Enantioselective desymmetrization of meso bicyclic hydrazines: A novel approach to the asymmetric synthesis of polysubstituted amino cyclopentanic cores

Article abstract of DOI:10.1021/jo011190e

Catalytic asymmetric hydroboration can be successfully applied to meso bicyclic hydrazines. The resulting alcohols are of great synthetic interest and can lead in a straightforward manner to cyclopentanic diamino alcohols with good enantiomeric purity.

Full text of DOI:10.1021/jo011190e

3522
J . Org. Chem. 2002, 67, 3522-3524
Sch em e 1
En a n tioselective Desym m etr iza tion of
Meso Bicyclic Hyd r a zin es: A Novel
Ap p r oa ch to th e Asym m etr ic Syn th esis of
P olysu bstitu ted Am in o Cyclop en ta n ic
Cor es
Sch em e 2a
A. Pe´rez Luna, M.-A. Ceschi, M. Bonin,*
L. Micouin,* and H.-P. Husson
Laboratoire de Chimie The´rapeutique UMR 8638 associe´e
au CNRS et a` l’Universite´ Rene´ Descartes Faculte´ des
Sciences Pharmaceutiques et Biologiques 4,
av. de l’Observatoire, 75270 Paris Cedex 06, France
S. Gougeon, G. Estenne-Bouhtou, B. Marabout,
M. Sevrin, and P. George
a
De´partement de Recherche Syste`me Nerveux Central,
Sanofi-Synthe´labo Recherche,31, Av. P. V. Couturier,
92220 Bagneux, France
Reagents and conditions: (a) R1NdNR2, CH2Cl2, 0 °C, quan-
titative, (b) (i) BH3‚THF, THF, 0 °C, 3 h, (ii) aq NaOH, H2O2, rt,
2 h.
micouin@pharmacie.univ-paris5.fr
Received December 31, 2001
on desymmetrization of 1 using asymmetric catalytic
hydroboration.6
Hydrazines 1a -c were prepared on a multigram scale
in quantitative yields from the corresponding commercial
dialkylazodicarboxylates and cyclopentadiene. Urazole
1d was prepared according to a reported procedure.7 The
corresponding racemic alcohols 3a -d were obtained by
standard hydroboration with BH3‚THF followed by oxi-
dative workup (Scheme 2). As previously noted, this
procedure led to the exclusive formation of exo alcohols.4
Our first trials of asymmetric hydroboration were made
on hydrazine 1b at low temperature, with [Rh(COD)Cl]2
as rhodium source and (S,S)-BDPP as chiral diphosphine
in various solvents (Table 1). The best results were
obtained with DME as a solvent. Under these experi-
mental conditions, (S,S)-BDPP proved to be the ligand
of choice, leading to the best chemical yield and enan-
tiomeric excess (Table 2). The stereochemical outcome of
the reaction8 was the same as previously reported for the
hydroboration of norbornene with this ligand.6r Interest-
ingly, the use of (S,S)-DIOP afforded alcohol 3b of
opposite configuration, as already observed in the case
Abstr a ct: Catalytic asymmetric hydroboration can be suc-
cessfully applied to meso bicyclic hydrazines. The resulting
alcohols are of great synthetic interest and can lead in a
straightforward manner to cyclopentanic diamino alcohols
with good enantiomeric purity.
Desymmetrization of meso compounds provides an
efficient route to asymmetric synthons of high value in
a limited number of steps.1 This approach is particularly
powerful when performed by a catalytic enantioselective
transformation, since a small amount of chiral nonrace-
mic material allows the simultaneous creation of several
asymmetric centers from an easily available precursor.2
In the course of our studies on cyclic hydrazines as
enantiopure R-ω polyfunctional diamine precursors,3 our
attention was drawn to an elegant racemic approach of
diaminocyclopentitols 2 based on hydroboration of meso
bicyclic hydrazines 1 followed by the reductive cleavage
of the N-N bond (Scheme 1).4
If one considers the obvious structural analogy between
compounds 1 and norbornene, it is possible to speculate
that the numerous desymmetrization operations per-
formed with norbornene could be used on bicyclic hydra-
zines 1 and lead to compounds of significant synthetic
and biological interest.5We report here our first studies
(6) (a) Burgess, K.; Ohlmeyer, M. J . J . Org. Chem. 1988, 53, 5178.
(b) Hayashi, T.; Matsumoto, Y.; Ito, Y. J . Am. Chem. Soc. 1989, 111,
3426. (c) Sato, M.; Miyaura, N.; Suzuki, A. Tetrahedron Lett. 1990,
31, 231. (d) Brown, J . M.; Lloyd-J ones G. C. Tetrahedron: Asymmetry
1991, 1, 869. (e) Hayashi, T.; Matsumoto, Y.; Ito, Y. Tetrahedron:
Asymmetry 1991, 2, 601. (f) Burgess, K.; Van der Donk, W. A.;
Ohlmeyer, M. J . Tetrahedron: Asymmetry 1991, 2, 613. (g) Zhang J .;
Lou, B.; Guo, G.; Dai, L. J . Org. Chem. 1991, 56, 1670. (h) Brown J .
M.; Hulmer, D. I.; Langzell, T. P. J . Chem. Soc., Chem. Commun. 1993,
1673. (i) Togni, A.; Breutel, C.; Schnyder, A.; Spindler, F.; Landert,
H.; Tijani, A. J . Am. Chem. Soc. 1994, 116, 4062. (j) Schnyder, A.;
Hintermann, L.; Togni, A. Angew. Chem., Int. Ed. Engl. 1995, 34, 931.
(k) Doucet, H.; Fernandez, E.; Layzell, T. P.; Brown, J . M. Chem. Eur.
J . 1999, 5, 1320. (l) Brunel, J .-M.; Buono, G. Tetrahedron Lett. 1999,
40, 3561. (m) Fernandez, E.; Maeda, K.; Hooper, M. W.; Brown, J . M.
Chem. Eur. J . 2000, 6, 1840. (n) McCarthy, M.; Guiry, P. Polyhedron
2000, 19, 541. (o) Demay, S.; Volant, F.; Knochel, P. Angew. Chem.,
Int. Ed. Engl. 2001, 40, 1235. Reviews: (p) Burgess, K.; Ohlmeyer, M.
J . Chem. Rev. 1991, 91, 1179. (q) Beletskaya, I.; Pelter, A. Tetrahedron
1997, 53, 4957. (r) Hayashi, T. In Comprehensive Asymmetric Catalysis;
J acobsen, E. N., Pfaltz A., Yamamoto H., Eds.; Springer-Verlag: Berlin,
1999.
(1) (a) Magnuson, S. R. Tetrahedron 1995, 51, 2167. (b) Angelaud,
R.; Babot, O.; Charvat, T.; Landais, Y. J . Org. Chem. 1999, 64, 9613.
(c) Trost, B. M.; Surivet, J .-P. Angew. Chem., Int. Ed. Engl. 2000, 39,
3122.
(2) For a recent impressive example of this strategy, see: Spivey, A.
C.; Woodhead, S. J .; Weston, M.; Andrews B. I. Angew. Chem., Int.
Ed. Engl. 2001, 40, 769.
(3) Roussi, F.; Chauveau, A.; Bonin, M.; Micouin, L.; Husson, H.-P.
Synthesis 2000, 1170.
(4) (a) Mellor, J . M.; Smith, N. M. J . Chem. Soc., Perkin. Trans. 1
1984, 2927. (b) For a similar approach with a biocatalytic desymme-
trization at a latter stage, see: Grabowski, S.; Armbruster, J .; Prinz-
bach, H. Tetrahedron Lett. 1997, 38, 5485.
(5) (a) Berecibar, A.; Grandjean, C.; Siriwardena, A. Chem. Rev.
1999, 99, 779. (b) Lai, Y.-S.; Mendoza, J . S.; J agdmann, E. G., J r.;
Menaldino, D. S.; Biggers, C. K.; Heerding, J . M.; Wilson J . W.; Hall,
S. E.; J iang, J . B.; J anzen W. P.; Ballas, L. M. J . Med. Chem. 1997,
40, 226.
(7) Moore, J . A.; Muth, R.; Sorace, R. J . Org. Chem. 1974, 39, 3799.
(8) Exo selectivity of the hydroboration was determined by 1H NMR
analysis. The absolute configuration of 3b was confirmed by X-ray
analysis of the final diamino alcohol protected as p-bromo dibenzamide
(Chiaroni, A.; Cesario, M., unpublished results).
10.1021/jo011190e CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/25/2002

Notes
J . Org. Chem., Vol. 67, No. 10, 2002 3523
Sch em e 3a
Ta ble 1
solvent
yield (%)
eea (%)
config
a
Reagents and conditions: (a) (i) H2, CH3COOH, Pt, (ii)
toluene
THF
Et2O
DME
CH2Cl2
40
47
56
90
3
66
64
60
(1R,4R,5R)
(1R,4R,5R)
(1R,4R,5R)
(1R,4R,5R)
PhCOCl, Py.
Sch em e 4a
84
ndb
a
b
Determined by chiral HPLC. ee not determined.
Ta ble 2
ligand
yield (%)
eea (%)
config
a
(S,S)-BDPP
(R)-BINAP
(R)-QUINAP
(S,S)-DIOP
90
20
11
46
84
0
24
44
(1R,4R,5R)
Reagents and conditions: (a) oxalyl chloride, DMSO, Et3N,
84%; (b) BH3‚THF, 76%; (c) Ac2O, Py, DMAP, 82%; (d) (i) H2,
CH3COOH, Pt, (ii) PhCOCl, Py, 78%.
(1R,4R,5R)
(1S,4S,5S)
Changing to the cationic rhodium source Rh(COD)2BF4
had little effect on the reaction, since compound 3b could
be obtained in 88% yield and 76% ee. Using optimal
conditions, no differences were observed between a 200
mg and a 5 g scale run, showing the high potential of
this synthetic pathway.
a
Determined by chiral HPLC.
Ta ble 3
Access to diaminocyclopentitol 2 was achieved in a
straightforward manner from 3b (Scheme 3). Optical
purity of the final compound was checked by chiral
HPLC. Enantiomeric excess could be increased to 92%
by a single recrystallization from methanol.
Alcohol 3b is of great synthetic interest. As an example,
it can be oxidized to the ketone 4 in a nearly quantitative
way, leading to the endo alcohol 5 after selective reduc-
tion. The final all-cis diamino alcohol 7 was obtained
after O-protection, subsequent reductive cleavage, and
benzoylation in a good overall yield (Scheme 4).
R1
CO2Et
CO2Bn
CO2tBu
CONPhCO
norbornene
R2
yield (%)
eea (%)
CO2Et
CO2Bn
CO2tBu
49
90
58
78
<10
83c
84
80c
60c
ndb
a
b
Determined by chiral HPLC. ee not determined. c Absolute
configuration not determined.
In conclusion, we have shown that desymmetrization
reactions with catalytic asymmetric hydroboration are
not restricted to norbornene or nonfunctionnalized sub-
strates and can be successfully applied to meso bicyclic
hydrazines. The resulting alcohols are of great synthetic
interest and can lead in a straightforward manner to
cyclopentanic diamino alcohols with good enantiomeric
purity. Scopes and limitations of this new synthetic
strategy are under investigation in our laboratory.
of the norbornene series. Surprisingly, a complete lack
of enantioselectivity and a low conversion was observed
when BINAP was used, although this chiral phosphine
has been reported to give good results in the hydrobora-
tion of norbornene.6r
The influence of the nitrogen protective groups was
studied (Table 3). In all cases, bicyclic hydrazines were
more reactive under these conditions than norbornene.
This enhanced reactivity is probably due to some neigh-
boring participation of the protected nitrogens, as previ-
ously observed in some regioselectivity studies on sub-
stituted norbornene, although the mechanistic features
of this phenomenon remain to be clarified.9
Finally, the best results were obtained with compound
1b, which could be hydroborated in very good yield and
good ee in less than 30 min at - 50 °C. The experimental
procedure had to be intensively optimized to get repro-
ducible results with standard commercially available
reagents (see the Experimental Section for more details).
Exp er im en ta l Section
Gen er a l Com m en ts. NMR spectra were obtained at 200,
300, or 400 MHz (1H field value). IR spectra were recorded as
thin film unless otherwise stated. Elemental analyses were
obtained from the Service de microanalyze of the Institut de
Chimie des Substances Naturelles, Gif-sur-Yvette, France.
Enantiomeric excesses were determined by chiral HPLC (Chiral-
pak AD column). Compounds 1a -d were prepared according to
literature procedures.4,7,10
Gen er a l P r oced u r e for Asym m etr ic Hyd r obor a tion .
Asymmetric hydroboration of 1b is representative: [Rh(COD)-
(9) Brands, K. M. J .; Kende, A. S. Tetrahedron Lett. 1992, 33, 5887.
(10) Heymn, M. L.; Snyder, J . P. Tetrahedron Lett. 1973, 30, 2859.

3524 J . Org. Chem., Vol. 67, No. 10, 2002
Notes
Cl]2 (2.5 mg, 0.005 mmol), (S,S)-BDPP (4.2 mg, 0.01 mmol), and
1b (0.5 mmol) were placed in a Schlenk tube, dried under
vacuum (0.1 mmHg) for 1 h, and then placed under argon. DME
(2 mL) was degassed at -50 °C and added to the mixture at
this temperature. The yellow-green slurry was stirred at -50
°C for 30 min. Catecholborane (0.11 mL, 1 mmol) was added,
and the mixture became orange but remained heterogeneous.
The reaction was kept at -50 °C for an additional 30 min.
Ethanol (0.5 mL) was then added, and the cooling bath was
removed. When the orange mixture became clear, hydrogen
peroxide (30% in water, 0.5 mL) and aqueous sodium hydroxide
(3 M, 0.85 mL) were added, turning the solution to black. After
15 h of stirring, aqueous sodium hydroxide (1 M, 5 mL) was
added, and the mixture was extracted with ethyl acetate (3 ×
10 mL). The organic layer was washed with sodium hydroxide
(1 M, 2 × 10 mL), water (10 mL), andbrine (10 mL) and
concentrated. Purification by flash chromatography (cyclo-
hexane/ethyl acetate ) 50:50) afforded 3b as a colorless oil (182
mg, 90%).
solid (370 mg, 76%): mp ) 235-237 °C; 1H NMR (400 MHz,
CD3OD) δ 1.88 (dt, J ) 13.5, 7.1 Hz, 1H), 2.10-2.26 (m, 2H),
2.79 (dt, J ) 13.5, 6.3 Hz, 1H),4.28 (m, 1H), 4.40 (m, 1H), 4.62
(quint, J ) 7.6 Hz, 1H), 4.92 (s, 3H), 7.52-7.69 (m, 6H) 7.90-
8.00 (m, 4H); 13C NMR (75 MHz, CD3OD) δ 36.8, 39.5, 49.2, 59.2,
76.9, 128.3, 128.4, 129.6, 132.7, 169.1, 171.0; IR (KBr) 3296,
1628, 1530, 1490; MS 325 (MH+). Anal. Calcd for C19H20N2O3:
C, 70.35; H, 6.21; N, 8.64. Found: C, 70.31; H, 6.33; N, 8.49.
5-Oxo-2,3-d ia za b icyclo[2.2.1]h ep t a n e-2,3-d ica r b oxylic
Acid Diben zyl Ester 4. Oxalyl chloride (0.2 mL, 2.3 mmol) was
dissolved in anhydrous CH2Cl2 (4 mL) under argon and cooled
to -30 °C, and DMSO (0.3 mL, 4.2 mmol) was added dropwise.
Compound 3b (382 mg, 1 mmol) in CH2Cl2 (3 mL) was added,
and the resulting mixture was stirred for 3 h at -50 °C.
Triethylamine (0.9 mL) was added, and the solution was stirred
for 20 min at -50 °C and allowed to reach 0 °C. The reaction
was quenched with water. The organic phase was separated and
washed with brine, aq HCl (1 M), aq NaHCO3, and brine. The
organic layer was dried over MgSO4 and concentrated to give a
residue that was purified by flash column chromatography
(AcOEt/cyclohexane ) 1:1) to give 4 as a white solid recrystal-
lized from AcOEt/hexane ) 9:1 (320 mg, 84%): mp ) 77-78
°C; 1H NMR (200 MHz, CDCl3) δ 1.50 (s, 2H), 2.25-2.30 (m,
2H), 4.40 (s, 1H), 4.95 (s, 1H), 5.07-5.19 (m, 4H), 7.10-7.36 (m,
10H); 13C NMR (75 MHz, CDCl3) δ 36.3, 40.4, 58.1, 65.2, 68.4,
68.5, 127.9, 127.9, 128.2, 128.5, 135.3, 156.4, 157.8, 201.6; IR
(neat) 1713, 1497; MS 381 (MH+), 132. Anal. Calcd for
5-Hyd r oxy-2,3-d ia za bicyclo[2.2.1]h ep ta n e-2,3-d ica r box-
ylic Acid Dieth yl Ester 3a . Spectral data are consistent with
those reported in the literature.4a
5-Hyd r oxy-2,3-d ia za bicyclo[2.2.1]h ep ta n e-2,3-d ica r box-
1
ylic Acid Diben zyl Ester 3b: H NMR (300 MHz, DMSO-d6,
70 °C) δ 1.46 (dt, J ) 13.7, 2.5 Hz, 1H), 1.54 (d, J ) 10.5 Hz,
1H), 1.98 (d, J ) 10.5 Hz, 1H), 1.98-2.04 (m, 1H), 4.28 (s, 1H),
4.52 (s, 1H), 4.68 (s, 1H), 5.16 (m, 4H), 7.35 (m, 10H); 13C NMR
(75 MHz, CDCl3) δ 34.0, 38.0 (br), 59.6, 64.3, 68.1, 68.2, 70.4,
128.0, 128.3, 135.8, 135.9, 155.0 (br); IR (neat) 3453, 3063, 3032,
2952, 1760, 1633, 1496; MS 400 (M + 18), 383 (MH+), 339, 249.
Anal. Calcd for C21H22N2O5: C, 65.96; H, 5.80; N, 7.33. Found:
C, 65.79; H, 5.96; N, 7.33.
5-Hyd r oxy-2,3-d ia za bicyclo[2.2.1]h ep ta n e-2,3-d ica r box-
ylic Acid Di-ter t-bu tyl Ester 3c. The title compound was
prepared from 1c according to the general procedure. Purifica-
tion by flash chromatography (cyclohexane/ethyl acetate ) 60:
40) afforded 3c as a white solid (91 mg, 58%): mp ) 58-59 °C;
1H NMR (300 MHz, CDCl3) δ 1.48 (s, 18H), 2.6 (m, 4H), 4.15-
4.60 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 28.2, 33.8, 39.0 (br),
59.3 (br) 63.5, 64.2, 69.3, 70.7, 81.6, 157.0 (br); IR (neat) 3691,
3606, 3413, 1772, 1735, 1688; MS 332 (M + 18), 315 (MH+), 215.
Anal. Calcd for C15H26N2O5: C, 57.31; H, 8.34; N, 8.91. Found:
C, 57.42; H, 8.42; N, 8.72.
C
21H20N2O5: C, 66.31; H, 5.30; N, 7.36. Found: C, 66.20; H, 5.50;
N, 7.15.
Red u ction of Keton e 4. Borane‚THF complex (6.13 mL, 1
M in THF) was added dropwise to a solution of ketone 4 (3.50 g,
9.20 mmol) in THF (34 mL) at 0 °C. The reaction mixture was
stirred at 0 °C for 2.5 h. A second portion of borane solution
(3.13 mL) was added, and the mixture was stirred for 30 min at
0 °C. The reaction was quenched with water (5 mL) and stirred
for 2 h at room temperature. Brine (30 mL) was added, and the
resultant mixture was extracted with EtOAc (3 × 50 mL). The
combined organic layers were dried over MgSO4 and concen-
trated. The crude product was purified by column chromatog-
raphy on silica gel (hexanes/AcOEt ) 6:4) to afford 5 (2.69 g,
76%).
Acetic Acid 2,4-Bis(ben zoyla m in o)cyclop en tyl Ester 7.
To a solution of the endo alcohol 5 (300 mg, 0.78 mmol) in CH2-
Cl2 (2 mL) at 0 °C were added freshly distilled pyridine (0.64
mL, 7.84 mmol) and DMAP (1 mg). To this mixture was added
acetic anhydride (0.8 mL, 7.84 mmol) over a 10 min period. After
being stirred at room temperature for 30 h, the reaction mixture
was quenched with H2O (20 mL). The mixture was stirred for 1
h and extracted with ethyl acetate twice. The combined organic
extracts were dried over MgSO4 and concentrated under reduced
pressure. The crude residue was purified by flash silica gel
chromatography to give 6 as a white oil (270 mg, 82%).
8-Hyd r oxy-4-p h en yl-2,4,6-tr ia za tr icyclo[5.2.1.0]d eca n e-
3,5-d ion e 3d . The title compound was prepared from 1d
according to the general procedure. Purification by flash chro-
matography (cyclohexane/ethyl acetate ) 50:50) afforded 3d as
1
a white solid (103 mg, 78%): mp ) 163-173 °C; H NMR (300
MHz, CDCl3) δ 1.65 (br d, J ) 14.1 Hz, 1H), 1.93 (br d, J ) 10.8
Hz, 1H), 2.21 (d, J ) 10.8 Hz, 1H), 2.30 (ddd, J ) 14.0, 6.8, 2.3
Hz, 1H), 4.26 (s, 1H), 4.48 (s, 1H), 4.65 (s, 1H), 7.35-7.49 (m,
5H); 13C NMR (75 MHz, CDCl3) δ 35.2, 39.4, 59.0, 64.2, 69.9,
125.5, 128.6, 129.3, 131.5, 156.7 (br); IR (CHCl3) 3692, 3606,
3470, 3040, 1771, 1713; MS 277 (M + 18), 260 (MH+). Anal.
Calcd for C13H13N3O5‚0.5H2O: C, 58.20; H, 5.26; N, 15.66.
Found: C, 58.21; H, 5.27; N, 15.51.
The nitrogen-nitrogen bond reductive cleavage of 6 (200 mg,
0.47 mmol) with Pt black and benzoylation was performed
according to the same procedure as for 3b. 7 was obtained as a
1
white oil (134 mg, 78%): H NMR (400 MHz, CDCl3) δ 1.92 (m,
P r ep a r a t ion of N-(4-Ben zoyla m in o-2-h yd r oxycyclo-
p en tyl)ben za m id e 2. A solution of 3b (580 mg, 1.52 mmol) in
AcOH (3 mL) was stirred over Pt black at room temperature
under hydrogen atmosphere for 48 h. After filtration, the solvent
was evaporated, the residue was dissolved in a 1:1 aq NaHCO3/
t-BuOH mixture (8 mL), and benzoyl chloride (0.528 mL, 4.55
mmol, 3 equiv) was added to the mixture. The reaction mixture
was stirred 16 h at 25 °C, and the excess t-BuOH was removed
under reduced pressure. Brine (30 mL) was added to the residue,
and the product was extracted with ethyl acetate (4 × 30 mL).
The combined organic layers were dried over MgSO4 and
concentrated to give a residue that was purified by flash column
chromatography (AcOEt/MeOH ) 86:14) to give 2 as a white
1H), 2.04-2.17 (m, 1H), 2.05 (s, 3H), 2.47 (m, 1H), 2.65 (dt, J )
14.3, 8.0 Hz, 1H), 4.36 (m, 1H), 4.62 (dt, J ) 12.6, 7.5 Hz, 1H),
5.22 (dt, J ) 10.7, 5.4 Hz, 1H), 7.39-7.54 (m, 8H), 7.60 (d, J )
7.1 Hz, 1H) 7.88 (d, J ) 7.1 Hz, 1H); 13C NMR (75 MHz, CDCl3)
δ 21.1, 36.1, 36.2, 47.2, 51.3, 74.5, 126.8, 127.1, 128.6, 131.5,
134.3, 167.1, 167.2, 170.3; IR (neat) 3027, 1736, 1658; MS 367
(MH+).
Ack n ow led gm en t. We thank MERT (M.-A.C.) and
CNRS (A.P.L.) for a grant.
J O011190E