A synthesis of (-)-ebelactones A and B

Article abstract of DOI:10.1016/j.tet.2010.05.072

A synthesis of the β-lactone esterase inhibitors (-)-ebelactones A and B is described. The synthesis features the use of a Hoppe homoaldol reaction and a Cu(I)-mediated 1,2-metallate rearrangement of a metallated enol carbamate as key fragment linkage rea

Full text of DOI:10.1016/j.tet.2010.05.072

Tetrahedron 66 (2010) 6462e6467
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A synthesis of (ꢀ)-ebelactones A and B
,
y
a
,
c
,
,
*
John P. Cookseya, Rhonan Ford b , Philip J. Kocienski , Beatrice Pelotier z, Jean-Marc Pons c
*
ꢀ
a School of Chemistry and Institute of Process Research and Development, Leeds University, Leeds LS2 9JT, UK
b Department of Chemistry, Glasgow University, Glasgow G12 8QQ, UK
c Aix-Marseille Université, Institut des Sciences Moléculaires de Marseille, CNRS UMR 6263, Campus de Saint-Jérôme, 13397 Marseille Cedex 20, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A synthesis of the
b
-lactone esterase inhibitors (ꢀ)-ebelactones A and B is described. The synthesis
Received 1 March 2010
Received in revised form 29 April 2010
Accepted 13 May 2010
features the use of a Hoppe homoaldol reaction and a Cu(I)-mediated 1,2-metallate rearrangement of
a metallated enol carbamate as key fragment linkage reactions.
Ó 2010 Elsevier Ltd. All rights reserved.
Available online 8 June 2010
Keywords:
Ebelactone A
Ebelactone B
1,2-Metallate rearrangement
Hoppe homoaldol reaction
Roush crotylmetallation
1. Introduction
The first synthesis of (ꢀ)-ebelactone A and (ꢀ)-ebelactone B by
Paterson and Hulme used three boron-mediated aldol reactions to
(ꢀ)-Ebelactones A and B were isolated from a soil Actinomycete
closely related to Streptomyces aburaviensis by Umezawa et al.1
during a screen for esterase activity. The structure of ebelactone
A was secured by X-ray analysis of its p-bromobenzoate while ebe-
lactone B was identified by spectroscopic comparison.2 The ebe-
lactones display a wide range of biological activity consequent to the
irreversible acylation of various serine hydrolases by the strained
create six of the seven stereogenic centres and an IrelandeClaisen
rearrangement to create the trisubstituted alkene.14,15 A noteworthy
feature of this synthesis is the preservation of the ketone function at
C9 with its two flanking stereogenic centres throughout the syn-
thesis without recourse to protection. A synthesis of (ꢀ)-ebelactone
A by Mandal16 used Evans aldol, crotylation, hydroxyl-directed re-
duction and substrate-controlled hydroboration reactions to gen-
erate the requisite stereogenic centres, the trisubstituted alkene
being generated by a SuzukieMiyaura coupling of an iodoalkene
with an alkylborane. Fleming et al.17 described the synthesis of an
advanced intermediate en route to ebelactone A, in which all of the
stereochemical relationships were controlled by silicon-based
methods. We now report syntheses of (ꢀ)-ebelactones A and B from
a common intermediate, which features the use of a 1,2-metallate
rearrangement to construct the trisubstituted alkene. Scheme 1 in-
dicates the provenance of five of the strategic bonds.
b
-lactone moiety.3,4 Examples together with their protein targets
include suppressed fat absorption (intestinal lipase),5 suppression of
platelet aggregation (cathepsin A/deamidase),6 antihypertension
(urinary kininase)7,8 and immunostimulation (N-formylmethionine
aminopeptidase).1 In addition, the ebelactones inhibit cutinases
produced by fungal plant pathogens thereby blocking the initial step
of plant infection,9,10 and they reduce the destruction of human
epidermal and epithelial tissue by pathogenic yeast.11 They also
inhibit prenylated methylated protein methyl esterase (PMPMEase)
involved in the regulation of prenylated protein function.12,13
2. Results and discussion
Our synthesis of (ꢀ)-ebelactones A and B began with the con-
struction of the C9eC14 fragment 3 (Scheme 2). The 1,2-anti-2,3-syn
stereochemical relationship between the three contiguous stereogenic
centres was created via a reagent-controlled crotylmetallation reaction
on the aldehyde 8 generated in two conventional steps from methyl
(R)-(ꢀ)-3-hydroxy-2-methylpropanoate (6).18 As crotylmetallation
reagent we chose Roush’s19 diisopropyl-2-crotyl-1,3,2-dioxaboralane-
* Corresponding
authors.
E-mail
addresses:
p.j.kocienski@leeds.ac.uk
ꢀ
(P.J. Kocienski), jean-marc.pons@univ-cezanne.fr (J.-M. Pons).
y
Present address: AstraZeneca Research and Development, Bakewell Road,
Loughborough, LE11 5RH, UK.
z
Present address: Institut de Chimie et Biochemie Moléculaires et Supra-
moléculaire, CNRS UMR 546, Université de Lyon, 43 boulevard du 11 Novembre,
1918, Villeurbanne F-69622, France.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.05.072

J.P. Cooksey et al. / Tetrahedron 66 (2010) 6462e6467
6463
alkene 10 using freshly prepared Wilkinson’s catalyst22 gave the sat-
urated alcohol 11 with none of the epimerization of the C12 stereo-
genic centre observed when Pd/C was used as catalyst. Deprotection of
the TBS ether 11 using trifluoroacetic acid gave the crystalline diol 12
(mp 68e69 ꢁC). Selective PMB-protection of the secondary alcohol in
12 was accomplished by regioselective reductive cleavage of the PMP
acetal 13 with DIBAL-H according to the procedure of Takano et al..23,24
Finally, DesseMartin oxidation of the primary alcohol 14 gave the
target C9eC14 fragment 3 in 53% overall yield for the eight steps
from 6.
The second phase of the synthesis entailed the construction of
the stannane 4 and its union with the aldehyde 3 via a Hoppe
homoaldol reaction25 (Scheme 3). Thus, deprotonation of the
(E)-crotyl carbamate 1526 with n-BuLi in the presence of (ꢀ)-spar-
teine in a 9:1 mixture of anhydrous pentane/cyclohexane at ꢀ78 ꢁC
initially generated
a
pair of configurationally labile di-
astereoisomeric organolithium$(ꢀ)-sparteine complexes, but after
ca. 3 h of vigorous mechanical stirring at ꢀ78 ꢁC, crystallisation-
induced diastereoselection resulted in a thick, white suspension of
diastereoisomer 16 whose structure has been rigorously defined by
X-ray crystallography.27 Treating the organolithium$(ꢀ)-sparteine
complex 16 with trimethylstannyl chloride in pentane then gave an
easily separable mixture of enantiomerically enriched stannanes 4
(68%, er¼83:17) and 17 (11%), both reactions having taken place by
anti-SE and anti-SE mechanisms, respectively.28 Stannane 4 could
0
be stored for up to three months at e20 ꢁC under an inert atmo-
sphere with no observable decomposition.
Scheme 1.
A Hoppe homoaldol reaction between stannane 4 and aldehyde
3 accomplished formation of the C8eC9 bond and installation of
O
OTBS
65%
O
OTBS
O
OH
a
b
MeO
MeO
100%
100%
N
6
8
7
n-BuLi
N
(–)-sparteine
i
Pr O2C
O
O
Li
O
B
cyclohexane–pentane
–78 °C, 3 h
c
i
Pr O2C
N(i-Pr)2
O
O
O
9
15
N(i-Pr)2
16
OH OH
OH OTBS
OH OTBS
e
d
Me3SnCl, –78 °C to rt, 2 h
92%
97%
Cl3
Ti
H
O
12
11
10
mp 68–69 °C
TiCl4, CH2Cl2
–78 °C, 1 min
Me3Sn
O
O
O
99%
f
N(i-Pr)2
N(i-Pr)2
PMP
O
4 (68%)
18
O
PMBO
OH
PMBO
O
PMBO
O
g
h
–78 °C, 15 min
+
95%
98%
3
SnMe3
O
H
Cl
Cl
13
14
3
Cl
Ti
R
Scheme 2. Reagents and conditions: (a) TBSCl (1.05 equiv), imidazole (1.6 equiv),
O
O
H
DMAP (1.0 mol %), CH2Cl2, 0 ꢁC to rt, 2 h, ca. 100%; (b) DIBAL-H (1.05 equiv), CH2Cl2,
O
ꢀ78 to ꢀ30 ꢁC, 75 min, ca. 100%; (c) 9 (1.75 equiv), 4 A MS, PhMe, ꢀ78 ꢁC to rt, 5 h,
ꢁ
N(i-Pr)2
O
65%; (d) H2, [Ph3P]3RhCl (2 mol %), PhH, rt, 30 h, 97%; (e) TFA (10 equiv), THF/H2O (2:1),
N(i-Pr)2
19
17(11%)
0
ꢁC to rt, 3 h, 92%; (f) PMP/CH(OMe)2 (5 equiv), p-TsOH$H2O (5 mol %), CH2Cl2, rt, 3 h,
99% (drꢂ97:3); (g) DIBAL-H (3.5 equiv), CH2Cl2, ꢀ78 ꢁC to rt, 2 h, 98%; (h) DesseMartin
periodinane (1.2 equiv), CH2Cl2, rt, 1 h, 95%.
δ 4.84, dd
δ 4.71, dd
J = 9.8, 6.4
J = 9.8, 6.8
4,5-dicarboxylate reagent 9 because it was cheap and easy to prepare
from trans-2-butene on a 200 mmol scale and it could be stored for
weeks at 0 ꢁC in the absence of moisture. The modest yield of the
crotylmetallation adduct 10 (65%) was compensated by the excellent
dr (ꢂ97:3) consistent with the complementary operation of reagent
control and substrate control (matched pair) in accordance with the
FelkineAnh model.20 Catalytic homogeneous hydrogenation21 of
PMBO
OH
H
7
PMBO
OH
H
7
+
O
O
O
O
N(i-Pr)2
Scheme 3.
N(i-Pr)2
20a (62%)
20b(22%)

6464
J.P. Cooksey et al. / Tetrahedron 66 (2010) 6462e6467
two new stereocentres in the required anti-relationship.28 The
reaction involved an anti-SE reaction of stannane 4 with titanium
temperature. Best results were obtained when the trans-
metallation reactions were performed with a mixture of lithium
reagent 24 (2.6 equiv) and the homocuprate 25 (2.0 equiv). On
gradual warming, the higher order cuprate 26 underwent a ste-
reospecific 1,2-metallate rearrangement with clean inversion of
configuration32 to give the alkenylcuprate 27. In the final step of
the sequence, the alkenylcuprate 27 reacted with a large excess
of MeI in the presence of HMPA with retention of configuration
to give the trisubstituted alkene 28 (E/Zꢂ97:3) in 59e63% yield.33
The (E)- and (Z)-isomers are inseparable at this stage but easily
distinguished in the 1H NMR spectrum (500 MHz) by integration
0
tetrachloride to give a crotyltitanium intermediate 18. Addition of
aldehyde 3 to the solution of intermediate 18 at ꢀ78 ꢁC gave
a separable 75:25 mixture of the (Z)-anti-adducts 20a and 20b,
respectively, in an overall 84% yield. The dr of the reaction was
assigned by integration of the signals corresponding to C7H
recorded in the 1H NMR spectrum of the crude mixture of 20a,b.
The nexus of our synthesis of (ꢀ)-ebelactones A and B was the
construction of the C6eC7 trisubstituted alkene via a 1,2-metallate
rearrangement of the metallated enol carbamate 26 (Scheme 4).29
A range of factors including the nature of the protecting group at
C9, the solvent, temperature, time, scale and stoichiometry affected
the course of the reaction. The sequence began with protection of
the alcohol in 20a as its 2-(trimethylsilyl)ethoxymethoxy (SEM)
ether30 (see below). The resultant enol carbamate 21 was then
metallated with t-BuLi in THF at ꢀ78 ꢁC and stannylated to afford
23. A major consideration in the choice of metallation conditions
was the instability of the lithiated carbamate 22, which underwent
of the C7H signals at
d
¼5.24 (d, J¼9.3 Hz) for the (E)-isomer 28
and
d
¼5.29 (d, J¼8.8 Hz) for the (Z)-isomer 29. Unfortunately, the
temperature required for the 1,2-metallate rearrangement (ꢀ35
to ꢀ20 ꢁC) coincides with the temperature at which
a-elimina-
tion to the vinylidene carbene 30 occurs. Consequently, a com-
peting FritscheButtenbergeWiechell rearrangement gave the
alkyne 31 in 11e24% yield. Hence success depends on stabilizing
the higher order cuprate 26 sufficiently to attain the requisite
temperature for 1,2-metallate rearrangement to compete
easy
a-elimination and thence FritscheButtenbergeWiechell
rearrangement31 to the alkyne 31. For example, when the enol
carbamate 21 was metallated with t-BuLi in Et2O at ꢀ78 ꢁC and
Me3SnCl added at ꢀ78 ꢁC and the reaction mixture allowed to
warm slowly over 6 h to ꢀ20 ꢁC, the alkyne 31 was formed in 94%
favourably with the a-elimination pathway. To that end stabili-
zation of the higher order cuprate 26 is favoured by weakly
coordinating solvents (Et2O/pentane, 5:1) and further augmented
by the presence of Me2S.34 Addition of even small amounts of
THF diminished the yield of the alkene 28, the E/Z ratio wors-
ened (10:1) and several additional unidentified minor products
were generated. An attempt to improve the ligand economy of
the sequence by deploying CuCN as the Cu(I) source instead of
CuBr$SMe2 failed to deliver improvements in yield and the
reproducibility was poor.
yield. This vexatious a-elimination reaction could be suppressed by
using THF as the solvent whilst maintaining the temperature at
ꢀ78 ꢁC until the stannylation was completed.
Under the optimum conditions depicted in Scheme 4, the
stannane 23 transmetallated to the lithium 22 and thence to the
higher order cuprate 26 both of which are stable at low
SEM
O
Fritsch–Buttenberg–Wiechell
PMBO
H
PMBO
OSEM
6
rearrangement
14
30
31 (11–24%)
α-elimination
2–
TESO
2Li+
PMBO
OR
PMBO
OSEM
M
PMBO
OSEM
9
t-BuLi, THF, –78 °C, 1.5 h
–78 °C, 30 min
Cu
O
9
O
O
O
O
R
O
N(i-Pr)2
N(i-Pr)2
N(i-Pr)2
26
22 M = Li
92%
20a R = H
Me3SnCl, –78 °C, 4 h
SEMCl, DIPEA
83%
then warm to –40 °C over 1 h
CH2Cl2, reflux, 5 h
21 R = SEM
–78 to –35 °C, 30 min
–35 to –10 °C, 1.5 h
–10 to 0 °C, 30 min
23 M = SnMe3
1,2-metallate
rearrangement
1. t-BuLi (13.0 equiv)
OTES
OTES
OTES
PMBO
OSEM
OTES
OTES
Et2O, –78 °C to rt, 55 min
+
Cu
Li
Li
I
2. CuBr•SMe2 (2.0 equiv)
SMe2, –78 to 0 °C, 2 h
CuLi
R
5
24
25
27
(6.6 equiv)
(2.6 equiv)
(2.0 equiv)
MeI (20 equiv), HMPA
–78 °C to rt, 1.5 h
PMBO
OSEM
PMBO
OSEM
OTES
7
7
3
9
14
OTES
29
Scheme 4.
28 (59–63%)

J.P. Cooksey et al. / Tetrahedron 66 (2010) 6462e6467
6465
Completion of the synthesis of (ꢀ)-ebelactone A was accom-
plished using a series of conventional transformations depicted in
Scheme 5 beginning with the deprotection of TES ether 28 using
Bu4NF$3H2O. DesseMartin oxidation of the resulting primary
alcohol 32 gave the aldehyde 33 that was used immediately in
benzenesulfonyl chloride at ꢀ20 ꢁC using the procedure of Adam
et al.41 and gave the
b-lactone 38a in 80% yield.
A major impediment to the completion of the synthesis was
the selective removal of the SEM protecting group in 38a
without detriment to the labile b-lactone ring or PMB protecting
a HornereWadswortheEmmons olefination. The
a
,
b
-unsaturated
group. For example, treatment of 38a with Bu4NF$3H2O or TASF
[(Me2N)3SþMe3SiFe2 ]42 in refluxing THF, HF in aqueous MeCN at
rt or HF$py in THF at rt resulted in destruction of the substrate.
However, SEM-deprotection was eventually accomplished by
gently refluxing compound 38a with pyridinium p-toluenesul-
fonate in t-BuOH to give the alcohol 39a in 86% yield.43 To
ester 34 (E/Zꢂ97:3) was obtained in 59% yield over two steps from
32. Subsequent reduction of the ester with DIBAL-H gave the allylic
alcohol 35 in 87% yield. At this stage any (Z)-trisubstituted alkene
formed during the 1,2-metallate rearrangement reaction could now
be separated by column chromatography.
Scheme 5. Reagents and conditions: (a) Bu4NF$3H2O (1.1 equiv), THF, 0 ꢁC, 2 h, 82%; (b) DesseMartin periodinane (2.0 equiv, CH2Cl2, 0 ꢁC to rt, 2 h; (c) (EtO)2P(O)CH2CO2Et
(1.5 equiv), NaH (1.5 equiv), THF, ꢀ30 ꢁC to rt, 17 h, 78% (two steps); (d) DIBAL-H (2.1 equiv), CH2Cl2, ꢀ78 ꢁC to rt, 2.5 h, 87%; (e) (þ)-DIPT (1.2 equiv), Ti(O-i-Pr)4 (1.0 equiv), t-BuOOH
(2.0 equiv), 4 A MS, CH2Cl2, ꢀ20 ꢁC, 48 h, 97%; (f) R2CuLi (15 equiv), Et2O, ꢀ40 ꢁC to rt, 7 h then NaIO4 (2.0 equiv), acetone/MeOH/H2O (1:1:1), rt, 2 h; (g) PhI(OAc)2 (1.5 equiv),
ꢁ
TEMPO (0.1 equiv), CH2Cl2, rt, 7 h; (h) NaClO2 (2.5 equiv), NaH2PO4 (7.7 equiv), 2-methyl-2-butene (5.7 equiv), t-BuOH/H2O, rt, 1 h; (i) PhSO2Cl (4.0 equiv), py, ꢀ20 ꢁC, 48 h; (j) PPTS
(5.0 equiv), t-BuOH, reflux, 5 h; (k) DesseMartin periodinane (1.1 equiv), CH2Cl2, 0 ꢁC to rt, 1 h; (l) DDQ (1.5 equiv), CH2Cl2/H2O (20:1), rt, 30 min; (m) 4-BrC6H4COCl (4.0 equiv),
DMAP (4.0 equiv), py, rt, 18 h, 92%.
The remaining C2 and C3 stereocentres in (ꢀ)-ebelactone
A were installed using an epoxidation/ring-opening protocol as
reported by Kishi et al..35,36 Sharpless asymmetric epoxidation37
of the allylic alcohol 35 gave the epoxy alcohol 36 in 97% yield
and dr ꢂ97:3. Treating epoxy alcohol 36 with a large excess of
lithium dimethylcuprate gave an inseparable 8:1 mixture of the
1,3-diol 37a and a 1,2-diol regioisomer. The regioisomeric ratio
was determined by integration of the C7H 1H NMR signals at
complete the synthesis, DesseMartin oxidation of compound
39a gave the labile ketone 40a (94% yield) from which the PMB
group was excised with 2,3-dichloro-5,6-dicyano-1,4-benzoqui-
none (DDQ)44 to give crystalline (ꢀ)-ebelactone
A (1a, mp
80e81 ꢁC) in 97% yield. Spectroscopic data (1H NMR, 13C NMR
and IR) recorded for 1a prepared using this route agreed with
the data reported by Umezawa et al.,2 Paterson and Hulme14,15
and Mandal.16 The structure and stereochemistry of (ꢀ)-ebe-
lactone A was confirmed by single crystal X-ray crystallography
of the p-bromobenzoate derivative 41 (Fig. 1). By an analogous
route (Scheme 5), crystalline (ꢀ)-ebelactone B (mp 71e72 ꢁC)
was prepared in seven steps (39% overall) from epoxy alcohol 37.
Spectroscopic data (1H NMR, 13C NMR and IR) recorded for our
synthetic (ꢀ)-ebelactone B (1b) agreed with the data reported
by Umezawa et al.2 and Paterson and Hulme.14,15
d
¼5.30 (1H, d, J¼8.6) for the 1,3-diol 37a and
d
¼5.24 (1H, d,
J¼9.0) for the 1,2-diol. Destruction of the 1,2-diol with sodium
periodate gave 37a in 75% yield from epoxy alcohol 36 after
column chromatography. Chemoselective oxidation of the pri-
mary alcohol in diol 37a gave the
overall 75% yield.38e40 Formation of the
plished by treating compound 2a with freshly distilled
b
-hydroxy acid 2a in an
b
-lactone was accom-

6466
J.P. Cooksey et al. / Tetrahedron 66 (2010) 6462e6467
Figure 1. X-ray structure of ebelactone A p-bromobenzoate (41).
3. Conclusions
temperature ꢃꢀ75 ꢁC. The resulting yellow suspension was
warmed to ꢀ20 ꢁC over 1.5 h and then to 0 ꢁC for 30 min forming
a white suspension. A solution of stannane 23 (1.83 g, 2.42 mmol,
In conclusion, we have accomplished the synthesis of (ꢀ)-ebe-
lactones A and B in 2.9% and 3.7% overall yields, respectively, for the
longest linear sequence (24 steps) from a commercial precursor 6.
The synthesis features the use of a Hoppe homoaldol reaction and
a Cu(I)-mediated 1,2-metallate rearrangement as key fragment
linkage reactions. We have shown that by careful choice of reaction
parameters, such as solvent and temperature, the 1,2-metallate
rearrangement of a metallated enol carbamate can prevail over
ꢁ
1.0 equiv) in Et2O (20 mLþ7 mL rinse, dried with activated 4 A MS
for 30 min prior to use) was added dropwise to the reaction mix-
ture at ꢀ78 ꢁC, at a rate sufficient to keep the internal reaction
temperature ꢃꢀ75 ꢁC. The resulting yellow/orange suspension was
stirred at ꢀ78 ꢁC for 30 min, warmed to ꢀ35 ꢁC over 30 min
forming a pale yellow suspension that was warmed to ꢀ10 ꢁC over
1.5 h and finally warmed to 0 ꢁC over 30 min. The resulting white
suspension containing the alkenylcuprate 27 was stirred at 0 ꢁC for
30 min and then re-cooled to ꢀ78 ꢁC whereupon a solution of
iodomethane (freshly distilled from CaCl2, 3.0 mL, 48.4 mmol,
competing a-elimination and the stereochemical integrity of the
resultant alkenylcuprate can be preserved during alkylationdboth
problems, which beset earlier attempts to exploit this chemistry in
the construction of trisubstituted alkenes in polyketide natural
products.45e48 Recently Gais et al.49 described an analogous route
to trisubstituted alkenes based on the 1,2-metallate rearrangement
of higher order sulfoximine-substituted cuprates, which are more
stable than their alkenyl carbamate analogues and therefore
potentially more practical.
ꢁ
20.0 equiv) in HMPA (1.8 mL), dried with activated 4 A MS for
30 min prior to use, was added dropwise at a rate sufficient to keep
the internal reaction temperature ꢃꢀ75 ꢁC. The resulting yellow
solution was stirred at ꢀ78 ꢁC for 1.5 h whereupon the cooling bath
was removed and the mixture allowed to warm to ambient tem-
perature over 25 min. The reaction was quenched at rt with
a mixture of saturated aqueous NH4OH (150 mL) and saturated
aqueous NH4Cl (150 mL). The layers were separated and the
aqueous layer extracted with Et2O (3ꢄ300 mL). The combined or-
ganic layers were dried over Na2SO4, filtered and concentrated in
vacuo. The residual yellow oil was purified by column chromatog-
raphy on SiO2 eluting with petrol/Et2O (15:1) to give in order of
elution the title compound 28 (995 mg,1.53 mmol, 63%) and alkyne
31 (185 mg, 0.41 mmol, 17%) as colourless oils.
4. Experimental
4.1. General
For general experimental details see the Supplementary data.
4.2. Procedure for the synthesis of alkene 28 via a
1,2-metallate rearrangement (Scheme 4)
4.2.1. Spectroscopic data for (2S,6R,7R,8S,9R,10R,E)-9-(4-methoxy-
benzyloxy)-2,4,6,8,10-pentamethyl-7-((2-trimethylsilyl)ethoxy-
A flame-dried 250 mL 3-neck round-bottom flask fitted with
a magnetic stirring bar, addition funnel, thermometer and nitrogen
methoxy)-1-(triethylsilyloxy)dodec-4-ene
(28). Rf
(SiO2)¼0.52
21
inlet was charged with
a
solution of iodoalkane
5
(5.02 g,
(petrol/Et2O, 15:1), E/Z ꢂ97:3. [
a
]
ꢀ16.4 (c 1.0, CHCl3). 1H NMR
D
ꢁ
16.0 mmol, 6.6 equiv, dried with activated 4 A MS for 30 min prior
to use) in Et2O (65 mL). The solution was cooled to ꢀ78 ꢁC and tert-
butyllithium (1.55 M solution in pentane; 20.3 mL, 31.4 mmol,
13.0 equiv) was added dropwise at a rate sufficient to keep the
internal reaction temperature ꢃꢀ75 ꢁC. The resulting white sus-
pension was stirred at ꢀ78 ꢁC for 30 min whereupon the cooling
bath was removed and the mixture allowed to warm to ambient
temperature over 25 min forming a pale yellow solution. The
reaction mixture was then re-cooled to ꢀ78 ꢁC and a solution of
freshly recrystallised Cu(I)Br$SMe2 complex (994 mg, 4.84 mmol,
2.0 equiv) in SMe2 (10 mLþ8 mL rinse) was added dropwise at
ꢀ78 ꢁC, again at a rate sufficient to keep the internal reaction
(500 MHz, CDCl3):
d
¼7.28 (2H, d, J¼8.6, ArH), 6.87 (2H, d, J¼8.6,
ArH), 5.24 (1H, d, J¼9.3, C7H), 4.75 (1H, d, J¼6.9, C16HAHB), 4.71
(1H, d, J¼6.9, C16HAHB), 4.58 (2H, s, C15H2), 3.80 (3H, s, OCH3), 3.77
(1H, apparent q, J¼8.8, C17HAHB), 3.60 (1H, apparent q, J¼8.8,
C17HAHB), 3.52 (1H, dd, J¼7.3, 1.5, C11H), 3.45 (1H, dd, J¼9.8, 5.6,
C3HAHB), 3.35 (1H, dd, J¼8.6, 2.2, C9H), 3.30 (1H, dd, J¼9.8, 7.5,
C3HAHB), 2.63 (1H, qdd, J¼9.3, 7.1, 2.2, C8H), 2.10 (1H, dd, J¼13.0,
5.4, C5HAHB), 1.86e1.72 (1H, m, C4H), 1.78e1.66 (3H, m, C5HAHB/
C12H/C13HAHB), 1.71e1.59 (1H, m, C10H), 1.59 (3H, s, C6CH3),
1.23e1.13 (1H, m, C13HAHB), 1.01e0.94 (2H, m, C18H2), 0.98 (3H, d,
J¼7.1, C8CH3), 0.96 (9H, t, J¼8.0, Si(CH2CH3)3), 0.93 (3H, t, J¼7.5,
C14H3), 0.89 (3H, d, J¼6.9, C10CH3), 0.85 (3H, d, J¼7.1, C12CH3), 0.83

J.P. Cooksey et al. / Tetrahedron 66 (2010) 6462e6467
6467
5. Nonaka, Y.; Ohtaki, H.; Ohtsuka, E.; Kocha, T.; Fukuda, T.; Takeuchi, T.; Aoyagi, T.
J. Enzym. Inhib. 1995, 10, 57.
6. Ostrowska, H.; Kalinowska, J.; Chabielska, E.; Stankiewicz, A.; Kruszewski, K.;
Buczko, W. J. Cardiovasc. Pharmacol. 2005, 45, 348.
7. Ostrowska, H.; Dabrowska, M.; Osada, J.; Mantur, M. Rocz. Akad. Med. Bialym-
stoku 2003, 48, 150.
(3H, d, J¼6.6, C4CH3), 0.59 (6H, q, J¼8.0, Si(CH2CH3)3), 0.02 (9H, s, Si
(CH3)3). 13C NMR (75 MHz, CDCl3):
¼159.0 (CAr), 133.1 (CAr), 132.3
d
(C6), 128.8 (2CArH), 127.5 (C7H), 113.8 (2CArH), 97.2 (C16H2), 86.9
(C9H), 83.0 (C11H), 73.5 (C15H2), 68.4 (C3H2), 65.8 (C17H2), 55.4
(OCH3), 44.1 (C5H2), 39.2 (C10H), 38.4 (C12H), 35.3 (C8H), 34.3
(C4H), 25.7 (C13H2), 19.2 (C8CH3), 18.4 (C18H2), 16.7 (C6CH3), 16.3
(C14H3), 16.2 (C12CH3), 12.0 (C10CH3), 11.1 (C4CH3), 7.0 (Si
(CH2CH3)3), 4.7 (Si(CH2CH3)3), ꢀ1.2 (Si(CH3)3). IR (neat):
nmax¼2956s, 2876s,1514m,1461m,1248s,1092s,1029s cmꢀ1. HRMS
(ESþ mode): found 673.4657 (MþþNa). C37H70NaO5Si2 requires
673.4659. Anal. calcd for C37H70O5Si2: C 68.25, H 10.84, found: C
68.50, H 10.90%.
8. Majima, M.; Ikeda, Y.; Kuribayashi, Y.; Mizogami, S.; Katori, M.; Aoyagi, T. Eur.
J. Pharmacol. 1995, 284, 1.
9. Voight, C. A.; Schafer, W.; Salomon, S. Plant J. 2005, 42, 364.
€
10. Koller, W.; Trail, F.; Parker, D. M. J. Antibiot. 1990, 43, 734.
11. Gacser, A.; Schafer, W.; Nosanchuk, J. S.; Salomon, S.; Nosanchik, J. D. Fungal
Genet. Biol. 2007, 44, 1336.
12. Oboh, O. T.; Lamango, N. S. J. Biochem. Mol. Toxicol. 2008, 22, 51.
13. Tan, E. W.; Rando, R. R. Biochemistry 1992, 31, 5572.
14. Paterson, I.; Hulme, A. N. Tetrahedron Lett. 1990, 31, 7513.
15. Paterson, I.; Hulme, A. N. J. Org. Chem. 1995, 60, 3288.
16. Mandal, A. K. Org. Lett. 2002, 4, 2043.
17. Archibald, S. C.; Barden, D. J.; Bazin, J. F. Y.; Fleming, I.; Foster, C. F.; Mandal, A.
K.; Mandal, A. K.; Parker, D.; Takaki, K.; Ware, A. C.; Williams, A. R. B.; Zwicky, A.
B. Org. Biomol. Chem. 2004, 2, 1051.
18. Burke, S. D.; Cobb, J. E.; Takeuchi, K. J. Org. Chem. 1990, 55, 2138.
19. Roush, W. R.; Ando, K.; Powers, D. B.; Palkowitz, A. D.; Halterman, R. L. J. Am.
Chem. Soc. 1990, 112, 6339.
4.2.2. Spectroscopic data for (3R,4R,5S,6R,7R)-9-(4-methoxy-
benzyloxy)-3,5,7-trimethyl-4-((2-trimethylsilyl)ethoxymethoxy)non-
21
1-yne (31). Rf (SiO2)¼0.37 (petrol/Et2O, 15:1). [
a
]
ꢀ38.4 (c 1.0,
D
CHCl3). 1H NMR (500 MHz, CDCl3):
d
¼7.27 (2H, d, J¼8.3, ArH), 6.87
(2H, d, J¼8.3, ArH), 4.80 (1H, d, J¼7.1, C16HAHB), 4.74 (1H, d, J¼7.1,
C16HAHB), 4.60 (1H, d, J¼11.2, C15HAHB), 4.56 (1H, d, J¼11.2,
C15HAHB), 3.80 (3H, s, OCH3), 3.77 (1H, apparent q, J¼8.8, C17HAHB),
3.64 (1H, apparent q, J¼8.8, C17HAHB), 3.55 (1H, d, J¼7.3, C11H),
3.37 (1H, dd, J¼8.6, 2.4, C9H), 2.82e2.75 (1H, m, C8H), 2.09 (1H, d,
J¼2.1, C6H), 2.06 (1H, qdd, J¼7.3, 7.1, 2.4, C10H), 1.77e1.65 (2H, m,
C12H/C13HAHB), 1.25 (3H, d, J¼7.1, C8CH3), 1.27e1.14 (1H, m,
C13HAHB), 1.00 (3H, d, J¼7.1, C10CH3), 1.01e0.91 (2H, m, C18H2),
0.94 (3H, t, J¼7.6, C14H3), 0.91 (3H, d, J¼6.6, C12CH3), 0.02 (9H, s, Si
20. Roush, W. R.; Palkowitz, A. D.; Ando, K. J. Am. Chem. Soc. 1990, 112, 6348.
21. Ireland, R. E.; Bey, P. Org. Synth. 1973, 53, 63.
22. Osborn, J. A.; Wilkinson, G. Inorg. Synth. 1990, 28, 77.
23. Takano, S.; Akiyama, M.; Sato, S.; Ogasawara, K. Chem. Lett. 1983, 1593.
24. Takano, S.; Kurotaki, A.; Sekiguchi, Y.; Sato, S.; Hirama, M. Synthesis 1986, 1593.
25. Hoppe, D. Synthesis 2009, 43.
€
26. Hoppe, D.; Hanko, R.; Bronneke, A.; Lichtenberg, F.; von Hülsen, E. Chem. Ber.
1985, 118, 2822.
27. Marsch, M.; Harms, K.; Zschage, O.; Hoppe, D.; Boche, G. Angew. Chem., Int. Ed.
Engl. 1991, 30, 321.
28. Paulsen, H.; Graeve, C.; Hoppe, D. Synthesis 1996, 141.
29. Kocienski, P.; Dixon, N. J. Synlett 1989, 52.
30. Lipshutz, B. H.; Pegram, J. J. Tetrahedron Lett. 1980, 21, 3343.
31. Knorr, R. Chem. Rev. 2004, 104, 3795.
32. Kocienski, P.; Wadman, S.; Cooper, K. J. Am. Chem. Soc. 1989, 111, 2363.
33. Isomerization of the alkenylcuprate 28 leading to formation of (Z)-29 is mini-
(CH3)3). 13C NMR (75 MHz, CDCl3):
d¼159.0 (CAr), 132.0 (CAr), 128.7
(2CArH), 113.8 (2CArH), 96.8 (C16H2), 85.8 (C7), 84.7 (C9H), 82.4
(C11H), 73.4 (C15H2), 70.1 (C6H), 65.9 (C17H2), 55.3 (OCH3), 39.1
(C10H), 38.2 (C12H), 29.4 (C8H), 25.8 (C13H2), 18.3 (2C, C8CH3/
C18H2), 15.9 (C12CH3), 12.0 (C14H3), 11.0 (C10CH3), ꢀ1.3 (Si(CH3)3).
IR (neat): nmax¼3310m, 2957s, 2877s, 1613m, 1514s, 1463m, 1248s,
1055s, 1029s cmꢀ1. HRMS (ESþ mode): found 471.2897 (MþþNa).
C26H44NaO4Si requires: 471.2907. Anal. calcd for C26H44O4Si: C,
69.59; H, 9.88. Found: C, 69.60; H, 10.05%.
mised by performing the alkylation with
temperature.
a large excess of MeI at low
34. Olmstead, M. M.; Power, P. P. J. Am. Chem. Soc. 1990, 112, 8008.
35. Johnson, M. R.; Nakata, T.; Kishi, Y. Tetrahedron Lett. 1979, 4343.
36. Nagoka, H.; Kishi, Y. Tetrahedron 1981, 37, 3873.
37. Gao, Y.; Klunder, J. M.; Hanson, R. M.; Masamune, H.; Ko, S. Y.; Sharpless, K. B.
J. Am. Chem. Soc. 1987, 109, 5765.
38. De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G. J. Org. Chem.
1997, 62, 6974.
Supplementary data
39. Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27, 888.
40. Bal, B. S.; Childers, W. E.; Pinnick, H. W. Tetrahedron 1981, 37, 2091.
41. Adam, W.; Baeza, J.; Liu, J.-C. J. Am. Chem. Soc. 1972, 94, 2000.
42. Scheidt, K. A.; Chen, H.; Follows, B. C.; Chemler, S. R.; Coffey, D. S.; Roush, W. R.
J. Org. Chem. 1998, 63, 6436.
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.05.072.
43. Williams, D. R.; Kissel, W. S. J. Am. Chem. Soc. 1998, 120, 11198.
44. Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982, 23, 885.
45. Ashworth, P.; Broadbelt, B.; Jankowski, P.; Kocienski, P.; Pimm, A.; Bell, R.
Synthesis 1995, 199.
References and notes
46. Smith, N. D.; Kocienski, P. J.; Street, S. D. A. Synthesis 1996, 652.
47. Fargeas, V.; Le Ménez, P.; Berque, I.; Ardisson, J.; Pancrazi, A. Tetrahedron 1996,
52, 6613.
48. Le Ménez, P.; Fargeas, V.; Berque, I.; Poisson, J.; Ardisson, J. J. Org. Chem. 1995,
60, 3592.
1. Umezawa, H.; Aoyagi, T.; Uotani, K.; Hamada, M.; Takeuchi, T.; Takahashi, S.
J. Antibiot. 1980, 33, 1594.
2. Uotani, K.; Naganawa, H.; Kondo, S.; Aoyagi, T.; Umezawa, H. J. Antibiot. 1982,
35, 1495.
3. Pommier, A.; Pons, J.-M. Synthesis 1995, 729.
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49. Gais, H.-J.; Venkateshwar Rao, C.; Loo, R. Chem.dEur. J. 2008, 14, 6510.