Highly enantioselective synthesis of tetrahydro-β-carbolines and tetrahydro-γ-carbolines via Pd-catalyzed intramolecular allylic alkylation

Article abstract of DOI:10.1021/ja054109o

A novel Pd-catalyzed intramolecular allylic alkylation of indoles allows THBCs and THGCs to be effectively synthesized in high yields and excellent enantiomeric excesses (ee up to 97%). Copyright

Full text of DOI:10.1021/ja054109o

Published on Web 01/20/2006
Highly Enantioselective Synthesis of Tetrahydro-â-Carbolines and
Tetrahydro-γ-Carbolines Via Pd-Catalyzed Intramolecular Allylic Alkylation
Marco Bandini,* Alfonso Melloni,† Fabio Piccinelli, Riccardo Sinisi, Simona Tommasi, and
Achille Umani-Ronchi*
Dipartimento di Chimica “G. Ciamician”, Alma Mater Studiorum,
UniVersita` di Bologna, Via Selmi 2, 40126 Bologna, Italy
Received June 22, 2005; E-mail: marco.bandini@unibo.it; achille.umanironchi@unibo.it
The astonishing growth of worldwide sales of stereochemically
defined pharmacological compounds calls for continuous research
addressed toward the development of novel and always more
effective asymmetric synthetic strategies.1,2
1,2,3,4-Tetrahydro-â-carbolines (THBCs) represent a deeply
investigated family of indole-containing alkaloids that possess a
wide diversity of important medicinal activities.3 The condensation
of tryptophan or tryptamine derivatives with carbonyls, under acidic
conditions (Pictet-Spengler, PS reaction),4 still represents the
primary route to the preparation of this prominent class of biologi-
cally active compounds. Herein, after the pioneering paper published
Figure 1.
almost one century ago, several milder diastereoselective versions
have been reported;5a,b however, only one example of catalytic
Table 1. Optimization of the Reaction Conditions for the
enantioselective PS condensation has been described to date.6
Despite the wide scope of the PS condensation, it turns out to
be less straightforward when 4-substituted THBC systems are
targeted.7 In these cases, in fact, time-demanding procedures for
the synthesis of appropriate â-substituted tryptamine precursors are
needed, and even more challenging synthetic approaches must be
contemplated to achieve enantiomerically pure molecules.
As a part of our research interest addressed toward the investiga-
tion of new catalytic chemo-, regio-, and stereocontrolled Friedel-
Crafts-type (FC) alkylation of indoles,8 we recently reported on
the use of Pd-catalyzed intramolecular allylic alkylation as an
alternative procedure to the conventional FC strategies.9 The
optimized catalytic conditions allowed inter- as well as intramo-
lecular allylic alkylation of variously functionalized indoles to be
performed with high yield and in highly regioselective manner,
simply by properly choosing reaction media and base additive.
Notably, the intramolecular variant (C3-alkylation), starting from
the readily synthesizable indolyl carbonate 1a, furnished regiose-
lectively polycyclic fused indoles, such as 4-vinyl-THBC, 2a, in
high yield (Scheme 1).
Intramolecular AAA of 1aa
2a
2a
d
entry
L*
1
yield (%)b
ee (%)c
2a/2a′
1
2
3
4
5
6
7
8
9
10
(R)-3a
(S)-3b
1a
1a
1a
1a
1a
1b
1a
1a
1a
1a
43
73f
90
88
88
90
88
>95
>98
95
46 (S)e
21 (R)
82 (R)g
74 (S)
92 (R)
90 (R)
72 (R)
30 (S)e
20 (S)e
66 (R)h
>50:1
>50:1
19:1
>50:1
>50:1
>50:1
>50:1
>50:1
>50:1
12:1
(R,R)-3c
(S)-3d
(S,S)-3e
(S,S)-3e
(R,R)-3f
(S)-3g
(R,S)-3h
(R)-3i
a All the reactions were carried out in anhydrous CH2Cl2 at room
temperature, by using 5 mol % of [Pd2(dba)3]‚CHCl3, 11 mol % of L*, and
2 equiv of Li2CO3. Reaction time was 16 h. b Isolated yields after flash
chromatography. c Determined by chiral HPLC analysis. The absolute
configuration was determined by X-ray analysis (see Supporting Informa-
tion). d Determined by HPLC. e Under reflux, 16 h. f Reaction time 7 days.
g Enantiomeric excess of 2a′ ) 60%. h Enantiomeric excess of 2a′ ) 61%.
the present catalytic system is described to be effective also in
promoting the synthesis of tetrahydro-γ-carbolines (THGCs, 7)11
with high stereoselectivity.
Scheme 1 a
By virtue of the readily synthetic availability, 1a was chosen as
the model substrate, and a brief survey of intramolecular AAA
conditions, by using both C1- and C2-symmetrical P/P and P/N
“privileged ligands” (3a-i), was performed (Figure 1).12
A representative collection of results is summarized in Table 1.
First, among all the chiral promoters employed, the DPPBA-based
ligands (3c-f), commonly known as Trost’s ligands, furnished the
highest level of regio- and stereoselectivity (entries 3-7, Table 1).13
In this context, we were particularly delighted to discover that
diphenyl derivative (S,S)-3e furnished the desired (R)-4-vinyl-THBC
2a in 88% isolated yield and 92% ee. Moreover, the stereochemical
reaction outcome was not affected by the nature of the leaving
group. As a matter of fact, when 2-indolyl allyl acetate 1b was
employed, 2a was isolated in comparable yield (90%) and enan-
a Reagents and conditions: (i) [PdCl(π-allyl)]2 (5 mol %), PPh3 (22 mol
%), BSA (2 equiv), Li2CO3 (2 equiv), CH2Cl2, rt.
The present paper will detail a practical and flexible alternative
to the PS methodology, based on the use of intramolecular Pd-
catalyzed asymmetric allylic alkylation (AAA, Trost reaction)10 for
the synthesis of 4-vinyl-THBCs in high optical purity. Moreover,
† Current address: Dipartimento di Chimica, Universita` di Siena.
9
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J. AM. CHEM. SOC. 2006, 128, 1424-1425
10.1021/ja054109o CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Proving the Generality of the Intramolecular AAA for the
Synthesis of 4-Vinyl-THBCs
Scheme 2. Highly Enantioselective Synthesis of 1-Vinyl-THGCs
via Intramolecular Pd-Catalyzed Allylic Alkylation of Indoles
1
2
2
intermediate derived by (Z)-6a, slightly faster than the corresponding
epimerization event.15
entry
4
R/R1/R2
yield (%)a
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
4a
4b
4b
4d
4e
4f
H/H/H
1a (33)
1c (37)
1c (37}
1d (52)
1e (41)
1f (28)
1g (19)
1h (25)
2a (88)
2c (95)
2c (60)d
2d (80)
2e (98)
2f (85)
2g (45)e
2h (49)f
92 (R)
90 (R)
94 (R)
82 (R)
97 (R)
95 (-)
90 (-)
94 (-)
In summary, we present a new versatile and practical Pd-
catalyzed reaction for the synthesis of 4-vinyl-THBCs and 1-vinyl-
THGCs, via regioselective intramolecular AAA. The excellent levels
in terms of yield and enantiomeric excess recorded suggest this
strategy as a valuable candidate for the preparation of several classes
of stereochemically defined polycyclic aromatic compounds.
OMe/H/H
OMe/H/H
Cl/H/H
Me/H/H
pyrrole/H/H
H/Me/H
4a
4a
H/H/Me
Acknowledgment. This work was supported by M.I.U.R.
(Rome), National project “Stereoselezione in Sintesi Organica:
Metodologie and Applicazioni”, FIRB Project (Progettazione,
preparazione e valutazione biologica e farmacologica di nuove
molecole organiche quali potenziali farmaci innovativi), and the
University of Bologna.
a Overall yield of five steps. b Isolated yields. c Determined by chiral
HPLC analysis. Absolute configuration assigned by analogy. d Reaction
temperature was 0 °C. e Reaction carried out under reflux. f 3c was used as
ligand.
tiomeric excess (90%, entry 6). Finally, the absolute configuration
of C4 in 2a was unambiguously determined to be R by X-ray
analysis (see the Supporting Information).
Supporting Information Available: Experimental procedures,
spectral data for all the new compounds. CIF file of the crystal data.
This material is available free of charge via the Internet at http://
pubs.acs.org.
Having identified a useful set of reaction conditions, we carried out
a study of substrate scope by performing the enantioselective cyclic-
alkylation of a series of (E)-5-substituted indolyl carbonates (1c-
h) that were obtained from the corresponding aldehydes 4b-e.
Remarkable tolerance toward steric and electronic demands of
substituents in the indole carbonate precursors was shown (Table
2). In particular, the presence of electron-donating groups (1c, 1e)
delivered (R)-4-vinyl-THBCs14 in good yields and high enantiomeric
excesses ranging from 90 to 97%. The scope of the process was
further extended to the synthesis of pyrrolyl-based polycyclic
systems, obtaining the 2f in 85% yield and 95% ee (entry 6).
Interestingly, quaternary stereocenters were also accessible through
this new approach (90% ee, entry 7), and excellent stereoinduction
was also obtained in the cyclization of substituted 1h leading to
2h in 94% ee (entry 8). Next, sequential intramolecular catalytic
AAA was also effectively applied to indolyl carbonates 6a,b, readily
prepared by analogous multistep sequence, starting from com-
mercially available 3-indole carbaldehydes 5. Notably, also in these
cases, the combined use of [Pd2dba3]‚CHCl3 and 3e in anhydrous
CH2Cl2 provided the corresponding 1-vinyl-THGCs 7 in good yield,
high regiochemistry (C3/N1 > 50:1), and excellent enantiomeric
excess (92-93%, Scheme 2). To our knowledge, this methodology
represents the first enantioselective metallo-catalyzed synthesis of
functionalized tetrahydro-â-carbolines and tetrahydro-γ-carbolines.
Interestingly, olefin geometry of the substrate 6 was found to
strongly influence the stereochemistry of the reaction course. In
fact, when (Z)-6a was reacted in the presence of (S,S)-3e, 7a of
opposite configuration was obtained (yield ) 65%), but with modest
enantiomeric excess (5%). This evidence could be rationalized by
considering the syn-anti isomerization of the π-allylpalladium
References
(1) Thayer, A. Chem. Eng. News 2005, 83, 40.
(2) (a) ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Berlin, 1999. (b) Ojima, I. Catalytic
Asymmetric Synthesis, 2nd ed.; Wiley-VCH: New York, 2000. (c) Trost,
B. M. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5348.
(3) (a) Rabindran, S. K.; He, H.; Singh, M.; Collins, E.; Annable, K. I.;
Greeberger, L. M. Cancer Res. 1998, 58, 5850. (b) Introduction to
Alkaloids: A Biosynthetic Approach; Cordell, G. A., Ed.; Wiley: New
York, 1981. (c) Ulven, T.; Kostenis, E. J. Med. Chem. 2005, 48, 898.
(4) (a) Pictet, A.; Spengler, T. Ber. Dtsch. Chem. Ges. 1911, 44, 2030. (b)
Cox, E. D.; Cook, J. M. Chem. ReV. 1995, 95, 1797.
(5) (a) Gremmen, C.; Willemse, B.; Wanner, M. J.; Koomen, G.-J. Org. Lett.
2000, 2, 1955. (b) Singh, K.; Deb, P. K.; Venugopalan, P. Tetrahedron
2001, 57, 7939.
(6) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 10558.
(7) Cox, E. D.; Diaz-Harauzo, H.; Huang, Q.; Reddy, M. S.; Ma, C.; Harris,
B.; McKernan, R.; Skolnick, P.; Cook, J. M. J. Med. Chem. 1998, 41,
2537.
(8) (a) Bandini, M.; Melloni, A.; Umani-Ronchi, A. Angew. Chem., Int. Ed.
2004, 43, 550. (b) Bandini, M.; Melloni, A.; Tommasi, S.; Umani-Ronchi,
A. Synlett 2005, 1199.
(9) Bandini, M.; Melloni, A.; Umani-Ronchi, A. Org. Lett. 2004, 6, 3199.
(10) (a) Trost, B. M.; van Vraken D. L. Chem. ReV. 1996, 96, 395. (b)
Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336. (c) Trost, B.
M.; Crawley, M. L. Chem. ReV. 2003, 103, 2921.
(11) Khorana, N.; Smith, C.; Herrick-Davis, K.; Purohit, A.; Teitler, M.; Grella,
B.; Dukat, M.; Glennon, R. A. J. Med. Chem. 2003, 46, 3930.
(12) Yoon, T. P.; Jacobsen E. N. Science 2003, 299, 1961.
(13) Ligands 3b and 3e already proved effectiveness in the stereocontrolled
N-alkylation of indoles with cyclopentenyl carbonate: Trost, B. M.;
Krische, M. J.; Berl, V.; Grenzer, E. M. Org. Lett. 2002, 4, 2005.
(14) The absolute configuration for THBCs 2c-e was assigned by analogy to
2a.
(15) Trost, B. M.; Shen, H. C.; Dong, L.; Surivet, J.-P.; Sylvain, C. J. Am.
Chem. Soc. 2004, 126, 11966.
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