Triol protection with 6-benzoyl-3,4-dihydro-(2H)-pyran

Article abstract of DOI:10.1039/b418035f

6-Benzoyl-3,4-dihydro-(2H)-pyran will protect 1,2,3-triols such as glycerol as their corresponding spiro-[5-phenyl-3,6,8-trioxabicyclo[3.2.1]octane-4, 2′-tetrahydropyran]s and 1,2,4-triols (less efficiently) as the corresponding trioxabicyclo[3.2.2]nonane

Full text of DOI:10.1039/b418035f

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COMMUNICATION
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Triol protection with 6-benzoyl-3,4-dihydro-(2H)-pyran{
Caroline D. L. Baker,a John Fawcett,b Christopher D. Insley,a Derek S. Messenger,a Claire L. Newland,a
Helen L. Overend,a Anup B. Patel,a Mufakhrul Shah,a Bhavna Vara,a Davinder Virdeea and
Bernard J. Rawlings*a
Received (in Cambridge, UK) 30th November 2004, Accepted 8th February 2005
First published as an Advance Article on the web 17th February 2005
DOI: 10.1039/b418035f
tuning effect between that of the corresponding benzylated and
benzoylated systems.5
6-Benzoyl-3,4-dihydro-(2H)-pyran will protect 1,2,3-triols such
as glycerol as their corresponding spiro-[5-phenyl-3,6,8-triox-
abicyclo[3.2.1]octane-4,29-tetrahydropyran]s and 1,2,4-triols
(less efficiently) as the corresponding trioxabicyclo[3.2.2]no-
nanes; the hexol mannitol is converted into the corresponding
bis-protected product.
In contrast to that of diols, the protection of triols has been
neglected. In this paper, we combine the protecting capability of
dihydropyran and a carbonyl group in a single molecule to
protect triols.
6-Benzoyl-3,4-dihydro-(2H)-pyran 1 can be conveniently pre-
pared in large multigramme quantities.6 Addition of tert-butyl
lithium (34 mmol) to 3,4-dihydro-(2H)-pyran (33 mmol) at 220 uC
forms the vinyl anion. Cooling to 278 uC followed by addition of
N,N-dimethylbenzamide (31 mmol) and warming to room
temperature gave a crude product (.95% pure) that was adequate
for subsequent reactions, and could be kept in the fridge for weeks.
Initial experiments involved the reaction of 1 with glycerol and
camphorsulfonic acid (CSA) in toluene under Dean and Stark
conditions which gave two products, the expected trioxabicyclo-
Ketones (or gem-dimethoxyalkanes) can react with 1,2 or 1,3-diols
with acid catalysis to form acetals, and dihydropyrans react with
alcohols under similar conditions to form tetrahydropyrans. Ley
and co-workers recently introduced bis-dihydropyrans to protect a
wide range of 1,2-diols as their dispiroketals, the products being
formed were those with maximum anomeric stabilisation at newly
formed centres.1 The Ley group has exploited the rigid architecture
of these ‘bispoke’ derivatives in subsequent asymmetric reactions,2
and exploited the bispoke derivatives of vicinal equatorial
carbohydrate diols to tune glycoside reactivity.3 Ley and co-
workers have also developed 1,2-diketones (as 1,1,2,2-
tetramethoxy derivatives) as 1,2-diol protecting groups, forming
in acidic methanol the corresponding 2,3-dimethoxy-1,4-dioxane.4
Reaction with glycerol gave triol protection resulting in 2-meth-
oxy-3,7,8-trioxabicyclo[3.2.1]octane. Reaction with vicinal equa-
torial carbohydrate diols resulted in a glycosidation reactivity
[3.2.1]octane 2,7 and
a second compound whose spectral
characteristics were consistent with a 2,5,7-trioxabicyclo[2,2,2]-
octane. However reaction of glycerol (2.7 mmol), CSA (5.5 mmol),
trimethylorthoformate (5.5 mmol) and 1 (5.5 mmol) in refluxing
(12 h) methanol (‘orthoformate’ conditions) rapidly formed a
single
racemic
crystalline
triol
protected
product
(1R,4(29)S,5S)-spiro[5-phenyl-3,6,8-trioxabicyclo[3.2.1]octane-4,29-
tetrahydropyran] 2 in good yield (42%) (Scheme 1). In the product,
2, the tetrahydropyranyl oxygen is axial relative to the 1,4-dioxane
chair due to the anomeric effect, as shown in the X-ray structure
(Fig. 1). Refluxing 2 in aqueous acid led to the recovery of 1.
{ Electronic supplementary information (ESI) available: experimental and
X-ray diffraction data. See http://www.rsc.org/suppdata/cc/b4/b418035f/
*bjr2@le.ac.uk
Scheme 1 Reaction of 6-benzoyl-3,4-dihydro-(2H)-pyran with trihydroxy-containing compounds in refluxing methanol containing trimethylorthofor-
mate and catalytic camphorsulfonic acid (with yields). (i) Glycerol (42%), (ii ) racemic butane-1,2,4-triol (6.5%), (iii) erythritol (68%), (iv) xylitol (5 + 6 37%),
(v) d-gluconolactone (48%), (vi) mannitol (39%), and (vii) 1,1,1-tris(hydroxymethyl)ethane (5%).
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Fig. 1 X-Ray structure of 2.
Reaction of 1 with 1,2,4-butantriol under ‘orthoformate’
conditions led to the isolation of crystalline racemic-
(1R,5R,8(29)R)-spiro[1-phenyl-2,7,9-trioxabicyclo[3.3.1]nonane-
8,29-tetrahydropyran] 3 in low yield (6%) (Scheme 1, Fig. 2).
Reaction with meso-erythritol under orthoformate conditions
gave one major racemic product 4 which was readily separable by
flash chromatography from a second minor isomer. Derivatisation
of the major isomer to the 4-nitrobenzoate and analysis by X-ray
crystallography showed that the remaining hydroxymethyl
group was attached to C-2. This equatorial hydroxymethyl
group could be converted into the corresponding bromide
(PPh3, CBr4), or oxidised (Swern conditions) to the aldehyde
and reacted with Grignard or Wittig reagents, or the
alcohol converted into an alkene in one pot using manganese
dioxide and the Wittig reagent.8 Refluxing 4 in water–THF with
Fig. 3 X-Ray structure of 8.
CSA led to the recovery of erythritol (as the tetraacetate) in
75% yield.
Reaction of
1 with the meso-pentol xylitol under the
orthoformate conditions gave two isomeric products 5 and 6.
Derivatisation of the isomer 6 to the bis-4-nitrobenzoate followed
by X-ray crystallography showed that 6 had the residual 1,2-
dihydroxyethyl group attached to C-7.
X-Ray analysis of the bis-4-nitrobenzoate derivative of 7
showed that reaction of 1 with d-gluconolactone gave methoxy-
carbonyl 7, where reaction had occurred on the three terminal
hydroxyl groups of the open chain form.
The reaction with D-(+)-mannitol under ‘orthoformate’ condi-
tions gave the fully protected highly crystalline product 8 in 40%
yield (Fig. 3).
Reaction with the 5-epimer of mannitol, D-sorbitol, gave a
complex mixture, as did reactions attempted with molecules
only containing secondary alcohols. However, reaction with 1,1,1-
tris(hydroxymethyl)ethane gave
a
product (5%) whose
spectral characteristics were consistent with the expected
trioxabicyclo[3.2.2]nonane 9.
In these preliminary studies, a convenient procedure for the
protection of triols has been developed, that should prove valuable
in synthesis of highly functionalised polyhydroxylated natural
products, desymmetrisation of meso-polyols and the synthesis of
isotopically labelled compounds.
Caroline D. L. Baker,a John Fawcett,b Christopher D. Insley,a
Derek S. Messenger,a Claire L. Newland,a Helen L. Overend,a
Anup B. Patel,a Mufakhrul Shah,a Bhavna Vara,a Davinder Virdeea and
Bernard J. Rawlings*a
aDepartment of Chemistry, University of Leicester, University Road,
Leicester, UK LE1 7RH. E-mail: bjr2@le.ac.uk;
Fax: +44 (0)116 252 3789; Tel: +44 (0)116 252 2093
bCrystallography Section, Department of Chemistry, University of
Leicester, University Road, Leicester, UK LE1 7RH
Fig. 2 X-Ray structure of 3.
1884 | Chem. Commun., 2005, 1883–1885
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Notes and references
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7 A 3,6,8-trioxabicyclo[3.2.1]octane has been reported previously:
P. Calinaud and J. Gelas, Can. J. Chem., 1978, 56, 2292.
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