On a chemoenzymatic desymmetrization-ring expansion strategy towards functionalized N-heterocycles

Article abstract of DOI:10.1055/s-0033-1338960

The direct combination of the desymmetrization of N-heterocyclic meso-diols using lipase from Mucor miehei as biocatalyst and subsequent ring expansion of the optically active products by activation of the remaining hydroxy group gives rise to functionalized nonsymmetrical piperidines in a highly enantio- and dia stereoselective manner. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1338960

LETTER
▌1529
letter
On a Chemoenzymatic Desymmetrization–Ring Expansion Strategy towards
Functionalized N-Heterocycles
Strategy towards Functionalized N-Heterocycles
Daniel Thiel, Jan Deska*
Department für Chemie, Universität zu Köln, Greinstr. 4, 50939 Cologne, Germany
Fax +49(221)4705102; E-mail: jan.deska@uni-koeln.de
Received: 17.04.2013; Accepted after revision: 07.05.2013
mediated rearrangement of β-amino alcohols being a
Abstract: The direct combination of the desymmetrization of N-
powerful tool for the preparation of nonsymmetrical N-
heterocyclic meso-diols using lipase from Mucor miehei as biocat-
heterocycles from symmetrical meso-diols. Thus, the ini-
tial step to create a nonracemic entity (2a–c) by enzymatic
alyst and subsequent ring expansion of the optically active products
by activation of the remaining hydroxy group gives rise to function-
alized nonsymmetrical piperidines in a highly enantio- and dia- desymmetrization is ought to be directly combined with a
stereoselective manner.
subsequent ring-expansion reaction as second symmetry-
breaking operation to substantially increase molecular
complexity (Scheme 1). This proposed sequence would
offer a very expeditious route towards entirely unsymmet-
ric and highly functionalized N-heterocycles 3a–c with
excellent control of both enantio- and diastereomeric
purity.
Keywords: desymmetrization, biocatalysis, ring expansion, hetero-
cycles, azasugars
Manipulations of hetero- and carbocyclic systems by
means of either ring-expansion or ring-contraction reac-
tions have gathered much attention over the past century,
from the very early examples taking advantage of Beck-
mann-1 or Faworsky-type2 rearrangements, respectively,
to modern transition-metal-catalyzed transformations
such as ring rearrangement olefin metathesis.3 From a
synthetic point of view, the controlled alteration of ring
sizes of cyclic compounds offers an elegant way to rapidly
increase complexity of a given system and in some cases
even allow for the preparation of otherwise troublesome
medium-sized cyclic products.4 In 1995, Cossy et al. pre-
sented a preparatively simple one-carbon ring-expansion
procedure for the rearrangement of prolinols to give β-hy-
droxy piperidines with perfect transfer of chirality.5 Upon
treatment of the pyrrolidine-based amino alcohols with
trifluoroacetic anhydride, reversible formation of aziridi-
nium trifluoroacetates is proposed that are preferentially
opened under thermodynamic control at the higher substi-
tuted position giving rise to ring-enlarged N-heterocycles.
In succession, a number of variations have been devel-
oped that also allow for the stereocontrolled synthesis of
3-amino-, 3-azido-, and 3-fluoro-substituted piperidines
based on this protocol.6
The enzymatic desymmetrization7 of meso-dialcohols
bearing N-heterocyclic core structures has been intensive-
ly studied and found numerous applications in the prepa-
ration of alkaloids and related synthetic motifs.8 Offering
a straightforward access to optically enriched pyrrolidine
and piperidine building blocks in excellent enantiopurity,
however, one limitation obviously lies in the remaining
symmetric substructure of the desymmetrized products
restricting their synthetic implementation to targets carry-
ing this kind of subunits. We envisaged the aziridinium-
OH
enantioselective
ring expansion
n
n
N
Bn
N
HO
OH
HO
Bn
1a–c
3a–c
enzymatic
desymmetrization
ring expansion/
deacylation
n
N
n = 1 or 2
AcO
OH
Bn
2a–c
creating
stereochemical
information
creating
molecular
complexity
Scheme 1 Formal enantioselective ring expansion
Although being a well-studied transformation for the
preparation of carbamate-protected N-heterocycles, there
was no literature precedence describing lipase-catalyzed
desymmetrizations of alkyl-protected N-heterocyclic
meso-diols.9 With the requirement of a nucleophilic nitro-
gen center for the subsequent ring expansion we started a
thorough investigation on the lipase-mediated enantiose-
lective transesterification of three different benzylamine-
containing diols. With the piperidine-based diol 1a as
model substrate, a series of lipases were tested with regard
to reactivity and enantioselectivity employing vinyl ace-
tate as acyl donor in toluene at 35 °C.10 Both lipases from
C. antarctica suffered from low selectivity as indicated by
the formation of undesired diacetate 4a and only minor
enantiomeric excess of 2a (Table 1, entries 1 and 2). Good
enantiomeric purity of 2a was achieved by means of lipas-
es from C. rugosa, T. lanuginosa, P. cepacia, and porcine
SYNLETT 2013, 24, 1529–1532
Advanced online publication: 11.06.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1338960; Art ID: ST-2013-B0350-L
© Georg Thieme Verlag Stuttgart · New York

1530
D. Thiel, J. Deska
LETTER
pancreas (Table 1, entries 3–6). However, best results product in 52% yield together with the desired azepane 3a
were obtained employing either P. fluorescens lipase or in only 23% yield after two days. Substantially higher re-
M. miehei lipase with almost quantitative conversion into gioselectivity towards the desired product was observed
monoacetate 2a in perfect optical purity (Table 1, entries for the saturated five-membered heterocycle 2b with a ra-
7 and 8). Changing from piperidine 1a to pyrrolidine 1b, tio of 2:1 in favor of the expanded product 3b and an iso-
the selectivity of all tested enzyme catalysts dropped more lated yield of 67%.11,12
or less severely as exemplified for TLL, PCL, and PFL
(Table 1, entries 9–11). Only lipase from Mucor miehei
OH
TFAA, Et3N
THF, reflux
n
n
n
maintained synthetically useful enantiotopic differentia-
tion and to the expense of a certain overacylation (21% di-
acetate 4b) enantiomerically pure 2b could be isolated in
74% yield (Table 1, entry 12). The same selectivity loss
occurred in the desymmetrization of pyrrolin 1c (Table 1,
entries 13–15) and again, MML proved to be the catalyst
of choice giving rise to the desired monoacetate 2c in 67%
yield and 95% enantiomeric excess.
+
N
N
N
then NaOH
MeOH, 0 °C
HO
OH
AcO
OH
HO
Bn
Bn
Bn
2a or b
n = 2: 3a, 23%
n = 1: 3b, 67%
+
+
1a, 52%
1b, 31%
Scheme 2 Trifluoroacetate-mediated ring expansion
With a generally applicable method for the highly enantio-
selective synthesis of the cyclic benzylamines 1a–c in
hand we started our studies on the ring-expanding nucleo-
philic substitution reactions. First, we chose Cossy’s orig-
inal protocol exploiting the reversible aziridinium
formation of initially generated trifluoroacetates under el-
evated temperature.5d To facilitate analysis, the reaction
mixtures were saponified prior to isolation yielding ring-
expanded diols 3a,b alongside with the meso-diols 1a,b
(Scheme 2). Under thermodynamic control, the ring ex-
pansion from piperidine 2a to azepane 3a proceeded slug-
gishly resulting in the isolation of meso-1a as major
During the course of our studies, Charette et al. reported
on a novel approach for the ring expansion of functional-
ized N-heterocycles employing trifluoromethanesulfonic
anhydride as activating reagent.13 Using 3-pyrolline de-
rivatives as starting material, the intermediate aziridinium
triflates were regioselectively and irreversably attacked at
the higher substituted position thanks to the allylic activa-
tion. Due to the non-nucleophilic character of the leaving
group, this protocol allows for the flexible use of different
kinds of oxygen-, nitrogen-, sulfur-, and carbon-centered
nucleophiles making this procedure a valuable comple-
ment to existing strategies. Hence, Charette’s conditions
Table 1 Lipase-Screening for the Desymmetrization of meso-1a
lipase
vinyl acetate
n
n
n
+
N
N
N
toluene, 16 h
35 °C
HO
OH
AcO
OH
AcO
OAc
Bn
Bn
Bn
meso-1
2
meso-4
Entry
Lipase
Diol
2 (%)b
ee (%)
4 (%)
1
2
3
4
5
6
7
8
CALA
CALB
CRL
TLL
PCL
PPL
34
26
52
30
69
5
95
>99 (85)
19
–33
87
92
97
89
>99
>99
28
73
1
1
N
<1
<1
2
HO
Bn
OH
PFL
MML
1a
<1
9
10
11
12
TLL
PCL
PFL
82
20
45
79 (74)
80
7
36
3
2
9
N
HO
OH
OH
Bn
MML
>99
21
1b
13
14
15
16c
TLL
PCL
PFL
56
9
10
74 (67)
76
8
–13
95
2
<1
<1
26
N
HO
Bn
MML
1c
a Reaction conditions: diol 1a–c (0.50 mmol), vinyl acetate (5.0 mmol), lipase, toluene (0.5 mL) at 35 °C for 16 h. Conversion and ee was de-
termined by HPLC on chiral phase from the crude mixture. For enzyme specifications see Supporting Information.
b Isolated yield of monoacetate 2 on 3 mmol scale given in parentheses.
c Reaction was performed at 22 °C.
Synlett 2013, 24, 1529–1532
© Georg Thieme Verlag Stuttgart · New York

LETTER
Strategy towards Functionalized N-Heterocycles
1531
were also tested for the ring expansion of the meso-diol- In conclusion, we have successfully developed a novel
derived amino alcohols 2a–c, employing sodium acetate protocol for the preparation of optically enriched, func-
as O-nucleophile and proton sponge [1,8-bis(dimethyl- tionalized piperidines based on the combination of enzy-
amino)naphthalin] as a base. Not surprisingly, at low tem- matic desymmetrization, and subsequent ring-expanding
perature the lack of allylic activation of the saturated rearrangement reactions. Currently, extension of the tri-
substrates 2a and 2b resulted in the preferential attack of flate-mediated substitution to other, more functionalized
the nucleophile at the less hindered position and thus, the nucleophiles is ongoing work. In continuation, applica-
desired ring-expanded compounds were obtained only as tion of this method in the context of alkaloid synthesis as
minor side products in 8% (5a) and 12% yield (5b), re- well as in the preparation of substituted cyclic amino acids
spectively (Scheme 3). The product selectivity changed will be studied in detail.
dramatically by switching to unsaturated amino alcohol
2c. Under identical conditions, the ring-expanded diace-
Acknowledgement
tate 5c was now accessible as major product with a selec-
tivity of 8:1 over the competing meso-diacetate 4c.11
Financial support by the Fonds der Chemischen Industrie (Liebig
fellowship) is gratefully acknowledged.
Tf2O
proton sponge
OAc
n
n
n
Supporting Information for this article is available online at
NaOAc
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
+
N
N
N
CH2Cl2
–20°C to r.t.
AcO
OH
AcO
OAc
Bn
AcO
Bn
Bn
References and Notes
2a–c
5a–c
4a–c
(1) (a) Beckmann, E. Ber. Dtsch. Chem. Ges. 1886, 19, 988.
(b) Wallach, O. Justus Liebigs Ann. Chem. 1900, 312, 171.
(2) Faworsky, A.; Boshowski, W. J. Russ. Phys. Chem. Soc.
1914, 46, 1097; Chem. Zentralbl. 1915, 984.
OAc
OAc
OAc
(3) For a review, see: Holub, N.; Blechert, S. Chem. Asian J.
2007, 2, 1064.
N
N
N
Bn
AcO
Bn
AcO
Bn
AcO
(4) For recent examples in natural product synthesis, see:
(a) Larionov, O. V.; Corey, E. J. J. Am. Chem. Soc. 2008,
130, 2954. (b) Matovic, R.; Ivkovic, A.; Manojlovic, M.;
Tokic-Vujosevic, Z.; Sicic, R. N. J. Org. Chem. 2006, 71,
9411.
5a, 8%
(+ 4a, 43%)
5b, 12%
(+ 4b, 46%)
5c, 45%
(+ 4c, 6%)
Scheme 3 Triflate-mediated ring expansion
(5) (a) Cossy, J.; Dumas, C.; Michel, P.; Gomez Pardo, D.
Tetrahedron Lett. 1995, 36, 549. (b) Cossy, J.; Dumas, C.;
Gomez Pardo, D. Synlett 1997, 905. (c) Déchamps, I.;
Gomez Pardo, D.; Cossy, J. ARKIVOC 1997, (v), 38.
(d) Cossy, J.; Dumas, C.; Gomez Pardo, D. Eur. J. Org.
Chem. 1999, 1693.
(6) (a) Déchamps, I.; Gomez Pardo, D.; Cossy, J. Eur. J. Org.
Chem. 2007, 4224. (b) Cochi, A.; Gomez Pardo, D.; Cossy,
J. Eur. J. Org. Chem. 2012, 2023.
While selective azepane formation still represents an un-
solved issue in our desymmetrization–ring-expansion
strategy, the enantio- and diastereoselective synthesis of
saturated and unsaturated six-membered N-heterocycles
opens up great opportunities for implementations into
more complex synthetic strategies of this preparatively
simple reaction sequence. In particular, the multifunction-
al dehydropiperidine 5c with four orthogonally modifi-
able groups will thus be studied in detail as synthetic
building block in our future investigations. Nonetheless,
also saturated ring-expanded diols such as piperidine 3b
have the potential to be employed as valuable precursors
for the synthesis of truncated azasugars as demonstrated
with the preparation of the unnatural manno-configured
epimer 6 of the alkaloid 1,3,4-trideoxynojirimycin (from
Angylocalyx pynaertii)14 which is easily obtained in quan-
titative yield by hydrogenative debenzylation (Scheme 4).
(7) For a review, see: García-Urdiales, E.; Alfonso, I.; Gotor, V.
Chem. Rev. 2011, 111, PR110.
(8) Selected examples: (a) Chênevert, R.; Dickman, M. J. Org.
Chem. 1996, 61, 3332. (b) Lesma, G.; Colombo, A.;
Landoni, N.; Sacchetti, A.; Silvani, A. Tetrahedron:
Asymmetry 2007, 18, 1948. (c) Donohoe, T. J.; Rigby, C. L.;
Thomas, R. E.; Nieuwenhuys, W. F.; Bhatti, F. L.; Cowley,
A. R.; Bhalay, G.; Linney, I. D. J. Org. Chem. 2006, 71,
6298. (d) Chênevert, R.; Jacques, F.; Giguère, P.; Dasser, M.
Tetrahedron: Asymmetry 2008, 19, 1333. (e) Donohoe, T. J.;
Thomas, R. E.; Cheeseman, M. D.; Rigby, C. L.; Bhalay, G.;
Linney, I. D. Org. Lett. 2008, 10, 3615.
(9) Kawanami et al. described the enzymatic kinetic resolution
of corresponding trans-2,5-disubstituted pyrrolidines:
Kawanami, Y.; Moriya, H.; Goto, Y.; Tsukao, K.;
Hashimoto, M. Tetrahedron 1996, 52, 565.
(10) Literature based on our recent studies on lipase-catalyzed
transformations of primary alcohols: (a) Deska, J.; Bäckvall,
J.-E. Org. Biomol. Chem. 2009, 7, 3379. (b) Manzuna Sapu,
C.; Bäckvall, J.-E.; Deska, J. Angew. Chem. Int. Ed. 2011,
OH
OH
H2 (1 atm)
cat. Pd(OH)2
N
N
MeOH, r.t.
99%
H
HO
manno-trideoxynojirimycin (6)
HO
Bn
3b
Scheme 4 Synthesis of manno-trideoxynojirimycin
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1529–1532

1532
D. Thiel, J. Deska
LETTER
50, 9731; Angew. Chem. 2011, 123, 9905. (c) Hammel, M.;
Deska, J. Synthesis 2012, 44, 3789.
(11) Formation of undesired trans-diastereomers was not
observed, neither for diols 1 and 3 nor for diacetates 4 and 5.
(12) Unfortunately, this protocol proved to be not suitable for the
ring expansion of unsaturated monoacetate 2c, as
(13) Jarvis, S. B. D.; Charette, A. B. Org. Lett. 2011, 13, 3830.
(14) Yasuda, K.; Kizu, H.; Yamashita, T.; Kameda, Y.; Kato, A.;
Nash, R. J.; Fleet, G. W. J.; Molyneux, R. J.; Asano, N.
J. Nat. Prod. 2002, 65, 198.
decomposition was observed under these conditions.
Synlett 2013, 24, 1529–1532
© Georg Thieme Verlag Stuttgart · New York

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