Organocatalysis in the Synthesis of Natural Products

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Current Organocatalysis, 2015, 2, 000-000 1
Organocatalysis in the Synthesis of Natural Products: Recent Develop-
ments in Aldol and Mannich Reactions, and 1,4-Conjugated Additions
Estefanía Dibello, Daniela Gamenara* and Gustavo Seoane
Organic Chemistry Department, Facultad de Química, Universidad de la República (UdelaR),
Montevideo, Uruguay
Abstract: The use of organocatalysis has simplified and increased the potential of synthetic ap-
proaches to natural products. Different aspects, regarding applications and even perspectives of imin-
ium- or enamine-catalysis have been studied in this increasingly developing area during the past dec-
ades. Addressing those features, this article aims to give an overview through selected examples, fo-
cusing on discussing academic insights of a variety of key reactions such as aldol and Mannich reac-
tions, and 1,4-conjugated additions, as well as applications to the synthesis of natural products, in the Daniela Gamenara
period 2012-to date.
Keywords: 1,4-conjugated addition, aldol reaction, asymmetric synthesis, enamine-activation, mannich reaction, natural prod-
ucts, organocatalysis.
1. INTRODUCTION McMillan et al. [7] the high potential of this methodology
was rediscovered and originated an intense study of its
The identification, isolation and synthesis of novel biolo-
synthetic possibilities [1, 2, 8-12].
gically active natural products represent a major goal in
organic chemistry. However, some potentially useful natural In those early works of the decade of 2000, two main
compounds cannot be easily isolated in adequate quantities, activation mechanisms were described for organocatalytic
so the development of synthetic routes to them is of para-
processes: enamine catalysis [6] and iminium catalysis [7].
mount importance. Over the history, the aim of organic
While in the latter a chiral imidazolium salt is used to
chemists has been the synthesis of complex molecules
activate α,β-unsaturated aldehydes by the reversible
mimicking the elegance and efficiency of biosynthetic path-
formation of an iminium ion, enamine-catalysis uses
ways in Nature. Due to the complex stereochemistry, high
aminoacids (or derivatives) and proceeds via an enamine
functionalization and structural diversity of many natural
intermediate. Scheme 1 shows that when the organocatalytic
products, asymmetric synthesis has been an important tool
reaction goes through this pathway, the catalyst plays two
for their preparation, since it allows to stereoselectively
functions. First, the nucleophile is activated via enamine
introduce stereogenic centers [1]. Among the available
formation, and then, activation and coordination of the
stereoselective strategies catalytic methods are considered
electrophile via the carboxylic acid leads to the formation of
appealing approaches, since the use of stoichiometric
a defined transition state, which explains the high selectivity
amounts of expensive chiral reagents can be avoided.
of the reaction [1, 13]. As this approach can be viewed as
Besides enzymes and transition metals, the use of small
reducing the function and activation mechanism of Type I
organic molecules, named organocatalysts, has proven to
possess an enormous potential for the catalysis of aldolases to small organic molecules, it can be stated beyond
stereoselective reactions. The introduction of organocatalytic doubt that it represents a powerful method for the
methodologies in synthetic routes to natural products, allows stereoselective α-functionalization of aldehydes and ketones,
to achieve more efficient, economical and environmentally not having to face the substrate limitation characteristic for
benign procedures, considering their tolerance to moisture enzyme catalysts [14].
and oxygen atmospheres, compatibility with mild reaction
In 2012, many excellent reviews regarding different
conditions, and absence or very low toxicity [2]. The use of
aspects, applications, and perspectives of iminium- or
small organic molecules as catalysts for the preparation of
chiral synthons was described independently for the first enamine-catalysis in the synthesis of natural products made
time by Eder and by Hajos [3-5]. valuable contributions to the knowledge in this increasingly
developing area [14-22]. Recently, Abbasov and Romo
Nevertheless, only in the 2000s, from the contribution of
briefly highlighted significant examples of iminium and
List, Lerner and Barbas III [6], and the seminal work of
enamine catalysis in the synthesis of natural products [23].

Herein a detailed account of recent developments in the
*Address correspondence to this author at the Department of Organic organocatalyzed synthesis of natural products will be
Chemistry, Faculty of Chemistry, Universidad de la República (UdelaR),
presented, focusing Mannich reactions, aldol and 1,4-
Av. Gral. Flores 2124, 11800, Montevideo, Uruguay;
conjugated additions- covering the period 2012-to date.
Tel/Fax: ++598-2-924-7881, [phone]; E-mail: [email protected]
2213-3372/15 $58.00+.00 © 2015 Bentham Science Publishers
2 Current Organocatalysis, 2015, Vol. 2, No. 2 Dibello et al.
COOH
O O N O OH
H (30mol%)
+
H
DMSO, Acetone
97% 96% ee
O
O OH
HN
R
O H2O
HO
HO
2
N
R N
O
OH O
O
O
N
O
R O O N
H
H O
HO
RCHO
Scheme 1. Example of a proline-catalyzed aldol reaction proceeding via an enamine mechanism [1].
1.1. Aldol Reactions the substrate for the aldol reaction (O-acetonyl-salicylal-
dehyde) was prepared in five steps with an overall yield of
The asymmetric aldol reaction is an outstanding method
34% (Scheme 2), in multigram scale without the need of
for the enantioselective carbon-carbon bond formation. The
purification steps. The aldol key step in the designed syn-
development of organocatalytic methods to perform these
thetic sequence, was carried out using (S)-proline as catalyst,
reactions, gave them an additional improvement regarding
and yielded the expected product in 71% yield, as a single
atom economy and milder and greener aspects [24]. Many
stereoisomer.
organocatalytic aldol reaction protocols have been developed
and included in synthetic routes to natural products. Some
relevant contributions are highlighted in this section.
In 2012 Enders and co-workers described for the first O O O O O O
time an organocatalytic asymmetric synthesis of smyrindiol
psoralen
[(+)-(2’S,3’R)-3-hydroxymarmesin, isolated from roots of angelicin
Smyrniopsis aucheri [25] and Brosimum gaudichaudii [26]
by using (S)-proline as catalyst, through an intramolecular
OH
aldol reaction as key step [27]. This natural furocoumarin
OH
was synthesized from commercially available 2,4-
dihydroxybenzaldehyde in 15 steps, with excellent stereose-
lectivity (de = 99%, ee = 99%). Naturally occurring furo- O O O
coumarins, a group of compounds structurally derived from smyrindiol
psoralen or angelicin (Fig. 1), are found in plants of the
Apiaceae and Rutaceae families, and are used in the treat-
Fig. (1). Structure of naturally occurring furocoumarins [27].
ment of skin diseases such as vitiligo and psoriasis. In addi-
tion, they show vasodilatory, antifungal and antibacterial The following nine steps of the synthetic route were
activities. The total synthesis of smyrindiol was carried from easily carried out with an overall yield of 27%. In summary,
2,4-dihydroxybenzaldehyde as starting material, from which an efficient and completely stereoselective asymmetric
Organocatalysis in the Synthesis of Natural Products Current Organocatalysis, 2015, Vol. 2, No. 2 3
O
H
HO OH
O O
H (S)-proline (40 mol %) HO
O
O O H2O, DMF, r.t., 15 h
71%, de: >99%, ee: >99%
I O
I O
O-acetonyl-salicylaldehyde
OH
OH
O O O
smyrindiol
Scheme 2. Synthetic route to smyrindiol [27].
organocatalyzed total synthesis of smyrindiol was achieved Florence and Wlochal used an organocatalytic aldol reac-
using (S)-proline to catalyze a 5-enolexo aldol reaction as the tion as the first step in the synthetic sequence to palmerolide
key step. The target compound was obtained in 15 steps with C, a polyketide-derived macrolide from the antarctic tunicate
an overall yield of 6.3%, using mild conditions and short Synoicum adereanum, which shows remarkable activity to-
reaction times in all steps. wards the UACC-62 human melanoma cell line (IC = 110
50
nm), [31] (Scheme 4).
In the same year, an efficient asymmetric synthesis of the
potential antitumor agent (-)-gonioheptolide A derivatives The synthesis of the first subunit in the designed
was described by the same group. The target compound 4- synthetic route began with an Enders´ proline-catalyzed aldol
epi-methoxy-gonioheptolide A and analogues belong to a reaction of suitably substituted dioxanone and aldehyde, to
group of secondary metabolites isolated from plants of the establish the anti-configuration in the newly formed
annonaceae family, genus goniothalamus, [28] called styryl- stereocenters [32, 33]. The reaction with 30 mol% (S)-
lactones. These compounds, which characteristic feature is proline in chloroform over five days provided the anti-aldol
the presence of mono- or bicyclic highly oxygenated tetra- in 44% yield with 96% enantiomeric excess.
hydrofuran ring systems, show cytotoxic, pesticidal and anti-
The diastereo- and enantioselective syntheses of 3-
tumor activity [29]. The first step in the designed synthetic acetlyl-4-hydroxyisochroman-1-ones (structural feature found
sequence was a (S)-proline-catalyzed aldol reaction, fol- in several natural products) via an intramolecular trans-
lowed by a RAMP hydrazone-α-alkylation and a diastereose- selective aldol reaction were described by Enders and co-
lective reduction with zinc borohydride, allowing to the es- workers, employing proline-type organocatalysts [34].
tablishment of the required five stereocenters in the mole-
A series of pyrrolidine-derived catalysts was evaluated
cule. The retrosynthetic analysis of the target compound is
for the preparation of an isochroman-1-one, carrying out the
shown in Scheme 3. As final result, 4-epi-methoxy-
reactions at room temperature in 1.0 M DMSO (Scheme 5).
gonioheptolide A was obtained in ten steps with 15% overall
yield and excellent diastereo- and enantiomeric excesses (de Catalysts A and B did not give significant conversions,
≥95%, ee ≥99%). while (S)-proline (C) afforded the desired isochromanone
4 Current Organocatalysis, 2015, Vol. 2, No. 2 Dibello et al.
MeO
Br
O
O OH SN2 cyclization
H +
O
MeO O
Ph
HO
OMe
O O
Diastereoselective
Organocatalytic
RAMP-hydrazone
anti-aldol reaction
alkylation
+
O
Ph
H
OTBS
Scheme 3. Retrosynthetic analysis for 4-epi-methoxy-gonioheptolide A [30].
O O OH
O (S)-proline, 30 mol%
+ CHCl, r.t., 5 days
O O H 44%3, 96% ee O O

Scheme 4. (S)-Proline-catalyzed first step in the synthetic route to the proposed structure of palmerolide C [31].
O OH O
catalyst A-D
H O 30 mol%
O DMSO, r.t. O
O O
HO
Ph
Ph
COOH N
N H OTMS
H
A B
N
N COOH N N
H H HN N
C D

Scheme 5. Catalyst screening for the organocatalytic isochroman-1-one synthesis [34].
within 23 hours in 67% yield, good enantioselectivity (84% The stereodivergent synthesis of two hyacinthacine ana-
ee) and excellent diastereoselectivity (> 95% de). The more logues relying on an organocatalyzed aldol addition was car-
acidic catalyst D, (R)-5-(pyrrolidin-2-yl)-1H-tetrazole, gave ried out with dioxanone and an α-N-carbobenzyloxy-
the final compound in reduced time (5 hours) with a slightly substituted chiral aldehyde, promoted by both (R)- and (S)-
increased yield (71%), the same diastereoselectivity and bet- proline (Scheme 6) [35]. A retrosynthetic analysis of hyacin-
ter enantioselectivity (99% ee). The scope of the reaction thacines on the basis of the organocatalyzed aldol addition as
was studied with several 2-oxopropyl 2-formylbenzoate de- a key step is given in Scheme 5. It shows that the stereogenic
rivatives, finding a robust procedure that allowed a broad centers at C1 and C2 should be created in an aldol reaction,
range of substituents on the aromatic ring. which was the first step in the synthetic sequence. The reac-
Organocatalysis in the Synthesis of Natural Products Current Organocatalysis, 2015, Vol. 2, No. 2 5
reduction/
HO lactamization HO reductive
3 5 amination
2* N * NH
HO 7a 6 HO
* COOEt
1 * * 7 * * *
HO HO
hyacinthacines
O
O
O
O
O
+ * O
aldol NH
OHC * COOEt addition HO * * 2
NH2 EtOOC
Scheme 6. Retrosynthetic analysis of hyacinthacines [35].
OHC COOEt
OH CBz
O
NHCbz (S)-proline (12 mol%) N
+ DMF, r.t., 12h O COOEt
70%, dr = 6:1 H
O OH
O
O
O OH
(R)-proline (12 mol%) COOEt
DMF, r.t., 12h O O NHCBz
77%, dr = 10:1

Scheme 7. (R)-and (S)-proline-catalyzed aldol reaction, first step in the synthetic route to hyacinthacines [35].
tion proceeded in good yields and diastereomeric ratios, obtained with 75% yield, 90% ee in 23:1 diastereomeric ra-
which may be due to the use of an acyclic chiral aldehyde as tio, and used for the construction of a potential intermediate
acceptor, allowing reagent control of the sterochemical out- of the natural product TMC-95A, a powerful reversible pro-
come of this key step in both, the matched and mismatched teasome inhibitor [37].
cases.
A L-proline-mediated direct cross-aldol condensation of
The preparation of ent-2-epi-hyacinthacine A started two advanced aldehyde-intermediates was utilized by
2
with the (S)-proline-catalyzed aldol addition of dioxanone to Volchkov and Lee for the construction of an α,β-unsaturated
the adequate N-carbobenzyloxy-protected aldehyde yielded epoxyaldehyde, a key compound in route to (-)-
the aldol adduct (the product adopted the cyclic hemiaminal amphidinolide V (Scheme 9) [38].
form) as the major product, along with a minor amount of its
The reaction was conducted in the presence of 4 Å mo-
diastereomers (70%; diastereomeric ratio (dr) = 6:1). The
lecular sieves (MS) with increased loading of L-proline in
mixture was easily separated by column chromatography. In
DMF as solvent and at 0°C. These conditions dramatically
turn, for the synthesis of ent-3-epi-hyacinthacine A , the al-
1 increased the ratio between cross-condensation and cross-
dol reaction was catalyzed by (R)-proline, affording aldol
aldol products, obtaining a sole product in 66% yield (E/Z =
adduct in 77% yield with 10:1 dr. The higher yield and 12.5:1).
stereoselectivity may indicate that this is the matched case
Phansavath and colleagues reported a convergent stereo-
(Scheme 7).
selective synthesis of one isomer of the C44-C65 fragment
Pearson and colleagues described the enantioselective al- of mirabalin, in which the first step is the organocatalytic
dol reaction of 7-iodoisatin and 2,2-dimethyl-1,3-dioxan-5- cross-aldol reaction of isobutyraldehyde and propanal, car-
one, using a N-prolinylanthranilamide-based pseudopeptide ried out at 4°C during 48 hours, and using L-proline as cata-
as catalyst (catalyst A, Scheme 8) [36]. The aldol adduct was lyst [39].
6 Current Organocatalysis, 2015, Vol. 2, No. 2 Dibello et al.
O O
O
HO
O
O
N
H O
I 20% mol catalyst A N
H
+ I
i-PrOH/HPO/HO
3 4 2
O 4 °C, 6 days syn adduct (major)
90% ee, 23:1 dr, 75% yield
+
O O
O
O
HO
O
O
N
H
O I
N
H anti adduct (minor)
NH
Catalyst A
O
HN N
N
HN
N

Scheme 8. Organocatalytic aldol reaction of 7-iodoisatin and 2,2-dimethyl-1,3-dioxan-5-one [36].
Ph Ph Ph Ph
L-proline
Si Si
O MS (4A) O
O O
O
DMF, 0 °C
O
+
O SiMe3 SiMe3
COOMe
COOMe
Scheme 9. Organocatalytic cross aldol reaction for the synthesis of a key intermediate in the route to (-)-amphidinolide V [38].
OMOM
O
H
O
OH O OMOM O
+
OH OMOM O

Scheme 10. Retrosynthetic analysis for 7-epi-goniodiol [40].
Veena and Sharma worked on an organocatalytic ap- retrosynthetic analysis of 7-epi-goniodiol is shown in
proach for the total synthesis of 7-epi-goniodiol, and devel- Scheme 10.
oped a strategy that involves a L-proline-catalyzed diastereo-
The synthetic route starts with the oxidation of (R)-
selective aldol reaction and a Baeyer-Villiger oxidation as
phenylethane-1,2-diol giving the corresponding aldehyde
key steps for the construction of the chiral lactone [40]. The
Organocatalysis in the Synthesis of Natural Products Current Organocatalysis, 2015, Vol. 2, No. 2 7
R
R 1
R N
O N
N OH
N N O
+ H H or
O
O
R OH
solvent
COOH
R
R1 N 1
COO
HO
Scheme 11. Organocatalyzed reactions between pyridine carbaldehyde derivatives and α-ketoacids [41].
O OR
2
H
N N O R
N N 3
O R1 S HN
Tuv = tubuvaline
COOH
Fig. (2). General structure of tubulysins, a family of tetrapeptides with potent anti-cancer activity [44].
which was subjected to a L-proline-catalyzed diastereoselec- crotonolactone and a suitable aldehyde, for the synthesis of a
tive direct aldol reaction with cyclopentanone. This key step functionalized γ-butenolide [45]. These aldol product was
was conducted at room temperature for 12 hours, affording a stereoselectively converted into 5-aminoalkyl butyrolactone,
diastereomeric mixture in a 88:12 ratio in 82% yield. The which isomerized to the key 2,3-disubstituted piperidinone, a
major diastereomer is the one shown in Scheme 10. common intermediate to (+)-febrifugine and (+)-
halofuginome (Scheme 12).
Landais and colleagues, focussed their interest in natu-
rally occurring isotetronic acids, which exhibit relevant bio- The initial vinylogous aldol reaction was conducted using
logical properties [41]. These simple motifs, are also found cyclohesanediamine, stilbenediamine and cinchonidine de-
in more complex compounds, such as erythronolide A [42]. rived thioureas [46, 47] and stilbenediamine derived
Their studies foccused on the organocatalyzed aldol reaction squaremides [48, 49]. Through the designed organocatalytic
between pyridine-2-carbaldehyde derivatives and various α- sequence, (+)-febrifutine was obtained in 14 steps with 6.8%
ketoacids (Scheme 11). overall yield.
Depending on the nature of the substituents on the pyri- The enantioselective synthesis of (+)-swainsonine was
dine skeleton, the reactions provided the expected isotetronic carried out by Saicic and co-workers, achieving the final
acid, and, surprisingly, their corresponding pyridinium salt. purpose in 9 steps with 24% overall yield [50]. The key fea-
Further functionalization of the pyridinium salt, provided ture of the synthesis was the combination of an organocata-
access to valuable building blocks in enantiomerically pure lyzed aldolization and a reductive amination, allowing for a
form, including indolizidines, aldol products and butyrolac- rapid construction of highly functionalized heterocyclic sys-
tones. tem. Employing a similar approach, also (+)-8-epi-
swainsonine was synthesized in 7 steps and 28% overall
Tubulysins are cytostatic peptides isolated from
yield. The retrosynthetic analysis for (+)-swainsonine is
myxobacteria Archangium gephyra and Angiococcus disci-
shown in Scheme 13.
formis, and act on microtubulin production (Fig. 2) [43]. A
direct flexible approach to the tubavaline (Tuv) core of tu- Chiral indane frameworks, such as indanone subunits, be-
busylins was established by Dash and co-workers, employ- ing widely distributed in biologically active natural products,
ing a reductive amination of precursors of tubuvaline (pre- are also desirable targets in organic synthesis [51-54]. Singh
Tuv) [44]. The analogues of the pre-Tuv were achieved us- described organocatalytic intramolecular aldolization of or-
ing a proline-catalyzed direct asymmetric aldol reaction of tho-diacylbencenes to construct highly funcionalized 3-
substituted thiazole-carbaldehydes with acetone. The first hydroxyindanones [55]. In this transformation, a high trans-
organocatalytic enantioselective approach to precursors of selectivity was achieved by the use of metal salts of amino-
pre-Tuv was presented, employing a prolineamide catalyzed acids. The method allowed the access to the strained spiro-
aldol reaction of thiazole-carbaldehyde with methyl isopro- cyclic 3-hydroxyindanones related to a number of natural
pyl ketone in water, obtaining excellent yields and regio- and product frameworks. Fig. (3) shows the structure of some
enantioselectivities. selected natural products bearing a 3-hydroxyindanone core.
Pansare and colleagues described the enantioselective or- Finally, our group designed the synthesis of Domini-
ganocatalytic direct vinylogous aldol reaction of γ- calure I, the major component of the aggregation pheromone
8 Current Organocatalysis, 2015, Vol. 2, No. 2 Dibello et al.
OH N R
1
O
N
H R
N 2
O
(+)-febrigugine: R = R = H
1 2
(+)-halofuginone; R = Br, R = Cl
1 2
OR OH
(+)-febrigugine 2
O
or O
(+)-halofuginonel Br
N O N
H
COOR O
1
amino lactone
isomerization
NH2 OH
* *
O O R O O R
amination vinylogous
aldol
Scheme 12. Retrosynthetic analysis of (+)-febrifugine and (+)-halofuginome [45].
reductive
amination
CbzN
O CbzN
N O
OH
O H O OHC
OH
O
H OH
OH
organometallic
(+)-swainsonine addition
reductive
CbzN
CbzN amination
O
OH
HO
O O O
proline-catalyzed
aldol addition
O
O OH
Cbz
+ N
Bn
O O
O O NCbz
Ph
Scheme 13. Retrosynthetic analysis for (+)-swainsonine [50].
of Rhyzopertha dominica (Fabricius) (Coleoptera: Bostrichi- for both steps. Together with an esterification under Corey’s
dae) using a pyrrolidine-catalyzed self aldol condensation of conditions [57] and enzymatic transesterification with (S)-2-
propanal as the key step (Scheme 14) [56]. pentanol, the three steps constituted the concise sequence
through which the target pheromone was prepared with an
The organocatalytic reaction was carried out in hexane at
overal yield of 68%, and > 99% ee starting from really inex-
room temperature during 48 hours, and then a 10% solution
pensive material.
of HCl was added, yielding the condensation product in 95%
Organocatalysis in the Synthesis of Natural Products Current Organocatalysis, 2015, Vol. 2, No. 2 9
O X
HO O
O 1) N H , hexane O
R
2
H
HO Cl R1 H r.t., 48 h
OH 2) 10% HCl
tripartin Cl OH pterosins OH 95%
HO
1) NaCN, AcOH, MnO,
ligustrone-C 2
O MeOH, 80%
2) (S)-2-pentanol, CaL B
OMe O Hexane, 150 rpm,
37 °C, 96h, 90%
O
O O O OMe OHO O
dominicalure I
Scheme 14. Pyrrolidine-catalyzed self-aldol condensation of pro-
panal, as key step in route to dominicalure I [56].
O O
HO HO
coleophomone-A coleophomone-D A good example of the usefulness and synthetic potential
of this kind of reactions was described by Keley et al. It con-
Fig. (3). Selected examples of natural products bearing a 3- sisted on the development of an asymmetric organocatalytic
hydroxyindanone core [55]. Mannich cyclization for the synthesis of the bicyclic skeleton
of izidine (pyrrolizidine, indolizidine and quinolizidine) al-
1.2. Mannich Reactions
kaloids, and its use as key strategy in the total synthesis of
The first report of an organocatalytic enantioselective (-)-epilupinine, (-)-tashiromine and (-)-trachelanthamidine
Mannich reaction was stated by List in 2000 [58]. Proline (Fig. 4) [60].
was used as catalyst and acetone or hydroxyacetone as the A set of pyrrolidine- and imidazolidinone-based organo-
Mannich donor, affording predominantly the syn-product.
catalysts was evaluated using a suitable starting material for
Scheme 15 shows the transition state for the aldol and the preparation of quinolizidine derivatives (Scheme 16).
Mannich reaction using proline as catalyst [15]. As it can be The pyrrolidine-based catalysts I-IV did not lead to the de-
seen, the presumed configurations of (E)-enamine and (E)- sired cyclization. However, using catalyst V-HCl the reac-
imine give rise to the preferred anti- and syn-products respec- tion took place in 74% yield, displaying a 12:1 trans/cis di-
tively, via chair-like, hydrogen-bonded transition states [59]. astereomeric ratio and 46% ee for trans-isomer.
COOH
N
aldol H Mannich
+ R3NH
2
R1CHCOR + R2CHO
2
R3 N
N
R1 R1
O
O
R2 O H N O
O
H
H
R2
H
syn-Mannich
anti-aldol
transition state
transition state
O OH O NHR3
H R2 H R2
R1 R1
Scheme 15. Comparison of the proposed transition states for aldol and Mannich reactions [15].
10 Current Organocatalysis, 2015, Vol. 2, No. 2 Dibello et al.
OH 38% overall yield, dr = 10:1, ee = 88%) and (-)-
OH trachelanthamidine (6 steps, 52% overall yield, dr = 7:1, ee =
H H
74%) respectively were also achieved through this method.
Rutjes and colleagues synthesized enantiomerically pure
N N
2,6-disubstituted piperidinones from furfural, involving an
organocatalyzed Mannich reaction as one of the initial steps.
(-)-trachelanthamidine (-)-tashiromine The overall synthetic approach allowed the preparation of (-
(pyrrolizidine structure) (indolizidine structure)
)-sedacryptine and one of its epimers (Scheme 17) [61]. De-
spite existing methods for the synthesis of such considered
OH privileged structural motif in Nature, that is the 3-
hydroxypiperidine scaffold, catalytic methodologies for the
H
asymmetric synthesis of these structures could give access to
new substitution patterns.
N
Proline-catalyzed Mannich reaction was chosen to pre-
(-)-epilupinine pare the needed enantiopure aminoalkyl furans from a fur-
(quinolizidine structure) fural derivative. Thus N-Boc (N-tert-butyloxycarbonyl)-
protected amines, substrates for the aza-Achmotowicz reac-
Fig. (4). Structures of izidine alkaloids (-)-epilupinine, (-)-
tion that follows in the designed synthetic sequence, were
tashiromine and (-)-trachelanthamidine [60].
prepared via the organocatalytic Mannich reaction. The pro-
Once the optimal reaction conditions were established, tocol involves basic conditions, under which the sulfone was
the authors also investigated the scope and generality of this eliminated to give the corresponding crude imine, which was
cyclization, finding that the yields of the six-membered ring- directly treated with L-proline (20 mol%) and an aldehyde to
closed products were obtained in good to very good yields give the corresponding β-amino aldehydes. The resulting
(63-88%). Additionally, dialkylsubstituted substrates and crude Mannich products were directly in situ reduced result-
sterically hindered cyclopentyl and cyclohexyl acetals af- ing in the expected γ-amino alcohols. Aliphatic, allylic and
forded the desired products in good yields and ee values up aromatic substituents were prepared with reasonable yields
to 97%. The process was also found useful for five- and and excellent selectivities according to this methodology.
seven-membered rings and provided the corresponding izidi-
Lee and co-workers described the synthesis of biologi-
none derivatives in very good yields and ee values (up to
cally interesting flavanone derivatives, through an ethyle-
87%). Finally, the total synthesis of representative natural
nediamine diacetate (EDDA)-catalyzed Mannich reaction
products with indolizidine, quinolizidine and pyrrolizidine
from 2-hydroxyacetophenone derivatives, aromatic alde-
alkaloids structures such as (-)-tashiromine (6 steps, 43%
hydes and aniline (Scheme 18).
overall yield, dr = 4:1, ee = 92%), (-)-epilupinine (7 steps,
OH
OMe H
1) catalyst (30 mol%),
OH
solvent
O N OMe
2) NaBH , MeOH, 0°C N
4
O
R
1
COOH
N N
H H R1
OR
2
I
II: R = Ph, R = H
1 2
III: R = Ph, R = Me
1 2
IV: R = 3,5-(CF ) CH, R = TMS
1 32 6 5 2
O O O
N N N
Bn N Bn N Bn N t-Bu
H H H
V VI VII
Scheme 16. Optimization of the enantioselective organocatalyzed cyclization for the synthesis of indolizidine derivatives [60].