Asymmetric synthesis of orthogonally protected trans-cyclopropane γ-amino acids via intramolecular ring closure

Article abstract of DOI:10.1039/b606879k

The synthesis of enantiomerically-enriched trans-cyclopropane amino- and hydroxy-acids can be achieved by intramolecular ring closure in moderate to good yields. The optically active cyclopropane precursors are easily prepared in a short sequence from ine

Full text of DOI:10.1039/b606879k

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Asymmetric synthesis of orthogonally protected trans-cyclopropane c-amino
acids via intramolecular ring closure†
David J. Fox,* Daniel Sejer Pedersen and Stuart Warren
Received 15th May 2006, Accepted 21st June 2006
First published as an Advance Article on the web 6th July 2006
DOI: 10.1039/b606879k
The synthesis of enantiomerically-enriched trans-cyclopropane amino- and hydroxy-acids can be
achieved by intramolecular ring closure in moderate to good yields. The optically active cyclopropane
precursors are easily prepared in a short sequence from inexpensive, commercially available olefins and
tert-butyl acetate. Several leaving groups and bases were compared for the cyclopropanation step,
showing that the diphenylphosphinate and tosyl leaving groups give the best results when used in
combination with either LDA or NaHMDS.
Cyclopropane amino acids are an important class of biologically
active compounds with unique properties.1–4 In recent years
cyclopropane amino acids have shown promise as therapeutics for
the treatment of various neurological diseases and disorders and
much research effort has been invested in identifying new drug can-
didates within this area.5–15 Moreover, cyclopropane amino acids
are useful for studying structure–activity relationships, because
in addition to exerting conformational constraints they maintain
the hydrophobic character of the linear alkyl chains.9,13,16,17 The
stereocontrolled synthesis of cyclopropanes is challenging and
much energy has been devoted to develop new methods for
the synthesis of optically active cyclopropane amino acids.8,17–36
However, there are still many problems associated with the current
methodology, particularly the use of transition metals at a late
stage of the synthetic sequence, making the rapid identification
of new drug candidates costly and difficult. The asymmetric
Scheme 1 Synthetic outline: i) Sharpless asymmetric dihydroxylation; ii)
synthesis of cyclopropanes via intramolecular ring closure has
double activation; iii) base induced cyclisation; iv) displacement with azide;
received less attention. Starting from optically active cyclopropane
v) double transesterification. R = Et and Ph.
precursors this approach has been demonstrated to work for
lithiated diphenylphosphine oxides displacing mesylates,37,38 lithi-
ated sulfones displacing tosylates,39 amide enolates opening cyclic
diphenylphosphinoyloxy group is a suitable leaving group for the
sulfites,34 and carboxylic ester enolates opening epoxides.34 We
formation of cyclopropanes by intramolecular ring closure and
confers a high degree of crystallinity to compounds.41,42
The use of a tert-butyl ester prevents lactonisation of the
diol during the dihydroxylation step and produces orthogonally
protected amino acids. Initially, we synthesised the doubly phos-
phinoylated cyclopropane precursor 10 from enantiomerically
enriched diol 9 (Scheme 2).
envisaged that the asymmetric synthesis of orthogonally protected
trans-cyclopropane c-hydroxy- and amino-acids might be achieved
by a short synthetic sequence starting from easily obtained olefins
1 (Scheme 1). Sharpless asymmetric dihydroxylation40 of olefins
1 gives a wide range of diols 2 with high enantiomeric excess.
Double activation of the diols with diphenylphosphinoyl chloride
followed by intramolecular ring closure by the carboxylic ester
enolates would generate cyclopropanes 4. Exclusive formation of
trans-cyclopropanes is expected as the substituents on the new
ring prefer to be anti in the transition state. The remaining leaving
group can finally be displaced with azide to produce protected
trans-cyclopropane c-amino acids 5. Alternatively, transesterifi-
cation of the phosphinate ester would yield trans-cyclopropane
c-hydroxy carboxylic esters 6. We have previously shown that the
Cambridge University, University Chemical Laboratory, Lensfield Road,
Cambridge, UK CB2 1EW. E-mail: djf34@cam.ac.uk
† Electronic supplementary information (ESI) available: experimental and
analytical details for all compounds. See DOI: 10.1039/b606879k.
Scheme 2 Reagents and conditions: i) LDA, HMPA, THF, (E)-cinnamyl
bromide, −78 ◦C, 96%; ii) AD-mix-b, 86% (>95% ee); iii) Ph2POCl, Et3N,
DMAP, CH2Cl2, 52%.
This journal is
The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 3113–3116 | 3113
©

View Article Online
Table 1 1H NMR data for epoxides 20 and 21
Treatment of bis-phosphinate 10 with LDA or KHMDS in THF
only gave small amounts (<10%) of the desired cyclopropane 11.
However, NaHMDS in THF produced the desired cyclopropane
in moderate yield and excellent enantiomeric excess (Scheme 3).
The purified cyclopropane product was surprisingly stable and
could be stored at room temperature for several days with no
observed decomposition. Attempted double transesterification
with sodium methoxide in methanol to give c-hydroxy methyl ester
d/ppm
J/Hz
20 Ha
21 Ha
20 Hb
21 Hb
3.26
3.37
4.08
4.14
td 6.5 and 4.0
ddd 7.5, 5.5 and 4.5
d 4.0
d 4.0
12 unfortunately resulted in substitution at the benzylic carbon,
with loss of stereochemistry to give four cyclopropanes 13 and 14.
To compare diphenylphosphinate with sulfur-based leaving
groups in the ring closure reaction cyclic sulfite 15, bis-mesylate 16
and bis-tosylate 17 were also synthesised from diol 9 (Scheme 4).
Upon treatment with base neither the cyclic sulfite 15 nor bis-
mesylate 16 gave cyclopropane, the mesylate producing only the
elimination product 18 (30% yield using NaHMDS, Scheme 5).
While treatment of the bis-tosylate 17 with LDA also failed to
produce any cyclopropane (only starting material was identified
in the complex NMR spectrum of the crude product), the crude
product from using KHMDS contained, along with elimination
product 19, a small quantity of a compound proposed as epoxide
20. The epoxide’s 1H NMR spectroscopic data are very similar to
those of the known phenyl ketone 21 (Table 1).41
Scheme 3 Reagents and conditions: i) NaHMDS, THF, −78 ◦C to rt, 41%
(>95% ee); ii) NaOMe, MeOH, reflux.
When bis-tosylate 17 was reacted with NaHMDS two diastere-
omeric cyclopropanes 24 and 25 were obtained in a 57 : 43 ratio
(Scheme 6). We have previously reported the formation of mixtures
of trans-cyclopropyl phenyl ketones by a related method41 and the
NMR spectra of cyclopropanes 24 and 25 were similar to the those
for these cyclopropanes ketone (Scheme 7). Hence, based on this
observation and the previously detected epoxide 20 we propose a
similar explanation for the outcome of this reaction. In the first
step a tosyl group is cleaved by the base (Scheme 6). This could
occur either by ortho-metalation of the tosyl group followed by
elimination of benzyne or by a single electron transfer reduction.
Each would produce two regioisomeric mono-tosylates 22 and 23.
Tosylate 22 can cyclise with displacement of the tosylate to give
cyclopropane 24 or epoxide 20a, whereas tosylate 23 can ring close
only to form an epoxide 20b. In a final step the two enantiomeric
epoxides can be ring opened by the ester enolate to form the two
cyclopropanes 25a and 25b.
Scheme 4 Reagents and conditions: i) SOCl2, pyridine, CH2Cl2, 15 85%;
ii) MsCl, pyridine, CH2Cl2, 16 73%; iii) TsCl, pyridine, 17 72%. SO = cyclic
sulfite (ca 1:1 mixture of epimers at sulfur).
Scheme 5 Reagents and conditions: i) LDA, NaHMDS or KHMDS, THF,
−78 ◦C to rt, 30% with NaHMDS; ii) KHMDS −78 ◦C to rt 19 10%, 20
trace, recovered 17 47%.
Scheme 6 Reagents and conditions: i) NaHMDS, THF, −78 ◦C to rt, 24 + 25 36%.
3114 | Org. Biomol. Chem., 2006, 4, 3113–3116
This journal is
The Royal Society of Chemistry 2006
©

View Article Online
Table 2 Cyclopropanation of phosphinate 27, mesylate 28 and tosylate
29
Substrate
Substrate
Yield (%), isolated
Basea
27/28/29
30
31
32/33
Scheme 7 R = phenyl (95%, >95% ee), furan-2-yl (30%, >96% ee).
27
t-BuOK
21b
18b
61b
—
We have previously reported an asymmetric synthesis of trans-
cyclopropane c-azido ketones where the cyclopropane is formed
via intramolecular ring closure by a ketone enolate to displace a
diphenylphosphinate leaving group (Scheme 7).41
28
28
28
28
LDA
41b
22
14
16
36b
13
62
44
5b
18b,c
—
—
LDAd
e
NaHMDS
KHMDS
2
7
—
We envisaged circumventing the problems associated with the
bis-activation strategy by installing the benzylic azide prior to
cyclisation. Hence, diol 9 (Scheme 8) was converted to the cyclic
sulfite using thionyl chloride and pyridine in dichloromethane
followed by treatment of the crude cyclic sulfite with sodium azide
in DMF at 60 ◦C to give the desired regioisomer of anti-azido
alcohol 26 exclusively. Activation of alcohol 26 gave cyclopropane
precursors 27 to 29 ready for the final cyclisation step.
29
29
29
LDA
NaHMDS
KHMDS
—
—
48
52
22b
—
—
15b
—
11f
—
63b
a Reaction conditions: THF, −78 ◦◦C to rt. b By 1H NMR. c Compound 32.
d Reaction conditions: THF −78 C. e Observed in 1H NMR spectrum of
the crude product. f Compound 33.
Finally, we explored the double activation strategy with a
terminal ethyl group. Bis-phosphinate 37, bis-mesylate 38 and bis-
tosylate 39 were synthesised from enantiomerically-enriched diol
36 (Scheme 10). When cyclopropanation of bis-phosphinate 37
was attempted all the reaction conditions produced the desired
cyclopropane (Scheme 11). LDA proved to be superior and gave
cyclopropane 40 in good yield and excellent enantiomeric excess.
Scheme 8 Reagents and conditions: i) SOCl2, pyridine, CH2Cl2; ii) NaN3,
DMF, 60 ◦C, 65% (2 steps); iii) Ph2POCl, DMAP, Et3N, CH2Cl2, 27 67%;
iv) MsCl, pyridine, CH2Cl2, 28 94%; v) TsCl, Et3N, DMAP, CH2Cl2, 29
73%.
Treatment of phosphinate 27 with LDA, NaHMDS or KHMDS
in THF resulted in recovery of the starting material, even after pro-
longed reaction times at room temperature. This was unexpected
given the cyclopropanation of the related ketones (Scheme 7).42
Treatment with potassium tert-butoxide produced cyclopropane
30 along with the two geometrical isomers of elimination product
31 (Scheme 9, Table 2). When treated with LDA, mesylate 28
produced the desired cyclopropane 30 as well as side-products 31
and 32. The formation of a 7-membered cyclic sulfonate 32 shows
that the mesyl group is deprotonated by LDA to some extent.
A higher yield of cyclopropane was obtained using NaHMDS,
but the product again contained elimination product 31. This
side-product could be removed by catalytic hydrogenation to give
the free amine 34. Tosylate 29 gave the desired cyclopropane 30
with lithium and sodium bases in moderate yield and free of any
unwanted by-products in the case of the lithium enolate.
Scheme 10 Reagents and conditions: i) LDA, HMPA, THF, −78 ◦C,
1-bromo-2-pentene, 91%; ii) AD-mix-b, 81%; iii) Ph2POCl, Et3N, DMAP,
CH2Cl2, 37 74% (>85% ee); iv) MsCl, pyridine, CH2Cl2, 38 67%; v) TsCl,
Et3N, DMAP, CH2Cl2, 39 64%.
Scheme 11 Reagents and conditions: i) base, THF, −78 ◦C to rt giving
40, LDA: 75% (>96% ee), NaHMDS: 18%, KHMDS: 23%; ii) NaHMDS,
◦
1
THF, −78 C to rt giving 41 and 45 (41 : 45 = 3 : 1 by H NMR); iii)
NaHMDS, THF, −78 ◦C to rt giving 42; iv) NaN3, DMF, 60 ◦C, 62%
(>94% ee, 2 steps from 39); v) NaOMe, MeOH, reflux, 72%. Inset: X-ray
crystal structure of cyclopropane 40 with ellipsoids at 50% probability.
Scheme 9 Reagents and conditions: i) see Table 2; ii) Pd(OH)2/C, H2,
MeOH, 91% (>92% ee).
This journal is
The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 3113–3116 | 3115
©

View Article Online
The absolute stereochemistry of cyclopropane 40 was confirmed
by X-ray crystallography43 (Scheme 11). Displacing phosphinate
40 with azide was not possible even under forcing conditions
(DMF, 110 ◦C) and mostly starting material was retrieved.
However, double transesterification with sodium methoxide in
refluxing methanol gave the desired c-hydroxy methyl ester 44
in a moderate yield.
9 U. S. Sørensen, T. J. Bleisch, A. E. Kingston, R. A. Wright, B. G.
Johnson, D. D. Schoepp and P. L. Ornstein, Bioorg. Med. Chem., 2003,
11, 197.
10 D. Fishlock, B. Perdicakis, H. J. Montgomery, J. G. Guillemette, E.
Jervis and G. A. Lajoie, Bioorg. Med. Chem., 2003, 11, 869.
11 D. Fishlock, J. G. Guillemette and G. A. Lajoie, J. Org. Chem., 2002,
67, 2352.
12 S. Shuto, S. Ono, Y. Hase, N. Kamiyama and A. Matsuda, Tetrahedron
Lett., 1996, 37, 641.
Cyclopropanation of bis-mesylate 38 to produce target cyclo-
propane 41 was best achieved with NaHMDS, although cyclic
sulfonate 45 was a by-product. The cyclic sulfonate was assigned
as the 7-membered rather than the 8-membered compound due
13 L. S. Tan, N. Yasuda, N. Yoshikawa, F. W. Hartner, K. K. Eng, W. R.
Leonard, F. R. Tsay, R. P. Volante and R. D. Tillyer, J. Org. Chem.,
2005, 70, 8027.
14 D. S. Coffey, M. K. Hawk, S. W. Pedersen and R. K. Vaid, Tetrahedron
Lett., 2005, 46, 7299.
15 R. Gonzalez, I. Collado, B. Lopez de Uralde, A. Marcos, L. M. Martin-
Cabrejas, C. Pedregal, J. Blanco-Urgoiti, J. Perez-Castells, M. Alejandro
Fernandez and S. L. Andis, Bioorg. Med. Chem., 2005, 13, 6556.
16 P. Rovero, M. Pellegrini, A. Di Fenza, S. Meini, L. Quartara, C. A.
Maggi, F. Formaggio, C. Toniolo and D. F. Mierke, J. Med. Chem.,
2001, 44, 274.
17 K.-H. Park and M. J. Kurth, Tetrahedron, 2002, 58, 8629.
18 M. Oba, N. Nishiyama and K. Nishiyama, Tetrahedron, 2005, 61, 8456.
19 J. Barluenga, F. Aznar, I. Gutierrez, S. Garcia-Granda and M. A.
Llorca-Baragano, Org. Lett., 2002, 4, 4273.
20 M. F. Brana, C. Guisado, L. F. Alguacil, E. Garrido, C. Perez-Garcia
and M. Ruiz-Gayo, Bioorg. Med. Chem. Lett., 2002, 12, 3561.
21 M. Pohlman and U. Kazmaier, Org. Lett., 2003, 5, 2631.
22 J. A. Miller, E. J. Hennessy, W. J. Marshall, M. A. Scialdone and S. T.
Nguyen, J. Org. Chem., 2003, 68, 7884.
23 P. Wipf and C. R. J. Stephenson, Org. Lett., 2005, 7, 1137.
24 M. Mart´ın-Vila`, N. Hanafi, J. M. Jime´nez, A. Alvarez-Larena, J. F.
Piniella, V. Branchadell, A. Oliva and R. M. Ortun˜o, J. Org. Chem.,
1998, 63, 3581.
25 J. M. Jime´nez, J. Rife´ and R. M. Ortun˜o, Tetrahedron: Asymmetry,
1996, 7, 537.
26 F. Gnad and O. Reiser, Chem. Rev., 2003, 103, 1603.
27 H. Lebel, J.-F. Marcoux, C. Molinaro and A. B. Charette, Chem. Rev.,
2003, 103, 977.
1
to striking similarities between the H NMR spectrum of this
compound and the previously isolated 7-membered sulfonate 32
(Scheme 9). Cyclopropane 41 was quite unstable and decomposed
during purification. Bis-tosylate 39 cyclised very cleanly using
NaHMDS (LDA and KHMDS returned the majority of starting
material) and mono-tosylate product 42 could be treated with
sodium azide without prior purification to give trans-cyclopropane
c-azido ester 43 in good yield and high enantiomeric excess.
In brief, we have demonstrated that one-step intramolecular
cyclisation is a useful way of constructing trans-cyclopropane
products devoid of any cis-cyclopropane side-products. The
synthetic routes presented herein are short (5–6 steps), starting
from cheap, commercially available starting materials, giving
orthogonally protected trans-cyclopropane c-amino acids in useful
overall yields (19–31%) and high enantiomeric excess (>92%
ee). Moreover, when bis-phosphinate activation is employed the
method can yield trans-cyclopropane c-hydroxy carboxylic esters
with terminal alkyl groups in good yield and high enantiomeric
excess.
28 A. S. Demir, C. Tanyeli, A. Cagir, M. N. Tahir and D. Ulku,
Tetrahedron: Asymmetry, 1998, 9, 1035.
29 J. Rife´ and R. M. Ortun˜o, J. Org. Chem., 1999, 64, 8958.
30 C. H. Stammer, Tetrahedron, 1990, 46, 2231.
31 C. D. Papageorgiou, M. A. Cubillo de Dios, S. V. Ley and M. J. Gaunt,
Angew. Chem., Int. Ed., 2004, 43, 4641.
32 C. D. Papageorgiou, S. V. Ley and M. J. Gaunt, Angew. Chem., Int. Ed.,
2003, 42, 828.
33 C. Cativiela and M. D. D´ıaz-de-Villegas, Tetrahedron: Asymmetry,
2000, 11, 645.
Acknowledgements
We thank Dr John Davies for crystallography and the EPSRC
for financial assistance towards the purchase of the Nonius CCD
diffractometer. D. S. P. thanks the Alfred Benzon Foundation for
financial support.
34 N. Yoshikawa, L. Tan, N. Yasuda, R. P. Volante and R. D. Tillyer,
Tetrahedron Lett., 2004, 45, 7261.
35 D. Diez, P. Garcia, I. S. Marcos, N. M. Garrido, P. Basabe, H. B.
Broughton and J. G. Urones, Org. Lett., 2003, 5, 3687.
36 E. Bunuel, S. D. Bull, S. G. Davies, A. C. Garner, E. D. Savory, A. D.
Smith, R. J. Vickers and D. J. Watkin, Org. Biomol. Chem., 2003, 1,
2531.
References and notes
1 P. Wipf, J. T. Reeves, R. Balachandran and B. W. Day, J. Med. Chem.,
2002, 45, 1901.
2 J. M. Janjic, Y. Mu, C. Kendall, C. R. J. Stephenson, R. Balachandran,
B. S. Raccor, Y. Lu, G. G. Zhu, W. Xie, P. Wipf and B. W. Day, Bioorg.
Med. Chem., 2005, 13, 157.
3 L. Q. Sun, K. Takaki, J. Chen, S. Bertenshaw, L. Iben, C. D. Mahle, E.
Ryan, D. D. Wu, Q. Gao and C. Xu, Bioorg. Med. Chem. Lett., 2005,
15, 1345.
4 A. Armstrong and J. N. Scutt, Org. Lett., 2003, 5, 2331.
5 R. J. Mattson, J. D. Catt, D. J. Denhart, J. A. Deskus, J. L. Ditta,
M. A. Higgins, L. R. Marcin, C. P. Sloan, B. R. Beno, Q. Gao, M. A.
Cunningham, G. K. Mattson, T. F. Molski, M. T. Taber and N. J.
Lodge, J. Med. Chem., 2005, 48, 6023.
6 I. Collado, C. Pedregal, A. B. Bueno, A. Marcos, R. Gonzalez, J.
Blanco-Urgoiti, J. Perez-Castells, D. D. Schoepp, R. A. Wright, B. G.
Johnson, A. E. Kingston, E. D. Moher, D. W. Hoard, K. I. Griffey and
J. P. Tizzano, J. Med. Chem., 2004, 47, 456.
7 J. B. Schwarz, S. E. Gibbons, S. R. Graham, N. L. Colbry, P. R. Guzzo,
V. D. Le, M. G. Vartanian, J. J. Kinsora, S. M. Lotarski, Z. Li, M. R.
Dickerson, T. Z. Su, M. L. Weber, A. El Kattan, A. J. Thorpe, S. D.
Donevan, C. P. Taylor and D. J. Wustrow, J. Med. Chem., 2005, 48,
3026.
37 T. Nemoto, M. Ojika and Y. Sakagami, Tetrahedron Lett., 1997, 38,
5667.
38 T. Nemoto, G. Yoshino, M. Ojika and Y. Sakagami, Tetrahedron, 1997,
53, 16699.
39 R. Tanikaga, N. Shibata and T. Yoneda, J. Chem. Soc., Perkin Trans.
1, 1997, 2253.
40 H. Kolb, M. S. VanNiewenhze and K. B. Sharpless, Chem. Rev., 1994,
94, 2483.
41 T. Boesen, D. J. Fox, W. Galloway, D. S. Pedersen, C. R. Tyzack and S.
Warren, Org. Biomol. Chem., 2005, 3, 630.
42 D. J. Fox, S. Parris, D. S. Pedersen, C. R. Tyzack and S. Warren, Org.
Biomol. Chem., 2006, DOI: 10.1039/b606874j.
43 Crystal data for 40. C23H29O4P, M = 400.43, triclinic, space group
˚
P1, a = 5.8939(2), b = 8.5144(3), c = 11.3355(4) A, a = 82.108(2),
◦
3
˚
b = 87.448(2), c = 82.337(2) , U = 558.23(3) A , Z = 1, l(Mo-Ka)
= 0.147 mm−1, 5699 reflections collected at 180(2) K using an Oxford
Cryosystems Cryostream cooling apparatus, 3689 unique (Rint = 0.025);
R1 = 0.035, wR2 = 0.096 [I > 2r(I)], absolute structure parameter
−0.08(8). CCDC reference number 600428. For crystallographic data
in CIF or other electronic format see DOI: 10.1039/b606879k.
8 M. G. Moloney, Nat. Prod. Rep., 2002, 19, 597.
3116 | Org. Biomol. Chem., 2006, 4, 3113–3116
This journal is
The Royal Society of Chemistry 2006
©