Applications of Sugar Nitrones in Synthesis: The Total Synthesis of (+)-Polyoxin J

Article abstract of DOI:10.1021/jo9702913

A convergent synthesis of the peptidyl nucleoside antibiotic (inhibitor of chitin biosynthesis) polyoxin J (2) by coupling of 5-O-carbamoyl polyoxamic acid (3) and thymine polyoxin C (4) is described. These compounds were prepared by chain elongation and

Full text of DOI:10.1021/jo9702913

J . Org. Chem. 1997, 62, 5497-5507
5497
Ap p lica tion s of Su ga r Nitr on es in Syn th esis: Th e Tota l Syn th esis
of (+)-P olyoxin J 1
Alessandro Dondoni,*,† Santiago Franco,‡ Federico J unquera,‡ Francisco L. Mercha´n,‡
Pedro Merino,*,‡,§ and Toma´s Tejero‡
Dipartimento di Chimica, Laboratorio di Chimica Organica, Universita` di Ferrara,
I- 44100 Ferrara, Italy, and Departamento de Quimica Orga´nica, ICMA, Universidad de Zaragoza,
E-50009 Zaragoza, Aragon, Spain
Received February 14, 1997X
A convergent synthesis of the peptidyl nucleoside antibiotic (inhibitor of chitin biosynthesis) polyoxin
J (2) by coupling of 5-O-carbamoyl polyoxamic acid (3) and thymine polyoxin C (4) is described.
These compounds were prepared by chain elongation and amination of sugar-derived aldehydes
employing their nitrones as iminium derivatives and the furan ring as a masked carboxyl. Thus,
the stereoselective addition of 2-lithiofuran to the L-threose derived N-benzyl nitrone 5 followed by
reduction of the resulting hydroxylamine to amine, carbamoylation of the free hydroxy group, and
oxidative cleavage of the furan ring to the carboxylate group gave a protected derivative of 3 (30%).
The same method was followed for the synthesis of the ribofuranosyl R-amino acid nucleoside 4
(12.6%) starting from the D-ribose derived nitrone 6. The final coupling was performed by the
N-hydroxysuccinimide active ester method in DMSO with the Hu¨nig base (i-Pr2EtNH) using a
derivative of 3 and unprotected 4.
The polyoxins are a group of peptidyl nucleoside
antibiotics produced in the fermentation broth of Strep-
tomyces cacaoi var asoensis and have been isolated and
characterized by Isono and co-workers about 30 years
ago.2 In total, about 15 compounds having closely related
structures have been identified and designated with
alphabetical letters. Their structure showed the presence
of a unique ribofuranosyl R-amino acid nucleoside that
constitutes the common skeleton to all of the members
of the family. The nucleoside portion that eventually
bears different pyrimidine bases is connected through
amide bonds to an open chain polyalkoxy R-amino acid
and to an azetidine-2-carboxylic acid. This tripeptide
structure is illustrated by the first member of the family,
polyoxin A (1).3 Some polyoxins, however, are simply
dipeptides incorporating in their structure only two of
the above amino acids. This is the case of polyoxin J (2)
where hydrolytic degradation leads to the polyalkoxy
R-amino acid 5-O-carbamoylpolyoxamic acid (3) and the
amino acid nucleoside thymine polyoxin C (4) (Chart 1).
The original interest for polyoxins and the closely
related natural products nikkomycins4 and neopolyoxins5
as well as their synthetic analogs6 stemmed from their
marked activity against phytopathogenic fungi while
being nontoxic to bacteria, plants, or animals. These-
biological effects apparently are due to the ability of
polyoxins to inhibit the enzyme chitin synthase and
therefore to prevent the biosynthesis of chitin, an es-
sential component of the fungal cell wall structure.
Hence, the polyoxin complex obtained by fermentative
processes proved to be an excellent agricultural fungicide
of wide use, particularly for the sheath blight disease of
rice plant.2 More recently, considerable attention to all
the above families of peptidyl nucleosides antibiotics,
especially nikkomycins and neopolyoxins, has been given
as inhibitors of opportunistic fungal infections by Can-
dida albicans in immunocompromised hosts, such as
AIDS victims and organ transplant patients.6,7
The usual procedure for the synthesis of polyoxins
involves the condensation of the amino acid portions,
which is the reversal of their hydrolytic cleavage. This
approach has been followed in the two total syntheses of
polyoxin J (2) that have been hitherto carried out and
reported in the form of short communications with a 20-
year gap betwen them.8,9 Both methods involved, as a
final step, the coupling between suitably protected de-
rivatives of 3 and 4 which in turn were obtained by
elaboration of two different monosaccharides in one case
(R-L-sorbopyranose and R-D-allofuranose)8 and by elabo-
ration of the antipode myo-inositol derivatives obtained
(4) (a) Ko¨nig, W. A.; Hass, W.; Dehler, W.; Fiedler, H. P.; Za¨hner,
H. Liebigs Ann. Chem. 1980, 622. (b) Ko¨nig, W. A.; Hahn, H.;
Rathmann, R.; Hass, W.; Keckeisen, A.; Hagenmaier, H.; Borrman,
C.; Dehelr, W.; Kurth, R.; Za¨hner, H. Liebigs Ann. Chem. 1986, 407.
(c) Barrett, A. G.; Lebold, S. J . Org. Chem. 1991, 56, 4875. (d) Saksena,
A. K.; Lovey, R. G.; Girijavallabhan, V. M.; Guzik, H.; Ganguly, A. K.
Tetrahedron Lett. 1993, 34, 3267.
(5) Uramoto, M.; Kobinata, K.; Isono, K.; Higashijima, T.; Miyazawa,
T.; J enkins, E. E.; McCloskey, J . A. Tetrahedron. Lett. 1980, 21, 3395.
Uramoto, M.; Kobinata, K.; Isono, K.; Higashijima, T.; Miyazawa, T.;
J enkins, E. E.; McCloskey, J . A. Tetrahedron 1982, 38, 1599.
(6) Shenbagamurthi, P.; Smith, H. A.; Becker, J . M.; Steinfeld, A.
S.; Naider, F. J . Med. Chem. 1983, 26, 1518. Emmer, G.; Ryder, N. S.;
Grassberger, M. A. J . Med. Chem. 1985, 28, 278. Boehm, J . C.;
Kingsbury, W. D. J . Org. Chem. 1986, 51, 2307. Fiandor, J .; Garcia-
Lo´pez, M.-T.; De las Heras, F. G.; Me´ndez-Castrillo´n, P. P. Synthesis
1987, 978. Krainer, E.; Becker, J . M.; Naider, F. J . Med. Chem. 1991,
34, 174. 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.
(7) For a review on this topic, see: Saksena, A. K.; Girijavallabhan,
V. M.; Cooper, B.; Loebenberg, D. Annu. Rep. Med. Chem. 1989, 24,
111.
† Universita` di Ferrara. Prof. A. Dondoni. Internet: adn@dns.unife.it.
‡ Universidad de Zaragoza. Dr. P. Merino. Internet: pmerino@
posta.unizar.es.
§ To whom correspondence relative to X-ray analysis should be
addressed.
X Abstract published in Advance ACS Abstracts, J uly 1, 1997.
(1) A preliminary account of this work has been published: Dondoni,
A.; J unquera, F.; Merchan, F. L.; Merino, P.; Tejero, T. J . Chem. Soc.,
Chem. Commun. 1995, 2127.
(2) (a) Isolation: Suzuki, S.; Isono, K.; Nagatsu, J .; Mizutani, T.;
Kawashima, Y.; Mizuno, T. J . Antibiot., Ser. A. 1965, 18, 131. Isono,
K.; Kobinata, K.; Suzuki, S. Agr. Biol. Chem. 1968, 32, 792. (b)
Structure elucidation: Isono, K.; Asahi, K.; Suzuki, S. J . Am. Chem.
Soc. 1969, 91, 7490. (c) Reviews: Isono, K.; Suzuki, S. Heterocycles
1979, 13, 333. Isono, K. J . Antibiot. 1988, 41, 1711.
(3) A stereochemical revision (cis instead of trans) of the 3-eth-
ylidene-L-azetine-2-carboxilic acid (polyoximic acid) that is present in
this compound has been recently reported. See: Hanessian, S.; Fu,
J .-M.; Tu, Y.; Isono, K. Tetrahedron Lett. 1993, 34, 4153.
(8) Kuzuhara, H.; Ohrui, H.; Emoto, S. Tetrahedron Lett. 1973, 5055.
(9) Chida, N.; Koizumi, K.; Kitada, Y.; Yokoyama, C.; Ogawa, S. J .
Chem. Soc., Chem. Commun. 1994, 111.
S0022-3263(97)00291-0 CCC: $14.00 © 1997 American Chemical Society

5498 J . Org. Chem., Vol. 62, No. 16, 1997
Dondoni et al.
Ch a r t 1
the cases the fundamental problem associated with the
stereocontrolled introduction of the amino group was
solved through nucleophilic substitution of the activated
hydroxy group using azide as the nitrogen nucleophile.
Other methods, particularly the Strecker reaction, ap-
peared less satisfactory. A conceptually new method was
described by Garner and Park some years ago by the use
of D-serinal as starting material.12c In this case the
nitrogen functionality was already in place and its
R-configuration was employed for the construction of the
other stereocenters. The first de novo asymmetric syn-
thesis of (+)-polyoxamic acid has been recently reported
by Trost and his co-workers via Pd-based opening of a
vinyl epoxide by phthalimide in the presence of a chiral
ligand.13
We considered that both the constituent fragments 3
and 4 of polyoxin J (2) could be obtained by our own
method of introducing the nitrogen functionality consist-
ing of the homologative amination of sugar-derived
aldehydes using their nitrones as iminium derivatives
and the furan as a masked carboxylic acid d1-synthon14,15
(eq 1). Thus, a synthetic plan was developed based on
the use of the readily available16 L-threose- and D-ribose-
derived nitrones 5 and 6 (see Chart 1). Following earlier
and concise reports17,18 that culminated in the total
synthesis1 of 2, we would like to describe here in extenso
the results of this work.
Resu lts a n d Discu ssion
Syn th esis of 5-O-Ca r ba m oyl P olyoxa m ic Acid (3).
In seeking a practical route to 3, and more usefully still,
to a derivative with suitable protection for peptide
coupling, we began with the protected L-threose N-benzyl
nitrones 5a and 5b. These compounds were prepared16
in gram quantities by condensation of N-benzylhydroxy-
lamine with the corresponding aldehydes 7a 19 and 7b20
(eq 2), themselves obtained from acetonide (S,S)-dimethyl
tartrate in three steps.
from racemic myo-inositol in the other case.9 Other
syntheses of 3 or 4 or their ultimate precursors have been
reported over the years starting from the most disparate
building blocks, mainly carbohydrates.10-12 In most of
(10) For early syntheses of polyoxamic acid derivatives and the
nucleoside portions of polyoxins, see: Garner, P. Studies in Natural
Products Chemistry. Vol. 1. Stereoselective Synthesis. Part A; Atta-Ur
Rahman, Ed., Elsevier: Amsterdam, 1988; p 397.
(11) Recent syntheses of polyoxamic acid derivatives: (a) Saksena,
A. K.; Lovey, R. G.; Girijavallabhan, V. M.; Ganguly, A. K. J . Org.
Chem. 1986, 51, 5024. (b) Dure´ault, A.; Carreaux, F.; Depezay, J . C.
Tetrahedron Lett. 1989, 30, 4527. (c) Mukaiyama, T.; Suzuki, K.;
Yamada, T.; Tabusa, F. Tetrahedron 1990, 46, 265. (d) Banik, B. K.
Manhas, M. S.; Bose, A. K. J . Org. Chem. 1993, 58, 307. (e) Paz, M.
M.; Sardina, F. J . J . Org. Chem. 1993, 58, 6990. (f) Matsumura, F.;
Hamada, Y.; Shioiri, T. Tetrahedron Lett. 1994, 35, 733.(g) Marshall,
J . A.; Seletsky, B. M.; Coan, P. S. J . Org. Chem. 1994, 59, 5139 (h)
J ackson, R. F. W.; Palmer, N. J .; Wythes, M. J .; Clegg, W.; Elsegood,
M. R. J . J . Org. Chem. 1995, 60, 6431.
(12) Recent syntheses of ribofuranosyl R-amino acid nucleosides
(polyoxins C): (a) ref 11b; (b) ref 11h. (c) Garner, P.; Park, J . M. J .
Org. Chem. 1990, 55, 3772. (d) Barrett, A. G. M.; Lebold, S. A. J . Org.
Chem. 1990, 55, 3853. (e) Auberson, Y.; Vogel, P. Tetrahedron 1990,
46, 7019. (f) Chen, A.; Savagen, I.; Thomas, E. J .; Wilson, P. D.
Tetrahedron Lett. 1993, 34, 6769. (g) Evina, C. M.; Guillerm, G.
Tetrahedron Lett. 1996, 37, 163. (h) Ohrui, H.; Kuzuhara, H.; Emoto,
S. Tetrahedron Lett. 1971, 4267.
(13) Trost, B. M.; Krueger, A. C.; Bunt, R. C.; Zambrano, J . J . Am.
Chem. Soc. 1996, 118, 6520.
(14) Dondoni, A.; J unquera, F.; Merchan, F. L.; Merino, P.; Tejero,
T. Synthesis 1994, 1450.
(15) Dondoni, A.; J unquera, F.; Mercha´n F. L.; Merino, P.; Scher-
rmann, M.-C.; Tejero, T., accompanying paper.
(16) Dondoni, A.; Franco S.; J unquera, F.; Mercha´n F. L.; Merino,
P.; Tejero, T. Synth. Commun. 1994, 24, 2537.
(17) Synthesis of 5-O-carbamoylpolyoxamic acid: Dondoni, A.;
Franco S.; Mercha´n F. L.; Merino, P.; Tejero, T. Tetrahedron Lett. 1993,
34, 5479.
(18) Synthesis of thymine polyoxin C: Dondoni, A.; J unquera, F.;
Mercha´n F. L.; Merino, P.; Tejero, T. Tetrahedron Lett. 1994, 35, 9439.
(19) Mukaiyama, T.; Suzuki, K.; Yamada, T.; Tabusa, F. Tetrahedron
1990, 46, 265.
(20) Iida, H.; Yamazaki, N.; Kibayashi, C. J . Org. Chem. 1987, 52,
3337.

The Total Synthesis of (+)-Polyoxin J
J . Org. Chem., Vol. 62, No. 16, 1997 5499
Sch em e 1a
completion of the synthetic plan. The main limitation
of the furan-carboxylic acid equivalence22 stems from the
harsh oxidizing conditions (ozone and ruthenium(IV))
under which the cleavage of the heterocyclic ring takes
place. These conditions are not tolerated by common
functionalities and protecting groups.23,24 In our pre-
liminary report17 we described the conversion of 10 into
3a by Ru-based oxidation of the furan ring using 1.2
equiv of RuO2 hydrate in the presence of excess NaIO4
as a carrier oxidant. This reaction showed the formation
of decomposition products that made the isolation of pure
3a quite troublesome. A reexamination of this oxidation
in the light of the original conditions described by
Sharpless and co-workers25 showed that the use of
catalytic RuCl3 hydrate and excess NaIO4 as a reoxidant
gives rise to the clean formation of the polyoxamic acid
derivative 3a in 87% yield after purification by a stan-
dard chemical procedure (30.3% from the nitrone 5a ).
X-ray crystallographic analysis of this compound con-
firmed the assigned configuration at C-2.26 Treatment
of 3a with CH2N2 provided the corresponding methyl
ester 3b which showed physical and spectral properties
1
([R]D, H and 13C NMR) identical to those of authentic
material.27 The conversion of 3b into unprotected 5-O-
carbamoyl L-polyoxamic acid 3 was reported earlier by
Saksena and Lovey and their co-workers.11a
Since the structure of 3 features an all syn arrange-
ment of the substituents at the three stereocenters (xylo
configuration), the initial problem was the stereoselective
addition of the furan ring to 5a in a syn-selective manner.
To this aim, the initial part of the synthetic plan was
easily carried out taking advantage of earlier observa-
tions.14 Addition of 2-lithiofuran to the 4-OBn L-threose
nitrone 5a in THF at -80 °C proceeded with good syn
diastereoselectivity (ds 92%) to give the R-alkoxyhydroxy-
lamine 8a as the major product in 87% yield after
chromatography21 (Scheme 1). The same reaction with
the 4-OTBDMS nitrone 5b was slightly more stereose-
lective (ds 94%) but gave the corresponding hydroxy-
lamine 8b in lower yield (68%). Then, hydroxylamines
8a and 8b were subjected to the titanium(III) chloride
promoted dehydration and hydrolysis of the benzaldimine
intermediates by treatment with wet silica gel.14 Under
these conditions also the removal of the TBDMS group
of 8b occurred almost completely. Crude amines were
treated with di-tert-butyl dicarbonate (Boc2O) to give the
corresponding N-Boc derivatives 9a and 9b, suitable for
isolation and characterization. The continuation of our
synthetic plan from these compounds involved unex-
plored steps. The choice was between the unmasking of
the latent carboxylic acid functionality embodied in the
furan ring and carbamoylation of the primary alcohol.
Since previous work demonstrated14 that the oxidative
cleavage of the furan ring of 9a by ruthenium dioxide-
sodium periodate complex was accompanied by the
formation of side products arising from the oxidation of
the benzyl group to benzoyl, the carbamoylation process
was given the precedence. While the required alcohol
9b formed directly from 8b, this compound was obtained
in markedly higher yield via debenzylation of 9a using
sodium in liquid ammonia. The carbamoylation of 9b
was carried out in one pot under standard conditions,
i.e. treatment with p-nitrophenyl chloroformate followed
by ammonolysis of the resulting carbonate to give the
urethane 10 in 62% isolated yield.
Syn th esis of Th ym in e P olyoxin C (4). Despite the
simple structure of this compound, its efficient synthesis
is far for being a trivial problem.12 Methods have been
described for the synthesis of the glycosidic moiety of
polyoxins employing various starting materials,10,12 mainly
carbohydrate and R-amino acid derivatives. Quite judi-
ciously, Barrett and Lebold employed the D-ribo-pento-
dialdofuranoside 11 (see eq 3) that in turn was easily
prepared in two steps from D-ribose in 35% overall
yield.12d This sugar aldehyde was condensed with (phe-
nylthio)nitromethane28 and the resultant nitro olefin was
elaborated into a furanosyl R-azido ester that served as
precursor to polyoxin C and uracyl polyoxin C. A similar
approach has been recently followed by J ackson and co-
workers11h who, however, obtained the C-5 epimer of the
sugar moiety of 4. Since the dialdose 11 was also the
(22) For earlier examples of the use of furan as precursor to
carboxylic acid, see: (a) Mukaiyama, T.; Tsuzuki, R.; Kato, J . Chem.
Lett. 1985, 837. (b) Danishefsky, S. J .; DeNinno, M. P.; Chen, S. J .
Am. Chem. Soc. 1988, 110, 3929. (c) Yamazaki, T.; Mizutani, K.;
Kitazume, T. J . Org. Chem. 1993, 58, 4346. (d) Dondoni, A.; Scher-
rmann, M.-C. Tetrahedron Lett. 1993, 34, 7323. (e) Marshall, J . A.;
Luke, G. P. J . Org. Chem. 1993, 58, 6229.
(23) It is worth mentioning that this problem does not exist in the
exploitation of the thiazole-formyl group equivalence since the cleav-
age of the thiazole ring involves almost neutral and nonoxidizing
reaction conditions. Aldehydes obtained by the thiazole-based method
can be converted into carboxylic acids under mild oxidizing conditions.
Both the unmasking of the aldehyde and the oxidation to carboxylic
acid are tolerant to a wide range of functional and protecting groups.
See for instance: (a) Dondoni, A.; Perrone, D. Synthesis 1993, 1162.
(b) Dondoni, A.; Marra, A.; Merino, P. J . Am. Chem. Soc. 1994, 116,
3324. (c) Dondoni, A.; Perrone, D.; Semola, T. Synthesis 1995, 181. (d)
Dondoni, A.; Marra, A.; Sansone, F. J . Org. Chem. 1996, 61, 5155.
(24) Although we have reported the stereoselective thiazole-based
homologation of aldehydes through their nitrones (Dondoni, A.; Franco,
S.; J unquera, F.; Merchan, F. L.; Merino, P. Tejero, T.; Bertolasi, V.
Chem. Eur. J . 1995, 1, 505), this synthetic approach to 3 was excluded
by the moderate syn-selectivity (ds 70%) and low yield of isolated
adducts (76%) in the reaction of 2-lithiothiazole with the nitrone 5a .
(25) Carlsen, P. H.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J .
Org. Chem. 1981, 46, 3936.
(26) The authors have deposited atomic coordinates and bond
lengths and angles for structure 3a with the Cambridge Crystal-
lographic Data Centre. The data can be obtained, upon request, from
the Director, Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge, CB2 1EZ, UK.
(27) This was kindly provided by Dr. A. K. Saksena and Dr. R. G.
Lovey (Schering-Plough Research Institute, Kenilworth, NJ ).
Next we considered the release of the carboxylate
function from the furan ring, a crucial operation for the
(21) The same reaction carried out with Et2AlCl precomplexed
nitrone 5a leads to the anti isomer of 9a (lyxo configuration) with 90%
diastereoselectivity.

5500 J . Org. Chem., Vol. 62, No. 16, 1997
Dondoni et al.
Sch em e 3a
starting material in our methodology, the challenge laid
in comparing the synthetic value of the nitrone-based
approach with the nitro olefin method.
The N-benzyl nitrone 6a , a crystalline and stable
compound, was prepared from the aldehyde 1129 by the
hydroxylamine method as described16 (eq 3). The ste-
reocontrolled addition of 2-lithiofuran to 6a was the key
step in this approach. Recent work showed15 that the
use of the nitrone 6a precomplexed with diethylalumi-
num chloride afforded the N-benzyl hydroxylamine 12a
as major product (ds 85%) (Scheme 2). Conditions were
also described15 for converting 12a into the carbon-linked
furanosyl glycinate 14, through the protected furylamine
13, by a TiCl3-based dehydroxylation and oxidative
cleavage of the furan ring.30 The acetolysis of 14 was
then considered as the necessary glycosyl activation for
other compounds the open chain R-amino ester 15.
However, no efforts were made to isolate this compound
because of the unsuccessful elaboration of a similar
product toward the target nucleoside.12c Hence, attention
was focussed on the anomeric activation of the glycosyl
amine 13.
Sch em e 2a
The acetolysis of the O-methyl glycoside 13 occurred
with concomitant exocylic and endocyclic mode of glycosyl
cleavage to give a mixture of the O-acetyl glycoside 16
and the aza sugar 17 in 1:3 ratio (Scheme 3). Although
compound 16 was isolated in low yield (16%), its elabora-
tion to the sugar-linked R-amino ester 18 was completed
by oxidative cleavage of the furan ring as described above
(RuCl3-NaIO4) and esterification. The conversion of 18
into thymine polyoxin C (4) (46%) was previously re-
ported by Garner and Park by sequential thymine
installation and a standard deprotection sequence (sa-
ponification and hydrogenolysis).12c
Although a formal synthesis of 4 had been achieved,
the unefficient anomeric activation of 13 via acetolysis
precluded a convenient application of this approach.
Hence we examined an alternative route33 to the R-amino
ester 18 starting from the hydroxylamine 12a . This
compound was converted into the O-acetyl, O-benzyl, and
O-benzyloxycarbonyl derivatives 19, 20, and 21 in quite
different yields (Scheme 4). The acetolysis of the almost
quantitatively formed compound 19 afforded the tetraac-
etate 22 in a 60% overall yield. The direct transforma-
tion of 12a into 22 by treatment with a mixture of Ac2O-
AcOH in aqueous HCl gave a much lower overall yield.
We next proceeded with the oxidative unmasking of the
carboxylate group from the furan ring by treatment of
22 with RuCl3-NaIO4 and esterification. The N,N-
diprotected R-amino ester 23 obtained in this way was
converted into the N-Cbz derivative 18 by hydrogenolysis
over Pd and treatment with benzyl chloroformate under
standard conditions. Having prepared a sufficient amount
the installation of the thymine moiety by the Vorbru¨ggen
pyrimidine nucleoside synthesis.31 The exposure of 14
to the Hudson acetolysis conditions32 gave numerous
products in low yields. Earlier observations by Garner
and Park12c suggested that endocyclic glycosyl cleavage
and deacetonization might have occurred to give among
(28) It has been pointed pointed out (ref 12d) that in the nucleophilic
additions to aldehydes of dialdose derivatives, modest to good diaste-
reoselectivity has been achieved only in the case where Lewis acid
catalysts or chelation control have been employed. Hence it is worth
recalling here that an exception to this behavior is the addition of the
organometal 2-(trimethylsilyl)thiazole to dialdoses wherein high levels
of nonchelation-controlled diastereoselectivity (ds g 95%) were regis-
tered. See: Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A.
Tetrahedron 1987, 43, 3533. Dondoni, A.; Fantin, G.; Fogagnolo, M.;
Medici, A.; Pedrini, P. J . Org. Chem. 1989, 54, 693. One of us (A.D.)
thanks Professor A. G. M. Barrett for the correspondence on this
matter.
(30) Details of this reaction sequence as well as the characteristics
of compounds 12a , 13, and 14 are reported in the Experimental Section
for convenience.
(31) (a) Niedbala, U.; Vorbru¨ggen, H. J . Org. Chem. 1974, 39, 3654.
(b) Vorbru¨ggen, H.; Krolikiewicz, K.; Bennua, B. Chem. Ber. 1981, 114,
1234.
(29) The reference for the preparation of the dialdose 11 has been
misreported in our paper quoted in ref 16. The procedure adopted is
that given in ref 12d.
(32) Hann, R. M.; Hudson, C. S. J . Am. Chem. Soc. 1934, 56, 2465.
(33) For an earlier report of this precedure, see ref 18.

The Total Synthesis of (+)-Polyoxin J
J . Org. Chem., Vol. 62, No. 16, 1997 5501
Sch em e 4a
tion of 24a with bulkier nitrogen-protecting groups such
as Boc, Cbz, or fluorenyl resulted in lower yields presum-
ably because of the considerable steric congestion around
the nitrogen atom. The necessary anomeric activation
was achieved by submitting 25a to the Hudson acetolysis
conditions32 which afforded 26 as a mixture of R- and
â-anomers in 1:3 ratio and 78% combined yield. We also
considered the use of the N-p-methoxybenzyl (PMB)
hydroxylamine 12b in this route since we thought that
the removal of the PMB group under oxidative condi-
tions35 would provide another oportunity for an improved
synthesis of 4. Both the deoxygenation of 12b to the
amine 24b and the acylation of the latter to 25b gave
comparable yields to the previous reactions starting from
12a . Unfortunately the modest diastereoselectivity (ds
) 70%) of the addition of 2-lithiofuran to the nitrone 6b
led to the isolation of the N-PMB hydroxylamine 12b in
low yield. Consequently, the synthetic route with PMB
derivatives became unfavorable and was abandoned.
Instead, the synthesis was continued with the N,N-
diprotected furylamine 26 which was first subjected to
the introduction of the thymine moiety by the Vorbru¨ggen
method.31 Trimethylsilyl triflate (TMSOTf) catalyzed
coupling of 26 and bis-silylated thymine 27 resulted in
the formation of the nucleoside 28 in 81% isolated yield
(eq 4). This route could not be followed since attempted
liberation of the carboxylate function from the furan ring
by exposure of 28 to the RuCl3-NaIO4 mixture produced
several oxidation products. Evidently the thymine moi-
ety did not tolerate the oxidative conditions employed.36
Hence the ruthenium(IV)-based oxidative cleavage of the
furan ring of 26 was carried out first (Scheme 6). This
reaction and the esterification (diazomethane) of the
Sch em e 5a
Sch em e 6a
of this key intermediate (15.3% from the nitrone 6a ), we
proceeded with its conversion into thymine polyoxin C
(4) following the same procedure of Garner and Park.12c
The nucleoside 4 was isolated in a rewarding comparable
yield (52%) and with identical characteristics (mp, [R]D,
1H and 13C NMR, see below). The overall yield of 4 from
the nitrone 6a was 7.6%.
Pursuing a higher yield synthesis of 4, we examined a
different protecting group scheme (Scheme 5). Deoxy-
genation of the N-Bn hydroxylamine 12a using the Zn-
Cu couple34 afforded the N-Bn amine 24a which upon
treatment with trifluoroacetic anhydride was converted
into the N,N-diprotected compound 25a in good yield
(90%). The use of the trifluoroacetyl as a protecting
group was suggested by the possibility of its easy removal
under mild basic conditions. Attempted double protec-
(34) Dhavale, D. D.; Gentilucci, L.; Piazza, M. G.; Trombini, C.
Liebigs Ann. Chem. 1992, 1289.

5502 J . Org. Chem., Vol. 62, No. 16, 1997
Dondoni et al.
Sch em e 7a
target product 2 which after purification by column
chromatography was identical in all respects (mp, [R]D,
1H and 13C NMR) with authentic material kindly pro-
vided by Professor Isono. The overall yield of pure
isolated 2 was 46.4%.
Con clu sion
The main feature of the above synthesis of the natural
product 2 is the nitrone-furan-based stereoselective
approach to the building block R-amino acids, i.e. the
polyoxamic acid derivative 3 and the amino-uronic nu-
cleoside 4. The successful synthesis of these compounds
with higher or comparable yields of earlier methods
demonstrates the utility of this aminohomologation
methodology. Other members of the polyoxin family and
analogues should be accessible by the application of these
techniques.
Exp er im en ta l Section
resulting R-amino acid proceeded without problems in
one pot to give the C-4 furanoside linked methyl glycinate
29 (mixture of R and â anomers). This material reacted
with the bis-silylated thymine 27 to give the â-linked N1-
nucleoside 30. Finally, compound 30 was completely
deprotected by the standard hydrogenolysis-saponifica-
tion sequence to give the free amino-uronic acid nucleo-
side 4, which was identical in all respects with the sample
which we had prepared from the R-amino ester 18 (see
Scheme 4). Quite gratifyingly the overall yield of isolated
4 (12.6%) by this route was almost twice that of Scheme
4. This yield compares with that of polyoxin C (16%)
obtained from the sugar aldehyde 11 by the nitro olefin
route.12d
Syn th esis of P olyoxin J (2). Having obtained the
R-amino acids 3 and 4, we saw that what remained to
complete the synthesis of 2 was their coupling via an
amide bond. The condensation of these amino acids was
earlier performed by the N,N-dicyclohexylcarbodiimide-
N-hydroxysuccinimide (DCC-HOSu) active ester method8
and more recently by the diethylphosphoryl cyanide
method.9 However, the lack of experimental details in
both reports and the poor yields that have been
registered4d in the coupling of similar amino acids by the
DCC-HOSu active ester protocol led us to perform our
own synthesis (Scheme 7). Thus, the polyoxamic acid
derivative 3a by treatment with DCC-HOSu was con-
verted into the active ester 32 which was then condensed
with unprotected thymine polyoxin C (4) to give the
dipeptide 33 in satisfactory yield (58%) after purification.
The key element of the coupling procedure was the use
of DMSO as solvent and N,N-diisopropylethylamine as
base, a simple yet efficacious expedient that has been
recently reported for the synthesis of small peptides of
the polyoxin family.37 Complete deprotection of 33 by
treatment with aqueous trifluoroacetic acid afforded the
Gen er a l Com m en ts. The reaction flasks and other equip-
ment were stored in an oven at 130 °C overnight and
assembled in a stream of argon. Syringes were assembled and
fitted with needles while hot and cooled in a stream of argon.
Special techniques were used in handling moisture- and air-
sensitive materials,38 and solvents were purified and dried by
standard methods.39 Preparative chromatography was per-
formed on columns of silica gel (60-240 mesh) with freshly
distilled solvents. Reactions were monitored by TLC on silica
gel 60 F254; the positions of the spots were detected with 254
nm UV light and by charring with 50% methanolic sulfuric
acid as staining system.
Melting points were determined on a Bu¨chi 510 melting
point apparatus and are uncorrected. Optical rotations were
measured on a Perkin Elmer 241 polarimeter at 20 °C in the
stated solvent. Elemental analyses were performed on a
Perkin Elmer 240B microanalyzer. 1H and 13C NMR spectra
were recorded either on a Varian 300 Unity or a Bruker 300
spectrometer operating at 300 MHz for 1H and 75.5 MHz for
13C at 20 °C in CDCl3 unless otherwise specified. Chemical
shifts are expressed in parts per million positive values
downfield from internal TMS. Mass spectra were recorded on
a VG Autospec mass spectrometer. Nitrones 5a , 5b, 6a , and
6b were prepared as described.16 2,4-Bis((trimethyl)silyloxy)-
5-methylpyrimidine (27) was prepared by a literature method.40
2-Lith iofu r a n . To a well-stirred solution of freshly distilled
furan (2.04 g, 2.18 mL, 30 mmol) in THF (100 mL), cooled to
-80 °C, was added butyllithium (20 mL of a 1.6 M solution in
hexanes, 32 mmol), and the mixture was stirred at 0 °C for 2
h. The solution of 2-lithiofuran in THF (ca. 0.2 M) was stored
at 0 °C and used within a few hours after preparation.
(1S )-N -Be n zyl-4-O-b e n zyl-1-d e oxy-1-(2-fu r yl)-1-(h y-
dr oxyam in o)-2,3-O-isopr opyliden e-L-th r eitol (8a). A cooled
(-90 °C) solution of 2-lithiofuran in THF (prepared from 30
mmol of furan) was treated with a solution of the nitrone 5a
(3.55 g, 10 mmol) in THF (60 mL) added drop by drop. The
rate of the addition was adjusted so as to keep the internal
temperature below -80 °C and took approximately 30 min to
complete. After stirring for 2 h at -80 °C, the reaction mixture
was quenched with saturated aqueous NH4Cl (50 mL). Stir-
ring was continued for 10 min at ambient temperature and
then diethyl ether (50 mL) was added. The organic layer was
separated, and the aqueous layer was extracted with diethyl
(35) It is worth mentioning that while the benzyl group is removed
by hydrogenolysis, the p-methoxy derivative is removed under oxidative
conditions using cerium ammonium nitrate. See: Yoshimura, J .;
Yamaura, M.; Suzuki, T.; Hashimoto, H.; Okamoto, T. Bull. Chem. Soc.
J pn. 1985, 58, 1413.
(36) Pyrimidine nucleosides have been reported to be unstable under
oxidative conditions by ruthenium(IV). See: Singh, A. K.; Varma, R.
S. Tetrahedron Lett. 1992, 33, 2307.
(37) Krainer, E.; Becker, J . M.; Naider, F. J . Med. Chem. 1991, 34,
174.
(38) Shriver, D. F.; Drezdzon, M. A. The Manipulation of Air-
Sensitive Compounds; 2nd ed.; Wiley-Interscience: New York, 1986.
(39) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory
Chemicals, 3rd ed.; Pergamon: Oxford, 1988.
(40) Nishimura, T.; Iwai, I. Chem. Pharm. Bull. 1964, 12, 352.

The Total Synthesis of (+)-Polyoxin J
J . Org. Chem., Vol. 62, No. 16, 1997 5503
ether (3 × 50 mL). The combined organic extracts were
washed with brine and dried over magnesium sulfate, and the
solvent was evaporated under reduced pressure (ds ) 92% by
1H NMR analysis). Column chromatography (hexane-diethyl
added. The aqueous solution was extracted with CH2Cl2 (3 ×
10 mL) and dried over magnesium sulfate, and the solvent
was evaporated under reduced pressure. Column chromatog-
raphy (hexane-diethyl ether, 60:40) afforded pure 9b (0.466
g, 95%) as an oil: [R]D ) -24.4 (c 1.72, CHCl3); 1H NMR δ
1.40 (s, 3 H), 1.42 (s, 9 H), 1.45 (s, 3 H), 2.21 (bs, 1 H, ex D2O),
3.57 (dd, 1 H, J ) 12.0, 4.2 Hz), 3.71 (dd, 1 H, J ) 12.0, 4.2
Hz), 3.90 (dt, 1 H, J ) 8.1, 4.2 Hz), 4.28 (dd, 1 H, J ) 8.1, 2.4
Hz), 4.90 (bd, 1 H, J ) 7.4 Hz), 5.22 (bd, 1 H, J ) 7.6 Hz), 6.24
(d, 1 H, J ) 3.2 Hz), 6.29 (t, 1 H, J ) 3.3 Hz), 7.34 (pseudo t,
1 H, J ) 0.9 Hz); 13C NMR δ 27.1, 27.9, 28.3, 61.6, 76.9, 77.8,
77.9, 80.2, 107.0, 109.6, 110.3, 142.1, 142.5, 155.6. Anal. Calcd
for C16H25NO6: C, 58.70; H, 7.70; N, 4.28. Found: C, 58.42;
H, 7.83; N, 4.59.
ether, 90:10) afforded pure 8a (3.68 g, 87%) as an oil; [R]D
)
1
-42.7 (c 1.03, CHCl3); H NMR δ 1.29 (s, 3 H), 1.43 (s, 3 H),
3.11 (dd, 1 H, J ) 10.8, 4.0 Hz), 3.24 (dd, 1 H, J ) 10.8, 6.0
Hz), 3.67 (d, 1 H, J ) 13.8 Hz), 3.93 (d, 1 H, J ) 13.8 Hz), 3.98
(d, 1 H, J ) 7.6 Hz), 4.11 (ddd, 1 H, J ) 7.2, 6.0, 4.0 Hz), 4.42
(d, 1 H, J ) 12.5 Hz), 4.45 (d, 1 H, J ) 12.5 Hz), 4.50 (t, 1 H,
J ) 7.4 Hz), 6.25 (bs, 1 H, ex D2O), 6.32 (dd, 1 H, J ) 3.2, 1.7
Hz), 6.36 (d, 1 H, J ) 3.2 Hz), 7.19-7.38 (m, 11 H); 13C NMR
δ 26.9, 27.3, 61.4, 65.3, 70.6, 73.3, 77.6, 78.0, 109.7, 110.3,
110.9, 127.2, 127.5, 127.6, 128.2, 128.2, 129.3, 137.2, 137.7,
142.2, 149.4. Anal. Calcd for C25H29NO5: C, 70.91; H, 6.90;
N, 3.31. Found: C, 70.64; H, 6.96; N, 3.49.
(1S)-4-O-(Am in ocar bon yl)-1-((ter t-bu toxycar bon yl)am i-
n o)-1-deoxy-1-(2-fu r yl)-2,3-O-isopr opyliden e-L-th r eitol (10).
To a solution of the alcohol 9b (0.440 g, 1.35 mmol) in pyridine
(7.2 mL) at 0 °C, was added p-nitrophenyl chloroformate (0.426
g, 2.1 mmol) was added. The mixture was stirred for 18 h at
0 °C, diluted with EtOAc (15 mL), and washed successively
with cold water (3 × 10 mL), saturated aqueous CuSO4 (3 ×
10 mL), and brine. The resulting organic extract was dried
over magnesium sulfate and the solvent evaporated under
reduced pressure. The gummy residue was dissolved in MeOH
(10 mL) and the solution cooled to 0 °C. This solution was
treated with 25 mL of 8% NH3-MeOH and stirred for 1 h at
0 °C. The solvent was evaporated under reduced pressure,
and the residue was purified by column chromatography
(hexane-diethyl ether, 40:60) to give pure 10 (0.309 g, 62%)
(1S)-N-Ben zyl-4-O-(ter t-bu tyld im eth ylsilyl)-1-d eoxy-1-
(2-fu r yl)-1-(h yd r oxya m in o)-2,3-O-isop r op ylid en e-L-th r ei-
tol (8b). From 5b (3.79 g, 10 mmol) as described for the
preparation of 8a . 1H NMR analysis of the crude showed ds
) 94%. Column chromatography (hexane-diethyl ether, 90:
10) afforded pure 8b (3.03 g, 68%) as an oil; [R]D ) -33.5 (c
1.40, CHCl3); 1H NMR δ -0.04 (s, 3 H), -0.01 (s, 3 H), 0.82 (s,
9 H), 1.23 (s, 3 H), 1.38 (s, 3 H), 3.65 (d, 1 H, J ) 12.9 Hz),
3.90 (d, 1 H, J ) 12.9 Hz), 4.02-4.10 (m, 2 H), 4.50 (dd, 1 H,
J ) 10.7, 4.5 Hz), 4.55 (t, 1 H, J ) 4.5 Hz), 5.20 (dd, 1 H, J )
10.7, 5.2 Hz), 6.39 (dd, 1 H, J ) 3.3, 1.7 Hz), 6.41 (dd, 1 H, J
) 3.3, 0.8 Hz), 6.80 (bs, 1 H, int D2O), 7.20-7.35 (m, 5 H),
7.46 (dd, 1 H, J ) 1.7, 0.8 Hz); 13C NMR δ -5.6, -5.5, 18.3,
25.8, 27.1, 27.4, 61.4, 64.1, 65.4, 78.2, 79.1, 109.4, 110.4, 110.7,
127.2, 128.2, 129.4, 137.5, 142.2, 150.1. Anal. Calcd for
C24H37NO5Si: C, 64.39; H, 8.33; N, 3.13. Found: C, 64.22; H,
7.96; N, 3.33.
1
as an oil: [R]D ) -24.0 (c 1.50, CHCl3); H NMR δ 1.36 (s, 3
H), 1.37 (s, 3 H), 1.40 (s, 9 H), 4.03 (dt, 1 H, J ) 7.8, 5.0 Hz),
4.11-4.13 (m, 2 H), 4.18 (dd, 1 H, J ) 7.8, 3.2 Hz), 4.82 (bs, 2
H), 4.92 (dd, 1 H, J ) 9.0, 3.2 Hz), 5.14 (d, 1 H, J ) 9.0 Hz),
6.23 (dd, 1 H, J ) 3.2, 0.7 Hz), 6.29 (dd, 1 H, J ) 3.2, 1.7 Hz),
7.32 (dd, 1 H, J ) 1.7, 0.7 Hz); 13C NMR δ 26.9, 27.0, 28.3,
49.4, 64.6, 75.8, 79.1, 80.1, 107.0, 110.1, 110.3, 142.1, 152.7,
155.4, 156.3. Anal. Calcd for C17H26N2O7: C, 55.13; H, 7.08;
N, 7.56. Found: C, 54.96; H, 7.34; N, 7.65.
(1S )-4-O-Be n zyl-1-((t er t -b u t oxyca r b on yl)a m in o)-1-
d eoxy-1-(2-fu r yl)-2,3-O-isop r op ylid en e-L-th r eitol (9a ). A
solution of the hydroxylamine 8a (1.69 g, 4 mmol) in MeOH
(50 mL) was treated with a 20% aqueous solution of TiCl3 (1.55
g, 10 mmol of TiCl3 in 6.2 mL of water) at ambient temperature
for 15 min. Then 5 M aqueous NaOH (10 mL) was added,
and stirring was continued for additional 10 min. After
extraction with EtOAc (4 × 25 mL), the organic layer was
washed with brine, dried over magnesium sulfate, and con-
centrated in vacuo. The residue was dissolved in CH2Cl2 (50
mL) and treated with SiO2 (9.0 g) and H2O (3 mL). The
mixture was stirred vigorously at ambient temperature for 12
h and then filtered. The filter was washed with EtOAc
containing 0.5% Et3N (3 × 120 mL), and the combined filtrates
were dried over magnesium sulfate and evaporated. The
residue was taken up in dioxane (30 mL) and treated with
Boc2O (1.53 g, 8.8 mmol). The resulting solution was stirred
at ambient temperature for 12 h. The mixture was partitioned
between saturated aqueous NaHCO3 (80 mL) and CH2Cl2 (50
mL), and the organic layer was separated. The aqueous layer
was extracted with CH2Cl2 (2 × 25 mL). The combined organic
extracts were dried over magnesium sulfate and evaporated
under reduced pressure. The crude product was purified by
column chromatography (hexane-diethyl ether, 80:20) to give
pure 9a (1.14 g, 68%) as an oil: [R]D ) -41.9 (c 0.47, CHCl3);
1H NMR δ 1.39 (s, 6 H), 1.49 (s, 9 H), 3.51 (dd, 1 H, J ) 10.4,
4.6 Hz), 3.56 (dd, 1 H, J ) 10.4, 4.9 Hz), 4.06 (dt, 1 H, J ) 8.0,
4.8 Hz), 4.23 (dd, 1 H, J ) 8.1, 3.0 Hz), 4.56 (s, 2 H), 4.91 (dd,
1 H, J ) 9.0, 3.0 Hz), 5.21 (d, 1 H, J ) 9.0 Hz), 6.22 (dd, 1 H,
J ) 3.2, 0.8 Hz), 6.28 (dd, 1 H, J ) 3.2, 1.8 Hz), 7.25-7.33 (m,
6 H); 13C NMR δ 26.9, 27.1, 28.4, 49.5, 70.2, 73.7, 76.8, 79.2,
79.9, 106.9, 109.9, 110.3, 127.7, 127.7, 128.4, 138.1, 141.9,
153.2, 155.4. Anal. Calcd for C23H31NO6: C, 66.17; H, 7.48;
N, 3.35. Found: C, 66.43; H, 7.32; N, 3.60.
5-O-(Am in oca r bon yl)-2-((ter t-bu toxyca r bon yla )m in o)-
2-d eoxy-3,4-O-isop r op ylid en e-L-xylon ic Acid (3a ) a n d
Meth yl Ester (3b). To a well-stirred solution of NaIO4 (0.351
g, 1.65 mmol) in H2O-CCl4-CH3CN 3:2:3 (7.4 mL) was added
RuCl3 (2.8 mg, 0.013 mmol). After 15 min stirring, the 2-furyl
derivative 10 (0.1 g, 0.27 mmol) in CH3CN (0.5 mL) was added.
The color of the solution turned instantaneously from yellowish
to black. Then enough NaIO4 was added to restore the
yellowish color. After 5 min, the mixture was diluted with
water (5 mL) and extracted with EtOAc (3 × 10 mL). The
organic combined extracts were washed successively with 20%
aqueous NaHSO3 until colorless and brine and dried over
magnesium sulfate, and the solvent was evaporated under
reduced pressure. This residue was taken up with saturated
aqueous K2CO3 (10 mL), the solution stirred for 10 min and
then washed with EtOAc (2 × 15 mL). Acidification (pH ) 2)
of the aqueous layer by addition of 2 N HCl, extraction with
CH2Cl2 (3 × 20 mL), drying of the combined organic extracts
over magnesium sulfate, and evaporation of the solvent under
reduced pressure gave pure 3a (0.082 g, 87%) as a white
solid: mp 50-52 °C; [R]D ) +0.4 (c 1.2, acetone) [Lit.11a mp
1
50 °C; [R]D ) +0.3 (c 1.0, acetone)]; H NMR (CDCl3 + D2O)
δ 1.38 (s, 3 H), 1.39 (s, 3 H), 1.42 (s, 9 H), 3.94-4.02 (m, 1 H),
4.22-4.34 (m, 3 H), 4.48 (dd, 1 H, J ) 9.3 Hz), 5.36 (bs, 2 H),
5.42 (d, 1 H, J ) 9.3 Hz); 13C NMR (CDCl3 + D2O) δ 26.7,
26.8, 28.3, 53.4, 63.8, 75.4, 77.9, 80.5, 110.0, 156.2, 157.3, 173.8.
Anal. Calcd for C14H24N2O8: C, 48.27; H, 6.94; N, 8.04.
Found: C, 48.40; H, 7.14; N, 8.32.
The acid 3a was dissolved in diethyl ether and treated with
an ethereal solution of diazomethane to give the ester 3b (0.09
1
(1S)-1-((ter t-Bu toxycar bon yl)am in o)-1-deoxy-1-(2-fu r yl)-
2,3-O-isop r op ylid en e-L-th r eitol (9b). To a solution of so-
dium (150 mg, 6 mmol) in liquid NH3 (20 mL), cooled at -50
°C, was added R-((tert-butoxycarbonyl)amino)-2-alkylfuran 9a
(0.621 g, 1.5 mmol) in diethyl ether (5 mL). The mixture was
stirred for 15 min and then treated with solid NH4Cl until
the solution become colorless. The NH3 was allowed to
evaporate at ambient temperature and water (10 mL) was
g, 100%) as an oil: [R]D ) -3.6 (c 0.49, CH2Cl2); H NMR δ
1.36 (s, 3 H), 1.39 (s, 3 H), 1.42 (s, 9 H), 3.76 (s, 3 H), 3.99 (dt,
1 H, J ) 8.3, 5.0 Hz), 4.20-4.24 (m, 2 H), 4.26 (dd, 1 H, J )
8.3, 1.8 Hz), 4.48 (dd, 1 H, J ) 9.8, 1.8 Hz), 4.49 (bs, 2 H),
5.27 (d, 1 H, J ) 9.8 Hz); 13C NMR δ 27.7, 26.8, 28.2, 52.8,
53.0, 64.1, 74.8, 78.2, 80.4, 110.1, 155.9, 156.2, 170.6. Anal.
Calcd for C15H26N2O8: C, 49.73; H, 7.23; N, 7.73. Found: C,
49.80; H, 7.35; N, 7.97.

5504 J . Org. Chem., Vol. 62, No. 16, 1997
Dondoni et al.
1
Meth yl N-Ben zyl-5-deoxy-5-(2-fu r yl)-5-(h ydr oxyam in o)-
2,3-O-isop r op ylid en e-â-D-a llo-1,4-p en tofu r a n osid e (12a ).
A 1.0 M solution of Et2AlCl in hexane (5 mL, 5 mmol) was
added via syringe under stirring to a solution of the nitrone
6a (3.08 g, 10 mmol) in diethyl ether (100 mL) at ambient
temperature. The mixture was stirred for 5 min, transferred
under argon atmosphere into a dropping funnel, and added
slowly to a cooled (-90 °C) solution of 2-lithiofuran in THF
(prepared from 30 mmol of furan). The rate of the addition
was adjusted so as to keep the internal temperature below -80
°C and took approximately 1 h to complete. The reaction
mixture was stirred for 2 h at -80 °C and then treated with
1.0 M aqueous NaOH (50 mL). After 15 min stirring at
ambient temperature, the mixture was extracted with diethyl
ether (3 × 50 mL). The combined organic extracts were
washed with brine and dried over magnesium sulfate, and the
solvent was evaporated under reduced pressure. 1H NMR
analysis of the residue showed a ds ) 85%. Column chroma-
tography on silica gel (80:20 hexane-diethyl ether) gave 12a
(2.88 g, 77%) as an oil: [R]D ) -12.2 (c 2.30, CHCl3); 1H NMR
δ 1.34 (s, 3 H), 1.46 (s, 3 H), 3.04 (s, 3 H), 3.64 (d, 1 H, J )
13.0 Hz), 3.72 (d, 1 H, J ) 13.0 Hz), 3.93 (d, 1 H, J ) 11.0 Hz),
4.58 (d, 1 H, J ) 6.1 Hz), 4.75 (dd, 1 H, J ) 11.0, 1.0 Hz), 4.88
(s, 1 H), 4.97 (s, 1 H, ex D2O), 5.16 (dd, 1 H, J ) 6.1, 1.0 Hz),
6.39 (dd, 1 H, J ) 3.3, 0.7 Hz), 6.43 (dd, 1 H, J ) 3.3, 1.8 Hz),
7.22-7.34 (m, 5 H), 7.47 (dd, 1 H, J ) 1.8, 0.7 Hz); 13C NMR
δ 25.2, 26.5, 55.1, 62.0, 65.4, 82.5, 85.1, 86.0, 109.5, 110.4,
110.4, 112.4, 127.4, 128.9, 129.3, 137.5, 142.2, 150.4. Anal.
Calcd for C20H25NO6: C, 63.99; H, 6.71; N, 3.73. Found: C,
63.84; H, 6.80; N, 3.79.
solvent was removed under reduced pressure.The H NMR of
the crude material showed a 1:3 ratio of products 16 and 17
which were separated by column chromatography (hexane-
diethyl ether, 40:60). Compound 17 was eluted first (0.222 g,
1
43%) as an oil; [R]D ) -32.5 (c 0.40, CHCl3); H NMR (55 °C)
δ 1.98 (s, 3 H), 2.00 (s, 3 H), 2.02 (s, 3 H), 2.13 (s, 3 H), 5.17
(pseudo t, 1 H, J ) 2.8 Hz), 5.20 (d, 1 H, J ) 12.4 Hz), 5.30
(dd, 1 H, J ) 12.4 Hz), 5.65 (pseudo t, 1 H, J ) 3.5 Hz), 5.68
(bs, 1 H), 5.78 (pst, 1 H, J ) 2.4 Hz), 6.32 (dd, 1 H, J ) 3.1,
1.7 Hz), 6.35 (dd, 1 H, J ) 3.1, 0.7 Hz), 6.85 (d, 1 H, J ) 1.9
Hz), 7.28-7.34 (m, 5 H), 7.36 (dd, 1 H, J ) 1.9, 0.7 Hz); 13C
NMR (55 °C) δ 20.3, 20.6, 20.6, 20.7, 52.8, 64.6, 66.3, 66.9,
68.3, 76.8, 107.1, 110.8, 127.9, 128.2, 128.5, 135.9, 142.2, 150.2,
155.2, 168.1, 169.5, 169.9, 169.9. Anal. Calcd for C25H27
-
NO11: C, 58.03; H, 5.26; N, 2.71. Found: C, 58.36; H, 5.11;
N, 2.64.
Eluted second was 16 (0.076 g, 16%) as an oil. 1H NMR of
this product showed a 2:7 ratio of R and â anomers. â-Anomer
1
(selected) H NMR δ 1.91 (s, 3 H), 1.97 (s, 3 H), 1.98 (s, 3 H),
4.47 (dd, 1 H, J ) 7.8, 4.9 Hz), 5.25-5.31 (m, 3 H), 5.20 (d, 1
H, J ) 4.9 Hz), 5.37 (dd, 1 H, J ) 7.8, 4.9 Hz), 5.56 (bd, 1 H,
J ) 8.1 Hz), 6.04 (s, 1 H), 6.25-6.30 (m, 2 H), 7.25-7.40 (m,
6 H); 13C NMR δ 20.3, 20.5, 20.8, 50.7, 67.2, 70.3, 74.0, 81.9,
97.7, 108.3, 110.5, 128.1, 128.3, 128.5, 136.0, 142.5, 149.9,
155.6, 168.3, 168.8, 169.4. Anal. Calcd for C23H25NO10: C,
58.10; H, 5.30; N, 2.95. Found: C, 58.23; H, 5.56; N, 3.14.
Meth yl 5-((Ben zyloxyca r bon yl)a m in o)-5-d eoxy-1,2,3-
tr i-O-a cetyl-D-a llo-h exofu r a n u r on a te (18). The oxidation
of the mixture of R- and â-anomers 16 (0.237 g, 0.5 mmol) with
RuCl3 in the presence of NaIO4 was carried out as described
for the preparation of compound 3a . Treatment of the reaction
mixture with diazomethane and purification by column chro-
matography (hexane-diethyl ether, 20:80) afforded 18 (0.137
g, 65%) as an oil; 1H NMR showed that this product was a
mixture of R and â anomers in 2:7 ratio. 1H NMR δ 2.00 (s, 3
H), 2.02 (s, 3 H), 2.09 (s, 3 H), 3.75 (s, 3 H), 4.45 (dd, 1 H, J )
7.5, 4.4 Hz), 4.67 (dd, 1 H, 8.5, 4.4 Hz), 5.08 (s, 2H), 5.28 (d, 1
H, J ) 4.6 Hz), 5.52 (dd, 1 H, J ) 7.5, 4.6 Hz), 5.61 (bd, 1 H,
J ) 8.5 Hz), 6.08 (s, 0.77 H, Hâ), 6.35 (d, 0.23 H, J ) 4.3 Hz,
HR), 7.38 (s, 5 H); 13C NMR δ 20.8, 20.5, 20.4, 52.6, 55.2, 67.0,
70.2, 73.9, 81.5, 97.9, 128.1, 128.5, 128.4, 135.9, 153.7, 168.4,
169.3, 169.4 (2C). Anal. Calcd for C21H25NO11: C, 53.96; H,
5.39; N, 3.00. Found: C, 53,68; H, 5.60; N, 3.37.
Meth yl 5-((Ben zyloxyca r bon yl)a m in o)-5-d eoxy-2,3-O-
isop r op ylid en e-5-(2-fu r yl)-â-D-a llo-1,4-p en t ofu r a n osid e
(13). The N-benzylhydroxylamine 12a (1.5 g, 4 mmol) was
subjected to the reductive process with 20% aqueous TiCl3 and
SiO2-H2O as described for compound 9a . The crude amine
was dissolved in dioxane (40 mL) and the solution treated with
7% aqueous NaHCO3 (20 mL). After stirring for 10 min at 0
°C, the reaction mixture was treated with benzyl chloroformate
(0.64 mL, 1.1 mmol) and stirred for 12 h at ambient temper-
ature. Then water (80 mL) was added, and the mixture was
extracted with CH2Cl2 (3 × 40 mL). The organic combined
extracts were dried over magnesium sulfate, and the solvent
was removed in vacuo. The residue was purified by column
chromatography (hexane-diethyl ether, 80:20) to give pure 13
(1.06 g, 66%) as a white solid: mp 86 °C; [R]D ) -88.1 (c 0.35,
Meth yl 5-(Acetoxya m in o)-N-ben zyl-5-d eoxy-2,3-O-iso-
p r op ylid en e-5-(2-fu r yl)-â-D-a llo-1,4-p en tofu r a n osid e (19).
A solution of 12a (0.375 g, 1 mmol) in pyridine (1.5 mL) was
treated with Ac2O (1.5 mL) and DMAP (2 mg) at ambient
temperature. After stirring for 2 h, the reaction mixture was
partitioned between saturated aqueous NaHCO3 (20 mL) and
EtOAc (20 mL). The aqueous layer was reextracted with
EtOAc (2 × 20 mL), and the combined organic extracts were
washed sequentially with saturated aqueous CuSO4 (3 × 20
mL) and brine and dried over magnesium sulfate.The solvent
was evaporated under reduced pressure. The column chro-
matography of the residue (hexane-diethyl ether, 60:40)
1
CHCl3); H NMR δ 1.28 (s, 3 H), 1.46 (s, 3 H), 3.18 (s, 3 H),
4.36 (d, 1 H, J ) 10.2 Hz), 4.61 (d, 1 H, J ) 5.8 Hz), 4.84-4.96
(m, 3 H), 5.06 (d, 1 H, J ) 12.5 Hz), 5.12 (d, 1 H, J ) 12.5 Hz),
5.20 (bd, 1 H, J ) 8.3 Hz), 6.27 (dd, 1 H, J ) 2.7, 0.9 Hz), 6.30
(dd, 1 H, J ) 2.7, 1.9 Hz), 7.30-7.35 (m, 5 H), 7.37 (dd, 1 H,
J ) 1.9, 0.9 Hz); 13C NMR δ 25.2, 26.6, 51.5, 55.5, 67.2, 81.9,
85.3, 87.7, 108.1, 110.1, 110.3, 112.6, 128.2, 128.2, 128.5, 135.6,
142.2, 152.4, 155.9. Anal. Calcd for C21H25NO7: C, 62.52; H,
6.25; N, 3.47. Found: C, 62.40; H, 6.48; N, 3.26.
Meth yl 5-((Ben zyloxyca r bon yl)a m in o)-5-d eoxy-2,3-O-
isop r op ylid en e-1-O-m et h yl-â-D-a llo-h exofu r a n u r on a t e
(14). The oxidation of 13 (0.201 g, 0.5 mmol) with RuCl3 in
the presence of NaIO4 was carried out as described for the
preparation of compound 3a . The treatment of the crude acid
with diazomethane and purification by column chromatogra-
phy (hexane-diethyl ether, 80:20) afforded 14 (0.14 g, 72%)
as a white solid: mp 68-70 °C; [R]D ) -12.8 (c 2.86, CHCl3);
1H NMR δ 1.27 (s, 3 H), 1.43 (s, 3 H), 3.30 (s, 3 H), 3.72 (s, 3
H), 4.31 (dd, 1 H, J ) 7.6, 1.1 Hz), 4.45 (pst, 1 H, J ) 7.9 Hz),
4.52 (d, 1 H, J ) 6.0 Hz), 4.89 (dd, 1 H, J ) 6.0, 1.1 Hz), 4.93
(s, 1 H), 5.10 (s, 2 H), 5.50 (bd, 1 H, J ) 7.9 Hz), 7.25-7.35
(m, 5 H); 13C NMR δ 25.1, 26.6, 52.3, 55.7, 56.8, 67.3, 81.4,
85.3, 87.9, 110.4, 112.7, 128.1, 128.2, 128.5, 136.2, 155.7, 170.3.
Anal. Calcd for C19H25NO8: C, 57.71; H, 6.37; N, 3.54.
Found: C, 57.64; H, 6.53; N, 3.79.
afforded 19 (0.417 g, 100%) as an oil; [R]D
) -94.4 (c 0.24,
1
CHCl3); H NMR δ 1.34 (s, 3 H), 1.44 (s, 3 H), 1.87 (s, 3 H),
2.97 (s, 3 H), 3.69 (d, 1 H, J ) 13.3 Hz), 3.97 (d, 1 H, J ) 13.3
Hz), 4.15 (d, 1 H, J ) 11.1 Hz), 4.50-4.55 (m, 2 H), 4.83 (s, 1
H), 5.40 (d, 1 H, J ) 5.6 Hz), 6.36 (dd, 1 H, J ) 3.2, 0.9 Hz),
6.44 (dd, 1 H, J ) 3.2, 1.9 Hz), 7.20-7.38 (m, 5 H), 7.50 (dd,
1 H, J ) 1.9, 0.9 Hz); 13C NMR δ 19.2, 25.3, 26.6, 55.2, 59.4,
64.1, 82.6, 85.0, 85.3, 110.2, 110.3, 110.9, 112.3, 127.7, 128.3,
129.3, 135.9, 142.5, 150.0, 169.2. Anal. Calcd for C22H27NO7:
C, 63.30; H, 6.52; N, 3.36. Found: C, 63.49; H, 6.79; N, 3.27
Meth yl N-Ben zyl-5-((ben zyloxy)a m in o)-5-d eoxy-2,3-O-
isop r op ylid en e-5-(2-fu r yl)-â-D-a llo-1,4-p en t ofu r a n osid e
(20). To a cooled (0 °C) solution of N-benzylhydroxylamine
12a (0.375 g, 1 mmol) in DMF (10 mL), was added NaH (43
mg of a 60% dispersion in mineral oil, 1.07 mmol). After
stirring for 30 min at 0 °C, benzyl bromide (0.187 g, 1 mmol)
was added and stirring was continued for 10 h. The reaction
mixture was treated with water (20 mL) and extracted with
diethyl ether (3 × 20 mL), and the combined organic extracts
were washed with brine and dried over magnesium sulfate.
The solvent was evaporated under reduced pressure. The
5-((Ben zyloxycar bon yl)am in o)-5-deoxy-5-(2-fu r yl)-1,2,3-
tr i-O-a cetyl-D-a llo-1,4-p en tofu r a n osid e (16) a n d N-(Ben -
zyloxycar bon yl)-5-deoxy-5-(2-fu r yl)-1,5-im in o-1,2,3,4-tetr a -
O-a cetytl-D-r-r ibitol (17). A solution of compound 13 (0.403
g, 1 mmol) in a 1:1 mixture of AcOH-Ac2O was treated with
aqueous HCl 0.5 N (7.5 mL) and stirred for 4 h at 70 °C. The

The Total Synthesis of (+)-Polyoxin J
J . Org. Chem., Vol. 62, No. 16, 1997 5505
column chromatography (hexane-diethyl ether, 80:20) of the
residue gave 20 (0.232 g, 50%) as an oil containing a 5% of an
impurity which could not be separated. 1H NMR δ 1.35 (s, 3
H), 1.47 (s, 3 H), 2.99 (s, 3 H), 3.60 (d, 1 H, J ) 12.0 Hz), 3.77
(d, 1 H, J ) 12.0 Hz), 3.92 (d, 1 H, J ) 11.7 Hz), 4.28 (d, 1 H,
J ) 10.5 Hz), 4.47 (d, 1 H, J ) 6.0 Hz), 4.66 (d, 1 H, J ) 10.5
Hz), 4.73 (d, 1 H, J ) 11.7 Hz), 4.84 (s, 1 H), 5.08 (d, 1 H, J )
6.0 Hz), 6.33 (dd, 1 H, J ) 3.1, 0.9 Hz), 6.40 (dd, 1 H, J ) 3.1,
1.2 Hz), 7.20-7.38 (m, 10 H), 7.44 (dd, 1 H, J ) 1.2, 0.9 Hz);
13C NMR δ 25.5, 26.6, 55.0, 60.1, 65.1, 76.3, 82.8, 85.0, 86.0,
109.5, 110.3, 110.3, 112.3, 127.41, 127.8, 128.1, 128.2, 128.8,
129.9, 137.1, 137.3, 141.8, 151.0.
mixture of R- and â-22 (0.244 g, 0.5 mmol) with RuCl3 in the
presence of NaIO4 as described for the preparation of 3a and
subsequent esterification with diazomethane gave crude 23
as a 2:3 mixture of R- and â-anomers. Purification by column
chromatography (hexane-diethyl ether, 60:40) gave first R-23
(0.043 g, 18%) as an oil: [R]D ) +68.3 (c 0.32, CHCl3); 1H
NMR δ 1.87 (s, 3 H), 2.02 (s, 3 H), 2.08 (s, 3 H), 2.15 (s, 3 H),
3.48 (d, 1 H, J ) 6.8 Hz), 3.83 (s, 3 H), 4.17 (d, 1 H, J ) 12.7
Hz), 4.30 (d, 1 H, J ) 12.7 Hz), 4.63 (dd, 1 H, J ) 6.8, 3.2 Hz),
5.07 (dd, 1 H, J ) 6.8, 4.4 Hz), 5.54 (dd, 1 H, J ) 6.8, 3.2 Hz),
6.29 (d, 1 H, J ) 4.4 Hz), 7.25-7.50 (m, 5 H); 13C NMR δ 19.1,
20.3, 20.6, 21.0, 52.2, 60.3, 65.8, 69.3, 70.4, 82.1, 93.1, 128.1,
128.6, 129.4, 135.2, 167.5, 168.1, 168.8, 169.2, 169.9. Anal.
Calcd for C22H27NO11: C, 54.88; H, 5.65; N, 2.91. Found: C,
54.79; H, 5.54; N, 2.83.
Eluted second was â-23 (0.067 g, 28%): oil; [R]D ) -43.1
(c 0.17, CHCl3); 1H NMR δ 1.73 (s, 3 H), 1.95 (s, 3 H), 2.00 (s,
3 H), 2.06 (s, 3 H), 3.43 (d, 1 H, J ) 9.3 Hz), 3.85 (s, 3 H), 4.14
(d, 1 H, J ) 11.7 Hz), 4.32 (d, 1 H, J ) 11.7 Hz), 4.60 (dd, 1 H,
J ) 9.3, 6.4 Hz), 5.18 (d, 1 H, J ) 4.9 Hz), 5.40 (t, 1 H, J ) 5.1
Hz), 6.03 (s, 1 H), 7.25-7.45 (m, 5 H); 13C NMR δ 19.3, 20.4,
20.5, 20.7, 52.2, 59.5, 67.3, 72.3, 73.8, 78.9, 98.5, 128.2, 128.6,
129.9, 134.8, 167.9, 168.1, 168.4, 169.4, 169.5. Anal. Calcd
for C22H27NO11: C, 54.88; H, 5.65; N, 2.91. Found: C, 54.76;
H, 5.71; N, 2.97.
Meth yl 5-((Ben zyloxyca r bon yl)a m in o)-5-d eoxy-1,2,3-
tr i-O-a cetyl-D-a llo-h exofu r a n u r on a te (18) fr om 23. To a
solution of R-23 and â-23 (0.240, 0.5 mmol) in acetic acid (10
mL) was added 10% palladium on activated charcoal (140 mg),
and the resulting mixture was hydrogenated at 7 atm for seven
days in a Parr hydrogenation apparatus. The crude mixture
was filtered through Celite previously washed with methanol
(30 mL). The filtrate was evaporated under reduced pressure,
and the residue was taken up in dioxane (5 mL). Aqueous
NaHCO3 (2.5 mL) was added, and the resulting solution was
cooled to 0 °C and then treated with benzyl chloroformate (0.08
mL, 0.55 mmol). After stirring for 30 min at 0 °C, water (15
mL) was added and the mixture was extracted with CH2Cl2
(3 × 10 mL). The combined organic extracts were washed with
brine and dried over magnesium sulfate, and the solvent was
evaporated under reduced pressure. The crude product was
purified by column chromatography (hexane-ethyl acetate, 60:
40) to give 18 (0.168 g, 72%) as a mixture of R- and â-anomers.
The characteristics of this material were identical to those of
the product obtained from 16 as described above.
Meth yl N-Ben zyl-5-(((ben zyloxyca r bon yl)oxy)a m in o)-
5-deoxy-2,3-O-isopr opyliden e-5-(2-fu r yl)-â-D-a llo-1,4-pen to-
fu r a n osid e (21). To a cooled (0 °C) solution of 12a (0.375 g,
1 mmol) in DMF (10 mL), was added NaH (43 mg of a 60%
dispersion in mineral oil, 1.07 mmol). After stirring for 30
min at 0 °C, the reaction mixture was treated with benzyl
chloroformate (0.16 mL, 1.07 mmol) and stirred for additional
20 h. Water (20 mL) was added carefully, and the mixture
was extracted with diethyl ether (3 × 20 mL). The combined
organic extracts were washed with brine and dried over
magnesium sulfate, and the solvent was evaporated under
reduced pressure. Purification of the residue by column
chromatography (hexane-diethyl ether, 95:5) afforded 21
(0.127 g, 25%) as an oil: [R]D ) -14.4 (c 1.07, CHCl3); 1H
NMR δ 1.31 (s, 3 H), 1.44 (s, 3 H), 2.99 (s, 3 H), 3.72 (d, 1 H,
J ) 13.1 Hz), 3.98 (d, 1 H, J ) 13.1 Hz), 4.21 (d, 1 H, J ) 11.0
Hz), 4.52 (d, 1 H, J ) 5.9 Hz), 4.59 (d, 1 H, J ) 11.0 Hz), 4.85
(s, 1 H), 5.00-5.10 (m, 2 H), 5.38 (d, 1 H, J ) 5.9 Hz), 6.41
(dd, 1 H, J ) 3.2, 0.8 Hz), 6.38 (dd, 1 H, J ) 3.2, 1.7 Hz), 7.20-
7.40 (m, 10 H), 7.49 (dd, 1 H, J ) 1.7, 0.8 Hz); 13C NMR δ
25.3, 26.6, 55.2, 59.9, 64.7, 69.8, 82.5, 85.0, 85.2, 110.1, 110.4,
111.1, 112.2, 127.7, 128.1, 128.2,128.3, 128.4, 129.5, 135.0,
135.4, 142.5, 149.6, 154.7. Anal. Calcd for C28H31NO8: C,
66.00; H, 6.13; N, 2.75. Found: C, 66.16; H, 6.27; N, 2.90.
5-(Acet oxya m in o)-N-b en zyl-5-d eoxy-5-(2-fu r yl)-1,2,3-
tr i-O-a cetyl-D-a llo-1,4-p en tofu r a n osid e (22). A solution of
19 (0.417 g, 1 mmol) in a 80:19:1 AcOH-H2O-HCl mixture
(37.1 mL) was stirred for 4 h at 70 °C. The solvent was
evaporated under reduced pressure, and the residue was
treated with pyridine (1.5 mL), Ac2O (1.5 mL), and DMAP (2
mg). After stirring for 2 h at ambient temperature, the
reaction mixture was partitioned between saturated aqueous
NaHCO3 (20 mL) and EtOAc (20 mL). The aqueous layer was
reextracted with EtOAc (2 × 20 mL), the combined organic
extracts were washed sequentially with saturated aqueous
CuSO4 and brine and dried over magnesium sulfate, and the
solvent was evaporated under reduced pressure. 1H NMR of
the crude material showed a 2:3 ratio of R- and â-anomers that
were separated by column chromatography (hexane-diethyl
ether, 60:40).
Met h yl 5-Deoxy-5-(2-fu r yl)-5-(h yd r oxya m in o)-2,3-O-
isop r op ylid en e-N-(p-m eth oxyben zyl)-â-D-a llo-1,4-p en to-
fu r a n osid e (12b). 2-Lithiofuran was added to the nitrone
6b (3.37 g, 1 mmol) in the presence of 1.0 equiv of Et2AlCl as
described above for the addition to 6a . The reaction mixture
was also worked up as above. The 1H NMR analysis of the
crude product showed ds ) 72%. Column chromatography
(hexane-diethyl ether, 80:20) afforded pure 12b (2.02 g, 50%)
R-22: 0.117 g, 24%; oil; [R]D ) +73.5 (c 0.23, CHCl3); 1H
NMR δ 1.85 (s, 3 H), 2.00 (s, 3 H), 2.06 (s, 3 H), 2.09 (s, 3 H),
3.80 (d, 1 H, J ) 12.9 Hz), 3.88 (d, 1 H, J ) 12.9 Hz), 4.29 (d,
1 H, J ) 4.8 Hz), 4.75 (t, 1 H, J ) 4.6 Hz), 4.81 (dd, 1 H, J )
7.3, 4.6 Hz), 5.18 (dd, 1 H, J ) 7.3, 4.2 Hz), 6.29 (d, 1 H, J )
4.8 Hz), 6.44 (dd, 1 H, J ) 3.3, 1.2 Hz), 6.49 (dd, 1 H, J ) 3.3,
0.9 Hz), 7.25-7.40 (m, 5 H), 7.48 (dd, 1 H, J ) 1.2, 0.9 Hz);
13C NMR δ 19.2, 20.2, 20,6, 21.0, 60.3, 63.7, 69.1, 70.5, 83.2,
93.9, 110.8, 111.9, 127.8, 128.4, 129.4, 135.5, 142.9, 147.4,
169.0, 169.2, 169.6, 170.0. Anal. Calcd for C24H27NO10: C,
58.59; H, 5.56; N, 2.86. Found: C, 58.72; H, 5.38; N, 2.94.
â-22: 0.176 g, 36%; oil; [R]D ) -25.0 (c 0.18, CHCl3); 1H
NMR δ 1.95 (s, 3 H), 2.02 (s, 3 H), 2.06 (s, 3 H), 2.15 (s, 3 H),
3.72 (d, 1 H, J ) 12.5 Hz), 3.99 (d, 1 H, J ) 7.2 Hz), 4.04 (d,
1 H, J ) 12.5 Hz), 4.67 (t, 1 H, J ) 7.0 Hz), 5.19 (d, 1 H, J )
4.9 Hz), 5.32 (dd, 1 H, J ) 6.8, 4.9 Hz), 5.98 (s, 1 H), 6.40 (dd,
1 H, J ) 3.4, 0.9 Hz), 6.43 (dd, 1 H, J ) 3.4, 1.9 Hz), 7.24-
7.40 (m, 5 H), 7.47 (dd, 1 H, J ) 1.9, 0.9 Hz); 13C NMR δ 19.5,
20.5, 20.5, 20.8, 59.6, 63.7, 72.5, 73.7, 81.0, 98.4, 110.5, 111.3,
127.9, 128.5, 129.6, 135.4, 142.7, 148.3, 168.6, 169.1, 169.4,
169.7. Anal. Calcd for C24H27NO10: C, 58.59; H, 5.56; N, 2.86.
Found: C, 58.67; H, 5.78; N, 2.94.
1
as an oil: [R]D ) -21.6 (c 1.92, CHCl3); H NMR δ 1.35 (s, 3
H), 1.48 (s, 3 H), 3.06 (s, 3 H), 3.61 (d, 1 H, J ) 13.2 Hz), 3.66
(d, 1 H, J ) 13.2 Hz), 3.79 (s, 3 H), 3.95 (d, 1 H, J ) 11.2 Hz),
4.58 (d, 1 H, J ) 6.1 Hz), 4.77 (d, 1 H, J ) 11.2 Hz), 4.82 (bs,
1 H, ex D2O), 4.90 (s, 1 H), 5.15 (d, 1 H, J ) 6.1 Hz), 6.41 (dd,
1 H, J ) 3.2, 0.7 Hz), 6.45 (dd, 1 H, J ) 3.2, 1.7 Hz), 6.86 (d,
2 H, J ) 8.5 Hz), 7.24 (d, 2 H, J ) 8.5 Hz), 7.49 (dd, 1 H, J )
1.7, 0.7 Hz); 13C NMR δ 25.3, 26.5, 55.1, 55.2, 61.4, 65.2, 82.6,
85.1, 86.0, 109.5, 110.4, 110.5, 112.4, 113.7, 129.5, 130.5, 142.2,
150.4, 158.9. Anal. Calcd for C21H27NO7: C, 62.21; H, 6.71;
N, 3.45. Found: C, 62.45; H, 6.70; N, 3.08.
Meth yl 5-(Ben zyla m in o)-5-d eoxy-5-(2-fu r yl)-2,3-O-iso-
p r op ylid en e-â-D-a llo-1,4-p en tofu r a n osid e (24a ). To a so-
lution of copper(II) acetate (18 mg, 0.1 mmol) in acetic acid
(1.4 mL) was added Zn dust (0.33 g, 5.1 mmol), and the mixture
was stirred at ambient temperature for 15 min. A solution of
12a (0.375 g, 1 mmol) in 3:1 acetic acid-water (2 mL) was
added, and the mixture was heated at 70 °C for 1 h. After
cooling to 20 °C, the sodium salt of EDTA (1.0 g) was added,
and the solution was basified with 3 M aqueous NaOH to pH
) 10. The resulting mixture was extracted with EtOAc (3 ×
20 mL), and the combined organic extracts were washed with
saturated aqueous EDTA (20 mL) and brine (20 mL). The
Meth yl 5-(Acetoxya m in o)-N-ben zyl-5-d eoxy-1,2,3-tr i-O-
a cetyl-D-a llo-h exofu r a n u r on a te (23). The oxidation of the

5506 J . Org. Chem., Vol. 62, No. 16, 1997
Dondoni et al.
organic layer was dried over magnesium sulfate and the
solvent evaporated under reduced pressure. Purification of
the residue by column chromatography (hexane-diethyl ether,
80:20) afforded 24a (0.258 g, 72%) as an oil: [R]D ) -95.9 (c
(100). Anal. Calcd for C23H26F3NO7: C, 56.91; H, 5.40; N, 2.89.
Found: C, 56.74; H, 5.35; N, 3.04.
N-Ben zyl-5-d eoxy-5-(2-fu r yl)-5-(t r iflu or oa cet a m id o)-
1,2,3-tr i-O-a cetyl-â-D-a llo-1,4-p en tofu r a n ose (26). Treat-
ment of 25a (0.228 g, 0.5 mmol) with a 80:19:1 AcOH-H2O-
HCl mixture and subsequent acetylation under the conditions
described above for the preparation of 22 gave 26 as a mixture
of R- and â-anomers in 24:76 ratio by 1H NMR analysis.
Column chromatography (hexane-diethyl ether, 60:40) af-
forded R-26 (0.05 g, 19%) as an oil: [R]D ) +13.5 (c 0.33,
CHCl3); 1H NMR (DMSO-d6, 140 °C) δ 2.01 (s, 3 H), 2.03 (s, 3
H), 2.06 (s, 3 H), 4.75 (bs, 2 H), 4.82 (dd, 1 H, J ) 6.9, 4.0 Hz),
5.15-5.22 (m, 3 H), 5.47 (d, 1 H, J ) 6.9 Hz), 6.35 (dd, 1 H, J
) 3.2, 1.9 Hz), 6.52 (bd, 1 H, J ) 3.2 Hz), 7.00 (bs, 2 H), 7.16-
7.28 (m, 3 H), 7.48 (dd, 1 H, J ) 1.9, 0.8 Hz); 13C NMR (DMSO-
d6, 95 °C) δ 19.4, 19.5, 20.2, 48.9, 56.4, 71.0, 73.8, 81.0, 93.6,
110.3, 111.7, 115.1 (q, J ) 285.0 Hz), 126.2, 126.7, 127.8, 135.4,
142.6, 146.9, 157.0 (q, J ) 32.0 Hz), 168.3, 168.4, 168.8; 19F
NMR (DMSO-d6, 140 °C) δ -66.6. Anal. Calcd for C24H24F3-
NO9: C, 54.65; H, 4.59; N, 2.66. Found: C, 54.73; H, 4.70; N,
2.56.
1
0.83, CHCl3); H NMR δ 1.32 (s, 3 H), 1.44 (s, 3 H), 1.71 (bs,
1 H), 3.17 (s, 3 H), 3.51 (d, 1 H, J ) 14.2 Hz), 3.67 (d, 1 H, J
) 8.2 Hz), 3.73 (d, 1 H, J ) 14.2 Hz), 4.34 (d, 1 H, J ) 8.2 Hz),
4.52 (d, 1 H, J ) 5.6 Hz), 4.88 (s, 1 H), 5.05 (d, 1 H, J ) 5.6
Hz), 6.23 (d, 1 H, J ) 3.3 Hz), 6.34 (dd, 1 H, J ) 3.3, 1.8 Hz),
7.20-7.32 (m, 5 H), 7.41 (d, 1 H, J ) 1.8 Hz); 13C NMR δ 25.2,
26.5, 51.0, 55.5, 57.9, 82.4, 85.3, 88.7, 108.4, 109.9, 110.0, 112.2,
127.0, 128.2, 128.3, 135.5, 142.0, 153.9. Anal. Calcd for
C20H25NO5: C, 66.83; H, 7.01; N, 3.90. Found: C, 66.99; H,
6.85; N, 4.11.
Meth yl 5-((p-Meth oxyben zyl)a m in o)-5-d eoxy-5-(2-fu -
r yl)-2,3-O-isop r op ylid en e-â-D-a llo-1,4-p en t ofu r a n osid e
(24b). The reduction of 12b (0.405 g, 1 mmol) was carried
out with Zn0/CuII as described above for the preparation of 24a .
Column chromatography (hexane-diethyl ether, 80:20) af-
forded pure 24b (0.303 g, 78%) as an oil: [R]D ) -95.5 (c 0.32,
1
CHCl3); H NMR δ 1.31 (s, 3 H), 1.45 (s, 3 H), 1.65 (bs, 1 H),
3.16 (s, 3 H), 3.44 (d, 1 H, J ) 12.9 Hz), 3.65 (d, 1 H, J ) 9.0
Hz), 3.66 (d, 1 H, J ) 12.9 Hz), 3.77 (s, 3 H), 4.34 (d, 1 H, J )
9.0 Hz), 4.52 (d, 1 H, J ) 6.1 Hz), 4.87 (s, 1 H), 5.02 (d, 1 H,
J ) 6.1 Hz), 6.22 (dd, 1 H, J ) 3.2, 0.9 Hz), 6.34 (dd, 1 H, J )
3.2, 1.9 Hz), 6.82 (d, 2 H, J ) 8.5 Hz), 7.17 (d, 2 H, J ) 8.5
Hz), 7.41 (dd, 1 H, J ) 1.9, 0.9 Hz); 13C NMR δ 25.2, 26.e`,
50.4, 55.3, 55.5, 57.8, 8.44, 85.3, 88.7, 108.3, 109.9, 110.0, 112.2,
113.7, 129.4, 132.1, 142.0, 154.0, 158.6. Anal. Calcd for
C21H27NO6: C, 64.77; H, 6.99; N, 3.60. Found: C, 64.98; H,
6.75; N, 3.57.
Eluted second was â-26 (0.155 g, 59%); oil; [R]D ) -33.9 (c
1.07, CHCl3); 1H NMR (DMSO-d6, 140 °C) δ 1.99 (s, 3 H), 2.04
(s, 3 H), 2.09 (s, 3 H), 4.72 (ABq, 2 H, J ) 18.3 Hz, ∆δ ) 0.01),
4.92 (dd, 1 H, J ) 8.3, 6.3 Hz), 5.24 (dd, 1 H, J ) 5.2, 1.0 Hz),
5.30 (dd, 1 H, J ) 6.3, 5.2 Hz), 5.35 (d, 1 H, J ) 8.3 Hz), 6.05
(d, 1 H, J ) 1.0 Hz), 6.32 (dd, 1 H, J ) 3.2, 1.9 Hz), 6.50 (bd,
1 H, J ) 3.2 Hz), 7.02 (bd, 2 H, J ) 6.3 Hz), 7.15-7.30 (m, 3
H), 7.45 (dd, 1 H, J ) 1.9, 0.9 Hz); 13C NMR (DMSO-d6, 95 °C)
δ 19.6, 19.8, 20.0, 49.0, 56.7, 71.0, 73.5, 79.4, 98.0, 110.2, 110.8,
116.3 (q, J ) 290.0 Hz), 126.3, 126.9, 127.8, 135.2, 142.9, 147.3,
157.2 (q, J ) 32.0 Hz), 167.9, 168.6 (2C); 19F NMR (DMSO-d6,
140 °C) δ -66.7. Anal. Calcd for C24H24F3NO9: C, 54.65; H,
4.59; N, 2.66. Found: C, 54.48; H, 4.81; N, 2.72.
Met h yl N-Ben zyl-5-d eoxy-5-(2-fu r yl)-2,3-O-isop r op -
ylid en e-5-(tr iflu or oa ceta m id o)-â-D-a llo-1,4-p en tofu r a n o-
sid e (25a ). To a solution of 24a (0.359 g, 1 mmol) in CH2Cl2
(15 mL) were added pyridine (6.05 mL, 3 mmol) and trifluo-
roacetic anhydride (0.471 g, 2.2 mmol). After stirring for 3 h,
the solvent was removed under reduced pressure, and the
residue was partitioned between saturated aqueous NaHCO3
(20 mL) and diethyl ether (20 mL). The aqueous layer was
reextracted with diethyl ether (2 × 20 mL), the organic
combined extracts were washed with saturated aqueous CuSO4
(3 × 30 mL) and brine and dried over magnesium sulfate, and
the solvent was evaporated under reduced pressure. The
residue was purified by column chromatography (hexane-
diethyl ether, 90:10) to give pure 25a (0.410 g, 90%) as an oil;
N-Ben zyl-1,5-dideoxy-1-(3,4-dih ydr o-5-m eth yl-2,4-dioxo-
1(2H)-p yr im id in yl)-5-(2-fu r yl)-5-(tr iflu or oa ceta m id o)-2,3-
d i-O-a cetyl-â-D-a llo-1,4-p en tofu r a n ose (28). To a solution
of 26 (0.263 g, 0.5 mmol) in CH2Cl2 (20 mL) were added
sequentially 2,4-bis(trimethylsiloxy)-5-methylpyrimidine (27)-
(0.448 g, 1.7 mmol) and TMSOTf (0.55 mL, 3 mmol) under an
argon atmosphere. The reaction mixture was refluxed for 2
h, cooled to 20 °C, diluted with CH2Cl2 (100 mL), and then
washed with saturated aqueous NaHCO3 (100 mL) and brine.
The organic phase was dried over magnesium sulfate and the
solvent evaporated under reduced pressure. Column chroma-
tography of the residue (hexane-diethyl ether, 20:80) gave
1
[R]D ) -71.1 (c 0.97, CHCl3); H NMR (DMSO-d6, 140 °C) δ
1.26 (s, 3 H), 1.38 (s, 3 H), 3.06 (s, 3 H), 4.43 (d, 1 H, J ) 6.1
Hz), 4.59 (d, 1 H, J ) 16.3 Hz), 4.63 (d, 1 H, J ) 6.1 Hz), 4.67
(d, 1 H, J ) 16.3 Hz), 4.78 (d, 1 H, J ) 10.2 Hz), 4.87 (s, 1 H),
5.33 (d, 1 H, J ) 10.2 Hz), 6.35 (dd, 1 H, J ) 3.4, 1.9 Hz), 6.49
(dd, 1 H, J ) 3.4, 0.6 Hz), 7.03-7.09 (m, 2 H), 7.20-7.28 (m,
3 H), 7.47 (dd, 1 H, J ) 1.9, 0.6 Hz);13C NMR (DMSO-d6, 95
°C) δ 24.5, 26.0, 54.3, 56.0, 80.5, 83.4, 84.2, 84.2, 109.1, 110.9,
110.3, 111.8, 116.1 (q, J ) 288.0 Hz), 126.8, 127.8, 135.2, 142.5,
142.6, 148.8, 156.7 (q, J ) 34.7 Hz); 19F NMR (DMSO-d6, 140
°C) δ -66.4; EI-MS m/ s (%): 455 (M+, 9), 440 (27), 423 (51),
173 (59), 91 (100). Anal. Calcd for C22H24F3NO6: C, 58.02;
H, 5.31; N, 3.08. Found: C, 58.20; H, 5.27; N, 3.21.
pure 28 (0.240 g, 81%) as a white solid: mp 64-66 °C; [R]D )
1
-17.7 (c 0.80, CHCl3); H NMR (at 55 °C) δ 1.86 (d, 3 H, J )
1.2 Hz), 2.02 (s, 3 H), 2.06 (bs, 3 H), 4.65 (d, 1 H, J ) 15.9 Hz),
4.70-4.85 (m, 2 H), 5.18-5.32 (m, 2H), 5.49 (d, 1 H, J ) 7.1
Hz), 5.73 (bs, 1 H), 6.27 (bs, 1 H), 6.37 (bs, 1 H), 6.72 (s, 1 H),
7.00-7.15 (m, 2 H), 7.17-7.38 (m, 4 H), 7.08 (bs, 1 H); 13C
NMR δ (at 55 °C) δ 12.5, 20.3 (2C), 50.6, 55.7, 70.8, 72.0, 80.0,
88.7, 110.8, 111.9, 111.9, 116.3 (q, J ) 277.0 Hz), 127.3, 128.0,
128.6, 135.0, 135.6, 142.8, 147.3, 149.9, 158.0 (q, J ) 45.0 Hz),
163.0, 169.3, 169.4; 19F NMR (55 °C) δ -72.7. Anal. Calcd
for C27H26F3N3O9: C, 54.64; H, 4.42; N, 7.08. Found: C, 54.72;
H, 4.70; N, 6.91.
Meth yl N-Ben zyl-5-d eoxy-1,2,3-tr i-O-a cetyl-5-(tr iflu o-
r oa ceta m id o)-D-a llo-h exofu r a n u r on a te (29). The oxida-
tion of the mixture of R- and â-26 (0.264 g, 0.5 mmol) with
RuCl3-NaIO4 was carried out as described for the preparation
of 3a . The esterification with diazomethane and purification
by column chromatography (hexane-diethyl ether, 60:40) gave
29 (0.156 g, 60%) as a mixture of R- and â-anomers in 24:76
Meth yl 5-Deoxy-5-(2-fu r yl)-2,3-O-isop r op ylid en e-5-(tr i-
flu or oacetam ido)-N-(p-m eth oxyben zyl)-â-D-a llo-1,4-pen to-
fu r a n osid e (25b). The trifluoroacetylation of 24b (0.389 g,
1 mmol) was carried out as described for the preparation of
25a . Purification of the crude product by column chromatog-
raphy (hexane-diethyl ether, 80:20) afforded 25b (0.339 g,
70%) as an oil: [R]D ) -62.3 (c 0.81, CHCl3); 1H NMR (DMSO-
d6, 120 °C) δ 1.27 (s, 3 H), 1.39 (s, 3 H), 3.07 (s, 3 H), 3.75 (s,
3 H), 4.46 (d, 1 H, J ) 5.7 Hz), 4.50 (d, 1 H, J ) 16.2 Hz), 4.60
(d, 1 H, J ) 5.7 Hz), 4.62 (d, 1 H, J ) 16.2 Hz), 4.80 (d, 1 H,
J ) 10.5 Hz), 4.88 (s, 1 H), 5.28 (d, 1 H, J ) 10.5 Hz), 6.40
(dd, 1 H, J ) 3.0, 1.5 Hz), 6.51 (d, 1 H, J ) 3.0 Hz), 6.84 (d, 2
H, J ) 8.6 Hz), 7.03 (d, 2 H, J ) 8.6 Hz), 7.52 (d, 1 H, J ) 1.5
Hz); 13C NMR (DMSO-d6, 120 °C) δ 24.4, 26.0, 54.2, 54.9, 55.0,
56.0, 80.4, 83.5, 84.2, 109.1, 110.2 (2C), 111.7, 113.7, 115.9 (q,
J ) 287.8 Hz), 127.1, 128.5, 142.5, 149.0, 156.4 (q, J ) 36.1
Hz), 158.6; 19F NMR (DMSO-d6, 120 °C) δ -66.3; EI-MS m/ s
(%): 485 (M+, 7), 453 (37), 364 (29), 332 (32), 173 (25), 121
1
ratio by H NMR analysis.
1
â-29: oil; [R]D ) -35.4 (c 1.06, CHCl3); H NMR δ 1.93 (s,
3 H), 2.00 (s, 3 H), 2.04 (s, 3 H), 3.67 (s, 3 H), 4.01 (d, 1 H, J
) 6.8 Hz), 4.75 (ABq, 2H, J ) 15.0 Hz, ∆δ ) 0.01), 5.09 (dd, 1
H, J ) 8.2, 4.6 Hz), 4.94 (dd, 1 H, J ) 8.2, 6.8 Hz), 5.15 (d, 1
H, J ) 4.6 Hz) 6.05 (s, 1 H), 7.24-7.50 (m, 5 H); 13C NMR δ
20.0, 20.2, 20.8, 52.6, 52.7, 61.1, 70.8, 73.3, 77.0, 97.7, 116.0
(q, J ) 287.3 Hz), 128.8, 128.9, 128.9, 133.2, 158.0 (q, J ) 42.9
Hz), 167.3, 168.3, 169.2, 169.2; 19F NMR δ -72.9. Anal. Calcd
for C22H24F3NO10: C, 50.87; H, 4.66; N, 2.70. Found: C, 50.72;
H, 4.73; N, 2.98.

The Total Synthesis of (+)-Polyoxin J
J . Org. Chem., Vol. 62, No. 16, 1997 5507
Meth yl N-Ben zyl-1,5-d id eoxy-1-(3,4-d ih yd r o-5-m eth yl-
2,4-d ioxo-1(2H)-p yr im id in yl)-2,3-d i-O-a cetyl-5-(tr iflu or o-
a ceta m id o)-â-D-a llo-h exofu r a n u r on a te (30). The reaction
of 29 (0.259 g, 0.5 mmol) with 27 as described above for the
preparation of 28 afforded, after column chromatography
(hexane-diethyl ether, 15:85), pure 30 (0.205 g, 70%) as a
M + 1, calcd (C11H16N3O7: 302.0988). Anal. Calcd for
C11H15N3O7: C, 43.86; H, 5.02; N, 13.95. Found: C, 43.90; H,
5.14; N, 14.06.
Cou p lin g betw een P olyoxa m ic Acid (3) a n d Th ym in e
P olyoxin C (4). To a cooled (0 °C) solution of the polyoxamic
acid derivative 3a (20.7 mg, 0.059 mmol) in EtOAc (7 mL) were
added DCC (11.7 mg, 0.059 mmol) and N-hydroxysuccinimide
(6.85 mg, 0.059 mmol). The mixture was stirred at 0 °C for 8
h and then the solvent was evaporated under reduced pres-
sure. The 1H NMR analysis showed the formation of the
activated amide 32. This crude product was dissolved in
DMSO (3 mL), and the solution was treated with 4 (18 mg,
0.06 mmol) and diisopropylethylamine (10.4 µl, 0.06 mmol).
The reaction mixture was stirred at ambient temperature for
24 h. The solvent was evaporated under reduced pressure at
a temperature below 40 °C. Purification of the residue by
column chromatography (CHCl3-MeOH-H2O, 5:2:0.5) gave
the product 33 (21 mg, 58%) as a slightly yellow solid: mp
164-165 °C (soft 110 °C); [R]D ) -17.7 (c 0.34, MeOH); 1H
NMR (D2O) δ 1.21 (s, 3 H), 1.27 (s, 9 H), 1.28 (s, 3 H), 3.90-
4.10 (m, 3 H), 4.11-4.38 (m, 6 H), 4.45 (bd, 1 H, J ) 1.5 Hz),
5.72 (bd, 1 H, J ) 6.1 Hz), 7.31 (bs, 1 H); 13C NMR (D2O) δ
11.6, 25.5, 25.8, 27.4, 54.3, 62.4, 63.1, 69.6, 73.2, 75.4, 76.3,
82.0, 85.1, 87.2, 110.6, 111.5, 137.2, 151.8, 157.2, 158.7, 163.2,
166.2, 170.8; FAB-MS m/ e (%) 632 (MH+, 62), 532 (100). Anal.
Calcd for C25H37N5O14: C, 47.54; H, 5.91; N, 11.09. Found:
C, 47.89; H, 5.87; N, 11.10.
1
white solid: mp 65-67 °C; [R]D ) -12.9 (c 0.78, CHCl3); H
NMR δ 1.90 (s, 3 H), 2.03 (s, 3 H), 2.05 (s, 3 H), 3.60 (s, 3 H),
4.45 (d, 1 H, J ) 5.1 Hz), 4.51 (t, 1 H, J ) 5.0 Hz), 4.70 (d, 1
H, J ) 15.8 Hz), 4.84 (d, 1 H, J ) 15.8 Hz), 5.29 (dd, 1 H, J )
6.2, 5.4 Hz), 5.38 (t, 1 H, J ) 5.6 Hz), 5.69 (d, 1 H, J ) 4.4
Hz), 6.97 (s, 1 H), 7.24-7.50 (m, 5 H), 8.63 (bs, 1 H, ex D2O);13C
NMR δ 12.4, 20.1, 20.4, 52.7, 52.7, 60.3, 70.9, 72.5, 80.1, 89.7,
111.7, 116.2 (q, J ) 286.0 Hz), 128.6, 128.8, 129.0, 133.5, 136.9,
150.0, 157.6 (q, J ) 45.0 Hz), 163.4, 167.6, 169.7, 169.7; 19F
NMR (at 55 °C) δ -72.5; FAB-MS m/ e (%) 586 (MH+, 35), 460
(48). Anal. Calcd for C25H26F3N3O10: C, 51.29; H, 4.48; N,
7.18. Found: C, 51.11; H, 4.53; N, 7.01.
Meth yl 1,5-Did eoxy-1-(3,4-d ih yd r o-5-m eth yl-2,4-d ioxo-
1(2H )-p yr im id in yl)-1,2,3-t r i-O-a cet yl-5-(t r iflu or oa cet a -
m id o)-â-D-a llo-h exofu r a n u r on a te (31). To a solution of 30
(0.293 g, 0.5 mmol) in MeOH (10 mL), was added 20% Pd-
(OH)2/C (70 mg). After stirring for 6 h under hydrogen and
ambient temperature, the reaction mixture was filtered through
Celite previously washed with methanol (40 mL). The filtrate
was evaporated under reduced pressure, and the residue was
purified by column chromatography (diethyl ether 100%) to
give pure 31 (0.235 g, 95%) as a white solid: mp 70 °C; [R]D
)
P olyoxin J (2). A solution of 33 (13 mg, 0.022 mmol) in
2:1 trifluoroacetic acid-water (3 mL) was stirred at 0 °C for 2
h. The solvent was evaporated under reduced pressure and
below 40 °C. The brownish solid residue was purified by
column chromatography (CHCl3-MeOH-H2O, 5:4:1) to give
pure polyoxin J (2) (8 mg, 80%) as a white solid: mp 198-205
°C dec; [R]D ) +30.0 (c 0.10, H2O) [lit. mp 198-208 °C,2b 200-
210 °C;9 [R]D ) +32 (c 1.00, H2O),2b +33 (c 0.75, H2O),8 +35
1
+24.2 (c 1.25, CHCl3); H NMR δ 1.90 (d, 3 H, J ) 1.0 Hz),
2.07 (s, 3 H), 2.09 (s, 3 H), 3.80 (s, 3 H), 4.48 (dd, 1 H, J ) 6.9,
3.9 Hz), 5.00 (dd, 1 H, J ) 7.2, 3.9 Hz), 5.47 (dd, 1 H, J ) 6.5,
3.8 Hz), 5.51 (d, 1 H, J ) 3.8 Hz), 5.64 (t, 1 H, J ) 6.7 Hz),
6.93 (d, 1 H, J ) 1.0 Hz), 8.00 (bd, 1 H, J ) 7.2 Hz), 9.21 (bs,
1 H, ex D2O); 13C NMR δ 12.3, 20.2, 20.4, 53.2, 53.5, 69.4, 73.1,
80.3, 92.2, 112.1, 115.5 (q, J ) 286.0 Hz), 137.3, 150.3, 157.5
(q, J ) 38.0 Hz), 163.2, 167.4, 169.5, 170.1; 19F NMR δ -76.1;
FAB-MS m/ e (%) 496 (MH+, 46), 370 (36), 185 (100). Anal.
Calcd for C18H20F3N3O10: C, 43.64; H, 4.07; N, 8.48. Found:
C, 43.52; H, 4.18; N, 8.20.
1
(c 0.80, H2O)9]; H NMR (D2O) δ 1.76 (s, 3 H), 3.85-4.05 (m,
4 H), 4.08 (dd, 1 H, J ) 5.0, 1.3 Hz), 4.12-4.15 (m, 2 H), 4.20
(t, 1 H, J ) 5.7 Hz), 4.35 (t, 1 H, J ) 5.7 Hz), 4.44 (d, 1 H, J
) 4.0 Hz), 5.70 (d, 1 H, J ) 5.6 Hz), 7.40 (s, 1 H); 13C NMR
(D2O) δ 10.1, 54.9, 55.2, 63.9, 67.1, 68.2, 68.7, 71.3, 82.6, 87.6,
110.3, 136.4, 150.5, 157.7, 165.1, 165.9, 172.2; MS (FAB-MS)
m/ e (%) 492 (MH+, 26), 219 (55), 176 (55), 149 (100); MS
(FAB-) m/ e (%) 490 [(M - H)-, 100]. Anal. Calcd for
C17H25N5O12: C, 41.56; H, 5.13; N, 14.25. Found: C, 41.63;
H, 4.95; N, 14.32.
5-Am in o-1,5-dideoxy-1-(3,4-dih ydr o-5-m eth yl-2,4-dioxo-
1-(2H)-pyr im idin yl)-â-D-a llo-h exofu r an u r on ic Acid (th ym -
in e p olyoxin C) (4). To a cooled (0 °C) solution of 31 (0.247
g, 0.5 mmol) in a 5:1 THF-H2O mixture (12 mL) was added
lithium hydroxide monohydrate (72 mg, 1.71 mmol). The
reaction mixture was stirred for 1 h at 0 °C and then treated
with water (20 mL). The resulting mixture was extracted with
CH2Cl2 (3 × 20 mL). The combined extracts were acidified
with 1 N HCl to pH 2 and then extracted with EtOAc (6 × 20
mL). The combined organic extracts were washed with brine
and dried over magnesium sulfate, and the solvent was
evaporated under reduced pressure. The residue was purified
by column chromatography (chloroform-methanol-water, 5:4:
1) to give pure 4 (0.121 g, 81%) as a white solid: mp 192 °C
(170 °C, soft); [R]D ) +8.8 (c 0.09, H2O) [lit. mp 180-183 °C;12e
182-185;12c 242-244;12h 240-244;2b [R]D ) +8.7 (c 0.23,
H2O);2b,12e +8.0 (c 0.37, H2O);12c +8.2 (c 0.70, H2O);12h 1H NMR
(D2O) δ 1.74 (s, 3 H), 4.00 (d, 1 H, J ) 2.7 Hz), 4.15-4.22 (m,
2 H), 4.45 (t, 1 H, J ) 5.8 Hz), 5.70 (d, 1 H, J ) 5.1 Hz), 7.33
(s, 1 H); 13C NMR (D2O) δ 10.1, 53.8, 68.0, 71.2, 80.6, 88.3,
110.3, 136.6, 150.5, 156.1, 168.7; FAB-HRMS m/ e 302.0987,
Ack n ow led gm en t. We are grateful to the Ministe-
rio of Educacion y Ciencia (DGICYT, Madrid, Project
PB94-0598) and the CNR (Rome) for financial support.
Special thanks by one of us (A.D.) are addressed to
Professor K. Isono (Tokai University, Shimizu, J apan)
for the correspondence and for providing a sample of
polyoxin J (2) and to Dr. A. K. Saksena and Dr. R. G.
Lovey (Schering-Plough Research Institute, New J ersey)
for a generous gift of the polyoxamic acid derivative 3a .
A fellowship from the DGA (Arago´n, Spain) to S.F. is
gratefully acknowledged.
J O9702913