Setbacks and hopes: En route to the synthesis of uncialamycin

Article abstract of DOI:10.1016/j.tet.2011.07.090

We herein report a new approach toward the synthesis of uncialamycin, an enediyne natural product isolated from the Streptomyces uncialis, bacteria present on the surface of the lichen Cladonia uncialis. A model for the preparation of uncialamycin has bee

Full text of DOI:10.1016/j.tet.2011.07.090

Tetrahedron 67 (2011) 7510e7516
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Setbacks and hopes: en route to the synthesis of uncialamycin
*
Sandy Desrat, Mickael Jean, Pierre van de Weghe
ꢀ
ꢀ
Universite de Rennes 1, UMR 6226, Sciences Chimiques de Rennes, Equipe PNSCM, UFR des Sciences Biologiques et Pharmaceutiques, 2 avenue du Prof Leon Bernard,
F-35043 Rennes Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 July 2011
Received in revised form 27 July 2011
Accepted 29 July 2011
Available online 5 August 2011
We herein report a new approach toward the synthesis of uncialamycin, an enediyne natural product
isolated from the Streptomyces uncialis, bacteria present on the surface of the lichen Cladonia uncialis. A
model for the preparation of uncialamycin has been achieved through a reaction cascade, an acetylide
addition to the activated quinoline moiety, and a ring closure reaction as key steps.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Total synthesis
Enediyne
Natural product
1. Introduction
O
Me
C26
OH
OH
O
Me
OH
In 2005, Davies, Andersen and co-workers disclosed the uncia-
lamycin 1, a new enediyne natural product isolated from an
undescribed streptomycete obtained from the surface of the lichen
Cladonia uncialis.1 First biological evaluations show that 1 possesses
potent in vitro antibacterial activity against Staphylococcus aureus,
Escherichia coli and Burkholderia cepacia. Despite of the small
amount of product available, the structure of 1 was resolved but
assigning the absolute configuration of C26 was not possible. Nic-
olaou and co-workers recently proved without ambiguity the
complete structure of 1 and determined the absolute stereochem-
istry at C26 after total synthesis of the racemic and then reported
the first asymmetric synthesis.2 Having ample quantities of 1 and
its C26-epimer in hand, they studied its biological properties in
DNA-cleavage, antibacterial, and cytotoxic activities. These in-
vestigations revealed impressive high potent antitumor activities
and broad-spectrum antibacterial properties.
Me
O
O
HN
N
N
O
X
OBn
OBn
OH
3
2
1
OMe
OMe
Scheme 1.
Based on the results reported by Hamada and co-workers con-
cerning a Michael-aldolisationecrotonisation reaction cascade to
prepare the quinoline core of the martinelline in good yield,4 we
planned to prepare our quinoline skeleton by using a similar ap-
proach. The retrosynthesis of the intermediate 4 is depicted in
Scheme 2. This strategy relied on three key steps: a Sugasawa re-
action5 to prepare 7, a Michael addition with methyl vinyl ketone 8
following by an aldol-crotonisation sequence to afford the quino-
line 5.
€
While Nicolaou reported an approach using a Friedlander
quinoline synthesis, we developed an intramolecular imino-Diel-
seAlder reaction promoted with BF3$OEt2/DDQ to synthesize the
chiral quinoline core 3.3 To prepare the intermediate 2, suitable for
the introduction of the enediyne moiety, we planned to accomplish
first a lactone opening reaction followed by a decarboxylation.
Despite several attempts, we never succeeded in this way (Scheme
1). Therefore, our first strategy has been completely reconsidered in
order to prepare an advanced intermediate of uncialamycin 1.
O
O
8
Me
OH
OH
O
Me
Me
X
Me
RO
N
N
O
HN
O
NH2
O
O
1
OR1
X
4
5
6
7
OMe
OMe
OMe
OMe
Scheme 2.
* Corresponding author. Tel.: þ33 (0) 2 23 23 38 03; fax: þ33 (0) 2 23 23 44 25;
e-mail address: pierre.van-de-weghe@univ-rennes1.fr (P. van de Weghe).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.07.090

S. Desrat et al. / Tetrahedron 67 (2011) 7510e7516
7511
2. Results and discussion
To understand the mechanism of the process of the formation of
the quinoline moiety, 6a has been placed in the presence of K2CO3
in methanol under an argon atmosphere. After 3 h under reflux, the
methanol was directly evaporated and the crude reaction mixture
rapidly analyzed by NMR. Only the compound I-7 was observed,
and after 2e3 h exposure to air atmosphere it was completely
converted to the furan 11 (Scheme 5). An attempt to explain the
formation of hemiketal 10 and/or furan 11 from 6a is proposed.
After formation of the enolate I-1, an aldolization could lead to the
tetrahydroquinoline I-3, which could provide a postulated dihy-
drofuran I-6 by nucleophilic substitution of the chloride and double
bond migration. From the key intermediate I-6 and depending of
the atmospheric reaction conditions, a loss of hydroxide could give
I-7 under an inert atmosphere followed by an oxidation of this
tetahydroquinoline leading to the furan 11. The structure of I-7 was
confirmed after isolation of N-acyl I-7 by exposure of the crude
reaction mixture from 6a and K2CO3 in dry methanol to acetic
anhydride in pyridine. On the other hand, under an oxygen atmo-
sphere, first I-6 would be oxidized in dihydroquinoline I-8 followed
by a sigmatropic transposition of the hydroxyl group favored by the
aromatization of the heterocycle to yield the expected product 10.
2.1. Construction of the quinoline moiety
Our first task was to prepare the aniline derivative 7a (X¼Cl)
from p-anisidine 9 (Scheme 3). Using the Sugasawa reaction con-
ditions as reported by Prasad,5c an ortho-acylation of 9 by con-
densation of chloroacetonitrile in the presence of TiCl4/BCl3 with
a substantial HCl expulsion, 7a has been obtained in satisfactory
yield (48%). Then 7a has been treated in the presence of NaOAc in
DMF to furnish the acetate 7b in good yield. Surprisingly 7b did not
react with an excess of methyl vinyl ketone 8. However, 6b was
obtained efficiently by simple reversing order of the last two steps
(Scheme 3).
NH
NH
O
2
2
1- TiCl , DCM, 0 °C
4
and BCl , Tol, 0 °C
3
Cl
then ClCH CN, 120 °C, 5 h
2
2- HCl (2 M), 100 °C, 1 h
48%
9
7a
OMe
OMe
O
O
NH
Me
NH
O
O
2
8
NaOAc
Me
Me
7a
OAc
OAc
DMF, rt, 24 h
90%
THF, reflux
overnight
< 5%
O
Me
Me
7b
6b
OMe
OMe
HN
O
HN
O
HN
O
MeO
MeO
O
6a
O
O
O
Cl
Cl
O
Me
NH
O
I-1
I-2
I-3
8
Me
NaOAc, TBAI cat
OMe
HN
OMe
OMe
Me
O
Cl
THF, reflux
overnight
99%
THF, reflux, 12 h
94%
O
HN
HN
6a
OMe
O
O
O
Scheme 3.
I-4
I-5
I-6
OMe
OMe
OMe
Me
HN
To build the quinoline core, the Michael adduct 6b was sub-
mitted to basic treatment (K2CO3/MeOH, LDA/THF, DBU/THF and t-
BuOK/THF). Whatever the reaction conditions employed, no
expected product was obtained and only a complex mixture of
degradation products was observed. On the other hand, submitting
6a to K2CO3 in methanol under air at 60 ꢀC led to the hemiketal 10
along with furan 11 as side product in variable ratio 10/11. After
careful examination of the reaction conditions, the chloride 6a has
been successfully converted to the expected hemiketal 10 after
stirring 2 h at 60 ꢀC in methanol in the presence of Cs2CO3 under an
oxygen atmosphere. After the reaction of the hemiketal 10 with
TBSCl, N-methylimidazole, and I2 in methylene chloride,6 the ke-
tone 5a was isolated in 63% yield over two steps (Scheme 4).
O
under Ar
oxidation, air
11
+
-
aromatization
- 2 H , -2 e
I-7
OMe
Me
O
N
sigmatropic
transposition
under O
2
10
OH
oxidation
+
-
I-8
- 2 H , -2 e
OMe
Scheme 5.
Having the ketone 5a in hand, its enantioselective reduction has
been undertaken by using different methods. Among the numerous
reductive process studied, best results were obtained either under
the Noyori reduction conditions7 or using a borane reduction in the
presence of the chiral phosphoramide derivative L.8 Unfortunately
the yield and the enantiomeric excess of the alcohol 12 are too low
to continue the synthesis under its asymmetric form. In parallel, we
decided to carry on our progress toward the preparation of a valu-
able intermediate with the racemic alcohol 12 obtained after
treatment of 5a with NaBH4 in methanol (Scheme 6).
HO
Me
O
Me
N
N
O
K2CO3
and / or
6a
MeOH, 60 °C
air, 3 h
10
11
(0 - 88%)
OMe
HO
OMe
O
Me
Me
N
N
TBSCl
O
Cs2CO3
N-methylimidazole
6a
OTBS
5a
I2 (1 equiv)
MeOH, 60 °C
O2 (1 atm), 2 h
2.2. Preliminary studies of enediyne addition
10
DCM, rt, 5 h
OMe
OMe
63% (2 steps)
Using a model,9 we then examined the influence of the pro-
Scheme 4.
tection of the secondary alcohol onto the diastereoselectivity in the

7512
S. Desrat et al. / Tetrahedron 67 (2011) 7510e7516
type addition in the presence of the Grignard reagent prepared in
situ from the enediyne 1610 and an excess of allyloxycarbonyl
chloride. The two diastereoisomers were not separable and were
isolated in 86% yield in a 7:3 ratio. In attempt to improve the effi-
ciency of the reaction, we decided to start with the protection of the
secondary alcohol of 12 as a 3,4-dimethoxybenzylether (DMB). This
protecting group leaving under oxidative conditions, we postulated
that it could be removed in the oxidative step of the aromatic ring
to the iminoquinone which is required to build the anthraquinone
core of 1 through a Hauser annulation. The activation of the ni-
trogen of the quinoline core 15 with allyloxycarbonyl chloride and
reaction with the corresponding enediyne 16 Grignard derivative
afforded the expected compound 17a isolated in good yield albeit
as an inextricable mixture of diastereoisomers in the same ratio as
previously. Consequently 17a was used as the cis/trans isomers
mixture to prepare the aldehyde 19 in three steps. After removal of
the silyl groups of 17a with TBAF, the product was then regiose-
lectively oxidized with TBHP/Ti(Oi-Pr)4 to afford a non-separable
mixture of isomers 18 in modest yield. In the presence of an ex-
cess of the DesseMartin periodinane, the alcohol was converted
quantitatively to its aldehyde 19. Once again it was not possible to
separate each stereoisomer, and thus to characterize them suitably
to identify the one who possesses the stereochemical relationship
corresponding to the pattern of the uncialamycin 1. Exposure of the
mixture of stereoisomers 19 to KHMDS in the presence of anhy-
drous CeCl3 afforded the 10-membered ring enediyne as a complex
mixture of isomers 4aa and 4ab in low yield. In spite of our efforts,
we were not able to separate each isomer during the purification
and thus in the impossibility to determine the selectivity of this
crucial cyclization step (Scheme 8).
OH
Me
Me
Me
cat =
N
Ts
N
Ph
Ph
5 mol% cat
5a
Ru
Me
OTBS
N
Ts
HCOONa, DCM
40 °C, 24 h
30 - 55%
Cl
OMe
12 e.e. = 15-30%
OH
Ph
L =
OH
N
Me
Ph
5 mol% L
N
N
Ph
HO
P
5a
O
Ph
N
OTBS
Ph
OH
BH3.Me2S
Ph
THF, 70 °C, 2 h
OMe
32%
12 e.e. = 48%
Scheme 6.
Reissert-type step reaction. Compounds 13aed were submitted to
phenylacetylene magnesium bromide with allyloxycarbonyl chlo-
ride as activating agent (Scheme 7). Whatever the protecting group
used, a moderate diastereomeric excess in favor of the cis-isomer
was observed, the relative configurations being confirmed by X-
ray analysis of 14-cis (Fig. 1).
Ph
Ph
Me
OR
Me
OH
Me
OH
Me
Ph
MgBr
(3 equiv)
Alloc
Alloc
N
N
N
+
AllocCl (3 equiv)
THF, -18 °C to rt, 1 h
then deprotection
76 - 91%
Me
Me
TIPS
OMe
OMe
OMe
14-cis
14-trans
ODMB
Me
Me
Alloc
R = H (13a)
R = Ac (13b), Piv (13c), TPS (13d)
7
6
3
4
N
N
ODMB
16
NaH, TBAI cat
TIPS
H
12
Scheme 7.
DMBBr, THF
0 °C to rt, 12 h
99%
EtMgBr
OTBS
OTBS
17a
then AllocCl, THF
-20 °C, 1 h
96%
15
OMe
OMe
cis / trans = 7 / 3
H
H
Me
Me
Alloc
Alloc
DMP, DCM
N
ODMB
N
ODMB
O
O
1- TBAF, THF, rt, 1 h, 88%
rt, 0.5 h, 99%
2- TBHP, Ti(Oi-Pr)4, MS 4 Å,
DCM, rt, 5 h, 45-62%
OH
O
18
19
OMe
O
OMe
Me
ODMB
Me
Alloc
Alloc
N
ODMB
OH
N
O
OH
KHMDS, CeCl3 anh
+
THF-Tol, -78 °C to -40 °C
40 - 60%
4aa
4ab
OMe
OMe
selectivity not determined
Scheme 8.
Facing these difficulties of isomers separation and in order to
facilitate the characterization of each product by NMR, we changed
the agent of activation of the quinoline 15 by using the methyl
chloroformate (Scheme 9).11 The addition of the Grignard reagent
of the enediyne 16 was achieved to furnish 17b in good yield as
a mixture of cis/trans isomers in an unchanged ratio 6:4. The ste-
reoisomers were separated by flash chromatography.12 Each of
these isomers were then submitted to the 2-steps sequence
Fig. 1. X-ray structure of 14-cis.
2.3. En route to the synthesis of uncialamycin
Because the best selectivity has been obtained with the quino-
line model 13a, the alcohol 12 was first submitted to the Reissert-

S. Desrat et al. / Tetrahedron 67 (2011) 7510e7516
7513
deprotectioneepoxidation and while the isomer 17b-cis led to
a single isomer of the corresponding oxirane, the trans-isomer gave
a complex mixture of compounds. This result led us to continue
only with the epoxide obtained from the isomer 17b-cis. After ox-
idation of the primary alcohol, the cyclization step was carried out
using KHMDS in the presence of anhydrous CeCl3 and afforded
a mixture of 4bb and 4ba in a ratio 7:3. The major product 4bb was
isolated and fully characterized. We were very pleased that the
NMR spectroscopic data of 4bb are consistent with the structure of
the quinoline/enediyne moiety of the uncialamycin 1.13
standard. d values are given in parts per million (ppm), coupling
constants (J values) are given in hertz (Hz), and multiplicity of
signals are reported as follows: s, singlet; br s, broad singlet; d,
doublet; t, triplet; q, quadruplet; dd, doublet of doublets; m, mul-
tiplet. HRMS analyses were obtained using a Waters Q-TOF 2 or
a Micromass ZABSpec TOF or a Bruker MicrO-TOF Q II instrument
for ESI. X-ray structures were obtained using an Oxford Diffraction
Xcalibur Saphir 3 diffractometer with graphite monochromatized
MoK a radiation. Chiral HPLC was performed using a Daicel
ChiralpakÒ AD-H column (5
mm, 4.6ꢁ250 mm). Melting points were
uncorrected and obtained on a hot bench. TLC analyses were per-
formed using precoated Merck TLC Silica Gel 60 F254 plates. Puri-
fications by column chromatography on silica gel were performed
using Merck Silica Gel 60 (70e230 mesh) and purifications by
preparative thin layer chromatography on silica gel using Merck
Silica Gel 60 PF254. Petroleum ether (PE) used for purifications was
the low boiling point fraction (40e60 ꢀC).
TIPS
ODMB
Me
O
Me
N
MeO
N
ODMB
16
TIPS
H
EtMgBr
OTBS
OTBS
17b
cis / trans = 6 / 4
then ClCO2Me, THF
-20 °C, 1 h
15
OMe
OMe
4.1.1. 1-(2-Amino-5-methoxyphenyl)-2-chloroethanone
(7a)5b. To
86%
a solution of p-anisidine 9 (6.16 g, 50.0 mmol, 1 equiv) in dry CH2Cl2
(50 mL) was added at 0 ꢀC titanium tetrachloride (5.45 mL,
50.0 mmol, 1 equiv), a solution of boron trichloride (1 M in PhMe,
55.0 mL, 55.0 mmol, 1.1 equiv) then chloroacetonitrile (15.2 mL,
240.0 mmol, 4.8 equiv) at room temperature. The resulting mixture
was then heated at 120 ꢀC for 5 h before being cooled down to room
temperature and quenched with a 2 M aqueous solution of HCl
(140 mL). The mixture was then heated at reflux for 1 h, cooled
down to 0 ꢀC, concentrated aqueous solution of NaOH was added
until pH 4. The titanium salts were eliminated by filtration over
a Celite pad and the product was extracted with EtOAc (three
times). The combined organic layers were washed with brine, dried
over MgSO4, filtered, and concentrated under reduced pressure.
The resulting dark residue was purified by column chromatography
on silica gel using PE/EtOAc 9:1 as eluent affording 7a as a yellow
solid (4.79 g, 48%). Rf¼0.3 (cyclohexane/EtOAc 7:3).
Mp¼104e106 ꢀC (lit. mp¼103e104 ꢀC). 1H NMR (500 MHz, CDCl3)
H
O
N
Me
MeO
ODMB
O
1- TBAF, THF, rt, 1 h, 90%
KHMDS, CeCl3 anh
17b-cis
THF-Tol, -78 °C to -40 °C
40 - 60%
2- TBHP, Ti(Oi-Pr)4, MS 4 Å,
DCM, rt, 5 h, 40-60%
3- DMP, DCM, rt, 0.5 h, 99%
O
20
OMe
Me
Me
O
O
ODMB
ODMB
OH
MeO
N
MeO
N
O
O
OH
+
4ba
3 / 7
4bb
OMe
OMe
Scheme 9.
d
3.77 (s, 3H), 4.65 (s, 2H), 6.02 (br s, 2H), 6.65 (d, J¼9.0, 1H), 7.01
(dd, J¼9.0, 3.0, 1H), 7.05 (d, J¼3.0, 1H). 13C NMR (125 MHz, CDCl3)
3. Conclusions
d
46.6, 55.9, 112.6, 114.6, 118.9, 124.5, 146.0, 149.8, 191.9. HRMS (ESI)
[MþNa]þ: calcd for C9H10NO2ClNa 222.0298, found 222.0303.
In conclusion, the synthesis of the valuable synthon 4bb as
model for the preparation of uncialamycin 1 has been achieved
through a Michael-aldolisationecrotonisation reaction cascade, an
acetylide addition to the activated quinoline moiety, and a ring
closure reaction as key steps. Using methyl chloroformate as acti-
vating agent in the Reissert-type step allowed us to confirm that the
major stereoisomer is consistent with the uncialamycin 1. As
reported by Sierra and de la Torre,14 the work described in this
article shows the failures in the planned synthetic scheme and also
the difficulties to obtain some synthetic intermediates with high
selectivities in spite of the use of well-established methods. Rec-
ognizing that the methyl carbamate protective group would be
difficult to remove, our approach will be modified in order to solve
the problem of isolation of the right isomer. More experimental
efforts must also be dedicated to succeed in the enantioselective
reduction of the ketone 5a.
4.1.2. 4-[2-(2-Chloroacetyl)-4-methoxyphenylamino]butan-2-one
(6a). To a solution of 7a (2.10 g, 9.4 mmol, 1 equiv) in dry THF
(40 mL) was added 3-buten-2-one 8 (1.53 mL, 18.8 mmol, 2 equiv).
The mixture was heated at 65 ꢀC in a sealed tube for 24 h then the
solvent was evaporated under reduced pressure. After trituration of
the brown residue in MeOH (10 mL) and filtration, the product 6a
was isolated as yellow solid (2.53 g, 99%). Rf¼0.2 (cyclohexane/
EtOAc 7:3). Mp¼130e132 ꢀC. 1H NMR (500 MHz, CDCl3)
d 2.20 (s,
3H), 2.81 (t, J¼7.0, 2H), 3.49 (t, J¼7.0, 2H), 3.78 (s, 3H), 4.65 (s, 2H),
6.75e6.77 (m, 1H), 7.10e7.12 (m, 2H), 8.52 (br s, 1H). 13C NMR
(125 MHz, CDCl3)
d 30.3, 37.6, 42.8, 46.6, 56.1, 113.5, 114.0, 114.3,
124.9, 146.7, 148.9, 191.9, 206.6. HRMS (ESI) [MþNa]þ: calcd for
C13H16NO3ClNa 292.0716, found 292.0714.
4.1.3. 4-[2-(2-Acetyloxyacetyl)-4-methoxyphenylamino]butan-2-one
(6b). Sodium acetate (75 mg, 0.91 mmol, 1.2 equiv) and tetrabuty-
lammonium iodide (25 mg, 0.07 mmol, 0.1 equiv) were added to
a solution of 6a (200 mg, 0.74 mmol, 1 equiv) in dry THF (5 mL). The
reaction mixture was stirred overnight at reflux and was cooled
down to room temperature before being quenched with water. The
product was extracted with Et2O (three times) and the combined
organic layers were washed with brine, dried over MgSO4, filtered,
and concentrated under reduced pressure. The residue was purified
by column chromatography on silica gel using PE/EtOAc 3:2 as elu-
ent to give 6b as a yellow oil (205 mg, 94%). Rf¼0.4 (cyclohexane/
4. Experimental
4.1. General methods
All reagents and solvents were used as purchased from com-
mercial suppliers or were purified/dried according to Armarego W.
L. F. and Chai C. L. L. (Purification of Laboratory Chemicals, sixth
edition, Elsevier.) 1H and 13C NMR spectra were recorded on
a Bruker DMX 500, a Bruker Avance 300 or a Jeol JNM-GSX270
instrument using TMS and CDCl3, respectively, as internal

7514
S. Desrat et al. / Tetrahedron 67 (2011) 7510e7516
EtOAc 1:1). Mp¼96e98 ꢀC; 1H NMR (500 MHz, CDCl3)
d
2.19 (s, 3H),
(2 mL) at 0 ꢀC was added a solution of isopropylmagnesium chlo-
2.24 (s, 3H), 2.79 (t, J¼6.9, 2H), 3.48 (t, J¼6.9, 2H), 3.77 (s, 3H), 5.29 (s,
ride 2 M in THF (900 mL, 1.80 mmol, 3 equiv). After 2 h at room
2H), 6.74 (d, J¼9.3, 1H), 7.04 (d, J¼3.0, 1H), 7.10 (dd, J¼9.3, 3.0, 1H),
temperature, the reaction mixture was cooled to ꢂ18 ꢀC then
8.38 (br s,1H).13C NMR (125 MHz, CDCl3)
d 20.6, 30.4, 37.5, 43.0, 56.2,
a solution of 13a (130 mg, 0.60 mmol, 1 equiv) in THF (2 mL) and
65.7, 112.9, 113.3, 114.3, 124.6, 146.3, 148.9, 170.5, 192.7, 206.7. HRMS
allyl chloroformate (191 mL, 1.80 mmol, 3 equiv) were added. The
(ESI) [MþNa]þ: calcd for C15H19NO5Na 316.1161, found 316.1158.
mixture was warmed to room temperature for 1 h and then treated
with water. The product was extracted with EtOAc (three times)
and the combined organic layers were washed with brine, dried
over MgSO4, filtered, and concentrated under reduced pressure.
The desired product was purified by column chromatography on
silica gel using cyclohexane/EtOAc 9:1 as eluent to giving a mixture
of two diastereoisomers A/B (7/3) as a yellow oil (244 mg, 83%).
4.1.4. 8-Methoxy-3-methyl-1,3-dihydrofuro[3,4-c]quinolin-3-ol
(10). To a solution of 6a (500 mg, 1.85 mmol, 1 equiv) in dry MeOH
(10 mL) was added Cs2CO3 (1.81 g, 5.55 mmol, 3 equiv). The sus-
pension was stirred at reflux under O2 atmosphere for 3 h and
a saturated aqueous solution of NH4Cl was added. The product was
extracted with EtOAc (four times) and the combined organic layers
were washed with brine, dried over MgSO4, filtered, and concen-
trated under reduced pressure. The dark residue was purified by
column chromatography on silica gel using cyclohexane/EtOAc 1:1
to 3:7 as eluent yielding to 10 as a pure beige solid (376 mg, 88%).
Rf¼0.1 (cyclohexane/EtOAc 1:1). Mp¼98e100 ꢀC. 1H NMR
Rf¼0.4 (cyclohexane/EtOAc 7:3). 1H NMR (500 MHz, CDCl3)
d 1.53
(d, J¼6.5, 3H, A), 1.63 (d, J¼6.5, 3H, B), 2.16 (s, 3H, A), 2.18 (s, 3H, B),
3.83 (s, 3H), 4.20 (dd, J¼12.5, 6.0, 1H), 4.47 (dd, J¼12.5, 6.0, 1H),
4.56e4.73 (m, 1H), 4.76 (dd, J¼13.3, 5.5, 1H, B), 4.79 (dd, J¼13.3, 5.5,
1H, A), 5.08 (d, J¼10.5, 1H), 5.14 (d, J¼17.0, 1H), 5.18e5.45 (m, 2H),
5.65e5.76 (m, 1H, A), 5.83e6.04 (m, 2H), 6.30 (br s, 1H), 6.79e6.89
(m, 1H), 6.91 (d, J¼2.5, 1H, B), 6.95 (d, J¼2.5, 1H, A), 7.13e7.25 (m,
(500 MHz, CDCl3)
d
1.82 (s, 3H), 3.83 (s, 3H), 5.12 (d, J¼14.0, 1H),
5.23 (d, J¼14.0, 1H), 5.89 (br s, 1H), 6.48 (d, J¼3.0, 1H), 7.24 (dd,
5H), 7.90 (br s, 1H). 13C NMR (125 MHz, CDCl3)
d 13.7 (A), 13.9 (B),
J¼8.8, 3.0, 1H), 7.85 (d, J¼8.8, 1H), 8.47 (s, 1H). 13C NMR (125 MHz,
19.0 (B), 19.2 (A), 42.9 (A), 43.3 (B), 55.4 (A), 66.8 (B), 66.9 (A), 68.4
(B), 68.5 (A), 71.6 (B), 73.0 (A), 81.7 (A), 82.8 (B), 86.2 (A), 86.9 (B),
109.7 (A), 110.2 (B), 112.8, 117.9, 118.3, 118.8, 122.6, 125.6, 127.3,
127.9, 128.0, 128.1, 128.2, 130.7, 130.9, 131.3, 131.6, 131.9, 132.2, 132.3,
152.8, 154.0 (A), 154.2 (B), 156.5. HRMS (ESI) [MþNa]þ: calcd for
C29H29NO6Na 510.1893, found 510.1902. To a solution of these two
diastereoisomers (134 mg, 0.27 mmol, 1 equiv) in MeOH (2 mL) at
room temperature was added potassium carbonate (4 mg,
0.03 mmol, 0.1 equiv) and the mixture was stirred overnight. Water
was added and the product was extracted with EtOAc (three times).
The combined organic layers were washed with brine, dried over
MgSO4, filtered, and concentrated under reduced pressure. The two
diastereoisomers (7/3) were separated by preparative TLC using
cyclohexane/EtOAc 7:3 as eluent to obtain 14-cis as a white solid
(76 mg, 70%) and 14-trans as a yellow oil (32 mg, 30%). Compound
14-cis: Rf¼0.20 (cyclohexane/EtOAc 7:3). Mp¼105e107 ꢀC. 1H NMR
CDCl3) d 26.8, 55.5, 69.5, 101.2,108.5, 122.4, 123.3, 130.5, 134.9, 142.1,
143.0, 144.1, 158.1. HRMS (ESI) [MþNa]þ: calcd for C13H13NO3Na
254.0793, found 254.0798.
4.1.5. 1-[4-(tert-Butyldimethylsilyloxymethyl)-6-methoxyquinolin-3-
yl]ethanone (5a). To a solution of tert-butyldimethylsilyl chloride
(528 mg, 3.50 mmol, 1 equiv) and N-methylimidazole (840
mL,
10.50 mmol, 3 equiv) in dry CH2Cl2 (10 mL) at room temperature
were added iodine (885 mg, 3.50 mmol, 1 equiv) and a solution of
crude 10 (from 3.50 mmol of 6a) in dry CH2Cl2 (10 mL). The mixture
was stirred 5 h at room temperature and quenched with a saturated
aqueous solution of Na2S2O5. The product was extracted with Et2O
(three times) and the combined organic layers were washed with
brine, dried over MgSO4, filtered, and concentrated under reduced
pressure. The resulting dark residue was purified by column chro-
matography on silica gel using cyclohexane/EtOAc 4:1 as eluent to
afford 5a as a brown solid (760 mg, 63% over two steps). Rf¼0.25
(cyclohexane/EtOAc 7:3). Mp¼74e76 ꢀC. 1H NMR (500 MHz, CDCl3)
(500 MHz, CDCl3)
d
1.40 (d, J¼6.6, 3H), 1.93 (br s, 1H), 2.04 (s, 3H),
3.83 (s, 3H), 4.66 (br s, 1H), 4.79 (dd, J¼13.2, 5.5, 1H), 5.08 (q, J¼6.6,
1H), 5.16e5.44 (m, 2H), 5.90e6.05 (m, 1H), 6.25 (br s, 1H), 6.84 (dd,
J¼8.8, 1H), 6.92 (d, J¼2.5, 1H), 7.09e7.25 (m, 5H), 7.56 (br s, 1H). 13C
d
0.11 (s, 6H), 0.90 (s, 9H), 2.69 (s, 3H), 3.96 (s, 3H), 5.26 (s, 2H), 7.43
(dd, J¼9.0, 2.7,1H), 7.51 (d, J¼2.7,1H), 8.02 (d, J¼9.0,1H), 8.83 (s,1H).
13C NMR (125 MHz, CDCl3)
NMR (125 MHz, CDCl3) d 13.5, 21.5, 43.0, 55.5, 66.8, 82.0, 87.5, 109.5,
d
ꢂ5.4, 18.3, 25.8, 31.3, 55.5, 58.9, 103.3,
112.2,118.1,122.5,125.0,125.5, 127.5, 128.0, 128.2, 131.2, 131.8, 132.0,
132.3, 137.4, 152.9, 156.4. HRMS (ESI) [MþNa]þ: calcd for
C25H25NO4Na 426.1681, found 426.1677. Compound 14-trans:
123.3,127.7,131.3,132.2,142.7,145.0,145.6,158.3, 202.2. HRMS (ESI)
[MþNa]þ: calcd for C19H27NO3NaSi 368.1658, found 368.1658.
Rf¼0.15 (cyclohexane/EtOAc 7:3). 1H NMR (500 MHz, CDCl3)
d 1.53
4.1.6. 1-[4-(tert-Butyldimethylsilyloxymethyl)-6-methoxyquinolin-3-
yl]ethanol (12). Sodium borohydride (75 mg,1.98 mmol,1.05 equiv)
was added by portion to a solution of 5a (650 mg, 1.88 mmol,
1 equiv) in MeOH (10 mL) at 0 ꢀC. After 15 min, water was added
and the product was extracted with Et2O (three times). The com-
bined organic layers were washed with brine, dried over MgSO4,
filtered, and concentrated under reduced pressure. The resulting
yellow residue was purified by column chromatography on silica
gel using cyclohexane/EtOAc 3:7 as eluent to obtain 12 as a pure
beige solid (674 mg, 98%). Rf¼0.2 (cyclohexane/EtOAc 1:1).
(d, J¼6.6, 3H),1.88 (br s, 1H), 2.09 (s, 3H), 3.83 (s, 3H), 4.65 (br s, 1H),
4.77 (dd, J¼13.2, 5.5, 1H), 5.03e5.10 (m, 1H), 5.22 (d, J¼9.0, 1H),
5.25e5.43 (m, 1H), 5.89e6.04 (m, 1H), 6.41 (s, 1H), 6.81e6.85 (m,
1H), 6.88 (d, J¼2.5, 1H), 7.14e7.25 (m, 5H), 7.57 (br s, 1H). 13C NMR
(125 MHz, CDCl3) d 13.6, 21.6, 43.0, 55.5, 65.1, 82.7, 87.2, 110.0, 112.3,
117.9, 122.8, 125.7, 127.6, 128.0, 128.1, 128.2, 131.3, 131.6, 131.8, 132.3,
153.2, 156.4. HRMS (ESI) [MþNa]þ: calcd for C25H25NO4Na
426.1681, found 426.1677.
4.1.8. 4-tert-Butyldimethylsilyloxymethyl-3-[1-(3,4-dimethoxybenzyl
oxy)ethyl]-6-methoxyquinoline (15). To a solution of 12 (500 mg,
1.44 mmol,1 equiv) in dry THF (10 mL) at 0 ꢀC was added by portion
sodium hydride 60% in mineral oil (86 mg, 2.16 mmol, 1.5 equiv).
After 15 min at 0 ꢀC, tetrabutylammonium iodide (106 mg,
0.29 mmol, 0.2 equiv) and 3,4-dimethoxybenzyl bromide (400 mg,
1.73 mmol, 1.2 equiv) were added. The suspension was warmed to
room temperature overnight then the reaction was quenched with
water. The product was extracted with Et2O (three times) and the
combined organic layers were washed with brine, dried over
MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by column chromatography on silica gel using
Mp¼130e132 ꢀC 1H NMR (500 MHz, CDCl3)
d 0.17 (s, 3H), 0.17 (s,
3H), 0.91 (s, 9H), 1.62 (d, J¼6.6, 3H), 3.09 (br s, 1H), 3.93 (s, 3H), 5.10
(s, 2H), 5.41 (q, J¼6.6, 1H), 7.32 (dd, J¼8.8, 2.7, 1 H), 7.37 (d, J¼2.7,
1 H), 7.96 (d, J¼8.8, 1H), 8.88 (s, 1H). 13C NMR (125 MHz, CDCl3)
d
ꢂ5.3, ꢂ5.2,18.3, 24.3, 25.8, 55.4, 57.2, 65.9,102.2,121.5,127.7,131.1,
136.0, 139.2, 143.7, 146.6, 158.0. HRMS (ESI) [MþH]þ: calcd for
C19H30NO3Si 348.1989, found 348.1989.
4.1.7. Allyl 3-(1-hydroxyethyl)-6-methoxy-4-methyl-2-(2-
phenylethynyl)quinoline-1(2H)-carboxylate (14). To a solution of
phenylacetylene (198 mL, 1.80 mmol, 3 equiv) in anhydrous THF

S. Desrat et al. / Tetrahedron 67 (2011) 7510e7516
7515
cyclohexane/EtOAc 7:3 as eluent to give 15 as a yellow solid
(702 mg, 98%). Rf¼0.25 (cyclohexane/EtOAc 3:2). Mp¼74e76 ꢀC. 1H
oil (0.95 g, 90%). Rf¼0.46 (PE/EtOAc 2:3). 1H NMR (300 MHz, CDCl3,
55 ꢀC)
d
1.54 (d, J¼6.7, 3H), 1.74 (s, 1H), 3.05 (dd, J¼2.0, 0.5, 1H), 3.76
NMR (500 MHz, CDCl3)
d
0.15 (s, 3H), 0.17 (s, 3H), 0.91 (s, 9H), 1.60
(s, 3H), 3.82 (s, 3H), 3.85 (s, 3H), 3.87 (s, 3H), 4.27 (d, J¼11.6, 1H),
4.48 (d, J¼11.6, 1H), 4.51 (d, J¼12.4, 1H), 4.61 (q, J¼6.7, 1H), 4.62 (d,
J¼12.4, 1H), 5.64 (dd, J¼11.0, 2.0, 1H), 5.71 (ddd, J¼11.0, 1.7, 0.5, 1H),
6.24 (d, J¼1.7, 1H), 6.80e6.88 (m, 3H), 6.93 (d, J¼1.6, 1H), 7.10 (d,
J¼2.8, 1H), 7.55 (d, J¼9.0, 1H). 13C NMR (75 MHz, CDCl3, 55 ꢀC)
(d, J¼6.6, 3H), 3.86 (s, 3H), 3.87(s, 3H), 3.95(s, 3H), 4.27 (d, J¼11.5,
1H), 4.43 (d, J¼11.5, 1H), 5.06 (q, J¼6.6, 1H), 4.98 (d, J¼11.3, 1H), 5.15
(d, J¼11.3,1H), 6.81 (s, 2H), 6.86 (s,1H), 7.36 (dd, J¼9.0, 3.0,1H), 7.44
(d, J¼3.0, 1H), 8.03 (d, J¼9.0, 1H), 8.96 (s, 1H). 13C NMR (125 MHz,
CDCl3)
d
ꢂ5.4, ꢂ5.3, 18.3, 24.1, 25.6, 25.8, 55.4, 55.8, 55.9, 57.0, 70.6,
d 20.8, 44.4, 53.1, 53.3, 55.6, 56.1, 57.6, 70.7, 71.8, 80.4, 84.7, 94.5,
72.3, 102.4, 110.9, 111.0, 120.3, 121.4, 127.9, 130.5, 131.0, 134.2, 140.0,
143.7, 147.2, 148.6, 149.0, 158.0. HRMS (ESI) [MþNa]þ: calcd for
C28H39NO5NaSi 520.2490, found 520.2490.
109.7, 111.6, 111.8, 113.4, 119.0, 120.4, 121.0, 125.6, 128.3, 129.1, 130.8,
131.2, 139.1, 149.0, 149.4, 153.7, 156.8. HRMS (ESI) [MþNa]þ: calcd
for C30H31NO7Na 540.1993, found 540.1993. To a mixture of mo-
ꢁ
lecular sieves 4 A in powder (900 mg) in dry CH2Cl2 (10 mL) at
4.1.9. (Z)-Methyl 3-[1-(3,4-dimethoxybenzyloxy)ethyl]-4-tert-butyldi
methylsilyloxymethyl-6-methoxy-2-(6-triisopropylsilylhexa-3-en-
1,5-diynyl)quinoline-1(2H)-carboxylate (17b). To a solution of ene-
diyne 16 (550 mg, 2.36 mmol, 1.2 equiv) in dry THF (5 mL) at 0 ꢀC
was added a solution of ethylmagnesium bromide 1 M in THF
(2.36 mL, 2.36 mmol, 1.2 equiv). The mixture was warmed to room
temperature for 2 h then cooled to ꢂ18 ꢀC. A solution of 15 (980 mg,
1.97 mmol, 1 equiv) in THF (5 mL) and methyl chloroformate
ꢂ20 ꢀC were added titanium isopropoxide (535
m
L, 1.80 mmol,
1.1 equiv) and TBHP (5 M solution in octane, 700
mL, 3.50 mmol,
2.5 equiv). After 30 min, a solution of (Z)-methyl 3-[1-(3,4-dimeth-
oxybenzyloxy)ethyl]-2-(hexa-3-en-1,5-diynyl)-4-hydroxymethyl-
6-methoxyquinoline-1(2H)-carboxylate (850 mg, 1.64 mmol,
1 equiv) in dry CH2Cl2 (5 mL) was added and the reaction mixture
was stirred at ꢂ20 ꢀC for 5 h before being quenched with water. The
product was then extracted with Et2O (three times) and the com-
bined organic layers were washed with brine, dried over MgSO4,
and concentrated under reduced pressure. The crude oil was pu-
rified by column chromatography on silica gel using PE/EtOAc 1:1
as eluent to give (Z)-methyl 1a-[1-(3,4-dimethoxybenzyloxy)
ethyl]-2-(hexa-3-en-1,5-diynyl)-7b-(hydroxymethyl)-6-methoxy-
1a,2-dihydrooxireno[2,3-c]quinoline-3(7bH)-carboxylate as a pale
yellow oil (455 mg, 52%). Rf¼0.38 (PE/EtOAc 1:1). 1H NMR
(182 mL, 2.36 mmol, 1.2 equiv) were then added to the reaction
mixture. After 1 h water was added and the product was extracted
with Et2O (three times). The combined organic phases were
washed with brine, dried over MgSO4, filtered, and concentrated
under reduced pressure to leave brown oil. The product was puri-
fied by column chromatography on silica gel using PE/EtOAc 4:1 as
eluent to afford 17b as a mixture of two diastereoisomers (6:4) as
a yellow oil (1.34 g, 86%). The two diastereoisomers were separated
by medium pressure liquid chromatography using an 80 g column
(300 MHz, CDCl3, 50 ꢀC)
d
1.48 (d, J¼6.7, 3H), 2.31 (t, J¼6.2, 1H), 3.09
(d, J¼0.7, 1H), 3.74 (s, 3H), 3.81 (s, 3H), 3.85 (s, 3H), 3.86 (s, 3H), 4.07
(dd, J¼12.7, 6.0, 1H), 4.19 (q, J¼6.7, 1H), 4.26 (dd, J¼12.6, 7.5, 1H),
4.55 (d, J¼11.0, 1H), 4.67 (q, J¼11.0, 1H), 5.69 (s, 2H), 5.97 (s, 1H),
6.81e6.87 (m, 2H), 6.91 (dd, J¼8.1, 1.8, 1H), 6.94e6.96 (m, 1H), 7.25
(br s, 1H), 7.27 (d, J¼2.8, 1H). 13C NMR (125 MHz, CDCl3, 50 ꢀC)
of silica gel (15
(flow¼60 mL/min).Compound 17b-trans: Rf¼0.19 (PE/EtOAc 9:1).
1H NMR (300 MHz, CDCl3, 55 ꢀC)
0.14 (s, 3H), 0.15 (s, 3H), 0.97 (s,
mm) loading at 0.5% and PE/EtOAc 9:1 as eluent
d
9H), 1.19 (s, 18H), 1.20 (s, 3H), 1.52 (d, J¼6.5, 3H), 3.88 (s, 3H), 3.91 (s,
3H), 3.95 (s, 3H), 3.95 (s, 3H), 4.38 (d, J¼11.8, 1H), 4.58 (d, J¼11.8,
1H), 4.74 (d, J¼11.8, 1H), 4.77 (d, J¼11.8, 1H), 4.80 (q, J¼6.5, 1H), 5.61
(dd, J¼11.0, 2.0, 1H), 5.77 (d, J¼11.0, 1H), 6.35 (s, 1H), 6.80e6.94 (m,
2H), 6.97 (dd, J¼8.2, 1.8, 1H), 7.02 (d, J¼1.7, 1H), 7.19 (d, J¼2.8, 1H),
d
18.2, 30.4, 46.5, 53.4, 55.6, 56.0, 56.0, 60.9, 61.0, 71.9, 74.8, 76.9,
80.3, 81.9, 85.1, 92.5, 111.5, 112.0, 113.8, 113.9, 119.7, 120.5, 120.8,
128.1, 128.3, 129.5, 130.3, 149.1, 149.4, 157.3. HRMS (ESI) [MþNa]þ:
calcd for C30H31NO8Na 556.1942, found 556.1943.
7.61 (d, J¼7.0,1H). 13C NMR (75 MHz, CDCl3, 55 ꢀC)
d
ꢂ5.4, ꢂ5.2,11.4,
To a solution of (Z)-methyl 1a-[1-(3,4-dimethoxybenzyloxy)
ethyl]-2-(hexa-3-en-1,5-diynyl)-7b-(hydroxymethyl)-6-methoxy-
1a,2-dihydrooxireno[2,3-c]quinoline-3(7bH)-carboxylate (250 mg,
0.47 mmol, 1 equiv) in dichloromethane (5 mL) was added
DesseMartin periodinane (400 mg, 0.94 mmol, 2 equiv) at 0 ꢀC. The
mixture was stirred at room temperature for 30 min then diluted
with dichloromethane and the organic layer washed with an
aqueous Na2S2O3 solution and brine. The combined aqueous layers
were extracted with EtOAc (two times) and the combined organic
layers washed with brine then dried over MgSO4. After filtration
solvent was removed under reduced pressure and the crude oil was
purified by column chromatography on silica gel using PE/EtOAc
1:1 as eluent to afford 20 as a pale yellow oil (245 mg, 99%). Rf¼0.51
18.3, 18.7, 21.3, 25.9, 43.8, 53.0, 55.5, 56.0, 56.1, 58.4, 71.2, 72.8, 79.2,
95.0, 99.6, 103.7, 109.7, 111.4, 111.6, 113.4, 119.6, 119.8, 120.1, 125.7,
128.3, 129.7, 130.6, 131.8, 148.7, 149.3, 153.4, 156.6. HRMS (ESI)
[MþNa]þ:
calcd
for
C45H65NO7Si2Na
810.4197,
found
810.4191.Compound 17b-cis: Rf¼0.18 (PE/EtOAc 9:1). 1H NMR
(300 MHz, CDCl3, 55 ꢀC)
d 0.15 (s, 6H), 0.97 (s, 9H), 1.20 (s, 18H), 1.20
(s, 3H), 1.60 (d, J¼6.7, 3H), 3.80 (s, 3H), 3.90 (s, 3H), 3.95 (s, 3H), 3.97
(s, 3H), 4.28 (d, J¼11.7, 1H), 4.54 (d, J¼11.7, 1H), 4.62 (s, 2H), 4.76 (q,
J¼6.7, 1H), 5.69 (dd, J¼11.0, 2.1, 1H), 5.81 (d, J¼11.0, 1H), 6.41 (s, 1H),
6.88e6.95 (m, 3H), 7.03 (s,1H), 7.18 (d, J¼2.8,1H), 7.61 (d, J¼8.5,1H).
13C NMR (75 MHz, CDCl3, 55 ꢀC)
d
ꢂ5.2, 11.4, 18.3, 18.7, 20.8, 25.9,
43.7, 53.0, 55.5, 56.1, 56.1, 58.1, 70.4, 71.3, 80.5, 94.8, 99.6, 103.8,
110.0, 111.6, 111.6, 113.6, 119.6, 119.7, 120.2, 125.4, 128.3, 129.7, 131.2,
131.4, 148.9, 149.4, 153.7, 156.6. HRMS (ESI) [MþNa]þ: calcd for
C45H65NO7Si2Na 810.4197, found 810.4192.
(PE/EtOAC 1:1). 1H NMR (300 MHz, CDCl3, 50 ꢀC)
d
1.45 (d, J¼6.6,
3H), 3.19 (d, J¼1.8, 1H), 3.75 (s, 3H), 3.80 (s, 3H), 3.86 (s, 3H), 3.88 (s,
3H), 4.19 (q, J¼6.6, 1H), 4.37 (d, J¼11.7, 1H), 4.43 (d, J¼11.7, 1H), 5.68
(dd, J¼11.0, 1.6, 1H), 5.74 (dd, J¼11.0, 2.2, 1H), 5.84 (s, 1H), 6.81 (d,
J¼8.0, 1H), 6.84 (dd, J¼8.0, 1.9, 1H), 6.87e6.90 (m, 2H), 7.27 (s, 1H),
7.38 (d, J¼2.5, 1H), 9.59 (s, 1H). 13C NMR (75 MHz, CDCl3, 50 ꢀC)
4.1.10. (Z)-Methyl 1a-[1-(3,4-dimethoxybenzyloxy)ethyl]-7b-formyl-
2-(hexa-3-en-1,5-diynyl)-6-methoxy-1a,2-dihydrooxireno[2,3-c]
quinoline-3(7bH)-carboxylate (20). To a solution of 17b-cis (1.60 g,
2.03 mmol, 1 equiv) in THF (12 mL) at 0 ꢀC was added TBAF (1 M
solution in THF, 4.5 mL, 4.50 mmol, 2.2 equiv). After 1 h, water was
added and the product was extracted with Et2O (three times). The
combined organic layers were washed with brine, dried over
MgSO4, filtered, and concentrated under reduced pressure to leave
a brown oil. The crude oil was purified by column chromatography
on silica gel using PE/EtOAc 2:3 as eluent to afford (Z)-methyl
3-[1-(3,4-dimethoxybenzyloxy)ethyl]-2-(hexa-3-en-1,5-diynyl)-4-
hydroxymethyl-6-methoxyquinoline-1(2H)-carboxylate as a yellow
d
16.8, 46.1, 53.6, 55.6, 56.0, 63.7, 70.8, 71.4, 80.1, 81.6, 82.8, 85.6,
90.6, 111.3, 111.9, 113.2, 114.9, 120.1, 120.6, 120.8, 123.8, 128.5, 128.8,
129.8, 149.1, 149.3, 157.1, 194.0. HRMS (ESI) [MþNa]þ: calcd for
C30H29NO8Na 554.1785, found 554.1786.
4.1.11. Cyclized product (4bb). To anhydrous cerium chloride
(167 mg, 0.68 mmol, 4 equiv) was added a solution of 20 (90 mg,
0.17 mmol, 1 equiv) in dry THF (3.4 mL, 0.05 M) at room tem-
perature and under argon. After 30 min of stirring, the mixture
was cooled to ꢂ78 ꢀC and a solution of KHMDS (0.5 M in toluene,

7516
S. Desrat et al. / Tetrahedron 67 (2011) 7510e7516
510
m
L, 0.26 mmol, 1.5 equiv) was added slowly. The reaction was
and 746985 for 14-cis, contain the supplementary crystallographic
data for this paper. Supplementary data associated with this article
can be found, in the online version, at doi:10.1016/j.tet.2011.07.090.
allowed to warm to ꢂ40 ꢀC then poured into a separated funnel
containing an aqueous saturated NH4Cl solution. EtOAc was added
and the organic layer was washed with a 5% acetic acid solution
and the combined aqueous layers extracted with EtOAc (three
times). The combined organic layers was washed with brine, sat-
urated aqueous NaHCO3 and brine then dried over MgSO4. After
filtration solvent was removed under reduced pressure and the
crude oil was purified by preparative thin layer chromatography
on silica gel using PE/EtOAc 1:4 as eluent to afford 4bb as a pale
yellow oil (31 mg, 34%). Rf¼0.52 (PE/EtOAc 1:4). 1H NMR
References and notes
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Lett. 2005, 7, 5233e5236; (b) Davies, J.; Andersen, R. J.; Wang, H.; Warabi, K.;
Huang, X.-H. Patent WO2007/038868.
2. (a) Nicolaou, K. C.; Zhang, H.; Chen, J. S.; Crawford, J. J.; Pasunoon, L. Angew.
Chem., Int. Ed. 2007, 46, 4704e4707; (b) Nicolaou, K. C.; Chen, J. S.; Zhang, H.;
Montero, A. Angew. Chem., Int. Ed. 2008, 47, 185e189.
(300 MHz, CDCl3, 50 ꢀC)
d
1.54 (d, J¼6.9, 3H), 2.43 (d, J¼3.7, 1H),
3. Desrat, S.; van de Weghe, P. J. Org. Chem. 2009, 74, 6728e6734.
4. Hara, O.; Sugimoto, K.; Makino, K.; Hamada, Y. Synlett 2004, 1625e1627.
5. (a) Sugasawa, T.; Toyoda, T.; Adachi, M.; Sasakura, K. J. Am. Chem. Soc. 1978, 100,
4842e4852; (b) Sugasawa, T.; Adachi, M.; Sasakura, K.; Kitagawa, A. J. Org.
Chem. 1979, 44, 578e586; (c) Prasad, K.; Lee, G. T.; Chaudhary, A.; Girgis, M. J.;
3.75 (s, 3H), 3.80 (s, 3H), 3.87 (s, 3H), 3.91 (s, 3H), 3.98 (q, J¼6.9,
1H), 4.50 (d, J¼11.0, 1H), 4.74 (d, J¼11.0, 1H), 5.26 (s, 1H),
5.64e5.68 (m, 1H), 5.77 (d, J¼10.1, 1H), 5.97 (s, 1H), 6.82e6.86 (m,
2H), 6.93e6.96 (m, 1H), 7.06 (s, 1H), 7.27 (s, 1H), 8.05 (d, J¼2.8, 1H).
ꢃ
Steemke, J. W.; Repic, O. Org. Process Res. Dev. 2003, 7, 723e732.
6. (a) Bartoszewicz, A.; Kalek, M.; Stawinski, J. Tetrahedron 2008, 64, 8843e8850;
(b) Stawinski and co-workers recommand the presence of 3 equiv of I2. In our
case, the reduction of the amount of I2 from 3 to 1 equiv was made necessary to
avoid the formation of the deacylated by-product 21.
7. (a) Hashigushi, S.; Fujii, A.; Takehara, J.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc.
1995, 117, 7562e7563; (b) Noyori, R.; Hashigushi, S. Acc. Chem. Res. 1997, 30,
97e102; (c) Wang, C.; Wu, X.; Xiao, J. Chem.dAsian J. 2008, 3, 1750e1770; (d)
Wu, X.; Li, X.; Hems, W.; King, F.; Xiao, J. Org. Biomol. Chem. 2004, 2, 1818e1821.
8. Du, D.-M.; Fang, T.; Xu, J.; Zhang, S.-W. Org. Lett. 2006, 8, 1327e1330; Ling, R.;
Yoshida, M.; Mariano, P. S. J. Org. Chem. 1996, 61, 4439e4449.
13C NMR (75 MHz, CDCl3, 50 ꢀC)
d 19.9, 46.0, 53.3, 55.5, 55.9, 64.8,
65.1, 71.9ESI) [MþNa]þ: 75.0, 76.8, 90.3, 92.5, 95.7, 98.8, 110.8,
110.9, 111.6, 111.7, 111.9, 113.7, 116.5, 121.0, 122.9, 123.5, 128.5, 129.8,
130.5, 148.7, 149.0, 156.3. HRMS (calcd for C30H29NO8Na 554.1785,
found 554.1785.
Acknowledgements
9. See Electronic Supplementary data for the synthesis of 13aed.
10. (a) Vollhardt, K. P.; Winn, L. S. Tetrahedron Lett. 1976, 26, 709e712; (b) Lu, Y.-F.;
Harwig, C. W.; Fallis, A. G. Can. J. Chem. 1995, 73, 2253e2262.
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We are grateful for the support provided by Rennes Metropole,
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the Region Bretagne, and the Universite de Rennes 1. We thank the
Ministere de la Recherche for the fellowship of S.D. We also
gratefully acknowledge Loic Toupet (Institut de Physique de Ren-
nes) for X-ray analytical data.
11. (a) Myers and co-workers employed the methyl chloroformate as activating
reagent with the aim to study the best route to access to the dynemicin A:
Myers, A. G.; Tom, N. J.; Fraley, M. E.; Cohen, S. B.; Madar, D. J. J. Am. Chem. Soc.
1997, 119, 6072e6094; (b) Isobe and co-workers reported the influence of the
steric hindrance of the chloroformate to the diastereoselectivity of the addition
of the acetylide Grignard reagent: Nishikawa, T.; Yoshikai, M.; Obi, K.; Kawai, T.;
Unno, R.; Jomori, T.; Isobe, M. Tetrahedron 1995, 51, 9339e9352.
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Supplementary data
12. See Electronic Supplementary data.
13. According to the X-ray structure reported in the literature,2a strong correlations
were found in 2D NMR (NOESY). See Supplementary data.
Full details of the experimental procedures including 1H, 13C
NMR spectra and HRMS data. CCDC reference number 771190 for 12
14. Sierra, M. A.; de la Torre, M. C. Angew. Chem., Int. Ed. 2000, 39, 1538e1559.