Synthetic studies toward cytostatin, a natural product inhibitor of protein phosphatase 2A

Article abstract of DOI:10.1016/j.tet.2008.05.012

Synthetic approaches toward the natural product cytostatin, an inhibitor of protein phosphatase 2A possessing cytotoxic and antimetastatic activities, have been investigated. A formal synthesis of cytostatin has been achieved according to a strategy relyi

Full text of DOI:10.1016/j.tet.2008.05.012

Tetrahedron 64 (2008) 6684–6697
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthetic studies toward cytostatin, a natural product inhibitor
of protein phosphatase 2A
a
a
,
a,
*
*
´ ´
Anne-Frederique Salit , Christophe Meyer , Janine Cossy
,
b
b
´ ´
´
Benedicte Delouvrie , Laurent Hennequin
a Laboratoire de Chimie Organique, ESPCI, CNRS (UMR 7084), 10 rue Vauquelin, 75231 Paris Cedex 05, France
b AstraZeneca, Chemin Vrilly, 51100 Reims, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthetic approaches toward the natural product cytostatin, an inhibitor of protein phosphatase 2A
possessing cytotoxic and antimetastatic activities, have been investigated. A formal synthesis of cytostatin
has been achieved according to a strategy relying on the formation of the C8–C9 bond by a nucleophilic
addition of a functionalized organolithium (C1–C8 subunit) to an aldehyde (C9–C13 subunit).
Ó 2008 Elsevier Ltd. All rights reserved.
Received 1 April 2008
Accepted 2 May 2008
Available online 7 May 2008
This article is dedicated to the memory of
Dr. Patrice Siret
1. Introduction
selected on the basis of the structural analogy between cytostatin
and fostriecin6 or the phoslactomycins7 as well as additional NMR
The natural product cytostatin was isolated in 1994 from cul-
tures of Streptomyces sp. MJ654-NF4.1 Cytostatin was found to
exhibit cytotoxic activity against several cancer cell lines at
submicromolar concentrations,1 to induce apoptosis and to inhibit
metastasis of B16-BL6 melanoma cells in mice.2 The mode of action
of this antitumor agent derives from a remarkably selective in-
hibition of serine–threonine phosphatase 2A (PP2A), an enzyme
implicated in the regulation of many crucial biological events in-
cluding cell division.3,4 The identification of the structural features
in natural products leading to selective inhibition of PP2A may be
important for the development of small molecule-based inhibitors
that could potentially be used in an alternative approach to cancer
therapy.4
studies on model diasteromeric a,b-unsaturated d-lactones in-
corporating the C4–C6 stereotriad.8 The spectroscopic data of the
synthetic material, which was found to inhibit PP2A at a level
comparable to cytostatin, were in agreement with those reported
for the natural product. The optical rotations were different but this
was attributed to the contamination of the natural product sample
by an impurity.5
O
O
P
NaO
14
1
4
O
O
9
OH
11
18
HO
6
16
13
Cytostatin is a polyketide natural product with an 18-carbon
Cytostatin
Figure 1. Structure of cytostatin.
backbone containing an
a,b-unsaturated d-lactone (C1–C5), two
syn,anti-stereotriads (C4–C6 and C9–C11), a phosphate group at C9,
and a (Z,Z,E)-conjugated triene (C12–C17) (Fig. 1). The basic struc-
ture of cytostatin was readily established by NMR experiments but
its absolute and relative configurations were not initially assigned.1
In 2002, Waldmann and Bialy reported the first total synthesis of
the (4S,5S,6S,9S,10S,11S)-stereoisomer of cytostatin according to
a linear approach.5 The configurations of the stereocenters were
The preparation of a C3–C13 precursor of cytostatin was sub-
sequently reported by Marshall and Ellis.9 The second total syn-
thesis of cytostatin and its C10,C11 diastereomers, according to
a convergent approach, was disclosed by Boger et al. in 2006.10
Recently, cytostatin and three stereoisomers were synthesized by
Curran et al. using fluorous mixture synthesis.11
Herein, we would like to report our studies on the development
of convergent approaches toward cytostatin12 that include the
synthesis of a C3–C13 fragment and a C1–C13 advanced in-
termediate accounting for a formal synthesis of the natural product.
* Corresponding authors. Tel.: þ33 1 40795845; fax: þ33 1 40794660 (C.M.); tel.:
þ33 1 40794429; fax: þ33 1 40794660 (J.C.).
E-mail addresses: christophe.meyer@espci.fr (C. Meyer), janine.cossy@espci.fr
(J. Cossy).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.05.012

A.-F. Salit et al. / Tetrahedron 64 (2008) 6684–6697
6685
2. First approach: formation of the C7–C8 bond by Horner–
Wadsworth–Emmons olefination
alcohols 6 and 60 were obtained in an 85:15 ratio (84%, two steps
from 4) (Scheme 2).17,18
2.1. Retrosynthetic analysis
Cl3C
O
O
NH, cat. PPTS
In our retrosynthetic analysis of cytostatin, the formation of the
C13–C14 bond was envisaged by using a palladium-catalyzed cross-
coupling between a (Z)-vinylic iodide, generated from the acety-
lenic iodide A (C1–C13 fragment), and a (Z,E)-dienyl organometallic
reagent B (C14–C18 fragment). The formation of the triene unit has
been successfully achieved by a Stille coupling in two of the three
6
6
PMBO
MeO
(S)-1
OH
MeO
OPMB
CH2Cl2, rt
93%
3
(MeO)MeNH.HCl, i-PrMgCl
90%
THF, −20 °C
O
O
reported total syntheses of cytostatin.5,11 The
-lactone would be constructed by ring-closing metathesis (RCM)
a
,b
-unsaturated
6
6
DIBAL-H
Me
THF, −78 °C
N
OPMB
H
OPMB
d
OMe
of the acrylate derived from the homoallylic alcohol C. In this
approach, a second key disconnection was considered at the C7–C8
bond whose formation would be achieved by a Horner–Wads-
worth–Emmons (HWE) olefination involving aldehyde D and the
5
4
i-PrO2C
O
(S,S)-I, 4Å MS
toluene, −78 °C
B
84%
O
i-PrO2C
(S,S)-I
PMP
b
-ketophosphonate E, followed by chemoselective hydrogenation
OH
5
O
O
7
of the C7–C8 alkene. The control of the configuration at C5 and C6
would rely on a diastereoselective crotylboration of an optically
active aldehyde derived from the Roche ester (S)-1 that contains the
C6 stereocenter of cytostatin. An enantioselective reduction of the
6
4
DDQ, 4Å MS
3
CH2Cl2, rt
63%
OPMB
5
6
7
6/6' = 85/15
+
rd = 85/15
OH
acetylenic
of the resulting
C11 and C10 stereocenters, respectively (Scheme 1).
b
-ketoester 2 followed by a diastereoselective alkylation
6
4
DIBAL-H
b
-hydroxyester would allow the installation of the
92%
5
OPMB
CH2Cl2, 0 °C to rt
6'
OPMBO
OPMB
IBX
THF/DMSO (1/1), rt
O
O
P
3
7
7
5
5
3
H
OH
NaO
14
1
4
9
8
O
O
O
9
OH
11
18
HO
6
16
Scheme 2. Synthesis of the C3–C7 subunit.
13
Pd-catalyzed
cross-coupling
The use of a (Z)-crotylboronate entails a syn relative orientation
of the C4 methyl and the C5 hydroxyl groups and a predominant
anti-Felkin addition mode (anti relationship between the C5
hydroxyl and the C6 methyl groups in the major diastereomer 6).
This addition mode is reinforced by the chiral ligand on boron in
a double stereodifferentiating reaction proceeding in the matched
manifold.17,19 To synthesize the C3–C7 aldehyde of type D having
the secondary hydroxyl group protected at C5, alcohol 6 was
treated with DDQ (4 Å MS, CH2Cl2, rt)20 and the p-methoxy-
benzylidene acetal 7 (85:15 mixture of epimers, 63%) was regio-
selectively reduced (DIBAL-H, CH2Cl2, 0 ꢁC to rt) to the primary
alcohol 8 (92%).21,22 Subsequent oxidation [IBX, THF/DMSO (1:1),
rt]23 led to aldehyde 9, which was not purified to avoid epimeri-
zation (Scheme 2). Aldehyde 9 constitutes the C3–C7 subunit of
cytostatin and has been prepared in seven steps from (S)-1 with an
overall yield of 41%.
Cytostatin
O
O
P
PGO
RCM
1
4
14
O
9
OH
11
PGO
6
18
+
16
M
13
I
A
B
HWE olefination
PG = protecting group
OH
O
9
OPG
11
6
4
SiMe3
C
Diastereoselective
Crotylboration
alkylation
O
P
O
9
OPG
11
OPG O
6
EtO
EtO
+
4
H
SiMe3
Enantioselective
D
E
reduction
O
O
9
O
6
2.3. Synthesis of the C8–C13 subunit
MeO
OH
11
EtO
SiMe3
(S)-1
2
The synthesis of the b-ketophosphonate of type E was carried
out from the acetylenic ester 10. Condensation of the lithium
Scheme 1. First retrosynthetic analysis of cytostatin.
enolate generated from ethyl acetate (LDA, THF, ꢀ78 ꢁC) with the
acetylenic ester 10 (THF, ꢀ85 ꢁC to ꢀ78 ꢁC) afforded the
b-ketoester
2.2. Synthesis of the C3–C7 subunit
2 (91%).24,25 Quenching the reaction with AcOH before hydrolytic
work-up avoided partial loss of the base-sensitive acetylenic TMS
The preparation of the C3–C7 subunit started with the protection
of (S)-1 by treatment with (p-methoxybenzyl) trichloroacetimidate
(cat. PPTS, CH2Cl2, rt) to afford the p-methoxybenzyl ether 3 (93%).13
This latter compound was converted to the Weinreb amide 4
(i-PrMgCl, (MeO)MeNH$HCl, THF, ꢀ20 ꢁC, 90%)14,15 and subsequent
reduction (DIBAL-H, THF, ꢀ78 ꢁC) led to aldehyde 5, which was not
purified to avoid racemization.15,16 To introduce the C4 and C5
stereocenters, aldehyde 5 was then treated with the optically active
(Z)-crotylboronate (S,S)-I derived from (S,S)-diisopropyl tartrate
(4 Å MS, toluene, ꢀ78 ꢁC) and the diastereomeric secondary
group.25 To create the C11 asymmetric carbon,
b-ketoester 2 un-
derwent an enantioselective reduction in the presence of Saccha-
romyces cerevisiae (type II) (glucose, H2O/EtOH, 30 ꢁC) to provide
the b
-hydroxyester 11 (72%) with an enantiomeric excess of 92%.26
The methyl group at C10, which is anti to the hydroxyl group at C11,
was then introduced by a Frater–Seebach diastereoselective alkyl-
ation of the
b
-hydroxyester 11 [LDA (2.8 equiv), THF, ꢀ78 ꢁC to
ꢀ25 ꢁC then MeI, HMPA, ꢀ78 ꢁC to ꢀ25 ꢁC] that led to the anti-
a-
methyl-
b
-hydroxyester 12 (dr¼93:7, 94%).27 The hydroxyl group at
C11 was protected as a tert-butyldimethylsilyl ether (TBSOTf,

6686
A.-F. Salit et al. / Tetrahedron 64 (2008) 6684–6697
2,6-lutidine, CH2Cl2, ꢀ40 ꢁC to ꢀ20 ꢁC) to provide compound 13
(95%) and subsequent Claisen condensation with lithiated methyl
dimethylphosphonate [(4.1 equiv), generated by addition of
(MeO)2P(]O)Me to n-BuLi, THF, ꢀ78 ꢁC to ꢀ60 ꢁC]28 afforded
16 as the single product (84%, two steps from enone 15)
(Scheme 4).
However, subsequent attempts to carry out the HWE reaction
between aldehyde 9 and b-ketophosphonate 14 on larger scale led
to non-reproducible results and extensive decomposition took
place. Although alternative conditions could have been used,15 our
initial synthetic plan was revised. With the aim of improving the
convergency of the synthesis, a second approach relying on the
formation of the C8–C9 bond by addition of an organolithium to an
aldehyde was examined.
b-ketophosphonate 14 (72%) (Scheme 3).
LiO
(from AcOEt
+ LDA)
1)
O
9
O
EtO
THF, −85 °C to −78 °C
11
EtO
EtO2C
SiMe3
2) AcOH, −78 °C to rt
13
13
SiMe3
SiMe3
10
2
91%
3. Second approach: formation of the C8–C9 bond by addition
of an organolithium to an aldehyde
Saccharomyces cerevisiae (type II)
72%
glucose, H2O, EtOH, 30 °C
1) LDA (2.8 equiv), THF
O
9
OH
11
O
OH
11
3.1. Retrosynthetic analysis
−78 °C to −25 °C
EtO
EtO 9
2) MeI, HMPA
−78 °C to −25 °C
A key disconnection at the C8–C9 bond was envisaged in our
second synthetic approach. The acetylenic iodide intermediate A
would be obtained by nucleophilic addition of an organolithium
derived from the primary alkyl iodide F to aldehyde G. The six-
13 SiMe3
12
dr = 93/7
11
94%
TBSOTf, 2,6-lutidine, CH2Cl2
95%
−40 °C to −20 °C
O
P
membered ring acetal (C1–C5), precursor of the
a,b-unsaturated
MeO
MeO
Li
lactone, would be constructed by RCM and a crotylboration of the
optically active aldehyde H would install the C4 and C5 stereo-
centers. On the other hand, the preparation of aldehyde G would be
O
OTBS
11
O
P
O
OTBS
11
MeO
MeO
(4.1 equiv)
EtO
9
8
THF
−78 °C to −60 °C
72%
SiMe3
13
13
SiMe3
achieved from the protected
b-hydroxyester 13 synthesized during
13
14
the course of our first approach toward cytostatin (Scheme 5).
Scheme 3. Synthesis of the C8–C13 subunit.
O
O
P
PGO
The b-ketophosphonate 14 corresponds to the C8–C13 subunit
1
4
O
O
9
OH
11
PGO
6
of cytostatin and has been prepared in six steps from ethyl trime-
thylsilylpropiolate 10 (41% overall yield). The coupling of the C3–C7
and C8–C13 subunits by a Horner–Wadsworth–Emmons (HWE)
reaction was then investigated.
8
I
Nucleophilic addition
A
OPG
RCM
1
O
O
9
OPG
11
6
4
I
+
2.4. Coupling of the C3–C7 and C8–C13 subunits by Horner–
Wadsworth–Emmons olefination
13
H
8
SiMe3
F
G
Crotylboration
b
-Ketophosphonate 14 was treated with LiCl and a tertiary
amine such as i-Pr2NEt or DBU and aldehyde 9 was added (MeCN,
rt).29 The desired (E)-
-unsaturated ketone 15 was obtained in
O
O
9
OTBS
a,b
6
OPG
13
11
H
H
moderate yields (46% or 54%, respectively) in the course of initial
attempts carried out on a small scale (typically 0.5 mmol). Sub-
sequent reduction of the C7–C8 alkene was accomplished che-
moselectively by treatment with an hydridocuprate generated in
situ from n-BuCu(CN)Li and DIBAL-H (THF, ꢀ50 ꢁC).30 The corre-
sponding ketone 16 was formed but reduction of its C9 carbonyl
group also took place to a small extent (15%). Therefore, the crude
material was oxidized [IBX, THF/DMSO (1:1), rt]23 to afford ketone
SiMe3
H
13
Scheme 5. Second retrosynthetic analysis of cytostatin.
3.2. Synthesis of the C1–C8 subunit
The creation of the C6 methyl-substituted stereocenter was first
achieved by an Evans diastereoselective alkylation. Thus, the mono-
protected butane-1,4-diol derivative 17 was oxidized to the corre-
sponding carboxylic acid 18 (PDC, DMF, rt, 80%).31 The latter acid was
activated by reaction with ClCO2Et (Et3N, Et2O, 0 ꢁC) and subsequent
addition of the lithium amide 20 (generated from (4S)-4-benzyl-
oxazolidin-2-one, n-BuLi, THF, ꢀ78 ꢁC) to the mixed anhydride 19
(THF, ꢀ78 ꢁC) afforded the corresponding N-acyloxazolidinone 21
(72%).32 Enolization of compound 21 (NaHMDS, THF, ꢀ78 ꢁC) and
alkylation of the resulting sodium enolate with MeI (THF, ꢀ78 ꢁC)
proceeded with high diastereoselectivity (dr>96:4) and led to the
alkylated compound 22 (80%).32,33 Reduction of 22 with LiBH4 (THF/
MeOH, 0 ꢁC to rt) produced the primary alcohol 2333 (85%) and
subsequent oxidation [IBX, DMSO/THF (1:1), rt]26 afforded aldehyde
24, which was not purified to avoid racemization (Scheme 6).
The next stage was the installation of the C4 and C5 stereo-
centers and the use of a crotylboration was considered. The stereo-
chemical outcome of the crotylation of protected derivatives of
O
P
O
OTBS
OPMBO
MeO
MeO
+
H
9
14
SiMe3
LiCl, i-Pr2NEt, MeCN, rt (46%)
or LiCl, DBU, MeCN, rt (54%)
OPMB
7
O
OTBS
10
3
5
13
8
15
SiMe3
1) BuCu(CN)Li + DIBAL-H
THF, −50 °C
2) IBX, THF/DMSO, rt
84%
O
OPMB
7
OTBS
10
3
5
13
16
SiMe3
Scheme 4. Synthesis of the C3–C13 fragment.

A.-F. Salit et al. / Tetrahedron 64 (2008) 6684–6697
6687
O
reduction to the lactol (DIBAL-H, THF, ꢀ78 ꢁC) and formation of the
corresponding methyl acetal [MeOH, PPTS (20 mol %), C6H6, reflux]
to deliver compound 28 (dr¼90:10, 95%, two steps from 27).35 The
hydroxyl group at C8 was then deprotected (TBAF, THF, 0 ꢁC to rt)
and the resulting alcohol 29 (94%) was transformed to the primary
alkyl iodide 30 (90%) under standard conditions (PPh3, I2, imid-
azole, THF, 0 ꢁC) (Scheme 6).36
The primary alkyl iodide 30 constitutes the C1–C8 subunit of
cytostatin and has been obtained in 10 steps from alcohol 17 with
an overall yield of 22%.
PDC
OTBDPS
OTBDPS
HO
HO
DMF, rt
80%
17
18
O
ClCO2Et, Et3N
Et2O, 0 °C
Li
N
O
O
O
O
O
Ph
OTBDPS
20
O
N
OTBDPS
EtO
O
THF
Ph
19
−78 °C to 0 °C
21
72%
1) NaHMDS, THF, −78 °C
2) MeI, THF, −78 °C to −50 °C
80%
3.3. Synthesis of the C9–C13 subunit and diastereoselectivity
of a nucleophilic addition to aldehyde 32
LiBH4
THF/MeOH
O
O
O
5
6
OTBDPS
OTBDPS
OTBDPS
HO
N
3.3.1. Preparation of the C9–C13 aldehyde
8
8
0 °C to rt
85%
The previously prepared protected b-hydroxyester 13 was con-
23
Ph
verted to the Weinreb amide 31 (Me(OMe)NH$HCl, i-PrMgCl, THF,
ꢀ20 ꢁC)14 and subsequent reduction (DIBAL-H, THF, ꢀ78 ꢁC) led to
the corresponding aldehyde 32 (C9–C13 subunit), which was not
purified to prevent epimerization. In agreement with our synthetic
plan, the next task was to achieve the formation of the C8–C9 bond
by nucleophilic addition of the organolithium 33 derived from the
primary alkyl iodide 30 (C1–C8 subunit). This operation would lead
to alcohol 34, a C1–C13 precursor of cytostatin, and create a
stereocenter at C9 (Scheme 7).
22
IBX, THF/DMSO (1/1), rt
OH
O
OTBDPS
(S,S)-I, 4Å MS
3
5
5
H
8
8
toluene, −78 °C
80% (2 steps from 23)
25
24
O
cat. DMAP, i-Pr2NEt
Cl
CH2Cl2, −78 °C
O
O
Grubbs II
(6 mol%)
1
O
5
O
Me
3
OTBDPS
OTBDPS
3
NH.HCl
5
8
8
CH2Cl2, reflux
O
9
OTBS
11
O
9
OTBS
11
MeO
95%
i-PrMgCl
26
27
Me
(2 steps from 25)
EtO
N
THF
1) DIBAL-H, THF, −78 °C
95%
13 SiMe3
OMe
SiMe3
13
−20 °C to −5 °C
(2 steps
2) MeOH, PPTS (20 mol%)
13
31
70%
C6H6, reflux
from 27)
DIBAL-H
CH2Cl2, −78 °C
OMe
1
OMe
OMe
1
1
n-Bu4NF
O
5
O
O
O
OTBS
11
OTBDPS
4
6
Li
OH
8
THF, 0 °C to rt
94%
3
+
3
9
5
H
8
8
13 SiMe3
28
29
33
32
OMe
dr = 90/10
PPh3, I2, imidazole
dr = 90/10
1
O
OH OTBS
*
90%
THF, 0 °C
6
4
9
11
8
Mes N
N Mes
Ph
OMe
13
SiMe3
34
i-PrO2C
i-PrO2C
Cl
O
B
Ru
PCy3
1
O
5
Scheme 7. Synthesis of the C9–C13 subunit.
Cl
I
O
3
8
Thus, preliminary experiments were carried out to investigate
the diastereoselectivity of a nucleophilic addition to aldehyde 32.
(S,S)-I
Grubbs II
30
dr = 90/10
Scheme 6. Synthesis of the C1–C8 subunit.
3.3.2. Diastereoselectivity of a nucleophilic addition to aldehyde 32
The C10 methyl-substituted stereocenter in aldehyde 32 was
anticipated to control the diastereoselectivity of nucleophilic addi-
tions to the carbonyl group at C9. According to the Felkin–Anh
model, a syn relationship between the hydroxyl group at C9 and the
methyl group at C10 was expected in the major diasteromeric
adduct.19 To check if this was indeed the case, the addition of a
primary organolithium such as n-BuLi to aldehyde rac-3237 was
investigated. Thus, treatment of compound rac-32 with n-BuLi
(Et2O, ꢀ78 ꢁC to ꢀ50 ꢁC) afforded a 70:30 mixture of the corre-
sponding epimeric secondary alcohols, which underwent desilyla-
tion (n-Bu4NF, THF, rt) to produce a mixture of the diastereomeric
1,3-diols 35 and 350 in a 70:30 ratio (68%, two steps from rac-32). On
the other hand, Weinreb amide rac-31 was converted to the corre-
sponding butylketone 36 (n-BuLi, Et2O, ꢀ78 ꢁC, 71%). Deprotection
2-methyl-4-hydroxybutanal is not well-documented compared to
protected 2-methyl-3-hydroxypropanal (Roche ester derivatives).
Despite the smaller steric difference that exists between methyl
and 2-alkoxyethyl groups compared to methyl and alkoxymethyl
substituents, addition of the optically active (Z)-crotylboronate
(S,S)-I to aldehyde 24 proceeded with a remarkably high diastereo-
selectivity (dr>96:4) and provided the anti,syn-homoallylic
alcohol 25 in 80% yield (two steps from 23). The secondary alcohol
25 was then acylated with acryloyl chloride [i-Pr2NEt, DMAP
(30 mol %), CH2Cl2, ꢀ78 ꢁC] and the resulting acrylate 26 un-
derwent RCM in the presence of Grubbs’ second generation cata-
lyst34 (6 mol %, CH2Cl2, reflux) to afford the
-lactone 27 in high yield (95%, two steps from 25). As an organo-
a,b-unsaturated
d
of the alcohol (HF$Py, THF, 0 ꢁC) led to the
b-hydroxyketone 37
lithium will have to be generated at C8 in the key coupling reaction,
the carbonyl group of lactone 27 was temporarily masked by
(75%), which underwent reduction with Me4NBH(OAc)3 (MeCN/
AcOH, ꢀ40 ꢁC to 0 ꢁC) to afford, after desilylation of the alkyne

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A.-F. Salit et al. / Tetrahedron 64 (2008) 6684–6697
(TBAF, THF, rt), a mixture of the epimeric 1,3-diols 35 and 350 in an
85:15 ratio (56%). As it is known that -hydroxyketones are reduced
32 to afford a mixture of the two epimeric secondary alcohols 34
and 340 in a 75:25 ratio (52%). The diastereomeric ratio was
somewhat difficult to evaluate at that stage due to partial equili-
bration of the acetal center at C1. The mixture of the epimeric
alcohols 34 and 340 underwent hydrolysis of the methyl acetal
(PPTS, acetone/H2O, rt) to afford the corresponding lactols 38/380,
which were chemoselectively oxidized with MnO2 and provided
a 75:25 mixture of the epimeric secondary alcohols 39 and 390
(65%, two steps from 34/340). Although the diastereomers could be
separated at this stage, the separation turned out to be easier later
in the synthesis. Phosphorylation of the hydroxyl group at C9
was accomplished, by treatment with the phosphoramidite
(i-Pr2N)P(OFm)2 [tetrazole, MeCN/CH2Cl2 (5:4), rt]40 but sub-
sequent oxidation of the phosphorus atom was best carried out
with TBHP instead of m-CPBA or I2.5,40 The corresponding dia-
steromeric mixture of phosphates 40/400 was obtained in 70% yield.
Deprotection of the alcohol at C11 was achieved by treatment with
HF$Py (THF, rt) and the alkynylsilanes 41/410 underwent iodode-
silylation (NIS, cat. AgNO3, DMF, rt) to afford the alkynyl iodide 42
(75%) after separation of the minor epimer at C9 (Scheme 9).
The physical and spectroscopic data of compound 42 matched
with those reported by Waldmann and Bialy5 who described the
preparation of this compound according to a linear approach (24
steps) and successfully completed the first total synthesis of
cytostatin in three steps from this intermediate. Indeed, trans-
formation of the acetylenic iodide 42 to the natural product was
previously achieved by reduction to the corresponding (Z)-alkenyl
iodide with diimide, Stille coupling with a (Z,E)-dienylstannane
to form the C13–C14 of the triene, and finally phosphate
deprotection.5
b
to anti-1,3-diols with Me4NBH(OAc)3,38 this latter result indicated
that the relative orientation of the methyl group at C9 and the hy-
droxyl group at C10 was syn in the major 1,3-diol 35. Thus, the major
diastereomer obtained during the nucleophilic addition of an orga-
nolithium to aldehyde 32 is indeed controlled by the C10 stereo-
center and corresponds to a Felkin–Anh addition mode (Scheme 8).
OH OH
Bu
Bu
9
11
1) n-BuLi, Et2O
−78 °C to −30 °C
SiMe3
SiMe3
O
9
OTBS
11
35
+
2) n-Bu4NF, THF, rt
H
OH OTBS
SiMe3
68%
32
9
11
35/35' = 70/30
35'
R
R
1) Me4NBH(OAc)3
H
H
HO
Me
MeCN/AcOH (1/1) 56%
H
H
BuLi
O
Me
−40 °C to 0 °C
2) n-Bu4NF, THF, rt
35/35' = 85/15
Bu
35
O
OH
(major)
R = C11-C13
Bu
9
11
SiMe3
37
HF.Py, THF, 0 °C 75%
O
9
OTBS
O
OTBS
11
n-BuLi, Et2O
Me
−78 °C to −30 °C
Bu
N
9
11
71%
SiMe3
OMe
SiMe3
31
36
4. Conclusion
Scheme 8.
We have reported two synthetic approaches toward cytostatin.
A first route involving the formation of the C7–C8 bond by a
Horner–Wadsworth–Emmons reaction between an aldehyde (C3–
The coupling of the C1–C8 and C9–C13 subunits was then
investigated.
C7 subunit) and a b-ketophosphonate (C8–C13 subunit) enabled
3.4. Synthesis of the C1–C13 fragment: formal synthesis of
cytostatin
the synthesis of a C3–C13 fragment containing five of the six stereo-
centers of the natural product. The second route relied on the
nucleophilic addition of a functionalized alkyllithium (C1–C8 sub-
The primary alkyl iodide 30 underwent lithium–iodine
exchange by treatment with t-BuLi (2.2 equiv) (Et2O, ꢀ78 ꢁC to
ꢀ50 ꢁC)39 and the resulting alkyllithium 33 reacted with aldehyde
unit), containing a cyclic methyl acetal as a precursor of the d-lac-
tone, to an aldehyde (C9–C13 subunit). A C1–C13 known precursor
of the natural product was prepared according to this strategy in
O
9
OTBS
OMe
OMe
O
OMe
1
11
H
O
OH OTBS
1
O
+ 34' (epimer at C9)
34/34' = 75/25
SiMe3
6
32
4
t-BuLi (2.2 equiv)
13
SiMe3
6
4
Li
9
I
11
Et2O, −78 °C to −50 °C
Et2O, −78 °C to −30 °C
8
13
30
33
34
52%
PPTS, acetone/H2O, rt
OH OTBS
1) (i-Pr2N)P(OFm)2
O
O
P
O
OH
O
FmO
tetrazole
1
4
MeCN/CH2Cl2 (5/4), rt
1
4
MnO2
O
O
OTBS
11
O
OH OTBS
FmO
6
6
2) t-BuOOH
CH2Cl2, rt
65%
9
9
11
70%
13 SiMe3
SiMe3
40
39
13
38
+ 38' (epimer at C9)
SiMe3
+ 40' (epimer at C9)
+ 39' (epimer at C9)
69% HF.Py, THF, rt
O
O
FmO
P
O
O
P
O
O
P
NaO
HO
FmO
FmO
1
4
O
O
9
OH
11
O
O
OH
O
O
OH
FmO
6
NIS, AgNO3 cat.
DMF, rt
(ref. 5)
13 SiMe3
I
41
+ 41' (epimer at C9)
42
Cytostatin
75%
Scheme 9. Formal synthesis of cytostatin.

A.-F. Salit et al. / Tetrahedron 64 (2008) 6684–6697
6689
16 steps for the longest linear sequence (3% overall yield), thereby
accounting for a formal synthesis of cytostatin. Other key step
features the installation of the C6 stereocenter by an Evans alky-
lation, a diastereoselective crotylboration to introduce the C4 and
C5 stereocenters, a Baker’s yeast enantioselective reduction of an
5.2.1.2. Methyl (S)-N-methyl-N-methoxy-3-(4-methoxybenzyloxy)-
2-methylpropanoate (4).14,15 To
mixture of ester (377 g,
a
3
15.8 mmol) and N,O-dimethylhydroxylamine hydrochloride
(2.32 g, 23.7 mmol, 1.5 equiv) in THF (30 mL) at ꢀ20 ꢁC was added
dropwise i-PrMgCl (24.0 mL, 2 M in THF, 48.0 mmol, 3 equiv). After
1 h 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 washed with brine, dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by
flash chromatography (petroleum ether/Et2O gradient: 85:15–
acetylenic
b-ketoester, and a Frater–Seebach diastereoselective
alkylation to create the C11 and C10 asymmetric carbons.
5. Experimental section
5.1. General procedures
60:40) and 3.80 g (90%) of 4 was obtained as a yellow oil
20
(C14H21NO4, MW¼267.32 g molꢀ1). [
a]
þ2.6 (c 2.5, CHCl3); IR
D
Infrared (IR) spectra were recorded on a Bruker Tensor 27 (IR-
1655, 1612, 1512, 1462, 1244, 1173, 1094, 1032, 991, 818 cmꢀ1
;
1H
FT), wavenumbers are indicated in cmꢀ1 1H NMR spectra were
.
NMR (300 MHz, CDCl3)
d
7.24 (d, J¼8.7 Hz, 2H), 6.86 (d, J¼8.7 Hz,
recorded on a Bruker AC300 (300 MHz) or a Bruker Avance 400
(400 MHz) and data are reported as follows: chemical shift in parts
per million from tetramethylsilane as an internal standard, multi-
plicity (s¼singlet, d¼doublet, t¼triplet, q¼quartet, m¼multiplet or
overlap of non-equivalent resonances), integration. 13C NMR spec-
tra were recorded at 75 or 100 MHz and data are reported as fol-
lows: chemical shift in parts per million from tetramethylsilane
2H), 4.48 (d, AB syst, J¼11.7 Hz, 1H), 4.40 (d, AB syst, J¼11.7 Hz, 1H),
3.79 (s, 3H), 3.69 (s, 3H), 3.71–3.65 (m, 1H), 3.39 (dd, J¼8.7, 5.7 Hz,
1H), 3.25–3.19 (m, 1H), 3.20 (s, 3H), 1.10 (d, J¼6.8 Hz, 3H); 13C NMR
(75 MHz, CDCl3) d 175.8 (s, weak intensity), 159.1 (s), 130.6 (s), 129.1
(d, 2C), 113.7 (d, 2C), 72.9 (t), 72.3 (t), 61.5 (q), 55.2 (q), 35.9 (d), 32.4
(q, weak intensity), 14.2 (q); MS-EI m/z (relative intensity) 267 (Mþ,
1), 236 (7), 131 (8), 122 (10), 121 (100), 100 (26), 78 (8), 77 (9).
with the solvent as an internal indicator (CDCl3,
d 77.0 ppm), mul-
tiplicity with respect to proton (deduced from DEPT experiments,
s¼quaternary C, d¼CH, t¼CH2, q¼CH3). Mass spectra with elec-
tronic impact (MS-EI) were recorded from a Hewlett-Packard tan-
dem 5890A GC (12 m capillary column)d5971 MS (70 eV). THF and
diethyl ether were distilled from sodium/benzophenone. CH2Cl2,
CH3CN, toluene, Et3N, i-Pr2NH, 2,6-lutidine, and DMF were distilled
from CaH2. Anhydrous EtOAc was obtained by distillation from
P2O5. Other reagents were obtained from commercial suppliers and
used as received. TLC was performed on silica gel plates and visu-
alized 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 chromatography was performed on silica
gel (230–400 mesh).
5.2.1.3. (S)-3-(4-Methoxybenzyloxy)-2-methylpropanal (5).16b To a
solution of Weinreb amide 4 (168 g, 6.28 mmol) in THF (15 mL) at
ꢀ78 ꢁC was added dropwise a solution of DIBAL-H (6.90 mL, 1 M in
hexanes, 6.90 mmol, 1.1 equiv). After 45 min at ꢀ78 ꢁC, the cold
reaction mixture was poured into a saturated aqueous solution of
sodium potassium tartrate (15 mL). The resulting mixture was
diluted with Et2O (15 mL) and vigorously stirred for 1 h. 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 last
traces of water were removed by azeotropic evaporation with
toluene to obtain 1.33 g (quantitative) of aldehyde 5 as a pale yellow
oil, which was directly engaged in the next step (C12H16O3,
MW¼208.25 g molꢀ1).1H NMR (300 MHz, CDCl3)
9.71 (d, J¼1.5 Hz,
d
5.2. First approach: formation of the C7–C8 bond by Horner–
Wadsworth–Emmons olefination
1H), 7.24 (d, J¼8.6 Hz, 2H), 6.88 (d, J¼8.7 Hz, 2H), 4.45 (s, 2H), 3.80 (s,
3H), 3.65–3.61 (m, 2H), 2.66–2.63 (m, 1H), 1.13 (d, J¼7.1 Hz, 3H); 13
C
NMR (75 MHz, CDCl3)
d 204.0 (d), 159.2 (s), 130.0 (s), 129.2 (d, 2C),
5.2.1. Synthesis of the C3–C7 fragment
113.8 (d, 2C), 73.0 (t), 69.7 (t), 55.2 (q), 46.8 (d), 10.7 (q).
5.2.1.1. Methyl (S)-3-(4-methoxybenzyloxy)-2-methylpropanoate (3).13
To a mixture of freshly prepared 4-methoxybenzyl 2,2,2-tri-
chloroacetimidate (8.40 g, 29.7 mmol, 1.75 equiv) and Roche ester
(S)-1 (2.00 g, 16.9 mmol, 1 equiv) in CH2Cl2 (30 mL) at rt was added
PPTS (254 mg, 1.01 mmol, 0.06 equiv). After 15 h at rt, the reaction
mixture was poured into a saturated aqueous solution of NaHCO3,
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 pres-
sure. The residue was taken-up in hexanes (20 mL) at 0 ꢁC and the
precipitate of trichloroacetamide was removed by filtration
through Celite (hexanes). The filtrate was evaporated under re-
duced pressure and the residue was purified by flash chromatog-
raphy (petroleum ether/EtOAc gradient: 90:10–80:20) to provide
5.2.1.4. (2S,3R,4S)-1-(4-Methoxybenzyloxy)-2,4-dimethylhex-5-en-
3-ol (6). A solution of aldehyde 5 (1.33 g, 6.28 mmol) in toluene
(9 mL) was added dropwise to a mixture of crotylboronate (S,S)-I
(13.5 mL, 0.79 M stock solution in toluene, 10.6 mmol, 1.7 equiv)17
and powdered activated 4 Å MS (250 mg) in toluene (9 mL) at
ꢀ78 ꢁC. After 15 h at ꢀ78 ꢁC, the reaction mixture was poured into
a 1 M aqueous solution of NaOH. After 1.5 h stirring at 0 ꢁC, the
layers were separated and the aqueous phase was extracted with
Et2O. The combined organic extracts were dried over K2CO3, fil-
tered, and concentrated under reduced pressure. Analysis of the 1H
NMR spectrum of the crude material indicated the formation of an
85:15 diastereomeric mixture of homoallylic alcohols 6 and 60. The
residue was purified by flash chromatography (toluene/EtOAc:
98:2, 96:4) to afford 400 mg (24%) of 6 and 993 mg (60%) of
3.77 g (93%) of 3 as a colorless oil (C13H18O4, MW¼238.28 g molꢀ1).
a mixture of 6 and 60 (drꢂ95:5) as colorless oils (C16H24O3,
20
20
[
a]
þ4.2 (c 1.47, CHCl3); IR 1735, 1612, 1512, 1244, 1199, 1173, 1085,
MW¼264.36 g molꢀ1). [
a]
þ5.2 (c 1.3, CHCl3); IR 3484, 1612, 1512,
D
D
1033, 872, 735 cmꢀ1
;
1H NMR (300 MHz, CDCl3)
d
7.23 (br d,
1456, 1245, 1079, 1034, 912, 819 cmꢀ1 1H NMR (300 MHz, CDCl3)
;
J¼8.5 Hz, 2H), 6.87 (d, J¼8.5 Hz, 2H), 4.45 (s, 2H), 3.79 (s, 3H), 3.68
(s, 3H), 3.63 (dd, J¼9.0, 7.5 Hz, 1H), 3.46 (dd, J¼9.0, 6.0 Hz, 1H),
2.81–2.72 (m, 1H), 1.16 (d, J¼7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d
7.24 (d, J¼8.7 Hz, 2H), 6.87 (d, J¼8.7 Hz, 2H), 5.91–5.79 (m, 1H),
5.07–4.99 (m, 2H), 4.44 (s, 2H), 3.80 (s, 3H), 3.63 (dd, J¼9.1, 4.2 Hz,
1H), 3.46 (dd, J¼9.1, 6.4 Hz,1H), 3.42–3.36 (m,1H), 3.25 (d, J¼4.1 Hz,
1H, OH), 2.36–2.25 (m,1H), 1.99–1.86 (m, 1H), 1.03 (d, J¼6.8 Hz, 3H),
d
175.2 (s), 159.1 (s), 130.2 (s), 129.1 (d, 2C), 113.7 (d, 2C), 72.7 (t),
71.6 (t), 55.2 (q), 51.6 (q), 40.1 (d), 13.9 (q); MS-EI m/z (relative in-
tensity) 238 (Mþ, 1), 138 (9), 137 (100), 136 (9), 122 (11), 121 (97),
109 (11), 101 (4), 91 (7), 78 (13), 77 (15), 59 (5).
0.94 (d, J¼7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 159.1 (s), 142.4
(d), 129.9 (s), 129.3 (d, 2C), 114.0 (t), 113.8 (d, 2C), 79.1 (d), 74.5 (t),
73.2 (t), 55.3 (q), 41.0 (d), 35.6 (d), 14.4 (q), 13.2 (q); MS-EI m/z

6690
A.-F. Salit et al. / Tetrahedron 64 (2008) 6684–6697
(relative intensity) 264 (Mþ, 1), 137 (20), 121 (100), 91 (32), 78 (5),
77 (3).
MgSO4, filtered, and concentrated under reduced pressure to afford
285 mg (quantitative) of aldehyde 9 as a colorless oil, which was
directly engaged in the next step (C16H22O3, MW¼262.34 g molꢀ1).
IR 1721, 1612, 1513, 1457, 1394, 1346, 1302, 1246, 1173, 1033, 1000,
5.2.1.5. (2RS,4R,5S)-2-(4-Methoxyphenyl)-5-methyl-4-((S)-1-meth-
ylallyl)-[1,3]dioxane (7).22 To a mixture of alcohol 6 (502 mg,
191 mmol) and powdered activated 4 Å molecular sieves (400 mg)
in CH2Cl2 (8 mL) at rt was added DDQ (516 mg, 2.28 mmol,
1.2 equiv). After 0.5 h, a saturated aqueous solution of Na2SO3
(5 mL) and Et2O (15 mL) were successively added. The reaction
mixture was stirred for 1 h and then filtered through Celite (Et2O).
The pH of the aqueous layer was adjusted to 8 by addition of
a saturated aqueous solution of NaHCO3, the layers were then
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 chromatography (petroleum ether/
Et2O: 90:10, 80:20, and 50:50) to afford 316 mg (63%) of 7 as an
951, 917, 820, 756 cmꢀ1 1H NMR (300 MHz, CDCl3)
; d 9.73 (d,
J¼1.9 Hz, 1H), 7.24 (d, J¼8.7 Hz, 2H), 6.87 (d, J¼8.7 Hz, 2H), 5.77
(ddd, J¼17.3, 10.2, 7.9 Hz, 1H), 5.11 (br d, J¼17.3 Hz, 1H), 5.08 (br d,
J¼10.2 Hz, 1H), 4.54 (d, AB syst, J¼10.7 Hz, 1H), 4.48 (d, AB syst,
J¼10.7 Hz, 1H), 3.80 (s, 3H), 3.54 (dd, J¼6.5, 5.1 Hz, 1H), 2.73–2.64
(m, 1H), 2.60–2.51 (m, 1H), 1.13 (d, J¼6.8 Hz, 3H), 1.00 (d, J¼6.8 Hz,
3H); 13C NMR (75 MHz, CDCl3)
d 204.4 (d), 159.2 (s), 140.7 (d), 130.2
(s), 129.3 (d, 2C), 115.8 (t), 113.7 (d, 2C), 84.2 (d), 73.4 (t), 55.2 (q),
48.6 (d), 40.7 (d), 15.5 (q), 11.1 (q).
5.2.2. Synthesis of the C8–C13 fragment
5.2.2.1. Ethyl 3-oxo-5-trimethylsilylpent-4-ynoate (2).25 To a solu-
tion of i-Pr2NH (109 mL, 78.0 mmol, 2.6 equiv) in THF (70 mL) at
ꢀ50 ꢁC was added dropwise n-BuLi (30.6 mL, 2.5 M in hexanes,
76.5 mmol, 2.55 equiv). After 20 min between ꢀ50 ꢁC and ꢀ10 ꢁC,
the resulting solution of LDA was cooled to ꢀ78 ꢁC and freshly
distilled anhydrous EtOAc (7.3 mL, 75.0 mmol, 2.5 equiv) was added
dropwise within 15 min. The reaction mixture was then cooled to
ꢀ85 ꢁC and a solution of ethyl trimethylsilylpropynoate (5.05 g,
30.0 mmol, 1 equiv) in THF (10 mL) was added dropwise at such
a rate that the internal temperature did not exceed ꢀ78 ꢁC. After 1 h
stirring at ꢀ78 ꢁC, AcOH (5.15 mL, 90.0 mmol) was added to the
reaction mixture, which was then warmed to 0 ꢁC and gradually
poured into ice-cold water whilst the aqueous layer was main-
tained to pH 3 by addition of a 3 M aqueous solution of hydrochloric
acid. After extraction with Et2O, 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 (hexanes/Et2O gradient: 96:4–90:10) to
85:15 inseparable mixture of epimers and a colorless oil (C16H22O3,
20
MW¼262.34 g molꢀ1). [
a
]
þ5.2 (c 1.3, CHCl3); IR 1615, 1517, 1460,
D
1390, 1370, 1301, 1247, 1170,1114, 1077, 1032, 911, 825, 732 cmꢀ1; 1H
NMR (300 MHz, CDCl3) only the signals corresponding to the major
epimer can be unambiguously described:
d
7.41 (d, J¼8.7 Hz, 2H), 6.89
(d, J¼8.7 Hz, 2H), 6.03 (ddd, J¼17.3, 10.2, 7.6 Hz 1H), 5.42 (s, 1H),
5.08 (br d, J¼17.3 Hz,1H), 5.00 (br d, J¼10.2 Hz,1H), 4.08 (dd, J¼11.0,
4.7 Hz, 1H), 3.79 (s, 3H), 3.48 (dd, apparent t, J¼10.9 Hz, 1H), 3.44
(dd, J¼10.2, 2.4 Hz, 1H), 2.53–2.44 (m, 1H), 2.10–1.95 (m, 1H), 1.10
(d, J¼7.1 Hz, 3H), 0.78 (d, J¼6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d
159.8 (s), 142.4 (d), 131.5 (s), 127.3 (d, 2C), 113.6 (t), 113.5 (d, 2C),
100.9 (d), 86.0 (d), 73.1 (t), 55.3 (q), 39.0 (d), 30.9 (d), 13.2 (q), 12.2
(q); MS-EI m/z (relative intensity) 262 (Mþ, 14), 261 (10), 208 (14),
207 (100), 137 (68), 136 (42), 135 (78), 121 (22), 109 (25), 77 (17), 67
(8), 55 (11). Anal. Calcd for C16H22O3: C, 73.25; H, 8.45. Found: C,
73.26; H, 8.54.
5.2.1.6. (2S,3R,4S)-3-(4-Methoxybenzyloxy)-2,4-dimethylhex-5-en-
1-ol (8).22 To a solution of acetal 7 (262 mg, 100 mmol) in CH2Cl2
(8 mL) at 0 ꢁC was added dropwise DIBAL-H (2.50 mL, 1 M in hex-
anes, 2.50 mmol, 2.5 equiv). After 3 h at rt, the reaction mixture was
poured into a saturated aqueous solution of sodium potassium
tartrate (10 mL) and Et2O (20 mL) was added. After 40 min of vig-
orous stirring, 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 (petroleum ether/Et2O: 80:20, 70:30) to afford 242 mg
afford 5.83 g (91%) of b-ketoester 2 as a yellow oil (C10H16O3Si,
MW¼212.32 g molꢀ1). IR 1745, 1682, 1650, 1607, 1234, 1145, 1097,
1033, 939, 841, 805, 760 cmꢀ1 1H NMR (300 MHz, CDCl3) (65:35
;
mixture of ketone/enol tautomers) ketone form:
2H), 3.58 (s, 2H), 1.28 (t, J¼7.2 Hz, 3H), 0.24 (s, 9H); enol form:
(s,1H, OH), 5.37 (s,1H), 4.25–4.19 (m, 2H),1.29 (t, J¼7.2 Hz, 3H), 0.24
(s, 9H); 13C NMR (75 MHz, CDCl3) ketone form:
178.5 (s), 165.9 (s),
101.0 (s), 100.4 (s), 61.6 (t), 51.1 (t),14.0 (q), ꢀ0.95 (q, 3C); enol form:
d
4.25–4.19 (m,
d
11.8
d
d
172.0 (s), 154.4 (s), 100.4 (s), 97.9 (s), 97.6 (d), 60.6 (t), 14.1 (q),
ꢀ0.69 (q, 3C); MS-EI m/z (relative intensity) 212 (Mþ, 4), 197
(MꢀMeþ, 28), 169 (17), 151 (18), 141 (14), 127 (31), 125 (100), 113
(10), 99 (12), 97 (35), 83 (10), 75 (19), 73 (18).
(92%) of alcohol
8
as
a
colorless oil (C16H24O3, MW¼
264.36 g molꢀ1). [
a]
ꢀ31.7 (c 0.82, CHCl3); IR 3424, 1612, 1513,
20
D
1457, 1301, 1246, 1173, 1032, 911, 820, 731 cmꢀ1; 1H NMR (300 MHz,
5.2.2.2. Ethyl (R)-3-hydroxy-5-trimethylsilylpent-4-ynoate (11).25
A
CDCl3)
d
7.26 (d, J¼8.7 Hz, 2H), 6.87 (d, J¼8.7 Hz, 2H), 5.90 (ddd,
mixture of S cerevisiae (type II) (10.5 g) and glucose (34 g) in water
J¼17.3, 10.2, 7.4 Hz, 1H), 5.09 (br d, J¼17.3 Hz, 1H), 5.04 (br d,
J¼10.2 Hz, 1H), 4.60 (d, AB syst, J¼10.6 Hz, 1H), 4.45 (d, AB syst,
J¼10.6 Hz, 1H), 3.80 (s, 3H), 3.70 (m, 1H), 3.57 (m, 1H), 3.30 (dd,
apparent t, J¼5.6 Hz, 1H), 2.73 (br s, 1H, OH), 2.58–2.47 (m, 1H),
1.94–1.87 (m, 1H), 1.11 (d, J¼6.8 Hz, 3H), 1.00 (d, J¼7.2 Hz, 3H); 13C
(previously boiled and cooled) (500 mL) was stirred at 30 ꢁC for
0.5 h and a solution of b-ketoester 2 (1.00 g, 4.71 mmol) in 95%
EtOH (3 mL) was added. After 15 h at 30 ꢁC, the reaction mixture
was cooled to 0 ꢁC and Celite (4 g) was added. The resulting mixture
was stirred for 1 h at 0–5 ꢁC and filtered through Celite (EtOAc). The
filtrate was saturated by addition of solid NaCl (with moderate
stirring). The layers were separated and the aqueous phase was
extracted with EtOAc (5ꢃ200 mL). The combined organic extracts
were dried over MgSO4, filtered, and concentrated under reduced
pressure. The crude material was purified by flash chromatography
(petroleum ether/EtOAc: 80:20) to afford 730 mg (72%) of
NMR (75 MHz, CDCl3)
d 159.3 (s), 142.1 (d), 130.3 (s), 129.5 (d, 2C),
114.4 (t), 113.9 (d, 2C), 88.4 (d), 74.7 (t), 66.1 (t), 55.3 (q), 40.9 (d),
37.3 (d), 15.6 (q), 14.7 (q). Anal. Calcd for C16H24O3: C, 72.69; H, 9.15.
Found: C, 72.63; H, 9.34.
5.2.1.7. (2R,3R,4S)-3-(4-Methoxybenzyloxy)-2.4-dimethylhex-5-enal
(9). To a solution of alcohol 8 (251 mg, 0.949 mmol, 1 equiv) in
DMSO/THF (1:1, 8 mL) at 0 ꢁC was added IBX (400 mg, 1.42 mmol,
1.5 equiv). After 1 h at rt, H2O (15 mL) was added and the resulting
mixture 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 washed with brine, dried over
b
-hydroxyester 11 (ee¼92%) as
a
colorless oil (C10H18O3Si,
20
MW¼214.33 g molꢀ1). [
a]
D
þ22.5 (c 1.0, CHCl3); IR 3427, 1720,
1372, 1346, 1249, 1162, 1055, 1024, 839, 759 cmꢀ1
;
1H NMR
(400 MHz, CDCl3)
d
4.73 (ddd, apparent br q, J¼6.0 Hz, 1H), 4.19–
4.12 (m, 2H), 3.23 (d, J¼6.0 Hz, 1H, OH), 2.75–2.65 (m, 2H), 1.25 (t,
J¼7.2 Hz, 3H), 0.13 (s, 9H); 13C NMR (100 MHz, CDCl3)
d 171.1 (s),

A.-F. Salit et al. / Tetrahedron 64 (2008) 6684–6697
6691
104.5 (s), 89.7 (s), 60.9 (t), 59.0 (d), 42.0 (t), 14.1 (q), ꢀ0.30 (q, 3C);
MS-EI m/z (relative intensity) 199 (MꢀMeþ, 70), 185 (15), 171 (17),
169 (13), 157 (38), 153 (46), 141 (13), 140 (13), 129 (51), 127 (44), 125
(33), 117 (30), 111 (60), 109 (28), 105 (13), 101 (28), 99 (52), 97 (14),
88 (13), 83 (24), 77 (24), 75 (100), 73 (50).
of MeI (0.15 mL, 2.40 mmol, 1.7 equiv) and HMPA (0.40 mL,
2.30 mmol,1.6 equiv) in THF (5 mL) was then added dropwise. After
1.5 h at ꢀ78 ꢁC and 0.5 h at ꢀ25 ꢁC, the cold reaction mixture was
poured into a 1 M aqueous solution of hydrochloric acid (40 mL).
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 chromatography
(petroleum ether/Et2O: 80:20) to afford 305 mg (94%) of 12 as
5.2.2.3. Determination of the enantiomeric excess of
b-hydroxyester
11. To a solution of -hydroxyester 11 (54 mg, 0.25 mmol) in THF
b
(2 mL) at rt were added (R)- or (S)-methoxyphenylacetic acid
(44 mg, 0.26 mmol, 1.05 equiv), one small crystal of DMAP and DCC
(60 mg, 0.29 mmol,1.15 equiv). After 15 h at rt, the reaction mixture
was diluted with Et2O, filtered through Celite (Et2O), and the filtrate
was evaporated under reduced pressure. Comparative analysis of
the 1H NMR spectra of the corresponding crude mandelates 43 and
430, respectively, showed that the minor diastereomer was in each
case at the limit of detection (drꢂ96:4) thus indicating an eeꢂ92%
a yellow oil and as a 93:7 mixture of anti/syn diastereomers
20
(C11H20O3Si, MW¼228.36 g molꢀ1). [
a
]
þ5.0 (c 0.2, CHCl3); IR
D
3453, 2174, 1719, 1249, 1180, 1038, 839, 759 cmꢀ1
;
1H NMR
(300 MHz, CDCl3)
d
4.48 (apparent t, J¼7.1 Hz, 1H), 4.23–4.13 (m,
2H), 2.90 (d, J¼6.7 Hz, 1H, OH), 2.73 (apparent quintet, J¼7.2 Hz,
1H), 1.28 (t, J¼7.1 Hz, 3H), 1.27 (d, J¼7.2 Hz, 3H), 0.17 (s, 9H); 13C
NMR (75 MHz, CDCl3) d 174.6 (s), 104.1 (s), 90.7 (s), 64.7 (d), 60.8 (t),
for
b
-hydroxyester 11.
46.3 (d), 14.1 (q), 13.8 (q), ꢀ0.30 (q, 3C); MS-EI m/z (relative in-
tensity) 228 (Mþ, 1), 213 (MꢀMeþ, 9), 195 (4), 185 (3), 167 (11), 139
(8), 127 (14), 111 (12), 102 (100), 99 (22), 83 (10), 75 (37), 74 (38), 73
(22), 56 (9), 55 (4).
O
Ph
O
HO
Ph
OMe
OMe
O
O
OH
OH
O
O
O
O
DCC, cat. DMAP
5.2.2.5. Ethyl (2S,3R)-3-(tert-butyldimethylsilyloxy)-2-methyl-5-tri-
methylsilylpent-4-ynoate (13). To a solution of b-hydroxyester 12
EtO
EtO
EtO
THF, rt
95%
SiMe3
SiMe3
SiMe3
11
43
(1.05 g, 4.60 mmol) in CH2Cl2 (30 mL) at ꢀ40 ꢁC were successively
added 2,6-lutidine (1.35 mL, 11.6 mmol, 2.5 equiv) and TBSOTf
(2.12 mL, 9.24 mmol, 2 equiv). After 2 h from ꢀ40 ꢁC to ꢀ20 ꢁC, the
reaction mixture was poured into a saturated aqueous solution of
NaHCO3 and extracted with Et2O. 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 (petroleum ether/Et2O: 95:5, 90:10) to
O
Ph
O
HO
Ph
OMe
DCC, cat. DMAP
OMe
SiMe3
EtO
THF, rt
95%
11
43'
After purification by flash chromatography (petroleum ether/
Et2O: 98:2), 86 mg (95%) of mandelate 43 or 87 mg (95%) of man-
afford 1.49 g (95%) of 13 as
a
colorless oil (C17H34O3Si2,
20
delate 430, respectively, was obtained as colorless oil.
MW¼342.62 g molꢀ1). [
a]
D
þ64.4 (c 1.0, CHCl3); IR 1737, 1250,
5.2.2.3.1. Ethyl (R)-3-((R)-2-methoxy-2-phenylacetoxy)-5-trimeth-
1178, 1091, 1052, 1024, 835, 778 cmꢀ1 1H NMR (300 MHz, CDCl3)
;
20
ylsilylpent-4-ynoate (43). C19H26O5Si, MW¼362.49 g molꢀ1; [
a
]
d
4.52 (d, J¼9.0 Hz, 1H), 4.21–4.04 (m, 2H), 2.68 (dq, J¼9.0, 7.2 Hz,
1H), 1.26 (t, J¼7.2 Hz, 3H), 1.21 (d, J¼7.2 Hz, 3H), 0.88 (s, 9H), 0.16 (s,
9H), 0.15 (s, 3H), 0.10 (s, 3H); 13C NMR (75 MHz, CDCl3)
174.1 (s),
D
þ22.6 (c 1.0, CHCl3); IR 2183, 1739, 1250, 1162, 1102, 1039, 997, 841,
760, 731, 697 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d
7.45–7.42 (m, 2H),
d
7.38–7.30 (m, 3H), 5.80 (dd, J¼8.7, 5.2 Hz,1H), 4.78 (s,1H), 4.14–4.02
(m, 2H), 3.44 (s, 3H), 2.86 (dd, J¼16.1, 8.7 Hz, 1H), 2.77 (dd, J¼16.1,
5.1 Hz, 1H), 1.20 (t, J¼7.1 Hz, 3H), 0.09 (s, 9H); 13C NMR (75 MHz,
105.9 (s), 90.7 (s), 65.8 (d), 60.4 (t), 47.7 (d), 25.7 (q, 3C), 18.1 (s),
14.2 (q), 13.6 (q), ꢀ0.3 (q, 3C), ꢀ4.5 (q), ꢀ5.2 (q); MS-EI m/z
(relative intensity) 327 (MꢀMeþ, 4), 286 (26), 285 (Mꢀt-Buþ, 100),
241 (20), 157 (8), 155 (7), 147 (68), 133 (11), 115 (13), 103 (21), 75
(25), 73 (40).
CDCl3)
d 169.2 (s), 168.5 (s), 135.6 (s), 128.7 (d), 128.5 (d, 2C), 127.3
(d, 2C), 100.1 (s), 91.5 (s), 82.3 (d), 61.1 (d), 60.9 (t), 57.4 (q), 39.8 (t),
14.1 (q), ꢀ0.50 (q, 3C); MS-EI m/z (relative intensity) 347 (MꢀMeþ,
1), 181 (3), 139 (2), 121 (100), 109 (5), 91 (6), 77 (8).
5.2.2.6. Dimethyl (3S,4R)-4-(tert-butyldimethylsilyloxy)-3-methyl-2-
oxo-6-trimethylsilylhex-5-ynyl-phosphonate (14). To a solution of n-
BuLi (1.91 mL, 2.5 M in hexanes, 4.7 mmol, 4.1 equiv) in THF (15 mL)
at ꢀ78 ꢁC was added freshly distilled dimethyl methylphosphonate
(0.640 mL, 5.84 mmol, 5 equiv). After 15 min at ꢀ60 ꢁC, a solution
of ester 13 (400 mg, 1.17 mmol, 1 equiv) in THF (5 mL) was added
slowly (internal temperatureꢄꢀ60 ꢁC). After 15 min at ꢀ60 ꢁC, the
cold reaction mixture was poured into a saturated aqueous solution
of NH4Cl, 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 concentrated under
reduced pressure. The crude material was purified by flash chro-
matography (petroleum ether/Et2O gradient: 80:20, 70:30, and
5.2.2.3.2. Ethyl (R)-3-((S)-2-methoxy-2-phenylacetoxy)-5-trime-
thylsilylpent-4-ynoate (430). C19H26O5Si, MW¼362.49 g molꢀ1
;
20
[
a]
þ87.8 (c 1.0, CHCl3); IR 2183, 1739, 1250, 1160, 1104, 1040, 991,
D
841, 760, 733, 697 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d 7.43–7.40 (m,
2H), 7.36–7.31 (m, 3H), 5.78 (dd, J¼8.8, 5.3 Hz, 1H), 4.79 (s, 1H),
3.96–3.88 (m, 1H), 3.86–3.78 (m, 1H), 3.41 (s, 3H), 2.75 (dd, J¼16.1,
8.8 Hz, 1H), 2.67 (dd, J¼16.1, 5.3 Hz, 1H), 1.08 (t, J¼7.1 Hz, 3H), 0.14
(s, 9H); 13C NMR (75 MHz, CDCl3)
d 169.1 (s), 168.2 (s), 135.8 (s),
128.7 (d), 128.5 (d, 2C), 127.2 (d, 2C), 100.4 (s), 91.6 (s), 82.2 (d), 61.0
(d), 60.8 (t), 57.3 (q), 39.9 (t), 13.9 (q), ꢀ0.4 (q, 3C); MS-EI m/z
(relative intensity) 347 (MꢀMeþ, 1), 181 (3), 139 (2), 121 (100), 109
(4), 91 (6), 77 (8).
50:50) to afford 354 mg (72%) of phosphonate 14 as a colorless oil
20
5.2.2.4. Ethyl
(2S,3R)-3-hydroxy-2-methyl-5-trimethylsilylpent-4-
(C18H37O5PSi2, MW¼420.63 g molꢀ1); [
a]
þ143 (c 1.0, CHCl3); IR
D
ynoate (12). To a solution of i-Pr2NH (0.60 mL, 4.30 mmol, 3 equiv)
in THF (10 mL) at ꢀ30 ꢁC was added dropwise n-BuLi (1.60 mL,
2.5 M in hexanes, 4.00 mmol, 2.8 equiv). After 25 min between
ꢀ30 ꢁC and 0 ꢁC, the resulting solution of LDA was cooled to ꢀ78 ꢁC
1716, 1250, 1182, 1028, 834, 778, 760 cmꢀ1 1H NMR (300 MHz,
;
CDCl3)
d
4.38 (d, J¼9.0 Hz, 1H), 3.80 (d, J3 ¼4.9 Hz, 3H), 3.76 (d,
H–P
J3 ¼4.9 Hz, 3H), 3.40 (dd, J2 ¼22.6 Hz, J¼13.9 Hz, 1H), 3.16–
H–P
H–P
3.06 (m, 1H), 3.05 (dd, J2 ¼22.6 Hz, J¼13.9 Hz, 1H), 1.13 (d,
H–P
and a solution of
b-hydroxyester 11 (302 mg, 1.42 mmol, 1 equiv) in
J¼6.8 Hz, 3H), 0.85 (s, 9H), 0.16 (s, 9H), 0.12 (s, 3H), 0.05 (s, 3H); 13
C
THF (5 mL) was added dropwise. The reaction mixture was stirred
for 20 min at ꢀ78 ꢁC, warmed to ꢀ25 ꢁC, and stirred at that tem-
perature for 20 min before being cooled again to ꢀ78 ꢁC. A solution
NMR (75 MHz, CDCl3)
d
204.3 (s, J2 ¼6.5 Hz), 105.2 (s), 91.3 (s),
C–P
66.8 (d), 53.2 (d), 53.0 (q, J2 ¼6.5 Hz), 52.9 (q, J2 ¼6.4 Hz), 43.2
C–P
C–P
(t, J1 ¼128 Hz), 25.7 (q, 3C),18.1 (s), 13.5 (q), ꢀ0.3 (q, 3C), ꢀ4.6 (q),
C–P

6692
A.-F. Salit et al. / Tetrahedron 64 (2008) 6684–6697
ꢀ5.3 (q); MS-EI m/z (relative intensity) 420 (Mþ, 1), 405 (MꢀMeþ,
3), 364 (22), 363 (Mꢀt-Buþ, 68), 238 (21), 237 (100), 151 (6), 109 (8),
89 (7), 75 (17), 73 (19). Anal. Calcd for C18H37O5PSi2: C, 51.40; H,
8.87. Found: C, 51.42; H, 8.65.
778, 760, 732 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
7.27 (d, J¼8.5 Hz,
2H), 6.85 (d, J¼8.5 Hz, 2H), 5.76 (ddd, J¼17.0, 10.1, 8.0 Hz 1H), 5.03
(br d, J¼17.0 Hz, 1H), 4.96 (dd, J¼10.1, 1.5 Hz 1H), 4.55–4.47 (m, 2H),
4.45 (d, J¼9.0 Hz, 1H), 3.79 (s, 3H), 3.08 (dd, J¼7.0, 3.5 Hz, 1H), 2.84
(qd, J¼9.0, 7.0 Hz, 1H), 2.63–2.55 (m, 1H), 2.48–2.40 (m, 1H),
1.76–1.47 (m, 4H), 1.08 (d, J¼6.5 Hz, 3H), 1.07 (d, J¼7.0 Hz, 3H), 0.90
(d, J¼6.5 Hz, 3H), 0.84 (s, 9H), 0.16 (s, 9H), 0.12 (s, 3H), 0.05 (s, 3H);
5.2.3. Synthesis of the C3–C13 subunit by HWE olefination
5.2.3.1. (E)-[(3R,4S,8S,9R,10S)-3-(tert-Butyldimethylsilyloxy)-9-(4-
methoxybenzyloxy)-4,8,10-trimethyl-1-trimethylsilyldodeca-6,11-
dien-1-yn-5-one (15). To a degassed solution of phosphonate 14
(267 mg, 0.645 mmol, 1.2 equiv) in MeCN (4 mL) (argon bubbling,
10 min) were successively added, at rt, anhydrous LiCl (41 mg,
0.97 mmol, 1.8 equiv) and DBU (0.12 mL, 0.78 mmol, 1.45 equiv).
After 0.5 h, a solution of aldehyde 9 (138 mg, 0.530 mmol, 1 equiv)
in MeCN (2 mL) was added dropwise within 15 min. After 72 h at rt,
the reaction mixture was hydrolyzed with H2O (3 mL) and evapo-
rated under reduced pressure. The residue was partitioned be-
tween H2O and Et2O, 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 concen-
trated under reduced pressure. The residue was purified by flash
chromatography (petroleum ether/Et2O: 90:10, 80:20) to afford
159 mg (54%) of 15 as a viscous colorless oil (C32H52O4Si2,
MW¼556.92 g molꢀ1). IR 1697, 1671, 1624, 1455, 1361, 1249, 1084,
13C NMR (100 MHz, CDCl3)
d 212.4 (s), 159.0 (s), 142.1 (d), 131.1 (s),
129.1 (d, 2C), 114.0 (t), 113.7 (d, 2C), 105.7 (s), 90.8 (s), 86.8 (d), 74.7
(t), 66.2 (d), 55.2 (q), 52.4 (d), 42.4 (t), 41.3 (d), 35.6 (d), 29.7 (t),
27.9 (q), 25.7 (q, 3C), 18.0 (s), 16.4 (q), 13.8 (q), ꢀ0.27 (q, 3C), ꢀ4.7
(q), ꢀ5.3 (q).
5.3. Second approach: formation of the C8–C9 bond by
addition of an organolithium to an aldehyde
5.3.1. Synthesis of the C1–C8 subunit
5.3.1.1. 4-(tert-Butyldiphenylsilyloxy)butanoic acid (18).31 To a solu-
tion of alcohol 17 (105 g, 32.0 mmol) in DMF (80 mL) at rt was
added portionwise PDC (42.1 g, 112 mmol, 3.5 equiv). After 15 h at
rt, Celite (20 g) was added and the reaction mixture was succes-
sively diluted with H2O (300 mL) and Et2O (150 mL) (while cooling
to 5 ꢁC). After stirring for 45 min at rt, the resulting mixture was
filtered through Celite (Et2O). The layers of the filtrate were
separated and the aqueous phase was extracted with Et2O
(3ꢃ100 mL). The combined organic extracts were successively
washed with a 1 M aqueous solution of HCl and brine, dried over
MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash chromatography (CH2Cl2/EtOAc:
95:5–80:20) to afford 8.77 g (80%) of carboxylic acid 18 as a col-
orless oil (C20H26O3Si, MW¼342.50 g molꢀ1). IR 3000 (br), 1703,
1427, 1294, 1258, 1093, 1032, 971, 825, 758, 736, 698 cmꢀ1; 1H NMR
1006, 836, 779, 732, 697 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d 7.30 (br
d, J¼8.7 Hz, 2H), 6.94 (dd, J¼15.8, 8.3 Hz, 1H), 6.88 (d, J¼8.7 Hz, 2H),
6.08 (dd, J¼15.8, 0.8 Hz, 1H), 5.65 (ddd, J¼17.3, 10.2, 7.9 Hz, 1H),
5.05–4.96 (m, 2H), 4.58–4.44 (m, 3H), 3.80 (s, 3H), 3.24–3.14 (m,
2H), 2.70–2.59 (m, 1H), 2.44–2.32 (m, 1H), 1.11 (d, J¼6.8 Hz, 3H),
1.09 (d, J¼6.8 Hz, 3H),1.07 (d, J¼6.8 Hz, 3H), 0.82 (s, 9H), 0.17 (s, 9H),
0.11 (s, 3H), 0.04 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 202.1 (s), 159.2
(s), 150.0 (d), 141.3 (d), 130.8 (d), 130.6 (s), 129.4 (d, 2C), 114.8 (t),
113.8 (d, 2C), 106.0 (s), 90.6 (s), 86.4 (d), 74.6 (t), 66.1 (d), 55.3 (q),
49.0 (d), 41.7 (d), 40.3 (d), 25.7 (q, 3C), 18.1 (s), 17.4 (q), 15.9 (q), 14.4
(q), ꢀ0.23 (q, 3C), ꢀ4.7 (q), ꢀ5.3 (q).
(400 MHz, CDCl3)
3.70 (t, J¼6.0 Hz, 2H), 2.51 (t, J¼7.5 Hz, 2H), 1.92–1.85 (m, 2H), 1.05
(s, 9H); 13C NMR (100 MHz, CDCl3)
180.3 (s), 135.6 (d, 4C), 133.7
d
7.65 (dd, J¼7.5, 1.5 Hz, 4H), 7.43–7.35 (m, 6H),
d
5.2.3.2. (3R,4S,8S,9S,10S)-3-(tert-Butyldimethylsilyloxy)-9-(4-meth-
oxybenzyloxy)-4,8,10-trimethyl-1-trimethylsilyldodeca-11-en-1-yn-
5-one (16). To a suspension of CuCN (40 mg, 0.44 mmol, 4.5 equiv)
in THF (2.2 mL) at ꢀ20 ꢁC was added dropwise n-BuLi (0.17 mL,
2.5 M in hexanes, 0.43 mmol, 4.4 equiv). After 0.5 h at ꢀ20 ꢁC, the
reaction mixture was cooled to ꢀ50 ꢁC and DIBAL-H (0.86 mL, 1 M
in hexanes, 0.86 mmol, 8 equiv) was added dropwise. After 1 h at
(s, 2C), 129.8 (d, 2C), 127.7 (d, 4C), 62.8 (t), 30.8 (t), 27.5 (t), 26.9 (q,
3C), 19.2 (s).
5.3.1.2.
(S)-4-Benzyl-3-[4-(tert-butyldiphenylsilyloxy)butanoyl]-
oxazolidin-2-one (21). To a solution of carboxylic acid 18 (3.17 g,
9.25 mmol) in Et2O (100 mL) at rt was added Et3N (1.29 mL,
9.25 mmol, 1 equiv). After 15 min at rt, the reaction mixture was
cooled to 0 ꢁC and freshly distilled ClCO2Et (0.880 mL, 9.25 mmol,
1 equiv) was added dropwise. After 1 h at rt, the reaction mixture
containing the mixed anhydride 19 was cooled to ꢀ78 ꢁC and
cannulated into a solution of the lithium salt 20 generated from (S)-
4-benzyloxazolidin-2-one (1.64 g, 9.25 mmol, 1 equiv) and n-BuLi
(3.70 mL, 2.5 M in hexanes, 9.25 mmol, 1 equiv) in THF (35 mL)
(ꢀ78 ꢁC, 15 min). After 0.5 h at ꢀ78 ꢁC and 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 brine,
dried over MgSO4, filtered, and concentrated under reduced pres-
sure. The residue was purified by flash chromatography (petroleum
ꢀ50 ꢁC,
a portion of the resulting hydridocuprate [HBu-
Cu(CN)Li(Ali-Bu2)] solution (1.6 mL, ca. 0.21 mmol, ca. 2.2 equiv)
was added rapidly, via a syringe, to a solution of enone 15 (54 mg,
0.097 mmol, 1 equiv) in THF (1.5 mL) at ꢀ50 ꢁC. After 0.5 h at
ꢀ50 ꢁC, the reaction mixture was poured into a saturated aqueous
solution of NH4Cl that had been adjusted to pH 7 by addition of
a 20% aqueous solution of NH4OH. 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 product was pu-
rified by rapid filtration through silica gel (Et2O), the filtrate was
evaporated under reduced pressure, and the residue was dissolved
in DMSO/THF (1:1, 2 mL). To the resulting solution at rt, was added
IBX (30 mg, 0.10 mmol, 1.1 equiv) and after 1 h, the reaction mix-
ture was hydrolyzed with H2O (5 mL). The resulting mixture was
filtered through Celite (Et2O), the layers of the filtrate were sepa-
rated, and the aqueous phase was extracted with Et2O. The com-
bined organic extracts were washed with brine, dried over MgSO4,
filtered, and concentrated under reduced pressure. The residue was
purified by flash chromatography (petroleum ether/Et2O: 90:10) to
ether/EtOAc: 90:10, 80:20) to afford 3.34 g (72%) of 21 as a colorless
20
oil (C30H35NO4Si, MW¼501.69 g molꢀ1). [
a
]
þ36.1 (c 1.63, CHCl3);
D
IR 1780, 1699, 1384, 1351, 1210, 1105, 822, 737, 700 cmꢀ1 1H NMR
;
(400 MHz, CDCl3)
d 7.69–7.65 (m, 4H), 7.44–7.25 (m, 9H), 7.21–7.18
(m, 2H), 4.66–4.60 (m, 1H), 4.18–4.13 (m, 2H), 3.75 (t, J¼6.5 Hz, 2H),
3.27 (dd, J¼13.6, 3.5 Hz, 1H), 3.07 (t, J¼7.5 Hz, 2H), 2.72 (dd, J¼13.6,
9.5 Hz, 1H), 2.00–1.93 (m, 2H), 1.06 (s, 9H); 13C NMR (100 MHz,
CDCl3)
d 173.1 (s), 153.4 (s), 135.6 (d, 4C), 135.4 (s), 133.8 (s, 2C),
afford 46 mg (84%, two steps from enone 15) of ketone 16 as
129.7 (d),129.6 (d),129.4 (d, 2C),129.0 (d, 2C),127.7 (d, 2C),127.6 (d,
2C),127.3 (d), 66.2 (t), 62.9 (t), 55.2 (d), 37.9 (t), 32.2 (t), 27.0 (t), 26.9
(q, 3C), 19.2 (s).
20
a colorless oil (C32H54O4Si2, MW¼558.94 g molꢀ1). [
a
]
D
þ59.8 (c
0.85, CHCl3); IR 1717, 1613, 1514, 1461, 1249, 1078, 1037, 909, 850,

A.-F. Salit et al. / Tetrahedron 64 (2008) 6684–6697
6693
5.3.1.3. (S)-4-Benzyl-3-[(S)-4-(tert-butyldiphenylsilyloxy)butanoyl]-
oxazolidin-2-one (22). To a solution of NaHMDS (3.95 mL, 2 M in
THF, 7.90 mmol, 1.2 equiv) in THF (12 mL) at ꢀ78 ꢁC was added
dropwise a solution of oxazolidinone 21 (3.30 g, 6.58 mmol) in THF
(3 mL). After 0.5 h at ꢀ78 ꢁC, MeI (0.615 mL, 9.87 mmol, 1.5 equiv)
was added. The reaction mixture was stirred for 2 h between
ꢀ60 ꢁC and ꢀ50 ꢁC and then poured into a saturated aqueous so-
lution 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 (petroleum ether/EtOAc gradient: 96:4–90:10 then
5.3.1.6. (3S,4S,5S)-7-(tert-Butyldiphenylsilyloxy)-3,5-dimethylhept-
1-en-4-ol (25). A solution of crude aldehyde 24 (415 mg,
1.20 mmol) in toluene (4 mL) was added to a mixture of cro-
tylboronate (S,S)-I17 (1.50 mL, 0.8 M in toluene, 1.20 mmol, 1 equiv)
and powdered activated 4 Å MS (50 mg) in toluene (4 mL) at
ꢀ78 ꢁC. After 15 h at ꢀ78 ꢁC, an additional quantity of crotylboro-
nate (S,S)-I (1.50 mL, 0.8 M in toluene, 1.20 mmol, 1 equiv) was
added and 6 h later, the reaction mixture was poured into a 1 M
aqueous solution of NaOH. After 1.5 h stirring at 0 ꢁC, the layers
were separated and the aqueous phase was extracted with Et2O.
The combined organic extracts were dried over K2CO3, filtered, and
concentrated under reduced pressure. Analysis of the 1H NMR
spectrum of the crude material indicated the formation of the de-
sired alcohol with high diastereoselectivity (drꢂ96:4). The residue
was purified by flash chromatography (petroleum ether/Et2O: 98:2,
70:30) to afford 2.71 g (80%) of 22 as a colorless oil (dr>96:4)
20
(C31H37NO4Si, MW¼515.17 g molꢀ1). [
a]
þ39.5 (c 0.96, CHCl3); IR
D
1778, 1697, 1382, 1206, 1105, 822, 737, 700 cmꢀ1
;
1H NMR
(400 MHz, CDCl3)
d
7.66–7.63 (m, 4H), 7.43–7.25 (m, 9H), 7.21–7.18
95:5) to afford 381 mg (80%, two steps from 22) of alcohol 25 as
a colorless oil (C25H36O2Si, MW¼396.64 g molꢀ1). [
a
]
ꢀ7.8 (c 1.65,
20
(m, 2H), 4.59–4.53 (m, 1H), 4.10 (dd, J¼9.0, 2.5 Hz, 1H), 4.04–4.00
(m, 1H), 3.98–3.88 (m, 1H), 3.76–3.67 (m, 2H), 3.24 (dd, J¼13.6,
3.5 Hz, 1H), 2.74 (dd, J¼13.6, 9.5 Hz, 1H), 2.18–2.09 (m, 1H), 1.71–
D
CHCl3); IR 3424, 1461, 1427, 1107, 1085, 994, 908, 822, 734,
700 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 7.70–7.67 (m, 4H), 7.46–7.37
1.63 (m, 1H), 1.23 (d, J¼7.0 Hz, 3H), 1.03 (s, 9H); 13C NMR
d
176.9 (s),
(m, 6H), 5.82 (ddd, J¼17.6,10.0, 7.5 Hz,1H), 5.08–5.01 (m, 2H), 3.81–
3.75 (m, 1H), 3.70–3.64 (m, 1H), 3.27–3.23 (m, 1H), 2.44–2.35 (m,
1HþOH), 1.92–1.76 (m, 2H), 1.59–1.51 (m, 1H), 1.06 (s, 9H), 1.06 (d,
J¼7.0 Hz, 3H), 0.91 (d, J¼7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3)
152.9 (s), 135.6 (d, 2C), 135.5 (d, 2C), 135.5 (s), 133.8 (s, 2C), 129.6 (d,
2C), 129.4 (d, 2C), 128.9 (d, 2C), 127.6 (d, 4C), 127.3 (d), 65.9 (t), 61.9
(t), 55.3 (d), 37.9 (t), 35.6 (t), 34.8 (d), 26.8 (q, 3C), 19.2 (s), 18.0 (q).
d
142.2 (d), 135.6 (d, 4C), 133.5 (s, 2C), 129.7 (d, 2C), 127.7 (d, 4C),
5.3.1.4. (S)-2-Methyl-4-(tert-butyldiphenylsilyloxy)butanol (23).41 To
a solution of 22 (100 g,1.94 mmol) in THF/MeOH (10:1,11 mL) at 0 ꢁC
was added dropwise a suspension of LiBH4 (6.0 mL, 1.6 M in THF,
9.6 mmol, 5 equiv). After 2 h at rt, the reaction mixture was cau-
tiously poured into a cold 0.5 M aqueous solution of sodium potas-
sium tartrate (15 mL). 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 residue was purified by flash
chromatography (petroleum ether/EtOAc: 80:20, 60:40) to afford
565 mg (85%) of alcohol 23 as a colorless oil and 282 mg (82%) of
114.3 (t), 78.9 (d), 61.9 (t), 40.9 (d), 33.9 (t), 33.2 (d), 26.8 (q, 3C),19.1
(s), 16.9 (q), 14.1 (q); MS-EI m/z (relative intensity) 339 (Mꢀt-Buþ,
2), 337 (2), 321 (2), 283 (6), 229 (5), 205 (7), 100 (18), 199 (100), 197
(12), 183 (10), 181 (12), 139 (11), 135 (13), 123 (53), 85 (23), 81 (25),
67 (7), 55 (10).
5.3.1.7. (5S,6S)-6-[(S)-3-(tert-Butyldiphenylsilyloxy)-1-methylpropyl]-
5-methyl-5,6-dihydro-pyran-2-one (27). To a solution of alcohol 25
(715 mg, 1.80 mmol), DMAP (66 mg, 0.54 mmol, 0.30 equiv), and i-
Pr2NEt (0.75 mL, 4.32 mmol, 2.4 equiv) in CH2Cl2 (10 mL) at ꢀ78 ꢁC
was added dropwise acryloyl chloride (1.08 mL, 1.80 mmol,
1 equiv). After 1 h at ꢀ78 ꢁC, the reaction mixture was poured into
a saturated aqueous solution of NH4Cl and extracted with EtOAc.
The combined organic extracts were washed with brine, dried over
MgSO4, filtered, and concentrated under reduced pressure. The
residue was filtered through a short pad of silica gel (Et2O) and the
filtrate was evaporated under reduced pressure. The resulting ac-
rylate 26 was dissolved in CH2Cl2 (30 mL) and to the resulting
degassed solution (argon bubbling, 10 min) was added Grubbs’
second generation catalyst (92 mg, 0.11 mmol, 0.06 equiv) (in three
portions at 1 h interval). After heating at reflux for a total duration
of 4 h, the reaction mixture was cooled to rt and evaporated under
reduced pressure. The residue was purified by flash chromatogra-
phy (petroleum ether/EtOAc: 95:5, 90:10, and 80:20) to afford
(4S)-4-benzyloxazolidin-2-one was also recovered (C21H30O2Si,
20
MW¼342.55 g molꢀ1). [
a]
D
ꢀ5.3 (c 0.95, CHCl3); IR 3346,1471, 1427,
1389, 1107, 1085, 1040, 996, 822, 736, 700 cmꢀ1; 1H NMR (400 MHz,
CDCl3)
d 7.68–7.66 (m, 4H), 7.46–7.36 (m, 6H), 3.79–3.67 (m, 2H),
3.52 (dd, J¼10.5, 5.5 Hz, 1H), 3.47 (dd, J¼10.5, 6.5 Hz, 1H), 2.43 (br s,
1H, OH), 1.90–1.79 (m, 1H), 1.67–1.59 (m, 1H), 1.53–1.45 (m, 1H), 1.05
(s, 9H), 0.90 (d, J¼6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 135.6 (d,
4C), 133.5 (s, 2C), 129.7 (d, 2C), 127.7 (d, 4C), 68.3 (t), 62.5 (t), 36.8 (t),
33.9 (d), 26.8 (q, 3C), 19.1 (s), 17.2 (q); MS-EI m/z (relative intensity)
285 (Mꢀt-Buþ, 3), 267 (3), 229 (31), 200 (19), 199 (100), 181 (9), 139
(9), 69 (9).
5.3.1.5. (S)-2-Methyl-4-(tert-butyldiphenylsilyloxy)butanal (24). To
a solution of alcohol 23 (410 mg, 1.20 mmol) in DMSO/THF (1:1,
10 mL) at rt was added IBX (670 mg, 2.40 mmol, 1 equiv). After 2 h,
H2O (10 mL) and Et2O (20 mL) were added, the resulting mixture
was then vigorously stirred for 10 min, and filtered through Celite
(Et2O). The layers of the filtrate were separated and the aqueous
phase was extracted with Et2O (3ꢃ20 mL). The combined organic
extracts were washed with brine, dried over MgSO4, filtered, and
concentrated under reduced pressure. Traces of water were re-
moved by azeotropic evaporation with toluene and the viscous
residue was dried under high vacuum (0.1 mmHg) for 2 h to afford
415 mg (quantitative) of aldehyde 24, which was directly engaged
in the next step (C21H28O2Si, MW¼340.53 g molꢀ1). 1H NMR
723 mg (95%, two steps from 25) of lactone 27 as a pale brown oil
(C26H34O3Si, MW¼422.63 g molꢀ1). [
a
]
D
þ42.6 (c 0.53, CHCl3); IR
20
1719, 1461, 1427, 1376, 1249, 1106,1049, 988, 822, 733, 700 cmꢀ1; 1H
NMR (400 MHz, CDCl3) d 7.63–7.59 (m, 4H), 7.37–7.29 (m, 6H), 6.89
(dd, J¼9.5, 6.5 Hz, 1H), 5.89 (d, J¼9.5 Hz, 1H), 3.96 (dd, J¼10.0,
3.0 Hz,1H), 3.75–3.65 (m, 2H), 2.41–2.34 (m, 1H), 2.21–2.13 (m, 1H),
2.01–1.91 (m, 1H), 1.34–1.26 (m, 1H), 0.97 (s, 9H), 0.94 (d, J¼7.0 Hz,
3H), 0.78 (d, J¼6.5 Hz, 3H). The 1H NMR spectrum of 27 was also
recorded in CD3OD for comparison with data reported for struc-
turally related lactones:8,10 1H NMR (400 MHz, CD3OD)
d 7.69–7.66
(m, 4H), 7.43–7.37 (m, 6H), 7.13 (dd, J¼9.6, 6.5 Hz, 1H), 5.92 (dd,
J¼9.6, 0.7 Hz, 1H), 4.11 (dd, J¼10.5, 3.1 Hz, 1H), 3.86–3.74 (m, 2H),
2.59–2.51 (m, 1H), 2.22–2.14 (m, 1H), 2.10–2.00 (m, 1H), 1.42–1.33
(m, 1H), 1.03 (s, 9H), 0.98 (d, J¼7.1 Hz, 3H), 0.84 (d, J¼6.8 Hz, 3H);
(400 MHz, CDCl3)
d
9.68 (d, J¼1.5 Hz, 1H), 7.67–7.64 (m, 4H),
7.46–7.37 (m, 6H), 3.78–3.66 (m, 2H), 2.63–2.54 (m, 1H), 2.06–1.97
(m, 1H), 1.66–1.58 (m, 1H), 1.09 (d, J¼7.0 Hz, 3H), 1.04 (s, 9H); 13C
13C NMR (100 MHz, CDCl3)
d 164.8 (s), 151.8 (d), 135.6 (d, 4C), 133.9
NMR (100 MHz, CDCl3)
d
204.9 (d), 135.6 (d, 4C), 133.5 (s, 2C), 129.7
(s, 2C),129.7 (d, 2C),127.7 (d, 4C),120.0 (d), 83.8 (d), 61.7 (t), 34.7 (t),
31.1 (d), 30.4 (d), 26.9 (q, 3C), 19.2 (s), 14.8 (q), 10.7 (q); MS-EI m/z
(relative intensity) 366 (MꢀC4Hþ8 , 22), 365 (Mꢀt-Buþ, 73), 287 (43),
(d, 2C), 127.7 (d, 4C), 61.1 (t), 43.5 (d), 33.4 (t), 26.8 (q, 3C), 19.2 (s),
13.1 (q).

6694
A.-F. Salit et al. / Tetrahedron 64 (2008) 6684–6697
225 (22), 200 (17), 199 (100), 197 (15), 183 (24), 181 (20), 175 (18),
149 (23), 139 (18),135 (13), 121 (13), 105 (11), 77 (11). Anal. Calcd for
(27); HRMS calcd for C11H20O3Na (MþNaþ): 223.13047, found:
223.13011.
C
26H34O3Si: C, 73.89; H, 8.11. Found: C, 73.55; H, 8.15.
5.3.1.10.
(2S,3S,6R)-2-((S)-3-Iodo-1-methylpropyl)-6-methoxy-3-
5.3.1.8. tert-Butyl-[(S)-3-((2S,3S,6R)-6-methoxy-3-methyl-3,6-dihy-
dro-2H-pyran-2-yl)butoxy]-diphenylsilane (28). To a solution of
lactone 27 (340 mg, 0.804 mmol) in THF (7 mL) at ꢀ78 ꢁC was
added dropwise DIBAL-H (0.88 mL, 1 M in hexanes, 0.88 mmol,
1.1 equiv). After 1 h at ꢀ78 ꢁC, the reaction mixture was poured into
a saturated aqueous solution of sodium potassium tartrate (10 mL).
After 1 h of vigorous stirring, 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
concentrated under reduced pressure. The crude lactol was dis-
solved in a mixture of C6H6 (5 mL) and MeOH (2.25 mL) and PPTS
(40 mg, 0.16 mmol, 0.2 equiv) was then added. After 1.5 h at reflux,
the reaction mixture was evaporated under reduced pressure and
the residue was partitioned between EtOAc and a saturated aque-
ous solution of NaHCO3 (10 mL). 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
concentrated under reduced pressure. The residue was purified by
flash chromatography (petroleum ether/EtOAc: 90:10, 80:20) to
afford 334 mg (95%, two steps from 27) of acetal 28 as mixture of
epimers at C1 (dr¼90:10) (C27H38O3Si, MW¼438.67 g molꢀ1). IR
1658, 1461, 1427, 1389, 1184, 1105, 1076, 1040, 987, 960, 822, 734,
methyl-3,6-dihydro-2H-pyran (30). To a solution of alcohol 29
(340 mg,1.70 mmol) in THF (15 mL) at 0 ꢁC were successively added
imidazole (277 mg, 4.08 mmol, 2.4 equiv), PPh3 (535 mg,
2.04 mmol, 1.2 equiv), and I2 (518 mg, 2.04 mmol, 1.2 equiv). After
15 min at 0 ꢁC, the reaction mixture was poured into a mixture of
a saturated aqueous solution of NaHCO3 and a saturated aqueous
solution of Na2S2O3 (1:1, 10 mL) and 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 chromatography (petroleum ether/
Et2O: 99:1, 95:5) to afford 480 mg (90%) of iodide 30 as a colorless
oil and
a
mixture of epimers at C1 (dr¼90:10) (C11H19IO2,
MW¼310.17 g molꢀ1). IR 1658, 1454, 1398, 1381, 1334, 1233, 1183,
1104, 1076, 1040, 988, 958, 890, 733 cmꢀ1 1H NMR (400 MHz,
;
CDCl3) only the signals corresponding to the major epimer can be
described unambiguously:
d
6.04 (ddd, J¼10.0, 6.0, 1.0 Hz, 1H), 5.66
(ddd, J¼10.0, 3.0, 1.0 Hz, 1H), 4.82 (d, J¼3.0 Hz, 1H), 3.57 (dd, J¼10.0,
3.0 Hz, 1H), 3.44 (s, 3H), 3.39–3.32 (m, 1H), 3.26–3.19 (m, 1H), 2.46–
2.38 (m, 1H), 2.11–2.03 (m, 1H), 1.81–1.67 (m, 2H), 0.92 (d, J¼7.0 Hz,
3H), 0.86 (d, J¼6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 135.9 (d),
124.0 (d), 96.4 (d), 73.1 (d), 55.6 (q), 38.1 (t), 35.3 (d), 30.2 (d), 14.6
(q), 11.7 (q), 4.3 (t); MS-EI m/z (relative intensity) 310 (Mþ, 0.5), 309
(1), 279 (MꢀOMeþ, 13), 199 (2), 183 (3), 167 (4), 151 (18), 123 (6), 99
(11), 98 (100), 97 (41), 95 (61), 86 (33), 83 (10), 81 (9), 69 (10), 67
(24), 55 (21); HRMS calcd for C11H19O2INa (MþNaþ): 333.03219,
found: 333.03182.
700, 612 cmꢀ1
;
1H NMR (400 MHz, CDCl3) only the signals corre-
sponding to the major epimer can be described unambiguously:
d
7.70–7.66 (m, 4H), 7.44–7.35 (m, 6H), 6.03 (ddd, J¼10.0, 6.0, 1.0 Hz,
1H), 5.64 (ddd, J¼10.0, 2.7, 1.0 Hz, 1H), 4.80 (br d, J¼2.7 Hz, 1H),
3.84–3.71 (m, 2H), 3.49 (dd, J¼10.0, 2.5 Hz, 1H), 3.38 (s, 3H), 2.27–
2.19 (m, 1H), 2.10–2.02 (m, 1H), 1.82–1.71 (m, 1H), 1.37–1.25 (m, 1H),
1.05 (s, 9H), 0.89 (d, J¼7.0 Hz, 3H), 0.79 (d, J¼7.0 Hz, 3H); 13C NMR
5.3.2. Synthesis of the C9–C13 subunit
(100 MHz, CDCl3)
d
136.1 (d), 135.6 (d, 4C), 134.2 (s, 2C), 129.5 (d,
5.3.2.1. (2S,3R)-N-Methyl-N-methoxy-3-(tert-butyldimethylsilyloxy)-
2-methyl-5-trimethylsilylpent-4-ynamide (31). To a mixture of ethyl
ester 13 (1.49 g, 4.35 mmol) and N,O-dimethylhydroxylamine hy-
drochloride (680 mg, 6.96 mmol, 1.6 equiv) in THF (10 mL) at
ꢀ20 ꢁC was added dropwise a solution of i-PrMgCl (5.45 mL, 2 M in
THF, 10.9 mmol, 2.2 equiv). After 1.5 h at ꢀ5 ꢁC, the reaction mix-
ture 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 residue was purified by flash chromatography (petroleum
ether/Et2O: 95:5) to afford 1.09 g (70%) of Weinreb amide 31 as
2C), 127.6 (d, 4C), 124.0 (d), 96.4 (d), 73.7 (d), 62.4 (t), 55.4 (q), 36.0
(t), 31.0 (d), 30.2 (d), 26.9 (q, 3C), 19.2 (s), 15.4 (q), 11.7 (q); MS-EI
m/z (relative intensity) 349 (MꢀMeOHꢀt-Buþ, 12), 284 (21), 283
(86), 253 (8), 227 (7), 213 (29), 205 (30), 200 (13), 199 (66), 197 (11),
183 (23), 181 (17), 175 (21), 151 (12), 139 (15), 135 (19), 133 (12), 123
(11), 106 (15), 98 (30), 97 (13), 95 (29), 91 (15), 79 (13), 78 (100), 77
(37), 56 (13), 55 (14), 52 (15), 51 (17); HRMS calcd for C27H38O3NaSi
(MþNaþ): 461.24824, found: 461.24803.
5.3.1.9. (S)-3-((2S,3S,6R)-6-Methoxy-3-methyl-3,6-dihydro-2H-py-
ran-2-yl)butan-1-ol (29). To a solution of silyl ether 28 (120 mg,
0.273 mmol) in THF (5 mL) at 0 ꢁC was added n-Bu4NF (0.68 mL,
1 M in THF, 0.68 mmol, 2.5 equiv). After 1 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
EtOAc. The combined organic extracts were washed with brine,
dried over MgSO4, filtered, and concentrated under reduced pres-
sure. The residue was purified by flash chromatography (petroleum
ether/EtOAc: 70:30) to afford 51 mg (94%) of 29 as a colorless oil
a pale yellow oil and 403 mg (27%) of the starting material 13 were
recovered (C17H35NO3Si2, MW¼357.63 g molꢀ1).
[
a
]
D
þ145.0
20
(c 1.0, CHCl3); IR 1662, 1250, 1086, 1024, 993, 835, 778, 760,
733 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d
4.53 (d, J¼10.0 Hz, 1H), 3.71
(s, 3H), 3.16 (br sþm, 3Hþ1H), 1.14 (d, J¼7.0 Hz, 3H), 0.85 (s, 9H),
0.16 (s, 9H), 0.11 (s, 3H), 0.07 (s, 3H); 13C NMR (75 MHz, CDCl3)
d
174.9 (s), 106.0 (s), 90.4 (s), 66.2 (q), 61.6 (d), 42.5 (d), 31.9 (q), 25.6
(q, 3C), 18.1 (s), 14.3 (q), ꢀ0.2 (q, 3C), ꢀ4.7 (q), ꢀ5.3 (q); MS-EI m/z
(relative intensity) 357 (Mþ, 1), 342 (MꢀMeþ, 9), 326 (7), 301 (26),
300 (Mꢀt-Buþ, 100), 241 (10), 143 (12), 142 (20), 123 (11), 115 (18),
89 (31), 75 (17), 73 (6), 68 (11). Anal. Calcd for C17H35NO3Si2: C,
57.09; H, 9.86. Found: C, 56.93; H, 9.86.
and
a
mixture of epimers at C1 (dr¼90:10) (C11H20O3,
MW¼200.27 g molꢀ1). IR 3442, 1455, 1379, 1334, 1241, 1184, 1103,
1074, 1038, 960, 891, 734 cmꢀ1; 1H NMR (400 MHz, CDCl3) only the
signals corresponding to the major epimer can be described un-
ambiguously:
d
6.05 (dd, J¼10.0, 6.0 Hz, 1H), 5.66 (dd, J¼10.0, 3.0 Hz,
1H), 4.84 (apparent br d, J¼2.0 Hz,1H), 3.83–3.76 (m,1H), 3.73–3.64
(m, 1H), 3.55 (dd, J¼10.5, 2.7 Hz, 1H), 3.46 (s, 3H), 2.20–2.06 (m,
2HþOH), 1.82–1.72 (m, 1H), 1.47–1.38 (m, 1H), 0.92 (d, J¼6.5 Hz,
5.3.2.2. (2S,3R)-3-(tert-Butyldimethylsilyloxy)-2-methyl-5-trimethyl-
silylpent-4-ynal (32). To a solution of Weinreb amide 31 (980 mg,
2.74 mmol) in THF (18 mL) at ꢀ78 ꢁC was added dropwise DIBAL-H
(3.0 mL, 1 M in hexanes, 3.0 mmol, 1.1 equiv). After 1 h at ꢀ78 ꢁC,
the reaction mixture was poured into a saturated aqueous solution
of sodium potassium tartrate (20 mL). After addition of Et2O
(20 mL) and 0.5 h of vigorous stirring at rt, the layers were sepa-
rated and the aqueous phase was extracted with Et2O. The
3H), 0.90 (d, J¼6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 136.0 (d),
123.9 (d), 96.3 (d), 73.9 (d), 60.9 (t), 55.6 (q), 36.7 (t), 31.0 (d), 30.2
(d), 16.0 (q), 11.7 (q); MS-EI m/z (relative intensity) 169 (MꢀOMeþ,
21), 105 (17), 98 (21), 97 (19), 95 (34), 94 (20), 91 (24), 85 (100), 84
(24), 83 (24), 81 (21), 79 (24), 69 (18), 68 (27), 67 (31), 55 (38), 53

A.-F. Salit et al. / Tetrahedron 64 (2008) 6684–6697
6695
combined organic extracts were washed with brine, dried over
MgSO4, filtered, and concentrated under reduced pressure. The
residual traces of water were removed by azeotropic evaporation
with toluene and the residue was dried under vacuum (0.1 mmHg)
during 1.5 h to afford 818 mg (quantitative) of aldehyde 32. This
compound was directly engaged in the next step without further
purification (C15H30O2Si2, MW¼298.57 g molꢀ1). 1H NMR (400 MHz,
with brine, dried over MgSO4, filtered, and concentrated under
reduced pressure. The crude product was dissolved in THF (5 mL)
and a solution of n-Bu4NF (0.40 mL, 1 M in THF, 0.40 mmol,
2.5 equiv) was added. After 20 min at rt, the reaction mixture was
poured into a saturated aqueous solution of NH4Cl and extracted
with Et2O. The combined organic extracts were washed with brine,
dried over MgSO4, filtered, and concentrated. The residue was pu-
rified by flash chromatography (petroleum ether/Et2O: 75:35) to
afford 18 mg (68%) of a 70:30 mixture of the diastereomeric alco-
hols anti- and syn-1,3-diols 35 and 350.
CDCl3)
d
9.82 (d, J¼1.5 Hz, 1H), 4.54 (d, J¼6.0 Hz, 1H), 2.63–2.56
(m, 1H), 1.12 (d, J¼7.0 Hz, 3H), 0.87 (s, 9H), 0.16 (s, 9H), 0.15 (s, 3H),
0.10 (s, 3H).
5.3.3.3.2. By reduction of b-hydroxyketone 37. To a solution of
5.3.3. Diastereoselectivity of a nucleophilic addition to aldehyde 32
Me4NBH(OAc)3 (264 mg, 1.12 mmol, 8 equiv) in CH3CN/AcOH (1:1,
1.6 mL) at ꢀ40 ꢁC was added dropwise a solution of ketone 37
(35 mg, 0.146 mmol) in CH3CN/AcOH (1:1, 1.6 mL). After 5 h stirring
at ꢀ40 ꢁC, 5 h at ꢀ20 ꢁC, and 12 h at 0 ꢁC, the reaction mixture was
poured into a saturated aqueous solution of sodium potassium
tartrate (10 mL). After 2 h of vigorous stirring, the layers were
separated and the aqueous phase was extracted with EtOAc. The
combined organic extracts were successively washed with a satu-
rated aqueous solution of NaHCO3, brine, dried over MgSO4, fil-
tered, and concentrated under reduced pressure. The residue was
dissolved in THF (2 mL) and a solution of n-Bu4NF (0.17 mL, 1 M in
THF, 0.17 mmol, 1.15 equiv) was added to the resulting solution at
0 ꢁC. After 20 min, the reaction mixture was poured into a saturated
aqueous solution of NH4Cl and 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 chromatography (petroleum ether/Et2O: 70:30) to
afford 14 mg (56%) of an 85:15 mixture of the anti- and syn-1,3-
diols 35 and 350.
5.3.3.1. (3R*,4S*)-3-(tert-Butyldimethylsilyloxy)-4-methyl-1-trimethyl-
silylnon-1-yn-5-one (36). To a solution of the Weinreb amide rac-31
(263 mg, 0.735 mmol) in Et2O (5 mL) at ꢀ78 ꢁC was added drop-
wise n-BuLi (0.588 mL, 2.5 M in hexanes, 1.47 mmol, 2 equiv). After
2 h at ꢀ30 ꢁC, the cold 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 (petroleum ether/Et2O: 96:4) to
afford 185 mg (71%) of ketone 36 as a colorless oil (C19H38O2Si2,
MW¼354.67 g molꢀ1). IR 2170, 1719, 1461, 1362, 1250, 1078, 1012,
834, 778, 760 cmꢀ1; 1H NMR (400 MHz, CDCl3)
1H), 2.85 (dq, J¼9.2, 7.0 Hz, 1H), 2.51–2.47 (m, 2H), 1.57–1.48 (m,
2H), 1.36–1.26 (m, 2H), 1.08 (d, J¼7.0 Hz, 3H), 0.90 (t, J¼7.3 Hz, 3H),
0.86 (s, 9H), 0.16 (s, 9H), 0.13 (s, 3H), 0.06 (s, 3H); 13C NMR
d
4.46 (d, J¼9.2 Hz,
(100 MHz, CDCl3)
d 212.6 (s), 105.8 (s), 90.7 (s), 66.2 (d), 52.3 (d),
43.9 (t), 25.7 (q, 3C), 25.2 (t), 22.3 (t), 18.1 (s), 13.9 (q), 13.8 (q), ꢀ0.3
(q, 3C), ꢀ4.7 (q), ꢀ5.3 (q); MS-EI m/z (relative intensity) 354 (Mþ,1),
339 (MꢀMeþ, 4), 298 (MꢀC4Hþ8 , 27), 297 (Mꢀt-Buþ, 100), 241 (15),
223 (13), 211 (9), 199 (8), 171 (40), 147 (54), 133 (14), 75 (56), 73
(55), 57 (11); HRMS (FAB) calcd for C19H38NaO2Si2 (MþNaþ):
377.2302, found: 377.2307.
Compound (35). C10H18O2, MW¼170.25 g molꢀ1; IR 3310 (br),
1459, 1379, 1251, 1117, 1075, 1024, 964 cmꢀ1 1H NMR (400 MHz,
;
CDCl3)
d 4.42 (m, 1H), 4.24–4.19 (m, 1H), 3.16 (apparent br s, 1H,
OH), 2.52 (d, J¼2.1 Hz, 1H), 2.10–1.96 (br m, 1H, OH), 1.85–1.78 (m,
1H),1.60–1.50 (m, 2H),1.48–1.28 (m, 4H),1.06 (d, J¼7.1 Hz, 3H), 0.92
(t, J¼7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 84.4 (s), 73.8 (d), 72.3
(d), 66.6 (d), 42.4 (d), 34.3 (t), 28.2 (t), 22.6 (t), 14.0 (q), 9.9 (q).
5.3.3.2. (3R*,4S*)-3-Hydroxy-4-methyl-1-trimethylsilylnon-1-yn-5-
one (37). To a solution of ketone 36 (112 mg, 0.316 mmol) in THF
(6 mL) at 0 ꢁC (polyethylene vessel) was added dropwise HF$Py
complex (70% HF, 1.0 mL). After 8 h at rt, the reaction mixture was
cooled to 0 ꢁC and a saturated aqueous solution of NaHCO3 (5 mL)
was cautiously added dropwise followed by neutralization by por-
tionwise addition of solid NaHCO3. After extraction with EtOAc, the
combined organic extracts were washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash chromatography (petroleum ether/
5.3.4. Formal synthesis of cytostatin
5.3.4.1. (3R,4R,5S,8S)-3-(tert-Butyldimethylsilyloxy)-8-((2S,3S,6R)-6-
methoxy-3-methyl-3,6-dihydro-2H-pyran-2-yl)-4-methyl-1-trime-
thylsilylnon-1-yn-5-ol (34) and (3R,4R,5R,8S)-3-(tert-butyldime-
thylsilyloxy)-8-((2S,3S,6R)-6-methoxy-3-methyl-3,6-dihydro-2H-
pyran-2-yl)-4-methyl-1-trimethylsilylnon-1-yn-5-ol
(340). To
a
solution of alkyl iodide 30 (566 mg, 1.82 mmol, 1 equiv) in Et2O
(10 mL) at ꢀ78 ꢁC was added a solution of t-BuLi (2.35 mL, 1.7 M in
pentane, 4.00 mmol, 2.2 equiv). After 10 min at ꢀ78 ꢁC and 15 min
at ꢀ30 ꢁC, the resulting organolithium 33 solution was cooled to
Et2O: 98:2) to afford 57 mg (75%) of b-hydroxyketone 37 as a color-
less oil (C13H24O2Si, MW¼240.41 g molꢀ1). IR 3424, 2173,1707,1457,
1375, 1249, 1022, 998, 840, 759, 700 cmꢀ1
;
1H NMR (400 MHz,
ꢀ78 ꢁC and
a solution of aldehyde 32 (818 mg, 2.74 mmol,
CDCl3)
d
4.48 (dd, apparent t, J¼6.9 Hz,1H), 2.90–2.83 (m,1H), 2.58–
1.5 equiv) in Et2O (10 mL) was added dropwise within 20 min. After
1.5 h at ꢀ78 ꢁC and 2 h at ꢀ30 ꢁC, the reaction mixture was poured
into a saturated aqueous solution of NH4Cl. The layers were sepa-
rated and the aqueous phase was extracted with Et2O. The com-
bined organic extracts were washed with brine, dried over MgSO4,
filtered, and concentrated under reduced pressure. The residue was
purified by flash chromatography (petroleum ether/Et2O gradient:
98:2–80:20) to afford 389 mg (52%) of a diastereomeric mixture of
alcohols 34 and 340 in a 75:25 ratio and as a colorless oil
(C26H50O4Si2, MW¼482.84 g molꢀ1). IR 3471, 2171, 1659, 1462,
1249, 1184, 1075, 1042, 962, 835, 777, 760, 734 cmꢀ1; major epimer
2.45 (m, 2H),1.62–1.54 (m, 2H),1.38–1.28 (apparent sextet, J¼7.4 Hz,
2H),1.20 (d, J¼7.2 Hz, 3H), 0.92 (t, J¼7.4 Hz, 3H), 0.18 (s, 9H); 13C NMR
(100 MHz, CDCl3) d 214.4 (s),104.7 (s), 90.6 (s), 64.8 (d), 51.5 (d), 42.7
(t), 25.4 (t), 22.3 (t),14.0 (q),13.8 (q), ꢀ0.2 (q, 3C); MS-EI m/z (relative
intensity) 225 (MꢀMeþ, 10), 207 (9), 183 (42), 167 (MꢀSiMeþ3 , 17),
165 (22), 138 (13), 123 (100), 114 (24), 111 (93), 99 (25), 97 (50), 85
(42), 83 (28), 75 (50), 73 (30), 72 (57), 57 (80), 55 (20).
5.3.3.3. (3R*,4S*,5R*)-4-Methylnon-1-yn-3,5-diol (35)
5.3.3.3.1. By nucleophilic addition of n-BuLi to aldehyde 32. To
a solution of aldehyde rac-32 (50 mg, 0.16 mmol) in Et2O (5 mL) at
ꢀ78 ꢁC was added n-BuLi (0.10 mL, 2.5 M in hexanes, 0.25 mmol,
1.5 equiv). After 2 h from ꢀ78 ꢁC to ꢀ30 ꢁC, the reaction mixture
was poured into a saturated aqueous solution of NH4Cl and
extracted with Et2O. The combined organic extracts were washed
(34): 1H NMR (400 MHz, CDCl3)
d
6.05 (dd, J¼9.8, 5.9 Hz, 1H), 5.65
(dd, J¼9.8, 1.3 Hz, 1H), 4.83 (apparent br s, 1H), 4.41 (d, J¼3.9 Hz,
1H), 4.23 (m, 1H), 3.62–3.49 (m, 1H), 3.44 (s, 3H), 2.13–1.87 (m, 1H),
1.75–1.58 (m, 2H), 1.40–1.22 (m, 4H), 1.01 (d, J¼7.0 Hz, 3H), 0.98 (d,
J¼6.9 Hz, 3H), 0.91 (s, 9H), 0.90–0.85 (m, 3H), 0.17 (s, 3H), 0.15 (s,

6696
A.-F. Salit et al. / Tetrahedron 64 (2008) 6684–6697
9H), 0.13 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
136.1 (d), 123.9 (d),
flash chromatography (petroleum ether/EtOAc: 40:60, 50:50 then
106.2 (s), 94.4 (d), 90.7 (s), 73.7 (d), 71.7 (d), 68.8 (d), 55.5 (q), 43.3
(d), 34.0 (d), 31.9 (t), 30.2 (d), 29.7 (t), 25.7 (q, 3C), 18.1 (s), 15.1 (q),
11.8 (q),10.1 (q), ꢀ0.3 (q, 3C), ꢀ4.6 (q), ꢀ5.4 (q); minor epimer (340):
1H NMR (400 MHz, CDCl3) some signals cannot be accurately de-
60:40) to separate the excess of phosphorus reagents and 9-fluo-
renylmethanol and then by chromatography on preparative TLC
plate (petroleum ether/EtOAc: 70:30) to afford 58 mg (70%) of
a mixture of diastereomeric phosphates 40 and 400 (75:25 ratio) as
a colorless oil (C53H67O7PSi2, MW¼902.41 g molꢀ1). IR 1717, 1449,
1249, 1103, 1070, 987, 908, 837, 757, 728 cmꢀ1; 1H NMR (400 MHz,
CDCl3) only the signals corresponding to the major epimer could be
scribed due to overlap:
d
6.05 (dd, J¼9.8, 5.9 Hz, 1H), 5.65 (dd, J¼9.8,
1.3 Hz, 1H), 4.83 (br s, 1H), 4.49 (d, J¼6.1 Hz, 1H), 3.62–3.49 (m, 2H),
3.44 (s, 3H), 2.13–1.87 (m, 1H), 1.84–1.78 (m, 1H), 1.75–1.58 (m, 1H),
1.40–1.22 (m, 4H), 1.04–0.85 (9H), 0.91 (s, 9H), 0.17–0.15 (15H); 13
C
unambiguously assigned:
d
7.78–7.19 (m, 16H), 6.95 (dd, J¼9.5,
NMR (100 MHz, CDCl3)
d
136.1 (d), 123.9 (d), 106.3 (s), 94.4 (d), 90.6
6.5 Hz, 1H), 5.93 (d, J¼9.5 Hz, 1H), 4.64–4.56 (m, 1H), 4.34–4.08 (m,
6H), 3.90 (dd, J¼10.3, 2.8 Hz, 1H), 2.44–2.38 (m, 1H), 1.90–1.56 (m,
6H), 0.99 (d, J¼7.0 Hz, 3H), 0.97 (d, J¼6.9 Hz, 3H), 0.86 (s, 9H), 0.82
(d, J¼6.7 Hz, 3H), 0.15 (s, 9H), 0.13 (s, 3H), 0.07 (s, 3H); 13C NMR
(s), 74.7 (d), 73.3 (d), 66.9 (d), 55.5 (q), 45.4 (d), 34.1 (d), 31.1 (t), 30.2
(d), 28.5 (t), 25.8 (q, 3C), 18.1 (s), 15.3 (q), 12.4 (q), 11.7 (q), ꢀ0.3 (q,
3C), ꢀ4.3 (q), ꢀ5.0 (q).
(100 MHz, CDCl3) d 164.5 (s), 151.6 (d), 143.9 (s), 143.6 (s), 143.2 (s),
5.3.4.2. (3R,4R,5S,8S)-3-(tert-Butyldimethylsilyloxy)-8-((2S,3S,6R)-
6-methoxy-3-methyl-3,6-dihydro-2H-pyran-2-yl)-4-methyl-1-trime-
thylsilylnon-1-yn-5-ol (39). To mixture of epimeric alcohols 34 and
340 (300 mg, 0.621 mmol, 1 equiv, 75:25 ratio) in acetone (15 mL)
and H2O (1 mL) was added PPTS (47 mg, 0.19 mmol, 0.3 equiv). After
12 h and 18 h at rt, additional quantities of PPTS (47 mg, 0.19 mmol,
0.3 equiv) were added. After a further 6 h, the reaction mixture was
neutralized by addition of an aqueous solution of NaHCO3 and
extracted with EtOAc. The combined organic extracts were washed
with brine, dried over MgSO4, filtered, and concentrated under re-
duced pressure. The crude mixture of the lactols 38/380 was dis-
solved in CH2Cl2 (18 mL) and MnO2 (1.36 g, 15.6 mmol, 25 equiv)
was added. After 15 h at rt, a second portion of MnO2 (1.36 g,
15.6 mmol, 25 equiv) was added and 12 h later the reaction mixture
was filtered through Celite (CH2Cl2). The filtrate was evaporated
under reduced pressure and the residue was purified by flash
chromatography (petroleum ether/EtOAc: 90:10, 80:20, and 60:40)
to afford 188 mg (65%) of a mixture of epimeric alcohols 39 and 390
143.0 (s), 141.4 (s), 141.3 (s, 2C), 141.2 (s), 127.8 (d), 127.7 (d, 2C),
127.6 (d), 127.0 (d, 2C), 126.9 (d, 2C), 125.1 (d, 2C), 125.0 (d, 2C),
124.9 (d), 120.0 (d), 119.9 (d, 2C), 119.8 (d), 106.3 (s), 90.9 (s), 83.7
(d), 79.9 (d, J2 ¼6.3 Hz), 69.0 (t, J3 ¼5.9 Hz), 67.2 (t, J3
¼
C–P
C–P
C–P
5.5 Hz), 64.2 (d), 48.2 (d, J3 ¼8.5 Hz), 47.9 (d, J3 ¼8.4 Hz), 43.6
C–P
C–P
(d, J3 ¼4.9 Hz), 33.9 (d), 30.3 (d), 30.1 (t), 28.0 (t), 25.7 (q, 3C), 18.1
C–P
(s), 14.5 (q), 10.7 (q), 10.1 (q), ꢀ0.3 (q, 3C), ꢀ4.1 (q), ꢀ4.8 (q); HRMS
(FAB) calcd for
925.4053.
C
53H67O7NaPSi2 (MþNaþ): 925.4055, found:
5.3.4.4. Bis-(9H-fluoren-9-ylmethyl) (1S,2S,3R)-3-hydroxy-2-methyl-
1-[(S)-3-((2S,3S)-3-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)butyl]-
5-trimethylsilylpent-4-ynylphosphate (41). To
a solution of the
mixture of phosphates 40 and 400 (75:25 ratio, 60 mg, 0.066 mmol,
1 equiv) in THF (4 mL) at 0 ꢁC (polyethylene vessel) was added
HF$Py (70% HF, 0.6 mL). After 15 h at rt, more HF$Py (0.2 mL) was
added and, 6 h later, the reaction mixture was cautiously neutral-
ized at 0 ꢁC by dropwise addition of a saturated aqueous solution of
NaHCO3 (5 mL) and then solid NaHCO3. After extraction with EtOAc,
the combined organic extracts were washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by chromatography on a preparative TLC plate
(petroleum ether/EtOAc: 50:50) to afford 36 mg (69%) of a mixture
of the diastereomeric propargylic alcohols 41 and 410 (75:25 ratio)
as a colorless oil (C47H53O7PSi, MW¼788.98 g molꢀ1). IR 3370, 2172,
(75:25 ratio) as a colorless oil (C25H46O4Si2, MW¼466.80 g molꢀ1).
20
[
a]
þ95.0 (c 0.4, CHCl3); IR 3436, 2170, 1719, 1462, 1378, 1249,
D
1073,1006, 990, 840, 778, 760 cmꢀ1; 1H NMR (400 MHz, CDCl3) only
the signals corresponding to the major epimer could be unambiguously
assigned:
d
6.99 (dd, J¼9.5, 6.5 Hz,1H), 5.97 (d, J¼9.5 Hz,1H), 4.42 (d,
J¼4.0 Hz, 1H), 4.22–4.18 (m, 1H), 4.02 (dd, J¼10.5, 3.2 Hz, 1H), 3.00
(br s, 1H, OH), 2.52–2.44 (m, 1H), 2.01–1.94 (m, 1H), 1.89–1.63 (m,
3H), 1.33–1.23 (m, 2H), 1.03 (d, J¼6.5 Hz, 3H), 1.01 (d, J¼6.8 Hz, 3H),
0.92 (d, J¼6.5 Hz, 3H), 0.91 (s, 9H), 0.17 (s, 9H), 0.16 (s, 3H), 0.13 (s,
1717, 1449, 1379, 1248, 1106, 986, 841, 757, 738 cmꢀ1 1H NMR
;
(400 MHz, CDCl3) only the signals corresponding to the major epimer
could be unambiguously assigned: 7.74–7.68 (m, 4H), 7.56–7.45 (m,
3H); 13C NMR (100 MHz, CDCl3)
d
164.8 (s), 151.8 (d), 119.9 (d), 106.0
d
(s), 90.9 (s), 84.1 (d), 71.6 (d), 68.7 (d), 42.9 (d), 34.0 (d), 31.8 (t), 30.9
(d), 28.9 (t), 25.6 (q, 3C), 18.0 (s), 14.5 (q), 10.7 (q), 10.1 (q), ꢀ0.3 (q,
3C), ꢀ4.6 (q), ꢀ5.4 (q); HRMS (FAB) calcd for C25H46NaO4Si2
(MþNaþ): 489.2827, found: 489.2826.
4H), 7.41–7.22 (m, 8H), 6.95 (dd, J¼9.6, 6.5 Hz, 1H), 5.94 (d,
J¼9.6 Hz, 1H), 4.73–4.67 (m, 1H), 4.36–4.30 (m, 1H), 4.26–4.09 (m,
6H), 3.86 (dd, J¼10.3, 2.9 Hz, 1H), 2.45–2.38 (m, 1H), 1.85–1.58 (m,
4H), 1.60–1.50 (m, 1H), 1.25–1.15 (m, 1H), 0.98 (d, J¼7.0 Hz, 3H),
0.91 (d, J¼6.9 Hz, 3H), 0.79 (d, J¼6.7 Hz, 3H), 0.19 (s, 9H); 13C
5.3.4.3. Bis-(9H-fluoren-9-ylmethyl) (1S,2S,3R)-3-(tert-butyldimethyl-
silyloxy)-2-methyl-1-[(S)-3-((2S,3S)-3-methyl-6-oxo-3,6-dihydro-
2H-pyran-2-yl)butyl]-5-trimethylsilylpent-4-ynylphosphate (40). To
a solution of the mixture of epimeric alcohols 39 and 390
(75:25 ratio) (43 mg, 0.092 mmol, 1 equiv) in CH3CN/CH2Cl2 (5:4,
5 mL) at rt, in a screw cap tube protected from light, at 0 ꢁC
were added tetrazole (22 mg, 0.32 mmol, 3.5 equiv) and bis-
NMR (100 MHz, CDCl3) d 164.5 (s), 151.6 (d), 143.2 (s), 142.9 (s),
142.8 (s, 2C), 141.4 (s, 2C), 141.3 (s, 2C), 127.9 (d, 2C), 127.8 (d, 2C),
127.2 (d), 127.1 (d, 3C), 125.0 (d, 4C), 120.05 (d, 2C), 120.0 (d, 2C),
119.9 (d), 106.0 (s), 89.4 (s), 83.6 (d), 78.5 (d, J2 ¼5.9 Hz), 69.4 (t,
C–P
J3 ¼6.4 Hz), 69.3 (t, J3 ¼6.4 Hz), 63.9 (d), 47.9 (d, J3 ¼8.6 Hz),
C–P
C–P
C–P
47.8 (d, J3 ¼8.4 Hz), 43.7 (d, J3 ¼3.8 Hz), 33.8 (d), 30.5 (t, J3
¼
C–P
C–P
C–P
4.7 Hz), 30.3 (d), 28.5 (t), 14.7 (q), 10.7 (q), 9.2 (q), ꢀ0.1 (q, 3C);
HRMS (FAB) calcd for C47H53O7NaPSi (MþNaþ): 811.31904, found:
811.3189.
(9-fluorenylmethyl)diisopropylphosphoramidite5,40
(120 mg,
0.230 mmol, 2.5 equiv). After 5 h at rt with exclusion of light,
additional quantities of tetrazole (22 mg, 0.32 mmol, 3.5 equiv) and
phosphoramidite (120 mg, 0.230 mmol, 2.5 equiv) were added.
After 3 h at rt, the reaction mixture was cooled to 0 ꢁC and t-BuOOH
(0.12 mL, 5.5 M in decane, 0.66 mmol, 7 equiv) was added drop-
wise. The resulting mixture was stirred for 1 h at rt and hydrolyzed
with a mixture of a saturated aqueous solution of NaHCO3 (1 mL)
and a 1 M aqueous solution of Na2S2O3 (1.5 mL). After extraction
with EtOAc, the combined organic extracts were washed with a 1 M
aqueous solution of KH2PO4, dried over Na2SO4, filtered, and con-
centrated under reduced pressure. The residue was purified by
5.3.4.5. Bis-(9H-fluoren-9-ylmethyl) (1S,2S,3R)-3-hydroxy-5-iodo-2-
methyl-1-[(S)-3-((2S,3S)-3-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)-
butyl]pent-4-ynylphosphate (42). To a mixture of compounds 41 and
410 (41/410¼75/25) (10 mg, 0.013 mmol) in DMF (1.5 mL) at 0 ꢁC
were successively added AgNO3 (0.3 mg, 0.002 mmol, 0.15 equiv)
and NIS (4.3 mg, 0.020 mmol, 1.5 equiv). After 1.5 h at rt, the re-
action mixture was diluted with H2O (2 mL) and extracted with
EtOAc. The combined extracts were washed with an aqueous solu-
tion of NaCl, dried over MgSO4, filtered, and concentrated under

A.-F. Salit et al. / Tetrahedron 64 (2008) 6684–6697
6697
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reduced pressure. The residue was purified by chromatography on
a silica gel preparative TLC plate (petroleum ether/EtOAc: 40:60) to
afford 8 mg (75%) of 42 as a white solid; mp 112 ꢁC (lit.5 mp 117 ꢁC)
20
(C44H44IO7P, MW¼842.69 g molꢀ1). [
a
]
þ46.5 (c 0.40, CHCl3) [lit.5
D
þ41.5 (c 0.50, CHCl3)]; IR 3353, 2360, 1714, 1449, 1380, 1250, 1106,
1070, 987, 739 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 7.75–7.67 (m, 4H),
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7.54–7.41 (m, 4H), 7.41–7.20 (m, 8H), 6.95 (dd, J¼9.5, 6.5 Hz, 1H),
5.93 (d, J¼9.5 Hz, 1H), 4.69–4.61 (m, 1H), 4.36–4.07 (m, 7H), 3.86
(dd, J¼10.3, 2.4 Hz,1H), 2.40 (m,1H),1.83–1.58 (m, 4H),1.51–1.41 (m,
1H), 1.15–1.05 (m, 1H), 0.98 (d, J¼7.0 Hz, 3H), 0.89 (d, J¼6.9 Hz, 3H),
16. (a) Shimizu, S.; Nakamura, S.; Nakada, M.; Shibasaki, M. Tetrahedron 1996, 52,
13363–13408; (b) Organ, M. G.; Wang, J. J. Org. Chem. 2003, 68, 5568–5574.
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0.78 (d, J¼6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 164.4 (s), 151.6
(d), 143.1 (s, 2C), 142.9 (s), 142.8 (s), 141.3 (s, 4C), 127.9 (d), 127.8 (d),
127.7 (d, 2C), 127.2 (d, 2C), 127.1 (d, 2C),125.0 (d, 4C),120.0 (d), 119.9
(d, 4C), 94.8 (s), 83.5 (d), 78.4 (d, J2 ¼5.8 Hz), 69.4 (t, J3 ¼4.0 Hz),
20. Sviridov, A. F.; Borodkin, V. S.; Ermolenko, M. S.; Yashunsky, D. V.; Kochetkov,
N. K. Tetrahedron 1991, 47, 2291–2316.
C–P
C–P
21. Takano, S.; Akiyama, M.; Sato, S.; Ogasawara, K. Chem. Lett. 1983, 1593–1596.
22. Sneddon, H. F.; Gaunt, M. J.; Ley, S. V. Org. Lett. 2003, 5, 1147–1150.
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24. Wasserman, H. H.; Frechette, R.; Oida, T.; van Duzer, J. H. J. Org. Chem. 1989, 54,
6012–6014.
69.3 (t, J3 ¼4.3 Hz), 65.1 (d), 47.9 (d, J3 ¼8.4 Hz), 47.8 (d,
C–P
C–P
J3 ¼8.7 Hz), 43.9 (d, J3 ¼3.6 Hz), 33.8 (d), 30.6 (t, J3 ¼4.1 Hz),
C–P
C–P
C–P
30.3 (d), 28.4 (t), 14.7 (q), 10.7 (q), 9.1 (q), 1.1 (s).
Acknowledgements
25. Cossy, J.; Schmitt, A.; Cinquin, C.; Buisson, D.; Belotti, D. Bioorg. Med. Chem. Lett.
1997, 7, 1699–1700.
26. The enantiomeric excess was confirmed by formation of the diastereomeric
O-methylmandelates and analysis of the 1H NMR spectra (drꢂ96:4, see Section
5.2.2.3): Trost, B. M.; Belletire, J. L.; Godleski, S.; McDougal, P. G.; Balkovec, J. M.;
Baldwin, J. J.; Christy, M. E.; Ponticello, G. S.; Varga, S. L.; Springer, J. P. J. Org.
Chem. 1986, 51, 2370–2374.
We thank Astra-Zeneca and the CNRS for financial support of
this work (BDI grant to A.-F.S.).
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