Oxetane δ-amino acids: Chemoenzymatic synthesis of 2,4-anhydro-5-N-(t-butoxycarbonyl)amino-D-lyxonic acid

Article abstract of DOI:10.1080/07328300600732485

Starting from 1,2-O-isopropylidene-D-xylose, methyl 2,4-anhydro-3,5-di-O- benzyl-D-lyxonate (4) was synthesized. Debenzylation and transformation of the primary hydroxyl group yielded methyl 2,4-anhydro-5- N-(t-butoxycarbonyl)amino- D-lyxonate (9). While

Full text of DOI:10.1080/07328300600732485

Journal of Carbohydrate Chemistry, 25:187–196, 2006
Copyright # Taylor & Francis Group, LLC
ISSN: 0732-8303 print 1532-2327 online
DOI: 10.1080/07328300600732485
Oxetane d-Amino Acids:
Chemoenzymatic Synthesis
of 2,4-Anhydro-5-N-
(t-butoxycarbonyl)amino-D-
lyxonic Acid
´
Susana Dias Lucas, Hans Iding, Andre Alker, and
Hans Peter Wessel
F. Hoffmann-La Roche Ltd., Pharmaceutical Research, Basel, Switzerland
´
Amelia Pilar Rauter
ˆ
´
´
Departamento de Quımica e Bioquımica, Faculdade de Ciencias da Universidade de
Lisboa, Campo Grande, Lisboa, Portugal
Starting from 1,2-O-isopropylidene-D-xylose, methyl 2,4-anhydro-3,5-di-O-benzyl-D-
lyxonate (4) was synthesized. Debenzylation and transformation of the primary
hydroxyl group yielded methyl 2,4-anhydro-5-N-(t-butoxycarbonyl)amino-D-lyxonate
(9). While transesterification of 4 under basic reaction conditions was straightforward,
an analogous reaction with 9 was not successful. After screening of several lipases, the
enzymatic transesterification of 9 was achieved with lipase L2 from Candida antarctica
to furnish the title compound 2,4-anhydro-5-N-(t-butoxycarbonyl)amino-D-lyxonic acid
in excellent yield. The stereochemistry at the oxetane ring was proven by an x-ray struc-
ture of the intermediate methyl 2,4-anhydro-5-azido-D-lyxonate.
Keywords Carbohydrate amino acids, d-Amino acids, Oxetanes, Carbohydrate scaf-
folds, Enzymatic hydrolysis
Received November 24, 2005; accepted January 7, 2006.
Address correspondence to Hans Peter Wessel, F. Hoffmann-La Roche Ltd., Pharma-
ceutical Research, Discovery Chemistry, Bldg. 92/7.92, Basel CH-4070, Switzerland.
E-mail: hans_p.wessel@roche.com
187

S. D. Lucas et al.
188
INTRODUCTION
Carbohydrate amino acids (CAAs) are interesting building blocks that have
been employed as rigid templates to induce specific conformations in peptide
mimetics[1] or to synthesize oligomeric carbohydrate-peptide hybrids.[2]
Moreover, they are useful scaffolds for parallel chemistry approaches.[3]
While there is ample precedence for pyranose and furanose scaffolds, there
are no reports on oxetane-based libraries. The four-membered ring has little
flexibility, and thus well-defined exit vectors that may orient substituents
into specific locations in space. Oxetane derivatives as shown in Scheme 1
are conformationally restricted d-amino acids with three different functional
groups for further extension. Strategically, we targeted the free carboxylic
acid to allow the coupling of the building blocks to a solid-phase carrier using
standard methodology.
Here we describe the synthesis of the D-lyxo configured CAA and in particu-
lar address the problem to prepare the free carboxylic acid by employing a
chemoenzymatic approach.
RESULTS AND DISCUSSION
Starting from commercial 1,2-O-isopropylidene-D-xylose, 3,5-di-O-benzyl-D-
xylose (1)[4] was prepared in a well-established benzylation/deisopropylidena-
tion sequence. For the acetal cleavage the use of 30% acetic acid gave the best
results, conditions that had been employed in the arabino series.[5] Oxidation of
1 with bromine furnished the known[6] 3,5-di-O-benzyl-D-xylono-g-lactone (2).
It was important to carry out this reaction in the dark to avoid radical-
mediated debenzylation. By optimizing the water/dioxane ratio, the yield
could be improved to reach 73%. Triflation of 2 furnished lactone 3, which
was subjected to treatment with potassium carbonate in methanol leading to
ring contraction and formation of the oxetane carboxylic acid ester 4 as
described by Witty et al.[6] At this stage we tested whether ester cleavage of
the oxetane carboxylic ester was feasible. Indeed, treatment of ester 4 with
lithium hydroxide gave the free carboxylic acid 6[7] in a clean reaction and in
excellent yield.
Scheme 1: Carbohydrate-derived oxetane d-amino acids.

Synthesis of an Oxetane d-Amino Acid
189
Palladium-catalyzed hydrogenation of 4 yielded the debenzylated oxetane
derivative 5. For this central intermediate an alternative synthetic approach
via 3,5-di-O-benzylidene-D-xylono-g-lactone was described recently.[8] For the
activation of the primary hydroxyl group we reacted 5 with triflic anhydride
in diethyl ether/dichloromethane in the presence of dry molecular sieves;
this methodology[9] allows triflation under nonbasic reaction conditions plus
facile and mild work-up. Best results were obtained in this case when the
reaction mixture was concentrated in the presence of molecular sieves. The
triflate 7 was obtained in pure form as judged by TLC, and the residue was
reacted without further purification. Crude 7 was then reacted with lithium
azide in acetone to furnish azide 8 in 65% yield over the two steps (Scheme 2).
The ring contraction of D-g-xylono-lactones had been described to result in
D-lyxo configurated oxetanes.[6] The observation of long-range coupling con-
stants in the resulting derivatives 4 (J2,4 ¼ 0.4 Hz) and 6 (J2,4 ¼ 0.8 Hz) did
not seem to be in keeping with this configuration as [4]J coupling constants
in sterically fixed systems are usually indicative of a W-configuration.[10]
[4]
Thus, with the observation of a
J
longe-range coupling, both protons H-2
2,4
and H-4 might be expected to be on the same side of the oxetane ring. There-
fore, the crystalline azide 8 was subjected to X-ray crystallographic
Scheme 2: i) NaH, DMF, rt, 2.5 h, BnBr, 2.5 h; AcOH 30%, reflux, 3 h, 88%; ii) Br2, BaCO3, H2O/
dioxane 2:1, rt, 4 h, 73%; iii) Tf2O, CH2Cl2, pyridine, 2178C, 40 min; iv) K2CO3, MeOH, 2128C,
30 min, 90%; v) H2, Pd/C, MeOH/dioxane, rt, 40 min, 85%; vi) 1 N LiOH, THF, 0–58C, 30 min,
˚
quant.; vii) Tf2O, Et2O/CH2Cl2 5:1, 4 A molecular sieves, 2158C, 50 min; viii) LiN3, acetone, rt,
30 min, 65%; ix) H2, Pd/C, EtOAc, Boc2O, rt, 2 h, 88%; x) L2- Candida antarctica, tBuOMe/H2O,
458C, 3 d, 95%.

S. D. Lucas et al.
190
investigation, (Unit cell parameters: a 7.2699(15) b 21.683(4) c 5.5554(11),
space group P212121. The crystal structure has been deposited at the Cam-
bridge Crystallographic Data Centre and was allocated the deposition
number CCDC 289842. CCDC 289842 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, by emailing data_request@ccdc.cam.a-
c.uk, or by contacting The Cambridge Crystallographic Data Centre, 12,
Union Road, Cambridge CB2 1EZ, UK; fax: þ44 1223 336033.) which clearly
showed the D-lyxo configuration with the protons H-2 and H-4 on opposite
faces of the oxetane ring (Fig. 1). While the oxetane ring has a relative high
pucker angle of 13.58, this could not account for a W-configuration. Thus, in
this case the “W-rule” for 1H NMR longe-range couplings does not apply.
X-ray structures of related nonannelated oxetane derivatives prepared by
[11]
or ring contraction reactions[12] have been
`
Paterno-Bu¨chi reactions
described.
The azide 8 was reduced by hydrogenolysis in the presence of Boc anhy-
dride to the protected amine 9 in a very good yield of 88%. To our surprise
and in contrast to our experience with the conversion of ester 4 to acid 6, the
transesterification of 9 under basic reaction conditions was not successful in
our hands. As interference of the amino group might be expected, the transes-
terification of azide 8 under basic reaction conditions was investigated, but also
led to compound mixtures.
Mild cleavage of the methyl ester 9 could be achieved with pig liver esterase
(PLE) under pH control in aqueous reaction media. However, a simple acidic
extractive isolation led to degradation of 10. To avoid the aqueous reaction
Figure 1: Ortep plot of compound 8.

Synthesis of an Oxetane d-Amino Acid
191
media, an enzyme screening for the ester hydrolysis of 9 in micro aqueous
systems—organic solvents containing small water contents—was carried out.
Several lipases from different microorganisms such as Candida antarctica,
Candida rugosa, Arthobacter ureafaciens, Rhizomucor miehei, Burkholderia
cepacia, Thermomyces lanuginose, or Aspergillus oryzae and the polyethylene
glycol co-lyophilized esterases[13] from pig liver and Mucor miehei displayed
hydrolysis activity. The highest activity was shown by lipase L2 from
Candida antarctica. The product isolation from microaqueous reaction
systems could be achieved by simply filtering off the enzyme and evaporation
of the organic solvent. Application of the immobilized form of the lipase facili-
tated the reuse of the enzyme. On a gram scale the free acid 10 was obtained in
91% to 95% yield as a hydroscopic white foam, without purification containing
ca. 3% to 4% of the ester 9 and ca. 5% tertiary butyl methyl ether (TBME).
EXPERIMENTAL
General Methods
Solvents and reagents were bought from Fluka; 1,2-O-isopropylidene-D-
xylose was purchased from Senn Chemicals. Lipase L2 from Candida antarc-
tica was purchased from Boehringer Mannheim as lyophilisate (Chirazyme
L-2, lyo., BM; 1836021) and in an immobilized form (Chirazyme L2, c.-f. C2,
lyo.; 1816969). Solutions were concentrated below 508C in vacuo on a Bu¨chi
rotary evaporator. Qualitative TLC was performed on precoated silica gel
60F-254 plates (Merck); compounds were detected by UV light (254 nm) and
spraying with a 10% solution of concd sulfuric acid in methanol or with a
cerium sulfate solution followed by heating. Column chromatography was
˚
carried out on silica gel (63-200, 60 A) from Chemie Brunschwig. Melting
points were determined with a Bu¨chi 510 capillary apparatus and are uncor-
rected. Optical rotations were measured on a Perkin Elmer 241 spectrometer
in a 1 dm cell at 208C. 1H NMR spectra were recorded in CDCl3 on Bruker spec-
trometers Avance 300 (300 MHz) and AM 400 (400 MHz) with an Aspect 3000
and process controller. Chemical shifts are given in ppm relative to tetra-
methylsilane. Mass spectra were recorded on API III Sciex, Perkin Elmer for
negative (ISN) and positive (ISP) electrospray ionization. For the single
crystal structure analysis a single crystal was mounted in a loop and cooled
to 150 K in a nitrogen stream; data were collected on a STOE Imaging Plate Dif-
˚
fraction System (STOE, Darmstadt) with Mo-radiation (0.71 A) and data pro-
cessed with STOE IPDS-software; the crystal structure was solved and
refined with ShelXTL (Bruker AXS, Karlsruhe).
3,5-Di-O-benzyl-D-xylofuranose (1). A suspension of 3,5-di-O-benzyl-1,2-O-
isopropylidene-a-D-xylofuranose[4,5] (43.9 g, 118.5 mmol) in aqueous acetic

S. D. Lucas et al.
192
acid (30%, 1400 mL) was stirred at reflux (ꢀ1128C) over 3 h. The acetic acid was
evaporated under high vacuum. Chromatography with cyclohexane/EtOAc
(2:1, 1:1, 2:3) gave 1 (34.63 g, 88%) as a mixture of isomers (a/b ¼ 4:1).
1
a 2 Isomer: [a]D ¼ þ58 (c ¼ 0.5; CHCl3). H NMR (COSY, 400 MHz, CDCl3) d
7.38–7.26 (m, 10H, 2Ph), 5.50 (t, 0.75H, J1a,2a ¼ 4.8 Hz, H-1a), 5.10
(d, 0.25H, J,1b-OH ¼11.5 Hz, J1b,2b ꢀ 0 Hz, H-1b), 4.71–4.47 (m, 4.25H, 2
OCH2, H-4b), 4.42 (q, 0.75H, H-4a), 4.26 (dd ꢀ t, 0.25 H, J2b,3b ¼ 2.4 Hz,
J3b,4b ¼ 5.0 Hz, H-2b), 4.22 (br ddd, 0.75 H, J2a,3a ¼ 2.4 Hz, H-2a), 4.02 (dd,
0.25 H, J3b,4b ¼ 5.0 Hz, H-3b), 4.00 (dd ꢀ t, 0.75H, J3a,4a ¼ 5.0 Hz, H-3a),
3.86 (d, 0.25H, OH-1b), 3.78 (dd, 0.75H, J4a,5aa ¼ 5.0 Hz, J5aa,5ba ¼ 9.8 Hz,
H-5aa), 3.73 (dd, 0.75H, J4a,5ba ¼ 4.8 Hz, H-5ba), 3.68 (dd, 0.25H,
J4b,5ab ¼ 5.5 Hz, J5ab,5bb ¼ 7.0 Hz, H-5ab), 3.67 (dd, 0.25H, J4b,5bb ¼ 3.8 Hz,
H-5bb), 3.63 (d, 0.75H, OH-1a), 2.80 (d, 0.75H, J2a, 2a OH
-
¼ 6.0 Hz, OH-2a),
2.13 (d, 0.25H, J2b, OH-2b ¼ 6.0 Hz, OH-2b).
3,5-Di-O-benzyl-D-xylono-g-lactone (2). To a solution of 1 (57.3 g; 0.173 mol)
in dioxane (550 mL) was added water (1,100 mL) and barium carbonate
(47.93 g; 0.243 mol). Then bromine (71.4 mL; 1.39 mol) was added dropwise at
08C. After stirring at rt for 4 h in the dark, the reaction mixture was cooled
to þ108C and sodium carbonate was added. Sodium thiosulfate was added
until a white precipitate appeared. The reaction mixture was then filtered
over Speedex. The filtrate was concentrated under high vacuum, and after
the addition of water (250 mL) the product was extracted with EtOAc
(3 ꢁ 500 mL). The organic phases were washed with brine and after drying
with Mg2SO4, filtration, and concentration, the product was crystallized from
a mixture of ether and hexane to give colorless crystals of 2 (41.5 g; 73%),
mp ¼ 64–658C, lit.:[6] mp ¼ 708C. [a]D ¼ þ548 (c 0.5, CHCl3), lit.:[6]
[a]D ¼ þ40.08 (c 1.00, CHCl3); MS (ionspray): m/z 346.1 [Mþ NH4]þ, 351.3
[M þ Na]þ. 1H NMR (COSY, 400 MHz, CDCl3): d 7.39–7.29 (m, 10H, 2Ph),
4.83, 4.66 (2d, 2H, Ja,b 12.0 Hz, OCHaHbPh), 4.81 (dd, 1H, J2,3 8.0 Hz, H-2),
0
0
0
4.58 (ddd ꢀ dt, 1H, J4,5a 2.2 Hz, H-4), 4.58, 4.52 (2d, 2H, Ja ,b 12.0 Hz, OCHa -
0
Hb Ph), 4.37 (dd ꢀ t, 1H, J3,4 8.0 Hz, H-3), 3.79 (dd, 1H, J5a,5b 11.0 Hz, H-5a);
3.71 (dd, 1H, J4,5b 2.8 Hz, H-5b).
3,5-Di-O-benzyl-2-O-trifluoromethanesulfonyl-D-xylono-g-lactone(3).
To a solution of 2 (27 g; 82.2 mmol) in dichloromethane (460 mL) was added
pyridine (11.9 mL; 147.9 mmol). Then trifluoromethanesulfonic anhydride
(29.8 mL; 139.7 mmol) was added dropwise at 2178C. After stirring for
40 min under argon, trimethanesulfonic acid was neutralized by aqueous
sodium carbonate solution (200 mL). The organic layer was extracted three
times with dichloromethane and washed with a saturated solution of sodium
carbonate. After drying the organic phases with MgSO4, filtration, and concen-
tration of the filtrate, the product was immediately used for the next reaction

Synthesis of an Oxetane d-Amino Acid
193
step without further purification. MS (ionspray): m/z 478.1 [Mþ NH4]þ, 483.3
[M þ Na]þ. 1H NMR (300 MHz, CDCl3): d 7.43–7.26 (m, 10H, Ph), 5.89 (d, 1H,
J2,3 ¼ 7.9 Hz, H-2), 4.79, 4.59 (2d, 2H, Ja,b ¼ 11.8 Hz, OCHaHbPh), 4.59, 4.52
0
0
0
0
(2d, 2H, Ja ,b ¼ 11.8 Hz, CHa Hb Ph); 4.56 (dd ꢀ t, 1H, J3,4 ¼ 7.9 Hz, H-3),
4.51 (ddd, 1H, J4,5a ¼ 1.2 Hz, H-4), 3.74 (dd, 1H, J5a,5b ¼ 11.0 Hz, H-5a), 3.66
(dd, 1H, J4,5b ¼2.4 Hz, H-5b).
Methyl 2,4-Anhydro-3,5-di-O-benzyl-D-lyxonate (4). To a suspension of
triflate 3 (37.8 g; 82 mmol) in absolute methanol (675 mL) at 2128C was
added potassium carbonate (11.4 g; 82 mmol). After stirring for 30 min the
reaction mixture was filtered over Speedex. The filtrates were concentrated,
and the residue was chromatographed (cyclohexane/EtOAc 1:2) to give the
expected product as a syrup (25.4 g, 90%); [a]D ¼ 2188 (c ¼ 0.5; CHCl3)
[lit.:[6] [a]D20 217.98 (c 1.0, CHCl3)]. MS (ionspray): m/z 360.1 [Mþ NH4]þ,
1
365.3 [M þ Na]þ. H NMR (300 MHz, CDCl3): d 7.32–7.27 (m, 10H, Ph), 5.06
(dd, 1H, J2,3 ¼ 5.1 Hz, J2,4 ¼ 0.4 Hz, H-2), 5.00 (dddd ꢀ dq, 1H, J4,5a ¼ 5.6 Hz,
H-4), 4.62 (dd, 1H, J3,4 ¼ 6.6 Hz, H-3), 4.60–4.53 (4d, 4H, Ja,b ¼ 12.0 Hz,
0
0
Ja ,b ¼ 11.7 Hz, OCHaHbPh), 4.42 (dd, 1H, J5a,5b ¼ 10.9 Hz, H-5a), 3.94 (dd,
1H, J4,5b ¼ 6.0 Hz, H-5b), 3.81 (s, 3H, CH3).
Methyl 2,4-Anhydro-D-lyxonate (5). To a solution of benzylated 4 (13 g;
38 mmol) in methanol (260 mL) and dioxane (260 mL) was added palladium
on charcoal (1.3 g). The reaction mixture was stirred under hydrogen atmos-
phere for 40 min. The catalyst was then removed by filtration. The filtrate
was concentrated and chromatographed over silica gel (EtOAc) to obtain the
desired product as syrup (5.24 g, 85%); [a]D ¼ 2188 (c 0.5, CHCl3) [lit.:[7] crys-
talline solid, [a]2D4 227.18 (c 0.92, CHCl3)]. MS: (ionspray) m/z 180.1 [Mþ
NH4]þ, 185.3 [M þ Na]þ. The 1H NMR data were in agreement with published
values.[7]
2,4-Anhydro-3,5-di-O-benzyl-D-lyxonic acid (6). To a suspension of 4
(100 mg; 0.292 mmol) in THF (5 mL) was added a solution of 1 N LiOH (1 mL;
1 mmol) at 0 to 58C. After stirring for 30 min, 1 N HCl (1.1 mL; 1.1 mmol) was
added, and the reaction mixture was kept at 108C overnight. The acid was
extracted with ethyl acetate. The organic phase was washed with brine,
dried, filtered, and concentrated to dryness to obtain after drying overnight
under high vacuum the desired compound (95 mg) as a foam, [a]D ¼ 210.68
(c 1.0, CHCl3). MS: (ionspray) m/z 346.4 (M þ NHþ4 ), 351.3 (M þ Naþ), 674.4
1
(2Mþ NHþ4 ). H NMR (300 MHz, CDCl3): d 7.28–7.38 (m, 10H, Ph), 5.10 (dd,
1H, J2,3 ¼ 5.1 Hz, J2,4 ¼ 0.8 Hz, H-2), 5.03 (dddd ꢀ dq, 1H, H-4), 4.64 (dd, 1H,
J3,4 ¼ 6.5 Hz, H-3), 4.62, 4.56 (2d, 2H, J7a,7b ¼ 11.6 Hz, CH2Ph), 4.65, 4.50
(d, 2H, J6a,6b ¼ 12.0 Hz, CH2Ph), 3.96 (d, 1H, J4,5a ¼ 5.7 Hz, J5a,5b ¼ 11.0 Hz,
H-5a), 3.92 (d, 1H, J4,5b ¼ 6.1 Hz, H-5b).

S. D. Lucas et al.
Anal. Calcd for C19H20O5 (328.37): C, 69.50; H, 6.14. Found: C, 69.39;
194
H, 6.16.
Methyl 2,4-Anhydro-5-azido-D-lyxonate (8). To a suspension of diol 5
˚
(1.014 g; 6.24 mmol) and molecular sieves (4 A, ca. 1 g) in dry CH2Cl2 and dry
ether (175 mL; 1:5) at 2158C was added dropwise a solution of trifluorometha-
nesulphonic anhydride (1.03 mL; 6.55 mmol) in dry ether (175 mL). After
stirring for 50 min the mixture was concentrated in a rotary evaporator
without heating, and the resulting triflate 7 was used immediately without
further purification for the next reaction. MS: m/z 312.0 [Mþ NH4]þ, 606.4
[2Mþ NH4]þ.
To the crude triflate 7 (1.836 g) in acetone (300 mL), still in the presence of
4 A molecular sieves, was added lithium azide (3.06 g; 62.4 mmol). After
˚
stirring for 30 min the reaction mixture was concentrated and then washed
with 100 mL of iced water. The organic layer was then extracted five times
with TBME, washed with brine, dried over Mg2SO4, and filtered, and the
filtrate was concentrated. Chromatography of the residue over silica gel
(ethyl acetate/cyclohexane 1:1) furnished the pure product 8 (766 mg; 65%)
1
as a colorless solid, m.p. 67–708C. H NMR (300 MHz, CDCl3): d5.08 (d, 1H,
J2,3 ¼ 5.3 Hz, H-2), 4.95 (ddd, 1H, J4,5a 4.3 ¼ Hz, H-4), 4.87 (dd, 1H,
J3,4 ¼ 7.0 Hz, H-3), 3.85 (dd, 1H, J5a,5b ¼ 13.6 Hz, H-5a), 3.83 (s, 3H, OCH3),
3.62 (dd, 1H, J4,5b ¼ 3.3 Hz, H-5b).
Methyl 2,4-Anhydro-5-N-(t-butoxycarbonyl)amino-D-lyxonate (9). A
suspension of palladium-on-charcoal (10%, 100 mg) in EtOAc (20 mL) was vigor-
ously stirred for 30 min under a hydrogen atmosphere. A mixture of azide 8
(510.2 mg; 2.73 mmol) and Boc2O (705 mg; 3.25 mmol) in EtOAc (15 mL) was
added. The reaction mixture was stirred for 2 h and filtered, and the solvent
was evaporated. Chromatography over silica gel (EtOAc/cyclohexane 1:2) of
the residue gave the pure product 9 (624.8 mg; 88%) as a colorless solid, m.p.
93–968C. MS: (ionspray) m/z 262.0 [M þ H]þ; 279.1 [Mþ NH4]þ, 280.3
1
[M þ Na]þ. H NMR (300 MHz, CDCl3): d 5.01 (dd ꢀ t, 2H, NH and OH), 4.81
(d, 1H, J2,3 ¼ 3.8 Hz, H-2), 4.79 (ddd, 1H, J4,5b ¼ 6.2 Hz, H-4), 4.76 (ddd ꢀ dd,
1H, J3,4 ¼ 3.2 Hz, H-3), 3.81 (s, 3H, OCH3), 3.78 (ddd ꢀ dd, 1H, J4,5a ¼ 7.1 Hz,
H-5a), 3.30 (ddd ꢀ dd, 1H, J5a,5b ¼ 13.4 Hz, H-5b), 1.44 (s, 9H, Boc).
Anal. Calcd for C11H19NO6 (261.28): C, 50.57; H, 7.33; N, 5.36. Found: C,
50.48; H, 7.36; N, 5.33.
2,4-Anhydro-5-N-(t-butoxycarbonyl)amino-D-lyxonic Acid (10). To a
solution of carboxylic ester 9 (1.0 g; 3.645 mmol) in TBME saturated with
water (330 mL) was added commercial lipase L2-Candida antarctica (500 mg)
at 458C. The reaction mixture was stirred for 3 days. After filtration of the
immobilized enzyme the concentration of filtrate gave the crude product 10
as a colorless foam (941 mg, 105%) containing 4.3% ester 9 and 5% TBME.

Synthesis of an Oxetane d-Amino Acid
195
[a]D ¼ 24.78 (c 1.1, MeOH) MS (ionspray neg.): m/z 246.3 [M-H]2, 493.3 [2M-
H]2, 515.3 [2M-H þ Na]2. 1H NMR (300 MHz, CD3OD): d 4.78 (d, 1H, H-2), 4.64
(dd ꢀ t, 1H, J2,3 ¼ 5.7 Hz, J3,4 ¼ 6.9 Hz, H-3), 4.61 (ddd, 1H, H-4), 3.44 (dd, 1H,
J4,5a ¼ 4.9 Hz, J5a,5b ¼ 14.5 Hz, H-5a), 3.36 (dd, 1H, J4,5b ¼ 6.2 Hz, H-5b), 1.34
(s, 9H, Boc).
Anal. Calcd for C10H17NO6 (247.25): C, 48.58; H, 6.93; N, 5.67. Found: C,
49.12; H, 6.92; N, 5.32.
ACKNOWLEDGEMENTS
´
`
We wish to thank Amelie Mourton and Solene Dussauge for preliminary
experiments.
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¨
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