Diastereoselective synthesis of α,α,α′-trisubstituted pyrrolidines and piperidines by directed sequential lithiation/alkylation Dedicated to the memory of Professor Bob Gawley who passed on in March 2013. His mentorship forever will be appreciated

Article abstract of DOI:10.1016/j.tetlet.2014.11.031

The stereocontrolled synthesis of α,α,α′-trisubstituted pyrrolidines and piperidines has been accomplished through α′-lithiation/trapping of the corresponding α,α-disubstituted Boc-protected azaheterocycle with various electrophiles. The relative configur

Full text of DOI:10.1016/j.tetlet.2014.11.031

Tetrahedron Letters xxx (2014) xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
0
Diastereoselective synthesis of
a
,a,a
-trisubstituted pyrrolidines and
piperidines by directed sequential lithiation/alkylation
⇑
Timothy K. Beng , Nathan Fox
Department of Chemistry, Susquehanna University, Selinsgrove, PA 17870, USA
a r t i c l e i n f o
a b s t r a c t
0
Article history:
The stereocontrolled synthesis of
a
,
a
,a
-trisubstituted pyrrolidines and piperidines has been
-disubstituted Boc-protected
Received 16 October 2014
Revised 5 November 2014
Accepted 6 November 2014
Available online xxxx
0
accomplished through
a
-lithiation/trapping of the corresponding
azaheterocycle with various electrophiles. The relative configuration of the major diastereomer has the
-substituent trans to the a-aryl group in the pyrrolidines but cis to the a-aryl group in the piperidines.
The diastereoselectivity of the lithiation/alkylation of pyrrolidines is unaffected by TMEDA but decreases
a,
a
0
a
in the presence of (ꢀ)-sparteine in diethyl ether.
Dedicated to the memory of Professor Bob
Gawley who passed on in March 2013. His
mentorship forever will be appreciated
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Directed lithiation
Trisubstituted pyrrolidines
Trisubstituted piperidines
Diastereoselective alkylation
Electrophilic substitution
The pyrrolidine and piperidine motifs are ubiquitous structural
motifs in bioactive molecules, including alkaloid natural products
and pharmaceuticals. Furthermore, functionalized pyrrolidines
96:4 dr (trans:cis).28 Later, O’Brien utilized a (+)-sparteine surro-
gate (i.e., 12) to synthesize proline ester derivative 4 in >99:1 er
and >95:5 dr (cis:trans), albeit in low yields as well. Mechanistic
1
20
and piperidines feature prominently as structural motifs in chiral
organocatalysts and chiral auxiliaries.3 Additionally, the versatil-
ity of substituted pyrrolidines and piperidines in the synthesis
has been amply demonstrated.4
studies conducted by Coldham and O’Brien have since revealed
that the minor rotamer of 1 rotates extremely slowly at low
temperatures (the half-life for rotation of the Boc-group was
2
–18
In 1989, Beak disclosed that unsubstituted Boc-protected
azaheterocycles may be effectively functionalized at the
19
a
-position through a lithiation/alkylation sequence.
Several
have since extended the
-functionalizations en
Ph
Me
Ph Ph
Ph
N
Boc
S-1
N
Boc
cis-2
N
MeO C
Ph
2
2
0–26
27,16
N
H
cis-4
researchers,
Beak methodology to include sequential
route to access
including one of us,
Boc
trans-3
a
0
a
,a- and
a,a
-disubstituted N-heterocycles, in both
Me
Ph
Me
racemic and enantioenriched forms. It has been shown that the
lithiation of phenyl pyrrolidine S-1 (Fig. 1) of >99:1 er using
R
Ph
Me
N
Boc
R-5
N
Boc
R-6
N
Boc
N
Boc
R-9
s-BuLi/(ꢀ)-sparteine then trapping with Me
2 4
SO proceeds highly
diastereoselectively, affording C-5 methylated pyrrolidine 2 in
R-7; R = Me
R-8; R = allyl
5% yield and 93:7 dr (cis:trans).24 In 2006, Campos and other
Me
4
Me
N
N
N
scientists at Merck reported that lithiation of R-1 of 96:4 er in
the presence of (ꢀ)-sparteine followed by transmetalation and
Pd-catalyzed coupling with phenyl bromide afforded enantiopure
Boc-protected 2,5-diphenylpyrrolidine, trans-3, in 57% yield and
H
t
Bu
Bu
Me
Me
N
t
H
N
N
Me
Me
TMEDA (10)
(—)-sparteine (11)
12
⇑
Corresponding author. Tel.: +1 4042736793.
E-mail address: beng@susqu.edu (T.K. Beng).
Figure 1. Selected examples of substituted pyrrolidines, piperidines, and diamine
ligands.
http://dx.doi.org/10.1016/j.tetlet.2014.11.031
040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
0
Please cite this article in press as: Beng, T. K.; Fox, N. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.11.031

2
T. K. Beng, N. Fox / Tetrahedron Letters xxx (2014) xxx–xxx
monosubstituted pyrrolidine 1 lithiated rather recalcitrantly.21
α '- lithiation/then E+
n
1
n
R
Ar
Since the H NMR spectrum of 5 shows ꢁ70:30 ratio of rotamers,
R
Ar
E
N
the fast and efficient lithiation of 5 suggests that the barrier to
N
21
Boc
rotation at ꢀ80 °C is probably much lower than that of 1.
Lithiation of rac-5 followed by trapping with Me SO affords C-5
methylated pyrrolidine 13 in high yield but in moderate dr (low
dr’s were also observed with other electrophiles such as Me SiCl
and allyl bromide). Gratifyingly, when sterically encumbered,
naphthyl-bearing 6 is lithiated and trapped with Me SO , a single
Boc
Evaluate dr and yield
n = 0 or 1, R = alkyl
2
4
0
Figure 2. Proposed synthetic plan for
a
,a,
a
-trisubstituted pyrrolidines and
3
piperidines.
2
4
21
diastereomer of trisubstituted pyrrolidine 14 is obtained. Addition-
ally, silylation, stannylation, and acylation of 5-lithio-6 proceed
efficiently and highly diastereoselectively (see 15–17). Whereas
direct allylation of lithiated 6 using allyl bromide proceeds
inefficiently and less selectively to afford 18 in 76:24 dr, copper-
mediated allylation affords 18 in respectable yield and in high
diastereoselectivity.
determined to be ꢁ10 h at ꢀ80 °C). It is thus likely that the
24
28
20
modest yields obtained by Beak, Campos, and O’Brien in the
0
a
-lithiation/alkylation of 1 were due to the restricted mobility of
the minor rotamer under their reaction conditions as well as due
to competitive benzylic lithiation.
Benzylic organolithiums derived from enantioenriched
N-Boc-2-aryl pyrrolidines2
4,29,30,28
and piperidines
31–36,23
can now
These studies have revealed that diamine-free lithiation39 of 6 is
possible when THF is employed as the solvent. Under this scenario,
complete lithiation of 6 is observed after 2 h at ꢀ80 °C or after 1 h
at ꢀ60 °C. Methylation and silylation of 5-lithio-6 generated under
these diamine-free conditions afford the C-5 substituted products
with similar diastereoselectivities, suggesting that although the
deprotonation of 6 is faster in the presence of TMEDA (in both
be functionalized at the 2-position with little or no loss of enantio-
3
7
27,21,38
purity, via a S
E
2ret process.
Figure 1 illustrates several of
the enantioenriched pyrrolidines and piperidines that have been
prepared by this route (see 5–9). As part of a program aimed at
synthesizing cyclic amine derivatives through the intermediacy
of functionalized organolithiums, and with a few a,a-disubstituted
pyrrolidines and piperidines in hand, we sought to investigate the
2
Et O and THF), the steric course is unaltered. Intriguingly, when
possibility of a third lithiation/alkylation sequence. An approach to
,2,5-trisubstituted pyrrolidines and 2,2,6-trisubstituted piperi-
the lithiation of rac-6 is carried out in the presence of s-BuLi/(ꢀ)-
2
0
sparteine in Et O, ꢁ75% lithiation is observed after 10 h at
dines was envisioned, whereby a diastereoselective
alkylation of
Fig. 2). Efforts toward the implementation of the proposed plan
a
-lithiation/
2
ꢀ
80 °C. Trapping of the partially deprotonated mixture with
Me SO affords trans-14 in 96:4 dr (68:32 er for the major diaste-
2 4
a,a-disubstituted azaheterocycles is implicated
(
reomer). Significantly, sparteine-mediated lithiation of 6 followed
by transmetalation and copper-mediated allylation affords 18 in
only 68:32 dr. The reason for the low diastereoselectivity under
the s-BuLi/(ꢀ)-sparteine conditions is unclear at this point.
are disclosed herein.
Starting with disubstituted pyrrolidine derivative rac-5 (see
Fig. 1), efficient conditions for lithiation/substitution at C-5 were
investigated. Knowing that N-Boc-pyrrolidine undergoes complete
and efficient lithiation under s-BuLi/TMEDA conditions at ꢀ80 °C
but phenyl pyrrolidine 1 does not, it was of interest to understand
the kinetics of deprotonation of 5. Fortuitously, after 1 h of lithia-
tion of a solution of rac-5 in Et
trapping with MeOD and analysis of the sample by GC-MS revealed
complete lithiation and 5 d was obtained (Scheme 1). The effi-
Table 1
2
O at ꢀ80 °C using s-BuLi/TMEDA,
Diastereoselective lithiation-substitution of N-Boc-2-phenyl-2-alkyl piperidines
1
sec-BuLi, TMEDA
R
Ph
R
Ph
R
Ph
ciency of the lithiation of disubstituted pyrrolidine 5 under these
reaction conditions is noteworthy since, as previously mentioned,
o
+
Et O, —80 C, 3 h
2
N
Boc
E
N
E
N
then E+
Boc
Boc
cis
19—22
trans
TMEDA, Et O
E+
2
Entry
R
Product
Yield (%)
100a
dr (cis:trans)
o
E+
E
H
Me
Ar
Me
Ar
Me
Ar
s-BuLi, —80
C
+
ndc
E
1
2
3
4
5
6
R = Me
R = Me
R = Me
R = allyl
R = allyl
R = allyl
MeOD
Me
EtCO
MeOD
Me
Me
7ꢂd
19
20
8ꢂd
21
22
1
N
Boc
N
Boc
minor
N
Boc
1 h
b
2
SO
4
85
70
100
81
>99:1
60:40
b
noe
2
Cl
a
c
major
1
nd
b
2
SO
SiCl
4
>99:1
>99:1
Me
PhMe
Me
Ph Me
Me
Np Me Si
Me
Np
b
3
77
D
N
N
N
3
N
a
b
c
GC yields.
Isolated yields.
Boc
1
Boc
Boc
14
Boc
5
·d
13
15
nd stands for ‘not determined’.
E+ = MeOD E+ = Me SO , 94% E = Me SO , 89% E = Me SiCl, 84%
+
+
2
4
2
4
3
8
Me
Np
6:14 dr
>99:1 dr
Me
Np
98:2 dr
Me
Np
EtO
Bu
3
Sn
Me
Ph
Me
Ph
N
N
Boc
17
N
Me
Ph
O
D
N
Boc
7⋅d1
Me
N
Boc
19
Boc
Boc
EtO C
2
N
Boc
20
16
18
E+ = Bu SnCl, 69%
E+ = EtOCOCl, 77%
98:2 dr
E+ = allyl bromide
3
noe
>
99:1 dr
54%, 76:24 dr
a
a
via zinc- and copper-mediated coupling 68%, 92:8 dr
using (—)-sparteine in place of TMEDA 68:32 dr
H
Me Si
b
a,b
D
N
Boc
Ph
Me
N
Boc
Ph
N
Ph
3
Boc
22
Scheme 1. Diastereoselective lithiation-substitution of N-Boc-2-aryl-2-methyl
pyrrolidines.4
0
8⋅d1
21
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T. K. Beng, N. Fox / Tetrahedron Letters xxx (2014) xxx–xxx
3
Acknowledgments
Li
N
Me Li
N
N
Ph
N
Me
Ph
Boc
Boc
Boc
Ph
Boc
Me
Ph
Li
Me
Li
This work was funded by Susquehanna University through a
Mini-grant from the University Committee for Faculty Scholarship
and the Chemistry Department. Professors Wade Johnson and Bill
Dougherty are thanked for initial help with logistics and
supplies. Scott Morris is acknowledged for help with some NOESY
experiments.
6
-lithio-7a 6-lithio-7b
7c
7d
6
-lithio-
+0.2
6-lithio-
+8.6
0
+24.0
Erel (kcal/mol)
Scheme 2. Calculated relative energies of the conformers obtained from lithiation
of -disubstituted piperidine 7.
a,a
Supplementary data
NOESY (or ROESY) experiments were performed on 14, 15, and
6. Each showed strong cross-peaks between the proton at C-5 and
the aromatic protons of the aryl group at C-2, thereby revealing a
trans arrangement of the aryl group and the C-5 substituent for
these three examples. The others were assigned the same relative
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.11.
1
0
31.
References and notes
configuration by analogy.
0
After successful
a
-lithiation/functionalization of
a,a-disubsti-
1
2
.
.
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homologous piperidine heterocycle. After some optimization, we
3. He, S.; Kozmin, S. A.; Rawal, V. H. J. Am. Chem. Soc. 2000, 122, 190.
4.
Mitchell, E. A.; Peschiulli, A.; Lefevre, N.; Meerpoel, L.; Maes, B. U. W. Chem. Eur.
found that the lithiation of a solution of rac-7 in Et
2
O at ꢀ80 °C
J. 2012, 18, 10092.
for 3 h, using sec-BuLi/TMEDA, is complete and efficient (see 7ꢂd
1
,
5.
Yan, L.-H.; Dagorn, F.; Gravel, E.; Seon-Meniel, B.; Poupon, E. Tetrahedron 2012,
68, 6276.
Table 1, entry 1). DFT calculations unsurprisingly indicate a prefer-
ence for equatorial lithiation (Scheme 2, 6-lithio-7a vs 6-lithio-7b
or 6-lithio-7c vs 6-lithio-7d). Interestingly, whereas the two equa-
torially lithiated epimers (i.e., 7a and 7c) are nearly isoenergetic,
the diastereomers bearing an axially disposed lithium are about
6. Wong, H.; Garnier-Amblard, E. C.; Liebeskind, L. S. J. Am. Chem. Soc. 2011, 133,
517.
7
7
8
.
.
Wilkinson, T. J.; Stehle, N. W.; Beak, P. Org. Lett. 2000, 2, 155.
Tsukano, C.; Zhao, L.; Takemoto, Y.; Hirama, M. Eur. J. Org. Chem. 2010, 4198.
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1
5 kcal/mol apart in energy.
D.; Danieli, B. Tetrahedron: Asymmetry 2009, 20, 192.
2 4
Trapping of 6-lithio-7 with Me SO affords 19 as a single
11. Kavala, M.; Mathia, F.; Kozisek, J.; Szolcsanyi, P. J. Nat. Prod. 2011, 74, 803.
diastereomer (Table 1, entry 2). NOESY experiments established
12. Guerrero, C. A.; Sorensen, E. J. Org. Lett. 2011, 13, 5164–5167.
1
1
1
1
3. Gouault, N.; Le Roch, M.; Pinto, G. D. C.; David, M. Org. Biomol. Chem. 2012, 10,
541.
4. Fellah, M.; Santarem, M.; Lhommet, G.; Mouries-Mansuy, V. J. Org. Chem. 2010,
75, 7803.
the relative configuration as having the
a-phenyl group and the
5
0
a
-methyl group cis. Indeed, DFT calculations indicate that the
cis-diaxial conformer is 4.7 kcal/mol more stable than the corre-
sponding cis-diequatorial conformer. These results suggest that
5. Bosque, I.; Gonzalez-Gomez, J. C.; Foubelo, F.; Yus, M. J. Org. Chem. 2012, 77,
780.
1
9 arises from 6-lithio-7c following a ring flip. Lithiation/trapping
with EtOCOCl affords acylated piperidine 20 in only 60:40 dr (entry
), probably due to facile epimerization at C-6. Trapping of allyl-
bearing 6-lithio-8 with Me SO also affords a single diastereomer
6. Beng, T. K.; Gawley, R. E. Heterocycles 2012, 84, 697–718.
17. Lapointe, G.; Schenk, K.; Renaud, P. Chem. Eur. J. 2011, 17, 3207.
1
1
2
8. Draper, J. A.; Britton, R. Org. Lett. 2010, 12, 4034.
9. Beak, P.; Lee, W. K. Tetrahedron Lett. 1989, 30, 119.
0. Stead, D.; O’Brien, P.; Sanderson, A. Org. Lett. 2008, 10, 1409.
3
2
4
of the trisubstituted piperidine (see 21, entry 5). NOESY experi-
21. Sheikh, N. S.; Leonori, D.; Barker, G.; Firth, J. D.; Campos, K. R.; Meijer, A. J. H.
M.; O’Brien, P.; Coldham, I. J. Am. Chem. Soc. 2012, 134, 5300.
22. Xiao, D.; Lavey, B. J.; Palani, A.; Wang, C.; Aslanian, R. G.; Kozlowski, J. A.; Shih,
N.-Y.; McPhail, A. T.; Randolph, G. P.; Lachowicz, J. E.; Duffy, R. A. Tetrahedron
Lett. 2005, 46, 7653.
ments again established the relative configuration as having the
0
a-aryl group and the
a
-methyl group cis. Analysis of coupling con-
stants revealed that the C-6 proton in 21 is equatorial, indicating
0
that the
a-phenyl and
a
-methyl groups are cis-diaxial. Silylation
23. Coldham, I.; Leonori, D. Org. Lett. 2008, 10, 3923.
2
2
2
4. Wu, S.; Lee, S.; Beak, P. J. Am. Chem. Soc. 1996, 118, 715.
5. Beak, P.; Lee, W. K. J. Org. Chem. 1990, 55, 2578.
6. Beak, P.; Lee, W. K. J. Org. Chem. 1993, 58, 1109.
3
of 6-lithio-8 with Me SiCl affords piperidine 22, also as a single
diastereomer (entry 6). However, in this example, although the
cis relationship between the aryl group at C-2 and the newly intro-
27. Beng, T. K.; Woo, J. S.; Gawley, R. E. J. Am. Chem. Soc. 2012, 134, 14764.
28. Campos, K. R.; Klapars, A.; Waldman, J. H.; Dormer, P. G.; Chen, C.-Y. J. Am.
Chem. Soc. 2006, 128, 3538.
1
duced substituent at C-6 is preserved, the H NMR of 22 shows a
double doublet due to 3J coupling between the proton at C-6 and
both equatorial (J = 7 Hz) and axial (J = 13 Hz) protons at C-5, indi-
cating that the C-6 proton is axial. Accordingly, NOESY experi-
29. Reddy, L. R.; Prashad, M. Chem. Commun. 2010, 222.
30. Barker, G.; McGrath, J. L.; Klapars, A.; Stead, D.; Zhou, G.; Campos, K. R.; O’Brien,
P. J. Org. Chem. 2011, 76, 5936.
3
3
1. Beng, T. K.; Gawley, R. E. Org. Lett. 2011, 13, 394.
2. Barbe, G.; Fiset, D.; Charette, A. B. J. Org. Chem. 2011, 76, 5354.
ments show cross-peaks between the C-6 proton and the
a-allyl
group. Calculations indicate a preference for equatorial dispensa-
tion of the TMS group, thus disfavoring the ring-flipped conformer.
Of note, a few activated arenes (e.g., methoxy-bearing and
33. Jarvis, S. B. D.; Charette, A. B. Org. Lett. 2011, 13, 3830.
3
3
4. Amat, M.; Canto, M.; Llor, N.; Bosch, J. Chem. Commun. 2002, 526.
5. Stead, D.; Carbone, G.; O’Brien, P.; Campos, K. R.; Coldham, I.; Sanderson, A. J.
Am. Chem. Soc. 2010, 132, 7260.
CF
3
-containing arenes) were evaluated on both the pyrrolidine
36. Millet, A.; Larini, P.; Clot, E.; Baudoin, O. Chem. Sci. 2013, 4, 2241.
37. Gawley, R. E. Tetrahedron Lett. 1999, 40, 4297.
and piperidine heterocycles (see SI for details) but complications
3
8. Cochrane, E. J.; Leonori, D.; Hassall, L. A.; Coldham, I. Chem. Commun. 2014,
910.
9. Barker, G.; O’Brien, P.; Campos, K. R. Org. Lett. 2010, 12, 4176.
arising from competing aryl lithiation were encountered.
9
0
In summary,
a
,a,a
-trisubstituted pyrrolidines and piperidines
3
are obtainable in good to excellent diastereoselectivity by directed
40. Typical Procedure (Synthesis of 15): To an oven-dried, septum-capped round
bottom flask equipped with a stir bar, was added freshly distilled TMEDA
lithiation/alkylation. The relative configuration of the major diaste-
(
1.0 mL, 0.6 mmol, 1.2 equiv) and Et
cooled to ꢀ80 °C and a solution of s-BuLi in cyclohexane (0.6 mL, 1.0 M,
1.2 equiv) was added via syringe. precooled solution of pyrrolidine
1.0 equiv) in Et O (3.0 mL) was added to the flask containing the TMEDA/s-
BuLi mixture. After 1 h at this temperature, the mixture was trapped with
Me SiCl (180 mg, 1.5 mmol, 3 equiv). After 4 h, MeOH was added and the
mixture was stirred for 5 min. After warming to room temperature, 10% H PO
was added. Layers were separated and the aqueous layer was extracted with
2
O (7.0 mL) under argon. The mixture was
0
reomer has the
a
-substituent trans to the
a-aryl group in the pyr-
rolidines but cis to the
a
-aryl group in the piperidines. The current
A
6
(
2
strategy sets the stage for the synthesis of enantioenriched trisub-
stituted pyrrolidines and piperidines since no racemization is
3
0
anticipated during
a
-lithiation/alkylation of the
a,a
-disubstituted
3
4
enantioenriched precursors.
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4
T. K. Beng, N. Fox / Tetrahedron Letters xxx (2014) xxx–xxx
Et
2
O. The combined organic layers were dried over MgSO
4
and evaporated to
2H), 2.15 (m, 2H), 1.90 (s, 3H), 0.80 (s, 9H), 0.22 (s, 9H); 13C NMR (100 MHz,
CDCl ) d 153.9, 143.0, 134.7, 130.3, 129.4, 127.7, 125.8, 124.8, 124.7, 124.2,
obtain the crude product as an oil. Purification by flash chromatography on
3
silica eluting with hexane–EtOAc (95:5) afforded 167 mg of 21 as an oil in 84%
78.1, 66.5, 49.8, 42.5, 28.6, 27.6, 1.2. HRMS calcd for C23
found 383.2273.
2
H33NO Si 383.2281,
yield. 1H NMR (300 MHz, CDCl
) d 8.03–7.46 (m, 7H), 3.73 (dd, 1H), 2.72 (m,
3
Please cite this article in press as: Beng, T. K.; Fox, N. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.11.031