Diastereoselective syntheses of N-protected derivatives of 1α,5α,6β- 6-amino-3-azabicyclo[3.1.0]hexane; a route to trovafloxacin 6β-diastereomer

Article abstract of DOI:10.1055/s-1998-2055

N-Protected derivatives 12, 13 and 17 of 1α,5α,6β-6-amino-3- azabicyclo[3.1.0]hexane 5 were synthesized via chloroenamines 6a or 6b. The specific N-protection was realized either by using a chloroenamine 6b with different protecting groups or by selective removal of identical protecting groups at the bicyclic target molecule 7. Dibenzylamino compound 13 allowed the preparation of naphthyridine derivative 25 which represents the 6β- diastereomer of trovafloxacin mesylate, a potent Gyrase inhibitor.

Full text of DOI:10.1055/s-1998-2055

May 1998
SYNTHESIS
739
a a b
Diastereoselective Syntheses of N-Protected Derivatives of 1 ,5 ,6 -6-Amino-3-
b
azabicyclo[3.1.0]hexane; A Route to Trovafloxacin 6 -Diastereomer
Elmar Vilsmaier,* Torsten Goerz
Fachbereich Chemie der Universität Kaiserslautern, Erwin-Schrödinger-Straße, D-67663 Kaiserslautern, Germany
Fax +49(631)2053921; E-mail: vils@rhrk.uni-kl.de
Received 12 September 1997; revised 10 November 1997
Dedicated to Professor Dr. C. G. Kreiter on the occasion of his 60th birthday
Abstract: N-Protected derivatives 12, 13 and 17 of 1a,5a,6b-6- amino function in 6-position, however, was strongly
doubted in the literature.6 We investigated, therefore, ste-
reoselective ways to N-protected species of 6b-isomer 5
on the basis of chloroenamines. The chloroenamine way
to 6b-amino-3-azabicyclohexane derivatives requires
non-deactivating substituents at N(3) (see ref 11) and at
the enamino-N-atom. Consequently, only allyl and benzyl
amino-3-azabicyclo[3.1.0]hexane 5 were synthesized via chloro-
enamines 6a or 6b. The specific N-protection was realized either
by using a chloroenamine 6b with different protecting groups or
by selective removal of identical protecting groups at the bicyclic
target molecule 7. Dibenzylamino compound 13 allowed the prep-
aration of naphthyridine derivative 25 which represents the 6b-
diastereomer of trovafloxacin mesylate, a potent Gyrase inhibitor.
Key words: trovafloxacin 6b-diastereomer, synthesis, chloro- groups are suitable candidates within the family of various
N-protecting groups.16, 17 Realization of a specific N-pro-
tection pattern was intended either by starting from a chlo-
enamines, N-protected 1a,5a,6b-6-amino-3-azabicyclo[3.1.0]hex-
anes
roenamine with different protecting groups (e.g. 6b) or by
regioselective removal of identical protecting groups at a
bicyclic derivative (e.g. 7) as shown already successfully
for selective N(3) debenzylation of bicyclic carbonitrile
8.12 The results of these investigations and a new synthe-
sis of the 6b-diastereomer of trovafloxacin are reported in
this paper.
1a,5a,6a-6-Amino-3-azabicyclohexane 1a represents
the amino moiety in trovafloxacin1 (2) which is strongly
active against Gram-negative and Gram-positive bacteria
as well as anaerobes and penicillin-resistant Streptococ-
cus pneumoniae pathogens.2, 3
Synthesis of Bicyclic Tribenzyl Derivative 7 and Its
Selective Debenzylation
Chloroenamine 6a as starting material is accessible in
87% yield by NCS chlorination of tribenzylenamine 9 as
described in ref 12. Reaction of chloroenamine 6a with
sodium methoxide in methanol gave 6a-N,O-acetal 10
(95% yield) (Scheme 1).
Scheme 1
6a-Amine 1a was synthesized as Boc-protected com- The methoxy moiety in 10 can be replaced with complete
pound 1b via carboxylic acid 31, 4, 5 or nitro derivative 46 retention of configuration by hydrogen by reaction with
both by multistep procedures. The 6-amino moiety at the lithium aluminum hydride or with diisobutylaluminum
cyclopropane system, thereby, is generated by a Curtius hydride to give the tribenzylic diamine 7. The resulting
degradation1, 4, 5 or the reduction of the nitro moiety.6 Pre- 6b-stereoisomer 7 is expected as consequence of the at-
dominantly or exclusively 6a-isomers were obtained in tack of the hydride nucleophile to the intermediate azabi-
all sequences. On the other hand, amino-chloroenamines cyclo[3.1.0]hexan-6-iminium ion from the sterically less
of type 6 proved to be simple starting materials for the hindered exo-side. Treatment of 7 with one equivalent of
synthesis of 6-amino-3-azabicyclo[3.1.0]hexane deri- hydrogen in methanol and a palladium charcoal catalyst
vatives7–15 leading mostly to 6b-isomers. The applicabili- led to a mixture of debenzylated products 11–14. The
ty of chloroenamines11 for the preparation of azabicyclo- missing selectivity in the hydrogenolytic debenzylation of
hexane derivatives such as 1a or 5 with an unsubstituted 7 with respect to the analogous reaction of carbonitrile 8

740
Papers
SYNTHESIS
Synthesis of Benzyl Derivative 12 Using an Orthogo-
nally Protected Chloroenamine
Chloroenamine 6b with an N(3) benzyl residue and a di-
allylamino moiety was selected for an alternative way to
an orthogonally protected derivative of 6b-amine 5. The
corresponding enamine 19 was prepared from N-ben-
zylpiperidone 18 with diallylamine in the presence of tita-
nium tetrachloride according to the Weingarten method.20
Chlorination of 19 by NCS gave chloroenamine 6b in
50% yield (based on 18) which was transformed into bi-
cyclic N,O-acetal 21 by interaction with sodium methox-
ide in methanol (85% yield). Reaction of N,O-acetal 21
with lithium aluminum hydride caused a displacement of
the methoxy moiety by hydrogen to give 20 (67% yield)
which could be deallylated to monobenzyldiamine 12
(69% yield) in the presence21 of tetrakis(triphenylphos-
phine)palladium and N,N¢-dimethylbarbituric acid (ND-
MBA) (Scheme 4).
Scheme 2
should be the consequence of the absence of a deactivat-
ing group at C(6) in the case of diamine 7 (Scheme 2).
A selective debenzylation, however, could be achieved
with vinyl chloroformate18 in chloroform at 50°C to give
carbamate 15 besides benzyl chloride. Dibenzylamine hy-
drochloride was formed as a byproduct in small amounts
from a partial decomposition of the azabicyclohexane sys-
tem. Carbamate 15 was isolated in 50% yield by distilla-
tion; its subsequent decomposition by hydrogen chloride
in chloroform produced diamine 13. The latter can be re-
garded as selective N–C(6) protected derivative of 6b-6-
amino-3-azabicyclo[3.1.0]hexane (5).
Scheme 4
b
Synthesis of Mesylate 25 of Trovafloxacin 6 -Diastere-
omer
Compound 25, the 6b-diastereomer of trovafloxacin me-
sylate, can be prepared from ethyl 7-chloro-1-(2,4-difluo-
rophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-
3-carboxylate (22) and the dibenzylamino derivative 13,
subsequent debenzylation of the resulting compound 23
and saponification of the ester 24 with aqueous methane-
sulfonic acid (Scheme 5).
Scheme 3
Structure of the 6-Amino-3-azabicyclo[3.1.0]hexane
Derivatives 7, 10–17, 20, 21, and 23–25
Methyl chloroformate can also be used for the debenzyla-
tion of 7. Chloroform/pyridine (20:3) at 50°C gave the
best results. The two different protecting groups in the re-
sulting carbamate 16 were removed either by hydrogen or
by iodotrimethylsilane19 leading to the selectively protect-
ed diamines 17 and 13, respectively (Scheme 3).
The new compounds 7, 10–17, 20 and 21 were identified
by 1H and 13C NMR spectroscopy (see experimental sec-
tion). The 3-azabicyclo[3.1.0]hexane skeleton, thereby, is
indicated unequivocally by the 13C NMR data. The mix-
ture of diamines 11–14 from the hydrogenolytic debenzy-

May 1998
SYNTHESIS
741
dard). Microanalyses were performed using a Perkin–Elmer 2400 El-
emental Analyzer. Reactions with TiCl4, NCS, vinyl chloroformate,
methyl chloroformate, iodotrimethylsilane, LiAlH4 or DIBAH were
run under N2. A pressure tube and argon were used for the deallyla-
tion reaction.
1-Benzyl-3-chloro-4-(dibenzylamino)-1,2,3,6-tetrahydropyridine
(6a):
A solution of NCS (4.14 g, 31.0 mmol) in CH2Cl2 (200 mL) was add-
ed dropwise at –78°C over 2 h to a stirred solution of enamine12
9
(11.42 g, 31.0 mmol) in CH2Cl2 (50 mL). Stirring was continued for
1 h at –78°C and under warming to –30°C for 2 h. Then the solvent
was removed in vacuo. Extraction of the residue with pentane (5 ´
150 mL) and cooling of the pentane solution gave chloroenamine 6a
as colorless solid; yield: 10.9 g (87%); mp 57°C.
1H NMR (CDCl3): d = 2.67 (HB1, 1H), 2.95 (HB2, 1H), 3.08 (HA1
,
=
1H), 3.39 (HA2, 1H), 4.68 (HX1, HX2, 2H) (2 ABX systems, HA1B1
12.5 Hz, JA1X1 = JB1X1 = 2.7 Hz; JA2B2 = 15.5 Hz, JA2X2 = 4.8 Hz,
JB2X2 ≈ 2.6 Hz), 3.52 (HB3, 1H), 3.82 (HA3, 1H) (AB system, JAB
=
13.2 Hz), 4.10 (HB4, 2H), 4.43 (HA4, 2H) (AB system, JAB = 16.1 Hz),
7.15–7.45 (m, 15H).
13C NMR (CDCl3): d = 141.1 (s), 138.7 (s), 137.6 (s), 128.9 (d), 128.3
(d), 128.2 (d), 127.3 (d), 127.0 (d), 126.8 (d), 101.1 (d), 61.5 (t), 57.4
(t), 54.3 (d), 52.49 (t), 52.46 (t).
Scheme 5
Anal. Calcd for C26H27ClN2: C, 77.50; H, 6.75; N, 6.95. Found: C,
77.23; H, 6.77; N, 6.90.
1
lation of 7 was analyzed by the H NMR spectrum: 5
benzyl 1H NMR signals at d = 3.53, 3.55, 3.59, 3.79, and
1a,5a,6b-3-Benzyl-6-(dibenzylamino)-3-azabicyclo[3.1.0]hexane
3.80 were observed for the mixture. Diamines 12 (d = (7):
Method A: A solution of N,O-acetal 10 (2.10 g, 5.27 mmol) in THF
3.59) and 13 (d = 3.55) were identified by comparison
with the data of the pure compounds. The main compo-
nent (about threefold excess) corresponds to the signals at
d = 3.53 and 3.80 both of equal intensity. Thus, structure
11 with two different benzyl moieties is indicated for this
(25 mL) was added slowly to a suspension of LiAlH4 (0.25 g,
6.59 mmol) in THF (5 mL). The mixture was stirred for 4 h at 60°C.
Then the solvent was removed in vacuo and the residue hydrolyzed
under ice-cooling by addition of 2 M aq KOH (30 mL). The resulting
solid was separated by centrifugation. Diamine 7 was obtained by ex-
traction of the solid and of the aqueous solution with Et2O (1 ´ 20 mL
and 4 ´ 20 mL, respectively), evaporation of the Et2O and crystalliza-
tion from pentane; yield: 1.65 g (85%); mp 75°C.
1
compound. The remaining benzyl H NMR signal at d =
3.79 finally must be assigned to monobenzyl derivative
14. The naphthyridine derivatives 23–25 were character-
ized by their 1H NMR spectra and by mass spectrometry.
Method B: 1 M DIBAH in THF (1.88 mL, 1,88 mmol) was added to
a solution of N,O-acetal 10 (0.5 g, 1.25 mmol) in THF (30 mL). The
The 6b-structure of all 6-H compounds can be deduced 1H solution was stirred for 5 h at 60°C and a further 3 d at r.t. and then
NMR spectroscopically by the 3JHH coupling of C(6)–H:
the observed values of 6.6–7.3 Hz correspond clearly to
syn neighboring hydrogen atoms at the cyclopropane
unit8, 11, 13 (20: 6.6 Hz; 7: 6.7 Hz; 14, 15, 16: 6.8 Hz; 13,
24: 6.9 Hz; 11: 7.1 Hz; 12: 7.2 Hz; 23, 25: 7.3 Hz). Pres-
ence of an ester moiety at N(3) as in 15–17 leads to un-
symmetrical compounds due to hindrance of O=C–N(3)
poured into a mixture of ice (20 g), water (40 mL) and 95–97% H2SO4
(1 mL). Subsequent addition of 3 M aq KOH (30 mL) under ice-cool-
ing and extraction with Et2O (5 ´ 25 mL) gave crude diamine 7 which
was distilled in a Kugelrohr apparatus (130°C/10–3 Torr) and crystal-
lized from pentane; yield: 0.4lg (89%); mp 75°C.
1H NMR (CDCl3): d = 1.73 (HX, HX¢, 2H), 2.01 (HY, 1H), 2.42 (HA,
HA¢, 2H), 2.95 (HB, HB¢, 2H) (AA¢BB¢XX¢Y system, JAB = JA¢B¢
9.5 Hz, JAX = JA¢X¢ ≈ 2.8 Hz, JBX = JB¢X¢ = 6.1 Hz, JXY = JX¢Y¢
6.7 Hz), 3.59 (s, 4H), 3.68 (s, 2H), 7.19–7.37 (m, 15H).
=
=
1
rotation. In these cases, the azabicyclohexane H NMR
13C NMR (CDCl3): d = 139.6 (s), 137.5 (s), 129.6 (d), 128.8 (d), 128. l
(d), 127.9 (d), 126.8 (d), 126.7 (d), 59.4 (t), 56.1 (t), 51.8 (t), 47.5 (d,
1JCH = 163 Hz), 25.8 (d,1JCH = 170 Hz).
signals appear as ABCDXYZ spin system instead of the
typical AA¢BB¢XX¢Y pattern which is obtained for the
symmetric compounds 7, 10–14, 20, and 21. The azabicy-
clohexane skeleton of the threefold substituted com-
pounds 7, 10, 20, and 21 adopts a chair conformation as
indicated by the clear detectable AX coupling (JAX = 2.4–
Anal. Calcd for C26H28N2: C, 84.74; H, 7.66; N, 7.60. Found: C,
84.58; H, 7.77; N, 7.43.
1 ,5 ,6 -3-Benzyl-6-(dibenzylamino)-6-methoxy-3-azabicyc-
a a a
1
2.8 Hz). The missing of this coupling in the H NMR
lo[3.1.0]hexane (10):
Chloroenamine 6a (3.83 g, 9.50 mmol) was added to a methanolic so-
lution of MeONa which was prepared from sodium (0.87 g, 37.84
mmol) and MeOH (90 mL). The mixture was stirred at 20°C for 20 h.
Then the solvent was removed in vacuo. Extraction of the residue
with Et2O (4 ´ 50 mL) gave N,O-acetal 10 as colorless oil which crys-
tallized at –15°C; yield: 3.59 g (95%); mp 69°C.
spectra of derivatives 11–14 establishes the presence of a
boat conformation for the azabicyclohexane ring system
in these cases (JAX < 0.6–0.9 Hz, the upper limit value is
deduced from the half line width of the HA/HA¢ signal; see
refs 9, 12, 14, 22).
1H NMR (CDCl3): d = 1.90 (Hx, Hx¢, 2H), 2.37 (HA1, HA¢1, 2H), 2.71
(HB1, HB¢1, 2H) (AA¢BB¢XX¢ system, JAB = JA¢B¢ = 9.9 Hz, JAX = JA¢X¢
1H NMR and 13C NMR spectra were obtained with a Bruker AMX
400, DPX 400 and DRX 500 spectrometer (TMS as internal stan-
≈ 2.4 Hz, JBX = JB¢X¢ = 6.0 Hz), 3.33 (s, 3H), 3.59 (s, 2H), 3.93 (HB2
,

742
Papers
SYNTHESIS
2H), 4.12 (HA2, 2H) (AB system, JAB = 13.8 Hz), 7.19–7.29, 7.39–
7.41(m, 15H).
at 60°C for 6.5 h. Then concd methanolic HCl (2 mL) was added at
r.t.; stirring was continued for 10 min. The solution was basified with
a solution of MeONa (0.65 g, 12.0 mmol) in MeOH (20 mL). Remov-
al of the solvent in vacuo and addition of 2M aq KOH (10 mL) gave
diamine 13 which was extracted with Et2O (5 ´ 20 mL) and purified
by distillation in a Kugelrohr apparatus (105°C/10–3 Torr); yield: 70
mg (84%).
13C NMR (CDCl3): d = 139.1 (s), 138.5 (s), 129.1(d), 128.4 (d), 127.7
(d), 127.4 (d), 126.4 (d), 126.3 (d), 85.0 (s), 59.4 (t), 55.3 (t), 55.0 (q),
52.9 (t), 32.7 (d, 1JCH = 169 Hz).
Anal. Calcd for C27H30N2O: C, 81.37; H, 7.59; N, 7.03. Found: C,
81.18; H, 7.59; N, 6.92.
1H NMR (CDCl3): d = 1.45 (HX, HX¢, 2H), 1.98 (HY, 1H), 2.52 (HA,
HA¢, 2H), 2.78 (HB, HB¢, 2H) (AA¢BB¢XX¢Y system, JAB = 12.2 Hz,
1a,5a,6b-6-(Dibenzylamino)-3-(vinyloxycarbonyl)-3-azabicyc-
lo[3.1.0]hexane (15):
JAX = JA¢X¢ < 0.8 Hz, JBX = JB¢X¢ ≈ 2.7 Hz, JXY = JX¢Y = 6.9 Hz), 1.85
(s (broad), 1H), 3.55 (s, 4H), 7.22–7.35 (m, 10 H).
13C NMR (CDCl3): d = 138.2 (s), 129.5 (d), 128.2 (d), 127.1 (d), 59.7
(t), 48.3 (t), 45.0 (d), 24.5 (d, 1JCH = 167 Hz).
A solution of vinyl chloroformate (0.5 mL, 5.88 mmol) in CHCl3
(5 mL) was added dropwise at 50°C over 15 min to a solution of
tribenzyldiamine 7 (1.95 g, 5.29 mmol) in CHCl3 (80 mL). The mix-
ture was stirred at 50°C for 1.75 h and at r.t. for 2 h. Then the solvent
was removed in vacuo and the residue was distilled in a Kugelrohr ap-
paratus (140–180°C/10–3 Torr). Carbamate 15 was separated from
the additional formed dibenzylammonium chloride (0.36 g) by ex-
traction of the distillate with pentane (4 ´ 20 mL) and redistilled at
l35°C/l0–3 Torr to give a colorless oil; yield: 0.93 g (50%).
1H NMR (CDCl3): d = 1.70 (HX, HY, 2H), 2.09 (Hz, 1H), 3.39 (HA,
1H), 3.49 (HC, 1H), 3.51 (HB, 1H), 3.56 (HD, 1H) (ABCDXYZ sys-
MS: m/z (%) = 278 (M+,10), 249 (25), 187 (45), 158 (56), 91 (100).
Anal. Calcd for C19H22N2: C, 81.97; H, 7.97; N, 10.06. Found: C,
81.66; H, 8.08; N, 9.96.
1a,5a,6b-6-Amino-3-(methoxycarbonyl)-3-azabicyclo[3.1.0]hex-
ane (17):
Carbamate 16 (0.13 g, 0.39 mmol) in Et2O/CHCl3 (1:1, 14 mL) was
treated with gaseous HCl. Then the solvent was evaporated; the re-
sulting salt was triturated with Et2O (2 ´ 10 mL) and dried in vacuo.
10% Pd/C (100 mg) was added to a solution of the salt (0.14 g,
0.38 mmol) in MeOH (30 mL); the mixture was saturated with H2 for
16 h. The catalyst was removed by filtration and the solvent was evap-
orated. The residue was triturated with Na2CO3 (0.65 g, 6.13 mmol)
and distilled in a Kugelrohr apparatus at 150°C/10–3 Torr. Sublima-
tion of the distillate at 70°C/10–3 Torr gave pure monoprotected di-
amine 17; yield: 40 mg (66%); mp 76°C.
tem, JAB = 11.2 Hz, JAX < 0.8 Hz, JBX = 5.0 Hz, JCD = 10.7 Hz, JCY
<
0.9 Hz, JDY = 4.9 Hz, JXZ = JYZ = 6.8 Hz), 3.60 (s, 4H), 4.45 (dd, 1H),
4.76 (dd, 1H), 7.20–7.36 (m, 11H).
13C NMR (CDCl3): d = 150.9 (s), 142.4 (d), 137.2 (s), 129.4 (d),
128.1 (d), 127.0 (d), 94.7 (dd), 57.7 (t), 46.0 (t), 45.2 (t), 43.4 (d), 23.2
(d, 1JCH = 171 Hz), 22.4 (d, 1JCH = 170 Hz).
Anal. Calcd for C22H24N2O2: C, 75.83 ; H, 6.94; N, 8.04. Found: C,
75.80; H, 7.00; N, 7.98.
1H NMR (CDCl3): d = 1.60 (HX, HY, 2H), 2.48 (Hz, 1H), 3.46, 3.53
(HA/HC, 2H), 3.56, 3.62 (HB/HD, 2H), (ABCDXYZ system, JAB = JCD
1a,5a,6b-6-(Dibenzylamino)-3-(methoxycarbonyl)-3-azabicyc-
lo[3.1.0]hexane (16):
= 11.2 Hz, JAX = JCY ≈ 1.6 Hz, JBX = JDY = 6.0 Hz, JXZ = JYZ
=
7.1 Hz), 3.68 (s, 3H).
A solution of methyl chloroformate (0.16 mL, 2.07 mmol) in CHCl3
(5 mL) was added dropwise at 50°C over 15 min to a solution of
tribenzyldiamine 7 (0.5 g, 1.36 mmol) in CHCl3 (15 mL) and pyridine
(3 mL). The mixture was stirred at 50°C for 4 h. Then again methyl
chloroformate (0.02 mL, 0.26 mmol) was added and stirring was con-
tinued for 30 min at 50°C. Removal of the solvent in vacuo and dis-
tillation of the residue in a Kugelrohr apparatus (220°C/10–3 Torr)
gave carbamate 16 which was separated from the additional formed
dibenzylammonium chloride (0.07 g) by extraction of the distillate
with Et2O (4 ´ 20 mL). Redistillation at 145°C/10–3 Torr led to a col-
orless oil; yield: 0.21 g (46%).
13C NMR (CDCl3): d = 154.6 (s), 52.2 (q), 44.9 (t), 44.3 (t), 31.4 (d),
21.3 (d, 1JCH = 170 Hz), 20.4 (d, 1JCH = 173 Hz).
Anal. Calcd for C7H12N2O2: C, 53.83 ; H, 7.74; N, 17.94. Found: C,
53.67; H, 7.55; N, 17.99.
1-Benzyl-3-chloro-4-(diallylamino)-1,2,3,6-tetrahydropyridine
(6b):
TiCl4 (4.5 mL, 40.9 mmol) in toluene (15 mL) was added at 0°C to a
solution of diallylamine (41.84 mL, 338.9 mmol) and 1-benzylpiperi-
din-4-one (18) (15 mL, 84.7 mmol) in toluene (200 mL). The mixture
was stirred for 1 h at 0°C and 20 h at r.t. Removal of the solid by suc-
tion, evaporation of the solvent in vacuo and distillation at 130–
150°C/10–3 Torr gave enamine 19 as light yellow oil [13.03 g, 55%
yield; purity 96% (4% ketone 18)]. A solution of NCS (6.22 g,
46.6 mmol) in CH2Cl2 (160 mL) was added dropwise at –78°C over
2 h to a stirred solution of enamine 19 (13.03 g of 96% purity, 46.6
mmol) in CH2Cl2 (20 mL). Stirring was continued for 1 h at –78°C
and under warming to –50°C for 4 h. Then the solvent was removed
in vacuo. Extraction of the residue with pentane (7 ´ 50 mL) and cool-
ing of the pentane solution gave chloroenamine 6b as colorless solid;
yield: 12.92 g (50% based on ketone 18); mp 34°C.
1H NMR (CDCl3): d = 1.70 (HX, HY, 2H), 2.09 (HZ, 1H), 3.37 (HA,
1H), 3.46 (HB, 1H), 3.52 (HC, 1H), 3.55 (HD, 1H) (ABCDXYZ sys-
tem, JAB = 11.2 Hz, JAX < 0.8 Hz, JBX = 4.8 Hz, JCD = 11.3 Hz, JCY
<
0.7 Hz, JDY = 4.5 Hz, JXZ = JYZ = 6.8 Hz), 3.61 (s, 4H), 3.74 (s, 3H),
7.22–7.34 (m, 10H).
13C NMR (CDCl3): d = 154.5 (s), 137.3 (s), 129.5 (d), 128.1 (d), 127.0
1
(d), 57.3 (t), 52.1 (q), 46.0 (t), 45.2 (t), 43.2 (d), 23.4 (d, JCH
=
l70 Hz), 22.7 (d, 1JCH = 170 Hz).
Anal. Calcd for C21H24N2O2: C, 74.97; H, 7.19; N, 8.33. Found: C,
74.85; H, 7.09; N, 8.56.
1H NMR (CDCl3): d = 2.64 (HB1, 1H), 2.94 (HB2, 1H), 3.07 (HA1
1H), 3.44 (HA2, 1H), 4.55 (HX1, 1H), 4.62 (HX2, 1H) (2ABX systems,
A1B1 = 12.6 Hz, JA1X1 = JB1X1 = 3.1 Hz; JA2B2 = 15.6 Hz, JA2X2 = 4.9
,
1a,5a,6b-6-(Dibenzylamino)-3-azabicyclo[3.1.0]hexane (13):
Method A: 37% aq HCl (7 mL) was added to solution of carbamate 15
(0.93 g, 2.67 mmol) in CHCl3 (30 mL); the mixture was stirred 14 h
at r.t. Then water (20 mL) was added, the CHCl3 was removed in vac-
uo and the aqueous solution extracted with Et2O (20 mL). Addition of
5 M aq KOH (25 mL) under ice-cooling and extraction with Et2O (80
mL) in a Kutscher–Steudel apparatus for 5 d gave diamine 13 which
was purified by distillation in a Kugelrohr apparatus (105°C/10–3
Torr) and by crystallization from pentane to give colorless crystals;
yield: 0.55 g (74%); mp 86°C.
J
Hz, JB2X2 ≈ 2.6 Hz), 3.52 (HB3, 1H), 3.79 (HA3, 1H) (AB system, JAB
= 13.4 Hz), 3.58 (HY, 2H), 3.78 (HX3, 2H), 5.10 (HM, 2H), 5.13 (HN,
2H), 5.78 (HA4, 2H) (AMNXY system, JAX = JAY = 5.6 Hz, JAM
10.4 Hz, JAN = 17.2 Hz, JXY = 16.2 Hz), 7.22–7.43 (m, 5H).
=
13C NMR (CDCl3): d = 140.5 (s), 137.5 (s), 134.7 (d), 128.6 (d), 127.9
(d), 126.8 (d), 116.1 (t), 99.3 (d), 61.3 (t), 57.2 (t), 54.0 (d), 52.4 (t),
51.0 (t).
Anal. Calcd for C18H23ClN2: C, 71.39; H, 7.65; N, 9.25. Found: C,
70.83; H, 7.34; N, 9.22.
Method B: A solution of iodotrimethylsilane (0.21 mL, 1.48 mmol)
and carbamate 16 (100 mg, 0.30 mmol) in CHCl3 (5 mL) was stirred

May 1998
SYNTHESIS
743
1a,5a,6a-3-Benzyl-6-(diallylamino)-6-methoxy-3-azabicyc-
lo[3.1.0]hexane (21):
Ethyl 7-[1a,5a,6b-6-(Dibenzylamino)-3-azabicyclo[3.1.0]hex-3-
yl]-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naph-
Chloroenamine 6b (4.00 g, 13.2 mmol) was added to a methanolic so- thyridine-3-carboxylate (23):
lution of MeONa which was prepared from sodium (0.91 g, Ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-
39.6 mmol) and MeOH (80 mL). The mixture was stirred at 20°C for 1,8-naphthyridine-3-carboxylate (22) (896.5 mg, 2.5 mmol) was sus-
3 d. Then the solvent was removed in vacuo. Extraction of the residue pended in acetonitrile (80 mL). Then NEt3 (9.5 mL) and 13
with pentane (4 ´ 50 mL) and distillation of the extract in a Kugelrohr (632.5 mg, 2.5 mmol) were added and the mixture was heated to
apparatus at 130°C/10–3 Torr gave N,O-acetal 21 as colorless oil; 60°C for 5 h. The resulting solution was evaporated at 60°C/15 Torr,
yield: 3.35 g (85%).
the residue was treated with water, the precipitated solid was filtered
1H NMR (CDCl3): d = 2.01 (HX1, HX¢1, 2H), 2.32 (HA1, HA¢1, 2H), off by suction, washed with water and dried at 70°C in vacuo to yield
3.07 (HB1, HB¢1, 2H) (AA¢BB¢XX¢ system, JAB = JA¢B¢ = 9.8 Hz, JAX 1.3 g of the title compound, which was purified by column chroma-
= JA¢X¢ ≈ 2.6 Hz, JBX = JB¢X¢ = 6.1 Hz), 3.29 (s, 3H), 3.58 (s, 2H), 3.50 tography [100 g silica gel (Amicon, 60A 35–70 mm), CH2Cl2/MeOH
(HX2, 4H), 5.14 (HM, 2H), 5.16 (HN, 2H), 5.89 (HA2, 2H) (AMNX2 95:5]; yield: 1.24 g (80%); mp 178–179°C (dec).
system, JAX = 6.4 Hz, JAM = 10.4 Hz, JAN = 17.0 Hz, JMX = 1.0 Hz, 1H NMR (400 MHz, CF3CO2D): d = 1.52 (t, J = 7.3 Hz, 3H), 2.20 (m,
J
NX = 1.5 Hz, JMN = 2.2 Hz), 7.22–7.31 (m, 5H).
2H), 3.06 (t, J = 7.3 Hz, 1H), 3.16–3.29 (m, 1H), 3.29–3.41 (m, 1H),
13C NMR (CDCl3): d = 139.1 (s), 136.1 (d), 128.3 (d), 127.8 (d), 3.65–3.83 (m, 2H), 4.54 (d, J = 12.9 Hz, 2H), 4.71 (q, J = 7.3 Hz, 2H),
126.4 (d), 116.5 (t), 87.2 (s), 58.9 (t), 54.5 (q), 53.28 (t), 53.18 (t), 4.72–4.83 (m, 2H), 7.23 (t, J = 8.4 Hz, 1H), 7.32 (t, J = 7.4 Hz, 1H),
33.7 (d, 1JCH = 169 Hz).
7.45–7.73 (m, 11H), 8.31 (d, J = 10.7 Hz, 1H), 9.14 (s, 1H).
Anal. Calcd for C19H26N2O: C, 76.47; H, 8.78; N, 9.39. Found: C, FAB/MS: m/z = 625 ([M+H]+).
76.23; H, 8.59; N, 9.29.
Ethyl 7-(1a,5a,6b-6-Amino-3-azabicyclo[3.1.0]hex-3-yl)-1-(2,4-
difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-
3-carboxylate (24):
1a,5a,6b-3-Benzyl-6-(diallylamino)-3-azabicyclo[3.1.0]hexane
(20):
A solution of 23 (1.2 g, 1.92 mmol) in EtOH (200 mL) and concd HCl
(1 mL) was hydrogenated for 20 h at 23°C under atmospheric pres-
sure using gaseous H2 and 5 % Pd/C (100 mg) as the catalyst. The in-
soluble reaction product was filtered off together with the catalyst and
was dissolved in a mixture of CH2Cl2/MeOH/17% aq NH3 (30:8:1).
The catalyst was removed by filtration and the filtrate concentrated in
vacuo to yield a residue, which was purified by column chromatogra-
phy [silica gel (Amicon, 60A 35–70mm), CH2Cl2/MeOH/17% aq
NH3 30:8:1]; yield: 660 mg (77%); mp 216–218°C (dec).
1H NMR (400 MHz, CDCl3): d = 1.07 (broad, 2H), 1.40 (t, J = 7.5 Hz,
3H), 1.66 (broad, 2H), 2.49 (t, J = 6.9 Hz, 1H), 3.45–3.85 (broad, 4H),
4.38 (q, J = 7.5 Hz, 2H), 7.04 (m, 2H), 7.37 (m, 1H), 8.04 (d, J = 12.9
Hz, 1H), 8.36 (s, 1H).
A solution of N,O-acetal 21 (5.00 g, 16.8 mmol) in THF (70 mL) was
added slowly to a suspension of LiAlH4 (2.54 g, 66.9 mmol) in THF
(20 mL). The mixture was stirred for 3 h at 50°C and for a further 16 h
at r.t. Then the solvent was removed in vacuo and the residue hydro-
lyzed under ice-cooling by addition of 4 M aq KOH (130 mL). The
resulting solid was separated by centrifugation. Diamine 20 was ob-
tained by extraction of the solid and of the aqueous solution with Et2O
(1 ´ 30 mL and 5 ´ 40 mL, respectively), evaporation of the Et2O and
distillation in a Kugelrohr apparatus; bp 115°C/10–3 Torr; yield: 3.01
g (67%).
1H NMR (CDCl3): d = 1.72 (HX, HX¢, 2H), 2.11 (HY, 1H), 2.35
(HA, HA¢, 2H), 3.10 (HB, HB¢, 2H) (AA¢BB¢XX¢Y system, JAB = JA¢B¢
= 9.7 Hz, JAX = JA¢X¢ ≈ 2.7 Hz, JBX = JB¢X¢ = 6.2 Hz, JXY= JX¢Y = 6.6 Hz),
FAB/MS: m/z = 445 ([M+H]+).
3.61 (s, 2H), 3.16 (HX2, 4H), 5.15 (HM, 2H), 5.18 (HN, 2H), 5.92 (HA2
,
2H) (AMNX2 system, JAX = 6.4 Hz, JAM = 10.1 Hz, JAN = 17.2 Hz,
7-(1a,5a,6b-6-Amino-3-azabicyclo[3.1.0]hex-3-yl)-1-(2,4-difluo-
rophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-
carboxylic Acid Methanesulfonic Acid Salt (25):
A suspension of 24 (400 mg, 0.9 mmol) in water (8 mL) and 70 % aq
CH3SO3H (2.8 mL) was heated to 70°C for 20 h. The resulting sus-
pension was cooled with ice and the solid was isolated by filtration,
washed with water and dried at 80°C in vacuo; yield: 276 mg (60%);
mp 244–247°C (dec).
J
MX = 1.0 Hz, JNX = 1.5 Hz, JMN = 2.2 Hz), 7.20–7.35 (m, 5H).
13C NMR (CDCl3): d = 139.7 (s), 134.7 (d), 128.4 (d), 127.9 (d),
126.4 (d), 117.1 (t), 58.7 (t), 55.1 (t), 51.8 (t), 46.9 (d, 1JCH = 165 Hz),
25.6 (d,1JCH = 170 Hz).
Anal. Calcd for C18H24N2: C, 80.55; H, 9.01; N, 10.44. Found: C,
80.18; H, 8.62; N, 10.35.
1H NMR (500 MHz, CF3CO2D): d = 2.38 (broad, 2H), 3.1 (s, 3H),
3.28 (t, J = 7.3 Hz 1H), 3.7–4.8 (broad, 4H), 7.26 (m, 2H), 7.61 (m,
1H), 7.82 (m, 1H), 7.96 (broad, 3H), 8.27 (d, J = 12.4 Hz, 1H), 9.21
(s, 1H).
1a,5a,6b-6-Amino-3-benzyl-3-azabicyclo[3.1.0]hexane (12):
A solution of diallylamino compound 20 (1.86 g, 6.9 mmol) in
CH2Cl2 (9 mL) was added to a mixture of Pd[PPh3]4 (160 mg,
0.14 mmol) and N,N¢-dimethylbarbituric acid (3.49 g, 22.4 mmol)
and stirred at 40°C for 5 h. Then the solvent was evaporated; sat. aq
Na2CO3 (40 mL) was added to the residue. The mixture was extracted
with Et2O (3 ´ 40 mL). The ethereal extract was acidified with 2 M
aq HCl (35 mL). Removal of the Et2O and extraction of the aqueous
solution with EtOAc (3 ´ 30 mL) led to an aqueous solution of pure
hydrochloride of diamine 12. The free base was obtained as colorless
oil by addition of solid Na2CO3 (10.6 g, 0.1 mol), extraction with
Et2O (5 ´ 30 mL) and distillation in a Kugelrohr apparatus (70°C/
10–3 Torr); yield: 900 mg (69%).
FAB/MS: m/z = 417 ([M+H]+).
We thank the Fonds der Chemischen Industrie for support of this
work.
(1) Brighty, K. E. WO Patent 91/02526, 1991; EU Patent 413455,
1991; Chem. Abstr. 1991, 115, 232216; U. S. Patent 5.164.402,
1992; Chem. Abstr. 1993, 119, 117227.
1H NMR (CDCl3): d = 1.37 (Hx, HX¢, 2H), 2.35 (HY, 1H), 2.65 (HB,
HB¢, 2H), 3.05 (HA, HA¢, 2H), (AA¢BB¢XX¢Y system, JAB = 9.3 Hz,
JAX = JA¢X¢ < 0.6 Hz, JBX = JB¢X¢ ≈ 3.6 Hz, JXY = JX¢Y = 7.2 Hz), 1.92
Brighty, K. E.; Castaldi, M. J. Synlett 1996, 1097.
(s (broad), 2H), 3.59 (s, 2H), 7.20–7.31 (m, 5H).
13C NMR (CDCl3): d = 139.4 (s), 128.2 (d), 128.1 (d), 126.7 (d), 59.8
(t), 52.5 (t), 34.5 (d,1JCH = 167 Hz), 19.9 (d,1JCH = 168 Hz).
Calcd for C12H16N2: C, 76.55; H, 8.57; N, 14.88. Found: C, 76.47; H,
8.67; N, 15.2.
(2) Gootz, T. D.; Brighty, K. E.; Anderson, M. R.; Schmieder, B. J.;
Haskell, S. L.; Sutcliffe, J. A.; Castaldi, M. J.; McGuirk, P. R.
Diagn. Microbiol. Infect. Dis. 1994, 19, 235; Chem. Abstr.
1995, 122, 27600.
Fromtling, R. A.; Castaner, R. A. Drugs Fut. 1996, 21, 496.

744
Papers
SYNTHESIS
(3) Paris, M. M.; Hickey, S. M.; Trujillo, M.; Shelton, S.; Mc-
Cracken, G. H. Jr. Antimicrob. Agents Chemother. 1995, 39,
1243; Chem. Abstr. 1995, 123, 25252.
(4) Kurihara, A.; Myamoto, Y.; Takahata, T. Jpn. Kokai Tokkyo
Koho JP 08325228, 1996; Chem. Abstr. 1997, 126, 104012.
(5) Urata, Y.; Fujita, M.; Sugiura, M.; Ooizumi, F.; Yoshida, N.
Jpn. Kokai Tokkyo Koho JP 0912547, 1997; Chem. Abstr.
1997, 126, 199452.
(13) Seibel, J.; Vilsmaier, E.; Fröhlich, K.; Maas, G.; Wagemann, R.
Tetrahedron 1994, 50, 715.
(14) Schlag, W.-R.; Vilsmaier, E.; Maas, G. Tetrahedron 1994, 50,
3123.
(15) Butz, V.; Vilsmaier, E.; Maas, G. J. Chem. Soc., Perkin Trans.
2 1993, 1907.
(16) Goulaouic-Dubois, C.; Guggisberg, A.; Hesse, M. Tetrahedron
1995, 51, 12573.
(6) Braish, T. F.; Castaldi, M.; Chan, S.; Fox, D. E.; Keltonic, T.;
McGarry, J.; Hawkins, J. M.; Norris, T.; Rose, P. R.; Sieser, J.
E.; Sitter, B. J.; Watson, H. Jr. Synlett 1996, 1100.
Braish, T. F. U. S. Patent 5.298.629, 1994; Chem. Abstr. 1994,
121, 9156; WO Patent 93/18001, 1993; Chem. Abstr. 1994, 120,
54448.
(17) Kocienski, P. J. Protecting Groups; Thieme: Stuttgart, 1994;
p 185.
(18) Olofson, R. A.; Yamamoto, Y. S.; Wancowicz, D. J. Tetrahe-
dron Lett. 1977, 1563.
Olofson, R. A.; Schnur, R. C.; Bunes, L.; Pepe, J. P. Tetrahe-
dron Lett. 1977, 1567.
(7) Tetzlaff, C.; Vilsmaier, E.; Schlag, W.-R. Tetrahedron 1990,
46, 8117.
(19) Jung, M. E.; Lyster, M. A. J. Chem. Soc., Chem. Commun.
1978, 315.
(8) Wagemann, R.; Vilsmaier, E.; Maas, G. Tetrahedron 1995, 51,
8815.
(20) White, W. A.; Weingarten, H. J. Org. Chem. 1967, 32, 213.
(21) Garro-Helion, F.; Merzouk, A.; Guibé, F. J. Org. Chem. 1993,
58, 6109.
(22) Tetzlaff, C.; Butz, V.; Vilsmaier, E.; Wagemann, R.; Maas, G.;
Ritter v. Onciul, A.; Clark, T. J. Chem. Soc., Perkin Trans. 2
1993, 1901.
(9) Vilsmaier, E.; Grosse, M.; Schlag, W.-R.; Milch, G.; Berg-
sträßer, U.; Ritter v. Onciul, A. J. prakt. Chem. 1996, 338, 479.
(10) Butz, V.; Vilsmaier, E. Tetrahedron 1993, 49, 6031.
(11) Vilsmaier, E.; Tetzlaff, C.; Butz, V.; Maas, G. Tetrahedron
1991, 47, 8133.
(12) Vilsmaier, E.; Milch, G.; Fröhlich, K.; Bergsträßer, U.; Ritter
von Onciul, A.; Clark, T. Tetrahedron 1995, 51, 3507.