Synthesis of biologically important guanidine-containing molecules using triflyl-diurethane protected guanidines

Article abstract of DOI:10.1055/s-1999-3653

The guanidine-containing biologically important molecules, guanadrel, guanoxan, guanethidine and smimovine have been synthesized using the recently developed triflyl-diurethane protected guanidines.

Full text of DOI:10.1055/s-1999-3653

PAPER
1423
Synthesis of Biologically Important Guanidine-Containing Molecules Using
Triflyl-Diurethane Protected Guanidines
Tracy J. Baker, Murray Goodman*
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, 92093–0343, USA
Fax +1(858)5340202; E-mail: mgoodman@ucsd.edu
Received 26 March 1999
temperatures and extended periods of time in polar sol-
Abstract: The guanidine-containing biologically important mole-
vents, such as H2O, methanol, tert-butanol, or DMF for
cules, guanadrel, guanoxan, guanethidine and smirnovine have
reasons of solubility. The precursor amine 10 of guanadrel
been synthesized using the recently developed triflyl-diurethane
(3) was prepared through ketalization of cyclohexanone
(7) with diol 87 to provide intermediate 9 (Scheme 1). The
subsequent removal of the acetyl group of compound 9
using aqueous hydrazine afforded amine 10 in a reason-
able overall yield for the two steps. Using either reagent 1
or 2, the guanidinylation step was carried out with a slight
excess of amine 10 at room temperature in the presence of
Et3N. After an aqueous workup, derivatives 11 and 12
were isolated in 95 and 93% yield, respectively. Catalytic
hydrogenolysis under parr conditions led to the deprotec-
tion of the Cbz groups of compound 11 in quantitative
yield to give guanadrel (3) as the free base. Deprotection
of the Boc groups of compound 12 was not possible in the
presence of the labile ketal (Scheme 1).
protected guanidines.
Key words: guanadrel, guanoxan, guanethidine, smirnovine,
guanidinylation
Numerous natural and non-natural guanidine-containing
compounds have had an significant impact on agricultural
and medicinal chemistry. Moreover, many of these novel
molecules have shown unprecedented activity ranging
from antimicrobial, antiviral, antifungal to neurotoxic
making these compounds and their derivatives clear tar-
gets for drug design and discovery.1 With increasing num-
bers of bioactive molecules containing the guanidine
moiety, there is a continuing need for a general and effi-
cient method for their syntheses. We have recently report-
ed the use of N,N’-di-Boc-N"-triflylguanidine (1) and
N,N’-di-Cbz-N"-triflylguanidine (2) for the guanidinyla-
tion of amines under mild conditions and in high yields.2
Application of this procedure has now been extended to
the facile syntheses of the therapeutic agents, guanadrel
(3),3 guanoxan (4),4 and guanethidine (5).5 We have also
applied this method to the preparation of the N,N-dialky-
lated guanidino-alkaloid, smirnovine (6).6
Scheme 1
The precursor amine 13 of guanoxan hydrochloride (15)
was prepared following literature procedure.8 In an analo-
To date, the preparation of compounds 3, 4, and 5 in- gous process to the guanidinylation of compound 12, ex-
volves either treatment of the appropriate amine with S- cess amine 13 was treated with reagent 1 in the presence
methylisothiourea4–6 or reaction of a tosylate derivative of Et3N to afford diBoc guanoxan (14) in quantitative
9
with guanidine.5 Both methods often require elevated yield. After deprotection with SnCl4 followed by crystal-
Synthesis 1999, No. SI, 1423–1426 ISSN 0039-7881 © Thieme Stuttgart · New York

1424
T. J. Baker, M. Goodman
PAPER
lization, guanoxan hydrochloride (15) was isolated in
94% yield (Scheme 2). Guanethidine hydrochloride (18)
was also prepared in a parallel method to that described
for compound 12 by guanidinylation of amine 1610 fol-
lowed by deprotection with SnCl4 providing target com-
pound 18 in 83% overall yield for the two steps (Scheme
3).
Scheme 4
Scheme 2
In summary, the guanidinylation methods described
above constitute a novel, simple and efficient route to bi-
ologically important guanidine-containing molecules.
Unless otherwise noted, all materials were obtained from commer-
cial suppliers and used without further purification. CH2Cl2 and
CHCl3 were dried first with neutral alumina (Brockman activity I,
Fisher Scientific) and NEt3 with KOH then distilled from CaH2. An-
alytical thin-layer chromatography was carried out on precoated sil-
ica gel plates (Kieselgel 60 F254, E. Merck & Co., Germany). Flash
column chromatography was performed using silica gel (230–400
mesh) from J. T. Baker. All NMR spectra were obtained on a 360
MHz spectrometer assembled at UCSD with a pulse programmer,
digitizer, and an Oxford Instruments superconducting magnet and a
400 MHz Varian Mercury spectrometer. Mass spectra were ob-
tained at the Scripps Research Institute, La Jolla, CA. Elemental
analysis was performed by Desert Analytics, Tucson, AZ. Melting
points were determined with a uni-melt capillary melting apparatus.
Scheme 3
The only published synthesis of smirnovine (6) employs
the conversion of the N-acetyl derivative of secondary
amine 20 to a nitrocarboxylic ester intermediate followed
by ammonolysis and acidification to give the picrate salt
of smirnovine (6) in modest yield.6 The synthesis of
smirnovine using S-methylisothiourea as the guanidinyla-
tion agent was unsuccessful.6 The secondary amine 20
was prepared according to literature procedure11 from
compound 19. The readily available monoBoc-protected
amine 1912 was used as our starting material rather than
the corresponding acetyl derivative as used by Hessing
and co-worker.11 The guanidinylation of amine 20 was
successfully carried out in a mixture of 1,4-dioxane/
CH2Cl2 using excess reagent 1 (Scheme 4). The target
compound 21 was isolated in 49% yield along with an un-
expected side product 22 which presumably was formed
by nucleophilic attack of amine 20 at the carbonyl carbon
of a Boc group rather than the imine of the guanidinyla-
tion reagent. (This side product 22 may be easily recycled
if the acetyl or Cbz derivative of compound 19 is used as
the starting material.) The Boc protecting groups were re-
moved with TFA followed by selective acylation with
acetic anhydride to give the trifluoroacetate salt of
smirnovine (23) in 97% yield (Scheme 4).
N-(1,4-dioxaspiro[4.5]dec-2-ylmethyl)acetamide (9)
To diol 8 (323 mg, 2.43 mmol) in benzene/MeOH (5:1, 15 mL) was
added p-toluenesulfonic acid (5 mg, 0.024 mmol) and cyclohex-
anone (7, 357 mg, 3.64 mmol) at r.t. The reaction flask was
equipped with a Dean–Stark trap, condenser and drying tube and
heated to reflux. After 24 h, the solution was cooled to r.t. and con-
centrated under reduced pressure. The resulting residue was dis-
solved in CH2Cl2 (25 mL) and washed with H2O (30 mL), sat.
NaHCO3 (30 mL), and brine (30 mL) and dried (MgSO4). After re-
moval of the solvent under reduced pressure, purification on silica
gel (95:5 CHCl3/MeOH) provided compound 9 (341 mg, 66%).
1H NMR (CDCl3; 360 MHz): δ = 1.26–1.45 (m, 2H, H-8), 1.46–
1.55 (m, 4H, H-7,9), 1.56–1.60 (m, 4H, H-6,10), 1.97 (s, 3H, Ac),
3.21 (ddd, 1H, J = 14.0, 6.1, 6.1 Hz, CH2NHAc), 3.51 (ddd, 1H,
J = 14.0, 6.1, 3.2 Hz, CH2NHAc), 3.57 (dd, 1H, J = 8.3, 6.1 Hz, H-
3), 3.99 (dd, 1H, J = 8.3, 6.5 Hz, H-3), 4.18 (dddd, 1H, J = 6.5, 6.1,
6.1, 3.2 Hz, H-2), 5.93 (br s, 1H, NH).
13C NMR (CDCl3; 100 MHz): δ = 23.0, 23.6, 23.9, 25.0, 34.6, 36.4,
41.8, 66.3, 74.0, 109.6, 170.2.
HRMS (FAB) calcd for C11H19NO3 (Mr) 214.1443 (M+H)+, found
214.1440 ∆ = 1.4 ppm.
1,4-Dioxaspiro[4.5]dec-2-ylmethanamine (10)
Compound 9 (724 mg, 3.40 mmol) was dissolved in 85% aq. hydra-
zine (10 mL) and heated at 100 °C for 18 h. The solution was cooled
to r.t. and diluted with H2O (35 mL) then extracted with CHCl3
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Synthesis of Biologically Important Guanidine-Containing Molecules
1425
(2 ¥ 30 mL), washed with H2O (35 mL) and brine (35 mL) and dried
(MgSO4). After removal of the solvent under reduced pressure,
amine 10 (517 mg, 89%) was purified on silica gel (3:1 CHCl3/
MeOH).
1H NMR (10, CDCl3; 400 MHz): δ = 1.30–1.37 (m, 2H, H-8), 1.49–
1.54 (m, 8H, H-6,7,9,10), 2.68 (dd, 1H, J = 13.2, 6.8 Hz, CH2NH2),
2.75 (dd, 1H, J = 13.2, 4.0 Hz, CH2NH2), 3.57 (dd, 1H, J = 7.2, 6.8
Hz, H-3), 3.94 (dd, 1H, J = 7.2, 7.2 Hz, H-3), 4.03 (dddd, 1H,
J = 7.2, 6.8, 6.8, 4.0 Hz, H-2)
13C NMR (10, CDCl3; 100 MHz): δ = 23.7, 24.0, 25.1, 34.8, 36.5,
44.8, 66.4, 76.7, 109.4.
HRMS (FAB) calcd for C9H17NO2 (Mr) 172.1338 (M+H)+, found
172.1339 ∆ = 0.6 ppm.
J = 8.4, 6.0 Hz, H-3), 3.98 (dd, 1H, J = 8.4, 6.4 Hz, H-3), 4.13
(dddd, 1H, J = 6.4, 6.0, 6.0, 4.8 Hz, H-2).
13C NMR (DMSO; 100 MHz): δ = 23.4, 23.6, 24.7, 34.5, 36.0, 43.2,
65.8, 73.4, 109.1, 157.6.
HRMS (FAB) calcd for C10H19N3O2 (Mr) 214.1556 (M+H)+, found
214.1558 ∆ = 0.9 ppm.
N-(1,4-Benzodioxan-2-ylmethyl)-N’,N"-bis(tert-butoxycarbon-
yl)guanidine (14)
Method as for compound 12: reagent 1 (284 mg, 0.73 mmol), amine
13 (132 mg, 0.80 mmol) and Et3N (0.11 mL, 0.80 mmol). After 40
min and standard workup, the product (15, 296 mg, 100%) was
shown to be greater than 95% pure by 1H NMR then recrystallized
from hexanes, mp 124–127 °C.
N-(1,4-Dioxaspiro[4.5]dec-2-ylmethyl)-N’,N"-bis(benzyloxy-
carbonyl)guanidine (11)
1H NMR (CDCl3; 360 MHz): δ = 1.48 (s, 18H, 2Boc), 3.61 (ddd,
1H, J = 14.0, 7.2, 5.2, CH2-guan), 3.86 (ddd, 1H, J = 14.0, 5.2, 4.0,
CH2-guan), 3.97 (dd, 1H, J = 11.3, 7.2 Hz, H-3), 4.29 (dd, 1H,
J = 11.3, 2.2 Hz, H-3), 4.34 (dddd, 1H, J = 7.2, 7.2, 4.0, 2.2 Hz, H-
2), 6.81–6.92 (m, 4H, ArH), 8.71 (br s, 1H, CH2NH), 11.46 (br s,
1H, NHBoc).
Reagent 2 (490 mg, 1.07 mmol) in CHCl3 (2 mL) was added to a so-
lution of amine 10 (200 mg, 1.18 mmol) and Et3N (0.16 mL, 1.18
mmol) in CHCl3 (5 mL) at r.t. After 8 h, the mixture was diluted
with CHCl3 (15 mL) and washed with 2M NaHSO4 (15 mL), sat.
NaHCO3 (15 mL) and brine (15 mL) and dried (MgSO4) (standard
workup). After removal of the solvent under reduced pressure, the
product (11, 488 mg, 95%) was purified on silica gel (4:1 hexanes/
EtOAc).
1H NMR (CDCl3; 400 MHz): δ = 1.39–1.41 (m, 2H, H-8), 1.54–
1.69 (m, 8H, H-6,7,9,10), 3.58 (ddd, 1H, J = 13.6, 6.0, 5.6 Hz, CH2-
guan), 3.66 (dd, 1H, J = 8.4, 6.0 Hz, H-3), 3.68 (ddd, 1H, J = 13.6,
4.8, 4.0 Hz, CH2-guan), 4.02 (dd, 1H, J = 8.4, 6.8 Hz, H-3), 4.29
(dddd, 1H, J = 6.8, 6.0, 6.0, 4.8 Hz, H-2), 5.12 (s, 2H, CH2Ar), 5.19
(s, 2H, CH2Ar), 7.28–7.39 (m, 10H, ArH), 8.65 (s, 1H, CH2NH),
11.72 (s, 1H, NHBoc).
MS (FAB): m/z (%) = 430 (14, {M+Na}+), 408 (100, {M+H}+).
(1,4-Benzodioxan-2-ylmethyl)guanidine Hydrochloride (Guan-
oxan•HCl, 15)
Neat SnCl4 (0.09 mL, 0.76 mmol) was added dropwise to com-
pound 14 (143 mg, 0.356 mmol) in anhyd EtOAc (2 mL) at r.t. After
3 h, the solvent and excess SnCl4 were removed under reduced pres-
sure. The resulting solid was dissolved in MeOH and precipitated
by the addition of Et2O. On standing at r.t., guanoxan•HCl (15, 43.3
mg, 94%) crystallized from solution, mp 145–147 °C (Lit.13 147–
148 °C)
13C NMR (CDCl3; 100 MHz): δ = 23.9, 24.1, 25.2, 34.7, 36.4, 43.2,
66.1, 67.2, 68.2, 73.3, 110.1, 127.8, 128.0, 128.2 (2C), 128.4 (2C),
128.5 (2C), 128.6 (2C), 134.4, 136.5, 153.4, 156.2, 163.3.
HRMS (FAB) calcd for C26H31N3O6 (Mr) 482.2291 (M+H)+, found
482.2280 ∆ = 2.3 ppm.
1H NMR (D2O; 360 MHz): δ = 3.36 (dd, 1H, J = 14.8, 6.8 Hz, CH2-
guan), 3.44 (dd, 1H, J = 14.8, 4.3 Hz, CH2-guan), 3.94 (dd, 1H,
J = 11.5, 5.8 Hz, H-3), 4.18 (dd, 1H, J = 11.5, 2.3 Hz, H-3), 4.28
(dddd, 1H, J = 6.8, 5.8, 4.3, 2.3 Hz, H-2), 6.79 (br s, 4H, ArH).
13C NMR (DMSO; 100 MHz): δ = 40.9, 64.7, 71.1, 116.8, 116.9,
121.2, 121.4, 142.1, 142.5, 157.0.
N-(1,4-Dioxaspiro[4.5]dec-2-ylmethyl)-N’,N"-bis(tert-butoxy-
carbonyl)guanidine (12)
N-(2-Azocan-1-ylethyl)-N’,N"-bis(tert-butoxycarbonyl)guani-
dine (17)
Method as for compound 12: reagent 1 (260 mg, 0.66 mmol), amine
16 (114 mg, 0.73 mmol) and Et3N (0.10 mL, 0.73 mmol). Com-
pound 17 (233 mg, 88%) was purified on silica gel (98:2 CHCl3/
MeOH).
1H NMR (CDCl3; 360 MHz): δ = 1.46 (s, 9H, Boc), 1.48 (s, 9H,
Boc), 1.53–1.60 (m, 10H, H-3,4,5,6,7), 2.48–2.53 (m, 4H, H-2,8),
2.58 (t, 2H, J = 4.7 Hz, H-1'), 3.42 (dt, 2H, J = 4.7, 4.7 Hz, H-2'),
8.73 (br s, 1H, CH2NH), 11.43 (br s, 1H, NHBoc).
Reagent 1 (421 mg, 1.08 mmol) was added as a solid to a solution
of amine 10 (203 mg, 1.18 mmol) and Et3N (0.17 mL, 1.18 mmol)
in CH2Cl2 (6 mL) at r.t. After 1.5 h and standard workup, the solvent
was evaporated in vacuo. The product (12, 413 mg, 93%) was
shown to be greater than 95% pure by 1H NMR but could be further
purified on silica gel (99:1 CHCl3/MeOH) or by recrystallization
from hexanes, mp 127–129 °C.
1H NMR (CDCl3; 360 MHz): δ = 1.34–1.41 (m, 2H, H-8), 1.47 (s,
18H, 2Boc), 1.51–1.68 (m, 8H, H-6,7,9,10), 3.53–3.67 (m, 3H,
CH2-guan+H-3), 4.01 (dd, 1H, J = 7.9, 6.8 Hz, H-3), 4.26 (m, 1H,
H-2), 8.66 (br s, 1H, CH2NH), 11.46 (br s, 1H, NHBoc).
13C NMR (CDCl3; 100 MHz) δ = 25.7 (5C), 28.1 (3C), 28.4 (3C),
29.8, 39.6, 54.8, 57.6, 79.1, 82.6, 152.6, 155.9, 163.4.
HRMS (FAB) calcd for C20H38N4O4 (Mr) 399.2971 (M+H)+, found
MS(FAB): m/z (%) = 436 (7, {M+Na}+), 414 (100, {M+H}+).
399.2982 ∆ = 2.8 ppm.
(1,4-Dioxaspiro[4.5]dec-2-ylmethyl)guanidine (Guanadrel, 3)
Compound 11 (133 mg, 0.276 mmol) was dissolved in MeOH/THF
(3:1, 10 mL) and transferred to a high pressure flask. After 10% Pd/
C (40 mg) was added, the solution was shaken under a pressure of
50 psi for 3 h. The resulting solution was filtered through Celite,
rinsed with MeOH, and the solvent removed under reduced pressure
to give guanadrel (3, 59 mg, 100%) as the free base. Compound 3
was shown to be greater than 95% pure by 1H NMR.
1H NMR (DMSO; 400 MHz): δ = 1.29–1.34 (m, 2H, H-8), 1.45–
1.54 (m, 8H, H-6,7,9,10), 3.19 (dd, 1H, J = 14.4, 6.0 Hz, CH2-
guan), 3.30 (dd, 1H, J = 14.4, 4.8 Hz, CH2-guan), 3.60 (dd, 1H,
(2-Azocan-1-ylethyl)guanidine Hydrochloride (Guanethi-
dine•HCl, 18)
Method as for compound 15: SnCl4 (0.04 mL, 0.36 mmol), com-
pound 17 (36 mg, 0.09 mmol). Guanethidine•HCl (18, 19.8 mg,
94%) was crystallized from MeOH/Et2O. Compound 18 was neu-
tralized with NaOH and acidified with H2SO4 to give guanethidine
sulfate,5 mp 275–279 °C (Lit.5 276–281 °C {dec.}).
1H NMR (18, D2O; 360 MHz): δ = 1.50–1.59 (m, 2H, CH2 of ring),
1.67–1.81 (m, 6H, CH2 of ring), 1.90–2.00 (m, 2H, CH2 of ring),
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T. J. Baker, M. Goodman
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3.19–3.24 (m, 2H, H-2), 3.37 (t, 2H, J = 6.4 Hz, H-1'), 3.43–3.50
(m, 2H, H-8), 3.61 (t, 2H, J = 6.4, H-2').
13C NMR (18, DMSO; 100 MHz): δ = 22.0 (2C), 23.9, 25.2 (2C),
36.0 (2C), 50.7, 53.4, 156.7.
HRMS (FAB) calcd for C10H22N4 (Mr) 199.1923 (M+H)+, found
added at r.t. After 10 min, Ac2O (8 µL, 0.081 mmol) was added and
allowed to stir for 1 h. The solution was concentrated under reduced
pressure and compound 23 (30.8 mg, 97%) was recrystallized from
MeOH/hexanes, mp 108–110 °C.
1H NMR (DMSO; 400 MHz): δ = 1.30–1.38 (m, 2H, CH2), 1.44–
1.51 (m, 2H, CH2), 1.66 (s, 3H, CH3), 1.71 (s, 3H, CH3), 1.78 (s, 3H,
Ac), 3.01 (dt, 2H, J = 6.0, 5.6 Hz, H-4'), 3.18 (t, 2H, J = 7.2 Hz, H-
1'), 3.89 (d, 2H, J = 6.4 Hz, H-1), 5.10 (t, 1H, J = 6.4 Hz, H-2), 7.37
(br s, 4H,+H2N = CNH2), 9.46 (br s, 1H, NH).
199.1921 ∆ = 1.0 ppm.
N-(4’-tert-Butoxycarbonylaminobutyl)-N-(3-methylbuten-2-
yl)amine (20)
13C NMR (DMSO; 100MHz): δ = 17.8, 22.6, 24.2, 25.4, 26.3, 37.9,
45.6, 47.0, 118.2, 136.5, 155.5, 168.9.
Compound 20 was prepared according to literature procedure11 in
30% overall yield from amine 19, mp 133–135 °C.
HRMS (FAB) calcd for C12H24N4O (Mr) 241.2028 (M+H)+, found
241.2030 ∆ = 0.8 ppm.
1H NMR (CDCl3; 360 MHz): δ = 1.43 (s, 9H, Boc), 1.50–1.56 (m,
4H, H-2',3'), 1.64 (s, 3H, CH3), 1.71 (s, 3H, CH3), 2.14 (br s, 1H,
NH), 2.62 (t, 2H, J = 7.6 Hz, H-1'), 3.11 (br s, 2H, H-4'), 3.21 (d,
2H, J = 6.8 Hz, H-1), 4.88 (br s, 1H, NHBoc), 5.25 (t, 1H, J = 6.8
Hz, H-2).
Acknowledgement
13C NMR (CDCl3; 100 MHz): δ = 17.6, 25.2, 25.3, 27.2, 28.0 (3C),
39.6, 45.7, 47.1, 78.1, 118.8, 136.5, 155. 5.
Financial support from NIGU-Chemie GmBH, Germany is grate-
fully acknowledged.
HRMS (FAB) calcd for C14H28N2O2 (Mr) 257.2229 (M+H)+, found
257.2233 ∆ = 1.6 ppm.
References
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Berlinck, R. G. S. Nat. Prod. Rep. 1996, 337.
(2) Feichtinger, K.; Zapf, C.; Sings, H. L.; Goodman, M. J. Org.
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Feichtinger, K.; Sings, H. L.; Baker, T. J.; Matthews, K.;
Goodman, M. J. Org. Chem. 1998, 8432.
(3) Hardie, W. R.; Aaron, J. E. U.S. Patent 3,547,951, 1970;
Chem. Abstr. 1969, 71, 3249.
(4) Augstein, J.; Green, S. M. U.S. Patent 3,247,221, 1966; Chem.
Abstr. 1964, 61, 8318.
(5) Mull, R. P. U.S. Patent 3,055,882, 1962; Chem. Abstr. 1963,
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(6) Benn, M. H.; Shustov, G.; Shustova, L.; Majak, W.; Bai, Y.;
Fairey, N. A. J. Agric. Food Chem. 1996, 2779.
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(8) Augstein, J.; Green, S. M.; Monro, A. M.; Potter, G. W. H.;
Worthing, C. R.; Wrigley, T. I. J. Med. Chem. 1965, 8, 446.
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(10) Hideg, K.; Hankovszky, H. O. J. Med. Chem. 1965, 8, 257.
(11) Hessing, A.; Eckard, R. Chem. Ber. 1970, 103, 534.
(12) Andruszkiewicz, R.; Wojciechowska, H.; Borowski, E. Pol. J.
Chem. 1978, 52, 1167.
N-(4’-Boc-aminobutyl)-N-(3-methylbuten-2-yl)-N’,N"-bis(Boc-
carbonyl)guanidine (21)
Method as for compound 12: reagent 1 (82.0 mg, 0.209 mmol),
amine 20 (44.7 mg, 0.175 mmol) and Et3N (0.06 mL, 0.420 mmol)
in 1,4-dioxane/CH2Cl2 (5:1, 3 mL). After 10 d and standard workup,
the product (21, 42.6 mg, 49%) was isolated and purified on silica
gel (100% CHCl3, 5:1 hexanes/EtOAc) to give a pale yellow oil
along with compound 22 (18.6 mg, 30%).
1H NMR (CDCl3; 400 MHz): δ = 1.39 (s, 9H, Boc), 1.44 (s, 18H,
2Boc), 1.53–1.56 (m, 4H, H-2',3'), 1.62 (s, 3H, CH3), 1.69 (s, 3H,
CH3), 3.09 (dt, 2H, J = 5.6, 5.6 Hz, H-4'), 3.35 (t, 2H, J = 6.8 Hz, H-
1'), 3.92 (d, 2H, J = 7.2 Hz, H-1), 4.87 (br s, 1H, BocNHCH2), 5.14
(t, 1H, J = 7.2 Hz, H-2), 9.60 (br s, 1H, N = CNHBoc).
13C NMR (CDCl3; 100 MHz): δ = 17.9, 24.3, 25.7, 27.0, 28.2 (6C),
28.5 (3C), 29.7, 39.8, 47.0, 78.8, 119.3, 136.5, 154.7, 155.7 (These
were the resonances observed. The resonances of the quaternary
carbons of two t-Bu groups may be overlapping with 78.8 or CHCl3,
and resonances corresponding to carbons of the imine and one car-
bonyl may be overlapping with 154.7 and 155.7. The 13C NMR
spectrum in DMSO did not resolve the peaks).
HRMS (FAB) calcd for C25H46N4O6 (Mr) 499.3496 (M+H)+, found
499.3506 ∆ = 2.0 ppm.
(13) Augstein, J.; Green, S. M.; Monro, A. M.; Potter, G. W. H.;
Worthing, C. R.; Wrigley, T. I. J. Org. Chem. 1965, 8, 446.
N-(4’-Acetaminobutyl)-N-(3-methylbuten-2-yl)guanidine Trif-
luoroacetate (Smirnovine•TFA, 23)
A solution of TFA/CH2Cl2 (1:1, 2 mL) was added to compound 21
(44.7 mg, 0.090 mmol) at r.t. The mixture was stirred for 1.5 h and
the volatiles removed under reduced pressure. The resulting residue
was dissolved in DMF (3 mL) and Et3N (10 µL, 0.072 mmol) was
Article Identifier:
1437-210X,E;1999,0,SI,1423,1426,ftx,en;C01899SS.pdf
Synthesis 1999, No. SI, 1423–1426 ISSN 0039-7881 © Thieme Stuttgart · New York