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The Selective Blocking of trans-Diequatorial Vicinal Diols; Applications in the Synthesis of Chiral Building Blocks and Complex Sugars.

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HIGHLIGHTS
The Selective Blocking of trans-Diequatorial, Vicinal Diols ; Applications in the
Synthesis of Chiral Building Blocks and Complex Sugars
Thomas Ziegler”
For efficient chemical synthesis of complex oligosaccharides,
protecting group strategies and blocking techniques are of overriding significance. It is usually unavoidable first to prepare
protected smaller saccharide units that enable a directed selective formation of the glycosidic bond and sequential construction of larger saccharides. To this end all functional groups with
the exception of the projected reaction center in the saccharide
building block to be glycosylated (the glycosyl acceptor) must,
as a rule, be protected, and only in particularly favorable cases
can partially protected glycosyl acceptors be used for regioselective glycosylation. In the glycosyl donor, the saccharide building
block that must be linked to the glycosyl acceptor, the protecting groups must be very precisely tuned to the planned glycosylation method. Both the reactivity of glycosyl donor and glycosyl acceptor and the anomeric selectivity of the glycosylation
step is dominated by the protecting groups. The search for novel
protecting group strategies is therefore as urgent for the carbohydrate chemist as the need for useful glycosylation methods.
Of the classical protecting groups of esters, ethers, and acetals
that are favored in saccharide synthesis, the benzylidene and
isopropylidene protecting groups have particular significance,
because both open the possibility of blocking two hydroxyl
functions in a monosaccharide simultaneously and selectively.
As the example of methyl-r-D-galactopyranoside in Scheme 1
illustrates, benzylidene acetals can be the major product from
1,3-diols, so that in the protected galactose derivative 1 the
hydroxyl functions of positions 2 and 3 are available for further
reaction. In contrast. isopropylidene acetals can be selectively
prepared from vicinal cis-diols, with the result that in the example 2 chosen here the hydroxyl functions of positions 2 and
6 remain free.“] Although isopropylidene acetals can also be
synthesized from monosaccharides with vicinal trans-diequatorial diols, these acetals are usually so acid-labile that they are
difficult to handle and are therefore less suitable for glycosylation reactions.
In the search for acetal protecting groups for vicinal transdiequatorial diols that can be selectively introduced, the research group of S. v. Ley in Cambridge, England, recently
developed the dispiroketal (Dispoke)[21 and cyclohexane-1 .2-diacetal (CDA) protecting groups.r31The former can
be intl-oducted by acetalization of a diol with the readily accessible 3,3‘.4.4‘-tetrahydr0-6,6’-bis-2H-pyran[~(bis-DHP, 3a),
the latter by acetalization with the just as easily obtainable
1,1.2.2.-tetramethoxycyclohexane4.l3IIn the case of the methyl3-D-galactopyranoside (Scheme l ) , the trans-diequatorial hydroxyl functions of positions 2 and 3 can be highly selectively
blocked as the Dispoke-protected galactoside 5a (76 %)[’I o r the
CDA-protected galactoside 6a (46Y0)[~]in this way. Dispoke
[*] Dr. T. Ziegler
Institut fiir OrKdnische Chemie und lsotopenforschung der Universitit
Pfaffenualdring 55. D-70569 Stuttgart ( F R G )
Telehx: I n t . code (711)685-4269
+
and CDA derivatives of monosaccharides are therefore useful
complements to benzylidene and isopropylidene derivatives.
Like the classical acetal protecting groups, the Dispoke group
can be removed hydrolytically under acidic conditions, preferably by transacetalization with ethylene glycol.[51
x&
0
HO
2
HoOMe
HohMe X ( H + )
(46%)
h
HO
OMe
5a
U
6
OMe
OMe
6a
R
3aR=H
3bR=Me
3CR=Ph
OMe
4
Scheme 1
The exceptionally high selectivity of the Dispoke and CDA
groups can be explained by a steric interaction of the neighboring spiro centers and the equatorial arrangement of the alkyl
residue as well as a strong anomeric effect of the two acetal
functions.[2.31 This high selectivity is particularly impressively
reflected in the reaction of (S)-I,2.4-butanetriol with bis-DHP
(3a) and a catalytic amount of camphorsulphonic acid (CSA), in
which the dispiroketal7 (96%) is obtained as exclusive stereoisomerr2](Scheme 2). In the case of the symmetric glycerine, a
“desymmetrization” of glycerine can even be achieved during
the Dispoke formation by the use of chiral C,-symmetric bisD H P derivative 3b. Here the only product is the enuntiomerically pure compound 8 (96%). The compounds 7 and 8 can be
transformed into the corresponding Dispoke-protected glycerinaldehydes 9, which not only are thermally more stable than the
isopropylidene glycerinaldehyde,[2.61 but also have a distinctly
higher anti-selectivity in the 1,2-addition of carbon nucleophiles
to the aldehyde functionrz1(Table 1 ) .
HIGHLIGHTS
Besides the 2,3-protected galactosides 5a and 6a (Scheme 1 ) .
other monosaccharides from the gluco. manno, rhamno, ,fuco,
q l o , Iy,ro, and arabino series can be converted into the corresponding Dispoke- and CDA-blocked derivatives 5 and 6.13.
However, the regioselectivity of the acetal formation of Dispoke
derivatives can in some cases (for instance, methyl-z-Lrhamnopyranoside) lead to mixtures of the 3,4- and 2Jderivatives 5b and 5b', respectively.['] For the CDA analogues 6. the
ratio is most often shifted so far to the side of the trans-diequatoriaily blocked compounds 6b that a preparative application
seems m e a n i n g f ~ l [ ~(Scheme
1
4).
t
HO
8
R
7
Me
1 ) TsCI. Py
2)BuOK
(61%)
3) 0 3
(70%)
9aR=H
9bR=MeR
5b
5 b'
HO
Scheme 2
R her Table 1
6b (74%)
Table 1 . Reaction o f 9a \bith organometallic compounds RM [2]
RM
Conditions [a]
MeLi
MeMgC'I
Me,CuLiMe,S
EtMgBr
Et,O THF. -78 C, 2 2 h
C. 2 4 h
EtlO, -78 C. 20 t i
THI-. -78 C. 6 h
THF. -78 C , 4 h
THF, 7 5 C. 4811
THF, -78 C 5h
THF. -78 C. 18h
T H E -7ti
H,C=CHMpBr
(HIC=CH),Zn
HC ~ C hgBr
l
CHI=CIICH,MgBr
Scheme 4
10
Yield [XI
82
92
69
62
56
84
65
ti9
Ref. [b]
m/;:.wii
82:lti
81:19
12:88
73:27
91.9
67.33
X9:11
6ti:32
6b' (8%)
60:40
~~
18:82
~
60:40
~
44:56
60.40
On the other hand the Dispoke and CDA protection for
D-glucopyranosides presents problems, because here all secondary OH groups are truns-diequatorially arranged. Both with
bis-DHP 3a and with l,t ,2,2-tetramethoxycyclohexane 4. mixtures of the 2,3- and 3,4-protected glucosides 5c,6c and 5c',6c',
respectively, are 0btair1ed.l~. If, however, analogous to the
"desymmetrization" of glycerine, phenyl-substituted, chiral bisD H P 3c is used. for glucose derivatives the two regioisomers 12
and 13 can be prepared in a highly selective synthesis through
double diastereoselection"'] (Scheme 5 ) .['
'3
[ti]
T H F = tetrahydrofuran [b] Reaction of isopropylidene glycerinaldehyde with
the correqwnding organometallic compound.
In the same way glycolic acid can be stereoselectively transformed into the Dispoke derivative 10 (61 %) with enantiomerically pure 3b.['] Formation of the ester enolate, alkylation with
methyl iodide, renewed enolate formation and treatment with
benzyl bromide then give highly diastereoselectively in 51 %
yield the protected a-hydroxycarbonic acid derivative 11
(Scheme 3)
It can be predicted that the C,-symmetric Dispoke group will rapidly become popular as auxilliary in the
stereoselective synthesis of small building blocks.
/OTBDPS
/
5c R=Dispoke (42%)
6~ R= CDA (50%)
/OTBDPS
,OTBDPS
5c' R=Dispoke (26%)
6 ~R=
' CDA (30%)
%ikq
HoOMe
+3c
\
Ph
(61%)
HO OMe
0
10
11
12 (88%)
=
lithium diisopropylamide.
y
Ph
Me
Schemc 3 LDA
Rh
12
TBDPSO
3b, (H')
HodOH
-
Scheme 5. TBDPS = rErr-butyldiphenylsilyl
13 (75%)
Ph
HIGHLIGHTS
For strategies with the Dispoke or CDA protecting groups in
oligosaccharide synthesis the concept of armed and disarmed
glycosyl donors["] is especially fruitful. According to this principle the reactivity of a glycosyl donor is diminished by deactivating protecting groups (e.g. acyl groups) or by restricting the
flexibility of the pyranose ring by bridging two hydroxyl functions (e.g. acetal protecting groups). Such a disarmed donor can
then function as a glycosyl acceptor and participate in a selective
reaction with a reactive armed (most often benzyl-protected)
glycosyl donor. The conformation-stabilizing Dispoke and
CDA groups are plainly predestined to disarm a glycosyl donor.
For example. the ethyl-l-thio-~-~-galactoside
14. conformationally fixed by a Dispoke group and thus disarmed, undergoes
a smooth reaction with thiogalactoside lS--reactive as a result
of benzyl protection- -and the mild activator iodonium dicollidine perchlorate (IDCP) to form disaccharide 16" 31
(Scheme 6). Through the subsequent use of the more reactive
The transformation of 18 as trisaccharide donor without further protecting group manipulation is achieved with the pseudo
disaccharide acceptor 19 and NIS after prolonged reaction
times. The pentasaccharide 20. a fragment of the GPI anchor of
Trjyunosoma hrucei. is thus obtained in 41 YOyield.['31
Based o n the concept of armed and disarmed glycosyl donors,
the trisaccharide 23 can be constructed very elegantly from the
two CDA-protected rhamnosides 6b and 6d in a one-pot reaction similar to the ciclamycin trisaccharide synthesis['41 in two
steps as follows:" 'I The IDCP-catalyzed condensation of
armed thiorhamnoside 21 and disarmed glycosyl acceptor 6d
yields as intermediate a disaccharide that reacts immediately
without further purification with the CDA derivative 6b under
NIS activation to form 23 (62%). The disaccharide 22 is also
found as by-product ( I 0 Y O )which
,
arises in the second glycosylation step from unconverted 21 and added 6b. The final deblocking of saccharide 23 furnishes the Strc,ptococcus antigen
trisaccharide 24 (Scheme 7).
fi
14
B
n
Me0
16
SEt
BnO
O
BnO
6b R=OMe
6d R=SEt
fi
H
OBn
21
Y
I a*oM
Bnb
2 1 , IDCP
2) + 6b, NIS,TfOH
15
1 ) 6d
+
a+ &+
OMe
0
Me0
B
n
O
0
Me0
I
(63%)
q
B
I
n
OBn
SEt
O
q
OBn
22 ( 1 0 % )
23 (62%)
O
, Bn
J
NIS. TfOH, 0°C
(41%)
a-L-Rhap(1 -2)-a-L-Rhap(l-Z)-a-L-Rhap-(l-OMe)
24 (53%)
Scheme I . Rhap
I
Af
=
rhamnopyratiose.
.OTBDPS
In particular, the examples given in Schemes 6 and 7 for the
application of Dispoke and CDA groups in oligosaccharide synthesis demonstrate magnificently that with these novel protecting groups complex sugars can be synthesized very efficiently.
The Dispoke and CDA acetals should therefore rapidly become
standard practice in carbohydrate chemistry.
Scheme 6. TfOH
=
trifluorornethansulfonic acid. PMB
activator N-iodosuccinimide (NIS), disaccharide 16 is armed
ford trisaccharide 18.
2274
German version: Angeic. Chrm 1994. iO6, 2362
= para-methoxybenzenyl
VCH V~r/ugsge~e//s~/~a/t
mhH, 0-69451 Wrinherm, 1994
[ l ] T. W. Greene, P. G . M. Wuts, Protective Groups in Organic Chemistry. 2nd ed.,
Wilev. New York, 1991; P. J. Kocienski. Profectrng Grorips. Thieme. Stuttgdrt,
2412; Angw. Clwin. In!. Ed. Engl. 1994, 33. 2290 2292
0570-0833/Y4!2222-2274 S 10.00f 2 5 . 0
Angel', L'hem. Int. E d Engl. 1994, 33, N o . 22
HIGHLIGHTS
[4] S. Gohsal. G . P. Luke, K. S. Kyler, J Orx. Chim. 1987, 52, 42964298.
[ i ] S. V. Ley. R. Leslie, P. D. Tiffin. M. Woods. Tcrrahrrlron Lett. 1992. 33, 47674770
[6] G.-.I. Boons. D. A. Entwistle. S. V. Ley, M. Woods. Z k r v o h e h n Lett. 1993. 34,
5649 5652.
[7] R . Downham. K S. Kim. S V. Ley. M. Woods, Terrohrdron Let[. 1994. 35,
769 772.
[XI S. V Ley. G:J. Boons, R. Leslie. M. Woods. D M. Hollinshend. &mthesis
1993. 689-692
[9] A . B. tluphcs. S. V Ley, H. W. M. Priepke. M. Woods. Zwdir&on h r r . 1994,
35. 77.3 776
Air,z.cw C ' h r r i i . l n l . E d Engl. 1994. 33. No. 22
(:'
[lo] S. Masdmune. W. Choy, J. S. Petersen. L. R Sita. A n p i , . ('hem. 1985. Y7.
3-31: Angeir. Chem. I n r . Ed. Enpl. 1985, 24. 1-30.
[I 11 D. A. Entwistle, A. B. Hughes, S. V. Ley. G. Visentin, Eirrohcdron Lrrt. 1994.
35. 777-780.
[12] B. Fraser-Reid. U. E. Udodong, Z. Wu, H. Ottoson. R. Merritt, C. S. Rao, C.
Roberts, Sydert 1992, 927-942; G. H. Veeneman. J. H. van Booin. Ewdfedron Lett. 1990. 31. 275-278.
[I31 G.-J. Boona, P. Grice, R. Leslie. S. V. Ley. L. L. Yeung, Tetrolirrlrow Lrtr. 1993.
34, 8523 -- 8526.
[14] S. Raghavan. D. Kahne, J An?. Chtn?.Sot.. 1993. f 15. 1580 - 1 581.
[I51 S. V. Ley, H. W. M. Priepke. Angcir. Cheni. 1994. 106,2412; Angrn.. ('i,cvn. I n / .
Ed Engl. 1994, 3.3, 2292.
VCH Ver/ugsgese//vr.huftmhH, 0.69451 Weinheirn, 1994
0570-0833/941?222-2275 S 10.00 + .25X
2275
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