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Preparative syntheses of 2,6-dideoxy-α-L -lyxo-hexose (2-deoxy-α-L -fucose) and its D -ribo epimer (digitoxose)
Curboh~drarc Research, 58 (1977) 139-I 51 $2~ Else~~er Screnufic Pubhshmg Company, Amsterdam
PREPARATIVE
SYNTHESES
(2-DEOXY-LY-L-FUCOSE) TAR
MING
2,6-DIDEOXY-z-L+.w-HEXOSE
AND ITS
DEREK HORTON. AND
CHEUNG.
01’ Chzmrslry,
Deparrmtvu
OF
The Ohro Stare
- Prmted III Belgum
D-rib0
EPIMER
WOLWAIUG
WECKERLE
(DIGiTOXOSEj
L, Columbus, Ohro +JIIO
Unw~r~~f
(Received Drccmtrer 31st. 1956: accepted for publisstlon.
(0.
S. A.)
January 20th. 1977)
ABSTRACT Methyl into
3.4di-U-benzoyl-6-bromo
the 3-O-brnzoyl Compound
(1) is converted
4,6-C)-ben~lideoe-2-deo\ry-a-D-ribo-he~opyranoside
methyl
deribatile
-2.6-dideoN)‘-;r-o-rrbo-hexopyraooside
(2) of 1 by subsequent
3 is the key intermediate
trtle drdeoxy
in high-yielding,
by hydrogen
with
preparative
glycoside 7. which undergoes
net intersion
at C-5
to gike methyl
are readily
obtained
gives the crystalline from
1 Hitbout
by catalytic
syntheses
stereospecific
reduction
of 3 pro1 ides the 9 (L-~,v.Yo) and 5
and mild,
and 6 (wibo)
title sugars 10 (L-(WI)
of the
3,4-di-U-benzoyl-2,6-dideoxy-
transejteriticatron,
the necessity of chromatographic
ria
Deh)drohalogenation
B-L-~~,.ro-he~opyranosidz (8), ~%hereas reducuw dehalogenation corresponding D-riho derivative 4. The unprotected glycosidss (D-fibs)
(3)
with Iv-bromoslrccinimide.
antibiotics.
of many
sugars, which are constituents
of 3 affords the 5,6-unsaturated
treatment
acid hydrolysis
in 45 and 57Ob overall yield
purificatron
at any of the steps.
INTRODUCTION A program anthracycline and/or
in this laboratory
antibiotics
stereochemically
are clinically
effective
modified3 against
severe cardiotoxicity” hoiiever,
broader
spectrum
might
already
been prepared
display
of antitumor
2,3,6-trideoxy-L-/_rvo-he\o+z). and L-ribo’
analogs,
and/or
the original by
activity
than
of daunorubicin
and
arc
sugar,
of the
structurally
Both antibiotics drawback
Structurally
possibly
its r-arabiuo’.
products”
the parent
dideoxy-L+*.t-o-hexopyranosyl)-daunomycinone* *Note added in proof: C36-C39.
and
exhibit
daunosamine
is a
related an eben
anthracyclinesb
have
(&amino-
6-hydroxy-L-arabino’, with ~-glucose
of daunomycinone
some of these products
appear
to show significant
drugs.
In order to study the effect of the amino the antibiotic
dose-levels.
semisynthetic
amino
of analogs
but their major
toxicity
Several
[hat
constituent.
of cancer,
decreased
as ~tell as coupled
less toticity
adriamycin’,’
at the most effective
IS replaced
and ‘-runino-‘-deoxv-D-glucose:; activity
forms
activity.
in which
wrth the synthesis
and
in the carbohydrate
various
manifested
analogs,
is concerned
daunorubicin’.’
group at C-3 in the sugar moiety adriamycin.
the
synthesis
and -adriamycinone
see E.-F. Fuchs, D. HOI-LO~,and W. Wsckerle.
upon
of 7-O-(2,6-
was considered
Curboh_tdr.
Res., 57 (1977)
110
T. hf. CHEUNC,
a desirable
objective.
antibiotics,
except for ewbangz
in mind.
3 new
designed, related
The ,z anomers
synthesis
and is described
10
Compound (the same s~othesis
n3s
\iith
in this p3per analog prepared
only minor
long before it WLS found in Nature’ (refs. (ref.
II
and
lblia.
The (D-
(D-
B (refs.
17), and. apparently.
ethers 3s
15) and
D
enantiomorph
LouId
together
HORTON,
be identical
by 3 hydrouyl (10;
with
W.
H’ECW
to the parent
function.
Wi!h
this
2-deoxy-L-fucose)
the preparation
HW
of [he closely
6 (digitoxose).
Iselin and Reichstein”
by
modifications
14 and
16).
cardrsc
of 10 is known frequently
quite recently)
of rhodomycins”,
the macrolide
antibiotic
cinerubin
X
3zalomycin-B
glycosidc ’ 8 from Peniopdia androsaemi-
as o-oliosc”:
occur
by the glycal method
has been reporred”
3 3s 3 constituent
as part ofa
and L-diginose)
group
of 2,6-dideoxy-L-!l,ro-hertosc
D-ribo
(kpimcric)
of these products
of the amino
D.
’ 3*20
the corresponding
in cardiac
3nd prcgnaoe
3-methyl glycosides,
do 2.6-dideo~y-D-rih~-heuose (6; digitosose) and the enantiomeric 3-methyl ethers (6) was first synthesized by Iselin and Rcichstzinz2 and L-cymarose). DlgltoYose”
through
the
rn moderate opening
v;orkers25
glycal
method.
yields
reaction
from
by Gur and Prinsz3
3 2,3-anhydro-D-a//o
prscursor
and Bolliger rhrough
and ULich”
au epo.tide
ring-
deosygcnatron at C-6. rn 1971. Hag3 and co3 route to compound 6 similar ro the one presented here.
and
described
and, later,
subsequenr
DISCLISSION The
(prepared
reaction either
of met hj I 4.6-0-benq by reductive
cleabagezh
lldene- 2-dcoxy-a-D-ribo-hexopyranosidc of the epoxidc
ring
in the corrzspondins
(1)
5
3
a
142
T. hf. CHEUNG,
2,3-anhydro-D-a//o aluminum 3-O-beozoyl ad-line
derivative,
hydride’,“) derivative
pattern
ion at /n/r
370:
physical
chloride
2. that sboHed
of ithe 3-keto proceeded
in its p.m.r.
analog
readily
spectrum
see Experimental
constants
of 2 were
section)
further
in good
apeement
WECKERLE
of 1 with
lithium
crystalline
to give the
I), in particular,
displayed
the anticipated
‘, and mass-spectrometric
at 1725 cm-
W.
(see Table
for H-3 at low field (Cs5.56). The i.r. spectrum
ester C=O absorption The
or by reduction
with benzoyl
D. HORTON,
data (intense
supported
molecular-
the structure
with
those
assigned.
in the
reported”’
literature for ttis compound. ‘Trcnuneilt
of the benzoatc
chloride,
by the general
dioxane
ring ar d formation
2 with
procedure
A’-bromosuccinimide
of Hanessian28~19,
of the 3.4-dl-Gbenzoyl-6-bromo-6-deoxy
isolated crystalline: in 7996 yield, and characterized q .m.r.
(see Table
precursor
in tie
rhe D-ribo”’
IIAJOR
by elemental
mass specirometry.
Compound
of the Sepimeric
title stigars,
in Lh: syntheses
established
TABLE
I), and
in dry
preparation
(D-ri~tosamine)
of the corresponding nnd L-~*xo3
following
tetra-
of the
1,3-
anal~g’~~”
3,
analysis,
3 constitutes
and
i.r..
the common
procedures
3-‘amino-3-deouy
(daunoszunine)
carbon
led to opening
analogs
wellhaving
configurations.
II F?.%ChlENT-IOhS
OBSERlED
13
THE
EUCX7Oh’-l~lP.4Cl
MASS
OF COhfPCLfNDS
SPECTRA
+6
AND
010
m,% of prrncrpul CompJunJ 4b
frJ,ormlrs=
_ J
(c.L oihw
6
.-tssrgnmmr
ped)
8’
.
10
9
162
(1.1)
(0.7) (0.4)
(0.05)
(0.01) (0.03)
149 1-U
371
370 309
370
(0.15)
16’
(0.06)
369
(0.25)
161
336
(0.03)
130”
10.9)
130
(1.5)
338
(0.02)
216#
(49) (0.1)
II’ 97 65’ 39 9-1 131 113’ 95 I IS IO0
11.3) (04-J) (I.?) 1Sj (0.5) (7.5) (3) (1) (6.2) (1.1)
I I’ 97 6R 39 34 I31
(3) (2.5) (II) (3’) (?.S) (0.8)
216’ 201 339
(0.5) (0.05)
(0.03;
I30 I12 97 68 39 9-l 131
(0.15) (I) (3) (0.6) (2.5) (13) (2) (0.4)
I13
(1.1)
2170
(0.1)
1130
(1.3)
I13
95 I04 S6
(2.5) (6.5) (75)
95* 326 -
(1.3) (O.-t)
95 IIS too
(1.4) (4) (0.9)
59’ 60* 59 43 5Y
(lo@ (94) (100) (7s) (55)
4s 60’ 59 43 4
(70) (100) (4.5) (89) (70)
268 5s
(1.1)
60’
(100)
(03)
59 43 5s
(90) (24) (56)
(6.5)
312
(0.08)
104.
(20)
XI1 339 217’ 95’ 376 -
(0.1) (1.6) (5.5) (0 !)
ZaJ s5
II)
(0.9)
313
(0.03)
IO-4
(27)
lo4
59. (90)
119
(0.04)
hf+
l-8
(0.01)
rb1:
130
(0.2)
Al
I I’* 97 65 39 91 I31
(0.3) (0.5) tl.8) (-5) (0.3) (I.Zj
A:
I
hl - I
9s
;:J A,’ A:=+ c,
(I)
(0.3)
::
tw 86
(8) (41)
D, Dj
45 60* 59 43 +i
(50) (100) (2.5) (37) (15)
D: Df D: D: E:
(S)
E:
10-t
fragments obsened m the spectra are iodlcstcd by ti asterisk at the dsughkr de\iollons bclecen observed cod calculated values arc fess than fO.l mass un~ti bAddllionzJ fragment ton5 a[ q’r ‘4s to 25, hl - BzOH), I05 (100, PhCO+), and 77 (20. Ph’). CAddlfloanl fragmeol 100s al m/e XS tO.lj, hf -BrOH). I05 (100, PhCO-), and 77 (25. Ph’j. ‘Adapted from the fragmsntstion pnthecl)s proposed by Taknhnsbl er uf. (ref. 17). JPrornlncnt
melaslsblc
wn of the process involved;
113
2,6-DIDEOXY-cr-L-I~XO-HEXOSE
Reductive debromination
trietbylamine resolved
p.m.r.
indicative 8-tine
spectrum
signal
(doubled
experiments;
croup
quartet)
the remainder the structure
data of 4 with Inversion
syrup
in high
spectrum Table
The
for
(ti 4.65),
two
preponderantly
predisposition
could
and the 3-benzoyloxy C-S
presumably
conformatIon
compound
or
evhlblts the other.
8 (see Table
of the ‘c,(D)
The
such coupling
We are indebted
and H-4,
conformation that*
used”
3 with
indicated protons
of
respectively.
data (see
(;i 4.75)
H-6 The
and
large values
the presence (at C-I-C-J),
of three
suggesting effect. br,hich
group33.
This
between the I-methoxyl
as the msthylenc
including
fabonng ihis
substituznt
either
spectrum
the
one
to that
of
the fact that H-2~ and H-3 and. that the ~all;es for J, ,ze
probides
for compound
no long-range
by its i.r.
for
I-merhoiyl
interactlon
silver
(by t.1.c.)
the spectrum
despite the anomerlc
interaction””
in
sIgnsIs,
(J6,hS I Hz).
of the
large,
derll atibe 8,
AO
\$a~ confirmed
doublets
resemblance
are relatively
further
indication
7 in solur;on.
couplin,o
of
the
in addition
between H-l
and H-3
\\ould ha\e been expected for the ‘C, (D) conformation
in the spectrum
but not for the ‘C4(~)
favored,
Ggnilicnnt close
the physical
as ~~11 as by p.m.r.
disposed
of a strong
little
there is the “ne,oati\e evidence” was observed;
respectively)
I ; see nevt paragraph),
preponderance
(as i\as verified
product
and aryl proton
orientation
L-/I
of the bromide
one-proton
is strongly the rrvial
composition
bstneen
7 33 a homogeneous
group in the ‘C, (D) conformation.
and 4.2 Hz)
l
narrow.
be the result
(3.5
Jze.3
this
metho\)
tra,rs-diauially
resonate at higher field than H-21
and
Treatment deribativc
a small gemtnal coupling
conformation to Tabor
and elemental
sequence succzssfullg
at I660 cm -‘)
to the anticipated shoiied
operates
by an
in the literature.
assigned
absorption
each displaying
that the ‘C,(D) generally
at
structure
J, ,2a and J2u,3 (6.2 and 8.9 Hz,
consecutive,
field (6 1.37j
by double-irradiation
at C-S, in order to prepare the
of daunosamine.
(vinyl-stretching
r). In addition
II)
the elimination-reduction
the SJSunsarurated
of 7 in benzene-d, H-6’
as demonstrated
as did the good correlation
of the configuration
yield.
is represented
6 4.53,
data (see Tab!e
indicated.
synthesis
at high
The
latter
of
presence
yield. The well-
a doublet
to H-5.
those given 2’ for this product
furnished
fluoridez3
I) shotled
in the
4 in 94%
of the spectrum closely resembled that of the precursor 3
Has achieved by exploiting the analogous
derivative
coupled
at
1). hlass-spcctromerric
supported
6-deoxy
of 4 (see Table
of the 5-C-methyl
(see Table
of 3 was effected by Raoey nickel
to give the crystalline
of the related
conformation.
to a rereree for this orgumenr.
compound
4, lvhere JJ,,3
is -
I Hz),
I44
T. hf.CHEUNG,
D. HORTON.
W. WECKERLE
Catalytic hydrogenation of 7 m tbe present of palladium on barium sulfate led to a single, crystalline product (8) that was different from the D-.&O compound 4 (by g.1.c.). although it gate a mass spectrum (see Table II) identical to that of 4, except for the Intensities of the fragment ions. The IOO-MHz. p.m.r. spectrum in benzene-cl, (see Table I) was essentially firsI-order, displaying, in particular, a Sproton doublet at hipb field (6 1.15, C-hle) and well-resolved, one-proton sigals for H-l (8 4.1 I), H-3 (b 5.20), and H--I (d 5.39); these data establish unequivocally the L-/I,VO rtercochcmijtry
of the product obtained.
Tbe assignment of the bigher-
(and lo~rsr-) field signaIr_ (6 2.14 and 2.32) of the geminal
protons
at C-2 to the
equatorialiy
(and axially) disposed hydrogen atoms is based on the observed couplingcomt3nt~. and is consistent nitb data for other 2-deosyhzuopyranoses that have been Although this interpretation contrasts thoroughly srudied 35 bv _ n . m.r. spectroscopy. \rith the convenrional tic\\. this assignment is considered correct, and is ascribed to the deshislding (or shielding) effect of rhe neighboring 0-benzoyl group upon the axial (or equatorial) hydrogen atom at C-3. Indeed, the frequently used generalization that equatorial-proton signals lie downfield from those of axial protons in pyranose systems has been sho!\n before to be reversed in such compounds 3s methyl 4,6-Oben~,Jidcne-~-decuy-~-o-~~~,~/~~~-be~o~yrano~id-~-uloje~7.36, its oxime”, and35P37 merhl
I 3-acetamido-l-0-acet~l
-2.3.6-lrideoky-r-L-riho-heuopyranoside
(methyl
di-
acetylrisrosamlnlde), 0-Dcacylalion
alrhough these ha\e heen said3’ to be e.uieptionnl. of-# and 8 tc’3sefTecredby catalytic transesterification to give the syrupy a-r&o (5) and crystalline L-/J*_YO (9) methyl glycosides in good yields: their physical con51antS wcrc consistent ~lth those recorded for”‘S’5*39 5 and” 9 in thz
liferaturc.
The final step in the two sequences ~3s accomplished by hydrolysis of the methyl glqcostde< 5 and 9 141th aqueous acetic acid. to yield cryjlnllinc XLdideo\yD-r&o-be\ose (digitokose, 6) and the slightly hygroscopic, c~stalline, Sepimeric, L-/JAO compound 10 (2-deohj-L-fucose). The physical data (m.p., specific rotation in methanol
and in water at equilibrium)
of compound
6 were in
gencr31
accord Hith
those recorded for digitosose obtained 2 I from natural sources and 2’-2 5 for synthetic producrs. Because of rhz cornpie\ mutarotarion, no assignment of the anomeric form IO the crqstsilin~ state V\~S made, alrhough Bolliger and Ulrich claimed’” that it is rhe /3 anomer. The L-!~:w analog 10, M hich is the cnanriomorph of the naturally occurring didcoky sugar oliose’9, crystalked In the ?r-~ form, as evidenced by its upward mutarotation in water and acetone; the final specific rotations sbobvad good corr-lation Hlth those recorded for the synthetic” and” natural product. The foregoinp syntheses afford the title sugars 6 and 10 from 1 in 57 and 15% nzt yield, based on intermediates isolated directly, with no chromatographic purificsrion involved at any of the steps: all of the reactions are readily amenable to scaled-up operations. hlass-specrromctric dara for the deriiatlles 2, 2, and 7 arz @ten in the ExperImental sectIon. For the other compounds described In this paper, the principal
fragments. together with their relative intensities, are summarized in Table II. The pathways deduced for the fragmentation, as detailed in Scheme I, are based on plausible mechanistic steps and accord, in part, \\ith those proposed” by Takahashi and co-workers.
Cleavage
of the glycosidic
undergo
successike
pyrylium
ions A,
AS.
Altemati\cly,
odd-electron
loss
of
and C,. A,
ion A:.
bond leads to ions of the ,A and C series: A,
two
The
more
former
may rearrange
Through
ring-subsrituents.
loses’ ’ t\so formyl ”
C-l-O-5
affording radicals
and C,
the substituted to furnish
A,
and
and gi\e. through elimination of water. the rupture of the pjranose ring, ions of the D
end E series arise by subsequent clca~a_ge of a cecond rin,a-bond between C-2 and C-3 (E series) or C-4 and C-S (D scriesj. Fragmentation of D, may proceed either by loss of Hater
and an oxiranyl
radical
spectra of the unsubstitutcd loss cf a C,-fragment, fragment proton
into
D:.
Ei through
elimination
or a hydrosyl
radical.
respectively.
to form
cornpounds This
Di
as one of the most abundant
($69,
odd-electron
of acetaldehyde; to form
ions in the
and 10). or D, may decompose. ion may alternatively it decays further
an open-chain
(Dj)
by expulsion
or cyclic
with
arise from
(Di)
of a
cation.
146
T. hl
The alCoremenrioned framents
observed
isomeric
assignments
in the spectra
structures
CHEUNG,
D.
arc in many instances
(as indicated
in Table
HORTON,
W.
supported
WECKERLE
by metastable
IT), but the possibility
of
is not precluded.
EW’ERlhfENT4L
Genrrul at
3
bath
Hoover I-dm
r?rrtirodq. -
temperature
apparatus
tubes \iere 3
kvith
spectra shifts
together Table
hlodcl 3t
100 hll-!z
to an internal
standard
111th spin-coupling
menrs.
Inlegations
dcrestrd
volumes
Column
hlicrosnalyses
were by C.
5pecrrometer
potsn:ial
of S kV:
probable
assignments
Scheme
I. The
/r-rupture Relative mately
of methyl
benzoyl rshich
ionizing
and
(direct-inlet
X-Ray
boiling
radiation. visually: (I,
The
strongest):
j(m).
spectra
Mass
high-
an accelersring
was
120’.
Data
in Table
oi compound
2 refer
diffraction
camera
IO’.
63-200
double-focusing.
system)
m, moderate,
heating.
at 65-I
7734;
of 70 eV and
poader
T.l.c.
zones were
subsequent
No.
in
euperi-
in all instances.
MS-9
potcntiol
listed,
of 250 Hz)
Darmstadt);
A-6 and S-10 are summarized
t-t al “.
time
with
-I,6-O-benzylicienein dry (5.;
1.1.~. (3:l
pyridine
dnts
and
and
II
to the
give inter-
113.59 mm.
diameter
was
s, stroog;
v, very;
w, weak.
numbers
indicate
approui-
double
dlchloromethane
Sulfaie).
(MO
from
and evaporated.
the residue.
to give pure 2: )i?ld
The
eiher-perrokum
was then poured
and
cooled
mixture ether)
into ice-water
l20-ml
portions).
in an ice-water was kept
indicated
Toluene
(t\!o m.p.
the
The extracts
hydrogenczrhonate
the crysrailine
for
-
bath,
reaction
to
marerial 94-93”,
was [a];’
be ~‘9s
were combined,
and
ZO-ml portions)
was
I2 h at -25’,
(600 ml), and the product
sodium
15.31 g (89%).
(2).
2-deo~y-r-D-ribo-he~opyranoside~.2h.’7
(ZOO ml),
ml. 45 mmol).
successively with aqueous
evaporated elhnnol.
chloride
The milrure
(magnesium
widrh
are
by decoupling
of this Department.
an AEI
chemical
and
_?-O-i7~n~o~~l-#,6-O-h~n~~~/n~-~-~~o.~~~-r-r)-ribo-he.ro~~~ranosi~r
13.3s g. 46.5 mmol)
\fajhed
acid
and /J? in the assignment
\ierc estimated
(1:
e\trsctcd
/I,
Rond
‘H-N.m.r.
intensities.
lifethr#
complete.
N.
rempcrature
.&. l-or CuKz
a solution
after
instances
gel (hferck
tvith
for compounds
To
added
at a sweep
refers to the fraction silica
by W.
lines are numbered
equal
ether
discs.
spectrometer: (8 = 0.00).
sulfuric
and
with solids dispersed
the peak assignments
U’cisenberger
by Chizhov
intensities
jrrongest
with
3t an
141 polarimeter
chloride
HA-100
in most
i\ith
operating
notations
sodium
measured
by sprayn g wirh
the source
proposed spacings,
planar
(Hz,
pressure
a Thomas-
with
1-r spectra were recorded
plates of Silica Gel 60 (E. hlerck,
performed R.
on
a Varisa
confirmed
~var performed
xserc recorded
hlodel
of tetramethylsilane
are k/k’: petroleum
filtration
re5OlutiOn
and
diminished
i.r. spccrrophotometer.
with
were consisrent
on precosted
by u.\*. light.
Sollent
\tere
under
were determined
A Perkin-Elmer
as films
values
assignments
~vasperformed
The
syrups
points
of specific rotations.
457 grating
and
recorded
I. The
were pxformed
Melting
and nre uncorrected.
bromide
\tere refer
50’.
used for measurement
Pcrhin-Elmer
in potassium
Evaporations
below
water,
dried
was added to and recrystallized
+ IS5’
(c I,
from chloro-
form) and
(lit.2”
(0.16,
95-97’,
m.p.
’ (aryl);
695 cmhi-LleO-),
[ctlD + 193.1’ in chloroform):
m/e (rd.
293 (0.4,
hl-
221 (50, 11,; m* at 132.0, talc.
caic. 44.35), 8.62 w,
intensity): Ph.),
370
7.72 s (3,3),
369
X-ray
powder
7.31 VW, 6.70 \c’, 8.84 s(3,3),
m” at 4-l.3, II.47 w,
ditiraction
5.45 m.
750
(5,
h, -BzOH:
l-19 (5, /I?), 99 (100.
105 (85). 91 (9.5j. and 77 (37):
C=O).
hl - H .), 339 347 (0.1, hl- BzOH),
hl*).
hl - FhCHO),
264 (0.5,
132.00),
Van: 1725 (ester
(17.2,
data:
6.6Os(l,l),
4.51 s(l,l),
5.64 w, 4.12 s (2,2), and 3.93 s (2.2). Anal. Calc. for C,,H,,O, (370.40): C, 68.10; H. 5.9s. Found: C, 68.26: H. 5.S5. ~Ilrill~~l3,4-di-O-ben,o~~l-6-bronlo-,$.6-didt~o.~~~-~-~-ri bo-lrelrop~ranosid~(3). - .A mixture of rhe benzyltdene acetal 2 (25.7 ,g. 69.4 mmol). N-bromosucc~n~m~dc (I 3.35 g, 75 mmol), and barium carbonate (20 g) in dry carbon tetrachloride (500 ml) was boiled for 5 h with stirring under rctIu\, during which time the color of the solution, originally colorless. became successively yelloiv. red. and finally pale-yellow. The solsent
was distilled
OR; and the residue eitractsd
portions).
The
extracts
of sodium
hydrogensulfite
and evaporated ethanol
and sodium
~2;
m.p.
172s (ester C=O).
intensity):
(0.2.
327
(0.25,
data:
dichloromethane
successively
hydrogencarbonate. crystallIne
3: yield
wirh
dried (ma?neslum
sulfate),
was rscryjtnllized
m.p.
96-g%.
IOO-102’.
[rlD
1580 cm - ’ (r,;onosubstltuted
hl-
IO.71 VW. 9.66 s (3).
I05 (100).
[r];’
in chloroform,
hl - MeO-),
(0.05,
BzOH).
+ 172.6’
117
and
I50-ml
solurions
residue
24.7 g (79?b),
(Ihrec
aqueous
1600 and
111t ). 4lS
449
RI - Br-),
fraction
(lit.”
purz
i\ith
washed
‘I he resulting,
to give analytically
96’): (1.7.
combined,
to dryness.
(LB0.6, chloroform) (rrl.
uere
and’”
m.p. 9C
phsnyl);
IIJ,‘LJ
hl - hIsOH).
(0. I,
77 (IS).
from + I92 5’
S-ray
369
poivdrr
8.62 w, 6.68 tv. 6.10 m. 5 53 w, 5 I7 \w,
dlf-
4.91 vi\.
4.34 s (2.2), and 3.82 vs (I). Anul. Calc. for C,, H,, BrO, (49.30): C. 56.13: H. 1.71; Br. l7.7Y. Found: C, 55.91; H, 4.69; Br, 17.97. Mril~_~~l _~.4-~i-O-bcn=o~‘f-,),6-did~o.~~~-~-D-ribo-/r~rop1 rurrosidc (4). - ,A mi \ture
4.75 s (2.3).
of the bromide in methanol whereupon catalyst
t.1.c.
(9:l
was removed
in chloroform
that \\ere
g, 22.7 mmol).
by filtration, The
bromide,
recrystallized
[*x]A3 +227.3’
nickel
hydrogen indicated
the filtrate
solution
uas
from
hexane
(c I. chloroform)
to afford
(lit.”
(-h
m.p.
g). and tnethylamine
at 4.2 hg.cm-” the
rcactlon
evaporated,
washed
dried (magnesium
twice
sulfate), 83-85’,
with
wafer
+214.6”
The
dissolked
to remove
and evaporated
data:
-35’.
to be complete.
and the residue
[xlD
(3 ml)
IX h at
for
to gi\e
pure 4; yield 7.9 8 (959;).
’ (ester C=O); X -rav powder diffraction 4.91 s(Z). 4.65 s. 4.is(3.3). 3.97 ~(3.3).
1720 cm-
5.15 vs(l),
Raney
under
benzene-ether)
(150 ml).
ethylammonium
v:!:
3 (10.2
(200 ml) was shaken
tri-
crystals
m.p. SO-d?‘.
in chloroform):
IO.21 s. 9.M
3.77 w’. 3.1s m,
m, 6.23 m. 3 35 m.
and
3.19 m.
.Arral. Calc. for CI,H2200
(370.40); C, 68.10; H, 5.98. Found: C, 67.91; H. 6.36.
hletlz_d 2.6-d~deo_u?,-r-D-n’bo-~~~.~o~~,~u~~~;de (S). - To 8 solution of compound 4 (l.37g. 2.7 mmol) in abs. methanol (30 ml) was added 51 sodium merholide (0.4 ml), and the mixture ~vas kept for I2 h at 33”. at which point f l.c. (19:l ethyl
T. V.
148 acetate-methanol)
indicated
that
transesterificafion
evaporated,
and
Chloroform
~c’as used first as eluant
washed
off the column
colorless syrup
distilled and
17S.4’
+
placzd
on a small to remove
lvith acetone,
at 40 mtorr
+ 169.1
was complete. column
methyl
(c 2.3,
and3’
for C,H,,O,
temperature
chloroform)
(lit.‘s
(D-tiigifo.rose.
6). -
A solution
in acetic acid (3 ml) and water
Eiaporatlon
gave a residue
little
The
iierc
qreld
(c 0.74.
crystals
303 mg
+47.5
(30min)+
methanol):
S-ray
AMID. Calc. +37.l I IO-I
I?‘,
&Z’
m.p.
109-I
1 I’, [a],,
f47.8”
(I h,
(l-IS.16):
in merhanol”; [r],
hiicheel
+5l
oa\e”
3’ (equil.) m.p.
r\frilI.~ / 3,-ihO&u:o
105-107~.
C, 5l.SO; under
reflux
upon addition acrtonz
(5.?0
min)
irater)
\I{.
5 for
that hydrolysis
frern
1.06,
8.2’
H, 9.00.
ofa
to gibe
-+
and
+51.7 $36.5’
7.31 LW, 6.63 vs (2).
3.88 wc, _7.65 m. 3.50 m. and 3.39 m. H. 8.16. [,z]~
-c + 50.2
Found:
C. 4S.79;
have been reported:
JOY-III’.
in \\*ater.
c
data:
constants
m.p.
A-3 (7 min)
+43.6
1.45,
in methanol:
indicated
+ 42-S
equii.:
C. 4S.64;
the follo\bing
+ I’
of the
(c
of the glycoside
crys!sllized
[r]:’
diffraction
4.33 s (3). -I.10 \s (I).
For this compound. [n]o
IO-S-103”.
po\\*der
for C,H,,OA
m.p.
that readily
m. p,
+ 192.4’
(7 ml) QBS boiled
off. and recrystsllized
filtered
(93O./,),
5.66 m. 5.01 iv. 4.71 \w.
source.
was then
to gibe 5 as a
in chloroform).
time t.1.c. (19.1 ethyl acetate-methanol)
itas complete.
[r]:’
ii. 8.70. Found:
C, 51.84;
(356 m,o. 7.2 mmol)
(7.50mio)-,
~35
of silrca gel.
The product
[mr], + 192.0
15 min. after which
6;
WESXERLE
solu!ion
The
was evaporated, 60-80’).
[,rJD f 173’
(162.18):
2,6-DiLjiOXL.-D-ribo-:le.ros~
pure
W.
(250 x 20 mm)
benzoate.
and the efluent
(bath
In chloroform”:
.-!~a/. Calc.
aceton?.
D. GORTON,
yield 560 mg (934/o). To secure an anal>%cal sample. a portion
syrup:
\\a~
methanol) ixlD
the residue
CHEUNG,
& 2
$38.1
(I h. equil.)
For digito’toje
[#x]~ +-i6.3’
~~l-2.6-didtw rl*-z-D-eryt
42’
m.p. in
H, 8.05. 108-l
in \\;lter2”:
isolated
IO’,
methanol’3:
from
and”
;i natural
in Lsaaterand +38.1” in merhanol. hro-/k* r-5mop~mnoside (7). X
mlvturc of the bromide 3 (9.1 g. 20.25 mm011 and dry, technical-grade (8 g) in do p)rldlne ( 100 ml) was thoroughly stirred for 40 h ar 25’.
silver fluoride”’ tihereupon t.1.c.
(chloro.form)
was poured
re$csled
that all of [he 3 had reacted.
The dark joluiion
into
ether (500 ml). and the resultant mit..turc was filtered. The filtrsre ~as evaporated, and toluene (three 30-ml portions) was added to and distilled from the residue to remove all of the pyridinc The rerrninipg, dark syrup \$a5 filtered through a small column (GOOx 20 mm) Evaporation yield
of silica
gel with
of the effluent
6.86 g (92X),
[z]g’
acetone
afforded + 123’
as eluant,
to remove
syrupy 7, sufficiently
(c 2.9,
chloroform);
residual
silver
pure for the following vet
1730 (ester
C=O).
salts. step: 1660
(C=C), 1600 and IjSOcm’ (monosubstituted phenyl); nl/e (rel. intensity): 369 (0.07. hl+l). 368 (002. hlf), 337 (0.13. hl-McO.), 215 (1.2, -‘37-&OH), 336 122 (7. BzOH’), (0.5, hl - hieOH). 214 (I .7. 336 - BzOH), Z-16 (4. hl -&OH). ICJS(100, PhCO ’ ; m+ at 90.-L talc. for I22 + 105: 90.37), and 77 (30). Although clber),
and
elemental
analysis
.;l/erlz~I unsaturated
the product
no signals
due
m&ted
as a slnple zone in t.1.c. (R,
to impuriries
dctzcted
0.83 in 9: I benzene-
in its n.m.r.
spectrum,
an
Iylng ivitbin acceptable limits could not be obtained.
3.J-(~l-O-bErl-q~~I-~,~-did~o
sugar
\iere
7 (4.45 g, 12. I mmol)
vl,-8-L-lyao-llz.uop~.ra~oside
(8).
-
The
in dry methanol (100 ml) was hydrogenated
149
~,~-D~EOXY-~X-L-(~‘.\.G-KEYOSE at
25’
under
sulfate
atmospheric
(450 m_e). After
up, and
t.1.c. (9:l
pressure
30 min,
benzene-ether)
by g.1.c. [Hewlett-Packard
lomzarlon
at 260’
min-‘1.
retention
technique.
-63
the reaction
palladium
equipped
Thecatalyst
5.43 m,
S-ray
(retention
time
-4
of min)
‘.6-didco~~-r-D-,.iho-he\op,ranoslde of the relention
homogeneous
8 as tine nwdlcs;
times.
(R,
a5 brell as by the residue
that
>Ield 3.32 g (38” L), m.p.
diKraction
-1.80 w.
\%a~ evaporated
0.75)
1600 and
__ (ester C=G). imJr nhBr I7Tq
pn\tdrr
5.1 I s(3).
gas at a Ho\v-raie
was filtered otT. and the tillrate
to furnish
As shown
H ith a tlam+
N ith 2”0 of OV- I on
a~ the carrier
3,+di-O-benzoyl-
chromatographically
phcnyl);
6.37 w.
helium
on barrum
had been taken
was complete.
only a single product
cl” (c 0.9, chloroform):
(monosubstitutrtd
6.53 \t,
10”;
of hydrogen
Series 5720.9.
by comparison
from ethanol
[x];’
with
contained
z 3 min)
a crystalline.
recrysrallized 123’.
(isothermal),
from methyl
time
miled-injection to gi\e
that
gas chromatosraph
1h e miltwe
rhat bias difkrsnr (4;
Lerificd
of
amount
detector and a glass column (1.83 m x 3 mm) packed
Chromosorb, 25 ml
in the presence
the theorerical
data-
4.53s(l.l).
12.90
m.
w;l~ IX-
IS5
cm - ’
S 00 5
7 31 s
3.51\w.
and
-Ll6s(l.I).
3.65 5 (3).
protected glycoslde 8 (5.3 p, 17 mmol) in abs. mrthsnol (50 ml) NBS sdded v sodium methoiide (0.75 ml). and the mtxture \5’93 hept for I2 h at 25’. sfrer which llme 1.1.c. (l9:l
ethyl
s01ver.t
acetate-methanol) distilled
~3s
small coiumn remo\‘e
(J% and
yield 3.2 g (809;). form);
X-ray
6.0015(l), Awl. For reported
x 20 mm)
the crystalline m.p.
pov.der
~3s
of rhe residue
complete.
wan plx~d
\\as used as rhe elunnt
The on
~1
first. 10
4.qSs(3,3), for CT H I .O,
this compound, 108-109~.
-Ll65(3.3). (162.
prepared [r$.,
glqcoside
recr,vsfnllized
+18“
3.00m.
3.82m,
IS): C, _$1.83:
f-l. 8.70.
eiher
and
LO gir*e pure
9:
_?.5Os!2).
Found.
by the glycal method.
C. 51.50:
Garep?
and
H, 900.
Norbcrg
rn chloroform.
(,7-tieo.yl’-I-L-~lcost~.
9 (990 mg, 6 IO mmol)
for 30 min under
from
+4-t’ (c 0 8. mcrhanol) and + 50.3 (c 1.2. chlorodata: ll.S9 m. IO.51 it. 9.45 m. 7.53 \k. 6.73 m.
diKraction
Calc.
’ 1 m.p.
product
I IO’. [xl:’
~.?5-Di~~~os~~-r-r-lyuo-he.~ose ~85. boiled
rransesterification
solurron
of silica sel. Chloroform
5.455,
of the merhyl
that
benzoate, and the producr was then elutsd with ace~onr. the et?lutsnt
methyl
evaporated,
indicated
ofi: and a chloroform
8r-r-oliorc.
IO). -
A so!urlon
in acetic acid (3 ml) and water (I 3. ml)
rcfluu, at I+ hich time t.1.c. (19: I ethyl acetste-methanol)
indicared that hydrolysis of the glycoside WCScomplete. The soltent ii;15 claporated OK and v.w~r (three success~\e IO-ml portions) ~3s added IO the concentrsr4 solution (- 2 ml) and ebaporared after each nddicion to remwe all of Ihe acetic acid Finally, syrup
rhe solulion (IO;
hydroxide
RF 0.29) for weral
H’~S evaporated
to dryness.
that
over
days:
was
dried
phosphorus
yield 890 mg (9896).
crystallization. and the crysrnls (IO) were filtered and dried; yield 630 mg, m.p. IO?-105’. [xl;” (4 min) _
- 73.S (6 min) -+ -64.8
(IO min) +
to afford Addition
off
pentaokide
and
hygroxopic potassium
of a Irtlle acetone
in an inert atmojpherc
-37 -Cl
a colorlc~s,
(initial.
e\rrapolated)
5’ (1 h, equil.;
efkcted
(nitrogen), ---) -81.3
c 1.0-L kvatzr) and
150
T. hf. CHEl.bJG,
D. HORTON,
W. WECmE
- I34 (initial, extrapolated) + - 13 1. I (7.50 min) -+ - 1X? (i 5 min) --D - 122.7 (30 rnin) -c -75.6” (JO b, equi!.; c 0.39, acetone): X-ray powder diffraction data: 7.93 s(3). 6.7s w. 6.12 vs(Z), 5.37 m, 4.S2 s\, 4.31 Vj(l), 4.12 ffl, 3.95 m, 3.72 W, and 3.48 m. .&al. Calc. for C,H,zC3, (145.16): C. 48.64: H. 3.16. Found: C, 4S.65: H, 3.37. Iselin and Reichstein reported * ’ ior this product m.p. 103-lr>6”, [& - 136.2 53’ in acetons and -90.4 +2 (5 min) 4 -61.6 1-2’ (90 min, eqtiil.) in Hater. Fcr a compound isolated from a mncrolide antibiotic, Takahashi and co-workers gave’ 7 m.p. 92-9-I”. [u],, - I34 (7 min) -L -S7’ (3 h) in acetone and -75 (5 min)+ -57” (90 rrun) ID \vBter.
supported by Contract No. NOi-Chl-57015 (The Ohio State Research Foundation Project 4226~Al) from the Division of Cancer National Cancer Institute, ktional Institutes of Health. Education. and
This
wwrh
Uni\ersirg Treatment,
was
Welfarr?. Belnesda. Md. 2OO!-l.
F. ARCA-.IOP*T. ci. CXS_C~~ELLV.G. FRANCESCHI, R. XIO~DELLI. P. GSELZI. AND S. Pi\CoI Ga:2. Chrm. Irol.. IO0 (19701 9-l9-959: R. B. LILTNGSTOIU AND S. K. CURTER, Dauno;nvcrn, Chenrorb~r.
National 1’mccr lm~irure, Bsth;sda, Md., 1970. hlsco, F. ARcahloluE, AND F. Z,wluo, in J. b’. C~RC~RAI~ Inrrbh>r~cs. Vol. Ill, Spnnger berlq. New York, 1975, pp. IOI-IX
Fucr
A.
Shyer,
DI
F. A~c~cmr.~,
Ci. FR~P~CUCHI,
S. Pikco.
AND
4. SELV~.
Ttrrohcdrcn
JND F.
E. HAHN fEds ),
Ltrr.,(1969)
1oO7-!0to;
h~~co. hl GHKWT, J. H. fc;R%hoFF, END G. ~I~THE (Eds.). Pror. Ink 51 mp. Adrrnmycrn, Springer C’erl_ip. Berlin. 1072. Scz D. HORTO?., R. J. SORENSON. AND U _ WECKECERLE. Curbah.vdr. Res , 2 (19771 175-l 38. and previous papers III this series. R. H. BLLIM AND S. K. CAREER, -IM. fvr?rn. .I!&, 60 (1974) 249-X9; J. J. RIMHART. R. P., LwE., AND S. P. BALcmP4h. AI., 67 (1974) 17547s. E. A. LEFR~K. J. Pmia. 5. ROSENHEM, A%D J. A. GOI-I-L~EB, Concrr, 32 (1973) 302-311. For comprehensibe srucles OII this subject, se< D. W’. f!EluRY, Confer Ciremofhrr. Rep., f’srl .?. 4 (1973) S-9; F. ARCXWONE. S. PENCO. w-m A. VLGEVAW. rbrd.. Purr 3. 6 (1975) 113-179. F. ARCWONE. S. Piruco. A. VIGEVA~W, S. REDAELLI, G. FRAkCHr, A. Dr ~~ARCO, .A. hf. CASAZZA. T. DAsDI%. F. FGRhfELLI. A. Nicco. AND C. SOR\NZO. /. ,W
K.
CARTER.
A.
DI
(1975) a-c5. 5. PENCO. C/urn. I&
( ,!fl/~n), 50 (1963) 90% B. ISEL!N AMI T. R~XWTEITV. f-I&. Chim. Acra, 27 (l94-l) 1X0-1233. P. J GARECC xrc~, 7 I+JRBERG, rlcru C.‘rrm. Scowi. So. B, 79 (1975) 507-512. For re\*irrrr.. see S HnMsslsh, Rdt. C~rb&_b.+. Orcnr., 2i (1966) 113-207; R. F. BIJXERWORTH AND S. ~~ANIsL%~. Adl~. Cnrboh.aar Ch?w. b’~ochmnr., ‘6 (1971) 279-296; S. f-&NuEsslAN AND T. H. H+btLLL, III W. FIGMAN ALD D. HORTON (Eds.), T/rr Corbolrg&~~?s. Vol. IIA, Academic Picss. New York, 197p. up, 139-11 I. H. BROCKMANN Ahm T’. ~I’AEHF~ELOT, AQrururswnschofian, 48 (1961) 717; l-l. BROcKhMr.N, Forrsciv.
Ch~fir.
TermheAm
org.
.\‘ufursr..
31 (1963)
Le;r , (1973) 3699-3701.
II-IS’:
i-f. BROCKhWN%. 2. SCKEFTER, AND C. Srtm,
AND W. RICHLE, Anrirrrirrob. Agenrs Cherwrher..
IS W. KELLER-SCHIERLEIN 16 \V.
RICHU.
E. K. W~KLER.
D.
hl.
Chim. Acra, 55 (1972) 367480. Ii S. TACAHASSHI. hf. K-JRAFJA~GHI.
HAWLEY.
AND
E. OHKI.
hf
DOBLER. Chrm.
AND
W’.
(1970) 68-77.
KELLER-SCHIERLERJ,
Heht
Pharrn. Burl/.. 15 (1967) :657-lh61.
I8 E. R’YSS. H. J&XX. AhD 0 Scirnwxr~. Heir. Chrm. Acra. 43 (1960) 66-l-675. 19 Yu. A. BERLTN. S. E. Ewov, hl. N. Ko~osov. AND hF. hl. SHE\!\ GRIN, T~~rahtxYrron krr.. (1966) I-131-1436; Yu. A. BERLW. 0. A. KIS:LE~A, hl. N. Ko~osov. h!. hl. SwhlvAF;rx. V. S SOIFER, I. V. VASINA, AND I. \’ YARTSEVA. Norue, 218 (1963) 193-19-l. 20 ?. &lCHSrrrh 4%D E WEISS. AdI?. Carboh,tdr. Chsut , I7 (1962) 65-120; T. REIChSrEIN. h’arrrr-
zrissznschafren.
53 (19~7) 53-67.
71 i-l. KJLIANI, Ber.. 55 (1922) 75-101
; F. hf!CHEEL. tbu_‘, 63 (1930) 345459. Heir. Chrm. Acra. 27 (194-t) 1203-l 209. HA,. Cirrfn Acfa. 30 (1947) l$_Z3-1232. P. ULRICH, H&L Chim. Acra. 35 (1952) 93-95.
B . :CELIN AND T. REICH~~. 23 hi. G~fi AND D. A. PUNS.
‘2
2-I f-i. R. BOLLIGER AND 25 hl. HAGA. hl. CHONAN. AND S. TUIhl~. Curboh~dr. Res.. I6 (1951) 456491. 26 D. A. PFUNS,J. Am. Chem. S,j:.. 70 (IQ-IS) 3955 X457: A. RU~EWHAL AND P. CATSWLACOS, J. C/rem.. 46 (1968) 2868-‘8X 27 P. J. BEYNON, P. hl. C~LLMS.
AND W. G. (%EREND.
1. Chevr. Sot..
Can.
C, (1969) 172-261.
78 S. i-iaFnsjL\N. Carbohpdr. Rex., 2 (1906) 66-8~ : A&. Chsm. Ser , 74 (1968) I +i’-?Oi : s. I-! tNES.SI AhD b4. R. PLFAM& J. Org. Chem.. 34 (1963) IONS-10-l-I. 15 S. HANE~SIAN AND N. R. PLESS~S, 1. Org. Chenr.. 31 (1969) IO-If-1053. 30 D. HORT@F(Aim \V. k%‘EChiRLE, Carboh>dr. Res., 46 (19761 227-235. ?I D. HORTON AND \b. WEcKfRLE, Carbohydr. Res., 44 (1975, ?27-210. 32 H’. ‘K\$As?-IK, IO C. BK\U~R (Ed.). Hc;tzibucl. &r procptirarilen anoryanischen Chemre, f’ol. F. Eoke Vcrlng.
Srutr~~rt.
I.
:95G. D 2Y.
33 P. L. DURETTE AND D. HoRToh. f&m. Carbohl& Chem. &or/rem., 34 S. J. ~~GYAL, .-ln5~u C/rem.. 81 I I i)h9) 17_‘-IS?- Anaw. Clzcm. Inr. 35 R. BOGNAR. F. SZTARICSI.XI. hl. E. hltivK, ANG J. T,\v$s, J Ory.
and rcfercnccs
\P
26 (1971) 43-125. Ed. Enyl.. S (1969) 157-166. CL-m. 35 t 1974) ?471-‘97-1.
36 R. F. BIJ~XRWORTH. P. I&l. COLLINS, ,A~D \V. G OvfRfND, Chem. Corrrmun.. (1969) 378-380. 37 W. W. LEE, H. ‘u. kbu. J. J. hivwi. JR., C. W. hbSHER. E. hl. &XON. L. Gocmhit~. AND D. W.
IS tic 75) 767-768: for the J en3ntiomorpll. see rci. 30. AND N. S. BHACCA. 1. 4m. Cbcm. Sot.. SS (1963) 2361; Fu. S BHCCL J. E. GL~FST. it-D D. H. WLLI~W, ibrd., Y7 (1963 302-305; J. F. STODD~RT, Sr~rro~/?emisrrr,oiCurbohvdrares. Wlcy -lotencwnce. New York. I97 I. pp. I29- 137. 39 .L\. &EK. J%rus Lisbqs Im. Ckm., (1975) 7Oi9-XYS. 40 0. S. CHIZI+OV. i_ S. ZOLOVKRUA. P&D N. S. \\ ULFSON, Carbohtdr. Res.. 6 (1965) 138-112 HENRY. 1. AI~YI
38 D. H. !!‘iLLIAhs
Chew
PREPARATIVE
SYNTHESES
(2-DEOXY-LY-L-FUCOSE) TAR
MING
2,6-DIDEOXY-z-L+.w-HEXOSE
AND ITS
DEREK HORTON. AND
CHEUNG.
01’ Chzmrslry,
Deparrmtvu
OF
The Ohro Stare
- Prmted III Belgum
D-rib0
EPIMER
WOLWAIUG
WECKERLE
(DIGiTOXOSEj
L, Columbus, Ohro +JIIO
Unw~r~~f
(Received Drccmtrer 31st. 1956: accepted for publisstlon.
(0.
S. A.)
January 20th. 1977)
ABSTRACT Methyl into
3.4di-U-benzoyl-6-bromo
the 3-O-brnzoyl Compound
(1) is converted
4,6-C)-ben~lideoe-2-deo\ry-a-D-ribo-he~opyranoside
methyl
deribatile
-2.6-dideoN)‘-;r-o-rrbo-hexopyraooside
(2) of 1 by subsequent
3 is the key intermediate
trtle drdeoxy
in high-yielding,
by hydrogen
with
preparative
glycoside 7. which undergoes
net intersion
at C-5
to gike methyl
are readily
obtained
gives the crystalline from
1 Hitbout
by catalytic
syntheses
stereospecific
reduction
of 3 pro1 ides the 9 (L-~,v.Yo) and 5
and mild,
and 6 (wibo)
title sugars 10 (L-(WI)
of the
3,4-di-U-benzoyl-2,6-dideoxy-
transejteriticatron,
the necessity of chromatographic
ria
Deh)drohalogenation
B-L-~~,.ro-he~opyranosidz (8), ~%hereas reducuw dehalogenation corresponding D-riho derivative 4. The unprotected glycosidss (D-fibs)
(3)
with Iv-bromoslrccinimide.
antibiotics.
of many
sugars, which are constituents
of 3 affords the 5,6-unsaturated
treatment
acid hydrolysis
in 45 and 57Ob overall yield
purificatron
at any of the steps.
INTRODUCTION A program anthracycline and/or
in this laboratory
antibiotics
stereochemically
are clinically
effective
modified3 against
severe cardiotoxicity” hoiiever,
broader
spectrum
might
already
been prepared
display
of antitumor
2,3,6-trideoxy-L-/_rvo-he\o+z). and L-ribo’
analogs,
and/or
the original by
activity
than
of daunorubicin
and
arc
sugar,
of the
structurally
Both antibiotics drawback
Structurally
possibly
its r-arabiuo’.
products”
the parent
dideoxy-L+*.t-o-hexopyranosyl)-daunomycinone* *Note added in proof: C36-C39.
and
exhibit
daunosamine
is a
related an eben
anthracyclinesb
have
(&amino-
6-hydroxy-L-arabino’, with ~-glucose
of daunomycinone
some of these products
appear
to show significant
drugs.
In order to study the effect of the amino the antibiotic
dose-levels.
semisynthetic
amino
of analogs
but their major
toxicity
Several
[hat
constituent.
of cancer,
decreased
as ~tell as coupled
less toticity
adriamycin’,’
at the most effective
IS replaced
and ‘-runino-‘-deoxv-D-glucose:; activity
forms
activity.
in which
wrth the synthesis
and
in the carbohydrate
various
manifested
analogs,
is concerned
daunorubicin’.’
group at C-3 in the sugar moiety adriamycin.
the
synthesis
and -adriamycinone
see E.-F. Fuchs, D. HOI-LO~,and W. Wsckerle.
upon
of 7-O-(2,6-
was considered
Curboh_tdr.
Res., 57 (1977)
110
T. hf. CHEUNC,
a desirable
objective.
antibiotics,
except for ewbangz
in mind.
3 new
designed, related
The ,z anomers
synthesis
and is described
10
Compound (the same s~othesis
n3s
\iith
in this p3per analog prepared
only minor
long before it WLS found in Nature’ (refs. (ref.
II
and
lblia.
The (D-
(D-
B (refs.
17), and. apparently.
ethers 3s
15) and
D
enantiomorph
LouId
together
HORTON,
be identical
by 3 hydrouyl (10;
with
W.
H’ECW
to the parent
function.
Wi!h
this
2-deoxy-L-fucose)
the preparation
HW
of [he closely
6 (digitoxose).
Iselin and Reichstein”
by
modifications
14 and
16).
cardrsc
of 10 is known frequently
quite recently)
of rhodomycins”,
the macrolide
antibiotic
cinerubin
X
3zalomycin-B
glycosidc ’ 8 from Peniopdia androsaemi-
as o-oliosc”:
occur
by the glycal method
has been reporred”
3 3s 3 constituent
as part ofa
and L-diginose)
group
of 2,6-dideoxy-L-!l,ro-hertosc
D-ribo
(kpimcric)
of these products
of the amino
D.
’ 3*20
the corresponding
in cardiac
3nd prcgnaoe
3-methyl glycosides,
do 2.6-dideo~y-D-rih~-heuose (6; digitosose) and the enantiomeric 3-methyl ethers (6) was first synthesized by Iselin and Rcichstzinz2 and L-cymarose). DlgltoYose”
through
the
rn moderate opening
v;orkers25
glycal
method.
yields
reaction
from
by Gur and Prinsz3
3 2,3-anhydro-D-a//o
prscursor
and Bolliger rhrough
and ULich”
au epo.tide
ring-
deosygcnatron at C-6. rn 1971. Hag3 and co3 route to compound 6 similar ro the one presented here.
and
described
and, later,
subsequenr
DISCLISSION The
(prepared
reaction either
of met hj I 4.6-0-benq by reductive
cleabagezh
lldene- 2-dcoxy-a-D-ribo-hexopyranosidc of the epoxidc
ring
in the corrzspondins
(1)
5
3
a
142
T. hf. CHEUNG,
2,3-anhydro-D-a//o aluminum 3-O-beozoyl ad-line
derivative,
hydride’,“) derivative
pattern
ion at /n/r
370:
physical
chloride
2. that sboHed
of ithe 3-keto proceeded
in its p.m.r.
analog
readily
spectrum
see Experimental
constants
of 2 were
section)
further
in good
apeement
WECKERLE
of 1 with
lithium
crystalline
to give the
I), in particular,
displayed
the anticipated
‘, and mass-spectrometric
at 1725 cm-
W.
(see Table
for H-3 at low field (Cs5.56). The i.r. spectrum
ester C=O absorption The
or by reduction
with benzoyl
D. HORTON,
data (intense
supported
molecular-
the structure
with
those
assigned.
in the
reported”’
literature for ttis compound. ‘Trcnuneilt
of the benzoatc
chloride,
by the general
dioxane
ring ar d formation
2 with
procedure
A’-bromosuccinimide
of Hanessian28~19,
of the 3.4-dl-Gbenzoyl-6-bromo-6-deoxy
isolated crystalline: in 7996 yield, and characterized q .m.r.
(see Table
precursor
in tie
rhe D-ribo”’
IIAJOR
by elemental
mass specirometry.
Compound
of the Sepimeric
title stigars,
in Lh: syntheses
established
TABLE
I), and
in dry
preparation
(D-ri~tosamine)
of the corresponding nnd L-~*xo3
following
tetra-
of the
1,3-
anal~g’~~”
3,
analysis,
3 constitutes
and
i.r..
the common
procedures
3-‘amino-3-deouy
(daunoszunine)
carbon
led to opening
analogs
wellhaving
configurations.
II F?.%ChlENT-IOhS
OBSERlED
13
THE
EUCX7Oh’-l~lP.4Cl
MASS
OF COhfPCLfNDS
SPECTRA
+6
AND
010
m,% of prrncrpul CompJunJ 4b
frJ,ormlrs=
_ J
(c.L oihw
6
.-tssrgnmmr
ped)
8’
.
10
9
162
(1.1)
(0.7) (0.4)
(0.05)
(0.01) (0.03)
149 1-U
371
370 309
370
(0.15)
16’
(0.06)
369
(0.25)
161
336
(0.03)
130”
10.9)
130
(1.5)
338
(0.02)
216#
(49) (0.1)
II’ 97 65’ 39 9-1 131 113’ 95 I IS IO0
11.3) (04-J) (I.?) 1Sj (0.5) (7.5) (3) (1) (6.2) (1.1)
I I’ 97 6R 39 34 I31
(3) (2.5) (II) (3’) (?.S) (0.8)
216’ 201 339
(0.5) (0.05)
(0.03;
I30 I12 97 68 39 9-l 131
(0.15) (I) (3) (0.6) (2.5) (13) (2) (0.4)
I13
(1.1)
2170
(0.1)
1130
(1.3)
I13
95 I04 S6
(2.5) (6.5) (75)
95* 326 -
(1.3) (O.-t)
95 IIS too
(1.4) (4) (0.9)
59’ 60* 59 43 5Y
(lo@ (94) (100) (7s) (55)
4s 60’ 59 43 4
(70) (100) (4.5) (89) (70)
268 5s
(1.1)
60’
(100)
(03)
59 43 5s
(90) (24) (56)
(6.5)
312
(0.08)
104.
(20)
XI1 339 217’ 95’ 376 -
(0.1) (1.6) (5.5) (0 !)
ZaJ s5
II)
(0.9)
313
(0.03)
IO-4
(27)
lo4
59. (90)
119
(0.04)
hf+
l-8
(0.01)
rb1:
130
(0.2)
Al
I I’* 97 65 39 91 I31
(0.3) (0.5) tl.8) (-5) (0.3) (I.Zj
A:
I
hl - I
9s
;:J A,’ A:=+ c,
(I)
(0.3)
::
tw 86
(8) (41)
D, Dj
45 60* 59 43 +i
(50) (100) (2.5) (37) (15)
D: Df D: D: E:
(S)
E:
10-t
fragments obsened m the spectra are iodlcstcd by ti asterisk at the dsughkr de\iollons bclecen observed cod calculated values arc fess than fO.l mass un~ti bAddllionzJ fragment ton5 a[ q’r ‘4s to 25, hl - BzOH), I05 (100, PhCO+), and 77 (20. Ph’). CAddlfloanl fragmeol 100s al m/e XS tO.lj, hf -BrOH). I05 (100, PhCO-), and 77 (25. Ph’j. ‘Adapted from the fragmsntstion pnthecl)s proposed by Taknhnsbl er uf. (ref. 17). JPrornlncnt
melaslsblc
wn of the process involved;
113
2,6-DIDEOXY-cr-L-I~XO-HEXOSE
Reductive debromination
trietbylamine resolved
p.m.r.
indicative 8-tine
spectrum
signal
(doubled
experiments;
croup
quartet)
the remainder the structure
data of 4 with Inversion
syrup
in high
spectrum Table
The
for
(ti 4.65),
two
preponderantly
predisposition
could
and the 3-benzoyloxy C-S
presumably
conformatIon
compound
or
evhlblts the other.
8 (see Table
of the ‘c,(D)
The
such coupling
We are indebted
and H-4,
conformation that*
used”
3 with
indicated protons
of
respectively.
data (see
(;i 4.75)
H-6 The
and
large values
the presence (at C-I-C-J),
of three
suggesting effect. br,hich
group33.
This
between the I-methoxyl
as the msthylenc
including
fabonng ihis
substituznt
either
spectrum
the
one
to that
of
the fact that H-2~ and H-3 and. that the ~all;es for J, ,ze
probides
for compound
no long-range
by its i.r.
for
I-merhoiyl
interactlon
silver
(by t.1.c.)
the spectrum
despite the anomerlc
interaction””
in
sIgnsIs,
(J6,hS I Hz).
of the
large,
derll atibe 8,
AO
\$a~ confirmed
doublets
resemblance
are relatively
further
indication
7 in solur;on.
couplin,o
of
the
in addition
between H-l
and H-3
\\ould ha\e been expected for the ‘C, (D) conformation
in the spectrum
but not for the ‘C4(~)
favored,
Ggnilicnnt close
the physical
as ~~11 as by p.m.r.
disposed
of a strong
little
there is the “ne,oati\e evidence” was observed;
respectively)
I ; see nevt paragraph),
preponderance
(as i\as verified
product
and aryl proton
orientation
L-/I
of the bromide
one-proton
is strongly the rrvial
composition
bstneen
7 33 a homogeneous
group in the ‘C, (D) conformation.
and 4.2 Hz)
l
narrow.
be the result
(3.5
Jze.3
this
metho\)
tra,rs-diauially
resonate at higher field than H-21
and
Treatment deribativc
a small gemtnal coupling
conformation to Tabor
and elemental
sequence succzssfullg
at I660 cm -‘)
to the anticipated shoiied
operates
by an
in the literature.
assigned
absorption
each displaying
that the ‘C,(D) generally
at
structure
J, ,2a and J2u,3 (6.2 and 8.9 Hz,
consecutive,
field (6 1.37j
by double-irradiation
at C-S, in order to prepare the
of daunosamine.
(vinyl-stretching
r). In addition
II)
the elimination-reduction
the SJSunsarurated
of 7 in benzene-d, H-6’
as demonstrated
as did the good correlation
of the configuration
yield.
is represented
6 4.53,
data (see Tab!e
indicated.
synthesis
at high
The
latter
of
presence
yield. The well-
a doublet
to H-5.
those given 2’ for this product
furnished
fluoridez3
I) shotled
in the
4 in 94%
of the spectrum closely resembled that of the precursor 3
Has achieved by exploiting the analogous
derivative
coupled
at
1). hlass-spcctromerric
supported
6-deoxy
of 4 (see Table
of the 5-C-methyl
(see Table
of 3 was effected by Raoey nickel
to give the crystalline
of the related
conformation.
to a rereree for this orgumenr.
compound
4, lvhere JJ,,3
is -
I Hz),
I44
T. hf.CHEUNG,
D. HORTON.
W. WECKERLE
Catalytic hydrogenation of 7 m tbe present of palladium on barium sulfate led to a single, crystalline product (8) that was different from the D-.&O compound 4 (by g.1.c.). although it gate a mass spectrum (see Table II) identical to that of 4, except for the Intensities of the fragment ions. The IOO-MHz. p.m.r. spectrum in benzene-cl, (see Table I) was essentially firsI-order, displaying, in particular, a Sproton doublet at hipb field (6 1.15, C-hle) and well-resolved, one-proton sigals for H-l (8 4.1 I), H-3 (b 5.20), and H--I (d 5.39); these data establish unequivocally the L-/I,VO rtercochcmijtry
of the product obtained.
Tbe assignment of the bigher-
(and lo~rsr-) field signaIr_ (6 2.14 and 2.32) of the geminal
protons
at C-2 to the
equatorialiy
(and axially) disposed hydrogen atoms is based on the observed couplingcomt3nt~. and is consistent nitb data for other 2-deosyhzuopyranoses that have been Although this interpretation contrasts thoroughly srudied 35 bv _ n . m.r. spectroscopy. \rith the convenrional tic\\. this assignment is considered correct, and is ascribed to the deshislding (or shielding) effect of rhe neighboring 0-benzoyl group upon the axial (or equatorial) hydrogen atom at C-3. Indeed, the frequently used generalization that equatorial-proton signals lie downfield from those of axial protons in pyranose systems has been sho!\n before to be reversed in such compounds 3s methyl 4,6-Oben~,Jidcne-~-decuy-~-o-~~~,~/~~~-be~o~yrano~id-~-uloje~7.36, its oxime”, and35P37 merhl
I 3-acetamido-l-0-acet~l
-2.3.6-lrideoky-r-L-riho-heuopyranoside
(methyl
di-
acetylrisrosamlnlde), 0-Dcacylalion
alrhough these ha\e heen said3’ to be e.uieptionnl. of-# and 8 tc’3sefTecredby catalytic transesterification to give the syrupy a-r&o (5) and crystalline L-/J*_YO (9) methyl glycosides in good yields: their physical con51antS wcrc consistent ~lth those recorded for”‘S’5*39 5 and” 9 in thz
liferaturc.
The final step in the two sequences ~3s accomplished by hydrolysis of the methyl glqcostde< 5 and 9 141th aqueous acetic acid. to yield cryjlnllinc XLdideo\yD-r&o-be\ose (digitokose, 6) and the slightly hygroscopic, c~stalline, Sepimeric, L-/JAO compound 10 (2-deohj-L-fucose). The physical data (m.p., specific rotation in methanol
and in water at equilibrium)
of compound
6 were in
gencr31
accord Hith
those recorded for digitosose obtained 2 I from natural sources and 2’-2 5 for synthetic producrs. Because of rhz cornpie\ mutarotarion, no assignment of the anomeric form IO the crqstsilin~ state V\~S made, alrhough Bolliger and Ulrich claimed’” that it is rhe /3 anomer. The L-!~:w analog 10, M hich is the cnanriomorph of the naturally occurring didcoky sugar oliose’9, crystalked In the ?r-~ form, as evidenced by its upward mutarotation in water and acetone; the final specific rotations sbobvad good corr-lation Hlth those recorded for the synthetic” and” natural product. The foregoinp syntheses afford the title sugars 6 and 10 from 1 in 57 and 15% nzt yield, based on intermediates isolated directly, with no chromatographic purificsrion involved at any of the steps: all of the reactions are readily amenable to scaled-up operations. hlass-specrromctric dara for the deriiatlles 2, 2, and 7 arz @ten in the ExperImental sectIon. For the other compounds described In this paper, the principal
fragments. together with their relative intensities, are summarized in Table II. The pathways deduced for the fragmentation, as detailed in Scheme I, are based on plausible mechanistic steps and accord, in part, \\ith those proposed” by Takahashi and co-workers.
Cleavage
of the glycosidic
undergo
successike
pyrylium
ions A,
AS.
Altemati\cly,
odd-electron
loss
of
and C,. A,
ion A:.
bond leads to ions of the ,A and C series: A,
two
The
more
former
may rearrange
Through
ring-subsrituents.
loses’ ’ t\so formyl ”
C-l-O-5
affording radicals
and C,
the substituted to furnish
A,
and
and gi\e. through elimination of water. the rupture of the pjranose ring, ions of the D
end E series arise by subsequent clca~a_ge of a cecond rin,a-bond between C-2 and C-3 (E series) or C-4 and C-S (D scriesj. Fragmentation of D, may proceed either by loss of Hater
and an oxiranyl
radical
spectra of the unsubstitutcd loss cf a C,-fragment, fragment proton
into
D:.
Ei through
elimination
or a hydrosyl
radical.
respectively.
to form
cornpounds This
Di
as one of the most abundant
($69,
odd-electron
of acetaldehyde; to form
ions in the
and 10). or D, may decompose. ion may alternatively it decays further
an open-chain
(Dj)
by expulsion
or cyclic
with
arise from
(Di)
of a
cation.
146
T. hl
The alCoremenrioned framents
observed
isomeric
assignments
in the spectra
structures
CHEUNG,
D.
arc in many instances
(as indicated
in Table
HORTON,
W.
supported
WECKERLE
by metastable
IT), but the possibility
of
is not precluded.
EW’ERlhfENT4L
Genrrul at
3
bath
Hoover I-dm
r?rrtirodq. -
temperature
apparatus
tubes \iere 3
kvith
spectra shifts
together Table
hlodcl 3t
100 hll-!z
to an internal
standard
111th spin-coupling
menrs.
Inlegations
dcrestrd
volumes
Column
hlicrosnalyses
were by C.
5pecrrometer
potsn:ial
of S kV:
probable
assignments
Scheme
I. The
/r-rupture Relative mately
of methyl
benzoyl rshich
ionizing
and
(direct-inlet
X-Ray
boiling
radiation. visually: (I,
The
strongest):
j(m).
spectra
Mass
high-
an accelersring
was
120’.
Data
in Table
oi compound
2 refer
diffraction
camera
IO’.
63-200
double-focusing.
system)
m, moderate,
heating.
at 65-I
7734;
of 70 eV and
poader
T.l.c.
zones were
subsequent
No.
in
euperi-
in all instances.
MS-9
potcntiol
listed,
of 250 Hz)
Darmstadt);
A-6 and S-10 are summarized
t-t al “.
time
with
-I,6-O-benzylicienein dry (5.;
1.1.~. (3:l
pyridine
dnts
and
and
II
to the
give inter-
113.59 mm.
diameter
was
s, stroog;
v, very;
w, weak.
numbers
indicate
approui-
double
dlchloromethane
Sulfaie).
(MO
from
and evaporated.
the residue.
to give pure 2: )i?ld
The
eiher-perrokum
was then poured
and
cooled
mixture ether)
into ice-water
l20-ml
portions).
in an ice-water was kept
indicated
Toluene
(t\!o m.p.
the
The extracts
hydrogenczrhonate
the crysrailine
for
-
bath,
reaction
to
marerial 94-93”,
was [a];’
be ~‘9s
were combined,
and
ZO-ml portions)
was
I2 h at -25’,
(600 ml), and the product
sodium
15.31 g (89%).
(2).
2-deo~y-r-D-ribo-he~opyranoside~.2h.’7
(ZOO ml),
ml. 45 mmol).
successively with aqueous
evaporated elhnnol.
chloride
The milrure
(magnesium
widrh
are
by decoupling
of this Department.
an AEI
chemical
and
_?-O-i7~n~o~~l-#,6-O-h~n~~~/n~-~-~~o.~~~-r-r)-ribo-he.ro~~~ranosi~r
13.3s g. 46.5 mmol)
\fajhed
acid
and /J? in the assignment
\ierc estimated
(1:
e\trsctcd
/I,
Rond
‘H-N.m.r.
intensities.
lifethr#
complete.
N.
rempcrature
.&. l-or CuKz
a solution
after
instances
gel (hferck
tvith
for compounds
To
added
at a sweep
refers to the fraction silica
by W.
lines are numbered
equal
ether
discs.
spectrometer: (8 = 0.00).
sulfuric
and
with solids dispersed
the peak assignments
U’cisenberger
by Chizhov
intensities
jrrongest
with
3t an
141 polarimeter
chloride
HA-100
in most
i\ith
operating
notations
sodium
measured
by sprayn g wirh
the source
proposed spacings,
planar
(Hz,
pressure
a Thomas-
with
1-r spectra were recorded
plates of Silica Gel 60 (E. hlerck,
performed R.
on
a Varisa
confirmed
~var performed
xserc recorded
hlodel
of tetramethylsilane
are k/k’: petroleum
filtration
re5OlutiOn
and
diminished
i.r. spccrrophotometer.
with
were consisrent
on precosted
by u.\*. light.
Sollent
\tere
under
were determined
A Perkin-Elmer
as films
values
assignments
~vasperformed
The
syrups
points
of specific rotations.
457 grating
and
recorded
I. The
were pxformed
Melting
and nre uncorrected.
bromide
\tere refer
50’.
used for measurement
Pcrhin-Elmer
in potassium
Evaporations
below
water,
dried
was added to and recrystallized
+ IS5’
(c I,
from chloro-
form) and
(lit.2”
(0.16,
95-97’,
m.p.
’ (aryl);
695 cmhi-LleO-),
[ctlD + 193.1’ in chloroform):
m/e (rd.
293 (0.4,
hl-
221 (50, 11,; m* at 132.0, talc.
caic. 44.35), 8.62 w,
intensity): Ph.),
370
7.72 s (3,3),
369
X-ray
powder
7.31 VW, 6.70 \c’, 8.84 s(3,3),
m” at 4-l.3, II.47 w,
ditiraction
5.45 m.
750
(5,
h, -BzOH:
l-19 (5, /I?), 99 (100.
105 (85). 91 (9.5j. and 77 (37):
C=O).
hl - H .), 339 347 (0.1, hl- BzOH),
hl*).
hl - FhCHO),
264 (0.5,
132.00),
Van: 1725 (ester
(17.2,
data:
6.6Os(l,l),
4.51 s(l,l),
5.64 w, 4.12 s (2,2), and 3.93 s (2.2). Anal. Calc. for C,,H,,O, (370.40): C, 68.10; H. 5.9s. Found: C, 68.26: H. 5.S5. ~Ilrill~~l3,4-di-O-ben,o~~l-6-bronlo-,$.6-didt~o.~~~-~-~-ri bo-lrelrop~ranosid~(3). - .A mixture of rhe benzyltdene acetal 2 (25.7 ,g. 69.4 mmol). N-bromosucc~n~m~dc (I 3.35 g, 75 mmol), and barium carbonate (20 g) in dry carbon tetrachloride (500 ml) was boiled for 5 h with stirring under rctIu\, during which time the color of the solution, originally colorless. became successively yelloiv. red. and finally pale-yellow. The solsent
was distilled
OR; and the residue eitractsd
portions).
The
extracts
of sodium
hydrogensulfite
and evaporated ethanol
and sodium
~2;
m.p.
172s (ester C=O).
intensity):
(0.2.
327
(0.25,
data:
dichloromethane
successively
hydrogencarbonate. crystallIne
3: yield
wirh
dried (ma?neslum
sulfate),
was rscryjtnllized
m.p.
96-g%.
IOO-102’.
[rlD
1580 cm - ’ (r,;onosubstltuted
hl-
IO.71 VW. 9.66 s (3).
I05 (100).
[r];’
in chloroform,
hl - MeO-),
(0.05,
BzOH).
+ 172.6’
117
and
I50-ml
solurions
residue
24.7 g (79?b),
(Ihrec
aqueous
1600 and
111t ). 4lS
449
RI - Br-),
fraction
(lit.”
purz
i\ith
washed
‘I he resulting,
to give analytically
96’): (1.7.
combined,
to dryness.
(LB0.6, chloroform) (rrl.
uere
and’”
m.p. 9C
phsnyl);
IIJ,‘LJ
hl - hIsOH).
(0. I,
77 (IS).
from + I92 5’
S-ray
369
poivdrr
8.62 w, 6.68 tv. 6.10 m. 5 53 w, 5 I7 \w,
dlf-
4.91 vi\.
4.34 s (2.2), and 3.82 vs (I). Anul. Calc. for C,, H,, BrO, (49.30): C. 56.13: H. 1.71; Br. l7.7Y. Found: C, 55.91; H, 4.69; Br, 17.97. Mril~_~~l _~.4-~i-O-bcn=o~‘f-,),6-did~o.~~~-~-D-ribo-/r~rop1 rurrosidc (4). - ,A mi \ture
4.75 s (2.3).
of the bromide in methanol whereupon catalyst
t.1.c.
(9:l
was removed
in chloroform
that \\ere
g, 22.7 mmol).
by filtration, The
bromide,
recrystallized
[*x]A3 +227.3’
nickel
hydrogen indicated
the filtrate
solution
uas
from
hexane
(c I. chloroform)
to afford
(lit.”
(-h
m.p.
g). and tnethylamine
at 4.2 hg.cm-” the
rcactlon
evaporated,
washed
dried (magnesium
twice
sulfate), 83-85’,
with
wafer
+214.6”
The
dissolked
to remove
and evaporated
data:
-35’.
to be complete.
and the residue
[xlD
(3 ml)
IX h at
for
to gi\e
pure 4; yield 7.9 8 (959;).
’ (ester C=O); X -rav powder diffraction 4.91 s(Z). 4.65 s. 4.is(3.3). 3.97 ~(3.3).
1720 cm-
5.15 vs(l),
Raney
under
benzene-ether)
(150 ml).
ethylammonium
v:!:
3 (10.2
(200 ml) was shaken
tri-
crystals
m.p. SO-d?‘.
in chloroform):
IO.21 s. 9.M
3.77 w’. 3.1s m,
m, 6.23 m. 3 35 m.
and
3.19 m.
.Arral. Calc. for CI,H2200
(370.40); C, 68.10; H, 5.98. Found: C, 67.91; H. 6.36.
hletlz_d 2.6-d~deo_u?,-r-D-n’bo-~~~.~o~~,~u~~~;de (S). - To 8 solution of compound 4 (l.37g. 2.7 mmol) in abs. methanol (30 ml) was added 51 sodium merholide (0.4 ml), and the mixture ~vas kept for I2 h at 33”. at which point f l.c. (19:l ethyl
T. V.
148 acetate-methanol)
indicated
that
transesterificafion
evaporated,
and
Chloroform
~c’as used first as eluant
washed
off the column
colorless syrup
distilled and
17S.4’
+
placzd
on a small to remove
lvith acetone,
at 40 mtorr
+ 169.1
was complete. column
methyl
(c 2.3,
and3’
for C,H,,O,
temperature
chloroform)
(lit.‘s
(D-tiigifo.rose.
6). -
A solution
in acetic acid (3 ml) and water
Eiaporatlon
gave a residue
little
The
iierc
qreld
(c 0.74.
crystals
303 mg
+47.5
(30min)+
methanol):
S-ray
AMID. Calc. +37.l I IO-I
I?‘,
&Z’
m.p.
109-I
1 I’, [a],,
f47.8”
(I h,
(l-IS.16):
in merhanol”; [r],
hiicheel
+5l
oa\e”
3’ (equil.) m.p.
r\frilI.~ / 3,-ihO&u:o
105-107~.
C, 5l.SO; under
reflux
upon addition acrtonz
(5.?0
min)
irater)
\I{.
5 for
that hydrolysis
frern
1.06,
8.2’
H, 9.00.
ofa
to gibe
-+
and
+51.7 $36.5’
7.31 LW, 6.63 vs (2).
3.88 wc, _7.65 m. 3.50 m. and 3.39 m. H. 8.16. [,z]~
-c + 50.2
Found:
C. 4S.79;
have been reported:
JOY-III’.
in \\*ater.
c
data:
constants
m.p.
A-3 (7 min)
+43.6
1.45,
in methanol:
indicated
+ 42-S
equii.:
C. 4S.64;
the follo\bing
+ I’
of the
(c
of the glycoside
crys!sllized
[r]:’
diffraction
4.33 s (3). -I.10 \s (I).
For this compound. [n]o
IO-S-103”.
po\\*der
for C,H,,OA
m.p.
that readily
m. p,
+ 192.4’
(7 ml) QBS boiled
off. and recrystsllized
filtered
(93O./,),
5.66 m. 5.01 iv. 4.71 \w.
source.
was then
to gibe 5 as a
in chloroform).
time t.1.c. (19.1 ethyl acetate-methanol)
itas complete.
[r]:’
ii. 8.70. Found:
C, 51.84;
(356 m,o. 7.2 mmol)
(7.50mio)-,
~35
of silrca gel.
The product
[mr], + 192.0
15 min. after which
6;
WESXERLE
solu!ion
The
was evaporated, 60-80’).
[,rJD f 173’
(162.18):
2,6-DiLjiOXL.-D-ribo-:le.ros~
pure
W.
(250 x 20 mm)
benzoate.
and the efluent
(bath
In chloroform”:
.-!~a/. Calc.
aceton?.
D. GORTON,
yield 560 mg (934/o). To secure an anal>%cal sample. a portion
syrup:
\\a~
methanol) ixlD
the residue
CHEUNG,
& 2
$38.1
(I h. equil.)
For digito’toje
[#x]~ +-i6.3’
~~l-2.6-didtw rl*-z-D-eryt
42’
m.p. in
H, 8.05. 108-l
in \\;lter2”:
isolated
IO’,
methanol’3:
from
and”
;i natural
in Lsaaterand +38.1” in merhanol. hro-/k* r-5mop~mnoside (7). X
mlvturc of the bromide 3 (9.1 g. 20.25 mm011 and dry, technical-grade (8 g) in do p)rldlne ( 100 ml) was thoroughly stirred for 40 h ar 25’.
silver fluoride”’ tihereupon t.1.c.
(chloro.form)
was poured
re$csled
that all of [he 3 had reacted.
The dark joluiion
into
ether (500 ml). and the resultant mit..turc was filtered. The filtrsre ~as evaporated, and toluene (three 30-ml portions) was added to and distilled from the residue to remove all of the pyridinc The rerrninipg, dark syrup \$a5 filtered through a small column (GOOx 20 mm) Evaporation yield
of silica
gel with
of the effluent
6.86 g (92X),
[z]g’
acetone
afforded + 123’
as eluant,
to remove
syrupy 7, sufficiently
(c 2.9,
chloroform);
residual
silver
pure for the following vet
1730 (ester
C=O).
salts. step: 1660
(C=C), 1600 and IjSOcm’ (monosubstituted phenyl); nl/e (rel. intensity): 369 (0.07. hl+l). 368 (002. hlf), 337 (0.13. hl-McO.), 215 (1.2, -‘37-&OH), 336 122 (7. BzOH’), (0.5, hl - hieOH). 214 (I .7. 336 - BzOH), Z-16 (4. hl -&OH). ICJS(100, PhCO ’ ; m+ at 90.-L talc. for I22 + 105: 90.37), and 77 (30). Although clber),
and
elemental
analysis
.;l/erlz~I unsaturated
the product
no signals
due
m&ted
as a slnple zone in t.1.c. (R,
to impuriries
dctzcted
0.83 in 9: I benzene-
in its n.m.r.
spectrum,
an
Iylng ivitbin acceptable limits could not be obtained.
3.J-(~l-O-bErl-q~~I-~,~-did~o
sugar
\iere
7 (4.45 g, 12. I mmol)
vl,-8-L-lyao-llz.uop~.ra~oside
(8).
-
The
in dry methanol (100 ml) was hydrogenated
149
~,~-D~EOXY-~X-L-(~‘.\.G-KEYOSE at
25’
under
sulfate
atmospheric
(450 m_e). After
up, and
t.1.c. (9:l
pressure
30 min,
benzene-ether)
by g.1.c. [Hewlett-Packard
lomzarlon
at 260’
min-‘1.
retention
technique.
-63
the reaction
palladium
equipped
Thecatalyst
5.43 m,
S-ray
(retention
time
-4
of min)
‘.6-didco~~-r-D-,.iho-he\op,ranoslde of the relention
homogeneous
8 as tine nwdlcs;
times.
(R,
a5 brell as by the residue
that
>Ield 3.32 g (38” L), m.p.
diKraction
-1.80 w.
\%a~ evaporated
0.75)
1600 and
__ (ester C=G). imJr nhBr I7Tq
pn\tdrr
5.1 I s(3).
gas at a Ho\v-raie
was filtered otT. and the tillrate
to furnish
As shown
H ith a tlam+
N ith 2”0 of OV- I on
a~ the carrier
3,+di-O-benzoyl-
chromatographically
phcnyl);
6.37 w.
helium
on barrum
had been taken
was complete.
only a single product
cl” (c 0.9, chloroform):
(monosubstitutrtd
6.53 \t,
10”;
of hydrogen
Series 5720.9.
by comparison
from ethanol
[x];’
with
contained
z 3 min)
a crystalline.
recrysrallized 123’.
(isothermal),
from methyl
time
miled-injection to gi\e
that
gas chromatosraph
1h e miltwe
rhat bias difkrsnr (4;
Lerificd
of
amount
detector and a glass column (1.83 m x 3 mm) packed
Chromosorb, 25 ml
in the presence
the theorerical
data-
4.53s(l.l).
12.90
m.
w;l~ IX-
IS5
cm - ’
S 00 5
7 31 s
3.51\w.
and
-Ll6s(l.I).
3.65 5 (3).
protected glycoslde 8 (5.3 p, 17 mmol) in abs. mrthsnol (50 ml) NBS sdded v sodium methoiide (0.75 ml). and the mtxture \5’93 hept for I2 h at 25’. sfrer which llme 1.1.c. (l9:l
ethyl
s01ver.t
acetate-methanol) distilled
~3s
small coiumn remo\‘e
(J% and
yield 3.2 g (809;). form);
X-ray
6.0015(l), Awl. For reported
x 20 mm)
the crystalline m.p.
pov.der
~3s
of rhe residue
complete.
wan plx~d
\\as used as rhe elunnt
The on
~1
first. 10
4.qSs(3,3), for CT H I .O,
this compound, 108-109~.
-Ll65(3.3). (162.
prepared [r$.,
glqcoside
recr,vsfnllized
+18“
3.00m.
3.82m,
IS): C, _$1.83:
f-l. 8.70.
eiher
and
LO gir*e pure
9:
_?.5Os!2).
Found.
by the glycal method.
C. 51.50:
Garep?
and
H, 900.
Norbcrg
rn chloroform.
(,7-tieo.yl’-I-L-~lcost~.
9 (990 mg, 6 IO mmol)
for 30 min under
from
+4-t’ (c 0 8. mcrhanol) and + 50.3 (c 1.2. chlorodata: ll.S9 m. IO.51 it. 9.45 m. 7.53 \k. 6.73 m.
diKraction
Calc.
’ 1 m.p.
product
I IO’. [xl:’
~.?5-Di~~~os~~-r-r-lyuo-he.~ose ~85. boiled
rransesterification
solurron
of silica sel. Chloroform
5.455,
of the merhyl
that
benzoate, and the producr was then elutsd with ace~onr. the et?lutsnt
methyl
evaporated,
indicated
ofi: and a chloroform
8r-r-oliorc.
IO). -
A so!urlon
in acetic acid (3 ml) and water (I 3. ml)
rcfluu, at I+ hich time t.1.c. (19: I ethyl acetste-methanol)
indicared that hydrolysis of the glycoside WCScomplete. The soltent ii;15 claporated OK and v.w~r (three success~\e IO-ml portions) ~3s added IO the concentrsr4 solution (- 2 ml) and ebaporared after each nddicion to remwe all of Ihe acetic acid Finally, syrup
rhe solulion (IO;
hydroxide
RF 0.29) for weral
H’~S evaporated
to dryness.
that
over
days:
was
dried
phosphorus
yield 890 mg (9896).
crystallization. and the crysrnls (IO) were filtered and dried; yield 630 mg, m.p. IO?-105’. [xl;” (4 min) _
- 73.S (6 min) -+ -64.8
(IO min) +
to afford Addition
off
pentaokide
and
hygroxopic potassium
of a Irtlle acetone
in an inert atmojpherc
-37 -Cl
a colorlc~s,
(initial.
e\rrapolated)
5’ (1 h, equil.;
efkcted
(nitrogen), ---) -81.3
c 1.0-L kvatzr) and
150
T. hf. CHEl.bJG,
D. HORTON,
W. WECmE
- I34 (initial, extrapolated) + - 13 1. I (7.50 min) -+ - 1X? (i 5 min) --D - 122.7 (30 rnin) -c -75.6” (JO b, equi!.; c 0.39, acetone): X-ray powder diffraction data: 7.93 s(3). 6.7s w. 6.12 vs(Z), 5.37 m, 4.S2 s\, 4.31 Vj(l), 4.12 ffl, 3.95 m, 3.72 W, and 3.48 m. .&al. Calc. for C,H,zC3, (145.16): C. 48.64: H. 3.16. Found: C, 4S.65: H, 3.37. Iselin and Reichstein reported * ’ ior this product m.p. 103-lr>6”, [& - 136.2 53’ in acetons and -90.4 +2 (5 min) 4 -61.6 1-2’ (90 min, eqtiil.) in Hater. Fcr a compound isolated from a mncrolide antibiotic, Takahashi and co-workers gave’ 7 m.p. 92-9-I”. [u],, - I34 (7 min) -L -S7’ (3 h) in acetone and -75 (5 min)+ -57” (90 rrun) ID \vBter.
supported by Contract No. NOi-Chl-57015 (The Ohio State Research Foundation Project 4226~Al) from the Division of Cancer National Cancer Institute, ktional Institutes of Health. Education. and
This
wwrh
Uni\ersirg Treatment,
was
Welfarr?. Belnesda. Md. 2OO!-l.
F. ARCA-.IOP*T. ci. CXS_C~~ELLV.G. FRANCESCHI, R. XIO~DELLI. P. GSELZI. AND S. Pi\CoI Ga:2. Chrm. Irol.. IO0 (19701 9-l9-959: R. B. LILTNGSTOIU AND S. K. CURTER, Dauno;nvcrn, Chenrorb~r.
National 1’mccr lm~irure, Bsth;sda, Md., 1970. hlsco, F. ARcahloluE, AND F. Z,wluo, in J. b’. C~RC~RAI~ Inrrbh>r~cs. Vol. Ill, Spnnger berlq. New York, 1975, pp. IOI-IX
Fucr
A.
Shyer,
DI
F. A~c~cmr.~,
Ci. FR~P~CUCHI,
S. Pikco.
AND
4. SELV~.
Ttrrohcdrcn
JND F.
E. HAHN fEds ),
Ltrr.,(1969)
1oO7-!0to;
h~~co. hl GHKWT, J. H. fc;R%hoFF, END G. ~I~THE (Eds.). Pror. Ink 51 mp. Adrrnmycrn, Springer C’erl_ip. Berlin. 1072. Scz D. HORTO?., R. J. SORENSON. AND U _ WECKECERLE. Curbah.vdr. Res , 2 (19771 175-l 38. and previous papers III this series. R. H. BLLIM AND S. K. CAREER, -IM. fvr?rn. .I!&, 60 (1974) 249-X9; J. J. RIMHART. R. P., LwE., AND S. P. BALcmP4h. AI., 67 (1974) 17547s. E. A. LEFR~K. J. Pmia. 5. ROSENHEM, A%D J. A. GOI-I-L~EB, Concrr, 32 (1973) 302-311. For comprehensibe srucles OII this subject, se< D. W’. f!EluRY, Confer Ciremofhrr. Rep., f’srl .?. 4 (1973) S-9; F. ARCXWONE. S. PENCO. w-m A. VLGEVAW. rbrd.. Purr 3. 6 (1975) 113-179. F. ARCWONE. S. Piruco. A. VIGEVA~W, S. REDAELLI, G. FRAkCHr, A. Dr ~~ARCO, .A. hf. CASAZZA. T. DAsDI%. F. FGRhfELLI. A. Nicco. AND C. SOR\NZO. /. ,W
K.
CARTER.
A.
DI
(1975) a-c5. 5. PENCO. C/urn. I&
( ,!fl/~n), 50 (1963) 90% B. ISEL!N AMI T. R~XWTEITV. f-I&. Chim. Acra, 27 (l94-l) 1X0-1233. P. J GARECC xrc~, 7 I+JRBERG, rlcru C.‘rrm. Scowi. So. B, 79 (1975) 507-512. For re\*irrrr.. see S HnMsslsh, Rdt. C~rb&_b.+. Orcnr., 2i (1966) 113-207; R. F. BIJXERWORTH AND S. ~~ANIsL%~. Adl~. Cnrboh.aar Ch?w. b’~ochmnr., ‘6 (1971) 279-296; S. f-&NuEsslAN AND T. H. H+btLLL, III W. FIGMAN ALD D. HORTON (Eds.), T/rr Corbolrg&~~?s. Vol. IIA, Academic Picss. New York, 197p. up, 139-11 I. H. BROCKMANN Ahm T’. ~I’AEHF~ELOT, AQrururswnschofian, 48 (1961) 717; l-l. BROcKhMr.N, Forrsciv.
Ch~fir.
TermheAm
org.
.\‘ufursr..
31 (1963)
Le;r , (1973) 3699-3701.
II-IS’:
i-f. BROCKhWN%. 2. SCKEFTER, AND C. Srtm,
AND W. RICHLE, Anrirrrirrob. Agenrs Cherwrher..
IS W. KELLER-SCHIERLEIN 16 \V.
RICHU.
E. K. W~KLER.
D.
hl.
Chim. Acra, 55 (1972) 367480. Ii S. TACAHASSHI. hf. K-JRAFJA~GHI.
HAWLEY.
AND
E. OHKI.
hf
DOBLER. Chrm.
AND
W’.
(1970) 68-77.
KELLER-SCHIERLERJ,
Heht
Pharrn. Burl/.. 15 (1967) :657-lh61.
I8 E. R’YSS. H. J&XX. AhD 0 Scirnwxr~. Heir. Chrm. Acra. 43 (1960) 66-l-675. 19 Yu. A. BERLTN. S. E. Ewov, hl. N. Ko~osov. AND hF. hl. SHE\!\ GRIN, T~~rahtxYrron krr.. (1966) I-131-1436; Yu. A. BERLW. 0. A. KIS:LE~A, hl. N. Ko~osov. h!. hl. SwhlvAF;rx. V. S SOIFER, I. V. VASINA, AND I. \’ YARTSEVA. Norue, 218 (1963) 193-19-l. 20 ?. &lCHSrrrh 4%D E WEISS. AdI?. Carboh,tdr. Chsut , I7 (1962) 65-120; T. REIChSrEIN. h’arrrr-
zrissznschafren.
53 (19~7) 53-67.
71 i-l. KJLIANI, Ber.. 55 (1922) 75-101
; F. hf!CHEEL. tbu_‘, 63 (1930) 345459. Heir. Chrm. Acra. 27 (194-t) 1203-l 209. HA,. Cirrfn Acfa. 30 (1947) l$_Z3-1232. P. ULRICH, H&L Chim. Acra. 35 (1952) 93-95.
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‘2
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