N,N-acetals as N-acyliminium ion precursors: Synthesis and absolute stereochemistry of epiquinamide

Article abstract of DOI:10.1021/ol801490m

(Chemical Equation Presented) A stereoselective synthesis of (+)-epiquinamide is presented in combination with determination of the absolute configuration of the natural product. Key steps in the sequence involved chemoenzymatic formation of an enantiomerically pure cyanohydrin, reductive cyclization to the corresponding cyclic N,N-acetal, and subsequent conversion into a suitable N-acyliminium ion precursor to enable construction of the second ring.

Full text of DOI:10.1021/ol801490m

ORGANIC
LETTERS
2008
Vol. 10, No. 18
4001-4003
N,N-Acetals as N-Acyliminium Ion
Precursors: Synthesis and Absolute
Stereochemistry of Epiquinamide
Marloes A. Wijdeven,† Roel Wijtmans,† Rutger J. F. van den Berg,†
Wim Noorduin,† Hans E. Schoemaker,‡ Theo Sonke,‡ Floris L. van Delft,†
Richard H. Blaauw,§ Richard W. Fitch,| Thomas F. Spande, John W. Daly, and
Floris P. J. T. Rutjes*,†
Radboud UniVersity Nijmegen, Institute for Molecules and Materials, ToernooiVeld 1,
NL-6525 ED Nijmegen, The Netherlands, DSM Pharma Chemicals-AdVanced
Synthesis, Catalysis & DeVelopment, P.O. Box 18, 6160 MD Geleen, The Netherlands,
Chiralix B.V., P.O. Box 31070, 6503 CB Nijmegen, The Netherlands, Department of
Chemistry, Indiana State UniVersity, 600 Chestnut Street, Terre Haute, Indiana 47809,
and Laboratory of Bioorganic Chemistry, National Institute of Diabetes and DigestiVe
and Kidney Diseases, National Institutes of Health, HHS, Bethesda, Maryland 20892
f.rutjes@science.ru.nl
Received July 1, 2008
ABSTRACT
A stereoselective synthesis of (+)-epiquinamide is presented in combination with determination of the absolute configuration of the natural
product. Key steps in the sequence involved chemoenzymatic formation of an enantiomerically pure cyanohydrin, reductive cyclization to the
corresponding cyclic N,N-acetal, and subsequent conversion into a suitable N-acyliminium ion precursor to enable construction of the second
ring.
N-Acyliminium ions are versatile intermediates for the
synthesis of heterocyclic structures and alkaloid natural
products.1 The generation of the highly reactive cationic
N-acyliminium species typically relies on (i) (Lewis) acidic
treatment of N,O-acetals, (ii) protonation of enamides,2 or
(iii) electrochemical oxidation of acylated amines.3 This
article details an unprecedented strategy to form N-acylimin-
ium ions based on the ready availability of functionalized
cyclic N,N-acetals. Besides providing the first example of
this conversion, it was also used as a key transformation in
a total synthesis of (+)-epiquinamide (1). Epiquinamide was
isolated in 2003 from the poison frog Epipedobates tricolor
by Daly and co-workers and was claimed to act as an agonist
† Radboud University Nijmegen.
‡ DSM Pharma Chemicals.
(3) (a) Shono, T.; Matsumura, Y.; Tsubata, K. J. Am. Chem. Soc. 1981,
103, 1172. (b) Yoshida, J.-I.; Suga, S.; Suzuki, S.; Kinomura, N.; Yamamoto,
A.; Fujiwara, K. J. Am. Chem. Soc. 1999, 121, 9546.
§ Chiralix B. V.
| Indiana State University.
NIH.
(4) Fitch, R. W.; Garrafo, M.; Spande, T. F.; Yeh, H. J. C.; Daly, J. W.
J. Nat. Prod. 2003, 66, 1345.
(1) For excellent reviews, see: (a) Speckamp, W. N.; Moolenaar, M. J.
Tetrahedron 2000, 56, 3817. (b) Maryanoff, B. E.; Zhang, H.-C.; Cohen,
J. H.; Turchi, I. J.; Maryanoff, C. A. Chem. ReV. 2004, 104, 1431. (c) Royer,
J.; Bonin, M.; Micouin, L. Chem. ReV. 2004, 104, 2311.
(2) (a) Sato, M.; Aoyagi, S.; Yago, S.; Kibayashi, C. Tetrahedron. Lett.
1996, 37, 9063. (b) Sun, Z.; Yu, S.; Ding, Z.; Ma, D. J. Am. Chem. Soc.
2007, 129, 9300.
(5) (a) Wijdeven, M. A.; Botman, P. N. M.; Wijtmans, R.; Schoemaker,
H. E.; Rutjes, F. P. J. T.; Blaauw, R. H. Org. Lett. 2005, 7, 4005. (b)
Suyama, T. L.; Gerwick, W. H. Org. Lett. 2006, 8, 4541. (c) Huang, P.-Q.;
Guo, Z.-Q.; Ruan, Y.-P. Org. Lett. 2006, 8, 1435. (d) Tong, S. T.; Barker,
D. Tetrahedron Lett. 2006, 47, 5017–10. (e) Voituriez, A.; Ferreira, F.;
Perez-luna, A.; Chemla, F. Org. Lett. 2007, 9, 4705.
10.1021/ol801490m CCC: $40.75
Published on Web 08/15/2008
2008 American Chemical Society

at nicotinic receptors.4 Despite synthetic efforts of several
groups including our own resulting in several total syntheses,
the absolute stereochemistry so far has not been elucidated.5
Interestingly, recent studies carried out by the Gallagher
group showed that no nicotinic activity could be observed
for the synthetic racemate of epiquinamide.6 In this manu-
script, we report a new enantioselective route to (+)-
epiquinamide, including unambiguous assignment of the
absolute configuration.
Scheme 2. Formation of Both Enantiomers of Cyanohydrin 6
Scheme 1. Retrosynthesis
appeared more difficult, eventually giving rise to a maximum
ee of 84% and 95% yield of (R)-6, again after TBS
protection. Fortunately, our synthetic strategy relied on the
(S)-enantiomer to prepare the targeted natural product.
Subsequent reductive amination of (S)-configured cyanohy-
drin 6 provided the corresponding N,N-acetal 7 as a 2:1
mixture of cis/trans-isomers in excellent yield using a
recently published procedure.9
The next crucial step was the conversion of N,N-acetal 7
into a suitable N-acyliminium ion precursor, requiring
conversion of the amine moiety into a leaving group
employing, for example, protonation, acylation, or diazota-
tion. The latter reaction proved to be the best. Sodium nitrite
in neat acetic acid worked well. Acetic acid in this reaction
acts both as the acid and as the nucleophile, attacking the
transient N-acyliminium ion 8 to give the stable acetate 9.
This N,O-acetal appeared to be a suitable precursor for
N-acyliminium ion chemistry under Lewis acid conditions.
Reaction with allyltrimethylsilane as the nucleophile gave
product 10 as a separable 4.2:1 mixture of cis/trans-isomers
in 82% overall yield starting from cyanohydrin (S)-6.10 The
relative configuration of the cis-isomer was proven using
X-ray crystallography (Figure 1).11
As depicted in Scheme 1, we envisaged obtaining epiquina-
mide from hydroxypiperidone derivative 2. Piperidone 2
should be obtained via N-acyliminium ion 3 using nucleo-
philic allylation. We envisioned 3 to be derived from N,N-
acetal 4, which should be accessible from aldehyde 5 via
chemoenzymatic enantioselective cyanohydrin formation and
subsequent reductive ring closure.
Thus, the forward synthesis commenced with the readily
prepared succinic semialdehyde 5,7 which was transformed
into both enantiomeric forms of the corresponding cyano-
hydrins 6 using crude cell lysates from rubber tree- and
almond-containing hydroxynitrile lyases. Hydroxynitrile
lyases are designed by nature to convert cyanohydrins into
the corresponding aldehydes and hydrogen cyanide, which
are used by some plants as a defense system.
By using a two-phase system of water and methyl tert-
butyl ether (MTBE), the equilibria can be directed to the
side of the cyanohydrins.8 In the case of semialdehyde 5,
the chemoenzymatic HCN addition provided, on a small scale
after extensive optimization, both cyanohydrins in excellent
yields and 95% ee using an (S)-selective HNL from HeVea
brasiliensis (HbHNL) and an (R)-selective HNL from Prunus
amygdalus (PaHNL, Scheme 2). We were also able to
perform the enzymatic conversion with HbHNL on a 25 g
scale in the same ee and a similar 91% yield after subsequent
TBS protection to give (S)-6. Scaling up using PaHNL
With the allyl-substituted piperidone 10 in hand, the stage
was set for the formation of the bicyclic skeleton of
epiquinamide. Allylation (NaH, allyl bromide) of the cis-
isomer of 10 (Figure 1), followed by RCM and hydrogena-
tion, provided 12 in a satisfactory yield of 81% (Scheme 3).
TBAF-mediated deprotection of the TBS ether, followed by
(6) Kanakubo, A.; Gray, D.; Innocent, N.; Wonnacott, S.; Gallagher, T.
Bioorg. Med. Chem. Lett. 2006, 16, 4648.
(7) Lotz, B. T.; Miller, M. J. J. Org. Chem. 1993, 58, 618.
(8) Fechter, M. H.; Griengl, H. In Enzyme catalysis in organic synthesis;
Drauz, K., Waldmann, H., Eds.; Wiley-VCH: Weinheim, 2002; Vol II, pp
974-989, and references therein.
(9) Vink, M. K. S.; Schortinghuis, C. A.; Mackova-Zabelinskaja, A.;
Fechter, M.; Po¨chlauer, P.; Castelijns, A. M. C. F.; van Maarseveen, J. H.;
Hiemstra, H.; Griengl, H.; Schoemaker, H. E.; Rutjes, F. P. J. T. AdV. Synth.
Catal. 2003, 345, 483.
Figure 1. Crystal structure of compound cis-10.
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Org. Lett., Vol. 10, No. 18, 2008

isomers thus represents a formal synthesis of the natural
product since recent work has shown that epiquinamide can
be prepared from 17 in four steps.5c
Scheme 3. Synthesis of Epiquinamide
Furthermore, this route was used to prepare the epimer of
epiquinamide (19) as depicted in Scheme 5. Mesylation of
Scheme 5. Synthesis of C(1)-Epiepiquinamide (19)
alcohol 13, followed by azide substitution, provided 18 in a
moderate 38% yield, caused by significant amounts of
elimination product which could not be avoided by altering
the conditions. Next, LiAlH4 reduction followed by acety-
lation gave epiepiquinamide (19) in 56% yield.
Finally, racemic and synthetic enantiopure (+)-epi-
quinamide5a were subjected to chiral GC as was the natural
compound showing that (+)-epiquinamide and the natural
compound were identical.
In conclusion, a synthetic pathway for (+)-epiquinamide
has been developed, involving chemoenzymatic enantiose-
lective cyanohydrin formation using hydroxynitrile lyases
and conversion of N,N-acetals into stable N-acyliminium ion
precursors. Having synthesized epiquinamide and determined
its absolute configuration, this pathway can be used for the
synthesis of analogues with potentially useful biological
activity, which is currently under investigation in our
laboratory.
Swern oxidation, gave the bicyclic ketone 14 in excellent
overall yield. Conversion of the ketone function into the
properly configured amine was initially attempted using
reductive amination. Indeed, reductive amination with ben-
zylamine provided the desired diastereoisomer 15 in a
selective manner in 94% over two steps. However, presum-
ably due to the acidic conditions of the reductive amination,
the intermediate imine partially racemizedspossibly via the
corresponding enamidesto give 15 in only 70% ee. Condi-
tions were varied to prevent racemization, but this appeared
not possible without a large decrease in yield or diastereo-
selectivity. Nevertheless, the synthetic plan was continued
by first reducing the lactam moiety using LiAlH4 to cleanly
afford diamine 16 in 90% yield. Next, the benzylic amine
moiety was acetylated and debenzylated through dissolving
metal reduction to afford (+)-epiquinamide 1 in 70% ee.
Analytical data were in accordance with literature data.5a
To circumvent the racemization step, ketone 14 in an
alternative approach was reduced with the small hydride
donor sodium borohydride (Scheme 4). This indeed resulted
Acknowledgment. This research is performed as part of
the IBOS Program (Integration of Biosynthesis & Organic
Synthesis) of ACTS-NWO. C. van den Broek (DSM
Pharma Chemicals) is kindly acknowledged for assistance
with the large scale HNL experiments.
Scheme 4. Formal Synthesis of Epiquinamide
Supporting Information Available: Procedures, synthe-
sis, and characterization of all new compounds (PDF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL801490M
(10) For a similar example of an endocyclic N-acyliminium ion reaction,
see: Huang, P.-Q.; Wei, B.-G.; Ruan, Y.-P. Synlett 2003, 1663.
(11) Crystallographic data have been deposited at the Cambridge
Crystallographic Data Centre as supplementary publication no. CCDC-
677971.
in the desired intermediate 17 without racemization but as
the minor reaction product along with the undesired epimer
13 in a 1:2 ratio. Chromatographic separation of the two
Org. Lett., Vol. 10, No. 18, 2008
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