Hemiaminals as substrates for sulfur ylides: Direct asymmetric syntheses of functionalised pyrrolidines and piperidines

Article abstract of DOI:10.1039/b602226j

Phenyl stabilised chiral sulfur ylides react with five-membered-ring hemiaminals to give functionalised pyrrolidines directly with high enantioselectivity. The reaction can be diverted to give piperidines instead by isolation of the intermediate epoxide and treatment with TMSOTf. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b602226j

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Hemiaminals as substrates for sulfur ylides: Direct asymmetric
syntheses of functionalised pyrrolidines and piperidines{
Christoforos G. Kokotos and Varinder K. Aggarwal*
Received (in Cambridge, UK) 14th February 2006, Accepted 17th March 2006
First published as an Advance Article on the web 13th April 2006
DOI: 10.1039/b602226j
Phenyl stabilised chiral sulfur ylides react with five-membered-
Table 1 Reaction of different hemiaminals 3 with sulfonium salt 4
ring hemiaminals to give functionalised pyrrolidines directly
with high enantioselectivity. The reaction can be diverted to
give piperidines instead by isolation of the intermediate epoxide
and treatment with TMSOTf.
1
2
Lactols 1 and related hemiaminals 2 are well known to react
with phosphorus ylides to give v-unsaturated alcohols or amines.
Such reactions occur via the ring opened aldehyde, which is only
present at very low concentrations. We wished to investigate
whether such readily available substrates3 could also react with
sulfur ylides, especially because the v-epoxy alcohol/amine product
had the potential to ring close directly to form heterocycles with
control of stereochemistry (Scheme 1). However, the low
concentration of the active electrophile posed significant problems
with sulfur ylides, especially semi-stabilised ones. With such
substrates, if reaction with the electrophile is slow (e.g. as is the
case with Michael acceptors4) competing ylide equilibration
followed by Sommelet–Hauser rearrangement can dominate
instead.5
Yielda (%)
Entry P
n Conditions
5b 6 (trans : cis)c
7
1
2
3
4
a
Boc 1 P2 base, THF, 0 uC, 18 h
Ts 1 P2 base, DCM, 0 uC, 3 h
Ts 2 P2 base, DCM, 0 uC, 18 h
80 14 (5 : 1)
0 54 (1:0)
70 33 (1.5 : 1)
0
18
0
Cbz 2 P2 base, DCM, 278 uC, 4 h 100
0
0
b
Yield based on 3.
Yield based on sulfonium salt 4.
Diastereoselectivity determined by 1H NMR of the crude reaction
mixture.
c
(Table 2), this base proved to be the most effective. Other bases
were either less efficient or generated the by-product 9 (entries 1, 2,
Table 2). The by-product 9 is formed from alkylation of the
aminoepoxide 6 by the sulfonium salt 4 acting as the electrophile.
Aware of these potential problems, we began our studies with
cyclic hemiaminals of different ring size bearing different groups
on nitrogen (Table 1). These studies showed that strong electron
withdrawing groups on nitrogen (Ts group), contained in a
5-membered rather than the more stable 6-membered ring were
required to provide sufficient concentration of the open chain
aldehyde to allow ylide reaction to proceed (entry 2, Table 1). In
the absence of such features, ylide equilibration followed by
Sommelet Hauser rearrangement leading to sulfide 5 was the
dominant pathway. We had selected the phosphazene base (P2
base)6 for this study because in parallel studies of different bases
Table 2 Optimisation of conditions for the reaction of hemiaminal 3
with sulfonium salt 4
Yield (%)
Entry Conditions
6(trans : cis) 7
8
9(trans : cis)
1
2
3
4
5
6
7
8
9
DBU, DCM, 5 h, 0 uC
DBU, DCM, 7 h, 0 uC
LiHMDS, THF, 7 h, 0 uC 5 (1:0)
NaH, THF, 7 h, 0 uC 31 (1:1)
KHMDS, THF, 7 h, 0 uC 26 (2:1)
P2 base, THF, 7 h, 0 uC 27 (1:0)
P2 base, THF, 18 h, 0 uC
21 (2:1)
24 (6:1)
traces 0 20 (2:1)
Scheme 1 Reaction of lactols 1 and hemiaminals 2 with ylides.
7
1
0 23 (2:1)
0
0
0
0
0
0
0
0
0
2
School of Chemistry, University of Bristol, Bristol, UK BS8 1TS.
E-mail: V.Aggarwal@bristol.ac.uk; Fax: +44 (0) 117 929 8611;
Tel: +44 (0) 117 954 6315
{ Electronic supplementary information (ESI) available: Detailed experi-
mental procedures and characterisation data for all products. See DOI:
10.1039/b602226j
4
0
0
0
18
22
61
89
0
0
P2 base, DCM, 3 h, 0 uC 54 (1:0)
P2 base, DCM, 18 h, 0 uC 24 (1:0)
44
2156 | Chem. Commun., 2006, 2156–2158
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Using the more basic P2 base, more of the sulfonium salt was
deprotonated, rendering it unavailable to act as an electrophile for
alkylation of the sulfonamide. Using the P2 base a mixture of
epoxide 6 together with pyrrolidines 7 and 8 were obtained
depending on the reaction conditions.
In dichloromethane at short reaction time, a mixture of trans
epoxide 6 and pyrrolidine 7 was obtained (entry 8, Table 2). This
indicated that the ratio of trans : cis epoxides initially obtained was
54 : 18 (3 : 1). At longer reaction time, more of the trans epoxide
was converted into pyrrolidine 8 (entry 9,Table 2). However in
THF, epoxide 6 was formed with trans selectivity (>95 : 5) (entry
6,Table 2) and at extended reaction time, pyrrolidine 8 was formed
exclusively (entry 7,Table 2). Through isolating trans epoxide 6
and subjecting it to the reaction conditions, we established that
pyrrolidine 8 was derived from the trans isomer and therefore that
pyrrolidine 7 was derived from the cis-isomer. This also allowed us
to predict the stereochemistry of 8 (assuming inversion), which was
subsequently proved by X-ray analysis.
Scheme 3 Ring opening of epoxide 6 at C1 position.
Table 3 Expansion of the methodology utilising aldehyde 13
Having discovered a highly diastereoselective synthesis of
pyrrolidines, we sought to make it asymmetric. Using the chiral
sulfonium salt 10,7 pyrrolidine 8 was obtained in good yield (79%)
with high enantiomeric excess (94% ee) and the sulfide was
efficiently reisolated (82% yield). The diastereoselectivity was
slightly lower this time (96 : 4) and a small amount of pyrrolidine 7
(3%) was also isolated (Scheme 2). This represents a very efficient
asymmetric route to functionalised pyrrolidines.
Products (%)
Conditions
Entry Time (Temp.)
Sulfonium salt 14 (trans : cis) 15 (% ee)
1
2
3
4
5
7 h (0 uC)
7 h (0 uC) 48 h (r.t.)
7 h (0 uC) 11 h (65 uC)
4
4
4
21 (1:0)
10 (1:0)
0
39 (—)
62 (—)
71 (—)
55
7 h (0 uC) 11 h (r. t.) 10
7 h (0 uC) 11 h (65 uC) 10
11 (1:0)
0
76 (91)
Under the reaction conditions, epoxide 6 underwent clean
regioselective ring opening at the C1 position to give the five-
membered ring pyrrolidine, in accordance with Baldwin’s rules.8,9
However, we wished to investigate whether ring opening could be
diverted to the C2 position to furnish piperidines instead. A survey
of the literature revealed that in the related ring opening reaction
involving oxygen nucleophiles, the normally favoured tetrahydro-
furan formation could be diverted to pyran formation in substrates
possessing cation stabilising groups under acidic/Lewis acidic
conditions.10,11 However, such reactions had not been extended to
the corresponding nitrogen analogues. We therefore isolated
epoxide 6 and subjected it to a variety of Lewis acids. Of the
Lewis acids tested,12 TMSOTf and Sc(OTf)3 were found to be
effective at promoting ring opening of the epoxide at the C1
position cleanly, affording piperidine 12 as a single diastereomer in
very high yield (Scheme 3). The trans diastereomer 12 was expected
but the low coupling constant (broad singlet) observed for the C1
proton was a concern. An X-ray structure proved that the relative
stereochemistry was indeed trans and that the low coupling
constant observed was due to the substituents adopting diaxial
positions leaving the protons H1 and H2 diequatorial. Once more,
the process was rendered asymmetric using the chiral sulfonium
salt 10 furnishing the piperidine 12 with high enantioselectivity
(93% ee).
The epoxidation–cyclisation sequence was further extended to
b-amino aldehyde 13 (Table 3). This substrate behaved similarly to
the aminal 3, but cyclisation reaction was slower. Simply heating
the reaction mixture, after the epoxidation reaction was complete
enhanced the rate of cyclisation giving pyrrolidine 15 in high yield
and as a single diastereomer (entry 3, Table 3). The stereochemistry
of 15 was proved by X-ray analysis again. Once again, use of the
chiral sulfonium salt 10 rendered the reaction asymmetric (91% ee,
entry 5, Table 3).
The high diastereoselectivity observed in the reaction was
unexpected since reaction of phenyl-stabilised sulfur ylides with
unbranched aliphatic aldehydes normally gives subtantial quan-
tities of the cis epoxide.13 The mechanism of the reaction involves
four distinct steps: formation of the betaine with charges adjacent
to each other, followed by bond rotation to the trans conforma-
tion, ring closure to the epoxide, and the final step is ring opening/
cyclisation (Scheme 4). From DFT calculations and cross-over
experiments we have established that the second step, bond
rotation, is the rate and selectivity determining step. The high trans
selectivity observed with the current electrophiles indicates that the
barrier to bond rotation is substantially higher for the syn betaine
resulting in reversibility back to the starting materials. The reaction
then partitions down the productive antibetaine pathway leading to
the trans epoxide.
The synthetic utility of this novel methodology was
demonstrated by its application in the synthesis of the potent
Scheme 2 Direct asymmetric synthesis of pyrrollidines.
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conditions (base) to give pyrrolidines or under Lewis acidic
conditions to give piperidines.
CCDC 298299–298301. For crystallographic data in CIF or
other electronic format see DOI: 10.1039/b602226j
We thank Avecia (Robin Fieldhouse), Johnson Matthey (Mark
Hooper), Syngenta (David Ritchie) and The DTI for support of
this work through an MMI grant.
Notes and references
1 (a) E. J. Corey and K. Shimoji, J. Am. Chem. Soc., 1983, 105,
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H. Kigoshi, J. Org. Chem., 2004, 69, 7802–7808.
Scheme 4 Mechanism of the ylide epoxidation reaction.
2 (a) K. Kawada and T. Tsushima, Heterocycles, 1989, 28, 573–578; (b)
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3 J. Ahman and P. Somfai, Tetrahedron, 1992, 48, 9537–9544, but see
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5 Amide stabilised ylides, which cannot undergo competing Sommelet–
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M. Valpuesta, P. Durante and F. J. Lopez-Herrera, Tetrahedron, 1993,
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neurokinin-1 (NK-1) receptor antagonist CP-122,721 16.14 Trans-
disubstituted piperidine 12 was transformed to cis-piperidine 19
(89% ee) by oxidation, followed by selective reduction of
methoxyimine 18 (Scheme 5), Finally, deprotection of 19 led to
the known intermediate 2014,15 which has been converted to 16.14
In conclusion, we have described a new method for directly
forming pyrrolidines and piperidines with control of relative and
absolute stereochemistry from readily available hemiaminals. The
methodology uses chiral sulfur ylides and the process occurs via
c-amino epoxides that undergo ring closure under the reaction
6 P2 base is N,N,N9,N9-tetramethyl-N9-(tris(dimethylamino) phosphora-
nylidene) phosphoric triamide ethylimine.
7 V. K. Aggarwal, E. Alonso, G. Hynd, K. M. Lydon, M. J. Palmer,
M. Porcelloni and J. R. Stundley, Angew. Chem., Int. Ed., 2001, 40,
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8 J. E. Baldwin, J. Chem. Soc., Chem. Commun., 1976, 734.
9 S. Singh and H. Han, Tetrahedron Lett., 2004, 45, 6349–6352.
10 (a) K. C. Nicolaou, M. E. Duggan, C. K. Hwang and P. K. Somers,
J. Chem. Soc., Chem. Commun., 1985, 1359; (b) K. C. Nicolaou,
V. C. Prasad, P. K. Somers and C. K. Hwang, J. Am. Chem. Soc., 1989,
111, 5330–5334.
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Int. Ed., 2006, 45, 810–812.
12 BF3?Et2O and camphor sulfonic acid were also tested, leading to a
mixture of epoxide and pyrrolidine.
13 V. K. Aggarwal and J. Richardson, Chem. Commun., 2003, 21,
2644–2651.
14 T. J. Rosen, K. J. Coffman, S. McLean, R. T. Crawford, D. K. Bryce,
Y. Gohda, M. Tsuchiya, A. Nagahisa, M. Nakane and J. A. Lowe, III,
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Scheme 5 Application of the methodology in the synthesis of CP-
122,721 16.
15 T. J. Rosen, US 5686615, 1997.
2158 | Chem. Commun., 2006, 2156–2158
This journal is ß The Royal Society of Chemistry 2006