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Cyclohexane-1 2-diacetals (CDA) A New Protecting Group for Vicinal Diols in Carbohydrates.

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Cyclohexane-l,2-diacetals(CDA): A New
Protecting Group for Vicinal Diols in
Carbohydrates
The required 1, I .2,2-tetramethoxycyclohexane (4) was readily obtained in 75 '$6 yield from inexpensive 2,2-cyclohexanedione by reaction with trimethyl orthoformate in methanol containing a few drops of conc. H,S04 (Scheme 3). In the initial
Steven V. Ley,* Henning W. M. Priepke, and
Stuart L. Warriner
Recently we introduced the dispiroketal protecting group
(Dispoke) as a selective protective group for diequatorial 1.2diol units in carbohydrates (Scheme
The regio- and
diastereoselectivity of the reaction of 3,3'.4,4'-tetrahydro-6,6'bi-2H-pyran (bis-DHP, 1 ) with pyranosides such as 2 arises
2
1
Scheme 1 . Only the i-elebant portioii of tlie pyranoside is shown.
from the stabilizing influence of the four anomeric effects in the
resulting dispiroketal 3 and the equatorial arrangement of all
four alkyl substituents of the central 1.4-dioxane unit. Although
we observed the exclusive formation of only one isomer with
many carbohydrates, the results with important mrmno-type
sugars were less satisfactory. The low yields and the lack of
regioselectivity were attributed to the low solubility of these
compounds in chloroform and the instability of 1 when heated
over prolonged periods of time.[31
To develop the general concept further, we considered the use
of 1 .I ,2,2-tetramethoxycyclohexane (4) as a new alternative
reagent for carbohydrate protection (Scheme 2). Reaction of 4
OMe
OMe
4
2
Scheme 7. Only the relevanl portion of the pyranoside
5
IS
shown
with 2 should furnish selectively the cyclohexane-l,2-diacetal5
where all the regulatory elements mentioned above should govern the outcome of the reaction. In the product 5 both methoxy
groups should be oriented in the axial position to obtain the
maximum anomeric stabilization, while all four sterically demanding alkyl substituents should be placed in the favored
equatorial positions. To overcome the solubility problem we
chose methanol, a solvent frequently used for acetalizations of
carbohydrate^.[^] With this solvent the diacetal 5 should be
formed under thermodynamically controlled conditions.
I*] Prof. Dr. S. V. Ley, Dr. H. W. M . Pricpke,
('$1
S. 1.Warriner
Department o f Cheinisri-y. University of Cambridge
Lenhfield Road. Cainbi-idgc CB7 1EW ( U K )
Telefax: hit. code + (123)116-442
C'yclohex;ine~l.7-diitcctnl~
in Synthesis, Part I . Weare grateful to Dr. P. Raitlib>. C'ambridye. for the X-ray structure determination and Dr. M. Thompson.
SniithKline Beccharn. for helpful discussions. This work was supported by
Schering Agrochemiciils Ltd (Schering Fellowship of €310-Organic Chemistrq
for H.W.M.P ). SniithKlinc Beecham(Research Studentshipfor S.L.W).Pfirer
Central Research. and [he BP Research Endonment.
6
c
Scheme 3. Synthesis of 4 and protection or methyl r-L-mannoside: a) MeOH.
CH(OMe),, cat. H2S0,. reflux. 7 5 % : b)4. MeOH. CH(OMe),, reflux, cat. CSA.
48% 6 and 11 YO7: c ) Ac20. pyridine. 97%.
experiment methyl a-D-mannoside was investigated. as this substrate failed to react under the standard dispoke reaction conditions (bis-DHP 1, CHCl,, ( +)-camphorsulfonic acid (CSA)) .I2]
By using 1.4 equivalents of 4 in boiling methanol with a trace of
trimethyl orthoforinate and a catalytic amount of CSA, the
acetalization reaction proceeded smoothly to give the 3,4-protected sugar 6 as the major reaction product in 48% yield.
Purification of 6 was achieved by recrystallization from diethyl
ether, and its structure was unambiguously assigned by X-ray
cry~tallography.~~'
Protection of the cis-2.3-diol unit occurred
only to a minor extent. Interestingly the major side product[''
was the 1.3-dioxolane 7 . Its structure was deduced from the
significant downfield shift of the signal of one of the acetal
carbons in the 13CN M R spectra (6 = Z 11.25 and 101.40 in 7 vs.
98.77 and 99.22 in 6)."] To confirm the assigned structure, 7 was
converted into the acetate 8, which showed the expected downfield shift for the H-4 signal (H-4: 6 = 4.41 in 7 , 6 = 5.02 in 8).
Moreover its ' H N M R spectra is very similar (Ad < 0.03,
AJ < 0.6 Hz) to that of the isopropylidene analogue.[']
To improve the yield of 6 the dioxolane 7 was treated in
boiling methanol with a trace of CSA. After four days 6 was
obtained in 35 YOyield and recovered 7 in 16 '$60 yield. This result
suggests that the acetalization reaction is reversible and that the
isomer ratio i s governed by thermodynamic control under the
prolonged reaction time.
Next, we converted other pyranosides into the corresponding
diacetals. Table 1 summarizes these results and compares them
with the related dispoke protection.", 2 . 9 . 'I We were able to
transform ethyl 1-thio-x-D-mannopyraiioside in good selectivity
and yield into the crystalline 3,4-protected adduct 9 and small
amounts of its isomer 10. Methyl 2-L-rhamnopyranoside, which
gave a disappointing 3: 2 mixture with dispoke protection,"'
was also converted in high yield into diacetal 11. Again the
3.4-protected derivative 11 could be easily separated from re-
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E t h l e 1 S\nthesis o f slmnle CDA- and DisDoke-Drotected pvranosides
Sugiir
**
CDA Protection
3.Cprotected
H:w
HO
Dispokc Protection
3,4
2.1
2.3-protected
48%
OMe
OM0
OMe
7
10 %
Pal
36 ?o
8%
41Yo
32?h
1 1 0%
62 3'%
0 !I
46 V o
0"
16?,,
50%
[dl
26 Yo
SEI
10
9
..-?
OMe
OH
&*
OMe
OMe
I
OH
14%
12
I1
"
bl
6Me
Me0
14
13
&
NI
O
H
OM0
42'!
0
16
[a] Confaininated w i t h minor amount5 of other isomers. [b] Other minor products were formed but not readily identified. [c] A multitude of products uerc evident but wcrc
not isolated. [d] An in\eparable mixture of 16 and 17 &;is obtained.
gioisomers by a combination of chromatography and crystallization. With methyl r-D-lyxopyranoside we obtained the 3.4adduct 13 in 45 YOyield along with dioxolane 14 in 11 % yield.
This is the only case in the series of sugars with an axially
oriented 2-hydroxyl group where bis-DHP 1 gives better selectivity and yield than diacetal 4."]
Next. we tried to protect methyl r-D-galactopyranoside which
could be converted regioselectively by the dispoke methodology.[21Disappointingly, we could see many more side products by
thin-layer chromatography than usual. This may have resulted
from epimerization at the anomeric center. However, we were
able to isolate the trans-protected adduct 15 in 46% yield, although here the separation from other isomers was rather difficult. The use of other solvents (acetonitrile, dimethylformamidc. CHCI,) neither improved the yield nor the selectivity of
the reaction. We observed the same difficulties for the corresponding arabino- and fucopyranosides." ' I Apparently CDA
protection is superior in the nzcmno-configurated pyranosides,
while dispoke protection is the method of choice for sugars
having the g~zlac.10ring configuration. The methods are thcrefore complementary.
We also converted methyl a-n-glucopyranoside into an inseparable 3 : 5 mixture of the corresponding 3,4- and 2J-protected
sugars 16 and 17 in 80% yield. Although we could not improve
the selectivity for either of the two tr(i17.sdiol units, the yield was
higher compared to the dispoke protection.[']
The usefulness of a protecting group is highly dependent on
the ease with which it is removed at the end of ii synthetic
sequence. Therefore the compatibility of the CDA unit was investigated with some protection/deprotection conditions. We
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could easily convert 6 in high yield into the corresponding
dibenzoate 18 or the dibenzvl ether 19 using standard conditions
(Scheme 4)' Finally'
Of the CDA moiety was achieved
by treatment with aqueous trifluoroacetic acid (TFA). A 1 9 : l
TFA: H,O mixture removed the cyclohexane diacetal group of
18 in 20 min to furnish 20 in -96% yield,["] while a *4:6
TFA:H,O mixture smoothly converted 19 into 21 in 16 h.
[31 Improvements to our original procedure for these derivatives can be achieved
by using ultrasound to enhance the solubility. R. Leslie. S. V. Ley. unpublished
v
results.
[4] A. Klausener. MPrhorlen Org. Chew. fHouheri- Wry/, , 4th ed 1952-, Bd. E14a:
1. 1991. .pp.
. 100 l l l a n d 167.
[5] Further details of the crystal structure investigation are available on
requeqt from the Director of the Cambridge Crystallographic Data
Centre. 12 Union Road. GB-Cambridge. CB2 I E Z (UK), on quoting the fiill journal citation.
161 Other isomers were also isolated but only in very
minor amounts. The spectral data of all isolated isomers usill be published in due course.
[7] J. G. Buchanan. M. E. Chacon-Fuertes. A. R.
c
HO
Edgar. S. J. Moorhouse. D. I. Rawson, R. H.
Wightman. Tcrruhedroii Lt'ri. 1980. 31. 1793 1796.
[XI M.E. Evans, F. W Parrish. C'urhohydr. Rcs. 1977.
OM9
OMe
OMe
54. 105-114.
10
20
[9] A. B. Hughes. S. V. Ley. H. W M. Priepke. M.
Woods. 7 h u h e c l r o n Lcrt. 1994. 3 i , 773-777.
[lo] All neu compounds gave satisfactory spectroscopic
and analytical data.
[ I I ] S. V. L K ~H.
. W. M . Priepke. S L. Warriner. unpublished results.
OMe 19
OMe
2,
OMe
[I21 For a "one-pot" preparation of ii-oct)l 2.6-di-hen~oyl-r-i,-mannopyranosidein 32% yield. see S. OaScheme 4. Derivatiation and demoteetion of 6. a ) BzCI. mridine. 94%. b) NaH. DMF. BnBr. iiBu,NI.
carson. A,-K. Tiden. Corhoh,-dr. Rrs. 1993, 247.
78%: c ) T F A : H 2 0 1 9 : l , 20min.-96%; d ) T F A , H , O 4 : 6 . i h h . 8 6 % .
323 -328.
[I31 V. Pozsgay. J:R. Brisson. H. J. Jennings. Cun. J
Chern 1987. 65. 2764-2769.
The new CDA methodology is a versatile procedure for the
[14] G:J. Boons. P.Grice, R. Leslie. S. V. Ley, L. L. Yeung. Tciruheriron L e t t . 1993,
34. x523-8527.
protection of diequatorial 1,2-diols especially in mani7o-type
1151 S. V. Ley. H. W. M. Pncpke. Aiigm'. C ' l r m 1994, 106, 2412: Angrit.. Chorr. ini.
sugars where t-egioselective introduction of 3,4-protection is
Ed. €ng/. 1994. 33. 2292.
-;
q
rather difficult. For rhamnosides this was, until now, only accessible by a four-step sequence." 31 Furthermore, the CDA unit
induces a conformational rigidity into the sugar ring which, by
analogy to our findings with dispoke derivative^."^] should
modify the reactivity of a potential glycosyl donor leaving
group. The behavior of CDA-protected sugars in glycosylations
is described in the following paper.["'
E.~peritnentcdProcedure
1.1.2.2-tctr.amethoxycyclohexanc (4): Conc. sulfuric acid (8drops) was added to a
stirred solution of 1.2-cyclohexanedione (11.2 g, 0.10 mmol) in methanol ( 1 5 mL)
and trimethyl orthoformate (30 mL). The resulting black solution was refluxed for
16 h and then neutralired with sodium bicarbonate (ca.1 g) After evaporation of
the solvent, the crude material was purified by column chromatography on silica gel
(Merck 0 3 8 5 ) to furnish 4 as colorless liquid (15.3 g. 7 5 % , ) . ' H N M R (CDCI,.
200 MHL): IS =1.?1-1 48 (m. 4 H ) . 1.60-1.75 (in.4 H ) . 3.32 (s, I l H ) : " C NMR
(CDCI,. 5 0 M H r ) : 17 = 21.67, 30.61. 49.25. 102.07.
Tipicui urr,tu/rzorion. Preparation o f 6 and 7: CSA (308 mg. 1.33 mmol) was addedto a stirred solution of methyl z-u-maniiopyranoside(3.46 g. I 7 8 mmolt. 4 (4 60 g.
24.4 mmol) and trimethyl orthoformate (2.0 mL) in dry methanol (25 m L ) . and the
mixtiire w a s heated under retlux lor 16 h. After neutralization with NaHCO, (ca.
0.5 g). the solvent w a s removed in vacuo. and the crude material was purified b)
column chi-omatography o n silica gel (Merck 9385) to furnish 7 (666 my. 1 1 %) as
an off-white foam and slightly impure 6. which %'as furthei- purified by slot%crystallization froin diethyl ether to give clean 6 (2.83 g, 48%). 6: [4X'= 191 ((, = 0.94,
CHCI,); n1.p. 168 ' C ( E t 2 0 ) .' H NMR(CDCI,.400 MHz): 4 =1.29 1.43(m. 2 H ) .
1.45 1 55 ( m . 2 H ) . 1.62-1 82 (m. 4 H ) . 2.25 (br t. J = 5 8 Hz. 1 H ) , 2.89 (s, 1 H).
A Facile One-Pot Synthesis of a Trisaccharide
Unit from the Common Polysaccharide Antigen
of Group B Streptococci Using Cyclohexane1 ,Zdiacetal (CDA) Protected Rhamnosides**
Steven V. Ley* and Henning W. M. Priepke
In the previous paper"] we introduced the use of cyclohexane-1,2-diacetals (CDA) in a new one-step procedure for the
regioselective protection of the 3,4-hydroxyl groups of rhamnosides and mannosides. We will show here that the CDA protecting group is also able to tune the reactivity of a glycosyl
donor in glycosylation reactions.
The important armed/disarmed concept introduced by
Fraser-Reid et al. has proven to be a powerful tool in the concise
preparation of complex oligosaccharides.[21It relies upon the
+
fact that the reactivity of a glycosyl donor can be regulated by
the
flanking protecting group at C-2 owing to stereoelectronic
3.20(s.3H).3.21(s.3H).3.35(s.3H).3.72-?.86(iii.3H).3.92(hr.s.IH).4.14
effects (e.g., ether = armed, ester = disarmed). According to
(dd,J=10.6.2.9H~.1H).4.25(dd,J=2x10.0H~,1H).4.72(d..J=0.9Hz,lH).
Fraser-Reid et al.,[31a sugar can be also considered to be dis" C NMR (CDCI,. 100 M H r ) : 6 = 21.35 (2 x ) , 27.00 (2 x ) . 46.79. 46.93. 54.XX.
61.41,63.XX. 65.84. 68.83. 70.05, 70.72. 98.77. 99.22. 101.21. 7: [r];' = +19.8
armed in glycosylation reactions when a cyclic acetal group is
( c , = 0.89. CHCI,): ' H NMR (CDCI,. 400 MHL): 6 =1.37-1.87 (ni. XH). 2.17
attached to the pyranose ring. In this case, the formation of the
(brt. J = 6.2 Hr. 1 H ) . 2.74 (d. J = 5.0 Hr, 1 H ) . 3.27 ( s . 3 H ) . 3.32 (s. 3 HI. 3.40 ( 8 .
intermediate cyclic oxocarbenium ion is more difficult because
3H).3.64iddd. J = 8.4. J = 2 ~ 4 . HZ.
2 1 H). 3.72 (ddd. J = 8.3, 6.5. 5.3 Hz. 1 H ) .
the required ring flattening in the pyranose ring is inhibited by
3.80-3.86(m, 2H).4.30(dd. J = 2 x 6 . 4 Hr. 1 H).4.41 (d. J = 6.3 Hr. 1 H).4.8X(s.
I H): ''C N M R (CDCI,, 100 MHz): 6 = 21.59. 22.89. 30 71. 35.68. 49.13, 49.9X.
the annulated acetal function.
55.23.6?.89,69.56.70.17. 78.37.98.92, 101.40. I l l 25.
Received: June 7. 1994 [Z 7006 IE]
German version: Ang<w. Chew. 1994. 106. 2410
111 S. V. Le), R. Lcsllr. P. D. Tiftin. M. Woods. l?,ti-nhm/ronLerr. 1992. 33, 47674770.
[2] S. V. Ley. G.-J Boons. R. Leslie. M. Woods. D. M. Hollinshead. Swrh(>\i.\
1993. 689 692.
2292
('
VCH l'~ririg.\~r.sr~/l,scliu{/
m h H , 0-094.53 Wt,rriheriii, lYY4
[*I
[**I
Prof. Dr. S. V. Ley. Dr. H. W. M. Priepke
Department of Chemistry, University of Cambridge
Lensfield Road. Cambridge CB? 1EW ( U K )
Tclrfax: Int. code + (223)336-442
Cyclohexane-1.2-di'icet~ils in S y n t h e k Part 2 This work w a s supported by
Schering Agrochemicals Ltd (Schering Fellowship in Bio-Organic Chemistry
for H.W.M.P.). Pfiier Central Rewirch. and the BP Research Endowment.
Part 1 : [I].
S 10.00 + .2XO
057U-U833:94:22~2-22Y2
A n g r n . Cliern. h
r.
En'. En,q/. 1994, 33. N o . 22
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