Conjugate addition of organocopper reagents to γ-alkoxybutenolides and application to the synthesis of non-racemic alkyl cyclopentenones

Article abstract of DOI:10.1039/b408255a

Simple organocopper reagents are shown to undergo anti-stereoselective 1,4-addition to menthyloxy-substituted lactone 1 in the presence of BF ₃·OEt₂; the Lewis acid causes partial epimerisation of the acetal centre after conjugate addition. Enolate alkylation of the adducts leads to di- and trisubstituted lactones that are converted, in favourable cases, into di- and trisubstituted cyclopentenones.

Full text of DOI:10.1039/b408255a

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A R T I C L E
Conjugate addition of organocopper reagents to c-alkoxybutenolides
and application to the synthesis of non-racemic alkyl
cyclopentenones
Jeremy Robertson,*a Morgan Ménard,a Rhonan Fordb and Stephen Bell†a
a
Department of Chemistry, University of Oxford, Chemistry Research Laboratory,
Mansfield Road, Oxford OX1 3TA
AstraZeneca R & D Charnwood, Medicinal Chemistry, Bakewell Road, Loughborough,
b
LE11 5RH
Received 2nd June 2004, Accepted 11th August 2004
First published as an Advance Article on the web 22nd September 2004
Simple organocopper reagents are shown to undergo anti-stereoselective 1,4-addition to menthyloxy-substituted
lactone 1 in the presence of BF3·OEt2; the Lewis acid causes partial epimerisation of the acetal centre after conjugate
addition. Enolate alkylation of the adducts leads to di- and trisubstituted lactones that are converted, in favourable
cases, into di- and trisubstituted cyclopentenones.
introduction of a simple alkyl group, and problems with this
Introduction
approach have been noted;10 (2) to the best of our knowledge,
Enantiomerically pure 4-alkylcyclopentenones are of central
importance in the construction of a diverse range of natural
products and biologically active non-natural analogues, and
routes to their synthesis are highly developed, largely driven
by prostaglandin research.1 A classical synthesis of this class of
compounds hinges on the anti-selective conjugate addition2 of
organometallic reagents, notably dialkyl cuprates, to 4-hydroxy-
cyclopentenone in protected form followed by elimination
(Scheme 1). Consequently, the problem is reduced to the need to
assemble optically active alkoxy- or silanyloxy-cyclopentenones,
the lactone–enone transformation has been reported only for
cases where the lactone carbonyl a-position is either fully substi-
tuted or forms part of a ring linked to the b-position.11
Scheme 2
for which chemical and chemoenzymatic solutions have been
developed and widely adopted.3
Results and discussion
Conjugate additions
Attention was first turned to the conjugate addition. Lithium
dialkylcuprates were not effective, leading to either incomplete
Scheme 1
reaction or complex product mixtures within which reduction
products were evident (see below), but organocopper reagents
could be added reasonably efficiently in the presence of a slight
excess of BF3·OEt2.12 Optimum results were obtained with a
three-fold excess of the organocopper/Lewis acid mixture, but
use of 1.5 equivalents led to only a slight reduction in yield
(Scheme 3, Table 1). The addition of methylcopper proceeded
poorly (entry a)—the use of zincate reagents offering only a
slight improvement13—but organocopper reagents derived from
1°-alkyllithiums added reliably in yields ranging from moderate
to excellent (entries b–g); branching at the adding centre was
tolerated (entries h and i) albeit with a reduction in yield, and
phenylcopper added in poor yield (entry j). Observation of enol
ether 5 and butyrolactone 6 implicated reagent-induced reduc-
tion as a major contributor to the lowered yields in at least some
cases; a plausible mechanism, based on electrocyclic ring-open-
ing of dianion 4 or an equivalent radical anion,14 is presented in
Scheme 4.
We first became interested in this area during the development
of our formal synthesis of (±)-roseophilin in which the relative
stereochemistry in the natural product derived ultimately
from stereoselective 1,4-addition to (±)-4-(6-chlorohexyl)-
cyclopentenone.4 The availability, on a large scale, of both
enantiomers of this enone was crucial to our projected synthesis
of both enantiomers of roseophilin and hence an assignment of
the absolute configuration of the natural product, which was not
known at the time. Mindful of the wealth of literature on this
general problem,5 we sought a practical alternative solution.
Our approach is based on the known reaction of alkoxy-
butyrolactones with lithiated phosphonates to yield cyclo-
pentenones directly in a tandem ring-opening/intramolecular
Horner–Wadsworth–Emmons olefination (Scheme 2).6 In
the context of the enantioselective synthesis of 4-alkylcyclo-
pentenones, this proposal requires access to 3-alkyl-4-
alkoxybutyrolactones in both enantiomeric series, which we
envisaged as deriving from (5R)-5-(l-menthyloxy)-2[5H]-
furanone 17 or its enantiomer, on the basis of the extensive
investigations of Feringa (see below). The realisation of this
proposal would constitute an effective four-step asymmetric syn-
thesis of 4-alkylcyclopentenones. However, two factors had to be
addressed at the outset: (1) most conjugate additions to lactone
1 involve heteroatoms or heteroatom-stabilised C-nucleophiles;8
we are aware of only a single report9 describing the direct
In the 1H NMR spectra of adducts 2 and 3, the acetal proton
resonance is a sensitive indicator of the product stereochemistry,
and the diastereoselectivity of these reactions was judged by
integration of this resonance in the spectra of the crude 1,4-addi-
tion products. The data in Table 1 show that for the major isomers
(2) this resonance shows a very consistent 2.2–2.6 Hz coupling
constant;15 in contrast, this resonance in the minor isomers (3)
appears as a slightly shifted doublet with a larger coupling con-
stant (4.6–4.8 Hz). On this basis, almost complete stereocontrol
was observed in some cases but, in general, the d.r. varied be-
tween ca. 2–4:1; fortunately, the diastereomers could be readily
† Responsible for obtaining the X-ray structure in Fig. 1.
2 9 8 8
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 9 8 8 – 2 9 9 7
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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Scheme 3 Reagents: RLi/CuI/BF3·OEt2, THF, −78 °C.
Table 1
dH/ppm (J/Hz) for CH(OR)2
a
Entry
RLi
Yield (%)
d.r. (2:3)
[a]D
2
3
a
b
c
d
e
f
g
h
i
MeLi
BuLi
i-BuLi
3-butenyl-Li
6-chlorohexyl-Li
7-octenyl-Li
8-TBDPSO-octyl-Li
s-BuLi
t-BuLi
PhLi
5
76
62
63
86
74
79
41
44
25
—
—
5.28 (2.2)
5.34 (2.4)
5.33 (2.4)
5.38 (2.4)
5.35 (2.4)
5.31 (2.3)
5.37 (2.3)
5.45/5.46 (2.6/2.4)d
5.52 (2.3)
5.59 (2.5)
—
4.2:1
3:1
4:1
−145.5
−107.3
−132.9
−136.3b
−124.6
−72.2
—
−157.7
−140.6
5.47 (4.8)
5.45 (4.8)
5.47 (4.7)
5.48 (4.7)
5.44 (4.8)
5.49 (4.6)
—
3.5:1
2.2:1
2.2:1
c,d
d
—
>95:<5
>95:<5
—
—
j
a Data for 2b–g and 2i,j; c 0.15–1.2, CHCl3. b Run in ethanol. c The 1H NMR spectrum of the crude material was insufficiently clean to allow a ratio to
be extracted with confidence. d Compound 2h is a 1:1 mixture of 2-epimers
Table 2
Enhancement (%)
Irradiate
H3
H4
H5
H1
H3
H4
H5
—
4.1
1.8
4.5
—
3.8
1.9
4.2
—
2.0
4.1
0
H1
3.3
6.3
0
—
Scheme 4
separated. In addition to this coupling constant information,
support for the stereochemical assignment for the major isomers
(2) was forthcoming from NOE experiments (see, for example,
Table 2), from the [a]D data (the trans- diastereomers being
characterised by a large negative specific rotation,16 see Table 1)
and, in the case of 2b, by X-ray crystallography (Fig. 1).17
The production of a second diastereomer in these conjugate
additions warrants comment. Most nucleophiles add to
butenolide 1 with essentially exclusive formation of the
anti-diastereomer therefore the formation of significant propor-
tions (up to 30%) of what appear to be cis-adducts was surpris-
ing. However, all published nucleophilic additions to lactone 1
proceed without Lewis acid mediation and it was thought likely
that the presence of BF3·OEt2 in the organocopper additions
led to this discrepancy. Control experiments were run to
establish whether the conjugate addition is inherently poorly
diastereoselective, or whether the Lewis acid compromises the
stereochemistry of the acetal centre in lactone 1 or adducts 2 (or
both). Treatment of a cold (−78 °C) THF solution of lactone 1
with one equivalent of BF3·OEt2 led to rapid epimerisation; on
this basis it might be concluded that the diastereomers 2 and 3
result from anti-stereoselective conjugate addition to epimeric
lactones 1 and 1. This possibility was ruled out by performing
a conjugate addition on pure lactone 1; the major diastereomer
2b from this reaction was not the minor isomer (3b) obtained
from the equivalent reaction with lactone 1. Secondly, treat-
ment of a cold (−78 °C) THF solution of adduct 2b with one
equivalent of BF3·OEt2 led to the formation of just two major
diastereomers, the starting material (2b) and the compound
obtained as a minor diastereomer from the original conjugate
Fig. 1 ORTEP view of lactone 2b taken from its crystal structure.17
addition experiment. On this basis, the minor diastereomer was
assigned as the cis-product 3b, arising from epimerisation at the
acetal centre; formation of the alternative cis-diastereomer 3b
was discounted because this would require epimerisation of just
the 4-position without concomitant isomerisation of the acetal
centre. These experiments are summarised in Scheme 5.
In summary, conjugate addition of alkylcopper reagents,
mediated by BF3·OEt2, appears to be highly stereoselective,
as expected, but the Lewis acidic environment leads to loss
of stereochemical integrity at the acetal centre. Since the
stereochemistry at the acetal centre is of no importance to
the projected chemistry, this epimerisation is of no conse-
quence.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 9 8 8 – 2 9 9 7
2 9 8 9

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Scheme 7 Reagents: (i) KHMDS, THF, −78 °C; prenyl bromide
(1.0 equiv.); (ii) LiHMDS, THF, −78 °C; prenyl bromide (2.0 equiv.);
(iii) MeP(O)(OMe)2, BuLi, LiBr, THF, −78 °C.
Scheme 5
lactone). Furthermore, a,a-dialkylated lactone 10 afforded tri-
substituted enone 12 in 72% yield. To establish deprotonation
of H3a (rather than H3b) as the crucial problem, an attempt
was made to produce a 3,4-cis-disubstituted lactone by hydro-
genation of an alkylidene lactone. Thus, enoate 14 (Scheme 8),
produced by condensation of lactone 2b with isobutyraldehyde,
was hydrogenated, but with difficulty and only in the presence of
triethylamine.10b Under these conditions the 3,4-stereochemistry
(in 15) was shown to be trans- by NOE (Table 2), and this aspect
of the project was discontinued.
Lactone to enone conversion
Addition of lithiated dimethyl methylphosphonate to
a
representative lactone (2e) under a variety of conditions
(T: −78 °C → 20 °C; solvent: Et2O, THF, or DME; with or with-
out added LiBr11a) produced (the enantiomer of) enone 7 in very
low yield, the ‘best’ result being 13% with the majority of the
product mixture being intractable polar material. To explore the
possibility that product trapping by the lithiated phosphonate
could be detrimental to this reaction, enone 718 was treated with
the lithiated phosphonate and, indeed, a rapid reaction ensued
to generate 3°-alcohol 8 (in 61% yield as a single diastereomer,
assigned by NOE experiments; enone 7 was recovered in 20%
1
yield) (Scheme 6). However, inspection of the H NMR data
obtained on the crude product from the reaction of lactone 2e
showed that none of the alcohol 8 was present, and this was
eliminated as a major cause of failure of this reaction.
Scheme 8 Reagents: (i) LHMDS, isobutyraldehyde, THF; (ii) MsCl,
Et3N, 1,2-dichloroethane; DBU, CH2Cl2; (iii) H2 (4 bar), Pd/C, Et3N
(0.1 equiv.), EtOH.
Scheme 6 Reagents: MeP(O)(OMe)2, BuLi, THF, −78 °C.
Synthetic applications
Substrate decomposition following enolisation by the
lithiated phosphonate was considered as an alternative potential
contributor to the failure of this reaction. On the basis of the
small JH4,H5 value (in lactones 2) the more populated of the
two envelope conformations of the ring is expected16 to be that
in which H3a is pseudoaxial and perfectly aligned for rapid
deprotonation (B, Figure 2); furthermore, this proton is anti- to
the C4 alkyl substituent and therefore sterically accessible.
In order to inhibit this mode of decomposition, the 3a
position was blocked by enolate alkylation of a representative
lactone (2b) to generate ‘3a-blocked’ substrate 9 (Scheme 7).
It was gratifying to find that this material responded to treat-
ment with the lithiated phosphonate to yield enone 11 in an
unoptimised 60% yield (the balance of material being starting
These studies raised the possibility of producing a variety of
biologically significant 3,4-dialkylcyclopentenones; therefore, in
anticipation of a synthesis of the methyl ester of chromomoric
acid B,19 lactones 16–19 (Scheme 9) were treated with the
lithiated phosphonate. Under the standard conditions, starting
lactone was returned in all cases with good mass recovery, just
traces of enone being present as inferred from 1H NMR analy-
sis of the crude product. Given the success of the butyl cases,
it was concluded that the longer, functionalised side-chains in
lactones 16–19, acted in combination with efficient shielding of
the carbonyl a-face by the pentenyl substituent to slow addition
to the lactone carbonyl relative to enolisation. In support of
this notion, non-enolisable but sterically encumbered substrate
20 was converted into enone 21 in 50% yield (80% based on
recovered lactone 20).
Conclusion
In summary, we have provided a number of anti-selective 1,4-
additions of simple alkyl copper reagents to c-alkoxybutenolide
1 in the presence of BF3·OEt2, and shown that the acetal centre
Fig. 2
2 9 9 0
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 9 8 8 – 2 9 9 7

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in most cases, a pale yellow solution. Where a mixture of two
diastereoisomers was obtained after rough purification by flash
column chromatography (95:5 petrol:ethyl acetate) the major
butyrolactone was isolated by a second, more careful, chromato-
graphy step.
General procedure B (for 1,4-addition of organocopper reagents
derived from non-commercially available organolithiums)
A solution of the appropriate 1°-iodoalkane (x mmol) in
anhydrous ether (ca. 3.5 mL per mmol of the iodoalkane)
was cooled to −78 °C and tert-butyllithium (1.7 M solution in
pentane, 2x mmol) was added. After 20 min, the solution was
added by cannula to a cold (−78 °C) slurry of CuI (x mmol, pre-
dried by evaporation with toluene) in anhydrous THF (30 mL).
With vigorous stirring, the black reaction mixture was allowed
to warm to −25 °C over 20 min, cooled to −78 °C and BF3·Et2O
(x mmol) was added followed by a solution of furanone 1
(0.33x mmol) in anhydrous THF (ca. 1.5 mL per mmol of
furanone 1). The reaction mixture was stirred at this temperature
for 2 h, then quenched with sat. aq. NH4Cl solution at −78 °C,
and allowed to warm to RT; the grey precipitate was filtered off
through a plug of Celite® (washing through thoroughly with
ether). The filtrate was washed with brine, the combined organic
layers were dried (MgSO4), filtered and concentrated in vacuo
giving, in most cases, a pale yellow solution. A mixture of two
diastereoisomers was obtained after rough purification by flash
column chromatography (95:5 petrol:ethyl acetate), from which
the major lactone was then isolated by a second, more careful,
chromatography step.
Scheme 9 Reagents:
(i)
LHMDS,
(Z)-EtCHCHCH2Br;
(ii) MeP(O)(OMe)2, BuLi, (LiBr), THF, −78 °C → 20 °C; (iii) TBAF;
(iv) TESCl, Et3N, DMAP.
is epimerised, under these conditions, subsequent to con-
jugate addition. We have also shown that tandem lactone
cleavage and Horner–Wadsworth–Emmons reaction affords
4-alkylcyclopentenones in a synthetically useful sense to gene-
rate di- and tri-substituted cyclopentenones. These latter reac-
tions are sensitive to the steric environment about the lactone
carbonyl and large 4-alkyl substituents appear to impede enone
formation. During this work we were not able to identify a
general practical route to alkylcyclopentenones based on this
route, but the availability of simple 3,4-dialkyl derivatives of
menthyloxybutyrolactone as single stereoisomers is of consider-
able synthetic value. For example, as a generic reaction for the
construction of 2,3-dialkylbutane-1,4-diols in five steps from
furfuraldehyde, lactone 9 was reduced in high yield to give diol
22 (Scheme 10).
(4R,5R)-4-Methyl-5-(l-menthyloxy)dihydro-2-furanone8d,g 2a
General procedure A [furanone 1 (100 mg, 0.42 mmol), R = Me]
gave the title compound (2a) as a white solid (5 mg, 5%). Rf
0.24 (9:1 petrol:ethyl acetate); m.p. 78–80 °C (lit.8d,g m.p.
78.2–79.8 °C); mmax (KBr disc)/cm−1 3020s, 2958s, 2927s, 1777s,
1456m, 1215s, 1122m, 931m, 906m, 756s; dH (500 MHz, CDCl3)
0.77 (3H, d, J 6.9, C(10)H3), 0.89 (3H, d, J 6.6, C(8)H3), 0.95
(3H, d, J 6.6, C(9)H3), 0.77–0.97 (2H, m, C(4)H, C(6)H),
0.95–1.09 (1H, m, C(3)H), 1.13 (3H, d, J 7.2, C(1)H3), 1.17–1.25
(1H, m, C(2)H), 1.34–1.43 (1H, m, C(7)H), 1.59–1.70 (2H, m,
C(3)H, C(4)H), 2.05–2.10 (2H, m, C(5)H, C(6)H), 2.11 (1H,
dd, J 17.5, 4.0, C(3)HA), 2.38–2.41 (1H, m, C(4)H), 2.84 (1H,
dd, J 17.5, 8.2, C(3)HB), 3.51 (1H, td, J 10.7, 4.2, C(1)H), 5.28
(1H, d, J 2.2, C(5)H); dC (125 MHz, CDCl3) 15.6, 17.0, 20.8,
22.1, 22.9, 25.3, 31.5, 34.2, 35.4, 36.2, 39.7, 47.6, 76.6, 106.0,
Scheme 10 Reagents: LiAlH4, THF, 82%.
+
176.1; m/z (CI, NH3) 272 (MNH4 , 20%), 255 (MH+, 60), 134
Experimental
(100), 99 (60), 81 (60); HRMS (ES) found 272.2227, calculated
+
for C15H30NO3 (MNH4 ) 272.2226.
For general experimental procedures see reference 4b.
Note on numbering: In the menthyloxy dihydrofuranones,
C4 side chain protons are indicated with ; menthyl protons
with ; C3 side chain protons with . In the cyclopentenones, C4
side chain protons are indicated with ; C5 side chain protons
with .
(4R,5R)-4-Butyl-5-(l-menthyloxy)dihydro-2-furanone 2b
General procedure A [furanone 1 (100 mg, 0.42 mmol), R = Bu]
gave the title compound (2b) and its C5-epimer (3b) in a 4.2:1
ratio (95 mg, 76%) from which the major diastereomer (2b)
was obtained as colourless crystals (76 mg, 61%). Rf 0.34
(95:5 petrol:ethyl acetate); m.p. 62–65 °C; [a]2D2 = −145.5 (c
0.4, CHCl3); mmax (KBr disc)/cm−1 2956s, 2927s, 2871s, 1788s,
1457m, 1370s, 1167s, 1129s, 941s; dH (400 MHz, CDCl3) 0.77
(3H, d, J 6.4, C(10)H3), 0.90 (3H, d, J 6.4, C(8)H3), 0.90 (3H,
t, J 8.4, C(4)H3), 0.93 (3H, d, J 6.4, C(9)H3), 0.77–0.97 (2H,
m, C(4)H, C(6)H), 0.94–1.05 (1H, m, C(3)H), 1.17–1.42 (7H,
m, C(1)H, C(2,3)2H4, C(2)H, C(7)H), 1.50–1.57 (1H, m,
C(1)H), 1.60–1.70 (2H, m, C(3)H, C(4)H), 2.02–2.12 (2H, m,
C(5)H, C(6)H), 2.16 (1H, dd, J 17.6, 4.4, C(3)HA), 2.22–2.28
(1H, m, C(4)H), 2.78 (1H, dd, J 17.6, 8.4, C(3)HB), 3.49 (1H, td,
J 10.8, 4.0, C(1)H), 5.34 (1H, d, J 2.4, C(5)H); dC (100.6 MHz,
CDCl3) 13.9, 15.6, 20.9, 22.5, 22.6, 23.1, 25.4, 29.1, 31.3, 31.6,
33.9, 34.3, 39.8, 41.6, 47.7, 76.9, 105.0, 176.1; m/z (CI, NH3) 297
(MH+, 15%), 176 (100), 159 (15); HRMS (ES) found 297.2430,
calculated for C18H33O3 (MH+) 297.2430. (4R,5S)-4-Butyl-5-
General procedure A (for 1,4-addition of organocopper reagents
derived from commercial organolithiums)
A solution of organolithium RLi (x mmol) was added to a cold
(−78 °C) slurry of CuI (x mmol, pre-dried by evaporation with
toluene) in anhydrous THF (ca. 2.5 mL per mmol of RLi). With
vigorous stirring, the black reaction mixture was allowed to
warm to −25 °C over 20 min, cooled to −78 °C and BF3·Et2O
(x mmol) was added followed by a solution of furanone 1
(0.33x mmol) in anhydrous THF (ca. 3 mL per mmol of
furanone 1). The reaction mixture was stirred at this temperature
for 2 h, then quenched with sat. aq. NH4Cl solution at −78 °C,
and allowed to warm to RT; the grey precipitate was filtered
off through a plug of Celite® (washing through thoroughly
with ether). The filtrate was washed with brine and the organic
layer dried (MgSO4), filtered and concentrated in vacuo giving,
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 9 8 8 – 2 9 9 7
2 9 9 1

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(l-menthyloxy)dihydro-2-furanone (3b) was also obtained, as a
colourless oil (18 mg, 15%). Rf 0.33 (95:5 petrol:ethyl acetate);
dH (400 MHz, CDCl3) 0.76 (3H, d, J 6.8, C(10)H3), 0.89 (3H,
d, J 6.8, C(8)H3), 0.90 (3H, t, J 6.4, C(4)H3), 0.91 (3H, d, J
6.8, C(9)H3), 0.76–1.03 (3H, m, C(3)H, C(4)H, C(6)H),
1.21–1.65 (10H, m, C(1–3)3H6, C(2)H, C(3)H, C(4)H,
C(7)H), 2.08–2.20 (2H, m, C(5)H, C(6)H), 2.29–2.48 (3H, m,
C(3)H2, C(4)H), 3.37 (1H, td, J 10.4, 4.4, C(1)H), 5.47 (1H, d, J
4.8, C(5)H); dC (100.6 MHz, CDCl3) 13.9, 15.7, 21.1, 22.1, 22.4,
25.1, 28.0, 29.9, 31.4, 33.1, 34.1, 41.6, 42.7, 48.4, 81.4, 106.0,
1.33–1.48 (2H, m, C(1 )H2), 1.60–1.71 (4H, m, C(2)H2, C(3)H,
C(4)H), 2.07–2.19 (2H, m, C(5)H, C(6)H), 2.19 (1H, dd, J
17.6, 4.6, C(3)HA), 2.27–2.33 (1H, m, C(4)H), 2.82 (1H, dd, J
17.6, 8.4, C(3)HB), 3.52 (1H, td, J 10.8, 4.4, C(1)H), 4.98–5.07
(2H, m, C(4)H2), 5.38 (1H, d, J 2.4, C(5)H), 5.78 (1H, app. ddt,
app. J 17.0, 10.0, 6.4, C(3)H); dC (100.6 MHz, CDCl3) 15.5, 20.9,
22.2, 23.0, 25.4, 31.0, 31.1, 31.3, 33.8, 34.3, 39.8, 41.0, 47.7, 76.7,
+
104.9, 115.8, 137.0, 175.9; m/z (CI, NH3) 312 (MNH4 , 5%),
295 (MH+, 10), 174 (50), 156 (35), 138 (50), 123 (45), 95 (100),
81 (85); HRMS (ES) found 295.2272, calculated for C18H31O3
(MH+) 295.2273. The minor diastereomer (3d) exhibits a distinc-
tive resonance in the 1H NMR spectrum at d 5.47 (1H, d, J 4.7).
+
176.7 (one resonance not seen); m/z (CI, NH3) 314 (MNH4 ,
20%), 297 (MH+, 40), 176 (100), 158 (30); HRMS (ES) found
297.2430, calculated for C18H33O3 (MH+) 297.2430.
(4R,5R)-4-(6-Chlorohexyl)-5-(l-menthyloxy)dihydro-2-furanone
2e
(4S,5S)-4-Butyl-5-(l-menthyloxy)dihydro-2-furanone 2b
General procedure A [furanone 1 (100 mg, 0.42 mmol), R = Bu]
gave the title compound (2b) and its C5-epimer (3b) in a 4.5:1
ratio (68 mg, 55%) from which the major diastereomer (2b) was
isolated as a colourless oil (56 mg, 45%). Rf 0.70 (7:3 petrol:ethyl
acetate); [a]22 = +26.9 (c 0.80, CHCl3); mmax (thin film)/cm−1
2959s, 2924sD, 2872s, 1779s, 1458m, 1422m, 1370s, 1167s, 1129s,
941s; dH (400 MHz, CDCl3) 0.79 (3H, d, J 6.9, C(10)H3), 0.90
(3H, d, J 6.8, C(8)H3), 0.91 (3H, t, J 6.8, C(4)H3), 0.92 (3H, d,
J 6.8, C(9)H3), 0.77–0.97 (2H, m, C(4)H, C(6)H), 0.95–1.07
(1H, m, C(3)H), 1.21–1.39 (7H, m, C(1)H, C(2,3)2H4,
C(2)H, C(7)H), 1.51–1.59 (1H, m, C(1)H), 1.59–1.67 (2H,
m, C(3)H, C(4)H), 2.03–2.10 (1H, m, C(5)H), 2.14 (1H, dd,
J 17.6, 5.2, C(3)HB), 2.14–2.20 (1H, m, C(6)H), 2.29–2.35 (1H,
m, C(4)H), 2.78 (1H, dd, J 17.6, 8.7, C(3)HA), 3.38 (1H, td, J
10.7, 4.4, C(1)H), 5.23 (1H, d, J 3.0, C(5)H); dC (100.6 MHz,
CDCl3) 13.8, 16.1, 21.0, 22.1, 22.4, 23.1, 25.6, 29.2, 31.3, 31.6,
34.0, 34.1, 41.9, 42.7, 48.2, 82.2, 110.3, 183.9; m/z (CI, NH3) 297
(MH+, 15%), 176 (100), 159 (15); HRMS (ES) found 297.2430,
calculated for C18H33O3 (MH+) 297.2430.
General procedure B [furanone 1 (700 mg, 2.94 mmol), R = 6-
chlorohexyl] gave the title compound (2e) and its C5-epimer (3e)
in a 3.5:1 ratio (908 mg, 86%) from which a sample of the major
diastereomer (2e) was isolated, as a colourless oil, for analytical
purposes. Rf 0.32 (9:1 petrol:ethyl acetate); [a]2D2 = −136.3 (c 1.0,
EtOH); mmax (thin film)/cm−1 2929s, 2860s, 1787s, 1456s, 1420m,
1370m, 1165s, 1108s, 939s; dH (400 MHz, CDCl3) 0.77 (3H, d, J
6.5, C(10)H3), 0.88 (3H, d, J 6.5, C(8)H3), 0.94 (3H, d, J 6.5,
C(9)H3), 0.87–0.91 (2H, m, C(4)H, C(6)H), 0.98–1.03 (1H, m,
C(3)H), 1.21–1.29 (2H, m, C(2)H, C(7)H), 1.32–1.36 (5H, m,
C(1)H, C(2,3)2H4), 1.42–1.46 (2H, m, C(4)H2), 1.53–1.57 (1H,
m, C(1)H), 1.62–1.69 (2H, m, C(3)H, C(4)H), 1.76 (2H, quin.,
J 6.8, C(5)H2), 2.06–2.10 (2H, m, C(5)H, C(6)H), 2.17 (1H,
dd, J 17.5, 4.5, C(3)HA), 2.23–2.31 (1H, m, C(4)H), 2.80 (1H, dd,
J 17.5, 8.4, C(3)HB), 3.50 (1H, td, J 10.7, 4.2, C(1)H), 3.53 (2H,
t, J 6.8, C(6)H2), 5.35 (1H, d, J 2.4, C(5)H); dC (100.6 MHz,
CDCl3) 15.6, 20.9, 22.2, 23.0, 25.4, 26.6, 26.8, 28.6, 31.3, 31.8,
32.4, 33.9, 34.2, 39.8, 41.5, 44.9, 47.7, 76.7, 105.0, 176.1; m/z
(CI, NH3) 361 (M37ClH+, 3%), 359 (M35ClH+, 10), 238 (95), 202
(100), 185 (30), 167 (30), 38 (65), 95 (40), 81 (45); HRMS (ES)
found 359.2353, calculated for C20H36O335Cl (MH+) 359.2355.
The minor diastereomer (3e) exhibits a distinctive resonance in
the 1H NMR spectrum at d 5.48 (1H, d, J 4.7).
(4R,5R)-4-Isobutyl-5-(l-menthyloxy)dihydro-2-furanone 2c
General procedure A (furanone 1 (100 mg, 0.42 mmol),
R = isobutyl) gave the title compound (2c) and its C5-epimer (3c)
in a 3:1 ratio (77 mg, 62%) from which the major diastereomer
(2c) was isolated as a pale yellow oil (57 mg, 46%). Rf 0.61 (9:1
petrol:ethyl acetate); [a]2D2 = −107.3 (c 0.34, CHCl3); mmax (thin
film)/cm−1 2960s, 2928s, 2872s, 1777s, 1106m, 930m, 756s, 670s;
dH (400 MHz, CDCl3) 0.79 (3H, d, J 7.0, C(10)H3), 0.89 (3H, d,
J 6.5, C(8)H3), 0.91 (3H, d, J 6.5, C(9)H3), 0.94 (2 × 3H, 2 × d,
J 6.5, C(3)H3, C(4)H3), 0.77–0.97 (2H, m, C(4)H, C(6)H),
0.95–1.07 (1H, m, C(3)H), 1.20–1.34 (2H, m, C(1)H, C(2)H),
1.34–1.44 (2H, m, C(1)H, C(7)H), 1.59–1.70 (3H, m, C(2)H,
C(3)H, C(4)H), 2.05–2.13 (2H, m, C(5)H, C(6)H), 2.16 (1H,
dd, J 17.5, 4.5, C(3)HA), 2.34–2.40 (1H, m, C(4)H), 2.80 (1H, dd,
J 17.5, 8.4, C(3)HB), 3.51 (1H, td, J 10.7, 4.2, C(1)H), 5.33 (1H,
d, J 2.4, C(5)H); dC (100.6 MHz, CDCl3) 15.5, 20.8, 22.1, 22.2,
22.6, 22.9, 25.3, 25.7, 31.2, 34.0, 34.2, 39.5, 39.7, 40.9, 47.6, 76.7,
105.1, 176.1; m/z (CI, NH3) 314 (MNH4+, 20%), 297 (MH+, 30),
176 (100), 159 (20); HRMS (ES) found 297.2429, calculated for
C18H33O3 (MH+) 297.2430. The minor diastereomer (3c) exhibits
a distinctive resonance in the 1H NMR spectrum at d 5.45 (1H,
d, J 4.8).
(4R,5R)-5-(l-Menthyloxy)-4-(oct-7-enyl)-4-dihydro-2-furanone 2f
General procedure B [furanone 1 (2.5 g, 10.6 mmol), R = oct-
7-enyl], gave the title compound (2f) and its C5-epimer (3f) in
a 2.2:1 ratio (2.74 g, 74%) from which the major diastereomer
(2f) was isolated as a colourless oil (1.44 g, 39%). Rf 0.48 (9:1
petrol:ethyl acetate); [a]2D2 = −124.6 (c 1.0, CHCl3); mmax (thin
film)/cm−1 2927s, 2856s, 1790s, 1641w, 1456m, 1164m, 1106m,
941m; dH (400 MHz, CDCl3) 0.74 (3H, d, J 6.8, C(10)H3), 0.84
(3H, d, J 6.8, C(8)H3), 0.90 (3H, d, J 6.8, C(9)H3), 0.86–0.92
(2H, m, C(4)H, C(6)H), 0.91–1.02 (1H, m, C(3)H), 1.15–1.38
(11H, m, C(1)H, C(2–5)3H8, C(2)H, C(7)H), 1.49–1.53 (1H,
m, C(1)H), 1.57–1.67 (2H, m, C(3)H, C(4)H), 1.97–2.07
(4H, m, C(6)H2, C(5)H, C(6)H), 2.12 (1H, dd, J 18.0, 4.4,
C(3)HA), 2.19–2.26 (1H, m, C(4)H), 2.74 (1H, dd, J 18.0, 8.4,
C(3)HB), 3.47 (1H, td, J 10.4, 4.4, C(1)H), 4.87–4.97 (2H, m,
C(8)H2), 5.31 (1H, d, J 2.3, C(5)H), 5.76 (1H, app. ddt, app. J
17.2, 10.4, 6.8, C(7)H); dC (50.3 MHz, CDCl3) 16.0, 21.3, 22.6,
23.5, 25.8, 27.3, 29.1, 29.2, 29.6, 31.7, 32.3, 34.0, 34.3, 34.7, 40.3,
41.9, 48.1, 77.5, 105.4, 114.7, 139.2, 176.4; m/z (CI, NH3) 368
(MNH4+, 5%), 351 (MH+, 15), 230 (100), 214 (20), 212 (15), 156
(10), 138 (20), 95 (20); HRMS (CI) found 368.3177, calculated
for C22H42NO3 (MNH4+) 368.3165. The minor diastereomer (3f)
(4R,5R)-4-(But-3-enyl)-5-(l-menthyloxy)dihydro-2-furanone 2d
General procedure B [furanone 1 (100 mg, 0.42 mmol), R = but-
3-enyl] gave the title compound (2d) and its C5-epimer (3d) in
a 4:1 ratio (78 mg, 63%) from which the major diastereomer
(2d) was obtained as pale yellow crystals (62 mg, 50%). Rf 0.62
(9:1 petrol:ethyl acetate); m.p. 49–53 °C; [a]2D2 = −132.9 (c 1.0,
CHCl3); mmax (KBr disc)/cm−1 2957s, 2928s, 2870s, 1778s, 1456m,
1418m, 1370m, 1170m, 1110m, 937s, 757s; dH (400 MHz, CDCl3)
0.79 (3H, d, J 6.8, C(10)H3), 0.89 (3H, d, J 6.8, C(8)H3), 0.95
(3H, d, J 6.8, C(9)H3), 0.78–0.95 (2H, m, C(4)H, C(6)H),
0.95–1.05 (1H, m, C(3)H), 1.19–1.29 (2H, m, C(2)H, C(7)H),
1
exhibits a distinctive resonance in the H NMR spectrum at d
5.44 (1H, d, J 4.8).
(4R,5R)-4-[8-(tert-Butyldiphenylsilanyloxy)octyl]-5-(l-
menthyloxy)dihydro-2-furanone 2g
General procedure B [furanone 1 (1.0 g, 4.2 mmol), R = 8-
(tert-butyldiphenylsilanyloxy)octyl] gave the title compound
(2g) and its C5-epimer (3g) in a 2.2:1 ratio from which the
2 9 9 2
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 9 8 8 – 2 9 9 7

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major diastereomer (2g) was isolated as a colourless oil (1.37 g,
54%). Rf 0.51 (9:1 petrol:ethyl acetate); [a]2D2 = −72.2 (c 1.2,
CHCl3); mmax (thin film)/cm−1 3071w, 2929s, 2856s, 1789s, 1462s,
1428s, 1388m, 1361m, 1164s, 1111s, 939s, 823m, 740m, 702s; dH
(400 MHz, CDCl3) 0.81 (3H, d, J 6.8, C(10)H3), 0.91 (3H, d,
J 6.8, C(8)H3), 0.96 (3H, d, J 6.8, C(9)H3), 0.86–1.06 (3H, m,
C(3)H, C(4)H, C(6)H), 1.08 (9H, s, t-Bu), 1.22–1.41 (13H,
m, C(1)H, C(2–6)5H10, C(2)H, C(7)H), 1.54–1.62 (1H, m,
C(1)H), 1.58 (2H, quin., J 6.8, C(7)H2), 1.64–1.71 (2H, m,
C(3)H, C(4)H), 2.09–2.14 (2H, m, C(5)H, C(6)H), 2.18 (1H,
dd, J 17.6, 4.4, C(3)HA), 2.26–2.30 (1H, m, C(4)H), 2.81 (1H,
dd, J 17.6, 8.4, C(3)HB), 3.53 (1H, td, J 10.4, 4.4, C(1)H), 3.68
(2H, t, J 6.8, C(8)H2), 5.37 (1H, d, J 2.3, C(5)H), 7.37–7.46
(6H, m, Ph), 7.69–7.71 (4H, m, Ph); dC (100.6 MHz, CDCl3)
15.6, 19.2, 20.9, 22.3, 23.1, 25.4, 25.7, 26.9, 27.0, 29.2, 29.4,
31.4, 31.9, 32.5, 33.9, 34.3, 39.9, 41.6, 47.8, 63.9, 77.0, 105.1,
127.6, 129.5, 134.2, 135.6, 176.1; m/z (CI, NH3) 629 (M + Na,
25%), 579 (100), 301 (80), 279 (85%); m/z (CI, ES) 629 (MNa+,
25%), 578 (100), 300 (80), 278 (85); HRMS (CI) found 607.4183,
calculated for C38H59O4Si (MH+) 607.4183. (4R,5S)-4-[8-(tert-
Butyldiphenylsilanyloxy)octyl]-5-(l-menthyloxy)dihydrofuran-
2-one 3g was also obtained, as a colourless oil (640 mg, 25%).
Rf 0.49 (9:1 petrol:ethyl acetate); [a]2D2 = −2.5 (c 1.1, CHCl3);
mmax (thin film)/cm−1 3071w, 3050w, 2929s, 2857s, 1790s, 1464m,
1428m, 1387w, 1361w, 1330w, 1184w, 1112s, 961m, 921m,
823m, 737m, 702m; dH (400 MHz, CDCl3) 0.78 (3H, d, J 6.8,
C(10)H3), 0.92 (3H, d, J 6.8, C(8)H3), 0.93 (3H, d, J 6.8,
C(9)H3), 0.86–1.10 (3H, m, C(3)H, C(4)H, C(6)H), 1.08
(9H, s, t-Bu), 1.25–1.41 (13H, m, C(1)H, C(2–6)5H10, C(2)H,
C(7)H), 1.50–1.68 (5H, m, C(1)H, C(7)H2, C(3)H, C(4)H),
2.13–2.49 (5H, m, C(3)H2, C(4)H, C(5)H, C(6)H), 3.39 (1H,
td, J 10.8, 4.4, C(1)H), 3.68 (2H, t, J 6.4, C(8)H2), 5.49 (1H, d,
J 4.6, C(5)H), 7.68–7.71 (6H, m, Ph), 7.73–7.76 (4H, m, Ph); dC
(100.6 MHz, CDCl3) 15.8, 19.2, 21.2, 22.2, 22.7, 25.2, 25.8, 26.6,
26.9, 27.8, 28.3, 29.3, 29.4, 31.6, 32.2, 33.1, 34.2, 41.6, 42.7, 48.4,
63.9, 81.4, 106.0, 127.6, 129.5, 134.1, 134.8, 135.6, 176.7; m/z
(CI, NH3) 629 (M + Na, 25%), 579 (100), 301 (80), 279 (85%);
HRMS (CI) found 607.4177, calculated for C38H59O4Si (MH+)
607.4183.
1105m, 905s, 732s; dH (400 MHz, CDCl3) 0.78 (3H, d, J 6.9,
C(10)H3), 0.89 (3H, d, J 6.8, C(8)H3), 0.92 (9H, s, t-Bu), 0.94
(3H, d, J 6.8, C(9)H3), 0.77–0.97 (2H, m, C(4)H, C(6)H),
0.95–1.07 (1H, m, C(3)H), 1.17–1.25 (1H, m, C(2)H), 1.34–
1.43 (1H, m, C(7)H), 1.61–1.68 (2H, m, C(3)H, C(4)H),
2.04–2.15 (3H, m, C(4)H, C(5)H, C(6)H), 2.35 (1H, dd, J
18.4, 4.7, C(3)HA), 2.69 (1H, dd, J 18.4, 9.8, C(3)HB), 3.52
(1H, td, J 10.7, 4.2, C(1)H), 5.52 (1H, d, J 2.3, C(5)H); dC
(100.6 MHz, CDCl3) 15.6, 20.9, 22.3, 23.0, 25.4, 26.8, 29.9,
31.3, 31.4, 34.3, 39.8, 47.8, 51.4, 76.7, 102.3, 176.6; m/z (CI,
+
NH3) 314 (MNH4 , 20%), 297 (MH+, 85), 176 (100), 159 (70),
138 (30); HRMS (ES) found 297.2438, calculated for C18H33O3
(MH+) 297.2430.
(4R,5R)-4-Phenyl-5-(l-menthyloxy)dihydro-2-furanone 2j
General procedure A [furanone 1 (100 mg, 0.42 mmol), R = Ph]
gave the title compound (2j) as a pale yellow crystalline solid
(33 mg, 25%); no other significant minor diastereomers were
1
visible in the H NMR spectrum of the crude material. Rf
0.40 (9:1 petrol:ethyl acetate); m.p. 79–85 °C; [a]2D2 = −140.6 (c
0.15, CHCl3); mmax (KBr disc)/cm−1 2956s, 2922s, 2855s, 1783s,
1454m, 1100m, 910s, 731s; dH (400 MHz, CDCl3) 0.82 (3H, d, J
6.9, C(10)H3), 0.88 (3H, d, J 6.8, C(8)H3), 0.90 (3H, d, J 6.8,
C(9)H3), 0.82–0.97 (2H, m, C(4)H, C(6)H), 0.95–1.06 (1H, m,
C(3)H), 1.22–1.29 (1H, m, C(2)H), 1.29–1.39 (1H, m, C(7)H),
1.63–1.68 (2H, m, C(3)H, C(4)H), 1.95–2.00 (1H, m, C(6)H),
2.04–2.14 (1H, m, C(5)H), 2.63 (1H, dd, J 17.8, 4.6, C(3)HA),
3.13 (1H, dd, J 17.8, 9.1, C(3)HB), 3.50–3.55 (1H, m, C(4)H),
3.55 (1H, td, J 10.8, 4.4, C(1)H), 5.59 (1H, d, J 2.5, C(5)H),
7.15–7.40 (5H, m, Ph); dC (100.6 MHz, CDCl3) 15.6, 20.9, 22.2,
23.0, 25.5, 31.3, 34.2, 35.1, 39.7, 47.2, 47.7, 77.3, 105.6, 126.7,
127.7, 129.1, 139.2, 175.8; m/z (CI, NH3) 317 (MH+, 25%), 196
(30), 179 (10), 104 (100); HRMS (ES) found 317.2117, calculated
for C20H29O3 (MH+) 317.2106.
(1S,4S)-[4-(6-Chlorohexyl)-1-hydroxycyclopent-2-en-1-
ylmethyl]phosphoric acid dimethyl ester 8
A solution of dimethyl methylphosphonate (57 lL, 0.53 mmol)
in THF (2.0 mL) was treated at −78 °C with n-BuLi (328 lL of
a 1.6 M solution in hexane, 0.53 mmol). After 30 min, a solution
of (S)-4-(6-chlorohexyl)cyclopent-2-enone18 (ent-7, 100 mg,
0.50 mmol) in THF (0.5 mL) was added to give a yellow solu-
tion. After a further 40 min, the reaction was quenched with
water (0.5 mL), extracted with ethyl acetate (3 × 5 mL), dried
(MgSO4) and concentrated in vacuo. The title compound (8) was
obtained as a pale yellow oil (98 mg, 61%; 81% based on recov-
ered ent-7) after purification by flash column chromatography
(99:1 dichloromethane:methanol). Rf 0.33 (95:5 dichloro-
methane:methanol); [a]D22 = −57.8 (c 1.0, CHCl3); dH (400 MHz,
CDCl3) 1.25–1.50 (8H, m, C(1–4)4H8), 1.63 (1H, ddd, J 13.2,
6.4, 2.4, C(5)H), 1.75 (2H, quin., J 6.8, C(5)H2), 2.13 (2H, d, J
17.2, C(1)H2), 2.30 (1H, dd, J 13.2, 7.6, C(5)H), 2.57 (1H, app.
quin., app. J 6.4, C(4)H), 3.51 (2H, t, J 6.8, C(6)H2), 3.73 (3H,
d, J 4.4) and 3.76 (3H, d, J 4.4, 2 × OCH3), 3.90 (1H, br.s, –OH),
5.76–5.80 (2H, m, C(2)H, C(3)H); dC (100.6 MHz, CDCl3) 26.8,
27.6, 28.9, 32.5, 35.8, 35.9 (d, J 133), 44.1, 45.1, 45.9 (d, J 10),
52.3 (two peaks, 2 × d, J 7), 81.7 (d, J 5), 135.5 (d, J 10), 137.2;
m/z (ES) 347 (M35ClNa+, 100%), 307 (50); HRMS (ES) found
347.1162, calculated for C14H27O435ClPNa (MNa+) 347.1155.
(4R,5R)-4-(2-Butyl)-5-(l-menthyloxy)dihydro-2-furanone 2h
General procedure A [furanone 1 (100 mg, 0.42 mmol),
R = s-Bu] gave a mixture of two diastereoisomers from which
the major diastereomer (2h) was isolated as a colourless oil
(51 mg, 41%) and as a 1 : 1 epimeric mixture at C2. Rf 0.60
(9 : 1 petrol : ethyl acetate); mmax (thin film)/cm−1 3054s, 2926s,
1778s, 1422s, 1265s, 740s; dH (400 MHz, CDCl3) 0.78 (3H,
d, J 6.9, C(10)H3), 0.88 (3H, d, J 7.0, C(8)H3), 0.91 (3H, t,
J 7.5, C(4)H3), 0.93 (3H, d, J 6.0, C(2)H3), 0.94 (3H, d, J
7.0, C(9)H3), 0.77–1.05 (3H, m, C(3)H, C(4)H, C(6)H),
1.14–1.58 (5H, m, C(2)H, C(3)H2, C(2)H, C(7)H), 1.62–
1.70 (2H, m, C(3)H, C(4)H), 2.06–2.12 (2H, m, C(5)H,
C(6)H), 2.17–2.41 (2H, m, C(3)HA, C(4)H), 2.68 (0.5H, dd,
J 18.5, 10.5) and 2.76 (0.5H, dd, J 17.5, 8.5, C(3)HB), 3.51
(0.5H, td, J 10.5, 4.0) and 3.52 (0.5H, td, J 10.5, 4.0, C(1)H),
5.45 (0.5H, d, J 2.6) and 5.46 (0.5H, d, J 2.4, C(5)H); dC
(100.6 MHz, CDCl3) 11.6, 11.7, 15.9, 16.1, 16.3, 21.4, 22.7
(C9), 23.5, 25.8, 27.0, 27.3, 31.0, 31.8, 32.6, 34.7, 36.1, 36.8,
40.3, 46.3, 46.6, 48.2, 77.5, 103.8, 104.4, 176.3; m/z (CI, NH3)
+
314 (MNH4 , 10%), 297 (MH+, 35), 176 (100), 100 (55), 95
(65); HRMS (ES) found 297.2430, calculated for C18H33O3
(3R,4R,5R)-4-Butyl-5-(l-menthyloxy)-3-(3-methylbut-2-enyl)-
dihydro-2-furanone 9
(MH+) 297.2430.
(4R,5R)-4-tert-Butyl-5-(l-menthyloxy)dihydro-2-furanone 2i
General procedure C (for lactone alkylations)
General procedure A [furanone 1 (100 mg, 0.42 mmol), R = t-
Bu] gave the title compound (2i) as a colourless oil (55 mg,
44%); no other significant minor diastereomers were visible
To a solution of lactone 2b (380 mg, 1.28 mmol) in THF (6 mL)
was added at −78 °C a solution of LiHMDS [prepared from
n-BuLi (642 lL of a 1.6 M solution in hexanes, 1.03 mmol) and
HMDS (214 lL, 1.03 mmol) in THF (4 mL)]. After 30 min, 4-
bromo-2-methyl-2-butene (118 lL, 1.03 mmol) was added to the
yellow solution and the mixture was stirred at −78 °C for 40 min
1
in the H NMR spectrum of the crude material. Rf 0.53 (9:1
petrol:ethyl acetate); [a]2D2 = −157.7 (c 0.7, CHCl3); mmax(thin
film)/cm−1 2954s, 2920s, 2862s, 1774s, 1468m, 1375m, 1179m,
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 9 8 8 – 2 9 9 7
2 9 9 3

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then quenched with water (10 mL) before being allowed to warm
up to RT. Extraction with ether (3 × 10 mL), drying (MgSO4),
solvent evaporation in vacuo, and purification by flash column
chromatography on silica gel (98:2 petrol:ether) afforded the
title compound (9) as a colourless oil (204 mg, 54%; 92% based on
recovered 2b). Rf 0.20 (95:5 petrol:ethyl acetate); [a]2D2 = −138.1
(c 1.0, CHCl3); mmax (thin film)/cm−1 2960s, 2921s, 2862s, 1777s,
1679w, 1458s, 1374s, 1320m, 1163m, 1109s, 941s; dH (400 MHz,
CDCl3) 0.78 (3H, d, J 6.8, C(10)H3), 0.84–0.92 (2H, m, C(4)H,
C(6)H), 0.89 (3H, d, J 6.8, C(8)H3), 0.91 (3H, t, J 6.8, C(4)H3),
0.94 (3H, d, J 6.8, C(9)H3), 1.00 (1H, qd, J 12.8, 3.6, C(3)H),
1.19–1.50 (8H, m, C(1–3)3H6, C(2)H, C(7)H), 1.62–1.70
(2H, m, C(3)H, C(4)H), 1.64 (3H, s) and 1.72 (3H, s,CMe2),
1.98–2.04 (1H, app. dtd, app. J 8.4, 6.0, 2.8, C(4)H), 2.07–2.12
(1H, m, C(6)H), 2.17 (1H, app. quin.d, J 7.6, 3.2, C(5)H), 2.26
(1H, q, J 6.0, C(3)H), 2.45 (2H, app. t, J 6.0, C(1)H2), 3.52 (1H,
td, J 10.8, 4.0, C(1)H), 5.12 (1H, br t., J 6.0, C(2)H), 5.30 (1H,
d, J 2.8, C(5)H); dC (100.6 MHz, CDCl3) 13.9, 15.5, 17.8, 20.9,
22.3, 22.5, 22.9, 25.4, 25.7, 28.8, 29.3, 31.3, 32.0, 34.3, 39.7, 45.5,
46.5, 47.8, 77.2, 104.4, 120.4, 134.6, 178.2; HRMS (CI) found
365.3056, calculated for C23H41O3 (MH+) 365.3056.
CDCl3) 13.9, 17.8, 22.7, 25.8, 29.1, 29.7, 34.0, 47.0, 51.7, 120.8,
132.8, 133.7, 167.6, 212.1; m/z (CI, NH3) 207 (MH+, 100%), 191
(10), 148 (10), 138 (15); HRMS (CI) found 207.1749, calculated
for C14H23O (MH+) 207.1749.
(4S)-4-Butyl-5,5-bis(3-methyl-but-2-enyl)cyclopent-2-en-1-one
12
LiBr (12 mg, 0.14 mmol, dried overnight at 135 °C under
high vacuum) was dissolved in anhydrous THF (0.65 mL)
and cooled to −78 °C. Dimethyl methylphosphonate (15 lL,
0.14 mmol) and n-BuLi (87 lL of a 1.6 M solution in hexanes,
0.14 mmol) were added successively and the mixture was stirred
at −78 °C for 30 min. Lactone 10 (60 mg, 0.14 mmol) in THF
(0.3 mL) was added, resulting in a yellow solution. The mixture
was stirred at −78 °C for 2 h then allowed to reach RT over
3 h. After addition of water (2 mL), the product was extracted
with ethyl acetate (3 × 5 mL), dried (Na2SO4), filtered, and
evaporated in vacuo. Purification by flash column chromato-
graphy (silica, 99:1 petrol:ether) gave the title compound (12)
as a colourless oil (21 mg, 55%; 72% based on recovered 10).
Rf 0.60 (9:1 petrol:ethyl acetate); [a]2D2 = +77.7 (c 0.3, CHCl3);
mmax (thin film)/cm−1 2954s, 2919s, 2850s, 1703s, 1453m, 1379m,
1254w, 1193w, 1103w, 1042w; dH (400 MHz, CDCl3) 0.94 (3H,
t, J 6.8, C(4)H3), 1.24–1.43 (6H, m, C(1–3)3H6), 1.57 and 1.59
(2 × 3H, 2 × s) and 1.66 (6H, s, 2 × CMe2), 2.11–2.22 (4H, m,
2 × C(1)H2), 2.61–2.66 (1H, m, C(4)H), 4.94 and 5.05 (2 × 1H,
2 × br t, J 7.2, 2 × CH), 6.12 (1H, dd, J 5.6, 2.4, C(2)H), 7.62
(1H, dd, J 5.6, 2.4, C(3)H); dC (100.6 MHz, CDCl3) 14.0, 17.8,
22.3, 22.6, 25.9, 28.4, 30.6, 32.6, 34.1, 34.5, 49.6, 54.2, 119.7,
120.0, 132.1, 133.0, 134.2, 166.2, 213.9; m/z (CI, NH3) 275
(MH+, 100%), 205 (20), 164 (5), 148 (10); HRMS (CI) found
275.2375, calculated for C19H31O (MH+) 275.2375.
(4R,5R)-4-Butyl-5-l-menthyloxy-3,3-di(3-methylbut-2-enyl)-
dihydro-2-furanone 10
General procedure C [using 2.0 equiv. of LiHMDS and
2.0 equiv. of 4-bromo-2-methyl-2-butene relative to lactone
2b (100 mg, 0.34 mmol)] gave the title compound (10) as a
colourless oil (121 mg, 83%). Rf 0.81 (9:1 petrol:ethyl acetate);
[a]D22 = −133.2 (c 1.0, CHCl3); mmax (thin film)/cm−1 2953s, 2916s,
2860s, 1770s, 1449s, 1380m, 1152m, 1133m, 1096m, 938m; dH
(400 MHz, CDCl3) 0.72–0.92 (2H, m, C(4)H, C(6)H), 0.81
(3H, d, J 6.8, C(10)H3), 0.89 (3H, t, J 8.0, C(4)H3), 0.89 (3H, d,
J 6.8, C(8)H3), 0.93 (3H, d, J 6.8, C(9)H3), 1.00 (1H, qd, J 12.8,
3.6, C(3)H), 1.16–1.43 (8H, m, C(1–3)3H6, C(2)H, C(7)H),
1.60 and 1.61 (2 × 3H, 2 × s) and 1.71 (6H, s, 2 × CMe2),
1.62–1.71 (2H, m, C(3)H, C(4)H), 2.02–2.08 (1H, m, C(6)H),
2.10–2.16 (3H, m, C(4)H, C(1)H, C(5)H), 2.23 (2H, app. q,
app. J 6.8, C(1)H2), 2.38 (1H, dd, J 14.8, 6.8, C(1)H), 3.51
(1H, td, J 10.4, 4.0, C(1)H), 5.04–5.11 (2H, m, 2 × CH), 5.23
(1H, d, J 6.6, C(5)H); dC (100.6 MHz, CDCl3) 13.9, 16.1, 18.0
(two peaks), 20.8, 22.3, 22.8, 23.4, 25.6, 25.9, 26.0, 26.3, 30.1,
31.3, 32.4, 34.3, 34.7, 40.0, 47.1, 47.8, 51.8, 77.9, 104.0, 118.8,
119.2, 134.8, 135.2, 178.9; m/z (CI, NH3) 433 (MH+, 5%), 279
(5), 233 (5), 207 (5), 155 (15), 148 (90), 131 (30), 112 (10), 95
(10), 87 (30), 70 (100); HRMS (CI) found 433.3682, calculated
for C28H49O3 (MH+) 433.3682.
(3S,4R,5R)-4-Butyl-3-(1-hydroxy-2-methylpropyl)-5-(l-
menthyloxy)dihydrofuran-2-one 13
General procedure C [using 1.0 equiv. of LiHMDS and 1.0 equiv.
of isobutyraldehyde relative to lactone 2b (195 mg, 0.66 mmol)]
gave the title compound (13) as a colourless oil (200 mg, 83%).
Rf 0.34 (9:1 petrol:ethyl acetate); [a]2D2 = −107.5 (c 1.0, CHCl3);
mmax (thin film)/cm−1 3508br, 2957s, 2928s, 2872s, 1760s, 1456s,
1371s, 1242s, 1135s, 1042s, 945s, 733w; dH (400 MHz, CDCl3)
0.77 (3H, d, J 6.8, C(10)H3), 0.88 (3H, d, J 6.8, C(8)H3), 0.91
(3H, t, J 7.6, C(4)H3), 0.93 (3H, d, J 6.8, C(9)H3), 0.94 and 1.01
(2 × 3H, 2 × d, J 6.8, –CH(CH3)2), 0.81–1.05 (3H, m, C(3)H,
C(4)H, C(6)H), 1.16–1.26 (1H, m, C(2)H), 1.30–1.42 (5H,
m, C(2,3)2H4, C(7)H), 1.47–1.53 (2H, m, C(1)H2), 1.61–1.69
(2H, m, C(3)H, C(4)H), 1.93 (1H, oct., J 6.8, –CH(CH3)2),
2.06–2.14 (3H, m, C(4)H, C(5)H, C(6)H), 2.40 (1H, app. t,
app. J 6.4, C(3)H), 3.18 (1H, d, J 3.2, –OH), 3.49–3.57 (2H, m,
C(1)H, C(1)H), 5.34 (1H, d, J 3.2, C(5)H); dC (100.6 MHz,
CDCl3) 13.8, 15.5, 16.1, 20.0, 20.9, 22.2, 22.5, 22.9, 25.3, 28.8,
30.5, 31.4, 31.9, 34.2, 39.8, 44.5, 47.7, 49.3, 76.2, 77.8, 104.3,
177.7; HRMS (CI) found 369.3005, calculated for C22H41O4
(MH+) 369.3005.
(4R,5R)-4-Butyl-5,5-di(3-methyl-but-2-enyl)cyclopent-2-en-1-
one 11
LiBr (19 mg, 0.22 mmol, dried overnight at 135 °C under high
vacuum) was dissolved in anhydrous THF (1.0 mL) and cooled
to −78 °C. Dimethyl methylphosphonate (24 lL, 0.22 mmol)
and n-BuLi (137 lL of a 1.6 M solution in hexanes, 0.22 mmol)
were added successively and the mixture was stirred at −78 °C
for 30 min. Lactone 9 (80 mg, 0.22 mmol) in THF (0.5 mL) was
added, resulting in a yellow solution. The mixture was stirred
at −78 °C for 2 h then allowed to reach RT over 3 h. After
addition of water (2 mL), the product was extracted with ethyl
acetate (3 × 5 mL), dried (Na2SO4), filtered, and evaporated in
vacuo. Purification by flash column chromatography (silica, 95:5
petrol:ethyl acetate) gave the title compound (11) as a colourless
oil (27 mg, 60%). Rf 0.45 (9:1 petrol:ethyl acetate); [a]2D2 = +85.6
(c 0.5, CHCl3); mmax (thin film)/cm−1 2960s, 2921s, 2852s, 1705s,
1587m, 1455s, 1376m, 1347m, 1175m; dH (400 MHz, CDCl3) 0.92
(3H, t, J 6.8, C(4)H3), 1.29–1.39 (4H, m, C(2,3)2H4), 1.42–1.53
(2H, m, C(1)H2), 1.62 (3H, s) and 1.69 (3H, d, J 0.8,CMe2),
2.00 (1H, ddd, J 7.2, 5.6, 2.4, C(5)H), 2.23 (1H, ddd, J 14.0, 7.2,
7.2, C(1)H), 2.42 (1H, ddd, J 14.0, 5.6, 5.6, C(1)H), 2.53–2.60
(1H, m, C(4)H), 5.01–5.08 (1H, m, C(2)H), 6.12 (1H, dd, J 5.6,
2.4, C(2)H), 7.60 (1H, dd, J 5.6, 2.4, C(3)H); dC (100.6 MHz,
(4R,5R)-4-Butyl-3-isobutylidene-5-(l-menthyloxy)dihydrofuran-
2-one 14
A solution of aldol adduct 13 (100 mg, 0.27 mmol) in
1,2-dichloroethane (1.5 mL) was treated with methanesulfonyl
chloride (42 lL, 0.54 mmol) and triethylamine (189 lL,
1.35 mmol) for 30 min at 0 °C, then 4 h at reflux. The cooled
reaction was quenched with water (1 mL), extracted with ether
(3 × 5 mL), and the extracts were washed with brine (5 mL). The
combined organic layers were dried (MgSO4) and evaporated in
vacuo. Purification by flash column chromatography on silica
gel (95:5 petrol:ethyl acetate) gave the mesylate, which was dis-
solved in dichloromethane (1 mL) and treated with DBU (57 lL,
0.38 mmol) at RT for 5 h. The solvent was evaporated and the
residue purified by flash column chromatography on silica gel
2 9 9 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 9 8 8 – 2 9 9 7

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(98:2 petrol:ethyl acetate) to give the title compound (14), an
equimolar mixture of the E and Z stereoisomers, as a colourless
oil (80 mg, 84% from 13). Rf 0.70/0.76 (9:1 petrol:ethyl acetate);
mmax (thin film)/cm−1 2957s, 2917s, 2870s, 1767s, 1683s, 1456s,
1386w, 1370m, 1344w, 1298w, 1202m, 1107m, 1072w, 944m;
dH (400 MHz, CDCl3) 0.76–1.08 (21H, m, 6 × CH3, C(3)H,
C(4)H, C(6)H), 1.16–1.56 (8H, m, C(1–3)3H6, C(2)H,
C(7)H), 1.60–1.68 (2H, m, C(3)H, C(4)H), 1.94–2.12 (2H, m,
C(5)H, C(6)H), 2.47–2.57 (0.5H, m, C(2)H), 2.60–2.64 (0.5H,
m, C(4)H), 2.85 (0.5H, ddd, J 7.6, 5.6, 2.0, C(4)H), 3.55 (1H, td,
J 10.4, 4.0, C(1)H), 3.69–3.81 (0.5H, m, C(2)H), 5.28 (0.5H, d,
J 2.0) and 5.38 (0.5H, s, C(5)H), 5.92 and 6.56 (2 × 0.5H, 2 × dd,
J 10.4, 2.0, CH); dC (100.6 MHz, CDCl3) 13.9, 15.8, 20.7, 20.8,
22.0, 22.2, 22.4 (two peaks), 22.5, 23.3, 23.4, 25.5 (two peaks),
26.3, 28.2, 28.5, 29.4, 31.3, 32.2, 32.6, 34.3, 39.8, 44.2, 47.0, 47.7,
47.8, 76.2, 76.3, 101.8, 101.9, 126.2, 127.3, 147.9, 151.4, 168.8,
32.3, 33.7, 34.3, 39.7, 45.2, 45.6, 46.3, 47.8, 77.2, 104.3, 114.3,
124.8, 134.5, 138.9, 177.9; m/z (CI, NH3) 419 (MH+, 25%), 298
(30), 281 (35), 263 (25), 219 (10), 172 (35), 156 (55), 149 (100),
137 (50), 95 (40); HRMS (CI) found 419.3521, calculated for
C27H47O3 (MH+) 419.3525.
(3R,4R,5R)-4-[8-(tert-Butyldiphenylsilanyloxy)octyl]-5-(l-
menthyloxy)-3-[(2Z)-pentenyl]dihydrofuran-2-one 17
General procedure C [using 1.0 equiv. of LiHMDS and 1.0
equiv. of (Z)-1-bromo-2-pentene relative to lactone 2g (163 mg,
0.27 mmol)] gave the title compound (17) as a colourless oil
(156 mg,%). Rf 0.24 (95:5 petrol:ethyl acetate); [a]2D2 = −67.4 (c
1.0, CHCl3); mmax (thin film)/cm−1 3071w, 3049w, 2929s, 2857s,
1778s, 1742s, 1590w, 1462s, 1428s, 1371m, 1330w, 1240m,
1166s, 1111s, 942s, 823m, 702s, 614m; dH (400 MHz, CDCl3)
0.81 (3H, d, J 6.8, C(10)H3), 0.91 (3H, d, J 6.8, C(8)H3), 0.95
(3H, d, J 6.8, C(9)H3), 0.98 (3H, t, J 7.6, C(5)H3), 1.07 (9H,
s, t-Bu), 0.86–1.08 (3H, m, C(3)H, C(4)H, C(6)H), 1.21–1.50
(14H, m, C(1–6)6H12, C(2)H, C(7)H), 1.58 (2H, quin., J
6.8, C(7)H2), 1.63–1.70 (2H, m, C(3)H, C(4)H), 2.01–2.15
(4H, m, C(4)H, C(4)H2, C(6)H), 2.13–2.20 (1H, m, C(5)H),
2.29 (1H, app. q, app. J 6.8, C(3)H), 2.52 (2H, app. t, app. J
6.8, C(1)H2), 3.53 (1H, td, J 10.4, 4.4, C(1)H), 3.67 (2H, t,
J 6.8, C(8)H2), 5.32 (1H, d, J 2.8, C(5)H), 5.31–5.37 (1H, m)
and 5.51–5.55 (1H, m, CHCHCH3), 7.37–7.46 (6H, m) and
7.67–7.70 (4H, m, Ph); dC (100.6 MHz, CDCl3) 14.1, 15.5,
19.2, 20.6, 21.0, 22.3, 22.9, 25.4, 25.7, 26.7, 26.9, 28.4, 29.3,
29.4, 31.4, 32.3, 32.6, 34.3, 39.7, 45.7, 46.3, 47.8, 63.9, 77.2,
104.3, 124.7, 127.5, 129.5, 134.1, 134.5, 135.6, 177.9; m/z (CI,
NH3) 697 (MNa+, 100%), 692 (40), 575 (10), 459 (10), 381 (10);
HRMS (CI) found 675.4803, calculated for C43H67O4Si (MH+)
675.4809.
+
170.9; m/z (CI, NH3) 368 (MNH4 , 10%), 351 (MH+, 60), 230
(50), 214 (70), 197 (100), 195 (50), 166 (20), 148 (100), 138 (15);
HRMS (CI) found 351.2891, calculated for C22H39O3 (MH+)
351.2899.
(3R,4R,5R)-4-Butyl-3-isobutyl-5-(2-l-menthyloxy)dihydrofuran-
2-one 15
A solution of alkylidene lactone 14 (60 mg, 0.17 mmol), tri-
ethylamine (0.02 mmol, 4 lL) and 10% Pd/C (6 mg) in ethanol
(1.0 mL) was stirred under a hydrogen atmosphere (4 bar) for
40 h and then filtered through Celite®, washing through with
ether (3 × 5 mL). The filtrate was evaporated in vacuo and the
residue purified by flash column chromatography on silica
gel (95:5 petrol:ethyl acetate) to give the title compound (15)
as a pale yellow oil (50 mg, 83%). Rf 0.48 (9:1 petrol:ethyl
acetate); [a]2D2 = −98.3 (c 1.7, CHCl3); mmax(thin film)/cm−1 2956s,
2924s, 2863m, 1777s, 1467m, 1367w, 1260m, 1167w, 1104m,
1028w, 942m, 804w; dH (400 MHz, CDCl3) 0.78 (3H, d, J 6.8,
C(10)H3), 0.84–0.92 (2H, m, C(4)H, C(6)H), 0.88 (3H, d, J
6.8, C(8)H3), 0.90–0.96 (9H, m, C(4)H3, –CH(CH3)2), 0.95 (3H,
d, J 6.8, C(9)H3), 1.00 (1H, qd, J 12.8, 3.6, C(3)H), 1.19–1.56
(9H, m, C(1–3)3H6, C(1)H, C(2)H, C(7)H), 1.61–1.74 (3H,
m, C(1)H, C(3)H, C(4)H), 1.81 (1H, app. sept., app. J 6.4,
C(2)H), 1.96–2.01 (1H, m, C(4)H), 2.08–2.15 (2H, m, C(5)H,
C(6)H), 2.27 (1H, ddd, J 8.4, 6.4, 4.4, C(3)H), 3.51 (1H, td, J
10.8, 4.4, C(1)H), 5.31 (1H, d, J 2.4, C(5)H); dC (100.6 MHz,
CDCl3) 13.9, 15.4, 20.9, 22.0, 22.2, 22.5, 22.6, 22.9, 25.4, 25.7,
28.9, 31.3, 32.2, 34.3, 39.5, 40.8, 44.1, 46.9, 47.7, 77.1, 103.9,
(3R,4R,5R)-4-(8-Hydroxyoctyl)-5-(l-menthyloxy)-3-[(2Z)-
pentenyl]dihydrofuran-2-one 18
A solution of silane 17 (144 mg, 0.21 mmol) in THF (2.0 mL)
was treated with TBAF (235 lL of a 1 M solution in THF,
0.24 mmol). After 2.5 h at RT, the reaction mixture was evapo-
rated in vacuo and purified by flash column chromatography on
silica gel (85:15 petrol:ethyl acetate) to give the title compound
(18) as a colourless oil (93 mg, quant.). Rf 0.35 (7:3 petrol:ethyl
acetate); [a]22 = −82.3 (c 1.2, CHCl3); mmax (thin film)/cm−1 3440
br s, 2927s,D2855s, 1770s, 1455s, 1370m, 1167m, 1109m, 942m,
755w; dH (400 MHz, CDCl3) 0.78 (3H, d, J 6.8, C(10)H3), 0.89
(3H, d, J 6.8, C(8)H3), 0.93 (3H, d, J 6.8, C(9)H3), 0.97 (3H,
t, J 7.6, C(5)H3), 0.86–1.07 (3H, m, C(3)H, C(4)H, C(6)H),
1.18–1.50 (14H, m, C(1–6)6H12, C(2)H, C(7)H), 1.57 (2H,
quin., J 6.8, C(7)H2), 1.60–1.69 (2H, m, C(3)H, C(4)H),
1.98–2.10 (4H, m, C(4)H, C(4)H2, C(6)H), 2.09–2.19 (1H, m,
C(5)H), 2.27 (1H, app. q, app. J 6.8, C(3)H), 2.49 (2H, app. t,
app. J 6.8, C(1)H2), 3.51 (1H, td, J 10.8, 4.4, C(1)H), 3.64 (2H,
t, J 6.8, C(8)H2), 5.30 (1H, d, J 2.4, C(5)H), 5.28–5.38 (1H, m)
and 5.49–5.55 (1H, m, CHCHCH3); dC (100.6 MHz, CDCl3)
14.1, 15.4, 20.6, 20.9, 22.3 22.9, 25.4, 25.7, 26.7, 28.4, 29.3, 29.4
(two peaks), 31.3, 32.3, 32.7, 34.3, 39.7, 45.6, 46.3, 47.8, 63.0,
+
179.0; m/z (CI, NH3) 370 (MNH4 , 15%), 353 (MH+, 70), 232
(100), 215 (60), 197 (30), 170 (10), 148 (10), 95 (10); HRMS (CI)
found 353.3057, calculated for C22H41O3 (MH+) 353.3056.
(3R,4R,5R)-5-(l-Menthyloxy)-4-oct-7-enyl-3-[(2Z)-pentenyl]-
dihydrofuran-2-one 16
General procedure C [using 1.1 equiv. of LiHMDS and
1.1 equiv. of (Z)-1-bromo-2-pentene relative to lactone 2f
(1.44 g, 4.1 mmol)] gave the title compound (16) as a colour-
less oil (1.39 g, 81%; NMR spectra indicate slight contamina-
tion by the (E)-side chain isomer). Rf 0.82 (95:5 petrol:ethyl
acetate); [a]2D2 = −104.4 (c 1.0, CHCl3); mmax (thin film)/cm−1
2926s, 2856s, 1781s, 1641w, 1457m, 1369m, 1166m, 1108m,
944m; dH (400 MHz, CDCl3) 0.79 (3H, d, J 6.8, C(10)H3), 0.89
(3H, d, J 6.8, C(8)H3), 0.94 (3H, d, J 6.8, C(9)H3), 0.84–0.96
(2H, m, C(4)H, C(6)H), 0.97 (3H, t, J 7.6, C(5)H3), 0.96–1.06
(1H, qd, J 12.4, 2.8 C(3)H), 1.19–1.51 (12H, m, C(1–5)5H10,
C(2)H, C(7)H), 1.62–1.71 (2H, m, C(3)H, C(4)H), 1.99–2.22
(7H, m, C(4)H, C(6)H2, C(4)H2, C(5)H, C(6)H), 2.27
(1H, app. q, app. J 6.8, C(3)H), 2.50 (2H, app. t, app. J 6.8,
C(1)H2), 3.52 (1H, td, J 10.4, 4.4, C(1)H), 4.90–5.01 (2H, m,
C(8)H2), 5.31 (1H, d, J 2.8, C(5)H) overlaying 5.29–5.40 (1H,
m) and 5.49–5.61 (1H, m, CHCHCH3), 5.81 (1H, app. ddt,
app. J 17.2, 10.4, 6.8, C(7)H); dC (100.6 MHz, CDCl3) 14.1,
15.5, 20.6, 20.9, 22.3, 22.9, 25.4, 26.6, 28.4, 28.8, 29.2, 31.3,
+
77.2, 104.3, 124.7, 134.6, 180.0; m/z (CI, NH3) 454 (MNH4 ,
65%), 437 (MH+, 75), 321 (15), 299 (35), 242 (100); HRMS (CI)
found 437.3631, calculated for C27H49O4 (MH+) 437.3631.
(3R,4R,5R)-5-(l-Menthyloxy)-3-[(2Z)-pentenyl-4-[(8-triethylsila
nyloxy)octyl]dihydrofuran-2-one 19
To a solution of chlorotriethylsilane (215 lL, 1.27 mmol),
triethylamine (205 lL, 1.47 mmol) and DMAP (8 mg,
0.07 mmol) in dichloromethane (2.0 mL) was added a solu-
tion of alcohol 18 (426 mg, 0.98 mmol) in dichloromethane
(3.0 mL). The reaction mixture was stirred at RT for 12 h,
quenched with sat. aq. NH4Cl solution (3.0 mL), extracted with
dichloromethane (3 × 5 mL) and the extracts dried (MgSO4).
Purification by flash column chromatography on silica gel (95:5
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 9 8 8 – 2 9 9 7
2 9 9 5

View Article Online
petrol:ethyl acetate) provided the title compound (19) (473 mg,
88%) as a colourless oil. Rf 0.43 (95:5 petrol:ethyl acetate);
[a]2D2 = −82.5 (c 1.0, CHCl3); mmax (thin film)/cm−1 2928s, 2874s,
1779s, 1457s, 1370m, 1240m, 1166s, 1104s, 1016m, 944m, 743m;
dH (400 MHz, CDCl3) 0.59 (6H, q, J 7.6, 3 × SiCH2), 0.78 (3H, d,
J 6.8, C(10)H3), 0.89 (3H, d, J 6.8, C(8)H3), 0.93 (3H, d, J 6.8,
C(9)H3), 0.96 (9H, t, J 8.4, 3 × SiCH2CH3), 0.97 (3H, t, J 7.6,
C(5)H3), 0.86–1.05 (3H, m, C(3)H, C(4)H, C(6)H), 1.19–1.48
(14H, m, C(1–C6)6H12, C(2)H, C(7)H), 1.52 (2H, quin., J 6.8,
C(7)H2), 1.62–1.69 (2H, m, C(3)H, C(4)H), 2.00–2.14 (4H, m,
C(4)H, C(4)H2, C(6)H), 2.10–2.18 (1H, m, C(5)H), 2.26 (1H,
app. q, app. J 6.8, C(3)H), 2.49 (2H, app. t, app. J 6.8, C(1)H2),
3.51 (1H, td, J 10.8, 4.4, C(1)H), 3.59 (2H, t, J 6.8, C(8)H2),
5.30 (1H, d, J 2.8, C(5)H), 5.28–5.35 (1H, m) and 5.49–5.53 (1H,
m, CHCHCH3); dC (100.6 MHz, CDCl3) 4.4, 6.7, 14.1, 15.5,
20.6, 20.9, 22.2, 22.9, 25.4, 25.8, 26.7, 28.4, 29.3, 29.4, 31.3, 32.3,
32.9, 34.3, 39.7, 45.7, 46.3, 47.8, 62.9, 77.2, 104.3, 124.7, 134.5,
177.9; m/z (CI, NH3) 568 (MNH4+, 60%), 551 (MH+, 100), 459
(10), 413 (20), 395 (10), 278 (15); HRMS (CI) found 551.4496,
calculated for C33H63O4Si (MH+) 551.4496.
28.9, 29.6, 31.5, 33.5, 33.7, 49.7, 53.6, 114.3, 123.8, 124.2, 132.0,
+
133.5, 134.5, 139.0, 166.1, 213.2; m/z (CI, NH3) 346 (MNH4 ,
10%), 329 (MH+, 100), 313 (20), 261 (20), 224 (10); HRMS (CI)
found 329.2855, calculated for C23H37O (MH+) 329.2844.
(5R,6R)-2-Methyl-5,6-di(hydroxymethyl)dec-2-ene 22
A solution of lactone 9 (125 mg, 0.34 mmol) in THF (2.0 mL)
was treated with LiAlH4 (26 mg, 0.68 mmol) and the mixture
was heated at reflux for 2 h. After cooling to 0 °C, the mixture
was quenched with water (1.0 mL) and treated with hydro-
chloric acid (0.5 mL, 1.0 M). The mixture was extracted with
ether (3 × 5 mL) and the organic layers were dried (MgSO4),
filtered, and concentrated in vacuo. Purification by flash column
chromatography (9:1 petrol:ethyl acetate) gave diol 22 as a
colourless oil (60 mg, 82%). Rf 0.38 (1:1 petrol:ethyl acetate);
[a]D22 = +12.9 (c 0.7, CHCl3); mmax (thin film)/cm−1 3292br s, 2941s,
2927s, 2874s, 2731m, 1456s, 1374s, 1037s, 998s; dH (400 MHz,
CDCl3) 0.91 (3H, t, J 7.2, C(10)H3), 1.21–1.62 (8H, m, C(5)H,
C(6)H, C(7–9)3H6), 1.64 and 1.71 (2 × 3H, 2 × s, CMe2), 2.05
and 2.18 (2 × 1H, 2 × ddd, J 13.4, 6.7, 6.7, CHCH2), 2.44
(2H, br s, 2 × –OH), 3.56–3.62 (2H, m) and 3.71–3.77 (2H,
m, 2 × CH2OH), 5.13 (1H, br t, J 6.7, CH); dC (100.6 MHz,
CDCl3) 14.1, 17.8, 22.9, 25.8, 28.3, 29.3, 29.8, 42.3, 43.2, 61.6,
61.7, 123.1, 132.8; m/z (CI, NH3) 215 (MH+, 20%), 197 (100),
179 (25), 123 (15), 109 (20), 95 (25), 82 (15); HRMS (CI) found
215.2017, calculated C13H27O2 (MH+) 215.2011.
(4R,5R)-5-(l-Menthyloxy)-4-oct-7-enyl-3,3-di[(2Z)-pentenyl)]-
dihydrofuran-2-one 20
General procedure C [using 1.0 equiv. of LiHMDS and
1.0 equiv. of (Z)-1-bromo-2-pentene relative to lactone 16
(300 mg, 0.72 mmol)] gave the title compound (20) as a colourless
oil (258 mg, 74%; NMR spectra indicate slight contamination
by the (E)-side chain isomer). Rf 0.62 (95:5 petrol:ether); mmax
(thin film)/cm−1 3077w, 3011w, 2962s, 2928s, 2869s, 1774s, 1640w,
1456m, 1370w, 1345w, 1124m, 946m; dH (400 MHz, CDCl3)
0.80 (3H, d, J 6.8, C(10)H3), 0.85–0.89 (14H, m, 2 × C(5)H3,
C(4)H, C(6)H, C(8)H3, C(9)H3), 0.98–1.06 (1H, qd, J 12.4,
2.8 C(3)H), 1.19–1.47 (12H, m, C(1–5)5H10, C(2)H, C(7)H),
1.60–1.69 (2H, m, C(3)H, C(4)H), 1.96–2.48 (13H, m, C(4)H,
C(6)H2, 2 × C(1)H2, 2 × C(4)H2, C(5)H, C(6)H), 3.50 (1H,
td, J 10.8, 4.0, C(1)H), 4.92–5.02 (2H, m, C(8)H2), 5.22–5.59
(4H, m, C(5)H, 2 × CHCHCH3) overlaying 5.29 (1H, d, J 6.6,
C(5)H), 5.81 (1H, app. ddt, app. J 17.2, 10.4, 6.8, C(7)H); dC
(100.6 MHz, CDCl3) 13.9, 14.1, 15.5, 20.6, 20.8, 20.9, 22.3, 22.9,
25.4, 26.6, 28.4, 28.8, 29.2, 31.3, 32.3, 33.7, 34.3, 39.7, 45.2, 45.6,
46.3, 47.8, 77.2, 104.3, 114.3, 124.8, 134.5, 138.9, 178.4 (some
peaks coincident in spectrum); m/z (CI, NH3) 487 (MH+, 100%),
366 (20), 349 (50), 333 (55), 331 (50), 287 (20), 172 (30), 148 (75),
95 (15); HRMS (CI) found 487.4150, calculated for C32H55O3
(MH+) 487.4151.
Acknowledgements
We are grateful to the EPSRC and AstraZeneca for the award of
an Industrial CASE Award to MM, and to the EPSRC National
Mass Spectrometry Service Centre, Swansea for obtaining ac-
curate mass data.
References and notes
1 For an overview see: N. Hamanaka, in Comprehensive Natural Prod-
ucts Chemistry, U. Sankawa (ed.), Elsevier Science Ltd., Oxford,
1999, vol. 1, ch. 1.07.
2 (a) C. J. Sih, P. Price, R. Sood, R. G. Salomon, G. Peruzzotti and
M. Casey, J. Am. Chem. Soc., 1972, 94, 3643–3644; (b) F. S. Alvarez,
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(c) A. F. Kluge, K. G. Untch and J. H. Fried, J. Am. Chem. Soc.,
1972, 94, 7827–7832; (d) For a recent variant see D. C. Blakemore,
J. S. Bryans, PCT Int. Appl., WO 02/00584 A1, 2002.
3 For representative procedures see: (a) M. Kitamura, I. Kasahara,
K. Manabe, R. Noyori and H. Takaya, J. Org. Chem., 1988, 53,
708–710; (b) D. R. Deardorff, C. Q. Windham and C. L. Craney,
Org. Synth., 1995, 73, 25–35; (c) A. G. Myers, M. Hammond and
Y. Wu, Tetrahedron Lett., 1996, 37, 3083–3086.
(4S)-4-Oct-7-enyl-5,5-di[(2Z)-pentenyl]cyclopent-2-enone 21
4 (a) J. Robertson and R. J. D. Hatley, J. Chem. Soc., Chem. Commun.,
1999, 1455–1456; (b) J. Robertson, R. J. D. Hatley and D. J. Watkin,
J. Chem. Soc., Perkin Trans. 1, 2000, 3389–3396.
5 An indication that the synthesis of optically active 4-alkylcyclo-
pentenones remains a non-trivial problem is given in a recent
approach to the prostaglandin analog TEI-9826 during which
(S)-4-octylcyclopent-2-enone is prepared in eleven steps and ca. 11%
yield from (±)-butyn-2-ol: R. Weaving, E. Roulland, C. Monneret
and J.-C. Florent, Tetrahedron Lett., 2003, 44, 2579–2581.
6 (a) D. R. Borcherding, S. A. Scholtz and R. T. Borchardt, J. Org.
Chem., 1987, 52, 5457–5461;seealso;(b) C. L. Marien, E. L. Esmans,
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T. C. Nugent, Synth. Commun., 1992, 22, 151–157.
LiBr (15 mg, 0.17 mmol, dried overnight at 135 °C under high
vacuum) was dissolved in anhydrous THF (1.0 mL) and cooled
to −78 °C. Dimethyl methylphosphonate (18 lL, 0.17 mmol)
and n-BuLi (103 lL of a 1.6 M solution in hexanes, 0.17 mmol)
were added successively and the mixture was stirred at −78 °C
for 30 min. Lactone 20 (80 mg, 0.16 mmol) in THF (0.5 mL) was
added, resulting in a yellow solution. The mixture was stirred
at −78 °C for 2 h then allowed to reach RT over 3 h. After
addition of water (2 mL), the product was extracted with ethyl
acetate (3 × 5 mL), dried (Na2SO4), filtered, and evaporated
in vacuo. Purification by flash column chromatography (silica,
99:1 petrol:ether) gave the title compound (21) as a colourless
oil (27 mg, 50%; 81% based on recovered 21; NMR spectra indi-
cate slight contamination by the (E)-side chain isomer). Rf 0. 30
(95:5 petrol:ether); mmax (thin film)/cm−1 3076w, 3010w, 2962s,
2930s, 2856s, 1709s, 1641w, 1590w, 1463m, 1182w, 1069w, 909m,
733m; dH (400 MHz, CDCl3) 0.94 and 0.95 (2 × 3H, 2 × t, J 7.2,
2 × C(5)H3), 1.27–1.69 (10H, m, C(1–5)5H10), 1.94–2.09 (6H,
m, C(6)H2, 2 × C(4)H2), 2.12–2.32 (4H, m, 2 × C(1)H2), 2.62–
2.72 (1H, m, C(4)H), 4.93–5.03 (2H, m, C(8)H2), 5.12–5.48 (4H,
m, 2 × CHCHCH3), 5.82 (1H, app. ddt, app. J 16.8.10.4, 6.8,
C(7)H), 6.09–6.25 (1H, m, C(2)H), 7.60–7.65 (1H, m, C(3)H);
dC (100.6 MHz, CDCl3) 13.9, 14.2, 20.6, 25.6, 28.3, 28.7, 28.8,
7 (a) A detailed, optimised procedure for the preparation of ent-1
from d-menthol and a survey of its synthetic applications is given
in: O. M. Moradei and L. A. Paquette, Org. Synth., 2003, 80,
66–74; (b) see also: B. L. Feringa, B. de Lange and J. C. de Jong,
J. Org. Chem., 1989, 54, 2471–2475; (c) S. Marinkovic, C. Brulé,
N. Hoffmann, E. Prost, J.-M. Nuzillard and V. Bulach, J. Org.
Chem., 2004, 69, 1646–1651.
8 The majority of reports on 1,4-addition of carbon-centred
nucleophiles to lactone
1 concern S-stabilised organolithium
reagents; see: (a) J. Brinksma, H. van der Deen, A. van Oeveren
and B. L. Feringa, J. Chem. Soc., Perkin Trans. 1, 1998,
4159–4163; (b) O. Middel, H. J. Woerdenbag, W. Vanuden,
2 9 9 6
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 9 8 8 – 2 9 9 7

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A. Vanoeveren, J. F. G. A. Jansen, B. L. Feringa, A. W. T. Konings,
N. Pras and R. M. Kellogg, J. Med. Chem., 1995, 38, 2112–2118;
(c) A. Vanoeveren, J. F. G. A. Jansen and B. L. Feringa, J. Org.
Chem., 1994, 59, 5999–6007; (d) J. F. G. A. Jansen and B. L. Feringa,
Synth. Commun., 1992, 22, 1367–1376; (e) J. F. G. A. Jansen
and B. L. Feringa, Tetrahedron Lett., 1991, 32, 3239–3242;
(f) J. F. G. A. Jansen, C. Jansen and B. L. Feringa, Tetrahedron:
Asymmetry, 1991, 2, 109–110; (g) J. F. G. A. Jansen and B. L.
Feringa, Tetrahedron Lett., 1989, 30, 5481–5484.
Reagents: A Practical Approach, R. J. K. Taylor (ed.), OUP, Oxford,
1994, ch. 7.
13 Thus, a 13% yield of the methyl adduct was obtained from the
reaction of lactone 1 with Me2Zn/MeMgCl; for a short review of
mixed trialkylzincate reagents, with lead references, see: T. Harada,
A. Oku, in Organozinc Reagents: A Practical Approach, P. Knochel
and P. Jones (eds.), OUP, Oxford, 1999, ch. 6.
14 For early reports concerning the mechanism of similar reductive
processes see: (a) R. A. Ruden and W. E. Litterer, Tetrahedron Lett.,
1975, 2043–2044; (b) D. J. Hannah and R. A. J. Smith, Tetrahedron
Lett., 1975, 187–190. Selected data for 5: dH (500 MHz, C6D6) 2.70
(2H, d, J 7.5, CH2CO2H), 5.05 (1H, dt, J 12.4, 7.5, CH2CH), 5.96
(1H, d, J 12.4, CH(OMen); selected data for 6: dH (400 MHz,
CDCl3) 5.59 (0.5H, dd, J 5.6, 2.2) and 5.71 (0.5H, dd, J 5.5, 1.6,
–CH(OMen)O–).
9 J. Mulzer and D. Riether, Tetrahedron Lett., 1999, 40, 6197–6199.
10 Thus: (a) B. L. Feringa and J. C. de Jong, Bull. Soc. Chim. Belg.,
1992, 101, 627–640: “Several attempts to prepare 4-alkyl substituted
butyrolactones […] via 1,4-additions of cuprate or zincate reagents
failedsofar.”;(b) N. Lee,Y.-W. Kim,K. Chang,K. H. Kim,S.-S. Jew
and D.-K. Kim, Tetrahedron Lett., 1996, 37, 2429–2432: “copper or
manganese(II) mediated conjugate additions of organometallic com-
pounds to [furanone 1] turned out to be unfruitful.”; (c) A. D. Reed
and L. S. Hegedus, J. Org. Chem., 1995, 60, 3787–3794: “Remark-
ably, although 4-alkylbutenolides were generally reactive towards
organocuprates, the 4-alkoxy systems failed to react with either
cuprates or zincates, implying some electronic impediment to cuprate
additions in these systems.”.
15 A. Pelter, R. S. Ward and D. M. Jones, Tetrahedron: Asymmetry,
1990, 1, 857–860.
16 F.-A. Kang and C.-L. Yin, Tetrahedron, 1998, 54, 13155–13166.
17 Crystal data for 2b: C18H32O3, M = 296.45, colourless plates,
monoclinic, a = 5.3730(2), b = 12.8737(4), c = 13.1459(4) Å,
b = 99.6165(12), V = 896.53(5) Å3, T = 190 K, space group P21,
Z = 2, l(Mo–Ka) = 0.072 mm−1
, 3912 reflections measured
11 In addition to variants of the examples in reference 6 see: (a) J. Knol
and B. L. Feringa, Tetrahedron Lett., 1997, 38, 2527–2530;
(b) H. Miyaoka, S. Sagawa, H. Nagaoka and Y. Yamada, Tetra-
hedron: Asymmetry, 1995, 6, 587–594.
12 (a) Y. Yamamoto and K. Maruyama, J. Am. Chem. Soc., 1978, 100,
3240–3241; (b) (a review) T. Ibuka, Y. Yamamoto, in Organocopper
(Rint = 0.0343), 2360 reflections used, R = 0.0403 (weighted). CCDC
reference number 240363. See http://www.rsc.org/suppdata/ob/b4/
b408255a/ for crystallographic data in .cif format.
18 M. Ménard, D.Phil. Thesis, Oxford, 2003.
19 X.-J. Chu, H. Dong and Z.-Y. Liu, Tetrahedron, 1995, 51, 173–180
and references cited therein.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 9 8 8 – 2 9 9 7
2 9 9 7