Regioselective isomerisation of highly substituted 1- methylenecyclohexenepoxides to the corresponding allylic alcohols. Influence of the base and of the protecting groups

Article abstract of DOI:10.1007/s00706-003-0153-7

Highly substituted 1-methylenecyclohexenepoxides 3, useful building blocks for a projected synthesis of wailupemycin A (1), were synthesized from (R)-carvone in eight synthetic steps in 23-40% overall yield. The regioselectivity of the subsequent isomeris

Full text of DOI:10.1007/s00706-003-0153-7

Monatshefte f€ur Chemie 135, 713–727 (2004)
DOI 10.1007/s00706-003-0153-7
Regioselective Isomerisation of Highly
Substituted 1-Methylenecyclohexenepoxides
to the Corresponding Allylic Alcohols.
Influence of the Base
and of the Protecting Groups
Stefan Kirsch1, Olaf Ackermann1, Klaus Harms2;ꢀ, and Thorsten Bach1;y
1
€
€
Lehrstuhl fur Organische Chemie I, Technische Universitat Munchen,
€
D-85747 Garching, Germany
2
€
Fachbereich Chemie, Philipps-Universitat Marburg, D-35032 Marburg, Germany
Received November 18, 2003; accepted December 9, 2003
Published online March 11, 2004 # Springer-Verlag 2004
Summary. Highly substituted 1-methylenecyclohexenepoxides 3, useful building blocks for a proj-
ected synthesis of wailupemycin A (1), were synthesized from (R)-carvone in eight synthetic steps in
23–40% overall yield. The regioselectivity of the subsequent isomerisation to the corresponding allylic
alcohols was shown to depend on the basicity of the reagent and on the bulkiness of the protecting
groups existing in 3. With diethylaluminum 2,2,6,6-tetramethylpiperidid (DATMP), secondary allylic
alcohols 5 were formed exclusively. With strong bases such as a mixture of lithium di-iso-propylamide
and potassium tert-butoxide (LIDAKOR), the tertiary allylic alcohol 6 was obtained as predominant
product.
Keywords. Epoxide rearrangement; Allylic alcohols; Regioselectivity.
Introduction
Recently, we became interested in wailupemycin A (1, Scheme 1) and its C7
epimer wailupemycin B, marine metabolites isolated from Streptomyces maritimus
by Davidson and co-workers [1]. The wailupemycins are bacteriostatic polyketides
possessing unprecedented carbon skeletons. Because of the limited supplies from
natural sources, the potentially useful biological activity has not been fully eval-
uated. The biosynthesis of these compounds has attracted considerable attention
ꢀ
To whom inquiries about the X-ray analysis should be addressed
y
Corresponding author. E-mail: thorsten.bach@ch.tum.de

714
S. Kirsch et al.
Scheme 1
[2]. Our efforts to develop a de novo synthesis of the wailupemycins have recently
culminated in a total synthesis of wailupemycin B [3].
The most notable features of wailupemycin A (1) from the perspective of a syn-
thetic chemist are the highly substituted cyclohexanone moiety and the 2-pyrone
containing side chain. It was envisaged that the protected intermediate 3 could be
used as a potential precursor (Scheme 1). Regioselective isomerisation of 1-methy-
lenecyclohexenepoxide 3 to the corresponding secondary allylic alcohol should facil-
itate an entry to the target compound. We previously reported a methodology for the
synthesis of 6-substituted 4-hydroxy-2-pyrones from aldehydes [4], which should
allow for the introduction of the 2-pyrone moiety by formation of the C4–C5 bond.
Key intermediate 3 could originate from precursor 4. In a synthetic direction, oxida-
tive transformation of the 2-propenyl group into a hydroxy group, followed by an
inversion of the C9-hydroxy would complete the synthesis of key intermediate 3. (R)-
Carvone (2), which is readily available in enantiomerically pure form, was identified
as an ideal inexpensive starting material for the projected synthesis. A C6–C7 bond
formation by diastereoselective enolate addition followed by directed diastereoselec-
tive epoxidation would allow for conversion of (R)-carvone (2) into precursor 4.
Rearrangement of epoxide 3 to the secondary allylic alcohol 5 (Scheme 2) turned
out to be a critical step in the projected synthesis of wailupemycin A (1). Unlike
compound 5, tertiary allylic alcohol 6 cannot act as precursor for wailupemycin A
(1). We therefore turned our attention to reagents able to lead selectively to compound
5. Several reagents have been developed so far to carry out such transformations under
mild conditions [5–10]. Amongst others, lithium dialkylamides [5], diethylaluminum
Scheme 2

Isomerisation of Substituted 1-Methylenecyclohexenepoxides
715
2,2,6,6-tetramethylpiperidide (DATMP) [6], and methylmagnesium N-cyclohexyl-N-
iso-propylamide (MICA) [7] have frequently been used as reagents to achieve regio-
selective isomerisations. In addition, a mixture of lithium di-iso-propylamide and
potassium tert-butoxide (LIDAKOR) is reported to promote the smooth ring opening
of oxiranes to afford allylic alcohols [8]. Treatment of oxiranes with trimethylsilyl
trifluoromethanesulfonate and 1,5-diazabicyclo[5.4.0]undec-5-ene (DBU) also gives
the corresponding allylic alcohol protected as trimethylsilyl ether [10]. All these
methods have in common that the ring opening takes place preferentially at the
more substituted carbon [5–10], when an unsymmetrically trisubstituted oxirane is
employed. To access the higher substituted alcohol a two-step procedure via an
organoselenium reagent was developed [11].
This report details the synthesis of key intermediate 3 and its isomerisation to
the corresponding allylic alcohols 5 and 6. Influences of different bases as reagents
and of the protecting groups in 1-methylenecyclohexenepoxide 3 on the regio-
selectivity of the epoxide opening by elimination have been studied.
Results and Discussion
Synthesis of Key Intermediate 3
Our synthesis of key epoxide 3 started from (R)-carvone (2) (Scheme 3). The
stereoselective aldol addition of ethyl acetate to carvone promoted by stoichio-
metric amounts of cerium(III) chloride [12] as well as the diastereoselective addi-
tion of tert-butyl acetate in the presence of 0.25 equiv. of CeF3 have been described
[13]. We found that a complete conversion of carvone to tertiary alcohols 7a and 7b
occurred even when using lithium enolates without cerium(III) salts as additives.
The reaction of (R)-carvone (2) gave rise to a single isomer 7a=b, presumably
Scheme 3. (a) LiCH2CO2Et, ꢁ78ꢂC (THF), d.r. > 95:5, 99%; (b) LiCH2CO2t-Bu, ꢁ78ꢂC (THF),
d.r. > 95:5, 85%; (c) LAH, rt (Et2O), 98% for R ¼ Et, 84% for R ¼ t-Bu; (d) MCPBA, ꢁ40ꢂC
(CH2Cl2), d.r. > 95:5, 87%; (e) 2-methoxypropene, [PPTS], 0ꢂC (CH2Cl2), 80%; (f) (i) O3, NaHCO3,
ꢁ78ꢂC (CH2Cl2, MeOH), (ii) Ac2O, NEt3, [DMAP], reflux (CH2Cl2), (iii) K2CO3, rt (MeOH), 74%;
(g) PhCOOH, PPh3, DIAD, 0ꢂC (THF), 94%

716
S. Kirsch et al.
as a result of the stereoelectronically favored axial addition to the carbonyl
group. Subsequent reduction of the esters was conducted with lithiumaluminum
hydride to give the 1,3-diol 8 in good yields. The regio- and stereoselective epox-
idation of tertiary allylic alcohol 8 was achieved with MCPBA and the free hydroxy
groups of the resulting epoxide 4 were protected as isopropylidene acetal. Oxida-
tive degradation of the 2-propenyl group of compound 9 was carried out by ozo-
nolysis in methanol to an ꢀ-methoxy hydroperoxide which upon treatment with
acetic anhydride and triethylamine underwent in situ Criegee rearrangement
affording epoxy alcohol 10 in 74% yield [14]. The rearrangement is known to
occur with retention of configuration. It is worthy to note, that ozonolysis of 9
without sodium bicarbonate as an acid scavenger resulted in decomposition of the
ꢀ-methoxy hydroperoxide. Our attempts to use a two-step C¼C-cleavage=Baeyer-
Villiger sequence failed. We were able to convert the 2-propenyl double bond to
the corresponding ketone by oxidative C¼C bond cleavage using OsO4 and NaIO4
[15]. Unexpectedly, the subsequent Baeyer-Villiger oxidation using different
reagents in a variety of solvents was very slow producing a number of byproducts.
At this stage the configuration of the C9-hydroxy group had to be inverted in
order to gain access to the correct configuration of the natural product. Mitsunobu
reaction [16] of alcohol 10 with benzoic acid in the presence of diisopropyl azo-
dicarboxylate (DIAD) and triphenylphosphine (TPP) occurred with inversion of
configuration at C9 affording benzoate 3a.
The success of the synthesis now hinged upon the selective isomerisation of
epoxide 3a to secondary allylic alcohol 5a. Several methods known to effect the
rearrangement of epoxides to allylic alcohols were tried [5–10]. Epoxide 3a was
exposed to the complex prepared in situ from Et2AlCl and lithium 2,2,6,6-tetra-
methylpiperidide (LTMP) [6], but the method failed to give more than a trace of the
desired product. Only cleavage of the isopropylidene acetal was observed under
Noyori’s conditions with TMSOTf=DBU [10]. Next, we explored strong bases as
lithium diethylamide [5] and LIDAKOR [8], and obtained the corresponding C9–
C10 cyclohexene as sole product of benzoic acid elimination.
These results prompted us to prepare several epoxides 3b–3f, which differ in
the protecting groups PG, PG1, and PG2 (Scheme 4). Benzoate 3a was saponified
Scheme 4. (h) NaOH, rt (MeOH), 93%; (i) TBSCl, im, rt (DMF), 92%; (j) BnBr, NaH, rt (DMF),
90%; (k) TIPSCl, im, rt (DMF), 72%

Isomerisation of Substituted 1-Methylenecyclohexenepoxides
717
with NaOH in methanol at room temperature yielding alcohol 11 in 93% yield.
Silyl ethers 3b and 3d were obtained by protection of the C9 hydroxy group as its
tert-butyldimethylsilyl (TBS) ether and its triisopropylsilyl (TIPS) ether, respec-
tively. The C9 alcohol function was also protected as the benzyl ether using BnBr,
NaH in DMF to give 3c. Silyl ethers 3e and 3f were prepared by standard protect-
ing group conversions starting from benzoate 3a [17].
Isomerisation of Epoxide 3 to Allylic Alcohols
The utility of the present substrates 3b–3f is largely dependent on the success of
the regioselective transformation of epoxide 3 into secondary allylic alcohol 5.
Several examples of this transformation are given in Table 1.
Surprisingly, the reaction of TBS ether 3b with strong bases as lithium di-
ethylamide, LTMP, and LIDAKOR gave tertiary alcohol 6b as sole product (entry
1–3). Proton abstraction from the C10 methylene group is obviously greatly pre-
ferred over that from the C13 methyl group. This preference has to be attributed to
the preferred geometry for proton abstraction. Notably, the reaction of LIDAKOR
with epoxide 3b (entry 3) afforded at ꢁ78ꢂC exclusively product 6b in 98% yield.
The reaction of methylmagnesium N-cyclohexyl-N-iso-propylamide with epoxide
3b (entry 4), however, led to a 2:1 mixture of the isomeric olefins 5b and 6b with
1
the latter predominating as determined by H NMR analysis. Next, we explored
butylmagnesium N-cyclohexyl-N-iso-propylamide without affecting the ratio of
regioisomers. The rearrangement proceeded slowly and incompletely at room tem-
perature. Reaction of 3b with methylmagnesium diethylamide gave no product of
epoxide isomerisation (entry 6). However, treatment of 3b with DATMP led to
regioselective formation of secondary allylic alcohol 5b in low and non-repro-
ducible yields (entry 7–8). No isomerisation was observed with TMSOTf=DBU
(entry 9) neither with Al(OiPr)3 [9] (entry 10). Longer reaction times led to extensive
decomposition, revealing the instability of 3b towards Lewis-acidic conditions.
It seemed logical to expect that the steric bulk of the C9-hydroxy protecting
group PG2 plays a significant role in the selectivity of isomerisation. Bulkier pro-
tecting groups PG2 should block the proton abstraction from the C10 methylene
group. Indeed, reaction of TIPS ether 3d with MICA under standard conditions gave
a mixture of the isomeric olefins 5d and 6d with the former prevailing (63:37 ratio)
(entry 13). Our observations are in line with what one would expect for a more
hindered substrate. However, an enhancement of the selectivity for the desired iso-
mer 5 in magnesium amide promoted rearrangements has not been successful. In
contrast, the less sterically biased benzyl ether 3c (entry 11–12) isomerized to the
tertiary alcohol 6c as the predominant product, showing enhanced selectivity and
reactivity compared to TBS ether 3b. Unlike acetonides 3b–3d, the fully silyl pro-
tected epoxide 3e was inert to the standard reaction conditions for MICA (entry 15).
TBS Substrate 3f did not react either (entry 17). The regioselectivity of the epoxide
isomerisation using magnesium amides seems to be strongly dependent on the bulki-
ness of the protecting group PG2. The proton abstraction from the C10 methylene
group is the favoured reaction pathway in case of small protecting groups PG2. The
proton abstraction from C13 methyl group becomes the more predominant the
bulkier the protecting group is. On the other hand, LIDAKOR and the other strong

718
S. Kirsch et al.
Table 1. Formation of allylic alcohols 5 and 6
Entry
# 3
PG
PG1
PG2
Reagent
1
2
b
b
b
b
b
b
b
b
b
b
c
–C(CH3)2–
–C(CH3)2–
–C(CH3)2–
–C(CH3)2–
–C(CH3)2–
–C(CH3)2–
–C(CH3)2–
–C(CH3)2–
–C(CH3)2–
–C(CH3)2–
–C(CH3)2–
–C(CH3)2–
–C(CH3)2–
–C(CH3)2–
TBS
TBS
TBS
TBS
TBS
TBS
TBS
TBS
TBS
TBS
Bn
LiNEt2
LTMP
3
LIDAKOR
MICA
4
5
BuMg-(c-Hex)(i-Pr)
MeMg-NEt2
DATMP
6
7
8
DATMP
9
Al(Oi-Pr)3
TMSOTf, DBU
MICA
10
11
12
13
14
15
16
17
18
c
Bn
MeMg-NEt2
MICA
d
d
e
TIPS
TIPS
TIPS
TIPS
TBS
TBS
DATMP
TBS
TBS
TBS
TBS
TES
TES
TES
TES
MICA
e
DATMP
f
MICA
f
DATMP
Entry
Reaction conditions
Ratioa 5:6
Compound, yield=%
1
2
(4 eq), reflux (Et2O)
0:100
0:100
0:100
33:67
33:67
=
6b, 62
(4 eq), 0ꢂC (benzene)
(2 eq), ꢁ78ꢂC ! 0ꢂC (THF)
(4 eq), 0ꢂC ! rt (THF)
(4 eq), 0ꢂC ! rt (THF)
(4 eq), 0ꢂC ! rt (THF)
(4 eq), 0ꢂC (benzene)
(4 eq), ꢁ78ꢂC (toluene)
(10 eq), reflux (toluene)
(1 eq), rt (benzene)
(4 eq), 0ꢂC ! rt (THF)
(4 eq), 0ꢂC ! rt (THF)
(4 eq), 0ꢂC ! rt (THF)
(4 eq), 0ꢂC (benzene)
(4 eq), 0ꢂC ! rt (THF)
(4 eq), 0ꢂC (benzene)
(4 eq), 0ꢂC ! rt (THF)
(4 eq), 0ꢂC (benzene)
6b, 87
3
6b, 98
4
5b þ 6b, 93
5b þ 6b, 62
n.r.e
5
6
7
100:0
100:0
=
5b, ꢃ16b
8
5b, 21
9
decompositionc
decompositiond
5c þ 6c, 71
5c þ 6c, 42
5d þ 6d, 65
5d, 78
10
11
12
13
14
15
16
17
18
=
25:75
11:89
63:37
100:0
=
n.r.
=
n.r.
=
100:0
n.r.
5f, 48
a
Ratio by 1H NMR of crude product; b yield was not reproducible; c decomposition to not isolated
d
e
products; mainly acetal cleavage; n.r. ¼ no reaction
lithium bases favour epoxide isomerisation via an E2 elimination pathway abstract-
ing exclusively the proton from the C10 methylene group. Possibly, the C–H bond is
already stretched to a significant extent in the transition state of these eliminations.
The steric environment at C9 is not important.

Isomerisation of Substituted 1-Methylenecyclohexenepoxides
719
Fig. 1. A molecule of compound 12 in the crystal
Exposure of TIPS ether 3d to DATMP gave rise to a single isomer 5d in good
yields (entry 14). In addition, TBS ether 3f reacted with DATMP under standard
conditions to give the secondary allylic alcohol 5f in moderate yield. The high
regioselectivity of reactions mediated by DATMP is in keeping with literature pre-
cedence [6]. The high affinity of aluminum to oxygen seems to be essential to ensure
proton abstraction from the C13 methyl group. For steric reasons, DATMP coordi-
nates to the exocyclic lone pair of the epoxide oxygen atom and facilitates a syn-
elimination at the exocyclic methyl group. Apparently, DATMP is the reagent of
choice for the conversion of epoxide 3d to secondary allylic alcohol 5d, and, there-
fore, was planned to be used in the envisioned total synthesis of wailupemycin A (1).
It was subsequently found that aqueous work-up led to the partially hydrolysis of the
isopropylidene acetal to give triol 12 as major byproduct. Since byproduct formation
became even more substantial on scale-up, we performed the isomerisation of 3d
with DATMP, affording exclusively triol 12 after acidic work-up procedure (HCl).
The configuration of 12 was additionally verified by X-ray analysis (Fig. 1).
Conclusion
In summary, we have shown that the success in the regioselective isomerisation of
1-methylenecyclohexenepoxide 3 depends on the basicity of the reagent in addition
to the sterical demand of the protecting groups for the three hydroxyl groups
present in 3. Reaction of epoxide 3b (PG=PG1 ¼ –CðCH3Þ2–, PG2 ¼ TBS) with
LIDAKOR at ꢁ78ꢂC in THF gave tertiary allylic alcohol 6b exclusively in 98%
yield. On the other hand, treatment of 3d (PG=PG1 ¼ –CðCH3Þ2–, PG2 ¼ TIPS)
with DATMP at 0ꢂC in benzene led to regioselective formation of secondary allylic
alcohol 5d in 78% yield. In view of all the results mentioned in the present study,
the application of this strategy to the synthesis of the more complex wailupemycins
is currently being pursued in our laboratory.
Experimental
All reactions involving water-sensitive chemicals were carried out in flame-dried glassware with
magnetic stirring under Ar. Tetrahydrofuran (THF) was distilled from sodium immediately prior to

720
S. Kirsch et al.
use. N,N-Di-iso-propylamine was distilled from calcium hydride. All other chemicals were either
commercially available or prepared according to the cited references. Ozonolyses were conducted
using a Fischer Ozone Generator 502. TLC: Merck glass sheets (0.25 mm silica gel 60, F254), eluent
given in brackets. Detection by UV or coloration with cerium ammonium molybdate (CAM). Optical
1
Rotation: Perkin-Elmer 241 MC. NMR: Bruker AV-360, AV-500. H and 13C NMR spectra were
recorded in CDCl3 at ambient temperature unless stated otherwise. Chemical shifts are reported
relative to tetramethylsilane as internal standard. Apparent multiplets which occur as a result of the
accidental equality of coupling constants of magnetically non-equivalent protons are marked as virtual
(virt.). The multiplicities of the 13C NMR signals were determined by DEPT experiments. IR: Perkin-
Elmer 1600 FT-IR. MS: Finnigan MAT 8200 (EI). Elemental Analysis: Elementar Vario EL. All
reported compounds show satisfying elemental analyses. Flash chromatography was performed on
silica gel 60 (Merck, 230–400 mesh) (ca. 50 g for 1 g of material to be separated) with the indicated
eluent. Common solvents for chromatography [pentane (P), cyclohexane (CH), ethyl acetate (EA)]
were distilled prior to use. The crystal structure of compound 12 has been deposited at the Cambridge
Crystallographic Data Centre and allocated the deposition number CCDC 221991.
Ethyl 2-[(1S,5R)-1-Hydroxy-5-isopropenyl-2-methyl-2-cyclohexenyl]acetate
(7a, C14H22O3) [12]
A THF (150 cm3) solution of diisopropylamine (11 cm3, 8.05g, 80mmol) was cooled to 0ꢂC. Butyl-
lithium, 2.5 M in hexanes (32 cm3, 80 mmol), was added over 10min, while maintaining the reaction
temperature at 0ꢂC. After stirring at that temperature for 5 min and then cooling to ꢁ78ꢂC, ethyl
acetate (7.8cm3, 7.0 g, 80 mmol) was added dropwise, while maintaining the reaction mixture below
ꢁ70ꢂC. After stirring at ꢁ78ꢂC for 25 min, (R)-(ꢁ)-carvone (2) (10.4 cm3, 10.0 g, 67mmol) was
added slowly. After stirring for 2 h at ꢁ78ꢂC, TLC analysis indicated complete reaction. The reaction
was quenched by the addition of a saturated aqueous NH4Cl solution (35 cm3). After the exotherm has
subsided, the cooling bath was removed, and the resulting thick suspension was diluted with diethyl-
ether (100 cm3) and water (100cm3), and allowed to warm to ambient temperature. The mixture was
extracted with diethylether (3 ꢄ 50 cm3). The combined organic phases were washed sequentially with
water (150cm3), and saturated aqueous NaCl solution (150cm3), dried over Na2SO4, filtered, and
concentrated to dryness. Flash chromatography (P:EA¼ 90:10) gave 15.7g (99%) of 7a as a colorless
20
oil (d.r.>95:5). Rf ¼ 0.51 (P:EA¼ 80:20); ½ꢀꢅD ¼ ꢁ35.8ꢂ cm3 gꢁ1 dmꢁ1 (c ¼ 0.94, CHCl3); IR (film):
ꢁꢀ¼ 3504 (m br), 3084 (w), 2978 (s), 2938 (s), 1712 (s), 1645 (m), 1371 (s), 1321 (s), 1203 (s), 1170
(s), 1043 (s) cmꢁ1; MS (EI, 70eV): m=z (%) ¼ 220 (24) [Mþ–H2O], 180 (11), 151 (37), 132 (54), 109
1
(100), 82 (98), 43 (64); H NMR (300 MHz): ꢂ ¼ 1.28 (t, J ¼ 7.0 Hz, CH2CH3), 1.65 (dd, J ¼ 12.5,
1.5 Hz, C6HH), 1.73 (s, CH3), 1.74 (s, CH3), 1.89–2.14 (m, C4H2, C6HH), 2.27–2.42 (m, H5), 2.58
(d, J ¼ 14.7Hz, CHHCO), 2.72 (d, J ¼ 14.7Hz, CHHCO), 3.86 (s, OH), 4.19–4.20 (m, OCH2), 4.76–
4.77 (m, C¼CH2), 5.46–5.48 (m, H3); 13C NMR (75.5 MHz): ꢂ ¼ 14.5 (q, OCH2CH3), 17.4 (q, CH3),
20.8 (q, CH3), 31.2 (t, C4), 40.0 (d, C5), 41.4 (t, C6), 42.3 (t, CH2CO), 61.1 (t, OCH2), 73.0 (s, C1),
109.5 (t, C¼CH2), 124.8 (d, C3), 137.3 (s, C2), 148.8 (s, C¼CH2), 173.3 (s, CO).
tert-Butyl 2-[(1S,5R)-1-Hydroxy-5-isopropenyl-2-methyl-2-cyclohexenyl]acetate
(7b, C16H26O3) [13]
The same procedure as for the preparation of 7a was used, starting with tert-butyl acetate (1.68 cm3,
1.43g, 12.5 mmol) and (R)-(ꢁ)-carvone (2) (1.56 g, 10.4mmol). Yield: 2.35g (85%) of 7b as a
20
colorless oil (d.r.>95:5). Rf ¼ 0.60 (P:EA¼ 80:20); ½ꢀꢅD ¼ ꢁ26.1ꢂ cm3 gꢁ1 dmꢁ1 (c ¼ 0.74, CHCl3);
IR (film): ꢁꢀ¼ 3499 (m br), 3082 (w), 2976 (s), 2934 (s), 1704 (s), 1369 (s), 1336 (s), 1250 (m), 1153
(s); MS (EI, 70 eV): m=z (%) ¼ 248 (9) [Mþ–H2O], 210 (11), 192 (88), 151 (87), 132 (70), 109 (100),
1
57 (96) cmꢁ1; HNMR (250MHz): ꢂ ¼ 1.41 [s, C(CH3)3], 1.57 (dd, J ¼ 13.1, 1.5Hz, C6HH), 1.68

Isomerisation of Substituted 1-Methylenecyclohexenepoxides
721
(s, CH3), 1.69 (s, CH3), 1.69–1.71 (m, C6HH), 1.78–1.99 (m, C4H2), 2.15–2.24 (m, H5), 2.48
(d, J ¼ 14.8 Hz, CHHCO), 2.62 (dd, J ¼ 14.8Hz, J ¼ 1.2 Hz, CHHCO), 4.00 (s, OH), 4.67–4.78
(m, C¼CH2), 5.38–5.40 (m, H3); 13C NMR (62.9 MHz): ꢂ ¼ 17.5 (q, CH3), 20.8 (q, CH3), 28.4 [q,
C(CH3)3], 31.1 (t, C4), 40.1 (d, C5), 41.5 (t, C6), 43.3 (t, CH2CO), 73.1 (s, C1), 82.1 [s, C(CH3)3],
109.5 (t, C¼CH2), 124.6 (d, C3), 137.5 (s, C2), 148.9 (s, C¼CH2), 172.9 (s, CO).
(1S,5R)-1-(2-Hydroxyethyl)-5-isopropenyl-2-methyl-2-cyclohexen-1-ol (8, C12H20O2)
A solution of ester 7a (15.3g, 64 mmol) in diethylether (80 cm3) was added to a suspension of LiAlH4
(2.53 g, 64 mmol) in diethylether (40 cm3) at 0ꢂC. The mixture was stirred for 2 h at rt, and sequentially
treated with water (2.5cm3), aqueous NaOH (15%) (2.5cm3), and water (7.5cm3). After stirring for
20min at rt, the solid was removed by filtration and washed with diethylether (2ꢄ 30 cm3). The
combined organic phases were washed, dried over Na2SO4, filtered, and concentrated to dryness. Flash
chromatography (P:EA¼ 80:20) gave 12.3g (98%) of 8 as a colorless solid. Rf ¼ 0.07 (P:EA ¼ 80:20);
20
mp 86ꢂC; ½ꢀꢅD ¼ ꢁ49.8ꢂ cm3 gꢁ1 dmꢁ1 (c ¼ 0.51, CHCl3); IR (film): ꢁꢀ¼ 3367 (s br), 3088 (w), 2924
(s), 1647 (s) cmꢁ1; MS (EI, 70 eV): m=z (%) ¼ 196 (0.1) [Mþ], 178 (13) [Mþ–H2O], 151 (74), 109
(100), 69 (25), 55 (25); 1H NMR (300MHz): ꢂ ¼ 1.66–1.86 (m, CHHCH2OH, C6HH), 1.85 (s, CH3),
1.85 (s, CH3), 1.87–2.09 (m, C4HH), 2.14–2.29 (m, CHHCH2OH, C6HH, C4HH, H5), 3.38 (s, OH),
3.75 (s br, OH), 3.77–3.86 (m, CHHOH), 3.92–4.10 (m, CHHOH), 4.82–4.83 (m, C¼CH2), 5.50 (m,
H3); 13C NMR (75.5 MHz): ꢂ ¼ 17.4 (q, CH3), 20.9 (q, CH3), 31.4 (t, C4), 38.4 (t, CH2CH2OH), 39.9 (d,
C5), 40.3 (t, C6), 59.6 (t, CH2OH), 75.7 (s, C1), 109.6 (t, C¼CH2), 123.7 (d, C3), 138.9 (s, C2), 149.2 (s,
C¼CH2).
(1S,2S,3S,5R)-2,3-Epoxy-1-(2-hydroxyethyl)-5-isopropenyl-2-methylcyclohexan-1-ol
(4, C12H20O3)
To a vigorously stirred solution of 8 (10.7 g, 54mmol) in CH2Cl2 (100 cm3) at ꢁ40ꢂC was added
MCPBA (70% purity, 9.32 g, 54mmol) in three portions. The resulting mixture was stirred at ꢁ40ꢂC
for 1 h, then warmed up to ꢁ10ꢂC over a period of 2 h. After stirring for additional 2 h at ꢁ10ꢂC, TLC
analysis indicated complete reaction. The solid was removed by filtration and washed with CH2Cl2
(2ꢄ 60cm3). The combined organic phases were washed with saturated aqueous NaHCO3
(3ꢄ 100 cm3), water (100cm3), and brine (100cm3), and dried over Na2SO4, filtered, and concentrated
to dryness. Flash chromatography (P:EA¼ 50:50) gave 10.6g (87%, d.r.>95:5) of 4 as a colorless
20
solid. Rf ¼ 0.08 (P:EA¼ 1:1); mp 92ꢂC; ½ꢀꢅD ¼ ꢁ25.8ꢂ cm3 gꢁ1 dmꢁ1 (c ¼ 0.99, CHCl3); IR (KBr):
ꢁꢀ¼ 3304 (s br), 3079 (w), 2958 (s), 2934 (s), 1441 (s), 1437 (s), 1378 (s), 1193 (s), 1120 (s), 1050 (s),
959 (s) cmꢁ1; MS (EI, 70eV): m=z (%) ¼ 212 (0.2) [Mþ], 194 (1) [Mþ–H2O], 149 (7), 123 (22), 109
1
(42), 97 (37), 73 (60), 55 (20), 43 (100); H NMR (360 MHz): ꢂ ¼ 1.39 (s, C3CH3), 1.53 (virt.
dt, J ¼ 12.8, 1.2Hz, C6HH), 1.66 [s, C(¼CH2)CH3], 1.71–1.81 (m, C4HH, CH2CH2OH), 1.91–2.15
(m, C6HH, C4HH, H5), 2.42 (s br, OH), 3.02 (s br, OH), 3.18 (d br, J ¼ 4.5 Hz, H3), 3.70–3.82 (m,
CHHOH), 3.87–3.95 (m, CHHOH), 4.67–4.68 (m, C¼CH2); 13C NMR (62.9 MHz): ꢂ ¼ 17.1 (q, CH3),
20.4 (q, CH3), 28.6 (t, C4), 35.5 (t, CH2CH2OH), 35.7 (t, C6), 38.9 (d, C5), 59.5 (t, CH2OH), 62.9 (d,
C3), 63.4 (s, C2), 75.7 (s, C1), 110.2 (t, C¼CH2), 147.8 (s, C¼CH2).
(6S,7S,8S,10R)-7,8-Epoxy-10-isopropenyl-2,2,7-trimethyl-1,3-dioxaspiro[5.5]undecane
(9, C15H24O3)
To a solution of diol 4 (7.5g, 35.3mmol) in CH2Cl2 (40 cm3) at 0ꢂC was added 2-methoxypropene
(3.64 cm3, 2.74g, 38mmol) and PPTS (ꢃ20mg). The resulting yellow solution was stirred at 0ꢂC for
30min and quenched with triethylamine (1cm3). The mixture was diluted with saturated aqueous
NaHCO3 (200cm3), followed by extraction with diethylether (2ꢄ 150 cm3). The combined extracts
were washed with water (200 cm3) and brine (200cm3), and dried over Na2SO4, filtered, and con-

722
S. Kirsch et al.
centrated to dryness. Flash chromatography (P:EA¼ 90:10) gave 7.12g (80%) of 9 as a colorless oil.
20
Rf ¼ 0.59 (P:EA¼ 80:20); ½ꢀꢅD ¼ ꢁ44.1ꢂ cm3 gꢁ1 dmꢁ1 (c ¼ 0.97, CHCl3); IR (film): ꢁꢀ¼ 3072 (w),
2972 (s), 2934 (s), 1436 (s), 1377 (s), 1267 (m), 1193 (s), 1161 (s), 1102 (s), 1050 (s) cmꢁ1; MS (EI,
70eV): m=z (%) ¼ 252 (5) [Mþ], 237 (17) [Mþ–CH3], 177 (32), 119 (44), 68 (40), 43 (100); 1H NMR
(360 MHz): ꢂ ¼ 1.36 (s, C7CH3), 1.40 (s, C2CH3), 1.43 (s, H3CC2), 1.66 [s, C(¼CH2)CH3], 1.63–2.08
(m, H9, H10, H11, H5), 3.02 (d br, J ¼ 4.9 Hz, H8), 3.81 (ddd, J ¼ 10.0, 5.5, 4.5 Hz, C4HH), 3.92 (ddd,
J ¼ 10.0, 9.5, 4.5 Hz, C4HH), 4.67 (s br, C¼CH2); 13C NMR (62.9 MHz): ꢂ ¼ 17.8 (q, C7CH3), 20.3
(q, C(¼CH2)CH3), 27.1 (q, C2CH3), 28.3 (t, C9), 28.5 (t, C5), 30.1 (q, H3CC2), 36.6 (t, C11), 39.1 (d,
C10), 56.6 (t, C4), 60.9 (d, C8), 62.4 (s, C7), 75.9 (s, C6), 98.9 (s, C2), 110.2 (t, C¼CH2), 148.4 (s,
C¼CH2).
(6R,7S,8S,10R)-7,8-Epoxy-2,2,7-trimethyl-1,3-dioxaspiro[5.5]undecan-10-ol
(10, C12H20O4)
To a solution of 9 (1.1g, 4.4 mmol) in CH2Cl2 (30 cm3) was added MeOH (6cm3) and sodium
bicarbonate (2.6g, 31 mmol). The reaction mixture was ozonized at ꢁ78ꢂC until a pale blue color
appeared. Nitrogen was bubbled through the mixture until it became colorless. After warming to room
temperature, Ac2O (8.5cm3, 9.2 g, 90mmol), NEt3 (6.3cm3, 4.5 g, 45mmol), and a catalytic amount of
DMAP (30 mg) was added. The reaction mixture was then refluxed overnight (12 h), cooled to room
temperature, and poured into saturated aqueous NH4Cl solution (40 cm3). The aqueous layer was
extracted with CH2Cl2 (2ꢄ 50cm3), and the combined organic layers were washed with saturated
aqueous NaHCO3 (50 cm3) and brine (50 cm3), dried over MgSO4, filtered, and concentrated. The
crude product was dissolved in MeOH (20 cm3) and treated with K2CO3 (1.6 g, 12mmol). The mixture
was stirred for 2 h at room temperature, filtered, and concentrated. The resultant liquid was then
dissolved in CH2Cl2 (30 cm3), washed with water (20 cm3) and brine (20 cm3), and subsequently dried
(MgSO4). After filtration, the solvent was evaporated in vacuo and the residue was purified by flash
chromatography (P:EA¼ 90:10) to yield alcohol 10 as a colorless oil (743mg, 74%). Rf ¼ 0.08
20
(P:EA¼ 1:1); ½ꢀꢅD ¼ ꢁ45.1ꢂ cm3 gꢁ1 dmꢁ1 (c ¼ 0.52, CHCl3); IR (film): ꢁꢀ¼ 3425 (s br), 2984 (s),
2938 (s), 1435 (m), 1370 (s), 1226 (s), 1184 (s), 1159 (s), 1092 (s), 1020 (s), 975 (s) cmꢁ1; MS (EI,
70eV): m=z (%) ¼ 213 (6) [Mþ–CH3], 153 (7), 109 (15), 99 (24), 93 (53), 82 (11), 71 (48), 43 (100);
1H NMR (250MHz): ꢂ ¼ 1.38 (s, C7CH3), 1.42 (s, C2CH3), 1.47 (s, H3CC2), 1.61 (virt. dt, J ffi 4.0,
13.7Hz, C5HH), 1.77–1.89 (m, C11HH, C9HH), 2.05 (ddd, J ¼ 13.7, 9.8, 5.5Hz, C5HH), 2.22–2.33
(m, C11HH, C9HH), 2.52 (s br, OH), 2.99 (d br, J ¼ 4.5 Hz, H8), 3.64–3.76 (m, H10), 3.84 (ddd,
J ¼ 11.9, 5.5, 4.0 Hz, C4HH), 4.01 (ddd, J ¼ 11.9, 9.8, 4.0 Hz, C4HH); 13C NMR (62.9 MHz): ꢂ ¼ 17.6
(q, C7CH3), 26.7 (q, C2CH3), 29.0 (t, C5), 30.1 (q, H3CC2), 32.9 (t, C9), 40.9 (t, C11), 56.5 (t, C4),
58.8 (d, C8), 62.5 (s, C7), 64.8 (d, C10), 75.2 (s, C6), 98.9 (s, C2).
(6R,7S,8S,10S)-10-Benzoyloxy-7,8-epoxy-2,2,7-trimethyl-1,3-dioxaspiro[5.5]undecane
(3a, C19H24O5)
Alcohol 10 (180 mg, 0.8 mmol), triphenylphosphine (210 mg, 0.8 mmol), and benzoic acid (97.6 mg,
0.8 mmol) were dissolved under argon in THF (5cm3) and cooled in ice. Then a solution of DIAD
(0.15 cm3, 161 mg, 0.8mmol) in THF (1cm3) was added dropwise over 1 h at 0ꢂC. Stirring was
continued for 24 h at 0ꢂC. The mixture was evaporated in vacuo. The residue was purified by flash
chromatography (P:EA¼ 70:30) to yield benzoate 3a as a colorless oil (250 mg, 94%). Rf ¼ 0.52
20
(P:EA¼ 1:1); ½ꢀꢅD ¼ ꢁ27.4ꢂ cm3 gꢁ1 dmꢁ1 (c ¼ 0.80, CHCl3); IR (film): ꢁꢀ¼ 3062 (w), 2985 (s),
2938 (s), 1715 (s), 1370 (s), 1276 (s), 1225 (m), 1175 (m), 1107 (s), 1089 (s) cmꢁ1; MS (EI,
1
70eV): m=z (%) ¼ 317 (6) [Mþ–CH3], 135 (65), 105 (100) [PhCOþ], 77 (30), 43 (62); H NMR
(500 MHz): ꢂ ¼ 1.39 (s, C7CH3), 1.40 (s, C2CH3), 1.43 (s, H3CC2), 1.90–2.19 (m, H5, H9), 2.42 (dd,
J ¼ 14.6, 2.1 Hz, C11HH), 2.52 (dd, J ¼ 14.6, 7.7 Hz, C11HH), 3.04 (s br, H8), 3.83 (ddd, J ¼ 11.7, 5.9,

Isomerisation of Substituted 1-Methylenecyclohexenepoxides
723
3.3 Hz, C4HH), 3.95 (ddd, J ¼ 11.7, 11.0, 4.1 Hz, C4HH), 5.23–5.25 (m, H10), 7.39 (dd, J ¼ 7.7,
7.4 Hz, 2HAr), 7.52 (t, J ¼ 7.4 Hz, 1HAr), 7.90 (d, J ¼ 7.7 Hz, 2HAr); 13C NMR (62.9 MHz): ꢂ ¼ 17.6 (q,
C7CH3), 27.3 (q, C2CH3), 29.2 (t, C5), 30.0 (t, C9), 30.1 (q, H3CC2), 35.8 (t, C11), 56.6 (t, C4), 58.9
(d, C8), 62.4 (s, C7), 68.9 (d, C10), 74.4 (s, C6), 98.8 (s, C2), 128.9 (d), 129.7 (d), 130.6 (s), 133.5 (d),
165.9 (s, C¼O).
(6R,7S,8S,10S)-7,8-Epoxy-2,2,7-trimethyl-1,3-dioxaspiro[5.5]undecan-10-ol
(11, C12H20O4)
Ester 3a (4.0g, 12 mmol) was dissolved in MeOH (150cm3). The solution was treated with NaOH (1g),
and stirred for 5 h at room temperature. The mixture was evaporated in vacuo. The residue was diluted
with CH2Cl2 (100cm3), washed with water (60 cm3), brine (100cm3), and dried over Na2SO4, filtered,
and concentrated to dryness. Flash chromatography (P:EA¼ 90:10) gave 2.53 g (93%) of 11 as a
colorless oil. Rf ¼ 0.20 (P:EA ¼ 50:50); IR (film): ꢁꢀ¼ 3463 (s br), 2986 (s), 1369 (s), 1230 (s), 1193
(s), 1166 (s), 1099 (vs), 1077 (vs), 864 (s) cmꢁ1; MS (EI, 70eV): m=z (%) ¼ 213 (20) [Mþ–CH3], 153
(38), 135 (36), 109 (28), 99 (50), 93 (74), 71 (72), 43 (100); 1H NMR (250 MHz): ꢂ ¼ 1.27 (s, 3H), 1.34
(s, 3H), 1.35 (s, 3H), 1.76–1.89 (m, 3H), 1.98–2.04 (m, 1H), 2.13–2.23 (m, 2H), 2.63 (ddd, J ¼ 14.0, 4.6,
2.4 Hz, H9), 3.27 (d, J ¼ 5.2Hz, H8), 3.62 (ddd, J ¼ 12.2, 6.1, 3.7 Hz, H4), 3.85 (dd, J ¼ 9.7, 2.1 Hz,
H10), 3.90–3.93 (m, H40); 13C NMR (62.9 MHz): ꢂ ¼ 18.1 (q), 24.5 (q), 26.9 (q), 32.6 (t, C5), 38.3 (t),
40.0 (t), 57.6 (t, C4), 63.8 (d, C10), 66.7 (d, C8), 72.5 (s, C7), 76.9 (s, C6), 100.5 (s, C2).
(6R,7S,8S,10S)-10-tert-Butyldimethylsilyloxy-7,8-epoxy-2,2,7-trimethyl-1,3-
dioxaspiro[5.5]undecane (3b, C18H34O4Si)
A solution of 11 (190mg, 0.83 mmol), tert-butyldimethylsilyl chloride (0.34 cm3, 1.0mmol, 2.9 M
solution in toluene), and imidazole (68 mg, 1.0 mmol) in DMF (4cm3) was stirred at 20ꢂC for 24 h.
Et2O (30 cm3) was added and the solution was washed with water (50 cm3). The aqueous layer was
extracted twice with Et2O (30 cm3). The combined organic phases were washed with water (50 cm3)
and brine (50 cm3), dried (Na2SO4), filtered, and the solvent was evaporated. Flash chromatography
(P:EA¼ 90:10) gave 262 mg (92%) of the protected alcohol 3b as a colorless oil. Rf ¼ 0.74
(P:EA¼ 50:50); IR (film): ꢁꢀ¼ 3450 (vs br), 2856 (s), 1368 (s), 1253 (vs), 1229 (s), 1120 (s), 1080
(vs), 1021 (s), 896 (s), 836 (vs), 775 (vs) cmꢁ1; MS (EI, 70 eV): m=z (%) ¼ 344 (1) [Mþ], 327 (15)
[Mþ–CH3], 227 (26) [Mþ–TBS], 197 (53), 157 (57), 135 (74), 107 (47), 93 (54), 75 (100)
1
[C2H7OSiþ], 43 (83); H NMR (250MHz): ꢂ ¼ ꢁ 0.01 (s, 6H, SiCH3), 0.81 [s, SiC(CH3)3], 1.37
(s, 3H), 1.38 (s, 3H), 1.40 (s, 3H), 1.70–1.86 (m, 2H), 1.71–1.81 (m, 1H), 1.84 (ddd, J ¼ 14.0, 4.0,
0.9 Hz, 1H), 1.99 (ddd, J ¼ 13.4, 5.8, 1.2 Hz, 1H), 2.05–2.16 (m, 2H), 2.24 (ddd, J ¼ 15.9, 6.7, 0.9Hz,
1H), 2.97 (d, J ¼ 3.0Hz, H8), 3.81 (ddd, J ¼ 11.6, 5.8, 3.0 Hz, C4HH), 3.92–4.02 (m, C4HH, H10);
13C NMR (62.9 MHz): ꢂ ¼ ꢁ 4.6 (q, SiCH3), ꢁ4.6 (q, SiCH3), 18.0 (q, C7CH3), 18.3 [s, SiC(CH3)3],
26.1 (q), 27.1 (q), 29.9 (t), 30.4 (q, C2CH3), 33.0 (t), 38.8 (t), 56.9 (t, C4), 59.4 (d, C8), 62.4 (s, C7),
65.7 (d, C10), 74.8 (s, C6), 98.5 (s, C2).
(6R,7S,8S,10S)-10-Benzyloxy-7,8-epoxy-2,2,7-trimethyl-1,3-dioxaspiro[5.5]undecane
(3c, C19H26O4)
To a solution of 11 (547mg, 2.4 mmol) in DMF (10 cm3) was added NaH (60% in oil, 108 mg,
2.7 mmol) at 0ꢂC. After 5 min stirring at 0ꢂC, the mixture was warmed to room temperature, and a
solution of benzyl bromide (0.32 cm3, 461 mg, 2.7 mmol) in THF (10 cm3) was added slowly. Stirring
was continued for 2 h at room temperature. Et2O (100cm3) was added and the solution was washed
with water (100 cm3). The aqueous layer was extracted twice with Et2O (50 cm3). The combined
organic phases were washed with water (1000 cm3) and brine (100cm3), dried (Na2SO4), filtered,

724
S. Kirsch et al.
and the solvent was evaporated. Flash chromatography (P:EA¼ 90:10) gave 688 mg (90%) of the
protected alcohol 3c as a colorless oil. Rf ¼ 0.70 (P:EA¼ 50:50); IR (film): ꢁꢀ¼ 2985 (m), 1368 (m),
1229 (m), 1193 (m), 1090 (s), 1028 (m), 738 (m) cmꢁ1; MS (EI, 70 eV): m=z (%) ¼ 303 (6), 243 (3),
197 (6), 91 (100) [C7H7þ], 43 (24); 1H NMR (250MHz): ꢂ ¼ 1.40 (s, C7CH3), 1.41 (s, C2CH3), 1.44
(s, H3CC2), 1.86–1.92 (m, 1H), 1.92–1.95 (m, 1H), 1.95–2.08 (m, 2H), 2.25 (dd, J ¼ 7.0, 1.2Hz,
C11HH), 2.30–2.37 (m, C11HH), 3.01 (d, J ¼ 2.4 Hz, H8), 3.68–3.72 (m, C4HH), 3.81–3.89 (m,
C4HH), 3.97–4.08 (m, H10), 4.43 (s, CH2Ph), 7.24–7.35 (m, HAr); 13C NMR (62.9 MHz): ꢂ ¼ 17.9 (q,
C7CH3), 27.1 (q, C2CH3), 29.3 (t, C5), 29.9 (t, C9), 30.3 (q, H3CC2), 35.8 (t, C11), 57.0 (t, C4), 59.4
(d, C8), 62.5 (s, C7), 70.8 (t, CH2Ph), 72.4 (d, C10), 74.8 (s, C6), 98.6 (s, C2), 127.6 (d), 127.8 (d),
127.9 (d), 128.8 (d), 128.8 (d), 138.8 (s).
(6R,7S,8S,10S)-7,8-Epoxy-2,2,7-trimethyl-10-tri-iso-propylsilyloxy-1,3-
dioxaspiro[5.5]undecane (3d, C21H40O4Si)
A solution of 11 (2.53 g, 11.1mmol), triisopropylsilyl chloride (3.52 cm3, 3.2 g, 16.6mmol), and
imidazole (1.13 g, 16.6mmol) in DMF (10 cm3) was stirred at 20ꢂC for 14h. Et2O (100 cm3) was
added and the solution was washed with water (150cm3). The aqueous layer was extracted with Et2O
(2ꢄ 50cm3). The combined organic phases were washed with water (150cm3) and brine (150cm3),
dried (Na2SO4), filtered, and the solvent was evaporated. Flash chromatography (P:EA¼ 99:1) gave
3.09g (72%) of the protected alcohol 3d as a light yellow oil which was still contaminated with silyl
side products. An analytical sample could not be obtained. Rf ¼ 0.82 (P:EA¼ 90:10); 1H NMR
(250 MHz): ꢂ ¼ 1.02 [s, 21H, SiCH(CH3)2], 1.37 (s, 3H), 1.40 (s, 3H), 1.42 (s, 3H), 1.67–2.08 (m,
4H), 2.18 (dd, J ¼ 13.7, 3.0 Hz, 1H), 2.33 (dd, J ¼ 16.2, 7.3 Hz, 1H), 2.99 (s, H8), 3.78–3.86 (m, 1H),
3.97–4.12 (m, 2H); 13C NMR (90.6 MHz): ꢂ ¼ 12.5 [d, SiCH(CH3)2], 12.6 [d, SiCH(CH3)2], 17.8 (q,
C7CH3), 18.4 [q, SiCH(CH3)2], 18.5 [q, SiCH(CH3)2], 26.8 (q, C2CH3), 29.9 (t), 30.5 (q, C2CH3), 33.4
(t), 39.6 (t), 57.0 (t, C4), 59.4 (d, C8), 62.5 (s, C7), 65.7 (d, C10), 74.9 (s, C6), 98.5 (s, C2).
Isomerisation of Epoxide 3 with DATMP
A solution of 2,2,6,6-tetramethylpiperidine (TMP, 0.38cm3, 318 mg, 2.25mmol) in dry benzene (5cm3)
was cooled to 0ꢂC and a solution of n-butyl lithium in hexane (2.5M, 0.9 cm3, 2.25 mmol) was added
dropwise. The resulting mixture was stirred at 0ꢂC for 10min, a solution of Et2AlCl in toluene (1.8M,
1.27cm3, 2.3mmol) was slowly added, and the reaction was stirred for 30min. A solution of epoxide 3
(0.45 mmol) inbenzene (1cm3) was added over10min at0ꢂC. Thereactionmixturewas stirred at0ꢂC for
30min and then quenched by addition of saturated aqueous NH4Cl (20 cm3). The layers were separated
and extracted with ethyl acetate (2ꢄ 20cm3). The combined organic layers were washed with water
(40 cm3) and brine (40 cm3), dried (Na2SO4), filtered, and concentrated. The ratio of regioisomers was
determined by 1H NMR of crude product. The residue was purified by flash chromatography.
Isomerisation of Epoxide 3 with MICA
N-Cyclohexylisopropylamine (0.25 cm3, 212mg, 1.5 mmol) was dissolved in THF (4cm3) and cooled
to 0ꢂC. Then a solution of n-butyllithium in hexane (2.5M, 0.6 cm3, 1.5 mmol) was added dropwise
and stirring was continued for 15min at 0ꢂC. A solution of methylmagnesium bromide in diethyl ether
(3M, 0.5 cm3, 1.5 mmol) was added dropwise and stirring continued for 15min at 0ꢂC. Finally, a
solution of epoxide 3 (0.3mmol) in THF (2cm3) was added at 0ꢂC, the temperature was allowed to rise
to room temperature, and stirring was continued at room temperature until TLC analysis indicated
complete conversion. The reaction mixture was treated with saturated aqueous NaH2PO4 (10 cm3). The
layers were separated and extracted with ethyl acetate (2ꢄ 10cm3). The combined organic layers were
washed with water (20 cm3) and brine (20 cm3), dried (Na2SO4), filtered, and concentrated. The ratio of

Isomerisation of Substituted 1-Methylenecyclohexenepoxides
725
regioisomers was determined by 1H NMR of crude product. The residue was purified by flash
chromatography.
(6R,8S,10S)-10-tert-Butyldimethylsilyloxy-2,2-dimethyl-7-methylene-1,3-
dioxaspiro[5.5]undec-8-ol (5b, C18H34O4Si)
Reaction with MICA: According to the procedure described above, a solution of compound 3b
(103 mg, 0.3mmol) in THF was treated with MICA (1.5mmol) for 3 h at room temperature. The crude
product contained secondary alcohol 5b and tertiary alcohol 6b (5b:6b¼ 1:2). The compounds could
not be separated by chromatography. Flash chromatography (P:EA¼ 90:10) yielded a (1:2)-mixture of
isomers 5b=6b as a colorless liquid (96 mg, 93%).
Reaction with DATMP: According to the procedure described above, a solution of compound 3b
(154 mg, 0.45 mmol) in benzene was treated with DATMP (2.25 mmol) for 30min at 0ꢂC. Flash
chromatography (P:EA¼ 90:10) yielded the allylic alcohol 5b as a colorless liquid (24.7 mg, 16%).
Rf ¼ 0.41 (P:EA¼ 80:20); IR (film, 5b=6b): ꢁꢀ¼ 3354 (s br), 2954 (s), 2878 (s), 1471 (m), 1255 (s),
1089 (s), 836 (vs), 775 (s) cmꢁ1; MS (EI, 70 eV, 5b pure): m=z (%) ¼ 327 (3) [Mþ–CH3], 285 (3)
[Mþ–tBu], 227 (10) [Mþ–C6H15Si], 135 (39), 105 (30), 75 (100) [C2H7OSiþ]; 1H NMR (250MHz, 5b
pure): ꢂ ¼ 0.06 (s, 6H, SiCH3), 0.86 [s, SiC(CH3)3], 1.41 (s, C2CH3), 1.45 (s, H3CC2), 1.50–1.60 (m,
2H), 1.83–1.88 (m, 1H), 2.01–2.17 (m, 3H), 3.31 (d, J ¼ 9.1Hz, OH), 3.89–4.02 (m, 2H), 4.28–4.38
(m, 2H), 5.07 (d, J ¼ 0.6 Hz, C¼CHH), 5.11 (d, J ¼ 0.6 Hz, C¼CHH); 13C NMR (62.9 MHz, 5b pure):
ꢂ ¼ ꢁ4.7 (q, SiCH3), ꢁ4.6 (q, SiCH3), 18.1 [s, SiC(CH3)3], 25.8 (q, C2CH3), 26.5 [q, SiC(CH3)3], 29.2
(q, C2CH3), 32.3 (t, C5), 44.8 (t), 49.4 (t), 56.9 (t, C4), 63.9 (d, C10), 73.7 (d, C8), 75.8 (s, C6), 99.2 (s,
C2), 109.8 (t, C¼CH2), 150.4 (s, C7).
(6R,7S,10R)-10-tert-Butyldimethylsilyloxy-2,2,7-trimethyl-1,3-
dioxaspiro[5.5]undec-8-en-7-ol (6b, C18H34O4Si)
To a solution of diisopropylamine (0.08 cm3, 58.7mg, 0.58 mmol) and KOt-Bu (65.1mg, 0.58mmol) in
THF (5cm3) was added a solution of n-butyllithium in hexane (2.5M, 0.23cm3, 0.58 mmol) at ꢁ78ꢂC.
Theyellowsolutionwasstirredfor15minatꢁ78ꢂC,thenasolutionofepoxide3b (188 mg, 0.55 mmol)in
THF (3cm3) was added dropwise. After stirring for 15 min atꢁ78ꢂC, the solution was warmed up to 0ꢂC,
and stirring was continued at 0ꢂC for 2 h. The reaction mixturewas diluted with saturated aqueous NH4Cl
(20 cm3) and diethyl ether (10 cm3). The layers were separated and extracted with diethyl ether
(2ꢄ 15cm3). The combined organic layers were washed with water (20 cm3) and brine (20 cm3), dried
(Na2SO4), filtered, and concentrated. The crude product contained tertiary alcohol 6b as sole product.
Flash chromatography (P:EA¼ 90:10) gave 185mg (98%) of tertiary alcohol 6b as a colorless oil.
Rf ¼ 0.42 (P:EA¼ 80:20); MS (EI, 70eV): m=z (%) ¼ 324 (3) [Mþ–H2O], 239 (10), 214 (100), 157
1
(40), 135 (30), 75 (87); H NMR (250 MHz): ꢂ ¼ 0.06 (s, 6H, SiCH3), 0.87 [s, SiC(CH3)3], 1.15 (s,
C7CH3), 1.16–1.26 (m, 1H), 1.37 (s, C2CH3), 1.50 (s, H3CC2), 1.51–166 (m, 1H), 2.19 (dt, J ¼ 12.8,
6.1 Hz, 1H),2.54(ddd, J ¼ 13.7, 5.5, 1.5 Hz, 1H),3.18(sbr, OH),3.83(ddd,J ¼ 12.2,5.8,1.8Hz, C4HH),
4.03 (dt, J ¼ 12.2, 3.3 Hz, C4HH), 4.36–4.42 (m, H10), 5.43 (dd, J ¼ 10.6, 1.5 Hz, 1H), 5.53 (d,
J ¼ 10.6Hz, 1H); 13C NMR (62.9MHz): ꢂ ¼ ꢁ4.2 (q, SiCH3), ꢁ4.1 (q, SiCH3), 18.5 [s, SiC(CH3)3],
23.3 (q, C2CH3), 24.9 (q, C2CH3), 26.2 [q, SiC(CH3)3], 27.3 (t, C5), 31.0 (q, C7CH3), 39.8 (t, C11), 56.6
(t, C4), 66.8 (d, C10), 72.3 (s, C7), 76.9 (s, C6), 98.9 (s, C2), 130.3 (d, C8), 134.6 (d, C9).
(6R,8S,10S)-10-Benzyloxy-2,2-dimethyl-7-methylene-1,3-dioxaspiro[5.5]undec-8-ol
(5c, C19H26O4)=(6R,7S,10S)-10-Benzyloxy-2,2,7-trimethyl-1,3-
dioxaspiro[5.5]undec-8-en-7-ol (6c, C19H26O4)
According to the procedure described above, a solution of compound 3c (95.5 mg, 0.3 mmol) in THF
was treated with MICA (1.5mmol) for 3 h at room temperature. The crude product contained second-

726
S. Kirsch et al.
ary alcohol 5c and tertiary alcohol 6c (5c:6c¼ 1:3). The compounds could not be separated by
chromatography. Flash chromatography (P:EA¼ 90:10) yielded a (1:3)-mixture of isomers 5c=6c as
a colorless liquid (68 mg, 71%). Rf ¼ 0.58 (P:EA¼ 50:50); 1H NMR (250MHz): ꢂ ¼ 1.16 (s, C7CH3,
6c), 1.15–1.27 (m, 3H, 5c), 1.33–1.44 (m, C2CH3, 6c; CH3, 5c), 1.58–1.68 (m, 1H, 6c; 1H, 5c), 2.02–
2.43 (m, 1H, 6c; 1H, 5c), 2.67 (ddd, J ¼ 13.6, 5.2, 1.5Hz, 1H, 6c), 3.16 (s br, OH, 6c), 3.54 (m br, OH,
5c), 3.84–4.18 (m, 3H, 6c; 3H, 5c), 4.42–4.45 (m, 1H, 5c), 4.56–4.58 (m, CH2Ph, 6c; CH2Ph, 5c), 5.07
(d, J ¼ 0.5 Hz, C¼CHH, 5c), 5.14 (d, J ¼ 0.5 Hz, C¼CHH, 5c), 5.53 (dd, J ¼ 4.4 Hz, J ¼ 2.6Hz, 1H,
6c), 5.74 (d, J ¼ 4.4 Hz, 1H, 6c), 7.23–7.31 (m, 5HAr, 5c=6c); 13C NMR (62.9 MHz): ꢂ ¼ 23.2 (q, 6c),
24.5 (q, 6c), 26.8 (q, 5c), 27.3 (t, 6c), 29.4 (q, 5c), 31.0 (q, 6c), 32.4 (t, 5c), 36.4 (t, 6c), 41.8 (t, 5c),
46.8 (5c), 56.6 (t, 6c), 57.3 (t, 5c), 70.6 (t, 6c), 70.7 (t, 5c), 72.6 (d, 6c), 72.6 (s, 6c), 74.7 (d, 5c), 76.2
(d, 5c), 76.9 (s, 6c), 98.9 (s, 6c), 99.7 (s, 5c),111.1 (t, 5c C¼CH2), 126.9 (d, 6c¼ CH), 127.9 (d, 6c),
127.9 (d, 5c), 128.0 (d, 6c), 128.1 (d, 5c), 128.8 (d, 6c), 128.8 (d, 5c), 136.1 (d, 6c¼ CH), 138.8 (s, 6c),
138.9 (s, 5c), 149.8 (s, 5c C¼CH2).
(1S,3R,5R)-3-(2-tert-Butyldimethylsilyloxyethyl)-3-triethylsilyloxy-5-tert-
butyldimethylsilyloxy-2-methylenecyclohexanol (5f, C27H58O4Si3)
According to the procedure described above, a solution of compound 3f (239 mg, 0.45mmol) in
benzene was treated with DATMP (2.25 mmol) for 30min at 0ꢂC. Flash chromatography
(P:EA¼ 95:5) yielded the allylic alcohol 5f as a colorless liquid (115mg, 48%) which was still
contaminated with silyl side products. An analytical sample could not be obtained. Rf ¼ 0.35
(P:EA¼ 80:20); IR (film): ꢁꢀ¼ 3354 (m br), 2954 (s), 1462 (m), 1255 (m), 1089 (s), 1061 (m), 836
1
(s), 775 (m) cmꢁ1; H NMR (250 MHz): ꢂ ¼ 0.00 [s, 12H, (CH3)3CSi(CH3)2], 0.60 [q, J ¼ 7.8 Hz,
Si(CH2CH3)3], 0.85 [s, 18H, (CH3)3CSi(CH3)2], 0.95 [t, J ¼ 7.9 Hz, Si(CH2CH3)3], 1.20–1.36 (m, 2H),
1.62–1.80 (m, 2H), 2.01–2.08 (m, 1H), 2.25–2.30 (m, 1H), 3.46 (dt, J ¼ 9.9, 5.8 Hz, CHHOTBS), 3.68
(dt, J ¼ 9.9, 5.2 Hz, CHHOTBS), 3.78–3.88 (m, 1H), 4.05–4.10 (m, 1H), 5.09 (s, C¼CHH), 5.18 (s,
C¼CHH); 13C NMR (62.9 MHz): ꢂ ¼ ꢁ5.0 [q, (CH3)3CSi(CH3)2], ꢁ4.9 [q, (CH3)3CSi(CH3)2], ꢁ4.3
[q, (CH3)3CSi(CH3)2], ꢁ4.2 [q, (CH3)3CSi(CH3)2], 7.4 [t, Si(CH2CH3)3], 7.5 [q, Si(CH2CH3)3],
18.5 [s, (CH3)3CSi(CH3)2], 18.7 [s, (CH3)3CSi(CH3)2], 26.0 [q, (CH3)3CSi(CH3)2], 26.4 [q,
(CH3)3CSi(CH3)2], 43.5 (t), 46.5 (t), 50.9 (t), 59.4 (t, CH2OTBS), 65.9 (d, C5), 68.0 (d, C1), 76.0
(s, C3), 105.1 (t, C2¼CH2), 153.5 (s, C2).
(1R,3S,5S)-1-(2-Hydroxyethyl)-5-tri-iso-propysilyloxy-2-methylenecyclohexan-1,3-diol
(12, C18H36O4Si)
According to the procedure described above, a solution of compound 3d (1.74 g, 4.5mmol) in benzene
(40 cm3) was treated with DATMP (15 mmol) for 45min at 0ꢂC. The reaction was quenched by
addition of saturated aqueous NH4Cl (40 cm3). The mixture was acidified with aqueous HCl (1N,
100 cm3) and stirred for 1 h at room temperature. After dilution with diethyl ether (100cm3), the layers
were separated and extracted with ethyl acetate (2ꢄ 50 cm3). The combined organic layers were
washed with water (100 cm3) and brine (100 cm3), dried (Na2SO4), filtered, and concentrated. Flash
chromatography (CH:EA ¼ 50:50) gave 945 mg (61%) of triol 12 as a colorless solid. Rf ¼ 0.13
20
(P:EA¼ 50:50); mp 90–96ꢂC; ½ꢀꢅD ¼ ꢁ84.6ꢂ cm3 gꢁ1 dmꢁ1 (c ¼ 0.23, CH2Cl2); IR (film): ꢁꢀ¼ 3286
(vs br), 2942 (vs), 2866 (s), 1384 (m), 1098 (m), 1058 (s), 914 (m) cmꢁ1; MS (EI, 70eV): m=z
1
(%) ¼ 301 (43) [Mþ–iPr], 283 (56), 135 (100), 107 (87), 81 (64), 75 (83), 43 (44) [iPrþ]; H NMR
(360 MHz): ꢂ ¼ 1.06 [s, 21H, SiCH(CH3)2], 1.78–2.01 (m, 5H,), 2.21 (d, J ¼ 6.1 Hz, C3OH), 2.27
(ddd, J ¼ 15.0, 5.9, 3.9Hz, C4HHb), 2.41 (t, J ¼ 4.6 Hz, CH2OH), 3.74 (s, C1OH), 3.85–3.87 (m,
CH2OH), 4.40 (virt. quint, J ffi 4.9 Hz, H5), 4.43–4.49 (m, H3), 5.17 (s, C¼CHH), 5.19 (s, C¼CHH);
13C NMR (90.6 MHz): ꢂ ¼ 12.2 [d, SiCH(CH3)2], 18.1 [q, SiCH(CH3)2], 18.1 [q, SiCH(CH3)2], 40.5 (t,
CH2CH2OH), 44.5 (t, C6), 47.8 (t, C4), 60.0 (t, CH2OH), 65.4 (d, C5), 70.4 (d, C3), 76.8 (s, C1), 107.0
(t, C¼CH2), 153.0 (s, C¼CH2).

Isomerisation of Substituted 1-Methylenecyclohexenepoxides
727
Acnowledgements
Financial support has been provided by Bayer AG (Wuppertal). We thank Wacker-Chemie (M€unchen)
for generously supplying chemicals.
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