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Synlett 2010(14): 2156-2158  
DOI: 10.1055/s-0030-1258524
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Practical Synthesis of the C-1027 Aminosugar Moiety

Keiichiro Hiraia, Yukio Tamuraa, Itaru Sato*b, Masahiro Hirama*a,b
Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
Research and Analytical Center for Giant Molecules, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
Fax: +81(22)7956566; e-Mail: isato@mail.tains.tohoku.ac.jp; e-Mail: hirama@mail.tains.tohoku.ac.jp;

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Publication History

Received 8 June 2010
Publication Date:
27 July 2010 (online)

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Abstract

A concise and reliable synthetic route to the aminosugar moiety of the C-1027 chromophore was developed. The aminosugar moiety was synthesized from l-glutamic acid in 11 steps and 13% overall yield.

Key words

C-1027 - enediyne - carbohydrate - natural products - synthesis

The enediyne antibiotic C-1027, [¹] isolated from the culture supernatant of Streptomyces globisporus C-1027 in 1988, possesses the most potent antitumor activity in the family of chromoprotein antibiotics. [²] C-1027 is composed of a biologically active chromophore and a stabilizing apoprotein. [³] [4] Synthesis of chromophore 1, which has the highly strained, labile nine-membered enediyne, [5] has attracted the attention of many chemists. [6] [7] In 1993, we reported the synthesis of the aminosugar moiety via intramolecular carbamate rearrangement and determined its absolute configuration. [³b] [8] However, a recent synthetic study of 1 indicated that glycosylation at a relatively early stage was preferable and it required an ample supply of the aminosugar moiety 2 (Figure  [¹] ). Unfortunately, our synthesis of 2 suffered from lengthy steps and a low overall yield. Thus, we developed a more concise and reliable synthetic route to 2. For the purpose of the stereoselective glycosylation [6b] and global deprotection at the end of the synthesis, 1,1,3,3,-tetraisopropoxydisiloxanylidene (TIPDS) protection of 2 should be a suitable choice.

Scheme 1 Reagents and conditions: (a) SOCl2, EtOH then 150 ˚C, 0.02 bar, 89%; (b) MeLi, THF, -78 ˚C then TMSCl, Et3N, r.t., 68%; (c) (Boc)2O, Et3N, MeCN, 90%; (d) LiN(SiMe3)2, THF, -78 ˚C then PhSeCl; (e) 30% aq H2O2, pyridine, 79% (2 steps); (f) cat. OsO4, NMO, acetone, H2O, 91%; (g) LiOH, THF, H2O then TsOH, CH2Cl2, 82%; (h) TFA-CH2Cl2 (1:1); (i) NaBH3CN, aq HCHO, formic acid, 79% (2 steps); (j) TIPDSCl2, imidazole, DMF, 56%; (k) DIBAL-H, CH2Cl2, -78 ˚C, 90%.

Figure 1 Structures of C-1027 chromophore 1 and aminosugar moiety 2

The aminosugar moiety 2 features a gem-dimethyl at C5, a cis-dihydroxy group at C2 and C3, and an N,N-dimethylamino group at the C4 position. Stereoselective construction of the three C2-C4 consecutive stereogenic centers was a major challenge in the synthesis (Scheme  [¹] ). The synthesis began with l-glutamic acid (3). According to the literature procedure, 3 was converted into γ-lactam ethyl ester. [9] Selective methylation of the ester functionality and subsequent trapping of the hydroxy group as a trimethylsilyl ether gave 4 after tert-butoxycarbonyl (Boc) protection of the lactam nitrogen. Introduction of the double bond and subsequent dihydroxylation of 5 using osmium tetroxide and N-methylmorpholine N-oxide provided cis-diol 6 as a single diastereomer. [¹0] Alkaline hydrolysis of the imide function selectively cleaved the γ-lactam, followed by the addition of p-toluenesulfonic acid, to give desired δ-lactone 7.

For the selective hydrolysis of the lactam, Boc protection of the amide group was essential. When hydrolysis of the corresponding imide 10 protected by a carbobenzyloxy (Cbz) group was attempted, the γ-lactam was not cleaved and instead the Cbz group migrated to the C5 hydroxy group (Scheme  [²] ). A similar migration of the alkoxycarbonyl group to the primary alcohol often occurred even if the Boc group was used. [¹¹] In the hydrolysis of 6, steric hindrance between the gem-dimethyl and the tert-butoxycarbonyl group suppressed intramolecular attack of the alkoxide. Acidic removal of the Boc group followed by reductive methylation of the resulting amine gave dimethylamine 8. Protection of the vicinal diol with TIPDSCl provided 9. [¹²] Reduction with DIBAL-H afforded desired hemiacetal 2 together with a small amount (<10%) of open-chain aldehyde. [¹³]

Scheme 2 Migration of carbobenzyloxy group of 10

In conclusion, we have developed a concise synthetic route to the C-1027 aminosugar moiety 2. The present synthesis (11 steps in 13% overall yield from l-glutamic acid), superior to the previous route (18 steps, 0.49%), will facilitate the synthetic study of the C-1027 chromophore 1. Further studies directed toward the total synthesis of 1 are currently under way in our laboratory.

Supporting Information for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/ejournals/toc/synlett.

Acknowledgment

This work was supported financially by a Grant-in-Aid for Specially Promoted Research from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT). A fellowship to Y.T. from the Japan Society for the Promotion of Science (JSPS) is gratefully acknowledged.

12

Selected Data for 9
Colorless needles; mp 162-164 ˚C (EtOAc); [α]D ²9 +8.6 (c 1.00, CH2Cl2). FT-IR (film): ν = 2944, 1742, 1458, 1275, 1179, 1114, 1041, 1014, 884, 801, 695 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 0.94-1.15 (28 H, m, TIDPS), 1.45 (3 H, s, H6), 1.61 (3 H, s, H6), 2.53 (6 H, s, NMe2), 2.71 (1 H, d, J = 1.6 Hz, H4), 4.43 (1 H, d, J = 2.4 Hz, H2), 4.82 (1 H, dd, J = 2.4, 1.6 Hz, H3). ¹³C NMR (100 MHz, CDCl3): δ = 12.8, 13.3, 14.0, 14.3, 16.8, 16.9, 17.2, 17.2, 17.3, 17.6, 17.6, 17.9, 25.7, 24.6 (C6), 31.4 (C6), 45.0 (NMe2), 68.7 (C4), 71.8 (C3), 76.7 (C2), 87.4 (C5), 169.3 (C1). ESI-HRMS: m/z calcd for C21H43NNaO5Si2 + [M + Na+]: 468.2572; found: 468.2575.

13

Selected Data for 2
Colorless oil; [α]D ²7 -19.0 (c 1.00, CHCl3). FT-IR (film): ν = 3386, 2867, 1465, 1386, 1364, 1248, 1137 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 1.03-1.13 (28 H, m, TIPDS), 1.30 (3 H, s, H6), 1.60 (3 H, s, H6), 2.46 (1 H, d, J = 2.4 Hz, H4), 2.55 (6 H, s, NMe2), 2.76 (1 H, br s, OH), 3.49 (1 H, dd, J = 8.0, 3.2 Hz, H2), 4.73 (1 H, dd, J = 3.2, 2.4 Hz, H3), 5.01 (1 H, br d, J = 8.0 Hz, H1). ¹³C NMR (100 MHz, CDCl3):
δ = 13.0, 13.1, 13.3, 13.6, 14.4, 17.1, 17.1, 17.4, 17.4, 17.5, 17.5, 17.6, 23.7 (C6), 30.8 (C6), 44.5 (NMe2), 69.4 (C4), 74.8 (C3), 78.1 (C2), 78.4 (C5), 90.5 (C1). ESI-HRMS:
m/z calcd for C21H46NO5Si2 + [M + H+]: 448.2909; found: 448.2910.

12

Selected Data for 9
Colorless needles; mp 162-164 ˚C (EtOAc); [α]D ²9 +8.6 (c 1.00, CH2Cl2). FT-IR (film): ν = 2944, 1742, 1458, 1275, 1179, 1114, 1041, 1014, 884, 801, 695 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 0.94-1.15 (28 H, m, TIDPS), 1.45 (3 H, s, H6), 1.61 (3 H, s, H6), 2.53 (6 H, s, NMe2), 2.71 (1 H, d, J = 1.6 Hz, H4), 4.43 (1 H, d, J = 2.4 Hz, H2), 4.82 (1 H, dd, J = 2.4, 1.6 Hz, H3). ¹³C NMR (100 MHz, CDCl3): δ = 12.8, 13.3, 14.0, 14.3, 16.8, 16.9, 17.2, 17.2, 17.3, 17.6, 17.6, 17.9, 25.7, 24.6 (C6), 31.4 (C6), 45.0 (NMe2), 68.7 (C4), 71.8 (C3), 76.7 (C2), 87.4 (C5), 169.3 (C1). ESI-HRMS: m/z calcd for C21H43NNaO5Si2 + [M + Na+]: 468.2572; found: 468.2575.

13

Selected Data for 2
Colorless oil; [α]D ²7 -19.0 (c 1.00, CHCl3). FT-IR (film): ν = 3386, 2867, 1465, 1386, 1364, 1248, 1137 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 1.03-1.13 (28 H, m, TIPDS), 1.30 (3 H, s, H6), 1.60 (3 H, s, H6), 2.46 (1 H, d, J = 2.4 Hz, H4), 2.55 (6 H, s, NMe2), 2.76 (1 H, br s, OH), 3.49 (1 H, dd, J = 8.0, 3.2 Hz, H2), 4.73 (1 H, dd, J = 3.2, 2.4 Hz, H3), 5.01 (1 H, br d, J = 8.0 Hz, H1). ¹³C NMR (100 MHz, CDCl3):
δ = 13.0, 13.1, 13.3, 13.6, 14.4, 17.1, 17.1, 17.4, 17.4, 17.5, 17.5, 17.6, 23.7 (C6), 30.8 (C6), 44.5 (NMe2), 69.4 (C4), 74.8 (C3), 78.1 (C2), 78.4 (C5), 90.5 (C1). ESI-HRMS:
m/z calcd for C21H46NO5Si2 + [M + H+]: 448.2909; found: 448.2910.

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Scheme 1 Reagents and conditions: (a) SOCl2, EtOH then 150 ˚C, 0.02 bar, 89%; (b) MeLi, THF, -78 ˚C then TMSCl, Et3N, r.t., 68%; (c) (Boc)2O, Et3N, MeCN, 90%; (d) LiN(SiMe3)2, THF, -78 ˚C then PhSeCl; (e) 30% aq H2O2, pyridine, 79% (2 steps); (f) cat. OsO4, NMO, acetone, H2O, 91%; (g) LiOH, THF, H2O then TsOH, CH2Cl2, 82%; (h) TFA-CH2Cl2 (1:1); (i) NaBH3CN, aq HCHO, formic acid, 79% (2 steps); (j) TIPDSCl2, imidazole, DMF, 56%; (k) DIBAL-H, CH2Cl2, -78 ˚C, 90%.

Figure 1 Structures of C-1027 chromophore 1 and aminosugar moiety 2

Scheme 2 Migration of carbobenzyloxy group of 10