A versatile cascade of intramolecular Vilsmeier-Haack and azomethine ylide 1,3-dipolar cycloaddition toward tricyclic cores of alkaloids

Article abstract of DOI:10.1021/ol802010n

(Chemical Equation Presented) In the pursuit of synthetic efficiency, we developed an innovative one-pot transformation of linear substrates into bi- and tricyclic adducts using a cascade of amide activation, nucleophilic cyclization, azomethine ylide generation, and subsequent inter- or intramolecular 1,3-dipolar cycloaddition, Despite the high density and variety of functional groups on the substrates, the sequence occurred with perfect chemoselectivity with good to excellent yields.

Full text of DOI:10.1021/ol802010n

ORGANIC
LETTERS
2008
Vol. 10, No. 21
4939-4942
A Versatile Cascade of Intramolecular
Vilsmeier-Haack and Azomethine Ylide
1,3-Dipolar Cycloaddition toward
Tricyclic Cores of Alkaloids†
Franc¸ois Le´vesque and Guillaume Be´langer*
De´partement de Chimie, UniVersite´ de Sherbrooke, 2500 bouleVard UniVersite´,
Sherbrooke, Que´bec J1K 2R1, Canada
guillaume.belanger@usherbrooke.ca
Received August 27, 2008
ABSTRACT
In the pursuit of synthetic efficiency, we developed an innovative one-pot transformation of linear substrates into bi- and tricyclic adducts using a
cascade of amide activation, nucleophilic cyclization, azomethine ylide generation, and subsequent inter- or intramolecular 1,3-dipolar cycloaddition.
Despite the high density and variety of functional groups on the substrates, the sequence occurred with perfect chemoselectivity with good to
excellent yields.
The pursuit of synthetic efficiency has been driving synthetic
chemists over the years. The rapid and controlled increase
Scheme 1. Planned Synthetic Strategy
in molecular complexity constitutes an enormous challenge
for the construction of polycyclic natural products. Reactions
in cascade certainly offer a powerful means to reach this
goal, as several bonds can be formed in a single operation.1
With this in mind, we became interested in exploring a new
cascade of reactions that combines our recently developed
Vilsmeier-Haack cyclization methodology2 with the genera-
tion of an azomethine ylide and a subsequent intramolecular
1,3-dipolar cycloaddition (Scheme 1).3
† Dedicated to Professor Pierre Deslongchamps on the occasion of his
70th birthday.
(1) (a) Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reactions in
Organic Chemistry; WILEY-VCH: Weinheim, 2006; p 672. (b) Nicolaou,
K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45,
7134.
(2) (a) Be´langer, G.; Larouche-Gauthier, R.; Me´nard, F.; Nantel, M.;
Barabe´, F. Org. Lett. 2005, 7, 4431. (b) Be´langer, G.; Larouche-Gauthier,
R.; Me´nard, F.; Nantel, M.; Barabe´, F. J. Org. Chem. 2006, 71, 704.
(3) For reviews on azomethine ylides, see: (a) Coldham, I.; Hufton, R.
Chem. ReV. 2005, 105, 2765. (b) Tsuge, O.; Kanemasa, S. AdV. Heterocycl.
Chem. 1989, 45, 231.
The versatility of our planned synthetic strategy is
noteworthy. The branches bearing the nucleophile and the
10.1021/ol802010n CCC: $40.75
Published on Web 10/09/2008
2008 American Chemical Society

dipolarophile can be attached anywhere about the amide.
Upon the proposed key transformation, the various possible
assemblies for a starting material substrate will lead to very
diverse skeletons that belong to a wide range of alkaloid
families of pharmaceutical interest.
Scheme 3. Cascade of Intramolecular
Vilsmeier-Haack-Azomethine Ylide Generation-1,3-Dipolar
Cycloaddition
We already demonstrated that iminium ions (cf. 2),
generated from intramolecular Vilsmeier-Haack reactions,
are stable and could sometimes be isolated.2 Addition of a
suitable tethered dipolarophile should trap the ylide 3, itself
formed through a deprotonation of 2, and generate the second
and third cycles of the desired cascade product 4. Such
structures are found in numerous steroidal alkaloids, such
as leptinidine,4 daphnane alkaloids, and others. The greatest
challenge in the development of this reaction sequence is
certainly the numerous chemoselectivity issues associated
with each step of the desired cascade since the reactivity
and the order of reaction of the four required functional
groups must be perfectly controlled.
In order to prove the viability of our planned synthetic
strategy, we prepared and then tested a first model compound
bearing a methyl enol ether as the nucleophile for the
Vilsmeier-Haack cyclization and a tethered dipolarophile
for the final 1,3-dipolar cycloaddition. Preparation of precur-
sor 9 started with iodination of known alcohol 55 (Scheme
2). Iodide 6 then served in the alkylation of formamide to
crystal X-ray analysis (Figure 1) and is the result of an endo
transition state for the cycloaddition of the ylide 10 in an S
conformation; endo/exo transition state preferences and ylide
conformation are discussed in detailed below.
Scheme 2. Synthesis of Cascade Precursor 9
Figure 1. ORTEP representation of the single-crystal X-ray
structure of 11.
With this especially encouraging result, we established the
feasibility of the rapid increase in molecular complexity in
one operation using our synthetic strategy. For the following
identification of the scope and limitations of the strategy,
we opted for the study of easily accessible model compounds
in a Vilsmeier-Haack cyclization-intermolecular cycload-
dition sequence.
Preparation of precursors 14b-d is detailed in Scheme
4.9 Acetamide was alkylated with iodide 6 to give
compound 13. Alkylation of the anion of either the
formamide 7 or the acetamide 13 with ethyl bromoacetate
furnished the precursors 14b and 14d, respectively. A
methyl Grignard addition to 14b at low temperature
produced the methylketone 14c.
generate 7. The latter was alkylated again, this time with
known bromoester 8.6
The possibility of generating three cycles in a single
sequence was then examined. When the highly function-
alized model substrate 9 was treated with triflic anhydride
in the presence of 2,6-di-tert-butyl-4-methylpyridine (DT-
BMP), the resulting triflyliminium ion reacted exclusively
with the electron-rich alkene in a Vilsmeier-Haack-type
cyclization (Scheme 3). Upon deprotonation, the azome-
thine ylide 10 was generated and then reacted with the
remaining electron-poor alkene in a highly diastereose-
lective intramolecular 1,3-dipolar cycloaddition.
The success of the reaction hinged on ylide generation at a
temperature that could then promote the dipolar cycloaddition.
Lower temperatures resulted in complete decomposition of the
reactive ylide.7 The whole cascade of reactions occurred with
perfect chemoselectivity. An 8:1 mixture of 11/12 was obtained
in 77% overall yield, which is excellent for this one-pot
tricyclization from linear 9.8 The relative stereochemistry of
all four adjacent stereocenters in 11 was confirmed by single-
Since the first part of the cascade, the Vilsmeier-Haack
type cyclization, has already been successfully developed,2
we concentrated our efforts on the azomethine ylide genera-
tion and the subsequent 1,3-dipolar cycloaddition. Therefore,
a series of bases was screened for the azomethine ylide
generation (tested with substrate 14b). Although many bases
were either unreactive10a or caused the decomposition of the
substrate,10b we found that DIPEA had the best balance of
4940
Org. Lett., Vol. 10, No. 21, 2008

of the acetamide (14d, entry 4), no cycloadduct was
observed, even though the iminium ion intermediate was
completely formed.14 We suspect that deprotonation leading
to the resulting enamine was preferred to the generation of
the ylide.15 This competing deprotonation pathway was
circumvented by replacing the methyl with a phenyl (14e,
entry 5). We were pleased to see that generation of a
quaternary center was thus possible at this position (16e/
17e, 63% combined yield), even though a higher cycload-
dition temperature was required.
Scheme 4. Synthesis of Cascade Precursor 14b-d
The relative stereochemistry of all cycloadducts was
examined. The relationship between C2 and C5 in the
cycloadducts 15 and 16 could be rationalized on the basis
of the geometry of the ylide (Scheme 5).
When the substituent R3 on the amide was an hydrogen
(entries 1-3), electrostatic stabilization in the S conformation
prevails,16 leading preferentially to 15a-c. Closely related
examples showed that such substrates give endo and exo
adducts resulting from a common S-ylide intermediate.17
However, 14a-c furnished only endo adducts 15a-c and
16a-c, regardless of the ylide geometry. In the case where
the amide substituent R3 was a phenyl (entry 5), steric
hindrance destabilized the S conformation, and the cycload-
ducts 16e and 17e obtained both stem from a W-ylide, via
endo and exo cycloaddition transtition states, respectively.
Structures of 16e and 17e were proven by single crystal
X-Ray diffraction.
high basicity and low nucleophilicity.10c We also rapidly
concluded that the azomethine ylide was unstable and needed
to react immediately with a dipolarophile upon its genera-
tion.11 To this end, N-phenylmaleimide was chosen as a
prototypic highly reactive dipolarophile.
In order to study the scope of the reaction cascade, the
optimized conditions were used with model compounds
14a-e (Table 1). Both the silyl (14a) and methyl (14b) enol
ethers led to the desired cycloadducts (entries 1 and 2,
respectively), although 14b gave a much better yield (92%),
presumably because of the lower acid12 sensitivity of the
methyl enol ether. Delightfully, excellent yields (82-92%)
were obtained with either the ester (14b, entry 2) or the
ketone (14c, entry 3).2,13
Note that in all of the cycloadducts, the enol ether had a
trans geometry, as a result of the initial Vilsmeier-Haack
reaction. For instance, after amide 18 is activated, the
nucleophilic addition of the tethered enol ether gerenates a
Finally, in order to verify the capacity of the reaction
cascade to withstand steric hindrance, we replaced the
formamide (14b, entry 2) with bulkier groups. In the case
Table 1. Scope of the Key Reaction Cascadea
a Reagent and conditions: (i) DTBMP, Tf2O, CH2Cl2, 0 °C, 5 min; (ii) N-phenylmaleimide; (iii) DIPEA, 15 min. (b) Ratio determined by NMR analysis
of crude material. (c) Combined yield of diastereoisomers. (d) Step (iii) conducted in refluxing toluene.
Org. Lett., Vol. 10, No. 21, 2008
4941

Scheme 5
.
Geometry of the Azomethine Ylide and endo/exo
Scheme 6. Geometry of Enol Ether in Cycloadducts
Transition States
approach to polycyclic alkaloid cores. The generation of
bicyclic and tricyclic adducts occurred in a single operation
from an acyclic substrate with perfect chemoselectivity.
Diastereoselectivity of the process is fully rationalized.
Applications of our strategy to the total synthesis of alkaloids
are now in progress.
Acknowledgment. This research was supported by the
Natural Science and Engineering Research Council (NSERC)
of Canada, FQRNT (Que´bec), the Canadian Fund for
Innovation (CFI), and the Universite´ de Sherbrooke. The
Universite´ de Sherbrooke is acknowledged for Ph. D.
fellowship to F.L.
carboxonium ion 19 (Scheme 6). The latter gets deprotonated
to give the less sterically congested trans enol ether 20,
leading to unsaturated iminium ion 21 upon triflate expulsion.
In conclusion, we demonstrated that a new synthetic
strategy that exploits our recently developed Vilsmeier-Haack
cyclization coupled to the generation and cycloaddition of
its azomethine ylide is a powerful, rapid, and efficient
Supporting Information Available: Experimental details
and spectra for all new compounds, including CIF files. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL802010N
(10) (a) DTBMP, DABCO, Cs2CO3. (b) KHMDS, LTMP, and NaH.
(c) Nucleophilic bases (such as DBU) initiated undesired anionic polym-
erization of N-phenylmaleimide presumably via Michael addition of the
base onto N-phenylmaleimide.
(11) Any attempts to form the azomethine ylide prior to the addition of
the dipolarophile led to low yield of cycloadduct.
(4) Coelho, R. M.; De Souza, M. C.; Sarragiotto, M. H. Phytochemistry
1998, 49, 893.
(5) Methyl enol ether 5 is obtained from a Wittig olefination of
γ-butyrolactol. See: Wasserman, H. H.; Cook, J. D.; Vu, C. B. J. Org. Chem.
1990, 55, 1701.
(6) Jones, R. C. F.; Howard, K. J.; Nichols, J. R.; Snaith, J. S. J. Chem.
Soc., Perkin Trans. 1 1998, 13, 2061.
(12) Compounds 15a/16a decomposed slowly upon purification on silica
gel.
(7) The electron withdrawing group (CO2Et) on the dipolarophile was
found to be necessary for the success of the cycloaddition. The unsubstituted
terminal alkene proved to not be reactive enough, in accordance with the
major HOMOazomethine ylide-LUMOdipolarophile interaction in such 1,3-dipolar
cycloadditions. See: Houk, K. N.; Sims, J.; Watts, C. R.; Luskus, L. J. J. Am.
Chem. Soc. 1968, 90, 543.
(13) For another example of chemoselective amide activation in the
presence of a ketone, see: Barbe, G.; Charette, A. B. J. Am. Chem. Soc.
2008, 130, 18.
1
(14) Confirmed by H NMR spectroscopy (see Supporting Informa-
tion).
(15) Even though the resulting enamine was not observed, its formation
has been proven in several occasions. For example, see: Smith, R.;
Livinghouse, T. Tetrahedron 1985, 41, 3559.
(16) Tsuge, O.; Kanemasa, S.; Takenaka, S. Chem. Lett. 1985, 355.
(17) To´th, G.; Frank, J.; Bende, Z.; Weber, L.; Simon, K. J. Chem. Soc.,
Perkin Trans. 1 1985, 1961.
(8) The increased thermal stability of methyl enol ether over silyl enol
ether was dramatic: for substrate 9, when the methyl group is substituted
for a TBDMS, only 29% overall yield of tricyclic adduct was obtained.
(9) Preparation of models 14a and 14e is described in Supporting
Information.
4942
Org. Lett., Vol. 10, No. 21, 2008