Synthetic studies on (+)-naphthyridinomycin: Stereoselective synthesis of the tetracyclic core framework

Article abstract of DOI:10.1021/ol048857e

(Chemical Equation Presented) The stereoselective synthesis of the tetracyclic intermediate 21 for (+)-naphthyridinomycin (1) has been accomplished. The convergent synthesis used the Ugi 4CC reaction with the amine derivative 10. The key features of the s

Full text of DOI:10.1021/ol048857e

ORGANIC
LETTERS
2004
Vol. 6, No. 18
3095-3097
Synthetic Studies on
(+)-Naphthyridinomycin:
Stereoselective Synthesis of the
Tetracyclic Core Framework
Kazuki Mori, Kentaro Rikimaru, Toshiyuki Kan, and Tohru Fukuyama*
Graduate School of Pharmaceutical Sciences, UniVersity of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo, Japan
fukuyama@mol.f.u-tokyo.ac.jp
Received June 16, 2004
ABSTRACT
The stereoselective synthesis of the tetracyclic intermediate 21 for (+)-naphthyridinomycin (1) has been accomplished. The convergent synthesis
used the Ugi 4CC reaction with the amine derivative 10. The key features of the stereoselective synthesis of 21 were the intramolecular
Mizoroki−Heck reaction, an aromatic−aldehyde cyclization, and a stereoselective hydroboration.
Naphthyridinomycin (1), an antitumor antibiotic alkaloid
isolated from Streptomyces lusitanus by Kluepfel et al. in
1974,1 has shown potent activity against both Gram-negative
and Gram-positive bacteria.2 In addition, it has displayed
activity against a penicillin-sensitive, resistant Staphylococcus
aureus but showed lethal toxicity against laboratory mice.
This remarkable biological activity, coupled with its highly
complex structure, has made naphthyridinomycin an attrac-
tive target for total synthesis, and several synthetic studies
on this family of compounds have been published.2 However,
only two total syntheses, by Evans3 and by our4 group in
the 1980s, of a stable derivative 2, that is readily converted
to 1, have been reported to date. One of the crucial steps in
the total synthesis of 1 is the construction of the highly
strained 3,8-diazabicyclo[3.2.1]octane framework in the
complex ring system of 1. During the course of our total
synthesis of ecteinascidin 743 (Et 743),5 we established an
efficient synthetic strategy for tetrahydroisoquinoline alka-
loids via the Ugi four-component condensation (4-CC) and
the intramolecular Mizoroki-Heck reaction. We thought that
this protocol could be applied to the synthesis of related
natural products. Herein, we report a stereocontrolled
synthesis of the tetracyclic intermediate 21 for the total
synthesis of 1.
The heart of our synthetic plan is illustrated in Scheme 1.
Since the hemiaminal and the quinone moiety of 1 would
be highly labile to many reaction conditions, they must be
formed in the latter stages of any total synthesis. Thus, the
tetracyclic diol 3, from which the oxazolidine ring could be
(1) (a) Kluepfel, D.; Baker, H. A.; Piattoni, G.; Sehgal, S. N.; Sidorowicz,
A,; Singh, K.; Vezina, C. J. Antibiot. 1975, 28, 497. (b)Sygusch, J.; Brisse,
F.; Hanessian, S. Tetrahedron Lett. 1974, 15, 4021. (c) erratum: Sygusch,
J.; Brisse, F.; Hanessian, S. Tetrahedron Lett. 1975, 16, 170. (c) Hanessian,
S.; Kluepfel, D. Acta Crystallogr. 1976, B32, 1139.
(2) For a recent review of tetrahydroisoquinoline alkaloids, see: Scott,
J. D.; Williams, R. M. Chem. ReV. 2002, 102, 1669.
(3) (a) Evans, D. A.; Biller, S. A. Tetrahedron Lett. 1985, 26, 1907. (b)
Evans, D. A.; Biller, S. A. Tetrahedron Lett. 1985, 26, 1911. (c) Evans, D.
A.; Illig, C. R.; Saddler, J. C. J. Am. Chem. Soc. 1986, 108, 2478.
(4) (a) Fukuyama, T.; Laird, A. A. Tetrahedron Lett. 1986, 27, 6173.
(b) Fukuyama, T.; Li, L.; Laird, A. A.; Frank, R. K. J. Am. Chem. Soc.
1987, 109, 1587. (c) Fukuyama, T. AdV. Heterocycl. Nat. Prod. Synth. 1992,
2, 189.
(5) Endo, A.; Yanagisawa, A.; Abe, M.; Tohma, S.; Kan, T.; Fukuyama,
T. J. Am. Chem. Soc. 2002, 124, 6552.
10.1021/ol048857e CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/13/2004

Scheme 1. Structure and Synthetic Strategy of 1
Scheme 2. Synthesis of the Left-Hand Segment 10
readily prepared, was designed as the key intermediate in
our total synthesis of 1. The primary alcohol of 3 was
expected to be constructed by a stereoselective hydroboration
of the exo-olefin of the tetracyclic intermediate after con-
struction of the B-ring from 4. According to our Et 743
synthesis,5 the bicyclo[3.2.1]octane ring of the enamide 4
could be formed by the intramolecular Mizoroki-Heck
reaction. We anticipated that the cyclization precursor would
be prepared by the Ugi 4-CC reaction through a diketopip-
erazine intermediate.
Synthesis of the highly functionalized (R)-arylglycinol 10
was accomplished via the Mannich-type reaction of the
phenol 66 with the chiral template 7, developed in our
laboratories7 (Scheme 2). Thus, coupling of the phenol 6 with
the chiral iminolactone 7 proceeded smoothly in high regio-
and stereoselectivity under acidic conditions to provide the
desired adduct 8 as a single product.8 Protection of the phenol
of 8 with the mesyl group, reductive ring opening of the
lactone, and selective silylation of the resulting primary
alcohol provided 9. Oxidative cleavage of the 1,2-amino
alcohol moiety was effected with Pb(OAc)4, and subsequent
treatment with NH2OH converted the imine to the desired
arylglycinol 10.
quantitative yield. Subsequent cleavage of the Boc group
gave the primary amine, which cyclized to afford 13 upon
reflux in toluene. Conversion of 13 into the cyclic enamide
14 was performed by a three-step sequence involving
introduction of a Boc group onto the lactam nitrogen,12 partial
reduction of the ring carbonyl group with NaBH4, and
dehydration of the resulting hemiaminal derivative by
treatment with CSA and quinoline. With the requisite
enamide 14 in hand, we then focused our attention on the
construction of the bicyclo[3.2.1]octane ring of 15. Although
the construction of the bicyclo[3.3.1] ring system in Et 743
was accomplished by common Mizoroki-Heck reaction
conditions,13 such as a combination of Pd2(dba)3, P(o-tol)3,
and Et3N, unfortunately, the desired reaction of 14 did not
proceed under these conditions. After an extensive search
for alternative conditions, we found that the combination of
the Pd2(dba)3 catalyst with Et3N in DMA without a phosphine
ligand was suitable for the construction of the bicyclo[3.2.1]
ring system of the enamide 15. The next challenge in the
synthesis was the production of the hydroxymethyl group
of 17 with control of the stereochemistry at the C-13c
position. According to the Et 743 synthesis,5 the enamide
of 15 was regioselectively oxidized with dimethyldioxirane14
in MeOH-acetone to generate an acid-sensitive epoxide,
which, without isolation, was immediately treated with CSA
to afford the methoxy alcohol 16 as a single isomer. The
subsequent acyliminium ion-mediated reduction under acidic
conditions occurred from the less hindered exo-face of the
molecule to afford the alcohol 17 as a single isomer with
the correct stereochemistry.15
Segments 10 and 119 were incorporated into the dike-
topiperazine 13 by means of the powerful Ugi 4-CC
reaction10 (Scheme 3). A mixture of the amine 10, the
carboxylic acid 11, p-methoxyphenyl isocyanide,11 and
acetaldehyde in MeOH afforded the dipeptide 12 in almost
(6) Fukuyama, T.; Yang, L. Tetrahedron Lett. 1986, 27, 6299.
(7) (a) Tohma, S.; Endo, A.; Kan, T.; Fukuyama, T. Synlett 2001, 1179.
(b) Tohma, S.; Rikimaru, K.; Endo, A.; Shimamoto, K.; Kan, T.; Fukuyama,
T. Synthesis 2004, 1179.
(8) The confirmation of the stereochemistry of 8 was performed by X-ray
analysis; see ref 7a,b.
(9) The allylglycine derivative 11 was synthesized by utilizing Oppolzer’s
camphorsultam chiral auxiliary, see: (a) Leanna, M. R.; Morton, H. E.
Tetrahedron Lett. 1993, 34, 4485. (b) Lopez, A, Pleixats, R. Tetrahedron:
Asymmetry 1998, 9, 1967.
(10) For a recent review, see: Do¨mling, A.; Ugi, I. Angew. Chem., Int.
Ed. 2000, 39, 3168.
(12) Flynn, D. L.; Zelle, R. E.; Grieco, P. A. J. Org. Chem. 1983, 48,
2425.
(13) For a recent review, see: (a) Link, J. T.; Overman, L. E. In Metal-
Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.;
Wiley-VCH Verlag GmbH: Weinheim, Germany, 1998; p 231.
(14) Murray, R. W.; Singh, M. Organic Syntheses; Wiley: New York,
1998; Collect. Vol. IX, p 288.
(11) Gokel, G. W.; Widera, R. P.; Weber, W. P. Organic Syntheses;
Wiley: New York, 1988; Collect. Vol. VI, p 232.
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Org. Lett., Vol. 6, No. 18, 2004

Scheme 3. Synthesis of the Tetracyclic Key Intermediate 21
Construction of the B-ring was accomplished by the
with control of the stereochemistry at the C-4 position. The
excess borane reagent was destroyed by treatment with
MeOH at -50 °C. Oxidative treatment with NaOH and H2O2
gave the desired diol 21 without any loss of the lactam ring.
The stereochemistry at C-13b and C-4 of 21 was confirmed
by a strong NOE between the H-13b and H2-5, as shown in
Scheme 3.
In summary, we have accomplished the efficient synthesis
of the tetracyclic backbone 21 of (+)-naphthyridinomycin
(1) including the highly strained bicyclic[3.2.1]octane frame-
work. The present synthesis features the powerful Ugi 4-CC
reaction for a ready access to the diketopiperazine 13, the
Mizoroki-Heck reaction of the cyclic enamide 14 to give
the highly strained tricycle 15, and the completely stereo-
selective hydroboration of 20. Further conversion of 21 to
(+)-naphthyridinomycin (1) is currently under investigation
in our laboratory.
coupling reaction between the aromatic ring and an aldehyde.
Since the reactivity of the aromatic ring was dependent on
its electron-donating nature, the protecting group of the
phenol 17 was changed from the mesyl to the corresponding
benzyl ether. After oxidation of the alcohol 18 with the
Dess-Martin periodinane,16 treatment of the resulting alde-
hyde 19 with TFA allowed the desired cyclization to proceed
smoothly providing 20 as a single isomer. The secondary
alcohol of 20 possessed the required oxidation state and
stereochemistry at the C-13b position for the formation of
the oxazolidine moiety. The construction of the hydroxy-
methyl group of 21 from the exo-methylene 20 was achieved
by stereoselective hydroboration.17 Treatment of 20 with 3
equiv of BH3‚SMe2 at 0 °C produced the desired reaction
(15) Since the bicyclo[3.2.1] octane skeleton was more reactive than the
related bicyclo[3.3.1] system of Et 743, the use of the weaker formic acid
was required for the generation of the acyliminium ion from 16.
(16) (a) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1982, 104, 902.
(b) Frigerio, M.; Santagostino, M.; Sputore, S. J. Org. Chem. 1999, 64,
4537.
(17) Presumably, the borane reagent attacked from the less hindered exo-
face of the bicyclo[3.3.1] skeleton to afford the desired stereochemistry at
the C-4 position. The selective-production of both stereochemistries at C-4
would be significant, since both stereochemistries were observed in this
family of natural products. The endo-oriented compounds belong to the
naphthyridinomycin family (naphthyridinomycin and dnacins), while the
corresponding exo-oriented compounds belong to the quinocarcin family
(quinocarcin, tetrazomine, and lemonomycin). See ref 2.
Acknowledgment. This work was financially supported
by CREST, JST, and a Grant-in-Aid from the Ministry of
Education, Science, Sports, Culture and Technology, Japan.
Supporting Information Available: Detailed experi-
mental procedures and spectroscopic data. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL048857E
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