A new one-pot method for the synthesis of α-siloxyamides from aldehydes or ketones and its application to the synthesis of (-)-bestatin

Article abstract of DOI:10.1021/ol006816m

(equation presented) A new one-pot method for the synthesis of α-siloxyamides is described. The three substrates, H-C(CN)₂O-SiMe₂t-Bu, aldehydes or ketones, and primary or secondary amines, are simply mixed in one portion in acetonitrile or ether; the α-siloxyamides are obtained within short peroids in excellent yields in many cases. As a demonstration of our method, the synthesis of (-)-bestatin was carried out.

Full text of DOI:10.1021/ol006816m

ORGANIC
LETTERS
2000
Vol. 2, No. 26
4245-4247
A New One-Pot Method for the
Synthesis of r-Siloxyamides from
Aldehydes or Ketones and Its
Application to the Synthesis of
(−)-Bestatin
Hisao Nemoto,* Rujian Ma, Ichiro Suzuki, and Masayuki Shibuya
Faculty of Pharmaceutical Sciences, The UniVersity of Tokushima,
1-78, Sho-machi, Tokushima, 770-8505, Japan
nem@ph2.tokushima-u.ac.jp
Received November 2, 2000
ABSTRACT
A new one-pot method for the synthesis of r-siloxyamides is described. The three substrates, H-C(CN)2O-SiMe2t-Bu, aldehydes or ketones,
and primary or secondary amines, are simply mixed in one portion in acetonitrile or ether; the r-siloxyamides are obtained within short
peroids in excellent yields in many cases. As a demonstration of our method, the synthesis of (−)-bestatin was carried out.
R-Hydroxyamides and the O-protected derivatives1 are
among the most important synthetic intermediates of biologi-
cally active peptide mimics.2 The most direct synthetic
methods involving multiple steps are based on the homolo-
gation of aldehydes 1 with various masked anions 2 to
prepare 3. This must be subsequently unmasked to give the
R-hydroxycarboxylic acids 4. Amide bond formation of 4
with amines 5 is then carried out to produce 63 as outlined
in Scheme 1.4 In the scheme, the H-C bond of 2 is activated
Scheme 1
(1) In the following papers, serious problems were encountered in the
protecting reaction of R-hydroxyamides. Therefore, if the O-protected
derivatives could be directly obtained by an alternative method, they could
be efficiently used for further synthetic steps toward the final target
molecules. (a) Maryanoff, B. E.; Greco, M. N.; Zhang, H.-C.; Andrade-
Gordon, P.; Kaufman, J. A.; Nicolau, K. C.; Liu, A.; Brungs, P. H. J. Am.
Chem. Soc. 1995, 117, 1225. (b) Greco, M. N.; Zhang, H. M.; Maryanoff,
B. E. Tetrahedron Lett. 1998, 39, 4959.
(2) (a) Babine, R. E.; Bender S. L. Chem. ReV. 1997, 97, 1359. (b) Nagai,
M.; Kojima, F.; Naganawa, H.; Hamada, M.; Aoyagi, T.; Takeuchi, T. J.
Antibiot. 1997, 50, 82. (c) Sakurai, M.; Higashida, S.; Sugano, M.; Komai,
T.; Yagi, R.; Ozawa, Y.; Handa, H,; Nishigaki, T.; Yabe, Y. Bioorg. Med.
Chem. 1994, 2, 807.
and three of C-Yn bonds are preserved in the first step. The
activation of the C-Yn bonds of 3 is carried out in the next
step. Additionally, independent activation of the resulting
carbonyl functionality of 4 is required for the following
subsequent amide bond formation.5 Hence, until now, it has
been very difficult to carry out these reactions in one pot
using ordinary reagents such as 2.
10.1021/ol006816m CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/17/2000

We report a new one-pot method to synthesize R-siloxy-
amides. When an aldehyde (or a ketone) 1, an amine 5, and
H-MAC6-TBS [H-C(CN)2O-TBS] (7)7 are simply mixed in
one portion, the R-siloxyamides 8 are obtained in good to
excellent yields (Scheme 2). Because of the migration of
acetonitrile.9 When weakly basic amines were used, an
additional tert-amine such as N,N-dimethyl-4-aminopyridine
(DMAP) or triethylamine was added (entries 3 and 4).
Next, the reactions for various aldehydes and ketones were
carried out (Table 2). In the case of aromatic aldehydes with
an electron-donating, electron-withdrawing, or ortho-substi-
tuted group and R,â-conjugated aldehydes, the desired
products were also obtained within 5 min in excellent yields
by using a slight excess of H-MAC-TBS and butylamine at
0 °C in acetonitrile (entries 1-7). In contrast, the reactions
of 3-phenylpropanal or 2-ethylhexanal, as representative
examples of aliphatic aldehydes, gave the corresponding
R-siloxyamide in moderate yields, along with the cyano-
hydrin of the starting aldehyde (entries 8 and 10).
Scheme 2
We examined the reaction in various solvents using
2-ethylhexanal10 as a representative aldehyde and found that
formation of the byproduct, the cyanohydrin of the starting
2-ethylhexanal, is effectively inhibited in ether at -25 °C.
In ether, the yields of 8 obtained were dramatically increased
(entries 9 and 11). Then, we carried out the reaction for
various aldehydes and ketones. The easily enolizable diphen-
ylacetaldehyde was also converted to the desired compound
in 85% yield in ether (entry 12). In the reaction of
pivaldehyde, the best yield obtained was 35% after numerous
attempts under various conditions (entry 13). Two typical
aromatic ketones, 4-nitroacetophenone and 4-methylaceto-
phenone, were transformed to the corresponding amides in
high yields, respectively (entries 14 and 15). In these cases,
acetonitrile is more effective than ether. The reaction of
cyclohexanone and 3-pentanone proceeded in good to
excellent yields (entries 16 and 17). No reaction took place
when 3,3-dimethyl-2-butanone was used even under condi-
tions similar to those used for the other entries (entry 18).
We applied the method to the synthesis of (-)-bestatin3a,5a
14 according to Scheme 3. A mixture of 7 (0.20 mmol),
the TBS group, cyanide anion is eliminated from the
oxymalononitrile moiety to generate the acyl cyanide, which
is condensed with amine.7 It is also noteworthy that we were
the first to observe this migration of O-protecting group of
MAC reagents.6-8
We first examined 1.1 equiv of various amines for the
reaction of 4-tolualdehyde. In all cases listed in Table 1, the
Table 1. Reaction of 4-CH3C6H4CHO to
4-CH3C6H4CH(OTBS)-CONR3R4 with Various Amines (1.1
equiv) and 7 (1.2 equiv) at 0 °C for 5 min in Acetonitrile
entry
R3R4NH
yield (%)
1
2
3
4
5
6
7
8
9
C4H9NH2
96
90
78c
88
88
94
89e
77
92
a
NH3
NH2OHb
d
PhNH2
H2N-CH2-CO2Me
HOCH2CH2NH2
(R)-PhCH(CH3)NH2
(C2H5)2NH
morphorine
a 10% aqueous solution was used. b 50% of aqueous solution and 1 equiv
of triethylamine were used. c Carried out at -25 °C for 2 h. d 0.1 equiv of
DMAP was added. e A mixture of diastereomers (1:1) was obtained.
Scheme 3
corresponding R-siloxyamides 8 were obtained in excellent
yields within 5 min by using 1.2 equiv of 7 at 0 °C in
(3) (a) Chen, J. J.; Coles, P. J.; Amold, L. D.; Smith, R. A.; MacDonald,
I. D.; Carrie´re, J.; Krantz, A. Bioorg. Med. Chem. Lett. 1996, 6, 435. (b)
Hagihara, M.; Schreiber, S. L. J. Am. Chem. Soc. 1992, 114, 6570. (c)
Dondoni, A.; Perrone, D.; Semola, T. Synthesis 1995, 181. (d) Aggarwal,
V. K.; Thomas, A.; Schade, S.; Tetrahedron 1997, 48, 16213. (e) Katritzky,
A. R.; Yang, Z.; Lam. J. N. Synthesis 1990, 666.
(4) Monenschein, H.; Dra¨ger, G.; Jung, A.; Kirschning, A. Eur. J. Chem.
Soc. 1999, 5, 2270.
(5) In recent years, several advanced methods have been reported for
the efficient combination of the steps B and C. In those methods, the
unmasking reactions directly produce the acyl chlorides or acyl cyanides.
(a) Wasserman, H. H.; Xia, M.; Peterson, A. K.; Jorgenson, M. R.; Curtis,
E. A. Tetrahedron Lett. 1999, 40, 6163. (b) Satoh, T.; Onda, K.-I.;
Yamakawa, K. Tetrahedron Lett. 1990, 25, 3567.
(6) MAC is the abbreviation for “masked acyl cyanide”. X-MAC-Y
means X-[C(CN)2O]-Y. When the X-MAC-Y has a deprotective proton (X
) H), we describe them as “MAC reagents”. Nemoto, H.; Ibaragi, T.; Bando,
M.; Kido, M.; Shibuya, M. Tetrahedron Lett. 1999, 40, 1319.
(7) Synthesis of 7 and the details of the transformation of MAC moiety
to amides: Nemoto, H.; Kubota, Y.; Yamamoto, Y. J. Org. Chem. 1990,
55, 4515.
leucine benzyl ester (10) (0.12 mmol), and aldehyde 9,
prepared from Cbz-phenylalanine (0.10 mmol),11 was simply
(8) (a) Kubota, Y.; Nemoto, H.; Yamamoto, Y. J. Org. Chem. 1991, 56,
7195. (b) Nemoto, H.; Kubota, Y.; Sasaki, N.; Yamamoto, Y. Synlett 1993,
465. (c) Nemoto, H. J. Synth. Org. Chem. Jpn. 1994, 52, 1044. (d)
Yamamoto, Y.; Kubota, Y.; Honda, Y.; Fukui, H.; Asao, N.; Nemoto, H.
J. Am. Chem. Soc. 1994, 116, 3161.
4246
Org. Lett., Vol. 2, No. 26, 2000

Table 2. Preparation R-Siloxyamides 8 from Aldehydes or Ketones with Butylamine and 7
entry
aldehyde
solvent
temp, °C
7 (equiv)
butylamine (equiv)
reaction period
yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
4-H3C-C6H4-CHO
2-HO-C6H4-CHO
furan-2-carbaldehyde
2-Br-C6H4-CHO
4-NC-C6H4-CHO
C6H5CHdCHCHO
CH3CHdCHCHO
C6H5CH2CH2CHO
C6H5CH2CH2CHO
2-ethylhexanal
2-ethylhexanal
Ph2CHCHO
(CH3)3CCHO
4-O2N-C6H4COCH3
4-H3C-C6H4COCH3
cyclohexanone
3-pentanone
CH3COC(CH3)3
acetonitrile
acetonitrile
acetonitrile
acetonitrile
acetonitrile
acetonitrile
acetonitrile
acetonitrile
ether
0
0
0
0
0
0
0
0
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
3.0
1.2
3.0
1.2
3.0
3.0
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
3.0
1.1
3.0
1.1
3.0
3.0
5 min
5 min
5 min
5 min
5 min
5 min
5 min
5 min
2 h
5 min
2 h
2 h
20 h
5 min
2 h
96
95
94
92
97b
91
82
63c
85
54c
94
84
35
94
98
96
75
-25
-25
0
-25
-25
-25
0
-25
0
-25
-25
acetonitrile
ether
ether
ether
acetonitrile
acetonitrile
ether
ether
ether
5 min
2 h
20 h
a Isolated yields by silica gel column chromatography. b We also carried out the direct synthesis of R-hydroxyamides. The overall yield from 4-NC-
C6H4-CHO was 94%. See Supporting Information for details. c Cyanohydrin of the starting aldehyde was obtained as a byproduct.
stirred at 0 °C for 5 h in the presence of 4-prorridinylpyridine
(11);12 a diastereomeric mixture of 12 and 13 (79:21) was
then obtained in 80% yield. The major isomer 12 was
transformed to (-)-bestatin 14 in 96% yield by the removal
of TBS, Cbz, and benzyl groups. It is noteworthy that the
overall yield obtained is considerably higher (ca. 61% from
Cbz-phenylalanine) than that from the previous synthetic
works.3a,5a
In conclusion, we have developed an efficient one-pot
method for the synthesis of R-siloxyamides. The reactions
of various aldehydes or ketones generally proceed in excel-
lent yields within a short period under the mild basic
conditions, which can be often produced by a primary or a
secondary amine as a substrate. We also demonstrate an
efficient synthesis of (-)-bestatin. Work investigating the
catalytic stereochemical control by optically active bases is
now being carried out.
(9) When another MAC reagent with nonmigratory protecting groups
such as ethoxyethyl or methoxymethyl groups are used, acetonitrile is the
best solvent for the reaction of aldehydes. (a) Nemoto, H.; Kubota, Y.;
Yamamoto, Y. J. Chem. Soc., Chem. Commun. 1994, 1665. (b) Nemoto,
H.; Ma, R.; Ibaragi, T.; Suzuki, I.; Shibuya, M. Tetrahedron 2000, 41, 1463.
(10) We investigated THF, CH2Cl2, toluene, hexane, 1,2-dimethoxy-
ethane, ether, and acetonitrile as reaction solvents. Whereas in the reaction
of 4-tolualdehyde the desired product was obtained in excellent yield (92-
98%) in all the solvents, other aldehydes revealed a distinct solvent
dependence. For example, in the case of 3-phenylpropanal yields were
mainly in the range of 60-80% in all the solvents employed. On the other
hand, the yields for 2-ethylhexanal in ether were better than in all six other
solvents.
(11) 3-Phenyl-2R-Cbz-aminopropanal (11) was prepared by the known
method. Fehrentz, J.-A.; Castro B. Synthesis 1983, 676.
(12) Without the additional base, the desired reaction was quite slow
and the yield was very low. By the use of N,N-dimethyl-4-aminopyridine,
imidazole, 2,6-lutidine, and pyridine, the chemical yields and diastereomeric
ratio of 12 vs 13 were lower than those from the use of 4-prorridinylpyridine.
Acknowledgment. We thank Dr. Yasushi Okamoto of
the Eisai Co. Ltd. for significant and important suggestions
on this project.
Supporting Information Available: Physical and spec-
troscopic data for 8 (all the compounds listed in Tables 1
and 2), 12, 13, and 14. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL006816M
Org. Lett., Vol. 2, No. 26, 2000
4247