Transformation of an optically active decahydro-6-isoquinolone scaffold: Perfect Felkin-Anh diastereoselectivity

Article abstract of DOI:10.1021/ol049831q

Diastereomerically and enantiomerically pure decahydro-6-isoquinolone derivative 7 (>99% de, 97% ee) was obtained from the Michael addition product 3. Interestingly, aldehyde 7 reacted with a number of different Grignard reagents to give the secondary alc

Full text of DOI:10.1021/ol049831q

ORGANIC
LETTERS
2004
Vol. 6, No. 7
1171-1173
Transformation of an Optically Active
Decahydro-6-isoquinolone Scaffold:
Perfect Felkin−Anh Diastereoselectivity
Jens Christoffers,* Heiko Scharl, Wolfgang Frey, and Angelika Baro
Institut fu¨r Organische Chemie, UniVersita¨t Stuttgart, Pfaffenwaldring 55,
70569 Stuttgart, Germany
jchr@po.uni-stuttgart.de
Received January 29, 2004
ABSTRACT
Diastereomerically and enantiomerically pure decahydro-6-isoquinolone derivative 7 (>99% de, 97% ee) was obtained from the Michael addition
product 3. Interestingly, aldehyde 7 reacted with a number of different Grignard reagents to give the secondary alcohols 9 in good yields as
single diastereomers. This result can be explained by taking the Felkin−Anh model into account.
Piperidines and 4-piperidones are very important structural
motifs in medicinal chemistry.1,2 The trans-decahydro-6-
isoquinolone scaffold, as is present in compound 7 (Scheme
1), may be regarded as an extended 4-piperidone derivative
with enhanced conformational rigidity due to the trans-fusion
of two six-membered rings. This type of bicyclic system is
rarely reported and, moreover, known only in racemic form
so far.3 Herein we report on the first optically active
decahydro-6-isoquinolone derivative with a quaternary ste-
reocenter.
vinyl ketone 2 as the key step.4 The chiral auxiliary L-valine
diethylamide thereby guarantees near-quantitative enantio-
selectivity in the construction of the quaternary stereocenter.5
Piperidone carboxylate 3 with (S)-configuration at the
stereogenic center6 was cyclized by Robinson annulation
(3) (a) MaGee, D. I.; Lee, M. L.; Decken, A. J. Org. Chem. 1999, 64,
2549-2554. (b) Simon, C.; Peyronel, J.-F.; Rodriguez, J. Org. Lett. 2001,
3, 2145-2148. (c) Simon, C.; Lieby-Muller, F.; Peyronel, J.-F.; Constan-
tieux, T.; Rodriguez, J. Synlett 2003, 2301-2304.
(4) (a) Christoffers, J.; Mann, A. Angew. Chem. 2000, 112, 2871-2874;
Angew. Chem., Int. Ed. 2000, 39, 2752-2754. (b) Christoffers, J.; Mann,
A. Chem. Eur. J. 2001, 7, 1014-1027. (c) Christoffers, J.; Scharl, H. Eur.
J. Org. Chem. 2002, 1505-1508. (d) Christoffers, J.; Kreidler, B.; Oertling,
H.; Unger, S.; Frey, W. Synlett 2003, 493-496. (e) Christoffers, J.; Kreidler,
B.; Unger, S.; Frey, W. Eur. J. Org. Chem. 2003, 2845-2853. (f)
Christoffers, J.; Schuster, K. Chirality 2003, 15, 777-782. Review: (g)
Christoffers, J. Chem. Eur. J. 2003, 9, 4862-4867.
The synthesis of aldehyde 7 is based on the copper-
catalyzed Michael reaction of chiral enamine 1 with methyl
(1) Review: Weintraub, P. M.; Sabol, J. S.; Kane, J. M.; Borcherding,
D. R. Tetrahedron 2003, 59, 2953-2989.
(2) (a) Egle, I.; MacLean, N.; Demchyshyn, L.; Edwards, L.; Slassi, A.;
Tehim, A. Bioorg. Med. Chem. Lett. 2003, 13, 3419-3421. (b) Dimmock,
J. R.; Jha, A.; Zello, G. A.; Quail, J. W.; Oloo, E. O.; Nienaber, K. H.;
Kowalczyk, E. S.; Allen, T. M.; Santos, C. L.; De Clercq, E.; Balzarini,
J.; Manavathu, E. K.; Stables, J. P. Eur. J. Med. Chem. 2002, 37, 961-
972. (c) Cicchi, S.; Revuelta, J.; Zanobini, A.; Betti, M.; Brandi, A. Synlett
2003, 2305-2308. (d) Novelli, F.; Sparatore, F. Farmaco 2002, 57, 871-
882. (e) Bleicher, K. H.; Wu¨thrich, Y.; De Boni, M.; Kolczewski, S.;
Hoffmann, T.; Sleight, A. J. Bioorg. Med. Chem. Lett. 2002, 12, 2519-
2522.
(5) Reviews: (a) Denissova, I.; Barriault, L. Tetrahedron 2003, 59,
10105-10146. (b) Christoffers, J.; Baro, A. Angew. Chem. 2003, 115,
1726-1728; Angew. Chem., Int. Ed. 2003, 42, 1688-1690. (c) Christoffers,
J.; Mann, A. Angew. Chem. 2001, 113, 4725-4732; Angew. Chem., Int.
Ed. 2001, 40, 4591-4597. (d) Corey, E. J.; Guzman-Perez, A. Angew. Chem.
1998, 110, 402-415; Angew. Chem., Int. Ed. 1998, 37, 388-401. (e) Fuji,
K. Chem. ReV. 1993, 93, 2037-2066. (f) Martin, S. F. Tetrahedron 1980,
36, 419-460.
(6) Christoffers, J.; Frey, W.; Scharl, H.; Baro, A. Z. Naturforsch. 2004,
59b, in press.
10.1021/ol049831q CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/02/2004

Scheme 1. Synthesis of the Decahydro-6-isoquinolone
Table 1. Grignard Addition Reaction of Scaffold 7
Scaffold 7
a With 26% of alcohol 6 as byproduct.
A series of various Grignard reagents 8a-j was converted
with racemic aldehyde 7 at 23 °C.8 Apart from allylmagne-
sium bromide (8d) and isopropylmagnesium bromide (8e),
the yields of Grignard addition are generally in the range of
70-84%. More interestingly, in all cases only a single
diastereomer of alcohol 9 is observed in the NMR spectra.
We would like to point out that Grignard addition to
aldehydes in a neopentyl environment has been reported so
far without any stereoselectivity at all.9
to give the octahydro-6-isoquinolone derivative 4.4c Hydro-
genation of the C-C double bond proceeded with high trans-
selectivity (>95%) by applying Pd/C and 1 atm H2 in
2-propanol as the solvent. With EtOH as the solvent,
acetalization of the ketone moiety to afford the diethyl ketal
was observed as a side reaction.
The minor cis-diastereomer was removed upon purification
all along the subsequent operations. Protection of the ketone
as 1,3-dioxolane derivative 5 was achieved with ethylene
glycol using standard conditions. Reduction of the ester
function with LiAlH4 afforded isoquinolone derivative 6.
Finally, the aldehyde moiety was installed by selective
reoxidation of the primary alcohol following the Ley
procedure.7 The (R)-configured compound 7 was obtained
as a diastereomerically pure material (>99% de) with an
optical purity of 97% ee. Analogously, racemic 7 was isolated
in diastereomerically pure form.
We succeeded to obtain single crystals of alcohol 9b which
are suitable for X-ray single-crystal analysis (Figure 1).10
As can be seen in Figure 1, the relative configuration of the
racemic material 9b is 4aR*,8aS*,9R*.
According to the Felkin-Anh model11 we assume the most
reactive conformation with the bridging C4a-C8a bond as
the largest group (RL), which is perpendicular to the aldehyde
moiety as shown in Scheme 2.
(8) For details, see the Supporting Information.
(9) (a) Vishnumurthy, K.; Cheung, E.; Scheffer, J. R.; Scott, C. Org.
Lett. 2002, 4, 1071-1074. (b) Schwede, W.; Cleve, A.; Ottow, E.; Wiechert,
R. Tetrahedron Lett. 1993, 34, 5257-5260. (c) Appendino, G.; Hoflack,
J.; De Clercq, P. J.; Chiari, G.; Calleri, M. Tetrahedron 1988, 44, 4605-
4618.
(10) Crystallographic data for the structure of 9b have been deposited
with the Cambridge Crystallographic Data Center (CCDC-229856). Copies
of the data can be obtained free of charge on application to the Director,
CCDC, 12 Union Road, Cambridge CB2 1EZ, U.K.; fax: (int.) +44-1223/
336-033; E-mail: deposit@ccdc.cam.ac.uk.
During our project to utilize scaffold 7 as an optically
active building block which allows for transformations at
the ketone, the piperidine NH and the aldehyde functions,
we first envisioned the Grignard reaction with the carbal-
dehyde group resulting in a number of secondary alcohols 9
as the addition products (Table 1).
(11) (a) Anh, N. T. Top. Curr. Chem. 1980, 88, 145-162. (b) Mulzer,
J. Nachr. Chem. Technol. Lab. 1984, 32, 16-18. (c) Wu, Y.-D.; Houk, K.
N. J. Am. Chem. Soc. 1987, 109, 908-910.
(7) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639-666.
1172
Org. Lett., Vol. 6, No. 7, 2004

Scheme 2. Diastereoselectivity of the Grignard Addition
by the relative configuration in Figure 1. As already
mentioned, high diastereoselectivity for the addition of
nucleophiles to carbaldehyde groups in a neopentyl environ-
ment has not been reported so far.
Acknowledgment. We thank the Aventis Pharma
Deutschland GmbH, the Fonds der Chemischen Industrie,
and the Deutsche Forschungsgemeinschaft for generous
support of this work.
Figure 1. ORTEP view of Grignard addition product 9b. The
depicted enantiomer has a (4aR,8aS,9R)-configuration.
Note Added after ASAP Posting. In the left column of the
last page, the Re face was incorrectly named Si in the version
posted ASAP March 2, 2004; the corrected version was
posted March 3, 2004.
Due to the shielding effect of the Boc protecting group,
the piperidine ring defines the medium-sized residue (RM).
From the crystal structure in Figure 1 it becomes apparent
that the dioxolane moiety does not have a significant
influence on the Grignard addition to the carbaldehyde
function. Thus, as shown in Scheme 2, the nucleophilic
Grignard reagent reacts preferentially along the Bu¨rgi-
Dunitz trajectory12 from the Re face of the aldehyde.
Consequently, a single diastereomer is formed, as is presented
Supporting Information Available: Experimental pro-
cedure and characterization of compound 9b. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL049831Q
(12) See the thematic issue of Chemical ReViews devoted to diastere-
oaddition, for example: Mengel, A.; Reiser, O. Chem. ReV. 1999, 99, 1191-
1223.
Org. Lett., Vol. 6, No. 7, 2004
1173