A novel route to the vinyl sulfide nine-membered macrocycle moiety of griseoviridin

Article abstract of DOI:10.1021/jo000116d

The synthetic potentialities of cerium(III) chloride are demonstrated by the synthesis of a nine-membered ring heterocycle component of Griseoviridin (3) in optically active form. The key step involves the stereospecific formation of the α-carbalkoxy alke

Full text of DOI:10.1021/jo000116d

J . Org. Chem. 2000, 65, 4553-4559
4553
A Novel Rou te to th e Vin yl Su lfid e Nin e-Mem ber ed Ma cr ocycle
Moiety of Gr iseovir id in †
Enrico Marcantoni,* Massimo Massaccesi, and Marino Petrini
Dipartimento di Scienze Chimiche, via S. Agostino 1, I-62032 Camerino (MC), Italy
Giuseppe Bartoli,* Maria Cristina Bellucci, Marcella Bosco, and Letizia Sambri
Dipartimento di Chimica Organica “A. Mangini”, v.le Risorgimento 4, I-40136 Bologna, Italy
Received J anuary 27, 2000
The synthetic potentialities of cerium(III) chloride are demonstrated by the synthesis of a nine-
membered ring heterocycle component of Griseoviridin (3) in optically active form. The key step
involves the stereospecific formation of the R-carbalkoxy alkenyl sulfide moiety using a combination
system of cerium(III) chloride heptahydrate and sodium iodide.
In tr od u ction
The streptogramin antibiotics, for which the name
streptogramin was derived from the soil microorganism
Streptomyces graminofaciens, from which the antibiotic
was first isolated in 1953,1 have been known for the past
five decades. During this time, they have proven to have
many useful applications, in particular as a broad-
spectrum antibiotic with in vitro inhibitory activity
toward various pathogenic bacteria and fungi.2 These
antibiotics occur as two distinctly different classes of
compounds. The antibiotics of group A are complex
macrocyclic lactam-lactones, for which six structures
have been reported to date,3 and their structures have
been confirmed by X-ray crystallography.4 Virginiamycin
M1 (1), Madumycin II (2), and Griseoviridin (3) are
representative examples of type A (Figure 1).5
The antibiotics of group B, on the other hand, are
hexadepsipeptides,6 and, despite their quite different
structures, the group A and B antibiotics in combination
exhibit a strong synergism in their antibacterial action.7
As a synthetic challenge, we have been interested in
one member of group A, Griseoviridin (3). The structure
of Griseoviridin, the most structurally complex member
of this class, was then determined and confirmed by
single-crystal X-ray analysis.8 Considerable progress has
F igu r e 1.
been reported in exploring novel synthetic routes to
streptogramins of group A during these last years,9 and
the same synthetic effort has been recently applied to
producing the key intermediates of Griseoviridin (3), for
which, like Madumycin II (2),10athe total synthesis of
Griseoviridin has recently been completed.10b
* To whom correspondence should be addressed. Tel: +39 0737
402255. Fax: +39 0737 637345. E-mail: enricom@camserv.unicam.it.
† This paper is dedicated to Professor Albert I. Meyers in recognition
of his remarkable contribution to the art and science of organic
chemistry.
A retrosynthetic scheme to the Griseoviridin (3) is
outlined in Scheme 1. The simple disconnection at the
amide bonds has revealed two fragments, 4 and 5.
Inspection of the target antibiotic reveals, in addition to
a wide array of functionality, the presence of a rare
(1) Charney, J .; Fisher, W. P.; Curran, C.; Machlowitz, R. A.; Tytely,
A. A. Antibiot. Chemother. (Washington, D. C.) 1953, 3, 1283.
(2) Ehrlich, J .; Coffey, G. L.; Fisher, M. W.; Galbraith, M. M.;
Kundsen, M. P.; Sarber, R. W.; Schlingman, A. S.; Smith, R. M.;
Weston, J . K. Antibiot. Ann. 1955, 790.
(3) Bycroft, B. W. J . Chem. Soc., Perkin Trans. 1 1977, 2464-2470.
(4) Durant, F.; Evard, G.; Declerq, J . P.; Germain, G. Cryst. Struct.
1974, 3, 503.
(5) (a) Paris, J . M.; Barriere, J . C.; Smith, C.; Bost, P. E. In Recent
Progress in the Chemical Synthesis of Antibiotics; Lucas, G.; Ohno, M.,
Eds.; Springer-Verlag: Berlin, 1990; pp 183-248. (b) Di Giambattista,
M.; Chinali, G.; Cocito, C. J . Antimicrob. Chemother. 1989, 24, 485-
488. (c) Cocito, C. Microbiol. Rev. 1979, 43, 145-169.
(6) Sheehan, J . C.; Ledis, S. L. J . Am. Chem. Soc. 1973, 95, 875-
879.
(7) Cocito, C. J . Gen. Microbiol. 1969, 57, 179-184.
(8) Birubaum, G. L.; Hall, S. R. J . Am. Chem. Soc. 1976, 98, 1926-
1931.
(9) (a) Bergdahl, M.; Hett, R.; Friebe, L. I.; Gangloff, R. A.; Iqbal,
J .; Wu, Y.; Helquist, P. Tetrahedron Lett. 1993, 34, 7371-7374. (b)
Adje, N.; Breulles, P.; Uguen, D. Tetrahedron Lett. 1992, 32, 2151-
2154. (c) Kazmierczak, F.; Helquist, P. J . Org. Chem. 1989, 54, 3988-
3992. (d) Meyers, A. I.; Lawson, J . P.; Walker, D. G.; Linderman, R. J .
J . Org. Chem. 1986, 51, 5111-5123.
(10) (a) Tavares, F.; Lawson, J . P.; Meyers, A. I. J . Am. Chem. Soc.
1996, 118, 3303-3304. (b) 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. Engl. 2000, 39, 1664-1666.
10.1021/jo000116d CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/22/2000

4554 J . Org. Chem., Vol. 65, No. 15, 2000
Marcantoni et al.
Sch em e 1
D-amino acid (C-8) and other chiral centers at C-5, C-18,
and C-20. Two of these chiral centers, as well as the
lactone and thiovinyl ether linkages, are present in the
nine-membered macrocycle 4, for which chemical degra-
dations have unambiguously established the absolute
configuration at C-5 and C-8. These developments have
established that 4 possesses the 5R,8S configuration.11
Further retrosynthetic analysis of the unusual sulfur-
containing nine-membered lactone system 6 of Griseovir-
idin (3) has shown the presence of the conjugated vinyl
sulfide moiety (7). Recently, the vinyl sulfides have
attracted special attention as important intermediates
in various synthetic transformations,12,13 and their ste-
reospecific synthesis has been attempted.14
In the course of our program, aimed to develop new
synthetic uses of cerium trichloride, a very cheap, non-
toxic, and water-tolerant reagent,15 in reactions that need
the presence of a Lewis acid activator, we have found
several synthetically useful procedures using this triva-
lent lanthanide salt.16 Moreover, during our studies on
the applications of cerium compounds in organic synthe-
sis, we have found that CeCl3‚7H2O, in conjunction with
NaI, acts as an efficient reagent in the cleavage of the
carbon-oxygen bond17 under neutral conditions. Thus,
we have considered the possibility of using cerium(III)
chloride to promote the formation of the R-carboalkoxy
alkenyl sulfide moiety in 7, and we wish to report herein
our recent results concerning a new strategy for the
stereospecific synthesis of the N-protected nine-mem-
bered macrocycle 6 in pure enantiomeric form.
Resu lts a n d Discu ssion
Griseoviridin 3, one of the active compounds in the
streptogramin family of antibiotics, has been the subject
of synthetic studies for several years. The nine-membered
ring heterocyclic component 6 has been previously pre-
pared by three different approaches.18-20 Because the
formation of the conjugated vinyl sulfide moiety in 7
has been the most important, and at the same time, the
most difficult, step in the three precedent sequences, our
approach was to obtain this moiety through use of
cerium(III) chloride.
Our synthetic approach began with the synthesis of
S-methylcarboethoxy-D-cysteine derivative 12. Therefore,
we decided to start from D-cystine 8 (Scheme 2), which
was transformed into the bis tert-butyl ester 9 by acid-
catalyzed transesterification21 of commercially available
D-cystine with tert-butyl acetate. It is imperative to use
a tightly stoppered flask in this reaction to prevent the
loss of isobutylene and the corresponding reduction in
yield. The formation of the bis benzamide 10 proceeds
quite cleanly using benzoyl chloride and pyridine, afford-
ing a 92% recrystallized yield. The disulfide bond is then
reductively cleaved using sodium borohydride in ethanol,
producing the free thiol compound 11 in 70% yield after
chromatography and crystallization. The final formation
of carbon-sulfur bond in the intermediate 12 was
obtained by deprotonation of the cysteinic sulfur and
successive substitution of bromine atom in ethyl R-bro-
moacetate. It should also be mentioned that the S-
methylethoxycarbonyl D-cysteine derivative is best pre-
pared without racemization when sodium methoxide is
used as the base.22
(11) (a) MacMillan, J .; Simpson, T. J . J . Chem. Soc., Perkin Trans.
1 1973, 1487-1491. (b) Kuo, C. H.; Taub, D.; Hoffsommer, R. D.;
Wendler, N. L.; Urry, W. H.; Mullenbach, G. J . Chem. Soc., Chem.
Commun. 1967, 761-762. (c) Kuhn, R.; Kum, K. Chem. Ber. 1962, 95,
2009-2014.
(12) Takeda, T.; Kanamori, F.; Matsusito, H.; Fujiwara, T. Tetra-
hedron Lett. 1991, 32, 6563-6566.
(13) Andres, D. F.; Laurent, E. G.; Marquet, B. S. Tetrahedron 1995,
51, 2605-2608.
(14) Moshi, M.; Masuda, Y.; Arase, A. J . Chem. Soc., Chem.
Commun. 1985, 1068-1069.
(15) Imamoto, T. Lanthanides in Organic Synthesis; Academic
Press: New York, 1994.
(16) (a) Liu, H. J .; Shia, K. S.; Shang, X.; Zhu, B. Y. Tetrahedron
1999, 55, 3803-3830. (b) Alessandrini, S.; Bartoli, G.; Bellucci, M. C.;
Dalpozzo, R.; Malavolta, M.; Marcantoni, E.; Sambri, L. J . Org. Chem.
1999, 64, 1986-1992. (c) Ballini, R.; Marcantoni, E.; Perella, S. J . Org.
Chem. 1999, 64, 2954-2957. (d) Bartoli, G.; Bosco, M.; Dalpozzo, R.;
De Nino, A.; Marcantoni, E.; Sambri, L. J . Org. Chem. 1998, 63, 3745-
3747. (e) Bartoli, G.; Bosco, M.; Dalpozzo, R.; Marcantoni, E.; Sambri,
L. Chem.sEur. J . 1997, 3, 1941-1950. (f) Bartoli, G.; Marcantoni, E.;
Petrini, M.; Sambri, L. Chem.sEur. J . 1996, 2, 973-979. (g) Bartoli,
G.; Marcantoni, E.; Sambri, L.; Tamburini, M. Angew. Chem., Int. Ed.
Engl. 1995, 34, 2046-2049.
(18) Meyers, A. I.; Amos, R. A. J . Am. Chem. Soc. 1980, 102, 870-
872.
(19) Butera, J .; Rini, J .; Helquist, P. J . Org. Chem. 1985, 50, 3676-
3678.
(20) Liu, L.; Yanke, R. S.; Miller, M. J . J . Org. Chem. 1986, 51,
5332-5337.
(17) (a) Bartoli, G.; Bellucci, M. C.; Bosco, M.; Cappa, A.; Marcantoni,
E.; Sambri, L.; Torregiani, E. J . Org. Chem. 1999, 64, 5696-5699. (b)
Bartoli, G.; Bosco, M.; Marcantoni, E.; Nobili, F.; Sambri, L. J . Org.
Chem. 1997, 62, 4183-4184.
(21) Amaral, M. J . S. A.; Macedo, M. A.; Oliveira, M. I. A. J . Chem.
Soc., Perkin Trans. 1 1977, 205-206.
(22) Tamikaga, R.; Nozaki, Y.; Tamura, T.; Kaji, A. Synthesis 1983,
134-135.

Novel Route to Macrocycle Moiety of Griseoviridin
J . Org. Chem., Vol. 65, No. 15, 2000 4555
Sch em e 2
a
Key: (a) CH3CO2But, 60% HClO4, r.t. 2 d, 83%; (b) PhCOCl, Pyridine, CH2Cl2, r.t. 15 h, 92%; (c) NaBH4, EtOH, r.t. 1.5 h, 70%; (d)
CH3ONa, BrCH2CO2Et, CH3OH, reflux 2 h, 86%.
strongly carcinogenic.29 For this reason the literature
Sch em e 3
contains a variety of methods for the preparation of MOM
ethers.30 Very recently, Marcune et al.31 reported that
methoxymethyl-2-pyridylsulfide (MOM-ON) is an ef-
ficiently methoxymethylating reagent of hydroxyl groups
of acid-sensitive molecules when used in conjunction with
AgOTf, NaOAc, and THF. But the use of very expensive
reagents prompted us to explore other methods, which
have some advantages over using chloromethyl methyl
ether. We have found that a suitable method is the
transacetalization reaction of dimethoxymethane with
a
Key: (a) Baker’s yeast, 30 °C, 3 d, 70%; (b) CH2(OCH3)2,
â-hydroxy ester 14 utilizing iodotrimethylsilane gener-
H2CdCHCH2SiMe3, I2 (5% mol), r.t. 40 h, 90%; (c) DIBAL-H,
CH2Cl2, -78 °C, 1 h 86%.
ated in situ as a catalyst.32 In fact, when a solution of
hydroxy ester in dimethoxymethane was stirred in the
presence of allyltrimethylsilane and catalytic iodine (5%
The C-3-C-5 fragment in the nine-membered ring of
mol), the methoxymethyl ether was obtained in good yield
4 was stereospecifically constructed as outlined in Scheme
(90%). A lengthy reaction time (40 h) was required to
3. In the interest of producing larger amounts and, more
ensure the complete consumption of the starting mate-
importantly, recognizing the need for a chiral molecule,
rial. However, refluxing the reaction in dry benzene gives
the enantioselective reduction of ethyl acetoacetate (13)
a shorter reaction time (15 h), but the yield is low (66%)
using a yeast fermentation broth23,24 was found to proceed
and produces a lot of byproduct.
quite well. The chiral â-hydroxy ester 14 in 70% yield
Diisobutylaluminum hydride (DIBAL-H) has proven to
has proven to be in 95.4% enantiomeric excess (ee). The
be a simple and versatile method33 for the reduction of
ester 15 to aldehyde 16 in 86% yield. The reduction was
ester with (S)-(-)-1-methoxy-1-trifluoromethylpheny-
enantiomeric purity was checked by formation of the
carried out at very low temperature (-78 °C), such that
the ester moiety is still reactive to the hydride, but the
aldehyde moiety is not.33c The difficulty with the solubil-
ity of the substrate, which occurs at the very low
temperature in toluene, the solvent generally required
in the use of DIBAL-H, was overcome using dichlo-
romethane without a loss in the yield. With R-alkylthio
ester 12 and aldehyde 16 in hand, we next examined the
coupling of these two frameworks. The initial attempts
to accomplish the Knoevenagel condensation (Scheme 4)
lacetyl (MTPA) chloride, Mosher’s chiral derivatizing
agent.25 It is important to note that the product from this
reduction is (S) in configuration, opposite of the (R)
required for the natural product. Thus, an inversion was
necessary and was performed in the final ring-closure
step.
The hydroxyl group was protected as methoxymethyl
ether (MOM) 15, frequently used as a protecting group
for alcohols and phenols.26,27 The MOM derivatives were
usually prepared by alkylation with an excess of chlo-
romethyl methyl ether.28 Although this reagent is itself
only a middling carcinogenic, it is usually contamined
with small amounts of bis-chloromethyl ether, which is
(29) Occupational Safety and Health Administration, U. S. Depart-
ment of Labor, Federal Register 39 (20); U. S. Government Printing
Office: Washington, D. C., 1974.
(30) (a) Kantam, M. L.; Sauthi, P. L. Synlett 1993, 429-430. (b)
Danheiser, R. L.; Romines, K. R.; Koyama, H.; Gee, S. K.; J ohnson, C.
R.; Medich, J . R. Org. Synth. 1992, 71, 133-139. (c) Olah, G. A.;
Husaine, A.; Gupta, B. G. B.; Narang, S. C. Synthesis 1981, 471-472.
(d) Yardley, J . P.; Fletcher, H. Synthesis 1976, 244-245. (e) Fuji, K.;
Nakano, S.; Fujita, E. Synthesis 1975. 276-277.
(23) (a) Seebach, D.; Giovannini, F.; Lamatsch, B. Helv. Chim. Acta
1985, 68, 958-960. (b) Seebach, D.; Sutter, M. A.; Weber, R. H.; Zu¨ger,
M. F. Org. Synth. 1984, 63, 1-9.
(24) Dahl, A. C.; Fjeldberg, M.; Madsen, J . O. Tetrahedron: Asym-
metry 1999, 10, 551-559.
(25) (a) Dale, J . A.; Mosher, H. S. J . Am. Chem. Soc. 1973, 95, 512-
519. (b) Ohtani, I.; Kashman, Y.; Kakisawa, H. J . Am. Chem. Soc. 1991,
113, 4092-4096.
(26) Greene, T. W. Protective Groups in Organic Chemistry; Wiley-
Interscience: New York, 1981; p 10.
(27) Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis; J ohn
Wiley & Sons: New York, 1967; Vol. 1, p 132.
(28) McComie, J . F. W. Advances in Organic Chemistry; Wiley-
Interscience: New York, 1963; p 232.
(31) Marcume, B. F.; Karady, S.; Dolling, U.-H.; Novak, T. J . J . Org.
Chem. 1999, 64, 2446-2449.
(32) Olah, G. A.; Husain, A.; Narang, S. C. Synthesis 1983, 896-
897.
(33) (a) Keck, G. E.; Palani, A.; McHardy, S. F. J . Org. Chem. 1994,
59, 3113-3122. (b) Ito, Y.; Kobayashi, Y.; Kawabat, T.; Takase, M.;
Terashima, S. Tetrahedron 1989, 45, 5767-5790. (c) J ohnstone, R. A.
W. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, 1991; Vol. 8, pp 259-281.

4556 J . Org. Chem., Vol. 65, No. 15, 2000
Marcantoni et al.
Sch em e 4
Sch em e 5
a
Key: (a) ButMgCl, CeCl3, THF, 16, -78 °C, 6.5 h, 65%; (b)
a
Key: (a) Piperidine, EtOH, 16, r.t. 24 h; (b) NaH, THF, -78
CeCl3‚7H2O, NaI, CH3CN, reflux 24 h, 96%.
°C, 16, 2 h, 88%.
ature.39 Under these simple conditions, the (Z)-vinyl
sulfide was exclusively obtained, and deprotection of the
hydroxyl and carboxyl groups was also accomplished. The
removal of the methoxymethyl protecting group by treat-
ment with CeCl3‚7H2O/NaI system in acetonitrile has
been reported,40 whereas a new methodology to remove
a tert-butyl ester has herein been reported, giving the
penultimate product 21 in 96% yield as a white solid. The
attempted column chromatography of the crude product
led to low recoveries, due to difficulties in extracting the
very polar hydroxy acid.
Finally, for the preparation of large-ring lactone from
the corresponding open-chain hydroxy acid 21, a rapid
esterification reaction is necessary to overcome the
unfavorable entropy factors leading to the formation of
polymers. The mildness of the reaction conditions is also
important if the method is to be applied to the synthesis
of complex natural substances, such as Griseoviridin,
with sensitive functionalities. Last decade, intensive
studies in this field have commenced, and several good
lactonization methods using different types of reagents
have been developed,41 some of them having been suc-
cessfully applied to the synthesis of macrolides.42 Con-
sequently, the literature contains a variety of methods
developed for the cyclization of medium and large ring
lactones.43 A limited number of those methods, however,
appeared applicable to the problem in hand. Thus, the
method employed has been an improved procedure of the
Mitsunobu coupling reaction,44,45 which uses the readily
available reagents diphenyl-2-pyridylphosphine (Ph2PyP)
and di-tert-butylazodicarboxylate (DTBAD), respectively.46
The reaction (Scheme 6) has been shown to proceed via
by the simple procedure of Tanikaga,34 which uses
reagents that are readily available and inexpensive, such
as piperidine and ethanol, met with unsuccess. In every
case, the starting ester 12 was recovered. An attempted
condensation under treatment of ester 12 with NaH in
THF at -78 °C resulted in removing the R-proton of
cysteine moiety to afford carbanion intermediate 17,
which spontaneously eliminates the R-carboethoxymeth-
ylthiolate 19 to give R,â-unsaturated ester 18 as the
major product. These observations suggested to us that
the condensation is sensitive to the countercation and the
degree of steric hindrance of the base employed for the
anion generation.35,36 From the literature, it is known
that tert-butyl Grignard reagent may be used as a base
to generate an anion in aldol condensation.37 Moreover,
it was found that dry cerium(III) chloride works as an
efficient activator for the addition of carbanion to the
carbonyl moiety.38 Thus, the protected D-cysteine deriva-
tive 12 (Scheme 5) was converted to the magnesium
derivative by reaction in THF with 1.35 equiv of tert-
butylmagnesium chloride at -78 °C, and subsequent
transfer by cannula to a mixture of chiral aldehyde 16
and dry CeCl3 in THF at -78 °C, afforded a mixture of
the desired diastereomeric alcohols 20 in 65% yield.
Although both diastereomers were chromatographically
separable, such separation was not necessary because
dehydration of either mixture of the diastereomers
proceeded efficiently. Attempted dehydration of 20, by
treatment with methanesulfonyl chloride and triethy-
lamine, gave a complex mixture of elimination products.
This problem was circumvented by repeating the dehy-
dration using a combination system of CeCl3 heptahy-
drate and sodium iodide in acetonitrile at reflux temper-
(39) Our results on the dehydration of â-hydroxy carbonyl com-
pounds by the CeCl3‚7H2O/NaI system in acetonitrile at reflux tem-
perature are submitted for publication.
(40) Bartoli, G.; Bosco, M.; Marcantoni, E.; Sambri, L.; Torregiani,
E. Synlett 1998, 209-211.
(41) (a) Inanaga, J .; Hirata, K.; Saeri, H.; Katsuki, T.; Yamaguchi,
M. Bull. Chem. Soc. J pn. 1979, 52, 1989-1993. (b) Narasaka, K.;
Masui, T.; Mukaiyama, T. Chem. Lett. 1977, 763-765. (c) Nicolaou,
K. C. Tetrahedron 1977, 33, 683-710.
(42) (a) Narasaka, K.; Murayama, K.; Mukaiyama, T. Chem. Lett.
1978, 885-887. (b) Masamune, S.; Bates, G. S.; Corcoran, J . W. Angew.
Chem., Int. Ed. Engl. 1977, 16, 585-607.
(43) Paterson, I.; Mausuri, M. M. Tetrahedron 1985, 41, 3569-3624.
(44) Mitsunobu, O. Synthesis 1981, 1-28.
(45) (a) Simon, C.; Sandor, H.; Sandor, M. J . Heterocycl. Chem. 1997,
34, 349-356. (b) Hughes, D. L. Org. React. 1992, 42, 335-398.
(46) Kiankarimi, M.; Lowe, R.; McCarthy, J . R.; Whitten, J . P.
Tetrahedron Lett. 1999, 40, 4497-4500.
(34) Tanikaga, R.; Nishida, M.; Ono, N.; Kaji, A. Chem. Lett. 1980,
781-782.
(35) Hoye, T. R.; Kurth, M. J . J . Org. Chem. 1980, 45, 3549-3554.
(36) (a) Yamagiwa, S.; Hoshi, N.; Sato, H.; Kosugi, H.; Uda, H. J .
Chem. Soc., Perkin Trans.
1 1978, 214-224. (b) House, H. O.;
Crumrune, D. S.; Teranishi, A. Y.; Olmstead, H. D. J . Am. Chem. Soc.
1973, 95, 3310-3324.
(37) (a) Corey, E. J .; Weigel, L. O.; Cho, A. R. C. H.; Hua, D. H. J .
Am. Chem. Soc. 1980, 102, 6613-6615. (b) House, H. O.; Melillo, D.
G.; Sauter, F. J . J . Org. Chem. 1973, 38, 741-748.
(38) (a) Bartoli, G.; Marcantoni, E.; Petrini, M. Angew. Chem., Int.
Ed. Engl. 1993, 32, 1061-1062. (b) Imamoto, T. In Comprehensive
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Oxford, 1991; Vol. 1, pp 231-260. (c) Imamoto, T.; Takiyama, N.;
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4392-4398.

Novel Route to Macrocycle Moiety of Griseoviridin
J . Org. Chem., Vol. 65, No. 15, 2000 4557
CH2Cl2 and cooled to 0 °C, followed by the addition of 0.43
mL of pyridine and a dropwise addition of benzoyl chloride
freshly distilled before use (0.67 g, 4.78 mmol) in 5 mL of dry
CH2Cl2. After being maintained for 30 min at the same
temperature, the mixture was warmed to room temperature
and stirred for 15 h. The mixture was diluted with CH2Cl2,
washed with brine containing sufficient 2N HCl to remove the
amine, washed with saturated aqueous NaHCO3, and dried
over Na2SO4. The evaporation of the solvent gave a solid that
was recrystallized from cyclohexane containing a minimum
amount of CHCl3. The solid can trap cyclohexane in the crystal
structure, which can be removed by redissolving the product
in CHCl3 and stripping it to dryness three times. This yielded
the isolated product 10, 1.0 g (92% yield): mp 160-162 °C;
[R]D +25.0° (c ) 1.84, CHCl3); 1H NMR (CDCl3) δ 1.48 (s, 18H),
3.36 (t, 4H, J ) 5.33 Hz), 4.90-4.98 (m, 2H), 7.08 (d, 2H, J )
7.04 Hz), 7.35-7.49 (m, 6H), 7.78-7.82 (m, 4H). Anal. Calcd
for C28H36N2O6S2: C, 59.97; H, 6.47; N, 4.99; S, 11.43. Found:
C, 59.95; H, 6.46; N, 4.95; S, 11.40.
N-Ben zoyl D-Cystein e ter t-Bu tyl Ester (11). Disulfide
10 (1.46 g, 2.6 mmol) was suspended in 100 mL of absolute
ethanol, and NaBH4 (0.98 g, 26 mmol) was added portionwise.
The reaction mixture was kept near 25 °C by means of an
external water bath. The mixture was essentially homogeneous
after 2 h and TLC indicated only traces of the disulfide. After
the majority of the ethanol was stripped, the mixture was
diluted with CH2Cl2, washed with saturated brine solution,
extracted several times with CH2Cl2, and dried over Na2SO4.
The product was purified by flash column chromatography
(30% EtOAc/hexane), yielding 1.13 g of D-cysteine derivative
(70% yield): mp 96-98 °C; [R]D +40.02° (c ) 1.5, CHCl3); IR
(CHCl3, cm-1) 3370, 1730; 1H NMR (CDCl3) δ 1.33 (t, 1H, 8.85
Hz), 1.50 (s, 9H), 3.02-3.21 (m, 2H), 4.90-4.95 (m, 1H), 7.05
(d, 1H, J ) 6.40 Hz), 7.40-7.53 (m, 3H), 7.80-7.84 (m, 2H);
13C NMR (CDCl3) δ 27.00, 27.13, 28.06, 54.13, 54.21, 83.27,
127.09, 128.55, 131.92, 133.71, 169.24, 170.05. Anal. Calcd for
Sch em e 6
inversion of the hydroxyl center, thus allowing inversion
of the (S) center obtained from the fermentation process
into the required (R) configuration for Griseoviridin. It
is crucial to the success of this lactonization that the
hydroxy acid 21 is added very slowly, probably to avoid
high stationary concentrations of hydroxy acid substrate.
When the addition was complete, the mixture was
additionally stirred several hours, to afford the desired
lactone 22 in good yield (68%). Furthermore, by the
combined use of the above two reagents, the purification
of reaction product was easily achieved because the
respective oxidation or reduction products of these re-
agents are either directly soluble in aqueous solution or
are converted to gaseous byproducts. On the other hand,
when the reaction was carried out in benzene at 25 °C,
using the classical method of Mitsunobu reaction in high
dilution conditions, the desired product was obtained in
low yield (47%).18
In summary, we have provided an efficient route to the
stereospecific preparation of the sulfur-containing nine-
membered macrocycle N-protected moiety of Griseoviri-
din (22) in optically active form. We have also shown a
method for the direct conversion in one step of the
diastereomeric alcohols 20 to the corresponding hydroxy
acid 21 required for the purpose at hand. We believe that
the simplicity of this approach, the low cost of friendly
reagents, the ease of use, and the high yield make
manifest the synthetic potentialities of this procedure.
Finally, further investigations obtaining the oxazole
dienylamine moiety 5 necessary for the Griseoviridin
synthesis are currently in progress in our laboratory.
C
14H19NO3S: C, 59.76; H, 13.25, N, 4.97; S, 11.39. Found: C,
59.75; H, 13.22; N, 4.96; S, 11.39.
ter t-Bu tyl(2S)-2-Ben zoyla m in o-3-{[(1-eth oxyca r bon yl)-
m eth yl]th io}p r op a n oa te (12). Sodium (0.075 g, 3.21 mmol)
was dissolved in methanol (25 mL). To this solution was added,
with stirring, a solution of N-benzoyl D-cysteine tert-butyl ester
(0.9 g, 3.21 mmol) in methanol (10 mL) and a solution of ethyl
bromoacetate (0.54 g, 3.21 mmol) in methanol (5 mL) at room
temperature. The resulting mixture was refluxed for 1 h, then,
after the methanol was stripped, neutralized with saturated
aqueous NH4Cl, and extracted thoroughly with Et2O. The
organic layer was dried over Na2SO4, filtered, and evaporated,
and the product 12 (1 g, 86% yield) was isolated as an oil by
flash column chromatography (25% EtOAc/hexane): [R]D
Exp er im en ta l Section
Gen er a l Meth od s. H and 13C NMR spectra are reported
1
1
-6.36° (c ) 1.1, CHCl3); IR (neat, cm-1) 3356, 1735; H NMR
at 200 and 50 MHz, respectively, and in CDCl3 unless
otherwise specified. Optical rotations were measured on a
Perkin-Elmer 241 polarimeter. Flash column chromatogra-
phy47 was used to separate and purify the crude reaction
mixtures. Anhydrous solvents were freshly distilled from either
sodium benzophenone ketyl, or CaH2.48
D-Cystin e d i-ter t-Bu tyl Ester (9). The D-cystine (1 g, 4.16
mmol) was dissolved in 60% HClO4, then 26 mL of tert-butyl
acetate was added, and the mixture was sealed tightly with a
glass stopper. The reaction was stirred for 2 d at room
temperature, during which time a white precipitate formed.
The mixture was cooled in a freezer for 24 h and then filtered.
The white solid was washed with (2 × 20 mL) ether. The
product was then neutralized (with extreme care) with satu-
rated NaHCO3 solution, extracted thoroughly with CH2Cl2, and
dried over Na2SO4. After the solvent was removed, 1.22 g of a
colorless oil was obtained , 83% crude yield, and used directly
without purification in the next step.
(CDCl3) δ 1.23 (t, 3H, J ) 7.15 Hz), 1.49 (s, 9H), 3.21 (t, 2H,
J ) 4.98 Hz), 3.26-3.37 (m, 2H), 4.13 (q, 2H, J ) 7.20 Hz),
4.89-4.97 (m, 1H), 7.22 (, 1H, J ) 7.25 Hz), 7.39-7.51 (m,
3H), 7.82-7.87 (m, 2H); 13C NMR (CDCl3) δ 14.09, 27.07, 34.28,
52.91, 61.55, 83.04, 127.18, 128.54, 131.76, 133.77, 167.01,
169.67, 170.29; ESI-MS m/z 390 [M + Na]+, 368 [M + H]+,
334 [M + Na - 56]+. Anal. Calcd for C18H25NO5S: C, 58.83;
H, 7.85; N, 3.81; S, 8.72. Found: C, 58.80; H, 6.81; N, 3.80; S,
8.72.
Eth yl (3S)-3-Hyd r oxybu ta n oa te (14). A 2-L, two-necked,
round-bottomed flask, equipped with mechanical stirrer and
a reflux condenser, was charged with 560 mL of water at 30
°C, 105.2 g of sucrose, and 70.13 g of Baker’s yeast, which were
added with stirring in this order. After 1 h, ethyl acetoacetate
25 (7.0 g, 0.054 mmol) was added with thorough mixing. The
broth was kept at 30 °C for 24 h, at which time the fermenta-
tion had essentially stopped. A warm (ca. 40 °C) solution of
70.13 g of sucrose in 350 mL of water was then added, and
CO2 evolution soon resumed. After 1 h, an additional keto ester
(7.0 g, 0.054 mmol) was added, and the resulting mixture was
kept at room temperature for 2 d. When the reaction is
complete by gas chromatography-mass, the mixture was
worked up by first adding 40 g of Celite and filtering through
a Bu¨chner funnel (17 cm diameter). After the filtrate was
N-Ben zoyl D-Cystin e d i-ter t-Bu tyl Ester (10). The crude
product 9 (0.68 g, 1.94 mmol) was diluted with 13 mL of dry
(47) Still, W. C.; Khan, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923-
2925.
(48) Leonard, J .; Lygo, B.; Procter, G. In Advanced Practical Organic
Chemistry; Blackie Academic & Professional: London, 1990.

4558 J . Org. Chem., Vol. 65, No. 15, 2000
Marcantoni et al.
washed with 100 mL of water, saturated with sodium chloride,
and extracts with five 150 mL portions of ethyl ether, the
combined ether extracts were dried over Na2SO4, filtered, and
and brine washing gave a viscous oil, which was chromato-
graphed on silica gel column using ethyl acetate-hexane (40:
60) as eluent to afford the two diastereomers (at the new chiral
center) of 20 in a ratio of about 1:1 (the total yield was 0.21 g,
65%). Both diastereomers were oils. Diastereomer 1: [R]D
+15.6 (c ) 1.05, CHCl3); IR (neat, cm-1) 3386, 1721; 1H NMR
(CDCl3) δ 1.18-1.26 (m, 6H), 1.48 (s, 9H), 2.47-2.59 (m, 2H),
3.18-3.30 (m, 3H), 3.32 (s, 3H), 3.74-3.82 (m, 2H), 4.13 (q,
2H, J ) 7.18 Hz), 4.63-4.67 (m, 2H), 4.91-4.95 (m, 1H), 7.30
(d, 1H, J ) 7.32 Hz), 7.42-7.50 (m, 3H), 7.81-7.86 (m, 2H),
9.45 (bs, 1H); ESI-MS m/z 538 [M + K]+, 522 [M + Na]+. Anal.
Calcd for C24H37NO8S: C, 57.69; H, 7.46; N, 2.80; S, 6.42.
Found: C, 57.68; H, 7.42; N, 2.80; S, 6.37. Diastereomer 2:
[R]D + 15.2° (c ) 1.05, CHCl3); IR (neat, cm-1) 3386, 1720; 1H
NMR (CDCl3) δ 1.18-1.23 (m, 6H), 1.46 (s, 9H), 2.40-2.49 (m,
2H), 3.18-3.30 (m, 3H), 3.32 (s 3,H), 3.79-3.86 (m, 2H), 4.13
(q, 2H, J ) 7.18 Hz), 4.75-4.78 (m, 2H), 4.99-5.04 (m, 1H),
5.70 (bs, 1H), 7.21 (d, 1H, J ) 7.32 Hz), 7.42-7.50 (m, 3H),
7.81-7.86 (m, 2H); ESI-MS m/z 538 [M + K]+, 522 [M + Na]+.
Anal. Calcd for C24H37NO8S: C, 57.69; H, 7.46; N, 2.80; S, 6.42.
Found: C, 57.65, H, 7.40, N, 2.69; S, 6.41.
(2S)-2-(Ben zoyla m in o)-3-{[(Z,4S)-1-(et h oxyca r b on yl)-
4-h yd r oxyp en t-1-en yl]th io}p r op a n oic a cid (21). A solu-
tion of a mixture of the diprotected diastereomeric alcohols
20 (98 mg, 0.196 mmol) in acetonitrile (3 mL) was treated with
CeCl3‚7H2O (0.11 g, 0.294 mmol) and NaI (29 mg, 0.196 mmol),
and the resulting mixture was stirred at reflux temperature
for 24 h (until no starting material remained, as monitored
by TLC). The reaction mixture was diluted with EtOAc and
treated with 0.5 N HCl (10 mL). The organic layer was
separated, and the aqueous layer was extracted with EtOAc
(3 × 25 mL). The combined organic layers were evaporated,
the residue was dissolved in 10% NaHCO3 solution (25 mL),
and the bicarbonate layer was washed with ether. Bicarbonate
solution was then made acidic to pH ) 3 and extracted with
ethyl acetate. The organic extracts were washed with water
and brine, dried over Na2SO4, and evaporated to give hydroxy
concentrated with
a rotary evaporator in a 35 °C bath
temperature to a volume of 30-35 mL. This residue was
fractionally distilled through a 10 cm Vigreux column, yielding
9.96 g of hydroxy ester 14: bp 71-73 °C/12 mmHg; [R]D
1
+38.75° (c ) 1, CHCl3); IR (neat, cm-1) 3440, 1730; H NMR
(CDCl3) δ 1.17-1.25 (m, 6H), 2.32-2.42 (m, 2H), 2.80 (bs, 1H;
OH), 4.09-4.17 (m, 3H); 13C NMR (CDCl3) δ 14.14, 22.39,
42.77, 60.65, 64.23, 172.91; GC-MS m/z 131 [M - 1]+, 117,
88, 87, 71, 60, 45, 31. Anal. Calcd for C6H12O3: C, 54.53; H,
9.15. Found: C, 54.50; H, 9.15.
E t h yl (3S)-3-(Met h oxym et h oxy)b u t a n oa t e (15). To a
solution of the â-hydroxy ester 14 (3.5 g, 26.4 mmol) in
dimethoxymethane (70 mL), allyltrimethylsilane (3.42 g, 30.8
mmol) and iodine (cat. 5% mol) were added, and the mixture
was stirred at room temperature under a nitrogen atmosphere,
while the progress of the reaction was monitored by GLC. After
completion of reaction, the mixture was poured into a mixture
of ether (300 mL), water (90 mL), and saturated sodium
thiosulfate solution (9 mL). The organic layer was washed with
water and saturated brine solution and dried over Na2SO4.
Evaporation of solvent the crude product was purified by flash
column chromatography on silica gel (30% EtOAc/hexane),
yielding 4.22 g of a colorless oil49 (90% yield): [R]D +10.83° (c
) 0.85, CHCl3); IR (neat, cm-1) 1735; 1H NMR (CDCl3) δ 1.15-
1.30 (m, 6H), 2.48 (dd, 2H, J ) 7.52 and 15.20 Hz), 3.31 (s,
3H), 4.05-4.20 (m, 3H), 4.62 (s, 2H); GC-MS m/z 175 [M -1]+,
161, 145, 131, 101, 73, 59, 43. Anal. Calcd for C8H16O4: C,
54.53; H, 9.15. Found: C, 54.53; H, 9.12.
(3S)-3-(Meth oxym eth oxy)bu ta n a l (16). A 1.0 M solution
of DIBAL-H in hexane (15 mL, 15 mmol) was added slowly to
a solution of ester 15 (2.31 g, 13 mmol) in dry CH2Cl2 (100
mL) at -78 °C. After stirring at the same temperature for 1
h, methanol (15 mL) was added dropwise (destruction of the
excess of DIBAL-H) and the mixture poured into 0.5N HCl
(450 mL). After stirring for additional 1 h to room temperature,
the organic layer was separated. The aqueous layer was
extracted with CH2Cl2 (120 mL, 6 times). The combined
organic extracts dried over Na2SO4, evaporated and the residue
purified by distillation to obtain 1.50 g of protected aldehyde,50
yield 86%: bp ) 65-68 °C/7.5 mmHg; [R]D ) +25.6° (c ) 1.2,
CHCl3); IR (neat, cm-1) 1731; 1H NMR (CDCL3) δ 1.25 (d, 3H,
J ) 6.0 Hz), 2.30-2.65 (m, 2H), 3.32 (s, 3H), 4.17 (sextet, 1H,
J ) 6.0 Hz), 4.55-4.75 (m, 2H), 9.75 (t, 1H, J ) 2.0 Hz); GC-
MS m/z 117, 114, 87, 75, 67, 41, 29. Anal. Calcd for C6H12O3:
C, 54.53; H, 9.15. Found: C, 54.51; H, 9.13.
acid 21 as
a white solid (72 mg, 96% yield) with (Z)-
configuration, not contaminated by any amount of the (E)-
diastereomer. Diastereomeric purity was determined by NMR
analysis: [R]D +2.96° (c ) 0.9, CHCl3); mp 140-142 °C; IR
(DMSO, cm-1) 3470, 1770, 1730, 1694; 1H NMR (DMSO) δ 0.95
(d, 3H, J ) 6.15 Hz), 1.23 (t, 3H, J ) 7.08 Hz), 2.26-2.49 (m,
2H), 3.26-3.62 (m, 2H), 4.12 (q, 2H, J ) 7.12 Hz), 4.30-4.46
(m, 1H), 4.72-4.80 (m, 1H), 7.20-7.55 (m, 5H), 7.84 (d, 2H, J
) 7.21 Hz), 8.68 (d, 1H, J ) 8.06 Hz), 12.70 (bs, 1H); ESI-MS
m/z 420 [M + K]+, 404 [M + Na]+. Anal. Calcd for C18H23
-
NO6S: C, 56.67; H, 6.07; N, 3.67; S, 8.41. Found: C, 56.63; H,
6.06; N, 3.65; S, 8.37.
ter t-Bu t yl (2S)-2-(Ben zoyla m in o)-3-{[(4S)-1-(et h oxy-
ca r bon yl)-2-h yd r oxy-4-(m eth oxy-m eth oxy)p en tyl]th io}-
p r op a n oa t e (20). In a 100-mL three-necked round-bottom
flask equipped with a magnetic stirrer and condenser, a
dropping funnel of finely ground CeCl3‚7H2O (0.36 g, 0.98
mmol) was dried by heating at 140 °C/0.1 mmHg for 2 h,51,52
and then it was suspended in 20 mL of dry THF and left to
stir overnight at room temperature. The white suspension was
cooled to 0 °C, and a solution of chiral aldehyde 16 (0.090 g,
0.68 mmol) in 2 mL of THF was added and left stir for 1 h. To
this mixture was transferred by cannula a THF (10 mL)
solution of D-cysteine derivative 12 (0.24 g, 0.66 mmol), which
has been precooled to -78 °C and in which a 1 M solution in
ether of tert-butylmagnesium chloride was added dropwise.
The resulting mixture was then left to stir untie TLC indicated
that no substrate 12 remained (6.5 h). The reaction mixture
was quenched by the addition of saturated aqueous NH4Cl (35
mL). A standard workup with CH2Cl2 extraction and water
Eth yl (5R,8S)-9-Ben zoyla m in o-5-m eth yl-7-oxo-4,5,8,9-
tetr a h yd r o-7H-1,6-oxa th ion in e-2-ca r boxyla te (22). To a
solution of diphenyl-2-pyridylphosphine (52.6 mg, 0.2 mmol)
in dry benzene (90 mL) at room temperature under an
atmosphere of nitrogen was added di-tert-butylazodicarboxy-
late (46 mg, 0.2 mmol) in one portion, and the resulting
mixture was stirred for 30 min. A solution of hydroxy acid 21
(50 mg, 0.131 mmol predissolved in 4 mL of dry THF) in dry
benzene (60 mL) was added dropwise over a period of 20 h to
the vigorously stirred reaction mixture at room temperature.
Upon completion of the addition, the mixture was stirred for
28 h at this temperature (the progress reaction was monitored
by TLC). To the mixture was added 10% citric acid (25 mL),
then the stirring was continued at room temperature for 1 h.
After the majority of the benzene was stripped under reduced
pressure, the product was extracted with CH2Cl2. The organic
solution was washed with water, saturated solution NaHCO3,
and brine. The dried (Na2SO4) extracts were concentrated, and
the crude product purified by flash column chromatography
(40% EtOAc-hexane) giving 32.6 mg of a white solid (68%
yield): [R]D -126.5° (c ) 1, CHCl3); mp 128-130 °C; IR (CHCl3,
(49) Cure, J .; Gaudemar, M. Bull. Soc. Chim. Fr. 1970, 2962-2967.
(50) Yamamoto, Y.; Komatsu, T.; Murayama, K. J . Organomet.
Chem. 1985, 285, 31-42.
1
cm-1) 3320, 1736, 1715; H NMR (CDCl3) δ 1.18 (t, 3H, J )
(51) Imamoto, T. Org. Synth. 1999, 76, 228-238.
7.15 Hz), 1.33 (d, 3H, J ) 6.67 Hz), 2.45-2.55 (m, 1H), 3.00-
3.20 (m, 2H), 3.32-3.49 (m, 1H), 4.15 (q, 2H, J ) 7.10 Hz),
4.96-5.01 (m, 1H), 5.20-5.30 (m, 1H), 7.01 (d, 1H, J ) 6.33
Hz), 7.40-7.50 (m, 4H), 7.58-7.69 (m, 2H); 13C NMR (CDCl3)
(52) The water molecule found in dry cerium(III) chloride seems to
have no effect because the material was highly efficient without a large
excess of organometallic compound. Cf. Evans, W. J .; Feldman, J . D.;
Ziller, J . W. J . Am. Chem. Soc. 1996, 118, 4581-4584.

Novel Route to Macrocycle Moiety of Griseoviridin
J . Org. Chem., Vol. 65, No. 15, 2000 4559
δ 14.63, 18.39, 29.20, 35.00, 40.38, 52.20, 68.36, 126.27, 128.20,
131.54, 148.23, 166.15, 170.91; ESI-MS m/z 402 [M + K]+, 386
[M + Na]+. Anal. Calcd for C18H21NO5S: C, 59.48; H, 5.82; N,
3.85; S, 8.82. Found: C, 59.45; H, 5.79; N, 3.84; S, 8.77.
ologies and Applications) is gratefully acknowledged.
The authors thank Dr. Giovanni Rafaiani for NMR
experiments and Dr. Massimo Ricciutelli for mass
spectrometry, as well as for every helpful discussions
with Professor Albert I. Meyers (Colorado State
University).
Ack n ow led gm en t. Financial support from the Uni-
versity of Camerino and MURST (Research National
Project “Stereoselection in Organic Synthesis. Method-
J O000116D