Recent Advances and Applications of
Enantioselective Pictet-Spengler
Reactions
Patrick S. Fier
University of California, Department of Chemistry, Berkeley, CA 94720, United States
patrickfier@berkeley.edu
ABSTRACT
The Pictet-Spengler reaction is a powerful method for the biomimetic synthesis of tetrahydro-β-carboline natural products from
tryptamines and aldehydes. Herein is provided an overview of the recent developments in asymmetric Pictet-Spengler reactions
and their applications in total synthesis.
The Pictet-Spengler reaction (PSR) has been widelyused for the synthesis of alkaloids since its intial
discovery in 1911 (eq 1).1 The longstanding interest in the
PSR stems from the presence of tetrahydro-β-carboline
frameworks in important natrual products (such as
yohimbine and reserpine) and pharmaceuticals (Cialis®,
tadalafil) (Figure 1).2 Furthermore, tetrahydro-βcarbolines are intermediates in the biosynthesis of other
alkaloids such as strychnine, camptothecin, and quinine.
Yet, only recently have catalytic enantioselective variants
of the PSR been developed. Herein is provided an
overview of stereoslective PSRs. A summary of
diastereoselective reactions conducted with substrates
containing chiral-auxillaries is presented first, followed
by a review of enantioselective PSRs and the applications
of these reactions to total synthesis.
controlled by the chiral environment proximal to the
iminium ion. Two strategies have been followed to
control the selecitivy of the nucleophilic attack; chiral
auxillaries bound to the nitrogen of the iminium ion and
chiral couterions, which bind to the iminium ion through
electrostatic interactions.
Figure 1. Selected
containing molecules.
The addition of the indole to the iminium ion is both
the rate-determining and the stereoselecivity-determining
step of the Pictet-Spengler reaction. In stereoselective
PSRs, the facial selectivity of the cyclization step is
(1) Pictet, A.; Spengler, T. Ber. Dtsch. Chem. Ges. 1911, 44, 2030.
(2) (a) Cox, E. D.; Cook, J. M. Chem. Rev. 1995, 95, 1797; (b)
Stockigt, J.; Antonchick, A. P.; Wu, F. R.; Waldmann, H. Angew. Chem.
Int. Ed. 2011, 50, 8538.
examples
of
tetrahydro-β-carboline
Early work on the development of stereoselective PSRs
focused on reactions with substrates containing a chiral
auxillary bound to the reacting nitrogen. The first
example of this approach was reported by Waldmann and
coworkers in 1993, wherein the reactions of tryptamine
containing a valine auxillary proceeded with high
diastereoslectivity (Scheme 1).3 However, multiple steps
and harsh reaction conditions were required to remove the
valine unit. The same group later reported reactions of
tryptamine containing a chiral amide auxillary that
reacted with equally high diasteroselectivity.4 The groups
of Cook5 and Nakagawa6 showed that a phenethyl
auxillary led to modest control of diastereoselectivity in
the PSR, and the auxillary could be removed through
hydrogenolysis after the reaction. More recently, Nsulfinyl tryptamines have been employed by Koomen and
coworkers in diastereoselective PSRs.7 Although the
reactions with this auxillary formed products in modest
dr, the diatereomeric purity of the N-sulfinyl tetrahydroβ-carbolines were improved to >99:1 after a single
recrystallization,
allowing
access
to
highly
enantioenriched tetrahydro-β-carbolines after acidic
cleavage of the N-S bond (HCl, EtOH, 5 min).
Scheme 1. Chiral-auxillary controlled PSRs.
Although reactions with chiral auxillaries allow for the
synthesis of enantioenriched tetrahydro-β-carbolines,
stereoselective reactions that do not require the
installation and removal of a chiral auxillary can be of
greater synthetic value. The first stereoselective PSR
without a covalently bound chiral auxillary was disclosed
by Nakagawa and coworkers in 1996 (Scheme 2).8 It was
shown that the PSR between hydroxylamines and
aldehydes in the presence of a stoichiometric amount of a
chiral boron Lewis acid formed products in up to 90%
ee.9 Hydroxylamines condense with aldehydes to form
highly reactive nitrone electrophiles, allowing the
reactions to be run at low temperature and proceed with
good enantioselectivity. The same group later reported a
binol-derived Brønsted acid for the same transformation
(3) (a) Waldmann, H.; Schmidt, G.; Jansen, M.; Geb, J. Tet. Lett.
1993, 34, 5867; (b) Waldmann, H.; Schmidt, G.; Jansen, M.; Geb, J.
Tetrahedron 1994, 50, 11865.
(4) Waldmann, H.; Schmidt, G.; Henke, H.; Burkard, M. Angew.
Chem. Int. Ed. 1995, 34, 2402.
(5) Reddy, M. S.; Cook, J. M. Tetrahedron Lett. 1994, 35, 5413.
(6) (a) Soe, T.; Kawate, T.; Fukui, N.; Hino, T.; Nakagawa, M.
Heterocycles 1996, 42, 347; (b) Soe, T.; Kawate, T.; Fukui, N.;
Nakagawa, M. Tetrahedron Lett. 1995, 36, 1857.
(7) Gremmen, C.; Willemse, B.; Wanner, M. J.; Koomen, G. J. Org.
Lett. 2000, 2, 1955.
(8) (a) Kawate, T.; Yamada, H.; Soe, T.; Nakagawa, M. Tetrahedron:
Asymmetry 1996, 7, 1249; (b) Yamada, H.; Kawate, T.; Matsumizu, M.;
Nishida, A.; Yamaguchi, K.; Nakagawa, M. J. Org. Chem. 1998, 63,
6348.
(9) Ipc = isopinocamphenyl
(Scheme 2).10 Although these reactions allowed for the
enantioselective synthesis of tetrahydro-β-carbolines
without chiral auxillaries, the synthetic utility was limited
by the need for hydoxylamine substrates and
stoichiometric amounts of chiral reagents.
Scheme 2. PSRs with stoichiometric chiral acids.
The first catalytic asymmetric PSR was developed with
a thiourea catalyst for the cyclization of in-situ generated
N-acyliminium ions. Strongly electrophilic Nacyliminium ion intermediates were chosen to promote
the stereo-determining cyclization at low temperature
under mild conditions. It was proposed that a chiral
thiourea would promote stereoselective cyclization
through hydrogen-bonding interactions with the
acyliminium ion. With this proposal in mind, the first
catalytic enantioselective PSR was reported in 2004 by
the Jacobsen group. These reactions were catalyzed by a
thiourea flanked by amino acid and 1,2-diamine
derivatives (Scheme 3).11 The scope of the reactions that
occurred in high yield and enantioselectivity
encompassed a range of aliphatic aldehydes. Aromatic
aldehydes did not react in the presence of this catalyst.
Scheme 3. Thiourea-catalyzed enantioselective acyl-PSRs.
The acyl-PSR reaction catalyzed by Jacobsen’s
thiourea catalyst was later used by the same group as a
key step in the total synthesis of (+)-yohimbine (Scheme
4).12 The reaction between tryptamine and silyl-protected
hydroxypropanal under the previously developed
conditions formed the alkyl-substituted product in 81%
(10) Kawate, T.; Yamada, H.; Matsumizu, M.; Nishida, A.;
Nakagawa, M. Synlett 1997, 761.
(11) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126,
10558.
(12) Mergott, D. J.; Zuend, S. J.; Jacobsen, E. N. Org. Lett. 2008, 10,
745.
yield and 94% ee. This interemediate was further
elaborated in 9 steps to complete the asymmetric
synthesis of (+)-yohimbine in 14% overall yield. The
Hiemstra group later used similar thiourea-catalyzed
PSRs in the enantioselective syntheses of mitragynine,
paynantheine, speciogynine and yohimbine (Scheme 4).13
Scheme 5. Enantioselective PSRs of hydroxylactams.
Scheme 4. Asymmetric syntheses via thiourea-catalyzed PSRs.
The Jacobsen group later showed that the scope of
thiourea-catalyzed PSRs encompasses the reactions of
hydroxylactams (Scheme 5).14 The hydroxylactam
reactants were formed by reduction of the corresponding
imide with NaBH4 (R’ = H) or by addition of
organolithium reagents (R’ = alkyl, aryl). TMSCl was
added as a stoichiometric Lewis acid in the PSRs to form
acyliminium ion intermediates. When R’ in the
hydroxylactam of Scheme 5 was an alkyl or aryl group, a
fully substituted stereocenter was generated in the
reaction in up to 98% ee. This was the first example for
the enantioselective generation of a fully-subsituted
stereocenter in a PSR. The hydroxylactam PSR was used
in a short synthesis of (+)-harmicine in 62% overall yield
and 97% ee from tryptamine and succinic anhydride.
After the initial report by the Jacobsen group, List and
coworkers showed that enantioselective PSRs could be
performed with a chiral phosphoric acid catalyst (Scheme
6).15 The stereoselectivity of the reactions is influenced
by the proximity and orientation of the chiral phosphate
anion and the iminium cation after proton transfer. Initial
(13) (a) Kerschgens, I. P.; Claveau, E.; Wanner, M. J.; Ingemann, S.;
van Maarseveen, J. H.; Hiemstra, H. Chem. Commun. 2012, 48, 12243;
(b) Herle, B.; Wanner, M. J.; van Maarseveen, J. H.; Hiemstra, H. J.
Org. Chem. 2011, 76, 8907.
(14) Raheem, I. T.; Thiara, P. S.; Peterson, E. A.; Jacobsen, E. N. J.
Am. Chem. Soc. 2007, 129, 13404.
(15) Seayad, J.; Seayad, A. M.; List, B. J. Am. Chem. Soc. 2006, 128,
1086.
attempts to perform the PSR between unsubstituted
tryptamines and alkyl aldehydes led to the exclusive
formation of aldol condensation products. To prevent
side-reactions and to facilitate cyclization, tryptamines
containing geminal dicarboxylates were used. The
reactions of alkyl and aryl aldehydes catalyzed by a
binapthol-derived phosphoric acid containing bulky aryl
groups occurred to give products in 62-96% ee. These
reactions were the first examples of enantioselective
PSRs to form N-H tetrahydro-β-carbolines, but the utility
of these reactions is limited by the need for geminal
disubstitution, high catalyst loadings (20 mol %), and
long reaction times (3-6 days).
Scheme 6. Chiral phosphoric acid catalyzed PSRs.
Following the work by List and coworkers conducted
with a chiral phosphoric acid catalyst, the Hiemstra group
reported an enantioselective PSR of N-sulfenyl
tryptamines (Scheme 7) catalyzed by a similar chiral
phosphopric acid.16 Reactions catalyzed by a phosphoric
acid containing bis(trifluoromethyl)phenyl groups on the
binol backbone occurred rapidly and with high
(16) Wanner, M. J.; van der Haas, R. N. S.; de Cuba, K. R.; van
Maarseveen, J. H.; Hiemstra, H. Angew. Chem. Int. Ed. 2007, 46, 7485.
enantioselectivity. These PSRs reactions of both aliphatic
and aryl aldehydes proceeded in modest yields and
enantioselectivities. However, these reactions are limited
by the need to install and remove the sulfenyl auxillary.
Scheme 8. Enantioselective PSR-type cyclization cascades.
Scheme 7. Chiral phosphoric acid catalyzed PSRs of Nprotected tryptamines.
The same group later developed enantioselective PSRs
of N-benzyl tryptamines with chiral phosphoric acid E
(Scheme 7).17 The authors suggest that a benzyl
protecting group is useful for subsequent oxidation
reactions to prepare pyrroloquinolones. The PSRs of Nbenzyl tryptamines encompassed a broader range of
aldehydes than the reactions reported earlier with a
sulfenyl auxillary. This reaction was used as a key step in
the enantioselective synthesis of (-)-arboricine.18 A
similar PSR catalyzed by SPINOL-phosphoric acids was
later reported.19 Recently, the You group demonstrated
that phosphoric acid catalyzed PSRs can be used in
tandem with olefin metathesis and/or isomerization to
prepare tetrahydro-β-carbolines from allyl amines.20
Two enantioselective, intramolecule PSR-type cascade
reactions via intermediate acyliminium ions have been
described by Dixon and coworkers. The first report
described the reaction of tryptamine with enol lactones
and phosphoric acid catalyst E to form N-acyl products in
high yields and enantioselectivities.21 A subsequent report
described the reactions of more readily available
ketoacids in place of enol lactones with catalyst E or H8E.22 These reactions formed products containing a fullysubsituted stereocenter in up to 99% ee (Scheme 8).
These reactions are useful in that tryptamines can be used
to form the same products as the reactions of pre-formed
hydroxylactams reported by Jacobsen (Scheme 5).14
(17) Sewgobind, N. V.; Wanner, M. J.; Ingemann, S.; de Gelder, R.;
van Maarseveen, J. H.; Hiemstra, H. J. Org. Chem. 2008, 73, 6405.
(18) Wanner, M. J.; Boots, R. N. A.; Eradus, B.; de Gelder, R.; van
Maarseveen, J. H.; Hiemstra, H. Org. Lett. 2009, 11, 2579.
(19) Huang, D.; Xu, F. X.; Lin, X. F.; Wang, Y. G. Chem. Eur. J.
2012, 18, 3148.
(20) (a) Cai, Q.; Liang, X. W.; Wang, S. G.; Zhang, J. W.; Zhang, X.;
You, S. L. Org. Lett. 2012, 14, 5022; (b) Cai, Q.; Liang, X. W.; Wang,
S. G.; You, S. L. Org. Biomol. Chem. 2013, 11, 1602
(21) Muratore, M. E.; Holloway, C. A.; Pilling, A. W.; Storer, R. I.;
Trevitt, G.; Dixon, D. J. J. Am. Chem. Soc. 2009, 131, 10796.
(22) Holloway, C. A.; Muratore, M. E.; Storer, R. I.; Dixon, D. J.
Org. Lett. 2010, 12, 4720.
Finally, the Jacobsen group has developed an
enantioselective PSR catalyzed by the combination of a
Brønsted acid and a thiourea (Scheme 9).23 This reaction
allows for the enantioselective synthesis of a broad range
of unprotected tetrahydro-β-carbolines in good yields and
enantioselectivities at room temperature. The modular
synthesis of the catalyst allowed for a large number of
thioureas to be prepared and screened for activity in the
PSR. Catalyst F was shown to provide products in high
enantiopurity at room temperature when combined with
benzoic acid as a co-catalyst. In contrast to their earlier
report on the acyl-PSR (Scheme 3) which could only be
applied to alkyl aldehydes, this reaction occurred in high
yield and enantioselectivity with both alkyl and aryl
aldehydes. To date, this reaction has the greatest scope
and synthetic utility of enantioselective PSRs.
Scheme 9. Enantioselective PSRs with Brønsted acid and
thiourea co-catalysts.
The Pictet-Spengler reaction has continued to be a
powerful reaction in alkaloid synthesis 100 years after its
discovery. Like several reactions in organic chemistry,
early worked focused on using chiral auxillaries to control
stereoselectivity, while more recent work has focused on
the design of chiral catalysts. The recent work in
enantioselective PSRs has allowed for efficient syntheses
of several tetrahydro-β-carboline natural products.
However, the main limitations of the reported
enantioselective PSRs are the need for high catalyst
loadings, long reaction times and/or a removable
auxillary. These limitations should be addressed by future
work in this area.
(23 Klausen, R. S.; Jacobsen, E. N. Org. Lett. 2009, 11, 887