Enantiospecific Total Synthesis of (-)-Polyoxamic Acid Using 2,3-Aziridino-γ-lactone Methodology

Article abstract of DOI:10.1021/jo035039b

The non-natural enantiomer of polyoxamic acid was synthesized in six steps from 2,3-aziridino-γ-lactone 7 with an overall yield of 10%. The key step of the strategy is a deprotection-protection sequence on the nitrogen atom of the aziridine ring required

Full text of DOI:10.1021/jo035039b

SCHEME 1
En a n tiosp ecific Tota l Syn th esis of
(-)-P olyoxa m ic Acid Usin g
2,3-Azir id in o-γ-la cton e Meth od ology
Aure´lie Tarrade, Philippe Dauban, and Robert H. Dodd*
Institut de Chimie des Substances Naturelles, CNRS,
Avenue de la Terrasse, F-91198 Gif-sur-Yvette Cedex, France
robert.dodd@icsn.cnrs-gif.fr
Received J uly 18, 2003
connection with the search for new ligands of the exci-
tatory amino acid receptors of the central nervous
system.6f-h However, the preparation of these bicyclic
aziridines starting from pentoses required 13 steps. Such
a strategy was not compatible with structure-activity
studies or its application to the total synthesis of natural
products. We therefore recently devised a much shorter
synthesis of 2,3-aziridino-γ-lactones, thereby circumvent-
ing this problem.7 In three steps starting from D-ribono-
lactone 1, the key intermediate 3 could be obtained
stereoselectively via 1,4-addition of benzylamine to tri-
flate 2 with an overall yield of 43% (Scheme 1).
With this methodology in hand, its initial application
to the total synthesis of polyoxamic acid 4 was envisaged.
The latter is a structural constituent of polyoxins, a class
of peptidyl-nucleoside antifungal antibiotics.8 Numerous
studies have been dedicated to the synthesis of polyox-
amic acid, most of them based on use of the chiral pool.9
The non-natural enantiomer of 4 has also been prepared
in the same enantiospecific manner.10 According to our
strategy, synthesis of natural (+)-polyoxamic acid re-
quired use of L-sugars and notably L-ribonolactone for
construction of the stereochemically appropriate 2,3-
Abstr a ct: The non-natural enantiomer of polyoxamic acid
was synthesized in six steps from 2,3-aziridino-γ-lactone 7
with an overall yield of 10%. The key step of the strategy is
a deprotection-protection sequence on the nitrogen atom of
the aziridine ring required for aziridine activation toward
nucleophilic ring opening.
Aziridines are highly useful intermediates for the
preparation of nitrogen-containing compounds. Their
value is reflected by the numerous studies that have been
and are still conducted to optimize their preparation and
behavior and to enhance the scope of their applications
in the total synthesis of natural and/or biologically active
products.1-3 Among the large variety of substituted
aziridines described, aziridine 2-carboxylates hold a
prominent place as precursors of R- and â-amino acids.4
Good regiocontrol of nucleophilic ring opening of these
species can generally be achieved allowing isolation of
the desired substituted amino acid.1b,5
By analogy with aziridine 2-carboxylates, 2,3-aziridino-
γ-lactones have been shown by us to be versatile precur-
sors for the preparation of optically pure polysubstituted
amino acids.5,6 A first application of our methodology was
the total synthesis of 3,4-disubstituted glutamic acids in
(6) (a) Dubois, L.; Dodd, R. H. Tetrahedron 1993, 49, 901-910. (b)
Dubois, L.; Mehta, A.; Tourette, E.; Dodd, R. H. J . Org. Chem.. 1994,
59, 434-441. (c) Dauban, P.; Chiaroni, A.; Riche, C.; Dodd, R. H. J .
Org. Chem. 1996, 61, 2488-2496. (d) Dauban, P.; Dodd, R. H. J . Org.
Chem. 1997, 62, 4277-4284. (e) Dauban, P.; Hofmann, B.; Dodd, R.
H. Tetrahedron 1997, 53, 10743-10752. (f) Dauban, P.; De Saint-
Fuscien, C.; Dodd, R. H. Tetrahedron 1999, 55, 7589-7600. (g) Dauban,
P.; De Saint-Fuscien, C.; Acher, F.; Pre´zeau, L.; Brabet, I.; Pin, J .-P.;
Dodd, R. H. Bioorg. Med. Chem. Lett. 2000, 10, 129-133. (h) Yan, Z.;
Weaving, R.; Dauban, P.; Dodd, R. H. Tetrahedron Lett. 2002, 43,
7593-7595.
(1) For recent reviews, see: (a) Sweeney, J . B. Chem. Soc. Rev. 2002,
31, 247-258. (b) McCoull, W.; Davis, F. A. Synthesis 2000, 1347-1365.
(c) Stamm, H. J . Prakt. Chem. 1999, 341, 319-331.
(2) For selected recent studies, see: (a) Watson, I. D. G.; Yudin, A.
K. J . Org. Chem. 2003, 68, 5160-5167. (b) Sweeney, J . B.; Cantrill, A.
A. Tetrahedron 2003, 59, 3677-3690. (c) Cossy, J .; Bellosta, V.; Alauze,
V.; Desmurs, J . R. Synthesis 2002, 2211-2214. (d) Hou, X. L.; Fan, R.
H.; Dai, L. X. J . Org. Chem. 2002, 67, 5295-5300. (e) Hu, X. E.
Tetrahedron Lett. 2002, 43, 5315-5318.
(3) For selected recent applications, see: (a) Hedley, S. J .; Moran,
W. J .; Price, D. A.; Harrity, J . P. A. J . Org. Chem. 2003, 68, 4286-
4292. (b) Song, Z. L.; Wang, B. M.; Tu, Y. Q.; Fan, C. A.; Zhang, S. Y.
Org. Lett. 2003, 5, 2319-2321. (c) Xiong, C.; Wang, W.; Hruby, V. J .
J . Org. Chem. 2002, 67, 3514-3517. (d) Lapinsky, D. J .; Bergmeier,
S. C. Tetrahedron 2002, 58, 7109-7117. (e) Andrews, D. R.; Daha-
nukar, V. H.; Eckert, J . M.; Gala, D.; Lucas, B. S.; Schumacher, D. P.;
Zavialov, I. A. Tetrahedron Lett. 2002, 43, 6121-6125. (f) Lopez, O.
L.; Ferna´ndez-Bolan˜os, J . G.; Lillelund, V. H.; Bols, M. Org. Biomol.
Chem. 2003, 1, 478-482. (g) Vedejs, E.; Little, J . J . Am. Chem. Soc.
2002, 124, 748-749.
(7) De Saint-Fuscien, C.; Tarrade, A.; Dauban, P.; Dodd, R. H.
Tetrahedron Lett. 2000, 41, 6393-6397.
(8) Isono, K.; Asahi, K.; Suzuki, S. J . Am. Chem. Soc. 1969, 91,
7490-7505.
(9) (a) Kuzuhara, H.; Emoto, S. Tetrahedron Lett. 1973, 5051-5054.
(b) Saksena, A. K.; Lovey, R. G.; Girijavallabhan, V. M.; Ganguly, A.
K. J . Org. Chem. 1986, 51, 5024-5028. (c) Hirama, M.; Hioki, H.; Ito,
S. Tetrahedron Lett. 1988, 29, 3125-3128. (d) Garner, P.; Park, J . M.
J . Org. Chem. 1988, 53, 2979-2984. (e) Dure´ault, A.; Carreaux, F.;
Depezay, J .-C. Tetrahedron Lett. 1989, 30, 4527-4530. (f) Paz, M.;
Sardina, F. J . Org. Chem. 1993, 58, 6990-6995. (g) Dondoni, A.;
Franco, S.; Merchan, F. L.; Merino, P.; Tejero, T. Tetrahedron Lett.
1993, 34, 5479-5482. (h) Marshall, J . A.; Seletsky, B. M.; Coan, P. S.
J . Org. Chem. 1994, 59, 5139-5140. (i) Matsura, F.; Hamada, Y.;
Shioiri, T. Tetrahedron Lett. 1994, 35, 733-736. (j) J ackson, R. F.;
Palmer, N. J .; Wyther, M. J .; Clegg, W.; Elsegood, M. J . Org. Chem.
1995, 60, 6431-6440. (k) Kang, S. H.; Choi, H. Chem. Commun. 1996,
1521-1522. (l) Veeresa, G.; Datta, A. Tetrahedron Lett. 1998, 39, 119-
122. (m) Savage, I.; Thomas, E. J .; Wilson, P. D. J . Chem. Soc., Perkin
Trans. 1 1999, 3291-3303. (n) Davis, F. A.; Prasad, K. R.; Carroll, P.
J . J . Org. Chem. 2002, 67, 7802-7806. (o) For an enantioselective
synthesis of (+)-polyoxamic acid, see: Trost, B.; Krueger, A.; Bunt, R.
C.; Zombrano, J . J . Am. Chem. Soc. 1996, 118, 6520-6521.
(4) For selected recent studies, see: (a) Yadav, J . S.; Reddy, B. V.
S.; Shesha Rao, M.; Reddy, P. N. Tetrahedron Lett. 2003, 44, 5275-
5278. (b) Davis, F. A.; Deng, J .; Zhang, Y.; Haltiwanger, R. C.
Tetrahedron 2002, 58, 7135-7143. (c) Tranchant, M.-J .; Dalla, V.;
J abin, I.; Decroix, B. Tetrahedron Lett. 2002, 58, 8425-8432 and
references therein. (d) Atkinson, R. S.; Draycott, R. D.; Hirst, D. J .;
Parratt, M. J .; Raynham, T. M. Tetrahedron Lett. 2002, 43, 2083-
2085. (e) Zwanenburg, B.; ten Holte, P. Top. Curr. Chem 2001, 216,
93-124.
(5) Dauban, P.; Dubois, L.; Tran Huu Dau, M. E.; Dodd R. H. J .
Org. Chem. 1995, 60, 2035-2043 and references therein.
10.1021/jo035039b CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/06/2003
J . Org. Chem. 2003, 68, 9521-9524
9521

of a chloroformate-mediated dealkylation reaction of the
tertiary amine12 unfortunately led to aziridine ring
opening by chloride ion,13 which could not be further
exploited.14
In view of these results, other primary amines were
considered for the preparation of suitably N-protected
2,3-aziridino-γ-lactones. We thus turned our attention to
methoxy-substituted benzylamines. Such electron-rich
nitrogen sources should display a higher reactivity in the
tandem Michael-type addition/cyclization leading to the
aziridine. Moreover, we presumed that their cleavage
under oxidative conditions by use of 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone (DDQ) or ceric ammonium
nitrate (CAN) would be compatible with the aziridine
ring.
F IGURE 1. Retrosynthetic analysis of (-)-polyoxamic acid.
SCHEME 2
Preliminary experiments with p-methoxybenzylamine
confirmed our assumptions to some extent, though more
satisfactory results were obtained by use of the more
reactive 3,4-dimethoxybenzyl (DMB) moiety. Thus, regi-
oselective silylation of compound 1 followed by treatment
of the resulting diol 5 with triflic anhydride under basic
conditions led to the moderately stable monotriflate 6
(Scheme 3). The latter reacted with 3,4-dimethoxyben-
zylamine to afford compound 7 as a white solid in 35%
overall yield from 1. As previously observed and indicated
1
by H and 13C NMR spectra,7 the formation of aziridine
7 is diastereoselective as a result of a Michael-type
addition of 3,4-dimethoxybenzylamine to the face opposite
to that of the bulky silyl group at C-5. Careful control of
the reaction conditions, i.e., dropwise addition of the
amine followed by 30 min of stirring at -60 °C in DMF,
appeared crucial to prevent concomitant lactone ring
opening. Subsequent removal of the DMB moiety was
then efficiently carried out with DDQ in a 10:1 mixture
of dichloromethane and water. The resulting N-depro-
tected aziridine was not isolated but was immediately
reacted with benzyl chloroformate to afford the N-Cbz
derivative 8 in an overall yield of 78%.15
We have previously demonstrated that, in the presence
of boron trifluoride etherate, ring opening of 2,3-aziridino-
γ-lactones by alcohols occurs regioselectively at C-3.5 In
the context of the present synthesis, we first attempted
to open the aziridine ring of 8 with benzyl alcohol.
Unexpectedly, however, no reaction was observed.16 In
contrast, use of allyl alcohol resulted in formation of allyl
ether 9 in an acceptable yield of 53%. Subsequent
removal of the allyl group then proved troublesome. After
several experiments, it was found that use of selenium
dioxide in the presence of acetic acid in dioxane17 cleanly
afforded the hydroxy derivative 10 in 60% yield. Finally,
sequential removal of the silyl and the Cbz groups
provided, after purification on a basic anion exchange
column (AG1-X4), (-)-polyoxamic acid 4. The optical
aziridino-γ-lactone. Thus, given the poor availability of
such derivatives, we turned our attention for reasons of
convenience to (-)-polyoxamic acid, whose retrosynthetic
analysis is described in Figure 1.
Before attempting this synthesis, selection of the
appropriate protecting groups ensuring efficient ring
opening of the 2,3-aziridino-γ-lactone moiety was re-
quired. The 5-O-trityl group of compound 3 was presumed
not to be stable enough to survive the acidic and thermal
conditions generally necessary for aziridine ring opening
by an alcohol. We therefore chose to protect the 5-O
position with a bulky tert-butyldiphenylsilyl group, which
like the trityl group can be selectively introduced at the
primary alcohol position. Initial experiments also re-
vealed that the N-benzyl protecting group of 3 was not
suitable for clean nucleophilic aziridine ring opening
(Scheme 2). Several conditions have been described for
the opening of N-alkyl aziridines,11 but all failed when
applied to N-benzyl-2,3-aziridino-γ-lactones. This lack of
reactivity was attributed to the poor electron-withdraw-
ing character of the benzyl group and the competitive
reactivity of the lactone function. N-Deprotection thus
became necessary in order to install a more activating
function but all attempts to do so (reductive debenzyla-
tion with hydrogen, ammonium formate, or sodium
naphthalenide) were unsuccessful. Similarly, application
(12) Cooley, J . H.; Evain, E. J . Synthesis 1989, 1-7.
(13) For a similar observation, see: Ennis, D. S.; Ince, J .; Rahman,
S.; Shipman, M. J . Chem. Soc., Perkin Trans. 1 2000, 2047-2053.
(14) Chuang, T.-H.; Sharpless, K. B. Org. Lett. 2000, 2, 3555-3557.
(15) The Cbz group was chosen for its ease of deprotection. The
N-(acetyl), N-(tert-butyloxycarbonyl) and N-(tosyl) analogues of com-
pound 8 could also be obtained under the same conditions with a yield
of 80%, 85%, and 83%, respectively.
(10) (a) Bose, A. K.; Banik, B. K.; Mathur, C.; Wagle, D. R.; Manhas,
M. S. Tetrahedron 2000, 56, 5603-5619. (b) Harwood: L.; Robertson,
S. Chem. Commun. 1998, 2641-2642.
(11) (a) Meguro, M.; Yamamoto, Y. Heterocycles 1996, 43, 2473-
2482. (b) Katagiri, T.; Takahashi, M.; Fujiwara, Y.; Ihara, H.; Un-
eyama, K. J . Org. Chem. 1999, 64, 7323-7329. (c) Davoli, P.; Forni,
A.; Franciosi, C.; Moretti, I.; Prati, F. Tetrahedron: Asymmetry 1999,
10, 2361-2371. (d) Park, C. S.; Choi, H. G.; Lee, H.; Lee, W. K.; Ha,
H.-J . Tetrahedron: Asymmetry 2000, 11, 3283-3292. (e) For recent
improvements in the opening of N-alkyl aziridines, see: ref 2a,c,d.
(16) In the case of compound 8, the steric bulk of the silyl group
could explain the lack of reactivity of the aziridine towards benzyl
alcohol.
(17) Kariyone, K.; Yazawa, H. Tetrahedron Lett. 1970, 2885-2888.
9522 J . Org. Chem., Vol. 68, No. 24, 2003

SCHEME 3. Syn th esis of (-)-P olyoxa m ic Acid 4
rotation of the latter, i.e. [R]21D -2.4 (c 0.52, H2O), showed
good agreement with those reported in the literature for
(-)-4 ([R]24 -2.5 (c 1.0, H2O))10b and (+)-4 ([R]23 +2.8
at -78 °C under argon were successively added pyridine (3.5
mL, 5.0 equiv) and solution of trifluoromethanesulfonic
a
anhydride (4.2 mL, 2.7 equiv) in dichloromethane (30 mL). After
15 min of stirring at -78 °C, the reaction mixture was slowly
warmed to -25 °C over a period of 3 h. The reaction solution
was then poured into cold diethyl ether (110 mL). The precipitate
was filtered, and the filtrate was evaporated under reduced
pressure at 0 °C. The resulting residue was purified by flash
chromatography on silica gel (heptane/ethyl acetate 2:1) to afford
compound 6 (3.55 g, 7.1 mmol, 78%) as a yellow oil. 1H NMR
(CDCl3, 300 MHz) δ 0.98 (s, 9H), 3.84 (ddd, 2H, J ) 11.5, 4.5,
3.8 Hz), 4.98 (td, 1H, J ) 4.1, 1.8 Hz), 7.03 (d, 1H, J ) 1.9 Hz),
7.2-7.6 (m, 10H); 13C NMR (CDCl3, 75 MHz) δ 22.7, 26.6, 62.7,
88.1, 121.0, 128.0, 128.3, 130.2, 132.0, 132.2, 135.5, 135.7, 138.0,
163.6; IR (film) ν 3073, 2934, 2861, 1792, 1656, 1433, 1221, 1137,
1104, 703 cm-1; ESMS m/z 539 [M + K+], 523 [M + Na+], 501
[M + H+]. HRESMS m/z calcd for C22H23F3O6SSi 523.0834 [M
+ Na+], found 523.0823.
D
D
(c 1.0, H2O)).8
In conclusion, an enantiospecific synthesis of (-)-
polyoxamic acid was accomplished from 2,3-aziridino-γ-
lactone 7 in six steps with an overall yield of 10%. A
notable feature of the strategy is a sequence of depro-
tection-protection reactions applied to compound 7 that
occurred in 78% yield without aziridine ring opening. It
allowed the replacement of an N-dimethoxybenzyl group
by a more activating electron-withdrawing moiety, in this
case a carbobenzyloxy group. This methodology is now
being applied to the preparation of unusual natural
amino acids and particularly of R-substituted â-amino
acids accessible from 2,3-aziridino-γ-lactones by reaction
with soft nucleophiles.5
(1R,4S,5S)-4-(ter t-Bu tyld ip h en ylsilyloxym eth yl)-N-(3′,4′-
d im eth oxyben zyl)-3-oxa -6-a za bicyclo[3.1.0]h exa n -2-on e, 7.
To a solution of compound 6 (3.55 g, 7.1 mmol) in DMF (35 mL)
held at -60 °C under argon was added dropwise 3,4-dimethoxy-
benzylamine (1.6 mL, 1.5 equiv). The reaction mixture was
stirred for 30 min at -60 °C before being diluted with ethyl
acetate (40 mL) and water (40 mL). The layers were separated,
and the aqueous phase was extracted with ethyl acetate (2 ×
30 mL). The combined organic extracts were dried over magne-
sium sulfate and evaporated to dryness. The resulting oily
residue was purified by flash chromatography on silica gel
(heptane/ethyl acetate 2:1). The aziridine-γ-lactone 7 (2.35 g, 4.5
Exp er im en ta l Section
5-O-(ter t-Bu tyld ip h en ylsilyl)-D-r ibon o-γ-la cton e, 5. To a
solution of D-ribonolactone 1 (4 g, 0.027 mol) in DMF (27 mL)
held at 0 °C under argon, were successively added imidazole
(4.04 g, 2.2 equiv) and tert-butyldiphenylsilyl chloride (7.6 mL,
1.1 equiv). After 30 min of stirring at 0 °C, the mixture was
warmed to room temperature and stirred for an additional 30
min. The reaction solution was diluted with ethyl acetate (35
mL) and water (35 mL). The layers were separated, and the
aqueous phase was extracted with ethyl acetate (2 × 30 mL).
The organic extracts were combined, washed with water (2 ×
30 mL), dried over magnesium sulfate, and evaporated to
dryness. The resulting residue was purified by flash chroma-
tography on silica gel (heptane/ethyl acetate 2:1) to afford
compound 5 (7.3 g, 0.0189 mol, 70%) as a white solid. Selected
data: mp 69.5-71 °C (lit.18 65-70 °C); [R]21D +43 (c 1.35, CHCl3)
(lit.18 [R]21D +46.3 (c 0.84, CHCl3));1H NMR (CDCl3, 300 MHz) δ
0.99 (s, 9H), 3.81 (m, 2H), 4.05 (broad s, 1H), 4.52 (m, 2H), 4.88
(broad d, 1H), 7.2-7.6 (m, 10H); 13C NMR (CDCl3, 75 MHz) δ
19.2, 26.5, 63.4, 69.4, 70.3, 85.6, 128.1, 130.2, 131.8, 132.2, 135.5,
mmol, 64%) was isolated as a viscous oil that crystallized on
1
standing. Mp 46-47 °C; [R]21 +15 (c 1.075, CH2Cl2); H NMR
D
(CDCl3, 300 MHz) δ 0.97 (s, 9H), 2.71 (AB syst, 2H, J ) 4.3 Hz),
3.43 (AB syst, 2H, J ) 13.4 Hz), 3.78 (dd, 2H, J ) 11.4, 2.9 Hz),
3.93 (s, 6H), 3.93 (dd, 1H, J ) 11.4, 3.9 Hz), 4.37 (m, 1H), 6.76-
7.64 (m, 13H); 13C NMR (CDCl3, 75 MHz) δ 19.1, 26.7, 39.9, 44.2,
55.9, 60.9, 63.5, 80.2, 111.1, 120.1, 127.9, 129.7, 130.8, 132.8,
135.5, 149.1, 172.0; IR (film) ν 3071, 2933, 1781, 1516, 1113,
704 cm-1; EIMS m/z 517 [M + H - TBDPS+]. Anal. Calcd for
C30H35NO5Si: C, 69.60; H, 6.81; N, 2.71. Found: C, 69.12; H, 6.87;
N, 2.51.
(1R,4S,5S)-N-(Ben zyloxyca r bon yl)-4-(ter t-bu tyld ip h en -
ylsilyloxym eth yl)-3-oxa -6-a za bicyclo[3.1.0]h exa n -2-on e, 8.
A solution of compound 7 (1.7 g, 3.3 mmol) and DDQ (0.75 g,
1.0 equiv) in a 10:1 mixture of dichloromethane and water (36.3
mL) was stirred for 24 h at room temperature. Pyridine (4 mL,
15 equiv), benzyl chloroformate (0.95 mL, 2.0 equiv), and DMAP
(81 mg, 0.1 equiv) were then successively added, and the mixture
was stirred for 2 h at room temperature. At the end of the
135.6, 176.8; IR (film) ν 3362, 1782, 1427, 1178, 1113, 701 cm-1
.
(5R)-[5-(ter t-Bu tyld ip h en ylsilyloxym eth yl)-2-(5H)-fu r a -
n on -3-yl]tr iflu or om eth a n esu lfon a te, 6. To a solution of
compound 5 (3.5 g, 9.1 mmol) in dichloromethane (85 mL) held
(18) Attwood, S. V.; Barrett, A. G. M. J . Chem. Soc., Perkin Trans.
1 1984, 1315-1322.
J . Org. Chem, Vol. 68, No. 24, 2003 9523

reaction period, dichloromethane (10 mL) was added followed
by 10% aqueous HCl (20 mL). The aqueous layer was separated,
and the organic phase was successively washed with 10%
aqueous HCl (30 mL), saturated aqueous NaHCO3 solution (30
mL), and water (30 mL) before being dried over magnesium
sulfate and evaporated to dryness. The resulting residue was
purified by flash chromatography on silica gel (heptane/ethyl
acetate 4:1) to give aziridine-γ-lactone 8 (1.29 g, 2.57 mmol, 78%)
1045, 702 cm-1; EIMS m/z 558 [M + K+], 542 [M + Na+].
HRESMS m/z calcd for C29H33NO6Si 542.1975 [M + Na+], found
542.1978.
2-N-(Ben zyloxyca r b on yl)a m in o-2-d eoxy-D-xylon o-1,4-
la cton e, 11. To a solution of compound 10 (289 mg, 0.56 mmol)
and acetic acid (32 µL, 1.0 equiv) in THF (1.6 mL) held at -60
°C under argon was added a 1 M solution of tetrabutylammo-
nium fluoride in THF (0.56 mL, 1.0 equiv). After 30 min of
stirring at -60 °C, the reaction mixture was gradually allowed
to come to room temperature over 2 h. It was then diluted with
ethyl acetate (10 mL) and washed with water (2 × 10 mL). The
organic phase was dried over magnesium sulfate and evaporated
to dryness. The resulting oily residue was purified by flash
chromatography on silica gel (heptane/ethyl acetate 1:2 then 1:4)
to afford compound 11 (96 mg, 0.34 mmol, 61%) as a white solid.
as a colorless oil. [R]21 -2 (c 1.5, CHCl3); 1H NMR (CDCl3, 300
D
MHz) δ 0.97 (s, 9H), 3.45 (AB syst, 2H, J ) 3.0 Hz), 3.71 (dd,
1H, J ) 11.8, 1.8 Hz), 3.93 (dd, 1H, J ) 11.8, 2.7 Hz), 4.62 (m,
1H), 5.10 (AB syst, 2H, J ) 11.9 Hz), 7.2-7.7 (m, 15H); 13C NMR
(CDCl3, 75 MHz) δ 19.2, 26.7, 37.9, 42.3, 63.5, 69.3, 128.1, 128.5,
128.7, 130.2, 131.9, 132.5, 134.8, 135.5, 135.7, 158.5, 168.9; IR
(film) ν 3070, 2930, 1792, 1734, 1112, 701 cm-1; EIMS m/z 540
[M + K+], 524 [M + Na+], 502 [M + H +]. Anal. Calcd for
Mp 101-103 °C; [R]21 +73 (c 1.00, EtOH); 1H NMR (MeOD,
D
C
29H31NO5Si: C, 69.43; H, 6.23; N, 2.79. Found: C, 69.12; H, 6.14;
N, 2.59.
3-O-Allyl-2-N-(ben zyloxyca r bon yl)a m in o-5-O-(ter t-bu tyl-
300 MHz) δ 3.89 (ABX syst, 2H, J ) 12.6, 2.5, 2.3 Hz), 4.44 (d,
1H, J ) 8.9 Hz), 4.52 (dd, 1H, J ) 7.8, 2.1 Hz), 4.66 (t, 1H, J )
8.3 Hz), 5.10 (d, 2H), 7.26-7.48 (m, 5H); 13C NMR (MeOD, 75
MHz) δ 58.7, 60.6, 67.8, 72.6, 81.5, 128.9, 129.1, 129.5, 138.0,
158.1, 175.4; IR (film) ν 3500-3300, 2953, 1779, 1700, 1532,
1428, 1278, 1034 cm-1; EIMS m/z 320 [M + K+], 304 [M + Na+].
Anal. Calcd for C13H15NO6: C, 55.51; H, 5.38; N, 4.98; O, 34.13.
Found: C, 55.81; H, 5.46; N, 4.86; O, 33.91.
d ip h en ylsilyl)-2-d eoxy-D-xylon o-1,4-la cton e, 9. Boron trif-
luoride etherate (66 µL, 2.0 equiv) was added to a solution of
compound 8 (130 mg, 0.26 mmol) in a mixture of allyl alcohol
(0.6 mL) and chloroform (1.5 mL) held at 0 °C under argon. The
reaction mixture was stirred for 20 h at 50 °C. At the end of the
reaction period, ethyl acetate (10 mL) was added followed by
saturated aqueous NaHCO3 solution (10 mL). The aqueous layer
was separated and extracted with ethyl acetate (2 × 5 mL). The
combined organic extracts were dried over magnesium sulfate
and evaporated to dryness. The resulting oily residue was
purified by flash chromatography on silica gel (heptane/ethyl
acetate 5:1) to give compound 9 (77 mg, 0.14 mmol, 53%) as a
(-)-P olyoxa m ic Acid , (-)-4. A solution of compound 11 (66
mg, 0.24 mmol) in a 5:1 mixture of methanol and water (2.6 mL)
was stirred at room temperature for 1 h under an atmosphere
of hydrogen in the presence of a catalytic quantity of 10%
palladium on charcoal (28 mg). The catalyst was then removed
by filtration through Celite, and the solvents were evaporated
under reduced pressure. The residue was purified by ion-
exchange chromatography as follows: AG1-X4 resin (700 mg,
OH- form) was placed in a cotton-plugged pasteur pipet and
washed successively with a 1 N solution of acetic acid (10 mL)
and water until neutral pH (∼20 mL). A solution of the crude
reaction mixture in water (10 mL) was brought to pH 9 by
addition of 1 M NaOH and then applied to the resin. The column
was first eluted with water until neutrality and then successively
with 0.2 M (10 mL), 0.3 M (10 mL), 0.4 M (10 mL), and 0.5 M
(10 mL) aqueous acetic acid. The combined ninhydrin-positive
fractions were evaporated under reduced pressure, and the
colorless solid residue was lyophilized for 24 h, affording
compound (-)-4 (26 mg, 0.26 mmol, 67%) as a white solid. Mp
151-153 °C (lit.10a 165-172 °C); [R]21D -2.4 (c 0.52, H2O) (lit.10b
colorless oil. [R]21 +40 (c 1.03, CHCl3); 1H NMR (CDCl3, 400
D
MHz) δ 0.99 (s, 9H), 3.88 (AB syst, 2H, J ) 11.5 Hz), 4.12 (m,
1H), 4.59 (m, 1H), 4.75 (m, 1H), 5.06 (s, 2H), 5.02-5.20 (m, 3H),
5.86 (m, 1H), 7.28-7.75 (m, 15H); 13C NMR (CDCl3, 75 MHz) δ
19.4, 26.8, 57.1, 61.7, 67.8, 71.9, 72.5, 78.7, 118.4, 128.1, 128.5,
128.6, 128.9, 129.0, 130.3, 134.2, 136.1, 136.3, 156.7, 172.6; IR
(film) ν 3339, 2929, 1791, 1724, 1527, 1427, 1111, 702 cm-1
;
EIMS m/z 598 [M + K+], 582 [M + Na+]. Anal. Calcd for
32H37NO6Si: C, 68.67; H, 6.66; N, 2.50. Found: C, 68.35; H, 6.79;
N, 1.91.
2-N-(Ben zyloxyca r bon yl)a m in o-5-O-(ter t-bu tyld ip h en yl-
C
silyl)-2-d eoxy-D-xylon o-1,4-la cton e, 10. To a solution of allyl
ether 9 (630 mg, 1.13 mmol) in 1,4-dioxane (8 mL) were added
selenium dioxide (138 mg, 1.1 equiv) and acetic acid (97 µL, 1.5
equiv). The reaction mixture was heated under reflux for 3 h.
At the end of the reaction period, the residual salts were filtered
off and washed with ethyl acetate. The filtrate and washings
were evaporated to dryness, and the resulting oily residue was
purified by flash chromatography on silica gel (heptane/ethyl
acetate 4:1) to give compound 10 (350 mg, 0.67 mmol, 60%) as
a slightly colored solid. Mp 47-49 °C; [R]21D +36 (c 1.00, CHCl3);
1H NMR (CDCl3, 300 MHz) δ 0.95 (s, 9H), 3.82 (dd, 1H, J )
11.7, 2.4 Hz), 4.03 (d, 1H, J ) 11.7 Hz), 4.58 (m, 1H), 4.71 (dd,
1H, J ) 8.2, 2.5 Hz), 5.10 (s, 2H), 5.54 (s, 1H), 7.32-7.85 (m,
15H); 13C NMR (CDCl3, 75 MHz) δ 19.0, 26.8, 58.0, 60.9, 67.8,
74.9, 79.6, 127.9, 128.2, 128.5, 128.7, 129.9, 135.6, 157.8, 172.3;
IR (film) ν 3409, 3342, 2929, 2857, 1778, 1705, 1525, 1428, 1112,
[R]24 -2.5 (c 1.0, H2O)); 13C NMR (D2O, 75 MHz) δ 58.3, 62.8,
D
68.4, 73.5, 173.0 (lit.9j 13C NMR (D2O, 75 MHz) δ 60.3, 64.7, 70.4,
75.4, 175.0); EIMS m/z 204 [M + K+], 188 [M + Na+], 166 [M +
H+].
Ack n ow led gm en t. We thank the MENRT for a
fellowship (A.T.).
Su p p or tin g In for m a tion Ava ila ble: General experimen-
1
tal procedures, H NMR spectra of compounds 6-11, and 13C
NMR spectrum of compound (-)-4. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O035039B
9524 J . Org. Chem., Vol. 68, No. 24, 2003