Enantioselective Formal Total Synthesis of (-)-Quinagolide

Article abstract of DOI:10.1021/acs.orglett.9b03477

The enantioselective formal total synthesis of (-)-quinagolide has been accomplished in a linear sequence of 8 purification steps from pyridine. The key steps are (a) organocatalyzed Diels-Alder reaction for fixing all three stereocenters on piperidine ri

Full text of DOI:10.1021/acs.orglett.9b03477

Letter
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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Enantioselective Formal Total Synthesis of (−)-Quinagolide
Subhash P. Chavan,*,†,‡ Appasaheb L. Kadam,†,‡ and Rajesh G. Gonnade‡,§
†Division of Organic Chemistry, CSIR-National Chemical Laboratory, Pune 411008, India
‡Academy of Scientific and Innovative Research (AcSIR), New Delhi 110025, India
§Physical and Materials Chemistry Division, CSIR-National Chemical Laboratory, Pune 411008, India
S
* Supporting Information
ABSTRACT: The enantioselective formal total synthesis of (−)-quinagolide has been accomplished in a linear sequence of 8
purification steps from pyridine. The key steps are (a) organocatalyzed Diels−Alder reaction for fixing all three stereocenters on
piperidine ring; (b) protecting group enabled deoxygenation of isoquinuclidine skeleton under Birch reduction condition; (c)
Lewis acid (TiCl4) catalyzed intramolecular Friedel−Crafts cyclization of dicarboxylic acid; and (d) one-pot diastereoselective
ketone reduction−intramolecular cyclization to form oxazolidinone which enables trans-geometry installation. During the
course of the synthesis, an interesting reductive cleavage of the C−N bond in the electron-deficient isoquinuclidine skeleton
under the Birch reduction conditions has been observed. This is the first synthetic effort to access the core skeleton of
(−)-quinagolide.
he isoquinuclidine (2-azabicyclo[2.2.2]octane) ring sys-
Ttem is found in a wide number of natural products,
namely iboga-type alkaloids.1 Elegant methods for the
synthesis of chiral isoquinuclidines have been developed,
especially since Fukuyama’s synthesis of oseltamivir using
organocatalyzed Diels−Alder reaction.2 Despite the high
functionalization ability of isoquinuclidine to provide complex
scaffolds in chiral fashion, its applications for the synthesis of
natural products and bioactive compounds are scarce.1 To
date, there are only three synthetic approaches (total synthesis
of oseltamivir by Fukuyama2 and (+)-luciduline by Charette3
and formal synthesis of catharanthine by Batey4) reported in
the literature in which application of the chiral isoquinuclidine
skeleton constructed via organocatalyzed Diels−Alder reaction
has been demonstrated.
Due to our continued interest in the synthesis of biologically
active compounds, we were interested in the enantioselective
synthesis of (−)-quinagolide (1) by taking advantage of the
chiral isoquinuclidine skeleton. Quinagolide (1), a selective D2
receptor agonist used for the treatment of elevated levels of
prolactin, has combined structural features of well-known
dopamine agonists, namely ergolines CQ 32-084 (2), pergolide
(3), and apomorphine (4) (Figure 1). Furthermore,
quinagolide (1) has distinct advantages over bromocriptine
(5) and cabergoline (6), which are currently available
medications for the treatment of hyperprolactinemia.5
Quinagolide hydrochloride as its racemate is marketed by
Figure 1. Available hyperprolactinemia medications on the market
and structural features of quinagolide (1).
Ferring Pharmaceuticals, Switzerland, under the trade name
Norprolac.
Received: October 1, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03477
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
In the year 1985, Nordmann et al. from Sandoz Ltd.
reported the synthesis and biological activity of quinagolide.6
Subsequently, in 2000, scalable synthesis of quinagolide
intermediate was reported by Banziger et al. from Novartis
Ltd.7 Recently, our group reported the entirely different
approach for the total synthesis of ( )-quinagolide.8 Though
Nordmann et al. resolved the intermediate of ( )-quinagolide
and found that the dopaminomimetic activity is entirely
associated with the (−)-enantiomer,6b to date, enantioselective
total synthesis of (−)-quinagolide is not reported in the
literature. In this context, the development of a new synthetic
route for the enantioselective synthesis of (−)-quinagolide is
highly desirable.
reaction followed by benzylic deoxygenation under Birch
reduction condition.
In initial attempts to establish a synthetic strategy toward 7,
our efforts commenced with pyridine, acrolein, and racemic β-
amino alcohol 1310 as an organocatalyst (Scheme 2).
Scheme 2. Initial Attempt
From the last few decades, pyridine has served as an ideal
choice of starting material for the effective total synthesis of
alkaloids in enantioselective fashion while also providing the
basic nitrogen atom as well.2−4,9 In this context, the nitrogen
atom and the three necessary stereocenters on the piperidine
ring of quinagolide could be introduced from pyridine via
organocatalyzed Diels−Alder reaction of the corresponding
dihydropyridine and acrolein.10 Further, the tricyclic ring
skeleton of quinagolide could be constructed by Grignard
addition followed by Friedel−Crafts cyclization.
On the basis of these deliberations, retrosynthetic analysis
for target molecule 1 is outlined in Scheme 1. We envisioned
Scheme 1. Retrosynthetic Analysis
Pyridine was treated with methyl chloroformate and NaBH4
in MeOH to afford dihydropyridine 12 in quantitative yield.
The Diels−Alder reaction of dihydropyridine 12 with acrolein
using ( )-13 as an organocatalyst furnished the desired adduct
14. For the characterization purpose, aldehyde 14 was reduced
using NaBH4 to corresponding bicyclic alcohol 15 (endo only)
in 43% yield over three steps. In the next step, the crude
aldehyde 14 was subjected for addition reaction of Grignard
reagent 16 derived from 2-bromoanisole to provide the
inseparable mixture of diastereomeric alcohol 17 in 36%
yield over three steps. At this stage, deoxygenation of 17 would
have provided bicyclic alkene 10. For deoxygenation of 17,
literature known reaction conditions were screened, but either
complex reaction mixture or desired product formation in very
poor yield was observed. Under the Birch reduction
conditions, instead of obtaining the expected product 10,
ring-opened carbamate 18 was isolated as a major product in
68% yield. The structure of 18 was confirmed by detailed 2D-
NMR analysis, and the ring-opening of isoquinuclidine 17
under the Birch reduction conditions could be explained on
the basis of the mechanism proposed (see the SI).11 It is
noteworthy to mention that this type of ring-opening of
isoquinuclidine under the Birch reduction conditions is the
first of its kind and hopefully will find more applications in the
context of the total synthesis of alkaloids and drug develop-
ment.
that bicyclic precursor 10 could be effectively converted to
tricyclic skeleton 7 of quinagolide (1) via functionalization of
olefin part of bicyclic precursor 10 into keto-ester 9. The steps
involved could be Lewis acid catalyzed intramolecular Friedel−
Crafts cyclization of dicarboxylic acid followed by epimeriza-
tion at tetracyclic intermediate 8, which in turn could be
synthesized from keto-ester 9 through one-pot reductive
cyclization. Bicyclic precursor 10 could be successively
constructed via Grignard addition on bicyclic aldehyde
corresponding to Fukuyama’s intermediate 11,2 which in
turn could be synthesized using organocatalyzed Diels−Alder
We thought that the methylcarbamate protecting group
played a vital role in the opening of bicyclic intermediate 17
under the Birch reduction condition. Synthesis of a bicyclic
amine having a protecting group like N-Cbz would solve our
problem as N-Cbz can be easily deprotected under Birch
B
DOI: 10.1021/acs.orglett.9b03477
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
reduction conditions, and thus, ring opening will be prevented.
Thus, Fukuyama’s intermediate 11 was successfully synthe-
sized on a gram scale (41% yield over three steps) and in high
enantiomeric excess (97% ee) following Nakano-type Diels−
Alder reaction using (−)-13 derived from L-valine as an
organocatalyst (Scheme 3).10
dicarboxylic acid 22 was converted into the corresponding
methyl diester 23 in 85% yield. At this stage, as per our plan,
intramolecular Friedel−Crafts cyclization of dicarboxylic acid
22 using Lewis acid would have provided tricyclic keto-acid 24.
But unfortunately, several attempts failed to cyclize dicarbox-
ylic acid 22 into tricyclic core 24.
Detailed literature analysis revealed that the methylcarba-
mate protection of α-amino acid might be essential for its
intramolecular Friedel−Crafts cyclization.13 Accordingly,
bicyclic amine 20 was protected as it is methylcarbamate
derivative 10 using methyl chloroformate in 64% yields
(Scheme 5). Following the same sequence of dihydroxyla-
tion−diol cleavage and Pinnick oxidation used in Scheme 4,
olefin 10 was converted into the corresponding dicarboxylic
acid 20 in 95% yield over three steps.
Scheme 3. Synthesis of Fukuyama’s Intermediate 11
Intramolecular Friedel−Crafts cyclization was found to be
the crucial step in this synthesis. Several attempts for the
intramolecular Friedel−Crafts cyclization of the dicarboxylic
acid 25 were made to arrive at an optimized condition as
shown in Table 1.
In the next step, the bicyclic aldehyde obtained from the
Diels−Alder reaction was subjected to the addition reaction of
Grignard reagent 16 derived from 2-bromoanisole to obtain
bicyclic intermediate 19 in 34% yield over three steps (Scheme
4).
The same was accomplished by converting dicarboxylic acid
25 into the corresponding acid chloride followed by TiCl4-
mediated Friedel−Crafts cyclization to afford tricyclic keto-
ester 9 in 62% yield. The relative stereochemistry of 9, which is
found to be cis, was determined by single-crystal X-ray analysis
of the corresponding acid 26. At this stage, our plan was the
two-center epimerization at the tricyclic core 9 to obtain the
desired stereochemistry. Many attempts for the epimerization
of 9 failed. Also, the deprotection of methyl carbamate was not
realized mainly because of either aromatization or decom-
position of starting material. When ketone 9 was subjected to
reduction using LiBH4 in THF, tetracyclic carbamate 27 was
isolated as a single diastereomer in 68% yield (Scheme 5). The
structure and absolute stereochemistry of compound 27 were
confirmed by single-crystal X-ray analysis. In the next step,
epimerization at the ester center of compound 27 was
performed using NaOCH3 in MeOH to obtain tetracyclic
skeleton 8 in 70% yield with the required stereochemistry. At
this stage also, the structure and absolute stereochemistry of
compound 8 were confirmed by single-crystal X-ray analysis.
The next task was the installation of a trans-ring junction. To
this end, the opening of tetracyclic carbamate 8 was performed
by refluxing in ethanolic NaOH14 and subsequent esterification
with diazomethane furnished corresponding tricyclic amino
alcohol 28 in 53% yield (Scheme 6). The amino-alcohol 28
was treated with PTSA under reflux in toluene15 in order to
form intermediate enamine followed by its reduction with
NaBH3CN and N-alkylation of the corresponding amine using
propyl iodide to afford compound 7 in 61% yield over two
steps. Compound 7 showed 1H and 13C NMR spectra,
identical with those of a racemic sample reported in the
literature,7,8b and since the synthesis of (−)-quinagolide (1)
from compound 7 was reported by Nordmann et al.,6 the
present work constitutes the formal total synthesis of
(−)-quinagolide.
Scheme 4. Attempted Synthesis of Tricyclic Skeleton
At this stage, deoxygenation of bicyclic intermediate 19
under the Birch reduction conditions worked well according to
our observations to furnish bicyclic amine 20. The next step
was the protection of bicyclic amine with a suitable group
which can be easily converted to tertiary propylamine in the
final product. Accordingly, bicyclic amine 20 was protected as
its amide derivative 21 using propionic anhydride in 63% yield
over two steps. The amide 21 was then dihydroxylated using
OsO4−NMO, and the crude diol was subjected to cleavage
using silica-supported NaIO4 to provide the corresponding
dialdehyde. The crude dialdehyde was immediately subjected
to Pinnick oxidation to afford dicarboxylic acid 22 in 95% yield
over three steps.12 For the purpose of characterization,
In summary, we have accomplished the enantioselective
formal total synthesis of (−)-quinagolide in a linear sequence
of eight purification steps from pyridine. The key steps used in
the synthesis were organocatalyzed Diels−Alder reaction for
fixing all three stereocenters on piperidine ring, Birch
deoxygenation, Lewis acid (TiCl4) catalyzed intramolecular
Friedel−Crafts cyclization of diacarboxylic acid, and one-pot
diastereoselective ketone reduction−intramolecular cyclization
C
DOI: 10.1021/acs.orglett.9b03477
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Organic Letters
Letter
Scheme 5. Successful Synthesis of the Core Skeleton of Quinagolide
Table 1. Intramolecular Friedel−Crafts Cyclization of
Dicarboxylic Acid 25
Scheme 6. Completion of the Formal Synthesis of
(−)-Quinagolide
a b
,
entry
reagents
CF3SO2H
TFA/TFAA
PPA
BF3.OEt
TFAA/BF3.OEt
FeCl3.MeNO2
SnCl4
AlCl3
AlCl3
TiCl4
TiCl4
equiv temp (°C) time (h) yield (%)
1
2
3
4
5
6
7
8
0.2
2.4
5
2.5
5
3.1
2.2
4.0
4.0
4.0
4.0
5
45
rt
80
0
40
0
1.5
3
2
3.5
4
2
c
d
d
NR
c
NR
c
c
0
1
c
0
0
0.5
2
25
37
40
52
62
9
10
11
12
0
0
0.5
2
ASSOCIATED CONTENT
* Supporting Information
■
S
TiCl4
0
2
a
b
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03477.
Isolated yield of 9. Reaction was performed on corresponding acid
c
d
chloride of 25. Complex reaction mixture. No reaction.
Detailed experimental procedures and characterization
data, 2D-NMR spectra of 18, X-ray details of
1
compounds 26, 27, and 8, and H, 13C and DEPT
to form tetracyclic oxazolidinone which provides required
trans-geometry. The reductive cleavage of C−N bond in an
electron-deficient isoquinuclidine skeleton under Birch reduc-
tion conditions to access substituted cyclohexenes was an
important finding and hopefully will find more applications in
total synthesis and drug development programs in the near
future.
NMR spectra of all compounds (PDF)
Accession Codes
CCDC 1846321, 1949867, and 1949869 contain the
supplementary crystallographic data for this paper. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
D
DOI: 10.1021/acs.orglett.9b03477
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sp.chavan@ncl.res.in.
ORCID
Subhash P. Chavan: 0000-0002-2889-3344
Appasaheb L. Kadam: 0000-0002-0452-2901
Rajesh G. Gonnade: 0000-0002-2841-0197
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
A.L.K. thanks UGC, New Delhi, for the award of a research
fellowship. The authors thank CSIR, New Delhi for financial
support as part of the XII year plan program under title
ORIGIN (CSC-0108) and ACT (CSC-0301). We also thank
Dr. P. R. Rajamohanan (CSIR-NCL, Pune) for help with 2D
NMR analysis and Dr. H. B. Borate (CSIR-NCL, Pune) for
carefully evaluating the manuscript.
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