Tandem ene-reaction/Intramolecular Sakurai Cyclisation (IMSC): A novel access to polysubstituted tetrahydropyrans and γ-butyrolactones using a unique allylation strategy

Article abstract of DOI:10.1055/s-2002-28506

The ene-reaction between a variety of aldehydes and allylsilane 22 generates highly functionalised homoallylic alcohols 23. These adducts undergo a subsequent Intramolecular Sakurai Cyclisation (IMSC), affording in good yields polysubstituted tetrahydropyran derivatives. Furthermore, oxidative desilylation of 23 provides an efficient, connective access to a range of γ-butyrolactones and α-methylene-γ-butyrolactones.

Full text of DOI:10.1055/s-2002-28506

958
SPECIAL TOPIC
Tandem Ene-Reaction/Intramolecular Sakurai Cyclisation (IMSC): A Novel
Access to Polysubstituted Tetrahydropyrans and -Butyrolactones Using a
Unique Allylation Strategy
T
andem
s
E
ne-Rea
c
t
tion/Int
v
ramolecular
á
Sakurai Cy
n
clisation E. Markó,* Raphaël Dumeunier, Cédric Leclercq, Bernard Leroy, Jean-Marc Plancher, Abdelaziz Mekhalfia,
Daniel J. Bayston
Université catholique de Louvain, Département de Chimie, Unité de Chimie Organique et Médicinale, Bâtiment Lavoisier, Place Louis
Pasteur 1, 1348 Louvain-la-Neuve, Belgium
Fax +32(10)478033; E-mail: marko@chim.ucl.ac.be
Received 11 April 2002
Abstract: The ene-reaction between a variety of aldehydes and al-
lylsilane 22 generates highly functionalised homoallylic alcohols
23. These adducts undergo a subsequent Intramolecular Sakurai Cy-
clisation (IMSC), affording in good yields polysubstituted tetrahy-
dropyran derivatives. Furthermore, oxidative desilylation of 23
provides an efficient, connective access to a range of -butyrolac-
tones and -methylene- -butyrolactones.
O
O
HO
O
O
O
O
Key words: ene-reactions, tetrahydropyrans, allylations -butyro-
lactones -methylene- -butyrolactones
O
MeO
O
O
OMe
POLYCAVERNOSIDE A
Me
OMe
1
Numerous biologically active natural products contain,
embeded in their complex architectural framework, one or
more polysubstituted tetrahydrofuran or tetrahydropyran
subunit. The ubiquitous presence of these heterocycles,
associated with the challenge offered by the total synthe-
OMe
HO
Figure 1 The structure of polycavernoside A (1).
sis of some of these natural products, has provided consid- ether such as 6 with an aldehyde or a ketone, provides a
erable impetus for the development of efficient ready access to a wide range of stereodefined, polysubsti-
methodologies for the preparation of tetrahydrofuran and tuted, exo-methylene tetrahydropyrans 76 (Scheme 1).
tetrahydropyran derivatives.1
During the course of these studies, we envisioned that the
During the course of the total synthesis of polycavernos- ISMS condensation of allyl silyl ether 8 and aldehydes 9
ide A (1),2 a potent marine toxin isolated by Yasumoto et might afford an easy route to the homologous exo-methyl-
al.2a in 1992 from the red alga Polycavernosa tsudai ene tetrahydrofuran skeleton 10. However, and in stark
(Gracilaria edulis), we had the opportunity to examine contrast to our expectation, none of the desired furan de-
novel and concise approaches towards the northern -bu- rivatives 10 was obtained when a mixture of 8 and 9 was
tyrolactone-derived subunit and the southern tetrasubsti- treated with a range of Lewis acids. Rather, diastereomer-
tuted terahydropyran fragment of 1 (Figure 1).3
ically pure, trisubstituted exo-methylene tetrahydropyrans
11 were produced, albeit in modest yields (Scheme 2).7
Interestingly, product 11 was not formed when the corre-
sponding acetals were used instead of the aldehydes in
this coupling reaction.
In this article, we wish to report our results on the success-
ful implementation of a connective methodology that al-
lows the efficient access to both families of heterocycles.
Sometime ago, we discovered that the addition of a cata-
lytic amount of trimethylsilyl triflate to a mixture of allyl-
silane 2, a carbonyl derivative 3 and a silyl ether 4 led to
Closer examination of heterocycles 11 clearly reveals that
two molecules of aldehyde 9 have been appended onto al-
lylsilane 8 via a novel three component coupling process.
It is interesting to note that all three substituents occupy
the thermodynamically more stable equatorial position.
The nature of the products formed in this cascade process
depends strongly upon the Lewis acid catalyst
(Scheme 3).
the smooth formation of homoallylic ethers
5
(Scheme 1).4 This three component coupling, coined as
the Silyl-Modified Sakurai (SMS) reaction, possesses
wide synthetic scope and has been employed, as a key-
step, in several synthetic ventures.5 Its intramolecular
variant, the Intramolecular Silyl-Modified Sakurai
(ISMS) cyclisation, which combines an homoallylic silyl Thus, whilst TiCl4 promotes the Sakurai addition8 of allyl-
silane 8 to aldehyde 9, generating after workup the diol
12, Et2AlCl catalyses the formation of the unique hydrox-
ysilyl enol ether 13. Allylsilane 13 was isolated as a single
geometric isomer, possessing the (E)-double bond config-
Synthesis 2002, No. 7, 21 05 2002. Article Identifier:
1437-210X,E;2002,0,07,0958,0972,ftx,en;C01102SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

SPECIAL TOPIC
Tandem Ene-Reaction/Intramolecular Sakurai Cyclisation
959
The SMS Condensation
OR2
O
TMSOTfcat
R2
TMS +
+
OTMS
R
R
R1
R1
(62-92%)
4
5
2
3
The ISMS Cyclisation
O
TMSO
TMSOTfcat
+
R1
R
R1
SiMe3
R
R4
(88-97%)
R4
O
6
3
7
R, R1, R2, R3, R4 = Alkyl, aryl, H,...
Scheme 1
TMS
OTMS
O
BF3.Et2O
(34-43%)
OH
R1
BF3.Et2O
+
R1
R1
H
O
R1
O
9
8
10
11
9a : R1 = nPr-
11a : R1 = nPr-
9b : R1 = cHex-
11b : R1 = cHex-
9c : R1 = PhCH2CH2-
11c : R1 = PhCH2CH2-
Scheme 2
TMS
OTMS
R1CHO
OH
OH
R1
R1CHO
OH
R1
TiCl4
BF3.Et2O
R1
O
8
12
11
R1CHO
Et2AlCl
TMS
OTMS
OH
R2
R1CHO
R2CHO
BF3.Et2O
BF3.Et2O
R1
R1
O
OH
13
R1, R2 = H, alkyl, aryl,...
14
Scheme 3
uration. Subsequent addition of aldehyde 9 to 13, in the For example, ketone 15, obtained by ozonolysis of 11,
presence of BF3 OEt2, afforded the tetrahydropyran 11, was smoothly reduced to the corresponding syn-diol
identical in all respect to the product obtained by the di- which afforded, after acetylation, the diastereomerically
rect, three-component condensation protocol. This last re- pure diacetate 16 in 82% yield. On the other hand, Luche
sult strongly suggests that the silyl enol ether 13 is an reduction9 of acetate 17 generated the stereocomplemen-
intermediate in the cascade transformation of 8 into 11. tary anti-diacetate 18 in 63% yield (Scheme 4). These
The availability of functionalised homoallylic alcohol 13 readily available heterocycles can be viewed as structural
offered a novel entry to the preparation of unsymmetrical- analogues of the core subunits of interesting biologically
ly substituted tetrahydropyrans 14, by condensation of a active natural products such as pseudomonic acid and am-
second aldehyde with 13.
bruticin.
Heterocycles 11 and 14 are useful synthetic intermediates Based upon these results, a simple retrosynthetic analysis
that could be further elaborated into stereocontrolled of polysubstituted tetrahydropyrans 19 can be devised
polyoxygenated fragments (Scheme 4).
(Scheme 5).
Synthesis 2002, No. 7, 958–972 ISSN 0039-7881 © Thieme Stuttgart · New York

960
I. E. Markó et al.
SPECIAL TOPIC
passage through a chair-like transition state, coupled with
the equatorial disposition of the substituents, is responsi-
ble for the observed, highly stereocontrolled, configura-
tion of the silyl enol ether double bond of 13. Subsequent
Lewis acid catalysed condensation of adduct 13 with a
second equivalent of aldehyde, generates the oxocarboni-
um cation E, which undergoes intramolecular capture by
the suitably positioned allylsilane residue, affording dias-
tereomerically pure exo-methylene tetrahydropyran 2112
(Scheme 6).
O
OAc
OH
OAc
Pr
1. LS-Selectride®
2. AcCl, Py
Pr
O
Pr
82%
63%
Pr
O
16
15
O
OAc
OAc
Pr
1. NaBH4 / CeCl3
2. AcCl, Py
OAc
Pr
Pr
O
Pr
O
The high regio- and stereo-selectivity observed in these
ene-reactions can be nicely explained by considering, for
all four possible transition states A–D, the stabilising -
silicon effect13 and the repulsive 1,3-diaxial interactions,
as shown in Figure 2.
17
18
Scheme 4
Excision of carbon-C2, bearing the R2 substituent, opens
the ring system of 14 and generates, besides the key-ho-
moallylic alcohol 13, the aldehyde 20. Subsequent retroal-
lyl cleavage of 13 produces aldehyde 9 and allylsilane 8.
In two straightforward operations, exo-methylene tetrahy-
dropyrans 14 has been disconnected into three basic, com-
mercially or readily available,10 building blocks
(Scheme 5). From the experiments described above, a
mechanistic proposal, rationalising the formation of 11
and 14 can be advanced (Scheme 6).
Transition state A, leading to the observed ene-adduct 23,
contains no 1,3-diaxial interactions and benefits fully
from the stabilising -silicon effect. In contrast, transition
state B, that would lead to the formation of the (Z)-double
bond isomer 24, suffers from severe 1,3-diaxial interac-
tions between the silyloxy substituent and the C2-hydro-
gen. The formation of the regioisomeric vinylsilanes 25
and 26 is also impeded by either the absence of a -silicon
effect (transition state C) or by a combination of destabi-
lising 1,3-diaxial repulsions coupled with a weakening of
the -silicon effect due to a distorsion from the optimum
angle of overlap between the interacting orbitals (transi-
tion state D).
Upon activation of the aldehyde by a suitable Lewis acid,
an initial ene reaction takes place via the six-membered
transition state A, in which both the R substituent and the
silyloxy group occupy pseudo equatorial positions.11 The
TMS
FG
OH
R2
OH
R2
OTMS
+
R1
R1
O
R1
O
OH
R2
O
19
14
13
20
TMS
+
R2
+
R1
O
OTMS
O
9
20
8
Scheme 5
TMS
OTMS
TMS
OTMS
R
O
R
O
8
9
+
H
H
LA
H
A
13
RCHO
TMS
OTMS
R
O
R
O
OTMS
R
R
21
E
Scheme 6
Synthesis 2002, No. 7, 958–972 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Tandem Ene-Reaction/Intramolecular Sakurai Cyclisation
961
OTBS
OTBS
TMS
OH
O
Et2AlCl
+
TMS
R1
R1
DCM, -78°C
9
22
23
product
transition state
H
OTBS
SiMe3
A.L.
R1
H
O
OH
H
OTBS
SiMe3
β effect
β effect
R1
δ+
H
23
24
A
SiMe3
OTBS
OTBS
OH
A.L.
R1
H
O
H
H
SiMe3
R1
1,3-diaxial interaction
δ+
H
B
H
SiMe3
OTBS
A.L.
R1
H
OH
O
H
SiMe3
OTBS
no β effect
25
26
R1
δ+
H
C
SiMe3
OTBS
SiMe3
OH
A.L.
R1
H
β effect
1,3-diaxial interaction
O
H
H
R1
OTBS
δ+
H
D
Figure 2 Transition states in the reaction of 9 with 22.
As mentioned previously (vide supra), the yields of ene- exo-methylene tetrahydropyran derivatives 27. Some rep-
adducts using the trimethylsilyloxy reagent 8 were rather resentative examples are displayed in Table 2.
moderate, probably owing to a competitive desilylation of
enophile 8. In order to improve the yield of homoallylic
alcohols 13, a more robust TBS protecting group was em-
ployed. Using reagent 22, smooth allylation of aldehydes
In general, good to excellent yields of heterocycles 27, in
which the robust TBS protecting group has been retained,
were obtained. In all cases, the substituents around the
ring system occupy equatorial positions, in accord with
occurred, affording the desired silyl enol ethers 23 in good
the previously suggested chair-like transition state A (vide
to excellent yields. Some selected examples are collected
supra). The reaction tolerates a wide range of functional-
in Table 1.
ities, both in the aldehyde and the silyl enol ether frag-
As can be seen from Table 1, linear and branched alde- ments. For example, , -unsaturated esters (entry 1), TBS
hydes are good substrates for the ene-reaction (entries 2 protected alcohols (entry 3) and cyclic acetals (entry 4)
and 3). The allylation process is also effective in the case undergo efficient IMSC condensation with saturated or
of formaldehyde, though Yamamoto’s bulky Lewis acid unsaturated aldehydes. It is noteworthy that allylic alcohol
MAD14 was required to promote the condensation. Inter- 23e, a substrate which is prone to dehydration, readily
estingly, the ene-reaction tolerates a large number of func- adds to crotonaldehyde, affording the bis-unsaturated
tionalities, such as halides, (Z)-alkenes, alkynes and tetrahydropyran adduct 24e in 85% yield (entry 5). In all
alkoxy groups (entries 4–7). In some cases, excellent di- these IMSC processes, ene-adduct 23 behaves as an allyl-
astereocontrol is exercised (entry 4) whilst in others the de silane, undergoing addition of the activated allylic residue
can be rather modest (entry 7). Finally, it is worth men- to the in situ generated oxocarbonium ion.
tioning that, using the Nakai–Mikami chiral titanium cat-
However, silyl enol ether 23 is also a masked aldehyde,
originating from the addition of an aldehyde homoenolate
(allylsilane 22) to a carbonyl derivative. It was therefore
envisioned that substituted -butyrolactones 28 could be
alyst,15 high levels of asymmetric induction can be
achieved in this ene-reaction (entry 8). In all cases, only
the (E)-silyl enol ether is formed.
With a variety of substituted homoallylic alcohols in readily accessed by chemoselective deprotection of the
hand, attention was then turned towards the Intramolecu- TBS function followed by subsequent oxidation of the re-
lar Sakurai Cyclisation. Addition of an aldehyde or an ac- sulting, cyclic lactol (Table 3).
etal to allylsilanes 23, in the presence of BF3 OEt2,
resulted in their smooth transformation into the desired
–78 °C, followed by the addition of TPAP and NMO16 re-
In the event, treatment of 23 with TBAF in THF, at
Synthesis 2002, No. 7, 958–972 ISSN 0039-7881 © Thieme Stuttgart · New York

962
I. E. Markó et al.
SPECIAL TOPIC
Table 1 Silyl Enol Ethers 23a–h
TMS
OTBS
TMS
O
Lewis acid
CH2Cl2
+
OTBS
R1
H
R1
OH
23
22
Entry
9
Aldehyde
Product
Yield (%)a
65
1
23a
O
OTBS
TMS
OH
H
H
2
3
23b
23c
73
52
OTBS
TMS
O
O
OH
OH
H
OTBS
TM
S
H
O
4
5
23d
23e
79b
55
OTBS
TM
OH
S
H
O
Br
Br
OTBS
TM
OH
OH
S
S
H
6
7
23f
61
O
O
OTBS
TM
H
H
23g
59c
OTBS
TMS
OH
Ph
O
O
O
O
Ph
8
23h
51d
O
OTBS
TMS
OH
EtO
H
EtO
O
O
a Isolated yields after purification by column chromatography.
b de = 85%.
c de = 51%.
d ee = 95%.
sulted in the transformation of ene-adducts 23 into the de- To illustrate their synthetic utility, a simple conversion of
sired -butyrolactones 28 in good to excellent overall 28 to exo-methylene- -butyrolactones 29 was devised
yields. The procedure tolerates a range of substituents and (Table 4).
protecting groups. The final lactones are usually obtained
Thus, addition of lactone 28 to a THF solution of LDA,
followed by capture of the resulting enolate with TMSCl,
as a mixture of cis- and trans-isomers; the diastereoselec-
tivity increasing as a function of the steric size of the R1
afforded the corresponding silylenol ether, which was im-
substituent. These -trimethylsilylmethyl- -butyrolac-
mediately reacted with an equivalent of NBS. The in situ
generated -bromolactone was then treated with a slight
tones 28 have been little studied previously17 though they
appear to be interesting precursors to a variety of 5-mem-
excess of TBAF, inducing a rapid bromodesilylation, ulti-
bered ring heterocycles.
Synthesis 2002, No. 7, 958–972 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Tandem Ene-Reaction/Intramolecular Sakurai Cyclisation
963
Table 2 exo-Methylene Tetrahydropyran Derivatives 27a–e Prepared
TMS
OTBS
+
OTBS
R2
BF3.Et2O
CH2Cl2
R2
O
R1
R1
OH
O
23
20
27
Entry
1
R1
H
Aldehyde
OMe
Product
Yield (%)a
80
27a
OTBS
MeO
O
CO2Oct
CO2Oct
2
3
Pr
Pr
27b
27c
63
79
O
H
OTBS
n-Pr
n-Pr
O
c-Hex
TBSO
O
OTBS
H
O
TBSO
4
27d
57
Ph
O
OTBS
H
O
O
Ph
O
O
H
O
5
CH3CH=CH
27e
85
O
OTBS
H
O
a Isolated yields after purification by column chromatography.
mately providing the desired exo-methylene- -butyrolac-
tones 29 in excellent overall yields18 (Table 4).
R
O
OTBS
TMS
NBS
OH
OTBS
TMS
Although this protocol proved efficient on small scale, af-
fording the desired products in a two-pot operation from
the ene-adducts 23, the stringent control of the reaction
conditions precluded its easy transposition to larger quan-
titites. Therefore, a shorter procedure, more amenable to
upscaling was developed, leading to exo-methylene- -bu-
tyrolactones 29 directly from homoallylic alcohols 23
(Scheme 7).19
R
Br
30
23
Bu4NF
R
OH
O
MnO2
KCN
H
O
R
O
31
29
Scheme 7
Addition of NBS to ene-adduct 23 resulted in a quantita-
tive bromocycloetherification, affording the correspond-
ing TBS protected lactol 30 as a single diastereoisomer.
Upon treatment with TBAF, double desilylation took
Synthesis 2002, No. 7, 958–972 ISSN 0039-7881 © Thieme Stuttgart · New York

964
I. E. Markó et al.
SPECIAL TOPIC
Table 3
-Butyrolactones 28a–c Prepared
TMS
TMS
O
?
OTBS
O
R1
R1
OH
28
23
Aldehyde
1. TBAF
2. TPAP / NMO
Entry
1
Ene adduct 23
Lactone 28
Yield (%)a
28a
28b
80
OTBS
TMS
O
O
OH
OH
O
(de = 45%)
TMS
2
3
60
OTBS
TMS
(de = 50%)
O
TMS
O
28c
99
OTBS
TMS
OH
O
(de = 75%)
BnO
BnO
TMS
a Isolated yields after purification by column chromatography.
Table 4 Conversion of 28 to exo-Methylene- -butyrolactones
TMS
1. LDA / TMSCl
O
O
2. NBS
3. TBAF
O
R1
O
R1
28
29
Entry
1
Lactone 28
Lactone 29
Yield (%)a
80
29a
29b
29c
TMS
O
O
O
O
2
3
70
74
TMS
O
O
O
O
BnO
BnO
TMS
O
O
O
O
a Isolated yields after purification by column chromatography.
place, generating the , -unsaturated aldehyde 31, in to excellent overall yields (Scheme 7). Some selected ex-
equilibrium with a small amount of the closed lactol. Un- amples are displayed in Table 5.
der Corey’s conditions,20 this mixture of equilibrating
As can be seen from Table 5, a variety of primary, second-
species underwent smooth oxidative cyclisation, leading
ary and tertiary homoallylic alcohols can be efficiently
to the desired exo-methylene- -butyrolactones 29 in good
converted into the final exo-methylene- -butyrolactones
Synthesis 2002, No. 7, 958–972 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Tandem Ene-Reaction/Intramolecular Sakurai Cyclisation
965
Table 5 Cyclization of 23 to exo-Methylene-g-butyrolactones 29
TMS
1. NBS
OTBS
O
2. TBAF
3. MnO2 / KCN
O
R1
R1
OH
23
29
Entry
1
Ene-Adduct 23
Lactone 29
Yield (%)a
61
29a
29b
O
OTBS
TMS
OH
O
2
76
OTBS
TMS
OH
O
O
O
O
3
4
29c
29d
66
57
OTBS
TMS
OBn OH
BnO
OTBS
TMS
O
O
OH
OH
O
O
5
6
29e
29f
60
74
OTBS
TMS
C5H11
OTBS
TMS
C5H11
O
OH
O
a Isolated yields after purification by column chromatography.
products by this simple protocol (entries 1–3). Interesting- In summary, we have shown that the ene-reaction be-
ly, the reaction tolerates a range of functionalities and pro- tween a variety of aldehydes and allylsilane 22 afforded,
tecting groups, including (E)- and (Z)-disubstituted in good yields, the corresponding adducts 23. These ho-
alkenes (entries 4 and 5) and terminal alkynes (entry 6). In moallylic alcohols, which embody an allylsilane and a si-
this last case, no competitive cyclisation on the triple bond lyl enol ether functions, are useful precursors to a range of
was observed.
polysubstituted heterocycles. By carefully selecting the
reaction conditions, either the allylsilane or the enol ether
function can be activated. Thus, addition of an aldehyde to
ene-adduct 23, in the presence of a Lewis acid, results in
the preparation of trisubstituted, diastereomerically pure,
exo-methylene tetrahydropyrans 27. These functiona-
lised, six-membered ring systems, are the core of a range
of biologically active natural products. Furthermore, by
recognising that adducts 23 were equivalent to aldehyde
homoenolate addition products, two simple routes to-
wards substituted -butyrolactones 28 and exo-methyl-
ene- -butyrolactones 29 have been established.
From all these results, a simple and general disconnection
for -butyrolactones and exo-methylene- -butyrolactones
29 can be proposed, as depicted in Scheme 8.
TMS
OTBS
O
22
+
O
R1
R1
O
29
9
Scheme 8
Synthesis 2002, No. 7, 958–972 ISSN 0039-7881 © Thieme Stuttgart · New York

966
I. E. Markó et al.
SPECIAL TOPIC
29.0 (CH2), 28.9 (CH2), 26.9 (CH2), 26.6 (CH2), 26.5 (CH2), 26.2
(CH2), 26.0 (CH2), 25.5 (CH2), 24.3 (CH2).
Current efforts are now being directed towards delineat-
ing the full scope of these connective methodologies, de-
fining enantioselective versions and applying them to the MS (EI, 70 eV): m/z (%) = 278 (M+ , 3), 166 (47), 135 (24), 96 (80),
81 (60), 71 (58), 55 (100), 41 (87).
total synthesis of various natural products, including poly-
cavernoside A (1).
Anal. Calcd for C18H30O2 (278.4): C, 77.65; H, 10.86. Found: C,
77.54; H, 10.73.
All air or moisture sensitive reactions were carried out in flame
dried glassware under Ar, unless otherwise noted. Reactive liquids
were transferred by syringe and were added into the reaction flask
through rubber septa. CH2Cl2 and THF were freshly distilled, the
former from CaH2 and the latter from sodium-benzophenone ketyl.
Purchased reagents were used as received unless otherwise indicat-
ed. TLC was performed on aluminum sheets coated with 0.20 mm
(2,3-anti,3,6-anti)-2,6-di-(2-phenylethyl)-4-methyleneoxacyclo-
hexan-3-ol (11c)
Compound 11c was prepared according to the protocol described
for the synthesis of 11a.
IR (KBr): 3416, 3040, 2925, 2860, 1649, 1594, 1497, 1460, 1105
cm–1.
silica gel 60 G/UV254 (Macherey-Nagel). 1H NMR spectra and 13
C
1H NMR (CDCl3): = 7.15–7.40 (10 H, m), 4.96 (1 H, q, J = 2.0
Hz), 4.83 (1 H, q, J = 1.9 Hz), 3.77 (1 H, br d, J = 9.1 Hz), 3.22–
3.36 (1 H, m), 2.67–3.03 (5 H, m), 2.38 (1 H, dd, J = 11.3, 2.1 Hz),
2.19–2.31 (1 H, m), 2.13 (1 H, br t, J = 11.3 Hz), 1.70–1.98 (3 H,
m), 1.53 (1 H, br s).
13C NMR (CDCl3): = 149.4 (C), 144.3 (C), 144.1 (C), 130.7 (CH),
130.6 (CH), 130.5 (CH), 130.4 (CH), 127.9 (CH), 127.8 (CH),
107.6 (CH2), 83.5 (CH), 79.2 (CH), 75.8 (CH), 43.3 (CH), 39.6
(CH), 36.5 (CH2), 34.1 (CH2), 33.8 (CH2).
NMR spectra were recorded on a Varian Gemini 200 (1H 200 MHz,
13C 50 MHz), Gemini 300 (1H 300 MHz, 13C 75 MHz) or Bruker
Advanced TM 500 (1H 500 MHz, 13C 125 MHz) spectrometer using
TMS as an internal standard. IR spectra were measured with a BIO-
RAD FTS 135 infrared spectrometer. Mass spectra were determined
on a Finnigan-Matt TSQ-70 or Varian Matt 44S spectrometer. High
resolution mass spectra were performed in Prof R. Flamant’s labo-
ratory (Université de Mons-Hainaut, Belgium) and elemental anal-
yses in Prof V. Jäger’s laboratory (Institut für Organishe Chemie,
Universität Stuttgart, Germany).
MS (EI, 70 eV): m/z = 322 (M+ , 37), 188 (20), 170 (17), 130 (33),
117 (25), 91 (100).
(2,3-anti,3,6-anti)-2,6-Dipropyl-4-methyleneoxacyclohexan-3-ol
(11a); Typical Procedure
Anal. Calcd for C22H26O2 (278.4): C, 81.95; H, 8.13. Found: C,
82.03; H, 8.10.
Neat BF3 OEt2 (1.0 equiv, 0.390 g, 0.35 mL, 2.78 mmol) was added
dropwise to a cold (–78 °C) mixture of butyraldehyde (2.0 equiv,
0.400 g, 5.56 mmol) and allylsilane 22 (1.0 equiv, 0.600 g, 2.78
mmol) in CH2Cl2 (15 mL). The resulting solution was allowed to
warm slowly (over 2 h) to r.t., and then poured onto sat. aq NaHCO3
(20 mL). The layers were separated and the aqueous phase was ex-
tracted with CH2Cl2 (2 20 mL). The combined organic extracts
were dried (K2CO3) and the volatiles removed in vacuo. Purification
by flash chromatography (silica gel, CH2Cl2) gave the title product
(0.236 g, 43%) as a white solid (mp 36–38 °C).
(2,3-anti,3,4-syn,4,6-anti)-2,6-dipropyl-3,4-diacetoxyoxacylo-
hexane (16)
To a cold (–78 °C) solution of compound 15 (0.58 g, 2.9 mmol, 1.0
equiv) in THF (6 mL) was added a 1.0 M solution of LS-Selectride
(3.77 mL, 3.77 mmol, 1.3 equiv). The resulting mixture was stirred
at –78 °C for 2 h and then allowed to warm to r.t. over a further 2 h.
The reaction was quenched by addition of H2O (3 mL) and EtOH (9
mL) followed by further treatment with 2.5 M aq NaOH (6 mL) and
30% aq H2O2 (6 mL). This slurry was stirred vigorously at r.t. for 2
h and then diluted with H2O (20 mL). The mixture was extracted
with Et2O (3 15 mL) and the combined organic extracts were
dried (MgSO4). The volatiles were removed in vacuo to leave a pale
yellow oil, which was immediately dissolved in CH2Cl2 (10 mL)
and the solution was cooled to 0 °C. To this solution was added, se-
quentially, acetyl chloride (2.5 equiv, 0.57 g, 0.52 mL, 7.25 mmol)
and pyridine (2.6 equiv, 0.6 g, 0.61 mL, 7.54 mmol) and the reaction
mixture was stirred at 0 °C for 7 h. The solution was poured onto aq
sat. NaHCO3 (20 ml), the layers were separated and the aqueous
phase was extracted with CH2Cl2 (3 15 mL). The combined or-
ganic extracts were dried (K2CO3) and the solvent was removed un-
der reduced pressure. Purification by flash column chromatography
(silica gel, hexane–EtOAc 10:1) furnished the title product (0.68 g,
82%) as a colourless oil.
IR (KBr): 3425, 2980, 2870, 1660, 1465, 1090, 895 cm–1.
1H NMR (CDCl3): = 4.99 (1 H, q, J = 2.1 Hz), 4.84 (1 H, q, J = 1.9
Hz), 3.74 (1 H, br d, J = 9.0 Hz), 3.21–3.31 (1 H, m), 2.98 (1 H, td,
J = 9.0, 2.2 Hz), 2.38 (1 H, dd, J = 10.9, 2.3 Hz), 1.99–2.11 (1 H,
m), 1.30–1.66 (1 H, m), 0.89–0.97 (6 H, m).
13C NMR (CDCl3): = 147.9 (C), 105.1 (CH2), 82.4 (CH), 78.1
(CH), 73.8 (CH), 41.3 (CH2), 37.9 (CH2), 34.7 (CH2), 18.9 (CH2),
18.7 (CH2), 14.0 (CH3), 14.0 (CH3).
MS (EI, 70 eV): m/z (%) = 198 (M+ , 26), 181 (78), 137 (41), 126
(69), 109 (33), 97 (96), 71 (100), 55 (84), 43 (89).
Anal. Calcd for C12H22O2 (198.3): C, 72.68; H, 11.18. Found: C,
72.56; H, 11.14.
IR (film): 2955, 2865, 1750, 1375, 1255, 1060 cm–1.
(2,3-anti,3,6-anti)-2,6-Dicyclohexyl-4-methyleneoxacyclohexan-
3-ol (11b)
Compound 11b was prepared according to the protocol described
for the synthesis of 11a.
1H NMR (CDCl3): = 5.38 (1 H, q, J = 3.0 Hz), 4.56 (1 H, dd,
J = 10.0, 3.0 Hz), 3.56–3.70 (2 H, m), 2.10 (3 H, s), 2.00 (3 H, s),
1.81 (1 H, ddd, J = 14.5, 3.5, 2.4 Hz), 1.22–1.86 (9 H, m), 0.90 (6
H, t, J = 6.8 Hz).
IR (KBr): 3390, 2925, 2855, 1660, 1455, 1075, 900 cm–1.
13C NMR (CDCl3): = 170.2 (C), 170.0 (C), 73.1 (CH), 72.1 (CH),
71.6 (CH), 67.7 (CH), 37.5 (CH2), 36.2 (CH2), 33.9 (CH2), 21.0
(CH3), 20.7 (CH3), 18.8 (CH2), 18.3 (CH2), 13.90 (CH3).
MS (EI, 70 eV) : 287 (M+, 18), 243 (11), 226 (17), 183 (30), 166
(54), 144 (25), 123 (48), 102 (46), 71 (27), 43 (100).
1H NMR (CDCl3): = 4.96 (1 H, s), 4.83 (1 H, s), 3.96 (1 H, br d,
J = 6.8 Hz), 2.94 (1 H, ddd, J = 12.5, 8.3, 1.8 Hz), 2.79 (1 H, dd,
J = 6.8, 1.9 Hz), 2.37 (1 H, dd, J = 12.5, 1.8 Hz), 0.90–2.10 (24 H,
m).
13C NMR (CDCl3): = 149.1 (C), 104.8 (CH2), 86.2 (CH), 82.6
(CH), 70.3 (CH), 42.8 (CH), 38.4 (CH), 38.3 (CH2), 30.6 (CH2),
Anal. Calcd for C15H26O5 (286.4): C, 62.91; H, 9.15. Found: C,
63.15; H, 9.26.
Synthesis 2002, No. 7, 958–972 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Tandem Ene-Reaction/Intramolecular Sakurai Cyclisation
967
(2,3-anti,3,4-anti,4,6-syn)-2,6-Dipropyl-3,4-diacetoxyoxacylo-
hexane (18)
equiv) in anhyd CH2Cl2 (100 mL) was added dropwise a 1 M hex-
ane solution of Et2AlCl (12.31 mL, 12.31 mmol, 1 equiv). The mix-
ture was stirred at this temperature for 1 h after which time the
cooling bath was removed and the solution was diluted by CH2Cl2
(50 mL). Aq sat. solution of NaHCO3 was then added. The layers
were separated and the aqueous phase was extracted with CH2Cl2
(3 100 mL). After washing the combined organic layers with H2O
(50 mL), the organic phase was dried (MgSO4), filtered and concen-
trated in vacuo. The residue was purified on silica gel using 30:1
hexane–EtOAc as eluent to afford the homoallylic alcohol 23b as a
viscous colourless oil (2.97 g, 73%).
To a cold (–20 °C) mixture of the ketone 17 (1.0 equiv, 0.48 g, 1.98
mmol) and CeCl3 7H2O (1.2 equiv, 0.89 g, 2.38 mmol) in THF–
MeOH (8 mL:4 mL) was added solid NaBH4 (1.2 equiv, 0.09 g,
2.38 mmol). Effervescence occurred immediately. The reaction
mixture was stirred at –20 °C for 1 h and then at r.t. for 1 h. The mix-
ture was poured onto sat. aq NaHCO3 (20 mL), the layers were sep-
arated and the aqueous phase was extracted with Et2O (3 15 mL).
The combined organic extracts were dried (MgSO4) and the sol-
vents were removed in vacuo. The crude alcohol was dissolved in
CH2Cl2 (10 mL) and treated, sequentially, with acetyl chloride (1.4
equiv, 0.22 g, 0.20 mL, 2.78 mmol) and pyridine (1.5 equiv, 0.24 g,
0.24 mL, 2.98 mmol) at 0 °C. The mixture was stirred at r.t. for 17
h and then poured onto sat. aq NaHCO3 (15 mL). The combined or-
ganic extracts were dried (K2CO3) and the volatiles were removed
under reduced pressure. Purification by flash column chromatogra-
phy (silica gel, hexane-EtOAc, 10:1) provided the title compound
(0.43 g, 76%) as a colourless oil.
IR (film): 3452 (O–H), 2956–2860 (C–H), 1645 (C=C), 1255, 1050,
835 cm–1.
1H NMR (CDCl3): = 6.09 (1 H, s), 3.65–3.57 (1 H, m), 2.04 (1 H,
ddd, J = 13.7, 3.1, 1.3 Hz), 1.81 (1 H, br s), 1.76 (1 H, dd, J = 13.7,
9.6 Hz), 1.76 (1 H, d, J = 13.4 Hz), 1.55–1.32 (4 H, m), 1.19 (1 H,
d, J = 13.4 Hz), 0.93 (3 H, t, J = 7.2 Hz), 0.91 (9 H, s), 0.10 (6 H, s),
0.01 (9 H, s).
13C NMR (CDCl3): = 134.2 (CH), 115.1 (C), 67.7 (CH), 41.8
(CH2), 39.0 (C-3), 25.7 (CH3), 18.9 (CH2), 18.1 (C), 17.2 (CH2),
14.0 (CH3), –0.74 (CH3), –5.26 (CH3), –5.39 (CH3).
MS (EI, 70 eV): m/z (%) = 330 (M+ , 7), 257 (7), 199 (26), 115 (11),
75 (100), 73 (47).
IR (film): 2955, 2840, 1745, 1350, 1240, 1015 cm–1.
1H NMR (CDCl3): = 4.93 (1 H, ddd, J = 11.4, 9.3, 5.2 Hz), 4.72
(1 H, t, J = 9.3 Hz), 3.19–3.43 (2 H, m), 2.00–2.13 (2 H, m), 2.01 (3
H, s), 1.99 (3 H, s), 1.25–1.60 (8 H, m), 0.82–0.93 (6 H, m).
13C NMR (CDCl3): = 170.4 (C), 170.0 (C), 76.9 (CH), 74.6 (CH),
73.4 (CH), 72.6 (CH), 37.3 (CH2), 36.6 (CH2), 33.6 (CH2), 20.7
(CH3), 20.7 (CH3), 18.6 (CH2), 18.3 (CH2), 13.7 (CH3).
(Z)-4-{[(tert-Butyldimethyl)silyl]oxy}-1-cyclohexyl-3-[(trimeth-
ylsilyl)methyl]but-3-en-1-ol (23c)
The ene adduct 23c was prepared from cyclohexanecarboxaldehyde
and 22 according to method B; colourless oil; yield: 52%.
MS (EI, 70 eV): m/z (%) = 287 (M+ , 3), 226 (53), 183 (50), 166
(100), 144 (50), 123 (97), 112 (82), 102 (64), 43 (39).
IR (film): 3567 (O–H), 2954–2855 (C–H), 1658 (C=C), 1472, 1450,
1250, 1161, 1001, 838 cm–1.
(Z)-4-{[(tert-Butyl(dimethyl)silyl]oxy}-3-[(trimethylsilyl)meth-
yl]but-3-en-1-ol (23a)
1H NMR (CDCl3): = 6.09 (1 H, s), 3.35 (1 H, ddd, J = 10.3, 5.9,
2.7 Hz), 2.10 (1 H, ddd, J = 13.7, 2.5, 1.4 Hz), 1.92–1.81 and 1.38–
0.95 (12 H, m), 1.82 (1 H, d, J = 13.4 Hz), 1.74 (1 H, dd, J = 13.7,
10.4 Hz), 1.15 (1 H, d, J = 13.4 Hz), 0.92 (9 H, s), 0.10 (6 H, s), 0.01
(9 H, s).
13C NMR (CDCl3): = 134.3 (CH), 115.2 (C), 71.5 (CH), 43.2
(CH), 38.4 (CH2), 29.1 (CH2), 28.5 (CH2), 26.6 (CH2), 26.3 (CH2),
26.2 (CH2), 25.7 (CH3), 18.1 (C), 16.8 (CH2), –0.73 (CH3), –5.23
(CH3), –5.39 (CH3).
Method A: To a solution of AlMe3 in toluene (2 M, 10.8 mL, 21.5
mmol, 3.0 equiv) was added slowly and at r.t., a solution of 2,6-
diphenylphenol (10.6 g, 43.0 mmol, 6 equiv) in freshly distilled
CH2Cl2 (50 mL). The resulting yellow mixture was stirred for 30
min after which time the temperature was lowered to 0 °C. A solu-
tion of trioxane (645 mg, 21.5 mmol, 3.0 equiv) in anhyd CH2Cl2 (6
mL) was then added. After stirring for 1 h at 0 °C, a siolution of al-
lylsilane 22 (1.86 g, 7.17 mmol, 1.0 equiv) in CH2Cl2 (10 mL) was
injected into the mixture. After 75 min, the solution was diluted
with CH2Cl2 (400 mL) and poured onto a aq sat. solution of
NaHCO3. The layers were separated and the aqueous phase was ex-
tracted with CH2Cl2 (3 250 mL). The combined organic layers
were dried (MgSO4), filtered and concentrated in vacuo. The resi-
due, 12.3 g of a yellow solid, was purified by MPLC (silica gel:
1000 g, eluent: CH2Cl2, flow: 150 mL/min, 235 nm UV detection)
to afford the homoallylic alcohol 23a as a viscous colourless oil
(1.35 g, 65%).
MS (EI, 70 eV): m/z (%) = 370 (M+ , 19), 355 (2), 257 (30), 239 (2),
185 (100), 147 (16), 127 (16), 73 (29).
Anal. Calcd for C20H42O2Si2: C, 64.80; H, 11.42. Found: C, 64.83;
H, 11.40.
(Z)-5-Bromo-1-{[tert-butyl(dimethyl)silyl]oxy}-2-[(trimethylsi-
lyl)methyl]oct-1-en-4-ol (23d)
The ene adduct 23d was prepared from 2-bromopentanal and 22 ac-
cording to method B. This compound is rather sensitive and should
be used as soon as possible in the subsequent step; colourless oil;
yield: 79%; de = 85%.
IR (film): 3354, 2955, 2931, 2888, 2859, 1664, 1249, 1160, 838 cm–
.
1H NMR (CDCl3): = 6.03 (1 H, br s), 3.55 (2 H, t, J = 10.0 Hz),
2.03 (2 H, td, J = 10.0, 1.0 Hz), 1.54 (1 H, br s), 1.45 (2 H, d, J = 1.0
Hz), 0.88 (9 H, s), 0.10 (6 H, s), 0.00 (9 H, s).
13C NMR (CDCl3): = 134.0 (CH), 114.4 (C), 60.1 (CH2), 36.7
(CH2), 25.8 (CH3), 18.2 (C), 17.1 (CH2), –0.62 (CH3), –5.16 (CH3).
1
IR (film): 447, 2958, 2933, 2888, 2860, 1660, 1468, 1251, 1201,
1158, 1105, 840, 781 cm–1.
1H NMR (CDCl3): (major isomer) = 6.09 (1 H, s), 4.05 (1 H, dt,
J = 8.4, 5.1 Hz), 3.68–3.79 (1 H, m), 2.29 (1 H, dd, J = 14.3, 3.7
Hz), 2.13 (1 H, m), 1.19–2.01 (7 H, m), 0.89 (9 H, s), 0.89–0.92 (3
H, m), 0.09 (6 H, s), 0.01 (9 H, s).
MS (EI, 70 eV): m/z (%) = 288 (M+, 48), 257 (15), 233 (33), 231
(35), 185 (65), 157 (7), 147 (100), 75 (28), 73 (75).
13C NMR (CDCl3): (major isomer) = 135.4 (CH), 114.9 (C), 71.9
(CH), 62.8 (CH), 38.8 (CH2), 36.4 (CH2), 26.3 (CH3), 21.7 (CH2),
18.7 (C), 17.8 (CH2), 14.1 (CH3), –0.05 (CH3), –4.54 (CH3), –4.64
(CH3).
Anal. Calcd for C14H32O2Si2 (288.6): C, 58.27; H, 11.18. Found: C,
58.17; H,11.06.
(Z)-1-{[(tert-Butyl(dimethyl)silyl]oxy}-2-[(trimethylsilyl)meth-
yl]hept-1-en-4-ol (23b)
Method B: To a cold (–78 °C) mixture of butyraldehyde (0.89 g,
12.31 mmol, 1 equiv) and allylsilane 22 (3.182 g, 12.31 mmol, 1
Synthesis 2002, No. 7, 958–972 ISSN 0039-7881 © Thieme Stuttgart · New York

968
I. E. Markó et al.
SPECIAL TOPIC
1H NMR (CDCl3): (minor isomer) = 6.13 (1 H, s), 4.04 (1 H, ddd,
J = 9.0, 4.8, 2.4 Hz), 3.54 (1 H, br t, J = 4.9 Hz), 1.21–2.19 (8 H, m),
0.91 (9 H, s), 0.87–0.94 (3 H, m), 0.09 (6 H, s), 0.00 (9 H, s).
13C NMR (CDCl3): (minor isomer) = 135.4 (CH), 114.7 (C), 71.5
(CH), 63.4 (CH), 40.4 (CH2), 38.4 (CH2), 26.3 (CH3), 21.7 (CH2),
18.7 (C), 17.9 (CH2), 14.0 (CH3), –0.06 (CH3), –4.61 (CH3).
(1 H, br q, J = 6.9 Hz), 2.65–2.17 (2 H, m), 1.30–1.95 (13 H, m),
0.98 (9 H, s), 0.15 (6 H, s), 0.06 (9 H, s).
13C NMR (CDCl3): (major isomer) = 139.3 (C), 134.3 (CH), 128.4
(CH), 128.0 (CH), 127.4 (CH), 114.0 (C), 109.6 (C), 84.8 (CH),
80.2 (CH), 69.1 (CH), 37.3 (CH2), 36.8 (CH2), 36.7 (CH2), 25.6
(CH3), 25.1 (CH2), 23.9 (CH2), 18.0 (C), 16.9 (CH2), –0.72 (CH3),
–5.21 (CH3), –5.33 (CH3).
(Z)-1-{[tert-Butyl(dimethyl)silyl]oxy}-2-[(trimethylsilyl)meth-
yl]dodeca-1,9-dien-4-ol (23e)
The ene adduct 23e was prepared from aldehyde 9e and allylsilane
22 according to method B; colourless oil; yield: 55%.
13C NMR (CDCl3): (minor isomer) = 138.2 (C), 134.3 (CH), 128.5
(CH), 128.1 (CH), 126.8 (CH), 114.1 (C), 109.5 (C), 84.0 (CH),
78.8 (CH), 66.1 (CH), 39.0 (CH2), 36.8 (CH2), 36.5 (CH2), 25.7
(CH3), 25.1 (CH2), 23.9 (CH2), 18.1 (C), 17.2 (CH2), –0.78 (CH3),
–5.33 (CH3).
MS (EI, 70 eV): m/z (%) = 504.3 (M+ , 100), 309.2 (98), 257.2 (46),
205.2 (62), 195.1 (49), 147.0 (45), 73.1 (69), 44.1 (62).
IR (film): 3447 (O–H), 3005–2858 (C–H), 1659 (C=C), 1472, 1463,
1405, 1362, 1248, 1167, 1100, 838 cm–1.
1H NMR (CDCl3): = 6.09 (1 H, s), 5.41–5.23 (2 H, m), 3.62–3.48
(1 H, m), 2.10–1.93 and 1.47–1.13 (5 H and 7 H, m), 1.77 (1 H, d,
J = 13.2 Hz), 1.75 (1 H, dd, J = 13.4, 8.2 Hz), 1.19 (1 H, d, J = 13.4
Hz), 0.95 (3 H, t, J = 7.7 Hz), 0.91 (9 H, s), 0.10 (6 H, s), 0.01 (9 H,
s).
13C NMR (CDCl3): = 134.4 (CH), 131.7 (CH), 129.1 (CH), 115.2
(C), 68.0 (CH), 41.9 (CH2); 36.8 (CH2), 29.9 (CH2), 27.1 (CH2),
25.8 (CH3), 25.5 (CH2), 20.2 (CH2), 18.2 (C), 17.3 (CH2), 14.4
(CH3), –0.63 (CH3), –5.13 (CH3), –5.26 (CH3).
Anal. Calcd for C28H48O4Si2 (504.9): C, 66.61; H, 9.58. Found: C,
66.12; H, 9.37.
(2S,4Z)-Ethyl 5-{[tert-Butyl(dimethyl)silyl]oxy}-2-hydroxy-4-
[(trimethylsilyl)methyl]pent-4-enoate (23h)
Method C: A solution of Cl2Ti(iPrO)2 (0.488 M, 225 L, 100 mol,
0.1 equiv) in toluene was added to (S)-Binol (29 mg, 100 mol, 0.1
equiv) in anhyd CH2Cl2 (1 mL). The mixture turned at once to red-
brown. In another flask, a suspension of hydrated molecular sieves
(4Å) was prepared by the addition of H2O (30 L) to activated MS
(500 mg) in CH2Cl2 (3 mL). The titanate solution was then trans-
ferred, via canula, on the molecular sieve suspension. The mixture
was stirred for 1 h at 17 °C, after which time it was cooled to 0 °C.
Allylsilane 22 (320 L, 258 mg, 1.0 mmol, 1.0 equiv) was added di-
rectly, followed by a solution of ethyl glyoxylate in toluene (re-
fluxed 1 h before, 50% weight, 300 L, 306 mg, 1.5 mmol, 1.5
equiv). After stirring for 20 h at this temperature, the reaction was
worked up by the addition of aq sat. solution of NaHCO3 and Et2O.
The layers were separated and the aqueous phase was extracted
twice with Et2O. The organic phase was dried (MgSO4), filtered and
concentrated in vacuo. The residue was purified on silica gel using
CH2Cl2 as eluent, affording homoallylic alcohol 23h as a viscous
colourless oil (185 mg, 51%). Enantiomerical excess was deter-
mined by CGC on a chiral phase (160 °C isotherm, 95% ee).
MS (EI, 70 eV): m/z (%) = 398 (M+ , 92), 383 (9), 257 (81), 213
(100), 147 (31), 123 (37), 73 (56).
Anal. Calcd for C22H46O2Si2: C, 66.26; H, 11.63. Found: C, 66.28;
H, 11.60.
(Z)- 1-{[tert-Butyl(dimethyl)silyl]oxy}-2-[(trimethylsilyl)meth-
yl]non-1-en-8-yn-4-ol (23f)
The ene adduct 23f was prepared from aldehyde 9f and allylsilane
22 according to method B; colorless oil; yield: 61%.
IR (film): 3449 (O–H), 3313, 2954–2858 (C–H), 1660 (C=C), 1463,
1408, 1362, 1248, 1144, 1101, 838 cm–1.
1H NMR (CDCl3): = 6.10 (1 H, s), 3.79–3.63 (1 H, m), 2.24 (2 H,
td, J = 6.6, 2.7 Hz), 2.04 (1 H, ddd, J = 13.5, 2.7, 1.5 Hz), 1.95 (1 H,
t, J = 2.7 Hz), 1.79 (1 H, dd, J = 13.2, 11.1 Hz), 1.77 (1 H, d,
J = 13.2 Hz), 1.76–1.48 (4 H, m), 1.19 (1 H, d, J = 13.8 Hz), 0.91 (9
H, s), 0.10 (6 H, s), 0.01 (9 H, s).
13C NMR (CDCl3): = 134.4 (CH), 114.9 (C), 84.2 (C), 68.4 (CH),
67.5 (CH2), 41.9 (CH2), 35.8 (CH2), 25.7 (CH3), 24.9 (CH2), 18.5
(CH2), 18.2 (C), 17.2 (CH2), –0.66 (CH3), –5.15 (CH3), –5.29
(CH3).
IR (film): 3482, 2956, 2931, 2869, 1735, 1664, 1251, 1201, 1162,
1101, 838 cm–1.
1H NMR (CDCl3): = 6.07 (1 H, br s), 4.14–4.24 (3 H, m), 2.49 (0.8
H, d, J = 5.9 Hz), 2.32 (1 H, ddd, J = 14.1, 4.4, 1.0 Hz), 2.13 (1 H,
dd, J = 14.1, 7.8 Hz), 1.56 (1 H, d, J = 13.6 Hz), 1.41 (1 H, d,
J = 13.6 Hz), 1.27 (1 H, t, J = 7.1 Hz), 0.89 (9 H, s), 0.07 (6 H, s),
0.00 (9 H, s).
13C NMR (CDCl3): = 174.6 (C), 134.9 (CH), 113.1 (C), 69.0 (CH),
61.3 (CH2), 38.7 (CH2), 25.7 (CH3), 18.1 (C), 17.2 (CH2), 14,2
(CH3), –0.73 (CH3), –5.24 (CH3).
MS (EI, 70 eV): m/z (%) = 354 (M+ , 72), 339 (4), 257 (68), 169
(100), 147 (43), 129 (33), 95 (41), 79 (44), 73 (56).
Anal. Calcd for C19H38O2Si2: C, 64.34; H, 10.80. Found: C, 63.88;
H, 10.60.
MS (EI, 70 eV): m/z (%) = 360.3 (M+ , 25), 257.2 (75), 185.2 (100),
157.1 (15), 147.1 (18), 73.1 (30).
4-{[tert-butyl(dimethyl)silyl]oxy}-1-(3-phenyl-1,4-dioxas-
piro[4.5]dec-2-yl)-3-[(trimethylsilyl)methyl]but-3-en-1-ol (23g)
The ene adduct 23g was prepared from the corresponding aldehyde
and allylsilane 22 according to method B; colourless oil; yield:
59%; de 51%.
Anal. Calcd for C17H36O4Si2 (360.2): C, 56.69; H, 10.07. Found: C,
57.24; H,10.17
tert-butyl[2-cyclohexyl-4-methylene-6-propyltetrahydro-2H-
pyran-3yl)oxy]dimethylsilane (27b); Typical Procedure
IR (film): 3500, 2934, 2886, 2858, 1685, 1249, 1164, 1103, 838,
780 cm–1.
To a cold (–78 °C) solution of silyl enol ether 23c (1.0 equiv, 0.227
g, 0.692 mmol) and cyclohexanecarboxaldehyde (1.0 equiv, 0.085
g, 0.761 mmol) in CH2Cl2 (5 mL) was added BF3 OEt2 (1.1 equiv,
0.108 g, 0.096 mL, 0.761 mmol). The reaction mixture was allowed
to warm slowly (over 2 h) to r.t. before being poured onto sat. aq
NaHCO3 (20 mL). The layers were separated and the aqueous phase
was extracted with CH2Cl2 (2 20 mL). The combined organic ex-
tracts were dried (K2CO3) and the solvent was removed under re-
duced pressure. Purification by flash column chromatography
1H NMR (CDCl3): (major isomer) = 7.30–7.53 (5 H, m), 5.96 (1
H, s), 5.06 (1 H, d, J = 7.4 Hz), 3.93 (1 H, dd, J = 7.4, 5.4 Hz), 3.88–
3.96 (1 H, m), 2.23 (1 H, dd, J = 14.6, 3.0 Hz), 2.02 (1 H, br s), 1.91
(1 H, dd, J = 14.3, 9.1 Hz), 1.48–1.87 (11 H, m), 1.29 (1 H, d,
J = 13.5 Hz), 0.96 (9 H, s), 0.12 (6 H, s), 0.07 (9 H, s).
1H NMR (CDCl3): (minor isomer) = 7.35–7.57 (5 H, m), 6.14 (1
H, s), 5.09 (1 H, d, J = 8.5 Hz), 3.86 (1 H, dd, J = 8.5, 1.9 Hz), 3.70
Synthesis 2002, No. 7, 958–972 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Tandem Ene-Reaction/Intramolecular Sakurai Cyclisation
IR (film): 2931, 2861, 1449, 1254, 1118, 1065, 831, 777 cm–1.
969
(silica gel, hexane–EtOAc, 50:1) afforded 27b (0.153 g, 63%) as a
colourless oil.
1H NMR (CDCl3): = 7.30–7.41 (5 H, m), 5.58 (1 H, dq, J = 15.4,
6.3 Hz), 5.45 (1 H, dd, J = 15.4, 6.6 Hz), 5.08 (1 H, s), 4,91 (1 H, s),
4.83 (1 H, d, J = 8.0 Hz), 3.90 (1 H, dd, J = 8.0, 5.2 Hz), 3.74 (1 H,
d, J = 9.1 Hz), 3.42–3.49 (2 H, m), 2.56 (1 H, br d, J = 11.3 Hz),
2.33 (1 H, br t, J = 12.3 Hz), 0.82–1.96 (10 H, m), 1.67 (3 H, d,
J = 6.3 Hz), 0.90 (9 H, s), 0.01 (6 H, s).
13C NMR (CDCl3): = 146.5 (C), 139.0 (C), 129.6 (CH), 129.2
(CH), 128.3 (CH), 128.0 (CH), 127.1 (CH), 110.4 (C), 107.2 (CH2),
84.5 (CH), 84.4 (CH), 80.8 (CH), 78.6 (CH), 74.0 (CH), 36.8 (CH2),
36.5 (CH2), 29.7 (CH2), 25.7 (CH3), 25.1 (CH2), 23.8 (CH2), 18.2
(C), 17.8 (CH3), –4.54 (CH3), –4.79 (CH3).
IR (film): 2925, 2860, 1640, 1460, 1250, 1120, 835 cm–1.
1H NMR (CDCl3): = 4.93 (1 H, s), 4.73 (1 H, s), 3.85 (1 H, d,
J = 8.9 Hz), 3.10–3.23 (1 H, m), 2.81 (1 H, d, J = 8.9 Hz), 2.26 (1
H, dd, J = 12.8, 1.9 Hz), 1.91 (1 H, t, J = 12.8 Hz), 1.10–1.78 (15 H,
m), 0.92 (9 H, s), 0.88 (3 H, t, J = 6.9 Hz), 0.05 (3 H, s), 0.00 (3 H,
s).
13C NMR (CDCl3): = 148.9 (C), 105.7 (CH2), 87.3 (CH), 78.5
(CH), 71.2 (CH), 41.8 (CH2), 38.0 (CH2), 37.5 (CH), 31.4 (CH2),
27.1 (CH2), 26.6 (CH2), 26.3 (CH2), 26.0 (CH3), 25.3 (CH2), 18.9
(CH2), 18.3 (C), 14.0 (CH3), –4.07 (CH3), –4.90 (CH3).
MS (EI, 70 eV): m/z (%) = 484.3 (M+ , 14), 266.2 (100), 149.1 (14).
MS (EI, 70 eV): m/z (%) = 352 (M+ , 100), 295 (9), 280 (19), 269
(22), 240 (44), 223 (58), 198 (29), 183 (95), 127 (25), 75 (24).
Anal. Calcd for C29H44O4Si (484.8): C, 71.85; H, 9.15. Found: C,
72.05; H, 9.29.
Octyl (E)-4-((2S-3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-meth-
ylenetetrahydro-2H-pyran-2-yl)-3-methylbut-2-enoate (27a)
Compound 27a was prepared according to the protocol described
for the synthesis of 27b; colourless oil; yield: 80%.
tert-Butyl(dimethyl)({4-methylene-2,6-di[(E)-prop-1-enyl]tet-
rahydro-2H-pyran-3-yl}oxy)silane (27e)
Compound 27e was prepared according to the protocol described
for the synthesis of 27b; colourles oil; yield: 85%.
IR (film): 2956, 2854, 1717, 1654, 1147, 838 cm–1.
IR (film): 2934, 2857, 1656, 1462, 1253, 1121, 1063, 836, 776 cm–1.
1H NMR (CDCl3): = 5.71 (1 H, s), 5.00 (1 H, br s), 4.82 (1 H, br
s), 4.84 (1 H, t, J = 6.7 Hz), 3.90–4.00 (1 H, ddd, J = 10.8, 4.7, 2.0
Hz), 3.70 (1 H, br d, J = 8.8 Hz), 3.28 (1 H, dt, J = 10.5, 4.7 Hz),
3.21 (1 H, ddd, J = 10.6, 8.8, 2.2 Hz), 1.91 (1 H, dd, J = 14.3, 9.1
Hz), 1.48–1.87 (11 H, m), 1.29 (1 H, d, J = 13.5 Hz), 0.96 (9 H, s),
0.12 (6 H, s), 0.07 (9 H, s).
13C NMR (CDCl3): = 139.3 (C), 134.3 (CH), 128.4 (CH), 128.0
(CH), 127.4 (CH), 114.0 (C), 109.6 (C), 84.8 (CH), 80.2 (CH), 69.1
(CH), 37.3 (CH2), 36.8 (CH2), 36.7 (CH2), 25.6 (CH3), 25.1 (CH2),
23.9 (CH2), 18.0 (C), 16.9 (CH2), –0.72 (CH3), –5.21 (CH3), –5.33
(CH3).
1H NMR (CDCl3): = 5.66–5.80 (2 H, m), 5.42–5.56 (2 H, m), 5.05
(1 H, q, J = 1.3 Hz), 4.84 (1 H, q, J = 1.8 Hz), 3.77–3.84 (1 H, m),
3.76 (1 H, d, J = 8.7 Hz), 3.52 (1 H, t, J = 8.2 Hz), 2.39 (1 H, dd,
J = 13.2, 2.5 Hz), 2.19 (1 H, bt, J = 12.3 Hz), 1.69 (3 H, d, J = 6.4
Hz), 1.68 (3 H, d, J = 6.4 Hz), 0.90 (9 H, s), 0.03 (3 H, s), 0.02 (3 H,
s).
13C NMR (CDCl3): = 146.7 (C), 131.1 (CH), 130.1 (CH), 130.0
(CH), 128.0 (CH), 106.7 (CH2), 84.3 (CH), 79.0 (CH), 74.0 (CH),
41.4 (CH2), 25.8 (CH3), 18.2 (C), 17.9 (CH3), 17.8 (CH3), –4.49
(CH3), –4.72 (CH3).
MS (EI, 70 eV): m/z (%) = 438.3 (M+ , 5), 257.1 (100), 157.1 (92),
MS (EI, 70 eV): m/z (%) = 308.1 (M+, 2), 238.2 (100), 181.1 (82),
114.1 (88), 97.1 (60), 73.1 (88), 57.1 (60), 43.1 (80).
163.1 (19), 74.9 (28).
Anal. Calcd for C28H48O4Si2 (504.9): C, 68.44; H, 10.57. Found: C,
68.40; H, 10.65.
Anal. Calcd for C18H32O2Si (308.5): C, 70.07; H, 10.45. Found: C,
69.94; H, 10.48.
3-{[tert-Butyl(dimethyl)silyl]oxy}-2-[1-{[tert-butyl(dimethyl)si-
lyl]oxy}propyl-4-methylene-6-propyltetrahydro-2H-pyran
(27c)
Compound 27c was prepared according to the protocol described
for the synthesis of 27b; colourless oil; yield: 79%.
5-Propyl-3-[(trimethylsilyl)methyl]dihydrofuran-2(3H)-one
(28a); Typical Procedure
A 1 M solution of TBAF (3.51 mL, 3.51 mmol, 2 equiv) in THF was
added slowly to a solution of the ene adduct 23b (0.58 g, 1.75 mmol,
1 equiv) in anhy THF (10 mL). The mixture was stirred overnight
(14 h), diluted with Et2O (10 mL) and then transferred to a separa-
tory funnel containing brine (15 mL). The aqueous phase was
washed with Et2O (3 20 mL) and the combined organic extracts
dried (MgSO4), filtered and concentrated in vacuo. The crude mate-
rial was judged to be of sufficient purity to be used as such in the
following oxidation step. A solution of this material in CH2Cl2 (5
mL) was injected into a 2-necked flask containing 0.9 g of dry 4 Å
molecular sieves. Solid NMO (0.31 g, 2.63 mmol, 1.5 equiv) was
then added. After cooling to 0 °C, TPAP (20 mg, 0.06 mmol, 0.03
equiv) was added portionwise and the mixture allowed to warm to
r.t. The reaction was monitored by TLC, and after 1 h of vigorous
stirring, the mixture was filtered on silica gel. The filtrate was con-
centrated in vacuo and the residue was purified by flash column
chromatography (silica gel, hexane–EtOAc, 15:1). After removal of
the eluent, 304 mg of the title compound was isolated (80%) as a
colorless oil.
IR (film): 2958, 2930, 2858, 1468, 1254, 1110, 836, 775 cm–1.
1H NMR (CDCl3): = 4.98 (1 H, d, J = 1.3 Hz), 4.77 (1 H, d, 1.8
Hz), 3.96–4.21 (1 H, m), 3.67 (1 H, d, J = 9.0 Hz), 3.16–3.23 (1 H,
m), 3.00 (1 H, ddd, J = 10.4, 8.9, 2.7 Hz), 2.33 (1 H, dd, J = 13.1,
2.2 Hz)¸ 2.02 (1 H, br t, J = 12.1 Hz), 1.86 (1 H, ddd, J = 13.3, 9.1,
2.6 Hz), 1.63 (1 H, ddd, J = 13.5, 10.4, 4.1 Hz), 1.24–1.54 (4 H, m),
1.12 (3 H, d, J = 6.1 Hz), 0.94 (12 H, br s), 0.88 (9 H, s), 0.08 (3 H,
s), 0.05 (6 H, br s), 0.03 (3 H, s).
13C NMR (CDCl3): = 148.5 (C), 106.6 (CH2), 81.5 (CH), 79.1
(CH), 75.8 (CH), 66.8 (CH), 43.8 (CH2), 42.4 (CH2), 38.6 (CH2),
22.7 (CH3), 23.5 (CH3), 19.6 (CH2), 18.9 (C), 14.7 (CH3), –3.69
(CH3), –3.79 (CH3), –3.93 (CH3).
MS (EI, 70 eV): m/z = 442.3 (M+ , 80), 385.2 (38), 253.2 (28), 159.1
(100), 73.0 (47).
HRMS: m/z calcd for C24H50O3Si2, 442.3298; found, 442.3305.
IR (film): 2958–2857 (C–H), 1772 (C=O), 1466, 1250, 1185, 842
cm–1.
1H NMR (CDCl3): (major isomer) = 4.30 (1 H, ddt, J = 10.4, 7.4,
5.3 Hz), 2.58 (1 H, tdd, J = 11.9, 8.5, 3.5 Hz), 2.48 (1 H, ddd,
J = 12.2, 8.5, 5.4 Hz), 1.80–1.70 (1 H, m), 1.60–1.30 (4 H, m), 1.29
tert-Butyl(dimethyl){[4-methylene-6-(3-phenyl-1,4-dioxa-
spiro[4.5]dec-2-yl)prop-2-enyltetrahydro-2H-pyran-3-
yl]oxy}silane (27d)
Compound 27d was prepared according to the protocol described
for the synthesis of 27b; colourless oil; yield: 57%.
Synthesis 2002, No. 7, 958–972 ISSN 0039-7881 © Thieme Stuttgart · New York

970
I. E. Markó et al.
SPECIAL TOPIC
(1 H, dd, J = 14.8, 3.3 Hz), 0.94 (3 H, t, J = 7.2 Hz), 0.58 (1 H, dd,
J = 14.8, 11.4 Hz), 0.07 (9 H, s).
13C NMR (CDCl3): = 180.8 (C), 138.8 (C), 128.7 (CH), 127.84
(CH), 127.9 (CH), 82.2 (CH), 76.8 (CH2), 73.7 (CH2), 38.1 (CH),
37.8 (C), 36.7 (CH), 32.6 (CH2), 31.0 (CH2), 20.5 (CH3), 20.2
(CH3), 19.8 (CH2), 18.1 (CH2), 0.8 (CH3).
MS (EI, 70 eV): m/z (%) = 334 (M+ , 100), 319 (21), 243 (9), 228
(16), 211 (16), 171 (4), 153 (20), 143 (15), 129 (10), 91 (64), 73
(19).
1H NMR (CDCl3): (minor isomer) = 4.49 (1 H, tt, J = 7.7, 4.8 Hz),
2.58 (1 H, m), 2.07 (1 H, ddd, J = 12.7, 8.8, 4.7 Hz), 1.95 (1 H, dt,
J = 12.7, 7.7 Hz), 1.70 (1 H, m), 1.60–1.30 (3 H, m), 1.18 (1 H, dd,
J = 14.8, 4 Hz), 0.94 (3 H, t, J = 7.2 Hz), 0.66 (1 H, dd, J = 14.8,
11.1 Hz), 0.07 (9 H, s).
13C NMR (CDCl3): = 180.2 (C), 78.2 (CH), 77.9 (CH), 37.8
(CH2), 37.7 (CH2), 35.9 (CH2), 35.5 (CH), 18.7 (CH2), 18.6 (CH2),
18.0 (CH2), 13.8 (CH3), 13.7 (CH3), –1.20 (CH3).
Anal. Calcd for C19H30O3Si: C, 68.22; H, 9.04. Found: C, 68.18; H,
9.10.
3-Methylene-5-propyldihydrofuran-2(3H)-one (29a); Typical
Procedures
MS (EI, 70 eV): 214 (M+ , 13), 199 (100), 171 (9), 143 (12), 129
(16), 73 (38), 55 (13), 43 (18).
Method A, Strating from 28a: A 1.6 M solution of BuLi in hexane
(405 L, 0.65 mmol, 1.15 equiv) was added to freshly distilled di-
isopropylamine (95 L, 0.68 mmol, 1.2 equiv) and anhyd THF (3
mL) cooled at –10 °C. The solution was stirred for 30 min, after
which time the temperature was lowered to –78 °C and a solution of
the lactone 28a (121 mg, 0.56 mmol, 1 equiv) in THF (2 mL) was
injected dropwise. The mixture was stirred for 1 h. After the addi-
tion of TMSCl (143 L, 1.13 mmol, 2 equiv), the cooling bath was
removed and the solution stirred for an additional hour. The mixture
was then cooled again to –10 °C and NBS (110 mg, 0.62 mmol, 1.1
equiv) was added. After 15 min, TBAF (1 M in THF, 677 L, 0.68
mmol, 1.2 equiv) was injected dropwise, and the mixture was stirred
for 15 min before being diluted with Et2O (10 ml) and poured onto
aq sat. solution of NH4Cl (15 mL). The aqueous layer was separated
and extracted with Et2O (2 10 mL). The combined organic ex-
tracts were dried (MgSO4), filtered and concentrated in vacuo. Pu-
rification of the resulting pale yellow oil by silica gel
chromatography (eluent: hexane–EtOAc, 13:1) afforded the title
compound (63 mg, 80%) as a colourless liquid.
Anal. Calcd for C11H22O2Si: C, 61.63; H, 10.34. Found: C 61.65; H
10.47.
5-Cyclohexyl-3-[(trimethylsilyl)methyl]dihydrofuran-2(3H)-
one (28b)
Compound 28b was prepared according to the protocol described
for the synthesis of 28a; colourless oil; yield: 70%.
IR (film): 2926–2854 (C–H), 1751 (C=O), 1448, 1249, 1201, 1184,
848 cm–1.
1H NMR (CDCl3): (major isomer) = 4.00 (1 H, ddd, J = 10.7, 7.7,
5.3 Hz), 2.59–2.47 (1 H, m), 2.38 (1 H, ddd, J = 12.1, 8.4, 5.2 Hz),
2.00–1.90 (1 H, m), 1.53–1.40 (2 H, m), 1.24 (1 H, dd, J = 14.9, 3.6
Hz), 1.79–1.56 and 1.29–0.75 (9 H, 2 m), 0.57 (1 H, dd, J = 14.8,
11.0 Hz), 0.06 (9 H, s).
1H NMR (CDCl3): (minor isomer) = 4.21 (1 H, td, J = 7.5, 5.6 Hz),
2.59–2.47 (1 H, m), 2.15 (1 H, ddd, J = 12.9, 9.1, 5.5 Hz), 2.00–1.90
(1 H, m), 1.86 (1 H, dt, J = 12.9, 7.3 Hz), 1.53–1.40 (1 H, m), 1.12
(1 H, dd, J = 14.8, 4.1 Hz), 1.79–1.56 and 1.29–0.75 (9 H, 2 m),
0.67 (1 H, dd, J = 14.8, 11.3 Hz), 0.06 (9 H, s).
13C NMR (CDCl3): (major isomer) = 180.0 (C), 82.3 (CH), 42.6
(CH), 37.4 (CH), 35.5 (CH2), 29.2 (CH2), 27.6 (CH2), 26.2 (CH2),
25.6 (CH2), 25.4 (CH2), 17.86 (CH2), –1.25 (CH3).
13C NMR (CDCl3): (minor isomer) = 180.7 (C), 82.1 (CH), 42.4
(CH), 35.7 (CH), 33.4 (CH2), 29.58 (CH2), 28.6 (CH2), 28.1 (CH2),
26.2 (CH2), 25.2 (CH2), 19.0 (CH2), –1.25 (CH3).
Method B, Starting from 23b: To a solution of the ene adduct 23b
(0.40 g, 1.22 mmol, 1 equiv) in anhyd THF (10 mL) was added a
solution of NBS (0.22 g, 1.22 mmol, 1 equiv) in THF (2 mL). After
stirring for 10 min, the THF was removed in vacuo. The resulting
white precipitate was filtered off and washed with pentane (20 mL).
The filtrate was concentrated under reduced pressure. This crude
and extremely sensitive material was directly used in the subsequent
double desilylation step. A 1 M solution of TBAF in THF (2.44 mL,
2.44 mmol, 2 equiv) was added to a solution of the crude product
dissolved in CH2Cl2 (15 mL). The resulting yellow mixture was
stirred for 5 min after which time TLC monitoring clearly indicated
the end of the reaction. The solution was then diluted with Et2O (20
mL) and transferred to a separatory funnel containing brine (20
mL). After separation, the aqueous layer was extracted with Et2O
(3 20 mL). The combined organic extracts were dried (MgSO4),
filtered and concentrated in vacuo. To a cold (0 °C) solution the re-
sulting oil in MeCN (23 mL) were successively introduced freshly
prepared MnO2 (4 g, 46 mmol, 20 equiv) and KCN (0.15 g, 2.3
mmol, 1 equiv). The resulting black slurry was stirred for 25 min af-
ter which time it was filtered through silica gel. The solvent was re-
moved in vacuo and the residue purified by flash column
chromatography (silica gel, eluent: 13:1 hexane–EtOAc). Evapora-
tion of the eluent afforded 275 mg of the pure lactone as a colourless
oil (61%).
MS (EI, 70 eV): m/z (%) = 254 (M+ , 8), 239 (100), 221 (44), 171
(8), 159 (48), 147 (82), 143 (64), 130 (22), 73 (98).
Anal. Calcd for C14H26O2Si: C, 66.06; H, 10.30. Found: C, 66.09;
H, 10.32.
5-(2-Benzyloxy-1,1-dimethylethyl)-3-[(trimethylsilyl)meth-
yl]dihydrofuran-2(3H)-one (28c)
Compound 28c was prepared according to the protocol described
for the synthesis of 28a; colourless oil; yield: 74%.
IR (film): 3031–2879 (C–H), 1771 (C=O), 1453, 1249, 1181, 843
cm–1.
1H NMR (CDCl3): (major isomer) = 7.39–7.28 (5 H, m), 4.53 (1
H, d, J = 12.1 Hz), 4.45 (1 H, d, J = 12.1 Hz), 4.38 (1 H, dd,
J = 11.1, 5.5 Hz), 3.35 (1 H, d, J = 9 Hz), 3.25 (1 H, d, J = 9 Hz),
2.62–2.50 (1 H, m), 2.21 (1 H, ddd, J = 12.4, 8.5, 5.5 Hz), 1.63 (1
H, q, J = 12.3 Hz), 1.28 (1 H, dd, J = 14.9, 3.6 Hz), 0.96 (3 H, s),
0.92 (3 H, s), 0.57 (1 H, dd, J = 14.9, 11.1 Hz), 0.04 (9 H, s).
1H NMR (CDCl3): (minor isomer) = 7.39–7.28 (5 H, m), 4.53 (1
H, d, J = 12.1 Hz), 4.45 (1 H, d, J = 12.1 Hz), 4.53–4.45 (1 H, m),
3.33 (1 H, d, J = 8.9 Hz), 3.24 (1 H, d, J = 8.9 Hz), 2.62–2.50 (1 H,
m), 2.79 (1 H, ddd, J = 13, 9.5, 6.7 Hz), 1.77 (1 H, ddd, J = 13.5, 8,
5.8 Hz), 1.15 (1 H, dd, J = 14.8, 3.9 Hz), 0.96 (3 H, s), 0.92 (3 H, s),
0.72 (1 H, dd, J = 14.7, 11.4 Hz), 0.04 (9 H, s).
IR (film): 2961–2874 (C–H), 1765 (C=O), 1666 (C=C), 1466,
1399, 1273, 1187, 1001, 940, 813 cm–1.
1H NMR (CDCl3): = 6.20 (1 H, t, J = 2.8 Hz), 5.61 (1 H, t, J = 2.7
Hz), 4.56–4.47 (1 H, m), 3.00 (1 H, ddt, J = 17, 7.6, 2.5 Hz), 2.56 (1
H, ddt, J = 17, 5.9, 2.8 Hz), 1.48–1.33 (4 H, m), 0.95 (3 H, t, J = 7.2
Hz).
13C NMR (CDCl3): = 170.2 (C), 134.9 (C), 121.7 (CH2), 77.2
(CH), 38.4 (CH2), 33.6 (CH2), 18.2 (CH2), 13.7 (CH3).
MS (EI, 70 eV): m/z (%) = 141 (M+ + H+, 80), 140 (M+ , 36), 111
(12), 97 (100), 69 (22), 43 (21).
Synthesis 2002, No. 7, 958–972 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Tandem Ene-Reaction/Intramolecular Sakurai Cyclisation
971
5-Cyclohexyl-3-methylenedihydrofuran-2(3H)-one (29b)
This lactone was prepared using the reaction conditions described
for compound 29a, starting from 28b (70%) as well as from 23c
(76%); colourless oil.
2.57 (1 H, ddt, J = 17.1, 6.3, 2.8 Hz), 2.04–2.17 (2 H, m), 1.96 (1 H,
q, J = 6.7 Hz), 1.58–1.86 (2 H, m), 1.16–1.36 (3 H, m), 0.87 (3 H, t,
J = 6.9 Hz).
13C NMR (CDCl3): = 170.2 (C), 134.7 (C), 132.1 (CH), 128.0
(CH), 121.8 (CH2), 76.8 (CH), 38.2 (CH2), 33.5 (CH2), 32.5 (CH2),
31.3 (CH2), 29.1 (CH2), 27.9 (CH2), 22.5 (CH2), 14.0 (CH3).
IR (film): 2932–2851 (C–H), 1754 (C=O), 1666 (C=C), 1445,
1278, 985, 945, 893 cm–1.
1H NMR (CDCl3): = 6.20 (1 H, t, J = 2.7 Hz), 5.60 (1 H, t, J = 2.7
Hz), 4.24 (1 H, q, J = 7.1 Hz), 2.95 (1 H, ddt, J = 17, 7.7, 2.7 Hz),
2.67 (1 H, ddt, J = 17, 6.6, 2.7 Hz), 1.98–1.44 and 1.28–0.97 (6 H
and 5 H, 2 m).
13C NMR (CDCl3): = 170.2 (C), 134.9 (C), 121.3 (CH2), 81.2
(CH), 43.0 (CH), 31.2 (CH2), 28.0 (CH2), 27.6 (CH2), 26.2 (CH2),
25.6 (CH2), 25.5 (CH2).
MS (EI, 70 eV) : 222.2 (M+, 7), 205.2 (12), 177.2 (38), 123.1 (9),
110.1 (100), 97.0 (23), 81.1 (28), 68.1 (16).
Anal. Calcd for C14H22O2 (222.7): C, 75.46; H, 10.02. Found: C,
75.50; H, 9.96.
3-Methylene-5-pent-4-enyldihydrofuran-2(3H)-one (29f)
This lactone was prepared using the reaction conditions described
for compound 29a, starting from ene adduct 23f.
MS (EI, 70 eV): m/z (%) = 180 (M+ , 60), 152 (42), 134 (40), 97
(100), 83 (12), 69 (20), 68 (16), 55 (19), 41 (8).
IR (film): 3288, 2950–2859, 2116, 1760 (C=O), 1665 (C=C), 1436,
1344, 1276, 1130, 997 cm–1.
5-(2-Benzyloxy-1,1-dimethylethyl)-3-methylenedihydrofuran-
2(3H)-one (29c)
This lactone was prepared using the reaction conditions described
for compound 29a, starting from 28c (74%) as well as from the ene-
adduct 23c (66%); colourless oil.
1H NMR (CDCl3): = 6.23 (1 H, t, J = 2.7 Hz), 5.64 (1 H, t, J = 2.5
Hz), 4.55 (1 H, quint, J = 6.3 Hz), 3.08 (1 H, ddt, J = 17.3, 7.7, 2.7
Hz), 2.56 (1 H, ddt, J = 17, 6, 3 Hz), 2.29–2.21 (2 H, m), 1.97 (1 H,
t, J = 2.8 Hz), 1.82–1.53 (4 H, m).
13C NMR (CDCl3): = 170.0 (C), 134.5 (C), 121.3 (CH2), 83.4 (C),
76.8 (CH), 70.0 (CH), 35.1 (CH2), 33.6 (CH2), 23.8 (CH2), 18.0
(CH2).
IR (film): 3036, 3030, 2966–2851 (C–H), 1764 (C=O),
1664 (C=C), 1477, 1280, 1130, 1100, 985, 945, 813, 737, 698 cm–1.
1H NMR (CDCl3): = 7.41–7.20 (5 H, m), 6.20 (1 H, t, J = 3.0 Hz),
5.60 (1 H, t, J = 2.7 Hz), 4.57 (1 H, t, J = 7.4 Hz), 4.52 (1 H, d,
J = 11.5 Hz), 4.44 (1 H, d, J = 11.5 Hz), 3.37 (1 H, d, J = 9 Hz), 3.25
(1 H, d, J = 9 Hz), 2.83 (2 H, dt, J = 7.5, 2.7 Hz), 0.95 (6 H, s).
13C NMR (CDCl3): = 170.3 (C), 138.4 (C), 135.2 (C), 128.5 (CH),
127.4 (CH), 121.3 (CH2), 80.9 (CH), 76.1 (CH2), 73.35 (CH2), 38.3
(C), 28.6 (CH2), 19.9 (CH3), 19.4 (CH3).
MS (EI, 70 eV): m/z (%) = 163 (M+ , 8), 136 (20), 123 (44), 120 (9),
97 (100), 69 (21), 68 (24).
Anal. Calcd for C13H20O2: C, 73.15; H, 7.37. Found: C, 72.88; H,
7.39.
Acknowledgements
MS (EI, 70 eV): m/z (%) = 261 (M+ + H+, 4), 242 (40), 213 (17),
186 (38), 139 (22), 91 (100), 69 (21).
Financial support of this work from the Université catholique de
Louvain, the Fond National de la Recherche Scientifique (FNRS)
(for R. Dumeunier, Aspirant FNRS), the Fonds pour la Recherche
dans l’Industrie et l’Agriculture (FRIA) (for B. Leroy and C. Le-
clercq), the Actions de Recherche Concertées (convention 96/01-
197) (for J.-M. Plancher), the Algerian Ministry of Higher Educati-
on and the Science and Engineering Research Council (SERC) is
gratefully acknowleged. IEM is thankful to Merck & Co. for its con-
tinuous support and for receiving the Merck Young Investigator
Award.
HRMS: m/z calcd for C16H20O3, 260.1412; found, 260.1413.
(Z)-3-Methylene-5-oct-5-enyldihydrofuran-2(3H)-one (29d)
This lactone was prepared using the reaction conditions described
for compound 29a, starting from ene adduct 23e; colourless oil;
yield: 57%.
IR (film): 3003–2859 (C–H), 1765 (C=O), 1665 (C=C), 1462, 1275,
1002 cm–1.
1H NMR (CDCl3): = 6.21 (1 H, t, J = 2.7 Hz), 5.61 (1 H, t, J = 2.7
Hz), 5.45–5.19 (2 H, m), 4.51 (1 H, m), 3.04 (1 H, ddt, J = 17, 7.7,
2.7 Hz), 2.56 (1 H, ddt, J = 17, 6.3, 2.7 Hz), 2.06–1.98 (4 H, m),
1.75–1.30 (6 H, m), 0.94 (3 H, t, J = 7.7 Hz).
13C NMR (CDCl3): = 170.2 (C), 134.8 (C), 132.0 (CH), 128.5
(CH), 121.7 (CH2), 77.5 (CH), 36.2 (CH2), 33.6 (CH2), 29.4 (CH2),
26.9 (CH2), 24.5 (CH2), 20.5 (CH2), 14.3 (CH3).
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Synthesis 2002, No. 7, 958–972 ISSN 0039-7881 © Thieme Stuttgart · New York

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Synthesis 2002, No. 7, 958–972 ISSN 0039-7881 © Thieme Stuttgart · New York