Use of epoxidation and epoxide opening reactions for the synthesis of highly functionalized 1-oxaspiro[4.5]decan-2-ones and related compounds

Article abstract of DOI:10.1016/j.tet.2003.08.010

Epoxidation of ethyl 3-(6-hydroxycyclohex-1-en-1-yl)propanoate (11) provided the syn epoxide 12. By invoking chelation controlled epoxide opening the triol derivatives 13 and 14 or the spiro lactone 25 could be obtained. Elimination of HBr from the bromides 26 and 27 produced the spiro cyclohexenones 28 and 29. Epoxidation of the double bond occurred in a diastereoselective manner to give epoxides 30 and 31, respectively. Treatment of the epoxide 31 with LiBr/AcOH gave the bromo hydrin 38. In a 'merry go round' fashion 38 was further functionalized on the cyclohexane ring by elimination, epoxidation, and epoxide opening resulting in the bromo hydrin 43. Other cyclohexane derivatives that were produced during these studies include the cyclohexenone 19 and the cyclohexanediol 23. In addition, enolate azidation of the spiro lactone 29 proceeded in a diastereoselective manner providing the α-azido lactone 32.

Full text of DOI:10.1016/j.tet.2003.08.010

Tetrahedron 59 (2003) 7949–7960
Use of epoxidation and epoxide opening reactions for the
synthesis of highly functionalized 1-oxaspiro[4.5]decan-2-ones
and related compounds
a
Martin Eipert, Cacilia Maichle-Mossmer and Martin E. Maier
b
a
,
*
¨
¨
a
¨
Institut fur Organische Chemie, Universitat Tubingen, Auf der Morgenstelle 18, 72076 Tubingen, Germany
Institut fur Anorganische Chemie, Universitat Tubingen, Auf der Morgenstelle 18, 72076 Tubingen, Germany
¨
¨
¨
b
¨
¨
¨
¨
Received 26 June 2003; revised 8 August 2003; accepted 8 August 2003
Abstract—Epoxidation of ethyl 3-(6-hydroxycyclohex-1-en-1-yl)propanoate (11) provided the syn epoxide 12. By invoking chelation
controlled epoxide opening the triol derivatives 13 and 14 or the spiro lactone 25 could be obtained. Elimination of HBr from the bromides 26
and 27 produced the spiro cyclohexenones 28 and 29. Epoxidation of the double bond occurred in a diastereoselective manner to give
epoxides 30 and 31, respectively. Treatment of the epoxide 31 with LiBr/AcOH gave the bromo hydrin 38. In a ‘merry go round’ fashion 38
was further functionalized on the cyclohexane ring by elimination, epoxidation, and epoxide opening resulting in the bromo hydrin 43. Other
cyclohexane derivatives that were produced during these studies include the cyclohexenone 19 and the cyclohexanediol 23. In addition,
enolate azidation of the spiro lactone 29 proceeded in a diastereoselective manner providing the a-azido lactone 32.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
A range of natural products contains a spiro lactone subunit.
This structure contributes to a unique shape of the
corresponding molecules and can also be essential for
biological activity if an a-methylene lactone is present that
can function as a Michael acceptor. Some representative
examples include the terpene pathylactone (1),1 the iridoid
gaertneroside (2),2 or some synthetic spiro lactones, such as
33 and 44 that were designed to restrict the conformational
flexibility in the carbocyclic sector (Fig. 1). In synthetic
approaches to spiro lactones one starts, as with any bicyclic
ring system, with one of the two rings to which the second
one is attached. This can be achieved by some kind of
cyclization or rearrangement reaction.5
Figure 1. Some natural products and synthetic intermediates containing a
spiro lactone subunit.
A special type of spiro lactones are spiro[4,5]decanes with a
highly functionalized cyclohexane ring. This class of
compounds encompasses several biologically active com-
pounds such as aranorosin (5),6 or some analogs thereof that
function as HMG-CoA synthase inhibitors or antifungal
agents. Another similar compound, although lacking the
spiro lactone is scyphostatin (6) which possesses inhibitory
activity against a neutral sphingomyelinase.7,8 The bio-
synthesis and also some synthetic strategies to these
compounds rely on the oxidation of tyrosine derivatives.
For example, treatment of N-protected tyrosine 7 with the
iodine reagent PhI(OAc)2 afforded the spirolactone 8 (40%
yield).6a While these oxidizing reactions deliver the spiro
system very efficiently, the corresponding ortho dienones
are susceptible to side reactions such as dimerization or
elimination reactions upon further derivatization (Fig. 2).9
2. Results
Therefore we opted for a different strategy to spiro[4.5]-
decanes that relies on the opening of a cyclohexane epoxide
carrying a suitable side chain. In this paper we report on
some feasibility studies that led to some unexpected results.
Keywords: epoxidation; 1-oxaspiro[4.5]decan-2-ones; Michael acceptor.
*
Corresponding author. Tel.: þ49-7071-29-75247; fax: þ49-7071-29-
5137; e-mail: martin.e.maier@uni-tuebingen.de
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.08.010

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M. Eipert et al. / Tetrahedron 59 (2003) 7949–7960
Initial studies focused on the regiochemistry of epoxide
opening of 2,3-epoxycyclohexan-1-ol carrying an ester side
chain in the 2-position. The corresponding substrate, the
epoxide 12 was prepared from cyclohexenone (9) by a
Baylis–Hillman type Michael addition to ethyl acrylate
yielding the enone 10.10 Subsequent Luche reduction11 gave
the allylic alcohol 11 whose directed epoxidation provided
the epoxy alcohol 12. In the presence of a stochiometric
amount of Ti(OiPr)4 the nucleophile could be steered to the
3-position of the epoxy alcohol. This is attributed to
complexation of the titanium between the alcohol and the
epoxy oxygen as shown in complex A.12 This way the triol
13 and the acetate 14 could be obtained (Scheme 1). The cis-
position of the two hydroxy functions was proven by
acetalization providing compound 15. Treatment of 15 with
LiAlH4 led to the diol 16 whose primary hydroxy group was
protected as silyl ether. Oxidation of 17 gave the ketone 18.
Alternatively, treatment of 17 with iodosobenzoic acid and
diphenyl diselenide effected oxidation to the enone 19.13,14
In order to reach the functionalization level of scyphostatin,
a modification of the g-position of the enone would be
necessary. However, attempts toward this goal by radical
bromination etc. met with failure. Therefore this position
was functionalized on the enone 10 by a manganese
Figure 2. Natural products with a highly functionalized cyclohexane
epoxide substructure.
Scheme 1. Synthesis of the epoxide 12, its opening to the triol derivatives 13 and 14, and the synthesis of compounds 18 and 19.

M. Eipert et al. / Tetrahedron 59 (2003) 7949–7960
7951
different conditions. Thus, the combination of Ti(OiPr)4 and
ethanol in CH2Cl2 gave rise to the spiro lactone 24
(Scheme 3). The formation of this compound can be
explained by epoxide opening with water during the
quenching process followed by lactonization. In a similar
fashion the combination of Ti(OiPr)4 with bromine
furnished the spiro lactone 25. This result supports the
notion that formation of 24 does not proceed by attack of
the carboxylic group at the quaternary carbon (C-2). The
presence of nine signals in the 13C NMR spectrum of 24 is
proof of the unsymmetrical structure. The X-ray structure of
spiro lactone 25 is included in Scheme 3, showing the axial
orientation of the C–Br and C–O (lactone) bonds.16
Continuing with the bromo alcohol 25, silylation to 26
and 27, respectively, followed by HBr elimination using
DBU in benzene produced the cyclohexenes 28 and 29.
These compounds could be converted to the epoxides 30
and 31. Attack of the perbenzoic acid anti to the lactone
C–O bond shows that mainly steric effects govern the
epoxidation. In the depicted model C the peracid even has to
approach anti to an acceptor bond.
Scheme 2. Acetoxylation of cyclohexenone 10 and synthesis of the epoxide
22. Attempted opening of epoxide 22.
triacetate mediated a-acetoxylation to give compound 20.15
This was followed by Luche reduction to the allylic alcohol
21 and subsequent epoxidation with meta chloroperbenzoic
acid resulting in the epoxy alcohol 22. However, in this case
the Ti(OiPr)4 induced epoxide opening did not work. The
reason for this failure is not known but it might be
speculated that conformational reasons are responsible
(Scheme 2).
Another departure from the spiro compound 29 was the
introduction of an amino group in a-position of the lactone.
This was achieved by electrophilic azidation of the lithium
enolate of 29 with 2,4,6-triisopropylbenzenesulfonyl azide
(Scheme 4).17 While only one diastereomer 32 was formed,
its relative configuration could not be assigned, but we
assume that the electrophile enters anti to the OTBDMS
group (cf. model D).18 Treatment of the azide 32 with
triphenylphosphine and water gave the amino lactone 33.
Acylation of 33 could provide simplified scyphostatin
analogs.
Accordingly, we turned back to substrate 12 subjecting it to
The stereochemical course of the epoxidation of the double
bond in the spiro lactone is not changed by a free hydroxy
group. Thus, epoxidation of the alkenol 34, obtained by
cleavage of the silyl ether 29 gave the epoxide 35, with the
epoxide being anti to the lactone C–O bond (Scheme 5).
The epoxy alcohol 35 was oxidized to the epoxy ketone 36
using iodosobenzoic acid in presence of diphenyldisele-
nide.13 Alternatively, treatment of the epoxide 35 with
lithium bromide/acetic acid in THF caused a regiospecific
opening of the epoxide leading to the bromo hydrin 37. The
structure of this compound was secured by X-ray analysis
(Scheme 5) which proves also the relative configuration of
related precursors.16
Scheme 3. Conversion of the epoxy alcohol 12 to the spiro compounds 28–
31. X-Ray structure of lactone 25.
Scheme 4. Diastereoselective azidation of the lactone 29 yielding amine 33.

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M. Eipert et al. / Tetrahedron 59 (2003) 7949–7960
In a similar manner to the transformation before, epoxide
opening of 31 gave the bromo hydrin 38 and the alcohol 39,
respectively (Scheme 6). The bromo atom serves as a handle
to introduce a further functionalization site. Thus, benzoyl-
ation of 38 followed by elimination of HBr with Hu¨nig’s
base led to the highly functionalized spiro cyclohexene 41.
Epoxidation of the double bond occurred in a diastereo-
specific manner yielding compound 42. Due to stereo-
electronic reasons the epoxide opening occurred selectively
at C-8 (product numbering).
3. Discussion
In order to rationalize the formation of the various
cyclohexane and cyclohexene derivatives one has to address
the issues of diastereoselective epoxidation and the regio-
selectivity of the epoxide opening. The epoxidation is
governed on the one hand by steric effects.19 On the other
hand this inherent selectivity can be reinforced or
compromised by directing groups like hydroxyl.20 Some
examples from the literature19,6a,8g that serve to illustrate
these points are depicted in Figure 3.
Scheme 5. Deprotection of silyl ether 29 to cyclohexenol 34, followed by
diastereoselective epoxidation to 35 and oxidation to cyclohexanone 36.
Opening of the epoxide 35 to give the bromo hydrin 37.
The regiochemistry of the opening of cyclohexene derived
epoxides is mainly controlled by the Fu¨rst–Plattner rule.
This rule calls for a trans-diaxial opening. The consequence
of this is that high regioselectivity can be realized if it is
possible to channel the opening through only one of the two
possible half chair conformations. In these instances as well
for acyclic epoxides, chelation control or the formation of
ate-complexes is an important strategy for controlling the
regiochemistry.21 Again, this is illustrated with some
literature examples (Fig. 4). Thus, if a hydroxyl or
hydroxymethyl group is present on the same side of the
epoxide, a chelate may form in presence of a Lewis acid or a
metal cation. This seems to favor the opening through one of
the half chair conformers. For example, treatment of the cis-
epoxide derived from 3-[(benzyloxy)methyl]cyclohexene
with nucleophiles (X¼Cl, OCH3, N3, CH3, H) gave
predominantly attack on the C-1 oxirane carbon (example
1).22 The reaction is much less selective with the
corresponding trans epoxide. In a similar manner the
complexation effect [Ti(OiPr)4, I2] guarantees a regio-
selective ring opening for the cis epoxide derived from
3-cyclohexenol (example 2).23
If there is an ester group in proximity to the epoxide this
group can be engaged in the epoxide opening or form a
lactone after opening of the epoxide. For example, reaction
of the epoxide N with HClO4 in THF/H2O gave the trans
diol O that cyclized to the lactone P.24 Under different
Scheme 6. ‘Merry go round’ functionalization of the cyclohexane ring of 31
by epoxide opening, elimination, epoxidation, and epoxide opening
providing bromo hydrin 43.
Figure 3. Steric and directing group control of diastereoselective
epoxidation of cyclohexene derivatives.

M. Eipert et al. / Tetrahedron 59 (2003) 7949–7960
7953
4. Experimental
4.1. General
1H and 13C NMR: Bruker Avance 400, spectra were
recorded either in CDCl3, acetone-d6 or C6D6; chemical
shifts are calibrated to the residual proton and carbon
resonance of the solvent: CDCl3 (dH 7.25, dC 77.00 ppm),
acetone-d6 (dH 2.095, dC 30.60, 205.87 ppm), C6D6 (dH
7.15, dC 128.62 ppm). Melting points: Bu¨chi Melting Point
B-540, uncorrected. IR: Jasco FT/IR-430. EI-MS: Finnigan
Triple-Stage-Quadrupol (TSQ-70). HRMS (FT-ICR):
Bruker Daltonic APEX 2 with electron spray ionization
(ESI). Flash chromatography: J. T. Baker silica gel 43–
60 mm. Thin-layer chromatography Machery-Nagel Poly-
gram Sil G/UV254. Solvents were distilled prior to use;
petroleum ether with a boiling range of 40–608C was used.
Reactions were generally run under a nitrogen atmosphere.
Compounds 10 and 11 were prepared according to the
literature.10,11a
4.2. General procedure 1 for cis epoxidation of cyclo-
hexyl allyl alcohols
To a well stirred solution of the allyl alcohol (1 equiv.) in
dry CHCl3 (4 mL/mmol) containing MgSO4 (0.08 g/mmol)
was added mCPBA (1.1 equiv.) in small portions within
10–15 min. The resulting suspension was stirred for 2 h at
room temperature, before cyclohexene (1 mL/mmol) was
added and the mixture stirred for an additional hour. The
white suspension was diluted with diethyl ether
(7 mL/mmol), filtered, washed twice with satd. NaHCO3
solution (3 mL/mmol), water and brine. The organic layer
was dried over MgSO4, filtered, and concentrated in vacuo.
Figure 4. Regiochemistry of epoxide opening in cyclohexane epoxides.
conditions (BF3·Et2O in toluene) the epoxy ester Q cyclized
via direct participation of the ester group providing lactone
S.25
Accordingly, the diastereoselective reactions presented in
this paper can be summarized as follows. The epoxidation
reactions leading to epoxy alcohols 12 and 22 are the result
of the directing effect of the hydroxyl group. The
epoxidation of the spiro lactones 28, 29, and 34 are
influenced by steric effects (equatorial alkoxy substituent
plus minimal steric interaction with the spiro lactone). For
the epoxidation of the lactone 41 a directing effect of the
axial benzoate group cannot be ruled out.
4.2.1. rel Ethyl 3-[(1S,2S,6R)-2-hydroxy-7-oxa-
bicyclo[4.1.0]hept-1-yl]propanoate (12). Starting from
alkenol 11 (1.0 g, 5.04 mmol) a yellow oil is obtained
according to general procedure 1. The crude product was
purified by flash chromatography (petroleum ether/diethyl
ether, 2:3) providing the epoxide 12 (0.85 g, 79%) as a
colorless oil. TLC (hexane/diethyl ether, 2:3): Rf¼0.35; 1H
NMR (acetone-d6): d 1.08 (t, J¼7.1 Hz, 3H, CH3), 1.28–
1.37 (m, 4H, CH2), 1.65–1.71 (m, 3H, CH2), 2.03–2.09 (m,
1H, CH2), 2.24–2.29 (m, 2H, CH2), 2.93 (d, J¼4.0 Hz, 1H,
epoxide-H), 3.74–3.77 (m, 1H, CHOH), 3.95 (q, J¼7.1 Hz,
2H, CH2); 13C NMR (acetone-d6): d 14.9 (CH3), 19.9 (C-4),
25.0 (C-5), 29.7 (C-3), 30.5 (CH2), 30.6 (CH2COO), 60.9
(C-6), 61.1 (CH2OR), 62.8 (C-1), 69.6 (C-2), 173.9 (CvO);
IR (film): 3460, 2940, 2908, 2866, 1734, 1421, 1403,
1274 cm21; MS (EI), m/z (%): 214 (18) [M]þ, 196 (34), 164
(45), 126 (100); HRMS (EI): calcd for C11H18O4
214.120302, found 214.120344.
The opening of the epoxide 12 can be rationalized by
invoking a chelation effect (conformer A, Scheme 1). The
opening of epoxides 31, 35, and 42 proceeds through the
most favored conformer. The conformation of these
compounds is characterized by one equatorial alkoxy
group having the alkyl part of the spiro lactone in equatorial
position.
In summary, we present a concise synthesis of the
cyclohexene epoxide 12 that served as an entry point to
spiro lactones such as 25 or 28. The cyclohexyl bromide 38
obtained by epoxide opening allowed for further function-
alization reactions of the cyclohexane ring via elimination
to the unsaturated spiro lactone 41. Highly functionalized
spiro lactones such as 31, 32, 35, 36, or 42 can serve as
interesting scaffolds for combinatorial chemistry and
diversity oriented synthesis. In the course of these studies
we found further support for the strong directing effect of
chelating Lewis acids on the regiochemistry of the opening
of epoxy alcohols.
4.3. General procedure 2 for the Ti(IV) directed epoxide
opening
A 0.5 M solution of the epoxide in dry CH2Cl2 was treated
with Ti(OiPr)4 (1.3 equiv.) at room temperature and the
resulting yellow solution stirred for 5 min at 258C, before
the nucleophile (1.4 equiv.), dissolved in dry CH2Cl2
(0.7 mL/mmol), was slowly added. Stirring was continued
for 14 h, then the reaction was diluted with diethyl ether

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M. Eipert et al. / Tetrahedron 59 (2003) 7949–7960
(2 mL/mmol) and quenched with a 0.3N acetic acid
solution. The mixture was neutralized with satd. NaHCO3
solution, the phases were separated and the organic layer
washed twice with water and brine (1 mL/mmol). Drying
(MgSO4), filtation, and concentration in vacuo gave the
crude product.
CH2), 3.90–3.91 (m, 1H, CHOR), 4.04–4.13 (m, 2H,
OCH2), 5.47 (dd, J¼11.9, 3.5 Hz, 1H, CHOR); 13C NMR
(C6D6): d 12.9 (CH3), 18.1 (C-6), 19.4 (H3CCO), 22.4 (C-7),
24.2 (C-5), 25.5 (CH3), 27.0 (CH3), 27.3 (C-3), 27.8 (C-2),
58.9 (CH2OR), 74.5 (C-7a), 76.2 (C-4), 80.7 (C-3a), 106.6
((RO)2C(CH3)2), 168.3 (COCH3), 172.0 (C-1); IR (film):
2942, 1726, 1694, 1354, 1246 cm21; MS (EI), m/z (%): 314
(10) [M]þ, 259 (8), 244 (67), 158 (100); HRMS (EI): calcd
for C16H26O6 314.17226, found 314.17538.
4.3.1. rel Isopropyl 3-[(2S,6S)-1,2,6-trihydroxycyclo-
hexyl]propanoate (13). According to general procedure 2,
the epoxide 12 (2.0 g, 9.33 mmol) was reacted with
propionic acid as nucleophile. Purification of the crude
product by flash chromatography (petroleum ether/diethyl
ether, 1:5) provided 1.26 g (55%) of 13 as white crystals, mp
4.3.4. rel (3aR,4S,7aS)-3a-(3-Hydroxypropyl)-2,2-
dimethylhexahydro-1,3-benzodioxol-4-ol (16). Com-
pound 15 (2.10 g, 6.66 mmol), dissolved in dry THF
(25 mL) was slowly added to a suspension of LiAlH4
(0.99 g, 26.70 mmol, 4 equiv.) in dry THF (15 mL) at 08C.
After complete addition, the cooling bath was removed and
the mixture stirred for 4 h at room temperature. The reaction
was quenched with water (25 mL) and the suspension
extracted with ethyl acetate (3£35 mL). The combined
organic phases were dried (MgSO4), filtered, and concen-
trated in vacuo. Purification of the residue by flash
chromatograpy with a gradient (diethylether!acetone)
yielded diol 16 (1.16 g, 76%) as a gel. TLC (acetone/
hexane, 2:3): Rf¼0.25; 1H NMR (acetone-d6): d 1.29 (s, 3H,
CH3), 1.42 (s, 3H, CH3), 1.50–1.70 (m, 7H, CH2), 1.95–
2.15 (m, 3H, CH2), 3.55–3.56 (m, 2H, CH2OH), 3.81–3.83
(m, 1H, CHOR), 3.90–3.91 (m, 1H, CHOH); 13C NMR
(acetone-d6): d 20.3 (C-6), 25.0 (C-7), 26.9 (C-1), 27.7
(CH3), 28.2 (C-2), 29.4 (CH3), 31.9 (C-5), 63.7 (C-3), 75.1
(C-7a), 77.7 (C-4), 85.6 (C-3a), 107.8 ((RO)2C(CH3)2); IR
(KBr): 3451, 3382 (br, OH), 2955, 2914, 1234 cm21; MS
(EI), m/z (%): 230 (8) [M]þ, 212 (14) [M2H2O]þ, 188 (54),
154 (100); HRMS (EI): calcd for C12H22O4 230.15108,
found 230.15244.
1
71–728C. TLC (hexane/diethyl ether, 1:5): Rf¼0.23; H
NMR (acetone-d6): d 1.07 (d, J¼6.3 Hz, 6H, 2£CH3),
1.34–1.37 (m, 2H, CH2), 1.48–1.49 (m, 3H, CH2), 1.50–
1.51 (m, 1H, CH2), 1.87–1.93 (m, 2H, CH2), 2.29–2.33 (m,
2H, CH2), 3.53–3.55 (m, 1H, CHOH), 3.62–3.63 (m, 1H,
CHOH), 4.80 (sep, J¼6.3 Hz, 1H, CHMe2); 13C NMR
(acetone-d6): d 19.5 (C-4), 22.5 (CH3), 29.3 (C-3), 23.0
(C-5), 30.9 (CH2), 31.2 (CH2COO), 68.2 (OCH(CH3)2),
71.6 (C-6), 72.3 (C-2), 75.6 (C-1), 175.4 (COO); IR (KBr):
3437, 2941, 1711, 1436, 1249 cm21; MS (EI), m/z (%): 246
(8) [M]þ, 220 (12), 205 (30), 186 (34), 168 (100), 158 (42);
HRMS (EI): calcd for C12H22O5 246.146038, found
246.146422.
4.3.2. rel Ethyl 3-[(1S,2S,6S)-2-(acetoxy)-1,6-dihydroxy-
cyclohexyl]propanoate (14). Reaction of epoxide 12
(1.0 g, 4.67 mmol) with predried nBu4NOAc (for 10 min
at 1008C in vacuo) according to general procedure 2
followed by flash chromatography (petroleum ether/diethyl
ether, 1:5) of the crude product yielded 0.75 g (59%) of 14
as colorless crystalline solid, mp 548C. TLC (hexane/diethyl
ether, 1:5): Rf¼0.35; 1H NMR (acetone-d6): d 1.01 (t,
J¼7.1 Hz, 3H, CH3), 1.32–1.37 (m, 3H, CH2), 1.45–1.49
(m, 2H, CH2), 1.55–1.70 (m, 2H, CH2), 1.83 (s, 3H, CH3),
1.88–1.89 (m, 1H, CH2), 2.12–2.27 (m, 2H, CH2), 3.46–
3.47 (m, 1H, CHOH), 3.86 (q, 7.1 Hz, 2H, OCH2), 4.72–
4.74 (m, 1H, CHOR); 13C NMR (acetone-d6): d¼14.6
(CH3), 19.2 (C-4), 21.2 (CH3), 27.0 (C-5), 28.5 (C-3), 29.3
(CH2), 30.3 (CH2COO), 60.6 (CH2OR), 72.3 (C-6), 74.1
(C-2), 85.6 (C-1), 170.5 (H3CCO), 174.6 (CO); IR (KBr):
3528, 2936, 1730, 1701, 1374, 1248 cm21; MS (EI), m/z
(%): 274 (7) [M]þ, 228 (16), 205 (4), 186 (20), 168 (100),
151 (30), 124 (80); HRMS (EI): calcd for C13H22O6
274.141206, found 274.141384.
4.3.5. rel (3aR,4S,7aS)-3a-(3-{[tert-Butyl(dimethyl)silyl]-
oxy}propyl)-2,2-dimethylhexahydro-1,3-benzodioxol-4-
ol (17). A solution of the diol 16 (1.55 g, 6.73 mmol) in dry
DMF (12 mL) was treated with TBDMSCl (1.1 g,
7.27 mmol, 1.08 equiv.) and DBU (1.41 mL, 9.42 mmol,
1.4 equiv.). The mixture was stirred for 24 h at room
temperature, diluted with water (10 mL) and extracted with
ethyl acetate (3£15 mL). After drying of the organic phase
over MgSO4, filtration, and concentration in vacuo, the
residue was purified by flash chromatography (petroleum
ether/diethyl ether, 4:6) to provide 1.81 g (88%) of 17 as a
colorless oil. TLC (hexane/diethyl ether, 3:2): Rf¼0.33; 1H
NMR (acetone-d6): d 0.00 (s, 6H, Si(CH3)2), 0.84 (s, 9H,
C(CH3)3), 1.23 (s, 3H, CH3), 1.35 (s, 3H, CH3), 1.45–1.53
(m, 4H, CH2), 1.61–1.64 (m, 2H, CH2), 1.89–1.93 (m, 2H,
CH2), 1.99–2.00 (m, 1H, CH2), 3.55–3.64 (m, 2H,
CH2OR), 3.76–3.77 (m, 1H, CHOR), 4.01–4.02 (m, 1H,
CHOH); 13C NMR (acetone-d6): d 24.6 (Si(CH3)2), 19.2
(C(CH3)3), 20.3 (C-6), 24.9 (C-7), 26.8 (C(CH3)3), 26.97
(C-1), 27.70 (CH3), 28.31 (C-2), 29.40 (CH3), 31.94 (C-5),
64.88 (C-3), 74.95 (C-7a), 77.73 (C-4), 85.52 (C-3a), 107.74
((RO)2C(CH3)2); IR (film): 3478, 2935, 2858, 1471, 1380,
1252, 1100, 889, 836 cm21; MS (FD), m/z (%): 344.9 (100)
[M]þ.
4.3.3. rel Ethyl 3-[(3aS,4S,7aS)-4-(acetoxy)-2,2-dimethyl-
tetrahydro-1,3-benzodioxol-3a(4H)-yl]propanoate (15).
A solution of the diol 14 (0.7 g, 2.55 mmol), 2,2-
dimethoxypropane (0.38 mL, 3.06 mmol, 1.2 equiv.), and
a small amount of pyridinium para toluenesulfonic acid
(PPTS) in dry acetone (10 mL) was stirred for 3 h at room
temperature. The reaction was diluted with diethyl ether
(30 mL) and washed twice with water (10 mL). The organic
layer was dried over MgSO4, filtered and concentrated in
vacuo. Purification of the residue by flash chromatography
(petroleum ether/diethyl ether, 1:2) gave 0.74 g (93%) of 15
as a colorless oil. TLC (hexane/diethyl ether, 1:4): Rf¼0.83;
1H NMR (C6D6): d 1.09 (t, J¼7.2 Hz, 3H, CH3), 1.19–1.31
(m, 4H, CH2), 1.32 (s, 3H, CH3), 1.67 (s, 3H, CH3), 1.78 (s,
3H, CH3), 1.89–1.94 (m, 2H, CH2), 2.48–2.63 (m, 4H,
4.3.6. rel (3aS,7aS)-3a-(3-{[tert-Butyl(dimethyl)silyl]-
oxy}propyl)-2,2-dimethyltetrahydro-1,3-benzodioxol-
4(3aH)-one (18). To a solution of alcohol 17 (1.8 g,

M. Eipert et al. / Tetrahedron 59 (2003) 7949–7960
7955
5.22 mmol) in dry CH2Cl2 (15 mL) was added dry pyridine
(1.64 mL, 20.9 mmol, 4 equiv.) followed by the slow
addition of Dess–Martin periodinane (DMP) (3.32 g,
7.83 mmol, 1.5 equiv.). After being stirred for 4 h at room
temperature, the brownish solution was diluted with diethyl
ether (15 mL) resulting in a brown precipitate. The solution
was filtered and the filtrate washed thoroughly with a
mixture of a freshly prepared satd. Na2S2O3 and NaHCO3
solution (1:1 v/v, 20 mL) and brine (10 mL). The organic
layer was dried over MgSO4, filtered, diluted with toluene
(10 mL) and concentrated in vacuo giving a yellow oil.
Purification of the residue by flash chromatography
(petroleum ether/diethyl ether, 4:1) gave 1.41 g (79%) of
18 as a yellow oil, which is not stable towards air or light
and must be stored in a cooling box under nitrogen. TLC
trap, dry benzene (130 mL) was heated to 1108C and
Mn(OAc)3·2H2O (24.61 g, 91.8 mmol, 1.5 equiv.) was
added in six portions every 20 min. Heating was continued
for 2–3 h at this temperature, until no more water separated.
The deep red suspension was cooled to room temperature
and the Dean–Stark trap replaced by a reflux condenser. At
this point a solution of cyclohexenone 10 (12.0 g,
61.2 mmol) in dry benzene (20 mL) was added and the
mixture refluxed for 24 h. After cooling, the deep brown
suspension was diluted with ethyl acetate (50 mL) and 1N
HCl solution (40 mL). After 10 min of vigorous stirring, the
mixture was neutralized with satd. NaHCO3 solution,
filtered from the brown solid, and the layers were separated.
The dark red organic solution was washed with brine
(3£30 mL), and dried over MgSO4. After filtration and
concentration of the filtrate, the residue was purified by flash
chromatography (petroleum ether/diethyl ether, 1:1) to
provide the acetate 20 (10.72 g, 69%) as a bright yellow
1
(hexane/diethyl ether, 3:2): Rf¼0.38; H NMR (C6D6): d
20.01, 20.00 (2 s, 6H, Si(CH3)2), 0.93 (s, 9H, C(CH3)3),
1.27 (s, 3H, CH3), 1.28–1.33 (m, 2H, CH2), 1.45 (s, 3H,
CH3), 1.51–1.54 (m, 2H, CH2), 1.67–1.71 (m, 2H, CH2),
1.80–1.86 (m, 3H, CH2), 2.17–2.20 (m, 1H, CH2), 3.42 (t,
J¼4.7 Hz, 2H, CH2OR), 3.86–3.88 (m, 1H, CHOR); 13C
NMR (C6D6): d 26.57 (Si(CH3)2), 17.09 (C(CH3)3), 19.75
(C-6), 24.76 (C(CH3)3), 24.88 (C-2), 25.79 (CH3), 26.06
(CH3), 26.32 (C-7), 28.75 (C-1), 38.91 (C-5), 61.58 (C-3),
80.19 (C-7a), 85.44 (C-3a), 106.91 ((RO)2C(CH3)2), 207.37
(C-4); IR (film): 2953, 2935, 1726, 1472, 1380, 1248,
1101 cm21; MS (FD), m/z (%): 342.3 (100) [M]þ.
1
oil. TLC (hexane/diethyl ether, 1:1): Rf¼0.34; H NMR
(CDCl3): d 1.05 (t, J¼7.7 Hz, 3H, CH3), 1.86–1.95 (m, 1H,
CH2), 1.98 (s, 3H, CH3), 2.05–2.09 (m, 1H, CH2), 2.24–
2.35 (m, 6H, CH2), 3.92 (q, J¼7.0 Hz, 2H, OCH2), 5.12–
5.17 (m, 1H, CHOR), 6.61–6.62 (m, 1H, CHR3); 13C NMR
(CDCl3): d 14.5 (CH3), 21.0 (C-4), 25.0 (C-3), 25.4 (CH3),
28.8 (CH2), 33.2 (CH2COO), 60.5 (CH2OR), 74.0 (C-5),
137.4 (C-2), 145.9 (C-1), 170.2 (COCH3), 172.9 (COOEt),
194.1 (C-6); IR (film): 1739, 1734, 1691, 1374, 1236, 1187,
1098, 1043 cm21; MS (EI), m/z (%): 239 (8) [M2CH3]þ,
196 (53) [M2OAc]þ, 179 (4), 150 (100), 122 (34); HRMS
(EI): calcd for C11H16O3 196.109124, found 196.109825
[M2OAc]þ.
4.3.7. rel (3aS,7aS)-3a-(3-{[tert-Butyl(dimethyl)silyl]-
oxy}propyl)-2,2-dimethyl-7,7a-dihydro-1,3-benzodioxol-
4(3aH)-one (19). A suspension of freshly prepared meta
iodoxybenzoic acid (1.26 g, 4.78 mmol, 3.3 equiv.) and
diphenyldiselenide (0.14 g, 0.44 mmol, 0.3 equiv.) in dry
toluene (9 mL) was heated to reflux. After 10–15 min the
suspension became colorless. The suspension was cooled to
808C before alcohol 17 (0.5 g, 1.45 mmol), dissolved in
2 mL of dry toluene was added dropwise to the reaction
mixture. Stirring was continued for 3 h at 1208C, then the
mixture was cooled to 808C, and further amount of meta
iodoxybenzoic acid (0.19 g, 0.72 mmol, 0.5 equiv.) was
added and the reaction was stirred for further 3 h at 1208C.
After cooling to room temperature, the mixture was diluted
with diethyl ether (20 mL) and washed with satd. NaHCO3
solution (10 mL), water (10 mL) and brine. Drying over
MgSO4, filtration and evaporation of the solvent gave a
yellow oil, which was purified by flash chromatography
(petroleum ether/diethyl ether, 4:1) to yield 0.38 g (76%) of
19 as a yellow, sticky oil. TLC (hexane/diethyl ether, 3:2):
Rf¼0.44; 1H NMR (C6D6): d 0.00, 20.01 (2 s, 6H,
Si(CH3)3), 0.93 (s, 9H, C(CH3)3), 1.27 (s, 3H, CH3), 1.32 (s,
3H, CH3), 1.59–1.62 (m, 2H, CH2), 1.70–1.74 (m, 2H, CH2),
2.00 (ddd, J¼20.2, 2.3, 2.3 Hz, 1H, CH2), 2.34 (dd, J¼20.2,
4.6 Hz, 1H, CH2), 3.42–3.43 (m, 2H, CH2OR), 3.93 (d,
J¼4.6 Hz, 1H, CHOR), 5.90 (dd, J¼11.9, 2.2 Hz, 1H, CHR3),
5.95–5.98 (m, 1H, CHR3); 13C NMR (C6D6): d 26.6
(Si(CH3)2), 17.1 (C(CH3)3), 24.7 (C(CH3)3), 24.9 (CH3),
25.6 (C-2), 26.3 (CH3), 26.5 (C-1), 28.6 (C-7), 61.9 (C-3), 76.0
(C-7a), 81.4 (C-3a), 106.5 ((RO)2C(CH3)2), 126.9 (C-5), 142.5
(C-6), 197.1 (C-4); IR (film): 2984, 2895, 1685, 1472, 138,
1251, 1097, 835 cm21; MS (FD), m/z (%): 340.2 (100) [M]þ.
4.3.9. rel Ethyl 3-[(5R,6R)-5-(acetoxy)-6-hydroxycyclo-
hex-1-en-1-yl]propanoate (21). To a solution of ketone 20
(3.0 g, 11.79 mmol) in dry methanol (6 mL) was added
CeCl3·7H2O (3.07 g, 8.25 mmol) in dry methanol (7 mL) at
room temperature while stirring. After 5 min the yellow
solution was cooled to 258C and NaBH4 (0.47 g,
12.38 mmol) was slowly added such that the temperature
stayed between 25 and 58C (15 min). The mixture was
stirred for 1.5 h at 258C and, after removing of the cooling
bath, stirring was continued for 1 h. The white suspension
was evaporated to dryness and the solid extracted with
diethyl ether (3£10 mL). The combined organic extracts
were washed with brine (10 mL), dried over MgSO4,
filtered, and concentrated in vacuo. The oily residue was
purified by flash chromatography (petroleum ether/diethyl
ether, 1:3) to yield 2.57 g (85%) of 21 as a colorless oil. TLC
1
(hexane/diethyl ether, 1:3): Rf¼0.3; H NMR (CDCl3): d
1.16–1.20 (m, 3H, CH3), 1.60–1.68 (m, 1H, CH2), 1.80–
1.94 (m, 1H, CH2), 1.97 (s, 3H, CH3), 2.00–2.15 (m, 2H,
CH2), 2.39–2.46 (m, 4H, CH2), 4.02–4.08 (m, 3H, CHOH,
OCH2), 4.80 (dt, J¼11.4, 3.4 Hz, 1H, CHOR), 5.51 (m, 1H,
CHR3); 13C NMR (CDCl3): d 14.6 (CH3), 21.6 (C-4), 22.0
(C-3), 24.3 (CH3), 30.0 (CH2), 33.4 (CH2COO), 60.7
(CH2OR), 67.5 (C-6), 73.5 (C-5), 126.0 (C-2), 136.3 (C-1),
170.9 (H3CCO), 173.8 (COOEt); IR (film): 3437, 2981, 1734,
1666, 1375, 1182, 1035 cm21; MS (EI), m/z (%): 255 (10)
[M2H]þ, 209(11), 194(23), 168(25), 148(100);HRMS(EI):
calcd for C13H19O5 255.12308, found 255.12365.
4.3.8. rel Ethyl 3-[5-(acetoxy)-6-oxocyclohex-1-en-1-
yl]propanoate (20). In a flask, fitted with a Dean–Stark
4.3.10. rel Ethyl 3-[(1S,2S,3R,6R)-3-(acetoxy)-2-hydroxy-
7-oxabicyclo[4.1.0]hept-1-yl]propanoate (22). According

7956
M. Eipert et al. / Tetrahedron 59 (2003) 7949–7960
to general procedure 1 the alkenol 21 (2.5 g, 9.75 mmol)
was converted to the epoxide 22. Purification was done by
flash chromatography (petroleum ether/diethyl ether, 2:3)
providing 1.91 g of 22 (72%) as a colorless oil. TLC
(petroleum ether/ethyl acetate, 1:1): Rf¼0.28; 1H NMR
(CDCl3): d 1.19 (t, J¼7.1 Hz, 3H, CH3), 1.36–1.37 (m, 1H,
CH2), 1.55–1.69 (m, 1H, CH2), 1.89–1.95 (m, 2H, CH2),
2.02 (s, 3H, CH3), 2.04–2.16 (m, 2H, CH2), 2.36–2.42 (m,
2H, CH2), 3.15–3.16 (m, 1H, epoxide-H), 4.04–4.09 (m,
3H, CHOH, OCH2), 4.49 (dt, J¼12.3 Hz, 3.8 Hz, 1H,
CHOR); 13C NMR (CDCl3): d 13.1 (CH3), 16.6 (C-5), 20.1
(C-4), 22.4 (CH3), 28.0 (CH2), 29.4 (CH2COO), 59.4 (C-6),
59.6 (CH2OR), 60.8 (C-1), 65.6 (C-2), 70.9 (C-3), 169.6
(H3CCO), 171.8 (COOEt); IR (film): 3497, 2939, 1734,
1730, 1371, 1246 cm21; MS (EI), m/z (%): 272 (7) [M]þ,
271 (8) [M-H]þ, 243 (20), 223 (13), 215 (15), 213 (5)
[M2OAc]þ, 198 (67), 165 (100); HRMS (EI): calcd for
C13H20O6 272.12502, found 272.12568.
1:3): Rf¼0.22; 1H NMR (acetone-d6): d 1.58–1.62 (m, 4H,
CH2), 1.78–1.81 (m, 1H, CH2), 2.03–2.16 (m, 3H, CH2),
2.38–2.57 (m, 2H, CH2), 3.96–3.97 (m, 1H, CHOH), 4.48–
4.50 (m, 1H, CHBr); 13C NMR (acetone-d6): d 21.1 (C-8),
30.2 (C-4), 30.4 (C-9), 30.7 (C-3), 33.7 (C-7), 59.2 (C-6),
72.7 (C-10), 88.9 (C-5), 177.2 (C-2); IR (KBr): 3415, 2955,
2927, 2532, 1749, 1450, 1232 cm21; MS (EI), m/z (%): 250
(4) [M]þ, 248 (3) [M]þ, 169 (6) [M2Br]þ, 151 (55), 124
(32), 101 (67); MS (FD), m/z (%): 250.1 (100) [M]þ, 248.1
(100) [M]þ.
4.3.13. rel (5R,6R,10R)-6-Bromo-10-[(trimethylsilyl)-
oxy]-1-oxaspiro[4.5]decan-2-one (26). A solution of 25
(0.7 g, 2.81 mmol) in dry CH2Cl2 (4 mL) was cooled to 08C
and treated with hexamethyldisilazane (0.7 mL, 3.37 mmol,
1.2 equiv.), TMSCl (0.4 mL, 3.09 mmol, 1.1 equiv.) and a
small amount of 4-DMAP. After being stirred for 2 h at
room temperature, the reaction was carefully quenched with
ice cold, satd. NaHCO3 solution at 08C and extracted with
diethyl ether (3£15 mL). The combined organic layers were
dried over MgSO4, filtered, and concentrated in vacuo. The
residue was purified by flash chromatography (petroleum
ether/diethyl ether, 3:2) resulting in 0.83 g (92%) of 26 as a
colorless gel. TLC (hexane/diethyl ether, 3:2): Rf¼0.45; 1H
NMR (CDCl3): d 20.07, 20.00 (2 s, 9H, Si(CH3)3), 1.57–
1.59 (m, 4H, CH2), 1.73–1.77 (m, 1H, CH2), 2.02–2.09 (m,
3H, CH2), 2.40–2.52 (m, 2H, CH2), 3.97–3.98 (m, 1H,
CHOR), 4.23–4.24 (m, 1H, CHBr); 13C NMR (CDCl3): d
0.0, 0.7 (Si(CH3)3), 19.3 (C-8), 29.8, 29.8, 29.9, 23.0 (C-3,
C-4, C-7, C-9), 57.2 (C-6), 72.5 (C-10), 87.3 (C-5), 176.4
(C-2); IR (film): 2960, 2876, 1762, 1274, 1168 cm21; MS
(FD), m/z (%): 321.4 (100) [M]þ; HRMS (FT-ICR): calcd
for [C12H21O3BrSiþNa]þ 343.03355, found 343.03368;
found 345.03162.
4.3.11. rel (6R,10R)-6,10-Dihydroxy-1-oxaspiro[4.5]-
decan-2-one (24). A solution of epoxide 12 (1.0 g,
4.67 mmol) in dry CH2Cl2 (4 mL) was treated with
Ti(OiPr)4 (1.66 mL, 5.60 mmol, 1.2 equiv.) at room tem-
perature. The mixture was stirred for 10 min, cooled to 08C
and then dry ethanol (1.5 mL) was added. After 5 min, the
cooling bath was removed and the mixture was stirred for
further 8 h at room temperature. The yellow solution was
quenched with water (1 mL) and extracted with ethyl
acetate (4£15 mL). The combined organic layers were dried
over MgSO4, filtered and concentrated in vacuo to obtain a
colorless oil, which was purified by flash chromatography
(ethyl acetate/petroleum ether, 4:1) yielding 0.56 g (64%) of
24 as a colorless gel. TLC (ethyl acetate/hexane, 7:3):
1
Rf¼0.24; H NMR (CDCl3): d 1.37–1.51 (m, 2H, CH2),
1.73–1.83 (m, 4H, CH2), 2.36–2.67 (m, 4H, CH2), 3.84–
3.85 (m, 1H, CHOH), 4.07–4.10 (m, 1H, CHOH); 13C NMR
(CDCl3): d 16.9 (C-8), 23.9 (C-4), 27.8 (C-7), 28.7 (C-9),
29.4 (C-3), 69.2 (C-6), 72.2 (C-10), 90.3 (C-5), 177.1 (C-2);
IR (KBr): 3427, 2942, 1757, 1458, 1213, 1044 cm21; MS
(EI), m/z (%): 187 (4) [MþH]þ, 168 (20) [M2H2O]þ, 151
(14), 124 (100), 111 (40), 84 (58); HRMS (EI): calcd for
C9H12O3 [M2H2O]þ 168.078631, found 168.080179.
4.3.14. rel (5R,6R,10R)-6-Bromo-10-{[tert-butyl-
(dimethyl)silyl]oxy}-1-oxaspiro[4.5]decan-2-one (27). To
a solution of the lactone 25 (3.0 g, 12.3 mmol) in dry
CH2Cl2 (10 mL) were added TBDMSOTf (0.35 mL,
1.5 mmol, 1.25 equiv.) and imidazole (0.17 g, 24.6 mmol,
2 equiv.) at 08C. After 10 min of stirring, the cooling bath
was removed and the mixture was stirred for further 3 h at
258C. After addition of brine (4 mL) the mixture was
extracted with diethyl ether (3£20 mL). The combined
organic layers were dried over MgSO4, filtered, and
concentrated leaving a yellow oil, which was purified by
flash chromatography (petroleum ether/diethyl ether, 8:3)
which gave 3.75 g (84%) of 27 as fine needles, mp 1398C.
TLC (hexane/diethyl ether, 4:1): Rf¼0.24; 1H NMR
(CDCl3): d 20.03, 20.00 (2 s, 6H, Si(CH3)2), 0.77 (s, 9H,
C(CH3)3), 1.53–1.65 (m, 4H, CH2), 1.76–1.77 (m, 1H,
CH2), 2.10–2.11 (m, 1H, CH2), 2.13–2.15 (m, 2H, CH2),
2.48–2.53 (m, 2H, CH2), 3.95–3.97 (m, 1H, CHOR), 4.31
(m, 1H, CHBr); 13C NMR (CDCl3): d 26.7 (Si(CH3)2), 16.0
(C(CH3)3), 17.7 (C-8), 23.7 (C(CH3)3), 27.7 (C-4), 27.7
(C-9), 27.9 (C-3), 28.3 (C-7), 55.3 (C-6), 71.3 (C-10), 85.9
(C-5), 174.4 (C-2); IR (KBr): 2951, 2891, 1760, 1409,
1281 cm21; MS (FD), m/z (%): 306.7 [M2tBu]þ, 304.7
[M2tBu]þ.
4.3.12. rel (5R,6R,10R)-6-Bromo-10-hydroxy-1-oxa-
spiro[4.5]decan-2-one (25). To a solution of epoxide 12
(3.51 g, 16.40 mmol) in dry CH2Cl2 (12 mL) was added
Ti(OiPr)4 (5.11 mL, 17.18 mmol, 1.05 equiv.) at room
temperature. The mixture was stirred for 10 min at 258C,
cooled to 258C and very slowly, a solution of bromine
(0.88 mL, 17.18 mmol, 1.05 equiv.) in dry CH2Cl2 (2 mL)
was added dropwise in such manner that the yellow color of
the bromine vanished immediately. After addition, the
cooling bath was removed and the reaction mixture stirred
for further 8 h at room temperature. The bright red solution
was quenched with a aqueous L-tartaric acid solution
(15 mL), diluted with diethyl ether (40 mL) and stirred for
5 min, until two clear phases were observed. The layers
were separated and the aqueous layer was extracted with
ethyl acetate (2£30 mL). The combined organic layers were
dried over MgSO4, filtered, and concentrated in vacuo.
Purification of the residue by flash chromatography
(petroleum ether/diethyl ether, 1:3) gave 2.77 g (68%) of
25 as white crystals, mp 1198C. TLC (hexane/diethyl ether,
4.4. General procedure 3 for HBr-elimination
A 0.3 M solution of the spirolactone in benzene was treated

M. Eipert et al. / Tetrahedron 59 (2003) 7949–7960
7957
with DBU (1.5 equiv.). The solution was heated at 808C for
2 h, cooled to room temperature and diluted with a mixture
of diethylether/water (1:1). The organic phase was separated
and the aqueous layer extracted three times with diethyl
ether. The combined organic layers were dried over MgSO4,
filtered, and concentrated in vacuo.
flash chromatography (petroleum ether/diethyl ether, 3:2)
delivered 0.28 g (74%) of 30 as a colorless, sticky oil. TLC
1
(hexane/diethyl ether, 3:2): Rf¼0.2; H NMR (CDCl3): d
20.05, 20.04 (2 s, 9H, Si(CH3)3), 1.64–1.75 (m, 1H, CH2),
1.80–1.90 (m, 1H, CH2), 1.93–2.05 (m, 1H, CH2), 2.15–
2.25 (m, 2H, CH2), 2.44–2.53 (m, 3H, CH2), 3.05 (d,
J¼4.1 Hz, 1H, epoxide-H), 3.15–3.17 (m, 1H, epoxide-H),
3.62–3.65 (m, 1H, CHOR); 13C NMR (CDCl3): d 0.0, 20.8
(Si(CH3)3), 21.5 (C-3), 25.3 (C-40), 28.6 (C-4), 29.6 (C-50),
53.4 (C-10), 58.4 (C-60), 71.3 (C-6), 83.9 (C-20), 176.7 (C-5);
IR (film): 2979, 2937, 2864, 1759, 142, 1290 cm21; MS
(FD), m/z (%): 256.2 (100) [M]þ.
4.4.1. rel (5S,10R)-10-[(Trimethylsilyl)oxy]-1-oxa-
spiro[4.5]dec-6-en-2-one (28). Lactone 26 (0.5 g,
1.56 mmol) was converted to the alkene 28 according to
the general procedure 3. Purification of the crude product by
flash chromatography (petroleum ether/diethyl ether, 3:2)
gave 0.23 g (62%) of 28 as a yellow oil. TLC (hexane/
diethyl ether, 3:2): Rf¼0.3; H NMR (CDCl3): d 20.08,
4.5.2. rel (10R,2S,30R,60R)-30-{[tert-Butyl(dimethyl)-
silyl]oxy}dihydro-5H-spiro[furan-2,20-[7]oxabicyclo-
[4.1.0]heptan]-5-one (31). Alkene 29 (1.2 g, 4.26 mmol)
was converted to the epoxide 31 according to general
procedure 4. Purification by flash chromatography
(petroleum ether/diethyl ether, 6:4) gave 0.83 g (65%) of
31 as a colorless solid, mp 498C. TLC (hexane/diethyl ether,
1
20.00 (2 s, 9H, Si(CH3)3), 1.54–1.56 (m, 1H, CH2), 1.75–
2.11 (m, 5H, CH2), 2.34–2.37 (m, 1H, CH2), 2.49–2.56 (m,
1H, CH2), 3.56–3.60 (m, 1H, CHOR), 5.39 (d, J¼11.9 Hz,
1H, CHR3), 5.79–5.80 (m, 1H, CHR3); 13C NMR (CDCl3):
d 20.1, 0.7 (Si(CH3)3), 25.0 (C-8), 26.8 (C-9), 29.6 (C-4),
32.3 (C-3), 75.0 (C-10), 83.3 (C-5), 128.0 (C-6), 133.5
(C-7), 177.0 (C-2); IR (film): 3023, 2954, 1761, 1423, 1384,
1242 cm21; MS (FD), m/z (%): 240.2 (100) [M]þ.
1
3:2): Rf¼0.29; H NMR (CDCl3): d 0.00, 20.02 (2 s, 6H,
Si(CH3)2), 0.81–0.84 (s, 9H, C(CH3)3), 1.37–1.39 (m, 1H,
CH2), 1.70–1.73 (m, 1H, CH2), 1.83–1.92 (m, 1H, CH2),
2.01–2.11 (m, 1H, CH2), 2.25–2.32 (m, 2H, CH2), 2.52–
2.60 (m, 2H, CH2), 3.11 (d, J¼3.5 Hz, 1H, epoxide-H),
3.22–3.23 (m, 1H, epoxide-H), 3.66–3.69 (m, 1H, CHOR);
13C NMR (CDCl3): d 25.8, 25.6 (Si(CH3)2), 16.9
(C(CH3)3), 20.5 (C-3), 24.3 (C-40), 24.6 (C(CH3)3), 27.7
(C-4), 28.4 (C-50), 52.7 (C-10), 57.5 (C-60), 70.4 (C-6), 83.1
(C-20), 175.8 (C-5); IR (KBr): 2952, 2927, 2884, 2856,
1764, 1472, 1294, 1252, 1196 cm21; MS (FD), m/z (%):
298.3 (100) [M]þ.
4.4.2. rel (5S,10R)-10-{[tert-Butyl(dimethyl)silyl]oxy}-1-
oxaspiro[4.5]dec-6-en-2-one (29). Starting from lactone 27
(3.0 g, 8.2 mmol), elimination according to general
procedure 3 and purification of the crude product by flash
chromatography (petroleum ether/diethyl ether, 6:4) gave
2.15 g (93%) of 29 as colorless oil with an unpleasant odour.
The oil solidified at 2208C, colorless crystals, mp 518C.
TLC (hexane/diethyl ether, 3:2): Rf¼0.39; 1H NMR
(CDCl3): d 0.00 (s, 6H, Si(CH3)2), 0.79 (s, 9H, C(CH3)3),
1.63–1.64 (m, 1H, CH2), 1.78–1.95 (m, 1H, CH2), 1.98–
2.01 (m, 2H, CH2), 2.12–2.18 (m, 2H, CH2), 2.42–2.44 (m,
1H, CH2), 2.55–2.58 (m, 1H, CH2), 3.61–3.65 (m, 1H,
CHOR), 5.44 (d, J¼10.6 Hz, 1H, CHR3), 5.83–5.86 (m, 1H,
CHR3); 13C NMR (CDCl3): d 25.3 (Si(CH3)3), 16.9
(C(CH3)3), 24.2 (C(CH3)3), 24.7 (C-8), 26.3 (C-9), 28.8
(C-4), 31.3 (C-3), 74.3 (C-10), 82.8 (C-5), 127.4 (C-6),
132.5 (C-7), 176.2 (C-2); IR (KBr): 3025, 2934, 1765, 1461,
1250, 1226, 1180, 1106 cm21; MS (FD), m/z (%): 283.2
[M]þ.
4.5.3. rel (3S,5S,10R)-3-Azido-10-{[tert-butyl(dimethyl)-
silyl]oxy}-1-oxaspiro[4.5]dec-6-en-2-one (32). To
a
solution of diisopropylamine (0.13 mL, 1.77 mmol) in dry
THF (5 mL) was added nBuLi (1.73 mmol, 0.98 equiv.,
2.5 M in hexane) dropwise at 2788C. The mixture was
stirred for 30 min at 2788C, before lactone 29 (0.5 g,
1.77 mmol), dissolved in dry THF (2 mL), was added
dropwise. After 30 min at this temperature, a solution of
trisylazide (0.71 g, 2.3 mmol, 1.3 equiv.) in dry THF (2 mL)
was added dropwise to the enolate solution. Stirring was
continued for 15 min, then the bright yellow solution was
treated with glacial acetic acid (0.47 mL, 8.14 mmol,
4.6 equiv.) and the mixture was slowly warmed to room
temperature and kept for 5 h at 258C. The mixture was
diluted with CH2Cl2 (20 mL) and washed with satd.
NaHCO3 solution (2£10 mL) and brine (10 mL). The
organic layer was dried over MgSO4, filtered and concen-
trated in vacuo. Purification by flash chromatography
(hexane/diethyl ether, 4:1) gave 0.51 g (89%) of 32 as
colorless needles, mp 1018C. TLC (hexane/diethyl ether,
4:1): Rf¼0.44; 1H NMR (CDCl3): d 20.02 (s, 6H,
Si(CH3)2), 0.78 (s, 9H, C(CH3)3), 1.59–1.62 (m, 1H,
CH2), 1.75–1.84 (m, 2H, CH2), 1.96–2.02 (m, 1H, CH2),
2.14–2.15 (m, 1H, CH2), 2.39–2.45 (m, 1H, CH2), 3.58–
3.62 (m, 1H, CHOR), 4.39 (t, J¼8.2 Hz, 1H, CHN3), 5.39
4.5. General procedure 4 for the epoxidation of com-
pounds 28, 29 and 34
A mixture of the alkene (0.5 M in dry CHCl3) and MgSO4
(0.4 g/mmol of alkene) was treated with mCPBA (4 equiv.)
at 258C. Stirring was continued for 8 h, then the mixture was
cooled to 08C and cyclohexene (3 mL/mmol) was added
dropwise. The cooling bath was removed and the mixture
stirred for 1.5 h at room temperature. The white suspension
was diluted with diethylether (8 mL/mmol) and washed
twice with satd. NaHCO3 solution (8 mL/mmol). The
aqueous phase was extracted with diethyl ether
(5 mL/mmol). The combined etheral layers were dried
over MgSO4, filtered and concentrated in vacuo.
4.5.1. rel (10R,2S,30R,60R)-30-[(Trimethylsilyl)oxy]dihy-
dro-5H-spiro[furan-2,20-[7]oxabicyclo[4.1.0]heptan]-5-
one (30). Conversion of lactone 28 (0.35 g, 1.46 mmol) to
the epoxycyclohexane 30 was performed according to
general procedure 4. Purification of the crude product by
(d, J¼11.5 Hz, 1H, CHR3), 5.89–5.92 (m, 1H, CHR3); 13
C
NMR (CDCl3): d 24.2 (Si (CH3)2), 23.8 (Si(CH3)2), 18.3
(C(CH3)3), 25.8 (C-8), 26.1 (C(CH3)3), 27.3 (C-9), 40.2
(C-4), 58.8 (C-3), 75.6 (C-10), 82.7 (C-5), 127.9 (C-6),
135.8 (C-7), 173.8 (C-2); IR (KBr): 2927, 2856, 2106 (N3),

7958
M. Eipert et al. / Tetrahedron 59 (2003) 7949–7960
1765, 1472, 1460, 1288, 1261, 1103 cm21; MS (FD), m/z
52.9 (C-10), 56.2 (C-60), 68.5 (C-30), 83.1 (C-20), 176.1 (C-5);
IR(KBr):3418, 2937, 1760, 1574, 1417, 1263 cm21; MS(EI),
m/z (%): 185 (7) [MþH]þ, 167 (8) [MþH2H2O]þ, 156 (72),
139, 127 (100); HRMS (EI): calcd for C9H13O4 185.081378,
found 185.082732.
(%): 323.4 [M]þ.
4.5.4. rel (3S,5S,10R)-3-Amino-10-{[tert-butyl(dimethyl)-
silyl]oxy}-1-oxaspiro[4.5]dec-6-en-2-one (33). A solution
of azide 20 (0.5 g, 1.54 mmol) in dry THF (3 mL) was
treated with triphenylphosphine (0.81 g, 3.08 mmol,
2 equiv.) at 258C. Stirring was continued until no more
gas bubbles were observed and the yellow color of the
solution vanished (after 45 min). Water (800 mL) was added
and the solution stirred for 24 h at 458C. Thereafter, Na2SO4
(0.2 g) was added and the suspension vigorously stirred for
5 min, and then diluted with ethyl acetate (30 mL). After
filtration, the mixture was evaporated to dryness. Purifi-
cation by flash chromatography (petroleum ether/ethyl
acetate 1:1!ethyl acetate) yielded 0.37 g (81%) of amine
21 as a colorless solid, mp 1558C. TLC (hexane/ethyl
4.5.7. rel (10R,2S,60R)-Dihydro-30H,5H-spiro[furan-2,20-
[7]oxabicyclo[4.1.0]heptane]-30,5-dione (36). A suspen-
sion of diphenyldiselenide (0.19 g, 0.65 mmol) and meta
iodoxybenzoic acid (0.86 g, 3.25 mmol) in dry toluene
(5 mL) was heated for 10 min at 1308C until the yellow
color had disappeared. The white suspension was cooled to
808C and slowly treated with a solution of 35 (0.4 g,
2.17 mmol) in dry toluene (3 mL). The mixture was stirred
for 1.5 h at 808C, cooled to room temperature and diluted
with diethyl ether (30 mL). The yellow suspension was
washed half saturated NaHCO3 solution (2£10 mL) and
brine (10 mL). After drying of the organic layer with
MgSO4, filtration and evaporation of the solvent in vacuo,
the residue was purified by flash chromatography
(petroleum ether/diethyl ether, 2:3) to yield 0.35 g (89%)
of 36 as a colorless gel. TLC (hexane/diethyl ether, 2:3):
1
acetate, 1:1): Rf¼0.1; H NMR (CDCl3): d 20.00 (s, 6H,
Si(CH3)2), 0.78 (s, 9H, C(CH3)3), 1.57–1.61 (m, 1H, CH2),
1.77–1.81 (m, 2H, CH2), 1.91–2.01 (m, 1H, CH2), 2.10–
2.15 (m, 1H, CH2), 2.47–2.53 (m, 1H, CH2), 3.62–3.65 (m,
1H, CHOR), 3.83 (t, J¼7.9 Hz, 1H, CHNH2), 5.40 (d,
J¼9.7 Hz, 1H, CHR3), 5.83–5.85 (m, 1H, CHR3); 13C
NMR (CDCl3): d 25.7, 25.4 (Si(CH3)2), 16.8 (C(CH3)3),
24.2 (C-8), 24.7 (C(CH3)3), 26.1 (C-9), 41.9 (C-4), 51.1
(C-3), 74.0 (C-10), 78.0 (C-5), 127.6 (C-6), 133.2 (C-7),
178.3 (C-2); IR (KBr): 3034, 2931, 2859, 1761, 1459, 1302,
1271 cm21; MS (FD), m/z (%): 297.3 [M]þ.
1
Rf¼0.2; H NMR (CDCl3): d 2.27–2.32 (m, 4H, CH2),
2.45–2.60 (m, 4H, CH2), 3.30–3.31 (m, 1H, epoxide-H),
3.45 (d, J¼2.7 Hz, 1H, epoxide-H); 13C NMR (CDCl3): d
21.8 (C-30), 26.1 (C-400), 27.3 (C-4), 30.3 (C-50),0 51.9 (C-60),
56.0 (C-1 ), 81.4 (C-2 ), 174.7 (C-5), 202.5 (C-3 ); IR (KBr):
2962, 2924, 1786, 1718, 1420, 1261, 1098, 1021 cm21; MS
(FD), m/z (%): 182.1 (100) [M]þ.
4.5.5. (5S,10R)-10-Hydroxy-1-oxaspiro[4.5]dec-6-en-2-
one (34). A solution of lactone 29 (0.5 g, 1.77 mmol) in
dry THF (3.5 mL) was treated with a TBAF solution
(1.77 mL, 1 M in THF) at room temperature. After stirring
for 30 min at 258C, the mixture was diluted with brine
(7 mL) and extracted with ethyl acetate (30 mL). The
organic layer was dried over MgSO4, filtered, and
concentrated in vacuo. Purification by flash chromatography
(petroleum ether/diethyl ether, 1:2) yielded 0.27 g (90%) of
34 as a sticky, clear oil. TLC (hexane/diethyl ether, 3:2):
4.6. General procedure 5 for the acid induced epoxide
cleavage
A solution of the epoxide (0.4 M in dry THF) was treated
with glacial acetic acid (3 equiv.) and dry LiBr (2 equiv.)
under nitrogen. After stirring for 5 h at room temperature,
the yellow mixture was treated with water (2 mL/mmol) and
extracted three times with diethyl ether (12 mL/mmol). The
combined organic extracts were dried over MgSO4, filtered
and concentrated in vacuo.
1
Rf¼0.13; H NMR (CDCl3): d 1.77–1.81 (m, 2H, CH2),
1.98–2.13 (m, 2H, CH2), 2.19–2.22 (m, 1H, CH2), 2.37–
2.38 (m, 1H, CH2), 2.53–2.55 (m, 1H, CH2), 2.66–2.71 (m,
1H, CH2), 3.59–3.63 (m, 1H, CHOH), 5.52 (d, J¼9.8 Hz,
1H, CHR3), 5.88–5.92 (m, 1H, CHR3); 13C NMR (CDCl3):
d 23.7 (C-8), 26.1 (C-9), 28.4 (C-4), 30.5 (C-3), 72.1 (C-10),
83.4 (C-5), 126.5 (C-6), 132.4 (C-7), 176.8 (C-2); IR (film):
3029, 2944, 2852, 1763, 1260, 1177 cm21; MS (EI), m/z
(%): 168 (15) [M]þ, 151 (9) [M2H2O]þ, 139 (100), 129
(45), 105 (67); HRMS (EI): calcd for C9H12O3 168.078631,
found 168.079532.
4.6.1. rel (5R,6S,7S,10R)-7-Bromo-6,10-dihydroxy-1-
oxaspiro[4.5]decan-2-one (37). Epoxide 35 (0.5 g,
2.71 mmol) was converted to 37 according to the general
procedure 5. Flash chromatography (petroleum ether/
diethyl ether, 1:9) of the crude product gave 0.63 g (89%)
of 37 as colorless crystals, mp 2158C (decomposition). TLC
(petroleum ether/diethyl ether, 1:9): Rf¼0.19; 1H NMR
(methanol-d4): d 1.50–1.53 (m, 1H, CH2), 1.64–1.68 (m,
2H, CH2), 1.95–2.01 (m, 1H, CH2), 2.20–2.24 (m, 2H,
CH2), 2.42–2.45 (m, 1H, CH2), 2.59–2.62 (m, 1H, CH2),
3.80–3.81 (m, 1H, CHOH), 3.89–3.90 (m, 1H, CHBr), 4.00
(d, J¼12 Hz, 1H, CHOH); 13C NMR (methanol-d4): d 27.3
(C-4), 30.3 (C-9), 31.9 (C-3), 32.2 (C-8), 56.3 (C-7), 75.1
(C-10), 77.3 (C-6), 93.2 (C-5), 180.8 (C-2); IR (KBr): 3408,
3278, 2954, 1743, 1458, 1419, 1249 cm21; MS (FD), m/z
(%): 265.0 (100) [M]þ, 267.0 (100) [M]þ.
4.5.6. rel (10R,2R,30R,60R)-30-Hydroxydihydro-5H-spiro-
[furan-2,20-[7]oxabicyclo[4.1.0]heptan]-5-one (35). Alkene
34 (0.6 g, 3.56 mmol) was converted to the epoxide 35
according to the general procedure 4. Flash chromatography
(petroleum ether/diethyl ether, 1:9) gave 0.47 g (73%) of35 as
a colorless solid, mp 70–718C. TLC (petroleum ether/diethyl
ether, 1:9): Rf¼0.33; 1H NMR (CDCl3): d 1.45–1.50 (m, 1H,
CH2), 1.69–1.87 (m, 1H, CH2), 1.91–1.97 (m, 1H, CH2),
2.10–2.25 (m, 1H, CH2), 2.31–2.33 (m, 2H, CH2), 2.59–2.64
(m, 2H, CH2), 3.11 (d, J¼3.6 Hz, 1H, epoxide-H), 3.26–3.28
(m, 1H, epoxide-H), 3.60–3.63 (m, 1H, CHOH); 13C NMR
(CDCl3): d 19.4 (C-3), 22.8 (C-40), 27.4 (C-4), 27.4 (C-50),
4.6.2. rel (5S,6S,7S,10R)-7-Bromo-10-{[tert-butyl-
(dimethyl)silyl]oxy}-6-hydroxy-1-oxaspiro[4.5]decan-2-
one (38). Epoxide 31 (0.5 g, 1.67 mmol) was converted to
38 according to general procedure 5. Purification by flash
chromatography (hexane/diethyl ether, 1:1) delivered 0.55 g

M. Eipert et al. / Tetrahedron 59 (2003) 7949–7960
7959
(87%) of 38 as white needles, mp 2018C (from hexane).
TLC (hexane/diethyl ether, 1:1): Rf¼0.19; 1H NMR
(CDCl3): d 20.01, 20.07 (2 s, 6H, Si(CH3)2), 0.84 (s, 9H,
C(CH3)3), 1.43–1.62 (m, 3H, CH2), 2.01–2.07 (m, 1H,
CH2), 2.26–2.29 (m, 2H, CH2), 2.32–2.44 (m, 1H, CH2),
2.71–2.76 (m, 1H, CH2), 3.79–3.80 (m, 1H, CHOR),
3.82–3.83 (m, 1H, CHBr), 4.15 (d, J¼13.9 Hz, 1H,
CHOH); 13C NMR (CDCl3): d 26.2, 25.6 (Si(CH3)2),
17.1 (C(CH3)3), 24.3 (C-4), 24.7 (C(CH3)3), 28.3 (C-9), 28.5
(C-3), 28.8 (C-8), 53.7 (C-7), 73.0 (C-10), 74.5 (C-6), 88.3
(C-5), 175.7 (C-2); IR (KBr): 3431, 2954, 2928, 2855, 1757,
1460, 1260, 1103, 1021, 926 cm21; MS (FD), m/z (%):
379.0 [M]þ, 381.0 [M]þ.
(COO), 173.9 (C-2); IR (KBr): 2965, 2939, 2844, 1769,
1725, 1421, 1203 cm21; MS (FD), m/z (%): 426.9
[M2tBu]þ, 424.9 [M2tBu]þ.
4.6.5. rel (5S,6R,10R)-10-{[tert-Butyl(dimethyl)silyl]-
oxy}-2-oxo-1-oxaspiro[4.5]dec-7-en-6-yl benzoate (41).
To a solution of spiro lactone 40 (1.0 g, 2.07 mmol) in dry
toluene (10 mL) was added N-ethyldiisopropylamine
(Hu¨nig’s base) (0.43 mL, 2.48 mmol, 1.2 equiv.) and the
mixture heated at 1558C under reflux for 2.5 h. The mixture
was cooled to room temperature, diluted with diethyl ether
(10 mL) and washed with diluted acetic acid (15 mL), satd.
NaHCO3 solution (20 mL) and brine (20 mL). The organic
layer was dried over MgSO4, filtrated, and concentrated
under reduced pressure. Purification by flash chromato-
graphy (petroleum ether/diethyl ether, 1:1) gave 0.59 g
(71%) of 41 as colorless gel, besides 0.12 g (12%) of
starting material 40. TLC (hexane/diethyl ether, 2:3):
Rf¼0.55; 1H NMR (CDCl3): d 0.00, 20.09 (2 s, 6H,
Si(CH3)2), 0.85 (s, 9H, C(CH3)3), 2.13–2.20 (m, 2H, CH2),
2.34–2.35 (m, 2H, CH2), 2.53–2.64 (m, 2H, CH2), 4.03–
4.06 (m, 1H, CHOR), 5.57 (d, J¼2.2 Hz, 1H, CHOR),
5.71–5.74 (m, 1H, CHR3), 5.81–5.84 (m, 1H, CHR3),
7.38–7.41 (m, 2H, aromatic H), 7.51–7.54 (m, 1H,
aromatic H), 7.90–7.92 (m, 2H, aromatic H); 13C NMR
(CDCl3): d 25.4, 25.7 (Si(CH3)2), 17.0 (C(CH3)3), 24.7
(C(CH3)3), 26.0 (C-4), 28.1 (C-9), 31.5 (C-3), 70.3 (C-10),
72.6 (C-6), 85.4 (C-5), 122.0 (C-7), 127.6, 128.5 (aromatic
C), 128.6 (C-8), 128.7, 132.4 (aromatic C), 164.5 (COO),
175.5 (C-2); IR (KBr): 3043, 2956, 2928, 1784, 1722, 1601,
1471, 1451, 1262, 1106 cm21; MS (FD), m/z (%): 402.3
[M]þ.
4.6.3. rel (5S,6R,7S,10R)-10-{[tert-Butyl(dimethyl)silyl]-
oxy}-6-hydroxy-7-methoxy-1-oxaspiro[4.5]decan-2-one
(39). To a solution of lactone 31 (1.0 g, 3.35 mmol) in dry
methanol (15 mL) were added 2 drops of concentrated
H2SO4. The mixture was stirred for 3 h at room temperature,
neutralized with satd. NaHCO3 solution, then most of the
solvents were removed in vacuo. The residue was
redissolved in diethyl ether (30 mL), the suspension filtered,
and the ether layer dried over MgSO4, filtered, and
concentrated in vacuo. Purification by flash chromatography
(petroleum ether/ethyl acetate, 1:1) yielded 0.9 g (81%) of
39 as colorless crystals, mp 132–1338C. TLC (hexane/ethyl
acetate, 1:1): Rf¼0.3; 1H NMR (CDCl3): d 0.00, 20.07 (2 s,
6H, Si(CH3)2), 0.84 (s, 9H, C(CH3)3), 1.36–1.38 (m, 1H,
CH2), 1.55–1.69 (m, 3H, CH2), 1.84–1.86 (m, 1H, CH2),
2.31–2.42 (m, 2H, CH2), 2.72–2.73 (m, 1H, CH2), 3.01–
3.02 (m, 2H, CH2, CHOR), 3.38 (s, 3H, OCH3), 3.75–3.76
(m, 1H, CHOR), 3.98 (d, J¼12.0 Hz, 1H, CHOH); 13C
NMR (CDCl3): d 26.2, 25.7 (Si(CH3)2), 17.1 (C(CH3)3),
21.1 (C-9), 24.7 (C(CH3)3), 25.0 (C-4), 25.5 (C-3),
28.9 (C-8), 56.0 (OCH3), 72.8 (C-6), 73.1 (C-10), 80.5
(C-7), 88.8 (C-5), 176.0 (C-2); IR (KBr): 3391, 2953,
2857, 1769, 1471, 1252 cm21; MS (FD), m/z (%): 330.3
[M]þ.
4.6.6. rel (10R,2S,20R,40R,60R)-40-{[tert-Butyl(dimethyl)-
silyl]oxy}-5-oxodihydro-3H-spiro[furan-2,30-[7]oxa-
bicyclo[4.1.0]heptan]-20-yl benzoate (42). To a suspension
of spirolactone 41 (0.5 g, 1.24 mmol) and MgSO4 (0.5 g) in
dry CHCl3 (5 mL) was added mCPBA (0.86 g, 4.96 mmol,
4 equiv.) in small portions at 258C. After complete
addition, the mixture was stirred for 6 h at 358C, cooled to
08C and slowly treated with cyclohexene (10 mL). After
further stirring for 30 min at 258C, most of the solvent was
removed in vacuo and the residue resuspended in ethyl
acetate (20 mL). This was washed with satd. NaHCO3
solution (3£20 mL). The organic layer was dried over
MgSO4, filtrated and concentrated in vacuo. Purification by
flash chromatography (petroleum ether/diethyl ether, 3:2)
yielded 0.38 g (63%) of 42 as colorless needles, mp 1248C.
TLC (hexane/diethyl ether, 1:1): Rf¼0.42; 1H NMR
(CDCl3): d 0.00, 0.08 (2 s, 6H, Si(CH3)3), 0.85 (s, 9H,
C(CH3)3), 1.97–1.98 (m, 1H, CH2), 2.09–2.11 (m, 2H,
CH2), 2.22–2.23 (m, 1H, CH2), 2.52–2.56 (m, 2H, CH2),
3.31–3.32 (m, J¼3.5 Hz, 1H, epoxide H), 3.57 (t,
J¼3.5 Hz, 1H, epoxide H), 3.89 (t, J¼4.8 Hz, 1H,
CHOR), 5.56 (d, J¼3.3 Hz, 1H, CHOR), 7.38–7.42 (m,
2H, aromatic H), 7.51–7.55 (m, 1H, aromatic H), 7.94–7.97
(m, 2H, aromatic H); 13C NMR (CDCl3): d 25.8, 25.7
(Si(CH3)2), 17.0 (C(CH3)3), 24.7 (C(CH3)3), 25.3 (C-3),
28.1 (C-50)0, 29.8 (C-4), 51.6 (C-10), 52.0 (C-60), 70.7 (C-40),
72.2 (C-2 ), 85.8 (C-30), 127.6, 128.3, 128.7, 132.5
(aromatic C), 164.65 (COO), 174.99 (C-5); IR (KBr):
3442, 2930, 2856, 1783, 1723, 1574, 1451, 1324, 1262,
1106 cm21; MS (FD), m/z (%): 418.3 [M]þ.
4.6.4. rel (5S,6S,7S,10R)-7-Bromo-10-{[tert-butyl(di-
methyl)silyl]oxy}-2-oxo-1-oxaspiro[4.5]dec-6-yl benzo-
ate (40). A solution of lactone 27 (0.9 g, 2.37 mmol) in
dry pyridine (10 mL) was treated with DMAP (29 mg,
0.24 mmol, 0.1 equiv.), cooled to 08C and benzoyl chloride
(0.3 mL, 2.6 mmol, 1.1 equiv.) was slowly added to the
mixture. After being stirred for 26 h at room temperature,
the mixture was diluted with half saturated NaHCO3
solution and extracted with diethyl ether (3£30 mL). The
combined etheral extracts were dried over MgSO4, filtrated
and concentrated in vacuo. The residue was purified by flash
chromatography (hexane/diethyl ether, 1:1) to give 1.0 g
(88%) of 31 as white crystals, mp 1778C. TLC (hexane/
diethylether, 4:7): Rf¼0.3; 1H NMR (CDCl3): d 0.00, 20.11
(2 s, 6H, Si(CH3)2), 0.87 (s, 9H, C(CH3)3), 1.53–1.54 (m,
1H, CH2), 1.69–1.76 (m, 2H, CH2), 2.12–2.13 (m, 1H,
CH2), 2.37–2.44 (m, 3H, CH2), 2.51–2.54 (m, 1H, CH2),
3.85–3.86 (m, 1H, CHOR), 3.94–4.00 (m, 1H, CHBr),
5.90–5.92 (d, J¼10.6 Hz, 1H, CHOR), 7.33–7.37 (m, 2H,
aromatic H), 7.46–7.50 (m, 1H, aromatic H), 7.92–7.94 (m,
2H, aromatic H); 13C NMR (CDCl3): d 26.2, 25.7
(Si(CH3)3), 17.1 (C(CH3)3), 24.6 (C-4), 24.7 (C(CH3)3),
27.9 (C-9), 28.4 (C-3), 28.5 (C-8), 47.6 (C-7), 72.9 (C-10),
74.5 (C-6), 87.4 (C-5), 127.6, 128.4, 128.7, 132.4, 163.5

7960
M. Eipert et al. / Tetrahedron 59 (2003) 7949–7960
N.; Fujimoto, K.; Kogen, H. Org. Lett. 2000, 2, 505–506.
(c) Runcie, K. A.; Taylor, R. J. K. Org. Lett. 2001, 3,
3237–3239. (d) Hoye, T. R.; Tennakoon, M. A. Org. Lett.
2000, 2, 1481–1483. (e) Arenz, C.; Giannis, A. Angew. Chem.
2000, 112, 1498–1500, Angew. Chem. Int. Ed. 2000, 39,
1440–1442. (f) Fujioka, H.; Kotoku, N.; Sawama, Y.;
Nagatomi, Y.; Kita, Y. Tetrahedron Lett. 2002, 43,
4825–4828. (g) Takagi, R.; Miyanaga, W.; Tamura, Y.;
Ohkata, K. Chem. Commun. 2002, 2096–2097. (h) Murray,
L. M.; O’Brien, P.; Taylor, R. J. K. Org. Lett. 2003, 5,
1943–1946.
4.6.7. rel (5S,6R,7S,8S,10R)-8-Bromo-10-{[tert-butyl-
(dimethyl)silyl]oxy}-7-hydroxy-2-oxo-1-oxaspiro[4.5]-
dec-6-yl benzoate (43). A solution of spirolactone 42
(0.4 g, 0.95 mmol) in dry THF (4 mL) was treated with
glacial acetic acid (0.16 mL, 2.85 mmol, 3 equiv.) and dry
LiBr (0.25 g, 2.85 mmol, 3 equiv.) and stirred for 5 h at
358C. The reaction was quenched with water (5 mL) and
extracted with diethyl ether (3£25 mL). The combined
organic layers were dried over MgSO4, filtered and
concentrated in vacuo. The residue was purified by flash
chromatography (petroleum ether/diethyl ether, 1:1) result-
ing in 0.35 g (74%) of 43 as colorless crystals, 235–2408C
(decomposition). TLC (hexane/diethyl ether, 1:1): Rf¼0.36;
1H NMR (CDCl3): d 0.00, 0.10 (2 s, 6H, Si(CH3)3), 0.82 (s,
9H, C(CH3)3), 2.05–2.10 (m, 2H, CH2), 2.35–2.39 (m, 2H,
CH2), 2.50–2.56 (m, 2H, CH2), 3.88–3.91 (m, 1H, CHOH),
4.13–4.16 (m, 2H, CHBr, CHOR), 5.57 (d, J¼1.8 Hz, 1H,
CHOR), 7.41–7.45 (m, 2H, aromatic H), 7.55–7.59 (m, 1H,
aromatic H), 7.92–7.96 (m, 2H, aromatic H); 13C NMR
(CDCl3): d 25.9, 25.2 (Si(CH3)2), 16.9 (C(CH3)3), 24.6
(C(CH3)3), 26.9 (C-4), 27.1 (C-3), 37.8 (C-9), 49.0 (C-8),
70.9 (C-7), 71.7 (C-10), 74.0 (C-6), 84.8 (C-5), 127.7,
127.7, 128.8, 132.8 (aromatic C), 164.6 (COO), 174.8 (C-2);
IR (KBr): 3442, 2962, 1785, 1735, 1261 cm21; MS (FD),
m/z (%): 499.6 (100) [M]þ.
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