3, hexanes-EtOAc); [R]D
+ 35.57 (c 1.28, CHCl3); IR (KBr) cm-1 3064, 3030, 2926, 2857,
1739, 1454, 1363, 1345, 1244, 1169, 1128, 1085, 1049, 985, 950,
905, 740, 700; 1H NMR (CDCl3) 300 MHz δ 7.41–7.28 (m, 10H),
5.61 (dd, J ) 3.6, 1.4 Hz, 1H), 5.58–5.53 (m, 1H), 5.36 (ddd, J )
Methyl 2,3,4-tri-O-benzyl-5,7-O-(4R,5R-epoxyoctanedioyl)-ꢀ-D-
glycero-D-guloseptanoside (6): Rf 0.33 (7:3, hexanes-EtOAc); [R]D
+14.65 (c 0.69, CHCl3); IR (KBr) cm-1 3088, 3062, 3030, 2926,
2856, 1736, 1454, 1385, 1362, 1275, 1223, 1180, 1097, 1072, 1043,
933; 1H NMR (CDCl3) 400 MHz δ 7.38–7.16 (m, 15H), 5.40 (dd,
J ) 9.9, 6.6 Hz, 1H), 4.82 (dd, J ) 12.2, 2.8 Hz, 1H), 4.78 (s,
(19) Vedejs, E.; Gapinski, D. M. J. Am. Chem. Soc. 1983, 105, 5058.
(20) Larionov, O. V.; Corey, E. J. J. Am. Chem. Soc. 2008, 130, 2954.
(21) (a) Braddock, D. C.; Cansell, G.; Hermitage, S. A.; White, A. J. P.
Tetrahedron: Asymmetry 2004, 15, 3123. (b) Lee, D.; Sello, J. K.; Schreiber,
S. L. J. Am. Chem. Soc. 1999, 121, 10648.
3628 J. Org. Chem. Vol. 73, No. 9, 2008