Towards a chemo-enzymatic method for the asymmetric synthesis of β-amino tertiary alcohols

Article abstract of DOI:10.1039/b916013b

The synthesis of a number of β-amino tertiary alcohols has been achieved via ring-opening of an unsymmetrical epoxide with primary and secondary amines. The results revealed that primary amines give symmetrical triol products following an undesired acyl m

Full text of DOI:10.1039/b916013b

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Towards a chemo-enzymatic method for the asymmetric synthesis of b-amino
tertiary alcohols†‡
Andrea March-Cortijosa and Timothy J. Snape*b
Received 5th August 2009, Accepted 16th September 2009
First published as an Advance Article on the web 15th October 2009
DOI: 10.1039/b916013b
The synthesis of a number of b-amino tertiary alcohols has been achieved via ring-opening of an
unsymmetrical epoxide with primary and secondary amines. The results revealed that primary amines
give symmetrical triol products following an undesired acyl migration reaction, whereas secondary
amines give the desired chiral (racemic) products. Furthermore, we demonstrate that asymmetric
products can be formed using enantiomerically pure epoxide and aromatic amines without any loss of
enantiomeric excess.
Tertiary alcohols and their derivatives are an important class of
compound, which are found in numerous natural products and
pharmaceuticals; they also represent useful chemical building
blocks for synthetic manipulation to other useful products.1–3
In particular, b-amino tertiary alcohols are present in natural
products including pumiliotoxin A and other alkaloids from
the poison dart frogs of the dendrobates genus,4 setoclavine,5
paraherquamide A,6 and the anticancer compound vincristine.7
Likewise, numerous biologically active non-natural compounds
possess this moiety.8–10 Despite the importance of tertiary al-
cohols, a general asymmetric synthesis of them still provides a
challenge to the synthetic community. Current methods towards
the development of enantiomerically enriched tertiary alcohols
include: the enantioselective addition of organometallic reagents
to ketones1–3,11,12 as well as various enzymatic methods by kinetic
resolution13 and desymmetrisation.14 However, due to the almost
spherical, bulky shape of tertiary alcohols, their direct enzymatic
resolution is difficult, as enzymes are unable to distinguish between
the enantiomers efficiently.13
The motivation behind that work was to develop an asymmetric
synthesis of a suitable building block that could be further
developed into a method for the synthesis of enantiopure tertiary
alcohols in an efficient and economical manner by opening
the epoxide.16–21 Herein, we report our results on the extension
of that work regarding the conversion of the aforementioned
enantiomerically pure epoxide to the corresponding asymmetric
tertiary alcohol.
In our previous work,15 we established the enzymatic conditions
necessary to obtain the enantiopure epoxide 2, and our attempts
to develop the method into an asymmetric synthesis of tertiary
alcohols began by ascertaining the conditions needed to open the
epoxide with a range of amines on racemic material, Scheme 2.
Scheme 2 Synthesis of b-amino tertiary alcohols.
Recently, we published a method for the desymmetrisation of the
prochiral diol (2-hydroxymethyl-oxiranyl)-methanol (1), in which
the enantiopure epoxide 2 was isolated in 46% yield with 97-99%
enantiomeric excess, Scheme 1.15
Initial experiments conducted to open the epoxide set out
with conditions closely related to established procedures, which
included the use of catalysts; microwave irradiation and by varying
the equivalents of amine nucleophile used. Unfortunately, all these
attempts failed to produce material in sufficient quantities due to
low conversion of the starting material.16–21 Eventually, suitable
conditions were found which opened the epoxide in good to
excellent yields: the epoxide was heated in the presence of the
amine (3 eq.) at reflux, in ethanol, for 1 h. Table 1 outlines the
results of this screen displaying isolated yields which vary from
21-96%. The results highlighted a few points that are worthy of
further discussion: 1] it appears as though secondary and primary
aromatic amines give the desired product 3 (entries 1-5, 10, 12,
14, 16, 17); and 2] primary amines, give the required epoxide ring-
opened product, but, in such cases, the acetate group seemingly
migrates from oxygen onto the newly introduced nitrogen atom
during the course of the reaction to give triol 4 (entries 6-9,
11, 13, 15); the structures of two of the products of this
rearrangement (amine = propargylamine and allylamine, entries
9 and 11, respectively) have been proved by X-ray crystallography,
Fig. 1.22
Scheme 1 Desymmetrisation of prochiral diol (1).
aSchool of Chemistry, Manchester Interdisciplinary Biocentre, University of
Manchester, 131 Princess Street, Manchester, M1, 7DN, UK
bSchool of Pharmacy and Pharmaceutical Sciences, Maudland Building,
University of Central Lancashire, Preston, PR1 2HE, UK. E-mail: tjsnape@
uclan.ac.uk; Tel: +44 (0)1772 895805
† This paper is part of an Organic & Biomolecular Chemistry web theme
issue on biocatalysis.
‡ Electronic supplementary information (ESI) available: Experimental
details. CCDC reference numbers 736703–736704. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/b916013b
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Table 1 Results of amine addition to epoxide ( )-2a
As can be seen from the X-ray structures (Fig. 1) and
NMR data (supporting information†), the result of this acyl
migration means these products are symmetrical and thus
would not give asymmetric products with enantiomerically pure
epoxide.
Entry
1
Compound
Amine
Isomerb
Yield (%)c
d
5
3
—
To confirm that the formation of isomer 3 (Scheme 2) was
due to the use of secondary amines, which lack a replaceable
hydrogen atom in the epoxide ring-opened product, thus pre-
venting acyl migration, and not due to other, unknown factors,
three secondary N-methylated amines were reacted alongside the
analogous primary amines (entries 9 and 10; 11 and 12; 13 and 14)
and indeed it was found that the products of the N-methylated
compounds (entries 10, 12 and 14) gave the desired isomer 3
exclusively without the concomitant acyl migration seen in the
cases with the primary amines, as expected, albeit in a slightly
lower yield. The low yield of entry 1 is surprising, however,
repeating the reaction numerous times resulted in the isolation
of a compound determined to be N-acyl pyrrolidine, presumably
formed via an intermolecular acyl transfer reaction between ( )-2
and pyrrolidine. It is assumed that the reduced steric bulk and
the higher nucleophilicity of pyrrolidine, compared to the other
6-membered ring amines, is the cause of this undesired by-product
being formed; as evidenced by the good yields with the less reactive,
more bulky amines. Also, the product from the reaction with
2,6-dimethylmorpholine produced a complex mixture of isomers
since the amine used was obtained as a mixture of cis and trans-
isomers (entry 4), however, mass spectral data was indicative of the
desired product (HRMS FAB [M+H]+ 262.1648 C12H23O5N+H+
requires 262.1654).
2
3
6
7
3
3
55
76
4
8
3
84
5
6
9
3
4
77
89
10
7
8
11
12
4
4
21
31
We assume that the reduced nucleophilicity of the primary
aromatic amines prevents the acyl migration seen with aliphatic
primary amines. From empirical observation, we believe that the
migration occurs after epoxide-opening has taken place and not via
acylation of the amine nucleophile followed by ring-opening with
the formed acetamide as nucleophile. In the case of allylamine,
carrying out the reaction at room temperature did not prevent acyl
migration taking place, however, the use of a suitable protecting
group (e.g. Bn) may allow a switch in the isomer being produced by
temporarily forming a secondary amine which can be deprotected
later.
9
13
14
4
3
93
10
80e,f
11
12
15
16
4
3
96
55e,f
13
17
4
74
Under the basic conditions used we did not detect any products
resulting from epoxide ring-opening at the more hindered carbon.
Following on from the work using racemic epoxide 2, outlined
in Table 1, we turned our attention to the reaction using
enantiomerically enriched (97% ee)15 epoxide to determine if the
conditions would allow us to develop an asymmetric synthesis
of tertiary alcohols. Compounds 20 and 21 were amenable to
enantiomeric separation using HPLC with a chiral stationary
phase, and thus were the compounds used to establish if the
enantiomeric excess of the starting material was maintained in
the ring-opened products. Indeed, when the enantiomerically pure
epoxide (S)-(+)-2 was used, no loss of enantiomeric excess was
observed with 4-fluoroaniline and o-anisidine, Table 2, confirming
that the method is suitable for the synthesis of enantiomerically
pure b-amino tertiary alcohols.23
14
15
18
19
3
4
63
54
16
17
20
21
3
3
96
93
a Reagents and conditions: Epoxide 2 was dissolved in ethanol (0.1 M), the
amine added (3 equivalents) and the reaction heated to reflux for 1 h. b See
Scheme 2. c Isolated yields. d Trace product was observed after 1 h or 4 h
at reflux. e The reaction was purified by the removal of excess amine under
high vacuum. f Reaction left for 4 h.
In summary, we have developed a method for the asymmetric
synthesis of b-amino tertiary alcohols via ring-opening of an
enantiomerically pure epoxide with primary aromatic amines. The
enantiomeric excess of the epoxide is maintained in the tertiary
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Fig. 1 X-Ray crystal structures of 13 and 15.
Table 2 Results of aromatic amine addition to (S)-(+)-2a
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Entry
1
Amine
Isomerb
Ee (%)c
97
3
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2
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a Reagents and conditions: See ref 23. b See Scheme 2. c Determined using
HPLC.
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22 X-Ray crystallographic data: 13: C9H15NO4, M = 201.22, monoclinic,
alcohol products, and thus we believe the method should be
applicable to the synthesis of similar b-amino tertiary alcohols.
Acknowledgements
˚
P2(1)/c, a = 9.2759(13), b = 14.318(2), c = 7.9435(11) A, b =
We would like to thank the Centre of Excellence for Biocatalysis,
Biotransformations and Biocatalytic Manufacture (CoEBio3)
for funding, Professor Nick Turner for continued support and
Dr Madeleine Helliwell for crystallographic analysis.
3
-1
˚
110.024(3), V = 991.2(2) A , T = 100(2) K, Z = 4, m = 0.106 mm , 5675
reflections collected, of which 2032 were unique, Rint = 0.0588, CCDC
736704; 15: C9H17NO4, M = 203.24, monoclinic, P2(1)/c, a = 9.763(6),
3
˚
˚
b = 14.702(10), c = 7.816(5) A, b = 108.886(10), V = 1061.5(12) A ,
T = 100(2) K, m = 0.099 mm-1, 3837 reflections collected, of which
1297 were unique, Rint = 0.1552, CCDC 736703. Because the crystal
was weakly diffracting, it was necessary to use rigid bond and similarity
restraints on the anisotropic atomic displacement parameters to avoid
them becoming unrealistic, leading to the application of a total of 108
restraints‡.
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of 1 (100 mg, 0.96 mmol), Amano L, AK (200 mg, 2 wt. eq.) and
˚
molecular sieves (4 A) in dichloromethane (10 ml, 0.1 M) was added
ace◦tic anhydride (1.8 equivalents) and the reaction left for one hour at
R
37 C. The mixture was filtered through Celiteꢀ and the filtrate was
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reduced in vacuo. Ethanol (10 ml, 0.1 M) and the corresponding amine
(see Table 2) was added and the mixture heated at reflux for 4 hours. The
mixture was reduced in vacuo and purified by column chromatography
(SiO2; 20% EtOH in EtOAc). The enantiomeric purity was determined
by HPLC; Agilent 1100 Series. Chiralpack AD, 1 ml/min, 80/20
isohexene in EtOH at 25 ◦C.
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The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 5163–5165 | 5165
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