Intramolecular nicholas reaction: Stereoselective synthesis of 5-alkynylproline derivatives

Article abstract of DOI:10.1021/ol800544a

(Chemical Equation Presented) The intramolecular Nicholas reaction of propargylic alcohols derived from N,N-acyl-diprotected ω-semialdehydes obtained from glutamic acid provided stereoselectively 5-alkynylproline derivatives. The suitable choice of the N-

Full text of DOI:10.1021/ol800544a

ORGANIC
LETTERS
2008
Vol. 10, No. 12
2349-2352
Intramolecular Nicholas Reaction:
Stereoselective Synthesis of
5-Alkynylproline Derivatives
J. Nicola´s Herna´ndez, Miguel A. Ram´ırez, Mat´ıas L. Rodr´ıguez,† and
V´ıctor S. Mart´ın*
Instituto UniVersitario de Bio-Orga´nica “Antonio Gonza´lez” UniVersidad de La
Laguna, AVenida Astrof´ısico Francisco Sa´nchez 2, 38206 La Laguna, Tenerife, Spain
Vmartin@ull.es
Received March 10, 2008
ABSTRACT
The intramolecular Nicholas reaction of propargylic alcohols derived from N,N-acyl-diprotected ω-semialdehydes obtained from glutamic acid
provided stereoselectively 5-alkynylproline derivatives. The suitable choice of the N-protecting group (tosyl or benzoyl derivative) permitted
control of the stereochemistry during the ring formation. Semiempirical calculations of the species involved in the cyclization support the
observed stereochemistry.
2,5-Disubstituted pyrrolidines are frequently encountered compo-
nents of natural and bioactive products.1 In particular, 5-alkylproline
derivatives have been used as constrained peptidomimetics.2 Much
effort has been expended in the development of suitable synthetic
methods to make these structural fragments available.3 5-Alky-
nylproline derivatives 1 are versatile intermediates that can be easily
transformed into a wide variety of related molecules simply taking
advantage of their acetylenic and carboxylic reactivity.2c,4 Typi-
cally, these acetylenic heterocycles are obtained by Lewis
acid catalyzed addition of TMS-acetylenes to 5-methoxypro-
line esters available by anodic oxidation of proline esters as
a diastereomeric mixture.2c,5
(3) (a) Pichon, M.; Figade`re, B. Tetrahedron: Asymmetry 1996, 7, 927–
964. (b) Shiosaki, K.; Rapoport, H. J. Org. Chem. 1985, 50, 1229–1239.
(c) Petersen, J. S.; Fels, G.; Rapoport, H. J. Am. Chem. Soc. 1984, 106,
4539–4547. (d) Moloney, M. G.; Panchal, T.; Pike, R. Org. Biomol. Chem.
2006, 4, 3894–3897. (e) Stapon, A.; Li, R.; Townsend, C. A. J. Am. Chem.
Soc. 2003, 125, 15746–15747. (f) Banfi, L.; Basso, A.; Guanti, G.; Riva,
R. Tetrahedron 2006, 62, 4331–4341. (g) Aubry, C.; Oulyadi, H.; Dutheuil,
G.; Leprince, J.; Vaudry, H.; Pannecoucke, X.; Quirion, J.-C. J. Peptide
Sci. 2006, 12, 154–160.
† Corresponding author for X ray analysis. E-mail: malopez@ull.es.
(1) (a) Husson, H.-P. J. Nat. Prod. 1985, 48, 894–906. (b) Jones, T. H.;
Laddago, A.; Don, A. W.; Blum, M. S. A. J. Nat. Prod. 1990, 53, 375–
381. (c) Pedder, D. J.; Fales, H. M.; Jaouni, T.; Blum, M.; MacConnell, J.;
Crewe, R. M. Tetrahedron 1976, 32, 2275–2279. (d) Michael, J. P. Nat.
Prod. Rep. 2004, 21, 625–649. (e) Kondo, T.; Nekado, T.; Sugimoto, I.;
Ochi, K.; Takai, S.; Kinoshita, A.; Tajima, Y.; Yamamoto, S.; Kawabata,
K.; Nakai, H.; Toda, M. Bioorg. Med. Chem. 2007, 15, 2631–2650.
(2) (a) Harris, P. W. R.; Brimble, M. A. Org. Biomol. Chem. 2006, 4,
2696–2709. (b) Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-G.;
Lubell, W. D. Tetrahedron 1997, 53, 12789–12854. (c) Beal, L. M.; Liu,
B.; Chu, W.; Moeller, K. D. Tetrahedron 2000, 56, 10113–10125.
(4) Pei, Z.; Li, X.; Longenecker, K.; Von Geldern, T. W.; Wiedeman,
P. E.; Lubben, T. H.; Zinker, B. A.; Stewart, K.; Ballaron, S. J.; Stashko,
M. A.; Mika, A. K.; Beno, D. W. A.; Long, M.; Wells, H.; Kempf-Grote,
A. J.; Madar, D. J.; McDermott, T. S.; Bhagavatula, L.; Fickes, M. G.;
Pireh, D.; Solomon, L. R.; Lake, M. R.; Edalji, R.; Fry, E. H.; Sham, H. L.;
Trevillyan, J. M. J. Med. Chem. 2006, 49, 3520–3535.
(5) Manfre´, F.; Kern, J.-M.; Biellmann, J.-F. J. Org. Chem. 1992, 57,
2060–2065.
10.1021/ol800544a CCC: $40.75
Published on Web 05/22/2008
2008 American Chemical Society

The intramolecular nucleophilic attack of a hydroxy group
on a Co2(CO)6-propargylic cation (Nicholas reaction) is a
robust method for the synthesis of cyclic ethers.6 Given the
similar chemical reactivity of the acyl amide and the alcohol,
we investigated the possibility of obtaining the title com-
pounds 1 from suitable amino alcohol derivatives 2 (Scheme
1).7 Taking advantage of our general method to gain access
provided the propargylic alcohol 4 in excellent yields.9
Selective cleavage of an N-Boc group10 and alkyne com-
plexation provided 2 (R1 ) H, R2 ) Boc). Alternatively,
the N,N-diBoc-derivative 2 was also obtained by direct
treatment of 4 with the Co2(CO)8 complex.
The acidic treatment of both N-Boc and N,N-diBoc-2
(BF3·OEt2, CH2Cl2) was performed at different temperatures
(Table 1). The corresponding complexed 5-alkynylproline
Scheme 1
.
Stereoselective 5-Alkynylproline Synthesis Using the
Nicholas Reaction
Table 1. Acidic Cyclization of Co2(CO)6-δ-propargylic Alcohols
R-Amino Acid Derivatives to 2,5-Disubstituted Pyrrolidines
entry
2
T (°C)
time (h)
yield
1a:1b
to ω-semialdehydes from R-amino diacids,8 we now report
a new method to obtain 5-alkynylproline derivatives from
glutamic acid. Stereochemical control of the ring substituents
was achieved by tuning the nature of the protecting acyl
group at the nitrogen.
To evaluate our approach the key intermediate 2 (R1 )
H, R2 ) Boc) was prepared from L-glutamic acid (Scheme
2). Semialdehyde 3 was prepared by controlled reduction
1
2
3
4
5
6
2a
2a
2a
2b
2b
2b
rt
0
-20
rt
0
-20
0.2
10
36
0.2
10
36
85
84
90
83
82
91
2.4:1
2.5:1
2.7:1
2.4:1
2.5:1
2.2:1
esters were obtained with very good yields, the cis-isomer
1a being predominant, in a ratio of approximately 2.5:1. Both
yield and stereochemistry were essentially independent of
Scheme 2
.
Synthesis of Co2(CO)6-δ-propargylic Alcohols
Derived from L-Glutamic Acid
Scheme 3. Preparation of Co2(CO)6-δ-propargylic Alcohols
N,N-Acyl Boc-R-amino Acid Derivatives
from dimethyl N,N-diBoc-glutamate8 and submitted to the
lithium acetylide of trimethylsilylacetylene. To avoid possible
racemization and interaction with the ester function, low
temperatures were used (-78 °C). Special care must be taken
with the concentration of the reaction mixture since the use
of low to medium concentration conditions (0.02-0.05 M)
in THF or THF-toluene mixtures provided low conversions
and yields. Fortunately, using a high concentration (0.2 M)
of the reaction mixture in a toluene/THF mixture (4:1)
temperature and whether the nitrogen is mono- or diprotected.
In both cases, the final product was the unprotected pyrro-
lidine.11 So considering step economy, the use of N,N-
(6) D´ıaz, D. D.; Betancort, J. M.; Mart´ın, V. S. Synlett 2007, 343–359.
(7) (a) Mukai, C.; Sugimoto, Y-I.; Miyazawa, K.; Yamaguchi, S.;
Hanaoka, M. J. Org. Chem. 1998, 63, 6281–6287. (b) Davis, F. A.; Song,
M.; Augustine, A. J. J. Org. Chem. 2006, 71, 2779–2786. (c) Carballo,
R. M.; Ram´ırez, M. A.; Rodr´ıguez, M. L.; Martin, V. S.; Padro´n, J. I. Org.
Lett. 2006, 8, 3837–3840.
(9) 1H NMR of the reaction mixture after workup shows virtually pure
samples of the propargylic alcohols even at 0.1 M scale.
(10) Herna´ndez, J. N.; Ram´ırez, M. A.; Mart´ın, V. S. J. Org. Chem.
2003, 68, 743–746.
(11) When performing the reaction at -20 °C, the protected N-Boc-
pyrolidine is detected in the reaction mixture that gives rise to the
unprotected amine.
(8) Kokotos, G.; Padro´n, J. M.; Mart´ın, T.; William, A.; Gibbons, W. A.;
Mart´ın, V. S. J. Org. Chem. 1998, 63, 3741–3744.
2350
Org. Lett., Vol. 10, No. 12, 2008

Table 2. Stereocontrolled Synthesis of 2,5-Disubstituted Pyrrolidines
entry
2
T (°C)
time (h)
yield
product
cis:trans
1
2
3
4
5
6
7
8
9
2c, R1 ) Ts, R2 ) H
rt
0
-20
rt
0
-20
rt
0
rt
0
0.25
2
2
2
2
2
1
20
17
30
88
85
84
86
85
82
87
1c
>99:1
>99:1
>99:1
1:10
1:10
1:10
2d, R1 ) Bz, R2 ) H
1d
2e, R1 ) Ts, R2 ) Boc
2f, R1 ) Bz, R2 ) Boc
1c
1d
>99:1
a
-
88
1:10
a
10
-
a Almost all of the starting material was recovered.
diprotected R-amino acids having at least one Boc-group
looks promising.
NMR data did not provide an unambiguous configuration
of the newly created stereocenter. A series of correlations
were performed to clarify the relative stereochemistry
(Scheme 4). The tosyl pyrrolidine 1c was submitted to CAN
oxidation to give the uncomplexed acetylene. The corre-
sponding silyl derivative was treated with TBAF to yield
the terminal acetylene 3c. Hydrogenation using Lindlar
catalysis provided known 4c.5 Additional information regard-
ing the trans-relationship between the 2,5-substituents was
obtained by oxidative double-bond cleavage with RuO4 and
methyl esterification of the resulting carboxylic acid, provid-
ing the meso diester 5c. In parallel, a similar sequence using
These results were encouraging, as they provide access
to a very important kind of molecules; however, the low
stereoselectivity and absence of control at the newly created
stereocenter prompted us to study the influence of additional
N-protected groups on the cyclization reaction. The p-
methylbenzenesulfonyl and -benzoyl groups were chosen as
acid-resistant protecting groups. The necessary precursors
2c and 2d were also prepared from L-glutamic acid following
a similar scheme to that outlined before (Scheme 3). In
addition, considering the lability of the Boc group in acidic
conditions, the N,N-acyl-Boc-diprotected precursors 2e and
2f were also prepared.
To our delight, we found the cyclization reaction to be
highly stereoselective and the stereochemistry at the newly
created stereocenter to be N-acyl-protecting group de-
pendent (Table 2). Thus, when 2c was submitted to acidic
conditions at room temperature, the cis-5-alkynylproline
ester 1c was formed as the only detected diastereoisomer
(entry 1).12 Alternatively, the benzamide 2d provided the
trans-isomer 1d in a 10:1 ratio (entry 2). As before,
treating N,N-Boc-acyl-protected derivatives 2e and 2f
yielded the corresponding 2,5-pyrrolidines 1c and 1d with
excellent stereocontrol, although in these cases the reaction
rate is strongly dependent on temperature (entries 8 and
10).
Scheme 4. Determination of the Relative Configuration
(12) Only one stereoisomer was detected by NMR analysis.
(13) The deposit numbers for compounds 3c and 3e are CCDC 676614
and 676613, respectively. Crystallographic data for 3c: (C15H17NO4S, Mw
) 307.4), monoclinic, space group P21, a ) 7.520(3) Å, b ) 11.111(4) Å,
c ) 9.544(5) Å, ꢀ ) 96.004(1)°, V ) 793.1(6) Å3, Z ) 2, µ(Mo KR) )
0.22 mm-1, Fcalc ) 1.29 g·cm-3; S ) 1.14, final R indices: R1 ) 0.0481
and Rw ) 0.127 (for 1595 observed reflections (θmax)26.4° and I > 2σ(I)
criterion) and 191 parameters); maximum and minimum residues are 0.31
and 0.27, respectively. Crystallographic data for 3e: C18H25NO4SSi, Mw
379.6), orthorhombic, space group P21212, a ) 9.540(4) Å, b ) 29.793(8)
Å, c ) 7.571(3) Å, V ) 2151.87(14) Å3, Z ) 4, µ(Cu KR) ) 1.94 mm-1
Fcalc ) 1.17 g·cm-3; S ) 1.07, final R indices: R1 ) 0.0537 and Rw
0.157 (for 2523 observed reflections (θmax ) 73.9° and I > 2σ(I) criterion)
and 228 parameters); maximum and minimum residues are 0.38 and 0.29,
respectively. These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre viawww.ccdc.cam.ac.uk/data_request/cif.
)
,
)
1e, obtained by tosylation of 1b, afforded the known 4e and
the chiral pyrrolidine 5e. In addition, X-ray analysis of both
3c and 3e were performed, confirming the correct stereo-
chemistry (Figure 1).13
Org. Lett., Vol. 10, No. 12, 2008
2351

Figure 1. X-ray crystallographic structures of cis- and trans-
tosylpyrrolidines 3c and 3e.
Semiempirical calculations with PM3(tm) Hamiltonian
were performed to investigate the stereochemical preferences
of the cyclization to obtain 1c and 1d (Figure 2).14 The
geometry of the reactants, products and transition states (TS)
were fully optimized for both N-tosyl (Ts) and N-benzoyl
(Bz) derivatives. Stereochemical results are in agreement with
relative energies of the final products in both N-protonated
and free species.13 In addition, the relative energies of the
transition states assuming the stereoselective trapping of a
preordered propargylic cation by the electron pair of the
nitrogen are also in agreement with the stereochemical
outcome of the cyclization. Although the overall processes
are exothermic, it should be considered that the calculations
are performed considering gaseous state, and the protonated
final products are highly energetic species. The distribution
of the relative energies could be the result of a combination
of steric interactions between the bulkiest groups and
electrostatic interactions between the highly polarized car-
bonyl group of the cobalt complex and the oxygens of the
acyl substitutents of the nitrogen.
Figure 2. Geometries of the optimized transititon states (hydrogens
were omitted by clarity) for the cyclization to protonated 1c and
1d. Red thinner lines denote electrostatic interactions between the
carbonyl group of the cobalt complex and the oxygens of the
sulfonamide and benzamides groups.
by the European Regional Development Fund (CTQ2005-
09074-C02-01/BQU) and the Canary Islands Government.
In summary, we have developed a simple, practical method
for the preparation of 5-alkynyl derivatives via an intramo-
lecular Nicholas reaction. The suitable choice of the protect-
ing group on the nitrogen permits control of the stereochem-
istry in the cyclization. The procedure offers a straightforward
way to construct 2,5-dialkylpyrrolidines in their enantiomeric
forms. Semiempirical theoretical calculations support the
stereochemical preferences.
Supporting Information Available: Experimental de-
tails, 1H NMR and 13C NMR spectra for all new
compounds, and geometries of the optimized minima and
transititon states (Figure 2). This material is available free
of charge via the Internet at http://pubs.acs.org.
OL800544A
(14) Semiempirical quantum mechanics method using a minimal valence
basis set of Slater-type orbitals. Spartan’06 package, Wavefunction, Inc.
(http://www.wavefun.com).
Acknowledgment. This research was supported by the
Ministerio de Educacio´n y Ciencia of Spain, cofinanced
2352
Org. Lett., Vol. 10, No. 12, 2008