Toward the total synthesis of lophotoxin - New methodologies and synthetic strategies

Article abstract of DOI:10.1139/V06-073

Our recent progress toward the synthesis of the furanocembranolide lophotoxin (1) is disclosed. Strategies for the stereoselective incorporation of the C₁₃ stereocenter by a catalytic desymmetrization of a cyclic meso-anhydride, as well as a no

Full text of DOI:10.1139/V06-073

1226
Toward the total synthesis of lophotoxin — New
methodologies and synthetic strategies1
Peter Wipf and Michel Grenon
Abstract: Our recent progress toward the synthesis of the furanocembranolide lophotoxin (1) is disclosed. Strategies
for the stereoselective incorporation of the C13 stereocenter by a catalytic desymmetrization of a cyclic meso-anhydride,
as well as a novel 1,6-addition reaction of organocuprates to unsaturated [1,3]dioxin-4-ones are discussed. Preliminary
results on the development of a rhodium-catalyzed asymmetric 1,6-addition reaction are also mentioned. Finally, modi-
fications of a previously reported transition-metal-catalyzed cyclization reaction involving α-propargyl β-keto esters al-
low furan ring formation either under thermal conditions or by microwave irradiation.
Key words: 1,6-addition, organocuprates, catalytic desymmetrization, furan cyclization, microwave.
Résumé : Nos plus récents progrès concernant la synthèse totale du furanocembranolide lophotoxine (1) sont décrits.
Des stratégies pour l’incorporation stéréosélective du substituant en C13 par la désymétrisation catalytique d’un anhy-
dride cyclique meso, ainsi qu’une nouvelle réaction d’addition 1,6-conjuguée d’organocuprates sur des [1,3]dioxin-4-
ones insaturées sont discutées. Des résultats préliminaires sur le dévelopement d’une réaction d’addition 1,6-conjugée
asymétrique catalysée par le rhodium sont aussi mentionnés. Finalement, la modification d’une réaction de cyclisation
catalysée par un métal de transition et mettant en jeu l’α-propargyl β-céto ester permet la formation d’un furane soit
sous certaines conditions thermiques ou par irradiation aux micro-ondes.
Mots clés : addition 1,6-, organocuprates, désymétrisation catalytique, cyclisation de furane, microonde.
Wipf and
Grenon 1241
Introduction
The presence of a 2,3,5-trisubstituted furan ring adjacent
to a trans-trisubstituted epoxide, along with an epoxidized
butenolide imbedded in a strained 14-membered macrocycle
are the most prominent structural features of this molecule.
In addition to the interesting biological activity displayed by
this compound, the synthetic challenge offered to organic
chemists has prompted a number of research groups to de-
velop strategies aimed at the total synthesis of lophotoxin (5,
6) and other furanocembranolides (7–10).
Our research group has been interested in this class of
molecules for a few years and we have recently disclosed a
method to construct the 2-alkenyl-3,5-trisubstituted furan (2)
from the simple acyclic α-propargyl β-keto ester (3) (Fig. 1)
(11). This method is based on a general strategy for the con-
struction of five-membered heterocycles (12) and features
the use of a palladium catalyst and an inorganic base to
induce the 5-exo-dig cyclization and concomitant aroma-
tization to the furan ring. High levels of selectivity for the
(Z)-isomer 2 were obtained as a result of the facial-selective
protonation of an allene intermediate. With the furan in
hand, the vinylsilane moiety was further elaborated to the
C19 methyl group attached to the trans-trisubstituted epoxide
in lophotoxin.
Lophotoxin (1) is a member of the furanocembranolides
(1), a growing class of natural products that comprise a
number of highly functionalized cyclic diterpenes (Fig. 1).
This compound is found in a number of marine invertebrates
(gorgonian octocorals) located in tropical and subtropical
waters (2). Lophotoxin acts as a potent neurotoxin by bind-
ing selectively and irreversibly to the Tyr190 residue present
in the α-subunit of nicotinic acetylcholine receptors, leading
to respiratory depression, paralysis, asphyxia, and ultimately
death (3). SAR studies have demonstrated that the key struc-
tural elements responsible for this unique biological activity
can be attributed to the C7–C8 epoxide and the lactone
oxygens, allowing for a direct structural correlation of the
pharmacophore in 1 with acetylcholine (4).
Received 2 November 2005. Accepted 21 December 2005.
Published on the NRC Research Press Web site at
http://canjchem.nrc.ca on 6 July 2006.
Dedicated to Dr. Alfred Bader, in recognition of his spirit for
entrepreneurship, and his appreciation for the legacy of
human accomplishment!
Some issues that were not addressed in our previous com-
munication concern the installation of the C13 acetate group
as well as a method to introduce the C1 isopropenyl group in
a stereoselective way. Previous synthetic work by others has
either exploited the chiral pool (8, 9), a diastereoselective
alkylation (5), or an intramolecular Nozaki–Hiyama–Kishi
reaction (7) to introduce the isopropenyl group, whereas the
P. Wipf2 and M. Grenon. Department of Chemistry,
University of Pittsburgh, 219 Parkman Avenue, Pittsburgh,
PA 15260, USA.
1This article is part of a Special Issue dedicated to Dr. Alfred
Bader.
2Corresponding author (e-mail: pwipf@pitt.edu).
Can. J. Chem. 84: 1226–1241 (2006)
doi:10.1139/V06-073
© 2006 NRC Canada

Wipf and Grenon
1227
Scheme 1. Strategy for the incorporation of the C13 stereogenic
Fig. 1. Lophotoxin and the structures of synthetic intermediates.
carbon center.
CHO
CO2Me
4
4
CO2Et
EtO2C
I
O
O
O
1
1
O
8
19
8
O
TMS
TMS
BzO
13
13
R1
R1
OTBDPS
O
OAc
O
2
OMEM
O
OTBDPS
CO2Me
CO2Me
Lophotoxin (1)
4
5
6
CO2Me
4
R1
R1
1
O
MeO2C
O
TMS
BzO
8
7
O
O
O
13
8
OTBDPS
OMEM
3
Scheme 2. Strategy for the incorporation of the C1 stereogenic
carbon center.
1
configuration of the C13 substituent was not addressed (5, 6)
or of no concern (7–9). In this paper, we wish to report on
our findings for the stereoselective introduction of these two
stereogenic carbons. A modification of our initial set of con-
ditions, which uses microwave irradiation for the furan
cyclization reaction, is also disclosed.
O
O
R3
O
O
4
R3M
R1
OR2
R1
OR2
11
2
R OH,
∆
–
( Acetone)
1
O
O
O
Results and discussions
O
R3
β-Keto esters, such as 3, are rapidly constructed by an
alkylation reaction with propargylic iodide (4) (11)
(Scheme 1). Segment 5 would need to be constructed in a
stereocontrolled fashion. Further simplification of 5 provides
6, which can be assembled from aldehyde 7 and an appropri-
ate phosphonate by a Horner–Wadsworth–Emmons olefination.
Finally, the highly symmetrical nature of aldehyde 7 led us
to consider the use of a catalytic desymmetrization reaction
of cyclic meso-anhydride (8) with an alcohol (13) to create
the stereocenter at C13.
We initially envisioned that a conjugate 1,4-addition of an
isopropenyl group to the unsaturated β-keto ester would be a
straightforward means to introduce the C1 side chain in 6.
However, owing to the ease of enolization of this particular
type of substrate, we opted for an indirect route in which the
1,3-dicarbonyl unit would be revealed at a later stage
(Scheme 2). We further anticipated that confinement of the
β-keto ester to a [1,3]dioxin-4-one ring system, such as in 9,
would solve the problem, however, instead of a conjugate
1,4-addition, this required an extended 1,6-additon reaction.
Thermolysis of adduct 10 in the presence of an alcohol
(R2OH) would then provide a number of different β-keto es-
ters 11, and an even greater number of derivatives could be
obtained if other heteronucleophiles such as thiols or amines
were to be used instead.
6
R3M
R1
O
R1
O
9
10
O
O
P
O
O
O
EtO
EtO
O
12
H
NaH, THF
R1
O
[1]
R1
O
−
78 °C to rt
13
13a, R1 = i-Pr, 68%
1
, R = Ph(CH2)2, 96%
13b
After some optimization of the reaction conditions, it was
found that the addition of these extended Michael acceptors
to solutions of Gillman-type organocuprates (R2CuLi) con-
taining chlorotrimethylsilane (16) at low temperature cleanly
afforded the desired 1,6-addition products in high yields (Ta-
ble 1). A small survey of different organocuprates revealed
that simple alkyl groups were readily added (Table 1, entries
1–4), as were aromatic (Table 1, entries 5 and 6) and even
silicon-based groups (17) (Table 1, entries 7 and 8). The ad-
dition of sterically encumbered organocuprates such as (t-
Bu)2CuLi also proceeded to afford the 1,6-addition adduct,
albeit in low yields (Table 1, entries 9 and 10). However, the
low yields observed were not because of a lack of reactivity
To test the feasibility of this route, [1,3]dioxin-4-ones (13)
were prepared from phosphonate (12) (14) and either
isobutyraldehyde or hydrocinnamaldehyde according to a lit-
erature procedure (15) and used as model substrates
(eq. [1]).
during the 1,6-addition, but rather the result of
a
© 2006 NRC Canada

1228
Can. J. Chem. Vol. 84, 2006
Table 1. 1,6-Addition of organocuprates to [1,3]dioxin-4-ones 13.
Scheme 3. Preparation of cyclic anhydrides 8. Reagents and con-
ditions: (a) chlorosilane, imidazole, CH2Cl2, rt (15a, R1 =
OTBDMS, 92%; 15b, R1 = OTBDPS, 96%); (b) NaOH, MeOH,
rt, 24–40 h; (c) Ac2O, C6H6, ∆, 1.5 h (8a, R1 = OTBDMS, 80%;
8b, R1 = OTBDPS, 46%).
O
O
(R2)2CuLi (1.5 equiv.)
TMSCl (6.0 equiv.)
R2
R1
O
14
OH
R1
13
a
THF, –20 oC
EtO2C
CO2Et
R1
EtO2C
CO2Et
Entry
Substrate
(R2)2CuLi
Me2CuLi
Yield (%)
15
1
13a
13b
13a
13b
13a
13b
13a
13b
13a
13b
91
77
88
92
79
66
60
61
17
43
2
Me2CuLi
Et2CuLi
Et2CuLi
Ph2CuLi
Ph2CuLi
b,c
3
O
O
O
4
8
5
6
Table 2. Catalytic desymmetrization of cyclic meso-anhydrides 8
with (DHQD)2AQN.
7
(PhMe2Si)2CuLi
(PhMe2Si)2CuLi
t-Bu2CuLi
8
R1
(DHQD)2AQN
(30 mol%)
MeOH (10 equiv.)
9
R1
10
t-Bu2CuLi
MeO2C
CO2H
Et2O, Conditions
O
O
O
16
nonselective protonation step of the intermediate extended
silyl enol ether formed after the 1,6-addition. No reaction
occured when less reactive sp-hybridized organocopper re-
agents (RCϵCCu) or organocuprates [(RCϵC)2CuLi] were
used. It should be pointed out that in all cases studied using
these sets of conditions, no adducts derived from 1,4- or 1,2-
addition were isolated (18).
8
Conditions
(°C, h)
Conversion
(%)
ee
(%)
Entry
R1
70a,b
72a,b
65c
1a
2a
3
4
5
Me
i-Pr
–40, 43a
–40, 43a
–40, 41
–40, 70
–40, 70
–20, 70
–40, 70
91
90
Ndd
Nd
95
OTBDMS (8a)
OTBDMS (8a)
OTBDPS (8b)
OTBDPS (8b)
OTBDPS (8b)
Having established that the extended conjugate addition
reaction was possible, we next turned our attention toward
the preparation of fragment 5 for our synthesis of lopho-
toxin. As we discussed previously, we planned on introduc-
ing the stereocenter at C13 by a catalytic desymmetrization
reaction on cyclic meso-anhydrides 8 (Scheme 3). These
were conveniently prepared according to a literature proce-
dure (19) from commercially available diethyl 3-hydroxy-
glutarate by protection of the free hydroxyl group as a silyl
ether to give 15, followed by exhaustive saponification and
dehydration of the resulting disodium acid salt with acetic
anhydride. The TBDMS-protected cyclic anhydride 8a was
obtained as an off-white solid upon recrystallization of the
crude material after the dehydration step, whereas the
TBDPS-protected anhydride 8b had to be filtered rapidly
over a pad of silica gel pretreated with acetic anhydride to
remove silanes before recrystallization was successful.3
Although there are a number of reported procedures to ef-
fect the desymmetrization of the cyclic anhydride 8a (20–
22), we opted for a method recently developed by Deng and
co-workers (23) that employs modified cinchona alkaloids,
initially adapted for the catalytic asymmetric dihydroxy-
lation of alkenes (24) (Table 2). Using substoichiometric
amounts (30 mol%) of (DHQD)2AQN in the presence of an
excess of methanol at low temperature, Deng and co-
workers (23) converted cyclic meso-anhydrides 8 (R1 = Me,
i-Pr) to acids 16 in good yields and high values of ee (Ta-
ble 2, entries 1 and 2). When these optimized conditions
were applied to the TBDMS-protected cyclic anhydride 8a,
a similar conversion to the desired acid was obtained (Ta-
90–95c
75–85e
100
6
7
88
—
96f
aData from ref. 23.
bIsolated yield.
cExtensive desilylation of the product was observed.
dNd (not determined).
eConversions from seven desymmetrizations under identical conditions.
fQuinuclidine was used as a catalyst.
ble 2, entry 3). Longer reaction times resulted in higher con-
versions (Table 2, entry 4), however extensive desilylation
of the product in both cases precluded the use of this sub-
strate. Fortunately, when the TBDPS-protected cyclic anhy-
dride 8b was submitted to the desymmetrization reaction,
conversions of 75%–85% were obtained, and more impor-
1
tantly, H NMR analysis of the crude mixture indicated that
no desilylation of 16 had occurred (Table 2, entry 5). An
aliquot of the crude acid, accumulated from seven
desymmetrizations under identical conditions, was reduced
to the corresponding alcohol and treated with dil. HCl to
provide the cyclic lactone 18 (Scheme 4) (25). Comparison
of the chiral HPLC trace of this material with the racemic
material prepared using quinuclidine as the organocatalyst
(Table 2, entry 7) showed that the desymmetrization reaction
occurred with a high level of enantioselectivity (95% ee).
Finally, conducting the desymmetrization of 8b at a higher
temperature (–20 °C, Table 2, entry 6) resulted in a com-
3 Extensive desilylation occurs during the two-step sequence leading to lower yields of 8b.
© 2006 NRC Canada

Wipf and Grenon
1229
Scheme 4. Preparation of furan cyclization precursor 22. Reagents and conditions: (a) BH3·DMS, THF, rt, 15–17 h; (b) 10% HCl, rt,
1 h (38% from 8b); (c) satd. aq. NaHCO3, rt, 20 min (71% from 8b); (d) TPAP (5 mol%), NMO, 4 Å MS, MeCN–CH2Cl2 (1:9),
30 min; (e) 12, NaH, THF, –78 °C to rt, 1 h (49%, two steps); (f) CuI, 2-lithiopropene, TMSCl, THF, –20 °C, 16 h (94%, 1:1 dr);
(g) EtOH, toluene, ∆; (h) NaH, 4, THF, 0 °C to rt (77%, two steps).
O
OTBDPS
a,b
O
MeO2C
CO2H
TBDPSO
O
16
18
a,c
O
O
O
O
P
EtO
EtO
O
OTBDPS
OH
OTBDPS
O
f
d,e
12
MeO2C
MeO2C
17
19
I
CO2Et
O
O
4
BzO
OTBDPS
TMS
TBDPSO
MeO2C
O
O
g,h
BzO
TMS
20
OTBDPS
OTBDPS
22
CO2Me
plete conversion to the acid, albeit with lower selectivity
(88% ee).
pointing; indeed, using conditions optimized for the catalytic
asymmetric 1,4-addition of diorganozincs to enones (28), no
reaction occurred and the starting material was recovered
unchanged (Table 3, entry 1). The addition of chlorotri-
methylsilane had no effect on the outcome of the reaction
and even the use of Et2Zn, which is often employed as a
nucleophile in catalytic asymmetric conjugate additions,
failed as well.
Over the past decade, rhodium catalysts have received in-
creasing attention as alternatives to copper catalysts for the
catalytic asymmetric 1,4-addition reaction, especially since
the pioneering work by the research groups of Miyaura and
Hayashi (29). However, a serious concern arises when con-
sidering the experimental conditions employed; most of the
procedures involve heating at elevated temperatures in a bi-
nary solvent mixture composed of water and a cosolvent. We
feared that thermal fragmentation of the [1,3]dioxin-4-one
ring would lead to the α,β-unsaturated methyl ketone derived
from 19 by a sequence that involves addition of 1 equiv. of
water to an acyl ketene intermediate, followed by intramole-
cular decarboxylation of the resulting β-keto acid. As shown
in Table 3 (entry 2), these concerns were confirmed when an
addition of lithium 2-propenylborate in the presence of
1 equiv. of water (30) resulted in hydrolysis of 19 and isola-
tion of the α,β-unsatured ester (65%).
With an efficient and stereoselective solution for introduc-
ing the protected alcohol at C13, we proceeded with our syn-
thesis of fragment 5. Reduction of the acid function in 16
with the borane – dimethyl sulfide complex followed by ba-
sic aqueous work up gave the alcohol 17 in good overall
yield from cyclic meso-anhydride 8b. Ley–Griffith oxidation
of this alcohol to the aldehyde (26) followed by a Horner–
Wadsworth–Emmons olefination with the stabilized
phosphonate 12 (15) provided the 1,6-addition precursor 19
as a single isomer. Using 3 equiv. of the organocuprate de-
rived from 2-lithiopropene, addition to the extended Michael
acceptor occurred smoothly to provide 20 in high yield as a
1:1 mixture of diastereomers. Thermolysis of the [1,3]di-
oxin-4-one ring with ethanol in refluxing toluene revealed
the β-keto ester (21) (see Table 3) that was then alkylated
with the previously reported iodide 4 (11) to give the furan
cyclization precursor 22 in good yield as a mixture of
stereoisomers.
We were not surprised by the lack of stereocontrol
obtained for the 1,6-addition of the organocuprate to [1,3]di-
oxin-4-one (19) (Scheme 4). By analogy to the diastere-
oselective 1,4-addition of copper-based organometallic
reagents to Michael acceptors possessing a stereogenic cen-
ter at the δ position under substrate control (27), we antici-
pated low levels of selectivity for the 1,6-addition. This gave
us the opportunity to develop a catalytic asymmetric variant
of the 1,6-addition reaction, and since stoichiometric copper-
based reagents were effective, we initially screened for cop-
per catalysts (Table 3). These studies proved quite disap-
Recent findings by Feringa and co-workers (31) and
Genêt and co-workers (32) have shown that potassium
organotrifluoroborates (RBF3K),
a class of air- and
moisture-stable organometallic reagents, can be used as
substitutes for boronic acids in the rhodium-catalyzed asym-
metric 1,4-addition to enones using phosporamidites or
© 2006 NRC Canada

1230
Can. J. Chem. Vol. 84, 2006
Table 3. Catalytic asymmetric 1,6-addition to [1,3]dioxin-4-one 19.
O
O
O
M
TBDPSO
O
TBDPSO
MeO2C
OEt
O
Catalyst, Ligand
MeO2C
19
Conditions
20
21
Entry Substrate
Catalyst (mol%),
Ligand (mol%)
Conditions
Yield
20,21 (%)
dra
M
—
—
19
19
1
2
Zn
Cu(OTf)2 (5),
L1 (10)
Toluene, –20 °C
0
0
2
Dioxane
H2O (1 equiv.), ∆
B(OMe)3Li R h(acac)(eth)2 (4),
Binap (6.5)
EtOH, 83 °C
EtOH, 82 °C
EtOH, 78 °C
1.7:1
4.0:1
3.7:1
3
4
5
19
19
24b
BF3K Rh(acac)(eth)2 (4),
L1 (13)
23,41
21,38
27,32
R h(acac)(eth)2 (4),
L2 (6)
R h(acac)(eth)2 (4),
L2
(6)
a
b
Diastereomeric ratio determined by 1H NMR.
OMe
Reaction performed on the acetate-protected derivative.
O
P
N
O
(MonoPhosTM
)
L1
L
2 (Carreira's diene)
bidentate phosphines as chiral ligands. Of particular interest
to us was the fact that these reactions can be performed in
the absence of water (pure EtOH) and at lower temperatures
(70 °C) (31), so that addition could occur before any signifi-
cant cleavage of the [1,3]dioxin-4-one ring could take place.
Gratifyingly, on our first try with MonophosTM (L1, see bot-
tom of Table 3) in a heated ethanolic solution, we obtained a
mixture of 1,6-addition products 20 and 21 in a moderate
combined yield, albeit in low diastereoselectivity (Table 3,
entry 3). We then turned our attention to chiral bidentate
phosphine ligands such as (R)-Binap, (R,R)-Me-Duphos, and
(S,S)-Chiraphos, however, the use of these ligands seemed to
considerably diminish the activity of the catalytic system
and only starting material was recovered.
Another class of promising chiral ligands for the catalytic
asymmetric 1,4-addition are chiral dienes (33), which have
been disclosed recently by Hayashi et al. (34) and Carreira
and co-workers (35). We chose to prepare Carreira’s diene
(see L2, bottom of Table 3) from commercially available
carvone. After heating 19 with the organotrifluoroborate in
the presence of a rhodium catalyst, we were able to isolate
the addition products 20 and 21 in a moderate combined
yield as a 4:1 mixture of isomers (Table 3, entry 4) (36).
Performing the reaction with a different neutral rhodium cat-
alyst, {[RhCl(eth)2]2} gave similar results (64% combined
yield, 3.1:1 dr), whereas lower temperatures (57–60 °C) re-
sulted in lower conversions.4 We also attempted the reaction
with the acetate-protected derivative 24 (Table 3, entry 5) as
well as the free-hydroxyl derivative 23, however, no in-
crease in selectivity was observed with the former and the
latter appeared to be unreactive.
Since we were unable to prepare the 1,6-addition products
20 and (or) 21 with high levels of stereoselectivity, we de-
cided to resume our synthesis of lophotoxin with the 1:1
mixture of diastereomers obtained in high yield from the
organocuprate addition (Scheme 4). The stage was now set
for the key cyclization step that would produce the 2,3,5-
trisubstituted furan ring and stereoselectively generate the
olefin with the appropriate geometry, all in a single transi-
tion-metal-catalyzed event. Unfortunately, treatment of the
α-propargyl β-keto ester 22 under our previously optimized
conditions (11) gave only trace amounts of furan 25 (Ta-
ble 4, entry 1). Although the starting material had been com-
pletely consumed, as judged by 1H NMR analysis, no
identifiable products could be isolated from the crude reac-
tion mixture. After a number of unsuccessful attempts, we
decided to conduct control experiments and we were quite
surprised to see that treatment of 22 with only K2CO3, pres-
ent under otherwise identical reaction conditions, resulted in
rapid desilylation (TMS group) of the starting material (ca.
1 h, Table 4, entry 2). In light of this result, we decided to
screen for other catalyst–base combinations and we were
pleased to see that the use of Pd(PPh3)4 and NaOAc·3H2O
provided a reasonable yield of furan 25 as a 6.8:1 mixture of
isomers (Table 4, entry 3). The addition of more base (Ta-
ble 4, entry 4) or the use of related bases (Table 4, entries 5
4 Comparable diastereomeric ratios (3.9:1) were obtained.
© 2006 NRC Canada

Wipf and Grenon
Table 4. Transition-metal-catalyzed cyclization of α-propargyl β-keto ester 22.
1231
CO2Et
CO2Et
Catalyst X (mol%)
Base Y (equiv.)
O
O
BzO
TMS
TMS
OTBDPS
CO2Me
MeCN/H2O (10:1)
84 °C, 12 h
TBDPSO
OTBDPS
CO2Me
OTBDPS
22
25
Entry
Catalyst X (mol%)
Base Y (equiv.)
E/Z (ratio)a
Yield (%)
1
2
3
4
5
6
7
Pd(OAc)2 (5), dppf (6)
none
K2CO3 (1.1)
—
Ndb
K2CO3 (1.1)
—
0
Pd(PPh3)4 (15)
Pd(PPh3)4 (15)
Pd(PPh3)4 (15)
Pd(PPh3)4 (15)
Pd(PPh3)4 (15)
NaOAc"3H2O (1.1)
NaOAc"3H2O (5.0)
NaOBz (1.1)
6.8:1
6.8:1
5.4:1
5.5:1
6.6:1
49
51
44
53
56
NaOPiv·H2O (1.1)
NaOAc·3H2O (1.1), 2,6-lutidine (1.1)
and 6) led to almost identical results, as did the combination
of NaOAc·3H2O and an organic base (Entry 7).
Cl
1
H
TMS O2CR1
Comparison of the H NMR spectra of 25 with our previ-
O
1. BuLi, Et2O, −78 °C
ously described furan 2 (Fig. 1) indicated that the major iso-
mer formed during the reaction was the undesired (E)-
isomer.5 To verify the olefin configuration, we converted the
vinylsilane moiety to the corresponding iodide and per-
formed a Negishi cross-coupling reaction with dimethylzinc
that yielded furan 26 (eq. [2]). A 1D-nOe analysis allowed
us to assign the stereochemistry of the major isomer as (Z)-
26 since an nOe enhancement was observed between the hy-
drogen atoms of the newly introduced methyl group and the
hydrogen atom of the alkene, establishing that the TMS
group in 25 was located trans to the furan ring.
[3]
TMS
2. R1COCl
Cl
−
78 °C to rt
1
R = Ph, 80%
27a,
27b, R1 = t-Bu, 58%
nal cyclization conditions, virtually no furan was formed and
the starting material decomposed (Table 5, entry 1). Using
the modified set of conditions [Pd(PPh3)4–NaOAc·3H2O] we
were pleased to see that cyclization had occured, although
we were alarmed by the much lower isolated yield (Table 5,
entry 2). Another product, possibly arising from migration
of the benzoate group across the alkyne, was recovered from
this reaction in ca. 32% yield. Since the benzoate might be
too readily eliminated, we prepared the pivaloate derivative
28b (R1 = t-Bu) and were relieved to see that under the new
set of conditions, the desired furan 29 was formed once
again in moderate yield (Table 5, entry 3). To decrease the
reaction times and possibly minimize side reactions, we next
turned our attention to the use of microwave irradiation to
promote the cyclization reaction. Gratifyingly, heating 28b
for only 40 min in the microwave under otherwise identical
reaction conditions led to furan 29 in a comparable yield and
high selectivity (Table 5, entry 4). While screening for other
transition-metal catalysts, we were pleased to find that the
allylpalladium chloride dimer was also an effective catalyst
for the cyclization. In this case, both pivalate and benzoate
derivatives could be used and the furan was obtained in ac-
ceptable yields (Table 5, entries 5 and 6). Although the
(E/Z) selectivity was severely diminished, isomerization of
the furan mixture with a catalytic amount (5–10 mol%) of
(PhSe)2 in THF at reflux produced pure (E)-29 in high yield
(Table 5, entry 5). With a more practical route to this furan
in hand, we are currently exploring a strategy that involves
further modification of the protected β-hydroxy ester frag-
ment followed by an intramolecular transition-metal-
CO2Et
2.3%
H
1. I2, Pyridine, AgClO4
THF, rt, 20 h
O
H
[2] (E)-25
2. Pd(PPh3)4, Me2Zn
THF, rt, 17 h (63%)
OTBDPS
TBDPSO
(Z)-26 CO2Me
Our inability to gain access to (Z)-25 forced a reconsider-
ation of our strategy to close the macrocyclic ring in
lophotoxin. Instead of relying on the furan cyclization reac-
tion to set the stereochemistry as shown in (Z)-25 and then
attach the C19 methyl group, we decided to prepare furan
(E)-29 (Table 5) that already had an attached C19 methyl
group and to use the vinylsilane moiety for further transfor-
mations. In addition to being more convergent, this approach
gave us the opportunity to focus on a different bond discon-
nection in which C8 and C9 would be joined together by a
transition-metal-catalyzed intramolecular cross-coupling re-
action. In any event, we prepared the α-propargyl β-keto es-
ters 28 from β-keto ester 21 and the appropriate halides 27
(eq. [3]).
When substrate 28a (R1 = Ph) was subjected to the origi-
5 The 1H NMR chemical shift of the TMS group is particularly diagnostic. Indeed, in 2 the TMS group has a δ of 0.11 ppm, whereas the ma-
jor isomer in 25 has a δ of 0.00 ppm and the minor isomer has a δ of 0.09 ppm.
© 2006 NRC Canada

1232
Can. J. Chem. Vol. 84, 2006
Table 5. Transition-metal-catalyzed cyclization of α-propargyl β-keto esters 28.
CO2Et
CO2Et
Catalyst X (mol%)
O
Base (1.1 equiv.)
O
R1CO2
TMS
TMS
OTBDPS
CO2Me
Conditions
OTBDPS
CO2Me
29
28
Base
(1.1 equiv.)
E/Z
Yield
(%)
Entry
R1
Catalyst X (mol%)
Conditionsa
(ratio)b
1
2
3
4
5
6
Ph (28a)
Pd(OAc)2 (5), dppf (6)
Pd(PPh3)4 (15)
K2CO3
A
A
A
B
C
C
—
Ndc
Ph (28a)
NaOAc·3H2O
NaOAc·3H2O
NaOAc·3H2O
None
5.1:1
6.6:1
8.6:1
1.4:1
1.5:1
30
t-Bu (28b)
t-Bu (28b)
t-Bu (28b)
Ph (28a)
Pd(PPh3)4 (15)
53
Pd(PPh3)4 (15)
51
59 (50d)
[(η3-C3H5)PdCl]2 (7.5), dppf (15)
[(η3-C3H5)PdCl]2 (7.5), dppf (15)
None
54
aReagents and conditions: (A) MeCN–H2O (10:1); (B) MeCN–H2O (10:1), 100 °C, µW, 40 min; (C) THF, 100 °C, µW, 20 min.
bIsomeric ratio determined by H NMR.
1
cNd (not determined).
dYield of pure (E)-29 from 28 after isomerization with (PhSe)2.
catalyzed cross-coupling reaction with the vinylsilane moi-
ety. These results will be disclosed in due course.
230–400 mesh) and visualization was accomplished with a
254 nm UV light and (or) by staining with a basic KMnO4
solution (1.5 g of KMnO4 and 1.5 g of K2CO3 in 100 mL of
a 0.1% aq. NaOH solution). NMR spectra were recorded at
Conclusion
1
300 MHz and 76 MHz for H NMR and 13C NMR, respec-
We have shown that a catalytic desymmetrization reaction
using a modified cinchona alkaloid allows for the stereo-
selective incorporation of the C13 substituent present in
lophotoxin from a simple prochiral cyclic anhydride. A
newly developed, highly regioselective 1,6-addition reaction
of organocuprates to unsaturated [1,3]dioxin-4-ones provided
a means to introduce the C1 isopropenyl group, and encour-
aging preliminary results have established that a rhodium-
catalyzed asymmetric 1,6-addition reaction provides moder-
ate levels of diastereocontrol. Problems encountered with the
transition-metal catalyzed furan cyclization reaction have led
to modifications of our original thermal procedure and to the
development of a microwave-assisted variant. We are
currently applying these modifications toward the total syn-
thesis of lophotoxin and other members of the furanocem-
branolide family of natural products.
tively, using a Bruker AVANCE 300 MHz spectrometer at
21 °C in CDCl3 unless stated otherwise. Chemical shifts (δ)
are reported as follows: chemical shift, multiplicity (singlet
(s), doublet (d), triplet (t), quartet (q), quintet (qn), hextet
(hex), multiplet (m), broad (b)), coupling constants, and in-
tegration. IR spectra were obtained on a Nicolet AVATAR
360 FT-IR ESP spectrometer. Mass spectra were obtained on
a Micromass Autospec double focusing instrument. Optical ro-
tations were measured on a PerkinElmer 241 polarimeter.
Microwave reactions were run on a CEM Discover instru-
ment.
2,2-Dimethyl-6-(3-methylbut-1-enyl)[1,3]dioxin-4-one (13a)
O
O
O
Experimental
General methods
All moisture-sensitive reactions were performed under an
atmosphere of N2 and glassware was flame-dried under vac-
uum prior to use. Et2O and THF were dried by distillation
over Na–benzophenone. Distilled hexane and ethyl acetate
were used for chromatographic purifications. Toluene and
CH2Cl2 were purified by filtration through activated alu-
mina. TMSCl was distilled over CaH2 and kept in a
dessicator. (DHQD)2AQN was prepared according to a liter-
ature procedure (24). Unless otherwise stated, all other re-
agents and solvents were used as received. Analytical thin
layer chromatography (TLC) was performed on precoated
silica gel 60 F-254 plates (particle size 0.040–0.055 mm,
To a solution of phosphonate 12 (1.11 g, 3.99 mmol) in
THF (20 mL) cooled to 0 °C was added NaH (192 mg of a
60% mineral dispersion, 4.80 mmol). The ice bath was re-
moved and the reaction mixture was stirred at rt for 30 min,
cooled to –78 °C, and treated with isobutyraldehyde
(400 µL, 4.4 mmol). The solution was allowed to gradually
warm to rt and stirred for 1 h. One drop of satd. aq.
NaHCO3 was added and the mixture was stirred for 5 min
(to complete the deprotonation step). After adding satd. aq.
NaHCO3 (50 mL), the reaction was transferred to a separa-
tory funnel and extracted with Et2O (3 × 50 mL). The or-
ganic layers were combined, dried (Na2SO4), filtered,
© 2006 NRC Canada

Wipf and Grenon
1233
concentrated under reduced pressure, and purified by chro-
matography on SiO2 to afford 532 mg of 13a (68%) as a
colourless oil. Rf 0.26 (20% EtOAc–hexane). FT-IR
(neat, cm–1): 2963, 2872, 1731, 1653, 1592, 1391, 1374,
reaction was stopped by adding satd. aq. NaHCO3 (30 mL)
at –20 °C, then warmed to rt, transferred to a separatory fun-
nel, and extracted with Et2O (4 × 30 mL). The organic lay-
ers were combined, dried (Na2SO4), filtered, concentrated
under reduced pressure, and purified by chromatography on
SiO2 to afford 97 mg of 14a (91%) as a colourless oil. Rf
0.36 (20% EtOAc–hexane). FT-IR (neat, cm–1): 2961, 2876,
1
1273, 1206, 1018. H NMR (CDCl3) δ: 6.54 (dd, J = 15.6,
6.8 Hz, 1H), 5.85 (dd, J = 15.6, 1.4 Hz, 1H), 5.26 (s, 1H),
2.46 (hexd, J = 6.8, 1.4 Hz, 1H), 1.72 (s, 6H), 1.08 (d, J =
6.8 Hz, 6H). 13C NMR (CDCl3) δ: 163.5, 161.8, 148.5,
119.6, 106.0, 93.1, 31.1, 24.8 (2), 21.3 (2). HR-MS (EI) m/e
calcd. for C11H16O3: 196.1099; found: 196.1102.
1
1735, 1633, 1390, 1272, 1205, 1013. H NMR (CDCl3) δ:
5.23 (s, 1H), 2.29 (dd, J = 14.1, 5.0 Hz, 1H), 1.96 (dd, J =
14.1, 9.4 Hz, 1H), 1.75–1.70 (m, 1H), 1.70 (s, 3H), 1.69 (s,
3H), 1.65–1.59 (m, 1H), 0.91 (d, J = 6.8 Hz, 3H), 0.87 (d,
J = 6.8 Hz, 3H), 0.86 (d, J = 6.8 Hz, 3H). 13C NMR (CDCl3)
δ: 171.7, 161.2, 106.1, 94.0, 38.5, 36.0, 31.8, 25.2, 24.7,
19.8, 17.7, 15.0. HR-MS (ESI–POS) m/e calcd. for
C12H20O3Na: 235.1310 [M + Na]; found: 235.1299.
2,2-Dimethyl-6-(4-phenylbut-1-enyl)[1,3]dioxin-4-one (13b)
O
O
O
2,2-Dimethyl-6-(2-methyl-4-phenylbutyl)[1,3]dioxin-4-one
(14b)
O
O
O
To a solution of phosphonate 12 (1.95 g, 7.01 mmol) in
THF (50 mL) cooled to 0 °C was added NaH (240 mg of a
60% mineral dispersion, 6.00 mmol). The ice bath was re-
moved and the reaction mixture was stirred at rt for 30 min,
cooled to –78 °C, and treated with hydrocinnamaldehyde
(730 µL, 5.0 mmol). The solution was allowed to gradually
warm to rt and stirred for 1 h. One drop of satd. aq.
NaHCO3 was added and the mixture was stirred for 5 min
(to complete the deprotonation step). After adding satd. aq.
NaHCO3 (50 mL), the reaction was transferred to a separa-
tory funnel and extracted with Et2O (4 × 50 mL). The
organic layers were combined, dried (Na2SO4), filtered, con-
centrated under reduced pressure, and purified by chroma-
tography on SiO2 to afford 1.23 g of 13b (96%) as a colourless
oil. Rf 0.20 (20% EtOAc–hexane). FT-IR (neat, cm–1): 2999,
Following the previous procedure for the 1,6-addition of
Me2CuLi, [1,3]dioxin-4-one 13b (124 mg, 0.480 mmol)
gave 101 mg (77%) of 14b as a colourless oil. Rf 0.29 (20%
EtOAc–hexane). FT-IR (neat, cm–1): 2998, 2929, 1732,
1
1633, 1390, 1272, 1204, 1014. H NMR (CDCl3) δ: 7.32–
7.27 (m, 2H), 7.22–7.15 (m, 3H), 5.22 (s, 1H), 2.73–2.67
(m, 1H), 2.63–2.57 (m, 1H), 2.28 (dd, J = 14.2, 6.1 Hz, 1H),
2.07 (dd, J = 14.2, 7.9 Hz, 1H), 1.86 (hex, J = 6.4 Hz, 1H),
1.73–1.67 (m, 1H), 1.67 (s, 3H), 1.66 (s, 3H), 1.56–1.47 (m,
1H), 1.02 (d, J = 6.7 Hz, 3H). 13C NMR (CDCl3) δ: 170.8,
161.1, 141.9, 128.3 (2), 128.2 (2), 125.8, 106.1, 94.2, 41.0,
38.3, 33.1, 30.1, 25.0, 24.9, 19.3. HR-MS (ESI–POS) m/e
calcd. for C17H22O3Na [M + Na]: 297.1467; found: 297.1447.
1
2941, 1725, 1653, 1592, 1390, 1274, 1205, 1020. H NMR
(CDCl3) δ: 7.34–7.18 (m, 5H), 6.61 (dt, J = 15.5, 7.1 Hz,
1H), 5.93 (dt, J = 15.6, 1.4 Hz, 1H), 5.25 (s, 1H), 2.82–2.76
(m, 2H), 2.58–2.50 (m, 2H), 1.72 (s, 6H). 13C NMR (CDCl3)
δ: 163.1, 161.9, 141.2, 140.6, 128.4 (2), 128.2 (2), 126.1,
122.9, 106.2, 93.4, 34.6, 34.4, 24.9 (2). HR-MS (EI) m/e
calcd. for C16H18O3: 258.1256; found; 258.1254.
6-(2-Ethyl-3-methylbutyl)-2,2-dimethyl[1,3]dioxin-4-one (14c)
O
O
O
6-(2,3-Dimethylbutyl)-2,2-dimethyl[1,3]dioxin-4-one (14a)
O
O
O
To a suspension of CuI (143 mg, 0.751 mmol) in THF
(2.0 mL) cooled to 0 °C was added dropwise a 0.39 mol/L
solution of EtLi in benzene–cyclohexane (90:10, 3.8 µL,
1.5 mmol) and the mixture was stirred at 0 °C for 30 min.
The resulting dark black solution was then cooled to –78 °C
and TMSCl (380 µL, 3.0 mmol) was added. After stirring
for ca. 5 min, a solution of 13a (97.6 mg, 0.497 mmol) in
THF (1.5 mL, 1.0 mL rinse) was added. The mixture was
stirred at –78 °C for 30 min, then at –20 °C for ca. 17 h. The
reaction was stopped by adding satd. aq. NaHCO3 (30 mL)
at –20 °C, then warmed to rt, transferred to a separatory fun-
nel, and extracted with Et2O (3 × 30 mL). The organic layers
were combined, dried (Na2SO4), filtered, concentrated under
To a suspension of CuI (143 mg, 0.751 mmol) in THF
(2.5 mL) cooled to –78 °C was added dropwise a solution of
MeLi in Et2O (1.6 mol/L, 940 µL, 1.5 mmol). The cold bath
was removed and the mixture was stirred at rt for 30 min.
The resulting colourless solution was then cooled to –78 °C
and TMSCl (380 µL, 3.0 mmol) was added. After stirring
for ca. 5 min, a solution of 13a (98.8 mg, 0.503 mmol) in
THF (1.5 mL, 1.0 mL rinse) was added. The mixture was
stirred at –78 °C for 30 min, then at –20 °C for ca. 18 h. The
© 2006 NRC Canada

1234
Can. J. Chem. Vol. 84, 2006
1
reduced pressure, and purified by chromatography on SiO2
to afford 99 mg of 14c (88%) as a colourless oil. Rf 0.35
(20% EtOAc–hexane). FT-IR (neat, cm–1): 2961, 2876,
1735, 1632, 1464, 1389, 1272, 1205, 1015. 1H NMR
(CDCl3) δ: 5.24 (s, 1H), 2.21 (dd, J = 14.4, 6.0 Hz, 1H),
2.06 (dd, J = 14.4, 7.7 Hz, 1H), 1.82–1.72 (m, 1H), 1.69 (s,
6H), 1.53–1.42 (m, 1H), 1.42–1.17 (m, 2H), 0.89 (t, J =
7.5 Hz, 3H), 0.88 (d, J = 7.3 Hz, 3H), 0.86 (d, J = 7.0 Hz,
3H). 13C NMR (CDCl3) δ: 172.3, 161.3, 106.1, 94.0, 42.8,
34.9, 28.6, 25.1, 24.9, 22.8, 19.0, 18.6, 11.6. HR-MS (EI)
m/e calcd. for C10H16O2: 168.1150 [M – CH3COCH3];
found: 168.1148.
1633, 1454, 1390, 1272, 1204, 1014. H NMR (CDCl3) δ:
7.29–7.24 (m, 2H), 7.22–7.17 (m, 1H), 7.10–7.06 (m, 2H),
5.05 (s, 1H), 2.76 (dd, J = 14.2, 4.3 Hz, 1H), 2.73–2.66 (m,
1H), 2.52 (dd, J = 14.2, 11.1 Hz, 1H), 1.84 (apparent hex, J
= 6.8 Hz, 1H), 1.51 (s, 3H), 1.32 (s, 3H), 0.98 (d, J =
6.7 Hz, 3H), 0.77 (d, J = 6.7 Hz, 3H). 13C NMR (CDCl3) δ:
170.7, 161.2, 141.4, 128.4 (2), 128.1 (2), 126.6, 106.2, 94.5,
49.5, 36.9, 33.6, 25.4, 24.0, 20.6, 20.1. HR-MS (EI) m/e
calcd. for C14H16O2: 216.1150 [M – CH3COCH3]; found:
216.1150.
6-(2,4-Diphenylbutyl)-2,2-dimethyl[1,3]dioxin-4-one (14f)
6-(2-Ethyl-4-phenylbutyl)-2,2-dimethyl[1,3]dioxin-4-one (14d)
O
O
O
O
O
O
Following the previous procedure for the 1,6-addition of
Ph2CuLi, [1,3]dioxin-4-one 13b (128 mg, 0.496 mmol) gave
110 mg (66%) of 14f as a colourless oil. Rf 0.24 (20%
EtOAc–hexane). FT-IR (neat, cm–1): 3027, 2999, 2939,
Following the previous procedure for the 1,6-addition of
Et2CuLi, [1,3]dioxin-4-one 13b (131 mg, 0.507 mmol) gave
134 mg (92%) of 14d as a colourless oil. Rf 0.28 (20%
EtOAc–hexane). FT-IR (neat, cm–1): 2998, 2935, 1731,
1
2858, 1728, 1632, 1495, 1454, 1390, 1272, 1204, 1014. H
1
1631, 1455, 1390, 1272, 1204, 1014. H NMR (CDCl3) δ:
NMR (CDCl3) δ: 7.36–7.31 (m, 2H), 7.29–7.23 (m, 3H),
7.21–7.15 (m, 3H), 7.12–7.07 (m, 2H), 5.07 (s, 1H), 2.97–
2.89 (m, 1H), 2.60 (dd, J = 14.5, 6.4 Hz, 1H), 2.56–2.40 (m,
3H), 2.05–1.88 (m, 2H), 1.53 (s, 3H), 1.46 (s, 3H). 13C
NMR (CDCl3) δ: 169.8, 161.0, 142.6, 141.6, 128.6 (2),
128.29 (2), 128.26 (2), 127.5 (2), 126.8, 125.8, 106.3, 94.5,
42.3, 40.7, 38.1, 33.3, 25.0, 24.6. HR-MS (EI) m/e calcd. for
C19H18O2: 278.1307 [M – CH3COCH3]; found: 278.1303.
7.32–7.26 (m, 2H), 7.22–7.14 (m, 3H), 5.23 (s, 1H), 2.67–
2.57 (m, 2H), 2.26–2.19 (m, 2H), 1.73–1.60 (m, 3H), 1.67
(s, 3H), 1.65 (s, 3H), 1.49–1.36 (m, 2H), 0.92 (t, J = 7.4 Hz,
3H). 13C NMR (CDCl3) δ: 171.2, 161.2, 142.0, 128.3 (2),
128.2 (2), 125.8, 106.2, 94.2, 37.7, 36.1, 34.7, 32.7, 25.5,
25.0, 24.9, 10.4. HR-MS (EI) m/e calcd. for C18H24O3:
288.1725; found: 288.1727.
2,2-Dimethyl-6-(3-methyl-2-phenylbutyl)-[1,3]dioxin-4-one
(14e)
6-[2-(Dimethylphenylsilanyl)-3-methylbutyl]-2,2-
dimethyl[1,3]dioxin-4-one (14g)
O
O
O
O
Si
O
O
To a suspension of CuI (143 mg, 0.751 mmol) in THF
(1.0 mL) cooled to –20 °C was added dropwise a solution of
PhMe2SiLi in THF (0.40 mol/L, 3.8 µL, 1.5 mmol), and the
mixture was stirred at –20 °C for 4 h. TMSCl (380 µL,
3.0 mmol) was added and the mixture was stirred for ca.
5 min after which a solution of 13a (95.4 mg, 0.486 mmol)
in THF (1.5 mL, 1.0 mL rinse) was added. The reaction
mixture was stirred at –20 °C for ca. 15 h, stopped by add-
ing satd. aq. NaHCO3 (30 mL) at –20 °C, then warmed to rt,
transferred to a separatory funnel, and extracted with Et2O
(4 × 30 mL). The organic layers were combined, dried
(Na2SO4), filtered, concentrated under reduced pressure, and
purified by chromatography on SiO2 to afford 97 mg of 14g
(60%) as a colourless oil. Rf 0.42 (20% EtOAc–hexane). FT-
IR (neat, cm–1): 2998, 2957, 2872, 1732, 1630, 1427, 1389,
To a suspension of CuI (143 mg, 0.751 mmol) in THF
(2.5 mL) cooled to 0 °C was added dropwise a solution of
PhLi (1.0 mol/L) in cyclohexane–Et2O (70:30, 1.5 mL,
1.5 mmol). After stirring at 0 °C for 30 min, the mixture was
cooled to –78 °C, at which point a dense precipitate formed.
TMSCl (380 µL, 3.0 mmol) was added and after ca. 5 min a
solution of 13a (99.2 mg, 0.506 mmol) in THF (1.5 mL,
1.0 mL rinse) was added. The mixture was stirred at –78 °C
for 30 min, then at –20 °C for ca. 18 h. The reaction was
stopped by adding satd. aq. NaHCO3 (30 mL) at –20 °C,
then warmed to rt, transferred to a separatory funnel, and ex-
tracted with Et2O (4 × 30 mL). The organic layers were
combined, dried (Na2SO4), filtered, concentrated under re-
duced pressure, and purified by chromatography on SiO2 to
afford 110 mg of 14e (79%) as a colourless oil. Rf 0.31 (20%
EtOAc–hexane). FT-IR (neat, cm–1): 2960, 2873, 1731,
1
1271, 1205, 1111, 1016. H NMR (CDCl3) δ: 7.54–7.47 (m,
© 2006 NRC Canada

Wipf and Grenon
1235
2H), 7.39–7.33 (m, 3H), 5.17 (s, 1H), 2.30–2.22 (m, 2H),
1.98–1.92 (m, 1H), 1.63 (s, 3H), 1.60 (s, 3H), 1.31–1.26 (m,
1H), 0.95 (d, J = 6.9 Hz, 3H), 0.88 (d, J = 7.0 Hz, 3H), 0.36
(s, 6H). 13C NMR (CDCl3) δ: 172.6, 161.2, 138.3, 133.7 (2),
129.0, 127.8 (2), 106.1, 93.5, 31.4, 29.8, 28.7, 25.2, 24.6,
22.0, 21.3, –2.2, –3.1. HR-MS (EI) m/e calcd. for
C18H25O3Si: 317.1573 [M – CH3]; found: 317.1557.
2.22 (d, J = 5.6 Hz, 2H), 2.11–2.06 (m, 1H), 1.69 (s, 6H),
1.50 (td, J = 5.7, 1.9 Hz, 1H), 0.93–0.92 (m, 12H), 0.87 (d,
J = 6.8 Hz, 3H). 13C NMR (CDCl3) δ: 174.1, 161.5, 106.1,
93.2, 49.9, 34.9, 30.4, 28.6 (3), 27.7, 25.2, 25.0, 24.4, 18.3.
HR-MS (EI) m/e calcd. for C15H27O3: 255.1960 [M + H];
found: 255.1964.
6-(3,3-Dimethyl-2-phenethylbutyl)-2,2-dimethyl[1,3]dioxin-
4-one (14j)
6-(2-(Dimethyl(phenyl)silyl)-4-phenylbutyl)-2,2-dimethyl-
4H-1,3-dioxin-4-one (14h)
O
O
O
O
Si
O
Ph
O
Following the previous procedure for the 1,6-addition of
(PhMe2Si)2CuLi, [1,3]dioxin-4-one 13b (129 mg,
0.499 mmol) gave 121 mg (61%) of 14h as a colourless oil.
Rf 0.26 (20% EtOAc–hexane). FT-IR (neat, cm–1): 2999,
Following the previous procedure for the 1,6-addition of
(t-Bu)2CuLi, [1,3]dioxin-4-one 13b (130 mg, 0.503 mmol)
gave 68 mg (43%) of 14j as a colourless oil. Rf 0.33 (20%
EtOAc–hexane). FT-IR (neat, cm–1): 3026, 2960, 1732,
1
1
2950, 2859, 1729, 1629, 1389, 1272, 1204, 1112, 1014. H
1630, 1454, 1389, 1272, 1204, 1014. H NMR (CDCl3) δ:
NMR (CDCl3) δ: 7.53–7.48 (m, 2H), 7.42–7.36 (m, 3H),
7.28–7.23 (m, 2H), 7.20–7.16 (m, 1H), 7.05–7.01 (m, 2H),
5.19 (s, 1H), 2.61–2.53 (m, 1H), 2.53–2.46 (m, 1H), 2.38
(dd, J = 14.9, 4.5 Hz, 1H), 2.16 (dd, J = 14.9, 9.6 Hz, 1H),
1.83–1.75 (m, 1H), 1.67–1.59 (m, 1H, hidden under two s),
1.65 (s, 3H), 1.64 (s, 3H), 1.32–1.25 (m, 1H), 0.363 (s, 3H),
0.360 (s, 3H). 13C NMR (CDCl3) δ: 171.9, 161.0, 141.8,
137.2, 133.8 (2), 129.3, 128.3 (2), 128.1 (2), 127.9 (2),
125.8, 106.2, 93.8, 35.2, 34.3, 31.9, 25.1, 24.7, 22.1, –4.1, –
4.2. HR-MS (EI) m/e calcd. for C24H30O3Si: 394.1964;
found: 394.1953.
7.32–7.25 (m, 2H), 7.22–7.13 (m, 3H), 5.32 (s, 1H), 2.74–
2.67 (m, 1H), 2.58–2.51 (m, 1H), 2.47 (dd, J = 15.0, 4.2 Hz,
1H), 2.07 (dd, J = 15.0, 7.5 Hz, 1H), 1.90–1.82 (m, 1H),
1.71 (s, 6H), 1.53–1.48 (m, 1H), 1.46–1.37 (m, 1H), 0.91 (s,
9H). 13C NMR (CDCl3) δ: 172.7, 161.2, 142.1, 128.4 (2),
128.2 (2), 125.9, 106.2, 93.8, 45.1, 35.9, 35.6, 33.9, 33.4,
27.5 (3), 25.3, 24.9. HR-MS (EI) m/e calcd. for C17H22O2:
258.1620 [M – (CH3)2CO]; found: 258.1616.
3-(tert-Butyldiphenylsilanyloxy)pentanedioic acid diethyl
ester (15, R1 = OTBDPS)
OTBDPS
6-(2-Isopropyl-3,3-dimethylbutyl)-2,2-dimethyl[1,3]dioxin-
4-one (14i)
EtO2C
CO2Et
O
O
O
To a solution of imidazole (1.36 g, 20.0 mmol) in CH2Cl2
(20 mL) at rt was added TBDPSCl (2.47 mL, 9.50 mmol).
After stirring for 10 min at rt, a solution of diethyl 3-
hydroxyglutarate (2.04 g, 10.0 mmol) in CH2Cl2 (5, 2, and
1 mL rinses) was added to the white suspension. The reac-
tion was stirred at rt for 16 h after which it was stopped by
the addition of water (25 mL) and diluted with Et2O
(125 mL). The mixture was then transferred to a separatory
funnel, extracted, the layers separated, and the organic layer
was washed with brine (25 mL). The aqueous layers were
combined and extracted with Et2O (50 mL). The organic lay-
ers were combined, dried (Na2SO4), filtered, concentrated
under reduced pressure, and purified by chromatography on
SiO2 to afford 4.05 g of 15 (96%) as a white solid; mp 44–
46 °C. Rf 0.48 (20% EtOAc–hexane). FT-IR (KBr, cm–1):
To a suspension of CuI (143 mg, 0.751 mmol) in THF
(2.5 mL) cooled to –78 °C was added dropwise a solution of
t-BuLi in pentane (1.4 mol/L, 1.1 µL, 1.5 mmol). The
mixture was stirred at –78 °C for 30 min and then TMSCl
(380 µL, 3.0 mmol) was added. After stirring for ca. 5 min,
a solution of 13a (101 mg, 0.515 mmol) in THF (1.5 mL,
1.0 mL rinse) was added. The mixture was stirred at –78 °C
for 30 min, then at –20 °C for ca. 15 h. The reaction was
stopped by adding satd. aq. NaHCO3 (30 mL) at –20 °C,
then warmed to rt, transferred to a separatory funnel, and ex-
tracted with Et2O (3 × 30 mL). The organic layers were
combined, dried (Na2SO4), filtered, concentrated under re-
duced pressure, and purified by chromatography on SiO2 to
afford 22 mg of 14i (17%) as a colourless oil. Rf 0.53 (20%
EtOAc–hexane). FT-IR (neat, cm–1): 2960, 1733, 1630,
1
2966, 1740, 1378, 1268, 1227, 1145, 1107, 1026. H NMR
(CDCl3) δ: 7.70–7.66 (m, 4H), 7.47–7.35 (m, 6H), 4.55 (qn,
J = 6.0 Hz, 1H), 4.08–3.97 (m, 4H), 2.60 and 2.54 (AB of
ABX, J = 15.2, 6.3 and 15.2, 5.9 Hz, 4H), 1.19 (t, J =
7.1 Hz, 6H), 1.03 (s, 9H). 13C NMR (CDCl3) δ: 170.8 (2),
135.8 (4), 133.5 (2), 129.7 (2), 127.6 (4), 67.2, 60.3 (2), 41.8
(2), 26.8 (3), 19.2, 14.1 (2). HR-MS (EI) m/e calcd. for
C24H31O5Si: 427.1941 [M – CH3]; found: 427.1931.
1
1389, 1271, 1205, 1016. H NMR (CDCl3) δ: 5.29 (s, 1H),
© 2006 NRC Canada

1236
Can. J. Chem. Vol. 84, 2006
ref. 25. This material was combined with other crude
desymmetrized material to provide 7.29 g of product. The
catalyst was recovered by basifying the acidic aqueous layer
with KOH pellets (a yellow precipitate formed). The aque-
ous layer was then extracted with Et2O until the organic
layer remained colourless. The organic layers were com-
bined, dried (Na2SO4), filtered, and concentrated under re-
duced pressure. The recovered catalyst was purified by
chromatography on SiO2 with 5% MeOH–CHCl3 containing
0.5% aq. NH4OH before being reused.
3-[(tert-Butyldiphenylsilyl)oxy]pentanedioic anhydride
(8b, R1 = OTBDPS)
OTBDPS
O
O
O
To a solution of diester 15 (8.85 g, 20.0 mmol) in MeOH
(30 mL) was added NaOH pellets (2.00 g, 50.0 mmol) and
the mixture was stirred vigorously at rt for 38 h. The result-
ing yellowish suspension was concentrated under reduced
pressure and kept under high vacuum. The flaky solid was
then crushed into smaller pieces, suspended in a mixture of
benzene (40 mL) and Ac2O (30 mL) and heated to reflux for
1.5 h. During this time, the colour changed to a deep purple.
After cooling to rt, the reaction was stopped by the addition
of brine (200 mL) and the mixture was transferred to a sepa-
ratory funnel with CHCl3 (400 mL). After extraction, the
layers were separated and the organic layer was washed with
satd. aq. NaHCO3 (3 × 200 mL). The organic layer was then
dried (MgSO4), filtered, concentrated under reduced pres-
sure, and purified by chromatography on SiO2 [pretreated
with hexane containing 1% Ac2O, solvent gradient from
pure hexane (+1% Ac2O) to 20% EtOAc–hexane (+1%
Ac2O)] to afford 3.40 g of 8b (46%) as a white solid.
Recrystallization from a hot mixture of hexane–EtOAc
(20:1) provided white needles; mp 107 to 108 °C (hexane–
EtOAc 20:1). Rf 0.27 (20% EtOAc–hexane containing 1%
Ac2O). FT-IR (KBr, cm–1): 2932, 1817, 1765, 1429, 1348,
(S)-3-((tert-Butyldiphenylsilyl)oxy)-5-hydroxypentanoic
acid, methyl ester (17)
OTBDPS
MeO2C
OH
To a solution of crude acid 16 (7.29 g, 19.8 mmol) in THF
(100 mL) at rt was added a solution of BH3·DMS in THF
(2.0 mol/L, 30 mL, 60 mmol) and the mixture was stirred
for 15 h. The reaction was stopped by slowly adding satd.
aq. NaHCO3 (350 mL) and stirred vigorously for 20 min.
The mixture was then transferred to a separatory funnel and
extracted with Et2O (3 × 300 mL). The organic layers were
combined, dried (Na2SO4), filtered, concentrated under re-
duced pressure, and purified by chromatography on SiO2 to
afford 5.41 g of 17 (71%) as a colourless oil. 1H NMR
(CDCl3) δ: 7.74–7.65 (m, 4H), 7.48–7.37 (m, 6H), 4.38 (qn,
J = 5.9 Hz, 1H), 3.70–3.61 (m, 2H), 3.54 (s, 3H), 2.55 (d,
J = 6.4 Hz, 2H), 1.86–1.80 (m, 1H), 1.78–1.72 (m, 1H), 1.62
1
1262, 1191, 1111, 1070, 1044. H NMR (CDCl3) δ: 7.71–
1
(bt, J = 5.5 and 5.2 Hz, 1H), 1.06 (s, 9H). The H NMR
7.56 (m, 4H), 7.55–7.35 (m, 6H), 4.31 (qn, J = 3.2 Hz, 1H),
2.86 (dd, J = 16.0, 3.6 Hz, 2H), 2.58 (dd, J = 16.0, 2.4 Hz,
2H), 1.05 (s, 9H). 13C NMR (CDCl3) δ: 165.3 (2), 135.8 (4),
132.4 (2), 130.6 (2), 128.3 (4), 62.9, 38.9 (2), 26.9 (3), 19.2.
HR-MS (EI) m/e calcd. for C17H15O4Si: 311.0740 [M –
C4H9]; found: 311.0744.
spectra was identical with the one reported in ref. 25.
(S)-3-((tert-Butyldiphenylsilyl)oxy)-5-hydroxypentanoic
acid lactone (18)
O
O
(S)-((3-tert-Butyldiphenylsilyl)oxy)pentanedioic acid
monomethyl ester (16)
TBDPSO
OTBDPS
MeO2C
CO2H
To a solution of crude acid 16 (115 mg, 0.287 mmol) in
THF (2.0 mL) at rt was added a solution of BH3·DMS in
THF (2.0 mol/L, 430 µL, 0.86 mmol) and the mixture was
stirred for 17 h. The reaction was stopped by slowly adding
10% HCl (3.5 mL) and stirred vigorously for 1 h. The mix-
ture was then transferred to a separatory funnel and ex-
tracted with Et2O (3 × 5 mL). The organic layers were
combined, dried (Na2SO4), filtered, concentrated under re-
duced pressure, and purified by chromatography on SiO2 to
afford 38 mg of 18 (38%) as a colourless oil. [α]D –12.3 (c
7.55, CHCl3). 1H NMR (CDCl3) δ: 7.67–7.62 (m, 4H), 7.50–
7.37 (m, 6H), 4.63 (ddd, J = 11.3, 8.6, 4.5 Hz, 1H), 4.28–
4.18 (m, 2H), 2.59 (d, J = 4.9 Hz, 2H), 1.94–1.75 (m, 2H),
To a previously dried flask containing cyclic anhydride 8b
(1.09 g, 2.96 mmol) was added Et2O (100 mL). The solution
was cooled to –40 °C, (DHQD)2AQN (760 mg, 0.887 mmol)
was added and the mixture was stirred for about 20 min.
MeOH (1.20 mL, 29.6 mmol) was then added and the reac-
tion was stirred at –40 °C for 70–72 h, stopped by the addi-
tion of 10% aq. HCl (90 mL) at –40 °C, and allowed to
warm to rt. After transferring to a separatory funnel, the
mixture was extracted, the layers were separated, and the
aqueous layer was reextracted with EtOAc (2 × 100 mL).
The organic layers were combined, dried (Na2SO4), filtered,
and concentrated under reduced pressure to provide 1.25 g
1
1.08 (s, 9H). The H NMR spectra was identical with the
1
of the crude acid 16 as a pale yellow oil. H NMR (CDCl3)
δ: 7.70–7.65 (m, 4H), 7.48–7.35 (m, 6H), 4.51 (qn, J =
6.1 Hz, 1H), 3.56 (s, 3H), 2.69–2.53 (m, 4H), 1.03 (s, 9H).
one reported in ref. 25. The enantiomeric excess was
determined by chiral HPLC (Chiralcel OD) using i-PrOH–
hexane (1.0%) at a flow rate of 1.0 mL/min (Rt minor =
22.8 min, Rt major = 24.5 min).
1
The H NMR spectra was identical with the one reported in
© 2006 NRC Canada

Wipf and Grenon
1237
then at 0 °C for 30–45 min. To a suspension of CuI (1.10 g,
5.78 mmol) in THF (20 mL) cooled to –78 °C was added the
solution of 2-lithiopropene (39 mL, 12 mmol). The dark
black mixture was stirred at –78 °C for 30 min and then
TMSCl (3.0 mL, 24 mmol) was added. After stirring for ca.
5 min, a solution of 19 (981 mg, 1.93 mmol) in THF
(6.0 mL, 2 × 2.0 mL rinse) was added. The mixture was
stirred at –78 °C for 30 min, then at –20 °C for ca. 16 h. The
reaction was stopped by adding satd. aq. NaHCO3 (100 mL)
at –20 °C, then warmed to rt, transferred to a separatory fun-
nel, and extracted with Et2O (4 × 100 mL). The organic lay-
ers were combined, dried (Na2SO4), filtered, concentrated
under reduced pressure, and purified by chromatography on
SiO2 to afford 999 mg of 20 (94%) as a colourless oil. Rf
0.38 (30% EtOAc–hexane). FT-IR (neat, cm–1): 2933, 2858,
3-(tert-Butyldiphenylsilanyloxy)-6-(2,2-dimethyl-6-oxo-6H-
[1,3]dioxin-4-yl)hex-5-enoic acid methyl ester (19)
O
OTBDPS
O
MeO2C
O
To a stirred solution of alcohol 17 (5.41 g, 14.0 mmol) in
a mixture of CH2Cl2 (63 mL) and CH3CN (7 mL) at rt was
added NMO (2.46 g, 21.0 mmol) and 4 Å molecular sieves
(7.0 g). TPAP (246 mg, 0.700 mmol) was added in three
portions over a period of 20 min and the resulting mixture
was stirred for 30 min at rt. The dark black mixture was then
filtered over Celite with CH2Cl2 and the filtrate was concen-
trated under reduced pressure. The resulting oil was rapidly
purified by chromatography on SiO2 with EtOAc–hexanes
(20%) to afford 4.23 g of the corresponding aldehyde (79%)
as a colourless oil. A solution of phosphonate 12 (4.28 g,
15.4 mmol) in THF (100 mL) cooled to 0 °C was treated
with 95% NaH (317 mg, 13.2 mmol). The cold bath was re-
moved and the mixture was stirred at rt for 20 min. After
cooling to –78 °C, a solution of the aldehyde (4.23 g,
11.0 mmol) in THF (5 mL, 5 mL rinse) was added, the bath
was removed, and the reaction was allowed to gradually
warm to rt and was stirred at that temperature for 1 h. One
drop of satd. aq. NaHCO3 was added and the mixture was
stirred for 5 min (to complete the deprotonation step). After
adding additional satd. aq. NaHCO3 (300 mL), the mixture
was transferred to a separatory funnel and extracted with
Et2O (3 × 300 mL). The organic layers were combined,
dried (Na2SO4), filtered, concentrated under reduced pres-
sure, and purified by chromatography on SiO2 to afford
3.50 g of 19 (49% from alcohol) as a colourless oil. [α]D
58.0 (c 0.21, CHCl3). Rf 0.33 (30% EtOAc–hexane). FT-IR
(neat, cm–1): 2932, 2858, 1728, 1655, 1592, 1428, 1390,
1
1732, 1633, 1428, 1390, 1272, 1205, 1111, 1015. H NMR
(CDCl3) δ: 7.75–7.62 (m, 4H), 7.51–7.34 (m, 6H), 5.08 and
5.05 (s, 1H), 4.66–4.62 (m, 1H), 4.54 and 4.41 (br s, 1H),
4.14–4.03 (m, 1H), 3.59 and 3.54 (s, 3H), 2.65–2.26 (m,
3H), 2.11–1.97 (m, 2H), 1.67–1.47 (m, 2H), 1.65 and 1.64
(s, 3H), 1.60 and 1.58 (s, 3H), 1.49 and 1.21 (s, 3H), 1.04
and 1.02 (s, 9H). 13C NMR (CDCl3) δ: 171.6 [171.3], 170.0
[169.8], 161.16 [161.09], 144.4 [144.3], 135.9 (8), 133.9
[133.7], 133.6 [133.5], 129.8 (4), 127.6 (8), 113.9 [113.3],
106.3 (2), 94.2 [94.1], 68.6 [68.4], 51.41 [51.36], 42.6
[41.2], 40.8 [40.7], 40.8 [40.4], 37.8 [37.4], 26.9 (3) [26.8
(3)], 25.40 [25.36], 25.0 [24.9], 19.3 [19.2], 17.6 [17.3]. HR-
MS (ESI–POS) m/e calcd. for C32H42O6NaSi: 573.2648
[M + Na]; found: 573.2642.
Rhodium-catalyzed asymmetric 1,6-addition of
potassium isopropenyl organotrifluoroborate to 19 in
the presence of Carreira’s diene
To a dry sealed tube was added the diene ligand (3.6 mg,
0.014 mmol), Rh(acac)(eth)2 (3 mg, 0.01 mmol), and EtOH
(0.5 mL) and the mixture was stirred at rt for 15 min. A so-
lution of 19 (117 mg, 0.230 mmol) in EtOH (0.75 mL,
0.75 mL rinse) was then added, followed by potassium
1
1274, 1206, 1111, 1020. H NMR (CDCl3) δ: 7.76–7.60 (m,
4H), 7.52–7.33 (m, 6H), 6.44 (dt, J = 15.5, 7.5 Hz, 1H), 5.78
(d, J = 15.6 Hz, 1H), 5.18 (s, 1H), 4.29 (qn, J = 6.0 Hz, 1H),
3.57 (s, 3H), 2.54 (A of ABX, JAB = 15.2, JAX = 6.4 Hz,
1H), 2.48–2.36 (m, 3H), 1.67 (s, 6H), 1.04 (s, 9H). 13C
NMR (CDCl3) δ: 171.3, 162.7, 161.9, 137.4, 135.81 (2),
135.78 (2), 133.4, 133.3, 129.8 (2), 127.6 (4), 125.2, 106.2,
93.8, 69.5, 51.5, 41.7, 40.2, 26.8 (3), 24.9 (2), 19.2. HR-MS
(EI) m/e calcd. for C25H27O6Si: 451.1577 [M – C4H9];
found: 451.1575.
isopropenyl
organotrifluoroborate
(37)
(102
mg,
0.689 mmol). The reaction mixture was stirred at 82 °C for
24 h, cooled to rt, and treated with satd. aq. NaHCO3
(15 mL). The mixture was transferred to a separatory funnel
and extracted with Et2O (3 × 15 mL). The organic layers
were combined, dried (Na2SO4), filtered, concentrated under
reduced pressure, and purified by chromatography on SiO2
to afford 27.2 mg (21%) of 20 and 47.5 mg of 21 (38%).
6-(2,2-Dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxyhex-
5-enoic acid methyl ester (23)
(3S)-Methyl 3-(tert-butyldiphenylsilyloxy)-5-((2,2-dimethyl-
4-oxo-4H-1,3-dioxin-6-yl)methyl)-6-methylhept-6-enoate (20)
O
O
O
OH
O
TBDPSO
MeO2C
O
MeO
O
O
A solution of t-BuLi in pentane (1.2 mol/L, 33 mL,
40 mmol) cooled to –78 °C was diluted with THF (33 mL)
and 2-bromopropene (1.78 mL, 20.0 mmol) was added
dropwise. The mixture was stirred at –78 °C for 30 min,
To a solution of 19 (234 mg, 0.460 mmol) in THF
(5.5 mL) in a plastic tube was added HF·pyridine (600 µL,
23 mmol) and the mixture was stirred vigorously at rt for
3 days. The reaction was stopped by dropwise addition to
© 2006 NRC Canada

1238
Can. J. Chem. Vol. 84, 2006
satd. aq. NaHCO3 (75 mL). After adding solid NaHCO3 to
the aqueous solution, the mixture was transferred to a sepa-
ratory funnel and extracted with Et2O (4 × 30 mL). The or-
ganic layers were combined, dried (Na2SO4), filtered,
concentrated under reduced pressure, and purified by chro-
matography on SiO2 to afford 34 mg (15%) of starting mate-
rial 19 and 101 mg of 23 (81%) as a colourless oil. [α]D 5.9
(c 2.38, CH2Cl2). Rf 0.17 (50% EtOAc–hexane). FT-IR
(neat, cm–1): 3454, 2999, 2952, 1728, 1651, 1592, 1392,
reduced pressure and kept under high vacuum. The crude β-
keto ester was redissolved in THF (20 mL) and cooled to
0 °C. The septum was temporarily removed to allow the
quick introduction of 98% NaH (52 mg, 2.2 mmol) and the
mixture was stirred at 0 °C for ca. 20 min. Afterwards, a so-
lution of iodide 4 [prepared from the corresponding chloride
(1.86 g, 3.30 mmol) and NaI (679 mg, 4.53 mmol) in
refluxing acetone (15 mL)] in THF (6.0 mL, 6.0 mL rinse)
was added and the reaction was gradually warmed to rt,
while maintaining the flask in the cold bath. After stirring
overnight, the reaction mixture was concentrated under re-
duced pressure and filtered over a pad of SiO2 with EtOAc–
hexane (20%). This material was then purified by chroma-
tography on SiO2 to afford 1.50 g of 22 (77%, two steps) as
a colourless oil. Since this α-propargyl β-keto ester exists as
a mixture of up to four different diastereomers, it was not
characterized.
1
1276, 1204, 1067, 1020. H NMR (CDCl3) δ: 6.59 (dt, J =
15.6, 7.6 Hz, 1H), 6.01 (d, J = 15.6 Hz, 1H), 5.28 (s, 1H),
4.23–4.13 (m, 1H), 3.74 (s, 3H), 3.10 (d, J = 3.6 Hz, 1H),
2.54 (A of ABX, JAB = 16.7, JAX = 3.4 Hz, 1H), 2.51–2.40
(m, 3H), 1.72 (s, 6H). 13C NMR (CDCl3) δ: 172.8, 162.7,
161.9, 137.2, 125.1, 106.4, 93.9, 66.9, 51.8, 40.6, 39.4, 24.9
(2). HR-MS (EI) m/e calcd. for C13H16O5: 252.0998 [M –
H2O]; found: 252.0999.
(S,E)-Methyl 3-acetoxy-6-(2,2-dimethyl-4-oxo-4H-1,3-
dioxin-6-yl)hex-5-enoate (24)
Ethyl 5-((E)-4-(tert-butyldiphenylsilyloxy)-2-(trimethyl-
silyl)but-1-enyl)-2-((4S)-4-(tert-butyldiphenylsilyloxy)-6-
methoxy-6-oxo-2-(prop-1-en-2-yl)hexyl)furan-3-
carboxylate (25)
O
O
OAc
O
CO2Et
MeO
O
To a solution of 23 (51.2 mg, 0.189 mmol) in pyridine
(1.56 mL, 19.3 mmol) was added Ac2O (910 µL, 9.6 mmol)
and the mixture was stirred at rt for 6.5 h. After concentrat-
ing under reduced pressure, the resulting mixture was puri-
fied by chromatography on SiO2 to afford 56.4 mg (95%) of
24 as a colourless oil. [α]D 11.9 (c 1.96, CH2Cl2). Rf 0.37
(50% EtOAc–hexane). FT-IR (neat, cm–1): 2999, 2954,
1732, 1656, 1594, 1438, 1376, 1244, 1020. 1H NMR
(CDCl3) δ: 6.45 (dt, J = 15.5, 7.5 Hz, 1H), 5.98 (dt, J = 15.6,
1.3 Hz, 1H), 5.36–5.27 (m, 1H), 5.28 (s, 1H), 3.69 (s, 3H),
2.64 (A of ABX, JAB = 15.8, JAX = 7.3 Hz, 1H), 2.59–2.52
(m, 2H), 2.04 (s, 3H), 1.71 (s, 6H). 13C NMR (CDCl3) δ:
170.3, 170.1, 162.5, 161.9, 135.6, 125.8, 106.5, 94.3, 68.8,
51.9, 38.2, 37.0, 25.0, 24.9, 20.9. HR-MS (EI) m/e calcd. for
C13H16O5: 252.0998 [M – CH3CO2H]; found: 252.0998.
O
TMS
TBDPSO
OTBDPS
CO2Me
A solution of α-propargyl β-keto ester 22 (76.0 mg,
0.0713 mmol) in a mixture of MeCN (1.0 mL) and H2O
(100 µL) was subjected to three freeze–pump–thaw cycles.
Afterwards, NaOAc·3H2O (10.7 mg, 0.0784 mmol) and
Pd(PPh3)4 (12 mg, 0.010 mmol) were added and the mixture
was stirred at 87 °C for 2 h. After cooling to rt, the crude
mixture was filtered over a pad of SiO2 with 20% EtOAc–
hexane and concentrated under reduced pressure. This mate-
rial was then purified by chromatography on SiO2 to afford
33.2 mg of 25 (49%, 6.8:1 mixture of (E)–(Z)-isomers) as a
colourless oil. Rf 0.28 (10% EtOAc–hexane). FT-IR
(neat, cm–1): 3071, 2931, 2857, 1741, 1716, 1590, 1428,
(7S)-Dimethyl 2-(4-(benzoyloxy)-6-(tert-butyldiphenylsilyl-
oxy)-4-(trimethylsilyl)hex-2-ynyl)-7-(tert-butyldiphenyl-
silyloxy)-3-oxo-5-(prop-1-en-2-yl)nonanedioate (22)
CO2Et
1
1388, 1230, 1111. H NMR (CDCl3) δ: 7.75–7.59 (m, 8H),
7.46–7.31 (m, 12H), 6.75 and 6.71 (s, 1H), 6.45 and 6.42 (s,
1H), 4.58 and 4.46 (brs, 1H), 4.46 and 4.41 (brs, 1H), 4.32–
4.20 (m, 2H), 4.18–4.03 (m, 1H), 3.71–3.61 (m, 2H), 3.55
and 3.49 (s, 3H), 2.94–2.72 (m, 4H), 2.61–2.33 (m, 2H),
1.75–1.48 (m, 3H), 1.57 and 1.21 (s, 3H), 1.33 and 1.30 (t,
J = 7.2 Hz, 3H), 1.063 and 1.056 (s, 9H), 1.00 (s, 9H),
–0.003 and –0.004 (s, 9H). 13C NMR (CDCl3) δ: 172.0
[171.5], 163.8 [163.7], 160.0 [159.7], 151.1 [151.0], 145.7
[144.9], 140.04 [139.99], 135.94, 135.88, 135.8, 135.6,
135.2, 134.8, 134.2, 133.8, 133.62, 133.58, 129.5, 127.7,
127.6, 127.5, 127.4, 126.6 [126.4], 115.6, 112.85 [112.80],
110.0, 69.0 [68.9], 62.5, 60.1, 51.33 [51.27], 43.2, 43.0,
42.5 41.0, 40.1, 39.6, 34.7, 32.4 [32.3], 26.9, 26.8, 26.5,
19.2, 19.1, 19.0, 18.0, 16.9, 14.33 [14.28], 0.14, –1.8.
O
TMS
PivO
OTBDPS
OTBDPS
CO2Me
To
a solution of [1,3]dioxin-4-one 20 (999 mg,
1.81 mmol) in toluene (20 mL) was added EtOH (530 µL,
9.1 mmol). The solution was heated at reflux for ca. 1.5 h
until TLC analysis showed complete consumption of the
starting material. The solution was then concentrated under
© 2006 NRC Canada

Wipf and Grenon
1239
TMS OBz
Ethyl 5-((Z)-4-(tert-butyldiphenylsilyloxy)-2-methylbut-1-
enyl)-2-((4S)-4-(tert-butyldiphenylsilyloxy)-6-methoxy-6-
oxo-2-(prop-1-en-2-yl)hexyl)furan-3-carboxylate (26)
Cl
CO2Et
–78 °C for 20 min, acetyltrimethylsilane (720 µL, 5.0 mmol)
was added dropwise. The mixture was stirred at –78 °C for
30 min and benzoyl chloride (870 µL, 7.8 mmol) was added.
The reaction was allowed to gradually warm up to rt, while
maintained in the cold bath and stirred overnight. The reac-
tion was stopped by adding H2O (50 mL) and the mixture
was transferred to a separatory funnel. After extraction, the
organic layer was separated and the aqueous layer was ex-
tracted once more with Et2O (50 mL). The organic layers
were combined, dried (Na2SO4), filtered, concentrated under
reduced pressure, and purified by chromatography on SiO2
to afford 1.2 g of 27a (80%) as a yellow-orange oil. For the
full spectral characterization of this compound, see ref. 11.
O
TBDPSO
OTBDPS
CO2Me
To a solution of I2 (105 mg, 0.414 mmol) in THF
(0.5 mL) was added pyridine (50 µL, 0.62 mmol) followed
by AgClO4 (85 mg, 0.41 mmol). The mixture was stirred at
rt for 15 min, then a solution of furan 25 (97.4 mg,
0.103 mmol) in THF (1.0 mL, 2 × 0.5 mL rinse) was added.
After stirring at rt for 19 h, the crude reaction mixture was
filtered over a pad of Celite with Et2O (25 mL). The solution
was transferred to a separatory funnel and extracted with a
mixture of 10% aq. Na2S2O3 (10 mL) and satd. aq. NaHCO3
(10 mL). The layers were separated and the aqueous layer
was extracted again with Et2O (2 × 10 mL). The combined
organic layers were dried (Na2SO4), filtered, and concen-
trated under reduced pressure to afford 113 mg of crude vi-
nyl iodide. The iodide was redissolved in THF (1.0 mL) and
subjected to two freeze–pump–thaw cycles. The degassed
solution was then cooled to 0 °C and Pd(PPh3)4 (6.0 mg,
0.0052 mmol) was added, followed by a 2.0 mol/L solution
of Me2Zn in toluene (160 µL, 0.32 mmol). The cold bath
was removed and the reaction was stirred at rt for ca. 17 h,
stopped by adding H2O (5 mL), and transferred to a separa-
tory funnel. The aqueous layer was extracted with Et2O (3 ×
5 mL), the organic layers were combined, washed with brine
(10 mL), dried (Na2SO4), filtered, concentrated under re-
duced pressure, and purified by chromatography on SiO2 to
afford 57.5 mg of 26 (63%, 4.7:1 mixture of (Z)–(E)-iso-
mers) as a colourless oil. Rf 0.28 (10% EtOAc–hexane). FT-
IR (neat, cm–1): 3071, 2931, 2857, 1740, 1715, 1600, 1428,
5-Chloro-2-(trimethylsilyl)pent-3-yn-2-yl pivalate (27b)
TMS OPiv
Cl
A solution of n-BuLi (1.6 mol/L, 8.8 mL, 14 mmol) in
Et2O (80 mL) cooled to –78 °C was treated with propargyl
chloride (1.09 mL, 15.0 mmol). After stirring at –78 °C for
20 min, acetyltrimethylsilane (1.43 mL, 9.98 mmol) was
added dropwise. The mixture was stirred at –78 °C for
30 min and trimethylacetyl chloride (1.85 mL, 15.0 mmol)
was added. The reaction mixture was allowed to gradually
warm up to rt, while maintained in the cold bath and stirred
overnight. The reaction was stopped by adding H2O
(100 mL) and transferred to a separatory funnel. After ex-
traction, the organic layer was separated and the aqueous
layer was extracted once more with Et2O (100 mL). The or-
ganic layers were combined, dried (Na2SO4), filtered, con-
centrated under reduced pressure, and purified by
chromatography on SiO2 to afford 1.59 g of 27b (58%) as a
yellow-orange oil. Rf 0.22 (5% EtOAc–hexane). FT-IR
1
1
(neat, cm–1): 2970, 1737, 1479, 1367, 1262, 1144, 1060. H
1385, 1227, 1111. H NMR (CDCl3) δ: 7.74–7.61 (m, 8H),
7.45–7.33 (m, 12H), 6.47 and 6.45 (s, 1H), 6.02 and 6.00 (s,
1H), 4.54 and 4.43 (brs, 1H), 4.43 and 4.37 (brs, 1H), 4.31–
4.20 (m, 2H), 4.16–4.04 (m, 1H), 3.87–3.79 (m, 2H), 3.55
and 3.50 (s, 3H), 2.98–2.77 (m, 2H), 2.77–2.59 (m, 2H),
2.55–2.35 (m, 2H), 1.86 and 1.85 (s, 3H), 1.71–1.50 (m,
3H), 1.56 and 1.09 (s, 3H), 1.32 and 1.30 (t, J = 7.2 Hz,
3H), 1.041 and 1.038 (s, 9H), 1.01 and 1.00 (s, 9H). 13C
NMR (CDCl3) δ: 172.0 [171.5], 163.93 [163.90], 159.2
[158.9], 151.05 [150.97], 145.8 [145.0], 137.43 [137.38],
135.91, 135.88, 135.81, 135.6, 135.2, 134.8, 134.2, 133.9,
133.7, 133.6, 133.5, 129.5, 127.7, 127.6, 127.5, 127.4,
115.37 [115.24], 115.15 [115.08], 112.7, 107.7 [107.6], 69.0
[68.9], 62.3, 60.0, 51.31 [51.25], 43.3, 43.0, 42.4, 41.0, 40.3,
39.7, 36.6, 32.3 [32.2], 26.9, 26.8, 26.5, 25.2, 19.2, 19.1,
18.4, 18.0, 17.0, 14.4 [14.3].
NMR (CDCl3) δ: 4.24 (s, 2H), 1.62 (s, 3H), 1.19 (s, 9H),
0.19 (s, 9H). 13C NMR (CDCl3) δ: 177.1, 87.6, 82.4, 67.2,
39.2, 31.3, 27.1 (3), 21.1, –4.2. HR-MS (EI) m/e calcd. for
C13H23O2SiCl: 274.1156; found: 274.1154.
(7S)-1-Ethyl 9-methyl 2-(4-(benzoyloxy)-4-(trimethyl-
silyl)pent-2-ynyl)-7-(tert-butyldiphenylsilyloxy)-3-oxo-5-
(prop-1-en-2-yl)nonanedioate (28a)
Following the same procedure as for the preparation of α-
propargyl β-keto ester 22, the alkylation of β-keto ester 21
CO2Et
O
TMS
BzO
5-Chloro-2-(trimethylsilyl)pent-3-yn-2-yl benzoate (27a)
A solution of n-BuLi (1.6 mol/L, 4.4 mL, 7.0 mmol) in
Et2O (40 mL) was cooled to –78 °C and treated with
propargyl chloride (540 µL, 7.5 mmol). After stirring at
OTBDPS
CO2Me
© 2006 NRC Canada

1240
Can. J. Chem. Vol. 84, 2006
1
[prepared from [1,3]dioxin-4-one 20 (422 mg, 0.765 mmol)]
with the iodide derived from 27a (406 mg, 1.38 mmol) gave
580 mg (95%, two steps) of 28a as a colourless oil. Since
this α-propargyl β-keto ester exists as a mixture of up to four
different diastereomers, it was not characterized.
2954, 2857, 1742, 1715, 1597, 1428, 1229, 1111. H NMR
(CDCl3) δ: 7.73–7.60 (m, 4H), 7.45–7.31 (m, 6H), 6.55 and
6.54 (s, 1H), 6.44 and 6.37 (apparent q, J = 1.5 and 1.6 Hz,
1H), 4.59 and 4.48 (bs, 1H), 4.46 and 4.43 (bs, 1H), 4.31–
4.19 (m, 2H), 4.18–4.04 (m, 1H), 3.56 and 3.50 (s, 3H),
3.00–2.75 (m, 2H), 2.63–2.36 (m, 2H), 2.01 and 2.00 (d, J =
1.6 and 1.6 Hz, 3H), 1.75–1.49 (m, 3H), 1.56 and 1.16 (s,
3H), 1.34 and 1.31 (t, J = 7.1 and 7.1 Hz, 3H), 1.00 (s, 9H),
0.14 (s, 9H). 13C NMR (CDCl3) δ: 171.9 [171.5], 163.9
[163.8], 159.4 [159.1], 151.83 [151.79], 145.7 [145.1], 140.2
[140.0], 135.92 (2) [135.88 (2)], 135.85 (2) [135.77 (2)],
134.2 [133.8], 133.6 (2), 129.6 (3), 129.5, 127.5 (6), 127.4
(2), 124.3 [124.2], 115.5 (2), 112.8 [112.6], 109.74 [109.71],
69.0 [68.8], 60.0 (2), 51.3 [51.2], 43.0 [42.9], 42.5 [41.0],
40.1 [39.6], 32.3 (2), 26.9 (3) [26.8 (3)], 19.2 (2), 18.0
[17.1], 17.1 (2), 14.34 [14.28], –2.3 (6). HR-MS (ESI–POS)
m/e calcd. for C39H54O6NaSi2 : 697.3357 [M + Na]; found:
697.3303.
(7S)-1-Ethyl 9-methyl 7-(tert-butyldiphenylsilyloxy)-3-oxo-
2-(4-(pivaloyloxy)-4-(trimethylsilyl)pent-2-ynyl)-5-(prop-1-
en-2-yl)nonanedioate (28b)
CO2Et
O
TMS
PivO
OTBDPS
CO2Me
Acknowledgements
Following the same procedure as for the preparation of α-
propargyl β-keto ester 22, the alkylation of β-keto ester 21
[prepared from [1,3]dioxin-4-one 20 (387 mg, 0.703 mmol)]
with the iodide derived from 27b (349 mg, 1.27 mmol) gave
350 mg (64%, two steps) of 28b as a colourless oil. Since
this α-propargyl β-keto ester exists as a mixture of up to four
different diastereomers, it was not characterized.
This work was supported by a postdoctoral fellowship
from the Natural Sciences and Engineering Research Coun-
cil of Canada (NSERC) and a research grant from the Na-
tional Institutes of Health (US Department of Health and
Human Services; No. GM55433).
Ethyl 2-((4S)-4-(tert-butyldiphenylsilyloxy)-6-methoxy-6-
oxo-2-(prop-1-en-2-yl)hexyl)-5-((E)-2-(trimethylsilyl)prop-
1-enyl)furan-3-carboxylate (29)
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© 2006 NRC Canada

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© 2006 NRC Canada