An enantioselective entry to cis-perhydroisoquinolines

Article abstract of DOI:10.1021/ol051242c

(Chemical Equation Presented) An enantioselective route to cis-perhydroisoquinolines, involving a cyclocondensation reaction of (R)-phenylglycinol with a racemic oxoester, a stereoselective conjugate addition to an unsaturated bicyclic lactam, and the clo

Full text of DOI:10.1021/ol051242c

ORGANIC
LETTERS
2005
Vol. 7, No. 17
3653-3656
An Enantioselective Entry to
cis-Perhydroisoquinolines
Mercedes Amat,* Maria Pe´rez, Annamaria T. Minaglia, Nu´ria Casamitjana, and
Joan Bosch*
Laboratory of Organic Chemistry, Faculty of Pharmacy, UniVersity of Barcelona,
08028-Barcelona, Spain
joanbosch@ub.edu; amat@ub.edu
Received May 26, 2005
ABSTRACT
An enantioselective route to cis-perhydroisoquinolines, involving a cyclocondensation reaction of (R)-phenylglycinol with a racemic oxoester,
a stereoselective conjugate addition to an unsaturated bicyclic lactam, and the closure of the carbocyclic ring by a ring-closing metathesis
as the key steps is reported. This route allows the preparation of 3-cyano derivatives as well as cis-octahydroisoquinolines bearing a quaternary
center at the C4-position.
The totally (or partially) reduced cis-isoquinoline ring system
is present in a large number of bioactive natural and synthetic
products. Among them, of particular interest are the indole
alkaloids of the yohimbine-reserpine type,1 the marine sponge
alkaloids of the manzamine2 and madangamine groups,3 all
of them displaying a variety of notable pharmacological
activities, and the HIV protease inhibitors nelfinavir and
saquinavir,4 which are characterized by the presence of a
carboxamide function at the C3-position of the isoquinoline
ring5 (Figure 1). This widespread occurrence has stimulated
the development of general methodologies and strategies for
the enantioselective synthesis of cis-perhydroisoquinoline
derivatives.6 In this context, we have recently reported7 an
enantiodivergent synthesis of cis-hydroisoquinolines, in
which the key step was a diastereoselective Diels-Alder
reaction of a phenylglycinol-derived unsaturated δ-lactam.
(1) (a) Sza´ntay, C.; Honty, K. In Monoterpenoid Alkaloids. Saxton, J.
E., Ed. In The Chemistry of Heterocyclic Compounds; Taylor, E. C., Ed.;
Wiley: Chichester, 1994; Supplement to Vol. 25, Part 4, pp 161-216. (b)
Creasey, W. A. In Monoterpenoid Alkaloids. Saxton, J. E., Ed. In The
Chemistry of Heterocyclic Compounds; Taylor, E. C., Ed.; Wiley: Chich-
ester, 1994; Supplement to Vol. 25, Part 4, pp 715-754.
(2) (a) For reviews, see: Andersen, R. J.; Van Soest, R. W. M.; Kong,
F. In Alkaloids: Chemical and Biogical PerspectiVes; Pelletier, S. W., Ed.;
Pergamon: Oxford, 1996; Vol. 10, pp 301-355. (b) Tsuda, M.; Kobayashi,
J. Heterocycles 1997, 46, 765-794. (c) Magnier, E.; Langlois, Y.
Tetrahedron 1998, 54, 6201-6258. (d) Nakagawa, M. J. Heterocycl. Chem.
2000, 37, 567-581.
(3) (a) Kong, F.; Andersen, R. J.; Allen, T. M. J. Am. Chem. Soc. 1994,
116, 6007-6008. (b) Kong, F. Graziani, E. I.; Andersen, R. J. J. Nat. Prod.
1998, 61, 267-271.
(5) For other bioactive perhydroisoquinoline-3-carboxylic acid derivatives
of pharmacological interest, see: (a) Parkes, K. E. B.; Bushnell, D. J.;
Crackett, P. H.; Dunsdon, S. J.; Freeman, A. C.; Gunn, M. P.; Hopkins, R.
A.; Lambert, R. W.; Martin, J. A.; Merrett, J. H.; Redshaw, S.; Spurden
W. C.; Thomas, G. J. J. Org. Chem. 1994, 59, 3656-3664. (b) Filla, S. A.;
Winter, M. A.; Johnson, K. W.; Bleakman, D.; Bell, M. G.; Bleisch, T. J.;
Castano, A. M.; Clemens-Smith, A.; del Prado, M.; Dieckman, D. K.;
Dominguez, E.; Escribano, A.; Ho, K. H.; Hudziak, K. J.; Katofiasc, M.
A.; Martinez-Perez, J. A.; Mateo, A.; Mathes, B. M.; Mattiuz, E. L.; Ogden,
A. M. L.; Phebus, L. A.; Stack, D. R.; Stratford, R. E.; Ornstein, P. L. J.
Med. Chem. 2002, 45, 4383-4386.
(6) (a) Houpis, I. N.; Molina, A.; Reamer, R. A.; Lynch, J. E.; Volante,
R. P.; Reider, P. J. Tetrahedron Lett. 1993, 34, 2593-2596. (b) Aube´, J.;
Ghosh, S.; Tanol, M. J. Am. Chem. Soc. 1994, 116, 9009-9018. (c) Kwak,
B. S.; Kim, T. J.; Lee, S. I. Catal. Lett. 2002, 83, 93-96. (d) Hattori, K.;
Grossman, R. B. J. Org. Chem. 2003, 68, 1409-1417. (e) Vila, X.; Quirante,
J.; Paloma, L.; Bonjoch, J. Tetrahedron Lett. 2004, 45, 4661-4664.
(7) Casamitjana, N.; Amat, M.; Llor, N.; Carreras, M.; Pujol, X.;
Ferna´ndez, M. M.; Lo´pez, V.; Molins, E.; Miravitlles, C.; Bosch, J.
Tetrahedron: Asymmetry 2003, 14, 2033-2039.
(4) Kaldor, S. W.; Kalish, V. J.; Davies, J. F., II; Shetty, B. V.; Fritz, J.
E.; Appelt, K.; Burgess, J. A.; Campanale, K. M.; Chirgadze, N. Y.;
Clawson, D. K.; Dressman, B. A.; Hatch, S. D.; Khalil, D. A.; Kosa, M.
B.; Lubbehusen, P. P.; Muesing, M. A.; Patick, A. K.; Reich, S. H.; Su, K.
S.; Tatlock, J. H. J. Med. Chem. 1997, 40, 3979-3985.
10.1021/ol051242c CCC: $30.25
© 2005 American Chemical Society
Published on Web 07/27/2005

Scheme 1. Enantioselective Synthesis of
cis-Perhydroisoquinolin-3-one
Figure 1. Compounds bearing a cis-perhydroisoquinoline moiety.
We present here an efficient enantioselective route to cis-
perhydroisoquinolines. The key steps are (i) the generation
of the first enantiopure intermediate, the bicyclic lactam 2,
by cyclocondensation of (R)-phenylglycinol with racemic
γ-substituted δ-oxoester 1, in a process that involves a
dynamic kinetic resolution; (ii) a highly stereoselective
conjugate addition to unsaturated lactam 3; and (iii) the
closure of the carbocyclic ring by a ring-closing olefin
metathesis (RCM).
The starting racemic oxoester 1 was conveniently prepared
in 64% yield by reaction of the piperidine enamine of
4-pentenal with methyl acrylate.8 Cyclocondensation of 1
with (R)-phenylglycinol at 0 °C in the presence of anhydrous
Na2SO4, followed by heating at 75-80 °C under vacuum
(10-15 mmHg), stereoselectively afforded the enantiopure
bicyclic lactam 2 in 71% yield (Scheme 1). Minor amounts
(10%) of the (8S,8aS)-diastereoisomer were also isolated. The
above result clearly indicated that a dynamic kinetic resolu-
tion,9 with epimerization of the configurationally labile
stereocenter R to the carbonyl group, had occurred during
the cyclocondensation reaction.
Lactam 2 was then converted to the unsaturated lactams
3 by sequential treatment with LHMDS (2.2 equiv), methyl
or benzyl chloroformate, and PhSeCl, followed by oxidation
of the resulting mixtures of selenides with H2O2 in the
presence of pyridine. Lactams 3 proved to be sensitive to
both mild acid and basic conditions, affording the corre-
sponding pyridones 9. For this reason, they were prepared
immediately before the next reaction and used without further
purification.
The conjugate addition of an allyl group was accomplished
in excellent chemical yield and complete exo facial diaste-
reoselectivity10 by reacting lactams 3a and 3b with allyl-
magnesium bromide in the presence of CuI, LiCl, and
TMSCl. The observed stereoselectivity can be explained by
considering that the attack of the nucleophile takes place,
under stereoelectronic control, axial to the electrophilic
carbon of the conjugated double bond of the conformationally
rigid lactams 3, and consequently cis with respect to the allyl
substituent, as depicted in Figure 2.
(8) (a) Costello, G.; Saxton, J. E. Tetrahedron 1986, 42, 6047-6069.
(b) Lawton, G. Saxton, J. E.; Smith, A. J. Tetrahedron 1977, 33, 1641-
1653.
(9) (a) For related examples, see: (a) Amat, M.; Canto´, M.; Escolano,
C.; Molins, E.; Espinosa, E.; Bosch, J. J. Org. Chem. 2002, 67, 5343-
5351. (b) Amat, M.; Pe´rez, M.; Llor, N.; Escolano, C.; Luque, J.; Molins,
E.; Bosch, J. J. Org. Chem. 2004, 69, 8681-8693. (c) For a recent review,
see: Pellissier, H. Tetrahedron 2003, 59, 8291-8327.
(10) For the stereochemical outcome of the conjugate addition of
organocuprates to phenylglycinol-derived lactams, see: (a) Amat, M.;
Bosch, J.; Hidalgo, J.; Canto´, M.; Pe´rez, M.; Llor, N.; Molins, E.; Miravitlles,
C.; Orozco, M.; Luque, J. J. Org. Chem. 2000, 65, 3074-3084. (b) Amat,
M.; Pe´rez, M.; Llor, N.; Lago, E.; Molins, E. Org. Lett. 2001, 3, 611-
614.
Figure 2. Stereoelectronic control in the conjugate addition.
The resulting cis-diallyl lactams 4a and 4b were isolated
as a mixture of epimers at the isomerizable stereocenter
3654
Org. Lett., Vol. 7, No. 17, 2005

adjacent to the ester and lactam carbonyl groups (ap-
proximate ratio of CO2R R:â isomers was 4:1 for 4a and
3:1 for 4b), which could be separated by column chroma-
tography.
of ZnCl2 to give perhydroisoquinoline-3-carbonitrile 14 in
good overall yield (Scheme 3).
The RCM11 of lactams 4a and 4b catalyzed by the second-
generation Grubbs catalyst 10a resulted in the closure of the
carbocyclic ring to give the respective hydroisoquinolones
5a and 5b in excellent yield. When the RCM from 4a was
carried out using the first-generation Grubbs catalyst 10b
(7.5 mol %), cyclization was slower and hydroisoquinolone
5a was isolated in only 66% yield after 20 h.
Scheme 3. Enantioselective Access to
cis-3-Cyanoperhydroisoquinolines
Catalytic hydrogenation of 5a using Pd/C as the catalyst
brought about both the reduction of the carbon-carbon
double bond and the debenzylation of the benzyloxycarbonyl
group to give a â-keto acid, which was then decarboxylated
by heating in refluxing toluene, leading to a single perhy-
droisoquinolone 6 in 85% overall yield.
The alkoxycarbonyl group present in 5b not only enhances
the reactivity of the conjugated system, thus allowing the
subsequent conjugate addition of an organocuprate, but also
can later be manipulated to ultimately lead to octahydroiso-
quinolines bearing a quaternary center at the C4-position.
Thus, keto ester 5b underwent stereoselective alkylation
on the most accessible face with complete facial selectivity
by treatment with LHMDS and ethyl iodide, allyl bromide,
3-(tert-butyldimethylsilyloxy) propyl iodide, or 2-(2-iodo-
ethyl)-1,3-dioxolane (Scheme 4). LiAlH4 reduction of the
Removal of the chiral auxiliary was performed in two
steps, by reduction with triethylsilane in the presence of
TiCl4, followed by debenzylation of the resulting 2-piperi-
done 7 with Na in liquid NH3. The enantiopure cis-
perhydroisoquinolin-3-one 8 [[R]22 -29.2 (c 0.8, MeOH);
D
lit.12a [R]22D -30.9 (c 1.02, MeOH)] was obtained in excellent
overall yield. Bicyclic lactam 8 has previously been used as
an advanced intermediate in the synthesis of (-)-alloyo-
himbane.6b,12
Alternatively, alane reduction of 6, followed by deben-
zylation of the resulting tertiary amine 11 by hydrogenation
in the presence of Pd(OH)2 and (Boc)2O, gave the enan-
tiopure N-protected cis-perhydroisoquinoline 1213 (Scheme
2).
Scheme 4. Toward the First Enantioselective Entry to the
Tricyclic Core of Madangamine Alkaloids
Scheme 2. Synthesis of Enantiopure N-Protected
cis-Perhydroisoquinoline
On the other hand, perhydroisoquinolone 8 provides easy
access to derivatives bearing a cyano substituent at the C3-
position. Thus, after protection of the nitrogen atom as an
N-benzyloxycarbonyl carbamate, the carbonyl group of 13
was reduced under Speckamp conditions,14 and the resulting
ethoxy derivative was treated with Me3SiCN in the presence
(11) (a) Handbook of Metathesis; Grubbs, R. H., Ed; Wiley-VCH:
Weinheim, 2003; Vols. 1-3. (b) Deiters, A.; Martin, S. F. Chem. ReV. 2004,
104, 2199-2238.
alkylated compounds 15b-d caused the cleavage of the
C-O bond of the oxazolidine ring and the simultaneous
reduction of the ester and amide carbonyl groups to give
the respective alcohols 16b-d in good yields. Functionalized
cis-octahydroisoquinolines 16, bearing the crucial quaternary
center of madangamines, may allow an enantioselective entry
to the tricyclic core of these alkaloids.15
(12) (a) Aube´, J.; Wang, Y.; Hammond, M.; Tanol, M.; Takusagawa,
F.; Velde, D. V. J. Am. Chem. Soc. 1990, 112, 4879-4891. (b) Sparks, S.
M.; Shea, K. J. Tetrahedron Lett. 2000, 41, 6721-6724.
(13) For NMR studies of cis-fused hydroisoquinolines, see: Booth, H.;
Bailey, J. M. J. Chem. Soc., Perkin Trans. 2 1979, 510-513.
(14) (a) Hubert, J. C.; Wijnberg, J. B. P. A.; Speckamp, W. N.
Tetrahedron 1975, 31, 1437-1441. (b) Wijnberg, J. B. P. A.; Schoemaker,
H. E.; Speckamp, W. N. Tetrahedron 1978, 34, 179-187.
Org. Lett., Vol. 7, No. 17, 2005
3655

1
The results reported in this letter further illustrate that
chiral nonracemic lactams generated by cyclocondensation
reactions of 1,2-amino alcohols and δ-oxoesters are versatile
building blocks for the enantioselective synthesis of piperi-
dine-containing derivatives.16
Supporting Information Available: Copies of H and
13C NMR spectra of compounds 2-8 and 11-16. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL051242C
Acknowledgment. Financial support from the Ministry
of Science and Technology (Spain)-FEDER through Project
BQU2003-00505 and the DURSI, Generalitat de Catalunya
(Grant 2001SGR-0084), is gratefully acknowledged.
(16) For reviews, see: (a) Meyers, A. I.; Brengel, G. P. Chem. Commun.
1997, 1-8. (b) Groaning, M. D.; Meyers, A. I. Tetrahedron 2000, 56, 9843-
9873. For more recent work, see: (c) Nieman, J. A.; Ennis, M. D. Org.
Lett. 2000, 2, 1395-1397. (d) Amat, M.; Canto´, M.; Llor, N.; Ponzo, V.;
Pe´rez, M.; Bosch, J. Angew. Chem., Int. Ed. 2002, 41, 335-338. (e) Allin,
S. M.; James, S. L.; Elsegood, M. R. J.; Martin, W. P. J. Org. Chem. 2002,
67, 9464-9467. (f) Amat, M.; Llor, N.; Hidalgo, J.; Escolano, C.; Bosch,
J. J. Org. Chem. 2003, 68, 1919-1928. (g) Amat, M.; Escolano, C.; Lozano,
O., Llor, N.; Bosch, J. Org. Lett. 2003, 5, 3139-3142. (h) Penhoat, M.;
Levacher, V.; Dupas, G. J. Org. Chem. 2003, 68, 9517-9520. (i) Allin, S.
M.; Thomas, C. I.; Doyle, K.; Elsegood, M. R. J. J. Org. Chem. 2005, 70,
357-359. (j) Amat, M.; Bassas, O.; Perica`s, M. A.; Pasto´, M.; Bosch, J.
Chem. Commun. 2005, 1327-1329. See also references cited therein.
(15) (a) For the racemic synthesis of a closely related bicyclic intermedi-
ate and its conversion to the tricyclic core of madangamines, see: Matzanke,
N.; Gregg, R. J.; Weinreb, S. M. J. Org. Chem. 1997, 62, 1920-1921. For
more recent synthetic studies in the madangamine field, also in the racemic
series, see: (b) Yamazaki, N.; Kusanagi, T.; Kibayashi, C. Tetrahedron
Lett. 2004, 45, 6509-6512. (c) Tong, H. M.; Martin, M.-T.; Chiaroni, A.;
Be´ne´chie, M.; Marazano, C. Org. Lett. 2005, 7, 2437-2440.
3656
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