Baeyer-Villiger oxidation of the bicyclo[2.2.2]octanone system revisited: Searching for a modular construction of heavily substituted cyclohexanes based on m-CPBA mediated selective oxygen insertion

Article abstract of DOI:10.1002/ejoc.200700321

Described herein is the use of Baeyer-Villiger oxidation for the selective insertion of oxygen into a variously substituted bicyclo[2.2.2]octanone system, synthesized by a consecutive domino process. By using the appropriate sequence of steps and starting

Full text of DOI:10.1002/ejoc.200700321

FULL PAPER
DOI: 10.1002/ejoc.200700321
Baeyer–Villiger Oxidation of the Bicyclo[2.2.2]octanone System Revisited:
Searching for a Modular Construction of Heavily Substituted Cyclohexanes
Based on m-CPBA Mediated Selective Oxygen Insertion
Laure Finet,[a] Mohamed Dakir,[a] Isabel Castellote,[a] and Siméon Arseniyadis*[a]
Keywords: Domino reactions/ Baeyer–Villiger oxidation / Quaternary centers / Configuration reversal / Ring-system inter-
change
Described herein is the use of Baeyer–Villiger oxidation for
the selective insertion of oxygen into a variously substituted
bicyclo[2.2.2]octanone system, synthesized by a consecutive
domino process. By using the appropriate sequence of steps
and starting from common intermediate 2a, six-membered
ring systems with appropriate substituents that could serve
as surrogates for several functionalities could be accessed.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
Introduction
Recently, a new class of domino transformations[1] was
developed in our laboratories through the reaction of bicy-
clic unsaturated diols, such as 1a derived from the Hajos–
Parrish ketone,[2] with two oxidants (the ecofriendly ver-
sion) and one base, in a consecutive way.[3] The two oxi-
dants promote the cleavage and ring expansion whereas the
base added at the end of the sequence provides the ring
system interchange, which leads to high isolated yields of
bicyclic[2.2.2]aldol 2a (Scheme 1). We sought to take advan-
tage of this rapid increase in the molecular complexity in
the construction of stereodefined six-membered rings. A
preliminary study was thus performed to determine the re-
giochemistry of the Baeyer–Villiger reaction[4] by varying
only one parameter (free or TBS-protected C2-hydroxy
group). This established that when 2a was treated with m-
CPBA in CH2Cl2,[5] product 3 with a migrated bridgehead
(electronic control) was isolated as the major bicyclic lac-
tone (through a spontaneous translactonization process)
along with methylene migrated (steric control) minor bicy-
clic lactone 4a (3/4a 17:1 ratio). Upon TBS protection of
the free hydroxy group to give 2b and followed by oxi-
dation, the formation of methylene migration product 4b
became competitive with the bridgehead migration product
(2.3:1 ratio, respectively); the yield decreased as large
amounts of starting material were recovered intact.[6]
Scheme 1.
Reversal of the relative configuration of a quaternary
center (C4) was achieved through a three-reaction sequence;
domino transformation of 1a, followed by m-CPBA medi-
ated Baeyer–Villiger oxidation of 2a, and subsequent re-
ductive lactone ring opening to yield 1,2,4,5-tetrasubsti-
tuted cyclohexane derivative 5 by C1–C7 bond cleavage
(Scheme 2). More recently, heavily functionalized ste-
reopure cyclic systems, which could be used as tridentate
ligands 6 (path “RM”)[7] or as precursors to the taxoid C-
ring 7a[8] (C1–C2 bond cleavage, MOM = methoxymethyl),
were prepared efficiently from a close derivative: conve-
niently elaborated bicyclic framework I.
These results led us to investigate whether the regio-
chemical outcome could be programmed by performing the
Baeyer–Villiger oxidation under conditions favoring any
one of the possible openings, as portrayed in Scheme 2.
Thus, breaking of the C7–C8 and C1–C7 bonds would en-
able inversion at the quaternary center, affording com-
pounds of type 5 and 8 whereas breaking of C1–C2 would
enable retention at the quaternary center, affording com-
pounds of type 7. Finally, a C4–C5 type opening through
tricyclic orthoester 9 could be viewed as a versatile synthesis
of stereopure 1,2,3,4,5-substituted cyclohexane frameworks
[a] Institut de Chimie des Substances Naturelles, CNRS
Avenue de la Terrasse 91198 Gif-sur Yvette, (France)
Fax: +33-1-69-82-30-29
E-mail: simeon.arseniyadis@icsn.cnrs-gif.fr
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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Baeyer–Villiger Oxidation of the Bicyclo[2.2.2]octanone System Revisited
FULL PAPER
90% overall yield. Protection of 2a by treatment with tert-
butyldimethylsilyl chloride (TBSCl, imidazole, DMF, 0 °C)
followed by silyl enol ether formation (TMSOTf, collidine,
CH2Cl2, 0 °C, 2 h) and treatment of the latter with NBS
(THF, 0 °C) afforded 2c as a single diastereomer (stereo-
chemistry as depicted in Scheme 3). On the other hand, the
cation-stabilizing effect of the lone pair of electrons on oxy-
gen would increase the relative migratory aptitude of the
attached carbon.[10] To verify this hypothesis, acyloins 12–
16 were synthesized according to our previous work. Start-
ing from known 15a, its free hydroxy derivative 16 was pre-
pared by desilylation with tetra-n-butylammonium fluoride
(TBAF, THF, 0 °C, 90%).
Scheme 2. Routes for practical syntheses of stereopure six-mem-
bered ring subunits by applying suitable reaction sequences to con-
veniently functionalized domino product I.
offering regio-, chemo-, and stereoselectivity in further syn-
theses. Before this methodology could be applied to natural
product synthesis, additional studies were needed to probe
the regio aspects of the Baeyer–Villiger oxidation of bridged
bicyclic aldols of type I, which could afford lactones with
reasonable control of bridgehead over methylene migration.
Opening of the lactones would in turn allow access to con-
figuration reversal/retention at C4. Accordingly, the pur-
pose of this work is to put forward routes that allow con-
struction of cyclohexane building blocks by using Baeyer–
Villiger oxidation and subsequent lactone ring opening,
starting from easily available bicyclic framework I (R = OH,
OAc, OTMS, Br; R1 = H, Ts, Ac, TBS, Scheme 2). We re-
port in this paper the syntheses of selected bicyclic[2.2.2]-
octane frameworks derived from bicyclic aldol 2a and their
reactivity pattern.
Scheme 3. (a) p-TsCl, py, DMAP, 0 °C to 25 °C; (b) Ac2O, py, DMAP,
0 °C, 1 h 30 min; (c) TBSCl, DMF/imidazole, 0 °C to 25 °C, 16 h;
(d) (i) TMSOTf, collidine, PhMe, 25 °C; (ii) NBS, THF, 0 °C; (e)
TMS/imidazole, CH2Cl2, 0 °C; (f) TBAF, THF, 0 °C.
Required orthoester 20 was readily prepared by Dess–
Martin oxidation of known alcohol 19 (Scheme 4). The
one-pot synthesis of 17b, obtained along with its α-OH epi-
mer 17c from 1b (71% combined isolated yield, 4:1 ratio,[11]
respectively) was identical with our published synthesis of
bicyclic aldol 2a, save that the tBu protecting group was
substituted with TBS (Scheme 4).
Results and Discussion
Preparation of the Substrates
The required bicyclic aldol frameworks for this process
were readily prepared by functional group interconversion
of known compounds 2a, 12, 15, and 19 that were synthe-
sized in our previous work by using consecutive domino
reactions as a key step of the sequence along with the atypi-
cal ozonolysis for the introduction of the oxygen function-
ality α to the ketone.[3,7,8] The problem of competitive mi-
gratory aptitudes could be reduced to the simple task of
preparing α-halogen or α-hydroxy ketones starting from key
intermediate 2a. Furthermore, as syn or anti-C8 substitu-
ents in bicyclo octanones could dictate the migration of the
methylene unit in preference to the bridgehead carbon, we
planned to use a bulky protecting group at C2 and oxo-
substitution at C8 to divert the reaction course in a more
elaborate fashion. The directing effect of the substituent α
to the carbonyl group was first targeted in an attempt to
Scheme 4. (a) Dess–Martin periodinane, CH2Cl2, py, 25 °C, 0.5 h;
(b) TBSCl, DMF/imidazole, 0 °C to 25 °C, 16 h; (c) 2.4 equiv.
Pb(OAc)4, PhMe then K2CO3/MeOH, H2O, 25 °C.
The Influence of Substituents on the Regiocontrol of
Oxygen Insertion
With the required substrates in hand, inspection of the
see whether the Baeyer–Villiger reaction of an α-bromo regiochemical outcome for oxygen insertion was carried
ketone[9] would permit regiospecific ring opening. To this out. To this end, the bicyclic aldols thus obtained were con-
end, conversion of bicyclic aldol 2a to its α-halogenated de- verted into their corresponding lactones by exposure to
rivative 2c was accomplished by a three-step sequence in Baeyer–Villiger oxidation, carried out with an excess
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FULL PAPER
amount of m-chloroperbenzoic acid (m-CPBA) in sodium offer very poor selectivity, showing very little preference for
hydrogencarbonate buffered dichloromethane, at room tem- methylene migration. Indeed, the presence or the absence
perature. To have a better comparison of the results we of the bulky protecting group in 18a and 17a, respectively,
chose to stay with the same peracid rather than complicat- do not change the reaction outcome (hydrogen bonding
ing comparisons by using various oxidants.[12] In every case with the free α-hydroxy group being unlikely). We did not
investigated, the regiochemistry of the Baeyer–Villiger reac- detect a similar regioreversal as in 2b versus 2a during the
tion was unambiguously confirmed by long-range hetero- oxidation of tert-butyldimethylsilyl protected bicyclic aldol
nuclear couplings observed in the HMBC spectra. Ratios 18a (α-OTBS), derived from corresponding alcohol 17a (α-
of the bridgehead- to methylene-migrated lactones were de- OH). When the latter, possessing a free α-hydroxy group at
termined by SiO2 separation and, where possible, by com- C2, was subjected to Baeyer–Villiger oxidation (4 h), lac-
parison of the integrated areas for the methylene protons tone 26 was produced accompanied by its regioisomer 27,
adjacent to the carbonyl group in the bridgehead-migrated in 88% isolated yield and 1:1.1 ratio. Subjected to the same
lactones to the oxygen in the methylene-migrated lactones Baeyer–Villiger conditions, 18a afforded a 48% isolated
and the bridgehead protons in both cases. It was anticipated yield of 29 together with 30% of 28 after 15 h of stirring at
that the regiochemistry of the Baeyer–Villiger oxidation of room temperature. In both cases, the major lactone arises
10 and 11 could, in principle, be a function of the inductive from migration of the methylene carbon as opposed to the
effect of the C2 substituent (OAc, OTs) rather than a steric carbon at the bridgehead position. Thus, upon protection
effect as for 2b. The m-CPBA oxidation of tosylate 10 and of the free β-hydroxy group of 2a, a 2.3:1 preference for
acetate 11 required long reaction times (4 d) for lactone for- methylene migration was observed; the sense of bridgehead
mation and furnished significantly lower yields of the versus methylene migration remained unchanged with re-
bridgehead- and methylene-migrated products as insepa- gard to the migration preference although the ratio slightly
rable mixtures. Thus, 10 afforded 22 and 23 in 24% com- increased in favor of methylene migration for the Baeyer–
bined yield (93% based on recovery of starting material) Villiger oxidation of 18a (28/29, 1:1.6).
and 1:1.5 ratio, whereas 11 gave 24 and 25 in 37% com-
A change in the protecting group at C5, tert-butyldi-
bined yield (91% based on recovery of starting material) methylsilyl (TBS) instead of tBu, did not have a significant
and 1:1 ratio (Scheme 5).
influence in controlling the outcome of the Baeyer–Villiger
reaction, since a 12:1 ratio of bridgehead versus methylene
migration was obtained, whereas yields remained modest
(slightly above 50% isolated yield). Thus, 17b gave mainly
lactone 30 (49%) resulting from bridgehead migration and
subsequent translactonization on treatment with m-CPBA,
but 4% of an isomer, lactone 31, was also detected though
not isolated pure. Our next experiment focused on the
course of the Baeyer–Villiger oxidation of acyloin 15m (C8
epimeric mixture), obtained from known 12m by acety-
lation.[7] Thus, upon treatment of 15m with m-CPBA (15 h,
25 °C), a single product, 21m, was obtained in over 75%
yield. This material was subjected to lactone ring opening
(K2CO3, MeOH, room temp. 1.5 h) and subsequent esterifi-
cation (TMSCHN2, Et2O, MeOH, 0 °C, 93% two steps)
and compared with the oxidative fission of 12m [Pb(OAc)4,
toluene/methanol, 0 °C, 90% isolated yield]; both afforded
cleanly aldehyde ester 8 (Scheme 6).
Scheme 5. Reagents and conditions: 3 equiv. m-CPBA, 1.2 equiv.
NaHCO3, CH2Cl2, 25 °C.
The tendency for methylene group migration is increased
(relative to 2a)[13] on introducing an electron-withdrawing
group at C2, although the latter may not be solely responsi-
ble for the regioselectivity observed. The electron demand
of the group at this position is obviously transmitted to C1,
which is then less able to support a build-up of positive
charge as required for the migrating group in the rearrange-
ment step, yet the roles played by electronic and steric fac-
Scheme 6. (a) Ac2O, py, DMAP, 0 °C, 1 h 30 min; (b) m-CPBA,
NaHCO3, CH2Cl2, 25 °C; (c) K2CO3, MeOH, 25 °C 1 h 30 min;
(d) TMSCHN2, Et2O, MeOH, 0 °C; (e) Pb(OAc)4, toluene, MeOH,
tors remain unclear. Substrates with a free α-hydroxy group 0 °C.
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Baeyer–Villiger Oxidation of the Bicyclo[2.2.2]octanone System Revisited
FULL PAPER
This result establishes firmly the course of the reaction
On the other hand, Baeyer–Villiger oxidation of 15b pro-
to be oxygen insertion α to acetoxy substituent, which has ceeded with exclusive migration of the acetoxy-substituted
taken precedence over the migration of a tertiary group carbon to afford lactone 21b (2 h, 95% isolated yield, single
(bridgehead migration). The reaction of acetoxy–acyloin product) as depicted in Scheme 8. An acetoxy group at C8
15m, although performed on an epimeric mixture, appears placed syn to the OtBu group appears to have an unusually
to have potential utility since oxygen insertion is regioselec- large rate-retarding effect. Thus, the Baeyer–Villiger reac-
tive. By investigating migration preferences, parallel studies tion of 15a was much slower (25 h) and gave lactone 21a
to those just detailed on 12m (epimeric mixture) were next along with unreacted starting material (56% isolated yield,
performed to examine the migrating preferences of stereod- 83% based on recovered starting material). Accordingly, in-
efined acyloins 12–16, with the aim of ultimately ensuring sofar as migrating preferences are concerned, it is apparent
their conversion to heavily substituted cyclohexanes that both 15a and 15b behave in a manner completely anal-
(Schemes 7 and 8). Bicyclic framework 12, which was ob- ogous to 15m in their reaction with m-CPBA. Both bicyclic
tained as the major isomer following atypical ozonolysis frameworks gave single lactones 21a and 21b, respectively,
was treated with m-CBPA (1.5 h) to afford a 79% combined derived from Baeyer–Villiger oxidation involving exclusive
yield of 32 and 33, both arising from cleavage, in a 1.7:1 migration of the oxygenated carbon. However, there is a
ratio, respectively. Esterification (TMSCHN2 Et2O, MeOH, noteworthy rate- and yield-lowering effect on 15a, indicat-
0 °C, 93%) of 32 gave 8 and similarly 33 gave 34 (Scheme 7). ing that the reaction course is affected by the configuration
In a complementary fashion, bis(silyl)-protected acyloin 13 at C8. When bicyclic aldol 16 possessing a free α-hydroxy
(22 h), as well as free acyloin 14 (3.5 h), upon Baeyer– group at C2 along with a syn OtBu acetoxy group at C8
Villiger oxidation afforded three or two products, respec- was subjected to Baeyer–Villiger oxidation, lactone 38 was
tively, but in both cases only the α oxygen bearing atom produced in 87% isolated yield, after 15 h at room tempera-
migrated to oxygen, (32, 33 and 37 being the corresponding ture as the sole reaction product (interestingly, bridgehead
ring-opened derivatives).[14]
migration was totally absent). Lactones 21a, 21b, 35, 36 and
38 were produced uncontaminated by their regioisomer
(Schemes 7 and 8), as confirmed by NMR spectroscopic
analyses.
Two additional substrates, issued from the common bicy-
clic[2.2.2]aldol framework 2a were straightforwardly syn-
thesized from known precursors 19 and 39, orthoester 20
(Scheme 9) and bicyclic aldol 40 (Scheme 10), respectively,
and subjected to Baeyer–Villiger conditions. It was expected
that oxidation of these substrates would proceed with
bridgehead migration and subsequent lactone ring opening
would provide pentasubstituted cyclohexanes with reten-
tion of configuration (relative configuration of the angular
methyl group and OtBu as in 1a) at the quaternary center.
Baeyer–Villiger oxidation of 20 (3 equiv. m-CPBA,
1.2 equiv. NaHCO3, CH2Cl2, 25 °C, 3 d) afforded 9, pro-
ceeding almost exclusively through bridgehead migration in
88% isolated yield along with recovered starting material
(8%), whereas methylene migrated lactone could not be de-
tected (Scheme 9).
Scheme 7. Reagents and conditions: (a) 3 equiv. m-CPBA, 1.2
equiv. NaHCO3, CH2Cl2, 25 °C. (b) TMSCHN2, Et2O, MeOH, 0 °C
to 25 °C.
Scheme 9. (a) 3 equiv. m-CPBA, 1.2 equiv. NaHCO3, CH2Cl2, 25 °C,
3 d.
Efforts to obtain desired[15] bicyclo[3.3.1]nonane 41
along the lines described above were less gratifying owing
to a modest regioselectivity in the Baeyer–Villiger oxidation
(3 equiv. m-CPBA, 1.2 equiv. NaHCO3, CH2Cl2, 25 °C,
20 h) of bicyclic aldol 40. However, methylene migrated iso-
mer comprised a considerably smaller proportion of the
crude product than in the aforementioned cases (Scheme 5).
Resulting lactones 41 (following an in situ translactoni-
Scheme 8. Reagents and conditions: (a) 3 equiv. m-CPBA, 1.2 equiv.
NaHCO3, CH2Cl2, 25 °C.
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L. Finet, M. Dakir, I. Castellote, S. Arseniyadis
FULL PAPER
zation via i, Scheme 10) and 42 (67% combined yield of 41, whereas on those having the C2β-hydroxy group protected,
42 in 4.4:1 ratio) were obtained pure along with recovered methylene migration increased significantly. A tosyloxy or
40 (30%).
acetoxy group on C2 appears to have an unusually large
rate-retarding effect. Regioselectivity was insignificant for
the former, nil for the latter and the yield decreased as large
amounts of starting material were recovered intact. (2) Sub-
strates with a free C2α-hydroxy group offered a poor selec-
tivity, showing very little preference for methylene mi-
gration. (3) The regiochemical outcome was completely re-
versed (whereas it was unbiased to the configuration of the
C8 carbon) with C8 acyloins (I, R = OH, OTMS, OAc)
where only hydroxy-, silyloxy- and acetoxy-substituted car-
bon migrates in preference to the tertiary bridgehead car-
bon.
Given the fact that the lactones thus obtained are readily
amenable to either hydrolytic or reductive opening, this al-
lows easy access to 1, 2, 4, 5- and 1, 2, 3, 4, 5-substituted
stereodefined cyclohexanes. Thus, by using the consecutive
domino reaction discovered in our laboratory, and proceed-
ing as portrayed in Scheme 2, we can target the synthesis of
either type 5 or 8 cyclohexanes (C1–C7 and C7–C8 cleav-
age, respectively) with inversion or those accessible from 7
and 9 (C1–C2 and C4–C5 cleavage, respectively), with re-
tention of configuration at the quaternary center, respec-
tively.
Scheme 10. (a) Dess–Martin periodinane, CH2Cl2, 25 °C; (b) 3 equiv.
m-CPBA, 1.2 equiv. NaHCO3, CH2Cl2, 25 °C, 20 h; (c) TBSCl,
DMF/imidazole, 0 °C to 25 °C, 16 h; (d) K2CO3, MeOH/H2O, 25 °C.
The illustrated configurations at the newly installed ste-
reogenic centers within these products follow from extensive
NMR spectroscopic studies and from an X-ray crystallo-
graphic study on 43 (see Supporting Information), a deriva-
tive of 41. The latter was first silyl-protected at C1 (TBSCl,
DMF/imidazole, 0 to 25 °C, 16 h, 92%) then saponified
(K2CO3, MeOH/H2O, 25 °C) to afford crystalline 43 along
with its translactonized counterpart 7b (90% yield, ca. 1:1),
which is indeed the ultimate target, being a precursor of
heavily functionalized six-membered ring system. We have
experimental evidence that bridged bicyclic lactone 43 is
formed initially but rapidly converts to fused bicyclic lac-
tone 7b by an intramolecular translactonization to give a
sterically less-crowded product (Scheme 9). Pure 43, sub-
jected to the same mild base treatment (K2CO3, MeOH/
H2O, 25 °C) was smoothly converted into 7b. Finally, at-
tempted Baeyer–Villiger oxidations (using an excess
amount of reagent and prolonged reaction times) of 2c
failed, presumably due to the electron withdrawing effect of
the α halogen, which completely suppressed the migration
of the carbon bearing it.[16]
Experimental Section
General Remarks: Commercially available m-CBPA (Aldrich) was
purified by washing with pH 7.4 phosphate buffer and drying un-
der reduced pressure. “Usual workup” means washing of the or-
ganic layer with brine, drying on anhydrous MgSO4, and evaporat-
ing in vacuo with a rotary evaporator at aspirator pressure. Melting
points are uncorrected. IR spectra were recorded with an FTIR
instrument through NaCl cell windows and absorptions are given
in cm–1. NMR spectra were run in CDCl3 unless otherwise noted.
Experimental evidence favoring the structures investigated came
from a comprehensive range of 1H and 13C NMR spectroscopic
data (500/125 and 300/75 MHz respectively, 1D and 2D experi-
ments) and corroborated by spatial proximity (n.O.e) studies using
1 and D techniques. 1H chemical shifts are expressed in ppm down-
field from TMS using the residual nondeuterated solvent as in-
1
ternal standard (CDCl3, H, 7.26 ppm). 13C chemical shifts are re-
ported relative to CDCl3 triplet centered at δ = 77.0 ppm. Mass
spectra acquired in the positive ion mode under electron spray ion-
ization (ES+) using a mobile phase of methanol, will be abbrevi-
ated as ESIMS (MeOH). HR will be added for the high resolution
mass measurements (HRESIMS).
Conclusions
CCDC-620081 (43) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
With the ultimate aim of selectively preparing heavily
functionalized cyclohexane derivatives, we inspected the re-
giochemical outcomes for the Baeyer–Villiger oxidation of
Typical Procedure for Baeyer–Villiger Oxidation: Sodium hydrogen
carbonate (0.12 mmol) and m-CPBA (0.3 mmol) were added to the
appropriate ketone (0.1 mmol) in dichloromethane (1 mL) at 0 °C.
The mixture was stirred at room temp (for approximately 17 h or
as indicated, TLC monitoring). The crude reaction mixture was
diluted with dichloromethane and filtered through a plug of Celite.
The excess peracid was decomposed by washing with aqueous 5%
sodium sulfite. Finally the organic phase was washed with sat.
variously substituted bicyclo[2.2.2]octanone system
I
(Scheme 2). Our key incentive for this work was to examine
whether the choice of the opening position would afford
practical control of the relative configuration at the quater-
nary center in bridgehead position C4. To summarize, un-
der the selected experimental conditions we observed that:
(1) In the absence of C8 substitution, bridgehead migration
was favored on free C2β-hydroxy-containing substrates NaHCO3, and worked up as usual.
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Baeyer–Villiger Oxidation of the Bicyclo[2.2.2]octanone System Revisited
FULL PAPER
Baeyer–Villiger Oxidation of the Substrates
tBu), 1.68 (ddd, J = 1.7, 5.2, 15.3 Hz, 1 H, H6), 1.75 (dd, J = 6.1,
15.4 Hz, 1 H, H7Ј), 2.00–2.16 (m, 5 H, H9Ј, H7Ј, H6, H8), 2.30 (ddd,
J = 5.7, 8.6, 16.2 Hz, 1 H, H9Ј), 2.39 (dd, J = 1.5, 18.7 Hz, 1 H,
H4), 2.44 (s, 3 H, TsЈ), 2.45 (s, 3 H, Ts), 2.98 (ddd, J = 1.7, 5.4,
6.6 Hz, 1 H, H5Ј), 3.12 (dd, J = 2.6, 18.7 Hz, 1 H, H4), 3.38–3.44
(m, 2 H, H9, H8Ј), 3.71 (dd, J = 1.2, 11.9 Hz, 1 H, H2Ј), 4.35 (ddd,
J = 1.8, 3.2, 5.6 Hz, 1 H, H1), 4.41 (dd, J = 1.4, 11.9 Hz, 1 H, H2Ј),
4.78–4.87 (m, 2 H, H7, H6Ј), 7.34 (d, J = 8.3 Hz, 4 H, Ts), 7.79 (d,
J = 8.3 Hz, 4 H, Ts) ppm. 13C NMR (75 MHz, CDCl3): δ = 24.2
(MeЈ), 27.4 (Me), 27.7 (2 Ac), 28.7 (6 C, 2 tBu), 32.2 (C9Ј), 35.0
(C5), 37.3 (C8), 38.4 (C7Ј), 38.8 (C6), 39.5 (C1Ј), 43.3 (C4), 46.0
(C5Ј), 68.7 (C8Ј), 69.1 (C9), 73.3 (C2), 73.7 (tBuЈ), 74.0 (tBu), 74.3
(C1), 74.8 (C6Ј), 75.2 (C7), 127.8 (4 C, Ts), 129.9 (4 C, Ts), 133.6
6-(tert-Butyldimethylsilanyloxy)-8-hydroxy-5-methyl-2-oxabicyclo-
[3.3.1]nonan-3-one (30): Starting from 17b (74 mg, 0.314 mmol) and
using the general procedure, 30 (46.5 mg, 49%) was obtained, after
stirring at room temp. for 14 h (silica gel chromatography, heptane/
EtOAc, 1:1), along with impure 31 (5.4 mg, 4%) and recovered
starting material (11 mg, 14.8%). [α]2D0 = 65 (c = 1.0, CHCl3). M.p.
1
188–189 °C (CH2Cl2). H NMR (300 MHz, CDCl3): δ = 0.04 (s, 3
H), 0.06 (s, 3 H), 0.87 (s, 9 H), 0.96 (s, 3 H), 1.29 (ddd, J = 11.6,
11.6, 13.7 Hz, 1 H), 1.46 (ddd, J = 1.7, 2.2, 14.6 Hz, 1 H), 1.94 (dd,
J = 4.6, 14.6 Hz, 1 H), 2.02 (dd, J = 0.9, 19.0 Hz, 1 H), 2.17 (dddd,
J = 1.0, 5.1, 5.1, 13.7 Hz, 1 H), 2.25 (br. s, 1 H), 2.94 (dd, J = 2.4,
19.0 Hz, 1 H), 3.37 (ddd, J = 0.7, 5.1, 11.4 Hz, 1 H), 3.65 (ddd, J
= 2.4, 5.2, 11.9 Hz, 1 H), 4.61 (dddd, J = 1.0, 1.7, 2.4, 4.6 Hz, 1
H) ppm. 13C NMR (75 MHz, CDCl3): δ = –4.8, –3.8, 18.1, 25.9,
26.6, 33.9, 34.8, 36.2, 37.2, 70.6, 73.8, 78.5, 171.6 ppm. IR (film):
1698, 1313, 1249, 1215, 1130, 993, 835, 775 cm–1. ESIMS (MeOH):
m/z (%) = 323.1 (100) [M + Na]+. HRESIMS (MeOH): calcd. for
C15H28O4NaSi 323.1655; found 323.1644. C15H28O4Si (300.46):
calcd. C 59.96, H 9.39; found C 60.04, H 9.46.
(2 C, Ts), 145.1 (2 C, Ts), 171.5 (2 C, C3, C4Ј) ppm. IR (film): ν =
˜
2963, 2927, 2873, 2856, 1782, 1731, 1598, 1365, 1190, 1176,
882 cm–1. ESIMS (MeOH): m/z (%) = 419.1 (100) [M + Na]+.
HRESIMS: calcd. for C20H28O6SNa 419.1504; found 419.1495.
C20H28O6S (396.16): calcd. C 60.58, H 7.12, S 8.09; found C 64.09,
H 8.06, S 5.68.
9-tert-Butoxy-5-methyl-3-oxo-2-oxabicyclo[3.2.2]non-7-yl Acetate
24 and 8-tert-Butoxy-1-methyl-4-oxo-3-oxabicyclo[3.2.2]non-6-yl
Acetate (25): Starting from 11 (43 mg, 0.16 mmol) and using the
general procedure, 24 and 25 (16.6 mg) were obtained as an insepa-
rable mixture, after stirring at room temp. for 4 d in 37% combined
yield and 1:1 ratio (silica gel chromatography, heptane/EtOAc, 10:1
to 3:1), along with recovered starting material 11 (23.2 mg, 54%).
1H NMR (300 MHz, CDCl3): δ = 0.84 (s, 3 H, Me), 0.88 (s, 3 H,
MeЈ), 1.10 (s, 18 H, tBu), 1.68 (dd, J = 5.7, 14.9 Hz, 1 H, H6), 1.75
(dd, J = 5.7, 15.0 Hz, 1 H, H7Ј), 1.85 (ddd, J = 1.4, 5.6, 15.3 Hz,
1 H, H9Ј), 1.92–2.12 (m, 3 H, H8, H7, H7Ј), 1.99 (s, 3 H, Ac), 2.02
(s, 3 H, Ac), 2.17 (ddd, J = 6.9, 8.5, 15.3 Hz, 1 H, H9Ј), 2.27 (ddd,
J = 5.4, 8.6, 16.2 Hz, 1 H, H8), 2.37 (dd, J = 1.4, 18.6 Hz, 1 H,
H4), 3.03 (ddd, J = 1.5, 5.1, 6.9 Hz, 1 H, H5Ј), 3.10 (dd, J = 2.7,
18.6 Hz, 1 H, H4), 3.41 (m, 2 H, H9, H8Ј), 3.64 (dd, J = 1.2,
11.9 Hz, 1 H, H2Ј), 4.41 (dd, J = 1.6, 11.9 Hz, 1 H, H2Ј), 4.44 (ddd,
J = 1.9, 3.5, 5.4 Hz, 1 H, H1), 4.89 (ddd, J = 3.4, 5.7, 9.6 Hz, 1 H,
H7), 4.95 (dt, J = 5.4, 9.2 Hz, 1 H, H6Ј) ppm. 13C NMR (75 MHz,
CDCl3): δ = 21.0 (Ac), 21.1 (Ac), 24.3 (MeЈ), 27.6 (Me), 28.8 (6 C,
2 tBu), 32.0 (C9Ј), 34.8 (C5), 37.2 (C8), 37.6 (C7Ј), 38.2 (C6), 39.4
(C1Ј), 43.4 (C4), 45.3 (C5Ј), 67.9 (C6Ј), 68.9 (2 C, C9, C8Ј), 69.5
(C7), 73.5 (C2Ј), 73.7 (tBu), 73.8 (tBuЈ), 74.3 (C1), 170.5 (Ac), 170.6
8-tert-Butoxy-6-(tert-butyldimethylsilanyloxy)-1-methyl-4-oxo-3-
oxabicyclo[2.2.2]non-2-yl Acetate (21a): Starting from 15a (37 mg,
0.09 mmol) and using the general procedure, 21a (21.5 mg, 56%)
was obtained, after stirring at room temp. for 25 h (silica gel
chromatography, heptane/EtOAc, 20:1 to 10:1), along with unre-
acted starting material 15a (9.6 mg, 26%). [α]2D0 = +13 (c = 0.7,
CHCl3). M.p. 146–147 °C (CH2Cl2). 1H NMR (300 MHz, CDCl3):
δ = 0.00 (2 s, 6 H), 0.81 (s, 9 H), 0.98 (s, 3 H), 1.09 (s, 9 H), 1.79
(m, 2 H), 2.02 (s, 3 H), 2.04–2.20 (m, 2 H), 2.97 (m, 1 H), 3.38 (t,
J = 8.0 Hz, 1 H), 3.99 (m, 1 H), 6.13 (s, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = –4.9, –4.8, 17.9, 20.9, 24.6, 25.6 (3 C), 28.8
(3 C), 31.3, 41.6, 43.6, 49.3, 65.6, 70.1, 73.3, 97.9, 169.1, 172.2 ppm.
IR (film): ν = 2960, 2858, 1752, 1363, 1016 cm–1. ESIMS (MeOH):
˜
m/z (%) = 437.2 (100) [M + Na]+. HRESIMS: calcd. for C21H38O6-
SiNa 437.2335; found 437.2328. C21H38O6Si (414.24): calcd. C
60.83, H 9.24; found C 60.69, H 9.24.
8-tert-Butoxy-6-(tert-butyldimethylsilanyloxy)-1-methyl-4-oxo-3-
oxabicyclo[3.2.2]non-2-yl Acetate (21b): Starting from 15b (110 mg,
0.27 mmol) and using the general procedure, 21b (106 mg, 95%)
was obtained, after stirring at room temp. for 2 h as a single prod-
uct (silica gel chromatography, heptane/EtOAc, 20:1 to 10:1). [α]2D0
= +100 (c = 1.2, CHCl3). M.p. 94–96 °C (CH2Cl2). 1H NMR
(300 MHz, CDCl3): δ = 0.07 (2 s, 6 H), 0.89 (s, 9 H), 0.99 (s, 3 H),
1.17 (s, 9 H), 1.66 (dd, J = 8.6, 15.2 Hz, 1 H), 1.89 (dt, J = 3.0,
15.4 Hz, 1 H), 1.97–2.09 (m, 2 H), 2.10 (s, 3 H), 3.06 (m, 1 H), 3.51
(dd, J = 3.5, 8.7 Hz, 1 H), 3.97 (m, 1 H), 6.42 (s, 1 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = –4.9 (2 C), 17.9, 21.0, 24.9, 25.6 (3
C), 28.7 (3 C), 32.2, 37.5, 42.3, 48.9, 66.0, 70.3, 74.0, 94.7, 169.1,
(Ac), 172.3 (C3), 173.0 (C4Ј) ppm. IR (film): ν = 2975, 1738, 1731,
˜
1366, 1242, 1049 cm–1. ESIMS (MeOH): m/z (%) = 307.1 (100)
[M + Na]+. HRESIMS: calcd. for C15H24O5Na 307.1521; found
307.1505. C15H24O5 (284.16): calcd. C 63.36, H 8.51; found C
63.61, H 8.45
6-tert-Butoxy-8-hydroxy-5-methyl-2-oxabicyclo[3.2.2]nonan-3-one
(26) and 6-tert-Butoxy-8-hydroxy-5-methyl-3-oxabicyclo[3.2.2]-
nonan-2-one (27): Starting from 17a (40 mg, 0.17 mmol) and using
the general procedure bridgehead migrated 26 (17.2 mg) and meth-
ylene migrated 27 (18.8 mg) were obtained in 88% combined yield
and 1:1.1 ratio after stirring at room temp. for 4 h (silica gel
171.5 ppm. IR (film): ν = 2930, 2857, 1749, 1225, 1173 cm–1. ES-
˜
IMS (MeOH): m/z (%) = 437.2 (100) [M + Na]+, 453.2 (12) [M +
K]+. HRESIMS: calcd. for C21H38O6NaSi 437.2335; found
437.2339. C21H38O6Si (414.24): calcd. C 60.83, H 9.24; found C
60.59, H 9.17.
chromatography, heptane/EtOAc, 2:1 to 1.5:1). Data for 26: [α]2D0
=
+28 (c = 0.8, CHCl3). M.p. 86–88 °C (heptane). 1H NMR
9-tert-Butoxy-5-methyl-3-oxo-2-oxabicyclo[3.2.2]non-7-yl Toluene- (300 MHz, CDCl3): δ = 0.95 (s, 3 H), 1.18 (s, 9 H), 1.45 (ddd, J =
4-sulfonate (23), 8-tert-Butoxy-1-methyl-4-oxo-3-oxabicy- 2.4, 5.0, 14.7 Hz, 1 H), 2.03 (m, 1 H), 2.18 (dd, J = 8.1, 14.7 Hz, 1
clo[3.2.2]non-6-yl Toluene-4-sulfonate (22): Starting from 10 (49 mg, H), 2.31 (dd, J = 1.1, 18.5 Hz, 1 H), 2.48 (ddd, J = 4.3, 8.5, 15.8 Hz,
0.12 mmol) and using the general procedure, 22 and 23 (11.5 mg)
were obtained as an inseparable mixture, after stirring at room
temp. for 4 d in 24 % combined yield and 1:1.5 ratio (silica gel
chromatography, heptane/EtOAc, 10:1 to 3:1), along with unre-
acted starting material 10 (33.8 mg, 69%). 1H NMR (300 MHz,
1 H), 3.01 (dd, J = 2.5, 18.5 Hz, 1 H), 3.64 (dd, J = 2.9, 8.5 Hz, 1
H), 4.29 (m, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 27.9, 28.8
(3 C), 34.4, 34.5, 42.0, 43.3, 67.1, 70.5, 73.7, 78.0, 173.9 ppm. IR
(film): ν = 3394, 2975, 2929, 1708, 1390, 1067 cm–1. ESIMS
˜
(MeOH): m/z (%) = 243.2 (100) [M + H]+, 265.2 (14) [M + Na]+,
CDCl3): δ = 0.89 (s, 3 H, MeЈ), 0.90 (s, 3 H, Me), 1.10 (s, 18 H, 281.1 (8) [M + K]+. HRESIMS: calcd. for C13H22O4Na m/z
Eur. J. Org. Chem. 2007, 4116–4123
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4121

L. Finet, M. Dakir, I. Castellote, S. Arseniyadis
FULL PAPER
265.1416, found: 265.1407. C13H22O4· 0.1H2O (242.15): calcd. C 1001 cm–1. ESIMS (MeOH): m/z (%) = 411.2 (100) [M + Na]+.
63.96, H 9.17; found C 63.99, H 9.19. Data for 27: [α]2D0 = +63 (c
HRESIMS: calcd. for C19H36O6SiNa 411.2179; found 411.2193.
C19H36O6Si (388.23): calcd. C 58.73, H 9.34; found C 58.79, H
= 1.1, CHCl3). M.p. 141–142 °C (heptane). 1H NMR (300 MHz,
CDCl3): δ = 0.89 (s, 3 H), 1.18 (s, 9 H), 1.58 (ddd, J = 1.5, 2.8, 9.36.
15.2 Hz, 1 H), 1.80 (dd, J = 5.3, 14.9 Hz, 1 H), 2.20 (dd, J = 8.0,
Esterification of the Free Carboxyl Functionalities with Diazometh-
ane
15.2 Hz, 1 H), 2.43 (ddd, J = 6.8, 8.2, 14.9 Hz, 1 H), 2.93 (d, J =
6.8 Hz, 1 H), 3.34 (b, 1 H), 3.61 (dd, J = 1.3, 11.8 Hz, 1 H), 3.72
(ddd, J = 1.3, 5.3, 8.2 Hz, 1 H), 4.29 (dt, J = 2.8, 8.0 Hz, 1 H),
4.51 (dd, J = 1.5, 11.8 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 24.3, 28.8 (3 C), 29.8, 37.7, 41.1, 48.6, 64.8, 69.1, 73.4, 74.1,
Dimethyl 2-tert-Butoxy-5-(tert-butyldimethylsilanoxy)-1-methyl-
cyclohexene-1,4-dicarboxylate (34): TMSCHN2 (2  in ether,
0.3 mL, excess) was added at 0 °C to a solution of diacid 33
(29.7 mg, 0.08 mmol) in a mixture of ether (3 mL) and methanol
(0.3 mL). After 15 min, the reaction mixture was evaporated and
chromatographed (heptane/EtOAc, 20:1 to 10:1) to afford bis(di-
174.5 ppm. IR (film): ν = 3383, 2970, 2930, 1719, 1195, 1075 cm–1.
˜
ESIMS (MeOH): m/z (%) = 243.1 (4) [M + H]+, 265.2 (100) [M +
Na]+, 281.1 (8) [M + K]+. HRESIMS: calcd. for C13H22O4Na
265.1416; found 265.1411. C13H22O4·0.15H2O (242.15): calcd. C
63.73, H 9.17; found C 63.99, H 8.99.
methyl ester) 34 (28.2 mg, 88%): [α]2D0 = +36 (c = 1.4, CHCl3). H
1
NMR (400 MHz, CDCl3): δ = 0.00 (2 s, 6 H), 0.82 (s, 9 H), 1.17
(s, 9 H), 1.22 (s, 3 H), 1.44 (dd, J = 3.1, 14.3 Hz, 1 H), 1.87 (dt, J
= 3.6, 13.7 Hz, 1 H), 2.47 (dt, J = 3.6, 11.0 Hz, 1 H), 2.51 (dd, J
= 5.0, 14.3 Hz, 1 H), 2.71 (dt, J = 10.1, 10.9, 13.7 Hz, 1 H), 3.23
(dd, J = 3.3, 10.0 Hz, 1 H), 3.65 (s, 3 H), 3.66 (s, 3 H), 4.22 (dt, J
= 3.1, 5.0 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = –5.7,
–4.1, 18.0, 25.8 (3 C), 26.0, 28.1, 28.8 (3 C), 42.3, 45.8, 47.7, 51.2,
9-tert-Butoxy-7-(tert-butyldimethylsilyloxy)-5-methyl-2-oxabicyclo-
[3.2.2]nonan-3-one (28) and 9-tert-Butoxy-7-(tert-butyldimethyl-
silyloxy)-5-methyl-3-oxabicyclo[3.2.2]nonan-2-one (29): Starting
from TBS-protected bicyclic aldol 18a (50 mg, 0.14 mmol) and
using the general procedure, 28 (15.6 mg, 30%) and 29 (25 mg,
48%) were obtained after stirring at room temp. for 15 h (silica gel
chromatography, heptane/EtOAc, 5:1 to EtOAc). Data for 28: Yel-
51.3, 67.4, 73.6, 74.9, 172.8, 174.8 ppm. IR (film): ν = 2953, 2930,
˜
2857, 1747, 1464, 836 cm–1. ESIMS (MeOH): 439.2 (100)
[M + Na]+. HRESIMS: calcd. for C21H40O6SiNa 439.2492; found
439.2513. C21H40O6Si·0.25C7H16 (416.26): calcd. C 61.87, H 10.04;
found C 61.91, H 10.16.
1
low oil. H NMR (300 MHz, CDCl3): δ = 0.05 (s, 3 H), 0.07 (s, 3
H), 0.88 (s, 9 H), 0.91 (s, 3 H), 1.16 (s, 9 H), 146 (dd, J = 2.1,
14.8 Hz, 1 H), 1.94 (dd, J = 3.3, 14.3 Hz, 1 H), 2.12 (dd, J = 7.5,
14.7 Hz, 1 H), 2.26 (d, J = 18.5 Hz, 1 H), 2.48 (ddd, J = 5.3, 8.5,
15.7 Hz, 1 H), 3.07 (dd, J = 2.7, 18.5 Hz, 1 H), 3.67 (ddd, J = 1.7,
5.0, 8.5 Hz, 1 H), 4.17 (m, 2 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = –4.9, –4.8, 17.8, 25.6 (3 C), 28.0 (3 C), 28.8, 34.3, 35.2,
6-tert-Butoxy-8-(tert-butyldimethylsilanyloxy)-5-methyl-4-(trimeth-
ylsilanyloxy)-3-oxabicyclo[2.2.2]nonan-2-one (35): Starting from
bis(silyl)-protected ketone 13 (22 mg, 0.05 mmol) and using the ge-
neral procedure, lactone 35 (10 mg, 45%) and a mixture of acid–
aldehyde 32 and diacid 33 (7.2 mg, 38%, 1:2) were obtained after
stirring at room temp. for 22 h (silica gel chromatography, heptane/
EtOAc, 3:1). Data for 35: [α]2D0 = +90 (c = 0.5, CHCl3). M.p. 81 °C
(diethyl ether). 1H NMR (300 MHz, CDCl3): δ = 0.06 (s, 6 H), 0.19
(s, 9 H), 0.89 (s, 9 H), 0.96 (s, 3 H), 1.15 (s, 9 H), 1.52 (dd, J = 9.0,
15.0 Hz, 1 H), 1.85 (dt, J = 2.9, 15.3 Hz, 1 H), 2.00 (ddd, J = 5.2,
9.0, 15.3 Hz, 1 H), 2.18 (dd, J = 3.5, 15.0 Hz, 1 H), 2.98 (td, J =
2.3, 5.5 Hz, 1 H), 3.48 (dd, J = 3.9, 9.0 Hz, 1 H), 3.90 (ddd, J = 3.5,
5.9, 9.0 Hz, 1 H), 5.48 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= –4.9 (2 C), 0.02 (3 C), 18.0, 25.7 (3 C), 28.7 (3 C), 32.8, 36.5,
43.4, 43.5, 67.3, 70.0, 73.4, 77.5, 172.4 ppm. IR (film): ν = 2953,
˜
2928, 2855, 1730, 1471, 1462, 1388, 1377, 1363, 1252, 1190, 1106,
1083, 1039, 835 cm–1. ESIMS (MeOH): m/z (%) = 379.2 (100) [M
+ Na]+. HRESIMS: calcd. for C19H36O4NaSi 379.2281; found
379.2310. C19H36O4Si (356.23): calcd. C 64.00, H 10.18; found C
63.87, H 10.13. Data for 29: Yellow oil. [α]2D0 = +65 (c = 1.0,
1
CHCl3). H NMR (500 MHz, CDCl3): δ = 0.05 (s, 3 H), 0.06 (s, 3
H), 0.88 (s, 3 H), 0.89 (s, 9 H), 1.16 (s, 9 H), 1.52 (dd, J = 1.3,
14.9 Hz, 1 H), 1.74 (dd, J = 5.9, 14.6 Hz, 1 H), 2.16 (dd, J = 7.2,
14.9 Hz, 1 H), 2.35 (m, 1 H), 2.87 (ddd, J = 1.7, 3.5, 7.1 Hz, 1 H),
3.53 (dd, J = 1.5, 11.8 Hz, 1 H), 3.78 (ddd, J = 1.5, 6.2, 8.0 Hz, 1
H), 4.18 (m, 1 H), 4.53 (dd, J = 1.5, 11.8 Hz, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = –4.9 (2 C), 17.7, 24.5, 25.6 (3 C), 28.8 (3
C), 30.0, 37.8, 42.5, 48.7, 65.8, 68.9, 73.1, 73.7, 173.9 ppm. IR
43.8, 49.2, 66.5, 70.2, 73.6, 99.1, 172.7 ppm. IR (film): ν = 2958,
˜
2930, 2858, 1734, 1252, 1136, 842 cm–1. ESIMS (MeOH): m/z (%)
= 467.2 (100) [M + Na]+. HRESIMS: calcd. for C22H44O5Si2Na
467.2625; found 467.2619. C22H44O5Si2 (444.27): calcd. C 59.41, H
9.97; found C 59.52, H 9.95.
(film): ν = 2953, 2929, 2856, 1730, 1471, 1369, 1250, 1190, 1053,
˜
998, 836 cm– 1 .ESIMS (MeOH): m/z (%) = 379.2 (100)
[M + Na]+. HRESIMS: calcd. for C19H36O4NaSi 379.2281; found
379.2270. C19H36O4Si·0.5H2O (356.23): calcd. C 62.42, H 10.20;
found C 62.28, H 9.78.
6-tert-Butoxy-4,8-dihydroxy-5-methyl-3-oxabicyclo[3.2.2]nonan-2-
one 36 and 5-tert-Butoxy-4-formyl-2-hydroxy-4-methylcyclohex-
anecarboxylic Acid (37): Starting from 14 (21 mg, 0.09 mmol) and
using the general procedure, 36 and 37 were obtained (and charac-
terized as a mixture), after stirring at room temp. for 3.5 h in 78%
(12.4 mg) combined yield and 4:1 ratio (silica gel chromatography,
2-tert-Butoxy-5-(tert-butyldimethylsilanoxy)-1-methyl-cyclohexane-
1,4-dicarboxylic Acid (33): Starting from acyloin 12 (200 mg,
0.56 mmol) and using the general procedure, acid–aldehyde 32
(29%, 60.5 mg) and diacid 33 (50%, 108 mg) were obtained after
stirring at room temp. for 1.5 h (silica gel chromatography, heptane/
EtOAc, 3:1). Both structures were methylated with diazomethane
for confirmation. Data for 33: [α]2D0 = +32 (c = 1.3, CHCl3). M.p.
1
heptane/EtOAc, 5:1 to EtOAc]. Data for the mixture of 36/37: H
NMR (300 MHz, CDCl3): δ = 1.10 (s, 3 H), 1.19 (s, 9 H), 1.74 (m,
1 H), 2.08–2.26 (m, 2 H), 2.35–2.41 (m, 2 H), 3.38 (dd, J = 6.3,
10.2 Hz, 1 H), 4.72 (d, J = 6.3 Hz, 1 H), 5.32 (s, 1 H) ppm. 13C
NMR (63 MHz, CDCl3): δ = 17.8, 29.0 (3 C), 31.3, 39.4, 46.3, 48.0,
1
144–145 °C (CH2Cl2). H NMR (300 MHz, CDCl3): δ = 0.00 (s, 3
72.4, 73.5, 75.9, 99.2, 177.4 ppm. IR (film): ν = 3442, 2975, 1714,
˜
H), 0.14 (s, 3 H), 0.84 (s, 9 H), 1.24 (s, 3 H), 1.30 (s, 9 H), 1.37 (m,
1 H), 1.96 (dt, J = 3.3, 13.4 Hz, 1 H), 2.34 (q, J = 12.0 Hz, 1 H),
2.49 (dt, J = 2.7, 12.0 Hz, 1 H), 2.71 (dd, J = 3.8, 14.4 Hz, 1 H),
3.50 (dd, J = 3.7, 10.9 Hz, 1 H), 4.32 (br. s, 1 H), 10.5 (b, 1 H)
1192, 1069 cm–1. ESIMS (MeOH): m/z = 281.1 (100) [36 + Na]+,
297.1 (32) [37 + Na]+.
8-tert-Butoxy-6-hydroxy-1-methyl-4-oxo-3-oxabicyclo[3.2.2]non-2-yl
ppm. 13C NMR (75 MHz, CDCl3): δ = –5.6, –4.3, 17.8, 25.9 (3 C), Acetate (38): Baeyer–Villiger oxidation was carried out on bicyclic
27.0, 27.8, 28.6 (3 C), 41.8, 45.5, 47.5, 66.6, 75.1, 76.9, 176.0, 177.6
ppm. IR (film): ν = 3100, 2975, 2931, 2858, 1750, 1711, 1413, 1062,
aldol 16 (30 mg, 0.10 mmol) in dichloromethane (1 mL) for 15 h
using the general procedure to give after chromatography (SiO2,
˜
4122
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 4116–4123

Baeyer–Villiger Oxidation of the Bicyclo[2.2.2]octanone System Revisited
heptane/EtOAc, 1:1) the corresponding lactone 38 (26 mg, 87%).
FULL PAPER
Acknowledgments
No bridgehead migration was detected. [α]2D0 = +13 (c = 1.0,
1
CHCl3). M.p. 131 °C (heptane). H NMR (500 MHz, CDCl3): δ =
The authors wish to thank Professor Jean-Yves Lallemand for his
kind interest and constant encouragements, Angéle Chiaroni for X-
ray crystallographic assistance, and Talbi Kaoudi for running the
Baeyer–Villiger reaction on substrate 40.
1.06 (s, 3 H), 1.14 (s, 9 H), 1.80 (dd, J = 6.7, 14.6 Hz, 1 H), 2.01
(dd, J = 9.1, 14.6 Hz, 1 H), 2.07 (s, 3 H), 2.12 (dd, J = 8.4, 14.8 Hz,
1 H), 2.25 (dt, J = 8.3, 14.8 Hz, 1 H), 2.39 (br. s, 1 H), 3.13 (dd, J
= 4.4, 8.4 Hz, 1 H), 3.45 (t, J = 8.4 Hz, 1 H), 4.18 (m, 1 H), 6.17
(s, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 20.8, 24.5, 28.7
(3 C), 31.0, 39.9, 43.6, 49.2, 64.9, 69.8, 73.3, 98.0, 168.9, 172.9 ppm.
[1] a) L. F. Tietze, U. Beifuss, Angew. Chem. 1993, 105, 115–136;
Angew. Chem. Int. Ed. Engl. 1993, 32, 131–163; b) L. F. Tietze,
Chem. Rev. 1996, 96, 115–136; c) L. F. Tietze, A. Modi, Med.
Res. Rev. 2000, 20, 304–322; d) L. F. Tietze, F. Haunert in Stim-
ulating Concepts in Chemistry (Eds.: M. Shibasaki, J. F. Stod-
dart, F. Vogtle), Wiley-VCH, Weinheim, 2000, pp. 39–64. For
an excellent book, see: L. F. Tietze, G. Brasche, K. M. Gericke
(Eds.), Domino Reactions in Organic Synthesis, Wiley-VCH,
2006. ISBN: 3-527-29060-5.
[2] Z. G. Hajos, D. R. Parrish, J. Org. Chem. 1973, 38, 3239–3243;
Z. G. Hajos, D. R. Parrish, (Hoffmann-La Roche), W. German
Patent 2,102,623, July 29, 1971 (Chem. Abstr. 1971, 75,
129414r); U. Eder, G. Sauer, R. Wiechert, Angew. Chem. Int.
Ed. Engl. 1971, 10, 496–497.
IR (film): ν = 3432, 2972, 1751, 1449, 1364, 1227, 1174, 1100, 1012,
˜
995 cm–1. ESIMS (MeOH): m/z (%) = 323.1 (100) [M + Na]+.
HRESIMS: calcd. for C15H24O6Na 323.1471; found 323.1448.
C15H24O6 (300.15): calcd. C 59.98, H 8.05; found C 59.31, H 8.24.
6-tert-Butoxy-8-hydroxy-1,5-dimethyl-3-oxo-2-oxabicyclo[3.3.1]non-
9-yl Acetate (41) and 9-tert-Butoxy-7-hydroxy-5,7-dimethyl-2-oxo-
3-oxabicyclo[3.2.2]non-6-yl Acetate (42): Baeyer–Villiger oxidation
was carried out on bicyclic aldol 40 (1.0 g, 3.35 mmol) in CH2Cl2
(1 mL) for 20 h by using the general procedure to give after
chromatography (SiO2, CH2Cl2/acetone, 4:1) isomeric lactones 41
(572 mg) and 42 (130 mg) in 67% combined yield and 4.4:1 ratio
along with recovered 40 (300 mg). Data for 41: [α]2D0 = +75 (c =
[3] L. Finet, J. I. Candela, T. Kaoudi, N. Birlirakis, S. Arseniyadis,
Chem. Eur. J. 2003, 9, 3813–3820.
1
0.84, CHCl3). M.p. 196–197 °C (heptane). H NMR (300 MHz,
[4] The regiochemical outcome of oxygen insertion into bridged
bicyclic ketones has been the subject of numerous articles since
the late 1950s. J. Meinwald, E. Frauenglass, J. Am. Chem. Soc.
1960, 82, 5235–5239. The factors that determine the regioselec-
tivity in Baeyer–Villiger oxidations, electronic, steric, and stere-
oelectronic have been reviewed: G. R. Krow, Org. React. 1993,
43, 251–798; G. R. Krow, C. A. Johnson, J. P. Guare, D. Kub-
rak, K. J. Henz, D. A. Shaw, S. W. Szczepanski, J. T. Carey, J.
Org. Chem. 1982, 47, 5239–5243.
[5] The regioselectivity of the Baeyer–Villiger oxidation varies
markedly as a function of the nature and stereochemistry of
the substituents and the peracid used: G. Krow, C. Johnson,
Synthesis 1979, 50–51.
[6] The significant regioreversal entails an involvement of the free
hydroxyl group in the oriented delivery of the peracid molecule
to the ketone (see ref.[4]).
[7] L. Finet, M. Dakir, I. Castellote, T. Kaoudi, L. Toupet, S. Ar-
seniyadis, Eur. J. Org. Chem. 2007, 335–341.
[8] L. Finet, M. Dakir, A. Chiaroni, S. Arseniyadis, Eur. J. Org.
Chem. 2007, 342–350.
[9] V. Dave, E. W. Warnhoff, J. Org. Chem. 1983, 48, 2590–2598.
[10] The acetoxy group is overall electron donating toward a cat-
ionic center: D. Calvert, P. B. D. De La Mare, N. S. Isaacs, J.
Chem. Res. Synop. 1978, 156.
[11] By prolonging the reaction time (thermodynamic equilibrium
mixture), this ratio goes as high as 10:1 for 17b/17c.
[12] Investigating migration preferences, Hawthorne demonstrated
that the nature of the peroxy acid used may influence the re-
sults obtained: M. F. Hawthorne, W. D. Emmons, K. S. McCal-
lum, J. Am. Chem. Soc. 1958, 80, 6393–6398.
[13] In the absence of oxygenation at C8, a C2 free β-hydroxy group
holds the peroxyacid on the same side as the OH unit (neigh-
boring group effect through H-bonding); this leads to bridge-
head migration. The TBS protecting group provides steric hin-
drance to the approach of the peracid, which leads to the for-
mation of the Criegee intermediate from the opposite side,
leading mainly to a methylene migration.
[14] The cation-stabilizing effect of the unshared oxygen electrons in-
creased the relative migratory aptitude of the attached carbon.
[15] Following hydrolytic opening and dehydration (Burgess), 41
should lead to a taxoid C-ring precursor containing an exocy-
clic C4,20 olefin Ϫ a useful taxoid right-half building block.
[16] An α-bromine atom usually retards migration of the attached
carbon.
CDCl3): δ = 0.90 (s, 3 H), 1.15 (s, 9 H), 1.34 (s, 3 H), 2.10 (s, 3 H),
2.06–2.18 (m, 3 H), 2.20 and 2.48 (ABquartet, J = 18.9 Hz, 2 H),
3.40 (t, J = 3.0 Hz, 1 H), 3.81 (dd, J = 4.8, 11.6 Hz, 1 H), 5.14 (s,
1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 19.0, 20.6, 22.3, 28.6
(3 C), 34.7, 37.6, 39.3, 70.5 (2 C), 72.8, 74.7, 85.6, 169.9, 170.5
ppm. ESIMS (MeOH): m/z (%) = 337.2 (100) [M + Na]+. IR (film):
ν = 3462, 3019, 2972, 2941, 2874, 1723, 1461, 1372, 1270, 1238,
˜
1215, 1064, 1027, 986 cm–1. HRESIMS: calcd. for C16H26O6Na
337.1627; found 337.1616. C16H26O6 (314.17): calcd. C 61.13, H
8.34; found C 60.56, H 8.23. Data for 42: [α]2D0 = +115 (c = 1.1,
CHCl3). M.p. 166–167 °C (CH2Cl2). 1H NMR (300 MHz, CDCl3):
δ = 0.75 (s, 3 H), 1.15 (s, 9 H), 1.33 (s, 3 H), 1.67 (ddd, J = 4.0,
6.5, 15.1 Hz, 1 H), 2.37 (s, 3 H), 2.41 (ddd, J = 3.5, 8.8, 15.1 Hz,
1 H), 3.99 (t, J = 3.5 Hz, 1 H), 3.68 (dd, J = 1.5, 12.2 Hz, 1 H),
3.81 (dd, J = 6.5, 8.8 Hz, 1 H), 4.52 (d, J = 12.2 Hz, 1 H), 5.03 (d,
J = 1.5 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 17.7, 19.9,
27.05, 27.8 (3 C), 31.4, 41.3, 52.4, 67.6, 70.5, 70.8, 73.3, 73.4, 169.2,
172.3 ppm. IR (film): ν = 3469, 2970, 2939, 2878, 1747, 1715, 1469,
˜
1374, 1364, 1270, 1229, 1178, 1158, 1095, 1058, 998, 913, 752 cm–1.
ESIMS (MeOH): m/z (%) = 337.1 (100) [M + Na]+. HRESIMS
calcd. for C16H26O6Na 337.1627; found 337.1604. C16H26O6
(314.17): calcd. C 61.13, H 8.34; found C 60.62, H 8.06.
Lactone 9: Baeyer–Villiger oxidation was carried out on 20 (70 mg,
0.31 mmol) in CHCl2 (1 mL) for 3 d by using the general procedure
to give after chromatography (SiO2, heptane/EtOAc, 5:1 to EtOAc)
9 in 88% (65 mg) yield along with recovered starting material 20
(5.8 mg, 8%). Data for 9: [α]2D0 = –70 (c = 1.1, CHCl3). M.p. 185–
1
186 °C. H NMR (500 MHz, CDCl3): δ = 1.49 (s, 3 H), 1.53 (s, 3
H), 1.57 (s, 3 H), 2.27 (ddd, J = 1.1, 5.9, 16.6 Hz 1 H), 2.39–2.48
(m, 3 H), 2.99 (dd, J = 7.1, 19.2 Hz, 1 H), 3.87 (d, J = 1.2 Hz, 1
H), 4.28 (t, J = 1.2 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 21.1, 21.6, 27.5, 34.0, 36.8, 39.0, 72.0, 79.3, 79.9, 83.5, 119.5,
170.0 ppm. IR (film): ν = 3423, 1712, 1409, 1300, 1264, 1197, 1176,
˜
1111, 1037, 858 cm–1. ESIMS (MeOH): m/z (%) = 263.1 (100) [M
+ Na]+. HRESIMS (CH2Cl2): calcd. for C12H16O5Na 263.0891;
found: 263.0895.
Supporting Information (see also the footnote on the first page of
this article): Experimental procedures for the synthesis and spectral
characterization of all compounds investigated, including those
presented here, and X-ray crystallographic data for 43.
Received: April 10, 2007
Published Online: June 25, 2007
Eur. J. Org. Chem. 2007, 4116–4123
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4123