Contiguously substituted cyclooctane polyols. Configurational assignments via 1H NMR correlations and symmetry considerations

Article abstract of DOI:10.1021/jo801443d

(Chemical Equation Presented) More advanced oxidation of the cyclooctadienol shown, readily available in enantiomerically pure form from D-glucose, has given rise to a series of intermediates whose relative (and ultimately absolute) configuration was assigned on the basis of ¹H/¹H coupling constant analysis. The selectivities that were deduced in this manner were drawn from the sequential application of CrO₃ oxidation in tandem with Luche reduction, two-step NMO-promoted osmylations bracketed by acetonide formation, and wholesale deprotection. The stereoselectivities of these reactions were traced by ¹H NMR spectroscopy, and the stereochemical assignments were confirmed by the presence or absence of symmetry in the final cyclooctane polyols (four shown) generated in this investigation.

Full text of DOI:10.1021/jo801443d

Contiguously Substituted Cyclooctane Polyols. Configurational
1
Assignments via H NMR Correlations and Symmetry
Considerations
Gustavo Moura-Letts and Leo A. Paquette*
EVans Chemical Laboratories, The Ohio State UniVersity, Columbus, Ohio 43210
paquette@chemistry.ohio-state.edu
ReceiVed July 7, 2008
More advanced oxidation of the cyclooctadienol shown, readily available in enantiomerically pure form
from D-glucose, has given rise to a series of intermediates whose relative (and ultimately absolute)
1
configuration was assigned on the basis of H/1H coupling constant analysis. The selectivities that were
deduced in this manner were drawn from the sequential application of CrO3 oxidation in tandem with
Luche reduction, two-step NMO-promoted osmylations bracketed by acetonide formation, and wholesale
1
deprotection. The stereoselectivities of these reactions were traced by H NMR spectroscopy, and the
stereochemical assignments were confirmed by the presence or absence of symmetry in the final
cyclooctane polyols (four shown) generated in this investigation.
SCHEME 1. Generic Route for Octacyclitols from
Enantiomerically Pure Cyclobutanone 1
Introduction
A program of research initiated in this laboratory several years
ago was aimed at developing the zirconocene-mediated ring
contraction1 of enantiopure vinyl pyranosides and furanosides
into a synthetically useful protocol.2 Several complex targets
and diverse glycomimetics were initially targeted. Representative
successful achievements from the first category include arrival
at (-)-neplanocin A,3 (+)-epiafricanol,4 and both enantiomers
of fomannosin.5 More extended application has led conveniently
to several cyclooctane-1,2,3-triols and 1,2,3,4,5-pentaols.6
Presently, we demonstrate that eight-membered ring systems
substituted with hydroxyl groups at each of the constituent
carbon atoms as in 3 are likewise readily available. These
attractive polyols, of potential value for their glycosidase
inhibition potential,7 have been secured by the extensive
controlled oxidation of D-glucose-derived 26 (Scheme 1). The
specific configurational assignments to each of the isomers of
3 are based upon steric considerations, in tandem with applica-
tion of the empirical Kishi rule for the OsO4-promoted dihy-
(1) Hanzawa, Y.; Ito, H.; Taguchi, T. Synlett 1995, 299.
(2) Paquette, L. A. J. Organomet. Chem. 2006, 691, 2083.
(3) Paquette, L. A.; Tian, Z.; Seekamp, C. K.; Wang, T. HelV. Chim. Acta
2005, 88, 1185.
(4) Paquette, L. A.; Arbit, R. M.; Funel, J.-A.; Bolshakov, S. Synthesis 2002,
2105.
(5) (a) Paquette, L. A.; Peng, X.; Yang, J. Angew. Chem., Int. Ed. 2007, 46,
7817. (b) Paquette, L. A.; Peng, X.; Yang, J.; Kang, H.-J. J. Org. Chem. 2008,
74, 4548.
(7) Sollogoub, M.; Sinay, P. Organic Chemistry of Sugars: CRC Press: Boca
(6) Paquette, L. A.; Zhang, Y. J. Org. Chem. 2006, 71, 4353.
Raton, FL, 2006, p 349.
10.1021/jo801443d CCC: $40.75
Published on Web 08/29/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 7663–7670 7663

Moura-Letts and Paquette
SCHEME 2. Conversion of 4 into the Diastereomers of 8
and 9
ratio of 6 to 7 was increased somewhat to 3:1 (entry 2). On the
other hand, constant cooling to 0 °C, again in benzene solution,
provided predominately 5 (55%, entry 3). A further drop in
temperature to -5 °C had the effect of enhancing further the
exclusive production of 5 (entry 4). Of the remaining probe
experiments, entries 8 and 10 are notable for serving as the best
preparative conditions for generating 6 or 5, respectively.
Next to be examined was the Luche11 reduction of this pair
of cyclooctadienones. Since our aim was to obtain 1:1 mixtures
of diastereomers, no attention was accorded to reducing agents
that would provide widely imbalanced distributions of dienols.
The reaction of 5 with sodium borohydride and cerium
trichloride in methanol at 0 °C led to the formation of 8a and
8b in 43 and 46% isolated yields, respectively (Scheme 2).
Under the same conditions, 6 was transformed into 9a (48%)
and 9b (39%). Not unexpectedly, NMR analysis of the two sets
of diastereomers did not lead to the unequivocal assignment of
configuration at the newly generated carbinol center. As outlined
in the sequel, however, more advanced functionalization studies
ultimately clarified this key issue.
Orthogonal protection of the four different diastereomers
followed. To this end, alcohols 8a and 8b were esterified with
acetic anhydride in pyridine to achieve conversion to acetates
10 and 11 (Scheme 3). The acquisition of 12 and 13, on the
other hand, was realized by treatment of 9a and 9b with tert-
butyldimethylsilyl chloride in the presence of imidazole. All
four products were in turn dihydroxylated with catalytic
quantities of OsO4 and NMO in aqueous THF. A salient feature
of this set of transformations is its exceptional regioselectivity
for attack at the site of the 6,7-double bond. The basis for this
assignment was derived from the upfield shifts of H-5 in 10-13
which originates as an allylic proton and experiences a status
change when progressing to 14a-17b (Table 2). The ratios of
the isolated diols 14a/14b and 16a/16b are consistent with the
operation of good substrate induction during the capture of OsO4
preferably from the top face. The product distributions realized
with 15a/15b (3.5:1) and 17a/17b (3:1) were more modest,
although again biased in the same facial direction. These data
are consistent with the stereoselectivities demonstrated by cyclic
allylic alcohols of smaller ring size where control by flanking
acyl and siloxy groups does not operate to a significant
degree.12-15 The present situation is further complicated by the
more extensive oxygenated patterns resident in these substrates.
Our analysis of the relative stereochemistry of the eight diols
generated in Scheme 3 has been derived in part by adaptation
of the empirical rule developed by Kishi8,13 for defining the
structures of the major osmylation products of allylic alcohols
and their derivatives. His studies revealed a constant pattern in
the vicinal H/H coupling patterns for acyclic polyhydroxylated
compounds in the same stereochemical series. These patterns
serve to unveil relative configuration among a set of contiguous
carbon stereocenters. When compound pairs 8a/8b and 9a/9b
are examined in this manner (Scheme 4), small J values are
seen to be equivalent to a syn relationship between the
TABLE 1. Oxidation of 4 with CrO3 and Ac2O/HOAc
equiv of equiv of equiv of
entry CrO3 AcOH Ac2O solvent
temperature yield ratio of
(°C)
(%) componentsa
1
2
3
4
5
6
7
8
9
5
5
5
5
2.5
10
20
5
2.5
2.5
33
33
33
33
16
66
132
33
16
16
9
9
9
9
benzene
benzene
benzene
benzene
5
20
0
-5
-5
20
20
20
20
-5
68
63
55
57
59
53
43
65
71
68
3:3:1:1
0:2:1:0
4:1:1:1
10:1:1:1
10:0:0:1
0:4:1:0
0:10:1:0
0:8:1:0
0:4:4:0
10:0:0:1
4.5 benzene
18
36
9
4.5 CH2CI2
4.5 CH2CI2
benzene
benzene
CH2CI2
10
a Ratio of 5:6:7:4 after separation/purification by column chromatogra-
phy.
droxylation of allylic alcohols,8 and ultimate reliance on the
presence or absence of molecular symmetry as determined by
NMR spectroscopy.
Results and Discussion
Following the selection of 2 as a suitable reactant, consid-
eration was given to its subsequent conversion to the bis-
silylated ether 4 in advance of allylic oxidation with chromium
trioxide in mixtures of acetic anhydride and acetic acid at or
near room temperature.9,10 In line with precedent, oxidation was
observed to occur competitively at the doubly allylic ring
position and the activated benzylic site (Scheme 2). Precise
adaptation of the Schultz conditions (Table 1, entry 1) gave
rise to dienones 5 and 6, benzoate 7, and unreacted 4 in a 3:3:
1:1 ratio and 68% combined yield. When the reaction temper-
ature was increased from 5 to 20 °C, no 5 was noted and the
(11) Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226.
(12) Carless, H. A. J.; Busia, K.; Dove, Y.; Malik, S. S. J. Chem. Soc., Perkin
Trans. 1 1993, 2505.
(13) (a) Higashibayashi, S.; Czechlitzky, W.; Kobayashi, Y.; Kishi, Y. J. Am.
Chem. Soc. 2003, 125, 14379. (b) Seike, H.; Ghosh, I.; Kishi, Y. Org. Lett.
2006, 8, 3861.
(8) (a) Cha, J. K.; Christ, W. J.; Kishi, Y. Tetrahedron Lett. 1983, 24, 3943.
(b) Christ, W. J.; Cha, J. K.; Kishi, Y. Tetrahedron Lett. 1983, 24, 3947.
(9) Rosenthal, D.; Grabowich, P.; Sabo, E. F.; Fried, J. J. Am. Chem. Soc.
1963, 85, 3971.
(10) Schultz, A. G.; Lavien, F. P.; Macielag, M.; Plummer, M. J. Am. Chem.
Soc. 1987, 109, 3991.
(14) (a) Donohoe, J. J.; Garg, R.; Moore, P. R. Tetrahedron Lett. 1996, 27,
2407. (b) Donohoe, T. J.; Moore, P. R.; Beddoes, R. L. J. Chem. Soc., Perkin
Trans. 1 1997, 43.
(15) Cha, J. K.; Kim, N.-S. Chem. ReV. 1995, 95, 1761.
7664 J. Org. Chem. Vol. 73, No. 19, 2008

SCHEME 3. Hydroxyl Protection OsO4-Promoted Dihydroxylation Results
TABLE 2. Chemical Shifts of H-5 in 8a/8b-17a/17b
by extracting the J values from the neighboring protons. This
analysis will be used for all the future new compounds.
Isomers 16a and 16b exhibit quite distinctive patterns
(Scheme 6). Instead of many broad singlets arising from
numerous syn relationships, doublets and small coupling
constants (2.5-3.5 Hz) are displayed. Nonetheless, analogous
trends were noted that conformed to the anti/syn/anti/syn/anti
relationship for 16a and the anti/syn/syn/syn/syn arrangement
for 16b.
Diols 17a and 17b exhibit coupling patterns that are consistent
with the expected stereochemical outcome of the osmylation
reaction. The predominant product 16a features a spectrum
compatible with a anti/syn/anti/syn/anti setting, while that
exhibited by 16b befits the anti/syn/syn/syn/anti stereochemical
assignment.
Although the Kishi empirical rule deals strictly speaking
with relative configurational assignments, the previously
established absolute stereochemistry of 4 permits full as-
signment for all of the functionalized cyclooctanes defined
herein. For these formulations to be irrefutable, however,
independent proof of the validity of the spectral extrapolations
is mandated. This verification was arrived at chemically, and
rests on the inherent symmetry or absence thereof in the
ultimate polyhydroxylated cyclooctane products.
8a
8b
9a
9b
4.60
4.68
6.33
6.35
14a
15a
16a
17a
3.80
3.88
5.63
5.49
14b
15b
16b
17b
3.91
3.79
5.62
5.45
stereocenters and large J values to reflect an anti relationship.
More specifically, the fact that stereocenters C-3, C-4, and C-5
in all pairs of diastereomers share in common an anti/syn relative
configuration is now made pictorially evident.
Comparable analysis of diols 14a and 14b provided sugges-
tive evidence that the H-5/H-6 and H-7/H-8 relationships in each
of the predominant isomers are anti (Scheme 5). It follows
therefore that 14a has an anti/syn/anti/syn/anti arrangement
along C-3 to C-8. When depicted analogously, the data for 14b
demonstrate that its configuration is anti/syn/syn/syn/syn across
the same structural span. Thus, the very small J values indicative
of syn configurational arrangements are often seen as broadened
singlets in this particular case. Examples 15a and 15b exhibit
distinctively different patterns (Scheme 5). For 15a, a J coupling
distribution is seen that is consistent with an anti/syn/anti/syn/
syn relative stereochemical relationship across the same C-3 to
C-8 component of the eight-membered ring. The added number
of broad singlets prevailing in the spectrum of 15b is compatible
with the anti/syn/syn/syn/anti configurational descriptor applied
to this diol. The broad singlets for diols 14a-15b were analyzed
The diol pairs 14a/14b, 15a/15b, 16a/16b, and 17a/17b
were individually transformed into their acetonides by
reaction with 2,2-dimethoxypropane in the presence of
J. Org. Chem. Vol. 73, No. 19, 2008 7665

Moura-Letts and Paquette
SCHEME 4. JHH Value Analysis for 8a/8b and 9a/9ba
a The x axis is the carbon number and y axis is the vicinal JHH value.
SCHEME 5. JHH Value Analysis for 14a/14b and 15a/15ba
a The x axis is the carbon number and y axis is the vicinal JHH value.
SCHEME 6. JHH Value Analysis of 16a/16b and 17a/17ba
a The x axis is the carbon number and y axis is the vicinal JHH value.
catalytic quantities of CSA. The unpurified products were in
turn reacted with catalytic OsO4 in the presence of NMO to
generate the respective diols (Scheme 7). The eight reactions
proceeded very slowly, and starting material often remained
after 48 h. The yields of products ranged from 20 to 68%
under normalized conditions. The stereodisposition of the
bulky TBS ether functionality flanking the olefinic reaction
center in these medium ring systems clearly controls the rate
of conversion to product. The acetonides of diols 15a/15b
and 17a/17b were transformed into the targeted diols by
reaction with OsO4 from the face opposite to the groups
around the double bond (OAc/OTBS for 15a/15b and OTBS/
OTBS for 17a/17b). The yields were good (61/59 and 67/
64%, respectively). In contrast, the acetonides of diols 14a/
14b and 16a/16b (C-1 has opposite stereochemistry) proceeded
to the corresponding diols in lower yields (43/41 and 20/
30%, respectively). The underlying reasons for this dropoff
in stereoselectivity are presumably complex.
7666 J. Org. Chem. Vol. 73, No. 19, 2008

SCHEME 7. Acetonide Protection and OsO4-Mediated Dihydroxylation Results
SCHEME 8. JHH Value Analysis of 18-21a
a The x axis is the carbon number and y axis is the vicinal JHH value.
In line with our goals, the vicinal JHH coupling constants for
all eight contiguous stereocenters in each of the diols 18-25
were measured. The charts for 18-21 exhibit a clear pattern of
large JHH /small JHH for prevailing anti/syn relationships
(Scheme 8). As expected, those stereocenters that are syn to
contiguous stereocenters have singlet patterns (C-2 for 18; C-1,
C-2, C-6, C-7, and C-8 for 19; C-8 for 20; and C-6 and C-7 for
21). In line with expectation, the newly introduced hydroxyl-
substituted stereocenters (C-1 and C-2) present a recurrent JHH
of 4 Hz when they are syn to their neighboring peripheral
stereocenters. The remaining JHH values proved consistent with
the patterns expected on the basis of forecasted stereochemistry.
From the charts for diols 22-25, there emerges again a clear
pattern of large JHH/small JHH for anti/syn relationships (Scheme
9). As above, resonances where a syn/syn relationship exists
among three contiguous stereocenters appear as singlets (e.g.,
C-3 for 22; C-3, C-6, C-7, and C-8 for 23; C-8 for 24; and C-6
and C-7 for 25). Like the PMB series, the newly formed
hydroxyl-substituted stereocenters (C-1 and C-2) present a
recurring JHH of 4-4.5 Hz when they are syn to their
neighboring stereocenters. Also, the remaining JHH values are
consistent with the patterns expected on the basis of their relative
stereochemistry.
The next goal involved removal of the protecting groups from
the series of diols 19-21 and 22-25. Substrates 19-21 were
initially treated individually with DDQ in CH2Cl2/H2O. The
crude reaction mixtures were subsequently stirred with 2.5 N
HCl in THF followed by K2CO3 to provide polyols 26-29 in
moderate to good yields (73, 81, 69, and 75%, respectively,
Scheme 10). Diols 27, 28, and 29 each exhibit a symmetric
spectrum based on the stereochemical predictions made during
the stepwise dihydroxylations. These data were intended to serve
as proof of concept for the assignment of relative stereochem-
istry for contiguous hydroxyl stereocenters in a cyclic molecule
J. Org. Chem. Vol. 73, No. 19, 2008 7667

Moura-Letts and Paquette
SCHEME 9. JHH Value Analysis of 22-25a
a The x axis is the carbon number and y axis is the vicinal JHH value.
SCHEME 10. Global Deprotection and JHH Value Analysis of 26-31
a (II) DDQ, CH2Cl2/H2O; (II) 2.5 N HCl in THF; (III) K2CO3, MeOH. b (I) LiAlH4; (II) 2.5 N HCl in THF.
1
based on vicinal JHH values. The H NMR of 27, 28, and 29
confirmed that these polyols are symmetric, and as a conse-
quence, the assignments of the stereochemical outcomes of the
dihydroxylation reactions were properly defined.
yields (56, 85, 51, and 62%, respectively, Scheme 10). The
products of the global deprotection of diols 24 and25 proved
to be identical to those obtained from 28 and 29. The symmetry
found in these compounds also served as further proof of the
unequivocal assignment of relative stereochemistry. The product
emanating from the global deprotection of 23 provided the
previously unknown symmetric polyol 31. Similarly, the global
deprotection of diol 22 provided the new compound 30. These
results established convincingly that this series of diastereomers
has the correct assignment of their relative stereochemistries
for contiguous hydroxyl stereocenters in a cyclic molecule based
on vicinal JHH values.
When the vicinal JHH values for isomers 26-29 were plotted
in the same manner as the previously synthesized intermediates
(Scheme 10), the plots clearly followed the previous trend (large
JHH for anti and small JHH for syn). This series of compounds
showed higher anti vicinal JHH values (9-9.5 Hz) than those
observed for the previously plotted intermediates. In contrast,
the syn vicinal JHH values (2-4 Hz) were entirely similar to
those of their counterparts.
The final objective involved removal of the protecting groups
from the series of diols 22-25. These were treated individually
with LiAlH4 in THF to remove the benzoate group. The resulting
reaction mixtures were next acidified with 2.5 N HCl in THF
and then purified to provide polyols 30,31, 28, and 29 in good
Also plotted were the vicinal JHH values for the isomers 30,
31, 28, and29 (Scheme 10). The plots clearly followed the trend
found in the previous intermediates. This series of compounds
showed higher anti vicinal JHH values (9-9.5 Hz) than the
7668 J. Org. Chem. Vol. 73, No. 19, 2008

bottomed flask was placed in an ice bath and charged with CrO3
(892 mg, 8.92 mmol) in advance of Ac2O (1.75 mL, 17.8 mmol)
and AcOH (3.52 mL, 63.4 mmol). The resulting solution was stirred
at 0 °C for 10 min, and dichloromethane (30 mL) was added. The
mixture was allowed to warm to rt, and a solution of 5 (1.0 g, 1.98
mmol) in CH2Cl2 (30 mL) was added dropwise. The resulting
mixture was stirred for 45 min and quenched with saturated
NaHCO3 solution. The aqueous layer was extracted with ether (2×),
and the combined organic fractions were dried and concentrated
prior to purification by silica gel flash chromatography (elution with
hexanes/ethyl acetate 90:10) to yield 6 (685 g, 65%) as a yellow
oil: [R]20D +28.1 (c 1.1, CHCl3); IR (thin film, cm-1) 3533, 1718,
previously plotted intermediates. On the other hand, the syn
vicinal JHH values (2-4 Hz) were similar to those previously
plotted.
Summary
In conclusion, this study has applied the previously developed
Zr-mediated ring contraction reaction to the acquisition of a
series of diastereomeric cyclooctane polyols. Determination of
vicinal JHH coupling patterns associated with each series of
intermediates provided the opportunity to predict the relative
stereochemistry of the dihydroxylated products of the respective
dienols. This analysis was applied with high accuracy to the
fully hydroxylated intermediates and ultimately to the polyols.
The final proof for this analysis was given by the symmetry
resident in compounds 27, 28, 29, and 31. These results
permitted full assignment of the stereochemistry of the five new
stereocenters generated in this investigation without further
derivatization of the polyols or any of their precursors.
1
1613, 1249; H NMR (500 MHz, CDCl3) δ 7.94 (d, J ) 6.4 Hz,
2H), 6.91 (d, J ) 6.4 Hz, 2H), 6.62 (dd, J ) 12.5, 7.5 Hz, 1H),
6.28 (dd, J ) 12.5, 7.5 Hz, 1H), 6.35-6.30 (m, 2H), 6.26 (d, J )
12.5 Hz, 1H), 4.64 (td, J ) 7.5, 2 Hz, 1H), 4.22 (dd, J ) 7.5, 2.5
Hz, 1H), 3.82 (s, 3H), 0.88 (s, 9H), 0.86 (s, 9H), 0.06 (s, 3H), 0.02
(s, 3H), -0.01 (s, 3H), -0.11 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 191.3, 165.6, 163.7, 147.8, 143.5, 132.8, 132.7, 132.3, 131.9,
129.8, 122.0, 113.7, 78.4, 76.2, 75.0, 73.0, 55.4, 26.1, 25.9, 18.2,
18.1, -3.1, -3.7, -4.1, -4.6; HRMS exact mass calcd for
C28H44O6Si2Na+ 555.2574, found 555.2581.
(2Z,4R,5R,6R,7Z)-4,5-Bis(tert-butyldimethylsilyloxy)-6-(4-meth-
oxybenzyloxy)cycloocta-2,7-dienol (8a). A 100 mL round-bottomed
flask was charged with enone 5 (698 mg, 1.34 mmol) and MeOH
(60 mL). The resulting solution was cooled to 0 °C, and
CeCl3 ·7H2O (499 mg, 1.34 mmol) was added, and the solution
was stirred for 5 min. NaBH4 (51 mg, 1.34 mmol) was next added
slowly. The resulting solution was stirred for 15 min and quenched
with saturated NH4Cl solution. The aqueous layer was extracted
with ether (2×), and the combined organic fractions were dried
and concentrated, and the crude mixture was purified by silica gel
flash chromatography (elution with hexanes/ethyl acetate 80:20)
to yield the less polar dienol 8a (300 g, 43%) as a pale yellow oil:
[R]20D -15.1 (c 2.6, CHCl3); IR (thin film, cm-1) 3521, 1639, 1469;
1H NMR (400 MHz, CDCl3) δ 7.22 (d, J ) 8.5 Hz, 2H), 6.82 (d,
J ) 6.6 Hz, 2H), 5.80 (dd, J ) 11.5, 7 Hz, 1H), 5.77 (dd, J ) 9,
2 Hz, 1H), 5.47 (dd, J ) 11, 7 Hz, 1H), 5.40 (dd, J ) 11.5, 7 Hz,
1H), 5.30 (t, J ) 7 Hz, 1H), 4.60 (dd, J ) 7, 2 Hz, 1H), 4.50 (d,
J ) 12 Hz, 1H), 4.32 (d, J ) 12 Hz, 1H), 4.22 (t, J ) 7 Hz, 1H),
3.92 (dd, J ) 7, 2 Hz, 1H), 3.77 (s, 3H), 0.83 (s, 9H), 0.79 (s, 9H),
0.08 (s, 3H), 0.06 (s, 3H), 0.04 (s, 3H), 0.02 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 158.9, 134.3, 131.3, 130.7, 129.1, 113,6, 75.8,
74.6, 71.0, 70.0, 67.8, 55.2, 25.8, 18.1, 18.0, -4.5, -4.4, -4.9,
-5.0; HRMS exact mass calcd for C28H48O5Si2Na+ 543.2938, found
543.2903.
(2Z,1R,4R,5R,6R,7S,8R)-4,5-Bis(tert-butyldimethylsilyloxy)-6-(4-
methoxybenzyloxy)-7,8-bishydroxycyclooct-2-enyl acetate (14a). A
25 mL round-bottomed flask was charged with acetate 10 (100 mg,
0.178 mmol), THF (2 mL), and H2O (500 µL). The resulting
solution was cooled to 0 °C, NMO (60 mg, 0.51 mmol) was added,
and the solution was stirred for 5 min. Then, OsO4 (9 mg, 0.034
mmol) was introduced. The resulting solution was stirred for 15
min in the cold and at rt for 16 h. The reaction mixture was
quenched with saturated Na2S2O3 solution. The aqueous layer was
extracted with ether (2×), and the combined organic fractions were
dried and concentrated, and the crude mixture was purified by silica
gel flash chromatography (elution with hexanes/ethyl acetate 70:
30) to yield the less polar isomer 14a (50 mg, 49%) as a light tan
oil: [R]20D -14.3 (c 2.2, CHCl3); IR (thin film, cm-1) 3432, 1721,
1614, 1579, 1445; 1H NMR (500 MHz, CDCl3) δ 7.21 (d, J ) 8.5
Hz, 2H), 6.83 (d, J ) 8.5 Hz, 2H), 5.83 (t, J ) 11 Hz, 1H), 5.73
(dd, J ) 11, 7 Hz, 1H), 5.54 (dd, J ) 9, 7.5 Hz, 1H), 4.49-4.46
(m, 2H), 4.23 (d, J ) 11.5, 1H), 4.05 (dd, J ) 7.5, 2.5 Hz, 1H),
3.94 (dd, J ) 7, 2 Hz, 1H), 3.90 (dd, J ) 7, 2 Hz, 1H), 3.80 (dd,
J ) 7.5, 2.5 Hz, 1H), 3.76 (s, 3H), 3.21 (d, J ) 10 Hz, 1H), 2.56
(d, J ) 11.5 Hz, 1H), 2.10 (s, 3H), 0.85 (s, 9H), 0.82 (s, 9H), 0.06
(s, 3H), 0.05 (s, 3H), 0.03 (s, 3H), 0.02 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 170.7, 159.2, 136.0, 130.0, 129.8, 129.7, 126.7,
Experimental Section
(2Z,4R,5R,6R,7Z)-4,5-Bis(tert-butyldimethylsilyloxy)-6-(4-meth-
oxybenzyloxy)cycloocta-2,7-dienone (5). A 250 mL round-bottomed
flask was charged with alcohol 2 (800 mg, 2.13 mmol) and CH2Cl2
(30 mL). The resulting solution was placed in an ice bath, and 2,6-
lutidine (371 µL, 3.32 mmol) and TBSOTf (590 µL, 2.55 mmol)
were added. The resulting mixture was stirred at 0 °C for 3 h and
quenched with saturated NH4Cl solution. The aqueous layer was
extracted with CH2Cl2 (2×), and the combined organic fractions
were dried and concentrated prior to purification by silica gel flash
chromatography (elution with hexanes/ethyl acetate 95:5) to yield
4 as a colorless oil (1.0 g, 93%): [R]20 -53.1 (c 1.2, CHCl3); IR
D
(thin film, cm-1) 3434, 1645, 1248; H NMR (400 MHz, CDCl3)
1
δ 7.21 (d, J ) 8.4 Hz, 2H), 6.83 (d, J ) 8.3 Hz, 2H), 5.66-5.56
(m, 2H), 5.48 (dd, J ) 12, 7 Hz, 1H), 5.38 (dd, J ) 12, 4 Hz, 1H),
4.68 (d, J ) 7 Hz, 1H), 4.51-4.48 (m, 2H), 4.27 (d, J ) 11 Hz,
1H), 3.78 (s, 4H), 2.83 (br s, 2H), 0.88 (s, 9H), 0.87 (s, 9H), 0.09
(s, 3H), 0.08 (s, 3H), 0.07 (s, 3H), 0.06 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 159.1, 134.5, 133.7, 132.4, 130.6, 129.8, 129.6,
128.7, 113.5, 78.1, 74.7, 68.8, 67.8, 55.2, 42.1, 30.2, 26.1, 26.0,
18.5, -3.8, -4.8, -5.1, -5.3. A 100 mL round-bottomed flask
was placed in an ice bath and charged with CrO3 (446 mg, 4.46
mmol) in advance of Ac2O (875 µL, 8.9 mmol) and AcOH (1.76
mL, 31.7 mmol). The resulting solution was stirred at 0 °C for 10
min, and CH2Cl2 (30 mL) was added. The mixture was cooled to
-5 °C, and a solution of silyl ether 4 (1.0 g, 1.9 mmol) in
dichloromethane (30 mL) was added dropwise. The resulting
mixture was stirred for 45 min and quenched with saturated
NaHCO3 solution. The aqueous layer was extracted with ether (2×),
and the combined organic fractions were dried and concentrated
prior to purification by silica gel flash chromatography (elution with
hexanes/ethyl acetate 90:10) to yield 5 (698 g, 68%) as a yellowish
oil: [R]20D +12.1 (c 1.6, CHCl3); IR (thin film, cm-1) 1718, 1641,
1
1607, 1513; H NMR (400 MHz, CDCl3) δ 7.07 (d, J ) 6.4 Hz,
2H), 6.78 (d, J ) 6.6 Hz, 2H), 6.54 (dd, J ) 12.4, 7 Hz, 1H), 6.28
(dd, J ) 12.4, 1.6 Hz, 1H), 6.24 (dd, J ) 10.8, 5.2 Hz, 1H), 6.08
(dt, J ) 12.8, 1.2 Hz, 1H), 4.56 (ddd, J ) 7.2, 3.2, 1.2 Hz, 1H),
4.50 (t, J ) 7.5 Hz, 1H) 4.42 (d, J ) 11.6 Hz, 1H), 4.21 (d, J )
11.6 Hz, 1H), 3.92 (dd, J ) 7.5, 2.5 Hz, 1H), 3.73 (s, 3H), 0.8 (s,
9H), 0.78 (s, 9H), -0.01 (s, 3H), -0.02 (s, 3H), -0.03 (s, 3H),
-0.09 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 191.9, 159.3, 149.6,
148.7, 133.7, 132.7, 129.8, 129.4, 113.7, 79.9, 76.1, 74.9, 71.1,
55.2, 26.1, 25.8, 18.4, 18.1, -3.5, -4.0, -4.1, -4.3; HRMS exact
mass calcd for C28H46O5Si2Na+ 541.2782, found 541.2791.
(1R,2Z,5Z,7R,8R)-7,8-Bis(tert-butyldimethylsilyloxy)-4-oxocy-
cloocta-2,5-dienyl 4-methoxybenzoate (6). A 100 mL round-
J. Org. Chem. Vol. 73, No. 19, 2008 7669

Moura-Letts and Paquette
122.9, 113.8, 83.3, 78.5, 73.7, 72.6, 70.3, 66.5, 55.2, 25.8, 25.6,
22.6, 18.1, 17.7, -4.4, -4.8, -4.9, -5.0; HRMS exact mass calcd
for C30H51O8Si2Na+ 619.3098, found 619.3073.
Hz, 2H), 3.83 (dd, J ) 9.0, 4 Hz, 2H) 3.69 (dd, J ) 9.5, 2.0 Hz,
2H), 3.43 (t, J ) 9.5 Hz, 1H); 13C NMR (125 MHz, D2O) δ 76.2,
72.0, 72.4, 71.2, 70.7, 70.2; HRMS exact mass calcd for
C8H16O8Na+ 263.0743, found 263.0735.
(1R,3R,4R,5R,6R,7S,8R,9R)-5,6-Bis(tert-butyldimethylsilyloxy)-
4-(4-methoxybenzyloxy)-octahydro-7,8-dihydroxy-2,2-
dimethylcycloocta[d][1,3]dioxol-9-yl acetate (18). A 25 mL round-
bottomed flask was charged with diol 14a (50 mg, 0.08 mmol),
acetone (1 mL), 2,2-dimethoxypropane (200 µL), and CSA (2 mg).
The resulting solution was stirred for 2 h at rt. The reaction mixture
was quenched with saturated NaHCO3 solution. The aqueous layer
was extracted with CH2Cl2 (2×), and the combined organic fractions
were dried and concentrated. The resulting crude mixture was
dissolved in THF (0.5 mL) and H2O (100 µL) and cooled to 0 °C.
NMO (27 mg, 0.23 mmol) was added, and the solution was stirred
for 5 min. Then, OsO4 (4.1 mg, 0.015 mmol) was introduced. The
resulting solution was stirred for 15 min in the cold and at rt for
48 h. The reaction mixture was quenched with saturated Na2S2O3
solution, the aqueous layer extracted with ether (2×), and the
combined organic fractions were dried and concentrated, and the
residue was purified by silica gel flash chromatography (elution
with hexanes/ethyl acetate 1:1) to yield diol 18 (42 mg, 43%) as a
(1S,2S,3R,4R,5S,6S,7R,8R)-Cyclooctan-1,2,3,4,5,6,7,8-octaol (29).
The global deprotection of diol 21 (11 mg, 0.02 mmol) provided
29 (3 mg, 75%) as a white solid: mp 286-289 °C; [R]20 0.0 (c
D
1
0.29, MeOH); IR (thin film, cm-1) 3442, 3220, 1462, 1068; H
NMR (500 MHz, D2O) δ 4.21 (d, J ) 9.5 Hz, 2H), 4.19 (t, J )
9.5, 9 Hz, 2H), 3.90 (d, J ) 3 Hz, 2H), 3.69 (dd, J ) 9, 3 Hz, 2H);
13C NMR (125 MHz, D2O) δ 73.0, 69.3, 69.1, 66.3; HRMS exact
mass calcd for C8H16O8Na+ 263.0743, found 263.0761.
(1R,2S,3S,4S,5S,6R,7S,8S)-Cyclooctan-1,2,3,4,5,6,7,8-octaol (30).
A 5 mL round-bottomed flask was charged LiAlH4 (5 mg, 0.1
mmol) and THF (1 mL) and then cooled to 0 °C. At that
temperature, a solution of diol 22 (12 mg, 0.02 mmol) in THF (1
mL) was added dropwise. The reaction mixture was stirred at rt
for 3 h, quenched with saturated NaHCO3 solution, and extracted
with EtOAc. The residue was filtered through a small pad of silica
gel and concentrated. The residue was mixed in a 5 mL round-
bottomed flask with THF (1 mL) and charged with 2.5 N HCl in
THF (1 mL). The reaction mixture was stirred at rt for 6 h and
quenched with solid sodium bicarbonate. The crude mixture was
purified by flash chromatography using a reverse phase column
(elution with MeOH/CHCl3 1:3) to yield 30 (2 mg, 56%) as a white
solid: mp 271-275 °C; [R]20D +3.5 (c 0.65, MeOH); IR (thin film,
cm-1) 3401, 3221, 1465; 1H NMR (500 MHz, D2O) δ 4.51 (dd, J
) 9.5, 3 Hz, 1H), 4.39 (dd, J ) 9.0, 3 Hz, 1H), 4.25 (dd, J ) 9.5,
4 Hz, 1H), 4.12 (dd, J ) 9, 4 Hz, 1H), 3.92 (dd, J ) 9.5, 2.5 Hz,
1H), 3.89 (s, 1H), 3.69 (dd, J ) 9.5, 3 Hz, 1H), 3.52 (t, J ) 9.5,
9 Hz, 1H); 13C NMR (125 MHz, D2O) δ 78.3, 76.1, 75.3, 72.1,
70.3, 69.4, 65.7, 63.1; HRMS exact mass calcd for C8H16O8Na+
263.0743, found 263.0729.
light yellow oil: [R]20D -48.3 (c 1.6, CHCl3); IR (thin film, cm-1
)
3452, 1714, 1496, 1286; 1H NMR (500 MHz, CDCl3) δ 7.24 (d, J
) 8.5 Hz, 2H), 6.86 (d, J ) 8.5 Hz, 2H), 5.69 (d, J ) 8 Hz, 1H),
4.80 (t, J ) 7.5, 7 Hz, 1H), 4.43 (s, 2H), 4.36 (dd, J ) 7.5, 4 Hz,
1H), 4.28 (dd, J ) 7, 2.5 Hz, 1H), 4.24-4.20 (m, 2H), 4.04 (dd,
J ) 7.5, 2 Hz, 1H), 3.82 (dd, J ) 7.5, 2.5 Hz, 1H), 3.79 (s, 3H),
3.52 (s, 1H), 3.11 (s, 1H), 2.15 (s, 3H), 1.53 (s, 3H), 1.46 (s, 3H),
0.89 (s, 9H), 0.86 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H), 0.04 (s, 3H),
0.03 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 170.7, 159.2, 130.0,
129.8, 126.7, 113.8, 98.1, 83.3, 80.9, 78.5, 77.2, 76.1, 73.7, 72.6,
70.3, 66.5, 55.2, 25.7, 25.3, 24.1, 23,7, 21.2, 18.1, 17.7, -4.4, -4.8,
-4.9, -5.0; HRMS exact mass calcd for C33H58O10Si2Na+ 693.3458,
found 693.3471.
(1S,2R,3R,4S,5S,6S,7R,8S)-Cyclooctan-1,2,3,4,5,6,7,8-octaol (31).
(1S,2S,3R,4S,5S,6S,7S,8R)-Cyclooctan-1,2,3,4,5,6,7,8-octaol (26).
A 5 mL round-bottomed flask was charged with diol 18 (43 mg,
0.06 mmol), CH2Cl2 (1 mL), H2O (250 µL), and DDQ (5 mg, 0.12
mmol). The reaction mixture was stirred at rt for 3 h and quenched
with saturated NaHCO3 aqueous solution and extracted with
CH2Cl2. The residue was filtered trough a small pad of silica gel
and concentrated. The residue was mixed in a 5 mL round-bottomed
flask with THF (1 mL) and charged with 2.5 N HCl in THF (1
mL). The reaction mixture was stirred at rt for 6 h and quenched
with solid sodium bicarbonate. The residue was triturated with
MeOH (2 mL) and reacted with K2CO3 (10 mg). The resulting
mixture was stirred at rt for 2 h, and the solvent was removed under
vacuum. The crude mixture was purified by flash chromatography
using a reverse phase column (elution with MeOH/CHCl3 1:3) to
The global deprotection of diol 23 (3 mg, 0.005 mmol) provided
31 (1 mg, 85%) as a white solid: mp 296-299 °C; [R]20 0.0 (c
D
1
0.14, MeOH); IR (thin film, cm-1) 3429, 3310, 1403, 1093; H
NMR (500 MHz, D2O) δ 4.22 (s, 1H), 3.97 (s, 2H), 3.76 (dd, J )
9, 2.5 Hz, 2H), 3.52 (s, 1H), 3.41 (dd, J ) 9, 4 Hz, 2H); 13C NMR
(125 MHz, D2O) δ 78.1, 76.7, 75.3, 72.4, 70.1; HRMS exact mass
calcd for C8H16O8Na+ 263.0743, found 263.0757.
(1R,2R,3S,4S,5S,6R,7R,8S)-Cyclooctan-1,2,3,4,5,6,7,8-octaol (28).
The global deprotection of diol 24 (32 mg, 0.04 mmol) provided
28 (5 mg, 51%) as a white solid: mp 283-285 °C; [R]20 0.0 (c
D
1
0.19, MeOH); IR (thin film, cm-1) 3487, 3259, 1421; H NMR
(500 MHz, D2O) δ 4.10 (t, J ) 2.0 Hz, 1H), 3.91 (dd, J ) 9.5, 4.0
Hz, 2H), 3.83 (dd, J ) 9.0, 4 Hz, 2H) 3.69 (dd, J ) 9.5, 2.0 Hz,
2H), 3.43 (t, J ) 9.5 Hz, 1H); 13C NMR (125 MHz, D2O) δ 76.2,
72.0, 72.4, 71.2, 70.7, 70.2; 13C NMR (125 MHz, D2O) δ 78.1,
76.1, 74.3, 70.9, 69.6, 65.6, 65.3, 63.5; HRMS exact mass calcd
for C8H16O8Na+ 263.0743, found 263.0735.
yield 26 (11 mg, 73%) as a white solid: mp 268-271 °C; [R]20
D
-69.1 (c 0.91, MeOH); IR (thin film, cm-1) 3401, 3365, 1421,
1
1099; H NMR (500 MHz, D2O) δ 4.26 (dd, J ) 9, 4 Hz, 2H),
3.91 (dd, J ) 9, 2.5 Hz, 1H), 3.78 (d, J ) 9.5 Hz, 2H), 3.60 (dd,
(1S,2S,3R,4R,5S,6S,7R,8R)-Cyclooctan-1,2,3,4,5,6,7,8-octaol (29).
The global deprotection of diol 25 (11 mg, 0.02 mmol) provided
29 (2.5 mg, 62%) as a white solid: mp 286-289 °C; [R]20D 0.0 (c
J ) 9.5, 2.5 Hz, 1H), 3.49 (t, J ) 9.5, 9 Hz, 1H), 3.38 (s, 1H); 13
C
NMR (125 MHz, D2O) δ 78.1, 75.9, 74.6, 70.3, 69.7, 64.9, 64.7,
63.2; HRMS exact mass calcd for C8H16O8Na+ 263.0743, found
263.0739.
1
0.25, MeOH); IR (thin film, cm-1) 3449, 3219, 1465, 1068; H
NMR (500 MHz, D2O) δ 4.21 (d, J ) 9.5 Hz, 2H), 4.19 (t, J )
9.5, 9 Hz, 2H), 3.90 (d, J ) 3 Hz, 2H) 3.69 (dd, J ) 9, 3 Hz, 2H);
13C NMR (125 MHz, D2O) δ 73.0, 69.3, 69.1, 66.3; HRMS exact
mass calcd for C8H16O8Na+ 263.0743, found 263.0761.
(1R,2R,3S,4S,5S,6S,7R,8R)-Cyclooctan-1,2,3,4,5,6,7,8-octaol (27).
The global deprotection of diol 19 (8 mg, 0.01 mmol) provided 27
(2.3 mg, 81%) as a white solid: mp 272-277 °C; [R]20D 0 (c 0.12,
1
MeOH); IR (thin film, cm-1) 3399, 3187, 1431, 1110; H NMR
Acknowledgment. This study was partially supported by The
Ohio State University.
(500 MHz, D2O) δ 4.12 (dd, J ) 9.5, 4 Hz, 2H), 3.96 (s, 2H), 3.76
(s, 2H), 3.71 (s, 1H), 3.51 (t, J ) 9.5, 9 Hz, 1H); 13C NMR (125
MHz, D2O) 77.1, 75.3, 74.4, 72.2, 70.1, 69.3; HRMS exact mass
calcd for C8H16O8Na+ 263.0743, found 263.0763.
1
Supporting Information Available: High-field H and 13C
(1R,2R,3S,4S,5S,6R,7R,8S)-Cyclooctan-1,2,3,4,5,6,7,8-octaol (28).
The global deprotection of diol 20 (30 mg, 0.05 mmol) provided
28 (7.4 mg, 69%) as a white solid: mp 283-285 °C; [R]20D 0.0 (c
NMR spectra and full characterization for all new compounds
are described herein. This material is available free of charge
via the Internet at http://pubs.acs.org.
1
0.35, MeOH); IR (thin film, cm-1) 3487, 3263, 1429; H NMR
(500 MHz, D2O) δ 4.10 (t, J ) 2.0 Hz, 1H), 3.91 (dd, J ) 9.5, 4.0
JO801443D
7670 J. Org. Chem. Vol. 73, No. 19, 2008