Tandem functionalization of nonactivated alkenes and alkynes in intramolecular N-acyloxyiminium ion carbocyclization. Synthesis of 6-substituted hydroindole 2-carboxylic acids

Article abstract of DOI:10.1021/ol040053b

(Chemical Equation Presented) Five-membered N-Boc acyliminium ions derived from L-pyroglutamic acid harboring 4-butenyl and 4-butynyl tethers undergo Lewis acid-mediated halo and tandem Friedel-Crafts carbocyclization within minutes at -78°C to give stere

Full text of DOI:10.1021/ol040053b

ORGANIC
LETTERS
2004
Vol. 6, No. 25
4683-4686
Tandem Functionalization of
Nonactivated Alkenes and Alkynes in
Intramolecular N-Acyloxyiminium Ion
Carbocyclization. Synthesis of
6-Substituted Hydroindole 2-Carboxylic
Acids
Stephen Hanessian* and Martin Tremblay
Department of Chemistry, UniVersite´ de Montre´al, C.P. 6128, Station Centre-Ville,
Montre´al, P.Q., H3C 3J7 Canada
stephen.hanessian@umontreal.ca
Received September 9, 2004
ABSTRACT
Five-membered N-Boc acyliminium ions derived from
L
-pyroglutamic acid harboring 4-butenyl and 4-butynyl tethers undergo Lewis acid-
78 C to give stereodefined 6-substituted octahydroindole and
mediated halo and tandem Friedel Crafts carbocyclization within minutes at
−
−
°
hexahydroindole 2-carboxylic acid methyl esters, respectively. The cyclic vinyl bromides are excellent substrates for Pd-catalyzed Suzuki
−
Miyaura, Heck, and Stille couplings. The method also provides access to enantiopure sp2- and sp3-arylated azabicyclics that are novel and
versatile scaffolds for chemical diversification.
The octahydrohydroindole ring and related heterocycles are
important components of many natural products and medici-
nally relevant compounds. For example, (6R,2R)-6-hydroxy-
2-carboxy-octahydroindole and its (5R,6R)-dihydroxy variant
are the core subunits of marine metabolites such as aerugi-
nosin 298A1 and dysinosin A,2 respectively. The octahy-
droindole motif is also embedded in the structures of several
polycylic alkaloids and the clinically relevant angiotensin
converting enzyme (ACE) inhibitor perindoprilat.3
recently reported a novel azonia-Prins-type (the prefix azonia
rather than aza is in accord with the IUPAC rules on no-
menclature; Heterocyclic Systems; rule B-6. Cationic hetero-
atoms) halocarbocyclization of readily available C-branched
(2) Carroll, A. R.; Pierens, G.; Fechner, G.; de Almeidaleona, P.; Ngo,
A.; Simpson, M.; Hooper, J. N. A.; Bo¨strom, S. L.; Musil, D.; Quinn, R. J.
J. Am. Chem. Soc. 2002, 124, 13340.
(3) (a) Vincent, M.; Marchand, B.; Remond, G.; Jaguelin-Guinamant,
S.; Damien, G.; Portevin, B.; Baumal, J. Y.; Volland, J. P. Drug Design
and DiscoVery 1992, 9, 11. For related structures (ramipril), see: (b) Warner,
G. T.; Perry, C. M. Drugs 2002, 62, 1381.
(4) For recent reviews, see: (a) Leusch, H.; Harrigan, G. G.; Goetz, G.;
Horgen, F. D. Curr. Med. Chem. 2002, 9, 179. (b) Burja, A. M.; Banaigs,
B.; Abou-Mansour, E.; Burgess, J.-G.; Wright, P. C. Tetrahedron 2001,
57, 9347. (c) Shiori, T.; Hamada, Y. Synlett 2001, 184. (d) Lewis, J. R.
Nat. Prod. Rep. 1998, 417. (e) Namikoshi, M.; Rinehart, K. L. J. Indust.
Microbiol. 1996, 17, 373. (f) Rinehart, K. L.; Namikoshi, M.; Choi, B. W.
J. Appl. Phycol. 1994, 6, 159.
(5) (a) Wipf, P.; Methot, J.-L. Org. Lett. 2000, 2, 4213. (b) Wipf, P.;
Maresko, D. A. Tetrahedron Lett. 2000, 41, 4723. (c) Wipf, P.; Li, W. J.
Org. Chem. 1999, 64, 4576. (d) Wipf, P.; Kim, Y.; Goustein, D. M. J. Am.
Chem. Soc. 1995, 117, 1106.
The occurrence of this bicyclic heterocycle in the aerugi-
nosin family of cyanobacterial metabolites4 has stimulated
interest in its synthesis by enantioselective methods.5-10 We
* Phone: (514) 343-6738. Fax: (514) 343-5728.
(1) (a) Rios Steiner, J. L.; Murakami, M.; Tulinsky, A. J. Am. Chem.
Soc. 1998, 120, 597. (b) Matsuda, H.; Okino, T.; Murakami, M.; Yamaguchi,
K. Tetrahedron 1996, 52, 14501. (c) Murakami, M.; Ishida, K.; Okino, T.;
Okita, Y.; Matsuda, H.; Yamaguchi, K. Tetrahedron Lett. 1995, 36, 2785.
(d) Murakami, M.; Okita, Y.; Matsuda, H.; Okino, H.; Yamaguchi, K.;
Tetrahedron Lett. 1994, 35, 3129.
10.1021/ol040053b CCC: $27.50
© 2004 American Chemical Society
Published on Web 11/13/2004

Scheme 1 N-Acyloxyiminium Ion Azonia-Prins Cyclizations
Scheme 2. Tandem Azonia-Prins/Friedel-Crafts Reactions
(Table 1) took place within a few minutes at temperatures
between -15 and -78 °C depending on the freezing tem-
perature of the solvent. Decreasing the amount of the arene
by mixing with increasing volumes of CH2Cl2 progressively
diminished the yield, but the main adducts were the same
as when the arene was used as a solvent. The reaction was
also done with the C-4-epimeric analogue of 2 to afford 6
in 74% yield (Scheme 2).
ω-alkenyl N-acyloxyiminium ion intermediates such as 2 in
connection with the total synthesis and structural confirma-
tion of oscillarin,11 a new member of the aeruginosin family
(Scheme 1). In the presence of SnCl4 or SnBr4 in CH2Cl2,
cyclization occurred within a few minutes at -78 °C to afford
the corresponding (2S,6S)-6-halo-octahydroindole 2-carboxy-
lic acid methyl esters 3a and 3b (Scheme 1). Nucleophilic
displacement with Bu4NOAc and NaN3 gave the (6R)-acetate
and (6R)-azido analogues 4a and 4b, respectively.
A plausible mechanism takes into account an antiperiplanar
alignment11-14 of the π-nucleophilic extremity with the endo-
N-acyloxyiminium ion15 in a chairlike conformation16 as
When the reaction was run in toluene as a solvent, a facile
Friedel-Crafts-type tandem carbocyclization took place re-
sulting in the formation of 3a, and an o/p-mixture of (6R)-
tolyl-octahydroindole 2-carboxylic acid methyl ester as a by-
product (Scheme 1). Using BF3OEt2 instead of SnCl4 and
using toluene as a solvent gave the Friedel-Crafts product
5 in 78% yield (Scheme 2). The stereochemistry at C-6 was
determined by NOESY experiments and by comparison with
an X-ray structure (see below). Other mono- and disubstituted
benzenes of similar nucleophilicity12 (o-xylene, methylene-
dioxy benzene, isopropylbenzene, anisole, etc.) gave analo-
gous results (Table 1, entries 1-6). Mesitylene and m-xylene
gave single positional isomers as major products (Table 1,
entries 7 and 8). Moderately nucleophilic halobenzenes gave
modest yields of the corresponding o/p-substituted (6S)-
halophenyl adducts, accompanied by 20-30% yield of the
5,6-elimination product and the ene-carbamate arising from
2. Electron-rich aromatics such as 2,4-dimethoxybenzene and
furan added to the iminium ion directly, even in the presence
of excess anisole.13 The formation of 5 and related adducts
Table 1. Tandem Azonia-Prins/Friedel-Crafts Reaction of 6
with a Variety of Arenes as a Solvent
(6) (a) Valls, N.; Lo´pez-Canet, M.; Vallribera, M.; Bonjoch, J. Chem.
Eur. J. 2001, 7, 3446. (b) Valls, N.; Lo´pez-Canet, M.; Vallribera, M.;
Bonjoch, J. J. Am. Chem. Soc. 2000, 122, 11248. (c) Bonjoch, J.; Catena,
J.; Isabal, E.; Lo´pez-Canet, M.; Valls, N. Tetrahedron: Asymmetry 1996,
7, 1899. (d) Bonjoch, J.; Catena, J.; Valls, N. J. Org. Chem. 1996, 61, 7106.
(7) Ohshima, T.; Gnanadesikan, V.; Shibughushi, T.; Fukuta, Y.; Nemoto,
T.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 11206.
(8) Hanessian, S.; Margarita, R.; Hall, A.; Johnstone, S.; Tremblay, M.;
Parlanti, L. J. Am. Chem. Soc. 2002, 124, 13342.
(9) Belvisi, L.; Colombo, L.; DiGiacomo, M.; Manzoni, L.; Vodopivec,
B.; Scolastico, C. Tetrahedron 2001, 57, 6463.
(10) Toyooka, N.; Okumura, M.; Himiyama, T.; Nakazawa, A.; Nemoto,
H. Synlett 2003, 55.
(11) Hanessian, S.; Tremblay, M.; Petersen, J. W. J. Am. Chem. Soc.
2004, 126, 6064.
a Isolated as o/p-mixtures, except for entries 7 and 8, which were single
adducts.
(12) Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66.
4684
Org. Lett., Vol. 6, No. 25, 2004

Scheme 3. Proposed Reactive Intermediates in the Tandem
Azonia-Prins/Friedel-Crafts Cyclizations
Scheme 4. Terminal Yne Tandem Azonia-Prins/
Friedel-Crafts Cyclization
shown in 7 (Scheme 3). A putative π-cationic specie 8,17,18
or the cyclic carbenium ion 9, is attacked by the solvent in
an equatorial trajectory to afford the observed stereochem-
istry. Vicinal H-abstraction from 9 can lead to the 5,6-un-
saturated analogue (in addition to the ene-carbamate of 2),
especially in the case of less reactive arenes. A synchronous
formation of a C-C and C-O bonds was originally sug-
gested16a in the formic acid-mediated intramolecular carbo-
cyclization of an iminium ion lactam. Although a similar
pathway as depicted in 7a cannot be excluded, it is more
likely that the carbocyclization of 2 proceeds in an asyn-
chronous manner especially when weak carbon nucleophiles
are involved.
We then extended the halocarbocyclization reaction to
N-acyloxyiminium ions bearing a C-tethered terminal alkyne19
(Scheme 4). Formation of the Li dianion from N-Boc di-
methyl L-glutamate 1, followed by alkylation with 4-trimeth-
ylsilanyl-but-3-yn-1-ol triflate 10 capitalizing on internal 1,3-
induction,20 gave 11 as a single isomer. Removal of the TMS,
followed by a two-step lactamization gave 12, which was
converted to the 5-acetoxy intermediate 13 as previously
reported.11,20 Treatment of 13 with BF3OEt2 in toluene gave
the vinylic 6-tolyl adduct 14, as an o/p-mixture in 69% yield.
An intermediate cyclic vinyl cation,21 15 (or a π-com-
plex),18,22 can be invoked as in the case of the alkene tether
(Scheme 3).23
(13) For selected examples of intermolecular Friedel-Crafts-type C-
arylation of N-acyloxyiminium ions, see: (a) Manfre´, F.; Pulicani, J. P.
Tetrahedron: Asymmetry 1994, 5, 235. (b) Matsumura, Y.; Terauchi, J.;
Yamamoto, T.; Konno, T.; Shono, T. Tetrahedron 1993, 49, 8503. (c)
Malmberg, M.; Nyberg, K. Acta Chem. Scand. 1981, B35, 411. See also
ref 18.
(14) For examples, see: (a) Ent, H.; de Koning, H.; Speckamp, W. N.
J. Org. Chem. 1986, 51, 1687. (b) Schoemaker, H. E.; Speckamp, W. N.
Tetrahedron Lett. 1978, 1515. (c) Hart, D. J.; Kanai, K. J. Am. Chem. Soc.
1983, 103, 1255. For Prins cyclization, see: (d) Jaber, J. J.; Mitsui, K.;
Rychnovsky, S. D. J. Org. Chem. 2001, 66, 4079. For related examples of
stereoelectronic effects in the intermolecular addition of nucleophiles to
iminium ions, see: (e) Heathcock, C. H.; Kleinman, E. F.; Binkley, E. S.
J. Am. Chem. Soc. 1982, 104, 1054. (f) Demailly, G.; Solladie´, G. J. Org.
Chem. 1981, 46, 3102. (g) Overman, L. E.; Freerks, R. L. J. Org. Chem.
1981, 46, 6, 2833. (h) Overman, L. E.; Fukaya, C. J. Am. Chem. Soc. 1980,
102, 1454. (i) Stevens, R. V.; Lee, A. W. M. J. Am. Chem. Soc. 1979, 101,
7032. (j) Wenkert, E.; Chang, C.-J.; Chawla, H. P. S.; Cochran, D. W.;
Hagaman, E. W.; King, J. C.; Orito, K. J. Am. Chem. Soc. 1976, 98, 3645.
(k) Ziegler, F. E.; Spitzner, E. B. J. Am. Chem. Soc. 1973, 95, 7146. (l)
Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry, Perga-
mon: New York, 1983; Chapter 6.
(19) For a recent example, see: Beyersbergen van Henegouwen, W. G.;
Hiemstra, H. J. Org. Chem. 1997, 62, 8862 and references therein.
(20) Hanessian, S.; Margarita, R. Tetrahedron Lett. 1998, 39, 5887.
(21) For examples of cyclic vinyl cations, see: (a) Pellicciari, R.; Natalini,
B.; Sadeghpour, B. M.; Marinozzi, M.; Snyder, J. P.; Williamson, B. L.;
Kuethe, J. T.; Padwa, A. J. Am. Chem. Soc. 1996, 118, 1. (b) Balog, A.;
Curran D. P. J. Org. Chem. 1995, 60, 337. (c) Johnson, W. S.; Yarnell, T.
M.; Myers, R. F.; Morton, D. R. Tetrahedron Lett. 1978, 2549. (d) Kozar,
L. G.; Clark, R. D.; Heathcock, C. H. J. Org. Chem. 1977, 42, 1386. (e)
Schleyer, P. V. R.; Pfeifer, W. D.; Bahn, C. A.; Bocher, S.; Harding, C. E.;
Hummel, K.; Hanack, M.; Stang, P. J. J. Am. Chem. Soc. 1971, 93, 1513.
(f) Peterson, P. E.; Kamat R. J. J. Am. Chem. Soc. 1969, 91, 4521. For
reviews on vinyl cations, see: (g) Nefedov, V. D.; Sinotova, E. N.; Lebedev,
V. P. Russ. Chem. ReV. 1992, 61, 283. (h) Stang, P. J.; Rappoport, Z.;
Hanack, M.; Subramanian, L. B. Vinyl Cations; Academic Press: New York,
1979. (i) Stang, P, J. Acc. Chem. Res. 1978, 11, 107. (j) Hanack, M. Angew.
Chem., Int. Ed. Engl. 1978, 17, 333. (k) Rappoport, Z. Acc. Chem. Res.
1976, 9, 265.
(15) For authoritative reviews, see: (a) Maryanoff, B. E.; Zhang, H.-C.;
Cohen, J. H.; Turchi, I. J.; Maryanoff, C. A. Chem. ReV. 2004, 104, 1431.
(b) Royer, J.; Bonin, M.; Micouin, J. Chem. ReV. 2004, 104, 2311. (c)
Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3817. (d)
Hiemstra, H.; Speckamp, W. N. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Heathcock, C. H., Eds.; Pergamon: New York, 1991,
2, 1047. (e) Speckamp, W. N.; Hiemstra, H. Tetrahedron 1985, 41, 4367.
(f) Speckamp, W. N. Recl. TraV. Chim. Pays-Bas 1981, 100, 345.
(16) Analogy with Stork-Eschenmoser proposals for polyene cyclizations
has been made; see: (a) Hiemstra, H.; Sno, M. H. A. M.; Vijn, R. J.;
Speckamp, W. N. J. Org. Chem. 1985, 50, 4014. (b) Stork, G.; Burgstahler,
A. W. J. Am. Chem. Soc. 1955, 77, 5068. (c) Eschenmoser, A.; Ruzicka,
L.; Jeger, O.; Arigoni, D. HelV. Chim. Acta 1955, 38, 1890.
(17) For an early example, see: Dijkink, J.; Schoemaker, H. E.;
Speckamp, W. N. Tetrahedron Lett. 1975, 4043.
(18) Fisher, M. J.; Overman, L. E. J. Org. Chem. 1990, 55, 1447.
Org. Lett., Vol. 6, No. 25, 2004
4685

Scheme 5. Terminal Yne Azonia-Prins Cyclizations and
Suzuki Cross-Coupling with 2b
Scheme 6. Heck and Stille Cross-Coupling reactions with 22b
tion in the presence of vinyltributylstannane and Pd(PPh3)4
in refluxing toluene gave the exocyclic diene 31 in 71% yield.
We have described novel and practical methods for the
synthesis of enantiopure 6-halo, 6-azido, and 6-C-substituted
hydroindole 2-carboxylic acid methyl esters from readily
available 4-ω-butenyl and butynyl N-Boc L-pyroglutamic
acid esters in the presence of Lewis acids. The terminal
alkene and alkyne tethers act as latent π-nucleophiles, which
also undergo concomitant attack by an external nucleophile
such as a halide or an aromatic hydrocarbon, most likely
via cationic intermediates. In the case of an alkene, an intra-
molecular tandem Friedel-Crafts-type carbocyclization takes
place with the creation of a new sp3 stereogenic carbon
bearing an equatorially disposed aryl substituent. Alkynes
lead to vinylic halides or vinylic aryls within the newly
formed 6-substituted hexahydroindole motif. Chemical ma-
nipulation of the vinylic halides and capitalizing on the
orthogonal functionality in the hexahydroindole 2-carboxylic
acids expands their utility as versatile scaffolds toward the
synthesis of pharmaceutically relevant entities and as inter-
mediates in natural product synthesis.
In the presence of SnCl4 or SnBr4 in CH2Cl2, 13 was
rapidly transformed into the versatile vinylic 6-halo hexahy-
droindoles 16a and 16b in 57 and 80% yields, respectively
(Scheme 5). We were then in a position to apply well-known
Pd-catalyzed substitution reactions of vinylic bromides in
an effort to introduce further functional diversification. Thus,
treatment of 16b with a variety of commercially available
substituted arylboronic acids in the presence of Pd(PPh3)4
and Cs2CO3 in aqueous THF at reflux temperature gave
excellent yields of the corresponding 6-aryl adducts 17-22.
This is a useful and practical alternative to the tandem
Friedel-Crafts azonia-Prins-type carbocyclization described
above (Scheme 4),24 since the latter is limited by the freezing
temperature of the solvent and can give o/p-mixtures.
Catalytic hydrogenation of 21 gave the corresponding (6S)-
phenyl analogue 23, whose absolute stereochemistry was
determined by X-ray crystallography.
The Suzuki-Miyaura25 products 17-22 are versatile 6-
aryl-functionalized appendages on the original hexahydroin-
dole 2-carboxylic acid core motif. Further exploitation of
the vinylic bromide functionality involved Heck26 and Stille27
coupling reactions (Scheme 6). Thus, treatment of 16b with
methyl acrylate in the presence of Pd(OAc)2 and P(o-tolyl)3
in refluxing toluene gave the extended diene ester 24. Reac-
Acknowledgment. We thank NSERC for financial as-
sistance. We thank Michel Simard for the X-ray analysis of
23. M.T. is grateful for NSERC and FQRNT fellowships.
Supporting Information Available: Typical experimen-
tal procedures of key reactions and NMR, X-ray, and other
data. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL040053B
(24) For recent examples of intramolecular Friedel-Crafts arylation of
N-acyliminium ions, see: (a) Hanessian, S.; Papeo, G.; Angiolini, M.; Fettis,
K.; Beretta, M.; Munro, A. J. Org. Chem. 2003, 68, 7204. (b) Luker, J.;
Koot, W.-J.; Hiemstra, H.; Speckamp, W. N. J. Org. Chem. 1998, 63, 220.
(c) Allin, S. M.; Northfield, C. J.; Page, M. I.; Slawin, A. M. Z. Tetrahedron
Lett. 1998, 39, 4905. (d) Lee, Y. S.; Kang, D. W.; Lee, S. J.; Park, H. J.
Org. Chem. 1995, 60, 7149. (e) Marson, C. M.; Pink, J. H.; Smith, C.
Tetrahedron Lett. 1995, 36, 8107. (f) Robl, J. A.; Cimarusti, M. P.; Simpkins,
L. M.; Weller, H. N.; Pan, Y. Y.; Malley, M.; DiMarco, J. D. J. Am. Chem.
Soc. 1994, 116, 2348. (g) Bailey, P. D.; Morgan, K. M.; Smith, D. I.;
Vernon, J. M. Tetrahedron Lett. 1994, 35, 7115. (h) Koot, W.-J.; Hiemstra,
H.; Speckamp, W. N. Tetrahedron Lett. 1992, 33, 7969. (i) Kano, S.; Yuasa,
Y.; Shibuya, S. Heterocycles 1985, 23, 365. (j) Maryanoff, B. E.; Molinari,
A. J.; McComsey, D. F.; Maryanoff, C. A.; Wooden, G. P.; Olofson, R. A.
J. Org. Chem. 1983, 48, 5074. See also ref 18a.
(22) Dewar, M. J. S.; Reynolds, C. H. J. Am. Chem. Soc. 1984, 106,
1744.
(23) For examples of vinyl cation arylations, see: (a) Stang, P. J.;
Anderson, A. G. J. Am. Chem. Soc. 1978, 100, 1520. (b) Roberts, R. M.;
Abdel-Baset, M. B. J. Org. Chem. 1976, 41, 1698.
(25) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
(26) (a) Heck, R. F. Org. React. 1982, 27, 345. (b) Crisp, G. T. Chem.
Soc. ReV. 1998, 27, 427.
(27) Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997, 50, 1.
4686
Org. Lett., Vol. 6, No. 25, 2004