Synthesis and applications of C2-symmetric guanidine bases

Article abstract of DOI:10.1016/j.tetlet.2003.09.162

The preparation of tetracyclic C₂-symmetric guanidinium salts is reported together with their application to enantioselective transformations.

Full text of DOI:10.1016/j.tetlet.2003.09.162

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8677–8680
Synthesis and applications of C2-symmetric guanidine bases
Matthew T. Allingham,a Andrew Howard-Jones,a Patrick J. Murphy,a,* Dafydd A. Thomasa and
Peter W. R. Caulkettb
aDepartment of Chemistry, University of Wales, Bangor, Gwynedd LL57 2UW, UK
bCVGI Department, AstraZeneca Pharmaceuticals, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
Received 8 July 2003; revised 11 September 2003; accepted 18 September 2003
Abstract—The preparation of the tetracyclic C2-symmetric guanidinium salts 5 and 11–13 is reported together with their
application to enantioselective transformations.
© 2003 Elsevier Ltd. All rights reserved.
We have previously1 reported the synthesis of the tetra-
cyclic C2-symmetric guanidine 5 in six steps from
commercially available ethyl R-3-hydroxybutyrate 1,
the key step in this synthesis being the conjugate
addition of guanidine to 2 equiv. of enone 4 (Scheme 1).
triphenylphosphorane 8 to give the intermediate phos-
phorane 9, which on reaction with formaldehyde gave
the required a,b-unsaturated ketone 10 in 72% yield.
Treatment of this substrate with guanidine in DMF at
rt for 24 h, followed by deprotection of the acetonide
using methanolic HCl gave, after chromatography, the
required guanidine base 11 in 45% yield. Purification
of 11 proved somewhat difficult as it was an
extremely polar material and very hygroscopic, factors
which led us to believe that it might be impractical to
use as a catalyst. We thus modified the final stage of
the reaction, in that after guanidine addition and
hydrolysis the crude reaction product was silylated
with an excess of TBDMSCl or TBDPSCl and the
chloride counterion exchanged with fluoroborate to
give 12 and 13 in 29 and 36% yields, respectively
(Scheme 2).
We wished to prepare a range of these compounds in
order that we might investigate their applications as
catalysts in asymmetric synthesis and envisaged that a
similar strategy using S-(−)-malic acid 6 as our chiral-
pool starting material would enable us to access a
wide range of catalysts. Thus esterification of 6, selec-
tive borane reduction of the C-1 ester2 and acetonide
formation was followed by LiAlH4 reduction of the
remaining ester function and iodination (PPh3/I2/imi-
dazole) to give iodide 7 in good overall yield. This
was then treated with lithiated acetylmethylene
Scheme 1. Reagents and conditions: (a) TBDMSCl/imid (99%); (b) DIBAL-H (95%); (c) TosCl/Py (85%); (d) NaI/acetone (89%);
(e) i. CH3COCHPPh3/nBuLi, ii. aq. CH2O (79%); (f) i. guanidine/DMF, ii. HCl/MeOH, iii. NaBF4 (aq.) (44%).
Keywords: phase transfer; catalysis; guanidine.
* Corresponding author.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.162

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M. T. Allingham et al. / Tetrahedron Letters 44 (2003) 8677–8680
Scheme 2. Reagents and conditions: (a) MeOH/HCl (70%); (b) BH3:SMe2/NaBH4 (92%); (c) (MeO)2CMe2, TosOH; (d) LiAlH4
(60%, two steps); (e) PPh3I2/imid (91%); (f) i. CH3COCHPPh3 8/nBuLi, ii. aq. CH2O (72%); (g) i. guanidine/DMF, ii. HCl/MeOH
(11; 45%); (h) as (g) then i. 3×R3SiCl/imid, DMF, ii. ion exchange (12; 29%, 13; 36%).
With these guanidinium salts in hand we investigated
their application as catalysts in the conjugate addition
of pyrrolidine 14 to the unsaturated lactone 15, which is
thought to involve an intermediate species such as 17.
(Fig. 1, Scheme 3).3 We had previously shown that
5·HBF4 could increase the rate of the conjugate addi-
tion reaction by ca. 4-fold over the uncatalysed process
and that exchanging the counterion to give 5·HBPh4 led
to a 16-fold increase. We decided to investigate the
catalysts 12·HBF4 and 13·HBF4 in this process and
found that the TBDMS substituted base 12 gave an
11-fold rate increase, whereas the TBDPS substituted
salt 13 gave only a 1.25 fold increase (Table 1, Scheme
3). In all of these reactions the product 16 was isolated
in racemic form.
Figure 1.
Nagasawa and co-workers have prepared a range of
structurally similar bases to ours and have investigated
this process. They found some correlation between
‘cavity’ size at the guanidine and relative rate of reac-
tion based on crystallographic evidence.4 Unfortunately
we were unable to grow crystals of 12 or 13 suitable for
X-ray analysis and can draw no direct conclusions of
this nature. It is interesting to note that the salt
12·HBF4 which has the most lipophilic substituent has
the highest catalytic activity, however the role the silyl
substituents has on the cavity size might be a more
telling factor.
Scheme 3. Reagents and conditions: (a) guanidinium salt, 5,
12, or 13 (0.1 equiv.), 0.3 M in CDCl3, rt.
Table 1.
Base
t1/2 (min)
Relative rate increase
None
135
35
12
–
4.0
11
5·HBF4
12·HBF4
13·HBF4
108
1.25
We were keen to investigate other catalytic activities
and were initially interested in the guanidine base
catalysed nitro-aldol5 (Henry reaction) and nitro-
Michael6 reactions. We found that all three of the free
guanidine bases were catalysts for both these processes
catalysing the reactions in good to high yields, however,
disappointingly only low enantiomeric excesses were
observed. For example, the best catalyst for the nitro-
aldol reaction was the free base 5 which for the reaction
of isovaleraldehyde 18 with nitromethane gave (R)-19
in 52% yield and in 20% ee.7 Similarly the base 5
catalysed the Michael addition of 2-nitropropane to
chalcone 20 to yield (S)-21 in 70% yield and 23% ee
(Scheme 4).8
Scheme 4. Reagents and conditions: (a) i. 5·HBF4 (0.1 equiv.),
NaOMe (0.09 equiv.), MeOH, 30 min then remove solvent; ii
CCl4 rt, 18, MeNO2, 16 h; (b) i. 5·HBF4 (0.1 equiv.), t-BuOK,
(0.09 equiv.), THF, (Me)2CHNO2, 20, rt, 24 h.

M. T. Allingham et al. / Tetrahedron Letters 44 (2003) 8677–8680
8679
We next investigated the application of these catalysts
in phase transfer catalysis (PTC)9 and firstly investi-
gated the benzylation of the glycinate Schiff’s base 22.10
Thus, 22 and an excess of benzyl bromide, dissolved in
cooled (0°C) CH2Cl2 were treated with the required
catalyst (5·HBF4, 11·Cl, 12·HBF4 or 13·HBF4) in the
presence of aqueous sodium hydroxide (2 M). A typical
set of results for these reaction is shown in Table 211
(Scheme 5).
We have also investigated the application of the cata-
lyst 5·HBF4 in the PTC epoxidation13 of the chalcones
24 and have found it to be an excellent catalyst for this
transformation. In the two examples shown the ee for
product 25 where R=Ph was found to be 93% and in
the case of 25 where R=C6H13 the ee was 91%.14 These
results compare very favourably with existing phase
transfer catalysts for these processes and again the
catalyst was isolated unchanged in an identical manner
as described previously (Scheme 6).
From these results is was apparent that the catalyst
5·HBF4 was the best catalyst for this transformation
effecting nearly complete conversion of 22 to the
desired product 23 which was obtained as the R-enan-
tiomer with 86% ee. The catalyst 11·Cl gave the worst
results with very low conversion and low ee, which
might be attributed to its poor solubility in the organic
phase of the reaction. The silyl protected catalysts
12·HBF4 and 13·HBF4 also suffered from incomplete
conversion; however, they still gave the alkylated prod-
ucts as the R-enantiomer in good ee’s, 65 and 74%,
respectively. The conversion rates for 12·HBF4 and
13·HBF4 could be raised to quantitative by increasing
the concentration of the sodium hydroxide in the reac-
tion or by allowing the reaction to progress for longer;
however, this did not increase the levels of enantioselec-
tivity. In all these reactions, the catalysts are very
robust and remain unchanged and are removed from
the reaction mixtures during isolation and purification
of the product and can then be recycled by repeating
the fluoroborate steps of their preparation (see Schemes
1 and 2). Our results and the selectivities are in agree-
ment with the reactions reported by Nagasawa using
structurally similar pentacyclic guanidine catalysts.12
In conclusion we have demonstrated that the tetracyclic
catalysts 12·HBF4 and 13·HBF4 are easily prepared in
high yield from (S)-malic acid and that these, and in
particular, the previously reported catalyst 5·HBF4, are
effective catalysts for phase transfer catalysed pro-
cesses. We are currently investigating further applica-
tions of these and related catalysts and will report our
findings in due course.
Acknowledgements
Particular thanks are given to Dr Lygo (The University
of Nottingham) and co-workers for help and advice on
many aspects of this work. Similarly we thank
AstraZeneca Pharmaceuticals and the EPSRC for fund-
ing (DAT) and the EPSRC Mass spectrometry centre at
Swansea.
References
1. Caulkett, P.; Howard-Jones, A.; Murphy, P. J.; Thomas,
D. J. Org. Chem. 1999, 64, 1039–1041.
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Table 2.
Entry
Catalyst
%Conv. (%)
ee (%)
1
2
3
4
5·HBF4
11·Cl
12·HBF4
13·HBF4
>97
15
70
86 (R)
21 (R)
65 (R)
74 (R)
4. Nagasawa, K.; Georgieva, A.; Takahashi, H.; Nakata, T.
Tetrahedron 2001, 57, 8959–8964.
5. Chinchilla, R.; Najera, C.; Sanchez-Agullo, P. Tetra-
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8. Bako´, P.; Bajor, Z.; Tike, L. J. Chem. Soc., Perkin Trans.
1 1999, 3651–3655.
Scheme 5. Reagents and conditions: (a) Base (0.1 equiv.),
NaOH (2 M), BnBr (2 equiv.), CH2Cl2, 16 h 0°C–rt.
9. For specific reviews, see: (a) Phase-Transfer Catalysis:
Mechanisms and Syntheses; Halpern, M. E., Ed.; Ameri-
can Chemical Society: Washington, DC, 1997; (b)
O’Donnell, M. J. In Catalytic Asymmetric Synthesis, 2nd
ed.; Ojima, I., Ed.; VCH: New York, 2000; pp. 725–755;
(c) Nelson, A. Angew. Chem., Int. Ed. 1999, 38, 1583–
1585; (d) T. Shioiri. In Handbook of Phase Transfer
Catalysis; Sasson, Y.; Neumann, R., Eds.; Chapman &
Hall; London, 1997; pp. 462–479.
Scheme 6. Reagents and conditions: (a) 5·HBF4 (0.05 equiv.),
NaOCl (aq.), Tol, 16 h 0°C–rt.
10. For this reaction and other related PTC alkylations, see:
(a) O’Donnell, M. J.; Wu, S.; Hoffman, C. Tetrahedron

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M. T. Allingham et al. / Tetrahedron Letters 44 (2003) 8677–8680
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14. Typical experimental procedure: The guanidinium salt
5·HBF4 (0.04 mmol) and the chalcone 24 (R=Ph, 166
mg, 0.8 mmol) were dissolved in toluene (2 ml) and the
mixture cooled (0°C) along with vigorous stirring.
Sodium hypochlorite solution (2.4 ml, 8% aqueous solu-
tion) was then added and the reaction stirred to rt over
16 h. Dichloromethane (15 ml) was added and the
organic layer separated, dried (MgSO4) and evaporated.
Purification by chromatography eluting with 3–5%
diethyl ether in petrol gave 25 (R=Ph, 178 mg, 99%
yield) as a solid, mp 74–76°C (lit. 76–77°C) [h]2D0 −250,
(lit. [h]D +195 for antipode of 86% ee).13b Enantiomeric
excesses ( 3%) were determined on a Chiralpak AD
column (90: 10 hexane:EtOH for R=Ph and 99.5: 0.5
hexane:IPA for R=C6H13).
11. Typical experimental procedure: The required guani-
dinium salt (0.04 mmol) and the glycinate Schiff’s base 22
(120 mg, 0.407 mmol) were dissolved in dichloromethane
(2 ml) and aqueous NaOH solution (2 ml, 2 M), was
added. This mixture was cooled (0°C), vigorously stirred
and BnBr (139 mg, 0.814 mmol, 120 mL) was then added
in one portion. After stirring for 16 h the reaction had
reached room temperature and further dichloromethane
(10–15 ml) was added and the organic layer separated,
dried (MgSO4) and evaporated. Conversion rates were
1
determined by H NMR and ees ( 3%) were determined