Enantiodivergent Synthesis of (+)- and (?)-Pyrrolidine 197B: Synthesis of trans-2,5-Disubstituted Pyrrolidines by Intramolecular Hydroamination

Article abstract of DOI:10.1002/chem.201602708

A highly efficient, diastereoselective, iron(III)-catalyzed intramolecular hydroamination/cyclization reaction involving α-substituted amino alkenes is described. Thus, enantiopure trans-2,5-disubstituted pyrrolidines and trans-5-substituted proline derivatives were synthesized by means of a combination of enantiopure starting materials, easily available from l-α-amino acids, with sustainable metal catalysts such as iron(III) salts. The scope of this methodology is highlighted in an enantiodivergent approach to the synthesis of both (+)- and (?)-pyrrolidine 197B alkaloids from l-glutamic acid. In addition, a computational study was carried out to gain insight into the complete diastereoselectivity of the transformation.

Full text of DOI:10.1002/chem.201602708

DOI: 10.1002/chem.201602708
Full Paper
&
Hydroamination
Enantiodivergent Synthesis of (+)- and (À)-Pyrrolidine 197B:
Synthesis of trans-2,5-Disubstituted Pyrrolidines by Intramolecular
Hydroamination
Sixto J. Pꢀrez,[a] Martꢁn A. Purino,[a] Daniel A. Cruz,[a] Juan M. Lꢂpez-Soria,[a, d]
Rubꢀn M. Carballo,[c] Miguel A. Ramꢁrez,[a] Israel Fernꢃndez,*[b] Vꢁctor S. Martꢁn,*[a] and
Juan I. Padrꢂn*[a, d]
Abstract: A highly efficient, diastereoselective, iron(III)-cata-
lyzed intramolecular hydroamination/cyclization reaction in-
volving a-substituted amino alkenes is described. Thus,
enantiopure trans-2,5-disubstituted pyrrolidines and trans-5-
substituted proline derivatives were synthesized by means
of a combination of enantiopure starting materials, easily
available from l-a-amino acids, with sustainable metal cata-
lysts such as iron(III) salts. The scope of this methodology is
highlighted in an enantiodivergent approach to the synthe-
sis of both (+)- and (À)-pyrrolidine 197B alkaloids from
l-glutamic acid. In addition, a computational study was car-
ried out to gain insight into the complete diastereoselectiv-
ity of the transformation.
Introduction
hydropyridines, which were applied to the synthesis of differ-
ent natural products such as coniine (Scheme 1).[5] On the
other hand, the synthesis of 3,5-disusbstituted pyrrolidines and
pyrroles was accomplished through the aza-Cope/Mannich
tandem cyclization, and applied to the synthesis of the male-
attracting pheromones from the poison glands of ants Lepto-
thoracini.[6] More recently, Cao et al. have used this aza-Cope/
Mannich procedure as the key reaction in the formal synthesis
of cycloclavine and the construction of the ACDE ring system
of daphenylline (Scheme 1).[7]
Five-membered azacycles are common structural units in the
fields of organic and medicinal chemistry. Thus, they can be
found in a good number of natural products containing the
parent pyrrolidine ring, organocatalysts having optically active
proline residues or derivatives thereof, and drugs.[1–3]
Over the last decade, we have been involved in the synthe-
sis of azacycles of several sizes using the Prins cyclization and
iron(III) salts as sustainable catalysts.[4] We have developed new
methodologies to generate substituted piperidines and tetra-
As a continuation of our previous work, we have now fo-
cused on the synthesis of trans-2,5-disubstituted pyrrolidines
and their application towards the synthesis of natural products.
However, direct formation of these type of azacyles through
an aza-Prins cyclization does not occur, which agrees with a dis-
favored 5-endo-trig cyclization according to Baldwin’s rules
(Scheme 2).[8,9]
[a] Dr. S. J. Pꢀrez, Dr. M. A. Purino, D. A. Cruz, J. M. Lꢁpez-Soria,
Prof. M. A. Ramꢂrez, Prof. V. S. Martꢂn, Dr. J. I. Padrꢁn
Instituto Universitario de Bio-Orgꢃnica “Antonio Gonzꢃlez” (CIBICAN)
“Sꢂntesis Orgꢃnica Sostenible, Unidad Asociada al CSIC”
Departamento de Quꢂmica Orgꢃnica, Universidad de La Laguna
C/Francisco Sꢃnchez 2, 38206, La Laguna, Tenerife (Spain)
Fax: (+34)922318571
Therefore, the development of new methodologies allowing
efficient and stereocontrolled access to these nitrogen hetero-
cycles is a challenge for synthetic organic chemists. Among
these methodologies, the intramolecular hydroamination reac-
tion (IHR) has become nowadays one of the most powerful
tools towards the synthesis of azacycles.[10] This process in-
volves the direct addition of nitrogen and hydrogen atoms to
carbon–carbon multiple bonds with atom economy. Moreover,
it is well-known that hydroamination of alkenes is more diffi-
cult than that of alkynes because of the lower reactivity and
electronic density of the C=C bond. Although enantioselective
olefin hydroamination is potentially a powerful and efficient
approach, the reported procedures so far are typically based
on using rare and expensive transition metals and li-
gands.[10,11,37e] It would therefore be desirable to overcome this
E-mail: vmartin@ull.es
[b] Dr. I. Fernꢃndez
Departamento de Quꢂmica Orgꢃnica I, Facultad de Ciencias Quꢂmicas
Universidad Complutense de Madrid, 28040 Madrid (Spain)
E-mail: israel@quim.ucm.es
[c] Dr. R. M. Carballo
Laboratorio de Quꢂmica Farmacꢀutica, Facultad de Quꢂmica
Universidad Autꢁnoma de Yucatꢃn, C/41, n8421ꢄ26 y 28
97150 Mꢀrida, Yucatꢃn (Mꢀxico)
[d] J. M. Lꢁpez-Soria, Dr. J. I. Padrꢁn
Instituto de Productos Naturales y Agrobiologꢂa
Consejo Superior de Investigaciones Cientꢂficas (CSIC)
C/Francisco Sꢃnchez 3, 38206, La Laguna, Tenerife (Spain)
Fax: (+34)922260135
E-mail: jipadron@ipna.csic.es
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201602708.
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Results and Discussion
Diasteroselective synthesis of trans-2,5-disubsti-
tuted pyrrolidines
With the idea to find a fully diastereoselective syn-
thesis of trans-2,5-disubstituted pyrrolidines as the
basis of the enantiodivergent synthesis, we initiated
this study by exploring the IHR involving enantio-
pure a-substituted aliphatic sulfonylamines 1 and
iron(III) chloride as catalyst in a sustainable context
(Table 1).[18] The a substituents in 1 come directly
from the corresponding initial a-amino acids used in
the preparation of the substrate.[19] This consists of
initial reduction of the amino acid to the b-amino al-
cohol with NaBH4 and iodine, followed by formation
of the corresponding N-tosyl aziridines by sequential
O-tosylation and intramolecular cyclization.[18a]
Scheme 1. Synthesis of five- and six membered azacycles, developed by us, and its appli-
cation in natural product synthesis.
Scheme 2. Direct aza-Prins cyclization in the synthesis of substitut-
ed pyrrolidines.
shortcoming by using a sustainable strategy that would
combine an inexpensive and biorelevant metal with ac-
cessible and abundant enantiopure compounds, such
as iron and amino acids, respectively.[12]
To the best of our knowledge, despite the enormous
interest in iron catalysis and hydroamination reac-
tions,[13] only a few examples of iron-catalyzed IHRs in-
volving protected or unprotected amines and unacti-
vated alkenes exist.[14] In these cases, the process in-
volves primary aliphatic amines and leads to the race-
mic synthesis of 2-substituted pyrrolidines.[15] Therefore,
a completely diastereoselective iron-catalyzed hydroa-
mination/cyclization reaction involving a-substituted
amino alkenes in an enantiomeric context is still miss-
ing (Scheme 3).[14a,16]
Herein, we describe the first diastereoselective syn-
thesis of enantiopure trans-2,5-disubstituted pyrroli-
dines and trans-5-substituted proline derivatives by
means of a combination of iron(III) salts, as sustainable
metal catalysts, and enantiopure starting materials such
as amino acids. Then, we hypothesized that, with this
methodology in hand, it could be possible to exploit
l-glutamic acid in an enantiodivergent manner that
would allow access to both (+)- and (À)-pyrrolidi-
ne 197B alkaloids (Scheme 4), which have hemolytic
and antibiotic activities.[17]
Scheme 3. Previous strategies and our work to access trans-2,5-disubstituted pyrroli-
dines.
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6 h. Under these reaction conditions, (2S, 5S)-2,5-dimethyl-1-to-
sylpyrrolidine (2) was isolated in quantitative yield (Table 1,
entry 1). Cyclization of this a-methyl-substituted tosylamino-
pentene 1 therefore proceeded with excellent trans diastereo-
selectivity. Indeed, pyrrolidine 2 was isolated exclusively, and
no traces of the corresponding cis-pyrrolidine isomer were de-
tected in the crude reaction products.[20] The IHR also works
well with different aliphatic a substituents and leads to similar
reaction yields (Table 1, entries 2 and 3). Replacement of the
a substituent by a benzyl group, coming from phenylalanine
as enantiopure starting source, also has no significant effect on
the reaction yield (84%, Table 1, entry 4).[21] Decreasing the
amount of FeCl3 increased the reaction time but provoked
only a slight decrease in the reaction yields, which was more
evident when 10 mol% of FeCl3 was used (see Table 1).[22] This
IHR is thus a stereoselective cyclization reaction that exclusive-
ly affords the corresponding trans-pyrrolidine derivative re-
gardless of the type of a substituents present in the initial sul-
fonylamino alkene and/or reaction conditions.
Scheme 4. Enantiodivergent strategy for the preparation of (+)- and (À)-pyr-
rolidine 197B.
Table 1. Intramolecular hydroamination of a-substituted sulfonyl amine al-
kenes with iron(III) chloride.[a]
Theoretical calculations on iron(III)-catalyzed alkene IHR
Two different reaction mechanisms can be envisaged for this
IHR: 1) a simple acid-catalyzed Markovnikov hydroamination
through direct or indirect interaction with the alkene functio-
nality[16a] and 2) direct participation of the transition metal
moiety in the cyclization, which therefore controls the diaste-
reoselectivity of the process. In our reactions, anhydrous FeCl3
was used at room temperature, and formation of HCl was not
expected. Furthermore, when the reactions were carried out in
the presence of trimethylsilyl chloride (1 equiv), which could
decompose generating HCl, no cyclization was observed. This
fact nicely agrees with the observations by Takaki and Komeya-
na (Scheme 3), which confirm that a simple acid-catalyzed
pathway does not contribute to the reaction. Indeed, these au-
thors used FeCl3·H2O at 808C, which can produce Fe2O3 and
HCl. In addition, HCl (30 mol%) and other catalysts, such as p-
toluenesulfonic acid or/and phenylacetic acid, were also
tested, with the finding that no reaction took place under simi-
lar conditions.[14a] Therefore, the acid-catalyzed mechanism can
be safely ruled out.
Product 2
Yield[b] [%]
100 mol%
FeCl3
50 mol%
25 mol%
FeCl3
10 mol%
FeCl3
FeCl3
1
2
3
>99
>99
96
>99
91
74
82
90
50
66
97
90
4
84
81
75
61
[a] Reaction conditions: 1 (1.0 mmol), FeCl3, dry CH2Cl2 (0.1m), RT, 6–15 h,
open to air. Ts=p-toluenesulfonyl. [b] Yields of isolated products after purifi-
cation by silica-gel column chromatography.
On the other hand, and in accordance with the precedents
highlighted in Scheme 3, the presence of the tosyl group is
not translated into a fully diastereoselective process. Hartwig
and Schlummer[16a] as well as Morimoto, Takaki, and Komeya-
ma[14a] obtained low diastereoselectivity favoring the trans-pyr-
rolidines by using triflic acid and FeCl3·H2O, respectively,
whereas Chemler, Stahl, and Nicewicz obtained the cis-pyrroli-
dines as major isomers using other catalysts based on copper,
palladium, or an organic iminium salt.[16c,d]
Finally, regioselective opening of the N-tosyl aziridine ring by
treatment with allylmagnesium bromide afforded the N-tosyl
bis-homoallyl amines 1 in very good yields (Scheme 5).
Thus, we began by treating (S)-N-(hex-5-en-2-yl)-tosylsulfo-
namide (1, R=Me) with an equimolecular amount of FeCl3
(100 mol%) in dry dichloromethane at room temperature for
In accordance with these results, we decided to decrease
the size of the N-sulfonyl group and study its influence on the
course of the IHR catalyzed by iron(III) chloride. The size of this
group was reduced by using a N-mesyl group instead of a N-
tosyl group (methanesulfonyl instead of p-toluensulfonyl,
Scheme 6). We synthesized the unsaturated N-mesyl analogues
of 1 by the same synthetic sequence as described above (see
Scheme 5. Synthesis of a-alkyl bis-homoallyl tosylamines 1.
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thermic reaction (DER =12.4 kcalmolÀ1). The complete diaste-
reoselectivity of the process arises under both kinetic and ther-
modynamic control, in view of the considerably higher activa-
tion energy (DE° =20.9 kcalmolÀ1 via TS1-cis) and endother-
micity (DDER =5.1 kcalmolÀ1) associated with the formation of
the alternative INT1-cis intermediate. Note that our calcula-
tions reveal the active effect of the N-tosyl group in the pro-
cess. As shown in the optimized geometries of the transition
states depicted in Figure 1, the oxygen atom of the sulfonyl
group is strongly coordinated to the FeCl3 catalyst and thus fa-
cilitates the cyclization reaction. This interaction is present
along the entire reaction coordinate. In addition, zwitterionic
intermediate INT1-trans (and its cis counterpart) is stabilized
by an intramolecular NH···ClFe hydrogen bond (computed
bond length of 1.885 ꢅ), which weakens the corresponding
FeÀCl bond (the associated computed Wiberg Bond Index for
this FeÀCl bond is 0.40, which is much lower than those of
0.63 and 0.65 computed for the adjacent FeÀCl bonds). As
a result, a molecule of HCl can be easily released with concom-
itant formation of a new FeÀCH2 bond in an exothermic pro-
cess leading to INT2 (DER =À2.2 kcalmolÀ1). The last step of
the process involves protonolysis of the FeÀCH2 bond in INT2
promoted by HCl through the transition state TS2 (DE° =
11.8 kcalmolÀ1), a saddle point associated with FeÀC bond rup-
ture/CÀH bond formation). This transformation produces the
FeCl3-coordinated trans-pyrrolidine INT3 in a highly exothermic
reaction (DER =À41.7 kcalmolÀ1). The great exothermicity of
this step compensates the endothermicity computed for the
initial intramolecular cyclization reaction and drives the entire
transformation forward. Finally, the reaction ends with the de-
Scheme 6. Synthesis of trans-2,5-disubstituted N-mesyl pyrrolidines.
Scheme 5). The treatment of the isobutyl and sec-butyl bis-ho-
moallyl mesylamines with FeCl3 (1 equiv) led to the corre-
sponding trans N-mesyl pyrrolidines in very good yields, that
is, the volume of the substituent attached to the sulfonyl
group has no direct influence on the diastereoselectivity of the
IHR (Scheme 6).
The diastereoselectivity of the reaction was not affected by
variation of the reaction temperature (refluxing or cooling),
which only modifies the reaction time. Nevertheless, it seems
that the tosyl or mesyl group is not a mere spectator in the
process, as was confirmed by theoretical calculations. DFT cal-
culations[23] were carried out to gain more insight into the
complete diastereoselectivity of the above-described FeCl3-cat-
alyzed hydroamination reaction. To this end, we computed the
reaction profile involving the tosylamino pentene 1 (R=Me) in
the presence of FeCl3 as catalyst (Figure 1).
From the data in Figure 1, it becomes clear that the intramo-
lecular cyclization reaction exclusively leads to the formation
of the trans-azacyclic intermediate INT1-trans through the
transition state TS1-trans (DE° =14.5 kcalmolÀ1) in an endo-
Figure 1. Computed reaction profiles for the reaction of tosylamino pentene 1 in the presence of FeCl3. Relative electronic energies DE [kcalmolÀ1], including
zero-point vibrational energy, and bond lengths [ꢅ] are given. All data were computed at the PCM(CH2Cl2)–M06/def2-TZVP//M06/def2-SVP level of theory.
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coordination of FeCl3 in INT3, which would enter in a new cat-
alytic cycle and release the experimentally observed trans-N-to-
sylpyrrolidine 2.
11, which may lead to the corresponding piperidine derivative
(Scheme 8). Under optimized conditions (Table 1), we treated
Diasteroselective synthesis of trans-5-substituted proline de-
rivatives
Next, we focused on the synthesis of enantiopure trans-5-sub-
stituted proline derivatives, exploring the compatibility of FeCl3
with tosylamino alkenes having an ester group as a substituent
and an internal double bond (Scheme 7).
Scheme 8. IHR of tosylamino alkenes with trisubstituted double bond and
and a longer aliphatic chain.
both compounds with 25 and 100 mol% FeCl3. As shown in
Scheme 8, substitution of the double bond does not affect the
IHR, and the trans-2-isopropyl-5-methyl-1-tosylpyrrolidine (10)
could be obtained in very good yield (Scheme 8). The reaction
works well under catalytic or stoichiometric conditions (86%
for 25 mol% and 91% for 100 mol% FeCl3). In the approach to
2,6-disubstituted piperidine, the treatment of N-tosyl-2-amino-
6-heptene (11) with FeCl3 leads to a mixture of five- and six-
membered rings, whereby the 2,5-trans pyrrolidine is the pre-
ferred reaction product. This behavior is similar to that ob-
served by Takaki, Komeyana, and Morimoto and might be
caused by isomerization of the double bond during the proc-
ess.[14a] In this particular case, no reaction was observed under
catalytic conditions (25 mol% of FeCl3).
Scheme 7. Diastereoselective intramolecular hydroamination. Synthesis of
trans-5-substituted proline derivatives. Boc=tert-butoxycarbonyl.
The Wittig olefination of aldehyde 4 with unstabilized or sta-
bilized ylides provided the desired unsaturated tosylamines 5
and 7, respectively (Scheme 7). Subsequent treatment of these
tosylamino alkenes with FeCl3 permitted us to remove the N-
Boc group with concomitant IHR in a single reaction step with
excellent reaction yields.[25] In both cases, the enantiopure
trans-5-substituted proline derivatives were obtained regard-
less of the stereochemistry of the initial double bond
(Scheme 7). The access to these trans-5-substituted prolines
could be achieved in a few steps by means of N-detosylation
and hydrolysis of the ester functionality.[26]
With this methodology for the synthesis of enantiopure
trans-2,5-disubstituted pyrrolidines and trans-5-substituted pro-
line derivatives in hand, we decided to synthesize the alkaloids
(+)- and (À)-pyrrolidine 197B by an enantiodivergent strat-
egy.[37] As depicted in the working plan (Scheme 4), we envis-
aged l-glutamic acid as the key enantiopure starting material.
The synthesis of (À)-pyrrolidine 197B was conducted via the
trans-5-substituted proline pathway, in which the a-substituent
ester group was modified after the intramolecular hydroamina-
tion/cyclization reaction. Homologation of aldehyde 4 through
Wittig olefination and N-Boc deprotection/IHR promoted by
iron(III) chloride led to the trans-proline derivative 6 previously
described above (Scheme 7). Reduction of the ester group was
performed with DIBAL-H to provide the primary alcohol 14, in
which the aliphatic chain was then installed (Scheme 9). This
linear aliphatic chain was generated in a three-step reaction se-
quence involving Parikh–Doering oxidation, Wittig reaction
with unstabilized ylide, and final hydrogenation of cis-olefin
15. The resulting (2R, 5R)-2-butyl-5-pentyl-1-tosylpyrrolidine
(16) constitutes the Davis intermediate to one step away from
the (À)-pyrrolidine 197B synthesis.[37g]
This methodology opens a new way to synthesize trans-5-
substituted prolines with potential applications in organocatal-
ysis and medicinal chemistry.[27] In six reaction steps, trans-5-
alkyl proline derivatives such as 6 can be produced by modu-
lating the size of the aliphatic chain by means of the corre-
sponding phosphonium salt (Scheme 7). On the other hand,
the synthesis of proline derivatives such as 8 having an addi-
tional ester in a distal position allows further modifications as
well. Furthermore, our method complements the known syn-
theses of 5-substituted prolines based, among others, on
Strecker-type reaction,[28] reductive amination,[29] 5-endo-dig
cyclization,[30] addition of Grignard reagents to oxazolidines,[31]
b-decarboxylation/N-cyclization,[32] carbenoid chemistry,[33] hy-
droboration/oxidation reaction,[34] oxidative cleavage of bicyclic
skeletons,[35] and radical cyclization.[36]
For synthesis of the (+)-enantiomer, the ester at the a posi-
tion was modified before IHR in the trans-2,5 pyrrolidine path-
way. Again, we started with a Wittig reaction of aldehyde 4
The scope of our methodology was checked next. To this
end, we used trisubstituted alkene 9 and tosylamino alkene
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steps starting from C2-symmetric diepoxides derived from
d-mannitol.[37a,b] Concerning the synthesis of (+)-pyrrolidi-
ne 197B, to the best of our knowledge, our approach with
nine steps is at the same level as the best published syntheses,
by Takahata, Ohkubo, and Momose (ten steps),[37c] Mandille
et al. (eight steps),[37d] and Marks et al. (ten steps).[37e] With re-
spect to the preparation of (À)-pyrrolidine 197B, our approach
is the shortest synthesis reported to date, besides those of
Lhommet et al. (eight steps) and Davis et al. (seven steps).[37f,g]
Conclusion
We have established a new method to obtain enantiopure
trans-2,5-disubstituted pyrrolidines and trans-5-substituted pro-
line derivatives by means of a combination of an iron(III) salt,
as a sustainable metal catalyst, and enantiopure a-amino acids.
A completely diastereoselective iron-catalyzed intramolecular
hydroamination/cyclization reaction involving a-substituted
amino alkenes in an enantiomeric context was thus described.
According to DFT calculations, the complete diastereoselectiv-
ity of the process arises under both kinetic and thermodynam-
ic control during the initial NÀC bond formation/cyclization re-
action. The interaction between the oxygen atom of the sulfo-
nyl group and iron(III) chloride plays a key role in the final dia-
stereoselectivity of the process. Finally, the utility of our syn-
thesis of trans-2,5-disubstituted azacycles was highlighted by
an enantiodivergent approach towards the formal synthesis of
both (+)- and (À)-pyrrolidine 197B alkaloids from l-glutamic
acid. The extension of this methodology to the synthesis of
2,6-disubstituted piperidines is under development.
Scheme 9. Formal synthesis of (+)- and (À)-pyrrolidine 197B. DIBAL-H=di-
isobutylaluminum hydride
Experimental Section
General methods and computational details are given in the Sup-
porting Information.
that permits, after the corresponding hydrogenation reaction,
the installation of one of the side chains of (+)-pyrrolidi-
ne 197B. This pathway is based on the formation of the tosyla-
ziridine 18, which was accomplished in three steps from ester
17. Iron(III)-promoted N-Boc deprotection generated the corre-
sponding N-tosyl a-amino ester,[25] which was subsequently re-
duced to the corresponding N-tosyl b-amino alcohol. The syn-
thesis of N-tosyl aziridine 18 (l-norleucine derivative) was car-
ried out in a single step that involves a sequential O-tosylation
and a final intramolecular cyclization.[18a] The regioselective
opening of the N-tosyl aziridine ring by treatment with allyl-
magnesium bromide afforded the desired N-tosyl bis-homoallyl
amine 19. Next, and prior to the final IHR, the second aliphatic
side chain was installed by an alkene-metathesis reaction. Fi-
nally, the trans-N-tosyl pyrrolidine ent-16 was obtained by the
iron(III) chloride-promoted IHR in excellent yield. This again
General procedure for FeCl3-catalyzed Prins cyclization
FeCl3 was added in one portion to a solution of a-alkyl bis-homo-
allyl tosylamine or a-alkyl bis-homoallyl mesylamine (1.0 equiv) in
anhydrous CH2Cl2 (0.1m) at room temperature. The reaction mix-
ture was stirred at this temperature and monitored by TLC until
complete formation of the corresponding heterocycle. The reaction
was quenched by addition of water and stirring for 30 min, and
the mixture was extracted with CH2Cl2. The combined organic
layers were dried with magnesium sulfate, filtered, and the solvent
was removed under reduced pressure. This crude reaction mixture
was purified by flash silica-gel column chromatography (n-hexane/
EtOAc).
confirmed that the final stereochemistry of ent-16 does not Acknowledgements
depend on the stereochemistry of the double bond in 20.
Compared to previous syntheses, our enantiodivergent ap-
proach to (+)- and (À)-pyrrolidine 197B is much shorter than
the only other enantiodivergent approach, reported by Machi-
naga and Kibayashi. Our syntheses required nine and seven
steps, respectively. In contrast, their syntheses required 16
This research was supported by the Spanish MINECO, co-fi-
nanced by the European Regional Development Fund (ERDF)
(CTQ2014-56362-C2-1-P, CTQ2013-44303-P). S.J.P. and D.A.C
thanks the Spanish MINECO for an F.P.U and an F.P.I fellowship,
respectively. J.M.L.-S. thanks the Fundaciꢂn CajaCanarias-Obra
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[15] The b,b-dialkyl amines are the typical and most widely used starting
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Social La Caixa for a fellowship. The ORFEO-CINQA network is
also acknowledged.
Keywords: alkaloids · cyclization · hydroamination · iron ·
nitrogen heterocycles
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Received: June 7, 2016
Published online on && &&, 0000
Chem. Eur. J. 2016, 22, 1 – 8
www.chemeurj.org
7
ꢄ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
FULL PAPER
&
Hydroamination
S. J. Pꢀrez, M. A. Purino, D. A. Cruz,
J. M. Lꢁpez-Soria, R. M. Carballo,
M. A. Ramꢂrez, I. Fernꢃndez,*
V. S. Martꢂn,* J. I. Padrꢁn*
&& – &&
Green route to 5-membered azacycles:
An innovative method to obtain enan-
tiopure trans-2,5-disubstituted pyrroli-
dines and trans-5-proline derivatives
was established. An enantiodivergent
approach to the synthesis of both (+)-
and (À)-pyrrolidine 197B from l-gluta-
mic acid is presented (see scheme). The
selectivity was explained by DFT calcula-
tions.
Enantiodivergent Synthesis of (+)-
and (À)-Pyrrolidine 197B: Synthesis of
trans-2,5-Disubstituted Pyrrolidines by
Intramolecular Hydroamination
&
&
Chem. Eur. J. 2016, 22, 1 – 8
www.chemeurj.org
8
ꢄ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!