New routes to N-alkylated cyclic sulfamidates

Article abstract of DOI:10.1021/jo0157019

BOC- and dibenzosuberyl-protected chiral and hindered cyclic sulfamidates ([1,2,3]-oxathiazolidine-2,2-dioxides) were synthesized and subsequently deprotected using trifluoroacetic acid. The resulting crystalline sulfamidates were then used in several alk

Full text of DOI:10.1021/jo0157019

New Rou tes to N-Alk yla ted Cyclic Su lfa m id a tes
J effrey J . Posakony,†,‡ J ohn R. Grierson, and Timothy J . Tewson*
†
,§
University of Iowa, PET Imaging Center, Department of Radiology, 0911Z J PP, 200 Hawkins Drive,
Iowa City, Iowa, 52242-1007 and University of Washington Medical Center, Imaging Research
Laboratory; Box 356004, 1959 NE Pacific Street, Seattle, Washington 98195
timothy-tewson@uiowa.edu
Received April 20, 2001
BOC- and dibenzosuberyl-protected chiral and hindered cyclic sulfamidates ([1,2,3]-oxathiazolidine-
2
,2-dioxides) were synthesized and subsequently deprotected using trifluoroacetic acid. The resulting
crystalline sulfamidates were then used in several alkylation reactions involving benzyl bromide
and alcohols in a versatile route to cyclic sulfamidates with differing N-alkyl substituents.
In tr od u ction
dioxides, produced from sulfamidates with easily removed
N-protecting groups (BOC and dibenzosuberyl (Sub)).
5
In general, cyclic sulfamidates ([1,2,3]-oxathiazolidine-
,2-dioxides) are reactive alkylating reagents which can
We have used 15 and 16 in alkylation reactions with
benzyl bromide, and 3-phenylpropanol as examples of
general syntheses with conditions that may be applied
to a variety of substrates in convergent syntheses of cyclic
sulfamidates previously not accessible via conventional
procedures.
2
be used to convert amino alcohols into a diverse set of
substituted amines and amino acids.1 Their use is
limited, however, as each substrate must be uniquely
synthesized from its corresponding amino alcohol under
,2
conditions (e.g., treatment with SOCl
2 4
and RuO ) that
are incompatible with many sensitive molecules.
Resu lts a n d Discu ssion
Cyclic sulfamidates have played an integral part in our
development of subtype-selective â-adrenergic ligands for
noninvasive, in-vivo imaging of the heart using positron
emission tomography (PET).3 In the interest of improv-
ing our â-adrenergic ligand syntheses, we sought a route
to N-deprotected cyclic sulfamidates which could then be
reacted with the ligand precursor in a convergent manner
with the aim to eliminate several steps in the ligand
synthesis with 18F. This would be a strategic advantage,
given the 110 min half-life of fluorine-18. We describe
here the syntheses of two cyclic sulfamidates, (R)-4-
methyl- (15) and 4,4-dimethyl- (16) oxathiazolidine-2,2-
Cyclic Su lfa m id a te Syn th eses. The cyclic sulfamid-
ites ([1,2,3]-oxathiazolidine-2-oxides), which are precur-
sors to the sulfamidates, are typically prepared from
,4
N-protected amino alcohols and SOCl
2
in low polarity
solvents at low temperature. Attempts to synthesize
2
carbamate-protected sulfamidites 5 and 7 in CH Cl ,
2,4
2
however, resulted in only fair yields (40-50%) and
required high dilution conditions (ca. 5 mM of 1 or 2, see
Supporting Information) for success. The acyclic sulfite
diesters 6 and 8 were the side products of these reactions,
and their relative amounts increased in more concen-
3
trated reactions. A change of solvent to CH CN permitted
higher concentrations to be used (ca. 0.48 M) and only
limited amounts of 6 or 8 (Scheme 1) were produced. The
carbamate nitrogens of 1 and 2 are expected to be less
nucleophilic than their N-alkyl counterparts, and it
*
To whom correspondence should be addressed. Ph: 319-356-8533.
Fax: 319-353-6512.
†
University of Washington Medical Center.
University of Iowa.
Present address: Fred Hutchinson Cancer Research Center, P.O.
§
‡
3
appears that the more polar nature of CH CN facilitates
Box 19024, Seattle, WA 98109-1024.
1) Some recent examples include: Lyle, T. A.; Magill, C. A.;
the nucleophilic reactions of the carbamates 1 and 2.
An optimized synthesis of the N-BOC sulfamidites (5,
7) was developed using amino alcohol (1) as a model
amino alcohol substrate. Best results were obtained by
(
Pitzenberger, S. M. J . Am. Chem. Soc. 1987, 109, 7890-7891. Okuda,
M.; Tomioka, K. Tetrahedron Lett. 1994, 35, 4584-4586. Stiasny, H.
C. Synthesis 1996, 259-264. Aguilera, B.; Fernandez-Mayoralas, A.;
J aramillo, C. Tetrahedron 1997, 53, 5863-5876. Zubovics, A.; Toldy,
L.; Varro, A.; Rabloczky, G.; K u¨ rthy, M.; Dvortsak, P.; J erkovich, G.;
Tomori, E. Eur. J . Med. Chem. 1986, 21, 370-378. Kim, B. M.; So, S.
M. Tetrahedron Lett. 1998, 39, 5381-5384. Ok, D.; Fisher, M. H.;
Wyvratt, M. J .; Meinke, P. T. Tetrahedron Lett. 1999, 40, 3831-3834.
Boulton, L. T.; Stock, H. T.; Raphy, J .; Horwell, D. C. J . Chem. Soc.,
Perkin Trans. 1 1999, 1421-1429. Atfani, M.; Wei, L.; Lubell, W. D.
Org. Lett. 2001, 3, 2965-2968. Wei, L.; Lubell, W. D. Can. J . Chem.
rapid addition of 1, as a solution in CH
3
CN, to a cold (-40
CN, and then
°
C) solution of SOCl (2.5 equiv) in CH
2
3
adding pyridine (5 equiv) to neutralize HCl produced in
the reaction (Scheme 1). Pyridinium hydrochloride was
conveniently removed by precipitation with EtOAc and
subsequent filtration. The product was simply purified
by filtration over silica, and it was convenient to use this
2
001, 79, 94-104.
2) For a review of cyclic sulfates and sulfamidates, see Lohray, B.
(
B.; Bhushan, V. In Advances in Heterocyclic Chemistry; Katritzky, A.
R., Ed.; Academic Press: San Diego, 1997; Vol. 68, pp 89-180.
isolated sulfamidite directly in the subsequent RuO
oxidation.
4
(3) Posakony, J . J .; Tewson, T. J . J . Labelled Compd. Radiopharm.
1
999, 42, S527-529.
(
4) Posakony, J . J .; Tewson, T. J . Synthesis, in press.
(5) Pless, J . Helv. Chim. Acta 1976, 59, 499-512.
1
0.1021/jo0157019 CCC: $22.00 © 2002 American Chemical Society
5
164
J . Org. Chem. 2002, 67, 5164-5169
Published on Web 06/29/2002

N-Alkylated Cyclic Sulfamidates
SCHEME 1
Under these conditions, the chlorosulfite ester of 1 (1a )
is the expected initial product of the reaction, which
would be converted to 5 after adding pyridine. The
presence of 1a was indicated by TLC which showed an
intermediate product (tentatively assigned as 1a or a
hydrolysis product thereof on the TLC plate) and a trace
of 5 before pyridine addition. After adding pyridine, large
quantities of 5 were observed, whereas the intermediate
was absent. Sulfite 6 was present both before and after
The dibenzosuberyl-protected sulfamidates 13 and 14
were synthesized from the corresponding protected amino
alcohols 3 and 4 under the same conditions used for
our previous synthesis of N-benzyl cyclic sulfamidates.
The overall yields of 13 and 14 were approximately
70%.
4
Su lfa m id a te Dep r otection . The utility of N-depro-
tected cyclic sulfamidates as general reagents is dictated
largely by their accessibility. In our hands, attempts at
synthesizing these unprotected sulfamidates using un-
protected amino alcohols with conventional cyclic sulfa-
midite/sulfamidate procedures were unsuccessful. Thus,
it encouraged us to develop a strategy to prepare cyclic
sulfamidates with protecting groups that are easily
the pyridine addition. Using less SOCl
2
or conducting the
reaction at rt led to increased production of unwanted 6.
5
removed by acid, such as BOC and dibenzosuberyl (Sub).
The trityl group was also investigated, but proved to be
incompatible with RuO .
4
There are only a few reported examples of unprotected
cyclic sulfamidates, one being [1,2,3]-oxathiazolidine-2,2-
dioxide (21) described by Corral et al.; however, few
We determined the overall yields of compounds 5 and
, and 7 and 8, using small-scale reactions. Compounds
and 6 (from 1) were isolated in 76% and 9% yields,
6
5
6
details were provided. Espino et al. recently described
the preparation of unprotected cyclic sulfamidates via Rh-
catalyzed oxidative cyclization of sulfamate esters, a
method that holds great promise for the synthesis of a
respectively, after chromatographic purification. In con-
trast, amino alcohol 2 yielded 7 in 95% yield, and no 8
was isolated. In the synthesis of 5, two products (assigned
as 5a and 5b) were separated by repeated column
chromatography. As expected for diastereomeric sulfa-
7
variety of cyclic sulfamidates. However, that method
appears unsuitable for the preparation of 15 and 16, in
part because of the bias to form oxathiazinanes (six-
membered cyclic sulfamidates) and a lack of enantiose-
lectivity given an achiral starting alcohol, a necessary
precursor to 15.
Deprotection of the BOC- and Sub-protected sulfami-
dates was readily accomplished at rt with an excess of
2 2
TFA in CH Cl (Scheme 1). Starting from 11 and 12,
6
midites, compounds 5a and 5b exhibited identical mass
1
spectra, but different H NMR spectra, and each yielded
1
1 when treated with RuO
of 5 in CH Cl afforded exclusively 5a (41% yield,
Supporting Information). The RuO oxidations of the
crude sulfamidites 5 and 7 yielded sulfamidates 11 and
2 in 78 and 87% overall yields, respectively.
4
. Interestingly, the synthesis
2
2
4
1
sulfamidates 15 and 16 were isolated in 86-90% yield.
(
6) Corral, C.; Lissavetzky, J .; Manzanares, I.; Darias, V.; Exp o´ sito-
Orta, M. A.; Conde, J . A. M.; S a´ nchez-Mateo, C. C. Bioorg. Med. Chem.
999, 7, 1349-1359.
(7) Espino, C. G.; When, P. M.; Chow, J .; Du Bois, J . J . Am. Chem.
Soc. 2001, 123, 6935-6936.
1
J . Org. Chem, Vol. 67, No. 15, 2002 5165

Posakony et al.
SCHEME 2
from a gradual loss of the starting sulfamidate. These
phase transfer-catalyzed conditions appear to be limited
to very reactive alkylating reagents such as benzyl
bromide.
Other attempts to deprotonate and alkylate sulfami-
date 15 with alkyl bromides, iodides and mesylates in
1
DMF or DMSO were also unsuccessful. H NMR experi-
ments demonstrated upfield shifts for sulfamidate CH
and CH signals and loss of the N-H signal when 15 was
2
treated with DBU. This was consistent with the forma-
tion of the anion of 15 in solution. Sulfamidate 15 could
also be deprotonated by KO-t-Bu, aqueous K
lithium bis-trimethylsilylamide, whereas Et
induce such changes in the H NMR spectra.
2
CO
N did not
3
, and
3
1
Deprotonated 15 reacted with benzyl bromide to form
7 in ∼50% yield, but no alkylation occurred when
1
deprotonated 15 was mixed with 1-bromo-3-phenylpro-
pane, 3-phenylpropyl methanesulfonate, or 1-iodo-2-
phenylethane. By 1H NMR, the alkyl halide/mesylate
signals remained unchanged, but a gradual loss of
deprotonated 15 was observed.
2 2
Addition of TFA to a solution of 13 (or 14) in CH Cl
The Mitsunobu reaction proved more useful for N-
alkylating 15 and 17. For example, 3-phenylpropanol and
yielded an orange/red solution, presumably due to the
presence of the dibenzosuberyl cation, and TLC indicated
the presence of 15 (or 16) along with materials with
1
5 and 16 yielded the 3-(3-phenylpropyl)-substituted
sulfamidates 19 and 20, in 43 and 89% yields, respec-
tively. The most favorable conditions used an excess of
f
higher R values. If the solvent was removed from this
orange/red solution, 13 (or 14) reformed, suggesting an
equilibrium between the free sulfamidate and 13 (or 14).
This unwanted process was minimized by adding MeOH
and then base after solvent evaporation. It appears that
the dibenzosuberyl cation was captured by MeOH and
diisopropyl azodicarboxylate (DIAD), PPh
hol (1.6 equiv each) in CH CN or THF.
3
and the alco-
3
To investigate the relatively low yield of 19, several
1
control reactions were conducted and monitored by H
NMR and TLC. The sulfamidates 15 and 17 (a model
5
-methoxydibenzosuberane was formed. Sulfamidate 15
substrate for 19) were not inherently sensitive to PPh
or DIAD, as shown by experiments in CD CN over a
period of 30 min. However, when DIAD (1 equiv) was
added portionwise to a solution of PPh and sulfamidate
CN, H NMR and TLC indicated that 15 was
3
was then isolated by chromatography in 32% yield (55%
yield of recovered 13). In contrast, 16 was isolated in high
yield (87%) without resorting to chromatography.
Alk yla tion Rea ction s. The challenges inherent in the
alkylation of sulfamidates 15 or 16 are not insignificant,
because the products of these reactions are themselves
potent electrophiles. The unprotected cyclic sulfamidates
3
3
1
1
5 in CD
being consumed and the quality of the H NMR spectrum
deteriorated. Similar results were obtained when PPh
3
1
3
was added to a solution of 17 and DIAD. Thus, the low
yield of 19 was presumably a result of 15 and/or 19
reacting with the PPh /DIAD adduct formed in-situ to
3
form ring-opened products. In contrast, the reactive
carbon centers on sulfamidates 16 and 20 are less
accessible, and this may have curtailed unwanted side-
reactions.
(
N-H forms) are relatively poor electrophiles compared
7
to their N-substituted counterparts. In addition, depro-
tonated 15 and 16 are also quite resistant to nucleophilic
attack, as shown by the stability of these sulfamidates
in aqueous NaOH (Experimental Section). Thus, we
sought conditions mild enough to preserve the N-alky-
lated products but under which the sulfamidate would
be deprotonated and, as such, be able to act as a
nucleophile (Scheme 2).
Con clu sion
Good results were obtained in phase-transfer-catalyzed
reactions. Sulfamidates 15 and 16 reacted with an excess
Routes to N-alkyl cyclic sulfamidates were developed
that should be applicable to the synthesis of previously
inaccessible cyclic sulfamidates. Cyclic sulfamidates with
BOC- and dibenzosuberyl protecting groups were syn-
thesized in good overall yield from their corresponding
amino alcohols. These protecting groups were conve-
niently removed from these sulfamidate derivatives using
TFA and sulfamidates 15 and 16 were isolated as stable,
crystalline compounds. A phase transfer-catalyzed alky-
lation of 15 and 16 was developed, but this was useful
only with benzyl bromide. The Mitsunobu reaction was
a practical alternative for alkylation of 15 and 16 with a
primary alcohol to yield 19 and 20.
(
(
4 equiv) of benzyl bromide under optimized conditions
5 mol % BnBu NCl and aqueous NaOH) to provide the
3
4
N-benzylated products, 17 and 18 in 76 and 93% yields,
respectively. TLC analysis of the organic and aqueous
phases revealed that the sulfamidate (15 or 16) was
transferred to the aqueous phase within minutes of
addition, presumably present as its deprotonated anion.
The yields were lower when less than 4 equiv of benzyl
bromide was used.
When these same phase-transfer catalyzed conditions
were applied to the less reactive 1-bromo-3-phenylpro-
8
pane or 3-phenylpropyl methanesulfonate, no reaction
Exp er im en ta l Section
was observed even after several days of stirring, apart
Low resolution mass spectrometry was performed using
1
(8) Weibull, B. Acta Chem. Scand. 1995, 49, 207-216.
electrospray ionization. H NMR coupling constants are rounded
5
166 J . Org. Chem., Vol. 67, No. 15, 2002

N-Alkylated Cyclic Sulfamidates
to the nearest 0.5 Hz. Elemental analyses were performed by
Galbraith Laboratories, Knoxville, TN. Prior to elemental
analysis, samples were dried under high vacuum at 40-50 °C.
Flash column chromatography was performed using silica gel
acetone) and a trace of 5. Dry pyridine (23 mL) was then added,
and TLC indicated larger quantities of 5 (R ) 0.7). The
f
mixture was then allowed to warm to room temperature. The
solvent volume was reduced to ca. 75 mL, EtOAc (100 mL)
was added, the resulting precipitate was filtered off, and the
filtrate was concentrated to a residual oil. This material was
filtered through a plug of silica (4 cm × 6 cm dia.), eluting
with EtOAc/hexanes (1:1, 400 mL). Solvent removal afforded
crude 5 as an oil (11.8 g) which also contained a small amount
of the corresponding sulfite 6. Crude 5 was used directly in
(Merck, grade 9385, 230-400 mesh). Analytical TLC was
performed using silica gel Analtech GF plates (0.25 mm);
preparative TLC was performed using silica gel Analtech GF
plates (1 mm). Product visualization on TLC was performed
using UV light or by spraying the plate with a sulfuric acid
reagent solution (1:1 v/v MeOH/concentrated H
2 4
SO or 0.25 g
K
2
Cr in 7 M H SO ) followed by heating. Unless otherwise
2
O
7
2
4
4
the RuO oxidation, described below.
noted, reagents were purchased from Aldrich Chemical Co.
Solvents were ACS reagent grade or better and anhydrous
solvents (Aldrich) were used as received unless otherwise
Small scale (× 0.1) reactions were performed and the
products isolated by chromatography on silica (50:1 to 20:1
CH Cl :acetone) to accurately determine the yields of 5 and 6
2
2
indicated. CH
activated, crushed 3 Å molecular sieves.
-((ter t-Bu t yloxyca r b on yl)a m in o)-2-m et h ylp r op a n -1-
3
CN and pyridine were dried by storing over
in these reactions. Sulfite 6 (0.21 g, 9.3%) was isolated as a
white solid and then recrystallized from CH Cl :hexanes for
2
2
2
analysis: mp 97-98 °C; R
f
) 0.25 (50:1 CH
2
Cl
2
:acetone); MS
9
1
ol (2). Reaction conditions described by Caputo et al., used
m/z: 397.1 (5, M + 1), 419.1 (100, M + 1); H NMR (CDCl
1.20 and 1.21 (two d, J ) 6.5 Hz, 6H), 1.45 (s, 18H), 3.9-4.1
(m, 6H), 4.7 (s br, 2H). Anal. Calcd for C16 S: C, 48.46;
3
)
to synthesize other BOC-amino alcohols, were adapted to
synthesize 2. Briefly, Et
-aminopropan-1-ol (1 mL, 10 mmol) were dissolved in dry
THF (30 mL), and the mixture was cooled to 0 °C. BOC O (2.3
3
N (1.4 mL, 10 mmol) and 2-methyl-
32 2 7
H N O
2
H, 8.14; N, 7.06. Found: C, 48.39; H, 8.26; N, 7.06. Sulfamidite
5 (0.955 g, 76%) was isolated as an oily mixture of 5a and 5b
(1.45:1 ratio), which were later separated by repeated chro-
2
g, 10 mmol) was added, and then the cooling bath was
removed. After stirring for 90 min at rt, the solvent was
removed. Water (50 mL) was added to the residue, and the
mixture was extracted with EtOAc (100 mL). The organic
matography (100:1 CH
respectively). 5a and 5b: MS m/z: 244 (25, M + Na), 239 (100,
M + NH ), 222 (20, M + H), 197.9 (20, M + K - C ), 183
(20, M + Na - C ). 5a : H NMR
(CDCl ) 1.28 (d, J ) 6.5 Hz, 3H), 1.52 (s, 9H), 4.30 (m, 2H),
5.03 (dd, J )9 Hz, J )5.5 Hz, 1H). Anal. Calcd for C
NO S: C, 43.44; H, 6.84; N, 6.33. Found: C, 43.51; H, 7.11;
N, 6.35. 5b: H NMR (CDCl
9H), 4.05 (m, 1H), 4.66 (dd, J
)7 Hz). Anal. Found: C, 43.39; H, 7.06; N, 6.29.
3-(ter t-Bu tyloxyca r bon yl)-4,4-d im eth yl-[1,2,3]-oxa th ia -
2 2 f
Cl :acetone, R ) 0.39 and 0.45,
4
4 8
H
1
extract was dried (Na
2
SO
4
), and the solvent was removed. The
4
H
8
4 8
), 165.9 (M + H - C H
product was recrystallized from EtOAc/heptane to yield 1.55
3
1
0
g (8.2 mmol, 82%): mp 59.5-60.5 °C (lit. 57-60 °C); R
.65 (CH Cl
M + H - C
f
)
1
2
8 15
H -
0
(
3
5
2
2
:acetone 20:1); MS m/z: 190.3 (100, M + H), 134.2
4
1
1
4
H
8
); H NMR (CD
.44 (s br, 3H), 5.15 (s br, 1H). Anal. Calcd for C
7.11; H, 10.12; N, 7.40. Found: C, 57.02; H, 10.30; N, 7.21.
R)-2-((5-d iben zosu ber yl)a m in o)p r op a n -1-ol (3). A solu-
tion of 5-chlorodibenzosuberane (0.59 g, 2.6 mmol) in dry
CH CN (10 mL) was added dropwise over 30 min to a solution
of (R)-2-aminopropan-1-ol (0.2 mL, 2.6 mmol) and Et N (0.37
mL, 2.7 mmol) in dry CH CN (15 mL). After the addition was
3
CN) 1.20 (s, 6H), 1.41 (s, 9H),
3
) 1.48 (d, J ) 6 Hz, 3H), 1.51 (s,
)J )9 Hz), 4.76 (dd, J )9 Hz,
9
H
19NO
3
: C,
1
2
1
J
2
(
zolid in e-2-oxid e (7). Sulfamidate 7 was synthesized with the
same procedure used to prepare 5. When carried out using 6
g of 2 (31.7 mmol), 7.1 g of crude 7 was isolated, which
contained only a trace of 8 by TLC. This crude product was
3
3
3
complete, the solution was stirred for 30 min, and then the
solvent was removed. The resulting product residue was
chromatographed on silica gel (1:1 hexanes:EtOAc) to yield two
used directly in the RuO oxidation step to prepare (12). The
4
reaction was also carried out using 1 g (5.3 mmol) of 2 which
yielded pure 7 (1.18 g, 95%) as an oil after column chroma-
tography: R ) 0.75, CH Cl :acetone 50:1; MS m/z: 274.1 (10,
products. The more mobile product (R
was identified as the O- and N-bis(dibenzosuberyl)-protected
amino alcohol and was discarded. Compound 3 (R
f
) 0.76; 0.19 g, 16%)
f
2
2
M + K), 258.1 (100, M + Na), 253.1 (M + NH ), 236.1 (M +
4
1
f
) 0.5, 0.4
H), 180.1 (40, M + H - C H ); H NMR (CDCl ) 1.40 (s, 3H),
4
8
3
g, 58%) was isolated as a colorless oil which solidified over
1.515 (s, 9H), 1.59 (s, 3H), 4.33 (d, 1H, J ) 9 Hz), 4.81 (d, 1H,
J ) 9 Hz). Anal. Calcd for C H NO S: C, 45.94; H, 7.28; N,
several days: mp 69.5-70.5 °C; MS m/z: 268.1 (10, M + 1),
9
17
4
+
1
1
2
(
)
8
93 (100, C15
H
13 ); H NMR (CDCl
3
) 1.11 (d, J ) 6.5 Hz, 3H),
5.95. Found: C, 46.01; H, 7.52; N, 5.91.
.0 (s br, 2H), 2.7 (m, 1H), 2.9-3.1 (m, 2H), ABX spin system
(
R)-3-(5-Diben zosu ber yl)-4-m eth yl-[1,2,3]-oxa th ia zoli-
3.2 (dd, 1H), 3.45 (dd, 1H), 3.85 (m, 1H), J AB ) 10.5 Hz, J AX
4 Hz, J BX ) 7 Hz), 3.55 (m, 1H), 4.95 (s, 1H), 7.1-7.3 (m,
H). Anal. Calcd for C18 21NO: C, 80.85; H, 7.92; N, 5.24.
Found: C, 80.71; H, 8.07; N, 5.24.
-((5-Diben zosu ber yl)a m in o)-2-m eth ylp r op a n -1-ol (4).
The synthetic procedure for preparing 3 was applied to
-amino-2-methylpropan-1-ol, but chromatography was per-
formed using hexanes/EtOAc (3:2) to afford 4 (70%) as a
d in e-2-oxid e (9). Sulfamidite 9 was synthesized using the
4
same conditions described for the N-benzyl sulfamidites. The
H
product was purified by flash chromatography (EtOAc:hexanes
1
:1) to afford pure 9 (82%) as a colorless oil which solidified
over several days: mp 105-111 °C; MS m/z: 193.1 (75,
C H H NMR (CDCl ): 0.71 (d), 1.26
2
+
1
1
5
13
), 336.1 (100, M + Na);
3
2
(d), 2.8 (m), 3.0 (m), 3.4 (m), 3.7 (m), 3.95 (m), 4.1 (m), 4.2 (m),
4.55 (d), 5.05 (dd), 5.17 (two s). Anal. Calcd for C H NO S:
1
8
19
2
+
colorless oil: MS m/z: 193 (100, C15
H
13 ), 282.1 (15, M + 1);
C, 68.98; H, 6.11; N, 4.47. Found: C, 68.87; H, 6.30; N, 4.46.
1
H NMR (CDCl
3
) 1.09 (s, 6H), 1.6 (s br, 2H), 2.95 (s br, 2H),
3
-(5-Diben zosu ber yl)-4,4-d im eth yl-[1,2,3]-oxa th ia zoli-
3
.17 (s, 2H), 3.8 (s br, 2H), 5.0 (s br, 1H), 7.1-7.3 (m, 8H).
d in e-2-oxid e (10). Sulfamidite 10 was synthesized using the
Compound 4 was used without further purification to synthe-
size 10.
4
same conditions described for the N-benzyl sulfamidites and
was purified by filtration through a plug of silica, eluted with
ether. Compound 10 was isolated in 88% yield: mp 110-139
(
R)-3-(ter t-Bu tyloxyca r bon yl)-4-m eth yl-[1,2,3]-oxa th ia -
zolid in e-2-oxid e (5). A solution of SOCl (10.4 mL, 143 mmol)
in dry CH CN (70 mL) under Ar was cooled to -40 °C, and
then (R)-2-((N-tert-butyloxycarbonyl)amino)propan-1-ol (1, 10
g, 57 mmol) in dry CH CN (50 mL) was added dropwise over
2 min. TLC indicated a new product (R ) 0.3; 10:1 CH Cl
+
2
°
C; MS m/z: 193 (100, C15
H
13 ), 350.1 (15, M + Na), 366.1 (10,
1
3
M + K); H NMR (CDCl
H), 3.85 (m, 1H), 4.05 (m, 1H), 4.23 (d, J ) 8.5 Hz, 2H), 4.77
d, J ) 8.5 Hz, 2H), 5.34 (s, 1H), 7.1-7.3 (m, 8H). Anal. Calcd
for C19 S: C, 69.71; H, 6.47; N, 4.28. Found: C, 69.88;
H, 6.74; N, 4.19.
Ru O Oxid a tion s. The RuO
) 1.01 (s, 3H), 1.27 (s, 3H), 2.9 (m,
3
9
2
(
3
1
f
2
2
:
H
21NO
2
(
9) Caputo, R.; Cassano, E.; Longobardo, L.; Palumbo, G. Tetrahe-
dron 1995, 51, 12337-12350.
10) Seki, T.; Nakao, T.; Masuda, T.; Hasumi, K.; Gotanda, K.;
4
4
oxidations were carried out
4,11
using the procedures described for N-benzyl sulfamidates.
(11) White, G. J .; Garst, M. E. J . Org. Chem. 1991, 56, 3177-3178.
J . Org. Chem, Vol. 67, No. 15, 2002 5167
(
Ishimori, T.; Honma, S.; Minami, N.; Shibata, K.; Yasuda, K. Chem.
Pharm. Bull. 1996, 44, 2061-2069.

Posakony et al.
However, in synthesizing the dibenzosuberyl-protected sulfa-
tion turned colorless. TLC then indicated a new UV-ab-
midates (11 and 12), a 2.5:1 CH
used.
3
CN/H
2
O solvent mixture was
f
sorbing product (R ) 0.8) as the main product. The solvent
was removed, and the light orange residue (the color likely
due to reformed dibenzosuberyl cation) was purified by col-
umn chromatography (1:1 EtOAc:hexanes) to afford 15 (22
mg, 32%); dibenzosuberyl sulfamidate 13 (92 mg, 0.28 mmol)
was also recovered from the reaction mixture. If the solvent
was removed before MeOH was added, the mixture’s color was
lost and 13 was regenerated as the main product according to
TLC.
3
-(ter t-Bu tyloxyca r bon yl)-(R)-4-m eth yl-[1,2,3]-oxa th ia -
zolid in e-2,2-d ioxid e (11). RuO oxidation of crude 5 (11.8 g)
afforded 11 (10.5 g, 78% from 1): mp 120-121 °C; MS m/z:
4
4
), 198.9 (100, M + NH
4
- C
4 8
H )
); [R]23589
2
9
1
55 (80, M + NH
.45 (c 1.06, MeOH); H NMR (CDCl
.58 (s, 9H), ABC spin system (4.19 (dd, 1H) 4.41 (m, 1H), 4.67
1
3
) 1.53 (d, 3H, J ) 6 Hz),
(
C
6
dd, 1 H), J AB ) 9 Hz, J AC ) 6 Hz, J BC ) 3 Hz). Anal. Calcd for
S: C, 40.49; H, 6.37; N, 5.90. Found: C, 40.62; H,
.54; N, 5.89.
-(ter t-Bu tyloxyca r bon yl)-4,4-d im eth yl-[1,2,3]-oxa th ia -
8
H
15NO
5
4,4-Dim et h yl-[1,2,3]-oxa t h ia zolid in e-2,2-d ioxid e (16).
The procedure used to prepare BOC-sulfamidate 11 was
applied to BOC-sulfamidate 12 to afford 16 (90%): mp 105.5-
3
1
zolid in e-2,2-d ioxid e (12). Oxidation of crude 7 afforded 12
108 °C; MS m/z: 174.0 (100, M + Na); H NMR (CD CN) 1.41
3
in 87% yield: mp 101-102 °C; MS m/z: 290.2 (100, M + Na),
(s, 6H), 4.31 (s, 2H), 5.6 (s br, 1H). Anal. Calcd for C H NSO :
4
9
2
1
2
1
18.1 (60, M + Na - C
4
H
8
); H NMR (CD
3
CN) 1.536 (s, 9H),
S: C, 43.01;
C, 31.79; H, 6.00; N, 9.26. Found: C, 31.86; H, 6.21; N, 9.21.
.54 (s, 6H), 4.35 (s, 2H). Anal. Calcd C
9
H
17NO
5
F r om 14: The same procedure for deprotecting the diben-
zosuberyl sulfamidate (13) was applied to 14. After MeOH
addition and subsequent solvent removal, 16 was crystallized
from the mixture using EtOAc:hexanes (87%).
H, 6.82; N, 5.57. Found: C, 42.86; H, 7.01; N, 5.35.
(
R)-3-(5-Diben zosu ber yl)-4-m eth yl-[1,2,3]-oxa th ia zoli-
d in e-2,2-d ioxid e (13). Sulfamidate 13 was purified by column
chromatography (1:1 EtOAc:hexanes) and subsequently re-
Alk yla tion Rea ction s. (R)-3-Ben zyl-4-m eth yl-[1,2,3]-
oxa th ia zolid in e-2,2-d ioxid e (17). P h a se Tr a n sfer Ca ta ly-
sis. A solution of 40 wt % NaOH (1.5 mL) was added to a
solution of 15 (0.2 g, 1.5 mmol), benzyl bromide (0.7 mL, 4
equiv), and benzyltributylammonium chloride (23 mg, 5 mol
crystallized from CH
2
Cl
2
/hexanes to afford a colorless solid
), 352.1
) 1.09 (d, J ) 6.5 Hz, 3H), 2.85 (m,
H), 3.05 (m, 1H), 3.65 (m, 2H), AMX spin system (4.03 (dd,
(
(
85%): mp 173.5-175 °C; MS m/z: 347.1 (M + NH
4
1
M + Na); H NMR (CDCl
3
1
1
J
H), 4.15 (m, 1H), 4.57 (dd, 1H), J AM ) 8.4 Hz, J AX ) 3 Hz,
2 2
%) in CH Cl (5 mL). The mixture was rapidly stirred for 5 h
MX ) 6.3 Hz), 5.20 (s, 1H), 7.1-7.3 (m, 8H). Anal. Calcd for
at rt. During this period, TLC indicated a gradual decrease
of 15 in the aqueous phase and an increase of 17 in the or-
ganic phase. Removal of the solvent from the organic phase
and purification of the crude product by preparative TLC
18 3
C H19NO S: C, 65.63; H, 5.81; N, 4.25. Found: C, 65.41; H,
5
.93; N, 4.17.
-(5-Diben zosu ber yl)-4,4-d im eth yl-[1,2,3]-oxa th ia zoli-
d in e-2,2-d ioxid e (14). Purification of 14 was achieved by
filtration through a silica plug using 1:1 CH Cl :Et O followed
by solvent removal and recrystallization from CH Cl :hexanes.
Yield was 81% of a colorless solid: mp 185-187.5 °C; MS
3
2 2
(CH Cl ) afforded 17 (0.25 g, 76%); this sample had charac-
2
2
2
terization data identical to 17 synthesized from N-benzyl-2-
2
2
aminopropan-1-ol.4
Dep r oton a tion Usin g KO-t-Bu . Freshly sublimed KO-t-
Bu (0.1 g, 0.9 mmol) was added to a solution of 15 (0.125 g,
+
m/z: 193 (100, C15
Na), 382.1 (40, M + K); H NMR (CDCl
m, 2H), 3.96 (m, 2H), 4.11 (s, 4H), 5.24 (s, 1H), 7.1-7.4 (m,
H). Anal. Calcd for C19 S: C, 66.46; H, 6.16; N, 4.08.
H
13 ), 361.1 (15, M + NH
4
), 366.1 (10, M +
1
3
) 1.16 (s, 6H), 2.93
0
.9 mmol) in dry THF (2.5 mL) at -10 °C under Ar, and the
solution was stirred for 5 min. Then, benzyl bromide (0.11 mL,
.8 mmol) and dry CH CN (2 mL) were added, and the solution
(
8
H21NO
3
1
3
Found: C, 66.19; H, 6.28; N, 4.02.
Su lfa m id a te Dep r otection . (R)-4-Meth yl-[1,2,3]-oxa th i-
a zolid in e-2,2-d ioxid e (15). F r om 11: Sulfamidate 11 (3 g,
was stirred for 3 h while allowing the solution to gradually
warm to room temperature. EtOAc was added, the mixture
was filtered, and the solvent was subsequently removed from
1
2 2
2.6 mmol) was dissolved in CH Cl (20 mL), and TFA (4.9
2
the filtrate. The product was purified by preparative TLC (CH -
mL, 5 equiv) was added. The mixture was stirred for 30 min
and then the solvent evaporated under reduced pressure. The
residual oil was treated with Et N (typically <5 drops), until
the mixture tested basic. The mixture was then filtered
through a plug of silica using EtOAc:hexanes (1:1, 300 mL).
The solvent was removed from the filtrate to afford 1.72 g of
an oil, and 15 (1.48 g, 86%) was crystallized from this mixture
Cl
2
) to yield 17 (0.11 g, 54%).
3
-Ben zyl-4,4-d im eth yl-[1,2,3]-oxa th ia zolid in e-2,2-d iox-
3
id e (18). The same procedure used for 17, above, was applied
to sulfamidite 16 (0.227 g, 1.5 mmol) to afford 18 (0.34 g, 93%).
This material was identical to 18 synthesized from N-benzyl-
2
-amino-2-methylpropan-1-ol.4
using CH
2
Cl
2
:hexanes: mp 40.5-42 °C; R
f
) 0.5 (1:1 EtOAc/
CN) 1.33
d, J ) 6.5 Hz, 3H), AMX spin system (4.05 (m, 1H), 4.11 (dd,
3-(P h en ylp r op yl)-4,4-d im eth yl-[1,2,3]-oxa th ia zolid in e-
1
hexanes); MS m/z: 159.9 (M + Na); H NMR (CD
(
3
2,2-d ioxid e (19). A solution of DIAD (0.32 mL, 1.6 mmol) in
dry CH CN (5 mL) was added in 4 portions to a solution of
PPh (0.43 g, 1.6 mmol), 3-phenyl-1-propanol (0.215 mL, 1.6
mmol), and 15 (0.137 g, 1 mmol) in dry CH CN (15 mL). Each
3
1
H), 4.63 (dd, 1H), J AM ) 8 Hz, J AX ) 8 Hz, J MX ) 6 Hz), 5.5
3
(s br, 1H). Anal. Calcd for C
3
H
7
NSO : C, 26.28; H, 5.15; N,
2
3
1
0.21. Found: C, 26.27; H, 5.35; N, 10.12.
When 1 equiv of DBU was added to a solution of 15 in
3
CN, the sulfamidate resonances shifted upfield with loss
DIAD portion was added dropwise at 15 min intervals with
each addition lasting 3-5 min. Fifteen minutes after the last
addition, the solvent was removed, and the mixture was
CD
chromatographed on silica/CH
0.41, 43%) as a colorless oil: MS m/z: 256.0 (M + H, 50), 278
(M + Na, 45), 294 (M + K, 100); H NMR (CDCl ) 1.27 (d, J )
2 2 f
Cl to afford 0.11 g of 19 (R )
of the N-H signal: 1.20 (d, J ) 6.5 Hz, 3H), AMX spin system
(
7
3.57 (dd, 1H), 3.85 (m, 1H), 4.30 (dd, 1H), J AM ) 8 Hz, J AX )
1
Hz, J MX ) 6.5 Hz). Similar shifts were observed when an
3
excess of NaOH was added to a solution of 15 in D
sulfamidate anion thus formed was stable over several hours
in solution. No such chemical shift changes were observed
2
O, and the
6 Hz, 3H), 2.04 (m, 2H), 2.73 (m, 2H), 3.02 (m, 1H), 3.13 (m,
1H), ABC spin system (3.68 (m, 1H), 4.1 (dd, 1H), 4.53 (dd,
1H), J AB ) 8 Hz, J AC ) 6.5 Hz, J BC ) 8.5 Hz), 7.2-7.35 (m,
5H). Anal. Calcd for C12H17NO S: C, 56.46; H, 6.71; N, 5.48.
3
Found: C, 56.51; H, 6.88; N, 5.54. More rapid addition of the
DIAD solution resulted in substantially lower yields.
when 1 equiv of Et
CD DN.
F r om 13: TFA (0.4 mL. 5 mmol) was added to a solution of
sulfamidate 13 (0.165 g, 0.5 mmol) in CH Cl (2-3 mL) at
which point the solution changed from colorless to a clear
orange/red color. Tlc analysis (silica/CH Cl ) of this solution
showed 15 (R ) 0.2), a trace of 13 (R ) 0.55) and at least
three other UV-absorbing products (R s ) 0.75 to 0.95). After
stirring for 5 min, MeOH (2 mL) was added and the solu-
3
N was added to a solution of 15 in
3
2
2
3-(P h en ylp r op yl)-4,4-d im eth yl-[1,2,3]-oxa th ia zolid in e-
2,2-d ioxid e (20). The same conditions used to synthesize 19
were applied to 16 (0.23 g, 1.5 mmol) to afford 20 (0.36 g, 89%)
2
2
f
f
as a colorless oil: MS m/z: 270.1 (M + H, 100), 287.1 (M +
1
f
NH
4
, 15), 292.1 (M + Na, 100); H NMR (CDCl
3
) 1.30 (s, 6H),
2.07 (m, 2H), 2.74 (t, J ) 8 Hz, 2H), 3.03 (t, J ) 7 Hz, 2H),
5
168 J . Org. Chem., Vol. 67, No. 15, 2002

N-Alkylated Cyclic Sulfamidates
.25 (s, 2H), 7.2 (m, 5H). Anal. Calcd for C13
4
H
19NO
3
S: C, 57.98;
By the fourth addition, the relative integration of the sulfa-
midate CH signals had decreased by 50%, the CH doublet
(1.3 ppm) was surrounded by broad peaks, and TLC suggested
that less 15 was present. In combination F, the PPh3 was
added all at once to the DIAD/17 mixture; results similar to
combination E were observed.
H, 7.11; N, 5.20. Found: C, 57.91; H, 7.25; N, 5.31.
2
3
1
H NMR Exp er im en ts. To investigate the low yield of 19,
combinations of PPh
mg, 0.1 mmol), sulfamidate 17 (23 mg, 0.1 mmol), and/or DIAD
20 µL, 0.1 mmol) were used in several experiments (A-F)
carried out in CD CN (ca. 1 mL). The solutions were monitored
by H NMR and TLC for any reaction. The following combina-
tions were used: (Experiment A) PPh /15; (B) PPh /17; (C)
DIAD/15; (D) DIAD/17; (E) DIAD was added in 4 equal
3
(26 mg, 0.1 mmol), sulfamidate 15 (14
(
3
1
Ack n ow led gm en t. This work was supported by the
National Institutes of Health: Grants HL60221 and
HL36728.
3
3
3 3
portions, 15 min apart to a solution of PPh /15; (F) PPh was
added to a solution of DIAD/17.
In experiments A-D, no significant reaction was observed
over 30 min. In experiment E, the first addition of DIAD
resulted in the loss of the N-H signal and an upfield shift
Su p p or tin g In for m a tion Ava ila ble: High dilution condi-
tions used for the synthesis of sulfamidites 5 and 7 which
yielded sulfite esters 6 and 8; the characterization details of 6
and 8. This material is available free of charge via the Internet
at http://pubs.acs.org.
(
∼0.5 ppm) of the sulfamidate CH
occurred. The relative integration (to the solvent peak) of the
CH signals was smaller, and the quality of the rest of the
spectrum had deteriorated, suggesting a number of products.
2
signals (4.1 and 4.6 ppm)
2
J O0157019
J . Org. Chem, Vol. 67, No. 15, 2002 5169