A Formal Enantioselective Synthesis of (-)-Epiquinamide by Proline-Catalyzed One-Pot Sequential α-Amination/Propargylation of Aldehyde and Asymmetric Dihydroxylation of Olefin

Article abstract of DOI:10.1055/s-0035-1561956

Two independent routes to the formal synthesis of (-)-epiquinamide, have been described: the first route utilizes an l -proline-catalyzed one-pot sequential α-amination/propargylation of aldehyde, while the second one employs asymmetric dihydroxylation as

Full text of DOI:10.1055/s-0035-1561956

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–D
letter
A
B. B. Ahuja et al.
Letter
Synlett
A Formal Enantioselective Synthesis of (–)-Epiquinamide by Pro-
line-Catalyzed One-Pot Sequential α-Amination/Propargylation of
Aldehyde and Asymmetric Dihydroxylation of Olefin
Brij Bhushan Ahujaa
Lourdusamy Emmanuvelb
Arumugam Sudalai*a
NHCbz
NHCbz
CbzN
CbzN
BnO
BnO
3
3
O
OH
O
O
a National Chemical Laboratory, Chemical Engineering & Process
HN
Development Division, Pune 411008, Maharastra, India
+
9
1
2
(
0
2
)
5
9
0
2
1
7
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1
2
(
0
2
)
5
9
0
2
6
7
6
b Karunya University, Department of Chemistry, Coimbatore
641114, Tamil Nadu, India
OPMB
N3
emmanuvel@karunya.edu
a.sudalai@ncl.res.in
N
OH
PMBO
(–)-epiquinamide
2
O
O
Received: 09.11.2015
Accepted after revision: 04.03.2016
Published online: 07.04.2016
herein describe an efficient approach to the formal synthe-
sis of (–)-epiquinamide (1) based upon either L-proline-cat-
alyzed one-pot sequential α-amination/propargylation or
regioselective asymmetric dihydroxylation (ADH) as the
key chiral inducing reactions.
DOI: 10.1055/s-0035-1561956; Art ID: st-2015-b0880-l
Abstract Two independent routes to the formal synthesis of (–)-
epiquinamide, have been described: the first route utilizes an L-proline-
catalyzed one-pot sequential α-amination/propargylation of aldehyde,
while the second one employs asymmetric dihydroxylation as the key
reaction to install the stereochemistry. While the first synthesis was ac-
complished in nine steps with 24.4% overall yield and dr 9:1, the second
strategy resulted in the synthesis in eight steps with 36.4% overall yield
and with perfect enantiocontrol.
The retrosynthetic analysis for the asymmetric synthe-
sis of (–)-epiquinamide (1) is shown in Scheme 1. We envi-
sioned that epiquinamide (1) can be easily prepared from
the key intermediate quinolizidine 2 by substitution of
mesyl group with azide followed by the reduction of azide
and amide groups. We further envisaged that the key inter-
mediate 2 can be prepared by two routes: (i) Route 1 shows
that the quinolizidine 2 could be synthesized from hydrazi-
no lactone 3 via hydrogenation over Raney Ni followed by
N-alkylation of the resulting amide. The hydrazino lactone
3 could be prepared by intramolecular hydroalkoxylation of
the alkyne 4, which in turn can be obtained by L-proline-
catalyzed one-pot sequential α-amination/propargylation
of aldehyde 5. (ii) Route 2 shows that the quinolizidine 2
could be synthesized from azido lactone 6 via hydrogena-
tion over Pd/C followed by N-alkylation of the resulting am-
ide. The azido lactone 6c can be obtained by asymmetric di-
hydroxylation of homoallylic ester 7, which in turn can be
prepared by the Claisen–Johnson rearrangement of allylic
alcohol 8.
Before starting the synthesis of (–)-epiquinamide, as
shown in route one, we examined the feasibility of proline-
catalyzed ‘one-pot’ sequential α-amination/propargylation
of aldehydes for the first time.3a As a model study, pro-
panaldehyde (9a) was α-aminated4 with dibenzyl azadicar-
boxylate catalyzed by L-proline (15 mol%) in MeCN at 0 °C
for three hours that produced the corresponding α-aminat-
ed aldehyde, in situ, followed by the sequential addition of
Zn powder (1.2 equiv), propargylic bromide (1.2 equiv) and
saturated aqueous NH4Cl at –20 °C to give anti-vicinal ami-
no alcohol 10a in 84% yield (dr 99:1). To generalize this
Key words amination, dihydroxylation, diastereoselective, proline,
quinolizidine
A diverse array of biologically active, lipid-soluble alka-
loids, have been discovered in amphibian skin. Such alka-
loids generally possess characteristic structural units like
quinazolines, indolizidines, pyrrolidines, piperidines, etc.
Epiquinamide (1), one of such quinazoline alkaloid, was re-
cently isolated from the skin extracts of the Ecuadorian poi-
son dart frog Epipedobates tricolor.1 Due to its structural
importance, several methods of synthesis have been report-
ed.2 To date only a few asymmetric syntheses of 1 have
been reported involving multiple steps or enzymatic reso-
lution as a key step.2a–f However, most of the reported syn-
thesis involves the use of chiral pool resources or chiral
auxiliary. Use of expensive chiral pool resources and multi-
ple reaction sequences are some of the other limitations as-
sociated with the reported methods. In this regard, it is apt
to search for a flexible and catalytic method for the synthe-
sis of epiquinamide from inexpensive starting materials.
Recently, proline-catalyzed sequential reactions have be-
come well recognized to synthesize diverse and complex
molecular architectures. In continuation of our work aimed
at the development of new sequential reactions and their
application in the synthesis of bioactive molecules,3 we
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

B
B. B. Ahuja et al.
Letter
Synlett
NHCbz
O
α-amination/
propargylation
Au-catalyzed
hydroalkoxylation
CbzN
NHCbz
OH
CbzN
BnO
4
BnO
4
O
BnO
4
route 1
NHAc
OMs
3
O
4
5
N
N
route 2
O
(–)-epiquinamide (1)
N3
2
Claisen–Johnson
rearrangement
O
OH
α-ADH
PMBO
4
PMBO
OMe
4
PMBO
4
O
7
6
O
8
Scheme 1 Retrosynthetic analysis of epiquinamide (1)
one-pot reaction, a series of aliphatic aldehydes bearing dif-
ferent functionalities (alkyl, arylalkyl, benzoyloxy or TBS
ether) were examined under the same protocol. We ob-
served complete diastereoselectivity in propargylation re-
action when R group was small (entry 1, Table 1). However,
as R group was changed to a bulky group, we observed a de-
crease in the diastereoselectivity (entries 2–6, Table 1).
ship, a Felkin–Ahn transition state6 model (Figure 1) has
been proposed, in which Zn atom of propargyliczinc re-
agent is coordinated to the carbonyl oxygen and the nucleo-
philic attack of the corresponding reagent takes place at the
‘Si’ face predominantly perpendicular to the bulky CbzN-
NHCbz group to deliver anti-amino alcohols 10a–f.
H
Zn
O
C
H
R
NHCbz
Cbz
Table 1 L-Proline-Catalyzed Asymmetric Sequential α-Amina-
N
tion/Propargylation Reaction of Aldehydesa
H
DBAD (1 equiv)
L-proline (10 mol%)
CH3CN, 0 °C, 3 h;
Figure 1 Felkin–Ahn transition state
OH
O
R
R
After finding the feasibility of one-pot sequential reac-
tion, the synthesis of (–)-epiquinamide (1) commenced
with the commercially available 1,6-hexanediol (11), which
was protected as monobenzyl ether followed by selective
oxidation with PCC to give the corresponding aldehyde 5 in
87% yield. Aldehyde 5 was then subjected to L-proline-cata-
lyzed sequential α-amination/propargylation protocol to
afford the anti-amino alcohol 4 in 79% yield (94% ee, dr 9:1).
Bromination7 of amino alcohol 4 [AgNO3 (10 mol%), NBS (1
equiv), acetone] gave the terminal alkyne bromide 13 in
82% yield, which was subjected to intramolecular hy-
droalkoxylation8 with AuCl3 (10 mol%) as catalyst in tolu-
ene/water (10:1) to furnish γ-butyrolactone 3 in 78% yield.
The γ-butyrolactone 3 was subjected over Raney Ni to the
hydrogenation condition to cleave N–N bond giving free
amine in situ as well as to deprotect benzyl ether. The free
amine underwent intramolecular opening with lactone to
give the stable six-membered amide 14, thus releasing the
free alcohol moiety. The diol 14 was mesylated completely
with two equivalents of mesyl chloride in the presence of
Et3N in THF to give the dimesylate 15 in 91% yield. Finally,
the N-alkylation of the amide using sodium hydride in THF
was carried out to construct the bicyclic ring, i.e. quinal-
izidine 2. The quinalizidine 2 can be readily converted to
the desired (–)-epiquinamide (1), as reported by previous
works2a (Scheme 2).
followed by
H
CbzN
propargylbromide
(1.2 equiv), Zn (1.2 equiv)
sat. aq NH4Cl, –20 °C, 1 h
NHCbz
9a–f
10a–f
Products (10a–f)
Entry Aldehydes (R) (9a–f)
Yield (%)b
ee (%)c
drc
99:1
1
2
3
4
5
6
Me (1a)
84
86
79
87
81
83
93
95
93
93
96
95
n-Bu (1b)
90:10
87:13
79:21
80:20
81:19
4-(TBS)-propyl (1c)
3,4,5-trimethoxybenzyl (1d)
4-methoxybenzyl (1e)
4-chlorobenzyl (1f)
a Reaction conditions: propanaldehyde (5 mmol), DBAD (5 mmol), L-pro-
line (10 mol%), propargyl bromide (7.5 mmol), Zn (7.5 mmol), sat. aq
NH4Cl (10 mL).
b Isolated yield.
c Determined by chiral HPLC analysis.
The stereochemical assignment of this sequential reac-
tion was made based on the previously established abso-
lute configuration of α-amino aldehydes.4a The relative ste-
reochemistry of vicinal amino alcohol 10a, was determined
by transformation into the oxazilidinone, which upon NOE
experiment showed amino alcohols in antirelationship.5 To
rationalize the observed high anti stereochemistry relation-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

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B. B. Ahuja et al.
Letter
Synlett
went intramolecular ring-closing lactonization forming a
stable six-membered hydroxyimide 14 with the release of
free alcohol in 97% yield. Finally, by essentially following
the same reaction sequence developed for the first strategy
the desired quinazoline intermediate 2 was obtained.
O
iii
ii
RO
OH
i
BnO
H
4
4
11, R = H
12, R = Bn
5
NHCbz
O
NHCbz
CbzN
CbzN
OH
v
vi
i
ii
PMBO
PMBO
BnO
3
O
BnO
dr = 9:1
2
2
3
OH
iv
R
O
8
16
3
OPMB
4, R = H
13, R = Br
O
OR
iii
PMBO
OMe
2
OR
OMs
RO
O
ref. 4d
3
viii–ix
O
(–)-1
HN
7
17,
18,
R = H
N
iv
R = Ms
O
O
OPMB
N3
14, R = H
15, R = Ms
OH
HN
O
2
vii
v
vi
Scheme 2 Reagents and conditions: (i) BnBr, NaH, DMF, 0 °C, 4 h, 78%;
(ii) PCC, CH2Cl2, r.t., 3 h, 87%; (iii) L-proline (10 mol%), DBAD (1 equiv),
MeCN, 0 °C, 3 h followed by propargylic bromide (1.2 equiv), Zn (1.2
equiv), sat. aq NH4Cl, –20 °C, 79%; (iv) AgNO3 (8 mol%), NBS (1.2
equiv), acetone, r.t., 82%; (v) AuCl3 (10 mol%), toluene–H2O (9:1), r.t.,
78%; (vi) Raney Ni, H2 (80 psig), MeOH, acetic acid (cat.), r.t., 24 h, 92%;
(vii) MsCl (2 equiv), Et3N, CH2Cl2, 0 °C, 1 h, 91%; (viii) NaH, THF, reflux,
86%.
O
OH
6
14
O
Scheme 3 Reagents and conditions: (i) vinyl magnesium bromide, THF,
3 h, 73%; (ii) EtC(OMe)3, EtCO2H, xylene, 135 °C, 4 h, 85%; (iii)
K2[Fe(CN)6], K2CO3, (DHQ)2AQN, K2OsO4·2H2O, t-BuOH–H2O (1:1),
89%; (iv) MeSO2Cl, Et3N, CH2Cl2, 0 °C, 98%; (v) NaN3, DMF, 60 °C, 5 h,
87%; (vi) 10% Pd/C, H2, MeOH, 25 °C, 99%.
Despite the short and efficient synthetic route as de-
scribed above, we could not enhance the diastereoselectivi-
ty (dr 9:1) of the α-amination/propargylation reaction.
Therefore, we have decided to employ asymmetric dihy-
droxylation for stereoinduction. According to route 2 the
synthesis of intermediate 14 commenced from allylic alco-
hol 8, prepared by addition of vinyl magnesium bromide
onto aldehyde 16. Allylic alcohol 8 upon Claisen–Johnson
[3,3]-sigmatropic rearrangement9 (trimethyl orthoacetate,
catalytic amount of propionic acid, xylene, 135 °C) pro-
duced (E)-homoallylic ester 7 exclusively in 85% yield
(Scheme 3). The dihydroxylation of the (E)-homoallylic es-
ter 7 was carried out under the Sharpless asymmetric dihy-
droxylation10 (SAD) conditions, using catalytic amounts of
K2OsO4·2H2O, and K3Fe(CN)6 as a co-oxidant in the presence
of (DHQ)2AQN ligand to give the hydroxylactone 17 in 89%
yield (98% ee). Under the basic condition the diol formed, in
situ, underwent lactonization with the ester regioselective-
ly to form the stable five-membered lactone 17. The forma-
tion of lactone helps to differentiate the two hydroxyl
groups and stepwise introduction of the heteroatoms into
the molecule. The hydroxyl group in 17 was protected as its
mesylate 18 (MsCl, Et3N, CH2Cl2,0 °C) followed by its SN2
displacement with NaN3 to give the azidolactone 6 in 85%
yield over two steps with complete inversion. The reduc-
tion of azide as well as the deprotection of PMB group was
carried out under hydrogenation conditions [10% Pd/C, H2
(1 atm), Et3N] to give the free amine, which, in situ, under-
In summary, we have developed two independent syn-
thetic methods to access the synthetic precursor quinazo-
line 2 of (–)-epiquinamide. In the first strategy L-proline-
catalyzed one-pot sequential α-amination/propargylation
of aldehyde afforded the anti-amino alcohol 4 from which
intermediate quinazoline 2 was derived. The second strate-
gy used Sharpless asymmetric dihydroxylation for the in-
troduction of stereochemistry to obtain the target com-
pound 2. The first synthesis was accomplished in nine steps
with 24.4% overall yield while the second one resulted in
eight steps with 36.4% overall yield. The synthetic strategy
described herein has significant potential for further exten-
sion to quinazolizidine-based bioactive molecules contain-
ing anti-vicinal amino alcohol or syn-vicinal diamines moi-
eties.
Acknowledgment
BBA thanks CSIR, New Delhi, India for the award of Senior Research
Fellowship and DST-SERB (no. SB/S1/OC-42/2014) for the financial
support. Authors thank Dr. V. V. Ranade, Chair and Head, Chemical
Engineering and Process Development Division for his constant en-
couragement.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561956.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

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B. B. Ahuja et al.
Letter
Synlett
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25 °C, 3 h
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10a
Scheme 4
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D