Synthesis of 3-fluoro-oxetane δ-amino acids

Article abstract of DOI:10.1080/07328300903261562

Starting from d-xylose, 2,4-anhydro-5-N-(tert-butoxycarbonyl)amino-5-deoxy- 3-fluoro-d-arabinonic acid 11 was synthesized over 10 steps including ring contraction, fluorination, and ester hydrolysis. Bromine oxidation of d-xylose followed by benzylidenati

Full text of DOI:10.1080/07328300903261562

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Synthesis of 3-Fluoro-Oxetane δ-Amino
Acids
Susana Dias Lucas a , Amélia Pilar Rauter a , Josef Schneider b &
Hans Peter Wessel b
a Centro de Química e Bioquímica, Departamento de Química e
Bioquímica , Faculdade de Ciências da Universidade de Lisboa ,
Edifício C8, 5° Piso, Campo Grande, 1749-016, Lisboa, Portugal
b F. Hoffmann-La Roche Ltd., Pharmaceutical Research , CH-4070,
Basel, Switzerland
Published online: 06 Nov 2009.
To cite this article: Susana Dias Lucas , Amélia Pilar Rauter , Josef Schneider & Hans Peter Wessel
(2009) Synthesis of 3-Fluoro-Oxetane δ-Amino Acids, Journal of Carbohydrate Chemistry, 28:7-8,
431-446
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Journal of Carbohydrate Chemistry, 28:431–446, 2009
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Copyright Taylor & Francis Group, LLC
ISSN: 0732-8303 print / 1532-2327 online
DOI: 10.1080/07328300903261562
Synthesis of 3-Fluoro-Oxetane
δ-Amino Acids
Susana Dias Lucas,1 Ame´lia Pilar Rauter,1 Josef Schneider,2
and Hans Peter Wessel2
1Centro de Qu´ımica e Bioqu´ımica, Departamento de Qu´ımica e Bioqu´ımica, Faculdade
de Cieˆncias da Universidade de Lisboa, Edif´ıcio C8, 5◦ Piso, Campo Grande 1749-016,
Lisboa, Portugal
2F. Hoffmann-La Roche Ltd., Pharmaceutical Research, CH-4070, Basel, Switzerland
Starting from D-xylose, 2,4-anhydro-5-N-(tert-butoxycarbonyl)amino-5-deoxy-3-fluoro-
D-arabinonic acid 11 was synthesized over 10 steps including ring contraction, fluori-
nation, and ester hydrolysis. Bromine oxidation of D-xylose followed by benzylidenation
in a one-pot procedure led to a ca. 1:1 mixture of lactone 3 and 2,4;3,5-dibenzylidene
xylonic acid (4) as by-product. For the synthesis of the D-xylo derivative 24, the chosen
starting material was 1,2-O-isopropylidene-α-D-xylofuranose. A total of 14 steps includ-
ing epimerization, ring contraction, fluorination, and saponification led to the desired
fluoro-oxetane δ-amino acid 24. Hydrolysis of the 3-fluoro-oxetane δ-amino esters 10
and 23 by means of LiOH was successful in agreement with the results previously re-
ported for similar 3-methoxy oxetanes, whereas chemical hydrolysis was not possible
for 3-hydroxy derivatives.
Keywords Carbohydrate amino acids; δ-Amino acids; Oxetanes; Carbohydrate
scaffolds
INTRODUCTION
Oxetane δ-amino acids (Fig. 1) are useful chiral scaffolds that can be synthe-
sized from carbohydrates.[1] The four-membered rings present little flexibil-
ity and exhibit well-defined exit vectors orienting the substituents in space.
Few contributions were made on the synthesis of oxetane amino acids,[1,2] and
the Fleet group has also investigated the conformational behavior of oxetane-
based oligomers.[3] Carbohydrate amino acids with pyranose and furanose
forms have already shown high potential as rigid templates to induce specific
Received July 23, 2009; accepted August 15, 2009.
Address correspondence to Hans Peter Wessel, F. Hoffmann-La Roche Ltd., Pharma-
ceutical Research, Discovery Chemistry, Bldg. 92/7.92 CH-4070, Basel, Switzerland.
E-mail: hans p.wessel@roche.com
431

S.D. Lucas et al.
432
Figure 1: Structure of oxetane δ-amino acids.
conformations in peptide mimetics[4] to construct oligomeric carbohydrate-
peptide hybrids[5] and are useful scaffolds for parallel chemistry purposes.[6]
In the present work we report the synthesis of oxetane δ-amino acids 1
with different configurations containing a fluoride substituent at C-3. It has
been well recognized that the presence of fluorine can induce favorable prop-
erties in bioactive compounds. In medicinal chemistry approaches, fluorine is
frequently introduced to improve the metabolic stability by blocking metaboli-
cally labile sites. Fluorine can also be used to modulate physicochemical prop-
erties such as lipophilicity or basicity. It may exert a substantial effect on the
conformation of a molecule and is being used to enhance the binding affinity to
target proteins.[7]
RESULTS AND DISCUSSION
Starting from D-xylose (2), we made use of a straightforward anomeric oxi-
dation and benzylidene protection previously reported by Fleet’s group[2b] to
furnish the 1,4-xylonolactone 3 (Scheme 1). Although the yields were reported
to be in the range of 50%, we could only reach 39% but were able to identify a
1
by-product formed in considerable amount (37%). MS, H-NMR, and IR spec-
troscopy allowed us to assign the structure of this compound as that of the
known 2,4;3,5-dibenzylidene xylonic acid (4).[8] NMR assignments were based
on 1D 1H NMR, 2D COSY, 2D HSQC, 2D HMBC, and 2D NOESY experiments.
From a 2D NOESY experiment, cross-peaks between H-7/H-3, H-7/H-5a, H-
3/H-5a and H-6/H-2, H-6/H-4, H-2/H-4 were observed, which proved the ex-
pected conformation of 4 as a cis-decalin system.
Scheme 1: One-pot anomeric oxidation of D-xylose and benzylidene protection.

Synthesis of 3-Fluoro-Oxetane δ-Amino Acids
433
Scheme 2: (i) Tf2O, DCM, Py, −30◦C, 1 h; (ii) K2CO3, MeOH, −12◦C, 4 h, 65% (2 steps); (iii) H2,
Pd/C, MeOH/dioxane 1:1, rt, 2 h, 87%; (iv) Tf2O, Et2O/DCM 5:1, 4 Å molecular sieves, −15◦C,
50 min; (v) NaN3, acetone, rt, 2 h, 72% (2 steps); (vi) DAST, MeCN, −20◦C to reflux, 1 h, 75%;
(vii) H2, Pd/C, EtOAc, Boc2O, rt, 2 h, 85%; (viii) LiOH 1N, HCl 1N, 0–5◦C, 1 h, 97%.
The 1,4-lactone 3 was submitted to ring contraction using the methodology
described by Witty et al.,[9] and triflation of the starting lactone was followed
by treatment with potassium carbonate, leading to the benzylidene-protected
oxetane 5[2b] in 65% yield (Sch. 2). Deprotection was accomplished by catalytic
hydrogenation to afford the known diol 6[1a,2b] in 87% yield. This compound
was reacted further to compound 7[1a] by nonbasic triflation,[10] followed by
selective introduction of a primary azide by means of sodium azide to furnish
the intermediate 8.[1a]
The oxetane derivative 8 containing a free hydroxyl group was the key
intermediate for the fluorine introduction at C-3. The first attempt to substi-
tute the hydroxyl group by fluoride made use of the standard reaction with
diethylaminosulfur trifluoride (DAST) in dichloromethane. However, reaction
either at room temperature or under reflux conditions gave the desired flu-
oro derivative 9 in poor yield. Theoretical studies on fluorination reaction
by DAST indicate that the formation of fluoride ions is endoenergetic when
the reaction takes place in solvents with low dielectric constants such as
dichloromethane.[11] In addition, fluoride ion formation may be facilitated by
the presence of pyridine; however, in this case it did not lead to any improve-
ment in the yield of 9. The reaction was then carried out using acetonitrile as
solvent, and the best results were obtained when DAST was added at −20◦C

S.D. Lucas et al.
434
and the mixture was warmed up to reach reflux conditions to afford the desired
fluoro derivative 9 in 75% yield.
One-pot reduction of azide 9 in the presence of tert-butoxycarbonyl an-
hydride furnished the protected amine 10 in a good yield. Saponification by
means of LiOH was a clean reaction and gave the desired oxetane δ-amino
acid 11 in 97% yield. This result is in keeping with the one obtained for the
hydrolysis of methyl esters in 3-methoxy oxetane derivatives,[1b] whereas for
a 3-hydroxy oxetane derivative this reaction was not successful by chemical
approaches.[1a]
With respect to structural assignments, the characteristic couplings of the
fluorine atom with the geminal and vicinal protons were observed; the H-3 sig-
nal for 9 is a ddd at δ 5.53 ppm with a characteristic J3,F of 56.1 Hz. The signals
for H-2 and H-4 exhibit coupling constants with the fluorine of 15.2 Hz and
19.1 Hz, respectively. The coupling constants of trans- and cis-oriented vicinal
protons in the obtained D-arabino configured oxetanes were in agreement with
the characteristic range of values observed for similar oxetane systems.[1b]
In view of the synthesis of oxetanes with D-xylo configuration we targeted
the benzyl protected D-ribono-1,4-lactone 18[9] (Sch. 3) as an intermediate for
the ring contraction step. Selective protection of the primary alcohol of com-
mercial 1,2-O-isopropylidene-α-D-xylofuranose (12) yielded the benzoate 13.[14]
The well-established PDC oxidation giving 14 was followed by NaBH4 reduc-
tion to achieve the required inversion of configuration at C-3 together with ben-
zoyl cleavage and afforded 1,2-O-isopropylidene-α-D-ribofuranose (15) in good
yield. Benzylation of the diol 15 gave 16, and isopropylidene hydrolysis led, in
this case, to the β-anomer 17, which was further oxidized with bromine to give
the desired α-hydroxy lactone 18[9] in 79% yield.
For the synthesis of the oxetane δ-azido ester 21, the best yields were ob-
tained when the crude lactone 18 was reacted. Ring contraction was achieved
by triflation and treatment with K2CO3 in methanol. The resulting crude 19[9]
was hydrogenated to yield the diol 20. Triflation of this product using the non-
basic procedure was not possible due to the low solubility of the diol 20 in
CH2Cl2. Hence, triflation was performed with triflic anhydride in CH2Cl2 and
in the presence of pyridine. After reaction with sodium azide in acetone, the
desired compound 21 was obtained in a 53% overall yield from the lactone 18.
An alternative synthesis of 20 using a longer synthetic scheme starting from
diacetone glucose was previously reported.[12]
In the first attempt to synthesize the fluoro derivative 22, the azide 21 was
reacted with DAST in MeCN at −20◦C. After workup and flash chromatogra-
phy, the MS of the product fractions suggested the presence of the intermediate
25 (Sch. 4) in agreement with Tewson and Welch’s[13] proposal for DAST reac-
tions.
The introduction of the fluorine atom in 22 will encounter some steric hin-
drance as all substituents are located on the same side of the oxetane ring.

Synthesis of 3-Fluoro-Oxetane δ-Amino Acids
435
Scheme 3: (i) BzCl, Et3N, DCM, 0–5◦C, 1.5 h, 90%; (ii) PDC, Ac2O, DCM, reflux, 2.5 h, 83%; (iii)
NaBH4, EtOH/H2O 7:1, rt, overnight, 89%; (iv) (a) NaH, DMF, rt, 2 h, (b) BnBr, DMF, rt, 2 h, 90%;
(v) AcOH (30%, aq.), reflux, 2 h, 91%; (vi) Br2, BaCO3, dioxane/H2O 1:2, rt, 3 h, 79%; (vii) Tf2O,
DCM, py, −30 to −10◦C, 15 min; (viii) K2CO3, MeOH, −12◦C, 1 h; (ix) H2, Pd/C 10%,
MeOH/dioxane 1:1, rt, 2 h; (x) Tf2O, DCM, py, −30◦C; (xi) NaN3, acetone, rt, overnight, 53%
from 18; (xii) DAST, Py, MeCN, −20◦C, 1.5 h, then 50◦C, 3 h; (xiii) H2, Pd/C, EtOAc, Boc2O, rt,
1.5 h, 52% over 2 steps; (xiv) LiOH 1N, HCl 1N, 0–5◦C, 30 min, 97%.
The intermediate 25 was therefore heated to 50◦C to afford the desired prod-
uct 22. In this case it was shown that addition of 1 eq of pyridine improved the
reaction rate.
Compound 22 is volatile, and the best results were obtained when no pu-
rification was performed, so that after DAST reaction and workup the crude
Scheme 4: Fluorination of 21 by DAST reagent.

S.D. Lucas et al.
436
22 was further hydrogenated in the presence of tert-butoxycarbonyl anhydride
to achieve the protected amine 23 (Sch. 3) in 52% yield over the two steps.
In agreement with the results for the saponification of the fluoro derivative
10, treatment of 23 with 1 N LiOH led to the δ-amino acid 24 in an excellent
yield of 97%.
In conclusion, the two diastereomeric fluorinated oxetane δ-amino acids 11
and 24 were synthesized in good overall yield. These scaffolds will be used for
the generation of various compound libraries.
EXPERIMENTAL
General Methods
Solvents and reagents were bought from Fluka, Merck, Aldrich, or Acros
Organics. The DAST reagent supplied by Acros Organics was used. Solutions
were concentrated below 50◦C in vacuo on Bu¨chi rotary evaporators. Qual-
itative 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 conc. sulfuric acid in methanol or with a cerium sulfate aqueous
solution, followed by heating. Column chromatography was carried out on
silica gel (63–200, 60 ) from Chemie Brunschwig or 60G (0.040–0.063 mm)
from Merck. Melting points were determined with an Electrothermal 9100
or Bu¨chi 510 capillary apparatus and are uncorrected. Optical rotations
were measured on a Perkin Elmer 241 spectrometer in a 1-dm cell at given
temperatures, either at Faculdade de Cieˆncias da Universidade de Lisboa
(FCUL) or at F. Hoffmann-La Roche Ltd. NMR spectra were recorded on
1
Bruker spectrometers: Avance 300 (300 MHz for H NMR) or AM 400 (400
1
MHz for H NMR and 100 MHz for 13C NMR) at F. Hoffmann-La Roche Ltd.,
1
and Avance 400 (400 MHz for H NMR and 100 MHz for 13C NMR) at FCUL.
Chemical shifts are given in ppm relative to tetramethylsilane. Mass spectra
were recorded on API III Sciex, Perkin Elmer for negative (ISN) and positive
(ISP) electrospray ionization. High-resolution mass spectra were recorded on
a Finnigan LTQ FT from Thermo for positive (ESI) and negative (NSI) elec-
trospray ionization at F. Hoffmann-La Roche Ltd. Elemental analyses were
performed by Solvias AG, Basel, Switzerland. Known compounds have the
following CAS registry numbers: 4 [20603-35-4], 5 [131550-06-6], 6 [134651-
25-5], 7 [908608-59-3], 8 [807617-89-6], 13 [6022-96-4], 14 [6698-46-0], 15
[37077-81-9], 18 [131139-05-4], 19 [131139], 20 [134651-21-1].
3,5-O-Benzylidene-D-xylono-1,4-lactone (3)[2b] and
2,4;3,5-Di-O-benzylidene-D-xylonic Acid (4)[8]
A solution of D-xylose (20.0 g, 0.13 mol) in water (54 mL) was cooled in an
ice water bath. Potassium carbonate (22.6 g, 0.16 mol) was added in portions

Synthesis of 3-Fluoro-Oxetane δ-Amino Acids
437
while keeping the temperature below 20◦C. The mixture was cooled to 5◦C, and
bromine (8 mL, 0.15 mol) was added dropwise over 45 min while keeping the
temperature below 10◦C. The resulting orange solution was stirred at 10◦C
for 30 min and then at rt overnight, when one major product was observed.
The reaction was quenched by careful addition of 88% formic acid (1.66 mL)
until the solution became colorless. The solution was concentrated at 50◦C,
and acetic acid (13.4 mL) was added. The reaction mixture was concentrated
at 50◦C to remove any residual water. The crude xylono-1,4-lactone was used
without purification.
To a solution of the crude lactone (assumed 19.7 g, 0.13 mol) in benzalde-
hyde (200 mL) was added conc. HCl (15 mL). The reaction was stirred at rt
overnight to give two different products identified by TLC (EtOAc/cyclohexane
1:1). The mixture was concentrated under high vacuum to a quarter volume.
Diethyl ether (80 mL) was added, and a precipitate formed. The mixture was
filtered, and the residue was washed with ether. The filtrate was concentrated
and chromatographed (1:3 EtOAc/cyclohexane) to give the desired benzylidene
protected lactone 3 as a colorless solid (12.0 g, 51 mmol, 39%). The solid residue
of the filtration was then washed with acetone to separate the by-product from
the residual salts. The filtrate was concentrated, and the by-product recrystal-
lized from acetone/n-hexane to give compound 4 as a colorless solid (16.5 g, 48
mmol, 37%).
20
Data for 3: α +11.2 (c 1.00, CH2Cl2). 1H NMR, COSY (400 MHz, CDCl3):
[ ]D
δ 7.46–7.44 (m, 2H, Ph), 7.38–7.36 (m, 3H, Ph) 5.54 (s, 1H, CHPh), 4.59–4.53
(m, 3H, H-2, H-4, H-5a), 4.32 (br s, 1H, H-3), 4.19 (B(ABX), 1H, J4,5b = 1.8 Hz,
J5a,5b = 13.5 Hz, H-5b), 3.41 (br s, 1H, OH).
20
20
Data for 4: α
[ ]D
−18.6 (c 1.00, DMF), lit.[8]: α
−21.13 (c 1.05, DMF).
[ ]D
m.p. 202.2–203.0◦C, lit.[8]: 198.5–200.0◦C. MS(ionspray): 343.1 [M+H]+, 360.4
[M+NH4]+, 365.1 [M+Na]+. H NMR (400 MHz, DMSO; COSY, NOESY): δ
1
12.90 (s, 1H, COOH), 7.52–7.50 (m, 2H, Ph), 7.44–7.35 (m, 8H, Ph), 5.75 (s,
1H, CHaHbPh), 5.69 (s, 1H, CHaHbPh), 4.78 (d, 1H, J2,3 = 2.1 Hz, H-2), 4.37
(br t, 1H, J2,3 ≈ J3,4 ≈ 1.8 Hz, H-3), 4.21 (A(ABX), 1H, J4,5a = 1.8 Hz, J5a,5b
=
12.8 Hz, H-5a), 4.16 (B(ABX), 1H, J4,5b = 1.3 Hz, H-5b), 4.04 (br q, 1H, H-4).
13C NMR (100 MHz, DMSO; HSQC, HMBC): δ 169.28 (COOH), 138.78 (Ph),
138.43 (Ph), 129.37 (Ph), 129.21 (Ph), 128.50 (Ph), 128.47 (Ph), 126.92 (Ph),
126.58 (Ph), 99.5 (CHaPh), 99.9 (CHbPh), 76.63 (C-2), 70.55 (C-3), 69.87 (C-4),
69.51 (C-5). IR (cm−1): 2580–2620 (COOH), 1738 (C = O(COOH)), 1608 and
1498 (aromatic), 1097 (COC), 763 and 700 (Ph, monosubstituted).
Methyl 2,4-anhydro-3,5-O-benzylidene-D-lyxonate (5)[2b]
To a solution of the starting 3,5-O-benzylidene-D-xylono-1,4-lactone 4 (11.9
g, 50.4 mmol) in CH2Cl2 (250 mL) and pyridine (7.3 mL, 1.8 eq) was added
dropwise at −30◦C trifluoromethanesulfonic anhydride (10.2 mL, 1.2 eq).

S.D. Lucas et al.
438
After 1 h the reaction mixture was diluted with CH2Cl2 and washed with sat-
urated solution of NaHCO3 and then with 1N HCl. After drying with MgSO4
and filtration and evaporation of the solvent, the crude 3,5-O-benzylidene-2-
O-trifluoromethanesulfonyl-D-xylono-1,4-lactone was immediately used for the
next reaction step without further purification. To a solution of triflated lactone
in absolute MeOH (420 mL) at −12◦C was added potassium carbonate (6.9 g,
1 eq). The resulting suspension was stirred over 4 h, and the reaction mixture
was filtered over Celite. The filtrate was concentrated and chromatographed
(EtOAc/cyclohexane 1:3) to furnish pure oxetane 5 (8.17 g, 32.7 mmol, 65%
20
1
yield) as a colorless solid. α
= −3.2 (c 1.00, CH2Cl2). H NMR (400 MHz,
[ ]D
CDCl3): δ 7.48–7.29 (m, 5H, Ph), 5.42 (s, 1H, CHPh), 4.99 (d, 1H, J2,3 = 2.2
Hz, H-2), 4.92 (dd, 1H, J3,4 = 5.1 Hz, H-3), 4.89 (dd, 1H, J4,5a = 0 Hz, J4,5b 2.5
Hz, H-4), 4.30 (d, 1H, J5a,5b = 14.0 Hz, H-5a), 3.99 (dd, 1H, H-5b), 3.94 (s, 3H,
OMe).
Methyl 2,4-Anhydro-5-azido-5-deoxy-3-fluoro-D-arabinonate (9)
To a solution of 8[1a] (500 mg, 2.7 mmol) in acetonitrile (40 mL) at −20◦C
was added DAST (1.0 mL, 8.1 mmol), and the mixture was stirred for 20 min.
The temperature was then raised to reflux temperature over 1 h. After concen-
tration, the mixture was dissolved in CH2Cl2 (50 mL) and washed with a satu-
rated solution of NaHCO3 (30 mL). After drying over MgSO4 and filtration and
concentration, the residue obtained was chromatographed (EtOAc/cyclohexane
1:4) to yield the desired fluoro derivative as a colorless oil (383 mg, 2.02 mmol,
20
1
75%). α +61 (c 1.00, CH2Cl2). MS: m/z 190.3 [M+H]+, 212.1 [M+Na]+. H
[ ]D
NMR (300 MHz, CDCl3): δ 5.53 (ddd, 1H, J2,3 = 6.7 Hz, J3,4 = 4.5 Hz, J3,F
=
56.1 Hz, H-3), 5.23 (ddd, 1H, J2,4 = 1.1 Hz, J2,F = 15.2 Hz, H-2), 5.14 (dddd,
1H, J4,5a = 3.4 Hz, J4,5b = 3.0 Hz, J4,F = 19.1 Hz, H-4), 3.89 (s, 3H, OMe), 3.72
(A(ABX), 1H, J5a,5b = 14.2 Hz, H-5a) 3.48 (B(ABX), 1H, H-5b). Anal. Calcd. for
C6H8FN3O3 (189.15): C, 38.10; H, 4.26; N, 22.22. Found: C, 38.38; H, 4.32; N,
21.98.
Methyl 2,4-Anhydro-5-N-(t-butoxycarbonyl)amino-5-deoxy-3-
fluoro-D-arabinonate (10)
To a 0.12 M solution of azide 9 (1.14 g, 6.0 mmol) in EtOAc was added
Pd/C (10% m/m), and the suspension was stirred vigorously for 30 min under
an atmosphere of hydrogen. A 0.12 M solution of Boc2O in EtOAc (52.5 mL,
1.05 eq) was then added, and the reaction mixture was stirred at rt under H2
atmosphere for 2 h. The catalyst was removed by filtration, and the solvent was
evaporated. Chromatography (EtOAc/cyclohexane 1:2) of the obtained residue
20
gave the pure product 10 (1.35 g, 5.1 mmol, 85%) as a colorless oil. α +42
[ ]D
1
(c 1.00, CH2Cl2). H NMR (400 MHz, CDCl3): δ 5.37 (ddd, 1H, J2,3 = 6.8 Hz,

Synthesis of 3-Fluoro-Oxetane δ-Amino Acids
439
J3,4 = 4.8 Hz, J3,F = 56.0 Hz, H-3), 5.13 (ddd, 1H, J2,F = 14.8 Hz, H-2), 5.03
(dddd, 2H, J4,5a = 3.4 Hz, J4,5b = 3.0 Hz, J4,F = 19.1 Hz, H-4), 4.93 (br s, 1H,
NH), 3.86 (s, 3H, OMe), 3.58 (dd, 1H, J4,5a = 4.4 Hz, J5a,5b = 14.8 Hz, J5a,NH
= 7.2 Hz, H-5a), 3.41 (ddd, 1H, J5b,NH = 4.7 Hz, J5a,5b = 14.8 Hz, H-5b), 1.46
(s, 9H, Boc). Anal. Calcd. for C11H18FNO5 (263.27): C, 50.19; H, 6.89; N, 5.32.
Found: C, 49.96; H, 6.74; N, 5.35.
2,4-Anhydro-5-N-(t-butoxycarbonyl)amino-5-deoxy-3-fluoro-D-
arabinonic Acid (11)
To a 0.06 M solution of ester 10 (1.5 g, 5.7 mmol) in THF was added 1N
aqueous LiOH (3 eq) at 0–5◦C, and the mixture was stirred for 1 h. Then,
maintaining the temperature range, 1N HCl (3 eq) was added, and the mixture
was stirred for 30 min. Brine was added, and the product was extracted three
times with tert-butylmethyl ether. The organic layers were combined, dried
over MgSO4, and filtered, and the solvent was evaporated to give the product
11 as a colorless hygroscopic foam (1.38 g, 5.54 mmol, 97%). MS (ionspray neg.):
1
m/z 248.3 [M-H]−. H NMR (300 MHz, acetone-d6) δ 5.41 (ddd, 1H, J2,3 = 6.7
Hz, J3,4 = 4.7 Hz, J3,F = 55.7 Hz, H-3), 5.18 (dd, 1H, J2,F = 15.3 Hz, H-2),
5.03 (br dq, 1H, J4,5a ≈ J4,5b ≈ 4.3 Hz, J4,F = 19.5 Hz, H-4), 3.54–3.39 (m, 2H,
H-5a, H-5b), 1.47 (s, 9H, Boc). HRMS (pNSI) m/z 272.09052 [M+Na]+, calcd.
272.09047 for C10H16FNO5Na.
5-O-Benzoyl-1,2-O-isopropylidene-α-D-xylofuranose (13)[14]
To a solution of commercial 1,2-O-isopropylidene-α-D-xylofuranose (50.02
g, 0.26 mol) in CH2Cl2 (1 L) in an ice bath was added Et3N (108 mL, 0.78
mol). Benzoyl chloride (33.2 mL, 0.29 mol) was added dropwise within 30 min.
The mixture was stirred for 1.5 h at 0–5◦C, and the reaction was quenched
by the addition of water (50 mL). The organic phase was washed twice with a
saturated solution of NaHCO3 (250 mL), dried with MgSO4, and filtered, and
the solvents were evaporated. Column chromatography (EtOAc/cyclohexane
1:3, 2:3, 1:1) of the residue gave the desired product as a colorless solid (68.9g,
0.23 mol, 90%). MS (ionspray): m/z 295.2 [M+H]+, 312.2 [M+NH4]+. 1H NMR
(300 MHz, CDCl3): δ 7.46–8.04 (m, 5H, Ph), 5.96 (d, 1H, J1,2 = 3.6 Hz, H-1),
4.81 (A(ABX), 1H, J4,5a = 9.4 Hz, J5a,5b = 12.7 Hz, H-5a), 4.60 (d, 1H, J2,3
≈
0 Hz, H-2), 4.38 (B(ABX), 1H, H-5b), 4.37 (ddd, H, J4,5b = 4.5 Hz, H-4), 4.17
(br dd, 1H, J3,4 = 2.2 Hz, H-3), 3.23 (d, 1H, J3,OH = 4.0 Hz, OH), 1.51 (s, 3H,
Me(i-prop)), 1.33 (s, 3H, Me(i-prop)).

S.D. Lucas et al.
440
5-O-Benzoyl-1,2-O-isopropylidene-α-D-erythro-pent-3-
ulofuranose (14)[14,15]
A solution of 5-O-benzoyl-1,2-O-isopropylidene-α-D-xylofuranose (20.03 g,
0.068 mol) in CH2Cl2 (200 mL) was treated with pyridinium dichromate (13.08
g, 0,035 mol) and acetic anhydride (19.3 mL, 0.204 mol) over 2.5 h at reflux. The
reaction mixture was diluted with ether (50 mL) and filtered through a silica
gel column (300g, ether/CH2Cl2 1:4, then 2:3). After evaporation of solvents the
residue was chromatographed over silica gel (EtOAc/cyclohexane, 1:3, 2:3, 1:1)
to afford a colorless solid (16.44 g, 83%). MS (ionspray): m/z 310.1 [M+NH4]+,
1
315.3 [M+Na]+. H NMR (300 MHz, CDCl3): δ 7.44–7.95 (m, 5H, Ph), 6.14 (d,
1H, J1,2 = 4.4 Hz, H-1), 4.71 (A(ABX), 1H, J4,5a = 2.8 Hz, H-5a), 4.69 (dd≈br
s, 1H, H-4), 4.47 (B(ABX), 1H, J4,5b = 4.7 Hz, J5a,5b = 13.4 Hz, H-5b), 4.44 (d,
1H, H-2), 1.52 (s, 3H, Me(i-prop)), 1.44 (s, 3H, Me(i-prop)).
1,2-O-Isopropylidene-α-D-ribofuranose (15)[15,16]
To a solution of the keto sugar 14 (15.34 g, 52 mmol) in EtOH/H2O (7:1,
180 mL) cooled in an ice bath was added sodium borohydride (2.38 g, 63 mmol)
under stirring. The reaction mixture was allowed to reach rt, and stirring
was continued overnight (16.5 h). The reaction mixture was passed through
Amberlite columns (IRC-50, 120 g followed by IRA-400, 120 g, washing with
EtOH). After concentration, the residue was chromatographed over silica gel
(450 g) with EtOAc/MeOH/H2O (93:5:2) to give the desired product 15 (8.9 g,
1
46.8 mmol, 89%). MS (ionspray): m/z 208.1 [M+NH4]+, 213.3 [M+Na]+. H
NMR (300 MHz, CDCl3): δ 5.83 (d, 1H, J1,2 = 3.9 Hz, H-1), 4.59 (dd≈t, 1H, J2,3
= 5.1 Hz, H-2), 4.01 (ddd≈dt, 1H, H-3), 3.97 (ddd, 1H, J4,5a = 2.4 Hz, H-5a),
3.84 (br ddd, 1H, J3,4 = 9.0 Hz, J4,5b = 3.6 Hz, H-4), 3.76 (ddd, 1H, J5a,5b = 12.0
Hz, H-5b), 2.38 (d, 1H, J3,OH-3 = 10.5 Hz, OH-3), 2.05 (br s, 1H, OH-5), 1.58 (s,
3H, Me(i-prop)), 1.38 (s, 3H, Me(i-prop)).
3,5-Di-O-benzyl-1,2-O-isopropylidene-α-D-ribofuranose (16)[9,17]
A 1 M solution of 1,2-isopropylidene-α-D-ribofuranose (15, 8.9 g, 46.8 mmol)
in absolute DMF was added dropwise at rt to a 1.3 M suspension of sodium hy-
dride (60% in mineral oil, 2.3 eq) in absolute DMF. After stirring the mixture
until release of H2 stopped, it was cooled to 10◦C, and benzyl bromide (14 mL,
2.5 eq) was added dropwise. The reaction mixture was allowed to reach rt and
was stirred for 2 h, and then the reaction was quenched by careful addition
of isopropanol (3% v/v). DMF was evaporated in vacuo. After addition of wa-
ter and brine (1:1) the product was extracted twice with EtOAc, and the com-
bined organic layers were washed with brine, dried over MgSO4, filtered, and
concentrated. The residue obtained was chromatographed (EtOAc/cyclohexane
1:9, 3:7) to give the desired product as colorless oil (15.6 g, 90%). MS

Synthesis of 3-Fluoro-Oxetane δ-Amino Acids
441
1
(ionspray): m/z 371.4 [M+H]+, 388.3 [M+ NH4]+, 393.3 [M+Na]+. H NMR
(300 MHz, CDCl3): δ 7.36–7.26 (m, 10H, 2Ph), 5.76 (d, 1H, J1,2 = 3.8 Hz, H-1),
5.54 (A(AB), 1H, Ja,b = 11.9 Hz, OCHaHbPh), 4.73 (B(AB), 1H, OCHaHbPh),
4.57 (A(AB), 1H, Ja’,b’ = 12.2 Hz, OCHa’Hb’Ph), 4.56 (dd≈t, 1H, H-2), 4.49
(B(AB), 1H, OCHa’Hb’Ph), 4.18 (ddd, 1H, J4,5a = 2.2 Hz, J4,5b = 3.8 Hz, H-4),
3.86 (dd, 1H, J2,3 = 4.3 Hz, J3,4 = 8.9 Hz, H-3), 3.76 (A(ABX), 1H, J5a,5b = 11.3
Hz, H-5a), 3.57 (B(ABX), 1H, H-5b), 1.59 (s, 3H, i-prop), 1.36 (s, 3H, i-prop).
3,5-Di-O-benzyl-β-D-ribofuranose (17)
A solution of 3,5-di-O-benzyl-1,2-O-isopropylidene-α-D-ribofuranose (89.3
g, 0.24 mol) in aqueous acetic acid (1.8 L, 30%) was stirred under reflux
conditions (≈112◦C) for 2 h, the reaction mixture was then cooled in an ice
bath over 1 h, and precipitation of the product was observed. The colorless
solid was filtered and dried to yield the title compound 17 (60.6 g, 0.18 mol,
76%). The filtrates were concentrated, and the residue was chromatographed
(EtOAc/cyclohexane 1:1) to obtain more of the desired substance (11.54 g, 0.035
mol, 15%, total yield 72.14 g, 0.22 mol, 91%). MS: m/z 348.3 [M+ NH4]+, 353.4
1
[M+Na]+. H NMR (300 MHz, CDCl3): δ 7.39–7.26 (m, 10H, Ph), 5.23 (d, 1H,
J1,2 = 7.4 Hz, H-1), 4.61 (A(AB), 1H, Ja,b = 8.3 Hz, OCHaHbPh), 4.56 (B(AB),
1H, OCHaHbPh), 4.51 (A(AB), 1H, Ja’,b’ = 5.6 Hz OCHa’Hb’Ph,), 4.48 (B(AB),
1H, OCHa’Hb’Ph), 4.28 (dd, 1H, J3,4 = 5.9 Hz, H-3), 4.21 (ddd, 1H, J4,5a = 3.0
Hz, J4,5b = 2.9 Hz, H-4), 4.03 (dd, 1H, J2,3 = 4.7 Hz, H-2), 3.64 (A(ABX), 1H,
J5a,5b = 10.3 Hz, H-5a), 3.55 (B(ABX), 1H, H-5b), 3.36 (br s, 1H, OH-1), 2.69
1
(d, 1H, OH-2). The H NMR of the chromatographed material showed a small
amount of the α-anomer (ca. 5%).
3,5-Di-O-benzyl-D-ribono-1,4-lactone (18)[9]
To a 0.03 M solution of 3,5-di-O-benzyl-β-D-ribofuranose (17.8 g, 53.8
mmol) in dioxane/water (1:2) was added barium carbonate (14.9 g, 1.4 eq). Af-
ter cooling the solution to 0◦C, bromine (11.0 mL, 8 eq) was added dropwise.
The reaction mixture was stirred in the dark for 3 h. The reaction mixture was
then allowed to warm up to +10◦C, and sodium carbonate was added until neu-
tralization. In order to destroy residual bromine, sodium thiosulfate was added
until a white precipitate appeared, and the reaction mixture was filtered over
Celite. The solvents were evaporated in vacuo, and after the addition of wa-
ter the product was extracted with EtOAc. The organic phases were washed
with brine, dried with MgSO4, filtered, and concentrated. The crude product
was chromatographed over silica gel (EtOAc/cyclohexane 1:2) to give the de-
1
sired lactone (14.02 g, 42.7 mmol, 79%) as a colorless oil. H NMR (300 MHz,
CDCl3): δ 7.38–7.22 (m, 10H, Ph), 4.72–4.64 (AB, 2H, Ja,b = 12.0 Hz, OCH2Ph),
4.67 (dd, 1H, J2,3 = 5.9 Hz, H-2), 4.55–4.23 (AB, 2H, Ja’,b’ = 11.9 Hz, OCH2’Ph),

S.D. Lucas et al.
442
4.50 (dd≈t, 1H, H-4), 4.19 (d, 1H, J3,4 ≈ 0 Hz, H-3), 3.67 (A(ABX), 1H, J4,5a
=
3.0 Hz, J5a,5b = 10.9 Hz, H-5a), 3.56 (B(ABX), 1H, J4,5b = 2.5 Hz, H-5b), 2.82
(d, 1H, J2,OH-2 = 9.5 Hz, OH-2).
Methyl 2,4-Anhydro-3,5-di-O-benzyl-D-ribonate (19)[9]
To a solution of the lactone 18 (4.3 g, 13.1 mmol) in CH2Cl2 (65.5 mL) and
pyridine (1.9 mL, 1.8 eq) at −30◦C, trifluoromethanesulfonic anhydride (1.2
eq) was added dropwise. After 45 min the reaction mixture was diluted with
CH2Cl2 and washed with a saturated solution of NaHCO3 and then with 1N
HCl solution. After drying with MgSO4 and filtration and evaporation of the
solvent, the crude 3,5-O-benzylidene-2-O-trifluoromethanesulfonyl-D-xylono-
1,4-lactone was immediately used for the next reaction step without further
purification. To a 0.12 M solution of triflated lactone in absolute MeOH at
−12◦C was added potassium carbonate (1.81 g, 1 eq). The resulting suspen-
sion was stirred over 3 h, and the reaction mixture was filtered over Celite
to give the crude 19. This was filtrated over a silica gel column (applied with
CH2Cl2 and eluted with EtOAc) in order to remove salts, and the obtained
residue (3.93 g) was used for the following reaction with no further purifica-
tion. 1H NMR (300 MHz, CDCl3): δ 7.36–7.28 (m, 10H, 2Ph), 5.01 (d, 1H, J2,3
=
5.2 Hz, H-2), 4.76 (ddd, 1H, J3,4 ≈ 4.9 Hz, H-4), 4.67–4.60 (AB, 2H, Ja,b = 8.7
Hz, OCH2Ph), 4.54–4.48 (AB, 2H, Ja’,b’ = 5.4 Hz, OCH2’Ph), 4.52 (dd≈t, 1H,
H-3), 3.61 (A(ABX), 1H, J4,5a = 3.7 Hz, J5a,5b = 11.5 Hz, H-5a), 3.55 (B(ABX),
1H, J4,5b = 4.0 Hz, H-5b), 3.25 (s, 3H, OMe).
Methyl 2,4-Anhydro-D-ribonate (20)[18]
To a 0.07 M solution of methyl 2,4-anhydro-3,5-di-O-benzyl-D-ribonate (19,
3.93 g, assumed 11.5 mmol) in MeOH/dioxane 1:1 was added Pd/C (10% m/m).
The reaction mixture was stirred at rt under hydrogen atmosphere for 3 h.
The catalyst was then removed by filtration. The filtrate was concentrated to
dryness, and the obtained crude product (colorless oil) was reacted without
1
further purification (1.62 g). H NMR (300 MHz, CDCl3): δ 4.95 (d, 1H, J2,3
=
4.9 Hz, H-2), 4.74 (t, 1H, H-3), 4.71 (ddd, 1H, J3,4 = 5.1 Hz, H-4), 3.84 (A(ABX),
1H, J4,5a = 2.5 Hz, J5a,5b = 13.4 Hz, H-5a), 3.80 (s, 3H, OMe), 3.65 (B(ABX),
1H, J4,5b = 2.0 Hz, H-5b).
Methyl 2,4-Anhydro-5-azido-5-deoxy-D-ribonate (21)
To a solution of the crude methyl 2,4-anhydro-D-ribonate (1.62 g, assumed
10.0 mmol) in CH2Cl2 (50 mL) pyridine (0.76 mL, 1.0 eq) was added dropwise
trifluoromethanesulfonic anhydride (2.0 mL, 1.2 eq) cooled below −30◦C. Af-
ter 30 min the reaction mixture was diluted with CH2Cl2 and washed with

Synthesis of 3-Fluoro-Oxetane δ-Amino Acids
443
saturated solution of NaHCO3 and then with 1N HCl solution. The organic
phases were dried over MgSO4 and filtered and the solvent was evaporated.
To a 0.1 M acetone solution of the crude triflate was added sodium azide
(3.9 g, 6 eq). After stirring overnight at rt the reaction mixture was con-
centrated. Iced water was added, and the product was extracted with tert-
butylmethyl ether. The combined organic layers were washed with brine,
dried with MgSO4, filtered, and concentrated. The residue obtained was chro-
matographed (EtOAc/cyclohexane 1:4) to furnish compound 21 as a colorless
20
1
oil (1.29 g, 6.9 mmol, 53% from lactone 18). α
−82 (c 1.00, CH2Cl2). H
[ ]D
NMR (300 MHz, CDCl3): δ 4.95 (d, 1H, J2,3 = 4.8 Hz, H-2), 4.76–4.69 (m, 2H,
H-3, H-4), 3.84 (s, 3H, OMe), 3.63 (A(ABX), 1H, J4,5a = 3.0 Hz, J5a,5b = 13.7
Hz, H-5a), 3.44 (B(ABX), 1H, J4,5b = 3.3 Hz, H-5b), 3.26 (br d, 1H, OH).
Methyl 2,4-Anhydro-5-azido-5-deoxy-3-fluoro-D-xylonate (22)
To a solution of azide 21 (263.4 mg, 1.41 mmol) in acetonitrile (10 mL) at
−20◦C was added DAST (0.36 mL, 2.75 mmol), and the mixture was stirred un-
til conversion into the intermediate (1.5 h, see Sch. 4). The solution was then
allowed to reach rt, and pyridine (0.11 mL, 1.4 mmol) was added while the tem-
perature was increased to 50◦C. After 3 h complete consumption of the inter-
mediate was observed, and the brown solution was cooled, diluted with diethyl
ether, and washed with a saturated solution of NaHCO3. The aqueous layer
was washed with diethyl ether and the organic phases were combined, dried,
and concentrated. The evaporation of diethyl ether was monitored so that evap-
oration of the product could be avoided. The crude compound 22 (282.9 mg)
was reacted without further purification. H1 NMR (300 MHz, CDCl3): δ 5.65
(dt, 1H, J2,3 ≈ J3,4 ≈ 5.8 Hz, J3,F = 56.2 Hz, H-3), 5.30 (dd, 1H, J2,F = 18.4 Hz,
H-2), 5.02–4.91 (m, 1H, J4,F = 15.5 Hz, H-4), 3.86 (s, 3H, OMe), 3.80 (A(ABX),
1H, J4,5a = 1.7 Hz, H-5a), 3.67 (B(ABX), 1H, J5a,5b = 13.0 Hz, H-5b).
Methyl 2,4-Anhydro5-N-(t-butoxycarbonyl)amino-5-deoxy-3-
fluoro-D-xylonate (23)
To a 0.12 M solution of the crude azide 22 (considered 1.41 mmol) in EtOAc
was added Pd/C (10% m/m), and the suspension was stirred vigorously for 30
min under hydrogen atmosphere. A 0.12 M solution of Boc2O (0.32 g, 1.05 eq)
in EtOAc (12.5 mL) was then added, and the reaction mixture was stirred
at rt under H2 atmosphere for 1.5 h. The catalyst was removed by filtra-
tion, and the solvent was evaporated. Chromatography of the obtained residue
(EtOAc/heptane 1:4 to 1:1) yielded the pure product 23 as a colorless oil (193
20
mg, 0.73 mmol, 52%). α +41.0 (c 0.89, CHCl3). H1 NMR (300 MHz, CDCl3): δ
[ ]D
5.60 (dt, 1H, J2,3 ≈ J3,4 ≈ 5.6 Hz, J3,F = 56.6 Hz, H-3), 5.28 (dd, 1H, J2,F = 18.9
Hz, H-2), 5.04–4.91 (m, 2H, H-4, NH), 3.84 (s, 3H, OMe), 3.69–3.54 (m, 2H,

S.D. Lucas et al.
444
H-5a, H-5b), 1.44 (s, 9H, Boc). HRMS (pNSI) m/z 264.12418 [M+H]+, calcd.
264.12418 for C11H18FNO5.
2,4-Anhydro-5-N-(t-butoxycarbonyl)amino-5-deoxy-3-fluoro-D-
arabinonic Acid (24)
To a 0.06 M solution of the methyl ester 23 (97.8 mg, 0.38 mmol) in THF
was added 1N aqueous LiOH (3 eq) at 0–5◦C, and the mixture was stirred for
30 min. Then, maintaining the temperature range, 1N HCl (3 eq) was added,
and the mixture was stirred for 30 min. Brine was added, and the product
was extracted three times with tert-butylmethyl ether. The organic layers were
combined, dried over MgSO4, and filtered and the solvent was evaporated to
give the product 24 as colorless hygroscopic foam (91.7 mg, 0.37 mmol, 97%).
MS (ionspray neg.): m/z 248.3 [M-H]−. H1 NMR (300 MHz, CDCl3): δ 5.64 (dt,
1H, J2,3 ≈ J3,4 ≈ 6.0 Hz, J3,F = 56.1 Hz, H-3), 5.29 (dd, 1H, J2,F = 17.8 Hz, H-2),
5.01–4.86 (m, 2H, H-4, NH), 4.08–3.95 (m, 1H, H-5a), 3.29–3.19 (m, 1H, H-5b),
1.46 (s, 9H, Boc). HRMS (pNSI) m/z 272.09057 [M+Na]+, calcd. 272.09047 for
C10H16FNO5Na.
ACKNOWLEDGEMENTS
The authors would like to thank Mr. Siegfried Stolz for recording HRMS spec-
tra at F. Hoffmann-La Roche, Basel. S.D. Lucas would like to thank Fundac¸a˜o
para a Cieˆncia e Tecnologia for a PhD grant (SFRH/BD/16592/2004).
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