Efficient Preparation of Chiral C2-Symmetrical 2,6,9-Trioxabicyclononanes from Cholesteryl Benzoate

Full text of DOI:10.1021/jo961818z

J . Org. Chem. 1997, 62, 1155-1158
1155
Notes
Sch em e 1
Efficien t P r ep a r a tion of Ch ir a l
C2-Sym m etr ica l
2,6,9-Tr ioxa bicyclo[3.3.1]n on a n es fr om
Ch olester yl Ben zoa te
Simone C. Vonwiller
School of Chemistry, University of Sydney,
NSW 2006, Australia
Received September 24, 1996
The formation of 2,6,9-trioxabicyclo[3.3.1]nonanes from
salicylaldehydes and related compounds has been known
for quite some time1,2 and since the discovery of these
compounds isolated examples of other dimerizations
involving â-hydroxy aldehydes and ketones have been
reported, mainly as unwanted side-reactions.3,4 In the
case of simple anhydro dimers of salicylaldehydes such
as 1, the trioxabicyclononane nucleus places the aryl
rings at an approximately 93° angle to one another
thereby imparting a convex and a concave face to the
molecule. As these compounds possess a C2-axis of
symmetry, there is potential for suitably functionalized
derivatives of the individual enantiomers to participate
in chiral recognition processes or to form inclusion
complexes. However, to date no examples of individual
resolved enantiomers have been reported. Attempts to
confer asymmetry onto these compounds by mono de-
rivatization have been made to enable separation of the
resulting diastereomers, but on the whole no high yield-
ing direct methods have been developed.5 Apart from
these reports, exploitation of the trioxabicyclononanes
has not been made, presumably due to the limited
synthetic methods and range of substrates available for
their preparation. Nevertheless, it is also worthy to note
that the trioxabicyclononane moiety features in the
preussomerins, a class of fungal metabolites in which
some of the members possess biological activity.6
products via simple enols.8 In those cases where the
carbonyl group and the hydroxyl group of the aldol are
anti, acid-catalyzed retroaldolization readily takes place
to give either the expected carbonyl products, or, in the
presence of Cu(II) and oxygen, R-hydroperoxy carbonyl
compounds.9 Cis aldols, on the other hand are resistant
to acid-catalyzed retroaldolization but susceptible to other
transformations. In the case of cis aldol 3 a remarkably
facile dimerization takes place to give 4a and 4b thereby
providing entry to a new class of functionalized trioxabi-
cyclononanes. Details of this reaction are now presented.
Treatment of the hydroperoxide 2, obtained from
cholesteryl benzoate and singlet oxygen, with FeCl3‚2Et2O,
in CH2Cl2 under nitrogen at -25 °C rapidly gave the aldol
as predominantly the cis diastereomer 3 (Scheme 1).
However, upon exposure to FeCl3‚2Et2O above -10 °C,
the hydroperoxide 2 was converted, via 3, into two
diastereomers of the 2,6,9-trioxabicyclo[3.3.1]nonane 4a
and 4b in a combined yield of 43% and a ratio of 2:1,
together with the aldol 3 (21%) and some enal 5. In
contrast, treatment of the hydroperoxide 2 with outer
As part of an ongoing study of the reactions of cyclic
allylic hydroperoxides7 we discovered that the acid-
catalyzed Hock cleavage affords aldols as the primary
10
sphere oxidants such as Fe(phen)3(PF6)3 or Cu(OSO2-
(1) J ones, P. R.; Gelinas, R. M. J . Org. Chem. 1981, 46, 194 and
cited references. Bachet, P. B.; Brassy, C.; Guidi-Morosini, C. Acta
Crystallogr. 1986, C42, 1630.
(2) Kulkarni, V. S.; Hosangadi, B. D. Synth. Commun. 1986, 16, 191.
(3) Lumma, W. C., J r.; Ma, O. H. J . Org. Chem. 1970, 35, 2391.
(4) Padmanabhan, S.; Ogawa, T.; Suzuki, H. Bull. Chem. Soc. J pn.
1989, 62, 2114.
(5) J ones, P. R.; Langan, M. E. Synth. Commun. 1988, 18, 433.
(6) Weber, H. A.; Baenziger, N. C.; Gloer, J . B. J . Am. Chem. Soc.
1990, 112, 6718; for compounds possessing Ras farnesyl-protein
transferase activity see: Singh, S. B.; Zink, D. L.; Liesch, J . M.; Ball,
R. G.; Goetz, M. A.; Bolessa, E. A.; Giacobbe, R. A.; Silverman, K. C.;
Bills, G. F.; Pelaez, F.; Cascales, C.; Gibbs, J . B.; Lingham, R. B. J .
Org. Chem. 1994, 59, 6296.
11
CF3)2 in MeCN/CH2Cl2 under nitrogen at -20 °C led
smoothly to the aldol 3; subsequent warming of the
reaction mixture did not provide the dimers. When the
isolated aldol was treated with FeCl3‚2Et2O (2 equiv) in
CH2Cl2 at -20 °C, TLC showed steady formation of 4a
(8) Vonwiller, S. C.; Warner, J . A.; Mann, S. T.; Haynes, R. K. J .
Am. Chem. Soc. 1995, 117, 11098.
(9) Vonwiller, S. C.; Warner, J . A.; Mann, S. T.; Haynes, R. K.
Tetrahedron Lett., submitted for publication.
(10) Schlesener, C. J .; Amatore, C.; Kochi, J . K. J . Am. Chem. Soc.
1984, 106, 3567.
(11) J enkins, C. L.; Kochi, J . K. J . Am. Chem. Soc. 1972, 94, 843.
(7) Haynes, R. K.; Vonwiller, S. C. J . Chem. Soc., Chem. Commun.
1990, 449.
S0022-3263(96)01818-X CCC: $14.00 © 1997 American Chemical Society

1156 J . Org. Chem., Vol. 62, No. 4, 1997
Notes
F igu r e 1. Summary of diagnostic NMR data and stereochemical features of 4a and 4b as indicated from energy-minimized
structures.12 Hydrogen atoms have been omitted for clarity.
and 4b which were isolated in a combined yield of 83%
and a ratio of ca. 2:1. Treatment of the hydroperoxide 2
with CF3SO3H led to the formation of the major dimer
4a (21%), only negligible amounts of 4b, and substantial
amounts of 5 resulting from competing dehydration. In
contrast, CF3SO3H catalyzes the smooth conversion of the
trans aldol 7 derived from the qinghao acid methyl ester
hydroperoxide 6 into the dicarbonyl compound 8 upon
warming from -25 °C to 25 °C in CD2Cl2, and no dimer
is observed.8
the calculated dihedral angle of 36° produced in an
energy-minimized structure with the assigned stereo-
centers. The conformation of the A-ring tended to
minimize as a boat rather than a chair such that the
3-benzoyloxy groups are aligned with the alkyl side
chains thereby increasing van der Waals contacts. Cou-
plings of J 3R,2R ) 8.9 Hz, J 3R,2â ) 8.9 Hz, J 3R,4R ) 6.7 Hz,
and J 3R,4â ) 3.3 Hz support a conformation in which H3R
is no longer equatorial and H2R has deviated from its
axial orientation. This is clearly evident when a com-
parison is made with the A-ring of the aldol 3 which is
in the chair conformation: the couplings for H3R in this
case are J 3R,2R ) J 3R,2â ) J 3R,4R ) J 3R,4â ) 3.4 Hz, indicating
an equatorial orientation. The minor dimer 4b which
differed only in the stereochemistry of the acetal car-
bons displayed no measurable coupling between H6
and H7, consistent with the calculated dihedral angle of
92°. Such a structure has the norcholestane ring sys-
tems aligned in one plane with the A-rings projecting
below the plane. In both cases the absence of doubling
up of signals in the NMR spectra clearly indicates C2-
symmetry.
The mixture of benzoate dimers 4a ,b was readily
hydrolyzed with 15% KOH in methanol/dimethoxyethane
under gentle reflux to give the diols 9a and 9b in high
isolated yields (59% and 26%, respectively, or total of
85%). The diastereomers differed substantially in polar-
ity and were readily separated by chromatography on
silica. NMR spectral data indicated that all stereocenters
were retained in the operation. Methylation of each of
the diols with sodium hydride/methyl iodide in THF was
sluggish at room temperature but proceeded at a steady
rate under gentle reflux to give the diethers 10a (92%)
and 10b (84%).
The structures of the dimers 4a,b are indicated through
1H and 13C NMR spectra, which reveal the absence of
double bonds, the presence of a methine proton adjacent
to two oxygen atoms at δ 5.29 (doublet, J ) 5.3 Hz) (4a )
and δ 5.03 (singlet) (4b), and an acetal carbon at 90.4
ppm (4a ) and 94.0 ppm (4b). The IR spectra contained
no OH absorptions. Both diastereomers displayed dis-
tinct M+ + 1 (m/ z 1028) and M+ + NH4 (m/ z 1045) peaks
in their CI(NH3) mass spectra.
The stereochemical features of each dimer were deter-
mined by a combination of 2D COSY and NOESY NMR
experiments and molecular modeling.12 The results are
summarized in Figure 1. The major dimer 4a has the
norcholestane ring systems placed at a 65° angle to one
another with the methyl groups projecting into the cavity.
This is supported by NOE enhancements between H6 and
H4′â and the o-phenyl protons of the benzoyl group.13 The
coupling between H6 and H7 of 5.3 Hz is consistent with
The ease with which the dimerization takes place
under the above conditions is noteworthy especially in
view of the fact that the usual conditions for preparation
of anhydro dimers of salicylaldehydes, such as heating
(12) MM2 in SPARTAN version 4.0; Wavefunction Inc., 18401 Von
Karman, Suite 370, Irvine, California 92715.
(13) Atom numbering is based on the parent cholestane skeleton.

Notes
J . Org. Chem., Vol. 62, No. 4, 1997 1157
1120 m cm-1; 1H NMR (400 MHz) δ 0.741 (3H, s), 0.863 (3H, d,
J ) 6.6 Hz), 0.867 (3H, d, J ) 6.6 Hz), 0.925 (3H, d, J ) 6.5 Hz),
1.005 (3H, s), 1.07-1.55 (18 H, m), 1.683 (1H, ddd, J ) 15.3,
9.0, 6.1 Hz), 1.79-1.89 (3H, m), 2.002 (1H, dd, J ) 15.5, 3.9 Hz),
2.086 (1H, ddd, J ) 12.9, 3.2, 3.2 Hz), 2.22-2.27 (2H, m), 2.32
(1H, dd, J ) 15.5, 3.2 Hz), 2.506 (1H, s, OH), 5.381 (1H, dddd,
J ) 3.4, 3.4, 3.4, 3.4 Hz), 7.43-7.47 (2H, m), 7.55-7.59 (1H, m),
7.96-7.99 (2H, m), 9.712 (1H, d, J ) 2.8 Hz). Preirradiation of
the signal at 1.00 ppm (19-CH3) resulted in enhancements at
2.51 ppm (OH) (1.1%), at 7.96-7.99 ppm (C6H5 ortho) (1.9%) and
at 9.71 ppm (CHO) (1.3%). Preirradiation of the signal at 2.51
ppm (OH) resulted in enhancements at 1.00 ppm (19-CH3) (3%),
7.96-7.99 (C6H5 ortho) (8.7%), and 9.71 ppm (CHO) (3.3%).
Preirradiation of the signal at 9.71 ppm (CHO) resulted in
enhancements at 1.00 ppm (19-CH3) (1.9%), 2.25 ppm (H7)
(6.1%), 2.51 ppm (OH) (1.4%). 13C NMR (100 MHz, CDCl3) δ
12.48, 18.31, 18.74, 21.55, 22.52, 22.77, 23.80, 24.49, 24.76,
27.98, 28.17, 28.32, 35.59, 36.17, 39.46, 39.50, 39.64, 42.29, 44.66,
45.62, 51.34, 55.67, 56.04, 70.74, 83.63, 128.56, 129.38, 130.15,
133.16, 165.52, 203.87. MS m/ z 505 (M - OH, < 1%), 400 (M
- C6H5COOH, 5), 383 (15), 3822 (27), 367 (11), 354 (51), 145
(22), 133 (22), 122 (33), 110 (58), 105 (100), 95 (38), 77 (50), 69
(31), 55 (51), 43 (88), 41 (52); Anal. Calcd for C34H50O4: C, 78.12;
H, 9.64. Found: C, 77.92; H, 9.41.
Sch em e 2
with PPE,2 cause facile dehydration of 3 to the enal 5.
Another example of dimerization of an aliphatic aldol
involves a substrate that by virtue of methyl substitution
is unable to undergo competing dehydration.3 The suc-
cess of the present example is attributed to a favorable
equilibrium induced by the ferric chloride, in which the
acid sensitive acetal groups become buried within a
hydrophobic shroud and are thereby shielded from com-
peting hydrolysis (Scheme 2). Addition of a water-
sequestering agent such as anhydrous Na2SO4 or pow-
dered 4 Å molecular sieves as distinct from a dehydrating
agent enables the reaction to go to near completion with
minimal competing enal formation.
As the starting aldol 3 is chiral and nonracemic the
dimers themselves are chiral and nonracemic and rep-
resent the first examples of this type. The C2-symmetry
and unusual topography in which these compounds, in
particular 4a and derivatives, are found to possess a
hydrophilic core and a hydrophobic outer surface suggest
the potential for interesting cation complexation and
transport properties. The consequences of this are cur-
rently under investigation.
F or m a tion of th e Dim er s 4a ,b. The aldol 3 (468.5 mg; 0.90
mmol) was dissolved in dichloromethane (21 mL) and treated
with FeCl3 dietherate (0.17 M in dichloromethane; 1.80 mmol;
10.4 mL; 2 equiv) at -20 °C under nitrogen. This imparted a
bright yellow coloration to the reaction mixture and resulted in
gradual formation of the dimers. Stirring was continued at -20
°C for 18 h during which time the reaction mixture remained a
deep orange color. Anhydrous sodium sulfate (1.0 g) was next
added as a solid, and stirring was continued for a further 7 h.
The reaction was quenched by pouring onto a stirred ice-cold
solution of saturated NaHCO3 solution. The iron residues were
removed by filtration through Celite, and the resulting mixture
was extracted with ether. The ether extracts were washed with
brine and dried (Na2SO4), and the solvent was evaporated under
reduced pressure. The product mixture was fractionated by
flash chromatography (ether/petroleum ether, 25:75) to give the
dimers 4a ,b in an approximately 2:1 ratio (381 mg; 83%) and
recovered aldol 3 (67 mg; 14%) as white solids. Higher reaction
temperatures led to substantial dehydration of the aldol and
lower yields of the dimers. The individual dimers were sepa-
rated by flash chromatography on silica (ether/petroleum ether,
2:98 to 7.5:92.5) to give first the major diastereomer 4a as a
white solid. This was recrystallized from acetonitrile/ether as
fine needles: mp 189-190.5 °C; IR (CCl4) 2951 vs, 2870 s, 1717
s (CdO), 1468 m, 1452 m, 1383 m, 1277 s, 1161 m, 1117 s, 1082
m, 1071 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.666 (3H, s), 0.878
(3H, d, J ) 6.5 Hz), 0.883 (3H, d, J ) 6.5 Hz), 0.916 (3H, d, J )
6.5 Hz), 1.063 (3H, s), 1.537 (1H, dd, J ) 10.8, 5.1 Hz), 1.63-
1.73 (2H, m), 1.796 (1H, dd, J ) 15, 6.5 Hz), 1.97-2.05 (2H, m),
2.09-2.18 (1H, m), 2.402 (1H, dd, J ) 15, 3.2 Hz), 5.186 (1H,
dddd, J ) 8.5, 8.5, 6.5, 3 Hz), 5.291 (1H, d, J ) 5.3 Hz), 7.39-
7.44 (2H, m), 7.52 -7.57 (1H, m), 7.98-8.01 (2H, m); 13C NMR
(100 MHz, CDCl3) δ 12.15, 17.74, 18.85, 21.16, 22.53, 22.80,
23.99, 24.76, 25.29, 28.02, 28.43, 32.79, 35.64, 36.32, 37.77, 38.70,
39.53, 39.60, 43.98, 46.83, 54.45, 55.92 (2C), 56.77, 71.42, 82.22,
90.44, 128.12, 129.63, 130.88, 132.57, 166.67; MS (CI/NH3) m/ z
1045 (M + NH4+, 1%), 1028 (M + 1, <1), 906 (2), 523 (100). Anal.
Calcd for C68H98O7: C, 79.49; H, 9.61. Found: C, 79.23; H, 9.45.
The more polar minor diastereomer 4b was obtained as a fine
powder: mp 102-104.5 °C from MeCN; IR (KBr) 2946 vs, 2867
s, 1720 s (CdO), 1467 m, 1451 m, 1383 m, 1277 s, 1188 s, 1117
Exp er im en ta l Section
Ma ter ia ls. Diethyl ether was distilled from 18 M H2SO4 and
stored over sodium wire. CH2Cl2 was dried over P2O5 and
distilled under nitrogen prior to use. MeCN was dried over P2O5,
distilled under reduced pressure from P2O5, and stored under
N2 over activated 4 Å molecular sieves. Fe(phen)3(PF6)3 was
prepared according to the method of Kochi.10 FeCl3 was dried
with thionyl chloride. The etherate was prepared by suspending
ferric chloride in CH2Cl2 and adding 2 equiv of dry ether with
stirring to give a clear yellow solution. Other solvents and
commercially available reagents were purified in the standard
manner.
P r ep a r a tion of th e Ald ol 3. Cholesteryl benzoate (1.00 g;
2.04 mmol) in pyridine (45 mL) containing hematoporphyrin
sensitizer was irradiated (tungsten lamp, 500 W) for 17 h in a
water-cooled Pyrex flask such that the bath temperature did not
exceed 20 °C. The reaction proceeded to near completion. The
pyridine was removed by distillation at 20 °C under high
vacuum, and then the residue was dissolved in ether (50 mL)
and stirred with activated charcoal for 30 min. Filtration
through Celite followed by evaporation of the solvent gave a
viscous oil which was purified by flash chromatography (ether/
petroleum ether, 20:80). The hydroperoxide mixture so obtained
(0.86 g) was then dissolved in CH2Cl2 (45 mL), and the solution
was cooled to -15 °C under N2. A solution of Fe(phen)3(PF6)3
(7.5 mL; 0.022 M in MeCN; 0.17 mmol) was added dropwise,
and then the reaction mixture was stirred for 1.75 h with slow
warming to 10 °C. Ether (150 mL) was added to precipitate the
catalyst, the red solid was filtered off with Celite, and the
colorless filtrate was evaporated to give a solid residue. The
solid was purified by flash chromatography (ether/petroleum
ether, 25:75) followed by recrystallization from petroleum ether
to give the aldol 3 as fine needles (0.53 g; 50% overall): mp 143-
145 °C; IR (CHCl3) 3600 w (OH), 3510 br w (OH), 2954 s, 2936
s, 2869 m, 2725 w, 1714 vs (CdO, ester and aldehyde), 1280 s,
1
s cm-1; H NMR (400 MHz, CDCl3) δ 0.654 (3H, s), 0.879 (3H,
d, J ) 6.5 Hz), 0.884 (3H, d, J ) 6.6 Hz), 0.919 (3H, d, J ) 6.4
Hz), 1.009 (3H, s), 2.022 (1H, d, J ) 12.5 Hz), 2.383 (1H, d, J )
15.4 Hz), 5.031 (1H, s), 5.04 (1H, br m, Wh/2 ) 11.7 Hz), 7.35-
7.39 (2H, m), 7.49-7.53 (1H, m), 8.04-8.06 (2H, m); 13C NMR
(100 MHz, CDCl3) δ 12.5, 18.8, 22.5, 22.8, 24.0, 24.5, 24.8, 28.0,
28.6, 30.1, 35.7, 36.3, 39.5, 39.7, 39.8, 43.8, 44.3, 46.8, 51.9, 54.7,
55.5, 56.6, 70.1, 82.7, 94.0, 128.0, 129.6, 131.5, 132.3, 166.1; MS
(CI/NH3) m/ z 1045 (M + NH4+, 15%), 1028 (M + 1, 6), 906 (2),
523 (100). Anal. Calcd for
Found: C, 79.70; H, 9.48.
C68H98O7: C, 79.49; H, 9.61.
Hyd r olysis to th e Diols 9a ,b. The dimer mixture from
above (381 mg; 0.37 mmol) was dissolved in DME (8 mL) and

1158 J . Org. Chem., Vol. 62, No. 4, 1997
Notes
then treated with KOH in methanol (7 mL; 15%) for 10 min at
room temperature. The mixture was then heated under gentle
reflux for 1 h, becoming orange in color, cooled, and then poured
onto water. The product was extracted into ether, and the
combined extracts were washed with brine and dried (Na2SO4).
Removal of the solvent left a residue which was fractionated by
flash chromatography (ether/petroleum ether; 80:20). The less
polar major isomer 9a was obtained as a pale yellow solid which
upon trituration with methanol, filtration, and drying was
obtained as a colorless powder (178 mg; 59% or 50% from 3):
mp 186-188 °C; IR (KBr) 2947 vs, 1467 m, 1158 s, 1102 s, 979
cm-1; 1H NMR (400 MHz, CDCl3) δ 0.668 (3H, s), 1.029 (3H, s),
0.742 (1H, ddd, J ) 11.8, 11.8, 5.1 Hz), 0.858 (3H, d, J ) 6.6
Hz), 0.863 (3H, d, J ) 6.6 Hz), 0.914 (3H, d, J ) 6.5 Hz), 1.029
(3H, s), 1.451 (1H, dd, J ) 15.4, 5.2 Hz), 1.535 (1H, dd, J ) 11.0,
5.5 Hz), 1.861 (1H, d, J ) 10.4 Hz), 1.960 (1H, ddd, J ) 11.7,
11.7, 11.7 Hz), 2.202 (1H, dddd, J ) 13.8, 10.2, 3.6, 3.6 Hz), 2.379
(1H, dd, J ) 15.1, 2.2 Hz), 3.972 (1H, br m, Wh/2 ) 19.6 Hz),
5.445 (1H, d, J ) 5.3 Hz); 13C NMR (100 MHz, CDCl3) δ 12.2,
16.9, 18.9, 21.0, 22.5, 22.8, 23.9, 25.4, 28.0, 29.9, 33.7, 35.6, 36.2,
37.3, 39.4 (2 signals), 39.5, 40.5, 43.9, 46.8, 55.5, 55.59, 55.61,
57.2, 67.4, 83.5, 89.8; MS (CI/NH3) m/ z 820 (M + 1, 100%), 837
(M + NH4, 3%). Anal. Calcd for C54H90O5: C, 79.16; H, 11.07.
Found: C, 78,91; H, 10.86.
The more polar minor isomer 9b was obtained, after changing
the eluting solvent to ether (100%), as a brittle glass (79 mg;
26% or 22% from 3): mp 95-97 °C; IR (KBr) 2942 vs, 2920 vs,
1468 m, 1181 s, 1100 m, 997 m, 969 m cm-1; 1H NMR (400 MHz,
CDCl3) δ 0.663 (3H, s), 0.860 (3H, d, J ) 6.6 Hz), 0.865 (3H, d,
J ) 6.6 Hz), 0.908 (3H, d, J ) 6.5 Hz), 1.019 (3H, s), 1.473 (1H,
d, J )10.0 Hz), 1.602 (1H, dd, J ) 14.8, 4.8 Hz), 1.681 (1H, ddd,
J ) 11.6, 10.2, 10.2 Hz), 1.856 (1H, br m, Wh/2 ) 22 Hz), 2.027
(1H, ddd, J ) 12.8, 3.2, 3.2 Hz), 2.251 (1H, dd, J ) 14.8, 1.7
Hz), 2.872 (1H, d, J ) 10.1 Hz), 3.931 (1H, br m, Wh/2 ) 17.8
Hz), 5.098 (1H, s); 13C NMR (100 MHz, CDCl3) δ 12.5, 18.0, 18.8,
21.2, 22.5, 22.8, 23.9, 24.6, 28.0, 28.5, 28.9, 30.7, 35.7, 36.2, 39.5,
39.6, 39.9, 44.4, 46.4, 46.9, 53.0, 54.9, 55.4, 56.1, 67.6, 85.7, 94.3;
MS (C. I./NH3) m/ z 820 (M + 1, 100%), 837 (M + NH4, 5%).
Anal. Calcd for C54H90O5: C, 79.16; H, 11.07. Found: C, 79.30;
H, 10.98.
chromatography (ether/petroleum ether; 10:90) to give the
dimethyl ether 10a as a white solid (117.8 mg; 92%). Crystal-
lization from methanol afforded small prisms, mp 79-82 °C. IR
(KBr) 3469 br m, 2946 vs, 1469 m, 1088 m, 981 m cm-1
.
1H
NMR (400 MHz, CDCl3) δ 0.652 (3H, s), 0.747 (1H, ddd, J )
11.9, 11.9, 4.4 Hz), 0.861 (3H, d, J ) 6.6 Hz), 0.865 (3H, d, J )
6.6 Hz), 0.915 (3H, d, J ) 6.5 Hz), 0.980 (3H, s), 1.510 (1H, dd,
J ) 10.5, 5.0 Hz), 1.642 (1H, dd, J ) 14.5, 5.5 Hz), 1.851 (1H,
dddd, J ) 13.0, J ) 9.0, J ) 5.3, J ) 3.6 Hz), 1.967 (1H, ddd, J
) 11.6, 11.6, 11.6 Hz), 2.009 (1H, ddd, J ) 12.7, 3.4, 3.4 Hz),
2.150 (1H, dd, J ) 14.4, 4.4 Hz), 3.254 (3H, s), 3.474 (1H, m,
Wh/2 ) 18 Hz), 5.279 (1H, d, J ) 5.1 Hz); 13C NMR (50 MHz,
CDCl3) δ 12.1, 17.6, 18.9, 21.1, 22.6, 22.8, 23.8, 24.6, 25.3, 28.0,
32.4, 35.6, 36.3, 37.4, 39.5, 39.6, 43.8, 46.6, 53.8, 55.6, 55.7, 56.1,
56.5, 75.7, 82.0, 90.3. MS (CI/NH3) m/ z 847 (M + 1, 3%), 816
[M - (2 × CH3), 35], 433 (100). Anal. Calcd for C56H94O5: C,
79.38; H, 11.18. Found: C, 79.51; H, 11.71.
Meth yla tion of th e Min or Diol. The minor diol 9b (93.0
mg; 114 µmol) in THF (5 mL) was methylated under the above
conditions, and then the crude product obtained after evapora-
tion of the solvent was purified by flash chromatography (ether/
petroleum ether; 20:80) to give the dimethyl ether 10b as a white
crystalline solid (81.1mg; 84%). Crystallization from methanol
afforded small prisms: mp 227-231 °C; IR (KBr) 3567 w, 3370
br m, 2946 vs, 1468 m, 1181 s, 1079 m, 970 m cm-1 1H NMR
;
(400 MHz, CDCl3) δ 0.663 (3H, s), 0.861 (3H, d, J ) 6.6 Hz),
0.867 (3H, d, J ) 6.6 Hz), 0.908 (3H, d, J ) 6.5 Hz), 0.959 (3H,
s), 1.609 (1H, d, J ) 10 Hz), 1.723 (1H, dd, J ) 14.4, 4.9 Hz),
2.015 (1H, ddd, J ) 12.7, 2.9, 2.9 Hz), 2.158 (1H, dd, J ) 14.4,
5.2 Hz), 3.331 (3H, s), 3.440 (1H, m, Wh/2 ) 16 Hz), 5.085 (1H,
s); 13C NMR (50 MHz, CDCl3) δ 12.6, 18.5, 18.8, 21.4, 22.5, 22.8,
23.9, 24.7, 25.5, 28.0, 28.6, 30.4, 35.7, 36.3, 39.5, 39.6, 39.8, 43.4,
44.4, 47.3, 52.1, 54.7, 55.4, 56.1, 56.3, 75.5, 84.0, 94.2. MS (CI/
NH3) m/ z 847 (M + 1, 14%), 816 [M - (2 × CH3), 68], 647 (100).
Anal. Calcd for C56H94O5: C, 79.38; H, 11.18. Found: C, 79.08;
H, 11.55.
Ack n ow led gm en t. S.C.V. is grateful for the award
of a Queen Elizabeth II Fellowship (1992-1996) by the
Australian Research Council.
Meth yla tion of th e Ma jor Diol. Sodium hydride (43.2 mg;
1.08 mmol; 60% dispersion in oil) was washed with dry pentane
(2 × 2 mL), dried under a nitrogen stream, and then suspended
in dry THF (6 mL). The diol 9a (122.8 mg; 0.150 mmol) in THF
(5 mL) was then added followed by methyl iodide (56 µL; 0.90
mmol). The resulting mixture was heated under gentle reflux
for 24 h. After cooling in ice the reaction mixture was treated
with water and extracted with ether. The combined extracts
were washed with brine and dried (Na2SO4). The crude product
obtained after evaporation of the solvent was purified by flash
Su p p or tin g In for m a tion Ava ila ble: Tabulated NMR
data with assignments for compounds 4a , 4b, 9a , 9b, 10a , and
10b (4 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead for ordering information.
J O961818Z