Synthesis of a novel C2-symmetric guanidine base

Full text of DOI:10.1021/jo981841f

J . Org. Chem. 1999, 64, 1039-1041
1039
Sch em e 1
Syn th esis of a Novel C2-Sym m etr ic
Gu a n id in e Ba se
Andrew Howard-J ones, Patrick J . Murphy,* and
Dafydd A. Thomas
Department of Chemistry, University of Wales,
Bangor, Gwynedd LL57 2UW, U.K.
Peter W. R. Caulkett
CM and M Department, Zeneca Pharmaceuticals, Mereside,
Alderley Park, Macclesfield, Cheshire SK10 4TG, U.K.
Received September 9, 1998
The hydrogen-bond-mediated interaction of guani-
dinium ions with phosphate- and carboxylate-containing
biomolecules is of considerable interest in bioorganic
chemistry.1 Not least of these are the key interactions of
the guanidine-containing side chain of arginine residues
involved in substrate recognition at enzyme active sites.1
In addition, the guanidinium motif has also been utilized
in synthetic host receptors for phosphate- and carboxy-
late-containing host molecules which, together with
bicyclic amidine systems, are of considerable current
interest.2
Sch em e 2a
Synthetic applications are also known; for example,
tetrasubstituted guanidines have been used in an asym-
metric variant of the base-catalyzed nitro-aldol (Henry)
reaction, with enantiomeric excesses as high as 54%
having been reported,3 and the Michael addition of
pyrrolidine 1 to unsaturated lactones 2 (n ) 1, 2) has
been reported to undergo an 8.4-fold increase in reaction
rate when catalyzed by C2-symmetric guanidinium salts
such as 3 (Scheme 1).4 The key interaction involved in
both these reactions is a two-point hydrogen-bonding
interaction of the guanidinium motif with the nitro-
enolate in the Henry reaction and an interaction such
as in 4 for the Michael addition (Figure 1).
a
Key: (a) (i) guanidine, DMF, (ii) MeOH, HCl, 0 °C, (iii)
saturated aqueous HBF4; 80% overall, 6:7, 1:1.
With these considerations in mind, it is not surprising
that considerable synthetic effort has been directed
toward the synthesis of guanidine- and amidine-contain-
ing bases of this general type.2 To access these homo-
chiral bicyclic guanidines, several groups have employed
amino acids or their derivatives as starting points in
multistep syntheses.2
During a synthetic project directed toward the total
synthesis of the marine natural products,5 we investi-
gated the conjugate addition of guanidine to the vinyl
ketone 5 (prepared in a high yielding sequence from 2,3-
dihydropyran) and found that, after acid-catalyzed depro-
tection and subsequent cyclization, the isomeric tetra-
F igu r e 1.
cyclic guanidinium salts 6 and 7 were formed as a 1:1
mixture in an 80% yield (Scheme 2). This distribution of
isomers was found to be the equilibrium mixture, as
isolation of either isomer and treatment with a catalytic
amount of acid resulted in the regeneration of this
mixture. On inspection of 7, it is apparent that if it were
available as a single enantiomer and that the propensity
for equilibrium could be suppressed, this system could
represent a new type of C2-symmetric guanidine base.
Further encouragement of the suitability of this system
for this application is illustrated on inspection of the
X-ray crystallographic structure of 7 (Figure 2), which
confirms that the fluoroborate ion associates with the
guanidine in a manner similar to that known in the nitro-
enolate case. It was apparent that if substituents were
present on the pyran rings of 7 they would act as
conformational “locks” for the system and drive any
equilibrium to favor an overall trans arrangement, thus
offering the potential for a new route to enantiomerically
pure C2-symmetric guanidine bases.
* To whom correspondence should be addressed. Tel: 01248 382392.
Fax: 01248 370528. E-mail: chs027@bangor.ac.uk.
(1) For a comprehensive review of the biological role of the guanidine
group see: Hannon, C. L.; Anslyn, E. V. Bioorganic Chemistry
Frontiers; Springer-Verlag: Berlin, Heidelberg, 1993; Vol. 3, pp 193-
255.
(2) For leading references see: Schmidtchen, F. P.; Berger, M. Chem
Rev. 1997, 97, 1609.
(3) Chinchilla, R.; Najerg, C.; Sanchez-Agullo, P. Tetrahedron:
Asymmetry 1994, 5, 1393.
(4) Alcazar, V.; Moran, J . R.; de Mendoza, J . Tetrahedron Lett. 1995,
36, 3941.
(5) Murphy, P. J .; Williams, H, L.; Hibbs, D. E.; Hursthouse, M. B.;
Abdul Malik, K. M. Tetrahedron 1996, 52, 8315.
10.1021/jo981841f CCC: $18.00 © 1999 American Chemical Society
Published on Web 01/15/1999

1040 J . Org. Chem., Vol. 64, No. 3, 1999
Notes
Sch em e 3a
a
Key: (a) TBDMSCl/Imid/DMF; 99%; (b) DIBAH/hexane/-78 °C; 82%; (c) TosCl/Py; 80%; (d) NaI/acetone; 85%; (e) (i) CH3COCHPPh3/
n-BuLi, (ii) H2O quench, (iii) excess aqueous formaldehyde; 69%; (f) (i) guanidine/DMF/0 °C/16 h, (ii) HCl/MeOH/3 h, (iii) NaBF4/DCM;
44%.
Ta ble 1
base
t1/2q/min
rel rate increase
none
115
27
7
13‚HBF4
4.3
16.3
8.4
13‚HBPh4
3‚HBPh4 (ref 4)
16.3-fold increase in reaction rate over the uncatalyzed
process, illustrating that 13 is very effective as a catalyst
in this process (Table 1). Disappointingly no asymmetric
induction was observed in this reaction.
Despite this, we have demonstrated that our method-
ology has great potential for the preparation of structur-
ally complex chiral guanidines, and we are currently
seeking to extend this chemistry to the preparation of
further bases and to investigate their applications in
asymmetric processes including catalytic aldol and Michael
reactions.
Exp er im en ta l Section
F igu r e 2.
(R)-6-Oxo((ter t-b u t yld im et h ylsilyl)oxy)oct -7-en e (12).
Acetylmethylenetriphenylphosphorane (6.53 g, 20.5 mmol) was
dissolved in dry THF (120 mL) and cooled (-78 °C), and n-BuLi
(9.32 mL, 20.5 mmol) was added. The deep red solution of 10
that formed was allowed to stir at -60 °C for 1 h, after which
time the reaction was cooled to -78 °C and (R)-3-((tert-butyldim-
ethylsilyl)oxy)-1-iodobutane 96 (6.95 g, 22.14 mmol) in THF (42
mL) was added. The reaction was then warmed slowly to
ambient temperature and stirred overnight. Water (90 mL) was
added, the solution was extracted with DCM (3 × 50 mL) and
dried (MgSO4), and the solvent was reduced by rotary evapora-
tion to a volume of approximately 50 mL. Formaldehyde solution
was prepared by adding aqueous formaldehyde (90 mL) to DCM
(50 mL) and the water removed by adding excess MgSO4; this
solution was then filtered into the reaction mixture, and stirring
was continued overnight. The reaction was then diluted with
ether (60 mL), washed with water (2 × 60 mL), and dried
(MgSO4), and the solvent was removed by rotary evaporation.
Column chromatography (4% ether/petroleum ether) gave the
title compound as a clear oil (3.62 g, 69%).
We embarked upon the synthesis of a suitable sub-
strate for the conjugate addition of guanidine, which was
prepared in a straightforward manner using a highly
convergent synthetic strategy. Commercially available
ethyl (R)-3-hydroxybutyrate 8 was converted in four steps
(55% overall yield, 7 g scale) to the chiral iodide 9.6 This
iodide was treated with the readily prepared7 anion 10
to give the intermediate phosphorane 11, which on
reaction with aqueous formaldehyde gave the R,â-
unsaturated ketone 12 in 69% overall yield. Treatment
of this substrate with guanidine gave after desilylation
and cyclization the required guanidine 13 as a single
enantiomer in 44% yield (Scheme 3).
With this material in hand, we decided to investigate
its application as a catalyst in the conjugate addition of
pyrrolidine 1 to unsaturated lactone 1 (n ) 1) (Scheme
1).4 The reaction was carried out under conditions identi-
cal to those reported (substrate concentration 0.3 M, 0.1
equiv of catalyst), and it was observed that a 4.3-fold
increase in reaction rate was obtained when 13‚HBF4 was
employed as a catalyst. In line with the report of de
Mendoza, exchanging the counterion to HBPh4 led to a
1
[R]21D: -13.4° (c ) 1.12 [CHCl3]). H NMR (250 MHz, CDCl3)
δ: 0.05 (6H, s, 2 × CH3), 0.88 (9H, s, 3 × CH3), 1.14 (3H, d, J )
6.1 Hz), 1.37-1.73 (4H, cm), 2.57 (2H, d, J ) 7.3 Hz), 3.79 (1H,
app sextet, J ) 6.0 Hz), 5.81 (1H, dd, J ) 1.5, 10.1 Hz), 6.21
(1H, dd, J ) 1.5, 17.6 Hz), 6.36 (1H, dd, J ) 10.1, 17.6 Hz) ppm.
13C NMR (62.5 MHz, CDCl3): 200.75 (CdO), 136.48 (CH), 127.8
(CH2), 68.3 (CH), 39.62 (CH2), 39.02 (CH2), 25.84 (3 × CH3),
23.68 (CH3), 20.19 (CH2), 18.06 (C), -4.44 (CH3), -4.79 (CH3)
ppm. IR vmax: 2942 (CH), 1684 (CdO), 1616 (CdC). m/z (CI):
257 (5, [M + H]+), 201 (45, [M + H - t-Bu]+), 132 (50), 74 (100).
HRMS: found, 257.1937 ([M + H]+), C14H29O2Si requires 257.1937.
Anal. Calcd for C14H28O2Si: C, 65.57; H, 11.00. Found: C, 65.71;
H, 10.81.
(6) (a) Singh, A. K.; Bakshi, R. K.; Corey, E. J . J . Am. Chem. Soc.
1987, 109, 6187. (b) Garegg, P. J .; Samuelsson, B.; J . Chem. Soc.,
Perkin Trans. 1 1980, 2866.
(7) Taylor, J . D.; Wolf, J . F. J . Chem. Soc., Chem. Commun. 1972,
876.

Notes
(6R,6′′R,2R,2′′R)-6,6′′-Dim eth yld isp ir o[tetr a h yd r op yr a n -
J . Org. Chem., Vol. 64, No. 3, 1999 1041
1.50-2.20 (14H, cm), 3.22 (2H, ddd, J ) 1.6, 5.8, 12.5 Hz, 2 ×
CH), 3.68 (2H, apparent dt, J ) 5.0, 12.5 Hz, 3.84 (2H, ddq, J )
2.1, 11.8, 6.1 Hz, 2 × CH) 7.50 (2H, br s, 2 × NH) ppm. 13C
NMR (62.5 MHz, CDCl3): 148.41 (C), 78.94 (2 × C), 67.02 (2 ×
CH), 42.83 (2 × CH2), 33.63 (2 × CH2), 33.10 (2 × CH2), 32.15
2,2′-(2,3,4,6,7,8-Hexa h yd r o-1H-p yr im id o[1,2-a ]p yr im id in e)-
8′,2′′-tetr a h yd r op yr a n ]-9′-iu m Tetr a flu r obor a te 13. (R)-6-
Oxo((tert-butyldimethylsilyl)oxy)oct-7-ene (12) (1.99 g, 7.77 mmol)
was dissolved in dry DMF (35 mL) and cooled (0 °C), and a
solution of guanidine (0.229 g, 3.89 mmol) in DMF (1 mL) was
added dropwise over 5 min. The reaction was stirred for 15 min
before being allowed to warm to ambient temperature and then
stirred overnight. The reaction was then cooled (0 °C), metha-
nolic HCl (40 mL; prepared by adding acetyl chloride (4 mL) to
methanol (36 mL)) was added, and the mixture was allowed to
warm to ambient temperature and stirred for 3 h. After dilution
with DCM (200 mL), the reaction was washed with saturated
LiBr solution (3 × 150 mL) and water (3 × 100 mL); the aqueous
washings were back-extracted with DCM, and the combined
organic washings were dried over MgSO4. The solvent was
removed by rotary evaporation until approximately 30 mL of
solution remained, whereupon a saturated solution of NaBF4
(30 mL) was added and the solution stirred vigorously overnight.
The organic phase was then separated, washed with water (3 ×
30 mL), and dried (MgSO4) and the solvent removed by rotary
evaporation. Purification by column chromatography (gradient
elution with neat chloroform to 1.5% methanol in chloroform in
0.25% steps of 140 mL each) gave the title compound as a
crystalline solid (670 mg, 44%, mp 181-182 °C (Et2O/petroleum
ether)).
(2 × CH2), 21.81 (2 × CH3), 17.56 (2 × CH2) ppm. IR vmax
:
(CHCl3) 3378 (NH), 3035, 2944 (CH), 1667, 1600 (CdN). m /z
(CI): 308 (100, [M]+). HRMS: found 308.2338 ([M]+), C17H30N3O2
requires 308.2338. Anal. Calcd for C17H30N3O2BF4: C, 51.66; H,
7.65; N, 10.63. Found: C, 51.34; H, 7.53; N, 10.30.
Ack n ow led gm en t. Thanks are given to Zeneca
Pharmaceuticals and the EPSRC for a CASE student-
ship to D.A.T. and the ESF and the University of Wales
for funding work performed by A.H.J . The support of
the EPSRC Mass Spectrometry Centre at Swansea and
the EPSRC X-ray crystallography service at Cardiff is
also acknowledged.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for 12 and 13 (8 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
[R]21D: +45.2° (c ) 0.65 [CHCl3]). 1H NMR (250 MHz, CDCl3)
δ: 1.11 (6H, d, J ) 6.1 Hz, 2 × CH3), 1.18 (2H, m, 2 × CH),
J O981841F