Palladium-catalyzed sequential alkylation-alkenylation reactions: Application towards the synthesis of polyfunctionalized fused aromatic rings

Article abstract of DOI:10.1016/j.tet.2005.03.128

The synthesis of polyfunctionalized fused aromatic carbo- and heterocycles from aryl iodides and bromoenoates via a tandem palladium-catalyzed aromatic substitution intramolecular Heck sequence is reported. Using Pd(OAc)₂ and tri-2-furylphosphine (TFP) in the presence of norbornene and Cs ₂CO₃ in CH₃CN at 85°C gave a variety of functionalized bi- and tricyclic fused aromatic rings in good yield.

Full text of DOI:10.1016/j.tet.2005.03.128

Tetrahedron 61 (2005) 6283–6297
Palladium-catalyzed sequential alkylation–alkenylation reactions:
application towards the synthesis of polyfunctionalized fused
aromatic rings
†
Dino Alberico, Jean-Franc¸ois Paquin and Mark Lautens
*
Davenport Laboratories, Department of Chemistry, University of Toronto, Toronto, Ont., Canada M5S 3H6
Received 5 November 2004; revised 28 January 2005; accepted 4 March 2005
Available online 13 May 2005
Abstract—The synthesis of polyfunctionalized fused aromatic carbo- and heterocycles from aryl iodides and bromoenoates via a tandem
palladium-catalyzed aromatic substitution intramolecular Heck sequence is reported. Using Pd(OAc)2 and tri-2-furylphosphine (TFP) in the
presence of norbornene and Cs2CO3 in CH3CN at 85 8C gave a variety of functionalized bi- and tricyclic fused aromatic rings in good yield.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
the most reliable and versatile transition metals for the
synthesis of fused aromatic carbocycles and heterocycles.
In particular, the intramolecular Heck reaction has gained
widespread acceptance due to its mild reaction conditions
and functional group tolerance.2
Carbocyclization is an important and valuable method for
the synthesis of carbocyclic and heterocyclic compounds.1
Over the past few years, palladium has emerged as one of
Scheme 1. Synthesis of fused aromatic carbocycles and 2,5-disubstituted-4-benzoxepines.
Keywords: Palladium; Catalysis; Intramolecular Heck reaction; Norbornene; ortho Functionalization; Fused aromatic rings; Catellani reaction.
*
Corresponding author. Fax: C1 416 978 1631; e-mail: mlautens@chem.utoronto.ca
¨
¨
Present address: Laboratorium fu¨r Organische Chemie, ETH Honggerberg, 8093 Zurich, Switzerland.
†
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.03.128

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Recently, we reported the synthesis of fused aromatic
carbocycles from aryl iodides and difunctional acceptors3
using modified Catellani4 conditions. A variety of functional
groups on the aryl moiety (1) were tolerated (Scheme 1)3
and numerous six and seven-membered polyfunctionalized
carbocycles (3) were synthesized using a variety of Heck
acceptors in the difunctional acceptor 2. This methodology
was also extended towards the synthesis of 2-substituted-4-
benzoxepines and 2,5-disubstituted-4-benzoxepines (5)
(Scheme 1).5
modification, thereby accessing a wide range of medicinally
important compounds from relatively simple and accessible
starting materials. We now report a further extension of our
methodology for the synthesis of more highly substituted
fused aromatic six- and seven-membered carbocycles 7
(Fig. 1).
2. Results and discussion
A number of functionalized bromoenoates (6) and aryl
iodides were prepared and subjected to standard reaction
conditions: Pd(OAc)2 (10 mol%), TFP (20 mol%), norbor-
nene (2 equiv), Cs2CO3 (2 equiv), CH3CN, 85 8C.
Although our previously reported methodology examined
the effect of substitution on the aromatic moiety, the effect
of substituents on the carbocyclic ring formed in this tandem
process was not evaluated. The resulting substituted fused
aromatic carbocyclic core is widely found in natural
products exhibiting notable biological and pharmaceutical
properties.6 Having a diverse range of substituents on the
carbocyclic moiety provides the opportunity for subsequent
We first examined the effect of substituents in the 40 position
of compounds 8–11 (Table 1). Using 2-iodotoluene and
bromoenoate 8 (R00ZMe), the desired product 12 was
obtained in 81% yield (entry 1). While the 40 hydroxyl
derivative yielded decomposition products, protection of the
40 hydroxyl group as a methoxymethyl (MOM) gave
moderate to good yields for 2-iodotoluene and 4-fluoro-2-
iodotoluene (entries 2, 3). Use of the tertiary protected
methyl amine 10 gave 15 in 22% yield, while the secondary
protected amine 11 provided the tricyclic lactam 16 in 45%
yield. This result is interesting and insight into the observed
product deserves further comment. The trans olefin
Figure 1.
Table 1. Formation of six-membered carbocycles from 40-substituted bromoenoates
R00
Entry
1
Bromoenoate
Aryl iodide
Product
Isolated yield (%)
Me
8
2-Iodotoluene
81
12
13
2
3
OMOM
OMOM
9
9
2-Iodotoluene
70
40
4-Fluoro-2-iodotoluene
14
15
4
5
NMeBoc
NHBoc
10
11
2-Iodotoluene
2-Iodotoluene
22
45
16

D. Alberico et al. / Tetrahedron 61 (2005) 6283–6297
Table 2. Formation of six-membered carbocycles from 50-substituted bromoenoates
6285
R00
Entry
1
Bromoenoate
Aryl iodide
Product
Isolated yield (%)
Me
17
2-Iodotoluene
83
70
20
21
2
3
Me
17
18
1-Iodonaphthalene
2-Iodotoluene
OBn
58
44
22
23
4
Ph
19
2-Chloro-6-iodotoluene
geometry of 11 prevents intramolecular attack of the
nitrogen onto the carbonyl functionality, thus making the
starting substrate unreactive toward lactamization. How-
ever, following the benzannulation catalytic cycle, the olefin
geometry sets the ester functionality in a position that allows
for lactamization to occur. Therefore, although this
unexpected product was obtained in modest yield, this
result is advantageous since three bonds and two additional
rings were formed in a relatively simple one-pot process.
2-iodotoluene afforded the desired product 23 in 44% yield
as well as 33% of elimination products 24 and 257 as
identified by 1H NMR spectroscopy and MS (Fig. 2). While
product 24 likely arises from the elimination of HBr
promoted by Cs2CO3, elimination product 25 is presumably
an isomerization product of 24. We note that the low yield
of products may be due to competing oxidative addition into
the aryl chloride. However, we previously reported the
reaction of 6-chloro-2-iodotoluene with bromoenoate 2
(nZ2, YZCO2Et) gave the desired product in 86% yield,3b
indicating that this process is not likely responsible for
reducing the yields. Again, no benzannulation was observed
when the unprotected alcohol was used, instead ethyl
(2E,4E)-6-hydroxy-2,4-hexadienoate was isolated.8
We next investigated the effect of substitution at the 50
position of the bromoenoate (Table 2). For 2-iodotoluene
and 1-iodonaphthalene, methyl substitution at the 50
position gave the expected carbocycles 20 and 21 in 83
and 70% yields, respectively. Protection of the secondary
alcohol using the larger benzyl protecting group afforded 22
in 58% yield, suggesting that steric effects play a role for
substituents at the 50 position. Reaction of 19 with 6-chloro-
Under typical reaction conditions (for 18 h), use of the 60
substituted bromoenoate 26 resulted in a very low yield
(!15%) of cyclized product 27 (Scheme 2) as well as
unreacted starting material. Attempts to increase conversion
by increasing reaction time also failed. While disappointing,
this result was not surprising since ortho insertion under
these reaction conditions has been reported to be very slow
for secondary alkyl halides.4a,b
Figure 2.
Scheme 2. Formation of a six-membered carbocycle 27 from a 60-substituted bromoenoate.

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D. Alberico et al. / Tetrahedron 61 (2005) 6283–6297
product could arise from insertion of Pd(0) into the
carbon–bromine bond, followed by a cyclopropylcarbinyl–
homoallyl rearrangement9 and subsequent b-hydride
elimination.
We next focused on the extension of reaction scope for
substituted seven-membered rings (Table 3). A tert-
butyldimethylsilylether (TBDMS) in the 60 position (32)
resulted in 54% yield of 35 when 2-iodotoluene was used.
Use of the smaller MOM protected alcohol (33) provided 36
in a slightly higher yield of 61%, further supporting our
steric arguments (vide supra). When 33 was reacted with
2-iodoanisole, a similar yield of 59% was obtained (37).
Lastly, when bromoenoate 34 and 2-chloro-6-iodotoluene
were subjected to the reaction conditions, carbocycle 38 was
obtained in a low 33% yield.
Figure 3. Tricyclic carbo- and heterocycles.
Successful cyc0lization reactions with substituents in the 40
position and 5 position led us to explor0e the potential of
tethered substituents joining positions 4 and 50 with the
objective of forming tricyclic products. Substrates 28 (28a:
XZCH2, 28b: XZOC(CH3)2O) were subjected to the
reaction conditions with different aryl iodides (Fig. 3).
Unfortunately, low yields (!30%) of the cyclized products
were obtained for all cases (Fig. 3).
Encouraged by the results obtained for the reactions of
functionalized bromoenoates, we attempted additional
benzannulation reactions using a substituted00 oxygenated
bromoenoate. We reported that when R ZCH3 (4)
(Scheme 1), the reaction with 1-iodonaphthalene afforded
the benzoxepine product in 72% yield.5 We therefore
synthesized the substituted oxygenated bromoenoate 39 and
subjected it to our reaction conditions in the presence of
different aryl iodides (Scheme 3). In general, good yields
of the expected benzoxepines 40 (76% yield) and 41 (64%
yield) were obtained.
For XZCH2 (28a), triene 31 was obtained in 25% yield in
addition to the desired cyclized product 29. The side-
Table 3. Formation of seven-membered carbocycles
G0, G00, G00
Entry
Bromoenoate
Aryl iodide
Product
Isolated yield (%)
1
H, H, OTBDMS
32
2-Iodotoluene
54
35
36
2
H, H, OMOM
33
2-Iodotoluene
61
3
4
H, H, OMOM
33
34
2-Iodoanisole
59
33
37
38
Me, H, OMOM
2-Chloro-6-iodotoluene

D. Alberico et al. / Tetrahedron 61 (2005) 6283–6297
6287
Scheme 3. Formation of 2,5-disubstituted-4-benzoxepines.
3. Conclusions
4.2. General procedure for the cyclization reaction
The palladium-catalyzed synthesis of highly substituted six-
and seven-membered fused aromatic carbocycles, as well as
2,5-disubstituted-4-benzoxepines from aryl iodides and
substituted oxygenated bromoenoates was described. A
variety of functional groups along the chain on the
bromoenoate (alkyl, OR, NR2) are tolerated, affording bi-
and tricyclic fused aromatic rings under relatively mild
reaction conditions in moderate to good yields. Further
manipulation of the functionalized compounds towards the
synthesis of more complex as well as bioactive molecules is
in progress.
A round-bottom flask equipped with a condenser was
charged with Cs2CO3 (0.400 mmol, 2 equiv), Pd(OAc)2
(0.020 mmol, 10 mol%), tri-2-furylphosphine (0.040 mmol,
20 mol%), and norbornene (0.400 mmol, 2 equiv). A
solution of bromoenoate (0.400 mmol, 2 equiv) and aryl
iodide (0.200 mmol, 1 equiv) in CH3CN (2 mL) was added.
The resulting mixture was heated at 85 8C for 19 h, cooled
and then quenched with saturated aqueous NH4Cl (3 mL).
The aqueous layer was extracted with Et2O (3!) and the
combined organic layers were washed with brine, dried with
anhydrous MgSO4 and filtered. Removal of the solvent gave
a crude product that was purified by flash chromatography.
4. Experimental
4.1. General
4.2.1. Ethyl (2E)-(2,8-dimethyl-3,4-dihydronaphthalen-
1(2H)-ylidene)acetate (12). Following the general pro-
cedure for the cyclization reaction using 2-iodotoluene and
8, 12 was isolated as a pale yellow oil (37.1 mg, 81%) by
flash chromatography using 5% EtOAc/hexanes as eluant.
RfZ0.68 on silica gel (10% EtOAc/hexanes). IR (neat) nZ
2952, 1714, 1621, 1467, 1371, 1263, 1158 cmK1; 1H NMR
(400 MHz, CDCl3) d 7.16–6.92 (m, 3H), 5.80 (s, 1H), 4.20
(q, 2H, JZ7.1 Hz), 4.08 (m, 1H), 2.64–2.36 (m, 2H), 2.43
(s, 3H), 2.22–2.12 (m, 1H), 1.30 (t, 3H, JZ7.1 Hz), 1.10 (d,
3H, JZ6.8 Hz), 1.06 (m, 1H); 13C NMR (100 MHz, CDCl3)
d 166.3, 160.2, 142.1, 136.1, 135.1, 129.3, 127.8, 124.4,
117.8, 59.8, 32.2, 30.1, 29.4, 21.5, 20.8, 14.4; HRMS calcd
for C16H20O2 [M]C 244.1463, found 244.1463.
The following includes general experimental procedures,
specific details for representative reactions, and isolation
and spectroscopic information for new compounds. Melting
points were recorded using a Fisher–Johns melting point
apparatus and are uncorrected. 1H, 13C and 19F NMR spectra
were obtained using either Varian Gemini 300 MHz or
Varian Unity 400 MHz spectrometers. 1H spectra were
referenced to tetramethylsilane (TMS, 0 ppm) and 13C
spectra were referenced to solvent carbons (77.23 ppm for
CDCl3). No special notation is used for equivalent carbons.
IR spectra were obtained using a Nicolet DX FT IR
spectrometer as thin films on NaCl plates. Optical rotations
were obtained using a Perkin–Elmer 243 B polarimeter.
High-resolution mass spectra were obtained using a VG 70-
250S (double focusing) mass spectrometer at 70 eV unless
otherwise noted.
4.2.2. Ethyl (2Z)-[2-(methoxymethoxy)-8-methyl-3,4-
dihydronaphthalen-1(2H)-ylidene]acetate (13). Follow-
ing the general procedure for the cyclization reaction using
2-iodotoluene and 9, 13 was isolated as a colorless oil
(41.0 mg, 70%) by flash chromatography using 10% EtOAc/
hexanes as eluant. RfZ0.40 on silica gel (10% EtOAc/
hexanes). IR (neat) nZ2931, 1714, 1632, 1465, 1374, 1268,
Diethyl ether and tetrahydrofuran (THF) were distilled
under nitrogen from Na/benzophenone immediately prior to
use. Dichloromethane and acetonitrile were distilled under
nitrogen from CaH2 immediately prior to use. Neutral silica
(Silicycle, Quebec, Canada) for flash chromatography was
used as received. All reagents, metal catalysts and ligands
were purchased from Sigma-Aldrich or Strem-Chemical
Company and used as received unless otherwise noted.
Reactions were performed under an atmosphere of nitrogen.
1
1158 cmK1; H NMR (300 MHz, CDCl3) d 7.16–6.94 (m,
3H), 6.04 (t, 1H, JZ3.8 Hz), 5.93 (s, 1H), 4.66 (dd, 2H, JZ
15.0, 6.6 Hz), 4.22 (q, 2H, JZ7.1 Hz), 3.16 (s, 3H), 3.06–
2.95 (m, 1H), 2.80–2.68 (m, 1H), 2.47 (s, 3H), 2.22–2.06
(m, 2H), 1.31 (t, 3H, JZ7.1 Hz); 13C NMR (74.5 MHz,
CDCl3) d 166.2, 154.1, 139.5, 135.8, 134.0, 129.4, 128.1,
125.9, 119.3, 95.4, 69.3, 60.2, 55.4, 29.3, 25.4, 21.2, 14.3;

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D. Alberico et al. / Tetrahedron 61 (2005) 6283–6297
HRMS calcd for C17H22O4 [M]C 290.1516, found
290.1518.
1.11 (d, 3H, JZ6.6 Hz); 13C NMR (74.5 MHz, CDCl3) d
167.2, 155.4, 141.2, 136.0, 135.0, 129.8, 128.2, 125.8,
117.9, 51.4, 39.3, 37.5, 29.7, 22.3, 22.2; HRMS calcd for
C15H18O2 [M]C 230.1316, found 230.1306.
4.2.3. Ethyl (2Z)-[5-fluoro-2-(methoxymethoxy)-8-
methyl-3,4-dihydronaphthalen-1(2H)-ylidene]acetate
(14). Following the general procedure for the cyclization
reaction using 4-fluoro-2-iodotoluene and 9, 14 was isolated
as a colorless oil (24.5 mg, 40%) by flash chromatography
using 10% EtOAc/hexanes as eluant. RfZ0.30 on silica gel
(10% EtOAc/hexanes). IR (neat) nZ2935, 1714, 1634,
1476, 1372, 1249, 1176 cmK1; 1H NMR (300 MHz, CDCl3)
d 7.12–6.84 (m, 2H), 6.04 (t, 1H, JZ3.8 Hz), 5.93 (s, 1H),
4.64 (dd, 2H, JZ10.7, 6.6 Hz), 4.23 (q, 2H, JZ7.1 Hz),
3.13 (s, 3H), 3.06–2.60 (m, 2H), 2.43 (s, 3H), 2.36–1.95 (m,
2H), 1.32 (t, 3H, JZ7.1 Hz); 13C NMR (74.5 MHz, CDCl3)
d 14.3, 18.1, 18.2, 21.0, 28.5, 55.5, 60.4, 68.9, 95.7, 114.3,
114.6, 119.6, 126.0, 126.3, 130.0, 130.1, 130.8, 131.3,
135.1, 135.2, 150.6, 150.7, 153.7, 153.8, 156.8, 160.0,
166.0; 19F NMR (376 MHz, CDCl3) d K120.88 (s, 1F);
HRMS calcd for C17H21FO4 [M]C 308.1421, found
308.1424.
4.2.7. Ethyl (2E)-(2-methyl-2,3-dihydrophenanthren-
4(1H)-ylidene)acetate (21). Following the general pro-
cedure for the cyclization reaction using 1-iodonaphthalene
and 17, 21 was isolated as a colorless oil (37.1 mg, 70%) by
flash chromatography using 10% EtOAc/hexanes as eluant.
RfZ0.61 on silica gel (10% EtOAc/hexanes). IR (neat) nZ
2950, 1714, 1625, 1433 cmK1; 1H NMR (400 MHz, CDCl3)
d 8.35 (d, 1H, JZ8.4 Hz), 7.81 (d, 1H, JZ7.9 Hz), 7.80 (d,
1H, JZ8.2 Hz), 7.71 (d, 1H, JZ8.2 Hz), 7.46 (m, 2H), 7.22
(d, 1H, JZ8.2 Hz), 6.27 (s, 1H), 3.77 (s, 3H), 3.53 (dd, 1H,
JZ16.3, 5.7 Hz), 2.91 (dd, 1H, JZ15.7, 4.2 Hz), 2.83 (dd,
1H, JZ16.1, 10.3 Hz), 2.51 (dd, 1H, JZ15.7, 10.3 Hz),
2.20–1.95 (m, 1H), 1.16 (d, 3H, JZ6.6 Hz); 13C NMR
(100 MHz, CDCl3) d 167.4, 154.5, 138.6, 133.3, 132.8,
130.1, 128.9, 128.5, 126.7, 126.6, 125.2, 125.1, 118.7,
51.1, 39.1, 37.1, 29.8, 21.7; HRMS calcd for C17H22O4
[MKOC2H5]C 266.1306, found 266.1307.
4.2.4. Ethyl (2Z)-[2-[(tert-butoxycarbonyl)(methyl)-
amino]-8-methyl-3,4-dihydronaphthalen-1(2H)-ylidene]-
acetate (15). Following the general procedure for the
cyclization reaction using 2-iodotoluene (0.300 mmol scale)
and 10, 15 was isolated as a colorless oil (25.0 mg, 22%) by
flash chromatography using 50% EtOAc/hexanes as eluant.
RfZ0.67 on silica gel (25% EtOAc/hexanes). IR (neat) nZ
2974, 1700, 1457, 1366 cmK1; 1H NMR (300 MHz, CDCl3)
d 7.18–6.87 (m, 3H), 6.03 (s, 1H), 5.84 (brs, 1H), 4.20
(q, 2H, JZ7.1 Hz), 2.66–2.56 (m, 2H), 2.55 (s, 3H), 2.48
(s, 3H), 2.44–2.32 (m, 2H), 1.50 (s, 9H), 1.29 (t, 3H, JZ
7.1 Hz); 13C NMR (74.5 MHz, CDCl3) d 165.3, 158.9,
149.7, 142.0, 136.4, 134.9, 130.1, 128.2, 124.8, 123.6, 79.6,
77.4, 60.4, 53.4, 30.2, 28.6, 26.7, 21.2, 14.5; HRMS calcd
for C17H22O4 [M]C 359.2101, found 359.2096.
4.2.8. Ethyl (2E)-[3-(benzyloxy)-8-methyl-3,4-dihydro-
naphthalen-1(2H)-ylidene]acetate (22). Following the
general procedure for the cyclization reaction using
2-iodotoluene and 18, 22 was isolated as a colorless oil
(37.0 mg, 58%) by flash chromatography using 10% EtOAc/
hexanes as eluant. RfZ0.53 on silica gel (10% EtOAc/
hexanes). IR (neat) nZ2947, 1711, 1620, 1433, 1361 cmK1
;
1H NMR (300 MHz, CDCl3) d 7.34–6.96 (m, 8H), 5.97 (s,
1H), 4.59 (q, 2H, JZ11.9 Hz), 3.87 (quintet, 1H, JZ
5.8 Hz), 3.74 (s, 1H), 3.55 (dd, 1H, JZ16.0, 5.8 Hz), 3.25
(dd, 1H, JZ16.1, 6.7 Hz), 2.99 (dd, 1H, JZ15.2, 4.5 Hz),
2.84 (dd, 1H, JZ15.1, 7.5 Hz), 2.46 (s, 1H); 13C NMR
(74.5 MHz, CDCl3) d 167.1, 152.7, 138.6, 137.5, 136.1,
134.8, 130.1, 128.5, 128.4, 127.7, 127.6, 126.6, 126.5,
119.2, 73.3, 70.4, 51.6, 36.9, 35.2, 22.2; HRMS calcd for
C21H22O3 [M]C 322.1562, found 322.1568.
4.2.5. tert-Butyl 9-methyl-2-oxo-2,3a,4,5-tetrahydro-3H-
benzo[e]indole-3-carboxylate (16). Following the general
procedure for the cyclization reaction using 2-iodotoluene
and 11 (0.300 mmol scale), 16 was isolated as a colorless oil
(41.0 mg, 45%) by flash chromatography using 25% EtOAc/
hexanes as eluant. RfZ0.36 on silica gel (25% EtOAc/
4.2.9. Methyl (2E)-(7-chloro-8-methyl-3-phenyl-3,4-
dihydronaphthalen-1(2H)-ylidene)acetate (23). Follow-
ing the general procedure for the cyclization reaction using
2-chloro-6-iodotoluene and 19, 23 was isolated as a brown
solid (28.5 mg, 44%) along with a mixture of elimination
products 24 and 25 (26.5 mg, 33%,) by flash chromato-
graphy using 3/5% Et2O/hexane as eluant. IR (neat) nZ
hexanes). IR (neat) nZ2977, 1770, 1698, 1608 1318 cmK1
;
1H NMR (300 MHz, CDCl3) d 7.25–7.04 (m, 3H), 6.21
(s, 1H), 4.62–4.54 (dd, 1H, JZ11.5, 3.0 Hz), 3.14–3.05 (m,
2H), 2.94–2.82 (m, 1H), 2.48 (s, 3H), 1.83–1.62 (m, 1H),
1.59 (s, 9H); 13C NMR (74.5 MHz, CDCl3) d 169.8, 158.2,
149.9, 138.6, 138.5, 130.2, 129.8, 127.7, 127.2, 120.1, 83.1,
62.0, 30.2, 28.9, 28.4, 22.6; HRMS calcd for C18H21NO3
[M]C 299.1523, found 299.1521.
3034, 2953, 1714, 1619, 1458, 1168 cmK1 1H NMR
;
(300 MHz, CDCl3) d 7.35–7.19 (m, 7H), 6.95 (d, 1H, JZ
8.1 Hz), 5.93 (t, 1H, JZ1.8 Hz), 3.73 (s, 3H), 3.48 (ddt, 1H,
JZ17.1, 6.9, 1.8 Hz), 3.32 (ddd, 1H, JZ17.1, 10.5, 1.8 Hz),
3.03–2.75 (m, 3H), 2.53 (s, 3H); 13C NMR (74.5 MHz,
CDCl3) d 166.7, 153.8, 144.9, 139.2, 138.1, 134.2, 132.9,
128.9, 128.6, 127.0, 126.5, 126.2, 119.6, 51.2, 40.3, 37.5,
36.7, 19.0; HRMS calcd for C20H19O2Cl [M]C 326.1074,
found 326.1064.
4.2.6. Ethyl (2E)-(3,8-dimethyl-3,4-dihydronaphthalen-
1(2H)-ylidene)acetate (20). Following the general pro-
cedure for the cyclization reaction using 2-iodotoluene and
17, 20 was isolated as a colorless oil (38.8 mg, 83%) by flash
chromatography using 5% EtOAc/hexanes as eluant. RfZ
0.59 on silica gel (10% EtOAc/hexanes). IR (neat) nZ2951,
1715, 1615, 1434, 1161 cmK1; 1H NMR (300 MHz, CDCl3)
d 7.18–6.94 (m, 3H), 5.94 (t, 3H, JZ1.8 Hz), 3.75 (s, 3H),
3.32 (dd, 1H, JZ16.7, 6.2 Hz), 2.80–2.70 (m, 2H), 2.48 (s,
3H), 2.34 (dd, 1H, JZ14.9, 10.7 Hz), 1.98–1.78 (m, 1H),
4.2.10. Ethyl (2E)-(4,8-dimethyl-3,4-dihydronaphthalen-
1(2H)-ylidene)acetate (27). Following the general pro-
cedure for the cyclization reaction using 2-iodotoluene and
26, 27 was isolated as a colorless oil (5.51 mg, 12%) by flash
chromatography using 10% EtOAc/hexanes as eluant. RfZ
0.63 on silica gel (10% EtOAc/hexanes). IR (neat) nZ2951,

D. Alberico et al. / Tetrahedron 61 (2005) 6283–6297
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1
1715, 1618, 1436 cmK1; H NMR (400 MHz, CDCl3) d
4.2.14. Methyl (2E)-[8-(methoxymethoxy)-4-methyl-
6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-ylidene]ace-
tate (36). Following the general procedure for the cycliza-
tion reaction using 2-iodotoluene (0.300 mmol scale) and
33, 36 was isolated as a colorless oil (53.0 mg, 61%) by flash
chromatography using 10% EtOAc/hexanes as eluant. RfZ
0.31 on silica gel (10% EtOAc/hexanes). IR (neat) nZ2947,
1715, 1639, 1435, 1353 cmK1; 1H NMR (300 MHz, CDCl3)
d 7.11 (brs, 2H), 6.99 (brs, 1H), 5.74 (brs, 1H), 4.70 (brs,
2H), 4.00 (brs, 1H), 3.75 (brs, 3H), 3.37 (brs, 3H), 2.87
(d, 1H, JZ5.1 Hz), 2.62–1.70 (m, 4H), 2.27 (brs, 3H); 13C
NMR (74.5 MHz, CDCl3) d 166.7, 161.9, 161.5, 142.7,
141.6, 135.5, 134.8, 133.4, 129.2, 127.6, 127.1, 118.8, 95.0,
75.5, 72.5, 55.5, 51.3, 41.5, 38.7, 34.6, 32.4, 28.4, 27.1,
20.4; HRMS calcd for C16H18O2 [M]C 290.1526, found
290.1518.
7.24–7.00 (m, 3H), 5.92 (t, 1H, JZ1.7 Hz), 4.21 (q, 2H, JZ
7.1 Hz), 3.33–3.22 (m, 1H), 3.14–3.04 (m, 1H), 2.76–2.68
(m, 1H), 2.47 (s, 3H), 2.10–1.82 (m, 2H), 1.31 (t, 3H, JZ
7.1 Hz), 1.26 (m, 3H); 13C NMR (100 MHz, CDCl3) d 14.6,
19.7, 21.8, 27.0, 29.5, 29.9, 33.9, 60.0, 118.4, 123.2, 128.2,
129.7, 134.9, 136.3, 146.2, 155.1, 167.1; HRMS calcd for
C16H20O2 [M]C 244.1468, found 244.1463.
4.2.11. Ethyl (2E)-(3-methyl-1,1a,7,7a-tetrahydro-2H-
cyclopropa[b]naphthalen-2-ylidene)acetate (29). Follow-
ing the general procedure for the cyclization reaction using
2-iodotoluene and 28a, 29 was isolated as a colorless oil
(12.5 mg, 26%) along with hepta-2,4,6-trienoic acid ethyl
ester (31)10 (7.61 mg, 25%) by flash chromatography using
10% EtOAc/hexanes as eluant and further purification by
flash chromatography using 80% CH2Cl2/hexanes. RfZ0.73
on silica gel (10% EtOAc/hexanes). IR (neat) nZ2979,
1704, 1613, 1466, 1270 cmK1; 1H NMR (300 MHz, CDCl3)
d 7.16–6.87 (m, 3H), 5.89 (s, 1H), 4.22 (q, 2H, JZ7.1 Hz),
3.75 (ddd, 1H, JZ8.2, 8.2, 4.4 Hz), 3.16–2.94 (m, 2H), 2.43
(s, 3H), 1.80–1.66 (m, 1H), 1.32 (t, 3H, JZ7.1 Hz), 0.92
(ddd, 1H, JZ8.0, 8.0, 5.0 Hz), 0.43 (q, 1H, 4.9 Hz); 13C
NMR (74.5 MHz, CDCl3) d 167.9, 157.9, 136.7, 135.2,
134.2, 130.3, 128.5, 126.5, 117.2, 59.9, 30.7, 21.5, 17.3,
14.7, 14.4, 11.2; HRMS calcd for C16H18O2 [M]C
242.1309, found 242.1307.
4.2.15. Methyl (2E)-[4-methoxy-8-(methoxymethoxy)-
6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-ylidene]ace-
tate (37). Following the general procedure for the cycliza-
tion reaction using 2-iodoanisole (0.300 mmol scale) and
33, 37 was isolated as a colorless oil (54.0 mg, 59%) by flash
chromatography using 25% EtOAc/hexanes as eluant. RfZ
0.18 on silica gel (75% CH2Cl2/hexanes). IR (neat) nZ
1
2947, 1714, 1643, 1578, 1470 cmK1; H NMR (400 MHz,
CDCl3) d 7.18 (t, 1H, JZ8.1 Hz), 6.83 (d, 1H, JZ8.2 Hz),
6.78 (d, 1H, JZ7.3 Hz), 5.88 (s, 1H), 4.68 (q, 2H, JZ
6.8 Hz), 3.90–3.84 (m, 1H), 3.76 (s, 3H), 3.74 (s, 3H), 3.38
(s, 3H), 3.25 (brs, 1H), 2.85 (d, 2H, JZ6.2 Hz), 2.70 (brs,
1H), 2.05–1.96 (m, 1H), 1.85–1.76 (m, 1H); 13C NMR
(100 MHz, CDCl3) d 167.1, 157.1, 155.4, 137.1, 131.0,
128.8, 122.4, 120.0, 110.2, 95.0, 74.1, 56.0, 55.5, 51.2, 40.0,
33.0, 27.9; HRMS calcd for C17H22O5 [M]C 306.1467,
found 306.1467.
4.2.12. Ethyl (2Z)-(2,2,5-trimethyl-9,9a-dihydro-
naphtho[2,3-d][1,3]dioxol-4(3aH)-ylidene)acetate (30).
Following the general procedure for the cyclization reaction
using 2-iodotoluene and 28b, 30 was isolated as a colorless
oil (14.0 mg, 23%) by flash chromatography using 5:35:60
EtOAc/CH2Cl2/hexanes as eluant. RfZ0.30 on silica gel
(5:35:60 EtOAc/CH2Cl2:hexanes). IR (neat) nZ2985, 1715,
1646, 1372 cmK1; 1H NMR (300 MHz, CDCl3) d 7.16–6.87
(m, 3H), 6.34 (d, 1H, JZ7.5 Hz), 5.99 (s, 1H), 4.80 (dt, 1H,
JZ7.3, 2.6 Hz), 2.94 (dd, 1H, JZ15.4, 2.3 Hz), 2.59 (dd,
1H, JZ15.3, 2.9 Hz), 2.43 (s, 3H), 1.35 (s, 3H), 1.33 (t, 3H,
JZ7.1 Hz), 0.93 (s, 3H); 13C NMR (74.5 MHz, CDCl3) d
166.0, 150.3, 136.4, 135.6, 134.8, 129.6, 128.5, 126.5,
122.1, 109.6, 73.6, 72.4, 60.7, 34.0, 26.2, 25.2, 20.2, 14.4;
HRMS calcd for C18H22O4 [MKCH3]C 287.1287, found
287.1283.
4.2.16. Methyl (2E)-[3-chloro-7-(methoxymethoxy)-4,7-
dimethyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl-
idene]acetate (38). Following the general procedure for the
cyclization reaction using 2-chloro-6-iodotoluene and 34,
38 was isolated as a colorless oil (35.0 mg, 33%) by flash
chromatography using 10% EtOAc/hexanes as eluant. RfZ
0.32 on silica gel (10% EtOAc/hexanes). IR (neat) nZ2936,
1721, 1640, 1445, 1368 cmK1; 1H NMR (300 MHz, CDCl3)
d 7.17 (brd, 1H, JZ8.0 Hz), 6.90 (d, 1H, JZ8.0 Hz), 5.75
(s, 1H), 4.88 (brs, 1H), 4.79 (brs, 1H), 4.55 (brs, 1H), 4.21
(q, 2H, JZ7.0 Hz), 3.36 (brs, 3H), 3.11 (brt, 1H, JZ
13.1 Hz), 2.57 (brs, 1H), 2.29 (s, 3H), 2.20–2.03 (m, 1H),
2.00–1.71 (m, 2H), 1.43 (brs, 3H), 1.32 (t, 3H, JZ7.1 Hz);
13C NMR (74.5 MHz, CDCl3) d 166.7, 166.3, 154.9, 153.3,
145.3, 139.4, 133.4, 133.1, 132.0, 128.2, 128.2, 127.2,
127.0, 123.2, 91.2, 90.8, 80.1, 60.3, 60.1, 55.4, 41.1, 39.3,
30.6, 29.3, 28.5, 22.4, 17.8, 14.5; HRMS calcd for
C19H25ClO4 [M]C 352.1448, found 352.1441.
4.2.13. Methyl (2E)-(8-{[tert-butyl(dimethyl)silyl]oxy}-4-
methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl-
idene)acetate (35). Following the general procedure for the
cyclization reaction using 2-iodotoluene (0.300 mmol scale)
and 32, 35 was isolated as a colorless oil (58.0 mg, 54%) by
flash chromatography using 5% EtOAc/hexanes as eluant.
RfZ0.75 on silica gel (10% EtOAc/hexanes). IR (neat) dZ
2952, 1727, 1659, 1435, 1256 cmK1; H NMR (300 MHz,
1
CDCl3) d 7.16 (s, 1H), 7.15 (s, 1H), 7.05 (brs, 1H), 5.89 (brs,
1H), 3.82 (brs, 3H), 3.76 (brs, 1H), 3.10–2.88 (m, 1H), 2.83–
2.65 (m, 2H), 2.32 (s, 3H), 2.20–1.87 (m, 3H), 0.97 (s, 9H),
0.14 (s, 9H); 13C NMR (74.5 MHz, CDCl3) n 166.9, 166.8,
161.9, 150.0, 143.5, 136.0, 133.3, 129.0, 127.7, 127.3,
120.0, 118.6, 71.7, 71.4, 71.2, 51.3, 45.3, 39.1, 37.6, 36.4,
35.0, 29.9, 29.1, 26.03, 25.98, 20.4, 18.3, 18.2, 0.2, K4.2,
K4.3, K4.4, K4.5; HRMS calcd for C21H32O3Si [M]C
360.2125, found 360.2121.
4.2.17. Methyl (2Z)-[(4R)-4-(2-phenylethyl)-4,5-dihydro-
naphtho[1,2-d]oxepin-1(2H)-ylidene]acetate (40). Fol-
lowing the general procedure for the cyclization reaction
using 1-iodonaphthalene and 39, 40 was isolated as slightly
yellow oil (56.6 mg, 76%) by flash chromatography using
10% Et2O/hexane as eluant. [a]2D5 K45.2 (c 1.0, CHCl3); IR
(neat) nZ3068, 3027, 2949, 2858, 1711, 1215, 1172 cmK1
;
1H NMR (300 MHz, CDCl3) d 8.12 (d, 1H, JZ7.8 Hz),
7.80 (m, 2H), 7.45 (m, 2H), 7.30–7.12 (m, 6H), 5.96 (t, 1H,

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D. Alberico et al. / Tetrahedron 61 (2005) 6283–6297
JZ2.7 Hz), 5.07 (m, 2H), 3.79 (s, 3H), 3.37 (dd, 1H, JZ
14.1, 7.5 Hz), 2.66 (m, 3H), 1.67 (m, 3H); 13C NMR
(74.5 MHz, CDCl3) d 166.4, 162.5, 141.8, 134.8, 133.2,
132.3, 130.7, 128.5, 128.3, 127.3, 126.6, 125.8, 125.1,
125.0, 118.8, 75.0, 69.2, 51.4, 37.9, 36.3, 32.1; HRMS calcd
for C25H24O3 [M]C 372.1725, found 372.1736.
water. The organic layer was dried over anhydrous MgSO4,
filtered and concentrated. The crude aldehyde was dissolved
in THF (50 mL) and added dropwise to a K78 8C solution
of vinylmagnesium bromide (47.2 mL, 47.2 mmol, 1.0 M in
THF, 1.5 equiv). The mixture was stirred for 2 h at K78 8C
then warmed to rt. The reaction was quenched with
saturated aqueous NH4Cl (50 mL) and the aqueous layer
was washed with EtOAc (3!). The combined organic
extracts were washed with water and brine, dried with
anhydrous MgSO4, filtered and concentrated. The crude oil
was purified by flash chromatography using 10% EtOAc/
hexanes as eluant to yield the desired product (4.20 g, 60%)
as a pale yellow oil. RfZ0.46 on silica gel (10% EtOAc/
4.2.18. Methyl (2Z)-[(4R)-9-methoxy-4-(2-phenylethyl)-
4,5-dihydro-3-benzoxepin-1(2H)-ylidene]acetate (41).
Following the general procedure for the cyclization reaction
using 2-iodoanisole and 39, 41 was isolated as a colorless oil
(45.0 mg, 64%) by flash chromatography using 10% Et2O/
hexanes as eluant and further purification by flash
chromatography using 0/10% acetone/CH2Cl2. [a]D25
K76.9 (c 1.0, CHCl3); IR (neat) nZ3027, 2965, 2838,
1710, 1269, 1172, 1110 cmK1; 1H NMR (300 MHz, CDCl3)
d 7.30–7.14 (m, 6H), 6.88 (d, 1H, JZ8.7 Hz), 6.70 (d, 1H,
JZ8.7 Hz), 6.00 (t, 1H, JZ2.4 Hz), 5.08 (dd, 1H, JZ18.9,
2.4 Hz), 4.82 (dd, 1H, JZ18.9, 2.4 Hz), 3.78 (s, 3H), 3.75
(s, 3H), 3.01 (dd, 1H, JZ14.1, 6.3 Hz), 2.71 (m, 2H), 2.43
(dd, 1H, JZ14.1, 3.0 Hz), 1.89 (m, 2H), 1.62 (m, 2H); 13C
NMR (74.5 MHz, CDCl3) d 166.8, 158.7, 156.2, 141.9,
137.4, 129.2, 128.5, 128.3, 126.7, 125.8, 121.3, 118.4,
110.2, 75.4, 67.6, 55.6, 51.2, 37.9, 35.4, 32.1; HRMS calcd
for C22H24O4 [M]C 352.1675, found 352.1684.
hexanes). IR (neat) nZ3424, 2955, 1472, 1256, 1099 cmK1
;
1H NMR (300 MHz, CDCl3) d 5.94–5.78 (m, 1H), 5.26 (dt,
1H, JZ17.3, 1.5 Hz), 5.08 (dt, 1H, JZ10.4, 1.5 Hz), 4.33
(brs, 1H), 3.94–3.72 (m, 2H), 3.34 (d, 1H, JZ3.6 Hz), 1.84–
1.62 (m, 2H), 0.88 (s, 9H), 0.06 (s, 6H); 13C NMR
(74.5 MHz, CDCl3) d 140.7, 114.1, 72.4, 68.9, 38.3, 25.9,
18.1, K5.5; HRMS calcd for C11H24O2Si [MKC(CH3)3]C
159.0836, found 159.0841.
4.2.21. Ethyl (2E)-6-{[tert-butyl(dimethyl)silyl]oxy}-4-
hydroxyhex-2-enoate (43). To a mixture of 42 (1.00 g,
4.62 mmol, 1 equiv) and methyl acrylate (12.5 mL,
116 mmol, 25 equiv) in CH2Cl2 (20 mL) was added Grubbs’
2nd generation catalyst (200 mg, 0.231 mmol, 5 mol%).
The mixture was stirred at rt overnight. Evaporation of the
volatiles gave a crude oil was purified by flash chromato-
graphy using 10% EtOAc/hexanes as eluant to yield the
desired product (1.18 g, 89%) as a pale yellow oil. RfZ0.67
on silica gel (10% EtOAc/hexanes). IR (neat) nZ3480,
4.2.19. Ethyl (2E)-6-bromo-4-methylhex-2-enoate (8).
A solution of carbon tetrabromide (289 mg, 0.870 mmol,
1.5 equiv) in CH2Cl2 (1 mL) was added dropwise to a 0 8C
solution of triphenylphosphine (228 mg, 0.870 mmol,
1.5 equiv) and ethyl (E)-6-hydroxy-4-methyl-hex-2-eno-
ate11 (100 mg, 0.581 mmol, 1 equiv) in CH2Cl2 (5 mL).
The reaction was stirred at 0 8C for 1 h, diluted with 10%
EtOAc/hexanes (20 mL) and filtered through celite.
Evaporation of the volatiles gave a crude product that was
purified by flash chromatography using 10% EtOAc/
hexanes as eluant to yield the desired product (118 mg,
87%) as a pale yellow oil. RfZ0.78 on silica gel (25%
EtOAc/hexanes). IR (neat) nZ1186, 1272, 1458, 1652,
1
2955, 1722, 1659, 1471, 1258 cmK1; H NMR (300 MHz,
CDCl3) d 6.92 (dd, 1H, JZ15.5, 4.1 Hz), 6.10 (dd, 1H, JZ
15.6, 1.8 Hz), 4.52 (brs, 1H), 4.17 (q, 2H, JZ7.1 Hz), 4.00–
3.55 (m, 2H), 3.78 (brs, 1H), 1.92–1.61 (m, 2H), 1.27 (t, 3H,
JZ7.1 Hz), 0.88 (s, 9H), 0.06 (s, 6H); 13C NMR (74.5 MHz,
CDCl3) d 166.9, 150.0, 120.4, 71.1, 60.5, 42.9, 37.5, 26.0,
18.3, 14.4, K5.4; HRMS calcd for C14H28O4Si [MKOEt]C
243.1414, found 243.1416.
1
1715, 2968 cmK1; H NMR (300 MHz, CDCl3) d 1.08 (d,
3H, JZ6.8 Hz), 1.27 (t, 3H, JZ7.1 Hz), 1.90 (m, 1H), 2.57
(m, 1H), 3.35 (ABX2, 2H, DnABZ29.3 Hz, JABZ3.7 Hz,
JAXZ6.4 Hz, JBXZ6.4 Hz), 4.17 (q, 2H, JZ7.0 Hz), 5.84
(d, 1H, JZ15.7 Hz), 6.89 (dd, 1H, JZ15.6, 8.2 Hz);
13C NMR (74.5 MHz, CDCl3) d 166.8, 152.2, 121.3, 60.5,
38.7, 35.2, 31.3, 19.3, 14.4; HRMS calcd for C9H14BrO2
[MKH]C 234.0253, found 234.0255.
4.2.22. Ethyl (2E)-6-{[tert-butyl(dimethyl)silyl]oxy}-4-
(methoxymethoxy)hex-2-enoate (44). To a 0 8C solution
of 43 (500 mg, 1.73 mmol, 1 equiv) in CH2Cl2 (7 mL) was
added dropwise diisopropylethylamine (910 mL,
5.20 mmol, 3 equiv), then chloromethyl methyl ether
(500 mL, 8.67 mmol, 5 equiv) was added dropwise and the
resulting mixture was warmed to rt and stirred for 18 h. The
reaction was quenched with saturated aqueous NH4Cl
(10 mL) and the aqueous layer was washed with EtOAc
(3!). The combined organic extracts were washed with
brine, dried with anhydrous MgSO4, filtered and concen-
trated. The crude oil was purified by flash chromatography
using 10% EtOAc/hexanes as eluant to yield the desired
product (419 mg, 73%) as a pale yellow oil. RfZ0.52 on
silica gel (10% EtOAc/hexanes). IR (neat) nZ2954, 1724,
1659, 1472, 1368, 1257 cmK1; 1H NMR (300 MHz, CDCl3)
d 6.84 (dd, 1H, JZ15.7 Hz), 5.97 (d, 1H, JZ15.7 Hz), 4.60
(q, 2H, JZ6.7 Hz), 4.37 (q, 1H, JZ6.3 Hz), 4.18 (q, 2H,
JZ7.1 Hz), 3.78–3.56 (m, 2H), 3.35 (s, 3H), 1.88–1.65 (m,
2H), 1.27 (t, 3H, JZ7.1 Hz), 0.87 (s, 9H), 0.03 (s, 6H); 13C
NMR (74.5 MHz, CDCl3) d 166.4, 148.2, 121.9, 95.1, 72.6,
60.6, 59.0, 55.8, 38.4, 26.1, 18.4, 14.4, K5.2; HRMS
4.2.20. 5-{[tert-Butyl(dimethyl)silyl]oxy}pent-1-en-3-ol
(42). A K78 8C solution of oxalyl chloride (3.16 mL,
36.2 mmol, 1.15 equiv) in CH2Cl2 (100 mL) was added
dropwise to a solution of dimethyl sulfoxide (5.14 mL,
72.5 mmol, 2.3 equiv) in CH2Cl2 (30 mL). The mixture was
stirred at K78 8C for 15 min. A solution of 3-(tert-butyl-
dimethylsilanyloxy)-propan-1-ol12 (6.00 g, 31.5 mmol,
1 equiv) in CH2Cl2 (100 mL) was added dropwise and the
reaction mixture was stirred for 1 h K78 8C. Triethylamine
(12.3 mL, 88.3 mmol, 2.8 equiv) was added dropwise and
the reaction mixture was stirred for 15 min at K78 8C then
warmed to rt over 2 h. The reaction was quenched with
water (100 mL) and the aqueous layer was extracted with
CH2Cl2 (3!). The combined organic extracts were washed
with 1% aqueous HCl, water, 5% aqueous NaHCO3 and

D. Alberico et al. / Tetrahedron 61 (2005) 6283–6297
6291
calcd for C16H32O5Si [MKC(CH3)3]C 275.1322, found
275.1315.
minor rotamer d 4.45 (brt, 1H, JZ9.1 Hz), 4.35 (brt, 1H,
JZ9.4 Hz), 4.23 (ddd, 1H, JZ9.1, 9.1, 6.9 Hz), 2.95 (brs,
3H), 2.45 (brs, 2H), 1.47 (s, 9H); 13C NMR (74.5 MHz,
CDCl3) d 174.3, 155.5, 154.4, 81.2, 80.6, 65.3, 57.1, 56.0,
34.0, 32.5, 29.8, 28.2, 26.3, 25.6; HRMS calcd for
C10H17NO4 [M]C 215.1165, found 215.1158.
4.2.23. Ethyl (2E)-6-hydroxy-4-(methoxymethoxy)hex-2-
enoate (45). To a 0 8C solution of 44 (75.0 mg, 0.225 mmol,
1 equiv) in THF (2 mL) was added hydrogen fluoride–
pyridine (70:30) (0.130 mL, 4.50 mmol, 20 equiv). The
resulting mixture was stirred at 0 8C for 30 min then
warmed to rt and stirred for 1 h. The reaction was diluted
with ether (10 mL) and quenched with saturated aqueous
NaHCO3 (10 mL). The organic layer was washed with
brine, dried with anhydrous MgSO4, and filtered. Removal
of the solvent gave a crude oil (38.1 mg, 78%) that was used
without further purification. RfZ0.13 on silica gel (25%
EtOAc/hexanes). IR (neat) nZ3418, 2951, 1714, 1659,
4.2.26. Ethyl (2E)-4-[(tert-butoxycarbonyl)(methyl)-
amino]-6-hydroxyhex-2-enoate (47). To a K78 8C solu-
tion of 46 (2.13 g, 9.89 mmol, 1 equiv) in THF (60 mL) was
added diisobutylaluminum hydride (15.0 mL, 15.0 mmol,
1.0 M in hexanes, 1.5 equiv). The resulting mixture was
stirred at K78 8C for 1.5 h. To a separate round-bottom
flask was added NaH (415 mg, 10.4 mmol, 60% dispersion
in oil, 1.05 equiv) and THF (40 mL). Triethyl phosphono-
acetate (1.96 mL, 9.89 mmol, 1 equiv) was added dropwise
at 0 8C then warmed to rt and stirred for 30 min. The
reaction mixture was cooled to K78 8C and the diisobutyl-
aluminum hydride solution of 46 was added via cannula.
The resulting mixture was stirred at K78 8C for 10 min then
warmed to rt and stirred for 18 h. The reaction was
quenched with 10% aqueous HCl (60 mL) and the aqueous
layer was washed with ether (3!). The combined organic
extracts were washed with brine, dried with anhydrous
MgSO4, filtered and concentrated. The crude oil was
purified by flash chromatography using 75% EtOAc/
hexanes as eluant to yield the desired product (1.60 g,
56%) as a pale yellow oil. The product is a mixture of
rotamers in a 3:1 ratio. RfZ0.30 on silica gel (50% EtOAc/
1
1446, 1370, 1275 cmK1; H NMR (400 MHz, CDCl3) d
6.85 (dd, 1H, JZ15.7, 6.3 Hz), 6.02 (dd, 1H, JZ15.7,
1.3 Hz), 4.64 (q, 2H, JZ6.7 Hz), 4.46 (dt, 1H, JZ7.1,
6.0 Hz), 4.21 (q, 2H, JZ7.1 Hz), 3.86–3.70 (m, 2H), 3.41
(s, 3H), 1.94–1.78 (m, 2H), 1.30 (t, 3H, JZ7.1 Hz);
13C NMR (100 MHz, CDCl3) d 166.1, 147.1, 122.0, 95.0,
73.8, 60.6, 59.2, 55.9, 37.2, 14.2; HRMS calcd for C10H18O5
[MKOEt]C 173.0813, found 173.0814.
4.2.24. Ethyl (2E)-6-bromo-4-(methoxymethoxy)hex-2-
enoate (9). A solution of carbon tetrabromide (63.5 mg,
0.191 mmol, 1.1 equiv) in CH2Cl2 (500 mL) was added
dropwise to a 0 8C solution of triphenylphosphine (50.2 mg,
0.191 mmol, 1.1 equiv) and 45 (38.0 mg, 0.174 mmol,
1 equiv) in CH2Cl2 (1.5 mL). The reaction was stirred at
0 8C for 1 h, diluted with 10% EtOAc/hexanes (10 mL) and
filtered through celite. Evaporation of the volatiles gave a
crude product that was purified by flash chromatography
using 10% EtOAc/hexanes as eluant to yield the desired
product (40.0 mg, 83%) as a pale yellow oil. RfZ0.71 on
silica gel (25% EtOAc/hexanes). IR (neat) nZ2951, 1723,
1660, 1445 cmK1; 1H NMR (300 MHz, CDCl3) d 6.80 (dd,
1H, JZ15.8, 6.6 Hz), 6.04 (dd, 1H, JZ15.8, 0.7 Hz), 4.64
(dd, 2H, JZ18.1, 6.9 Hz), 4.46 (dt, 1H, JZ7.0, 5.5 Hz),
4.21 (q, 2H, JZ7.1 Hz), 3.60–3.42 (m, 2H), 3.40 (s, 3H),
2.24–2.00 (m, 2H), 1.30 (t, 3H, JZ7.1 Hz); 13C NMR
(74.5 MHz, CDCl3) d 165.9, 146.3, 122.9, 94.9, 73.2, 60.6,
55.9, 37.9, 28.9, 14.2; HRMS-ESI calcd for C10H17O4NaBr
[M]C 303.0202, found 303.0201.
1
hexanes). IR (neat) nZ3441, 2978, 1694, 1392 cmK1; H
NMR (400 MHz, CDCl3) major rotamer d 6.90 (dd, 1H, JZ
16.1, 3.5 Hz), 5.99–5.87 (m, 1H), 5.09 (brs, 1H), 4.21 (q,
2H, JZ7.1 Hz), 3.74–3.38 (m, 2H), 2.67 (brs, 3H), 1.94–
1.64 (m, 2H), 1.48 (s, 9H), 1.30 (t, 3H, JZ7.0 Hz); minor
rotamer d 6.90 (dd, 1H, JZ16.1, 3.5 Hz), 5.99–5.87 (m,
1H), 4.21 (q, 2H, JZ7.1 Hz), 3.74–3.38 (m, 2H), 3.33 (brs,
1H), 2.67 (brs, 3H), 1.94–1.64 (m, 2H), 1.46 (s, 9H), 1.30 (t,
3H, JZ7.0 Hz); 13C NMR (100 MHz, CDCl3) d 166.3,
146.9, 122.9, 121.2, 81.0, 60.9, 60.7, 58.8, 58.3, 51.6, 33.0,
29.6, 28.6, 28.5, 14.4; HRMS calcd for C10H17NO4 [M]C
215.1165, found 215.1158.
4.2.27. Ethyl (2E)-6-bromo-4-[(tert-butoxycarbonyl)-
(methyl)amino]hex-2-enoate (10). A solution of carbon
tetrabromide (1.63 g, 4.93 mmol, 1.05 equiv) in CH2Cl2
(10 mL) was added dropwise to a 0 8C solution of
triphenylphosphine (1.29 g, 4.93 mmol, 1.05 equiv) and 47
(1.35 g, 4.70 mmol, 1 equiv) in CH2Cl2 (50 mL). The
reaction was stirred at 0 8C for 1 h, diluted with 10%
EtOAc/hexanes (10 mL) and filtered through celite. Evap-
oration of the volatiles gave a crude product that was
purified by flash chromatography using 25% EtOAc/
hexanes as eluant to yield the desired product (49.0 mg,
30%) as an orange oil. RfZ0.56 on silica gel (25% EtOAc/
4.2.25. tert-Butyl methyl(2-oxotetrahydrofuran-3-yl)-
carbamate (46). To a 0 8C solution of 2-(tert-butoxycarbo-
nylamino)-g-butyrolactone13 (500 mg, 2.50 mmol, 1 equiv)
and iodomethane (464 mL, 7.45 mmol, 3 equiv) in DMF
(15 mL) was added NaH (130 mg, 3.23 mmol, 60%
dispersion in oil, 1.3 equiv). The resulting mixture was
warmed to rt and stirred for 18 h. The reaction was diluted
with EtOAc (15 mL) and quenched with water (15 mL). The
aqueous layer was washed with EtOAc (3!) and the
combined organic extracts were washed with brine, dried
with anhydrous MgSO4 and filtered. Removal of the solvent
gave a crude white solid (46.0 mg, 87%) that was used
without further purification. The product is a mixture of
rotamers in a 3:2 ratio. RfZ0.49 on silica gel (50% EtOAc/
hexanes). IR (neat) nZ2978, 1694, 1454, 1392, 1367 cmK1
;
1H NMR (300 MHz, CDCl3) d 6.83 (dd, 1H, JZ15.9,
4.9 Hz), 5.87 (dd, 1H, JZ15.9, 1.9 Hz), 4.92 (brs, 1H), 4.21
(q, 2H, JZ7.1 Hz), 3.35 (t, 2H, JZ6.0 Hz), 2.74 (s, 3H),
2.35–2.15 (m, 2H), 1.48 (s, 9H), 1.30 (t, 3H, JZ7.1 Hz); 13C
NMR (74.5 MHz, CDCl3) d 166.2, 155.8, 145.6, 122.7,
80.6, 60.9, 55.0, 34.3, 29.9, 29.2, 28.5, 14.4; HRMS calcd
for C17H22O4 [MKC(CH3)3]C 293.0274, found 293.0262.
hexanes). IR (neat) nZ2977, 1782, 1694, 1455 cmK1
;
1H NMR (300 MHz, CDCl3) major rotamer d 4.84 (brt, 1H,
JZ11.3 Hz), 4.45 (brt, 1H, JZ9.1 Hz), 4.23 (ddd, 1H, JZ
9.1, 9.1, 6.9 Hz), 2.87 (brs, 3H), 2.45 (brs, 2H), 1.47 (s, 9H);

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D. Alberico et al. / Tetrahedron 61 (2005) 6283–6297
4.2.28. Ethyl (2E)-4-[(tert-butoxycarbonyl)amino]-6-
hydroxyhex-2-enoate (48). To a K78 8C solution of
2-(tert-butoxycarbonylamino)-g-butyrolactone13 (2.00 g,
9.94 mmol, 1 equiv) in THF (60 mL) was added diisobutyl-
aluminum hydride (15.0 mL, 15.0 mmol, 1.0 M in hexanes,
1.5 equiv). The resulting mixture was stirred at K78 8C for
1.5 h. To a separate round-bottom flask was added NaH
(41.7 mg, 10.4 mmol, 60% dispersion in oil, 1.05 equiv) and
THF (40 mL). Triethyl phosphonoacetate (1.96 mL,
9.89 mmol, 1 equiv) was added dropwise at 0 8C then
warmed to rt and stirred for 30 min. The reaction mixture
was cooled to K78 8C and the diisobutylaluminum hydride
solution was added via cannula. The resulting mixture was
stirred at K78 8C for 10 min then warmed to rt and stirred
for 18 h. The reaction was quenched with 10% aqueous HCl
and the aqueous layer was washed with ether (3!). The
combined organic extracts were washed with brine, dried
with anhydrous MgSO4, filtered and concentrated. The
crude oil was purified by flash chromatography using 75%
EtOAc/hexanes as eluant to yield the desired product
(1.68 g, 62%) as an orange oil. RfZ0.34 on silica gel (50%
EtOAc/hexanes). IR (neat) nZ3350, 2979, 1698, 1504,
1366, 1249 cmK1; 1H NMR (300 MHz, CDCl3) d 6.91 (dd,
1H, JZ15.6, 4.7 Hz), 5.97 (dd, 1H, JZ15.9, 1.9 Hz), 5.03
(d, 1H, JZ8.5 Hz), 4.56 (brs, 1H), 4.20 (q, JZ14.2, 7.1 Hz),
3.71 (t, 2H, JZ9.3 Hz), 3.07 (brs, 1H), 2.03–1.52 (m, 2H),
1.45 (s, 9H), 1.29 (t, 3H, JZ7.1 Hz); 13C NMR (74.5 MHz,
CDCl3) d 166.3, 156.2, 147.9, 121.0, 80.3, 60.6, 58.6, 48.5,
37.2, 28.3, 14.2; HRMS-ESI calcd for C14H25NO5Na [M]C
310.1648, found 310.1624.
yellow oil. NMR spectra are identical to its enatiomerically-
enriched form previously reported.15
4.2.31. Methyl (2E)-6-{[tert-butyl(dimethyl)silyl]oxy}-5-
methylhex-2-enoate (50). To a solution of 58 (300 mg,
1.40 mmol, 1 equiv) and methyl acrylate (3.15 mL,
35.0 mmol, 25 equiv) in CH2Cl2 (5 mL) was added Grubbs’
2nd generation catalyst (59.4 mg, 0.070 mmol, 5 mol%).
The mixture was stirred at rt overnight. Evaporation of the
volatiles gave a crude product that was purified by flash
chromatography using 10% EtOAc/hexanes as eluant to
yield the desired product (290 mg, 76%) as a colorless oil.
RfZ0.52 on silica gel (10% EtOAc/hexanes). IR (neat) nZ
1
2954, 1729, 1657, 1436, 1257 cmK1; H NMR (300 MHz,
CDCl3) d 6.93 (dt, 1H, JZ15.6, 7.3 Hz), 5.78 (d, 1H, JZ
15.6 Hz), 3.69 (s, 3H), 3.40 (ABX, 2H, DnABZ25.2 Hz,
JABZ9.9 Hz, JAXZ5.5 Hz, JBXZ6.4 Hz), 2.33 (m, 1H),
1.98 (m, 1H), 1.75 (octet, 1H, JZ6.7 Hz), 0.86 (s, 9H), 0.84
(s, 3H), 0.55 (s, 6H); 13C NMR (74.5 MHz, CDCl3) d 167.1,
148.5, 122.2, 77.5, 77.2, 76.9, 67.6, 51.4, 36.2, 35.5, 26.0,
18.4, 16.5, K5.3; HRMS calcd for C14H28O3Si [MK
OCH3]C 241.1631, found 241.1624.
4.2.32. Methyl (2E)-6-bromo-5-methylhex-2-enoate (17).
To a solution of dibromotriphenylphosphorane (271 mg,
0.649 mmol, 1.2 equiv) in CH2Cl2 (1.5 mL) was added a
solution of 50 in CH2Cl2 (1 mL). The mixture was stirred at
rt for 1 h then diluted with CH2Cl2 (5 mL) and quenched
with water (2 mL). The organic layer was washed with
brine, dried with anhydrous MgSO4, filtered and concen-
trated. The crude product was purified by flash chroma-
tography using 10% ether/hexanes as eluant to yield the
desired product (108 mg, 86%) as a yellow oil. RfZ0.32 on
silica gel (10% EtOAc/hexanes). IR (neat) nZ2927, 1725,
1657, 1435, 1272, 1196 cmK1; 1H NMR (300 MHz, CDCl3)
d 6.89 (dt, 1H, JZ15.5, 7.5 Hz), 5.89 (dt, 1H, JZ15.5,
1.3 Hz), 3.73 (s, 3H), 3.35 (d, 2H, JZ5.5 Hz), 2.38 (m, 1H),
2.18 (m, 1H), 2.00 (m, 1H), 1.04 (d, 3H, JZ6.8 Hz); 13C
NMR (74.5 MHz, CDCl3) d 166.9, 146.4, 123.4, 51.7, 40.2,
37.5, 34.8, 18.9; HRMS calcd for C8H12BrO2 [MKH]C
220.0098, found 220.0099.
4.2.29. Ethyl (2E)-6-bromo-4-[(tert-butoxycarbonyl)-
amino]hex-2-enoate (11). A solution of carbon tetrabro-
mide (890 mg, 2.69 mmol, 1.05 equiv) in CH2Cl2 (10 mL)
was added dropwise to a 0 8C solution of triphenylphos-
phine (700 mg, 2.69 mmol, 1.05 equiv) and 48 (700 mg,
2.56 mmol, 1 equiv) in CH2Cl2 (30 mL). The reaction was
stirred at 0 8C for 1 h then warmed to rt. Evaporation of the
volatiles gave a crude product that was purified by flash
chromatography using 50% EtOAc/hexanes as eluant to
yield the desired product (436 mg, 51%) as an oil. RfZ0.49
on silica gel (25% EtOAc/hexanes). IR (neat) nZ3360,
1
2980, 1715, 1682, 1520 1453 cmK1; H NMR (300 MHz,
4.2.33. Methyl (2E)-6-bromo-5-hydroxyhex-2-enoate
(51). To a solution of 1-bromopent-4-en-2-ol16 (700 mg,
4.24 mmol, 1 equiv) and methyl acrylate (9.88 mL,
106 mmol, 25 equiv) in CH2Cl2 (15 mL) was added Grubbs’
2nd generation catalyst (180 mg, 0.212 mmol, 5 mol%).
The mixture was stirred at rt overnight. Evaporation of the
volatiles gave a crude product that was purified by flash
chromatography using 10% EtOAc/hexanes as eluant to
yield the desired product (756 g, 80%) as a colorless oil.
RfZ0.19 on silica gel (25% EtOAc/hexanes). IR (neat) nZ
CDCl3) d 6.83 (dd, 1H, JZ15.7, 5.5 Hz), 5.97 (dd, 1H, JZ
15.7, 1.2 Hz), 4.59 (brs, 1H), 4.50 (brs, 1H), 4.20 (q, JZ
7.1 Hz), 3.50–3.27 (m, 2H), 2.24–2.02 (m, 2H), 1.45 (s, 9H),
1.29 (t, 3H, JZ7.1 Hz); 13C NMR (74.5 MHz, CDCl3) d
166.0, 154.9, 146.5, 121.7, 80.1, 60.6, 50.5, 37.4, 28.6, 28.3,
14.2; HRMS calcd for C13H23BrNO4 [MKC(CH3)3]C
279.0103, found 279.0106.
4.2.30. tert-Butyl(dimethyl)[(2-methylpent-4-enyl)oxy]-
silane (49). To a 0 8C solution of imidazole (420 mg,
6.11 mmol, 1.15 equiv) and 2-methyl-4-pentenol14
(536 mg, 5.35 mmol, 1 equiv) in CH2Cl2 (15 mL) was
added tert-butyldimethylsilyl chloride (930 mg, 6.16 mmol,
1.15 equiv). The mixture was stirred for 10 min at 0 8C then
warmed to rt overnight. The reaction was quenched with
saturated aqueous NH4Cl (10 mL) and the organic layer was
washed with saturated aqueous NaHCO3, brine, dried with
anhydrous MgSO4, filtered and concentrated. The crude oil
was purified by flash chromatography using hexanes
yielding the desired product (812 mg, 71%) as a as a pale
1
3444, 2952, 1715, 1652, 1436 cmK1; H NMR (300 MHz,
CDCl3) d 6.95 (dt, 1H, JZ15.6, 7.3 Hz), 5.69 (dt, 1H, JZ
15.6, 1.5 Hz), 3.99–3.92 (m, 1H), 3.74 (s, 3H), 5.2 (ABX,
2H, DnABZ45.4 Hz, JABZ10.4, JAXZ3.8 Hz, JBX
Z
6.4 Hz), 2.55–2.47 (m, 2H), 2.35 (brs, OH); 13C NMR
(74.5 MHz, CDCl3) d 166.8, 143.9, 124.3, 69.9, 51.8, 39.3,
38.0; HRMS calcd for C7H11BrO3 [M]C 222.9966, found
222.9969.
4.2.34. Methyl (2E)-5-(benzyloxy)-6-bromohex-2-enoate
(18). To a 0 8C solution of 51 (750 mg, 3.36 mmol, 1 equiv)

D. Alberico et al. / Tetrahedron 61 (2005) 6283–6297
6293
CH2Cl2 (7 mL) and cyclohexane (14 mL) was added benzyl
trichloroacetimidate (94.0 mL, 5.04 mmol, 1.5 equiv) and
trifluoromethanesulfonic acid (5 mL, 0.504 mmol,
15 mol%). The resulting mixture was stirred at 0 8C for
20 min then warmed to rt and stirred for 1 h. The reaction
was diluted with CH2Cl2 (10 mL) and quenched with 3%
aqueous NaOH (10 mL). The organic layer was washed
with water (3!), dried with anhydrous MgSO4, filtered and
concentrated. The crude product was purified by flash
chromatography using 10% EtOAc/hexanes as eluant to
yield the desired product (71.3 mg, 83%) as a colorless oil.
RfZ0.48 on silica gel (25% EtOAc/hexanes). IR (neat) nZ
gave a crude brown oil (1.40 g, 87%) that was used without
further purification. NMR spectra match the previously
reported data.19
4.2.38. Ethyl (2E)-6-bromohept-2-enoate (26). To a
K78 8C solution of oxalyl chloride (402 mL, 10.5 mmol,
1.1 equiv) in CH2Cl2 (30 mL) was added a solution of
dimethyl sulfoxide (654 mL, 9.22 mmol, 2.2 equiv) in
CH2Cl2 (15 mL). The mixture was stirred at K78 8C for
30 min. A solution of 53 (700 mg, 4.19 mmol, 1 equiv) in
CH2Cl2 (45 mL) was then added dropwise and the reaction
mixture was stirred at K78 8C for 15 min. Triethylamine
(2.92 mL, 9.22 mmol, 5 equiv) was added dropwise and the
reaction mixture was stirred at K78 8C for 15 min then
warmed to rt and stirred for 1 h. The reaction mixture was
cooled to K78 8C and a solution of (carbethoxymethylene)-
triphenylphosphorane (2.92 g, 8.38 mmol, 2 equiv) in
CH2Cl2 (45 mL) was added dropwise. The mixture was
stirred at K78 8C for 15 min then warmed to rt and stirred
for 2 h. The reaction was quenched with saturated aqueous
NH4Cl (100 mL) and the aqueous layer was extracted with
CH2Cl2 (3!). The combined organic extracts were washed
with water, brine, dried with anhydrous MgSO4, filtered and
concentrated. The crude product was purified by flash
chromatography using 10% EtOAc/hexanes as eluant to
yield the desired product (716 mg, 73%) as an orange oil.
RfZ0.70 on silica gel (10% EtOAc/hexanes). IR (neat) nZ
2982, 1721, 1656, 1268 cmK1; 1H NMR (300 MHz, CDCl3)
d 6.90 (dt, 1H, JZ15.5, 6.9 Hz), 5.86 (dt, 1H, JZ17.1,
1.5 Hz), 4.17 (q, 2H, JZ7.1 Hz), 4.13–4.02 (m, 1H), 2.52–
2.27 (m, 2H), 2.05–1.83 (m, 2H), 1.72 (d, 3H, JZ6.7 Hz),
1.28 (t, 3H, JZ7.1 Hz); 13C NMR (74.5 MHz, CDCl3) d
166.4, 147.1, 122.5, 60.6, 50.6, 39.5, 30.8, 26.9, 14.8;
HRMS calcd for C9H15BrO2 [MKH]C 234.0264, found
234.0255.
2590, 1725, 1660, 1435, 1322, 1177 cmK1 1H NMR
;
(300 MHz, CDCl3) d 7.41–7.20 (m, 5H), 6.93 (dt, 1H, JZ
14.8, 7.3 Hz), 5.94 (dd, 1H, JZ15.7, 1.3 Hz), 4.61 (q, 2H,
JZ37.5, 11.5 Hz), 3.74 (s, 3H), 3.77–3.68 (m, 1H), 3.48–
3.38 (m, 2H), 2.68–2.50 (m, 2H); 13C NMR (74.5 MHz,
CDCl3) d 166.8, 144.1, 137.8, 129.0, 128.7, 128.2, 128.1,
124.2, 72.1, 51.8, 36.0, 34.0; HRMS-ESI calcd for
C14H17O3NaBr [M]C 335.0253, found 335.0251.
4.2.35. [1-(Bromomethyl)but-3-enyl]benzene (52). To a
0 8C solution of 2-phenylpent-4-enol17 (834 mg,
5.14 mmol, 1 equiv) in CH2Cl2 (50 mL) was added carbon
tetrabromide (2.39 g, 7.20 mmol, 1.4 equiv) and triphenyl-
phosphine (3.78 g, 14.4 mmol, 2.8 equiv). The mixture was
stirred for 10 min at 0 8C then warmed to rt and stirred
overnight. Evaporation of the volatiles gave a crude product
that was purified by flash chromatography using hexane as
eluant to yield the desired product (724 mg, 63%) as a
colorless liquid. IR (neat) nZ3073, 3028, 2918, 2850, 1640,
149, 1451, 1233, 918; 1H NMR (300 MHz, CDCl3) d 7.36–
7.15 (m, 5H), 5.65 (m, 1H), 5.04 (m, 2H), 3.60 (dd, 2H,
JZ6.6, 2.7 Hz), 3.06 (m, 1H), 2.65 (m, 1H), 2.46 (m, 1H);
13C NMR (74.5 MHz, CDCl3) d 141.7, 135.3, 128.4, 127.6,
127.0, 117.1, 47.3, 38.3, 38.0; HRMS calcd for C11H13Br
[M]C 224.0201, found 224.0210.
4.2.39. [2-({[tert-Butyl(dimethyl)silyl]oxy}methyl)cyclo-
propyl]methanol (54). Diethylzinc (1.10 mL, 10.7 mmol,
2 equiv) and diiodomethane (865 mL, 10.7 mmol, 2 equiv)
were added dropwise to a solution of (2Z)-4-{[tert-
butyl(dimethyl)silyl]oxy}but-2-en-1-ol20 (1.00 g, 5.37 mmol,
1 equiv) in ether (100 mL). The reaction was stirred at rt for
24 h then quenched with saturated aqueous NH4Cl
(100 mL). The aqueous layer was washed with ether (3!)
and the combined organic extracts were washed with brine,
dried with anhydrous MgSO4, filtered and concentrated. The
crude product was purified by flash chromatography using
25% EtOAc/hexanes as eluant to yield the desired product
(700 mg, 60%) as a colorless oil. RfZ0.64 on silica gel
(25% EtOAc/hexanes). IR (neat) nZ3484, 2956, 1472,
4.2.36. Methyl (2E)-6-bromo-5-phenylhex-2-enoate (19).
To a solution of 52 (479 mg, 2.13 mmol, 1 equiv) and
methyl acrylate (4.80 mL, 53.3 mmol, 25 equiv) in CH2Cl2
(5 mL) was added Grubbs’ 2nd generation catalyst
(93.0 mg, 0.110 mmol, 5 mol%). The mixture was stirred
at rt overnight. Evaporation of the volatiles gave a crude
product that was purified by flash chromatography using
10% EtOAc/hexanes as eluant to yield the desired product
(381 mg, 63%) as a slightly pink oil. IR (neat) nZ3076,
3030, 2950, 2854, 1726, 1658, 1433, 1275, 1207; 1H NMR
(300 MHz, CDCl3) d 7.36–7.14 (m, 5H), 6.80 (m, 1H), 5.83
(dt, 1H, JZ15.6, 1.2 Hz), 3.67 (s, 3H), 3.57 (m, 2H), 3.13
(m, 1H), 2.84 (m, 1H), 2.60 (m, 1H); 13C NMR (74.5 MHz,
CDCl3) d 166.5, 145.6, 140.7, 128.7, 127.5, 127.4, 123.1,
51.4, 46.7, 37.6, 36.4; HRMS calcd for C11H13Br
[MKOMe]C 251.0072, found 251.0077.
1
1255 cmK1; H NMR (300 MHz, CDCl3) d 4.11 (dd, 1H,
JZ11.5, 5.3 Hz), 3.95 (ddd, 1H, JZ11.8, 5.6 Hz), 3.34–
3.16 (m, 2H), 1.44–1.30 (m, 1H), 1.30–1.15 (m, 1H), 0.91
(s, 9H), 0.82–0.69 (m, 1H), 0.19 (q, 1H, JZ5.3 Hz), 0.11 (d,
6H, JZ5.3 Hz); 13C NMR (74.5 MHz, CDCl3) d 63.9, 63.1,
25.8, 18.2, 17.3, 8.4, K5.3, K5.6; HRMS calcd for
C11H24O2Si [M]C 217.1612, found 217.1623.
4.2.37. 4-Bromopentan-1-ol (53). To a mixture of 4-bro-
mopentyl acetate18 (2.00 g, 9.57 mmol, 1 equiv) in MeOH
(70 mL) was added K2CO3 (1.45 g, 10.5 mmol, 1.1 equiv).
The reaction was stirred at rt for 2 h then quenched with
saturated aqueous NH4Cl (70 mL). The aqueous layer was
washed with EtOAc (3!) and the combined organic
extracts were washed with brine, dried with anhydrous
MgSO4, filtered and concentrated. Removal of the solvent
4.2.40. Ethyl (2E)-3-[2-({[tert-butyl(dimethyl)silyl]oxy}-
methyl)cyclopropyl]acrylate (55). To a K78 8C solution
of oxalyl chloride (440 mL, 5.07 mmol, 1.1 equiv) in
CH2Cl2 (30 mL) was added a solution of dimethyl sulfoxide
(720 mL, 10.0 mmol, 2.2 equiv) in CH2Cl2 (15 mL). The

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D. Alberico et al. / Tetrahedron 61 (2005) 6283–6297
mixture was stirred at K78 8C for 30 min. A solution of 54
(1.00 g, 4.61 mmol, 1 equiv) in CH2Cl2 (45 mL) was then
added dropwise and the reaction mixture was stirred at
K78 8C for 15 min. Triethylamine (3.21 mL, 23.0 mmol,
5 equiv) was added dropwise and the reaction mixture was
stirred at K78 8C for 15 min then warmed to rt and stirred
for 1 h. The reaction mixture was cooled to K78 8C and a
solution of (carbethoxymethylene)triphenylphosphorane
(3.21 g, 9.22 mmol, 2 equiv) in CH2Cl2 (45 mL) was
added dropwise. The mixture was stirred at K78 8C for
15 min then warmed to rt and stirred for 2 h. The reaction
was quenched with saturated aqueous NH4Cl (100 mL) and
the aqueous layer was extracted with CH2Cl2 (3!). The
combined organic extracts were washed with water, brine,
dried with anhydrous MgSO4, filtered and concentrated. The
crude product was purified by flash chromatography using
10% EtOAc/hexanes as eluant to yield the desired product
(1.21 g, 92%) as an orange oil. RfZ0.61 on silica gel (10%
EtOAc/hexanes). IR (neat) nZ2955, 1718, 1645, 1472,
as a colorless oil. RfZ0.28 on silica gel (10% EtOAc/
1
hexanes). IR (neat) nZ2983, 1714, 1368, 1262 cmK1; H
NMR (300 MHz, CDCl3) d 6.65 (dd, 1H, JZ15.6, 7.0 Hz),
6.16 (d, 1H, JZ15.8 Hz), 4.20 (q, 2H, JZ7.1 Hz), 3.49–
3.36 (m, 3H), 3.24 (ddd, 1H, JZ5.6, 5.6, 1.8 Hz), 1.29 (t,
3H, 7.0 Hz); 13C NMR (74.5 MHz, CDCl3) d 165.3, 142.4,
125.1, 61.1, 59.9, 58.2, 31.5, 14.7; HRMS calcd for
C9H15BrO3 [M]C 234.9965, found 234.9969.
4.2.43. Ethyl (2E)-6-bromo-4,5-dihydroxyhex-2-enoate
(57). To a solution of 56 (100 mg, 4.25 mmol, 1 equiv) in
THF (2 mL) was added 0.75 M aqueous H2SO4 (3.12 mL,
2.34 mmol, 5.5 equiv). The mixture was stirred at rt for 24 h
then neutralized to pH 7 with 1.0 M aqueous NaHCO3.The
aqueous layer was extracted with EtOAc (3!) and the
combined organic layers were washed with brine, dried with
anhydrous MgSO4, filtered and concentrated. The crude
product that was purified by flash chromatography using
50% EtOAc/hexanes as eluant to yield the desired product
(76.9 mg, 71%) as a colorless oil. RfZ0.31 on silica gel
(50% EtOAc/hexanes). IR (neat) nZ3427, 2981, 1698,
1
1260 cmK1; H NMR (300 MHz, CDCl3) d 6.73 (dd, 1H,
JZ15.4, 10.2 Hz), 5.92 (d, 1H, JZ15.4 Hz), 4.17 (q, 2H,
JZ7.1 Hz), 3.83 (dd, 1H, JZ11.3, 5.8 Hz), 3.59 (dd, 1H,
JZ11.3, 7.4 Hz), 1.75–1.67 (m, 1H), 1.56–1.47 (m, 1H),
1.27 (t, 3H, JZ7.1 Hz), 1.17–1.09 (m, 1H), 0.89 (s, 9H),
0.71 (q, 2H, JZ5.2 Hz), 0.05 (d, 6H, JZ2.7 Hz); 13C NMR
(74.5 MHz, CDCl3) d 166.7, 150.1, 120.6, 62.8, 60.2, 26.1,
23.5, 19.5, 18.5, 14.6, 13.1, K5.1; HRMS calcd for
C15H28O3Si [MKC(CH3)3]C 227.1106, found 227.1103.
1
1370 cmK1; H NMR (300 MHz, CDCl3) d 7.01 (dd, 1H,
JZ15.6, 4.8 Hz), 6.16 (d, 1H, JZ15.8 Hz), 4.50 (t, 1H, JZ
3.6 Hz), 4.21 (q, 2H, JZ7.1 Hz), 3.90 (dt, 2H, JZ11.2,
4.8 Hz), 3.60–3.49 (m, 2H), 3.2 (brs, 2H), 1.30 (t, 3H,
7.1 Hz); 13C NMR (74.5 MHz, CDCl3) d 166.4, 145.0,
122.9, 73.4, 72.3, 60.9, 35.4, 14.2; HRMS-ESI calcd for
C10H18O4Br [M]C 253.0069, found 253.0061.
4.2.41. 3 Ethyl (2E)-3-[2-(bromomethyl)cyclopropyl]-
acrylate (28a). To a solution of dibromotriphenylphos-
phorane (2.24 mg, 5.06 mmol, 1.2 equiv) in CH2Cl2
(10 mL) was added a solution of 55 in CH2Cl2 (7 mL).
The mixture was stirred at rt for 1 h then diluted with
CH2Cl2 (25 mL) and quenched with water (15 mL). The
organic layer was washed with brine, dried with anhydrous
MgSO4, filtered and concentrated. The crude product was
purified by flash chromatography using 10% EtOAc/
hexanes as eluant to yield the desired product (904 mg,
92%) as a yellow oil. RfZ0.63 on silica gel (10% EtOAc/
4.2.44. Ethyl (2E)-3-[5-(bromomethyl)-2,2-dimethyl-1,3-
dioxolan-4-yl]acrylate (28b). To a solution of 57 (780 mg,
3.08 mmol, 1 equiv) in acetone (20 mL) was added iodine
(160 mg, 0.616 mmol, 20 mol%). The reaction mixture was
stirred at rt for 3 h. The reaction was quenched with
saturated aqueous Na2S2O3 (1 mL). The volatiles were
evaporated and the resulting mixture was diluted with
CH2Cl2 (25 mL). Saturated aqueous Na2S2O3 (25 mL) was
added and the aqueous layer was extracted with CH2Cl2
(3!). The combined organic layers were washed with
brine, dried with anhydrous MgSO4, filtered and concen-
trated. The crude product was purified by flash chromato-
graphy using 10% EtOAc/hexanes as eluant to yield the
desired product (750 mg, 83%) as a colorless oil. RfZ0.64
on silica gel (25% EtOAc/hexanes). IR (neat) nZ2986,
hexanes). IR (neat) nZ2981, 1713, 1646, 1311, 1266 cmK1
;
1H NMR (300 MHz, CDCl3) d 6.68 (dd, 1H, JZ15.4,
9.9 Hz), 5.99 (d, 1H, JZ15.4 Hz), 4.19 (q, 2H, JZ7.1 Hz),
3.56 (dd, 1H, JZ10.4, 7.7 Hz), 3.39 (dd, 1H, JZ10.4,
8.2 Hz), 1.96–1.74 (m, 2H), 1.38–1.31 (m, 1H), 1.29 (t, 3H,
JZ7.1 Hz), 0.78 (q, 1H, JZ5.8 Hz); 13C NMR (74.5 MHz,
CDCl3) d 166.4, 147.2, 122.2, 60.5, 34.0, 23.8, 22.6, 17.2,
14.5; HRMS calcd for C9H13BrO2 [M]C 232.0092, found
232.0099.
1
1716, 1661, 1382 cmK1; H NMR (300 MHz, CDCl3) d
6.93 (dd, 1H, JZ15.5, 5.5 Hz), 6.17 (dd, 1H, JZ15.5,
1.0 Hz), 4.84 (t, 1H, 6.2 Hz), 4.51 (q, 1H, JZ6.6 Hz), 4.22
(q, 2H, JZ7.0 Hz), 3.27 (ABX, 2H, DnABZ28.1 Hz, JAB
Z
10.4 Hz, JAXZ6.7 Hz, JBXZ7.0 Hz), 1.53 (s, 3H), 1.40 (s,
3H), 1.30 (t, 1H, JZ7.0 Hz); 13C NMR (74.5 MHz, CDCl3)
d 165.7, 141.0, 123.8, 109.9, 78.0, 76.6, 60.7, 30.1, 27.9,
25.4, 14.2; HRMS calcd for C11H17BrO4 [MKCH3]C
277.0073, found 277.0075.
4.2.42. Ethyl (2E)-3-[3-(bromomethyl)oxiran-2-yl]acryl-
ate (56). To a solution of 3-chloroperoxybenzoic acid
(4.32 g, 18.0 mmol, 70% active, 3 equiv) in CH2Cl2
(30 mL) was added to a solution of ethyl (2E,4E)-6-
bromohexa-2,4-dienoate21 (1.28 g, 5.84 mmol, 1 equiv) in
CH2Cl2 (2 mL). The mixture was stirred at rt for 24 h. The
reaction was quenched with saturated aqueous NH4Cl
(30 mL) and the aqueous layer was extracted with CH2Cl2
(3!). The combined organic layers were washed with
saturated aqueous NaHCO3, brine, dried with anhydrous
MgSO4, filtered and concentrated. The crude product was
purified by flash chromatography using 25% EtOAc/
hexanes as eluant to yield the desired product (1.34, 92%)
4.2.45. {[1-(Bromomethyl)pent-4-enyl]oxy}(tert-butyl)di-
methylsilane (58). To a 0 8C solution of 1-bromohex-5-en-
2-ol22 (1 g, 5.58 mmol, 1 equiv) in CH2Cl2 (35 mL) was
added 2,6-lutidine (980 mg, 8.38 mmol, 1.5 equiv) and tert-
butyldimethylsilyl trifluoromethanesulfonate (1.54 mL,
6.70 mmol, 1.2 equiv). The mixture was stirred at 0 8C for
30 min then warmed to rt and stirred for 2 h. The reaction
was quenched with water (35 mL) and the aqueous layer
was extracted with CH2Cl2 (3!). The combined organic

D. Alberico et al. / Tetrahedron 61 (2005) 6283–6297
6295
layers were washed with brine, dried with anhydrous
MgSO4, filtered and concentrated. The crude product was
purified by flash chromatography using 10% EtOAc/
hexanes as eluant to yield the desired product (1.40 g,
88%) as a pale yellow oil. RfZ0.91 on silica gel (25%
chromatography using 10% EtOAc/hexanes as eluant to
yield the desired product (1.48 g, 78%) as a colorless oil.
RfZ0.25 on silica gel (10% EtOAc/hexanes). IR (neat) nZ
2950, 1722, 1658, 1436 cmK1; 1H NMR (300 MHz, CDCl3)
d 6.97 (dt, 1H, JZ15.5, 6.9 Hz), 5.87 (d, 1H, JZ15.7 Hz),
4.74 (AB, 1H, JZ7.0 Hz), 4.68 (AB, 1H, JZ7.0 Hz), 3.73
(s, 3H), 3.80–3.65 (m, 1H), 3.47 (d, 2H, JZ5.0 Hz), 3.41
(s, 3H), 2.33 (septet, 2H, JZ8.2 Hz), 3.80–3.65 (m, 1H),
2.28–1.79 (m, 2H); 13C NMR (74.5 MHz, CDCl3) d 167.1,
148.4, 121.7, 96.6, 76.4, 56.1, 51.6, 35.4, 32.0, 27.9; HRMS
calcd for C10H17BrO4 [MKOCH3]C 249.0121, found
249.0126.
EtOAc/hexanes). IR(neat) nZ2956, 1642, 1472, 1256 cmK1
;
1H NMR (300 MHz, CDCl3) d 5.81 (dddd, 1H, JZ17.0,
10.1, 6.5, 6.5 Hz), 5.07–4.94 (m, 2H), 3.85 (quintet, 1H, JZ
5.8 Hz), 3.38–3.27 (m, 2H), 2.16–2.06 (m, 2H), 1.82–1.55
(m, 2H), 0.90 (s, 9H), 0.08 (d, 6H, JZ6.0 Hz); 13C NMR
(74.5 MHz, CDCl3) d 138.4, 115.0, 71.5, 37.8, 34.9,
29.3, 26.0, 18.3, K4.2; HRMS calcd for C12H25BrOSi
[MKC(CH3)3]C 235.0156, found 235.0154.
4.2.49. 5-{[tert-Butyl(dimethyl)silyl]oxy}-3-methylpen-
tane-1,3-diol (60). A solution of tert-butyldimethylsilyl
chloride (4.68 g, 31.0 mmol, 1.0 equiv) in CH2Cl2 (10 mL)
was added dropwise to a solution of 3-methyl-1,3,5-
pentanetriol (5.00 g, 37.3 mmol, 1.2 equiv) and triethyl-
amine (5.19 mL, 37.3 mmol, 1.2 equiv) in CH2Cl2 (15 mL).
The mixture was stirred at rt overnight then quenched with
water (25 mL). The aqueous layer was separated and
extracted with EtOAc (3!). The combined organic extracts
were dried with anhydrous MgSO4, filtered and concen-
trated. The crude oil was purified by flash chromatography
using 50% EtOAc/hexanes as eluant to yield the desired
product (3.73 g, 50%) as a pale yellow oil. RfZ0.50 on
silica gel (50% EtOAc/hexanes). IR (neat) nZ3382, 2929,
1470, 1256 cmK1; 1H NMR (300 MHz, CDCl3) d 4.43 (brs,
1H), 4.02–3.77 (m, 4H), 3.61 (brs, 1H), 1.98–1.77 (m, 2H),
1.70–1.54 (m, 2H), 1.30 (s, 3H), 0.90 (s, 3H), 0.10 (s, 3H);
13C NMR (74.5 MHz, CDCl3) d 74.6, 60.7, 59.8, 42.5, 41.7,
26.6, 26.0, 18.2, K5.5; HRMS calcd for C12H28O3Si [M]C
249.1871, found 249.1885.
4.2.46. Methyl (2E)-7-bromo-6-{[tert-butyl(dimethyl)-
silyl]oxy}hept-2-enoate (32). To a solution of 58 (1.00 g,
3.42 mmol, 1 equiv) and methyl acrylate (7.71 mL,
85.6 mmol, 25 equiv) in CH2Cl2 (12 mL) was added
Grubbs’ 2nd generation catalyst (145 mg, 0.171 mmol,
5 mol%). The mixture was stirred at rt overnight. Evapo-
ration of the volatiles gave a crude product that was purified
by flash chromatography using 10% EtOAc/hexanes as
eluant to yield the desired product (770 mg, 64%) as a pale
orange oil. RfZ0.79 on silica gel (25% EtOAc/hexanes).
IR (neat) nZ2952, 1732, 1435, 1256 cmK1 1H NMR
;
(300 MHz, CDCl3) d 5.81 (dddd, 1H, JZ17.0, 10.2, 6.5,
6.5 Hz), 5.07–4.94 (m, 2H), 3.85 (quintet, 1H, JZ5.8 Hz),
3.39–3.26 (m, 2H), 2.22–2.00 (m, 2H), 1.82–1.53 (m, 2H),
0.90 (s, 9H), 0.08 (d, 6H, JZ6.0 Hz); 13C NMR (74.5 MHz,
CDCl3) d 167.2, 148.9, 121.4, 71.2, 51.7, 37.1, 33.8,
27.6, 25.9, 18.2, K4.3; HRMS calcd for C14H27BrO3Si
[MKCH3]C 335.0671, found 335.0678.
4.2.47. 6-Bromo-5-(methoxymethoxy)hex-1-ene (59).
To a 0 8C solution of 1-bromohex-5-en-2-ol22 (2.00 mL,
11.2 mmol, 1 equiv) in CH2Cl2 (50 mL) was added drop-
wise diisopropylethylamine (5.84 mL, 33.5 mmol, 3 equiv).
Chloromethyl methyl ether (3.21 mL. 55.9 mmol, 5 equiv)
was added dropwise and then the reaction mixture was
warmed to rt and stirred overnight. The reaction was
quenched with saturated aqueous NH4Cl (50 mL) and the
aqueous layer was extracted with CH2Cl2 (3!). The
combined organic layers were washed with brine, dried
with anhydrous MgSO4, filtered and concentrated. The
crude product was purified by flash chromatography using
10% EtOAc/hexanes as eluant to yield the desired product
(2.12 g, 85%) as a colorless oil. RfZ0.57 on silica gel (10%
4.2.50. Ethyl (2E)-7-{[tert-butyl(dimethyl)silyl]oxy}-5-
hydroxy-5-methylhept-2-enoate (61). To a K78 8C solu-
tion of oxayl chloride (579 mL, 6.64 mmol, 1.1 equiv) in
CH2Cl2 (35 mL) was added a solution of dimethyl sulfoxide
(943 mL, 13.3 mmol, 2.2 equiv) in CH2Cl2 (20 mL). The
mixture was stirred at K78 8C for 30 min. A solution of 60
(1.50 g, 6.04 mmol, 1 equiv) in CH2Cl2 (60 mL) was then
added dropwise and the reaction mixture was stirred at
K78 8C for 15 min. Triethylamine (4.21 mL, 30.2 mmol,
5 equiv) was added dropwise and the reaction mixture was
stirred at K78 8C for 15 min then warmed to rt and stirred
for 1 h. The reaction mixture was cooled to K78 8C and a
solution of (carbethoxymethylene)triphenylphosphorane
(4.21 g, 12.1 mmol, 2 equiv) in CH2Cl2 (60 mL) was
added dropwise. The mixture was stirred at K78 8C for
15 min and warmed to rt and stirred for 24 h. The reaction
was quenched with water (150 mL) and the aqueous layer
was extracted with CH2Cl2 (3!). The combined organic
layers were washed with brine, dried with anhydrous
MgSO4, filtered and concentrated. The crude product was
purified by flash chromatography using 25% EtOAc/
hexanes as eluant to yield the desired product (1.14 g,
60%) as a colorless oil. RfZ0.55 on silica gel (25% EtOAc/
1
EtOAc/hexanes). IR (neat) nZ2947, 1641, 1442 cmK1; H
NMR (300 MHz, CDCl3) d 5.80 (dddd, 1H, JZ17.0, 6.6,
3.5, 3.5 Hz), 5.08–4.93 (m, 2H), 4.69 (AB, 2H, JZ7.1 Hz),
3.78–3.65 (m, 1H), 3.50–3.43 (m, 2H), 3.40 (s, 3H), 2.23–
2.02 (m, 2H), 1.80–1.65 (m, 2H); 13C NMR (74.5 MHz,
CDCl3) d 137.9, 115.4, 96.4, 76.4, 56.1, 36.0, 32.7, 29.4;
HRMS calcd for C8H15BrO2 [MKOCH3]C 189.9988,
found 189.9993.
4.2.48. Methyl (2E)-7-bromo-6-(methoxymethoxy)hept-
2-enoate (33). To a solution of 59 (1.50 g, 6.72 mmol,
1 equiv) and methyl acrylate (15.1 mL, 168 mmol,
25 equiv) in CH2Cl2 (25 mL) was added Grubbs’ 2nd
generation catalyst (285 mg, 0.336 mmol, 5 mol%). The
mixture was stirred at rt overnight. Evaporation of the
volatiles gave a crude product that was purified by flash
hexanes). IR (neat) nZ3500, 2931, 1722, 1652, 1472 cmK1
;
1H NMR (300 MHz, CDCl3) d 7.01 (dt, 1H, JZ15.4,
7.7 Hz), 5.87 (d, 1H, JZ15.7 Hz), 4.19 (q, 2H, JZ4.4 Hz),
3.95–3.87 (m, 2H), 2.42 (d, 2H, JZ7.7 Hz), 1.83–1.60 (m,
2H), 1.29 (t, 3H, JZ7.1 Hz), 1.24 (s, 3H), 0.90 (s, 9H), 0.10
(s, 3H); 13C NMR (74.5 MHz, CDCl3) d 166.5, 145.2, 124.2,

6296
D. Alberico et al. / Tetrahedron 61 (2005) 6283–6297
72.8, 60.8, 60.4, 45.5, 41.1, 27.0, 26.0, 18.2, 14.5, K5.5;
HRMS calcd for C16H22O4Si [MKOH]C 299.2037, found
299.2042.
RfZ0.65 on silica gel (25% EtOAc/hexanes). IR (neat) nZ
2980, 1714, 1656, 1447 cmK1; 1H NMR (300 MHz, CDCl3)
d 6.93 (ddd, 1H, JZ15.6, 7.6, 7.6 Hz), 5.88 (ddd, 1H, JZ
15.4, 1.1, 1.1 Hz), 4.71 (s, 2H), 4.20 (q, 2H, JZ7.1 Hz),
3.48–3.40 (m, 2H), 3.38 (s, 3H), 2.52–2.36 (m, 2H), 2.23–
2.00 (m, 2H), 1.30 (t, 3H, JZ7.1 Hz), 1.26 (s, 3H); 13C
NMR (74.5 MHz, CDCl3) d 166.2, 143.6, 124.6, 91.1, 78.8,
60.4, 55.7, 43.6, 42.7, 27.4, 23.5, 14.3; HRMS calcd for
C12H21BrO5 [M]C 309.0709, found 309.0701.
4.2.51. Ethyl (2E)-7-{[tert-butyl(dimethyl)silyl]oxy}-5-
(methoxymethoxy)-5-methylhept-2-enoate (62). To a
0 8C solution of 61 (336 mg, 1.06 mmol, 1 equiv) in
CH2Cl2 (5 mL) was added dropwise diisopropylethylamine
(555 mL, 3.18 mmol, 3 equiv). Chloromethyl methyl ether
(306 mL, 5.31 mmol, 5 equiv) was added dropwise and then
the reaction mixture was warmed to rt and stirred overnight.
The reaction was quenched with saturated aqueous NH4Cl
(5 mL) and the aqueous layer was extracted with CH2Cl2
(3!). The combined organic layers were washed with
brine, dried with anhydrous MgSO4, filtered and concen-
trated. The crude product that was purified by flash
chromatography using 10% EtOAc/hexanes as eluant to
yield the desired product (300 g, 79%) as a colorless oil.
RfZ0.85 on silica gel (10% EtOAc/hexanes). IR (neat) nZ
2954, 1723, 1656, 1467 cmK1; 1H NMR (300 MHz, CDCl3)
d 7.01 (ddd, 1H, JZ15.7, 7.7, 7.7 Hz), 5.83 (ddd, 1H, JZ
16.8, 1.1, 1.1 Hz), 4.71 (AB, 1H, JZ7.0 Hz), 4.68 (AB, 1H,
JZ7.7 Hz), 4.17 (q, 2H, JZ7.1 Hz), 3.71 (ddd, 2H, JZ7.1,
7.1, 1.1 Hz), 3.35 (s, 3H), 2.44 (dd, 2H, JZ7.4, 1.1 Hz),
1.78 (ddd, 2H, JZ6.7, 6.7, 2.2 Hz), 1.27 (t, 3H, JZ7.1 Hz),
1.23 (s, 3H), 0.87 (s, 9H), 0.03 (s, 6H); 13C NMR (74.5 MHz,
CDCl3) d 166.5, 145.2, 124.1, 91.0, 77.3, 60.4, 59.1, 55.6,
43.2, 42.2, 26.1, 24.4, 18.4, 14.4, K5.2; HRMS calcd for
C18H36O5Si [MKCH3]C 229.1436, found 229.1439.
4.2.54. Ethyl (2R)-2-(allyloxy)-4-phenylbutanoate (64).
To a suspension/solution of ethyl (R)-(K)-2-hydroxy-4-
phenylbutyrate (2.01 g, 9.65 mmol, 1 equiv) and silver(I)
oxide (6.70 g, 29.0 mmol, 3 equiv), MgSO4 (289 mg,
2.40 mmol, 25 mol%) in Et2O (40 mL) was added allyl
bromide (2.51 mL, 29.0 mmol, 3 equiv). The reaction
mixture was stirred at rt for 3 days protected from the
light. Celite was then added and the mixture was filtrated
through Celite and washed with Et2O. Evaporation of the
solvent gave the crude product which was purified by flash
chromatography using 10% Et2O/hexane as the eluant to
give the desired product (1.19 g, 49%) as a colorless liquid.
[a]2D5 C35.8 (c 1.1, CHCl3); IR (neat) nZ3027, 2982, 2932,
2865, 1746, 1178, 1027 cmK1; 1H NMR (300 MHz, CDCl3)
d 7.31–7.14 (m, 5H), 5.92 (m, 1H), 5.25 (m, 2H), 4.18 (m,
3H), 3.88 (m, 2H), 2.75 (m, 1H), 2.06 (q, 2H, JZ8.4 Hz),
1.26 (t, 3H, JZ7.2 Hz); 13C NMR (74.5 MHz, CDCl3) d
172.6, 141.0, 134.0, 128.3, 128.2, 125.8, 117.5, 77.1, 71.3,
60.6, 34.4, 31.2, 14.1; HRMS calcd for C15H20O3 [M]C
248.1412, found 248.1423.
4.2.52. Ethyl (2E)-7-hydroxy-5-(methoxymethoxy)-5-
methylhept-2-enoate (63). To a 0 8C solution of 62
(920 mg, 2.55 mmol, 1 equiv) in THF (20 mL) was added
hydrogen fluoride–pyridine (70:30) (1.40 mL, 51.0 mmol,
20 equiv). The resulting mixture was stirred at 0 8C for
30 min then warmed to rt and stirred for 2 h. The reaction
was diluted with ether (60 mL) and quenched with saturated
aqueous NaHCO3 (50 mL). The organic layer was washed
with brine, dried with anhydrous MgSO4, filtered and
concentrated. The crude product that was purified by flash
chromatography using 25% EtOAc/hexanes as eluant to
yield the desired product (511 mg, 81%) as a colorless oil.
RfZ0.15 on silica gel (25% EtOAc/hexanes). IR (neat) nZ
4.2.55. [(3R)-3-(Allyloxy)-4-bromobutyl]benzene (65).
To a 0 8C suspension of lithium aluminum hydride
(199 mg, 5.25 mmol, 1.1 equiv) in Et2O (5 mL) was added
slowly a solution 64 (1.19 g, 4.77 mmol, 1 equiv) in Et2O
(5 mL). The resulting mixture was warmed to rt and stirred
for 6 h. Water (5 mL) was then carefully added at 0 8C
followed by 10% aqueous KOH (7.5 mL) at rt and finally
water (10 mL). The mixture was extracted with Et2O (4!)
and the combined organic layers were washed with brine,
dried with anhydrous MgSO4, filtered and concentrated. The
crude alcohol was then dissolved in CH2Cl2 (20 mL) and
cooled to 0 8C. Carbon tetrabromide (2.37 g, 7.16 mmol,
1.5 equiv) and triphenylphosphine (1.88 g, 7.16 mmol,
1.5 equiv) were then added and the reaction mixture was
stirred for 15 min before warming to rt overnight. The
mixture was diluted with Et2O (20 mL) was added and the
resulting suspension was filtrated through celite and
concentrated. The crude product was purified by flash
chromatography using 2/5% Et2O/hexane as eluant to
provide the desired product (1.03 g, 80% over 2 steps) as a
colorless liquid. [a]2D5 C18.1 (c 0.95, CHCl3); IR (neat) nZ
1
3440, 2980, 1714, 1652, 1455 cmK1; H NMR (300 MHz,
CDCl3) d 6.93 (ddd, 1H, JZ15.4, 7.7, 7.7 Hz), 5.87 (ddd,
1H, JZ15.6, 1.1, 1.1 Hz), 4.78 (AB, 1H, JZ7.4 Hz), 4.73
(AB, 1H, JZ7.7 Hz), 4.19 (q, 2H, JZ7.1 Hz), 3.80 (m, 2H),
3.39 (s, 3H), 2.59 (brs, 1H), 2.52 (d, 2H, JZ7.7 Hz), 1.95–
1.65 (m, 2H), 1.32 (s, 3H), 1.29 (t, 3H, JZ7.1 Hz); 13C
NMR (74.5 MHz, CDCl3) d 166.4, 144.2, 124.6, 91.1, 78.9,
60.5, 59.2, 55.9, 42.9, 41.6, 23.9, 14.4; HRMS calcd for
C12H22O5 [MKOH]C 345.2101, found 345.2097.
1
3027, 2926, 2859, 1495, 1454, 1080, 929 cmK1; H NMR
(300 MHz, CDCl3) d 7.35–7.15 (m, 5H), 5.95 (m, 1H), 5.31
(dq, 1H, JZ17.1, 1.5 Hz), 5.20 (dd, 1H, JZ10.5, 1.5 Hz),
4.14 (ddt, 1H, JZ12.5, 6.0, 0.9 Hz), 4.00 (ddt, 1H, JZ12.5,
6.0, 0.9 Hz), 3.55–3.39 (m, 3H), 2.72 (m, 2H), 1.97 (m, 2H);
13C NMR (74.5 MHz, CDCl3) d 141.4, 134.5, 128.3, 128.2,
125.8, 117.2, 77.1, 70.7, 34.8, 34.6, 31.2; HRMS calcd for
C13H17OBr [M]C 268.0463, found 268.0468.
4.2.53. Ethyl (2E)-7-bromo-5-(methoxymethoxy)-5-
methylhept-2-enoate (34). A solution of carbon tetrabro-
mide (722 mg, 2.18 mmol, 1.05 equiv) in CH2Cl2 (20 mL)
was added dropwise to a 0 8C solution of triphenylphos-
phine (571 mg, 2.18 mmol, 1.05 equiv) and 63 (512 mg,
2.07 mmol, 1 equiv) in CH2Cl2 (20 mL). The reaction was
stirred at 0 8C for 1 h then warmed to rt. Evaporation of the
volatiles gave a crude product that was purified by flash
chromatography using 20% EtOAc/hexanes as eluant to
yield the desired product (272 mg, 45%) as a colorless oil.
4.2.56. Methyl (2E)-4-{[(1R)-1-(bromomethyl)-3-phenyl-
propyl]oxy}but-2-enoate (39). To a mixture of 65 (342 mg,

D. Alberico et al. / Tetrahedron 61 (2005) 6283–6297
6297
39, 1045–1046. (b) Lautens, M.; Paquin, J.-F.; Piguel, S.;
Dahlmann, M. J. Org. Chem. 2001, 66, 8127–8134.
4. (a) Catellani, M.; Fagnola, M. C. Angew. Chem. 1994, 106,
1.27 mmol, 1 equiv) and methyl acrylate (2.83 mL,
31.7 mmol, 25 equiv) in CH2Cl2 (5 mL) was added Grubbs’
2nd generation catalyst (53.9 mg, 0.0635 mmol, 5 mol%).
The mixture was stirred at rt overnight. Evaporation of the
volatiles gave a crude product that was purified by flash
chromatography using 15% Et2O/hexane as eluant to yield
the desired product (306 mg, 74%) as an amber oil. [a]D25
C26.9 (c 0.96, CHCl3); IR (neat) nZ3034, 2950, 2865,
2559–2561.
Angew. Chem., Int. Ed. Engl. 1994, 33,
2421–2422. (b) Catellani, M.; Frignani, F.; Rangoni, A.
Angew. Chem. 1997, 109, 142–145. Catellani, M.; Frignani, F.;
Rangoni, A. Angew. Chem., Int. Ed. Engl. 1997, 36, 119–122.
(c) Catellani, M.; Mealli, C.; Motti, E.; Paoli, P.; Perez-
Carreno, E.; Pregosin, P. S. J. Am. Chem. Soc. 2002, 124,
4336–4346. (d) Catellani, M. Synlett 2003, 298–313.
5. Lautens, M.; Paquin, J.-F.; Piguel, S. J. Org. Chem. 2002, 67,
3972–3974.
1
1725, 1665, 1304, 1279, 1171 cmK1; H NMR (300 MHz,
CDCl3-d) d 7.32–7.24 (m, 2H), 7.22–7.15 (m, 3H), 6.97
(dt, 1H, JZ15.9, 4.2 Hz), 6.15 (dt, 1H, JZ15.9, 1.8 Hz),
4.30 (ddd, 1H, JZ15.9, 4.2, 1.8 Hz), 4.12 (ddd, 1H, JZ
15.9, 4.2, 1.8 Hz), 3.75 (s, 3H), 3.50 (m, 1H), 3.42 (d,
2H, JZ5.1 Hz), 2.72 (m, 2H), 1.97 (m, 2H); 13C NMR
(74.5 MHz, CDCl3-d) d 166.6, 144.1, 141.1, 128.4, 128.3,
126.0, 120.9, 78.1, 68.2, 51.5, 34.7, 34.3, 31.2; HRMS calcd
for C15H19O3Br [M]C 326.0518, found 326.0525.
6. (a) Chavan, S. P.; Rao, Y. T. S.; Govande, C. A.; Zubaidha,
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Acknowledgements
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We gratefully acknowledge the financial support of the
Natural Sciences and Engineering Research Council
(NSERC) of Canada, the Merck Frosst Centre for
Therapeutic Research for an Industrial Research Chair,
and the University of Toronto. J.- F. P. thanks NSERC, the
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´ ´
Fonds quebecois de la recherche sur la nature et les
technologies (FQRNT), the Walter C. Sumner Foundation,
and the University of Toronto for postgraduate scholarships.
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