Asymmetric synthesis of (+)- and (-)-deoxyfebrifugine and deoxyhalofuginone

Article abstract of DOI:10.1016/j.tetlet.2015.09.146

Both enantiomers of deoxyfebrifugine (4) and deoxyhalofuginone (5), analogues of the quinazolinone-containing biologically active compounds febrifugine (1) and halofuginone (3), have been prepared in a six-step reaction sequence featuring an organocatalyzed Mannich reaction as the key stereo-inducing step. The compounds were isolated as their dihydrobromide salts in 29-42% overall yield and in 74-80% enantiomeric excess.

Full text of DOI:10.1016/j.tetlet.2015.09.146

Tetrahedron Letters 56 (2015) 6433–6435
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Tetrahedron Letters
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Asymmetric synthesis of (+)- and (ꢀ)-deoxyfebrifugine and
deoxyhalofuginone
y
⇑
Raed K. Zaidan , Shaun Smullen, Paul Evans
Centre for Synthesis and Chemical Biology, School of Chemistry, University College Dublin, Dublin 4, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
Both enantiomers of deoxyfebrifugine (4) and deoxyhalofuginone (5), analogues of the quinazolinone-
containing biologically active compounds febrifugine (1) and halofuginone (3), have been prepared in
a six-step reaction sequence featuring an organocatalyzed Mannich reaction as the key stereo-inducing
step. The compounds were isolated as their dihydrobromide salts in 29–42% overall yield and in
Received 31 August 2015
Revised 25 September 2015
Accepted 29 September 2015
Available online 20 October 2015
74–80% enantiomeric excess.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Stereoselective carbon–carbon bond
formation
Natural product analogues
Racemisation
Muscle development
Febrifugine (1) is a naturally occurring substance found in
Dichroa febrifuga (Chinese quinine) and a species from the Hydran-
gea family of plants. Dichroa febrifuga has been used for centuries
improve the clinical indications in Muscular Dystrophy patients.9
We have previously synthesised both (+)- and (ꢀ)-febrifugine (1)
1
4v
and halofuginone (3) and were keen to investigate how the
in traditional Chinese medicine for the treatment of a variety of ail-
ments and since the first scientific papers concerning the plant-
based active ingredient appeared (approximately sixty years ago)
presence of the 3-hydroxyl group affected activity. In part this
was because the epimerisation event, likely occurring via a retro-
conjugate addition, is complicated by hemiketal formation to
2
2
febrifugine (1) and its analogues have received attention from
generate isofebrifugine (2). ‘Deoxyfebrifugine’ (4) has previously
both a biological and a chemical standpoint.4 In relation to the
latter, the precise structure of febrifugine (1) was only finally con-
firmed in 1999—partly due to its isomerisation into isofebrifugine
3
been prepared in racemic form three times and in one report its
antimalarial activity was compared with febrifugine itself.10 As
yet there are no reports concerning the synthesis of
deoxyhalofuginone (5). In this work we wish to report the first
asymmetric synthesis of both enantiomers of deoxyfebrifugine (4)
4
b,5
(2) (Fig. 1).
Despite potent antimalarial activity febrifugine (1) proved too
toxic to develop as an antimalarial medicine and attempts to miti-
gate this produced halofuginone (3), an analogue in which the
6
metabolically vulnerable aromatic protons are masked. This com-
pound has been used as a racemate in veterinary medicine to cure
protozoal infections in livestock (particularly poultry) and
serendipitously the anti-fibrotic activity of this compound was also
OH
N
O
O
N
OH
O
N
N
N
H
7
N
H
uncovered. Since this discovery a great deal of effort has been
1
2
O
dedicated to investigating and understanding halofuginone’s prop-
8
erties in animal models for numerous diseases. These studies have
OH
N
Br
Cl
N
R
O
O
ultimately supported the development of 3 as a human drug
candidate and racemic halofuginone, has been the subject of clinical
trials associated with its anticancer activity and its ability to
N
N
N
H
N
R'
H
O
O
3
·2HBr
4: R = R' = H;
: R = Br; R' = Cl
5
⇑
Corresponding author. Tel.: +353 1 7162291.
E-mail address: paul.evans@ucd.ie (P. Evans).
Department of Chemistry, College of Science, Basra University, Basra, Iraq.
Figure 1. Naturally occurring febrifugine (1) and isofebrifugine (2) and the
synthetic analogues: halofuginone (3), deoxyfebrifugine (4) and deoxyhalofuginone
(5).
y
http://dx.doi.org/10.1016/j.tetlet.2015.09.146
040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
0

6
434
R. K. Zaidan et al. / Tetrahedron Letters 56 (2015) 6433–6435
and deoxyhalofuginone (5) as well as a preliminary racemisation
study.
Finally, the Cbz group was removed with HBr in acetic acid, pro-
viding either (+)-4 or (+)-5, as their dihydrobromide salts, in yields
of approximately 55% for the four steps. In the case of 8 this reac-
tion was performed with DCM as a solvent, however, due to its
poor solubility in this solvent the conversion of 9 into 5 was
performed solely in neat HBr/AcOH. Similarly, (+)-Cbz protected
pelletierine 7 was converted into the enantiomeric dihydrobro-
mide salts of (ꢀ)-4 and (ꢀ)-5.
The asymmetric Mannich reaction between an imine and an
enolizable ketone, proceeding via enamine-based organocataly-
1
1
12
sis, has been reported. Recently, the range of imines utilised
1
in this type of process has been widened to incorporate
ideine (6), which Bella and co-workers have demonstrated reacts
D -piper-
1
3
with several methyl ketones in the presence of several secondary
amines possessing
a
Brønsted acidic group.14 Proline itself
Since the interconversion between 1 and 2 (Fig. 1) has both
been reported (and indeed taken advantage of synthetically)2
and the epimerisation/racemisation of pelletierine (and related
,4
performs well in this chemistry and in this manner unnatural pel-
letierine was prepared in good yield and enantioselectivity. Since
the functionalisation and alkylation of a methyl ketone with quina-
1
5
b-amino heterocycles like hygrine) is also well-known, the integ-
rity of the stereogenic centre (in 4 and 5) was of interest. This point
was addressed following the Cbz-protection of 5 to again give 9
and then analysing HPLC data.
zolin-4(3H)-one (4-hydroxyquinazoline) has been well-established
in febrifugine synthesis4
b,10b
we felt that the asymmetric
Mannich chemistry would be ideally suited for the synthesis of
deoxyfebrifugine and deoxyhalofuginone.
As Scheme 1 illustrates, at room temperature 6 undergoes a
rapid Mannich reaction with L-proline and excess acetone in a
3
Initially, (+)-5 was converted into (ꢀ)-9 using Et N, CbzCl at 0 °C
to room temperature in a water–dichloromethane solvent mixture.
Chiral HPLC analysis of (ꢀ)-9 prepared in this manner indicated
that the enantiomeric ratio of the re-protected material was iden-
tical to that used for the original preparation of (+)-5, thereby, con-
firming that no erosion of enantiomeric purity had taken place over
the deprotection sequence. Next, salt (ꢀ)-5 was dissolved in water
and left to stand for five days before treatment with a mixture of
DMSO–water mixture (8:1). The crude material obtained after
aqueous work-up was directly converted into the corresponding
carbamate in order to minimise the loss of enantiomeric purity
1
5
of the b-amino ketone by a retro-conjugate addition process
and (ꢀ)-7 was isolated in reasonable to good yields with
1
6
enantiomeric ratios ranging from 85:15 to 90:10. Use of
D
-proline
3
Et N and CbzCl in dichloromethane. Similarly, (+)-9 prepared in
provided (+)-7 in an otherwise identical sequence.17
this manner demonstrated that racemisation had not taken place.
With the enantioenriched 2-substituted piperidines (ꢀ)- and
Finally, (ꢀ)-5 was dissolved in water and then treated with Et
3
N
(
+)-7 in hand their conversion into deoxyfebrifugine and deoxy-
in dichloromethane and stirred for five days. The biphasic mixture,
containing the free-base, was then treated with CbzCl. After purifi-
cation, chiral HPLC indicated that racemisation had taken place.
In summary, we report the Mannich-based stereoselective syn-
thesis of both enantiomers of deoxyfebrifugine (4) and deoxy-
halofuginone (5). Following the short, telescoped reaction
halofuginone was considered. As shown in Scheme 2, the methyl
group in (ꢀ)-7 was brominated using a two-step, one-pot proce-
dure involving the formation of a trimethylsilyl enol ether. The
crude bromide, obtained after work up, was then treated with
quinazolin-4(3H)-one (10), or 7-bromo-6-chloroquinazolin-4
(
3H)-one (11), to form (ꢀ)-8 and (ꢀ)-9 respectively. The efficiency
sequence (+)- and (ꢀ)-4 as well as (+)- and (ꢀ)-5 were accessed
1
of this sequence was improved by the inclusion of activated 4 Å
molecular sieves during silyl enol ether formation. Chiral HPLC
confirmed that no change in stereochemical integrity had occurred
over the three-step reaction sequence and it should be mentioned
that recrystallisation of (ꢀ)-9 from MeOH did not enhance its
enantiomeric ratio.
from
D
-piperideine (6) in 29–42% overall yield and in 74–80%
ee. We have shown that loss of stereochemical integrity does not
readily take place when the secondary amine is stored as the cor-
responding ammonium salt. However, in solution the free-base
does undergo racemisation. Studies concerning the enantiomer
specific ability of deoxyfebrifugine and deoxyhalofuginone to
(
1) L-Proline (0.2 eq.),
(1) D-Proline (0.2 eq.),
acetone (46 eq.),
acetone (46 eq.),
DMSO-H O (8:1), rt, 1 h
DMSO-H O (8:1), rt, 1 h
O
2
2
O
N
(2) CbzCl, Na CO3(aq),
N
3(aq)
(2) CbzCl, Na CO ,
N
2
2
Cbz
Cbz
DCM, 0 °C to rt, 18 h,
DCM, 0 °C to rt, 18 h,
63%, e.r. 13:87
6
(
)-7
72%, e.r. 90:10
(+)-7
Scheme 1. Synthesis of (+)- and (ꢀ)-Cbz-protected pelletierine (7) via Bella’s asymmetric Mannich reaction.
(
1) TMSOTf, DIPEA,
Å mol. sieves,
DCM, 0 °C to rt, 1h;
N
O
R
N
O
R
4
HBr, AcOH,
°C to rt, 1 h
O
O
0
N
N
(
)-7
N
R'
N
H
R'
(
2) NBS, rt, 2 h;
3) 10 (or 11), K CO ,
Cbz
(
2
3
DMF, rt, 18 h
( )-8: R = R' = H, 66%;
(+)-4·2HBr: R = R' = H, 89%;
(
)-9: R = Br, R' = Cl, 66%
(+)-5·2HBr: R = Br, R' = Cl, 86%
(
4
1) TMSOTf, DIPEA,
Å mol. sieves,
DCM, 0 °C to rt, 1h;
N
O
R
HBr, AcOH,
°C to rt, 1 h
N
O
R
O
0
(
+)-7
N
N
N
R'
N
H
R'
(
2) NBS, rt, 2 h;
Cbz
+)-8: R = R' = H, 60%;
(
3) 10 (or 11), K CO ,
O
2
3
DMF, rt, 18 h
(
( )-4·2HBr: R = R' = H, 82%;
(
+)-9: R = Br, R' = Cl, 56%
( )-5·2HBr: R = Br, R' = Cl, 81%
Scheme 2. Conversion of (+)- and (ꢀ)-Cbz-protected pelletierine (7) into (+)- and (ꢀ)-deoxyfebrifugine (4) and deoxyhalofuginone (5).

R. K. Zaidan et al. / Tetrahedron Letters 56 (2015) 6433–6435
6435
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enantioselectivity (up to 95% ee) for this process. However, the high boiling
point of this solvent and the lengthy reaction period meant that we opted for
the practical and scalable conditions reported herein.