Zinc-acetic acid reductive cyclisation in a two-step synthesis of the S1-N10 nine-membered lactone core of ent-griseoviridin

Article abstract of DOI:10.1055/s-2004-834899

The synthesis of the S1-N10 nine-membered lactone core 28 of enf-griseoviridin is reported. Starting from cystine derivative 25, encompassing a terminal ynoate, treatment under Zn/AcOH conditions led to the formation of lactone 28 in 12% yield. Therefore, the lactone moiety of enf-griseoviridin is obtained in 10.7% overall yield for two steps. An access to the corresponding 5-epi-griseoviridin lactone 29 is also described.

Full text of DOI:10.1055/s-2004-834899

PAPER
3029
Zinc–Acetic Acid Reductive Cyclisation in a Two-Step Synthesis of the S1–N10
Nine-Membered Lactone Core of ent-Griseoviridin
iridin Chaume, Carine Kuligowski, Sophie Bezzenine-Laffolée, Louis Ricard,* Ange Pancrazi, Janick Ardisson*b
a
R
G
eductive Cyclisat
r
ion in
a
é
Synthesis
o
g
f
the Lactone
o
Core of
e
nt
r
G
riseov
y
a
Laboratoire Hétéroéléments et Coordination, UMR CNRS 7653, Ecole Polytechnique, 91128 Palaiseau, France
Laboratoire de Synthèse Organique Selective et Chimie Organométallique, CNRS-UCP-ESCOM, UMR 8123, ESCOM, Bat E, 13 Bd de
l’Hautil, 95092 Cergy-Pontoise, France
b
Fax +33(1)30756186 ; E-mail: janick.ardisson@chim.u-cergy.fr
Received 5 August 2004
lying upon
a final macrolactonisation step after
Abstract: The synthesis of the S1–N10 nine-membered lactone
core 28 of ent-griseoviridin is reported. Starting from cystine deriv-
ative 25, encompassing a terminal ynoate, treatment under Zn/
AcOH conditions led to the formation of lactone 28 in 12% yield.
Therefore, the lactone moiety of ent-griseoviridin is obtained in
3
installation of the thiovinyl ether function. To date, only
one total synthesis of griseoviridin has been reported, by
A. I. Meyers.4
1
5
0.7% overall yield for two steps. An access to the corresponding
-epi-griseoviridin lactone 29 is also described.
O
5
7
H
O
Key words: lactones, antibiotics, reductions, cyclisations,
griseoviridin
8
S
1
PGHN
1
0
CO2R
2
Path A
Path B
In the ensuing decades following the introduction of pen-
icillin into clinical practice, the widespread use of antibi-
otics led to the selection of resistant bacteria. A particular
cause of concern is the increasing resistance observed
among Gram-positive organisms, and the pharmaceutical
industry is today confronted with the challenge of finding
O
O
HO
5
2
7
7
H
H
OH
O
8
SX
1
PGHN
PGHN
1
0
2
S
1
1
active compounds. The streptogramins are a class of an-
Y
3
6
tibiotics that responds to this need and are produced as a
mixture of two synergetic structurally unrelated group A
and group B compounds. These two groups of compounds
are respectively polyunsaturated macrolactones and cy-
clic hexadepsipeptides.
O
O
5
2
PGO
7
5
7
HO
H
H
OPG
OH
6
+
+
SX
1
PGHN
PGHN
1
0
SY
1
2
Griseoviridin (1) which was isolated from Streptomyces
Y
2
griseus is a representative member of group A molecules
4
5
7
8
(
Scheme 1), and possesses a cyclic structure enclosing an
Scheme 2
original nine-membered lactone built on a D-(R)-cysteine
moiety. Several preparations of the nine-membered lac-
tone of griseoviridin have been described, all of them re-
In our research program aimed at the total synthesis of
griseoviridin and analogues, we first focused our efforts
on the discovery of an alternative easy and efficient prep-
aration of the nine-membered lactone core 2. With this
goal in mind, we planned two approaches (Scheme 2): in
Path A, a Mitsunobu macrolactonisation reaction was en-
visioned, to form 2 via the seco-lactone 3, this later being
synthesized from the two moieties 4 and 5. This approach
was earlier investigated, using the natural less expensive
(S)-cysteine in place of the (R)-enantiomer, to prepare the
nine-membered lactone 10c in a 13% overal yield for nine
steps (Scheme 3).5
O
O
5
7
7
5
H
0
N
H
O
O
H
O
S
1
8
8
1
0
1
1
6
S
1
PGHN
9
9
2
2
1
3
27
O
N
CO R
O
NH
1
4
18
20
2
1
7
2
2
24
OH OH
Griseoviridin 1
Scheme 1
SYNTHESIS 2004, No. 18, pp 3029–3036
x
x.
x
x
.
2
0
0
4
Advanced online publication: 02.11.2004
DOI: 10.1055/s-2004-834899; Art ID: P09404SS
Georg Thieme Verlag Stuttgart · New York
©

3
030
G. Chaume et al.
PAPER
R1
5
‘9-endo-dig’ cyclisation into an unsaturated nine-mem-
bered lactone.
O
O
H
H
OMe
S)2
O
Although these first results were quite exciting, they were
not directly applicable to the total synthesis of griseoviri-
din where the lactone core is substituted by an amide func-
tion at the C-2 centre. Therefore, we turned our attention
toward the acetylenic ester 16 (Scheme 5) which was pre-
8
S
1
H2N
BocHN
R2
9
10a–c
1
1
1
2
1
1
1
0a
0b
0c
R
R
R
= H, R = H
[α]D = +48.2
[α]D = –10.3
= Me, R = CO2Me [α]D = +12.5
2
= H, R = CO2Me
2
pared in 77% yield by coupling amino acid 11 with ethyl
9
5
-hydroxy-2-pentynoate (15), under DCC–DMAP con-
Scheme 3
ditions.
Parallel efforts were invested along Path B. In this new
strategy, the key step involves a cyclisation of the thio-
acetylenic intermediate 6 to the unsaturated nine-mem-
bered lactone 2 by creation of a sulfur–carbon bond.
Preparation of 6 was envisaged via an esterification of
amino acid 7 with alcohol 8.
HO
CO2Et
15
O
O
DCC, DMAP
EtOAc
H
H
OH
S)2
O
S)2
BocHN
77%
BocHN
In a model study, the acetylenic disulfide compound 12
was prepared from L-NHBoc-cystine 11 by esterification
(
CO2Et
1
1
16
3-butynol, DCC, DMAP, 95% yield) (Scheme 4).6
Scheme 5
First attempts to realise a ring closure of 12 using radical
conditions (Bu SnH–AIBN) afforded the expected unsat-
3
Applying the previous S–S bond-breaking conditions to
disulfide 16 (Zn excess, HOAc, EtOAc), the expected un-
saturated lactone 17 was obtained in 26% yield after puri-
urated nine-membered lactone 13 in a moderated 15%
yield, beside the reduced starting material 14 (5–10%
yield) and vinyltin adducts stemming from the addition of
1
0
fication by forming the silver salt 19 (Scheme 6).
Bu SnH to the triple bond (26% yield).
3
Zn, HOAc
EtOAc
r.t., 12 h
O
O
HO
H
H
O
O
O
S
O
DCC, DMAP
+
1
6
SH
H
EtOAc, 20 °C, 12 h
H
OH
S)2
O
BocHN
BocHN
6
2%
S)2
BocHN
BocHN
CO2Et
>
95%
CO2Et
11
12
1
7 (26% yield overall)
[α]D = –5.6)
18
(
O
a)
or
b)
or
c)
O
O
5
7
H
H
H
AgNO3 aq
THF
O
O
O
S
1
SH
BocHN
BocHN
1
8
1
2
BocHN
8
S
Ag
2
CO Et
1
3 ([α]D = + 38.9)
14
1
9
a) Bu3SnH, AIBN, toluene, ∆
b) PBu3, acetone, MeOH aq
15%
5–15%
Scheme 6
10–15%
50–60%
10%
c) Zn, HOAc, EtOAc, 20 °C, 3 h
51%
However, analysis of the optical rotations of the two lac-
Scheme 4
tones 10a,b prepared from Path A ([a] +48.2 and –10.3,
D
respectively) and lactones 13 and 17 from Path B ([a]
D
A comparable yield (10–15%) of lactone 13 was obtained +38.9 and –5.6) clearly showed that a racemisation takes
when the S–S bond fragmentation was performed under place at the C-8 position under Zn–AcOH conditions.
7
reductive conditions (PBu –acetone–aq MeOH), and as This epimerisation at the C8 centre was not expected con-
3
previously observed, the sulfur derivative 14 was also sidering reports about the use of Zn–AcOH in the reduc-
tion of disulfide compounds.11
formed in this case (50–60% yield).
Nevertheless, carrying out the reaction in the presence of In spite of this partial C8 epimerisation, the Path B was
8
zinc in acetic acid resulted in an improved yield of lac- very attractive due to the shortness of the synthesis.
tone 13 (51%). This result was quite noteworthy, consid- Therefore, for an access to ent-griseoviridin, we decided
ering that no favourable Thorpe–Ingold effect favours this to go with the two acetylenic derivatives 22 and 25
(
Scheme 7).
Synthesis 2004, No. 18, 3029–3036 © Thieme Stuttgart · New York

PAPER
Reductive Cyclisation in a Synthesis of the Lactone Core of ent-Griseoviridin
3031
O
O
5
5
EDA•Li
5
Zn, HOAc
EtOAc
HO
H
H
O
S
O
S
2
+
O
22
8
8
71%
BocHN
BocHN
20
21
2
6 (ent-serie)
1%
α]D = + 113.7
27 (5-epi-serie)
3
4.5%
21
O
O
[
7
DCC, DMAP
EtOAc
7
5
H
H
27.5% yield for 2 steps
4% yield for 2 steps
OH
S)2
O
from 11
from 11
S)2
BocHN
BocHN
9
89%
9
2
1
1
22
O
O
5
5
1
) Zn, HOAc
EtOAc
H
O
H
O
Li
CO2Et
+
BocHN
2
5
8
BocHN
S
8
S
2
3
2
) AgNO3
HO
5
BF3•OEt2
CO Et
2
CO Et
2
2
O
CO2Et
8
4%
28 (ent-serie)
2%
α]D = + 25.9
29 (5-epi-serie)
8%
[α]D = –17.9
2
0
1
24
1
[
2
4
O
10.7% yield for 2 steps
7.1% yield for 2 steps
DCC, DMAP
EtOAc
7
5
from 11
from 11
H
O
1
S)2
Scheme 8
BocHN
89%
9
2
25
CO2Et
Work is currently under investigations about total synthe-
sis of griseoviridin.
Scheme 7
1
2
Starting from the (2S)-4-butyn-2-ol (21), prepared by re-
Mass spectra were obtained via direct introduction by chemical ion-
1
action of the lithium acetylide ethylenediamine complex isation with ammonia (CI, NH ). H NMR spectra were recorded at
with commercial optically active (S)-epoxide 20 200 and 400 MHz, and C NMR at 50.3 and 100.6 MHz. The chem-
Scheme 7), an esterification of amino acid 11 led to the
expected precursor 22 in 89% yield. The corresponding
ethyl ynoate 25 was synthesized by esterification of the
amino acid 11 with alcohol 24, obtained by ring opening
of epoxide 20 with the lithio ester 23.
3
1
3
ical shifts are expressed in parts per million (ppm) downfield from
(
tetramethylsilane (TMS, d = 0) and referenced to residual CDCl
3
(
d = 7.27). Assignments were obtained using J-mod experiments,
and when necessary, COSY, HMBC, HMQC and NOESY experi-
ments. TLC was performed on precoated plate of silica gel 60F 254
or aluminium oxide 60F 254. Flash chromatography was performed
on silica gel 60, 230–400 mesh.
1
3
Treatment of 22 under previous reductive conditions (Zn,
HOAc, EtOAc) led to the pure separated lactones 26 and
7 in 31% and 4.5% yield, respectively (Scheme 8), and
compound 25 to the two epimeric lactones 28 and 29 in
2% and 8% yield, respectively.
N,N¢-Bis(tert-butoxy)carbonylcystine (11)
To a solution of commercial L-cystine (15 g, 0.06 mol) in aq NaOH
2
14
(1 M; 125 mL) was added at 0 °C a solution of di-tert-butyldicar-
1
bonate (41 g, 0.187 mol, 3 equiv) in dioxane (60 mL). The reaction
mixture was stirred at 0 °C for 5 min, then at r.t. overnight. Half the
dioxane was evaporated under reduced pressure and the mixture
was extracted with EtOAc (3 × 50 mL). The combined aq phases
were acidified (pH 1) with aq HCl (1 M) and extracted with EtOAc
As observed in the precedent cases, cyclisation of the
ynoate derivative 25 under Zn/HOAc conditions took
place with partial racemisation at C8 while this side reac-
tion seemed to be less favored for the acetylenic com- (3 × 50 mL). The combined organic layers were washed with brine,
pound 22. As an important result, it was checked that dried (MgSO ), filtered and concentrated under reduced pressure to
4
afford protected cystine 11.
lactones 26–29 placed under Zn/HOAc conditions were
recovered unchanged, with no isomerisation occurring at Yield: 18.6 g (66%); white solid; mp 144–145 °C; [a] –136.8 (c
D
C8. On the other hand, it was also confirmed that the L- 1.63, MeOH).
cystine dimethyl ester 9 was reduced into the correspond-
Anal. Calcd for C H O N S : C, 43.62; H, 6.41; N, 6.36. Found:
1
6
28
8
2 2
ing sulfur derivative without racemisation when treated C, 43.49; H, 6.49; N, 6.23.
with Zn/HOAc.
Esterification of 11 with diazomethane in Et O led to the corre-
2
sponding methyl ester derivative.
In conclusion, via a key reductive cyclisation step under
Zn/HOAc conditions, the synthesis of the S1–N10 nine- Mp: 96–97 °C; [a] –96.7 (c 1.98, MeOH).
D
membered lactone core 28 of ent-griseoviridin was per-
formed in 10.7% overall yield for two steps from L-NH
Boc-cystine. An access to the corresponding 5-epi-
griseoviridin lactone 29 was also described in 7.1% over-
all yield.
–1
IR (CCl ): 3458, 1753, 1722, 1493, 1167 cm .
4
1
H NMR (400 MHz): d = 1.29 [s, 18 H, 2 C(CH ) ], 3.16 (d, J = 5.0
3
3
Hz, 4 H, 2 H -3), 3.76 (s, 6 H, 2 CH , 2 OCH ), 4.60 (dt, J = 6.3, 5.0
2
3
3
Hz, 2 H, 2 H-2), 5.38 (d, J = 6.3 Hz, 2 H, 2 NH).
Synthesis 2004, No. 18, 3029–3036 © Thieme Stuttgart · New York

3
032
G. Chaume et al.
PAPER
1
3
C NMR (100.6 MHz): d = 28.3 [6 CH , 2 C(CH ) ], 41.3 (2 CH ,
and the aq layer extracted with Et O (3 × 30 mL). The combined or-
3
3
3
2
2
2
C-3), 52.6 (2 CH , 2 OCH ), 52.8 (2 CH, 2 C-2), 80.2 [2 C, 2
ganic phases were washed with brine, (Na SO ) and evaporated un-
3
3
2
4
C(CH ) ], 155.0 (2 C, 2 NC=O), 171.1 (2 C, 2 C-1).
der reduced pressure. The crude residue was purified by
chromatography (silica gel; hexane–EtOAc, 9:1) to give the lactone
3
3
+
+
MS (CI, NH ): m/z = 486 (MH + NH ), 469 (MH ), 413, 369, 313,
3
3
1
3 (22 mg, 11% yield) as a white solid, and the sulfide 14 (126 mg,
2% yield).
2
69, 197, 179, 136, 102.
6
Anal. Calcd for C H O N S : C, 46.14; H, 6.88; N, 5.98. Found:
1
8
32
8
2 2
C, 46.03; H, 6.94; N, 5.89.
Entry c, Scheme 4
To a solution of disulphide 12 (255.9 mg, 0.47 mmol) in EtOAc (5
mL) and HOAc (40 mL), zinc was added at 20 °C. The zinc was
added in five portions (1.25 g, 40 equiv) until the starting material
was consumed (6.5 h). The reaction mixture was then filtered
through a pad of Celite and the solvent removed under reduced pres-
sure. The crude residue was then purified by chromatography (silica
gel; hexane–EtOAc, 85:15) to deliver lactone 13 (131 mg, 51%
yield) and the sulfide 14 (26 mg, 10% yield).
[
2R(2R)]-2-[N-(tert-Butoxy)carbonyl]-3-{2-[N-(tert-butoxy)car-
bonyl]-2-[(but-3-yn-1-yl)oxycarbonyl]ethyldisulfanyl}propion-
ic Acid But-3-yn-1-yl Ester (12)
To a solution of 11 (1.8 g, 4.1 mmol), n-butynol (0.7 mL, 9.3 mmol,
2
.3 equiv), and DMAP (105 mg, 0.85 mmol, 0.21 equiv) in EtOAc
(30 mL) was added at 0 °C a solution of DCC (2.02 g, 9.8 mmol, 2.4
equiv) in EtOAc (10 mL). The reaction mixture was stirred for 30
min at 0 °C, and at 20 °C for 12 h. After dilution in CH Cl (20 mL),
2
2
aq HCl (0.5 M; 5 mL) was added at 0 °C and the organic phase was
Compound 13
Mp 82–83 °C; [a] +38.9 (c 1.25, MeOH).
extracted with CH Cl (3 × 20 mL). The combined organic layers
2
2
D
were washed with sat. aq solutions of NaCl, NaHCO and NaCl, and
3
–1
IR (CCl ): 3454, 3011, 2985, 2933, 1750, 1716, 1491, 1165 cm .
4
the solvent was removed under reduced pressure. The residue was
then purified by chromatography (silica gel; hexane–EtOAc, 7:3) to
furnish compound 12.
1
H NMR (400 MHz): d = 1.43 (s, 9 H, 3 CH , 2 CO C(CH ) ], 2.37
3
2
3 3
(m, 1 H, H-4a), 2.79 (m, 1 H, H-4b), 3.02 (d, J = 5.0 Hz, 2 H, H -5),
2
3
4
.88 (t, J = 8.5 Hz, 1 H, H-9a), 4.55 (dt, J = 7.2, 5.0 Hz, 1 H, H-8),
.72 (m, 1 H, H-9b), 5.40 (d, J = 7.2 Hz, 1 H, NH), 6.20 (quint,
Yield: 2.12 g (95%); white solid; mp 77–78 °C; [a] –98.3 (c 0.77,
D
MeOH).
J = 8.4 Hz, 1 H, H-3), 6.35 (d, J = 8.4 Hz, 1 H, H-2).
13
–
1
IR (CCl ): 3455, 3326, 2985, 2937, 1749, 1721, 1492, 1165 cm .
4
C NMR (100.6 MHz): d = 27.8 (CH , C-4), 28.2 [3 CH ,
2
3
1
H NMR (400 MHz): d = 1.43 [s, 18 H, 2 CO C(CH ) ], 2.01 (t,
2
3 3
CO C(CH ) ], 41.3 (CH , C-7), 53.4 (CH, C-8), 62.3 (CH , C-5),
80.1 [C, CO C(CH ) ], 126.6 (CH, C-3), 138.7 (CH, C-2), 154.8 (C,
2 3 3
NC=O), 171.4 (C, C-7).
2
3
3
2
2
J = 2.6 Hz, 2 H, 2 H-4¢), 2.55 (td, J = 6.7, 2.6 Hz, 4 H, 2 H -2¢), 3.17
(
2
d, J = 4.2 Hz, 4 H, 2 H -3), 4.22, 4.28 (2 dt, J = 10.6, 6.7 Hz, 4 H,
2
2
2
H -1¢), 4.52 (dt, J = 7.4, 4.2 Hz, 2 H, 2 H-2), 5.38 (d, J = 7.4 Hz,
2
+
MS (CI, NH ): m/z = 274 (MH ), 235, 218, 174, 156.
3
H, 2 NH).
1
3
Anal. Calcd for C12
H O NS: C, 52.73; H, 7.01; N, 5.12. Found: C,
19 4
C NMR (100.6 MHz): d = 18.5 (2 CH , 2 C-2¢), 28.0 [6 CH , 2
2
3
5
2.83; H, 7.12; N, 4.98.
CO C(CH ) ], 40.8 (2 CH , 2 C-3), 52.7 (2 CH, 2 C-3), 62.9 (2 CH ,
2
3
3
2
2
2
C-1¢), 70.5 (2 C, 2 C-3¢), 79.3 (2 CH, 2 C-4¢), 79.8 [2 C, 2
Compound 14
CO C(CH ) ], 154.7 (2 C, 2 NC=O), 170.2 (2 C, 2 C-1).
2
3 3
IR (CCl ): 3454, 3327, 2984, 2935, 1750, 1722, 1492, 1368, 1343,
4
+
MS (CI, NH ): m/z = 545 (MH ), 489, 445, 433, 389, 345, 274, 218,
1
–1
3
1247, 1161 cm .
84, 174, 140.
1
H NMR (400 MHz): d = 1.44 [s, 9 H, CO C(CH ) ], 2.01 (t, J = 2.6
2
3 3
Anal. Calcd for C H O N S : C, 52.92; H, 6.66; N, 5.14. Found:
C, 53.01; H, 6.79; N, 5.18.
2
4
36
8
2
2
Hz, 1 H, H-4¢), 2.56 (td, J = 6.6, 2.6 Hz, 2 H, H -2¢), 2.98 (m, 2 H,
2
H -3), 4.21, 4.34 (2 dt, J = 10.4, 6.6 Hz, 2 H, H -1¢), 4.59 (m, 1 H,
2
2
H-2), 5.40 (d, J = 7.2 Hz, 1 H, NH).
(
3R)-3-[N-(tert-Butoxy)carbonyl]-3,4,8,9-tetrahydro[1,5]oxa-
1
3
C NMR (100.6 MHz): d = 18.9 (CH , C-2¢), 27.3 (CH , C-3), 28.2
2
2
thionin-2-one (13) and (2R)-2-[N-(tert-Butoxy)carbonyl]-3-mer-
[
7
1
3 CH , C(CH ) ], 54.4 (CH, C-2), 63.2 (CH , C-1¢), 70.3 (C, C-3¢),
3 3 3 2
captopropionic Acid But-3-yn-1-yl Ester (14)
Entry a, Scheme 4
To a solution of disulphide 12 (391 mg, 0.72 mmol) in boiling tolu-
ene (650 mL) was slowly added (3 h) a solution of tributyltin hy-
dride (0.58 mL, 2.16 mmol, 3 equiv) and AIBN (36 mg, 0.22 mmol,
9.0 (CH, C-4¢), 79.9 [C, C(CH ) ], 155.0 (C, NC=O), 170.5 (C, C-
3 3
).
+
MS (CI, NH ): m/z = 274 (MH ), 235, 217, 200, 174.
3
0
.3 equiv) in toluene (15 mL). After stirring for 3.5 h in boiling tol-
5-Hydroxypent-2-ynoic Acid Ethyl Ester (15)
uene, the solvent was removed under reduced pressure and the
To a solution of 3-butyn-1-ol (5 mL, 66 mmol) and imidazole (9 g,
132 mmol, 2 equiv) in CH Cl (30 mL) at 0 °C was slowly added a
crude residue was taken into Et O (2 mL) and treated with sat. aq
2
2
2
potassium fluoride (10 mL). After stirring for 3 h at 20 °C, the mix-
ture was filtered through a pad of Celite, and the aq layer was ex-
solution of tert-butyldimethylsilyl chloride (13 g, 87 mmol, 1.3
equiv) in CH Cl (40 mL). After stirring for 3 h at 20 °C, extraction
2
2
tracted with Et O (3 × 30 mL). The combined organic phases were
with CH Cl followed by classical treatment and purification by
chromatography (silica gel; cyclohexane–EtOAc, 99:1) gave the 4-
2
2 2
washed with brine, dried (Na SO ) and evaporated under reduced
2
4
pressure. The crude residue was purified by chromatography (silica
gel; hexane–EtOAc, 9:1) to give the lactone 13 (58.8 mg, 15%
yield) as a white solid, and the sulfide 14 (19.6 mg, 5% yield).
{[(tert-butyldimethyl)silyl]oxy}but-1-yne.
Yield: 11.6 g (95%).
–
1
IR (CCl ): 2961, 2935, 2860, 2114, 1109 cm .
4
Entry b, Scheme 4
To a solution of disulphide 12 (201.9 mg, 0.371 mmol) in acetone
1
H NMR (400 MHz): d = 0.05 [s, 6 H, 2 CH , Si(CH ) ], 0.87 [s, 9
3
3 2
H, 3 CH , SiC(CH ) ], 1.93 (t, J = 2.6 Hz, 1 H, H-1), 2.37 (td,
J = 7.2, 2.6 Hz, 2 H, H -3), 3.71 (t, J = 7.2 Hz, 2 H, H -4).
3
3 3
(
0
(
5 mL) was added at 20 °C tributylphosphine (0.18 mL, 146.2 mg,
.722 mmol, 1.95 equiv). After dilution with aq MeOH solution
10%; 50 mL), the reaction mixture was stirred for 15 min at 20 °C,
2
2
1
3
C NMR (100.6 MHz): d = –5.0 [2 CH , Si(CH ) ], 18.6 [C,
3
3 2
SiC(CH ) ], 23.1 (CH , C-3), 26.1 [3 CH , SiC(CH ) ], 62.0 (CH ,
C-4), 69.6 (C, C-2), 81.8 (CH, C-1).
3
3
2
3
3 3
2
before the solvent was removed under reduced pressure. The resi-
due was taken into a mixture of Et O and H O (1:1; 10 mL/10 mL)
2
2
Synthesis 2004, No. 18, 3029–3036 © Thieme Stuttgart · New York

PAPER
Reductive Cyclisation in a Synthesis of the Lactone Core of ent-Griseoviridin
3033
+
+
1
MS (CI, NH ): m/z = 202 (MH + NH ), 185 (MH ), 144, 132, 91.
H NMR (400 MHz): d = 1.31 (t, J = 7.1 Hz, 6 H, 2 OCH CH ),
3
3
2
3
1
(
4
2
.45 [s, 18 H, 2 CO C(CH ) ], 2.73 (t, J = 6.7 Hz, 4 H, 2 H -2¢), 3.18
2 3 3 2
Anal. Calcd for C H OSi: C, 65.15; H, 10.95. Found: C, 58.96; H,
10
20
d, J = 6.7 Hz, 4 H, 2 H -3), 4.22 (q, J = 7.1 Hz, 4 H, 2 OCH CH ),
2
2
3
1
0.25.
.31 (t, J = 6.7 Hz, 4 H, 2 H -1¢), 4.60 (dt, J = 7.6, 6.7 Hz, 2 H, 2 H-
2
To a solution of 4-{[(tert-butyldimethyl)silyl]oxy}but-1-yne (vide
supra, 2.26 g, 12.3 mmol) in THF (20 mL) at –40 °C, was added a
solution of BuLi in hexane (1.6 M; 8.45 mL, 13.5 mmol, 1.1 equiv).
After 5 min at –40 °C and 30 min at –5 °C, ethylchloroformate was
added (1.3 mL, 13.5 mmol, 1.1 equiv). The reaction mixture was
stirred for 1 h at 0 °C. After addition of NH Cl, extraction with Et O
), 5.41 (d, J = 7.6 Hz, 2 H, 2 NH).
1
3
C NMR (100.6 MHz): d = 13.8 (2 CH , 2 OCH CH ), 18.8 (2 CH ,
3
2
3
2
2
C-2¢), 28.0 [6 CH , 2 C(CH )], 40.8 (2 CH , 2 C-3), 52.7 (2 CH, 2
3 3 2
C-2), 61.7 (2 CH , 2 OCH CH ), 61.9 (2 CH , 2 C-1¢), 74.4 (2 C, 2
2
2
3
2
C-4¢), 80.0 [2 C, 2 C(CH )], 83.6 (2 C, 2 C-3¢), 153.0 (2 C, 2 C-5¢),
3
4
2
1
54.8 (2 C, 2 NC=O), 170.0 (2 C, 2 C-1).
followed by classical treatment and purification by chromatography
silica gel; cyclohexane–EtOAc, 95:5), gave the 5-{[(tert-butyldi-
+
+
(
MS (CI, NH ): m/z = 707 (MH + NH ), 690 (MH ), 590, 534, 406,
3
3
methyl)silyl]oxy}pent-2-ynoic acid ethyl ester.
346, 290, 246, 212.
Yield: 2.9 g (92%).
Anal. Calcd for C H N O S : C, 52.31; H, 6.44; N, 4.07. Found:
3
0
44
2
12 2
–
1
C, 52.48; H, 6.62; N, 4.12.
IR (CCl ): 2233, 1714, 1250 cm .
4
1
H NMR (400 MHz): d = 0.0 [s, 6 H, Si(CH ) ], 0.85 [s, 9 H,
3
2
(3R,6Z)-3-[N-(tert-Butoxy)carbonyl]-6-[(ethoxy)carbonyl]-
3,4,8,9-tetrahydro[1,5]oxathionin-2-one (17)
SiC(CH ) ], 1.25 (t, J = 7.0 Hz, 3 H, OCH CH ), 2.47 (t, J = 7.0 Hz,
2
OCH CH ).
1
3
3
2
3
H, H -4), 3.68 (t, J = 7.0 Hz, 2 H, H -5), 4.15 (q, J = 7.0 Hz, 2 H,
2
2
To a solution of 16 (2.05 g, 2.98 mmol) in EtOAc (8 mL) and HOAc
(48 mL), zinc powder was added in five portions (7.8 g, 40 equiv)
until the starting material was consumed (6.5 h). The mixture was
then filtered through a pad of Celite, and the solvent removed under
reduced pressure. The crude residue was purified by flash chroma-
tography (silica gel; hexane–EtOAc, 8:2) to give an inseparable
mixture of 17 and 18 (60:40; 1.3 g, 62%).
2
3
3
C NMR (100.6 MHz): d = –4.0 [2 CH , Si(CH ) ], 13.9 (CH ,
3
3 2
3
OCH CH ), 18.2 [C, SiC(CH ) ], 23.0 (CH , C-4), 25.7 [3 CH ,
SiC(CH ) ], 60.6 (CH , C-5), 61.6 (CH , OCH CH ), 74.0 (C, C-2),
8
2
3
3 3
2
3
3
3
2
2
2
3
6.1 (C, C-3), 153.5 (C, C-1).
+
+
MS (CI, NH ): m/z = 274 (MH + NH ), 257 (MH ), 241, 199.
3
3
The crude residue was diluted with THF (55 mL), then aq AgNO3
To a solution of the 5-{[(tert-butyldimethyl)silyl]oxy}pent-2-ynoic
acid ethyl ester (vide supra, 2.9 g, 11.5 mmol) in MeCN (57 mL) at
0
equiv). After stirring for 2 h at 20 °C, the reaction mixture was ex-
tracted with Et O followed by classical treatment and purification
by chromatography (silica gel; cyclohexane–EtOAc, 60:40), to
gave the title product 15.
(0.1 M; 28 mL, 1.2 equiv, 2.76 mmol) was added at 0 °C. After vig-
orous stirring for 4 h, the reaction mixture was filtered through a pad
°C, was added aq fluorhydric acid (16%, 35 mL, 27.6 mmol, 2.4
of Celite, extracted with Et O, and the combined organic layers
2
were washed with brine (100 mL), dried (MgSO ) and concentrated
4
2
under reduced pressure. Purification by chromatography (silica gel;
cyclohexane–EtOAc, 7:3) gave the pure compound 17.
Yield: 534 mg (26% overall yield); [a] –5.6 (c 0.70; MeOH).
D
Yield: 1.52 g (93%).
IR (CCl ): 3455, 2986, 2936, 1754, 1722, 1611, 1485, 1368, 1338,
4
IR (CCl ): 3665, 3631, 3468, 2309, 2237, 1717, 1389, 1367, 1322,
1
–1
4
1
237, 1165, 1059, 1045 cm .
–1
243, 1073, 1051 cm .
1
H NMR (400 MHz): d = 1.33 (t, J = 7.1 Hz, 3 H, OCH CH ), 1.45
1
2
3
H NMR (400 MHz): d = 1.30 (t, J = 7.0 Hz, 3 H, OCH CH ), 2.60
2
3
[
(
s, 9 H, CO C(CH ) ], 2.45 (dd, J = 12.7, 7.7 Hz, 1 H, H-4a), 2.98
2 3 3
(
t, J = 6.3 Hz, 2 H, H -4), 2.88 (wide s, 1 H, OH), 3.80 (t, J = 7.0
2
dd, J = 14.1, 4.0 Hz, 1 H, H-9a), 3.15 (dddd, J = 12.7, 9.6, 7.7, 5.2
Hz, 2 H, H -5), 4.22 (q, J = 7.1 Hz, 2 H, OCH CH ).
1
2
2
3
Hz, 1 H, H-4b), 3.36 (dd, J = 14.1, 2.0 Hz, 1 H, H-9b), 3.84 (t,
J = 9.6 Hz, 1 H, H-5a), 4.33 (q, J = 7.1 Hz, 2 H, OCH CH ), 4.57
3
C NMR (100.6 MHz): d = 13.9 (CH , OCH CH ), 22.9 (CH , C-
3
2
3
2
2
3
4
), 59.9 (CH , C-5), 62.0 (CH , OCH CH ), 74.5 (C, C-2), 86.9 (C,
(ddd, J = 7.2, 4.0, 2.0 Hz, 1 H, H-8), 4.84 (dd, J = 9.6, 5.2 Hz, 1 H,
H-5b), 5.46 (d, J = 7.2 Hz, 1 H, NH), 7.45 (t, J = 7.7 Hz, 1 H, H-3).
2
2
2
3
C-3), 153.9 (C, C-1).
+
+
13
MS (CI, NH ): m/z = 160 (MH + NH ), 143 (MH ), 97.
C NMR (100.6 MHz): d = 14.2 (CH , OCH CH ), 28.3 [3 CH ,
3
3
3
2
3
3
C(CH )], 29.2 (CH , C-4), 41.5 (CH , C-9), 53.5 (CH, C-8), 61.0
3
2
2
Anal. Calcd for C H O : C, 59.14; H, 7.09. Found: C, 59.26; H,
7
10
3
(
CH , C-5), 61.9 (CH , OCH CH ), 80.2 [C, C(CH )], 148.7 (CH,
2 2 2 3 3
7
.17.
C-3), 154.7 (C, NC=O), 165.5 (C, COO), 169.9 (C, C-7), 171.1 (C,
C-2).
[
2R(2R)]-2-[N-(tert-Butoxy)carbonyl]-3-(2-[N-(tert-Butoxy)car-
+
+
bonyl]-2-[({4-[(ethoxy)carbonyl]-but-3-yn}oxy)carbonyl]eth-
yldisulfanyl)propionic Acid {4-[(Ethoxy)carbonyl]but-3-yne}
Ester (16)
To a solution of 11 (465 mg, 1.1 mmol) and DMAP (55 mg, 0.45
mmol, 0.43 equiv) in EtOAc (10 mL), were added at 0 °C a solution
of DCC (540 mg, 2.6 mmol, 2.48 equiv) then a solution of 15 (268
mg, 1.8 mmol, 1.7 equiv) in EtOAc (10 mL). Stirring was main-
tained at 0 °C for 30 min and at 20 °C for 12 h. The reaction mixture
was extracted with CH Cl and the combined organic layers were
MS (CI, NH ): m/z = 363 (MH + NH ), 346 (MH ), 307, 290, 275,
258, 246, 214.
3
3
Anal. Calcd for C H NO S: C, 52.16; H, 6.71; N, 4.06. Found: C,
1
5
23
6
5
2.42; H, 6.62; N, 4.12;
(
2S)-2-Hydroxypent-4-yne (21)
To a suspension at 0 °C of lithium acetylide–ethylenediamine (1.71
g, 18.6 mmol, 1.3 equiv) in DMSO (15 mL) was added (S)-(–)-pro-
pylene oxide 20 (1 mL, 143 mmol) over 10 min. After the addition
was complete, the reaction mixture was allowed to warm slowly to
2
2
washed with aq HCl (0.5 M), sat. aq NaHCO , brine, dried (MgSO )
3
4
and the solvent removed under reduced pressure. Purification by
chromatography (silica gel; cyclohexane–EtOAc, 60:40) of the
crude residue led to the title product 16.
2
0 °C and stirred overnight. The reaction was quenched at 0 °C by
addition of sat. aq NH Cl (20 mL) and diluted with Et O (50 mL).
The aqueous phase was extracted with Et O (3 × 50 mL) and the
combined organic extracts were washed with cold aq HCl (2 M,
4
2
2
Yield: 564 mg (90%).
5
× 5 mL), sat. aq CuSO (5 × 5 mL), and brine (5 mL). The solu-
4
IR (CCl ): 3457, 2238, 1753, 1720, 1487, 1241, 1165, 1096, 1079
cm .
4
–
1
tion was dried (Na SO ), filtered and carefully concentrated under
2 4
Synthesis 2004, No. 18, 3029–3036 © Thieme Stuttgart · New York

3
034
G. Chaume et al.
PAPER
1
3
reduced pressure, and the crude residue was obtained and used with-
out further purification for the next step.
C NMR (CDCl , 100.6 MHz): d = 14.0 (CH , OCH CH ) 22.6
3
3
2
3 ,
(CH , C-1), 29.1 (CH , C-3), 62.0 (CH , OCH CH ), 65.8 (CH, C-
3
2
2
2
3
1
2), 75.0 (C, C-4), 85.9 (C, C-5), 153.7 (C, C=O).
H NMR (CDCl , 400 MHz): d = 1.26 (d, J = 5.9 Hz, 3 H, H -1),
3
3
+
+
1
.98 (br s, 1 H, OH), 2.04 (t, J = 2.6 Hz, 1 H, H-5), 2.29 (ddd,
MS (CI, CH ): m/z = 185 (MH + C H ), 157 (MH ), 139, 111.
4
2
5
J = 16.7, 5.1, 2.6 Hz, 1 H, H-3a), 2.39 (ddd, J = 16.7, 6.4, 2.6 Hz,
H, H-3b), 3.96 (dqd, J = 6.4, 5.9, 5.1 Hz, 1 H, H-2).
Anal. Calcd for C H O : C, 61.52; H, 7.74. Found: C, 61.61; H,
8
12
3
1
7
.82.
[
2R(2R)]-2-[N-(tert-Butoxy)carbonyl]-3-{2-[N-(tert-butoxy)car-
[
2S(5S)]-2-[N,N¢-Bis(tert-butoxycarbonyl)][5-(hex-2-ynoic Acid
bonyl]}-2-({[(but-3-yn-1-yl)oxy]carbonyl}ethynyldisulfa-
nyl)propionic Acid (Pent-4-yn-2-yl) Ester (22)
To a solution of 11 (1.57 g, 3.56 mmol) and DMAP (190 mg, 1.53
mmol, 0.43 equiv) in EtOAc (50 mL) was added, at 0 °C under ni-
trogen atmosphere, a solution of freshly distilled DCC (1.84 g, 8.9
mmol, 2.5 equiv), in EtOAc (25 mL), and a solution of alcohol 21
Ethyl Ester)] L-Cystine Diester (25)
To a solution of 11 (146 mg, 0.32 mmol) and DMAP (17 mg, 0.14
mmol, 0.43 equiv), in EtOAc (3.2 mL), was added, at 0 °C under ni-
trogen atmosphere, a solution of freshly distilled DCC (177 mg,
0
.86 mmol, 2.7 equiv) in EtOAc (1.8 mL), and a solution of alcohol
4 (100 mg, 0.64 mmol, 2 equiv) in EtOAc (3.2 mL). The reaction
2
(
500 mg, 5.95 mmol, 1.6 equiv) in EtOAc (25 mL). The reaction
mixture was stirred for 30 min at 0 °C and overnight at r.t.,
quenched with aq NH Cl (5 mL) and diluted in CH Cl (15 mL).
mixture was stirred for 30 min at 0 °C, and overnight at r.t.,
quenched with aq NH Cl (50 mL) and diluted in CH Cl (150 mL).
The layers were separated and the aq phase was extracted with
CH Cl (3 × 150 mL). The combined organic layers were washed
with aq HCl (0.5 M; 50 mL), sat. aq NaHCO (until pH 7), brine (50
mL), dried (MgSO ), filtered and concentrated under reduced pres-
sure. Purification by chromatography (silica gel; cyclohexane–
EtOAc, 7:3) gave 22.
4
2
2
4
2
2
The layers were separated and the aq phase was extracted with
CH Cl (3 × 30 mL). The combined organic layers were washed
with aq HCl (0.5 M; 5 mL), sat. aq NaHCO (until pH 7), brine (5
mL), dried (MgSO ), filtered and concentrated under reduced pres-
sure. Purification by chromatography (silica gel; cyclohexane–
EtOAc, 8:2) gave compound 25.
2
2
2
2
3
3
4
4
Yield: 208 mg (89%); colourless oil.
Yield: 1.42 g (85% yield); white solid; [a] –98 (c 0.82, MeOH).
D
IR (NaCl): 3366, 2239, 1744, 1722, 1710, 1693, 1512, 1502, 1367,
1
–
1
IR (CCl ): 3365, 2240, 1512, 1367, 1250, 1163 cm .
–1
4
254, 1168 cm .
1
H NMR (CDCl , 400 MHz): d = 1.37 (d, J = 6.3 Hz, 6 H, 2 H -1¢),
1
3
3
H NMR (CDCl , 270 MHz): d = 1.29 (t, J = 7.3 Hz, 6 H, 2
3
1
.45 [s, 18 H, 2 C(CH ) ], 2.04 (t, J = 2.4 Hz, 2 H, 2 H-5¢), 2.49 (dd,
3 3
OCH CH ), 1.38 (d, J = 6.3 Hz, 6 H, 2 H -1¢), 1.43 [s, 18 H, 2
2
3
3
J = 5.7, 2.4 Hz, 4 H, 2 H -3¢), 3.13 (dd, J = 13.8, 5.9 Hz, 2 H, 2 H-
3
5
2
C(CH ) ], 2.60 (dd, J = 17.2, 6.3 Hz, 2 H, 2 H-3¢a), 2.65 (dd,
3
3
a), 3.23 (dd, J = 13.8, 4.4 Hz, 2 H, 2 H-3b), 4.56 (m, 2 H, 2 H-2),
.06 (qt, J = 6.3, 5.7 Hz, 2 H, 2 H-2¢), 5.38 (m, 2 H, 2 NH).
J = 17.2, 5.6 Hz, 2 H, H-3¢b), 3.04–3.22 (m, 4 H, 2 H -3), 4.20 (q,
2
J = 7.3 Hz, 4 H, 2 OCH CH ), 4.50–4.60 (m, 2 H, 2 H-2), 5.09
2
3
1
3
C NMR (CDCl , 100.6 MHz): d = 18.9 (2 CH , 2 C-1¢), 25.4 (2
(sexd, J = 6.3, 5.6 Hz, 2 H, 2 H-2¢), 5.40 (d, J = 7.6 Hz, 2 H, 2 NH).
13
3
3
CH , 2 C-3), 28.3 [6 CH , 2 C(CH ) ], 41.3 (2 CH , 2 C-3), 53.1 (2
2
3
3
3
2
C NMR (CDCl , 67.8 MHz): d = 13.8 (2 CH , 2 OCH CH ), 19.0
3
3
2
3
CH, 2 C-2), 70.3 (2 CH, 2 C-2¢), 70.9 (2 C, 2 C-4¢), 79.2 (2 CH, 2
(
(
(
2 CH , 2 C-1¢), 25.4 (2 CH , 2 C-3¢), 28.1 [6 CH , 2 C(CH ) ], 41.0
3 2 3 3 3
C-5¢), 80.2 [2 C, 2 C(CH ) ], 154.9 (2 C, 2 NC=O), 169.8 (2 C, 2 C-
3
3
2 CH , 2 C-3), 53.0 (2 CH, 2 C-2), 61.7 (2 CH , 2 OCH CH ), 69.2
2 CH, 2 C-2¢), 75.0 and 80.0 (4 C, 2 C-4¢ + 2 C-5¢), 83.5 [2 C, 2
2
2
2
3
1
).
+
+
MS (CI, NH ): m/z = 590 (MH + NH ), 573 (MH ).
C(CH ) ], 153.1 (2 C, 2 C=O, 2 C-6¢), 154.9 (2 C, 2 NC=O), 169.8
(
3
3
3 3
2 C, 2 C-1).
Anal. Calcd for C H N O S : C, 54.52; H, 7.04; N, 4.89. Found:
C, 54.66; H, 7.21; N, 4.92.
2
6
40
2
8 2
+
MS (CI, CH ): m/z = 717 (MH )
4
Anal. Calcd for C H N O S : C, 53.61; H, 6.75; N, 3.91. Found:
C, 53.72; H, 6.82; N, 3.85.
3
2
48
2
12 2
(
5S)-5-Hydroxyhex-2-ynoic Acid Ethyl Ester (24)
To a solution of ethyl propiolate (1.68 g, 17 mmol, 1.2 equiv) in
THF (20 mL) was added, at –78 °C under nitrogen atmosphere, a
solution of BuLi in hexane (1.6 M; 10.7 mL, 17 mmol, 1.2 equiv) to
form the corresponding acetylide 23. After stirring for 10 min at
(
3R,9S,6Z)-3-[N-(tert-Butoxy)carbonyl]-9-methyl-3,4,8,9-tet-
rahydro[1,5]oxathionin-2-one (26) and (3S,9S,6Z)-3-[N-(tert-
Butoxy)carbonyl]-9-methyl-3,4,8,9-tetrahydro[1,5]oxathionin-
–
78 °C, a BF ·Et O solution (2.3 mL) was added dropwise. The re-
3 2
2
-one (27)
To a solution of 22 (0.5g, 0.89 mmol) in EtOAc (5 mL) and HOAc
55 mL) was added at r.t. zinc powder (293 mg, 4.45 mmol, 5 equiv
each 30 min) until the reaction was completed (usually 7 h, total
.51 g, 53 mmol, 60 equiv of zinc). The reaction mixture was fil-
action mixture was stirred for another 10 min at –78 °C, then a so-
lution of (S)-(–)-propylene oxide (20) (1 mL, 14.3 mmol) was
slowly added to the acetylide 23. After stirring for 30 min at –78 °C,
the reaction mixture was quenched at 0 °C by addition of sat. aq
NH Cl (30 mL) and diluted with Et O (50 mL). The layers were
separated and the aq phase was extracted with Et O (3 × 50 mL).
The combined organic extracts were washed with brine, dried
(
(
3
4
2
tered through a pad of Celite, then concentrated under reduced pres-
sure. The crude residue (75 mg) was diluted with THF (7 mL), then,
2
aq AgNO (0.1 M; 3.3 mL, 0.33 mmol, 1.2 equiv) was added at
3
MgSO ), filtered and concentrated under reduced pressure. Purifi-
4
0
°C. After vigorous stirring at 20 °C for 4 h, the reaction mixture
cation by chromatography (cyclohexane–EtOAc, 7:3) gave the title
product 24.
was filtered trough a pad of Celite, extracted with EtOAc and the
combined organic layers were washed with a sat. aq NaHCO and
3
Yield: 1.87 g (84%); colourless oil.
brine, dried (MgSO ) and concentrated under reduced pressure. The
4
–
1
residue was purified by chromatography (silica gel; cyclohexane–
EtOAc, 7:3) to afford the two separable diastereomers 26 and 27.
IR (CCl ): 3389, 2236, 1721, 1710, 1691, 1680, 1368, 1252 cm .
4
1
H NMR (CDCl , 400 MHz): d = 1.30 (d, J = 6.3 Hz, 3 H, H -1),
3
3
1
2
.30 (t, J = 7.3 Hz, 3 H, OCH CH ), 2.17 (d, J = 4.9 Hz, 1 H, OH),
2 3
Compound 26
Yield: 157 mg (31%).
.47 (dd, J = 17.2, 6.3 Hz, 1 H, H-3a), 2.64 (dd, J = 17.2, 5.6 Hz, 1
H, H-3b), 4.05 (qdd, J = 6.3, 5.6, 4.9 Hz, 1 H, H-2), 4.21 (q, J = 7.3
Hz, 2 H, OCH CH ).
IR (NaCl): 3344, 1737, 1710, 1640, 1491, 1249, 1161, 1053, 988
2
3
–1
cm .
Synthesis 2004, No. 18, 3029–3036 © Thieme Stuttgart · New York

PAPER
Reductive Cyclisation in a Synthesis of the Lactone Core of ent-Griseoviridin
3035
1
H NMR (CDCl , 270 MHz): d = 1.32 (t, J = 6.5 Hz, 3 H, H -1¢),
4), 53.6 (CH, C-8), 61.8 (CH , OCH CH ), 69.6 (CH, C-5), 80.1 [C,
3
3
2
2
3
1
2
.43 [s, 9 H, C(CH ) ], 2.09 (ddd, J = 13.5, 7.3, 6.3 Hz, 1 H, H-4a),
C(CH ) ], 132.5 (C, C-2), 148.2 (CH, C-3), 154.7 (C, NC=O), 165.2
3
3
3 3
.87 (ddd, J = 13.5, 8.3, 3.0 Hz, 1 H, H-4b), 2.86 (dd, J = 14.2, 6.4
(C, C=O), 171.2 (C, C-7).
Hz, 1 H, H-9a), 3.09 (dd, J = 14.2, 5.7 Hz, 1 H, H-9b), 4.48 (ddd,
J = 6.6, 6.4, 5.7 Hz, 1 H, H-8), 5.14 (qdd, J = 6.6, 6.3, 3.0 Hz, 1 H,
H-5), 5.32 (d, J = 6.6 Hz, 1 H, NH), 6.22 (ddd, J = 9.2, 8.3, 7.3 Hz,
+
MS (GC, MS, EI): m/z = 359 (M ), 303, 242, 198, 57.
Anal. Calcd for C H NO S: C, 53.46; H, 7.01; N, 3.90. Found: C,
16 25
6
5
3.62; H, 7.17; N, 3.95.
1
H, H-3), 6.32 (d, J = 9.2 Hz, 1 H, H-2).
+
+
MS (CI, NH ): m/z = 305 (M + NH ), 288 (MH ), 249, 232, 188.
3
4
Compound 29
Yield: 76 mg (8%); [a] –17.9 (c 0.73, MeOH).
Anal. Calcd for C H NO S: C, 54.33; H, 7.37; N, 4.87. Found: C,
13
21
4
D
5
4.47; H, 7.48; N, 4.81.
IR (NaCl): 3455, 2984, 2937, 1750, 1710, 1611, 1494, 1370, 1259,
–
1
1
162, 1067, 1042 cm .
Compound 27
1
H NMR (CDCl , 400 MHz): d = 1.30 (t, J = 7.1 Hz, 3 H,
Yield: 23 mg (4.5%); [a] +113.7. (c 1.04, MeOH).
3
D
OCH CH ), 1.43 (d, J = 6.6 Hz, 3 H, H -1¢), 1.45 [s, 9 H, C(CH ) ],
2
2
3
3
3 3
IR (NaCl): 3344, 1737, 1710, 1640, 1491, 1249, 1161, 1053, 988
.20–2.40 (m, 1 H, Ha-4a), 2.85–3.05 (m, 2 H, H-4b + H-9a), 3.36
–
1
cm .
(
dd, J = 14.9, 3.8 Hz, 1 H, H-9b), 4.23 (q, J = 7.1 Hz, 2 H,
1
H NMR (CDCl , 400 MHz): d = 1.38 (d, J = 6.4 Hz, 3 H, H -1¢),
OCH CH ), 4.45–4.55 (m, 1 H, H-5), 4.95–5.10 (m, 1 H, H-8),
3
3
2
3
1
2
.45 [s, 9 H, C(CH ) ], 2.09 (ddd, J = 13.2, 6.7, 2.0 Hz, 1 H, H-4a),
5.35–5.45 (m, 1 H, NH), 7.47 (t, J = 8.5 Hz, 1 H, H-7).
3
3
.87 (m, ddd, 1 H, J = 13.2, 9.8, 7.5 Hz, 1 H, H-4b), 3.05 (dd,
13
C NMR (CDCl , 67.8 MHz): d = 14.1 (CH , OCH CH ), 20.4
3
3
2
3
J = 14.5, 3.2 Hz, 1 H, H-9a), 3.08 (dd, J = 14.5, 3.2 Hz, 1 H, H-9b),
(
CH , CH -1¢), 28.2 [3 CH , C(CH ) ], 37.7 (CH , C-9), 41.6 (CH ,
3
3
3
3 3
2
2
4
1
.49 (dt, J = 7.0, 3.2 Hz, 1 H, H-8), 5.05 (dqd, J = 9.8, 6.4, 2.0 Hz,
H, H-5), 5.47 (d, J = 7.0 Hz, 1 H, NH), 6.15 (ddd, J = 9.5, 7.5, 6.7
C-4), 53.2 (CH, C-8), 62.0 (CH , OCH CH ), 68.8 (CH, C-5), 80.2
2
2
3
[
C, C(CH ) ], 130.1 (C, C-2), 149.0 (CH, C-3), 154.8 (C, NC=O),
3 3
Hz, 1 H, H-3), 6.19 (d, J = 9.5 Hz, 1 H, H-2).
1
64.8 (C, C=O), 169.4 (C, C-7).
1
3
C NMR (CDCl , 67.8 MHz): d = 20.2 (CH , C-1¢), 28.3 [3 CH ,
+
+
3
3
3
MS (CI, CH ): m/z = 375 (M + CH ), 359 (M ).
4
4
C(CH ) ], 36.2 (CH , C-9), 42.0 (CH , C-4), 53.2 (CH, C-8), 69.6
3
3
2
2
Anal. Calcd for C H NO S: C, 53.46; H, 7.01; N, 3.90. Found: C,
(
CH, C-5), 80.3 [C, C(CH ) ], 125.3 (C, C-2 or C-3), 138.3 (CH, C-
16 25
6
3
3
5
3.54; H, 7.12; N, 3.78.
3
or C-2), 155.0 (C, NC=O), 169.7 (C, C-7).
+
+
MS (CI, NH ): m/z = 305 (M + NH ), 288 (MH ), 249, 232, 188.
3
4
Acknowledgements
Anal. Calcd for C H NO S: C, 54.33; H, 7.37; N, 4.87. Found: C,
13
21
4
5
4.41; H, 7.42; N, 4.78.
Aventis Pharma Industry is thanked for financial support and for a
fellowship for C. K. We wish to thank J. Mahuteau for NMR stu-
dies.
(3R,9S,6Z)-3-[N-(tert-Butoxy)carbonyl]-9-methyl-6-
[(ethoxy)carbonyl]-3,4,8,9-tetrahydro[1,5]oxathionin-2-one
(28) and (3S,9S,6Z)-3-[N-(tert-Butoxy)carbonyl]-9-methyl-6-
[(ethoxy)carbonyl]-3,4,8,9-tetrahydro[1,5]oxathionin-2-one
(29)
References
To a solution of 2 5 (1 g, 1.40 mmol) in EtOAc (14.4 mL) and
AcOH (86.4 mL) was added at r.t. zinc powder (375 mg, 5.74 mmol,
(1) Paris, J. M.; Barrière, J. C.; Smith, C.; Bost, P. E. In Recent
Progress in the Chemical Synthesis of Antibiotics; Lukacs,
G.; Ohno, M., Eds.; Springer: Berlin, Heidelberg, 1990.
(2) (a) Ehrlich, J.; Coffey, G. L.; Fisher, M. W.; Galbraith, M.
M.; Knudsen, M. P.; Sarber, R. W.; Schlingman, A. S.;
Smith, R. M.; Weston, J. K. Antibiot. Ann. 1954-1955, 790.
(b) Birnbaum, G. I.; Hall, S. R. J. Am. Chem. Soc. 1976, 98,
1926. (c) Bycroft, B. W.; King, T. J. J. Chem. Soc., Perkin
Trans. 1 1976, 1996.
4
.1 equiv each 30 min) until the reaction was completed (usually 7
h, total 5.25 g, 80.4 mmol, 57 equiv of zinc). The reaction mixture
was filtered through a pad of Celite, then concentrated under re-
duced pressure. The crude residue (826 mg) was diluted with THF
(
55 mL), then aq AgNO (0.1 M; 28 mL, 1.2 equiv, 2.76 mmol) was
3
added at 0 °C. After a vigorous stirring for 4 h, the reaction mixture
was filtered through a pad of Celite, extracted with Et O and the
2
combined organic layers were washed with brine (100 mL), dried
(3) (a) Meyers, A. I.; Amos, R. A. J. Am. Chem. Soc. 1980, 102,
870. (b) Meyers, A. I.; Lawson, J. P.; Amos, R. A.; Walker,
D. G.; Spohn, R. F. Pure Appl. Chem. 1982, 54, 2537.
(c) Butera, J.; Rini, J.; Helquist, P. J. Org. Chem. 1985, 50,
(
MgSO ) and concentrated under reduced pressure. The residue was
4
purified by chromatography (silica gel; cyclohexane–EtOAc, 8:2)
to afford the two separable diastereomers 28 and 29.
3676. (d) Liu, L.; Tanke, R. S.; Miller, M. J. J. Org. Chem.
Compound 28
Yield: 125 mg (12%); [a] +25.9 (c 0.73, MeOH).
1986, 51, 5332. (e) Marcantoni, E.; Massaccesi, M.; Petrini,
M.; Bartoli, G.; Bellucci, M. C.; Bosco, M.; Sambri, L. J.
Org. Chem. 2000, 65, 4553. (f) Moreau, X.; Campagne, J.
M. J. Org. Chem. 2003, 68, 5346.
D
IR (NaCl): 3455, 2984, 2937, 1750, 1710, 1611, 1494, 1370, 1259,
–1
1
162, 1067, 1042 cm .
(
4) Dvorak, C. A.; Schmitz, W. D.; Poon, D. J.; Pryde, D. C.;
Lawson, J. P.; Amos, R. A.; Meyers, A. I. Angew. Chem. Int.
Ed. 2000, 39, 1664.
(5) Kuligowski, C.; Bezzenine-Lafollée, S.; Chaume, G.;
Mahuteau, J.; Barriere, J.-C.; Bacqué, E.; Pancrazi, A.;
Ardisson, J. J. Org. Chem. 2002, 67, 4565.
1
H NMR (CDCl , 400 MHz): d = 1.32 (t, J = 7.1 Hz, 3 H,
3
OCH CH ), 1.34 (d, J = 6.6 Hz, 3 H, H -1¢), 1.43 [s, 9 H, C(CH ) ],
2
3
2
3
3
3 3
.40–2.55 (m, 1 H, H-4a), 2.90–3.05 (m, 2 H, H-4b + H-9a), 3.20–
.35 (m, 1 H, H-9b), 4.25 (q, J = 7.1 Hz, 2 H, OCH CH ), 4.45–4.60
2
3
(
m, 1 H, H-5), 5.15–5.30 (m, 1 H, H-8), 5.30–5.40 (m, 1 H, NH),
7
.51 (t, J = 8.5 Hz, 1 H, H-7).
(6) (a) Boden, E. P.; Keck, G. E. J. Org. Chem. 1985, 50, 2394.
(b) Garner, P.; Park, J. M. Org. Synth. 1992, 70, 18.
1
3
C NMR (CDCl , 67.8 MHz): d = 14.1 (CH , OCH CH ), 18.8
3
3
2
3
(
CH , C-1¢), 28.2 [3 CH , C(CH ) ], 34.6 (CH , C-9), 41.1 (CH , C-
3 3 3 3 2 2
Synthesis 2004, No. 18, 3029–3036 © Thieme Stuttgart · New York

3
036
G. Chaume et al.
PAPER
(11) (a) Ellis, F.; Mills, L. S.; North, P. C. Tetrahedron Lett.
(
7) (a) Humphrey, R. E.; Potter, J. L. Anal. Chem. 1965, 37,
1
2
1
1
64. (b) Overman, L. E.; Petty, S. T. J. Org. Chem. 1975, 40,
779. (c) Dugave, C.; Ménez, A. Tetrahedron: Asymmetry
997, 8, 1453. (d) Moore, C. G.; Trego, B. R. Tetrahedron
982, 18, 205. (e) Overman, L. E.; O’Connor, E. M. J. Am.
1982, 23, 3735. (b) Roth, G. A. J. Org. Chem. 1995, 60,
8105. (c) Feldman, K. S.; Quideau, S.; Appel, H. M. J. Org.
Chem. 1996, 61, 6656.
(12) (a) Adams, M. A.; Duggan, A. J.; Smolanoff, J.; Meinwald,
J. J. Am. Chem. Soc. 1979, 101, 5364. (b) Rzasa, R. M.;
Romo, D.; Stirling, D. J.; Blunt, J. W.; Munro, M. H. G.
Tetrahedron Lett. 1995, 36, 5307. (c) Cotterill, A. S.; Gill,
M.; Milanovic, N. M. J. Chem. Soc., Perkin Trans. 1 1995,
1215.
(13) (a) Trost, B. M.; Müller, T. J. J.; Martinez, J. J. Am. Chem.
Soc. 1995, 117, 1888. (b) Yamaguchi, M.; Hirao, I.
Tetrahedron Lett. 1983, 24, 391.
Chem. Soc. 1976, 98, 771. (f) Crich, D. In Organosulfur
Chemistry, Synthetic Aspect; Page, P., Ed.; Academic Press,
Harcourt Brace & Company: London, New York, 1995,
Chap. 2, 49–88.
(
8) Baggioloni, E. G.; Lee, H. L.; Pizzolato, G.; Uskokovic, M.
R. J. Am. Chem. Soc. 1982, 104, 6460.
9) Jones, R. C. F.; Howard, K. J.; Snaith, J. S. Tetrahedron Lett.
(
1
997, 38, 1647.
10) Cavelier, F.; Daunis, J.; Jacquier, R. Bull. Soc. Chim. Fr.
990, 127, 210.
(
(14) X-ray crystallographic data, lists of refined coordinates and
ESDs, of compound 29, are deposited at the Cambridge
Crystallographic Centre.
1
Synthesis 2004, No. 18, 3029–3036 © Thieme Stuttgart · New York