Mechanistic insights into the stereocontrolled synthesis of hexahydropyrrolo[2,3-b]indoles by electrophilic activation of tryptophan derivatives

Article abstract of DOI:10.1021/ol702732j

A three-step mechanism involving the formation and rearrangement of an intermediate with indoline-azetidine spirocyclic core structure was shown by DFT computations to account for the electrophilic cyclization of tryptophan derivatives to hexahydropyrrolo

Full text of DOI:10.1021/ol702732j

ORGANIC
LETTERS
2008
Vol. 10, No. 1
77-80
Mechanistic Insights into the
Stereocontrolled Synthesis of
Hexahydropyrrolo[2,3-b]indoles by
Electrophilic Activation of Tryptophan
Derivatives
Carlos Silva Lo´pez, Carlos Pe´rez-Balado, Paula Rodr´ıguez-Gran˜a, and
AÄ ngel R. de Lera*
Departamento de Qu´ımica Orga´nica, UniVersidade de Vigo, Lagoas-Marcosende,
36310 Vigo, Spain
qolera@uVigo.es
Received November 12, 2007
ABSTRACT
A three-step mechanism involving the formation and rearrangement of an intermediate with indoline−azetidine spirocyclic core structure was
shown by DFT computations to account for the electrophilic cyclization of tryptophan derivatives to hexahydropyrrolo[2,3-b]indoles. The
corresponding 3a-bromo derivatives have been obtained in high yields and synthetically useful exo/endo ratios.
The hexahydropyrrolo[2,3-b]indole1 skeleton is found em-
bedded in a number of biologically active alkaloids, such as
ardeemins,2 okaramines,3 sporidesmins,4 brevianamides,5
gypsetins,6 roquefortines,7 and leptosins8 (Figure 1). The
construction of this structural motif has been classically
carried out by treatment of N-protected tryptophan esters with
electrophilic reagents. Presumably, activation of the indole
C2-C3 bond by the electrophile followed by nucleophilic
attack of the tryptophan amine group results in the formation
of the hexahydropyrrolo[2,3-b]indole core, usually as a
mixture of diastereoisomers. Hino and co-workers observed
that NR-methoxycarbonyl L-tryptophan methyl ester under-
goes cyclization in strong acidic media to give a mixture of
(1) Crich, D.; Banerjee, A. Acc. Chem. Res. 2007, 40, 151.
(2) Hochlowski, J. E.; Mullaly, M. M.; Spanton, S. G.; Whittern, D. N.;
Hill, P.; McAlpine, J. B. J. Antibiot. 1993, 46, 380.
(3) (a) Furutsuka, K.; Hayashi, H.; Shiono, Y. J. Nat. Prod. 1992, 62,
315. (b) Roe, J. M.; Webster, A. B.; Ganesan, A. Org. Lett. 2003, 5, 2825.
(4) Francis, E.; Rahman, R.; Safe, S.; Taylor, A. J. Chem. Soc., Perkin
Trans. 1 1972, 470.
(5) Birch, A. J.; Wright, J. J. J. Chem. Soc., Chem. Commun. 1969, 644.
(6) Schkeryantz, J.; Woo, J.; Siliphaivanh, P.; Depew, K.; Danishefsky,
S. J. Am. Chem. Soc. 1999, 121, 11964.
(7) (a) Ohmomo, S.; Utagawa, S.; Abe, M. Agric. Biol. Chem 1977, 41,
2097. (b) Scott, P. M.; Kennedy, B. P. C. J. Agric. Food Chem. 1976, 24,
868.
(8) Takahashi, C.; Numata, A.; Matsumura, E.; Minoura, K.; Eto, H.;
Shingu, T.; Ito, T.; Hasegawa, T. J. Antibiot. 1994, 47, 1242.
Figure 1. Relevant biologically active alkaloids containing a
hexahydropyrrolo[2,3-b]indole motif.
10.1021/ol702732j CCC: $40.75
© 2008 American Chemical Society
Published on Web 12/11/2007

hexahydropyrroloindoles, which can be trapped by acylation
at the indole nitrogen.9 Dimethyl dioxirane (DMDO) has
been utilized for the preparation of 3a-hydroxypyrroloindoles
with good stereoselectivities.10 More interestingly, N-phe-
nylselenophthalimide (N-PSP)11 effects selenocyclization to
give 3a-(phenylselenyl)hexahydropyrrolo[2,3-b]indoles in
high yields and diastereoselectivities. These seleno interme-
diates have been successfully exploited in the total syntheses
of okaramine C12 1 and 5-N-acetylardeemin13 2 (Figure 1).
First described by Danishefsky and co-workers in 1994,14
the reaction of tryptophan methyl esters with N-PSP has been
studied by Crich, who showed the dependence of the reaction
outcome with the protecting groups used.15 The selenocy-
clization reaction affords a mixture of diastereomeric hexahy-
dropyrrolo[2,3-b]indoles, corresponding to the exo-4 and
endo-5 C2 acyl systems.16 As shown in Table 1, an important
nucleus.17 Table 1 summarizes the reaction conditions and
exo/endo ratios reported.
Danishefsky and co-workers have proposed that the
diastereoselectivity obtained in this process could stem from
two equilibrating pre-endo and pre-exo arrangements of the
side chain in the intermediate selenonium ions,13 with the
former undergoing greater destabilization by steric contacts.
Being involved in a project directed toward the synthesis of
natural products containing the hexahydropyrrolo[2,3-b]-
indole core, we decided to carry out a computational study
on this mechanistic hypothesis in order to better understand
the sources of selectivity, optimize the reaction conditions,
and determine the reaction scope with regard to other
electrophilic species. The model system depicted as R in
Scheme 1 was selected as surrogate of the protected
tryptophan 3 reacting with the simplified electrophile MeSe+.
Scheme 1. Computed Reaction Profile for the
Selenocyclization Reaction of R, a Model System of 3
Table 1. Selenocyclization of Tryptophan Derivatives
yield
(%)
exo/endo
ratio
entry
R1
R2
Boc
conditionsa
1
2
3
4
5
6
t-Bu
Me
Me
Me
t-Bu
Bn
A
A
A
A
B
B
65
76
83
40
93
93
9:115
12:115
Cbz
CO2Me
SO2Ph
Boc
11:115
>98:215
18:213
Boc
>98:212
a Conditions: A: 1.5 equiv of N-PSP, 0.1 equiv of PTSA; B: 1.5 equiv
of N-PSP, 1.0 equiv of PPTS.
bias exists in favor of the exo product, which is considered
kinetically favored. Under basic equilibrating conditions, the
exo products undergo epimerization at the C2 position to
give the thermodynamic endo products.1 This striking
thermodynamic bias for the endo isomer has been attributed
to torsional interactions around the bicyclo[3.3.0]octane
(9) Taniguchi, M.; Hino, T. Tetrahedron 1981, 37, 1487.
(10) (a) Kameneka, T. M.; Danishefsky, S. J. Angew. Chem., Int. Ed.
1998, 37, 2995. (b) Kameneka, T. M.; Danishefsky, S. J. Chem.sEur. J.
2001, 7, 41. (c) May, J.; Fournier, P.; Pellicelli, J.; Patrick, B.; Perrin, D.
J. Org. Chem. 2005, 70, 8424. (d) May, J.; Patrick, B.; Perrin, D. Synlett
2006, 3403.
(11) Nicolaou, K. C.; Claremon, D. A.; Barnette, W. E.; Seitz, S. P. J.
Am. Chem. Soc. 1979, 101, 3704.
(12) (a) Hewitt, P. R.; Cleator, E.; Ley, S. V. Org. Biomol. Chem. 2004,
2, 2417. (b) Ley, S. V.; Cleator, E.; Hewitt, P. R. Org. Biomol. Chem.
2003, 1, 3492.
(13) Depew, M. K.; Marsden, S. P.; Zatorska, D.; Zatorski, A.; Bornmann,
W. G.; Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121, 11953.
(14) Marsden, S. P.; Depew, K. M.; Danishefsky, S. J. J. Am. Chem.
Soc. 1994, 116, 11143.
(15) Crich, D.; Huang, X. J. Org. Chem. 1999, 64, 7218.
(16) The exo/endo ratio is readily established by 1H NMR due to the
characteristic methyl ester resonance of both diastereoisomers. The endo
isomer shows a remarkably upfield signal at δ ∼3.1 ppm, whereas the exo
isomer shows a more common resonance at δ ∼3.7 ppm.
Density functional theory18 was employed throughout this
study. Geometry optimizations and frequency calculations
were performed with the B3LYP functional.19 The LANLDZ
ECP20 and its associated basis functions were used for Se
and Br, whereas the 6-31G(d) basis set was assigned to the
remaining atoms. Solvent effects were included through the
PCM21 model with CH2Cl2 parameters. All of these calcula-
(17) (a) Chan, C. O.; Cooksey, C. J.; Crich, D. J. Chem. Soc., Perkin
Trans. 1 1992, 777. (b) Crich, D.; Brunko, M.; Natarajan, S.; Teo, B. K.;
Tocher, D. A. Tetrahedron 1995, 51, 2215.
(18) Hohenberg, P.; Kohn, W. Phys. ReV. A 1964, 136, B864.
(19) Stephens, P. J.; Devlin, F. J.; Chabalowski, C. F.; Frisch, M. J. J.
Phys. Chem. 1994, 98, 11623.
(20) Wadt, W. R.; Hay, P. J. J. Chem. Phys. 1985, 82, 284.
78
Org. Lett., Vol. 10, No. 1, 2008

tions were performed with the Gaussian03 package.22 Long-
range dispersion interactions were also included through an
energy refinement step with the double hybrid B2PLYP
functional23 in conjunction with a basis set of triple-ú quality
with polarization functions (TZVP)24 for all of the atoms.25
The latter single-point energy refinement was performed with
the Orca package.26
does take place, but the reaction mechanism detours con-
siderably from the direct attack of the carbamate nitrogen
to C2 (see Scheme 1). The electrophilic selenium activates
the indole ring in a first step that occurs with neither facial
nor positional selectivity, in clear contrast with the textbook
hypothesis summoned initially (vide supra). For the very
unsymmetrical indole C2-C3 bond, the activation occurs
by MeSe+ attacking either the C2 or the C3 positions, with
formation of a benzyl carbenium ion or an iminium ion,
respectively (see A1-A2 and B1-B2 species in Scheme 1).
These four species are dynamically exchanging in fast
equilibrium processes. Actually, it is remarkable that only
the benzyl carbenium ions are active regarding the seleno-
cyclization reaction, whereas A2 and B2 are unproductive
species. Since the carbamate nitrogen captures the benzyl
carbenium ions, the attack occurs on C3 instead of C2, thus
forming a spirocyclic intermediate (Int-1A and Int-1B).
Subsequently, a concerted double rearrangement of the N
and the Se atoms with ring expansion of the azetidine to the
final fused pyrrol unit was located.27
In keeping with the textbook explanation, the first step in
this mechanism is seemingly the activation of the C2-C3
bond of R by the electrophilic species, with formation of a
charged three-membered ring that is subsequently opened
by the nucleophile. For the case at hand, the activation step
is likely not diastereoselective since the steric cluttering upon
selenonium ion formation is similar on both faces of the
indole side chain due to its considerable flexibility. The good
diastereomeric ratios (dr) of the selenocyclization reactions
(Table 1) argue against the activation step being rate-limiting
since low dr should be expected in that case. The mechanistic
proposal by Danishefsky involves the attack of the carbamate
N lone pair to the C2 position of the electrophile-activated
intermediate. All attempts to locate this transition structure
and its associated cyclic intermediate were unsuccessful.
These calculations, in turn, suggest that the carbamate lone
pair is very compromised in its conjugation with the carbonyl
group and lacks the nucleophilicity required for an effective
attack. Since these cyclization reactions are performed under
acid catalysis (pTSA or PPTS), we instead considered likely
the involvement of the carbamate keto-enol equilibrium,
thus leaving the N lone pair in the enol form isolated from
the carbonyl group and enhancing its nucleophilic character.
In fact, when this tautomer is proposed as the reactive species
of the tryptophan model system R, the nucleophilic attack
The formation of the azetidine is the rate-limiting step with
an activation barrier of ca. 23 kcal/mol (see Table 2). There
Table 2. Relative Free Energies in Solution (CH2Cl2) for the
Seleno- and Bromocyclization Mechanismsa
selenocyclization
bromocyclization
exo
A1
A2
TS-1A
Int-1A
TS-2A
P-1A
0.00
1.61
23.14
11.56
19.01
-5.83
0.00
-2.30
15.69
-0.41
18.29
-15.11
(21) (a) Tomasi, J.; Persico, M. Chem. ReV. 1994, 94, 2027. (b) Mineva,
T.; Russo, N.; Sicilia, E. J. Comput. Chem. 1998, 19, 290.
endo
B1
B2
TS-1B
Int-1B
TS-2B
P-1B
-3.81
-4.12
24.16
11.86
20.33
-6.37
-10.13
-3.10
16.17
0.22
19.76
-15.74
(22) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K.
N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li,
X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich,
S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A.
D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A.
G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham,
M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian
03, revision C.02; Gaussian, Inc.: Wallingford, CT, 2004.
(23) Grimme and co-workers have demonstrated that intramolecular long-
range dispersion is very important to obtain an accurate electronic description
of molecules in general and oligopeptides in particular (Schwabe, T.;
Grimme, S. Phys. Chem. Chem. Phys. 2007, 9, 3397). They introduced
long-range dispersion by perturbative methods (Grimme, S. J. Chem. Phys.
2006, 124, 034108) and developed a semiempirical scheme to further
improve the latter functionals (Grimme, S. J. Comput. Chem. 2004, 25,
1463). In particular, the double hybrid B2PLYP functional with dispersion
corrections included semiempirically has proved to yield errors considerably
smaller than those of the venerable B3LYP for the G3 set.
a Relative free energies in kcal/mol.
is about 1 kcal/mol difference in activation energy favoring
TS-1A over TS-1B, which we surmise is the source of the
final exo/endo selectivity. Danishefsky’s finding that the exo
adduct is the kinetic product in the rearrangement of 3 (Table
1) is in good agreement with our calculations.
After thorough inspection of these two transition structures,
we concluded that there are no obvious structural features
responsible for the difference in activation energies. Both
transition structures exhibit similar geometries (bond lengths,
angles, and dihedrals); in fact, the energy difference between
both transition structures is only ∼0.5 kcal/mol in the gas
phase, which means that half of the energy difference
(24) Schaefer, A.; Horn, H.; Ahlrichs, R. J. Chem. Phys. 1992, 97, 2571.
(25) To make the perturbative part more affordable given the large basis
functions employed, the resolution of the identity (RI) was used as
implemented in the Orca program: (a) Weigend, F.; Ha¨ser, M. Theor. Chem.
Acc. 1997, 97, 331. (b) Weigend, F.; Ko¨hn, A.; Ha¨ttig, C. J. Chem. Phys.
2002, 116, 3175.
(27) Similar ring expansions on indole motifs can be found in recent
literature: (a) Li, C.; Chan, C.; Heimann, A. C.; Danishefsky, S. J. Angew.
Chem., Int. Ed. 2007, 46, 1444. (b) Baran, P. S.; Shenvi, R. A. J. Am.
Chem. Soc. 2006, 128, 14028.
(26) See http://www.thch.uni-bonn.de/tc/orca/.
Org. Lett., Vol. 10, No. 1, 2008
79

between TS-1A and TS-1B corresponds to solvation effects.
The rearrangement to the final products preserves the chiral
information created in the cyclization reaction. The spiranic
intermediate formed must have a kinetically insignificant
lifetime since it is only 7-8 kcal/mol lower in energy than
the subsequent transition structures (Table 2). Ring expansion
is probably the driving force for the double concerted
rearrangement and the source of such a low-energy barrier.
The cyclization reaction of tryptophan derivatives has been
typically performed with selenium electrophiles such as
N-PSP, but the latter mechanistic proposal might also be
compatible with reaction conditions using more popular
electrophiles such as NBS. We therefore considered the
development of the bromocyclization as an alternative to the
selenocyclization since the formed 3a-bromohexahydro-
pyrrolo[2,3-b]indole motif can be also synthetically useful.28
In fact, the mechanistic path computed for the activation with
the electrophilic bromine (Table 2) closely resembles the one
depicted in Scheme 1.
Table 3. Bromocyclization of Tryptophan Derivatives
yield
(%)
exo/endo
3
R1
R2
Boc
Boc
Boc
PhSO2
PhSO2
PhSO2
ratioa
a
b
c
d
e
f
t-Bu
Bn
Me
t-Bu
Bn
Me
85
87
90
65
72
83
24:1
ND
30:1
>98:2
ND
ND
a The diastereomeric ratio is provided only when the NMR signals do
not overlap. ND: not determined.
Differences are limited to the following: (a) the rate-
limiting step is not the intermediate spirocyclic ring forma-
tion, but the concerted rearrangement with ring expansion
(see Table 2); and (b) the rate-limiting transition structures
exhibit barriers considerably lower (ca. 4-5 kcal/mol) than
those of the selenocyclization. The lower activation energy
at the rate-limiting step should allow the use of shorter
reaction times or milder thermal activation conditions. For
the experimental validation of the computational suggestion,
protected tryptophan 3 of the D series was treated with 1
equiv of NBS and 1 equiv of PPTS in CH2Cl2. The results,
listed in Table 3, confirm the feasibility of the bromocy-
clization reaction and the predominance of the exo diaste-
reomer.
ions, followed by their capture by the carbamate nitrogen
with formation of spirocyclic skeletons, and last, double
concerted rearrangement of the electrophile and the azetidine
nitrogen to give the hexahydropyrrolo[2,3-b]indole core.
Using an electrophilic halogen species, versatile 3a-bromo
derivatives are obtained efficiently in high exo/endo diaster-
eomeric ratios.
Acknowledgment. The authors are grateful to the Eu-
ropean Union (EPITRON) and the MEC-Spain (SAF2007-
63880-FEDER) for financial support. C.S. is grateful to the
Xunta de Galicia for an IPP Contract and to CESGA for
computational resources.
In summary, a mechanistic proposal for formation of the
hexahydropyrrolo[2,3-b]indole skeleton by electrophilic ac-
tivation of tryptophan derivatives is suggested based on DFT
computations. It comprises three steps: indol C2-C3 activa-
tion by the electrophile to give diastereomeric carbenium
Supporting Information Available: Experimental in-
formation and data for all new compounds. SCF energies,
Cartesian coordinates, free energies, and number of imagi-
nary frequencies for all the computed stationary points. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(28) Movassaghi, M.; Schmidt, M. A. Angew. Chem., Int. Ed. 2007, 46,
3725.
OL702732J
80
Org. Lett., Vol. 10, No. 1, 2008