Stereoselective synthesis of fluorinated 1,3- cis -diaminocyclopentanes

Article abstract of DOI:10.1021/jo2001512

Several fluorinated 1,3-diaminocyclopentanes, previously reported to be useful RNA structural probes, can be prepared in a diastereoselective manner from a single bicyclic hydrazine precursor, in 3 to 9 steps.

Full text of DOI:10.1021/jo2001512

NOTE
pubs.acs.org/joc
Stereoselective Synthesis of Fluorinated
1,3-cis-Diaminocyclopentanes
Morgane Pasco,† Roba Moumnꢀe,† Thomas Lecourt, and Laurent Micouin*
UMR8638, CNRS-Paris Descartes University, Laboratoire de Chimie Thꢀerapeutique, Facultꢀe des Sciences Pharmaceutiques et
Biologiques, 4 av. de l'Observatoire, 75006 Paris, France
S Supporting Information
b
ABSTRACT: Several fluorinated 1,3-diaminocyclopentanes, previously reported to
be useful RNA structural probes, can be prepared in a diastereoselective manner from
a single bicyclic hydrazine precursor, in 3 to 9 steps.
he presence of a fluorine atom in a molecule is known to
significantly influence its physicochemical properties.1 As a
requires the fluorination with inversion of configuration. As this
stereochemical outcome is not possible, working on the bicyclic
structure, hydrazine 3 was first reductively cleaved and the two
amines were protected by several protective groups (Scheme 3).
The fluorination of the protected diaminocyclopentanols
having a 1,2-aminoalcohol trans configuration without participa-
tion of the neighboring groups proved to be difficult. Thus,
treatment of compound 8 with DAST led to the oxazolidinone 9
in 52% isolated yield, accompanied with a diastereomeric mixture
of 10 as side products. Tosyl protective groups were introduced
in order to avoid the participation of the carbonyl groups of the
carbamates. However, the fluorination proved also to be trouble-
some, leading to a mixture of products with meso aziridine 12 as a
major component. The use of N,N0-tetrabenzyl 14 led to a single
fluorinated isomer, albeit with the trans configuration, again via a
transient meso aziridinium intermediate. Finally, protection of the
diamino alcohol 3 with 2,4-dinitrophenyl (DNP)10 enabled the
fluorination of 16 with full inversion of configuration in 21%
yield. This modest chemical yield can be explained by the low
solubility of DNP-protected compounds, leading to purification
problems. As this transformation does not involve any meso
intermediate, it could also be conducted from enantioenriched
material, leading to enantioenriched compound 17. Compound
1b was finally obtained after a sequence of deprotectionꢀprotec-
tion for purification, followed by removal of the Boc groups
under acidic conditions (Scheme 4).
T
result, selective introduction of fluorine atoms into an organic
compound is a classical way to tune its biological properties.2 The
great NMR sensitivity of the naturally abundant 19F nucleus can
also be exploited to investigate biophysical events using the
detection of fluorinated molecular probes.3 In our ongoing work
on the fragment-based design of small molecular RNA binders,4
we have recently reported that fluorinated diamino cyclopen-
tanes 1 can be useful small external probes to study RNA
structures (Figure 1).5 Herein, we present how to prepare these
compounds in an enantio- and/or diastereoselective manner
from bicyclic hydrazine 2 as a single precursor.
Although a direct electrophilic fluorination of the strained
double bond of compound 2 can be envisaged, all the reaction
conditions previously reported on norbornene or structurally
related compounds failed to deliver any fluorinated adducts with
compound 2.6 We then decided to introduce the fluorine atom
starting from the corresponding alcohol (Scheme 1).
Alcohol 3 was prepared using either racemic or asymmetric
hydroboration.7 Reaction with N,N-diethylaminosulfur trifluor-
ide (DAST) led to the corresponding fluorinated bicycle 4 as a
single diastereomer. The full retention of relative configuration
can be explained by the formation of a transient aziridinium.8,9
The formation of this meso intermediate was confirmed by the
obtention of racemic material 4 from enantioenriched (er = 92:8)
alcohol 3. Racemic diamine 1a was then obtained in 80% yield
after reductive hydrogenolysis.
As the fluorination of bicyclic alcohol 3 is a racemizing process,
we envisaged the preparation of nonracemic 1a from the all-cis
protected diamino-alcohol 7 (Scheme 2). The cis relationship
between the leaving group and the neighboring bound car-
bonꢀnitrogen precludes any anchimeric participation, enabling
the formation of enantioenriched 1a with full inversion of
configuration. Nonracemic compound 7 could be prepared from
3 by oxidation and reduction, delivering enantioenriched com-
pound 6, which was hydrogenolyzed and protected by tert-butyl
carbamate groups.
A similar protective group strategy was used for the prepara-
tion of compound 1c (Scheme 5). Dihydroxylation of compound
2, followed by reductive cleavage and protection, led to the diol
19. Monoprotection of 19 led to compound 20, which could be
treated by DAST to deliver the protected fluorinated tetrasub-
stituted cyclopentane as a single diastereomer. The two dinitro-
phenyl groups of compound 21 were removed under basic
conditions, and the amines were reprotected by tert-butyl
carbamates. 1,2,3,4-tetrasubstituted cyclopentane 22 was puri-
fied at this stage and isolated in 13% overall yield from 19.
The preparation of cis-compound 1b from alcohol 3 was then
investigated. Obtention of a 1,2 syn relative configuration
Received: January 26, 2011
Published: May 16, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/jo2001512 J. Org. Chem. 2011, 76, 5137–5142
|

The Journal of Organic Chemistry
NOTE
Scheme 3. Protective Group Influence on the
Fluorination Stepa
Figure 1. General strategy for the synthesis of fluorinated diaminocy-
clopentanes from bicyclic hydrazine 2.
Scheme 1. Synthesis of Compound rac-1aa
a Reagents and conditions: (a) BH3 THF, THF, 0 °C, then H2O2,
3
NaOH, 0 °C to rt; (b) Catecholborane, 1% [Rh(COD)Cl]2, 2% (R,R)-
bdpp, DME, ꢀ50 °C, then H2O2, NaOH, 0 °C to rt; (c) DAST, CH2Cl2,
0 °C; (d) H2, Pd/C, MeOH.
a Reagents and conditions: (a) H2, Pd/C, MeOH or H2, PtO2, AcOH;
(b) Boc2O, K2CO3, THFꢀH2O; (c) TsCl, CH2Cl2ꢀNaOH (1 M); (d)
BnBr, H2OꢀAcetone, K2CO3; (e) 2,4-dinitro-1-fluorobenzene, Et3N,
THF; (f) DAST, CH2Cl2.
Scheme 2. Synthesis of Enantioenriched 1aa
Scheme 4. Synthesis of Compound 1ba
a Reagents and conditions: (a) Amberlite 400 IRA resin (OHꢀ form),
acetoneꢀH2O; (b) Boc2O, THFꢀNaOHaq; (c) HCl, AcOEt.
a Reagents and conditions: (a) (COCl)2, Et3N, DMSO; (b) BH3 THF,
3
THF; (c) H2, Pd/C, MeOH; (d) Boc2O, K2CO3, THFꢀH2O; (e)
DAST, CH2Cl2, 0 °C; (f) HCl, AcOEt.
Scheme 5. Synthesis of Compound 1ca
Compound 1c was then obtained as its hydrochloride form after
hydrogenolysis and acidification in a quantitative yield.
The synthesis of 1,2,4,5-tetrasubstituted cyclopentane 1d was
then envisaged (Scheme 6). Compound 24 was prepared in two
steps from 2 in 28% yield. The treatment of 24 with DAST delivered
compound 25 as a single product in a diastereoselective manner.
Compound 1d was then obtained quantitatively after hydrogenolysis.
The chemo- and diasteroselectivity for the fluorination of diol
249 is noteworthy. This selective process can be explained as
follows (Scheme 7). Both hydroxyl groups can probably react
with the excess of DAST, leading to a bis-activated intermediate
A. The presence of the hydroxymethylene bridge restricts the
conformational freedom of the carbamates, enabling the nitrogen
lone pairs of the hydrazine to be either pseudo equatorial or
pseudo endo axial.
a Reagents and conditions: (a) OsO4, NMO, THFꢀH2O (b) H2, PtO2,
AcOH; (c) 2,4-dinitro-1-fluorobenzene, NaHCO3, H2O; (d) BnBr,
KHMDS, THF; (e) DAST, THF, 0 °C; (f) Amberlite 400 IRA resin
(OHꢀ form), acetoneꢀH2O; (g) Boc2O, THFꢀNaOHaq; (h) H2, Pd/
C, MeOH; (i) HCl, AcOEt.
As a consequence, stereoelectronic effects will favor the
departure of the leaving group located on the ethylene bridge,
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The Journal of Organic Chemistry
NOTE
Scheme 6. Synthesis of Compound 1ca
’ EXPERIMENTAL SECTION
The following compounds have been previously described: 2, 3, and 5
(ref 7); 4, 6, 7, 1a, 1b, 1c, and 1d (ref 5); 8 (ref 11); 23, 24, and 26
(ref 9); 27 (ref 12).
(2-Oxo-hexahydrocyclopentaoxazol-5-yl)carbamic Acid
tert-Butyl Ester 9. DAST (82 μL, 0.62 mmol) was added to a cooled
(ꢀ78 °C) suspension of compound 8 (100 mg, 0.32 mmol) in
anhydrous CH2Cl2 (3 mL). After stirring for 2 h, the reaction mixture
was allowed to reach 0 °C and quenched with an aqueous saturated
solution of NaHCO3 (10 mL). CH2Cl2 (10 mL) was added, and the
organic layer was separated, washed with brine (3 ꢁ 10 mL), dried over
MgSO4, filtered, and evaporated in vacuo. Purification by flash chroma-
tography (CH2Cl2/MeOH 97:3) gave compound 9 (40 mg, 0.17 mmol,
a Reagents and conditions: (a) m-CPBA, CH2Cl2, 40 °C; (b) H2SO4,
CF3CH2OH; (c) DAST, THF, 0 °C to rt; (d) H2, Pd/C, MeOH.
1
52%) as a white powder: mp 186 °C. H NMR (300 MHz, 300 K,
CD3OD) δ: 6.54 (br. s, 1H), 5.06 (ddd, J = 7.9, 6.3, 3.5 Hz, 1H), 4.23
(td, J = 6.3, 3.5 Hz, 1H), 3.92 (sext., J = 6.3 Hz, 1H), 2.26 (dt, J = 13.8, 6.3
Hz, 1H), 2.15 (dt, J = 13.4, 6.3 Hz, 1H), 2.08ꢀ1.97 (m, 1H), 1.83 (dt, J =
13.8, 6.3 Hz, 1H), 1.44 (s, 9H). 13C NMR (75 MHz, 300 K, CD3OD) δ:
161.4, 158.0, 82.7, 80.3, 57.1, 51.6, 40.8, 39.9, 28.7. ESI HRMS: [MNaþ]
calculated for C11H18N2O4Na 265.1164, found 265.1164.
Scheme 7. Fluorination of Bicyclic Hydrazinodiols
2,4-Ditosylaminocyclopentanol 11. A solution of 3 (2.5 g,
6.54 mmol) in MeOH (50 mL) was stirred under a hydrogen atmo-
sphere in the presence of Pd/C (1 g) for 3 days. The reaction mixture
was then filtered through a Celite pad, washed with a 1:1 MeOH/
CH2Cl2 mixture, and evaporated in vacuo to give the deprotected
diaminoalcohol (610 mg, 5.26 mmol). The diaminoalcohol (410 mg,
3.53 mmol) was dissolved in a 1:1 mixture of CH2Cl2/1 M NaOH
(15 mL). Tosylchloride (1.35 g, 7.1 mmol) was added and the reaction
mixture was stirred for 15 h. The aqueous phase was separated and
extracted twice with CH2Cl2. The combined organic layers were washed
with brine, dried over MgSO4, filtered, and evaporated in vacuo.
Purification by flash chromatography (cyclohexaneꢀAcOEt, 4:6) gave
1
compound 11 (850 mg, 57%) as a white powder: mp 78ꢀ80 °C. H
NMR (300 MHz, 300 K, CDCl3) δ: 7.70 (d, J = 8.5 Hz, 2H), 7.67 (d, J =
8.5 Hz, 2H), 7.23 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 8.5 Hz, 2H), 6.00 (d, J =
6.5 Hz, 1H), 5.77 (d, J = 6.8 Hz, 1H), 4.15 (q, J = 6.5 Hz, 1H), 3.61 (sext.,
J = 6.8 Hz, 1H), 3.21 (quint., J = 6.5 Hz, 1H), 2.37 (s, 3H), 2.36 (s, 3H),
2.07 (dt, J = 14.3, 6.8 Hz, 1H), 1.79 (dt, J = 14.1, 6.8 Hz, 1H), 1.68 (dt, J =
14.1, 6.8 Hz, 1H), 1.36 (dt, J = 14.3, 6.8 Hz, 1H). 13C NMR (75 MHz,
300 K, CDCl3) δ: 143.8, 143.6, 136.9, 136.4, 129.9, 129.8, 127.2, 127.1,
60.2, 50.2, 39.0, 37.8, 21.5. ESI MS: [MNaþ] 447, [MKþ] 463.
Compounds 12 and 13. To a cooled (0 °C) solution of 11 (150mg,
0.35 mmol) in anhydrous CH2Cl2 (5 mL) under an argon atmosphere was
added DAST (95 μL, 0.71 mmol). The mixture was stirred at room
temperature for 3 h and quenched with an aqueous saturated solution of
NaHCO3 (10 mL). The organic layers were separated, washed with brine
(3 ꢁ 10 mL), dried over MgSO4, filtered, and evaporated in vacuo.
Purification by flash chromatography (cyclohexaneꢀAcOEt, 7:3) gave an
inseparable mixture of compounds 12 and 13 (75:25, 85 mg, 59% yield of
the mixture). Each compound was characterized from the mixture but not
isolated. 4-Methyl-N-[6-(toluene-4-sulfonyl)-6-azabicyclo[3.1.0]hex-3-
yl]benzenesulfonamide 12: 1H NMR (300 MHz, 300 K, CDCl3) δ: 7.81
(d, J = 8.2 Hz, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.25
(d, J = 8.2 Hz, 1H), 5.04 (d, J = 10.8 Hz, 1H), 3.85 (dt, J = 10.8, 7.4 Hz,
1H), 3.35 (s, 2H), 2.50 (s, 3H), 2.43 (s, 3H), 1.95 (dd, J = 14.9, 7.4 Hz,
2H), 1.77 (m, 2H). 13C NMR (75 MHz, 300 K, CDCl3) δ: 144.9, 143.4,
138.2, 135.0, 129.9, 129.8, 127.9, 126.9, 50.9, 46.1, 35.3, 21.7, 21.6. ESI MS:
[MNaþ] 429. 4-Fluorocyclopentane-1,3-ditosylamine 13: 1H NMR
(300 MHz, 300 K, CDCl3) δ: 7.71 (dd, J = 8.1, 5.0 Hz, 4H), 7.29 (d,
J = 6.4 Hz, 4H), 5.14 (d, J = 9.6 Hz, 1H), 4.96 (d, J = 9.2 Hz, 1H), 4.51 (dt,
J = 54.2, 3.6 Hz, 1H), 3.68 (td, J = 8.5, 3.6 Hz, 1H), 3.59ꢀ3.38 (dm, J = 27
Hz, 1H), 2.43 (s, 6H), 2.17 (dt, J = 13.9, 8.5 Hz, 1H), 1.78ꢀ1.72 (m, 1H),
1.66 (m, 2H), 1.38 (m, 1H). 13C NMR (75 MHz, 300 K, CDCl3) δ: 143.7,
leading to an aziridinium intermediate B. A direct attack of the
hydroxymethylene group by a fluoride is probably inhibited by
the presence of one of the carbamate groups. This effect was
confirmed by the absence of reactivity of compound 26 under
similar conditions. The regioselective opening of this intermedi-
ate is the result of a steric hindrance caused by the second
activated hydroxyl group. Interestingly, this selective fluorination
could not be observed starting from 1,2-diol 27,12 as the
competitive highly diastereoselective formation of a cyclic sulfite
28 was observed.
In conclusion, we have shown that several fluorinated 1,3-
diaminocyclopentanes can be prepared in a diastereoselective
manner from a single bicyclic hydrazine precursor, in 3 to 9 steps.
The use of DAST as a fluorinating agent enabled the selective
formation of the carbon fluorine bond from an alcohol, with
inversion or retention of configuration, and in some cases
skeleton rearrangement. The final fluorinated diamines not only
have been shown to be interesting topological probes to study
RNA structures but also can serve as novel building blocks for the
design of bioactive compounds.
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NOTE
143.6, 137.5, 137.4, 129.9, 129.8, 127.2, 127.0, 94.6 (d, J = 177 Hz), 55.6 (d,
J = 19 Hz), 49.7, 38.1 (d, J = 20 Hz), 36.8, 21.7, 21.6. 19F NMR (282 MHz,
300 K, CDCl3) δ: ꢀ189.4. ESI MS: [MNaþ] 449, [MKþ] 465.
1H), 8.84 (d, J = 2.7 Hz, 1H), 8.75 (br. d, J = 8.2 Hz, 1H), 8.67 (br. d, J =
7.5 Hz, 1H), 8.33 (dd, J = 9.6, 2.7 Hz, 1H), 8.30 (dd, J = 9.6, 2.7 Hz, 1H),
7.41 (d, J = 9.6 Hz, 1H), 7.27 (d, J = 9.6 Hz, 1H), 5.34 (dt, J = 57.0, 3.7
Hz, 1H), 4.59ꢀ4.36 (m, 2H), 2.95 (dt, J = 12.8, 7.7 Hz, 1H), 2.67 (dddd,
J = 41.0, 15.6, 8.4, 4.2 Hz 1H), 2.50 (ddd, J = 26.4, 15.6, 3.7 Hz, 1H),
2.00ꢀ1.91 (ddd, J = 12.8, 10.4, 7.7 Hz, 1H). 13C NMR (75 MHz, 300 K,
DMSO-d6) δ: 147.5, 147.1, 135.5, 135.2, 130.2, 130.1, 130.0, 123.4,
115.8, 115.5, 94.3, 55.1, 50.2, 37.4, 35.8. 19F NMR (282 MHz, 300 K,
DMSO-d6) δ: ꢀ189.0 (ddt, J = 57.0, 41.0, 26.4 Hz). HRMS calculated
for C17H15FN6O8 450.0935, found 450.0935.
(3-tert-Butoxycarbonylamino-4-fluorocyclopentyl)carba-
mic Acid tert-Butyl Ester 18. The crude product 17 (0.9 mmol) was
dissolved in an acetoneꢀwater mixture (50:15, 65 mL). Amberlite 400
IRA resin (OHꢀ form, 6 g) was added, and the reaction mixture was
stirred at room temperature for 2 days, filtered through a Celite pad, and
washed with a THFꢀMeOHꢀH2O (1:1:1) solution. The organic
solvents were removed in vacuo, and the resulting aqueous solution
was basified to pH 10 using NaOH (1 M). THF (15 mL) and Boc2O
(590 mg, 2.7 mmol) were added. After stirring for 20 h, THF was
evaporated, and AcOEt (25 mL) and H2O (25 mL) were added. The
aqueous phase was separated and extracted with AcOEt (3 ꢁ 15 mL).
The combined organic layers were washed with brine, dried over
MgSO4, filtered, and evaporated in vacuo. Purification by flash chroma-
tography (CH2Cl2/MeOH 98:2) gave compound 18 (120 mg, 0.38
mmol, 42% yield from 16) as an amorphous white solid: 1H NMR (300
MHz, 300 K, CDCl3) δ: 4.89 (br. d, J = 55.3 Hz, 1H), 4.81 (br. s, 1H),
4.67 (br. s, 1H), 4.10ꢀ3.78 (m, 2H), 2.52 (dt, J = 15.5, 7.7 Hz, 1H), 2.28
(dddd, J = 42.0, 15.7, 9.5, 4.1 Hz, 1H), 1.81 (ddd, J = 26.8, 15.7, 3.4 Hz,
1H), 1.56ꢀ1.30 (m, 19H). 13C NMR (75 MHz, 300 K, DMSO-d6) δ:
155.2, 155.1, 94.7 (d, J = 178 Hz), 79.8, 79.5, 53.8 (d, J = 17 Hz), 47.7,
38.9 (d, J = 20 Hz), 37.1, 28.4. 19F NMR (282 MHz, 300 K, CDCl3)
δ: ꢀ190 (m). ESI HRMS: [MNaþ] calculated for C15H27FN2O4Na
341.1853, found 341.1855. [R]D22: ꢀ5.1 (c = 1, CHCl3).
2,4-Bis-dibenzylaminocyclopentanol 14. To a suspension of
2,4-diaminocyclopentanol (420 mg, 3.6 mmol) in a waterꢀacetone
mixture (1:3, 36 mL) were added potassium carbonate (4.48 g, 32.4
mmol) and benzyl bromide (1.88 mL, 15.8 mmol). The reaction mixture
was stirred at room temperature for 42 h, and then acetone was
evaporated in vacuo. Water was added (15 mL), and the product was
extracted with CH2Cl2 (3 ꢁ 25 mL). The combined organic layers were
dried over MgSO4, filtered, and concentrated in vacuo. Purification by
flash chromatography (cyclohexaneꢀAcOEt, 85:15 then 80:20) gave
compound 14 (1.36 g, 80%) as a pale yellow solid: mp 101ꢀ102 °C. 1H
NMR (400 MHz, 300 K, CDCl3) δ: 7.45 (m, 16H), 7.33 (m, 4H), 4.24
(q, J = 7.5 Hz, 1H), 3.91 (d, J = 13.7 Hz, 1H), 3.71 (s, 4H), 3.62 (d, J =
13.7 Hz, 1H), 3.44 (m, 1H), 2.98 (td, J = 11.7, 7.5 Hz, 1H), 2.1 (m, 2H),
1.75 (m, 2H). 13C NMR (100 MHz, 300 K, CDCl3) δ: 172.6, 139.9,
128.5, 128.3, 128.2, 127.0, 126.8, 72.1, 67.1, 55.8, 55.0, 54.7, 34.2, 25.4.
HRMS calculated for C33H37N2O 477.2906, found 477.2905.
1,3-Bis-dibenzylamino-4-fluorocyclopentanol 15. A solution
of 14 (194 mg, 0.41 mmol) in anhydrous CH2Cl2 (5 mL) was cooled to
0 °C. After addition of DAST (110 μL, 0.82 mmol), the reaction mixture
was stirred at room temperature for 1 h. Water was added, and the solution
was extracted with CH2Cl2. The combined organic layers were washed
with an aqueous saturated solution of NH4Cl, dried over MgSO4, filtered,
and evaporated in vacuo. Purification by flash chromatography
(cyclohexaneꢀAcOEt, 99:1) gave compound 15 (98 mg, 50%) as a white
1
powder: mp 123ꢀ125 °C. H NMR (300 MHz, 300 K, CDCl3) δ:
7.31ꢀ7.48 (m, 20H), 5.20 (br. d, J = 54 Hz, 1H), 3.64ꢀ3.80 (m, 8H),
3.35ꢀ3.46 (m, 2H), 2.09ꢀ2.21 (m, 2H), 1.87ꢀ2.06 (m, 1H), 1.68ꢀ1.79
(m, 1H). 13C NMR (75 MHz, 300 K, CDCl3) δ: 139.7 (d, J = 23 Hz),
128.7, 128.6, 128.3, 126.3, 96.4, 65.7 (d, J = 23 Hz), 57.8, 55.3 (d, J = 3 Hz),
35.7 (d, J = 22 Hz), 30.3 (d, J = 5 Hz). 19F NMR (282 MHz, 300 K,
CDCl3) δ: ꢀ168.8 (ddt, J = 54, 30, 24 Hz). ESI HRMS: [MNaþ]
calculated for C33H35FN2Na 501.2682, found 501.2681.
Synthesis of rac-3,5-Diamino-2-fluorocyclopentanol 1c.
Compound 2 (5 g, 13.7 mmol) was dissolved in THFꢀH2O
(145 mL:15 mL). NMO (2 g, 16.8 mmol) and potassium osmate (40
mg, 0.11 mmol) were added, and the reaction mixture was stirred at
room temperature for 18 h. HCl (6 N, 200 mL) and NaHSO3 (15% in
water, 100 mL) were added, and the mixture was stirred for 2 h. With
AcOEt (200 mL) added, the organic phase was separated, and the
aqueous layer was extracted with AcOEt (3 ꢁ 200 mL). The combined
organic phases were dried (MgSO4) and concentrated in vacuo. Pur-
ification by flash chromatography (cyclohexaneꢀAcOEt 60:40) gave
compound 27 as a colorless oil (5 g, 12.6 mmol, 90% yield). Compound
27 (5 g) was then stirred in acetic acid (80 mL) under a hydrogen
atmosphere in the presence of PtO2 (750 mg, 3 mmol) for 3 days. After
filtration through a Celite pad and concentration in vacuo, the crude
product was purified on a DOWEX resin (50WX8-400) using a 1 M
aqueous solution of ammonia as an eluting phase, to give a colorless oil in
a quantitative yield (1.65 g). 1H NMR (300 MHz, 323 K, CD3OD) δ:
3.66 (m, 2H), 3.09 (ddm, J = 8.8, 8.0 Hz, 2H), 2.36 (dt, J = 13.5, 8.0 Hz,
1H), 1.06 (dt, J = 13.5, 8.8 Hz, 1H). 13C NMR (75 MHz, 323 K,
CD3OD) δ: 79.8, 57.0, 39.0. ESI MS: [MHþ] 133, [MNaþ] 155. This
diaminodiol (1.3 g, 9.8 mmol) was dissolved in an aqueous saturated
solution of NaHCO3 (75 mL), and 2,4-dinitrofluorobenzene (2.5 mL,
19.9 mmol) was added. The bright yellow solution was stirred for 18 h.
The precipitate was filtered, stirred in CH2Cl2 for 3 h, and dried under
vacuum to give compound 19 (4.1 g, 90%) as a yellow amorphous solid.
2,4-Bis-(2,4-dinitrophenylamino)cyclopentanol 16. 2,4-Diami-
nocyclopentanol, prepared from enantioenriched 3 by Pd/C catalyzed
hydrogenolysis (185 mg, 1.6 mmol, 83% ee), was dissolved in anhydrous
THF (5 mL) containing Et3N (500 μL, 3.5 mmol). 2,4-Dinitro-1-
fluorobenzene (440 μL, 3.5 mmol) was added. The bright yellow solution
was stirred for 5 h at room temperature, and the solvent was evaporated in
vacuo. The crude mixture was stirred in MeOH (5 mL) for 15 h, and the
resulting solid was filtered, washed with CH2Cl2, and dried in vacuo to give
16 (580 mg, 1.3 mmol, 81%) as an amorphous yellow solid: 1H NMR (300
MHz, 300 K, DMSO-d6) δ: 8.85 (d, J = 2.7 Hz, 2H), 8.63 (br. d, J = 8.2 Hz,
1H), 8.61 (br. d, J= 8.2 Hz, 1H), 8.31 (dd, J=9.6, 2.7Hz, 1H),8.30(dd, J=
9.6, 2.7 Hz, 1H), 7.39 (d, J = 9.6 Hz, 1H), 7.26 (d, J = 9.6 Hz, 1H), 5.49 (s,
1H), 4.43 (sext., J = 7.8 Hz, 1H), 4.31ꢀ4.22 (m, 1H), 4.12ꢀ3.98 (m, 1H),
2.82 (dt, J = 13.4, 7.8 Hz, 1H), 2.21ꢀ2.02 (m, 2H), 1.95 (dt, J = 13.4, 7.8
Hz, 1H). 13C NMR (75 MHz, 300 K, DMSO-d6) δ: 147.9, 147.3, 135.1,
135.0, 130.1, 130.0, 129.9, 123.5, 116.0, 115.6, 74.6, 60.4, 50.2, 38.6,
36.2. HRMS calculated for C17H16N6O9Na 471.0871, found 471.0875.
[R]D22: þ19.8 (c = 0.17, CHCl3).
4-Fluorocyclopentane-1,3-bis-(2,4-dinitrophenylamine)
17. DAST (55 μL, 0.43 mmol) was added to a cooled (0 °C) suspension
of compound 16 (96 mg, 0.21 mmol) in anhydrous CH2Cl2 (5 mL)
under an argon atmosphere. The reaction mixture was stirred at room
atmosphere for 45 min and quenched with an aqueous saturated
solution of NaHCO3. The aqueous phase was separated and extracted
twice with CH2Cl2 (2 ꢁ 10 mL). The combined organic layers were
washed with brine (5 mL), dried over MgSO4, filtered, and evaporated
in vacuo. Purification by flash chromatography (CH2Cl2/AcOEt 90:10)
gave compound 17 (20 mg, 0.05 mmol, 21%) as an amorphous yellow
solid: 1H NMR (300 MHz, 300 K, DMSO-d6) δ: 8.86 (d, J = 2.7 Hz,
1
3,5-Bis-(2,6-dinitrophenylamino)cyclopentane-1,2-diol 19: H
NMR (300 MHz, 323 K, DMSO-d6) δ: 8.87 (d, J = 2.6 Hz, 2H), 8.66
(br. s, 2H), 8.31 (dd, J = 9.6, 2.6 Hz, 2H), 7.39 (d, J = 9.6 Hz, 2H),
6.22 (br. s, 2H), 4.20ꢀ4.06 (m, 2H), 3.97 (d, J = 3.8 Hz, 2H), 2.77
(dt, J = 13.0, 8.2 Hz, 1H), 1.89 (dt, J = 13.0, 8.2 Hz, 1H). 13C NMR
(75 MHz, 323 K, DMSO-d6) δ: 147.9, 135.1, 130.0, 129.9, 123.5,
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The Journal of Organic Chemistry
NOTE
116.0, 75.3, 57.1, 32.7. ESI HRMS: [MNaþ] calculated for
(282 MHz, 293 K, CD3OD) δ: ꢀ199.1 (dt, J = 52.1, 23.3 Hz). ESI
HRMS: [MHþ] calculated for C5H12FN2O 135.0934, found 135.0923.
Synthesis of rac-2,5-Diamino-3-fluorocyclopentanol 1d.
To a dry THF (10 mL) solution of diol 24, (375 mg, 0.94 mmol),
prepared according to ref 9, cooled at 0 °C under a argon atmosphere,
was added DAST (190 μL, 1.95 mmol). The reaction mixture was stirred at
room temperature for 15 h and hydrolyzed by an aqueous NaHCO3 solution
(5 mL). The mixture was extracted with AcOEt (3 ꢁ 10 mL), and the
combined organic layers were washed with brine, dried (MgSO4), and then
concentrated in vacuo. Purification by flash chromatography (cyclohexaneꢀ
AcOEt 80:20) gave compound 25 as a colorless oil (215 mg, 57% yield).
5-Fluoro-7-hydroxy-2,3-diazabicyclo[2.2.1]heptane-2,3-dicarboxylic
C
17H16N6O10Na 487.0826, found 487.0824.
To a cooled (0 °C) solution of compound 19 (1.4 g, 3 mmol) and
benzylbromide (1.45 mL, 12 mmol) in anhydrous THF (45 mL) was
slowly (2 mL hꢀ1) added KHMDS (0.5 M in toluene, 7.3 mL,
3
3.5 mmol). The reaction mixture was then stirred at room temperature
for 20 h and quenched with an aqueous saturated solution of NH4Cl.
The aqueous layer was extracted with AcOEt (4 ꢁ 100 mL), and the
combined organic phases were dried (MgSO4) and concentrated in
vacuo. The crude product was stirred in CH2Cl2 for 4 h and dried under
vacuum to give a 1:1 mixture of compounds 19 and 20. A small portion
was purified by flash chromatography (TolueneꢀTHF 80:20, then
70:30, then THF) for characterization of compound 20. 2-Benzyloxy-
3,5-bis-(2,6-dinitrophenylamino)cyclopentanol 20: 1H NMR (300
MHz, 293 K, DMSO-d6) δ: 8.88 (d, J = 2.6 Hz, 1H), 8.86 (d, J = 2.6 Hz,
1H), 8.67 (d, J = 8.2 Hz, 1H), 8.60 (d, J = 8.2 Hz, 1H), 8.35 (dd, J = 9.6,
2.6 Hz, 1H), 8.24 (dd, J = 9.6, 2.6 Hz, 1H), 7.44ꢀ7.20 (m, 7H), 5.57 (d,
J = 5.5 Hz, 1H), 4.74 (d, J = 12.3 Hz, 1H), 4.50 (d, J = 12.3 Hz, 1H), 4.38
(q, J = 8.2 Hz, 1H), 4.19 (q, J = 5.5 Hz, 1H), 4.11 (dd, J = 8.2, 5.5 Hz),
4.02 (t, J = 5.5 Hz, 1H), 2.81 (dt, J = 13.0, 8.2 Hz, 1H), 1.91 (dt, J = 13.0,
8.2 Hz, 1H). 13C NMR (75 MHz, 293 K, DMSO-d6) δ: 147.8, 147.6,
138.3, 135.2, 135.1, 130.1, 130.0, 129.9, 129.8, 128.1, 127.4, 127.3, 123.5,
116.0, 115.9, 82.5, 73.3, 71.3, 57.5, 55.4, 32.4.
1
acid dibenzyl ester 25: H NMR (300 MHz, 323 K, DMSO-d6) δ:
7.53ꢀ7.18 (m, 10H), 5.30(br.s, 1H), 5.17(s, 2H), 5.15 (s, 2H), 4.80 (dm,
J = 53 Hz, 1H), 4.33ꢀ4.29 (m, 2H), 4.10 (s, 1H), 2.29 (dm, J = 4.2 Hz,
1H), 2.21 (m, 1H). 13C NMR (75 MHz, 323 K, DMSO-d6) δ: 156.6;
155.7, 135.6, 128.1, 127.8, 127.3, 89.8 (d, J = 193 Hz), 73.6, 67.2, 61.6,
34.6 (d, J = 19 Hz). 19F NMR (282 MHz, 323 K, DMSO-d6) δ: ꢀ174.0
(m). ESI HRMS: [MNaþ] calculated for C21H21FN2O5Na 423.1327,
found 423.1327. [MKþ] calculated for C21H21FN2O5K 439.1066,
found 439.1057.
Compound 25 (40 mg, 0.1 mmol) was stirred in methanol (3 mL)
under a hydrogen atmosphere in the presence of Pd/C (21 mg, 0.02
mmol) for 15 h. The mixture was filtered through a Celite pad, and the
solvent was concentrated in vacuo. The crude product was dissolved in
AcOEtꢀMeOH (1:1, 10 mL), and HCl(g) was bubbled through the
solution for 1 min. Compound 1d (20 mg, 0.1 mmol) was isolated as its
hydrochloride salt in a quantitative yield. 1H NMR (300 MHz, 293 K,
CD3OD) δ: 5.17 (dddd, J = 52.7, 8.2, 5.2, 3.0 Hz, 1H), 4.17 (t, J = 9.4
Hz, 1H), 3.67 (q, J = 9.4 Hz, 1H), 3.62 (ddd, J = 24.2, 9.4, 5.2 Hz, 1H),
2.39 (m, 2H). 13C NMR (75 MHz, 293 K, CD3OD) δ: 91.3 (d, J = 185
Hz), 75.7 (d, J = 5 Hz), 62.4 (d, J = 25 Hz), 54.2, 33.1 (d, J = 24 Hz). 19F
NMR (282 MHz, 293 K, CD3OD) δ: ꢀ176.7 (dq, J = 52.7, 24.2 Hz).
ESI HRMS: [MHþ] calculated for C5H12FN2O 135.0934, found
135.0935.
To a cooled (0 °C) suspension of compounds 19 and 20 (1:1, 200
mg) in anhydrous THF (8 mL) under an argon atmosphere was added
DAST (190 μL, 1.44 mmol). The reaction mixture was stirred at room
temperature for 3 h and quenched by an aqueous saturated solution of
NaHCO3. The aqueous layer was extracted with AcOEt, and the combined
organic phases were dried (MgSO4) and concentrated in vacuo. The crude
product was not purified at this stage and dissolved in acetoneꢀwater
(36:4, 40 mL). Amberlite 400 IRA resin (OHꢀ form, 3 g) was added, and
the mixture was stirred at room temperature for 2 days, filtered through a
Celite pad, and washed with a THFꢀMeOHꢀH2O (1:1:1) solution. The
organic solvents were removed in vacuo, and the resulting aqueous solution
was basified using NaOH (1M, 20 mL). THF (20 mL) and Boc2O (630
mg, 2.88 mmol) were added. After 15 h of stirring, THF was evaporated,
and AcOEt (30 mL) and H2O(10mL) wereadded. Theaqueouslayerwas
extracted with AcOEt (3 ꢁ 20 mL), the combined organic phases were
dried (MgSO4), and concentrated in vacuo. Purification by flash chroma-
tography (cyclohexaneꢀAcOEt 70:30 to 50:50) gave 22 as an amorphous
solid (17 mg, 13% yield from 19). (3-Benzyloxy-4-tert-butoxycarbony-
lamino-2-fluorocyclopentyl)carbamic acid tert-Butyl Ester 22: 1H
NMR (300 MHz, 333 K, DMSO-d6) δ: 7.46ꢀ7.18 (m, 5H), 6.67 (s,
1H), 6.46 (s, 1H), 4.77 (ddd, J = 52, 4.9, 2.5 Hz, 1H), 4.62 (s, 2H),
3.99ꢀ3.69 (m, 3H), 2.29ꢀ2.15 (dt, J = 11.1, 7.5 Hz, 1H) 1.64 (q,
J = 11.1 Hz, 1H), 1.42 (s, 9H), 1.41 (s, 9H). 13C NMR (75 MHz, 293 K,
DMSO-d6) δ: 155.0, 154.9, 137.9, 128.1, 127.4, 127.4, 94.0 (d, J = 183
Hz), 86.4 (d, J = 25 Hz), 77.9, 77.8, 70.6, 52.7, 49.8 (d, J = 19 Hz), 32.8.
19F NMR (282 MHz, 293 K, CD3OD) δ: ꢀ199.3 (dt, J = 52, 24 Hz).
ESI HRMS: [MNaþ] calculated for C22H33FN2O5Na 447.2271, found
447.2274.
Compound 22 (35 mg, 0.08 mmol) in MeOH (4 mL) was stirred
under a hydrogen atmosphere in the presence of Pd/C (9 mg) for 50 h.
The reaction mixture was filtered through a Celite pad, and the solvent
was concentrated in vacuo. The crude product (28 mg, 0.08 mmol) was
dissolved in AcOEt (10 mL), and HCl(g) was bubbled through the
solution for 45 min. Compound 1c (17 mg, 0.1 mmol) was isolated as its
hydrochloride salt in a quantitative yield. 1H NMR (300 MHz, 293 K,
CD3OD) δ: 5.03 (ddd, J = 52.1, 5.5, 2.1 Hz, 1H), 4.31 (ddd, J = 23.3, 6.3,
2.1 Hz, 1H), 3.90 (dddd, J = 23.3, 11.7, 7.3, 5.5 Hz, 1H), 3.47 (ddd, J =
11.7, 7.3, 6.3 Hz, 1H), 2.66 (dt, J = 11.7, 7.3 Hz, 1H), 2.00 (q, J = 11.7 Hz,
1H). 13C NMR (75 MHz, 293 K, CD3OD) δ: 96.9 (d, J = 185 Hz), 78.8
(d, J = 27 Hz), 55.2 (d, J = 6 Hz), 49.7 (d, J = 18 Hz), 31.6. 19F NMR
4-Oxo-3,5-dioxa-4-thia-8,9-diazatricyclo[5.2.1.02,6]decane-8,
9-dicarboxylic Acid Dibenzyl Ester 28. To a cooled (0 °C)
solution of compound 27 (200 mg, 0.5 mmol) in anhydrous THF
(2.5 mL) was added DAST (75 μL, 0.56 mmol). The reaction mixture
was stirred at room temperature for 1 h and quenched with an aqueous
saturated solution of NaHCO3. The aqueous layer was separated and
extracted with AcOEt (3 ꢁ 5 mL). The combined organic layers were
dried over MgSO4, filtered, and concentrated in vacuo. Purification by
flash chromatography (cyclohexane/AcOEt 80:20) gave compound
28 as a colorless oil (176 mg, 0.4 mmol, 79%, dr endo/exo 92:8). 1H
NMR (300 MHz, 323 K, CDCl3) δ: 7.34 (m, 10H), 5.20 (br. s, 4H),
4.78 (br. s, 2H), 4.76 (br. s, 2H), 2.81 (d, J = 12.3 Hz, 1H), 1.76 (dm,
J = 12.3 Hz, 1H). 13C NMR (75 MHz, 323 K, CDCl3) δ: 156.5, 135.4,
128.7, 128.6, 128.1, 85.9, 68.9, 61.1, 31.1. MS (ES): [MNaþ] 467,
[MKþ] 483.
’ ASSOCIATED CONTENT
1
Supporting Information. copies of H, 19F, and 13C
S
b
NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: laurent.micouin@parisdescartes.fr.
Author Contributions
†These authors contributed equally.
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The Journal of Organic Chemistry
NOTE
’ ACKNOWLEDGMENT
Financial support from CNRS, MRT (grant to M.P.), ANRS
(grant to R.M.), and ANR (research project PCV TriggeRNA) is
acknowledged.
’ REFERENCES
(1) Smart, B. E. J. Fluorine Chem. 2001, 109.
(2) (a) Purser, S.; Moore, P. R.; Gouverneur, V. Chem. Soc. Rev.
2008, 37, 320. (b) Morgenthaler, M.; Schweizer, E.; Hoffmann-R€oder,
A.; Benini, F.; Martin, R. E.; Jaeschke, G.; Wagner, B.; Fischer, H.;
Bendels, S.; Zimmerli, D.; Schneider, J.; Diederich, F.; Kansy, M.;
M€uller, K. ChemMedChem 2007, 2, 1100. (c) M€uller, K.; Faeh, C.;
Diederich, F. Science 2007, 317, 1881.
(3) Dalvit, C. Prog. Nucl. Magn. Reson. Spectrosc. 2007, 51, 243.
(4) (a) Chung, F.; Tisnꢀe, C.; Lecourt, T.; Seijo, B.; Dardel, F.;
Micouin, L. Chem.—Eur. J. 2009, 15, 7109. (b) Chung, F.; Tisnꢀe, C.;
Lecourt, T.; Dardel, F.; Micouin, L. Angew. Chem., Int. Ed. 2007,
46, 4489.
(5) Moumnꢀe, R.; Pasco, M.; Prost, E.; Lecourt, T.; Micouin, L.;
Tisnꢀe, C. J. Am. Chem. Soc. 2010, 132, 13111.
(6) (a) Stavber, S.; Zupan, M. Tetrahedron 1986, 42, 5035.
(b) Zupan, M.; Gregorcic, A.; Pollak, A. J. Org. Chem. 1977, 42, 1562.
(c) Shackelford, S. A. J. Org. Chem. 1979, 44, 3485. (d) Zupan, M.; Skulj,
P.; Stavber, S. Tetrahedron 2001, 57, 10027.
(7) Pꢀerez Luna, A.; Ceschi, M.-A.; Bonin, M.; Micouin, L.; Husson,
H.-P.; Gougeon, S.; Estenne-Bouhtou, G.; Marabout, B.; Sevrin, M.;
George, P. J. Org. Chem. 2002, 67, 3522.
(8) For the rearrangement of β-aminoalcohols via aziridiniums, see:
Mꢀetro, T.-X.; Duthion, B.; Gomez Pardo, D.; Cossy, J. Chem. Soc. Rev.
2010, 39, 89 and references cited therein.
(9) Bournaud, C.; Bonin, M.; Micouin, L. Org. Lett. 2006, 8, 3041.
(10) For a similar strategy, see: Borthwick, A. D.; Evans, D. N.; Kirk,
B. E.; Biggadike, K.; Exall, A. M.; Youds, P.; Roberts, S. M.; Knight, D. J.;
Coates, J. A. V. J. Med. Chem. 1990, 33, 179.
(11) Lombꢁes, T.; Bꢀegis, G.; Maurice, F.; Turcaud, S.; Lecourt, T.;
Dardel, F.; Micouin, L. ChemBioChem 2008, 9, 1368.
(12) Bꢀegis, G.; Bonin, M.; Bournaud, C.; Dardel, F.; Maurice, F.;
Micouin, L.; Tisne, C.; Pꢀerez Luna, A. WO2006024784.
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