Synthesis of an Advanced Fragment of (+)-Trienomycinol

Article abstract of DOI:10.1055/s-0035-1562735

The synthesis of the fully functionalized eastern fragment of trienomycins A-F, ansamycin antibiotics is described. A key step involves a peptidic coupling between a sulfonyl aniline and an enantiopure carboxylic acid obtained by a completely diastereosel

Full text of DOI:10.1055/s-0035-1562735

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
©
Georg Thieme Verlag Stuttgart · New York
2016, 48, A–I
A
paper
Synthesis
S. Choppin et al.
Paper
Synthesis of an Advanced Fragment of (+)-Trienomycinol
Sabine Choppin*
Marie Barbarotto
16
I
OH
OTBDPS
O
Michel Obringer
9
t-Bu
Si
1
5
O
OTBS
Françoise Colobert*
14
16
t-Bu
NH
1
NH
OTBDPS
1
3
+
HO
O
O
SO2Ph
Laboratoire de chimie moléculaire (UMR CNRS 7509)
University of Strasbourg, ECPM, 25 rue Becquerel,
12
O
1
1
9
3
4
t-Bu
Si
HO
OMe
2
PhO S
10
O
OTBDMS
OMe
p-Tol
t-Bu
NH
O
67087 Strasbourg, France
O
S
francoise.colobert@unistra.fr
sabine.choppin@unistra.fr
(
+)-trienomycinol
3
p-Tol
S
OMe
Dedicated with great respect to Jean Normant
O
Received: 07.07.2016
Accepted: 20.07.2016
Published online: 18.08.2016
DOI: 10.1055/s-0035-1562735; Art ID: ss-2016-c0451-op
The structural particularity of trienomycins, compared
to other members of the ansamycin family bearing a p-qui-
none or p-hydroquinone moiety, is to display a nonredox
active phenol as the aromatic bridge. This specificity has a
deep influence on the biological properties. Indeed trieno-
mycin A displays well-known anticancer activity (IC of
Abstract The synthesis of the fully functionalized eastern fragment of
trienomycins A–F, ansamycin antibiotics is described. A key step in-
volves a peptidic coupling between a sulfonyl aniline and an enantio-
pure carboxylic acid obtained by a completely diastereoselective reduc-
tion of a β-ketosulfoxide to generate the stereogenic carbinol. Studies
on the coupling with the western part were also performed, giving ac-
cess to an advanced fragment of trienomycinol.
5
0
4
1
28 nM against HeLa cervical cancer cells), but no antifun-
gal activity while mycotrienin II bearing a p-hydroquinone
moiety is recognized as a powerful antifungal agent with
promising antitumor properties.5 Besides it has been re-
ported that trienomycin A was found to be significantly less
toxic to nontransformed cells that renders this compound
Key words ansamycin, trienomycin, antitumor, sulfoxide
6
a very attractive target for anticancer therapy.
Mycobacteria, generally Streptomyces produce the
Absolute and relative stereochemistry of the stereogenic
centers of trienomycin A have been determined or assigned
by Smith and co-workers through careful degradative and
triene-containing C17-benzene ansamycin’s family also
1
called ansatrienins showing powerful biological activities
7
(
antibacterial, antifungal, and antitumor properties). The
spectroscopic methods. To date elegant total synthesis of
structural characteristics of this family of macrocyclic
polyketides are a 21-membered cyclic lactam including an
E,E,E-triene and four stereogenic centers.
trienomycin A and F have been reported first in 1995 by
8
9
Smith and only 20 years later by Krische. Total synthesis
of different members of ansatrienins have been also de-
scribed by Panek,5
b,10
Hayashi, Kirschning, and Krische.
11
12
13
Trienomycin A (Figure 1) was first isolated from Strepto-
myces sp. no. 83-16 by Umezawa and co-workers.2 Later,
trienomycin B–F and trienomycinol with different R groups
A series of SAR studies were performed to screen the
most active parts of the triene ansamycins. These results
indicate that the stereotriad C11–C13, the methyl group at
C14, and the stereogenic methoxy group at C3 are essen-
3
were reported.
OH
5a,14
tial.
Following a program devoted to asymmetric synthesis
mediated by sulfoxides, we reported the synthesis of the
C9–C16 unit of ansamycins 5a (Scheme 1). The anti, syn ste-
reotriad C11–C13 was constructed via a stereoselective
Reformatsky-type reaction followed by the reduction of the
β-ketosulfoxide.15
In this paper, we describe the synthesis of the eastern
part 6 of (+)-trienomycinol (1), a common advanced inter-
mediate of trienomycin’s family. The stereogenic center C3
essential for the biological activity of trienomycinol would
1
5
1
4
16
17
trienomycinol, R = H 1
NH
trienomycin A, X = cyclohexyl
trienomycin B, X = isobutyl
trienomycin C, X = (S)-sec-butyl
trienomycin D, X = cyclohexenyl
trienomycin E, X = isopentyl
trienomycin F, X = (E)-2-butenyl
1
3
1
HO
O
O
1
2
1
1
9
3
RO
OMe
10
O
H
R =
N
X
Figure 1 Members of trienomycin’s family
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

B
Synthesis
S. Choppin et al.
Paper
be controlled by reduction of the corresponding β-ketosulf-
oxide obtained by condensation of methyl acetoacetate
with enantiopure menthyl p-toluenesulfinate. Peptidic cou-
pling between aniline derivative 8 and the enantiopure car-
boxylic acid 7 would afford the eastern fragment 6. In addi-
tion, attempts to couple 6 with the western part 5b giving 4
are reported.
with diisobutylaluminum hydride (DIBAL-H) to afford β-
hydroxysulfoxide 10. Notably the absolute configuration R
at the new hydroxylic center is in accordance with the
mechanism proposed for the reduction of such β-ketosulf-
oxide.17 From the numerous examples of reduction of β-ke-
tosulfoxides reported in literature, a noticeable difference
in the nonequivalence of the methylene hydrogen atoms α
to the sulfoxide for the R,(S)R and the S,(S)R epimers has
been observed. For the S,(S)R configuration, the Δν value
The all trans-triene would be therefore constructed by
means of Na(Hg) or low valent titanium reductive elimina-
tion of 1,6-dibenzoate-2,4-dienes 2. Accordingly the 1,6-
dibenzoate-2,4-dienes would be accessed by acetylene ad-
dition to the dialdehyde 3, followed by diyne reduction
between these two hydrogen atoms is smaller (~30 Hz)
than in the R,(S)R diastereomer (~70 Hz).1
7,18
For the β-hy-
droxysulfoxide 10, Δν of 93.9 Hz was measured indicating
the 3R,(S)R absolute configuration.
16
with Zn/Cu and benzoylation (Scheme 1).
The synthesis of 7 commenced by the addition of the
lithiated dianion of the commercially available methyl ace-
toacetate to (+)-(S)R-menthyl p-toluenesulfinate yielding
the β-ketosulfoxide 9 (Scheme 2). To ensure a yield of 91%,
two equivalents of the dianion of methyl acetoacetate were
necessary. The β-ketosulfoxide 9 was subsequently reduced
O
O
1) LDA (4 equiv)
THF, –78 °C
O
S
O
O
OMe
2
)
O
S
:
OMe
(2 equiv)
p-Tol
p-Tol
9
Omenthyl
91%
DIBAL-H
THF, –78 °C
67%
OH
OPG
1) Ag O (1 equiv)
2
MeI
O
S
OMe
O
CH2Cl2, reflux
75%
1
5
15
1
4
16
14
13
12
O
OH
O
1
6
NH
1
NH
:
OH
1
3
S
p-Tol
2) KOH
MeOH, 25 °C
85%
:
OMe
HO
O
O
OBz
9
7
O
1
2
t-Bu
t-Bu
1
1
9
4
3
11
4
p-Tol
Si
10
HO
OMe
O
OMe
10
2
OBz
1
trienomycinol
Scheme 2 Synthesis of the carboxylic acid 7
OTBDPS
OTBDPS
According to our retrosynthetic analysis, the next steps
concern the protection of the hydroxyl group and the sa-
ponification of the ester function. The methyl ether was ob-
NH
NH
SO2Ph
O
O
O
O
t-Bu
t-Bu
t-Bu
Si
CHO
tained in 75% yield using Ag O (1 equiv), freshly prepared
2
Si
O
OHC
OMe
O
OTBDMS
OMe
19
t-Bu
from AgNO and NaOH, in the presence of methyl iodide
3
O
S
3
12
4
p-Tol
(5 equiv) in CH Cl at reflux. Notably when NaH/MeI sys-
2
2
tem was used in DMF at –20 °C, elimination of the hydroxyl
group was observed. Finally treatment of the methyl ether
OTBDPS
20
with excess KOH in methanol delivered the carboxylic acid
7 in 85% yield. An X-ray crystal structure of 7 confirmed the
absolute configuration R of the stereogenic carbinol (Figure
1
6
PhO2S
R
NH
O
+
9
O
21
Si
3
2).
O
OTBS
p-Tol
S
OMe
To complete the synthesis of the eastern part 6 of tri-
6
O
5
5
a R = CO2Me
b R = CH2I
enomycinol, a peptidic coupling with the aniline derivative
and the acid 7 was envisaged. An efficient synthesis of 8
8
8b
OTBDPS
was already reported by Smith in the total synthesis of
trienomycin A and F starting from the commercially avail-
able 3,5-dinitrobenzoic acid. Inspired by this work, we fol-
lowed the reaction sequence including 1) treatment of 3,5-
dinitrobenzoic acid with MeOLi in DMSO to give the anisole
derivative in 86% yield; 2) deprotection of the methyl ether
with HBr in AcOH at reflux yielding 3-hydroxy-5-nitroben-
zoic acid; 3) reduction of the carboxylic acid with borane in
THF; 4) treatment with CBr and PPh in THF delivering the
O
OMe O
+
S
:
PhO2S
OH
NH2
p-Tol
8
7
NO2
O
S
O
O
+
p-Tol
OMent
OMe
4
3
HOOC
NO2
benzylic bromide, which was 5) converted into the sulfone
Scheme 1 Retrosynthesis of trienomycinol (1)
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

C
Synthesis
S. Choppin et al.
Paper
O
S
OMe
O
OTBDPS
3
OH
p-Tol
PhO2S
7
NH
DMAP, PPTS, DCC
CH2Cl2, 25 °C
+
O
O
OTBDPS
80%
S
OMe
p-Tol
SO2Ph
6
H2N
8
Scheme 4 Synthesis of the eastern part 6
In order to establish the best conditions to perform the
coupling between the eastern and western fragments 6 and
5b of trienomycinol, we investigated the coupling of the
eastern part 6 obtained on large scale with a model sub-
strate 15 bearing the allylic iodine and the trisubstituted Z-
double bond in the α position of a TBDMS ether. This model
was efficiently obtained starting from commercially avail-
able oct-1-yn-3-ol by protection as a TBDMS ether 11 fol-
lowed by treatment with n-BuLi and addition of methyl
chloroformate affording the acetylenic ester 12. Following
the addition of methyl cuprate in THF at –20 °C afforded the
corresponding trisubstituted Z-alkene 13 in an excellent di-
astereoselectivity. The ester group was then reduced with
DIBAL-H giving the allylic alcohol 14 and the attempt to in-
troduce directly the iodine failed. Therefore, first treatment
Figure 2 X-ray crystal structure of (–) [3R,(SR)]-3-methoxy-4-(p-tolyl-
sulfinyl)butanoic acid (7)
in presence of sodium phenylsulfinate in DMF; and 6) pro-
tection of the phenol as a TBDPS ether followed 7) by the
reduction of the nitro group in the presence of Pd/C and H2
in MeOH to afford the final aniline derivative 8 in 7 steps
and an overall yield of 26% (Scheme 3). Notably, the scale-
up for the synthesis of the aniline derivative could be per-
formed on a 5 gram scale.
MeOLi
DMSO, r.t.
reflux
HBr, AcOH
with NCS and dimethyl sulfide in CH Cl and second with
NO2
OMe
OH
2
2
reflux
5%
7
NaI in acetone led to the primary allylic iodine 15 in high
yield (Scheme 5).
86%
HOOC
PhO2S
PhO2S
NO2
HOOC
NO2
HOOC
NO2
The eastern part 6 bearing the sulfone moiety was sub-
jected to the coupling reaction with the allylic iodine 15
under different conditions (Table 1) to provide compound
16 in excellent yield. The best result was obtained when an
excess of the base NaHMDS was added to a mixture of 6 and
15 in THF at –78 to –10 °C affording compound 16 in 83%
yield as a mixture of diastereomers (Table 1, entry 7).
Indeed when the sulfone 6 in THF was deprotonated by
NaHMDS during thirty minutes at –78 °C and followed by
addition of the allylic iodine 15, no reaction occurred
whatever the temperature at which the iodine was added
BH3/THF
0
7
–25 °C
0%
CBr4, Ph3P
THF
0–25 °C
PhSO2Na
DMF, 60 °C
OH
OH
OH
85%
75%
Br
HO
NO2
NO2
NO2
TBDPSCl
imidazole
DMF, 25 °C
92%
(–78 °C, –40 °C, 0 °C) (entries 1–3) and whatever the ratio
sulfone 6/iodine 15 (1:1.5 or 1.5:1) used (entries 3 and 4).
Therefore, once the anion of sulfone 6 is formed in the ab-
sence of 15, we suspected its decomposition as confirmed
OTBDPS
OTBDPS
H2, Pd/C
MeOH, 25 °C
9%
9
PhO S
2
NO2
NH2
by the absence of deuteration when D O was added (entry
2
8
5).
Finally en route to trienomycinol, the optimized cross-
coupling conditions were applied to the reaction between
the eastern and western parts 6 and 5b bearing the primary
iodine. The substrate 5b was easily synthesized from the al-
ready reported methyl ester 5a15 using the reaction se-
quence described for the synthesis of the model 15, that is,
reduction of the ester with DIBAL-H followed by chlorina-
Scheme 3 Synthesis of the aniline derivative 8
Having in hand both coupling partners, the carboxylic
acid 7 and the aniline derivative 8, we performed the pep-
tidic coupling using classical conditions, that is, DCC, PPTS,
catalytic DMAP in CH Cl to afford the eastern part 6 of
2
2
trienomycinol in 80% yield (Scheme 4).
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

D
Synthesis
S. Choppin et al.
Paper
imidazole
TBDMSiCl
OH
OTBMS
1) n-BuLi
THF, –78 °C
OTBDMS
DMF, 25 °C
2) ClCO2Me
–78 to 25 °C
97%
11
2
MeO C
76%
12
Me2CuLi,
THF, –20 °C
6%
9
1) NCS, (1.3 equiv)
DMS (1.6 equiv)
OTBDMS
OTBDMS
OTBDMS
CH2Cl2, –40 to 25 °C
I
HO
MeO2C
85%
DIBAL-H
2
) NaI (1 equiv)
acetone, 25 °C
Z/E 98:2
THF, –78 °C
15
14
82%
13
97%
Scheme 5 Synthesis of the primary allylic iodine 15 as a model substrate
Table 1 Screened Conditions for the Coupling between Sulfone 6 and Allylic Iodine 15
OTBDPS
OTBDPS
PhO2S
OTBDMS
NH
NH
I
base
SO Ph
TBDMSO
2
O
O
+
O
O
THF, T °C
S
OMe
S
OMe
p-Tol
p-Tol
15
16
6
Entry
Base, equiv
Sulfone 6 (equiv)
Iodine 15 (equiv)
Temp (°C)
Yield (%)
1a
2a
3a
4a
5a
6b
NaHMDS, 3 equiv
NaHMDS, 3 equiv
NaHMDS, 3 equiv
NaHMDS, 3.4 equiv
NaHMDS, 3.4 equiv
NaHMDS, 3.4 equiv
NaHMDS, 3 equiv
1
1.5
1.5
1.5
1
–78
no reaction
no reaction
no reaction
no reaction
no reaction
60
1
–40
1
0
1.5
1.5
1.5
1
–78 to –30
–78 to 0
–78
D
1
2
O, 1.5 equiv
7b
1.1
–78 to –10
83
a
Base was added to 6 at –78 °C and after 30 min, 15 was added.
Base was added to a mixture of 6 and 15.
b
tion with NCS and iodination with NaI (Scheme 5). The cou-
pling reaction between 6 and 5b afforded 4 with an accept-
able yield of 59% (Scheme 6).
In conclusion, the synthesis of the advanced intermedi-
ate 4 (northern part) of the highly potent cytotoxic trieno-
mycinol has been achieved by coupling of the western part
es are given. Air- and moisture-sensitive materials were stored in
Schlenk tubes under argon. THF was dried by distillation from sodi-
um/benzophenone after the characteristic blue color of sodium di-
phenyl ketyl (benzophenone sodium ‘radical anion’) had been found
22
to persist. CH Cl was dried over CaH . (i-Pr) NH was dried over KOH
2
2
2
2
under argon. Melting ranges (mp) given were found to be reproduc-
ible after recrystallization, unless stated otherwise (dec.), and are un-
corrected. TLC was carried out on 0.25 mm Merck silica gel (60-F254).
Column chromatography was carried out on silica gel by using Merck
silica gel (40–63 μm). BuLi (1.6 M in hexanes, Aldrich) was used as
solution and its concentration was determined following the Wittig–
Harborth Double Titration method [(total base) – (residual base after
5b and the eastern part 6 obtained in 5 steps with an over-
all yield of 31% from commercially available methyl aceto-
acetate. Further macrocyclization through obtention of the
all-trans triene will be reported in due course.
23
reaction with 1,2-dibromoethane)]. NMR spectra were recorded on
1
13
Bruker Avance 300 ( H NMR, 300 MHz; C NMR, 75.5 MHz) and
Starting materials and anhydrous solvents, if commercially available,
were purchased and used as received. When known compounds had
to be prepared according to literature procedures, pertinent referenc-
1
13
Bruker Avance 400 ( H NMR, 400 MHz; C NMR, 100.6 MHz). Chemi-
cal shifts were referred on partial deuterated chloroform (δH = 7.26
and accordingly δ = 77.06) and given in ppm on the δ scale. Standard
C
abbreviations are used to denote multiplicities. Coupling constants
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

E
Synthesis
S. Choppin et al.
Paper
1
2
) DIBAL-H
THF, –78 °C
1%
) NCS, DMS
CH2Cl2
3 H, CO CH ), 3.72 (s, 3 H, CO CH ), 3.56 (AB, J = 16.2 Hz, Δν = 22.0
2
3
2
3
AB
Hz, 2 H, CH CO CH ), 3.51 [AB, J = 12.6 Hz, Δν = 7.6 Hz, 2 H,
I
2
2
3
AB
8
CH S(O)], 2.42 (s, 3 H, ArCH ).
2
3
CO2Me
13
O
C NMR (75 MHz, CDCl ): δ = 194.2 (C=O ketone), 172.1 and 166.1
3
–
7
40 to 25 °C
9%
O
Si
(C=O and CO CH enol form) 166.9 (CO CH ), 142.4 and 139.1 (C ),
2 3 2 3 Ar
O
OTBDMS
130.2 and 124.1 (CHAr keto form), 130.0 and 124.0 (CHAr enol form),
Si
O
3) NaI
OTBDMS acetone, 0 °C
6
7.1 and 63.4 [CH S(O) ketone and CH S(O) enol], 52.5 (CO CH ), 51.6
2
2
2
3
52%
5a
and 50.7 (CH CO CH enol and CH CO CH ketone), 21.5 (ArCH ).
5
b, 1.1 equiv
2 2 3 2 2 3 3
+
Methyl (–)-[3R,(S)S]-3-Hydroxy-4-(p-tolylsulfinyl)butyrate (10)
To a solution of β-ketosulfoxide 9 (773 mg, 3.04 mmol, 1 equiv) in THF
OTBDPS
(
18 mL) was added dropwise a solution of DIBAL-H in toluene (2.45
mL, 1.5 M, 3.65 mmol, 1.2 equiv) at –78 °C. After 2 h at –78 °C, MeOH
1 mL), sat. aq solution of sodium tartrate (10 mL) and EtOAc (25 mL)
OTBDPS
PhO2S
NH
(
NaHMDS (3 equiv)
THF
O
O
were added. The mixture was vigorously stirred at r.t. until two clear
phases were obtained. The two phases were separated and the aque-
ous phase was extracted with EtOAc (2 × 30 mL). The combined or-
NH
OMe
S
–
78 to –10 °C
SO2Ph
O
O
59%
p-Tol
, 1 equiv
ganic phases were washed with brine (50 mL), dried (MgSO ), filtered,
4
Si
6
O
OMe
p-Tol
and concentrated under reduced pressure. The crude product was pu-
OTBDMS
rified by column chromatograph (SiO , CH Cl /Et O, 1:1) to afford 10
2
2
2
2
O
S
25
4
(523 mg, 2.04 mmol, 67%) as a white solid; mp 81–82 °C (Lit.
mp 81–82 °C); R = 0.3 (EtOAc); [α]D –230 (c = 2, CHCl ) {Lit. [α]D
20
25
20
f
3
Scheme 6 Synthesis of the coupling product 4 en route towards trien-
–
224 (c = 2, CHCl )}.
3
omycinol
IR (ATR): 3281 (O–H), 1732 (C=O ester), 1437, 1304, 1229, 1172, 1137,
–1
1
085, 1000, 1012, 1024, 981, 802 cm .
1H NMR (300 MHz, CDCl
): δ = 7.53 and 7.35 (d, A B , J = 8.1 Hz, 4 H,
were given in Hz. The spectra were processed with the program
Bruker TOPSIN 2.1. IR spectra of neat products were recorded on
PerkinElmer Spectrum One spectrophotometer with ATR accessory.
Mass spectra and elementary analysis were carried out by the Analyt-
ical Service of the University of Strasbourg. The angles of rotation
were measured on a PerkinElmer Polarimeter 341 and denoted as
3
2
2
CHAr), 4.60 (m, X of ABX, 1 H, CHOH), 4.16 (s, 1 H, OH), 3.67 (s, 3 H,
CO CH ), 2.92 [AB of ABX, JAB = 13.4 Hz, JAX = 9.6 Hz, JBX = 2.5 Hz,
Δν = 93.9 Hz, 2 H, CH S(O)], 2.56 (d, J = 6.1 Hz, 2 H, CH CO CH ), 2.42
2
3
2
2
2
3
(s, 3 H, ArCH
).
3
13
C NMR (75 MHz, CDCl ): δ = 171.6 (CO CH ), 141.7 and 139.6 (C ),
3
2
3
Ar
20
specific rotations: [α]D . X-ray crystal analysis was carried out by the
Radiocrystallography Service of the University of Strasbourg, France.
130.1 and 124.0 (CH
Ar), 63.6 (CHOH), 61.1 [CH
CO CH ), 21.4 (ArCH ).
S(O)], 51.9 (CO CH ),
2
2 3
40.8 (CH
2
2
3
3
Methyl (–)-(S)-3-Oxo-4-(p-tolylsulfinyl)butyrate (9)
Preparation of Compound 7 Starting from 10 (Scheme 2)
To a solution of freshly distilled (i-Pr) NH (3.84 mL, 27.17 mmol, 4
2
equiv) in THF (100 mL) was added a solution n-BuLi in hexanes (17.0
mL, 1.6 M, 27.17 mmol, 4 equiv) at –78 °C under argon. After 1 h at
Methyl (–)-[3R,(S)S]-3-Methoxy-4-(p-tolylsulfinyl)butyrate
To a solution of β-hydroxysulfoxide 10 (4.32 g, 16.84 mmol, 1 equiv)
–78 °C, methyl acetoacetate (1.50 mL, 13.58 mmol, 2 equiv) was slow-
in CH Cl was added freshly prepared Ag O (3.90 g, 16.84 mmol, 1
2
2
2
ly added and the reaction mixture was stirred for 2 h at 0 °C. To the
yellow-orange solution obtained and cooled at –78 °C was added
19
equiv). The reaction mixture was stirred at reflux for 5 h. The crude
residue was purified by column chromatography (SiO , CH Cl /Et O,
2
2
2
2
24
dropwise a solution of (SR)-(+)-menthyl p-toluenesulfinate (2.0 g,
.79 mmol, 1 equiv) in THF (40 mL). After 1 h at –78 °C, the reaction
1
:1) to afford the intermediate methyl ester (2.96 g, 10.95 mmol, 75%)
6
20
as a yellow oil; R = 0.3 (CH Cl /Et O, 1:1); [α] –216 (c = 1.00,
f
2
2
2
D
was hydrolyzed with sat. aq NH Cl (40 mL). The mixture was acidified
4
CHCl3).
with aq 5% HCl (100 mL) until pH 3. The organic phase was diluted
with EtOAc (40 mL), the two phases were separated, and the aqueous
phase was extracted with EOAc (3 × 40 mL). The combined organic
IR (ATR): 3021–2834 (C–H), 1735 (C=O ester), 1495, 1438, 1372, 1304,
–1
1
208, 1178, 1144, 1100, 1044, 1016, 815 cm .
1H NMR (300 MHz, CDCl
): δ = 7.52 and 7.31 (d, A B
, J = 8.4 Hz,
), 3.70 (s,
), 3.01–2.90 [m, AB, ABX, 2 H,
S(O)] 2.63 (AB, ABX, JAB = 15.3 Hz, JAX = 5.7 Hz, JBX = 5.7 Hz,
Δν = 9.5 Hz 2 H, CH CO CH ), 2.43 (s, 3 H, ArCH ).
C NMR (75 MHz, CDCl ): δ = 170.6 (CO CH ), 141.5 and 141.2 (C ),
phases were washed with brine (80 mL), dried (MgSO ), filtered, and
3
2
2
4
concentrated under reduced pressure. The crude product was purified
Δν = 63.3 Hz, 4 H, CHAr), 4.24 (dq, J = 7.5, 5.7 Hz, 1 H, CHOCH
3 H, CO CH ), 3.54 (s, 3 H, CHOCH
CH
3
by column chromatography (SiO , EtOAc/hexane, 1:1) to remove men-
2
3
3
2
thol and (EtOAc/hexane, 2:1 to EtOAc 100%) to give the desired ester 9
2
2
5
(
1.571 g, 6.17 mmol, 91%) as a pale yellow solid; mp 83 °C (Lit.
2
2
3
3
20
mp 83–84 °C); R = 0.21 (hexane/EtOAc, 1:1); [α] +229 (c = 1, CH-
13
f
D
3
2
3
Ar
25
20
Cl ) {Lit. [α]D +231 (c = 1, CHCl )}.
3
3
130.0 and 123.8 (CHAr), 72.1 (CHOCH3), 63.6 [CH S(O)], 58.1
2
IR (ATR): 3050–2850, 1741 and 1711 (C=O and C=O ester), 1438, 1354,
(CHOCH
), 51.8 (CO CH ), 38.6 (CH CO CH ), 21.4 (ArCH ).
3 2 3 2 2 3 3
–1
1325, 1284, 1257, 1195, 1111, 1033, 1011, 813 cm .
Anal. Calcd for C13H18O S: C, 57.76; H, 6.71. Found: C, 57.98; H, 6.72.
4
1
H NMR (300 MHz, CDCl ): δ = 11.90 (s, 1 H, H enol form), 7.52 and
3
7
.5 (A B , J = 8.3 Hz, Δν = 34.8 Hz, 4 H, CH p-Tol), 5.10 (s, 1 H, =CHOH,
2
2
A
r
vinylic enol), 3.97 [AB, JAB = 13.4 Hz, Δν = 29 Hz, 2 H, CH S(O)], 3.74 (s,
2
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

F
Synthesis
S. Choppin et al.
Paper
(
–)-[3R,(S)S]-3-Methoxy-4-(p-tolylsulfinyl)butanoic Acid (7)
1H NMR (300 MHz, CDCl ): δ = 4.33 (td, J = 6.3, 1.8 Hz,
1
H,
CHOTBDMS), 2.36 (d, J = 2.1 Hz, 1 H, C≡CH), 1.71–1.63 (m, 2 H,
CH CHOTBDMS), 1.45–1.27 [m, 6 H, (CH ) CH CHOTBDMS], 0.93–0.91
3
To a solution of the above intermediate methyl ester (2.75 g, 10.17
mmol, 1 equiv) in MeOH (17 mL) was added dropwise a solution of 1
N aq KOH (17.30 mL, 17.30 mmol, 1.7 equiv) at 0 °C. The reaction
mixture was stirred 1 h at 0 °C and 2 h at r.t. The mixture was diluted
with CH Cl (20 mL) then acidified to pH 2 with 10% aq HCl. The aque-
2
2
3
2
(
m, 3 H, CH ), 0.90 (s, 9 H, t-C H ), 0.13 and 0.12 [2 s, 6 H, Si(CH ) t-
3
4
9
3
2
Bu].
13C NMR (75 MHz, CDCl ): δ = 85.7 (C≡CH), 76.9 (C≡CH), 62.7
2
2
3
ous phase was extracted with CH Cl (3 × 50 mL). The combined or-
(CHOTBDMS), 38.5 (CH CHOTBDMS), 31.4 (CH ), 25.9 [C(CH ) ], 24.8
2
2
2
2
3 3
ganic extracts were dried (Na SO ), filtered, and evaporated under re-
and 22.5 (CH CH ), 18.1 [C(CH ) ], 13.9 (CH3), –4.2 and –4.8
2
4
2 2 3 3
duced pressure. The resulting crude was recrystallized from Et O to
[Si(CH ) t-Bu].
3 2
2
give butanoic acid 7 (2.22 g, 8.66 mmol, 85%) as a white solid;
HRMS (ESI+): m/z (M + Na) calcd for C14H28OSiNa: 263.1812; found:
63.1831.
20
mp 91 °C; R = 0.1 (EtOAc); [α] –213.5 (c = 1.00, CHCl3).
f
D
2
IR (ATR): 2980–2500, 1717 (C=O acid), 1305, 1259, 1230, 1178, 1101,
–
1
1
1
087, 1069, 1019, 1000, 978, 818, 806 cm .
Methyl 4-(tert-Butyldimethylsilyloxy)non-2-ynoate (12)
H NMR (300 MHz, CDCl ): δ = 79.40 (s, 1 H, CO H), 7.55 and 7.30 (d,
J = 8.3 Hz A B , 4 H, CH ), 4.24–4.27 (m, 1 H, CHOCH ), 3.53 (s, 3 H,
CHOCH ), 3.09 [AB, ABX, J = 13.4 Hz, JAX = 2.8 Hz, JBX = 10.0 Hz,
Δν = 139.3 Hz, 2 H, CH S(O)], 2.63 (AB, ABX, J = 15.0 Hz, JAX = 4.6 Hz,
3
2
To a solution of protected oct-1-ynol 11 (2.02 g, 8.37 mmol, 1 equiv)
in anhyd THF (74 mL) at –78 °C was added dropwise a solution of BuLi
in hexanes (5.8 mL, 1.6 M, 9.25 mmol, 1.1 equiv). The mixture was
stirred at –78 °C for 1 h and then methyl chloroformate (0.965 mL,
12.55 mmol, 1.5 equiv) was added dropwise. The solution was
warmed to r.t. over 2 h and stirred at r.t. for an additional 2 h. The
2
2
Ar
3
3
AB
2
AB
JBX = 7.7 Hz, Δν = 90.5 Hz, 2 H, CH CO H), 2.40 (s, 3 H, ArCH ).
2
2
3
13
C NMR (75 MHz, CDCl )): δ = 172.9 (CO H), 141.9 and 139.8 (C ),
3
2
Ar
1
30.1 and 124.3 (CHAr), 72.2 (CHOCH3), 63.2 [CH S(O)], 57.8
reaction mixture was diluted with Et
aq NaHCO (50 mL), H O (50 mL), and brine (50 mL). The organic
phase was dried (Na SO ), filtered, and concentrated under reduced
2
O (50 mL) and washed with sat.
2
(CHOCH ), 38.2 (CH CO H), 21.4 (ArCH ).
3
2
3
2
2
3
2
4
Anal. Calcd for C12H16O S: C, 56.23; H, 6.29. Found: C, 56.28; H, 6.29.
4
pressure. The crude product was purified by column chromatography
SiO , cyclohexane/CH Cl , 6:4) to give 12 (1.90 g, 6.36 mmol, 76%) as
(
2
2
2
X-ray Crystallographic Data for 7
a colorless oil; R = 0.34 = (cyclohexane/CH Cl , 6:4).
f
2
2
White crystals; monoclinic. At 173 K, a = 11.6939(5), b = 7.5299(3),
c = 15.6209(7) Å; β = 110.0530(10)°; V = 1292.09 Å ; M = 256.21; Z =
1
H NMR (300 MHz, CDCl ): δ = 4.43 (t, J = 6.3 Hz, 1 H, CHOTBDMS),
3
3
3
.23 (s, 3 H, CO CH ), 1.73–1.66 (m, 2 H, CH CHOTBDMS), 1.44–1.25
2
3
2
4; space group P 21.
[
m, 6 H, (CH ) CH CHOTBDMS], 0.92–0.89 (m, 3 H, CH ), 0.88 (s, 9 H,
2
3
2
3
Full details, including bond lengths and bond angles have been sub-
mitted to the Cambridge Crystallographic Data Centre (CCDC
t-C H ), 0.13 and 0.09 [2 s, 6 H, Si(CH ) t-Bu].
4
9
3 2
13
C NMR (75 MHz, CDCl ): δ = 154.0 (C=O), 89.3 (C≡C–CO Me), 75.6
21
3
2
1486380).
(
C≡C–CO Me), 62.6 (CHOTBDMS), 52.6 (OCH ), 37.7 (CH CHOTBDMS),
2
3
2
3
1.3 (CH ), 25.7 [C(CH ) ], 24.6 and 22.5 (CH CH ), 18.1 [C(CH ) ], 13.2
2 3 3 2 2 3 3
(
3-Benzenesulfonylmethyl-5-tert-butyldiphenylsilyloxy)aniline
(CH ), –4.6 and –5.1 [Si(CH ) t-Bu].
3
3
2
(8)
HRMS (ESI+): m/z (M + Na) calcd for C16H30O SiNa: 321.1868; found:
3
Compound 8 was prepared using the procedure described by Smith
and starting from the commercially available 3,5-dinitrobenzoic acid.
Its physical data were in agreement with the literature data. The
compound 8 was obtained as a white solid; mp 46–48 °C; R = 0.65
321.1871.
8b
Methyl (Z)-4-(tert-Butyldimethylsilyloxy)-3-methylnon-2-enoate
13)
f
(
(cyclohexane/EtOAc, 1:2).
To a suspension of CuI (0.452 g, 2.38 mmol, 3.3 equiv) in THF (11.6
mL) cooled to 0 °C was added a solution of MeLi in Et O (2.7 mL, 1.6
IR (ATR): 3469–2857, 1592, 1315, 1306, 1296 cm–1
1
.
2
H NMR (300 MHz, CDCl ): δ = 7.65–7.34 [m, 15 H, SO C H and
3
2
6
5
M, 4.32 mmol, 6 equiv). The resulting colorless solution was stirred at
0 °C for 1 h. The mixture was cooled to –25 °C. This solution of methyl
cuprate was added to a solution of alkyne 12 (0.214 g, 0.720 mmol, 1
equiv) in THF (23.5 mL) at –25 °C with syringes previously cooled
with dry ice. The resulting pale yellow solution was stirred at –20 °C
Si(C H ) ], 6.04–6.03 (m, 1 H, CH ) 5.98–5.97 (m, 1 H, CH ), 5.87–
5
H, t-C H ).
1
6
5
2
Ar
,
Ar
.86 (m, 1 H, CH ), 4.05 (s, 2 H, CH SO Ph), 3.39 (s, 2 H, NH ) 1,05 (s, 9
Ar 2 2 2
4
9
3
C NMR (75 MHz, CDCl ): δ = 156.5 (COTBDPS), 146.7 (CNH ), 137.9
3
2
(
C , SO C H ), 135.5, 133.5, 132.8, 128.7, 128.6, 127.8 [CH , SO C H
for 2 h. The reaction was quenched by the addition of sat. aq NH
sat. aq NH OH, and H O (1:1:1, 10 mL). The two phases were separat-
ed and the aqueous phase was extracted with Et O (3 × 10 mL), the
combined organic extracts were dried (Na SO ), filtered, and concen-
4
Cl,
Ar
2
6
5
Ar
2
6
5
and Si(C H ) ], 129.9 [C , Si(C H ) ], 129.8 (C –CH SO Ph), 113.2
4
2
6
5
2
Ar
6
5
2
Ar
2
2
(CH ) 110.9 (CH ), 107.2 (C ), 62.8 (CH SO Ph), 26.5 [C(CH ) ], and
2
Ar
Ar
Ar
2
2
3 3
1
9.4 [C(CH ) ].
2
4
3
3
trated under reduced pressure. The crude product was purified by
column chromatography (SiO , cyclohexane/CH Cl , 1:1) to afford 13
tert-Butyldimethyl(oct-1-ynyloxy)silane (11)
2
2
2
1
(0.19 g, 0.69 mmol, 96%) as a colorless oil; Z/E ratio = 98:2 ( H NMR
A solution of oct-1-yn-3-ol (4 g, 31.70 mmol, 1 equiv), imidazole (5.4
g, 79.25 mmol, 2.5 equiv), and tert-butyldimethylsilyl chloride (7.2 g,
analysis); R = 0.3 (cyclohexane/CH Cl , 1:1).
f
2
2
1
H NMR (300 MHz, CDCl ): δ = 5.61 [s, 1 H, C(CH )=CHCO CH ], 5.58–
47.50 mmol, 1.5 equiv) in anhyd DMF (210 mL) was stirred at r.t. for 4
3
3
2
3
5
.54 (m, 1 H, CHOTBDMS), 3.67 (s, 3 H, CO CH ), 1.87 [d, J = 1.5 Hz, 3
h. The mixture was diluted with Et O (100 mL), and the Et O layer was
2 3
2
2
H, C(CH )=CHCO CH ], 1.57–1.51 (m, 2 H, CH CHOTBDMS), 1.43–1.25
washed with H O (100 mL) and brine (100 mL). The organic phase
3
2
3
2
2
[
m, 6 H, (CH ) CH CHOTBDMS], 0.93–0.90 (m, 3 H, CH ), 0.88 (s, 9 H,
was dried (Na SO ), filtered, and concentrated under reduced pres-
2
3
2
3
2
4
t-C H ), 0.05 and –0.023 [2 s, 6 H, Si(CH ) t-Bu].
sure. The crude product was purified by column chromatography
SiO , cyclohexane/CH Cl , 7:3) to give 11 (7.39 g, 30.75 mmol, 97%)
4
9
3 2
(
2
2
2
as a pale yellowish oil; R = 0.25 (cyclohexane/CH Cl , 7:3).
f
2
2
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

G
Synthesis
S. Choppin et al.
Paper
13
C NMR (75 MHz, CDCl ): δ = 166.2 (C=O), 163.6 (=CCH ), 114.8 (CH-
3 H, C(CH )=CHCH Cl], 1.65–1.56 (m, 2 H, CH CHOTBDMS), 1.41–1.23
3
3
3
2
2
CO Me), 69.7 (CHOTBDMS), 50.9 (OCH ), 36.5 (CH CHOTBDMS), 31.7
[m, 6 H, (CH ) CH CHOTBDMS], 1.18–1.10 (m, 3 H, CH ), 0.89 (s, 9 H,
2
3
2
2
3
2
3
(
CH ), 26.9 [C(CH ) ], 25.8 and 25.3 (CH CH ), 22.6 (=CCH ), 18.6
t-C H ), 0.07 and 0.02 [2 s, 6 H, Si(CH ) t-Bu].
4 9 3 2
2
3
3
2
2
3
[
C(CH ) ], 14.0 (CH ), –5.0 [Si(CH ) t-Bu].
13
3
3
3
3
2
C NMR (75 MHz, CDCl ): δ = 144.9 (=CCH ), 120.9 (CHCH Cl), 70.4
3 3 2
Anal. Calcd for C17H34O Si: C, 64.92; H, 10.90. Found: C, 65.08; H,
(CHOTBDMS), 39.8 (CH Cl), 36.6 (CH CHOTBDMS), 36.4 (CH ), 26.0
3
2
2
2
10.90.
[C(CH ) ], 25.4 and 22.6 (CH CH ), 18.3 (=CCH ), 17.5 [C(CH ) ], 14.0
3 3 2 2 3 3 3
(
CH ), –4.8 and –5.0 [Si(CH ) t-Bu].
3
3
2
(
Z)-4-(tert-Butyldimethylsilyloxy)-3-methylnon-2-en-1-ol (14)
Anal. Calcd for C16H33ClOSi: C, 63.01; H, 10.91. Found: C, 63.45; H,
11.02.
To a solution of ester 13 (0.41 mg, 1.31 mmol, 1 equiv) in THF (3.6 mL)
was added a solution of DIBAL-H in toluene (3.29 mL, 1.0 M, 3.29
mmol, 2.5 equiv) at –78 °C. The resulting mixture was stirred for 2 h
at this temperature. The reaction was quenched with MeOH (10 mL),
diluted with EtOAc (100 mL), and treated with a sat. aq solution of di-
sodium L-tartrate (100 mL). The mixture was vigorously stirred at r.t.
overnight (until two clear phases were obtained). The two phases
were separated and the aqueous phase was extracted with EtOAc
(Z)-tert-Butyl(1-iodo-3-methylnon-2-en-4-yloxy)dimethylsilane
(15)
To a solution of allylic chloride prepared as above (78 mg, 0.256
mmol, 1 equiv) in anhyd acetone (2.2 mL) was added NaI (0.153 mg,
1.02 mmol, 4 equiv) at r.t.. After 1.5 h at this temperature, the solution
was concentrated under reduced pressure. The residue was filtered
on a short pad of neutral alumina (EtOAc/hexane, 3:7) to give the un-
stable iodide 15 (97 mg, 0.248 mmol, 97%) as a pale yellowish oil;
Rf = 0.2 (EtOAc/hexane, 3:7).
(3 × 50 mL). The combined organic extracts were dried (Na SO ), fil-
2 4
tered, and concentrated under reduced pressure. The crude product
was purified by column chromatography (SiO , CH Cl /cyclohexane,
7
2
2
2
:3) to give 14 (0.308 g, 1.07 mmol, 82%) as a colorless oil; R = 0.45
f
1
H NMR (300 MHz, CDCl ): δ = 5.67 [t, J = 17.4 Hz, C(CH )=CHCH I, 1
3
3
2
(CH Cl /cyclohexane, 7:3).
2 2
H], 4.49 (td, J = 8.4 and 4.5 Hz, CHOTBDMS, 1 H), 3.94 [d, J = 10.5 Hz,
C(CH )=CHCH I, 2 H], 2.04 [s, 3 H, C(CH )=CHCH I], 1.68–1.57 (m, 2 H,
1H NMR (300 MHz, CDCl ): δ = 5.33 [t, J = 6.6 Hz,
C(CH )=CHCH OH], 4.38 (t, J = 7.2 Hz, 1 H, CHOTBDMS), 4.13 [AB part
of ABX, JAB = 20.1 Hz, JAX = 12.9 Hz, JBX = 7.5 Hz, Δν = 36.8 Hz, 2 H,
C(CH )=CHCH OH], 1.67 [s, 3 H, C(CH )=CHCH OH], 1.61–1.52 (m, 2 H,
CH CHOTBDMS), 1.40–1.15 [m, 6 H, (CH ) CH CHOTBDMS], 1.11–1.02
1
H,
3
3
2
3
2
3
2
CH CHOTBDMS), 1.41–1.26 [m, 6 H, (CH ) CH CHOTBDMS], 1.14–1.10
2
2
3
2
(m, 3 H, CH ), 0.89 (s, 9 H, t-C H ), 0.08 and 0.02 [2 s, 6 H, Si(CH ) t-
3
4
9
3 2
3
2
3
2
Bu].
2
2
3
2
(
m, 3 H, CH ), 0.86 (s, 9 H, t-C H ), 0.02 and –0.02 [2 s, 6 H, Si(CH ) t-
3
4
9
3
2
Preparation of Compound 5b Starting from 5a (Scheme 6)
Bu].
13
C NMR (75 MHz, CDCl ): δ = 142.1 (=CCH ), 124.3 (CHCH OH), 70.9
3
3
2
(
–)-(Z)-3{(4R,5S,6S)-2,2-Di-tert-butyl-6-[2-(tert-butyldimethyl-
(
CHOTBDMS), 58.7 (CH OH), 36.5 (CH CHOTDBMS), 31.8 (CH ), 25.8
2
2
2
silyloxy)ethyl]-5-methyl-1,3,2-dioxasilinan-4-yl}but-2-en-1-ol
[
C(CH ) ], 25.5 and 22.6 (CH CH ), 18.4 [C(CH ) ], 14.0 (CH ), –4.8 and
3 3 2 2 3 3 3
Starting from ester 5a15 (65 mg, 0.134 mmol, 1 equiv) the same proce-
dure as described for the preparation of compound 12 was used. The
crude product was purified by column chromatograph (SiO , CH Cl )
to afford the corresponding alcohol (49 mg, 0.108 mmol, 81%) as a
colorless oil; R = 0.33 (CH Cl ); [α] –18 (c = 0.5, CHCl3).
–
5.0 [Si(CH ) t-Bu].
3 2
HRMS (ESI+): m/z (M + Na) calcd for C16H34O SiNa: 309.2229; found:
2
2
2
2
3
09.2213.
Synthesis of Compound 15 Starting from 14 (Scheme 5)
Z)-tert-Butyl(1-chloro-3-methylnon-2-en-4-yloxy)dimethylsilane
20
f
2
2
D
1
H NMR (300 MHz, CDCl ): δ = 5.57 (t, J = 6.6 Hz, CHCH OH, 1 H), 4.98
3
2
(d, J = 4.5 Hz, CHC(CH )=CHCH OH,
1
H), 4.18 (t, J = 5.7 Hz,
3
2
(
CHCH CH OTBDMS, 2 H), 4.12–4.06 (m, 1 H, CHCH CH OTBDMS),
2
2
2
2
Me S (38.8 μL, 0.53 mmol, 1.6 equiv) was added dropwise to a solu-
3.86–3.73 (m, 2 H, CH OH), 1.95–1.84 (m, 1 H, CHCH ), 1.77–1.70 (m,
2
2
3
tion of N-chlorosuccinimide (57.5 mg, 0.43 mmol, 1.3 equiv) in CH Cl2
2 H, CHCH CH OTBDMS), 1.75 [s, 3 H, C(CH )=CHCH OH], 1.06 and
2 2 3 2
2
(1.2 mL) cooled to –40 °C. The mixture was stirred for 10 min at 0 C
1.03 (2 s, 18 H, 2 × t-C H ), 0.94 (d, J = 7.2 Hz, 3 H, CH ), 0.89 (s, 9 H, t-
4
9
3
and a white precipitate was observed. Then, the reaction mixture was
cooled to –40 °C and a solution of allylic alcohol 14 (95 mg, 0.33
mmol, 1 equiv) in CH Cl (0.2 mL) was added via a cannula. The mix-
ture was warmed to 0 °C over 1 h, stirred at 0 °C for 2 h, and stirred at
r.t. for 1 h. The reaction mixture was quenched with brine (5 mL) at
C H of TBDMS), 0.05 [s, 6 H, Si(CH ) t-Bu].
4 9 3 2
13
C NMR (75 MHz, CDCl ): δ = 139.6 (=CCH ), 127.3 (CHCH OH), 74.6
3
3
2
2
2
and 74.4 (2 × CHOSi), 60.0 (CH OH), 59.0 (CH OTDBMS), 41.3 (CHCH ),
2
2
3
4
1.0 (CH CH OTBDMS), 28.3 and 28.2 {Si[C(CH ) ] }, 26.4 [C(CH ) of
2 2 3 3 2 3 3
TBDMS], 22.2 and 22.1 {Si[C(CH ) ] }, 22.0 (=CCH ), 18.7 [C(CH ) of
3
3
2
3
3 3
0
°C. The two phases were separated and the aqueous phase was ex-
TBDMS], 14.1 (CHCH ), –4.9 [Si(CH ) t-Bu].
3
3 2
tracted with CH Cl (3 × 10 mL). The combined organic extracts were
2
2
HRMS (ESI+): m/z (M + Na) calcd for C24H50O Si Na: 481.3129; found:
4
2
dried (Na SO ), filtered, and concentrated under reduced pressure.
2
4
481.3142.
The residue was dissolved in a mixture hexane/H O (4:1, 25 mL), the
2
two phases were separated, and the aqueous phase was extracted
with hexane (3 × 10 ml).The combined organic extracts were dried
[
4S,5S,6R]-2,2-Di-tert-butyl-4-[2-(tert-butyldimethylsilyloxy)eth-
yl]-6-[(Z)-4-chlorobut-2-en-2-yl]-5-methyl-1,3,2-dioxasilinane
(
Na SO ), filtered, and concentrated under reduced pressure to give
2 4
the allylic chloride (85.54 mg, 0.280 mmol, 85%) as a colorless oil,
which was used in the next step without any additional purification;
R = 0.26 (CH Cl /cyclohexane, 7:3).
Starting from the above allylic alcohol (57 mg, 0.11 mmol, 1 equiv),
the same procedure was performed as for the allylic chloride from 14.
The desired allylic chloride obtained (39 mg, 0.09 mmol, 79%) was
used in the next step without any additional purification; colorless
f
2
2
1
H NMR (300 MHz, CDCl ): δ = 5.39 [t, J = 8.1 Hz, 1 H, C(CH )=CHCH Cl],
3
3
2
20
oil; R = 0.40 (CH Cl /hexane, 7:3); [α]
–25 (c = 0.44, CHCl3).
4.48–4.44 (m, 1 H, CHOTBDMS), 4.27 [AB part of ABX, JAB = 20.1 Hz,
f
2
2
D
JAX = 11.7 Hz, JBX = 8.7 Hz, Δν = 17.9 Hz, 2 H, C(CH )=CHCH Cl], 1.73 [s,
3
2
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

H
Synthesis
S. Choppin et al.
Paper
1
H NMR (300 MHz, CDCl ): δ = 5.53 (t, J = 8.1 Hz, 1 H, CHCH Cl), 5.11
(3R)-N-{3-[(Z)-5-(tert-Butyldimethylsilyloxy)-4-methyl-1-(phe-
nylsulfonyl)dec-3-enyl]-5-(tert-butyldiphenylsilyloxy)phenyl}-3-
methoxy-4-[(S)-p-tolylsulfinyl]butanamide (16)
3
2
[
d, J = 6.3 Hz,
1 H, CHC(CH )=CH Cl], 4.27–4.17 (m, 3 H,
3 2
CHCH CH OTBDMS + CHCH CH OTBDMS), 3.86 (d, J = 5.7 Hz, 2 H,
2
2
2
2
CH Cl), 2.12 (q, J = 7.2 Hz, 1 H,CHCH ), 1.83 [s, 3 H, CHC(CH )=CH Cl],
2
3
3
2
To a solution of sulfone 6 (46.5 mg, 0.063 mmol, 1 equiv) and freshly
prepared allylic iodide 15 (27.4 mg, 0.069 mmol, 1.1 equiv) in THF
(1.1 mL) cooled to –78 °C was added dropwise NaHMDS in THF (189
μL, 1.0 M, 0.189 mmol, 3 equiv). The solution immediately turned
flashy yellow and was progressively warmed to –10 °C over a period
of 3 h. The reaction mixture was quickly poured into a vigorously
1
.81–1.75 (m, 1 H, CHCH CH OTBDMS), 1.06 and 1.03 (2 s, 18 H, 2 × t-
2 2
C H ), 0.94 (d, J = 7.2 Hz, 3 H, CHCH ), 0.89 (s, 9 H, t-C H of TBDMS),
4
9
3
4
9
0
.05 [s, 6 H, Si(CH ) t-Bu].
3 2
13
C NMR (75 MHz, CDCl ): δ = 141.4 (=CCH ), 123.8 (CHCH Cl), 77.8
3
3
2
and 73.1 (2 × CHOSi), 61.7 (CH Cl), 59.6 (CHCH CH OTBDMS), 41.7
2
2
2
(
[
[
CHCH ), 41.2 (CHCH CH OTBDMS), 27.9 and 27.5 {Si[C(CH ) ] }, 26.0
stirred mixture of pH 7 buffer [prepared by mixing 500 mL of KH
[0.1 M aq solution) and 290 mL of NaOH (0.1 M aq solution)] and Et
2
PO
4
3
2
2
3 3 2
C(CH3)3 of TBDMS], 21.9 and 21.7 {Si[C(CH ) ] }, 21.3 (=CCH ), 18.4
2
O
3
3
2
3
C(CH ) of TBDMS], 14.2 (CHCH ), –5.27 [Si(CH ) t-Bu].
(1:1, 10 mL) at 0 °C. The two phases were separated and the aqueous
phase was extracted with EtOAc (3 × 10 mL). The combined organic
extracts were dried (Na SO ), filtered, and concentrated under re-
3
3
3
3 2
HRMS (ESI+): m/z (M + Na) calcd for C24H49ClO Si Na: 501.2787;
found: 501.2803.
3
2
2
4
duced pressure. The crude product was purified by column chroma-
tography (CH Cl /EtOAc, 1:1) to give the coupling product 16 (52.7
mg, 0.052 mmol, 83%) as a complex mixture of diastereomers; pale
2
2
[
4S,5S,6R]-2,2-Di-tert-butyl-4-[(2-tert-butyldimethylsilyloxy)eth-
yl]-6-[(Z)-4-iodobut-2-en-2-yl]-5-methyl-1,3,2-dioxasilinane (5b)
yellowish oil; R = 0.6 (CH Cl /EtOAc, 1:1).
f
2
2
Starting from the above allylic chloride (42.5 mg, 0.09 mmol, 1 equiv)
the same procedure as described for the preparation of the allylic io-
dide 15 was used. The allylic iodide 5b (26.3 mg, 0.05 mmol, 52%) was
obtained as an unstable pale yellowish oil. It was immediately used in
1
H NMR (400 MHz, CDCl ): δ (mixture of diastereomers) = 7.98, 7.95
3
(
2 s, 1 H, NH), 7.64 (m, 4 H, CH ), 7.55–7.30 (m, 15 H, CH ), 7.14, 7.11
Ar
Ar
(
2 s, 1 H, CHAr), 6.79, 6.77 (2 s, 1 H, CH ), 6.24, 6.21 (2 s, 1 H, CH ),
A
r
A
r
4
.54–4.53 (m, 1 H, CHSO Ph), 4.32–4.26 (m, 1 H, CHOTBS), 4.21–4.13
2
the next step; R = 0.8 (EtOAc/hexane, 3:7).
f
(m, 1 H, CHOMe), 3.67–3.57 (m, 1 H, C(CH )=CHCH CHSO Ph), 3.50 (s,
3 2 2
1
H NMR (300 MHz, CDCl ): δ = 5.61 (t, J = 8.4 Hz, 1 H, CHCH I), 5.08 [d,
3
2
3 H, OCH ), 3.02–2.86 [m, 2 H, CH S(O)], 2.74–2.68 (m, 1 H, CH C=O),
2.49–2.32 (m, 6 H, ArCH3 + CH C=O + CH CHSO Ph), 1.49 [s, 3 H,
2 2 2
C(CH )=CHCH CHSO Ph], 1.33–1.16 [m, 11 H, CH(OTBS)(CH ) CH ],
1.07 and 0.85 (2 s, 18 H, 2 × t-C H ), –0.02 and –0.11 [2 s, 6 H,
4 9
Si(CH ) t-Bu].
13
3
2
2
J = 4.5 Hz,
1
H, CHC(CH )=CH I], 4.23–4.16 (m,
2
H,
3
2
CHCH CH OTBDMS), 4.14–3.98 (m, 1 H, CHCH CH OTBDMS), 3.88–
2
2
2
2
3
2
2
2
4
3
3
.71 (m, 2 H, CH I), 2.07–1.91 (m, 1 H, CHCH ), 1.80–1.72 (m, 2 H,
2
3
CHCH CH OTBDMS), 1.74 [s, 3 H, CHC(CH )=CH I], 1.07 and 1.06 (2 s,
2
2
3
2
3 2
1
8 H, 2 × t-C H ), 0.99 (d, J = 7.5 Hz, 3 H, CHCH ), 0.90 (s, 9 H, t-C H of
4
9
3
4
9
C NMR (100 MHz, CDCl ): δ (mixture of diasteromers) = 167.4
3
TBDMS), 0.06 [s, 6 H, Si(CH ) t-Bu].
3
2
(C=O), 156.2, 142.1, 140.7 (C ), 139.0 and 138.7 (=CCH ), 138.9, 138.2,
A
r
3
1
1
1
37.6 (C ), 135.7, 133.5 (CH ), 132.5 (C ), 131.3, 130.4, 129.1, 128.8,
Ar Ar Ar
(
–)-[3R,(S)S]-N-[3-Benzenesulfonylmethyl-5-(tert-butyldiphenyl-
27.9, 124.0 (CH ), 123.9 and 123.8 [C(CH )=CHCH CHSO Ph], 118.8,
Ar
3
2
2
silyloxy)phenyl]-3-methoxy-4-(p-tolylsulfinyl)butyramide (6)
18.6, 112.2 (CH ), 73.1 and 72.8 (CHOTBDMS), 71.4 and 71.3 (CH-
Ar
To a solution of 7 (588 mg, 2.30 mmol, 1.05 equiv) and aniline 8
SO Ph), 71.1 (CHOMe), 62.4 [CH S(O)p-Tol), 58.2 (OCH3), 49.3
2
2
(
1.097 g, 2.19 mmol, 1 equiv) in CH Cl was added DCC (529 mg, 2.51
[CH C(O)NH], 41.5, 36.5, 34.1, 32.1 (4 × CH ), 26.7 and 25.9 [C(CH ) ],
2
2
2
2
3
3
mmol, 1.15 equiv), DMAP (0.053 mg, 0.44 mmol, 0.2 equiv), and PPTS
0.166 mg, 0.66 mmol, 0.3 equiv) and the mixture was stirred at r.t.
25.0 (CH CHSO Ph), 22.8 (ArCH3), 21.6 (=CCH3), 18.3 and 18.0
2 2
(
[C(CH ) ], 14.2 [(CH ) CH ], –4.6 [Si(CH ) (t-Bu)].
3 3 2 4 3 3 2
for 15 h. The mixture was concentrated under reduced pressure and
the crude reaction mixture was pre-purified by column chromatogra-
phy (SiO , ETOAc/CH Cl , 1:1). The crude product was dissolved in a
HRMS (ESI+): m/z (M + Na) calcd for C57H77NO S Si Na: 1031.4610;
found: 1031.4574.
7
2
2
2
2
2
minimum amount of CH Cl and cyclohexane was added. The precipi-
tation of a white solid (1.30 g, 1.75 mmol, 80%) occurred after keeping
2
2
(
3R)-N-[3-(tert-Butyldiphenylsilyloxy)-5-((Z)-4-{(4R,5S,6S)-2,2-di-
tert-butyl-6-[2-(tert-butyldimethylsilyloxy)ethyl]-5-methyl-1,3,2-
dioxasilinan-4-yl}-1-(phenylsulfonyl)pent-3-enyl)phenyl]-3-
methoxy-4-[(S)-p-tolylsulfinyl]butanamide (4)
the mixture overnight in the fridge; mp 77–80 °C; R = 0.20 (EtOAc/
f
20
CH Cl , 1:1); [α] –59.9 (c = 1, CHCl3).
2
2
D
IR (ATR): 3027, 3072, 2931, 2858, 1686, 1599, 1553, 1460, 1428, 1307,
To a solution of sulfone 6 (28 mg, 0.037 mmol, 1 equiv) and freshly
prepared allylic iodide 5b (23.7 mg, 0.042 mmol, 1.1 equiv) in THF
(0.7 mL) cooled to –78 °C was added NaHMDS in THF dropwise (111
μL, 1.0 M, 0.111 mmol, 3 equiv). The solution immediately turned
flashy yellow and was progressively warmed to –10 °C over 3 h. The
reaction mixture was quickly poured into a vigorously stirred mix-
ture of pH 7 buffer and Et O (1:1, 10 mL) at 0 °C. The two phases were
separated and the aqueous phase was extracted with EtOAc (3 × 10
mL). The combined organic extracts were dried (Na
concentrated under reduced pressure. The crude product was puri-
fied by column chromatography (SiO , CH Cl /EtOAc, 1:1). The cou-
pling product 4 (25.78 mg, 0.022 mmol, 59%) was obtained as a com-
–1
1
151, 1106, 1085, 1028, 820, 741, 700, 688 cm .
1
H NMR (300 MHz, CDCl ): δ = 7.99 (br s, 1 H, NH), 7.67–7.33 (m, 19
3
H, ArH), 7.00 (s, 1 H, ArH), 6.87 (s, 1 H, ArH), 6.22 (s, 1 H, ArH), 4.17
(
m, 1 H, CHOCH ), 4.07 (s, 2 H, CH SO Ph), 3.50 (s, 3 H, OCH ) 2.95 [AB
3
2
2
3
of ABX, 2 H, JAB = 13.5 Hz, CH S(O), J = 4.8 Hz, JBX = 8.1 Hz, Dn = 23.1
2
AX
Hz], 2.60 [AB of ABX, 2 H, JAB = 14.7 Hz, CH C(O)NH, J = 4.2 Hz,
2
AX
2
JBX = 5.7 Hz, Dn = 73.6 Hz] 2.43 (s, 3 H, ArCH ) 1.08 (s, 9 H, Sit-C H ).
3
4
9
13
C NMR (75 MHz, CDCl ): δ = 167.4 [C(O)NH], 155.9 (COTBDPS),
2 4
SO ), filtered, and
3
1
41.8 and 138.9 (C , p-Tol) 140.5 (C –NH) 137.8 (C –SO Ph) 135.4,
Ar
Ar
Ar
2
1
33.5, 130.1, 130.0 (CH ), 128.7, 128.4, 127.7, 123.8, 132.4 (C ,
2
2
2
Ar
Ar
Si(C H ) ], 129.3 (C –CH SO Ph), 117.7 (CH ) 114.9 (CH ), 111.6
6
5
2
Ar
2
2
Ar
Ar
(
(
[
CH ), 72.9 (CHOCH ), 62.4 [2 × CH SO Ph and CH S(O)p-Tol], 57.9
plex mixture of diastereomers; colorless oil; R = 0.53 (CH Cl /EtOAc,
1:1).
f 2 2
Ar
3
2
2
2
CHOCH ), 41.2 [CH C(O)NH], 26.4 [SiC(CH ) ], 21.4 (ArCH ), 19.5
3
2
3
3
3
SiC(CH ) ].
1
3
3
H NMR (300 MHz, CDCl ): δ = 7.93, 7.92 (2 s, 1 H, NH), 7.71–7.62 (m,
3
4
7
H, CH ), 7.55–7.52 (m, 3 H, CH ), 7.47–7.29 (m, 12 H, CH ), 7.13,
Ar Ar Ar
.10 (2 s, 1 H, CH ), 6.75, 6.74 (2 s, 1 H, CHAr), 6.26, 6.25 (2 s, 1 H,
Ar
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

I
Synthesis
S. Choppin et al.
Paper
CH ), 4.96–4.93 [m, 1 H, C(CH )=CHCH CHSO Ph], 4.72–4.58 (m, 1 H,
(7) (a) Smith, A. B. III; Wood, J. L.; Wong, W.; Gould, A. E.; Rizzo, C. J.
J. Am. Chem. Soc. 1990, 112, 7425. (b) Smith, A. B. III; Wood, J. L.;
Wong, W.; Gould, A. E.; Rizzo, C. J.; Barbosa, J.; Komiyama, K.;
Omura, S. J. Am. Chem. Soc. 1996, 118, 8308.
Ar
3
2
2
CHSO Ph), 4.27–4.13 [m,
3
H, CHC(CH )=CHCH CHSO Ph
+
2
3
2
2
CHCH CH OTBDMS], 4.08–4.03 (m, 1 H, CHOMe), 3.84–3.74 (m, 3 H,
2
2
CHCH CH OTBDMS + CH CHSO Ph), 3.50, 3.48 (2 s, 3 H, OCH ), 3.11–
2
2
2
2
3
2
.86 [m, 2 H, CH S(O)], 2.74–2.68 (m, 1 H, CH C=O), 2.49–2.27 (m, 1 H,
(8) (a) Smith, A. B. III; Barbosa, J.; Wong, W.; Wood, J. L. J. Am. Chem.
Soc. 1995, 117, 10777. (b) Smith, A. B. III; Barbosa, J.; Wong, W.;
Wood, J. L. J. Am. Chem. Soc. 1996, 118, 8316.
2
2
CH C=O), 2.41 (s, 3 H, ArCH ), 1.94–1.85 (m, 1 H, CHCH ), 1.74–1.55
2
3
3
(
m,
2
H, CHCH CH OTBDMS), 1.61, 1.59 [2 s,
3
H,
2
2
CHC(CH )=CHCH CHSO Ph], 1.07 and 1.04 (2 s, 18 H, 2 × t-C H ), 1.03
(9) Del Valle, D. J.; Krische, M. J. J. Am. Chem. Soc. 2013, 135, 10986.
(10) (a) Panek, J. S.; Masse, C. E. J. Org. Chem. 1997, 62, 8290.
(b) Evano, G.; Schaus, J. V.; Panek, J. S. Org. Lett. 2004, 6, 525.
(11) Hayashi, Y.; Shoji, M.; Ishikawa, H.; Yamaguchi, J.; Tamaru, T.;
Imai, H.; Nishigaya, Y.; Takabe, K.; Kakeya, H.; Osada, H. Angew.
Chem. Int. Ed. 2008, 47, 6657.
3
2
2
4
9
(
s, 9 H, t-C H ), 0.9 (s, 9 H, t-C H ), 0.75 (d, J = 7.5 Hz, 3 H, CHCH ),
4
9
4
9
3
0
.07 [s, 6 H, Si(CH ) t-Bu].
3 2
13
C NMR (75 MHz, CDCl ): δ = 167.3 (C=O), 156.1 (CAr), 142.2 (CAr),
3
1
41.1 (C ), 139.7 and 139.5 (=CCH ), 138.7 (C ), 138.2 (C ), 137.5
Ar
3
Ar
Ar
(
C ), 135.4, 133.2 (CH ), 132.3 (C ), 131.2, 130.3, 129.4, 128.0, 127.5,
Ar Ar Ar
(
(
(
12) Kashin, D.; Meyer, A.; Wittenberg, R.; Schöning, K.-U.; Kamlage,
S.; Kirschning, A. Synthesis 2007, 304.
13) Rössle, M.; Del Valle, D. J.; Krische, M. J. Org. Lett. 2011, 13,
124.3 (CH ), 122.9 and 122.7 [C(CH )=CHCH CHSO Ph], 117.8, 117.6,
Ar 3 2 2
1
11.9 (CHAr), 76.8 and 74.5 (2 × CHOSi), 73.3 and 73.2 (CHSO Ph), 72.3
2
(
CHOMe), 60.4 [CH S(O)p-Tol], 59.4 (CH CH OTDBMS), 56.5 (OCH ),
2
2
2
3
1482.
4
2.2 (CHCH3), 41.5 [CH C(O)NH], 41.0 (CH CH OTBDMS), 28.0
2
2
2
14) (a) Kawamura, T.; Tashiro, E.; Yamamoto, K.; Shindo, K.; Imoto,
M. J. Antibiot. 2008, 61, 303. (b) Kawamura, T.; Tashiro, E.;
Shindo, K.; Imoto, M. J. Antibiot. 2008, 61, 312. (c) Tashiro, E.;
Hironiwa, N.; Mitsuhiro, K.; Futamura, Y.; Suzuki, S.-I.; Nishio,
M.; Masaya, I. J. Antibiot. 2007, 60, 549.
{
Si[C(CH ) ] }, 26.5 and 25.4 [2 × C(CH ) ], 25.0 (CH CHSO Ph), 21.2
3 3 2 3 3 2 2
(
ArCH ), 19.9 (=CCH ), 19.1, 18.8, 18.4 [4 × C(CH ) ], 15.0 (CHCH ),
3
3
3
3
3
–
2.3 [Si(CH ) t-Bu].
3
2
HRMS (ESI+): m/z (M + Na) calcd for C65H93NO S Si Na: 1203.5535;
9
2
3
found: 1203.5521.
(15) Obringer, M.; Barbarotto, M.; Choppin, S.; Colobert, F. Org. Lett.
2
009, 11, 3542.
16) (a) Solladié, G.; Colobert, F.; Stone, G. B. Synlett 1995, 1135.
b) Solladié, G.; Adamy, M.; Colobert, F. J. Org. Chem. 1996, 61,
369.
(
Acknowledgment
(
4
This work was supported by the CNRS and Ministère de la Recherche.
M.O. and M.B. thank the Ministère de la Recherche for a fellowship.
(17) (a) Carreno, M. C.; García Ruano, J. L.; Martín, A.; Pedregal, C.;
Rodríguez, J. H.; Rubio, A.; Sanchez, J.; Solladié, G. J. Org. Chem.
1990, 55, 2120. (b) Carreno, M. C.; García Ruano, J. L.; Rubio, A.
Tetrahedron Lett. 1987, 28, 4861.
18) (a) Rival, N.; Hazelard, D.; Hanquet, G.; Kreuzer, T.; Bensoussan,
C.; Reymond, S.; Cossy, J.; Colobert, F. Org. Biomol. Chem. 2012,
Supporting Information
(
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1562735.
10, 9418. (b) Hernández-Torres, G.; Carreño, M. C.; Urbano, A.;
S
u
p
p
ortioIgnfrm oaitn
S
u
p
p
ortioIgnfrm oaitn
Colobert, F. Chem. Eur. J. 2011, 17, 1283. (c) Colobert, F.;
Choppin, S.; Ferreiro, L.; Obringer, M.; Luengo Arratta, S.;
Urbano, A.; Carreño, M. C. Org. Lett. 2007, 9, 4451.
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(
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©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I