Synthesis of novel mucic acid 1,4-lactone methyl ester 3-O-ferulate related to an extractive component isolated from the peels of Citrus sudachi

Article abstract of DOI:10.1016/j.tetlet.2011.11.066

Synthesis of a new type of mucic acid 1,4-lactone methyl ester 3-O-ferulate related to an extractive component isolated from Citrus sudachi, and its diastereomer has been achieved by employing stereodivergent dihydroxylation as a key step. The structures of the final products are fully characterized by spectroscopic methods and compared with that of the natural product.

Full text of DOI:10.1016/j.tetlet.2011.11.066

Tetrahedron Letters 53 (2012) 435–437
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Tetrahedron Letters
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Synthesis of novel mucic acid 1,4-lactone methyl ester 3-O-ferulate related
to an extractive component isolated from the peels of Citrus sudachi
⇑
Tetsuya Sengoku, Yusuke Murata, Hiromi Mitamura, Masaki Takahashi, Hidemi Yoda
Department of Materials Science, Faculty of Engineering, Shizuoka University, Johoku 3-5-1, Naka-ku, Hamamatsu 432-8561, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis of a new type of mucic acid 1,4-lactone methyl ester 3-O-ferulate related to an extractive com-
ponent isolated from Citrus sudachi, and its diastereomer has been achieved by employing stereodiver-
gent dihydroxylation as a key step. The structures of the final products are fully characterized by
spectroscopic methods and compared with that of the natural product.
Received 21 October 2011
Revised 10 November 2011
Accepted 14 November 2011
Available online 22 November 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Citrus sudachi
Mucic acid 1,4-lactone methyl ester 3-O-
ferulate
Chiral pool synthesis
L
-(+)-Tartaric acid
Citrus sudachi Hort. ex Shirai (Rutaceae), called sudachi, is an
OsO4 dihydroxylation, oxidative cleavage with NaIO4, and oxidative
esterification with bromine in aqueous methanol,5 giving rise to
methyl ester 4 in an 89% yield (for 3 steps). Methanolysis of 4 and
subsequent mesylation led to C–C double bond formation to afford
evergreen tree grown traditionally in the Tokushima prefecture
of Japan. In the course of investigating constituents contained in
the fruits of Citrus sudachi, a variety of flavonoids1a,b and limo-
noids,1c such as sudachitin and sudachinoid A, have been isolated
(Fig. 1).
a,b-unsaturated ester 5 with excellent E-selectivity (E/Z >95/5).
The following OsO4 dihydroxylation proceeded diastereoselectively
to furnish 6 as an inseparable mixture of 6a and 6b (6a/6b = 10/1) in
a combinedyield of 99%.6,7 Indeed, 6 was readilycyclized upon treat-
Mucic acid 1,4-lactone methyl ester 3-O-ferulate 1 has been
reported as an unexplored extractive component from the peels of
sudachi, whose planar structure with its relative stereochemistry
has been determined as shown in Figure 1.2 The polyoxygenated
structure of this natural product, which may possess the real and
potential biological properties such as antioxidant and/or antimi-
crobial effect, has attracted our intense interest from biological
and synthetic viewpoints. As part of our continuing investigations
in the natural product synthesis based on the chiral pool strategies,3
we envisioned this molecule as an architecturally sophisticated
target for total synthesis. In the present Letter, we report the first to-
tal synthesis of 1, which has made a remarkable finding that the
reported structure of this natural product is incorrect.
mentwithpyridiniump-toluenesulfonate to form c-lactone, provid-
ing an inseparable 10/1 mixture of 7a and 7b through exchange of
the protecting groups from Bn to TBS function due to the introduc-
tion of a ferulic acid part (67% yield for 4 steps).
Condensation of 7 with TBS-protected ferulic acid 88 in the
presence of1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydro-
chloride (EDCI) and 4-dimethylaminopyridine (DMAP) gave a dia-
stereomeric mixture, which could be separated by silica gel
column chromatography providing 9 as a single isomer. In the next
step, exposure of 9 to acidic methanol solution (TsOH or PPTS in
MeOH) resulted unexpectedly in the elimination of two TBS groups
and concomitant methanolysis to the ring opened product 10 (58%
yield) with unidentified side products. Instead, we achieved the
deprotection of 9 with BF3ꢀOEt2,9 producing the target compound 1
(77% yield).10
The synthesis started with the preparation of C2 symmetrical
amide
2 from L-(+)-tartaric acid according to the literature
(Scheme 1).4 Ring opening alkylation of 2 with allylmagnesium bro-
mide under Barbier conditions afforded the hemiaminal intermedi-
ate in an 86% yield.3c Reduction of this intermediate with NaBH4 and
the following benzoylation provided 3 in a 90% yield over the two
steps. This product was subjected to reaction sequences involving
Remarkably, we observed inconstant specific rotations for mea-
surement on the synthetic sample of 1 in MeOH, which could be
understood in terms of gradual decomposition to 10.11,12
Moreover, significant difference in the 1H NMR chemical shifts
was noticed between the synthetic and original samples;
Dd =
⇑
Corresponding author. Tel./fax: +81 53 478 1150.
E-mail address: tchyoda@ipc.shizuoka.ac.jp (H. Yoda).
dsynthetic ꢁ doriginal = ꢁ0.17 ppm for H2, d = ꢁ0.13 ppm for H3 and
D
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.066

436
T. Sengoku et al. / Tetrahedron Letters 53 (2012) 435–437
O
OH
HO
O
O
1
O
OMe
OH
MeO
4
OMe
OH
O
O
O
3
HO
O
O
O
OH
O
MeO
MeO
O
O
O
MeO
HO
1
sudachitin
sudachinoid A
Figure 1. Structures of compounds isolated from Citrus sudachi.
Bn
OBz
MeO2C
OBz
MeO2C
N
O
O
a
HO2C
HO
CO2H
OH
b
c
d
CONHBn
OBn
CONHBn
OBn
CONHBn
OBn
BnO
OBn
BnO
BnO
BnO
2
3
4
5
L-(+)-tartaric acid
O
MeO
OTBS
O
O
OTBS
O
HO
OH
HO
MeO2C
OH
CONHBn
OBn
CONHBn
OBn
O
O
e
f
MeO
MeO2C
CO2H
BnO
BnO
HO
OTBS
HO
OTBS
6a
6b
7a
7b
6 (inseparable mixture, 6a/6b = 10/1)
7 (inseparable mixture, 7a/7b = 10/1)
O
OH
OH
O
OTBS
O
O
OH
O
4
O
5
O
MeO
CO2Me
MeO
MeO
in MeOH
MeO
TBSO
O
O
O
2
3
O
O
O
OH
OTBS
OH
8
h
g
MeO
HO
MeO
MeO
HO
9
1
10
i
TBSO
Scheme 1. Reagents and conditions: (a) (i) see Ref. 4; (ii) BnBr, Ag2O, EtOAc; 76%; (b) (i) allyl bromide, Mg, THF, ꢁ40–0 °C; 86%; (ii) NaBH4, MeOH; (iii) BzCl, Et3N, DMAP,
CH2Cl2; 90% (2 steps); (c) (i) OsO4, NMO, acetone/H2O = 2/1; (ii) NaIO4, THF/H2O = 4/1, 0 °C–rt; (iii) Br2, MeOH/H2O = 9/1; 89% (3 steps); (d) (i) K2CO3, MeOH, ꢁ15 °C; (ii) MsCl,
Et3N, DMAP, (CH2Cl)2, 0–70 °C; 58% (2 steps); (e) OsO4, NMO, acetone/H2O = 2/1; 99%; (f) (i) PPTS, toluene, 80 °C; (ii) TBSCl, imidazole, DMF; 86% (2 steps); (iii) H2, Pd/C, EtOH;
(iv) TBSCl, imidazole, DMF; 78% (2 steps); (g) 8, EDCI, DMAP, CH2Cl2, 0 °C; 72%; (h) BF3ꢀOEt2, CH3CN, 0 °C; 77% (i) PPTS, 1,4-dioxane, 50 °C; 92%, see Ref. 12.
D
d = ꢁ0.38 ppm for H4.13 We assume that this clear mismatch in
of 7a and 7b (17% overall yield from 5). Condensation of 70 with
TIPS-protected ferulic acid 11 provided required diastereomerically
pure 90 in a 35% yield after the chromatographic separation. Finally,
deprotection of the silyl groups accomplished the synthesis of 10 in a
75% yield, however, its 1H NMR chemical shifts proved to be incon-
sistent again with the reported data.15
the resonance values would originate from the different stereo-
chemistry.
Thus, we next turned to synthesize its diastereomeric isomer 10
that would be readily prepared from 6b by following the above reac-
tion sequences (Scheme 2). In the presence of AD-mix-a (0.2 mol %)
and additional (DHQ)2PHAL (10 mol %), 5 underwent the dihydr-
In summary, we have achieved the first synthesis of a new type
of mucic acid 1,4-lactone methyl ester 3-O-ferulate 1 and its dia-
oxylation with reverse stereoselectivity to provide 60 as a 5/13 mix-
ture of 6a and 6b.14 Subsequent cyclization of the
c
-lactone ring,
stereomer 10 from commercially available
L-(+)-tartaric acid. Com-
and exchange of the protecting groups afforded 70 as a 5/13 mixture
parison of the characterization data for 1 with those reported in
the literature has given an indication of the clear inconsistency
in the structural assignment, leading to a conclusion that the re-
ported structure of this natural product should be incorrect and
the revised form will be described in the near future.
O
OTBS
O
HO
OH
O
MeO
CONHBn
OBn
a
b
MeO2C
5
BnO
HO
OTBS
6' (6a/6b = 5/13)
7' (7a/7b = 5/13)
Acknowledgments
CO2H
O
OR'
We thank Professor Yoshihisa Takaishi (University of Tokushi-
ma) for providing a copy of the 1H NMR spectrum of the natural
sample. This work was supported in part by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Culture, Sports,
Science and Technology, Japan.
O
O
MeO
MeO
RO
R = H
c
O
R = TIPS (11)
O
OR'
d
MeO
RO
Scheme 2. Reagents and conditions: (a) AD-mix-
BuOH/H2O = 1/1; (b) (i) PPTS, toluene, 100 °C; (ii) TBSCl, imidazole, DMF; 29% (3
steps); (iii) H2, Pd/C, EtOH; (iv) TBSCl, imidazole, DMF; 58% (2 steps); (c) (i) TIPSOTf,
2,6-lutidine, CH2Cl2; (ii) K2CO3, THF/H2O = 1/1; 84% (2 steps); (d) 11, EDCI, DMAP,
CH2Cl2, 0 °C; 35%; (e) BF3ꢀOEt2, CH3CN, 0 °C; 75%.
R = TIPS
R' = TBS (9')
e
Supplementary data
R = R' = H (1')
Supplementary data (1H NMR and 13C NMR spectra for syn-
thetic mucic acid 1,4-lactone 6-methyl ester 3-O-ferulate and its
diastereomer in CD3OD) associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.2011.11.066.
a, (DHQ)2PHAL, MeSO2NH2, t-

T. Sengoku et al. / Tetrahedron Letters 53 (2012) 435–437
437
9. King, S. A.; Pipik, B.; Thompson, A. S.; DeCamp, A.; Verhoeven, T. R. Tetrahedron
Lett. 1995, 36, 4563.
References and notes
10. Characterization data for 1: Rf = 0.57 (silica gel, hexane/EtOAc = 1/6); ½a D27
ꢂ
1. (a) Horie, T.; Masumura, M.; Okumura, F. S. Bull. Chem. Soc. Jpn. 1961, 34, 1547;
(b) Horie, T.; Tsukayama, M.; Nakayama, M. Bull. Chem. Soc. Jpn. 1982, 55, 2928;
(c) Nakagawa, H.; Duan, H.; Takaishi, Y. Chem. Pharm. Bull. 2001, 49, 649.
2. Nakagawa, H.; Takaishi, Y.; Tanaka, N.; Tsuchiya, K.; Shibata, H.; Higuti, T. J. Nat.
Prod. 2006, 69, 1177.
3. (a) Matsuura, D.; Takabe, K.; Yoda, H. Tetrahedron Lett. 2006, 47, 1371; (b) Yoda,
H.; Naito, S.; Takabe, K.; Tanaka, N.; Hosoya, K. Tetrahedron Lett. 1990, 31, 7623;
(c) Yoda, H.; Shirakawa, K.; Takabe, K. Tetrahedron Lett. 1991, 32, 3401; (d)
Yoda, H.; Kitayama, H.; Katagiri, T.; Takabe, K. Tetrahedron 1992, 48, 3313.
4. (a) Nagel, U.; Kinzel, E. Chem. Ber. 1986, 119, 3326; (b) Skarzewski, J.; Gupta, A.
Tetrahedron: Asymmetry 1997, 8, 1861.
+7.87 (c 1.22, acetone); IR (KBr) 3422(O–H), 1798 (C@O), 1749 (C@O), 1631
(C@C), 1592 (C@C), 1518 (C@C), 1269 (C–O), 1150 (C–O), 1021 (C–O), 821
(C@C) cmꢁ1 1H NMR (300 MHz, CD3OD) d 7.71 (d, J = 15.9 Hz, 1H, CH@CH),
;
7.21 (d, J = 1.8 Hz, 1H, ArH), 7.10 (dd, J = 1.8, 8.1 Hz, 1H, ArH), 6.82 (d, J = 8.1 Hz,
1H, ArH), 6.43 (d, J = 15.9 Hz, 1H, CH@CH), 5.63 (dd, J = 6.9, 7.5 Hz, 1H, CH), 4.76
(dd, J = 2.1, 6.9 Hz, 1H, CH), 4.76 (d, J = 7.5 Hz, 1H, CH), 4.55 (d, J = 2.1 Hz, 1H,
CH), 3.89 (s, 3H, OCH3), 3.78 (s, 3H, OCH3); 13C NMR (75 MHz, CD3OD) d 174.6
(C@O), 173.0 (C@O), 168.4 (C@O), 151.2 (C), 149.6 (C), 148.6 (CH@CH), 127.6
(C), 124.6 (CH@CH), 116.7 (C), 114.2 (C), 112.0 (C), 81.4 (CH), 76.4 (CH), 73.4
(CH), 70.5 (CH), 56.5 (OCH3), 53.0 (OCH3). Anal. calcd for C17H18O10: C, 53.41; H,
4.75. Found C, 53.11; H, 5.10.
5. Williams, D. R.; Klingler, F. D.; Allen, E. E.; Lichtenthaler, F. W. Tetrahedron Lett.
1988, 29, 5087.
6. The absolute stereochemistry of 6 was determined as follows. After protecting
11. Similar decomposition has been reported for a mucic acid gallate, see: Zhang,
Y.-J.; Tanaka, T.; Yang, C.-R.; Kouno, I. Chem. Pharm. Bull. 2001, 49, 537.
12. We observed that 10 could readily regenerate 1 upon heating with PPTS in 1,4-
dioxane.
13. Analogous coupling pattern and coupling constant were observed for these
H2–H4 protons.
the diol of 6 as an acetonide,
ester 12 via oxidative C–C bond cleavage. Comparison of specific rotation of 12
with the literature data indicated that major isomer of 12 should be dimethyl
(+)-2,3-O-isopropylidene-D-tartarate. Further analysis on the basis of the
spectroscopic data led to a conclusion that the major isomer of 6 should
have a 2S,3S configuration.
a,b-dihydroxyamide was converted to methyl
14. Ermolenko, L.; Sasaki, A. N. J. Org. Chem. 2006, 71, 693.
15. Characterization data for 10: Rf = 0.57 (silica gel, hexane/EtOAc = 1/6); ½a 2D7
ꢂ
+100 (c 1.39, acetone); IR (KBr) 3439 (O–H), 1798 (C@O), 1746 (C@O), 1632
(C@C), 1594 (C@C), 1516 (C@C), 1265 (C–O), 1154 (C–O), 1029 (C–O), 818
1) TsOH, 2, 2-dimethoxypropane
2) H2, Pd/C
3) NaIO4
(C@C) cmꢁ1 1H NMR (300 MHz, CD3OD) d 7.75 (d, J = 15.9 Hz, 1H, CH@CH),
;
O
O
7.23 (d, J = 1.8 Hz, 1H, ArH), 7.13 (dd, J = 1.8, 8.1 Hz, 1H, ArH), 6.83 (d, J = 8.1 Hz,
1H, ArH), 6.47 (d, J = 15.9 Hz, 1H, CH@CH), 5.51 (t, J = 8.4 Hz, 1H, CH), 5.18 (dd,
J = 1.2, 8.4 Hz, 1H, CH), 4.93 (d, J = 8.4 Hz, 1H, CH), 4.12 (d, J = 1.2 Hz, 1H, CH),
3.90 (s, 3H, OCH3), 3.79 (s, 3H, OCH3); 13C NMR (75 MHz, CD3OD) d 175.3
(C@O), 173.3 (C@O), 168.5 (C@O), 151.2 (C), 149.6 (C), 148.8 (CH), 127.6 (CH),
124.6 (C), 116.7 (CH), 113.9 (CH), 112.0 (CH), 78.9 (CH), 77.1 (CH), 71.1 (CH),
69.7 (CH), 56.5 (OCH3), 53.1 (OCH3); Anal. calcd for C17H18O10: C, 53.41; H, 4.75.
Found: C, 53.33, H, 5.15.
4) Br2, NaHCO3, MeOH
MeO2C
CO2Me
6
12
[α]D27+52.5 (c 0.980, MeOH)
lit: [α]D20+48.8 (c 1.00, MeOH)7
7. Li, B.; Yang, X.; Yang, K.; Fu, E. Synth. Commun. 2005, 35, 2603. Dimethyl (+)-2,
3-O-isopropylidene- -tartarate is also commercially available from Aldrich.
8. Fache, F.; Suzan, N.; Piva, O. Tetrahedron 2005, 61, 5261.
D