A highly efficient synthesis of (-)-PI-091 construction of the 4-alkoxy-2-butene-4-lactam skeleton from Fischer-type carbene complexes, alkynyllithiums, and tosyl isocyanate

Full text of DOI:10.1021/jo9700686

1918
J . Org. Chem. 1997, 62, 1918-1919
Sch em e 1
A High ly Efficien t Syn th esis of (-)-P I-091
Con str u ction of th e
4-Alk oxy-2-bu ten e-4-la cta m Sk eleton fr om
F isch er -Typ e Ca r ben e Com p lexes,
Alk yn yllith iu m s, a n d Tosyl Isocya n a te
Nobuharu Iwasawa* and Katsuya Maeyama
Department of Chemistry, Graduate School of Science, The
University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113, J apan
Received J anuary 14, 1997
The 4-alkoxy-2-butene-4-lactam skeleton has attracted
much attention because it forms the basic structure of
several pharmacologically promising natural products
such as PI-091,1 epolactaene,2 and so on.3 However, the
construction of this carbon framework with appropriate
substituents is not necessarily easy, and multiple trans-
formations are usually required.4 In a previous paper,
we reported that a new type of propargyl metallic species
is generated by the addition of alkynyllithiums to Fis-
cher-type carbene complexes and that these propargyl
metallic species react with various carbon electrophiles
such as aldehydes, sulfonylimines, and carbon dioxide to
give furans, pyrroles, and 5-alkoxybutenolides, respec-
tively.5 We considered employing an isocyanate, a ni-
trogen analogue of carbon dioxide, as an electrophile with
the expectation that the 4-alkoxy-2-butene-4-lactam skel-
eton bearing various substituents could be constructed
in a single step. In this paper is described a successful
realization of this approach and its application to a
concise enantioselective synthesis of (-)-PI-091.
Examination of several isocyanates revealed that tosyl
isocyanate6 reacts with the propargyl metallic species
generated from Fischer-type carbene complexes and
alkynyllithiums. Thus, propargyl metallic species A,
generated by the addition of (phenylethynyl)lithium to
isopropylcarbene complex 1a (M ) W) at -78 °C, was
reacted with tosyl isocyanate at this temperature over-
night to give either an allenyl intermediate B or a [3 +
2] cycloaddition intermediate C.6,7 The reaction mixture
was then treated with trifluoroacetic acid to promote
either cyclization (in the case of B) or protonation (in the
case of C), giving a mixture of an O-cyclized product 2a
and an N-cyclized product 3a in 69 and 18% yield,
respectively (Scheme 1). When the corresponding mo-
lybdenum complex 1a (M ) Mo) was used for this
reaction, the O-cyclized product 2a was obtained in 92%
yield, and only a trace amount of the N-cyclized product
3a was produced.8 Furthermore, it was found that the
purified 2a was quantitatively isomerized to 3a by
treatment with ethylaluminum dichloride in dichlo-
romethane at -78 °C. To obtain the N-cyclized product
3a selectively, the crude product of the addition reaction
with tosyl isocyanate was directly treated with ethyl-
aluminum dichloride in dichloromethane to give 3a in
79% overall yield based on the carbene complex 1a
(M ) Mo).
We then examined the generality of this reaction. As
summarized in Table 1, N-cyclized product 3 was ob-
tained in good yields in every case.9 Thus, this reaction
is a highly efficient method for the construction of the
4-alkoxy-2-butene-4-lactam skeleton with various sub-
stituents from carbene complexes, alkynyllithiums, and
tosyl isocyanate.
We next applied this reaction to the enantioselective
synthesis of (-)-PI-091. PI-091 was isolated in 1990 by
the research group at Taisho Pharmaceutical Co. from
* To whom correspondence should be addressed. Tel.: 81-3-3812-
2111 ext 4643. Fax: 81-3-5800-6891. E-mail: niwasawa@chem.s.u-
tokyo.ac.jp.
(1) Kawashima, A.; Yoshimura, Y.; Sakai, N.; Kamigoori, K.; Mi-
zutani, T.; Omura, S. J pn. Kokai Tokkyo Koho J P 02 62859[90 62,-
859](C1.C07D207/38), 02 Mar 1990, Appl. 88/215,393,30 Aug 1988;
Chem Abstr. 1990, 113, 113856d.
(8) No isomerization of O-cyclized product 2a to N-cyclized product
3a was observed under these conditions (trifluoroacetic acid in THF
at rt).
(9) The reaction was carried out as follows: To a THF solution (5
mL) of an alkyne (0.90-1.2 mmol) was added dropwise a 1.56 M hexane
solution (0.40-0.53 mL, 0.62-0.83 mmol) of n-butyllithium at -78 °C.
After the mixture was stirred for 30 min at this temperature, a THF
solution (2 mL) of a tungsten or a molybdenum carbene complex (0.30
mmol) was slowly added. After the mixture was stirred for 1 h at -78
°C, a THF solution (4 mL) of tosyl isocyanate (2.0 mmol) was added
and the mixture was stirred overnight at -78 °C. Trifluoroacetic acid
(0.50 mL) was added at -78 °C, and the mixture was warmed to rt.
After the mixture was stirred overnight at rt, triethylamine (1.0 mL)
was added at 0 °C and then pH 7 phosphate buffer was added. The
organic layer was extracted three times with ethyl acetate, and the
combined extracts were dried over MgSO4. After removal of the solvent,
the residue was dissolved in 10 mL of CH2Cl2 and a 1.0 M hexane
solution of ethylaluminum dichloride (2.0 mL, 2 mmol) was added
dropwise at -78 °C. After the mixture was stirred at this temperature
for 3 h, 10% aqueous Rochelle salt solution was added carefully to the
reaction mixture. The aqueous layer was extracted three times with
ethyl acetate, and the combined extracts were dried over MgSO4. After
removal of the solvent, the residue was purified using preparative TLC
(hexane:ethyl acetate ) 6:4), yielding the corresponding N-cyclized
product 3.
(2) Kakeya, H.; Takahashi, I.; Okada, G.; Isono, K.; Okada, H. J .
Antibiot. 1995, 48, 733.
(3) (a) Lam, Y. K. T.; Hensens, O, D.; Ransom, R.; Giacobbe, R. A.;
Polishook, J .; Zink, D. Tetrahedron 1996, 52, 1481. (b) Singh, S. B.;
Goetz, M. A.; J ones, E. T.; Bills, G. F.; Giacobbe, R. A.; Herranz, L.;
Stevens-Miles, S.; Williams, D. L., J r. J . Org. Chem. 1995, 60, 7040.
(4) Dittami, J . P.; Xu, F.; Qi, F.; Martin, M. W.; Bordner, J .; Decosta,
D. L.; Kiplinger, J .; Reiche, P.; Ware, R. Tetrahedron Lett. 1995, 36,
4201. References are cited therein.
(5) Iwasawa, N.; Maeyama, K.; Saitou, M. J . Am. Chem. Soc. 1997,
119, 1486.
(6) For examples of the reactions of transition metal propargyl
metallic species with tosyl isocyanate: (a) Giering, W. P.; Raghu, S.;
Rosenblum, M.; Cutler, A.; Ehntholt, D.; Fish, R. W. J . Am. Chem.
Soc. 1972, 94, 8251. (b) Raghu, S.; Rosenblum, M. J . Am. Chem. Soc.
1973, 95, 3060. (c) Bell, P. B.; Wojcicki, A. Inorg. Chem. 1981, 20, 1585.
(d) Shuchart, C. E.; Willis, R. R.; Wojcicki, A. J . Organomet. Chem.
1992, 424, 185. (e) Welker, M. E. Chem. Rev. 1992, 92, 97.
(7) We have not yet succeeded in isolating this intermediate.
S0022-3263(97)00068-6 CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 7, 1997 1919
Ta ble 1. P r ep a r a tion of 4-Meth oxy-2-bu ten e-4-la cta m s
Sch em e 3
R
R′
Ph
n-Hex
Ph
M
yield of 3 (%)
i-Pr
i-Pr
Ph
Moa
Moa
W
79 (3a )
83
80
Ph
n-Hex
W
87
a
The molybdenum complex gave slightly better yield than the
corresponding tungsten complex.
Sch em e 2
Regio- and enantioselective dihydroxylation of the side
chain olefin was achieved by using AD-mix R13 to give a
diastereomeric mixture of diols 8a and 8b.14 These two
isomers were easily separated by TLC, and the optical
purities of 8a and 8b were determined to be 93% ee and
91% ee by using chiral shift reagents Eu(hfc)3 and
Pr(hfc)3, respectively. Although reductive removal of the
tosyl group from 8 turned out to be quite troublesome
due to facile over-reduction, finally it was found that
samarium(II) diiodide in methanol gave about 80% yield
of the deprotected product 9. The final stage of the
synthesis was the oxidation of the secondary hydroxyl
group, which was carried out in good yield by using
Paecilomyces sp. F-3430 and exhibits modest arachidonic
acid-induced platelet aggregation-inhibitory activity.1
PI-091 contains the 4-alkoxy-2-butene-4-lactam skeleton
and was isolated as a 1:1 diastereomeric mixture at the
N,O-acetal carbon. Tadano et al. have already reported
the first total synthesis of PI-091 starting from D-
glucose.10
It was expected that the basic structure of PI-091 could
be synthesized from the isopropyl carbene complex 1a ,
(E)-4-methyl-3-decen-1-yne (6), and tosyl isocyanate by
using our procedure.
The requisite enyne 6 was prepared in a straightfor-
ward manner as shown in Scheme 2. Methylalumination
of 1-octyne was carried out employing trimethylalumi-
num and zirconocene dichloride, and the resulting al-
kenyl aluminum species was treated with iodine to give
an alkenyliodide 4 in 78% yield.11 It was then coupled
with (trimethylsilyl)acetylene by using Pd(CH3CN)2Cl2
and CuI in piperidine12 to give 5, which was desilylated
by tetrabutylammonium fluoride to give the enyne 6 in
79% yield from 4.
With the enyne 6 in hand, we examined formation of
the 4-alkoxy-2-butene-4-lactam. According to the proce-
dure described above, the lithiated enyne 6 was reacted
with isopropylcarbene complex 1a to generate a propargyl
metallic species, and then tosyl isocyanate was added.
After two successive acid treatments (trifluoroacetic acid
and then ethylaluminum dichloride), the expected 4-al-
koxy-2-butene-4-lactam 7 was obtained in 87% yield.
Conversion of this intermediate 7 to PI-091 was carried
out in a straightforward manner as shown in Scheme 3.
1
SO3‚pyridine in DMSO. The H and 13C NMR spectra
and optical rotations of the products obtained, 10a and
10b, agreed well with those of the natural product.15
In conclusion, we have developed a facile method for
the construction of the 4-alkoxy-2-butene-4-lactam skel-
eton by the reaction of the propargyl metallic species,
generated from Fischer-type carbene complexes and
alkynyllithiums, and tosyl isocyanate. Furthermore, a
highly efficient total synthesis of PI-091 was achieved
by using this method.
Ack n ow led gm en t. We are grateful to the Research
Laboratories for Applied Biology, Taisho Pharmaceuti-
1
cal Co., Ltd. for donating H and 13C NMR spectra of
PI-091. This work was financially supported in part by
the Fujisawa Foundation and a Grant-in-Aid for Scien-
tific Research from the Ministry of Education, Science
and Culture, J apan.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectroscopic data are included for compounds
2-10 (9 pages).
J O9700686
(12) Takahashi, S.; Kuroyama, Y.; Sonogashira, K.; Hagihara, N.
Synthesis 1980, 627.
(13) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J .; J eong, K.; Kwong, H.; Morikawa, K.; Wang, Z.; Xu, D.;
Zhang, X. J . Org. Chem. 1992, 57, 2768.
(10) (a) Shiraki, R.; Sumino, A.; Tadano, K.; Ogawa, S. Tetrahedron
Lett. 1995, 36, 5551. (b) Shiraki, R.; Sumino, A.; Tadano, K.; Ogawa,
S. J . Org. Chem. 1996, 61, 2845.
(11) Rand, C. L.; Van Horn, D. E.; Moore, M. W.; Negishi, E. J . Org.
Chem. 1981, 46, 4093.
(14) Diastereomers arise from configuration at the N,O-acetal car-
bon. The relative stereochemistries of 8a and 8b were not determined.
(15) Although natural PI-091 is a mixture of diastereomers, both
10a and 10b show nearly the same optical rotation as the natural
product.