Intramolecular Michael addition of N- and O-centred nucleophiles to tethered acrylates. The role of double-bond geometry in controlling the diastereoselectivity of cyclizations teading to 2,6-disubstituted tetrahydropyrans and piperidines

Article abstract of DOI:10.1071/C97173

The oxyanion derived from hydroxyacrylate E-(5) undergoes smooth intramolecular Michael addition to give the trans-2,6-disubstituted tetrahydropyran (7) as the major product of reaction. In contrast, the oxyanion obtained from isomer Z-(5) cyclizes to give the cis-2,6-disubstituted tetrahydropyran (6) as the major product. Such chemistry has been extended to the enantioselective synthesis of (+)-(6) the acquisition of which constitutes a formal total synthesis of acid (+)-(2), a constituent of the glandular secretion from the civet cat (Viverra civetta). Reductive amination of keto acrylate (12) affords an intermediate amine which cyclizes, in situ, to give the cis-2,6-disubstituted piperidine (26). Analogous treatment of compound (13) delivers the isomeric trans-2,6-disubstituted piperidine (27) as the exclusive product of reaction. Transition state structures have been proposed to account for the diastereoselectivities observed in all of the cyclization reactions.

Full text of DOI:10.1071/C97173

C S I R O P U B L I S H I N G
Australian Journal
of Chemistry
Volume 51, 1998
© CSIRO Australia 1998
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in all branches of chemistry and chemical technology
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Aust. J. Chem., 1998, 51, 9–18
Intramolecular Michael Addition of N- and O-Centred
Nucleophiles to Tethered Acrylates. The Role of
Double-Bond Geometry in Controlling the Diastereo-
selectivity of Cyclizations Leading to 2,6-Disubstituted
Tetrahydropyrans and Piperidinesꢀ
Martin G. Banwell,A,B Brett D. Bissett,A Chinh T. Bui,A,C
Ha T. T. Pham C and Gregory W. Simpson D
A
Research School of Chemistry, Institute of Advanced Studies,
The Australian National University, Canberra, A.C.T. 0200.
B
To whom correspondence should be addressed.
School of Chemistry, The University of Melbourne, Parkville, Vic. 3052.
CSIRO Molecular Science, Private Bag 10, Clayton South MDC, Vic. 3169.
C
D
The oxyanion derived from hydroxyacrylate E-(5) undergoes smooth intramolecular Michael addition
to give the trans-2,6-disubstituted tetrahydropyran (7) as the major product of reaction. In contrast,
the oxyanion obtained from isomer Z-(5) cyclizes to give the cis-2,6-disubstituted tetrahydropyran
(6) as the major product. Such chemistry has been extended to the enantioselective synthesis of
(+)-(6) the acquisition of which constitutes a formal total synthesis of acid (+)-(2), a constituent of
the glandular secretion from the civet cat (Viverra civetta). Reductive amination of keto acrylate (12)
aꢀords an intermediate amine which cyclizes, in situ, to give the cis-2,6-disubstituted piperidine (26).
Analogous treatment of compound (13) delivers the isomeric trans-2,6-disubstituted piperidine (27) as
the exclusive product of reaction. Transition state structures have been proposed to account for the
diastereoselectivities observed in all of the cyclization reactions.
O
O
O
Introduction
OH
In connection with studies1,2 directed towards assem-
bly of the tetrahydropyranyl core of the novel herbicide
herboxidiene (1),3 we had occasion to consider eꢀecting
intramolecular Michael addition of an oxyanion to a
tethered acrylate moiety as a means of preparing cis-2,6-
disubstituted tetrahydropyrans.4 The seminal studies5
of Martꢁꢂn and coworkers on analogous approaches
to 2,3-disubstituted tetrahydropyrans prompted us to
consider what role, if any, the C–C double-bond geom-
etry of the acrylate moiety might play in controlling
the stereochemical outcome of cyclization reactions
leading to the 2,6-disubstituted systems. Surprisingly,
no relevant work appears to have been described.
In the original synthesis (Scheme 1)6 of compound
(2),† a cis-2,6-disubstituted tetrahydropyran isolated
from glandular secretions of the civet cat (Viverra
civetta), lactol (3) was treated with a combination of
OH
2'
O
H
O
OMe
6'
OH
(+)-(2)
(1)
methyl diethylphosphonoacetate and sodium methoxide
which resulted in formation of a mixture of the methyl
esters (6) and (7). This conversion is presumed to
involve the open-chain form of compound (3), viz.
aldehyde (4), which engages in a Wadsworth–Emmons
reaction with in situ generated phosphonate anion
thereby producing the expected acrylate (5). How-
ever, under the relatively vigorous reaction conditions
employed this last compound is not observed because it
undergoes ready intramolecular Michael addition to give
ꢀ
Aspects of this work have been reported in preliminary form: Banwell, M. G., Bui, C. T., Pham, H. T. T., and Simpson, G.
W., J. Chem. Soc., Perkin Trans. 1, 1996, 967.
† For previously reported syntheses of (2) see refs 6,7.
Manuscript received 30 September 1997
᭧ CSIRO Australia 1998
0004-9425/98/010009$05.00

10
M. G. Banwell et al.
hydroxyoct-2-enoate (5). In a new approach to this
previously reported10 compound, Grigg’s synthesis of
keto acrylate (12) was implemented (Scheme 2).11
Thus, ethyl acetoacetate (9) was reacted with com-
mercially available bromide (8) and sodium ethoxide.
The resulting C-alkylated product was not isolated
but immediately treated with aqueous sodium hydrox-
ide then aqueous acid which provided the volatile
and somewhat water-soluble keto aldehyde (10) [41%
from (9)]. In an alternate and slightly more eꢅcient
route to compound (10), a commercial sample of 1-
methylcyclopentene (11)12 was subjected to treatment
with ozone then triphenylphosphine13 and in this way
the required keto aldehyde was again produced but
now in 68% yield. Immediate subjection of compound
(10) to a Wadsworth–Emmons reaction14 with the
anion derived from methyl diethylphosphonoacetate
aꢀorded the previously reported11 acrylate (12) (82%).
Chemoselective reduction of compound (12) was readily
achieved with sodium borohydride and in this way
the key alcohol E-(5) was produced in 82% yield.
The spectroscopic data obtained on the compound
were in full accord with the assigned structure. Most
O
O
OH
OMe
(EtO)2P(O)CH2CO2Me
NaOMe
OH
O
OH
(3)
(4)
(5)
O
O
O
OMe
OMe
2'
2'
NaOH
then H3O+
O
(±)-(2)
6'
6'
(6)
(7)
Scheme 1
the tetrahydropyrans (6) and (7). Furthermore, under
such conditions the cyclization products interconvert
(via a retro-Michael/Michael addition sequence) and at
equilibrium the more stable isomer (6) predominates
to the extent of about 7 : 1.ꢀ As a consequence, it
was not possible to establish what impact, if any, the
geometry about the double bond in the acrylate (5) has
on the stereochemical outcome of the initial cycliza-
tion reaction. Two more recent and enantioselective
syntheses of compound (+)-(2) (Lichtenthaler et al.
1984;7 Ragoussis and Theodorou 19937) as well as a
diastereoselective synthesis of (+)-decarestricticine L
(a 2,3,6-trisubstituted tetrahydropyran)8 have involved
analogous Michael addition reactions but in none of
these cases was there any study of the possible impact
of acrylate geometry on the diastereoselectivity of the
cyclization reaction. However, Mandai et al.9 have
shown that intramolecular 1,4-addition of oxyanions to
tethered ꢀ,ꢁ-unsaturated sulfoxides aꢀords the corre-
sponding 2,6-disubstituted tetrahydropyrans and that
the geometry of the C–C double bond within the
Michael acceptor does aꢀect the diastereoselectivity of
this type of cyclization reaction. The work described
herein has demonstrated that the diastereoselectivity
of the title reactions is also strongly inꢃuenced by
acrylate geometry.
1
importantly, the 300 MHz H n.m.r. spectrum revealed
a pair of low-ꢄeld resonances (ꢂ 6ꢁ93 and 5ꢁ84) which
are assigned to the oleꢄnic protons and the magnitude
(J 16 Hz) of the vicinal coupling between these two
signals is indicative15 of an E-geometry about the
double bond.
O
O
O
O
O3/PPh3
ref. 11
O
+
O
OEt
(11)
Br
(9)
(10)
(8)
(EtO)2P(O)CH2CO2Me/NaH
O
O
OMe
OMe
NaBH4
NaH
(6) + (7)
OH
O
(12)
E-(5)
Scheme 2
Cyclization of compound E-(5) was initially attempt-
Results and Discussion
ed under conditions (sodium hydride in tetrahydrofuran
at ꢂ78ꢁC) deꢄned by Martꢁꢂn et al.5 for eꢀecting related
conversions. At low temperatures no reaction was
observed but upon warming to 18ꢁC rapid cyclization
occurred and after 1 h the starting material had been
completely consumed. Extractive workup provided a
mixture of two compounds which could be separated
(a) Intramolecular Michael Addition of O-
Centred Nucleophiles to Tethered Acrylates. For-
mation of 2,6-Disubstituted Tetrahydropyrans
(i) Preliminary Studies
The cyclization substrate chosen for the ꢄrst part
of this study was the E-isomer of methyl (ꢀ)-7-
ꢀ
This is consistent with our own molecular mechanics calculations which show that the cis-isomer (6) is c. 10 kJ/mol more
stable than its trans-counterpart (7).

Addition of Nucleophiles to Tethered Acrylates
11
from one another by m.p.l.c. Each compound was
characterized spectroscopically and, by comparison
with literature data,6,7 the major product (70%) was
shown to be the trans-disubstituted tetrahydropyran
(7) while the minor product (28%) proved to be
the corresponding cis-isomer (6). N.O.e. diꢀerence
studies have provided further conꢄrmation of these
assignments. Thus, independent irradiation of the
resonances due to either H 20 or H 60 in compound (6)
led to c. 3% enhancements of the signal due to the
other. In contrast, analogous experiments involving
the trans-isomer (7) failed to produce any equivalent
enhancements, although irradiation of the doublet due
to the C 60 methyl protons (ꢂ 1ꢁ14) resulted in a 7%
n.O.e. to H 60 and a 4% n.O.e. to H 20. This latter
enhancement suggests that in the preferred conforma-
tion for compound (7) the C 60 methyl group is in an
axial orientation, a result consistent with molecular
mechanics calculations.
The observation that substrate E-(5) cyclizes prefer-
entially to give the trans-disubstituted tetrahydropyran
(7) precludes the intervention of an extended chair-like
transition state (A) (Fig. 1) as has been proposed by
others5,8 for related reactions. While the (non-extended)
chair-like transition state (B) would account for the
observed outcome [viz. E-(5) → (7)] we favour interven-
tion of the boat-like structure (C) because, in contrast
to structure (B), both non-hydrogen substituents are
in equatorial-type environments. Transition state (D)
associated with cyclization of compound Z-(5) might
be expected to form a tight ion pair with the metal
counter ion (Na+) so that the cyclization proceeds
under chelation control17 and thus accounting for the
high diastereoselectivity observed. Examination of
molecular models suggests such pronounced chelation
is not achieved in structure (C) so cyclization of com-
pound E-(5) may involve some ‘leakage’ through an
alternative transition state [e.g. (A)] thereby resulting
in a more pronounced mixture of diastereoisomers. In
an eꢀort to examine the eꢀect of metal counter ions on
the stereochemical outcome of the cyclization reactions,
substrates (5) were each treated with lithium, sodium
and potassium hydrides but there was little diꢀerence
in the ratio of cyclization products obtained at the
completion of each of the reactions.
O
MeO
(CF3CH2O)2P(O)CH2CO2Me
(10)
O
K2CO3/18-crown-6
(13)
OMe
NaBH4
MeO
δ−
H
O
H
O
H
O
δ−
H
OMe
O
δ−
H
NaH
H
O
δ−
(6) + (7)
(±)-(2)
OH
(A)
(B)
H
O
H
H
H
Z-(5)
Scheme 3
H
OMe
δ−
O
O
δ−
H
δ−
O
OMe
The observation that, under the conditions speciꢄed
above, acrylate E-(5) is preferentially converted into
the less-stable trans-cyclization product prompted an
investigation of the cyclization behaviour of the Z-(5)
under the same conditions. The precursor (13) of this
substrate was prepared (Scheme 3) in 80% yield by
reaction of keto aldehyde (10) with a mixture of Still’s
methyl bis(triꢃuoroethyl)phosphonoacetate,16 K2CO3
and 18-crown-6/acetonitrile complex. Chemoselective
reduction of keto ester (13) was readily achieved with
sodium borohydride and the required alcohol Z-(5)
thereby obtained in 80% yield. The 300 MHz 1H n.m.r.
spectrum of the latter compound displayed signals at
ꢂ 6ꢁ23 and 5ꢁ76 due to the oleꢄnic protons and the
magnitude (J 12 Hz) of the vicinal coupling between
these resonances is indicative15 of a Z-geometry about
the double bond. Cyclization of compound Z-(5) was
readily eꢀected under the same conditions as used
earlier. However, in dramatic contrast to the previous
case, a c. 20 : 1 mixture of tetrahydropyrans (6) and
(7) was obtained (98% combined yield).
δ−
(C)
(D)
Fig. 1. Possible transition state structures associated with the
base-promoted cyclization reactions of compounds E-(5) and
Z-(5) (metal counter ions omitted for clarity).
(ii) Stereoselective Syntheses of (ꢀ)- and (+)-( cis-6 0-
Methyltetrahydropyran-2 0-yl)acetic Acid (2)
With signiꢄcant quantities of the methyl ester
(ꢀ)-(6) available via cyclization of compound Z-(5),
a puriꢄed sample was hydrolysed, under previously
speciꢄed conditions,6 to give the racemic modiꢄcation
of the natural product (+)-(2) (93%). The physical
and spectroscopic properties of this material were in
excellent agreement with previously reported6,7 data.
This result encouraged us to develop an enantio-
as well as diastereo-selective synthesis of the natu-
ral product (+)-(S,S)-(cis-60-methyltetrahydropyran-
20-yl)acetic acid (+)-(2). To these ends (Scheme 4), the
commercially available alcohol (14) was subjected to

12
M. G. Banwell et al.
O
O
O
O
pyridinium chlorochromate-promoted oxidation thereby
aꢀording the corresponding aldehyde (15)18 in 65%
chemical yield. Reaction of compound (15) with
dimethylzinc in the presence of catalytic amounts
of a bissulfonamideꢀ under conditions established by
Knochel et al.19 provided the secondary alcohol (+)-(16)
in 78% chemical yield. von dem Bussche-Huennefeld
and Seebach have previously reported20 making com-
pound (+)-(16) in 95% enantiomeric excess (e.c.)
(as determined by chiral g.l.c.) and comparisons of
appropriately determined optical rotations led to the
conclusion that our own sample of this alcohol had been
obtained in c. 87% e.e. Acetylation of alcohol (+)-(16)
was readily achieved under standard conditions and the
resulting acetate (+)-(17) (77%) was then subjected
to ozonolytic cleavage. The aldehyde (+)-(18) (90%)
obtained in this way was then submitted to Still’s
modiꢄcation of the Wadsworth–Emmons reaction which
provided the (Z)-alkene (ꢂ)-(19) in 81% yield. Treat-
ing this latter compound with potassium carbonate in
methanol resulted in sequential acetate hydrolysis and
intramolecular Michael addition with the result that
tetrahydropyran (+)-(6) was produced (70% yield).
The speciꢄc rotation of product (+)-(6) {[ꢀ]D +29ꢁ6
(c, 0ꢁ7 in C6H6)} was compared with that reported
(Seebach et al. 19827) {[ꢀ]D +32ꢁ9 (c, 1ꢁ05 in C6H6)}
for enantiomerically pure material and these data are
consistent with our material being of c. 87% e.e. Since
ester (+)-(6) has previously6,7 been converted into the
natural product (+)-(2), the present work constitutes
a formal total synthesis of the naturally occurring
antipode of this highly popular6,7 synthetic target.
R''
R''
OH
OH
OH
H
OMe
O
O
O
O
O
O
R'
R
R'
(22)
R' R''
H
(23)
H
H
H
(24) Me
(25) Me Me
H
(21)
(20)
(iii) Attempted Synthesis of Cyclic Peroxides via
Intramolecular Michael Addition of a Peroxyanion
to a Tethered Acrylate
Over the last decade or so there have been an
increasing number of reports on the isolation of norses-
terterpene natural products which contain a 1,2-dioxan
ring with a propionic acid side chain attached at
C 3.21 Two representative members of this class of
compound are muqubilin (20)22 and trunculin A (21)23
obtained from an undescribed Prianos species from
Tonga and an Australian sponge Latrunculia brevis,
respectively. On the basis of the work described
above, it seemed reasonable to suppose that the
heterocyclic core of these compounds might be con-
structed by intramolecular Michael addition/cyclization
of hydroperoxy-substituted acrylates of the general type
(22).24 In our eꢀorts to construct such cyclization sub-
strates, we prepared the 2,6-dienoates (23)–(25) but
have been unable to obtain convincing evidence for their
conversion into appropriate hydroxperoxy derivatives.
Thus, each of compounds (23)–(25) was subjected to
Bloodworth’s hydroperoxymercuration conditions25 in
the expectation that the non-conjugated and, there-
fore, more nucleophilic carbon–carbon double bond
would react preferentially. While substrates (23)–
(25) were consumed, no fully characterizable products
could be isolated from the complex reaction mixtures.
Compounds (23)–(25) were also subjected to thiol–
oxygen cooxidation (TOCO) reactions26 on the basis
that the ꢆ6 double bond would react to produce
hydroperoxy sulꢄde derivatives that could engage in
the desired type of cyclization reaction. Once again,
however, only complex mixtures of products were
observed and we could never obtain any sustainable
evidence that the required hydroperoxides were being
formed. At this point our eꢀorts in the area were
abandoned.
pyridinium
Me2Zn
OH
O
OH
SO2CF3
N
chlorochromate
H
H
(15)
(14)
(+)-(16)
N
Ac2O/
dmap
SO2CF3
MeO2C
(CF3CH2O)2P(O)CH2CO2Me
KN(SiMe3)2
O
O3/PPh3
OAc
OAc
OAc
(–)-(19)
(+)-(18)
(+)-(17)
K2CO3/
MeOH
O
OMe
2'
O
6'
(+)-(6)
Scheme 4
ꢀ
0
(1R-trans)-N ,N -(Cycohexane-1,2-diyl)bis(triꢀuoromethanesulfonamide).

Addition of Nucleophiles to Tethered Acrylates
13
(b) Intramolecular Michael Addition of
N-Centred Nucleophiles to Tethered Acrylates.
Formation of 2,6-Disubstituted Piperidines
Thus, we suggest that the conversion (12) → (26)
involves structure (E) while conversion (13) → (27)
involves structure (F). A signiꢄcant diꢀerence between
the O- and N-centred cyclizations described here is
that in the former but not the latter case there is
potential for chelation control via the participating
metal ions. It may be this feature which accounts
for the divergent stereochemical outcomes between the
two series of cyclization reaction.
Considerable eꢀort has been devoted to the synthesis
of 2,6-disubstituted piperidines because this structural
unit is encountered in a large number of biologically
active alkaloids.27 Intramolecular Michael addition of
an amine nucleophile to a suitable tethered acrylate
moiety seemed to be an obvious approach28 to this
type of ring system but, remarkably, there appears to
have been no use of this method at all let alone any
examination of the impact the acrylate geometry might
have on the stereoselectivity of such cyclizations. As
a consequence, the keto acrylates (12) and (13) were
each subjected to a reductive amination reaction in
an attempt to prepare the amino acrylate substrates
required for such a study. However, in both cases direct
and completely diastereoselective cyclization to a 2,6-
disubstituted piperidine was observed. Thus, reaction
of compound (12) with ammonium acetate and sodium
cyanoborohydride in methanol at 60ꢁC for 16 h aꢀorded
the cis-2,6-disubstituted piperidine (26) in 86% yield.
The spectroscopic data obtained for this cyclization
product were completely consistent with the assigned
structure and matched those obtained on an authentic
sample27 which had kindly been provided to us by
Professor A. I. Meyers (Colorado State University).
When keto acrylate (13) was treated in exactly the
same manner as isomer (12) the trans-2,6-disubstituted
piperidine (27) was obtained (73%) as the exclusive
product of reaction (Scheme 5).
MeO
δ−
O
δ−
H
O
H
H
OMe
H
δ+
H2
δ+
N
N
H
H
H2
(E)
(F)
Fig. 2. Possible transition state structures associated with
cyclization of the amines derived from compounds (12) and
(13).
It is worth noting that the acquisition of compound
(26) constitutes formal total syntheses of the racemic
modiꢄcations of alkaloids monomorine (28) and pini-
dinone (29) since Meyers has recently reported27 the
synthesis of these natural products from (+)-(26).
O
N
H
N
(+)-(28)
(+)-(29)
O
O
Conclusion
OMe
MeO
The title reactions would seem to oꢀer consid-
erable potential for the diastereoselective synthesis
of 2,6-disubstituted tetrahydropyrans and piperidines.
Indeed, since our original communication on this topic,
Edmunds and coworkers29 have exploited this approach
in enantio- and diastereo-selective syntheses of 2,6-
disubstituted tetrahydropyrans. In addition, we have
recently succeeded1 in the enantioselective construction
of the core of herboxidiene (1) by using the same
strategy. Similar work has also been reported by
Kocienski et al.30
NH4OAc
H
2'
O
N
NaBH3CN
6'
(12)
(26)
O
O
MeO
MeO
NH4OAc
H
2'
N
O
NaBH3CN
6'
Experimental
(27)
(13)
Melting points were recorded with a Koꢀer hot-stage appara-
tus and are uncorrected. Proton (1H) and carbon (13C) n.m.r.
spectra were recorded with a Varian Unity 300, Varian Gemini
300 or JEOL GX-400 spectrometer operating at 300 or 400 MHz
for proton and 75 or 100 MHz for carbon. All such spectra were
recorded in (D)chloroform solution at 22ꢁC. The protonicities
of the carbon atoms observed in 13C n.m.r. spectra were
determined by distortionless enhancement polarization transfer
(d.e.p.t.) or attached proton test (a.p.t.) experiments. Infrared
spectra (ꢀmax) were recorded with either a Perkin–Elmer 983G
infrared spectrophotometer or a Perkin–Elmer 1800 Fourier-
transform infrared spectrophotometer. Samples were analysed
Scheme 5
Intriguingly, for those cyclizations involving an
N-centred nucleophile the relationship between the
double-bond geometry of the substrate and the stere-
ochemistry of the product is exactly opposite to that
observed for the analogous process involving an O-
centred nucleophile. The transition state structures
that might be involved in the cyclization reactions
leading to piperidines (26) and (27) are shown in Fig. 2.

14
M. G. Banwell et al.
either as thin ꢁlms on sodium chloride plates (for liquids)
or as potassium bromide disks (for solids). Low-resolution
electron-impact mass spectra (m/z) were recorded at 70 eV on
either a VG Micromass 7070F mass spectrometer or a JEOL
AX-505H mass spectrometer. High-resolution mass spectra
were recorded with a VG Micromass 7070F instrument. Unless
otherwise stated, optical rotations were measured in chloroform
at 22ꢁC with a Perkin–Elmer 241 polarimeter. Medium-
pressure liquid chromatography (m.p.l.c.) was conducted by
using a Buꢂchi 681 pump, Buꢂchi ‘plastiglass’ columns packed
with Kieselgel 60 (230–400 mesh ASTM) and a Buꢂchi 684 frac-
tion collector. Chiral capillary g.l.c. analyses were conducted
on a 25 m by 0ꢀ22 mm Cydex-B column purchased from SGE
Pty Ltd, Melbourne, Australia. A carrier gas (helium) ꢀow
rate of 38 cm/s was used in conjunction with ꢀame ionization
detection. Unless otherwise speciꢁed, the following gradient
temperature program was used: initial temperature of 50ꢁC
held for 1 min then heating at 5ꢁC/min to a ꢁnal temperature of
200ꢁC. Molecular mechanics calculations were carried out with
Chem3D PlusT M software provided by Cambridge Scientiꢁc
Computing Inc. (Cambridge, Massachusetts). Diethyl ether
and tetrahydrofuran (thf) were distilled under nitrogen from
sodium benzophenone ketyl. Dichloromethane and hexane were
each distilled from calcium hydride.
1174, 1151, 1042, 983 cmꢂ1
.
1H n.m.r. ꢁ 6ꢀ93, dt, J 16 and
7 Hz, 1H, H 3; 5ꢀ84, dt, J 16 and 2 Hz, 1H, H 2; 3ꢀ70, s, 3H,
OMe; 2ꢀ43, t, J 7 Hz, 2H; 2ꢀ17, m, 2H; 2ꢀ11, s, 3H, H 8; 1ꢀ72,
p, J 8 Hz, 2H, H 5. 13C n.m.r. ꢁ 208ꢀ0, 166ꢀ9, 148ꢀ3, 121ꢀ5,
51ꢀ3, 42ꢀ5, 31ꢀ3, 29ꢀ9, 21ꢀ8. Mass spectrum m/z 170 (1%,
M+ꢃ); 138 [75, (M ꢁ MeOH)+ꢃ]; 113 (100); 81 (98).
Methyl (E)-7-Hydroxyoct-2-enoate E-(5)
A magnetically stirred solution of methyl (E)-7-oxooct-
2-enoate (12) (2ꢀ00 g, 11ꢀ8 mmol) in methanol (20 ml) was
treated with sodium borohydride (140 mg, 3ꢀ54 mmol). The
resulting mixture was allowed to stir at room temperature for
0ꢀ5 h then diluted with water (20 ml) and extracted with diethyl
ether (3ꢂ50 ml). The combined organic phases were dried
(MgSO4), ꢁltered and concentrated under reduced pressure
to give the title compound E-(5)10 (1ꢀ65 g, 82%) as a clear
colourless oil (Found: M+ꢃ, 172ꢀ1019. Calc. for C9H16O3:
M+ꢃ, 172ꢀ1021). ꢀmax (NaCl) 3414, 2931, 1721, 1654, 1434,
1311, 1271, 1200, 1165, 1129, 1036 cmꢂ1
.
1H n.m.r. ꢁ 6ꢀ93,
dt, J 16 and 7 Hz, 1H, H 3; 5ꢀ84, d, J 16 Hz, 1H, H 2; 3ꢀ75,
m, 1H, H 7; 3ꢀ65, s, 3H, OMe; 2ꢀ30, m, 1H, OH; 2ꢀ16, m,
2H; 1ꢀ62–1ꢀ32, complex m, 4H; 1ꢀ11, d, J 6 Hz, 3H, H 8. 13C
n.m.r. ꢁ 167ꢀ0, 149ꢀ2, 120ꢀ9, 67ꢀ4, 51ꢀ3, 38ꢀ4, 31ꢀ9, 24ꢀ0,
23ꢀ3. Mass spectrum m/z 171 [0ꢀ3%, (M ꢁ Hꢃ)+]; 154 [8,
(M ꢁ H2O)+ꢃ]; 140 [13, (M ꢁ MeOH)+ꢃ]; 100 (100).
5-Oxohexanal (10)
Cyclization of Compound E-(5)
A solution of 1-methylcyclopentene (11) (5ꢀ00 g, 61 mmol)
(Aldrich) in dry dichloromethane (200 ml) was cooled to ꢁ78ꢁC
and treated with a stream of ozone (40% ozone in oxygen)
being produced by a Fischer 502 ozone generator. When the
blue colour of ozone persisted, triphenylphosphine (15ꢀ90 g,
60ꢀ9 mmol) was added to the reaction mixture which was
allowed to warm to room temperature. The solvent was
then cautiously removed under reduced pressure on a rotary
evaporator and the residue subjected to Kugelrohr distillation
(75ꢁC/3 mmHg). In this way the title compound (10)11 (4ꢀ7 g,
68%) was obtained as a clear, colourless but somewhat impure
oil. ꢀmax (NaCl) 2938, 2893, 2828, 1709, 1409, 1369, 1186,
A magnetically stirred suspension of sodium hydride (117 mg
of a 60% dispersion in mineral oil, 2ꢀ9 mmol) in tetrahydrofuran
(15 ml) was cooled to ꢁ78ꢁC while being maintained under a
nitrogen atmosphere. Methyl (E)-7-hydroxyoct-2-enoate E-(5)
(500 mg, 2ꢀ9 mmol) in tetrahydrofuran (5 ml) was injected
via syringe after which the reaction mixture was allowed to
warm to room temperature (c. 18ꢁC) over 1 h then diluted
with water (50 ml) and extracted with diethyl ether (3ꢂ30 ml).
The combined organic phases were dried (MgSO4), ꢁltered
and concentrated under reduced pressure to give a light-yellow
oil. Subjection of this material to m.p.l.c. (silica, 15 : 85 ethyl
acetate/hexane elution) aꢃorded two major components (RF
0ꢀ8 and 0ꢀ7).
1162 cmꢂ1
.
1H n.m.r. ꢁ 9ꢀ67, br s, 1H, H 1; 2ꢀ42, m, 4H,
H 2 and H 4; 2ꢀ06, s, 3H, H 6; 1ꢀ80, m, 2H, H 3. Mass
spectrum m/z 114 (5%, Mꢃ+); 113 [71, (M ꢁ Hꢃ)+]; 85 [100,
(M ꢁ HCOꢃ)+]; 71 [70, (M ꢁ MeCOꢃ)+]. RF 0ꢀ4 (silica, 1 : 1
ethyl acetate/hexane elution).
This material was identical with an authentic sample
prepared from ethyl acetoacetate and 2-(20-bromoethyl)-1,3-
dioxolan (Aldrich) according to the method of Grigg and
coworkers.11
Concentration of the fractions containing the less mobile com-
ponent aꢃorded methyl (ꢃ)-(trans-60-methyltetrahydropyran-
20-yl)acetate (7)6,7 (350 mg, 70%) as a clear colourless oil
(Found: M+ꢃ, 172ꢀ1097. Calc. for C9H16O3: M+ꢃ, 172ꢀ1099).
ꢀmax (NaCl) 2968, 1737, 1435, 1285, 1210, 1165, 1136, 1047,
1023 cmꢂ1
.
1H n.m.r. ꢁ 4ꢀ25, m, 1H, H 20; 3ꢀ88, m, 1H, H 60;
3ꢀ66, s, 3H, OMe; 2ꢀ65, dd, J 15 and 8 Hz, 1H, H 2; 2ꢀ42, dd,
J 15 and 7 Hz, 1H, H 2; 1ꢀ77–1ꢀ55, complex m, 4H; 1ꢀ43–1ꢀ20,
complex m, 2H; 1ꢀ14, d, J 6 Hz, 3H, Me. 13C n.m.r. ꢁ 171ꢀ9,
67ꢀ9, 67ꢀ5, 51ꢀ6, 38ꢀ9, 31ꢀ2, 29ꢀ6, 19ꢀ5, 18ꢀ2. Mass spectrum
m/z 172 (4%, M+ꢃ); 130 [34, (M ꢁ MeOH)+ꢃ]; 129 (41); 116
(71); 99 (100); 54 (91).
Methyl (E)-7-Oxooct-2-enoate (12)
Methyl diethylphosphonoacetate (4ꢀ42 g, 21 mmol) was
added dropwise to a magnetically stirred suspension of sodium
hydride (840 mg of a 60% dispersion in mineral oil, 35 mmol)
in 1,2-dimethoxyethane (20 ml) maintained at 10ꢁC under a
nitrogen atmosphere. After the addition was complete the
reaction mixture was stirred for a further 1 h at room tem-
perature then cooled to ꢁ5ꢁC and 5-oxohexanal (10) (2ꢀ00 g,
17ꢀ5 mmol) was injected via syringe at such a rate that the
temperature was maintained below 0ꢁC. The reaction mixture
was stirred at this temperature for a further 0ꢀ5 h then poured
onto ice (50 g) and extracted with diethyl ether (1ꢂ50 ml).
The separated organic phase was washed with water (3ꢂ50 ml)
and brine (1ꢂ50 ml) before being dried (MgSO4), ꢁltered and
concentrated under reduced pressure to give a light-yellow
oil. Subjection of this material to m.p.l.c. (silica, 2 : 3 ethyl
acetate/hexane elution) aꢃorded, after concentration of the
appropriate fractions (RF 0ꢀ6 in 1 : 1 ethyl acetate/hexane),
the title compound (12)11 (2ꢀ45 g, 82%) as a clear colourless oil
(Found: M+ꢃ, 170ꢀ0947. Calc. for C9H14O3: M+ꢃ, 170ꢀ0943).
ꢀmax (NaCl) 2995, 1709, 1654, 1433, 1359, 1315, 1271, 1196,
Concentration of the fractions containing the more mobile
component aꢃorded methyl (ꢃ)-(cis-60-methyltetrahydropyran-
20-yl)acetate (6)6,7 (140 mg, 28%) as a clear colourless oil (Found:
M+ꢃ, 172ꢀ1102. Calc. for C9H16O3: M+ꢃ, 172ꢀ1099). ꢀmax
(NaCl) 2968, 2931, 2858, 1738, 1435, 1371, 1342, 1285, 1203,
1169, 1086, 1072, 1042 cmꢂ1
.
1H n.m.r. ꢁ 3ꢀ75, m, 1H, H 20;
3ꢀ66, s, 3H, OMe; 3ꢀ44, m, 1H, H 60; 2ꢀ54, dd, J 15 and 8 Hz,
1H, H 2; 2ꢀ37, dd, J 15 and 7 Hz, 1H, H 2; 1ꢀ82–1ꢀ73, complex
m, 1H; 1ꢀ66–1ꢀ42, complex m, 3H; 1ꢀ26–1ꢀ06, complex m,
2H; 1ꢀ12, d, J 6 Hz, 3H, Me. 13C n.m.r. ꢁ 171ꢀ8, 74ꢀ2, 74ꢀ0,
51ꢀ5, 41ꢀ5, 32ꢀ9, 30ꢀ9, 23ꢀ4, 22ꢀ0. Mass spectrum m/z 172
(9%, M+ꢃ); 130 [34, (M ꢁ MeOH)+ꢃ]; 129 (47); 116 (77); 99
(87); 54 (100).
Methyl (Z)-7-Oxooct-2-enoate (13)
Potassium carbonate (7ꢀ30 g, 52ꢀ8 mmol) and 18-crown-
6/acetonitrile complex31 (32ꢀ2 g, 105ꢀ6 mmol) in dry toluene

Addition of Nucleophiles to Tethered Acrylates
15
(80 ml) were stirred under a nitrogen atmosphere at room
temperature for 1 h. The reaction mixture was then cooled to
ꢁ20ꢁC and methyl bis(triꢀuoroethyl)phosphonoacetate (2ꢀ80 g,
8ꢀ8 mmol) and 5-oxohexanal (10) (1ꢀ00 g, 8ꢀ8 mmol) in toluene
(5 ml) were added sequentially via syringe. The reaction mixture
was then stirred at 0ꢁC for a further 0ꢀ5 h before being poured
onto ice (50 g). The resulting mixture was extracted with
diethyl ether (3ꢂ50 ml) and the combined organic phases were
then dried (MgSO4), ꢁltered and concentrated under reduced
pressure to give a light-yellow oil. Subjection of this material
to m.p.l.c. (silica, 35 : 65 ethyl acetate/hexane elution) aꢃorded,
after concentration of the appropriate fractions (RF 0ꢀ7), the
title compound (13) (1ꢀ20 g, 80%) as a clear colourless oil
(Found: M+ꢃ, 170ꢀ0947. C9H14O3 requires M+ꢃ, 170ꢀ0943).
ꢀmax (NaCl) 2947, 1712, 1642, 1436, 1406, 1365, 1198, 1175,
74ꢀ5, 73ꢀ9, 41ꢀ2, 32ꢀ7, 30ꢀ8, 23ꢀ2, 22ꢀ0. Mass spectrum m/z
158 (6%, M+ꢃ); 102 (48); 54 (100).
Hex-5-enal (15)
Hex-5-en-1-ol (14) (5ꢀ00 g, 0ꢀ05 mol) (Aldrich) was added
dropwise to a magnetically stirred suspension of pyridinium
chlorochromate (12ꢀ90 g, 60 mmol) and sodium acetate (1ꢀ96 g,
24 mmol) in dichloromethane (30 ml) maintained at 0ꢁC. The
resulting mixture was stirred at room temperature overnight
and then subjected to vacuum ꢁltration through a sintered
glass funnel. The ꢁltrate was concentrated under reduced
pressure and residue subjected to ꢀash chromatography (sil-
ica, 1 : 9 ethyl acetate/hexane elution). Concentration of the
appropriate fractions (RF 0ꢀ5) then gave the title aldehyde
(15)18 (3ꢀ20 g, 65%) as a clear, colourless oil. ꢀmax (NaCl)
822 cmꢂ1
.
1H n.m.r. ꢁ 6ꢀ16, dt, J 11 and 8 Hz, 1H, H 3;
2940, 1728, 1640, 1440, 1410, 1240, 995, 915 cmꢂ1 1H n.m.r.
.
5ꢀ77, dt, J 11 and 1 Hz, 1H, H 2; 3ꢀ66, s, 3H, OMe; 2ꢀ62, m,
2H; 2ꢀ44, t, J 9 Hz, 2H; 2ꢀ10, s, 3H, H 8; 1ꢀ70, p, J 9 Hz,
2H, H 5. 13C n.m.r. ꢁ 208ꢀ3, 166ꢀ6, 149ꢀ3, 120ꢀ0, 50ꢀ9, 42ꢀ8,
29ꢀ8, 28ꢀ1, 22ꢀ7. Mass spectrum m/z 170 (1%, M+ꢃ); 138
(96) [(M ꢁ MeOH)+ꢃ]; 113 (100).
ꢁ 9ꢀ72, t, J 1ꢀ7 Hz, 1H, H 1; 5ꢀ78–5ꢀ62, complex m, 1H, H 5;
5ꢀ01–4ꢀ90, complex m, 2H, H 6; 2ꢀ39, td, J 7ꢀ9 and 1ꢀ6 Hz,
2H; 2ꢀ08–1ꢀ96, complex m, 2H; 1ꢀ67, quintet, J 7ꢀ0 Hz, 2H,
H 3. 13C n.m.r. ꢁ 202ꢀ4, 137ꢀ5, 115ꢀ4, 43ꢀ0, 32ꢀ9, 21ꢀ1. Mass
spectrum m/z 97 [32%, (M ꢁ Hꢃ)+]; 81 (32); 71 (33); 68 (52);
60 (85); 55 (100).
Methyl (Z)-7-Hydroxyoct-2-enoate Z-(5)
Reduction of compound (13) (500 mg, 2ꢀ95 mmol) with
sodium borohydride in methanol was achieved by the same
procedure as employed for the conversion of ketone (12) into
alcohol E-(5). In this way the title compound Z-(5) (400 mg,
80%) was obtained as a clear colourless oil (Found: M+ꢃ ꢁ H2O,
154ꢀ0991. C9H16O3 requires M+ꢃ ꢁ H2O, 154ꢀ0994). ꢀmax
(NaCl) 3417, 2962, 2928, 2862, 1720, 1641, 1437, 1406, 1199,
(S)-(+)-Hept-6-en-2-ol (+)-(16)
Titanium tetraisopropoxide (4ꢀ20 g, 14ꢀ76 mmol) was added
to a magnetically suspension of a bissulfonamide32ꢀ (200 mg
0ꢀ053 mmol) in toluene (25 ml). The resulting mixture was
stirred at 40ꢁC for 0ꢀ5 h then cooled to ꢁ78ꢁC and treated with
dimethylzinc (6ꢀ5 ml of a 2 M solution in toluene, 13 mmol).
The reaction mixture immediately turned orange in colour.
Hex-5-enal (15) (1ꢀ20 g, 12ꢀ3 mmol) was injected via syringe
into the cooled reaction mixture which was maintained at ꢁ30ꢁC
overnight then poured onto ice (50 g) and extracted with diethyl
ether (3ꢂ50 ml). The combined organic phases were washed
with water (1ꢂ20 ml) and brine (1ꢂ20 ml) before being dried
(MgSO4), ꢁltered and concentrated under reduced pressure to
give a pale-yellow oil. Subjection of this material to ꢀash
chromatography (silica, 1 : 4 ethyl acetate/hexane elution) and
concentration of the appropriate fractions (RF 0ꢀ7, 2 : 3 ethyl
acetate/hexane elution) aꢃorded the title compound (+)-(16)20
(1ꢀ20 g, 78%) as a clear colourless oil. [ꢂ]D +8ꢀ6 (c, 2ꢀ4 in
ethanol) {lit.20 [ꢂ]D +9ꢀ4 (c, 5ꢀ0 in ethanol)}. ꢀmax (NaCl)
1173, 1128, 818 cmꢂ1
.
1H n.m.r. ꢁ 6ꢀ23, dt, J 12 and 7 Hz,
1H, H 3; 5ꢀ76, dt, J 12 and 1 Hz, 1H, H 2; 3ꢀ81, m, 1H, H 7;
3ꢀ69, s, 3H, OMe; 2ꢀ63, m, 2H; 1ꢀ69, s, 1H, OH; 1ꢀ62–1ꢀ38,
complex m, 4H; 1ꢀ18, d, J 6 Hz, 3H. 13C n.m.r. ꢁ 166ꢀ8, 150ꢀ4,
119ꢀ5, 67ꢀ6, 51ꢀ0, 38ꢀ6, 28ꢀ7, 25ꢀ1, 23ꢀ5. Mass spectrum m/z
154 [5%, (M ꢁ H2O)+ꢃ]; 140 [8, (M ꢁ MeOH)+ꢃ]; 100 (100).
Cyclization of Compound Z-(5)
Subjection of compound Z-(5) to the same reaction condi-
tions as employed in the cyclization of isomer E-(5) aꢃorded
a light-yellow oil on workup. A 300 MHz 1H n.m.r. analysis
of this material indicated that it consisted of a c. 20 : 1 mix-
ture of esters (6) and (7). This material was subjected to
m.p.l.c. (silica, 15 : 85 ethyl acetate/hexane elution) and con-
centration of those fractions containing the major component
(RF 0ꢀ8) aꢃorded methyl (ꢃ)-(cis-60-methyltetrahydropyran-
20-yl)acetate (6) (280 mg, 93%) as a clear colourless oil which
was identical, in all respects, with the material obtained earlier.
3350, 2965, 2925, 1640, 1460, 1375, 1120, 995, 910 cmꢂ1 1H
.
n.m.r. ꢁ 5ꢀ87–5ꢀ72, complex m, 1H, H 6; 5ꢀ05–4ꢀ90, complex m,
2H, H 7; 3ꢀ84–3ꢀ73, complex m, 1H, H 2; 2ꢀ10–2ꢀ00, complex
m, 2H; 1ꢀ89, s, 1H, OH; 1ꢀ55–1ꢀ35, complex m, 4H; 1ꢀ17, d, J
6ꢀ9 Hz, 3H, H 1. 13C n.m.r. ꢁ 139ꢀ2, 115ꢀ1, 68ꢀ5, 39ꢀ2, 34ꢀ2,
25ꢀ5, 24ꢀ0.
(ꢃ)-( cis-6 0-Methyltetrahydropyran-2 0-yl)acetic Acid (ꢃ)-(2)
(S)-(+)-Hept-6-en-2-ol Acetate (+)-(17)
A solution of the acetate (6) (200 mg, 1ꢀ16 mmol) in
methanol (5 ml) was treated with sodium hydroxide (10 ml of a
10% aq. solution) and the resulting mixture heated at reꢀux for
1 h. The cooled reaction mixture was washed with diethyl ether
(1ꢂ20 ml) and the separated aqueous phase acidiꢁed with 10%
aqueous hydrochloric acid then extracted with diethyl ether
(3ꢂ20 ml). The combined organic phases were dried (MgSO4),
ꢁltered and concentrated under reduced pressure to give a
yellow oil which solidiꢁed at ꢁ5ꢁC. Recrystallization (hexane)
of this material aꢃorded the title acid (ꢃ)-(2)6,7 (170 mg, 93%)
Acetic anhydride (0ꢀ83 ml, 8ꢀ8 mmol) was added to
a
magnetically stirred solution of (+)-hept-6-en-2-ol (+)-
(16) (1ꢀ00 g, 8ꢀ8 mmol) in pyridine (5 ml) containing 4-
(dimethylamino)pyridine (5 mg, 0ꢀ04 mmol). The reaction
mixture was stirred at room temperature for 1 h then poured
onto ice (20 g) and extracted with ether (3ꢂ20 ml). The
combined organic phases were washed with HCl (1ꢂ20 ml
of a 0ꢀ1 M aqueous solution) and NaHCO3 (1ꢂ20 ml of a
saturated aqueous solution). The organic phase was then dried
(MgSO4), ꢁltered and concentrated under reduced pressure
to give a light-yellow oil. This material was subjected to
ꢀash chromatography (silica, 1 : 9 ethyl acetate/hexane elution)
and concentration of the appropriate fractions (RF 0ꢀ9, silica,
1 : 4 ethyl acetate/hexane elution) then gave the title acetate
(+)-(17) (1ꢀ05 g, 77%) as a clear, colourless oil. [ꢂ]D +1ꢀ32 (c,
6ꢀ0). ꢀmax (NaCl) 3030, 2980, 2940, 1745, 1640, 1370, 1240,
as white prisms, m.p. 52–53ꢁC (lit.6 52–53ꢁC) (Found: M+ꢃ
,
158ꢀ0947. Calc. for C8H14O3: M+ꢃ, 158ꢀ0943). ꢀmax (KBr)
1719 cmꢂ1
.
1H n.m.r. ꢁ 10ꢀ45, br s, 1H; 3ꢀ76, m, 1H; 3ꢀ52, m,
1H; 2ꢀ57, dd, J 16 and 8 Hz, 1H, H 2; 2ꢀ47, dd, J 16 and 5 Hz,
1H, H2; 1ꢀ82, m, 1H; 1ꢀ70–1ꢀ45, complex m, 3H; 1ꢀ32–1ꢀ12,
complex m, 2H; 1ꢀ18, d, J 6 Hz, 3H, Me. 13C n.m.r. ꢁ 175ꢀ3,
ꢀ
(1R-trans)-N ,N 0-(Cyclohexane-1,2-diyl)bis(triꢀuoromethanesulfonamide).

16
M. G. Banwell et al.
1130, 1020, 910 cmꢂ1
.
1H n.m.r. ꢁ 5ꢀ80–5ꢀ64, complex m,
concentrated H2SO4. The resulting mixture was stirred at room
temperature for 5 h then the solvent was removed under reduced
pressure and the oil thereby obtained was taken up in diethyl
ether (100 ml). The solution thus obtained (fraction B) was
washed with NaHCO3 (1ꢂ50 ml of saturated aqueous solution).
Fractions A and B were combined then dried (MgSO4), ꢁltered
and concentrated under reduced pressure to give a light-yellow
oil. This material was subjected to ꢀash chromatography
(silica, 3 : 7 ethyl acetate/hexane elution) and concentration of
the appropriate fractions (RF 0ꢀ7) aꢃorded the title compound
(+)-(6)7 (160 mg, 70%) as a clear colourless oil. [ꢂ]D +29ꢀ6
(c, 0ꢀ7 in C6H6) {lit. (Seebach et al. 1982)7 [ꢂ]D +32ꢀ9 (c,
1ꢀ05 in C6H6)}. Compound (+)-(6) was identical, as judged
by 1H and 13C n.m.r. spectroscopic methods, with the racemic
material (6) obtained earlier. Chiral capillary g.l.c. analysis of
the former material established that it was composed of a c.
6 : 94 mixture of the R,R- and S,S- enantiomers (Rt 931 and
933 s, respectively).
1H, H 6; 5ꢀ00–4ꢀ80, complex m, 3H, H 2 and H 7; 2ꢀ10–1ꢀ95,
complex m, 2H; 1ꢀ96, s, 3H, COCH3; 1ꢀ60–1ꢀ29, complex m,
4H; 1ꢀ15, d, J 6ꢀ0 Hz, 3H, H 1. 13C n.m.r. ꢁ 170ꢀ5, 138ꢀ2,
114ꢀ6, 70ꢀ6, 35ꢀ2, 33ꢀ4, 24ꢀ5, 21ꢀ2, 19ꢀ8.
(S)-(+)-5-Hydroxyhexanal Acetate (+)-(18)
A magnetically stirred solution of alkene (+)-(17) (600 mg,
3ꢀ8 mmol) in dry dichloromethane (100 ml) was cooled to
ꢁ78ꢁC (dry-ice/acetone bath) then treated with a stream of
ozone gas until a blue colour persisted. Triphenylphosphine
(1ꢀ00 g, 3ꢀ8 mmol) was then added to the reaction mixture
which was allowed to warm to room temperature. The solution
thus obtained was concentrated under reduced pressure and the
resulting oil was subjected to ꢀash chromatography (silica, 1 : 9
ethyl acetate/hexane elution). Concentration of the appropriate
fractions (RF 0ꢀ5, silica, 3 : 7 ethyl acetate/hexane elution)
then aꢃorded the title compound (+)-(18) (540 mg, 90%) as a
clear, colourless oil. [ꢂ]D +3ꢀ84 (c, 5ꢀ24). ꢀmax (NaCl) 2940,
Methyl (E)-Hepta-2,6-dienoate (23)
1730, 1370, 1245, 1140, 1020, 950 cmꢂ1
.
1H n.m.r. ꢁ 9ꢀ68, t, J
1ꢀ4 Hz, 1H, H 1; 4ꢀ87–4ꢀ75, complex m, 1H, H 5; 2ꢀ42–2ꢀ35,
complex m, 2H; 1ꢀ94, s, 3H, COMe; 1ꢀ64–1ꢀ38, complex m,
4H; 1ꢀ13, d, J 6ꢀ9 Hz, 3H, H 6. 13C n.m.r. ꢁ 201ꢀ8, 170ꢀ5,
70ꢀ1, 43ꢀ3, 35ꢀ0, 21ꢀ1, 19ꢀ7, 17ꢀ7. Mass spectrum m/z 127
(34%); 115 [71, (M ꢁ MeCOꢃ)+]; 99 [90, (M ꢁ MeCO2ꢃ)+]; 70
(91); 55 (100).
The Masamune–Roush modiꢁcation33 of the Horner–
Wadsworth–Emmons reaction was used in the preparation
of the title compound. Thus, methyl diethylphosphonoac-
etate (2ꢀ24 g, 10 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene
(1ꢀ5 ml, 10 mmol) were added, sequentially, to a magnetically
stirred suspension of lithium chloride (425 mg, 10 mmol) in
anhydrous acetonitrile (100 ml) maintained at room temperature
under argon. After 5 min pent-4-enal34 (840 mg, 10 mmol) was
added and the resulting mixture stirred at room temperature
for a further 2 h. The reaction mixture was then quenched with
water (50 ml) and extracted with diethyl ether (2ꢂ50 ml). The
combined ethereal solutions were washed with brine (1ꢂ50 ml)
then dried (MgSO4), ꢁltered and concentrated under reduced
pressure to give a yellow oil. Subjection of this material to
ꢀash chromatography (silica, 1 : 4 ethyl acetate/hexane elution)
aꢃorded, after concentration of the appropriate fractions (RF
0ꢀ5), the title compound (23)35 (970 mg, 56%) as a clear,
pale-yellow oil. ꢀmax (NaCl) 2950, 1725, 1660, 1640, 1437,
Methyl (S,Z)-(ꢁ)-7-Acetyoxyoct-2-enoate (ꢁ)-(19)
Potassium bis(trimethylsilyl)amide (6ꢀ4 ml of a 0ꢀ5 M solu-
tion in toluene, 3ꢀ2 mmol) then aldehyde (+)-(18) (500 mg,
3ꢀ2 mmol) were added, via syringe, to a magnetically stirred
solution of methyl bis(2,2,2-triꢀuoroethyl)phosphonoacetate
(1ꢀ00 g, 3ꢀ2 mmol) and 18-crown-6/acetonitrile complex31
(4ꢀ90 g, 16 mmol) in dry thf (30 ml) maintained at ꢁ78ꢁC
(dry-ice/acetone bath) under a nitrogen atmosphere. The
reaction mixture was maintained at ꢁ78ꢁC for 0ꢀ5 h then
poured into NH4Cl (20 ml of a saturated aqueous solution).
The resulting mixture was extracted with ether (3ꢂ50 ml) and
the combined organic phases were dried (MgSO4), ꢁltered and
concentrated under reduced pressure to give a light-yellow oil.
Subjection of this material to ꢀash chromatography (silica,
1 : 4 ethyl acetate/hexane elution) and concentration of the
appropriate fractions (RF 0ꢀ8, silica, 3 : 7 ethyl acetate/hexane
elution) aꢃorded the title compound (ꢁ)-(19) (550 mg, 81%) as
a clear colourless oil. [ꢂ]D ꢁ3ꢀ8 (c, 5ꢀ25). ꢀmax (NaCl) 2980,
2940, 1730, 1645, 1440, 1370, 1240, 1200, 1170, 1135, 1020,
1318, 1270, 1205, 1170, 1142, 988, 915, 852 cmꢂ1 1H n.m.r.
.
ꢁ 7ꢀ20, dt, J 16 and 7 Hz, 1H; 5ꢀ80–5ꢀ60, complex m, 2H;
5ꢀ10–4ꢀ95, complex m, 2H; 3ꢀ97, s, 3H; 2ꢀ60–2ꢀ45, m, 4H.
13C n.m.r. ꢁ 167ꢀ0, 148ꢀ5, 136ꢀ9, 121ꢀ1, 115ꢀ4, 51ꢀ3, 32ꢀ0,
31ꢀ3.
Methyl (E)-6-Methylhepta-2,6-dienoate (24)
4-Methylpent-4-enal36 was converted into the title compound
(75% yield) under the same conditions as described above for
the conversion of pent-4-enal into compound (23). In this way
compound (24) (76%) was obtained as a clear, colourless oil
(Found: M+ꢃ, 154ꢀ0996. C9H14O2 requires M+ꢃ, 154ꢀ0994).
ꢀmax (NaCl) 2950, 1725, 1660, 1435, 1268, 1200, 1153, 1042,
820, 735 cmꢂ1
.
1H n.m.r. ꢁ 6ꢀ18, dt, J 11ꢀ6 and 7ꢀ8 Hz, 1H,
H 3; 5ꢀ75, dt, J 11ꢀ6 and 1ꢀ4, 1H, H 2; 4ꢀ92–4ꢀ80, complex
m, 1H, H 7; 3ꢀ67, s, 3H, OCH3; 2ꢀ68–2ꢀ58, complex m, 2H;
2ꢀ00, s, 3H, OCOMe; 1ꢀ66–1ꢀ36, m, 4H; 1ꢀ18, d, J 6ꢀ5 Hz,
3H, H 8. 13C n.m.r. ꢁ 170ꢀ6, 166ꢀ6, 149ꢀ9, 119ꢀ6, 70ꢀ6, 50ꢀ9,
35ꢀ4, 28ꢀ6, 24ꢀ8, 21ꢀ2, 19ꢀ9. Mass spectrum m/z 215 [31%,
(M+H)+]; 182 [12, (M ꢁ MeOH)+ꢃ]; 155 [74, (M ꢁ MeCO2ꢃ)+];
141 (39); 122 (42); 111 (89); 95 (98); 81 (100); 68 (74).
890 cmꢂ1
.
1H n.m.r. ꢁ 6ꢀ97, dt, J 16 and 7 Hz, 1H; 5ꢀ84, dt, J
16 and 1ꢀ5 Hz, 1H; 4ꢀ76, s, 1H; 4ꢀ70, s, 1H; 3ꢀ73, s, 3H; 2ꢀ36,
m, 2H; 2ꢀ16, m, 2H; 1ꢀ73, s, 3H. 13C n.m.r. ꢁ 166ꢀ9, 148ꢀ8,
144ꢀ0, 120ꢀ9, 110ꢀ6, 51ꢀ3, 35ꢀ8, 30ꢀ1, 22ꢀ2. Mass spectrum
m/z 154 (13%, M+ꢃ); 139 (45); 122 (34); 95 (100); 81 (38);
68 (24); 55 (71).
Methyl (+)-(S,S)-( cis-6 0-Methyltetrahydropyran-2 0-
yl)acetate (+)-(6)
A mixture of compound (ꢁ)-(19) (300 mg, 1ꢀ4 mmol) and
K2CO3 (966 mg, 7 mmol) in methanol (5 ml) was stirred mag-
netically at room temperature overnight. The reaction mixture
was then poured into water (50 ml), extracted with diethyl
ether (3ꢂ30 ml) and the combined organic phases (fraction
A) were washed with NaHCO3 (1ꢂ50 ml of saturated aqueous
solution). The combined aqueous phases were acidiꢁed to pH
c. 2–3 with HCl (concentrated aqueous solution). The resulting
mixture was extracted with ether (3ꢂ30 ml) and the combined
organic phases were dried (MgSO4), ꢁltered and concentrated
under reduced pressure to give a colourless oil. This material
was dissolved in methanol (50 ml) containing a few drops of
Methyl (E)-2,6-Dimethylhepta-2,6-dienoate (25)
Methyl 2-(diethylphosphono)propionate37 (2ꢀ24 g, 10 mmol)
and 1,8-diazabicyclo[5.4.0]undec-7-ene (1ꢀ5 ml, 10 mmol) were
added, sequentially, to a magnetically stirred suspension of
lithium chloride (425 mg, 10 mmol) in anhydrous acetonitrile
(100 ml) maintained at room temperature under argon. After
5 min pent-4-enal34 (840 mg, 10 mmol) was added and the
resulting mixture stirred at room temperature for a further
2 h. The reaction mixture was then quenched with water
(50 ml) and extracted with diethyl ether (2ꢂ50 ml). The
combined ethereal solutions were washed with brine (1ꢂ50 ml)

Addition of Nucleophiles to Tethered Acrylates
17
3
4
5
then dried (MgSO4), ꢁltered and concentrated under reduced
pressure to give a yellow oil. Subjection of this material to
ꢀash chromatography (silica, 1 : 4 ethyl acetate/hexane elution)
aꢃorded, after concentration of the appropriate fractions (RF
0ꢀ5), compound (25)38 (71%) as a clear, colourless oil (Found:
M+ꢃ, 168ꢀ1152. Calc. for C10H16O2: M+ꢃ, 168ꢀ1150). ꢀmax
(NaCl) 2950, 1715, 1647, 1433, 1270, 1192, 1120, 1083, 890,
Edmunds, A. J. F., Trueb, W., Oppolzer, W., and Cowley,
P., Tetrahedron, 1997, 53, 2785, and references cited therein.
For a review on the synthesis of tetrahydropyrans see
Boivin, T. L. B.,Tetrahedron, 1987, 43, 3309.
Palazoꢄn, J. M., Soler, M. A., Ramꢄꢅrez, M. A., and Martꢄꢅn,
V. S., Tetrahedron Lett., 1993, 34, 5467, and references
cited therein.
6
7
747 cmꢂ1
.
1H n.m.r. ꢁ 6ꢀ75, t, J 7 Hz, 1H; 4ꢀ75, br s, 1H;
Maurer, B., Grieder, A., and Thommen, W., Helv. Chim.
Acta, 1979, 62, 44.
4ꢀ70, br s, 1H; 3ꢀ74, s, 3H; 2ꢀ32, m, 2H; 2ꢀ15, m, 2H; 1ꢀ84,
s, 3H; 1ꢀ74, s, 3H. 13C n.m.r. ꢁ 168ꢀ5, 144ꢀ5, 141ꢀ8, 127ꢀ5,
110ꢀ4, 51ꢀ6, 36ꢀ2, 25ꢀ7, 22ꢀ3, 12ꢀ3. Mass spectrum m/z 168
(14%, M+ꢃ); 153 (24); 136 (73); 121 (42); 109 (64); 93 (61);
81 (100); 67 (46); 55 (61).
Seebach, D., and Pohmakotr, M., Helv. Chim. Acta, 1979,
62, 843; Seebach, D., Pohmakotr, M., Schregenberger, C.,
Weidmann, B., Mali, R. S., and Pohmakotr, S., Helv. Chim.
Acta, 1982, 65, 419; Kim, Y., and Mundy, B. P., J. Org.
Chem., 1982, 47, 3556; Ley, S. V., Lygo, B., Molines, H.,
and Morton, J. A., J. Chem. Soc., Chem. Commun., 1982,
1251; Masaki, Y., Serizawa, Y., Nagata, K., and Kaji, K.,
Chem. Lett., 1983, 1601; Bates, H. A., and Deng, P.-N., J.
Org. Chem., 1983, 48, 4479; Lichtenthaler, F. W., Klinger,
F. D., and Jarglis, P., Carbohydr. Res., 1984, 132, C1;
Gallagher, T., J. Chem. Soc., Chem. Commun., 1984, 1554;
Semmelhack, M. F., and Bodurow, C., J. Am. Chem. Soc.,
1984, 106, 1496; Keinan, E., Seth, K. K., and Lamed, R.,
J. Am. Chem. Soc., 1986, 108, 3474; Nussbaumer, C., and
Frater, G., Helv. Chim. Acta, 1987, 70, 396; Greenspoon,
N., and Keinan, E., J. Org. Chem., 1988, 53, 3723; Coppi,
L., Ricci, A., and Taddei, M., J. Org. Chem., 1988, 53,
911; Kotsuki, H., Ushio, Y., Kadota, I., and Ochi, M.,
Chem. Lett., 1988, 927; Wei, Z. Y., Wang, D., Li, J.
S., and Chan, T. H., J. Org. Chem., 1989, 54, 5768;
Homma, K., and Mukaiyama, T., Chem. Lett., 1989, 893;
Kobayashi, K., and Suginome, H., Bull. Chem. Soc. Jpn,
1989, 62, 951; Ishihara, K., Mori, A., and Yamamoto, H.,
Tetrahedron, 1990, 46, 4595; Hansson, S., Miller, J. F., and
Liebeskind, L. S., J. Am. Chem. Soc., 1990, 112, 9660;
Ragoussis, V., and Theodorou, V., Synthesis, 1993, 84;
Lee, E., Tae, J. S., Lee, C., and Park, C. M., Tetrahedron
Lett., 1993, 34, 4831; Varelis, P., Graham, A. J., Johnson,
B. L., Skelton, B. W., and White, A. H., Aust. J. Chem.,
1994, 47, 1735; Muraoka, O., Okumura, M., Maeda, T.,
Wang, L., and Tanabe, G., Chem. Pharm. Bull., 1995, 43,
517.
Machinaga, N., and Kibayashi, C., Tetrahedron Lett., 1993,
34, 5739.
Mandai, T., Ueda, M., Kashiwagi, K., Kawada, M., and
Tsuji, J., Tetrahedron Lett., 1993, 34, 111.
Ngooi, T. K., Scilimati, A., Guo, Z., and Shi, C. J., J. Org.
Chem., 1989, 54, 911.
Grigg, R., Markandu, J., Perrior, T., Surendrakumar, S.,
and Warnock, W. J., Tetrahedron, 1992, 48, 6929.
Traynelis, V. J., Hergenrother, W. L., Hanson, H. T., and
Valicenti, J. A., J. Org. Chem., 1964, 29, 123.
Pappas, J. J., Keaveney, W. P., Berger, M., and Rush, R.
V., J. Org. Chem., 1968, 33, 787.
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Soc., 1961, 83, 1733.
Jackman, L. M., and Sternhell, S., ‘Applications of Nuclear
Magnetic Resonance Spectroscopy in Organic Chemistry’
2nd Edn, p. 301 (Pergamon: Oxford 1969).
Methyl (ꢃ)-( cis-6 0-Methylpiperidin-2 0-yl)acetate (26)
Keto ester (12) (360 mg, 2ꢀ12 mmol) was added to a magnet-
ically stirred solution of ammonium acetate (1ꢀ60 g, 21 mmol)
and NaBH3CN (144 mg, 2ꢀ3 mmol) in methanol (10 ml) and
the resulting mixture heated at 60ꢁC for 16 h. The cooled
reaction mixture was then concentrated under reduced pres-
sure to give a light-yellow oil. This material was dissolved in
dichloromethane (50 ml) and the resulting solution washed with
NaHCO3 (2ꢂ10 ml of a saturated aqueous solution) then dried
(MgSO4), ꢁltered and concentrated under reduced pressure to
give a light-yellow oil. Subjection of this material to ꢀash
chromatography (silica, 1 : 9 methanol/dichloromethane elu-
tion) aꢃorded, after concentration of the appropriate fractions
(RF 0ꢀ6), the title compound (26)27 (310 mg, 86%) as a clear
colourless oil (Found: M+ꢃ, 171ꢀ1260. Calc. for C9H17NO2:
M+ꢃ, 171ꢀ1259). ꢀmax (NaCl) 3320, 2920, 2860, 1740, 1440,
1380, 1290, 1200, 1160, 1005, 930 cmꢂ1
.
1H n.m.r. ꢁ 3ꢀ62,
s, 3H, OMe; 2ꢀ97–2ꢀ86, complex m, 1H; 2ꢀ70–2ꢀ58, complex
m, 1H; 2ꢀ36, s, 1H; 2ꢀ34, d, J 2ꢀ0 Hz, 1H; 2ꢀ12, br s, 1H,
NH; 1ꢀ77–1ꢀ67, m, 1H; 1ꢀ59–1ꢀ49, m, 2H; 1ꢀ41–1ꢀ24, m, 1H;
1ꢀ12–0ꢀ95, m, 2H; 1ꢀ01, d, J 6ꢀ5 Hz, 3H, Me. 13C n.m.r. ꢁ
172ꢀ8, 53ꢀ3, 52ꢀ1, 51ꢀ4, 41ꢀ2, 33ꢀ7, 31ꢀ9, 24ꢀ4, 22ꢀ8. Mass
spectrum m/z 171 (6%, M+ꢃ); 156 [42, (M ꢁ CH3ꢃ)+]; 98
(100); 82 (16).
Methyl (ꢃ)-( trans-6 0-Methylpiperidin-2 0-yl)acetate (27)
Keto ester (13) (100 mg, 0ꢀ59 mmol) was treated with
ammonium acetate (450 mg, 5ꢀ8 mmol) and NaBH3CN (40 mg,
0ꢀ64 mmol) in methanol (5 ml) under similar conditions to those
described above for the preparation of compound (26). In this
manner the title compound (27) (73 mg, 73%) was obtained
as a clear, colourless oil (Found: M+ꢃ, 171ꢀ1257. C9H17NO2
requires M+ꢃ, 171ꢀ1259). ꢀmax (NaCl) 3340, 2930, 2860, 1735,
8
9
10
11
12
13
14
15
1440, 1380, 1290, 1200, 1160, 1000, 760 cmꢂ1
.
1H n.m.r. ꢁ
4ꢀ75, br s, 1H, NH; 3ꢀ64, s, 3H, OMe; 3ꢀ10–2ꢀ99, complex m,
1H; 2ꢀ82–2ꢀ70, complex m, 1H; 2ꢀ56, dd, J 16ꢀ5 and 7ꢀ4 Hz,
1H; 2ꢀ46, dd, J 16ꢀ5 and 6ꢀ1 Hz, 1H; 1ꢀ81–1ꢀ71, complex m,
1H; 1ꢀ69–1ꢀ58, complex m, 2H; 1ꢀ46–1ꢀ15, complex m, 3H;
1ꢀ13, d, J 6ꢀ7 Hz, 3H, Me. 13C n.m.r. ꢁ 172ꢀ1, 53ꢀ5, 52ꢀ7,
51ꢀ6, 40ꢀ1, 32ꢀ8, 30ꢀ8, 23ꢀ9, 21ꢀ9. Mass spectrum m/z 171
(6%, M+ꢃ); 156 [31, (M ꢁ CH3ꢃ)+]; 98 (100).
Acknowledgments
16
17
18
19
20
21
We thank the Australian Research Council and
Dunlena Pty Ltd for ꢄnancial support and Mr Robert
Longmore for assistance with g.l.c. analyses. C.T.B.
gratefully acknowledges receipt of an APA (Industry)
Award.
Still, W. C., and Gennari, C., Tetrahedron Lett., 1983, 24,
4405.
Smith, M. B., ‘Organic Synthesis’ p. 580 (McGraw–Hill:
New York 1994).
LeBel, N. A., Post, M. E., and Whang, J. J., J. Am. Chem.
Soc., 1964, 86, 3759.
Nowotny, S., Vettel, S., and Knochel, P., Tetrahedron Lett.,
1994, 35, 4539, and references cited therein.
von dem Bussche-Huennefeld, J. L., and Seebach, D.,
Tetrahedron, 1992, 48, 5719.
Casteel, D. A., Nat. Prod. Rep., 1992, 9, 289, and references
cited therein.
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