Approach toward the total synthesis of griseoviridin: Formation of thioethynyl and thiovinyl ether-containing nine-membered lactones through a thioalkynylation-macrolactonization-hydrostannylation sequence

Article abstract of DOI:10.1021/jo0103120

Synthesis of the lactone core 17 of 8-epi-griseoviridin is reported. Thioethynyl derivative 11 was easily prepared via an anionic coupling reaction between acetylenic compound 9 and sulfone 10. After desilylation of 11, saponification of the resulting hydroxy ester 12 followed by a Mitsunobu macrolactonization furnished the unusual triple-bond-containing nine-membered lactone 13 in 50% yield for the last two steps (39% after recrystallization). Stannylation under Magriotis conditions led to the pure regio- and stereocontrolled vinyltin 14 (80% yield). After a Sn/I exchange, palladium-catalyzed carbonylation delivered either the ester lactone 16 in 67% yield or the propargyl amide 17 in 65% yield. Synthesis of propargyl amide 17 of the lactone core of 8-epi-griseoviridin was achieved in 11.9% overall yield from commercial L-cystin dimethyl ester (nine steps).

Full text of DOI:10.1021/jo0103120

J . Org. Chem. 2002, 67, 4565-4568
4565
Ap p r oa ch Tow a r d th e Tota l Syn th esis of Gr iseovir id in : F or m a tion
of Th ioeth yn yl a n d Th iovin yl Eth er -Con ta in in g Nin e-Mem ber ed
La cton es th r ou gh a
Th ioa lk yn yla tion -Ma cr ola cton iza tion -Hyd r osta n n yla tion
Sequ en ce
Carine Kuligowski,† Sophie Bezzenine-Lafolle´e,† Gre´gory Chaume,† J acqueline Mahuteau,‡
J ean-Claude Barrie`re,§ Eric Bacque´,§ Ange Pancrazi,*,† and J anick Ardisson*,†
“Laboratoire de Synthe`se Organique Se´lective et Chimie Organome´tallique”, CNRS-UCP-ESCOM,
FRE 2126, 13 Bd de l’Hautil, 95092 Cergy-Pontoise Cedex, France, Service de RMN, CNRS-BIOCIS,
Universite´ de Chaˆtenay-Malabry, Faculte´ de Pharmacie, 92296 Chaˆtenay-Malabry, France, and Aventis
Pharma, Medicinal Chemistry, Bat Grignard 3A, 13 Quai J ules Guesde, 94403 Vitry sur Seine, France
a.pancrazi@escom.fr
Received March 21, 2001
Synthesis of the lactone core 17 of 8-epi-griseoviridin is reported. Thioethynyl derivative 11 was
easily prepared via an anionic coupling reaction between acetylenic compound 9 and sulfone 10.
After desilylation of 11, saponification of the resulting hydroxy ester 12 followed by a Mitsunobu
macrolactonization furnished the unusual triple-bond-containing nine-membered lactone 13 in 50%
yield for the last two steps (39% after recrystallization). Stannylation under Magriotis conditions
led to the pure regio- and stereocontrolled vinyltin 14 (80% yield). After a Sn/I exchange, palladium-
catalyzed carbonylation delivered either the ester lactone 16 in 67% yield or the propargyl amide
17 in 65% yield. Synthesis of propargyl amide 17 of the lactone core of 8-epi-griseoviridin was
achieved in 11.9% overall yield from commercial L-cystin dimethyl ester (nine steps).
Streptogramin antibiotics are made of two structurally
different components: polyunsaturated macrolactones
(group A) and cyclic hexadepsipeptides (group B). Strep-
togramin derivatives of group A and B are bacteriostatic
separately but exhibit synergetic activities against gram-
positive organisms when associated. Furthermore, little
resistance among staphylococci has been observed over
30 years of clinical practice in Europe for this class of
antibiotics.1 The significant antibiotic activity of strep-
togramin derivatives has attracted considerable attention
from synthetic organic chemists.2
subunit 2 built from non natural D-(R)-cysteine (Scheme
1). Several synthetic approaches to griseoviridin 1 have
been reported by Meyers,4 Helquist,5 Miller,6 and Mar-
cantoni,7 but the only total synthesis of 1 was very
recently described by Meyers.8
Our synthesis of lactone 2 is based on a thioalkynyla-
tion-macrolactonization-hydrostannylation sequence as
shown in Scheme 2. This approach relies on a regio- and
stereoselective Magriotis hydrostannylation9 of a thioet-
hynyl ether, which should lead selectively to (E)-vinyl-
stannane 3. The regioselectivity in this reaction should
be controlled by the sulfur atom. Transformation of 3 into
the target 2 could be effected by Sn/I exchange, followed
by a Heck carbonylation reaction.10
This route involves an initial Mitsunobu lactonization
of thioethynyl ether 5 to form lactone 4. This intermedi-
ate 5 would be made by coupling acetylide 6 with the
S-activated cysteine derivative 7.
In this preliminary study, we decided to use the
natural, less expensive L-(S)-cysteine, in place of the (R)-
enantiomer, and therefore undertook the construction of
the lactone core of the 8-epi-griseoviridin.
Griseoviridin 1, a representative member of group A
molecules, was first isolated from Streptomyces griseus.3
The cyclic structure of griseoviridin encompasses the
unsaturated sulfur-containing nine-membered lactone
* Corresponding Authors. Phone: (33) 1 30 75 61 86. Fax: (33) 1
30 75 60 15. E-mail (J .A.): j. ardisson@escom.fr.
† “Laboratoire de Synthe`se Organique Se´lective et Chimie Organo-
me´tallique”.
‡ Universite´ de Chaˆtenay-Malabry. Phone: (33) 1 46 83 56 52.
§ Aventis Pharma. Phone: (33) 1 55 71 88 14. Fax: (33) 1 55 71 80
14.
(1) Paris, J . M.; Barrie`re, J . C.; Smith, C.; Bost, P. E. In Recent
Progress in the Chemical Synthesis of Antibiotics; Lukacs, G., Ohno,
M., Eds.; Springer-Verlag: Berlin, Heidelberg, 1990. Barrie`re, J . C.;
Berthaud, N.; Beyer, D.; Dutka-Malen, S.; Paris, J . M.; Desnottes, F.
F. Curr. Pharm. Des. 1998, 4, 155. Chu, D. T. W.; Plattner, J . J .; Katz,
L. J . Med. Chem. 1996, 39, 3853.
(4) Meyers, A. I.; Amos, R. A. J . Am. Chem. Soc. 1980, 102, 870.
Meyers, A. I.; Lawson, J .; Amos, R. A.; Walker, D. G.; Spohn, R. F.
Pure Appl. Chem. 1982, 54, 2537.
(2) For total syntheses of streptogramin derivatives, see the follow-
ing. Madumycin II: Tavares, F.; Lawson, J . P.; Meyers, A. I. J . Am.
Chem. Soc. 1996, 118, 3303. Virginiamycin M2: Schlessinger, R. H.;
Li, Y. J . Am. Chem. Soc. 1996, 118, 3301. Pristinamycin IIB: Entwistle,
D. A.; J ordan, S. I.; Montgomery, J .; Pattenden, G. J . Chem. Soc.,
Perkin Trans. 1 1996, 1315.
(3) 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. Birnbaum, G. I.; Hall,
S. R. J . Am. Chem. Soc. 1976, 98, 1926. Bycroft, B. W.; King, T. J . J .
Chem. Soc., Perkin Trans. 1 1976, 1996.
(5) Butera, J .; Rini, J .; Helquist, P. J . Org. Chem. 1985, 50, 3676.
(6) Liu, L.; Tanke, R. S.; Miller, M. J . J . Org. Chem. 1986, 51, 5332.
(7) Marcantoni, E.; Massaccesi, M.; Petrini, M. J . Org. Chem. 2000,
65, 4553.
(8) 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.
(9) Magriotis, P. A.; Brown, J . T.; Scott, M. E. Tetrahedron Lett.
1991, 38, 5047.
(10) Schoenberg, A.; Bartoletti, I.; Heck, R. F. J . Org. Chem. 1974,
39, 3318. Crisp, G. T.; Glink, P. T. Tetrahedron 1994, 50, 2623.
10.1021/jo0103120 CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/31/2002

4566 J . Org. Chem., Vol. 67, No. 13, 2002
Kuligowski et al.
Sch em e 1
Sch em e 4
Sch em e 5
Sch em e 2
Sch em e 3
Sch em e 6
The required acetylenic compound 9 was prepared by
opening (S)-propylene oxide 8 with lithium acetylide-
ethylenediamine complex,11 followed by protection of the
secondary alcohol as a triethylsilyl ether (TES) in 57%
yield for the two steps (Scheme 3).12 Reaction of 2 equiv
of the lithioacetylide derived from 9 (2 equiv of 9, 2 equiv
of n-BuLi, -78 °C, 45 min) with thiosulfonate 1013 at -78
°C for 5 min furnished the expected thioacetylenic
derivative 11 in 74% yield.
unsaturated nine-membered lactone 13 as a white solid
in 50% yield for the two steps (39% after recrystallization)
(Scheme 5).
This cyclization step was followed by a Magriotis
hydrostannylation of 13 [Bu3SnH, Pd(PPh3)4, toluene, 20
°C, 45 min], which gave pure vinyltin lactone 14 in 80%
yield. Formation of the corresponding iodo lactone 15 (I2,
CH2Cl2, 0 °C, 30 min) was then achieved in 87% yield by
a Sn/I exchange.
Deprotection of the triethylsilyl ether was effected
under acidic conditions (Amberlyst 15/MeOH) to give
hydroxy ester 12 in 94% yield (Scheme 4).
After saponification of 12 with LiOH in THF-H2O (0
°C, 2 h), the crude hydroxy acid was directly sub-
jected to Mitsunobu conditions,14 previously used by
Meyers, Helquist, and Miller (PPh3/DEAD, 2:1 toluene/
THF, 25 °C, 1.4 × 10-2 M), to furnish the expected
The final carbonylation reaction step was first checked
using CO (8 bar) and PdCl2(PPh3)2 in CH3CN/EtOH in
the presence of NEt3. Under these conditions, vinyl iodide
15 led to the ester 16 in 67% yield (Scheme 6). Since this
reaction proceeded in good yield, we decided to use
propargylamine in place of ethanol [CO, 8 bar, PdCl2-
(PPh3)2, CH3CN, propargylamine, ∆]. Thus, amide 17, an
advanced intermediate in the synthesis of 8-epi-griseovir-
idin, was obtained in 65% yield from 15.
(11) Cotterill, A. S.; Gill, M.; Milanovic, N. M. J . Chem. Soc., Perkin
Trans. 1 1995, 1215.
(12) Tanabe, Y.; Okumura, H.; Maeda, A.; Murakami, M. Tetrahe-
dron Lett. 1994, 45, 8413.
(13) Billard, T.; Langlois, B. R.; Large, S.; Anker, D.; Roidot, N.;
Roure, P. J . Org. Chem. 1996, 61, 7545.
(14) Kurihara, T.; Nakajima, Y.; Mitsunobu, O. Tetrahedron Lett.
1976, 28, 2455. Mitsunobu, O. Synthesis 1981, 1.
The synthesis of lactone core 17 of 8-epi-griseoviridin
was achieved in 11.9% yield from commercial L-cystine
dimethyl ester (nine steps) using a Mitsunobu macrolac-

Total Synthesis of Griseoviridin
J . Org. Chem., Vol. 67, No. 13, 2002 4567
romethane (18 mL) at 0 °C was slowly added, under an argon
atmosphere, a solution of bromine (160 mL, 3.2 mmol, 1.5
equiv) in dichloromethane (3.5 mL). A persistent red-orange
color appeared during the addition. The mixture was then
stirred for 20 h at 20 °C before filtration through a pad of Celite
and the filtrate concentrated under reduced pressure. Chro-
matography of the crude product on silica gel (75:25 cylohex-
ane/ethyl acetate) gave sulfone 10 (1.59 g, 100% yield) as a
colorless oil: 1H NMR (CDCl3, 400 MHz) δ 1.41 (s, 9 H), 3.41
(dd, 1 H, J ) 13.9, 5.5 Hz), 3.54 (dd, 1 H, J ) 13.9, 4.8 Hz),
3.73 (s, 3 H), 4.55 (ddd, 1 H, J ) 6.4, 5.5, 4.8 Hz), 5.34 (d, 1 H,
J ) 6.4 Hz), 7.56 (t, 2 H, J ) 7.7 Hz), 7.64 (t, 1 H, J ) 7.7 Hz),
7.92 (d, 2 H, J ) 7.7 Hz); 13C NMR (CDCl3, 100.6 MHz) δ 27.8
(3 CH3), 37.1 (CH2), 52.4 (CH + CH3), 79.8 (C), 126.5 (2 CH),
129.0 (2 CH), 133.6 (CH), 143.9 (C), 154.6 (C), 169.8 (C); IR
(CCl4) ν 3450, 3010, 2986, 2962, 2938, 1755, 1721, 1492, 1368,
1164, 1149 cm-1; MS (CI, NH3) m/z 393 (M + NH4+), 376
(MH+), 337, 320, 276. Anal. Calcd for C15H21O6NS2: C, 47.98;
H, 5.64; N, 3.73. Found: C, 47.82; H, 5.60; N, 3.65. [R]D -47.6
(c 0.55, MeOH).
[2R(4S)]-2-[N-(ter t-Bu toxy)ca r bon yl]-3-{[4-(tr ieth yl)si-
lyloxy]p en t-1-yn ylsu lfa n yl}p r op ion ic Acid Meth yl Ester
(11). To a solution of hexyne 9 (1.67 g, 8.4 mmol, 2 equiv) in
THF (9 mL) at -78 °C was added a solution of n-BuLi (1.5 M
in hexanes, 5.5 mL, 8.25 mmol, 2.04 equiv). The resulting
solution was stirred for 45 min at -78 °C. A cooled (-78 °C)
solution of the sulfone 10 (1.58 g, 4.2 mmol, 1 equiv) in THF
(9 mL) was then slowly added to the acetylide solution. After
stirring for 5 min, the mixture was diluted with diethyl ether
(50 mL) and water (20 mL). After extraction with diethyl ether
(3 × 50 mL), the combined organic phases were washed
successively with 2 N aqueous HCl, water, and saturated
aqueous NaCl and dried over MgSO4, and the solvent was
evaporated under reduced pressure. Chromatography on silica
gel of the crude residue (cylohexane/ethyl acetate, 9:1) led to
the title product 11 (1.35 g, 74% yield) as a pale yellow oil: bp
180 °C/0.6 mmHg: 1H NMR (CDCl3, 400 MHz) δ 0.61 (q, 6 H,
J ) 7.9 Hz), 0.97 (t, 9 H, J ) 7.9 Hz), 1.24 (d, 3 H, J ) 6.0
Hz), 1.46 (s, 9 H), 2.35 (dd, 1 H, J ) 16.7, 7.4 Hz), 2.48 (dd, 1
H, J ) 16.7, 5.3 Hz), 3.15 (d, 2 H, J ) 4.7 Hz), 3.78 (s, 3 H),
3.94 (ddd, 1 H, J ) 7.4, 6.0, 5.3 Hz), 4.65 (dt, 1 H, J ) 7.7, 4.7
Hz), 5.46 (d, 1 H, J ) 7.7 Hz); 13C NMR (CDCl3, 100.6 MHz)
δ 4.7 (3 CH2), 6.7 (3 CH3), 23.4 (CH3), 28.2 (3 CH3), 31.0 (CH2),
37.5 (CH2), 52.4 (CH3), 53.3 (CH), 67.3 (CH), 68.8 (C), 80.1 (C),
91.9 (C), 154.9 (C), 170.6 (C); IR (CCl4) ν 3458, 1755, 1722,
1482, 1248, 1210, 1169, 1102 cm-1; MS (CI, NH3) m/z 432
(MH+). Anal. Calcd for C20H37O5NSSi: C, 55.64; H, 8.64; N,
3.26. Found: C, 55.64; H, 8.61; N, 3.28. [R]D -49.3 (c 0.73,
MeOH).
tonization-Magriotis hydrostannylation-Heck carbony-
lation sequence. The key step in this strategy is the
formation of the novel thioethynyl-containing nine-
membered lactone 13 in 50% yield (39% yield after
recrystallization). The strategy developed here is being
transposed to the synthesis of the natural lactone core 2
of griseoviridin from D-(R)-cysteine methyl ester. The
synthesis of the remaining part of 1 is also in progress.
Exp er im en ta l Section
Mass spectra were obtained via direct introduction by
chemical ionization with ammonia (CI, NH3). 1H NMR spectra
were recorded at 200 and 400 MHz and 13C NMR at 50.3 and
100.6 MHz. Assignments were obtained using J -mod experi-
ments and, when necessary, COSY, HMBC, HMQC, and
NOESY experiments. Thin layer chromatography (TLC) was
performed on a precoated plate of silica gel 60F 254 or
aluminum oxide 60F 254. Flash chromatography was per-
formed on silica gel 60, 230-400 mesh.
(4S)-4-[(Tr ieth yl)silyloxy)]p en t-1-yn e (9). To a solution
of commercial lithium acetylide-ethylenediamine complex (1.7
g, 18.6 mmol, 1.3 equiv) in DMSO (15 mL) at 5 °C was added
commercial (S)-propylene oxide 8 (1 mL, 14.3 mmol). The
reaction mixture was stirred at 20 °C for 12 h and poured into
an aqueous NH4Cl/diethyl ether mixture (20:50 mL) at 0 °C.
The aqueous phase was extracted with diethyl ether (3 × 50
mL), and the combined organic phases were washed with 2 N
HCl and brine. After the solution was dried over Na2SO4, the
solvent was concentrated under reduced pressure. The crude
residue was taken up in DMF (15 mL), and to this solution
were added imidazole (1.96 g, 28.8 mmol, 2.02 equiv) and
triethylsilyl chloride (3.6 mL, 21.4 mmol, 1.5 equiv). After
stirring for 12 h at 20 °C, the reaction mixture was extracted
with diethyl ether (3 × 50 mL) and washed with 2 N HCl and
brine. After the solution was dried over Na2SO4, the solvent
was concentrated under reduced pressure. Purification by flash
chromatography of the crude residue on silica gel (cyclohexane)
gave 1.62 g (57%) of 9: 1H NMR (CDCl3, 400 MHz) δ 0.61 (q,
6 H, J ) 7.9 Hz), 0.96 (t, 9 H, J ) 7.9 Hz), 1. 26 (d, 3 H, J )
6.0 Hz), 1.98 (t, 1 H, J ) 2.6 Hz), 2.27 (ddd, 1 H, J ) 16.5, 5.3,
2.6 Hz), 2.39 (ddd, 1 H, J ) 16.5, 5.3, 2.6 Hz), 3.97 (dqd, 2 H,
J ) 7.3, 6.0, 5.3 Hz); 13C NMR (CDCl3, 100.6 MHz) δ 4.8 (3
CH2), 6.7 (3 CH3), 23.1 (CH3), 29.4 (CH2), 67.2 (CH), 69.7 (C),
81.6 (CH); IR (CCl4) ν 3327, 2113 cm-1; MS (CI, NH3) m/z 216
(M + NH4+), 199 (MH+), 186, 170, 159, 132, 119; [R]D -2.5 (c
4.34, MeOH).
N-(ter t-Bu toxy)ca r bon yl-S-p h en ylsu lfon yl-L-cystein e
Meth yl Ester (10). To a solution of commercial dihydrochlo-
ride L-cystine dimethyl ester (0.94 g, 2.76 mmol) in dichlo-
romethane (5 mL) was added a solution of di-tert-butyl
dicarbonate (2.77 g, 12.7 mmol, 4.6 equiv) in dichloromethane
(5 mL), followed by triethylamine (3 mL, 22 mmol, 8 equiv),
and the reaction mixture was stirred at reflux for 2.5 h. After
addition of water at 0 °C, the aqueous phase was extracted
with dichloromethane (3 × 50 mL). The combined organic
phases were washed successively with 2 N aqueous HCl, water,
and saturated aqueous NaCl and dried over MgSO4, and the
solvent was evaporated under reduced pressure. Chromatog-
raphy of the crude residue on silica gel (7:3 cyclohexane/ethyl
acetate) delivered the N,N′-bis(tert-butoxy)carbonyl-L-cystine
dimethyl ester (1.08 g, 83% yield) as a white solid: mp 96-97
[2R(4S)]-2-[N-(ter t-b u t oxy)ca r b on yl]-3-[(4-h yd r oxy)-
p en t-1-yn ylsu lfa n yl]p r op ion ic Acid Meth yl Ester (12). To
a solution of 11 (706 mg, 1.64 mmol) in methanol (5 mL) was
added Amberlyst 15 (50 mg). The mixture was stirred at 20
°C until the reaction was complete (120 min). Triethylamine
was added to the mixture, which was filtered and concentrated
under reduced pressure. Chromatography on silica gel (7:3
cylohexane/ethyl acetate) gave the hydroxy ester (490 mg, 94%
yield) as a yellow oil: 1H NMR (CDCl3, 400 MHz) δ 1.25 (d, 3
H, J ) 6.3 Hz), 1.46 (s, 9 H), 2.37 (dd, 1 H, J ) 16.8, 6.9 Hz),
2.52 (dd, 1 H, J ) 16.8, 4.0 Hz), 2.76 (d, 1 H, J ) 4.3 Hz), 2.98
(dd, 1 H, J ) 13.5, 6.1 Hz), 3.16 (dd, 1 H, J ) 13.5, 4.6 Hz),
3.79 (s, 3 H), 3.97 (dqdd, 1 H, J ) 6.9, 6.3, 4.3, 4.0 Hz), 4.741
(ddd, 1 H, J ) 8.2, 6.1, 4.6 Hz), 5.43 (d, 1 H, J ) 8.2 Hz); 13C
NMR (CDCl3, 100.6 MHz) δ 22.2 (CH3), 28.1 (3 CH3), 30.5
(CH2), 37.3 (CH2), 52.6 (CH3), 52.7 (CH), 66.1 (CH), 69.3 (C),
80.2 (C), 91.9 (C), 155.0 (C), 171.0 (C); IR (CCl4) ν 3375, 1744,
1694, 1507, 1366, 1347, 1247, 1216, 1160 cm-1; MS (CI, NH3)
m/z 318 (MH+), 279, 262, 244, 218, 200, 117. Anal. Calcd for
1
°C; H NMR (CDCl3, 400 MHz) δ 1.29 (s, 18 H), 3.16 (d, 4 H,
J ) 5.0 Hz), 3.76 (s, 6 H), 4.60 (dt, 2 H, J ) 6.3, 5.0 Hz), 5.38
(d, 2 H, J ) 6.3 Hz); 13C NMR (CDCl3, 100.6 MHz) δ 28.3 (6
CH3), 41.3 (2 CH2), 52.6 (2 CH3), 52.8 (2 CH), 80.2 (2 C), 155.0
(2 C), 171.1 (2 C); IR (CCl4) ν 3458, 1753, 1722 cm-1; MS (CI,
NH3) m/z 486 (M + NH4+), 469 (MH+), 413, 369, 313, 269, 197,
179, 136, 102. Anal. Calcd for C18H32O8N2S2: C, 46.14; H, 6.88;
N, 5.98. Found: C, 46.03; H, 6.94; N, 5.89.
To a solution of the N,N′-bis(tert-butoxy)carbonyl-L-cystine
dimethyl ester (vide supra, 994 mg, 2.12 mmol) and sodium
phenylsulfonate (1.04 g, 6.36 mmol, 3 equiv) in dichlo-
C
14H23O5NS: C, 52.98; H, 7.30; N, 4.41. Found: C, 52.78; H,
7.44; N, 4.26. [R]D -79.1 (c 1.32, MeOH).
(5R,8R)-8-[N-(ter t-Bu toxy)car bon yl]-5-m eth yl-2,3,4,5,8,9-
h exa h yd r o-2-yn e-7H-[1,6]-oxa th ion in -7-on e (13). To a so-
lution of 12 (926 mg, 2.92 mmol) in THF (30 mL) at 0 °C was
added a 1 M aqueous LiOH solution (5.8 mL, 5.8 mmol, 2
equiv). The mixture was stirred at 0 °C for 2 h and diluted

4568 J . Org. Chem., Vol. 67, No. 13, 2002
Kuligowski et al.
with a mixture of diethyl ether and water (40/20 mL), and the
etheral phase was washed with water (3 × 50 mL). The
aqueous phases were acidified (pH 2) and extracted with ethyl
acetate (3 × 80 mL). The ethyl acetate phases were dried over
Na2SO4 and concentrated under reduced pressure to give the
crude [2R(4S)]-2-[N-(tert-butoxy)carbonyl]-3-[(4-hydroxy)pent-
1-ynylsulfanyl]propionic acid (854 mg).
gave 332 mg (87%) of iodide 15: 1H NMR (400 MHz) δ 1.32
(d, 3 H, J ) 6.4 Hz), 1.41 (s, 9 H), 1.91 (m, 1 H), 2.73 (m, 1 H),
3.12 (m, 1 H), 3.39 (dd, 1 H, J ) 14.8, 3.6 Hz), 4.59 (ddd, 1 H,
J ) 14.8, 3.6, 2.8 Hz), 5.02 (m, 1H), 5.37 (d, 1 H, J ) 7.6 Hz),
6.86 (t, 1H, J ) 8.4 Hz); 13C NMR (50.3 MHz) δ 19.9 (CH3),
28.3 (3CH3), 40.2 (CH2), 43.2 (CH2), 52.5 (CH), 68.8 (CH), 80.3
(C), 92.2 (C), 150.4 (CH), 154.7 (C), 168.5 (C); IR (CCl4) ν 3450,
1743, 1710, 1490, 1210, 1162, 1046 cm-1; MS (CI, NH3) m/z
414 (MH+). Anal. Calcd for C13H20O4NSI: C, 37.78; H, 4.88;
N, 3.39. Found: C, 38.03; H, 4.93; N, 3.19. [R]D +121 (c 0.93,
MeOH).
To a solution of triphenylphosphine (978 mg, 3.73 mmol,
1.50 equiv) in THF (255 mL) at reflux was added, over a period
of 12 h, a solution of the crude hydroxy acid obtained above
(765 mg, 2.49 mmol) and diethyl azodicarboxylate (590 mL,
3.73 mmol, 1.55 equiv) in THF (25 mL). The reflux was
maintained for an additional 12 h and then the solvent
removed under reduced pressure. The crude residue was
purified by chromatography on silica gel (9:1 cylohexane/ethyl
acetate) to give lactone 13 (351 mg, 50% yield) as a white solid.
Recrystallization in pentane-diethyl ether gave 274 mg of 13
as white crystals (39% yield): mp 117 °C; 1H NMR (400 MHz)
δ 1.45 (d, 3 H, J ) 6.4 Hz), 1.49 (s, 9 H), 2.46 (dd, 1 H, J )
16.1, 6.5 Hz), 2.52 (dd, 1 H, J ) 16.1, 8.95 Hz), 3.08 (dd, 1 H,
J ) 12.8, 5.9 Hz), 3.93 (dd, 1 H, J ) 12.8, 1.7 Hz), 4.87 (ddd,
1 H, J ) 7.3, 5.9, 1.7 Hz), 5.33 (ddq, 1 H, J ) 8.9, 6.5, 6.4 Hz),
5.41(d, 1H, J ) 7.3 Hz); 13C NMR (100.6 MHz) δ 20.0 (CH3),
28.3 (3 CH3), 29.1 (CH2), 40.3 (CH2), 52.7 (CH), 70.0 (CH), 77.0
(C), 80,3 (C), 97.3 (C), 155.1 (C), 171.9 (C); IR (CCl4) ν 3437,
(2E,5R,8R)-8-[N-(ter t-Bu toxy)ca r bon yl]-2-eth oxyca r bo-
n yl-5-m et h yl-4,5,8,9-t et r a h yd r o-7H -[1,6]-oxa t h ion in -7-
on e (16). To a solution of 15 (100 mg, 0.24 mmol), ethanol
(240 mL, 3.6 mmol), and triethylamine (510 mL, 3.6 mmol,
15 equiv), in acetonitrile (6 mL), was added PdCl2(PPh3)2 (34
mg, 0.2 equiv). The reaction mixture was stirred at 50 °C for
3 h under 8 bar of pressure of carbon monoxide. The solution
was then cooled and the solvent evaporated under reduced
pressure. Purification by flash chromatography on silica gel
of the crude residue (9:1 cyclohexane/ethyl acetate) gave 59
mg (67%) of lactone ester 16: 1H NMR (400 MHz) δ 1.30 (t,
3H, J ) 7.1 Hz), 1.43 (d, 3H, J ) 8.0 Hz), 1.45 (s, 9H), 2.38
(m, 1H), 3.00 (m, 1H), 3.04 (m, 1H), 3.36 (dd, 1H, J ) 14.9,
3.8 Hz), 4.23 (q, 2H, J ) 7.1 Hz), 4.48 (m, 1H), 5.10 (m, 1H),
5.42 (d, 1H, J ) 8.1 Hz), 7.47 (t, 1H, J ) 8.5 Hz); 1H NMR
(400 MHz, C6D6, 77 °C) δ 0.91 (d, 1H, J ) 6.5 Hz), 1.0 (t, 3H,
J ) 7.1 Hz), 1.38 (s, 9H), 1.78 (dd, 1H, J ) 12.5, 8.6 Hz), 2.60
(ddd, 1H, J ) 12.5, 8.6, 8.0 Hz), 2.90 (dd, J ) 14.9, 3.1 Hz,
1H), 3.37 (dd, J ) 14.9, 4.0 Hz, 2H), 4.02, 4.0 (2q, 2H, J ) 7.1
Hz), 4.52 (m, 1H), 4.74 (dq, 1H, J ) 8.0, 6.5 Hz), 5.23 (m, 1H),
7.25 (t, 1H, J ) 8.6 Hz); 13C NMR (100.6 MHz) δ 14.1 (CH3),
20.4 (CH3), 28.2 (3CH3), 37.7 (CH2), 41.6 (CH2), 53.2 (CH), 62.0
(CH2), 68.8 (CH), 80.2 (C), 130.1 (C), 149.0 (CH), 154.8 (C),
164.8 (C), 169.4 (C); IR (CCl4) ν 3455, 2984, 2937, 1750, 1710,
1611, 1494, 1370, 1259, 1162, 1067, 1042 cm-1; MS (CI, NH3)
m/z 360 (MH+). Anal. Calcd for C16H25O6NS: C, 53.46; H, 7.01;
N, 3.90. Found: C, 53.28; H, 7.24; N, 3.78. [R]D +12.5 (c 0.72,
MeOH).
2184, 1740, 1731, 1713, 1638, 1490, 1293, 1145, 1060 cm-1
;
MS (CI, NH3) m/z 303 (M + NH4+), 286 (MH+), 247, 230, 212,
202, 186, 158. Anal. Calcd for C13H19O4NS: C, 54.72; H, 6.71;
N, 4.91. Found: C, 54.64; H, 6.70; N, 4.93. [R]D +127.6 (c 1.76,
MeOH).
(2E,5R,8R)-8-[N-(ter t-Bu toxy)ca r bon yl]-2-tr ibu tylsta n -
n yl-5-m et h yl-4,5,8,9-t et r a h yd r o-7H -[1,6]-oxa t h ion in -7-
on e (14). To a solution of lactone 13 (235 mg, 0.82 mmol) in
toluene (1.5 mL) was added a suspension of Pd(PPh3)4 (190
mg, 0.17 mmol, 0.2 equiv) in toluene (5 mL) via cannula.
Bu3SnH (270 mL, 0.99 mmol, 1.2 equiv) was then slowly added
to the reaction mixture. After the mixture was stirred for 45
min at 20 °C, the solvent was removed under vacuum at 20
°C. The crude residue was purified by chromatography on silica
gel (92:8 cyclohexane/ethyl acetate) to give tin compound 14
(380 mg, 80% yield) as a colorless oil: 1H NMR (400 MHz) δ
0.89 (t, 9 H, J ) 7.3 Hz), 0.97 (t, 6 H, J ) 8.2 Hz), 1.31 (sext,
6 H, J ) 7.3 Hz), 1.37 (d, 3H, J ) 6.4 Hz),1.45 (s, 9H), 1.49 (tt,
6H, J ) 8.2, 7.3 Hz), 2.13 (ddd, 1 H, J ) 11.7, 7.8, 6.1 Hz),
2.89 (dd, 1 H, J ) 14.3, 3.5 Hz), 3.00 (ddd, 1 H, J ) 11.7, 7.8,
6.1 Hz), 3.07 (dd, 1 H, J ) 14.3, 1.9 Hz), 4.47 (ddd, 1 H, J )
7.9, 3.5, 1.9 Hz), 5.01 (qd, 1 H, J ) 6.4, 6.1 Hz), 5.46 (d, 1 H,
(2E,5R,8R)-8-[N-(ter t-Bu toxy)ca r bon yl]-5-m eth yl-2-[(N-
p r op a r gyl)ca r b oxa m id e ]-4,5,8,9-t e t r a h yd r o-7H -[1,6]-
oxa th ion in -7-on e (17). To a solution of 15 (100 mg, 0.24
mmol), in acetonitrile (6 mL), were added PdCl2(PPh3)2 (38 mg,
0.054 mmol, 0.2 equiv) and propargylamine (249 mL, 3.6 mmol,
15 equiv). The reaction mixture was stirred at 50 °C for 3 h
under 8 bar of pressure of carbon monoxide. The solution was
then cooled and the solvent evaporated under reduced pres-
sure. Purification by flash chromatography on silica gel of the
crude residue (9:1 cyclohexane/ethyl acetate) gave 58 mg (65%)
of 17 as a white crystalline solid:1H NMR (400 MHz) δ 1.45
(m, 12H), 2.24 (t, 1H, J ) 2.4 Hz), 2.50 (m, 1H), 2.90 (m, 1H),
3.08 (m, 2H), 4.10 (m, 2H), 4.50 (m, 1H), 5.05 (m, 1H), 5.33
117
119
J ) 7.9 Hz), 6.25 (t, 1 H, J ) 7.8 Hz, J
) J
) 45.1
Sn-H
Sn-H
Hz); 13C NMR (100.6 MHz) δ 10.5 (3CH2, J 119Sn- ) 333.6
13
C
117
13
Hz, J
) 318.9 Hz), 13.6 (3 CH3), 20.2 (CH3), 27.3 (3
Sn-
C
119
13
117
13
CH2, J
C ) J
C ) 58.6 Hz), 28.2 (3 CH3), 28.9 (3 CH2,
Sn-
119 13 117
Sn-
119
13
117
13
13
Sn- C
J
C ) J
C ) 13.7 Hz), 37.7 (CH2 J
C ) J
Sn-
Sn-
Sn-
) 40.4 Hz), 42.4 (CH2), 53.4 (CH), 69.9 (CH), 79.9 (C), 142.8
(C), 148.2 (CH), 154.8 (C), 169.0 (C); IR (CCl4) ν 3462, 1743,
1716, 1491, 1457, 1391, 1366, 13308, 1166, 1056 cm-1; MS (CI,
NH3) for the 120Sn major isotope m/z 578 (MH+), 478, 308, 291,
232, 188. Anal. Calcd for C25H47O4NSSn: C, 52.10; H, 8.22;
N, 2.43. Found: C, 52.54; H, 8.53; N, 2.19. [R]D +33.3 (c 0.77,
MeOH).
(2E,5R,8R)-8-[N-(ter t-Bu toxy)ca r bon yl]-2-iod o-5-m eth -
yl-4,5,8,9-tetr a h yd r o-7H-[1,6]-oxa th ion in -7-on e (15). To a
solution of the stannyl compound 14 (530 mg, 0.92 mmol) in
dichloromethane (5 mL) at 0 °C was slowly added a solution
of iodine (245 mg, 0.97 mmol, 1.05 equiv) in dichloromethane
(13 mL). The resulting brown solution was stirred at 0 °C for
30 min and concentrated under reduced pressure. The crude
residue was taken up in diethyl ether (15 mL) and treated with
an aqueous KF solution (2 g/10 mL). After 3 h at 20 °C, the
mixture was filtered through a pad of Celite. The aqueous
phase was extracted with diethyl ether, and the combined
organic phases were washed with brine, dried over MgSO4,
filtered, and concentrated in vacuo. Purification by flash
chromatography on silica gel (9:1 cyclohexane/ethyl acetate)
1
(m, 1H), 7.28 (m, 1H), 7.51 (t, 1H, J ) 8.6 Hz); H NMR (400
MHz, C6D6, 77 °C) δ 0.93 (d, 1H, J ) 6.5 Hz), 1.39 (s, 9H),
1.85 (t, 1H, J ) 2.5 Hz), 1.94 (dd, 1H, J ) 11.0, 8.5 Hz), 2.41
(ddd, 1H, J ) 11.0, 8.5, 8.0 Hz), 2.63 (dd, 1H, J ) 14.2, 3.1
Hz), 2.75 (dd, 1H, J ) 14.2, 4.2 Hz), 3.86, 3.93 (2ddd, 2H, J )
17.5, 5.5, 2.5 Hz), 4.46 (m, 1H), 4.59 (dq, 1H, J ) 8.0, 6.6 Hz),
5.15 (m, 1H), 6.90 (m, 1H), 7.39 (t, 1H, J ) 8.5 Hz); 13C NMR
(100.6 MHz) δ 20.2 (CH3), 28.2 (3CH3), 29.8 (CH2), 37.0 (CH2),
41.8 (CH2), 53.3 (CH), 69.5 (CH), 71.8 (C), 79.2 (CH), 80.3 (C),
131.0 (C), 146.0 (CH), 154.8 (C), 163.5 (C), 168.9 (C); IR (CCl4)-
ν 3450, 3308, 1744, 1709, 1666, 1611, 1493, 1262, 1162 cm-1
;
MS (CI, NH3) m/z 369 (MH+). Anal. Calcd for C17H24O5N2S:
C, 55.42; H, 6.57; N, 7.60. Found: C, 55.31; H, 6.56; N, 7.53.
[R]D + 23.8 (c 0.42, MeOH).
Ack n ow led gm en t. Aventis Pharma Industry is
thanked for financial support and for a fellowship to
C.K.
J O0103120