A convergent approach toward phoslactomycins and leustroducsins

Article abstract of DOI:10.1016/j.tet.2010.05.050

Synthetic studies devoted to the development of a convergent approach toward phoslactomycins and leustroducsins, a family of natural products inhibitors of serine/threonine phosphatase 2A, are reported. A formal synthesis of phoslactomycin B was achieved

Full text of DOI:10.1016/j.tet.2010.05.050

Tetrahedron 66 (2010) 6358e6375
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A convergent approach toward phoslactomycins and leustroducsins
,
Valérie Druais a, Michael J. Hall a, Camilla Corsi b, Sebastian V. Wendeborn b, Christophe Meyer a
,
*
,
Janine Cossy a
*
a Laboratoire de Chimie Organique, ESPCI ParisTech, CNRS (UMR 7084), 10 rue Vauquelin, 75231 Paris Cedex 05, France
b Syngenta Crop Protection Muenchwilen AG, WST-820.2.15, Schaffhauserestra
be, 4332 Stein, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthetic studies devoted to the development of a convergent approach toward phoslactomycins and
leustroducsins, a family of natural products inhibitors of serine/threonine phosphatase 2A, are reported.
A formal synthesis of phoslactomycin B was achieved in which the key steps are a [2,3]-Wittig
rearrangement to control the C4 and C5 stereocenters, a diastereoselective addition of an acetylenic
Received 3 March 2010
Received in revised form 6 May 2010
Accepted 13 May 2010
Available online 20 May 2010
Grignard reagent to an
tathesis to construct the
ther directly or indirectly, from catalytic enantioselective reductions of acetylenic ketones.
Ó 2010 Elsevier Ltd. All rights reserved.
a
-alkoxy ketone to create the C8 tertiary alcohol, and a relay ring-closing me-
a,b
-unsaturated -lactone. In this approach, all the stereocenters originate, ei-
d
Keywords:
Phoslactomycins
Leustroducsins
Metathesis reactions
Noyori reduction
Wittig rearrangement
1. Introduction
O
O
Phoslactomycins (PLMs) AeF are six antibiotics isolated in 1989
by Seto et al. from the culture broth of a strain of Streptomyces
nigrescens (SC-273), which were found to be active against resistant
phytopathogenic fungi.1 In the same year, phospholine, a com-
pound which turned out to be identical to PLM B, was isolated from
the fermentation broth of Streptomyces hygroscopicus. This com-
pound showed strong in vitro cytotoxicity against L1210, P388, and
EL-4 tumor cell lines.2 A few years later, while using a new
screening method for colony-stimulating factors (CSFs) inducers,
researchers from the Sankyo group identified three active com-
pounds, leustroducsins (LSNs) AeC, isolated from cultures of
Streptomyces platensis SANK 600191.3 Finally, LSN H, a synthetic
analogue prepared by saponification, was also found to possess
thrombopoietic activity.4 PLMs and LSNs feature a common back-
HO
15
P
1
4
O
HO
O
OH
7
8
18
13
9
5
11
OH
R
H2N
phoslactomycins (PLMs) and leustroducsins (LSNs)
R
R
O
O
PLM A
PLM B
PLM D
PLM E
O
O
O
O
H
O
O
O
PLM C
LSN A
PLM F
LSN C
O
O
O
O
O
bone comprising an
a,b-unsaturated d-lactone (C1eC5), a di-
O
substituted olefin of E configuration (C6eC7), a tertiary alcohol at
C8 substituted by an aminoethyl side-chain, a phosphorylated
secondary alcohol at C9, a secondary hydroxyl group at C11, and
a conjugated diene (C12eC15) consisting of two olefins of Z con-
figuration (Fig. 1).
LSN B
LSN H
OH
O
O
O
HO
15
P
1
O
HO
O
OH
Naturally occurring PLMs and LSNs only differ by the nature of
the substituent attached to the cyclohexyl ring at C18 (a hydrogen
7
OH
13
3
9
5
11
18
OH
fostriecin
* Corresponding authors. Tel.: þ33 1 40794429; fax: þ33 1 40794660; e-mail
addresses: christophe.meyer@espci.fr (C. Meyer), janine.cossy@espci.fr (J. Cossy).
Figure 1. Phoslactomycins, leustroducsins, and fostriecin.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.05.050

V. Druais et al. / Tetrahedron 66 (2010) 6358e6375
6359
for PLM B or an acyloxy group for the other members), which does
not seem to exert a marked effect on the biological activity. These
compounds are also structurally related to the natural product
fostriecin from which they differ by the presence of an ethyl group
at C4, a 2-aminoethyl side-chain at C8 rather than a simple methyl
group and a (Z,Z)-diene substituted by the cyclohexyl group at C15
instead of a labile (Z,Z,E)-triene subunit (Fig. 1).5
approach toward PLMs and LSNs. Although the chelation-con-
trolled addition of vinylmagnesium bromide to a ketone of type C
(P2¼TBS, P3¼TBDPS, P4¼PMB) was used by Kobayashi et al. in their
total synthesis of PLM B to create the tertiary alcohol at C8, 11 steps
were subsequently required to introduce the C4 and C5 stereo-
centers (Evans aldolization) and create the lactone ring (by Ando
olefination and subsequent lactonization).7 Therefore, the more
Like fostriecin, PLMs and LSNs are potent selective inhibitors of
protein phosphatase 2A (PP2A), an enzyme playing important roles
in the regulation of cell growth and division, signaling pathways,
inhibition of metastasis through activation of natural killer cells,
and also in the transcription and regulation of HIV-1.6 It is therefore
not surprising that PLMs and LSNs have elicited considerable in-
terest from the synthetic community. To date, two total syntheses
of both PLM B7,8 and LSN B9,10 and one total synthesis of PLM A11
have been reported. Formal syntheses of LSN B12 and PLM B13,14
have also been recently disclosed.
convergent chelation-controlled addition of a functionalized
alkenyl Grignard reagent B to a ketone C appeared particularly
appealing.
The use of RCM was obvious to create the
a,b-unsaturated
d-lactone or its protected cyclic mixed acetal precursor B and an
original approach relying on the [2,3]-Wittig rearrangement of
an allylic and propargylic ether of type D was envisaged for the
control of the C4 and C5 stereocenters.17,18 The synthesis of the
a,g-dialkoxy ketone C (C8eC13 subunit), which was planned
from enone E, would involve a diastereoselective reduction to
create the C9 stereocenter and an ozonolysis of the methylene
unit at C8. The initial C11 stereocenter would, in turn, be in-
Herein, we report a full account of our studies on the de-
velopment of convergent approaches toward members of the
phoslactomycins/leustroducsins family that have resulted in the
formal synthesis of phoslactomycin B.
troduced by enantioselective reduction of an acetylenic
ketoester (Scheme 1).
b-
2.2. Synthesis of the C1eC7 subunit
2. Examination of a convergent approach toward the C1eC13
subunit of PLMs and LSNs
The control of the configuration of the C4 and C5 stereo-
centers is the key issue in the synthesis of the C1eC7 subunit.
Evans aldol condensations7,9,11 or Brown-type pentenylations8,12
have been successfully used to achieve this task. However,
these reactions imply the use of stoichiometric quantities of
chiral auxiliaries or reagents. The ring-opening of an epoxy-al-
cohol derivative (prepared by Sharpless asymmetric epoxidation)
with an alkynylaluminum reagent has also been reported.10 In
another convergent approach, the C4 stereocenter was first
established through a lipase promoted resolution of a racemic
alcohol by acetylation and a Nozaki/Hiyama/Kishi reaction was
used to create the C5 allylic alcohol, though the desired config-
uration was only attained after an oxidation/stereoselective re-
duction sequence.10b
As a novel approach for the control of C4 and C5, the use of
a [2,3]-Wittig rearrangement of an allylic and propargylic ether D
was considered. The goal was to create the initial asymmetric car-
bon by a catalytic enantioselective reduction and to subsequently
transfer the chirality by the [2,3]-Wittig rearrangement to C4 and
C5 in the resulting alcohol F while a disubstituted olefin would be
created at the same time.17,18 One critical issue regarding the use of
the [2,3]-Wittig rearrangement, combined with subsequent for-
2.1. Retrosynthetic analysis
The C1eC13 subunit A, common to all PLMs and LSNs, was se-
lected as the target. With the aim of developing a convergent route,
an appropriate disconnection appears to be at the C7eC8 bond. In
the forward sense, the tertiary alcohol at C8 would be created by
nucleophilic addition of an alkenyl Grignard reagent B, containing
a cyclic mixed acetal as a temporarily masked form of the lactone
(with the C4 and C5 stereocenters in place), to an
a,g-dialkoxy
ketone C. The syn relationship between the tertiary hydroxyl group
at C8 and the alkoxy group at C9 entails that the nucleophilic ad-
dition of the Grignard reagent B has to be performed under che-
lation control.15 This would be achieved by the appropriate choice
of the protecting group of the hydroxyl at C9 (P4¼PMB or MOM)
(Scheme 1).
The chelation-controlled addition of vinylic organometallic
species to a methyl ketone has been used as a key step in several
syntheses of fostriecin (Fig. 1)16 and it was surprising to see that
a similar strategy had never been implemented in a convergent
mation of the unsaturated d-lactone by RCM, was the appropriate
O
Nucleophilic addition
selection of the R group in compound D and in the future acrylate
intermediate G. Although the R residue would be expelled in the
form of an alkene H (RCH]CH2) during the RCM, having a di-
substituted olefin as well as an alkyne in the acrylate G may hamper
the initial formation of the ruthenium carbene at C3 and hence be
detrimental to the success of this step.19e21 A relay ring-closing
metathesis (RRCM) appeared to be an attractive solution to this
problem.22 The presence of an appropriately located terminal olefin
in the R group (R¼CH2eXeCH2CH]CH2) should result in an initial
RCM expelling the relay in the form of a five-membered ring alkene
I and producing the ruthenium carbene J at C3. This should facili-
1
O
OP4 OP2
I
7
13
3
9
5
11
OH
Diastereoselective reduction
OP4 OP2
P3O
OP1
A
RCM
1
O
O
7
9
11
4
5
+
MgX
13
R
(R = H or TMS)
B
C
P3O
Enantioselective reduction
[2,3]-Wittig
R
tate the second RCM leading to the unsaturated
(Scheme 2).
d-lactone K
O
OP2
3
4
O
9
11
8
The preparation of propargylic ethers D was first examined.
Commercially available hex-5-enoic acid (1) or allyloxyacetic acid
(2)23 were activated as mixed anhydrides and converted to Weinreb
amides 3 (73%) and 4 (81%), respectively.24,25 Addition of the
acetylenic organolithium reagent generated from 1-butyne (n-BuLi,
THF, ꢀ78 ꢁC) to Weinreb amides 3 and 4 provided ketones 5 (97%)
5
13
SiMe3
7
P3O
SiR'3
D
E
Scheme 1. Retrosynthetic analysis of the C1eC13 subunit.

6360
V. Druais et al. / Tetrahedron 66 (2010) 6358e6375
1) i-BuOCOCl (1.5 equiv)
N-methylmorpholine (3 equiv)
CH2Cl2, 15 °C
R
X
OH
3
[2,3]-Wittig
X
O
R
Me
5
N
OMe
O
7
2) (MeO)MeNH.HCl (1.8 equiv)
CH2Cl2, 15 °C to rt
SiR'3
HO
O
1
D
F
SiR'3
O
(73%)
(81%)
3
4
X = CH2
X = O
X = CH2
X = O
Ts
2
Ph
N
Cl
Ru
Li
Et
O
O
N
H
Ph
THF, 78 °C to
40 °C or 10 °C
X
RCM
R
1
O
5
1
O
5
(S,S)-Ru-I
3
X
R
3
7
(S,S)-Ru-I (5 mol %)
i-PrOH, rt
H
7
SiR3
SiR'3
K
G
OH
O
RRCM
R = CH2-X-CH2-CH=CH2
X = CH2 or O
7
8
X = CH2 (32%) (ee = 81%)
X = O (97%) (ee = 91%)
5
6
X = CH2 (97%)
[Ru]
RCM
X = O
(88%)
[Ru]
O
O
Zn, Br(CH2)2Br, CuBr, LiBr
THF, i-PrOH, reflux
96%
O
RCM
1
1
O
X
O
3
3
Br
n-Bu4NHSO4 (cat.)
50% aq NaOH, toluene, rt
LDA, THF, 78 °C
then TMSCl, 78 °C to rt
O
O
5
5
1)
2)
[Ru]
7
7
SiR'3
SiR'3
X
I
OH
J
Br
Scheme 2. RCM vs RRCM for the synthesis of the d-lactone.
or
SiR3
9
, t-BuOK, THF, 0 °C
TIPS
10 R = Me (70%)
11 R = i-Pr (87%)
and 6 (88%). Enantioselective reduction of these acetylenic ketones
was achieved under Noyori’s catalytic conditions using the
16-electron catalyst (S,S)-Ru-I (5 mol %) in isopropanol.26 Surpris-
ingly, the reduction of 5 provided propargylic alcohol 7 in low yield
(32%) and modest enantiomeric excess (ee¼81%).27 Better results
were obtained with acetylenic ketone 6 possessing an allylic ether
linkage, which led to the corresponding propargylic alcohol 8 in
very high yield (97%) with an enantiomeric excess of 91%.27 The
synthesis of the C1eC7 subunit of PLMs and LSNs was thus pursued
from 8 only. Chemoselective reduction of the alkyne, using an in
situ prepared zinc/copper couple in refluxing THF/isopropanol,
afforded the Z-disubstituted alkene 9 (96%).28 To prepare the cor-
responding (trimethylsilyl)propargylic ether, the secondary alcohol
was first alkylated with propargyl bromide under phase-transfer
catalysis conditions and the terminal alkyne underwent sub-
sequent lithiation (LDA) and silylation with TMSCl to provide
compound 10 (70%, two steps from 9). Propargylic ether 11 was
more conveniently prepared in a single step (87%) by alkylation of
the secondary alcohol 9 with 3-(triisopropylsilyl)propargyl bro-
mide,29 owing to the slower cleavage of acetylenic TIPS group
(compared to TMS) under alkaline conditions. With the propargylic
ethers 10 and 11 in hand, the stage was set to create the C4 and C5
stereocenters by the [2,3]-Wittig rearrangement, which was trig-
gered by treatment with n-BuLi (THF, ꢀ78 ꢁC). The corresponding
propargylic alcohols 12 and 13 were generated as single detectable
diastereomers (dr>96:4 by 1H NMR) and were isolated in high
yields (90% and 99%, respectively) (Scheme 3).
n-BuLi
THF, 78 °C
H
H
O
OH
3
Li
[2,3]-Wittig
O
5
O
7
H
SiR3
SiR3
12 R = Me
13 R = i-Pr (99%) (dr > 96:4)
(dr > 96:4)
(90%)
Scheme 3. Control of C4 and C5 by a [2,3]-Wittig rearrangement.
produces 2,5-dihydrofuran and a new ruthenium carbene 16 that
undergoes subsequent RCM leading to lactone (ꢂ)-18. The rate of
this latter step being probably slow, carbene 16 can act as a me-
tathesis initiator itself and competitively react with the starting
material (ꢂ)-14 to provide acrylate (ꢂ)-17, resulting from trunca-
tion of the unsaturated relay,22 and carbene 15. Performing the
reaction under harsher conditions (toluene, 80 ꢁC) or in the pres-
ence of Ti(Oi-Pr)4 as an additive33 did not significantly affect the
results. Indeed, we demonstrated that acrylate (ꢂ)-17 was com-
pletely unable to undergo RCM to the unsaturated
d
-lactone (ꢂ)-18,
whatever the conditions, presumably due to the presence of the
trimethylsilylalkyne.19,20 This result highlights the tremendous
importance of the RRCM strategy to achieve the formation of the
unsaturated
d
-lactone (ꢂ)-18 bearing a trimethylsilylethynyl group.
The relative configuration of C4 and C5 was confirmed by 1H NMR
As anticipated, the stereochemical outcome is in agreement
with a five-membered ring transition state of envelope conforma-
tion wherein the allylyoxymethyl chain preferentially occupies
a pseudo-equatorial position whereas an exo orientation is known
spectroscopy through the determination of the 3J coupling constant
between H4 and H5 suggesting
a syn relative orientation
(3JH4‑H5¼4.9 Hz) (Scheme 4).34e36
The reactivity of acrylate 19, synthesized by acylation of the
triisopropylsilyl-substituted propargyl alcohol 13 with acryloyl
chloride (97%), was next investigated. When acrylate 19 was treated
with Grubbs II catalyst (8 mol %) (CH2Cl2, reflux), lactone 21 was
isolated in 76% yield, whereas acrylate 20 resulting from truncation
of the relay was a minor product (19%). The truncated acrylate 20
to be favored for
p-donating anionic stabilizing groups such as
alkynes.30,31 The syn relative orientation of the ethyl group at C4
and the hydroxyl group at C5 has been confirmed later in the
synthesis after construction of the
d-lactone.
The formation of the unsaturated
d-lactone moiety by RRCM
was next investigated and the initial studies were carried out in the
racemic series. The trimethylsilyl-substituted propargylic alcohol
(ꢂ)-12, prepared from alcohol (ꢂ)-8, was acylated with acryloyl
chloride. The resulting acrylate (ꢂ)-14 (73%) was then treated with
Grubbs II catalyst32 (8 mol %) in refluxing CH2Cl2. Under these
could undergo RCM to the corresponding unsaturated d-lactone 21
presumably because the bulky TIPS group sterically shields the
alkyne and disfavors its interaction with ruthenium carbenes.21 It is
worth pointing out that the RCM of acrylate 20 required a higher
catalyst loading (13 mol %) and provided lactone 21 in lower yield
(61%) compared to the RRCM route from acrylate 19. Once again,
the syn relationship between H4 and H5 was confirmed by 1H NMR
for lactone 21 (3JH4‑H5¼5.1 Hz).34e36 As a vinylic organometallic
conditions, acrylate (ꢂ)-17 and the desired -lactone (ꢂ)-18 were
d
formed in nearly identical amounts and were isolated in 33% and
35% yield, respectively. Thus, a first RCM triggered by carbene 15

V. Druais et al. / Tetrahedron 66 (2010) 6358e6375
6361
epimers at C1. Subsequent hydrozirconation of 24 with Schwartz’s
reagent followed by iodinolysis delivered alkenyl iodide 25 (54%).
The latter compound, which constitutes the C1eC7 subunit of PLMs
and LSNs, was synthesized in 11 steps from a-allyloxyacetic acid
(shortest linear route) in 14% overall yield at best (Scheme 6). The
synthesis of the C8eC13 subunit was then carried out.
OMe
OMe
OMe
O
O
O
OH
3
PPTS (cat.)
3
5
5
7
7
C6H6, reflux
71%
TIPS
TIPS
13
23
Grubbs II (12 mol %)
CH2Cl2, reflux
82%
OMe
OMe
1
O
1
O
PPTS (cat.)
3
5
3
MeOH, rt, 9 h
87%
5
7
7
TIPS
22 (dr = 1:1)
TIPS
22 (dr = 5:1)
67% TBAF, THF, rt
OMe
Scheme 4. RRCM of acrylate (ꢂ)-14.
OMe
1
O
1
O
Cp2ZrHCl, THF, rt
species will have to be generated at C7 later in the synthesis, lac-
tone 21 was temporarily masked as a mixed methyl ketal by
reduction with DIBAL-H followed by treatment of the crude lactol
with a catalytic amount of PPTS in MeOH. The cyclic methyl acetal
22 was isolated as a 5:1 equilibrium mixture of epimers (87%, two
steps from lactone 21) (Scheme 5).35e37
7
3
3
5
5
I
7
then I2, THF, rt
54%
24 (dr = 12:1)
25(dr = 12:1)
Scheme 6. Synthesis of the C1eC7 subunit.
An alternative approach was also examined for a more direct
preparation of the cyclic methyl ketal 22 by RRCM. Propargylic al-
cohol 13 was engaged in a transacetalisation with acrolein dimethyl
acetal to deliver the mixed methyl acetal 23 (1:1 mixture of epi-
mers).38 RRCM of 23 was initiated with Grubbs II catalyst (12 mol %,
CH2Cl2, reflux) and provided the cyclic methyl ketal 22 (82%) as
a 1:1 mixture of epimers.39 Thermodynamic equilibration could be
achieved by treatment with a catalytic amount of PPTS in MeOH to
afford, as previously observed from the preceding route, a 5:1
mixture of epimers (87%). Removal of the TIPS group was accom-
plished by treatment of 22 with TBAF and the volatile terminal
alkyne 24 was isolated in moderate yield (67%) as a 12:1 mixture of
2.3. Synthesis of the C8eC13 subunit
The preparation of the C8eC13 subunit was achieved from the
optically active -hydroxyester 27, easily prepared (72% yield,
ee¼92%) by reduction of the acetylenic -ketoester 26 using Sac-
charomyces Cerevisiae type II (Baker’s yeast).36 The hydroxyl group
was protected as a TBS ether to provide the -silyloxyester 28 (97%),
b
b
b
which was converted to Weinreb amide 29 (95%).40 Condensation
of the organolithium reagent generated from the readily available
alkenyl iodide 3041 (n-BuLi, Et2O, ꢀ78 ꢁC) with Weinreb amide 29
led to enone 31 in 66% yield. The diastereoselective reduction of the
carbonyl group was then achieved through a reagent-controlled
reduction using BH3$SMe2 in the presence of oxazaborolidine
(S)-32.42 The resulting allylic alcohol 33 was obtained with high
diastereoselectivity (dr>95:5) and was isolated in 76% yield.43 The
hydroxyl group at C9 was protected as a PMB ether using
p-methoxybenzyl trichloroacetimidate and La(OTf)3 as the catalyst
to deliver 34 (64%).44 The latter compound contains two PMB
ethers but it was reasonable to consider that the primary and
secondary alcohols resulting from their deprotection could be se-
lectively manipulated. To achieve the oxidative cleavage of the
methylene unit at C8, a dihydroxylation/1,2-diol cleavage sequence
was initially considered but osmylation was unsuccessful under
a variety of conditions.45 This operation was therefore accom-
plished by a carefully controlled ozonolysis of 34,46 followed by
O
O
Cl
O
O
O
OH
DMAP (cat.)
i-Pr2NEt
3
3
5
5
7
7
CH2Cl2, 78 °C
97%
TIPS
TIPS
13
19
Grubbs II (8 mol %)
CH2Cl2, reflux
OMe
O
O
1) DIBAL-H
CH2Cl2, 78 °C
1
O
1
O
1
O
3
+
3
2) PPTS (cat.)
MeOH, rt, 16 h
87% (2 steps from 21)
3
5
5
5
7
7
TIPS
TIPS
TIPS
22 (dr = 5:1)
21 (76%)
20 (19%)
reduction of the ozonide with PPh3, and the a-alkoxy ketone 35 was
obtained in 73% yield. Compound 35, which corresponds to the
C8eC13 subunit of PLMs and LSNs, was thus synthesized in seven
Grubbs II (13 mol %)
CH2Cl2, reflux
61%
steps from
b-ketoester 26 (16% overall yield) (Scheme 7).
Scheme 5. RRCM of acrylate 19.
The coupling of the C1eC7 and C8eC13 subunits was attempted.

6362
V. Druais et al. / Tetrahedron 66 (2010) 6358e6375
O
O
O
OH
would lead to the tertiary alcohol at C8 and a convergent approach
toward the C1eC11 subunit of PLMs and LSNs was devised.
Saccharomyces cerevisiae (type II)
9
9
EtO
11
EtO
11
glucose, H2O, EtOH, 30 °C
26
27
TMS
TMS
TMS
13
13
72%
(ee = 92%)
97%
3. Convergent approach toward the C1eC11 subunit of PLMs
and LSNs. Formal synthesis of PLM BRetrosynthetic analysis
TBSCl, imidazole,
DMAP (cat.), CH2Cl2, rt
O
OTBS
O
OTBS
3.1. Retrosynthetic analysis
i-PrMgCl, (MeO)MeNH.HCl
MeO
9
9
11
11
N
Me
EtO
THF, 40 °C to 0 °C
29
28
13
13
TMS
In this revised convergent approach, the C1eC11 subunit of
PLMs and LSNs L was selected as the new target and the formation
of the C7eC8 bond was envisaged by nucleophilic addition of the
acetylenic Grignard reagent M to an a-alkoxy ketone N. This sim-
plification was aimed at reducing the number of steps involved in
95%
I
30 + n-BuLi
66%
PMBO
Et2O, 78 °C to 0 °C
OTBS
30
O
OH OTBS
the preparation of the two subunits prior to the evaluation of the
BH3.SMe2, (S)-32
9
9
11
11
THF, 78 °C
76%
O
PMBO
TMS
13
13
31
PMBO
33
TMS
Nucleophilic addition
(dr > 95:5)
O
OP2 OP3
1
(Cl3C)(PMBO)C=NH
La(OTf)3 (cat.)
toluene, rt
Ph
Ph
7
N
64%
3
9
5
11
B
O
OH
Me
(S)-32
P1O
1) O3, sudan red III
CH2Cl2, 78 °C
L
PMBO
OTBS
PMBO
OTBS
OP2 OP3
O
9
8
11
O
OMgX
9
11
2) Ph3P, 78 °C to rt
PMBO
8
3
O
13
TMS
13
PMBO
35
TMS
34
73%
9
11
+
5
7
MgX
Scheme 7. Synthesis of the C8eC13 subunit.
N
M
P1O
2.4. Coupling attempts between the C1eC7 and C8eC13
subunits
Scheme 9. Retrosynthetic analysis of the C1eC11 subunit.
feasibility of the coupling but the organometallic reagent M still
incorporates the C4 and C5 stereocenters (Scheme 9).
In the previous approach, alkynylsilanes 12 or 13 that are suit-
able precursors of the Grignard reagent M have already been pre-
The alkenyl iodide 25 was subjected to lithium/iodine exchange
(n-BuLi, Et2O, ꢀ78 ꢁC) and the generated alkenyllithium was
transmetallated with MgBr2$OEt2 (ꢀ78 to ꢀ40 ꢁC). Unfortunately,
no addition of the resulting vinylic Grignard reagent to the a-alkoxy
pared. The preparation of the a-alkoxy ketone N (C8eC11 subunit)
ketone 35 took place, even upon warming to rt. Attempts to add the
acetylenic Grignard reagent generated from alkyne 24 (n-BuLi,
Et2O, ꢀ78 ꢁC then MgBr2$OEt2, ꢀ78 to ꢀ40 ꢁC) to ketone 35 were
also unsuccessful (Scheme 8).
In some of these unsuccessful experiments, we noticed that the
recovered ketone 35 had undergone partial epimerization at C9
suggesting that enolization presumably took place as a side-
reaction. The apparent lack of reactivity of ketone 35 toward
Grignard reagents seemed to compromise the development of
a convergent approach toward PLMs and LSNs based on the for-
mation of the C7eC8 bond.
was therefore required and we sought to develop a catalytic
enantioselective route to this compound.
3.2. Synthesis of the C8eC11 subunit
The synthesis of the C8eC11 subunit began with the mono-
protection of propane-1,3-diol (36) as a TBDPS ether followed by
oxidation of the second hydroxyl group with PCC.47 The resulting
aldehyde was treated with the acetylenic organolithium generated
from propargyl trityl ether48 to afford the racemic propargylic al-
cohol (ꢂ)-37 (70%, three steps from 36). Oxidation of (ꢂ)-37 with
MnO2 provided the acetylenic ketone 38 (88%), which underwent
enantioselective reduction catalyzed by (R,R)-Ru-I26 in an i-PrOH/
CH2Cl2 (10:1) mixture. The use of CH2Cl2 as a co-solvent was ne-
cessary to ensure solubilization of the starting material and the
enantiomerically enriched propargylic alcohol 37 (ee¼97%) was
isolated in high yield (89%).27 Conversion of this propargylic alcohol
At this point of our studies, we decided to modify the structures
of the partners involved in the planned coupling reaction that
1) n-BuLi, Et2O, 78 °C
2) MgBr2.OEt2
78 °C to 40 °C
X
OMe
OMe
1
O
PMBO
OTBS
1
O
7
8
7
37 into the a-hydroxyketone 40 formally requires the regioselective
3
5
9
3
5
11
I
hydration of the disubstituted alkyne. However, in the presence of
a metal catalyst or a Brønsted acid, a Meyer/Schuster rearrange-
ment would take place leading to the regioisomeric enone.49 To
formally achieve hydration of 37 with the desired regioselectivity,
a cyclofunctionalization process could be used whereby an appro-
priate nucleophile (generated from the hydroxyl group) would add
across the triple bond through a 5-exo dig process. Thus, alcohol 37
was treated with tosyl isocyanate in the presence of a catalytic
amount of CuI and Et3N (THF, reflux) and the 4-alkylidene-oxazo-
lidin-2-one 39 was obtained in high yield (92%).50,51 It is worth
noting that an alkoxymethyl substituent on the alkyne was per-
fectly tolerated.50 Compound 39 contains an enamide moiety,
which was seen as a suitable precursor for the corresponding
ketone at C8 but its hydrolysis had to be achieved under carefully
PMBO
OTBS
3)
OH
TMS
13
O
PMBO
25
9
11
8
35
13
TMS
TMS
PMBO
78 °C to rt
OMe
1) n-BuLi, Et2O, 78 °C
2) MgBr2.OEt2
78 °C to 40 °C
PMBOX
OMe
1
O
1
O
PMBO
OTBS
3
5
8
5
7
9
3
11
OTBS
3)
7
OH
TMS
13
O
9
24
11
8
PMBO
35
13
PMBO
78 °C to rt
Scheme 8. Coupling attempts between C1eC7 and C8eC13 subunits.

V. Druais et al. / Tetrahedron 66 (2010) 6358e6375
6363
controlled conditions to avoid racemization.52,53 In order to reduce
the concentration of the base in the organic solvent, hydrolysis of
39 was achieved in THF as the solvent in the presence of a 1 M
allylic alcohol at C5 with acryloyl chloride delivered acrylate 45 in
quantitative yield (Scheme 11).
aqueous solution of NaOH. The a-hydroxyketone 40 was isolated in
76% yield with an acceptable optical purity (eeꢃ94%).27 The
hydroxyl group has to be protected in the form of an ether that
would allow the nucleophilic addition to the adjacent carbonyl
group to proceed under chelation control. Attempts to protect the
alcohol at C9 as a PMB ether were unsuccessful under a variety of
different conditions. A MOM ether could not be introduced under
standard conditions (MOMCl, i-Pr2NEt, CH2Cl2) but the reaction
proceeded in almost quantitative yield (99%) in the presence of
DMAP and NaI to afford a
-alkoxy ketone 41.54 This latter compound
(C8eC11 subunit) was thus synthesized in eight steps from pro-
pane-1,3-diol (38% overall yield) (Scheme 10).
1) TBDPSCl, Et3N, CH2Cl2, rt
2) PCC, MS 4Å, AcONa, CH2Cl2, rt
OH OTBDPS
OH OH
11
9
9
11
Li
3)
TrO
, THF, 40 °C to 0 °C
36
( )-37
70% (3 steps from 36)
TrO
TrO
MnO2
CH2Cl2, rt
88%
OH OTBDPS
O
OTBDPS
(R,R)-Ru-I (5 mol %)
11
11
9
9
i-PrOH/CH2Cl2 (10:1), rt
37
(ee = 97%)
38
89%
TrO
TsN=C=O, CuI (1 mol %)
Et3N (5 mol %), THF, reflux
92%
O
OH OTBDPS
O
OTBDPS
aq 1M NaOH
Ts
N
O
11
11
8
THF, rt
76%
8
TrO
40
39
(ee 94%)
MOMCl, i-Pr2NEt
TrO
99%
Ts
DMAP, NaI
CH2Cl2, rt
Ph
Ph
N
Ru
N
MOMO
OTBDPS
Scheme 11. Synthesis of the C1eC11 subunit of PLMs and LSNs. Formal synthesis of
PLM B.
H
O
11
8
(R,R)-Ru-I
41
TrO
Scheme 10. Preparation of the C8eC11 subunit.
The formation of the unsaturated d-lactone moiety has been
previously achieved by classical RCM either with the C8eC9 pro-
tected 1,2-diol in place12 or with a conjugated diene (C6eC9).8
Acrylate 45 was initially treated with Grubbs II catalyst (5 mol %,
CH2Cl2, reflux). After 2 h, the starting material was completely
consumed and a mixture of lactone 46 and acrylate 47, resulting
from truncation of the unsaturated relay, was obtained in a 75:25
ratio. These two compounds were isolated in 65% and 13% yield,
respectively. The use of a higher catalyst loading (17 mol %, suc-
cessive additions every 2 h) and a longer reaction time (reflux, 20 h)
allowed the transformation of acrylate 45 into the desired lactone
46 as the sole product, which was isolated in 88% yield. These re-
sults indicate that the RRCM of acrylate 45 to lactone 46 is a fast
reaction since the latter compound is already obtained as the major
product after only 2 h and using 5 mol % catalyst. By contrast, the
RCM of acrylate 47 is a slower process, which requires a higher
catalyst loading (12 mol % to convert the initially formed 75:25
mixture of 46:47 to 46 exclusively within 12 h).
The trityl group was cleaved by acid-catalyzed methanolysis and
the resulting primary alcohol (77%) was converted into the
corresponding mesylate 48 (85%). Nucleophilic substitution with
NaN3 (DMF, 70 ꢁC) led to azide 49 in 10% yield only since extensive
decomposition was observed. However, under milder conditions
(DMF, rt, 3 days), azide 49 could be obtained in 70% yield.
Staudinger reduction of 49 followed by in situ acylation of the
primary amine with allyl chloroformate provided allyl carbamate
The key coupling reaction with an acetylenic Grignard reagent
corresponding to the C3eC7 subunit was then tested.
3.3. Synthesis of the C1eC11 subunit of PLMs and LSNs.
Formal synthesis of PLM B
The previously prepared propargylic alcohol 13 was desilylated
to afford the terminal alkyne 42 in quantitative yield. This com-
pound was treated with i-PrMgCl (2 equiv, Et2O, ꢀ20 to 0 ꢁC) and
the resulting acetylenic Grignard reagent was condensed with
ketone 41. In this reaction, an excess of the alkyne partner 42 was
conveniently used (3.5 equiv) to ensure complete consumption of
41. Indeed, the use of an alkynyl rather than an alkenyl organo-
metallic species has a significant advantage since the terminal
alkyne precursor of the former can be recovered and recycled after
protonation (adventitious or work-up), whereas the alkenyl halide
precursor cannot. Under these conditions, we were pleased to see
that the desired tertiary alcohol 43 was obtained as a 92:8 mixture
of diastereomers and isolated in good yield (84%). It was reasonable
to assume that the stereochemical outcome was the result of
a Cram-chelate control exerted by the OMOM ether at C9.15
Hydroalumination of the alkyne with Red-Al delivered the allylic
diol 44 (62%)55 and subsequent selective acylation of the secondary

6364
V. Druais et al. / Tetrahedron 66 (2010) 6358e6375
50 (64%), which corresponds to the targeted C1eC11 subunit of
PLMs and LSNs. In order to check the stereochemical assignments
made previously, the MOM and TBDPS ethers in compound 50 were
cleaved by brief hydrolysis under acidic conditions [6 M aq HCl/THF
(1:1), rt, 55%] and all hydroxyl groups of the resulting triol were
silylated with TESOTf to provide the protected triol 51 (73%). The
spectroscopic data of 51 matched with those previously reported
for this key intermediate in the total synthesis of PLM B reported by
Hatakeyama et al.,8 thereby accounting for a formal synthesis of
this natural product (Scheme 11).
In conclusion, we have achieved a formal convergent and cata-
lytic asymmetric synthesis of phoslactomycin B. The diastereo-
selective addition of an alkynyl Grignard reagent to an a-alkoxy
ketone was involved as a key step to create the C8 tertiary alcohol.
The lactone was constructed by a RRCM whereas a [2,3]-Wittig
rearrangement was used to control C4 and C5. A copper-catalyzed
afford 4.81 g (73%) of Weinreb amide 325 as a colorless oil; IR 1661,
1414, 1384, 1177, 1118, 994, 910 cmꢀ1 1H NMR (400 MHz, CDCl3)
;
d
5.81 (ddt, J¼17.1, 10.3, 6.6 Hz, 1H), 5.04 (dq, J¼17.1, 1.5 Hz, 1H), 4.98
(dq, J¼10.3, 1.5 Hz, 1H), 3.68 (s, 3H), 3.18 (s, 3H), 2.43 (t, J¼7.5 Hz,
2H), 2.15e2.08 (m, 2H), 1.75 (apparent quintuplet, J¼7.2 Hz, 2H);
13C NMR (100 MHz, CDCl3)
d 174.5 (s), 138.1 (d), 115.0 (t), 61.2 (q),
33.3 (t), 32.2 (q), 31.1 (t), 23.7 (t); HRMS: MþNaþ, found 180.0991.
C8H15O2NNa requires 180.0995.
4.2.1.2. 2-Allyloxy-N-methoxy-N-methyl-acetamide (4). To a so-
lution of allyloxyacetic acid (2)23 (3.55 g, 30.6 mmol) in CH2Cl2
(55 mL) at ꢀ15 ꢁC were added N-methyl-morpholine (10.1 mL,
91.8 mmol, 3 equiv) and isobutyl chloroformate (6.0 mL, 46 mmol,
1.5 equiv). After 1.5 h at ꢀ15 ꢁC, N,O-dimethylhydroxylamine hy-
drochloride (5.37 g, 55.1 mmol, 1.8 equiv) was added in one por-
tion. After 15 min at 0 ꢁC and 16 h at rt, the reaction mixture was
poured into a saturated aqueous solution of NH4Cl, the layers
were separated and the aqueous phase was extracted with Et2O.
The combined organic extracts were dried over MgSO4, filtered,
and concentrated under reduced pressure. The residue was pu-
rified by flash chromatography on silica gel (petroleum ether/
Et2O: 60/40, 50/50 then petroleum ether/EtOAc: 50/50, 40/60) to
afford 3.95 g (81%) of Weinreb amide 4 as a colorless oil; IR 1677,
cyclofunctionalization allowed to elaborate an
a-hydroxyketone
from a propargylic alcohol. Notably, all the stereocenters originate,
either directly or indirectly, from catalytic enantioselective re-
ductions of acetylenic ketones.
4. Experimental section
4.1. General
1421, 1327, 1148, 1084, 991, 921, 791 cmꢀ1
CDCl3)
;
1H NMR (400 MHz,
5.95 (ddt, J¼17.2, 10.3, 5.8 Hz, 1H), 5.32 (dq, J¼17.2,
d
Infrared (IR) spectra were recorded on a Bruker Tensor 27 (IR-
FT), wavenumbers are indicated in cmꢀ1. Optical rotations were
measured using a Perkin Elmer 343 plarimeter at 25 ꢁC. 1H NMR
spectra were recorded on a Bruker Avance 400 (400 MHz) and
data are reported as follows: chemical shift in parts per million
from tetramethylsilane as an internal standard, multiplicity
(s¼singlet, d¼doublet, t¼triplet, q¼quartet, m¼multiplet or
overlap of non-equivalent resonances), integration. 13C NMR
spectra were recorded in CDCl3 at 75 or 100 MHz and data are
reported as follows: chemical shift in parts per million from
tetramethylsilane with the solvent as an internal indicator (CDCl3,
1.0 Hz, 1H), 5.23 (dq, J¼10.3, 1.0 Hz, 1H), 4.27 (s, 2H), 4.13 (ap-
parent br d, J¼5.8 Hz, 2H), 3.69 (s, 3H), 3.20 (s, 3H); 13C NMR
(100 MHz, CDCl3)
d 170.7 (s), 133.9 (d), 117.5 (t), 72.0 (t), 66.8 (t),
61.2 (q), 32.0 (q); EIMS m/z (relative intensity) 128 (MꢀOMeþ, 2),
103 (100), 86 (29), 74 (48), 73 (43), 71 (63), 60 (21), 58 (12), 56
(12); HRMS: MþNaþ, found 182.0787. C7H13O3NNa requires
182.0788.
4.2.1.3. Dec-9-en-3-yn-5-one
(5). 1-Butyne
gas
(10 mL,
100 mmol, 5.0 equiv) was condensed at ꢀ78 ꢁC and dissolved in
THF (60 mL). The resulting solution was cooled to ꢀ78 ꢁC and
a solution of n-BuLi (20 mL, 2.5 M in hexanes, 50 mmol, 2.5 equiv)
was added dropwise. After 40 min stirring from ꢀ78 to 0 ꢁC, the
resulting but-1-ynyllithium solution was cooled to ꢀ78 ꢁC and
a solution of Weinreb amide 3 (3.18 g, 20.2 mmol) in THF (10 mL)
was added dropwise. After 45 min at ꢀ78 ꢁC, the reaction mixture
was warmed to ꢀ10 ꢁC over 4 h and then poured into an ice-cold
2 M solution of hydrochloric acid. The layers were separated and
the aqueous phase was extracted with Et2O. The combined organic
extracts were dried over MgSO4, filtered, and concentrated under
reduced pressure. The crude material was purified by flash chro-
matography on silica gel (petroleum ether/Et2O: 98/2 to 96/4) to
afford 2.95 g (97%) of ketone 5 as an orange oil; IR 2212, 1670, 1641,
d
77.0 ppm), multiplicity with respect to proton (deduced from
DEPT experiments, s¼quaternary C, d¼CH, t¼CH2, q¼CH3). Mass
spectra with electronic impact (MS-EI) were recorded from
a Hewlett/Packard tandem 5890A GC (12 m capillary column)d
5971 MS (70 eV). THF and diethyl ether were distilled from
sodium/benzophenone.
CH2Cl2,
CH3CN,
toluene,
Et3N,
i-Pr2NH, i-Pr2NEt, pyridine, 2,6-lutidine, i-PrOH, and TMSCl were
distilled from CaH2. Other reagents were obtained from com-
mercial suppliers and used as received. TLC was performed on
silica gel plates and visualized either with a UV lamp (254 nm),
or by using solutions of p-anisaldehyde/H2SO4/AcOH in EtOH or
KMnO4/K2CO3 in water followed by heating. Flash chromatogra-
phy was performed on silica gel (230e400 mesh).
1315, 1238, 1162, 994, 912 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d 5.78
(ddt, J¼17.0, 10.3, 6.7 Hz, 1H), 5.03 (dq, J¼17.0, 1.5 Hz, 1H), 4.99 (dq,
J¼10.3, 1.5 Hz, 1H), 2.54 (t, J¼7.4 Hz, 2H), 2.38 (q, J¼7.5 Hz, 2H),
2.12e2.06 (m, 2H), 1.80e1.74 (m, 2H), 1.21 (t, J¼7.5 Hz, 3H); 13C
4.2. Examination of a convergent approach toward the
C1eC13 subunit of PLMs and LSNs
NMR (100 MHz, CDCl3)
d 188.0 (s), 137.6 (d), 115.3 (t), 95.1 (s), 80.1
4.2.1. Synthesis of the C3eC7 subunit.
(s), 44.6 (t), 32.7 (t), 23.0 (t), 12.7 (t), 12.5 (q); EIMS m/z (relative
intensity) 150 (Mþ, 5), 135 (MꢀMeþ, 19), 121 (13), 107 (12), 96 (59),
81 (100), 67 (11), 53 (47); HRMS: MþNaþ, found 173.0938.
C10H14ONa requires 173.0937.
4.2.1.1. N-methoxy-N-methyhex-5-enamide (3). To a solution of
hex-5-enoic acid (1) (5.2 mL, 44 mmol) in CH2Cl2 (70 mL) at ꢀ15 ꢁC
were added N-methyl-morpholine (14.4 mL, 131 mmol, 3 equiv)
and isobutyl chloroformate (8.5 mL, 66 mmol, 1.5 equiv). After 1.5 h
at ꢀ15 ꢁC, N,O-dimethylhydroxylamine hydrochloride (7.69 g,
78.8 mmol, 1.8 equiv) was added in one portion. After 15 min at
0 ꢁC and 16 h at rt, the reaction mixture was poured into a saturated
aqueous solution of NH4Cl, the layers were separated and the
aqueous phase was extracted with Et2O. The combined organic
extracts were dried over MgSO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash chromatogra-
phy on silica gel (petroleum ether/Et2O gradient: 80/20 to 40/60) to
4.2.1.4. 1-(Allyloxy)hex-3-yn-2-one (6). 1-Butyne gas (10 mL,
129 mmol, 6.5 equiv) was condensed at ꢀ78 ꢁC and dissolved in
THF (60 mL). The resulting solution was cooled to ꢀ78 ꢁC and
a solution of n-BuLi (20 mL, 2.5 M in hexanes, 50 mmol, 2.8 equiv)
was added dropwise. After 40 min stirring from ꢀ78 to 0 ꢁC, the
resulting but-1-ynyllithium solution was cooled to ꢀ78 ꢁC and
a solution of Weinreb amide 4 (3.19 g, 20.0 mmol) in THF (15 mL)
was added dropwise. After 45 min at ꢀ78 ꢁC, the reaction mixture

V. Druais et al. / Tetrahedron 66 (2010) 6358e6375
6365
was warmed to ꢀ40 ꢁC and then poured into an ice-cold 2 M so-
lution of hydrochloric acid. The layers were separated and the
aqueous phase was extracted with EtOAc. The combined organic
extracts were dried over MgSO4, filtered, and concentrated under
reduced pressure. The crude material was purified by flash chro-
matography on silica gel (petroleum ether/EtOAc: 90/10) to afford
2.68 g (88%) of ketone 6 as a yellow oil; IR 2207, 1689, 1671, 1422,
rt, the reaction mixture was filtered through Celite (EtOAc) and the
filtrate was hydrolyzed with a saturated aqueous solution of NH4Cl.
The layers were separated and the aqueous phase was extracted
with EtOAc. The combined organic extracts were dried over MgSO4,
filtered, and concentrated under reduced pressure. The crude ma-
terial was purified by flash chromatography on silica gel (petroleum
ether/EtOAc gradient: 70/30 to 60/40) to afford 502 mg (96%) of the
1315, 1228, 1183, 1126, 1065, 992, 927, 786 cmꢀ1
(400 MHz, CDCl3)
;
1H NMR
(Z)-allylic alcohol 9 as a yellow oil; [
3407, 1648, 1461, 1422, 1304, 1104, 1066, 996, 923, 892, 797,
736 cmꢀ1 1H NMR (400 MHz, CDCl3)
a
]
ꢀ63.1 (c 0.47, CHCl3); IR
D
d
5.92 (ddt, J¼17.0, 10.4, 5.8 Hz, 1H), 5.32 (dq,
J¼17.0, 1.5 Hz, 1H), 5.24 (dq, J¼10.4, 1.5 Hz, 1H), 4.19 (s, 2H), 4.10 (br
;
d
5.92 (ddt, J¼17.2, 10.3,
d, J¼5.8 Hz, 2H), 2.41 (q, J¼7.5 Hz, 2H), 1.22 (t, J¼7.5 Hz, 3H); 13C
5.7 Hz, 1H), 5.56 (dtd, J¼11.0, 7.4, 1.5 Hz, 1H), 5.35e5.26 (m, 2H),
5.20 (dq, J¼10.3,1.5 Hz,1H), 4.65 (m,1H), 4.04 (dt, J¼5.7,1.5 Hz, 2H),
3.42 (dd, J¼9.7, 3.4 Hz, 1H), 3.32 (dd, J¼9.7, 8.4 Hz, 1H), 2.44 (br s,
1H, OH), 2.19e2.04 (m, 2H), 0.99 (t, J¼7.5 Hz, 3H); 13C NMR
NMR (100 MHz, CDCl3)
d 184.9 (s), 133.5 (d), 117.8 (t), 98.2 (s), 77.7
(s), 75.5 (t), 72.1 (t), 12.5 (t), 12.4 (q); HRMS: MþNaþ, found
175.0763. C9H12O2Na requires 175.0730.
(100 MHz, CDCl3)
d 135.6 (d), 134.4 (d), 127.2 (d), 117.2 (t), 73.9 (t),
4.2.1.5. (S)-Dec-9-en-3-yn-5-ol (7). To a solution of ketone 5
(731 mg, 4.86 mmol) in i-PrOH (48 mL) was added freshly prepared
Noyori’s catalyst (S,S)-Ru-I26 (147 mg, 0.245 mmol, 0.05 equiv).
After 1 h at rt, the reaction mixture was concentrated under re-
duced pressure. The residue was purified by flash chromatography
on silica gel (petroleum ether/Et2O: 80/20) to afford 236 mg (32%)
of alcohol 7 as a pale brown oil (ee¼81%). The ee value was de-
termined by analysis of the corresponding p-nitrobenzoate by
super-critical fluid chromatography (SFC) on chiral stationary
72.1 (t), 66.7 (d), 21.2 (t), 14.2 (q); EIMS m/z (relative intensity) 138
(MꢀH2Oþ, 46), 109 (10), 99 (21), 97 (24), 85 (100), 81 (49), 67 (88),
57 (59), 53 (23); HRMS: MþNaþ, found 179.1038. C9H16O2Na re-
quires 179.1043.
4.2.1.8. (Z)-(R)-1-Allyloxy-2-(prop-2-ynyloxy)hex-3-ene (52).
O
O
phase;27
[
;
a
]
ꢀ0.2 (c 1.23, CHCl3); IR 3326, 1640, 1318, 1065, 993,
909 cmꢀ1
1DH NMR (400 MHz, CDCl3)
d
5.81 (ddt, J¼17.0 Hz, 10.3,
6.6 Hz, 1H), 5.03 (dq, J¼17.0, 1.5 Hz, 1H), 4.97 (m, 1H), 4.36 (m, 1H),
2.22 (qd, J¼7.5, 2.0 Hz, 2H), 2.10 (apparent dt, J¼7.0, 1.5 Hz, 2H), 1.89
(br s, 1H, OH), 1.75e1.63 (m, 2H), 1.62e1.51 (m, 2H), 1.14 (t, J¼7.5 Hz,
52
3H); 13C NMR (100 MHz, CDCl3)
d 138.5 (d), 114.7 (t), 86.9 (s), 80.5
(s), 62.5 (d), 37.5 (t), 33.3 (t), 24.4 (t), 13.8 (q), 12.3 (t); EIMS m/z
(relative intensity) 137 (MꢀMeþ, 8), 123 (16), 119 (9), 109 (21), 105
(30), 91 (36), 83 (100), 79 (32), 67 (14), 55 (47); HRMS: MþLiþ,
found 159.1353. C10H16OLi requires 159.1356.
To a solution of alcohol 9 (830 mg, 5.32 mmol) in toluene (5 mL)
were added a 35% aqueous solution of NaOH (5 mL), propargyl
bromide (650 mL, 80% solution in toluene, 5.85 mmol, 1.1 equiv),
4.2.1.6. (R)-1-(Allyloxy)hex-3-yn-2-ol (8). To
a
solution of
and n-Bu4NHSO4 (885 mg, 2.66 mmol, 0.5 equiv). After 16 h of
vigorous stirring at rt, Et2NH (5 mL) was added. The reaction mix-
ture was stirred for a further 1 h, poured onto ice, cautiously neu-
tralized by addition of a 3 M solution of hydrochloric acid and
extracted with EtOAc. The combined organic extracts were washed
with brine, dried over MgSO4, filtered, and concentrated under
reduced pressure. The crude material was purified by flash chro-
matography on silica gel (pentane/Et2O: 95/5) to afford 854 mg
(83%) of propargyl ether 52 as a colorless oil; [Found: C, 74.21; H,
ketone 6 (2.04 g, 13.4 mmol) in i-PrOH (134 mL) was added
freshly prepared Noyori’s catalyst (S,S)-Ru-I26 (403 mg,
0.672 mmol, 0.05 equiv). After 45 min at rt, the reaction mixture
was concentrated under reduced pressure. The residue was pu-
rified by flash chromatography on silica gel (petroleum ether/
Et2O gradient: 70/30 to 60/40) to afford 2.00 g (97%) of alcohol 8
as a pale brown oil (ee¼91%). The ee value was determined by
analysis of the corresponding p-nitrobenzoate by super-critical
fluid chromatography (SFC) on chiral stationary phase;27
ꢀ11.6 (c 1.07, CHCl3); IR 3396, 1646, 1422, 1319, 1141, 1106, 1070,
992, 924, 883, 780, 733 cmꢀ1 1H NMR (400 MHz, CDCl3)
5.91
[a
]
9.41. C12H18O2 requires C, 74.19; H, 9.41%]; [
IR 3301, 2215, 1648, 1460, 1442, 1360, 1243, 1079, 993, 921, 748, 664,
627 cmꢀ1 1H NMR (400 MHz, CDCl3)
a
]D ꢀ127 (c 1.00, CHCl3);
D
;
d
;
d
5.92 (ddt, J¼17.3, 10.3,
(ddt, J¼17.0 Hz, 10.4, 5.4 Hz, 1H), 5.30 (dq, J¼17.0, 1.5 Hz, 1H), 5.21
(dq, J¼10.4, 1.5 Hz, 1H), 4.54 (m, 1H), 4.07 (dm, apparent br d,
J¼5.4 Hz, 2H), 3.60 (dd, J¼10.0, 3.4 Hz, 1H), 3.49 (dd, J¼10.0,
8.0 Hz, 1H), 2.43 (d, J¼4.2 Hz, 1H, OH), 2.22 (qd, J¼7.5, 2.0 Hz, 2H),
5.7 Hz, 1H), 5.72 (dtd, J¼11.0, 7.6, 0.7 Hz, 1H), 5.30e5.16 (m, 3H),
4.59 (m, 1H), 4.24 (dd, J¼15.8, 2.5 Hz, 1H), 4.10 (dd, J¼15.9, 2.5 Hz,
1H), 4.06e4.03 (m, 2H), 3.54 (dd, J¼10.5, 6.7 Hz, 1H), 3.44 (dd,
J¼10.5, 4.0 Hz, 1H), 2.40 (t, J¼2.5 Hz, 1H), 2.26e2.08 (m, 2H), 1.01 (t,
1.14 (t, J¼7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d
134.2 (d), 117.4
J¼7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 137.9 (d),134.7 (d),125.3
(t), 87.7 (s), 77.0 (s), 73.9 (t), 72.2 (t), 61.6 (d), 13.6 (q), 12.3 (t);
EIMS m/z (relative intensity) 139 (MꢀMeþ, 1), 136 (MꢀH2Oþ, 1.5),
125 (MꢀEtþ, 5), 98 (14), 95 (10), 83 (100), 81 (9), 79 (8), 71 (12),
69 (12), 67 (8), 55 (45), 53 (15); HRMS: MþLiþ, found 161.1147.
C9H14O2Li requires 161.1149.
(d), 117.0 (t), 80.1 (s), 73.9 (d), 72.8 (t), 72.7 (d), 72.3 (t), 55.2 (t), 21.2
(t), 14.2 (q); EIMS m/z (relative intensity) 165 (MꢀEtþ, 0.1), 124 (9),
123 (MꢀAllylOCHþ2 , 100), 95 (12), 83 (39), 81 (29), 79 (8), 77 (7), 67
(19), 55 (26) 53 (8).
4.2.1.9. {3-[(Z)-(R)-1-(Allyloxymethyl)pent-2-enyloxy]prop-1-
ynyl}trimethylsilane (10). To a solution of propargyl ether 52
(834 mg, 4.29 mmol) in THF (20 mL) at ꢀ78 ꢁC was added LDA
(7.5 mL, from a freshly prepared 0.62 M stock solution in THF/
4.2.1.7. (Z)-(R)-1-(Allyloxy)hex-3-en-2-ol (9). To a suspension of
Zn dust (5.1 g, 78 mmol, 23.3 equiv) in i-PrOH was added
1,2-dibromoethane (0.64 mL, 7.4 mmol, 2.2 equiv) and the resulting
mixture was heated at reflux for 15 min. A solution of CuBr (1.44 g,
10.1 mmol, 3.0 equiv) and LiBr (1.54 g, 17.8 mmol, 5.3 equiv) in THF
(20 mL) was then added slowly. After 20 min heating at reflux,
a solution of the propargylic alcohol 8 (517 mg, 3.35 mmol) in
i-PrOH (15 mL) was added dropwise. After 8 h at reflux, and 10 h at
hexanes, 4.7 mmol, 1.1 equiv). After 1 h at 0 ꢁC, TMSCl (712
mL,
5.57 mmol, 1.3 equiv) was added. After 1 h at 0 ꢁC, the reaction
mixture was poured into a saturated aqueous solution of NH4Cl.
The layers were separated and the aqueous phase was extracted
with Et2O. The combined organic extracts were washed with

6366
V. Druais et al. / Tetrahedron 66 (2010) 6358e6375
brine, dried over MgSO4, filtered, and concentrated under re-
duced pressure. The crude material was purified by flash chro-
matography on silica gel (pentane/Et2O: 96/4) to afford 966 mg
(84%, 70% for the two steps from alcohol 9) of the propargylic
ether 10 as a colorless oil; [Found: C, 67.66; H, 10.04. C15H26O2Si
(MꢀAllylꢀH2Oþ, 0.4), 193 (1), 179 (2), 127 (7), 111 (13), 99 (18), 83
(21), 82 (100), 73 (15), 67 (33), 55 (9); HRMS: MþNaþ, found
289.1594. C15H26O2NaSi requires 289.1594.
4.2.1.12. (E)-(3R,4S)-7-Allyloxy-4-ethyl-1-(triisopropylsilyl)hept-
5-en-1-yn-3-ol (13). To a solution of ether 11 (3.09 g, 8.80 mmol)
in THF (88 mL) at ꢀ78 ꢁC was added dropwise a solution of n-BuLi
(5.26 mL, 2.5 M in hexanes, 10.6 mmol, 1.5 equiv). After 1 h at
ꢀ78 ꢁC, the reaction mixture was poured into a saturated aqueous
solution of NH4Cl. The layers were separated and the aqueous
phase was extracted with Et2O. The combined organic extracts
were dried over MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash chromatography on
silica gel (petroleum ether/Et2O gradient: 90/10 to 70/30) to afford
3.09 g (99%) of propargylic alcohol 13 as a colorless oil; [Found: C,
requires C, 67.61; H, 9.84%]; [
1648, 1250, 1081, 1012, 989, 923, 840, 759 cmꢀ1
(400 MHz, CDCl3)
a
]
ꢀ129.0 (c 1.08, CHCl3); IR 2173,
D
;
1H NMR
d
5.92 (ddt, J¼17.4, 10.5, 5.6 Hz, 1H), 5.71 (dtd,
J¼11.0, 7.8, 0.7 Hz, 1H), 5.30e5.16 (m, 3H), 4.61 (ddd, J¼6.5, 4.0,
0.7 Hz, 1H), 4.24 (d, AB syst, J¼16.0 Hz, 1H), 4.12 (d, AB syst,
J¼16.0 Hz, 1H), 4.04 (dt, J¼5.6, 1.4 Hz, 2H), 3.55 (dd, J¼10.5,
6.6 Hz, 1H), 3.44 (dd, J¼10.5, 4.1 Hz, 1H), 2.28e2.08 (m, 2H), 1.01
(t, J¼7.5 Hz, 3H), 0.17 (s, 9H); 13C NMR (100 MHz, CDCl3)
d 137.9
(d), 134.8 (d), 125.5 (d), 117.0 (t), 102.0 (s), 90.9 (s), 72.8 (t), 72.3
(2C, dþt), 56.0 (t), 21.2 (t), 14.3 (q), ꢀ0.2 (q, 3C); EIMS m/z (rel-
ative intensity) 195 (MꢀAllylOCHþ2 , 43), 121 (20), 111 (73), 85 (17),
83 (100), 75 (37), 73 (62), 55 (16).
71.63; H, 11.28. C21H38O2Si requires C, 71.94; H, 10.92%]; [
(c 0.62, CHCl3); IR 1462, 1018, 996, 973, 919, 882, 674 cmꢀ1
NMR (400 MHz, CDCl3)
(dd, J¼15.4, 5.4 Hz, 1H), 5.73e5.63 (m, 1H), 5.28 (dq, J¼17.2, 1.5 Hz,
1H), 5.18 (dq, J¼10.4, 1.5 Hz, 1H), 4.35 (dd, J¼8.2, 4.7 Hz, 1H),
4.04e3.94 (m, 4H), 2.23 (m, 1H), 2.10 (br d, J¼8.2 Hz, 1H, OH),
1.65e1.55 (m, 1H), 1.50e1.39 (m, 1H), 1.07 (m, apparent br s,
a
]
D þ52.6
1H
5.92 (ddt, J¼17.2, 10.3, 5.7 Hz, 1H), 5.73
;
d
4.2.1.10. 3-{(Z)-(R)-1-[(Allyloxymethyl)pent-2-enyloxy]prop-1-
ynyl}triisopropylsilane (11). To a solution of alcohol 9 (2.28 g,
14.6 mmol) in THF (25 mL) at 0 ꢁC were successively added t-BuOK
(2.46 g, 21.9 mmol, 1.5 equiv) and (triisopropylsilyl)propargyl bro-
mide29 (4.42 g, 16.1 mmol, 1.1 equiv). After 0.5 h at 0 ꢁC, the re-
action mixture was poured into a saturated aqueous solution of
NH4Cl. The layers were separated and the aqueous phase was
extracted with Et2O. The combined organic extracts were dried
over MgSO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash chromatography on silica gel
(petroleum ether/Et2O: 98/2) to afford 4.47 g (87%) of the pro-
pargylic ether 11 as a yellow oil; [Found: C, 71.87; H, 10.97.
18Hþ3H), 0.91 (t, J¼7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 134.7
(d), 132.5 (d), 130.9 (d), 117.0 (t), 106.6 (s), 86.7 (s), 70.9 (t), 70.5 (t),
65.4 (d), 51.0 (d), 24.0 (t), 18.5 (q, 6C), 11.8 (q), 11.1 (d, 3C); EIMS m/z
(relative intensity) 289 (MꢀH2Oꢀi-Prþ, 1), 249 (6), 210 (5), 168
(10), 167 (59), 167 (59), 139 (46), 131 (14), 127 (12), 125 (16), 111
(72), 103 (22), 99 (16), 97 (28), 85 (15), 83 (48), 82 (100), 75 (25),
69 (20), 67 (38).
C21H38O2Si requires C, 71.94; H, 10.92%]; [
IR 1462,1073, 987, 920, 882, 797, 748, 676 cmꢀ1; 1H NMR (400 MHz,
CDCl3)
a
]
D ꢀ113.9 (c 0.53, CHCl3);
4.2.1.13. (E)-(1R
*
,2S )-5-Allyloxy-2-ethyl-1-(trimethylsilyl-
*
ethynyl)pent-3-enyl acrylate (ꢂ)-(14). To a solution of alcohol
(ꢂ)-12 (635 mg, 2.38 mmol) (synthesized from the racemic alcohol
(ꢂ)-8 prepared by reduction of acetylenic ketone 6 with DIBAL-H,
see Supplementary data) in CH2Cl2 (25 mL) were added DMAP
(87 mg, 0.71 mmol, 0.3 equiv) and i-Pr2NEt (1.24 mL, 7.12 mmol,
3.0 equiv). The resulting mixture was cooled to ꢀ78 ꢁC and acryloyl
d
5.90 (ddt, J¼17.2, 10.4, 5.6 Hz, 1H), 5.71 (dtd, J¼11.0, 7.5,
0.8 Hz, 1H), 5.29e5.20 (m, 2H), 5.16 (dq, J¼10.4, 1.4 Hz, 1H), 4.70 (m,
1H), 4.27 (d, AB syst, J¼16.2 Hz, 1H), 4.14 (d, AB syst, J¼16.2 Hz, 1H),
4.04 (dt, J¼5.6, 1.4 Hz, 2H), 3.55 (dd, J¼10.6, 6.6 Hz, 1H), 3.46 (dd,
J¼10.6, 4.0 Hz, 1H), 2.28e2.10 (m, 2H), 1.08 (m, apparent br s,
18Hþ3H), 1.00 (t, J¼7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d
137.7
chloride (388 mL, 4.77 mmol, 2 equiv) was added dropwise. After
(d), 134.8 (d), 125.5 (d), 116.7 (t), 103.9 (s), 86.8 (s), 72.6 (t), 72.1 (t),
71.8 (d), 55.7 (t), 21.1 (t), 18.5 (q, 6C), 14.3 (q), 11.1 (d, 3C); EIMS m/z
(relative intensity) 280 (23), 279 (MꢀAllylOCHþ2 , 100), 237 (16), 195
(35), 169 (26), 153 (69), 139 (40), 125 (34), 11 (43), 103 (33), 97 (29),
83 (34), 75 (35), 59 (29).
3 h at ꢀ78 ꢁC, the reaction mixture was poured into a saturated
aqueous solution of NH4Cl. The layers were separated and the
aqueous phase was extracted with Et2O. The combined organic
extracts were washed with brine, dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude material was
purified by flash chromatography on silica gel (petroleum ether/
Et2O: 94/6) to afford 557 mg (73%) of acrylate (ꢂ)-14 as a colorless
oil; IR 1741, 1250, 1162, 1129, 1094, 1048, 990, 973, 920, 841,
4.2.1.11. (E)-(3R,4S)-7-Allyloxy-4-ethyl-1-(trimethylsilyl)hept-5-
en-1-yn-3-ol (12). To a solution of ether 10 (266 mg, 1.00 mmol) in
THF (10 mL) at ꢀ78 ꢁC, was added dropwise a solution of n-BuLi
(0.40 mL, 2.5 M in hexanes,1.0 mmol,1.0 equiv). After 1 h at ꢀ78 ꢁC,
the reaction mixture was poured into a saturated aqueous solution
of NH4Cl. The layers were separated and the aqueous phase was
extracted with Et2O. The combined organic extracts were washed
with brine, dried over MgSO4, filtered, and concentrated under
reduced pressure. Analysis of the residue by 1H NMR indicated the
formation of a single detectable diastereomer. After purification by
flash chromatography on silica gel (pentane/Et2O: 80/20), 239 mg
(90%) of the propargylic alcohol 12 were isolated as a colorless oil;
760 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
6.43 (dd, J¼17.3, 1.3 Hz, 1H),
6.13 (dd, J¼17.3,10.5 Hz,1H), 5.92 (ddt, J¼17.2,10.5, 5.6 Hz,1H), 5.85
(dd, J¼10.5, 1.3 Hz, 1H), 5.66e5.67 (m, 2H), 5.47 (d, J¼5.2 Hz, 1H),
5.28 (dq, J¼17.2, 1.5 Hz, 1H), 5.18 (dd, J¼10.5, 1.5 Hz, 1H), 4.01e3.99
(m, 2H), 3.98 (dt, J¼5.6, 1.5 Hz, 2H), 2.36 (m, 1H), 1.67e1.57 (m, 1H),
1.47e1.36 (m, 1H), 0.92 (t, J¼7.4 Hz, 3H), 0.17 (s, 9H); 13C NMR
(100 MHz, CDCl3) d 164.9 (s), 134.8 (d), 131.9 (d), 131.4 (t), 130.0 (d),
128.1 (d), 116.9 (t), 100.7 (s), 91.9 (s), 70.5 (t), 70.4 (t), 67.1 (d), 48.0
(d), 23.6 (t), 11.6 (q), ꢀ0.25 (q, 3C); HRMS: MþNaþ, found 343.1698.
C18H28O3NaSi requires 343.1700.
[
a]
þ73.5 (c 1.19, CHCl3); IR 3402, 2170, 1647, 1455, 1379, 1249,
D
1087, 1029, 974, 919, 839, 759, 699 cmꢀ1; 1H NMR (400 MHz, CDCl3)
4.2.1.14. RRCM of acrylate (ꢂ)-14. To a refluxing solution of
acrylate (ꢂ)-14 (45 mg, 0.14 mmol) in CH2Cl2 (10 mL) was added
Grubbs II catalyst (2 mg, 0.002 mmol, 2 mol %). Three additional
portions of the catalyst (2 mg, 0.002 mmol, 2 mol %) were added at
1 h interval. After a total duration of 4 h heating at reflux, the re-
action mixture was cooled to rt and evaporated under reduced
pressure. Analysis of the crude material by 1H NMR showed the
formation of an equimolar mixture of truncated acrylate (ꢂ)-17 and
lactone (ꢂ)-18. After purification by flash chromatography on silica
d
5.93 (ddt, J¼17.2, 10.5, 5.6 Hz, 1H), 5.71 (dt, J¼15.5, 5.7 Hz, 1H),
5.61 (dd, J¼15.5, 9.0 Hz, 1H), 5.29 (dq, J¼17.2, 1.6 Hz, 1H), 5.19 (dq,
J¼10.5, 1.4 Hz, 1H), 4.31 (dd, J¼7.9, 4.9 Hz, 1H), 4.05e3.95 (m, 4H),
2.21 (m, 1H), 2.11 (d, J¼8.2 Hz, 1H, OH), 1.64e1.53 (m, 1H), 1.46e1.35
(m, 1H), 0.91 (t, J¼7.5 Hz, 3H), 0.17 (s, 9H); 13C NMR (100 MHz,
CDCl3)
d 134.7 (d), 132.3 (d), 130.9 (d), 117.0 (t), 104.8 (s), 90.7 (s),
70.8 (t), 70.4 (t), 65.4 (d), 50.9 (d), 23.7 (t), 11.8 (q), ꢀ0.16 (q, 3C);
EIMS m/z (relative intensity) 225 (MꢀAllylþ, 0.1), 207

V. Druais et al. / Tetrahedron 66 (2010) 6358e6375
6367
gel (pentane/Et2O: 4/1 to 2/1), 11.5 mg (33%) of acrylate (ꢂ)-17 and
11 mg (35%) of lactone (ꢂ)-18 were isolated as colorless oils. Similar
results were obtained if the RRCM of (ꢂ)-14 was conducted in
toluene at 80 ꢁC or if Ti(Oi-Pr)4 (30 mol %) was added prior to
Grubbs II catalyst.
catalyst (12 mg, 0.014 mmol, 2 mol %) and the reaction mixture was
heated to reflux. Additional portions of the catalyst (12 mg,
0.014 mmol, 0.02 equiv) were added every 2 h (total quantity of
catalyst used: 48 mg, 0.057 mmol, 8 mol %). After 9 h at reflux, the
reaction mixture was cooled to rt and evaporated under reduced
pressure. The residue was purified by flash chromatography on
silica gel (petroleum ether/Et2O gradient: 99/1 to 80/20) to afford
46 mg (19%) of acrylate 20 as a colorless oil and 166 mg (76%) of
lactone 21 as a brown oil.
4.2.1.15. (1R
acrylate (ꢂ)-(17). IR 2181, 1729, 1636, 1405, 1251, 1182, 1126, 1044,
984, 918, 842, 808, 760 cmꢀ1 1H NMR (400 MHz, CDCl3)
6.44
*
,2S
*
)-2-Ethyl-1-(trimethylsilylethynyl)but-3-enyl
;
d
(dd, J¼17.3, 1.5 Hz, 1H), 6.14 (dd, J¼17.3, 10.5 Hz, 1H), 5.85 (dd,
J¼10.5, 1.5 Hz, 1H), 5.74 (ddd, J¼17.0, 10.2, 9.0 Hz, 1H), 5.48 (d,
J¼5.1 Hz, 1H), 5.17 (dd, J¼10.2, 1.8 Hz, 1H), 5.09 (dd, J¼17.0, 1.8 Hz,
1H), 2.32 (m, 1H), 1.65e1.57 (m, 1H), 1.44e1.37 (m, 1H), 0.91 (t,
4.2.1.19. (1R,2S)-2-Ethyl-1-[(triisopropylsilyl)ethynyl]-but-3-enyl
acrylate (20). [
1260, 1180, 1126, 1042, 984, 917, 882, 807, 675 cmꢀ1
(400 MHz, CDCl3)
a
]
D þ83.7 (c 0.43, CHCl3); IR 1730, 1636, 1462, 1404,
;
1H NMR
J¼7.4 Hz, 3H), 0.17 (s, 9H); 13C NMR (100 MHz, CDCl3)
d
165.0 (s),
d
6.43 (dd, J¼17.3, 1.3 Hz, 1H), 6.13 (dd, J¼17.3,
136.7 (d), 131.4 (t), 128.2 (d), 118.0 (t), 100.6 (s), 91.9 (s), 67.2 (d),
49.5 (d), 23.4 (t), 11.6 (q), ꢀ0.22 (q, 3C); EIMS m/z (relative in-
tensity) 250 (Mþ, 0.3), 249 (MꢀHþ, 2), 235 (MꢀMeþ, 2), 221
(MꢀEtþ, 2), 181 (21), 163 (9), 129 (14), 111 (5), 83 (7), 75 (7), 73
(26), 55 (100); HRMS: MþNaþ, found 273.1285. C14H22O2NaSi
requires 273.1281.
10.4 Hz, 1H), 5.84 (dd, J¼10.4, 1.3 Hz, 1H), 5.77 (ddd, J¼17.1, 10.2,
9.0 Hz, 1H), 5.50 (d, J¼5.2 Hz, 1H), 5.15 (dd, J¼10.3, 1.5 Hz, 1H), 5.09
(dd, J¼17.1, 1.5 Hz, 1H), 2.36e2.30 (m, 1H), 1.70e1.61 (m, 1H),
1.50e1.38 (m, 1H), 1.06 (m, apparent br s, 18Hþ3H), 0.92 (t,
J¼7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 165.0 (s), 136.9 (d), 131.1
(t), 128.3 (d), 117.8 (t), 102.6 (s), 88.0 (s), 67.3 (d), 49.5 (d), 23.6 (t),
18.5 (q, 6C), 11.5 (q), 11.4 (d, 3C); EIMS m/z (relative intensity) 291
(Mꢀi-Prþ, 6), 185 (100), 157 (6), 55 (12); HRMS: MþNaþ, found
357.2217. C20H34O2NaSi requires 357.2220.
4.2.1.16. (5S
dropyran-2-one (ꢂ)-(18). IR 2176, 1731, 1249, 1234, 1218, 1069,
1057, 1017, 841, 822, 760 cmꢀ1 1H NMR (400 MHz, CDCl3)
6.81
*
,6R )-5-Ethyl-6-(trimethylsilylethynyl)-5,6-dihy-
*
;
d
(ddd, J¼9.9, 4.0, 0.4 Hz, 1H), 6.03 (dd, J¼9.9, 1.9 Hz, 1H), 5.18 (d,
J¼4.9 Hz, 1H), 2.60e2.54 (m, 1H), 1.86e1.76 (m, 1H), 1.71e1.60 (m,
1H), 1.04 (t, J¼7.4 Hz, 3H), 0.17 (s, 9H); 13C NMR (100 MHz, CDCl3)
4.2.1.20. (5S,6R)-5-Ethyl-6-[(triisopropylsilyl)ethynyl]-5,6-dihy-
dro-pyran-2-one (21). [Found: C, 70.53; H, 9.86. C18H30O2Si re-
quires C, 70.53; H, 9.87%]; [
1381, 1233, 1216, 1159, 1102, 1058, 1015, 996, 882, 847, 821, 732,
676 cmꢀ1; 1H NMR (400 MHz, CDCl3)
a]
D þ52.4 (c 0.52, CHCl3); IR 1732, 1461,
d
162.8 (s), 148.7 (d), 120.5 (d), 98.5 (s), 93.9 (s), 71.3 (d), 39.0 (d),
22.7 (t), 11.0 (q), ꢀ0.4 (q, 3C); EIMS m/z (relative intensity) 222
(Mþ, 0.1), 192 (4), 179 (5), 164 (4), 163 (25), 149 (4), 137 (5), 135 (7),
119 (4), 111 (5), 97 (10), 96 (100), 95 (6), 81 (53), 75 (13), 73 (12), 67
(10), 53 (13); HRMS: MþNaþ, found 245.0966. C12H18O2NaSi re-
quires 245.0968.
d
6.75 (ddd, J¼9.9, 3.5, 0.9 Hz,
1H), 6.04 (dd, J¼9.9, 2.1 Hz, 1H), 5.21 (dd, J¼5.1, 0.9 Hz, 1H),
2.68e2.61 (m, 1H), 1.86e1.77 (m, 1H), 1.75e1.65 (m, 1H), 1.05 (m,
apparent br s, 18Hþ3H), 1.04 (t, J¼7.5 Hz, 3H); 13C NMR (100 MHz,
CDCl3)
d 162.9 (s), 148.6 (d), 120.5 (d), 100.5 (s), 90.3 (s), 71.3 (d),
39.1 (d), 23.0 (t), 18.5 (q, 6C), 11.0 (dþq, 3Cþ1C); EIMS m/z (relative
intensity) 263 (Mꢀi-Prþ, 40), 263 (40), 221 (100), 193 (13), 177 (26),
165 (32), 149 (16), 137 (13), 111 (10), 81 (10), 75 (12), 59 (10).
4.2.1.17. (E)-(1R,2S)-5-Allyloxy-2-ethyl-1-[(triisopropylsilyl)ethy-
nyl]pent-3-enyl acrylate (19). To a solution of propargylic alcohol 13
(71 mg, 0.20 mmol) in CH2Cl2 (1.5 mL) were added DMAP (7.5 mg,
0.060 mmol, 0.3 equiv) and i-Pr2NEt (0.09 mL, 0.5 mmol, 2.4 equiv).
The reaction mixture was cooled to ꢀ78 ꢁC and acryloyl chloride
(0.02 mL, 0.2 mmol, 1 equiv) was added dropwise. After 1 h at
ꢀ78 ꢁC, more i-Pr2NEt (0.09 mL, 0.5 mmol, 2.4 equiv) and acryloyl
chloride (0.02 mL, 0.2 mmol, 1 equiv) were added. After 1 h at
ꢀ78 ꢁC, the reaction mixture was poured into brine. The layers
were separated and the aqueous phase was extracted with EtOAc.
The combined organic extracts were dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude material was
purified by flash chromatography on silica gel (petroleum ether/
Et2O: 90/10) to afford 79 mg (97%) of acrylate 19 as a colorless oil;
[Found: C, 71.64; H, 10.35. C24H40O3Si requires C, 71.23; H, 9.96%];
4.2.1.21. RCM of acrylate 20. To a solution of acrylate 20 (18 mg,
0.054 mmol) in CH2Cl2 (5.5 mL) was added Grubbs II catalyst (2 mg,
0.002 mmol, 0.05 equiv) and the reaction mixture was heated at
reflux. Additional portions of the catalystwereadded every 3 h(total
quantity of catalyst used: 6 mg, 0.08 mmol, 13 mol %). After a total
duration of 11 h heating at reflux, the reaction mixture was cooled to
rt and evaporated under reduced pressure. The residue was purified
by flash chromatography on silica gel (petroleum ether/Et2O: 80/20)
to afford 10 mg (61%) of lactone 21 as a brown oil.
4.2.1.22. [(E)-(3R,4S)-7-Allyloxy-4-ethyl-3-((1RS)-1-methoxy-
allyloxy)hept-5-en-1-ynyl]-triisopropylsilane (23). To a solution of
alcohol 13 (77 mg, 0.22 mmol) in C6H6 (20 mL) were added acrolein
dimethyl acetal (0.13 mL, 1.1 mmol, 5 equiv) and PPTS (6.0 mg,
0.02 mmol, 0.1 equiv). The resulting mixture was heated at reflux
with azeotropic removal of MeOH (using a small Dean/Stark ap-
paratus filled with activated 3 Å molecular sieves). After 7 h, the
reaction mixture was poured into water, the layers were separated
and the aqueous phase was extracted with Et2O. The combined
organic extracts were washed with brine, dried over MgSO4, fil-
tered, and concentrated under reduced pressure. The crude mate-
rial was purified by flash chromatography on silica gel (petroleum
ether/Et2O gradient: 98/2 to 95/5) to afford 65 mg (71%) of acetal 23
as a colorless oil (1:1 mixture of diastereomers); IR 1648, 1462,
1365, 1073, 1028, 983, 920, 882, 675 cmꢀ1; HRMS: MþNaþ, found
443.2946. C25H44O3NaSi requires 443.2952. To facilitate charac-
terization, fractions obtained during chromatographic purification,
enriched in one of each diastereomer, were used to record the NMR
spectra.
[
a]
þ85.0 (c 0.67, CHCl3); IR 1729, 1635, 1462, 1404, 1259, 1179,
D
1042, 970, 920, 882, 807, 675 cmꢀ1 1H NMR (400 MHz, CDCl3)
;
d
6.42 (dd, J¼17.3, 1.5 Hz, 1H), 6.12 (dd, J¼17.3, 10.4 Hz, 1H), 5.91
(ddt, J¼17.2, 10.4, 5.6 Hz, 1H), 5.84 (dd, J¼10.4, 1.5 Hz, 1H),
5.70e5.61 (m, 1H), 5.61 (dd, J¼15.4, 5.4 Hz, 1H), 5.49 (d, J¼5.1 Hz,
1H), 5.27 (qd, J¼17.2, 1.5 Hz, 1H), 5.17 (qd, J¼10.4, 1.5 Hz, 1H),
3.99e3.95 (m, 4H), 2.41e2.34 (m, 1H), 1.70e1.59 (m, 1H), 1.50e1.39
(m, 1H), 1.06 (m, apparent br s, 18Hþ3H), 0.93 (t, J¼7.4 Hz, 3H); 13C
NMR (100 MHz, CDCl3)
d 164.9 (s), 134.8 (d), 132.3 (d), 131.1 (t),
129.8 (d), 128.3 (d), 116.9 (t), 102.6 (s), 88.1 (s), 70.5 (t, 2C), 67.2 (d),
48.0 (d), 23.8 (t), 18.5 (q, 6C), 11.6 (q), 11.1 (d, 3C); EIMS m/z (relative
intensity) 361 (Mꢀi-Prþ, 2), 347 (MꢀAllylOþ, 0.5), 303 (3), 291 (4),
289 (4), 263 (0.3), 249 (10), 186 (15), 185 (100), 129 (10), 101 (9), 75
(9), 55 (42).
4.2.1.18. RRCM of acrylate 19. To a solution of acrylate 19
(288 mg, 0.711 mmol) in CH2Cl2 (71 mL) was added Grubbs II

6368
V. Druais et al. / Tetrahedron 66 (2010) 6358e6375
Less polar (first eluted) diastereomer: 1H NMR (400 MHz, CDCl3)
5.87 (m, 1H), 5.86e5.76 (m, 1H), 5.67e5.63 (m, 2H), 5.40 (dt,
87.2 (s), 62.8 (d), 55.4 (q), 39.0 (d), 22.7 (t), 18.6 (q, 6C), 11.3 (q), 11.2
d
(d, 3C); EIMS m/z (relative intensity) 322 (Mþ, 1), 291 (MꢀOMeþ, 7),
279 (Mꢀi-Prþ, 94), 247 (70), 205 (24), 177 (40), 163 (18), 149 (44),
145 (22), 117 (98), 112 (100), 103 (35), 97 (49), 89 (55), 75 (66), 59
(33); HRMS: MþNaþ, found 345.2216. C19H34O2NaSi requires
345.2220.
J¼17.3, 1.5 Hz, 1H), 5.30e5.22 (m, 3H), 5.18e5.14 (m, 1H), 4.42 (d,
J¼5.4 Hz,1H), 3.98 (d, J¼5.2 Hz, 2H), 3.96 (dt, J¼5.6,1.5 Hz, 2H), 3.29
(s, 3H), 2.34e2.26 (m, 1H), 1.78e1.66 (m, 1H), 1.48e1.37 (m, 1H),
1.07 (m, apparent br s, 18Hþ3H), 0.91 (t, J¼7.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 134.9 (d), 134.7 (d), 133.6 (d), 128.9 (d), 118.6 (t),
116.8 (t), 102.7 (s), 99.7 (d), 87.8 (s), 70.7 (t), 70.4 (t), 68.9 (d), 52.0
(q), 49.0 (d), 23.5 (t), 18.5 (q, 6C), 11.7 (q), 11.1 (d, 3C).
4.2.3.2. (2R,3S,6R, and S)-3-Ethyl-2-ethynyl-6-methoxy-3,6-
dihydro-2H-pyran (24). To a solution of alkynylsilane 22 (136 mg,
0.420 mmol) in THF (7 mL) was added a solution of n-Bu4NF
(0.42 mL, 1 M in THF, 0.42 mmol, 1 equiv). After 2.5 h at rt, the
reaction mixture was poured into a saturated aqueous solution of
NH4Cl. The layers were separated and the aqueous phase was
extracted with Et2O. The combined organic extracts were dried
over MgSO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash chromatography on silica gel
(petroleum ether/Et2O: 98/2) to afford 47 mg (67%) of the ter-
minal alkyne 24 as a colorless oil (12:1 mixture of diastereomers);
IR 3290, 1657, 1462, 1401, 1335, 1186, 1108, 1043, 1021, 962, 739,
660, 628 cmꢀ1; minor diastereomer: 1H NMR (400 MHz, CDCl3)
More polar (second eluted) diastereomer: 1H NMR (400 MHz,
CDCl3)
d 5.91 (m, 1H), 5.82 (m, 1H), 5.72e5.60 (m, 2H), 5.38 (dt,
J¼17.3, 1.5 Hz, 1H), 5.31e5.22 (m, 3H), 5.18e5.14 (m, 1H), 4.11 (d,
J¼5.2 Hz,1H), 3.98 (d, J¼5.2 Hz, 2H), 3.96 (dt, J¼5.6,1.5 Hz, 2H), 3.42
(s, 3H), 2.34e2.26 (m, 1H), 1.78e1.66 (m, 1H), 1.48e1.37 (m, 1H),
1.07 (m, apparent br s, 18Hþ3H), 0.89 (t, J¼7.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 134.9 (d), 134.6 (d), 133.4 (d), 129.0 (d), 118.8 (t),
116.8 (t), 105.2 (s), 104.7 (d), 87.6 (s), 70.7 (t), 70.5 (t), 68.8 (d), 54.4
(q), 49.2 (d), 23.5 (t), 18.5 (q, 6C), 11.7 (q), 11.1 (d, 3C).
4.2.2. Synthesis of the cyclic acetal 22.
4.2.2.1. Synthesis from lactone 21. To a solution of lactone 21
(167 mg, 0.544 mmol) in CH2Cl2 (11 mL) at ꢀ78 ꢁC was added
a solution of DIBAL-H (0.71 mL, 1 M in hexanes, 0.71 mmol,
1.3 equiv). After 45 min at ꢀ78 ꢁC, the cold reaction mixture was
poured intoa saturated aqueoussolution ofNaHCO3. After extraction
with EtOAc, the combined organic extracts were dried over
MgSO4, filtered, and concentrated under reduced pressure. The
crude lactol was dissolved in MeOH (9 mL) and PPTS (14 mg,
0.054 mmol, 0.1 equiv) was added. After 16 h at rt, the reaction
was quenched by addition of Et3N (0.2 mL) and the resulting
mixture was concentrated under reduced pressure. The residue
was purified by flash chromatography on silica gel (petroleum
ether/Et2O: 98/2) to afford 152 mg (87%) of 22 as a colorless oil
(5:1 mixture of diastereomers).
d
5.90 (dt, J¼10.2, 2.0 Hz, 1H), 5.76 (ddd, apparent dt, J¼10.4,
2.2 Hz, 1H), 4.97 (br q, J¼1.9 Hz, 1H), 4.63 (dd, J¼5.4, 2.4 Hz, 1H),
3.49 (s, 3H), 2.39 (d, J¼2.4 Hz, 1H), 1.72e1.64 (m, 1H), 1.63e1.51
(m, 2H), 1.00 (t, J¼7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 131.6
(d), 125.4 (d), 96.0 (d), 81.1 (s), 73.5 (d), 63.3 (d), 55.1 (q), 38.7 (d),
23.8 (t), 11.2 (q); EIMS m/z (relative intensity) 165 (MꢀHþ, 29),
135 (MꢀOMeþ, 53), 112 (MꢀHC^CCHOþ, retro DielseAlder, 100),
97 (62), 91 (30), 79 (29), 67 (13), 53 (10); major diastereomer: 1H
NMR (400 MHz, CDCl3)
d
6.09 (ddd, J¼10.2, 5.5, 1.1 Hz, 1H), 5.90
(ddd, J¼10.2, 2.8, 1.2 Hz, 1H), 4.88e4.87 (m, 1H), 4.80 (dd, ap-
parent br t, J¼3.0 Hz, 1H), 3.46 (s, 3H), 2.51 (d, J¼2.4 Hz, 1H),
2.04e1.98 (m, 1H), 1.94e1.84 (m, 1H), 1.63e1.51 (m, 1H), 0.99 (t,
J¼7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 132.3 (d), 124.7 (d),
95.8 (d), 81.1 (s), 74.3 (d), 61.7 (d), 55.5 (q), 38.6 (d), 22.3 (t), 11.2
(q); EIMS m/z (relative intensity) 166 (Mþ, 9), 135 (MꢀOMeþ, 53),
112 (MꢀHC^CCHOþ, retro DielseAlder, 100), 105 (20), 97 (77), 91
(62), 79 (47), 67 (20), 53 (15); HRMS: MþNaþ, found 189.0884.
C10H14O2Na requires 189.0886.
4.2.3. Synthesis from acetal 23 by RRCM. To a solution of mixed
acetal 23 (62 mg, 0.15 mmol) in CH2Cl2 (16 mL) was added Grubbs II
catalyst (3 mg, 0.004 mmol, 2 mol %) and the reaction mixture was
heated at reflux. Additional portions of the catalyst (3 mg,
0.004 mmol, 0.02 equiv) were added every 2 h (total quantity of
catalyst used: 15 mg, 0.018 mmol, 12 mol %). After 7 h at reflux, the
reaction mixture was cooled to rt and evaporated under reduced
pressure. The residue was purified by flash chromatography on
silica gel (petroleum ether/Et2O: 80/20) to afford 39 mg (82%) of
dihydropyran 22 as a brown oil (1:1 mixture of diastereomers).
Treatment of 22 (38.6 mg, 0.120 mmol, 1:1 mixture of di-
astereomers) with PPTS (3.0 mg, 0.012 mmol, 10 mol %) in MeOH
(2 mL) at rt for 9 h, subsequent work-up (as described for the
preparation from lactone 21) and purification by flash chromato-
graphy on silica gel (petroleum ether/Et2O: 98/2) provided 33.5 mg
(87%) of 22 as a 5:1 mixture of diastereomers.
4.2.3.3. (2R,3S,6R, and S)-3-Ethyl-2-((E)-2-iodovinyl)-6-methoxy-
3,6-dihydro-2H-pyran (25). To a solution of alkyne 24 (71 mg,
0.43 mmol) in THF (5 mL) was added Cp2ZrHCl (143 mg,
0.554 mmol, 1.3 equiv). After 15 min at rt, I2 (130 mg, 0.511 mmol,
1.2 equiv) was added. After 15 min at rt, the reaction mixture was
hydrolyzed with a saturated aqueous solution of NH4Cl. The layers
were separated and the aqueous phase was extracted with Et2O.
The combined organic extracts were washed with an aqueous so-
lution of Na2S2O3 and the suspension was filtered through Celite
(Et2O). The layers of the filtrate were separated and the aqueous
phase was extracted with Et2O. The combined organic extracts
were dried over MgSO4, filtered, and concentrated under reduced
pressure. The crude material was purified by flash chromatography
on silica gel (petroleum ether/Et2O: 98/2) to afford 68 mg (54%) of
25 as a colorless oil (12:1 mixture of diastereomers); IR 1655, 1613,
1462, 1398, 1333, 1186, 1108, 1046, 1022, 961, 909, 728 cmꢀ1; minor
4.2.3.1. (2R,3S,6R and S)-3-Ethyl-6-methoxy-3,6-dihydro-2H-
pyran-2-ylethynyl)triisopropylsilane (22). IR 2924, 2865,1462, 1185,
1110, 1046, 1020, 964, 882, 718, 664 cmꢀ1; minor diastereomer: 1H
NMR (400 MHz, CDCl3)
d
5.84 (apparent dt, J¼10.3, 2.2 Hz, 1H), 5.72
diastereomer: 1H NMR (400 MHz, CDCl3)
d
6.57 (d, J¼14.5 Hz, 1H),
(m, 1H), 4.95 (ddd, apparent q, J¼1.8 Hz, 1H), 4.64 (d, J¼5.5 Hz, 1H),
3.45 (s, 3H), 2.31e2.24 (m, 1H), 1.73e1.52 (m, 2H), 1.09e1.05 (m,
apparent br s, 18Hþ3H), 0.99 (t, J¼7.5 Hz, 3H); 13C NMR (100 MHz,
6.38 (ddd, J¼14.4, 2.9, 1.2 Hz, 1H), 5.95 (ddd, J¼10.3, 3.7, 1.5 Hz, 1H),
5.69 (ddd, J¼10.3, 2.7, 1.1 Hz, 1H), 4.99 (apparent br q, J¼1.8 Hz, 1H),
4.26 (ddd, J¼7.3, 4.7, 1.1 Hz, 1H), 3.42 (s, 3H), 2.19e2.14 (m, 1H),
1.41e1.29 (m, 2H), 0.91 (t, J¼7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3)
CDCl3) d 131.6 (d), 125.6 (d), 104.5 (s), 96.0 (d), 86.3 (s), 63.9 (d), 55.0
(q), 39.0 (d), 24.2 (t), 18.5 (q, 6C), 11.4 (q), 11.2 (d, 3C); major di-
d 144.2 (d), 133.1 (d), 125.1 (d), 96.9 (d), 76.7 (d), 72.3 (d), 54.8 (q),
astereomer: 1H NMR (400 MHz, CDCl3)
d
6.05 (dd, J¼10.2, 5.2 Hz,
38.7 (d), 23.0 (t), 11.4 (q); EIMS m/z (relative intensity) 293 (MꢀHþ,
0.4), 263 (MꢀOMeþ, 2), 167 (11), 136 (16), 112 (MꢀICH]CHCHOþ,
retro DielseAlder, 100), 97 (72), 79 (17), 67 (8); major diastereomer:
1H), 5.72 (m, 1H), 4.92 (br d, J¼2.6 Hz, 1H), 4.83 (d, J¼3.8 Hz, 1H),
3.45 (s, 3H), 2.08e2.03 (m, 1H), 1.92e1.82 (m, 1H), 1.73e1.52 (m,
1H), 1.09e1.05 (m, apparent br s, 18Hþ3H), 0.98 (t, J¼7.5 Hz, 3H);
1H NMR (400 MHz, CDCl3)
d
6.59 (ddd, J¼14.5, 4.8, 0.3 Hz, 1H), 6.40
13C NMR (100 MHz, CDCl3)
d 132.6 (d), 124.9 (d), 104.7 (s), 95.8 (d),
(dd, J¼14.4, 1.8 Hz, 1H), 6.11 (ddd, J¼10.1, 5.6, 1.1 Hz, 1H), 5.74 (ddd,

V. Druais et al. / Tetrahedron 66 (2010) 6358e6375
6369
J¼10.1, 2.8, 1.2 Hz, 1H), 4.86 (apparent br d, J¼2.8 Hz, 1H), 4.48 (ddd,
J¼4.7, 3.5, 1.7 Hz, 1H), 3.40 (s, 3H), 2.92 (m, 1H), 1.57e1.47 (m, 1H),
1.41e1.29 (m, 1H), 0.91 (t, J¼7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3)
solution of Na2S2O3 (25%), brine, dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude material was
purified by flash chromatography on silica gel (pentane/Et2O: 95/5)
to afford 7.8 g (61%) of ether 30 as a colorless oil; IR 1613, 1586, 1511,
d
144.3 (d), 133.1 (d), 124.9 (d), 95.8 (d), 76.7 (d), 72.0 (d), 55.2 (q),
38.7 (d), 21.6 (t),11.5 (q); EIMS m/z (relative intensity) 294 (Mþ, 0.1),
263 (MꢀOMeþ, 4), 167 (8), 136 (22),125 (8),112 (MꢀICH]CHCHOþ,
retro DielseAlder, 100), 97 (72), 79 (13); HRMS: MþNaþ, found
317.0009. C10H15O2INa requires 317.0005.
1462, 1361, 1301, 1243, 1172, 1138, 1091, 1033, 896, 811 cmꢀ1 1H
;
NMR (400 MHz, CDCl3)
d
7.26 (m, apparent br d, J¼8.5 Hz, 2H), 6.88
(m, apparent br d, J¼8.5 Hz, 2H), 6.12 (q, J¼1.4 Hz, 1H), 5.78 (d,
J¼1.4 Hz, 1H), 4.47 (s, 2H), 3.80 (s, 3H), 3.58 (t, J¼6.4 Hz, 2H), 2.67
(td, apparent br t, J¼6.0 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 159.2
4.2.4. Synthesis of the C8eC13 subunit.
(s), 130.2 (s), 129.3 (d, 2C), 127.3 (t), 113.8 (d, 2C), 107.4 (s), 72.7 (t),
68.3 (t), 55.2 (q), 45.3 (t); EIMS m/z (relative intensity) 318 (Mþ, 1),
192 (MꢀIþ, 6), 191 (4), 163 (4), 137 (6), 136 (10), 135 (11), 122 (10),
121 (100), 78 (9), 77 (8), 55 (5).
4.2.4.1. Ethyl (R)-3-(tert-butyldimethylsilyloxy)-5-(trimethylsilyl)
pent-4-ynoate (28). To a solution of b
-hydroxyester 2736 (1.03 g,
4.79 mmol) in CH2Cl2 (25 mL) were successively added imidazole
(815 mg, 12.0 mmol, 2.5 equiv), TBSCl (866 mg, 5.75 mmol,
1.2 equiv) and DMAP (29 mg, 0.24 mmol, 0.05 equiv). After 16 h at
rt, the reaction mixture was hydrolyzed with water. The layers were
separated and the aqueous phase was extracted with Et2O. The
combined organic extracts were dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by
flash chromatography on silica gel (petroleum ether/Et2O: 98/2 to
96/4) to afford 1.53 g (97%) of silyl ether 28 as a colorless oil;
[Found: C, 58.31; H, 9.71. C16H32O3Si2 requires C, 58.48; H, 9.82%];
4.2.4.4. (R)-6-(tert-Butyldimethylsilyloxy)-1-(4-methoxy-
benzyloxy)-3-methylene-8-(trimethylsilyl)oct-7-yn-4-one
(31). To
a solution of alkenyl iodide 30 (1.91 g, 6.00 mmol, 2 equiv) in Et2O
(15 mL) at ꢀ78 ꢁC was added a solution of n-BuLi (2.40 mL, 2.5 M in
hexanes, 6.00 mmol, 1 equiv, 2 equiv). After 0.5 h at ꢀ78 ꢁC, a so-
lution of Weinreb amide 29 (1.03 g, 3.00 mmol) in Et2O (30 mL) was
added dropwise. After 0.5 h at ꢀ78 ꢁC, the reaction mixture was
warmed to 0 ꢁC over 0.5 h and poured into a saturated aqueous
solution of NH4Cl. The layers were separated and the aqueous phase
was extracted with Et2O. The combined organic extracts were
washed with brine, dried over MgSO4, filtered, and concentrated
under reduced pressure. The residue was purified by flash chro-
matography on silica gel (pentane/Et2O gradient: 94/6 to 90/10) to
afford 944 mg (66%) of enone 31 as a colorless oil; [Found: C, 65.46;
[
a
]
D þ55.6 (c 1.00, CHCl3); IR 1740, 1250, 1165, 1092, 1029, 996, 952,
836, 778, 760 cmꢀ1 1H NMR (400 MHZ, CDCl3)
;
d
4.82 (dd, J¼9.0,
4.5 Hz, 1H), 4.20e4.07 (m, 2H), 2.71 (dd, J¼15.0, 9.1 Hz, 1H), 2.62
(dd, J¼15.0, 4.6 Hz, 1H), 1.26 (t, J¼7.1 Hz, 3H), 0.88 (s, 9H), 0.15 (s,
9Hþ3H), 0.11 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 170.1 (s), 106.0
(s), 89.4 (s), 60.5 (t), 60.2 (d), 44.0 (t), 25.7 (q, 3C), 18.1 (s), 14.2 (q),
ꢀ0.3 (q, 3C), ꢀ4.6 (q), ꢀ5.2 (q); EIMS m/z (relative intensity) 313
(MꢀMeþ, 3), 272 (MꢀC4Hþ8 , 24), 271 (Mꢀt-Buþ, 100), 201 (10), 147
(82), 133 (11), 103 (21), 75 (27), 73 (39).
H, 9.02. C26H42O4Si2 requires C, 65.77; H, 8.92%]; [
CHCl3); IR 1679, 1613, 1513, 1361, 1247, 1173, 1086, 1037, 983, 942,
835, 778, 759 cmꢀ1; 1H NMR (400 MHz, CDCl3)
7.23 (m, apparent
a]
D þ45.9 (c 1.04,
d
br d, J¼8.7 Hz, 2H), 6.86 (m, apparent br d, J¼8.7 Hz, 2H), 6.10 (s,
1H), 5.90 (t, J¼0.9 Hz, 1H), 4.90 (dd, J¼8.8, 4.1 Hz, 1H), 4.43 (d, AB
syst, J¼11.8 Hz, 1H), 4.40 (d, AB syst, J¼11.8 Hz, 1H), 3.79 (s, 3H),
3.52 (td, J¼6.7, 2.2 Hz, 2H), 3.27 (dd, J¼15.6, 8.8 Hz, 1H), 2.77 (dd,
J¼15.6, 4.1 Hz,1H), 2.58 (br t, J¼6.6 Hz, 2H), 0.85 (s, 9H), 0.15 (s, 9H),
4.2.4.2. (R)-3-(tert-Butyldimethylsilyloxy)-N-methoxy-N-methyl-
5-trimethylsilylpent-4-ynamide (29). To a solution of ethyl ester 28
(2.79 g, 8.49 mmol) in THF (40 mL) was added N,O-dimethylhy-
droxylamine hydrochloride (1.24 g, 12.7 mmol, 1.5 equiv). The re-
action mixture was cooled to ꢀ40 ꢁC and a solution of i-PrMgCl
(12.7 mL, 2 M in THF, 25.5 mmol, 3 equiv) was added dropwise
over 15 min. The reaction mixture was allowed to warm to 0 ꢁC
over 3 h and then poured into a saturated aqueous solution of
NH4Cl. The layers were separated and the aqueous phase was
extracted with Et2O. The combined organic extracts were dried
over MgSO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash chromatography on silica gel
(petroleum ether/Et2O: 80/20) to afford 2.78 g (95%) of Weinreb
amide 29 as a colorless oil; [Found: C, 55.93; H, 9.71; N, 3.99.
0.14 (s, 3H), 0.08 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 198.2 (s),159.1
(s), 146.0 (s), 130.5 (s), 129.2 (d, 2C), 126.9 (t), 113.7 (d, 2C), 106.7 (s),
89.1 (s), 72.5 (t), 68.5 (t), 60.0 (d), 55.2 (q), 46.0 (t), 31.2 (t), 25.7 (q,
3C), 18.1 (s), ꢀ0.27 (q, 3C), ꢀ4.7 (q), ꢀ5.2 (q).
4.2.4.5. (4R,6R)-6-(tert-Butyldimethyl-silyloxy)-1-(4-methoxy-
benzyloxy)-3-methylene-8-trimethylsilyloct-7-yn-4-ol (33). To a so-
lution of oxazaborolidine (S)-32 (4.9 mL, 1 M in toluene, 4.9 mmol,
2 equiv) in THF (5 mL) at 0 ꢁC was added BH3$SMe2 complex
(0.46 mL, 4.9 mmol, 2 equiv). After 0.5 h at 0 ꢁC, the reaction
mixture was cooled to ꢀ78 ꢁC and a pre-cooled solution of enone
31 (1.16 g, 2.45 mmol) in THF (10 mL) was added via a cannula.
After 3 h at ꢀ78 ꢁC, the reaction was quenched with MeOH
(5 mL), the resulting mixture was allowed to warm to rt and was
then evaporated under reduced pressure. The residue was taken-
up in MeOH (10 mL) and the mixture was evaporated again under
reduced pressure. The crude material was purified by flash
chromatography on silica gel (pentane/Et2O gradient: 94/6 to 90/
10) to afford 884 mg (76%) of allylic alcohol 33 as a colorless oil;
[Found: C, 65.45; H, 9.42. C26H44O4Si2 requires C, 65.50; H, 9.30%];
C16H33NO3Si2 requires C, 55.93; H, 9.68; N, 4.08%]; [
1.21, CHCl3); IR 1664, 1385, 1250, 1086, 1063, 1013, 979, 945, 836,
778, 759 cmꢀ1 1H NMR (400 MHz, CDCl3)
a]
þ70.9 (c
D
;
d
4.91 (dd, J¼9.1,
4.3 Hz, 1H), 3.71 (s, 3H), 3.18 (s, 3H), 3.02 (dd, J¼14.3, 9.6 Hz, 1H),
2.58 (dd, J¼14.8, 4.3 Hz, 1H), 0.88 (s, 9H), 0.15 (s, 9H), 0.14 (s, 3H),
0.11 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 107.7 (s, weak), 106.8 (s),
88.9 (s), 61.5 (q), 60.4 (d), 40.7 (t), 32.0 (q, weak), 25.7 (q, 3C), 18.1
(s), ꢀ0.3 (q, 3C), ꢀ4.8 (q), ꢀ5.1 (q); EIMS m/z (relative intensity)
328 (MꢀMeþ, 5), 312 (MꢀOMeþ, 3), 287 (MꢀC4Hþ8 , 24), 286
(Mꢀt-Buþ, 100), 256 (4), 155 (4), 130 (4), 109 (5), 89 (14), 86 (5),
75 (9), 73 (30), 70 (7), 56 (6).
[a
]
þ40.2 (c 1.10, CHCl3); IR 3440, 2172, 1613, 1586, 1513, 1248,
D
1173, 1085, 1037, 836, 778, 759 cmꢀ1 1H NMR (400 MHz, CDCl3)
;
4.2.4.3. 1-[(3-Iodobut-3-enyloxy)methyl]-4-methoxybenzene
(30). To a solution of 3-iodobut-3-en-1-ol41 (7.92 g, 40 mmol) in
toluene (150 mL) were added a solution of p-methoxybenzyl tri-
chloroacetimidate (16.5 g, 80 mmol, 2 equiv) in toluene (50 mL)
and La(OTf)3 (234 mg, 0.400 mmol, 10 mol %). After 16 h at rt, the
reaction mixture was diluted with Et2O and poured into water. The
layers were separated and the aqueous phase was extracted with
Et2O. The combined organic extracts were washed with an aqueous
d
7.25 (m, apparent br d, J¼8.6 Hz, 2H), 6.87 (m, apparent br d,
J¼8.6 Hz, 2H), 5.13 (s, 1H), 4.91 (s, 1H), 4.63 (dd, J¼6.5, 4.9 Hz, 1H),
4.45 (s, 2H), 4.41 (m, 1H), 3.80 (s, 3H), 3.64e3.54 (m, 2H), 3.36 (d,
J¼3.6 Hz, 1H, OH), 2.43 (m, 1H), 2.30 (m, 1H), 1.92e1.81 (m, 2H),
0.91 (s, 9H), 0.17 (s, 3H), 0.16 (s, 9H), 0.14 (s, 3H); 13C NMR
(100 MHz, CDCl3)
113.8 (d, 2C), 111.5 (t), 106.8 (s), 89.5 (s), 72.7 (t), 71.4 (d), 69.5 (t),
d 159.2 (s), 148.6 (s), 130.1 (s), 129.3 (d, 2C),
61.6 (d), 55.2 (q), 43.6 (t), 32.4 (t), 25.7 (q, 3C), 18.1 (s), ꢀ0.27 (q,

6370
V. Druais et al. / Tetrahedron 66 (2010) 6358e6375
3C), ꢀ4.5 (q), ꢀ5.1 (q); EIMS m/z (relative intensity) 476 (Mþ, 0.1),
295 (1), 241 (6), 201 (6), 137 (5), 122 (10), 121 (100), 75 (12), 73
(11). The relative configuration of 33 was ascertained by a chem-
ical correlation, see Supplementary data.
23.8 mmol,1.2 equiv) in THF (32 mL) at ꢀ78 ꢁC was added dropwise
a solution of n-BuLi (8.70 mL, 2.5 M in hexanes, 21.8 mmol,
1.1 equiv). The reaction mixture was stirred at 0 ꢁC for 10 min,
cooled to ꢀ40 ꢁC and a solution of 3-(tert-butyldiphenylsilyl-oxy)
propanal [prepared from propane-1,3-diol (36)]47 (6.20 g,
19.9 mmol) in THF (28 mL) was then added. After 10 min at ꢀ40 ꢁC
and 20 min at 0 ꢁC, the reaction mixture was poured into a satu-
rated aqueous solution of NH4Cl. The layers were separated and the
aqueous phase was extracted with Et2O. The combined organic
extracts were dried over MgSO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash chromatogra-
phy on silica gel (petroleum ether/Et2O gradient: 90/10 to 70/30) to
afford 10.8 g (89%, 70% for the three steps from 36) of racemic
propargylic alcohol (ꢂ)-37 as a colorless oil (see the characteriza-
tion of the (R) enantiomer below).
4.2.4.6. (4R,6R)-6-(tert-Butyldimethylsilyl-oxy)-1-(4-methoxy-
benzyloxy)-3-methylene-8-trimethylsilyloct-7-yn-4-ol (34). To a so-
lution of alcohol 33 (168 mg, 0.352 mmol) in toluene (5 mL) was
added
p-methoxybenzyl
trichloroacetimidate
(150 mg,
0.530 mmol,1.5 equiv) and La(OTf)3 (10 mg, 0.05 mmol, 0.14 equiv).
After 16 h at rt, the reaction mixture was diluted with Et2O and
poured into water. The layers were separated and the aqueous phase
was extracted with Et2O. The combined organic extracts were
washed with a saturated aqueous solution of NaHO3, brine, dried
over MgSO4, filtered, and concentrated under reduced pressure. The
crude material was purified by flash chromatography on silica gel
(pentane/Et2O: 91/9) toafford 133 mg (64%) of ether 34 as a colorless
oil; [Found: C, 68.16; H, 9.16. C34H52O5Si2 requiresC, 68.41; H, 8.78%];
4.3.1.2. 1-(tert-Butyldiphenylsilyloxy)-6-(trityloxy)hex-4-yn-3-
one (38). To a solution of the racemic propargylic alcohol (ꢂ)-37
(100 mg, 0.164 mmol) in CH2Cl2 (10 mL) was added MnO2 (437 mg,
4.89 mmol, 30 equiv). After 7 h at rt, more MnO2 (110 mg,
1.23 mmol, 7.5 equiv) was added. After 15 h at rt, the reaction
mixture was filtered through Celite (CH2Cl2) and the filtrate was
evaporated under reduced pressure. The crude material was pu-
rified by flash chromatography on silica gel (petroleum ether/
Et2O: 90/10) to afford 88 mg (88%) of ketone 38 as a white solid;
mp 110 ꢁC; IR 1677, 1590, 1448, 1427, 1363, 1264, 1167, 1105, 1068,
[
a]
D þ44.7 (c 1.05, CHCl3); IR 2171,1613,1586,1512,1246,1172,1089,
1035, 836, 777, 759 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
7.26 (m, ap-
parent br d, J¼8.7 Hz, 2H), 7.21 (m, apparent br d, J¼8.7 Hz, 2H),
6.88e6.83 (m, 4H), 5.12 (m, apparent br s, 1H), 5.02 (q apparent br s,
J¼1.4 Hz, 1H), 4.56 (dd, J¼9.8, 3.2 Hz, 1H), 4.45 (s, 2H), 4.40 (d, AB
syst, J¼10.9 Hz, 1H), 4.11 (d, AB syst, J¼10.9 Hz, 1H), 3.97 (dd, J¼9.6,
3.2 Hz, 1H), 3.80 (s, 6H), 3.64e3.59 (m, 2H), 2.43e2.28 (m, 2H), 1.93
(ddd, J¼14.0, 9.6, 3.2 Hz, 1H), 1.83 (ddd, J¼14.0, 9.8, 3.2 Hz, 1H), 0.89
(s, 9H), 0.14 (s, 3H), 0.13 (s, 9H), 0.10 (s, 3H); 13C NMR (100 MHz,
908, 822, 732, 699 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d 7.66e7.64
CDCl3)
d
159.1 (s),159.0 (s),145.6 (s),130.7 (s),130.5 (s),129.3 (d, 2C),
(m, 4H), 7.46e7.43 (m, 6H), 7.40e7.22 (m, 15H), 3.98 (t, J¼6.2 Hz,
129.2 (d, 2C),113.7 (d, 4C),113.0 (t),107.8(s), 88.5 (s), 78.9 (d), 72.6 (t),
79.9 (t), 68.7 (t), 59.8 (d), 55.2 (q, 2C), 44.2 (t), 30.9 (t), 25.8 (q, 3C),
18.2 (s), ꢀ0.3 (q, 3C), ꢀ4.3 (q), ꢀ5.0 (q).
2H), 3.95 (s, 2H), 2.73 (t, J¼6.2 Hz, 2H), 1.03 (s, 9H); 13C NMR
(100 MHz, CDCl3)
d 185.6 (s), 143.1 (s, 3C), 135.6 (d, 4C), 133.4 (s,
2C), 129.7 (d, 2C), 128.6 (d, 6C), 128.0 (d, 6C), 127.7 (d, 4C), 127.4 (d,
3C), 89.0 (s), 87.9 (s), 84.3 (s), 59.2 (t), 52.8 (t), 48.1 (t), 26.8 (q, 3C),
19.2 (s); HRMS: MþNaþ, found 631.2636. C41H40O3NaSi requires
631.2639.
4.2.4.7. (4R,6R)-6-(tert-Butyldimethylsilyl-oxy)-1,4-bis-(4-me-
thoxybenzyloxy)-8-trimethylsilyloct-7-yn-3-one
(35). A
slow
stream of ozone in oxygen was passed through a solution of 34
(411 mg, 0.688 mmol) containing Sudan red III (0.24 mL, 0.05% in
MeOH) in CH2Cl2 (24 mL) at ꢀ78 ꢁC. Once the red color fainted
(ca. 15 min), excess ozone was immediately removed by bubbling
argon through the cold reaction mixture (until the exhausted gas
showed a negative test against a wet KI/starch paper). Triphe-
nylphosphine (217 mg, 0.826 mmol, 1.2 equiv) was then added in
one portion and the reaction mixture was allowed to warm to rt.
After 0.5 h, the reaction mixture was concentrated under reduced
pressure. The residue was purified by flash chromatography on
silica gel (petroleum ether/Et2O gradient: 90/10 to 80/20) to af-
ford 300 mg (73%) of enone 35 as a colorless oil; [Found: C, 66.18;
4.3.1.3. (3R)-1-(tert-Butyldiphenylsilyloxy)-6-(trityloxy)hex-4-
yn-3-ol (37). To a solution of Noyori’s catalyst (R,R)-Ru-I26 (360 mg,
0.600 mmol, 0.05 equiv) in i-PrOH (120 mL) was added a solution of
ketone 38 (7.3 g, 12 mmol) in CH2Cl2 (12 mL). After 1.5 h at rt, the
reaction mixture was concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel (pe-
troleum ether/Et2O gradient: 90/10 to 70/30) to afford 6.5 g (89%)
of optically active propargyl alcohol 37 as a colorless oil (ee¼97%).
The ee value was determined by super-critical fluid chromatog-
raphy (SFC) analysis on chiral stationary phase;27
0.52, CHCl3); IR 1590, 1489, 1471, 1448, 1427, 1106, 1054, 822, 763,
741, 698, 632 cmꢀ1 1H NMR (400 MHz, CDCl3)
7.72e7.65 (m,
[
a]
þ0.03 (c
D
H, 8.34. C33H50O6Si2 requires C, 66.18; H, 8.41%]; [
1.00, CHCl3); IR 2173, 1720, 1586, 1612, 1513, 1247, 1173, 1086,
1034, 837, 778, 759, 732 cmꢀ1 1H NMR (400 MHz, CDCl3)
a
]
þ31.7 (c
;
d
D
4H), 7.47e7.45 (m, 6H), 7.40e7.33 (m, 6H), 7.30e7.27 (m, 6H),
7.24e7.21 (m, 3H), 4.70 (q, J¼5.2 Hz, 1H), 4.03e3.98 (m, 1H),
3.85e3.77 (m, 1H), 3.81 (d, J¼1.5 Hz, 2H), 3.03 (d, J¼6.0 Hz, 1H,
OH), 2.03e1.95 (m, 1H), 1.91e1.82 (m, 1H), 1.05 (s, 9H); 13C NMR
;
d
7.26e7.21 (m, 4H), 6.87e6.84 (m, 4H), 4.58 (dd, J¼9.8, 3.1 Hz,
1H), 4.47 (d, AB syst, J¼10.8 Hz, 1H), 4.43 (s, 2H), 4.27 (d, AB syst,
J¼10.8 Hz, 1H), 4.07 (dd, J¼9.8, 3.0 Hz, 1H), 3.795 (s, 3H), 3.79 (s,
3H), 3.75e3.69 (m, 2H), 2.77 (td, J¼6.1, 2.0 Hz, 2H), 2.01 (ddd,
J¼14.0, 9.8, 3.0 Hz, 1H), 1.89 (ddd, J¼14.0, 9.8, 3.1 Hz, 1H), 0.90 (s,
9H), 0.15 (s, 3H), 0.13 (s, 9H), 0.09 (s, 3H); 13C NMR (100 MHz,
(100 MHz, CDCl3)
d 143.5 (s, 3C), 135.5 (d, 4C), 133.1 (s), 133.0 (s),
129.8 (d, 2C), 128.6 (d, 6C), 127.9 (d, 6C), 127.7 (d, 4C), 127.1 (d, 3C),
87.4 (s), 85.9 (s), 81.6 (s), 61.6 (t), 61.4 (d), 53.1 (t), 38.9 (t), 26.8 (q,
3C), 19.1 (s); HRMS: MþNaþ, found 633.2794. C41H42O3NaSi re-
quires 633.2795.
CDCl3)
d 210.5 (s), 159.3 (s), 159.2 (s), 130.2 (s), 129.7 (s), 129.6 (d,
2C), 129.3 (d, 2C), 113.8 (d, 2C), 113.7 (d, 2C), 106.9 (s), 89.3 (s),
81.2 (d), 72.9 (t), 72.1 (t), 64.9 (t), 59.3 (d), 55.3 (q), 55.2 (q), 40.8
(t), 38.2 (t), 25.8 (q, 3C), 18.2 (s), ꢀ0.3 (q, 3C), ꢀ4.3 (q), ꢀ4.9 (q).
4.3.1.4. (R)-5-[2-(tert-Butyldiphenylsilyl-oxy)ethyl]-3-(toluene-4-
sulfonyl)-4-[2-trityloxyeth-(Z)-ylidene]oxazolidin-2-one
a suspension of CuI (0.3 mg, 2 mol, 0.01 equiv) in THF (0.1 mL)
were added Et3N (58 L, 8 mol, 0.05 equiv) and a solution of
alcohol 37 (97 mg, 0.16 mmol) in THF (0.9 mL). The reaction mix-
ture was cooled to 0 ꢁC and tosyl isocyanate (25
L, 0.17 mmol,
(39). To
m
4.3. Convergent approach toward the C1eC11 subunit of PLMs
and LSNs. Formal synthesis of PLM B
m
m
m
4.3.1. Synthesis of the C8eC11 subunit.
1.05 equiv) was added. After 7 h heating at reflux, the reaction
mixture was filtered through Celite (CH2Cl2) and the filtrate was
evaporated under reduced pressure. The residue was purified by
4.3.1.1. 1-(tert-Butyldiphenylsilyloxy)-6-(trityloxy)hex-4-yn-3-ol
((ꢂ)-37). To
a
solution of propargyl trityl ether48 (7.11 g,

V. Druais et al. / Tetrahedron 66 (2010) 6358e6375
6371
flash chromatography on silica gel (petroleum ether/Et2O gradient:
85/15 to 70/30) to afford 118 mg (92%) of oxazolidinone 39 as
4.3.2. Synthesis of the C1eC11 subunit of the PLMs and LSNs. Formal
synthesis of phoslactomycin B.
a white solid; mp 68 ꢁC; [
a
]
þ14.9 (c 0.43, CHCl3); IR 1794, 1375,
4.3.2.1. (E)-(3R,4S)-7-Allyloxy-4-ethylhept-5-en-1-yn-3-ol
(42). To a solution of alkynylsilane 13 (788 mg, 2.25 mmol) in THF
(7 mL) was added a solution of n-Bu4NF (2.30 mL, 1 M in THF,
2.30 mmol, 1.02 equiv). After 0.5 h at rt, the reaction mixture was
poured into a saturated aqueous solution of NH4Cl. The layers were
separated and the aqueous phase was extracted with Et2O. The
combined organic extracts were dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by
flash chromatography on silica gel (petroleum ether/Et2O gradient:
70/30 to 60/40) to afford 436 mg (100%) of the terminal alkyne 42
D
1176, 1153, 1087, 816, 760, 744, 701, 661 cmꢀ1
CDCl3)
;
1H NMR (400 MHz,
d
7.69 (d, J¼8.3 Hz, 2H), 7.65e7.61 (m, 4H), 7.47e7.33 (m,
12H), 7.29e7.20 (m, 9H), 7.08 (d, J¼8.3 Hz, 2H), 4.97 (m, 1H), 4.84
(apparent t, J¼6.4 Hz, 1H), 4.17 (dd, J¼14.7, 3.0 Hz, 1H), 4.02 (dd,
J¼14.7, 7.0 Hz, 1H), 3.77e3.66 (m, 2H), 2.37 (s, 3H), 1.72e1.68 (m,
2H), 1.06 (s, 9H); 13C NMR (100 MHz, CDCl3)
d 152.4 (s), 145.4 (s),
144.2 (s, 3C), 143.5 (s), 135.5 (d, 4C), 135.0 (s), 133.3 (s), 133.1 (s),
129.9 (d, 2C), 129.6 (d, 2C), 128.6 (d, 6C), 128.2 (d, 2C), 127.8 (d, 10C),
127.1 (d, 3C), 113.9 (d), 87.4 (s), 78.0 (d), 62.6 (t), 58.7 (t), 36.9 (t),
26.8 (q, 3C), 21.7 (q), 19.2 (s); HRMS: MþNaþ, found 830.2939.
C49H49O6NNaSSi requires 830.2942.
as a colorless oil; [
1379, 1265, 1086, 1036, 974, 923, 835, 777, 628 cmꢀ1
(400 MHz, CDCl3)
J¼15.5, 5.8 Hz, 1H), 5.63 (dd, J¼15.5, 9.0 Hz, 1H), 5.28 (dq, J¼17.2,
1.7 Hz, 1H), 5.19 (dq, J¼10.4, 1.4 Hz, 1H), 4.33 (ddd, J¼8.0, 4.8,
2.2 Hz, 1H), 4.05e3.95 (m, 4H), 2.45 (d, J¼2.2 Hz, 1H), 2.32 (br s,
1H, OH), 2.27e2.20 (m, 1H), 1.64e1.54 (m, 1H), 1.49e1.37 (m, 1H),
a
]
þ49.0 (c 1.19, CHCl3); IR 3304, 1646, 1455,
D
;
1H NMR
d
5.92 (ddt, J¼17.2, 10.4, 5.6 Hz, 1H), 5.73 (dt,
4.3.1.5. (R)-6-(tert-Butyldiphenylsilyloxy)-4-hydroxy-1-(trity-
loxy)hexan-3-one (40). To a solution of oxazolidinone 39 (2.06 g,
2.55 mmol) in THF (112 mL) was added a 1 M aqueous solution of
NaOH (112 mL). After 2.5 h of vigorous stirring, the reaction mixture
was neutralized by addition of a 1 M solution of hydrochloric acid.
The layers were separated and the aqueous phase was extracted with
Et2O. The combined organic extracts were washed with brine and
dried over MgSO4, filtered, and concentrated under reduced pres-
sure. The residue was purified by flash chromatography on silica gel
(petroleum ether/Et2O gradient: 80/20 to 70/30) to afford 1.22 g
0.93 (t, J¼7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 134.7 (d), 132.1
(d), 131.2 (d), 117.1 (t), 83.0 (s), 74.0 (d), 70.9 (t), 70.4 (t), 64.7 (d),
50.7 (d), 23.6 (t), 11.7 (q); EIMS m/z (relative intensity) 194 (0.08),
139 (7), 123 (11), 109 (6), 107 (18), 95 (58), 93 (24), 82 (100), 79
(43), 69 (78), 67 (67), 57 (20), 55 (82), 53 (19); HRMS: MþNaþ,
found 217.1199. C12H18O2Na requires 217.1199.
(76%) of
was determined by super-critical fluid chromatography (SFC) ana-
lysis on chiral stationary phase;27
D ꢀ7.4 (c 0.63, CHCl3); IR 1711,
1597, 1105, 1068, 761, 736, 698, 632, 613 cmꢀ1 1H NMR (400 MHz,
CDCl3) 7.66e7.64 (m, 4H), 7.44e7.34 (m, 12H), 7.30e7.25 (m, 6H),
7.24e7.20 (m, 3H), 4.37 (ddd, apparent dt, J¼7.5, 4.0 Hz, 1H),
3.88e3.78 (m, 2H), 3.69 (d, J¼4.3 Hz,1H, OH), 3.46 (dt, J¼9.2, 6.4 Hz,
1H), 3.41 (dt, J¼9.2, 6.2 Hz, 1H), 2.76 (t, J¼6.4 Hz, 2H), 2.10e2.02 (m,
1H), 1.84e1.75 (m, 1H), 1.03 (s, 9H); 13C NMR (100 MHz, CDCl3)
a
-hydroxyketone 40 as a colorless oil (eeꢃ94%). The ee value
4.3.2.2. (E)-(3R,4R,7R,8S)-11-Allyloxy-1-(tert-butyldiphenylsilyl-
oxy)-8-ethyl-3-methoxymethoxy-4-[2-(trityloxy)ethyl]undec-9-en-5-
yne-4,7-diol (43). To a solution of alkyne 42 (126 mg, 0.648 mmol,
3.5 equiv) in Et2O (4 mL) at ꢀ20 ꢁC was added dropwise a solution
of i-PrMgCl (0.60 mL, 2.0 M in THF, 1.2 mmol, 6.5 equiv). After 1 h at
0 ꢁC, the reaction mixture was cooled to ꢀ20 ꢁC and a solution of
ketone 41 (125 mg, 0.185 mmol) in Et2O (5 mL) was added. After
1.5 h stirring at ꢀ20 ꢁC, the reaction mixture was poured into
a saturated aqueous solution of NH4Cl. The layers were separated
and the aqueous phase was extracted with Et2O. The combined
organic extracts were dried over MgSO4, filtered, and concentrated
under reduced pressure. The residue was purified by flash chro-
matography on silica gel (petroleum ether/Et2O gradient: 70/30 to
40/60) to afford 134 mg (84%) of 43 as a colorless oil. The excess of
[a]
;
d
d
210.9 (s),143.8 (s, 3C),135.5 (d, 4C),133.3 (s, 2C),129.7 (d, 2C),128.6
(d, 6C),127.8 (d, 6C),127.7 (d, 4C),127.0 (d, 3C), 86.9 (s), 74.9 (d), 60.2
(t), 59.1 (t), 38.6 (t), 35.7 (t), 26.8 (q, 3C), 19.1 (s); HRMS: MþNaþ,
found 651.2901. C41H44O4NaSi requires 651.2901.
4.3.1.6. (R)-6-(tert-Butyldiphenylsilyloxy)-4-methoxymethoxy-1-
(trityloxy)hexan-3-one (41). To a solution of
a
-hydroxyketone 40
alkyne 42 (90 mg, 2.5 equiv) was quantitatively recovered; [
þ34.7 (c 1.32, CHCl3); IR 3439, 1449, 1428, 1153, 1087, 1031, 975,
923, 823, 763, 744, 704 cmꢀ1 1H NMR (400 MHz, CDCl3)
7.69e7.64 (m, 4H), 7.46e7.34 (m, 12H), 7.32e7.28 (m, 6H),
a]
D
(55 mg, 0.087 mmol) in CH2Cl2 (2 mL) were successively added
i-Pr2NEt (0.15 mL, 0.87 mmol, 10 equiv), DMAP (10 mg,
0.087 mmol, 1 equiv), and NaI (13 mg, 0.087 mmol, 1 equiv). The
;
d
reaction mixture was cooled to 0 ꢁC and MOMCl (80
mL, 1.05 mmol,
7.25e7.20 (m, 3H), 5.85 (ddt, J¼17.2, 10.4, 5.6 Hz, 1H), 5.63 (dt,
J¼15.4, 6.1 Hz, 1H), 5.45 (apparent br dd, J¼15.4, 9.3 Hz, 1H), 5.22
(dq, J¼17.2, 1.5 Hz, 1H), 5.12 (dq, J¼10.3, 1.5 Hz, 1H), 4.69 (d, AB syst,
J¼6.6 Hz,1H), 4.67 (d, AB syst, J¼6.6 Hz, 1H), 4.47 (br s, 1H, OH), 4.19
(d, J¼4.8 Hz, 1H), 3.93e3.84 (m, 4H), 3.83e3.76 (m, 2H), 3.72 (dd,
J¼9.2, 2.6 Hz, 1H), 3.63e3.55 (m, 1H), 3.52e3.47 (m, 1H), 3.27 (s,
3H), 2.19e2.06 (m, 3H), 1.84 (dt, J¼14.1, 4.7 Hz, 1H), 1.76e1.63 (m,
2H, 1HþOH), 1.47e1.37 (m, 1H), 1.30e1.20 (m, 1H), 1.05 (s, 9H), 0.81
12 equiv) was added. After 12 h stirring at rt, the same quantities of
i-Pr2NEt (0.15 mL, 0.87 mmol, 10 equiv), DMAP (10 mg, 0.09 mmol,
1 equiv), NaI (13 mg, 0.09 mmol, 1 equiv), and MOMCl (80 mL,
1.1 mmol,12 equiv) were added. After 4 h at rt, the reaction mixture
was hydrolyzed with water. The layers were separated and the
aqueous phase was extracted with Et2O. The combined organic
extracts were dried over MgSO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash chromatogra-
phy on silica gel (petroleum ether/Et2O: 80/20) to afford 58 mg
(t, J¼7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 143.8 (s, 3C), 135.6 (d,
4C), 134.8 (d), 133.8 (s), 133.7 (s), 132.5 (d), 130.9 (d), 129.6 (d, 2C),
128.6 (d, 6C), 127.9 (d, 6C), 127.6 (d, 4C), 127.1 (d, 3C), 117.0 (t), 98.4
(t), 87.6 (s), 86.8 (s), 84.9 (s), 82.2 (d), 73.7 (s), 70.9 (t), 70.6 (t), 65.0
(d), 61.7 (t), 60.8 (t), 56.0 (q), 50.9 (d), 36.1 (t), 34.4 (t), 26.9 (q, 3C),
23.5 (t), 19.2 (s), 11.8 (q); HRMS: MþNaþ, found 889.4481.
C55H66O7NaSi requires 889.4470.
(99%) of
CHCl3); IR 1719, 1613, 1513, 1248, 1110, 1065, 1035, 822, 745, 705,
683, 669 cmꢀ1 1H NMR (400 MHz, CDCl3)
7.67e7.64 (m, 4H),
a
-alkoxy ketone 41 as a colorless oil; [
a
]
þ5.9 (c 0.95,
D
;
d
7.43e7.34 (m, 12H), 7.30e7.25 (m, 6H), 7.23e7.19 (m, 3H), 4.60 (d,
AB syst, J¼6.7 Hz, 1H), 4.58 (d, AB syst, J¼6.7 Hz, 1H), 4.30 (dd,
J¼8.6, 3.9 Hz, 1H), 3.83e3.74 (m, 2H), 3.40 (t, J¼6.4 Hz, 2H), 3.29 (s,
3H), 2.74 (dt, J¼6.4, 2.1 Hz, 2H), 2.00e1.91 (m, 1H), 1.82e1.75 (m,
4.3.2.3. (5E,9E)-(3R,4R,7S,8S)-11-Allyloxy-1-(tert-butyldiphe-
nylsilyloxy)-8-ethyl-3-methoxymethoxy-4-(2-trityloxyethyl) undeca-
5,9-diene-4,7-diol (44). To a solution of alkynyl 1,4-diol 43 (711 mg,
0.820 mmol) in Et2O (13 mL) at 0 ꢁC, was added a solution of Red-Al
(2 mL, 3.33 M in toluene, 6.72 mmol, 8.2 equiv). After 1.5 h and 3 h
at 0 ꢁC, more Red-Al (2 mL, 3.33 M in toluene, 6.72 mmol, 8.2 equiv)
1H),1.05 (s, 9H); 13C NMR (100 MHz, CDCl3)
d 209.4 (s),144.0 (s, 3C),
135.5 (d, 4C), 133.6 (s), 133.5 (s), 129.7 (d, 2C), 128.6 (d, 6C), 127.7 (d,
6C), 127.7 (d, 4C), 126.9 (d, 3C), 96.6 (t), 86.8 (s), 79.3 (d), 59.6 (t),
58.9 (t), 56.0 (q), 39.0 (t), 34.6 (t), 26.8 (q, 3C), 19.2 (s); HRMS:
MþNaþ, found 695.31633. C43H48O5NaSi requires 695.31632.

6372
V. Druais et al. / Tetrahedron 66 (2010) 6358e6375
was added. After a further 1.5 h at 0 ꢁC, the reaction mixture was
poured into a saturated aqueous solution of sodium potassium
tartrate. After dilution with EtOAc and 1 h of vigorous stirring at rt,
the layers were separated and the aqueous phase was extracted
with EtOAc. The combined organic extracts were dried over MgSO4,
filtered, and concentrated under reduced pressure. The crude ma-
terial was purified by flash chromatography on silica gel (petroleum
ether/Et2O: 50/50) to afford 442 mg (62%) of 1,4-diol 44 as a color-
heated at reflux. Additional portions of the catalyst (10 mg,
0.012 mmol, 0.025 equiv) were added every 2 h (total quantity of
catalyst used: 70 mg, 0.082 mmol, 0.17 equiv). After a total duration
of 20 h at reflux, the reaction mixture was cooled to rt and evapo-
rated under reduced pressure. The residue was purified by flash
chromatography on silica gel (petroleum ether/Et2O gradient: 70/30
to 50/50) to afford 353 mg (88%) of lactone 46 as a pale brown solid.
When acrylate 45 (30 mg, 0.032 mmol) was treated with Grubbs
II catalyst (1.4 mg, 0.0016 mmol, 5 mol %) in CH2Cl2 (3.2 mL) (reflux,
2 h), 1H NMR analysis of the crude material indicated the formation
less oil; [
1027, 976, 921, 822, 736, 700 cmꢀ1
7.67e7.64 (m, 4H), 7.43e7.35 (m, 12H), 7.30e7.27 (m, 6H),
a]
þ18.8 (c 0.50, CHCl3); IR 3474, 1448, 1427, 1147, 1067,
D
;
1H NMR (400 MHz, CDCl3)
d
of d-lactone 46 and the truncated acrylate 47 in a 75:25 ratio. After
7.24e7.20 (m, 3H), 5.88 (ddt, J¼17.1, 10.7, 5.6 Hz, 1H), 5.72 (dd,
J¼15.4, 6.8 Hz, 1H), 5.59 (dt, J¼15.5, 6.1 Hz, 1H), 5.52 (d, J¼15.4 Hz,
1H), 5.37 (dd, J¼15.5, 9.2 Hz, 1H), 5.24 (dm, apparent br d,
J¼17.2 Hz, 1H), 5.13 (dm, apparent br d, J¼10.4 Hz, 1H), 4.61 (d, AB
syst, J¼6.5 Hz, 1H), 4.56 (d, AB syst, J¼6.5 Hz, 1H), 4.06 (br s, 1H,
OH), 3.97 (dd, apparent t, J¼6.0 Hz, 1H), 3.94e3.85 (m, 4H),
3.77e3.67 (m, 2H), 3.49 (dd, J¼8.6, 2.7 Hz, 1H), 3.36e3.24 (m, 2H),
3.26 (s, 3H), 2.12e2.02 (m, 2H), 1.95e1.87 (m, 1H), 1.82 (dt, J¼14.3,
5.0 Hz, 1H), 1.54e1.38 (m, 3H, 2HþOH), 1.23e1.13 (m, 1H), 1.04 (s,
purification of the crude product by chromatography on a pre-
parative TLC silica gel plate (petroleum ether/EtOAc: 70/30), 3.4 mg
(13%) of 47 and 17.2 mg (65%) of 46 were isolated.
4.3.2.6. (5S,6S)-6-[(E)-(3R,4R)-6-(tert-Butyldiphenyl-silyloxy)-3-
hydroxy-4-methoxymethoxy-3-(2-trityloxyethyl)hex-1-enyl]-5-ethyl-
5,6-dihydropyran-2-one (46). Mp 47e49 ꢁC; [
a
]
þ58.7 (c 0.88,
D
CHCl3); IR 3469, 1726, 1448, 1428, 1382, 1149, 1109, 1085, 1028, 823,
763, 745, 704 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
7.68e7.64 (m, 4H),
9H), 0.82 (t, J¼7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 143.8 (s,
7.45e7.36 (m, 12H), 7.32e7.27 (m, 6H), 7.25e7.21 (m, 3H), 6.87 (dd,
J¼9.8, 5.3 Hz, 1H), 5.99 (d, J¼9.8 Hz, 1H), 5.86 (dd, J¼15.5, 5.1 Hz,
1H), 5.78 (d, J¼15.5 Hz, 1H), 4.91 (dd, apparent t, J¼4.6 Hz, 1H), 4.60
(d, AB syst, J¼6.6 Hz, 1H), 4.56 (d, AB syst, J¼6.6 Hz, 1H), 4.26 (br s,
1H, OH), 3.78e3.69 (m, 2H), 3.49 (dd, J¼8.7, 2.8 Hz, 1H), 3.35e3.30
(m, 2H), 3.28 (s, 3H), 2.34e2.28 (m, 1H), 2.06 (apparent dt, J¼14.2,
7.1 Hz, 1H), 1.97e1.91 (m, 1H), 1.79 (apparent dt, J¼14.2, 5.6 Hz, 1H),
1.57e1.37 (m, 2H), 1.32e1.18 (m, 1H), 1.04 (s, 9H), 0.84 (t, J¼7.4 Hz,
3C), 135.6 (d, 4C), 134.9 (d), 134.3 (d), 133.8 (s), 133.7 (s), 133.6 (d),
131.0 (d), 129.7 (d), 129.6 (d, 2C), 128.6 (d, 6C), 127.9 (d, 6C), 127.6 (d,
4C),127.1 (d, 3C),116.9 (t), 98.2 (t), 87.5 (s), 83.5 (d), 76.6 (s), 74.8 (d),
70.8 (t), 70.7 (t), 61.1 (t), 60.9 (t), 55.9 (q), 50.7 (d), 35.7 (t), 33.9 (t),
26.9 (q, 3C), 23.1 (t), 19.2 (s), 12.0 (q); HRMS: MþNaþ, found
891.4635. C55H68O7NaSi requires 891.4626.
3H); 13C NMR (100 MHz, CDCl3)
d 164.0 (s), 149.8 (d), 143.9 (s, 3C),
4.3.2.4. (E)-(1S,4R,5R)-1-((E)-(S)-4-Allyloxy-1-ethylbut-2-enyl)-
7-(tert-butyldiphenyl-silyloxy)-4-hydroxy-5-methoxymethoxy-4-(2-
trityloxyethyl)hept-2-enyl acrylate (45). To a solution of compound
44 (29.6 mg, 0.034 mmol) in CH2Cl2 (0.5 mL) were added DMAP
(1.0 mg, 0.01 mmol, 0.3 equiv) and i-Pr2NEt (0.07 mL, 0.41 mmol,
12 equiv). The reaction mixture was cooled to ꢀ78 ꢁC and acryloyl
chloride (0.022 mL, 0.27 mmol, 8 equiv) was added. After 2 h at
ꢀ78 ꢁC, the reaction mixture was poured into brine. The layers
were separated and the aqueous phase was extracted with Et2O.
The combined organic extracts were dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude material was
purified by flash chromatography on silica gel (petroleum ether/
Et2O: 70/30) to afford 31 mg (quantitative) of acrylate 45 as a co-
135.7 (d), 135.5 (d, 4C), 133.7 (s), 133.6 (s), 129.6 (d, 2C), 128.5 (d,
6C),127.9 (d, 6C),127.6 (d, 4C),127.0 (d, 3C),125.3 (d),120.8 (d), 98.2
(t), 87.5 (s), 83.7 (d), 80.1 (d), 76.5 (s), 61.0 (t), 60.8 (t), 56.0 (q), 39.4
(d), 35.5 (t), 33.8 (t), 26.8 (q, 3C), 21.4 (t), 19.2 (s), 11.0 (q); HRMS:
MþNaþ, found 847.3985. C52H60O7NaSi requires 847.4001.
4.3.2.7. (E)-(1S,4R,5R)-7-(tert-Butyldiphenylsilyloxy)-1-((S)-1-
ethyl-allyl)-4-hydroxy-5-methoxymethoxy-4-(2-trityloxyethyl)hept-
2-enyl acrylate (47). [
1192, 1151, 1109, 1088, 1070, 1033, 982, 920, 762, 744, 704 cmꢀ1; 1H
NMR (400 MHz, CDCl3) 7.66e7.62 (m, 4H), 7.43e7.34 (m, 12H),
a
]
D þ24.6 (c 0.33, CHCl3); IR 3475, 1722, 1265,
d
7.28e7.18 (m, 9H), 6.33 (dd, J¼17.3, 1.6 Hz, 1H), 6.06 (dd, J¼17.3,
10.4 Hz, 1H), 5.79 (dd, J¼15.5, 7.2 Hz, 1H), 5.77 (dd, J¼10.4, 1.6 Hz,
1H), 5.59 (d, J¼15.5 Hz, 1H), 5.43 (ddd, apparent dt, J¼17.0, 10.3 Hz,
1H), 5.28 (m, 1H), 5.00 (dd, J¼10.3, 1.9 Hz, 1H), 4.95 (dd, J¼17.0,
1.9 Hz, 1H), 4.55 (d, AB syst, J¼6.6 Hz, 1H), 4.52 (d, AB syst, J¼6.6 Hz,
1H), 4.05 (s, 1H, OH), 3.75e3.65 (m, 2H), 3.40 (dd, J¼8.8, 3.0 Hz, 1H),
3.37e3.26 (m, 2H), 3.23 (s, 3H), 2.24e2.17 (m, 1H), 2.01e1.94 (m,
1H), 1.91e1.83 (m, 1H), 1.75 (apparent dt, J¼14.0, 5.8 Hz, 1H),
1.51e1.41 (m, 2H), 1.24e1.13 (m, 1H), 1.03 (s, 9H), 0.83 (t, J¼7.4 Hz,
lorless oil; [
1448, 1427, 1403, 1266, 1189, 1147, 1067, 1030, 972, 921, 761, 743,
700 cmꢀ1 1H NMR (400 MHz, CDCl3)
7.67e7.63 (m, 4H),
a
]
D þ19.9 (c 0.54, CHCl3); IR 3476,1721,1635,1618,1598,
;
d
7.41e7.34 (m, 12H), 7.28e7.24 (m, 6H), 7.22e7.18 (m, 3H), 6.32 (dd,
J¼17.4, 1.5 Hz, 1H), 6.05 (dd, J¼17.4, 10.5 Hz, 1H), 5.87 (ddt, J¼17.3,
10.4, 5.6 Hz, 1H), 5.78 (dd, J¼15.4, 7.4 Hz, 1H), 5.77 (dd, J¼10.5,
1.5 Hz, 1H), 5.61 (d, J¼15.5 Hz, 1H), 5.52 (dt, J¼15.5, 6.0 Hz, 1H), 5.38
(dd, J¼15.5, 9.0 Hz, 1H), 5.29 (dd, apparent t, J¼6.0 Hz,1H), 5.23 (dq,
J¼17.3, 1.5 Hz, 1H), 5.13 (dq, J¼10.4, 1.5 Hz, 1H), 4.56 (d, AB syst,
J¼6.6 Hz, 1H), 4.51 (d, AB syst, J¼6.6 Hz, 1H), 4.07 (br s, 1H, OH),
3.90e3.88 (m, 4H), 3.75e3.65 (m, 2H), 3.42 (dd, J¼8.6, 3.0 Hz, 1H),
3.36e3.24 (m, 2H), 3.23 (s, 3H), 2.28e2.21 (m, 1H), 2.03e1.94 (m,
1H), 1.91e1.83 (m, 1H), 1.76 (apparent dt, J¼14.2, 5.6 Hz, 1H),
1.55e1.40 (m, 2H), 1.30e1.15 (m, 1H), 1.03 (s, 9H), 0.83 (t, J¼7.4 Hz,
3H); 13C NMR (100 MHz, CDCl3)
d 165.2 (s), 144.0 (s, 3C), 137.4 (d),
136.1 (d),135.5 (d, 4C),133.8 (s, 2C),130.4 (t),129.6 (d, 2C),128.9 (d),
128.6 (d, 6C), 127.8 (d, 6C), 127.6 (d, 4C), 127.0 (d, 3C), 126.6 (d), 117.4
(t), 98.2 (t), 87.5 (s), 83.7 (d), 61.1 (t), 60.9 (t), 55.9 (q), 49.6 (d), 35.5
(t), 33.9 (t), 26.8 (q, 3C), 23.1 (t), 19.1 (s), 11.6 (q); HRMS: MþNaþ,
found 875.4314. C52H64O7NaSi requires 875.4306.
3H); 13C NMR (100 MHz, CDCl3)
d 165.1 (s), 143.9 (s, 3C), 136.5 (d),
4.3.2.8. (5S,6S)-6-[(E)-(3R,4R)-6-(tert-Butyl-diphenylsilyloxy)-3-
hydroxy-3-(2-hydroxy-ethyl)-4-methoxymethoxyhex-1-enyl]-5-
ethyl-5,6-dihydropyran-2-one (53).
135.5 (d, 4C), 134.9 (d), 133.8 (s), 133.7 (s), 132.9 (d), 130.3 (t), 129.6
(d, 2C), 129.5 (d), 128.9 (d), 128.5 (d, 6C), 127.8 (d, 6C), 127.6 (d, 4C),
127.0 (d, 3C), 126.4 (d), 116.8 (t), 98.1 (t), 87.5 (s), 83.4 (d), 76.6 (d),
76.5 (s), 70.6 (t), 70.5 (t), 61.1 (t), 60.9 (t), 55.9 (q), 48.2 (d), 35.6 (t),
33.9 (t), 26.8 (q, 3C), 23.2 (t), 19.1 (s), 11.7 (q); HRMS: MþNaþ, found
945.4734. C58H70O8NaSi requires 945.4732.
4.3.2.5. RRCM of acrylate 45. To a solution of acrylate 45
(450 mg, 0.488 mmol) in CH2Cl2 (49 mL) was added Grubbs II cat-
alyst (20 mg, 0.024 mmol, 0.05 equiv) and the reaction mixture was

V. Druais et al. / Tetrahedron 66 (2010) 6358e6375
6373
To a solution of trityl ether 46 (66 mg, 0.080 mmol) in MeOH
IR 3425, 2094, 1725, 1253, 1107, 1027, 823, 740, 703, 614 cmꢀ1
;
1H
(3.3 mL) was added TsOH$H2O (1.50 mg, 0.008 mmol, 0.1 equiv).
After 1.5 h at rt, the reaction mixture was hydrolyzed with a satu-
rated aqueous solution of NaHCO3 and MeOH was evaporated un-
der reduced pressure. The residue was partitioned between H2O
and EtOAc, the layers were separated, and the aqueous phase was
extracted with EtOAc. The combined organic extracts were dried
over MgSO4, filtered, and concentrated under reduced pressure.
The crude material was purified by flash chromatography on silica
gel (petroleum ether/EtOAc gradient: 60/40 to 40/60) to afford
NMR (400 MHz, CDCl3) 7.66e7.60 (m, 4H), 7.46e7.36 (m, 6H), 6.95
d
(dd, J¼9.8, 5.4 Hz, 1H), 6.07 (dd, J¼9.8, 1.0 Hz, 1H), 5.97 (dd, J¼15.4,
4.4 Hz, 1H), 5.89 (dd, J¼15.4, 1.0 Hz, 1H), 5.00 (apparent td, J¼4.2,
1.0 Hz, 1H), 4.61 (s, 2H), 4.20 (s, 1H, OH), 3.78e3.69 (m, 2H), 3.58
(dd, J¼8.6, 3.3 Hz, 1H), 3.46e3.41 (m, 1H), 3.39 (s, 3H), 3.32e3.25
(m, 1H), 2.44e2.38 (m, 1H), 1.97 (ddd, J¼13.7, 9.5, 6.1 Hz, 1H),
1.91e1.83 (m, 1H), 1.78 (ddd, J¼13.7, 9.4, 5.8 Hz, 1H), 1.64e1.53 (m,
2H), 1.50e1.41 (m, 1H), 1.04 (s, 9H), 0.95 (t, J¼7.5 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 163.9 (s), 149.8 (d), 135.5 (d, 4C), 134.6 (d), 133.3
36 mg (77%) of the primary alcohol 53 as a brown oil; [
(c 0.66, CHCl3); IR 3368, 1713, 1427, 1382, 1250, 1146, 1104, 1083,
1024, 982, 919, 822, 737, 701, 688, 613 cmꢀ1 1H NMR (400 MHz,
CDCl3)
7.66e7.61 (m, 4H), 7.46e7.37 (m, 6H), 6.96 (dd, J¼9.8,
a
]
þ71.8
(s), 133.2 (s), 129.8 (d, 2C), 127.8 (d, 4C), 126.0 (d), 120.9 (d), 98.5 (t),
85.6 (d), 79.7 (d), 75.2 (s), 60.4 (t), 56.1 (q), 47.1 (t), 39.2 (d), 34.3 (t),
33.9 (t), 26.8 (q, 3C), 21.6 (t), 19.1 (s), 11.0 (q); HRMS: MþNaþ, found
630.2962. C33H45O6N3NaSi requires 630.2970.
D
;
d
5.4 Hz, 1H), 6.07 (dd, J¼9.8, 1.1 Hz, 1H), 6.00 (dd, J¼15.4, 4.1 Hz, 1H),
5.93 (dd, J¼15.5, 1.2 Hz, 1H), 5.03 (apparent td, J¼4.2, 1.1 Hz, 1H),
4.70 (br s, 1H, OH), 4.62 (s, 2H), 3.86e3.81 (m, 1H), 3.75e3.71 (m,
3H), 3.59 (dd, J¼8.3, 3.6 Hz, 1H), 3.40 (s, 3H), 2.98 (br s, 1H, OH),
2.45e2.39 (m,1H), 2.04 (ddd, J¼14.5,10.0, 4.2 Hz,1H),1.94e1.85 (m,
1H), 1.71e1.42 (m, 4H), 1.04 (s, 9H), 0.95 (t, J¼7.4 Hz, 3H); 13C NMR
4.3.2.11. Allyl
{(3R,4R)-6-(tert-Butyldiphenylsilyloxy)-3-[(E)-2-
((1S,2S)-2-ethyl-5-oxo-cyclohex-3-enyl)vinyl]-3-hydroxy-4-
methoxymethoxyhexyl}carbamate (50). To a solution of azide 49
(5.0 mg, 8.2
(4.3 mg, 16
22 h at rt pyridine (4.0
(3.0 L, 25 mol, 3 equiv) were added. After 20 min stirring at rt,
m
m
mol) in THF (0.3 mL) were successively added PPh3
mol, 2 equiv) and H2O (1.5 L, 82 mol, 10 equiv). After
L, 49 mol, 6 equiv) and allyl chloroformate
m
m
(100 MHz, CDCl3)
d
164.0 (s), 150.0 (d), 135.5 (d, 4C), 134.9 (d), 133.2
m
m
(s), 133.1 (s), 129.8 (d, 2C), 127.7(d, 4C), 125.9 (d), 120.8 (d), 98.2 (t),
85.2 (d), 79.8 (d), 77.7 (s), 60.6 (t), 59.7 (t), 56.1 (q), 39.2 (d), 36.5 (t),
33.8 (t), 26.8 (q, 3C), 21.5(t), 19.1 (s), 11.0 (q); HRMS: MþNaþ, found
605.2894. C33H46O7NaSi requires 605.2905.
m
m
the reaction mixture was hydrolyzed with a saturated aqueous
solution of NaHCO3. The layers were separated and the aqueous
phase was extracted with EtOAc. The combined organic extracts
were washed with brine, dried over MgSO4, filtered, and concen-
trated under reduced pressure. The crude material was purified by
flash chromatography on silica gel (petroleum ether/EtOAc gra-
dient: 60/40 to 40/60) to afford 3.5 mg (64%) of carbamate 50 as
4.3.2.9. (3R,4R)-6-(tert-Butyldiphenylsilyl-oxy)-3-[(E)-2-((2S,3S)-
3-ethyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)vinyl]-3-hydroxy-4-me-
thoxymethoxyhexyl methanesulfonate (48). To a solution of alcohol
53 (42 mg, 0.072 mmol) in CH2Cl2 (1.3 mL) were added DMAP
a colorless oil; [
1463, 1428, 1382, 1247, 1148, 1107, 1027, 997, 985, 924, 823, 741, 703,
689, 614 cmꢀ1 1H NMR (400 MHz, CDCl3)
7.65e7.60 (m, 4H),
a
]
D þ58.0 (c 0.50, CHCl3); IR 3367, 1719, 1650, 1514,
(3.7 mg, 0.030 mmol, 0.41 equiv), pyridine (40
mL, 0.53 mmol,
7.3 equiv) and MsCl (20 L, 0.27 mmol, 3.8 equiv). After 14 h at rt,
m
;
d
the reaction mixture was poured into a 0.01 M solution of hydro-
chloric acid. The layers were separated and the aqueous phase was
extracted with EtOAc. The combined organic extracts were dried
over MgSO4, filtered, and concentrated under reduced pressure.
The crude material was purified by flash chromatography on silica
gel (petroleum ether/Et2O gradient: 30/70 to 10/90) to afford 40 mg
7.46e7.37 (m, 6H), 6.95 (dd, J¼9.8, 5.4 Hz, 1H), 6.07 (d, J¼9.8 Hz,
1H), 5.97 (dd, J¼15.5, 4.2 Hz, 1H), 5.96e5.87 (m, 2H), 5.43 (br s, 1H,
NH), 5.29 (dq, J¼17.2, 1.5 Hz, 1H), 5.19 (dq, J¼10.4, 1.5 Hz, 1H), 5.01
(apparent br t, J¼3.8 Hz, 1H), 4.61 (d, AB syst, J¼6.8 Hz, 1H), 4.59 (d,
AB syst, J¼6.8 Hz, 1H), 4.54 (d, J¼5.3 Hz, 2H), 4.39 (s, 1H, OH),
3.77e3.68 (m, 2H), 3.56 (dd, J¼8.3 Hz, 3.5 Hz, 1H), 3.38 (s, 3H),
3.38e3.33 (m, 1H), 3.23e3.15 (m, 1H), 2.43e2.37 (m, 1H), 1.90e1.83
(m, 2H), 1.73e1.54 (m, 3H), 1.51e1.40 (m, 1H), 1.04 (s, 9H), 0.94 (t,
(85%) of mesylate 48 as a colorless oil; [
3386, 1720, 1353, 1250, 1174, 1104, 1086, 1023, 972, 950, 822, 736,
702, 613 cmꢀ1 1H NMR (400 MHz, CDCl3)
7.66e7.60 (m, 4H),
a
]
D þ56.7 (c 0.96, CHCl3); IR
;
d
J¼7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 164.0 (s), 156.2 (s), 149.9
7.47e7.36 (m, 6H), 6.94 (dd, J¼9.8, 5.3 Hz, 1H), 6.07 (dd, J¼9.8,
1.1 Hz, 1H), 6.01 (dd, J¼15.4, 5.0 Hz, 1H), 5.91 (dd, J¼15.4, 0.8 Hz,
1H), 5.00 (apparent t, J¼4.0 Hz, 1H), 4.61 (d, AB syst, J¼6.7 Hz, 1H),
4.59 (d, AB syst, J¼6.7 Hz, 1H), 4.45e4.39 (m, 2H, 1HþOH),
4.29e4.27 (m, 1H), 3.79e3.68 (m, 2H), 3.57 (dd, J¼8.7, 3.4 Hz, 1H),
3.40 (s, 3H), 2.99 (s, 3H), 2.45e2.39 (m, 1H), 2.16 (ddd, J¼13.8, 8.8,
5.7 Hz, 1H), 1.97 (ddd, J¼13.8, 8.7, 6.1 Hz, 1H), 1.90e1.81 (m, 1H),
1.66e1.44 (m, 3H), 1.04 (s, 9H), 0.94 (t, J¼7.5 Hz, 3H); 13C NMR
(d), 135.5 (d, 4C), 134.8 (d), 133.3 (s), 133.2 (s), 129.8 (d, 2C), 127.8 (d,
4C), 125.9 (d, 2C), 120.9 (d), 117.4 (t), 98.4 (t), 85.7 (d), 79.7 (d), 76.5
(s), 65.3 (t), 60.5 (t), 56.1 (q), 39.3 (d), 36.9 (t), 34.7 (t), 33.9 (t), 26.8
(q, 3C), 21.6 (t), 19.2 (s), 11.0 (q); HRMS calcd for C37H51NO8NaSi
(MþNaþ): 688.3267. Found: 688.3276.
4.3.2.12. (5S,6S)-6-((E,3R,4R)-3-(2-(Allyloxycarbonylamino)
ethyl)-3,4,6-tris(triethylsilyloxy)-3-hex-1-enyl)-5-ethyl-5,6-dihy-
dropyran-2-one (51). To a solution of compound 50 (13.5 mg,
0.020 mmol) in THF (2.4 mL) was added a 6 M solution of hydro-
chloric acid (2.4 mL). After 2.5 h of vigorous stirring at rt, the re-
action was quenched by addition of solid NaHCO3. The layers were
separated and the aqueous phase was extracted with EtOAc. The
combined organic extracts were directly concentrated under re-
duced pressure and the residue was dried by azeotropic evapora-
tion with toluene. The crude material was purified by preparative
TLC on a silica gel plate (EtOAc/EtOH: 95/5) to afford 4.3 mg (55%) of
the fully deprotected triol. To a solution of this triol (3.2 mg,
(100 MHz, CDCl3) d 163.8 (s), 149.8 (d), 135.5 (d, 4C), 134.9 (d), 133.2
(s), 133.1 (s), 129.8 (d, 2C), 127.8 (d, 4C), 126.1 (d), 120.9 (d), 98.5 (t),
85.9 (d), 79.9 (d), 74.7 (s), 67.1 (t), 60.3 (t), 56.1 (q), 39.2 (d), 37.3 (q),
34.8 (t), 33.8 (t), 26.8 (q, 3C), 21.6 (t), 19.1 (s), 11.0 (q); HRMS:
MþNaþ, found 683.2678. C34H48O9NaSSi requires 683.2681.
4.3.2.10. (5S,6S)-6-[(E)-(3R,4R)-3-(2-Azidoethyl)-6-(tert-butyl-
diphenylsilyloxy)-3-hydroxy-4-methoxymethoxyhex-1-enyl]-5-ethyl-
5,6-dihydropyran-2-one (49). To a solution of mesylate 48 (40 mg,
0.061 mmol) in DMF (1.7 mL) was added NaN3 (39.7 mg,
0.610 mmol, 10 equiv). After 3 days stirring at rt, the reaction
mixture was diluted in water. The layers were separated and the
aqueous phase was extracted with EtOAc. The combined organic
extracts were dried over MgSO4, filtered, and concentrated under
reduced pressure. The crude material was purified by flash chro-
matography on silica gel (petroleum ether/EtOAc: 80/20) to afford
8.3
83
mmol) in CH2Cl2 (0.3 mL) was added 2,6-lutidine (10 mL,
m
mol, 10 equiv). The reaction mixture was cooled to ꢀ78 ꢁC and
TESOTf (13 mL, 58 mmol, 7 equiv) was added. After 1 h stirring at
ꢀ78 ꢁC and 1 h at 0 ꢁC, the reaction mixture was hydrolyzed with
brine. The layers were separated and the aqueous phase was
extracted with EtOAc. The combined organic extracts were dried
over MgSO4, filtered, and concentrated under reduced pressure.
26 mg (70%) of azide 49 as a colorless oil; [
a]
D þ60.5 (c 0.52, CHCl3);

6374
V. Druais et al. / Tetrahedron 66 (2010) 6358e6375
10. (a) Miyashita, K.; Tsunemi, T.; Hosokawa, T.; Ikejiri, M.; Imanishi, T. Tetrahedron
Lett. 2007, 48, 3829e3833; (b) Miyashita, K.; Tsunemi, T.; Hosokawa, T.; Ikejiri,
M.; Imanishi, T. J. Org. Chem. 2008, 73, 5360e5370.
The crude material was purified by preparative TLC on a silica gel
plate (petroleum ether/EtOAc: 70/30) to afford 4.4 mg (73%) of 51 as
a colorless oil; [
a
]
þ71.8 (c 0.44, CHCl3), lit.8
[
a
]
þ52.2 (c 0.65,
€
D
D
11. (a) Konig, C. M.; Gebhardt, B.; Schleth, C.; Dauber, M.; Koert, U. Org. Lett. 2009,
€
11, 2728e2731; (b) Gebhardt, B.; Konig, C. M.; Schleth, C.; Dauber, M.; Koert, U.
CHCl3); IR 3351, 1720, 1520, 1459, 1381, 1239, 1100, 1006, 791,
737 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
6.93 (dd, J¼9.8, 5.2 Hz, 1H),
Chem.dEur. J. 2010, 16, 5934e5941.
12. Moïse, J.; Sonawane, R. P.; Corsi, C.; Wendeborn, S. V.; Arseniyadis, S.; Cossy, J.
Synlett 2008, 2617e2620.
13. Sarkar, S. M.; Wanzala, E. N.; Shibahara, S.; Takahashi, K.; Ishihara, J.;
Hatakeyama, S. Chem. Commun. 2009, 5907e5909.
14. Druais, V.; Hall, M. J.; Corsi, C.; Wendeborn, S. V.; Meyer, C.; Cossy, J. Org. Lett.
2009, 11, 935e938.
15. (a) Still, W. C.; McDonald, J. H., III. Tetrahedron Lett. 1980, 21, 1031e1034;
6.05 (dd, J¼9.8, 1.2 Hz, 1H), 5.96e5.87 (m, 2H), 5.81 (dd, J¼15.6,
6.1 Hz, 1H), 5.29 (dd, J¼17.2, 1.5 Hz, 1H), 5.19 (d, J¼10.4 Hz, 1H),
5.03e5.00 (m, 1H), 4.91 (br s, 1H, NH), 4.55 (d, J¼5.3 Hz, 2H), 3.72
(dt, J¼9.0, 1.9 Hz, 1H), 3.69e3.57 (m, 2H), 3.34e3.27 (m, 1H),
3.19e3.11 (m, 1H), 2.44e2.39 (m, 1H), 2.08e2.01 (m, 1H), 1.89e1.80
(m, 1H), 1.79e1.72 (m, 1H), 1.68e1.44 (m, 2H), 1.33e1.26 (m, 1H),
0.99e0.92 (m, 30H), 0.69e0.53 (m, 18H); 13C NMR (100 MHz,
(b) Mengel, A.; Reiser, O. Chem. Rev. 1999, 99, 1191e1224.
16. (a) Chavez, D. E.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2001, 40, 3667e3670; (b)
Wang, Y.-G.; Kobayashi, Y. Org. Lett. 2002, 4, 4615e4618; (c) Trost, B. M.;
Frederiksen, M. U.; Papillon, J. P. N.; Harrington, P. E.; Shin, S.; Shireman, B. T.
J. Am. Chem. Soc. 2005, 127, 3666e3667.
17. (a) Nakai, T.; Mikami, K. Chem. Rev. 1986, 86, 885e902; (b) Marshall, J. A. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon:
London, 1991; Vol. 3, pp. 975e1014; (c) Kallmerten, J. In Houben-Weyl, Methods
of Organic Chemistry; Helmchen, G., Hoffman, R. W., Mulzer, J., Schaumann, E.,
Eds.; Thieme: Stuttgart, 1995; Vol. e 21d, pp 3757e3809.
18. For selected synthetic applications of [2,3]-Wittig rearrangements see:
(a) Parker, K. A.; Xie, Q. Org. Lett. 2008, 10, 1349e1352; (b) Cao, H.; Parker,
K. A. Org. Lett. 2008, 10, 1353e1356; (c) Liang, J.; Hoard, D. W.; Van Khau, V.;
Martinelli, M. J.; Moher, E. D.; Moore, R. E.; Tius, M. A. J. Org. Chem. 1999, 64,
1459e1463.
19. Dienes RCM can be problematic in the presence of an alkyne, see: (a) Ono, K.;
Nagata, T.; Nishida, A. Synlett 2003, 1207e1209; (b) Vedrenne, E.; Royer, F.;
Oble, J.; El Kaïm, L.; Grimaud, L. Synlett 2005, 2379e2381; (c) Bressy, C.;
Bargiggia, F.; Guyonnet, M.; Arseniyadis, S.; Cossy, J. Synlett 2009,
565e568.
CDCl3)
d 163.7 (s), 155.9 (s), 149.5 (d), 136.5 (d), 132.9 (d), 124.4 (d),
120.7 (d), 117.1 (t), 80.2 (d), 79.8 (s), 74.9 (d), 65.1 (t), 59.4 (t), 39.4
(d), 37.6 (t), 36.4 (t), 35.5 (t), 21.4 (t), 10.8 (q), 7.0 (q, 3C), 6.8 (q, 3C),
6.7 (t, 3C), 6.5 (q, 3C), 5.2 (t, 3C), 4.2 (q, 3C); HRMS: MþNaþ, found
758.4421. C37H71O7NNaSi requires 748.4431. The spectroscopic data
of compound 51 were in agreement with those previously reported
for the same advanced intermediate in Hatakeyama’s total syn-
thesis of phoslactomycin B.8
Acknowledgements
We gratefully acknowledge Syngenta for financial support. One
of us (V.D.) thanks the MRES for a grant.
20. Dicobalt hexacarbonyl complexes of alkynes are compatible with dienes RCM,
see: Ref. 19a and (a) Young, D. G. J.; Burlison, J. A.; Peters, U. J. Org. Chem. 2003,
68, 3494e3497; (b) Geng, X.; Danishefsky, S. J. Org. Lett. 2004, 6, 413e416;
(c) Yang, Z.-Q.; Geng, X.; Solit, D.; Pratilas, C. A.; Rosen, N.; Danishefsky, S. J.
J. Am. Chem. Soc. 2004, 126, 7881e7889.
Supplementary data
Determination of the optical purities of alcohols 7, 8, 37 and
21. Unsaturated d-lactones can be formed by RCM in the presence of the (triiso-
a
-hydroxyketone 40, chemical correlation for the attribution of the
propylsilyl)ethynyl group, see: Langille, N. F.; Panek, J. S. Org. Lett. 2004, 6,
3203e3206.
relative configuration of allylic alcohol 33. Supplementary data
associated with this article can be found in online version at
doi:10.1016/j.tet.2010.05.050.
22. (a) Michaut, M.; Parrain, J.-L.; Santelli, M. Chem. Commun. 1998, 2567e2568;
(b) Hoye, T. R.; Jeffrey, C. S.; Tennakoon, M. A.; Wang, J.; Zhao, H. J. Am. Chem.
Soc. 2004, 126, 10210e10211; (c) Wallace, D. J. Angew. Chem., Int. Ed. 2005, 44,
1912e1915; (d) Hoye, T.R.; Jeon, J. In Metathesis in Natural Product Synthesis,
Cossy, J.; Arseniyadis, S.; Meyer, C.; Wiley-VCH, Weinheim, 2010.
23. Allyloxyacetic acid was prepared according to: Taillier, C.; Hameury, T.; Bellosta,
V.; Cossy, J. Tetrahedron 2007, 63, 4472e4490.
24. (a) Angelastro, M. R.; Peet, N. P.; Bey, P. J. Org. Chem. 1989, 54, 3913e3916;
(b) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815e3818.
25. (a) Ng, S. M.; Bader, S. J.; Snapper, M. L. J. Am. Chem. Soc. 2006, 128, 7315e7319;
(b) Satcharoen, V.; McLean, N. J.; Kemp, S. C.; Camp, N. P.; Brown, R. C. D. Org.
Lett. 2007, 9, 1867e1869.
References and notes
1. (a) Fushimi, S.; Nishikawa, S.; Shimazu, A.; Seto, H. J. Antibiot. 1989, 42,
1019e1025; (b) Fushimi, S.; Furihata, K.; Seto, H. J. Antibiot. 1989, 42,
1026e1036 For the isolation of structurally similar or identical phosphazo-
mycins, see:
(c) Uramoto, M.; Shen, Y.-C.; Takizawa, N.; Kusakabe, H.; Isono, K. J. Antibiot.
1985, 38, 665e668; (d) Tomiya, T.; Uramoto, M.; Isono, K. J. Antibiot. 1990,
43, 118e121.
2. (a) Ozasa, T.; Suzuki, K.; Sasamata, M.; Tanaka, K.; Kobori, M.; Kadota, S.; Nagai,
K.; Saito, T.; Watanabe, S.; Iwanami, M. J. Antibiot. 1989, 42, 1331e1338;
(b) Ozasa, T.; Tanaka, K.; Sasamata, M.; Kaniwa, H.; Shimizu, M.; Matsumoto, H.;
Iwanami, M. J. Antibiot. 1989, 42, 1339e1343.
3. (a) Kohama, T.; Enokita, R.; Okazaki, T.; Miyaoka, H.; Torikata, A.; Inukai, M.;
Kaneko, I.; Kagasaki, T.; Sakaida, Y.; Satoh, A.; Shiraishi, A. J. Antibiot. 1993, 46,
1503e1511; (b) Kohama, T.; Nakamura, T.; Kinoshita, T.; Kaneko, I.; Shiraishi, A.
J. Antibiot. 1993, 46, 1512e1519; (c) Shibata, T.; Kurihara, S.; Yoda, K.; Haruyama,
H. Tetrahedron 1995, 51, 11999e12012; (d) Kohama, T.; Maeda, H.; Sakai, J. I.;
Shiraishi, A.; Yamashita, K. J. Antibiot. 1996, 49, 91e94.
4. Shibata, T.; Kurihara, S.; Oikawa, T.; Ohkawa, N.; Shimazaki, N.; Sasagawa, K.;
Kobayashi, T.; Kohama, T.; Asai, F.; Shiraishi, A.; Sugimura, Y. J. Antibiot. 1995, 48,
1518e1520.
5. (a) Tunac, J. B.; Graham, B. D.; Dobson, W. E. J. Antibiot. 1983, 36, 1595e1600;
(b) Stampwala, S. S.; Bunge, R. H.; Hurley, T. R.; Willmer, N. E.; Brankiewicz,
A. J.; Steinman, C. E.; Smitka, T. A.; French, J. C. J. Antibiot. 1983, 36,
1601e1605.
6. (a) Usui, T.; Marriott, G.; Inagaki, M.; Swarup, G.; Osada, H. J. Biochem. 1999, 125,
960e965; (b) Kawada, M.; Kawatsu, M.; Masuda, T.; Ohba, S.; Amemiya, M.;
Kohama, T.; Ishizuka, M.; Takeuchi, T. Int. Immunopharmcol. 2003, 3, 179e188;
(c) Faulkner, N. E.; Lane, B. R.; Bock, P. J.; Markovitz, D. M. J. Virol. 2003, 77,
2276e2281.
26. Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1997, 119,
8738e8739.
27. The enantiomeric excess was determined by super-critical fluid chromatogra-
phy analysis on chiral stationary phase, see Supplementary data.
28. Aerssens, M. H. P. J.; Brandsma, L. J. Chem. Soc., Chem. Commun. 1984, 735e736.
29. Wright, J. M.; Jones, G. B. Tetrahedron Lett. 1999, 40, 7605e7609.
30. Wu, Y.-D.; Houk, K. N.; Marshall, J. A. J. Org. Chem. 1990, 55, 1421e1423.
31. Mikami, K.; Uchida, T.; Hirano, T.; Wu, Y.-D.; Houk, K. N. Tetrahedron 1994, 50,
5917e5926.
32. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953e956.
33. (a) Fürstner, A.; Langemann, K. J. Am. Chem. Soc. 1997, 119, 9130e9136;
(b) Ghosh, A. K.; Cappiello, J.; Shin, D. Tetrahedron Lett. 1998, 39, 4651e4654.
34. Bialy, L.; Lopez-Canet, M.; Waldmann, H. Synthesis 2002, 2096e2104.
35. Lawhorn, B. G.; Boga, S. B.; Wolkenberg, S. E.; Colby, D. A.; Gauss, C.-M.;
Swingle, M. R.; Amable, L.; Honkanen, R. E.; Boger, D. L. J. Am. Chem. Soc. 2006,
128, 16720e16732.
36. Salit, A.-F.; Meyer, C.; Cossy, J.; Delouvrié, B.; Hennequin, L. Tetrahedron 2008,
64, 6684e6697.
37. Valverde, S.; Bernabé, M.; Garcia-Ochoa, S.; Gómez, A. M. J. Org. Chem. 1990, 55,
2294e2298.
38. (a) Coates, R. M.; Rogers, B. D.; Hobbs, S. J.; Peck, D. R.; Curran, D. P. J. Am. Chem.
Soc. 1987, 109, 1160e1170; (b) Panda, J.; Ghosh, S. Tetrahedron Lett. 1999, 40,
6693e6694.
39. For the RCM of dienes containing mixed methyl acetals, see: Rutjes, F. P. J. T.;
Kooistra, T. M.; Hiemstra, H.; Schoemaker, H. E. Synlett 1998, 192e193.
40. Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.; Dolling, U.-H.;
Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 5461e5464.
41. This compound was prepared from 3-iodobut-3-en-1-ol which, in turn, was
obtained from homopropargyl alcohol by hydroiodination, see: (a) Kamiya, N.;
Chikami, Y.; Ishii, Y. Synlett 1990, 675e676; (b) Sugiyama, H.; Yokokawa, F.;
Shioiri, T. Org. Lett. 2000, 2, 2149e2152.
7. (a) Wang, Y.-G.; Takeyama, R.; Kobayashi, Y. Angew. Chem., Int. Ed. 2006, 45,
3320e3323; (b) Nonaka, H.; Maeda, N.; Kobayashi, Y. Tetrahedron Lett. 2007, 48,
5601e5604.
8. (a) Shibahara, S.; Fujino, M.; Tashiro, Y.; Takahashi, K.; Ishihara, J.; Hatakeyama,
S. Org. Lett. 2008, 10, 2139e2142; (b) Shibahara, S.; Fujino, M.; Tashiro, Y.;
Okamoto, N.; Esumi, T.; Takahashi, K.; Ishihara, J.; Hatakeyama, S. Synthesis
2009, 2935e2953.
9. Shimada, K.; Kaburagi, Y.; Fukuyama, T. J. Am. Chem. Soc. 2003, 125, 4048e4049.

V. Druais et al. / Tetrahedron 66 (2010) 6358e6375
6375
42. (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987, 109, 5551e5553;
(b) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh, V. K. J. Am. Chem. Soc.
1987, 109, 7925e7926.
43. The relative configuration of the allylic alcohol 33 was ascertained by de-
protection of the alcohol at C11 and comparison with authentic samples of the
corresponding syn- and anti-1,3-diols, see Supplementary data.
44. Rai, A. N.; Basu, A. Tetrahedron Lett. 2003, 44, 2267e2269.
45. (a) Van Rheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976, 17, 1973e1976;
(b) Dupau, P.; Epple, R.; Thomas, A. A.; Fokin, V. V.; Sharpless, K. B. Adv. Synth.
Catal. 2002, 3, 421e433.
50. Ohe, K.; Ishihara, T.; Chatani, N.; Kawasaki, Y.; Murai, S. J. Org. Chem. 1991, 56,
2267e2268.
51. For alternative procedures using copper, silver or gold catalysts, see: (a) Kimura,
M.; Kure, S.; Yoshida, Z.; Tanaka, S.; Fugami, K.; Tamaru, Y. Tetrahedron Lett.
1990, 31, 4887e4890; (b) Ritter, S.; Horino, Y.; Lex, J.; Schmalz, H.-G. Synlett
2006, 3309e3313; (c) Buzas, A.; Gagosz, F. Org. Lett. 2006, 8, 515e518.
52. One example dealing with the use of this strategy to prepare an a-hydroxy-
ketone bearing an adjacent tertiary alcohol has been reported: Matsuura, T.;
Nishiyama, S.; Yamamura, S. Chem. Lett. 1993, 1503e1504.
53. When oxazolidinone 39 was treated with K2CO3 in a MeOH/H2O (19:1) mixture,
46. Veysoglu, T.; Mitscher, L. A.; Swayze, J. K. Synthesis 1980, 807e810.
47. (a) Caprio, V.; Brimble, M. A.; Furkert, D. P. Tetrahedron 2001, 57, 4023e4034;
(b) Brimble, M. A.; Fares, F. A.; Turner, P. Aust. J. Chem. 2000, 53, 845e852.
48. Achmatowicz, B.; Raubo, P.; Wicha, J. J. Org. Chem. 1992, 57, 6593e6598.
49. (a) Swaminathan, S.; Narayanan, K. V. Chem. Rev. 1971, 71, 429e438; (b) Ramón,
R. S.; Marion, N.; Nolan, S. P. Tetrahedron 2009, 65, 1767e1773 and references
cited therein.
the desired a-hydroxyketone 40 was obtained in good yield (80%) but racemi-
zationwas observed under those condtions (ee¼80%). Less racemization occurred
with KOH in MeOH/H2O (2:1) (ee¼91%) but the yield of 40 was lower (69%).
54. Narasaka, K.; Sakakura, T.; Uchimaru, T.; Guédin-Vuong, D. J. Am. Chem. Soc.
1984, 106, 2954e2961.
55. Chan, K.-K.; Cohen, N.; De Noble, J. P.; Specian, A. C., Jr.; Saucy, G. J. Org. Chem.1976,
41, 3497e3505; (b) Denmark, S. E.; Jones, T. K. J. Org. Chem. 1982, 47, 4595e4597.