An enantioselective synthesis of (+)-polyoxamic acid via phase-transfer catalytic conjugate addition and asymmetric dihydroxylation

Article abstract of DOI:10.1021/jo102272h

A new enantioselective synthetic method of (+)-polyoxamic acid is reported. (+)-Polyoxamic acid could be obtained in 7 steps with 46% overall yield from diphenylmethyl-glycineimine tert-butyl ester via an enantioselective phase-transfer conjugate addition

Full text of DOI:10.1021/jo102272h

pubs.acs.org/joc
agents which inhibit serinepalmitoyl transferase to block the
An Enantioselective Synthesis of (þ)-Polyoxamic
Acid via Phase-Transfer Catalytic Conjugate
Addition and Asymmetric Dihydroxylation
biosynthesis of sphingolipids.3 In both cases of polyoxins
and sphingofungins, it is well-known that 3,4-dihydroxy-
amino acid moieties (1 and 2) are very important pharmaco-
phores and their configurations are closely related to their
biological activities.4
Yeon-Ju Lee,† Yohan Park,‡ Mi-hyun Kim,‡ Sang-sup Jew,‡
and Hyeung-geun Park*,‡
Due to their significance on the biological activities of
polyoxins and sphingofungins along with their structural
uniqueness, a variety of methods for the synthesis of poly-
oxamic acid and its stereoisomers have been developed over
the past several years. Most commonly, they could be syn-
thesized from chiral carbohydrates5 or amino acids6 depend-
ing on the stereogenic centers; however, only two methods
were reported for the enantioselective synthesis of 1.7
In continuation of our studies on the synthesis of non-
proteinogenic amino acids of pharmaceutical interest thro-
ugh phase-transfer reactions, we tried to develop an enan-
tioselective synthesis of 1, which would later enable the
synthesis of various stereoisomers of 1, including 2.
†Marine Natural Products Chemistry Laboratory, Korea
Ocean Research and Development Institute, Ansan 426-744,
Korea, and Research Institute of Pharmaceutical Science and
‡
College of Pharmacy, Seoul National University, Seoul
151-742, Korea
hgpk@snu.ac.kr
Received November 16, 2010
As shown in the retrosynthetic strategy (Scheme 1), the
C2(S) chirality can, in principle, be induced by the enantio-
selective phase-transfer catalytic conjugate addition of di-
phenylmethylglycineimine tert-butyl ester (4).8 Both C(3S)
and C(4S) configurations of the dihydroxy group can be
derived from asymmetric dihydroxylation of 2, which can be
obtained by olefination of 3.
First, the phase-transfer catalytic conjugate addition was
carried out with 4 and methyl acrylate to introduce an
R-carbomethoxyethyl moiety of 3 under phase-transfer cataly-
tic reaction conditions. But, much to our disappointment,
only moderate enantioselectivity (68% ee) was observed.9
In addition, significant racemization might be possible during
theR-phenylselenylation of 3in basic condition for olefination.
A new enantioselective synthetic method of (þ)-polyoxa-
mic acid is reported. (þ)-Polyoxamic acid could be
obtained in 7 steps with 46% overall yield from diphenyl-
methyl-glycineimine tert-butyl ester via an enantioselec-
tive phase-transfer conjugate addition (99% yield, 96%
ee) and an asymmetric dihydroxylation (98% yield, 94%
de) as the key reactions.
(3) VanMiddlesworth, F.; Giacobbe, R. A.; Lopez, M.; Garrity, G.;
Bland, J.; Zweerink, M.; Edison, A. M.; Rozdilsky, W.; Wilson, K. E.;
Monaghan, R. A. J. Antibiot. 1992, 45, 861.
(4) (a) Kharem, R. K.; Becker, J. M.; Naider, F. J. Med. Chem. 1983, 31,
650. (b) Shemnatamurth, P.; Smith, H. A.; Becker, J. M.; Steinfeld, A.;
Naider, F. J. Med. Chem. 1983, 26, 1518. (c) Kobayashi, S.; Furuta, T.;
Hayashi, T.; Nishijima, M.; Hanada, K. J. Am. Chem. Soc. 1998, 120, 908.
(5) For recent examples, see: (a) Kim., I. S.; Li., Q. R.; Dong., G. R.;
Woo., S. H.; Park, H.-j.; Zee, O. P.; Jung., Y. H. Synlett 2008, 19, 2958.
ꢀ
(b) Falentin, C.; Beaupere, D.; Denailly, G.; Stasik, I. Tetrahedron 2008, 64,
9989. (c) Li, S.; Hui, X.-P.; Yang, S.-B.; Jia, Z.-J.; Xu, P.-F.; Lu, T.-J.
Tetrahedron: Asymmetry 2005, 16, 1729. (d) Ichikawa, Y.; Ito, T.; Isobe, M.
Polyoxamic acid (1) is an amino acid bearing three con-
tiguous hydroxyl groups, two of which are attached to
stereogenic centers.1 It is a key component of peptidyl
nucleoside antibiotics called polyoxins, which inhibit chitin
synthetase of Candida albicans, a human fungi pathogen, and
of various phytopathogenic fungi as well.2
ꢀ
Chem.;Eur. J. 2005, 11, 1949. (e) Ulgheri, F.; Orru, G.; Crisma, M.; Spanu,
P. Tetrahedron Lett. 2004, 45, 1047. (f) Soengas, R. G.; Estevez, J. C.;
ꢁ
ꢁ
Estevez, R. J. Teterahedron: Asymmetry 2003, 14, 3955.
(6) For selected examples, see: (a) Veeresa, G.; Datta, A. Tetrahedron
Lett. 1998, 39, 119. (b) Harwood, L. M.; Robertson, S. M. Chem. Commun.
1998, 2641. (c) Bandini, E.; Martelli, G.; Spunta, G.; Bongini, A.; Panunzio,
M.; Piersanti, G. Tetrahedron: Asymmetry 1997, 8, 3717. (d) Matsuura, F.;
Hamada, Y.; Shioiri, T. Tetrahedron Lett. 1994, 35, 733. (e) Paz, M. M.;
Sardina, J. J. Org. Chem. 1993, 58, 6990. (f) Ikota, N. Chem. Pharm. Bull.
1989, 37, 3399. (g) Garner, P.; Park., J. M. J. Org. Chem. 1988, 53, 2979.
(7) (a) Trost, B. M.; Krueger, A. C.; Bunt, R. C.; Zambrano, J. J. Am.
Chem. Soc. 1996, 118, 6520. (b) Enders, D.; Vrettou, M. Synthesis 2006, 2155.
(8) For recent reviews on the phase-transfer catalysis, see: (a) Maruoka,
K.; Ooi, T. Chem. Rev. 2003, 103, 3013. (b) O’Donnell, M. J. Acc. Chem. Res.
2004, 37, 506. (c) Lygo, B.; Andrews, B. I. Acc. Chem. Res. 2004, 37, 518.
(d) Hashimoto, T.; Maruoka, K. Chem. Rev. 2007, 107, 5656. (e) Jew, S.-s.;
Park, H.-g. Chem. Commun. 2009, 7090.
On the other hand, 3,4-diepipolyoxamic acid (2) constitu-
tes the structures of sphingofungins A-D, potent antifungal
*Address correspondence to this author. Phone: 82-2-880-8264. Fax:
82-2-872-9129.
(1) Isono, K; Suzuki, S. Heterocycles 1979, 13, 333.
(2) (a) Naider, F.; Shenbagamurthi, P.; Steinfeld, A. S.; Smith, H. A.;
Boney, C.; Becker, J. M. Antimicrob. Agents Chemother. 1983, 24, 787.
(b) Mehta, R. J.; Kingsbury, W. D.; Valenta, J.; Actor, P. Antimicrob. Agents
Chemother. 1984, 25, 373.
(9) A Michael reaction between 5 and ethyl acrylate under the same
condition (12, 50% KOH, CH2Cl2, 0 °C) as that depicted in Table 1 afforded
the alkylated product with 68% ee in 87% yield.
740 J. Org. Chem. 2011, 76, 740–743
Published on Web 12/30/2010
DOI: 10.1021/jo102272h
r
2010 American Chemical Society

Lee et al.
JOCNote
SCHEME 1. Retrosynthesis of (þ)-Polyoxamic Acid (1)
TABLE 1. Enantioselective Phase-Transfer Catalytic Conjugate
Addition of 5a
entry chiral PTC temp (°C) time (h) yield of 6b (%) % ee of 9c,d
1
2
3
4
5
6
10
11
12
12
13
14
0
0
0
1
2
1
1
1
2
99
99
99
99
98
99
48
59
90
96
78
69
-20
0
0
aThe reaction was carried out with 3.0 equiv of 5 and 10.0 equiv of
50% KOH in the presence of chiral catalysts (10 mol %) in methylene
chloride. bIsolated yields after purification by column chromatography.
cEnantiopurity was determined by HPLC analysis, using a chiral column
(DAICEL Chiralcel AD-H) with hexanes/2-propanol (volume ratio =
99:1) as a solvent. In this case, it was established by analysis of the
racemate, of which enantiomers were fully resolved. dDiastereomer
ratios of 6 correspond to enantiomer ratios of 9. See the Supporting
Infomation for details.
SCHEME 2. Synthesis of 3,4-Didehydroamino Acid 3a
the two major diasteromers to the two minor diastereomers of
6 was in accordance with the enantiomer ratio of 9. The
absolute stereochemistry of C(2) in the conjugate addition
adduct (6) was confirmed by comparison of the optical
rotation of the final product 1 with the reported value.6f
So our strategy needed modification and we chose ethyl
R-phenylselenylacrylate (5)10 as an alternate Michael acceptor,
which already contains a phenylselenyl group. The phase-
transfer catalytic Michael addition was performed with 4
and ethyl R-phenylselenylacrylate (5) under PTC conditions
with 50% aqueous KOH in CH2Cl2 (Scheme 2).
To find an optimal catalyst for the conjugate addition,
five representative catalysts11 (PTCs, 10-14, Table 1), which
exhibited excellent catalytic efficiencies in the enantioselective
catalytic conjugate addition of 4, were examined. As shown in
Table 1, all of the catalysts provided 6 as 1:1 mixtures of
diastereomers in almost quantitative chemical yields, but the
enantioselectivities were dramatically dependent on the PTC
catalysts. Among the catalysts used, catalyst 12 yielded the
highest enantioselectivity at 0 °C (entry 3, 90% ee) and even
higher enantioselectivity was observed at -20 °C (entry 4, 96%
ee). The stereoselectivities were determined by the diaster-
eomer ratios of 6 as well as enantiomer ratios of 9 using chiral
column chromatography.12 In all cases examined, the ratio of
Next, the direct oxidation of selenyl ester 6 was avoided
due to the tendency of isomerization of the olefinated
product 2 to the more conjugated benzophenone imine 2,3-
didehydroglutamate.13 To prevent the isomerization, a ben-
zophenone imine group was hydrolyzed to 7 in acidic con-
ditions. The resulting amino ester was protected with a
9-phenylfluorenyl (Pf) group by treatment with 9-bromo-9-
phenylfluorene in the presence of K3PO4 and PbNO2, which
proved to prevent the isomerization by stereoelectronic
hindrance.14 N-9-Phenylfluorenyl-glutamate 8 was then con-
verted to 3,4-didehydroglutamate 9 by using NaIO4 and
NaHCO3 at an ambient temperature with 98% yield without
isomerization.
With 3,4-dihydroglutamate 9 in hand, efforts have been
made to find the optimal conditions for asymmetric dihy-
droxylation (Table 2). Without any ligand, less than 2% con-
version of 9 to 15 was observed with quantitative recovery of
the starting material after 24 h (entry 1). In the presence of
(10) For the preparation, see: Berlin, S.; Engman, L. Tetrahedron Lett.
2000, 41, 3701.
(11) (a) O’Donnell, M. J.; Bennett, W. D.; Wu, S. J. Am. Chem. Soc. 1989,
111, 2353. (b) Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119,
12414. (c) Jew, S.-s.; Yoo, M.-S.; Jeong, B.-S.; Park, H.-g. Org. Lett. 2002, 4,
4245. (d) Park, H.-g.; Jeong, B.-S.; Yoo, M.-S.; Lee, J.-H.; Park, M.-K.; Lee,
Y.-J.; Kim, M.-J.; Jew, S.-s. Angew. Chem., Int. Ed. 2002, 41, 3036.
(12) The diastereomer ratio of 6 corresponds to the enantiomer ratio of 9.
See the Supporting Infomation for details.
(13) Rubio, A.; Ezquerra, J. Tetrahedron Lett. 1995, 36, 5823.
(14) Gmeiner, P.; Feldman, P. L.; Chu-moyer, M. Y.; Rapport, H. J. Org.
Chem. 1990, 55, 3068 and references cited therein.
J. Org. Chem. Vol. 76, No. 2, 2011 741

Lee et al.
JOCNote
TABLE 2. Asymmetric Dihydroxylation of 9a
SCHEME 3. Completion of the Synthesis of 1
entry
ligand
none
DABCO
16
17
18
19
20
time (h)
yieldb (%)
% dec
1
2
3
4
5
6
7
24
24
<2
84
91
88
91
93
99
<2
75
83
87
88
94
3.5
4.0
2.5
5.0
3.5
ment with trifluoroacetic acid provided (þ)-polyoxamic
acid (1) after purification by Dowex ion-exchange resin
(Scheme 3). The physical characteristics of 1 were in full
aSee the Supporting Infomation for detailed reaction conditions.
bIsolated yields after purification by column chromatography. cDiaster-
eopurity was determined by HPLC analysis, using a chiral column
(DAICEL Chiralcel AD-H) with hexanes/2-propanol (volume ratio =
92:8) as a solvent.
agreement with the reported values in the literature {([R]23
D
2.5 (c 0.2, H2O) (lit.6f [R]23D 2.8 (c 1.0, H2O)}.
In conclusion, we have developed an efficient and enan-
tioselective synthesis of (þ)-polyoxamic acid from a com-
mercially available diphenylmethyl glycineimine tert-butyl
ester (4) in 7 steps (46% overall yield, 96% ee) by an
enantioselective phase-transfer catalytic conjugate addition
and asymmetric dihydroxylation. It is worthwhile to point
out that all three stereogenic centers were constructed by the
use of cinchona derived catalysts (12, 20) which are easily
prepared from inexpensive materials. Further applications to
the synthesis of similar polyoxamic acid-type compounds with
an aminotriol core structure including 2 are now under
investigation.
the achiral ligand DABCO, the reaction proceeded effi-
ciently (94% yield) to yield 15 with no stereoselectivity
(<2% de), indicating that the stereogenecity of C(2) does
not affect the facial selectivities of 3,4-dihydroxylations
(entry 2). As chiral ligands, five quinine derivatives
(16-20) were examined. The absolute configuration of the
products was determined by the application of the mnemonic
devices for predicting facial selectivity in asymmetric dihydro-
xylations15 and confirmed later by comparison of the optical
rotation of final product 1 with the reported value.6f In the case
of dimeric quinine derivative 16 and 17, which usually provide
highly enantioselective dihydroxylations,15 moderate facial
selectivities were observed (entries 3 and 4, 75% de and 83%
de). Monomer ligands 18 and 19 were also examined and
surprisingly, products were obtained with higher diastereos-
electivities (entries 5 and 6, 87% de and 88% de). When 20
(HQN-CLB) was used as a chiral ligand based upon the
expectation that reducing the steric hindrance of the chiral
ligand might be beneficial, the highest diastereoselectivity
(94% de) was obtained providing 15 in a quantitative yield.
The successful results prompted us to apply HQD-CLB under
the optimal conditions for the preparation of 3,4-diepipo-
lyoxamic acid (2). However, much to our disappointment,
only moderate enantioselectivity of 3,4-diepi-15 with compar-
able chemical yield was obtained (42% de, 93% yield).
Experimental Section
Representative Procedure for the Enantioselective Phase-
Transfer Catalytic Alkylation of 4 (6). A solution of ethyl
2-(phenylselanyl)acrylate 5 (383 mg, 1.5 mmol) in dichloromet-
hane (0.3 mL) was added to a solution of N-(diphenylmethylene)-
glycine tert-butyl ester 4 (148 mg, 0.50 mmol) and chiral catalyst
12 (30.3 mg, 0.05 mmol) in dichloromethane (1.2 mL). The
reaction mixture was then cooled to -20 °C, 50% aqueous
KOH (0.56 mL) was added, and the resulting mixture was allowed
to stir at -20 °C for 1.0 h. The resulting mixture was diluted with
dichloromethane (20 mL), washed with water (2 ꢀ 5 mL), dried
over anhydrous MgSO4, filtered, and concentrated in vacuo. The
resulting brown oil was purified by silica gel column chromatog-
raphy to afford 6 (273 mg, 0.50 mmol, 99% yield) as a pale yellow
oil. 1H NMR (300 MHz, CDCl3) δ 7.60 (d, J=7.0 Hz, 1H), 7.55
(d, J=7.5 Hz, 1H), 7.53 (d, J=7.0 Hz, 1H), 7.42-7.33 (m, 5H),
7.29-7.22 (m, 4H), 7.19-7.15 (m, 2H), 7.11 (dd, J=2.5, 6.0 Hz,
1H), 4.10 (dd, J = 4.2, 9.5 Hz, 0.5H), 3.97-3.86 (m, 2H),
3.82-3.75 (m, 1H), 3.60 (dd, J = 6.5, 8.8 Hz, 0.5H), 2.54-2.48
(m, 1H), 2.44-2.40 (m, 0.5H), 2.30-2.24 (m, 0.5H), 1.36 (s, 4.5H),
1.35 (s, 4.5H), 1.04 (t, J=7.0 Hz, 1.5H), 1.01 (t, J=7.5 Hz, 1.5H)
ppm; 13C NMR (100 MHz, CDCl3) δ 172.8, 172.5, 171.9, 171.4,
170.9, 170.5, 139.6, 139.5, 136.6, 136.4, 136.0, 135.8, 130.6, 130.5,
129.2, 129.1, 128.5, 128.5, 128.2, 128.1, 128.1, 128.0, 81.6, 81.5,
64.5, 64.1, 61.1, 61.0, 40.5, 40.3, 36.3, 35.1, 28.2, 28.2, 14.1, 14.0
ppm; IR (KBr) 3348, 2970, 1467, 1379, 1305, 1160, 1129, 952, 817,
760 cm-1; LRMS (FABþ) m/z 552.0 [M þ H]þ; HRMS (ESI)
[M þ H]þ calcd for C30H33NO4Se 552.1648, found 552.1641.
Treatment of 15 with NaBH4/LiCl in methanol at 0 °C
afforded aminotriol 21 with 88% yield, which upon treat-
[R]23 -10.7 (c 1.0, CHCl3). The diasteromeric ratio was deter-
D
mined by HPLC analysis in comparison with authentic racemic
materials. {DAICEL chiralpak AD-H, hexane:2-propanol=99:1,
(15) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev.
1994, 94, 2483 and references cited therein.
742 J. Org. Chem. Vol. 76, No. 2, 2011

Lee et al.
JOCNote
flow rate = 1.0 mL/min, 23 °C, λ = 254 nm, retention times:
14.71 (minor), 18.79 (minor), 19.86 (major), 28.17 (major),
1.3:1.7:40:53 dr}.
119.9, 82.4, 72.8, 72.3, 71.2, 61.6, 57.5, 27.8, 14.1 ppm; IR
(KBr) 3492, 2979, 1734, 1451, 1394, 1369, 1213, 1155, 1073,
844, 754, 699 cm-1; LRMS (FABþ) m/z 504 [M þ H]þ; HRMS
(ESI) [M þ H]þ calcd for C30H34O6N 504.2386, found 504.2389.
Representative Procedure for the Asymmetric Dihydroxylation
of 9 (15). To a solution of 9 (117 mg, 0.25 mmol) and methane-
sulfonamide (35 mg, 0.37 mmol) in tert-butanol (2.0 mL) and
water (2.0 mL) was added K2CO3 (104 mg, 0.75 mmol) and
chiral ligand 20 (23 mg, 0.05 mmol). The mixture was then
cooled to 0 °C, then K3Fe(CN)6 (247 mg, 0.75 mmol) was added
followed by K2OsO2(OH)4 (9.2 mg, 0.025 mmol). The mixture
was allowed to stir at 0 °C for 3.5 h, after which time the reaction
was quenched by dropwise addition of saturated NaHSO3
aqueous solution. The mixture was then diluted with ethyl
acetate (20 mL), washed with water (2 ꢀ 5 mL), dried over
anhydrous MgSO4, filtered, and concentrated in vacuo. The
resulting yellow oil was purified by silica gel column chroma-
tography to afford 15 (125 mg, 0.25 mmol, 99% yield) as a
colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.85 (d, J=7.5 Hz,
2H), 7.38-7.29 (m, 5H), 7.21-7.14 (m, 6H), 4.17 (dd. J=7.1 Hz,
2H), 4.02 (s, 1H), 3.72 (d, J=5.5 Hz, 1H), 2.76 (d, J=6.0 Hz,
1H), 1.23 (t, J=7.1 Hz, 3H), 1.17 (s, 9H) ppm; 13C NMR (100
MHz, CDCl3) δ 172.3, 171.8, 148.0, 147.8, 143.5, 141.1, 128.8,
128.5, 128.5, 128.2, 127.8, 127.4, 126.4, 125.8, 125.2, 120.3,
[R]23 5.3 (c 1.0, CHCl3). The diasteromeric ratio was deter-
D
mined by HPLC analysis in comparison with authentic racemic
materials. {DAICEL chiralpak AD-H, hexane:2-propanol =
92:8, flow rate =1.0 mL/min, 23 °C, λ = 254 nm, retention
times: 13.92 (minor), 14.85 (minor), 18.48 (major), 32.66
(minor), 2.4:0.6:95.5:1.5 dr, 94% de from 9 (96% ee)}.
Acknowledgment. This work was supported by the Mid-
career Researcher Support Programs of the National Re-
search Foundation of Korea (2009-0078814) and by the
National Research Foundation of Korea Grant funded by
the Korean Government (MEST) (NRF-C1ABA001-2010-
0020428)
Supporting Information Available: Characterizations of all
compounds, additional experimental procedures, and analytical
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
J. Org. Chem. Vol. 76, No. 2, 2011 743