From common carbohydrates to enantiopure cyclooctane polyols and glycomimetics via deoxygenative zirconocene ring contraction

Article abstract of DOI:10.1021/jo051989g

D-Arabinose and D-glucose are transformed into the identical vinyl furanoside, whose role is to serve as the precursor to enantiopure cyclooctadienone 6. The key steps of this relay involve a zirconocene-promoted ring contraction and [3,3] sigmatropic rea

Full text of DOI:10.1021/jo051989g

VOLUME 71, NUMBER 12
JUNE 9, 2006
© Copyright 2006 by the American Chemical Society
From Common Carbohydrates to Enantiopure Cyclooctane Polyols
and Glycomimetics via Deoxygenative Zirconocene Ring Contraction
Leo A. Paquette* and Yunlong Zhang
EVans Chemical Laboratories, The Ohio State UniVersity, Columbus, Ohio 43210
paquette.1@osu.edu
ReceiVed September 22, 2005
D-Arabinose and D-glucose are transformed into the identical vinyl furanoside, whose role is to serve as
the precursor to enantiopure cyclooctadienone 6. The key steps of this relay involve a zirconocene-
promoted ring contraction and [3,3] sigmatropic rearrangement of an enynol. Subsequently defined are
convenient synthetic routes to several cyclooctane-1,2,3-triols, 1,2,3,4,5-pentaols, and structurally related
glycomimetics.
Introduction
mediated cyclization. Herein, we detail an entirely different
approach that is based on use of the zirconocene-mediated ring
contraction of a vinyl furanoside to generate an enantiopure
cyclobutanol7 and subsequent adaptation of a [3.3] sigmatropic
rearrangement.8 More extended functionalization provides the
opportunity to generate stereodefined cyclooctane-1,2,3-triols
and 1,2,3,4,5-pentaols9 and to elaborate authentic carbasugar
analogues as well.
In recent years, the search for new, therapeutically useful
glycosidase inhibitors has turned to carbohydrate mimetics
consisting of medium-sized carbocyclic cores. The potential
advantages associated with this group of analogues include, but
are not limited to, improved affinity for their cognate acceptors
arising from greater degrees of conformational mobility, im-
proved bioavailability, and enhanced stability toward degradative
enzymes.1-4 The probing of carbohydrate recognition events
has consequently been extended beyond the realm of five- and
six-membered cyclitols1,2 to include polyhydroxylated cyclo-
heptanes5 and cyclooctanes.6 From among the several ap-
proaches that have been developed to access these polyols, the
most popular approaches have involved ring-closing metathesis,
ring-expansion via Claisen rearrangement, and free radical
Results and Discussion
Arrival at the first pivotal intermediate 3 was achieved from
two directions as shown in Scheme 1. In the first approach, the
(5) (a) Jia, C.; Zhang, Y.; Zhang, L. Tetrahedron: Asymmetry 2003,
14, 2195. (b) Rassu, G.; Auzzas, L.; Pinna, L.; Zambrano, V.; Zanardi, F.;
Battistini, L.; Gaetani, E.; Curti, C.; Casiraghi, G. J. Org. Chem. 2003, 68,
5881. (c) Marco-Contelles, J.; de Opazo, E. J. Org. Chem. 2002, 67, 3705.
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Sisu, E.; Sollogoub, M.; Mallet, J.-M.; Sinay¨, P. Tetrahedron 2002, 58,
10189. (f) Gravier-Pelletier, C.; Maton, W.; Lecourt, T.; Le Merrer, Y.
Tetrahedron Lett. 2001, 42, 4475. (g) Pearson, A.; Katiyar, S. Tetrahedron
2000, 5, 2297. (h) Le Merrer, Y.; Gravier-Pelletier, C.; Maton, W.; Muma,
M.; Depezay, J.-C. Synlett 1999, 1322. (i) Patra, R.; Bar, N. C.; Roy, A.;
Achari, B.; Goshal, N.; Mandal, S. B. Tetrahedron 1996 52, 11265.
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Y., Ed.; Wiley-VCH: Weinheim, 1998; pp 87-106.
(2) Tang, Y.-Q.; Maul, C.; Ho¨fs, R.; Sattler, I.; Grabley, S.; Feng, X.-
Z.; Zeeck, A.; Thiericke, R. Eur. J. Org. Chem. 2000, 149.
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10.1021/jo051989g CCC: $33.50 © 2006 American Chemical Society
Published on Web 01/17/2006
J. Org. Chem. 2006, 71, 4353-4363
4353

Paquette and Zhang
SCHEME 1a
SCHEME 2a
a Key: (a) Dess-Martin periodinane, NaHCO3, CH2Cl2; (b) NaBH4,
MeOH (88% for two steps); (c) TBSCl, imid, DMAP, CH2Cl2 (87%); (d)
1% HCl, MeOH; TBSCl, imid, DMAP, CH2Cl2 (67%); (e) PMBBr, (n-
Bu)4NI, NaH, THF (70%); (f) HCl, MeOH, H2O, 0 °C f rt (59%); (g)
TsCl, py (96%); (h) Zn, NaI, DMF, reflux overnight (87%); (i) 1% HCl,
MeOH (79%); (j) TBSCl, imid, DMAP (88%); (k) Cp2ZrCl2, n-BuLi,
toluene; BF3‚OEt2 (65%).
known alcohol 1, readily available from D-arabinose,8a,10 was
subjected to Dess-Martin oxidation,11 reduction with sodium
borohydride,12 silylation, and subsequent anomerization. The
alternative route began with D-glucose diacetonide, whose
conversion to 2 by the Horton protocol12 was followed by
formation of the PMB ether and controlled hydrolysis to the
exocyclic vicinal diol. The targeted advancement to 3 was next
realized by reductive elimination of the ditosylate with zinc dust
and sodium iodide in hot DMF.13-15 Acetalization and repro-
tection followed. The next transformation involved exposing 3
to the action of Cp2Zr and boron trifluoride etherate in the
a Key: (a) Dess-Martin periodinane, NaHCO3, CH2Cl2. (b) BrMg-t-
SiMe3, THF, 0 °C (65% over two steps); (c) K2CO3, CH3OH, rt; (d) C6H6,
∆ (98% for two steps); (e) NaBH4, CeCl3, CH3OH; (f) NaBH4, CH3CH2OH;
(g) NaBH4, CH3OH; (h) H2, Pd/C, CH3OH (51-62%); (i) TBAF, THF
(65-81%).
expectation that 4 would result from adoption of the less
sterically congested transition state A. Indeed, excellent forward
progress was realized in that 4 was isolated as the only product
in 65% yield.
Oxidation of 4 to the cyclobutanone level could be ac-
complished without the loss of stereochemical integrity by
involvement of the Dess-Martin periodinane.11 In addition, the
vinylic double bond does not migrate into conjugation as long
as chromatography on silica gel is avoided. The ability to
preclude isomerization to the R,â-unsaturated four-membered
ring ketone has been noted in other contexts.15-17 The next
tactical move involved 1,2-addition of the Grignard reagent
generated from trimethylsilylacetylene. Not unexpectedly, carbinol
5 was formed with complete diastereocontrol (Scheme 2). Mild
basic desilylation of 5 led to the tertiary carbinol, an advanced
intermediate that proved notably responsive to its inherent ring
strain. Thus, refluxing desilylated 5 in benzene led quantitatively
to the enantiopure, dextrorotatory cyclooctadienone (+)-6.
The first experiments designed to extend the level of
functionalization in (+)-6 involved reduction with sodium
borohydride under various conditions. With cerium(III) chloride
as additive in methanol solution,18 (-)-7 was formed exclusively
via R-hydride delivery. Omission of the lanthanide gave rise to
7 and its dextrorotatory epimer (+)-9 in a 4.3:1 ratio. A similar
(6) (a) Andriuzzi, O.; Gravier-Pelletier, C.; Vogel, P.; Le Merrer, Y.
Tetrahedron 2005, 61, 7094. (b) Andriuzzi, O.; Gravier-Pelletier, C.; Y.
Le Merrer. Y. Tetrahedron Lett. 2004, 45, 8043. (c) Ble´riot, Y.; Giroult,
A.; Mallet, J.-M.; Rodriguez, E.; Vogel, P.; Sinay¨, P. Tetrahedron:
Asymmetry 2002, 13, 2553. (d) Mehta, G.; Pallavi, K. Tetrahedron Lett.
2004, 45, 3865. (e) Gravier-Pelletier, C.; Andriuzzi, O.; Le Merrer, Y.
Tetrahedron Lett. 2002, 43, 245. (f) Fawcett, J.; Griffiths, G. A.; Percy, J.
M.; Pintat, S.; Smith, C. A.; Spencer, N. S.; Unemaya, E. Chem. Commun.
2002, 2828. (g) Wang, W.; Zhang, Y.; Zhou, H.; Ble´riot, Y.; Sinay¨, P.
Eur. J. Org. Chem. 2001, 1053. (h) van Hooft, P. A. V.; van der Marel, G.
A.; van Boeckel, C. A. A.; van Boom, J. H. Tetrahedron Lett. 2001, 42,
1769. (i) Boyer, F.-D.; Hanna, I.; Nolan, S. P. J. Org. Chem. 2001, 66,
4094. (j) van Hooft, P. A. V.; Litjens, R. E. J. N.; van der Marel, G. A.;
van Boeckel, C. A. A.; van Boom, J. H. Org. Lett. 2001, 3, 731. (k)
McNulty, J.; Grunner, V.; Mao, J. Tetrahedron Lett. 2001, 42, 5609. (l)
Hanna, I.; Ricard, L. Org. Lett. 2000, 2, 2651.
(7) Reviews: (a) Paquette, L. A. J. Organomet. Chem., in press. (b)
Hanzawa, Y.; Ito, H.; Taguchi, T. Synlett 1995, 299.
(8) (a) Paquette, L. A.; Cunie`re, N. Org. Lett. 2002, 4, 1927. (b) Paquette,
L. A.; Kim, I. H.; Cunie`re, N. Org. Lett. 2003, 5, 221.
(9) Paquette, L. A.; Zhang, Y. Org. Lett. 2005, 7, 511.
(10) Dahlman, O.; Garegg, P. J.; Mayer, H.; Schramek, S. Acta Chem.
Scand. B 1986, 40, 15.
(11) (a) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(b) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(12) Baker, D. C.; Horton, D.; Tindall, C. G., Jr. Carbohydr. Res. 1972,
24, 192.
(13) Tipson, R. S.; Cohen, A. Carbohydr. Res. 1965, 1, 338.
(14) Paquette, L. A.; Arbit, R. M.; Funel, J. A.; Bolshakov, S. Synthesis
2002, 2105.
(16) Miller, S. A.; Gadwood, R. C. Org. Synth. 1989, 67, 210.
(17) Ollivier, J.; Salaun, J. Tetrahedron Lett. 1984, 25, 1269.
(18) Luche, J.-L.; Gemal, A. L. J. Chem. Soc., Chem. Commun. 1978,
976.
(15) Harris, N. J.; Gajewski, J. J. J. Am. Chem. Soc. 1994, 116, 6121.
4354 J. Org. Chem., Vol. 71, No. 12, 2006

DeoxygenatiVe Zirconocene Ring Contraction
SCHEME 3a
consisting of catalytic hydrogenation over 10% palladium on
charcoal followed by desilylation with TBAF (Scheme 2). When
processed in this manner, 7 and 8 were both converted to (-)-
13, where the absence of symmetry was evidenced by its eight-
line 13C NMR spectrum and significant optical rotation. Alcohol
9 reacted with comparable efficiency. In contrast, triol 14
generated in this manner exhibited no optical rotation and was
characterized by only five carbon signals. These properties are
a direct consequence of its Cs symmetry.
When (+)-6 was exposed at -78 °C to L-Selectride as the
reducing agent, 1,4-addition operated smoothly with generation
of the levorotatory cyclooctenone 15 (Scheme 3). This trans-
formation allowed for subsequent conversion to the â-configured
carbinol (-)-16 with sodium borohydride in methanol. Without
making a direct comparison of 6 and 15 because of their
different connectivities, we point out that their MM3-derived
minimum energy conformations (Figure 1) are quite disparate.
The different spatial projections of their carbonyl double bond
is especially pronounced and may be the root cause underlying
the divergent stereochemical pathways associated with their 1,2-
reductions.20 More to the point are the essentially isoenergetic
Es values for 16 and 17. This matchup precludes any key role
assignable to thermodynamic control. The absolute configuration
of the hydroxyl group in 16 was corroborated via its hydrogena-
tion to give (-)-10.
a Key: (a) L-Selectride, THF, -78 °C (93%); (b) NaBH4, MeOH (84%);
(c) L-Selectride, THF, rt (95%); (d) H2, Pd/C, CH3OH (93%); (e) OsO4,
NMO, 8:1 acetone/water (62%); (f) TBAF, THF (87%); (g) H2, Pd/C,
CH3OH (77%).
dropoff in stereoselectivity was not manifested in ethanol
solution, but the silyl-migrated isomer (+)-8 now emerged as
the major product.19
Unequivocal definition of the stereochemical assignments to
7-9 was achieved in each case by a two-step sequence
Advancement to the pentahydroxy cyclooctane (+)-21 was
conveniently initiated by L-Selectride reduction of (-)-15 at
room temperature, a process that gave rise to the R-oriented
carbinol (-)-17 and its silyl migrated isomer (-)-18 in a ratio
of 1.5:1. After chromatographic separation, (-)-17 was dihy-
FIGURE 1. MM3-based global low energy conformations for 6 and 15-17 and their associated steric energy (Es) values.
J. Org. Chem, Vol. 71, No. 12, 2006 4355

Paquette and Zhang
SCHEME 4
SCHEME 6a
SCHEME 5a
a Key: (a) Me2C(OMe)2, PPTS (83%); (b) Ph3PdCH2, THF (50%); (c)
BH3‚THF; H2O2, NaOH (65%); (d) DDQ, CH2Cl2, H2O, rt, 2 h (81%); (e)
1 M HCl, CH3OH (37% of 33; 28% of 34).
identification of (+)-26 as the silyl-migrated isomer of 25. The
centrally important transformations involved those TBAF-
promoted desilylations that demonstrated triol 27 to arise
uniquely from 24 and 28 to be the common end product from
both 25 and 26.
a Key: (a) OsO4‚NMO, acetone-H2O (1:1) (56% of 24, 38% of 25, 4%
of 36); (b) THF, rt (41% of 27, 80% of 28 from 25, 65% of 28 from 26).
droxylated with osmium tetraoxide in the presence of NMO to
produce (+)-19, thereby setting the stage for stepwise depro-
tection. The display by 21 of a positive optical rotation and
eight distinct 13C NMR signals indicated it not to be the meso
isomer. Consequently, the osmylation step had necessarily
proceeded by approach to the â-face of the π-bond as shown.
Heating solutions of (+)-6 in toluene at the reflux temperature
led to double bond migration and generation of a 1:1 mixture
of (-)-22 and (+)-23 (1H NMR analysis). As seen in Scheme
4, this equilibration could also be brought about under varying
basic conditions. The further chemical transformations of these
thermodynamically more favored isomers will be reported at a
later date.
Access to cyclooctane glycomimetics was achieved by early
dihydroxylation of the double bond in (-)-15. This particular
unsaturated ketone was transformed in the presence of OsO4
and NMO into three bicyclic products, the chromatographic
separation of which could be readily achieved (Scheme 5). The
major constituent proved to be a colorless solid amenable to
X-ray crystallographic analysis. These data identified the
substance to be (+)-24, whose formation arises as the conse-
quence of expected â-attack by the oxidant followed by
transannular hemiketal formation. The next most prevalent
product was shown to be (-)-25 by direct NMR comparison
with its stereoisomer and on the basis of several chemical
transformations. Similar interconversions made possible the
The experiments reported below involve disassembly of the
hemiacetal bridge in 24 and 25 by acetonide generation on the
periphery of the cyclooctane ring. In the case of 25, acid-
catalyzed reaction with 2,2-dimethoxypropane furnished ketone
(+)-29 efficiently (Scheme 6). Unmasking of a carbonyl group
in this fashion allowed for homologation to the dextrorotatory
exomethylene derivative 30. In line with our expectation that
the stereochemical course of the hydroboration of 30 would be
largely controlled by steric considerations, its exposure to the
borane tetrahydrofuran complex led uniquely to (-)-31. Evi-
dently, the R-orientation of all four vicinal protected oxygen
atoms in 30 is conducive to attack entirely from the â-face.
Arrival at carbasugar (-)-33 was most expediently accomplished
by dismantling of the p-methoxybenzyl ether with DDQ in wet
dichloromethane in advance of acid-catalyzed hydrolysis. The
pentahydroxy product (-)-33 formed in this manner was
amenable to chromatographic separation from an oxygen-
1
bridged triol tentatively assigned as 34 on the basis of H and
13C NMR spectroscopy.
The same protocol was successfully applied to (+)-24
(Scheme 7). In this stereoisomeric series, the â-configured
acetonide has the consequence of eroding the level to which
â-approach of the borane reagent operates in (-)-36. Although
this stereochemical channel continues to be dominant (76% of
38), modest amounts (9%) of 37 are now formed competitively.
The two-step sequences leading to (+)-41 and (+)-42 proceeded
smoothly, efficiently, and without evidence of dehydrative
transannular cyclization as seen with 34. For confirmatory
purposes, (-)-42 was subjected to X-ray crystallographic
analysis. The ORTEP diagram of this pentaol (see the Support-
ing Information) addresses the engaging question of the solid
state conformation of its medium-sized ring, information that
(19) For other examples of related silyl transfers, consult: (a) Paquette,
L. A.; Hartung, R. E.; Hofferberth, J. E.; Vilotijevic, I.; Yang, J. J. Org.
Chem. 2004, 69, 2454. (b) Hartung, R. E.; Hilmey, D. G.; Paquette, L. A.
AdV. Synth. Catal. 2004, 346, 713.
(20) (a) Still, W. C.; Galynker, I. Tetrahedron 1981, 37, 3981. (b) Amann,
A.; Ourisson, G.; Luu, B. Synthesis 1987, 1002. (c) Paquette, L. A.; Hartung,
R. E. J. Ind. Chem. Soc. 2003, 80, 1201.
(21) Zhang, Y. M.S. Thesis, The Ohio State University, 2005.
4356 J. Org. Chem., Vol. 71, No. 12, 2006

DeoxygenatiVe Zirconocene Ring Contraction
SCHEME 7a
manner in which differing levels of hydroxylation can be
incorporated into a cyclooctane ring in enantiocontrolled fashion.
Experimental Section
Periodinane Oxidation/Sodium Borohydride Reduction of 1.
A magnetically stirred mixture of 1 (107 mg, 0.38 mmol) and
sodium bicarbonate (638 mg, 7.6 mmol) in CH2Cl2 (20 mL) was
treated with the Dess-Martin periodinane (486 mg, 1.14 mmol).
After 3 h at rt, the resulting white suspension was filtered through
a pad of Celite (hexanes/ethyl acetate 8:1 rinse) and the filtrate
was evaporated to leave a residue that was dissolved in methanol
(10 mL). After the addition of sodium borohydride (43 mg, 1.14
mmol) at 0 °C, the reaction mixture was stirred for 30 min at this
temperature, quenched with saturated NH4Cl solution, and freed
of methanol under reduced pressure. After extraction of the product
into ethyl acetate, the combined organic layers were dried, filtered,
and evaporated. Purification of the residue by chromatography on
silica gel (elution with hexanes/ethyl acetate 2:1) gave the R-alcohol
as a colorless oil (94 mg, 88%): IR (neat, cm-1) 3552, 1612, 1586;
1H NMR (300 MHz, CDCl3) δ 7.27 (d, J ) 8.5 Hz, 2H), 6.88 (d,
J ) 8.6 Hz, 2H), 5.71 (ddd, J ) 17.0, 10.4, 6.5 Hz, 1H), 5.26 (d,
J ) 17.1 Hz, 1H), 5.13 (d, J ) 10.4 Hz, 1H), 4.90 (d, J ) 4.6 Hz,
1H), 4.68 (d, J ) 11.9 Hz, 1H), 4.56 (d, J ) 11.9 Hz, 1H), 4.52-
4.41 (m, 1H), 4.10 (ddd, J ) 11.1, 7.0, 4.7 Hz, 1H), 3.80 (s, 3H),
3.60 (dd, J ) 7.0, 3.8 Hz, 1H), 3.48 (s, 3H), 2.93 (d, J ) 10.7 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 159.4, 135.8, 129.6, 129.5 (2C),
116.6, 113.8 (2C), 102.6, 82.9, 79.0, 72.7, 71.3, 55.6, 55.2; ES
HRMS m/z (M + Na)+ calcd 303.1203, obsd 303.1215; [R]22
+109.7 (c 0.4, CHCl3).
D
TBS Protection and Anomerization of the R-Alcohol. A
mixture of the above product (64 mg, 0.23 mmol), imidazole (63
mg, 0.92 mmol), DMAP (3 mg, 0.02 mmol), and tert-butyldi-
methylsilyl chloride (69 mg, 0.46 mmol) in CH2Cl2 (5 mL) was
stirred for 2 days at rt, filtered through a short column of silica gel
(hexanes/ethyl acetate 10:1 rinse), and evaporated. Chromatography
of the residue on silica gel (elution with hexanes/ethyl acetate 10:
1) afforded the silyl ether as a colorless oil (78 mg, 87%): IR (neat,
a Key: (a) Me2C(OMe)2, PPTS (91%); (b) Ph3PdCH2, THF (81%); (c)
BH3‚THF; H2O2, NaOH (76% of 38; 9% of 37); (d) DDQ, CH2Cl2, H2O,
rt (81% of 39; 93% of 40); (e) 1 M HCl, CH3OH (83% of 41; 87% of 42).
1
cm-1) 1613, 1514, 1249; H NMR (300 MHz, CDCl3) δ 7.26 (d,
J ) 8.5 Hz, 2H), 6.85 (d, J ) 8.6 Hz, 2H), 5.72 (ddd, J ) 17.0,
10.3, 6.5 Hz, 1H), 5.25 (d, J ) 17.1 Hz, 1H), 5.10 (d, J ) 10.4
Hz, 1H), 4.80 (d, J ) 4.4 Hz, 1H), 4.73 (d, J ) 12.6 Hz, 1H), 4.54
(d, J ) 12.6 Hz, 1H), 4.50-4.47 (m, 1H), 4.06 (dd, J ) 6.6, 4.4
Hz, 1H), 3.80 (s, 3H), 3.54 (dd, J ) 6.6, 4.0 Hz, 1H), 3.46 (s, 3H),
0.94 (s, 9 H), 0.12 (s, 3H), 0.11 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 159.1, 136.4, 130.3, 129.3 (2C), 116.3, 113.6 (2C), 103.3, 82.9,
78.9, 72.8, 71.9, 55.5, 55.2, 25.9 (3C), 18.4, -4.7, -4.9; ES HRMS
m/z (M + Na)+ calcd 417.2068, obsd 417.2070; [R]22D +108.7 (c
1.32, CHCl3).
has otherwise proven difficult to secure by 1H NMR spectrosopy
(e.g., NOE effects and coupling constants). Thus, the quasiequa-
torial nature of the -CH2OH substituent is quite apparent, as
are the comparable projections of the -OH groups bonded to
C-3, C-4, and C-5. In this context, the quasiaxial orientation of
the C-2 hydroxyl is not unexpected.
Summary
A sample of the preceding product (512 mg, 1.29 mmol) in 1%
methanolic HCl (130 mL) was stirred overnight at rt, cooled to 0
°C, and neutralized with saturated NaHCO3 solution. After methanol
removal under reduced pressure, the remaining oil was triturated
with ethyl acetate, the combined organic layers were dried and
evaporated, and the residue was taken up in CH2Cl2 (10 mL), mixed
with imidazole (263 mg, 3.86 mmol), DMAP (32 mg, 0.31 mmol),
and tert-butyldimethylsilyl chloride (292 mg, 1.94 mmol), and
stirred for 2 days at rt. The resulting white heterogeneous mixture
was filtered through a short pad of silica gel (CH2Cl2 rinse),
evaporated, and chromatographed on silica gel (elution with
hexanes/ethyl acetate 10:1) to give 3 as a colorless oil (345 mg,
67%) and return unreacted starting material (44 mg, 9%): IR (neat,
To recapitulate, readily available D-arabinose and D-glucose
have been transformed enantioselectively into the pivotal
cyclooctadienone (+)-6 via a relatively short series of trans-
formations. Zirconocene-promoted ring contraction and [3.3]
sigmatropic rearrangement proved to be the notably productive
steps that allowed for convenient elaboration of the function-
alized eight-membered ring. The platform provided by 6 proved
to be highly utilitarian in paving the way to stereoisomeric
cyclooctane-1,2,3-triols (controlled hydride reduction, hydro-
genation, and desilylation) and the pentahydroxy derivative (+)-
21 (an added dihydroxylation step). Also defined experimentally
was the feasibility of migrating the double bonds in 6 so as to
generate (-)-22 and/or (+)-23. In addition, the dihydroxylation
of (-)-15, which leads to hemiketals 24-26, makes possible
straightforward homologation in a manner that ultimately
provides the glycomimetics (-)-33, (+)-41, and (-)-42. The
chemistry undertaken here provides a unique illustration of the
1
cm-1) 1613, 1514, 1250; H NMR (300 MHz, CDCl3) δ 7.24 (d,
J ) 8.7 Hz, 2H), 6.86 (d, J ) 8.6 Hz, 2H), 5.83 (ddd, J ) 17.2,
10.3, 6.4 Hz, 1H), 5.36 (d, J ) 17.1 Hz, 1H), 5.16 (d, J ) 10.3
Hz, 1H), 4.73 (s, 1H), 4.58 (d, J ) 11.5 Hz, 1H), 4.48 (t, J ) 7.2
Hz, 1H), 4.42 (d, J ) 11.5 Hz, 1H), 4.11 (d, J ) 4.0 Hz, 1H), 3.80
(s, 3H), 3.80-3.77 (m, 1H), 3.37 (s, 3H), 0.92 (s, 9 H), 0.10 (s, 6
H); 13C NMR (75 MHz, CDCl3) δ 159.2, 138.0, 130.1, 129.2 (2C),
J. Org. Chem, Vol. 71, No. 12, 2006 4357

Paquette and Zhang
116.9, 113.7 (2C), 108.6, 82.1, 81.7, 74.7, 72.0, 55.2, 55.1, 25.8
(300 MHz, CDCl3) δ 7.28 (d, J ) 8.8 Hz, 2H), 6.88 (d, J ) 8.7
Hz, 2H), 5.79 (ddd, J ) 17.2, 10.4, 6.7 Hz, 1H), 5.73 (d, J ) 3.8
Hz, 1H), 5.44 (d, J ) 17.0 Hz, 1H), 5.25 (d, J ) 10.3 Hz, 1H),
4.67 (d, J ) 11.9 Hz, 1H), 4.56 (d, J ) 11.9 Hz, 1H), 4.54-4.52
(m, 1H), 4.48-4.43 (m, 1H), 3.81 (s, 3H), 3.48 (dd, J ) 9.0, 4.3
Hz, 1H), 1.61 (s, 3H), 1.35 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
159.0, 134.6, 129.1 (3C), 118.1, 113.4 (2C), 112.3, 103.3, 81.1,
78.6, 77.1, 71.4, 54.8, 26.3, 26.1; ES HRMS m/z (M + Na)+ calcd
(3C), 18.2, -4.7, -4.8; ES HRMS m/z (M + Na)+ calcd 417.2068,
obsd 417.2099; [R]22 +12.0 (c 1.22, CHCl3).
D
Conversion of 2 to 3. A cold (0 °C) suspension of sodium
hydride (1.59 g, 40 mmol) in dry THF (20 mL) was treated with 2
(6.9 g, 26.5 mmol) dissolved in dry THF (60 mL) and stirred for
20 min at 0 °C and for 10 min at rt. Following a return to 0 °C,
p-methoxybenzyl bromide (6.9 g, 34 mmol) in THF (20 mL)
containing tetra-n-butylammonium iodide (1.0 g, 2.7 mmol) was
introduced. The reaction mixture was stirred at rt for 3 h, quenched
with saturated NH4Cl solution (100 mL) at 0 °C, and extracted
with ethyl acetate. The combined organic layers were dried and
evaporated, leaving a residue that was chromatographed on silica
gel (elution with hexanes/ethyl acetate 2:1) to furnish 7.0 g (70%)
of the ether as a white solid: mp 75-77 °C; IR (neat, cm-1) 1614,
1514, 1462; 1H NMR (300 MHz, CDCl3) δ 7.32 (d, J ) 8.7 Hz, 2
H), 6.89 (d, J ) 8.7 Hz, 2H), 5.74 (d, J ) 3.8 Hz, 1H), 4.70 (d, J
) 11.9 Hz, 1H), 4.56-4.51 (m, 1H), 4.53 (d, J ) 11.5 Hz, 1H),
4.35 (dt, J ) 7.1, 3.1 Hz, 1H), 4.12 (dd, J ) 8.7, 3.1 Hz, 1H),
4.02-3.92 (m, 2H), 3.86 (dd, J ) 8.7, 4.5 Hz, 1H), 3.80 (s, 3H),
1.58 (s, 3H), 1.39 (s, 3H), 1.37 (s, 3H), 1.35 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 159.2, 129.5 (2C), 129.3, 113.5 (2C), 112.5, 109.2,
103.6, 77.7, 77.5, 76.9, 74.5, 71.4, 64.7, 54.9, 26.5, 26.3, 25.9, 24.8;
329.1359, obsd 329.1379; [R]22 +59.9 (c 1.61, CHCl3).
D
A solution of the above intermediate (21.2 g, 69.2 mmol) in
methanolic 1% HCl (1300 mL) was stirred overnight, cooled to 0
°C, neutralized with saturated NaHCO3 solution, and evaporated.
The residue was extracted with ethyl acetate, the combined organic
layers were dried and evaporated, and the residue was chromato-
graphed on silica gel (elution with hexanes/ethyl acetate 3:2) to
give the hydroxy methyl acetal as a colorless oil (15.4 g, 79%)
consisting of an inseparable 8:1 mixture of â- and R-anomers. This
mixture was subsequently dissolved in CH2Cl2 (200 mL), treated
sequentially with imidazole (11.2 g, 165 mmol), DMAP (672 mg,
0.55 mmol),and tert-butyldimethylsilyl chloride (10.8 g, 71.7
mmol), and stirred at rt for 2 days prior to dilution with ethyl acetate
and washing with water and brine. The organic solution was dried
and evaporated to leave a residue that was chromatographed on
silica gel (elution with hexanes/ethyl acetate 10:1). There was
isolated 19.2 g (88%) of 3 and 2.4 g (11%) of the R-anomer.
(1R,2S,3R,4S)-3-(4-Methoxybenzyloxy)-2-(tert-butyldimethyl-
silyloxy)-4-vinylcyclobutanol (4). A cold (-78 °C) solution of
zirconocene dichloride (4.6 g, 15.7 mmol) in toluene (30 mL) was
treated with n-butyllithium (18.2 mL of 1.67 M, 30.4 mmol) and
stirred for 1 h at this temperature. After the introduction of 3 (2.0
g, 5.1 mmol) as a solution in toluene (120 mL), the reaction mixture
was stirred at rt for 3 h, cooled to 0 °C, and exposed to boron
trifluoride etherate (3 mL, 24 mmol). After 30 min, 1 N HCl was
added, and the product was extracted into ethyl acetate. The
combined organic layers were washed with saturated NaHCO3
solution, dried, and evaporated. The residue was chromatographed
on silica gel (elution with hexanes/ethyl acetate 7:1) to give 4 as a
ES HRMS m/z (M + Na)+ calcd 403.1727, obsd 403.1717; [R]20
+95.5 (c 1.0, CHCl3).
D
To a cold (0 °C) solution of the OPMB derivative (54.8 g, 144
mmol) in methanol (600 mL) were added concentrated HCl (0.6
mL) and water (6 mL). The reaction mixture was stirred for 2 h in
the cold, maintained at rt for 3 h, returned to 0 °C, neutralized
with saturated NaHCO3 solution, and evaporated. The product was
extracted into ethyl acetate, the combined organic layers were dried
and evaporated, and the residue was chromatographed on silica gel
(elution with hexanes/ethyl acetate 1:5) to give the diol as a colorless
1
oil (28.7 g, 59%): IR (neat, cm-1) 3444, 1613, 1514; H NMR
(300 MHz, CDCl3) δ 7.30 (d, J ) 8.6 Hz, 2H), 6.89 (d, J ) 8.6
Hz, 2H), 5.76 (d, J ) 3.7 Hz, 1H), 4.72 (d, J ) 11.1 Hz, 1H), 4.59
(t, J ) 4.0 Hz, 1H), 4.49 (d, J ) 11.0 Hz, 1H), 4.09 (dd, J ) 8.9,
3.2 Hz, 1H), 4.01-3.97 (m, 1H), 3.90 (dd, J ) 8.9, 4.3 Hz, 1H),
3.80 (s, 3H), 3.77-3.61 (m, 2H), 2.46 (br s, 2H), 1.59 (s, 3H),
1.36 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 159.2, 129.6 (2C),
128.8, 113.6 (2C), 112.7, 103.8, 78.7, 77.1, 76.2, 71.5, 70.8, 62.8,
54.9, 26.5, 26.3; ES HRMS m/z (M + Na)+ calcd 363.1414, obsd
1
colorless oil (1.2 g, 65%): IR (neat, cm-1) 3454, 1613, 1514; H
NMR (300 MHz, CDCl3) δ 7.27 (d, J ) 8.3 Hz, 2H), 6.86 (d, J )
8.6 Hz, 2H), 5.79 (ddd, J ) 17.3, 10.5, 8.4 Hz, 1H), 5.25 (d, J )
10.5 Hz, 2H), 5.14 (d, J ) 17.3 Hz, 1H), 4.66 (d, J ) 11.3 Hz,
1H), 4.45 (d, J ) 11.4 Hz, 1H), 4.41-4.36 (m, 1H), 4.09 (td, J )
6.2, 1.0 Hz, 1H), 3.94 (dd, J ) 6.0, 1.9 Hz, 1H), 3.80 (s, 3H), 2.99
(br t, J ) 8.4 Hz, 1H), 1.80 (br s, 1H), 0.93 (s, 9H), 0.13 (s, 3H),
0.12 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 159.1, 133.9 (2C),
130.4, 129.4 (2C), 118.5, 113.7, 76.2, 76.0, 75.1, 71.3, 55.2, 45.8,
25.8 (3C), 18.2, -4.7, -5.0; ES HRMS m/z (M + Na)+ calcd
363.1418; [R]22 +96.4 (c 1.32, CHCl3).
D
A solution of the above diol (24.0 g, 70.5 mmol) and p-
toluenesulfonyl chloride (54.1 g, 282 mmol) in pyridine (150 mL)
was stirred at rt for 2 days, diluted with ethyl acetate, and washed
sequentially with 1 N HCl, saturated NaHCO3 solution, and brine
prior to drying and solvent evaporation. The residue was purified
by chromatography on silica gel (elution with hexanes/ethyl acetate
1:1) to afford the ditosylate as a colorless oil (43.9 g, 96%): IR
(neat, cm-1) 1612, 1514, 1458; 1H NMR (300 MHz, CDCl3) δ 7.72
(d, J ) 8.3 Hz, 2H), 7.65 (d, J ) 8.4 Hz, 2H), 7.28 (br d, J ) 8.0
Hz, 4H), 7.24 (d, J ) 8.7 Hz, 2H), 6.87 (d, J ) 8.7 Hz, 2H), 5.44
(d, J ) 3.5 Hz, 1H), 4.99-4.94 (m, 1H), 4.59 (d, J ) 11.2 Hz,
1H), 4.42 (d, J ) 11.2 Hz, 1H), 4.43-4.40 (m, 1H), 4.13-4.01
(m, 3H), 3.82 (s, 3H), 3.82-3.75 (m, 1H), 2.44 (s, 6 H), 1.48 (s,
3H), 1.30 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 159.6, 145.2,
144.9, 133.8, 132.2, 129.9 (2C), 129.7 (6C), 129.1, 127.9 (2C),
113.9 (2C), 113.3, 104.2, 77.8, 77.7 (2C), 77.3, 71.7, 66.9, 55.2,
26.8, 26.5, 21.6 (2C); ES HRMS m/z (M + Na)+ calcd 671.1591,
387.1962, obsd 387.1955; [R]22 +10.6 (c 1.44, CHCl3).
D
(1R,2R,3R,4R)-3-(4-Methoxybenzyloxy)-2-(tert-butyldimeth-
ylsilyloxy)-1-(2-trimethylsilyl)ethynyl)-4-vinylcyclobutanol (5).
A mixture of 4 (144 mg, 0.39 mmol) and sodium bicarbonate (655
mg, 7.8 mmol) in CH2Cl2 (40 mL) was treated with the Dess-
Martin periodinane (496 mg, 1.17 mmol), stirred at rt for 3 h,
filtered through a pad of Celite (hexanes rinse), and evaporated.
The residue was taken up in THF (2 mL) and added at 0 °C to the
Grignard of trimethylsilylacetylene. This reagent was prepared by
treating a solution of the alkyne (0.18 mL, 1.3 mmol) in THF (1.5
mL) with n-butyllithium (0.7 mL of 1.67 M, 1.17 mmol) at -78
°C, gradual warming to 0 °C, and treatment with an excess of
magnesium bromide etherate. The white suspension was stirred at
0 °C for 30 min prior to use.
obsd 671.1562; [R]22 +42.8 (c 1.16, CHCl3).
D
A heterogeneous mixture of the ditosylate from above (46.6 g,
71.8 mmol), sodium iodide (108 g, 720 mmol), and zinc dust (47
g, 719 mmol) in DMF (500 mL) was refluxed overnight, diluted
with water, filtered, diluted with ethyl acetate, and washed with
brine. After drying and evaporation of the organic phase, the residue
was chromatographed on silica gel (elution with hexanes/ethyl
acetate 5:1) to furnish the deprotected vinyl furanoside as a colorless
The original reaction mixture was stirred for 3 h at 0 °C,
quenched with saturated NH4Cl solution (5 mL), and extracted with
ethyl acetate. The combined organic layers were dried and
evaporated to leave a residue that was purified chromatographically
on silica gel (elution with hexanes/ethyl acetate 10:1). There was
isolated 118 mg (65%) of 5 as a colorless oil: IR (neat, cm-1
)
3511, 2169, 1613; 1H NMR (300 MHz, CDCl3) δ 7.23 (d, J ) 8.6
Hz, 2H), 6.86 (d, J ) 8.6 Hz, 2H), 6.01-5.89 (m, 1H), 5.14 (d, J
1
oil (19.2 g, 87%): IR (neat, cm-1) 1613, 1514, 1374; H NMR
4358 J. Org. Chem., Vol. 71, No. 12, 2006

DeoxygenatiVe Zirconocene Ring Contraction
) 16.0 Hz, 1H), 5.13 (d, J ) 11.4 Hz, 1H), 4.48 (d, J ) 11.4 Hz,
1H), 4.43 (d, J ) 11.4 Hz, 1H), 4.36 (d, J ) 4.8 Hz, 1H), 3.81 (s,
3H), 3.81-3.74 (m, 1H), 3.31 (s, 1H), 2.99 (t, J ) 8.2 Hz, 1H),
0.94 (s, 9H), 0.17 (s, 9 H), 0.15 (s, 3H), 0.14 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 159.2, 135.3, 130.1, 129.2 (2C), 116.9, 113.6
(2C), 103.8, 92.7, 76.2, 73.6, 71.0, 68.2, 59.1, 55.2, 25.8 (3C), 18.4,
-0.1 (3C), -4.6, -4.9; ES HRMS m/z (M + Na)+ calcd 483.2357,
(75 MHz, CDCl3) δ 159.1, 133.6, 130.9, 130.2, 129.3 (2C), 128.9,
128.0, 113.7 (2C), 75.1, 73.9, 73.4, 70.0, 55.3, 30.0, 25.8 (3C),
18.2, -4.6, -4.7; ES HRMS m/z for C22H34O4SiNa+ calcd
413.2119, obsd 413.2131; [R]25 + 42.0 (c 1.11, CHCl3).
D
(1S,2Z,5Z,7R,8S)-7-(4-Methoxybenzyloxy)-8-(tert-butyldimeth-
ylsilyloxy)cycloocta-2,5-dienol (9). A solution of (+)-6 (121 mg,
0.31 mmol) in methanol (3 mL) was treated with sodium borohy-
dride (47.1 mg, 1.24 mmol) at 0 °C and processed as in part B.
There was isolated 79 mg (65%) of 7 alongside 18 mg (15%) of 9
as a colorless oil: IR (neat, cm-1) 3439, 1613; 1H NMR (300 MHz,
CDCl3) δ 7.25 (d, J ) 8.7 Hz, 2H), 6.87 (d, J ) 8.7 Hz, 2H),
5.81-5.71 (m, 2H), 5.38-5.32 (m, 1H), 5.25-5.19 (m, 1H), 4.56-
4.52 (m, 1H), 4.54 (d, J ) 11.6 Hz, 1H), 4.41 (d, J ) 4.6 Hz, 1H),
4.36 (d, J ) 11.6 Hz, 1H), 4.18 (br s, 1H), 3.81 (s, 3H), 2.74-
2.66 (m, 1H), 2.53 (dd, J ) 13.8, 6.9 Hz, 1H), 2.00 (d, J ) 6.9 Hz,
1H), 0.87 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 159.0, 132.0, 130.5 (2C), 129.3, 129.0 (2C), 128.8, 113.6
(2C), 78.4, 76.3, 73.0, 69.8, 55.3, 28.5, 25.9 (3C), 18.3, -4.2, -5.2;
ES HRMS m/z for C22H34O4SiNa+ calcd 413.2119, obsd 413.2128;
obsd 483.2375; [R]22 +3.0 (c 1.0, CHCl3).
D
(2Z,5Z,7R,8R)-7-(4-Methoxybenzyloxy)-8-(tert-butyldimeth-
ylsilyloxy)cycloocta-2,5-dienone (6). A mixture of 5 (118 mg, 0.26
mmol) and K2CO3 (54 mg, 0.39 mmol) in methanol (5 mL) was
stirred for 1 h at rt, cooled to 0 °C, and quenched with saturated
NH4Cl solution. The methanol was carefully removed under reduced
pressure, and the aqueous phase was extracted with CH2Cl2. The
combined organic phases were dried and evaporated. The residue
was purified by chromatography on silica gel (elution with
hexanes-ethyl acetate 10:1) to give the unsubstituted alkyne as a
colorless oil that was used directly.
The above material in benzene (5 mL) was refluxed for 2 h,
cooled to rt, and evaporated. The residue was chromatographed on
silica gel (elution with hexane-ethyl acetate 10:1) to provide 6 as
a colorless oil (84 mg, 98%): IR (neat, cm-1) 1703, 1612, 1514;
1H NMR (300 MHz, CDCl3) δ 7.26 (d, J ) 8.4 Hz, 1H), 6.87 (d,
J ) 8.6 Hz, 2H), 6.11-6.03 (m, 1H), 5.88-5.75 (m, 3H), 4.79 (d,
J ) 2.7 Hz, 1H), 4.62 (dd, J ) 6.8, 2.8 Hz, 1H), 4.56 (d, J ) 11.6
Hz, 1H), 4.49 (d, J ) 11.6 Hz, 1H), 3.81 (s, 3H), 2.93-2.80 (m,
2H), 0.93 (s, 9H), 0.13 (s, 3H), 0.05 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 202.2, 159.1, 137.3 (2C), 133.8, 130.2, 129.4, 129.1,
127.2, 113.6 (2C), 81.8, 74.5, 70.7, 55.2, 29.0, 25.8, 18.6 (3C),
-4.7, -5.2; ES HRMS m/z (M + Na)+ calcd 411.1962, obsd
[R]25 +18.7 (c 0.72, CHCl3).
D
Catalytic Hydrogenation of the Cyclooctadienols. A. Involving
(-)-7. A solution of (-)-7 (51 mg, 0.13 mmol) in methanol (3
mL) was mixed with 5 mg of 10% Pd/C and stirred overnight under
55 psi of hydrogen. After catalyst removal by filtration and
subsequent solvent evaporation, the residue was chromatographed
on silica gel. Elution with hexanes/ethyl acetate 2:1 afforded 22
mg (61%) of 10 as a white solid: mp 84-86 °C; IR (neat, cm-1
)
1
3365, 1064; H NMR (300 MHz, CDCl3) δ 3.93-3.79 (m, 3H),
2.43 (d, J ) 1.9 Hz, 1H), 2.35 (s, 1H), 1.91-1.86 (m, 2H), 1.75-
1.51 (m, 7H), 1.42-1.31 (m, 1H), 0.94 (s, 9H), 0.17 (s, 3H), 0.15
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 77.4, 72.7, 68.5, 33.5, 29.2,
28.3, 25.8 (3C), 21.9, 21.7, 18.1, -4.4, -4.6; ES HRMS m/z for
411.1968; [R]20 +0.17 (c 1.0 CHCl3).
D
(1R,2Z,5Z,7R,8S)-7-(4-Methoxybenzyloxy)-8-(tert-butyldimeth-
ylsilyloxy)cycloocta-2,5-dienol (7). A solution of (+)-6 (125 mg,
0.32 mmol) in methanol (3 mL) was cooled to 0 °C, treated with
cerium trichloride heptahydrate (120 mg, 0.32 mmol), and stirred
for 5 min. After the careful introduction of sodium borohydride
(12 mg, 0.32 mmol), the reaction mixture was stirred in the cold
for 10 min, quenched with saturated NH4Cl solution, and freed of
methanol under reduced pressure. The residue was extracted into
ethyl acetate, and the combined organic layers were dried and
evaporated. Purification of the product by chromatography on silica
gel (elution with hexanes/ethyl acetate 30:1) afforded 7 as a
colorless oil (107 mg, 86%): IR (neat, cm-1) 3434, 1645, 1248;
1H NMR (300 MHz, CDCl3) δ 7.23 (d, J ) 8.6 Hz, 2H), 6.86 (d,
J ) 8.6 Hz, 2H), 5.79-5.73 (m, 1H), 5.60-5.52 (m, 2H), 5.41-
5.33 (m, 1H), 4.66-4.61 (m, 1H), 4.53-4.50 (m, 1H), 4.52 (d, J
) 11.4 Hz, 1H), 4.29 (d, J ) 11.5 Hz, 1H), 3.81 (s, 3H), 3.69 (dd,
J ) 8.1, 3.3 Hz, 1H), 2.87 (br s, 2H), 2.25 (br s, 1H), 0.87 (s, 9H),
0.08 (s, 3H), 0.06 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 159.0,
132.0, 130.6, 130.4, 129.7, 129.6 (2C), 128.8, 113.5 (2C), 76.3,
75.5, 73.1, 70.1, 55.2, 30.2, 26.1 (3C), 18.5, -3.8, -4.8; ES HRMS
C14H30O3SiNa+ calcd 297.1856, obsd 297.1853; [R]25 -35.7 (c
D
0.35, CHCl3).
B. Involving (+)-8. Comparable reduction of 8 (48 mg, 0.12
mmol) resulted in the isolation of 11 (21 mg, 62%) as a colorless
1
oil: IR (neat, cm-1) 3428; H NMR (300 MHz, CDCl3) δ 4.02-
3.96 (m, 2H), 3.68 (dd, J ) 2.4, 8.2 Hz, 1H), 3.23 (d, J ) 0.8 Hz,
1H), 2.68 (d, J ) 2.6 Hz, 1H), 1.83-1.51 (m, 10H), 0.91 (s, 9H),
0.11 (s, 3H), 0.10 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 74.8,
70.8, 70.1, 35.9, 28.6, 27.4, 25.8 (3C), 21.6, 21.4, 18.0, -4.3, -4.9;
ES HRMS m/z for C14H30O3SiNa+ calcd 297.1856, obsd 297.1862;
[R]25 -31.1 (c 0.71, CHCl3).
D
C. Involving (+)-9. Analogous processing of (+)-9 (20 mg,
0.051 mmol) furnished 7.2 mg (51%) of 12 as colorless needles:
mp 109-110 °C; IR (neat, cm-1) 3386, 1250; 1H NMR (300 MHz,
CDCl3) δ 4.00-3.99 (m, 1H), 3.86 (br s, 2H), 2.71 (d, J ) 4.2 Hz,
2H), 1.91-1.77 (m, 6H), 1.58-1.52 (m, 2H), 1.36-1.25 (m, 2H),
0.94 (s, 9H), 0.12 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 75.8 (2C),
75.3, 31.6 (2C), 28.3 (2C), 25.9 (3C), 22.3, 18.2, -4.6 (2C); ES
HRMS m/z for C14H30O3SiNa+ calcd 297.1856, obsd 297.1853;
[R]25 0 (c 0.57, CHCl3).
m/z for C22H34O4SiNa+ calcd 413.2119, obsd 413.2144; [R]25
-44.9 (c 1.11, CHCl3).
D
D
(1R,3R)-Cyclooctane-1,2,3-triol. A. From (-)-10. Compound
(-)-10 (6.4 mg, 0.023 mmol) dissolved in THF (2 mL) was treated
with tetra-n-butylammonium fluoride (0.027 mL of 1 M in THF,
0.027 mmol) and stirred at rt for 1 h prior to solvent evaporation.
Chromatography on silica gel (elution with hexanes/ethyl acetate
1:3) afforded 13 (2.4 mg, 65%) as a white solid: mp 69-71 °C;
IR (neat, cm-1) 3443, 1460; 1H NMR (300 MHz, CDCl3) δ 4.05-
3.99 (m, 1H), 3.93-3.87 (m, 1H), 3.73-3.71 (m, 1H), 3.12 (br s,
1H), 2.44 (br s, 2H), 1.93-1.41 (series of m, 10H); 13C NMR (75
MHz, CDCl3) δ 76.3, 71.3, 70.3, 33.5, 30.3, 27.4, 23.1, 22.7; ES
(1R,2R,3Z,6Z,8R)-2-(4-Methoxybenzyloxy)-8-(tert-butyldimeth-
ylsilyloxy)cycloocta-3,6-dienol (8). A solution of (+)-6 (99 mg,
0.25 mmol) in 95% ethanol (3 mL) was treated with sodium
borohydride (38.5 mg, 1.02 mmol) at 0 °C, stirred at this
temperature for 1 h, and quenched with saturated NH4Cl solution.
The ethanol was removed under reduced pressure and the residue
was extracted with ethyl acetate. The combined organic solutions
were dried and concentrated. Subsequent chromatography on silica
gel (elution with hexanes/ethyl acetate 80:1) afforded the less polar
7 (25 mg, 25%) followed by the more polar 8 (50 mg, 50%) as a
colorless oil; IR (neat, cm-1) 3473, 1613, 1249; 1H NMR (300 MHz,
CDCl3) δ 7.25 (d, J ) 8.7 Hz, 2H), 6.86 (d, J ) 8.7 Hz, 2H),
5.75-5.69 (m, 1H), 5.59-5.53 (m, 2H), 5.40-5.33 (m, 1H), 4.63-
4.57 (m, 2H), 4.55 (d, J ) 11.5 Hz, 1H), 4.42 (d, J ) 11.5 Hz,
1H), 3.80 (s, 3H), 3.78-3.75 (m, 1H), 2.86 (br s, 2H), 2.45 (d, J
) 1.5 Hz, 1H), 0.89 (s, 9H), 0.08 (s, 3H), 0.06 (s, 3H); 13C NMR
HRMS m/z for C8H16O3Na+ calcd 183.0992, obsd 183.0993; [R]25
-61.8 (c 0.55, CHCl3).
D
B. From (-)-11. Comparable treatment of (-)-11 (15 mg, 0.055
mmol) delivered 6.7 mg (76%) of 13, spectroscopically identical
to the material obtained above.
(1R,3S)-Cyclooctane-1,2,3-triol (14). Entirely analogous pro-
cessing of meso-12 (7.9 mg, 0.03 mmol) yielded 3.9 mg (81%) of
J. Org. Chem, Vol. 71, No. 12, 2006 4359

Paquette and Zhang
14 as a white solid: mp 93-95 °C; IR (neat, cm-1) 3428, 1450;
1H NMR (300 MHz, CDCl3) δ 3.97-3.93 (m, 3H), 3.39 (d, J )
5.5 Hz, 1H), 3.00-2.98 (m, 2H), 2.09-1.98 (m, 2H), 1.89-1.60
(m, 6H), 1.51-1.26 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 75.5
(2C), 72.2, 32.1 (2C), 28.8, 22.7 (2C); ES HRMS m/z for C8H16O3-
0.87 (s, 9H), 0.05 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 159.1,
131.3, 130.2, 129.9, 129.5 (2C), 113.7 (2C), 78.6, 74.6, 73.9, 69.8,
55.2, 27.2, 25.8 (3C), 25.4, 24.4, 18.0, -4.7, -4.9; ES HRMS m/z
for C22H36O4SiNa+ calcd 415.2275, obsd 415.2279; [R]21 -30.5
D
(c 0.55, CHCl3).
Na+ calcd 183.0992, obsd 183.0996; [R]25 0 (c 0.43, CHCl3).
(1S,2S,3R,4S,5S)-3-(4-Methoxybenzyloxy)-4-(tert-Butyldimeth-
ylsilyloxy)cyclooctane-1,2,5-triol (19). A solution of (-)-17 (11
mg, 0.028 mmol) in 8:1 acetone/water (2 mL) was treated with
N-methylmorpholine N-oxide (8.2 mg, 0.07 mmol) followed by
osmium tetraoxide (0.7 mg, 0.0028 mmol). The reaction mixture
was stirred at rt for 4 days, freed of acetone under reduced pressure,
and extracted with ethyl acetate. The combined organic layers were
dried and evaporated to leave a residue that was chromatographed
on silica gel (elution with hexanes/ethyl acetate 1:1) to provide
7.4 mg (62%) of 19 as a colorless oil: IR (neat, cm-1) 3435, 1513;
1H NMR (300 MHz, CDCl3) δ 7.26 (d, J ) 8.6 Hz, 2H), 6.89 (d,
J ) 8.6 Hz, 2H), 4.64 (d, J ) 11.1 Hz, 1H), 4.44 (d, J ) 11.1 Hz,
1H), 4.25 (s, 1H), 4.12 (br s, 1H), 4.05-4.02 (m, 1H), 3.81 (s,
3H), 3.59-3.52 (m, 2H), 2.96 (s, 1H), 2.52 (br s, 1H), 1.90-1.47
(m, 7H), 0.92 (s, 9H), 0.12 (s, 3H), 0.11 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 159.5, 129.8 (2C), 129.4, 114.0 (2C), 78.5, 76.1,
73.9, 72.7, 71.1, 69.4, 55.3, 29.3, 29.1, 26.0 (3C), 18.8, 18.4, -4.1,
-5.0; ES HRMS m/z for C22H38O6SiNa+ calcd 449.2330, obsd
D
(2R,3R,4Z)-3-(4-Methoxybenzyloxy)-2-(tert-butyldimethylsi-
lyloxy)cyclooct-4-enone (15). A solution of (+)-6 (100 mg, 0.26
mmol) in 10 mL of THF was treated with L-Selectride (1 M in
THF, 0.39 mL, 0.39 mmol) at -78 °C, stirred at this temperature
for 1 h, quenched with saturated NH4Cl solution, and extracted
with ethyl acetate. The combined organic layers were dried and
evaporated. Purification of the residue by chromatography on silica
gel (elution with hexanes/ethyl acetate 30:1) afforded 15 (95 mg,
94%) as a colorless oil: IR (neat, cm-1) 1612; 1H NMR (300 MHz,
CDCl3) δ 7.25 (d, J ) 8.6 Hz, 2H), 6.87 (d, J ) 8.6 Hz, 2H),
5.78-5.69 (m, 2H), 4.51 (d, J ) 11.5 Hz, 1H), 4.44 (br s, 1H),
4.41 (d, J ) 11.5 Hz, 1H), 4.22 (d, J ) 5.2 Hz, 1H), 3.81 (s, 3H),
3.06-2.97 (m, 1H), 2.10-2.03 (m, 1H), 1.99-1.82 (m, 3H), 1.59-
1.51 (m, 1H), 0.89 (s, 9H), 0.07 (s, 3H), 0.03 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 213.9, 159.0, 132.7 (2C), 130.2, 129.1 (2C),
113.6 (2C), 84.4, 75.5, 70.1, 55.2, 33.5, 25.8, 25.7 (3C), 23.8, 18.3,
-4.8, -5.2; ES HRMS m/z for C22H34O4SiNa+ calcd 413.2119,
obsd 413.2099; [R]21 -56.8 (c 0.71, CHCl3).
449.2344; [R]21 +38.9 (c 0.54, CHCl3).
D
D
(1R,2S,3R,Z)-2-(tert-Butyldimethylsilanyloxy)-3-(4-methoxy-
benzyloxy)cyclooct-4-enol (16). A solution of (-)-15 (24 mg, 0.061
mmol) in methanol (4 mL) was treated with sodium borohydride
(3.4 mg, 0.09 mmol) at rt, stirred for 10 min, and worked up in the
predescribed manner. Chromatographic purification on silica gel
(elution with hexanes/ethyl acetate 30:1) afforded 20.1 mg (83%)
(1S,2S,4S,5S)-3-(4-Methoxybenzyloxy)cyclooctane-1,2,4,5-tet-
raol (20). A solution of (+)-19 (10.1 mg, 0.024 mmol) in THF (2
mL) was treated with tetra-n-butylammonium fluoride (0.04 mL
of 1 M in THF, 0.04 mmol), stirred at rt for 2 h, and freed of
solvent prior to the usual workup. Following chromatography on
silica gel (elution with ethyl acetate/methanol 15:1), 20 was isolated
as a colorless oil (6.4 mg, 87%): IR (neat, cm-1) 3503, 1514, 1248;
1H NMR (300 MHz, CDCl3) δ 7.27 (d, J ) 8.7 Hz, 2H), 6.89 (d,
J ) 8.7 Hz, 2H), 4.61 (d, J ) 10.9 Hz, 1H), 4.55 (d, J ) 10.9 Hz,
1H), 4.23 (s, 1H), 4.15-4.12 (m, 1H), 4.06-4.02 (m, 1H), 3.81
(s, 3H), 3.71 (dd, J ) 7.6, 1.5 Hz, 1H), 3.69-3.65 (m, 1H), 3.19
(s, 1H), 2.87 (d, J ) 3.2 Hz, 1H), 2.76 (d, J ) 2.3 Hz, 1H), 2.51
(d, J ) 8.2 Hz, 1H), 1.97-1.48 (m, 6H); 13C NMR (75 MHz,
CDCl3) δ 159.7, 129.9 (2C), 129.1, 114.1 (2C), 78.0, 77.2, 73.2,
71.9, 70.3, 69.3, 55.3, 28.7, 28.4, 19.2; ES HRMS m/z for C16H24O6-
Na+ calcd 335.1465, obsd 335.1447; [R]21D +16.8 (c 0.31, CHCl3).
(1S,2S,4S,5S)-Cyclooctane-1,2,3,4,5-pentaol (21). Hydrogena-
tion of (+)-20 (16.1 mg, 0.052 mmol) over 10% Pd/C (2 mg) in
methanol (3 mL) at 60 psi overnight returned 7.6 mg (77%) of 21
as a colorless oil: IR (neat, cm-1) 3436; 1H NMR (300 MHz, D2O)
δ 4.32-4.26 (m, 1H), 4.10 (d, J ) 2.9 Hz, 1H), 3.92-3.83 (m,
2H), 3.78-3.72 (m, 1H), 1.77-1.56 (m, 5H), 1.34-1.20 (m, 1H);
13C NMR (75 MHz, D2O) δ 79.7, 78.2, 76.1, 75.0, 71.2, 31.1, 29.7,
20.5; ES HRMS m/z for C8H16O5Na+ calcd 215.0890, obsd
1
of 16 as a colorless oil: IR (neat, cm-1) 3435, 1248; H NMR
(400 MHz, CDCl3) δ 7.25 (d, J ) 8.8 Hz, 2H), 6.89 (d, J ) 8.8
Hz, 2H), 5.87 (dd, J ) 18.8, 8.0 Hz, 1H), 5.64 (dt, J ) 9.6, 1.1
Hz, 1H), 4.56 (d, J ) 11.6 Hz, 1H), 4.34-4.32 (m, 1H), 4.31 (d,
J ) 11.6 Hz, 1H), 3.84 (s, 3H), 3.72 (dd, J ) 7.6, 2.8 Hz, 1H),
3.54 (t, J ) 7.6 Hz, 1H), 2.20 (s, 1H), 2.20-2.14 (m, 1H), 2.04-
1.96 (m, 1H), 1.80-1.37 (m, 4H), 0.87 (s, 9H), 0.09 (s, 6H); 13C
NMR (75 MHz, CDCl3) δ 159.0, 132.0, 131.4, 130.4, 129.7 (2C),
113.6 (2C), 80.9, 75.8, 73.2, 69.5, 55.2, 32.0, 27.5, 26.8, 26.1 (3C),
18.4, -3.8, -4.9; ES HRMS m/z for C22H36O4SiNa+ calcd
415.2275, obsd 415.2279; [R]22 -23.8 (c 2.59, CHCl3).
D
Catalytic Hydrogenation of (-)-16. Hydrogenation of (-)-16
(20 mg, 0.051 mmol) over 10% Pd-C (2 mg) in methanol (3 mL)
in the predescribed manner gave 13 mg (93%) of (-)-10, identical
in all respects to the material isolated earlier.
L-Selectride Reduction of (-)-15. Ketone 15 (19 mg, 0.049
mmol) dissolved in THF (2 mL) was treated with L-Selectride (0.12
mL of 1 M in THF, 0.12 mmol) at rt, stirred for 3 h, quenched
with saturated NH4Cl solution, and extracted with ethyl acetate.
After the usual workup and chromatography on silica gel (elution
with hexanes/ethyl acetate 30:1), there was isolated 11 mg (58%)
of 17 and 7.1 mg (37%) of 18, both as colorless oils.
215.0891; [R]21 +8.7 (c 0.46, CH3OH).
D
(3Z,5Z,7R,8R)-7-(4-Methoxybenzyloxy)-8-(tert-butyldimeth-
ylsilyloxy)cycloocta-3,5-dienone (22). A solution of (+)-6 (21 mg,
0.054 mmol) in THF (2 mL) was treated with triethylamine (0.15
mL, 0.11 mmol) and stirred at rt for 2 days. Removal of the solvent
and purification of the residue chromatographically on silica gel
(elution with hexanes/ethyl acetate 30:1) gave 22 (19 mg, 90%) as
For 17: IR (neat, cm-1) 3400, 1642; 1H NMR (300 MHz, CDCl3)
δ 7.24 (d, J ) 8.6 Hz, 2H), 6.86 (d, J ) 8.6 Hz, 2H), 5.66-5.58
(m, 2H), 4.52 (d, J ) 11.6 Hz, 1H), 4.31 (d, J ) 11.6 Hz, 1H),
4.20 (br s, 1H), 4.10 (d, J ) 4.8 Hz, 1H), 3.81 (s, 3H), 3.49 (dt, J
) 9.1, 1.9 Hz, 1H), 2.35-2.30 (m, 1H), 2.06-1.94 (m, 2H), 1.89
(d, J ) 9.6 Hz, 1H), 1.76-1.71 (m, 1H), 1.50-1.47 (m, 1H), 1.24-
1.17 (m, 1H), 0.90 (s, 9H), 0.12 (s, 3H), 0.08 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 158.9, 131.8, 130.5, 129.4, 129.2 (2C), 113.6
(2C), 79.4, 76.0, 73.4, 69.7, 55.2, 27.8, 26.0 (3C), 25.5, 24.7, 18.5,
-3.9, -5.3; ES HRMS m/z for C22H36O4SiNa+ calcd 415.2275,
1
a colorless oil: IR (neat, cm-1) 3413, 1514; H NMR (300 MHz,
CDCl3) δ 7.22 (d, J ) 8.7 Hz, 2H), 6.86 (d, J ) 8.7 Hz, 2H),
6.06-6.01 (m, 2H), 5.88-5.75 (m, 2H), 4.51 (d, J ) 11.5 Hz,
1H), 4.43 (d, J ) 11.5 Hz, 1H), 4.30 (s, 1H), 4.25 (d, J ) 6.5 Hz,
1H), 3.80 (s, 3H), 3.56 (dd, J ) 12.7, 7.8 Hz, 1H), 2.82 (dd, J )
12.7, 6.8 Hz, 1H), 0.90 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 206.6, 159.1, 134.2, 130.2, 129.5, 129.2
(2C), 127.5, 126.7, 113.7 (2C), 77.7, 77.3, 70.6, 55.2, 39.8, 25.7
(3C), 18.3, -5.0 (2C); ES HRMS m/z for C22H32O4Na+ calcd
obsd 415.2284; [R]21 -73 (c 0.1, CHCl3).
D
For 18: IR (neat, cm-1) 3649, 1613; 1H NMR (300 MHz, CDCl3)
δ 7.26 (d, J ) 8.5 Hz, 2H), 6.87 (d, J ) 8.5 Hz, 2H), 5.81-5.63
(m, 2H), 4.62 (d, J ) 11.8 Hz, 1H), 4.35 (d, J ) 11.8 Hz, 1H),
4.13 (d, J ) 6.3 Hz, 1H), 4.07 (s, 1H), 3.80 (s, 3H), 3.56 (dd, J )
8.7, 2.1 Hz, 1H), 2.32-2.24 (m, 1H), 2.32 (s, 1H), 2.09-1.87 (m,
2H), 1.69-1.58 (m, 1H), 1.54-1.44 (m, 1H), 1.21-1.14 (m, 1H),
411.1962, obsd 411.1959; [R]22 -196.8 (c 0.57, CHCl3).
D
(2Z,4Z,7R,8R)-7-(4-Methoxybenzyloxy)-8-(tert-butyldimeth-
ylsilyloxy)cycloocta-2,4-dienone (23). A solution of (+)-6 (24 mg,
0.062 mmol) in isopropyl alcohol (1 mL) was treated with aluminum
isopropoxide (8.9 mg, 0.044 mmol). The mixture was refluxed for
4360 J. Org. Chem., Vol. 71, No. 12, 2006

DeoxygenatiVe Zirconocene Ring Contraction
6 h with provision for the slow evaporation of solvent. The residue
was heated at 94 °C for 2 h prior to partitioning between ethyl
acetate and water. The organic phase was dried and evaporated to
leave a residue that was purified chromatographically on silica gel
(elution with hexanes/ethyl acetate 30:1) to afford 22 (8.1 mg, 34%)
and the more polar 23 (11.9 mg, 50%) as a colorless oil: IR (neat,
cm-1) 1670, 1124; 1H NMR (400 MHz, CDCl3) δ 7.32 (d, J ) 8.7
Hz, 2H), 6.87 (d, J ) 8.7 Hz, 2H), 6.57-6.53 (m, 1H), 6.34-6.31
(m, 2H), 6.22 (d, J ) 12.8 Hz, 1H), 4.98 (d, J ) 11.9 Hz, 1H),
4.80 (d, J ) 3.3 Hz, 1H), 4.66 (d, J ) 11.9 Hz, 1H), 4.04 (ddd, J
) 11.3, 6.0, 3.4 Hz, 1H), 3.82 (s, 3H), 2.50-2.44 (m, 1H), 2.26-
2.18 (m, 1H), 0.90 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 199.7, 159.1, 135.9, 135.7, 132.2, 131.0, 130.3,
129.5 (2C), 113.6 (2C), 84.7, 79.0, 73.2, 55.3, 33.0, 25.9 (3C), 18.4,
-4.7, -5.0; ES HRMS m/z for C22H32O4Si Na+ calcd 411.1962,
MHz, CDCl3) δ 7.26 (d, J ) 8.7 Hz, 2H), 6.90 (d, J ) 8.7 Hz,
2H), 4.63 (d, J ) 11.1 Hz, 1H), 4.55 (d, J ) 11.1 Hz, 1H), 4.16
(d, J ) 9.3 Hz, 1H), 3.97 (d, J ) 6.0 Hz, 1H), 3.88 (t, J ) 4.8 Hz,
1H), 3.81 (s, 3H), 3.73-3.70 (m, 1H), 2.83 (br s, 2H), 2.29-2.09
(m, 2H), 1.85-1.72 (m, 1H), 1.58-1.49 (m, 2H), 1.42-1.32 (m,
1H); 13C NMR (75 MHz, CDCl3) δ 159.6, 129.7 (2C), 129.4, 114.1
(2C), 97.1, 79.4, 77.3, 72.9, 71.2, 70.0, 55.3, 30.8, 25.0, 16.8; ES
HRMS m/z for C16H22O6Na+ calcd 333.1308, obsd 333.1307; [R]21
D
+3.7 (c 0.86, CHCl3).
(1S,2R,3R,4R,5R)-3-(4-Methoxybenzyloxy)-9-oxabicyclo[3.3.1]-
nonane-1,2,4-triol (28). A solution of 25 (29 mg, 0.068 mmol) in
3 mL of THF was treated with TBAF (1 M in THF, 0.1 mL, 0.1
mmol), stirred at rt for 2 h, and freed of solvent. The residue was
purified chromatographically on silica gel (elution with hexanes/
ethyl acetate 1:4) to give 28 (17.1 mg, 80%) as a white solid: mp
obsd 411.1964; [R]22 +272.5 (c 0.63, CHCl3).
1
104-105 °C; IR (neat, cm-1) 3397, 1612, 1076; H NMR (400
D
(1R,2R,3R,4R,5R)-3-(4-Methoxybenzyloxy)-1-(tert-butyldimeth-
ylsilyloxy)-9-oxabicyclo[3.3.1]nonane-2,4-diol (26). To a solution
of (-)-15 (151 mg, 0.39 mmol) in acetone/water (8:1, 20 mL) were
added NMO (91 mg, 0.78 mmol) and osmium tetraoxide (2 mg,
0.0078 mmol) at rt. Stirring for 3 days was followed by removal
of the acetone. The residue was extracted with ethyl acetate, dried,
and evaporated. The mixture was purified chromatographically on
silica gel (elution with hexanes/ethyl acetate 4:1 to 1:1) to give the
MHz, CDCl3) δ 7.32 (d, J ) 8.8 Hz, 2H), 6.92 (d, J ) 8.7 Hz,
2H), 4.71 (d, J ) 11.2 Hz, 1H), 4.62 (d, J ) 11.1 Hz, 1H), 4.51 (s,
1H), 4.33 (d, J ) 6.4 Hz, 1H), 3.89 (t, J ) 4.0 Hz, 1H), 3.82 (s,
3H), 3.74 (br s, 2H), 3.40-3.39 (m, 1H), 3.06 (br s, 1H), 1.98-
1.87 (m, 2H), 1.81-1.74 (m, 1H), 1.68-1.64 (m, 1H), 1.53-1.36
(m, 2H); 13C NMR (100 MHz, CDCl3) δ 159.7, 129.7 (2C), 129.4,
114.1 (2C), 94.4, 74.9, 73.1, 72.5, 70.2, 69.7, 55.3, 30.1, 23.4, 18.9;
ES HRMS m/z for C16H22O6Na+ calcd 333.1308, obsd 333.1300;
least polar product 26 (6 mg, 4%) as a colorless oil: IR (neat, cm-1
)
[R]21 +13.2 (c 0.63, CHCl3).
D
1
3456, 1514, 1178; H NMR (300 MHz, C6D6) δ 7.28 (d, J ) 8.8
Hz, 2H), 6.82 (d, J ) 8.8 Hz, 2H), 4.53 (d, J ) 11.1 Hz, 1H), 4.47
(d, J ) 11.1 Hz, 1H), 4.27 (d, J ) 6.9 Hz, 1H), 3.75-3.73 (m,
1H), 3.64-3.58 (m, 2H), 3.54-3.50 (m, 1H), 3.37 (s, 3H), 3.00
(d, J ) 4.8 Hz, 1H), 1.63-1.59 (m, 1H), 1.44-1.34 (m, 2H), 1.19-
1.13 (m, 1H), 1.07-0.98 (m, 1H), 1.06 (s, 9H), 0.81-0.73 (m,
1H), 0.38 (s, 3H), 0.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
159.4, 129.9, 129.6 (2C), 113.9 (2C), 97.0, 76.5, 73.2, 72.1, 69.8,
69.2, 55.3, 32.9, 25.8 (3C), 23.2, 19.1, 18.0, -2.4, -2.8; ES HRMS
m/z for C22H36O6SiNa+ calcd 447.2173, obsd 447.2188; [R]21D +9.7
(c 0.64, CHCl3).
Comparable processing of (+)-26 also returned exclusively (+)-
28 (65%).
(3aR,4R,5R,9aR)-4-(4-Methoxybenzyloxy)-5-(tert-butyldimeth-
ylsilyloxy)-2,2-dimethylhexahydrocycloocta[d][1,3]dioxol-6(3aH)-
one (29). To a solution of 25 (265 mg, 0.62 mmol) in 2,2-
dimethoxypropane (10 mL) was added PPTS (15 mg, 0.06 mmol).
The mixture was refluxed for 4 h, and the solvent was removed.
After the usual workup, the residue was purified chromatographi-
cally on silica gel (elution with hexanes/ethyl acetate 5:1) to give
29 (241 mg, 83%) as a colorless oil: IR (neat, cm-1) 1728, 1248;
1H NMR (400 MHz, CDCl3) δ 7.31 (d, J ) 8.5 Hz, 2H), 6.84 (d,
J ) 8.5 Hz, 2H), 4.95 (d, J ) 10.8 Hz, 1H), 4.64 (d, J ) 10.8 Hz,
1H), 4.35-4.34 (m, 1H), 4.34 (s, 1H,), 4.18 (d, J ) 3.5 Hz, 1H),
4.14-4.09 (m, 1H), 3.79 (s, 3H), 2.63-2.53 (m, 2H), 2.22-2.15
(m, 1H), 1.97-1.89 (m, 1H), 1.75-1.72 (m, 1H), 1.67-1.56 (m,
1H), 1.44 (s, 3H), 1.33 (s, 3H), 0.91 (s, 9H), 0.09 (s, 3H), 0.02 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 210.3, 158.8, 131.4, 128.8
(2C), 113.5 (2C), 106.0, 84.3, 82.0, 78.2, 77.4, 76.6, 55.2, 37.0,
27.7, 26.8, 25.7 (3C), 24.0, 23.2, 18.3, -4.7 (2C); ES HRMS m/z
(1S,2R,3R,4R,5R)-3-(4-Methoxybenzyloxy)-2-(tert-butyldimeth-
ylsilyloxy)-9-oxabicyclo[3.3.1]nonane-1,4-diol (25). Further elution
gave the more polar 25 (60 mg, 38%) as a colorless oil: IR (neat,
1
cm-1) 3540, 1514, 1122; H NMR (300 MHz, CDCl3) δ 7.30 (d,
J ) 8.6 Hz, 2H), 6.89 (d, J ) 8.6 Hz, 2H), 4.72 (d, J ) 11.2 Hz,
1H), 4.48 (d, J ) 11.2 Hz, 1H), 4.34 (d, J ) 7.4 Hz, 1H), 3.87 (s,
1H), 3.83-3.80 (m, 1H), 3.82 (s, 3H), 3.76-3.73 (m, 2H), 3.37
(d, J ) 8.4 Hz, 1H), 1.95-1.81 (m, 2H), 1.79-1.69 (m, 1H), 1.65-
1.42 (m, 2H), 1.37-1.25 (m, 1H), 0.9 (s, 9H), 0.11 (s, 6H); 13C
NMR (75 MHz, CDCl3) δ 159.3, 130.0, 129.5 (2C), 113.7 (2C),
94.1, 76.2, 76.1, 72.6, 69.4, 69.0, 55.2, 29.9, 26.0 (3C), 22.8, 18.6,
18.4, -4.2, -5.1; ES HRMS m/z for C22H36O6SiNa+ calcd
for C25H40O6SiNa+ calcd 487.2486, obsd 487.2474; [R]21 +13.1
D
(c 0.61, CHCl3).
((3aR,4R,5S,9aR)-4-(4-Methoxybenzyloxy)-2,2-dimethyl-6-
methyleneoctahydrocycloocta[d][1,3]dioxol-5-yloxy)(tert-butyl)-
dimethylsilane (30). A suspension of Ph3P+CH3 Br- (428 mg, 1.2
mmol) in THF (5 mL) was treated with n-butyllithium (2.0 M, 0.45
mL, 0.9 mmol) at 0 °C and stirred for 30 min. The system was
warmed to rt for 20 min and returned again to 0 °C. Ketone 29
(140 mg, 0.30 mmol) in THF (3 mL) was introduced at 0 °C. The
reaction mixture was quenched with saturated NH4Cl solution after
2 h and extracted with ethyl acetate. The combined organic layers
were dried and evaporated. The residue was purified chromato-
graphically on silica gel (elution with hexanes/ethyl acetate 40:1
447.2173, obsd 447.2173; [R]21 -16.3 (c 1.04, CHCl3).
D
(1R,2R,3R,4S,5S)-3-(4-Methoxybenzyloxy)-2-(tert-butyldimeth-
ylsilyloxy)-9-oxabicyclo[3.3.1]nonane-1,4-diol (24). The most
polar product 24 was obtained upon further elution as a white solid
(88 mg, 56%): mp 107-109 °C; IR (neat, cm-1) 3383, 1612, 1122;
1H NMR (300 MHz, CDCl3) δ 7.28 (d, J ) 8.9 Hz, 2H), 6.88 (d,
J ) 8.9 Hz, 2H), 4.74 (d, J ) 11.2 Hz, 1H), 4.44 (d, J ) 11.2 Hz,
1H), 4.15-4.07 (m, 2H), 3.80 (s, 3H), 3.79-3.72 (m, 2H), 2.26-
2.19 (m, 3H), 1.79-1.69 (m, 1H), 1.63-1.55 (m, 2H), 1.30-1.20
(m, 1H), 0.91 (s, 9H), 0.12 (s, 3H), 0.10 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 159.3, 130.6, 129.2 (2C), 113.8 (2C), 98.9, 80.5,
77.6, 74.0, 73.1, 69.8, 55.3, 33.4, 25.9 (3C), 25.8, 18.3, 17.2, -4.5,
-4.8; ES HRMS m/z for C22H36O6SiNa+ calcd 447.2173, obsd
to 20:1) to give 30 (69 mg, 50%) as a colorless oil: IR (neat, cm-1
)
1
1614, 1248; H NMR (400 MHz, CDCl3) δ 7.33 (d, J ) 8.5 Hz,
2H), 6.85 (d, J ) 8.5 Hz, 2H), 5.29 (s, 1H), 4.98 (s, 1H), 4.97 (d,
J ) 11.2 Hz, 1H), 4.63 (d, J ) 11.1 Hz, 1H), 4.18 (d, J ) 6.9 Hz,
1H), 4.14 (d, J ) 2.6 Hz, 1H), 4.13-4.08 (m, 1H), 4.06 (d, J )
2.8 Hz, 1H), 3.79 (s, 3H), 2.79-2.68 (m, 1H), 2.53-2.48 (m, 1H),
1.80-1.71 (m, 1H), 1.68-1.63 (m, 1H), 1.59-1.50 (m, 2H) 1.44
(s, 3H), 1.32 (s, 3H), 0.92 (s, 9H), 0.08 (s, 3H), 0.04 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 158.6, 147.3, 132.2, 128.4 (2C), 114.1,
113.4 (2C), 105.5, 86.3, 78.8, 78.7, 78.3, 76.2, 55.2, 29.5, 27.7,
27.0, 26.9, 25.9 (3C), 24.2, 18.3, -4.8, -5.2; ES HRMS m/z for
447.2170; [R]19 +12.3 (c 0.6, CHCl3).
D
(1R,2R,3R,4S,5S)-3-(4-Methoxybenzyloxy)-9-oxabicyclo[3.3.1]-
nonane-1,2,4-triol (27). A solution of 24 (37 mg, 0.087 mmol) in
2 mL of THF was treated with TBAF (1 M in THF, 0.1 mL, 0.1
mmol), stirred at rt for 6 h, and freed of solvent. The residue was
purified chromatographically on silica gel (elution with hexanes/
ethyl acetate 1:4) to give 27 (11.2 mg, 41%) as a white solid: mp
1
119-121 °C; IR (neat, cm-1) 3378, 1612, 1094; H NMR (300
J. Org. Chem, Vol. 71, No. 12, 2006 4361

Paquette and Zhang
C26H42O5SiNa+ calcd 485.2694, obsd 485.2684; [R]21 +15.5 (c
(3aS,4R,5R,9aS)-4-(4-Methoxybenzyloxy)-5-(tert-butyldimeth-
ylsilyloxy)-2,2-dimethylhexahydrocycloocta[d][1,3]dioxol-6(3aH)-
one (35). To a solution of (+)-24 (41 mg, 0.1 mmol) in 2,
2-dimethoxypropane (3 mL) was added PPTS (2.5 mg, 0.01 mmol).
The mixture was refluxed overnight, and the solvent was removed.
The residue was purified chromatographically on silica gel (elution
with hexanes/ethyl acetate 5:1) to give 35 as a colorless oil (40.2
mg, 91%): IR (neat, cm-1) 1612, 1167; 1H NMR (400 MHz,
CDCl3) δ 7.33 (d, J ) 8.6 Hz, 2H), 6.88 (d, J ) 8.6 Hz, 2H), 4.70
(s, 2H), 4.47 (dd, J ) 9.3, 5.4 Hz, 1H), 4.32 (d, J ) 1.8 Hz, 1H),
3.92-3.86 (m, 2H), 3.81 (s, 3H), 2.54-2.48 (m, 1H), 2.16-2.09
(m, 1H), 1.88-1.78 (m, 1H), 1.76-1.56 (m, 3H), 1.38 (s, 3H),
1.33 (s, 3H), 0.91 (s, 9H), 0.05 (s, 6H); 13C NMR (75 MHz, CDCl3)
δ 211.6, 159.2, 130.0, 129.8 (2C), 113.7 (2C), 107.1, 80.0, 77.1,
76.5, 76.0, 72.1, 55.2, 36.1, 30.0, 28.1, 25.7 (3C), 25.5, 23.8, 18.4,
-5.0 (2C); ES HRMS m/z for C25H40O6SiNa+ calcd 487.2486, obsd
D
2.38, CHCl3).
((3aR,4R,5S,6R,9aR)-4-(4-Methoxybenzyloxy)-5-(tert-butyl-
dimethylsilyloxy)-2,2-dimethyloctahydrocycloocta[d][1,3]dioxol-
6-yl)methanol (31). A solution of 30 (66 mg, 0.14 mmol) in THF
(5 mL) was treated with BH3‚THF complex (1 M, 0.42 mL, 0.42
mmol) under N2 at 0 °C. After 10 min of stirring, the temperature
was raised to rt and the mixture was stirred for another 2 h. Ethanol
(0.2 mL) was introduced, and stirring was maintained for 10 min
prior to treatment with aqueous NaOH solution (2 M, 0.4 mL) and
H2O2 (30%, 0.24 mL). After being stirred at rt for 2 h, the reaction
mixture was quenched with saturated NH4Cl solution and extracted
with ethyl acetate. The organic layers were combined, dried, and
evaporated. The residue was purified chromatographically on silica
gel (elution with hexanes/ethyl acetate 5:1) to give 31 (45 mg, 65%)
as a colorless oil: IR (neat, cm-1) 3462, 1249; 1H NMR (400 MHz,
CDCl3) δ 7.31 (d, J ) 8.5 Hz, 2H), 6.85 (d, J ) 8.5 Hz, 2H), 4.86
(d, J ) 10.9 Hz, 1H), 4.64 (d, J ) 10.9 Hz, 1H), 4.24 (ddd, J )
11.2, 7.1, 2.0 Hz, 1H), 4.19 (d, J ) 4.0 Hz, 1H), 4.13 (d, J ) 7.6
Hz, 1H), 3.96 (t, J ) 3.8 Hz, 1H), 3.85-3.79 (m, 1H), 3.80 (s,
3H), 3.61-3.57 (m, 1H), 2.71-2.62 (m, 1H), 2.19-2.11 (m, 1H),
2.0 (br s, 1H), 1.81-1.75 (m, 1H), 1.73-1.68 (m, 1H), 1.61-1.56
(m, 1H), 1.51 (s, 3H), 1.41-1.37 (m, 1H), 1.33 (s, 3H), 1.07-
0.99 (m, 1H), 0.91 (s, 9H), 0.11 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ 158.8, 131.6, 128.6 (2C), 113.5 (2C), 105.2, 85.2, 79.2,
77.6, 75.5, 73.8, 64.2, 55.2, 44.8, 29.7, 26.8, 26.0, 25.9 (3C), 23.9,
23.1, 18.1, -4.0, -5.1; ES HRMS m/z for C26H44O6SiNa+ calcd
487.2486; [R]19 -29.4 (c 0.68, CHCl3).
D
((3aS,4R,5S,9aS)-4-(4-Methoxybenzyloxy)-2,2-dimethyl-6-meth-
yleneoctahydrocycloocta[d][1,3]dioxol-5-yloxy)(tert-butyl)dimeth-
ylsilane (36). A suspension of Ph3P+CH3Br- (600 mg, 1.68 mmol)
in THF (5 mL) was treated with n-butyllithium (2.0 M, 0.63 mL,
1.26 mmol) at 0 °C and stirred for 30 min. The system was warmed
to rt for 20 min and returned to 0 °C again when 35 (196 mg, 0.42
mmol) dissolved in THF (5 mL) was added. The reaction mixture
was quenched after 2 h with saturated NH4Cl solution. After
extraction with ethyl acetate, the combined organic layers were dried
and evaporated. The residue was purified chromatographically on
silica gel (elution with hexanes/ethyl acetate 20:1) to afford 36 (157
mg, 81%) as a colorless oil: IR (neat, cm-1) 1513, 1125; 1H NMR
(400 MHz, CDCl3) δ 7.35 (d, J ) 8.5 Hz, 2H), 6.87 (d, J ) 8.5
Hz, 2H), 5.20 (s, 1H), 4.89 (s, 1H), 4.74 (d, J ) 11.8 Hz, 1H),
4.67 (d, J ) 11.8 Hz, 1H), 4.43 (dd, J ) 9.8, 5.6 Hz, 1H), 4.25 (d,
J ) 1.4 Hz, 1H), 4.09-4.05 (m, 1H), 3.81 (s, 3H), 3.68 (dd, J )
9.7, 2.2 Hz, 1H), 2.19-2.13 (m, 1H), 1.77-1.68 (m, 1H), 1.65-
1.49 (m, 4H), 1.41 (s, 3H), 1.34 (s, 3H), 0.9 (s, 9H), 0.09 (s, 3H),
0.0 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.1, 148.2, 130.8,
130.0 (2C), 113.6 (2C), 113.2, 106.2, 77.9, 77.1, 76.1, 75.8, 72.5,
55.5, 30.3, 28.8, 28.6, 28.2, 26.0 (3C), 25.4, 18.4, -4.4, -5.0; ES
HRMS m/z for C26H42O5SiNa+ calcd 485.2694, obsd 485.2699;
503.2799, obsd 503.2803; [R]19 -6.5 (c 3.7, CHCl3).
D
(3aS,4R,5S,6R,9aR)-5-(tert-Butyldimethylsilyloxy)-6-(hydroxy-
methyl)-2,2-dimethyloctahydrocycloocta[d][1,3]dioxol-4-ol (32).
A solution of 31 (77 mg, 0.16 mol) in CH2Cl2/H2O (20:1, 10 mL)
was treated with DDQ (55 mg, 0.24 mmol) and stirred at rt for 2
h. The reaction mixture was quenched with saturated NaHCO3
solution and extracted with CH2Cl2. The combined organic layers
were combined, dried, and evaporated. The residue was purified
chromatographically on silica gel (elution with hexanes/ethyl acetate
5:1) to give 32 (47 mg, 81%) as a colorless oil: IR (neat, cm-1
)
3471, 1172; 1H NMR (400 MHz, CDCl3) δ 4.42 (dd, J ) 5.0, 1.0
Hz, 1H), 4.21 (ddd, J ) 11.0, 7.0, 1.8 Hz, 1H), 4.04 (dd, J ) 7.0,
1.0 Hz, 1H), 4.01 (dd, J ) 5.0, 2.0 Hz, 1H), 3.53 (dd, J ) 9.6, 9.4
Hz, 1H), 3.42 (dd, J ) 9.9, 6.0 Hz, 1H), 2.71-2.60 (m, 1H), 2.55
(br s, 1H), 1.95-1.78 (m, 3H), 1.70-1.66 (m, 1H), 1.50 (s, 3H),
1.34-1.23 (m, 2H), 1.32 (s, 3H), 0.99-0.95 (m, 1H), 0.90 (s, 9H),
0.12 (s, 3H), 0.10 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 105.3,
79.7, 76.1, 75.1, 70.1, 64.9, 44.7, 31.6, 28.0, 27.2, 25.8 (3C), 23.8,
23.6, 18.1, -4.5, -5.0; ES HRMS m/z for C18H36O5SiNa+ calcd
[R]18 -24.5 (c 2.63, CHCl3).
D
((3aS,4R,5S,6S,9aS)-4-(4-Methoxybenzyloxy)-5-(tert-butyl-
dimethylsilyloxy)-2,2-dimethyloctahydrocycloocta[d][1,3]dioxol-
6-yl)methanol (37). A solution of 36 (153 mg, 0.33 mol) in THF
(5 mL) was treated with BH3‚THF complex (1 M, 0.99 mL, 0.99
mmol) under N2 protection at 0 °C. After 10 min of stirring, the
temperature was raised to rt, and stirring was continued for another
2 h. Ethanol (0.4 mL) was introduced, and stirring was maintained
for 10 min, followed by addition of 2 M NaOH solution (0.85 mL)
and H2O2 (30%, 0.5 mL). After a further 2 h of agitation, the
reaction mixture was quenched with saturated NH4Cl solution and
extracted with ethyl acetate. The organic layers were combined,
dried, and evaporated. The residue was purified chromatographically
on silica gel (elution with hexanes/ethyl acetate 10:1) to afford 37
383.2224, obsd 383.2238; [R]19 -1.9 (c 1.89, CHCl3).
D
(1R,2R,3S,4S,5R)-5-(Hydroxymethyl)cyclooctane-1,2,3,4-tet-
raol (33). A solution of 32 (47 mg, 0.13 mmol) in methanol (2
mL) was treated with HCl (1 M, 2 mL), stirred for 24 h at rt, and
freed of solvent under vacuum. The residue was purified chro-
matographically on silica gel (elution with ethyl acetate/methanol
5:1) to give the more polar 33 as a colorless oil (9.8 mg, 37%): IR
1
(15 mg, 9%) as a colorless oil: IR (neat, cm-1) 3453, 1249; H
1
(neat, cm-1) 3354, 1250, 1078; H NMR (400 MHz, D2O) δ 4.17
NMR (400 MHz, CDCl3) δ 7.33 (d, J ) 8.5 Hz, 2H), 6.86 (d, J )
8.5 Hz, 2H), 4.77 (d, J ) 11.6 Hz, 1H), 4.65 (d, J ) 11.6 Hz, 1H),
4.50 (dd, J ) 9.5, 5.3 Hz, 1H), 4.17 (dd, J ) 9.7, 5.3 Hz, 1H,),
3.81 (s, 3H), 3.75 (d, J ) 9.8 Hz, 1H), 3.70 (d, J ) 9.6 Hz, 1H),
3.65 (dd, J ) 9.8, 4.3 Hz, 1H), 3.49 (dd, J ) 10.1, 5.4 Hz, 1H),
1.80-1.74 (m, 2H), 1.71-1.68 (m, 1H), 1.65-1.48 (m, 3H), 1.44
(s, 3H), 1.40-1.32 (m, 1H), 1.35 (s, 3H), 0.99-0.90 (m, 1H), 0.87
(s, 9H), 0.10 (s, 3H), 0.04 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
159.1, 130.9, 130.0 (2C), 113.5 (2C), 106.3, 78.3, 77.2, 76.4, 74.2,
72.6, 66.0, 55.2, 45.8, 32.8, 28.4, 26.7, 26.2 (4C), 25.5, 18.5, -3.4,
-5.0; ES HRMS m/z for C26H44O6SiNa+ calcd 503.2799, obsd
(s, 2H), 3.96-3.93 (m, 1H), 3.80 (s, 1H), 3.50 (d, J ) 6.6 Hz,
2H), 2.08-1.95 (m, 2H), 1.80-1.74 (m, 1H), 1.70-1.64 (m, 1H),
1.61-1.55 (m, 1H), 1.49-1.43 (m, 1H), 1.40-1.32 (m, 1H); 13C
NMR (75 MHz, D2O) δ 81.6, 77.0, 76.7, 76.3, 67.8, 46.0, 33.5,
26.4, 26.2; ES HRMS m/z for C9H18O5Na+ calcd 229.1046, obsd
229.1052; [R]19 -3.9 (c 0.81, CH3OH).
D
Also isolated was the less polar 34 (6.8 mg, 28%): IR (neat,
cm-1) 3393, 1096, 1020; 1H NMR (400 MHz, D2O) δ 4.20 (d, J )
2.0 Hz, 1H), 4.01 (s, 1H), 3.97-3.93 (m, 3H), 3.90 (dd, J ) 4.0,
1.6 Hz, 1H), 2.21 (t, J ) 5.2 Hz, 1H), 2.11-2.02 (m, 1H), 1.82-
1.75 (m, 1H), 1.70-1.62 (m, 1H), 1.57-1.50 (m, 2H), 1.46-1.38
(m, 1H); 13C NMR (75 MHz, D2O) δ 94.7, 82.4, 76.2, 74.5, 73.7,
48.6, 33.7, 31.7, 18.2; ES HRMS m/z for C9H16O4Na+ calcd
503.2814; [R]19 -18.9 (c 1.01, CHCl3).
D
((3aS,4R,5S,6R,9aS)-4-(4-Methoxybenzyloxy)-5-(tert-butyl-
dimethylsilyloxy)-2,2-dimethyloctahydrocycloocta[d][1,3]dioxol-
6-yl)methanol (38). Continued elution gave 38 (121 mg, 76%) as
211.0946, obsd 211.0946; [R]19 -4.4 (c 0.48, CH3OH).
D
4362 J. Org. Chem., Vol. 71, No. 12, 2006

DeoxygenatiVe Zirconocene Ring Contraction
1
a colorless oil: IR (neat, cm-1) 3462, 1248; H NMR (400 MHz,
106.6, 77.3, 74.1, 71.4, 71.0, 65.6, 41.6, 27.9, 26.2 (3C), 25.6, 25.1,
CDCl3) δ 7.33 (d, J ) 8.5 Hz, 2H), 6.86 (d, J ) 8.5 Hz, 2H), 4.69
(d, J ) 11.2 Hz, 1H), 4.63-4.58 (m, 1H), 4.53 (dd, J ) 9.1, 6.3
Hz, 1H), 4.30 (br s, 1H), 4.16-4.11 (m, 1H), 3.79 (s, 3H), 3.44 (d,
J ) 8.2 Hz, 2H), 3.33 (br s, 1H), 1.79-1.69 (m, 3H), 1.63-1.55
(m, 2H), 1.52-1.33 (m, 2H), 1.45 (s, 3H), 1.36 (s, 3H), 1.02-
0.87 (m, 1H), 0.87 (s, 9H), 0.10 (s, 3H), 0.01 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 158.9, 131.0, 129.5 (2C), 113.5 (2C), 105.9,
81.4, 76.4, 76.2, 72.9, 71.6, 65.7, 55.2, 43.3, 27.7, 26.5, 26.1 (3C),
24.9, 24.2, 20.6, 18.5, -3.4, -5.5; ES HRMS m/z for C26H44O6-
SiNa+ calcd 503.2799, obsd 503.2777; [R]19D +3.0 (c 3.11, CHCl3).
(3aR,4R,5S,6S,9aS)-5-(tert-Butyldimethylsilyloxy)-6-(hydroxy-
methyl)-2,2-dimethyloctahydrocycloocta[d][1,3]dioxol-4-ol (39).
A solution of (-)-37 (33 mg, 0.069 mol) in CH2Cl2/H2O (20:1, 6
mL) was treated with DDQ (23 mg, 0.1 mmol), stirred at rt for 2
h, quenched with saturated NaHCO3 solution, and extracted with
CH2Cl2. The organic layers were combined, dried, and evaporated.
The residue was purified chromatographically on silica gel (elution
with hexanes/ethyl acetate 3:1) to give 39 (20 mg, 81%) as a
23.4, 20.9, 18.7, -3.2, -5.3; ES HRMS m/z for C18H36O5SiNa+
calcd 383.2224, obsd 383.2221; [R]18 +11.1 (c 2.07, CHCl3).
D
(1S,2S,3S,4S,5S)-5-(Hydroxymethyl)cyclooctane-1,2,3,4-tet-
raol (41). A solution of (-)-39 (20.1 mg, 0.056 mmol) in methanol
(1 mL) was treated with HCl (1 M, 1 mL), stirred for 24 h at rt,
and freed of solvent under vacuum. The residue was triturated with
chloroform (3 × 5 mL) and dried under vacuum to give pure 41
1
(9.6 mg, 83%) as a colorless oil: IR (neat, cm-1) 3381, 1360; H
NMR (400 MHz, D2O) δ 3.99-3.97 (m, 1H), 3.83-3.80 (m, 1H),
3.72 (d, J ) 8.4 Hz, 1H), 3.65-3.61 (m, 2H), 3.44-3.40 (m, 1H),
1.84-1.77 (m, 2H), 1.61-1.51 (m, 4H), 1.30-1.25 (m, 1H); 13C
NMR (75 MHz, D2O) δ 76.0, 75.5, 75.4, 72.7, 67.7, 47.5, 33.1,
28.8, 28.5; ES HRMS m/z for C9H18O5Na+ calcd 229.1046, obsd
229.1050; [R]22 +3.7 (c 0.71, CH3OH).
D
(1S,2S,3S,4S,5R)-5-(Hydroxymethyl)cyclooctane-1,2,3,4-tet-
raol (42). A solution of (+)-40 (51 mg, 0.14 mmol) in methanol
(2 mL) was treated with HCl (1 M, 2 mL), stirred for 24 h at rt,
and freed of solvent under vacuum. The residue was triturated with
chloroform (3 × 5 mL) and dried under vacuum to give pure 42
1
colorless oil: IR (neat, cm-1) 3446, 1096; H NMR (400 MHz,
CDCl3) δ 4.38 (dd, J ) 9.6, 5.7 Hz, 1H), 4.21 (ddd, J ) 10.5, 5.7,
1.8 Hz, 1H), 3.98 (dd, J ) 9.6, 1.9 Hz, 1H), 3.84 (dd, J ) 9.8, 2.0
Hz, 1H), 3.73 (dd, J ) 9.8, 4.2 Hz, 1H), 3.56 (dd, J ) 10.2, 5.6
Hz, 1H), 2.42 (br s, 1H), 1.89-1.78 (m, 2H), 1.76-1.64 (m, 1H),
1.62-1.58 (m, 2H), 1.42 (s, 3H), 1.33 (s, 3H), 1.30-1.23 (m, 2H),
1.22-1.15 (m, 1H), 0.90 (s, 9H), 0.15 (s, 3H), 0.11 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 106.6, 78.3, 75.1, 73.8, 70.3, 65.9, 45.5,
31.9, 28.1, 27.4, 26.4, 26.2 (3C), 25.3, 18.6, -3.4, -4.8; ES HRMS
(25 mg, 87%) as a white solid: mp 137-139 °C; IR (neat, cm-1
)
1
3384, 1343; H NMR (400 MHz, D2O) δ 4.05 (br s, 1H), 4.04-
4.0 (m, 1H), 3.84 (dd, J ) 7.9, 2.7 Hz, 1H), 3.72 (d, J ) 8 Hz,
1H), 3.42 (dd, J ) 10.8, 7.6 Hz, 1H), 3.33 (dd, J ) 10.9, 6.6 Hz,
1H), 1.65-1.54 (m, 4H), 1.34-1.25 (m, 3H); 13C NMR (75 MHz,
D2O) δ 73.2, 73.1, 72.4, 70.1, 64.4, 43.4, 28.4, 21.0, 20.9; ES
HRMS m/z for C9H18O5Na+ calcd 229.1046, obsd 229.1051; [R]22
-3.4 (c 1.0, CH3OH).
D
m/z for C18H36O5SiNa+ calcd 383.2224, obsd 383.2232; [R]21
D
-22.0 (c 1.82, CHCl3).
Acknowledgment. A large part of this investigation was
made possible by financial support provided by the Astellas
USA Foundation. We thank Dr. In Ho Kim and Dr. Nicolas
Cunie`re for early experiments, Mr. David Hilmey for MM3
calculations, and Dr. Judith Gallucci for X-ray crystallography.
Peter Selvaraj and Sean Butler contributed to the cover artwork.
Photo credit: NASA, Andrew Fruchter and the ERO Team
[Sylvia Baggett (STScI), Richard Hook (ST-ECF), Zoltan Levay
(STScI)].
(3aR,4R,5S,6R,9aS)-5-(tert-Butyldimethylsilyloxy)-6-(hydroxy-
methyl)-2,2-dimethyloctahydrocycloocta[d][1,3]dioxol-4-ol (40).
A solution of (+)-38 (30.1 mg, 0.063 mol) in CH2Cl2/H2O (20:1,
5 mL) was treated with DDQ (21.4 mg, 0.094 mmol) and stirred
at rt for 2 h. The reaction mixture was quenched with saturated
NaHCO3 aqueous solution and extracted with CH2Cl2. The organic
layers were combined, dried, and evaporated. The residue was
purified chromatographically on silica gel (elution with hexanes/
ethyl acetate 5:1) to give 40 (21 mg, 93%) as a colorless oil: IR
(neat, cm-1) 3522, 1124; 1H NMR (400 MHz, CDCl3) δ 4.45 (dd,
J ) 9.3, 5.7 Hz, 1H), 4.28 (s, 1H), 4.15 (ddd, J ) 11.5, 5.6, 3.5
Hz, 1H), 3.57-3.53 (m, 2H), 3.45 (dd, J ) 10.0, 6.3 Hz, 1H),
3.10 (s, 1H), 1.98-1.94 (m, 1H), 1.79-1.69 (m, 1H), 1.65-1.49
(m, 5H), 1.44 (s, 3H), 1.38 (s, 3H), 1.04-1.03 (m, 1H), 0.89 (s,
9H), 0.14 (s, 3H), 0.10 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
Supporting Information Available: High-field 1H and 13C
NMR spectra for 3-42 and X-ray crystallographic data for (+)-24
and (-)-42 (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
JO051989G
J. Org. Chem, Vol. 71, No. 12, 2006 4363