Stereoselective synthesis of 5-monoalkyl and 5,5-dialkylsubstituted noviose derivatives

Article abstract of DOI:10.1016/S0040-4039(99)02177-2

The stereoselective synthesis of 5-monosubstituted and 5,5- dialkylsubstituted noviose derivatives has been achieved starting from L- arabinose. These noviose derivatives could be used as useful building blocks in probing structure-activity relationships

Full text of DOI:10.1016/S0040-4039(99)02177-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 867–871
Stereoselective synthesis of 5-monoalkyl and
5,5-dialkylsubstituted noviose derivatives
Anne-Marie Periers,a Patrick Laurin,a Yannick Benedetti,a Sylvette Lachaud,a Didier Ferroud,a
Alain Iltis,a Jean-Luc Haesslein,a Michel Klich,a Guillaume L’Hermite b and
Branislav Musicki a,∗
aMedicinal Chemistry, Hoechst Marion Roussel, 102 route de Noisy, 93235 Romainville Cedex, France
bBIO-XTAL, Department of Crystallography, 16 Rue de L’Alouette, 59100 Roubaix, France
Received 21 October 1999; accepted 18 November 1999
Abstract
The stereoselective synthesis of 5-monosubstituted and 5,5-dialkylsubstituted noviose derivatives has been
achieved starting from L-arabinose. These noviose derivatives could be used as useful building blocks in probing
structure–activity relationships (SAR) of coumarin antibiotics that are inhibitors of DNA gyrase. © 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: antibiotics; Grignard reaction; Grignard reagents; stereoselection; structure–activity.
Novobiocin (1),1a clorobiocin (2)1b and closely related synthetic analogues (3)2 are coumarin-
containing antibiotics possessing a broad spectrum of Gram-positive antibacterial activity, including
methicilin-resistant strains of the staphylococci species, MRSA and MRSE,3 which are currently one
of the major concerns in treatment of bacterial infections. These coumarins have been shown to inhibit
the ATPase activity of subunit B of DNA gyrase,4 a tetrameric A2B2 enzyme that belongs to a family
of enzymes known as topoisomerase. These ubiquitous enzymes play an important role in resolving
topological problems that arise during the various processes of DNA metabolism, including transcription,
recombination, replication and chromosome partitioning during cell division.5
∗
Corresponding author. Tel: +33 1 49 91 40 07; fax: +33 1 49 91 50 87; e-mail: branislav.musicki@hmrag.com (B. Musicki)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02177-2
tetl 16105

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Recently, we reported structure–activity relationships of a series of coumarin inhibitors of DNA gyrase
wherein the L-noviosyl sugar portion was replaced by L-rhamnose. These are noviose analogues bearing
a 50-hydrogen atom instead of the 50-methyl axial group.6 As this novel series provided interesting
biological activity, we decided to expand SAR around this part of the molecule by varying the size of alkyl
substituents. We disclose herein a stereoselective synthesis of 5-monoalkyl and 5,5-dialkyl substituted
noviose analogues starting from L-arabinose.
The preparation of 5,5-dialkyl noviose derivatives is outlined in Scheme 1. Lactone 5, readily available
from L-arabinose in five steps,2a was reacted with different alkyl Grignards in THF to provide the diols
6a–e.7 These were oxidatively cyclised to the corresponding lactones 7a–c, 7e,f with PySO3 (2 equiv.)
in the presence of DMSO/Et3N and then reduced with DIBALH to lactols 8a–e in quantitative yield.
Acid-catalysed deprotection of the acetonides with H2SO4 afforded 5,5-dialkyl noviose analogues 9a,b
and 9d,e. 5,5-Diallyl lactone 7c was subjected to ring-closing metathesis in the presence of Grubbs
ruthenium catalyst8 in dichloromethane to give the spirocyclopentene lactone 7d in 80% yield, which
was further transformed to spirocyclopentene noviose 9c, as described.
Scheme 1. Reagents and conditions: (a) for 6a MeMgBr, THF, 0°C, 86%; for 6b EtMgBr, THF, 0°C; for 6c
CH2_CH–CH2MgBr, THF, 0°C; for 6d BrMg-(CH2)4-MgBr,9 THF, 0°C; for 6e BrMg-(CH2)5-MgBr, THF, 0°C 56%; (b)
PySO3, TEA, DMSO, CH2Cl2; (c) DIBALH, THF, 0°C (d) H2SO4, H2O, 65°C (e) RuCl2(CHPh)[P(C6H11)3]2 cat, CH2Cl2, rt,
80%
Facing the more challenging problem of stereoselective introduction of the 5-equatorial alkyl sub-
stituents while keeping the methyl group or the hydrogen atom in the 5-axial position, we modified
the above described methodology for preparation of our new targets, as depicted in Scheme 2. The
nucleophilic addition of various Grignard reagents (∼4 equiv.) to a protected arabinolactol 10 proceeded
stereoselectively in THF affording as major products (4S,5R)-diastereomers 11a–d.10 However, this

869
configuration was not the desired one as was proven by oxidative cyclisation of the diol 11a with
PySO3/DMSO/Et3N to give the lactone 18. The NOE experiments performed on 18 (Fig. 1) indicated
cis-4H,5H orientation. The NOE between the endo-methyl group of acetonide and 5H and J4H–5H=1.5 Hz
coupling constant indicated a boat conformation of the six-membered lactone ring. In contrast, in lactone
15a (vide infra), NOE and J4H–5H=10 Hz clearly establishes trans-diaxial orientation of 4H,5H atoms as
observed with L-rhamnose derivative 19.11
Scheme 2. Reagents and conditions: (a) for 11a EtMgBr, THF, 0°C; for 11b CH2_CH–MgBr, THF, 0°C; for 11c
CH2=CH–CH2–MgBr, THF, 0°C; for 11d PhCH2MgCl, THF, 0°C; (b) tBuPh2SiCl, Im, DMF, rt; (c) PCC, CH2Cl2, molecular
sieves 4 Å, rt; (d) for 13a Zn(BH4)2, Et2O, THF, 0°C; (e) for 13a–d MeMgBr, THF, 0°C; (f) Bu4NF, THF, rt; (g) PySO3, DMSO,
TEA, CH2Cl2, rt; (h) DIBALH, THF, 0°C; (i) H2SO4, H2O, 65°C
Fig. 1. Observed NOEs for the lactones 15a and 18
In order to correct the undesired diastereoselectivity of Grignard addition, the diols 11a–d were
regioselectively protected at a primary hydroxyl group with tBuPh2SiCl under standard silylating
conditions, and the secondary alcohols were oxidised with PCC in the presence of molecular sieves
12
(4 Å) to the corresponding ketones 13a–d. Reduction of the ketone 13a with Zn(BH4)2 in ether or
nucleophilic addition of MeMgBr in THF to 13b–d proceeded diastereoselectively [(4R,5S) for 14a,
(4S,5S) for 14b–d] to establish the axial orientation of the hydrogen atom or methyl group, respectively.13
The alcohols 14a–d were smoothly desilylated with Bu4NF in THF and the resulting diols were subjected
to the same reaction sequence as described above and gave the noviose analogues 17a–e. Thus, the above
proposed synthetic scheme allows access to noviose derivatives having either 5,5-R1(eq)/R2(ax) or 5,5-
R1(ax)/R2(eq) configuration depending on the order of addition of Grignard reagents to lactol 10 and
ketone 13.
The configurations of the newly formed alcohols were confirmed by X-ray structure analysis14 or by
NOE experiments. The observed stereoselectivity of the nucleophilic addition of Grignard reagents to
lactol 10 or with ketones 13b–d as well as the reduction of ketone 13a with Zn(BH4)2 follow Cram’s

870
rule.15 Presumably, the nucleophilic reactions proceed through an α-chelated transition state which is
consistent with Still’s finding16 that Grignard reagents in THF solutions prefer α-chelation (Scheme 3).
Scheme 3.
In conclusion, we have described a highly stereoselective approach to 5-monoalkylsubstituted and 5,5-
dialkylsubstituted noviose derivatives, as well as a general synthetic approach to 5,5-bisalkyl noviose,
including 5,5-spiro analogues. These synthetic intermediates could serve as useful scaffolds in probing
SAR related to coumarin antibiotics.
Acknowledgements
We would like to thank the Analytical Department (HMR, Romainville) for performing the spectral
analysis.
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7. The yields in parentheses refer to isolated yields. Selected data: Compound 15d: white solid, mp 95–96°C; 1H NMR (300
MHz, CDCl3): δ (ppm) 1. 31 (s, 3H), 1.38 (s, 3H), 1.47 (s, 3H), 2.46 (d, 2H, J=7 Hz), 3.31 (d, 1H, J=6.5 Hz), 3.5 (s, 3H),
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24.7, 26.7, 43.2, 58.0, 71.1, 77.2, 81.4, 82.9, 111.0 119.6, 131.6, 168.7; Anal. calcd for C13H20O5: C, 60.92; H, 7.87. Found:
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38 (s, 3H), 1.52 (s, 3H), 1.72 (qdd, 1H, J=6, 7, 15 Hz), 1.90 (qdd, 1H, J=7, 8.5, 15 Hz), 3.34 (dd, 1H, J=1.5, 2.5 Hz), 3.48
(s, 3H), 4.45 (ddd, 1H, J=1.5, 6, 8.5 Hz); 4.56 (dd, 1H, J=2.5, 7 Hz), 4.65 (d, 1H, J=7 Hz); 13C NMR (75 MHz, CDCl3) δ
(ppm): 9.9, 23.7, 23.8, 25.9, 58.4, 72.3, 72.7, 76.6, 77.9, 111.1, 167.3; anal. calcd for C11H18O5: C, 57.38; H, 7.88. Found:
C, 57.20; H, 7.90.

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