Highly Functionalized Cyclopentanes by Radical Cyclization of Unsaturated Bromolactones. 2. A Facile Synthesis of the First Carbaaldohexofuranoses and Their Conversion to Carbapentofuranoses

Article abstract of DOI:10.1021/jo971928l

A novel type of carbasugars, carbaaldohexofuranoses, has been prepared using a 5-exo-trig radical cyclization of C-2 substituted 2,3-unsaturated 7-bromoheptono-1,4-lactones as the key step. During the cyclization step, two stereogenic centers were formed with high stereoselectivity. The lactone moieties of the cyclopentane derivatives were reduced to the alcohols, and the following carbahexofuranoses were synthesized: carba-β-D-mannofuranose, carba-α-L-glucofuranose and 5-amino5-deoxycarba-α-L-glucofuranose. Side chain degradation of the two former compounds gave the carbapentofuranoses: carba-α-L-xylofuranose and carba-β-D-lyxofuranose.

Full text of DOI:10.1021/jo971928l

J . Org. Chem. 1998, 63, 1919-1928
1919
High ly F u n ction a lized Cyclop en ta n es by Ra d ica l Cycliza tion of
Un sa tu r a ted Br om ola cton es. 2. A F a cile Syn th esis of th e F ir st
Ca r ba a ld oh exofu r a n oses a n d Th eir Con ver sion to
Ca r ba p en tofu r a n oses
Anne Marie Horneman and Inge Lundt*
Department of Organic Chemistry, Technical University of Denmark, Building 201,
DK-2800 Lyngby, Denmark
Received October 17, 1997
A novel type of carbasugars, carbaaldohexofuranoses, has been prepared using a 5-exo-trig radical
cyclization of C-2 substituted 2,3-unsaturated 7-bromoheptono-1,4-lactones as the key step. During
the cyclization step, two stereogenic centers were formed with high stereoselectivity. The lactone
moieties of the cyclopentane derivatives were reduced to the alcohols, and the following carba-
hexofuranoses were synthesized: carba-â-D-mannofuranose, carba-R-L-glucofuranose and 5-amino-
5-deoxycarba-R-L-glucofuranose. Side chain degradation of the two former compounds gave the
carbapentofuranoses: carba-R-L-xylofuranose and carba-â-D-lyxofuranose.
In tr od u ction
starting material or some intermediate at an early stage
in the synthesis. Thus, using chiral substrates several
approaches to the synthesis of polyoxygenated car-
bocycles from carbohydrates have been reported,7 and the
use of achiral starting materials such as norbornene8,9
or cyclopentene derivatives10 has also been described.
An attractive method for the preparation of cyclopen-
tanes is intramolecular radical cyclization, especially
when the substrates are carbohydrates, because radical
cyclizations can be run under neutral conditions. This
means that base-catalyzed epimerization and â-elimina-
tion are not competing reactions as in carbanionic
carbon-carbon bond-forming reactions.11 Internal radi-
cal cyclization of a suitable carbohydrate derivative
possessing both a radical donor as well as a radical
acceptor gives rise to cyclic products with preservation
of all stereocenters and in the best cases also with
stereocontrol at the new C-C bond formed in the ring
closing reaction. This strategy to prepare carbocyclic
analogues of carbohydrates was first recognized by Wil-
cox and co-workers who prepared carbafructofuranose
from an acyclic unsaturated carbohydrate derivative,
where only the Z-isomer gave full stereocontrol.12 Our
approach to obtain carbafuranoses was to use 2,3-
unsaturated 7-bromo-7-deoxy-heptono-1,4-lactones as syn-
thons. We have shown that a 5-exo-trig-radical cycliza-
tion could be initiated, resulting in formation of a
cyclopentane ring fused to the five-membered lactone
ring,13 thereby generating one stereocenter with high
Highly functionalized cyclopentanes as well as cyclo-
hexanes are structural features found in biologically
interesting compounds. Polyoxygenated derivatives are
often referred to as carbasugars, since they may be
viewed as furanose- or pyranose-analogues where the
ring oxygen has been replaced by a methylene group. The
lack of the acetal moiety preserves them from hydrolysis
as compared to the sugar derivatives, thus rendering
them biologically resistant, and many glycosidase inhibi-
tors and antiobiotics are found within this class of
compounds.1 The importance of carbafuranoses stems
from the interest in having access to carbocyclic ana-
logues of nucleosides2,3 which have attracted particular
interest as antitumor and antiviral agents. (-)-Carbovir
has been an attractive synthetic target as exemplified
by the recently published synthesis by Trost and co-
workers.4 Oxygenated cyclopentanes, substituted with
other functional groups as well, have also been recognized
as glycosidase inhibitors, exemplified by the powerful
R-mannosidase inhibitor Mannostatin, which has been
synthesized in the optically pure form by Ganem and co-
workers5 as well as in the racemic form by the Trost
group.6
Stereocontrol in the synthesis of such compounds is
quite challenging, and the synthons can either be chosen
among compounds from the chiral pool or from achiral,
easily available compounds, with resolution of either the
* Corresponding author. Phone: +45 4525 2133, Fax: +45 4593
3968, e-mail: okil@pop.dtu.dk.
(1) Nishimura, Y. In Studies in Natural Products Chemistry; Atta-
ur-Rahman, Ed.; Elsevier Publishers B. V.: Amsterdam, 1992; Vol.
10, p 495.
(8) Vogel, P.; Fattori, D.; Gasparoni, F.; Le Drian, C. Synlett 1990,
173.
(9) Marschner, C.; Penn, G.; Griengl, H. Tetrahedron Lett. 1990, 31,
2873. Idem. Tetrahedron 1993, 49, 5067.
(2) Borthwick, A. D.; Biggadike, K. Tetrahedron 1992, 48, 571.
(3) Agrofolio, L.; Suhas, E.; Farese, A.; Condom, R.; Challand, S.
R.; Earl, R. A.; Guedj, R. Tetrahedron 1994, 50, 10611.
(4) Trost, B. M.; Madsen, R.; Guile, S. G.; Elia, A. E. H. Angew.
Chem., Int. Ed. Engl. 1996, 35, 1569.
(5) King, S. B.; Ganem, B.; J . Am. Chem. Soc. 1994, 116, 562.
(6) Trost, B. M.; van Vranken, D. L. J . Am. Chem. Soc., 1993, 115,
444.
(10) (a) Shoberu, K. A.; Roberts, S. M. J . Chem. Soc., Perkin Trans.
1 1992, 2419. (b) Parry, R. J .; Haridas, K.; De J ong, R.; J ohnson, C. R.
Tetrahedron Lett., 1990, 31, 7549.
(11) (a) Motherwell, W. B.; Crich, D.; Free Radical Chain Reactions
in Organic Synthesis; Academic Press: London, 1992. (b) Giese, B.
Radicals in Organic Synthesis, Formation of Carbon-Carbon Bonds;
Pergamon Press: Oxford, 1986.
(12) (a) Wilcox, C. S.; Thomasco, L. M. J . Org. Chem. 1985, 50, 546.
(b) Gaudino, J . J .; Wilcox, C. S. Carbohydr. Res. 1990, 206, 233.
(7) Ferrier, R. J .; Middleton, S. Chem. Rev. 1993, 93, 2779.
S0022-3263(97)01928-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 02/27/1998

1920 J . Org. Chem., Vol. 63, No. 6, 1998
Horneman and Lundt
Sch em e 1
available 7-bromo-7-deoxy-D-glycero-D-galacto-heptono-
1,4-lactone (1)17 was chosen. The exocyclic hydroxyl
groups of 1 were protected with an isopropylidene group
to give 2 for the purpose of avoiding elimination in the
side chain during the subsequent elimination step18
(Scheme 1). Lactone 2 was acetylated in pyridine to give
the esterified heptonolactone 3. Since no elimination was
observed during the acylation procedure18 a stronger base
was required. It was found that triethylamine in dichlo-
romethane caused a fast â-elimination to give a 2,3-
unsaturated 1,4-heptonolactone. The â-elimination was,
however, always accompanied by an isomerization at C-4
to give the two C-4 epimeric R,â-unsaturated lactones 4
and 5. The epimers could be separated by crystallization
to give 5 in 51% yield, followed by flash chromatographic
separation of the remaining mixture. Comparison of the
NMR data for 4 and 5 with NMR data for other 2,3-
unsaturated aldonolactones19 did not allow definite as-
signments of the configurations at C-4, and therefore a
chemical proof was performed (Scheme 2).20 Thus, the
unsaturated lactones were assigned as 2-O-acetyl-7-
bromo-3,7-dideoxy-5,6-O-isopropylidene-D-arabino-hept-
2-enono-1,4-lactone (4) and 2-O-acetyl-7-bromo-3,7-dideoxy-
5,6-O-isopropylidene-D-ribo-hept-2-enono-1,4-lactone (5).
Investigation of the radical cyclization of the two C-2
substituted 2,3-unsaturated lactones was now under-
taken (Scheme 3). Thus, 4 was treated with tributyltin
hydride to give only one compound as judged by 1H NMR
of the crude product, and the bicyclic lactone 11 was
isolated in 90% yield. This indicated that formation of
two stereogenic centers during the cyclization reaction
occurred stereoselectively. Assignment of the configu-
ration at C-4 of 11 was based on the coupling constant
between H-4 and H-5, which was 7.5 Hz and thus
indicated cis-oriented protons in the five-membered ring
system. The coupling constant between H-1 and H-5, J 1,5
) 4.5 Hz, did not give a definite proof of cis-oriented
protons. It was, however, assumed that the ring closing
reaction leading to a cyclopentane ring fused to the five-
membered lactone ring should give the thermodynami-
cally more stable cis-fused bicyclic system.21 The unsat-
urated lactone 5 was similarly treated with tributyltin
hydride to give a bicyclic lactone 17 which was isolated
in 90 % yield. 1H NMR of the crude product revealed no
byproducts, again indicating that the formation of two
stereoselectivity. The products obtained were used for
preparation of 5-deoxy-carbahexofuranoses.13 We also
showed that the intermediate radical in a tandem reac-
tion could be trapped stereospecifically by unsaturated
species giving rise to C-2 alkylated bicyclic systems.13a
It was now of interest to investigate the reactivity of
the double bond of C-2 substituted 2,3-unsaturated
heptono-1,4-lactones in carbocyclization reactions. Using
a 2-oxy-substituent, carbaanalogues of aldohexofuranoses
might be prepared. While carbahexopyranoses have been
prepared and well studied,14 the corresponding furanoses
of aldohexoses have, to our knowledge, not been prepared
except for some 5-deoxy analogues.13,15,16 The already
mentioned carba-D-fructofuranose12 together with the
reported racemic ribo-carb-2-ulofuranose analogue9 are
the only known carbaanalogues of 2-ketohexofuranoses.
Using a nitrogen substituent at C-2 the carbocyclization
might give access to biologically important carbaana-
logues of aminodeoxy hexofuranoses.
(17) Lundt, I.; Madsen, R.; Synthesis, 1995, 787.
(18) Lederkremer, R. M. de; Varela, O. Adv. Carbohydr. Chem.
Biochem. 1994, 50, 125.
Resu lts
(19) (a) Vekemans, J . A. J . M.; Dapperens, C. W. M.; Claessen, R.;
Koeten, A. M. J .; Godefrei, E. F.; Chittenden, G. J . F. J . Org. Chem.
1990, 55, 5336. (b) Vekemans, J . A. J . M.; De Bruyn, R. G. M.; Caris,
R. C. H. M.; Kokx, A. J . P. M.; Konings, J . J . H. G.; Godefrei, E. F.;
Chittenden, G. J . F. J . Org. Chem. 1987, 52, 1093. (c) Vekemans, J . A.
J . M.; Franken, G. A. M.; Dapperens, C. W. M.; Godefrei, E. F.;
Chittenden, G. J . F. J . Org. Chem. 1988, 53, 627.
Previously we have prepared 2,3-unsaturated 7-bromo-
7-deoxy-heptono-1,4-lactones from the corresponding 2-bro-
mo-2-deoxy-heptono-1,4-lactones, generating the double
bond by a reductive trans-â-bromo-acetoxy-elimination
promoted by NaHSO3.13 For the preparation of C-2
substituted 2,3-unsaturated lactones, a different ap-
proach was needed. Esterified aldono-1,4-lactones readily
undergo a â-hydrogen-acyloxy-elimination under alkaline
conditions due to the acidic proton R to the carbonyl
group. As starting material for this reaction the readily
(20) The unsaturated lactones were converted into 3,7-dideoxy-
heptono-1,4-lactones for comparison with known compounds (Scheme
2). Thus, the double bond of 4 and 5 was catalytically hydrogenated
over palladium on charcoal, without the presence of base, to give
saturated heptonolactones. It is known that catalytic hydrogenations
of C-2 substituted unsaturated aldono-1,4-lactones give saturated
lactones with cis-oriented substituents at C-2 and C-4.31 Further
catalytic hydrogenation in the presence of triethylamine caused
reduction of the bromine to give the 7-deoxy derivatives 6 and 9,
respectively. Deprotection using acidic methanol yielded the two 3,7-
(13) (a) Horneman, A. M.; Lundt, I.; Soetofte, I. Synlett 1995, 918.
(b) Horneman, A. M.; Lundt, I. Tetrahedron 1997, 53, 6879.
(14) Suami, T.; Ogawa, S. Adv. Carbohydr. Chem. Biochem. 1990,
48, 21.
dideoxy-heptono-1,4-lactones, 7 (mp 129-131 °C, [R]20 -54 (c 1.2,
D
H2O)) and 10 (mp 153 °C, [R]20 -17 (c 1.5, MeOH)), respectively. A
D
comparison of melting points and specific rotations with the data for
(15) Marschner, C.; Baumgartner, J .; Griengl, H. J . Org. Chem.
1995, 60, 5224.
(16) Roberts, S. M.; Shoberu, K. A. J . Chem. Soc., Perkin Trans. 1
1992, 2625.
the known 3,7-dideoxy-D-gluco-heptono-1,4-lactone (7) (mp 133-134
°C, [R]20 -59 (c 1.5, H2O))32 established the configuration at C-4 of 7
D
and 10.
(21) Giese, B. Org. React. 1996, 48, 301.

Radical Cyclization of Unsaturated Bromolactones
J . Org. Chem., Vol. 63, No. 6, 1998 1921
Sch em e 2. Str u ctu r e P r oof for 4 a n d 5
Sch em e 3
stereogenic centers occurred stereoselectively. Assign-
ment of the configuration at C-5 was as above based on
the assumption that the thermodynamically more stable
cis-fused bicyclic system had been formed, and the
coupling constant of 9 Hz between H-4 and H-5 indicated
cis-oriented protons. Confirmation of the assignment was
obtained by X-ray crystallography of compound 17.13a
The bicyclic lactones 11 and 17 were used for the
preparation of carbahexofuranoses and carbapentofura-
noses (Scheme 3). Reduction of the lactone moiety to the
corresponding alcohol using sodium borohydride in the
presence of sodium methoxide allowed the preservation
of the isopropylidene group in the carbahexose series. By
oxidative cleavage of the exocyclic diol, using sodium
periodate, the carbahexoses were degraded to isopropyli-
dene-protected carbapentofuranoses. Thus lactone 11
gave the protected crystalline carbahexofuranose 12,
which was deprotected to give carba-R-L-glucofuranose
(15). Acetylation gave the crystalline pentaacetate 16.
Likewise, reduction of lactone 17 gave the carbahexose
derivative 18, which after hydrolysis gave crystalline
carba-â-D-mannofuranose (21). Compound 12 was de-
graded to the isopropylidene-protected carbapentofura-
nose 13, which was hydrolyzed to give the new crystalline
R-L-xylofuranose (14). The enantiomer has previously
been reported as a syrup15 and as a crystalline com-
pound.22 By the same procedure compound 18 gave the
carbapentose derivative 19, which by deprotection gave
crystalline carba-â-D-lyxofuranose (20), previously re-
ported as a syrup.15
ment of 2,7-dibromo-2,7-dideoxy-D-glycero-D-ido-heptono-
1,4-lactone (22)32 with sodium azide was performed. The
crude product, containing a mixture of C-2 epimers of a
2-azido-7-bromo-2,7-dideoxy-heptono-1,4-lactone, was
acetylated using pyridine as the solvent to give the 2,3-
unsaturated lactone 23, due to a simultaneous â-elimina-
tion of acetic acid. Lactone 23 could be isolated by
crystallization (24% yield). Flash chromatographic pu-
rification of the mother liquor material gave a further
amount (13%) of 23 together with a 3,4-unsaturated
heptonolactone (32%), which was characterized by NMR
alone. The presence of the latter lactone indicates that
an isomerization at C-4 of 23 possibly could take place
in the presence of pyridine, and thus a proof of structure
for compound 23 was performed, as discussed below.
Interestingly, the â-elimination in this case was induced
by pyridine. Pyridine could not induce â-elimination of
the 2-acetoxylactone 3, and this indicates a more acidic
H-2 proton in the 2-azidolactone. Treatment of the
2-azidolactone 23 with 2 equiv of tributyltin hydride
To study further the reactivity of the double bond and
the stereoselectivity at C-2 in the radical cyclization step,
a C-2 nitrogen substituted 2,3-unsaturated 7-bromo-
heptonolactone was prepared (Scheme 4). Previously we
have reported a convenient access to 2-amino-2-deoxy-
aldonolactones via nucleophilic substitution of 2-bromo-
2-deoxy-aldonolactones with azide ions.23 Hence, treat-
(23) Bock, K.; Lundt, I.; Pedersen, C. Acta Chem. Scand. 1987, B41,
435. Bols, M.; Lundt, I. Ibid. 1988, B42, 67.
(22) Tadano, K.; Hoshino, H.; Ogawa, S.; Suami, T. J . Org. Chem.
1988, 53, 1427.
(24) Wassermann, H. H.; Brunner, R. K.; Buynak, J . D.; Carter, C.
G.; Oku, T.; Robinson, R. P. J . Am. Chem. Soc., 1985, 107, 519.

1922 J . Org. Chem., Vol. 63, No. 6, 1998
Horneman and Lundt
often tend to undergo dimerization.26 The dimerization
was avoided by acylation of the amino group prior to
cyclization. Thus the amine 24 was treated with tri-
fluoroacetic acid anhydride to give the trifluoroacetamide
substituted unsaturated lactone 25, which by reaction
with tributyltin hydride gave a major cyclization product,
26, together with a minor one, 27. The major product
could be isolated by direct crystallization in 76% yield,
and the remaining mixture was separated by flash
chromatography. Dimerization in the radical cyclization
step could also be avoided by protecting amine 24 with a
trimethylsilyl group. This gave a cyclization product with
the same configuration as compound 26, but the workup
of the TMS-protected product was troublesome due to
cleavage of the protecting group. The configurations at
C-4 of the two cis-fused bicyclic lactones 26 and 27 were
determined from the coupling constants between H-4 and
H-5, which was 9 Hz in the major product and 6 Hz in
the minor product. Hence, cis-oriented protons were
assigned to 26 and trans-oriented protons were assigned
to 27. The crystalline bicyclic lactone 26, was deprotected
by treatment with aqueous HCl to give the amino acid
derivative 28. This compound was reduced by treatment
with sodium borohydride to give an amino substituted
cyclopentane 29, which can be recognized as the carbocy-
clic analogue of 5-amino-5-deoxy-R-L-glucofuranose. It
should be noted that lactone 28 could possibly be used
as a synthon for the preparation of a new stereoisomer
of carbaanalogues of Nikkomycin.27 Nikkomycins con-
stitute a class of nucleosides in which the 5′-position is
substituted with an amino acid.
Sch em e 4
Since both a 2,3- and a 3,4-unsaturated heptonolactone
had been isolated from the base-catalyzed â-elimination
leading to compound 23, a chemical proof of structure
was carried out for the purpose of confirming the con-
figuration at C-4 of 23. The structural proof was done
by converting the unsaturated heptonolactone 25 and
heptonolactone 7 into the same amino substituted hep-
tonolactone 33 (Scheme 5). Thus the unsaturated lactone
25 was reduced by hydrogenation using palladium on
charcoal as the catalyst. By analogy with the reduction
of 4 and 5 and with related work28,31 this was expected
to give a saturated lactone with cis-oriented substituents
at C-2 and C-4. Further hydrogenation in the presence
of triethylamine reduced the primary bromide to a deoxy
function to give 32, which by treatment with acidic
methanol gave the aminolactone hydrochloride 33. The
second part of the structure proof started from the known
compound 3,7-dideoxy-D-gluco-heptono-1,4-lactone (7).32
Protection of the exocyclic hydroxyl groups gave 34.
Upon treatment with an excess of methanesulfonyl
chloride the hydroxyl group at C-2 was mesylated, and
caused reduction of the azido group to an amino sub-
stituent,24 and the 2,3-unsaturated-2-aminolactone 24
was isolated by crystallization. No traces of a cyclized
product were observed in the NMR spectra of the crude
product; neither was a product from a debromination at
C-7 observed. An alternative attempt to prepare the
amine 24 by a Staudinger reduction using PPh3 to reduce
the azide25 was not successful due to the stability of the
intermediate vinylic iminophosphorane. Further treat-
ment of the unsaturated 2-aminolactone 24 with an
excess of tributyltin hydride and AIBN in refluxing
(27) Aggarwal, V. K.; Monteiro, N.; Tarver, G. J .; Lindell, S. D. J .
Org. Chem. 1996, 61, 1192.
(28) Varela, O.; Nin, A. P.; Lederkremer, R. M. de. Tetrahedron Lett.
1994, 35, 9359.
(29) (a) Stork, G.; Sher, P. M.; Chen, H. L. J . Am. Chem. Soc. 1986,
108, 6384. (b) Keck. G. E.; Burnett, D. A. J . Org. Chem. 1987, 52, 2958.
(c) Renaud, P.; Schubert, S. Angew. Chem. 1990, 102, 416. (d) For a
general treatment of stereoselectivity in radical reactions see Curran,
D. P.; Porter, N. A.; Giese, B. Stereochemistry of Radical Reactions;
Verlag Chemie: New York, 1996.
1
toluene gave rise to a cyclized compound. The H NMR
spectra revealed the absence of a proton on the amino
substituted carbon. This showed that the product was
not the expected bicyclic compound, but presumably a
symmetrical dimer, 31, of the bicyclic compound. Ac-
cording to earlier studies, amino acid derived radicals
(30) Hayashi, K.; Iyoda, J .; Shiihara, I. J . Organomet. Chem. 1967,
10, 81.
(31) (a) Bock, K.; Lundt, I.; Pedersen, C. Acta Chem. Scand. 1981,
B35, 155. (b) Hussain, S. A. M. T.; Ollis, W. D.; Smith, C.; Stoddart, J .
F. J . Chem. Soc., Perkin Trans. 1 1975, 1480.
(32) Bock, K.; Lundt, I.; Pedersen, C.; Sonnichsen, R. Carbohydr.
Res. 1988, 174, 331.
(25) Knouzi, N.; Vaultier, M.; Carrie´, R. Bull. Soc. Chim. Fr. 1985,
815.
(26) (a) Obata, N.; Niimura, K. J . Chem. Soc., Chem. Commun. 1977,
238. (b) For reviews on amino acid derived radicals see Easton, C. J .
Chem. Rev. 1997, 97, 53. (c) Renaud, P.; Giraud, L. Synthesis 1996,
913.

Radical Cyclization of Unsaturated Bromolactones
J . Org. Chem., Vol. 63, No. 6, 1998 1923
Sch em e 5. Str u ctu r e P r oof for 25 a n d Th u s 23
for the preparation of carbaaldohexofuranoses, a novel
class of compounds, which by side chain degradation
yielded carbapentofuranoses.
Exp er im en ta l Section
Melting points are uncorrected. Optical rotations were
determined on a Perkin-Elmer 241 polarimeter. NMR spectra
were recorded at 500, 300, or 250 MHz (1H) and 125.8, 75.5,
or 62.9 MHz (13C). Chemical shifts were measured in ppm
and coupling constants (J ) in Hz. For spectra in D2O, either
dioxane (δ ) 67.4), acetone (δ ) 29.8), or methanol (δ ) 49.0)
was used as the internal reference for 13C NMR spectra, and
the solvent peak (δ ) 4.63) for 1H NMR spectra. For spectra
in CDCl3, chloroform-d (δ ) 76.9) was used as internal
reference for 13C NMR spectra while chloroform-H (δ ) 7.27)
1
was used for H NMR spectra. For spectra in acetone (CD3, δ
) 29.8) was used for 13C spectra and (CD2H, δ ) 2.05) was
used for 1H spectra. Assignments of 1H NMR signals were
done by homonuclear decoupling experiments, and assign-
ments of 13C NMR signals were, if reported, done by HETCOR
experiments. Bu3SnH was prepared from bis(tributytin) oxide
and polymethylhydrosiloxane.30 Reactions using Bu3SnH were
performed in a nitrogen atmosphere. All concentrations were
performed in vacuo. Dry solvents were obtained by storing
over molecular sieves. Microanalyses were carried out by Leo
Microanalytical Laboratory and Research Institute for Phar-
macy and Biochemistry, Prague, Czech Republic.
7-Br om o-7-d eoxy-5,6-O-isop r op ylid en e-D-glycer o-D-ga -
la cto-h ep ton o-1,4-la cton e (2). Bromolactone 117 (8.70 g,
32.1 mmol) was suspended in dry acetone, and camphorsul-
fonic acid (0.74 g, 3.2 mmol) was added to the suspension. The
flask was equipped with a Soxhlet apparatus containing 3 Å
molecular sieves (20 g), and the reaction mixture was refluxed
for 24 h, after which it was neutralized with solid NaHCO3
(20 g), filtered, and concentrated. The residue was suspended
in H2O and extracted with EtOAc. The combined organic
phases were dried (MgSO4) and concentrated to give a crystal-
line residue (9.80 g). Recrystallization from EtOAc:hexane of
the residue and of the evaporated mother liquor gave isopro-
pylidene-protected 2 as colorless crystals (8.50 g, 86%), mp
subsequent nucleophilic substitution of the mesylate with
chloride gave the chlorolactone 35. Nucleophilic substi-
tution of the chloride with sodium azide gave the azi-
dolactone 36 which was hydrogenated under acidic
conditions to give the aminolactone hydrochloride 33.
Melting points, specific rotations, and NMR spectra
showed the aminolactones obtained by the two routes to
be identical. The configuration at C-4 could not have
been affected in either reaction sequence. Thereby the
configuration at C-4 of the unsaturated lactone 25 was
established, which meant that the configuration of 23 was
also established. Furthermore, the configuration at C-2
in 36 was proven.
The radical cyclizations of compounds 4, 5, and 25
showed a high degree of stereoselectivity in the genera-
tion of two stereogenic centers. The first stereogenic
center which is formed upon the addition of the alkyl
radical to the double bond was in all three cases ste-
reospecific in the formation of two cis-annelated five-
membered rings. The second stereogenic center, which
is formed upon the trapping of tributyltin hydride by the
enolate radical,13 was stereospecific in the case of 4 and
5 as judged by 1H NMR of the crude products, and highly
stereoselective in the case of 25. The stereoselectivity is
most likely caused by steric shielding of the enolate
radical by the cyclopentane ring. This shielding we also
found when the enolate radical was trapped by allyl
tributylstannane13a and high stereoselectivity has been
observed in similar cyclic systems.29
1
159-160 °C. H NMR (500 MHz, CD3COCD3): δ 5.28 (d, 1 H,
C3-OH), 5.15 (d, 1 H, C2-OH), 4.65 (ddd, H-6, J 6,7 ) 5.5, J 6,7′
) 8), 4.49 (dd, H-5, J 5,6 ) 6.5), 4.42 (dd, H-2, J 2,3 ) 8), 4.32
(m, H-3, H-4), 3.76 (dd; H-7, J 7,7′ ) 11), 3.62 (dd, H-7′), 1.38,
1.35 (2 s, 6 H). 13C NMR (CD3COCD3, 62.9 MHz): δ 174, 109.9,
74.6, 74.9, 75.1, 77.8, 77.9, 31.0, 26.9, 25.5. Anal. Calcd for
C
10H15BrO6 (311.13): C, 38.6; H, 4.86; Br, 25.68. Found: C,
38.74; H, 4.89; Br, 25.82.
2,3-Di-O-a cetyl-7-br om o-7-d eoxy-5,6-O-isop r op ylid en e-
D-glycer o-D-ga la cto-h ep ton o-1,4-la cton e (3). Lactone 2
(8.76 g, 28.2 mmol) was dissolved in pyridine (40 mL) and Ac2O
(20 mL). The solution was left at room temperature for 1.5 h
after which it was concentrated to give a slightly colored
crystalline residue (14.58 g). The residue was dissolved in
CH2Cl2 and washed with H2O. The organic phase was dried
(Na2SO4), filtered through activated charcoal, and concentrated
to give acetylated 3 (11.27 g, quant) as colorless crystals, mp
109-115 °C. Recrystallization of an aliquot from Et2O:hexane
gave 3, mp 115 °C, [R]20 -99 (c 1.0, CHCl3). 1H NMR (500
D
MHz, CDCl3): δ 5.68 (d, H-2, J 2,3 ) 6.5), 5.60 (dd, H-3, J 3,4
6.5), 4.63 (dd, H-4, J 4,5 ) 1), 4.62 (m, H-6, J 6,7′ ) 5.5, J 6,7
)
)
9.5), 4.45 (dd, H-5, J 5,6 ) 6), 3.66 (dd, H-7′, J 7,7′ ) 10.5), 3.56
(dd, H-7), 2.19, 2.15 (2s, 6 H), 1.47, 1.39 (2 s, 6 H). 13C NMR
(CDCl3, 62.9 MHz): δ 170, 169.4, 168.5, 110.3, 77.3, 76.2, 74.9,
73.5, 71.3, 28.2, 26.2, 25.0, 20.5, 20.3. Anal. Calcd for C14H19
-
Con clu d in g Rem a r k s
BrO8 (395.20): C, 42.55; H, 4.85; Br, 20.22. Found: C, 42.56;
H, 4.88; Br, 20.15.
In conclusion, we have reported the preparation and
radical cyclization of C-2 substituted 2,3-unsaturated
7-bromo-7-deoxy-heptono-1,4-lactones. The 5-exo-trig-
radical cyclizations generate two stereogenic centers with
high stereoselectivity. The cyclized compounds were used
2-O-Acetyl-7-br om o-3,7-d id eoxy-5,6-O-isop r op ylid en e-
D-a r a bin o-h ep t-2-en on o-1,4-la cton e (4) a n d 2-O-Acetyl-
7-br om o-3,7-d id eoxy-5,6-O-isop r op ylid en e-D-r ibo-h ep t-2-
en on o-1,4-la cton e (5). Protected lactone 3 (8.00 g, 20.3
mmol) was dissolved in CH2Cl2 (65 mL) and Et3N (3.34 mL,

1924 J . Org. Chem., Vol. 63, No. 6, 1998
Horneman and Lundt
24.3 mmol) and left at room temperature for 2.5 h. The
solvents were evaporated, the residue was dissolved in CH2-
Cl2 (100 mL), and the organic phase was washed with H2O,
dried (Na2SO4), filtered through activated charcoal, and evapo-
rated to give a crystalline crude product (6.89 g, quant).
Recrystallization of the residue and of the product from the
resulting mother liquor from EtOAc:Et2O (ca. 1:10) gave 5
(3.51 g, 51%) as colorless crystals, mp 121-124 °C. Flash
chromatography of the mother liquor (EtOAc:hexane 1:3) gave
crystalline 5 (0.61 g, 9%) and 4 (1.83 g, 27%) as a semicrys-
talline solid. 2-O-Acetyl-7-bromo-3,7-dideoxy-5,6-O-isopropy-
lidene-D-ribo-hept-2-enono-1,4-lactone (5): Repeated crystal-
lizations from EtOAc:Et2O afforded the product, mp 127-128
Calcd for C12H17BrO6 (337.17): C, 42.75; H, 5.08; Br, 23.70.
Found: C, 42.96; H, 5.09; Br, 23.74.
2-O-Acet yl-3,7-d id eoxy-5,6-O-isop r op ylid en e-D-a ltr o-
h ep ton o-1,4-la cton e (9). Saturated lactone 8 (0.70 g, 2.1
mmol) was dissolved in EtOAc (25 mL). Palladium on charcoal
(5%, 70 mg) and Et3N (0.56 mL, 4.2 mmol) was added, and
the mixture was hydrogenated in a H2 atmosphere for 20 h at
high pressure (ca. 100 Bar). Filtration and concentration gave
9 as a slightly colored syrup (0.55 g, quant). 13C NMR (CDCl3,
62.9 MHz): δ 172, 67.4, 72.5, 72.9, 31.8, 78.7, 13.9.
3,7-Did eoxy-D-a ltr o-h ep t on o-1,4-la ct on e (10). Com-
pound 9 (0.55 g, 2.1 mmol, crude product) was dissolved in
HCl/MeOH (0.3 M, 30 mL) and left at room temperature for
for 72 h. The solution was concentrated to give a crystalline
product (0.4 g). Recrystallization from EtOH:Et2O gave 10
(0.28 g, 76%), mp 149-153 °C, as slightly colored crystals.
Flash chromatography of an aliquot (EtOAc) and crystalliza-
tion from EtOH:Et2O gave an analytical sample of 10, mp 153
°C, [R]20 -37 (c 1, CHCl3). 1H NMR (CDCl3, 500 MHz): δ
D
7.41 (H-3, d, J 3,4 ) 2), 5.03 (H-4, dd, J 4,5 ) 9), 4.58 (H-6, ddd,
J 5,6 ) 5.5, J 6.7′ ) 4.8, J 6.7 ) 8.5), 3.92 (H-5, dd), 3.77 (H-7′, dd,
J 7,7′ ) 11), 3.58 (H-7, dd), 2.35 (s, 3 H), 1.55, 1.40 (2 s, 6 H).
13C NMR (CDCl3, 62.9 MHz): 166.7, 165.5, 138.2, 132.8, 110.0,
°C, [R]20 -17 (c 1.5, MeOH). 1H NMR (D2O, 500 MHz): δ
78.2, 77.6, 75.6, 28.8, 27.6, 25.0, 20.8. Anal. Calcd for C12H15
-
D
4.64 (m, H-2, H-4), 3.72 (dd, H-5, J 4,5 ) 3.5, J 5,6 ) 6), 3.66 (dq,
H-6, J 6,7 ) 6), 2.56 (ddd, H-3′, J 3,3′ ) 12), 2.05 (m, H-3), 1.13
(d, 3 H-7). 13C NMR (D2O (dioxane), 62.9 MHz): δ 180.1, 78.3,
74.7, 68.0, 68.8, 31.5, 19.2. Anal. Calcd for C7H12O5 (176.17):
C, 47.73; H, 6.87. Found: C, 47.60; H, 6.90.
BrO6 (335.15): C, 43.01; H, 4.51; Br, 23.84. Found: C, 43.02;
H, 4.51; Br, 23.80. 2-O-Acetyl-7-bromo-3,7-dideoxy-5,6-O-
isopropylidene-D-arabino-hept-2-enono-1,4-lactone (4): Re-
peated crystallizations from EtOAc:Et2O gave colorless crys-
tals, mp 91-93 °C, [R]20D -78 (c 0.5, CHCl3). 1H NMR (CDCl3,
500 MHz): δ 7.21 (H-3, d, J 3,4 ) 2), 5.36 (H-4, dd, J 4,5 ) 1.2),
4.65 (H-6, ddd, J 5,6 6.5, J 6,7′ ) 6, J 6,7 ) 9), 4.41 (H-5), 3.72 (H-
7′, dd, J 7,7′ ) 10), 3.69 (H-7, dd), 2.30 (s, 3 H), 1.42, 1.37 (2 s,
6 H). 13C NMR (CDCl3): δ 166.7, 166.6, 138.3, 130.2, 110.3,
(1R,5R)-4(R)-O-Acet yl-7(R),8(R)-O-isop r op ylid en e-2-
oxa bicyclo[3.3.0]oct-3-on e (11). Compound 4 (0.90 g, 2.7
mmol) was dissolved in dry EtOAc (20 mL) and heated at
reflux under a N2 atmosphere. Via a syringe pump a solution
of Bu3SnH (0.85 mL, 3.2 mmol) and AIBN (44 mg, 0.3 mmol)
in EtOAc (9.2 mL) was added over 3 h. The reaction mixture
was evaporated, and the residue was suspended in CH3CN (25
mL) and washed with hexane (4 × 30 mL). The CH3CN was
evaporated to give a colorless crystalline product (0.68 g, 99%),
mp 85-95 °C. 1H NMR showed only one product. Flash
chromatography (hexane f EtOAc:hexane 2:5) gave the cy-
clized product 11 (0.62 g, 90%) as colorless crystals, mp 93-
100 °C. Repeated crystallizations of an aliquot gave mp 101-
76.4, 76.3, 75.3, 28.3, 26.2, 24.9, 20.7. Anal. Calcd for C12H15
-
BrO6 (335.15): C, 43.01; H, 4.51; Br, 23.84. Found: C, 43.13;
H, 4.41; Br, 23.90.
2-O-Acet yl-3,7-d id eoxy-5,6-O-isop r op ylid en e-D-glu co-
h ep ton o-1,4-la cton e (6). Compound 4 (0.10 g, 0.3 mmol) was
dissolved in EtOAc (4 mL). Palladium on charcoal (5%,15 mg)
was added, the suspension was hydrogenated for 5 h at 1 atm,
Et3N (0.08 mL, 0.6 mmol) was added, and the hydrogenation
was continued at 1 atm for 40 h. Filtration and concentration
gave a crystalline residue which was dissolved in CH2Cl2 and
washed with H2O. The organic phase was dried (MgSO4), and
evaporation of the solvent gave 6 as slightly colored crystals
(60 mg, 78%). 1H NMR (CDCl3, 500 MHz): δ 5.48 (dd, H-2,
104 °C, [R]20 -106 (c 1, CHCl3). The product could also be
D
purified by recrystallization: Starting from 4 (0.41 g, 1.2 mmol)
following the procedure described above, the crude product
from evaporation of the acetonitrile was recrystallized from
Et2O:hexane to give 11 as slightly colored crystals (0.23 g,
74%). 1H NMR (CDCl3, 500 MHz): δ 5.64 (d, H-4, J 4,5 ) 7.5),
4.81 (dd, H-7, J 6′,7 ) 4.5, J 7,8 ) 5), 4.71 (d, H-8), 4.66 (d, H-1,
J 1,5 ) 4.5), 3.49 (m, H-5, J 5,6 ) 7.5, J 5,6′ ) 11,5), 2.18 (s, 3 H),
2.13 (ddd, H-6, J 6,6′ ) 15), 1.81 (ddd, H-6′), 1.32, 1.43 (2 s, 6
H). 13C NMR (CDCl3, 62.9 MHz): 172, 169.5 (C-3, OAc), 110.9
(acetal), 85.5 (C-1), 83.7 (C-8), 81.0 (C-8), 70.7 (C-4), 41.2 (C-
5), 31.0 (C-6), 26.2, 23.8, 20.3. Anal. Calcd for C12H16O6
(256.25): C, 56.25; H, 6.29. Found: C, 56.27; H, 6.44.
J 2,3′ ) 9, J 2,3 ) 10.5), 4.45 (m, H-4, H-6), 4.00 (dd, H-5, J 4,5
)
2.5, J 5,6 ) 6.5), 2.68 (ddd, H-3′, J 3,3′ ) 12.5, J 3′,4 ) 6), 2.29 (ddd,
H-3, J 3,4 ) 10), 1.49, 1.38 (2 s, 6 H), 1.39 (d, H.7, J 6,7 ) 6.5).
13C NMR (CDCl3, 62.9 MHz): δ 171.8, 169.7, 108.8, 77.6, 74.3,
72.2, 67.6, 30.6, 26.7, 25.2, 20.3, 14.8.
3,7-Dideoxy-D-glu co-h epton o-1,4-lacton e (7). Compound
6 (53 mg, 0.2 mmol) was dissolved in 3 mL of HCl/MeOH (0.06
mL AcCl in 3 mL of MeOH), and the solution was left at room
temperature for 48 h and then concentrated. The residue was
purified by flash chromatography (EtOAc:MeOH 9:1) to give
1,2-O-Isop r op ylid en eca r ba -r-L-glu cofu r a n ose (12). Bi-
cyclic lactone 11 (1.53 g, 6.0 mmol) was added to a solution of
NaBH4 (0.44 g, 12.0 mmol) and NaOMe (2.4 M in MeOH, 2.5
mL, 6.0 mmol) in dry MeOH (25 mL) at 0 °C. The temperature
was raised to room temperature during 1 h, and the solution
was left at this temperature for 15 h. The solution was cooled
in an ice bath, and HOAc (50%, 6.7 mL, 59 mmol) was added.
After 0.5 h the solvent was evaporated. The residue was
coevaporated with H2O (40 mL) and then with MeOH (6 × 30
mL). It was then purified by flash chromatography (EtOAc:
acetone 3:1). This gave 12 as colorless crystals (1.15 g, 88%),
mp 73-75 °C. The compound could be recrystallized from
7 as colorless crystals (25 mg, 69%), mp 125-127 °C, [R]20
D
-48 (c 1.5, H2O). The compound was crystallized from EtOH:
Et2O, mp 129-131 °C, [R]20 -54 (c 1.2, H2O) [lit.32 mp 133-
D
134 °C, [R]20 -59 (c 1.5, H2O)]. 1H NMR (D2O, 500 MHz): δ
D
4.66 (m, H-2, H-4), 3.77 (dq, H-6, J 6,7 ) 6.5), 3.36 (dd, H-5, J 4,5
) 3.5, J 5,6 ) 7), 2.56 (ddd, H-3′, J ) 5.5, 7.5, J 3′,3 ) 12.5), 2.06
(dd, H-3), 1.15 (d, 3 H, H-7). 13C NMR (D2O (dioxane), 62.9
MHz): δ 180.5, 77.5, 75.6, 68.7, 67.6, 33.1, 19.1.
2-O-Acetyl-7-br om o-3,7-d id eoxy-5,6-O-isop r op ylid en e-
D-a ltr o-h ep ton o-1,4-la cton e (8). The unsaturated lactone
5 (1.00 g, 3.0 mmol) was dissolved in EtOAc (20 mL), Pd on
charcoal (5%, 0.1 g) was added, and the reaction mixture was
hydrogenated for 18 h at atmospheric pressure. Filtration and
concentration gave 2-O-acetyl-7-bromo-3,7-dideoxy-5,6-di-O-
isopropylidene-D-altro-heptono-1,4-lactone (8) as colorless crys-
tals (1.04 g, quant), mp 98-112 °C. Recrystallization from
Et2O:hexane afforded compound 8, mp 119 °C. 1H NMR
(CDCl3, 500 MHz): δ 5.46 (dd, H-2, J 2,3 )10.5, J 2,3′ ) 8.5), 4.55
(m, H-4, H-6, J 6,7′ ) 4, J 6,7 ) 8.5), 4.16 (dd, H-5, J 4,5 ) 8.5, J 5,6
) 5.5), 3.65 (dd, H-7′, J 7,7′ ) 11), 3.46 (dd, H-7), 2.88 (ddd, H-3′,
J 3,3′ )13.5, J 3′,4 ) 6), 2.20 (ddd, H-3, J 3,4 ) 9.5), 2.17 (s, 3 H),
1.49, 1.40 (2 s, 6 H). 13C NMR (CDCl3, 62.9 MHz): δ 172, 169,
109.6, 78.7, 77.4, 72.7, 67.4, 32.4, 29.1, 27.6, 25.0, 20.3. Anal.
EtOAc:Et2O; mp 74-75.5 °C, [R]20 +17.0 (c 0.51, EtOH). 1H
D
NMR (D2O, 500 MHz): δ 4.76 (m, H-1), 4.40 (d, H-2, J 1,2
)
5.5), 4.06 (d, H-3, J 3,4 ) 4), 3.68 (ddd, H-5, J 4,5 ) 9, J 5,6 ) 6.5,
J 5,6′ ) 3), 3.58 (dd, H-6′, J 6,6′ ) 12), 3.39 (dd, H-6), 2.12 (m,
H-4). 1.63 (m, H-4a, H-4a′), 1.34, 1.22 (2 s, 6 H). 13C NMR
(D2O (dioxane), 62.9 MHz): δ 111.2, 86.0, 80.6, 75.6, 71.2, 65.8,
43.6, 32.6, 25.8, 23.7. Anal. Calcd for C10H18O5 (218.25): C,
55.03; H, 8.31. Found: C, 54.81; H, 8.27.
1,2-O-Isop r op ylid en eca r ba -r-L-xylofu r a n ose (13). Pro-
tected carbahexofuranose 12 (0.20 g, 0.92 mmol) was dissolved
in H2O (2.0 mL) and cooled in an ice bath in a flask protected
from light. A solution of NaIO4 (0.24 g, 1.1 mmol) in H2O (2
mL) was added, and stirring was maintained for 1 h at 0 °C,

Radical Cyclization of Unsaturated Bromolactones
J . Org. Chem., Vol. 63, No. 6, 1998 1925
after which a solution of NaBH4 (0.14 g, 3.7 mmol) in H2O (2
mL) was added. The reaction mixture was left at room
temperature for 18 h and then quenched at 0 °C by addition
of HOAc (1.05 mL, 17.8 mmol). The solvents were evaporated
and the residue was coconcentrated with MeOH (4 × 30 mL).
Flash chromatography (EtOAc:Acetone 7:1) afforded 13 (0.17
g, 98%), as a semicrystalline solid. The crude product could
also be purified by extraction. Thus 0.57 g (2.6 mmol) of the
starting material 12 was treated as described above with
NaIO4 (0.67 g, 3.1 mmol) and NaBH4 (0.38 g, 10.4 mmol) and
was quenched with HOAc (2.4 mL), evaporated, and then
evaporated from MeOH. The residue was dissolved in H2O
(20 mL) and extracted with EtOAc (12 × 25 mL). The organic
phase was dried (Na2SO4) and concentrated. This afforded
crystalline 13, (0.42 g, 86%) which was recrystallized from
2.01 (5 s, 15 H), 2.06 (m, 1 H), 1.92 (m, 1 H). 13C NMR (CDCl3,
75.5 MHz): δ 170.6, 170.2, 169.9, 169.4, 169.3, 76.1, 74.8, 71.7,
69.4, 63.9, 39.6, 30.5, 20.6, 20.5, 20.45, 20.4, 20.3. Anal. Calcd
for C17H24O10 (388.38): C, 52.57; H, 6.23. Found: C, 52.50;
H, 6.13.
(1S,5S)-4(S)-O-Acet yl-7(R),8(R)-O-isop r op ylid en e-2-
oxa bicyclo[3.3.0]oct-3-on e (17). Unsaturated lactone 5 (0.8
g, 2.4 mmol) was cyclized as described for preparation of
compound 11. The crude product contained only one compo-
nent according to 1H NMR. Flash chromatography (hexane
f EtOAc:hexane 1:1) gave 17 (0.55 g, 90%) as colorless
crystals, mp 105-113 °C, which was recrystallized from
EtOAc:Et2O (ca.. 1:10); mp 113-114 °C, [R]20D +87 (c 1, CHCl3).
X-ray crystallography confirmed the structure of compound
17.13a The product could also be worked up by recrystalliza-
tion: Starting from 5 (2.01 g, 6.0 mmol) following the proce-
dure described for the preparation of 11, the crude product
from evaporation of the acetonitrile was recrystallized from
EtOAc:Et2O (ca. 1:10) to give 17 as colorless crystals (1.30 g,
85%), mp 110-112 °C. 1H NMR (CDCl3, 500 MHz): δ 5.55
(d, H-4, J 4.5 ) 9), 4.74 (ddd, H-7, J 7,8 ) 5.5, J 6,7 ) 3), 4.72 (dd,
Et2O:hexane; mp 35-36 °C, [R]20 +26.5 (c 0.56, EtOH) [lit.15
D
for enantiomer: oil, [R]20 -18.8 (c 1.6, 90% CHCl3, 10%
D
MeOH)]. CI-MS (NH3): m/z 206 (M + NH4+), 189 (M + H+).
1H NMR (D2O, 500 MHz): δ 4.76 (dd, H-1, J 1,2 ) 5.5, J 1,4a
5.5), 4.40 (d, H-2), 4.00 (d, H-3, J 3,4 ) 4), 3.64 (dd, H-5′, J 4.5′
)
)
8, J 5′,5 ) 11), 3.55 (dd, H-5, J 4,5 ) 6.5), 2.26 (m, H-4), 1.74 (dd,
H-4a′, J 4a′,4a ) 14, J 4a′,4 ) 6.5), 1.58 (ddd, H-4a, J 4a,4 ) 14),
1.35, 1.23 (2 s, 6 H). 13C NMR (D2O (acetone), 62.9 MHz): δ
109.9; 85.3, 79.1, 74.3, 59.5, 41.8, 31.7, 24.4, 22.3. Anal. Calcd
for C9H16O4 (188.22):C, 57.43; H, 8.57. Found: C, 57.43; H,
8.59.
H-1, J 1,5 ) 5.5, J 1,8 ) 5.5), 4.68 (dd, H-8), 3.31 (m, H-5, J 5,6
)
7, J 5,6′ ) 9.5), 2.21 (s, 3 H) 2.10 (ddd, H-6, J 6,6′ ) 15), 2.05
(ddd, H-6′) 1.52, 1.30 (2 s, 6 H). 13C NMR (CDCl3, 62.9 MHz):
171.5, 169.5 (C-3, OAc), 113.5, 81.8 (C-8), 80.6 (C-7), 79.8 (C-
1), 70.0 (C-4), 41.6 (C-5), 27.1 (C6) 25.2, 25.1, 20.3. Anal.
Calcd for C12H16O6 (256.25): C, 56.25; H, 6.29. Found: C,
56.16; H, 6.30.
Ca r ba -r-L-xylofu r a n ose (14). Protected carbafuranose 13
(0.30 g, 1.6 mmol) was suspended in aqueous HCl (1 M, 1.5
mL) and left at room temperature for 18 h. The solvent was
evaporated, and the residue was dissolved in H2O (10 mL) and
neutralized with ion-exchange resin (IR 420 OH-, 3 mL) for 5
min. The ion-exchange resin was filtered off, and the solvent
was evaporated. This afforded 14 (0.23 g, 96%), as colorless
crystals, mp 82-84 °C. The compound was recrystallized from
1,2-O-Isopr opyliden ecar ba-â-D-m an n ofu r an ose (18). Bi-
cyclic lactone 17 (4.0 g, 15.6 mmol) was reduced as described
for compound 12 using a solution of NaBH4 (1.16 g, 3.31 mmol)
and NaOMe (6.5 mL, 2.4 M in MeOH, 15.6 mmol) in dry MeOH
(80 mL). After repeated co-concentrations with MeOH the
residue was dissolved in H2O (20 mL) and extracted with
EtOAc (18 × 25 mL). The organic phases were dried (MgSO4)
and the solvent was evaporated to give 18 as colorless crystals
(3.1 g, 91%), mp 123-127 °C. Recrystallization from EtOAc
gave crystals with mp 133-135 °C, [R]20D -55.5 (c 0.49, EtOH).
1H NMR (D2O, 500 MHz): δ 4.69 (m, H-1, J 1,2 ) 7), 4.46 (dd,
H-2, J 2,3 ) 4.5), 4.02 (dd, H-3), 3.81 (ddd, H-5, J 5,6′ ) 2.5, J 5,6
) 5.5), 3.58 (dd, H-6′, J 6,6′ ) 12), 3.37 (dd, H-6), 1.99 (m, H-4,
J 4,5 ) 9.5), 1.94 (m, H-4a′), 1.52 (m, H-4a), 1.43, 1.28 (2 s, 6
H). 13C NMR (D2O (acetone), 62.9 MHz): 113.3, 80.5, 78.7,
70.3, 69.6, 63.7, 44.6, 29.7, 24.4, 23.4. Anal. Calcd for
C10H18O5 (218.25): C, 55.03; H, 8.31. Found: C, 55.22; H, 8.37.
1,2-O-Isop r op ylid en eca r ba -â-D-lyxofu r a n ose (19). Diol
18 (1.40 g, 6.4 mmol) was oxidized using NaIO4 (1.65 g, 7.7
mmol, in 14 mL H2O) and subsequently reduced with NaBH4
(0.95 g, 25.7 mmol in 14 mL H2O) similarly to the preparation
of 13. After repeated evaporations from MeOH the residue
was dissolved in H2O (20 mL) and extracted with EtOAc (12
× 25 mL). The organic phases were dried (Na2SO4), filtered,
and evaporated to yield a slightly colored oil (1.26 g) which
was purified by flash chromatography (EtOAc) to give 19 (1.10
g, 91%) as colorless crystals, mp 57-62 °C. Repeated crystal-
lizations from Et2O:hexane gave crystals with mp 58-62 °C,
EtOH:CH3CN; mp 84-86 °C, [R]20 -18.6 (c 0.7, MeOH) [lit.
D
for the enantiomer: oil, [R]20D +12.1 (c 0.7, MeOH);15 mp 79.5-
80.5 °C, [R]20 +13.4 (c 0.78, MeOH)22]. 1H NMR (D2O, 500
D
MHz): δ 4.06 (m, H-1, H-3), 3.78 (dd, H-2, J 1,2 ) 5, J 2,3 ) 5),
3.59 (dd, H-5′, J 4,5′ ) 7, J 5,5′ ) 11), 3.42 (dd, H-5, J 4,5 ) 7.5),
2.36 (m, H-4), 1.67 (m, H-4a, H-4a′). 13C NMR (D2O (dioxane),
62.9 MHz): δ 79.4, 76.8, 71.6, 62.6, 40.2, 32.9. Anal. Calcd
for C6H12O4 (148.16): C, 48.64; H, 8.16. Found: C, 48.55; H,
8.15.
Ca r ba -r-L-glu cofu r a n ose (15). For deprotection, 12 (0.40
g, 1.8 mmol) was dissolved in aqueous HCl (1 M, 2 mL) and
left at room-temperature overnight. Evaporation of the solvent
gave 15 as a colorless oil which was dried in a desiccator over
KOH, 0.31 g (94%). [R]20 +2.0 (c 1.0, MeOH). CI-MS (NH3):
D
m/z 196 (M + NH4+), 178 (M + H+). 1H NMR (D2O, 500
MHz): δ 4.21 (ddd, H-1, J 1.2 ) 4.5), 4.09 (H-3, dd, J 3.4 ) 6),
3.85 (dd, H-2, J 2,3 )3) 3.63 (ddd, H-5, J 5,6 ) 6.5, J 5,6′ ) 2.5,
J 4,5 ) 9), 3.59 (dd, H-6′, J 6,6′ ) 12), 3.41 (dd, H-6), 2.31 (m,
H-4), 1.68 (m, H-4a′, J 4a,4a′ ) 13.5), 1.57 (m, H-4a). 13C NMR
(D2O (dioxane), 62.9 MHz): δ 79.0, 77.2, 72.5, 72.2, 65.4, 41.8,
32.4.
Deacetylation of 16 (132 mg, 0.34 mmol) in MeOH (5 mL)
using a catalytic amount of NaOMe/MeOH (pH ) 12) for 2 h
at room temperature followed by neutralization with acidic ion-
exchange resin (Amberlite 120, H+) and concentration gave
[R]20 -38.6 (c 0.51, EtOH). CI-MS (NH3): m/z 206 (M +
D
NH4+), 189 (M + H+). 1H NMR (D2O, 500 MHz): δ 4.66 (m,
H-1), 4.47 (dd, H-2, J 1,2 ) 5, J 2,3 ) 5), 4.02 (dd, H-3, J 3,4 ) 5),
3.74 (dd, H-5′, J 5,5′ ) 10.5, J 4,5′ ) 7), 3.58 (dd, H-5, J 4,5 ) 8.5),
2.16 (m, H-4), 1.86 (ddd, H-4a′, J 4a,4a′ ) 14.5), 1.63 (ddd, H-4a),
1.41, 1.25 (2 s, 6 H). 13C NMR (D2O (methanol), 62.9 MHz):
δ 112.7, 80.7, 79.3, 71.6, 60.9, 44.7, 30.3, 25.0, 23.4. Anal.
Calcd for C9H16O4 (188.22): C, 57.43; H, 8.57. Found: C,
57.45; H; 8.62.
1
15 (57.7 mg, 95%). A H NMR spectrum was identical with
the one described above. The product was dried in a desiccator
(concentrated H2SO4, solid KOH) to give a syrup having [R]20
+1.7 (c 1.0, MeOH).
D
1,2,3,5,6-P en ta -O-a cetylca r ba -r-L-glu cofu r a n ose (16).
Compound 15 (0.060 g, 0.34 mmol) was dissolved in Ac2O (0.8
mL, 8.5 mmol), and a drop of perchloric acid was added. H2O
was added after stirring at room temperature for 3 h. The
water phase was extracted with CH2Cl2, and the organic
phases were washed with H2O and aqueous NaHCO3, dried
(MgSO4), and concentrated. The crude product was purified
by flash chromatography (EtOAc:heptane 2:3) to give 16 (0.111
g, 84%) which crystallized from Et2O:hexane; mp 66-67 °C ,
Ca r ba -â-D-lyxofu r a n ose (20). Compound 19 (0.73 g, 3.9
mmol) was deprotected as described for the preparation of 14.
This afforded carbafuranose 20 (0.55 g, 96%) as colorless
crystals; mp 69-72 °C. The compound was recrystallized from
EtOH; mp 74-75.5 °C, [R]20 -21.3 (c 1.0, CH3OH) [lit.,15 oil,
D
[R]20 -12.9° (c 1.0, CH3OH)]. CI-MS (NH3): m/z 166 (M +
D
NH4+), 149 (M + H+). 1H NMR (D2O, 500 MHz): δ 4.02 (m,
H-1, H-3), 3.78 (dd, H-2, (J 1,2, J 2,3) ) (4.5, 5.5)), 3.67 (dd, H-5′,
J 4,5′ ) 7.5, J 5,5′ ) 10.5), 3.51 (dd, H-5, J 4,5 ) 6.5), 2.10 (m,
H-4a′), 2.02 (m, H-4), 1.33 (ddd, H-4a, J 4a,4a′ ) 13.5). 13C NMR
[R]20 -31.4 (c 1, CHCl3). 1H NMR (CDCl3, 300 MHz): δ 5.42
D
(dtr, 1H), 5.35 (dd, 1 H), 5.17 (dd, 1 H), 5.11 (ddd, 1 H), 4.39
(dd, 1 H), 3.97 (dd, 1 H), 2.85 (ddd, 1 H), 2.09, 2.08, 2.04, 2.03,

1926 J . Org. Chem., Vol. 63, No. 6, 1998
Horneman and Lundt
3, d, J 3,4 ) 2.2), 5.28 (H-6, ddd, J 5,6 ) 7.0, J 6,7 ) 2.7, J 6,7′
5.3), 5.23 (H-5, dd, J 4,5 ) 2), 5.20 (H-4, dd), 3.84 (H-7, dd, J 7,7′
) 11.5), 3.65 (H-7′, dd), 4.79 (NH2), 2.10, 2.0. 13C NMR (CD3-
COCD3, 62.9 MHz): δ 171, 170, 136.5, 108.7, 78.2, 71.3, 71.3,
32.4, 20.7, 20.4.
(D2O (dioxane), 62.9 MHz): δ 74.7, 73.5, 71.6, 62.3, 41.0, 34.0.
Anal. Calcd for C6H12O4 (148.16): C, 48.64; H, 8.16. Found:
C, 48.75; H; 8.08.
)
Ca r ba -â-D-m a n n ofu r a n ose (21). Compound 18 (0.58 g, 2.7
mmol) was dissolved in aqueous HCl (1 M, 6 mL) and left at
room temperature for 16 h. The solvent was evaporated, the
oil was dissolved in H2O (10 mL), and ion-exchange resin (IR
420 OH-, 10 mL) was added and stirred slowly for 0.5 h. The
mixture was filtered and the ion-exchange resin was washed
thoroughly with H2O followed by EtOH. The combined
solvents were evaporated to give carba-â-D-mannofuranose 21
(0.36 g, 77%) as colorless crystals, mp 109-113 °C. Repeated
crystallizations from EtOH:acetone gave a sample with mp
5,6-Di-O-a ce t yl-7-b r om o-2,3,7-t r id e oxy-2-t r iflu or o-
a ceta m id o-D-a r a bin o-h ep t-2-en on o-1,4-la cton e (25). Ami-
nolactone 24 (1.70 g, 5.05 mmol) was dissolved in dry EtOAc
(40 mL) and cooled to 0 °C. (CF3CO)2O (1.43 mL, 10.1 mmol)
was added slowly, the solution was stirred at 0 °C for 45 min
and at room temperature for another 45 min followed by
concentration. Recrystallization of the residue from EtOAc:
hexane gave trifluoroacetamidolactone 25 as slightly colored
crystals (1.80 g, 83%), mp 138 °C. Repeated crystallizations
from EtOAc:hexane gave mp 138-141 °C, [R]20D -14.4 (c 0.36,
CHCl3). 1H NMR (CDCl3, 500 MHz): δ 8.25 (bs, NH), 7.51
(H-3, d, J 3.4 ) 2), 5.49 (H-5, dd, J 4,5 ) 2.5, J 5,6 ) 7.5), 5.39
(H-4, dd), 5.31 (H-6, ddd, J 6.7 ) 3.5, J 6.7′ ) 4.5), 3.78 (H-7′, dd,
J 7.7′ ) 12.0), 3.49 (H-7, dd), 2.17, 2.04 (2 s, 6 H). 13C NMR
(CDCl3, 62.9 MHz): δ 169.2, 169.0, 167.3, 155.3 (q, J C,F ) 39.9
Hz), 129.0, 124.9, 114.8 (q, J C,F ) 287.5), 79.3, 70.0, 69.3, 30.6,
20.6, 20.2. Anal. Calcd for C13H13BrF3NO7 (432.15): C, 36.13;
H, 3.03; N, 3.24. Found: C, 36.36; H, 3.21; N, 3.47.
113-115 °C, [R]20 -26 (c 1.0, H2O). 1H NMR (D2O, 500
D
MHz): δ 4.04 (m, 2H, H-3, H-5), 3.78 (dd, H-2, J 2,3 ) 4), 3.71
(ddd, H-1, J 1,2 ) 6, J 1,4a′ ) 9.5, J 1,4a ) 3), 3.58 (dd, H-6′, J 6,6′
)
12.5, J 5,6′ ) 2.5), 3.38 (dd, H-6, J 5,6 ) 6.5), 2.08 (m, H-4), 1.80
(m, H-4a′, J
) 11), 1.35 (ddd, H-4a). 13C NMR (D2O
4a,4a′
(dioxane), 62.9 MHz): δ 74.4, 73.9, 72.6, 71.6, 65.1, 41.4, 34.2.
Anal. Calcd for C7H14O5 (178.18): C, 47.19; H, 7.92. Found:
C, 47.38; H, 7.91.
5,6-Di-O-a cet yl-2-a zid o-7-b r om o-2,3,7-t r id eoxy-D-a r a -
bin o-h ep t-2-en on o-1,4-la cton e (23). Dibromoheptonolac-
tone 2232 (14.69 g, 44 mmol) was dissolved in dry DMF (75
mL), and dry NaN3 (29.0 g, 446 mmol) was added. The
suspension was protected from light and stirred vigorously at
room temperature for 6.5 h. EtOAc (300 mL) was added to
the suspension, which afterward was filtered and concentrated
at 25 °C to give a brown oil (20.7 g). The oil was dissolved in
dry pyridine (75 mL) and Ac2O (42 mL), and the solution was
kept in a light-protected flask for 3.5 h at room temperature.
The reaction mixture was poured into aqueous HCl (2 M, 450
mL) at 0 °C, and stirring was continued at room temperature
for 1 h followed by extraction with CH2Cl2 (3 × 100 mL). The
combined organic phases were washed with H2O (6 × 100 mL),
dried (Na2SO4), treated with activated charcoal, filtered, and
concentrated (max. 25 °C). The residue was kept at 5 °C for
4 days which resulted in a semicrystalline substance. The
residue was suspended in cold Et2O (3 mL) and filtered to give
23 as slightly colored crystals (3.87 g, 24%), mp 108-112 °C.
The mother liquor from the crystallization was purified by
flash chromatography (EtOAc:hexane 1:6). This gave a 3,4-
unsaturated azidolactone as a syrup (5.10 g, 32%), see below,
together with crystalline 23 (2.02 g, 13%). Compound 23 was
purified for analysis by flash chromatography (EtOAc:hexane
1:4), followed by solvation in EtOAc at room temperature,
treatment with activated charcoal, filtration, and precipitation
with hexane. A repeated crystallization from EtOAc:hexane
at room temperature gave colorless crystals, mp 111-112 °C.
1H NMR (CDCl3, 500 MHz): 6.48 (d, H-3, J 3,4 ) 2.5), 5.40 (dd,
H-5, J 5,6 ) 7.5), 5.29 (m, H-6, J 6,7′ ) 3.5, J 6,7 ) 4.5), 5.24 (dd,
H-4, J 4,5 ) 2.5), 3.82 (dd, H-7′, J 7,7′ ) 12), 3.50 (dd, H-7), 2.16,
2.09 (2 OAc). 13C NMR (CDCl3, 62.9 MHz): 169, 126.8, 119.2,
77.4, 69.7, 69.1, 30.8, 20.2, 20.5. Anal. Calcd for C11H12BrN3O6
(362.14): C, 36.48; H, 3.34; N, 11.60. Found: C, 36.63; H, 3.37;
N, 11.32. The 3,4-unsaturated azidolactone was tentatively
assigned as 5,6-di-O-acetyl-2-azido-7-bromo-2,3,7-trideoxy-
hept-3-enono-1,4-lactone based on the following spectra: 1H
NMR (CDCl3, 500 MHz): δ 6.35 (d, H-2, J 2,3 ) 7), 5.48 (dd,
H-3, J 3,5 ) 2.5), 5.28 (ddd, H-6), 4.82 (dd, H-5, J 5,6 ) 9.5), 3.83
(ddd, H-7′, J 6,7′ ) 3.3, J 7′,7 ) 11.5), 3.78 (dd, H-7, J 6,7 ) 3). 13C
NMR (CDCl3, 62.9 MHz): δ 170, 169 (C-1, 2 OAc), 119.2 (C-
3), 76.7, 66.8 (C-5, C-6), 60.8 (C-2), 31.7 (C-7), 20.5, 20.3 (2 ×
OAc).
(1R,5S)-7(R),8(R)-Di-O-a cetyl-4(R)-tr iflu or oa ceta m id o-
2-oxa bicyclo[3.3.0]oct-3-on e (26) a n d (1R,5S)-7(R),8(R)-
d i-O-a cetyl-4(S)-tr iflu or oa ceta m id o-2-oxa bicyclo[3.3.0]-
oct-3-on e (27). Cyclization of trifluoroacetamidolactone 25
(1.98 g, 4.6 mmol) dissolved in EtOAc (20 mL) was done
according to the method described for the preparation of 11,
using Bu3SnH (1.6 mL, 6.0 mmol) and AIBN (0.08 g, 0.5 mmol)
dissolved EtOAc (8.5 mL). The crude product was treated with
activated charcoal, and the solvents were evaporated to give
a crystalline residue (1.58 g, 98%). The main product, 26, was
isolated by crystallization from EtOAc:hexane as colorless
crystals (1.23 g, 76%). The residue from concentration of the
mother liquor was purified by flash chromatography (EtOAc:
hexane 1:2), to give crystalline 26 (0.13 g, 8%), and the C-4-
isomer 27 as a colorless syrup (0.09 g, 6%). Title compound
26: Repeated crystallizations from EtOAc:Et2O gave an
analytically pure sample; mp 134-139 °C, [R]20D -153 (c 0.49,
CHCl3). 1H NMR (CDCl3, 500 MHz): δ 7.15 (bs, 1H, NH), 5.36
(m, H-7, H-8), 4.95 (dd, H-1, J 1,5 ) 6.5, J 1,8 ) 1.5), 4.78 (m,
H-4, J 4,5 ) 9), 3.75 (m, H-5), 2.11, 2.07 (2 s, 6 H), 2.01 (ddd,
H-6′, J 6,6′ ) 14), 1.88 (m, H-6). 13C NMR (CDCl3, 125.8 MHz):
δ 171.9, 169.8, 169.3 (C-3, 2 × OAc), 158.3 (q, NHCO, J C,F
)
39.2), 115.2 (q, CF3, J C,F ) 287.7), 84.3 (C-1), 76.9 (C-8), 72.0
(C-7), 52.2 (C-4), 39.2 (C-5), 28.1 (C-6), 20.6, 20.4 (2 × OAc).
Anal. Calcd for C13H14F3NO7 (353.25): C, 44.20; H, 3.99; N,
3.97. Found: C, 44.11; H, 4.02; N, 3.91.
(1R,5S)-7(R),8(R)-Di-O-a cetyl-4(S)-tr iflu or oa ceta m id o-
2-oxa b icyclo[3.3.0]oct -3-on e (27): 1H NMR (CDCl3, 500
MHz): δ 7.24 (bd, 1H, NH), 5.42 (ddd, H-7, J 7,8 ) 4.5), 5.23
(dd, H-8), 5.09 (dd, H-1, J 1,8 ) 5.5, J 1,5 ) 9.5), 4.20 (dd, H-4,
J 4.5 ) 6, J 4,NH ) 6), 3.14 (m, H-5), 2.48 (ddd, H-6′, J 6′,7 ) 4, J
) 9, J 6,6′ ) 15), 2.26 (ddd, H-6, J 6,7 ) 5, J 6,5 ) 5), 2.1, 2.07.
6′,5
13C NMR (CDCl3, 125.8 MHz): 172.7, 169.7, 169.6 (C-3, 2 ×
OAc), 157.7 (q, NHCO, J C,F ) 38.6), 115.2 (q, CF3, J C,F ) 286.1),
83.9 (C-1), 76.5 (C-8), 72.4 (C-7), 56.9 (C-4), 40.5 (C-5), 34.4
(C-6), 20.6, 20.5 (2 × OAc).
(1R,5S)-4(R)-Am in o-7(R),8(R)-d ih yd r oxy-2-oxa bicyclo-
[3.3.0]oct-3-on e h yd r och lor id e (28). Protected aminolac-
tone 26 (1.0 g, 2.8 mmol) was suspended in aqueous HCl (1 N,
20 mL) and refluxed overnight. Concentration and recrystal-
lization from CH3CN:MeOH gave 28 as slightly colored
crystals, (0.59 g, 85%), [R]20D -49 (c 0.73, MeOH). Treatment
with activated charcoal and repeated crystallizations from
MeOH:CH3CN gave colorless crystals; mp 210-215 °C dec,
5,6-Di-O-a cetyl-2-a m in o-7-br om o-2,3,7-tr id eoxy-D-a r a -
bin o-h ep t-2-en on o-1,4-la cton e (24). Azido heptonolactone
23 (3.07 g, 8.48 mmol) was dissolved in dry toluene (60 mL)
at 80 °C under a N2 atmosphere. Bu3SnH (4.95 mL, 18.7
mmol) and AIBN (0.14 g, 0.85 mmol) dissolved in dry toluene
(15 mL) were added during 1 h. Evaporation of the solvent
resulted in a solid residue which was dissolved in CH3CN (600
mL) and washed with hexane (5 × 100 mL). The CH3CN was
evaporated to give a solid (3.01 g) which was triturated with
cold EtOAc and filtered to give 24 (2.20 g, 77%) as slightly
colored crystals. 1H NMR (CD3COCD3, 250 MHz): δ 5.67 (H-
[R]20 -45.8° (c 0.71, MeOH). 1H NMR (D2O, 500 MHz,): δ
D
4.84 (dd, H-1, J 1,5 ) 6.5, J 1,8 ) 2.3), 4.53 (d, H-4, J 4,5 ) 9.5),
4.20 (ddd, H-7, J 7,8 ) 4), 4.14 (dd, H-8), 3.49 (m, H-5), 1.92
(ddd, H-6′, J 6,6′ ) 14, J 5,6′ ) 9, J 6′,7 ) 5), 1.79 (ddd, H-6, J 5,6
)
8.5, J 6,7 ) 5). 13C NMR (D2O (CH3CN), 62.9 MHz): δ 174, 88.3,
77.4, 72.3, 51.3, 37.7, 29.4. Anal. Calcd for C7H12ClNO4
(209.63): C, 40.11; H, 5.77; Cl-, 16.91; N, 6.68. Found: C,
40.01; H, 5.81; Cl-, 16.35; N, 6.65.

Radical Cyclization of Unsaturated Bromolactones
J . Org. Chem., Vol. 63, No. 6, 1998 1927
5-Am in o-5-d eoxyca r ba -r-L-glu cofu r a n ose Hyd r och lo-
r id e (29). Bicyclic aminolactone 28 (0.40 g, 1.9 mmol) was
dissolved in H2O (2 mL) and cooled in an ice bath. A solution
of NaBH4 (0.3 g, 8.1 mmol) in H2O (2 mL) was added at 0 °C,
and the solution was kept for 1 h at 0 °C stored at 5 °C for
another 40 h. Aqueous HCl (1 N) was added until pH 1, and
the solution was concentrated to a residue which was cocon-
centrated with MeOH (3 × 30 mL). The residue was dissolved
in H2O (25 mL) and stirred slowly for 2.5 h with ion-exchange
resin (IR 120 H+, 40 mL). The ion-exchange resin was filtered
off, washed with H2O and then poured into H2O (50 mL). The
resin was cooled in an ice bath and aqueous ammonia (25%,
30 mL) was added and stirred for 1 h. The resin was filtered
off and washed with H2O, and the filtrate was concentrated.
The residue was concentrated with aqueous HCl (1 N, 10 mL)
followed by coconcentration with MeOH to give 29 as a slightly
colored syrup (0.33 g, 80%). 1H NMR (D2O, 500 MHz): δ 4.16
(m, H-1), 4.11 (dd, H-3, J 2,3 ) 4.5, J 3,4 ) 7.5), 3.87 (dd, H-2,
J 1,2 ) 5), 3.75 (dd, H-6′, J 6,6′ ) 12.5, J 5,6′ )3.5), 3.57 (dd, H-6,
J 5,6 ) 6.5), 3.27 (m, H-5), 2.51 (m, H-4), 1.74 (m, 2H, H-4, H-4a).
13C NMR (D2O (methanol), 62.9 MHz): δ 79.1, 75.5, 70.9, 60.3,
53.8, 36.8, 32.4.
N-Acetyl-1,2,3,6-tetr a -O-a cetyl-5-a m in o-5-d eoxyca r ba -
r-L-glu cofu r a n ose (30). Compound 29 (0.18 g, 1.0 mmol)
was dissolved in pyridine (3 mL), and Ac2O (2.4 mL, 25 mmol)
was added. The solution was stirred for 48 h at room
temperature after which time it was evaporated and cocon-
centrated with toluene (3 × 10 mL). Flash chromatography
(EtOAc) gave crystalline 30 (0.25 g, 65%) which was recrystal-
lized from EtOAc; mp 161-162 °C, [R]20D -11.2 (c 1.2, CHCl3).
1H NMR (CDCl3, 300 MHz): δ 5.69 (bd, 1 H), 5.37 (dtr, 1 H),
5.30 (dd, 1 H), 5.10 (dd, 1 H), 4.27 (m, 1 H), 4.06 (d, 2 H), 2.62
(m, 1 H), 2.04 (s, 3 H), 2.03 (s, 3 H), 2.02 (s, 3 H), 1.98 (s, 3 H),
1.88 (s, 3 H), 2.04-1.80 (m, 2 H). 13C NMR (CDCl3, 75.5
MHz): δ 170.7, 169.8, 169.7, 169.5, 169.3, 79.4, 74.9, 71.6, 65.1,
47.1, 39.9, 31.6, 22.9, 20.6, 20.5, 20.4, 20.3. Anal. Calcd for
2-Am in o-2,3,7-tr ideoxy-D-glu co-h epton o-1,4-lacton e Hy-
d r och lor id e (33) fr om 32. Trifluoroacetamidolactone 32
(1.24 g, 3.5 mmol) was dissolved in aqueous HCl (2 N, 8 mL)
and refluxed for 2.5 h. Evaporation of the solvent and
coconcentration with toluene (3 × 20 mL) gave an oil (1.1 g)
which was dissolved in H2O, treated with activated charcoal,
concentrated, and crystallized from MeOH:CH3CN to give 33
as a colorless crystalline compound (0.65 g, 88%); mp 139-
145 °C, [R]20D -35.2° (c 0.56, MeOH). Repeated crystallizations
from MeOH:CH3CN gave mp 160-162 °C, [R]20 -40 (c 0.52,
D
MeOH). CI-MS (NH3): m/z 176 (M - HCl + H+). 1H NMR
(D2O, 500 MHz): δ 4.88 (ddd, H-4, J 4,5 ) 2.5), 4.43 (dd, H-2,
J 2,3′ ) 9, J 2,3 ) 11.5), 3.77 (dq, H-6, J 6,7 ) 6.5), 3.39 (dd, H-5,
J 5.6 ) 7.5), 2.69 (ddd, H-3′, J 3,3′ ) 12.5, J 3′,4 ) 5.5), 2.31 (ddd,
H-3, J 3,4 ) 10), 1.18 (d, 3H, H-7). 13C NMR (D2O (CH3CN),
62.9 MHz): δ 174.5, 49.6, 28.7, 78.7, 74.5, 67.2, 18.9. Anal.
Calcd for C7H14ClNO4 (211.64): C, 39.73; H, 6.67; N, 6.62.
Found: C, 39.80; H, 6.69; N, 6.59.
3,7-Did eoxy-5,6-O-isop r op ylid en e-D-glu co-h ep ton o-1,4-
la ct on e (34). 3,7-Dideoxy-D-gluco-heptono-1,4-lactone (7)32
(1.51 g, 8.6 mmol) was dissolved in dry acetone (250 mL), and
camphorsulfonic acid (0.3 g) was added. A Soxhlet extractor
was equipped with molecular sieves (3 Å), and the reaction
was refluxed overnight. The solution was stirred with NaH-
CO3 (6 g) until neutral and then filtered and evaporated. The
crude product was suspended in H2O (10 mL) and extracted
with EtOAc (4 × 30 mL). The organic phases were dried (Na2-
SO4) and evaporated to give compound 34 as a syrup (2.17 g).
The compound was used immediately as it was unstable upon
storage. 13C NMR (CDCl3, 62.9 MHz): δ 176, 108.0, 77.6, 74.1,
71.8, 66.7, 32.4, 26.2, 24.6, 14.4.
2-Ch lor o-2,3,7-tr id eoxy-5,6-O-isopr opyliden e-D-ma n n o-
h ep ton o-1,4-la cton e (35). Isopropylidene-protected lactone
34 (2.17 g) was dissolved in dry pyridine (20 mL), methane-
sulfonyl chloride (2.94 g, 25.7 mmol) was added, and the
solution was stirred at 40 °C for 3 h. H2O (10 mL) was added
and after stirring for 15 min the suspension was extracted with
CH2Cl2. The organic phases were washed with H2O, dried
(MgSO4), stirred with activated charcoal, and filtered, and the
solvent was evaporated. The crude product was purified by
flash chromatography (EtOAc:hexane 1:3) to give compound
35 as a crystalline solid (1.12 g, 56% from 3,7-dideoxy-D-gluco-
heptono-1,4-lactone), mp 68-70 °C. Repeated crystallizations
C
17H25NO9 (387.38): C, 52.71; H, 6.50; N, 3.61. Found: C,
53.00; H, 6.49; N, 3.58.
Dim er ic Com p ou n d 31. Unsaturated aminolactone 24
(0.40 g, 1.2 mmol) was suspended in refluxing toluene (150
mL), a solution of Bu3SnH (2.1 mL, 7.8 mmol) and AIBN (0.12
g) in toluene (40 mL) was added during 7 h, and the solution
was refluxed for another 15 h, after which the solvent was
evaporated. The crude product was suspended in CH3CN (50
mL) and washed with hexane (5 × 100 mL), and the CH3CN
was evaporated. Flash chromatography (EtOAc:hexane 3:1)
gave as the main product, compound 31, as an oil (90 mg, 30%).
1H NMR (CDCl3, 500 MHz): δ 5.38 (ddd, H-7, J 6,7 ) J 6′,7 ) J
from Et2O:hexane gave a sample with mp 70-70.5 °C, [R]20
D
-81 (c 0.80, CHCl3). 1H NMR (CDCl3, 500 MHz): δ 4.67 (ddd,
H-4, J 4,5 ) 1), 4.66 (dd, H-2, J 2,3′ ) 8, J 2,3 ) 6.5), 4.45 (dq, H-6,
J 6,7 ) 6.5), 4.04 (dd, H-5, J 5,6 ) 7), 2.79 (ddd, H-3′, J 3,3′ ) 13.5,
J 3′,4 ) 4.5), 2.51 (ddd, H-3, J 3,4 ) 8), 1.43 (d, 3H, H-7), 1.41,
1.34 (2 s, 6 H). 13C NMR (CDCl3, 62.9 MHz): δ 172.4, 108.6,
78.7, 76.0, 72.4, 50.3, 36.2, 26.2, 24.7, 14.9. Anal. Calcd for
) 4), 5.22 (dd, H-8), 4.87 (dd, H-1, J 1,8 ) 4.5, J 1,5 ) 8), 3.19
7,8
(m, H-5), 2.28 (ddd, H-6, J 6,6′ ) 14, J ) 5, J ) 7), 2.07 (s, 6 H),
2.01 (ddd, H-6′, J ) 4, J ) 9). 13C NMR (CDCl3, 62.9 MHz):
δ 177, 170, 169, 83.8, 77.2, 72.3, 64.3, 40.7, 29.2, 20.7, 20.4.
5,6-Di-O-a cetyl-2,3,7-tr id eoxy-2-tr iflu or oa ceta m id o-D-
glu co-h ep ton o-1,4-la cton e (32). Unsaturated amidolactone
25 (0.84 g, 1.9 mmol) was dissolved in EtOAc (25 mL), and
palladium on charcoal (5%, 0.13 g) was added. The compound
was hydrogenated at high pressure (300 psi) for 5 days, after
which Et3N (0.53 mL, 3.8 mmol) was added, and the suspen-
sion was hydrogenated at atmospheric pressure for 20 h.
Filtration and evaporation gave a solid which was taken up
in CH2Cl2 and washed with H2O. The combined water phases
were washed with CH2Cl2, and the combined organic phases
were dried (MgSO4) and evaporated to give an amorphous
compound (0.77 g). Flash chromatography (EtOAc:hexane 1:2)
afforded 32 as a crystalline compound (0.60 g, 90%), mp 192-
194 °C. Repeated crystallizations from EtOAc gave compound
C
10H15ClO4 (234.68): C, 51.18; H, 6.44. Found: C, 51.24; H,
6.49.
2-Azid o-2,3,7-t r id eoxy-5,6-O-isop r op ylid en e-D-glu co-
h ep ton o-1,4-la cton e (36). NaN3 (2.0 g, 30.8 mmol) was
added to a solution of chlorolactone 35 (0.71 g, 3.0 mmol) in
CH3CN (20 mL). The suspension was stirred at reflux
overnight. The suspension was filtered and concentrated to
a syrup which was dissolved in CH2Cl2, washed with H2O,
dried (MgSO4), stirred with activated charcoal, filtered, and
concentrated. The crude product was crystallized from Et2O:
hexane to give 36 as slightly colored crystals (0.58 g, 79%),
mp 52-58 °C. Repeated crystallizations from Et2O:hexane at
room temperature gave the product as colorless crystals, mp
64-64.5 °C, [R]20 +46 (c 0.80, CHCl3). 1H NMR (CDCl3, 500
D
MHz): δ 4.43 (dq, H-6, J 6,7 ) 6.5), 4.42 (ddd, H-4), 4.29 (dd,
H-2, J 2,3 ) 10.5, J 2,3′ ) 9.5), 3.98 (dd, H-5, J 4,5 ) 2.5, J 5,6
)
32, mp 199-201 °C, [R]20 +10.2 (c 1.0, EtOAc). CI-MS
6.5), 2.53 (ddd, H-3′, J 3′,4 ) 6.5, J 3,3′ ) 13), 2.20 (ddd, H-3, J 3,4
) 9.5), 1.46, 1.36 (2 s, 6 H), 1.38 (d, 3H, H-7). 13C NMR (CDCl3,
125.8 MHz): 172.5, 109.0, 77.7, 75.1, 72.3, 56.7, 30.5, 26.7,
25.2, 14.9. Anal. Calcd for C10H15N3O4 (241.25): C, 49.79; H,
6.27. Found: C, 49.88; H, 6.27.
D
(NH3): m/z 373 (M + NH4+), 356 (M + H+). 1H NMR (CDCl3,
500 MHz): δ 6.99 (bs, NH), 5.19 (dd, H-5, J 4,5 ) 5, J 5,6 ) 5),
5.10 (dq, H-6, J 6,7 ) 6.5), 4.68 (m, H-2, H-4), 2.89 (ddd, H-3′,
J 3,3′ ) 12.5), 2.04 (m, H-3), 2.18, 2.06 (2 s, 6 H), 1.30 (d, 3H,
H-7). 13C NMR (CDCl3, 62.9 MHz): δ 174, 171, 170, 75.6, 72.6,
68.2, 49.9, 31.4, 21.0, 20.6, 15.4. Anal. Calcd for C13H16F3-
NO7 (355.26): C, 43.97; H, 4.54; N, 3.94. Found: C, 43.94; H,
4.52; N, 3.70.
2-Am in o-2,3,7-tr ideoxy-D-glu co-h epton o-1,4-lacton e Hy-
d r och lor id e (33) fr om 36. Azidolactone 36 (0.75 g, 3.1 mmol)
was dissolved in HCl/MeOH (40 mL, 1% AcCl in MeOH),
palladium on charcoal (5%, 0.1 g) was added, and the com-

1928 J . Org. Chem., Vol. 63, No. 6, 1998
Horneman and Lundt
pound was hydrogenated at atmospheric pressure for 17 h. The
suspension was refluxed for 1.5 h and filtered through
activated charcoal, the solvent was evaporated, and the residue
was concentrated with H2O (4 × 30 mL) and toluene (3 × 30
mL) to give a crude product (0.63 g) which was crystallized
from MeOH:CH3CN to give 33 (0.30 g, 46%), mp 150.5-155.5
°C. Recrystallization from MeOH:CH3CN gave a sample with
13C NMR data were identical with the values given above for
33.
Ack n ow led gm en t. We thank J ytte Grove-Rasmus-
sen for skilled technical assistance. We also thank Dr.
J ørgen Øgaard Madsen for recording the mass spectra.
mp 159-161 °C, [R]20 -39.4 (c 0.51, MeOH). 1H NMR and
J O971928L
D