Highly enantioselective phase-transfer catalytic α-alkylation of α-tert-butoxycarbonyllactams: Construction of β-quaternary chiral pyrrolidine and piperidine systems

Article abstract of DOI:10.1002/adsc.201100542

A new enantioselective α-alkylation of α-tert- butoxycarbonyllactams for the construction of β-quaternary chiral pyrrolidine and piperidine core systems is reported. α-Alkylations of N-methyl-α-tert-butoxycarbonylbutyrolactam and N-diphenylmethyl-α- tert-

Full text of DOI:10.1002/adsc.201100542

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DOI: 10.1002/adsc.201100542
Highly Enantioselective Phase-Transfer Catalytic a-Alkylation of
a-tert-Butoxycarbonyllactams: Construction of b-Quaternary
Chiral Pyrrolidine and Piperidine Systems
Yohan Park,a Young Ju Lee,b Suckchang Hong,b Mi-hyun Kim,b Myungmo Lee,b
Taek-Soo Kim,b Jae Kyun Lee,c Sang-sup Jew,b and Hyeung-geun Parkb,*
a
College of Pharmacy, Inje University, 607 Obang-dong, Gimhae, Gyeongnam 621-749, Republic of Korea
College of Pharmacy, Seoul National University, San 56-1, Shinlim-Dong, Gwanak-Gu, Seoul 151-742, Republic of Korea
b
Fax : (+82)-2-872-9129; phone: (+82)-2-880-8264; e-mail: hgpk@snu.ac.kr
Neuro-Medicine Center, Korea Institute of Science and Technology, PO Box 131, Cheongyang, Seoul 130-650, Republic
c
of Korea
Received: July 8, 2011; Published online: December 8, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100542.
Abstract: A new enantioselective a-alkylation of a-
tert-butoxycarbonyllactams for the construction of
b-quaternary chiral pyrrolidine and piperidine core
systems is reported. a-Alkylations of N-methyl-a-
tert-butoxycarbonylbutyrolactam and N-diphenyl-
there are a lot of biologically important alkaloids
having pyrrolidine and piperidine ring core structures
with b-chiral quaternary centers (Figure 1).[2]
There are a lot of synthetic methods for construct-
ing b-chiral pyrrolidine and piperidine structures via
lactams.[3] Most synthetic methods firstly introduce
the stereocenter ahead of the formation of the lac-
tams, followed by the reduction of amides to afford
pyrrolidine and piperidine ring skeletons. Although a
few cases were reported as a part of studies, such as
a-substitution of imides with aziridines[4] or cyclic
sulamidates[5] and a-arylation of lactams via SNAr re-
actions,[6] there are no systematic studies on the asym-
metric a-alkylation of lactams with high enantioselec-
tivity. In this communication, we report a new and
highly efficient enantioselective a-alkylation of lac-
tams for the construction of b-chiral pyrrolidines and
piperidines systems.
methyl-a-tert-butoxycarbonylvalerolactam
under
phase-transfer catalytic conditions (solid potassium
hydroxide, toluene, À408C) in the presence of
(S,S)-3,4,5-trifluorophenyl-3,3’,5,5’-tetrahydro-2,6-
bis(3,4,5-trifluorophenyl)-4,4’-spirobi[4H-dinaphth-
ACHTUNGTRENNUNG[2,1-c:1’,2’-e]azepinium] bromide [(S,S)-NAS Br] (5
mol%) afforded the corresponding a-alkyl-a-tert-
butoxycarbonyllactams in very high chemical (up to
99%) and optical yields (up to 98% ee). Our new
catalytic systems provide attractive synthetic meth-
ods for pyrrolidine- and piperidine-based alkaloids
and chiral intermediates with b-quaternary carbon
centers.
The phase-transfer catalytic reaction is historically
well known as one of the most efficient synthetic
methods from the viewpoint of economical and envi-
ronmental aspects.[7] Although there are various car-
bonyl substrates, which are amenable to the asymmet-
ric a-alkylation under phase-transfer catalytic condi-
tion, researches on new substrates applicable to PTC
reaction are still demanded.[8] Therefore we attempt-
Keywords: a-tert-butoxycarbonyllactams; phase-
transfer catalytic a-alkylation; b-quaternary chiral
piperidines; b-quaternary chiral pyrrolidines
Alkaloids are a group of naturally occurring chemical ed to extend systematically the PTC alkylation reac-
compounds, produced by various organisms, which tion to lactam systems.
mostly contain basic nitrogen atoms and show various
First, we needed to design an a-carboxylactam as
biological activities.[1] Their high potential of pharma- substrate for an initial study of PTC a-alkylation.
cological effects leads many organic chemists and me- Since the tert-butyl ester group has been known as es-
dicinal chemists to develop efficient synthetic meth- sential for high enantioselectivity in enantioselective
ods and structure-activity relationship studies for new PTC a-alkylations, the ester group was chosen as a
drug developments. Most of the alkaloids have cyclic tert-butyl group.[9] For the preliminary study, a-tert-
ring systems or fused bicyclic structures. Especially butACHTUNTRGNEUNGoxycarbonyl-N-methylbutyrolactam (5) was pre-
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Yohan Park et al.
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Figure 1. Natural products containing b-chiral pyrrolidine or piperidine moiety.
Figure 2. Chiral phase-transfer catalysts.
pared and examined for a-benzylation under typical enantioselectivities with 3 in the PTC alkylation of
PTC conditions. The enantioselective PTC benzyla- glycinimine esters.[10d] Both of the Cinchona-derived
tion of 5 was performed by the representative chiral catalysts (1 and 2) unfortunately afforded quite low
phase-transfer catalysts (1–4) (Figure 2),[10] along with enantioselectivities with similar chemical yields com-
benzyl bromide (5.0 equiv.) and 50% KOH (aqueous, pared to those of catalyst 3. Use of a lower tempera-
5.0 equiv.) at 08C in toluene. Recently, we reported a ture afforded a similar enantioselectivity but with
new enantioselective synthetic method for chiral a- lower chemical yield (entry 5, 56%, 92% ee). Best
mono-alkylmalonamide esters by phase-transfer cata- enantioselectivity was observed in case of solid KOH
lytic (PTC) mono-a-alkylation of N,N-diarylmalona- as base at À408C (entry 6, 95%, 94% ee), but an even
mide esters.[8g] However the alkylation of a-methyl- lower reaction temperature gave both lower enantio-
malonamide esters for the construction of the quater- selectivity and chemical yield (entry 7, 20%, 86% ee).
nary carbon center revealed disappointingly both low
These preliminary promising results encouraged us
chemical yields (up to 65%) and poor enantioselectiv- to optimize the structure of lactam substrates includ-
ities (up to 42% ee) due to the low acidity of the ing expansion of the ring size. Two additional a-tert-
second a-proton, which made us expect at the begin- butoxycarbonyl-N-alkylbutyrolactams (6 and 7) and
ning that the generation of a chiral quaternary center three a-tert-butoxycarbonyl-N-alkylvalerolactams (8–
in high enantioselectivity via the direct a-alkylation 10) were prepared by varying the N-alkyl groups.
of lactams would be quite challenging.
Their substrate efficiencies were evaluated by benzy-
However, as shown Table 1, catalyst 3 surprisingly lation in the presence of catalyst 3 (5 mol%) under
afforded the a-benzylated product (5c) with 91% ee the optimized PTC condition (Table 1, entry 6). As
and 96% chemical yield (entry 3). Lower enantiose- shown in Table 2, enantioselectivities were dramati-
lectivity was observed with 4 (entry 6, 85%, 73% ee), cally dependent on the size of the N-alkyl groups. It is
which previously showed comparablely excellent notable that the general tendency in enantioselectivity
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Highly Enantioselective Phase-Transfer Catalytic a-Alkylation of a-tert-Butoxycarbonyllactams
Table 1. Optimization of reaction conditions with regard to catalysts and base.
Entry
PTC
Base
Temperature [8C]
Time [h]
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
7
1
2
3
4
3
3
3
50% KOH
50% KOH
50% KOH
50% KOH
50% KOH
KOH (s)
0
0
0
0
À40
À40
À60
16
16
7
7
24
3
86
82
96
85
56
95
20
32
51
91
73
92
94
86
KOH (s)
24
[a]
Isolated yields.
[b]
The enantiopurity was determined by HPLC analysis of a-benzylated product (5b) using a chiral column (Chiralcel OD-
H) with hexanes/2-propanol as eluents.
Table 2. Scope of substrates in PTC alkylations.
68% ee), the larger N-alkyl group in the 6-membered
valerolactams (8–10) gave the higher enantioselectivi-
ties (entry 4, 65% ee; entry 5, 75% ee, entry 6, 98%
ee). The ring size of the lactam and the bulkness of
the N-1 substituents might play an integral role for
the enantioselectivity. We speculated that the confor-
mational change of two lactams due to the N-alkyl
group and ring size might be so sensitive for the fa-
vorable binding to the PTC catalyst 3.
Entry
Substrate
Time
[h]
Yield
[%][a]
ee
[%][b]
The lactam substrates 5 and 10 were chosen for fur-
ther investigation into the scope and limitations of
our enantioselective PTC alkylation with various elec-
trophiles. Both of lactam systems gave quite high
enantioselectivities, and valerolactams gave slightly
higher enantioselectivity compared to the butyrolac-
tams (Table 3). The very high enantioselectivities (up
to 98% ee) indicate that this reaction is a very effi-
cient enantioselective synthetic method for a-car-
boxy-a-alkyllactams. The absolute configurations of
5d and 10d were confirmed as R and S, respectively,
by X-ray crystallographic analysis (Figure 3).
In conclusion, a novel enantioselective synthetic
method for the construction of b-chiral quaternary
pyrrolidine and piperidine systems was developed.
The asymmetric PTC a-alkylation of a-tert-butoxycar-
bonyllactams afforded the corresponding a-alkyl-a-
tert-butoxycarbonyllactams in high chemical (up to
99%) and optical yields (up to 98% ee). It is notable
that the N-alkyl group and the ring size play integral
roles for enantioseletivity. Our new catalytic systems
provides attractive synthetic methods for chiral pyrro-
lidine- and piperidine-based alkaloids with b-quater-
nary carbon centers. The synthetic potential of this
1
2
3
5
6
7
3
95
92
95
94
75
68
20
24
4
5
8
9
3
90
70
88
65
75
98
24
6
10 24
[a]
Isolated yields.
[b]
The enantiopurity was determined by HPLC analysis of
a-benzylated products using a chiral column (Chiralcel
OD-H) with hexanes/2-propanol as eluents.
was exactly opposite to that between the lactam ring method for other applications is now under investiga-
size. While the larger N-alkyl group in the 5-mem- tion.
bered butyrolactams (5–7) showed the lower enantio-
selectivities (entry 1, 94% ee; entry 2, 75% ee, entry 3,
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Table 3. Enantioselective phase-transfer alkylation of 5 and 10 with various alkyl halides.
Ent
1
RX
Product
Time [h]
8
Yield [%][a]
92
ee [%][b] ([a]D)
82 (+)
allyl bromide (a)
5a
5b
2
3
BnBr (b)
3
6
95
99
94 (+)
94 (+)
4-Me-C6H4CH2Br (c)
5c
4
4-Br-C6H4CH2Br (d)
5d
5
99
89
93 (R)c)
5d)
2-naphthylmethyl bromide (e)
5e
24
91 (+)
6
7
allyl bromide (a)
BnBr (b)
10a
10b
24
24
87
88
87 (+)
98 (+)
8
9
4-Me-C6H4CH2Br (c)
4-Br-C6H4CH2Br (d)
10c
10d
24
24
84
91
98 (+)
98 (S)[c]
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Highly Enantioselective Phase-Transfer Catalytic a-Alkylation of a-tert-Butoxycarbonyllactams
Table 3. (Continued)
Ent
RX
Product
Time [h]
Yield [%][a]
ee [%][b] ([a]D)
10[d]
2-naphthylmethyl bromide (e)
10e
24
78
98 (+)
[a]
Isolated yields.
[b]
The enantiopurity was determined by HPLC analysis of a-benzylated products (5a–e to 10a–e) using a chiral column
(Chiralcel OD-H or Chiralpak AD-H) with hexanes/2-propanol as eluents.
The absolute configuration was assigned by the X-ray analysis of 5d and 10d.
[c]
[d]
The enantiopurity was determined by the corresponding methyl esters, prepared from 5e and 10e.
Figure 3. X-ray crystallographic structures of 5d and 10d.
ethyl acetate (10 mL), washed with brine (2ꢁ2 mL), dried
over anhydrous MgSO4, filtered, and concentrated under
vacuum. The residue was purified by column chromatogra-
phy (silica gel, hexanes:EtOAc=10:1) to afford 5b or 10b,
respectively.
Experimental Section
For details on the synthesis, see Supporting Information.
General Procedure for the Enantioselective Catalytic
Alkylation of N1-Methyl-2-pyrrolidinone-3-carboxylic
Acid tert-Butyl Ester (5) and N1-Diphenylmethyl-2-
piperidone-3-carboxylic Acid tert-Butyl Ester (10)
under Phase-Transfer Conditions (Benzylation)
N1-Methyl-2-benzyl-2-pyrrolidinone-3-carboxylic acid tert-
butyl ester (5b): Pale yellow viscous oil; yield: 95%. The
enantioselectivity was determined by chiral HPLC analysis
(DIACEL Chiralcel OD-H, hexanes:2-propanol=95:5, flow
rate=1.0 mLminÀ1, 238C, l=254 nm): retention times R
(major) 7.5 min, S (minor) 11.1 min, 94% ee. 1H NMR
(300 MHz, CDCl3): d=7.29–7.19 (m, 5H), 3.20 (dd, J1 =
63.6 Hz, J2 =13.8 Hz, 2H), 3.24~3.16 (m, 1H), 2.75 (s, 3H),
2.60~2.52 (m, 1H), 2.39~2.30 (m, 1H), 2.05~1.96 (m, 1H),
1.47 (s, 9H); 13C NMR (125 MHz, CDCl3): d=172.34,
170.94, 136.85, 130.12, 128.11, 126.66, 81.77, 57.27, 46.83,
38.87, 29.98, 27.86, 26.92; IR (KBr): n=2977, 1734, 1694,
Benzyl bromide (0.27 mmol) was added to a solution of 5 or
10 (0.094 mmol) and (S,S)-3,4,5-trifluorophenyl-3,3’,5,5’-tet-
rahydro-2,6-bis(3,4,5-trifluorophenyl)-4,4’-spirobi[4H-di-
naphth[2,1-c:1’,2’-e]azepinium] bromide [(S,S)-NAS Br] (3,
4.6 mg, 0.005 mmol) in toluene (0.4 mL). Solid KOH (28 mg,
0.5 mmol) was added to the reaction mixtures at À408C,
and stirred for 24 h. The reaction mixture was diluted with
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Yohan Park et al.
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1497, 1454, 1403, 1368, 1254, 1160, 1032, 849, 703 cmÀ1; HR-
MS (FAB): m/z=290.1753, calcd. for [C17H24NO3]+:
290.1756; [a]2D3: +70.94 (c 0.43, CHCl3).
[3] a) J. M. Flaniken, C. J. Collins, M. Lanz, B. Singaram,
Org. Lett. 1999, 1, 799; b) K. Takasu, N. Nishida, A. To-
mimura, M. Ihara, J. Org. Chem. 2005, 70, 3957; c) Y.
Uenoyama, T. Fukuyama, I. Ryu, Org. Lett. 2007, 9,
935.
N1-Benzhydryl-2-piperidone-3-carboxylic acid tert-butyl
ester (10b): White solid; yield: 88%. The enantioselectivity
was determined by chiral HPLC analysis (DIACEL Chiral-
[4] T. A. Moss, D. R. Fenwick, D. J. Dixon, J. Am. Chem.
Soc. 2008, 130, 10076.
cel
OD-H,
hexanes:2-propanol=95:5,
flow
rate=
1.0 mLminÀ1, 238C, l=254 nm): retention times S (major)
5.2 min, R (minor) 10.1 min, 98% ee. 1H NMR (300 MHz,
CDCl3): d=7.40~7.27 (m, 14H), 7.09~7.06 (m, 2H), 3.39
(dd, J1 =244.95 Hz, J2 =13.35 Hz, 2H), 3.03~2.96 (m, 1H),
2.61~2.53 (m, 1H), 2.09~1.82 (m, 4H), 1.44 (s, 9H);
13C NMR (75 MHz, CDCl3): d=172.38, 168.65, 138.49,
138.16, 136.98, 130.72, 129.14, 128.25, 128.09, 128.04, 127.97,
127.21, 127.04, 126.33, 81.59, 60.09, 55.78, 43.76, 41.25, 29.56,
27.81, 20.12; IR (KBr): n=2935, 1733, 1637, 1495, 1454,
1367, 1293, 1253, 1149, 1032, 850, 751, 702 cmÀ1; HR-MS
(FAB): m/z=456.2544, calcd. for [C30H34NO3]+: 456.2539;
m.p 898C; [a]2D3: +71.61 (c 0.86, CHCl3).
CCDC 837890 and CCDC 837891 contain the supplemen-
tary crystallographic data for compounds 5d and 10d, re-
spectively. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[5] T. A. Moss, B. Alonso, D. R. Fenwick, D. J. Dixon,
Angew. Chem. 2010, 122, 578; Angew. Chem. Int. Ed.
2010, 49, 568.
[6] M. Bella, S. Kobbelgaard, K. A. Jørgensen, J. Am.
Chem. Soc. 2005, 127, 3670.
[7] For recent reviews on the phase-transfer catalysis, see:
a) K. Maruoka, T. Ooi, Chem. Rev. 2003, 103, 3013;
b) M. J. OꢂDonnell, Acc. Chem. Res. 2004, 37, 506; c) B.
Lygo, B. I. Andrews, Acc. Chem. Res. 2004, 37, 518;
d) T. Hashimoto, K. Maruoka, Chem. Rev. 2007, 107,
5656; e) S.-s. Jew, H.-g. Park, Chem. Commun. 2009,
7090.
[8] For our recent reports on the development of new sub-
strates for enantioselective phase-transfer catalytic re-
actions, see: a) S.-s. Jew, B.-S. Jeong, M.-S. Yoo, H.
Huh, H.-g. Park, Chem. Commun. 2001, 1244; b) H.-g.
Park, B.-S. Jeong, M.-S. Yoo, M.-k. Park, H. Huh, S.-s.
Jew, Tetrahedron Lett. 2001, 42, 4645; c) H.-g. Park, B.-
S. Jeong, M.-S. Yoo, J.-H. Lee, M.-k. Park, Y.-J. Lee,
M.-J. Kim, S.-s. Jew, Angew. Chem. 2002, 114, 3162;
Angew. Chem. Int. Ed. 2002, 41, 3036; d) S.-s. Jew, M.-
S. Yoo, B.-S. Jeong, I. Y. Park, H.-g. Park, Org. Lett.
2002, 4, 4245; e) M.-S. Yoo, B.-S. Jeong, J.-H. Lee, H.-g.
Park, S.-s. Jew, Org. Lett. 2005, 7, 1129; f) S.-s. Jew, Y.-J.
Lee, J. Lee, M. J. Kang, B.-S. Jeong, J.-H. Lee, M.-S.
Yoo, M.-J. Kim, S.-h. Choi, J.-M. Ku, H.-g. Park,
Angew. Chem. 2004, 116, 2436; Angew. Chem. Int. Ed.
2004, 43, 2382; g) Y.-J. Lee, J. Lee, M. J. Kim, T.-S.
Kim, H.-g. Park, S.-s. Jew, Org. Lett. 2005, 7, 1557;
h) Y.-J. Lee, J. Lee, M. J. Kim, B.-S. Jeong, J. H. Lee, T.-
S. Kim, J.-M. Koo, S.-s. Jew, H.-g. Park, Org. Lett. 2005,
7, 3207; i) T.-S. Kim, Y.-J. Lee, B.-S. Jeong, H.-g. Park,
S.-s. Jew, J. Org. Chem. 2006, 71, 8276; j) T.-S. Kim, Y.-
J. Lee, K. Lee, B.-S. Jeong, H.-g. Park, S.-s. Jew, Synlett
2009, 671; k) Y. Park, S. Kang, Y. J. Lee, T.-S. Kim, B.-
S. Jeong, H.-g. Park, S.-s. Jew, Org. Lett. 2009, 11, 3738;
l) M.-h. Kim, S.-h. Choi, Y.-J. Lee, J. Lee, K. Nahm, B.-
S. Jeong, H.-g. Park, S.-s. Jew, Chem. Commun. 2009,
782; m) S. Hong, J. Lee, M. Kim, Y. Park, C. Park, M.-
h. Kim, S.-s. Jew, H.-g. Park, J. Am. Chem. Soc. 2011,
133, 4924.
Acknowledgements
This work was supported by grants of the Mid-career Re-
searcher Support Programs of National Research Foundation
of Korea (2009-0078814) and the Korea Healthcare technolo-
gy R&D Project, Ministry for Health, Welfare & Family Af-
fairs, Republic of Korea (A092006).
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