Asymmetric synthesis of highly substituted γ-amino acids from allyltitanium sulfoximines

Article abstract of DOI:10.1021/ol063082q

Figure presented Asymmetric syntheses of the highly substituted protected γ-amino adds 10a, 10b, 18, and 21 have been developed starting from the allyltitanium sulfoximines V and VI, respectively, and furan-2-carbaldehyde.

Full text of DOI:10.1021/ol063082q

ORGANIC
LETTERS
2007
Vol. 9, No. 7
1231-1234
Asymmetric Synthesis of Highly
Substituted -Amino Acids from
Allyltitanium Sulfoximines
γ
Franz Ko1hler, Hans-Joachim Gais,* and Gerhard Raabe
Institut fu¨r Organische Chemie der RheinischsWestfa¨lischen Technischen Hochschule
(RWTH) Aachen, Landoltweg 1, D-52056 Aachen, Germany
gais@rwth-aachen.de
Received December 20, 2006
ABSTRACT
Asymmetric syntheses of the highly substituted protected γ-amino acids 10a, 10b, 18, and 21 have been developed starting from the allyltitanium
sulfoximines V and VI, respectively, and furan-2-carbaldehyde.
The asymmetric synthesis of γ-amino acids,1 and in particular
that of R- and â-hydroxy-γ-amino acids,2 is a topic of current
interest. For example, γ-aminobutyric acid is an important
neurotransmitter, and there is a strong quest for pharmaco-
logically active analogues.3 In addition, γ-amino acids are
found in γ-lactams, and they are key components of natural
and non-natural peptidomimetic protease inhibitors.4 Finally,
γ-amino acids can form peptides with stable secondary
structures.5 Besides the asymmetric synthesis of γ-amino
acids, that of â-amino acids has gained much attention
because of their natural occurrence as such or in â-lactams
and the design of non-natural â-peptides.6 We have therefore
developed an interest in the asymmetric synthesis of R-hy-
droxy-γ-amino acids of types I-IV (Figure 1) which are
analogues of not only γ-aminobutyric acid but also of
â-aminopropionic acid and â-aminoadipic acid. R-Amino
adipic acid, for example, has been shown to act as a
N-methyl-D-aspartate receptor (NMDA) antagonist,7a and a
â-aminoadipic acid derivative of type I is a constituent of
(1) (a) Trabocchi, A.; Guarna, F.; Guarna, A. Curr. Org. Chem. 2005,
9, 1127. (b) Zhenliang, C.; Zhiyong, C.; Yaozhong, J.; Wenhao, H.
Tetrahedron 2005, 61, 1579. (c) Rilatt, I.; Caggiano, L.; Jackson, R. F. W.
Synlett 2005, 18, 2701. (d) Takigawa, Y.; Ito, H.; Omodera, K.; Koura,
M.; Kai, Y.; Yoshida, E.; Taguchi, T. Synthesis 2005, 2046. (e) Moutevelis-
Minakakis, P.; Sinanoglou, C.; Loukas, V.; Kokotos, G. Synthesis 2005,
933. (f) Ordo´n˜ez, M.; Cativiela, C. Tetrahedron: Asymmetry 2007, 18,
3-99.
(2) (a) Dixon, D. J.; Ley, S. V.; Rodr´ıguez, F. Org. Lett. 2001, 3, 3753.
(b) Sun, I.-C.; Chen, C.-H.; Kashiwada, Y.; Wu, J.-H.; Wang, H.-K.; Lee,
K.-H. J. Med. Chem. 2002, 45, 4271. (c) Yuste, F.; D´ıaz, A.; Ortiz, B.;
Sanchez-Obrego´n, R.; Walls, F.; Ruano, J. L. G. Tetrahedron: Asymmetry
2003, 14, 549. (d) Kondekar, N. B.; Kandula, S. R. V.; Kumar, P.
Tetrahedron Lett. 2004, 45, 5477. (e) Kambourakis, S.; Rozzel, J. D.
Tetrahedron 2004, 60, 663. (f) Tamura, O.; Shiro, T.; Ogasawara, M.;
Toyao, A.; Ishibashi, H. J. Org. Chem. 2005, 70, 4569. (g) Capriati, V.;
Degennaro, L.; Florio, S.; Luisi, R.; Punzi, P. Org. Lett. 2006, 8, 4803.
(3) (a) Galeazzi, R.; Mobbili, G.; Orena, M. Curr. Org. Chem. 2004, 8,
1799. (b) Bryans, J. S.; Wustrow, D. J. Med. Res. ReV. 1999, 19, 149.
(4) (a) Shiraki, R.; Tadano, K. ReV. Heteroatom Chem. 1999, 20, 283.
(b) Bang, J. K.; Naka, H.; Teruya, K.; Aimoto, S.; Konno, H.; Nosaka, K.;
Tatsumi, T.; Akaji, K. J. Org. Chem. 2005, 70, 10596. (c) Tamamura, H.;
Araki, T.; Ueda, S.; Wang, Z.; Oishi, S.; Esaka, A.; Trent, J. O.; Nakashima,
H.; Yamamoto, N.; Peiper, S. C.; Otaka, A.; Fujii, N. J. Med. Chem. 2005,
48, 3280.
(5) Vasudev, P. G.; Shamala, N.; Ananda, K.; Balaram, P. Angew. Chem.,
Int. Ed. 2005, 44, 4972.
(6) (a) Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991. (b) Lelais, G.;
Seebach, D. Biopolymers 2004, 76, 206. (c) EnantioselectiVe Synthesis of
â-Amino Acids; Juaristi, E., Soloshonok, V. A., Eds.; Wiley: Hoboken,
NJ, 2005.
10.1021/ol063082q CCC: $37.00
© 2007 American Chemical Society
Published on Web 02/28/2007

3-methylbutanal, cyclohexylacetaldehyde, and cyclopen-
tanone, respectively. Lithiation of 1a-c in THF followed
by the titanation of the lithiated allylic sulfoximines with 1
equiv of ClTi(OiPr)3 furnished the corresponding allyltita-
nium complexes V and VI8a which reacted with furan-2-
carbaldehyde in the presence of 1.1 equiv of ClTi(Oi-Pr)3
with high regio- and diastereoselectivities and afforded the
homoallylic alcohols 2aA-2cA, respectively. Alcohols
2aA-2cA were obtained diastereopure in good yields by
washing the crude reaction products with Et2O or Et2O/
pentane. HPLC of the washings allowed the isolation of the
minor diastereomers 2aB, 2aC, and 2cB.11 We had previ-
ously observed that in reactions of complexes V and VI with
unsaturated aldehydes only the transfer of the first allylsul-
foximine moiety, which is much faster than that of the second
one, occurs with high diastereoselectivity.8a,c We now found
that both high conversion and diastereoselectivity can be
achieved in the reaction of complexes V and VI derived from
1a-c with furan-2-carbaldehyde.12a It is important to use an
additional 1.1 equiv of ClTi(OiPr)3 and only 1.1 equiv of
the aldehyde, a solution of which has to be slowly added to
the solution of V and VI at -40 °C.12b
Conversion of the homoallylic alcohols 2aA-2cA into
γ-amino acids of types I-IV required, besides the oxidation
of the furan ring and the substitution of the sulfoximine group
by a carboxy group, a stereoselective amination of the double
bond. We had previously developed an asymmetric synthesis
of â-amino acids from homoallylic alcohols of type 2 using
an intramolecular carbamate amination and chloride substitu-
tion of the sulfoximine group.13 Thus treatment of 2aA and
2bA with trichloroacetyl isocyanate and the subsequent
hydrolysis of the trichloroacetyl group with (NH4)2CO3 in
MeOH gave carbamates 3a and 3b, respectively, as E/Z-
mixtures (Scheme 2). The crude carbamates 3a and 3b were
directly subjected to the treatment with LiN(H)t-Bu in THF,
which gave the oxazinones 4a and 4b, respectively, both as
single diastereoisomers (1H NMR) in good yields. The
configuration of 4a was determined by X-ray crystal structure
analysis. Independent experiments with the pure E- and
Z-configured carbamates, (E)-3a, (Z)-3a, (E)-3b, and (Z)-
3b, showed that both the E- and Z-isomers undergo a highly
diastereoselective cyclization with formation of oxazinones
4a and 4b, respectively.
Figure 1. Substituted γ-amino acids and allyltitanium sulfoximines.
the microbial pseudopeptide AI-77-B, which has a strong
and selective gastroprotective activity but suffers from a low
oral activity.7b Thus, the synthesis of I-III could also
contribute to both the development of medicinally useful
analogues of AI-77-B and new NMDA receptor antagonists
as potential drugs for Alzheimer’s disease.7c,d We envisioned
a synthesis of I-IV from allyltitanium sulfoximines of types
V and VI and furan-2-carbaldehyde.8 The starting allylic
sulfoximines 1a-c (Scheme 1) were prepared as described
Scheme 1. Synthesis of Furyl-Substituted Homoallylic
Alcohols
Having achieved an efficient amination, we replaced the
sulfoximine group of 4a and 4b with a carboxy group.
Treatment of sulfoximines 4a and 4b with ClCO2CH(Cl)-
(9) Gais, H.-J.; Mu¨ller, H.; Bund, J.; Scommoda, M.; Brandt, J.; Raabe,
G. J. Am. Chem. Soc. 1995, 117, 2453.
previously by the addition-elimination-isomerization route8a,9
from (S)-N,S-dimethyl-S-phenylsulfoximine (g98% ee)10 and
(10) Brandt, J.; Gais, H.-J. Tetrahedron: Asymmetry 1997, 8, 909.
(11) 2cB has the SS,S,S-configuration according to X-ray crystal structure
analysis. The NMR data suggest that 2aB-2cB have the same configuration.
The configurations of 2aC and 2bC have not been determined.
(12) (a) This protocol was also successfully used for the reaction of 1a
with crotonaldehyde: Lejkowski, M.; Gais, H.-J.; Banerjee, P.; Vermeeren,
C. J. Am. Chem. Soc. 2006, 128, 15378. (b) The intermediate monoallylti-
tanium sulfoximines, which are formed in the reaction of V and VI with
the aldehyde, most likely feature a coordination of both sulfoximine groups
to the Ti atom. It is assumed that these intermediates are activated by ClTi-
(OiPr)3 through coordination to one of the sulfoximine groups, thereby
creating a free coordination site at the Ti atom for the aldehyde.
(13) Gais, H.-J.; Loo, R.; Roder, D.; Das, P.; Raabe, G. Eur. J. Org.
Chem. 2003, 1500.
(7) (a) Wong, H. F.; Kemp, J. A. Annu. ReV. Pharmacol. Toxicol. 1991,
31, 401. (b) Ghosh, A. K.; Bischoff, A.; Cappiello, J. Eur. J. Org. Chem.
2003, 821. (c) Pallas, M.; Carmins, A. Curr. Pharm. Des. 2006, 12, 4389.
(d) Golde, T. E. J. Neurochem. 2006, 99, 689.
(8) (a) Gais, H.-J.; Hainz, R.; Mu¨ller, H.; Bruns, P. R.; Giesen, N.; Raabe,
G.; Runsink, J.; Nienstedt, S.; Decker, J.; Schleusner, M.; Hachtel, J.; Loo,
R.; Woo, C.-W.; Das, P. Eur. J. Org. Chem. 2000, 3973. (b) Schleusner,
M.; Gais, H.-J.; Koep, S.; Raabe, G. J. Am. Chem. Soc. 2002, 124, 7789.
(c) Reddy, L. R.; Gais, H.-J.; Woo, C.-W.; Raabe, G. J. Am. Chem. Soc.
2002, 124, 10427. (d) Koep, S.; Gais, H.-J.; Raabe, G. J. Am. Chem. Soc.
2003, 125, 13243.
1232
Org. Lett., Vol. 9, No. 7, 2007

Scheme 2. Asymmetric Synthesis of Substituted Acyclic γ-Amino Acids
Me in CH2Cl2 at ambient temperatures furnished, besides
respectively, in a two-pot sequence without purification of
8a and 8b in high yields. Finally, an oxidative degradation
of the furan ring was required. Therefore, the furan deriva-
tives 9a and 9b were treated with RuCl3 and NaIO4,16 which
gave the γ-amino acids 10a and 10b, respectively, in good
yields. According to NMR and LC/MS analysis, lactones
10a and 10b contained small amounts of the corresponding
hydroxy acids 11a (11%) and 11b (13%), respectively.
The same route was successfully applied to the synthesis
of the cyclic γ-amino acid 18 (Scheme 3). Carbamate 12
was obtained from the homoallylic alcohol 2cA as a single
Z-isomer in high yield.
The cyclization of 12 under the conditions described above
occurred with high diastereoselectivity and afforded the bicy-
clic oxazinone 13 in high yield. Chloride 14 was obtained
together with the enantiopure sulfinamide 5a upon treatment
of sulfoximine 13 with ClCO2CH(Cl)Me in good yield. The
reaction of 14 with KCN gave nitrile 15 in almost quantita-
tive yield. The complete hydrolysis of 15 turned out to be more
difficult than that of 7a and 7b. It could be accomplished,
however, upon treatment of the nitrile with aqueous CsOH
in dioxane at reflux, which afforded the â-amino acid 16 in
good yield. Protection and lactonization of 16 upon treatment
with Boc2O under nonaqueous conditions in MeCN17 pro-
ceeded readily despite the steric hindrance of the amino group
and gave lactone 17 in 60% overall yield based on 15. Oxi-
sulfinamide 5a, chlorides 6a and 6b, respectively, in high
yields. Acylation of the sulfoximine group of 4a and 4b at
the N atom generates the corresponding N-acyl aminosul-
foxonium salts which undergo a facile substitution by the
Cl- ion because of the high nucleofugacity of the amino-
sulfoxonium group.13,14 The conversion of sulfinamide 5a
(g98% ee with regard to the S atom) to the starting (S)-
(+)-N,S-dimethyl-S-phenylsulfoximine of g98% ee has
already been described.14a
Reaction of chlorides 6a and 6b with KCN at elevated
temperatures afforded nitriles 7a and 7b, respectively, in
good yields. Nitriles 7a and 7b were submitted to a treatment
with 1 N aqueous NaOH in dioxane at reflux, whereby the
cyano and carbamate groups were hydrolyzed. The thus
obtained â-amino acids 8a and 8b were not isolated but
directly treated in basic aqueous solution with an excess of
Boc2O in order to protect not only the amino but also,
through lactonization, the hydroxy and carboxy group.15 This
led to the formation of mixtures of lactones 9a and 9b and
the corresponding Boc-protected â-amino acids. In order to
convert the hydroxy acids into the lactones, the mixture of
both were treated with Boc2O following the removal of the
water. Thereby the diastereomerically pure lactones 9a and
9b could be prepared starting from nitriles 7a and 7b,
(14) (a) Gais, H.-J.; Babu, G. S.; Gu¨nter, M.; Das, P. Eur. J. Org. Chem.
2004, 1464. (b) Tiwari, S. K.; Gais, H.-J.; Lindenmaier, A.; Babu, G. S.;
Raabe, G.; Reddy, L. R.; Ko¨hler, F.; Gu¨nter, M.; Koep, S.; Iska, V. B. R.
J. Am. Chem. Soc. 2006, 128, 7360.
(16) (a) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J.
Org. Chem. 1981, 46, 3936. (b) Kasai, M.; Ziffer, H. J. Org. Chem. 1983,
48, 2346.
(15) Baldwin, J. E.; Flinn, A. Tetrahedron Lett. 1987, 28, 3605.
Org. Lett., Vol. 9, No. 7, 2007
1233

Scheme 3. Asymmetric Synthesis of a Substituted Cyclic γ-Amino Acid
iodides19 and ready cross-coupling reaction with cuprates.20
dation of the furan derivative 17 with RuCl3 and NaIO4
furnished the pure bicyclic γ-amino acid 18 in high yield.
Finally, the synthesis of γ-amino acids of type IV was
probed. Although chlorides 6a and 6b could serve as starting
material, â-amido iodides of type 19 (Scheme 4) should be
Thus, it was of interest to see whether iodide 19 can also be
directly synthesized from sulfoximine 4a by the haloformate
method. The required ICO2Ph was prepared by treatment of
ClCO2Ph with NaI in MeCN at 70 °C.21 The reaction of
sulfoximine 4a with ICO2Ph in MeCN for 2 h at 25 °C gave,
besides sulfinamide 5b (g98%), iodide 19 in high yield.
Iodide 19 readily reacted with Me2CuLi and Ph2CuLi and
afforded the 1,3-amino alcohols 20a and 20b, respectively,
in good yields. The subsequent oxidative degradation of the
furan ring of 20a furnished the protected γ-amino acid 21
in good yield.
Scheme 4. Synthesis of an Acyclic R-Hydroxy-γ-Amino Acid
Acknowledgment. Financial support of this work by the
Gruenenthal Company, Aachen, and the Deutsche For-
schungsgemeinschaft (SFB 380 and GK 440) is gratefully
acknowledged.
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds 2cA, 17,
1
and 18; copies of H and 13C NMR spectra of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL063082Q
(18) (a) Enders, D.; Moser, M.; Geibel, G.; Laufer, M. C. Synthesis 2004,
2040. (b) Murai, T.; Sano, H.; Kawai, H.; Aso, H.; Shibahara, F. J. Org.
Chem. 2005, 70, 8148.
(19) Carrillo-Marquez, T.; Caggiano, L.; Jackson, R. F. W.; Grabowska,
U.; Rae, A.; Tozer, M. J. Org. Biomol. Chem. 2005, 3, 4117.
(20) Adrien, A.; Gais, H.-J. Unpublished results.
synthetically more versatile building blocks for the synthesis
of not only IV but also for 1,3-amino alcohols13,18 because
of their potential conversion to the corresponding alkylzinc
(17) Cativiela, C.; Lo´pez, P.; Lasa, M. Eur. J. Org. Chem. 2004, 3898.
(21) Hoffmann, H. M. R.; Iranshahi, L. J. Org. Chem. 1984, 49, 1174.
1234
Org. Lett., Vol. 9, No. 7, 2007