Highly enantioselective sequential Claisen-Ireland/metathesis: Synthesis of cycloalkenes bearing two contiguous highly functionalized asymmetric centres

Article abstract of DOI:10.1016/j.tetasy.2004.12.029

A sequence of two reactions, consisting of a highly stereoselective silylated ketene acetal Claisen-Ireland rearrangement followed by a ring closing metathesis, gave a stereocontrolled access to various carbocycles.

Full text of DOI:10.1016/j.tetasy.2004.12.029

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1141–1155
Highly enantioselective sequential
Claisen–Ireland/metathesis: synthesis of cycloalkenes bearing
two contiguous highly functionalized asymmetric centres
Antoine Franc¸ais,a Olivier Bedel,a Willy Picoul,b Abdelkrim Meddour,c
Jacques Courtieuc and Arnaud Haudrechyd,*
a
`
´
´
Laboratoire de Synthese des Substances Naturelles, Associe au CNRS, Bat. 410, Universite de Paris Sud, 91405 Orsay Cedex, France
AB Science, Universite Claude Bernard Lyon 1, CPE Bat. 308, 43 Bd du 11 Novembre 1918, 69622 Villeurbanne Cedex, France
b
´
ˆ
c
´
Laboratoire de Chimie Structurale Organique, UMR 8074, Bat. 410, Universite de Paris Sud, 91405 Orsay Cedex, France
`
Laboratoire de Glycosynthese, UMR 6519, UFR Sciences Exactes et Naturelles, Bat. 18, BP1039, 51687 Reims Cedex 2, France
d
Received 23 November 2004; accepted 16 December 2004
Abstract—A sequence of two reactions, consisting of a highly stereoselective silylated ketene acetal Claisen–Ireland rearrangement
followed by a ring closing metathesis, gave a stereocontrolled access to various carbocycles.
ꢀ 2005 Published by Elsevier Ltd.
1. Introduction
neously, Piscopio et al.,3b described the same approach
in a racemic version and extended the scope to carbo-
cycles, sulfur heterocycles, pipecolinic acid derivatives
and one seven-atom oxacycle.
The challenge of controlling the configuration of nearby
asymmetric centres is crucial in modern organic synthe-
sis. Despite numerous available methods, the formation
of quaternary asymmetric positions still remains prob-
lematic.1 An elegant approach to solving this problem
can be found in the Claisen–Ireland rearrangement.2
When a side chain alkene function is present, a subse-
quent metathesis transformation can also be applied.
To the best of our knowledge, only five groups have de-
scribed the Claisen–Ireland rearrangement/metathesis
approach (CIM),3 two of them using it in an asymmetric
manner.3a,e
In 2000, Barrett et al.3c reported the synthesis of bicyclic
b-lactams, for which no selectivity was observed for the
Claisen–Ireland rearrangement under classical condi-
tions. In 2003, Ogilvie and Beaulieu3d published exam-
ples of the creation of a quaternary carbon centre,
rediscovering, on this occasion, the KHMDS/toluene
deprotonation conditions we showed as crucial four
years before4a in order to promote excellent diastereo-
selectivities. Their work opened the way to spiro-
derivatives, although with poor diastereoselectivity
(maximum 4.6:1 ratio). Recently, Kim et al.3e applied
In 1998, Burke et al.3a developed the synthesis of substi-
tuted dihydropyran-2-carboxylates. Formation of silyl
ketene acetal with LDA in THF at ꢀ100 ꢁC followed
by the addition of TMSCl gave good selectivities (up
to 20:1 ratio) and yields (up to 84%), but were somewhat
limited. For more oxygenated substrates, addition of
HMPA (20%) was necessary. Metathesis using Grubbs
I catalyst in various solvents needed long reaction times
(4–5 days) for highly substituted compounds. Simulta-
this concept to pancratistatin total synthesis.
A
Claisen–Ireland rearrangement was obtained by LDA
deprotonation in THF/HMPA, and silylation with
TBDMSCl with moderate diastereoselectivity (6:1
ratio). Ring closing metathesis afforded the desired
intermediate in 91% yield.
2. Results and discussion
*
Several years ago, over the course of our studies
concerning the formal total synthesis of fumagillin,4
Corresponding author. Fax: +33 (0) 326913166; e-mail: arnaud.
haudrechy@univ-reims.fr
0957-4166/$ - see front matter ꢀ 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2004.12.029

1142
A. Franc¸ais et al. / Tetrahedron: Asymmetry 16 (2005) 1141–1155
Table 1. Preparation of esters
we explored an efficient two-step process. A Claisen–
Ireland rearrangement (CI), which ensured highly
stereoselective formation of one predictable open diaste-
reoisomer, and the subsequent ring-closing metathesis
(M), which gave a carbocyclic framework. Encouraged
by this result, we decided to study the possibility of gen-
eralizing this strategy to various esters, in order to intro-
duce various functional groups and to obtain different
sized rings (Scheme 1).
Allylic Carboxylic Ester
alcohol acid
Yield
(%)
CH2OTBDPS
CH2OTBDPS
CH2OTBDPS
PMBO
1
1
1
4
5
6
44
89
80
O
24
25
26
O
PMBO
O
R'
2
O
MeO2C
R
O
R''
R'
O
CIM
PMBO
n
R''
O
R
CIM:
1) KHMDS; PhMe -78˚C
n
3
O
2) TMSCl -78˚C
(sat NH4Cl for 2 steps
procedure)
3) Grubbs I or II, CH2Cl2
4) CH2N2; Et2O
rt
CH2OTBDPS
PMBO
2
3
1
1
1
5
5
7
8
9
90
69
71
72
83
O
O
27
2
Scheme 1. CIM transformation.
O
O
PMBO
In order to prepare model esters 24–31 reported in Table
1, three chiral allylic alcohols 1–3 and six carboxylic
acids 4–9 were used.
CH2OTBDPS
2
28
CH2OTBDPS
2.1. Preparation of allylic alcohols 1–3
PMBO
2
O
O
O
Alcohol 15 was obtained in six steps starting from (S)-
ethyl lactate following a modified procedure described
by Isobe.5c,d Slightly modified procedures gave the tri-
substituted allylic alcohols 2 and 3 from the known alde-
hyde 10. Wittig–Horner–Emmons reaction gave a 1:1
mixture of isomeric esters 11 and 12 in 81% yield. After
DIBAH reduction, silica gel column chromatography
gave the E-diastereoisomer 13 and Z-diastereoisomer
14 in respectively 24% and 27% yield. An intermediate
fraction containing the other E- and Z-stereoisomers
with respect to the THP asymmetric centre explains
the limited yields. Alternatively, mixtures of 11 and 12
gave pure E-15 by treatment with PPTS in ethanol
(Scheme 2).
29
30
31
O
O
O
CH2OTBDPS
CH2OTBDPS
BocHN
2
2.2. Preparation of carboxylic acids 4–9
Finally, protection of 14 with a TBDPS group and care-
ful cleavage of the THP furnished the desired 3, along
with some concomitant dehydration under reaction con-
ditions. Similarly, selective protection of 16 with a
TBDPS group gave 2 (Scheme 3).
The carboxylic acid 46 was obtained in only two steps
starting from allyl-tri-n-butylstannane and glyoxylic
acid, in the presence of triflic acid, giving compound
18, followed by direct protection (Scheme 4).
PMBO
OH
CH2OTBDPS
PMBO
CH2OTBDPS
OH
O
OH
OH
OH
CH2OTBDPS
tBOCN H
2
1
O
3
4
PMBO
PMBO
OH
OH
OH
OH
2
2
2
3
O
O
O
O
5
8
9
6
7

A. Franc¸ais et al. / Tetrahedron: Asymmetry 16 (2005) 1141–1155
1143
CH2OH
CHO
(EtO)2PO-CHCH3 -CO2Et
NaH, THF
DIBAH
+
Toluene
OTHP
CH2OH
OTHP
13
OTHP
10
OTHP
CO2Et
CO2Et
14
11
+
CO2Et
CH2OH
PPTS
EtOH
DIBAH
Toluene
OH
OTHP
OH
15
12
16
Scheme 2.
PPTS
CH2OTBDPS MeOH 45°C
in the presence of copper (I) iodide gave alcohol 21.
After PMB protection and trityl cleavage with an acidic
resin, Ley oxidation8 followed by NaClO2 treatment
gave the desired carboxylic acid 6 (Scheme 6).
14
3 56%
OTHP
17
TBDPSCl
Imidazole
CH2Cl2
16
2
Alkyne carboxylic acid 7 was synthesized from 5 in 4
steps. After esterification with diazomethane and ozono-
lysis, aldehyde 22 was obtained by Ph3P treatment.
Subsequent treatment with Bestmann–OhiraÕs reagent9
gave the alkyne 23 in 69% overall yield. Finally, hy-
drated barium hydroxide saponification gave the desired
7 in 71% yield (Scheme 7).
Scheme 3.
Carboxylic acid 5 was obtained from aldehyde 19 (pre-
viously described by Evans et al.7) by oxidation with
NaClO2 in a buffered medium (Scheme 5).
For the synthesis of 6, some convenient modifications
were brought to the Evans procedure.7 The opening of
trityl glycidol 20 with homoallyl magnesium bromide
The known carboxylic acid 810 was obtained in one step
starting from allylglycine, by reaction with (tBoc)2O in
OH
O
CF3SO3H
SnBu3
NaH
PMBO
PMBBr
OH
OH
OH
+
H2O
THF
DMF
O
O
O
4
24%
18
Scheme 4.
Scheme 5.
Scheme 6.
NaClO2
NaH2PO4
PMBO
PMBO
H
OH
2
2
5
92%
tBuOH, H2O
Isobutene
O
O
19
1) NaH, PMBBr, DMF
2) Dowex 50 W, MeOH,
OH
PMBO
O
MgBr
OTr
OTr
OH
6 56%
CuI
THF
3) TPAP, NMO, CH2Cl2
4) NaClO2, NaH2PO4
tBuOH, H2O, Isobutene
3
3
20
O
21 50%
CH3CO-CN2 -PO(OEt)2
K2CO3, MeOH
PMBO
PMBO
OMe
PMBO
1) CH2N2
Ba(OH)2 8H2O
MeOH
OMe
OH
5
O
2) O3, CH2Cl2
-78°C MeOH
then Ph3P
2
2
2
O
O
O
22
7 99%
23 69%
Scheme 7.

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A. Franc¸ais et al. / Tetrahedron: Asymmetry 16 (2005) 1141–1155
the presence of NaHCO3. Carboxylic acid 9 is commer-
cially available.
Thorpe–Ingold effect generated by the quaternary car-
bon centre.
2.3. Preparation of esters 24–31
It should be noted that the final configuration can easily
be predicted using a pre-chair representation of a silyl
enol ester as shown below (Scheme 8).
All esterifications were realized using the standard DCC,
DMAP coupling procedure, giving precursors for CIM
studies.
The strategy is efficient in generating rings regardless of
their size. Thus, entries A and H show that the forma-
tion of 5-carbon carbocycles 33 and 39 is a convenient
process. Entries B, D, E, G and I exemplify clean
Structures and yields are reported in Table 1.
2.4. CIM transformation study
The CIM optimized procedure, which was applied to
our fumagillin formal total synthesis,4b,11 was extended
to the esters 24–31 and Table 2 summarizes our results
(see Procedure A in Experimental procedure). As we
have already shown,4a the choice of KHMDS used as
a base at ꢀ78 ꢁC is crucial. The subsequent metathesis
step can be easily accomplished, probably due to a
Side Chain
R2
Side Chain
R2
OR3 or H
OR3 or H
Me
Me
O
O
R1
OTMS
R1
OTMS
Scheme 8. Pre-chair transition state.
Table 2. CIM transformations
Entry
Starting material
Product
Claisen–Ireland yield (%)
60
Metathesis yield (%)
70
MeO2C
OPMB
CH2OTBDPS
A
24
33
MeO2C
MeO2C
OPMB
CH2OTBDPS
B
25
26
27
90
75
77
98
76
90
34
OPMB
CH2OTBDPS
C
D
35
MeO2C
OPMB
CH2OTBDPS
Me
36
MeO2C
MeO2C
OPMB
Me
CH2OTBDPS
E
28
29
78
88
37
OPMB
CH2OTBDPS
F
F: 90
maj (7/3)
80 (under ethylene
atmosphere)
CH2OTBDPS
G: 98 (quant. for
deprotection of TMS)
PMBO
TMS
G
38
32
O
2
O
MeO2C
MeO2C
NHBoc
CH2OTBDPS
H
30
70
98
Quant.
39 maj (7/3)
CH2OTBDPS
I
31
98
40

A. Franc¸ais et al. / Tetrahedron: Asymmetry 16 (2005) 1141–1155
1145
Entry H is another case with poor diastereoselectivity
(7:3), which can also be explained the same way. Even
if the hypothesis of a base aggregation state seems pos-
sible, in reality it is probably not so simple, because of
the thermodynamic equilibration of a dianionic species,
or more complex aggregation states for metallated inter-
mediates can take place.
Side Chain
R2
Side Chain
R2
H
H
Me
Me
O
O
R1
OTMS
R1
OTMS
Scheme 9.
6-carbon carbocycle formation (34–36–37–38 and 40)
and C is an example of a 7-carbon framework (35).
Compounds 36 and 37 were isolated in excellent yields,
without any trace of another diastereoisomer. This re-
sult strongly points to the role of the equatorial methyl
group in directing the stereochemical outcome of the
transposition in the transition state (Scheme 8). In a rele-
vant application, we were pleased to see smooth forma-
tion of two nearby quaternary centres in entries D
and E.
Entry G shows that ene–yne metathesis occurs effi-
ciently,13 extending the scope of functionalities. The
remarkably efficient metathesis, even in the presence of
diverse functions and by-products, allowed us to con-
sider a Ôone-potÕ process. In a preliminary study (with
entries B–D–I), we discovered that a Ôone-potÕ CIM is
possible (47–74% yield) in cases where the rearrange-
ment doesnÕt need any significant excess of reagents
(more than 1 mmol, see Procedure B in Experimental
procedure). This is especially interesting and convenient
on gram-scale reactions.11 The lower yields can be ex-
plained by the fact that an excess of reagents (TMSCl,
Comparison of entry I with the others could mistakenly
lead to the conclusion that a-chelation with an alkoxy
group doesnÕt play any role. In fact, the relative orienta-
tion of the enolates remains essentially the same in tolu-
ene, meaning that the side chain on the carboxylic acid
fragment is always E-oriented (OTMS versus side chain)
(Scheme 9).
KHMDS) is involved in Grubbs
decomposition.
I
reagent
In order to control chirality transfer, deuterated deriva-
tives were prepared from compounds 34–37 (Scheme
12). The introduction of deuterium atoms has been
achieved by reducing the ester group to alcohol using
lithium aluminium deuteride leading to compounds
41b, 43–45. Compound 34 (Table 2, entry B) was also re-
duced with lithium aluminium hydride to give 41a,
which was subsequently pivaloylated yielding ester 42a
used for an NOE study. The reduction of compound
35 (Table 2, entry C) gave 43 as a major product, with
the loss of the TBDPS protecting group.
Unfortunately, some cases proved to be more problem-
atic. It is important to note that an acetylenic function
needs to be protected.12 After double deprotonation
with LiHMDS at ꢀ78 ꢁC and reaction with TMSCl in
order to form a doubly silylated intermediate, careful
low temperature acidic quenching afforded the protected
acetylenic ester 32 (Scheme 10).
Even if the yield remains good, when the acetylenic moi-
ety is unprotected (entry F), the diastereoselectivity in
Claisen–Ireland rearrangement is low (7:3 ratio). This
particular behaviour could tentatively be explained by
an intramolecular deprotonation (via a chelated species)
through a transition state represented as follows
(Scheme 11), giving a reverse configuration for the eno-
late and the subsequent silylated ketene acetal.
The stereoselectivity of this set of reactions as well as the
enantiomeric purity of the compounds have been
assessed using deuterium NMR in chiral liquid crystals.
When embedded in such media, stereoisomers (enantio-
mers or diastereoisomers) do not assume the same orient-
ation. This behaviour leads to a difference in their NMR
spectra. The best results of this methodology were ob-
tained using mesophases of poly-c-benzyl-L-glutamate
CH2OTBDPS
PMBO
CH2OTBDPS
PMBO
LiHMDS
AcOH
TMS
TMS
29
O
O
THF TMSCl
-78°C
THF -78°C
puis TA
2
2
32
O
OTMS
Scheme 10.
CH OTBDPS
2
CH OTBDPS
2
CH OTBDPS
2
R
R
K
R
N
K
N
R
O
O
O
H
OTMS
OTMS
OPMB
O
H
PMBO
Side Chain
PMBO
Side Chain
Reverse Enolate Configuration
Expected Enolate Configuration
Scheme 11.

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A. Franc¸ais et al. / Tetrahedron: Asymmetry 16 (2005) 1141–1155
MeO2C
PivOR2C
HOR2C
OPMB
CH2OTBDPS
OPMB
CH2OTBDPS
OPMB
CH2OTBDPS
PivCl
LiAlH4 or LiAlD4
THF
Pyridine
41a: R = H
41b: R = D
42a: R = H
34
MeO2C
OPMB
HOD2C
OPMB
CH2OTBDPS
LiAlD4 / THF
CH2OH
35
43
HOD2C
MeO2C
OPMB
OPMB
CH2OTBDPS
Me
LiAlD4 / THF
CH2OTBDPS
Me
44
36
MeO2C
HOD2C
OPMB
Me
OPMB
Me
CH2OTBDPS
45
LiAlD4 / THF
CH2OTBDPS
37
Scheme 12.
(PBLG) in various organic solvents, through proton-
decoupled deuterium (2H–{1H}) NMR.14 For this
nucleus, the NMR dominant observable is the quadru-
polar interaction, which results in the splitting of a deu-
terium signal into a doublet. This technique is of general
use in the case of enantiomeric analysis.15 It is also extre-
mely efficient in the observation of diastereoisomers.16
2
The H–{1H} NMR spectra of compounds 41b, 43, 44
and 45 in PBLG liquid crystals are presented in Figures
1–4, respectively. A typical spectrum exhibits two quad-
rupolar doublets, one for each diastereotopic deuterons.
The spectra of compounds 41b, 43 and 45 suggest the
absence of any other stereoisomer. At this point, it
should be noted that we did not analyze the racemic
Figure 2. 2H–{1H} NMR spectrum of alcohol 43 in PBLG/CH2Cl2
liquid crystal. d are the signals of one of the diastereotopic deuterium
and m are due to the second one.
signals of the cosolvent (CH2Cl2).
are the 2H natural abundance
mixtures of compound 41b, 43, 44 and 45 to confirm
that the enantiomers could be discriminated. However,
these alcohols bear two diastereotopic deuterons, and
to date enantiomers of such compound have always
been discriminated, at least on one kind of deuterium
in PBLG liquid crystals.17 The diastereoisomeric purity
of compound 34 was further supported by an NOE
analysis of 42a, which showed only one diastereoisomer
(no trace of the other diastereoisomer was detected).
The 2H–{1H} NMR spectrum of alcohol 44 (Fig. 3) pre-
sents additional signals, which reveal the presence of the
minor enantiomer. The ee thus measured is 93%.
Figure 1. 2H–{1H} NMR spectrum of alcohol 41b in PBLG/CHCl3
liquid crystal. d are the signals of one of the diastereotopic deuterons
and m are due to the second one.
signals of the cosolvent (CHCl3).
are the 2H natural abundance
When considering chirality transfer, all entries showed
two crucial points:

A. Franc¸ais et al. / Tetrahedron: Asymmetry 16 (2005) 1141–1155
1147
was analyzed in a PBLG/CHCl3 liquid crystal (17 wt %
PBLG). H NMR spectra were recorded (61.42 MHz)
2
2
on a Bruker DRX 400 spectrometer with a H-probe
with broad-band proton decoupling. The temperature
was kept at 298 K.
4.2. (2S,3E) 5-(tert-Butyl-diphenyl-silyloxy)-4-methyl-
pent-3-en-2-ol 2
A mixture of 11 and 12 (see procedure to obtain 13 and 14;
3.5 g, 14.52 mmol, 1 equiv) and pyridinium toluene-p-sul-
fonate (600 mg, 2.3 mmol, 0.15 equiv) were dissolved in
ethanol (35 mL) and stirred at 45 ꢁC for 1 h. The mixture
was then diluted with water and concentrated to a low
volume under reduced pressure. The resulting aqueous
phase was extracted with diethyl ether (3 · 15 mL). The
organic layer was dried, filtered and concentrated in
vacuo. Purification of the resulting residue by silica gel
column chromatography(55 g SiO2, pentane/diethylether:
3:1) afforded allylic alcohol 15 (1.8 g, 11.47 mmol, 79%
yield). Compound 15 (1 g, 6.37 mmol) was dissolved in
toluene (10 mL) under an argon atmosphere and cooled
to ꢀ78 ꢁC. Diisobutylaluminium hydride (commercial
solution in toluene 1 M, 21 mL, 21 mmol, 3.3 equiv)
was added in 10 min. After 1 h, the reaction was stopped
by the introduction of a small amount of methanol (until
gas evolution ceased). A solution of sodium–potassium
tartrate (30.4 g) in water (76 mL) was mixed with the reac-
tion and the resulting mixture vigorously stirred over-
night at room temperature. The layers were separated
and the aqueous one extracted with methylene chloride
(2 · 70 mL). The organic layer was dried, filtered and
concentrated. The crude product was purified by silica
gel column chromatography (cyclohexane/ethyl acetate:
4:1, 3:1, 2:1, 1:1). Three fractions were collected to give
16 (672 mg, 5.8 mmol, 91% yield). To a solution of diol
16 (398 mg, 3.43 mmol) and imidazole (466 mg,
11.7 mmol, 3.2 equiv) dissolved in methylene chloride
(13 mL) was added tert-butylchlorodiphenylsilane
(943 mg, 3.43 mmol, 1 equiv) dropwise. After stirring at
room temperature for 12 h, the reaction mixture was
poured into water. The separated aqueous layer was ex-
tracted with diethyl ether (3 · 10 mL). The combined ex-
tracts were washed with water and brine, dried and then
concentrated to give 2 (871 mg, 2.47 mmol, 72% yield).
Figure 3. 2H–{1H} NMR spectrum of alcohol 44 in PBLG/CH2Cl2
liquid crystal. d and m are the signals of the two diastereotopic
deuterons for the major enantiomer whereas n and s are the signals of
the minor one. are the 2H natural abundance signals of the cosolvent
(CH2Cl2) and + is the signal of residual CDCl3.
Figure 4. 2H–{1H} NMR spectrum of alcohol 45 in PBLG/CH2Cl2
liquid crystal. d are the signals of one of the diastereotopic deuterium
and m are due to the second one.
signals of the cosolvent (CH2Cl2).
are the 2H natural abundance
(1) The asymmetric centre of the starting material con-
trols the chirality transfer in an enantioselective
manner (verified by 2H NMR in chiral liquid
crystals14).
(2) An E double bond (in the allylic part) gave exclusive
formation of one diastereoisomer. This was easily
verified by derivatization of several cycloalkenes.
3. Conclusion
1
In conclusion, we believe that our approach to building
contiguous asymmetric centres using CIM extends this
concept towards the synthesis of complex biologically
active natural products.
Compound 2 H NMR (250 MHz, CDCl3): d (ppm):
7.63–7.70 (4H, m, CAr–H), 7.30–7.50 (6H, m, CAr–H),
5.48 (1H, d, C3–H, J = 8 Hz), 4.58 (1H, m, C2–H),
4.02 (2H, s, C5–H · 2), 1.61 (3H, s, C4–Me), 1.22 (3H,
d, C1–H · 3, J = 6.25 Hz), 1.04 (9H, s, tBu) 13C NMR
(62.5 MHz, CDCl3): d (ppm): 135.7 (C4), 135.5 (CAr),
133.6 (C3), 129.5 (CAr), 128.4 (CqAr), 128.2 (CqAr),
127.6 (CAr), 68.2 (C2), 64.2 (C5), 26.8 (SiCMe3), 23.4
(C4–Me), 19.2 (C1), 13.6 (SiCMe3) HRMS (electrospray)
(M+Na) calculated: 377.1913; found: 377.1921.
Rf = 0.25 (ethyl acetate/n-heptane: 1:2).
4. Experimental
4.1. Liquid-crystalline sample preparation and NMR
spectra measurements
PBLG (120 mg, Mw 70,000–150,000, Sigma Chem. Co.)
and dideuteroalcohol (1–5 mg) were placed in an NMR
tube (5 mm) and CH2Cl2 added till about 22 wt %
PBLG. After complete dissolution of the polymer, the
tube was centrifuged upside and down (20 times) to
homogenize the viscous solution. Dideuteroalcohol 41b
4.3. (2S,3Z) 5-(tert-Butyl-diphenyl-silyloxy)-4-methyl-
pent-3-en-2-ol 3
To a solution of allylic alcohol 14 (200 mg, 1 mmol)
and imidazole (136 mg, 2 mmol, 2 equiv) dissolved in

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A. Franc¸ais et al. / Tetrahedron: Asymmetry 16 (2005) 1141–1155
THF/DMF (1:1) (6 mL) (or methylene chloride) was
added tert-butylchlorodiphenylsilane (350 lL, 1.5 mmol,
1.5 equiv) dropwise. After stirring at room temperature
for 12 h, the reaction mixture was poured into water.
The separated aqueous layer was extracted with diethyl
ether (3 · 10 mL). The combined extracts were washed
with water and brine, dried and then concentrated. A
solution of the resulting silyl ether 17 and pyridinium
toluene-p-sulfonate (26 mg, 0.1 mmol, 0.1 equiv) was
dissolved in methanol (8 mL) and stirred at 40–45 ꢁC
for 1 h. The mixture was then diluted with water and
concentrated to a low volume under reduced pressure.
The resulting aqueous phase was extracted with diethyl
ether (3 · 15 mL). The organic layer was dried, filtered
and concentrated in vacuo. Purification of the resulting
residue by silica gel column chromatography (55 g SiO2,
pentane/diethyl ether: 3:1) afforded allylic alcohol
3 (56% yield). Compound 3: 1H NMR (250 MHz,
CDCl3): d (ppm): 7.63–7.70 (4H, m, CAr–H), 7.30–7.50
(6H, m, CAr–H), 5.48 (1H, d, C3–H, J = 8 Hz), 4.58
(1H, m, C2–H), 4.02 (2H, s, C5–H · 2), 1.61 (3H, s,
C4–Me), 1.22 (3H, d, C1–H · 3, J = 6.25 Hz), 1.04
(9H, s, tBu) 13C NMR (62.5 MHz, CDCl3): d (ppm):
136.1 (C4), 135.4 (CAr), 133.3 (C3), 131.5 (CqAr), 131.2
(CqAr), 129.6 (CAr), 127.6 (CAr), 63.4 (C2), 62.7 (C5),
26.7 (SiCMe3), 23.3 (C4–Me), 21.1 (C1), 19.1 (SiCMe3)
HRMS (electrospray) (M+Na) calculated: 377.1913;
found: 377.1921. Rf = 0.25 (ethyl acetate/heptane: 1:2).
4.5. 2-(4-Methoxy-benzyloxy)-hex-5-enoic acid 5
Aldehyde 19 (1.11 mmol, 1 equiv) was dissolved in tert-
butanol (25 mL) and 2-methylbut-2-ene (13 mL). A solu-
tion of NaClO2 (6.44 mmol, 6 equiv) and NaH2PO4
(3.99 mmol, 3.6 equiv) in water (5.5 mL) was added
dropwise during 15 min. The reaction mixture was stir-
red for 1 h. The reaction was stopped by addition of a
saturated aqueous solution of NH4Cl (50 mL) and the
layers were separated. The aqueous layer was extracted
with diethyl ether (3 · 50 mL). The combined organic
layers were dried, filtered and concentrated. Crude mate-
rial was purified by silica gel column chromatography
(60 g SiO2, pentane/diethyl ether 2:1). 157 mg of product
was obtained for acid 5 (59% yield for two steps). Com-
pound 5: 1H NMR: 250 MHz, CDCl3, d (ppm): 7.27 (2H,
d, CPMBar–H, J = 8.6 Hz), 6.86 (2H, d, CPMBar–H,
J = 8.6 Hz), 5.60–5.90 (1H, m, C5–H), 4.90–5.10 (2H,
m, C6–H · 2), 4.20–4.75 (2H, syst AB, Ar–CH2), 3.90–
4.15 (1H, m, C2–H), 3.79 (3H, s, OMe), 2.10–2.30 (2H,
m, C4–H · 2), 1.75–1.95 (2H, m, C3–H · 2) 13C NMR
(50 MHz, CDCl3): d (ppm): 177.9 (C1), 159.5 (CqAr
–
OMe), 137.1 (C5), 129.8 (CAr), 129.0 (CqAr), 115.6 (C6),
113.9 (CAr), 76.3 (C2), 72.3 (CPMBar–CH2O), 55.2
(OCH3), 31.7 (C4), 29.1 (C3) HRMS (electrospray)
(RCOOꢀ) calculated: 249.1126; found: 249.1125.
4.6. 2-(4-Methoxy-benzyloxy)-hept-6-enoic acid 6
4.4. 2-(4-Methoxy-benzyloxy)-pent-4-enoic acid 4
Sodium hydride was washed twice with n-pentane under
an argon atmosphere (150 mg, 6.25 mmol, 1.5 equiv),
and a solution of p-methoxybenzylbromide (1.01 g,
5 mmol, 1.2 equiv) in DMF (10 mL) added. The mixture
was cooled to 0 ꢁC, and alcohol 21 (1.5 g, 4.7 mmol)
dissolved in dry THF (10 mL) added dropwise. The
reaction mixture was allowed to warm to room
temperature and stirred for 4 h. The reaction was
stopped by hydrolysis with aqueous HCl (1 N, 10 mL),
and then extracted with diethyl ether (3 · 15 mL). The
organic layer was dried, filtered and the diethyl ether re-
moved under reduced pressure. The crude product was
dissolved in methanol (10 mL) and Dowex 50W (1 g)
added in one portion. The reaction was stirred overnight,
then the acidic resin was removed by filtration. The fil-
trate was concentrated under reduced pressure and the
residue purified by chromatography on silica gel (80 g
SiO2, pentane/diethyl ether: 1:1). The primary alcohol
(monoprotected with a PMB group) was obtained as a
Glyoxylic acid (92 mg, 1 mmol, 1 equiv) was dissolved in
water (1 mL), then allyltributyltin (309 lL, 1 mmol,
1 equiv) was added under strong stirring. Triflic acid
(88 lL, 1 mmol, 1 equiv) was introduced by syringe
and the mixture stirred overnight. The reaction was
quenched with brine (4 mL), and extracted with diethyl
ether (2 · 10 mL) and ethylacetate (2 · 10 mL). The
combined organic layers were dried, filtered and concen-
trated. The crude product was used in the next step with-
out further purification.
Sodium hydride was washed twice with n-pentane under
an argon atmosphere (84 mg, 2.5 mmol, 2.5 equiv), and
a
solution of p-methoxybenzylbromide (442 mg,
2.2 mmol, 2.2 equiv) in DMF (5 mL) added. The mix-
ture was cooled to 0 ꢁC, and acid 18 (1 mmol, 1 equiv)
dissolved in dry THF (5 mL) added dropwise. The reac-
tion mixture was allowed to warm to room temperature
and stirred overnight. The reaction was stopped by
hydrolysis with aqueous HCl (1 M, 10 mL), and then ex-
tracted with diethyl ether (3 · 10 mL). The organic layer
was dried, filtered and the diethyl ether removed under
reduced pressure. Purification on silica gel column
(30 g; pentane/diethyl ether 2:1 then diethyl ether), afford-
ed 58 mg of the desired compound 4 (24.6% yield for
1
colourless oil (787 mg, 67% yield). H NMR: 250 MHz,
CDCl3, d (ppm): 7.20–7.40 (2H, m, CPMBar–H), 6.80–
6.95 (2H, m, CPMBar–H), 5.60–5.90 (1H, m, C6–H),
4.90–5.10 (2H, m, C7–H · 2), 4.40–4.60 (2H, syst AB,
Ar–CH2), 3.82 (3H, s, OMe), 3.60–3.80 (1H, m, C2–H),
3.40–3.60 (2H, m, C1–H · 2), 2.00–2.20 (2H, m, C5–
H · 2), 1.85–2.00 (1H, m, OH), 1.30–1.75 (4H, m, C4–
H · 2, C3–H · 2) MS (electrospray) (M+Na) found:
273.1. Rf (pentane/diethyl ether: 1:1) = 0.25.
1
two steps). Compound 4: H NMR: 250 MHz, CDCl3,
d (ppm): 7.15–7.30 (2H, m, CPMBar–H), 6.75–6.90 (2H,
m, CPMBar–H), 5.65–5.90 (1H, m, C4–H), 5.00–5.20
(2H, m, C5–H · 2), 4.60 (2H, s, Ar–CH2), 4.03 (1H, t,
C2–H), 3.75 (3H, s, OMe), 2.45–2.60 (2H, m, C3–
H · 2) HRMS (electrospray) (RCOOꢀ) calculated:
235.0970; found: 235.0960. Rf (ether) = 0.2.
The alcohol (345 mg, 1.38 mmol) and NMO (254 mg,
2.17 mmol, 1.6 equiv) were dissolved in dry methylene
chloride (7 mL) and the mixture cooled to 0 ꢁC. TPAP
(38 mg, 0.14 mmol, 0.1 equiv) was added dropwise in
methylene chloride (2 mL) and the resulting black

A. Franc¸ais et al. / Tetrahedron: Asymmetry 16 (2005) 1141–1155
1149
mixture stirred for 3 h at 0 ꢁC. The reaction was filtered
on Celite, washed three times with methylene chloride
(25 mL), and the filtrate concentrated under reduced
pressure. The aldehyde was pure enough for the second
oxidation step (88% yield). 1H NMR: 250 MHz, CDCl3,
d (ppm): 9.61 (1H, br s or d, CHO), 7.10–7.30 (2H, m,
CPMBar–H), 6.75–6.90 (2H, m, CPMBar–H), 5.65–5.85
(1H, m, C6–H), 4.85–5.05 (2H, m, C7–H · 2), 4.40–
4.65 (2H, syst AB, Ar–CH2), 3.89 (3H, s, OMe), 3.60–
3.90 (1H, m, C2–H), 1.90–2.20 (2H, m, C5–H · 2),
1.30–1.80 (4H, m, C4–H · 2, C3–H · 2) MS (electro-
spray) (M+Na) found: 271.1. Rf (pentane/diethyl ether:
2:1) = 0.22.
sphere. After the introduction of dry THF (25 mL),
the NaH suspension was cooled to 0 ꢁC and the phos-
phonate introduced (3.50 mL, 16.5 mmol, 1.3 equiv) in
dry THF (50 mL). After 10 min, aldehyde 10 (2 g,
12.7 mmol, 1 equiv) dissolved in THF (10 mL) was
added dropwise. The reaction mixture was allowed to
warm to room temperature and stirred for 2 h. The
reaction was quenched with 50 mL of a 10% NH4Cl
aqueous solution and the layers separated. The aque-
ous layer was extracted with diethyl ether
(3 · 40 mL), and the combined organic layers dried
and filtered and the solvent removed under reduced
pressure. Crude material was purified by silica gel col-
umn chromatography (300 g SiO2, heptane/ethyl ace-
tate: 7:3) giving 2.53 g of a mixture of the four
diastereoisomers of ester 11 and 12 (82% yield). This
mixture of 11 and 12 (2 g, 8.3 mmol, 1 equiv) was dis-
solved in dry methylene chloride (50 mL) under an
argon atmosphere and cooled to ꢀ78 ꢁC. Diiso-
butylaluminium hydride (commercial solution in
CH2Cl2 1 M, 20 mL, 20 mmol, 2.31 equiv) was added
in 10 min. After 1 h, the reaction was stopped by the
introduction of a small amount of methanol (until
gas evolution ceased). A solution of sodium-potassium
tartrate (30.4 g) in water (76 mL) was mixed with the
reaction and the resulting mixture vigorously stirred
overnight at room temperature. The layers were sepa-
rated and the aqueous one was extracted with methyl-
ene chloride (2 · 70 mL). The organic layer was
dried, filtered and concentrated. The crude product
was purified by silica gel column chromatography
(cyclohexane/ethyl acetate: 4:1, 3:1, 2:1, 1:1). Three
fractions were collected (1.87 g, 90% yield: 24% of Z al-
kene, 49% Z + E and 27% E alkene). Compound 13:
1H NMR (250 MHz, CDCl3): d (ppm): 5.49 (1H, d,
The obtained aldehyde (1.11 mmol, 1 equiv) was dis-
solved in tert-butanol (25 mL) and 2-methylbut-2-ene
(13 mL). A solution of NaClO2 (6.44 mmol, 6 equiv)
and NaH2PO4 (3.99 mmol, 3.6 equiv) in water
(5.5 mL) was added dropwise during 15 min. The reac-
tion mixture was then stirred for 1 h. The reaction was
stopped by the addition of a saturated aqueous solution
of NH4Cl (50 mL) and the layers were separated. The
aqueous layer was extracted with diethyl ether
(3 · 50 mL). The combined organic layers were dried,
filtered and concentrated. The crude material was puri-
fied by silica gel column chromatography (60 g SiO2,
pentane/diethyl ether 2:1), to give 157 mg of acid 6
(52% yield for two steps). Compound 6: 1H NMR:
250 MHz, CDCl3, d (ppm): 9.50–9.90 (1H, br s, COOH),
7.25–7.35 (2H, m, CPMBar–H), 6.85–7.00 (2H, m,
CPMBar–H CPMBar–H), 5.70–5.90 (1H, m, C6–H), 4.90–
5.10 (2H, m, C7–H · 2), 4.30–4.75 (2H, syst AB, Ar–
CH2), 3.80–4.05 (1H, m, C2–H), 3.80 (3H, s, OMe),
2.00–2.20 (2H, m, C5–H · 2), 1.70–1.90 (2H, m, C3–
H · 2), 1.40–1.65 (2H, m, C4–H · 2) HRMS (electro-
spray) (RCOOꢀ) calculated: 263.1283; found: 263.1280.
0
C3–H, J = 7.5 Hz), 4.68 (1H, m, C1 –H), 4.56 (1H, m,
0
C4–H), 3.96 (2H, m, C6 –H Â 2), 3.65 (2H, syst AB,
4.7. 2-(4-Methoxy-benzyloxy)-hex-5-ynoic acid 7
C1–H · 2), 2.64 (1H, br s, OH), 1.3–1.95 (6H, m,
0
0
0
C3 –H Â 2, C4 –H Â 2, C5 –H Â 2), 1.50 (3H, s, C2–
Me), 1.18 (3H, d, C5–H · 3, J = 6 Hz) MS (electro-
spray) (M+Na); found: 223.1. Rf = 0.26 (ethyl acetate/
cyclohexane: 1:1).
Ester 23 (181 mg, 0.69 mmol, 1 equiv) was dissolved in
methanol (5 mL). Barium oxide octahydrate (2.2 g,
6.9 mmol, 10 equiv) was introduced in one portion.
The reaction stirred at room temperature for 4 h. Meth-
anol was removed by evaporation under reduced pres-
sure and the residue dissolved in diethyl ether (10 mL)
and washed with 0.5 N HCl solution (10 mL). The acidic
layer was then extracted with diethyl ether (2 · 10 mL).
The organic layer was dried, filtered and concentrated
to give 171 mg of acid 7 (99% yield). Compound 7:
1H NMR (250 MHz, CDCl3): d (ppm): 7.31 (2H, d,
CPMBar–H, J = 8 Hz), 6.80 (2H, d, CPMBar–H,
J = 8 Hz), 4.30–4.75 (2H, syst AB, Ar–CH2), 4.05–4.15
(1H, m, C2–H), 3.80 (3H, s, OMe), 3.76 (3H, s,
CO2CH3), 2.25–2.45 (2H, m, C3–H · 2), 1.85–2.05
(3H, m, C4–H · 2, C6–H) HRMS (electrospray)
(RCOOꢀ) calculated: 247.0970; found: 247.0968.
Rf = 0.3–0.5 (diethyl ether/pentane: 2:1).
1
Compound 14: H NMR (360 MHz, CDCl3): d (ppm):
0
5.08 (1H, d, C3–H, J = 10.4 Hz), 4.75 (1H, m, C1 –H),
4.60 (1H, m, C4–H), 4.32 (1H, dd, C1–Ha, J = 2.9 Hz
0
J = 12 Hz), 3.80 (2H, m, C6 –H Â 2), 3.60 (1H, d,
C1Hb, J = 11 Hz), 2.87 (1H, br s, OH), 1.5–1.95 (9H,
0
0
0
m, C3 –H Â 2, C –H Â 2, C5 –H · 2, C2–Me), 1.26
(3H, d, C5–H ·43, J = 6.1 Hz) MS (electrospray)
(M+Na) calculated: 223.1; found: 223.1. Rf = 0.37 (ethyl
acetate/cyclohexane: 1:1).
4.9. 1-Trityloxy-hept-6-en-2-ol 21
Magnesium turnings (972 mg, 40 mmol) were intro-
duced in a round-bottom flask under argon with a mag-
netic stirrer. After mechanical activation (overnight),
dry diethyl ether (10 mL) was added. Homoallylbromide
(4.78 g, 30 mmol, 3 equiv) dissolved in dry THF (37 mL)
was slowly introduced. The mixture was heated to reflux
for 2 h. The supernatant was transferred by cannula in a
solution of tritylglycidol 20 (3 g, 10 mmol, 1 equiv) and
4.8. (4S)-2-Methyl-4-(tetrahydro-pyran-20-yloxy)-pent-2-
en-1-ol 13 and 14
Sodium hydride (320 mg, 13.3 mmol, 1.05 equiv) was
washed twice with n-pentane under an argon atmo-

1150
A. Franc¸ais et al. / Tetrahedron: Asymmetry 16 (2005) 1141–1155
copper iodide (286 mg, 1.5 mmol, 0.13 equiv) in dry
THF (13 mL) at ꢀ10 ꢁC. The resulting black solution
was allowed to warm to room temperature and stirred
for two hours. The reaction mixture was quenched with
aqueous saturated NH4Cl solution (30 mL), the layers
separated and the aqueous one was extracted with
diethyl ether (3 · 30 mL). The combined organic layers
were dried, filtered and concentrated to afford 1.6 g of
a pale yellow oil (50% yield). The crude product was
used in the next step without further purification. Com-
4.11. General procedure for DCC esterification
The chiral allylic alcohols 1–3 (1 mmol) and carboxylic
acid 4–9 (1 mmol or 1.1 mmol when possible) were dis-
solved in dry methylene chloride (10 mL) with a cata-
lytic amount of DMAP (0.1 mmol). The flask was
cooled to 0 ꢁC with an ice bath and stirred for 10 min.
A solution of DCC (1.2 mmol) in methylene chloride
(4 mL) was added dropwise in 10 min. The mixture
was allowed to warm to room temperature and stirred
overnight. The reaction was then filtered on Celite,
washed with methylene chloride (5 mL) and the filtrate
concentrated under reduced pressure. The residue was
triturated in diethyl ether in order to remove traces of
DCU by filtration. The crude material was purified by
silica gel column chromatography (75 g SiO2, pentane/
diethyl ether: 4:1) to afford the desired compound as a
colourless oil.
1
pound 21: H NMR: 200 MHz, CDCl3, d (ppm): 7.15–
7.50 (15H, m, CAr–H), 5.60–5.85 (1H, m, C6–H), 4.85–
5.05 (2H, m, C7–H · 2), 3.65–3.90 (1H, m, C2–H), 3.20
(1H, dd, C1–H, J = 5 Hz, J = 17 Hz), 3.01 (1H, dd,
C1–H, J = 8Hz, J = 17 Hz), 2.25–2.45 (1H, br s, OH),
1.90–2.10 ppm (2H, m, C5–H · 2), 1.20–1.60 (4H,
m, C4–H · 2, C3–H · 2) MS (electrospray) (M+Na)
calculated: 395.2; found: 395.2. Rf (methylene
chloride) = 0.55.
4.12. (2RS,10S,20E) 2-(4-Methoxy-benzyloxy)-pent-4-
enoic acid 40-(tert-butyl-diphenyl-silyloxy)-10-methyl-but-
20-enyl ester 24
4.10. 2-(4-Methoxy-benzyloxy)-hex-5-ynoic acid methyl
ester 23
Acid 6 (250 mg, 1 mmol, 1 equiv) was esterified by treat-
ment with diazomethane. After evaporation of the sol-
vent, the methyl ester was dissolved in a methylene
chloride/methanol mixture (9:1) and cooled to ꢀ78 ꢁC.
This solution was submitted to ozone bubbling until a
blue colour appeared. Excess triphenylphosphine was
then added, and the reaction allowed to warm to room
temperature and stirred overnight. The reaction mixture
was then concentrated under reduced pressure and the
residue triturated in diethyl ether (10 mL) in order to re-
move triphenylphosphine oxide by filtration. The filtrate
was concentrated to afford crude aldehyde 22, which
was used in the next step without further purification.
Compound 22 was dissolved in methanol (10 mL) with
K2CO3 (2.2 mmol, 2.2 equiv, 304 mg). The freshly pre-
pared Bestmann–Ohira reagent (211 mg, 2.2 mmol,
2.2 equiv) was then added over 2 min with stirring. After
1 h, methanol was removed by evaporation under re-
duced pressure. The crude product was dissolved in
diethyl ether (10 mL) and washed with water (10 mL),
and the layers separated. The aqueous layer extracted
with diethyl ether (3 · 10 mL), the combined organic
layers dried and filtered and the solvent removed under
reduced pressure. Purification by silica gel column chro-
matography (20 g SiO2, pentane/diethyl ether: 5:1) gave
181 mg of alkyne 23 (69% yield for three steps).
44% yield 24: 1H NMR: 250 MHz, CDCl3, d (ppm):
7.55–7.75 (4H, m, CAr–H), 7.28–7.45 (6H, m, CAr–H),
7.25 (2H, d, CPMBAr–H, J = 8.6 Hz), 6.85 (2H, d,
0
CPMBAr–H, J = 8.6 Hz), 5.70–5.85 (2H, m, C2 –H,
0
C3 –H), 5.40–5.55 (1H, m., C4–H), 5.00–5.20 (2H, m,
0
C5–H · 2), 4.60–4.70 (1H, m, C1 –H), 4.35 (2H, syst
0
AB, C4 –H Â 2), 4.15–4.25 (2H, m, Ar–CH2), 3.95
(1H, t, C2–H, J = 6.4 Hz), 3.75 (3H, s, OMe), 2.40–
0
2.60 (2H, m, C3–H · 2), 1.20–1.40 (3H, m, C1 –Me),
1.10 (9H, s, Si–tBu) 13C NMR: 62.5 MHz, CDCl3, d
(ppm): 172.8 (C1), 159.5 (CPMBAr–OMe), 135.7 (C4),
0
135.5 (CAr), 133.5 (CqAr), 131.3 and 130.9 (C2 and
CPMBAr–CH2O), 130.1 and 129.2 (CAr et CPMBAr),
0
128.8 (C3 ), 127.9 (CAr), 115.6 (C5), 113.7 (CPMBAr),
0
0
77.0 (C2), 71.8 (CPMBar–CH2O), 71.0 (C1 ), 63.4 (C4 ),
55.2 (ArOMe), 28.7 (C3), 26.4 (SiCMe3), 20.1
0
(C1 –Me), 19.1 (SiCMe3) HRMS (electrospray)
(M+Na) calculated: 581.2699; found: 581.2695. Rf
(pentane/diethyl ether: 6:1) = 0.55.
4.13. (2RS,10S,20E) 2-(4-Methoxy-benzyloxy)-hex-5-
enoic acid 40-(tert-butyl-diphenyl-silyloxy)-10-methyl-
but-20-enyl ester 25
89% yield 25: 1H NMR: 250 MHz, CDCl3, d (ppm):
7.50–7.75 (4H, m, CAr–H), 7.30–7.43 (6H, m, CAr–H),
7.26 (2H, d, CPMBar–H, J = 8.6 Hz), 6.85 (2H, d,
0
CPMBar–H, J = 8.6 Hz), 5.77–5.83 (2H, m, C2 –H,
0
C3 –H), 5.55–5.85 (1H, m, C5–H), 5.38–5.57 (1H, m,
1
Compound 23: H NMR (360 MHz, CDCl3): d (ppm):
7.28 (2H, d, CPMBar–H, J = 9 Hz), 6.87 (2H, d,
CPMBar–H, J = 9 Hz), 4.30–4.75 (2H, syst AB, Ar–
CH2), 4.10 (1H, dd, C2–H, J = 5 Hz J = 5.75 Hz), 3.80
(3H, s, OMe), 3.76 (3H, s, CO2CH3), 2.25–2.45 (2H,
m, C3–H · 2), 2.01 (1H, d, C6–H, J = 2.5 Hz), 1.85–
1.99 (2H, m, C4–H · 2) 13C NMR (62.5 MHz, CDCl3):
d (ppm): 172.8 (C1), 159.2 (CqAr–OMe), 129.6 (CAr),
129.3 (CqAr), 113.6 (CAr), 82.8 (C5), 75.8 (C6), 72.2
(CPMBar–CH2O), 69.0 (C2), 55.1 (ArOMe), 51.8
(CO2Me), 31.5 (C4), 14.4 (C3) HRMS (electrospray)
(M+Na) calculated: 285.1103; found: 285.1099.
Rf = 0.6 (diethyl ether/pentane: 1:5).
0
C1 –H), 4.90–5.05 (2H, m, C6–H · 2), 4.63 (1H, d,
PhCH–Ha, J = 11.1 Hz (dia 1 and 2)), 4.30 (1H, d,
PhCH–Hb, J = 11.1 Hz (dia 1)), 4.28 (1H, d, PhCH–
0
Hb, J = 11.1 Hz (dia 2)), 4.15–4.25 (2H, m, C4 H Â 2),
3.89 (1H, t, C2–H, J = 6.4 Hz), 3.78 (3H, s, OMe),
2.10–2.25 (2H, m, C4–H · 2), 1.72–1.91 (2H, m, C3–
0
H · 2), 1.33 (3H, d, C1 –Me, J = 6.5 Hz (dia1)), 1.32
(3H, d, C1 –Me, J = 6.5 Hz (dia 2)), 1.04 (9H, s, Si–
0
tBu) 13C NMR: 62.5 MHz, CDCl3, d (ppm): 172.1
(C1), 159.5 (CPMBAr–OMe), 135.7 (C5), 135.5 (CAr),
0
133.5 (CqAr), 131.4 and 131.2 (C2 and CPMBar–CH2O),

A. Franc¸ais et al. / Tetrahedron: Asymmetry 16 (2005) 1141–1155
1151
0
129.7 and 129.6 (CAr and CPMBar), 128.8 (C3 ), 127.9
(CAr), 115.6 (C6), 113.7 (CPMBar), 77.0 (C2), 71.8
4.16. (2RS,10S,20Z) 2-(4-Methoxy-benzyloxy)-hex-5-
enoic acid 40-(tert-butyl-diphenyl-silyloxy)-10,30-dimethyl-
but-20-enyl ester 28
0
0
(CPMBar–CH2O), 71.0 (C1 ), 63.4 (C4 ), 55.2 (ArOMe),
29.4 and 32.1 (C3 and C4), 26.7 (SiCMe3), 20.3 (C1–
Me), 19.2 (SiCMe3) HRMS (electrospray) (M+Na) cal-
culated: 595.2855; found: 595.2856. Rf (pentane/diethyl
ether: 8:3) = 0.75.
1
69% yield 28: H NMR (250 MHz, CDCl3): d (ppm):
7.65–7.76 (4H, m, CAr–H), 7.32–7.50 (6H, m, CAr–H),
7.25 (2H, d, J = 8.6 Hz, CPMBar–H), 6.86 (2H, d,
0
J = 8.6 Hz, CPMBar–H), 5.65–5.82 (2H, m, C2 –H, C5–
0
H), 5.50–5.65 (1H, m, C1 –H), 5.19–5.31 (1H, m,
4.14. (2RS,10S,20E) 2-(4-Methoxy-benzyloxy)-hept-6-
enoic acid 40-(tert-butyl-diphenyl-silyloxy)-10-methyl-
but-20-enyl ester 26
0
C1 –H), 4.92–5.05 (2H, m, C6–H · 2), 4.57 (1H, dd,
J = 11.5 Hz J = 3 Hz, PhCH–Ha), 4.28 (1H, dd,
J = 12.3 Hz J = 9.3, PhCH–Hb), 4.18–4.32 (2H, m,
80% yield 26: 1H NMR: 250 MHz, CDCl3, d (ppm):
7.65–7.75 (4H, m, CAr–H), 7.30–7.50 (6H, m, CAr–H),
7.27 (2H, d, CPMBar–H, J = 8.6 Hz), 6.86 (2H, d,
0
C4 H Â 2), 3.77–3.89 (1H, m, C2–H), 3.79 (3H, s,
OMe), 2.08–2.22 (2H, m, C4–H · 2), 1.68–1.89 (2H, m,
0
C3–H · 2), 1.86 (3H, s, C3 –Me), 1.22 (3H, d,
J = 6.8 Hz, C1 –Me (dia 1 and 2)), 1.08 (9H, s, Si–tBu)
HRMS (electrospray) (M+Na) calculated: 609.3012;
found: 609.3011. Rf = 0.65 (diethyl ether/pentane: 1:5).
0
0
CPMBar–H, J = 8.6 Hz), 5.78–5.86 (2H, m, C2 –H,
0
C3 –H), 5.65–5.90 (1H, m, C6–H), 5.40–5.55 (1H, m,
0
C1 –H), 4.88–5.05 (2H, m, C7–H · 2), 4.62 (1H, d,
PhCH–Ha, J = 11.1 Hz), 4.31 (1H, d, PhCH–Hb,
4.17. (2RS,10S,20E) 2-(4-Methoxy-benzyloxy)-hex-5-
ynoic acid 40-(tert-butyl-diphenyl-silyloxy)-10-methyl-
but-20-enyl ester 29
0
J = 11.1 Hz), 4.18–4.25 (2H, m, C4 –H Â 2), 3.88 (1H,
t, C2–H, J = 6.5 Hz), 3.79 (3H, s, OMe), 1.95–2.11
(2H, m, C5–H · 2), 1.65–1.82 (2H, m, C3–H · 2), 1.39–
0
1.65 (2H, m, C4–H · 2), 1.34 (3H, dd, C1 –Me,
1
71% yield 29: H NMR (360 MHz, CDCl3): d (ppm):
7.67 (4H, m, CAr–H), 7.39 (6H, m, CAr–H), 7.27 (2H,
d, CPMBar–H, J = 8.6 Hz), 6.86 (2H, d, CPMBar–H,
J = 3.1 Hz J = 5.1 Hz (dia 1 and 2)), 1.06 (9H, s, Si–
tBu).
0
J = 8.6 Hz), 5.81 (2H, m, C2 –H, C3 –H), 5.47 (1H, m,
0
C1 –H), 4.65 (1H, d, PhCH–Ha, J = 11 Hz), 4.34 (1H,
0
13C NMR: 62.5 MHz, CDCl3, d (ppm): 172.1 (C1), 159.5
(CPMBAr–OMe), 135.7 (C6), 135.5 (CAr), 133.5 (CqAr),
0
131.0 et 130.9 (C2 and CPMBar–CH2O), 129.7 and
0
129.3 (CAr and CPMBar), 128.5 (C3 ), 128.0 (CAr), 116.6
(C7), 113.9 (CPMBAr), 77.3 (C2), 71.7 (CPMBar–CH2O),
dd, PhCH–Hb, J = 11 Hz J = 2.3 Hz), 4.20 (2H, m,
0
C4 H Â 2), 4.03–4.09 (1H, m, C2–H (dia 1 and 2)), 3.79
(3H, s, OMe), 2.34 (2H, m, C4–H · 2), 1.89–2.01 (3H,
0
m, C3–H · 2, C6–H), 1.34 (3H, dd, C1 –Me (dia 1 and
0
0
69.7 (C1 ), 63.5 (C4 ), 55.2 (ArOMe), 28.4 and 31.1 (C5
and C4), 27.2 (C3), 26.6 (SiCMe3), 19.9 (C1–Me), 19.1
(SiCMe3) HRMS (electrospray) (M+Na) calculated:
609.3012; found: 609.3010. Rf (pentane/diethyl ether:
5:1) = 0.65.
2)), 1.06 (9H, s, Si–tBu) HRMS (electrospray) (M+Na)
calculated: 593.2699; found: 593.2697. Rf = 0.55 (diethyl
ether/pentane: 1:5).
4.18. (2RS,10S,20E) 2-tert-Butoxycarbonylamino-pent-
4-enoic acid 40-(tert-butyl-diphenyl-silyloxy)-10-methyl-
but-20-enyl ester 30
4.15. (2RS,10S,20E) 2-(4-Methoxy-benzyloxy)-hex-5-
enoic acid 40-(tert-butyl-diphenyl-silyloxy)-10,30-dimethyl-
but-20-enyl ester 27
1
72% yield 30: H NMR (250 MHz, CDCl3): d (ppm):
7.62–7.74 (4H, m, CAr–H), 7.32–7.50 (6H, m, CAr–H),
1
90% yield 27: H NMR (250 MHz, CDCl3): d (ppm):
7.59–7.74 (4H, m, CAr–H), 7.25–7.50 (6H, m, CAr–H),
7.29 (2H, d, J = 8.6 Hz, CPMBar–H), 6.87 (2H, d,
0
5.76–5.83 (2H, m, C2 –H, C3 –H), 5.59–5.78 (1H, m,
0
0
C4–H), 5.38–5.50 (1H, m, C1 –H), 5.02–5.20 (2H, m,
C5–H · 2), 4.32–4.42 (1H, m, C2–H), 4.18–4.28 (2H,
0
J = 8.6 Hz, CPMBar–H), 5.60–5.77 (2H, m, C2 –H, C5–
0
H), 5.50–5.60 (1H, m, C1 –H), 4.85–5.05 (2H, m, C6–
H · 2), 4.63 (1H, d, J = 11.1 Hz, PhCH–Ha), 4.28 (1H,
d, J = 11.1 Hz, PhCH–Hb), 4.00–4.10 (2H, m,
0
m, C4 H Â 2), 2.43–2.62 (2H, m, C3–H · 2), 1.86 (3H,
0
0
s, C3 –Me), 1.44 (9H, s, O–tBu), 1.32 (3H, dd, C1 –Me
(dia 1 and 2), J = 6.8 Hz J = 6.5 Hz), 1.06 (9H, s, Si–
tBu) 13C NMR (62.5 MHz, CDCl3): d (ppm): 171.1
(C1), 155.1 (C(O)Boc), 135.4 (CAr), 133.4 (CqAr), 132.2
0
C4 H Â 2), 3.88 (1H, t, J = 6.4 Hz, C2–H), 3.78 (3H, s,
OMe), 2.06–2.28 (2H, m, C4–H · 2), 1.71–1.90 (2H, m,
0
(C2 ), 131.4 (C3 ), 129.6 (CAr), 128.5 (C4), 127.6 (CAr),
0
0
C3–H · 2), 1.63 (3H, s, C3 –Me), 1.32 (3H, dd,
J = 3.1 Hz, J=5.2 Hz, C1 –Me (dia 1 and 2)), 1.05 (9H,
0
0
119.0 (C5), 79.6 (OCMe3), 71.6 (C1 ), 63.3 (C4 ), 52.8
(C2), 36.8 (C3), 28.2 (OCMe3), 26.7 (SiCMe3), 20.1
0
s, Si–tBu) 13C NMR (62.5 MHz, CDCl3): d (ppm):
0
(C1 –Me), 19.1 (SiCMe3) HRMS (electrospray)
(M+Na) calculated: 560.2808; found: 560.2805.
Rf = 0.65 (diethyl ether/pentane: 1:2).
0
172.3 (C1), 159.3 (CPMBAr–OMe), 138.2 (C2 ), 138.1
0
(C3 ), 137.5 (CqAr), 135.4 (CAr), 133.4 (CPMBar–CH2O),
129.7 (CAr and CPMBar), 127.6 (CAr), 123.2 (C5),115.3
(C6), 113.7 (CPMBar), 77.0 (C2), 71.8 (CPMBar–CH2O),
4.19. (10S,20E) Hex-5-enoic acid 40-(tert-butyl-diphenyl-
silyloxy)-10-methyl-but-20-enyl ester (31)
0
0
68.2 (C1 ), 67.7 (C4 ), 55.2 (ArOMe), 32.2 (C4), 29.4
(C3), 26.8 (SiCMe3), 20.8 (C1–Me), 19.4 (SiCMe3),
83% yield 31: 1H NMR (360 MHz, CDCl3): (ppm):
7.63–7.72 (4H, m, CAr–H), 7.32–7.48 (6H, m, CAr–H),
0
5.69–5.88 (1H, m, C5–H), 5.73–5.82 (2H, m, C2 –H,
0
13.8 (C3 ) HRMS (electrospray) (M+Na) calculated:
609.3012; found: 609.3009. Rf = 0.65 (diethyl ether/pen-
tane: 1:5).

1152
A. Franc¸ais et al. / Tetrahedron: Asymmetry 16 (2005) 1141–1155
0
C3 –H), 5.32–5.43 (1H, m, C1 –H), 4.92–5.08 (2H, m,
0
5.3. (1S,2S) Methyl 2-({[tert-butyl(diphenyl)silyl]oxy}-
methyl)-1-[(4-methoxybenzyl)oxy]-3-cyclopentene-1-
carboxylate 33
0
C6–H · 2), 4.19 (2H, s, C4 H Â 2), 2.31 (2H, t, C2–
H · 2, J = 7.8 Hz), 2.19 (2H, q, C4–H · 2, J = 7.8 Hz),
1.73 (2H, quint, C3–H · 2, J = 7.4 Hz), 1.29 (3H, d,
C1 –Me, J = 6.5 Hz), 1.06 (9H, s, Si–tBu) 13C NMR
Procedure A: 42% yield.
0
(62.5 MHz, CDCl3): d (ppm): 172.8 (C1), 137.7 (C4),
1
0
135.5 (CAr), 133.4 (CqAr), 130.7 (C2 ), 129.6 (CAr),
Compound 33: H NMR (250 MHz, CDCl3): d (ppm):
0
129.2 (C3 ), 128.8 (C5), 127.9 (CAr), 115.3 (C6), 70.2
7.60–7.75 (4H, m, CAr–H), 7.25–7.45 (6H, m, CAr–H),
7.18 (2H, d, CPMBar–H, J = 8.6 Hz), 6.80 (2H, d,
CPMBar–H, J = 8.6 Hz), 5.70–5.85 (2H, m, C3–H, C4–
H), 4.25–4.55 (2H, AB syst, Ar–CH2, J = 11 Hz), 3.75–
4.15 (2H, AB syst, C2–CH2–OSi), 3.78 (3H, s, OMe),
3.71 (3H, s, COOMe), 3.25–3.35 (1H, m, C2–H), 3.01
(1H, d, C5–Ha, J = 16Hz), 2.80 (1H, d, C5–Hb,
J = 16Hz), 1.03 (9H, s, t-Bu) 13C NMR (62.5 MHz,
CDCl3): d (ppm): 174.8 (COOMe), 158.8 (CqAr–OMe),
135.7 (CAr), 135.5 (CqAr), 130.8 (CqAr), 130.5 (C4),
129.4 (CAr), 128.5 (C3), 128.0 (CAr), 127.5 (CAr), 113.5
(CAr), 87.5 (C1), 67.5 (CPMBar–CH2O), 62.4 (C2–CH2–
OSi), 56.6 (ArOMe), 55.2 (COOMe), 52.2 (C2), 39.8
0
(C1 ), 63.5 (C4 ), 33.8 (C2), 24.9 (C3), 26.8 (SiCMe3),
0
0
20.3 (C1 –Me), 19.2 (SiCMe3) HRMS (electrospray)
(M+Na) calculated: 459.2331; found: 459.2333.
Rf = 0.65 (diethyl ether/pentane: 1:4).
5. CIM sequence
5.1. Two-step general procedure A
The ester (1 mmol) was dissolved in dry toluene (10 mL)
under argon and then cooled to ꢀ78 ꢁC. A solution of
KHMDS in toluene (0.5 M) was added dropwise
(3 mL, 1.5 mmol) over 15 min. After 45 min, freshly dis-
tilled TMSCl (2.5 mmol) was added and the resulting
mixture stirred for 5 min. The mixture was warmed to
room temperature and stirred for an additional 3 h.
The mixture was hydrolyzed with a 10% NH4Cl aqueous
solution and the layers separated. The aqueous layer
was extracted with diethyl ether (3 · 10 mL), and the
combined organic layers dried, filtered and the solvent
removed under reduced pressure. The crude product
was esterified with diazomethane, so the resulting
methyl ester could be purified by silica gel column
chromatography.
(C5), 26.7 (SiCMe3), 19.2 (SiCMe3) IR (film): m (cmꢀ1):
20
D
3658, 2931, 2856, 1736, 1614, 1514, 1463, 1250 ½aŠ
¼
ꢀ28:6 (c 0.2, CHCl3) HRMS (electrospray) (M+Na)
calculated: 553.2386; found: 553.2378. Rf = 0.4 (diethyl
ether/pentane: 1:5).
5.4. (1S,2S) Methyl 2-({[tert-butyl(diphenyl)silyl]oxy}-
methyl)-1-[(4-methoxybenzyl)oxy]-cyclohex-3-ene-1-
carboxylate 34
Procedure A: 88% yield.
Procedure B: 74% yield.
1
The resulting compound (1 mmol) was dissolved in
methylene chloride (5 mL) and then added to a flask
containing Grubbs catalyst (first or second generation)
(0.1 mmol) in CH2Cl2 or toluene (5 mL). This solution
was heated to 40 ꢁC for 1 h. After cooling, the mixture
was concentrated, and the crude product purified on sil-
ica gel column to afford pure cyclized methyl ester.
Compound 34: H NMR (250 MHz, CDCl3): d (ppm):
7.55–7.75 (4H, m, CAr–H), 7.25–7.42 (6H, m, CAr–H),
7.16 (2H, d, CPMBar–H, J = 8.6 Hz), 6.78 (2H, d,
CPMBar–H, J = 8.6 Hz), 5.65–5.83 (2H, m, C3–H, C4–
H), 4.25–4.60 (2H, AB syst, Ar–CH2, J = 11 Hz), 3.70–
3.95 (2H, AB syst, C2–CH2–OSi), 3.78 (3H, s, OMe),
3.53 (3H, s, COOMe), 3.15–3.25 (1H, m, C2–H), 1.95–
2.30 (4H, m, C5–H · 2, C7–H · 2), 1.20–1.40 (2H, m,
C6–H · 2), 1.02 (9H, s, t Bu) 13C NMR (62.5 MHz,
CDCl3): d (ppm): 173.8 (COOMe), 158.8 (CqAr–OMe),
135.6 (CAr), 133.2 (CqAr), 131.4 (CAr), 131.2 (CqAr),
130.2 (CAr), 129.5 (CAr), 128.6 (C3), 127.6 (C4), 113.5
(CAr), 81.6 (C1), 65.4 (CPMBar–CH2O), 64.2 (C2–CH2–
OSi), 55.2 (ArOMe), 51.6 (COOMe), 46.9 (C2), 35.8
(C5), 28.5 (C7), 26.8 (SiCMe3), 21.9 (C6), 19.2 (SiCMe3)
IR (film): m (cmꢀ1): 3020, 3000, 2920, 2840, 1733, 1505.
5.2. One-pot general procedure B
The ester (1 mmol) was dissolved under argon in dry tolu-
ene (10 mL) and then cooled to ꢀ78 ꢁC. A solution of
KHMDS in toluene (0.5 M) was added dropwise
(3 mL, 1.5 mmol) over 15 min. After 45 min, freshly dis-
tilled TMSCl (2.5 mmol) was added and the resulting
mixture was stirred for 5 min. The mixture was warmed
to room temperature and stirred for an additional 3 h.
The solution was then transferred by cannula to a flask
containing Grubbs catalyst (first or second generation)
(0.1 mmol) in CH2Cl2 or toluene (10 mL). This solution
was heated to 40 ꢁC for 2 h. After cooling, the reaction
was quenched with 10% NH4Cl solution and the layers
separated. The aqueous layer was extracted with methyl-
ene chloride or diethyl ether (3 · 10 mL), the combined
organic layers dried, filtered and the solvent removed
under reduced pressure. The crude product was esteri-
fied with diazomethane, and the resulting methyl ester
purified by silica gel column chromatography to give
the cyclized methyl ester.
20
½aŠ ¼ ꢀ35:3 (c 1.60, CHCl3) HRMS (electrospray)
D
(M+Na) calculated: 567.2542; found: 567.2542.
Rf = 0.52 (diethyl ether/pentane: 1:5).
5.5. (1S,2S) Methyl 2-({[tert-butyl(diphenyl)silyl]oxy}-
methyl)-1-[(4-methoxybenzyl)oxy]-3-cycloheptene-1-
carboxylate 35
Procedure A: 57% yield.
1
Compound 35: H NMR (250 MHz, CDCl3): d (ppm):
7.55–7.75 (4H, m, CAr–H), 7.25–7.50 (6H, m, CAr–H),

A. Franc¸ais et al. / Tetrahedron: Asymmetry 16 (2005) 1141–1155
1153
7.19 (2H, d, CPMBar–H, J = 8.6 Hz), 6.82 (2H, d,
CPMBar–H, J = 8.6 Hz), 5.65–5.92 (2H, m, C3–H, C4–
H), 4.25–4.60 (2H, AB syst, Ar–CH2, J = 11 Hz), 3.70–
3.95 (2H, AB syst, C2–CH2–OSi), 3.78 (3H, s, OMe),
3.53 (3H, s, COOMe), 3.15–3.25 (1H, m, C2–H), 1.95–
2.30 (4H, m, C5–H · 2, C7–H · 2), 1.20–1.40 (2H, m,
C6–H · 2), 1.02 (9H, s, tBu).
C6–H), 2.00–2.15 (2H, m, C5–H, C6–H), 1.20 (3H, s,
C2–Me), 1.06 (9H, s, tBu).
13C NMR (62.5 MHz, CDCl3):
d (ppm): 173.3
(COOMe), 158.8 (CqAr–OMe), 135.7 (CAr), 133.3 (CqAr),
131.9 (CAr), 130.8 (CqAr), 129.5 (CAr), 128.5 (CAr), 127.8
(CAr), 127.5 (CAr), 125.9 (C3), 113.5 (C4), 82.0 (C1), 69.2
(CPMBar–CH2O), 65.6 (C2–CH2–OSi), 55.2 (ArOMe),
51.5 (COOMe), 45.0 (C2), 26.8 (SiCMe3), 24.0 (C5),
21.5 (C6), 19.3 (C2–Me), 18.5 (SiCMe3) IR (film): m
13C NMR (62.5 MHz, CDCl3):
d (ppm): 173.8
(COOMe), 158.8 (CqAr–OMe), 135.6 (CAr), 133.2 (CqAr),
131.4 (C4), 131.2 (CqAr), 130.2 (C3), 129.5 (CAr), 128.6
(CAr), 127.6 (CAr), 113.5 (CAr), 81.6 (C1), 65.4
(CPMBar–CH2O), 64.2 (C2–CH2–OSi), 55.2 (ArOMe),
51.6 (COOMe), 46.9 (C2), 35.8 (C5), 28.5 (C7), 26.8
(SiCMe3), 21.9 (C6), 19.2 (SiCMe3) IR (film): m (cmꢀ1):
(cmꢀ1): 3663, 2998, 2933, 2858, 1728, 1613, 1588,
20
1513, 1464, 1302 ½aŠ ¼ þ133:3 (c 1.3, CHCl3) HRMS
D
(electrospray) (M+Na) calculated: 581.2699; found:
581.2710. Rf = 0.55 (diethyl ether/pentane: 1:5).
3648, 2998, 2933, 2858, 1735, 1613, 1588, 1514, 1464,
5.8. (1S,2S) Methyl 2-({[tert-butyl(diphenyl)silyl]oxy}-
methyl)-1-[(4-methoxybenzyl)oxy]-4-vinyl-3-cyclohexene-
1-carboxylate 38
20
D
1249 ½aŠ ¼ ꢀ40:9 (c 1.1, CHCl3) HRMS (electro-
spray) (MH+) calculated: 559.2880; found: 559.2897.
Rf = 0.55 (diethyl ether/pentane: 1:5).
Ester 29 (350 mg, 0.61 mmol) was dissolved in dry THF
(5 mL) under argon and cooled to ꢀ78 ꢁC. LiHMDS
(1 M solution in hexane, 1.6 mL, 1.6 mmol, 2.6 equiv)
was added dropwise over 15 min. The reaction was stir-
red for 2 h to form the dianionic species. Freshly dis-
tilled TMSCl (0.6 mL, 2.4 mmol, 4 equiv) was
introduced over 2 min and the mixture stirred for an
additional 30 min at ꢀ78 ꢁC. A solution of acetic acid
(0.5 mL) in dry THF (2 mL) was quickly added and
the mixture allowed to warm to room temperature.
After 3 h, the reaction was hydrolyzed by a 10% NH4Cl
aqueous solution and extracted with diethyl ether
(3 · 5mL). The combined organic layers were washed
with a saturated NaHCO3 solution (30 mL). The organ-
ic layer was then dried, filtered and concentrated to
afford 420 mg of pure TMS protected acetylenic ester
(98% yield).
5.6. (1S,2S) Methyl 2-({[tert-butyl(diphenyl)silyl]oxy}-
methyl)-1-[(4-methoxybenzyl)oxy]-2-methyl-3-cyclo-
hexene-1-carboxylate 36
Procedure A: 69% yield.
Procedure B: 47% yield.
1
Compound 36: H NMR (360 MHz, CDCl3): d (ppm):
7.60–7.70 (4H, m, CAr–H), 7.30–7.50 (6H, m, CAr–H),
7.10 (2H, d, CPMBar–H, J = 8.4 Hz), 6.77 (2H, d,
CPMBar–H, J = 8.4 Hz), 5.87 (1H, d, C3–H,
J = 10.2 Hz), 5.60–5.70 (1H, m, C4–H), 4.10–4.40 (2H,
AB syst, Ar–CH2, J = 10.7 Hz), 3.99 (2H, AB syst,
C2–CH2–OSi), 3.77 (3H, s, OMe), 3.56 (3H, s,
COOMe), 2.00–2.30 (4H, m, C5–H · 2, C6–H · 2),
1.06 (9H, s, tBu), 1.04 (3H, s, C2–Me) 13C NMR
(62.5 MHz, CDCl3): d (ppm): 173.3 (COOMe), 158.6
(CqAr–OMe), 135.7 (CAr), 133.9 (CqAr), 131.0 (CAr),
130.6 (CqAr), 129.3 (CAr), 128.0 (CAr), 127.8 (CAr),
127.4 (CAr), 123.9 (C3), 113.4 (C4), 83.5 (C1), 66.8
(CPMBar–CH2O), 66.3 (C2–CH2–OSi), 55.1 (ArOMe),
51.3 (COOMe), 43.7 (C2), 26.9 (SiCMe3), 23.6 (C5),
22.3 (C2–Me), 21.6 (C6), 19.4 (SiCMe3) IR (film): m
1
Compound 32: H NMR (250 MHz, CDCl3): d (ppm):
7.66 (4H, m, CAr–H), 7.39 (6H, m, CAr–H), 7.28 (2H,
d, CPMBar–H, J = 8.5 Hz), 6.85 (2H, d, CPMBar–H,
0
0
J = 8.5 Hz), 5.80 (2H, m, C2 –H, C3 –H), 5.47 (1H, m,
0
C1 –H), 4.65 (1H, d, PhCH–Ha, J = 11 Hz), 4.34 (1H,
dd, PhCH–Hb, J = 11 Hz J=2.3 Hz), 4.20 (2H, m,
0
C4 H Â 2), 4.00–4.05 (1H, m, C2–H), 3.78 (3H, s,
(cmꢀ1): 3657, 2996, 2952, 2858, 1729, 1613, 1588,
OMe), 2.36 (2H, m, C4–H · 2), 1.85–1.95 (2H, m, C3–
20
0
1464, 1302 ½aŠ ¼ þ64:6 (c 1.45, CHCl3) HRMS (elec-
H · 2), 1.34 (3H, dd, C1 –Me (dia 1 and 2)), 1.06 (9H,
s, Si–tBu), 0.13 (9H, s, SiMe3).
D
trospray) (M+Na) calculated: 581.2699; found:
581.2699. Rf = 0.55 (diethyl ether/pentane: 1:5).
13C NMR (62.5 MHz, CDCl3): d (ppm): 171.7 (C1),
159.3 (CqAr–OMe), 135.4 (CAr), 133.4 (CqAr), 131.4 and
0
131.2 (C2 and CPMBar–CH2O), 129.6 (CAr), 128.7
5.7. (1S,2R) Methyl 2-({[tert-butyl(diphenyl)silyl]oxy}-
methyl)-1-[(4-methoxybenzyl)oxy]-2-methyl-3-cyclo-
hexene-1-carboxylate 37
0
(C3 ), 127.6 (CAr and CPMBar), 113.7 (CPMBar), 105.8
(C6), 85.2 (C5), 76.2 (C2), 72.2 (CPMBar–CH2–O), 71.1
0 0
(C1 ), 63.3 (C4 ), 55.1 (ArOMe), 31.7 (C4), 26.7
Procedure A: 68% yield.
0
(SiCMe3), 20.2 (C1 –Me), 19.1 (SiCMe3), 16.0 (C3), 0.1
1
Compound 37: H NMR (360 MHz, CDCl3): d (ppm):
(SiMe3) HRMS (electrospray) (M+Na) calculated:
665.3094; found: 665.3090. Rf = 0.7 (diethyl ether/pen-
tane: 1:5).
7.65–7.75 (4H, m, CAr–H), 7.30–7.50 (6H, m, CAr–H),
7.30 (2H, d, CPMBar–H, J = 8.4 Hz), 6.85 (2H, d,
CPMBar–H, J = 8.4 Hz), 5.70–5.80 (1H, d, C3–H,
J = 10.2 Hz), 5.20–5.30 (1H, d, C4–H, J = 10.2 Hz),
4.15–4.45 (2H, AB syst, Ar–CH2, J = 10.6 Hz), 3.77
(3H, s, OMe), 3.60 (3H, s, COOMe), 3.40 (2H, AB syst,
C2–CH2–OSi), 2.40–2.50 (1H, m, C5–H), 2.23 (1H, m,
The TMS protected acetylenic ester 32 (330 mg,
0.51 mmol) was dissolved under argon in dry toluene
(5 mL) and then cooled to ꢀ78 ꢁC. A solution of
KHMDS in toluene (0.3 M) was added dropwise

1154
A. Franc¸ais et al. / Tetrahedron: Asymmetry 16 (2005) 1141–1155
(2.2 mL, 0.66 mmol, 1.3 equiv) over 15 min. After
45 min, freshly distilled TMSCl (300 lL) was added
and the resulting mixture was stirred for 5 min. The mix-
ture was warmed to room temperature and stirred for an
additional 3 h. The mixture was hydrolyzed with a 10%
NH4Cl solution and the layers separated. The aqueous
layer was extracted with diethyl ether (3 · 10 mL), the
combined organic layers dried, filtered and the solvent
was removed under reduced pressure. The crude product
was esterified with diazomethane, and after evaporation,
dissolved in methanol (5 mL). Solid K2CO3 (300 mg,
2.1 mmol, 4 equiv) was added in one portion and this
suspension stirred for 4 h at room temperature. After
evaporation under reduced pressure, the product was
dissolved in diethyl ether (10 mL) and washed with
water (5 mL). The layers were separated and the aque-
ous one extracted with diethyl ether (2 · 10 mL). The
combined organic layers were dried, filtered and
concentrated.
3.65–3.95 (2H, m, C2–CH2–OSi), 3.73 (3H, s, COOMe),
3.30–3.45 (1H, m, C5–Ha), 2.95–3.05 (1H, m, C2–H),
2.65–2.80 (1H, m, C5–Hb), 1.43 (9H, s, O–tBu), 1.09
(9H, s, Si–tBu) 13C NMR (62.5 MHz, CDCl3): d
(ppm): 174.8 (COOMe), 156.0 (COOtBu), 135.6 (CAr),
132.6 (CqAr) 131.4 (C4), 129.9 (CAr), 127.8 (CAr), 127.3
(C3), 79.2 (OCMe3), 67.0 (C1), 62.8 (C2–CH2–OSi),
54.7 (COOMe), 52.4 (C2), 43.6 (C5), 28.3 (OCMe3),
26.7 (SiCMe3), 19.1 (SiCMe3).
IR (film): m (cmꢀ1): 3377, 2932, 2859, 1740, 1708, 1590,
20
D
1500, 1367, 1290 ½aŠ ¼ ꢀ13:2 (c 0.88, CHCl3) HRMS
(electrospray) (MH+) calculated: 510.2676; found
510.2666. Rf = 0.4 (diethyl ether/pentane: 1:2).
5.10. (1R,2R) Methyl 2-({[tert-butyl(diphenyl)silyl]oxy}-
methyl)-cyclohex-3-ene carboxylate 40
Procedure A: 96% yield.
Procedure B: 48% yield.
The compound was dissolved in toluene (5 mL) and then
added to a flask under an ethylene atmosphere contain-
ing a second generation Grubbs catalyst (0.05 mmol)
solution in toluene (3 mL). This solution was heated to
50 ꢁC for 1 h. After cooling, the mixture was concen-
trated, and the crude product was purified on silica gel
column chromatography (30 g SiO2, pentane/diethyl
ether: 4:1) to afford pure cyclized methyl ester 35.
(226 mg, 78% yield).
1
Compound 40: H NMR (250 MHz, CDCl3): d (ppm):
7.55–7.75 (4H, m, CAr–H), 7.25–7.45 (6H, m, CAr–H),
5.55–5.85 (2H, m, C3–H, C4–H), 3.45–3.70 (2H, AB syst,
C2–CH2–OSi), 3.61 (3H, s, COOMe), 2.70–2.85 (1H, m,
C2–H), 2.50–2.65 (1H, m, C1–H), 1.65–2.15 (4H, m, C5–
H · 2, C6–H · 2), 1.04 (9H, s, tBu) 13C NMR
(62.5 MHz, CDCl3): d (ppm): 176.2 (COOMe), 135.6
(CAr), 133.6 (CqAr), 129.5 (C4), 127.6 (CAr), 127.2 (C3),
66.3 (C2–CH2–OSi), 51.5 (COOMe), 41.9 (C1), 40.1
(C2), 26.8 (SiCMe3), 25.0 (C5), 24.2 (C6), 19.2 (SiCMe3)
1
Compound 38: H NMR (250 MHz, CDCl3): d (ppm):
7.60–7.70 (4H, m, CAr–H), 7.30–7.50 (6H, m, CAr–H),
7.17 (2H, d, CPMBar–H, J = 8.4 Hz), 6.79 (2H, d,
dd,
IR (film): m (cmꢀ1): 3053, 2932, 2859, 1731, 1472, 1428,
20
D
CPMBar–H,
J = 8.4 Hz),
6.32–6.43
(1H,
1265 ½aŠ ¼ ꢀ68:3 (c 1.05, CHCl3) HRMS (electro-
J = 10.7 Hz, J = 17.5 Hz, C4–CHCH2), 5.74 (1H, d,
C3–H, J = 2.5 Hz), 4.95–5.11 (2H, m, C4–CHCH · 2),
4.30–4.60 (2H, AB syst, Ar–CH2, J = 12.5 Hz), 3.40–
3.99 (2H, AB syst, C2–CH2–OSi), 3.78 (3H, s, OMe),
3.60 (3H, s, COOMe), 3.08 (1H, m, C2–H), 2.10–2.40
(4H, m, C5–H · 2, C6–H · 2), 1.03 (9H, s, tBu) 13C
NMR (62.5 MHz, CDCl3): d (ppm): 174.0 (COOMe),
158.7 (CqAr–OMe), 139.1 (C4–CHCH2), 135.5 (CAr),
135.1 (C4), 133.6 (CqAr), 133.5 (CqAr), 130.8 (CqAr),
129.4 (CAr), 128.4 (C3), 128.3 (CAr), 127.5 (CAr), 113.5
spray) (MH+) calculated: 409.2199; found: 409.2187.
Rf = 0.6 (diethyl ether/pentane: 1:4).
Acknowledgements
The Ministry of Education is acknowledged for a grant
´
to O.B. and Universite de Paris Sud and CNRS for
financial support. We also thank K. Ple, Y. Langlois
´
and C. Kouklovsky for helpful discussions.
(CAr), 111.1 (C4–CHCH2), 79.1 (C1), 65.4 (CPMBar
–
CH2O), 63.5 (C2–CH2–OSi), 55.2 (ArOMe), 51.8
(COOMe), 45.5 (C2), 27.1 (C5), 26.7 (SiCMe3), 20.8
(C6), 19.1 (SiCMe3) IR (film): m (cmꢀ1): 3657, 2952,
2932, 2857, 1742, 1613, 1587, 1514, 1463, 1248.
References
1. (a) Fuji, K. Chem. Rev. 1993, 93, 2037; (b) Corey, E. J.;
Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388;
(c) Christoffers, J.; Mann, A. Angew. Chem., Int. Ed. 2001,
40, 4591.
2. Ireland, R. E.; Wipf, P.; Xiang, J. N. J. Org. Chem. 1991,
56, 3572.
20
½aŠ ¼ ꢀ87:5 (c 1.32, CHCl3) HRMS (electrospray)
D
(M+Na) calculated: 593.2699; found: 593.2698.
Rf = 0.45 (diethyl ether/pentane: 1:5).
3. (a) Burke, S. D.; Ng, R. A.; Morrison, J. A.; Alberti, M. J.
J. Org. Chem. 1998, 63, 3160; (b) Miller, J. F.; Termin, A.;
Koch, K.; Piscopio, A. D. J. Org. Chem. 1998, 63, 3158;
(c) Barrett, A. G. M.; Ahmed, M.; Baker, S. P.; Baugh, S.
P. D.; Braddock, D. C.; Procopiou, P. A.; White, A. J. P.;
Williams, D. J. J. Org. Chem. 2000, 65, 3716; (d) Beaulieu,
P.; Ogilvie, W. W. Tetrahedron Lett. 2003, 44, 8883;
Burke, S. D.; Ng, R. A.; Morrison, J. A.; Alberti, M. J. J.
Org. Chem. 1998, 63, 3160; (e) Ko, H.; Kim, E.; Park, J.
E.; Kim, D.; Kim, S. J. Org. Chem. 2004, 69, 112.
5.9. (1S,2S) Methyl 1-[(tert-butoxycarbonyl)amino]-2-
({[tert-butyl(diphenyl)silyl]oxy}methyl)-3-cyclopentene-1-
carboxylate 39
Procedure A: 46% yield.
1
Compound 39: H NMR (250 MHz, CDCl3): d (ppm):
7.60–7.80 (4H, m, CAr–H), 7.30–7.55 (6H, m, CAr–H),
5.70–5.80 (1H, m, C3–H), 5.25–5.40 (1H, m, C4–H),

A. Franc¸ais et al. / Tetrahedron: Asymmetry 16 (2005) 1141–1155
1155
4. (a) Picoul, W.; Urchegui, R.; Haudrechy, A.; Langlois, Y.
Tetrahedron Lett. 1999, 40, 4797; (b) Picoul, W.; Bedel, O.;
Haudrechy, A.; Langlois, Y. Pure Appl. Chem. 2003, 75, 235.
5. (a) Burgess, K.; Cassidy, J.; Henderson, I. J. Org. Chem.
1991, 56, 2050; (b) Nowotny, S.; Vettel, S.; Knochel, P.
Tetrahedron Lett. 1994, 35, 4539; (c) Ichikawa, Y.; Tsuboi,
K.; Isobe, M. J. Chem. Soc., Perkin Trans. 1 1994, 2791;
(d) (a) DHP, PPTS, CH2Cl2, quant.; (b) DIBAH, CH2Cl2,
ꢀ78 ꢁC, 93%; (c) (EtO)2PO–CH2CO2Et, DBU, LiCl,
CH3CN, 90%; (d) DIBAH, CH2Cl2, quant.; (e) TBDPSCl,
imidazole, CH2Cl2, 80%; (f) PPTS, MeOH, 55 ꢁC, 89%.
6. Loh, T. P.; Xu, J. Tetrahedron Lett. 1999, 40, 2431.
7. Four steps starting from trityl glycidol Evans, D. A.;
Ripin, D. H. B.; Halstead, D. P.; Campos, K. R. J. Am.
Chem. Soc. 1999, 121, 789.
10. Biagini, S. C. G.; Gibson, S. E.; Keen, S. P. J. Chem. Soc.,
Perkin Trans. 1 1998, 2485.
11. Bedel, O.; Haudrechy, A.; Langlois, Y. Eur. J. Org. Chem.
2004, 3813.
12. (a) OÕNeil, S. V.; Quickley, C. A.; Snider, B. B. J. Org.
Chem. 1997, 62, 1970; (b) Rancourt, J.; Burke, S. D.
J. Am. Chem. Soc. 1991, 113, 2335.
13. Chatterjee, A. K.; Grubbs, R. H. Org. Lett. 1999, 1,
1751.
14. Bayle, J. P.; Courtieu, J.; Gabetty, E.; Loewenstein, A.;
´
´
Pechine, J.-M. New J. Chem. 1992, 16, 837.
15. Canet, I.; Meddour, A.; Loewenstein, A.; Pechine, J.-M.;
´
Courtieu, J. J. Am. Chem. Soc. 1995, 117, 6520.
´
16. (a) Meddour, A.; Canlet, C.; Blanco, L.; Courtieu, J.
Angew. Chem., Int. Ed. 1999, 38, 2391; (b) Canlet, C.;
Merlet, D.; Lesot, P.; Meddour, A.; Loewenstein, A.;
Courtieu, J. Tetrahedron: Asymmetry 2000, 11, 1911.
8. Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D.
J. Chem. Soc., Chem. Commun. 1987, 21, 1625.
´
9. (a) Ohira, S. Synth. Commun. 1989, 19, 561; (b) Muller, S.;
17. Meddour, A.; Haudrechy, A.; Berdague, P.; Picoul, W.;
¨
Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996,
521.
Langlois, Y.; Courtieu, J. Tetrahedron: Asymmetry 1996,
7, 2492.