Stereocontrolled synthesis of (+)-L-noviose using a versatile sugar building block

Article abstract of DOI:10.1016/S0040-4039(00)00216-1

(+)-L-Noviose, the sugar moiety of the antibiotic novobiocin, has been synthesized diastereoselectively using a man-made sugar building block. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00216-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2609–2611
Stereocontrolled synthesis of (+)-L-noviose using a versatile
sugar building block
Miwako Takeuchi, Takahiko Taniguchi and Kunio Ogasawara ∗
Pharmaceutical Institute, Tohoku University, Aobayama, Sendai 980-8578, Japan
Received 11 January 2000; revised 25 January 2000; accepted 28 January 2000
Abstract
(+)-L-Noviose, the sugar moiety of the antibiotic novobiocin, has been synthesized diastereoselectively using a
man-made sugar building block. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: antibiotics; carbohydrates; enantiocontrol; neighboring group effects; stereocontrol.
The antibiotic novobiocin 1 carries a sugar moiety which is responsible for its biological activity.1
The sugar moiety was found to be removed under acidic conditions to give 4-O-methyl-5,5-dimethyl-L-
lyxose, (+)-L-noviose2 2 (Fig. 1). Although this rare sugar has been synthesized3 in both racemic and
enantiomeric forms, only one procedure, namely, that by Pankau and Kreiser3d,e using a chiral building
block4 seemed to be the most practical so far. In relation to our recent project on sugar synthesis, we
chose (+)-L-noviose 2 as a target to extend the synthetic applicability of our sugar building block5,6
3
which was originally designed for the diastereocontrolled construction of eight possible aldohexoses in
both enantiomeric forms.5,7 We wish to report here a new synthesis of (+)-L-noviose 2 starting from
our sugar building block5,6 (+)-3 which was prepared from furfural in enantiomerically pure forms by
employing either a chemical5,8 or an enzymatic6 procedure (Scheme 1).
Fig. 1.
Owing to its biased structure, the building block (+)-3 having a dioxabicyclo[3.2.1]octane frame-
work allowed diastereoselective epoxidation from the convex face on reaction with alkaline hydrogen
∗
Corresponding author. Fax +81-22-217-6845; e-mail: konol@mail.cc.tohoku.ac.jp (K. Ogasawara)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00216-1
tetl 16496

2610
Scheme 1.
peroxide8 to give the exo-epoxide 4 as a single product. Reduction of 4 with sodium borohydride-
cerium(III) chloride9 also took place diastereoselectively from the convex face to give the endo-alcohol
5, [α]D27 +17.7 (c 1.1, CHCl3), as a single product. Benzoylation of 5 followed by treating the resulting
29
benzoate 6, [α]D −18.2 (c 1.1, CHCl3), with boron trifluoride etherate10 in toluene brought about
regio- and diastereoselective epoxy cleavage to give the monobenzoate mixture 8. Without separation,
the mixture was subjected to alkaline methanolysis to give the single triol 9 which allowed specific ketal
29
formation to afford the crystalline hydroxy-acetonide 10, mp 109–110°C, [α]D −52.2 (c 1.1, CHCl3),
as the single product. The observed diastereoselective conversion of the epoxide 6 into the single triol 9
may be readily presumed by taking account of the participation of the benzoate group which produced
the benzoate mixture 8 through 6a and 7 as shown.
Having created three consecutive oxygen-bearing stereogenic centers, which are those required in the
target molecule, the secondary alcohol 10 was first treated with methyl iodide under standard conditions
29
to give the methyl ether 11, [α]D −53.9 (c 1.0, CHCl3), whose benzyl functionality was then removed
27
under hydrogenolysis conditions to give the crystalline primary alcohol 12, mp 83–84°C, [α]D −85.5
(c 1.0, CHCl3). Mesylation of 12 followed by treating the resulting mesylate 13 with lithium iodide
28
afforded the iodide 14, [α]D −47.8 (c 1.0, CHCl3), without difficulty. Overall yield of 14 from (+)-3
was 54% in 10 steps (Scheme 2).
Scheme 2. Reagents and conditions: (i) 30% H2O2, 0.5N NaOH, THF, 0°C. (ii) NaBH4–CeCl3·7H2O, MeOH, 0°C (82% for
two steps). (iii) BzCl, pyridine, CH2Cl2 (96%). (iv) BF3·OEt2, toluene. (v) NaOMe, MeOH. (vi) Me2C(OMe)2, PPTS (cat.),
toluene, reflux (84% for three steps). (vii) MeI, NaH, THF (99%). (viii) H2, 10% Pd–C, MeOH (91%). (ix) MesCl, Et3N,
CH2Cl2. (x) LiI, THF, reflux (90% for two steps)
In order to attain the target molecule, the iodide 14 was treated with zinc in methanolic acetic acid
to initiate reductive elimination to cleave the internal acetal functionality to give rise to the hemiacetal
15 as a mixture of epimers. Since an anhydro-sugar type internal acetal functionality requires rather
severe conditions for its hydrolytic cleavage, the sugar building block 3 exerts its potential with respect

2611
to this point. On oxidation with tetrapropylammonium perruthenate in the presence of N-morphorine
29
N-oxide (TPAP–NMO),5,11 15 gave the δ-lactone 16, mp 59–60°C, [α]D +89.9 (c 1.1, CHCl3), as
colorless needles (Scheme 3). Treatment of 16 with an excess amount of methyllithium gave the acyclic
27
diol 17, [α]D −51.7 (c 1.0, CHCl3), whose extra two-carbon moiety was oxidatively removed under
Lemieux–Johnson conditions12 to give the hemiacetal 19 via the transient hydroxy-aldehyde 18. Finally,
19 was acid-hydrolyzed in the presence of Dowex 50-W13 to remove the acetonide protecting group to
20
give rise to (+)-L-noviose 2, mp 128–129°C, [α]D29 +31.2 (c 0.94, 50% EtOH) [lit.3e: mp 128°C, [α]D
−29.2 (c 1.00, 50% EtOH) for D-enantiomer], as colorless crystals. Overall yield of 2 from 14 was 43%.
Scheme 3. Reagents and conditions: (i) Zn, AcOH:MeOH (1:10) (97%). (ii) TPAP–NMO, 4 Å sieves, CH2Cl2 (90%). (iii)
MeLi, THF, 0°C (83%). (iv) OsO4 (cat.), NaIO4, 50% aq. THF. (v) Dowex 50-W, H2O, 70°C (59% for two steps)
In summary, we have synthesized (+)-L-noviose 2 in 23% overall yield in 15 steps with complete
diastereoselection from our sugar building block (+)-3 on the basis of its inherent convex-face selectivity
and high functionality.
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