Bronsted acid-catalyzed highly stereoselective arene-ynamide cyclizations. A novel keteniminium Pictet-Spengler cyclization in total syntheses of (±)-desbromoarborescidines A and C

Article abstract of DOI:10.1021/ol0473391

(Chemical Equation Presented) A Bronsted acid-catalyzed highly stereoselective arene-ynamide cyclization is described. These reactions constitute a keteniminium variant of Pictet-Spengler cyclizations, leading to efficient synthesis of nitrogen heterocycl

Full text of DOI:10.1021/ol0473391

ORGANIC
LETTERS
2005
Vol. 7, No. 6
1047-1050
Brønsted Acid-Catalyzed Highly
Stereoselective Arene-Ynamide
Cyclizations. A Novel Keteniminium
Pictet
Syntheses of
)-Desbromoarborescidines A and C
−Spengler Cyclization in Total
(±
Yanshi Zhang, Richard P. Hsung,* Xuejun Zhang, Jian Huang,
Brian W. Slafer, and Allison Davis
Department of Chemistry, UniVersity of Minnesota, Minneapolis, Minnesota 55455
hsung@chem.umn.edu
Received December 24, 2004
ABSTRACT
A Brønsted acid-catalyzed highly stereoselective arene-ynamide cyclization is described. These reactions constitute a keteniminium variant of
Pictet Spengler cyclizations, leading to efficient synthesis of nitrogen heterocycles and related alkaloids. Total syntheses of desbromo-
arborescidines A and C are illustrated here as first applications of this methodology.
−
Ynamides have become prevalent in organic synthesis.1-6
Given that enyne cyclizations have become a powerful
synthetic method for synthesizing complex carbo- or
heterocycles,7-10 en-ynamide cyclization using N-tethered
(3) For a recent elegant account on PtCl2-catalyzed en-ynamide cycliza-
tion, see: Marion, F.; Coulomb, J.; Courillon, C.; Fensterbank, L.; Malacria,
M. Org. Lett. 2004, 6, 1509.
(1) For reviews, see: (a) Zificsak, C. A.; Mulder, J. A.; Hsung, R. P.;
Rameshkumar, C.; Wei, L.-L. Tetrahedron 2001, 57, 7575. (b) Mulder, J.
A.; Kurtz, K. C. M.; Hsung, R. P. Synlett 2003, 1379.
(4) For our recent contributions, see: (a) Tracey, M. R.; Zhang, Y.;
Frederick, M. O.; Mulder, J. A.; Hsung, R. P. Org. Lett. 2004, 6, 2209. (b)
Shen, L.; Hsung, R. P. Tetrahedron Lett. 2003, 44, 9353. (c) Frederick, M.
O.; Hsung, R. P.; Lambeth, R. H.; Mulder, J. A. Tracey, M. R. Org. Lett.
2003, 5, 2663. (d) Mulder, J. A.; Kurtz, K. C. M.; Hsung, R. P.; Coverdale,
H. A.; Frederick, M. O.; Shen, L.; Zificsak, C. A. Org. Lett. 2003, 5, 1547.
(e) Huang, J.; Xiong, H.; Hsung, R. P.; Rameshkumar, C.; Mulder, J. A.;
Grebe, T. P. Org. Lett. 2002, 4, 2417. (f) Mulder, J. A.; Hsung, R. P.;
Frederick, M. O.; Tracey, M. R.; Zificsak, C. A. Org. Lett. 2002, 4, 1383.
(5) For copper-catalyzed amidations of alkynyl bromides, see: (a) Zhang,
Y.; Hsung R. P.; Tracey, M. R.; Kurtz, K. C. M.; Vera, E. L. Org. Lett.
2004, 6, 1151. (b) Frederick, M. O.; Mulder, J. A.; Tracey, M. R.; Hsung,
R. P.; Huang, J.; Kurtz, K. C. M.; Shen, L.; Douglas, C. J. J. Am. Chem.
Soc. 2003, 125, 2368.
(2) For recent efforts in synthesis and applications of ynamides, see: (a)
Rosillo, M.; Dom´ınguez, G.; Casarrubios, L.; Amador, U.; Pe´rez-Castells,
J. J. Org. Chem. 2004, 69, 2084. (b) Couty, S.; Lie´gault, B.; Meyer, C.;
Cossy, J. Org. Lett. 2004, 6, 2511. (c) Rodr´ıguez, D.; Castedo, L.; Saa´, C.
Synlett 2004, 783. (d) Rodr´ıguez, D.; Castedo, L.; Saa´, C. Synlett 2004,
377. (e) Hirano, S.; Tanaka, R.; Urabe, H.; Sato, F. Org. Lett. 2004, 6,
727. (f) Klein, M.; Ko¨nig, B. Tetrahedron 2004, 60, 1087. (g) Marion, F.;
Courillon, C.; Malacria, M. Org. Lett. 2003, 5, 5095. (h) Witulski, B.;
Alayrac, C.; Tevzaadze-Saeftel, L. Angew. Chem., Int. Ed. 2003, 43, 4392.
(i) Tanaka, R.; Hirano, S.; Urabe, H.; Sato, F. Org. Lett. 2003, 5, 67. (j)
Witulski, B.; Lumtscher, J.; Bergstra¨sser, U. Synlett 2003, 708. (k) Naud,
S.; Cintrat, J.-C. Synthesis 2003, 1391. (l) Witulski, B.; Alayrac, C. Angew.
Chem., Int. Ed. 2002, 41, 3281. (m) Saito, N.; Sato, Y.; Mori, M. Org.
Lett. 2002, 4, 803. (n) Timbart, J.-C.; Cintrat. J.-C. Chem. Eur. J. 2002, 8,
1637.
(6) Also see: (a) Dunetz, J. R.; Danheiser, R. L. Org. Lett. 2003, 5,
4011. (b) Reference 2e.
10.1021/ol0473391 CCC: $30.25
© 2005 American Chemical Society
Published on Web 02/10/2005

ynamides 1 should represent an attractive strategy for alkaloid
To establish the feasibility, the keteniminium Pictet-
Spengler cyclization of C-tethered arene-ynamide 12, pre-
pared from Cu(II)-catalyzed coupling of the respective
sulfonamide and alkynyl bromide,5a was examined [Scheme
2]. Surprisingly, transition metal π-acids such as PtCl2, PtCl4,
syntheses.3 As shown in Scheme 1, upon activations of en-
Scheme 1
Scheme 2
ynamides 1 using either Brønsted acids or transition metal
π-acids, various possible pathways can lead to nitrogen
heterocycles 4, 5, and 7.3
In our pursuit of en-ynamide cyclizations, we have focused
on employing arene-ynamides 8 that are tethered with aryl
groups through the nitrogen atom because of the potential
in constructing useful nitrogen heterocycles [Scheme 1]. In
this regard, the keteniminium intermediate 9 could be
generated upon activation with Brønsted acids or π-acids,
and this particular arene-ynamide cyclization pathway would
inspire a unique keteniminium Pictet-Spengler cyclization,11-13
leading to heterocycles such as 11. We report here a Brønsted
acid-catalyzed, highly stereoselective cyclization of arene-
ynamides and total syntheses of desbromoarborescidines A
and C14-17 as first applications of ynamides in natural product
synthesis.
and AgNTf2 that are useful in various enyne cyclizations3,7,8
were not successful here [entries 1-3], while Lewis acids
such as Cu(OTf)2 also failed [entry 4].
Instead, Brønsted acids10 proved to be effective in initiating
18
the cyclization of 12. Only 1 mol % HNTf2 was needed,
and dihydroamino-naphthalene 1319 was isolated in 91%
yield after stirring in CH2Cl2 at room temperature for 3 min
[entry 6]. A series of cyclized products 14-17 were obtained
in good yields from their respective C-tethered arene-
ynamides.
However, the success with C-tethered arene-ynamides did
not translate completely to N-tethered arene-ynamides. As
summarized in Table 1, N-tethered arene-ynamides 18a and
18b were only marginally successful in the keteniminium
Pictet-Spengler [entries 1-5]. In fact, only π-acids such as
PtCl2 and PtCl4 were modestly useful, providing cyclized
products 19a and 19b in 30 and 40% yields, respectively
[entries 2 and 5].
(7) For a review, see: Aubert, C.; Buisine, O.; Malacria, M. Chem. ReV.
2002, 102, 813.
(8) For other reviews, see: (a) Me´ndez, M.; Mamane, V.; Fu¨rstner, A.
ChemTracts 2003, 16, 397. (b) Lloyd-Jones, G. C. Org. Biomol. Chem.
2003, 1, 215.
(9) For recent examples of enyne cyclizations, see: (a) Fensterbank, L.;
Malacria, M.; Marco-Contelles, J. J. Am. Chem. Soc. 2004, 126, 3408. (b)
Pastine, S. J.; Youn, S. W.; Sames, D. Org. Lett. 2003, 5, 1055. (c)
Nishizawa, M.; Takao, H.; Yadav, V. K.; Imagawa, H.; Sugihara, T. Org.
Lett. 2003, 5, 4563. (d) Inoue, H.; Chatani, N.; Murai, S. J. Org. Chem.
2002, 67, 1414. (e) Fu¨rstner, A.; Mamune, V. J. Org. Chem. 2002, 67,
6264.
Since the cyclization of 18a or 18b could suffer from the
strain in the oxazolidinone ring, we used ynamides 20a and
(10) For some examples of Brønsted acid catalysis, see: (a) Williams,
A. L.; Johnston, J. N. J. Am. Chem. Soc. 2004, 126, 1612. (b) Zhang, L.;
Kozmin, S. A. J. Am. Chem. Soc. 2004, 126, 10204. (c) Cossy, J.; Lutz, F.;
Alauze, V.; Meyer, C. Synlett 2002, 45. (d) Ishihara, K.; Hiraiwa, Y.;
Yamamoto, H. Synlett 2001, 1851.
(11) (a) For an excellent review, see: Cox, E. D.; Cook, J. M. Chem.
ReV. 1995, 95, 1797. (b) For an excellent review on additions to N-acyl or
N-sulfonyl iminium ions, see: Royer, J.; Bonin, M.; Micouin, L. Chem.
ReV. 2004, 104, 2311.
(12) For some elegant examples of Pictet-Spengler cyclizations, see:
(a) Yu, J.; Wang, T.; Liu, X.; Deschamps, J.; Flippen-Anderson, J.; Liao,
X.; Cook, J. M. J. Org. Chem. 2003, 68, 7565-7581. (b) Yu, J.; Wearing,
X.; Cook, J. M. Tetrahedron Lett. 2003, 44, 543.
(13) For a recent example on catalytic asymmetric Pictet-Spengler
cyclization, see: Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004,
126, 10558.
(14) For isolation of 10-desbromoarborescidine A, see: Johns, S. R.;
Lamberton, J. A.; Occolowitz, J. L. Aust. J. Chem. 1966, 19, 1951.
(15) For total syntheses of arborescidine A, see: (a) Hua, D. H.; Bharathi,
S. N.; Panangadan, J. A. K.; Tsujimoto, A. J. Org. Chem. 1991, 56, 6998.
(b) Meyers, A. I.; Sohda, T.; Loewe, M. F. J. Org. Chem. 1986, 51, 3108.
(16) For isolation of arborescidines A-D, see: Chbani, M.; Pa¨ıs, M. J.
Nat. Prod. 1993, 56, 99.
(17) For total syntheses of arborescidine C, see: (a) Burm, B. E. A.;
Meijler, M. M.; Korver, J.; Wanner, M. J. Koomen, G.-J. Tetrahedron 1998,
54, 6135. (b) Santos, L. S.; Pilli, R. A.; Rawal, V. H. J. Org. Chem. 2004,
69, 1283.
(18) For a study on the acidity of HNTf2, see: Thomazeau, C.; Olivier-
Bourbigou, H.; Magna, L.; Luts, S.; Gilbert, B. J. Am. Chem. Soc. 2003,
125, 5264.
(19) Relevant procedures for all new compounds and their characteriza-
tions can be found in Supporting Information.
1048
Org. Lett., Vol. 7, No. 6, 2005

using PtCl4. These stereochemical outcomes can be ac-
counted for as shown in Scheme 3.
Table 1. N-Tethered Arene-Ynamide Cyclizations
Scheme 3
When using Brønsted acids, the cyclization of the keten-
iminium intermediate that favors the (Z)-enamide [left] is
devoid of the steric interaction between the R1 group and
the incoming arene [the (E)-model at center]. This selectivity
is reversed when PtCl4 was used since Pt is now more of a
hindrance than the R1 group [the (E)-model at right]. This
would be especially true if the Pt metal could help stabilize
the keteniminium carbon [see the dotted bond], thereby
blocking even further the addition pathway at the bottom
face.
a Isolated yields only. b As a mixture of rotamers and the isomer resulting
from para substitution [the ortho isomer is shown]. c Dr is ∼9:1 but
unassigned.
The distinct advantage of this keteniminium Pictet-
Spengler cyclization is the formation of a useful enamide
motif that can be subjected to various transformations.21-23
While these are among our current pursuits, we have here
hydrogenated the rather hindered trisubstituted enamide in
29a and 29b at 80 psi H2 using 20 mol % Pd(OH)2 to
complete the concept that this method represents a Pictet-
Spengler equivalent [Scheme 4].
20b [entries 6-8], but these were met with similar difficul-
ties. The only discernible product was 21b from 20b, which
contains a more electron-rich arene [entry 8]. Interestingly,
the regiochemistry of the cyclization also changed to favor
the addition of the arene to the â-carbon of the ynamide,
presumably because both R- and â-carbons can be electro-
philic when the ynamide is complexed with a transition
metal.
With an additional methylene unit as shown in 22a and
22b [entries 9-12], HNTf2 in 5 mol % [entries 11 and 12]
was again effective in promoting the cyclization to give the
corresponding products 23a and 23b in good yields. Other
related ynamides 24 and 26 also led to cyclized products 25
and 27, respectively, with the latter providing a 9:1 diaster-
eomeric ratio [entries 13 and 14].
Scheme 4
When we examined indole-tethered ynamides 28a and
28b, we found that PNBSA [p-nitrobenzenesulfonic acid]
was the best Brønsted acid in 20 mol % [entries 17 and 19],
while HNTf2 was not useful. This is presumably due to
competing protonation of the indole ring when a much
stronger Brønsted acid such as HNTf2 is used.18,20
On the other hand, protonations of N-acyl ynamides require
a stronger Brønsted acid because they are much less reactive
than N-sulfonyl ynamides given that the nitrogen lone pair
is more delocalized into the acyl carbonyl.11b Ynamide 30,
substituted with a Nosyl [Ns] group, worked equally well
when using PNBSA [entry 17 vs 20].
To illustrate the synthetic potential of this methodology,
total syntheses of desbromoarborescidines A and C were
pursued. The synthesis of 10-desbromoarborescidine A
[36],16,24 which is a natural product in itself,14 was completed,
featuring the keteniminium Pictet-Spengler cyclization of
ynamide 33 that contains a Cl group, albeit at 90 °C [Scheme
5]. To provide some alternatives for the reduction, the
(21) For a review on enamides, see: Rappoport, Z. The Chemistry of
Enamines in The Chemistry of Functional Groups; John Wiley and Sons:
New York, 1994.
(22) For recent studies involving enamides, see: (a) Fuchs, J. R.; Funk,
R. L. Organic Lett. 2001, 3, 3349. (b) Maeng, J.-H.; Funk, R. L. Org. Lett.
2000, 3, 1125.
(23) For oxdiations of enamides, see: (a) Xiong, H.; Hsung, R. P.; Shen,
L.; Hahn, J. M. Tetrahedron Lett. 2002, 43, 4449. (b) Poon, T.; Turro, N.
J.; Chapman, J.; Lakshminarasimhan, P.; Lei, X.; Jockusch, S.; Franz, R.;
Washington, I.; Adam, W.; Bosio, S. G. Org. Lett. 2003, 5, 4951.
(24) Specific carbon numbering systems were based on Pa¨ıs’s isolation
paper: see ref 16.
It is noteworthy that cyclizations of N-tethered arene-
ynamides are highly stereoselective. The (Z)-enamide forma-
tion is favored in all cases using Brønsted acids. Only for
18a and 18b was the (E)-enamide formation observed when
(20) Attempts to disfavor the alleged competition were made. However,
when the indole nitrogen atom in 28a was protected with Boc, the cyclization
still proceeded only with PNBSA.
Org. Lett., Vol. 7, No. 6, 2005
1049

Scheme 5
Scheme 6
enamide in 35 was reduced under cationic conditions using
TFA and NaCNBH3. Reductive removal of the Ts group
occurred concomitantly with N-alkylation when using Smith’s
protocol involving Na-Hg and Na2HPO4.25
The synthesis of 11-desbromoarborescidine C [42]16,24 was
more involved due to issues related to protecting groups.
This is largely due to the fact that we had trouble in the
preparation of ynamide 37 in which the nitrogen atom is
substituted as a urethane group.
Ultimately, after hydrogenation of 38, which was obtained
in 67% yield from the keteniminium Pictet-Spengler cy-
clization of 37, the Ts group was removed using Heathcock’s
sodium naphthalide protocol [Scheme 6].26 We were sur-
prised and uncertain why the benzyl ether in 38 survived
the hydrogenation step. The secondary amine intermediate
was then protected as a urethane using ClCO2Me. Subsequent
protection of the indole nitrogen with Boc anhydride gave
40 in 70% overall yield from 38.
and (4) reduction of the urethane to the corresponding
methylamine using AlH3 generated in situ from LAH and
AlCl3.28 Both desbromoarborescidines A and C are spectro-
scopically identical to those reported.15a,17a
We have reported here a Brønsted acid-catalyzed, highly
stereoselective arene-ynamide cyclization. Total syntheses
of desbromoarborescidines A and C were accomplished from
tryptamine in 5 and 11 steps, respectively, representing the
first applications of ynamides in natural product synthesis.
Future applications of this keteniminium Pictet-Spengler
cyclization are currently underway.
Acknowledgment. The authors thank NSF [CHE-
0094005] for support.
With the protecting group issue being resolved, 11-
desbromoarborescidine C [42] was obtained in four steps
from 40, featuring (1) debenzylation via hydrogenation, (2)
Swern oxidation, (3) removal of the indole Boc group
concomitant with the aminal formation27 using 8.0 N aq HCl,
Supporting Information Available: Experimental and
1H NMR spectral and characterizations for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(25) Smith, A. B., III; Kim. D.-S. Org. Lett. 2004, 6, 1493.
(26) Heathcock, C. H.; Blumenkopf, T. A.; Smith, K. M. J. Org. Chem.
1989, 54, 1548.
OL0473391
(27) A minor isomer was observed during the aminal formation and
believed to be desbromoarborescidine D, which is diastereomeric at C-17.
It was not vigorously characterized given the small quantity.
(28) Hsung, R. P.; Cole, K. P.; Zehnder, L. R.; Wang, J.; Wei, L.-L.;
Yang, X.-F.; Coverdale, H. A. Tetrahedron 2003, 59, 311.
1050
Org. Lett., Vol. 7, No. 6, 2005