Synthesis of α-cyclopropyl-β-homoprolines

Article abstract of DOI:10.1021/jo9004684

(Chemical Equation Presented) 1-(2-Pyrrolidinyl)cyclopropanecarboxylic acids (α-cyclopropyl-β-homoprolines) were prepared by 1,3-dipolar cycloadditions of cyclic nitrones onto bicyclopropylidene followed by trifluoroacetic acid induced thermal fragmentati

Full text of DOI:10.1021/jo9004684

Synthesis of r-Cyclopropyl-ꢀ-homoprolines†
Franca M. Cordero,*,‡ Maria Salvati,‡ Carolina Vurchio,‡ Armin de Meijere,§ and
Alberto Brandi*,‡
Department of Organic Chemistry “Ugo Schiff” and HeteroBioLab, UniVersity of Florence, Via della
Lastruccia 13, 50019 Sesto Fiorentino (FI), Italy, and Institut fu¨r Organische und Biomolekulare Chemie
der Georg-August-UniVersita¨t Go¨ttingen, Tammannstrasse 2, D-37077 Go¨ttingen, Germany
alberto.brandi@unifi.it; franca.cordero@unifi.it.
ReceiVed March 4, 2009
1-(2-Pyrrolidinyl)cyclopropanecarboxylic acids (R-cyclopropyl-ꢀ-homoprolines) were prepared by 1,3-
dipolar cycloadditions of cyclic nitrones onto bicyclopropylidene followed by trifluoroacetic acid induced
thermal fragmentative rearrangement. With the use of enantiopure pyrroline N-oxides derived from easily
available chiral pool molecules, ꢀ-homoprolines were formed with high stereocontrol. The incorporation
of one of these new cyclic ꢀ-amino acids into a simple tripeptide was also evaluated. In particular, the
sterically hindered nitrogen atom of the highly substituted pyrrolidine 30 was smoothly acylated through
the intermediate formation of a mixed anhydride.
Introduction
Of special interest are R- and ꢀ-amino acids containing a 1,1-
disubstituted cyclopropane ring adjacent to the carboxyl moiety.6
In general, the introduction of the relatively small cyclopropyl
moiety significantly influences the conformational flexibility of
the respective amino acid and peptides derived from it.6 For
example, the parent 1-(aminomethyl)cyclopropanecarboxylic
acid (1) has been incorporated by Varie et al. in cryptophycin
analogues with potent antitumor activity,7 and Seebach et al.
have shown that oligomers of 1 have interesting secondary
structures.8 In addition, the benzyl ester 2 is an interesting
inhibitor of monoamine oxidase,9 and other derivatives of 1 have
ꢀ-Amino acids are important targets in organic chemistry
because of their roles as synthetic intermediates1 and as key
components of a variety of biologically active compounds2
including peptidomimetics3 and ꢀ-peptides.4,5
† Dedicated to Professor Francesco De Sarlo on the occasion of his 70th
birthday.
‡ University of Florence.
§ Georg-August-Universita¨t Go¨ttingen.
(1) For some selected examples, see: (a) Escalante, J.; Gonza`lez-Tototzin,
M. A.; Avin˜a, J.; Mun˜oz-Mun˜iz, O.; Juaristi, E. Tetrahedron 2001, 57, 1883–
1890. (b) Krishnaswamy, D.; Govande, V. V.; Gumaste, V. K.; Bhawal, B. M.;
Deshmukh, A. R. A. S. Tetrahedron 2002, 58, 2215–2225. (c) Sleeman, M. C.;
MacKinnon, C. H.; Hewitson, K. S.; Schofield, C. J. Bioorg. Med. Chem. Lett.
2002, 12, 597–599. (d) Brashear, K. M.; Hunt, C. A.; Kucer, B. T.; Duggan,
M. E.; Hartman, G. D.; Rodan, G. A.; Rodan, S. B.; Leu, C.; Prueksaritanont,
T.; Fernandez-Metzler, C.; Barrish, A.; Homnick, C. F.; Hutchinson, J. H.;
Coleman, P. J. Bioorg. Med. Chem. Lett. 2002, 12, 3483–3486. (e) Martinek,
T.; To´th, G. K.; Vass, E.; Hollo´si, M.; Fu¨lo¨p, F. Angew. Chem., Int. Ed. 2002,
41, 1718–1721. (f) Gedey, S.; Van der Eycken, J.; Fu¨lo¨p, F. Org. Lett. 2002, 4,
1967–1969. (g) Bonache, M. A.; Gerona-Navarro, G.; Garc´ıa-Aparicio, C.; Al´ıas,
M.; Mart´ın-Mart´ınez, M.; Garc´ıa-Lo´pez, M. T.; Lo´pez, P.; Cativiela, C.;
Gonza´lez-Mun˜iz, R. Tetrahedron: Asymmetry 2003, 14, 2161–2169.
(2) (a) Ojima, I.; Lin, S.; Wang, T. Curr. Med. Chem. 1999, 6, 927–953. (b)
Scarborough, R. M. Curr. Med. Chem. 1999, 6, 971–981.
(4) (a) Seebach, D.; Abele, S.; Sifferlen, T.; Ha¨ngi, M.; Gruner, S.; Seiler,
P. HelV. Chim. Acta 1998, 81, 2218–2243. (b) Abele, S.; Vo¨gtli, K.; Seebach,
D. HelV. Chim. Acta 1999, 82, 1539–1549.
(5) For some reviews on ꢀ-peptides, see: (a) Seebach, D.; Matthews, J. L.
J. Chem. Soc., Chem. Commun. 1997, 21, 2015–2022. (b) Gellman, S. H. Acc.
Chem. Res. 1998, 31, 173–180. (c) Gademann, K.; Hintermann, T.; Schreiber,
J. V. Curr. Med. Chem. 1999, 6, 905–925. (d) DeGrado, W. F.; Schneider, J. P.;
Hamuro, Y. J. Peptide Res. 1999, 54, 206–217. (e) Cheng, R. P.; Gellman, S. H.;
DeGrado, W. F. Chem. ReV. 2001, 101, 3219–3232.
(6) For a recent review on cyclopropyl-group-containing R- and ꢀ-amino
acids, see: (a) Brackmann, F.; de Meijere, A. Chem. ReV. 2007, 107, 4493–
4537. (b) Brackmann, F.; de Meijere, A. Chem. ReV. 2007, 107, 4538–4583. (c)
Gnad, F.; Reiser, O. Chem. ReV. 2003, 103, 1603–1623.
(7) Varie, D. L.; Shih, C.; Hay, D. A.; Andis, S. L.; Corbett, T. H.; Gossett,
L. S.; Janisse, S. K.; Martinelli, M. J.; Moher, E. D.; Schultz, R. M.; Toth, J. E.
Biorg. Med. Chem. Lett. 1999, 9, 369–374.
(3) (a) Steer, D. L.; Lew, R. A.; Perlmutter, P.; Smith, A. I.; Aguilar, M. I.
Curr. Med. Chem. 2002, 9, 811–822. (b) Porter, E. A.; Wang, X. F.; Lee, H. S.;
Weisblum, B.; Gellman, S. H. Nature 2000, 404, 565–565.
10.1021/jo9004684 CCC: $40.75
Published on Web 05/04/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 4225–4231 4225

Cordero et al.
SCHEME 1. Intra- and Intermolecular Approach to
Monobactams and 3,4-Fused Azetidinones by the 1,3-DC/
ATR Sequence
been shown to be potent binders of the R2-δ protein10 and have
been used as direct precursors of R-methylene-γ-butyrolac-
tones.11
Despite their high potential as building blocks in organic
synthesis and tools in medicinal chemistry, ꢀ-amino acids with
a cyclopropane ring in the 2-position have not been explored
to a large extent, and this may be due to difficulties in preparing
some of their more complex derivatives in a stereoselective
manner.12,13
SCHEME 2. Intra- and Intermolecular Approach to
3-Spirocyclopropane-ꢀ-lactams by the 1,3-DC/ATR Sequence
Recently, we disclosed a new general approach to ꢀ-lactams
and ꢀ-amino acids based on the 1,3-dipolar cycloaddition (1,3-
DC) of nitrones to methylenecyclopropane (MCP) and its
derivatives, followed by fragmentative thermal rearrangement
of the protonated cycloadducts (spiroCycloPropaneIsoxazolidine
Acidic Thermal Rearrangement, CPI-ATR).14 In particular,
monobactams and 3,4-cis-fused azetidinones are produced in
good yields starting from the cycloadducts of acyclic nitrones
formed in an inter- or intramolecular process, respectively
(Scheme 1).14,15
The method exploits the stereoselectivity of the cycloaddition
to control the configuration of the stereocenters on the azeti-
dinone ring, which is retained during the CPI-ATR step.
Actually, the use of nitrones obtained from chiral pool precursors
allowed the synthesis of optically active azetidinones with high
stereocontrol.
and it caused the direct formation of the stable N-(trifluo-
roacetyl)-ꢀ-amino acids by trifluoroacetolysis of the lactam
bond.17 For example, cycloadducts of pyrroline N-oxides did
not afford the expected carbapenams but the corresponding
ꢀ-homoprolines.15b
The practicability of the 1,3-DC/CPI-ATR approach to the
synthesis of variously decorated azetidinones and ꢀ-amino acids
prompted us to investigate new applications in order to establish
the real scope of the process.
Herein we report a study of the CPI-ATR of several
cycloadducts of cyclic nitrones onto BCP. In addition, the
feasibility of using a highly functionalized R-cyclopropyl-ꢀ-
homoproline as a building block in peptide synthesis was
evaluated.
The same two-step approach could be easily extended to the
synthesis of highly strained 3-spirocyclopropane-ꢀ-lactams by
the use of bicyclopropylidene (BCP) as the dipolarophile in the
cycloaddition step (Scheme 2).16
Results and Discussion
Usually, various protic acids such as TFA, p-TsOH, and
HCl could be used to initiate the fragmentative rearrangement
of 5-spirocyclopropaneisoxazolidines into ꢀ-lactams. In the
case of highly reactive products, TFA was the acid of choice,
Usually, the reaction rate of BCP with cyclic nitrones is slow
between room temperature and 60 °C, but the corresponding
adducts, the 2,3-fused 4,5-(bis)spirocyclopropanated isoxazo-
lidines, are obtained in good yields and with high diastereose-
lectivity.18 At higher temperature the conversion of the reagents
is faster, but the in situ transformation of cycloadducts into
4-piperidones by the well-known thermal rearrangement of
5-spirocyclopropaneisoxazolidines19 (CPI-TR; Brandi-Guarna
reaction20) is also observed.
The spirocyclopropaneisoxazolidine 4a derived from the
nitrone of methyl prolinate 3a21 was obtained under standard
conditions (BCP, toluene, 60 °C, 3 d) in 69% yield (Scheme
3). Surprisingly, the corresponding tert-butyl ester 4b proved
(8) Abele, S.; Seiler, P.; Seebach, D. HelV. Chim. Acta 1999, 82, 1559–
1571.
(9) (a) Silverman, R. B.; Lu, X.; Blomquist, G. D.; Ding, C. Z.; Yang, S.
Biorg. Med. Chem. 1997, 5, 297–304. (b) Silverman, R. B.; Ding, C. Z.; Borrillo,
J. L.; Chang, J. T. J. Am. Chem. Soc. 1993, 115, 2982–2983.
(10) Schwarz, J. B.; Gibbons, S. E.; Graham, S. R.; Colbry, N. L.; Guzzo,
P. R.; Le, V.-D.; Vartanian, M. G.; Kinsora, J. J.; Lotarski, S. M.; Li, Z.;
Dickerson, M. R.; Su, T.-Z.; Weber, M. L.; El-Kattan, A.; Thorpe, A. J.; Donevan,
S. D.; Taylor, C. P.; Wustrow, D. J. J. Med. Chem. 2005, 48, 3026–3035.
(11) Saimoto, H.; Nishio, K.; Yamamoto, H.; Shinoda, M.; Hiyama, T.;
Nozaki, H. Bull. Chem. Soc. Jpn. 1983, 56, 3093–3098.
(12) For selected syntheses of achiral or racemic derivatives, see: (a)
Murakami, M.; Ishida, N.; Miura, T. Chem. Lett. 2007, 36, 476–477. (b) Bertus,
P.; Szymoniak, J. Synlett 2003, 265–267, and ref 10.
(13) For some optically active derivatives, see: (a) Hegedus, L. S.; Bates,
R. W.; Soderberg, B. C. J. Am. Chem. Soc. 1991, 113, 923–927. (b) Bartels, A.;
Jones, P. G.; Liebscher, J. Synthesis 1998, 1645–1654. (c) Nakamura, I.; Nemoto,
T.; Yamamoto, Y.; de Meijere, A. Angew. Chem., Int. Ed. 2006, 45, 5176–
5179, and ref 11.
(17) (a) Sharma, R.; Stoodley, R. J.; Whiting, A. J. Chem. Soc., Perkin Trans.
1 1987, 2361–2369. (b) Crackett, P. H.; Pant, C. M.; Stoodley, R. J. J. Chem.
Soc., Perkin Trans. 1 1984, 2785–2793. (c) Brennan, J.; Richardson, G.; Stoodley,
R. J. J. Chem. Soc., Perkin Trans. 1 1983, 649–655.
(18) (a) Goti, A.; Anichini, B.; Brandi, A.; Kozhushkov, S.; Gratkowski, C.;
de Meijere, A. J. Org. Chem. 1996, 61, 1665–1672. (b) Zorn, C.; Anichini, B.;
Goti, A.; Brandi, A.; Kozhushkov, S. I.; de Meijere, A.; Citti, L. J. Org. Chem.
1999, 64, 7846–7855. (c) Revuelta, J.; Cicchi, S.; de Meijere, A.; Brandi, A.
Eur. J. Org. Chem. 2008, 1085–1091.
(19) (a) Goti, A.; Cordero, F. M.; Brandi, A. Top. Curr. ReV. 1996, 178,
1–97. (b) Brandi, A.; Cicchi, S.; Cordero, F. M.; Goti, A. Chem. ReV. 2003,
103, 1213–1269.
(20) Hassner, A.; Stumer, C. Organic Syntheses Based on Name Reactions,
Pergamon: Oxford, 2002; Tetrahedron Organic Chemistry Series, Vol. 22.
(21) (a) Murahashi, S.-I.; Mitsui, H.; Shiota, T.; Tsuda, T.; Watanabe, S. J.
Org. Chem. 1990, 55, 1736–1744. (b) Marcantoni, E.; Petrini, M.; Polimanti,
O. Tetrahedron Lett. 1995, 36, 3561–3562. (c) Goti, A.; Nannelli, L. Tetrahedron
Lett. 1996, 37, 6025–6028. (d) Murray, R. W.; Iyanar, K.; Chen, J.; Wearing,
J. T. J. Org. Chem. 1996, 61, 8099–8102.
(14) Cordero, F. M.; Pisaneschi, F.; Goti, A.; Ollivier, J.; Salau¨n, J.; Brandi,
A. J. Am. Chem. Soc. 2000, 122, 8075–8076.
(15) (a) Cordero, F. M.; Pisaneschi, F.; Salvati, M.; Paschetta, V.; Ollivier,
J.; Salau¨n, J.; Brandi, A. J. Org. Chem. 2003, 68, 3271–3280. (b) Cordero, F. M.;
Salvati, M.; Pisaneschi, F.; Brandi, A. Eur. J. Org. Chem. 2004, 220, 5–2213.
(c) Cordero, F. M.; De Sarlo, F.; Brandi, A. Monatsh. Chem. 2004, 135, 649–
669. (d) Brandi, A.; Cicchi, S.; Cordero, F. M. Chem. ReV. 2008, 108, 3988–
4035.
(16) (a) Zanobini, A.; Gensini, M.; Magull, J.; Vidoviæ, D.; Kozhushkov,
S. I.; Brandi, A.; de Meijere, A. Eur. J. Org. Chem. 2004, 415, 8–4166. (b)
Zanobini, A.; Brandi, A.; de Meijere, A. Eur. J. Org. Chem. 2006, 125, 1–1255.
(c) Marradi, M.; Brandi, A.; Magull, J.; Schill, H.; de Meijere, A. Eur. J. Org.
Chem. 2006, 5485–5494.
4226 J. Org. Chem. Vol. 74, No. 11, 2009

Synthesis of R-Cyclopropyl-ꢀ-homoprolines
TABLE 1. CPI-ATR of 4,5-(Bis)spirocyclopropanated
Isoxazolidines
SCHEME 3
SCHEME 4
to be extremely thermally labile. In particular, a mixture of the
adduct 4b and the ketone 5b was obtained by heating nitrone
3b22 and BCP at 60 °C for 2 days or at 50 °C for 1 day, and 5b
was the only product after 4.5 days at 40 °C (Scheme 3). No
rearrangement was observed at room temperature, and the
isoxazolidine 4b was obtained in 84% yield by stirring the
reagents at 20 °C for 5 days.
Enantiopure hydroxylated pyrroline N-oxide 6,23 easily
derived from tartaric acid, reacted with BCP at 60 °C to afford
the anti- and syn-(3-Ot-Bu)-adducts 7a and 7b in a 4.4:1 ratio
and 90% overall yield (Scheme 4). The other (bis)spiro-
isoxazolidines 8-13 used in the study were prepared as
previously described.18
The results of the ATR of 4,5-(bis)spirocyclopropaneisox-
azolidines 4 and 7-12 are shown in Table 1. Analogously
to the monospiro-annelated 2-spirocyclopropane-pyrrolo[1,2-
b]isoxazolidines,15b ATR of dispiro-fused derivatives 4 and
7-10 in the presence of TFA afforded R-cyclopropyl-ꢀ-
homoprolines 13-17 (entries 1-7, Table 1). The N-protected
amino acids were isolated in good yields (62-94%) after
chromatography. The reaction could also be carried out on a
1 g scale, and microwave irradiation often provided better
results than conventional heating. As in the previous cases,
the intermediate carbapenames could not be detected in the
reaction mixtures.
The presence of the trifluoroacetamide moiety in homopro-
lines 13-17 is evidently discernible in proton decoupled 13C
NMR spectra, which show the two characteristic quartets at
156-157 (JC-F ) 36-37 Hz) and 116-117 ppm (JC-F
)
287-288 Hz). A long-range C-F coupling constant is also
observed between pyrrolidine C-5 carbon and the fluorine atoms
(46.5-63.8 ppm, JC-F ) 2.6-4.0 Hz). In one case (16), the
structure was confirmed by a single crystal X-ray analysis.
CPI-ATR of adducts 11 and 1218a of six-membered ring
cyclic nitrones afforded different results, and in the case of
11 the unopened azetidinone 18 could be isolated, albeit in
a TFA (1.1-2 equiv) was used as the protic acid in all cases
except in experiments 10 and 13, for which p-TsOH (1 equiv) was
used. b MW irradiation power of 150 W with simultaneous cooling
(CEM Discover microwave reactor with IR temperature monitoring).
c 72% conversion. d In experiment 12, 1-[1-(1-isoquinolinyl)cyclo-
propyl]-1-propanone 20 was obtained in 7% yield in addition to the
amino acid 19, whereas in experiment 13, 20 was the only observed
product (20% yield).
(22) Salvati, M.; Cordero, F. M.; Pisaneschi, F.; Bucelli, F.; Brandi, A.
Tetrahedron 2005, 61, 8836–8847.
(23) (a) Cicchi, S.; Goti, A.; Brandi, A. J. Org. Chem. 1995, 60, 4743–
4748. (b) Cicchi, S.; Ho¨ld, I.; Brandi, A. J. Org. Chem. 1993, 58, 5274–5275.
J. Org. Chem. Vol. 74, No. 11, 2009 4227

Cordero et al.
SCHEME 5
poor yields (entries 8-10, Table 1). The use of p-TsOH gave
slightly better results than TFA in the rearrangement of 11.
In either case, no formation of the corresponding ring-opened
ꢀ-amino acid was observed. When the tetrahydroisoquinoline
derivative 12 was heated at 60 °C in the presence of a slight
excess of TFA, the N-trifluoroacetyl ꢀ-amino acid 19 was
obtained in 46% yield (entry 11, Table 1). In close analogy
to the formation of other ꢀ-homoprolines, the first product
of the ATR of 12 was probably the spirocyclopropane-
annelated azeto[2,1-a]isoquinolin-2-one, which must be more
reactive than azetidinone 18 and therefore spontaneously
undergoes trifluoroacetolysis under the reaction conditions.
At 110 °C, protonated 12 was converted into a 6:1 mixture
of 19 and the isoquinoline 20, which had previously been
obtained by the purely thermal rearrangement of 12 under
neutral conditions (entry 12, Table 1).18a Finally, heating of
12 in the presence of p-TsOH led to the ketone 20 along
with a complex mixture of decomposition products (entry
13, Table 1).
SCHEME 6
These results prove that the 1,3-DC/ATR process consti-
tutes an easy and efficient access to the new class of
R-cyclopropyl-ꢀ-homoprolines. Obviously, a possible ap-
plication of these densely functionalized amino acids is in
the area of peptidomimetics, provided that they can be
incorporated into simple peptides. As a matter of fact, cyclic
and/or sterically crowded amino acids often exhibit a rather
poor reactivity in peptide couplings with natural amino acids.
Accordingly, the reactivity of the synthesized ꢀ-homoprolines
had to be tested.
The synthesized homoprolines have the convenient feature
to be protected at the amino group, therefore they can be
directly used in peptide synthesis. The carboxyl group of 15
and 17 underwent condensation with L-Phe-OMe under
standard conditions, affording the pseudodipeptides 21 and
22 in 77-79% yield (Scheme 5). After removal of the
trifluoroacetyl group in 22, any attempt to couple 23 with
L-Fmoc-Val and even with the less sterically demanding Boc-
Gly totally failed (Scheme 5).
This failure is probably due to the pyrrolidine substituents
that sterically interfere with the accessibility of the nitrogen
atom. By analogy with the formation of 17, which presumably
involves the initial formation of a mixed anhydride by
trifluoroacetolysis of carbapenam 25 followed by O-N
trifluoroacetyl shift (Scheme 6),17 the N-acylation should be
easily available through an intramolecular approach. Partici-
pation of a transitional mixed anhydride was also postulated
intheN-acylationofpyroglutamicacidundermildconditions.24,25
To test this hypothesis, a suitable mixed anhydride was
necessary. The trifluoroacetamide group in 17 was hydrolyzed
to obtain the unprotected amino acid 27. Deprotonation of
27 with N-methylmorpholine (NMM) and treatment with the
active ester A, generated in situ from L-Boc-Phe-OH,
2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT, 28), and
NMM,26 by heating at 60 °C for 30 min under microwave
irradiation, gave amide 29 in 70% yield after chromatographic
purification (Scheme 7). As expected, no formation of the
homodimer of the deprotected amino acid 27 was observed.
The formation of the mixed anhydride B could not be directly
observed, but the success of N-acylation of the unprotected
amino acid clearly supports the existence of such inter-
mediate24,25 and indicates that a 6-exo-trig cyclization in B
is stereoelectronically viable.
Finally, the coupling of 29 with L-Val-OMe under standard
conditions afforded the pseudotripeptide 30 in satisfactory yield
of 47%.
Conclusions
In conclusion, the 1,3-DC/ATR two-step process has been
applied to several cyclic nitrones using BCP as dipolarophile.
Six-membered ring nitrones afforded cyclopropanated ꢀ-lactams
or ꢀ-homopipecolic acids in moderate yields, whereas pyrroline
N-oxides gave R-cyclopropane-ꢀ-homoprolines in good overall
yields.
Particularly interesting was the use of enantiopure hydroxy-
lated pyrroline N-oxides for the selective synthesis of highly
functionalized ꢀ-amino acids. The tribenzyloxy derivative 23
could not be directly coupled at the nitrogen with natural amino
acids, but this problem was nicely overcome by performing an
intramolecular N-acylation through the intermediate formation
(24) Imaki, K.; Niwa, H.; Sakuyama, S.; Okada, T.; Toda, M.; Hayashi, M.
Chem. Pharm. Bull. 1981, 29, 2699–2701.
(25) For a recent approach to dipeptides of hindered R-amino acids through
the formation of a transient anhydride and related reactions, see: Brown, Z. Z.;
Schafmeister, C. E. J. Am. Chem. Soc. 2008, 130, 14382–14383, and references
therein.
(26) (a) Kamin˜ski, Z. J. Synthesis 1987, 917–920. (b) Kamin˜ski, Z. J.
Biopolymers (Pept. Sci.) 2000, 55, 140–164.
4228 J. Org. Chem. Vol. 74, No. 11, 2009

Synthesis of R-Cyclopropyl-ꢀ-homoprolines
SCHEME 7
C-3), 27.7 (q, 3C; CH3), 27.4 (s; c-Pr), 23.8 (t; C-4), 16.0 (t; c-Pr),
14.7 (t; c-Pr) ppm. IR: V 2979, 2932, 1726, 1699, 1602, 1456, 1370,
1237, 1214, 1151 cm-1. MS (EI): m/z (%) 351 (0.1, M+), 278 (4),
250 (41), 232 (80), 204 (20), 182(15), 136 (14), 69 (24), 57 (100).
HRMS: calcd for C15H19F3NO5 [M - H]- 350.12098, found
350.12058.
1-[(2S,3S,4S)-3,4-Di-tert-butoxy-1-(trifluoroacetyl)pyrrolidinyl]-
cyclopropanecarboxylic Acid (14). A mixture of 7a (50 mg, 0.16
mmol) and TFA (19 µL, 0.24 mmol) in toluene (4.0 mL) in a sealed
vial was irradiated in a microwave reactor using an irradiation power
of 150 W (with simultaneous cooling) at 55-61 °C for 10 min.
The reaction mixture was concentrated under reduced pressure, and
the crude product was purified by chromatography on silica gel
(pentane/AcOEt/TFA ) 4: 1: 0.01) to give 14 (58 mg, 91%) as a
pale yellow oil. Rf )0.30. [R]24D ) +10.1 (c 0.78, CHCl3). 1H NMR
(400 MHz): δ 4.19-4.15 (m, 2H; 2-H, 3-H), 3.94-3.87 (m, 1H;
5-Ha), 3.85-3.79 (m, 1H; 4-H), 3.55 (dd, J ) 11.0, 4.8 Hz, 1H;
5-Hb), 1.56-1.49 (m, 1H; c-Pr), 1.44-1.37 (m, 1H; c-Pr),
1.36-1.28 (m, 1H; c-Pr), 1.23 (s, 9H; tBu), 1.19 (s, 9H; tBu), 1.08-
1.01 (m, 1H; c-Pr) ppm. 13C NMR (100 MHz): δ 180.2 (s; CO2H),
156.4 (q, JCF ) 36.3 Hz; COCF3), 116.3 (q, JCF ) 288.1 Hz; CF3),
78.3 (d; C-3), 75.4 (d; C-4), 75.1 (s; tBu), 74.5 (s; tBu), 66.5 (d;
C-2), 53.2 (tq; JCF ) 3.1 Hz; C-5), 28.9 (q, 3C; CH3), 28.3 (q, 3C;
CH3), 24.2 (s; c-Pr), 18.3 (t; c-Pr), 15.4 (t; c-Pr) ppm. IR (CDCl3):
V 2959, 2933, 2871, 2254, 1730, 1690, 1464, 1367, 1190 cm-1
.
MS (EI): m/z 395 (0.3, M+), 338 (1), 296 (15), 282 (2), 264 (10),
240 (51), 222 (20), 128 (16), 100 (24), 57 (100). C18H28F3NO5
(395.41): calcd C 54.68, H 7.14, N 3.54; found C 54.96, H 7.16, N
3.32.
1-[(2R,3S)-3-tert-Butoxy-1-(trifluoroacetyl)pyrrolidinyl]cy-
clopropanecarboxylic Acid (15). A mixture of 8 (570 mg, 2.4
mmol) and TFA (0.28 mL, 3.6 mmol) in toluene (49.5 mL) in
a sealed vial was irradiated in a microwave reactor using an
irradiation power of 150 W (with simultaneous cooling) at 55-65
°C for 1 h. The reaction mixture was concentrated under reduced
pressure, and the crude product was purified by chromatography
on silica gel (CH2Cl2/MeOH ) 20:1) to give 15 (567 mg, 73%)
as a colorless solid. Rf ) 0.27. Mp 111-112 °C. [R]24D ) +24.6
of a mixed anhydride. In particular, the successful incorporation
of the highly functionalized and sterically encumbered amino
acid 27 into the pseudotripeptide 30 suggests that the synthesized
R-cyclopropane-ꢀ-homoprolines can be used as building blocks
in the synthesis of peptidomimetics.
Experimental Section
1
(c 0.61, CHCl3). H NMR (400 MHz): δ 4.46 (dt, J ) 4.9, 6.1
1-[2-(Methoxycarbonyl)-1-(trifluoroacetyl)-2-pyrrolidinyl]cyclo-
propanecarboxylic Acid (13a). A mixture of 4a (30 mg, 0.13 mmol)
and TFA (0.016 mL, 0.20 mmol) in CH3CN (3 mL) was refluxed
for 3 h. The reaction mixture was concentrated under reduced
pressure, and the crude product was purified by chromatography
on silica gel (petroleum ether/AcOEt/TFA ) 1:1:0.01) to give 13a
Hz, 1H; 3-H), 3.92-3.84 (m, 1H, 5-Ha), 3.80-3.71 (m, 1H,
5-Hb), 3.58 (d, J ) 4.7 Hz, 1H; 2-H), 2.24 (dddd, J ) 12.8, 6.7,
6.1, 4.5 Hz, 1H; 4-Ha) 1.85-1.76 (m, 1H, 4-Hb), 1.52 (ddd, J )
9.8, 7.6, 4.7 Hz, 1H; c-Pr), 1.42-1.36 (m, 1H; c-Pr), 1.32-1.24
(m, 1H; c-Pr), 1.21 (s, 9H; CH3), 1.14 (ddd, J ) 9.3, 7.7, 4.2
Hz, 1H; c-Pr) ppm. 13C NMR (50 MHz): δ 179.6 (s; CO2H),
156.0 (q, JC-F ) 36.2 Hz; COCF3), 116.3 (q, JC-F ) 287.8 Hz;
CF3), 74.5 (s; CMe3), 74.3(d; C-3), 68.4 (d; C-2), 46.5 (tq, JC-F
) 3.5 Hz; C-5), 34.2 (t; C-4), 28.6 (q, 3C; CH3), 23.7 (s; c-Pr),
17.7 (t; c-Pr), 15.1 (t; c-Pr) ppm. IR (KBr): V 3600-2800, 2985,
1720, 1687, 1447, 1397, 1203, 1141, 1000, 758, 613 cm-1. MS
(EI): m/z 323 (0.3, M+), 267 (9), 250 (6), 198 (23), 156 (14),
69 (14), 57 (100). C14H20F3NO4 (323.31): calcd C 52.01, H 6.24,
N 4.33; found C 52.18, H 6.09, N 4.43.
1-[(3aS,4S,6aR)-2,2-Dimethyl-5-(trifluoroacetyl)tetrahydro-3aH-
[1,3]dioxolo[4,5-c]pyrrol-4-yl]cyclopropanecarboxylic Acid (16). A
mixture of 9 (50 mg, 0.21 mmol) and TFA (24 µL, 0.32 mmol)
in toluene (5.2 mL) in a sealed vial was irradiated in a microwave
reactor using an irradiation power of 150 W (with simultaneous
cooling) at 55-70 °C for 35 min. The reaction mixture was
concentrated under reduced pressure, and the crude product was
purified by chromatography on silica gel (pentane/Et2O ) 2:3)
to give 16 (52 mg, 77%) as a uncolored crystalline solid.
Crystallization from diethyl ether and petroleum ether afforded
crystals suitable for X-ray analysis. Rf ) 0.32. Mp 117-118
°C. [R]24D ) +7.4 (c 0.57, CHCl3). 1H NMR (400 MHz): δ 4.98
(pseudo t, J ) 5.4 Hz, 1H; 6a-H), 4.91 (dd, J ) 6.1, 1.3 Hz,
1H; 3a-H), 4.14 (dd, J ) 12.3, 5.0 Hz, 1H; 6-Ha), 3.95 (br d, J
) 12.3 Hz, 1H; 6-Hb), 3.72 (br s, 1H; 4-H), 1.77 (ddd, J ) 9.5,
7.6, 4.9 Hz, 1H; c-Pr), 1.59 (ddd, J ) 9.9, 7.5, 4.9 Hz, 1H;
1
(26 mg, 62%) as a waxy solid. Rf ) 0.35. H NMR (400 MHz,
CD3OD): δ 3.98-3.90 (m, 1H; 5-Ha), 3.78-3.70 (m, 1H; 5-Hb),
3.70 (s, 3H; OCH3), 2.64-2.48 (m, 2H; 3-H), 2.11-1.88 (m, 2H;
4-H), 1.37-1.15 (m, 3H; c-Pr), 1.00-0.94 (m, 1H; c-Pr) ppm. 13
C
NMR (50 MHz, CD3OD): δ 175.8 (s; CO2H), 172.2 (s; CO2Me),
157.2 (q, JC-F ) 36.4 Hz; COCF3), 117.6 (q, JC-F ) 287.2 Hz;
CF3), 74.1 (s; C-2), 53.2 (q, CH3), 50.5 (tq, JC-F ) 3.9 Hz; C-5),
38.5 (t; C-3), 28.1 (s; c-Pr), 24.7 (t; C-4), 15.7 (t; c-Pr), 14.0 (t;
c-Pr) ppm. IR (KBr): V 3031, 2955, 1788, 1733, 1698, 1448, 1436,
1238, 1153 cm-1. MS (ESI): 308.3 [M - H]-. C12H140F3NO5
(309.24): calcd C 46.61, H 4.56, N 4.53; found C 46.72, H 4.81, N
4.36.
1-[2-(tert-Butoxycarbonyl)-1-(trifluoroacetyl)-2-pyrrolidinyl]cy-
clopropanecarboxylic Acid (13b). A mixture of 4b (53 mg, 0.20
mmol) and TFA (0.03 mL, 0.39 mmol) in MeCN (3 mL) was heated
at 70 °C for 26 h. The reaction mixture was concentrated under
reduced pressure, and the crude product was purified by chroma-
tography on silica gel (petroleum ether/AcOEt ) 2:1) to give 13b
(22 mg, 63%) as a waxy solid. Rf ) 0.14. 1H NMR (400 MHz): δ
3.97-3.89 (m, 1H; 5-Ha), 3.66 (dt, J ) 7.0, 10.1 Hz, 1H; 5-Hb),
2.55-2.44 (m, 2H; 3-H), 2.06-1.86 (m, 2H; 4-H), 1.45-1.36 (m,
3H; c-Pr), 1.43 (s, 9H; CH3), 1.10-1.03 (m, 1H; c-Pr) ppm. 13C
NMR (50 MHz): δ 178.5 (s; CO2H), 168.6 (s; CO2t-Bu), 155.8 (q,
JC-F ) 36.5 Hz; COCF3), 116.2 (q, JC-F ) 287.8 Hz; CF3), 82.8
(s; CMe3), 72.7 (s; C-2), 49.0 (tq, JC-F ) 4.0 Hz; C-5), 37.5 (t;
J. Org. Chem. Vol. 74, No. 11, 2009 4229

Cordero et al.
c-Pr), 1.40 (s, 3H; CH3), 1.38 (ddd, J ) 9.9, 7.6, 4.3
Hz, 1H; c-Pr), 1.32 (s, 3H; CH3), 1.15 (ddd, J ) 9.5, 7.5, 4.3
Hz, 1H; c-Pr) ppm. 13C NMR (100 MHz): δ 179.8 (s; CO2H),
156.9 (q, JC-F ) 36.9 Hz; COCF3), 116.3 (q, JC-F ) 287.8 Hz;
CF3), 112.0 (s; C-2), 83.7 (d; C-3a), 80.1 (d; C-6a), 70.8 (d;
C-4), 53.4 (tq, JC-F ) 3.3 Hz; C-6), 26.8 (q, 3C; CH3), 26.1 (s;
c-Pr), 24.7 (q, 3C; CH3), 17.8 (t; c-Pr), 16.3 (t; c-Pr) ppm. IR:
V 3500, 3400-2600, 2992, 1693, 1448, 1384, 1253, 1206, 1154
cm-1. MS (EI): m/z 323 (0.9, M+), 308 (100), 266 (14), 248
(64), 202 (69), 196 (30), 135 (22), 67 (23), 57 (57). C13H16F3NO5
(323.27): calcd C 48.30, H 4.99, N 4.33; found C 48.01, H 5.08,
N 4.00.
1-[(2R,3R,4R,5R)-3,4-Bis(benzyloxy)-5-[(benzyloxy)methyl]-1-
(trifluoroacetyl)pyrrolidinyl]cyclopropanecarboxylic Acid (17). A
mixture of 10 (1 g, 2.01 mmol) and TFA (0.23 mL, 2.98 mmol)
in toluene (50 mL) was heated at 110 °C for 10 min. The reaction
mixture was concentrated under reduced pressure, and the crude
product was purified by chromatography on silica gel (petroleum
ether/AcOEt ) 3:1) to give 17 (1.1 g, 94%) as a yellow oil.
The NMR analysis revealed the presence of two conformers;
only signals corresponding to the major one are given. Rf )
0.24. [R]21D ) -10.2 (c 0.36, CHCl3). 1H NMR (400 MHz, major
conformer): δ 7.44-7.25 (m, 15 H; Ph), 5.08 (br s, 1H; 2-H),
4.71-4.44 (m, 7H; OCH2Ph, 5-H), 4.14 (br s, 1H; 4-H), 4.04
(br s, 1H; 3-H), 3.71 (pseudo t, J ) 9.4 Hz, 1H; CHHOBn),
3.57 (dd, J ) 9.2, 5.3 Hz, 1H; CHHOBn), 1.50-1.42 (m, 3H;
c-Pr), 0.93-0.84 (m, 1H; c-Pr) ppm. 13C NMR (100 MHz, major
conformer): δ 180.48 (s; CO2H), 157.2 (q, JC-F ) 37.1 Hz;
COCF3), 137.4 (s; Ph), 137.2 (s; Ph), 136.9 (s; Ph), 128.5-127.6
(d, 15C; Ph), 116.1 (q, JC-F ) 288.2 Hz; CF3), 84.5 (d; C-3),
82.7 (d; C-4), 73.2 (t; OCH2Ph), 71.6 (t; OCH2Ph), 71.3 (t;
1-((2R,3R,4R,5R)-3,4-Bis(benzyloxy)-5-[(benzyloxy)methyl]-
1-{(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}pyr-
rolidinyl)cyclopropanecarboxylic Acid (29). A solution of CDMT
(102 mg, 0.58 mmol) and NMM (0.067 mL, 0.58 mmol) in
anhydrous CH2Cl2 (0.1 mL) was stirred at -10 °C for 30 min.
Boc-L-phenylalanine (154 mg, 0.58 mmol) was added at 0 °C,
the reaction mixture was stirred for 1 h, and then a solution of
27 (236 mg, 0.48 mmol) and NMM (107 µL, 0.98 mmol) in
anhydrous CH2Cl2 (0.2 mL) was added at 0 °C. The reaction
mixture was then heated in the microwave reactor (50 W, 60
°C) for 30 min, cooled to rt, and diluted with CH2Cl2. The
solution was sequentially washed with a 10% aqueous solution
of KHSO4 and brine, dried over Na2SO4, filtered, and concen-
trated under reduced pressure. The crude residue was purified
by flash chromatography on silica gel (toluene/Et2O ) 2:1) to
afford 29 (248 mg, 70%) as a colorless oil. The NMR analysis
revealed the presence of two conformers. Rf )0.22. [R]21
)
D
-21.5 (c 0.65, EtOH). 1H NMR (400 MHz, mixture of
conformers): δ 7.41-6.90 (m, 20H; Ph), 5.45 (d, J ) 8.9 Hz)
and 5.36 (br d, J ) 8.2 Hz, 1H, NHBoc), 4.95-4.86 and
4.80-4.70 (m, 2H; CHCH2Ph, 2-H), 4.66-4.28 (m, 6 H;
OCH2Ph), 4.27-3.58 (m, 4H; 3-H, 4-H, 5-H, CHHOBn),
3.05-2.84 (m, 3H; CHCH2Ph, CHHOBn), 1.50-0.75 (m, 4H;
c-Pr), 1.39 and 1.38 (s, 9H; tBu) ppm. 13C NMR (50 MHz, major
conformer): δ 178.5 (s; CO2H), 172.4 (s; NC ) O), 154.5 (s;
NCO2tBu), 138.2 (s; Ph), 137.8 (s; Ph), 137.3 (s; Ph), 135.5 (s;
Ph), 129.4-126.8 (d, 20C; Ph), 87.1 (d; C-3), 82.9 (d; C-4),
79.6 (s; tBu), 72.9 (t; OCH2Ph), 71.04 (t; OCH2Ph), 70.98 (t;
OCH2Ph), 66.6 (t; CH2OBn), 64.3 (d; C-5), 62.4 (d; C-2), 53.8
(d; NCHCH2Ph), 40.9 (t; NCHCH2Ph), 29.6 (s; c-Pr), 28.3 (q,
3C; tBu), 15.6 (t; c-Pr), 14.7 (t; c-Pr) ppm. MS (ESI): 735
(MH+); IR (CDCl3): V 3432, 3032, 2928, 1706, 1641, 1497, 1455,
1368, 1166, 1098 cm-1. C44H50N2O8 (734.88): calcd C 71.91, H
6.86, N 3.81; found C 71.66, H 7.12, N 4.07.
OCH2Ph), 69.2 (t; CH2OBn), 65.3 (d; C-2), 63.8 (dq, JC-F
)
2.6 Hz; C-5), 25.5 (s; c-Pr), 18.7 (t; c-Pr), 14.5 (t; c-Pr) ppm.
IR: V 3033, 2928, 2867, 1691, 1455, 1204, 1155, 1099 cm-1
.
Methyl (2S)-2-({[1-((2R,3R,4R,5R)-3,4-Bis(benzyloxy)-5-[(ben-
zyloxy)methyl]-1-{(2S)-2-[(tert-butoxycarbonyl) amino]-3-phen-
ylpropanoyl}pyrrolidinyl)cyclopropyl]carbonyl}amino)-3-me-
thylbutanoate (30). NMM (0.042 mL, 0.38 mmol) was added to
a solution of 29 (70 mg, 0.09 mmol) and L-valine methyl ester
hydrochloride (32 mg, 0.19 mmol) in anhydrous CH2Cl2 (0.5
mL) at 0 °C. After 30 min, HOBt (26 mg, 0.19 mmol) and EDCI
(36 mg, 0.19 mmol) were added at 0 °C, and the mixture was
stirred at rt for 5 h. The reaction mixture was sequentially
concentrated, diluted with AcOEt, washed with a saturated
solution of NaHCO3 and brine, dried over Na2SO4 filtered, and
concentrated under reduced pressure. The crude residue was
purified by flash chromatography on silica gel (toluene/Et2O )
5:1) to afford 30 (38 mg, 47% yield) as a colorless oil. The
NMR analysis revealed the presence of two conformers. Rf )
MS (EI): m/z (%) 583 (0.04, M+), 492 (5), 386 (51), 354 (6),
253 (7), 181 (13), 91 (100). C32H32F3NO6 (583.59): calcd C
65.86, H 5.53, N 2.40; found C 65.76, H 5.83, N 2.32.
1-{(2R,3R,4R,5R)-3,4-Bis(benzyloxy)-5-[(benzyloxy)methyl]py-
rrolidinyl}cyclopropanecarboxylic Acid (27). K2CO3 (4.368 g,
31.61 mmol) was added to a solution of 17 (1.274 g, 2.18 mmol)
in H2O/MeOH (8.7 mL/21.7 mL) cooled at 0 °C. The mixture
was heated at 60 °C for 20 h and then concentrated under reduced
pressure, and a solution of KHSO4 (9.045 g, 66.42 mmol) in
H2O (200 mL) was added at 0 °C. The aqueous phase was
extracted with CH2Cl2 (3 × 100 mL), and the combined organic
phases were washed with brine and dried over Na2SO4. After
filtration and evaporation of the solvent, 27 (1.007 g, 95%) was
obtained as a colorless solid that was pure enough to be used in
the next step of the synthesis without further purification. An
analytically pure sample was obtained by flash chromatography
on silica gel (AcOEt/MeOH ) 10:1). Rf ) 0.10. Mp 136-137
0.29. [R]23 ) -137.1 (c 0.49, EtOH). 1H NMR (400 MHz,
D
mixture of conformers): δ 8.46-8.32 and 7.83-7.74 (m, 1H;
NHVal), 7.38-7.04 (m, 20H; Ph), 5.45 (br d, J ) 9.6 Hz) and
5.22-5.16 (m, 1H, NHBoc), 4.97-4.86 (m, 1H; CHCH2Ph),
4.62-4.25 (m, 8 H; 3-H, NHCHCHMe2, OCH2Ph × 3),
4.23-3.93 (m, 3H; 2-H, 4-H, 5-H), 3.80-3.60 (m, 1H;
CHHOBn), 3.77 and 3.62 (br s, 3H; OMe), 3.09-2.73 (m, 3H;
CHCH2Ph, CHHOBn), 2.31-2.14 (m, 1H; CHMe2), 1.44-0.62
(m, 4H; c-Pr), 1.40 and 1.37 (br s, 9H; tBu), 0.99 (br d, J ) 6.8
Hz) and 0.97 (d, J ) 6.9 Hz, 6H; CHMe2) ppm. 13C NMR (50
MHz, major conformer): δ 173.8 (s; CO), 172.7 (s; CO), 172.4
(s; CO), 154.8 (s; NCO2tBu), 138.2 (s, 2C; Ph), 137.2 (s; Ph),
135.1 (s; Ph), 129.4-126.8 (d, 20C; Ph), 87.4 (d; C-3), 83.3 (d;
C-4), 79.8 (s; tBu), 72.8 (t; OCH2Ph), 70.9 (t, 2C; OCH2Ph),
66.5 (t; CH2OBn), 64.2, 64.5 (d; C-2, C-5), 58.1(d; NCHCHMe2),
53.5 (d; NCHCH2Ph), 51.8 (q; OCH3), 41.6 (t; NCHCH2Ph),
30.6 (s; c-Pr), 30.0 (d; CHMe2), 28.2 (q, 3C; tBu), 19.1 (q;
CHCH3), 18.2 (q; CHCH3), 14.1 (t; c-Pr), 9.9 (t; c-Pr) ppm. MS
(ESI): 848 (MH+), 870 [(M + Na)+], 886 [(M + K)+]. IR
(CDCl3): V 3673, 3433, 3307, 3032, 2969, 2932, 1740, 1699,
°C. [R]23 ) -14.3 (c 1.12, EtOH). 1H NMR (400 MHz): δ
D
7.38-7.22 (m, 15H; Ph), 4.62-4.40 (m, 6H; OCH2Ph), 4.16-4.07
(m, 1H; 3-H), 3.88-3.82 (m, 1H; 4-H), 3.67-3.41 (m, 3H; 5-H,
CH2OBn), 2.79-2.70 (m, 1H; 2-H), 1.55-1.45 (m, 1H; c-Pr),
1.18-1.07 (m, 1H; c-Pr), 0.95-0.86 (m, 1H; c-Pr), 0.73-0.63
(m, 1H; c-Pr) ppm. 13C NMR (50 MHz): δ 177.3 (s; CO2H),
137.2 (s; Ph), 136.9 (s; Ph), 136.8 (s; Ph), 128.33 (d, 2C; Ph),
128.29 (d, 2C; Ph), 128.2 (d, 2C; Ph), 128.0 (d, 2C; Ph), 127.93
(d, 1C; Ph), 127.89 (d, 3C; Ph), 127.7 (d; Ph), 127.5 (d, 2C;
Ph), 84.0 (d; C-3), 81.5 (d; C-4), 73.3 (t; OCH2Ph), 73.2 (t;
OCH2Ph), 72.5 (t; OCH2Ph), 66.4 (t; CH2OBn), 66.1 (d; C-2),
60.3 (d; C-5), 21.0 (s; c-Pr), 16.6 (t; c-Pr), 14.5 (t; c-Pr) ppm.
MS (EI): m/z ) 488 (M+, 1), 396 (16), 366 (62), 230 (8), 169
(16), 126 (15), 91 (100). IR (CDCl3): V 3032, 2927, 2867, 1725
1605, 1497, 1454, 1364, 1265, 1092 cm-1. C30H33NO5 (487.59):
calcd C 73.90, H 6.82, N 2.87; found C 73.50, H 6.77,
N 2.50.
4230 J. Org. Chem. Vol. 74, No. 11, 2009

Synthesis of R-Cyclopropyl-ꢀ-homoprolines
1641, 1498, 1367, 1167, 1098 cm-1. C50H61N3O9 (848.03): calcd
C 70.81, H 7.25, N 4.96; found: C 71.21, H 7.08, N 4.68.
Research and University (MiUR Rome, Italy) is acknowledged
for financial support (PRIN).
Supporting Information Available: Experimental proce-
dures, characterization data for compounds 4a, 4b, 5b, 7a, 7b,
Acknowledgment. Ms. Simone Dietz and Mr. Peter Lohse,
Sokrates exchange students from the University of Go¨ttingen
(Germany), Mr. Federico Lemmetti, and Ms. Camilla Matassini
are acknowledged for their experimental contribution to this
work. Dr. Cristina Faggi is acknowledged for X-ray crystal-
lographic analysis. Maurizio Passaponti and Brunella Innocenti
are acknowledged for their technical support. The Ministry of
1
18, 19, 21, 22, and 23. H and 13C NMR spectra for all new
compounds. X-ray crystallographic analysis of 16 (CCDC
722377). This material is available free of charge via the Internet
at http://pubs.acs.org.
JO9004684
J. Org. Chem. Vol. 74, No. 11, 2009 4231