Diastereoselective organocatalytic Mannich access to azacyclic system en route to lyconadin A

Article abstract of DOI:10.1016/j.tetlet.2014.07.079

Organocatalytic and stereoselective Mannich coupling of hindered and chiral cyclohexylcarboxaldehyde is described for a synthetic approach to the pyrrolidine core of lyconadin A. The strategy led concisely and stereoselectively to complex azaheterocyclic system containing up to five stereocenters.

Full text of DOI:10.1016/j.tetlet.2014.07.079

Tetrahedron Letters 55 (2014) 5074–5077
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Tetrahedron Letters
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Diastereoselective organocatalytic Mannich access to azacyclic
system en route to lyconadin A
Morgan Cormier a, Alexandre Jean a,b, Jérôme Blanchet b, Jacques Rouden b, Jacques Maddaluno a,
Michael De Paolis a,
⇑
a COBRA, CNRS UMR 6014 & FR 3038, Université de Rouen et INSA de Rouen, 76821 Mont Saint-Aignan, France
b LCMT, CNRS UMR 6509 & FR 3038, ENSICAEN et Université de Caen Basse-Normandie, 14050 Caen, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Organocatalytic and stereoselective Mannich coupling of hindered and chiral cyclohexylcarboxaldehyde
is described for a synthetic approach to the pyrrolidine core of lyconadin A. The strategy led concisely and
stereoselectively to complex azaheterocyclic system containing up to five stereocenters.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 14 June 2014
Revised 16 July 2014
Accepted 21 July 2014
Available online 27 July 2014
Keywords:
Organocatalysis
Azaheterocyclic system
Spirocycles
Diastereoselective Mannich
H-bonding
Lyconadin
A
(1) is an alkaloid isolated from Lycopodium
Diastereoselective organocatalytic Mannich coupling of alde-
hyde is scarcely documented.8 The objective was therefore to eval-
uate the ability of catalyst 6 based on the 3-aminopyrrolidine
scaffold to forge two new stereocenters that would match the
required configuration of the natural product (Scheme 2). Our ste-
reochemical analysis was based on the fact that aldehyde 5 has two
stereocenters at C12 and C7 that are epimerizable. While the C7
stereocenter is irrelevant for the stereochemical outcome of the
reaction due to the enamine formation, the C12 stereocenter was
projected to direct the stereoselectivity of the coupling at C7 by
favoring one approach of the electrophile but also by hampering
the (E/Z)-isomerization of the enamine moiety. The C6 stereocenter
was expected to be controlled by the organocatalyst through
H-bonding as in 7. Then at a further stage, we anticipated inverting
the C12 stereocenter of 3 to match the configuration of the target
by controlled epimerization.
complanatum. Its peculiar structure features pyrrolidine and
2-pyridone rings embedded into a complex polycyclic carbon
framework (Scheme 1).1 This challenging skeleton has inspired
elegant total syntheses from Smith,2 Sarpong,3 Fukuyama,4 and
Dai,5 using innovative methodologies and disconnections to solve
the complexity of the target. Additionally, Castle disclosed a
synthetic approach to the bicyclo[5.4.0]undecane framework of
lyconadin A.6 In connection with our program of organocatalytic
access to chiral pyrrolidines containing basic N-heteroaryl substit-
uents, we sought to explore a new disconnection toward the core
of lyconadin A.7 We report herein a stereoselective organocatalytic
access to a highly substituted azapolycyclic framework.
Our initial retrosynthetic analysis was based on a Mannich
reaction of chiral aldehyde 5 and imine 4a entailing the key
methoxypyridine as
a
protected precursor of 2-pyridone
(Scheme 1). Structural modifications of the resulting adduct 3
would involve decarbonylation and hemiaminal reduction
followed by the construction of the piperidine scaffold to give 2.
Unveiling the 2-pyridone ring of 1 by demethylation of 2 according
to Sarpong would conclude the synthesis.
To add to the challenge of building a stereogenic quaternary
carbon in a crowded structural environment, we anticipated a
low reactivity of imine 4a for electronic reasons. Yet, a recent
report about a Mannich coupling promoted by proline involving
a structurally close imine (4c in Scheme 3) and glutaraldehyde
was encouraging for our synthetic plan.9
Thus, the synthesis of aldehyde 5 was carried out from rac-
8, itself prepared in one step from ethylacetoacetate and
crotonaldehyde and for which an asymmetric synthesis is known
⇑
Corresponding author. Tel.: +33 2 35 52 24 48; fax: +33 2 35 52 29 71.
E-mail address: michael.depaolis@univ-rouen.fr (M. De Paolis).
http://dx.doi.org/10.1016/j.tetlet.2014.07.079
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

M. Cormier et al. / Tetrahedron Letters 55 (2014) 5074–5077
5075
2-chloropyridine and quenching with I2 (80%).14 The resulting
2-chloro-6-iodopyridine was then lithiated (nBuLi) and treated
with N,N-dimethylformamide to provide aldehyde 11b in 42%
(Scheme 3).
OMe
OMe
PMP
HN
H
7
O
N
6
HN
N
N
N
CHO
CO2R
12
O
The Mannich coupling was investigated using an organocatalyst
based on the recently unveiled 3-aminopyrrolidine scaffold which
has the advantages of being reactive and readily available.15 In
order to avoid a match/mismatch effect, the study was carried
out with the racemic catalyst since racemic aldehyde was
employed. Resorting to reaction parameters in line with our previ-
ous studies, all attempts to couple aldehyde 5a with 4a met with
failure (Scheme 4). Unfortunately, swapping to imines 4b and 4c
did not improve the outcome of the reaction. In all cases, the 1H
NMR monitoring of the reaction indicated hydrolysis of the imine
and degradation of the aldehyde. The same result was obtained
with proline as the catalyst. With the objective of decreasing the
LUMO of imine 4a, the coupling was attempted in the presence
of a Brønsted acid co-catalyst. Thus, several acids (CF3CO2H,
2,5-dinitrobenzoic, 2,6-difluorobenzoic, benzoic and acetic acid)
of variable strengths were tested (1.1 equiv) with the degradation
of imine 4a as the sole result.
To evaluate the reactivity of aldehyde 5a, the reaction was
eventually tested with more reactive electrophile 12 derived from
ethyl glyoxalate (Scheme 5). Interestingly, the reaction proceeded
to completion with a stoichiometric ratio of reagents 5a and 12
but the presence of a Brønsted acid was required. Hence, the com-
bination of catalyst 6 and a substoichiometric amount of CF3CO2H
(0.8 equiv) was needed to prepare 13a in 42% alongside degrada-
tion products.16 Mannich adduct 13a was directly isolated as a sta-
ble hemiaminal, probably because the dehydration would give an
anti-Bredt iminium. Importantly, the stereoselectivity of the reac-
tion reached a promising value of 6:1. The reaction worked like-
wise with the simplified aldehyde 5b (dr = 9:1), prepared from
cyclohex-2-en-1-one, giving the corresponding Mannich adduct
13b in 39% (dr = 6:1). 1H NMR NOESY analysis of 13a confirmed
(+)-lyconadin A (1)
2
3
PMP = 4-(MeO)-C6H4
NHTf
OMe
N
enamine mediated
N
Mannich
4a
5
PMP
O
3
N
H
CHO
6
6
CO2R
Scheme 1. Retrosynthetic analysis of 1.
(Scheme 3).10 The 1,4-addition of vinylmagnesium bromide in the
presence of CuI led to the intermediate enolate 9 that was inter-
cepted with bromo t-butylacetate in HMPA to give 10a.11 To our
knowledge, 1,4-additions to 5-methylcyclohex-2-en-1-one fol-
lowed by stereoselective alkylation of the resulting enolate are
not trivial.12 Pleasingly though, this 2-step process delivered tri-
substituted cyclohexanone 10a in 40% yield with a good anti-selec-
tivity of 9:1 between the two newly created 2,3-stereogenic
centers, which giving the level of substitution and functionaliza-
tion could certainly find applications in other contexts. Interest-
ingly, trapping enolate 9 with bromo acetonitrile led to 10b with
a substantial drop of selectivity (dr = 3:1). Oxidative cleavage of
the olefin (98%) completed the stereoselective preparation of the
Mannich partner 5a. NOESY analysis confirmed the 3,5-trans con-
figuration of the major isomer of cyclohexanone 5a.
With the objective of testing imines with different electronic
properties and reactivity, pyridine carboxaldehydes 11a–c were
treated with anisidine to generate the corresponding imines
4a–c.13 While 11a,c are commercially available, the 6-chloropico-
linaldehyde 11b was prepared in two steps by lithiation of
irrelevant
H-bonding
+
control of C6
configuration
+
H
P
N
NTf
OMe
N
N
H
MeO
N
CHO
H2O
6 + 4a
P
H
N
H
O
CO2R
H
CHO
O
steric control
of C7
CO2R
5
O
CO2R
C12 epimerizable
at a further stage
relevant
7
3
configuration
P = PMP
Scheme 2. Steric and H-bonding control of Mannich coupling.
E
O
O
E
O
O
MgBr
BrCH2E
K2OsO4.2H2O
NaIO4, acetone
7
CuI, THF,
-78°C
15'
HMPA, rt
OHC
H
10a, E
rac-
= CO2tBu, 40%, dr = 9:1
= CN, 37%, dr = 3:1
rac-8
rac-9
rac-5a, 98%
10b, E
rac-
NOESY
MeO
PMP
O
N
a
Cl
. nBuLi, Me2N(CH2)2OLi; I2 (80%)
NH2
N
N
X
N
X
b. nBuLi; DMF (42%)
MgSO4, EtOH
(> 95%)
11b, X = Cl
11a,
4b
, X = Cl
4a, X = OMe
X = OMe
11c, X = H
4c
, X = H
Scheme 3. Synthesis of the Mannich coupling partners.

5076
M. Cormier et al. / Tetrahedron Letters 55 (2014) 5074–5077
6
or proline
PMP
HN
PMB
tBuO2C
OHC
O
X
N
(10 mol%)
N
3a, X = OMe
3b
N
X
+
, X = H
3c, X = Cl
additive
(1.1 equiv)
DMF, rt
CHO
CO2R
O
5a
(3 equiv)
4a
, X = OMe
4b, X = Cl
4c, X = H
Scheme 4. Attempts to couple 5a with 4a–c.
PMP
PMP
H
H
O
O
tBuO2C
O
6
6
PMB
N
H
CO2Et
N
a
15
b, c
N
15
7
+
R
7'
12 CHO
CO2tBu
13
CO2Et
HO
OHC
R
HO
12'
CO2tBu
12
5a, R = Me, dr = 9:1
5b,
13a, R = Me, 42%, dr = 6:1
14, 59% (2 steps)
( 1equiv)
13b
R = H, dr = 9:1
, R = H, 39%, dr = 6:1
tBuO2C
OH
7'
OHC
NOESY
16
13a
7
15'
EtO2C
N
H
6
PMP
a
b
6
. rac- (10 mol%), CF3CO2H (0.8 equiv), DMF, 1 h 30, rt
. NaBH4, MeOH, -40°C to -20°C
c. 2-hydroxypyridine , toluene, reflux
Scheme 5. Stereoselective Mannich coupling of 5a,b with 12.
the cis configuration of H70 and H150. Furthermore, a NOESY
contact from H6 to H16 was observed, validating the analysis of
the stereoselectivity of the transition state outlined in Scheme 2.
To further ascertain the relative configuration of 13a, synthetic
manipulations were carried out. Hence, reduction (NaBH4, MeOH)
of the carboxaldehyde and lactonization (2-hydroxypyridine,
PhMe)17 of the resulting hydroxyl furnished the spiro lactone 14
(59% for 2 steps). Gratifyingly, 1H NMR NOESY experiments con-
firmed the cis configuration of H70 and H120, while H6 exhibited
NOESY correlations to H15 in agreement with the stereochemistry
proposed for 13a. The exact role of the Brønsted acid remains yet to
be completely elucidated but plausible scenarios can be suggested.
The reactivity of the hindered carboxaldehyde could be
enhanced by protonation to favor the enamine formation. Another
possibility could involve the protonation of the imine, raising the
reactivity of the electrophile. Still, formation of the E-enamine 7
followed by the nucleophilic attack of the imine activated and
directed by the trifluoromethanesulfonamide appendage of the
catalyst seemed to prevail in view of the selectivity observed.
In conclusion, even if the chiral aldehyde 5a failed to react with
any imines of pyridine carboxaldehydes, we were able to promote
the coupling of 5a with a more reactive imine to furnish a complex
Mannich adduct containing five stereocenters under steric and
H-bonding control. This study highlights also the potential and
the reactivity of catalyst 6 to promote and steer the stereoselectiv-
ity of an organocatalyzed coupling involving a chiral, functional-
ized, and hindered aldehyde. Thus, this methodology leads
partially supported this work. M.C. thanks the Ministère de
l’Enseignement Supérieur for a doctoral fellowship. Lina Truong
(CRUS, Laboratoire COBRA) is gratefully acknowledged for 2D
NMR (600 MHz) experiments.
Supplementary data
Supplementary data (1D and 2D NMR data of 5a, 13a and 14)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2014.07.079. These data include
MOL files and InChiKeys of the most important compounds
described in this article.
References and notes
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a densely substituted azaheterocyclic framework,
providing a scaffold ready for further chemical modifications to
prepare complex alkaloids.
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for 1 h 30 (1H NMR monitoring). Then, saturated solution of NaHCO3 was
added and the mixture was extracted with Et2O (3ꢀ). Combined organic layers
were brined, dried on MgSO4, and filtered. The volatiles were removed under
reduced pressure and the crude was purified by flash chromatography
(pentane/AcOEt: 90:10, 60:10, 20:10) on silica gel to obtain 32 mg (43%
yield) of 13a contaminated with isomeric product (dr = 6:1, determined by 1H
NMR). Purification on preparative TLC (pentane/AcOEt: 60:10) afforded 27 mg
of isomerically pure 13a; 1H NMR (300 MHz, CDCl3) d 0.90 (d, 3H, J = 5.2 Hz),
1.26–1.34 (m, 6H), 1.44 (s, 9H, H), 1.78 (m, 1H, H), 2.28 (dd, 1H, J = 7.6,
16.9 Hz), 2.48 (dd, 1H, J = 5.7, 16.9 Hz), 2.49 (m, 1H), 3.21 (t, 1H, J = 6.9 Hz),
3.39 (s, 1H), 3.75 (s, 3H), 3.87 (s, 1H), 4.17–4.32 (m, 2H), 6.80 (d, 2H, J = 9.2 Hz),
6.98 (d, 2H, J = 9.2 Hz), 9.46 (s, 1H); 13C NMR (75 MHz, CDCl3) d 199.8 (CH),
171.6 (Cq), 171.4 (Cq), 152.6 (Cq), 138.0 (Cq), 114.8 (2ꢀCH), 114.7 (2ꢀCH), 93.5
(Cq), 81.7 (Cq), 66.7 (CH), 61.9 (CH2), 56.2 (Cq), 55.6 (CH3), 46.2 (CH), 34.1
(CH2), 32.2 (CH2), 30.1 (CH2), 28.0 (3ꢀCH3), 24.5 (CH), 20.9 (CH3), 14.1 (CH3); IR
(neat): 3402, 2935, 1718, 1510, 1244, 1149, 1031, 822 cmꢁ1. HRMS (TOF MS
ES+) calcd for (M+H)+ C25H36NO7: 462.2492, found: 462.2484.
16. Synthesis of 13a: To a solution of aldehyde 5 (40 mg, 0.166 mmol, 1 equiv) and
imine 12 (34 mg, 0.166 mmol, 1 equiv) in DMF (1.1 mL) was added catalyst 6 at
room temperature (4 mg, 0.0166 mmol, 0.1 equiv) in one portion followed by
17. No lactonization occurred without 2-hydroxypyridine. For the first report of
amide synthesis using this promoter, see: Openshaw, H. T.; Whittaker, N. J.
Chem. Soc. 1969, 1, 89–91.
TFA (10 lL, 0.133 mmol, 0.8 equiv). The reaction mixture was allowed to react