Synthesis of Stereoisomeric Medium-Ring α,α′-Dihydroxy Cycloalkanones

Article abstract of DOI:10.1021/jo0358675

The stereochemical course of the epoxidation of the silyl enol ethers of 2-tert-butyldimethylsilyl-oxycycloheptanone and -cyclooctanone has been investigated and shown to proceed exclusively anti to the existing α-substituent. 2-(Benzyloxy)cyclooctanone b

Full text of DOI:10.1021/jo0358675

Syn th esis of Ster eoisom er ic Med iu m -Rin g r,r′-Dih yd r oxy
Cycloa lk a n on es
Leo A. Paquette,* Ryan E. Hartung, J ohn E. Hofferberth, Ivan Vilotijevic, and J iong Yang
Evans Chemical Laboratories, The Ohio State University, Columbus, Ohio 43210
paquette.1@osu.edu
Received December 23, 2003
The stereochemical course of the epoxidation of the silyl enol ethers of 2-tert-butyldimethylsilyl-
oxycycloheptanone and -cyclooctanone has been investigated and shown to proceed exclusively anti
to the existing R-substituent. 2-(Benzyloxy)cyclooctanone behaves similarly, and the presence of a
transannular double bond does not alter the outcome. R-Ketol rearrangements are seen to operate
during ensuing fluoride ion-induced removal of the silyl protecting groups in select examples. The
preferred means for generating the cis isomers of the R,R′-dihydroxy cycloalkanones involves
methylenation of the monoprotected trans-dihydroxy ketones with the Nysted reagent, followed by
oxidation and subsequent reduction with sodium borohydride. Ozonolysis and fluoride ion-induced
desilylation complete the route.
The literature documents several options for acquiring
acyclic R,R′-dihydroxy ketones. These approaches include
the ruthenium-catalyzed oxidation of allenes,1 the over-
oxidation of silyl enol ethers with m-chloroperbenzoic
acid,2 the use of 1-chloroalkyl p-tolyl sulfoxides as hy-
droxycarbonyl anion equivalents,3 and most notably the
addition of 2-lithio-1,4-dioxane to aldehydes and ketones
followed by peracid oxidation, borohydride reduction, and
acidic hydrolysis as reflected in the conversion of 1 to 2.4
ligands. The latter overwhelmingly deny anti oxygenation
at the enolizable positions.
A synthetic investigation being undertaken by us
required the availability of the stereoisomers of R,R′-
dihydroxy cycloheptanone and cyclooctanone.7 The study
described below underscores a number of factors that
must be given consideration as these targets are ap-
proached.
Curiously, the preparation of cyclic variants of this
compound class has not been pursued despite the attrac-
tive density of functionality resident therein. To our
knowledge,5 the only example reported to this time is the
conversion of 3 to 4.6 When rings are involved, the
nuances associated with the cis or trans disposition of
the pair of hydroxyl groups warrant consideration. In the
case of 3, pertinent stereochemical considerations are
obviously overridden by the iron atom and its attached
Resu lts a n d Discu ssion
tr a n s-2,7-Dih ydr oxycycloh eptan on e. The first phase
of the program began with cycloheptene oxide (5), the
ring opening of which with dimethyl sulfoxide and triflic
acid,8 with subsequent exposure to triethylamine, oc-
curred uneventfully to give R-ketol 6a in 76% yield
(Scheme 1). The hydroxyl group was protected as defined
by TBS ether 6b in advance of regioselective enolate
anion generation.9 This reactive intermediate was trapped
with TBS chloride in advance of oxidation with m-
chloroperbenzoic acid. Spontaneous rearrangement of the
epoxide followed, with generation of a lone doubly func-
tionalized cycloheptanone. To define the stereochemistry
of 7, we turned to sodium borohydride reduction, where-
upon a 2.7:1 mixture of 8 and 9 was generated. The silyl
(1) Laux, M.; Krause, N. Synlett 1997, 765.
(2) Horiguchi, Y.; Nakamura, E.; Kuwajima, I. Tetrahedron Lett.
1989, 30, 3323.
(3) Satoh, T.; Onda, K.; Yamakawa, K. J . Org. Chem. 1991, 56, 4129.
(4) Fetizon, M.; Goulaouic, P.; Hanna, I. Tetrahedron Lett. 1985, 26,
4925.
(5) (a) For a timely review covering the generation of R-hydroxy
carbonyl systems, see: Chen, B.-C.; Zhou, P.; Davis, F. A.; Ciganek,
E. Org. React. 2003, 62, 1. (b) Following completion of the present
investigation, a synthetic route to enantiomerically pure, orthogonally
protected 2,4,6-trihydroxycyclohexanones was reported: Kirsch, S.;
Bach, T. Synthesis 2003, 1827. All of the compounds prepared by us
are racemic.
(7) Paquette, L. A.; Hartung, R. E.; Hofferberth, J . E.; Gallucci, J .
C. Org. Lett. 2004, 6, 969.
(8) Trost, B. M.; Fray, M. J . Tetrahedron Lett. 1988, 29, 2163.
(9) Paquette, L. A.; O’Neill, S. V.; Guillo, N.; Zeng, Q.; Young, D. G.
Synlett 1999, 1857.
(6) Pearson, A. J .; Chang, K. J . Org. Chem. 1993, 58, 1228.
10.1021/jo0358675 CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/09/2004
2454
J . Org. Chem. 2004, 69, 2454-2460

Stereoisomeric Medium-Ring R,R′-Dihydroxy Cycloalkanones
SCHEME 1
SCHEME 3
2,7-isomer. Since 11 and 12 are not interconverted under
the reaction conditions, some level of kinetic control is
clearly operative. In the present context, it is evident that
operation of the R-ketol rearrangement10 must be care-
fully monitored and curtailed if maximum overall ef-
ficiency with regard to the acquisition of 11 is to be
achieved.
cis-2,7-Dih yd r oxycycloh ep t a n on e. In light of the
findings defined in Schemes 1 and 2, the stereochemical
markers present in 20 were considered to require con-
figurational inversion at either the R or R′ position. To
facilitate this process while simultaneously minimizing
possible operation of an R-ketol rearrangement, the trans
monoprotected dihydroxy ketone 15 was prepared and
homologated to the exomethylene cycloheptane 16 by
reaction with the Nysted reagent11 (Scheme 3). As
indicated by the modest yields, both steps were plagued
by competing side reactions. Nonetheless, the ease of
execution and the significantly reduced polarity of 16
allowed for suitable scaling of this two-step process.
The allylic alcohol generated in this manner reacted
with IBX12 to give the R,â-unsaturated ketone 17 ef-
ficiently. The formation of this product served to allow
for subsequent Luche reduction13 and conversion exclu-
sively to 18. The elevated stereoselectivities associated
with the epoxidation reaction that delivers 15 and the
borohydride reduction that leads to 18 can be adequately
explained by taking into account conformations such as
A and B with reagent approach relegated to the exo-
surface of the respective π bonds for obvious steric
reasons.
SCHEME 2
migration involved in the production of 9 was anticipated.
Independent exposure of 8 and 9 to fluoride ion in THF
resulted in smooth conversion to the identical triol 10.
Should the OTBS groups in 7 be cis-oriented, reduction
of its ketone carbonyl followed by desilylation could lead
to two symmetrical products, both of which would exhibit
four 13C NMR signals. In contrast, comparable processing
of the trans isomer would generate a single unsym-
metrical triol featuring seven carbon signals. The lower
symmetry criterion was uniquely met by 10, which must
therefore be defined as the syn,anti isomer shown.
We next addressed the direct desilylation of 7 with
TBAF in THF. In the event, the dihydroxy ketones 11
and 12 were formed in a ratio of 2:1 (Scheme 2). The
nonidentity of 7 and 14 provided confirmatory evidence
of a structural change. The isomerization embodied in
the 11 f 12 conversion was not expected since MM3
calculations show trans-2,3-dihydroxycycloheptanone to
be 6-7 kcal/mol more sterically strained than the trans-
The route to 20 was completed by conventional ozon-
olysis to introduce the carbonyl group and subsequent
(10) Paquette, L. A.; Hofferberth, J . E. Org. React. 2003, 62, 477.
(11) Nysted, L. N. U.S. Patent 3,865,848, 1975. This reagent was
purchased from the Aldrich Chemical Co.
(12) Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Barluenga, S.; Hunt,
K. W.; Kranich, R.; Vega, J . A. J . Am. Chem. Soc. 2002, 124, 2233.
(13) Luche, J . L. J . Am. Chem. Soc. 1978, 100, 2226.
J . Org. Chem, Vol. 69, No. 7, 2004 2455

Paquette et al.
SCHEME 4
SCHEME 6
SCHEME 7
SCHEME 5
exposure of 19 to TBAF in THF. The spectral properties
of 11 (C2v-symmetric) and 20 (Cs-symmetric) are suf-
ficiently distinctive to permit their independent recogni-
tion (see the Experimental Section).
tr a n s-2,8-Dih ydr oxycyclooctan on e. The ready avail-
ability of R-ketol 21 by oxidative acid-catalyzed ring
opening of 1,5-cyclooctadiene monoxide in the presence
of dimethyl sulfoxide followed by treatment with diiso-
propylethylamine8 caused us to regard it as a serviceable
starting material (Scheme 4). The R′-hydroxyl was in-
troduced by exposure of the potassium enolate to oxygen,
followed by the addition of triethyl phosphite. A single
dihydroxy ketone was isolated from this reaction (26%
yield at 74% conversion). The relative stereochemical
disposition of the two OH groups was shown to be trans
by a two-step sequence involving catalytic hydrogenation
in tandem with lithium aluminum hydride reduction.
Based on the eight 13C NMR signals exhibited by 24, its
OH substituents must be related in a cis,anti fashion.
A route to 23 involving early reduction of the unsatu-
rated bond in 21 was simultaneously explored as a
potential means for improving overall efficiency. To this
end, the hydroxyl group in 25 was transformed into the
tert-butyldimethylsilyl ether as well as the benzyl ether14
to gauge if differing protective measures would be
influential. Both intermediates were O-silylated and
epoxidized. The generation of 26 and 28 in this manner
(Scheme 5) proceeded in entirely comparable fashion.
Desilylation of 26 with TBAF and hydrogenolysis of 28
over 10% palladium on charcoal furnished 23 in 72-80%
yield. Thus, both intermediates can be regarded as
equivalently useful progenitors of 23.
cis-2,8-Dih yd r oxycycloocta n on e. The first reaction
sequence targeting 36 involved the initial oxidation of
28 to R-diketone 29 (Scheme 6). The preparation of this
material was projected to be of interest in connection with
its possible regio- and stereocontrolled monoreduction.
We were cognizant of a report by Hekmatshoar and co-
workers15 describing the ready conversion of R-diketones
to R-ketols upon treatment with zinc dust and saturated
ammonium chloride solution in THF. However, the
examples provided by the Iranian group were exclusively
acyclic and offered no insight into the two key consider-
ations of interest here. Under the conditions defined
earlier, 29 was smoothly transformed into a single
1
product recognized convincingly by H NMR analysis to
be an isomer with the “external” carbonyl intact. The cis
stereochemistry resident in 30 was established by con-
version via 31 to a mixture of the triols 24 and 32.
Although the regioselectivity associated with the forma-
(14) Paquette, L., A.; Vilotijevich, I.; Hilmey, D.; Yang, J . Org. Lett.
2003, 5, 463.
(15) Hekmatshoar, R.; Heravi, M. M.; Beheshtiha, Y. S.; Faridbod,
F. Monathsh. Chem. 2002, 133, 195.
2456 J . Org. Chem., Vol. 69, No. 7, 2004

Stereoisomeric Medium-Ring R,R′-Dihydroxy Cycloalkanones
SCHEME 8
SCHEME 9
allylic alcohols proved to be amenable to further useful
transformations. The structural assignment to minor
constituent 38 was corroborated by IBX oxidation to
enone 40, the subsequent Luche reduction of which
resulted in production of both 41 and 42. Ozonolysis of
42 provided the previously synthesized R-ketol 35, an
immediate precursor of the well characterized dihydroxy
ketone 31.
Turning subsequently to 37, we observed its smooth
oxidation to 39 (94%, Scheme 8), fully stereocontrolled
Luche reduction to 42 (93%, Scheme 9), desilylation
without rearrangement, and ultimate ozonolytic cleavage
to generate 36 in a preparatively useful manner.
Su m m a r y
Synthetic routes to the cis and trans isomers of R,R′-
dihydroxy cycloheptanone and cyclooctanone have been
developed. The trans isomers are readily accessed by
Rubottom oxidation of R-alkoxy or R-silyloxy cyclic ke-
tones, a likely result of the involvement of transition-
state conformations such as that depicted in A. The
competitive operation of R-ketol rearrangements needs
to be curtailed in order to realize maximum efficiency.
The preferred route to the cis isomers involves early
application of the Nysted reagent. Once the exomethylene
group is introduced, inversion of stereochemistry at the
unprotected carbinol center is possible by sequential
oxidation/reduction. It is anticipated that the lessons
learned in this series of experiments can be fruitfully
applied to other goals associated with the chemistry of
medium-sized rings.
tion of 30 is of interest, care must be exercised in
attributing chemical inertness to the “external” carbonyl
group. It is possible that reduction of this functionality
is actually favored kinetically and that R-ketol re-
arrangement ensues to deliver 30. Whatever the precise
mechanistic pathway, this transformation was not com-
patible with our goals.
The brief interlude outlined in Scheme 7 was taken to
explore the possible role of a neighboring group effect, if
operative. Accordingly, R-diketone 33 was reduced by
several reagent combinations. The results recorded for
the zinc/ammonium chloride system gave only 35 in a
yield comparable to that realized in the case of 30.
Recourse to both Dibal-H and L-Selectride in THF did
not lead to a crossover in product composition. However,
sodium borohydride proved unique in giving rise to 34,
and predominantly so (59%). In light of the ease in
separating 34 from 35 by chromatographic means, this
routing came quickly to be regarded as the likely route
of choice for preparing 36. However, exposure of 34 to
TBAF for desilylation purposes was met with competing
R-ketol rearrangement. The need for repetitive chroma-
tography ultimately caused this scheme to be disfavored
and prompted the development of a pathway involving
utilization of the Nysted reagent as in the cycloheptane
series.
Exp er im en ta l Section
2-Hyd r oxycycloh ep ta n on e (6a ). Trifluoromethanesulfon-
ic acid (6.7 mL, 75.9 mmol) was added to cold dimethyl
sulfoxide (18.8 mL) and transferred to a solution of cyclohep-
tene oxide (8.5 g, 75.9 mmol) in DMSO (55 mL). The reaction
mixture was stirred for 45 min, diluted with CH2Cl2 (119 mL),
cooled to -78 °C, and treated with diisopropylethylamine (66
mL, 378 mmol). After arrival at rt, the mixture was poured
into 10% sodium bisulfate solution (200 mL) and transferred
to a separatory funnel where 500 mL of water was added.
Extraction with CH2Cl2 (4 × 100 mL) was followed by drying
and concentration of the combined organic phases. The residue
was chromatographed on silica gel (elution with 2:1 hexane/
ethyl acetate) to give 7.4 g (76%) of 6a as a colorless oil having
the reported spectral features.16
t r a n s-2,7-Bis(t er t -b u t yld im e t h ylsilyloxy)cycloh e p -
ta n on e (7). A cold (-78 °C), stirred solution of 6b (11.46 g,
47.4 mmol) in anhydrous THF (320 mL) was treated with
The methylenation of 26 led to a mixture of two
isomeric products rich in 37 as desired (Scheme 8). Both
J . Org. Chem, Vol. 69, No. 7, 2004 2457

Paquette et al.
lithium hexamethyldisilazide (57 mL of 1 M in THF, 57 mmol).
After 1 h, tert-butyldimethylchlorosilane (9.97 g, 66.4 mmol)
was introduced, and the reaction mixture was allowed to warm
to rt, quenched with saturated NaHCO3 solution, and extracted
with ether (3 × 200 mL). The combined organic layers were
dried and concentrated to leave an oily residue that was
dissolved in CH2Cl2 (575 mL) and cooled to 0 °C in advance of
the addition of m-chloroperbenzoic acid (12.78 g, 56.9 mmol).
The reaction mixture was stirred for 2 h, allowed to warm to
rt, quenched with 1 M sodium hydroxide solution (700 mL),
and extracted with CH2Cl2 (2 × 400 mL). The combined organic
phases were washed with brine and saturated NaHCO3
solution, dried, and concentrated. Chromatography of the
residue on silica gel (elution with 10:1 hexane/ethyl acetate)
and concentrated. The product was purified by chromatogra-
phy on silica gel (elution with 20:1 hexane/ethyl acetate) to
furnish 54 mg (88%) of 18 as a colorless oil: IR (neat, cm-1
)
1
3437, 1472, 1254; H NMR (300 MHz, CDCl3) δ 5.08 (d, J )
7.7 Hz, 2 H), 4.47 (t, J ) 5.4 Hz, 1 H), 4.35 (dd, J ) 7.3, 5.6
Hz, 1 H), 2.00-1.94 (m, 1 H), 1.90-1.77 (m, 3 H), 1.74-1.59
(m, 2 H), 1.53-1.46 (m, 1 H), 1.43-1.36 (m, 1 H), 0.94 (s, 9
H), 0.12 (s, 3 H), 0.11 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ
154.2, 112.9, 76.4, 75.3, 38.4, 37.5, 26.2 (3C), 24.8, 24.5, 18.4,
-4.4, -4.5; ES HRMS m/z (M + Na)+ calcd 279.1750, obsd
279.1757.
cis-2-(ter t-Bu tyld im eth ylsilyloxy)-7-h yd r oxycycloh ep -
ta n on e (19). Ozone was bubbled through a cold (-78 °C)
solution of 18 (43 mg, 0.17 mmol) in CH2Cl2 (14 mL) until a
faint blue color persisted. Oxygen bubbling followed until the
reaction mixture became clear, at which point triphenylphos-
phine (53 mg, 0.20 mmol) was introduced and warming to rt
ensued. The solvent was evaporated, and the residue was
chromatographed on silica gel (elution with 10:1 hexane/ethyl
acetate) to deliver 19 as a colorless oil (37 mg, 86%): IR (neat,
cm-1) 3482, 1722, 1472; 1H NMR (300 MHz, CDCl3) δ 4.43 (dd,
J ) 7.9, 4.1 Hz, 1 H), 4.29 (m,1 H), 1.99-1.30 (series of m, 8
H), 0.93 (s, 9 H), 0.14 (s, 3 H), 0.09 (s, 3 H); 13C NMR (75 MHz,
CDCl3) δ 212.8, 75.4, 75.2, 34.7, 33.6, 26.1 (3C), 24.9, 24.8, 18.7,
-4.2, -4.7; ES HRMS m/z (M + Na)+ calcd 281.1543, obsd
281.1548.
tr a n s-2,8-Dih yd r oxy-4-cycloocten -1-on e (22). Dry oxy-
gen was bubbled through a solution of 21 (15 mg, 0.14 mmol)
in THF (3 mL) for 5 min at -15 °C, at which point potassium
hexamethyldisilazide (640 µL of 0.5 M in THF) was introduced.
Stirring was maintained in the cold for 3 min prior to
treatment with triethyl phosphite (1 mL), quenching with
brine, and extraction with ethyl acetate. The combined organic
layers were dried, filtered, and evaporated. The above protocol
was repeated five times and the combined residues were
chromatographed on silica gel (elution with 14-16% ethyl
acetate in hexane) to give 20 mg (26%) of recovered 21 and 22
afforded 7 as a pale yellow oil (11.65 g, 66%): IR (neat, cm-1
)
1
1728, 1472, 1255; H NMR (300 MHz, CDCl3) δ 4.53 (t, J )
4.4 Hz, 2 H), 1.98-1.43 (m, 8 H), 0.90-0.83 (m, 18 H), 0.11-
0.00 (m, 12 H); 13C NMR (75 MHz, CDCl3) δ 211.9, 76.8 (2C),
33.6 (2C), 25.7 (6C), 21.4 (2C), 18.2 (2C), 18.2 (2C), -5.0 (2C),
-5.3 (2C); ES HRMS m/z (M + Na)+ calcd 395.2408, obsd
395.2402.
tr a n s-2-(ter t-Bu t yld im et h ylsilyloxy)-7-h yd r oxym et h -
ylen ecycloh ep ta n e (16). To a flame-dried flask equipped
with a stirring bar and a N2-filled balloon was added a 20%
suspension of the Nysted reagent (4.23 g in THF, 1.9 mmol)
together with 3.5 mL of THF. The suspension was cooled to 0
°C, and neat titanium tetrachloride (0.21 mL, 1.9 mmol) was
introduced dropwise followed by a solution of 15 (0.32 g, 1.24
mmol) in THF (2.4 mL). The mixture was stirred at rt for 24
h, quenched with 10% HCl (100 mL), and transferred to a
separatory funnel. The product was extracted into ether (3 ×
100 mL), and the combined organic phases were dried and
concentrated to leave a residue that was chromatographed on
silica gel (elution with 10:1 hexane/ethyl acetate) to give 74
mg (31%) of 16 as a colorless oil: IR (neat, cm-1) 3400, 1472,
1
1255; H NMR (300 MHz, CDCl3) δ 5.16 (d, J ) 5.9 Hz, 2 H),
4.49-4.44 (m, 2 H), 2.18-2.15 (m, 1 H), 1.91-1.86 (m, 1 H),
1.73-1.30 (series of m, 6 H), 0.92 (s, 9 H), 0.09 (s, 3 H), 0.07
(s, 3 H); 13C NMR (75 MHz, CDCl3) δ 156.9, 111.8, 73.2, 72.4,
39.5, 36.7, 26.2 (3C), 25.3, 24.1, 18.5, -4.3, -4.5; ES HRMS
m/z (M + Na)+ calcd 279.1750, obsd 279.1757.
mg (26%) of 22 as white needles: mp 81-83 °C; IR (neat, cm-1
)
3406, 1715, 1458; 1H NMR (300 MHz, CDCl3) δ 5.83-5.68 (m,
2 H), 4.89 (dd, J ) 8.9, 8.9 Hz, 1 H), 4.56-4.50 (m, 1 H), 3.40-
3.29 (m, 1 H), 2.81-2.64 (m, 1 H), 2.40-2.31 (m, 2 H), 2.01-
1.80 (m, 3 H); 13C NMR (75 MHz, CDCl3) δ 215.0, 132.1, 128.9,
77.8, 76.0, 33.1, 29.4, 20.0; ES HRMS m/z (M + Na)+ calcd
179.0679, obsd 179.0688.
3-(ter t-Bu tyld im eth ylsilyloxy)-2-(m eth ylen e)cycloh ep -
ta n on e (17). A solution of 16 (74 mg, 0.29 mmol) and IBX (97
mg, 0.35 mmol) in an 8:1 mixture of THF and DMSO (1.6 mL)
was stirred at rt for 12 h, quenched with saturated NaHCO3
solution, and extracted with ether (3 × 30 mL). The combined
organic phases were dried and concentrated to leave a residue
that was chromatographed on silica gel (elution with 20:1
hexane/ethyl acetate) to provide 61 mg (82%) of 17 as a
tr a n s-2-(ter t-Bu tyld im eth ylsilyloxy)-8-h yd r oxycyclo-
octa n on e (26). A solution of 25 (1.0 g, 7.0 mmol), imidazole
(720 mg, 10.6 mmol), and DMAP (86 mg, 0.70 mmol) in CH2Cl2
(38 mL) was treated with tert-butyldimethylchlorosilane (1.59
g, 10.6 mmol) in one portion, heated at reflux, and stirred for
24 h. After cooling, saturated NaHCO3 solution was introduced
and the product was extracted into CH2Cl2 (3×). The combined
organic phases were dried and concentrated to leave a residue
that was chromatographed on silica gel. Elution with 10:1
hexane/ethyl acetate furnished the siloxy ketone as a colorless
1
colorless oil: IR (neat, cm-1) 1693, 1472, 1253; H NMR (300
MHz, CDCl3) δ 5.95 (d, J ) 1.9 Hz, 1 H), 5.38 (s, 1 H), 4.62 (d,
J ) 7.0 Hz, 1 H), 2.81-2.75 (m, 1 H), 2.58-2.53 (m, 1 H), 2.09-
1.29 (series of m, 6 H), 0.92 (s, 9 H), 0.09 (s, 3 H), 0.04 (s, 3
H); 13C NMR (75 MHz, CDCl3) δ 203.8, 152.2, 121.7, 73.8, 43.8,
38.9, 26.1 (3C), 25.4, 24.7, 18.5, -4.5, -4.7; ES HRMS m/z (M
+ Na)+ calcd 277.1594, obsd 277.1594.
cis-2-(ter t-Bu t yld im et h ylsilyloxy)-7-h yd r oxym et h yl-
en ecycloh ep ta n e (18). A solution of 17 (61 mg, 0.24 mmol)
and cerium trichloride heptahydrate (89 mg, 0.24 mmol) in
methanol (1.1 mL) was cooled to 0 °C and treated with sodium
borohydride (9.0 mg, 0.24 mmol) in one portion. The reaction
mixture was stirred for 10 min, allowed to warm to rt,
quenched with saturated NaHCO3 solution, and extracted with
ether (3 × 20 mL). The combined organic phases were dried
1
oil (1.63 g, 86%): IR (neat, cm-1) 1706, 1464, 1254; H NMR
(300 MHz, CDCl3) δ 4.19-4.18 (m, 1 H), 2.76-2.67 (m, 1 H),
2.24-1.51 (series of m, 11 H), 0.90 (s, 9 H), 0.05 (s, 3 H), 0.04
(s, 3 H); 13C NMR (75 MHz, CDCl3) δ 218.2, 78.1, 45.1, 39.2,
35.4, 27.2, 25.7 (3C), 25.2, 25.1, 20.8, 18.1, -5.0, -5.1; ES
HRMS m/z (M + Na)+ calcd 279.1750, obsd 279.1753.
A 0.91 g (3.6 mmol) sample of the above material was
dissolved in THF (25 mL), cooled to -78 °C, treated with a
solution of lithium hexamethyldisilazide in THF (4.26 mL of
1 M, 4.26 mmol), and stirred for 1 h in the cold. Chlorotri-
methylsilane (0.75 g, 5.0 mmol) was introduced, and the
reaction mixture was stirred at -78 °C for 1 h prior to warming
to rt, quenching with saturated NaHCO3 solution, and extrac-
tion with ether (3 × 50 mL). The combined organic phases were
dried and concentrated in advance of chromatographic puri-
fication of the residue on silica gel. Elution with 10:1 hexane/
ethyl acetate gave 26 as a colorless oil (56 mg, 60%): IR (neat,
cm-1) 3489, 1702, 1471; 1H NMR (300 MHz, CDCl3) δ 4.51 (dd,
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Commun. 1989 19, 2773. (c) Larson, G. L.; Prieto, J . A.; Hernandez,
A. Tetrahedron Lett. 1981, 22, 1575.
2458 J . Org. Chem., Vol. 69, No. 7, 2004

Stereoisomeric Medium-Ring R,R′-Dihydroxy Cycloalkanones
J ) 5.2, 2.3 Hz, 1 H), 4.48 (dd, J ) 5.8, 2.2 Hz, 1 H), 3.59 (s,
1 H), 2.96-2.90 (m, 1 H), 2.01-1.34 (series of m, 9 H), 0.95 (s,
9 H), 0.10 (s, 3 H), 0.07 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ
219.6, 77.7, 74.6, 39.4, 27.6, 26.0 (3C), 24.8, 21.9, 19.1, 18.3,
-4.4, -4.9; ES HRMS m/z (M + Na)+ calcd 295.1699, obsd
295.1682.
(2.25 mL) was stirred at rt for 12 h and quenched with
saturated NaHCO3 solution. The aqueous layer was extracted
with ether (3 × 50 mL), and the combined organic phases were
dried and purified.
Chromatography of the residue on silica gel (elution with
10:1 hexane/ethyl acetate) gave 33 as a colorless oil (46 mg,
1
92%): IR (neat, cm-1) 1707, 1464, 1253; H NMR (300 MHz,
3-Ben zyloxy-1,2-cycloocta n ed ion e (29). A solution of 28
(500 mg, 2.0 mmol) in dry CH2Cl2 (10 mL) was added to a
stirred suspension of the Dess-Martin periodinane (1.27 g,
3.0 mmol) in 30 mL of the same solvent. The reaction mixture
was stirred at rt for 2 h and quenched with water. The
separated aqueous phase was extracted with CH2Cl2 (3×), and
the combined organic solutions were washed with brine, dried,
and evaporated. The residue was chromatographed on silica
gel (elution with 10% ethyl acetate in hexane) to yield 490 mg
CDCl3) δ 4.66 (dd, J ) 8.8, 4.9 Hz, 1 H), 2.94-2.80 (m, 1 H),
2.40-2.34 (m, 1 H), 2.09-1.41 (series of m, 8 H), 0.94 (s, 9 H),
0.15 (s, 3 H), 0.08 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 210.6,
208.5, 75.9, 40.0, 31.9, 27.3, 26.1 (3C), 21.2, 20.3, 18.7, -4.4,
-5.0; ES HRMS m/z (M + Na)+ calcd 293.1543, obsd 293.1532.
B. With th e Dess-Ma r tin P er iod in a n e. A solution of 26
(50 mg, 1.82 mmol) and the Dess-Martin periodinane (924
mg, 2.18 mmol) in 8:1 THF/DMSO (2.25 mL) was stirred at rt
for 4 h, quenched with saturated NaHCO3 solution, and
extracted with ether (3 × 50 mL). The combined organic phases
were dried and concentrated, and the residue was chromato-
graphed on silica gel (elution with 10:1 hexane/ethyl acetate)
to give 33 as a colorless oil (47 mg, 90%), identical in all
respects with the material prepared above.
(99%) of 29 as a yellow solid: mp 46-48 °C; IR (neat, cm-1
)
1704, 1464, 1454; 1H NMR (300 MHz, CDCl3) δ 7.39-7.27 (m,
5 H), 4.77 (d, J ) 11.6 Hz, 1 H), 4.43 (d, J ) 11.6 Hz, 1 H),
4.39-4.35 (m, 1 H), 2.88 (ddd, J ) 19.5, 11.7, 3.8 Hz, 1 H),
2.37 (ddd, J ) 19.1, 13.5, 3.3 Hz, 1 H), 2.12-2.03 (m, 1 H),
2.02-1.71 (m, 4 H), 1.66-1.57 (m, 2 H), 1.49-1.35 (m, 1 H);
13C NMR (75 MHz, CDCl3) δ 209.5, 207.7, 137.4, 128.5 (2C),
128.0, 127.9 (2C), 81.2, 72.3, 39.0, 29.0, 27.4, 20.6, 19.9; ES
HRMS m/z (M + Na)+ calcd 269.1148, obsd 269.1138.
Red u ction of 33. A. With Zin c a n d Sa tu r a ted Am -
m on iu m Ch lor id e. A solution of 33 (70 mg, 0.29 mmol) in
THF (0.7 mL) containing ammonium chloride (0.7 mg) was
treated with zinc dust (36 mg, 0.57 mmol) in one portion. The
reaction mixture was stirred for 2 h, quenched with saturated
NaHCO3 solution, and extracted with ether (3 × 50 mL). The
combined organic phases were dried, concentrated, and sub-
jected to chromatograpy on silica gel. Elution with 20:1
hexanes/ethyl acetate furnished 42 mg (60%) of 35 as a
yellowish oil: IR (neat, cm-1) 3487, 1702, 1472; 1H NMR (300
MHz, CDCl3) δ 4.35 (d, J ) 2.9 Hz, 1 H), 4.30 (dt, J ) 9.2, 3.1
Hz, 1 H), 2.59-2.51 (m, 2 H), 2.01-1.89 (series of m, 5 H),
0.94 (s, 9 H), 0.15 (s, 3 H), 0.12 (s, 3 H); 13C NMR (75 MHz,
CDCl3) δ 213.0, 79.5, 73.9, 40.1, 31.2, 27.9 (3C), 24.4, 20.5, 18.5,
-4.3, -4.4; ES HRMS m/z (M + Na)+ calcd 295.1699, obsd
295.1713.
cis-3-Ben zyloxy-2-h yd r oxycycloocta n on e (30). A solu-
tion of 29 (50 mg, 0.20 mmol) in 1 mL of a 1:1 mixture of
saturated NH4Cl and THF was treated with zinc dust (26 mg,
0.4 mmol), stirred vigorously at rt for 2 h, and diluted with
CH2Cl2 and water. The separated aqueous layer was extracted
with CH2Cl2, and the combined organic phases were dried and
concentrated. Purification of the residue by chromatography
on silica gel (elution with 10% ethyl acetate in hexane)
furnished 30 mg (60%) of 30 as a colorless oil: IR (neat, cm-1
)
3466, 1703, 1465; 1H NMR (300 MHz, CDCl3) δ 7.39-7.27 (m,
5 H), 4.65 (s, 2 H), 4.45 (d, J ) 2.5 Hz, 1 H), 4.09 (ddd, J )
13.2, 6.6, 2.8 Hz,1 H), 3.55 (br s, 1 H), 2.50-2.45 (m, 2 H),
2.00-1.83 (m, 3 H), 1.80-1.49 (m, 3 H), 1.43-1.30 (m, 1 H),
1.16-1.02 (m, 1 H); 13C NMR (75 MHz, CDCl3) δ 213.0, 138.2,
128.4 (2C), 127.73, 127.68 (2C), 77.7, 77.6, 71.0, 38.6, 27.9, 26.9,
26.6, 21.6; ES HRMS m/z (M + Na)+ calcd 271.1305, obsd
271.1303.
Desilyla tion of 34. To a solution of 34 (10 mg, 0.037 mmol)
in THF (1 mL) was added 30 µL (0.039 mmol) of 1 M TBAF in
the same solvent. After 15 min at rt, the reaction mixture was
concentrated in vacuo, and the residue was chromatographed
on silica gel. Elution with 50% hexane in ethyl acetate afforded
2.8 mg (48%) of 36 and 1.4 mg (24%) of 31, both as colorless
oils.
cis-2,3-Dih yd r oxycycloocta n on e (31). A solution of 30
(10 mg, 0.04 mmol) in ethanol (1.5 mL) was admixed with 10%
palladium on carbon (5 mg), and the mixture was stirred for
2 h under 1 atm of hydrogen. The predescribed workup
For 36: white solid; mp 120-121 °C; IR (neat, cm-1) 3693,
afforded 6 mg (99%) of 31 as a colorless oil: IR (neat, cm-1
)
1
3398, 1702, 1059; 1H NMR (300 MHz, CDCl3) δ 4.49-4.39 (m,
1 H), 4.44 (d, J ) 3.5 Hz, 1 H), 2.67 (ddd, J ) 14.3, 10.7, 3.6
Hz, 1 H), 2.50-2.46 (m, 1 H), 2.00-1.68 (series of m, 6 H),
1.50-1.41 (m, 1 H), 1.03-0.96 (m, 1 H); 13C NMR (75 MHz,
CDCl3) δ 213.1, 79.6, 70.9, 38.6, 31.6, 28.1, 26.5, 22.6; ES
HRMS m/z (M + Na)+ calcd 181.0835, obsd 181.0839.
1705, 1246; H NMR (300 MHz, CDCl3) δ 4.41 (dd, J ) 7.7,
3.7 Hz, 2 H), 3.26 (s, 2 H), 2.33-2.27 (m, 2 H), 1.97-1.90 (m,
2 H), 1.84-1.66 (m, 4 H), 1.48-1.40 (m, 2 H); 13C NMR (75
MHz, CDCl3) δ 218.2, 74.1 (2C), 33.4 (2C), 24.6, 21.9 (2C); ES
HRMS m/z (M + Na)+ calcd 181.0835, obsd 181.0829.
Nysted Hom ologa tion of 26. Into a flame-dried flask
equipped with a stirring bar and a N2-filled balloon was placed
a 20% suspension of the Nysted reagent in THF (14.7 g, 6.45
mmol) and additional THF (12 mL). The suspension was cooled
to 0 °C, and neat titanium tetrachloride (0.71 mL, 6.45 mmol)
was introduced dropwise followed by the addition of 26 (1.17
g, 4.3 mmol) dissolved in THF (8 mL). The reaction mixture
was stirred at rt for 24 h, quenched with 10% HCl (100 mL),
transferred to an addition funnel, and extracted with ether (3
× 100 mL). The combined organic layers were dried and
evaporated to leave a residue that was purified by chroma-
tography on silica gel. Elution with 20:1 hexane/ethyl acetate
gave 48 mg (42%) of 37 and 157 mg (14%) of 38, both as
colorless oils.
Bor oh yd r id e Red u ction of 31. A solution of 31 (2.6 mg,
0.015 mmol) in methanol (0.5 mL) was cooled to 0 °C, treated
with sodium borohydride (0.2 mg, 0.015 mmol), and stirred
for 10 min prior to being quenched with saturated NaHCO3
solution. The separated aqueous layer was extracted with
ether (3 × 15 mL), and the combined organic phases were dried
and concentrated. Chromatographic purification of the residue
on silica gel (elution with 50% hexane/ethyl acetate) gave an
inseparable 1:1 mixture of 24 and 32 as recognized by high-
field 1H NMR analysis.
Pure triol 32 was independently prepared by comparable
reduction of 34 followed by desilylation: white solid; mp 84-
1
85 °C; IR (neat, cm-1) 3614, 1477, 1236; H NMR (300 MHz,
For 37: IR (neat, cm-1) 3581, 1462, 1253; 1H NMR (300
MHz, CDCl3) δ 5.18 (s, 1 H), 5.18 (d, J ) 0.6 Hz, 1 H), 4.48
(dd, J ) 9.2, 4.7 Hz, 1 H), 4.27 (dd, J ) 8.4, 4. Hz, 1 H), 2.04-
1.99 (m,1 H), 1.83-1.38 (m, 9 H), 0.91 (s, 9 H), 0.08 (s, 3 H),
0.05 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 157.0, 113.5, 73.6,
71.7, 36.8, 35.3, 26.2 (3C), 26.1, 22.4, 21.7, 18.4, -4.2, -4.4;
ES HRMS m/z (M + Na)+ calcd 293.1907, obsd 293.1901.
CDCl3) δ 4.03-3.99 (m, 2 H), 3.96 (d, J ) 2.5 Hz, 1 H), 2.37 (s,
OH), 2.10-2.04 (m, 2 H), 1.92-1.80 (m, 4 H), 1.71-1.34 (m, 4
H); 13C NMR (75 MHz, CDCl3) δ 77.6, 76.1 (2C), 32.6 (2C),
29.1, 22.9 (2C); ES HRMS m/z (M + Na)+ calcd 183.0991, obsd
183.0993.
Oxid a tion of 26. A. With IBX. A solution of 26 (50.0 mg,
1.82 mmol) and IBX (608 mg, 2.18 mmol) in 8:1 THF/DMSO
J . Org. Chem, Vol. 69, No. 7, 2004 2459

Paquette et al.
For 38: IR (neat, cm-1) 3581, 1462, 1253; 1H NMR (300
MHz, CDCl3) δ 5.24 (s, 1 H), 5.09 (s, 1 H), 3.98 (d, J ) 8.4 Hz,
1 H), 3.61 (dt, J ) 9.0, 3.3 Hz, 1 H), 2.41-2.29 (m, 2 H), 1.84-
1.50 (m, 8 H), 0.96 (s, 9 H), 0.18 (s, 3 H), 0.16 (s, 3 H); 13C
NMR (75 MHz, CDCl3) δ 149.4, 114.8, 79.1, 78.2, 34.3, 32.8,
27.3, 26.1 (3C), 26.1, 22.8, 18.4, -3.6, -4.2; ES HRMS m/z (M
+ Na)+ calcd 293.1907, obsd 293.1902.
Lu ch e Red u ction of 40. A solution of 40 (30 mg, 0.11
mmol) in methanol (0.5 mL) containing cerium trichloride
heptahydrate (42 mg, 0.11 mmol) was cooled to 0 °C, treated
with sodium borohydride (4.3 mg, 0.11 mmol), and after 5 min
quenched with water (30 mL). The products were extracted
into ether (3 × 30 mL), and the combined organic phases were
dried and concentrated. Chromatography of the residue on
silica gel (elution with 10:1 hexane/ethyl acetate) furnished
11 mg (37%) of 38 and 18 mg (60%) of 41, both as colorless
oils.
and the residue was purified by chromatography on silica gel
(elution with 10:1 hexane/ethyl acetate) to provide 9.5 mg
(100%) of 35.
Desilyla tion of 35. A solution of 35 (70.7 mg, 0.26 mmol)
in dry THF (3 mL) was treated with a 1 M solution of TBAF
in THF (312 µL, 0.312 mmol), stirred for 30 min, and worked
up in the usual manner to give 38 mg (93%) of 31 as a white
solid, identical to the substance isolated earlier.
cis-2-(ter t-Bu t yld im et h ylsilyloxy)-8-h yd r oxym et h yl-
en ecycloocta n e (42). A solution of 39 (85 mg, 0.32 mmol)
and cerium trichloride heptahydrate (119 mg, 0.32 mmol) in
methanol (1.4 mL) was cooled to 0 °C, at which point sodium
borohydride (12 mg, 0.32 mmol) was introduced in one portion.
The reaction mixture was stirred for 10 min, allowed to warm
to rt, and worked up in the predescribed manner. Chroma-
tography on silica gel (elution with 10:1 hexane/ethyl acetate)
gave 79 mg (93%) of 42 as a colorless oil: IR (neat, cm-1) 3395,
For 41: IR (neat, cm-1) 3581, 1462, 1253; 1H NMR (300
MHz, CDCl3) δ 5.24 (s, 1 H), 5.09 (s, 1 H), 3.98 (d, J ) 8.4 Hz,
1 H), 3.61 (dt, J ) 9.0, 3.3 Hz, 1 H), 2.41-2.29 (m, 2 H), 1.84-
1.50 (m, 8 H), 0.96 (s, 9 H), 0.18 (s, 3 H), 0.16 (s, 3 H); 13C
NMR (75 MHz, CDCl3) δ 149.4, 114.8, 79.1, 78.2, 34.3, 32.8,
27.3, 26.1 (3C), 26.1, 22.8, 18.4, -3.6, -4.2; ES HRMS m/z (M
+ Na)+ calcd 293.1907, obsd 293.1902.
1
1461, 1253; H NMR (300 MHz, CDCl3) δ 5.15 (s, 2 H), 4.36
(dd, J ) 8.5, 5.7 Hz, 1 H), 4.28 (dd, J ) 9.2, 4.5 Hz, 1 H), 2.07-
1.27 (series of m, 10 H), 0.93 (s, 9 H), 0.11 (s, 3 H), 0.10 (s, 3
H); 13C NMR (75 MHz, CDCl3) δ 152.7, 114.5, 77.0, 75.6, 36.9,
35.5, 27.4, 26.2 (3C), 22.4, 22.3, 18.4, -4.4, -4.5; ES HRMS
m/z (M + Na)+ calcd 293.1907, obsd 293.1901.
cis-(3-t er t -Bu t yld im e t h ylsilyloxy)-2-h yd r oxycyclo-
octa n on e (35). A solution of 42 (9.5 mg, 0.035 mmol) in
CH2Cl2 (3 mL) was cooled to -78 °C and ozonolyzed until a
faint blue color persisted. Oxygen was bubbled through the
system until the solution became clear, at which point tri-
phenylphosphine (11 mg, 0.042 mmol) was introduced. After
being warmed to rt, the reaction mixture was concentrated
Su p p or tin g In for m a tion Ava ila ble: Select experimental
1
details and copies of the high-field H and 13C NMR spectra of
all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O0358675
2460 J . Org. Chem., Vol. 69, No. 7, 2004