A total synthesis of nannochelin A. A short route to optically active Nω-hydroxy-α-amino acid derivatives

Article abstract of DOI:10.1021/jo961458f

The total synthesis of nannochelin A, a lysine-basd cinnamoyl hydroxamate produced by Nannocystis exedens, is described. The key transformation involves construction of the N^ε-cinnamoyl-N^ε-hydroxy-L-lysine methyl ester fragment by partial reduction of the lactam carbonyl of 6 derived from L-lysine, oximation of this aldehyde equivalent compound 8 with O-[2-(trimethylsilyl)ethyl]hydroxylamine, and reduction of the oxime 10, followed by N-acylation prior to coupling with the external carbonyls of citric acid. This methodology will be applicable to synthesis of other hydroxamate-containing siderophores bearing hydrogenolyzable groups in the molecule.

Full text of DOI:10.1021/jo961458f

8496
J . Org. Chem. 1996, 61, 8496-8499
A Tota l Syn th esis of Na n n och elin A. A Sh or t Rou te to Op tica lly
Active Nω-Hyd r oxy-r-a m in o Acid Der iva tives
Takeshi Sakamoto, Hao Li, and Yasuo Kikugawa*
Faculty of Pharmaceutical Sciences, J osai University, 1-1 Keyakidai,
Sakado, Saitama 350-02, J apan
Received J uly 30, 1996X
The total synthesis of nannochelin A, a lysine-basd cinnamoyl hydroxamate produced by Nannocystis
exedens, is described. The key transformation involves construction of the Nꢀ-cinnamoyl-Nꢀ-hydroxy-
L-lysine methyl ester fragment by partial reduction of the lactam carbonyl of 6 derived from L-lysine,
oximation of this aldehyde equivalent compound 8 with O-[2-(trimethylsilyl)ethyl]hydroxylamine,
and reduction of the oxime 10, followed by N-acylation prior to coupling with the external carbonyls
of citric acid. This methodology will be applicable to synthesis of other hydroxamate-containing
siderophores bearing hydrogenolyzable groups in the molecule.
Siderophores are low molecular weight iron-sequester-
refluxing trifluoroacetic acid (TFA) and N-tert-butoxy-
carbonylation gave methyl 1-Boc-L-6-oxopipecolate (6).5
These N-acylated esters (5 and 6) are the key intermedi-
ates for the synthesis. The key transformation involves
partial reduction of the lactam carbonyl with DIBAL6 or
LiBEt3H7 to produce the aldehyde equivalent derivatives
(7 and 8) which reacted readily with O-[2-(trimethylsilyl)-
ethyl]hydroxylamine8 to give the oximes (9 and 10). This
transformation is novel and useful to introduce a nitrogen
source into the molecules. Compound 14 also reacted
with the hydroxylamine to give 10. Reduction of the
oximes with pyridine-borane2l,9 or NaBH3CN10 and
subsequent N-acylation produced 11 and 12 in high yield.
ing agents produced by most microorganisms.1 The most
common iron-binding functional groups incorporated into
hydroxamate-containing siderophores are derived from
derivatives of Nδ-hydroxy-L-ornithine (1) and Nꢀ-hydroxy-
L-lysine (2). Although several syntheses of these modified
amino acids have been reported,2 the methods are either
multistep or low yielding and sometimes do not yield
derivatives having suitable protecting groups for further
reactions.
Nannochelin A11 which contains two cinnamoyl moi-
eties in the molecule, is an interesting target for the
synthesis because previous strategies utilizing O-benzyl
protected hydroxamates are not applicable. Mulqueen
and co-workers overcame this problem by use of a BF3‚
Et2O-ethanethiol reagent for the debenzylation without
affecting the cinnamoyl double bonds12 and Bergeron and
Phanstiel IV used O-benzoyl protection and O-deprotec-
tion with 10% NH3/MeOH.13
We report an alternate approach to the synthesis of
this siderophore utilizing two key transformations which
involve construction of the Nꢀ-cinnamoyl-Nꢀ-hydroxy-L-
lysine methyl ester fragment by use of the above men-
tioned strategy and use of the 2-(trimethylsilyl)ethyl
group, which is readily removed by boron trifluoride
We now report simple alternate approaches to the
syntheses of the protected 1 and 2 from readily available
and inexpensive starting materials. L-Pyroglutamic acid
and L-lysine were chosen as the starting materials, since
they are commercially available chiral compounds and
contain the appropriate carbon framework. L-Pyro-
glutamic acid was converted to benzyl 1-Boc-L-pyro-
glutamate (5) by esterification and N-acylation using
literature procedures.3 L-Lysine was also readily con-
verted to methyl ester of NR-Boc-Nδ-Boc-amide of L-2-
aminoadipic acid (13) and small amounts of 1-Boc-6-Boc-
aminopiperidine-2-carboxylic acid methyl ester (14) by
N-protection, esterification, and oxidation of the ω-amino
function with ruthenium dioxide/sodium periodate using
a literature procedure.4 Cyclization of the adipamide in
(4) Yoshifuji, S.; Tanaka, K.-I.; Nitta, Y. Chem. Pharm. Bull. 1987,
35, 2994.
(5) (a) Hermitage, S. A.; Moloney, M. G. Tetrahedron: Asymmetry
1994, 5, 1463. (b) Davies, C. E.; Heightman, T. D.; Hermitage, S. A.;
Moloney, M. G. Synth. Commun. 1996, 26, 687.
(6) (a) Langlois, N.; Rojas, A. Tetrahedron 1993, 49, 77. (b) Langlois,
N.; Rojas, A. Tetrahedron Lett. 1993, 34, 2477. (c) Panday, S. K.;
Griffart-Brunet, D.; Langlois, N. Tetrahedron Lett. 1994, 35, 6673.
(7) (a) Pedregal, C.; Ezquerra, J .; Escribano, A.; Carren˜o, M. C.;
Garc´ıa Ruano, J . L. Tetrahedron Lett. 1994, 35, 2053. (b) Collado, I.;
Ezquerra, J .; Vaquero, J . J .; Pedregal, C. Tetrahedron Lett. 1994, 35,
8037.
(8) Henmi, T.; Sakamoto, T.; Kikugawa, Y. Org. Prep. Proced. Int.
1994, 26, 111.
(9) Kawase, M.; Kikugawa, Y. J . Chem. Soc., Perkin Trans. 1 1979,
643.
(10) (a) Sternbach, D. D.; J amison, W. C. L. Tetrahedron Lett. 1981,
22, 3331. (b) Hutchins, R. O.; Natale, N. R. Org. Prep. Proced. Int. 1979,
11, 201.
(11) Kunze, B.; Trowitzsch-Kienast, W.; Ho¨fle, G.; Reichenbach, H.
J . Antibiot. 1992, 45, 147.
(12) Mulqueen, G. C.; Pattenden, G.; Whiting, D. A. Tetrahedron
1993, 49, 9137.
(13) Bergeron, R. J .; Phanstiel IV, O. J . Org. Chem. 1992, 57, 7140.
X Abstract published in Advance ACS Abstracts, November 1, 1996.
(1) (a) Miller, M. J . Chem. Rev. 1989, 89, 1563. (b) Miller, M. J .;
Malouin, F. Acc. Chem. Res. 1993, 26, 241. (c) Neilands, J . B. Arch.
Biochem. Biophys. 1993, 302, 1.
(2) Nδ-Hydroxy-L-ornithine: (a) Benz, G. Liebigs Ann. Chem. 1984,
1424. (b) Lee, B. H.; Miller, M. J . Tetrahedron Lett. 1984, 25, 927. (c)
Olsen, R. K.; Ramasamy, K.; Emery, T. J . Org. Chem. 1984, 49, 3527.
(d) Gould, S. J .; J u, S. J . Am. Chem. Soc. 1989, 111, 2329. (e) Dolence,
E. K.; Minnick, A. A; Miller, M. J . J . Med. Chem. 1990, 33, 461. (f)
Dolence, E. K.; Lin, C.-E.; Miller, M. J . J . Med. Chem. 1991, 34, 956.
(g) Dolence, E. K.; Miller, M. J . J . Org. Chem. 1991, 56, 492. (h) Gould,
S. J .; J u, S. J . Am. Chem. Soc. 1992, 114, 10166. Nꢀ-Hydroxy-L-
lysine: (i) Genet, J .-P.; Thorimbert, S.; Touzin, A.-M. Tetrahedron Lett.
1993, 34, 1159. (j) Hu, J .; Miller. M. J . J . Org. Chem. 1994, 59, 4858.
Nδ-Hydroxy-L-cycloornithine: (k) Kolasa, T.; Miller. M. J . J . Org.
Chem. 1990, 55, 1711. (l) Sakamoto, T.; Kikugawa, Y. J . Org. Chem.
1994, 59, 929.
(3) Li, H.; Sakamoto, T.; Kato, M.; Kikugawa, Y. Synth. Commun.
1995, 25, 4045.
S0022-3263(96)01458-2 CCC: $12.00 © 1996 American Chemical Society

Total Synthesis of Nannochelin A
J . Org. Chem., Vol. 61, No. 24, 1996 8497
Sch em e 1
etherate or fluoride ion, as a protection of the hydroxamic
acid group.2l,8 Thus, methyl 1-Boc-L-6-oxopipecolate (6)
was prepared from L-lysine following the literature
procedures described above. Partial reduction of 6 with
LiEt3BH in THF at -78 °C for 30 min and subsequent
treatment of the crude hemiaminal 8 with O-[2-(trimeth-
ylsilyl)ethyl]hydroxylamine in CH3CN-H2O (1:1) reflux-
ing for 1.5 h gave the oxime 10 (73%). Pyridine-borane
reduction of 10 in EtOH-10% HCl (1:1) at 0 °C for 15
min followed by N-acylation with trans-cinnamoyl chlo-
ride under Schotten-Baumann conditions gave 12 (76%).
To determine the optical purity of 12, the enantiomer of
12 was prepared from D-lysine using the same proce-
dures, and the HPLC analyses of 12 and its enantiomer
on a chiral column showed that the optical purity of 12
was fully retained.
Treatment of 12 with TFA-CH2Cl2 (1:1) at room
temperature for 30 min gave Nꢀ-cinnamoyl-Nꢀ-[2-(tri-
methylsilyl)ethoxy]-L-lysine methyl ester TFA salt (15).
Coupling of the crude 15 with 2-tert-butyl 1,3-di-N-suc-
cinimidyl citrate14 in dioxane in the presence of trieth-
ylamine afforded the fully protected O-[2-(trimethylsilyl)-
ethyl]nannochelin A tert-butyl ester 16 in 72% yield. An
initial attempt to generate nannochelin A by deprotection
of the O-[2-(trimethylsilyl)ethyl] group with BF3‚Et2O in
CH3CN and subsequent treatment with TFA-CH2Cl2 (1:
1) to remove the Boc group gave ambiguous results,
probably because the Boc group was partially removed
with BF3‚Et2O and undesirable side reactions occurred.
On the other hand, stepwise removal of Boc with TFA-
CH2Cl2 (1:1) and O-[2-(trimethylsilyl)ethyl] groups with
BF3‚Et2O afforded the “free” nannochelin A in 70% yield,
and the total yield is 11% from L-lysine.
1H and 13C NMR, UV, and MS spectra of the synthetic
nannochelin A were in agreement with those reported
for the natural product,11 and the optical rotation was
almost the same as the literature values (see Experi-
mental Section).
This methodology will be applicable to syntheses of
other hydroxamate-containing siderophores, especially to
siderophores bearing hydrogenolyzable groups in the
molecule.
Exp er im en ta l Section
1
Gen er a l. All melting points are uncorrected. The H NMR
(270 MHz) and 13C NMR (67.8 MHz) spectra were measured
in CDCl3 as solvent, unless otherwise noted. Chemical shifts
for 1H NMR spectra and 13C NMR are reported in ppm
downfield from tetramethylsilane (TMS). Elemental analyses
were performed in the Microanalytical Laboratory of this
University.
Rea gen ts a n d Ma ter ia ls. Tetrahydrofuran (THF) was
distilled from sodium benzophenone ketyl. CH3CN and CH2-
Cl2 were distilled from CaH2. Compound 5,3 O-[2-(trimethyl-
silyl)ethyl]hydroxylamine hydrochloride8 and pyridine-bo-
rane15 were prepared according to the published procedures.
Compound 13 and 14 were prepared by the procedure of
Yoshifuji.4 2-tert-Butyl 1,3-di-N-succinimidyl citrate was pre-
pared by the literature procedure14 using 1-ethyl-3-[3-(dim-
ethylamino)propyl]carbodiimide hydrochloride instead of di-
cyclohexylcarbodiimide (48%): pale yellow crystals; mp 185-
187 °C (CH3CN) (lit.13 188-189 °C).
Meth yl L-2-Oxop ip ecola te (4). A solution of L-13 (5.00
g, 13.4 mmol), TFA (25 mL), and CH2Cl2 (25 mL) was refluxed
(14) Milewska, M. J .; Chimiak, A.; Glowacki, Z. J . Prakt. Chem.
1987, 329, 447.
(15) Taylor, M. D.; Grant, L. R.; Sands, C. A. J . Am. Chem. Soc.
1955, 77, 1506.

8498 J . Org. Chem., Vol. 61, No. 24, 1996
Sakamoto et al.
for 45 min. The solvent was concentrated under reduced
pressure, and the residue was chromatographed on a column
of silica gel with AcOEt-EtOH (100:0-10:1) as the eluent to
brine (2 × 25 mL), dried (Na2SO4), filtered, and concentrated.
The crude product containing hemiaminal (8) was dissolved
in CH3CN-H2O (1:1, 30 mL). To the solution were added Me3-
SiCH2CH2ONH2‚HCl (1.02 g, 6.02 mmol) and NaHCO3 (241
mg, 2.87 mmol), and then the reaction mixture was refluxed
for 1 h. The solution was extracted with AcOEt (2 × 30 mL).
The combined organic layers were washed with brine (2 × 25
mL), dried (Na2SO4), filtered, and concentrated. The residue
was chromatographed on a column of silica gel with benzene-
AcOEt (8:1-5:1) as the eluent to give L-10 (1.56 g, 73%) as a
give L-4 (1.87 g, 89%): colorless oil; [R]22 -11.0° (c 3.2, CH2-
D
Cl2); IR (film) 3340, 1745, 1660 cm-1 1H NMR δ 1.72-1.98
;
(m, 3H), 2.17-2.29 (m, 1H), 2.39 (q, J ) 7.2 Hz, 2H), 3.79 (s.
3H), 4.12 (t, J ) 5.8 Hz, 1H), 6.41 (br s, 1H); 13C NMR δ 19.3,
25.3, 31.0, 52.7, 54.6, 171.8, 172.0; HRMS m/ z calcd for C7H11
-
NO3 157.0739, found 157.0754.
Compound D-4 (2.90 g, 82%) was prepared similarly using
the methyl ester of NR-Boc-Nδ-Boc-amide of D-2-aminoadipic
acid (D-13) (8.38 g, 22.4 mmol) which was prepared from
D-lysine.
mixture of E and Z isomers (1:1): colorless oil; [R]22 +9.9° (c
D
4.9, CH2Cl2); IR (film) 3375, 1750, 1720, 1250, 1170 cm-1; H
1
NMR δ 0.03 (s, 9H), 0.91-1.12 (m, 2H), 1.32-1.90 (m, 4H),
1.45 (s, 9H), 2.18 (dd, J ) 14.0, 6.4 Hz, 1H), 2.32 (dd, J )
14.0, 6.4 Hz, 1H), 3.74 (s, 3H), 4.01-4.15 (m, 2H), 4.28 (dd, J
) 14.0, 6.4 Hz, 1H), 5.02 (br s, 1H), 6.59 (t, J ) 7.4 Hz, 0.5 H),
7.34 (t, J ) 7.4 Hz, 0.5 H); 13C NMR δ -1.4, 17.5, 17.6, 22.2,
22.6, 25.4, 28.3, 29.2, 32.2, 32.5, 52.3, 53.2, 71.0, 71.4, 79.9,
149.3, 150.1, 155.4, 183.2; HRMS (FAB, added KI) calcd for
D-4: [R]22 +11.1° (c 3.6, CH2Cl2).
D
Meth yl 1-Boc-L-6-oxop ip ecola te (6). To a mixture of L-4
(2.00 g, 12.7 mmol) and 4-(dimethylamino)pyridine (DMAP)
(0.31 g, 2.54 mmol) in CH3CN (40 mL) was added di-tert-butyl
dicarbonate (3.5 mL, 15.2 mmol) at room temperature, and
the mixture was stirred for 7.5 h. After the solvent was
concentrated under reduced pressure, the residue was diluted
with AcOEt (50 mL). The solution was washed with 10% HCl
(2 × 25 mL) and brine, dried (Na2SO4), filtered, and concen-
trated. The residue was chromatographed on a column of
silica gel with AcOEt-hexanes (1:2-1:1) as the eluent to give
C
17H34N2O5SiK 413.1874, found 413.1873.
Compound D-10 (901 mg, 69%) was prepared similarly as a
mixture of E and Z isomers (1:1) using D-6 (897 mg, 3.49
mmol).
D-10: colorless oil; [R]22 -10.0° (c 5.0, CH2Cl2).
D
L-6 (2.91 g, 89%): colorless oil; [R]22 +3.5° (c 3.1, CH2Cl2);
Com p ou n d 10 fr om 14. A mixture of L-14 (1.41 g, 3.93
mmol), Me3SiCH2CH2ONH2‚HCl (733 mg, 4.31 mmol), and
NaHCO3 (165 mg, 1.97 mmol) in CH3CN-H2O (1:1, 24 mL)
was refluxed for 1.5 h. The reaction mixture was extracted
with AcOEt (2 × 30 mL). The combined organic layers were
washed with brine (2 × 25 mL), dried (Na2SO4), filtered, and
concentrated. The residue was chromatographed on a column
of silica gel with benzene-AcOEt (8:1-5:1) as the eluent to
give L-10 (1.57 g, 82%) as a mixture of E and Z isomers (1:1):
D
mp 52-53 °C (cyclohexane); IR (film) 1780, 1750, 1735 cm-1
;
1H NMR δ 1.50 (s, 9H), 1.66-1.83 (m, 2H), 1.89-2.22 (m, 2H),
2.41-2.63 (m, 2H), 3.77 (s, 3H), 4.71 (dd, J ) 6.0, 3.8 Hz, 1H);
13C NMR δ 18.3, 25.9, 27.9, 34.6, 52.5, 58.6, 83.5, 152.2, 170.1,
172.1; MS (CI, isobutane) m/ z 258 (M+ + 1). Anal. Calcd for
C
12H19NO5: C, 56.02; H, 7.44; N, 5.44. Found: C, 55.85; H,
7.55; N, 5.29.
Compound D-6 (3.22 g, 68%) was prepared similarly using
D-4 (2.90 g, 18.5 mmol).
colorless oil; [R]22 +9.9° (c 5.0, CH2Cl2).
D
Compound D-10 (544 mg, 77%) was prepared similarly as a
mixture of E and Z isomers (1:1) using D-14 (676 mg, 1.89
mmol).
D-6: mp 52-53 °C (cyclohexane); [R]22 -3.4° (c 3.5, CH2-
D
Cl2).
Ben zyl Ester of Nr-Boc-Oγ-[2-(tr im eth ylsilyl)eth yl]-
oxim e of L-Glu ta m ic Acid Sem ia ld eh yd e (9). A solution
of DIBAL in toluene (1.5 M, 0.78 mL, 1.11 mmol) was added
to a solution of L-5 (1.01 g, 3.15 mmol) in THF (15 mL) at -78
°C under argon. After being stirred for 20 min, the reaction
mixture was quenched with saturated aqueous NH4Cl (15 mL)
and warmed to room temperature. The mixture was extracted
with AcOEt (2 × 20 mL), and the combined organic layers were
washed with brine (2 × 15 mL), dried (Na2SO4), filtered, and
concentrated. The crude product was dissolved in CH3CN-
H2O (1:1, 14 mL). To the solution were added Me3SiCH2CH2-
ONH2‚HCl (587 mg, 3.46 mmol) and NaHCO3 (132 mg, 1.57
mmol), and then the reaction mixture was refluxed for 1 h.
The solution was extracted with AcOEt (2 × 25 mL). The
combined organic layers were washed with brine (2 × 15 mL),
dried (Na2SO4), filtered, and concentrated. The residue was
chromatographed on a column of silica gel with benzene-
AcOEt (15:1) as the eluent to give L-9 (937 mg, 71%) as a
D-10: colorless oil; [R]22 -9.9° (c 5.0, CH2Cl2).
D
Nδ-Acetyl-Nδ-[2-(tr im eth ylsilyl)eth oxy]-L-or n ith in e Ben -
zyl Ester (11). This compound (388 mg, 73%) was prepared
from the oxime (L-9) (489 mg, 1.12 mmol), analogous to 12
described below: colorless oil; HPLC (Daicel Chiralpak AD,
hexane/i-PrOH ) 9/1, flow rate ) 0.4 mL/min) tR ) 39.6 min;
[R]22D -16.6° (c 5.9, CH2Cl2); IR (film) 3325, 1750, 1720, 1660,
1
1250, 1170 cm-1; H NMR δ 0.01 (s, 9H), 0.95 (t, J ) 9.0 Hz,
2H), 1.43 (s, 9H), 1.59-1.92 (m, 4H), 2.09 (s, 3H), 3.60 (t, J )
7.0 Hz, 2H), 3.82 (t, J ) 9.0 Hz, 2H), 4.23-4.41 (m, 1H), 5.08
(br s, 1H, NH), 5.16 (d, J ) 2.0 Hz, 2H), 7.31-7.39 (m, 5H);
13C NMR δ -1.4, 16.8, 20.3, 23.1, 28.3, 29.8, 44.3, 53.4, 67.0,
71.7, 79.8, 128.2, 128.3, 128.6, 155.4, 171.8, 172.2; HRMS
(FAB) calcd for C24H41N2O6Si 481.2734, found 481.2695.
Compound DL-11 (79 mg, 72%) was prepared similarly using
DL-9 (100 mg, 0.229 mmol).
DL-11: colorless oil; HPLC (Daicel Chiralpak AD, hexane/
i-PrOH ) 9/1, flow rate ) 0.4 mL/min) tR ) 32.4, 39.6 min.
mixture of E and Z isomers (2:3): colorless oil; [R]22 -12.5°
D
(c 3.8, MeOH); IR (film) 3370, 1750, 1725, 1505, 1370, 1250,
NE-Cin n a m oyl-NE-[2-(t r im et h ylsilyl)et h oxy]-L-lysin e
Meth yl Ester (12). Pyridine-borane (950 mg, 10.2 mmol)
was added to a solution of L-10 (1.28 g, 3.41 mmol) in EtOH-
10% aqueous HCl (6:1, 22 mL) with ice cooling. After being
stirred for 15 min, the reaction mixture was concentrated
under reduced pressure, and the residue was diluted with
AcOEt (50 mL). The organic layer was washed with brine (2
1
1175 cm-1; H NMR δ 0.03 (s, 9H), 0.94 -1.06 (m, 2H), 1.44
(s, 9H), 1.74-2.45 (m, 4H), 4.03-4.21 (m, 2H), 4.31-4.46 (m,
1H), 5.05-5.17 (m, 3H), 6.61 (t, J ) 5.2 Hz, 0.4H), 7.25-7.45
(m, 5.6H); 13C NMR δ -1.4, 17.4, 21.8, 28.8, 28.3, 29.0, 29.5,
53.1, 67.1, 71.0, 71.4, 79.9, 128.2, 128.4, 128.6, 135.2, 148.5,
149.1, 155.3, 172.1; HRMS (FAB) calcd for C22H37N2O5Si
437.2472, found 437.2443.
× 20 mL), dried (Na2SO4), filtered, and concentrated.
A
Meth yl Ester of Nr-Boc-Oδ-[2-(tr im eth ylsilyl)eth yl]-
oxim e of L-2-Am in oa d ip ic Acid Sem ia ld eh yd e (10) fr om
6. A solution of lithium triethylborohydride in THF (1 M, 6.3
mL, 6.31 mmol) was added to a solution of L-6 (1.48 g, 5.73
mmol) in THF (30 mL) at -78 °C under argon. After being
stirred for 20 min, the reaction mixture was quenched with
saturated aqueous NaHCO3 (10 mL) and warmed to 0 °C. H2O2
(30%) (1 mL) was added, and the mixture was stirred at 0 °C
for 20 min. The organic solvent was removed under reduced
pressure, and the aqueous layer was extracted with AcOEt (3
× 20 mL). The combined organic layers were washed with
solution of trans-cinnamoyl chloride (795 mg, 4.77 mmol) in
AcOEt (6 mL) was added dropwise to the mixture of the crude
reduction product of L-10, AcOEt (24 mL), and 5% aqueous
NaHCO3 (11.5 mL) at 0 °C. After being stirred for 5 h, the
mixture was extracted with AcOEt (2 × 25 mL), and the
combined organic layers were washed with brine (2 × 25 mL),
dried (Na2SO4), filtered, and concentrated. The residue was
chromatographed on a column of silica gel with benzene-
AcOEt (1:8) as the eluent to give L-12 (1.32 g, 76%): colorless
oil; HPLC (Daicel Chiralcel OD, hexane/i-PrOH ) 5/5, flow
rate ) 0.5 mL/min) tR ) 36 min; [R]21 +3.8° (c 3.7, CH2Cl2);
D

Total Synthesis of Nannochelin A
J . Org. Chem., Vol. 61, No. 24, 1996 8499
IR (film) 3325, 1750, 1710, 1650, 1620, 1365, 1250, 1170, 1060,
1040 cm-1; 1H NMR δ 0.07 (s, 9H), 1.05 (dd, J ) 10.0, 8.0 Hz,
2H), 1.32-1.52 (m, 2H), 1.43 (s, 9H), 1.60-1.93 (m, 4H), 3.63-
3.79 (m, 2H), 3.73 (s, 3H), 3.93 (dd, J ) 10.0, 8.0 Hz, 2H), 4.22-
4.34 (m, 1H), 5.09 (br s, 1H), 7.01 (d, J ) 15.5 Hz, 1H), 7.32-
7.44 (m, 3H), 7.50-7.59 (m, 2H), 7.33 (d, J ) 15.5 Hz, 1H);
13C NMR δ -1.4, 16.8, 22.5, 26.7, 28.3, 32.1, 45.0, 52.2, 53.4,
72.7, 79.7, 116.3, 128.0, 128.8, 129.8, 135.3, 143.3, 155.5, 166.9,
173.3; HRMS (FAB, added KI) calcd for C26H42N2O6SiK
545.2449, found 545.2473.
Compound D-12 (296 mg, 73%) was prepared similarly using
D-10 (300 mg, 0.801 mmol).
D-12: colorless oil; HPLC (Daicel Chiralcel OD, hexane/i-
PrOH ) 5/5, flow rate ) 0.5 mL/min) tR ) 43 min; [R]22D -3.7°
(c 4.0, CH2Cl2).
Nr,Nr′-[3-Car boxy-3-h ydr oxy-1,5-dioxo-1,5-pen tan ediyl]-
b is{NE-cin n a m oyl-NE-[2-(t r im et h ylsilyl)et h oxy]-L-lysin e
Meth yl Ester } (17). A solution of 16 (214 mg, 0.209 mmol),
CH2Cl2 (2 mL), and TFA (2 mL) was stirred for 5 h at 0 °C.
The solution was warmed to room temperature and stirred for
an additional 2 h. After the solvents were removed under
reduced pressure, the residue was diluted with AcOEt (40 mL).
The solution was washed with brine (2 × 15 mL), dried (Na2-
SO4), filtered, and concentrated. The residue was chromato-
graphed on a column of silica gel with AcOEt-EtOH (100:1-
10:1) as the eluent to give 17 (182 mg, 90%): white form; [R]22
D
-2.3° (c 4.4, MeOH); IR (film) 3424, 2920, 2880, 1740, 1692,
1
1655, 1610, 1420, 1210, 1123 cm-1; H NMR δ 0.03 (s, 18H),
1.01 (t, J ) 8.3 Hz, 4H), 1.20-1.43 (m, 4H), 1.52-1.90 (m, 8H),
2.61-2.92 (m, 4H), 2.82-3.44 (m, 9H), 3.52-3.32 (m, 4H), 3.66
(s, 6H), 3.89 (t, J ) 8.3, 4H), 4.28-4.61 (m, 2H), 6.96 (d, J )
15.3 Hz, 2H), 7.25-7.42 (m, 6H), 7.43-7.59 (m, 4H), 7.73 (d,
J ) 15.3 Hz, 2H); 13C NMR (CD3OD) δ -1.3, 17.6, 23.7, 27.5,
32.1, 44.0, 44.3, 45.9, 52.9, 53.2, 53.4, 73.9, 76.7, 116.8, 116.9,
129.3, 130.1, 131.4, 136.2, 145.2, 145.4, 168.4, 168.5, 173.2,
NE-Cin n a m oyl-NE-[2-(t r im et h ylsilyl)et h oxy]-L-lysin e
Meth yl Ester TF A Sa lt (15). A solution of 12 (1.14 g, 2.24
mmol), TFA (12 mL), and CH2Cl2 (12 mL) was stirred for 0.5
h at room temperature. The volatiles were removed under
high vacuum to give the crude 13 (1.17 g, 100%), which was
subjected to condensation with 2-tert-butyl 1,3-di-N-succinim-
idyl citrate.
173.5, 173.7, 173.9, 181.8; MS (FAB, added NaI) 1013 (M+
2Na).
+
Nr,Nr′-[3-Boc-3-h yd r oxy-1,5-d ioxo-1,5-p en ta n ed iyl]bis-
{NE-cin n am oyl-NE-[2-(tr im eth ylsilyl)eth oxy]-L-lysin e Meth -
yl Ester } (16). Triethylamine (1.6 mL, 11.2 mmol) was added
dropwise to a mixture of 15 (1.17 g, 2.24 mmol), 2-tert-butyl
1,3-di-N-succinimidyl citrate (496 mg, 1.12 mmol), and dioxane
(20 mL) at room temperature. After being stirred for 20 h,
the solvent was removed under reduced pressure, and the
residue was diluted with AcOEt (50 mL). The solution was
washed with brine (2 × 25 mL), dried (Na2SO4), filtered, and
concentrated. The residue was chromatographed on a column
of silica gel with AcOEt-hexanes (3:1) as the eluent to give
Na n n och elin A. To a solution of 17 (243 mg, 0.251 mmol)
in CH3CN (10 mL) was added boron trifluoride etherate (0.15
mL, 1.26 mmol) at 0 °C. After being stirred for 0.5 h, the
reaction mixture was concentrated under reduced pressure,
and deionized water (10 mL) was added to the residue. The
mixture was extracted with AcOEt (2 × 25 mL), and the
combined organic layers were washed with deionized water
(2 × 15 mL). The organic solvent was removed under reduced
pressure and the residue was eluted on Sephadex G-15 (20 g)
with 30% MeOH-H2O to give nannochelin A (135 mg, 70%):
colorless glass; [R]21 -13° (c 1.1, MeOH) (lit.11 [R]25 -13.0°
D
D
16 (827 mg, 72%): colorless oil; [R]21 +1.8° (c 3.6, CH2Cl2);
(c 0.9, MeOH); lit.13 [R]26D -12° (c 0.65, MeOH)); IR (film) 3400,
D
IR (film) 3475, 3350, 1750, 1680, 1655, 1620, 1250, 1210, 1175,
1740, 1650, 1580, 1455, 1440, 1220, 980 cm-1 1H NMR
;
1
1160, 860, 840 cm-1; H NMR δ 0.06 (s, 18H), 1.01 (dd, J )
(DMSO-d6/CDCl3 (1:1)) δ 1.27-1.46 (m, 4H), 1.52-1.86 (m, 8H)
2.58-2.71 (m, 4H), 3.52-3.80 (m, 4H), 3.65 (s, 6H), 4.22-4.38
(m, 2H), 7.19 (d, J ) 15.9 Hz, 2H), 7.31-7.45 (m, 6H), 7.53 (d,
J ) 15.9 Hz, 2H), 7.52-7.63 (m, 4H), 8.18 (d, 1H), 8.25 (d,
1H), 9.86 (br s, 1H); 13C NMR (CD3OD) δ 23.8, 27.2, 32.1, 44.5,
44.8, 52.8, 53.5, 53.6, 75.2, 117.6, 129.1, 130.0, 131.1, 136.6,
143.81, 143.84, 172.0, 172.1, 174.1, 176.6; HRMS (FAB, added
NaI) calcd for C38H47N4O13Na2 813.2935 (M+ + 2Na), found
813.2966.
9.4, 7.8 Hz, 4H), 1.30-1.93 (m, 13H), 1.48 (s, 9H), 2.62 (d, J )
14.0 Hz, 1H), 2.79 (d, J ) 14.0 Hz, 1H), 2.72 (s, 2H), 3.60-
3.81 (m, 2H), 3.71 (s, 3H), 3.73 (s, 3H), 3.93 (dd, J ) 9.4, 7.8
Hz, 4H), 4.43-4.59 (m, 1H), 7.03 (d, J ) 15.5 Hz, 2H), 7.34-
7.59 (m, 10H), 7.72 (d, J ) 15.5 Hz, 2H); 13C NMR δ -1.4,
16.9, 22.7, 22.8, 26.6, 27.8, 31.0, 31.2, 41.0, 44.9, 45.0, 52.1,
52.3, 52.45, 52.52, 72.6, 72.7, 72.8, 82.5, 116.2, 116.3, 128.0,
128.1, 128.8, 129.8, 129.9, 135.2, 135.3, 143.3, 143.5, 166.9,
167.0, 169.6, 171.2, 171.5, 173.5, 179.9; HRMS (FAB, added
NaI) calcd for C52H80N4O13Si2Na 1047.5160, found 1047.5136.
J O961458F