5-Pyrrolidin-2-yltetrazole: A New, Catalytic, More Soluble Alternative to Proline in an Organocatalytic Asymmetric Mannich-type Reaction

Article abstract of DOI:10.1055/s-2004-817745

A Mannich-type addition of ketones to N-PMP protected α-imino ethyl glyoxalate is catalyzed by a new proline analogue, 5-pyrrolidin-2-yltetrazole 1. The new organocatalyst has significant advantage over its parent in that it can be used in non-polar solvents without loss of enantioselectivity.

Full text of DOI:10.1055/s-2004-817745

558
LETTER
5-Pyrrolidin-2-yltetrazole: A New, Catalytic, More Soluble Alternative to
Proline in an Organocatalytic Asymmetric Mannich-type Reaction
5
-Pyrrolidin-2-ylte
l
trazoleexander J. A. Cobb, David M. Shaw, Steven V. Ley*
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
Fax +44(1223)336442; E-mail: svl1000@cam.ac.uk
Received 9 January 2004
Abstract: A Mannich-type addition of ketones to N-PMP protected
a-imino ethyl glyoxalate is catalyzed by a new proline analogue, 5-
pyrrolidin-2-yltetrazole 1. The new organocatalyst has significant
advantage over its parent in that it can be used in non-polar solvents
without loss of enantioselectivity.
Key words: asymmetric, Mannich, organocatalysis, proline, tetra-
zole
Catalytic asymmetric synthesis, which avoids the use of
Scheme 1
metals to co-ordinate a stereogenic environment is of
great interest.1 There are many advantages that organocat-
alysts have over their metal-mediated counterparts. They
can often be used under aerobic conditions, are cheap to
use, and in most cases only a small molecule is required to
affect a high enantioselectivity. Furthermore, attachment
of such compounds to a solid-phase would allow easier
scale up and recycling of the catalyst. An organocatalytic
Scheme 2 General scheme for the addition of ketones into N-PMP-
protected a-imino ethyl glyoxalate.
system that has been studied extensively2 is an enantio-
selective proline-based one which accelerates a range of
transformations such as aldol reactions,3 Robinson
annulations4 and Mannich reactions.5 Although these re-
actions are highly enantioselective, they all rely on fairly
polar solvents such as DMSO due to the insoluble nature
of proline itself.
serves as an excellent comparison with the new tetrazole
catalyst.
Dichloromethane, wet acetonitrile and wet tetrahydrofu-
ran were all screened in the reaction of cyclohexanone to
the imine in order to determine the best solvent (Table 1).
The highest yielding reaction was found to be that carried
out in dichloromethane, with tetrazole 1 being used at a
level of 5 mol%. In this system, the catalyst appeared in-
soluble at first, though after time (ca. 1 h) partial solubili-
zation was achieved which presumably aided the course
of the reaction.7 It is interesting to note that the same reac-
tion conditions with L-proline gave no observable product
after the same amount of time, indicating that organocat-
alyst solubility is key in this reaction. This was empha-
sized when further optimization showed that tetrazole 1,
at extended reaction times, could be used at the level of 1
mol% (where it appeared to dissolve completely) without
compromising enantioselectivity. These catalytic
amounts are very significant; proline is routinely used at
levels of 20 mol%.2 Furthermore, organocatalyst 1 ap-
pears to give more rapid reaction in dichloromethane than
DL-proline does in DMSO as visualized by thin layer
chromatography.
A proline alternative with greater solubility in conven-
tional solvents, which would not affect enantioselectivity
would be highly desirable and ideally it would have a
greater turnover number.
Tetrazoles are generally used in medicinal chemistry as
bioisosteres for carboxylic acids to increase the solubility
of the drug whilst retaining the properties of the acid. Tet-
razole 1 was synthesized in order to capitalize on the im-
proved solubility using a slight modification of the
literature procedure6 (Scheme 1) in the hope that this
would provide the extra solubility required in catalytic re-
actions.
In order to test the efficacy of this new catalyst against
proline itself, the Mannich-type addition of a carbonyl-
containing compound (in a large excess) to N-PMP-pro-
tected a-imino ethyl glyoxalate was selected (Scheme 2).
This reaction has been investigated recently by Barbas
and co-workers, using proline as a catalyst5a and therefore
The lower yields obtained where a small amount of water
was present is possibly due to hydrolysis of the imine,
although this did not appear to affect the high enantio-
SYNLETT 2004, No. 3, pp 0558–0560
Advanced online publication: 06.02.2004
DOI: 10.1055/s-2004-817745; Art ID: D00804ST.pdf
© Georg Thieme Verlag Stuttgart · New York
1
8.
0
2.
2
0
0
4

LETTER
5-Pyrrolidin-2-yltetrazole
Table 2 Carbonyl-Containing Products
559
Table 1 Experimental Data
Product
Reaction
time (h)
Yield
(%)a
Dr
Ee
syn:antib
(%)c
2
8
65
59
63
72
>19: 1
>19: 1
>19: 1
>19: 1
>99
>99
>99
>99
Catalyst
(mol%)
Solvent
CH2Cl2
Reaction Yield dr syn:antib ee
time (h) (%)a (%)c
1
2
3
4
5
1 (5)
2
2
658
0
>19: 1
–
>99
–
L-Proline (5) CH2Cl2
16
8
1 (5)
1 (5)
1 (1)
Wet MeCN
2
49
37
70
>19: 1
>19: 1
>19: 1
>99
>99
>99
Wet THF
CH2Cl2
2
16
a Based on isolated product.
b Determined by 1H NMR spectroscopy.
c Determined by chiral HPLC.
24d
24
31
74
–
14
94
>19: 1
8
99e
75
–
>99
95g
Figure 1 Transition state of the tetrazole organocatalyzed Mannich
reaction.9 The PMP group on the imine sits axially to avoid clash with
the tetrazole, thereby forcing the E-enamine (which is preferred) to
produce the syn-product.
24
7: 1f
a Based on isolated product.
selectivities. These reactions are thought to proceed via a
hydrogen bonded transition state similar to that suggested
by Houk and Bahmanyar (Figure 1).9
b Determined by 1H NMR spectroscopy.
c Determined by chiral HPLC.10
d Reaction stopped after 24 h at 55% conversion.
e Reaction performed in acetone.
Encouraged by the observation that this reaction proceed-
ed in dichloromethane where L-proline did not, a range of
different carbonyl-containing compounds was screened
(Table 2) using tetrazole 1. Reactions were performed at a
f Epimerization on the silica column led to a deterioration of dr.5d,e
g Ee measured on corresponding lactone.11
level of 5 mol% for practical reasons and also to ensure action using L-proline in DMSO5a and compound 5 was
complete saturation of the system.
only produced in a 51% yield using DL-proline at 5 mol%
in DMSO compared to 72% yield using 1). Compound 6
was produced at a slower rate due to the formation of a bi-
phasic mixture between the dichloromethane and a fluo-
rous phase. It was also observed to proceed in high
regioselectivity and reduced enantioselectivity (this is as-
cribed to disruption of the hydrogen bonding within the
transition state) as reported previously.5a
Pleasingly, the catalyst performed very well, giving gen-
erally good yields and excellent diastereoselectivities and
enantioselectivities. Cyclic compounds 2, 3 and 7 were
produced in excellent enantiomeric excess, as were acy-
clic compounds 4, 5 (the thermodynamic product) and 8.
The reaction to form compound 8 was performed in neat
acetone and hence purification just required evaporation
of the solvent and filtration of the residue through a plug Aldehyde 9 was also synthesized5d,e and reduced to its
of silica.
lactone in order to analyze the ee by HPLC.11
In all but one case, the reactions using tetrazole 1 were just In summary, tetrazole catalyst 1 has been made and cata-
as or more efficient than the corresponding L-proline reac- lyzes the Mannich-type addition of a carbonyl-containing
tion (for example the yield of compound 4 represents an compound to N-PMP-protected a-imino ethyl glyoxalate
improvement on that previously described of the same re- in non-polar solvents. This represents an attractive alter-
Synlett 2004, No. 3, 558–560 © Thieme Stuttgart · New York

560
A. J. A. Cobb et al.
LETTER
(8) General Procedure: N-PMP-protected a-imino ethyl
native to L-proline, particularly as it avoids the use of sol-
vents such as DMSO and can also be used in smaller
quantities without compromising on enantioselectivity.
Further uses of this catalyst will be reported in due course.
glyoxalate (93.5 mg, 0.5 mmol) was dissolved in anhydrous
CH2Cl2 (4 mL). Carbonyl-containing compound (1 mL, 20
vol%) was added to this solution followed by 5-pyrrolidin-
2-yltetrazole (3.5 mg, 5 mol%) and the resulting mixture
stirred under argon for 2–24 h. After this time, the mixture
was quenched with sat. NH4Cl solution (10 mL) and the
aqueous layer extracted with EtOAc (2 × 25 mL). The
combined organic layers were dried (MgSO4), filtered and
evaporated under reduced pressure to give a residue which
was further purified by column chromatography using
varying mixtures of EtOAc and petroleum ether 40–60 as
eluent.
Acknowledgment
We thank Pentraxin Therapeutics for funding (to A.J.A.C.) and
AstraZeneca (to D.M.S.). The authors also wish to thank Dr Ed
Cleator and Dr Matthew Gaunt for useful discussions.
References
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(7) The tetrazole is not soluble in neat ketone.
Scheme 3
Synlett 2004, No. 3, 558–560 © Thieme Stuttgart · New York