Stereospecific synthesis of chiral N-(ethynyl)allylglycines and their use in highly stereoselective intramolecular Pauson-Khand reactions

Article abstract of DOI:10.1039/a905898b

The first synthesis of an enantiopure N-ethynylated allylglycine and its application in the intramolecular Pauson-Khand reaction, which leads to a novel highly functionalised proline derivative with complete control of stereoselectivity, is reported.

Full text of DOI:10.1039/a905898b

Stereospecific synthesis of chiral N-(ethynyl)allylglycines and their use in
highly stereoselective intramolecular Pauson–Khand reactions
Bernhard Witulski* and Matthias Gößmann
Fachbereich Chemie, Universität Kaiserslautern, Erwin Schrödinger Straße, D-67663 Kaiserslautern, Germany.
E-mail: Bernhard@chemie.uni-kl.de
Received (in Cambridge, UK) 21st July 1999, Accepted 2nd August 1999
The first synthesis of an enantiopure N-ethynylated allylgly-
cine and its application in the intramolecular Pauson–
Khand reaction, which leads to a novel highly functionalised
proline derivative with complete control of stereoselectivity,
is reported.
and directly affording the terminal N-functionalised
1-alkynylamide.
With the idea of exploring the scope of the ethynylation
sequence based on 3b and developing a flexible protecting
group strategy,9 the amides 2a–f were synthesised starting from
allylglycine 1 (Scheme 1, Table 1).† Deprotonation of 2a–f with
either KHMDS in toluene or Cs2CO3 in DMF, followed by the
addition of 3b (1.3 equiv.) in CH2Cl2 at room temperature,
yielded the N-ethynylamides 5a–d in 70–95%.‡ A plausible
mechanism for the alkyne formation embodies the in situ
generation of the alkenylidene carbenes 4, which immediately
rearrange via an 1,2-H migration towards the N-ethynylamides
5a–d. The observation that no 1,5-C–H insertion product was
formed indicated that the migration aptitude of the hydrogen
towards the carbenoid centre in 4 must have been, as
anticipated,10 significantly greater than an alternative intra-
molecular 1,5-C–H carbene insertion.11 However, following
N-Functionalised 1-alkynylamides of type A are a new class of
electronically tuneable acetylenes whose protecting group (PG)
serves both in masking a secondary amine and in tuning the
electron density, and hence the reactivity, of the adjacent
acetylene moiety.1 These new building blocks for organic
synthesis were designed with the goal of combining the richness
and diversity of the chemical reactivity of a carbon–carbon
triple bond with one of the most substantial functional groups in
chemistry and biology: the amino function.
Recently we described the synthesis of these novel acetylenes
based on a two step sequence—ethynylation of secondary
amides with trimethylsilylethynyl(phenyl)iodonium triflate2
followed by desilylation with TBAF—and the use of the thus
derived N-ethynylamides, whose reactivity differs significantly
from those of regular ynamines,3 in both the Pauson–Khand
reaction1 and in RhI-catalysed cyclotrimerisations.4 Given our
interest in N-functionalised 1-alkynylamides as versatile build-
ing blocks for nitrogen-containing heterocycles, we considered
the N-ethynylamides B derived from a-amino acids as even
more attractive targets, because their application in transition
metal mediated cycloadditions should allow the asymmetric
formation of conformationally constrained amino acids5 and the
synthesis of novel proline derivatives that are closely related to
the highly potent ACE (angiotensine converting enzyme)
inhibitor Ramipril.6 Furthermore their use as alkynylogous
amino acids in peptide chemistry seems to be an interesting
endeavour.7
However, although the previously described route to N-
functionalised 1-alkynylamides allowed some degree of func-
tional diversity,1, 3 a-branched 1-alkynylamides could only be
obtained in low yields with trimethylsilylethynyl(phenyl)iodon-
ium triflate 3a. Furthermore all attempts to N-alkynylate the a-
amino acid derivatives 2a–f with 3a (R2 = SiMe3) failed. We
assumed that the observed lack of reactivity was caused by
increased steric hindrance inherent in a-branched amino acid
derivatives interfering with the nucleophilic addition of the
amide nitrogen to the b-carbon of the alkyne 3a (R2 = SiMe3).
The ethynyl(phenyl)iodonium triflate8 3b (R2 = H) was
therefore thought to be more suitable for the intended N-
ethynylation. Moreover its use would shorten the previously
applied sequence effectively by avoiding the desilylation step
Scheme 1 Reagents and conditions: i, SOCl2, MeOH, 210 °C, 24 h; ii, R1Cl
(for 2a–c and 2f) or R12O (for 2d,e), Et3N, CH2Cl2, 0 °C, 6–12 h, for yield
of isolated 2a–f (2 steps) see Table 1; iii, Cs2CO3 (1.3 equiv.), 3b (1.3
equiv.), DMF–CH2Cl2, room temp., 3 h, for yield of isolated 5a–f see Table
1; iv, Co2(CO)8 (1.1 equiv.), THF, 30 min. 0–20 °C, then NMO or Me3NO
(6 equiv.), room temp., 25 min, for yield of isolated 6a–d see Table 1.
Table 1 Yield of isolated 2a–f, 5a–f, and 6a–d†
Yield (%)
[de (%)]
Entry R1
2
Yield (%)
5
Yield (%)
6
1
2
3
4
5
6
Ts
2a 88
5a 70
5b 78
5c 95
5d 94
6a 69 [ > 96]
6b 69 [ > 95]
6c 35 [ > 97]
6d 60 [ > 95]
2-pyridyl-SO2 2b 71
4-NO2C6H4SO2 2c 89
Tf
Boc
Ac
2d 83
2e 80
2f 94
5e
5f
0
0
—
—
—
—
Chem. Commun., 1999, 1879–1880
1879

this protocol the allylglycines 2e (R1 = Boc) and 2f (R1 = Ac)
could not be ethynylated with 3b (R2 = H) and were recovered
unchanged. Obviously the increase of basicity12 and likewise
the change of nucleophilicity of the potassium salts of 2e and 2f
prevented their addition to 3b and instead caused its decomposi-
tion presumably initiated by deprotonation.
Gratifyingly, the application of enantiomerically pure (S)-2a
[ee > 98%, [a]D +13 (c 1.0, CHCl3]13 in the outlined protocol
afforded enantiomerically pure N-(ethynyl)allylglycine methyl
ester (S)-5a, testifying that N-ethynylation proceeded without
racemisation. HPLC analysis of the crude product with a chiral
stationary phase (Chiralpak AD column) stated that (S)-5a [ee
> 98%, [a]D 260 (c 2.0, CHCl3] was obtained essentially
enantiomerically pure.14
allowed the stereoselective formation of novel proline deriva-
tives. Additional applications of N-alkynylated amino acids for
the synthesis of conformationally constrained amino acids via
cycloaddition strategies are part of our ongoing research.
This work was supported by the Deutsche Forschungsge-
meinschaft (Wi 1696/1) and by the Fonds der Chemischen
Industrie. We gratefully acknowledge the help of Dr C. Alayrac
and M. Lemarié (ISMRA-Université Caen, France) with the
HPLC analyses and [a]D measurements. We also thank
Professor Dr M. Regitz for his support.
Footnote and references
† All new compounds exhibited satisfactory spectra (1H, 13C NMR, IR and
MS) and elemental analyses. The compounds 2b-f, 5b–d, 6b–d, 8 and 9
were synthesised starting from racemic (rac)-1. The compounds 2a, 5a, 6a
and 7 were synthesised starting from both (rac)-1 and enantiopure (S)-1.
‡ Selected data for (S)-5a: mp 39–40 °C (Et2O–hexanes) (Calc. for
Having established a short and efficient route to chiral and
enantiopure N-ethynylated allylglycines, we tested their appli-
cability as building blocks for the synthesis of functionalised
proline derivatives via the intramolecular Pauson–Khand reac-
tion.15 Although [2+2+1] cycloadditions of 6a–d could be
affected at 80 °C in toluene in the presence of a stoichiometric
amount of Co2(CO)8, the mild amine N-oxide promoted
protocol developed by Schreiber was most effective with
respect to yield and diastereoselectivity.16 Treatment of 5a–d
with Co2(CO)8 at room temperature for 25 min and subsequent
addition of either NMO or Me3NO in CH2Cl2 at room
temperature provided the proline derivatives 6a–d in yields of
69, 69, 35 and 60%, respectively. The lower yield achieved with
the sulfonamide 5c was caused by a concurrent reduction of the
4-nitrophenylsulfonyl moiety to the corresponding aniline and
led to a mixture of products. Pauson–Khand reactions with 5a–d
proceeded with high diastereoselectivity giving almost ex-
clusively one single diastereomer (de > 95%, determined by
1H-NMR, diastereomeric pure 6a–d were obtained by crystal-
lisation).§ The structural assignment of compound 6a was based
on a combination of H, H and C, H COSY experiments and the
analysis of distinct NOE relationships. The use of enantiopure
(S)-5a afforded the optically active (2S,4R)-6a [[a]D +145 (c
2.0, CHCl3)] in 69% yield.¶
Preliminary attempts to further elaborate the obtained highly
functionalised proline derivatives were successful (Scheme 2).
Pauson–Khand product 6a was stereoselectively hydrogenated
on Pd-C/(H2) to the cyclopentanone 7 in 90% yield. Luche
reduction of 6a proceeded with distinctive stereoselectivity
giving exclusively the allylic alcohol 8 in 80% yield. Compound
8 was obtained as colorless crystals (mp 139–140 °C, CH2Cl2–
pentane) after column chromatography on silica gel with
CH2Cl2 containing 0.5% Et3N. However, the allylic alcohol 8
being extremely sensitive to traces of acid, rearranged under H+
catalysis with ring cleavage to the cyclopentenones 9 (2+1
mixture of two diastereoisomers).
C
15H17NO4S (307.37): C, 58.61; H, 5.57; N, 4.56. Found: C, 58.54; H, 5.63;
N, 4.61%); dH (400 MHz, CDCl3) 7.79 (d, J 8.3, 2H), 7.33 (d, J 8.3, 2H),
5.60–5.71 (m, 1H), 5.04–5.19 (m, 2H), 4.53 (dd, J 9.8, 5.2, 1H), 3.57 (s,
3H), 2.84 (s, 1H), 2.54–2.74 (m, 2H), 2.45 (s, 3H).
¶ Selected data for (2S,4R)-6a: mp 132–134 °C (CH2Cl2–hexanes) (Calc.
for C16H17NO5S (335.38): C, 57.30; H, 5.11; N, 4.18. Found: C, 57.01; H,
5.06; N, 4.23%); dH(400 MHz, CDCl3) 7.81 (d, J 8.3, 2H), 7.36 (d, J 8.3,
2H), 5.67 (d, J 1.5, 1H), 4.64 (dd, J 10.3, 5.7, 1H), 3.85 (s, 3H), 2.85–2.95
(m, 1H), 2.56–2.63 (m, 1H), 2.53 (dd, J 17.1, 6.7, 1H), 2.45 (s, 3H), 2.21
(dd, J 17.1, 5.2, 1H), 1.76–1.86 (m, 1H).
§ The stereochemical course of the intramolecular Pauson–Khand reaction
with the compounds 5a–d follows the one previously noticed by us with
other N-ethynylamides. See ref. 1. A detailed discussion will be presented
in the full account of this study.
1 B. Witulski and T. Stengel, Angew. Chem., Int. Ed., 1998, 37, 489.
2 P. J. Stang and V. V. Zhdankin, Chem. Rev., 1996, 96, 1123.
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5 J. Gante, Angew. Chem., Int. Ed. Engl., 1994, 33, 1699; A. E. P. Adang,
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7 M. T. Reetz, T. J. Strack, J. Kanand and R. Goddard, Chem. Commun.,
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8 For the preparation of 3b and its reaction with carbon nucleophiles see:
M. Ochiai, T. Ito, Y. Takaoka, Y. Masaki, M. Kunishima, S. Tani and
Y. Nagao, J. Chem. Soc., Chem. Commun., 1990, 118; P. J. Stang, in
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9 T. W. Greene and P. G. M. Wuts, Protective Groups in Organic
Synthesis, Wiley, New York, 1991; C. Goulaouic-Dubois, A. Guggis-
berg and M. Hesse, J. Org. Chem., 1995, 60, 5969; T. Fukuyama, C.-K.
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11 K. S. Feldman and D. A. Mareska, J. Am. Chem. Soc., 1998, 120, 4027
and references therein.
12 The pKa values of 2a–e can be estimated by comparison with the
following model compounds (in DMSO): NH3 (41), PhSO2NH2 (16.1),
CF3SO2NH2 (9.7), CH3CONH2 (25.5), EtOCONH2 (24.8); all data
taken from F. G. Bordwell, Acc. Chem. Res., 1988, 21, 456.
13 (S)-Allylglycine is commercially available. For its synthesis, see: Y. N.
Belokon, V. I. Bakhmutov, N. I. Chernoglazova, K. A. Kochetkov, S. V.
Vitt, N. S. Garbalinskaya and V. M. Belikov, J. Chem. Soc., Perkin
Trans 1, 1988, 305.
14 Baseline separation of (S)-5a and (R)-5a from (rac)-5a could be
achieved by using the Chiralpak AD column.
Scheme 2 Reagents and conditions: i, H2 (1 atm.), (10%) Pd/C, EtOH–
·
AcOH (1+1), room temp., 24 h; ii, NaBH4 (2 equiv.), CeCl3 7 H2O (1
15 For recent reviews, see A. C. Comely and S. E. Gibson, J. Chem. Soc.,
Perkin Trans 1, 1999, 223; O. Geis and H.-G. Schmalz, Angew. Chem.,
Int. Ed., 1998, 37, 911; N. E. Schore, Comprehensive Organometallic
Chemistry II, ed. L. S. Hegedus, Pergamon, 1995, vol. 12, p. 703.
16 S. Shambayati, W. E. Crowe and S. L. Schreiber, Tetrahedron Lett.,
1990, 31, 5289.
equiv.), MeOH–CH2Cl2, 20 0C, 0.5 h; iii, cat. H+, CHCl3, room temp.
In conclusion, we have established a short and efficient
synthesis of a first set of N-ethynylated amino acid derivatives
and proved, for the example 2a/5a, that N-ethynylation with the
alkynyliodonium salt 3b proceeded without detectable racemi-
sation. Their use in the intramolecular Pauson–Khand reaction
Communication 9/05898B
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Chem. Commun., 1999, 1879–1880