Synthesis of methyl α-caryophylloside

Article abstract of DOI:10.1016/S0040-4039(99)02039-0

The convergent synthesis of caryophyllose, a new C-4 branched dodecose isolated from Pseudomonas caryophylli, is described from two monosaccharidic precursors. The key step is the diiodosamarium-promoted coupling of two six-carbon fragments: an acid chloride and a cyclic ketone.

Full text of DOI:10.1016/S0040-4039(99)02039-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 49–52
Synthesis of methyl α-caryophylloside
Jacques Prandi a,b,∗ and Gwénaëlle Couturier b
aInstitut de Pharmacologie et de Biologie Structurale du CNRS, 205 route de Narbonne, F-31077 Toulouse Cedex, France
bInstitut de Chimie Organique et Analytique, Université d’Orléans, BP 6759, F-45067 Orléans Cedex 2, France
Received 8 October 1999; accepted 27 October 1999
Abstract
The convergent synthesis of caryophyllose, a new C-4 branched dodecose isolated from Pseudomonas caryo-
phylli, is described from two monosaccharidic precursors. The key step is the diiodosamarium-promoted coupling
of two six-carbon fragments: an acid chloride and a cyclic ketone. © 1999 Elsevier Science Ltd. All rights reserved.
Caryophyllose 1 (see Fig. 1) is a member of the family of C-4 branched sugars1–3 and was isolated in
1995 from the cell wall of a strain of Pseudomonas caryophylli, the causal agent of the bacterial wilt of
carnation.4 The complete structure of this dodecose has been elucidated early after5 as 3,6,10-trideoxy-4-
C-(D-glycero-1-hydroxyethyl)-D-erythro-D-gulo-decose and it was later shown to occur in the cell wall
as a highly unusual homopolysaccharidic chain with (1→7)-α and -β linkages.6,7
Fig. 1.
Pursuing our work on the synthesis of C-4 branched sugars,8 we now report the stereoselective
preparation of methyl α-D-caryophylloside 2, starting from ketone 38 and a six-carbon carboxylic acid
derived from 2,6-dideoxy-D-ribo-hexose 4, D-digitoxose (Fig. 1).
∗
Corresponding author. Fax: 33(0)5 61 17 59 94; e-mail: prandi@ipbs.fr (J. Prandi)
0040-4039/00/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02039-0
tetl 15967

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Treatment of 4, easily prepared from methyl α-D-glucopyranoside,9 with an excess of ethanethiol
and concentrated HCl gave the diethyldithioacetal 5 in 81% yield after three hours (see Scheme 1).10
Perbenzylation (NaH, BnBr, DMF) and dithioacetal hydrolysis with mercuric chloride and mercuric
oxide10,11 in aqueous acetone gave the aldehyde 7a in 69% yield from 5. This aldehyde was smoothly
oxidized to the carboxylic acid 8a with Jones reagent12 in acetone (92%). All attempts to prepare the
acid chloride 9a from 8a were plagued by intramolecular nucleophilic attack of the oxygen atom of the
C-4 benzyloxy group on the carbonyl bond13 and formation of the five-membered lactone 10; only low
yields of 9a were obtained (<10%).
Scheme 1. (a) EtSH, concd HCl, 0°C, 3 h, 81%. (b) BnBr, NaH, DMF, rt, 2 h. (c) TBDMSOTf, pyridine, CH2Cl2, rt, 24 h, 90%.
(d) HgO, HgCl2, acetone:water 10:1, rt, 3 h. (e) Jones reagent, acetone, 0°C, 30 min, 92%. (f) (COCl)2, pyridine, THP, 0°C. (g)
KMnO4, 5% NaH2PO4, t-BuOH, rt, 1 h, 83%
We assumed that steric crowding should lower the nucleophilicity of this C-4 oxygen atom and
introduced the bulky tert-butyldimethylsilyl ethers as protecting groups for the hydroxyl functions of
5. Thus, 5 was treated with an excess of tert-butyldimethylsilyltriflate and pyridine in CH2Cl2 and gave
the trisilylated dithioacetal derivative 6b in 90% yield. Unmasking of the aldehydic group was effected
as above in excellent yield with HgCl2 and HgO in aqueous acetone and gave 7b in 93% yield. The
presence of the acid-sensitive silyl protecting groups precluded the use of the Jones reagent on 7b but
oxidation to the carboxylic acid 8b could be accomplished in 83% yield with buffered KMnO4 in aqueous
t-BuOH.14 In this case, formation of the acid chloride 9b from 8b proceeded cleanly with oxalyl chloride
and pyridine in CH2Cl2.15
Ketone 38 was treated at room temperature with 1.3 equiv. of crude 9b and 5 equiv. of samarium
diiodide in tetrahydropyran16 to give the expected coupling products in 63% yield (based on 3) and in an
8:1 diastereoisomeric ratio8,17 (Scheme 2). Reduction of the keto group of the major equatorial isomer
11 was done in chelating conditions18 with sodium borohydride in methanol at 0°C and was very slow;
some starting material was still present after 24 hours at room temperature but a mixture of the 5S alcohol
12 and its 5R epimer was obtained in 73% isolated yield.
Due to the higher reaction temperature, the observed diastereoselectivity of the reduction was 5 to
1 in favor of the desired alcohol 12, which is somewhat lower than our previous results on related
compounds.8 The silyl ethers were removed with dilute HCl in aqueous methanol and gave methyl α-

51
Scheme 2. (a) 1 equiv. 3, 1.3 equiv. 9b, 5 equiv. SmI2, THP, rt, 10 min, 63%, 8/1. (b) NaBH4, MeOH, rt, 24 h, 73% and 10%
recovered 11. (c) HCl, MeOH/water, rt, 3 h, 77%. (d) Ac2O, pyridine, 80°C, 30 min, 82%
D-caryophylloside 219 in 77% yield which was fully characterized as the pentaacetylated derivative 13.
Comparison of the spectral data for 2 and 13 with the natural product derivatives4 showed their identity.
Finally, methyl yersiniosides A and B1,2 were also synthesized in good yields from the reaction of
ketone 3 and acetyl chloride with SmI2 (Scheme 3). Reduction of ketone 14 (obtained in 79% yield
and 13:1 diastereoselectivity) with NaBH4 under chelating conditions as above gave 15 with the 5S
configuration (75%, 7:1). This compound was deprotected with acidic aqueous methanol to methyl
yersinioside A 16.1 The other diastereoisomer with the 5R configuration was also synthesized from 14
after trimethylsilyl protection of the tertiary C-4 hydroxyl group of 14 and Red-Al® reduction of the
TMS ether 17.17 Compound 18 was obtained as a single diastereoisomer in 78% yield. Acid hydrolysis
of the silyl ether gave methyl yersinioside B 192 (69%).
Scheme 3. (a) 1 equiv. 3, 3 equiv. AcCl, 3 equiv. SmI2, THP, rt, 15 min, 79%, 13/1. (b) NaBH4, MeOH, 0°C, 20 min, 75%, 7/1.
(c) HCl, MeOH. (d) TMSOTf, pyridine, CH2Cl2, 0°C, 3 h, 67%. (e) Red-Al®, toluene, 0°C, 4 h, 78%
In conclusion, a short and convergent synthesis of the complex sugar caryophyllose from readily
available precursors was devised. The diiodosamarium-promoted coupling reaction of a ketone with an
acid chloride proved to be very valuable for the rapid and efficient synthesis of various C-4 branched
sugars8 and should be generally applicable in complex natural products synthesis.

52
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19. Selected data for 2. [α]D20=+56 (c 0.82, water). 1H NMR (CD3OD) δ 4.68 (d, 1H, J 3.5 Hz, H-1); 4.24 (q, 1H, J 6.5 Hz,
H-10); 4.05 (m, 1H, H-2); 4.00–3.86 (m, 2H, H-7, H-9); 3.82 (dd, 1H, J 4.0, 5.0 Hz, H-5); 3.50 (s, 3H, OCH3); 3.49 (m, 1H,
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34.15, 32.72, 18.91, 13.75. 13. [α]D20=+49 (c 0.88, chloroform). 1H NMR (C6D6) δ 5.53 (dd, 1H, J 6.5, 3.5 Hz, H-8); 5.37
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2.5 Hz, H-6); 2.39 (dd, J 12.5 Hz, H-3ax); 2.09 (ddd, 1H, J 14.5, 11.5, 2.5 Hz, H-6); 2.04 (dd, 1H, J 12.5, 6.0 Hz, H-3eq);
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δ 96.21, 74.15, 73.59, 70.03, 68.23, 67.70, 67.51, 66.06, 55.38, 29.63, 27.44, 16.26, 13.34. Anal. calcd for C23H36O13: C,
53.07; H, 6.97. Found: C, 53.31; H, 6.87.