A ring-closing metathesis-mediated route to novel enantiopure conformationally restricted cyclic amino acids

Article abstract of DOI:10.1039/b001253j

A combination of palladium-catalysed N,O-acetal formation, ruthenium- catalysed ring-closing metathesis and N-sulfonyliminium ion-mediated C-C bond formation constitutes an efficient and versatile route to a set of enantiomerically pure 2,6-disubstituted unsaturated pipecolic acid derivatives.

Full text of DOI:10.1039/b001253j

A ring-closing metathesis-mediated route to novel enantiopure
conformationally restricted cyclic amino acids†
Kim C. M. F. Tjen,a Sape S. Kinderman,a Hans E. Schoemaker,b Henk Hiemstraa and Floris P. J. T. Rutjes*ac
a Institute of Molecular Chemistry, University of Amsterdam, Nieuwe Achtergracht 129, 1018 WS Amsterdam, The
Netherlands
b Department of Organic Chemistry and Biotechnology, DSM Research, P.O. Box 18, 6160 MD Geleen, The
Netherlands
c
Department of Organic Chemistry, University of Nijmegen, Toernooiveld 1, 6525 ED Nijmegen, The Netherlands
Received (in Cambridge, UK) 15th February 2000, Accepted 15th March 2000
A combination of palladium-catalysed N,O-acetal forma-
tion, ruthenium-catalysed ring-closing metathesis and N-
sulfonyliminium ion-mediated C–C bond formation con-
stitutes an efficient and versatile route to a set of
enantiomerically pure 2,6-disubstituted unsaturated pipe-
colic acid derivatives.
The pipecolic acid derivatives 1, heterocycles containing a
variety of functional groups, constitute an interesting compound
Scheme 2 Reagents and conditions: i, methyl propadienyl ether, Pd(OAc)2,
class. They are rigid amino acids and may therefore be used to
introduce conformational restriction in peptides.1 Furthermore,
this class of cyclic amino acid derivatives is a versatile starting
point for the construction of (libraries of) biologically active
compounds and for the synthesis of naturally occurring
alkaloids.2 Although a few approaches towards the synthesis of
such systems are known,3 general access to a wide range of
these types of amino acids is still rather limited. Here we present
an efficient and flexible route to the unsaturated 2,6-di-
substituted pipecolic acid derivatives 1 consisting of (i) a novel
amidopalladation reaction of an alkoxy-substituted allene to
form the allylic N,O-acetals 2a and 2b, (ii) Ru-mediated ring-
closing metathesis of these intermediates and (iii) selective
functionalisation at the 6-position via allylic N-sulfonyliminium
ion chemistry (Scheme 1).4 The starting material is enantiomer-
ically pure allylglycine (3), which is commercially available but
alternatively can be efficiently prepared in both enantiomeric
forms.5
dppp, Et3N, MeCN, sealed tube, reflux, 50%; ii, benzyl propadienyl ether,
Pd(OAc)2, dppp, Et3N, MeCN, room temperature, 85%.
went to completion in one hour at room temperature to
selectively give the desired N,O-acetal 2a in 85% yield.9 Most
probably, at higher temperatures the thermodynamic product is
formed, whereas at room temperature the kinetic product is
produced.
The N,O-acetal formation proceeded well for both the Ts- and
Ns (4-nitrobenzenesulfonyl)-protected allylglycine derivatives
(yield of 2b: 84%; both 2a and 2b were obtained as ca. 1+1
mixtures of diastereomers), but did not work satisfactorily for
the corresponding carbamates. It should be stressed that this
amidopalladation of benzyl propadienyl ether represents a novel
method of generating N,O-acetals. More general application of
this smooth reaction to convert sulfonylamides into the
corresponding N,O-acetals10 in principle paves the way to a
large variety of N-sulfonyliminium ion precursors.4
Having these stable diolefins in hand, the compounds were
subjected to standard ring-closing metathesis conditions using
the well-established Grubbs Ru–benzylidene catalyst11 to give
the desired cyclic N,O-acetals 6a and 6b in excellent yields as
ca. 1+1 mixtures of cis/trans-isomers (Scheme 3)
Scheme 1 Retrosynthesis.
This route was inspired by previous work in our group on the
synthesis of oxygen heterocycles, where one of the key steps
consisted of a highly efficient acetal formation via oxy-
palladation of methyl propadienyl ether.6 We envisioned that
formation of the corresponding N,O-acetals should be possible
in a similar fashion.7 However, treatment of Ts-protected
allylglycine methyl ester (4) with methyl propadienyl ether in
the presence of Pd(OAc)2 at 80 °C surprisingly led to the
undesired enol ether 5, formed by reaction of the tosylamide at
the least hindered g-position of the allene (Scheme 2).
Interestingly, a similar reaction with benzyl propadienyl ether8
did not require these refluxing conditions to proceed, but instead
Scheme 3 Reagents and conditions: i, Cl2(Cy3P)2RuNCHPh, CH2Cl2, room
temperature; ii, BF3·OEt2, CH2Cl2, 278 °C, 90%.
Treatment of this mixture with BF3·OEt2 at 278 °C led to
isomerisation of 6b to the thermodynamically more stable
vinylogous N,O-acetal 7,† which consisted of an 8+1 mixture of
cis/trans isomers. After comparison with literature data3c and
1
based on the observed NOE signals in the H NMR spectrum,
the major isomer was identified as the cis-product. This
isomerisation was a useful indication of the feasibility of
cationic reactions via such types of N-sulfonyliminium ions.
To establish CC-bond formation, precursors 6a and 6b where
treated with a variety of nucleophiles in the presence of different
Lewis acids. In Table 1, the results with BF3·OEt2 are shown,
† Electronic supplementary information (ESI) available: characterisation
data for compounds 7, 9 and 16. See http://www.rsc.org/suppdata/cc/b0/
b001253j/
DOI: 10.1039/b001253j
Chem. Commun., 2000, 699–700
This journal is © The Royal Society of Chemistry 2000
699

Table 1 Reagents and conditions: i, nucleophile, BF3·OEt2, CH2Cl2,
278 °C ? room temperature; yields were determined after flash column
chromatography. The enantiopurity of the products was checked by chiral
HPLC (Chiracel OD, heptane–isopropyl alcohol = 80+20)
Scheme 4 Reagents and conditions: i, PhSH, K2CO3 DMF, room
temperature; ii, LiOH, MeOH–H2O (1+1), room temperature.
derivatives including the natural product baikiain. At present,
we are further extending the scope of the cyclic N,O-acetals as
synthetic intermediates in different (metal-catalysed) types of
C–C bond forming reactions and are also exploring the
possibilities to apply these building blocks in natural product
synthesis.
DSM Research is kindly acknowledged for providing a
research grant to K. C. M. F. T. This research has been
financially supported by the Council for Chemical Sciences of
the Netherlands Organisation for Scientific Research (CW-
NWO).
since this Lewis acid appeared superior in terms of selectivity
and yield. The most simple nucleophile (Et3SiH, entry 1)
provided selectively the unsaturated pipecolic acid 9 in 88%
yield. The enantiopurity of the product was checked by analysis
of the enantiopure and the racemic product with chiral HPLC
(as in all other entries) to confirm that racemisation during the
N-sulfonyliminium ion reaction does not take place. With
allyltrimethylsilane as the nucleophile (entries 2 and 3),
mixtures of 1,2- and 1,4-addition products were obtained, both
as single diastereoisomers. The stereochemistry of the 1,2-ad-
Notes and references
1 For a review, see: S. Hanessian, G. McNaughton-Smith, H.-G. Lombart
and W. D. Lubell, Tetrahedron, 1997, 53, 12 789.
2 For some recent examples, see: (a) J. Åhman and P. Somfai,
Tetrahedron Lett., 1995, 36, 303; (b) S. A. Angle and J. G.
Breitenbucher, Tetrahedron Lett.,1993, 34, 3985; (c) T. Hamada, T.
Zenkoh, H. Sato and O. Yonemitsu, Tetrahedron Lett., 1991, 32,
1649.
3 For some recent examples, see: (a) D. Craig, R. McCague, G. A. Potter
and M. R. V. Williams, Synlett, 1998, 55; (b) J. Åhman and P. Somfai,
J. Am. Chem. Soc., 1994, 116, 9781; (c) Y. Matsumura, Y. Yoshimoto,
C. Horikawa, T. Maki and M. Watanabe, Tetrahedron Lett., 1996, 37,
5715; (d) P. D. Bailey, R. D. Wilson and G. R. Brown, J. Chem. Soc.,
Perkin Trans. 1, 1991, 1337; (e) S. R. Angle, J. G. Breitenbucher and
D. O. Arnaiz, J. Org. Chem., 1992, 57, 5947.
4 For a review on related N-acyliminium ion chemistry, see: H. Hiemstra
and W. N. Speckamp, in Comprehensive Organic Synthesis, ed. B. M.
Trost and I. Fleming, Pergamon, Oxford, 1991, vol. 2, p. 1047.
5 (a) H. E. Schoemaker, W. H. J. Boesten, Q. B. Broxterman, E. C. Roos,
B. Kaptein, W. J. J. van den Tweel, J. Kamphuis and F. P. J. T. Rutjes,
Chimia, 1997, 51, 308; (b) F. P. J. T. Rutjes and H. E. Schoemaker,
Tetrahedron Lett., 1997, 38, 677.
1
duct was assigned on the basis of H NMR NOE studies after
deprotection to the free amino acid (10% enhancement of H6
upon irradiation of H2 and vice versa) and was in accordance
with previously published observations.3a The cis-configuration
of the 1,4-adduct was concluded via comparison with 1H NMR
data of 7. The regioselectivity of this reaction could not be
influenced by using different Lewis acids, but instead by
applying the more reactive nucleophile allyltributyltin a highly
selective reaction took place at the six-position. In addition,
both trimethylsilylcyanide and 1,2-propadienyltributyltin12 (en-
tries 5–7) reacted solely and with complete diastereoselectivity
at the six-position to give the corresponding cyanide- and
propargyl-substituted product, respectively. Inversely, the
chloromethyl-substituted allylsilane (entry 8) provided again a
mixture of regioisomers.
6 F. P. J. T. Rutjes, T. M. Kooistra, H. Hiemstra and H. E. Schoemaker,
Synlett, 1998, 192.
7 For a review on metal-catalyzed amination, see: T. E. Mu¨ller and M.
Beller, Chem. Rev., 1998, 98, 675.
Eventually, most of the Ns-protected products were con-
verted into the corresponding free pipecolic acid derivatives
(Scheme 4). A straightforward sequence involving (i) cleavage
of the sulfonamide with K2CO3 and PhSH, (ii) LiOH-mediated
hydrolysis of the ester and (iii) purification by ion exchange
chromatography yielded the cyclic amino acids in good to
moderate yields over these two steps without detectable
epimerisation of the stereocentres. Thus, a number of differently
substituted amino acid building blocks were obtained, including
the natural product baikiain (17: [a]D = 2182.6 (c 0.3, H2O);
lit.,13 2201.6 (c 1, H2O)) and the allylic sulfide 19, which arose
from nucleophilic substitution of the chloride during the
deprotection.
8 For the use of benzyl propadienyl ether in allylic acetal formation, see:
H. Ovaa, M. A. Leeuwenburgh, H. S. Overkleeft, G. A. van der Marel
and J. H. van Boom, Tetrahedron Lett., 1998, 39, 3025.
9 A similar mild reacton was previously observed in our lab upon
oxypalladation of benzyl propadienyl ether. The remarkable difference
in reactivity with methyl propadienyl ether is not yet understood. R.
Doodeman, unpublished work.
10 For example, N-tosylallylamine and its homologue give comparable
yields for the reaction with benzyl propadienyl ether.
11 For a recent review on ring-closing metathesis, see: Alkene Metathesis
in Organic Synthesis in Topics in Organometallic Chemistry, ed. A.
Fu¨rstner, Springer, Berlin, 1998.
12 J. S. Prasad and L. S. Liebeskind, Tetrahedron Lett., 1988, 29, 4257.
13 Isolation: F. E. King, T. J. King and A. J. Warwick, J. Chem.Soc., 1950,
3590. For an entry into recent syntheses of baikiain, see: A. Mazon and
C. Najera, Tetrahedron: Asymmetry, 1997, 11, 1855.
In summary, we developed a practical and concise transition
metal-catalyzed route to a variety of substituted pipecolic acid
700
Chem. Commun., 2000, 699–700