Synthesis of enantiopure pyrrolidine and piperidine derivatives via ring closing metathesis

Article abstract of DOI:10.1016/S0040-4039(00)01423-4

The additions of lithiated allylsulfone carbanion to chiral N-sulfinylimines were found to proceed with good to excellent selectivity. The resulting intermediates 4a-d after transformation to dienylamides 7a-d and 16a-d, were converted to functionalized enantiopure piperidines and pyrrolines, respectively, via ring closing metathesis (RCM). (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01423-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8157–8162
Synthesis of enantiopure pyrrolidine and piperidine
derivatives via ring closing metathesis†
Ramaiah Kumareswaran, Thiagarajan Balasubramanian and Alfred Hassner*
Department of Chemistry, Bar-Ilan University, Ramat Gan 52 900, Israel
Received 5 July 2000; revised 17 August 2000; accepted 23 August 2000
Abstract
The additions of lithiated allylsulfone carbanion to chiral N-sulfinylimines were found to proceed with
good to excellent selectivity. The resulting intermediates 4a–d after transformation to dienylamides 7a–d
and 16a–d, were converted to functionalized enantiopure piperidines and pyrrolines, respectively, via ring
closing metathesis (RCM). © 2000 Elsevier Science Ltd. All rights reserved.
Synthetic approaches to enantiopure 5- and 6-membered azaheterocycles have elicited a great
deal of interest recently, because of their potential use as valuable intermediates for the synthesis
of complex organic molecules. Several of these functionalized pyrrolidines and piperidines have
been shown recently to exhibit diverse biological activities, especially as excellent glycosidase
inhibitors.1 Furthermore, chiral 2-substituted pyrrolidines and piperidines occur as natural
products and are useful as chiral bases, chiral auxiliaries, and chiral ligands.2 Therefore,
considerable attention has been focussed in recent years on the synthesis of enantiopure
pyrrolidine3 and piperidine4 derivatives.
In connection with our studies leading to chiral pyrrolidine and piperidine derivatives, we
recently disclosed the synthesis of chiral non-racemic 2-arylpyrrolines via a [3+2] MIRC reaction 5a
and of 2-arylpiperidines via stereoselective addition5b of lithiated allylsulfone carbanions to
optically pure (+)-(S)-(E)-N-p-toluenesulfinylimines. However, the addition of allylsulfone 1 was
found to proceed only with moderate diastereoselectivity (45–57%, major isomer), presumably due
to the coordinating hydroxyl appendage. In this communication we report a general enantio-
selective synthesis of functionalized 2-arylpiperidines, as well as of 2-aryl-3-pyrroline derivatives,
utilizing the highly diastereoselective addition of simple allylsulfone 2 to arylsulfinylimines 3a–d.
* Corresponding author. Fax: 972-3-5351250; e-mail: hassna@mail.biu.ac.il
†
Synthetic Methods 52. For paper 51, see: Basel, Y.; Hassner, A. J. Org. Chem. 2000, 65, in press.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01423-4

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The required sulfinylimines were prepared by following the procedure of Davis et al.6 The
allylsulfone 2 was deprotonated by lithium diisopropylamide (LDA) in THF at −100°C followed
by the addition of representative sulfinylimines 3a–d in THF to afford the adducts 4a–d in
85–100% yields (Eq. (1)).
(1)
1
The H NMR spectra of these adducts 4a–d indicated the presence of only two of the four
possible diastereomers suggesting that control of stereoselectivity of the addition was total at
one of the two prochiral centers. The observed diastereoselectivity can be rationalized by
invoking a six membered cyclic transition state (Fig. 1), wherein Li+ chelation between one of
the sulfonyl oxygens and the sulfinylimine nitrogen forms a six membered chair, which directs
the aryl group to the equatorial position due to 1,3-diaxial Ar/Ph (SO2) repulsion7 thus allowing
the sulfonyl carbanion to attack exclusively from the si face on the CꢀN bond.
Figure 1.
Desulfinylation of compounds 4a–d by treatment with trifluoroacetic acid (TFA) in methanol
at 0°C afforded chromatographically separable (SiO2), diastereomeric free amines, the syn 5a–d
being major (62–88%). Monoallylation followed by protection of the secondary amines 6a–d by
means of an acyl group set the stage for a metathesis ring closure. While amine 6a did not
undergo metathesis, treatment of a 0.1 M CH2Cl2 solution of the amides 7a–d with 5 mol% of
Grubbs RCM catalyst8 10 at room temperature for 2–3 h afforded functionalized piperidine
derivatives 8a–d in high yields (Scheme 1). Hydrolysis of the amide function of 8a–d furnished
the target functionalized piperidines 9a–d. The results of our studies are summarized in Table 1.
Scheme 1.

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Table 1
Synthesis of 4a–d and elaboration to functionalized piperidines 9a–d
Yield (%)a
9c
Entry
Ar
4b
(90:10)
(95:5)
(89:11)
(67:33)
5
6
7
8
9
[h]2D5
A
B
C
D
Ph
84
100
88
74
88
71
62
76
72
76
79
79
74
73
83
86
82
80
89
69
74
70
60
+128° (c 1.05)
+112° (c 1.9)
+118° (c 1.2)
+148° (c 0.7)
p-MePh
p-MeOPh
2-Furyl
96
a All yields refer to isolated yields.
b Numbers in paranthesis for 4 refer to diastereomeric ratio.
c Solvent methanol.
In order to determine the absolute configurations of (+)-2-arylpiperidines 9a–d, it was first
1
necessary to establish the relative stereochemistry of the aryl and phenylsulfonyl groups. H
NMR and NOESY experiments indicated a trans relationship with the Ar and PhSO2 groups
occupying pseudo diaxial positions9 since the H5 and H6 protons are in a gauche relationship
(J5,6=2.7 Hz) in accordance with our previously reported (+)-2-arylpiperidines, whose absolute
configurations were established as 5(S)-phenylsulfonyl-6(R)-aryl-1,2,5,6-tetrahydropyridine
based on a conversion to (S)-anatabine.5b Furthermore, to ascertain that there was no difference
in the stereochemical course of our previous reactions leading to (S)-anatabine and that of
5(S)-phenylsulfonoyl-6(R)-aryl-1,2,5,6-tetrahydropyridines reported here, we effected reductive
desulfonation on 9a to get 11 using sodium amalgam (Eq. (2)). The observed negative specific
rotation [h]D20 −80° (c 0.6, CHCl3) for 1110 again suggested that the absolute configuration is the
same as that of optically pure (S)-anatabine11 whose [h]D is −176°.
(2)
After having established a general route for the enantioselective synthesis of functionalized
piperidines, our attention was turned toward the possibility of employing one of the above
intermediates also for the construction of enantiopure pyrrolidine derivatives. In order to
demonstrate this strategy, we started with optically pure amine diastereomer 5a, which was
isomerised to 12a using a catalytic amount of KOtBu in THF at 0°C. Monoallylation of amine
12a to procure 13a followed by protection of the secondary amine function by means of an acyl
group to afford 14 (cf. Scheme 2), set the stage for a critical ring closure. Application of Grubbs
RCM catalyst 10 and Schrock’s Mo catalyst for the RCM process under standard reaction
conditions led only to a total recovery of the starting material.

8160
Scheme 2.
Since we suspected that failure of a metathesis was due to the presence of the electron
withdrawing sulfone moiety on the double bond, we attempted to remove the phenylsulfonyl
group in compound 13a. While this was not successful with other reagents (NaꢁHg,12 AlꢁHg,13
Na2S2O7,14 K on graphite,15 and n-Bu3SnH16), SmI2–THF/HMPA,17 (4 equiv., −20°C) did effect
a smooth desulfonation to yield amine 15a in 62% yield and similar reduction of compounds
13b–d followed by benzoyl protection of the derived amines 15a–d furnished amides 16a–d in
good yield. Indeed, treatment of a 0.1 M CH2Cl2 solution of these amides with 5 mol% of
catalyst 10 yielded pyrrolidine derivatives 17a–d in excellent yield (cf. Table 2). The synthetic
sequence is as shown in Scheme 2.
Table 2
Synthesis of 2-aryl-3-pyrroline derivatives
Yield (%)a
17b
Entry
Ar
12
13
15
16
17
[h]2D5
A
B
C
D
Ph
78
73
85
74
72
83
78
78
62
65
59
59
100
96
82
94
89
90
85
−144° (c 0.95)
−301° (c 1.7)
−277° (c 0.86)
−119° (c 2)
p-MePh
p-MeOPh
2-Furyl
75
a All yields refer to isolated yields.
b Solvent methanol.
In order to assess the enantiopurity of 2-aryl-3-pyrroline derivatives 17a–d obtained as shown
in Scheme 2, we targeted the known N-Boc-2-phenylpyrrolidine,3d thereby showing the absolute
stereochemistry as well by extrapolating this sequence to (S)-2-phenylpyrrolidine. To implement
our plan, we protected amine 15a by means of the Boc group, and subsequent olefin metathesis
produced pyrroline 19. Hydrogenation of 19 in the presence of 10% Pd/C afforded the known
pyrrolidine 20, whose analysis by chiral stationary phase HPLC on the Whelk-0 column
indicated that it to be single isomer (>99.9%). Further, removal of the Boc group as shown in
Scheme 3 afforded the known (S)-2-phenylpyrrolidine which showed [h]2D5 −23° (c 1.9, MeOH),
lit.3a [h]D −22° (c 0.3, MeOH).

8161
Scheme 3. N-TBCS=N-tert-butyloxycarbonyloxysuccinimide
In conclusion, we have developed efficient protocols for the syntheses of both 5- and
6-membered enantiopure azaheterocycles, which do not rely on amino acids as a chiral source.
This methodology which utilizes a simple allylsulfone and (S)-arylsulfinylimines via ring closing
metathesis should also be applicable to procure the enantiomers of 9a–d and 17a–d by
employing (R)-sulfinylimines. Further elaboration of these molecules into biologically important
azasugars is underway in our laboratory.
Acknowledgements
Support of this research by a grant from the US–Israel Binational Science Foundation is
gratefully acknowledged. We thank Prof. E. Ghera for useful suggestions, Prof. P. Beak for
providing us HPLC analysis of 20 and Dr. H. E. Gottlieb for valuable help with NMR spectra
and by the Marcus Center for Pharmaceutical and Medicinal Chemistry.
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