TMSOTf mediated '5/6-: Endo-dig ' reductive hydroamination for the stereoselective synthesis of pyrrolidine and piperidine derivatives

Article abstract of DOI:10.1039/c9cc03127h

A TMSOTf mediated 5/6-endo-dig reductive hydroamination cascade on internal alkynylamines gave expedient, stereoselective access to pyrrolidine and piperidine derivatives. We also demonstrate that a protecting group on nitrogen has a profound effect on the reactivity as well as diastereoselectivity of the reductive hydroamination cascade.

Full text of DOI:10.1039/c9cc03127h

View Article Online
View Journal
ChemComm
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: S. J. Gharpure, D.
S. Vishwakarma and R. K. Patel, Chem. Commun., 2019, DOI: 10.1039/C9CC03127H.
This is an Accepted Manuscript, which has been through the
Volume 52 Number
1 4 January 2016 Pages 1–216
Royal Society of Chemistry peer review process and has been
accepted for publication.
ChemComm
Accepted Manuscripts are published online shortly after
Chemical Communications
www.rsc.org/chemcomm
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1359-7345
COMMUNICATION
Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
first methanofullerene derivatives of Sc N@D5h-C80
=
3
rsc.li/chemcomm

Page 1 of 4
ChemComm
Please do not adjust margins
View Article Online
DOI: 10.1039/C9CC03127H
COMMUNICATION
TMSOTf Mediated ‘5/6-endo-dig’ Reductive Hydroamination for
the Stereoselective Synthesis of Pyrrolidine and Piperidine
derivatives
Received 00th January 20xx,
Accepted 00th January 20xx
Santosh J. Gharpure,* Dharmendra S. Vishwakarma, Raj K. Patel
DOI: 10.1039/x0xx00000x
TMSOTf mediated 5/6-endo-dig reductive hydroamination cascade attention.4 However, the corresponding hydroamination of
on internal alkynylamines gave an expedient, stereoselective alkynylamines is difficult and much less explored for the
access to pyrrolidine and piperidine derivatives. We also synthesis of dihydropyrrole and their derivatives. Complexes of
demonstrate that protecting group on nitrogen has profound effect transition metals such as gold, silver, platinum and palladium
on the reactivity as well as diastereoselectivity of reductive have been used to promote 5-endo-dig hydroamination of
hydroamination cascade.
alkynylamines leading to dihydropyrroles.5 Surprisingly, the
endo-dig reductive hydroamination of alkynylamines leading to
the synthesis of pyrrolidines and piperidines remains hitherto
unknown.3 In continuation of our interest on the synthesis of
oxa and aza-cycles,6 herein we disclose the first examples of
transition metal free 5/6-endo-dig reductive hydroamination
cascade mediated by TMSOTf for the stereoselective synthesis
of pyrrolidines and piperidines. This general method is further
used in the formal synthesis of biologically active compound
McN-4612-Z.
The Pyrrolidine and piperidine structural motifs are present in
many bioactive alkaloid natural products. Isosolenopsin (1) is a
constituent of the venom of fire ant Solenopsis.1a It was found
to be a blocker of the neuromuscular transmission and is also a
potent selective inhibitor of the neuronal nitric oxide
synthase.1b-c Coniine (2) is a volatile poisonous compound found
in hemlock and other plants. It affects the motor nerves, causing
paralysis and asphyxia (Fig. 1).1d-e McN-4612-Z (3) is a potential
antidepressant
agent.1f
Cycloalkane-fused
pyrrolidine
Ar
( )n
( )n
( )n
derivatives such as rampiril (4) and trandolapril (5) are
angiotensin-converting enzyme (ACE) inhibitors used for
treating hypertension and congestive heart failure.2
Et3SiH
( )n
Ar
R
Ar
R
Ar
TMSOTf
R
N
N
N
H
NH
P
P
R
P
P
iminium ion
Int-B
6
7
Int-A
H
Scheme 1: Envisioned 5/6-endo-dig reductive hydroamination for aza-
n-C11H23
N
Me
N
CH3
H
cycle synthesis.
H
H
N
Isosolenopsin A
1
H
Coniine
2
McN-4612-Z
3
In a program directed at studying synthesis of various oxa- and
aza-cycles using Lewis/Brønsted acid mediated alkyne
functionalization, we envisioned that alkynylamines 6 in the
presence of Lewis/Brønsted acid would form transiently more
O
O
OH
N
OH
N
O
O
H
N
H
N
H
O
H
O
O
O
CH3
CH3
reactive
cyclic
enamine
Int-A
via
5/6-endo-dig
CH3
Ramipril
4
CH3
Trandolapril
Ph
Ph
hydroalkoxylation. Enamine Int-A would subsequently generate
iminium ion Int-B whose trapping with hydride would furnish
aza-cyclic derivatives 7 (Scheme 1).
5
Figure 1. Natural products and bioactive molecules having pyrrolidines and
piperidines core.
In order to test the proposed hypothesis, known alkynylamines
Recent years have seen emergence of transition metal
catalyzed intramolecular hydroamination as a method of choice
for the synthesis of aza-cycles.3 Intramolecular hydroamination
of o-alkynylanilines, which favoured due to formation of
aromatic system (indole derivatives), has attracted more
6a,7 derived from L-alanine, was subjected to treatment with
.
BF3 OEt2 (1 equiv) and Et3SiH in CH2Cl2 as solvent. Gratifyingly,
the reaction proceeded smoothly to give the desired pyrrolidine
derivative 7a in good yield as a single diastereomer (Table 1,
entry 1). Various other Lewis as well as Brønsted acids were
screened for optimizing the reaction. TfOH and TMSOTf were
found to give the pyrrolidine derivative 7a in comparable yield
and diastereoselectivity (Table 1, entries 2-3). In order to make
the process more economical, we tried to reduce the catalyst
a. Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai
– 400076, India.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
Please do not adjust margins

ChemComm
Please do not adjust margins
Page 2 of 4
COMMUNICATION
Journal Name
loading. Interestingly, 50 mol% of TfOH gave product 7a in Next, different protective groups bearing alkynylamines were
View Article Online
excellent yield, but further lowering catalyst loading to 10 subjected to reductive amination underDoOpI:t1im0.1i0ze39d/Cc9oCnCd0it3i1o2n7Hs,
mol%resulted in slight drop in efficiency (Table 1, entries 4-5).
to understand their effect on this cascade reaction.
Alkynylamine bearing sulfonyl protecting groups such as o- and
p-nosyl as well as triflate gave the corresponding pyrrolidine
derivatives 7b-d in good yield albeit with poor
diastereoselectivity (Scheme 2). On the other hand, mesyl
protected alkynylamine gave the pyrrolidine 7e in good yield as
a single diastereomer. Trifluroacetyl protected amine 6f also
provided the corresponding pyrrolidine derivative 7f, albeit in
lower yield. However, other protecting group such as Cbz and
Boc failed to give corresponding pyrrolidine derivatives 7g-h
and only starting material was recovered back.
Table 1. Optimization of reductive hydroamination for the synthesis of
pyrrolidine 7a.
Ph
Et3SiH (1 equiv)
Lewis/Brønsted acid
Me
Ph
N
CH2Cl2
H
H
Me
NH
Ts
Ts
6a
7a
entry
acid
equiv temp (oC) time (h) yield (%)a drb
1
2
3
4
5
6
7
8
9
BF3·OEt2
TfOH
1
1
0-rt
0-rt
0-rt
0-rt
0-rt
0-rt
0-rt
0-rt
0-rt
0-rt
0-rt
11
10
8
70
70
74
80
61
83
84
³
³
³
³
³
³
³
19:1
19:1
19:1
19:1
19:1
19:1
19:1
-
TMSOTf
TfOH
1
These results indicate that the reductive hydroamination is
affected by nitrogen’s nucleophilicity. Higher the ability of
protecting group to coordinate with Lewis acid, lower is the
nucleophilicity of nitrogen and slower is the rate of
hydroamination step (amides and carbamate protection fared
poorly). Similarly, Tf protection is more electron withdrawing
compared to Ns, and was found to give sluggish reactions
compared to latter, which in turn reacted slowly as against Ms
and Ts protected derivatives.
0.5
0.1
23
24
24
48
48
48
48
48
TfOH
TMSOTf 0.1
Ag(OTf) 0.1
Cu(OTf)2 0.1
c
-
FeCl3
0.1
13
³
19:1
-
10 TMSOTfd 0.1
11 TMSOTfe 0.1
-
f
-
-
Ar
aisolated yield. bmeasured on the crude reaction mixture by 1H NMR.
cstarting material was recovered. dtoluene was used as solvent. eCH3CN was
used as solvent. corresponding hydrolyzed product 4-methyl-N-(5-oxo-5-
H
H
Et3SiH
TMSOTf (10 mol %)
CH2Cl2, 0 oC-rt
f
Ar
N
NH
Ts
H
H
H
H
phenylpentan-2-yl)benzenesulfonamide was obtained in 68% yield.
H
Ts
6
7
Me
Using 10 mol% of TMSOTf or Ag(OTf) furnished the pyrrolidine
7a in excellent yield with excellent diastereoselectivity, albeit
latter required long reaction time (Table 1, entries 6-7). While
Cu(OTf)2 failed to furnish pyrrolidine 7a, FeCl3 reacted only
sluggishly and most of the starting material was recovered back
(Table 1, entries 8-9). Reaction didn’t procced in toluene as
solvent, whereas in acetonitrile, corresponding hydrolyzed
Me
Me
Me
N
N
N
H
H
H
H
Me
OMe
Ts
Ts
Ts
7i
dr >
7j
7k
dr >
Me
19:1
89%,
83%, dr >19:1
48%,
19:1
R
H
Me
Me
N
R
N
N
H
H
H
H
H
S
Ts
Ts
Ts
isobutyl,
isopropyl,
rac-
Ph,
dr >
81%
76%
80%
7o,
7p,
7q,
R=
R=
R=
R =
m-OMe,
7l, 86%,
, 7m
, 0%
dr >19:1
7n
75%,
dr >
R =
H
p-NO
19:1
2
product
4-methyl-N-(5-oxo-5-phenylpentan-2-
19:1
H
Me
H
yl)benzenesulfonamide was obtained (Table 1, entries 10-11).
After all this screening, TMSOTf (0.1 equiv) and Et3SiH (1 equiv)
in CH2Cl2 at 0 oC to room temperature was identified as optimal
condition to study the substrate scope. The stereochemistry of
the major diastereomer was assigned as cis based on NOE
experiments and was further confirmed by single crystal X-ray
( )n
Ph
Ph
N
H
N
N
N
H
H
H
Ts
H
H
Ts
Ts
Ts
rac-7r
81%, >19:1
rac-7s, n=2, 87%
rac-7t, n=1, 82%
(dr >19:1)
rac-7u
91%, dr 9:1
rac-7v,
90%
Scheme 3. Reductive hydroamination for the stereoselective synthesis
diffraction study.8
of pyrrolidines 7.
Ph
Et3SiH
TMSOTf (10 mol %)
Further scope and limitation of the reductive hydroamination
cascade for the synthesis of pyrrolidine derivatives was then
Me
Ph
N
CH2Cl2, 0 oC-rt
H
H
Me
NH
rac-6
P
investigated
using
optimized
reaction
conditions.
rac-7
P
Alkynylamines 6i-j with electron releasing group on aryl ring
gave corresponding pyrrolidine derivatives 7i-j in good yield as
a single diastereomer (Scheme 3). Alkynylamines 6k bearing
strong electron releasing OMe group in para position furnished
desired pyrrolidine derivative 7k in slightly lower yield,
however, meta-OMe substitution gave good yield of the
pyrrolidine 7l. Alkynylamine 6m with strongly electron
withdrawing NO2 substituent did not participated in the
reductive hydroamination cascade. These observations are
consistent with formation of enamine via a vinyl cation
intermediate as the first step of cascade process. Heteroaryl
Me
Me
Me
Me
Me
N
N
N
H
H
H
H
H
H
p-Ns
o-Ns
Tf
23h
7c,
rac-7d, 36h
76%, dr 2.1:1
7b,14h
rac-
rac-
dr 2.3:1
dr
4:1
89%,
87%,
Me
N
N
H
Ms
N
H
H
O
H
H
H
P
CF3
rac-7f, 36h
36%, dr 1.8:1
BRSM = 72%
rac-7e, 26h
90%, dr >19:1
rac-7g; Cbz = 0%
rac-7h; Boc = 0%
Scheme 2. Effect of nitrogen protecting group on the reductive
hydroamination.
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 4
ChemComm
Please do not adjust margins
Journal Name
COMMUNICATION
substituted pyrrolidine derivative 7n was also obtained in good completely. Furthermore, alkynylamine 8h-i andVrieawcA-r8ticj-lekOanllisnoe
yield and excellent diastereoselectivity. Alkynylamines 6o-q lead to the requisite piperdine derivativDeOsI9: 1h0-.i10a3n9d/Cr9aCcC-093j-1k27iHn
having isobutyl, isopropyl and phenyl substituent on carbon good yield and poor to moderate diastereoselectivity. The
bearing amine group furnished corresponding pyrrolidine stereochemistry of the major diastereomer was confirmed
derivatives 7o-q uneventfully. Both the trans- and cis-fused based on single crystal X-ray diffraction studies on the
cyclohexyl pyrrolidine derivatives rac-7r (on 1.6 mmol scale) pyrrolidine 9a, 9c, 9d’, 9h.8
and rac-7s as well as cis-fused cyclopentyl pyrrolidine derivative
Et3Si
rac-7t were obtained in good yield from corresponding
H
Ar
H
H
Ar
N
H
alkynylamine rac-6r-t. These derivatives of cycloalkane-fused
pyrrolidines rac-7r-t are found in the core structures of Ramipril
and Trandolapril and could potentially serve as precursors for
their synthesis.9,5g The 2,4-disubstitued pyrrolidine rac-7u was
also obtained with good yield and diastereoselectivity. In all the
cases the stereochemistry of the cis-diastereomer was
confirmed by NOE studies. It was further confirmed by single
crystal X-ray diffraction study on the pyrrolidine 7n.8
H
N
N
Ar
Ts
Ts
R
Int-C
R
Ts
R
H
Int-D
cis-7
SiEt3
N
SiEt3
H
R
R
N
Ar
Ts
Ar
H
R
Ts
H
H
Et3Si
Int-E
Int-F
H
R
Ts
N
H
Ar
H
H
N
Et3SiH
H
Ar
TMSOTf (1 equiv)
H
Ts
cis-9
trans-9
CH2Cl2, 0 oC-rt
Ar
N
Ar
NH
Ts
H
H
Scheme 5. Rationale for stereoselectivity.
H
Ts
8
9
The diastereoselectivity of reductive hydroamination cascade
can be explain by model shown in Scheme 5. It is plausible that,
because of the A1,2 steric repulsion between the tosyl group and
alkyl substituent at C5, Int-C is less stable than Int-D. Thus,
‘inside attack’ of hydride to the more stable iminium ion Int-D
affords the pyrrolidine cis-7 as the major product.10 In the 6-
membered cyclic iminium ion, half chair conformation Int-E
having R in the pseudoequatorial position would be preferred
over half chair conformation Int-F. Similar to oxonium ion
trapping in six-membered rings, axial attack of the hydride to
the iminium ion is preferred as it would generate more stable
chair conformation (as against attack from equatorial side
which generates twist boat conformation).11 Thus, more stable
iminium ion Int-E upon axial attack by hydride from
triethylsilane gives the piperidine cis-9 as the major product.
Me
Me
N
Me
N
Me
N
H
H
H
H
H
Ts
Ts
Ts
R
OMe
R = H, 9a 80%, dr 6.7:1
R = Me, 9b 69%, dr 9:1
9c
70%, dr 4:1
9d'
62%
Me
R
Me
N
N
Me
N
H
H
R
H
H
H
Ts
Ts
Ts
S
9g'
46%
R = Ph, 9h, 70%, dr 3:1
R = isopropyl, 9i, 68%, dr 7.8:1
R = m-OMe, 9e, 59%, dr 1.3:1
R = p-NO2, 9f, 0%
H
H
H
N
N
N
H
H
H
H
H
H
Ts
Ts
Ts
rac-9j
67%, dr 1.5:1a
rac-9k
71%, dr 2.3:1
rac-9l
80%
Scheme 4. Reductive hydroamination for the stereoselective synthesis
of piperidines 9
Ph
Me3SiCN
TMSOTf
To further expand the scope of the reductive hydroamination
cascade, the strategy was applied to the synthesis of piperidine
derivatives 9. Thus, alkynylamine 8a was subjected to optimized
condition of pyrrolidine i.e. TMSOTf (0.1 equiv) and Et3SiH (1
equiv) in CH2Cl2 at 0 oC, unfortunately only trace amount of
conversion was observed. With further screening, it was found
that when the reaction of alkynamine 8a was carried out using
TMSOTf (1 equiv) and Et3SiH (2 equiv) in CH2Cl2 at 0 oC to room
temperature, the piperidine derivative 9a was obtained in good
yield albeit with moderate diastereoselectivity. Alkynylamine
8b-c with electron releasing group on aryl ring (Me) gave
corresponding piperidine derivatives 9b-c in good yield (Scheme
4). Alkynylamine 8d bearing strong electron releasing OMe
group on aryl ring gave hydrolyzed product instead of desired
product, perhaps due to slow reduction of the enamine
intermediate. However, intermediate cyclic enamine 9d’ could
be isolate by stopping reaction early. Similarly, alkynylamine
with heteroaryl ring 8g also gave cyclic enamine 9g’ in 46 % yield
instead of piperidine 9g. Even in this case, alkynylamine 8f with
electron withdrawing NO2 substituent on the aryl ring did not
participate in reaction and starting material was recovered back
Me
Ph
CN
N
CH2Cl2, 0 oC-rt
81%
H
Me
NH
Ts
Ts
6a
10, dr 9:1
Scheme 6. Hydroamination-iminium ion trapping cascade for the
synthesis of trisubstituted pyrrolidine 10.
In continuation of this idea, we envisaged that the in situ
generated iminium ion can be trapped by other nucleophiles.
To test this hypothesis, alkynylamine 6a was treated with
TMSCN (2 equiv) and TMSOTf (1 equiv) in CH2Cl2. Gratifyingly,
the trisubstituted pyrrolidine 10 was obtained in good yield and
excellent diastereoselectivity (Scheme 6).
OH
1. BH3.Me2S
THF
Me
N
Me
N
2. H2O2, NaOH
EtOH
Ts
Ts
11
67%, dr > 19:1
OMe
OMe
9d'
Scheme 7. Enantiospecific synthesis of 3-hydroxy piperidine 9d’.
Since the enamine 9d’ was readily available, we explored its
functionalization to gain access to 3-hydroxy piperidine
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

ChemComm
Please do not adjust margins
Page 4 of 4
COMMUNICATION
Journal Name
2
3
(a) J. E. Frampton and D. H. Peters, Drugs, 1995, 49, 440. (b)
derivative. Thus, piperidine 9d’ (cf. Scheme 4) was subjected to
hydroboration using BH3 SMe2 followed by oxidation to furnish
the 3-hydroxy piperidine derivative 11 with excellent
diastereoselectivity (Scheme 7). The stereochemistry of the 3-
hydroxy piperidine 11 was confirmed by the single crystal X-ray
diffraction studies.11
View Article Online
D. C. Peters, S. Noble and G. l. Plosker, Drugs, 1998, 56, 871.
DOI: 10.1039/C9CC03127H
.
For reviews on hydroamination: (a) T. E. Müller, K. C. Hultzsch,
M. Yes, F. Foubelo and M. Tada, Chem. Rev., 2008, 108, 3795.
(b) L. Huang, M. Arndt, K. Gooßen, H. Heydt and J. Gooßen,
Chem. Rev., 2015, 115, 2596.
4
(a) D. E. Rudisill and J. K. Stille, J. Org. Chem., 1989, 54, 5856.
(b) X. Zeng, R. Kinjo, B. Donnadieu and G. Bertrand, Angew.
Chem. Int. Ed., 2010, 49, 942. (c) X. Li, A. R. Chianese, T. Vogel
and R. H. Crabtree, Org. Lett., 2014, 16, 2058. (d) C. Zheng, J.
J. Chen and R. Fan, Org. Lett., 2014, 16, 816. (e) G. Xia, X. Han
and X. Lu, Org. Lett., 2014, 16, 2058. (f) E. A. Filatova, A. F.
Pozharskii, A. V. Gulevskaya and V. A. Ozeryanskii, J. Org.
Chem. 2015, 80, 872. (g) B. Yao, Q. Wang and J. Zhu, Chem.
Eur. J., 2015, 21, 7413. (h) M. Jash, B. Das and C. Chowdhury,
J. Org. Chem., 2016, 81, 10999. (i) Y. Luo, R. S. Basha, D. M.
Reddy, Y. Xue, T. Chen and C. Lee, Org. Lett., 2018, 20, 6872.
and the reference are cited there in.
(a) B. C. J. van Esseveldt, F. L. van Delft, R. de Gelder and F. P.
J. T. Rutjes, Org. Lett., 2003, 5, 1717. (b) W. V. Rossom, Y.
Matsushita, K. Ariga and J. P. Hill, Rsc. Adv., 2014, 4, 4897. (c)
Y. F. Yu, C. Shu, B. Zhou, J. Q. Li, J. M. Zhoua and L. W. Ye,
Chem. Commun., 2015. 51, 2126. (d) A. Galván, J. Calleja, F. J.
Fañanás and F. Rodráguez, Chem. Eur. J., 2015, 21, 3409. (e)
S.ꢀN. Miaskiewicz, J. M. Weibel, P. Pale and A. Blanc, Org.
Lett., 2016, 18, 844. (f) S. Miaskiewicz, B. Gaillard, N. Kern, J.
M. Weibel, P. Pale and A. Blanc, Angew. Chem. Int. Ed., 2016,
55, 9088. (g) M. C. Chung, Y. H. Chan, W. J. Chang and D. R.
Hou, Org. Biomol Chem. 2017, 15, 3783. (h) X. Yu, Z. Guo, H.
Song, Y. Liu and Q. Wang, Adv. Synth. Catal., 2018, 360, 1077.
(i) Y. Li, R. Pi, X. Ouyang, R. Song and J. Li, Org. lett., 2019, 21,
397.
(a) S. J. Gharpure, M. K. Shukla and U. Vijayasree, Org. Lett.,
2009, 11, 5466. (b) S. J. Gharpure and S. R. B. Reddy, Org. Lett.,
2009, 11, 2519. (c) S. J. Gharpure and J. V. K. Prasad, J. Org.
Chem., 2011, 76, 10325. (e) S. J. Gharpure, D. Anuradha, J. V.
K. Prasad and P. S. Rao, Eur. J. Org. Chem., 2015, 86. (f) S. J.
Gharpure, S. K. Nanda, P. A. Adate and Y. G. Shelke, J. Org.
Chem., 2017. 82. 2067. (g) S. J. Ghrpure, S. K. Nanda, Padmaja
and Y. G. Shelke, Chem. Eur. J., 2017, 23, 1. (h) S. J. Ghrpure,
D. S. Vishwakarma and S. K. Nanda, Org. Lett., 2017, 19, 6534.
C. H. Ding, L. X. Dai and X. L. Hou, Tetrahedron, 2005, 61, 9586.
CCDC 1907330-1907336 contain the supplementary
crystallographic data for this paper. These data can be
Ph
H
Et3SiH
TMSOTf
PhSH
Cs2CO3
N
ref-15b
N
N
H
CH2Cl2
0o C-rt
THF, 82%
NH
Ns
Ns
7w
94%
6w
12
Ph
rac-McN-4612-Z
3
Scheme 8. Formal synthesis of McN-4612-Z.
Finally, this reductive hydroamination cascade was employed as
a key step in the formal synthesis of McN-4612-Z 3. Towards this
end, alkynylamine 6w (1 mmol) was subjected reductive
amination cascade to furnish pyrrolidine 7w. Deprotection of
nosyl group using thiophenol led to the 2-phenylpyrrolidine 12
(Scheme 8). 2-Phenylpyrrolidine 12 was converted to McN-
4612-Z 3 following the protocol developed by Hou and co-
worker.12 Thus, synthesis of 2-phenylpyrrolidine 13 constituted
formal total synthesis of racemic McN-4612-Z rac-3.
In conclusion, we have developed transition metal free, Lewis
acid mediated 5/6-endo-dig reductive hydroamination cascade
of alkynylamine for the stereoselective synthesis of pyrrolidine
and piperidine derivatives. Protecting group on nitrogen alters
it nucleophilicity, which in turn affects reactivity and
diastereoselectivity of 5-endo-dig reductive hydroamination
cascade. The in situ generated iminium ion can also be trapped
by another nucleophile to furnish trisubstituted pyrrolidine
derivative. The developed method was applied in highly
stereoselective synthesis of 3-hydroxy piperidine and in the
forma total synthesis of biologically active compound McN-
4612-Z.
5
6
7
8
Acknowledgment
We thank SERB, New Delhi for financial support. We thank Mr.
Darshan Mhatre of the X-ray facility of the Department of Chemistry,
IIT Bombay for collecting the crystallographic data and IRCC, IIT
Bombay for funding central facilities. We are grateful to UGC, New
Delhi for the award of research fellowship to DSV and RKP.
obtained
free
of
charge
via
www.ccdc.cam.ac.uk/data_request/cif.
9
(a) F. Brion, C. Marie, P. Mackiewicz, J. M. Roul and J. Buendia,
Tetrahedron lett., 1992, 33, 4889. (b) G. C. M. Kondaiah, M.
Vivekanandareddy, L. A. Reddy, S. V. Anurkar, V. M. Gurav, M.
Ravikumar, A. Bhattacharya, R. Bandichhor, Synth. Commun.,
2011, 41, 1186.
10 (a) S. Chamberland, J. W. Ziller and K. A. Woerpel, J. Am.
Chem. Soc., 2005, 127, 4232 (b) L. Ayala, C. G. Lucero, J. A. C.
Romero, S. A. Tabacco and K. A. Woerpel, J. Am. Chem. Soc.,
2003, 125, 15521.
Conflicts of interest
“There are no conflicts to declare”.
11 (a) P. R. Sultane and R. G. Bhat, J. Org. Chem., 2012, 77, 11349
(b) J. M. Humphrey, E. P. Arnold, T. A. Chappie, J. B.
Feltenberger, A. Nagel, W. Simon, S. C. Countreras, N. J. Tom
and B. T. O’Neill, J. Org. Chem., 2009, 74, 4525 (c) C. E. Neipp
and S. F. Martin, Tetrahedron lett., 2002, 43, 1779 (d) C. W.
Jefford and J. B. Wang, Tetrahedron lett., 1993, 34, 2911 (e) R.
V. Stevens, Acc. Chem. Res. 1984, 17, 289 (f) Y. Matsumura, K.
Maruoka and H. Yamamoto, Tetrahedron lett., 1982, 23, 1929.
12 (a) B. E. Maryanoff, D. F. McComsey, R. R. Inners, M. S. Mutter,
M. S. Wooden, S. L. Mayo and R. A. Olofson. J. Am. Chem. Soc.,
1989, 111, 2487 (b) Y. Zhang, D. Kong, R. Wang and G. Hou,
Org. Biomol. Chem., 2017, 15, 3006 and the references cited
therein.
References
1
(a) S. Leclercq, D. Daloze and J. C. Braekman, Org. Prep.
Proced. Int., 1996, 28, 499. (b) G. Howell, J. Butler, R. D. de
Shazo, J. M. Farley, H. –L. Liu, N. P. D. Nanayakkara, A. Yates,
G. B. Yi and R. W. Rockhold, Ann. Allergy, Asthma Immunol.,
2005, 94, 380. (c) N. Gouault, M. Le Roch, G. de Campos Pinto
and M. David, Org. Biomol. Chem., 2012, 10, 5541. (d) J.
Vetter, Food Chem. Toxicol., 2004, 42, 1373. (e) T. Reynolds,
Phytochemsitry, 2005, 66, 1399. (f) B. E. Maryanoff, D. F.
McComsey, M. J. Costanzo, P. E. Setler, J. F. Gardocki, R. P.
Shank and C. R. Schneider, J. Med. Chem., 1984, 27, 943.
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins