Application of Pd(0)-catalyzed intramolecular oxazine formation to the efficient total synthesis of ( - )-anisomycin

Article abstract of DOI:10.1021/ol701519b

The enantioselective total synthesis of ( - )-anisomycin, a potent antibiotic agent, has been achieved. The key steps are a Pd(0)-catalyzed stereoselective intramolecular oxazine formation from D-tyrosine and pyrrolidine formation by catalytic hydrogenation of the oxazine.

Full text of DOI:10.1021/ol701519b

ORGANIC
LETTERS
2007
Vol. 9, No. 18
3627-3630
Application of Pd(0)-Catalyzed
Intramolecular Oxazine Formation to the
Efficient Total Synthesis of
(−)-Anisomycin
Jae-Eun Joo,† Kee-Young Lee,‡ Van-Thoai Pham,† Yong-Shou Tian,† and
Won-Hun Ham*,†
College of Pharmacy, SungKyunKwan UniVersity, Suwon 440-746, Korea, and
Yonsung Fine Chemicals Co., Ltd., 129-9 Suchon-ri Jangan-myeon, Hwaseong-si,
Gyeonggi-do, 445-944, Korea
whham@skku.edu
Received June 27, 2007
ABSTRACT
The enantioselective total synthesis of (−)-anisomycin, a potent antibiotic agent, has been achieved. The key steps are a Pd(0)-catalyzed
stereoselective intramolecular oxazine formation from
D-tyrosine and pyrrolidine formation by catalytic hydrogenation of the oxazine.
The antibiotic (-)-anisomycin (1) (Figure 1) was first
isolated from the fermentation broths of Streptomyces
griseolous and Streptomyces roseochromogens by Sobin and
Tanner in 19541 and has since been obtained from Strepto-
myces sp. No. 638 and SA 3097.2 It was reported to possess
the 2S,3S,4S absolute configuration.3
(-)-Anisomycin exhibits strong and selective activity
against pathogenic protoza and fungi.4 It has been used
clinically for treatment of both amoebic dysentery and
Trichomonas Vaginitis and as a fungicide to eradicate bean
mildew and to inhibit other pathogenic fungi in plants.5 It
has also been shown to exhibit antiviral and antitumor
activities due to apoptotic activity.6
Because of its promising biological profile, much effort
has been devoted to the development of an efficient synthesis
of this antibiotic and its deacetyl analogue. More than 20
syntheses of anisomycin and its analogues have been reported
in the past several years. However, many of the published
procedures suffer from inefficient protecting group chemistry
in the later stages.7
Recently, we have described a new Pd(0)-catalyzed
procedure for the stereoselective formation of an oxazine
ring from a γ-allylic benzamide having a benzoyl substituent
† SungKyunKwan University.
‡ Yonsung fine chemicals Co., Ltd.
(1) Sobin, B. A.; Tanner, F. W. J. Am. Chem. Soc. 1954, 76, 4053.
(2) (a) Ishida, S.; Yamada, O.; Futatsuya, F.; Ito, K.; Yamamoto, H.;
Munakata, K. Proc. Int. Congr. IAMS 1st 1974, 3, 641. (b) Hosoya, Y.;
Kameyama, T.; Naganawa, H.; Okami, Y.; Takeuchi, T. J. Antibiot. 1993,
46, 1300.
(3) Wong, C. M. Can. J. Chem. 1968, 46, 1101.
(4) Jimenez, A.; Vazquez, D. In Antibiotics; Hahn, F. E., Ed.; Springer-
Verlag: Berlin, 1979; pp 1-19. Grollman, A. P. J. Biol. Chem. 1967, 242,
3226.
(5) (a) Schumacher, D. P.; Hall, S. S. J. Am. Chem. Soc. 1982, 104,
6076. (b) Han, G.; LaPorte, M. G.; McIntosh, M. C.; Weinreb, S. M.; Parvez,
M. J. Org. Chem. 1996, 61, 9483.
Figure 1. (-)-Anisomycin.
10.1021/ol701519b CCC: $37.00
© 2007 American Chemical Society
Published on Web 08/08/2007

Scheme 1
as an N-protection group in the presence of Pd(PPh3)4, NaH,
ethanol furnished amino alcohol 7 in 95% yield. Oxidation
of the alcohol with Dess-Martin periodinane gave the
corresponding aldehyde, which was reacted with vinylmag-
nesium bromide in THF at 0 °C to afford allyl alcohol 8 as
a 1.1:1 mixture of syn/anti isomers (1H NMR) in 79% yield.
Acetylation of the hydroxyl group yielded the secondary
allylic acetate, and the palladium-catalyzed oxazoline ring
formation of the allylic acetate 9 gave the desired trans-
oxazoline 10 as a single diastereomer in good yield (75%).9
and n-Bu4NI. Unlike other palladium-catalyzed reactions, the
diastereoselectivity of oxazine ring formation is predomi-
nantly controlled by the temperature.8
Our study into intramolecular oxazine formation from
2a-d has shown that the stereoselectivity of these cycliza-
tions can be critically dependent upon whether the reaction
temperature results in kinetic or thermodynamic control of
the products (Scheme 1). Oxazines syn-3a-d require condi-
tions giving kinetic control (0 °C), whereas anti-3a-d are
observed under thermodynamic control (40 °C).
Scheme 3
We envisioned that this method could be utilized to set
the three contiguous stereocenters of (-)-anisomycin (1). The
pendant vinyl group of oxazine 4 could be converted to the
corresponding aldehyde, which could be employed in forma-
tion of the pyrrolidine ring by catalytic hydrogenation of
oxazine. We now report an enantioselective synthesis of 1
in accordance with these strategies. Our retrosynthetic
analysis is displayed in Scheme 2.
Scheme 2. Retrosynthetic Analysis
Our initial efforts in the synthesis of the requisite trans-
oxazoline allyl chloride 12 commenced with the protected
N-benzoyl-D-tyrosine methyl ester (6) as shown in Scheme
3. Reduction of the ester 6 with sodium borohydride in
Ozonolysis of the olefin 10 and subsequent Horner-
Wardsworth-Emmons reaction afforded the R,â-unsaturated
ester 11 with good E/Z selectivity (>15:1, 1H NMR).
Reduction of compound 11 by DIBAL-H at -78 °C and
conversion of this allylic alcohol to the chloride under TsCl/
DMAP conditions gave the desired allyl chloride 12 in good
yield (89%).
(6) (a) Stadheim, T. A.; Kucera, G. L. Leuk. Res. 2002, 26, 55. (b)
Torocsik, B.; Szeberenyi, J. Biochem. Biophys. Res. Commun. 2000, 278,
550. (c) Lee, Y. S.; Wurster, R. D. Cancer Lett. 1995, 93, 157.
(7) (a) Kim, J. H.; Crutis-Long, M. J.; Seo, W. D.; Ryu, Y. B.; Yang,
M. S.; Park, K. H. J. Org. Chem. 2005, 70, 4082 and references therein.
(b) Hulme, A. N.; Rosser, E. M. Org. Lett. 2002, 4, 265 and references
therein.
(9) (a) Lee, K. Y.; Oh, C. Y.; Ham, W. H. Org. Lett. 2002, 4, 4403. (b)
Lee, K. Y.; Kim, Y. H.; Oh, C. Y.; Ham, W. H. Org. Lett. 2000, 2, 4041.
(c) Lee, K. Y.; Kim, Y. H.; Park, M. S.; Oh, C. Y.; Ham, W. H. J. Org.
Chem. 1999, 64, 9450.
(8) Joo, J. E.; Lee, K. Y.; Pham, V. T.; Ham, W. H. Eur. J. Org. Chem.
2007, 1586.
3628
Org. Lett., Vol. 9, No. 18, 2007

However, the preparation of allyl chloride 12 was plagued
by protecting group manipulations and functional group
interconversions, leading to synthetic inefficiency. Conse-
quently, a new method for synthesizing 12 was conceived
(Scheme 4).
Table 1. Oxazine Formation Catalyzed by Pd(0)
Scheme 4
entry substrate temp (°C) time (h) yielda (%) ratiob (syn/anti)
1
2
3
4
5
5
5
0
12
12
12
12
79
81
68
72
15:1
1:5
1:9
rt
50
0
17
>30:1
a
b
Yields refer to the isolated and mixture products. Ratio was
1
determined by H NMR.
the case of the more bulky TBDPS group, the syn isomer
was formed predominantly (entry 4). It is interesting that
the palladium-catalyzed reaction was so dependent on
temperature. Starting from 5, both syn and anti isomers can
be stereoselectively prepared simply by changing the reaction
temperature: syn under kinetic control (0 °C) and anti under
thermodynamic control (50 °C). The configuration of the
newly generated chiral center in oxazine 4 could not be
deduced from the NMR spectra but could be anticipated to
possess the syn configuration on the basis of previous
results.8,11
The ester 6 was readily converted into Weinreb amide 13
by treatment with N,O-dimethylhydroxylamine in the pres-
ence of trimethylaluminum in 98% yield. Reaction of
Weinreb amide 13 with vinyltin 14 and MeLi in THF at -78
°C gave R,â-unsaturated ketone 15 in 86% yield. To
investigate the anti-selective reduction, amino ketone 15 was
treated with various reducing agents, and we found that
reaction with lithium tri-tert-butoxyaluminohydride in ethanol
at -78 °C gave the desired alcohol 16 as the major
compound in good yield (93%) with excellent stereoselec-
tivity (anti/syn ) 10:1).10 A p-nitrobenzoic acid catalyzed
Mitsunobu-type reaction of anti-amino alcohol 16 gave the
trans-oxazoline 12 in good yield (83%). The spectroscopic
data of the resulting oxazoline 12 were identical to those of
oxazoline 10. Subsequent acid-catalyzed hydrolysis of the
oxazolines, followed by the addition of sodium bicarbonate
to increase the pH of the reaction mixture to 9.0, furnished
the syn-amino alcohol. Protection of the resulting alcohol
by TBSCl or TBDPSCl afforded the cyclization precursors
5 and 17 in excellent yield.
Under the conditions of Pd(PPh3)4, NaH, and n-Bu4NI in
THF at 0 °C, the stereoselective intramolecular cyclization
of allyl chloride 5 afforded the syn-oxazine 4 as a 15:1
mixture of syn/anti isomers (1H NMR) in good yield (Table
1, entry 1). The reaction at room temperature showed a
different selectivity, where the anti adduct (4′) was obtained
as the major isomer (entry 2). When the reaction temperature
was increased to 50 °C, a better diastereoselectivity was
observed (1:9 mixture of the syn/anti isomer, entry 3). In
Completion of the synthesis of (-)-anisomycin was
achieved via deprotection of the silyl ether of the oxazine 4
and acetylation of this alcohol (Scheme 5). Ozonolysis of
Scheme 5
the oxazine 19 gave the corresponding aldehyde. Hydro-
genolysis of the aldehyde in a 9:1 MeOH/AcOH mixture
was performed under 70 psi of H2 catalyzed by Pd(OH)2/C
at ambient temperature. Under these conditions, we achieved
not only hydrogenolysis of the oxazine moiety but also
cyclization of the intermediate aminoaldehyde to 1 as a single
isomer.
The synthetic compound was spectroscopically in good
agreement with the natural and synthetic (-)-anisomycin.
25
The optical rotation of our compound 1, [R]D -29.0° (c
1.0, MeOH), compared to the reported value,12 [R]D23 -30.4°
(c 1.0, MeOH), confirms the absolute configuration.
(11) Compound 4 has a pattern almost similar with the previously
reported benzyl oxazine compound at TLC and 1H NMR. The proton of
terminal olefin and H5 have peaks at 6.0 and 4.1 ppm. In addition, the
coupling constants of the newly generated chiral center (H5-H6) of
compound 4 have the same value of 1.5 Hz compared to that of all syn-
oxazine compounds previously reported.
(10) (a) Pham, V. T.; Joo, J. E.; Tian, Y. S.; Oh, C. Y.; Ham, W. H.
Arch. Pharm. Res. 2007, 30, 22. (b) Hoffman, R. V.; Maslouh, N.; Lee, F.
C. J. Org. Chem. 2002, 67, 1045.
Org. Lett., Vol. 9, No. 18, 2007
3629

In summary, we report a new asymmetric synthetic method
for (-)-anisomycin utilizing oxazine 4. The net result is a
synthesis having a longest linear sequence of 11 steps and
proceeding in 27% yield. The key features in this strategy
are the stereoselective intramolecular oxazine formation by
palladium(0) and pyrrolidine formation by catalytic hydro-
genation of the oxazine.
Acknowledgment. This work was financially supported
by Yonsung Fine Chemicals Co., Ltd., and Seoul R&BD
Program (10541).
Supporting Information Available: Complete experi-
mental procedures and spectral data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(12) Iida, H.; Yamazaki, N.; Kibayashi, C. J. Org. Chem. 1986, 51, 1069.
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