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An Interactive Strategy for the Assembly of Complex Branched Oligosaccharide Domains on a Solid Support A Concise Synthesis of the Lewisb Domain in Bioconjugatable Form.

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ods und Appliculions rn Medicmul Chrmistrj, Purt 1. VCH. Weinheim. 1992.
desired peracetylated p-ally1 pentasaccharide which was
deacetylated by the action of methoxide to provide the target
Leyhapten as its p-ally1 glycoside 8.12n1
The aldehyde. derived by
ozonolysis of 8, was conjugated to BSA by the method of Bernstein and Hall.[sa1Approximately 15 carbohydrate pentamers
were introduced, presumably at lysine residues.
In summary, the work demonstrates the versatility of glycals
both as donors and as acceptors, takes advantage of 1,2 glycal
epoxides and their presumed N-sulfonylaziridine counterparts,
and opens the way for analogous syntheses of this kind. The
biological properties of such systems linked to carrier proteins
will be investigated and described in due course.
Chapter 4.
[4] For pioneering work on the use of glycals as glycosyl donors in glycoside
synthesis seea) R. ti. Lemieux, Cirn. J. Chem 1964.42. 1417: b) R. U. Lemieux.
B. Faser-Reid. ihid. 1965.43. 1460; c) R. U. Lemieux. A R. Morgan, ihid. 1965.
43, 2190: d) J. Thiem, P. Ossowski, J Carbohwlr. Chrm. 1984. 3, 2x7; e) J.
Thiem. A. Prahst. T. Wendt, Lirbrgs Ann Chem 1986. 1044; f ) J. Thiem in
7kncls in Sjntheric Curbohjdrutc C/rm?i.s/r~~
(Eds.: D. Horton. L. D. Hawkins.
G L. McGarvvey). American Chemical Society. Washington D . X . 1989.
Chapter 8 (AC'S Syrup. Ser. 1989. 386).
[5] R. R. Race. R Sanger. BloodGruups rn .Mun, 6th ed. Blackwell. Oxford. 1975
[6] a ) K . 0. Lloyd. Am. J. Clinwul Purb 1987,87. 129: b) C(mcrr.Eiol. 1991. 2,421
[7] a) T. Toyokuni, B. Dean, S. Cai. D. Boiviii, S. Hakomori. A . K. Singhal, J An?.
Chrnr. Soc. 1994,116.395: b) G. Dranoff. E. Jaffee. A. Lazenby. P. Golumbck,
H. Levitsky. K. Brose. V. Jackson. H. Hamada, D. Paardoll. R. Mulligan,
Proc. Nut/. Acad. Scr. U S A 1993,90,3539; c) M.-H. Tao. R. Levy. Nutirrr 1993,
362, 755.
Experimental Procedure
[8] a) M. A. Bernstein. L. D. Hall. Curbohylr. Re.c.1980. 7X. C1, b) R. U. Lemieux.
Chrm. Soc. R r r . 1978, 7. 423: c) R. U. Lemieux. D. R. Bundle. D. A. Bakcr.
3: To lactal carbonate 2 (2.00 g, 2.47 mmol) was added fucosyl fluoride 5 (4.44 g,
J. Am. Chem. Soc. 1975. 97. 4076 and references therein.
9.86 mmol). The mixture was azeotroped five times with benzene and placed under
high vacuum for two hours. tinder an argon atmosphere di-ieri-butyl pyridine
[9] For previous syntheses see: a) J. C. Jacquinet, P. Sinay, J. Urg. Cizrm. 1977. 41.
(2.77 mL, 12.33 mmol) and dry ether (16 mL) were added. 2.0 g offreshly activated
720, b) S. Nilsson. H. Lohn, T. Norberg. Glycoconjupte J 1989. 6, 21 : c ) R.
R. Schmidt. A. Topfer. fi,ciruhcdon L e f t . 1991.32. 3353: d) W. Kinry. A. Lo\+.
4 A molecular sieves were added and the mixture stirred for one hour at room
Carhohydr. Res. 1993. 245. 193.
temperature. In an argon glove bag, SnC1, (2.34 g, 12.33 mmol) and AgCIO,
(2.56 g, 12.33 mmol) were added. The flask was equipped with a reflux condenser
[lo] a) K. 0. Lloyd. E. A. Kabat. E. J. Layug. F. Gruezo. B/ochern. 1966.5, 1489:
b) M. 1. Potapov, Prohi. Hernutol Blood Transfus. (USSR) 1970. 15. 45.
and the reaction heated to reflux for 72 h. The reaction was quenched with saturated
[ I l l T. Kaizu, S. B. Levery. E Nudelman, R . E. Stenkamp. S. Hakomori. J Biol
bicarbonate ( 5 mL) and filtered through a pad ofcelite. The filtrate was diluted with
ethyl acetate (50 mL) and washed twice with saturated bicarbonate. twice with
Chern. 1986. 261. 11254.
saturated copper sulfate, and twice with saturated brine. The organic phase was
[12] S. B. Levery, E. Nudelman, N. H. Anderson. S. Hakomori. Cuuho/i.vdr. Rci.
dried over MgSO, and concentrated. Flash chromatography in 20% ethyl acetate,'
1986, 1.71, 311.
[13] a ) S. Hakomori, E. Nudelman, S. B. Levery, R. Kannagi, J. Brol. Chem. 1984.
hexanes afforded 2.10 g(51 %) o f a white foam 3: [a]" = -78.9 ( c = 0.555. CHCI,);
IR (thin film): i; = 3040.3000.2905.2860,2830,1820,1800,1710,1635,1585.1570,
259.4672: b) Y Fukushi. S . Hakomori, E. Nudelman. N . Cochran. ihid 1984.
3480. 1460. 1440. 1115, 1370, 1350. 1300, 1260, 1205, 1145. 1100. 950, 735,
259. 4681; c) Y Fukushi. E. Nudelman. S. B. Levery. S. Hakomori, H. Rau695 cm-'; 'H NMR (400 MHz. CDCI,): 6 = 8.09 (d, J = 8.12 Hz. 2H), 8.00 (d.
vala, ihrd. 1984, 259. 10511
[14] W. N. Haworth, E. L. Hirst. M. M. T. Plant, R. J. W. Reynolds. .
I
Chem. Sot.
J = 8.26 Hz, 2H) 7.66 (m. 4H), 7.59 (d, J = 6 . 7 4 H z 4H), 7.56 (t. J =7.27 Hz, 1H).
7.30-7.50 (m. 22H) 7.16-7.26 (m, 10H) 7.09 (m, 2H), 6.99 (t. J =7.59 Hr. 2H) 6.89
1930, 2644.
(t.J=7.97H~,lH),6.43(d,J=6.08H~,lH),5.46(bs,lH),5.38(bs,lH),5.35(d,
[15] S. J. Danishefsky, J Gervay. J. M. Peterson, F. E. McDonald. K. Koseki. T.
J = 3.42 Hz, 1H). 4.89 (d, J = 11.35 Hz. 1H). 4 75-4.80 (m, 4H). 4.72 (d. J = 5.88
Oriyama, D. A. Griffith. C.-H. Wong. D. P. Dumas. J Am. Ci?crn.So<. 1992.
Hr, 2H), 4.69 (d. J = 4.27 Hz, 2H), 4.36-4.55 (m. 5H), 4.28 (9. J = 6.51 Hr, 1H).
114. 8329.
[16] T. Mukaiyama, Y. Murai, S. Shoda, Chem. Lett. 1981, 431
4.17 (bd, J = 5.46 Hz, I H ) , 3.90-4.00 (m, 6H), 3.85 (d. J = 2.99 Hz, l H ) , 3.82 (d,
J = 2.89 Hz, l H ) , 3.56-3.78 (m. 4H), 1.07 (m, 24H); HR-MS (FAB): calcd for
[17] D. A. Griffith, S. J. Danishefsky, J. Am. Chem. So<. 1990. 112, 5811.
[18] S. J. Danishefsky, K. Koseki, D. A. Griffith, J. Gervay, J. M. Peterson. F. E.
C,,H,,,O,,Si,Na
1694.6740; found 1694.6787.
McDonald. T. Oriyama. J. A m . Chem. Soc. 1992. 114. 8331.
6: Iodosulfonamide 4 (230 mg, 0.12 mmol) was azeotroped five times with dry
[19] R. L. Halcomb, S. J. Danishefsky, J. Am. Chem. Soc. 1989, 111, 6661.
benzene and placed under high vacuum for two hours. A solution of tin ether 9
[20] 8: [%ID-72.7 (c = 0.1. MeOH); IR (thin film): i= 3350, 2940. 2900, 2830.
(15 equiv) (generated by azeotropic removal of water overnight with a Dean-Stark
1650.1550,1365.1300.1155,1070.1030cm~';'H NMR(400MHz.CD30D):
trap equipped with freshly activated 4 8, molecular sieves from 6-TIPS-galactal
d = 5.95 (m, I H ) , 5.32 (d. J = 1 7 . 2 5 H z . l H ) , 5 14-5.19 (m. 2H). 5.04 (d,
(561 mg. 1.80inmol) and bisftributyltin) oxide (673 wL, 1.32 mmol) in benzene
J = 3.83 Hz, l H ) , 5 . 0 2 ( d . J = 3.50 Hz, 1H),4.68(d. J = X.15 Hz.2H),4.51 (d,
(80 mL)) in T H F (2.4 mL). To this solution stirring under an argon atmosphere was
.I = 5.70 Hr. 1H). 3.40-4.38 (m, 27H). 1.96 (s, 3H), 1.23 (m, 6H); FAB-HRadded 200 mg of freshly activated 4 8, powdered molecular sieves. After the mixture
MS (C,,H,,NO,,Na): calcd 900.3325; found 900.3310.
had been stirred for one hour a t rnom temperature it was cooled to - 7.3 "C and a
solution of silver tetrafluoroborate (187 mg, 0.96 mmol) in T H F (2.4 mL) was
added by cannula. The mixture was allowed to warm to room temperature over 15
hours, during which time it had turned bright yellow, and the reaction was quenched
by the addition of saturated bicarbonate (2 mL). The reaction mixture was filtered
through a pad of celite into a separating funnel. The celite pad was washed thoroughly with ethyl acetate. The organic phase was washed twice with saturated
bicarbonate and twice with SdtUrdted brine. The organic phase was dried over
MgSO,. Concentration and chromatography in 25% ethyl acetateihexanes gave
193 mg (75%) as a white foam 6: [a], - 126.4 (c = 0.505, CHCI,); IR (thin film):
i. = 3500, 3040, 3000, 2905, 2840, 1820, 1800, 1705. 1635, 1590, 1440, 1410, 1255,
1195.1100,1080.1035,815.730,695cm~i; 'HNMR(4O0MHz,CDCI3): 6 = 8.09
(app t, 4H), 7.08-7.65 (m, 46H), 6.90 (t, J =7.65 Hz, 3H), 6.76 (d, J = 6.91 Hz,
ZH), 6.12 (d. J = 6.59 Hz, l H ) , 5.50 (bs, l H ) , 5.45 (bs. I H ) , 5.28 (app t, 2H),
3.03-4.91 (m. 36H), 1.09(m,45H);LR-MS (FAB): calcd forC,,,H,,,NO,,SSi,Na
2153; found 2153.
Received: March 9, 1994 [Z67441E]
German version: Angew. Chrm. 1994, 106, 1536
[ l ] a ) M. L. Phillips, E. Nudelman, F. C. A. Gaeta, M. Perez, A. K . Singhal, S.
Hakomori, J. C. Paulson, Science 1990, 250, 1130; b) M. J. Polley, M. L.
Phillips, E. Wagner, E. Nudelman, A. K. Singhal, S.Hakomori. J. C. Paulson,
Proc. N u t / . A L U ~
Sci.
. U S A 1991, 88, 6224.
[2] a) Y. Hirabayashi, A. Hyogo, T. Nakao, K. Tsuchiya, Y. Suzuki, M. Matsumoto, K. Kon. S. Ando, J. Biol. Chem. 1990. 265. 8144; b) U. Spohr, R. U.
Lemieux Curhohw. Res. 1988, 174, 211, and references therein.
[3] For recent reviews of glycosylation see: a) K. Toshimd, K. Tatsuta, Chrrn. Rev.
1993,93,1503; b) H. Paulsen, Angew. Chem. 1982.94, 184; Angew. Chem. Int.
Ed. Engl. 1982,Zl. 155; c) R. R. Schmidt, ibid. 1986,98.213 and 1986,25,212;
d) R. R. Schmidt, Comprehensive Orgunic S.vrrthesis, Nil 6 , Pergamoii Press,
Oxford, 1991. Chapter 1 (2); e) R. R. Schmidt, Carbohydrates, Syntheric Mdh-
1470
C VCH Verlu~sge.sell.schaftmbH, 0-69451 Weinheim, 1994
An Interactive Strategy for the Assembly of
Complex, Branched Oligosaccharide Domains on
a Solid Support: A Concise Synthesis of the
Lewisb Domain in Bioconjugatable Form **
John T. Randolph* and Samuel J. Danishefsky*
In the previous communication, we described an application
of the glycal assembly method to the construction of the LewisY
[*I
Prof. S. J. Danishefsky, J T. Randolph
Department of Chemistry, Havemeyer Hall
Columbia University. New York, NY 10027
Telepdx: Int. code + (212)854-7142
['I
Alternative address:
Memorial Sloan-Kettering Cancer Center
1275 York Avenue. New York, NY 10021
Telefax: Int. code + (212)772-8691
[**I This research was supported by National Institutes of Health (NIH, grant no.
A1 16943). An NIH National Research Service Award Postdoctoral Fellowship
to J. T. R. is gratefully acknowledged.
+
0570-0R33~94!1414-14708 10.00 .25,10
Angeiv. Chem. Int. Ed. Engl. 1994, 33. No. 14
COMMUNICATIONS
pG pG
determinant."] In this report, we describe the construction of
0-0
the Lewis' determinant.[*] As before, our synthesis results in
POI
equipping the reducing end of the antigen with a suitable device
PO
PO
0
PO
for subsequent attachment to carrier protein. An intervening
spacer element (lactose) is incorporated to insulate the recogniOH
4
1
2
tion domain from the bioconjugation module.
The Leb blood group determinant is of particular current
POI
interest. Thus, Boren et al. have recently identified the Leb blood
group antigen as a mediator for the binding of Helicobacter
0
pylori to human gastric epithelium.[3]In addition, it was found
2) 3, ZnClp
that a Leh hexasaccharide as well as a soluble neoglycopeptide
PO
conjugate of the Le' antigenic determinant were highly effective
PO
agents for inhibiting bacterial binding. This finding is, in prinScheme 1. A strategy for the solid-phase synthesis of oligosaccharides using the
ciple, of considerable interest. Thus, clinical studies have identiglycal assembly method. @ = solid support, P = protecting group.
fied H . pylori as a causative agent in gastric and duodenal
Considerable evidence exists to suggest that antimicrobial treatments are an effective means of dealing with H . pyluri
0-0
0-0
infection.['] Since bacterial attachment is a prerequisite to infecPOI
PO I
tion,16]soluble Le' receptor analogues may emerge as therdpeuglycosyl
donor
tic candidates which could well serve as alternatives to broadsugar o
spectrum antibiotics.
4
5
The assembly of the Leb (type 1) domain was, from our perScheme 2. Application of the solid-support method to the assembly of branching
spective, a more difficult undertaking than was the Ley (type 2)
patterns of complex carbohydrates. @ = solid support, P = protecting group.
target, wherein lactal was used as a very convenient starting
material. In the case of a type 1 determinant, lactal is obviously
not a useful starting material. It seemed appropriate to use the
polymer-bound oligosaccharide can serve as donor or as accepsynthesis of the Le' system as an opportunity to explore signiftor wherever appropriate.
icant extensions to our recently disclosed polymer-based
The tetrasaccharide glycal 6 , bearing H-type 2 blood group
oligosaccharide construction method.''] The essence of that
specificity, was our initial goal (Scheme 3 ) . Polymer-supported
strategy is summarized in Scheme 1 . Polymer-bound glycal 1 is
galactal 7['01 was allowed to react with a solution of 3,3activated for glycosyl donation by direct formation of a 1,2-andimethyldioxirane" 'I to provide the corresponding 1,2-anhyhydro derivative 2. Reaction of 2 with acceptor glycal3 furnishdrosugar glycosyl donor, which was treated with a solution of
es 4. Reiteration is achieved by direct epoxidation and reaction
glucal derivative 8 in the presence of ZnC1, to provide 9.[lZ1This
with the next acceptor 3. The self-policing nature of the method,
polymer-bound disaccharide acted as a glycosyl acceptor upon
and the major simplification arising from "one time" purification at the end of the synthesis, have been described.[',
treatment with a solution of fucosyl fluoride
in the presence of Sn(OTf), . Polymer-bound 11 was thus generated. ReIn the work reported herein, we explore an important additrieval of the trisaccharide glycal from the support was accomtional dimension of the polymer-bound method. Here we take
cognizance that each glycosylation event generates a
unique C,- hydroxyl
(marked
with an asterisk in Scheme 2).
In principle, (and in fact, vida
b
infra) this hydroxyl group
can function as a glycosyl acceptor upon reaction with a
7
9
solution-based donor. The
a 1 1 3 : R = TIPS
glycal linkage of 5, still
housed on the support, can
be further elongated. In this
OTlPS
OT IPS
way, branching at C, is accomplished while minimizing
f
9_
the requirement for protectNHS02Ph
ing group machinations.'']
d O B n
In principle, this branching
dBn
16
can be implemented at any
pyranose site in a growing
OTlPS
chain. For such an application, it would be necessary to
Bu,SnO
cap all previously generated
hydroxyl groups generated
on the "polymer side" (nonScheme 3. Synthesis of a tetrasaccharide having H-type 2 blood group specificity. a) i: 3,3-dimethyldioxirane, CH,CI,: ii: 8,
reducing end) of the growing
ZnCI,, T H F ; b) 10, Sn(OTf),, di-rerf-butylpyridine,THF; c) TBAF, AcOH, T H F ; d) TIPSCI, imidazole, DMF; e) I(coll),CIO,.
domain. In short, the nexus
PhSO,NH,, CH,CI,; f ) 15, AgBF,, 4 A molecular sieves, THF; g) i: TBAF, AcOH, THF; i i : Na/NH,; iii: Ac,O, pyridine.
of the proposal is that the
@ = solid support.
%-
!&3
0-0
-
-
-
BnA
AnRew. C'lieni. I n [ . Ed. Engl. 1994. 33, N o . 14
3
1
VCH Verlugsgesellschafi mhH, D-69451 Weinheim, 1994
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o57(J-oX33/94/1414-i471S 10.00 .25/0
1471
COMMUNICATIONS
hyde
(R = CH,CHO).
Coupling to the protein
a
y0O*'& osIoPr),@
b
oy'oLOo&
OTIPS
human serum albumin
(HSA) by the method of
Bernstein and Hall was acOH
0
0
0
PhS02NH
0
complished.['
Approximately 33 carbohydrate
7
18
W O B n
W O B n
hexamer units were incorBnO OBn
BnOoBn
porated. presumably at
20: R = SI(IPT)~@ R'
23
dr
21 R = R ' = H
3
c
lysine residue sites.
22: R = R' =TIPS
In summary, we have
extended our solid-support
glycal
assembly
method for complex carbohydrate domain synthesis to include the branching patterns needed for
critical systems in bio@OH
recognition processes. SpeHO OH
cifically, the determinant
17: R = CH2CH=CH2
25: R =TIPS; R' = H, R2 = SOnPh; R3 = Bn; R4 = C=O 7
for the binding of H. pylnri
26: R = R' = R2 = R3 = R4 = AC
to human gastirc epithelium has been stereospecifiOTIPS
OTlPS
OTIPS
cally fashioned, with simplicity, in a way which
provides significant relief
from some of the complexities of protecting group
Scheme 4. Synthesis of a Leh hexasaccharide in bioconjugatable form. a ) i : 3.3-diniethyldioxirane. CH,CI,. i i . 19. ZnCI,, T H F , b)
manipulations. The bio10. Sn(OTf),, di-lerr-butylpyridine, T H F ; c) TBAF, AcOH. T H F ; d) TIPSCI. imidazole. DMF: e ) I(coll),CIO,. PhSO,NH,.
CH,Cl2: f ) 24. AgBF,. 4 A molecular sieves, T H F ; g) i : TBAF, AcOH, T H F : ii: N a N H , ; iii: Ac,O, pyridine; h) I : 3,3-dimethyllogical properties of our
dioxirane. CH,CI,; ii: ally1 alcohol. ZnCI,; iii: NaOMe. MeOH. S = solid support
new glycoprotein construct
will be reported in due
course.
plished by using tetrabutylammonium fluoride (TBAF) to afThere is every reason to believe that the solid-phase methodolford 12 in 50% overall yield from 7.[14]
ogy to date is only a first generation version of what is posWe next demostrated how the trisaccharide, retrieved from
sible.['*.
Important new variations of the technique and new
applications will be described shortly.
the polymer, could be further elaborated. Toward this end, compound 12 was converted to silyl ether 13 by reaction with triisopropylsilyl chloride (TIPSCI) . The latter was converted to the
E-xperinientul Procedure
iodosulfonamide derivative 14 by the action of I(coll),CIO, in
6: ' H N M R ( 4 0 0 M H ~ CDCI,).
.
6 = 6.39 (d, 3H. J = 6.2 Hz. H, gdlactal). 5.65 (d,
the presence of PhSO,NH, .[15] Reaction of 14 with the galactal
l H , J = 8.9 Hz, NHAc). 5.35 (d, IH. J = 3.8 Hz), 5.33 (m, IH). 5.29 (d. IH.
stannyl ether derivative 15 in the presence of AgBF, gave 16 in
J = 2.6 Hz). 5.37 (d, IH. J = 3.1 H r ) , 5.17-5.09(m, 2H). 4.97-4.90 (m, 2H), 4.81
77 Yo
Tetrasaccharide glycal 16 was deprotected and
(dd,1H.J=3Hz,J=6.1Hr.H,galactal),4.75(d,1H.J=8.0Hz).4.52(m,1H),
4.4X(dd.1H.J=12.0Hz,J=1.6Hz.1H),4.44~4.06(m,8H).3.88-3.77(m.4H),
then peracetylated to afford 6 (62% overall yield for three
3.61 (m, IH). 2.18-1.97 (m. 33H, COCH,), 1.18 (d. 3H, J = 6.5 Hz, C H , fucose);
steps).
"C N M R (CDCI,): 0 =170.80. 170.77. 170.72, 170.67, 170.62. 170.34, 170.21,
Having accomplished the synthesis of the full H-type determi170.09. 170.01, 169.99. 169.65. 144.92 ( C , galactal), 100 22. 98.83. 98.58, 98.55.
nant by sequential polymer- and solution-based maneuvers, we
74.48, 73.38. 73.13, 73.06. 71.48. 71.01. 70.68, 67.97. 67.42, 67.18. 67.05, 65.94.
64.83. 67.35. 62.22, 60.88, 60.37. 54.21. 23.23, 22.15. 20.85. 10.82. 20.79. 20.76.
could direct our attention to the synthesis of the more complex
20.65. 20.61, 20.57. 15.51 (C, fucose); IR (thin film): i.= 3368.7 (NH). 2965.6,
Leb hexasaccharide 17 (Scheme 4). Polymer-bound galactal 7
2934.6, 1746.5 (C=O). 1537.5. 14.35.9. 1371.3. 1228.5, 1065.0, 1046.0 cm-':
was converted to 18 upon epoxidation with 3,3-dimethyldioxi[a];" = - 51.1 (( = I . X , CH,CI,): HRMS (FAB) (C,,,H,,NNaO,,):
calcd:
rane followed by reaction with glucal derivative 19. This disac1100.3434. found 1100,3436
charide diol was then bisfucosylated by using fucosyl donor 10
21: Polymer-bound galactal 7 (loading = 0.75 inmol glycalg-'). which had been
placed in a round-bottom flask equipped with a fritted outlet. was suspended i n
in the presence to Sn(OTf), to afford 20. Retrieval from the
CH2CI, under N,. cooled to 0 C. and then treated with a solution of 3,3-dimethylsupport with TBAF provided 21, which was obtained in 40%
dioxirane. The mixture was stirred (teflon-coated magnetic stir bar) for 40 min at
overall yield from 7. Compound 21 reacted with TIPSCl to give
0 C, after wjhich time the soluble material was removed by filtration through the
22.
fritted outlet (N: pressure). The polymer-bound 1.2-anhydrosugar wils evacuated
(ca. 0.1 Torr) for several hours in order to dry the material for the next step. This
Iodosulfonamide 23. obtained from 22 using I(coll),CiO, and
material was once again placed under N, before being treated with 19 (ca. 10 molar
PhSO,NH,, reacted with lactal derivative 24 in the presence of
equivalents as a 0 . 8 ~
solution in T H F ) . The suspension was cooled to 0 - C , and
AgBF, to provide the hexasaccharide glycal25 in 55 % yield.""'
treated with ZiiCI, (ca. 7 molar equivalent, as a 1 . 0 holution
~
in THF). The
Deprotection of 25 was accomplished in two stages (TBAF to
reaction mixture w i s allowed to warm slowly to room temperature (over ca. 2 h),
and then stirred for an additional 3-4 h. Soluble material was removed by filtration.
remove the silyl ethers, followed by Na/NH, reduction to reand polymer 18 was washed scveral times with T H F and then dried in ~ a c u oSolid
move the aromatic protecting groups). The crude product was
Sn(OTf), (ca.4 molar equivalents) was added to compound 18 in a glove bag, and
peracetylated to give 26 in a 51 O h overall yield. Compound 26
the mixture was placed under N 2 and cooled to 0 C before being treated with 10 (ca.
was converted, via the 1,2-anhydrosugar derivative. to ally1 glyI 0 . 2 solution
~
in THF) and di-tr,.r-butylpyridine (ca. X
inolar equivalents). The suspension wds allowed to witrm to iroom temperature and
coside 17, which was readily activated by ozonolysis to the aldeOTIPS
BnTOB;Tlps
-
-
3
1
COMMUNICATIONS
stirred 8 - 10 h. The mixture was rinsed with anhydrous T H F (2 times). 1,4-dioxane
(2 times). ayuin with THF, and then dried in vacuo. Compound 20 (100 mg) was
suspended in THF, treated with a 1.3 mixture of AcOH and TBAF (ca. 02ki i n
TBAF, c ; ~10
. molar equivalents), and the mixture was stirred for 18 h at 40 C. The
polymer w a s rinsed with T H F (3 times). and the combined rinsings were concentrated and purified by column chromatography on silica gel ( 1 : l Et0Ac:hexanes).
Compound 21 (1 8 mg) was obtained as a colorless solid (40 % overall yield from 7):
'H NMR (400MHr. CDCI,): 6 =7.40-7.25 (m. 30H, ArH). 6.18 (d, l H ,
[7] a) S . J. Danishefsky, K. F. McClure, J. T. Randolph, R. B. Ruggeri. Srren<e
1993, 260, 1307. For additional references on the use of polymer supports for
oligosaccharide synthesis, see: b) G . H . Veeneman, S Notermans. R. M. J.
Liskamp. G. A. van der Marel, J. H. van Boom. leiruhedron Lr,tt. 1987, 28.
6695: c) A. Malik. H. Bauer, J. Tschakert. W. Voelter, Chrm.-Z~g.1990. 114.
371; d) J. M. J. Frechet in Po/ymer-Supported Reactions in Orgunir Synlhesrs
(Eds.: P. Hodge. D. C. Sherrington). Wiley, Chichester. UK. 1980. Chapter X.
[XI Recently. van Boom et al. (C. M. Timmers. G . A. van der Marel. J. ti. van
.1=6.0H~,H,glucal),5.26(d,lH,J=3.5Hz,H,fucose),5.09(d.lH,J=3.7Hz,
Boom, Reel. True. c'him. Pays-Bus, 1993. 112,609) found that glycoaylation o f
H , fucosc).4.96(dd.J=lO.XHz,2H.PhCH,).(4.90-4.56(rn,13H).4.43(m. 1H).
a particular acceptor with the a epoxide derived froin 3.4.6~tri-0-benzyl-u-gIu4.15-4.0h(ni.4H)..1.97(dt.lH.J=
8.3Hz.J=2.4Hz).3.87-3.65(m.10H),3.64
cal gave only a 4: 1 ratio of / l : a linked disaccharides. The minor product wiis
(d. ./ = 1 7 HI. I H ) . 3.57 (d, J =1.7 Hz. IH).2.69 (br, 1H. OH). ?.52(br. IH. OH),
previously missed [I21 because of its close chromatographic correspondence to
the unreacted glycosyl acceptor. With a more complicated acceptor. van Boom
1.11 (d. 3H. J = 7 . 0 H z . C I f , fucose). 1.09 (d. 3H. J = 7 . 0 H z . C H , fucose); I3C
N M R ( C D C I , ) .[ j =is3.37 (c=o).
145.75 (c, giucai). 138 60, 138.52. 138.19,
confirmed strict p-glycoside preference. Subsequent to our earliest publication.
137.61, 128.55. 12X.52, 128.44, 128.24, 128.16. 128.07. 127.62. 127.56. 127.45,98.71,
it has been found that the epoxide derived from 3.4,6-tri-O-ben~yl-o-glucalIS
98 38. 97 65. 97.34. 79.26, 78.87. 78.67. 78.01. 77.19. 77.65. 76.37, 76.10, 74.92.
the most problematic of the glycosyl donors. which we have occasionally employed, leading to modest amounts of x-glycoside. The implication that the
74.40.74 16. 73.95. 72.86,72.64,72.53,67.43,67.29.
61.31.60.90. 16.65(CC,fucose).
finding of minor amounts of a-glycoside in a particular solution-based experi16.53 (CGtfiicose): IR (thin film): i. = 3467.0 (OH), 3029.6. 2923.6. 1807.2 (C=O),
ment invalidates the solid-phase method. which uses completely different resi1647.3. 1496.0. 1453.5. 1358.1. 1240.2. 1095.6. 1049.2. 738.5, 697.2; [a];' = - 82.5
( c , = 0.4. CH,CI,):
HRMS (FAB): (C,,H,,NaO,,):
cakd. 1189.4772, found
dent protecting groups. is. as will be shown. premature.
I 189.~1;7
[Y] For an application of this strategy in the synthesis of a complex saponin. scc
J. T. Randolph. S. J. Danishefsky, J An7. Chrm. Soc. 1993. 115. 8473.
25: To ii ini\ture of 23 (60 ing. 34 pmol) and powdered 4 8. molecular sieves
[lo] The polymer support used in this study was polystyrene crosslinked with 1 Y O
(200 mg) uiidcr N, was added. by canula. a solution of24 (0.21 mmol) in anhydrous
divinylbenrene. which was functionalired by using published procedures T.-H.
T H F (1 5 m L ) . The stirred suspension was cooled to -78 'C before being treated
Chan, W:Q. Huang. J Chem. SIX.Cliem. Comnzun. 1985, 909;M. J. Farrall. J.
with ii solution of AgBF, (0.21 mmol) in anhydrous T H F (0.25 mL). The mixture
M. J. Frechet. .I. Org. C k m . 1976, 41. 3877.
w a s stirrcd and alloued to slowly warm to room temperature overnight. The suspen1111 R. W. Murray. R. Jeyaraman, J Org. Chrm. 1985, 50. 2847.
sion. which had devcloped a bright yellow color. was heated, with stirring. at 4S'C
[I21 R. L. Halcomb, S. J. Danishefsky. J A m . Chem. Soc. 1989. 111. 6661
for :in additional 36 h. until the TLC ( 2 : s Et0Ac:hexanes) showed no trace of 23.
[13] K. C. Nicoloau. C . W. Hummel. Y. Iwabuchi, ./. A m . Chrm. Soc. 1992. 114,
The mixture was treated with saturated aqueous NH,CI ( 5 mL) and then extracted
3126.
with EtOAc (3 x 10 inL). and the organic phase was dried over MgSO,. The crude
[I41 We moved our operations to the solution phase because, at this writing, we can
product n a b purified by silicd gel chromatography (1 : 3 EtOAc: hexanes) to give 25
not yet implement the azaglycosylation protocols with complex acceptors in
as a colorless oil (42 ing, 55%): 'H NMR (400 MHz. [DJacetone): 6 = 8.17 (d. 2H,
the solid phase mode. Work on this goal is in progress.
J = 7 3 HA.PhSO,), 7.50-7.20(m. 33H. ArH).6.52(d. 1H. J =10.5 Hz. N H ) , 6.30
[I51 D. A. Griffith. S. J. Danishefsky, J Am. Chem. Sor. 1990. 11-7. 5811
(dd, J = 6.0 Hz. .I = 1 5 H7,. 1H. H , glucal). 5.35-5.32 (m. 2H), 5.25 (d. IH,
[I61 S. J. Danishefsky. K . Koseki. I).A. Griffith, J. Gervay. J. M. Peterson. F. E.
J =7.9 Hz).5.15 (m. 2H). 4.99-4.92 (m, 3H). 4.86-4.52 (in. 14H), 4.45 (dd. I H ,
McDonald, T. Oriyama. J A m . Cham Sur. 1992, 114, 8331
./=7.91 H/. J = 2 . 4 H r ) . 4.32 4.23 (m. 3H). 4.22 (m. IH). 4.17 (d, l H ,
[17] M. A. Bernstein, L. D. Hall, Curbohydr. Res. 1980, 78. C1.
J =10.1 H7). 4.08-3.84 (m, IXH). 3.79-3.73 (m. 2H), 3.66 (m. l H ) , 3.55 (t. l H ,
[I81 Cf. A. Giannis, Angeiv. Cl7em. 1994, 106, 188; Angew. Cben?. /nt. Ed. Engl.
J = 6 H L ) . 3.50 (dd. .I = 9.7 Hz, J = 2.8 Hz, IH). 1.33 (d. 3H. J = 6.5 Hz. CH,
1994, 33, 178.
fucose). 1 .?I (d. 3H, J = 6.4 Hz, C H , fucose). 1.20-0.98 (m, 84H, 3 x Si(iPr),): ',C
1191 A recent report by Wong et al. describes a major accomplishment in the field
NMR ([D,,]acctone): d =145.66 (C=O), 132.72. 131.48, 131.45. 131.28. 131.16.
in which chenio-enzymatic methods are used to assemble a glycopeptide on a
130.77. 130.18. 121.31. 120.11. 119.86, 119.78. 119.25. 95.63. 94.70, 91.37, 89.64.
solid support: M. Schuster. P. Wang, J. C. Paulson, C.-H. Wong. J Am. Chcm.
89.31, X O 52. 73.38. 72.24, 71.00, 70.71. 70.37, 69.80, 69.59, 69.06, 68.23, 67.92.
Suc. 1994, 116, 1135.
61.3X, 67 10. 66.49. 65.67. 65.33, 64.60. 64.34, 64.03, 63.45. 63.30, 59.46, 58.83.
58.37,54.45.53.32,49.86. 19.67(C,,fucose),18.42(C,fucose).9.55.9.48,9.45.9.31.
9.13, 3.X2. 3 70. 3.64: IR (thin film): i. = 3491.9 (OH), 3030.1. 2941.2. 2865.5,
1835.8. 1x19 5 . 1649.8. 1496.2, 1462.3. 1349.9, 1245.5. 1155.2. 1095.1, 1049.4, 882.2.
734.8. 692.0cm -'; [2]y = - 33.8 (C = 2.0. CH,CI,);
HRMS (FAB):
('iC,,,i'CH,-,NNaOL,SSi,): calcd 2278.1292. found 2278.1296.
17: ' H NMR (400 MHz, CD,OD): 6
6.00 (m, IH. CH,CH=CH,), 5.37 (dd, 1H.
The First Mononuclear Nitrosyl(oxo)molybdenum
Complex: Side-On Bonded and p3-Bridging NO
f u c o s e ) . 4 . 6 4 ( d . l I I , . / = 6 . 9 H~),4.45(d,lH.J=7.4Hz).4.43-4.23(m.2H),4.27Ligands in [(MoL(NO)(O)(OH)},]NaPF, *
( d d . l H . J = ' ) . 3 H z . J = 1 0 . 6 H ~ ) , 4 . 2 3 4.11 (m.2H),4.0?-3.29(m,31H).2.06(s.
H,O**
3H. NAc). 1.31 (d. 3H. J = 6.6 Hz. C H , fucose). 1.29 (d. 3H. J = 6.6 Hz. C N ,
=
J = l . h H / . J = 7 . 3 H z . CH,CH=CH,), 5.20 (dd. 1H. J = 1 . 6 H / . J = Y . S H z ,
CH,CH=CHZ), 5.18 (d. 1H. J = 3.9 Hz. H , fucose). 5.10 (d, I H , J = 3.8 Hz, H ,
fucose): ' 'C NMR (CD,OD): 6 = 173.20 (C < = > 0),135.73 (CH,CH = CH,).
117.51 (CH,CH = CH,). 105.13. 103.30, 102.49. 101.62.99.63, 96.86, 80.79, 80.67.
78.44. 7667. 76.49. 75.89, 74.80, 74.59. 73.94. 73.61. 73.40, 71.55, 71.3X. 71.16.
70.96. 70 42. 70 26. 70.14, 67.77. 67.30. 67.21. 62.79. 62.34. 61.99.55.54, 22.97
(NAc). 1 6 65 ( 2 C's. C 6 fucose); IR (thin film): = 3376.6 (OH). 2924.2, 1652.5
( C = O ) . 1383.1. 1032.4 c m - ' : ';IX[
= -12.8 (c = 0.25. MeOH): HRMS (FAB):
(C,,H,,,,NNaO,,): calcd 1062.3853. found 1062.3837.
Received March 9, 1994 [Z6745IE]
German version. Anymi. Chcm 1994. 106. 1538
[I] V. Behar. S. J. Danishefsky. Angew. Cl7em. 1994, 106, 1536; Angew. Chem. I n r .
Ed E J f r / 1994,
.
33. 1468.
[2] For alternative methods for synthesizing Leb oligosaccharides. see: a) S. S.
Rana. J. J. Barlow. K. L. Matta. Curbohydr. Rex 1981. 96. 231; b) U . Spohr.
R. U. Lemieux. Curbo/iwIr. Re.s. 1988, 174. 211.
131 T. Boren. P. Falk, K. A. Roth. G. Larson. S. Normark. Sriencc., 1993. 262.
1897.
[4] J. Alper. Sc m w 1993, 261). 159.
[5] a ) D. Y. Graham. G . M. Lew. P. D. Klein, D. G . Evans. D. J. Evans, 2. A.
Saeed. H. M Malaty. Ann. Intern. Med. 1992. 116. 705; b) E. Hentschel, G.
Brandstatter. B. Dragosics. A. M. Hirschl, H. Nemeg, K. Schutze, M. Taufer.
H. Wurrer. .Y. Eng/. J. Med. 1993. 328, 308.
[6] N. Shei-on in Tbe Leerins. Prop
, Functions und App1icution.rin Bio/og,v und
M c d f c i n c (Eds.: 1. E. Liener, N. Sharon. 1. J. Goldstein). Academic, New York.
1986. pp. 494 -525.
A u g m . Chnf I n l . Ed. Eng/. 1994. 33, N o . I4
!ii
Jochen Bohmer, Gabriele Haselhorst,
Karl Wieghardt,* and Bernhard Nuber
The combination of a strong TC donor and a n acceptor ligand
in a transition metal complex leads to an interesting situation in
terms of electron density, because a strong (p, --t d,)-donor
bond requires an electron-deficient metal center, whereas stable
(d, --t p,)-backbonding requires an electron-rich metal center.
An example of a strong 71 acceptor is the nitrosyl ligand, and the
terminal 0x0 group is a good n donor. Mononuclear nitrosyloxo
complexes are as yet unknown,"] but two p-0x0-bridged nitrosylmolybdenum complexes". 31 of the { Mo -NO}4 typec4' have
been structurally characterized. In both cases, the Mo-O,,, dis[*] Prof. Dr. K . Wieghardt, J. Bohmer, G. Haselhorst
Lehrstuhl fur Anorganische Chemie I der Universitit
D-44780 Bochum (FRG)
Telefax: Int. code + (234)7094-378
[**I
Dr. 6. Nuber
Anorganisch-Chemisches lnstitut der Universitit
Heidelberg (FRG)
This work was supported by the Fonds der Chemischen lndustrie
VCH Verkugsge.srNschufrmbH, 0-69451 Weinheim, 1994
0570-0833i94/i414-1473 S 10.00f .ZS/0
1473
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forma, complex, solis, domain, support, strategy, oligosaccharides, bioconjugatable, concise, synthesis, branches, assembly, interactiv, lewis
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