Iron-catalyzed cross-coupling between C-bromo mannopyranoside derivatives and a vinyl Grignard reagent: Toward the synthesis of the C31-C52 fragment of amphidinol 3

Article abstract of DOI:10.1016/j.tet.2013.05.067

A chemo- and diastereoselective iron-catalyzed cross-coupling between C-bromo mannopyranoside derivatives and 2-methyl-1-propenylmagnesium bromide was developed. This method was used as the key step for the synthesis of the mirror image of the C31-C40 and

Full text of DOI:10.1016/j.tet.2013.05.067

Tetrahedron 69 (2013) 7759e7770
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Iron-catalyzed cross-coupling between C-bromo mannopyranoside
derivatives and a vinyl Grignard reagent: toward the synthesis of the
C31eC52 fragment of amphidinol 3
a
b
b
b
ꢀ
Charlelie Bensoussan , Nicolas Rival , Gilles Hanquet , Franc¸ oise Colobert ,
a,
a,
*
*
ꢀ
Sebastien Reymond , Janine Cossy
a Laboratoire de Chimie Organique, ESPCI ParisTech, UMR CNRS 7084, 10 rue Vauquelin, 75231 Paris Cedex 05, France
b
ꢁ
ꢀ
ꢀ
Laboratoire de Synthese et Catalyse Asymetrique, Universite de Strasbourg (ECPM), UMR CNRS 7509, 25 rue Becquerel, 67087 Strasbourg Cedex 02,
France
a r t i c l e i n f o
a b s t r a c t
Article history:
A chemo- and diastereoselective iron-catalyzed cross-coupling between C-bromo mannopyranoside
derivatives and 2-methyl-1-propenylmagnesium bromide was developed. This method was used as the
key step for the synthesis of the mirror image of the C31eC40 and C43eC52 fragments of amphidinol 3
Received 2 March 2013
Received in revised form 15 May 2013
Accepted 17 May 2013
(AM3). These syntheses were achieved from a common trans-tetrahydropyran derived from D-mannose.
Available online 30 May 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Iron
Catalysis
Cross-coupling
Natural product
Asymmetric synthesis
1. Introduction
absolute configuration of the tetrahydropyran moieties. Indeed, the
structure of karlotoxin
2 has been reported to incorporate
Marine dinoflagellates are a rich source of natural products such
as polyketides, amphidinolides, or cyclic polyethers.1,2 Among di-
noflagellates, the genus Amphidinium klebsii has been recognized as
a source of bioactive secondary metabolites such as amphidinol 3
(AM3), which was isolated from a growth culture of A. klebsii in
1996.3 Amphidinol 3 displays antifungal and hemolytic activities,
and was revealed to be a stronger hemolytic agent against human
erythrocytes than other well-known antibiotics such as ampho-
tericin B and filipin III. Biological assays have indicated that
amphidinol 3 exhibits different mechanisms than for amphotericin
B and filipin III as pores or lesions in biomembranes are formed
depending on dosage concentrations.4 The structure of AM3 is
characterized by a skipped polyenic chain, a long irregular poly-
hydroxy chain both connected by a fragment containing two tet-
rahydropyran rings (Scheme 1). The absolute configuration of the
stereogenic centers was first established in 19965 but, in 2008, the
C2-stereocenter was revised to be (S),6 and more recently, the
isolation of karlotoxins has entailed some doubts concerning the
a C39eC50 fragment similar to the C42eC52 fragment of AM3, but
with opposite configurations (Scheme 1).7 Even if a recent report
from Murata et al. seems to support the initially proposed config-
urations for the C42eC52 fragment of AM3,8 the stereochemistry of
AM3 is not yet unambiguously established.
Owing to its interesting structural features as well as its po-
tential antifungal and hemolytic activities related to its membrane-
permeabilizing abilities, AM3 has stimulated the work of several
organic synthetic chemists involved in total synthesis and an array
of fragments has been prepared, but the total synthesis of AM3 has
not been completed yet.9
Since 2002, our group has embarked on the synthesis of
AM3.10e14 In our retrosynthetic approach, we decided to disconnect
AM3 at the C29eC30 bond, which would be built through a Suzuki-
type cross-coupling reaction between a vinylic iodide and a B-alkyl
boronate, and the C52eC53 bond would be installed through a Julia
olefination between an aldehyde at C52 and a polyenic sulfone
(Scheme 1). We have already reported the synthesis of various
polyol fragments such as the C1eC14,10 C18eC30,11 and C17eC3012
fragments. On the other hand, the C53eC67 polyenic fragment has
also been synthesized.13 Herein, we would like to report our syn-
thetic effort toward the synthesis of the bis-tetrahydropyranic
fragment C31eC52 using as the key step an iron-catalyzed cross-
* Corresponding authors. Tel.: þ33 1 40 79 46 59; fax: þ33 1 40 79 46 60; e-mail
addresses: sebastien.reymond@espci.fr (S. Reymond), janine.cossy@espci.fr
(J. Cossy).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.05.067

7760
C. Bensoussan et al. / Tetrahedron 69 (2013) 7759e7770
Julia-Kocienski
olefination
OH
HO
HO
OH
HO
HO
H
O
OH
OH
O
H
H
OH
HO
H
OH
OH Me OH OH
HO
B-alkyl Suzuki
coupling
OH
OH
OH
OH
OH
OH
Amphidinol 3 (AM3)
OH
O
HO
HO
OH
HO
HO
OH
OH
H
O
OH
OH
Cl
H
H
OH
HO
H
Me
OH
Me OH
HO
OH
OH
O
OH
OH Me OH
OH OH
Karlotoxin 2
Scheme 1.
Nozaki-Hiyama-Kishi
O
O
O
OP
OP
OP
PO
PO
43
PO
H
O
H
O
43
O
O
OP
PO
O
O
O
H
O
42
40
52
52
40
H
H
PO
H
PO
OP
OP
H
PO
H
A
OP
PO
OP
OP
ent-A
31
31
PO
PO
H
O
I
O
O
O
O
42
40
O
PO
O
+
H
PO
PO
43
H
OP
H
OP
52
H
PO
31
OP
B
C
SnBu3
R
E
H
O
40
O
O
O
O
O
36
O
35
O
O
OP
PO
38
H
Our study
(43) 40
43 (40)
OP
PO
PO
O
OP
31 (52)
52 (31)
H
H
OP
H
H
PO
31
OP
D
ent-F
F
O
OP
O
PO
OH
OP
37
37
O
PO
OH
O
31
39
H
G
H
H
Fe
MgBr
OH
O
OH
O
OP
OH
OH
HO
HO
HO
HO
PO
Br
OH
OH
OP
OP
O
D-Mannose
I
L-Mannose
Scheme 2.

C. Bensoussan et al. / Tetrahedron 69 (2013) 7759e7770
7761
coupling of a C-bromo mannopyranoside with a vinyl Grignard
reagent to form the C33eC34 and C49eC50 bonds of the
tetrahydropyrans.
C33eC34 bond as well as the C49eC50 bond (Scheme 2). Consid-
ering the high cost of -mannose and the controversy about the
L
absolute configuration of the C42eC52 fragment of AM3 compared
In our approach, the C31eC52 fragment A would be the result of
a NozakieHiyamaeKishi coupling between aldehyde B and vinyl
iodide C (Scheme 2). Vinyl iodide C would be obtained through the
regioselective opening of epoxide D with allylstannane E. As frag-
ments B and D feature seven stereocenters with identical config-
urations, they should be both prepared from the same tetra-
hydropyran F. Vinyl tetrahydropyran F would be obtained from G
after aldehyde methylenation and diastereoselective dihydrox-
ylation of the C32eC33 double bond, and G would be obtained after
functional modifications of the trisubstituted olefin, deoxygenation
at C37, and deprotection/oxidation of the alcohol at C39 in H. In
contrast to the strategies developed by other groups, in the syn-
thesis of the tetrahydropyran moieties, by forming either the tet-
rahydropyranyl C38eO or C34eO bond or the C35eC36 bond
through a ring-closing metathesis, the construction of the tetra-
hydropyranyl core has been envisaged through a challenging iron-
catalyzed cross-coupling between a vinyl Grignard and a C-halo-
to karlotoxin 2,7,8 we decided to focus on the synthesis of ent-A,
which would be accessible from ent-F starting from D-mannose
(Scheme 2).
2. Results and discussion
2.1. Iron-catalyzed cross-coupling
In 2007, we have reported an iron-catalyzed cross-coupling of
primary and secondary alkyl halides with alkenyl Grignard re-
agents.14,15 This cross-coupling, using FeCl3 (5 mol %) and TMEDA
(1.9 equiv) in THF, is chemoselective as it tolerates ethers, carba-
mates, and esters, and displays low level of b-H elimination.
In order to extend this method to the synthesis of ent-H from
ent-I using Grignard reagents, we first prepared C-bromo man-
nopyranose derivatives 1e3.16 The optimization of the conditions of
this cross-coupling is reported in Table 1. When the acetyl protected
C-bromo mannopyranoside 1 in the presence of FeCl3 (10 mol %), in
geno mannopyranoside I derived from L-mannose, installing the
Table 1
Optimization of the iron-catalyzed cross-coupling of C-bromo sugars 1e3 and vinyl Grignard reagents
R'
MgBr
OR
OR
RO
RO
OR
Br
(x equiv)
RO
RO
OR
R'
TMEDA (x equiv)
FeCl3 (10 mol %), THF
O
1-3
O
4-5
Entry
1
Substrate
Grignard
Conditions
Product (yield)
OAc
AcO
OAc
Br
(2 equiv)
TMEDA (1.9 equiv)
Addition rate 2.5 mmol hꢀ1
ꢁC to rt
d
BrMg
BrMg
AcO
0
OAc
OAc
O
1
AcO
2
3
4
5
6
1
(4 equiv)
(2 equiv)
(2 equiv)
TMEDA (3.8 equiv)
(40e65%)
Addition rate 200 mmol hꢀ1
rt, 2.5 mmol scale
AcO
O
4
1
1
1
TMEDA (1.9 equiv)
4 (72%)
BrMg
BrMg
Addition rate 200 mmol hꢀ1
rt, 50 mmol scale
TMEDA (1.9 equiv)
d
d
Addition rate 200 mmol hꢀ1
rt
BrMg
OBn (2 equiv)
TMEDA (1.9 equiv)
Addition rate 200 mmol hꢀ1
rt
OBz
OBz
OBz
O
BzO
BzO
(2 equiv)
TMEDA (1.9 equiv)
(43%)
BzO
BzO
OBz
Br
BrMg
BrMg
Addition rate 200 mmol hꢀ1
rt
O
5
2
7
(2 equiv)
TMEDA (1.9 equiv)
d
Addition rate 200 mmol hꢀ1
rt
O
O
O
O
O
Br
3

7762
C. Bensoussan et al. / Tetrahedron 69 (2013) 7759e7770
THF at 0 ꢁC, was treated with a THF solution containing 2-methyl-1-
propenylmagnesium bromide (2 equiv) and 1.9 equiv of TMEDA
alcohol 11 (83% yield), which was then protected as a PMB ether
(t-BuOK, PMBBr, THF, 0 ꢁC to rt) providing 12 in 78% yield
(Scheme 3).
with an addition rate of 2.5 mmol hꢀ114
no cross-coupling was
,
observed (Table 1, entry 1). When C-bromo mannopyranoside 1 in
the presence of FeCl3 (10 mol %) in THF at room temperature was
treated with 2-methyl-propenylmagnesium bromide (4 equiv) and
3.8 equiv of TMEDA with an addition rate of 200 mmol hꢀ1, a full
conversion of bromide 1 was observed and the desired cross-
coupling product 4 was isolated in variable yields (40e65%)
depending on the quality of the starting C-bromo mannopyrano-
side (Table 1, entry 2). Gratifyingly, on a larger scale (50 mmol of
freshly prepared C-bromo mannopyranoside 1), the cross-coupling
was efficient with only 2 equiv of 2-methyl-propenylmagnesium
bromide (addition rate of 200 mmol hꢀ1) and 1.9 equiv of TMEDA as
it allows the isolation of the cross-coupling product 4 in 72% yield
(Table 1, entry 3). This cross-coupling is chemoselective as it tol-
erates acetate groups on the substrate, and diastereoselective as
only the trans-tetrahydropyran 4 was obtained (dr>9:1, the trans-
relationship was confirmed by NOE studies).17 At this stage, we
were interested to know if vinylmagnesium bromide (Table 1, entry
4) or a functionalized Grignard reagent (Table 1, entry 5) could be
involved in this cross-coupling. Unfortunately, the cross-coupling
of 1 with these Grignard reagents produced mixture of com-
pounds with no traces of the desired products (Table 1, entries 4
and 5). Different protecting groups of the C-bromo mannopyrano-
side were investigated (Table 1, entries 6 and 7). When the benzoyl
protected C-bromo mannopyranoside 2 was involved in the cross-
coupling with 2-methyl-1-propenylmagnesium bromide, the ex-
pected trans-tetrahydropyran 5 was diastereoselectively obtained
(dr>9:1) and isolated in 43% yield (Table 1, entry 6), whereas the
acetonide protected C-bromo mannopyranoside 3 was unable to
deliver the corresponding cross-coupling product as only de-
composition of the starting material was observed (Table 1,
entry 7).
1) K2CO3, MeOH
OAc
O
O
2) TBDPSCl
O
AcO
AcO
OAc
HO
TBDPSO
imidazole, DMF
O
3)
MeO
OMe
4
6
TsOH, acetone
84% (3 steps)
NaH, imidazole
CS2, MeI
THF
quant.
S
S
O
O
Bu3SnH (4 equiv)
AIBN (25 mol %)
O
O
O
TBDPSO
C6H6, 60 °C
83%
TBDPSO
O
O
8
7
1) OsO4 cat., NMO
t-BuOH/pH 7 buffer
2) NaIO4
THF/pH 7 buffer
O
O
O
Ph3P
O
O
OEt
OEt
O
TBDPSO
TBDPSO
O
O
CH2Cl2, rt
75% (from 8)
O
H
10
9
DIBAL-H
Toluene, -78 °C
83%
Considering the observed
a-diastereoselectivity of the cross-
O
O
O
O
t-BuOK, PMBBr
coupling, leading to the trans-tetrahydropyran, one can suppose
that an anomeric radical intermediate is formed during the oxi-
dative addition of the low-valent iron species on the CeBr bond of
the electrophile.14,18 These results are in agreement with our re-
cently reported diastereoselective cobalt-catalyzed cross-coupling
of C-bromo glycosides with aryl and vinyl Grignard reagents pro-
32
TBDPSO
TBDPSO
THF, 0 °C to rt
78%
O
O
39
33
OPMB
OH
12
11
Scheme 3.
cessing with an a-selectivity due to the formation of an anomeric
radical intermediate.19
In order to install the C32 and C33 stereogenic centers,
a Sharpless asymmetric cis-dihydroxylation of the C32eC33 double
bond in 12 was envisaged.21 Because of diastereoselectivity issues,
2.2. Synthetic approach toward the C31eC52 fragment (ent-A)
the dihydroxylation was realized with OsO4/NMO, AD-mix-
AD-mix- . The latter reagent should theoretically give the expected
stereoisomer through the dihydroxylation of the -face of the
olefin. The results are highlighted in Table 2. The dihydroxylation of
12 with OsO4/NMO provided a 1:1 mixture of the two di-
astereoisomers 13 and 14 with a global yield of 71%, without any
diastereoselectivity in the absence of any chiral ligand (Table 2,
entry 1). When the asymmetric dihydroxylation was achieved us-
b, and
Having obtained 4, featuring four of the six stereocenters in
ent-F, the C37 position had to be deoxygenated. Methanolysis of
the acetate groups in 4, followed by selective protection of the
primary alcohol at C39 as a TBDPS ether delivered a triol, which
was directly treated with 2,2-dimethoxypropane in acetone to
provide the secondary alcohol 6. The resulting tetrahydropyran 6
was deoxygenated under the BartoneMcCombie conditions.20
The secondary alcohol in 6 was first transformed to a xanthate
(NaH, imidazole, CS2, MeI) leading quantitatively to 7, which was
treated with Bu3SnH (4 equiv) in the presence of AIBN (0.25 mol
%) in benzene at 60 ꢁC, providing the deoxygenated product 8 in
83% yield. At this stage, the C32eC33 double bond had to be
transformed to generate the C32 and C33 stereogenic carbinols.
As olefin 8 appeared to be unreactive with ethyl acrylate under
cross-metathesis conditions (HoveydaeGrubbs II cat., CH2Cl2,
reflux), the double bond was oxidatively cleaved in two steps
(OsO4, NMO, then NaIO4) providing aldehyde 9, which was di-
rectly treated with (carbethoxymethylene)triphenylphosphorane
a
a
ing AD-mix-b, in the presence of methanesulfonamide, with rein-
forced conditions in ligand (DHQD)2PHAL and osmium reagent
(K2OsO4$2H2O), a 1:9 mixture of 13 and 14 was obtained in favor of
the undesired diastereomer 14 with a 75% global yield (Table 2,
entry 2) whereas AD-mix-
a,
in the presence of meth-
anesulfonamide, with reinforced conditions in ligand (DHQ)2PHAL
and osmium reagent (K2OsO4$2H2O), afforded a 9:1 mixture of the
two diastereoisomers 13 and 14 in favor of the desired isomer 13
(71% yield) (Table 2, entry 3).22b,c With these results in hand, we can
conclude that no match/mismatch effect is existing in the Sharpless
dihydroxylation of 12.
to yield the
a
,
b
-unsaturated ester 10 in 75% yield (from 8, three
The synthesis of vinyl tetrahydropyran 18, which is a synthetic
equivalent of ent-F, was then completed in four steps from 13
steps). Reduction of ester 10 with DIBAL-H delivered allylic

C. Bensoussan et al. / Tetrahedron 69 (2013) 7759e7770
7763
Table 2
Stereoselective dihydroxylation of olefin 12
O
O
O
O
O
O
conditions
OH
OH
32
+
33
TBDPSO
TBDPSO
TBDPSO
33
32
32
O
O
O
t-BuOH/pH 7 buffer
33
H
H
H
H
H
H
14
OPMB
OPMB
OPMB
OH
OH
12
13
Entry
Conditions
Yield (%)
13/14
1
2
OsO4 cat., NMO
71
75
1:1
1:9
AD-mix-
(DHQD)2PHAL, K2OsO4$2H2O
AD-mix- , MeSO2NH2
(DHQ)2PHAL, K2OsO4$2H2O
b, MeSO2NH2
3
a
71
9:1
(Scheme 4). Diol 13 was protected as an acetonide (2,2-
dimethoxypropane, TsOH, acetone, 98%) delivering 15; the TBDPS
ether was cleaved using n-Bu4NF and the obtained primary alcohol
16 (96%) was oxidized to aldehyde 17 (Swern oxidation) and, after
methylenation with methylenetriphenylphosphorane, 18 was iso-
lated in 62% yield (for the two steps). To summarize, the common
fragment 18, required to access the two tetrahydropyran moieties of
ent-A, was obtained in 18 steps from D-mannose with an overall yield
of 10%.
Starting from 18, the synthesis of the mirror image of the
C31eC42 fragment of AM3 (ent-C), requires the introduction of the
C39 oxygenated stereocenter. To achieve the challenging asym-
metric Sharpless dihydroxylation of the terminal olefin in 18,
a systematic study was realized varying the ligand required for the
Sharpless dihydroxylation. The results are reported in Table 3.
When (DHQ)2PHAL (AD-mix-
a)
(Table 3, entry 1) and
(DHQD)2PHAL (AD-mix- ) (Table 3, entry 2) were used, the same
b
undesired epimer 20, possessing the (R)-configuration at C39, was
obtained with a 19/20 ratio of 20:80 and 30:70, respectively. When
(DHQD)2AQN was used as the ligand (Table 3, entry 3), the same
diastereoselectivity was observed with a 30:70 ratio of 19/20. We
were pleased to observe that the use of (DHQD)2PYR (Table 3, entry
MeO
TsOH, acetone
OMe
O
O
O
O
O
O
O
n-Bu4NF, THF
OH
O
O
98%
96%
TBDPSO
TBDPSO
HO
O
O
O
H
H
13
H
H
15
H
H
OPMB
OPMB
OPMB
OH
O
16
(COCl)2, DMSO
Et3N, CH2Cl2
-78 °C
O
O
t-BuOK
PPh3CH3Br
O
O
O
O
O
THF
62% (from 16)
31
40
O
O
H
H
H
H
OPMB
H
OPMB
O
O
17
18
Scheme 4.
Table 3
Asymmetric dihydroxylation of terminal olefin 18
K3Fe(CN)6, K2CO3
O
O
O
Ligand
O
O
O
O
K2OsO4 2H2O
OH
40
O
OH
40
O
(39S)
(39R)
31
31
40
+
31
O
O
MeSO2NH2
t-BuOH/ pH 7 buffer
O
H
H
H
H
H
H
OPMB
O
HO
OPMB
O
HO
OPMB
O
18
19
20
Entry
Ligand
Yield
19/20
1
2
3
4
(DHQ)2PHAL
(DHQD)2PHAL
(DHQD)2AQN
(DHQD)2PYR
d
20:80
30:70
30:70
65:35
d
d
Quant.

7764
C. Bensoussan et al. / Tetrahedron 69 (2013) 7759e7770
Table 4
3. Experimental
1H NMR analysis (400 MHz, CDCl3) of the two methoxyphenyl esters 26 and 27
R of 26
dS of 27
DdRS
¼
dR dS
ꢀ
3.1. General remarks
d
H36
H37
H37
H38
H40
4.30
1.98
1.65
4.17
3.69
0.96
4.22
1.90
1.59
4.09
3.86
1.04
0.08
0.08
0.06
Infrared (IR) spectra were recorded on a Bruker TENSOR TM
27 (IRFT), wave numbers are indicated in cmꢀ1. NMR spectra
were recorded on a Bruker AVANCE 400. 1H NMR spectra were
recorded at 400 MHz and data are reported as follows: chemical
shift in parts per million (ppm) from tetramethylsilane as an
internal standard with the residual solvent peak as an internal
0
0.08
ꢀ0.17
H(t-Bu)
ꢀ0.08
4) led to the opposite diastereoselectivity as 19, possessing the (S)-
configuration at C39, was obtained as the major product however
with a diastereomeric ratio 19/20 of 65:35. Unfortunately, these
epimers could not be separated by chromatography. It is worth
pointing out that the (S)- and (R)-configurations at C39 in 19 and 20
were, respectively, determined by synthesizing the corresponding
methoxyphenylacetic esters and by analyzing their 1H NMR spectra
(Table 4).22,23
indicator (CDCl3
d
: 7.26 ppm), multiplicity (s¼singlet, d¼doublet,
t¼triplet, q¼quartet, sept¼septuplet, m¼multiplet or overlap of
non-equivalent resonances, br¼broad), integration. 13C NMR
spectra were recorded at 100 MHz and the data are reported as
follows: chemical shift in parts per million from tetramethylsi-
lane as an internal standard with the residual solvent peak as an
internal indicator (CDCl3
d
: 77.1), multiplicity (s¼C, d¼CH, t¼CH2,
q¼CH3). THF was dried over Na/benzophenone prior to distilla-
tion or using a MBraun MB SPS-800 solvent, purification system.
TMEDA was dried over CaH2 prior to distillation. All commercially
obtained chemicals were used as received without further puri-
fication. TLC was performed on silica gel plates visualized either
with a UV lamp (254 nm), or using solution of p-anisaldehy-
deesulfuric acideacetic acid in EtOH followed by heating. Puri-
fication was performed on silica gel (Merck-Kieselgel 60,
230e400 mesh). Chromatography solvents used were ethyl ace-
tate (EtOAc), and low-boiling petroleum ether (PE) (40e60 ꢁC).
Mass spectra with electronic impact (MS-EI) were recorded on
a GC/MS (70 eV). HRMS were performed at the Laboratoire de
The 65:35 mixture of 19 and 20 was then transformed to the
corresponding epoxides in
a one-pot three-step procedure
(CH3C(OMe)3, PPTS; then AcCl; then K2CO3, MeOH) and epoxide 21
was separated from its epimer at C39 by silica gel chromatography
(Scheme 5). The ring-opening of epoxide 21 was realized with the
lithiated anion of allylstannane 22, leading to vinylsilane 23 that
was finally protected as a TBS ether (TBSOTf, 2,6-lutidine, 19% from
19). Vinylsilane 24, the enantiomer of the C31eC42 fragment of
AM3, and the precursor of vinyl iodide ent-C, was finally synthe-
sized in six steps from 18 in 15% yield. We have to point out that
compound 19 should also be the precursor of the mirror image of
the C43eC52 fragment of AM3, and should be transformed in four
steps in ent-B.
ꢀ
ꢀ
Spectrometrie de Masse SM3E de l’Universite Pierre et Marie
Curie de Paris.
SnBu3
Me3Si
22
O
O
O
i) CH3C(OMe)3
O
O
PPTS, CH2Cl2
O
O
n-BuLi, -78 °C
OH
O
O
O
ii) AcCl, CH2Cl2
iii) K2CO3, MeOH
CH2Cl2
31(52)
40(43)
O
O
Me3Si
O
H
H
H
H
H
H
O
OPMB
OPMB
HO
OPMB
O
O
OH
21
23
(dr = 65/35)
19
TBSOTf
2,6-lutidine
CH2Cl2, -78 °C
19%
(3 steps, from 19)
O
O
O
O
O
O
O
O
O
O
43
H
31
31
Me3Si
O
42
I
O
52
42
O
H
H
H
H
TBSO
OPMB
H
H
O
ent-B
O
TBSO
OPMB
O
OP
OP
ent-C
Scheme 5.
24
2.3. Conclusion
3.2. Synthesis of vinylsilane 24
We have developed a chemoselective and diastereoselective
iron-catalyzed cross-coupling between C-bromo mannopyranoside
derivatives and a vinyl Grignard reagent, providing trans-tetrahy-
dropyrans. Using this method, a common precursor to both tetra-
3.2.1. 1,2,3,4,6-Penta-O-acetyl-
of -mannose (21.6 g, 120.0 mmol, 1.0 equiv) in acetic anhydride
a-D
-mannopyranose.16a To a solution
D
(62.3 mL, 660.0 mmol, 5.5 equiv) at 0 ꢁC were added DMAP (1.46 g,
12.0 mmol, 10 mol %) and pyridine (240 mL) and the mixture was
allowed to warm to room temperature. The solution was stirred for
3 h and the reaction was quenched by addition of a 10% aqueous
solution of CuSO4 (250 mL) and Et2O (250 mL). The two phases
were separated and the organic layer was washed with a 10%
aqueous solution of CuSO4 (5ꢂ150 mL) in order to remove pyridine.
hydropyrans embedded in AM3 was obtained starting from
D-
mannose and used in the synthesis of the mirror image of the
C31eC42 and C43eC52 fragments of amphidinol 3. These two
tetrahydropyrans incorporate 14 of the 15 stereocenters present in
the C31eC52 fragments of AM3.

C. Bensoussan et al. / Tetrahedron 69 (2013) 7759e7770
7765
The organic layer was dried over MgSO4, filtered, and concentrated
under reduced pressure to afford 1,2,3,4,6-penta-O-acetyl-
mannopyranose (46.5 g, quant.) as a white waxy solid. 1H NMR
(400 MHz, CDCl3)
1.0 equiv) in MeOH (8.5 mL) was added K2CO3 (35 mg, 0.25 mmol,
0.25 equiv) and the solution was stirred overnight at room tem-
perature. The solvent was then removed under reduced pressure,
the crude product was diluted with acetonitrile, and the solvents
were co-evaporated again; this procedure was repeated thrice to
remove all traces of methanol. The obtained tetraol
((2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-(2-methylprop-1-en-1-yl)
tetrahydro-2H-pyran-3,4,5-triol) was directly engaged in the next
step without further purification.
a-D-
d
6.07 (d, J¼1.8 Hz, 1H), 5.34e5.32 (m, 2H),
5.25e5.24 (m, 1H), 4.27 (dd, J¼12.4, 4.9 Hz, 1H), 4.08 (dd, J¼12.4,
2.5 Hz), 4.06e4.00 (m, 1H), 2.16 (s, 3H) 2.16 (s, 3H), 2.08 (s, 3H), 2.04
(s, 3H), 1.99 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 170.8 (s), 170.1 (s),
169.9 (s), 169.6 (s), 168.2 (s), 90.7 (d), 70.7 (d), 68.8 (d), 68.4 (d), 65.6
(d), 62.2 (t), 21.0 (q), 209.0 (q), 20.8 (3q).
To a solution of this tetraol (1.0 mmol, 1.0 equiv) in DMF (5 mL)
3.2.2. 2,3,4,6-Tetra-O-acetyl-
a solution of 1,2,3,4,6-penta-O-acetyl-
a
-
D
-mannopyranosyl bromide (1).16b To
-mannopyranose (9.98 g,
at 0 ꢁC were added imidazole (143 mg, 2.1 mmol, 2.1 equiv) and,
a-
D
dropwise, TBDPSCl (272 mL, 1.05 mmol, 1.05 equiv). The solution
25.6 mmol, 1.0 equiv) in CH2Cl2 (120 mL) at 0 ꢁC was added slowly
a solution of HBr (150 mL, 33 wt % in acetic acid) and the solution
was allowed to warm up to room temperature. The solution was
then stirred for 3 h and diluted with water (100 mL). The two
phases were separated and the aqueous layer was extracted with
CH2Cl2 (3ꢂ75 mL). The combined organic layers were washed with
a saturated aqueous solution of NaHCO3 (with care, very exo-
thermic) until neutral pH, and then with brine (50 mL). The organic
layer was then dried over MgSO4, filtered, and concentrated under
reduced pressure. The crude product was purified by flash chro-
matography on silica gel (PE/EtOAc: 6:4) to afford the brominated
compound 1 (10.50 g, quant.) as a yellow waxy solid. 1H NMR
was warmed to room temperature, stirred for 5 h, and a saturated
aqueous solution of NaHCO3 (5 mL) was added. The two phases
were separated and the aqueous layer was extracted with EtOAc
(3ꢂ10 mL). The combined organic layers were washed with water
(2ꢂ5 mL) and brine (2ꢂ5 mL), dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude triol
((2R,3S,4R,5S,6R)-2-(2-methylprop-1-en-1-yl)-6-((tert-butyldiphe-
nylsilyloxy)methyl)tetrahydro-2H-pyran-3,4,5-triol) was directly
engaged in the next step without any further purification.
To a solution of the obtained triol (1.0 mmol, 1.0 equiv) in
acetone (10 mL) at 0 ꢁC, were added 2,2-dimethoxypropane
(370
mL, 3.0 mmol, 3.0 equiv) and TsOH (35 mg, 0.2 mmol,
(400 MHz, CDCl3)
d
6.28 (d, J¼1.6 Hz, 1H), 5.70 (dd, J¼10.2, 3.4 Hz,
0.2 equiv). The mixture was allowed to warm to room tempera-
ture over 1 h and then stirred for 3 h at room temperature. Et3N
(100 mL) was added, and the solvent was removed under reduced
pressure. The mixture was diluted with water (10 mL) and the
solution was extracted with EtOAc (3ꢂ10 mL). The combined
organic layers were washed with brine (10 mL), dried over
MgSO4, filtered, and concentrated under reduced pressure to af-
1H), 5.43 (dd, J¼3.4, 1.6 Hz, 1H), 5.35 (t, J¼10.2 Hz, 1H), 4.31 (dd,
J¼12.6, 5.0 Hz, 1H), 4.21 (ddd, J¼10.2, 5.0, 2.3 Hz, 1H), 4.12 (dd,
J¼12.6, 2.3 Hz,1H), 2.16 (s, 3H), 2.09 (s, 3H), 2.06 (s, 3H),1.99 (s, 3H);
13C NMR (100 MHz, CDCl3)
d 170.6 (s), 169.8 (s), 169.7 (2s), 83.2 (d),
72.9 (d), 72.2 (d), 68.0 (d), 65.4 (d), 61.6 (t), 20.9 (q), 20.8 (2q), 20.7
(q).
ford alcohol 6 (418 mg, 84% over three steps) as a colorless oil.
20
3.2.3. (2R,3R,4R,5R,6R)-2-(Acetoxymethyl)-6-(2-methylprop-1-en-1-
yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (4). A freshly prepared
solution of FeCl3 (0.1 M in THF, 25.0 mL, 2.50 mmol, 0.1 equiv) was
mixed with 1 (10.275 g, 25.0 mmol, 1.0 equiv). To this solution was
[
a
]
þ7.9 (c 1.55, CHCl3); IR (neat) 3448, 2931, 2857, 2361, 1668,
D
1589, 1472, 1428, 1380, 1243, 1217, 1111, 1067 cmꢀ1
(400 MHz, CDCl3) 7.71e7.65 (m, 4H, Har), 7.46e7.34 (m, 6H, Har),
;
1H NMR
d
5.21 (dsept, J¼8.0, 1.4 Hz, 1H), 4.53 (dd, J¼8.0, 5.8 Hz, 1H), 4.17
(dd, J¼7.8, 6.9 Hz, 1H), 4.12e4.07 (m, 2H), 3.89 (dd, J¼10.6, 4.3 Hz,
1H), 3.85 (dd, J¼10.6, 5.3 Hz, 1H), 3.53 (ddd, J¼9.5, 5.3, 4.3 Hz,
1H), 2.79 (d, J¼2.8 Hz, 1H, OH), 1.77 (d, J¼1.4 Hz, 3H), 1.67 (d,
added dropwise via a syringe pump (200 mmol hꢀ1; 400 mL hꢀ1
)
at room temperature, a mixture of commercially available 2-
methyl-1-propenylmagnesium bromide (0.5 M in THF, 100.0 mL,
50.0 mmol, 2.0 equiv) and TMEDA (7.11 mL, 47.5 mmol, 1.9 equiv).
The mixture was then stirred at room temperature for 1 h and
quenched by the addition of a saturated aqueous solution of NH4Cl
(100 mL) and a 0.5 M aqueous solution of HCl (10 mL) in order to
dissolve the magnesium salts. The mixture was filtered on CeliteÒ,
the two phases were separated and the aqueous layer was
extracted with CH2Cl2 (2ꢂ50 mL). The combined organic layers
were dried over MgSO4, filtered, and concentrated under reduced
pressure. The crude product was purified by flash chromatography
on silica gel (PE/EtOAc: 7:3e6:4) to afford the coupling product 2
J¼1.4 Hz, 3H), 1.53 (s, 3H), 1.37 (s, 3H), 1.07 (s, 9H, SieC(CH3)3); 13
C
NMR (100 MHz, CDCl3)
d 140.4 (s), 135.8 (2d), 135.7 (2d), 133.0 (s),
132.9 (s), 130.1 (d), 130.0 (d), 128.0 (2d), 127.9 (2d), 121.9 (d), 109.7
(s), 78.4 (d), 77.4 (d), 72.7 (d), 71.6 (d), 70.4 (d), 65.6 (t), 27.8 (q),
27.0 (3q, SieC(CH3)3), 26.2 (q), 25.6 (q), 19.3 (s, SieC(CH3)3), 18.8
(q); MS (EI) m/z 381 (2), 303 (12), 241 ([MꢀOTBDPS]þ, 15), 199
(34), 181 (17), 163 (31), 139 (41), 135 (30), 123 (15), 121 (14), 111
(28), 105 (13), 97 (37), 95 (19), 93 (14), 91 (20), 85 (31), 83 (21), 81
(23), 79 (26), 77 ([Ph]þ, 21), 69 (100), 67 (12), 59 (34), 57 ([t-Bu]þ,
29), 55 (31), 53 (15); HRMS (ESI): m/z calcd for C29H40NaO5Si
[MþNa]þ 519.2537, found: 519.2532.
(6.96 g, 72%) as a colorless oil. [
a
]
20 þ25.5 (c 1.00, CHCl3); IR (neat):
D
2973, 2944, 1741, 1668, 1437, 1368, 1218, 1116, 1045 cmꢀ1; 1H NMR
(400 MHz, CDCl3)
d
5.35 (dsept, J¼7.0, 1.4 Hz, 1H), 5.31e5.22 (m,
3.2.5. O-((3aR,4R,6R,7R,7aR)-6-((tert-Butyldiphenylsilyloxy)methyl)-
2,2-dimethyl-4-(2-methylprop-1-en-1-yl)tetrahydro-3aH-[1,3]diox-
olo[4,5-c]pyran-7-yl)-S-methyl carbonodithioate (7). To a solution of
alcohol 6 (824 mg, 1.66 mmol, 1.0 equiv) in THF (30 mL) at 0 ꢁC were
added NaH (60% in oil, 332 mg, 8.31 mmol, 5.0 equiv) and imidazole
(45 mg, 0.66 mmol, 0.4 equiv). The mixture was warmed to room
2H), 5.18e5.16 (m, 1H), 4.67 (br d, J¼7.0 Hz, 1H), 4.27 (dd, J¼12.3,
5.5 Hz, 1H), 4.04 (dd, J¼12.3, 2.6 Hz, 1H), 3.89 (ddd, J¼9.4, 5.5,
2.6 Hz, 1H), 2.14 (s, 3H), 2.08 (s, 3H), 2.02 (s, 3H), 2.00 (s, 3H), 1.79
(s, 3H), 1.73 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 170.9 (s), 170.6 (s),
170.3 (s), 169.8 (s), 143.1 (s), 116.8 (d), 73.1 (d), 71.7 (d), 70.3 (d),
69.5 (d), 67.0 (d), 63.0 (t), 26.2 (q), 21.2 (q), 20.9 (3q), 18.8 (q); MS
(EI) m/z: 284 (1), 206 (17), 193 (45), 164 (21), 151 (100), 139 (29),
111 (14), 98 (20), 97 (28), 85 (46), 83 (19), 81 (22), 69 (20), 55 (13);
HRMS (ESI): m/z calcd for C18H26NaO9 [MþNa]þ 409.1469, found
409.1464.
temperature and after 15 min, CS2 (971
was added. The solution was stirred at room temperature for
30 min and then iodomethane (310 L, 4.98 mmol, 3.0 equiv) was
mL, 16.61 mmol, 10.0 equiv)
m
added. After 10 min, a saturated aqueous solution of NaCl (20 mL)
was added, the two phases were separated and the aqueous layer
was extracted with Et2O (3ꢂ20 mL). The combined organic layers
were dried over MgSO4, filtered, and concentrated under reduced
pressure. The crude product was purified by flash chromatography
on silica gel (PE/Et2O: 9:1e7:3) to afford xanthate 7 (946 mg, 97%)
3.2.4. (3aR,4R,6R,7R,7aS)-6-((tert-Butyldiphenylsilyloxy)methyl)-
2,2-dimethyl-4-(2-methyl-prop-1-en-1-yl)tetrahydro-3aH-[1,3]diox-
olo[4,5-c]pyran-7-ol (6). To a solution of 4 (386 mg, 1.0 mmol,

7766
C. Bensoussan et al. / Tetrahedron 69 (2013) 7759e7770
20
as a yellow oil. [
a
]
þ13.6 (c 0.65, CHCl3); IR (neat) 3424, 2955,
To a solution of (carbethoxymethylene)triphenylphosphorane
(522 mg, 1.50 mmol, 2.0 equiv) in CH2Cl2 (7.5 mL) was added
dropwise a solution of aldehyde 9 in CH2Cl2 (7.5 mL) and the
mixture was stirred at room temperature for 1 h and concen-
trated under reduced pressure. The crude product was purified by
D
2927, 2856,1718,1463,1428,1362,1253,1211,1158,1114,1062,1104,
1006 cmꢀ1 1H NMR (400 MHz, CDCl3)
;
d
7.71e7.64 (m, 4H, Har),
7.43e7.32 (m, 6H, Har), 6.19 (dd, J¼7.2, 6.1 Hz, 1H), 5.28 (dsept,
J¼8.0, 1.4 Hz, 1H), 4.62 (dd, J¼8.0, 4.9 Hz, 1H), 4.37 (tapp, J¼5.9 Hz,
1H), 4.10 (dd, J¼5.8, 4.9 Hz, 1H), 3.89e3.73 (m, 3H), 2.55 (s, 3H), 1.78
(d, J¼1.4 Hz, 3H), 1.69 (d, J¼1.4 Hz, 3H), 1.52 (s, 3H), 1.36 (s, 3H), 1.03
flash chromatography on silica gel (PE/EtOAc: 9:1) to afford 10
20
(293 mg, 75%) as a colorless oil. [
a
]
þ14.9 (c 1.30, CHCl3); IR
D
(s, 9H, SieC(CH3)3); 13C NMR (100 MHz, CDCl3)
d
215.4 (s), 140.8 (s),
(neat) 2933, 2858, 1720, 1660, 1589, 1472, 1428, 1371, 1301, 1265,
1284, 1210, 1163, 1111, 1048 cmꢀ1 1H NMR (400 MHz, CDCl3)
7.69e7.64 (m, 4H, Har), 7.44e7.34 (m, 6H, Har), 7.00 (dd, J¼15.8,
135.9 (2d),135.8 (2d),133.5 (s),133.4 (s),129.7 (2d),127.8 (2d),127.7
(2d), 121.5 (d), 109.9 (s), 78.0 (d), 77.1 (d), 75.4 (d), 73.0 (d), 69.7 (d),
62.8 (t), 27.8 (q), 26.9 (3q, SieC(CH3)3), 26.3 (q), 26.1 (q), 19.5 (q),
19.4 (s, SieC(CH3)3), 18.9 (q); MS (EI) m/z 371 (1), 289 (10), 200 (19),
199 (100), 157 (12), 147 (51), 133 (15), 131 (45), 89 (11), 79 (12), 78
(16), 77 ([Ph]þ, 31), 75 (23), 73 (82), 59 (14), 57 ([t-Bu]þ, 18); HRMS
(ESI) m/z calcd for C31H42NaO5S2Si [MþNa]þ 609.2159, found
609.2165.
;
d
4.0 Hz, 1H), 6.16 (dd, J¼15.8, 1.8 Hz, 1H), 4.37 (dtapp, J¼9.2, 6.5 Hz,
1H), 4.33 (ddd, J¼8.0, 4.0, 1.8 Hz, 1H), 4.21 (q, J¼7.2 Hz, 2H), 3.93
(dd, J¼8.0, 6.5 Hz, 1H), 3.88 (dtapp, J¼10.2, 4.6 Hz, 1H), 3.76 (dd,
J¼10.7, 5.0 Hz, 1H), 3.70 (dd, J¼10.7, 5.0 Hz, 1H), 2.10 (ddd, J¼13.9,
6.2, 4.6 Hz, 1H), 1.96 (ddd, J¼13.9, 10.2, 9.2 Hz, 1H), 1.43 (s, 3H),
1.34 (s, 3H), 1.30 (t, J¼7.2 Hz, 3H), 1.05 (s, 9H, SieC(CH3)3); 13C
NMR (100 MHz, CDCl3)
d 166.5 (s), 145.3 (d), 135.8 (4d), 133.4 (2s),
3.2.6. tert-Butyl(((3aS,4R,6S,7aS)-2,2-dimethyl-4-(2-methylprop-1-
en-1-yl)tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-6-yl)methoxy)di-
phenylsilane (8). To a solution of xanthate 7 (120 mg, 0.20 mmol,
1.0 equiv) in benzene (1 mL) at 60 ꢁC were added AIBN (8.5 mg,
129.9 (d), 129.8 (d), 127.9 (4d), 122.0 (d), 109.3 (s), 75.4 (d), 71.9
(d), 71.7 (d), 71.4 (d), 66.1 (t), 60.6 (t), 29.0 (t), 27.7 (q), 26.9 (3q,
SieC(CH3)3), 25.4 (q), 19.4 (s, SieC(CH3)3), 14.4 (q); MS (EI) m/z
468 ([Mꢀt-Bu]þ, 1), 241 (31), 225 (14), 199 (19), 197 (10), 184 (13),
183 (100), 163 (24), 139 (12), 137 (18), 135 (37), 113 (18), 105 (12),
97 (18), 91 (12), 85 (28), 77 ([Ph]þ, 11), 69 (11), 55 (12); HRMS
(ESI) m/z calcd for C30H40NaO6Si [MþNa]þ 547.2486, found:
547.2477.
0.05 mmol, 0.25 equiv) and Bu3SnH (220 mL, 0.82 mmol, 4 equiv).
The solution was stirred at reflux for 2.5 h and was then cooled to
room temperature. The solvent was removed under reduced pres-
sure and the crude oil was purified by flash chromatography on
silica gel (PE/Et2O: 9:1) to afford 8 (80 mg, 83%) as a colorless oil.
20
[
a
]
þ18.9 (c 0.70, CHCl3); IR (neat) 2961, 2931, 1589, 1462, 1428,
3.2.8. (E)-3-((3aS,4R,6S,7aS)-6-((tert-Butyldiphenylsilyloxy)methyl)-
2,2-dimethyltetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-4-yl)prop-2-
en-1-ol (11). To a solution of ester 10 (1.26 g, 2.40 mmol, 1.0 equiv)
in toluene (20 mL) at ꢀ78 ꢁC was added dropwise a solution of
DIBAL-H (1.0 M in hexanes, 6.00 mL, 6.00 mmol, 2.5 equiv). The
reaction medium was allowed to warm to 0 ꢁC and after 1 h at 0 ꢁC,
the reaction was quenched by addition of a saturated aqueous so-
lution of Rochelle salt (20 mL) and the mixture was stirred for 3 h.
The two phases were separated and the aqueous layer was
extracted with EtOAc (3ꢂ20 mL). The combined organic layers were
dried over MgSO4, filtered, and concentrated under reduced pres-
sure. The crude product was purified by flash chromatography on
D
1379, 1240, 1210, 1160, 1111, 1052 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
7.69e7.64 (m, 4H, Har), 7.44e7.34 (m, 6H, Har), 5.19 (dsept, J¼8.1,
1.4 Hz, 1H), 4.43 (tapp, J¼7.8 Hz, 1H), 4.39 (dt, J¼9.4, 6.6 Hz, 1H), 3.93
(dd, J¼7.5, 6.6 Hz), 3.82e3.67 (m, 3H), 2.13 (ddd, J¼13.6, 6.4, 3.9 Hz,
1H), 1.95 (ddd, J¼13.6, 10.5, 9.4 Hz, 1H), 1.77 (d, J¼1.4 Hz, 3H), 1.68
(d, J¼1.4 Hz, 3H), 1.47 (s, 3H), 1.35 (s, 3H), 1.05 (s, 9H, SieC(CH3)3);
13C NMR (100 MHz, CDCl3)
d 139.6 (s), 135.8 (4d), 133.6 (2s), 129.8
(2d), 127.8 (4d), 122.8 (d), 108.7 (s), 76.8 (d), 71.9 (d), 70.6 (d), 69.4
(d), 66.5 (t), 29.6 (t), 27.8 (q), 27.0 (3q, SieC(CH3)3), 26.3 (q), 25.4 (q),
19.4 (s, SieC(CH3)3), 18.9 (q); MS (EI) m/z 465 ([MꢀMe]þ, 1), 365
(21), 287 (12), 241 ([MꢀTBDPS]þ, 35), 225 ([MꢀOTBDPS]þ, 16), 199
(24), 197 (11), 183 (18), 181 (12), 163 (24), 140 (11), 139 (100), 135
(40), 123 (22), 121 (23), 111 (23), 105 (16), 97 (52), 95 (16), 93 (12),
91 (11), 83 (12), 81 (23), 79 (22), 77 ([Ph]þ, 10), 69 (39), 55 (14);
HRMS (ESI) m/z calcd for C29H40NaO4Si [MþNa]þ 503.2588, found
503.2579.
silica gel (PE/EtOAc: 65:35) to afford alcohol 11 (962 mg, 83%) as
20
a colorless oil. [
a
]
þ25.7 (c 1.05, CHCl3); IR (neat) 3424, 2932,
D
2858,1738,1589,1461,1428,1373,1239,1211,1162,1111,1048 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
7.70e7.64 (m, 4H, Har), 7.44e7.34 (m,
6H, Har), 5.97 (dtd, J¼15.6, 5.2, 1.4 Hz, 1H), 5.77 (ddtapp, J¼15.6, 5.5,
1.5 Hz, 1H), 4.37 (dtapp, J¼9.3, 6.4 Hz, 1H), 4.24e4.16 (m, 3H), 3.95
(dd, J¼7.7, 6.7 Hz, 1H), 3.85 (dqapp, J¼10.5, 4.8 Hz, 1H), 3.76 (dd,
J¼10.5, 4.8 Hz, 1H), 3.70 (dd, J¼10.5, 4.8 Hz, 1H), 2.12 (ddd, J¼13.8,
6.4, 4.4 Hz, 1H), 1.94 (ddd, J¼13.8, 10.5, 9.3 Hz, 1H), 1.45 (s, 3H), 1.35
3.2.7. (E)-Ethyl
3-((3aS,4R,6S,7aS)-6-((tert-butyldiphenylsilyloxy)
methyl)-2,2-dimethyl-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-4-yl)
acrylate (10). To a solution of olefin 8 (360 mg, 0.75 mmol,
1.0 equiv) and NMO (175 mg, 1.50 mmol, 2.0 equiv) in a mixture t-
BuOH/buffer pH 7 (1:1, 10 mL) was added a solution of OsO4 in t-
(s, 3H), 1.05 (s, 9H, SieC(CH3)3); 13C NMR (100 MHz, CDCl3)
d 135.8
(4d), 133.6 (s), 133.5 (s), 132.4 (d), 129.8 (2d), 129.1 (d), 127.8 (4d),
109.0 (s), 76.1 (d), 72.4 (d), 71.9 (d), 71.1 (d), 66.3 (t), 63.3 (t), 29.3 (t),
27.7 (q), 27.0 (3q, SieC(CH3)3), 25.4 (q), 19.4 (s, SieC(CH3)3); MS (EI)
m/z 349 (1), 241 (27), 199 (47), 197 (18), 183 (22), 181 (22), 163 (36),
141 (100), 139 (36), 135 (54), 123 (17), 121 (15), 117 (19), 111 (17), 105
(35), 95 (27), 91 (31), 85 (18), 83 (21), 81 (30), 79 (19), 77 ([Ph]þ, 28),
71 (22), 69 (49), 67 (21), 59 (62), 57 ([t-Bu]þ, 65), 55 (61), 53 (18);
HRMS (ESI) m/z calcd for C28H38NaO5Si [MþNa]þ 505.2381, found:
505.2380.
BuOH (2.5 wt %, 376
mL, 30 mmol, 0.04 equiv). The solution was
stirred overnight at room temperature, and then a saturated
aqueous solution of Na2S2O3 (10 mL) was added. The mixture was
stirred with CeliteÒ for 30 min and filtered through a pad of CeliteÒ.
The two phases were separated and the aqueous layer was
extracted with EtOAc (3ꢂ10 mL). The combined organic layers were
dried over Na2SO4, filtered, and concentrated under reduced pres-
sure to afford a diol, which was engaged in the next step without
further purification.
To a solution of the obtained diol in a mixture THF/buffer pH 7
(1:1, 10 mL) was added NaIO4 (482 mg, 2.25 mmol, 3.0 equiv). The
solution was stirred at room temperature for 4 h and then filtered
through a pad of CeliteÒ. The two phases were separated and the
aqueous layer was extracted with EtOAc (3ꢂ10 mL). The combined
organic layers were dried over MgSO4, filtered, and concentrated
under reduced pressure to afford aldehyde 9, which was engaged in
the next step without further purification.
3.2.9. tert-Butyl(((3aS,4R,6S,7aS)-4-((E)-3-(4-methoxybenzyloxy)
prop-1-en-1-yl)-2,2-dimethyltetrahydro-3aH-[1,3]dioxolo[4,5-c]py-
ran-6-yl)methoxy)diphenylsilane (12). To a solution of alcohol 11
(651 mg, 1.35 mmol, 1.0 equiv) in THF (30 mL) at 0 ꢁC were added t-
BuOK (302 mg, 2.70 mmol, 2.0 equiv) and, dropwise, PMBBr
(326 mg, 1.62 mmol, 1.2 equiv). The solution was allowed to warm
to room temperature and after 3 h, the reaction was quenched with
a saturated aqueous solution of NH4Cl (25 mL). The two phases

C. Bensoussan et al. / Tetrahedron 69 (2013) 7759e7770
7767
were separated and the aqueous layer was extracted with Et2O
(3ꢂ25 mL). The combined organic layers were washed with brine
(25 mL), dried over MgSO4, filtered, and concentrated under re-
duced pressure. The crude product was purified by flash chroma-
room temperature over 1 h and after 3 h at room temperature,
triethylamine (100 L) was added, and the solvent was removed
m
under reduced pressure. The mixture was then diluted with water
(15 mL) and the solution was extracted with EtOAc (3ꢂ20 mL). The
combined organic layers were washed with brine (15 mL), dried
over MgSO4, filtered, and concentrated under reduced pressure.
The crude product was purified by flash chromatography on silica
gel (PE/EtOAc: 8:2) to afford alcohol 15 (363 mg, 98%) as a colorless
tography on silica gel (PE/EtOAc: 7:3) to afford PMB ether 12
20
(633 mg, 78%) as a yellow oil. [
a
]
D
þ8.4 (c 0.95, CHCl3); IR (neat)
2932, 2857,1736,1612,1512,1462,1428,1371,1302,1247,1212,1163,
1111, 1047 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
7.70e7.65 (m, 4H, Har),
7.43e7.34 (m, 6H, Har), 7.26 (d, J¼8.5 Hz, 2H), 6.87 (d, J¼8.5 Hz, 2H),
5.94 (dtm, J¼15.7, 5.6 Hz, 1H), 5.80 (ddm, J¼15.7, 5.1 Hz, 1H), 4.45 (s,
2H), 4.36 (dtapp, J¼9.3, 6.3 Hz, 1H), 4.26 (tapp, J¼6.1 Hz, 1H), 4.04 (d,
J¼5.6 Hz, 2H), 3.97 (tapp, J¼6.9 Hz, 1H), 3.88e3.81 (m, 1H), 3.80 (s,
3H), 3.76 (dd, J¼10.5, 4.8 Hz, 1H), 3.70 (dd, J¼10.5, 5.3 Hz, 1H), 2.09
(ddd, J¼13.5, 6.1, 4.3 Hz, 1H), 1.91 (dtapp, J¼13.5, 10.0 Hz, 1H), 1.45 (s,
3H),1.35 (s, 3H),1.06 (s, 9H, SieC(CH3)3); 13C NMR (100 MHz, CDCl3)
oil. [
a]
20 ꢀ1.4 (c 1.15, CHCl3); IR (neat) 2932, 2858, 1719, 1612, 1588,
D
1513, 1461, 1428, 1370, 1302, 1247, 1215, 1169, 1105, 1052 cmꢀ1
;
1H
NMR (400 MHz, CDCl3)
d 7.69e7.63 (m, 4H, Har), 7.44e7.33 (m, 6H,
Har), 7.21 (d, J¼8.5 Hz, 2H), 6.82 (d, J¼8.5 Hz, 2H), 4.48 (d, J¼11.8 Hz,
1H), 4.44 (d, J¼11.8 Hz, 1H), 4.36e4.26 (m, 3H), 4.05 (dd, J¼8.5,
3.2 Hz, 1H), 3.88e3.80 (m, 2H), 3.77 (s, 3H), 3.73 (dd, J¼10.7, 4.9 Hz,
1H), 3.67 (dd, J¼10.7, 5.1 Hz, 1H), 3.52 (d, J¼4.5 Hz, 2H), 2.01 (ddd,
J¼13.6, 5.2, 4.7 Hz, 1H), 1.83 (dtapp, J¼13.6, 9.8 Hz, 1H), 1.43 (s, 9H),
1.34 (s, 3H), 1.03 (s, 9H, SieC(CH3)3); 13C NMR (100 MHz, CDCl3)
d
159.3 (s), 135.8 (4d), 133.5 (2s), 130.5 (d), 130.5 (s), 129.8 (2d),
129.5 (d), 129.5 (d), 127.8 (4d), 113.9 (2d), 108.9 (s), 76.0 (d), 72.5 (d),
72.0 (t), 71.9 (d), 70.9 (d), 70.0 (t), 66.3 (t), 55.4 (q), 29.4 (t), 27.8 (q),
26.9 (3q, SieC(CH3)3), 25.5 (q, Cb), 19.4 (s, SieC(CH3)3); MS (EI) m/z
424 (3), 423 (10), 241 (22), 225 (15), 199 (22), 197 (10), 183 (15), 181
(11), 163 (24), 140 (10), 139 (100), 135 (39), 125 (27), 123 (10), 121
([PMB]þ, 10), 117 (15), 105 (14), 91 (14), 81 (19), 77 ([Ph]þ, 11), 69
(27), 59 (11), 55 (13), 53 (12); HRMS (ESI) m/z calcd for
C36H46NaO6Si [MþNa]þ 625.2956, found 625.2958.
d
159.3 (s), 135.7 (4d), 133.5 (2s), 130.2 (s), 129.8 (2d), 129.4 (2d),
127.8 (4d), 113.8 (2d), 109.9 (s), 108.8 (s), 79.0 (d), 76.8 (d), 73.2 (t),
72.8 (d), 72.1 (d), 71.5 (d), 71.4 (d), 70.3 (t), 66.2 (t), 55.4 (q), 29.3 (t),
28.0 (q), 27.4 (q), 27.0 (q), 26.9 (3q, SieC(CH3)3), 25.7 (q), 19.4 (s,
SieC(CH3)3); HRMS (ESI) m/z calcd for C39H52NaO8Si [MþNa]þ
699.3324, found 699.3323.
3.2.12. ((3aS,4S,6S,7aS)-4-((4R,5S)-5-((4-Methoxybenzyloxy)
methyl)-2,2-dimethyl-1,3-dioxo-lan-4-yl)-2,2-dimethyltetrahydro-
3aH-[1,3]dioxolo[4,5-c]pyran-6-yl)methanol (16). To a solution of 15
(970 mg, 1.43 mmol, 1.0 equiv) in THF (3 mL) at 0 ꢁC was added
dropwise a solution of TBAF (1 M in THF, 2.9 mL, 2.87 mmol,
2.0 equiv). The solution was allowed to warm to room temperature
over 2 h and after an additional 2 h at room temperature, the re-
action was quenched by addition of a saturated aqueous solution of
NaHCO3 (10 mL). The two phases were separated and the aqueous
layer was extracted with EtOAc (3ꢂ10 mL). The combined organic
layers were dried over MgSO4, filtered, and concentrated under
reduced pressure. The crude product was purified by flash chro-
3.2.10. (1R,2S)-1-((3aS,4R,6S,7aS)-6-((tert-Butyldiphenylsilyloxy)
methyl)-2,2-dimethyltetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-4-yl)-
3-((4-methoxybenzyl)oxy)propane-1,2-diol (13). To a solution of
olefin 12 (545 mg, 0.91 mmol, 1.0 equiv) in a mixture t-BuOH/
buffer pH 7 (1:1, 25 mL) at 5 ꢁC were successively added
(DHQ)2PHAL (106 mg, 0.136 mmol, 0.15 equiv), AD-mix-a (1.27 g,
1.4 g/mmol),21b K2OsO4$2H2O (6.7 mg, 0.018 mmol, 0.02 equiv),
and CH3SO2NH2 (90 mg, 0.951 mmol, 1.05 equiv).21c The mixture
was stirred at 5 ꢁC for 40 h, and diluted with a saturated aqueous
solution of Na2S2O3 (20 mL). EtOAc (20 mL) and CeliteÒ were
added and the mixture was stirred for 30 min and then filtered
through a pad of CeliteÒ. The two phases were separated and the
aqueous layer was extracted with EtOAc (3ꢂ20 mL). The com-
bined organic layers were dried over Na2SO4, filtered, and con-
centrated under reduced pressure. The crude product was
matography on silica gel (PE/EtOAc: 5:5) to afford primary alcohol
20
16 (602 mg, 96%) as a colorless oil. [
a]
þ3.5 (c 0.88, CHCl3); IR
D
(neat) 3474, 2985, 2934, 1737, 1613, 1586, 1513, 1457, 1370, 1302,
1244, 1215, 1168, 1033 cmꢀ1 1H NMR (400 MHz, CDCl3)
;
d
7.26 (d,
purified by flash chromatography on silica gel (PE/EtOAc: 6:4) to
J¼8.8 Hz, 2H), 6.87 (d, J¼8.8 Hz, 2H), 4.52 (s, 2H), 4.34 (dt, J¼8.6,
6.0 Hz, 1H), 4.26e4.20 (m, 2H), 4.08 (dd, J¼8.3, 3.5 Hz,1H), 3.92 (dd,
J¼5.5, 3.5 Hz, 1H), 3.87e3.80 (m, 1H), 3.80 (s, 3H), 3.66e3.57 (m,
3H), 3.55e3.48 (m, 1H), 2.12e2.07 (m, 1H, OH), 1.92 (ddd, J¼13.8,
6.0, 4.3 Hz, 1H), 1.63 (ddd, J¼13.8, 9.6, 8.8 Hz, 1H), 1.46 (s, 3H), 1.42
20
afford diol 13 (410 mg, 71%; dr¼9:1). [
a
]
þ6.6 (c 0.90, CHCl3);
D
IR (neat) 3416, 3071, 2931, 2858, 1699, 1612, 1513, 1463, 1428,
1363, 1303, 1248, 1111, 1036 cmꢀ1 1H NMR (400 MHz, CDCl3)
7.68e7.64 (m, 4H, Har), 7.43e7.34 (m, 6H, Har), 7.24 (d,
;
d
J¼8.8 Hz, 2H), 6.85 (d, J¼8.8 Hz, 2H), 4.51e4.45 (m, 2H), 4.37
(dtapp, J¼9.0, 6.2 Hz, 1H), 4.29 (dd, J¼8.0, 6.8 Hz, 1H), 4.03e3.96
(m, 1H), 3.90e3.80 (m, 1H), 3.85e3.77 (m, 1H), 3.79 (s, 3H),
3.77e3.69 (m, 2H), 3.65 (dd, J¼10.7, 4.9 Hz, 1H), 3.62e3.55 (m,
2H), 3.23 (d, J¼4.5 Hz, 1H, OH), 2.91 (d, J¼5.5 Hz, 1H, OH), 2.06
(dtapp, J¼13.8, 5.3 Hz, 1H), 1.84 (dtapp, J¼13.8, 9.7 Hz, 1H), 1.42 (s,
3H), 1.34 (s, 3H), 1.04 (s, 9H, SieC(CH3)3); 13C NMR (100 MHz,
(s, 3H), 1.42 (s, 3H), 1.33 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 159.4
(s), 130.0 (s), 129.6 (2d), 113.9 (2d), 110.0 (s), 108.8 (s), 79.4 (d), 76.9
(d), 73.3 (t), 72.5 (d), 71.5 (d), 71.3 (d), 71.2 (d), 70.3 (t), 64.8 (t), 55.4
(q), 29.1 (t), 28.1 (q), 27.3 (q), 27.0 (q), 25.9 (q); MS (EI) m/z 439
([M]þꢃ, 1), 137 (7), 136 (5), 122 (10), 121 (100), 99 (6), 83 (6), 71 (6),
69 (8), 59 (10); HRMS (ESI) m/z calcd for C23H34NaO8 [MþNa]þ
461.2146, found 461.2138.
CDCl3)
d 159.4 (s), 135.7 (4d), 133.4 (2s), 130.1 (s), 129.9 (2d),
129.6 (2d), 127.9 (4d), 113.9 (2d), 109.3 (s), 73.4 (d), 73.4 (t), 72.6
(d), 72.3 (d), 72.0 (d), 71.8 (t), 71.7 (d), 69.3 (d), 65.9 (t), 55.4 (q),
28.8 (t), 27.6 (q), 26.9 (3q, SieC(CH3)3), 25.4 (q), 19.3 (s,
SieC(CH3)3); HRMS (ESI) m/z calcd for C36H48NaO8Si [MþNa]þ
659.3011, found 659.3005.
3.2.13. (3aS,4S,6S,7aS)-4-((4R,5S)-5-((4-Methoxybenzyloxy)methyl)-
2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-6-vinyltetrahydro-
3aH-[1,3]dioxolo[4,5-c]pyran (18). To a solution of oxalyl chloride
(81
m
L, 0.94 mmol, 1.1 equiv) in CH2Cl2 (0.5 mL) at ꢀ60 ꢁC was
added dropwise DMSO (122 mL, 1.72 mmol, 2.0 equiv) and after
20 min, a solution of alcohol 16 (376 mg, dr¼9:1, 0.86 mmol,
3. 2.11. tert-Butyl (((3aS, 4S, 6S, 7aS)-4-((4R, 5S)-5- ((4-
methoxybenzyloxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-
dimethyltetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-6-yl)methoxy)-di-
phenylsilane (15). To a solution of diol 13 (350 mg, 0.55 mmol,
1.0 equiv) in CH2Cl2 (2.0 mL) was added dropwise. After an addi-
tional 20 min at ꢀ60 ꢁC, triethylamine (478
mL, 3.43 mmol,
4.0 equiv) was added and the mixture was stirred for 10 min at
ꢀ60 ꢁC, and then warmed up to room temperature and stirred for
an additional 2 h. The reaction was then stopped by the addition of
a saturated aqueous solution of NaCl (5 mL), the two phases were
separated, and the aqueous layer was extracted with CH2Cl2
1.0 equiv) in acetone (15 mL) at
dimethoxypropane (338 L, 2.75 mmol, 5.0 equiv) and TsOH
(38 mg, 0.22 mmol, 0.4 equiv). The mixture was allowed to warm to
0
ꢁC, were added 2,2-
m

7768
C. Bensoussan et al. / Tetrahedron 69 (2013) 7759e7770
(2ꢂ5 mL) and petroleum ether (5 mL). The combined organic layers
were dried over MgSO4, filtered, and concentrated under reduced
pressure. The crude product was quickly filtered through a pad of
silica gel (PE/EtOAc: 7:3e6:4) to afford aldehyde 17 (291 mg, 78%)
as a colorless oil. This aldehyde was not stable and was directly
engaged in the next step.
dimethyltetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-6-yl)-4-(trime-
thylsilyl)pent-4-en-1-yl)oxy)dimethylsilane (24). To a solution of 19
(122 mg, 0.26 mmol, 1.0 equiv, 65:35 epimeric mixture) in CH2Cl2
(1.3 mL) were added PPTS (5.2 mg, 0.021 mmol, 0.05 equiv) and
trimethyl orthoacetate (69 mL, 0.55 mmol, 2.1 equiv). After 2 h at
room temperature, the solvent and excess trimethyl orthoacetate
were removed under reduced pressure and the product was di-
To a solution of PPh3CH3Br (480 mg, 1.34 mmol, 2.1 equiv),
previously dried at 60 ꢁC under vacuum, in THF (1.2 mL) at ꢀ10 ꢁC
was added dropwise a solution of t-BuOK (143 mg, 1.28 mmol,
2.0 equiv) in THF (1.2 mL). The mixture was allowed to warm up to
room temperature, stirred for 10 min at this temperature, and then
cooled to ꢀ10 ꢁC. A solution of aldehyde 17 (279 mg, 0.64 mmol,
1.0 equiv) in THF (0.6 mL) was then added and the solution was
allowed to warm up to room temperature and stirred for 1 h. The
solvent was removed under reduced pressure and the crude
product was purified by flash chromatography on silica gel (PE/
EtOAc: 9:1) to afford olefin 18 (219 mg, 79%, drw9:1) as a colorless
luted in CH2Cl2 (1.3 mL). Acetyl chloride (39
mL, 0.55 mmol,
2.1 equiv) was added, the mixture was stirred for 5 h at room
temperature and the solvents were removed under reduced
pressure. The mixture was diluted with MeOH (2.2 mL) and po-
tassium carbonate (79 mg, 0.57 mmol, 2.2 equiv) was added. After
one night at room temperature, the reaction was stopped by the
addition of a saturated aqueous solution of NH4Cl (2.5 mL). The
two phases were separated and the aqueous layer was extracted
with CH2Cl2 (3ꢂ5 mL). The combined organic layers were dried
over MgSO4, filtered, and concentrated under reduced pressure.
The crude product was filtered through silica gel (EP/EtOAc: 7:3) to
afford epoxide 21 (64 mg, 55%), which was directly engaged in the
next step.
oil. [
a]
20 þ8.9 (c 0.95, CHCl3); IR (neat) 2985, 2935, 1737, 1612, 1586,
D
1513, 1457, 1370, 1302, 1245, 1216, 1168, 1056 cmꢀ1
;
1H NMR
(400 MHz, CDCl3)
d
7.25 (d, J¼8.5 Hz, 2H), 6.86 (d, J¼8.5 Hz, 2H),
5.88 (ddd, J¼17.2, 10.6, 5.3 Hz, 1H), 5.24 (dt, J¼17.2, 1.5 Hz, 1H), 5.13
(dt, J¼10.6, 1.5 Hz, 1H), 4.52 (br s, 2H), 4.34 (dtapp, J¼8.4, 6.0 Hz, 1H),
4.30e4.25 (m, 2H), 4.25e4.18 (m, 1H), 4.09 (dd, J¼8.5, 3.5 Hz, 1H),
3.88 (dd, J¼6.1, 3.5 Hz, 1H), 3.80 (s, 3H), 3.59 (d, J¼4.5 Hz, 2H),
2.10e2.01 (m, 1H), 1.73 (dtapp, J¼13.7, 8.7 Hz, 1H), 1.44 (s, 6H), 1.43
To a solution of 22 (25 mg, 0.063 mmol, 1.35 equiv) in THF
(150
29
m
L) at ꢀ78 ꢁC was added dropwise n-BuLi (2.2 M in hexanes,
m
L, 0.063 mmol, 1.35 equiv) and the (3-lithioprop-1-en-2-yl)
trimethylsilane solution was stirred for 20 min at this temperature.
To a solution of 21 (21 mg, 0.047 mmol,1.0 equiv) in THF (150 L)
m
(s, 3H), 1.34 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
159.3 (s), 137.8 (d),
at ꢀ78 ꢁC was added dropwise the freshly prepared solution of (3-
lithioprop-1-en-2-yl)trimethylsilane and the reaction was stirred
for 1 h at this temperature. The reaction was then stopped by the
addition of water (1 mL) and the mixture was allowed to warm up
to room temperature. The two phases were separated and the
aqueous layer was extracted with Et2O (3ꢂ5 mL). The combined
organic layers were washed with brine (5 mL), dried over MgSO4,
filtered, and concentrated under reduced pressure. The crude
product was filtered through silica gel (PE/EtOAc: 8:2) to afford
vinylsilane 23 (14 mg, 53%), which was directly engaged in the next
step.
130.2 (s), 129.5 (2d), 115.9 (t), 113.9 (2d), 109.9 (s), 108.8 (s), 79.2 (d),
76.9 (d), 73.3 (t), 72.1 (d), 71.8 (d), 71.4 (d), 71.2 (d), 70.3 (t), 55.4 (q),
32.6 (t), 28.1 (q), 27.3 (s), 27.0 (q), 26.0 (q); MS (EI) m/z 434 ([M]þ
,
ꢃ
1), 221 (6), 137 (5), 136 (5), 125 (5), 122 (9), 121 (100), 95 (8), 85 (6),
71 (5), 67 (10), 59 (9), 55 (7); HRMS (ESI) m/z calcd for C24H34NaO7
[MþNa]þ 457.2197, found: 457.2193.
3.2.14. (S)-1-((3aS,4S,6S,7aS)-4-((4R,5S)-5-((4-Methoxybenzyloxy)
methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydro-
3aH-[1,3]dioxolo[4,5-c]pyran-6-yl)ethane-1,2-diol (19). To a solu-
tion of 18 (204 mg, 0.47 mmol, 1.0 equiv) in a mixture t-BuOH/
buffer pH 7 (1:1, 15 mL) at 5 ꢁC were successively added
(DHQD)2PYR (66 mg, 0.075 mmol, 0.16 equiv), K3Fe(CN)6 (461 mg,
0.98 g/mmol), K2CO3 (178 mg, 0.41 g/mmol), K2OsO4$2H2O (4 mg,
0.010 mmol, 0.022 equiv), and CH3SO2NH2 (47 mg, 0.49 mmol,
1.05 equiv). The mixture was stirred at 5 ꢁC for 24 h, and a saturated
aqueous solution of Na2S2O3 (10 mL) was added. EtOAc (10 mL) and
CeliteÒ were added and the mixture was stirred for 30 min and
filtered on CeliteÒ. The two phases were separated and the aqueous
layer was extracted with EtOAc (3ꢂ10 mL). The combined organic
layers were dried over Na2SO4, filtered, and concentrated under
reduced pressure. The crude diol was purified by flash chroma-
tography on silica gel (PE/EtOAc: 3:7) to afford diol 19 as a mixture
of two diastereoisomers (220 mg, quant., dr¼65:35). IR (neat) 3402,
2930, 2858, 1788, 1723, 1612, 1586, 1514, 1463, 1370, 1302, 1249,
To a solution of 23 (14 mg, 0.025 mmol, 1.0 equiv) in CH2Cl2
(200
m
L) at ꢀ78 ꢁC were added dropwise 2,6-lutidine (11.5
mL,
0.099 mmol, 4.0 equiv) and TBSOTf (11.4 mL, 0.050 mmol, 2.0 equiv).
The mixture was then allowed to warm up to room temperature
overnight and the reaction was stopped by the addition of a satu-
rated aqueous solution of NaHCO3 (1 mL). The two phases were
separated and the aqueous layer was extracted with CH2Cl2
(3ꢂ2.5 mL). The combined organic layers were dried over MgSO4,
filtered, and concentrated under reduced pressure. The crude
product was purified by flash chromatography on silica gel (PE/
EtOAc: 9:1) to afford silyl ether 24 (11 mg, 65%, dr>95:5, 19% from
19) as a colorless oil. [
a
]
20 þ6.7 (c 0.50, CHCl3); IR (neat) 2953, 2933,
D
2857,1613,1586,1514,1461,1370,1302,1247,1215,1170,1064 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
7.25 (dm, J¼8.8 Hz, 2H), 6.86 (dm,
J¼8.8 Hz, 2H), 5.54 (dm, J¼2.8 Hz, 1H), 5.30 (dm, J¼2.8 Hz, 1H), 4.54
(d, J¼11.5 Hz, 1H), 4.52 (d, J¼11.5 Hz, 1H), 4.36e4.27 (m, 2H), 4.25
(ddd, J¼8.7, 5.1, 4.2 Hz, 1H), 4.06 (dd, J¼8.7, 2.7 Hz, 1H), 3.93 (dd,
J¼5.7, 2.7 Hz, 1H), 3.80 (s, 3H), 3.72 (dt, J¼12.3, 3.8 Hz, 1H), 3.60
(ddd, J¼7.6, 4.9, 3.8 Hz, 1H), 3.58e3.54 (m, 2H), 2.26e2.15 (m, 1H),
2.11e2.01 (m, 1H), 1.88 (ddd, J¼13.2, 5.8, 3.8 Hz, 1H), 1.80e1.69 (m,
2H), 1.54e1.44 (m, 1H), 1.46 (s, 3H), 1.42 (s, 3H), 1.42 (s, 3H), 1.33 (s,
3H), 0.87 (s, 9H, SieC(CH3)3), 0.07 (s, 9H, Sie(CH3)3), 0.05 (s, 3H,
Sie(CH3)2), 0.03 (s, 3H, Sie(CH3)2); 13C NMR (100 MHz, CDCl3)
1174, 1083, 1035 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d 7.26 (dm,
J¼8.8 Hz, 2H), 6.88 (dm, J¼8.8 Hz, 2H), 4.54 (d, J¼11.7 Hz, 1H), 4.50
(d, J¼11.7 Hz, 1H), 4.38e4.30 (m, 1H), 4.27e4.17 (m, 2H), 4.06 (ddd,
J¼8.0, 7.3, 3.4 Hz, 1H), 3.93 (dtapp, J¼6.2, 3.4 Hz, 1H), 3.85e3.76 (m,
1H, H38), 3.81 (s, 3H, Hh), 3.74e3.53 (m, 5H, H31, H310, H39, H40, H400),
2.00 (ddd, J¼13.9, 6.1, 4.7 Hz,1H, H37), 1.81 (dtapp, J¼13.9, 9.3 Hz,1H,
H370), 1.46 (s, 3H, Hb), 1.41 (s, 6H, Hb), 1.32 (s, 3H, Hb); 13C NMR
(100 MHz, CDCl3)
d 159.5 (s), 129.9 (s), 129.0 (2d), 114.0 (2d), 109.0
(2s), 79.7 (d), 76.4 (d), 73.3 (t), 72.9 (d), 72.6 (d), 71.8 (d), 71.6 (d),
71.3 (d), 70.5 (t), 63.5 (t), 55.4 (q), 29.0 (t), 27.9 (q), 27.3 (q), 27.0 (q),
25.7 (q); HRMS (ESI) m/z calcd for C24H36NaO9 [MþNa]þ 491.2252,
found 491.2259.
d 159.3 (s), 152.3 (s), 130.2 (s), 129.4 (2d), 123.7 (t), 113.9 (2d), 110.1
(s), 108.7 (s), 79.8 (d), 76.7 (d), 74.5 (d), 73.6 (d), 73.2 (t), 72.9 (d),
72.8 (d), 71.7 (d), 70.5 (t), 55.4 (q), 32.0 (t), 31.8 (t), 28.4 (t), 27.8 (q),
27.3 (q), 27.0 (q), 26.0 (3q, SieC(CH3)3), 25.6 (q),18.2 (s, SieC(CH3)3),
ꢀ1.3 (3q, Sie(CH3)3), ꢀ4.2 (q, Sie(CH3)2), ꢀ4.3 (q, Sie(CH3)2);
HRMS (ESI) m/z calcd for C36H62NaO8Si2 [MþNa]þ 701.3875, found
701.3867.
3.2.15. tert-Butyl(((S)-1-((3aS,4S,6S,7aS)-4-((4R,5S)-5-((4-
methoxybenzyloxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-

C. Bensoussan et al. / Tetrahedron 69 (2013) 7759e7770
7769
3.3. Methoxyphenylacetic esters 26 and 27
O
O
(R)
Ph
O
HO
TBDPSO
O
OMe
(39S)
31
DCC, DMAP
CH2Cl2
Ph
O
(R)
MeO
H
H
O
OPMB
O
O
TBDPSCl
imidazole
O
O
26 (dr = 75/25)
TBDPSO
O
19 (dr = 65/35)
(39S)
31
O
DMF
64%
H
H
O
HO
OPMB
O
O
O
25 (dr = 75/25)
TBDPSO
O
(39S)
(S)
31
Ph
Ph
O
HO
H
H
(S)
O
OPMB
O
OMe
MeO
DCC, DMAP
CH2Cl2
O
27 (dr = 75/25)
3.3.1. (S)-2-(tert-Butyldiphenylsilyloxy)-1-((3aS,4S,6S,7aS)-4-
((4R,5S)-5-((4-methoxybenzyloxy)methyl)-2,2-dimethyl-1,3-
dioxolan-4-yl)-2,2-dimethyltetrahydro-3aH-[1,3]dioxolo[4,5-c]py-
ran-6-yl)ethanol (25). To a solution of diol 19 (dr¼65:35, 54 mg,
1105 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
7.71e7.15 (m, 17H, Har),
6.91e6.78 (m, 2H, Har), 5.34e5.26 (m, 1H, H39), 4.79 (s, 1H), 4.54 (d,
J¼11.8 Hz, 1H), 4.50 (d, J¼11.8 Hz, 1H), 4.34e4.25 (m, 3H, H32, H35
,
H36), 4.20e4.14 (m, 1H, H38), 3.94e3.64 (m, 4H, H33, H34, H40, H400),
3.78 (s, 3H), 3.58e3.53 (m, 1H); 3.50e3.43 (m, 1H), 3.39 (s, 3H),
2.03e1.94 (m, 1H, H37), 1.71e1.60 (m, 1H, H370), 1.42 (s, 3H), 1.41 (s,
3H), 1.41 (s, 3H), 1.35 (s, 3H), 0.98 (s, 9H, SieC(CH3)3); 13C NMR
0.124 mmol, 1.0 equiv) in DMF (150 m
L) at 0 ꢁC were added imid-
azole (18 mg, 0.260 mmol, 2.1 equiv) and, TBDPSCl dropwise (35 mL,
0.136 mmol, 1.05 equiv). The solution was warmed to room tem-
perature, and after 4 h, and a saturated aqueous solution of NaHCO3
(3 mL) was added. The two phases were separated and the aqueous
layer was extracted with EtOAc (3ꢂ5 mL). The combined organic
layers were washed with water (2ꢂ5 mL) and brine (2ꢂ5 mL), dried
over MgSO4, filtered, and concentrated under reduced pressure.
The crude product was purified by flash chromatography on silica
gel (PE/EtOAc: 8:2e7:3) to afford product 25 (54 mg, 64%) as
a colorless oil and with a dr of 75:25. IR (neat) 3502, 3071, 2985,
2931, 2858, 2249, 1737, 1612, 1588, 1513, 1462, 1428, 1371, 1302,
(100 MHz, CDCl3)
d 170.6 (s), 159.3 (s), 135.8 (2d), 135.6 (2d), 135.5
(2d), 133.3 (s), 133.1 (s), 133.0 (s), 130.4 (s), 129.9 (3d), 129.5 (2d),
128.8 (d), 128.7 (d), 127.9 (2d), 127.8 (d), 127.4 (d), 113.8 (2d), 109.9
(s), 109.2 (s), 83.0 (d), 79.1 (d), 76.3 (d), 71.6 (d), 73.2 (t), 71.8 (d),
71.3 (d), 70.7 (d), 70.4 (t), 70.0 (d), 63.0 (t), 57.7 (q), 55.4 (q), 28.3 (t),
27.9 (q), 27.0 (q), 26.9 (q), 26.8 (3q, SieC(CH3)3), 25.8 (q), 19.3 (s,
SieC(CH3)3); HRMS (ESI) m/z calculated for C49H62NaO11Si
[MþNa]þ 877.3954, found 877.3945.
1245, 1217, 1165, 1110, 1047 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
3.3.4. (S)-(S)-2-(tert-Butyldiphenylsilyloxy)-1-((3aS,4S,6S,7aS)-4-
((4R,5S)-5-((4-methoxybenzyloxy)methyl)-2,2-dimethyl-1,3-
dioxolan-4-yl)-2,2-dimethyltetrahydro-3aH-[1,3]dioxolo-[4,5-c]py-
ran-6-yl)ethyl 2-methoxy-2-phenylacetate (27). Compound 27
(dr¼75:25, 24 mg, 90%) was prepared from 25 (dr¼75:25, 22 mg,
d
7.70e7.62 (m, 4H), 7.44e7.34 (m, 6H), 7.27e7.18 (m, 2H),
6.88e6.80 (m, 2H), 4.53e4.43 (m, 2H), 4.34 (dtapp, J¼8.7, 6.0 Hz,
1H), 4.27e417 (m, 2H), 4.06 (dd, J¼8.5, 2.8 Hz, 1H), 3.99e3.89 (m,
2H), 3.86e3.64 (m, 3H), 3.78 (s, 3H), 3.57 (m, 1H), 3.54e3.48 (m,
1H), 2.02e1.92 (m, 1H), 1.83e1.72 (m, 1H), 1.44 (s, 3H), 1.41 (s, 3H),
1.40 (s, 3H), 1.32 (s, 3H), 1.05 (s, 9H, SieC(CH3)3); 13C NMR
31.2 mmol) and (S)-methoxyphenylacetic acid (7.8 mg, 46.7 mmol)
according to the general procedure for esterification. IR (neat) 2931,
(100 MHz, CDCl3)
d
159.4 (s), 135.7 (4d), 133.4 (s), 133.2 (s), 130.1 (s),
2857,1751,1706,1670,1612,1588,1513,1454,1428,1370,1302,1247,
130.0 (d), 129.9 (d), 129.5 (2d), 127.9 (4d), 113.9 (2d), 110.0 (s), 108.8
(s), 79.9 (d), 76.5 (d), 73.5 (d), 73.3 (t), 72.6 (d), 71.9 (d), 71.2 (d), 71.0
(d), 70.5 (t), 64.6 (t), 55.4 (q), 29.2 (t), 28.0 (q), 27.3 (q), 27.0 (4q),
25.8 (q), 19.4 (s, SieC(CH3)3); HRMS (ESI) m/z calcd for
C40H54NaO9Si [MþNa]þ 729.3429, found 729.3427.
1212, 1172, 1105 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d 7.71e7.18 (m,
17H, Har), 6.88e6.80 (m, 2H, Har), 5.33e5.27 (m, 1H, H39), 4.68 (s,
1H), 4.53e4.46 (m, 2H), 4.25e4.15 (m, 3H, H32, H35, H36), 4.13e4.04
(m, 1H, H38), 3.89e3.83 (m, 1H, H40), 3.81e3.75 (m, 1H, H400), 3.78
(s, 3H), 3.55e3.32 (m, 4H, H31, H310, H33, H34), 3.37 (s, 3H), 1.97e1.85
(m, 1H, H37), 1.68e1.52 (m, 1H, H370), 1.44e1.25 (4s, 12H), 1.04 (s, 9H,
SieC(CH3)3); 13C NMR (100 MHz, CDCl3)
d 170.5 (s), 159.4 (s), 135.8
3.3.2. General procedure for the esterification. To a solution of an
alcohol (1.0 equiv) in CH2Cl2 (30 mL/mmol) were added DCC
(1.2 equiv), DMAP (0.2 equiv), and (R)- or (S)-methoxyphenylacetic
acid (1.5 equiv). The mixture was stirred overnight at room tem-
perature and the cloudy solution was filtered on cotton. The solu-
tion was then washed with water, dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude product was pu-
rified by flash chromatography on silica gel (PE/Et2O: 100:0e7:3) to
afford the corresponding ester.
(2d), 135.7 (d), 135.6 (3d), 133.3 (2s), 133.2 (s), 130.4 (s), 130.0 (2d),
129.5 (2d), 129.4 (d), 128.8 (d), 128.7 (d), 127.9 (2d), 127.8 (d), 127.5
(d), 113.9 (2d), 109.8 (s), 109.0 (s), 82.6 (d), 79.1 (d), 76.2 (d), 74.4 (d),
73.2 (t), 71.7 (d), 71.1 (d), 70.6 (d), 70.5 (t), 69.8 (d), 63.3 (t), 57.5 (q),
55.4 (q), 28.3 (t), 27.8 (q), 27.4 (q), 26.9 (q), 26.8 (3q, SieC(CH3)3),
25.8 (q), 19.4 (s, SieC(CH3)3); HRMS (ESI) m/z calcd for
C49H62NaO11Si [MþNa]þ 877.3954, found 877.3937.
Acknowledgements
3.3.3. (R)-(S)-2-(tert-Butyldiphenylsilyloxy)-1-((3aS,4S,6S,7aS)-4-
((4R,5S)-5-((4-methoxybenzyloxy)methyl)-2,2-dimethyl-1,3-
dioxolan-4-yl)-2,2-dimethyltetrahydro-3aH-[1,3]dioxolo-[4,5-c]py-
ran-6-yl)ethyl 2-methoxy-2-phenylacetate (26). Compound 26
(dr¼75:25, 22 mg, 70%) was prepared from 25 (dr¼75:25, 26 mg,
We are grateful to the Agence Nationale pour la Recherche (ANR
program 08-BLAN-0262-01, Amphi 3) for a PhD grant to N.R. and
C.B. and for financial support.
References and notes
36.8 mmol) and (R)-methoxyphenylacetic acid (9.2 mg, 55.2 mmol)
according to the general procedure for esterification. IR (neat) 2933,
2858, 2250,1749,1612,1513, 1456, 1428, 1371, 1302, 1247, 1214,1171,
1. See for example: Kobayashi, J.; Shimbo, K.; Kubota, T.; Tsuda, M. Pure Appl.
Chem. 2003, 75, 337e342.

7770
C. Bensoussan et al. / Tetrahedron 69 (2013) 7759e7770
ꢀ
2. For a review, see: Kobayashi, J.; Kubota, T. J. Nat. Prod. 2007, 70, 451e460.
3. (a) Paul, G. K.; Matsumori, N.; Konoki, K.; Sasaki, M.; Murata, M.; Tachibana, K.
In Harmful and Toxic Algal Blooms; Yasumoto, T., Oshima, Y., Fukuyo, Y., Eds.;
UNESCO: Paris, 1996; pp 503e506; (b) Paul, G. K.; Matsumori, N.; Murata, M.;
Tachibana, K. Tetrahedron Lett. 1995, 36, 6279e6282.
14. Guerinot, A.; Reymond, S.; Cossy, J. Angew. Chem., Int. Ed. 2007, 46, 6521e6524.
15. For a related work, see: Cahiez, G.; Duplais, C.; Moyeux, A. Org. Lett. 2007, 9,
3253e3257.
16. (a) Timmons, S. C.; Jakeman, D. L. Org. Lett. 2007, 9, 1227e1230; (b) Montero, J.
L.; Winum, J. Y.; Leydet, A.; Kamal, M.; Pavia, A. A.; Roque, J. P. Carbohydr. Res.
4. (a) Houdai, T.; Matsuoka, S.; Morsy, N.; Matsumori, N.; Sakate, M.; Murata, M.
Tetrahedron 2005, 61, 2795e2802; (b) Houdai, T.; Matsumori, N.; Murata, M.
Org. Lett. 2008, 10, 4191e4194.
5. Murata, M.; Matsuoka, S.; Matsumori, N.; Paul, G. K.; Tachibana, K. J. Am. Chem.
Soc. 1999, 121, 870e871.
6. (a) Oishi, T.; Kanemoto, M.; Swasono, R.; Matsumori, N.; Murata, M. Org. Lett.
2008, 10, 5203e5206; (b) The C2 stereocenter of AM2 was also proposed to be
(2R) by chemical correlation on a model structure, see: Kommana, P.; Chung, S.
W.; Donaldson, W. A. Tetrahedron Lett. 2008, 49, 6209e6211.
1997, 297, 175e180.
17.
OAc
AcO
AcO
OAc
38
O
34
H33
39
H
2
7. Peng, J.; Place, A. R.; Yoshida, W.; Anklin, C.; Hamann, M. T. J. Am. Chem. Soc.
2010, 132, 3277e3279.
nOe
8. (a) Swasono, R. T.; Kanemoto, M.; Matsumori, N.; Oishi, T.; Murata, M. Het-
erocycles 2011, 82, 1359e1369; (b) Manabe, Y.; Ebine, M.; Matsumori, N.;
Murata, M.; Oishi, T. J. Nat. Prod. 2012, 75, 2003e2006.
18. (a) Lin, X.; Zheng, F.; Qing, F.-L. Organometallics 2012, 31, 1578e1582; (b) Ha-
takeyama, T.; Okada, Y.; Yoshimoto, Y.; Nakamura, M. Angew. Chem., Int. Ed.
2011, 50, 10973e10976; (c) Bedford, R. B.; Betham, M.; Bruce, D. W.; Dano-
poulos, A. A.; Frost, R. M.; Hird, M. Chem. Commun. 2005, 4161e4163; (d)
Martin, R.; Furstner, A. Angew. Chem., Int. Ed. 2004, 43, 3955e3957; (e) Hayashi,
Y.; Shinokubo, H.; Oshima, K. Tetrahedron Lett. 1998, 39, 63e66.
19. Nicolas, L.; Angibaud, P.; Stansfield, I.; Bonnet, P.; Meerpoel, L.; Reymond, S.; Cossy,
J. Angew. Chem., Int. Ed. 2012, 51, 11101e11104 and references cited therein.
20. Barton, D.; McCombie, S. J. Chem. Soc., Perkin Trans. 1 1975, 1574e1585.
21. (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94,
9. (a) Huckins, J. R.; de Vicente, J.; Rychnovsky, S. D. Org. Lett. 2007, 9, 4757e4760;
(b) Flamme, E. M.; Roush, W. R. Org. Lett. 2005, 7, 1411e1414; (c) Paquette, L. A.;
Chang, S. K. Org. Lett. 2005, 7, 3111e3114; (d) Crimmins, M. T.; Martin, T. J.;
Martinot, T. A. Org. Lett. 2010, 12, 3890e3893; (e) Kanemoto, M.; Murata, M.;
Oishi, T. J. Org. Chem. 2009, 74, 8810e8813; (f) Hicks, J. D.; Roush, W. R. Org. Lett.
2008, 10, 681e684; (g) Bedore, M. W.; Chang, S. K.; Paquette, L. A. Org. Lett. 2007,
9, 513e516; (h) de Vicente, J.; Huckins, J. R.; Rychnovsky, S. D. Angew. Chem., Int.
Ed. 2006, 45, 7258e7262; (i) Hicks, J. D.; Flamme, E. M.; Roush, W. R. Org. Lett.
2005, 7, 5509e5512; (j) de Vicente, J.; Betzemeier, B.; Rychnovsky, S. D. Org. Lett.
2005, 7, 1853e1856; (k) Dubost, C.; Marko, I. E.; Bryans, J. Tetrahedron Lett. 2005,
46, 4005e4009; (l) Chang, S. K.; Paquette, L. A. Synlett 2005, 2915e2918.
10. Bouzbouz, S.; Cossy, J. Org. Lett. 2001, 3, 1451e1454.
€
2483e2547; (b) Commercially available AD-mix-b (1.4 g/mmol of olefin is
constituted of (DHQD)2PHAL (0.01 mmol), potassium osmate (K2OsO4$2H2O, 0.
002 mmol), K3FeCN6 (3 mmol), and K2CO3 (3 mmol). Commercially available
11. Cossy, J.; Tsuchiya, T.; Reymond, S.; Kreuzer, T.; Colobert, F.; Marko, I. E. Synlett
AD-mix-a (1.4 g/mmol of olefin is constituted of (DHQ)2PHAL (0.01 mmol),
2009, 2706e2710.
potassium osmate (K2OsO4$2H2O, 0.002 mmol), K3FeCN6 (3 mmol) and K2CO3
(3 mmol). (c) With reinforced conditions in osmium and ligand, the total
amount of potassium osmate related to olefin 11 was 0.022 equiv and the total
amount of ligand was 0.16 equiv.
12. Rival, N.; Hazelard, D.; Hanquet, G.; Kreuzer, T.; Bensoussan, C.; Reymond, S.;
Cossy, J.; Colobert, F. Org. Biomol. Chem. 2012, 10, 9418e9428.
ꢀ
13. (a) Colobert, F.; Kreuzer, T.; Cossy, J.; Tsuschiya, T.; Ferrie, L.; Reymond, S.;
Marko, I. E.; Jourdain, P. Synlett 2007, 2351e2354; (b) Cossy, J.; Tsuchiya, T.;
~
ꢀ
22. Seco, J. M.; Quinoa, E.; Riguera, R. Chem. Rev. 2004, 104, 17e117.
ꢀ
Ferrie, L.; Reymond, S.; Kreuzer, T.; Colobert, F.; Jourdain, P.; Marko, I. E. Synlett
23. See Experimental part and Table 4.
2007, 2286e2288.