Stereoselective Synthesis of Piperidines by Iridium-Catalyzed Cyclocondensation

Article abstract of DOI:10.1002/anie.201706374

An iridium-catalyzed cyclocondensation of amino alcohols and aldehydes is reported. Intramolecular allylic substitution by an enamine intermediate and subsequent in situ reduction furnishes 3,4-disubstituted piperidines with high enantiospecificity and good diastereoselectivity. The modular approach and the broad functional group tolerance provide access to diverse piperidine derivatives, which were further functionalized to give a versatile set of products.

Full text of DOI:10.1002/anie.201706374

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Stereoselective Synthesis of Piperidines via Iridium-Catalyzed
Cyclocondensation
Authors: Erick Moran Carreira, Tobias Sandmeier, and Simon
Krautwald
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201706374
Angew. Chem. 10.1002/ange.201706374
Link to VoR: http://dx.doi.org/10.1002/anie.201706374
http://dx.doi.org/10.1002/ange.201706374

10.1002/anie.201706374
Angewandte Chemie International Edition
COMMUNICATION
Stereoselective Synthesis of Piperidines via Iridium-Catalyzed
Cyclocondensation
Tobias Sandmeier, Simon Krautwald, and Erick M. Carreira*
Abstract: Iridium-catalyzed cyclocondensation of amino alcohols
and aldehydes is reported. Intramolecular allylic substitution by an
enamine intermediate and subsequent in situ reduction furnishes
3,4-disubstituted piperidines with high enantiospecificity and good
diastereoselectivity. The modular approach and the broad functional
group tolerance give access to diverse piperidine derivatives, which
are further functionalized to give a versatile set of products.
powerful tool for the synthesis of piperidines bearing
substituents at C-2.[5] In addition, hydroamination[6] and kinetic
resolution[7] have been employed in various transformations
affording
chiral
N-heterocycles,
including
piperidines.
Furthermore, the dearomatization of pyridine derivatives through
asymmetric hydrogenation or the addition of nucleophiles has
been established as a reliable method.[8] Recently, Ito and
coworkers reported the enantioselective synthesis of 3,4-
disubstituted
dihydropyridines
via
a
stepwise
Piperidines are privileged structures in medicinal chemistry and
found in numerous natural products.[1] A variety of strategies for
the stereoselective synthesis of these valuable building blocks
have been developed.[2] While these approaches are generally
applicable to the synthesis of piperidines with substitution at the
C-2 and C-6 positions, methods for the synthesis of 3,4-
disubstituted piperidines are less developed.[3] This is striking,
since trans-3,4-disubstituted piperidines have emerged as
important structures in biologically active small molecules and
are a common motif in drug development.[4] Herein, we describe
an iridium-catalyzed cyclocondensation that couples readily
available enantiopure aminoalcohols and aldehydes to yield the
corresponding 3,4-disubstituted piperidines (Scheme 1). The
versatility of the products was showcased by further elaboration
into useful building blocks in good yields and high selectivities.
dearomatization/borylation protocol.[9] However, reactions that
give direct access to 3,4-disubstituted piperidines are rare. Most
commonly, a two-step sequence consisting of cyclization to a
lactam followed by reduction is employed.[10] While this approach
is well suited for the synthesis of various piperidine derivatives,
the conditions required for lactam reduction limit its utility. A
more direct approach is cyclocondensation, wherein two simple
starting materials are coupled to afford chiral piperidines.[11] The
modularity of this approach would give rapid access to a broad
range of substituted piperidines in one pot.
Our laboratory has developed various allylic substitution
reactions employing iridium (P,olefin) complexes as catalysts.[12]
Based on our reports on the intermolecular reaction of in situ
generated enamines and π-allyliridium complexes to give
optically active aldehydes,[13] we hypothesized that we could
design a process affording chiral piperidines in highly modular
fashion (Scheme 1). Specifically, condensation of aminoalcohol
1 with aldehyde 2 would give the corresponding enamine 5,
which is poised to undergo iridium-catalyzed cyclization. This
approach would allow generation of additional molecular
complexity through interception of iminium 6 or enamine 7 with a
suitable nucleophile or electrophile, respectively. For example,
iminium 6 could be reduced in situ by addition of a borohydride
reagent to give 3,4-disubstituted piperidine 4. Importantly, for
such a process to be successful, the combined steps of enamine
formation and cyclization would need to outcompete iridium-
catalyzed etherification[14] or tertiary amine formation.[15] The
proposed approach to piperidines would be highly modular since
the structure of the aldehyde and aminoalcohol are readily
altered; moreover optically active allylic alcohols are readily
available.[16] Furthermore, the vinyl group as well as a cleavable
protecting group on nitrogen represent additional points of
divergence for the synthesis of a diverse library of piperidines.
The initial prospecting reactions were carried out with 3-
phenylpropanal (2a) and amino alcohol 1 (Table 1), which can
be conveniently accessed in >99:1 enantiomeric ratio in three
steps from 2-deoxy-D-ribose.[17] With dichloroacetic acid as the
promoter in combination with [Ir/(L)] as catalyst and sodium
borohydride as reductant, piperidine 4a was obtained in 66%
yield, albeit with moderate stereocontrol (Table 1, entry 1). In
line with our previous report on the stereospecific iridium-
catalyzed substitution of allylic alcohols with primary amines,[12a]
we found that the selectivity could be improved by addition of
iodide salts (entries 2-4). Subsequent experimentation revealed
that different promoters such as benzoic acid derivative 3
afforded the desired product with higher enantiomeric ratios but
Scheme 1. Stereoselective iridium-catalyzed cyclocondensation.
Over the years, considerable efforts have been made
towards developing new strategies for the assembly and
functionalization of chiral piperidines. Direct, asymmetric α-
functionalization through lithiation has been shown to be a
[*]
T. Sandmeier, S. Krautwald, Prof. Dr. E. M. Carreira
Laboratorium für Organische Chemie
HCI H335, Eidgenössische Technische Hochschule Zürich
Vladimir-Prelog-Weg 3, 8093 Zürich (Switzerland)
E-mail: carreira@org.chem.ethz.ch
Supporting information for this article is available on the WWW
under xxx
This article is protected by copyright. All rights reserved.

10.1002/anie.201706374
Angewandte Chemie International Edition
COMMUNICATION
lower yield and diastereomeric ratios (entry 5). Careful analysis
of the unpurified reaction mixture by 1H NMR spectroscopy
indicated the presence of tetrahydropyridine 7a (R = Bn,
Scheme 1) as the only co-product. Additional screening of
Brønsted acids (see SI) led to the hypothesis that 3 (pKa = 3.5)
was insufficiently acidic to promote in situ reduction. Thus,
employing trifluoroacetic acid (pKa = 0.2) in the reduction step
improved both overall conversion as well as diastereomeric ratio
(entry 6).[18]
products. Remarkably, α-aminoacetaldehyde derivative 2n
readily formed piperidine 4n with a nitrogen substituent at C-3 in
good yield, albeit somewhat diminished enantiospecificity.
Table 1. Optimization of reaction conditions[a]
Entry
Promoter
additive A
additive B
yield[b]
e.r.[c]
d.r.[d]
1[e]
2
Cl2HCCO2H
Cl2HCCO2H
Cl2HCCO2H
Cl2HCCO2H
3
-
LiI
-
66%
67%
57%
48%
47%[f]
76%
83:17
94:6
90:10
95:5
97:3
99:1
12:1
8:1
-
3
KI
-
10:1
7:1
4
(tBu)4NI
LiI
-
5
-
4:1
Scheme
2. Aldehyde substrate scope in the enantiospecific
cyclocondensation of 1. Yields refer to isolated products after flash
chromatography; Diastereomeric ratios shown in parentheses were
determined by 1H NMR analysis of unpurified reaction mixtures. For details on
reaction conditions, see Table 1 and Supporting Information. [a] Absolute
6
3
LiI
F3CCO2H
12:1
[a] Reaction conditions: 1)
1 (1.0 equiv), [{Ir(cod)Cl}2] (3 mol%), L
stereochemistry determined by X-ray analysis of
Cl2HCCO2H (1.0 equiv) instead of F3CCO2H. [c] prepared on 5 mmol scale.
a derivative of 2f. [b]
(12 mol%), additive 1 (10 mol%), 2a (2.0 equiv), promoter (1.2 equiv),
1,4-dioxane (0.3 M), RT; 2) NaBH4 (2.0 equiv), additive 2 (2.0 equiv),
dioxane/CH2Cl2/MeOH (1/1/1, 0.1 M) 0°C; [b] determined by 1H NMR
integration with 1,4-dinitrobenzene as internal standard; [c] enantiomeric
ratios determined by supercritical fluid chromatography (SFC); [d]
diastereomeric ratios determined by 1H NMR analysis of unpurified reaction
mixture; [e] CH2Cl2 was used as solvent; [f] in situ reduction did not go to
completion.
Among the most powerful synthetic methods are those that
rapidly build molecular complexity.[19] Accordingly, we sought to
leverage this cyclocondensation approach for the synthesis of
bicyclic piperidines (Scheme 3). Reaction of amino alcohol 1
with hemiacetal 2o under standard conditions afforded N,O-
With optimized conditions for one-pot cyclization and
reduction in hand, we next investigated the scope of the reaction
with regard to different aldehydes (Scheme 2, 2a-2n). For
aldehydes with sterically demanding sidechains (2b and 2c)
good enantiospecificities and diastereomeric ratios were
observed. Smaller substrates (2d and 2e), however, resulted in
lower selectivities. Presumably, the cis and trans stereoisomers
of iminium intermediate 6 can interconvert via tetrahydropyridine
7 (Scheme 1). Hence, larger substituents favor formation of the
thermodynamically more stable trans isomer.
Aldehydes incorporating alkenes were also found to be
suitable substrates. Piperidines 4g and 4h were isolated with
excellent enantiomeric ratios and without detectable double
bond isomerization. We next explored the scope of the reaction
with regard to carbonyl-derived side chains (2i-2k). Nitriles,
acetals and esters were well tolerated, giving the corresponding
piperidines in good yields and selectivities. To test the
robustness of this reaction, 2k was prepared on 5 mmol scale,
furnishing 1.1 g of the product with comparable yield and
Scheme 3. Formation of bicyclic piperidines in the Ir-catalyzed
cyclocondensation.
diastereoselectivity. In addition, aldehydes incorporating
a
protected alcohol (2l) and amine (2m) also formed the desired
This article is protected by copyright. All rights reserved.

10.1002/anie.201706374
Angewandte Chemie International Edition
COMMUNICATION
acetal 4o. Subjecting 4-chlorobutanal (2p) to the reaction
conditions resulted in formation of spirocycle 4p as the major
range of transformations for the building blocks. Piperidine 4g
bearing an alkene side chain readily underwent ring closing
metathesis upon treatment with Grubbs II catalyst to form
bicyclic amine 18. Ester 4k was reduced to aldehyde 19 in
nearly quantitative yield using diisobutylaluminum hydride.
Subsequent oxime formation, oxidation and dipolar [3+2]
cycloaddition gave decahydroisoquinoline 20, a common motif in
alkaloid natural products such as Yohimbine.[21]
product.
In
a
control
experiment
employing
cyclopropanecarboxaldehyde, 4p was not formed and reductive
amination was found to be the predominant reaction pathway.
This indicates that in the case of 4-chlorobutanal (2p), allylic
substitution occurs before intramolecular enamine alkylation.
Hence, we have demonstrated both, electrophilic and
nucleophilic reactivity for the intermediates of this cyclization
reaction, which can serve as the basis for one-pot synthesis of
more elaborate piperidine scaffolds.
Finally, we aimed to expand the scope of the reaction with
respect to the allylic alcohol component. To this end,
diastereomerically pure amino alcohols 9 and 11 were prepared.
Submitting these substrates to the standard reaction conditions
with 2a as the aldehyde component resulted in the formation of
trisubstituted piperidines 10 and 12, respectively, with good to
excellent stereoselectivity (Scheme 4). The relative configuration
of 10 and 12 was assigned by X-ray crystallographic analysis.
Collectively, this data suggests that the configuration of the
allylic position largely dictates the stereochemical outcome of
the reaction, irrespective of the stereocenter adjacent to the
amine.
Scheme 4. Preparation of trisubstituted piperidines via cyclocondensation. For
details on reaction conditions, see Table 1 and Supporting Information.
Scheme 5. Functionalization of 3,4-disubstituted piperidines. Reagents and
conditions: a) 4-methylmorpholine N-oxide (2.2 equiv), OsO4 (0.1 equiv),
THF/H2O (3:1 v/v), RT, 10 h, then NaIO4 (2.2 equiv), RT, 3 h; b) 9-BBN (2.0
equiv), THF, 0 °C to RT, 2 h then NaOH (aq., 3 M), H2O2 (19 equiv), 0 °C to
RT; c) NEt3 (1.2 equiv), MsCl (1.2 equiv), toluene, 0 °C, 30 min; d) toluene,
80 °C, 10 h; e) Pd(OH)2 (1.0 equiv), H2 (7 bar), EtOH, RT, 36 h; f) Cbz-Cl (1.2
equiv), toluene, 80 °C, 30 min; g) Fmoc-Cl (1.2 equiv), toluene, 80°C, 30 min;
The 3,4-disubstituted piperidines offer diverse handles for
further transformations, making them valuable building blocks for
the preparation of various substituted piperidines. Some
representative functionalization reactions are shown in
Scheme 5. Lemieux-Johnson oxidation of 4a (d.r. >20:1 after
chromatography) afforded aldehyde 13 in 65 % yield without
epimerization. Furthermore, standard hydroboration/oxidation
conditions cleanly formed alcohol 14 which was further
converted to quinuclidine derivative 15 in an efficient three-step
sequence. Due to their rigid framework, quinuclidines are
valuable building blocks in drug discovery[20] and our approach
represents a versatile strategy for the asymmetric synthesis of
this compound class.
h) Grubbs II (0.1 equiv), CH2Cl2, reflux,
4 h; i) DIBAL-H (1.2 equiv),
CH2Cl2/hexane (1.8:1 v/v), –78 °C, 30 min. 99 % yield; j) NEt3 (1.4 equiv),
NH2OH•HCl (1.2 equiv), EtOH, RT, 13 h; k) NaClO (3.7 equiv), CH2Cl2, 0°C to
RT, 3h.
In summary, we have developed a stereocontrolled,
iridium-catalyzed cyclocondensation of amino alcohols with
aldehydes to afford 3,4-trans-disubstituted piperidines in good
yields and stereoselectivity. It is noteworthy that this highly
modular approach combined with high functional group
tolerance gives access to a large number of substituted
piperidines with this otherwise difficult-to-access substitution
pattern. Functionalization of the adducts gave a number of
versatile piperidine derivatives including bi- and tricyclic products,
thus demonstrating the synthetic utility of this method. Given the
The benzyl protecting group on nitrogen could readily be
exchanged by carbamates (16 and 17) following treatment with
the corresponding chloroformates, thus enabling a broader
This article is protected by copyright. All rights reserved.

10.1002/anie.201706374
Angewandte Chemie International Edition
COMMUNICATION
Curtis, P. Beak, J. Am. Chem. Soc. 2002, 124, 11689-11698; c) M. S.
Taylor, E. N. Jacobsen, J. Am. Chem. Soc. 2003, 125, 11204-11205; d)
S. Brandau, A. Landa, J. Franzén, M. Marigo, K. A. Jørgensen, Angew.
Chem. 2006, 118, 4411-4415; Angew. Chem. Int. Ed. 2006, 45, 4305-
4309; e) M. Ito, A. Sakaguchi, C. Kobayashi, T. Ikariya J. Am. Chem.
Soc. 2007, 129, 290-291; f) J. F. Bower, T. Riis-Johannessen, P. Szeto,
A. J. Whitehead, T. Gallagher, Chem. Commun., 2007, 728-730.
[11] a) M. Amat, M. Cantó, N. Llor, C. Escolano, E. Malins, E. Espinosa, J.
Bosch, J. Org. Chem. 2002, 67, 5343-5351; b) J. M. Aurrecoechea, J.
M. Gorgojo, C. Saornil, J. Org. Chem. 2005, 70, 9640-9643; c) J. M.
Aurrecoechea, R. Suero, E. de Torres, J. Org. Chem. 2006, 71, 8767-
8778; d) B. V. S. Reddy, S. Yarlagadda, C. R. Reddy, M. R. Reddy, B.
Sridhar, D. Satyanarayana, B. Jagadeesh, Eur. J. Org. Chem. 2015,
3076-3085.
importance of piperidines in drug discovery and natural product
synthesis, the method reported herein will prove useful to
synthetic chemists.
Acknowledgements
We are grateful to the ETH Zürich and the Swiss National
Science Foundation (200020_152898 ) for financial support. We
thank Dr. N. Trapp and M. Solar for X-ray crystallographic
analysis.
[12] a) M. Roggen, E. M. Carreira J. Am. Chem. Soc. 2010, 132, 11917-
11919 b) M. A. Schafroth, D. Sarlah, S. Krautwald, E. M. Carreira, J.
Am. Chem. Soc. 2012, 134, 20276-20278; c) J. Y. Hamilton, D. Sarlah,
E. M. Carreira, J. Am. Chem. Soc. 2014, 136, 3006-3009; d) J. Y.
Hamilton, N. Hauser, D. Sarlah, E. M. Carreira, Angew. Chem. 2014,
126, 10935-10938; Angew. Chem. Int. Ed. 2014, 53, 10759-10762; e) J.
Ruchti, E. M. Carreira, J. Am. Chem. Soc. 2014, 136, 16756-16759; f)
S. Breitler, E. M. Carreira, J. Am. Chem. Soc. 2015, 137, 5296-5299; g)
J. Y. Hamilton, D. Sarlah, E. M. Carreira, Angew. Chem. 2015, 127,
7754-7757; Angew. Chem. Int. Ed. 2015, 54, 7644-7647; h) S. L.
Rössler, S. Krautwald, E. M. Carreira J. Am. Chem. Soc. 2017, 139,
3603-3606.
Keywords: Iridium • piperidines • allylation • catalysis •
stereoselective
[1]
[2]
For reviews, see: a) F. Lovering, J. Bikker, C. Humblet, J. Med. Chem.
2009, 52, 6752-6756; c); b) T. J. Ritchie, S. J. F. Macdonald, Drug
Discov. Today 2009, 14, 1011-1020; c) T. J. Ritchie, S. J. F. Macdonald,
S. Peace, S. D. Pickett, C. N. Luscombe, Med. Chem. Commun. 2012,
3, 1062-1069; d) E. Vitaku, D. T. Smith, J. T. Njardarson, J. Med. Chem.
2014, 57, 10257-10274.
For reviews on the synthesis of piperidines, see: a) P. D. Bailey, P. A.
Millwood, P. D. Smith, Chem. Commun. 1998, 633-640; b) M. G. P.
Buffat, Tetrahedron 2004, 60, 1701-1729; c) J. Cossy, Chem. Rec.
2005, 5, 70-80; d) E. A. Mitchell, A. Peschiulli, N. Lefevre, L. Meerpoel,
B. U. W. Maes, Chem. Eur. J. 2012, 18, 10092-10142.
[13] a) S. Krautwald, D. Sarlah, M. A. Schafroth, E. M. Carreira, Science
2013, 340, 1065-1068; b) S. Krautwald, D. Sarlah, M. A. Schafroth, E.
M. Carreira, J. Am. Chem. Soc. 2014, 136, 3020-3023; c) M. A.
Schafroth, G. Zuccarello, S. Krautwald, D. Sarlah, E. M. Carreira,
Angew. Chem. 2014, 126, 14118-14121; Angew. Chem. Int. Ed. 2014,
53, 13898-13901; d) T. Sandmeier, S. Krautwald, H. F. Zipfel, Angew.
Chem. 2015, 127, 14571-14575; Angew. Chem. Int. Ed. 2015, 54,
14363-14367.
[3]
[4]
C. De Risi, G. Fanton, G. P. Pollini, C. Trapella, F. Valente, V. Zanirato,
Tetrahedron: Asymmetry 2008, 19, 131-155.
a) H. Kawamoto, S. Ozaki, Y. Itoh, M. Miyaji, S. Arai, H. Nakashima, T.
Kato, H. Ohta, Y. Iwasawa, J. Med. Chem. 1999, 42, 5061-5063; b) S.
K. Ghorai, C. Cook, M. Davis, S. K. Venkataraman, C. George, P. M.
Beardsley, M. E. A. Reith, A. K. Dutta, J. Med. Chem. 2003, 46, 1220-
1228; c) M. Bourin, P. Chue, Y. Guillon, CNS Drug Rev. 2001, 7, 25-47.
a) D. Stead, G. Carbone, P. O’Brien, K. R. Campos, I. Coldham, A.
Sanderson, J. Am. Chem. Soc. 2010, 132, 7260-7261; b) T. K. Beng, W.
S. Tyree, T. Parker, C. Su, P. G. Williard, R. E. Gawley, J. Am. Chem.
Soc. 2012, 134, 16845-16855; c) G. Gelardi, G. Barker, P. O’Brien, D.
C. Blakemore, Org. Lett. 2013, 15, 5424-5427.
[14] a) M. Roggen, E. M. Carreira, Angew. Chem. 2011, 123, 5683-5686
Angew. Chem. Int. Ed. 2011, 50, 5568-5571; b) M. A. Schafroth, S. M.
Rummelt, D. Sarlah, E. M. Carreira, Org. Lett. 2017, 19, 3235-3238; c)
J. Y. Hamilton, S. L. Rössler, E. M. Carreira, J. Am. Chem. Soc. 2017, .
[15] a) see ref 14b; b) C. Defieber, M. A. Ariger, P. Moriel, E. M. Carreira,
Angew. Chem. 2007; 119, 3200-3204; Angew. Chem. Int. Ed. 2007, 46,
3139-3143; c) M. Roggen, E. M. Carreira, J. Am. Chem. Soc. 2010, 132,
11917-11919.
[5]
[6]
[7]
a) L. M. Lutete, I. Kadota, Y. Yamamoto, J. Am. Chem. Soc. 2004, 126,
1622-1623; b) D. M. Barber, H. J. Sanganee, D. J. Dixon, Org. Lett.
2012, 14, 5290-5293.
[16] a) A. Lumbroso, M. Cooke, B. Breit, Angew. Chem. 2013, 125, 1942-
1986; Angew. Chem. Int. Ed. 2013, 52, 1890-1932; b) S. Akai, Chem.
Lett. 2014, 43, 746-754; c) B. Bernet, A. Vasella, Helv. Chim. ActaI,
1984, 67, 1328-1347.
For enzymatic resolutions, see: a) E. Eichhorn, J.-P. Roduit, N. Shaw,
K. Heinzmann, A. Kiener Tetrahedron: Asymmetry 1997, 8, 2533-2536;
b) M. D. Weingarten, K. Sekanina, W. C. Still, J. Am. Chem. Soc. 1998,
120, 9112-9113; c) M. Angoli, A. Barilli, G. Lesma, D. Passarella, S.
Riva, A. Silvani, B. Daniel, J. Org. Chem. 2003, 68, 9525-9527; d) Z.
Peng, J. W. Wong, E. C. Hansen, A. L. A. Puchlopek-Dermenci, H. J.
Clarke, Org. Lett. 2014, 16, 860-863.
[17] See supporting information for details on substrate synthesis.
[18] For reports on reductions employing sodium borohydride and
trifluoroacetic acid see: a) Y. Suseela, M. Periasamy, Tetrahedron,
1992, 48, 371-376; b) K. Turnbull, D. M. Krein, Synthesis, 1999, 3, 391-
392.
[19] a) A. J. McCarroll, J. C. Walton, Angew. Chem. 2001,113, 2282-2307;
Angew. Chem. Int. Ed. 2001, 40, 2224-2248; b) M. M. Heravi, V. F.
Vavsari, RSC Adv. 2015, 5, 50890-50912; c) R. Ardkhean, D. F. J.
Caputo, S. M. Morrow, H. Shi, Y. Xiong, E. A. Anderson, Chem. Soc.
Rev. 2016, 45, 1557-1569.
For chemical resolutions, see: a) M. Binanzer, S.-Y. Hsieh, J. W. Bode,
J. Am. Chem. Soc. 2011, 133, 19698-19701; b) B. Wanner, I. Kreituss,
O. Gutierrez, M. C. Kozlowski, J. W. Bode, J. Am. Chem. Soc. 2015,
137, 11491-11497; c) I. Kreituss, K.-Y. Chen, S. H. Eitel, J.-M. Adam, G.
Wuitschik, A. Fettes, J. W. Bode, Angew. Chem. 2016, 128, 1579-1582;
Angew. Chem. Int. Ed. 2016, 55, 1553-1556; d) I. Kreituss, J. W. Bode,
Acc. Chem. Res. 2016, 49, 2807-2821.
[20] a) C. J. Swain, T. M. Fong, K. Haworth, S. N. Owen, E. M. Seward, C.
D. Strader, Bioorg. Med. Chem. Lett. 1995, 5, 1261-1264; b) S. B.
Cammerer, C. Jimenez, S. Jones, L. Gros, S. O. Lorente, C. Rodrigues,
J. C. F. Rodriuges, A. Caldera, L. M. R. Perez, W. da Souza, M. Kaiser,
R. Brun, J. A. Urbina, D. G. Pacanowska, I. H. Gilbert, Antimicrob.
Agents Chemother. 2007, 51, 4049-4061; c) F.-Y. Chan, N. Sun, Y.-C.
Leung, K.-Y. Wong, J. Antibiot. 2015, 68, 253-258.
[8]
[9]
For recent reviews on asymmetric dearomatization see: a) C.-X. Zhuo,
W. Zhang, S.-L. You, Angew. Chem. 2012, 124, 12834-12858; Angew.
Chem. Int. Ed. 2012, 51, 12662-12686; b) Q. Ding, X. Zhou, R. Fan,
Org. Biomol. Chem. 2014, 12, 4807-4815.
K. Kubota, Y. Watanabe, K. Hayama, H. Ito, J. Am. Chem. Soc. 2016,
138, 4338-4341.
[21] a) E. van Tamelen, M. Shamma, A. Burgstahler, J. Wolinsky, R. Tamm,
P. Aldrich, J. Am. Chem. Soc. 1958, 80, 5006-5007; b) D. D. Weller, H.
[10] a) M. S. Yu, I. Lantos, Z.-Q. Peng, J. Yu, T. Cacchio, Tetrahedron Lett.
2000, 41, 5647-5651; b) T. A. Johnson, D. O. Jang, B. W. Slafer, M. D.
This article is protected by copyright. All rights reserved.

10.1002/anie.201706374
Angewandte Chemie International Edition
COMMUNICATION
Rapoport, J. Am. Chem. Soc. 1976, 98, 6650-6657; c) F.-E. Chen, J.
Huang, Chem. Rev. 2005, 105, 4671-4706.
This article is protected by copyright. All rights reserved.

10.1002/anie.201706374
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 2:
COMMUNICATION
Tobias Sandmeier, Simon Krautwald,
and Erick M. Carreira**
Page No. – Page No.
Stereoselective Synthesis of
Piperidines via Iridium-Catalyzed
Cyclocondensation
Iridium-catalyzed cyclocondensation of amino alcohols and aldehydes is reported.
This method furnishes trans-3,4-disubstituted piperdines in high yield,
enantiospecificity and diastereoselectivity.
This article is protected by copyright. All rights reserved.