A stereoselective approach to the core structure of the polyoxin and nikkomycin antibiotics

Article abstract of DOI:10.1055/s-2003-40341

A stereoselective synthesis of the core structure of the polyoxin and nikkomycin antibiotics is described. Notable elements of the synthesis include the use of an IBX-based oxidation protocol in the high-yielding production of ribosyl aldehydes, and the u

Full text of DOI:10.1055/s-2003-40341

LETTER
1307
A Stereoselective Approach to the Core Structure of the Polyoxin and
Nikkomycin Antibiotics
S
tereosele
e
ctive
A
ppr
o
s
ac
h
to Po
s
lyoxin an
e
d
N
ikkomycin A
n
D
tibiotics . More, Nathaniel S. Finney*
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, 92093-0358 California, USA
E-mail: nfinney@ucsd.edu
Received 31 March 2003
Dedicated to the memory of Professor Ray Lemieux, in honor of his many contributions to organic chemistry.
O
O
Abstract: A stereoselective synthesis of the core structure of the
NH
polyoxin and nikkomycin antibiotics is described. Notable elements
NH
HO
O
O
OH
O
CO2H
of the synthesis include the use of an IBX-based oxidation protocol
in the high-yielding production of ribosyl aldehydes, and the use of
a diastereoselective zinc-mediated acetylide addition for the gener-
ation of the C-5 stereocenter. The synthesis only requires three
chromatographic purifications and should be amenable to the large-
scale preparation of numerous polyoxin analogs.
N
O
N
O
O
O
H2N
H2N
O
N
H
OH NH2
HO
OH
HO
OH
Polyoxin L
1 Uracil Polyoxin C
O
Key words: antifungal agents, amino acids, carbohydrates, diaste-
reoselectivity, stereoselective synthesis
NH
HO
CH3
O
CO2H
N
O
O
N
N
H
OH NH2
As part of our ongoing program to develop novel inhibi-
tors of fungal chitin synthase,1 we desired efficient syn-
thetic access to the microbial secondary metabolite uracil
polyoxin C (1). Polyoxin C is the simplest member of a
large class of peptide-nucleoside hybrid natural products
that are distinguished by their competitive inhibition of
chitin synthase (Figure 1).2 As a result of this inhibitory
activity, the polyoxins and the related nikkomycins have
long been regarded as possible lead compounds for anti-
fungal drug discovery. However, despite medicinal chem-
istry studies that involved extensive variation of the amino
acid side-chain,3 no member of this class has emerged as
an effective antifungal agent. Nonetheless, we felt that the
polyoxin scaffold would be a useful starting point for in-
hibitor design due to its modular structure and several
points of possible diversity, and below describe a formal
asymmetric synthesis of polyoxin C.
HO
OH
Nikkomycin Z
Figure 1
fashion to provide the homologated ribose derivative (A,
Scheme 1).5 Conversion of the nucleophilic component to
a carboxylate, followed by simple functional group inter-
conversion and protecting group manipulation would then
lead to polyoxin C and analogs thereof. Previous polyoxin
syntheses have featured highly stereocontrolled nucleo-
philic additions to ribose-based electrophiles, albeit to ni-
tro-olefin and nitrone species.4e,i Recent work has shown
that only modest stereocontrol can be achieved by addi-
tion of a vinyl Grignard reagent or a lithium acetylide to
aldehyde 3.4l,6 Thus, we adopted a strategy based on re-
agent rather than substrate control.
Several total and formal syntheses of the polyoxin C ami-
no acid have been recorded, using both chiral pool and de
novo construction approaches.3a,4 We chose ribose as a
starting material due to its commercial availability and
low cost. Perhaps more importantly, beginning with ri-
bose allows for eventual variation of the nucleoside base
during analog synthesis. With this strategy in mind, we
recognized the central challenges of such a synthesis as
being one-carbon homologation of C5 of ribose and con-
trolled generation of the C5 stereocenter.
We were drawn to the method recently disclosed by
Carreira and co-workers for in-situ generation of zinc
acetylides in the presence of N-methyl ephedrine and an
aldehyde substrate, leading to enantiomerically enriched
propargyl alcohols.7 The mild reaction conditions and
stereoselectivity of this process were critical in our
reagent controlled
stereoselectivity
MeO
N3
O
O
O
OH
The most direct approach would then involve generation
of an aldehyde from a protected form of ribose followed
by addition of a carbon nucleophile in a stereoselective
R
R
R
O
O
O
H
Nu
Nu
steps
O
O
O
O
O
one carbon
or equivalent
A
Synlett 2003, No. 9, Print: 11 07 2003.
Art Id.1437-2096,E;2003,0,09,1307,1310,ftx,en;S04403ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 General strategy for polyoxin synthesis.

1308
J. D. More, N. S. Finney
LETTER
choice, since the ribosyl aldehyde chosen for study is overall retention of stereochemistry. Toward this end
noted for its general instability, as well as for low dia- (Scheme 3), 4 was subjected to a Mitsunobu inversion
stereofacial bias to incoming nucleophiles.4l,8 It was envi- with benzoic acid to give the corresponding benzoate 5 in
sioned that the alkyne would act as a one-carbon synthetic 86% yield after chromatography.13
equivalent after oxidative cleavage (Scheme 1).
Ph
Aldehyde 3 was efficiently prepared from known alcohol
2 using our recently reported o-iodoxybenzoic acid
OMe
(IBX)-based protocol and subjected to the appropriate
O
BzO
conditions for acetylide addition (Scheme 2).9–11 In an
a.
4
early experiment, addition of phenyl acetylene to alde-
O
O
hyde 3 using the reported conditions gave an approxi-
mately 60% yield of diastereomerically pure propargyl
alcohol, along with inseparable side products. Under opti-
mized conditions [2.0 equiv of phenyl acetylene, 2.1
equiv each of NEt3 and Zn(OTf)2, 2.2 equiv (–)-N-methyl
ephedrine, toluene, 18 hours], the alcohol 4 could be iso-
lated in 87% yield over two steps (IBX oxidation and
acetylide addition).12 Notably, the product was obtained
without detectable impurities (1H NMR, 400 MHz) after a
simple aqueous workup, and the N-methyl ephedrine was
recovered in high yield using acid-base extraction. Based
on literature precedent,7a we expected that the newly
formed stereocenter would be of the R configuration, and
this was confirmed via chemical correlation (vide infra).
5
b.
MeO
HO
O
O
Ph
BzO
OMe
OMe
O
O
c.
O
O
O
6
7
Scheme 3 Reagents and Conditions: (a) PhCO2H, PPh3, DEAD,
THF, 0 °C, 86%; (b) H2, Pd/BaSO4, quinoline, THF, 48 h, 96%; (c) i.
KMNO4, acetone, r.t.; ii. LiOH, THF/H2O, r.t.; iii. TMSCHN2,
MeOH/PhH, r.t., 29% from 6.
Numerous attempts to directly cleave the alkyne of inter-
mediate 5 and related compounds were unsuccessful, so it
was necessary to reduce the triple bond prior to cleavage.
In the event, compound 5 was hydrogenated over Pd/
BaSO4 in the presence of quinoline to give olefin 6 in 96%
yield. The sequence of oxidative scission with KMnO4,
benzoate cleavage, and esterification with TMS–diazo-
methane gave the key intermediate 7 in 28% overall yield
from 6 after chromatography.14 Spectroscopic data for this
compound matched those reported in the literature,4l and
thus served to confirm the relative stereochemistry of 4.
O
OMe
OMe
O
O
HO
H
IBX, CH3CN, 80 °C
O
O
O
O
Ph
2
3
OMe
O
HO
see text
87% (2 steps)
O
O
An alternate route from 6 to 7 was devised to improve
yield and efficiency (Scheme 4). The allylic benzoate 6
was subjected to methanolysis to give alcohol 8 in 90%
4
Scheme 2
The acetylide addition described above deserves further
comment. The use of (–)-N-methyl ephedrine as ligand
gives the R alcohol with high diastereoselectivity, but use
of the antipode of the chiral auxiliary results in an ex-
tremely sluggish reaction. Inspection of the crude reaction
mixture revealed an approximately 3:1 mixture of isomers
favoring the S alcohol along with several decomposition
products. Matched/mismatched stereoselectivity has been
noted for this reaction by Carreira,7d but it is surprising in
the case of aldehyde 3 to see such a strong effect, given the
low inherent facial bias to metal acetylides previously not-
ed.4l
Ph
OMe
O
HO
a
6
O
O
8
b.
MeO
HO
O
O
MeO
N3
O
O
OMe
OMe
O
O
c
O
O
With a convenient route to intermediate 4 in hand, we
completed a formal synthesis of polyoxin C by converting
4 to intermediate 7,4l and then to compound 9 (Scheme 4),
which had been reported in the literature on three separate
occasions.4i,l,o This required oxidative cleavage of the
alkyne as well as installation of the azide moiety with
7
9
Scheme 4 Reagents and Conditions: (a) NaOMe, MeOH, 65 °C,
90%; (b) O3, NaOH, CH2Cl2/MeOH, –78 °C, 55%; (c) HN3, PPh3,
DEAD, THF/PhCH3, 0 °C, h, 80%.
Synlett 2003, No. 9, 1307–1310 ISSN 1234-567-89 © Thieme Stuttgart · New York

LETTER
Stereoselective Approach to Polyoxin and Nikkomycin Antibiotics
1309
Tetrahedron Lett. 1996, 37, 163. (k) Trost, B. M.; Shi, Z. J.
Am. Chem. Soc. 1996, 118, 3037. (l) Kato, K.; Chen, C. Y.;
Akita, H. Synthesis 1998, 1527. (m) Gethin, D. M.;
Simpkins, N. S. Tetrahedron 1997, 53, 14417. (n) Ghosh,
A. K.; Wang, Y. J. Org. Chem. 1998, 63, 6735. (o) Ghosh,
A. K.; Wang, Y. J. Org. Chem. 1999, 64, 2789.
(p) Dehoux, C.; Gorrichon, L.; Baltas, M. Eur. J. Org. Chem.
2001, 1105. (q) Mita, N.; Tamura, O.; Isgibashi, H.;
Sakamoto, M. Org. Lett. 2002, 4, 1111.
yield. The olefin was then converted to hydroxy ester 7
via ozonolysis under basic conditions in moderate yield.15
By utilizing the route depicted in Scheme 4, the overall
yield of 4 to 7 was increased by a factor of two. Hydroxy-
ester 7 could be then be directly converted to azide 9 in
80% yield via a Mitsunobu reaction with hydrazoic acid.
In conclusion, we have developed an efficient synthesis of
the polyoxin scaffold 9 from ribose, which proceeds with
minimal purification in 22% overall yield (8 steps, aver-
age yield/step of 83.5%) and is amenable to multi-gram
scale. Notable features include the use of our newly devel-
oped IBX oxidation protocol and a highly diastereoselec-
tive zinc-mediated asymmetric acetylide addition.7,10
Current efforts are focused on the synthesis and biological
evaluation of polyoxin analogs and results will be report-
ed in due course.
(5) (a) Early studies involved the use of uridine as a starting
material, with the intention of utilizing an asymmetric Ugi
condensation or an asymmetric Strecker reaction as the key
operation. Unfortunately, the required imine derivatives
were either unstable or resulted in poor selectivity upon
nucleophilic addition. In the ribose series, the key
stereocenter could be formed using a chiral auxiliary-
mediated Strecker reaction, but the resulting amino-nitrile
could not be hydrolyzed. (b) For the asymmetric Ugi
reaction, see: Kunz, H.; Pfrengle, W.; Sager, W.
Tetrahedron Lett. 1989, 30, 4109. (c) For a catalytic
asymmetric Strecker reaction, see: Sigman, M. S.; Vachal,
P.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2000, 39, 1279.
(d) For an auxiliary-based Strecker reaction, see: Davis, F.
A.; Portonovo, P. S.; Reddy, R. E.; Chiu, Y.-H. J. Org.
Chem. 1996, 61, 440.
Acknowledgment
The authors gratefully acknowledge the National Institutes of
Health for support of this research (NIGMS-GM60875; NIGMS-
GM07240 training grant support for JDM) and the National Science
Foundation for support of the departmental NMR facilities (CHE-
9709183). The authors thank Judy Mitchell for helpful discussions.
(6) For a study of the addition of allylmetal reagents to aldehyde
3, see: Danishefsky, S. J.; Deninno, M. P.; Phillips, G. B.;
Zelle, R. E.; Lartey, P. A. Tetrahedron 1986, 42, 2.
(7) (a) Frantz, D. E.; Fassler, R.; Tomooka, C. S.; Carreira, E.
M. Acc. Chem. Res. 2000, 33, 373. (b) Frantz, D. E.;
Fassler, R.; Carreira, E. M. J. Am. Chem. Soc. 2000, 122,
1806. (c) Boyall, D.; Frantz, D. E.; Carreira, E. M. Org. Lett.
2002, 4, 2605. (d) El-Sayed, E.; Anand, N. K.; Carreira, E.
M. Org. Lett. 2001, 3, 3017.
References
(1) Chang, R.; Yeager, A. R.; Finney, N. S. Org. Biomol. Chem.
2003, 1, 39.
(2) Isono, K.; Suzuki, S. Heterocycles 1979, 13, 333.
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Des. 1999, 5, 73. (b) Isono, K.; Azuma, T.; Suzuki, S. Chem.
Pharm. Bull. 1971, 19, 505. (c) Azuma, T.; Isono, K.; Crain,
P. F.; McCloskey, J. A. J. Chem. Soc. Chem. Commun. 1977,
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Smith, H. A.; Boney, C.; Becker, J. M. Antimicrob. Agents
Chemother. 1983, 24, 787. (e) Shenbagamurthi, P.; Smith,
H. A.; Becker, J. M.; Steinfeld, A.; Naider, F. J. Med. Chem.
1983, 26, 1518. (f) Emmer, G.; Ryder, N. S.; Grassberger,
M. A. J. Med. Chem. 1985, 28, 278. (g) Shenbagamurthi,
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Med. Chem. 1985, 29, 802. (h) Khare, R. K.; Becker, J. M.;
Naider, F. J. Med. Chem. 1988, 31, 650. (i) Krainer, E.;
Becker, J. M.; Naider, F. J. Med. Chem. 1991, 34, 174.
(j) Cooper, A. B.; Desai, J.; Lovey, R. G.; Saksena, A. K.;
Girijavallabhan, V. M.; Ganguly, A. K.; Loebenberg, D.;
Parmegiani, R.; Cacciapuoti, A. Bioorg. Med. Chem. Lett.
1993, 3, 1079. (k) Obi, K.; Uda, J.; Iwase, K.; Sugimoto, O.;
Ebisu, H.; Matsuda, A. Bioorg. Med. Chem. Lett. 2000, 10,
1451. (l) Suda, A.; Ohta, A.; Sudoh, M.; Tsukuda, T.;
Shimma, N. Heterocycles 2001, 55, 1023.
(4) (a) Ohrui, H.; Kuzahara, H.; Emoto, S. Tetrahedron Lett.
1971, 4267. (b) Damodaran, N. P.; Jones, G. H.; Moffatt, J.
G. J. Am. Chem. Soc. 1971, 93, 3812. (c) Tabusa, F.;
Yamada, T.; Suzuki, K.; Mukaiyama, T. Chem. Lett. 1984,
405. (d) Garner, P.; Park, J. M. J. Org. Chem. 1990, 55,
3772. (e) Barrett, A. G. M.; Lebold, S. A. J. Org. Chem.
1990, 55, 3853. (f) Auberson, Y.; Vogel, P. Tetrahedron
1990, 46, 7019. (g) Chen, A.; Thomas, E. J.; Wilson, P. D. J.
Chem. Soc. Perkin Trans. 1 1999, 3305. (h) Chida, N.;
Koizumi, K.; Kitada, Y.; Yokoyama, C.; Ogawa, S. J. Chem.
Soc., Chem. Commun. 1994, 111. (i) Dondoni, A.;Santiago,
F.; Junquera, F.; Merchan, F. L.; Merino, P.; Tejero, T. J.
Org. Chem. 1997, 62, 5497. (j) Evina, C. M.; Guillerm, G.
(8) Attempted use of the zinc acetylide addition with a uridine-
derived aldehyde was thwarted by a complete lack of
reactivity with a variety of alkynes.
(9) Alcohol 2 was prepared on a 30-gram scale in 79% yield by
a modification of the procedure found in: Leonard, N. J.;
Carraway, K. L. J. Heterocycl. Chem. 1966, 3, 485.
(10) More, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001.
(11) Other methods of oxidation investigated (e.g. PCC, Swern,
CrO3/pyridine, TPAP, IBX/DMSO, Dess–Martin) proved to
be much less reliable for this transformation, being difficult
to reproduce and providing aldehyde of lower purity than
with IBX.
(12) Experimental Details for the Synthesis of Compound 4:
The alcohol 2 (6.2 g, 30.18 mmol, 1.0 equiv) was dissolved
in 250 mL CH3CN and IBX (16.9 g, 60.35 mmol, 2.0 equiv)
was added. The flask was fitted with a reflux condenser and
the suspension was immersed in an oil bath heated to 80 °C
with vigorous stirring. After 75 min, an aliquot was removed
and analyzed by 1H NMR, which indicated consumption of
starting material and clean conversion to product. The
reaction was stopped, cooled to room temperature and
filtered, washing the flask and filter thoroughly with EtOAc.
The combined filtrate and washings were combined and
concentrated to yield a white, glassy semi-solid, which was
used without further purification in the next step. 1H NMR
(400 MHz, CDCl3) d 9.56 (s, 1 H), 5.08 (s, 1 H), 5.04 (d,
1 H, J = 8 Hz), 4.48 (d, 1 H, J = 8 Hz), 4.46 (s, 1 H), 3.44 (s,
3 H), 1.48 (s, 3 H), 1.32 (s, 3 H). An oven-dried 1 L round
bottom flask was cooled under N2, then charged with (–)-N-
methyl ephedrine (11.9 g, 66.39 mmol, 2.2 equiv) and
Zn(OTf)2 (23.0 g, 63.37 mmol, 2.1 equiv), and purged with
N2. Freshly distilled NEt3 (8.9 mL, 63.37 mmol, 2.1 equiv)
was added via syringe, followed by 250 mL anhydrous
Synlett 2003, No. 9, 1307–1310 ISSN 1234-567-89 © Thieme Stuttgart · New York

1310
J. D. More, N. S. Finney
LETTER
toluene via cannula. The heterogeneous mixture was stirred
vigorously for 2 h, and phenyl acetylene (6.6 mL, 60.35
mmol, 2.0 equiv) was added via syringe. After stirring for an
additional 30 min, the aldehyde 3 (azeotropically dried twice
with benzene) was added in 80 mL toluene via cannula. The
reaction was stirred overnight (approx. 18 h), at which time
TLC analysis showed formation of a new, UV-active spot
(Rf 0.24, 30% ethyl acetate in hexanes). The reaction was
stopped, diluted with 300 mL EtOAc, and poured into a
separatory funnel containing 700 mL 0.1 M sodium EDTA.
The aqueous layer was removed and extracted twice with
EtOAc (approx 300 mL each). The combined organics were
washed twice with 0.1 M sodium EDTA (500 mL total), 3
times with 1.0 M HCl (to remove and recycle N-methyl
ephedrine), and brine, then dried over Na2SO4, filtered and
concentrated to afford pure 4 as a brown semi-solid (8.05 g,
26.5 mmol, 87.6% over 2 steps). Rf = 0.24 (20% in EtOAc /
hexanes); 1H NMR (400 MHz, CDCl3) d 7.46–7.48 (m, 2 H),
7.30–7.32 (m, 3 H), 5.08 (d, 1 H, J = 6 Hz), 5.03 (s, 1 H),
4.71 (br s, 1 H), 4.63 (d, 1 H, 6 Hz), 4.55 (d, 1 H, J = 2 Hz),
3.99 (br s, 1 H), 3.48 (s, 3 H), 1.50 (s, 3 H), 1.35 (s, 3 H); 13
C
NMR (125 MHz, CDCl3) d 131.7, 128.5, 128.1, 122.1,
112.2, 110.7, 91.0, 86.5, 85.6, 85.5, 80.8, 64.4, 55.9, 26.4,
24.8; FTIR (thin film; NaCl) 3415, 2986, 2943, 1492, 1375,
1212, 1095, 1037, 868, 763 cm-1; HRMS (DCI) m/z: (M +
+
NH4 ) calc. for C17H24O5N 322.1654, found 322.1657.
(13) Mitsunobu, O. Synthesis 1981, 1.
(14) For the first use of TMSCHN2 in esterification, see:
Aoyama, T.; Shioiri, T. Tetrahedron Lett. 1980, 21, 4461.
(15) Marshall, J. A.; Garofalo, A. W.; Sedrani, R. C. Synlett 1992,
643.
Synlett 2003, No. 9, 1307–1310 ISSN 1234-567-89 © Thieme Stuttgart · New York