Total syntheses of (-)-Asperlicin and (-)-Asperlicin C [9]

Full text of DOI:10.1021/ja9809408

J. Am. Chem. Soc. 1998, 120, 6417-6418
6417
opened by an SN1 process to give a cationic intermediate
analogous to 9 that reacted with MeOH from both faces.
Hydroxyl-directed reduction13 of this mixture with sodium boro-
hydride in acetic acid gave 80% of a 1.1:1 mixture of alcohols
10a and 12a in which an alkoxy borohydride such as 9a is formed
from 7a and delivers a hydride intramolecularly to give 10a with
H and OH on the same face of the imidazoindolone. Hydro-
genolysis over Pd/C in MeOH proceeded quantitatively to give
11a and 13a. The structures of 11a and 13a were established by
NOE studies and confirmed for 11a by X-ray crystal structure
determination.14 Since the ratio of 10a to 12a is determined in
the epoxidation step, we investigated other oxidants. Use of 3-n-
butyl-1,2-benzisothiazole-1,1-dioxide oxide (26)15 followed by
reduction gave 60% of a 2.3:1 mixture favoring the desired isomer
10a while use of dimethyldioxirane16 afforded 80% of a 1:1.9
mixture favoring the undesired isomer 12a. More hindered
oxaziridines did not epoxidize 6a. Epoxidations with dioxiranes
often give very different stereoselectivity than those with peracids
and oxaziridines,17a and calculations indicate transition state
geometries for these reactions are quite different.17b
Total Syntheses of (-)-Asperlicin and (-)-Asperlicin
C
Feng He, Bruce M. Foxman, and Barry B. Snider*
Department of Chemistry, Brandeis UniVersity
Waltham, Massachusetts 02254-9110
ReceiVed March 20, 1998
We recently reported an efficient synthesis of the tripeptide
quinazolinone antibiotic fumiquinazoline G.1 To extend this
synthesis to the structurally more complex tetrapeptide members
of this family such as fumiquinazoline A (1),2-4 we needed to
develop a route to the 9-hydroxy-1H-imidazo(1,2-a)indol-3-one
moiety from the indole ring of tryptophan. This ring system also
occurs in the potent cholecystokinin antagonist asperlicin (2),5
but has only been synthesized in the stereochemically and
structurally simpler tryptoquivalines by Bu¨chi,6 Ban,7 and Naka-
gawa and Hino.8 The initial challenge was therefore to develop
a practical, stereochemically controlled method to the hydroxy-
imidazoindolone moiety 10 from a 3-alkyl indole.
A similar series of reactions with N-CBZ-L-leucine afforded
6b with the larger isobutyl side chain of asperlicin. Epoxidation
was now more selective for the less hindered R-face, giving 10b
and 12b as a 3.4:1 mixture with 26, a 1.7:1 mixture with m-CPBA,
and a 1:1.4 mixture with dimethyldioxirane. Hydrogenolysis
completed the model study, giving 11b with spectral data very
similar to that of asperlicin.
We chose to apply this procedure to the synthesis of asperlicin
since the top half of the molecule is more readily accessible than
that of fumiquinazoline A. Bock and co-wokers reported an
efficient synthesis of asperlicin C by reacting 14 with Lawesson’s
reagent to give a 1:1 mixture of monothioamides which were
separated; the desired thioamide was elaborated to 16 in two
steps.18 This synthesis can be improved by using the Eguchi
protocol for elaboration of a quinazolin-4-one onto an amide.1,19,20
Reaction of 14 with o-azidobenzoyl chloride,19,21 Et3N, and DMAP
occurred selectively on the more acidic anilide nitrogen, giving
exclusively the desired isomer 15 in 83% yield. Reaction of 15
with Bu3P in benzene at 60 °C formed the aza-Wittig reagent,
which cyclized to provide 80% of asperlicin C (16) (Scheme 2),
with spectra identical with those of the natural product.22
Condensation of 3-methylindoline (3)9 with N-CBZ-L-alanine
and DCC afforded 90% of the amide, which was oxidized10 with
DDQ in toluene at reflux to provide 90% of acylated indole 4a.
Mercuration11 of 4a with Hg(OTFA)2, exchange with KI, and then
iodination afforded 82% of iodoindole 5a and 14% of recovered
4a. The palladium-catalyzed amidation reaction recently devel-
oped by Buchwald (Pd2(dba)3, P(o-tolyl)3, K2CO3, toluene, 105
°C)12 provided 83% of 6a containing the crucial imidazoindolone
moiety.
Completion of the model study required the syn addition of H
and OH to the double bond of 6a. Hydroboration failed, so we
turned our attention to epoxidation-reduction sequences. Ep-
oxidation of 6a with m-CPBA in MeOH afforded 77% of a
mixture of four methoxy alcohols 7a and 8a, in which the epoxide
(1) He, F.; Snider, B. B. Synlett 1997, 483-484.
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276. (b) Hoveyda, A.; Evans, D. A.; Fu, G. Chem. ReV. 1993, 93, 1307-
1368.
(14) The authors have deposited atomic coordinates for the structure of
11a with the Cambridge Crystallographic Data Centre. The coordinates can
be obtained upon request from the Director, Cambridge Crystallographic
Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.
(2) (a) Takahashi, C.; Matsushita, T.; Doi, M.; Minoura, K.; Shingu, T.;
Kumeda, Y.; Numata, A. J. Chem. Soc., Perkin Trans. 1 1995, 2345-2353.
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Usami, Y.; Matsumura, E.; Inoue, M.; Ohishi, H.; Shingu, T. Tetrahedron
Lett. 1992, 33, 1621-1624.
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Cooper, R. J. Antibiot. 1993, 46, 545-553.
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4368. (b) Davis, F. A.; Towson, J. C.; Vashi, D. B.; ThimmaReddy, R.;
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V. J.; Chen, T. B. J. Antibiot. 1985, 36, 1633-1637. (b) Liesch, J. M.; Hensens,
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1638-1641. (c) Sun, H. H.; Byard, S. J.; Cooper, R. J. Antibiot. 1994, 47,
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2377. (b) Adam, W.; Reinhardt, D.; Reissig, H.-U.; Paulini, K. Tetrahedron
1995, 51, 12257-12262.
(6) Bu¨chi, G.; DeShong, P. R.; Katsumura, S.; Sugimura, Y. J. Am. Chem.
Soc. 1979, 101, 5084-5086.
(17) (a) Schwesinger, R.; Willaredt, J. In Methods of Organic Chemistry
(HoubenWeyl); Thieme: Stuttgart, 1995; Vol. E21e, pp 4601-4648. (b) Houk,
K. N.; Liu, J.; DeMello, N. C.; Condroski, K. R. J. Am. Chem. Soc. 1997,
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S0002-7863(98)00940-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/11/1998

6418 J. Am. Chem. Soc., Vol. 120, No. 25, 1998
Communications to the Editor
Scheme 1
Scheme 3
Scheme 2
Application of these sequences to the synthesis of asperlicin
required careful consideration of the order of steps to avoid
problems with functional group incompatibility. DCC coupling
of phenol with NR-(trichloroethoxycarbonyl)-L-tryptophan (17)23
with phenol afforded 88% of phenyl ester 18. Reduction of the
indole with BH3•THF in TFA24 afforded 81% of the indoline,
which was acylated with N-CBZ-L-leucine to give 81% of
N-acylindole 19 after oxidation with DDQ.10 Iodination11 as
described above for 4 followed by the Buchwald palladium-
catalyzed condensation12 afforded 48% of the desired imidazoin-
dolone 20 and 11% recovered 19. The trichloroethoxycarbonyl
(Troc) group was removed with Zn in AcOH to give 21, which
was coupled with o-TrocHNC6H4CO2H23 and DCC to afford 72%
of amide 22. Deprotection of the Troc group with Zn in AcOH
and EtOAc gave an amine phenyl ester that spontaneously
cyclized to give benzodiazepinedione 23 in 93% yield.
The quinazolinone was now elaborated by the Eguchi proto-
col;19 reaction with o-N3C6H4COCl, Et3N, and DMAP afforded
82% of 24, which was treated with Bu3P in benzene at 60 °C to
provide 91% of 25 and 8% of recovered 23. We were delighted
to find that the epoxidation of 25 with oxaziridine 2615 was much
more selective than in the model study, giving 71% of an 11:1
mixture favoring the desired R-alcohol. Reduction of this mixture
with NaBH4 in AcOH was slower than that of 7 and 8; the
procedure was repeated 4 to 5 times to remove the methoxy group
completely. Competitive reduction of the quinazolinone occurred
under these conditions so that we obtained 14% of 28, 70% of
dihydroquinazolinone 27a, and 8% of 27b. The unstable dihy-
droquinazolinones could be easily separated; oxidation of 27a
with DDQ in CHCl3 at room temperature afforded 85% of 28.
Hydrogenolysis of the CBZ group of 28 over Pd/C in MeOH at
1 atm for 15 min gave 87% of asperlicin (2) with spectra identical
with those of the natural product.22
We prepared the diastereomer of 25 from N-CBZ-D-leucine to
examine the factors responsible for the vastly improved stereo-
selectivity of the epoxidation of 25 as compared to 6b. Epoxi-
dation of this diastereomer with 26 gave a 5.5:1 mixture of
isomers in which the major product is formed from epoxidation
on the face opposite the isobutyl group as in 27a. Since the
stereoselectivity of the epoxidation of the diastereomer is better
than that of 6b, but worse than that of 25, both double asymmetric
induction and the steric bulk of the side chain must contribute to
the excellent selectivity observed in the epoxidation of 25 with
oxaziridine 26.
In conclusion we have shortened and improved the synthesis
of asperlicin C, developed a general route to the hydroxyimida-
zoindolone ring system, and applied it to the first synthesis of
asperlicin, which proceeds efficiently (15 steps, 8% overall yield)
and stereospecifically.
Acknowledgment. We thank the National Institute of General Medical
Sciences for generous financial support and Drs. Mark Bock and Steven
Pitzenberger, Merck & Co., for spectral data and samples of asperlicin
and asperlicin C.
Supporting Information Available: Experimental procedures and
X-ray data for 11a (27 pages, print/PDF). See any current masthead
page for ordering information and Web access instructions.
(22) We thank Drs. Mark Bock and Steven Pitzenberger, Merck & Co.,
for spectral data and samples of asperlicin and asperlicin C.
(23) Carson, J. F. Synthesis 1981, 268-270.
(24) Maryanoff, B. E.; McComsey, D. F.; Nortey, S. O. J. Org. Chem.
1981, 46, 355-360.
JA9809408