Cerium(III) chloride-mediated reactions of sulfonamide dianions

Article abstract of DOI:10.1021/jo034001w

Presented here is the first report on the ability of cerium(III) chloride to mediate high-yielding and, oftentimes, highly diastereoselective additions of N-benzyl-α, N-dilithio methanesulfonamide to aldehydes and ketones of biological importance. Smooth addition was effected to base-sensitive substrates such as Fmoc-protected alaninal, citral, 5-cholesten-3-one, uridine 5′-aldehyde, 3′-ketouridine, and 3′-ketothymidine. The reaction was chemoselective for aldehydes in the presence of nitriles. Acetoxy groups are labile and thus not suitable protecting groups for alcohols under these conditions. N-Benzyl-α, N-dilithio methanesulfonamide was found to be of sufficient basicity to cause enolate formation with sensitive substrates, such as 1-phenylacetone. However, the addition of cerium(III) chloride mediated the basicity of the dianion and suppressed enolate formation in these cases. Further, cerium(III) has general utility for the addition of various N-aliphatic/aromatic methanesulfonamide dianions to 3′-ketouridine.

Full text of DOI:10.1021/jo034001w

Cer iu m (III) Ch lor id e-Med ia ted Rea ction s of Su lfon a m id e Dia n ion s
David C. J ohnson II and Theodore S. Widlanski*
Department of Chemistry, Indiana University, Bloomington, Indiana 47405
twidlans@indiana.edu
Received J anuary 1, 2003
Presented here is the first report on the ability of cerium(III) chloride to mediate high-yielding
and, oftentimes, highly diastereoselective additions of N-benzyl-R, N-dilithio methanesulfonamide
to aldehydes and ketones of biological importance. Smooth addition was effected to base-sensitive
substrates such as Fmoc-protected alaninal, citral, 5-cholesten-3-one, uridine 5′-aldehyde, 3′-
ketouridine, and 3′-ketothymidine. The reaction was chemoselective for aldehydes in the presence
of nitriles. Acetoxy groups are labile and thus not suitable protecting groups for alcohols under
these conditions. N-Benzyl-R, N-dilithio methanesulfonamide was found to be of sufficient basicity
to cause enolate formation with sensitive substrates, such as 1-phenylacetone. However, the addition
of cerium(III) chloride mediated the basicity of the dianion and suppressed enolate formation in
these cases. Further, cerium(III) has general utility for the addition of various N-aliphatic/aromatic
methanesulfonamide dianions to 3′-ketouridine.
CHART 1. Sa m p lin g of Su lfon a m id e Sca ffold s
In tr od u ction a n d Ba ck gr ou n d
The sulfonamide functional group has received con-
siderable attention in the pharmaceutical arena. Sul-
fonamides are the bioactive moiety in compounds with
antibacterial, antibiotic, and antidiabetic properties and
are found in compounds used to treat glaucoma and
edema. Sulfanilamide, an antibacterial sulfonamide, has
played a historically fundamental role in the advance-
ment of structure-activity relationships, the theory of
antimetabolites, the understanding of prodrugs, and the
use of pharmacokinetics in drug development.1 The
pharmaceutical industry continues to explore new scaf-
folds that incorporate the sulfonamide moiety. A few
examples are shown in Chart 1 and include 5-substituted
thiophene-2-sulfonamides (1),2 â-sultams (2),3 and N-alkyl-
â-hydroxy-sulfonamides (3).4 Interest in new sulfonamide
scaffolds has also extended to such compounds as 2H-1,
2, 4-thiadiazin-3(4H)-one 1,1-dioxides (4) and 5,6-dihydro-
1,4,3-oxathiazin-2(3 H)-one 4,4-dioxides (5).5 Other moi-
eties related to N-alkyl-â-hydroxy-sulfonamides are
N-alkyl-2-oxoalkanesulfonamides (6). This group, whose
properties and applications6 are not yet fully realized,
has received limited description in the literature.7,8 Aside
from these important sulfonamide functional moieties,
sulfonamide derivatives such as N-alkyl sulfonamides are
of current interest in a variety of applications.9 The zinc-
chelating properties of N-alkyl sulfonamides have been
utilized in ligands for the enantioselective titanium
tetraisopropoxide-promoted addition of dialkylzinc to
aldehydes.10-12 In addition, N-alkyl sulfonamides have
been exploited as nuclease-resistant phosphate sur-
rogates13,14 and as peptide mimetics.15-18
(9) Tozer, M. J .; Woolford, A. J . A.; Linney, I. D. Synlett 1998, 2,
186-188.
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2000, 11, 1629-1644.
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J . Organometallics 2000, 19, 4840-4851.
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2985.
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Drug Action; Academic Press: San Diego, 1992; pp 146-219.
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2876.
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1975, 31, 2517-2521.
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10.1021/jo034001w CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/31/2003
5300
J . Org. Chem. 2003, 68, 5300-5309

Reactions of Sulfonamide Dianions
SCHEME 1. N-Acyl Su lfon a m id e-Br id ged Din u cleosid e
We have recently described the synthesis of N-acyl
sulfonamide derivatives of nucleosides.19,20 In one of these
studies, we prepared the first N-acyl sulfonamide-bridged
dinucleoside (7). The strategy relied upon condensation
of sulfonamide 8 with adenosine carboxylic acid 9. The
synthesis of sulfonamide 8 was lengthy and necessitated
a functional group interconversion from a sulfonate to a
sulfonamide. Briefly, sulfonamide 8 was obtained from
ketouridine 11 through the intermediacy of isobutyl
sulfonate 1021 (Scheme 1). We desired a more facile entry
into molecules resembling sulfonamide 8. One approach
would be to C-alkylate methanesulfonamide with keto-
uridine 11, thus introducing the sulfonamide functional
group in a more direct fashion. Thompson has described
a direct and useful method for the C-alkylation of
N-protected methanesulfonamide derivatives via the
corresponding sulfonamide dianion.22 We felt that this
method could be adapted to provide a more facile entry
to nucleoside sulfonamides such as 8. However, the
possible detrimental effects of a dianion on base-sensitive
3′-ketonucleosides such as 11 raised some concerns.
Miyasaka and co-workers have shown that ketouridine
11 decomposes under strongly basic conditions providing
uracil as one of the byproducts.23
Generally, ketonucleosides give moderate yields of the
carbonyl addition product upon reaction with Grig-
nard,23,24 organolithium,21,23 organoaluminum,23 and mag-
nesium aluminate25 reagents. Particularly problematic
are carbonyl addition reactions involving 2′-deoxy-3′-
ketonucleosides with basic reagents, where â-elimination
of the nucleobase readily occurs. A significant advance-
ment in carbonyl addition reactions of 3′-ketonucleosides
was detailed by Bender and Moffett.26 They demonstrated
that organocerium reagents facilitate carbonyl addition
reactions with 2′-deoxy-3′-ketonucleosides giving yields
in excess of 90%. Since Bender and Moffet’s original
report, several groups have used organocerium reagents
derived from vinyl,27 allyl,28 or trimethylsilylacetylide29-31
to effect carbonyl addition reactions with 3′-ketonucleo-
sides. The products were often obtained in high yields
and with good diastereoselectivity. Since their introduc-
tion,32 organocerium reagents have been utilized to
promote mild and selective addition reactions to alde-
hydes, ketones, esters, nitriles, hydrazones, and other
functional groups while minimizing side reactions.33-39
It is interesting to note that an organocerium reagent of
a dianion has never been utilized for addition to a
carbonyl substrate.40,41,42
Typically, dianions have been employed as chiral
auxiliaries43 for cerium in synthetic applications.44-46 In
nonsynthetic applications, cerium complexes with cy-
clooctatetraene dianion,47-49 porphyrin dianion,50 and
(27) Lenz, R.; Giese, B. J . Am. Chem. Soc. 1997, 119, 2784-2794.
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1995, 36, 1031-1034.
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16, 2387-2392.
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62, 8309-8314.
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Commun. 1982, 1042-1044.
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E. Recent Res. Dev. Org. Chem. 2001, 5, 181-191.
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55, 3803-3830.
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60, 1725-1730.
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Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 1, pp 231-
250.
(39) Imamoto, T. Pure Appl. Chem. 1990, 62, 747-752.
(40) An exception is 1,1′-dilithio ferrocene. However, in these
instances, each cyclopentadiene anion can be considered to be a
monoanion, each being substituted individually rendering no free anion
after addition. For examples, see refs 41 and 42.
(41) Dimitrov, V.; Kostova, K.; Genov, M. Tetrahedron Lett. 1996,
37, 6787-6790.
(42) Panev, S.; Dimitrov, V. Tetrahedron: Asymmetry 2000, 11,
1517-1526.
(43) One example of a chiral auxiliary is the dialkoxide TADDOL;
see refs 44 and 45. Another example of a chiral auxiliary is the
dialkoxide of binaphthol; see ref 46.
(44) Greeves, N.; Pease, J . E.; Bowden, M. C.; Brown, S. M.
Tetrahedron Lett. 1996, 37, 2675-2678.
(45) Greeves, N.; Pease, J . E. Tetrahedron Lett. 1996, 37, 5821-
5824.
(19) J ohnson, D. C., II; Widlanski, T. S. Tetrahedron Lett. 2001, 42,
3677-3679.
(20) J ohnson, D. C., II; Widlanski, T. S. Synthesis 2002, 6, 809-
815.
(21) Xie, M.; Widlanski, T. S. Tetrahedron Lett. 1996, 37, 4443-
4446.
(22) Thompson, M. E. J . Org. Chem. 1984, 49, 1700-1703.
(23) Hayakawa, H.; Tanaka, H.; Itoh, N.; Nakajima, M.; Miyasaka,
T.; Yamaguchi, K.; Iitaka, Y. Chem. Pharm. Bull. 1987, 35, 2605-
2608.
(24) Huss, S.; De las Heras, F. G.; Camarasa, M. J . Tetrahedron
1991, 47, 1727-1736.
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1647.
(46) Chibale, K.; Greeves, N.; Lyford, L.; Pease, J . E. Tetrahedron:
Asymmetry 1993, 4, 2407-2410.
(47) Hodgson, K. O.; Mares, F.; Starks, D. F.; Streitwieser, A., J r.
J . Am. Chem. Soc. 1973, 95, 8650-8658.
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175.
J . Org. Chem, Vol. 68, No. 13, 2003 5301

J ohnson and Widlanski
benzene dianion51 have been investigated to illuminate
bonding, structural, and atomic properties. We felt that
it would be interesting to evaluate if cerium could
mediate the basicity of a dianion sufficiently to promote
the addition of the dianion to an easily enolizable
carbonyl substrate. Heterofunctional dianions such as
amides and sulfonamides have wide utility in synthe-
sis.52,53 Myers et al. have demonstrated the use of
pseudoephedrine as a chiral auxiliary for the asymmetric
alkylation of the pseudoephedrine amide enolate dian-
ion.54,55 The alkylation of this dianion gives facile access
to enatiomerically enriched carboxylic acids, alcohols,
aldehydes, and ketones.56 Additionally, both enantiomers
of R-amino acids57 are obtainable by this methodology as
are γ-lactones and γ-hydroxy ketones.58 The methodology
for alkylation of sulfonamide dianions introduced by
Thompson was extended by Poss and Reid in the con-
struction of sulfonamide-containing rennin inhibitors.4
Campbell and Hart have utilized sulfonamide dianions
in the construction of reagents for Mitsunobu reactions,
subsequently used for the synthesis of manzamine alka-
loids.59 Additionally, Graham and Scholz have used
sulfonamide dianions in the development of topically
active carbonic anhydrase inhibitors for the treatment
of glaucoma.2 Numerous other examples, including meth-
odology for the construction of heterocycles,60-64 asym-
metric synthesis of sulfonamides,65 and directed ortho
metalation of arylsulfonamides,66 attest to the synthetic
utility of sulfonamide dianions.
to investigate the effect cerium(III) chloride might have
upon C-alkylation of N-benzyl-R, N-dilithio methane-
sulfonamide by a variety of carbonyl compounds of
biological importance such as nucleosides, R-amino al-
dehydes, steroids, and sugars.
Resu lts a n d Discu ssion
Our first attempts to alkylate N-benzyl-R, N-dilithio
methanesulfonamide (12) were with ketouridine 11.
Because ketouridine 11 contains an acidic ureido proton,
the literature procedure22 was modified to account for the
additional acidic proton of 11. Using this modified
procedure, the desired C-alkylated sulfonamide was
obtained in 69% yield (eq 1) with no recovery of ketou-
ridine 11. Further optimization, (careful titration67 of
BuLi/changes in BuLi stoichiometry/temperature/reac-
tion time/cosolvents such as HMPA) led to little further
improvement in yield (70-71%, OHR:OHâ ) 13:87).68 The
conditions described in the literature were clearly already
optimal. We then sought to improve the yield for the
addition of dianion 12 to ketouridine 11 by employing
cerium(III) chloride.
The utility of dianions and the applications being
discovered for N-alkyl sulfonamides are but a few reasons
to explore new methodology with N-alkyl sulfonamides.
Further, the lack of precedent for alkylation of dianions
in the presence of cerium raises a more fundamental
question. Is cerium(III) chloride capable of mediating the
basicity of a dianion such as N-benzyl-R, N-dilithio
methanesulfonamide to promote clean, high-yielding
additions with carbonyl substrates? Therefore, we sought
Subjecting ketouridine 11 to the dianion 12/CeCl3
mixture afforded uridine-sulfonamide 13 in 28% yield as
a single diastereomer69 (3′-OHâ). Significantly, ketouri-
dine 11 was recovered in 69% yield. Thus, the cerium-
mediated addition showed potential in both its ability to
provide a single diastereomer and for the recovery of
unreacted starting material. Optimization of this reaction
(Table 1) led to a procedure utilizing a molar ratio of 1:8:
8.2 (ketone:12:CeCl3). This ratio provided the desired
uridine-sulfonamide 13 in 99% yield as a single diaste-
reomer (3′-OHâ).
We were curious about the effect cerium(III) would
have upon dianion 12 in reaction with a variety of base-
sensitive compounds. Was the improved yield and dias-
tereoselection obtained for ketouridine 11 a general
trend? To examine this possibility, we subjected citral
(14) and 1,2,5,6-di-O-isopropylidene-3-oxo-R-D-glucofura-
nose (16) to reaction with dianion 12. These compounds
were chosen because citral has allylic protons that could
be deprotonated by strong base, and glucofuranose 16 is
similar to ketouridine 11 yet lacks the acidic ureido
proton and ligation sites of the nucleobase. In the absence
of cerium(III), moderate yields were obtained for the
(49) Mares, F.; Hodgson, K.; Streitwieser, A., J r. J . Organomet.
Chem. 1970, 24, C68-C70.
(50) Tashiro, K.; Konishi, K.; Aida, T. J . Am. Chem. Soc. 2000, 122,
7921-7926.
(51) Cassani, M. C.; Gun’ko, Y. K.; Hitchcock, P. B.; Lappert, M. F.;
Laschi, F. Organometallics 1999, 18, 5539-5547.
(52) Kaiser, E. M.; Petty, J . D.; Knutson, P. L. A. Synthesis 1977,
509-550.
(53) Thompson, C. M.; Green, D. L. C. Tetrahedron 1991, 47, 4223-
4285.
(54) Myers, A. G.; Yang, B. H.; Chen, H.; Gleason, J . L. J . Am. Chem.
Soc. 1994, 116, 9361-9362.
(55) Myers, A. G.; Schnider, P.; Kwon, S.; Kung, D. W. J . Org. Chem.
1999, 64, 3322-3327.
(56) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky,
D. J .; Gleason, J . L. J . Am. Chem. Soc. 1997, 119, 6496-6511.
(57) Myers, A. G.; Gleason, J . L.; Yoon, T.; Kung, D. W. J . Am. Chem.
Soc. 1997, 119, 656-673.
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2440.
(59) Campbell, J . A.; Hart, D. J . J . Org. Chem. 1993, 58, 2900-
2903.
(60) Grunder-Klotz, E.; Ehrhardt, J .-D. Synlett 1991, 800-802.
(61) Grunder-Klotz, E.; Humbert, P.; Ehrhardt, J .-D. Heterocycles
1993, 36, 733-742.
(62) Takahashi, M.; Yoshizawa, S. Heterocycles 1996, 43, 2733-
2739.
(63) Vierfond, J . M.; Legendre, L.; Martin, C.; Rinjard, P.; Miocque,
M. Eur. J . Med. Chem. 1990, 25, 251-255.
(64) Davis, F. A.; Weismiller, M. C.; Lal, G. S.; Chen, B. C.;
Przeslawski, R. M. Tetrahedron Lett. 1989, 30, 1613-1616.
(65) Davis, F. A.; Zhou, P.; Carroll, P. J . Org. Chem. 1993, 58, 4890-
4896.
(67) Watson, S. C.; Eastham, J . F. J . Organomet. Chem. 1967, 9,
165-168.
(68) Several reports have appeared in the literature documenting
problems with the generation and/or chemoselective reactivity of
sulfonamide dianions (refs 3, 9, 59-61). Therefore, to ensure generation
of the sulfonamide dianion was being accomplished under the reaction
conditions, the dianion was generated and quenched with perdeutero
acetic acid. Isolation of the products afforded N-benzyl methane-
sulfonamide with a D:H ratio of 92:8 as determined by 1H NMR
integration (See Supporting Information for procedure). The failure
to quantitatively incorporate deuterium into the dianion is a result of
a kinetic isotope effect. However, these results qualitatively established
the formation of the sulfonamide dianion.
(66) BFamiloni, O. B. Synlett 2002, 8, 1181-1210.
(69) Within the limits detectable by NMR analysis.
5302 J . Org. Chem., Vol. 68, No. 13, 2003

Reactions of Sulfonamide Dianions
TABLE 1. Op tim iza tion of CeCl3-Med ia ted Ad d ition of Dia n ion 12 to Ketou r id in e 11a
% yield
ketone 11
dianion 12
(equiv)
CeCl3
(equiv)
temp
(°C)
time
(h)
entry
(M)
product
ketone
1
2
3
0.65
0.65
0.65
0.65
0.65
2.1
4.0
6.4
8.0
8.0
2.15
4.2
6.6
8.2
0
28
43
72
99
30
69
55
25
c
-75 to -30
-75 to -30
-75 to -30
-75 to -30
-75 to -30
5
2
5
5
5
4
5b
c
a
b
All reactions were performed with 200 mg of ketone 11. The concentration of sulfonamide was 0.29 M for entries 1-4. Control
reaction: sulfonamide was diluted with the volume of THF used to suspend CeCl3 in entry 4. c No ketone detected within the limits of
NMR analysis.
of the alkylating species.26 Similarly Lenz and Giese,27
SCHEME 2. Ad d ition of Dia n ion 12 to
Ba se-Sen sitive Su bstr a tes F ollow in g a Liter a tu r e22
P r otocol
Wengel and co-workers,28 as well as Biellmann and
colleagues29,31 employed in excess of 6 equiv of organoc-
erium reagent with ketonucleosides.
Why such an excess of organocerium reagent is neces-
sary in reaction with ketonucleosides is unknown. How-
ever, during optimization of the reaction, it was found
that varying the stoichiometry of the cerium resulted in
varying yields of the product. It is possible that the hard
Lewis acidity70,71 of cerium(III) promotes ligation to the
nitrogen and oxygen functionalities of the nucleobase.
Another possibility is that in this reaction the kinetic
order in cerium is quite high. Our current results do not
clarify which of these possibilities is operative. However,
the ligation possibility is supported by the reaction of
glucofuranose 16 with dianion 12/CeCl3, where a near
stoichiometric ratio of substrate to organocerium reagent
provides the desired product in good yield.
TABLE 2. Op tim iza tion of Selected Su bstr a tes w ith
a ,b
Dia n ion 12/CeCl3
procedure/% yield
literaturec
A series of molecules with base-sensitive functionalities
were chosen to test the general ability of cerium(III)
chloride to mediate the addition of dianion 12 to carbonyl
substrates. For this study we selected a representative
assortment of substrates that collectively possess mul-
tiple electrophilic sites and contain base-sensitive pro-
tecting groups, acidic protons (i.e., benzylic or â, γ-en-
ones capable of isomerization), and functionality known
to be reactive toward organocerium reagents (i.e., nitrile,
ester, aldehyde. etc.). Table 3 summarizes the results
obtained for a representative collection of biologically
important molecules subjected to the optimized condi-
tions for synthesis of uridine-sulfonamide 18 (substrate:
12:CeCl3 ) 1:8:8.2). It should be mentioned that these
conditions are not optimal for each substrate tested.
However, applying these conditions involving an excess
of the organocerium reagent toward sensitive molecules
demonstrates the potential for the reagent combination
of dianion 12/CeCl3 for future applications.
Dianion 12 added smoothly to carbonyl groups in the
presence of CeCl3 to substrates possessing base-sensitive
functionality. Although we employed a protocol that had
been optimized for ketouridine 11, many other substrates
were obtained in good to high yield with recovery of the
unconverted starting material noted in several instances.
Excellent diastereoselection was also obtained for many
of the substrates. Particularly notable examples include
reaction of 2′-deoxy-3′-ketothymidine 19 and ketouridine
11. Reaction of both nucleosides with dianion 12/CeCl3
substrate
product
this study
14
16
15
17
82
84 (67)
54
40
a
Reactions conducted as described in the Experimental Section
with a molar ratio of 1:1.2:1.3 (substrate/12/CeCl3). Value in
parentheses is the yield of reaction without CeCl3 added, all other
factors remaining constant. c Protocol for the general addition of
sulfonamide dianions to carbonyl substrates.22
b
addition of dianion 12 to citral (54%) or glucofuranose
16 (40%) using the conditions described for the addition
of sulfonamide dianions with carbonyl substrates in the
published protocol (Scheme 2). However, in the presence
of cerium(III), dianion 12 added to citral (82%) and
glucofuranose 16 (84%) in considerably higher yield
(Table 2). In contrast to the cerium-mediated reaction
with ketouridine 11, a more moderate molar ratio of
reactants of 1:1.2:1.3 (substrate:12:CeCl3) was found to
provide good yields of the products. This stoichiometry
is markedly different from that employed with ketouri-
dine 11.
To ensure that CeCl3 was responsible for the improved
yield with ketouridine 11 and glucofuranose 16, these
reactions were run in the absence of CeCl3 maintaining
the same concentrations and reaction conditions used for
the cerium-mediated reactions. Both ketouridine 11 and
glucofuranose 16 were converted to product in reduced
yield in the absence of CeCl3 (30 and 67% yields,
respectively; Table 1, entry 5; Table 2). It should be noted
that the excess of organocerium reagent required for
reaction with ketonucleosides appears to be general. For
example, Bender and Moffett detailed the addition of
alkyl, alkenyl, and alkynyl organocerium reagents to 2′-
deoxy-3′-ketonucleosides requiring in excess of 6 equiv
(70) Anwander, R. In Lanthanides: Chemistry and Use in Organic
Synthesis; Kobayashi, S., Ed.; Springer: Berlin, 1999; Vol. 2, pp 1-61.
(71) Molander, G. A. In The Chemistry of the Metal-Carbon Bond;
Hartley, F. R., Ed.; J ohn Wiley & Sons: Chichester, UK, 1989; Vol. 5,
pp 319-396.
J . Org. Chem, Vol. 68, No. 13, 2003 5303

J ohnson and Widlanski
TABLE 3. CeCl3-Med ia ted Ad d ition of N-Ben zyl-r, N-Dilith io Meth a n esu lfon a m id e to Ba se-Sen sitive Su bstr a tesa ,b
a
Reactions conducted as described in the Experimental Section using procedure A with a molar ratio of 1:8:8.2 (substrate:12:CeCl3).
Values in parentheses are yields of reaction without CeCl3 added, all other factors remaining constant. c Ratio of OHR:OHâ ) 20:80.
Ratio of OHR:OHâ ) 15:85. e Recovered as the hydrate.
b
d
were fully diastereoselective.72 However, in the absence
of CeCl3, mixtures of diastereomers were obtained. In this
regard, the addition of dianion 12/CeCl3 to 5-cholesten-
3-one (26) merits comment.
Large nucleophiles such as dianion 12 approach six-
membered cyclic ketones on trajectories that minimize
steric strain in the transition state.73 Presumably, mini-
mization of steric strain is achieved by an equatorial
approach of the nucleophile.74 Therefore, addition of
dianion 12/CeCl3 to 5-cholesten-3-one (26) is expected to
yield product with the hydroxyl group R as the major
product. However, the major diastereomer formed in a
ratio of 3:2 is formed by axial addition of the reagent,
resulting in the hydroxyl group being â. This suggests
(72) Within the limits detectable by NMR analysis.
(73) Ashby, E. C.; Laemmle, J . T. Chem. Rev. 1975, 75, 521-546.
(74) Atkinson, R. S. In Stereoselective Synthesis; J ohn Wiley &
Sons: Chichester, UK, 1995; pp 273-314.
5304 J . Org. Chem., Vol. 68, No. 13, 2003

Reactions of Sulfonamide Dianions
TABLE 4. CeCl3-Med ia ted Ad d ition of Va r iou s
Su lfon a m id e Dia n ion s w ith Ketou r id in e 11a ,b
that the methyl substituent at C10 of 5-cholesten-3-one
is not providing sufficient steric hindrance to afford a
single diastereomer. However, Imamoto et al. added
phenylethynyllithium/CeCl3 to 26 and reported the for-
mation of a single diastereomer.75
The addition of dianion 12/CeCl3 to acyclic R-amino
aldehyde 30 yielded a mixture of diastereomers (dr ) 69:
31). Notably, the base-sensitive Fmoc protecting group
is stable under these reaction conditions. The diastereo-
selection obtained for this reaction is comparable to
vinylmagnesium bromide additions to Boc-L-phenylalani-
nal (dr ) 70: 30).76 Moderate diastereoselection was also
evident in the addition of dianion 12/CeCl3 to uridine
aldehyde 28 (dr ) 76: 24). Unreacted starting material
was recovered from this reaction as the hydrated form
of aldehyde 28. The hydrated form was not detected
spectroscopically in the starting material. Since many
aldehydes and some ketones readily hydrate, we tested
whether dianion 12/CeCl3 would react with the hydrated
form of a ketone. The hydrated form of glucofuranose 16
was subjected to reaction with dianion 12/CeCl3, and a
diminished yield of the addition product was obtained
that roughly corresponded to the percentage of free
ketone present in the starting material. These results
may suggest that the hydrated forms of ketones/alde-
hydes are unreactive toward the dianion 12/CeCl3 re-
agent combination.
The addition of dianion 12/CeCl3 to 5R-androstan-3â-
ol-17-one acetate (23) and 7-oxo-heptanenitrile (32) was
performed to examine the chemoselectivity of reagent 12/
CeCl3. We found that acetoxy groups are labile, but the
nitrile functionality is stable under these reaction condi-
tions. It is likely that the low temperatures employed
precluded attack upon the nitrile, which generally re-
quires higher temperatures (0 °C to rt) to react with
organocerium reagents.34
R
yield (%)
Me
Et
iPr
88
90
90
hexyl
phenyl
benzhydryl
95 (64c)
96
96
a
Reactions conducted as described in the Experimental Section
using procedure B with a molar ratio of 1:8:8.2 (ketouridine:
b
sulfonamide:CeCl3). Value in parentheses is the yield of reaction
without CeCl3 added, all other factors remaining constant. c Ratio
of OHR:OHâ ) 29: 71.
addition of N-benzhydryl dianion 44 is notable, because
the benzhydryl group can be removed by hydrogenolysis
with Pearlman’s catalyst.4 Similarly, high-pressure hy-
drogenolysis using Pearlman’s catalyst was effective for
the debenzylation of allofuranose 17 (eq 2). Further
investigations are underway to explore the scope and
limitations of the benzyl group for protection of a sul-
fonamide moiety.
Next, we examined the generality of cerium(III) to
mediate the basicity of various sulfonamide dianions in
reaction with ketouridine 11. The procedure used for
addition of N-benzyl methanesulfonamide dianion to
ketouridine 11 was unsuitable for addition of simple
N-aliphatic or N-aromatic sulfonamides, as the dianions
precipitated from solution. These dianions can be solu-
bilized by the addition of 5% HMPA (v/v) to the reaction
medium. However, HMPA has a detrimental effect on the
yields obtained. For example, N-hexyl and N-phenyl
methanesulfonamide dianions added to ketouridine 11
in 50 and 45% yields, respectively in the presence of
HMPA. We subsequently found that the simple expedient
of diluting the reaction mixture was sufficient to solve
this problem. Under these conditions, N-hexyl and N-
phenyl methanesulfonamide dianions added diastereo-
selectively to ketouridine 11 in 95 and 96% yields,
respectively. Cerium(III) was still required to obtain high
diastereoselectivity and optimal yields under these condi-
tions. When N-hexyl methanesulfonamide dianion was
added to ketone 11 in the absence of cerium(III), a
reduced yield of the product was obtained (64%) as a
mixture of diastereomers (OHR:OHâ ) 29:71). Table 4
summarizes these results. The high-yield obtained for the
Given the successful addition of N-substituted aliphatic
and aromatic sulfonamide dianions to many carbonyl
compounds mediated by cerium(III), we wanted to ex-
amine the possibility for enolate formation promoted by
dianion 12. We chose 1-phenylacetone (47) as a model
for ketones extremely prone to enolate formation. Sub-
jecting dianion 12 to 1-phenylacetone under the condi-
tions described in the literature and quenching the
reaction prior to completion with perdeutero acetic acid
provided â-hydroxy-sulfonamide 48 in 73% yield (eq 3).
The recovered sulfonamide (24%) contained a R-CH2D:
R-CH3 ratio of 17:83. Significant proton incorporation into
the recovered N-benzyl methanesulfonamide was ob-
served over that of the control (R-CH2D:R-CH3 ) 92:8).
Although no starting ketone (47) was recovered, a
complicated mixture of byproducts was isolated by chro-
matography and a small amount of the aldol product of
47 was present. Under identical reaction conditions,
1-phenylacetone was subjected to cerium-mediated di-
anion addition (47:12:CeCl3 ) 1:1.2:1.3). Product 48 was
obtained in 73% yield, and unreacted 1-phenylacetone
was recovered in 26% yield. Further, the recovered
starting material contained no deuterium incorporation
(75) Imamoto, T.; Sugiura, Y.; Takiyama, N. Tetrahedron Lett. 1984,
25, 4233-4236.
(76) J unusz, J .; Golebiowski, A. Chem. Rev. 1989, 89, 149-164.
J . Org. Chem, Vol. 68, No. 13, 2003 5305

J ohnson and Widlanski
1
by mass spectroscopy or H NMR analysis. These results
not explicitly investigated but are worth mentioning for
their future potential. Other potential uses for the
method demonstrated include the construction of pepti-
domimetics by way of Fmoc-protected R-amino aldehydes.
This protecting group has not been utilized with dianionic
organometallic reagents, presumably due to its base
lability.83-85
demonstrate that cerium(III) is an effective additive for
suppressing side reactions resulting from the basicity of
dianion 12.
Exp er im en ta l Section
Gen er a l. Solvents were distilled from potassium benzophe-
none ketyl (THF and Et2O) or calcium hydride (CH3CN, DCM,
HMPA, and pyridine) under an atmosphere of dry N2. Cerium-
(III) chloride heptahydrate was dehydrated according to the
method of Dimitrov.41 In the procedures below, NaCl and
NaHCO3 refer to saturated aqueous solutions. Flash column
chromatography was performed with 60 Å 230-400 mesh silica
gel. Compounds 11,86,87 26,88 and 3089 were prepared according
to previous literature procedures. Preparation of starting
materials 16, 19, 21, 38, 32, N-benzyl methanesulfonamide,
and N-benzyl deuteriomethanesulfonamide can be found in
Supporting Information. Stereochemistry was determined from
a combination of HMQC, two-dimensional NOE and one-
dimensional NOE NMR experiments. 1H and 13C spectra were
recorded at 300 and 75 MHz or 400 and 100 MHz, respectively.
Fourier transformed infrared spectra were recorded as neat
liquids or as thin films (obtained from the evaporation of
chloroform). The method used to obtain high-resolution mass
spectra (FAB, EI, and CI) are indicated.
Cer iu m (III) Ch lor id e-Med ia ted Ad d ition of Su lfon a -
m id e Dia n ion s to Ca r bon yl Com p ou n d s. P r oced u r e A:
Ad d ition of N-Ben zyl Meth a n esu lfon a m id e Dia n ion to
Ca r bon yl Su bstr a tes. A 0.25 M THF solution of dehydrated
CeCl3 [8.2 equiv (1.025 equiv Ce/equiv sulfonamide)] was
stirred overnight to homogeneity under an atmosphere of N2.
Separately, a 0.5 M THF solution of N-benzyl methanesulfona-
mide (8 equiv) was cooled to -75 °C, and titrated BuLi (16
equiv) was added dropwise under an atmosphere of N2. The
temperature of the cold bath was raised gradually to -30 °C
over 15 min and the solution stirred for an additional 45 min
at -30 °C. After the dianion solution was cooled to -75 °C, it
was introduced via cannula into the cerium solution, also
cooled to -75 °C. The temperature of the cold bath was raised
gradually to -30 °C over 15 min and the solution stirred for
an additional 45 min at -30 °C. The heterogeneous yellow/
light orange cerium-dianion solution was recooled to -75 °C.
A 0.65 M THF solution of the carbonyl compound (1 equiv),
cooled to -75 °C, was then introduced via cannula. The
temperature of the cold bath was raised gradually to -30 °C
over 15 min. The solution was stirred at -30 °C until complete
by TLC (usually 1 h). The reaction was then quenched with
AcOH (16.2 equiv) and warmed to rt, at which time water was
added (10 mL/mmol). THF was removed by rotary evaporator,
and the resulting slurry was partitioned between ethyl acetate
and water. The ethyl acetate phase was extracted with water
then NaHCO3. The aqueous phases, kept separate, were
individually extracted with ethyl acetate; then, all organic
phases were combined, dried (Na2SO4), and concentrated by
rotary evaporation of the volatiles. Products were obtained by
flash-column chromatography using the solvent systems in-
dicated.
Finally, several procedures are reported in the litera-
ture for dehydrating cerium(III) chloride heptahydrate
to provide what is commonly referred to as anhydrous
CeCl3.38,77-79 However, Evans and co-workers have shown
by X-ray crystallography that water is still present in
these preparations to give dehydrated CeCl3.78,79 Dimitrov
and co-workers published an alternative dehydrating
procedure and found that there was an effect on the
activity and efficiency of CeCl3-mediated reactions with
carbonyl substrates.41 We chose to use Dimitrov’s dehy-
dration procedure throughout this study and evaluate its
efficacy for removing any adventitious moisture that
might be detrimental toward dianion 12. Transmetala-
tion of dianion 12 with dehydrated CeCl3 followed by
quenching with excess CD3CO2D/D2O80 resulted in the
incorporation of deuterium into N-benzyl methanesulfona-
mide with a R-CH2D:R-CH3 ratio of 83:17.81 In a control
experiment where CeCl3 was omitted, N-benzyl meth-
anesulfonamide was obtained with a R-CH2D:R-CH3 ratio
of 85:15. From these results, the amount of detrimental
water present in dehydrated CeCl3 obtained by Dim-
itrov’s method is 0.1%, corresponding to a mole fraction
of 0.01.82 Therefore, any water present in the dehydrated
CeCl3 obtained by Dimitrov’s procedure has no effect on
the overall course of the reactions investigated with
sulfonamide dianions.
Con clu sion
We have shown that modifying the basicity of a
sulfonamide dianion with cerium(III) chloride gives high
yields of addition products with carbonyl substrates,
suppresses side reactions, and in many cases enhances
diastereoselection. It seems likely that this methodology
will be broadly applicable to other types of dianions as
well. The methodology presented in this study holds
potential for the construction of N-alkyl-â-hydroxy-sul-
fonamides under milder conditions than previously re-
ported. Further, base-sensitive functionality and protect-
ing groups are tolerated, providing good to high yields of
the desired products. This methodology may find applica-
tion for the construction of N-alkyl-2-oxo-alkanesulfona-
mides (6) by reaction of a sulfonamide dianion/CeCl3 with
Weinreb amides or oxidation of the N-alkyl-â-hydroxy-
sulfonamide products of aldehydes. These reactions were
(83) For addition of Grignard and Reformatsky reagents to an Fmoc-
protected R-amino aldehyde derivative, see refs 86 and 87.
(84) Blaskovich, M. A.; Evindar, G.; Rose, N. G. W.; Wilkinson, S.;
Luo, Y.; Lajoie, G. A. J . Org. Chem. 1998, 63, 3631-3646.
(85) Blaskovich, M. A.; Lajoie, G. A. J . Am. Chem. Soc. 1993, 115,
5021-5030.
(86) Ogilvie, K. K.; McGee, D. P. C.; Boisvert, S. M.; Hakimelahi,
G. H.; Proba, Z. A. Can. J . Chem. 1983, 61, 1204-1212.
(87) Samano, V.; Robins, M. J . J . Org. Chem. 1990, 55, 5186-5188.
(88) Mancuso, A. J .; Huang, S.-L.; Swern, D. J . Org. Chem. 1978,
43, 2480-2482.
(89) Rodriguez, M.; Llinares, M.; Doulut, S.; Heitz, A.; Martinez, J .
Tetrahedron Lett. 1991, 32, 923-926.
(77) Paquette, L. A. In Encyclopedia of Reagents for Organic
Synthesis; Paquette, L. A., Ed.; Wiley: Chichester, UK, 1995; pp 1031-
1034.
(78) Evans, W. J .; Feldman, J . D.; Ziller, J . W. J . Am. Chem. Soc.
1996, 118, 12252.
(79) Evans, W. J .; Feldman, J . D.; Ziller, J . W. J . Am. Chem. Soc.
1996, 118, 4581-4584.
(80) See Supporting Information for procedure.
(81) Deuterium ratios reported are averages of both Gaussian line-
shape analysis and manual integration.
(82) See Supporting Information for calculation.
5306 J . Org. Chem., Vol. 68, No. 13, 2003

Reactions of Sulfonamide Dianions
P r oced u r e B: Used w h en Dia n ion P r ecip ita ted fr om
Reaction Mediu m u n der th e Con dition s Descr ibed above.
A 0.50 M THF solution of dehydrated CeCl3 [8.2 equiv (1.025
equiv Ce/equiv sulfonamide)] was stirred overnight to homo-
geneity under an atmosphere of N2. Separately, a 0.08 M THF
solution of sulfonamide (8 equiv) was cooled to -75 °C, and
titrated BuLi (16 equiv) was added dropwise under an
atmosphere of N2. The temperature of the cold bath was raised
gradually to -30 °C over 15 min and the solution stirred for
an additional 45 min at -30 °C. After the dianion solution
was cooled to -75 °C, it was introduced via cannula into the
cerium solution, also cooled to -75 °C. The temperature of the
cold bath was raised gradually to -30 °C over 15 min and the
solution stirred for an additional 45 min at -30 °C. The
heterogeneous yellow/light orange cerium-dianion solution was
recooled to -75 °C. A 0.65 M THF solution of the carbonyl
compound (1 equiv), cooled to -75 °C, was then introduced
via cannula. The temperature of the cold bath was raised
gradually to -30 °C over 15 min. The solution was stirred at
-30 °C until complete by TLC (usually 1 h). The reaction was
then quenched with AcOH (16.2 equiv) and warmed to rt, at
which time water was added (10 mL/mmol). THF was removed
by rotary evaporator, and the resulting slurry was partitioned
between ethyl acetate and water. The ethyl acetate phase was
extracted with water and then NaHCO3. The aqueous phases,
kept separate, were individually extracted with ethyl acetate;
then, all organic phases were combined, dried (Na2SO4), and
concentrated by rotary evaporation of the volatiles. Products
were obtained by flash-column chromatography using the
solvent systems indicated.
N-Ben zyl-2-h yd r oxy-4, 8-d im et h yl-n on a -3,7-d ien e-1-
m eth ylen esu lfon a m id e (15). Procedure A; eluent ) 2:1 Hex/
EtOAc; 1.3 equiv of CeCl3, 1.2 equiv of N-benzyl methane-
sulfonamide, and 2.4 equiv of BuLi were used; 14 (225 µL,
1.314 mmol) was converted to 15 (363 mg, 1.076 mmol); yield
) 82%. (The product was obtained as an inseparable mixture
of diastereomers. The identity was confirmed by HRMS.)
HRMS (CH4) m/z calcd for C18H27NO3S (M+) 337.17116, found
337.17111.
3-â-(N-Ben zyl Meth ylen esu lfon a m id e)-1,2:5,6-d i-O-iso-
p r op ylid en e-R-D-a llofu r a n ose (17). Procedure A; eluent )
2:1 Et2O/Hex; 16 (242 mg, 0.9370 mmol) was converted to 17
(302 mg, 0.6809 mmol); yield ) 73%; 1H NMR (400 MHz,
CDCl3) δ 7.36 (m, 5H), 5.77 (d, J ) 3.9 Hz, 1 H), 5.15 (d, J )
3.9 Hz, 1 H), 5.11 (m, 1 H), 4.33 (A of ABX, J AB ) 13.3 Hz, J AX
) 8.2 Hz, 1 H), 4.24 (B of ABX, J BA ) 13.3 Hz, J BX ) 4.0 Hz,
1 H), 4.07 (dd, J ) 8.1, 6.0 Hz, 1 H), 3.96 (m, 1 H), 3.90 (dd, J
) 8.1, 4.5 Hz, 1 H), 3.82 (A of AB, J AB ) 15.0 Hz, 1 H), 3.75 (d,
8.5 Hz, 1 H), 3.31 (br s, 1 H), 3.01 (B of AB, J BA ) 15.0 Hz, 1
H), 1.56 (s, 3 H), 1.45 (s, 3 H), 1.35 (s, 3 H), 1.34 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 136.53, 128.86, 128.31, 128.12,
112.92, 110.04, 103.71, 82.83, 79.82, 77.97, 73.41, 67.98, 50.38,
47.91, 26.85, 26.65, 26.53, 25.31; IR (film) 3499, 3298, 3062,
3035, 2988, 2937, 2887, 2254, 1496, 1456, 1374, 1329, 1267,
1216, 1154, 1070; HRMS (CH4) m/z calcd for C19H26NO8S (M+
- CH3) 428.13791, found 428.13671.
-4.17, -5.26, -5.48 (2); IR (film) 3276, 3113, 3064, 2954, 2930,
2885, 2858, 1704, 1699, 1695, 1683, 1652, 1471, 1412, 1391,
1331, 1269, 1118, 1066; HRMS (FAB) m/z calcd for C29H49N3O8-
SSi2Na (M + Na+) 678.26766, found 678.26606.
3′-R-(N-Ben zyl Meth ylen esu lfon a m id e)-5′-(O-ter t-bu -
tyld im eth ylsilyl)- 3′-â-h yd r oxy-th ym id in e (20). Procedure
A; eluent ) 3:5 EtOAc/DCM; 19 (100 mg, 0.2821 mmol) was
converted to 20 (102 mg, 0.1889 mmol); yield ) 67%; 1H NMR
(400 MHz, CDCl3) δ 11.45 (br s, 1 H), 7.54 (d, J ) 0.91 Hz, 1
H), 7.28 (m, 5 H), 6.11 (d, J ) 6.2 Hz, 1 H), 5.71 (dd, J ) 8.5,
3.4 Hz, 1 H), 5.10 (s, 1 H), 4.37 (A of ABX, J AB ) 13.7 Hz, J AX
) 4.4 Hz, 1 H), 4.24 (B of ABX, J BA ) 13.7 Hz, J BX ) 4.2 Hz,
1 H), 4.11 (A of ABX, J AB ) 10.3 Hz, J AX ) 7.0 Hz, 1 H), 3.95
(B of ABX, J BA ) 10.3 Hz, J BX ) 4.8 Hz, 1 H,) 3.84 (t, J ) 6.0
Hz, 1 H), 3.80 (A of AB, J AB ) 15.0 Hz, 1 H), 3.15 (B of AB,
J BA ) 15.0, 1H) 2.93 (A of ABX, J AB ) 7.6 Hz, J AX ) 2.9 Hz, 1
H), 2.87 (B of ABX, J BA ) 15.8 Hz, J BX ) 2.9 Hz, 1 H), 1.61 (s,
3 H), 0.97 (s, 9 H), 0.17 (s, 3 H), 0.16 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 165.06, 151.24, 138.36, 137.11, 128.67, 127.96,
127.844, 108.16, 88.18, 86.40, 75.19, 60.40, 57.53, 47.58, 44.67,
26.08, 18.47, 12.30, -5.18; IR (film) 3408, 3290, 3070, 3039,
2954, 2929, 2884, 2857, 1699, 1683, 1472, 1432, 1331, 1275,
1154, 1098; HRMS (FAB) m/z calcd for C24H57N3O7SSiNa (M
+ Na+ ) 562.20195, found 562.20254.
17R-(N-Ben zyl Meth ylen esu lfon a m id e)-3-(-O-ter t-bu -
tyld im eth ylsilyl)-â-estr a d iol (22). Procedure A; eluent ) 3:1
Hex/EtOAc; 21 (100 mg, 0.2593 mmol) was converted to 22
(116 mg, 0.2032 mmol); yield ) 78%; 1H NMR (400 MHz,
CDCl3) δ 7.38 (m, 5H), 7.10 (d, J ) 8.6 Hz, 1 H), 6.63 (dd, J )
8.5, 2.4 Hz, 1 H), 6.57 (d, J ) 2.3 Hz, 1 H), 5.28 (t, J ) 6.2 Hz,
1 H), 4.33 (d, J ) 6.2 Hz, 2 H), 3.40 (br s, 1 H), 3.24 (A of AB,
J AB ) 14.1 Hz, 1 H), 3.08 (B of AB, J BA ) 14.1 Hz, 1 H), 2.81
(m, 2 H), 2.73 (ddd, J ) 15.3, 9.5, 6.6 Hz, 1 H), 2.27 (m, 1 H),
2.07 (m, 1H), 1.88-1.67 (m, 3 H), 1.59-1.25 (m, 5 H), 1.11 (m,
2 H), 1.00 (s, 9 H), 0.89 (s, 3 H), 0.21 (s, 6 H). 13C NMR (100
MHz, CDCl3) δ 153.58, 137.90, 136.88, 132.71, 129.06, 128.40,
128.27, 126.18, 120.15, 117.36, 81.57, 59.73, 49.55, 48.00,
47.53, 43.80, 39.53, 34.26, 31.67, 29.69, 27.59, 26.20, 25.86,
23.81, 18.33, 13.81, -4.23; IR (film) 3515, 3297, 3065, 3031,
2961, 2931, 2858, 2249, 1607, 1571, 1496, 1472, 1456, 1418,
1288, 1258, 1148, 1062; HRMS (EI) m/z calcd for C32H47NO4-
SSi (M+) 569.29951, found 569.30046.
5R-An d r osta n -17R-(N-ben zyl Meth ylen esu lfon a m id e)-
3â-17â-d iol (24). Procedure A; eluent ) 2:1 Hex/EtOAc; 23
(215 mg, 0.6467 mmol) was converted to 25 (223 mg, 0.4307
mmol); yield ) 71%; relevant data for 1H NMR (400 MHz,
CDCl3) δ 7.34 (m, 5H), 5.32 (t, J ) 6.2 Hz, 1 H), 4.28 (d, J )
6.2 Hz, 2 H), 3.57 (m, 1 H), 3.36 (br s, 1 H), 3.18 (A of AB, J AB
) 14.0 Hz, 1 H), 3.02 (B of AB, J BA ) 14.0 Hz, 1 H), 2.64 (m,
1 H), 0.82 (s, 3 H), 0.79 (s, 3 H); 13C NMR (100 MHz, CDCl3)
δ 136.88, 129.02, 128.32, 128.19, 81.55, 71.32, 59.52, 54.29,
50.56, 47.76, 47.46, 45.01, 38.16, 37.17, 36.36, 35.65, 34.23,
31.87, 31.67, 31.51, 28.62, 24.09, 20.91, 13.91, 12.46; IR (film)
3505, 3296, 3066, 3027, 2927, 2856, 2251, 1720, 1605, 1496,
1454, 1384, 1320, 1299, 1272, 1142, 1085, 1042; HRMS (FAB)
m/z calcd for C27H41NO4SNa (M + Na+) 498.26543, found
498.26597.
5R-An d r osta n -17R-(N-ben zyl Meth ylen esu lfon a m id e)-
17â-ol-3â Aceta te (25). Obtained as the minor product (19
mg, 0.0367 mmol) from above reaction; yield ) 6%; relevant
data for 1H NMR (400 MHz, CDCl3) δ 7.33 (m, 5H), 5.34 (t, J
) 6.2 Hz, 1 H), 4.66 (m, 1 H), 3.40 (br s, 1 H), 3.15 (A of AB,
J AB ) 14.1 Hz, 1 H), 3.00 (B of AB, J BA ) 14.1 Hz, 1 H), 2.63
(ddd, J ) 15.6, 9.4, 6.4 Hz, 1 H), 2.00 (s, 3 H), 0.81 (s, 3 H),
0.80 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 170.93, 136.89,
128.99, 128.32, 128.16, 81.47, 73.71, 59.62, 54.11, 50.43, 47.71,
47.42, 44.78, 36.89, 36.28, 35.60, 34.11, 34.01, 31.74, 31.57,
28.45, 27.50, 24.04, 21.58, 20.83, 13.86, 12.32; IR (film) 3515,
3286, 3065, 3031, 2939, 2856, 2254, 1725, 1496, 1455, 1381,
1366, 1323, 1303, 1250, 1149, 1083, 1027; HRMS (FAB)
m/z calcd for C29H43NO5SNa (M + Na+) 540.27600, found
540.27755.
3′-R-(N-Ben zyl Meth ylen esu lfon a m id e)-2′,5′-bis-(O-ter t-
bu tyld im eth ylsilyl)-3′-â-h yd r oxy- u r id in e (18). Procedure
A; eluent ) 10% EtOAc/DCM; 11 (200 mg, 0.4249 mmol) was
converted to 28 (275 mg, 0.4192 mmol); yield ) 99%; 1H NMR
(400 MHz, CDCl3) δ 9.90 (br s, 1 H), 7.80 (d, J ) 8.1 Hz, 1 H),
7.33 (m, 5H), 5.68 (t, J ) 6.19 Hz, 1 H), 5.64 (s, 1 H), 5.60 (dd,
J ) 8.1, 1.9, 1 H), 5.12 (s, 1 H), 4.43 (s, 1 H), 4.31 (A of ABX,
J AB ) 14.3 Hz, J AX ) 7.0 Hz, 1 H), 4.25(B of ABX, J BA ) 14.3
Hz, J BX ) 4.1 Hz, 1 H), 4.19 (A of ABX, J AB ) 12.0 Hz, J AX
)
4.1 Hz, 1 H), 4.12 (B of ABX, J BA ) 12.0 Hz, J BX ) 2.4 Hz, 1
H), 4.05 (m, 1 H), 3.60 (A of AB, J AB ) 14.8 Hz, 1 H), 3.35 (B
of AB, J BA ) 14.8 Hz, 1 H), 3.35 (d, J ) 14.8 Hz, 1 H), 0.94 (s,
9 H), 0.92 (s, 9 H), 0.24 (s, 3 H), 0.23 (s, 3 H), 0.18 (s, 3 H),
0.17 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 164.42, 150.27,
141.10, 136.80, 128.81, 127.96, 127.90, 100.60, 91.22, 82.77,
81.53, 79.85, 61.59, 52.40, 47.13, 26.06, 25.86, 18.19, 18.06,
J . Org. Chem, Vol. 68, No. 13, 2003 5307

J ohnson and Widlanski
1
3-â-(N-Ben zyl Meth ylen esu lfon a m id e)-R-h yd r oxy-ch o-
lester ol (27). Procedure A used and modified as follows. A
room-temperature solution of THF (1 mL) and 26 (100 mg,
0.260 mmol) was added dropwise to the CeCl3-dianion suspen-
sion. Following the usual workup, trituration from EtOAc
provided 27 (123 mg, 0.216 mmol) as a mixture of diastereo-
mers; yield ) 83%. An analytical sample of the minor diaste-
reomer was obtained by silica gel chromatography (DCM):
relevant data for 1H NMR (400 MHz, CDCl3) δ 7.35 (m, 5 H),
5.44 (m, 1 H), 4.95 (t, J ) 6.3 Hz, 1 H), 4.30 (d, J ) 6.3 Hz, 2
H), 3.14 (A of ABX, J AB ) 14.6 Hz, J AX ) 0.6 Hz, 1 H), 3.11 (B
of ABX, J BA ) 14.6 Hz, J BX ) 1.1 Hz, 1 H), 2.59 (s, 1 H), 2.42
(A of ABX, J AB ) 14.4 Hz, J AX ) 2.2 Hz, 1 H), 2.26 (B of ABX,
J BA ) 14.4 Hz, J BX ) 2.9 Hz, 1 H), 2.00 (m, 2 H), 1.82 (m, 2
H), 1.68 (m, 1 H), 0.97 (s, 3 H), 0.91 (d, J ) 6.6 Hz, 3 H), 0.87
(d, J ) 1.7 Hz, 3 H), 0.85 (d, J ) 1.8 Hz, 3 H), 0.67 (s, 3 H);
13C NMR (100 MHz, CDCl3) δ 138.28, 136.80, 128.99, 128.33,
128.22, 125.31, 71.08, 61.92, 56.84, 56.25, 50.29, 47.74, 43.97,
42.46, 39.84, 39.68, 36.76, 36.34, 35.96, 34.47, 33.38, 32.11,
31.95, 29.89, 28.39, 28.19, 24.44, 23.99, 23.02, 22.75, 21.04,
18.89, 18.74, 12.02; IR (film) 3497, 3219, 3089, 3031, 2940,
2899, 2867, 2844, 2360, 1453, 1321, 1264, 1145, 1062; HRMS
(CH4) m/z calcd for C35H53NO2S (M+ - H2O) 551.37970, found
551.37842.
converted to 37 (113 mg, 0.1904 mmol); yield 90%; H NMR
(400 MHz, CDCl3) δ 9.43 (br s, 1 H), 7.80 (d, J ) 8.1 Hz, 1 H),
5.65 (s, 1 H), 5.58 (d, J ) 8.1 Hz, 1 H), 5.17 (t, J ) 6.0 Hz, 1
H), 4.43 (s, 1 H), 4.24 (A of ABX, J AB ) 11.8 Hz, J AX ) 4.2 Hz,
1 H), 4.14(B of ABX, J BA ) 11.8 Hz, J BX ) 1.8 Hz, 1 H), 4.03
(m, 1 H), 3.56 (A of AB, J AB ) 14.7 Hz, 1 H), 3.35 (B of AB,
J BA ) 14.7 Hz, 1 H), 3.13 (m, 2 H), 1.19 (t, J ) 7.3 Hz, 3 H),
0.92 (s, 9 H), 0.91 (s, 9 H), 0.24 (s, 3 H), 0.23 (s, 3 H), 0.15 (s,
3 H), 0.15 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 164.21,
150.14, 141.08, 100.53, 91.32, 82.58, 81.52, 79.92, 61.71, 51.19,
38.12, 18.22, 18.12, 15.65, -4.16, -5.19, -5.51, -5.55; HRMS
(EI) m/z calcd for C24H48N3O8SSi2 (M + H+) 594.27007, found
594.27131.
3′-R-(N-Isop r op yl Meth ylen esu lfon a m id e)-2′,5′-bis-(O-
ter t-bu tyld im eth ylsilyl)-3′-â-h yd r oxy-u r id in e (39). Pro-
cedure B; eluent ) 20% EtOAc/DCM; 11 (100 mg, 0.2126
mmol) was converted to 39 (116 mg, 0.1908 mmol); yield = 90%;
1H NMR (400 MHz, CDCl3) δ 9.37 (br s, 1 H), 7.81 (d, J ) 8.1
Hz, 1 H), 5.66 (s, 1 H), 5.58 (dd, J ) 8.1, 1.3, 1 H), 5.06 (d, J
) 6.8 Hz, 1 H), 4.94 (s, 1 H), 4.42 (s, 1 H), 4.2 (A of ABX, J AB
) 11.5 Hz, J AX ) 4.3 Hz, 1 H), 4.13(B of ABX, J BA ) 11.5 Hz,
J BX ) 2.1 Hz, 1 H), 4.03 (A of AB, J AB ) 2.6 Hz, 1 H), 4.02 (B
of AB, J BA ) 2.6 Hz, 1 H), 3.63 (m, J ) 6.8 Hz, 1 H), 3.59 (A
of AB, J AB ) 14.7 Hz, 1 H), 3.37 (B of AB, J BA ) 14.7 Hz, 1 H),
1.21 (d, J ) 6.8 Hz, 6 H), 0.92 (s, 9 H), 0.91 (s, 9 H), 0.24 (s, 3
H), 0.23 (s, 3 H), 0.14 (s, 3 H), 0.14 (s, 3 H); 13C NMR (100
MHz, CDCl3) δ 164.26, 150.11, 141.24, 100.48, 91.32, 82.72,
81.64, 79.93, 77.50, 61.55, 53.21, 46.40, 26.12, 25.92, 24.63,
23.98, 18.28, 18.12, -4.16 (2), -5.20, -5.46; IR (film) 3354,
3257, 3117, 3058, 2955, 2931, 2885, 2858, 2361, 2256, 1712,
1696, 1683, 1471, 1390, 1327, 1269, 1118, 1065; HRMS (EI)
m/z calcd for C25H50N3O8SSi2 (M + H+) 608.28572, found
608.28603.
3′-R-(N-Hexyl Meth ylen esu lfon a m id e)-2′,5′-bis-(O-ter t-
bu tyld im eth ylsilyl)-3′-â-h yd r oxy-u r id in e (41). Procedure
B; eluent ) 10% EtOAc/DCM; 11 (100 mg, 0.2126 mmol) was
converted to 41 (131 mg, 0.2015 mmol); yield ) 95%; 1H NMR
(400 MHz, CDCl3) δ 9.60 (br s, 1 H), 7.79 (d, J ) 8.1 Hz, 1 H),
5.64 (s, 1H), 5.58 (d, J ) 8.1 Hz, 1 H), 5.17 (t, J ) 5.6 Hz, 1
H), 5.04 (s, 1 H), 4.42 (s, 1 H), 4.23 (A of ABX, J AB ) 11.5 Hz,
J AX ) 4.3 Hz, 1 H), 4.13 (B of ABX, J BA ) 11.5 Hz, J BX ) 2.1
Hz, 1 H), 4.04 (m, 1 H), 3.54 (A of AB, J AB ) 14.9 Hz, 1 H),
3.35 (B of AB, J BA ) 14.9 Hz, 1 H), 3.04 (m, 2 H), 1.52 (m, 2
H), 1.28 (m, 2 H), 0.92 (s, 9 H), 0.90 (s, 9 H), 0.86 (t, J ) 6.4
Hz, 3 H), 0.23 (s, 3 H), 0.23 (s, 3 H), 0.15 (s, 3 H), 0.14 (s, 3 H);
13C NMR (100 MHz, CDCl3) δ 164.32, 150.19, 141.10, 100.53,
91.28, 82.66, 81.55, 79.89, 77.52, 61.68, 51.05, 43.53, 31.43,
30.17, 26.39, 26.12, 25.87, 22.63, 18.22, 14.12, -4.14, -5.20,
-5.48, -5.54; IR (film) 3319, 3113, 3050, 2957, 2931, 2887,
2859, 2253, 1712, 1695, 1471, 1424, 1391, 1363, 1329, 1269,
1117; HRMS (EI) m/z calcd for C28H56N3O8SSi2 (M + H+)
650.33267, found 650.33474.
5′-(N-Ben zyl Meth ylen esu lfon a m id e)-2′, 3′-isop r op y-
lid en e-u r id in e (29). Procedure A; eluent ) 2:1 EtOAc/Hex;
28 (116 mg, 0.2821 mmol) was converted to 29 (135 mg, 0.2889
mmol); yield = 70%; (The product was obtained as an in-
separable mixture of diastereomers: dr ) 76:24. The identity
was confirmed by HRMS.) HRMS (FAB) m/z calcd for
C
20H25N3O8SNa (M + Na+ ) 490.12604, found 490.12600.
(1S)-(3-Ben zylsu lfa m oyl-2-h yd r oxy-1-m eth yl-p r op yl)-
ca r ba m ic Acid 9H-flu or en -9-ylm eth yl Ester (31). Proce-
dure A; eluent ) 10% EtOAc/ DCM; 30 (100 mg, 0.3398 mmol)
was converted to 31 (110 mg, 0.2303 mmol); yield ) 68%; (The
product was obtained as an inseparable mixture of diastere-
omers: dr ) 69:31 and 62:38 for two separate runs. The
identity was confirmed by HRMS.) HRMS (FAB) m/z calcd for
C
26H28N2O5SNa (M + Na+ ) 503.16170, found 503.16159.
N-Ben zyl-7-cyan o-2-h ydr oxy-h eptan esu lfon am ide (33).
Procedure A; eluent ) Et2O; 32 (25 mg, 0.1997 mmol) was
1
converted to 33 (57 mg, 0.1836 mmol); yield ) 92%; H NMR
(400 MHz, CDCl3) δ 7.29 (m, 5H), 4.90 (br s, 1 H), 4.24 (d, J )
5.4 Hz, 2 H), 4.03 (m, 1 H), 3.01 (br s, 1 H), 2.95 (A of ABX,
J AB ) 14.4 Hz, J AX ) 9.8 Hz, 1 H), 2.88 (B of ABX, J BA ) 14.4
Hz, J BX ) 1.6 Hz, 1 H), 2.28 (t, J ) 7.0 Hz, 2 H), 1.58 (p, J )
7.1 Hz, 2 H), 1.44-1.26 (m, 6 H); 13C NMR (100 MHz, CDCl3)
δ 136.76, 129.09, 128.34, 128.25, 119.91, 66.74, 58.74, 47.38,
36.17, 28.41, 25.28, 24.37, 17.20; IR (film) 3424, 3148, 3027,
2944, 2922, 2895, 2852, 2362, 2241, 1455, 1420, 1294, 1130,
1088; HRMS (CH4) m/z calcd for C15H22N2O3SNa (M + Na+)
333.12492, found 333.12402.
3′-R-(N-P h en yl Meth ylen esu lfon a m ide)-2′,5′-bis-(O-ter t-
bu tyld im eth ylsilyl)-3′-â-h yd r oxy-u r id in e (43). Procedure
B; eluent ) 20% EtOAc/DCM; 11 (100 mg, 0.2126 mmol) was
converted to 43 (131 mg, 0.2041 mmol); yield ) 96%; 1H NMR
(400 MHz, CDCl3) δ 9.44 (br s, 1 H), 8.08 (br s, 1 H), 7.83 (d,
J ) 8.1 Hz, 1 H), 7.29-7.08 (m, 5H), 5.62 (s, 1 H), 5.55 (d, J
) 8.1 Hz, 1 H), 5.03 (s, 1 H), 4.53 (s, 1 H), 4.14 (A of ABX, J AB
) 11.9 Hz, J AX ) 4.0 Hz, 1 H), 3.95 (B of ABX, J BA ) 11.9 Hz,
J BX ) 0 Hz, 1 H), 3.91 (m, 1 H), 3.54 (A of AB, J AB ) 15.0 Hz,
1 H), 3.35 (B of AB, J BA ) 15.0 Hz, 1 H), 0.86 (s, 9 H), 0.83 (s,
9 H), 0.24 (s, 3 H), 0.24 (s, 3 H), 0.02 (s, 3 H), -0.02 (s, 3 H);
13C NMR (100 MHz, CDCl3) δ 164.70, 149.79, 141.54, 137.37,
129.75, 125.17, 120.64, 100.03, 91.82, 82.65, 81.39, 80.34,
61.47, 49.64, 26.10, 25.92, 18.23, 18.09, -4.08, -5.28, -5.64
(2); IR (film) 3381, 3265, 3109, 3054, 2955, 2930, 2885, 2858,
2254, 1712, 1700, 1683, 1600, 1497, 1471, 1404, 1390, 1348,
1269, 1152, 1119; HRMS (EI) m/z calcd for C28H48N3O8SSi2 (M
+ H+) 642.27007, found 642.26933.
3′-R-(N-Meth yl Meth ylen esu lfon a m id e)-2′,5′-bis-(O-ter t-
bu tyld im eth ylsilyl)-3′-â-h yd r oxy-u r id in e (35). Procedure
B; eluent ) 20% EtOAc/DCM; 11 (100 mg, 0.2126 mmol) was
converted to 35 (108 mg, 0.1863 mmol); yield ) 88%; 1H NMR
(400 MHz, CDCl3) δ 9.32 (br s, 1 H), 7.79 (d, J ) 8.2 Hz, 1 H),
5.65 (s, 1 H), 5.58 (dd, J ) 7.94, 1.83 Hz, 1 H), 5.49 (q, J )
5.49, 1 H), 5.10 (s, 1 H), 4.42 (s, 1 H), 4.25 (A of ABX, J AB
)
11.6 Hz, J AX ) 3.8 Hz, 1 H), 4.14 (B of ABX, J BA ) 11.6 Hz,
J BX ) 2.12 Hz, 1 H), 4.05 (m, 1 H), 3.54 (A of AB, J AB ) 14.8
Hz, 1 H), 3.36 (B of AB, J BA ) 14.8 Hz, 1 H), 2.77 (d, J ) 14.8
Hz, 1 H), 0.93 (s, 9 H), 0.91 (s, 9 H), 0.24 (s, 3 H), 0.23 (s, 3 H),
0.16(s, 3 H), 0.15 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 164.17,
150.15, 141.04, 100.59, 91.26, 82.52, 81.52, 79.89, 61.81, 49.52,
29.48, 26.12, 25.86, 18.23, 18.15, -4.14, -5.17, -5.46, -5.55;
IR (film) 3376, 3265, 3142, 2949, 2929, 2899, 2859, 1717, 1683,
1464, 1390, 1320, 1268, 1125, 1046; HRMS (EI) m/z calcd for
C23H46N3O8SSi2 (M + H+) 580.25442, found 580.25677.
3′-R-(N-Eth yl Meth ylen esu lfon a m id e)-2′,5′-bis-(O-ter t-
bu tyld im eth ylsilyl)-3′-â-h yd r oxy-u r id in e (37). Procedure
B; eluent ) 20% EtOAc/DCM; 11 (100 mg, 0.2126 mmol) was
3′-R-(N-Ben zh yd r yl Meth ylen esu lfon a m id e)-2′,5′-bis-
(O-ter t-bu tyldim eth ylsilyl)-3′-â-h ydr oxy-u r idin e (45). Pro-
5308 J . Org. Chem., Vol. 68, No. 13, 2003

Reactions of Sulfonamide Dianions
cedure B; eluent ) 10% EtOAc/DCM; 11 (100 mg, 0.2126
mmol) was converted to 45 (150 mg, 0.2050 mmol); yield )
79.55, 78.10, 73.31, 68.40, 54.81, 26.93, 26.79, 26.64, 25.38;
IR (film) 3382, 3299, 3264, 2989, 2934, 2883, 1375, 1344, 1272,
1217, 1160, 1071; HRMS (EI) m/z calcd for C13H24NO8S (M +
H+) 354.12226, found 354.12147.
1
96%; H NMR (400 MHz, CDCl3) δ 9.33 (br s, 1 H), 7.83 (d, J
) 8.1 Hz, 1 H), 7.35-7.24 (m, 10H), 5.79 (s, 1 H), 5.59 (s, 1
H), 5.57 (d, J ) 8.1 Hz, 1 H), 4.98 (s, 1 H), 4.26 (s, 1 H), 4.05
(A of AB, J AB ) 11.8 Hz, 1 H), 3.99 (B of AB, J BA ) 11.8 Hz, 1
H), 3.90 (br s, 1 H), 3.40 (A of AB, J AB ) 14.7 Hz, 1 H), 3.05 (B
of AB, J BA ) 14.7 Hz, 1 H), 0.89 (s, 9 H), 0.84 (s, 9 H), 0.17 (s,
3 H), 0.11 (s, 3 H), 0.10 (s, 6 H); 13C NMR (100 MHz, CDCl3)
δ 164.08, 150.32, 141.42, 141.01, 140.93, 129.07, 128.88,
128.09, 127.97, 127.69, 127.43, 100.86, 91.26, 83.01, 82.08,
80.10, 61.79, 61.32, 54.89, 26.06, 25.97, 18.32, 18.06, -4.16,
-5.20, -5.30, -5.40; IR (film) 3463, 3346, 3262, 3063, 3027,
2954, 2929, 2884, 2857, 1708, 1695, 1680, 1471, 1390, 1326,
1268, 11118, 1062; HRMS (FAB) m/z calcd for C35H53N3O8SSi2-
Na (M + Na+) 754.29900, found 754.29575.
2-(N-Ben zyl Meth ylen esu lfon a m id e)-2-h yd r oxy-1-p h e-
n ylp r op a n e (48). Procedure A; eluent ) 2:1 Et2O/Hex; 1.3
equiv of CeCl3, 1.2 equiv of N-benzyl methanesulfonamide, and
2.4 equiv of BuLi were used; CD3CO2D was used in place of
AcOH; 47 (54 mg, 0.4025 mmol) was converted to 48 (93 mg,
0.2912 mmol); yield ) 72%; 1H NMR (400 MHz, CDCl3) δ 7.35-
7.17 (m, 10H), 5.29 (t, J ) 6.1 Hz, 1 H), 4.22 (A of ABX, J AB
)
14.3 Hz, J AX ) 6.3 Hz, 1 H), 4.18 (B of ABX, J BA ) 14.3 Hz,
J BX ) 6.5 Hz, 1 H), 3.19 (br s, 1 H), 3.11 (A of AB, J AB ) 14.3
Hz, 1 H), 3.02 (B of AB, J BA ) 14.3 Hz, 1 H), 2.85 (br s, 2 H),
1.35 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 136.73, 136.10,
130.77, 128.93, 128.42, 128.16, 128.13, 127.00, 71.45, 61.06,
48.37, 47.30, 27.13; IR (film) 3470, 3284, 3147, 3063, 3033,
2981, 2921, 1454, 1309, 1269, 1152, 1139, 1087, 1068; HRMS
(CH4) m/z calcd for C10H14NO3S (M+ - C7H7) 228.06944, found
228.06982.
3-â-Meth ylen esu lfon am ide-1,2:5,6-di-O-isopr opyliden e-
R-D-a llofu r a n ose (46). Allofuranose 17 (10 mg, 0.02255 mmol)
was dissolved in EtOH (0.5 mL). Pearlman’s catalyst [Pd(OH)2,
6 mg] was added to the solution. The reaction was stirred
under an atmosphere of hydrogen gas at 22 lbs/in2 for 2 days
at which time the reaction was filtrated through Celite 545.
Purification by flash-column chromatography (ether) provided
Su p p or tin g In for m a tion Ava ila ble: Complete experi-
mental procedures for the synthesis of 16, 19, 21, 28, 32, 34,
36, 38, 40, 42, 44, N-benzyl methanesulfonamide, and N-
benzyl deuteriomethanesulfonamide and appropriate spectral
data, including 1H and 13C NMR, IR, MS, HMQC, and NOESY
diagrams. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
46 (7.5 mg, 0.02122 mmol) as a white solid; yield ) 94%; H
NMR (400 MHz, CDCl3) δ 5.79 (d, J ) 3.9 Hz, 1 H), 5.23 (d, J
) 3.9 Hz, 1 H), 5.01 (br s, 2 H), 4.13 (A of AB, J AB ) 8.5 Hz,
J AX ) 6.1 Hz, 1 H), 3.98 (m, 1 H), 3.92 (B of ABX, J BA ) 8.5
Hz, J BX ) 4.8 Hz, 1 H), 3.85 (A of AB, J AB ) 14.9 Hz, 1 H),
3.75 (d, 8.7 Hz, 1 H), 3.39 (s, 1 H), 3.19 (B of AB, J BA ) 14.9
Hz, 1 H), 1.60 (s, 3 H), 1.46 (s, 3 H), 1.39 (s, 3 H), 1.37 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 113.18, 110.47, 103.74, 83.01,
J O034001W
J . Org. Chem, Vol. 68, No. 13, 2003 5309