Organocatalytic domino Mannich aza-Michael reactions towards the stereoselective synthesis of highly substituted pipecolic esters

Article abstract of DOI:10.1055/s-0028-1083377

Readily available chiral 7-oxo-2-enimides have been converted into highly substituted pipecolic esters in moderate yields and excellent stereocontrol through a proline-catalyzed domino Mannich aza-Michael reaction.

Full text of DOI:10.1055/s-0028-1083377

LETTER
2705
Organocatalytic Domino Mannich Aza-Michael Reactions towards the
Stereoselective Synthesis of Highly Substituted Pipecolic Esters
Stereoselective
o
S
ynthesis
o
u
f
Highly
S
ub
a
stituted
P
ip
d
ecolic Esters Khaliel,a Mecheril Valsan Nandakumar,a Harald Krautscheid,b Christoph Schneider*a
a
Institut für Organische Chemie, Universität Leipzig, Johannisallee 29, 04103 Leipzig, Germany
Institut für Anorganische Chemie, Universität Leipzig, Johannisallee 29, 04103 Leipzig, Germany
Fax +49(341)9736599; E-mail: schneider@chemie.uni-leipzig.de
b
Received 20 June 2008
Barbas and co-workers had established that proline-
catalyzed Mannich reactions of aldehydes and glyoxyl
imines furnished a-amino esters with high degrees of dia-
stereo- as well as enantiocontrol.5 Building on this prece-
dence we treated Cope product 2a with N-PMP-imino
ethyl glyoxylate (3a) and L-proline (20 mol%) in DMF for
20 hours at –20 °C and obtained after subsequent alde-
hyde reduction 48% of pipecolic ester 4a as a single ste-
reoisomer (Scheme 2).6 This domino-type7 reaction
comprised an initial proline-catalyzed Mannich reaction
followed by a subsequent aza-Michael addition of the in
situ formed amine onto the a,b-unsaturated imide moiety.
Small amounts (<5%) of the corresponding uncyclized
Mannich product were also isolated.
Abstract: Readily available chiral 7-oxo-2-enimides have been
converted into highly substituted pipecolic esters in moderate yields
and excellent stereocontrol through a proline-catalyzed domino
Mannich aza-Michael reaction.
Key words: aza-Michael reaction, Cope rearrangement, domino
reaction, Mannich reaction, organocatalysis, pipecolic ester
In recent years we have investigated the silyloxy-Cope re-
arrangement of 1,5-hexadienes 1 embedded in a syn-aldol
structure giving rise to chiral 7-oxo-2-enimides 2 in good
yields and typically excellent diastereoselectivity
(Scheme 1).1 On the basis of their unique functional group
pattern we have successfully employed these products for
the stereoselective preparation of a broad range of diverse
structural motifs such as heterocycles, carbocycles, ter-
penes, and polyol chains.2
O
1. L-proline (cat.)
DMF, –20 °C
2. NaBH(OAc)3
3
H
2a
HO
O
+
O
2
6
EtO2C
N
Xc
TBSO
O
48%
EtO2C
NPMP
Bn
O
R1
O
Bn
PMP
O
N
3a
1. 180 °C
R1
N
O
H
N
4a
R3
R3
2. PTSA
80–95%
R2
Bn
O
O
O
O
R2
Scheme 2
(up to >95:5 dr)
1
2
OTBS
For the unambiguous assignment of product configuration
4a was converted into the corresponding acetate 5a which
gave crystals suitable for crystallographic analysis8 prov-
ing the 2,3-trans and 2,6-cis configuration within the
piperidine ring (Figure 1). This analysis corresponds to
the expected highly syn-selective Mannich reaction5 and
an aza-Michael reaction onto a preaxially oriented conju-
gate double bond as had been found in other aza-Michael
R1
R2
COXc
Xc = chiral auxiliary
R3
Scheme 1
With the advent of asymmetric organoenamine catalysis
that allows for the highly enantioselective a-functional-
ization of aldehydes we wondered whether we could em-
ploy the Cope products as substrates in organocatalytic
C–C bond-forming reactions.3 We now wish to report that
chiral 7-oxo-2-enimides 2 containing an aldehyde moiety
tethered to an a,b-unsaturated imide undergo proline-
catalyzed domino Mannich aza-Michael reactions4 with
glyoxyl imines 3 furnishing highly substituted pipecolic
esters 4 in moderate yields and typically excellent stereo-
control.
SYNLETT 2008, No. 17, pp 2705–2707
x
x
.x
x
.2
0
0
8
Advanced online publication: 01.10.2008
DOI: 10.1055/s-0028-1083377; Art ID: G22008ST
© Georg Thieme Verlag Stuttgart · New York
Figure 1 X-ray crystal structure of acetate 5a (50% ellipsoids)

2706
S. Khaliel et al.
LETTER
additions with these substrates previously.2d Interestingly, Table 1 L-Proline-Catalyzed Domino Mannich Aza-Michael
Reactions towards Pipecolic Esters 4a–fa
the piperidine ring accommodates the 2- and 6-substitu-
ents in pseudoaxial positions which are bent away from
each other in order to avoid significant 1,3-diaxial interac-
tions.
Entry
Product
Yield (%)b
In order to determine the scope and limitations of this new
domino process we subsequently reacted various 7-oxo-2-
enimides 2a–d with glyoxyl imines 3a–c according to this
protocol and obtained the desired highly substituted pipe-
colic esters 4a–f (Scheme 3) in generally moderate yields
and mostly as single stereoisomers (Table 1). In select
cases small amounts (<5%) of the corresponding 6-epimers
were additionally formed but could be readily removed by
chromatography. Less reactive imines failed to furnish the
piperidines according to this scheme because the initial
Mannich reaction did not proceed.
HO
O
O
O
1
48
N
N
O
O
PMP
Bn
4a
HO
O
O
O
2
3
56
54
N
N
O
O
PMP
Bn
4b
O
R1
R1
1. L-proline (cat.)
DMF, –20 °C
HO
O
O
O
H
2. NaBH(OAc)3
HO
O
2a–d
N
N
+
O
R2O2C
N
Xc
R2O2C
46–56%
O
O
PMP
NPMP
Bn
PMP
4a–f
O
N
3a–c
4c
O
Bn
Scheme 3
HO
O
O
O
4
49
N
N
O
When the reaction of 2a and 3a was repeated with D-pro-
line as organocatalyst a 2:1-mixture of diastereomers with
respect to the 6-position was obtained. Both of the diaste-
reomers shared the opposite configuration at the 2- and 3-
position within the piperidine ring (relative to the L-pro-
line-catalyzed reaction) indicating that the initial Mannich
reaction is a catalyst-controlled event whereas the subse-
quent aza-Michael addition apparently proceeds under
substrate control.
O
PMP
Bn
4d
HO
O
O
O
5
6
51
46
N
N
N
O
O
O
O
PMP
Bn
O
4e
The chiral auxiliary may be readily cleaved off with mag-
nesium methoxide as was demonstrated for pipecolic ester
4e giving rise to methyl ester 6 in good yield (Scheme 4).
Likewise the PMP group in 4f was exchanged for a Boc
group through an oxidative cleavage with CAN followed
by an in situ Boc protection to yield pipecolic ester 7
(Scheme 4).
HO
O
O
N
PMP
Bn
4f
a Reagents and conditions: 7-oxo-2-enimide 2 (1 equiv), imine 3 (1.5
equiv), 0.3 M in DMF, –20 °C, 20 h; then NaBH(OAc)3 (3.0 equiv) in
EtOAc, 0 °C, 15 min.
R
b Isolated yield of purified product.
HO
O
EtO
i
N
OMe
R
In conclusion, we have established a novel organocatalyt-
ic domino process for the rapid synthesis of highly substi-
tuted pipecolic esters in just one step. Two new s bonds
and three new stereogenic centers are formed with excel-
lent stereocontrol. Further work along these lines will be
reported in due course.
75%
O
PMP
HO
O
O
6 R = Pr
EtO
R
N
N
O
O
PMP
HO
EtO
O
O
Bn
4e,f
ii
N
N
O
O
Boc
47%
Bn
Acknowledgment
7 R = H
We gratefully acknowledge financial support in the form a PhD fel-
lowship awarded to S.K. by the University of Garyounis (Bengazi,
Scheme 4 Reagents and conditions: (i) MeMgCl, MeOH, CH2Cl2,
0 °C; (ii) (a) CAN, H2O–MeCN, 0 °C to r.t.; (b) Boc2O, DMAP.
Synlett 2008, No. 17, 2705–2707 © Thieme Stuttgart · New York

LETTER
Stereoselective Synthesis of Highly Substituted Pipecolic Esters
2707
Libya). Wacker AG and Evonik AG are thanked for the generous
donation of chemicals.
mixture had been stirred for further 15 min, the reaction was
quenched with phosphate buffer (pH 7) and the crude
product was extracted with EtOAc. The organic layer was
washed with brine, dried over MgSO4, filtered and
References and Notes
concentrated. The residue was purified by flash column
chromatography (PE–EtOAc, 1:2 → 1:1) to afford the
product 4d (40 mg, 49%) as a viscous oil, which was
recrystallized from EtOAc–PE; mp 50 °C; [a]D21 +15.8° (c =
0.07, CHCl3). 1H NMR (300 MHz, CDCl3): d = 0.96 (t, J =
7.2 Hz, 3 H, Me), 1.14 (t, J = 7.2 Hz, 3 H, Me), 1.31–1.88
(m, 6 H, 4-CH, 5-CH2, CH2CH3, OH), 2.43 (m, 1 H, 3-CH),
2.60 (dd, J = 13.5, 9.6 Hz, 1 H, CH-benzyl), 3.10 (dd,
J = 17.7, 3.0 Hz, 1 H, CHCO), 3.21 (dd, J = 13.5, 3.0 Hz,
1 H, CH-benzyl), 3.53 (dd, J = 17.7, 10.0 Hz, 1 H, CHCO),
3.61–3.72 (m, 2 H, CH2OH), 3.73 (s, 3 H, MeO), 4.09–4.14
(m, 4 H, OCH2CH3, 5¢¢-CH2), 4.40–4.46 (m, 1 H, 6-CH),
4.50 (d, J = 4.2 Hz, 1 H, 2-CH), 4.62 (mc, 1 H, 4¢¢-CH), 6.81
(d, J = 8.8 Hz, 2 H, phenyl-CH), 7.04 (d, J = 8.8 Hz, 2 H,
phenyl-CH), 7.14 (d, J = 6.8 Hz, 2 H, phenyl-CH), 7.25–7.29
(m, 3 H, phenyl-CH). 13C NMR (75 MHz, CDCl3): d = 11.79
(Me), 14.22 (Me), 24.01 (CH2CH3), 27.03 (C4), 31.71
(CH2CO), 32.04 (C5), 37.99 (benzyl-C), 42.55 (C3), 49.59
(C6), 55.24 (C¢¢4), 55.97 (OMe), 59.86 (C2), 59.97 (CH2CO),
61.06 (CH2OH), 66.22 (C¢¢5), 114.5, 118.7, 127.4, 129.05,
129.4, 135.4, 142.3, 153.7 (phenyl-C), 153.2 (CO-urethane),
172.4 (CO-amide), 174.0 (CO-ester). IR (film): 3500 (OH),
3029, 2959, 2875, 2833 (CH), 1785 (CO-urethane), 1720
(CO-ester), 1695 (CO-amide), 1605, 1512, 1454, 1384, 1351
(Me, CH2), 1244, 1180, 1087, 1043, 970, 941, 788, 702, 626
cm–1. MS (ESI, Na): m/z = 539.2 [M + H]+, 561.2 [M + Na]+.
Anal. Calcd for C30H38N2O7 (538.63): C, 66.90; H, 7.11; N,
5.20. Found: C, 66.46; H, 7.00; N, 5.19.
(1) (a) Schneider, C.; Rehfeuter, M. Synlett 1996, 212.
(b) Schneider, C.; Rehfeuter, M. Tetrahedron 1997, 53, 133.
(c) Schneider, C. Synlett 2001, 1079. (d) Schneider, C.;
Khaliel, S. Synlett 2006, 1413.
(2) For the application of the Cope products in organic
synthesis, see: (a) Schneider, C. Synlett 1997, 815.
(b) Schneider, C.; Schuffenhauer, A. Eur. J. Org. Chem.
2000, 73. (c) Schneider, C.; Börner, C. Synlett 1998, 652.
(d) Schneider, C.; Börner, C.; Schuffenhauer, A. Eur. J. Org.
Chem. 1999, 3353. (e) Schneider, C. Eur. J. Org. Chem.
1998, 1661. (f) Schneider, C.; Rehfeuter, M. Tetrahedron
Lett. 1998, 39, 9. (g) Schneider, C.; Rehfeuter, M. Chem.
Eur. J. 1999, 5, 2850. (h) Schneider, C.; Reese, O. Angew.
Chem. Int. Ed. 2000, 39, 2948; Angew. Chem. 2000, 112,
3074. (i) Schneider, C.; Reese, O. Chem. Eur. J. 2002, 8,
2585. (j) Schneider, C.; Tolksdorf, F.; Rehfeuter, M. Synlett
2002, 2098.
(3) For leading recent reviews about organoenamine catalysis,
see: (a) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B.
Chem. Rev. 2007, 107, 5471. (b) List, B. Chem. Commun.
2006, 819. (c) List, B. Acc. Chem. Res. 2004, 37, 548.
(d) Notz, W.; Tanaka, F.; Barbas, C. F. III Acc. Chem. Res.
2004, 37, 580.
(4) For a related aza-Diels–Alder reaction which proceeds by a
domino Mannich aza-Michael mechanism, see: (a) Sunden,
H.; Ibrahem, I.; Eriksson, L.; Cordova, A. Angew. Chem. Int.
Ed. 2005, 44, 4877; Angew. Chem. 2005, 117, 4955. (b)
Rueping, M.; Azap, C. Angew. Chem. Int. Ed. 2006, 45,
7832; Angew. Chem. 2006, 118, 7996.
(7) For general reviews, see: (a) Tietze, L. F.; Brasche, G.;
Gericke, K. Domino Reactions in Organic Synthesis; Wiley-
VCH: Weinheim, 2006. (b) Tietze, L. F. Chem. Rev. 1996,
96, 115. (c) For a specific review about asymmetric
organocatalytic domino reactions, see: Enders, D.; Grondal,
C.; Hüttl, M. R. M. Angew. Chem. Int. Ed. 2007, 46, 1570;
Angew. Chem. 2007, 119, 1590.
(8) The structural data have been deposited with the Cambridge
Crystallographic Data Centre and allocated the deposition
number CCDC 686773, which contains the supplementary
crystallographic data for this paper.
(5) Cordova, A.; Watanabe, S.; Tanaka, F.; Notz, W.; Barbas,
C. F. III J. Am. Chem. Soc. 2002, 124, 1866.
(6) Typical Experimental Procedure: To a stirred solution of
N-PMP-protected a-imino ethyl glyoxalate (3a; 47 mg,
0.228 mmol) and L-proline (3.5 mg, 20 mol%) in DMF
(0.5 mL) at –20 °C was added aldehyde 2b (R1 = Et; 50 mg,
0.152 mmol) and the stirring was continued for 20 h at
–20 °C. The reaction mixture was then diluted with EtOAc
(1 mL) and added to a solution of sodium triacetoxyboro-
hydride (3 equiv) in EtOAc at 0 °C. After the reaction
Synlett 2008, No. 17, 2705–2707 © Thieme Stuttgart · New York

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