Synthesis of caryophyllose. Use of n-BuLi/Na-O-t-Bu in the coupling of highly functionalized ketones and dithioacetals

Article abstract of DOI:10.1016/S0040-4039(00)00752-8

The C-4 branched monosaccharide caryophyllose 2a was synthesized by, convergent approach relying on the coupling of metalated dithioacetal 4b with ketone 3. Combined use of n-BuLi and t-Bu-ONa as deprotonation system for 4b turned out to be decisive for the success of this coupling. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00752-8

Tetrahedron Letters 41 (2000) 4981±4985
Synthesis of caryophyllose. Use of n-BuLi/Na-O-t-Bu in the
coupling of highly functionalized ketones and dithioacetals
Matteo Adinol®, Gaspare Barone, Pasquale Festa, Luigi Guariniello
and Alfonso Iadonisi*
Á
Dipartimento di Chimica Organica e Biologica, Universita degli Studi di Napoli Federico II, Via Mezzocannone 16,
I-80134 Napoli, Italy
Received 15 March 2000; accepted 8 May 2000
Abstract
The C-4 branched monosaccharide caryophyllose 2a was synthesized by a convergent approach relying
on the coupling of metalated dithioacetal 4b with ketone 3. Combined use of n-BuLi and t-Bu-ONa as
deprotonation system for 4b turned out to be decisive for the success of this coupling. # 2000 Elsevier
Science Ltd. All rights reserved.
Caryose 1 and caryophyllose 2a are two structurally peculiar monosaccharides isolated1 3 from
the phitopathogenic bacterium Pseudomonas caryophylli as components of cell wall lipopoly-
saccharides. We have recently reported4 the ®rst total synthesis of caryose, a unique example of a
carbocyclic monosaccharide to date. In this paper we report the synthesis of caryophyllose, one
of the few members in the family of C-4 branched monosaccharides. Recently, Prandi et al.5 have
reported the synthesis of various natural and unnatural C-4 branched monosaccharides possessing
a functionalized seven-carbon side chain. For this purpose the attachment of the side chain onto
the pyranoid ring was performed elegantly by SmI2-mediated addition of a suitably functionalized
acyl chloride to ketone 3 in tetrahydropyran. During the preparation of this manuscript the use
of this strategy for the ®rst synthesis of methyl a-caryophylloside 2b using acyl chloride 4a was
reported.6 Herein, we propose an ecient alternative approach for the synthesis of caryophyllose
relying on the coupling of the metalated dithioacetal 4b with ketone 3. This approach could be
attractive in view of the easier manipulation of the branching precursor as well as its high yielding
and ready preparation (two steps from commercially available d-digitoxose). In Prandi's synthesis
compound 4a was prepared from d-digitoxose through 4c, the silylated analogue of 4b.
* Corresponding author. Fax: +39 0815521217; e-mail: iadonisi@unina.it
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00752-8

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Utilization of lithiated dithioacetals (more commonly, 1,3-dithianes) as nucleophiles in organic
transformations is well known.7 However, the exploitation of this chemistry has often been
plagued in the case of functionalized substrates by the low yielding or even ine€ective initial
deprotonation with alkyl-lithium bases.8,9 In our hands any attempted deprotonation of 4b with
n-BuLi failed, even at rt,8 as shown by the lack of deuterium incorporation at C-1 after D2O
quenching. However Lipshutz has demonstrated9 that partially or fully protected hydroxylated
dithianes can be quantitatively metalated by combined use of n-BuLi and t-Bu-ONa. Under this
protocol, the coupling step between the caryophyllose building blocks 4b5 and 3 was performed
(Scheme 1) to provide the desired adduct 5a together with minor amounts of epimer 6 (60% yield,
1
5a:6, 3.5:1).10 The con®guration at the position 4 of these compounds was inferred by H NMR
analysis, which showed that the bulky appendage was equatorially oriented in both 5a and 6,
which possess a 4C1 and a 1C4 conformation of the ring, respectively. In fact, the spectrum of the
major product displayed a trans-diaxial relationship between one H-3 proton and the H-2 proton
(J2ax,3ax=11.0 Hz). On the other hand, the spectrum of the minor epimer 6 did not display any
trans-diaxial relationship for the H-2 proton, as shown by the small values (<4 Hz) of both J2,3
constants. In addition, a long-range W-coupling (<2 Hz) between H-11 and one H-3 proton of
the minor compound was observed. The expected stereochemistry of the major product has been
also con®rmed unambiguously on a later intermediate of the synthesis (see below).
After the key coupling step, hydrolysis of the dithioketal function was attempted by exposure
of 5a to HgO/HgCl2 in several aqueous solvents (MeOH, MeCN, Me2CO) but in all cases
predominant formation of thioenol ether 8a [undetermined double-bond con®guration; 1H NMR
(CDCl3): ꢀ 5.06 (d, J6,7=8.1 Hz, 6-H); 13C NMR (CDCl3): ꢀ 145.4 (C-5), 125.3 (C-6)] was
observed besides minor amounts of the desired ketone 7a [13C NMR (CDCl3) : ꢀ 209.8 (5-CˆO)].
This unfavourable outcome, not unusual for other desulfurization systems,12 was mainly ascribed
to the low solubility of 5a in mixtures containing amounts of water higher than 5%. This
consideration led us to remove, before the hydrolytic step, the apolar silyl protecting group (1.5
eq. TBAF in THF, room temperature, 8 h, 90% yield) to obtain 5b. Exposure of 5b to HgO/
HgCl2 in 9:1 MeCN:H2O furnished ketone 7b [52% yield; 13C NMR (CDCl3): ꢀ 209.7 (5-CˆO)]
predominantly even though substantial amounts of the corresponding elimination product 8b [1H
NMR (CDCl3): ꢀ 5.05 (d, J6,7=8.1 Hz, 6-H); 13C NMR (CDCl3): ꢀ 144.8 (C-5), 125.0 (C-6)] were

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Scheme 1. (a) See Ref. 10; (b) TBAF (1.5 equiv.), THF, 8 h, rt, 90%; (c) HgCl2 (2 equiv.), 9:1 MeCN:H2O, 0.5 h, rt,
79% (7b) and 13% (8b); (d) NaBH4, MeOH, 0ꢀC, 2 h, 9a:9b 9:1, 66%; (e) 1:2 Me2C(OMe)2:Me2CO, Dowex-50WX8/
H+, 8 h, rt, >95%, (f) 9:1 MeOH:HCOOH, C/Pd, sonication, 2 h, 10ꢀC, >95%; (g) 0.125 M CF3COOH, 100ꢀC, 1.5 h,
>95%
again isolated (29% yield). However, when the reaction was performed in the same solvent
system but in the absence of the basic HgO, in order to minimize elimination to 8b, compounds
7b and 8b were obtained in 79 and 13% yields, respectively.
Compound 7b was reduced diastereoselectively with NaBH4 in MeOH at 0ꢀC. In contrast to
the corresponding persilylated intermediate of Prandi's synthesis, this reduction was not sluggish
on our substrate and proceeded with higher diastereoselectivity (66% yield; 9a:9b=9:1, in favour
1
of the desired epimer: H NMR (CDCl3): ꢀ 3.58, dd, J5,6a=10.2 Hz, J5,6b=1.2 Hz, 5-H). The
stereochemistry of this compound was con®rmed by 1H NMR NOESY analysis (see Fig. 1) of the
corresponding acetonide 9c (acetone:2,2-dimethoxypropane 2:1, Dowex 50WX8/H+, 8 h, >95%).
At this stage it should be noted that the choice of two di€erently protected building blocks 3 and
4b, initially dictated by considerations of preparative convenience, was bene®cial for the ®nal
purpose. As a matter of fact, selective removal of the protecting group from O-2 immediately
after the coupling step, in addition to the ecient hydrolysis of the dithioketal function, allowed
us to achieve high diastereoselectivity in the reduction step to 9a exploiting the chelation control
arising from the vicinal location of 5-CˆO and 4-OH. Preservation of protecting groups at O-7,
O-8 and O-9 avoided alternative and unpredictable chelation e€ects which could operate.
Finally, debenzylation of 9a a€orded almost quantitatively methyl a-caryophylloside 2b,1
whose conversion into the corresponding monose 2a was performed quantitatively by hydrolysis
with 0.125 M aqueous tri¯uoroacetic acid (100ꢀC, 1 h). Synthetic monose 2a was identical (TLC,
1H and 13C NMR) to the natural product.1,2

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Figure 1. Selected NOE contacts observed for 9c (NOESY, 400 MHz, CDCl3)
This paper highlights the notable synthetic potential of the coupling between a functionalized
dithioacetal and a functionalized ketone in the convergent assemblage of complex structures. In
this regard, use of the t-Bu-ONa/n-BuLi system was found to be crucial for the in situ generation
of a highly reactive carbanionic nucleophile from 4b.
Acknowledgements
Financial support by MURST (PRIN 1999±2000), CNR and Universita di Napoli (Progetto
Giovani Ricercatori 2000) is acknowledged. NMR spectra were performed at the `Centro di
Metodologie Chimico-Fisiche dell'Universita di Napoli'.
References
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10. n-BuLi [1.45 M in hexanes (determined by titration),11 550 mL, 0.80 mmol] is added at 0ꢀC to a suspension of t-Bu-
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dropwise in 10 min. The resulting dark red solution is left for 1 h at ^78ꢀC under stirring and then a solution of 3
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water. Removal of chloroform under reduced pressure and column chromatography (silica gel, hexane:ethyl
acetate, 95:5) a€ords unreacted 4b (253 mg), 6 (41 mg, 13% yield), and 5a (150 mg, 47% yield). Compound 5a: 1H
NMR (400 MHz, CDCl3) ꢀ ^0.08 and ^0.05 (6H, 2 s, -Si(CH3)2-t-Bu), 0.81 (9H, s, -Si(CH3)2C(CH3)3), 1.06 and
1.14 (6H, 2 t, J=7.4 Hz, 2Â-SCH2CH3), 1.34 (3H, d, J9,10=5.9 Hz, H-10), 1.43 (3H, d, J11,12=6.4 Hz, H-12), 2.1±2.25

4985
(3H, H-3ax, H-3eq and H-6a), 2.35±2.8 (5H, 2Â-SCH2CH3 and H-6b), 3.40 (3H, s, -OCH3), 3.65 (1H, dq, J8,9=7.2
Hz, H-9), 3.75 (1H, bd, H-8), 3.99 (1H, ddd, J1,2=3.7 Hz, J2,3ax=11.0 Hz, J2,3eq=5.7 Hz, H-2), 4.10 (1H, bs,
exchange with D2O, 4-OH), 4.34 (1H, q, H-11), 4.50 (2H, H-1 and H-8), 4.4±4.9 (6H, 3 ABq, 3x-O-CH2-Ph), 7.2±
7.5 (15H, 3Â-Ph). 13C NMR (CDCl3): ꢀ ^4.9 and ^4.6 (-Si(CH3)2-t-Bu), 13.3 and 13.8 (2Â-SCH2CH3), 16.7 and
17.5 (C-10 and C-12), 18.1 (-Si(CH3)2C(CH3)3), 22.6 (2Â-SCH2CH3), 25.9 (-Si(CH3)2C(CH3)3), 37.3 and 37.8 (C-3
and C-6), 67.4, 68.4, 75.2, 78.2, 82.9 (C-2, C-7, C-8, C-9, and C-11), 70.0 and 79.2 (C-4 and C-5), 70.6, 71.4 and
73.9 (3Â-OCH2Ph), 99.1 (C-1), 127.2±128.5 (aromatic CH), 134.5±138.3 (quaternary aromatic carbons).
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