New uses for the Burgess reagent in chemical synthesis: Methods for the facile and stereoselective formation of sulfamidates, glycosylamines, and sulfamides

Article abstract of DOI:10.1002/chem.200400503

Although the Burgess reagent (methoxycarbonylsulfamoyltriethylammonium hydroxide, inner salt) has found significant use in chemical synthesis as a dehydrating agent, almost no work has been directed towards its potential in other synthetic applications. As this article will detail, we have found that the Burgess reagent is remarkably effective at accomplishing a number of non-dehydrative synthetic tasks when applied to appropriate substrates, such as the formation of sulfamidates from 1,2-diols or epoxyalcohols, α- and β-glycosylamines from carbohydrates, and cyclic sulfamides from 1,2-aminoalcohols. Beyond delineating the power of these new reaction manifolds, we also describe the construction of a group of alternative Burgess-type reagents that extends the scope of these new reactions even further.

Full text of DOI:10.1002/chem.200400503

K. C. Nicolaou et al.
Chem. Eur. J. 2004, 10, 5581 – 5606
DOI: 10.1002/chem.200400503
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5581

FULL PAPER
New Uses for the Burgess Reagent in Chemical Synthesis: Methods for the
Facile and Stereoselective Formation of Sulfamidates, Glycosylamines, and
Sulfamides
K. C. Nicolaou,*[a, b] Scott A. Snyder,[a] Deborah A. Longbottom,[a]
Annie Z. Nalbandian,[a] and Xianhai Huang[a]
Abstract: Although the Burgess re-
agent (methoxycarbonylsulfamoyltri-
ethylammonium hydroxide, inner salt)
has found significant use in chemical
plishing a number of non-dehydrative
synthetic tasks when applied to appro-
priate substrates, suchas the formation
of sulfamidates from 1,2-diols or
epoxyalcohols, a- and b-glycosylamines
from carbohydrates, and cyclic sulf-
amides from 1,2-aminoalcohols. Beyond
delineating the power of these new re-
action manifolds, we also describe the
construction of a group of alternative
Burgess-type reagents that extends the
scope of these new reactions even fur-
ther.
synthesis as
a
dehydrating agent,
almost no work has been directed to-
wards its potential in other synthetic
applications. As this article will detail,
we have found that the Burgess re-
agent is remarkably effective at accom-
Keywords: amines
reagent diazo compounds
sulfamides · sulfur
·
Burgess
·
·
Introduction
was the latter of these processes that originally brought the
Burgess reagent to our attention as we sought methods to
complete the heteroaromatic core of the originally proposed
structure of diazonamide A (2) by transforming advanced
intermediate 3 into 4.[7] While the Burgess reagent would ul-
timately fail to accomplish that rather difficult dehydration,
our efforts in that context inspired us to ponder the follow-
ing, more general, question: are there powers for this re-
agent beyond its capacity to remove water?
As a subsequent search of the literature revealed, there
were only a few suchreports in existence, all dedicated to
the same process shown in Scheme 1c: the conversion of pri-
mary alcohols into their corresponding methyl urethane de-
rivatives.[8] This finding, in turn, led us to wonder if related
processes leading to the incorporation of nitrogen could be
accomplished on other substrate types, such as 1,2-diols (a
compound type that had seemingly never been subjected to
its powers). Our subsequent efforts to answer that question
began a line of investigation that ultimately revealed a
wealthof newfound potential for the Burgess reagent, not
as a dehydrative agent, but rather as a convenient source of
multiple heteroatoms (S, O, and N). This article recounts
those studies, work which has led to new methods for the
stereoselective formation of diverse sulfamidates, a- and b-
glycosylamines, and sulfamides.[9]
Ever since its introduction over three decades ago, the Bur-
gess reagent (1, Scheme 1)[1] has proven to be a powerful
tool in chemical synthesis as an agent for effecting a diverse
set of dehydration reactions.[2] For example, it has been em-
ployed on numerous occasions to smoothly convert secon-
dary and tertiary alcohols into their corresponding alkenes
by means of cis-elimination pathways[3] as well as to dehy-
drate amides to their nitrile counterparts (Scheme 1a,b).[4]
The Burgess reagent is also an excellent initiator of cyclode-
hydrations leading to heterocycles, such as the transforma-
tion of hydroxyamides into oxazolines[5] and the Robinson–
Gabriel reaction converting ketoamides into oxazoles.[6] It
[a] Prof. K. C. Nicolaou, S. A. Snyder, Dr. D. A. Longbottom,
A. Z. Nalbandian, Dr. X. Huang
Department of Chemistry
and The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 NorthTorrey Pines Road, La Jolla
California 92037 (USA)
Fax : (+1)858-784-2469
E-mail: kcn@scripps.edu
[b] Prof. K. C. Nicolaou
Department of Chemistry and Biochemistry
University of California, San Diego
9500 Gilman Drive, La Jolla, California 92093 (USA)
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Scheme 1. Selected uses of the Burgess reagent (1) in chemical synthesis.
Results and Discussion
Sulfamidate synthesis from 1,2-diols using the Burgess re-
agent: Our expectation for what could happen to a 1,2-diol-
containing substrate (I) following exposure to an excess
amount of the Burgess reagent (at least two equivalents) is
drawn in Scheme 2. Namely, if that starting material could
be coaxed to form an intermediate of type II prior to either
alcohol participating in a typical dehydrative pathway, then
perhaps a sulfamidate (III) product could arise through the
indicated SN2 reaction. Assuming that this transformation
would proceed through displacement of the more activated
of the two potential leaving groups, then variation of the R1
and R2 substituents on enantiopure I could enable the
stereo- and regioselective synthesis of sulfamidates (III) on
a potentially large number of diverse structural types.
Abstract in Greek:
Scheme 2. Proposed conversion of 1,2-diols (I) to cyclic sulfamidates (IV)
using Burgess reagent (1) and proof of principle (5!6).
The proposed chemistry appealed to us not only because
it would highlight a new use for the Burgess reagent if it
worked, but also because its success would deliver an impor-
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FULL PAPER
Table 1. Regioselective synthesis of sulfamidates from precursor 1,2-diols
using Burgess reagent (1).
With this important proof of principle achieved, we next
sought to test the generality of this reaction process on a se-
lection of styrene-derived diols possessing a broad range of
aromatic substitution patterns to explore whether inductive
effects would have any impact on the regioselectivity of the
SN2-based cyclization. Although we could have chosen any
number of diols to probe the process further, we selected
this particular class of compounds for two key reasons:
1) styrenes are the best substrates for Sharpless asymmetric
dihydroxylation (AD)[14] in terms of bothcatalytic activity
and enantioselectivity, and 2) styrene-type olefins display
good, but highly variable, yields and regioselection in carba-
mate-based asymmetric aminohydroxylation (AA).[15]
As indicated by the results in Table 1, our Burgess-medi-
ated sulfamidate synthesis proved quite effective with this
group of substrates as long as the aromatic ring was elec-
tron-rich(entries 1–4) or electron-neutral (entry 5). Howev-
er, when substituents with increasing electronegativity were
appended onto the styrene core (entries 6 and 7), a second
reactive pathway leading to substantial amounts of a seven-
membered side-product was opened up. Scheme 3 provides
two mechanisms that could account for the formation of
these types of products (i.e., 23), using styrene for the sake
of their illustration. The first of these scenarios invokes the
resonance form of 21 (i.e., 22) as the source of an oxygen
nucleophile that could displace the activated benzylic leav-
ing group and lead to 23 directly. The second assumes only
partial reaction of the Burgess reagent with substrate 24 to
initiate entry into a different intramolecular displacement
reaction leading to epoxide 26, a compound already demon-
strated to provide heterocycle 23 in its reaction withthe
Burgess reagent.[16] Although the results described thus far
did not allow us to discern which, if either, of these two pos-
sible pathways was active, one experiment described below
Entry
Starting
material
Major
product
Ratio of
Yield
products[a] [%]
1
>98:2
91
88
2
3
4
95:5
95:5
95:5
87
79
5
6
7
93:7
92
83
86
85:15
55:45
1
[a] As determined by H NMR analysis of the crude reaction products.
tant pharmacophore in far fewer steps than other methods
could achieve.[10] Equally attractive, since sulfamidates are
well precedented to undergo highly selective reactions with
O-, S-, N-, and F-based nucleophiles to afford compounds of
general structure IV,[11] we could subsequently use our syn-
thesized materials to access a diverse array of products, in-
cluding suchvaluable syntohns as
b-aminoalcohols.[12] To
test the key element of this hypothesis, we heated a solution
of diol 5 (synthesized from the precursor olefin by dihydrox-
ylation under standard conditions) in THF at reflux for one
hour in the presence of 2.5 equivalents of the Burgess re-
agent (1).[13] In line with our expectations, at the end of this
time we obtained the desired sulfamidate product (6) in
84% yield as a single regioisomer based on NMR spectro-
scopic analysis.
Scheme 3. Degenerate mechanistic proposals to account for the forma-
tion of the minor seven-membered ring product 23 in the reaction of 1,2-
diols withexcess Burgess reagent.
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would provide such an insight. For now, however, we think
it important to note that the desired sulfamidate products
listed in Table 1 could be readily separated from their
seven-membered ring counterparts by standard chromatog-
raphy. In addition, the especially poor selectivity observed
in the conversion of 19 to 20 (entry 7) could be improved to
75:25 by performing the reaction at 258C, albeit at the ex-
pense of yield (35%).
Having explored electronic effects, we then sought to ex-
amine the role of steric encumbrance on the reaction pro-
cess as well as its applicability to non-styrene derived diols
by testing the substrates listed in Table 2. As one might
expect, increasing steric bulk at the terminal position of the
styrene core, simply through the addition of a single methyl
group (entry 1), increased the selectivity of cyclic sulfami-
date formation compared to that observed for the corre-
sponding example in Table 1. This outcome suggests that the
epoxide pathway mentioned above is the source of any
seven-membered products, as the other mechanistic picture
would not predict a different ratio based on this one simple
change. Importantly, no decrease in yield or selectivity for
the desired five-membered sulfamidate was observed when
steric bulk was added onto the aromatic ring (entries 2 and
3). Equally significant, esters were well tolerated in the reac-
tion. In entry 5, the near exclusive formation of sulfamidate
36 was achieved from 35 due to the reinforcing effects of a-
position deactivation by the ester moiety and steric bulk im-
posed at that site by a methyl group, while competitive
steric and electronic effects in entry 6 led to retarded SN2
displacement at the preferred terminal site, leading to in-
creased formation of the seven-membered side product and
decreased reaction yield. Simple aliphatic examples (en-
tries 7 and 8) proceeded withextremely highregioselectivity,
presumably due to the well-established preference for nucle-
ophilic displacement of primary or activated leaving groups
over their secondary counterparts. Finally, to verify the po-
tential of this reaction manifold for asymmetric synthesis, as
all of the examples listed in Tables 1 and 2 were performed
on racemic diol substrates, an X-ray crystal structure was
obtained for sulfamidate 36; this confirmed that inversion of
stereochemistry had occurred at the benzylic position rela-
tive to the racemic cis-diol starting material (see Figure 1).
Table 2. Further examples of the regioselective synthesis of sulfamidates
from precursor 1,2-diols using Burgess reagent (1).
Entry
Starting
material
Major
product
Ratio of
Yield
products[a] [%]
1
>98:2
>98:2
72
92
2
3
>98:2
94
4
5
85:15
82
81
>98:2
Figure 1. X-ray crystallographic structures for sulfamidates 36 and 42.
6
7
8
71:29
>98:2
>98:2
41
76
71
Additionally, bothracemic and enantiopure 33 were synthe-
sized,[17] and comparison of the chiral HPLC traces of the
resultant products (34) indicated that preexisting stereo-
chemical information was communicated in the reaction
[18]
withcomplete fidelity.
Witha muchclearer sense of the scope possessed by our
Burgess-mediated sulfamidate synthesis, we now desired to
extend its overall utility one step further by constructing
compounds bearing N-protection other than a methyl carba-
mate, a task which could be achieved simply by modification
of 1. To our surprise, however, such reagents represented
novel chemical entities, as an extensive search of the litera-
1
[a] Determined by H NMR analysis of the crude reaction products.
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Table 3. Use of the new Burgess-type reagents 48–51 to prepare orthogo-
nally protected sulfamidates (52–60).
ture indicated that no efforts had been expended to prepare
any Burgess-type salts other than those originally described
almost thirty years ago.[19] This result was unexpected, as 1 is
known to be boththermal and moisture sensitive, [2a] features
which might be modulated by differentiation of the carba-
mate portion. In any case, as shown in Scheme 4, we found
Entry
Starting
material
Major
product
Ratio of
Yield
products[a] [%]
1
>98:2
90
81
2
3
4
5
95:5
Scheme 4. Synthesis of the novel variants (48–51) of the original Burgess
reagent: a) chlorosulfonyl isocyanate (1.0 equiv), ROH (1.05 equiv),
CH2Cl2, 08C, 30 min, 89–95%; b) Et3N (2.5 equiv), C6H6, 258C, 1 h, 81–
87%.
>98:2
>98:2
>98:2
87
82
89
it quite easy to prepare four different Burgess-type reagents
(48–51), representing an orthogonal set of amine-protecting
groups (based on deprotection by hydrogenation, photolysis,
exposure to palladium-based catalysts, or treatment withZn,
respectively) by treating chlorosulfonylisocyanate (43) with
the alcohol of interest and then exposing the resultant prod-
uct to Et3N.[20] Now the question was whether these reagents
would perform withequal facility as 1 in sulfamidate synthe-
sis. Pleasingly, the answer was yes as their exposure to sever-
al diol substrates resulted in the formation of the desired
sulfamidate products (52–60, Table 3) in comparable effi-
ciency and selectivity as observed previously with 1.
6
7
8
>98:2
>98:2
>98:2
87
81
78
Having synthesized such a diverse group of sulfamidates,
we were now in a position to attempt their conversion into
b-aminoalcohols. Accordingly, using
a literature proce-
dure[11k] that had been examined on only one sulfamidate
substrate, we exposed a variety of these products (see
Table 4) to a 1:1 mixture of aqueous HCl and 1,4-dioxane at
258C. In every case, a high yield of b-aminoalcohol product
was observed irrespective of carbamate protecting group
used. As such, the applicability of this method to a diverse
set of 1,2-diol classes, combined withits facile use in a sub-
sequent step to deliver b-aminoalcohol products, renders it
an attractive alternative to protocols suchas Sharpless AA
should they fail to deliver a given product with acceptable
levels of regio- and/or stereocontrol.
9
>98:2
83
Glycosylamine synthesis using the Burgess reagent: In as-
sessing additional directions in which we could take the Bur-
gess reagent, new inspiration came when we thought more
carefully about the conversion reported in entry 8 of Table 2
leading to the synthesis of 42 (whose cis-fused sulfamidate
ring was verified by the X-ray crystal structure shown in
Figure 1). Specifically, we wondered what would happen if
this reaction were applied to a sugar template (V, see
Scheme 5). Our experience suggested that the same type of
sulfamidate product (VII) should arise through the depar-
ture of the most activated hydroxyl, either by the indicated
SN2 mechanism or by an oxonium alternative (not shown),
with the C-2 group orchestrating the stereoselective delivery
[a] As determined by 1H NMR analysis of the crude reaction products.
Cbz=CO2CH2Ph, o-NO2Cbz=CO2CH2-o-NO2Ph, Alloc=CO2CH2CH=
CH2, Troc=CO2CH2CCl3.
of nitrogen. In this case, however, subsequent opening of
this ring with a heteroatomic nucleophile would afford a
1,2-trans-difunctionalized glycosylamine product.[11] Thus,
based on this model, a starting material derived from d-glu-
cose would provide an a-glycosylamine product (VIII). Al-
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Table 4. Deprotection of cyclic sulfamidates using aqueous HCl in 1,4-di-
oxane at ambient temperature to yield b-aminoalcohols (61–68).
Entry
Starting
material
Product
Time Yield
[h]
[%]
1
10
94
2
30
95
3
4
5
12
8
92
88
92
2
Scheme 5. Proposed synthesis of both a- and b-glycosylamines using Bur-
gess-type reagents.
kov aminations,[24] and a-hydroxy nitriles,[25] among others,
typically lack substrate generality and often result in vari-
able stereoselectivity, especially in complex contexts. In ad-
dition, none of these methods singularly provides a means
to obtain both a- and b-anomers at will and in a controlled
manner. As such, we immediately set out to test whether
the Burgess reagent could rise to this task.
6
7
8
26
24
16
95
93
90
Gratifyingly, the Burgess reagent (1) and its relatives (50
and 51) did just that. As shown in Table 5, a variety of diols
on diverse carbohydrate templates (d-glucose, d-galactose,
l-rhamnose) were smoothly converted into their a-disposed
sulfamidate counterparts (cis-fused rings) upon the action of
2.5 equivalents of 1, 50, or 51 in refluxing THF/CH2Cl2 (4:1)
over the course of 6 h.[26] In every case, yields and a:b selec-
tivity (determined by 1H NMR spectroscopy; the minor
isomer presumed to be the trans-fused b-anomer was not
isolated but observed by NMR spectroscopy) were excep-
tionally high irrespective of which Burgess-type reagent was
employed. As such, these findings can be taken as a sign
that any carbamate-protecting group can be appended onto
the sulfamidate products in Table 5, though we have only
demonstrated that principle directly for d-glucose. Suchflex-
ibility is important, since we were able to subsequently open
these products with nucleophiles to afford a-disposed glyco-
sylamines suchas 83, or alternatively, convert them into
functionalized sulfamidates like 84 simply by removing the
carbamate protecting group and alkylating as shown in
Scheme 6. Both of these manipulations should prove impor-
tant in future applications relevant to the study of chemical
biology, though compounds of type 84 offer several unique
advantages as their sulfamidate ring provides untapped
ternatively, if lactols bearing C-2 protection (IX) were ex-
posed to the same general reaction conditions, it would be
reasonable to expect that these materials would afford N,O-
acetal products instead of sulfamidates, through the indicat-
ed mechanism, with stereocontrol in this “self-displacement”
reaction arising from the established preference for anome-
ric triflates to exist as a-anomers (XI) over their b-disposed
counterparts (X).[21] As such, d-glucose-based materials
would afford only b-glycosylamine products (XII) in this re-
action paradigm.[22]
While relatively simple ideas based on our previous suc-
cess in reacting 1,2-diol substrates, their success would be of
considerable value, since glycosylamines have proven to be
exceedingly difficult to synthesize. Indeed, available meth-
ods based on the use of glycosyl azides, glycals,[23] Kochet-
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Table 5. Synthesis of sulfamidates on carbohydrate templates.
structural novelty and ensures that the disposition of the ni-
trogen atom cannot anomerize (as often occurs withunpro-
tected a-glycosylamines simply upon standing in solution).
As indicated in Table 6, C-2 protected lactols reacted with
Burgess-type reagents in a level of smoothness that matched
their diol counterparts, affording a b-disposed, protected
glycosylamine on every six-membered carbohydrate probed
(entries 1–5), as verified by bothX-ray crystallographic (see
Entry
Starting
material
Product
Ratio
Yield
[%]
a:b[a]
1
Figure 2)[27] and H NMR analyses. Five-membered furanose
1
2
3
8:1 88
15:1 75
15:1 83
4
5
6
10:1 79
Figure 2. X-ray crystallographic structure of compound 86.
substrates performed equally well (entries 6–8), withanome-
ric stereochemistry in these products presumably controlled
by the orientation of the C-2 substituent in a level commen-
surate to its bulk.[28] As discussed earlier, the reactions per-
formed equally well irrespective of which Burgess-type re-
agent was employed in this manifold, though Alloc protec-
tion did provide one important benefit over the other carba-
mate alternatives: facile removal in near quantitative yield
under conditions[29] that did not initiate any anomerization
(see, for example, 89!102) to afford free glycosylamines.
In closing this section, it is clear that the Burgess reagent
(1) and its analogues (50 and 51) afford powerful and highly
selective tools for the synthesis of both a- and b-glycosyl-
amines on a wide variety of carbohydrate scaffolds. This
new approachis not only exceedingly mild, operationally
simple, and tolerant of numerous functional and protecting
groups, but also appears to be applicable for large-scale syn-
theses (reactions up to 5 mmol have been performed with
no drop in efficiency) and late-stage operations relevant to
the synthesis of complex aminoglycosides and/or N-linked
glycopeptides.[30]
10:1 82
>20:1 79
7
8
–
91
>20:1 74
[a] The minor isomer (b-anomer, trans-fused ring) was not isolated, but
presumed to be that on the basis of 1H NMR data (of the a/b mixture).
Hydroxysulfamidate synthesis using epoxyalcohols and the
Burgess reagent: Having proven that 1,2-diol substrates
could lead to sulfamidate products, we then wondered
whether or not additional classes of molecules could be con-
verted into similar materials. For example, would
a
hydroxylepoxide (XIII) derived from an allylic alcohol
prove to be a willing participant in the pathway delineated
in Scheme 7 leading to a hydroxysulfamidate product (XV)?
As matters would transpire, the answer to that question was
yes, though a great deal of reaction scouting was required
before we identified conditions capable of reliably effecting
that conversion.
Scheme 6. Synthesis of functionalized a-glycosylamines from precursor
sulfamidates: a) NaN3 (5.0 equiv), DMF, 608C, 5 h, 83%; b) Pd(OAc)2
(0.1 equiv), TPPTS (0.2 equiv), Et2NH (40 equiv), MeCN/H2O (1:1),
258C, 30 min; c) NaH (5.0 equiv), DMF, 258C, 5 min, then allyl bromide
(4.0 equiv), 258C, 15 min, 73% over two steps. TPPTS=3,3’,3’’-phosphi-
dinynetris(benzenesulfonic acid) trisodium salt.
Table 7 shows the final solution leading to five hydroxy-
sulfamidate products: heating a hydroxyepoxide substrate
with1.3 equivalents of the Burgess reagent for 3 hin a 4:1
solvent mixture of THF/CH2Cl2, followed by column purifi-
cation using the slightly basic material Florisilꢁ instead of
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Table 6. Direct conversion of anomeric alcohols to b-glycosylamines.
standard, acidic silica gel. Any
deviation from this procedure
led to a multiplicity of prod-
ucts.[31] We think it important to
emphasize that, although we
could reliably obtain the sulf-
amidate adducts shown in the
yields indicated withthis proto-
col, this particular reaction with
the Burgess reagent is by far
the most capricious of those
that have been described to this
point, and certainly the most
experimentally challenging.[32]
Entry
Starting
material
Product
Ratio
Yield
[%]
b:a[a]
1
>20:1
68
2
3
>20:1
>20:1
73
78
Sulfamide synthesis using the
Burgess reagent and 1,2-amino-
alcohols: Within the realm of
proven pharmacophores, the
sulfamide functional group
(thiadiazine-1,1-dioxide) stands
out as one of the most impor-
tant structural motifs found in
high-affinity protein ligands and
pharmaceutically useful agents.
Indeed, a survey of the recent
patent literature reveals several
hundred proprietary documents
illustrating that the incorpora-
4
>20:1
72
5
6
>20:1
>20:1
76
73
tion of
a
sulfamide group
7
8
8:1
10:1
72
81
within a suitable scaffold, often
cyclic, leads to compounds with
an impressive and diverse array
of biological activities.[33] For in-
stance, these agents have
proven to be particularly effec-
tive as inhibitors of key en-
zymes, including HIV pro-
tease[34] and serine protease,[35]
and have demonstrated utility
as bothagonists and antagonists
of critical molecular receptors
suchas those used to regulate
endogenous levels of serato-
nin[36] and histamine.[37] Beyond
their evident significance in the
treatment of disease, cyclic sulf-
amides have also been em-
ployed withconsiderable suc-
cess as chiral ligands and auxil-
9
3:1
5:1
70
71
10
iaries,[38] and constitute an increasingly popular set of build-
ing blocks within the field of supramolecular chemistry.[39]
Despite the indisputable utility of these compounds, exist-
ing routes for their construction, particularly in a cyclic set-
ting, are far from ideal. For example, typical procedures to
fashion cyclosulfamides rely upon the reaction of a diamine
witheitehr SO 2Cl2 or H2NSO2NH2 at elevated tempera-
tures,[40] conditions which often lead to a low yield of prod-
uct due to the concomitant formation of polycondensation
Scheme 7. Proposed conversion of epoxyalcohols into sulfamidates
through the action of the Burgess reagent (1).
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Table 7. Synthesis of sulfamidates from epoxyalcohols.
these compounds for generating pharmaceutically relevant
molecular diversity.
Entry
Starting
material
Product
Yield
[%]
Once again, we felt that the power of the Burgess reagent
could be employed to solve these problems and smoothly
deliver sulfamide products. As shown in Scheme 8, our ex-
pectation was that treatment of an aminoalcohol starting
material (XVI, R1 =H or alkyl) withat least two equivalents
of the Burgess reagent would lead to a monoprotected, non-
symmetrical, cyclic sulfamide (XVIII) in a single, stereocon-
trolled operation. Assuming that this reaction course could
be successfully realized in preference to the typical rear-
rangement/dehydration pathways promoted by these re-
agents, subsequent deprotection of the carbamate in XVIII,
followed by substitution withan appropriate electrophile,
would then provide access to an assorted collection of sulf-
amides (XIX) withthe potential to incorporate diversity at
all possible sites.
1
87
82
85
2
3
To test this attractive hypothesis, we began our investiga-
tions of this new Burgess-mediated reaction by exploring a
representative set of commercially available and easily syn-
thesized secondary b-aminoalcohols. Most gratifyingly, expo-
sure of all substrates listed in Table 8 to excess Burgess re-
agent (1) or its relatives (48 and 50) in refluxing THF for
8 h led to the formation of the desired cyclic sulfamide prod-
uct in high yield, regardless of the nature of the group at-
tached onto the amine. Of particular note, neither placing
the amine in a hindered cyclic setting (entries 8 and 9) nor
adding a bulky tert-butyl substituent (entries 6 and 7) retard-
ed product formation. The latter of these substrates (122) is
a particularly effective test for the power of this synthetic
technology, as starting materials bearing this functionality
4
5
89
81
[a] All reactions were performed in THF/CH2Cl2 (4:1) at reflux with
1.3 equiv of 1, followed by column chromatography using Florisilꢁ.
side-products. Equally problematic is the scarcity of these
starting materials in the repertoire of commercially available
chemicals,[41] thereby resulting in only a limited collection of
sulfamides. While these issues have led to the development
of several alternative protocols for sulfamide synthesis,[42]
these additional technologies have proven amenable only to
specific substrate classes and have not yet alleviated the
need for multistep protocols. Most significantly, none of
these methods has enabled the efficient and selective syn-
thesis of nonsymmetrical N,N’-disubstituted cyclosulfamides
(see XIX, Scheme 8), perhaps the most versatile class of
have, in general, proven recalcitrant to sulfamide formation
[36]
withother available methods.
Of equal importance, all
aniline-derived systems (entries 12–14) proved readily ame-
nable to the cyclization process regardless of the electron-
withdrawing (entries 12 and 13) or donating (entry 14) prop-
erties of the appended aromatic ring, results indicative of
the versatility of this intramolecular Burgess-mediated cycli-
zation.[43]
While certainly satisfied by these initial successes in which
the two nitrogen atoms of the sulfamide product had been
effectively differentiated, we next sought to more fully
probe the limits of the Burgess-mediated sulfamide synthesis
by exploring more challenging substrates. As shown in
Table 9, employing a secondary alcohol (entry 1), even in a
relatively hindered context, failed to engender any particu-
lar difficulties, although extension of the reaction time
beyond the standard 8 h of heating was required to optimize
yields. A double cyclization seeking to generate a bis-sulf-
amide (140, entry 2) was also smoothly effected, with re-
duced yield in this case solely due to difficulties encountered
during isolation, because of this productꢂs polar nature. Fi-
nally, following optimization of the reaction conditions, ex-
tension of the sulfamide cyclization to ring sizes beyond the
five-membered ring products formed in the previous exam-
ples also proved attainable. Initial efforts focused on 141
(entry 3), wherein commencing the reaction at 08C and al-
lowing it to warm to 258C overnight led to the desired prod-
uct (142) in 45% yield. All other conditions probed led to
Scheme 8. Proposed conversion of amino alcohols (XVI) to cyclic sulfa-
mides (XVIII) using Burgess (1) and related reagents (48 and 50) and
further elaboration leading to nonsymmetrically substituted, structurally
diverse products (XIX).
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Burgess Reagent
5581 – 5606
Table 8. Synthesis of nonsymmetrical cyclic sulfamides from precursor
aminoalcohols using Burgess-type reagents: initial explorations.
Table 9. Synthesis of nonsymmetrical cyclic sulfamides from secondary ami-
noalcohols: advanced examples and exploration of ring size.
Entry
Starting
material
Product
Yield
[%]
Entry
Starting
material
Product
Yield
[%]
1
2
75
82
1
89[a]
3
4
5
85
89
92
2
3
55[b]
45[c]
4
5
6
93[d]
87[d]
83[d]
6
7
81
75
8
9
77
75
7
8
9
89[d]
81[d]
90[d]
10
11
92
82
12
13
75
82
[a] THF, D, 21 h; [b] THF, D, 8 h; [c] 0 8C, 1 h, then 258C, 5 h; [d] THF, D,
2 h .
zodiazepine nucleus, a molecular scaffold that has been the
subject of intensive biological investigations and the source
of several clinically employed agents.[44]
14
69
Based on the successful formation of the latter sulfamide
substrate in Table 9, we were hopeful that other primary ali-
phatic aminoalcohol substrates would perform in this Bur-
gess-based protocol withequal proficiency as bothsides of
the resultant sulfamide product could then be substituted in
turn, leading to greater structural diversity. Unfortunately,
all three substrates examined within this class (entries 1–3,
Table 10) gave rather disappointing yields of sulfamide
products, leading in eachcase to the formation of side-prod-
ucts resulting from undesired rearrangements. In retrospect,
the poor performance of these substrates in an intramolecu-
lar cyclization relative to their secondary amine counterparts
is not so surprising, as in the absence of an additional alkyl
or aryl substituent the nitrogen atom is far less nucleophilic,
thereby leading to prolonged reaction times and greater op-
[a] All reactions were performed in refluxing THF for 2 h.
significant amounts of a major rearrangement side-product
in which the alcohol had been converted to a urea deriva-
tive[8] (see Scheme 1c) instead of serving as a leaving group
for the desired cyclization. Fortunately, when non-benzylic
(i.e., less activated) alcohols were employed instead (en-
tries 4–9), the propensity for this side-reaction was com-
pletely suppressed, leading to a series of six- and seven-
membered ring analogues in excellent yield under standard
reaction conditions (THF, reflux, 2 h). The smooth genera-
tion of compound 154 among these is of particular signifi-
cance, because this bicyclic product is analogous to the ben-
Chem. Eur. J. 2004, 10, 5581 – 5606
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5591

K. C. Nicolaou et al.
FULL PAPER
Table 10. Synthesis of nonsymmetrical cyclic sulfamides from primary
aminoalcohols.
Table 11. Deprotection of carbamate protecting groups from selected sul-
famides.
Entry
Starting
material
Product
Yield
[%]
1
62[a]
39[a]
42[a]
90[b]
Entry
Starting
material
Product
Yield
[%]
2
3
4
1
99[a]
2
99[a]
3
4
5
6
82[b]
98[b]
84[c]
87[c]
5
76[b]
[a] THF, D, 8 h; [b] THF, 0 8C, 1 h, then 258C, 5 h.
portunities for material to travel down alternative pathways.
The modest yields observed in these examples, however, do
not really reflect a limitation in strategy, as the successful
debenzylation of 117 (entry 3, Table 8) through hydrogena-
tion in the presence of Pearlmanꢂs catalyst [Pd(OH)2/C] pro-
vided a route to the same product (159, entry 1, Table 10) in
quantitative yield, thus alleviating the need to start with
ethanolamine (155). As such, this approach provides a tactic
to sequentially substitute bothsides of any cyclic sulfamide
product, if so desired. Finally, in contrast to the results in
the rest of Table 10, when primary aliphatic amines were uti-
lized in conjunction witha secondary benzylic alcohol (en-
tries 4 and 5), product yields were excellent when the reac-
tion was performed at low temperature. While these results
were unanticipated based on the preceding discussion, they
suggest that the activated nature of the leaving group (i.e.,
benzylic) is responsible for this altered, but useful, reactivity.
The smooth formation of the last of these products (164) is
especially interesting, for it is a desymmetrized, meso-sulf-
amide that could, in principle, be employed as a chiral
ligand for applications in asymmetric synthesis.
[a] NaOH, MeOH/H2O (1:1), 258C, 2 h; [b] cat. Pd(PPh3)4, dimethyl mal-
onate, THF, 258C, 3 h; [c] 10% Pd/C, H2, EtOH/EtOAc (4:1), 258C, 2 h.
While this same conversion is more typically achieved by
adding the amine to an appropriate chlorosulfonylisocya-
nate,[37,46] the present conditions provide a mild alternative,
avoiding the direct use of these rather toxic and corrosive
agents which often contain traces of HCl, making them in-
compatible withacid-sensitive functionality (suchas taht
carried by amine 186, entry 8).[47]
With this collection of cyclic sulfamides in hand, we then
verified that the subsequent removal of the carbamate
group can be easily achieved (see Table 11) with convention-
al procedures and can be readily followed by substitution of
appropriate electrophiles (see, for example, the conversion
of 166 into 171).[45] As such, the general and efficient synthe-
sis of compounds represented by structure XIX (Scheme 8)
has been realized.
Finally, beyond the synthesis of cyclic sulfamides, we have
also verified that the Burgess reagent (1) can smoothly
effect the generation of nonsymmetrical, linear sulfamides
from all classes of amines in excellent yield (Table 12).
Conclusion
As these investigations have revealed, the Burgess reagent
(1) and its relatives (48–51) are notably effective at accom-
plishing a number of non-dehydrative synthetic tasks when
applied to appropriate substrates, suchas the formation of
sulfamidates from 1,2-diols or epoxyalcohols, a- and b-glyco-
sylamines from carbohydrates, and cyclic sulfamides from
1,2-aminoalcohols. In each case, the synthetic approach is a
marked improvement over those currently in the literature
and should extend the potential of these synthons as tools
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Burgess Reagent
5581 – 5606
Table 12. Synthesis of linear sulfamides from primary and secondary
amines.
were purchased at the highest commercial quality and used without fur-
ther purification, unless otherwise stated. Reactions were monitored by
thin-layer chromatography (TLC) carried out on 0.25 mm E. Merck silica
gel plates (60F-254) using UV light as visualizing agent and an ethanolic
solution of phosphomolybdic acid and cerium sulfate, and heat as devel-
oping agents. E. Merck silica gel (60, particle size 0.040–0.063 mm) was
used for flash column chromatography. Preparative thin-layer chromatog-
raphy (PTLC) separations were carried out on 0.25 or 0.50 mm E. Merck
silica gel plates (60F-254). NMR spectra were recorded on Bruker DRX-
600, DRX-500, AMX-500 or AMX-400 instruments and calibrated using
residual undeuterated solvent as an internal reference. The following ab-
breviations were used to explain the multiplicities: s=singlet, d=dou-
blet, t=triplet, q=quartet, m=multiplet, quin=quintuplet, sext=sextet,
sep=septet, br=broad, app=apparent, AB=AB quartet. IR spectra
were recorded on a Perkin–Elmer 1600 series FT-IR spectrometer. Elec-
trospray ionization (ESI) mass spectrometry (MS) experiments were per-
formed on an API 100 Perkin–Elmer SCIEX single quadrupole mass
spectrometer at 4000 V emitter voltage. High-resolution mass spectra
(HRMS) were recorded on a VG ZAB-ZSE mass spectrometer using
MALDI (matrix-assisted laser-desorption ionization).
Entry
1
Starting
material
Product
Yield
[%]
83
91
2
3
General procedure for diol synthesis: The appropriate styrene (2.0 mmol,
1.0 equiv) was dissolved in acetone/H2O (19:1, 20 mL) and OsO4
(0.641 mL, 2.5 wt% in tBuOH, 0.05 mmol, 0.025 equiv) and quinuclidine
(0.010 g, catalytic) were added sequentially at 258C. The resultant mix-
ture was then stirred for 12 h at 258C. Upon completion, the reaction
contents were quenched by the addition of saturated aqueous Na2SO3
(5 mL). After the resultant slurry had been stirred for an additional
30 minutes at 258C, the reaction mixture was poured into water (25 mL)
and extracted withCH 2Cl2 (3”25 mL). The combined organic layers
were then washed with water (50 mL), dried (MgSO4), and concentrated.
The resultant yellow-brown residue was purified by flash column chroma-
tography (silica gel) in an appropriate solvent system to give the desired
product in high purity.
82
4
5
6
87
73
97
Data for 7: Rf =0.29 (silica gel, EtOAc/hexanes, 2:1); IR (film): nmax
=
3359, 1616, 1515, 1459, 1247, 1182, 1081, 1026, 893, 818, 548 cmꢀ1
;
1H NMR (500 MHz, CDCl3): d=7.35 (d, J=8.8 Hz, 2H), 6.96 (d, J=
8.5 Hz, 2H), 4.83 (dd, J=8.1, 3.3 Hz, 1H), 3.88 (s, 3H), 3.78 (dd, J=11.4,
3.3 Hz, 1H), 3.71 (dd, J=11.0, 8.1 Hz, 1H), 2.61 (brs, 2H); 13C NMR
(125 MHz, CDCl3): d=159.3, 132.6, 127.3, 113.9, 74.3, 68.0, 55.3; MS
(ESI) calcd for C9H12O3Clꢀ [M+Clꢀ] 203; found: 203.
7
8
66
Data for 9: Rf =0.11 (silica gel, EtOAc/hexanes, 2:1); IR (film): nmax
=
3447, 1739, 1636, 1508, 1373, 1236, 1202, 1081, 1019, 670 cmꢀ1 1H NMR
;
98[a]
(400 MHz, CDCl3): d=7.33 (d, J=8.2 Hz, 2H), 7.04 (d, J=8.2 Hz, 2H),
4.71 (dd, J=7.6, 2.6 Hz, 1H), 3.66 (d, J=11.2 Hz, 1H), 3.56 (dd, J=10.8,
8.2 Hz, 1H), 3.37 (s, 2H), 2.29 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3): d=169.8, 150.0, 138.2, 127.2, 121.5, 74.0, 67.8, 21.1 ppm; HRMS
(MALDI-FTMS) calcd for C10H12O4Na+ [M+Na]+: 219.0628; found:
219.0623.
[a] THF, ꢀ10!258C, 24 h.
Data for 11: Rf =0.60 (silica gel, EtOAc/hexanes, 2:1); IR (film): nmax
=
for chemical biology, ligands for asymmetric synthesis, or
starting materials for a variety of other applications. On a
more global level, these discoveries validate the power of
natural product total synthesis in leading to new chemistry,
as we would not have been inspired to pursue these reac-
tions in the absence of our attempts to use the Burgess re-
agent as part of our campaign to synthesize diazon-
amide A.[7]
3418, 2961, 1636, 1467, 1360, 1247, 1194, 1085, 1027, 873, 713 cmꢀ1
;
1H NMR (500 MHz, CDCl3): d=7.39 (s, 1H), 7.22 (s, 2H), 4.83 (dd, J=
8.1, 3.7 Hz, 1H), 3.78 (dd, J=11.4, 3.7 Hz, 1H), 3.72 (dd, J=11.4, 8.5 Hz,
1H), 2.00 (brs, 2H), 1.34 ppm (s, 18H); 13C NMR (125 MHz, CDCl3): d=
151.1, 140.0, 122.2, 120.2, 75.4, 68.2, 34.9, 31.4 ppm; HRMS (MALDI-
FTMS) calcd for C16H26O2Na+ [M+Na]+: 273.1825; found: 273.1831.
Data for 13: Rf =0.31 (silica gel, EtOAc/hexanes, 2:1); IR (film): nmax
=
3448, 1636, 1512, 1225, 1080, 656 cmꢀ1 1H NMR (500 MHz, CDCl3): d=
;
7.34 (dd, J=8.1, 5.5 Hz, 2H), 7.06 (t, J=8.4 Hz, 2H), 4.82 (brs, 1H), 3.76
(brs, 1H), 3.64 (brs, 1H), 2.31 ppm (brs, 2H); 13C NMR (125 MHz,
CDCl3): d=162.4 (d, J=977 Hz), 136.2, 127.7 (d, J=30.6 Hz), 115.4 (d,
+
J=83.9 Hz), 74.0, 68.0 ppm; MS (GC/MS) calcd for C8H9FO2 [M]+:
Experimental Section
156; found: 156.
Data for 15: Rf =0.35 (silica gel, EtOAc/hexanes, 2:1); IR (film): nmax
=
General procedures: All reactions were carried out under an argon at-
mosphere with dry solvents under anhydrous conditions, unless otherwise
noted. Dry tetrahydrofuran (THF), toluene, diethyl ether (Et2O), and
methylene chloride (CH2Cl2) were obtained by passing commercially
available pre-dried, oxygen-free formulations through activated alumina
columns. Yields refer to chromatographically and spectroscopically
(1H NMR) homogeneous materials, unless otherwise stated. Reagents
3448, 1636, 1490, 1454, 1194, 1071, 1025, 890, 760, 702 cmꢀ1 1H NMR
;
(500 MHz, CDCl3): d=7.35–7.28 (m, 5H), 4.79 (dd, J=8.5, 3.3 Hz, 1H),
3.72 (dd, J=11.4, 3.3 Hz, 1H), 3.63 (dd, J=11.7, 8.4 Hz, 1H), 3.28 ppm
(brs, 2H); 13C NMR (125 MHz, CDCl3): d=140.4, 128.5, 127.9, 126.0,
74.7, 68.0 ppm; HRMS (MALDI-FTMS) calcd for C8H10O2Na+
[M+Na]+: 161.0573; found: 161.0575.
Chem. Eur. J. 2004, 10, 5581 – 5606
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5593

K. C. Nicolaou et al.
FULL PAPER
Data for 17: Rf =0.23 (silica gel, EtOAc/hexanes, 2:1); IR (film): nmax
=
General procedure for the synthesis of CO2Me-protected sulfamidates:
The diol (0.5 mmol, 1.0 equiv) was dissolved in anhydrous THF (5 mL)
and methoxycarbonylsulfamoyl-triethylammonium hydroxide (1, 0.293 g,
1.25 mmol, 2.5 equiv) was added at 258C in a single portion. The resul-
tant solution was immediately warmed to reflux (using a preheated oil
bath) and stirred for 2 h. Upon completion, the reaction contents were
cooled to 258C, poured into saturated aqueous NH4Cl (25 mL), and ex-
tracted withCH 2Cl2 (3”20 mL). The combined organic layers were then
washed with water (50 mL), dried (MgSO4), and concentrated. The resul-
tant yellow residue was purified by flash column chromatography (silica
gel) in an appropriate solvent system to give the desired product in high
purity. Note: although analysis by thin-layer chromatography (TLC) indi-
cated reaction completion after a few minutes, some non-cyclized materi-
al (II, Scheme 2) remained at the baseline, and heating for additional
time was required to effect complete conversion to product. The use of a
preheated oil bath also ensured high yield, as the reaction proceeded
slowly at ambient temperature and appeared to have other reaction path-
ways apart from the desired formation of III.
3391, 1620, 1323, 1174, 1117, 1059, 887, 830, 601 cmꢀ1
;
1H NMR
(400 MHz, CDCl3): d=7.63 (d, J=8.2 Hz, 2H), 7.50 (d, J=7.9 Hz, 2H),
4.90 (dd, J=8.2, 3.2 Hz, 1H), 3.81 (dd, J=11.4, 3.5 Hz, 1H), 3.65 (dd, J=
11.4, 8.2 Hz, 1H), 2.11 ppm (brs, 2H); 13C NMR (100 MHz, CDCl3): d=
+
126.3, 125.5, 125.4, 74.0, 67.9 ppm; MS (GC/MS) calcd for C9H9F3O2
[M]+: 206; found: 206.
Data for 19: Rf =0.14 (silica gel, EtOAc/hexanes, 2:1); IR (film): nmax
=
3391, 2932, 1528, 1352, 1195, 1072, 809, 736, 686 cmꢀ1 1H NMR
;
(400 MHz, CDCl3): d=8.28 (s, 1H), 8.16 (dd, J=8.2, 1.2 Hz, 1H), 7.72
(d, J=7.9 Hz, 1H), 7.55 (t, J=7.9 Hz, 1H), 4.96 (dd, J=8.0, 3.2 Hz, 1H),
3.86 (dd, J=11.2, 3.2 Hz, 1H), 3.67 (dd, J=11.4, 8.2 Hz, 1H), 2.40 ppm
(s, 2H); 13C NMR (100 MHz, CDCl3): d=142.7, 132.2, 129.5, 122.9, 121.1,
+
73.5, 67.7 ppm; MS (GC/MS) calcd for C7H6NO3 [MꢀCH2OH]+: 152;
found: 152.
Data for 27: Rf =0.38 (silica gel, EtOAc/hexanes, 2:1); IR (film): nmax
=
3448, 1636, 1455, 1318, 1075, 594 cmꢀ1 1H NMR (500 MHz, CDCl3): d=
;
7.39–7.36 (m, 4H), 7.30 (m, 1H), 4.69 (d, J=4.4 Hz, 1H), 4.03 (dq, J=
6.6, 4.4 Hz, 1H), 2.08 (brs, 2H), 1.10 ppm (d, J=6.3 Hz, 2H); 13C NMR
(125 MHz, CDCl3): d=140.3, 128.4, 127.8, 126.6, 77.5, 71.3, 17.3 ppm; MS
Data for 6: Rf =0.12 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax
2948, 1747, 1555, 1439, 1369, 1322, 1188, 1089, 898, 845, 822, 752, 607,
554 cmꢀ1 1H NMR (500 MHz, CDCl3): d=7.51 (d, J=8.1 Hz, 1H), 7.45
=
+
(GC/MS) calcd for C9H12O2 [M]+: 152; found: 152.
;
(s, 1H), 7.41 (d, J=7.7 Hz, 1H), 7.32 (s, 1H), 7.16 (t, J=7.7 Hz, 1H),
5.47 (s, 2H), 5.34 (s, 1H), 3.93 (brs, 3H), 3.31 (s, 3H), 1.91 (s, 3H),
1.46 ppm (s, 3H); 13C NMR (150 MHz, CDCl3): d=163.4, 150.4, 137.7,
131.1, 127.3, 126.2, 124.4, 114.1, 110.2, 104.1, 89.5, 78.2, 64.2, 56.5, 55.2,
51.3, 27.1, 24.4 ppm; HRMS (MALDI-FTMS) calcd for C19H21BrN3O7S+
[M+H]+: 514.0278; found: 514.0280.
Data for 29: Rf =0.29 (silica gel, EtOAc/hexanes, 2:1); IR (film): nmax
=
3418, 1636, 1491, 1461, 1243, 1075, 1025, 756 cmꢀ1 1H NMR (600 MHz,
;
CDCl3): d=7.37 (d, J=7.4 Hz, 1H), 7.26 (t, J=7.7 Hz, 1H), 6.96 (t, J=
7.4 Hz, 1H), 6.86 (d, J=7.9 Hz, 1H), 5.05 (dd, J=7.9, 3.1 Hz, 1H), 3.83
(s, 1H), 3.79 (m, 1H), 3.66 ppm (dd, J=11.0, 8.3 Hz, 1H); 13C NMR
(150 MHz, CDCl3): d=156.4, 128.8, 128.3, 127.2, 120.8, 110.3, 71.1, 66.5,
55.2 ppm; HRMS (MALDI-FTMS) calcd for C9H12O3Na+ [M+Na]+:
191.0679; found: 191.0678.
Data for 8: Rf =0.62 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax
=
2961, 1746, 1612, 1516, 1441, 1380, 1321, 1252, 1189, 1031, 921, 822 cmꢀ1
;
1H NMR (500 MHz, CDCl3): d=7.44 (d, J=8.8 Hz, 2H), 7.01 (d, J=
6.6 Hz, 2H), 5.38 (dd, J=6.3, 3.7 Hz, 1H), 4.98 (dd, J=9.2, 6.6 Hz, 1H),
4.54 (dd, J=9.6, 4.1 Hz, 1H), 3.91 (s, 3H), 3.89 ppm (s, 3H); 13C NMR
(125 MHz, CDCl3): d=160.3, 150.1, 128.3, 127.8, 114.6, 72.4, 60.7, 55.3,
54.6 ppm; HRMS (MALDI-FTMS) for C11H13NO6SNa+ [M+Na]+: calcd
310.0356; found: 310.0364.
Data for 31: Rf =0.28 (silica gel, EtOAc/hexanes, 2:1); IR (film): nmax
=
3444, 2953, 1636, 1440, 1081, 598 cmꢀ1 1H NMR (400 MHz, CDCl3): d=
;
6.83 (s, 2H), 5.26 (dd, J=9.7, 2.6 Hz, 1H), 3.97 (t, J=11.2 Hz, 1H), 3.59
(d, J=9.1 Hz, 1H), 2.52 (brs, 2H), 2.41 (s, 6H), 2.25 ppm (s, 3H);
13C NMR (100 MHz, CDCl3): d=137.2, 136.6, 132.4, 130.1, 72.6, 64.6,
20.8, 20.7 ppm; HRMS (MALDI-FTMS) calcd for C11H16O2Na+
[M+Na]+: 203.1042; found: 203.1040.
Data for 10: Rf =0.30 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax
=
2949, 1742, 1634, 1373, 1320, 1192 cmꢀ1; H NMR (500 MHz, CDCl3): d=
7.46 (d, J=6.6 Hz, 2H), 7.16 (d, J=7.2 Hz, 2H), 5.36 (dd, J=6.6, 3.3 Hz,
1H), 4.94 (dd, J=9.2, 6.6 Hz, 1H), 4.49 (dd, J=9.5, 3.7 Hz, 1H), 3.87 (s,
3H), 2.32 ppm (s, 3H); 13C NMR (125 MHz, CDCl3): d=169.3, 151.3,
143.1, 134.0, 127.6, 122.6, 72.2, 60.5, 54.8, 21.1 ppm; HRMS (MALDI-
FTMS) calcd for C12H13NO7SNa+ [M+Na]+: 388.0305; found: 338.0304.
1
Data for 33: Rf =0.29 (silica gel, EtOAc/hexanes, 2:1); IR (film): nmax
=
3190, 2931, 1089, 1049, 903, 863, 823, 742 cmꢀ1 1H NMR (600 MHz,
;
CDCl3): d=7.85 (m, 4H), 7.49 (m, 3H), 5.02 (dd, J=7.9, 3.5 Hz, 1H),
3.87 (dd, J=11.4, 3.5 Hz, 1H), 3.77 ppm (dd, J=11.3, 8.3 Hz, 1H);
13C NMR (125 MHz, 310 K, CDCl3): d=138.0, 133.3, 133.2, 128.4, 128.0,
127.7, 126.3, 126.1, 125.1, 124.0, 74.8, 68.0 ppm; HRMS (MALDI-FTMS)
calcd for C12H12O2Na+ [M+Na]+: 211.0729; found: 211.0727.
Data for 12: Rf =0.79 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax
=
2950, 1750, 1636, 1441, 1383, 1320, 1191, 947, 821 cmꢀ1 1H NMR
;
Data for 35: Rf =0.46 (silica gel, EtOAc/hexanes, 2:1); IR (film): nmax
=
3441, 2953, 1735, 1632, 1453, 1370, 1254, 1119, 1046, 977, 906, 710 cmꢀ1
;
(500 MHz, CDCl3): d=7.45 (s, 1H), 7.26 (s, 2H), 5.35 (dd, J=6.6, 3.3 Hz,
1H), 4.94 (dd, J=9.2, 6.3 Hz, 1H), 4.50 (dd, J=9.2, 3.3 Hz, 1H), 3.87 (s,
3H), 1.33 ppm (s, 18H); 13C NMR (125 MHz, CDCl3) d=151.9, 150.2,
135.7, 123.4, 120.3, 72.7, 61.6, 54.6, 35.0, 31.4 ppm; MS (ESI) calcd for
C18H28NO5S+ [M+H]+: 370; found: 370.
1H NMR (600 MHz, CDCl3): d=7.39–7.32 (m, 5H), 4.83 (s, 1H), 3.83 (s,
3H), 1.17 ppm (s, 3H); 13C NMR (150 MHz, CDCl3): d=176.3, 138.6,
128.3, 128.1, 127.8, 78.0, 77.4, 53.1, 22.1 ppm; HRMS (MALDI-FTMS)
calcd for C11H14O4Na+ [M+Na]+: 233.0784; found: 233.0782.
Data for 14: Rf =0.56 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax
=
Data for 37: Rf =0.22 (silica gel, EtOAc/hexanes, 2:1); IR (film): nmax
=
2953, 1750, 1654, 1608, 1512, 1442, 1381, 1321, 1231, 1190, 922, 815 cmꢀ1
;
3420, 2981, 1736, 1639, 1443, 1381, 1277, 1215, 1163, 1095, 982, 756 cmꢀ1
;
1H NMR (500 MHz, CDCl3): d=7.43 (dd, J=8.5, 4.8 Hz, 2H), 7.12 (t,
J=8.8 Hz, 2H), 5.35 (dd, J=6.6, 3.7 Hz, 1H), 4.94 (dd, J=9.2, 6.6 Hz,
1H), 4.46 (dd, J=9.5, 3.3 Hz, 1H), 3.86 ppm (s, 3H); 13C NMR
(125 MHz, CDCl3): d=164.1, 162.1, 150.0, 128.2 (d, J=30.6 Hz), 116.3 (d,
J=87.8 Hz), 72.2, 60.4, 54.7 ppm; HRMS (MALDI-FTMS) calcd for
C10H10FNO5SNa+ [M+Na]+: 298.0156; found: 298.0153.
1H NMR (600 MHz, CDCl3): d=3.94 (s, 1H), 3.76 (s, 3H), 3.33 (brs,
2H), 1.24 (s, 3H), 1.16 ppm (s, 3H); 13C NMR (150 MHz, CDCl3): d=
173.4, 72.0, 52.3, 43.1, 25.6, 24.8 ppm; HRMS (MALDI-FTMS) calcd for
C6H12O4Na+ [M+Na]+: 171.0628; found: 171.0626.
Data for 39: Rf =0.18 (silica gel, EtOAc/hexanes, 2:1); IR (film): nmax
=
3389, 2931, 2859, 1643, 1528, 1460, 1346, 1127, 1063 cmꢀ1 1H NMR
;
Data for 16: Rf =0.56 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax
=
(400 MHz, CDCl3): d=3.68 (brm, 2H), 3.44 (brt, J=10.3 Hz, 1H), 2.67
(s, 2H), 1.43–1.33 (brm, 6H), 0.91 ppm (m, 3H); 13C NMR (100 MHz,
CDCl3): d=72.3, 66.7, 32.8, 27.7, 22.7, 14.0 ppm; MS (GC/MS) calcd for
C5H11O+ [MꢀCH2OH]+: 87; found: 87.
2955, 1744, 1654, 1636, 1442, 1380, 1321, 1191 cmꢀ1 1H NMR (600 MHz,
;
CDCl3): d=7.44–7.40 (m, 5H), 5.36 (dd, J=6.6, 3.5 Hz, 1H), 4.95 (dd,
J=9.2, 6.6 Hz, 1H), 4.49 (dd, J=9.7, 4.0 Hz, 1H), 3.86 ppm (s, 3H);
13C NMR (150 MHz, CDCl3): d=150.1, 136.4, 129.3, 129.2, 126.2, 72.3,
61.0, 54.7 ppm; HRMS (MALDI-FTMS) calcd for C10H11NO5SNa+
[M+Na]+: 280.0250; found: 250.0253.
Data for 41: Rf =0.24 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax
=
1
3440, 2949, 1643, 1138, 1071, 1027, 658 cmꢀ1; H NMR (500 MHz, CDCl3,
1:1 mixture of anomers): d=5.50 (d, J=4.8 Hz, 1H), 4.95 (d, J=5.5 Hz,
1H), 4.92 (s, 1H), 4.78 (dd, J=5.9, 4.4 Hz, 1H), 3.95–3.87 (m, 3H), 3.67
(brs, 1H), 3.52–3.44 (m, 2H), 3.42–3.35 (m, 2H), 2.02 (m, 1H), 1.82 (m,
1H), 1.57 (m, 2H), 1.56 (m, 2H), 1.43 ppm (m, 2H); 13C NMR
(125 MHz, CDCl3, 1:1 mixture of anomers): d=98.5, 93.4, 70.2, 67.7, 65.1,
Data for 18: Rf =0.66 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax
2924, 1747, 1622, 1443, 1384, 1324, 1193, 1117, 1069, 1017, 1002, 923, 822,
771, 665 cmꢀ1 1H NMR (500 MHz, CDCl3): d=7.78 (d, J=8.1 Hz, 2H),
=
;
7.65 (d, J=8.1 Hz, 2H), 5.49 (dd, J=6.3, 3.3 Hz, 1H), 5.06 (dd, J=9.6,
6.6 Hz, 1H), 4.54 (dd, J=9.5, 3.3 Hz, 1H), 3.96 ppm (s, 3H); 13C NMR
(125 MHz, CDCl3): d=150.0, 140.4, 126.8, 126.5, 126.4, 71.9, 60.5,
+
61.8, 29.3, 27.3, 24.1, 22.2 ppm; MS (GC/MS) calcd for C5H10O3 [M]+:
118; found: 118.
5594
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 5581 – 5606

Burgess Reagent
5581 – 5606
55.0 ppm; HRMS (MALDI-FTMS) calcd for C11H10F3NO5SNa+
General procedure for the synthesis of alternative Burgess reagents 48–
51: A solution of the appropriate alcohol (105 mmol, 1.05 equiv) in
CH2Cl2 (25 mL) was added over the course of 30 minutes to a solution of
chlorosulfonylisocyanate (8.71 mL, 100 mmol, 1.0 equiv) in CH2Cl2
(25 mL) at 08C. Once the addition was complete, the reaction contents
were concentrated directly to give the desired sulfamoyl chloride inter-
mediate (44–47) as a white solid. Pressing forward without any additional
purification steps, a solution of the newly formed sulfamoyl chloride
(20.0 mmol, 1.0 equiv) in benzene (40 mL) was added dropwise to a so-
lution of Et3N (6.27 mL, 45 mmol, 2.25 equiv) in benzene (25 mL) at
258C. After the addition was complete (~1 hour), the triethylammonium
hydrochloride precipitate was removed by filtration, and the filtrate was
concentrated to give 48–51 as clear oils which solidified upon standing.
[M+Na]+: 348.0124; found: 348.0121.
Data for 20: Rf =0.36 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax
=
2994, 1732, 1643, 1538, 1324, 1192 cmꢀ1; H NMR (500 MHz, CDCl3): d=
8.36 (d, J=8.1 Hz, 1H), 8.28 (d, J=7.4 Hz, 1H), 7.87 (t, J=7.7 Hz, 1H),
7.67 (t, J=7.7 Hz, 1H), 5.48 (dd, J=6.6, 2.9 Hz, 1H), 5.02 (dd, J=9.2,
6.6 Hz, 1H), 4.48 (dd, J=9.3, 6.3 Hz, 1H), 3.91 ppm (s, 3H); 13C NMR
(125 MHz, CDCl3): d=150.1, 132.2, 132.0, 130.7, 125.3, 124.4, 121.7, 78.4,
60.2, 55.0 ppm; MS (ESI) calcd for C10H10N2O7SNa+ [M+Na]+: 325;
found: 325.
1
Data for 28: Rf =0.60 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax
2977, 1747, 1439, 1375, 1311, 1188, 1136, 1037, 964, 914, 870, 830, 755,
700, 611, 551 cmꢀ1 1H NMR (600 MHz, CDCl3): d=7.43–7.39 (m, 5H),
=
;
Cbz-protected Burgess-type reagent 48: Rf =0.03 (silica gel, EtOAc); IR
(film): nmax =2985, 1688, 1455, 1376, 1330, 1255, 1097, 853, 786, 740, 700,
4.93 (d, J=7.4 Hz, 1H), 4.77 (quin, J=6.1 Hz, 1H), 3.80 (s, 3H),
1.61 ppm (d, J=6.1 Hz, 3H); 13C NMR (150 MHz, CDCl3): d=150.3,
135.5, 129.6, 126.8, 82.6, 68.4, 54.6, 17.4 ppm; HRMS (MALDI-FTMS)
calcd for C11H13NO5SNa+ [M+Na]+: 294.0407; found: 294.0402.
598, 548 cmꢀ1 1H NMR (500 MHz, CDCl3): d=7.41–7.28 (m, 5H), 5.13
;
(s, 2H), 3.44 (q, J=7.4 Hz, 6H), 1.39 ppm (t, J=7.4 Hz, 9H); 13C NMR
(125 MHz, CDCl3): d=157.5, 136.3, 128.4, 128.2, 128.0, 67.9, 50.4,
9.4 ppm; MS (ESI) calcd for C14H22N2O4SNa+ [M+Na]+: 337; found:
337.
Data for 30: Rf =0.58 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax
2961, 1747, 1603, 1493, 1441, 1381, 1323, 1249, 1194, 1085, 1025, 1002,
921, 827, 777, 663 cmꢀ1 1H NMR (600 MHz, CDCl3): d=7.38–7.34 (m,
=
;
o-NO2-Cbz-protected Burgess-type reagent 49: Rf =0.03 (silica gel,
EtOAc); IR (film): nmax =3516, 1697, 1527, 1485, 1341, 1246, 1100, 1060,
2H), 7.02 (t, J=7.4 Hz, 1H), 6.93 (d, J=7.9 Hz, 1H), 5.74 (d, J=5.7 Hz,
1H), 4.93 (dd, J=9.2, 6.6 Hz, 1H), 4.44 (dd, J=9.2, 2.2 Hz, 1H), 3.89 (s,
3H), 3.87 ppm (s, 3H); 13C NMR (150 MHz, CDCl3): d=155.9, 150.3,
130.1, 125.9, 124.2, 121.1, 110.6, 72.5, 56.7, 55.5, 54.8 ppm; HRMS
(MALDI-FTMS) calcd for C11H30NO6Na+ [M+Na]+: 310.0356; found:
310.0369.
856, 730, 600, 548 cmꢀ1 1H NMR (400 MHz, CDCl3): d=7.99 (d, J=
;
8.0 Hz, 1H), 7.61 (d, J=7.6 Hz, 1H), 7.55 (t, J=7.6 Hz, 1H), 7.36 (t, J=
7.6 Hz, 1H), 5.42 (s, 2H), 3.38 (q, J=7.0 Hz, 6H), 1.32 ppm (t, J=7.3 Hz,
9H); 13C NMR (100 MHz, CDCl3): d=157.0, 133.8, 132.9, 129.0, 128.5,
128.3, 124.8, 64.5, 50.6, 9.3 ppm; MS (ESI) calcd for C14H22N3O6S+
[M+H]+: 360; found: 360.
Data for 32: Rf =0.63 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax
2954, 1747, 1612, 1442, 1378, 1312, 1190, 1047, 962, 931, 819, 776, 734,
632 cmꢀ1 1H NMR (500 MHz, CDCl3): d=6.89 (s, 2H), 5.87 (t, J=
=
Alloc-protected Burgess-type reagent 50: Rf =0.03 (silica gel, EtOAc);
IR (film): nmax =2995, 2948, 1693, 1457, 1332, 1161, 1098, 970, 859, 788,
;
8.8 Hz, 1H), 4.74 (dd, J=9.6, 8.1 Hz, 1H), 4.59 (t, J=7.5 Hz, 1H), 3.84
(s, 3H), 2.45 (s, 6H), 2.27 ppm (s, 3H); 13C NMR (125 MHz, CDCl3): d=
150.6, 138.9, 136.8, 136.6, 126.3, 68.4, 57.3, 54.6, 20.8, 20.2 ppm; MS (ESI)
calcd for C14H17NO5S+ [M+H]+: 300; found: 300.
714, 597, 548 cmꢀ1 1H NMR (500 MHz, CDCl3): d=5.91 (m, 1H), 5.30
;
(d, J=16.2 Hz, 1H), 5.18 (d, J=10.3 Hz, 1H), 4.54 (s, 2H), 3.45 (q, J=
7.4 Hz, 6H), 1.39 ppm (t, J=7.0 Hz, 9H); 13C NMR (125 MHz, CDCl3):
d=157.2, 132.5, 117.9, 66.6, 50.5, 9.3 ppm; MS (ESI) calcd for
C10H21N2O4S+ [M+H]+: 265; found: 265.
Data for 34: Rf =0.59 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax
=
2961, 1740, 1435, 1376, 1317, 1188, 1000, 923, 812, 753 cmꢀ1 1H NMR
;
Troc-protected Burgess-type reagent 51: Rf =0.03 (silica gel, EtOAc); IR
(film): nmax =2950, 1702, 1457, 1368, 1339, 1254, 1111, 1059, 857, 816, 716,
(500 MHz, CDCl3): d=7.94–7.85 (m, 4H), 7.56–7.52 (m, 3H), 5.53 (dd,
J=6.6, 3.7 Hz, 1H), 5.00 (dd, J=9.6, 7.0 Hz, 1H), 4.56 (dd, J=9.6,
4.0 Hz, 1H), 3.85 ppm (s, 3H); 13C NMR (125 MHz, CDCl3): d=150.2,
133.6, 133.5, 133.1, 129.6, 128.2, 127.8, 126.9, 126.8, 126.1, 123.0, 72.1,
61.2, 54.7 ppm; HRMS (MALDI-FTMS) calcd for C14H13NO5SNa+
[M+Na]+: 330.0407; found: 330.0409.
605, 548 cmꢀ1 1H NMR (400 MHz, CDCl3): d=4.75 (s, 2H), 3.48 (q, J=
;
7.4 Hz, 6H), 1.43 ppm (t, J=7.3 Hz, 9H); 13C NMR (100 MHz, CDCl3):
d=156.0, 95.4, 75.3, 50.7, 9.3 ppm; MS (ESI) calcd for C9H18Cl3N2O4S+
[M+H]+: 355; found: 355.
General procedure for synthesizing sulfamidates with alternate protec-
tion: The diol (0.5 mmol, 1.0 equiv) was dissolved in anhydrous THF
(5 mL) and the appropriate Burgess-type reagent (48–51, 1.25 mmol,
2.5 equiv) was added at 258C in a single portion. The resultant solution
was immediately warmed to reflux (using a preheated oil bath) and stir-
red for 2 h. Upon completion, the reaction contents were cooled to 258C,
poured into saturated aqueous NH4Cl (25 mL), and extracted with
CH2Cl2 (3”20 mL). The combined organic layers were then washed with
water (50 mL), dried (MgSO4), and concentrated. The resultant yellow
residue was purified by flash column chromatography (silica gel) in an
appropriate solvent system to give the desired product in high purity.
Data for 36: Rf =0.40 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax
=
2966, 1746, 1441, 1376, 1311, 1194, 1135, 1059, 959, 918, 841, 765,
694 cmꢀ1 1H NMR (500 MHz, CDCl3): d=7.43 (m, 2H), 7.36 (m, 3H),
;
5.23 (s, 1H), 3.86 (s, 3H), 3.31 (s, 3H), 2.11 ppm (s, 3H); 13C NMR
(125 MHz, CDCl3): d=163.3, 150.0, 134.3, 129.8, 128.9, 127.8, 88.7, 69.7,
55.1, 53.1, 23.9 ppm; HRMS (MALDI-FTMS) calcd for C13H15NO7SNa+
[M+Na]+: 352.0461; found: 352.0474.
Data for 38: Rf =0.65 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax
=
2955, 1749, 1588, 1443, 1378, 1321, 1227, 1177, 1115, 1049, 976, 837,
1
643 cmꢀ1; H NMR (600 MHz, CDCl3): d=5.32 (s, 1H), 3.93 (s, 3H), 3.85
(s, 3H), 1.58 (s, 3H), 1.56 ppm (s, 3H); 13C NMR (150 MHz, CDCl3): d=
164.9, 158.6, 83.4, 59.2, 53.5, 25.3, 19.3 ppm; MS (ESI) calcd for
C8H13NO7SNa+ [M+Na]+: 290; found: 290.
Data for 52: Rf =0.49 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax
=
2998, 1740, 1612, 1516, 1381, 1306, 1252, 1192, 1030, 974, 808, 750 cmꢀ1
;
1H NMR (600 MHz, CDCl3): d=7.33–7.30 (m, 5H), 7.25 (m, 2H), 6.90
(d, J=8.8 Hz, 2H), 5.28 (dd, J=6.6, 4.4 Hz, 1H), 5.21 (AB, J=12.3 Hz,
nab =59.2 Hz, 2H), 4.87 (dd, J=9.2, 6.5 Hz, 1H), 4.44 (dd, J=9.2, 4.4 Hz,
1H), 3.81 ppm (s, 3H); 13C NMR (150 MHz, CDCl3): d=161.2, 150.4,
135.2, 129.4, 129.3, 129.2, 128.8, 128.7, 115.5, 73.1, 70.2, 61.6, 56.2 ppm;
HRMS (MALDI-FTMS) calcd for C17H17NO6SNa+ [M+Na]+: 386.0669;
found: 386.0666.
Data for 40: Rf =0.60 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax
=
2948, 1747, 1444, 1375, 1328, 1194, 985, 851, 764 cmꢀ1 1H NMR
;
(600 MHz, CDCl3): d=4.86 (m, 1H), 4.12 (dd, J=10.1, 4.8 Hz, 1H), 3.91
(s, 3H), 3.73 (t, J=9.7 Hz, 1H), 1.95 (m, 1H), 1.78 (m, 1H), 1.47 (m,
1H), 1.40 (m, 3H), 0.94 ppm (t, J=5.0 Hz, 3H); 13C NMR (150 MHz,
CDCl3): d=150.7, 80.5, 54.8, 51.0, 32.3, 26.8, 22.3, 13.9 ppm; HRMS
(MALDI-FTMS) calcd for C8H15NO5SNa+ [M+Na]+: 260.0563; found:
260.0556.
Data for 53: Rf =0.51 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax
=
2974, 1746, 1637, 1457, 1377, 1306, 1195, 1136, 1065, 847, 764, 700 cmꢀ1
;
Data for 42: Rf =0.15 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax
2962, 1749, 1443, 1380, 1327, 1295, 1182, 1123, 1071, 965, 899, 877, 831,
603, 560 cmꢀ1 1H NMR (500 MHz, CDCl3): d=5.50 (d, J=2.6 Hz, 1H),
=
1H NMR (600 MHz, CDCl3): d=7.41–7.23 (m, 10H), 5.23 (AB, J=
12.2 Hz, nab =65.8 Hz, 2H), 5.21 (s, 1H), 3.29 (s, 3H), 2.08 ppm (s, 3H);
13C NMR (150 MHz, CDCl3): d=167.0, 150.1, 134.9, 130.5, 129.6, 129.5,
128.6, 128.4, 89.2, 70.5, 70.3, 53.7, 24.6 ppm; HRMS (MALDI-FTMS)
calcd for C19H19NO7SNa+: [M+Na]+ 428.0774; found: 428.0780.
;
4.83 (q, J=3.0 Hz, 1H), 4.02 (m, 1H), 3.91 (s, 3H), 3.58 (ddd, J=13.2,
10.3, 3.3 Hz, 1H), 2.36 (dt, J=13.2, 2.2 Hz, 1H), 2.01–1.85 (m, 2H),
1.60 ppm (m, 1H); 13C NMR (125 MHz, CDCl3): d=149.5, 81.9, 76.6,
63.4, 54.6, 23.8, 17.6 ppm; HRMS (MALDI-FTMS) calcd for
C7H11NO6SNa+ [M+Na]+: 260.0199; found: 260.0200.
Data for 54: Rf =0.36 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax
=
2967, 1746, 1603, 1529, 1493, 1464, 1383, 1345, 1317, 1250, 1194, 1025,
Chem. Eur. J. 2004, 10, 5581 – 5606
www.chemeurj.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5595

K. C. Nicolaou et al.
FULL PAPER
921, 815, 729 cmꢀ1
;
1H NMR (500 MHz, CDCl3): d=8.15 (d, J=8.1 Hz,
Data for 61: Rf =0.53 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax
=
3204, 1694, 1537, 1438, 1265, 1053, 833, 750 cmꢀ1 1H NMR (600 MHz,
;
1H), 7.81–7.62 (brm, 2H), 7.51 (t, J=8.4 Hz, 1H), 7.38 (d, J=7.0 Hz,
1H), 7.36 (t, J=8.1 Hz, 1H), 7.01 (t, J=7.7 Hz, 1H), 6.94 (d, J=8.1 Hz,
1H), 5.82–5.79 (m, 2H), 5.69 (brm, 1H), 4.99 (dd, J=9.2, 6.3 Hz, 1H),
4.50 (dd, J=9.2, 2.6 Hz, 1H), 3.87 ppm (s, 3H); 13C NMR (150 MHz,
CDCl3): d=155.9, 149.0, 146.6, 134.3, 131.3, 130.2, 128.8, 128.2, 125.8,
125.1, 123.8, 121.1, 110.7, 72.6, 66.0, 56.6, 55.5 ppm; HRMS (MALDI-
FTMS) calcd for C17H12N2O8SNa+ [M+Na]+: 431.0520; found: 431.0530.
CDCl3): d=7.87–7.84 (m, 3H), 7.79 (brs, 1H), 7.50 (m, 2H), 7.42 (brd,
J=8.3 Hz, 1H), 5.47 (brs, 1H), 5.25 (brs, 1H), 3.72 (s, 3H), 2.16 ppm (m,
2H); 13C NMR (125 MHz, CDCl3): d=156.3, 136.0, 133.2, 133.0, 128.7,
128.0, 127.7, 126.5, 126.3, 125.6, 124.2, 55.7, 52.5, 47.9 ppm; MS (GC/MS)
+
calcd for C14H13NO2 [MꢀH2O]+: 227; found: 227.
Data for 62: Rf =0.59 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax
=
3418, 2966, 1698, 1534, 1452, 1376, 1254, 1192, 1058, 852, 776, 703 cmꢀ1
;
Data for 55: Rf =0.50 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax
=
1H NMR (500 MHz, CDCl3): d=6.85 (s, 2H), 5.42 (brs, 1H), 5.24 (brs,
2H), 3.89 (t, J=9.9 Hz, 1H), 3.73 (dd, J=11.4, 6.6 Hz, 1H), 3.68 (s, 3H),
2.42 (s, 6H), 2.25 ppm (s, 3H); 13C NMR (125 MHz, CDCl3): d=156.5,
137.6, 136.0, 131.7, 130.5, 52.4, 46.2, 44.8, 20.9, 20.7 ppm; MS (GC/MS)
2969, 1740, 1612, 1528, 1381, 1301, 1193, 962, 814, 730, 633 cmꢀ1
;
1H NMR (600 MHz, CDCl3): d=8.15 (d, J=7.9 Hz, 1H), 7.64–7.57 (m,
2H), 7.50 (t, J=7.9 Hz, 1H), 6.87 (s, 2H), 5.92 (t, J=8.8 Hz, 1H), 5.68
(AB, J=12.8 Hz, nab =15.3 Hz, 2H), 4.77 (t, J=8.3 Hz, 1H), 4.64 (t, J=
9.2 Hz, 1H), 2.43 (s, 6H), 2.26 ppm (s, 3H); 13C NMR (150 MHz,
CDCl3): d=163.1, 149.4, 146.5, 139.1, 134.3, 131.1, 128.8, 128.3, 128.0,
126.0, 125.1, 68.6, 66.0, 57.4, 20.8, 20.3 ppm; MS (ESI) calcd for
C19H20N2O7SNa+ [M+Na]+: 443; found: 443.
+
calcd for C12H16NO2 [MꢀOMe]+: 206; found: 206.
Data for 63: Rf =0.68 (silica gel, EtOAc/hexanes, 1:2); IR (film): nmax
=
3431, 2987, 1697, 1642, 1535, 1453, 1252, 1091, 702 cmꢀ1 1H NMR
;
(500 MHz, CDCl3): d=7.37–7.31 (m, 5H), 5.54 (brs, 1H) 4.93 (brs, 1H),
4.46 (brs, 1H), 3.68 (s, 3H), 1.38 ppm (d, J=6.6 Hz, 3H); 13C NMR
(125 MHz, CDCl3): d=156.1, 137.0, 128.3, 128.1, 127.9, 60.8, 59.6, 52.4,
Data for 56: Rf =0.43 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax
2945, 1745, 1603, 1494, 1464, 1380, 1314, 1249, 1193, 1025, 925, 826,
757 cmꢀ1 1H NMR (500 MHz, CDCl3): d=7.37 (t, J=7.7 Hz, 1H), 7.34
=
+
21.6 ppm; GC-MS (ESI) calcd for C9H9NO2 [MꢀCH3CH2OH]+: 164;
;
found: 164.
(d, J=7.7 Hz, 1H), 7.02 (t, J=7.3 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 5.89
(m, 1H), 5.76 (dd, J=6.3, 2.2 Hz, 1H), 5.37 (brm, 1H), 5.27 (d, J=
10.3 Hz, 1H), 4.94 (dd, J=9.2, 6.2 Hz, 1H), 4.75 (ddd, J=25.3, 13.2,
5.1 Hz, 2H), 4.45 (dd, J=9.2, 2.2 Hz, 1H), 3.87 ppm (s, 3H); 13C NMR
(125 MHz, CDCl3): d=155.9, 149.4, 130.5, 130.0, 125.8, 124.1, 121.0,
119.1, 110.6, 72.4, 68.1, 56.5, 55.4 ppm; HRMS (MALDI-FTMS) calcd for
C13H15NO6SNa+ [M+Na]+: 336.0512; found: 336.0515.
Data for 64: Rf =0.72 (silica gel, EtOAc/hexanes, 1:2); IR (film): nmax
=
3349, 2958, 1698, 1643, 1535, 1463, 1259, 614 cmꢀ1 1H NMR (500 MHz,
;
CDCl3): d=5.13 (brs, 1H), 3.99 (t, J=4.1 Hz, 1H), 3.69 (s, 3H), 3.64
(ddd, J=14.7, 7.3, 3.3 Hz, 1H), 3.24 (ddd, J=14.0, 8.1, 5.5 Hz, 1H), 1.74
(m, 1H), 1.68 (m, 1H), 1.53 (m, 1H), 1.44–1.30 (m, 3H), 0.91 ppm (t, J=
7.3 Hz, 3H); 13C NMR (125 MHz, CDCl3): d=157.0, 63.2, 52.3, 47.5, 35.2,
+
28.4, 22.1, 13.9 ppm; GC-MS (ESI) calcd for C3H6NO2
Data for 57: Rf =0.56 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax
=
[MꢀCH3CH2CH2CH2CHOH]+: 88; found: 88.
2953, 1740, 1649, 1381, 1305, 1192, 964, 819, 767, 632 cmꢀ1 1H NMR
;
Data for 65: Rf =0.56 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax
=
(500 MHz, CDCl3): d=6.89 (s, 2H), 5.87 (dd, J=8.8, 8.1 Hz, 1H), 5.82
(m, 1H), 5.31 (d, J=16.9 Hz, 1H), 5.24 (dd, J=10.6, 1.1 Hz, 1H), 4.75–
4.71 (m, 2H), 4.66 (m, 1H), 4.58 (t, J=9.2 Hz, 1H), 2.44 (s, 6H),
2.27 ppm (s, 3H); 13C NMR (125 MHz, CDCl3): d=158.1, 149.9, 138.9,
136.8, 130.4, 126.3, 119.2, 68.3, 68.0, 57.3, 20.8, 20.3 ppm; MS (ESI) calcd
for C15H19NO5SNa+ [M+Na]+: 348; found: 348.
3332, 2956, 1693, 1611, 1513, 1462, 1294, 1248, 1179, 1036, 831, 740,
1
698 cmꢀ1; H NMR (500 MHz, CDCl3): d=7.40–7.29 (m, 5H), 7.24 (d, J=
8.4 Hz, 2H), 6.90 (d, J=8.4 Hz, 1H), 5.35 (brs, 1H), 5.12 (AB, J=
12.1 Hz, nab =16.9 Hz, 2H), 5.03 (brs, 1H), 3.85 (m, 2H), 3.81 ppm (s,
3H); 13C NMR (100 MHz, CDCl3): d=159.4, 155.6, 136.1, 130.6, 128.5,
128.2, 128.1 (2C), 127.7, 114.1, 114.0, 67.1, 55.3, 55.1, 47.9 ppm; MS (GC/
Data for 58: Rf =0.48 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax
2954, 1749, 1455, 1373, 1306, 1189, 1131, 1060, 931, 849, 760, 696,
549 cmꢀ1 1H NMR (600 MHz, CDCl3): d=7.45 (m, 2H), 7.36 (m, 2H),
=
+
MS) calcd for C17H17NO3 [MꢀH2O]+: 283; found: 283.
Data for 66: Rf =0.48 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax
=
;
3417, 3342, 2955, 1712, 1609, 1523, 1463, 1344, 1244, 1050, 756, 731 cmꢀ1
;
5.86 (m, 1H), 5.34 (d, J=17.1 Hz, 1H), 5.25 (d, J=10.6 Hz, 1H), 5.24 (s,
1H), 4.73 (ABX, J=13.6, 5.7 Hz, nab =39.5 Hz, 2H), 3.32 (s, 3H),
2.11 ppm (s, 3H); 13C NMR (150 MHz, CDCl3): d=166.4, 149.4, 134.6,
130.6, 129.8, 128.9, 127.9, 119.5, 88.6, 69.9, 68.7, 53.0, 24.1 ppm; HRMS
(MALDI-FTMS) calcd for C15H17NO7SNa+ [M+Na]+: 378.0618; found:
378.0612.
1H NMR (500 MHz, CDCl3): d=8.10 (d, J=8.1 Hz, 1H), 7.63 (m, 2H),
7.47 (t, J=7.0 Hz, 1H), 7.32 (t, J=7.0 Hz, 1H), 7.26 (d, J=8.7 Hz, 1H),
6.98 (t, J=7.7 Hz, 1H), 6.93 (d, J=8.5 Hz, 1H), 5.94 (d, J=9.2 Hz, 1H),
5.54 (AB, J=15.0 Hz, nab =31.2 Hz, 2H), 5.22 (dt, J=9.2, 6.3 Hz, 1H),
3.89 (s, 3H), 3.85 ppm (d, J=5.5 Hz, 2H); 13C NMR (125 MHz, CDCl3):
d=156.7, 155.2, 133.7, 133.1, 129.5, 129.1, 128.8, 128.5, 125.8, 124.9, 120.8,
+
Data for 59: Rf =0.47 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax
2966, 1754, 1603, 1494, 1464, 1384, 1316, 1250, 1196, 1149, 1025, 924, 830,
752 cmꢀ1 1H NMR (500 MHz, CDCl3): d=7.40 (d, J=7.3 Hz, 1H), 7.36
=
110.9, 63.5, 55.4, 54.2, 46.5 ppm; MS (GC/MS) calcd for C16H15N2O5
[MꢀOMe]+: 315; found: 315.
;
Data for 67: Rf =0.56 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax
=
(dd, J=7.7, 1.5 Hz, 1H), 7.02 (t, J=7.3 Hz, 1H), 6.93 (d, J=8.5 Hz, 1H),
5.84 (dd, J=6.3, 2.6 Hz, 1H), 4.98 (dd, J=9.2, 6.3 Hz, 1H), 4.86–4.78 (m,
2H), 4.48 (dd, J=9.2, 2.6 Hz, 1H), 3.87 ppm (s, 3H); 13C NMR
(125 MHz, CDCl3): d=156.0, 148.3, 130.2, 126.0, 123.6, 121.1, 110.6, 75.7,
72.4, 56.6, 55.5, 43.3 ppm; MS (ESI) calcd for C12H13Cl3NO6S+ [M+H]+:
404; found: 404.
3318, 1682, 1643, 1539, 1484, 1235, 1049, 932, 752 cmꢀ1
;
1H NMR
(500 MHz, CDCl3): d=7.30 (dt, J=8.1, 1.5 Hz, 1H), 7.25 (d, J=7.3 Hz,
1H), 6.97 (t, J=7.7 Hz, 1H), 6.91 (d, J=8.1 Hz, 1H), 5.92 (m, 1H), 5.80
(d, J=8.8 Hz, 1H), 5.32 (d, J=16.5 Hz, 1H), 5.22 (m, 2H), 4.59 (m, 2H),
3.88 (s, 3H), 3.84 ppm (d, J=5.9 Hz, 2H); 13C NMR (125 MHz, CDCl3):
d=156.7, 132.7, 129.4, 129.2, 126.1, 120.8, 118.0, 110.8, 65.8, 55.3, 54.0,
+
46.6 ppm; MS (GC/MS) calcd for C12H9NO3 [MꢀOMe]+: 220; found:
Data for 60: Rf =0.30 (silica gel, EtOAc/hexanes, 1:2); IR (film): nmax
=
2938, 1750, 1376, 1315, 1270, 1198, 1137, 1098, 902, 830, 752, 607 cmꢀ1
;
220.
1H NMR (500 MHz, CDCl3): d=7.52 (d, J=9.7 Hz, 1H), 7.44 (s, 1H),
7.42 (d, J=8.8 Hz, 1H), 7.35 (s, 1H), 7.17 (t, J=9.7 Hz, 1H), 5.48 (s,
2H), 5.39 (s, 2H), 4.97 (d, J=14.1 Hz, 1H), 4.78 (brs, 1H), 3.30 (s, 3H),
1.95 (s, 3H), 1.50 ppm (s, 3H); 13C NMR (125 MHz, CDCl3): d=156.3,
148.6, 147.1, 137.7, 131.1, 127.3, 126.3, 126.1, 124.4, 114.1, 110.2, 104.1,
93.8, 89.7, 78.2, 76.2, 64.3, 56.5, 27.2, 24.5; HRMS (MALDI-FTMS) calcd
for C20H20BrCl3N3O7SNa+ [M+Na]+: 629.9265; found: 629.9263.
Data for 68: Rf =0.68 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax
=
3435, 1716, 1636, 1497, 1244, 1033, 721 cmꢀ1 1H NMR (600 MHz,
;
CDCl3): d=7.38 (t, J=7.4 Hz, 1H), 7.27 (m, 1H), 6.98 (t, J=7.4 Hz,
1H), 6.93 (d, J=8.3 Hz, 1H), 6.93 (d, J=8.3 Hz, 1H), 6.00 (d, J=8.8 Hz,
1H), 5.23 (dd, J=15.3, 6.1 Hz, 1H), 4.75 (AB, J=11.9 Hz, nab =39.1 Hz,
2H), 3.91 (s, 3H), 3.86 ppm (dd, J=6.6, 2.6 Hz, 2H); 13C NMR
(150 MHz, CDCl3): d=156.7, 154.0, 129.6, 129.0, 125.5, 120.9, 110.9, 74.6,
+
55.4, 54.3, 46.3 ppm; MS (GC/MS) calcd for C11H11Cl3NO3 [MꢀOMe]+:
General procedure for synthesizing 1,2-aminoalcohols from sulfamidates:
The desired substrate (0.05 mmol, 1.0 equiv) was dissolved in 4m aqueous
HCl/1,4-dioxane (1:1, 1 mL), and the resultant solution was stirred at
258C until complete conversion was observed by TLC (~10–12 h). Once
finished, the reaction mixture was poured into EtOAc (10 mL), washed
310; found: 310.
3,4,6-Tri-O-benzyl-d-glucosyldiol (69): 4-Methylmorpholine N-oxide
(0.351 g, 3.0 mmol, 3.0 equiv) and OsO4 (0.641 mL, 2.5 wt% in tBuOH,
0.05 mmol, 0.05 equiv) were added sequentially at 258C to a solution of
3,4,6-tri-O-benzyl-d-glucal (0.417 g, 1.0 mmol, 1.0 equiv) in THF/tBuOH/
H2O (7:3:1, 5 mL), and the resulting orange solution was stirred for 12 h
with5% aqueous NaHCO (10 mL) and brine (10 mL), dried (MgSO4),
3
and concentrated to give the desired 1,2-aminoalcohol in high purity.
5596
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 5581 – 5606

Burgess Reagent
5581 – 5606
at 258C. Upon completion, the reaction contents were then diluted with
73.8, 73.4, 72.3, 69.6, 69.2, 68.9 ppm; HRMS (MALDI-FTMS) calcd for
water (10 mL), treated withNa SO3 (0.630 g, 5.0 mmol, 5.0 equiv), and al-
C27H30O6Na+ [M+Na]+: 473.1934; found: 473.1921.
2
lowed to stir for an additional 2 hat 25 8C. Once this operation was com-
plete, the reaction mixture was poured into water (10 mL) and extracted
with EtOAc (3”25 mL). The combined organic layers were then washed
withwater (2”15 mL), dried (MgSO 4), and concentrated. The resultant
light yellow solid was purified by flash column chromatography (silica
gel, EtOAc/hexanes, 1:1) to give diol 69 (0.414 g, 92%) as an amorphous
3,5-Di-O-TBS-d-ribosyldiol (81): The requisite d-ribose glycal intermedi-
ate was prepared from thymidine following the procedure of Larsen and
co-workers.[48] The resultant product was then dihydroxylated in
a
manner similar to the preparation of 71 to give diol 81 (0.378 g, 88%
yield) as a white amorphous solid. Rf =0.35 (silica gel, EtOAc/hexanes,
1:2); IR (film): nmax =3425, 2930, 2858, 1471, 1391, 1255, 1095, 937,
779 cmꢀ1 1H NMR (400 MHz, CDCl3, 1:1 mixture of anomers): d=5.24
;
white solid. Rf =0.13 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax
=
3410, 2938, 1452, 1390, 1190, 1080, 886, 590 cmꢀ1 1H NMR (500 MHz,
;
(d, J=6.8 Hz, 1H), 5.13 (d, J=10.6 Hz, 1H), 4.24 (brd, J=8.5 Hz, 1H),
4.18 (appt, J=2.6 Hz, 1H), 4.09–4.06 (m, 2H), 3.91 (brd, J=11.1 Hz,
1H), 3.86–3.81 (m, 2H), 3.77 (dd, J=8.6, 2.6 Hz, 1H), 3.71 (d, J=1.8 Hz,
1H), 3.63 (dd, J=10.8, 2.0 Hz, 1H), 0.89 (s, 9H), 0.87 (s, 9H), 0.84 (s,
9H), 0.82 (s, 9H), 0.10 (s, 6H), 0.07–0.04 ppm (m, 18H); 13C NMR
(100 MHz, CDCl3, 1:1 mixture of anomers): d=104.1, 97.6, 87.1, 84.8,
78.8, 78.5, 77.3, 69.9, 65.7, 63.5, 63.1, 25.7, 25.5, 17.7, 15.1, ꢀ4.7, ꢀ5.0,
ꢀ5.1, ꢀ5.6, ꢀ5.7, ꢀ5.8 ppm; HRMS (MALDI-FTMS) calcd for
C17H38O5Si2Na+ [M+Na]+: 401.2150; found: 401.2147.
CDCl3, 1:1 mixture of anomers): d=7.38–7.10 (m, 30H), 5.18 (d, J=
4.8 Hz, 1H), 4.81 (s, 2H), 4.75 (d, J=13.9 Hz, 2H), 4.54–4.49 (m, 3H),
4.47 (appt, J=5.5 Hz, 3H), 4.43 (d, J=3.3 Hz, 1H), 4.01 (t, J=6.4 Hz,
1H), 3.98 (d, J=6.2 Hz, 1H), 3.74 (appt, J=11.4 Hz, 1H), 3.63–3.58 (m,
3H), 3.51–3.46 ppm (m, 2H); 13C NMR (125 MHz, CDCl3, 1:1 mixture of
anomers): d=138.5, 138.4, 138.0, 137.8, 137.6, 128.5, 128.4, 128.0, 127.9,
127.8, 127.7, 96.7, 92.3, 84.3, 82.5, 77.6, 77.5, 75.5, 75.3, 74.8, 73.4, 72.7,
70.4, 68.7 ppm; HRMS (MALDI-FTMS) calcd for C27H30O6Na+
[M+Na]+: 473.1934; found: 473.1925.
General procedure for the synthesis of sulfamidates on carbohydrates:
The appropriate carbohydrate diol (0.5 mmol, 1.0 equiv) was dissolved in
THF/CH2Cl2 (4:1, 5 mL) and the desired Burgess-type reagent (1, 50, or
51, 1.25 mmol, 2.5 equiv) was added at 258C in a single portion. The re-
sultant solution was immediately warmed to reflux (using a preheated oil
bath) and stirred for 6 h. Upon completion, the reaction contents were
cooled to 258C, poured into saturated aqueous NH4Cl (25 mL), and ex-
tracted withCH 2Cl2 (3”25 mL). The combined organic layers were then
washed with water (50 mL), dried (MgSO4), and concentrated. The resul-
tant yellow residue was purified by flash column chromatography (silica
gel) in an appropriate solvent system to give the desired product in high
purity.
3,4,6-Tri-O-TBS-d-glucosyldiol (73): 3,4,6-Tri-O-TBS-b-D-glucal (0.416 g,
1.0 mmol, 1.0 equiv) was dihydroxylated in a manner similar to the prep-
aration of 71 to give diol 73 (0.391 g, 87% yield) as a white amorphous
solid. 73: Rf =0.32 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax =3446,
2931, 2858, 1472, 1255, 1095, 837 cmꢀ1 1H NMR (500 MHz, CDCl3): d=
;
4.96 (d, J=12.1 Hz, 1H), 4.03 (m, 3H), 4.00 (d, J=9.2 Hz, 1H), 3.93
(appt, J=7.7 Hz, 1H), 3.83 (dd, J=9.6, 6.3 Hz, 1H), 3.80 (m, 1H), 3.71
(d, J=11.0 Hz, 1H), 3.40 (dd, J=11.0, 3.7 Hz, 1H), 0.88 (s, 9H), 0.87 (s,
9H), 0.86 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H), 0.09 (apps, 6H), 0.03 (s,
3H), 0.02 ppm (s, 3H); 13C NMR (125 MHz, CDCl3): d=87.7, 80.9, 71.5,
70.9, 68.2, 61.3, 25.8, 25.6 (2C), 18.1, 17.8, 14.1, ꢀ4.8, ꢀ5.0, ꢀ5.1, ꢀ5.2,
ꢀ5.4 ppm (2C); HRMS (MALDI-FTMS) calcd for C24H54O6Si3Na+
[M+Na]+: 545.3120; found: 545.3110.
Data for 70: Rf =0.68 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax
=
3037, 2866, 1753, 1444, 1385, 1312, 1196, 1094, 842, 741, 699, 665 cmꢀ1
;
1H NMR (600 MHz, CDCl3): d=7.39–7.29 (m, 13H), 7.21 (m, 2H), 6.02
(d, J=4.8 Hz, 1H), 4.90 (t, J=4.0 Hz, 1H), 4.60 (s, 2H), 4.47 (AB, J=
11.8 Hz, nab =88.6 Hz, 2H), 4.44 (AB, J=11.9 Hz, nab =88.6 Hz, 2H), 4.09
(t, J=3.5 Hz, 1H), 3.96 (dd, J=11.4, 2.6 Hz, 1H), 3.94 (s, 3H), 3.92 (dd,
J=9.2, 3.5 Hz, 1H), 3.68 (dd, J=11.0, 2.2 Hz, 1H), 3.61 ppm (dd, J=
10.9, 3.5 Hz, 1H); 13C NMR (150 MHz, CDCl3): d=149.8, 137.8, 137.3,
136.6, 128.7, 128.5, 128.4, 128.3, 128.1, 128.0 (2C), 127.8, 127.7, 81.6, 75.5,
73.3, 73.1, 72.9, 72.4, 68.9, 54.9 ppm; HRMS (MALDI-FTMS) calcd for
C29H31NO9SNa+ [M+Na]+: 592.1612; found: 592.1608.
3,4-Di-O-benzyl-l-rhamnosyldiol (75): 4-O-Benzyl-l-rhamnal (0.220 g,
1.0 mmol, 1.0 equiv) was dissolved in DMF (5 mL) and treated withNaH
(0.400 g, 60% dispersion in mineral oil, 2.0 mmol, 2.0 equiv) at 258C.
After stirring the resultant solution for 5 minutes at 258C, the reaction
contents were cooled to 08C and benzyl bromide (0.238 mL, 2.0 mmol,
2.0 equiv) was added dropwise over the course of 10 minutes. The reac-
tion mixture was then warmed to 258C over the course of 30 minutes.
Upon completion, the reaction mixture was poured into 1n aqueous HCl
(10 mL) and extracted withEt 2O (3”25 mL). The combined organic
layers were then washed with water (2”15 mL), dried (MgSO4), and con-
centrated. The resultant light yellow solid was purified by flash column
chromatography (silica gel, Et2O) to give the desired di-O-benzylated-l-
rhamnal intermediate (0.292 g, 94%) as an amorphous white solid. This
compound was then dihydroxylated in a manner similar to the prepara-
tion of 71 to give diol 75 (0.314 g, 91% yield) as a white amorphous
solid. Rf =0.40 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax =3388,
Data for 71: Rf =0.67 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax
=
3363, 2923, 1763, 1453, 1390, 1294, 1199, 1092, 847, 738, 699 cmꢀ1
;
1H NMR (500 MHz, CDCl3): d=7.30–7.20 (m, 15H), 6.09 (d, J=5.2 Hz,
1H), 4.95 (d, J=4.4 Hz, 1H), 4.90 (AB, J=12.1 Hz, nab =48.4 Hz, 2H),
4.62 (s, 2H), 4.45 (AB, J=11.7 Hz, nab =101.2 Hz, 2H), 4.43 (AB, J=
11.8 Hz, nab =44.8 Hz, 2H), 4.12 (t, J=3.7 Hz, 1H), 3.99 (dt, J=9.2,
2.6 Hz, 1H), 3.93 (dd, J=9.2, 3.3 Hz, 1H), 3.68 (dd, J=11.0, 2.2 Hz, 1H),
3.61 ppm (dd, J=11.0, 3.3 Hz, 1H); 13C NMR (125 MHz, CDCl3): d=
148.1, 137.8, 137.3, 136.6, 128.7, 128.5, 128.4, 128.1, 128.0, 127.8, 127.7,
93.6, 81.8, 76.0, 75.4, 73.4, 73.3, 72.9, 72.8, 72.5, 68.8 ppm; HRMS
(MALDI-FTMS) calcd for C30H30Cl3NO9SNa+ [M+Na]+: 708.0599;
found: 708.0611.
2870, 1645, 1453, 1363, 1091, 994, 734, 694 cmꢀ1 1H NMR (500 MHz,
;
CDCl3, 1:1 mixture of anomers): d=7.40–7.32 (m, 20H), 5.34 (d, J=
3.0 Hz, 1H), 4.98 (d, J=2.6 Hz, 1H), 4.95 (d, J=2.6 Hz, 1H), 4.77 (brd,
J=8.4 Hz, 1H), 4.71–4.62 (m, 5H), 4.04 (m, 2H), 3.64 (ddd, J=13.1, 8.5,
4.8 Hz, 1H), 3.40 (dd, J=9.6, 6.3 Hz, 1H), 3.21 (brs, 1H), 3.15 (dt, J=
8.7, 3.7 Hz, 1H), 2.60 (brs), 2.43 (ddd, J=12.5, 5.2, 2.2 Hz, 1H), 2.32
(ddd, J=13.2, 5.2, 1.5 Hz, 1H), 1.74 (m, 1H), 1.43 (m, 1H), 1.35 (d, J=
6.3 Hz, 3H), 1.28 ppm (d, J=6.3 Hz, 3H); 13C NMR (125 MHz, CDCl3,
1:1 mixture of anomers): d=138.6, 138.5, 138.3, 138.2, 128.4 (3C), 128.3,
128.0 (2C), 127.7 (2C), 127.6 (2C), 93.8, 92.0, 84.3, 83.4, 78.9, 76.8, 75.2
(2C), 71.8 (2C), 71.5, 71.4, 67.4, 38.3, 37.7, 18.2 ppm (2C); MS (ESI)
Data for 72: Rf =0.68 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax
=
3398, 2865, 1746, 1453, 1376, 1300, 1284, 1197, 1088, 1028 cmꢀ1 1H NMR
;
(500 MHz, CDCl3): d=7.36–7.29 (m, 13H), 7.20–7.18 (m 2H), 6.02 (d,
J=4.8 Hz, 1H), 5.93 (m, 1H), 5.42 (dd, J=17.0, 1.1 Hz, 1H), 5.30 (m,
1H), 4.88 (dt, J=8.1, 0.7 Hz, 1H), 4.79 (ABX, J=16.1, 5.5 Hz, nab
=
21.6 Hz, 2H), 4.60 (s, 2H), 4.53 (AB, J=12.1 Hz, nab =21.3 Hz, 2H), 4.38
(AB, J=12.1 Hz, nab =22.4 Hz, 2H), 4.08 (t, J=3.7 Hz, 1H), 3.95 (td, J=
7.4, 2.8 Hz, 1H), 3.89 (dd, J=7.4, 3.7 Hz, 1H), 3.67 (dd, J=9.3, 2.2 Hz,
1H), 3.59 ppm (dd, J=9.1, 3.7 Hz, 1H); 13C NMR (125 MHz, CDCl3):
d=149.1, 137.9, 137.4, 136.7, 31.4, 130.4, 128.7, 128.5, 128.4 (2C), 128.1
(2C), 127.9, 127.7, 119.6, 119.2, 81.6, 77.4, 75.6, 73.5, 73.4, 72.9, 72.8, 72.4,
69.0, 68.5, 66.8 ppm; HRMS (MALDI-FTMS) calcd for C31H33NO9SNa+
[M+Na]+: 618.1768; found: 618.1773.
+
calcd for C20H22O4 [MꢀH2O]+: 327; found: 327.
3,4,6-Tri-O-benzyl-d-galactosyldiol (77): 3,4,6-Tri-O-benzyl-b-d-galactal
(0.417 g, 1.0 mmol, 1.0 equiv) was dihydroxylated in a manner similar to
the preparation of 71 to give diol 77 (0.379 g, 91% yield) as a white
amorphous solid. Rf =0.13 (silica gel, EtOAc/hexanes, 1:1); IR (film):
nmax =3401, 2919, 2861, 1455, 1361, 1085, 738, 691 cmꢀ1
;
1H NMR
(400 MHz, CDCl3): d=7.41–7.26 (m, 15H), 5.31 (d, J=3.5 Hz, 1H), 4.87
(dd, J=11.8, 3.5 Hz, 1H), 4.70 (m, 2H), 4.61–4.39 (m, 4H), 4.14 (dd, J=
10.0, 3.8 Hz, 1H), 3.88 (m, 1H), 3.73 (dd, J=10.0, 2.6 Hz, 1H), 3.61–3.50
(m, 3H), 3.41 ppm (m, 1H); 13C NMR (100 MHz, CDCl3): d=138.3,
138.0, 137.6, 128.5, 128.4, 128.2, 128.0 (2C), 127.8, 127.7, 92.6, 79.0, 74.5,
Data for 74: Rf =0.75 (silica gel, EtOAc/hexanes, 1:2); IR (film): nmax
2932, 2858, 1757, 1636, 1442, 1389, 1314, 1256, 1196, 1114, 1008, 836,
778 cmꢀ1 1H NMR (600 MHz, CDCl3): d=5.86 (d, J=4.4 Hz, 1H), 4.70
(t, J=1.2 Hz, 1H), 4.11 (d, J=3.1 Hz, 1H), 3.95 (s, 3H), 3.87 (d, J=
=
;
Chem. Eur. J. 2004, 10, 5581 – 5606
www.chemeurj.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5597

K. C. Nicolaou et al.
FULL PAPER
7.4 Hz, 1H), 3.81–3.73 (m, 3H), 0.89 ppm (s, 27H), 0.16–0.06 (m, 18H);
13C NMR (150 MHz, CDCl3): d=150.2, 81.3, 75.7, 75.0, 70.8, 68.8, 62.4,
54.7, 25.8, 25.5 (2C), 18.2, 17.8, 17.7, ꢀ4.2, ꢀ4.5, ꢀ4.8, ꢀ4.9, ꢀ5.2,
ꢀ5.5 ppm; HRMS (MALDI-FTMS) calcd for C26H55NO9SSi3Na+
[M+Na]+: 664.2797; found: 664.2790.
Upon completion, the reaction contents were poured into water (5 mL),
and extracted withEtOAc (3”10 mL). Teh combined organic layers
were then dried (MgSO4) and concentrated to give the desired deprotect-
ed sulfamidate (0.075 g, 87% yield) as a white oil.[29] Pressing forward
without any additional purification steps, this material (0.075 g,
0.146 mmol, 1.0 equiv) was dissolved in DMSO (2 mL) and treated with
NaH (0.029 g, 60% dispersion in mineral oil, 0.730 mmol, 5.0 equiv) at
258C. After stirring the resultant reaction mixture for 10 minutes at
258C, allyl bromide (0.051 mL, 0.584 mmol, 4.0 equiv) was added in a
single portion; the reaction mixture was then stirred for an additional
15 minutes at 258C. Upon completion, the reaction contents were poured
into water (5 mL), and extracted withEtOAc (3”10 mL). The combined
organic layers were then washed with water (2”15 mL), dried (MgSO4),
and concentrated. The resultant light yellow oil was purified by flash
column chromatography (silica gel, EtOAc/hexanes, 1:3!1:1) to give the
allylated sulfamidate 84 (0.067 g, 73% yield over two steps) as an amor-
phous white solid. Rf =0.64 (silica gel, EtOAc/hexanes, 1:1); IR (film):
Data for 76: Rf =0.60 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax
=
3248, 1752, 1636, 1494, 1444, 1381, 1314, 1196, 1146, 1077, 1001, 740 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d=7.41–7.29 (m, 8H), 7.27–7.25 (m, 2H),
5.88 (d, J=5.3 Hz, 1H), 4.90 (ddd, J=6.2, 3.5, 1.2 Hz, 1H), 4.57 (AB, J=
10.8 Hz, nab =11.8 Hz, 2H), 4.44 (AB, J=12.0 Hz, nab =34.9 Hz, 2H), 4.02
(dd, J=3.2, 2.0, Hz, 1H), 3.98 (m, 1H), 3.95 (s, 3H), 3.36 (ddd, J=8.8,
1.8, 1.2 Hz, 1H), 1.28 ppm (d, J=6.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=150.0, 137.3, 136.5, 128.8, 128.5 (2C), 128.1, 128.0 (3C), 81.5,
80.5, 75.2, 74.4, 72.6, 72.4, 67.9, 54.9, 19.3 ppm; HRMS (MALDI-FTMS)
calcd for C22H25NO8SNa+ [M+Na]+: 486.1193; found: 486.1202.
Data for 78: Rf =0.66 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax
=
2961, 1755, 1443, 1384, 1320, 1290, 1190, 1061, 991, 855, 732, 697 cmꢀ1
;
nmax =2890, 1452, 1352, 1193, 1114, 1052, 988, 741, 694, 606 cmꢀ1
;
1H NMR (600 MHz, CDCl3): d=7.39–7.25 (m, 15H), 5.89 (d, J=4.0 Hz,
1H), 5.02 (dd, J=5.2, 3.5 Hz, 1H), 4.75 (AB, J=11.0 Hz, nab =160.4 Hz,
2H), 4.73 (AB, J=11.9 Hz, nab =68.8 Hz, 2H), 4.53 (AB, J=11.9 Hz,
nab =31.1 Hz, 2H), 4.20 (m, 1H), 4.15 (dd, J=4.0, 1.7 Hz, 1H), 4.03 (dd,
J=5.3, 1.8 Hz, 1H), 3.92 (s, 3H), 3.71 (dd, J=9.7, 7.4 Hz, 1H), 3.65 ppm
(dd, J=9.7, 6.5 Hz, 1H); 13C NMR (150 MHz, CDCl3): d=149.5, 137.7,
137.4, 136.8, 128.6, 128.4, 128.2, 128.1, 128.0, 127.8 (2C), 127.6, 84.1, 80.3,
78.7, 75.4, 75.3, 73.7, 72.1, 66.9, 54.9 ppm; HRMS (MALDI-FTMS) calcd
for C29H31NO9SNa+ [M+Na]+: 592.1612; found: 592.1633.
1H NMR (600 MHz, CDCl3): d=7.30–7.24 (m, 15H), 5.87 (m, 1H), 5.35
(d, J=17.1 Hz, 1H), 5.29 (s, 1H), 5.28 (d, J=16.7 Hz, 1H), 4.95 (dd, J=
7.4, 5.3 Hz, 1H), 4.75 (AB, J=11.0 Hz, nab =185.9 Hz, 2H), 4.73 (AB, J=
11.8 Hz, nab =76.7 Hz, 2H), 4.43 (AB, J=11.8 Hz, nab =26.3 Hz, 2H), 4.12
(dd, J=7.4, 2.6 Hz, 1H), 4.04 (t, J=5.3 Hz, 1H), 4.00 (apps, 1H), 3.79
(dd, J=14.5, 5.7 Hz, 1H), 3.73 (dd, J=14.5, 7.9 Hz, 1H), 3.52 ppm (AB,
J=9.6 Hz, nab =16.2 Hz, 2H); 13C NMR (150 MHz, CDCl3): d=137.8,
137.6, 137.4, 130.4, 128.5 (2C), 128.4, 128.2, 128.0 (2C), 127.9, 127.7 (2C),
121.1, 84.3, 82.2, 78.5, 74.9, 73.5 (2C), 72.8, 72.4, 67.7, 47.0 ppm; HRMS
(MALDI-FTMS) calcd for C30H33NO7SNa+ [M+Na]+: 574.1870; found:
574.1866.
Data for 80: Rf =0.33 (silica gel, EtOAc/hexanes, 1:2); IR (film): nmax
2978, 1746, 1437, 1412, 1294, 1249, 1187, 1073, 1023, 973, 861, 797,
609 cmꢀ1 1H NMR (400 MHz, CDCl3): d=5.98 (d, J=3.8 Hz, 1H), 5.13
=
;
(d, J=2.4 Hz, 1H), 4.72 (dd, J=15.0, 2.9 Hz, 1H), 4.71 (d, J=3.5 Hz,
1H), 4.36 (q, J=2.6 Hz, 1H), 4.09 (dd, J=15.0, 2.6 Hz, 1H), 3.86 (s, 3H),
1.49 (s, 3H), 1.33 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=151.9,
113.0, 104.9, 87.3, 82.5, 70.6, 54.9, 48.2, 26.5, 26.1 ppm; HRMS (MALDI-
FTMS) calcd for C10H15NO8SNa+ [M+Na]+: 332.0411; found: 332.0418.
2,3,4-Tri-O-benzyl-d-fucose (90): Concentrated H2SO4 (1 mL) was added
to a solution of d-fucose (1.64 g, 10.0 mmol, 1.0 equiv) in MeOH (30 mL)
at 258C, and the resultant mixture was stirred for 5 h. Upon completion,
the reaction contents were neutralized by the addition of 3n aqueous
NaOH (monitored using standard pH paper) and concentrated directly.
The resulting white solid was then taken up in EtOAc (50 mL), filtered
through a short silica gel, and concentrated to give 1-O-methyl-d-fucose
(1.78 g, 100% yield) as a white solid. Pressing forward without any addi-
tional purification steps, this newly-formed material (1.78 g, 10.0 mmol,
1.0 equiv) was dissolved in DMF (10 mL) and treated withNaH (3.60 g,
60% dispersion in mineral oil, 90.0 mmol, 9.0 equiv) at 258C. After stir-
ring the resultant solution for 5 minutes at 258C, the reaction contents
were cooled to 08C and benzyl bromide (5.95 mL, 50.0 mmol, 5.0 equiv)
added dropwise over the course of 10 minutes. The reaction mixture was
then warmed to 258C over the course of 4 h. Upon completion, the reac-
tion mixture was poured into 1n aqueous HCl (25 mL) and extracted
withEt 2O (3”25 mL). The combined organic layers were then washed
withwater (2”15 mL), dried (MgSO 4), and concentrated. The resultant
light yellow solid was purified by flash column chromatography (silica
gel, Et2O/hexanes, 1:3!1:1) to give the desired tri-O-benzylated–fucose
intermediate (3.7 g, 82%) as an amorphous white solid. Finally, a portion
of this newly-formed product (0.452 g, 1.0 mmol, 1.0 equiv) was dissolved
6m aqueous HCl/concentrated HCl (1:1, 5 mL) at 258C. The resultant
mixture was then warmed to 608C and stirred for 12 h. Upon completion,
the reaction contents were concentrated directly. The resultant yellow oil
was purified by flash column chromatography (silica gel, Et2O/hexanes,
1:1) to give the desired d-fucose-derived starting material 90 (0.297 g,
68%) as an amorphous white solid. Rf =0.54 (silica gel, EtOAc/hexanes,
1:1); IR (film): nmax =3416, 3031, 2867, 1453, 1364, 1208, 1098, 740,
Data for 82: Rf =0.68 (silica gel, EtOAc/hexanes, 1:2); IR (film): nmax
2954, 2858, 1759, 1442, 1392, 1313, 1257, 1196, 1098, 1011, 838, 806,
781 cmꢀ1 1H NMR (500 MHz, CDCl3): d=6.12 (d, J=4.4 Hz, 1H), 4.93
=
;
(d, J=4.1 Hz, 1H), 4.61 (s, 1H), 4.12 (ddd, J=8.5, 5.2, 1.9 Hz, 1H), 3.96
(s, 3H), 3.77 (dd, J=10.7, 5.5 Hz, 1H), 3.71 (dd, J=10.6, 8.8 Hz, 1H),
0.90 (s, 18H), 0.14 (d, J=5.5 Hz, 6H), 0.07 ppm (d, J=2.6 Hz, 6H);
13C NMR (125 MHz, CDCl3): d=149.8, 88.8, 87.7, 86.2, 74.3, 61.7, 55.0,
25.8, 25.5, 18.3, 17.9, ꢀ4.9, ꢀ5.0, ꢀ5.5 ppm (2C); HRMS (MALDI-
FTMS) calcd for C19H40NO8Si2S+ [M+H]+: 498.2008; found: 498.2015.
Azide-opened tri-benzylated glucose derivative 83: NaN3 (0.033 g,
0.50 mmol, 5.0 equiv) was added in a single portion to a solution of glu-
cose-derived sulfamidate 70 (0.057 g, 0.10 mmol, 1.0 equiv) in THF/
CH2Cl2 (4:1, 1 mL) at 258C. The resulting clear solution was then
warmed to 608C and stirred for 5 h. Upon completion, the reaction con-
tents were diluted withEt 2O (5 mL), treated with10% aqueous H 2SO4
(1 mL), and allowed to stir for an additional 30 minutes at 258C. Once
this operation was complete, the reaction mixture was poured into water
(10 mL) and extracted withEt 2O (3”25 mL). The combined organic
layers were then washed with water (2”15 mL), dried (MgSO4), and con-
centrated. The resultant light yellow solid was purified by flash column
chromatography (silica gel, Et2O/hexanes, 1:1) to give the azide-opened
tri-benzylated glucose derivative 83 (0.049 g, 92%) as an amorphous
white solid. Rf =0.47 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax
=
3318, 2924, 2106, 1732, 1532, 1454, 1357, 1243, 1098, 1027, 738, 699 cmꢀ1
;
1H NMR (600 MHz, CDCl3): d=7.26–7.15 (m, 15H), 5.42 (brs, 1H), 5.27
(brm, 1H), 4.65–4.47 (m, 5H), 3.82 (m, 2H), 3.74 (m, 2H), 3.68 ppm (s,
3H); 13C NMR (125 MHz, CDCl3): d=155.7, 138.0, 137.6, 137.1, 128.6,
128.4, 128.3, 128.1, 128.0, 127.9, 127.8, 127.6, 78.3, 73.8, 73.2, 72.8, 68.2,
698 cmꢀ1 1H NMR (500 MHz, CDCl3, 1:1 mixture of anomers): d=7.48–
;
7.34 (m, 30H), 5.55 (s, 1H), 5.41 (dd, J=9.5, 4.4 Hz, 1H), 4.83–4.49 (m,
11H), 4.35 (appt, J=5.2 Hz, 1H), 4.30 (brd, J=11.4 Hz, 1H), 4.25 (appt,
J=5.2 Hz, 1H), 4.13 (dd, J=5.5, 4.8 Hz, 1H), 4.10 (dd, J=2.2, 1.1 Hz,
1H), 4.05 (dd, J=5.2, 2.2 Hz, 1H), 3.99 (dd, J=4.8, 3.0 Hz, 1H), 3.78 (m,
1H), 3.63 (dd, J=6.3, 3.0 Hz, 1H), 3.55 (brs, 1H), 3.48 (m, 1H), 1.38 (d,
J=4.6 Hz, 3H), 1.28 ppm (d, J=4.8 Hz, 3H); 13C NMR (125 MHz,
CDCl3, 1:1 mixture of anomers): d=138.5, 137.7, 137.5, 137.4 (2C), 137.3,
128.4 (2C), 128.3 (2C), 128.2, 128.0, 127.9 (2C), 127.8 (3C), 127.7, 127.5,
127.4, 126.9, 100.7, 96.0, 87.3, 85.2, 84.5, 84.4, 82.8, 82.2, 74.0, 73.9, 71.9
(2C), 71.8, 71.6, 71.2, 71.1, 65.1 ppm; MS (ESI) calcd for C27H30O9Clꢀ
[M+Cl]ꢀ: 470; found: 470.
+
60.0, 52.7, 53.4 ppm; HRMS (MALDI-FTMS) calcd for C34H38NO5
[M+H]+: 555.2214; found: 555.2217.
Allylated sulfamidate 84: Et2NH (0.354 mL, 6.71 mmol, 40 equiv) was
added to a solution of sulfamidate 72 (0.100 g, 0.167 mmol, 1.0 equiv) in
CH3CN/H2O (1:1, 3 mL) at 258C. After stirring this mixture for 5 mi-
nutes at 258C, Pd(OAc)2 (0.002 g, 0.017 mmol, 0.1 equiv) and TPPTS
(0.019 g, 0.033 mmol, 0.2 equiv) were added sequentially, providing a
yellow solution which was stirred for an additional 30 minutes at 258C.
5598
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 5581 – 5606

Burgess Reagent
5581 – 5606
2,3,4,6-Tetra-O-methyl-d-mannose (92): d-Mannose (1.80 g, 10.0 mmol)
was converted into 92 in a manner similar to the preparation of 90 by
substituting methyl iodide for benzyl bromide, ultimately providing com-
pound 92 (0.146 g, 62% yield) as a white amorphous solid. Rf =0.15
(silica gel, EtOAc/hexanes, 1:2); IR (film): nmax =3402, 2932, 2828, 1644,
1537, 1453, 1360, 1280, 1071, 735, 697 cmꢀ1
;
1H NMR (600 MHz, CDCl3):
d=7.45–7.32 (m, 18H), 7.19–7.17 (m, 2H), 5.93 (ddd, J=22.7, 10.9,
5.7 Hz, 1H), 5.32 (d, J=17.1 Hz, 1H), 5.23 (d, J=10.1 Hz, 1H), 5.07 (d,
J=10.1 Hz, 1H), 4.92 (m, 1H), 4.91 (AB, J=11.0 Hz, nab =18.8 Hz, 2H),
4.82 (d, J=10.9 Hz, 2H), 4.72 (d, J=11.0 Hz, 1H), 4.64–4.60 (m, 3H),
4.53 (d, J=10.5 Hz, 1H), 4.47 (d, J=12.3 Hz, 1H), 3.73 (m, 4H), 3.52 (d,
J=7.9 Hz, 1H), 3.38 ppm (t, J=8.3 Hz, 1H); 13C NMR (150 MHz,
CDCl3): d=155.3, 138.3, 138.0, 137.7, 132.4, 128.5, 128.4 (3C), 128.3
(3C), 128.2, 128.0, 127.8, 127.7, 127.6, 117.8, 85.9, 81.6, 80.1, 77.4, 76.1,
75.6, 74.9, 74.7, 73.5, 68.1 ppm; HRMS (MALDI-FTMS) calcd for
C38H41NO7Na+ [M+Na]+: 646.2775; found: 646.2766.
1453, 1193, 1109, 1030, 958, 792 cmꢀ1 1H NMR (500 MHz, CDCl3): d=
;
5.25 (s, 1H), 4.62 (brs, 1H), 3.86 (td, J=7.3, 1.8 Hz, 1H), 3.59–3.51 (m,
4H), 3.45 (s, 3H), 3.44 (s, 3H), 3.43 (s, 3H), 3.32 (s, 3H), 3.26 ppm (t, J=
9.2 Hz, 1H); 13C NMR (125 MHz, CDCl3): d=91.5, 80.8, 74.5, 77.1, 72.7,
70.3, 60.6, 59.1, 58.8, 57.6 ppm; HRMS (MALDI-FTMS) calcd for
C10H20O6Na+ [M+Na]+: 259.1152; found: 259.1152.
2,3,5-Tri-O-benzyl-l-arabinofuranose (95): Lactol 95 was prepared from
l-arabinose using the sequence established by Tejima and Fletcher.[49]
Rf =0.51 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax =3418, 3030,
CO2Me-protected 2,3,4-tri-O-benzyl-b-d-fucosylamine (91): Rf =0.70
(silica gel, EtOAc/hexanes, 1:1); IR (film): nmax =3326, 2927, 1730, 1504,
1453, 1351, 1067, 736, 697 cmꢀ1 1H NMR (400 MHz, CDCl3): d=7.36–
;
2866, 1495, 1454, 1365, 1264, 1208, 1099, 1028, 738, 698 cmꢀ1
;
1H NMR
7.31 (m, 15H), 5.81 (brd, J=6.4 Hz, 1H), 5.76 (brs, 1H), 4.69 (AB, J=
9.4 Hz, nab =21.4 Hz, 2H), 4.67 (m, 1H), 4.57 (m, 3H), 4.24 (dd, J=4.7,
2.6 Hz, 1H), 4.04 (d, J=1.5 Hz, 1H), 3.98 (brs, 1H), 3.80 (m, 1H), 3.77
(brs, 3H), 1.20 ppm (d, J=4.9 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=155.8, 138.6, 137.2, 128.5, 128.4, 128.3, 128.0, 127.9, 127.8 (2C), 127.6,
127.4, 86.1, 85.3 (2C), 82.4, 74.1, 71.8, 71.4, 52.3, 15.7 ppm; HRMS
(MALDI-FTMS) calcd for C29H33NO6Na+ [M+Na]+: 514.2200; found:
514.2191.
(500 MHz, CDCl3, 1:1 mixture of anomers): d=7.36–7.26 (m, 30H), 5.40
(s, 1H), 5.34 (d, J=3.7 Hz, 1H), 4.66 (d, J=9.5 Hz, 1H), 4.61–4.52 (m,
10H), 4.48–4.45 (m, 2H), 4.17 (t, J=4.0 Hz, 1H), 4.09 (q, J=3.7 Hz,
1H), 4.02 (t, J=4.0 Hz, 1H), 3.98 (d, J=1.5 Hz, 1H), 3.94 (m, 1H), 3.61–
3.50 ppm (m, 4H); 13C NMR (125 MHz, CDCl3, 1:1 mixture of anomers):
d=138.0, 137.4, 137.3, 137.2 (2C), 128.6, 128.5 (4 C), 128.4 (2C), 128.3,
128.0 (2C), 127.9 (2C), 127.8 (2C), 127.7 (2C), 127.6, 101.1, 96.2, 86.3,
84.0, 82.6, 82.0, 81.8, 80.5, 76.8, 73.5, 73.3, 72.2, 72.0 (2C), 71.7, 70.4,
70.1 ppm; HRMS (MALDI-FTMS) calcd for C26H28O5Na+ [M+Na]+:
443.1829; found: 443.1809.
CO2Me-protected 2,3,4,6-tetra-O-methyl-b-d-mannosylamine (93): Rf =
0.27 (silica gel, EtOAc); IR (film): nmax =3205, 2928, 1722, 1445, 1257,
1100 cmꢀ1 1H NMR (500 MHz, CDCl3): d=5.59 (brs, 1H), 5.44 (brs,
;
Furanose 98: The requisite lactol intermediate was prepared from d-
ribose following the procedure of Kaskar and co-workers.[50] Rf =0.51
(silica gel, EtOAc/hexanes, 1:2); IR (film): nmax =3416, 2934, 2858, 1469,
1H), 3.83 (m, 1H), 3.80 (s, 3H), 3.67–3.64 (m, 4H), 3.62 (m, 1H), 3.61 (s,
6H), 3.58 (s, 3H), 3.48 (m, 1H), 3.46 ppm (s, 3H); 13C NMR (125 MHz,
CDCl3): d=156.3, 80.4, 77.1, 76.4, 73.3, 71.7, 68.4, 60.5, 59.7, 58.8, 58.4,
53.0 ppm; HRMS (MALDI-FTMS) calcd for C12H23NO7Na+ [M+Na]+:
316.1367; found: 316.1362.
1381, 1257, 1211, 1075, 1004, 939, 838, 779 cmꢀ1 1H NMR (500 MHz,
;
CDCl3): d=5.24 (d, J=11.4 Hz, 1H), 4.74 (d, J=11.7 Hz, 1H), 4.66 (d,
J=5.9 Hz, 1H), 4.47 (d, J=5.9 Hz, 1H), 4.31 (s, 1H), 3.75–3.72 (m, 2H),
1.45 (s, 3H), 1.29 (s, 3H), 0.90 (s, 9H), 0.11 (s, 3H), 0.10 ppm (s, 3H);
13C NMR (100 MHz, CDCl3): d=111.9, 103.3, 87.5, 86.8, 81.7, 64.7, 26.4,
25.7, 24.8, 18.1, ꢀ5.7 ppm; HRMS (MALDI-FTMS) calcd for
C14H28O5SiNa+ [M+Na]+: 327.1598; found: 327.1592.
Alloc-protected 2,3,4,6-tetra-O-methyl-b-d-mannosylamine (94): Rf =0.38
(silica gel, EtOAc); IR (film): nmax =3332, 2934, 1726, 1529, 1450, 1305,
1237, 1100 cmꢀ1 1H NMR (500 MHz, CDCl3): d=5.90 (ddd, J=23.1,
;
10.7, 4.8 Hz, 1H), 5.52 (brs, 1H), 5.32 (d, J=17.2 Hz, 1H), 5.22 (d, J=
10.3 Hz, 1H), 4.60 (s, 2H), 3.63–3.48 (m, 15H), 3.45–3.42 ppm (m, 4H);
13C NMR (100 MHz, CDCl3): d=155.5, 132.7, 118.7, 80.4, 77.1, 76.4, 73.3,
71.6, 66.5, 59.7, 58.8, 58.3, 51.5 ppm; HRMS (MALDI-FTMS) calcd for
C14H25NO7Na+ [M+Na]+: 342.1523; found: 342.1522.
General procedure for the synthesis of b-disposed glycosylamines: Th e
lactol starting material (0.5 mmol, 1.0 equiv) was dissolved in THF/
CH2Cl2 (4:1, 5 mL) and the desired Burgess-type reagent (1, 50, or 51,
0.75 mmol, 1.5 equiv) was added at 258C in a single portion. The resul-
tant solution was immediately warmed to reflux (using a preheated oil
bath) and stirred for 6 h. Upon completion, the reaction contents were
cooled to 258C, poured into saturated aqueous NH4Cl (25 mL), and ex-
tracted withCH 2Cl2 (3”25 mL). The combined organic layers were then
washed with water (50 mL), dried (MgSO4), and concentrated. The resul-
tant yellow residue was purified by flash column chromatography (silica
gel) in an appropriate solvent system to give the desired product in high
purity.
CO2Me-protected 2,3,5-tri-O-benzyl-b-l-arabinofuranosylamine (96):
Rf =0.63 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax =3317, 3030,
2865, 1732, 1498, 1454, 1363, 1238, 1058, 739, 698 cmꢀ1
;
1H NMR
(400 MHz, CDCl3): d=7.35–7.27 (m, 15H), 5.88 (brd, J=9.4 Hz, 1H),
5.76 (brd, J=10.0 Hz, 1H), 4.61–4.45 (m, 6H), 4.38 (appt, J=5.6 Hz,
1H), 4.02 (s, 1H), 3.93 (s, 1H), 3.70 (brs, 3H), 3.64 (dd, J=9.4, 5.9 Hz,
1H), 3.52 ppm (appt, J=8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=
155.8, 137.9, 137.1, 128.4 (2C), 128.3, 128.2, 127.9, 127.8, 127.7, 127.6
(2C), 85.5, 84.9, 82.7, 82.1, 73.2, 71.6, 71.4, 70.0, 52.2 ppm; HRMS
(MALDI-FTMS) calcd for C28H31NO6Na+ [M+Na]+: 500.2043; found:
500.2033.
CO2Me-protected 2,3,4,6-tetra-O-methyl-b-d-glucosylamine (86): Rf =
0.13 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax =3329, 2937, 2836,
1712, 1544, 1450, 1278, 1158, 1099, 989, 945, 647 cmꢀ1
;
1H NMR
Alloc-protected 2,3,5-tri-O-benzyl-b-l-arabinofuranosylamine (97): Rf =
0.55 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax =3322, 3030, 2866,
(400 MHz, CDCl3): d=5.30 (d, J=8.8 Hz, 1H), 4.75 (t, J=8.4 Hz, 1H),
3.68 (brs, 3H), 3.62 (s, 3H), 3.58–3.53 (m, 2H), 3.52 (s, 3H), 3.51 (s, 3H),
3.41 (s, 3H), 3.30 (m, 1H), 3.22 (d, J=6.7 Hz, 2H), 2.91 ppm (brm, 1H);
13C NMR (100 MHz, CDCl3): d=156.1, 99.5, 87.2, 82.8, 81.6, 78.9, 75.8,
70.5, 60.8, 60.3, 59.1, 52.4 ppm; HRMS (MALDI-FTMS) calcd for
C12H23NO7Na+ [M+Na]+: 316.1367; found: 316.1363.
1730, 1503, 1454, 1366, 1232, 1094, 992, 738, 698 cmꢀ1
;
1H NMR
(500 MHz, CDCl3): d=7.41–7.32 (m, 15H), 6.01 (ddd, J=22.8, 11.0,
5.9 Hz, 1H), 5.94 (d, J=9.9 Hz, 1H), 5.84 (d, J=9.9 Hz, 1H), 5.40 (d, J=
16.9 Hz, 1H), 5.31 (dd, J=10.2, 1.1 Hz, 1H), 4.69–4.58 (m, 7H), 4.53 (d,
J=11.7 Hz, 1H), 4.48 (ddd, J=9.8, 7.3, 1.8 Hz, 1H), 4.08 (brs, 1H), 4.00
(brs, 1H), 3.70 (dd, J=9.5, 5.5 Hz, 1H), 3.59 ppm (appt, J=7.7 Hz, 1H);
13C NMR (125 MHz, CDCl3): d=155.5, 138.5, 137.6, 133.0, 129.0, 128.9,
128.8 (2C), 128.3, 128.2, 128., 1280, 118.5, 86.1, 85.4, 83.2, 82.8, 73.8, 72.2,
71.9, 70.6, 66.3 ppm; HRMS (MALDI-FTMS) calcd for C30H33NO6Na+
[M+Na]+: 526.2200; found: 526.2190.
CO2Me-protected 2,3,4,6-tetra-O-benzyl-b-d-glucosylamine (88): Rf =
0.67 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax =3326, 2869, 1733,
1535, 1496, 1454, 1362, 1252, 1101, 737, 698 cmꢀ1 1H NMR (400 MHz,
;
CDCl3): d=7.34–7.27 (m, 18H), 7.17 (m, 2H), 5.12 (brd, J=6.4 Hz, 1H),
4.97 (m, 1H), 4.93 (AB, J=10.8 Hz, nab =15.0 Hz, 2H), 4.84 (dd, J=10.8,
3.5 Hz, 1H), 4.74 (d, J=11.1 Hz, 1H), 4.65 (d, J=12.0 Hz, 1H), 4.56 (d,
J=10.8 Hz, 1H), 4.51 (d, J=11.1 Hz, 1H), 3.76 (m, 4H), 3.72 (brs, 3H),
3.54 (brd, J=7.9 Hz, 1H), 3.38 ppm (appt, J=6.8 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d=156.1, 138.3, 137.9, 137.7, 128.4, 128.3 (2C), 128.2,
127.9, 127.7, 127.6, 85.8, 81.7, 80.1, 77.4, 76.0, 75.6, 74.8, 74.6, 73.4, 68.0,
52.3 ppm; HRMS (MALDI-FTMS) calcd for C36H39NO7Na+ [M+Na]+:
620.2610; found: 620.2614.
CO2Me-protected ribosylamine 99: Rf =0.67 (silica gel, EtOAc/hexanes,
1:2); IR (film): nmax =3347, 2933, 1737, 1509, 1461, 1377, 1251, 1082, 931,
837, 779 cmꢀ1 1H NMR (400 MHz, CDCl3): d=6.27 (brd, J=11.8 Hz,
;
1H), 5.68 (brd, J=10.0 Hz, 1H), 4.72 (d, J=5.9 Hz, 1H), 4.50 (d, J=
6.2 Hz, 1H), 4.29 (s, 1H), 3.77 (m, 1H), 3.71 (m, 3H), 3.66 (brs, 3H),
1.51 (s, 3H), 1.33 (s, 3H), 0.94 (s, 9H), 0.13 ppm (s, 6H); 13C NMR
(100 MHz, CDCl3): d=155.8, 112.2, 89.0, 86.6, 86.0, 82.1, 79.4, 65.0, 51.8,
25.7, 24.8, 18.1 ppm; HRMS (MALDI-FTMS) calcd for C16H31NO6SiNa+
[M+Na]+: 84.1813; found: 384.1814.
Alloc-protected 2,3,4,6-tetra-O-benzyl-b-d-glucosylamine (89): Rf =0.64
(silica gel, EtOAc/hexanes, 1:1); IR (film): nmax =3331, 3030, 2867, 1703,
Chem. Eur. J. 2004, 10, 5581 – 5606
www.chemeurj.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5599

K. C. Nicolaou et al.
FULL PAPER
CO2Me-protected 101: Rf =0.41 (silica gel, EtOAc/hexanes, 1:1); IR
(film): nmax =3304, 2988, 1702, 1541, 1377, 1296, 1248, 1209, 1067, 1039,
1H NMR (400 MHz, CD3CN): d=7.37–7.28 (m, 5H), 4.70 (dd, J=11.8,
2.5 Hz, 1H), 4.24 (dd, J=11.7, 6.6 Hz, 1H), 3.90 (d, J=2.1 Hz, 1H), 3.72
(s, 3H), 3.40 ppm (dt, J=6.4, 2.5 Hz, 1H); 13C NMR (100 MHz, CD3CN):
d=152.1, 136.9, 129.4, 126.7, 73.5, 59.1, 56.5, 54.2 ppm; HRMS (MALDI-
FTMS) calcd for C11H14NO6S+ [M+H]+: 288.0536; found: 288.0537.
1018, 850 cmꢀ1 1H NMR (400 MHz, CDCl3): d=5.61 (brs, 1H), 5.22
;
(brs, 1 h), 4.87 (brs, 2H), 4.36 (m, 1H), 4.08–3.98 (m, 3H), 3.67 (s, 3H),
3.67 (s, 3H), 1.47 (s, 3H), 1.43 (s, 3H), 1.35 (s, 3H), 1.32 ppm (s, 3H);
13C NMR (100 MHz, CDCl3): d=156.1, 112.9, 109.1, 87.9, 85.2, 73.3, 66.6,
52.4, 26.9, 25.9, 25.0, 24.8 ppm; HRMS (MALDI-FTMS) calcd for
C14H23NO7Na+ [M+Na]+: 340.1367; found: 340.1364.
Sulfamidate 106: Rf =0.32 (silica gel, EtOAc/MeOH, 98:2); IR (film):
nmax =3480, 2955, 1743, 1649, 1446, 1291, 1167, 1108, 1050, 987, 885, 796,
749, 702, 621 cmꢀ1 1H NMR (400 MHz, CDCl3): d=7.24–7.17 (m, 5H),
;
4.22 (AB, J=17.2 Hz, nab =68.6 Hz, 2H), 4.15 (s, 1H), 3.55 (s, 3H),
1.03 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=157.3, 134.6, 128.0,
127.7, 126.5, 126.3, 72.3, 61.7, 61.0, 53.5, 13.1 ppm; MS (ESI) calcd for
C12H15NO6NaS+ [M+Na]+: 323; found: 323.
2,3,4,6-Tetra-O-benzyl-b-d-glucosylamine (102): Et2NH (0.179 mL,
3.40 mmol, 40 equiv) was added to a solution of intermediate 89 (0.053 g,
0.085 mmol, 1.0 equiv) in CH3CN/H2O (1:1, 2 mL) at 258C. After stirring
this mixture for 5 minutes at 258C, Pd(OAc)2 (0.002 g, 0.009 mmol,
0.1 equiv) and TPPTS (0.010 g, 0.017 mmol, 0.2 equiv) were added se-
quentially, providing a yellow solution which was stirred for an additional
30 minutes at 258C. Upon completion, the reaction contents were poured
into water (5 mL), and extracted withEtOAc (3”10 mL). The combined
organic layers were then dried (MgSO4) and concentrated to give 2,3,4,6-
tetra-O-benzyl-b-d-glucosylamine (0.043 g, 95% yield)[29] as an amor-
phous white solid. Rf =0.48 (silica gel, EtOAc/hexanes, 1:1); IR (film):
Sulfamidate 108: Rf =0.28 (silica gel, EtOAc/MeOH, 98:2); IR (film):
nmax =3482, 2930, 1735, 1650, 1442, 1290, 1166, 1107, 985, 885 cmꢀ1
;
1H NMR (500 MHz, CD3CN): d=5.09 (m, 1H), 4.17 (dd, J=11.4, 3.7 Hz,
1H), 3.88 (dd, J=11.8, 7.0 Hz, 1H), 3.50 (s, 3H), 2.99 (dd, J=7.0, 4.0 Hz,
1H), 2.05 (m, 2H), 1.65 (s, 3H), 1.58 (s, 3H), 1.55 (m, 1H), 1.40 (m, 1H),
1.24 ppm (s, 3H); 13C NMR (125 MHz, CD3CN): d=161.8, 132.6, 124.4,
68.1, 61.2, 60.7, 52.5, 38.8, 25.6, 24.1, 17.5, 16.9 ppm; HRMS (MALDI-
FTMS) calcd for C12H21NO6SNa+ [M+Na]+: 330.0982; found: 330.0987.
nmax =3352, 3030, 2862, 1453, 1351, 1122, 1094, 1086, 1027, 750, 698 cmꢀ1
;
1H NMR (600 MHz, CDCl3): d=7.48–7.21 (m, 20H), 5.08 (d, J=13.2 Hz,
1H), 5.03 (d, J=13.1 Hz, 1H), 4.94–4.86 (m, 3H), 4.65 (AB, J=14.3 Hz,
nab =37.4 Hz, 2H), 4.58 (m, 1H), 4.20 (d, J=9.9 Hz, 1H), 3.85–3.80 (m,
5H), 3.56 (dd, J=11.5, 3.3 Hz, 1H), 3.30 (t, J=10.4 Hz, 1H), 1.97 ppm
(brs, 2H); 13C NMR (150 MHz, CDCl3): d=138.6, 138.3, 138.0, 137.9,
128.7, 128.4 (2C), 128.3, 128.2, 127.9, 127.8 (2C), 127.7 (2C), 127.6, 86.2,
85.8, 83.4, 78.1, 75.7, 75.6, 75.0, 74.9, 73.5, 68.9 ppm; HRMS (MALDI-
Sulfamidate 110: Rf =0.31 (silica gel, EtOAc/MeOH, 98:2); IR (film):
nmax =3260, 2937, 1755, 1644, 1452, 1382, 1247, 1173, 959, 890, 776,
599 cmꢀ1 1H NMR (600 MHz, CD3CN): d=4.72 (t, J=1.3 Hz, 1H), 4.68
;
(q, J=0.9 Hz, 1H), 4.18 (AB, J=10.9 Hz, nab =178.0 Hz, 2H), 3.73 (s,
3H), 3.23 (brs, 1H), 2.12–2.08 (m, 1H), 2.05–1.95 (m, 2H), 1.78 (ddd, J=
17.5, 11.4, 6.1 Hz, 1H), 1.67 (s, 3H), 1.54 (m, 1H), 1.24–1.18 ppm (m,
2H); 13C NMR (150 MHz, CD3CN): d=151.9, 149.8, 109.6, 77.8, 58.1,
57.3, 54.2, 37.1, 30.6, 26.1, 20.9 ppm; HRMS (MALDI-FTMS) calcd for
C12H19NO6SNa+ [M+Na]+: 328.0825; found: 328.0826.
+
FTMS) calcd for C34H38NO5 [M+H]+: 540.2744; found: 540.2750.[25]
General procedure for making epoxy alcohol starting materials: All
epoxy alcohols were prepared following the method of Katsuki and
Sharpless, and their spectral data matched that published.[51]
Sulfamidate 112: Rf =0.30 (silica gel, EtOAc/MeOH, 98:2); IR (film):
nmax =3482, 2924, 1644, 1445, 1389, 1296, 1166, 1109, 1052, 964, 883, 804,
736, 619 cmꢀ1 1H NMR (500 MHz, CD3CN): d=4.05 (AB, J=11.8 Hz,
;
Perillyl epoxide 109: Rf =0.33 (silica gel, EtOAc/hexanes, 1:1); IR (film):
nmax =3347, 2933, 1632, 1509, 1461, 1371, 1224, 1042, 939, 837, 777 cmꢀ1
;
nab =162.9 Hz, 2H), 3.52 (s, 3H), 3.32 (m, 1H), 2.15 (t, J=5.9 Hz, 1H),
2.06 (dt, J=7.2, 5.8 Hz, 1H), 1.96 (m, 2H), 1.72 (m, 1H), 1.54 (d, J=
9.6 Hz, 1H), 1.29 (s, 3H), 0.92 ppm (s, 3H); 13C NMR (125 MHz,
CD3CN): d=162.3, 70.1, 62.2, 54.0, 52.9, 41.2, 40.9, 40.7, 27.7, 26.7, 26.0,
20.3 ppm; HRMS (MALDI-FTMS) calcd for C12H19NO6SNa+ [M+H]+:
328.0825; found: 328.0820.
1H NMR (400 MHz, CDCl3): d=4.67 (s, 1H), 4.64 (s, 1H), 3.58 (AB, J=
12.0 Hz, nab =43.7 Hz, 2H), 3.32 (s, 1H), 2.36 (brs, 3H), 2.12 (AB, J=
13.5 Hz, nab =22.6 Hz, 2H), 1.80 (m, 2H), 1.66 (s, 3H), 1.58 (appt, J=
11.4 Hz, 2H), 1.17 ppm (dd, J=11.4, 6.8 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d=148.6, 109.1, 64.2, 60.0, 56.7, 36.7, 30.2, 24.6, 20.8 ppm; MS
+
(GC/MS) calcd for C10H16O2 [M]+: 168; found: 168.
Synthesis of aminoalcohol starting materials (Procedure A): The appro-
priate aniline (5.0 mmol, 1.0 equiv) was dissolved in 2-bromoethanol
(5 mL), and the resulting solution was heated at 708C until most of the
starting material had been consumed (typically 2–8 h). Upon completion,
the reaction contents were cooled to 258C, poured into water (5 mL),
and extracted withEtOAc (3”10 mL). Teh combined organic layers
were then washed with water (2”15 mL), dried (MgSO4), and concen-
trated. The resultant oil was purified by flash column chromatography
(silica gel) in an appropriate solvent system to give the desired aminoal-
cohol product in high purity.
Myrtenol epoxide 111: VO(acac)2 (0.100 g, catalytic) and tert-butyl hydro-
peroxide (0.70 mL, 2.0 mmol, 2.0 equiv) were added sequentially to a so-
lution of (ꢀ)-myrtenol (0.152 g, 1.0 mmol, 1.0 equiv) in CH2Cl2 (5 mL) at
258C. After stirring the resultant solution for 2 h at 258C, the reaction
mixture was diluted withCH 2Cl2 (10 mL) and quenched by the addition
of water (5 mL) and Na2SO3 (0.063 g, 0.5 mmol, 0.5 equiv). The reaction
contents were then poured into water (25 mL) and extracted with CH2Cl2
(3”25 mL). The combined organic layers were washed with water
(50 mL), dried (MgSO4), and concentrated. The resultant yellow residue
was purified by flash column chromatography (silica gel, EtOAc/hexanes,
1:1) to provide myrtenol epoxide 111 (0.146 g, 87%) as a colorless oil.
Rf =0.42 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax =2976, 2908,
Data for 131: Rf =0.32 (silica gel, CH2Cl2); IR (film): nmax =3385, 2919,
1602, 1537, 1504, 1467, 1305, 1185, 1112, 1049, 833 cmꢀ1 1H NMR
;
(500 MHz, CD3CN): d=8.10 (dd, J=7.0, 1.9 Hz, 2H), 6.72 (dd, J=7.0,
1.9 Hz, 2H), 3.77 (brt, J=5.2 Hz, 2H), 3.39 ppm (t, J=5.5 Hz, 2H);
13C NMR (125 MHz, CD3CN): d=154.8, 137.5, 126.5, 111.4, 60.2,
1461, 1433, 1368, 1270, 1230, 1088, 1062, 1025, 865, 835, 770, 692 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d=3.66 (AB, J=12.6 Hz, nab =69.5 Hz,
2H), 3.37 (d, J=4.1 Hz, 1H), 2.15 (brs, 1H), 2.04 (m, 1H), 2.01 (d, J=
2.9 Hz, 1H), 1.98 (t, J=5.6 Hz, 1H), 1.93–1.87 (m, 1H), 1.75 (brm, 1H),
1.63 (d, J=9.7 Hz, 1H), 1.25 (s, 3H), 0.89 ppm (s, 3H); 13C NMR
+
45.6 ppm; HRMS (MALDI-FTMS) calcd for C8H11N2O3 [M+H]+:
183.0764; found: 183.0765.
Data for 133: Rf =0.28 (silica gel, CH2Cl2); IR (film): nmax =3280, 2955,
1618, 1519, 1465, 1391, 1292, 1119, 964, 870, 700 cmꢀ1
;
1H NMR
(100 MHz, CDCl3): d=63.9, 62.9, 53.3, 40.5, 40.1, 27.1, 26.4, 25.5,
+
20.0 ppm; HRMS (MALDI-FTMS) calcd for C6H11O2
115.0754; found: 115.0758.
[M+H]+:
(400 MHz, CDCl3): d=7.16 (s, 1H), 6.97 (s, 2H), 3.89 (t, J=5.0 Hz, 2H),
3.87 (dd, J=5.6, 4.1 Hz, 1H), 3.67 (dd, J=5.3, 5.0 Hz, 1H), 3.35 ppm
(brt, J=4.7 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=148.7, 132.3 (d,
J=133.4 Hz), 112.1, 110.5, 60.8, 45.4 ppm; MS (ESI) calcd for
C10H10F6NO+ [M+H]+: 274; found: 274.
General procedure for the synthesis of sulfamidates from epoxy alcohols:
The epoxy alcohol (1.0 mmol, 1.0 equiv) was dissolved in THF/CH2Cl2
(4:1, 5 ml) and the Burgess reagent (0.309 g, 1.3 mmol, 1.3 equiv) was
added at 258C in a single portion. The resultant solution was immediately
warmed to reflux (using a preheated oil bath) and stirred for 3 h. Upon
completion, the reaction contents were concentrated directly, and the re-
sultant residue was purified by flash column chromatography (Florisilꢁ,
EtOAc/MeOH, 1:0!98:2) to give the desired sulfamidate product in
high purity.
Data for 135: Rf =0.22 (silica gel, CH2Cl2); IR (film): nmax =3378, 2937,
1606, 1512, 1459, 1236, 1128, 1005, 601 cmꢀ1
;
1H NMR (400 MHz,
CDCl3): d=5.89 (s, 2H), 3.83 (t, J=5.3 Hz, 2H), 3.81 (s, 6H), 3.76 (s,
3H), 3.27 ppm (t, J=5.3 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=
153.9, 144.9, 92.6, 90.8, 61.3, 61.1, 55.9, 46.6 ppm; HRMS (MALDI-
+
FTMS) calcd for C11H18NO4 [M+H]+: 228.1230; found: 228.1239.
Sulfamidate 104: Rf =0.35 (silica gel, EtOAc/MeOH, 98:2); IR (film):
Synthesis of aminoalcohol starting materials (Procedure B): NaCNBH3
(0.200 g, 3.5 mmol, 1.0 equiv) was added to a solution of the desired alde-
nmax =3436, 3002, 1744, 1636, 1467, 1383, 1255, 1174, 953, 700, 597 cmꢀ1
;
5600
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 5581 – 5606

Burgess Reagent
5581 – 5606
hyde (3.5 mmol, 1.0 equiv) and amine (10.0 mmol, 2.85 equiv) in MeOH
(25 mL) at 258C, and the resultant mixture was stirred for 12 h. Upon
completion, the pH of the reaction media was acidified to a value of less
than 2 using concentrated HCl; the contents were then concentrated di-
rectly. The resultant yellow residue was dissolved in water (10 mL) and
poured into saturated aqueous NH4Cl (25 mL), and extracted with
CH2Cl2 (3”20 mL). The combined organic layers were then washed with
water (50 mL), dried (MgSO4), and concentrated. The resultant yellow
residue was purified by flash column chromatography (silica gel) in an
appropriate solvent system to give the desired product in high purity.
extracted withEt O (15 mL) to remove any neutral impurities. The aque-
ous layer was then made alkaline (pH >10) using saturated aqueous
2
Data for 114: Rf =0.33 (silica gel, CH2Cl2); IR (film): nmax =3447, 2877,
1730, 1458, 1328, 1245, 1217, 1159, 1133, 1081, 1018, 963, 936, 792, 764,
712, 644, 614 cmꢀ1 1H NMR (400 MHz, CDCl3): d=3.84 (s, 3H), 3.82 (t,
;
K2CO3 and was extracted withCH Cl2 (3”25 mL). The combined organic
2
J=6.8 Hz, 2H), 3.33 (t, J=6.8 Hz, 2H), 2.75 ppm (s, 3H); 13C NMR
(100 MHz, CDCl3): d=150.9, 54.1, 46.0, 42.7, 33.1 ppm; HRMS
(MALDI-FTMS) calcd for C5H10N2O4SNa+ [M+Na]+: 217.0253; found:
217.0250.
layers were washed with water (50 mL), dried (MgSO4), and concentrat-
ed. The resultant yellow residue was purified by flash column chromatog-
raphy (silica gel) in an appropriate solvent system to give the desired
aminoalcohol product in high purity.
Data for 118: Rf =0.01 (silica gel, EtOAc); IR (film): nmax =3435, 2940,
Data for 115: Rf =0.40 (silica gel, CH2Cl2); IR (film): nmax =2966, 1731,
1636, 1513, 1357, 694 cmꢀ1 1H NMR (600 MHz, CD3CN): d=8.18 (s,
;
1458, 1390, 1323, 1166, 1079, 1018, 976, 942, 908, 842, 760, 700, 643 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d=7.42–7.32 (m, 5H), 5.30 (s, 2H), 3.84 (t,
J=6.4 Hz, 2H), 3.33 (t, J=6.8 Hz, 2H), 2.77 ppm (s, 3H); 13C NMR
(100 MHz, CDCl3): d=150.4, 134.7, 128.5, 128.4, 127.8, 68.8, 46.0, 42.7,
33.2 ppm; HRMS (MALDI-FTMS) calcd for C11H14N2O4SNa+ [M+Na]+:
293.0566; found: 293.0568.
1H), 8.04 (d, J=7.9 Hz, 1H), 7.70 (d, J=7.5 Hz, 1H), 7.52 (t, J=7.9 Hz,
1H), 3.85 (s, 2H), 3.55 (t, J=5.3 Hz, 2H), 2.65 (t, J=5.2 Hz, 2H),
2.58 ppm (brs, 2H); 13C NMR (150 MHz, CD3CN): d=149.2, 144.2,
135.3, 130.2, 123.4, 122.5, 61.5, 52.9, 51.6 ppm; HRMS (MALDI-FTMS)
+
calcd for C9H13N2O3 [M+H]+: 197.0921; found: 197.0921.
Data for 120: Rf =0.04 (silica gel, EtOAc); IR (film): nmax =3439, 1636,
Data for 117: Rf =0.67 (silica gel, EtOAc); IR (film): nmax =2984, 1730,
1452, 1041, 629, 542 cmꢀ1 1H NMR (600 MHz, CD3CN): d=6.70 (d, J=
;
1449, 1349, 1320, 1216, 1174, 1146, 1059, 1001, 972, 945, 919, 780, 732,
698, 641, 601, 542, 488 cmꢀ1 1H NMR (400 MHz, CDCl3): d=7.36 (m,
;
3.1 Hz, 1H), 6.59 (d, J=2.2 Hz, 1H), 3.85 (s, 2H), 3.54 (t, J=5.3 Hz,
2H), 2.82 (brs, 2H), 2.66 (t, J=5.3 Hz, 2H), 2.41 ppm (s, 3H); 13C NMR
(150 MHz, CD3CN): d=142.8, 139.6, 125.8, 125.5, 61.3, 51.4, 48.6,
15.3 ppm; HRMS (MALDI-FTMS) calcd for C8H14NOS+ [M+H]+:
172.0791; found: 172.0791.
5H), 4.21 (s, 2H), 3.90 (s, 3H), 3.80 (t, J=6.8 Hz, 2H), 3.24 ppm (t, J=
6.4 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=151.1, 133.8, 128.9, 128.8,
128.5, 54.3, 50.4, 43.0, 42.9 ppm; HRMS (MALDI-FTMS) calcd for
C11H14N2O4SNa+ [M+Na]+: 293.0566; found: 293.0565.
Data for 143: Rf =0.01 (silica gel, EtOAc); IR (film): nmax =3418, 2953,
Data for 119: Rf =0.20 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax
=
1636, 1514, 1467, 1303, 1249, 1180, 1030, 818, 602 cmꢀ1
;
1H NMR
2957, 1736, 1636, 1532, 1442, 1326, 1162, 729, 645, 545 cmꢀ1 1H NMR
;
(600 MHz, CD3CN): d=7.24 (d, J=8.3 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H),
3.75 (s, 3H), 3.67 (brs, 2H), 3.59 (t, J=6.2 Hz, 2H), 2.69 (t, J=6.6 Hz,
2H), 1.65 ppm (quin, J=6.1 Hz, 2H); 13C NMR (150 MHz, CD3CN): d=
159.6, 132.7, 130.5, 114.5, 62.0, 55.8, 53.4, 47.9, 32.4 ppm; HRMS
(MALDI-FTMS) calcd for C11H18NO2S+ [M+H]+: 196.1332; found:
196.1330.
(600 MHz, CDCl3): d=8.24 (s, 1H), 8.20 (d, J=8.3 Hz, 1H), 7.76 (d, J=
7.5 Hz, 1H), 7.59 (t, J=7.9 Hz, 1H), 4.33 (s, 2H), 3.90 (s, 3H), 3.88 (t,
J=6.2 Hz, 2H), 3.34 ppm (t, J=6.6 Hz, 2H); 13C NMR (150 MHz,
CDCl3): d=150.9, 148.4, 136.3, 134.6, 130.0, 123.5, 123.4, 54.4, 49.8, 43.7,
42.9 ppm; HRMS (MALDI-FTMS) calcd for C11H13N3O6SNa+ [M+Na]+:
338.0417; found: 338.0416.
Data for 145: Rf =0.02 (silica gel, EtOAc); IR (film): nmax =3434, 2970,
Data for 121: Rf =0.43 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax
=
1
1636, 1471, 1409, 1309, 1061, 639 cmꢀ1; H NMR (600 MHz, CD3CN): d=
2957, 1737, 1640, 1442, 1323, 1221, 1161, 1096, 1040, 792, 758, 645 cmꢀ1
;
1H NMR (600 MHz, CDCl3): d=6.85 (d, J=3.5 Hz, 1H), 6.62 (m, 1H),
3.90 (s, 2H), 3.77 (t, J=6.5 Hz, 2H), 3.48 (s, 3H), 3.34 (t, J=6.5 Hz, 2H),
2.46 ppm (s, 3H); 13C NMR (150 MHz, CDCl3): d=151.1, 141.9, 133.3,
128.5, 124.9, 54.3, 45.7, 43.2, 42.7, 15.4 ppm; HRMS (MALDI-FTMS)
calcd for C10H14N2O4S2Na+ [M+Na]+: 313.0287; found: 313.0297.
7.65 (d, J=8.3 Hz, 2H), 7.47 (d, J=8.3 Hz, 2H), 3.79 (s, 2H), 3.58 (t, J=
5.7 Hz, 2H), 2.77 (brs, 2H), 2.66 (t, J=6.6 Hz, 2H), 1.63 ppm (quin, J=
6.1 Hz, 2H); 13C NMR (150 MHz, CD3CN): d=147.5, 133.0, 129.6, 119.8,
111.0, 62.1, 53.7, 48.1, 32.7 ppm; HRMS (MALDI-FTMS) calcd for
C11H15N2O+ [M+H]+: 191.1179; found: 191.1178.
Data for 147: Rf =0.02 (silica gel, EtOAc); IR (film): nmax =3429, 2940,
Data for 123: Rf =0.34 (silica gel, CH2Cl2); IR (film): nmax =2981, 1728,
1641, 1566, 1471, 1067, 778, 667 cmꢀ1 1H NMR (600 MHz, CD3CN): d=
;
1446, 1364, 1343, 1314, 1255, 1198, 1148, 1077, 1007, 954, 866, 806, 760,
675, 616, 501 cmꢀ1 1H NMR (400 MHz, CDCl3): d=3.86 (s, 3H), 3.77 (t,
;
7.49 (s, 1H), 7.37 (d, J=7.8 Hz, 1H), 7.26 (d, J=7.4 Hz, 1H), 7.21 (t, J=
7.9 Hz, 1H), 3.69 (s, 2H), 3.57 (t, J=6.2 Hz, 2H), 3.05 (brs, 2H), 2.65 (t,
J=6.5 Hz, 2H), 1.63 ppm (quin, J=6.1 Hz, 2H); 13C NMR (150 MHz,
CD3CN): d=144.3, 131.8, 131.1, 130.6, 127.9, 122.8, 62.0, 53.5, 48.0,
32.8 ppm; HRMS (MALDI-FTMS) calcd for C10H15BrNO+ [M+H]+:
244.0331; found: 244.0333.
J=6.0 Hz, 2H), 3.40 (t, J=6.4 Hz, 2H), 1.41 ppm (s, 9H); 13C NMR
(100 MHz, CDCl3): d=151.0, 57.1, 54.1, 41.6, 39.7, 27.3 ppm; HRMS
(MALDI-FTMS) calcd for C8H16N2O4SNa+ [M+Na]+: 259.0723; found:
259.0721.
Data for 124: Rf =0.30 (silica gel, CH2Cl2); IR (film): nmax =2989, 2908,
Data for 149: Rf =0.05 (silica gel, EtOAc); IR (film): nmax =3447, 2940,
1724, 1472, 1455, 1378, 1314, 1208, 1143, 1079, 1002, 938, 901, 862, 803,
1636, 1469, 1060, 798, 602 cmꢀ1 1H NMR (600 MHz, CD3CN): d=6.70
;
761, 673, 615 cmꢀ1 1H NMR (400 MHz, CDCl3): d=5.90 (m, 1H), 5.41
;
(d, J=3.1 Hz, 1H), 6.59 (d, J=2.2 Hz, 1H), 3.83 (s, 2H), 3.59 (t, J=
6.1 Hz, 2H), 3.09 (brs, 2H), 2.70 (t, J=6.2 Hz, 2H), 2.41 (s, 3H),
2.13 ppm (quin, J=6.1 Hz, 2H); 13C NMR (150 MHz, CD3CN): d=142.7,
139.5, 125.8, 125.6, 62.2, 48.9, 47.9, 32.7, 15.4 ppm; HRMS (MALDI-
FTMS) calcd for C9H16NOS+ [M+H]+: 186.0947; found: 186.0946.
(dd, J=17.2, 1.6 Hz, 1H), 5.25 (dd, J=10.4, 1.6 Hz, 1H), 4.74 (dt, J=5.2,
1.6 Hz, 2H), 3.77 (t, J=6.0 Hz, 2H), 3.41 (t, J=6.4 Hz, 2H), 1.42 ppm (s,
9H); 13C NMR (100 MHz, CDCl3): d=150.3, 130.9, 118.6, 67.4, 57.1, 41.5,
39.6, 27.3 ppm; HRMS (MALDI-FTMS) calcd for C10H18N2O4SNa+
[M+Na]+: 285.0879; found: 285.0879.
Data for 151: Rf =0.07 (silica gel, EtOAc/hexanes, 1:2); IR (film): nmax
=
Data for 126: Rf =0.29 (silica gel, CH2Cl2); IR (film): nmax =2957, 1734,
3376, 2934, 2861, 1650, 1528, 1476, 1349, 1062, 806, 733, 690 cmꢀ1
;
1444, 1320, 1273, 1224, 1183, 1159, 1006, 944, 896, 787, 761, 612 cmꢀ1
;
1H NMR (600 MHz, CDCl3): d=8.13 (s, 1H), 8.06 (d, J=8.3 Hz, 1H),
7.66 (d, J=7.4 Hz, 1H), 7.47 (t, J=7.9 Hz, 1H), 3.86 (s, 2H), 3.56 (t, J=
4.9 Hz, 2H), 3.28 (brs, 2H), 2.66 (t, J=5.7 Hz, 2H), 1.61 ppm (m, 4H);
13C NMR (125 MHz, CDCl3): d=148.1, 141.4, 134.4, 129.4, 122.9, 122.1,
62.3, 52.8, 49.1, 31.5, 27.6 ppm; HRMS (MALDI-FTMS) calcd for
C11H17N2O3S+ [M+H]+: 225.1234; found: 225.1239.
1H NMR (400 MHz, CDCl3): d=3.90 (dd, J=9.2, 6.0 Hz, 1H), 3.86 (s,
3H), 3.48 (m, 1H), 3.42 (dd, J=10.4, 9.2 Hz, 1H), 3.24 (m, 1H), 2.71 (dt,
J=9.2, 2.8 Hz, 1H), 1.94 (m, 1H), 1.87 (m, 2H), 1.61 (m, 1H), 1.47–
1.31 ppm (m, 2H); 13C NMR (100 MHz, CDCl3): d=150.9, 54.1, 53.5,
49.3, 42.6, 28.5, 23.1, 22.0 ppm; HRMS (MALDI-FTMS) calcd for
C8H14N2O4SNa+ [M+Na]+: 257.0566; found: 257.0558.
General procedure for the synthesis of sulfamides from precursor amino-
alcohols: The aminoalcohol (0.5 mmol, 1.0 equiv) was dissolved in anhy-
drous THF (5 mL) and the appropriate Burgess-type reagent (1.25 mmol,
2.5 equiv) was added at 258C in a single portion. The resultant solution
was immediately warmed to reflux (using a preheated oil bath) and stir-
red for 8 h. Upon completion, the reaction contents were cooled to 258C,
Data for 127: Rf =0.51 (silica gel, CH2Cl2); IR (film): nmax =3423, 2931,
1731, 1390, 1320, 1167, 1002, 885, 615 cmꢀ1 1H NMR (400 MHz, CDCl3):
;
d=7.42–7.32 (m, 5H), 5.30 (s, 2H), 3.92 (dd, J=9.2, 5.6 Hz, 1H), 3.50
(dt, J=11.2, 3.4 Hz, 1H), 3.45 (appt, J=9.2 Hz, 1H), 3.22 (m, 1H), 2.74
(dt, J=12.4, 3.2 Hz, 1H), 1.91–1.82 (m, 2H), 1.64 (m, 2H), 1.40 ppm (m,
2H); 13C NMR (100 MHz, CDCl3): d=150.5, 134.9, 128.6, 128.4, 127.8,
Chem. Eur. J. 2004, 10, 5581 – 5606
www.chemeurj.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5601

K. C. Nicolaou et al.
FULL PAPER
68.8, 53.6, 49.3, 42.7, 28.7, 23.3, 22.1 ppm; HRMS (MALDI-FTMS) calcd
47.4, 46.6, 19.2 ppm; HRMS (MALDI-FTMS) calcd for C13H18N2O5SNa+
for C14H18N2O4SNa+ [M+Na]+: 333.0879; found: 333.0875.
[M+Na]+: 337.0829; found: 337.0828.
Data for 129: Rf =0.30 (silica gel, CH2Cl2); IR (film): nmax =2955, 1743,
Data for 146: Rf =0.24 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax
2982, 2231, 1732, 1636, 1435, 1359, 1297, 1253, 1170, 1032, 949, 864,
584 cmꢀ1 1H NMR (600 MHz, CDCl3): d=7.65 (d, J=8.3 Hz, 2H), 7.46
=
1602, 1590, 1496, 1149, 1372, 1326, 1273, 1214, 1167, 1143, 1079, 1061,
950, 756, 703, 650, 585 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d=7.43–7.34
;
(m, 4H), 7.27 (t, J=7.2 Hz, 1H), 4.00 (t, J=6.4 Hz, 2H), 3.91 (s, 3H),
3.83 ppm (t, J=6.8 Hz, 2H); 13C NMR (75 MHz, CDCl3): d=150.9,
136.3, 129.6, 126.6, 121.7, 54.4, 43.5, 42.2 ppm; HRMS (MALDI-FTMS)
calcd for C10H12N2O4SNa+ [M+Na]+: 279.0410; found: 279.0411.
(d, J=7.9 Hz, 2H), 4.42 (s, 2H), 4.06 (t, J=5.7 Hz, 2H), 3.86 (s, 3H),
3.49 (t, J=5.7 Hz, 2H), 1.86 ppm (quin, J=6.1 Hz, 2H); 13C NMR
(150 MHz, CDCl3): d=153.5, 140.8, 132.5, 128.6, 118.3, 111.9, 54.4, 51.9,
48.2, 47.5, 19.5 ppm; HRMS (MALDI-FTMS) calcd for C13H15N3O4SNa+
[M+Na]+: 332.0675; found: 332.0681.
Data for 130: Rf =0.43 (silica gel, CH2Cl2); IR (film): nmax =1720, 1661,
1543, 1496, 1422, 1332, 1198, 1010, 920, 740, 602 cmꢀ1
;
1H NMR
Data for 148: Rf =0.44 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax
2956, 1729, 1571, 1437, 1383, 1307, 1273, 1176, 1023, 953, 843, 777, 609,
564 cmꢀ1 1H NMR (600 MHz, CDCl3): d=7.46 (s, 1H), 7.42 (d, J=
=
(500 MHz, CDCl3): d=7.43–7.40 (m, 2H), 7.39–7.35 (m, 2H), 7.28 (t, J=
6.6 Hz, 1H), 5.96 (m, 1H), 5.47 (dd, J=17.3, 1.5 Hz, 1H), 5.30 (dt, J=
11.8, 1.5 Hz, 1H), 4.81 (dt, J=5.5, 1.5 Hz, 2H), 4.04 (t, J=6.6 Hz, 2H),
3.87 ppm (t, J=5.9 Hz, 2H); 13C NMR (125 MHz, CDCl3): d=150.3,
136.5, 130.8, 129.7, 126.8, 21.9, 119.1, 68.0, 43.6, 42.2 ppm; HRMS
(MALDI-FTMS) calcd for C12H14N2O4SNa+ [M+Na]+: 305.0566; found:
305.0566.
;
7.9 Hz, 1H), 7.24 (d, J=7.9 Hz, 1H), 7.21 (t, J=7.4 Hz, 1H), 4.31 (s,
2H), 4.02 (t, J=5.7 Hz, 2H), 3.84 (s, 3H), 3.45 (t, J=5.7 Hz, 2H),
1.81 ppm (quin, J=6.1 Hz, 2H); 13C NMR (150 MHz, CDCl3): d=153.6,
137.4, 131.2, 131.1, 130.3, 126.8, 122.7, 54.3, 51.5, 47.5, 47.4, 19.4 ppm;
HRMS (MALDI-FTMS) calcd for C12H16BrN2O4S+ [M+H]+: 363.0009;
found: 363.0011.
Data for 132: Rf =0.22 (silica gel, CH2Cl2); IR (film): nmax =2986, 1727,
1639, 1509, 1433, 1339, 1286, 1163, 1133, 1081, 834, 751, 722, 687,
Data for 150: Rf =0.45 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax
=
1
622 cmꢀ1; H NMR (400 MHz, CD3CN): d=8.28 (dt, J=9.2, 3.2 Hz, 2H),
2970, 1726, 1636, 1439, 1383, 1298, 1265, 1176, 854, 775, 596 cmꢀ1
;
7.47 (dt, J=8.8, 3.6 Hz, 2H), 4.05 (t, J=6.2 Hz, 2H), 3.98 (t, J=6.4 Hz,
2H), 3.88 ppm (s, 3H); 13C NMR (100 MHz, CD3CN): d=151.6, 126.3,
119.2, 118.3 (2C), 55.1, 43.9, 43.0 ppm; HRMS (MALDI-FTMS) calcd
for C10H11N3O6SNa+ [M+Na]+: 324.0261; found: 324.0257.
1H NMR (600 MHz, CDCl3): d=6.78 (s, 1H), 6.59 (s, 1H), 4.46 (s, 2H),
4.00 (t, J=6.1 Hz, 2H), 3.86 (s, 3H), 3.52 (t, J=5.7 Hz, 2H), 2.45 (s, 3H),
1.78 ppm (brm, 2H); 13C NMR (150 MHz, CDCl3): d=153.8, 141.4,
134.7, 127.8, 124.9, 54.4, 47.5, 47.3, 46.7, 19.6, 15.4 ppm; HRMS
(MALDI-FTMS) calcd for C11H16N2O4S2Na+ [M+Na]+: 327.0444; found:
327.0443.
Data for 134: Rf =0.40 (silica gel, CH2Cl2); IR (film): nmax =2958, 1733,
1619, 1472, 1437, 1390, 1325, 1273, 1173, 1120, 1073, 1006, 871, 806, 760,
1
698, 682, 612 cmꢀ1; H NMR (400 MHz, CD3CN): d=7.89 (s, 1H), 7.86 (s,
Data for 152: Rf =0.42 (silica gel, EtOAc/hexanes, 1:2); IR (film): nmax
=
2H), 4.04 (m, 2H), 3.98 (m, 2H), 3.88 ppm (s, 3H); 13C NMR (100 MHz,
CD3CN): d=151.3, 139.9, 133.1 (d, J=132.0 Hz), 120.9, 119.7, 54.9, 44.0,
43.1 ppm; HRMS (MALDI-FTMS) calcd for C12H10F6N2O4SNa+
[M+Na]+: 415.0158; found: 415.0169.
2953, 1725, 1531, 1437, 1350, 1274, 1164, 925, 765, 602 cmꢀ1 1H NMR
;
(600 MHz, CDCl3): d=8.25–8.19 (m, 2H), 7.78 (d, J=9.2 Hz, 1H), 7.59
(t, J=8.3 Hz, 1H), 7.69 (s, 2H), 3.90 (s, 3H), 3.85 (t, J=4.8 Hz, 2H), 3.35
(t, J=5.2 Hz, 2H), 1.97 (brm, 2H), 1.87 ppm (brm, 2H); 13C NMR
(150 MHz, CDCl3): d=153.6, 148.2, 138.0, 133.7, 129.9, 123.0, 122.5, 54.2,
51.1, 46.3, 46.1, 28.0, 23.7 ppm; HRMS (MALDI-FTMS) calcd for
C13H18N3O6S+ [M+H]+: 344.0911; found: 344.0909.
Data for 136: Rf =0.14 (silica gel, CH2Cl2); IR (film): nmax =2942, 2837,
1713, 1601, 1502, 1461, 1431, 1326, 1249, 1213, 1112, 1014, 864, 806, 763,
622 cmꢀ1 1H NMR (400 MHz, CD3CN): d=6.64 (s, 2H), 3.97 (t, J=
;
6.4 Hz, 2H), 3.85 (s, 3H), 3.83 (m, 2H), 3.82 (s, 6H), 3.72 ppm (s, 3H);
13C NMR (100 MHz, CD3CN): d=155.5, 152.6, 138.3, 134.3, 101.7, 61.5,
57.5, 55.5, 45.5, 44.1 ppm; HRMS (MALDI-FTMS) calcd for
C13H18N2O7SNa+ [M+Na]+: 369.0727; found: 369.0738.
Data for 154: Rf =0.63 (silica gel, EtOAc); IR (film): nmax =3251, 2958,
1743, 1661, 1602, 1473, 1455, 1367, 1237, 1167, 1108, 1061, 985, 856, 756,
591 cmꢀ1 1H NMR (400 MHz, CDCl3): d=7.31 (d, J=8.0 Hz, 1H), 7.20–
;
7.16 (m, 2H), 7.03 (t, J=7.6 Hz, 1H), 5.28 (brs, 1H), 4.31 (t, J=8.8 Hz,
2H), 3.64 (s, 3H), 3.15 ppm (t, J=8.8 Hz, 2H); 13C NMR (100 MHz,
CDCl3): d=151.7, 140.6, 131.5, 127.6, 125.3, 123.8, 113.9, 53.5, 51.6,
27.9 ppm; HRMS (MALDI-FTMS) calcd for C10H12N2O5SNa+ [M+Na]+:
279.0410; found: 279.0412.
Data for 138: Rf =0.46 (silica gel, CH2Cl2); IR (film): nmax =3472, 2966,
1737, 1572, 1455, 1443, 1396, 1326, 1273, 1243, 1179, 1149, 1096, 1070,
955, 861, 791, 773, 621 cmꢀ1 1H NMR (400 MHz, CDCl3): d=8.26 (m,
;
1H), 7.83 (m, 1H), 7.54–7.47 (m, 3H), 7.37 (t, J=7.6 Hz, 1H), 6.89 (d,
J=7.6 Hz, 1H), 4.67 (dt, J=11.6, 8.4 Hz, 1H), 4.44 (dd, J=9.2, 3.6 Hz,
1H), 4.35 (t, J=9.2 Hz, 1H), 3.94 (s, 3H), 3.88 (sep, J=6.4 Hz, 1H), 3.58
(m, 2H), 1.30 ppm (appt, J=7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3):
d=153.6, 151.1, 134.5, 127.6, 126.6, 125.8, 125.5, 121.7, 121.2, 104.9, 65.4,
52.7, 43.3, 41.0, 20.9, 19.8 ppm; HRMS (MALDI-FTMS) calcd for
C18H22N2O5SNa+ [M+Na]+: 401.1142; found: 401.1129.
Data for 156: Rf =0.25 (silica gel, CH2Cl2); IR (film): nmax =3252, 2962,
1730, 1443, 1408, 1337, 1208, 1167, 1097, 1021, 950, 921, 786, 757, 651,
633 cmꢀ1 1H NMR (400 MHz, CDCl3): d=3.81 (t, J=6.4 Hz, 2H), 3.76
;
(s, 3H), 3.49 (brs, 1H), 3.40 ppm (t, J=6.4 Hz, 2H); 13C NMR
(100 MHz, CDCl3): d=151.5, 54.0, 48.2, 39.1 ppm; HRMS (MALDI-
FTMS) calcd for C4H8N2O4SNa+ [M+Na]+: 203.0097; found: 203.0097.
Data for 140: Rf =0.40 (silica gel, EtOAc); IR (film): nmax =3420, 1637,
Data for 158: Rf =0.49 (silica gel, CH2Cl2); IR (film): nmax =3286, 1732,
1432, 1329, 1156, 1024, 984, 756, 702, 657 cmꢀ1
;
1H NMR (400 MHz,
1470, 1454, 1347, 1252, 1154, 1057, 882, 771, 590 cmꢀ1 1H NMR
;
DMSO-d6): d=2.90 (t, J=6.4 Hz, 4H), 2.84 (s, 6H), 2.57 (t, J=6.4 Hz,
4H), 2.35 ppm (s, 4H); 13C NMR (100 MHz, DMSO-d6): d=150.6, 54.0,
(500 MHz, CDCl3): d=5.63 (brs, 1H), 3.89 (s, 3H), 3.62 (s, 2H),
1.40 ppm (s, 6H); 13C NMR (125 MHz, CDCl3): d=152.5, 69.6, 58.9, 53.9,
24.3 ppm; HRMS (MALDI-FTMS) calcd for C6H12N2O4SNa+ [M+Na]+:
231.0410; found: 231.0412.
44.8,
C10H18N4O8S2Na+ [M+Na]+: 409.0458; found: 409.0447.
Data for 142: Rf =0.24 (silica gel, MeOH/CH2Cl2, 3:97); IR (film): nmax
3272, 2919, 1731, 1496, 1455, 1355, 1326, 1237, 1161, 961, 861, 756,
591 cmꢀ1 1H NMR (400 MHz, CDCl3): d=7.45 (d, J=7.6 Hz, 1H), 7.29
44.0,
43.5 ppm;
HRMS
(MALDI-FTMS)
calcd
for
=
Data for 160: Rf =0.44 (silica gel, CH2Cl2); IR (film): nmax =3270, 1731,
1443, 1351, 1270, 1174, 1081, 1010, 774, 625, 568 cmꢀ1
;
1H NMR
;
(500 MHz, CDCl3): d=4.91 (brt, J=7.7 Hz, 1H), 4.09 (t, J=5.5 Hz, 2H),
3.93 (s, 3H), 3.62 (dt, J=7.4, 5.9 Hz, 2H), 1.95 ppm (quin, J=5.9 Hz,
2H); 13C NMR (125 MHz, CDCl3): d=153.7, 54.5, 47.3, 44.3, 24.7 ppm;
HRMS (MALDI-FTMS) calcd for C5H10N2O4SNa+ [M+Na]+: 217.0253;
found: 217.0254.
(dt, J=8.4, 1.6 Hz, 1H), 7.22 (dd, J=8.0, 1.6 Hz, 1H), 7.16 (t, J=7.2 Hz,
1H), 5.29 (brs, 1H), 4.72 (s, 2H), 3.71 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3): d=151.9, 135.1, 131.8, 129.5, 129.2, 125.9, 122.3, 63.2, 53.7 ppm;
HRMS (MALDI-FTMS) calcd for C9H10N2O4SNa+ [M+Na]+: 265.0253;
found: 265.0256.
Data for 162: Rf =0.52 (silica gel, CH2Cl2); IR (film): nmax =3288, 1732,
1
Data for 144: Rf =0.40 (silica gel, EtOAc/hexanes, 1:1); IR (film): nmax
=
1472, 1352, 1250, 1160, 1065, 874, 764, 702, 587 cmꢀ1; H NMR (600 MHz,
2957, 1724, 1636, 1513, 1440, 1382, 1291, 1250, 1176, 1030, 775, 624 cmꢀ1
;
CDCl3): d=7.32–7.25 (m, 5H), 6.10 (brt, J=5.7 Hz, 1H), 4.87 (dd, J=
8.8, 3.1 Hz, 1H), 3.72 (s, 3H), 3.37 (m, 1H), 3.22 ppm (m, 1H); 13C NMR
(150 MHz, CDCl3): d=152.5, 140.6, 128.9, 128.4, 126.1, 72.7, 53.9,
50.8 ppm; HRMS (MALDI-FTMS) calcd for C10H12N2O4SNa+ [M+Na]+:
279.0410; found: 279.0411.
1H NMR (600 MHz, CDCl3): d=7.23 (d, J=8.8 Hz, 2H), 6.87 (d, J=
8.3 Hz, 2H), 4.30 (s, 2H), 4.01 (t, J=5.7 Hz, 2H), 3.86 (s, 3H), 3.79 (s,
3H), 3.42 (t, J=6.1 Hz, 2H), 1.79 ppm (quin, J=6.1 Hz, 2H); 13C NMR
(150 MHz, CDCl3): d=159.4, 153.7, 129.8, 126.6, 114.0, 55.2, 54.2, 51.5,
5602
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 5581 – 5606

Burgess Reagent
5581 – 5606
Data for 164: Rf =0.55 (silica gel, CH2Cl2); IR (film): nmax =3540, 3301,
(m, 2H), 2.67 (dt, J=11.2, 3.2 Hz, 1H), 1.90–1.80 (m, 3H), 1.59 (m, 1H),
1.42–1.26 ppm (m, 2H); 13C NMR (100 MHz, CDCl3): d=57.6, 47.6, 43.1,
29.6, 23.6, 22.5 ppm; HRMS (MALDI-FTMS) calcd for C6H12N2O2SNa+
[M+Na]+: 199.0512; found: 199.0515.
1730, 1455, 1416, 1360, 1253, 1165, 1092, 1060, 969, 852, 772, 702, 606,
552 cmꢀ1 1H NMR (600 MHz, CD3CN): d=7.30–7.21 (m, 10H), 6.46 (d,
;
J=9.2 Hz, 1H), 4.98 (d, J=6.1 Hz, 1H), 4.54 (dd, J=9.2, 6.1 Hz, 1H),
3.43 ppm (s, 3H); 13C NMR (150 MHz, CD3CN): d=152.4, 142.1, 138.4,
129.3, 129.3, 128.8, 128.6, 128.5, 128.4, 127.7, 76.4, 64.6, 53.4 ppm; HRMS
(MALDI-FTMS) calcd for C16H16N2O4SNa+ [M+Na]+: 355.0723; found:
355.0724.
Alkylated sulfamide 171: Sulfamide 166 (0.053 g, 0.250 mmol, 1.0 equiv)
was dissolved in DMSO (2 mL) and treated withNaH (0.050 g, 60% dis-
persion in mineral oil, 1.25 mmol, 5.0 equiv) at 258C. After stirring the
resultant reaction mixture for 10 minutes at 258C, 4-bromo-1-butene
(0.102 mL, 1.0 mmol, 4.0 equiv) and TBAI (0.01 g, catalytic) were added
sequentially; the reaction mixture was then stirred for an additional
15 minutes at 258C. Upon completion, the reaction contents were poured
into water (5 mL), and extracted withEtOAc (3”10 mL). The combined
organic layers were then washed with water (2”15 mL), dried (MgSO4),
and concentrated. The resultant light yellow oil was purified by flash
column chromatography (silica gel, EtOAc/hexanes, 1:3!1:1) to give al-
kylated sulfamidate 171 (0.059 g, 89% yield) as an amorphous white
solid. Rf =0.18 (silica gel, CH2Cl2/hexanes, 2:1); IR (film): nmax =3524,
General conditions for the removal of methyl carbamate protection from
cyclic sulfamides: 10% aqueous NaOH (0.5 mL) was added to a solution
of the CO2Me-protected sulfamidate (0.2 mmol, 1.0 equiv) in MeOH/
H2O (2:1, 3 mL) at 258C. After stirring this mixture for 2 h at 258C, the
reaction contents were poured into saturated aqueous NH4Cl (5 mL),
acidified with1 m aqueous HCl (2 mL), and extracted withEtOAc (3”
10 mL). The combined organic layers were then dried (MgSO4) and con-
centrated to give the desired deprotected sulfamidate in high purity.
Data for 165: Rf =0.14 (silica gel, MeOH/CH2Cl2, 3:97); IR (film): nmax
=
3440, 3225, 1621, 1473, 1387, 1318, 1282, 1176, 1127, 1002, 788 cmꢀ1
;
2925, 1635, 1448, 1301, 1166, 1143, 1113, 914, 779, 689 cmꢀ1 1H NMR
;
1H NMR (600 MHz, CDCl3): d=7.61 (s, 1H), 7.58 (s, 2H), 4.99 (t, J=
7.9 Hz, 1H), 4.00 (t, J=6.5 Hz, 2H), 3.77 ppm (q, J=6.6 Hz, 2H);
13C NMR (150 MHz, CDCl3): d=139.4, 132.9 (q, J=137.3 Hz), 123.8,
122.0, 116.8, 48.8, 39.4 ppm; MS (ESI) calcd for C10H7F6N2O2S+ [MꢀH]+:
333; found: 333.
(500 MHz, CDCl3): d=7.37–7.30 (m, 5H), 5.82 (m, 1H), 5.14 (dd, J=
17.0, 2.0 Hz, 1H), 5.11 (dd, J=10.5, 1.6 Hz, 1H), 4.19 (s, 2H), 3.29 (dd,
J=6.0, 1.2 Hz, 2H), 3.18–3.13 (m, 4H), 2.40 ppm (m, 2H); 13C NMR
(125 MHz, CDCl3): d=134.9, 134.5, 128.7, 128.6, 128.1, 77.2, 51.3, 47.3,
45.6, 44.8, 32.1 ppm; HRMS (MALDI-FTMS) calcd for C13H18N2O2SNa+
[M+Na]+: 289.0981; found: 289.0981.
Data for 166: Rf =0.12 (silica gel, CH2Cl2); IR (film): nmax =3244, 2904,
1449, 1296, 1161, 1021, 897, 779, 715, 688, 616 cmꢀ1 1H NMR (400 MHz,
;
General conditions for the synthesis of linear sulfamides: The diol
(0.5 mmol, 1.0 equiv) was dissolved in anhydrous THF (5 mL) and the
Burgess reagent (1, 0.75 mmol, 1.5 equiv) was added at 258C in a single
portion. The resultant solution was immediately warmed to reflux (using
a preheated oil bath) and stirred for 2 h. Upon completion, the reaction
contents were cooled to 258C, poured into saturated aqueous NH4Cl
(25 mL), and extracted withCH 2Cl2 (3”20 mL). The combined organic
layers were then washed with water (50 mL), dried (MgSO4), and concen-
trated. The resultant yellow residue was purified by flash column chro-
matography (silica gel) in an appropriate solvent system to give the de-
sired product in high purity.
CDCl3): d=7.37–7.30 (m, 5H), 4.71 (brs, 1H), 4.17 (s, 2H), 3.46 (t, J=
6.4 Hz, 2H), 3.27 ppm (t, J=6.8 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d=135.1, 128.7, 128.6, 128.1, 50.4, 48.1, 39.9 ppm; HRMS (MALDI-
FTMS) calcd for C9H12N2O2SNa+ [M+Na]+: 235.0512; found: 235.0515.
General conditions for the removal of allyl carbamate protection from
cyclic sulfamides: Et2NH (0.828 mL, 8.0 mmol, 40 equiv) was added to a
solution of the Alloc-protected sulfamidate (0.2 mmol, 1.0 equiv) in
CH3CN/H2O (1:1, 3 mL) at 258C. After stirring this mixture for 5 mi-
nutes at 258C, Pd(OAc)2 (0.002 g, 0.020 mmol, 0.1 equiv) and TPPTS
(0.023 g, 0.040 mmol, 0.2 equiv) were added sequentially, providing a
yellow solution which was stirred for an additional 30 minutes at 258C.
Upon completion, the reaction contents were poured into water (5 mL),
and extracted withEtOAc (3”10 mL). Teh combined organic layers
were then dried (MgSO4) and concentrated to give the desired deprotect-
ed sulfamidate in high purity.[29]
Data for 173: Rf =0.25 (silica gel, CH2Cl2); IR (film): nmax =3276, 3201,
2940, 1714, 1490, 1454, 1348, 1166, 1084, 1008, 850, 778, 608 cmꢀ1
;
1H NMR (600 MHz, CDCl3): d=7.83 (s, 1H), 5.29 (d, J=7.0 Hz, 1H),
3.81 (s, 3H), 3.30 (brdd, J=7.0, 3.5 Hz, 1H), 1.94 (m, 2H), 1.74 (m, 2H),
1.58 (m, 1H), 1.36–1.27 (m, 4H), 1.18 ppm (m, 1H); 13C NMR (150 MHz,
CDCl3): d=152.0, 53.6, 53.5, 33.2, 25.1, 24.5 ppm; HRMS (MALDI-
FTMS) calcd for C8H16N2O4SNa+ [M+Na]+: 259.0723; found: 259.0728.
Data for 167: Rf =0.11 (silica gel, CH2Cl2); IR (film): nmax =3258, 3056,
2982, 1374, 1266, 1206, 1155, 1005, 739 cmꢀ1
;
1H NMR (600 MHz,
CDCl3): d=4.27 (brs, 1H), 3.51 (d, J=6.6 Hz, 6H), 3.45 (d, J=6.6 Hz,
2H), 1.42 ppm (s, 9H); 13C NMR (100 MHz, CDCl3): d=63.2, 45.2, 39.0,
27.2 ppm; HRMS (MALDI-FTMS) calcd for C6H14N2O4SNa+ [M+Na]+:
201.0668; found: 201.0665.
Data for 175: Rf =0.16 (silica gel, CH2Cl2); IR (film): nmax =3260, 2924,
1750, 1460, 1419, 1355, 1231, 1155, 1131, 1002, 943, 855, 773, 732, 603,
579 cmꢀ1 1H NMR (300 MHz, CD3CN): d=7.31–7.20 (m, 5H), 5.24 (s,
;
1H), 4.43 (s, 2H), 3.74 (s, 3H), 2.80 ppm (s, 3H); 13C NMR (100 MHz,
CD3CN): d=152.0, 135.6, 128.7, 128.1 128.0, 55.1, 53.5, 35.1 ppm; HRMS
(MALDI-FTMS) calcd for C10H14N2O4SNa+ [M+Na]+: 281.0566; found:
281.0567.
Data for 168: Rf =0.14 (silica gel, CH2Cl2); IR (film): nmax =3190, 1596,
1417, 1298, 1232, 1154, 1118, 1031, 950, 747, 688, 615, 464 cmꢀ1 1H NMR
;
(600 MHz, CDCl3): d=7.38–7.35 (m, 2H), 7.23 (d, J=7.5 Hz, 2H), 7.15
(t, J=7.4 Hz, 1H), 4.86 (brs, 1H), 3.88 (t, J=6.1 Hz, 2H), 3.65 ppm (t,
J=6.6 Hz, 2H); 13C NMR (125 MHz, CDCl3): d=137.7, 129.5, 124.1,
118.2, 48.7, 39.6 ppm; MS (ESI) calcd for C8H10N2O2SNa+ [M+Na]+:
221; found: 221.
Data for 177: Rf =0.38 (silica gel, CH2Cl2); IR (film): nmax =3448, 3271,
2919, 1748, 1449, 1361, 1331, 1225, 1137, 1102, 1049, 1026, 979, 861,
585 cmꢀ1 1H NMR (400 MHz, CD3CN): d=7.49 (brs, 1H), 3.75 (s, 3H),
;
3.43 (brm, 2H), 1.81–1.60 (m, 14H), 1.31–1.24 (m, 4H), 1.08 ppm (m,
2H); 13C NMR (100 MHz, CD3CN): d=151.3, 58.9, 53.1, 32.1, 26.3,
25.1 ppm; HRMS (MALDI-FTMS) calcd for C14H26N2O4SNa+ [M+Na]+:
341.1505; found: 341.1501.
General conditions for the removal of benzyl carbamate protection from
cyclic sulfamides: Pd/C (0.002 g, 10 wt%, catalytic) was added to a so-
lution of the Cbz-protected sulfamidate (0.2 mmol, 1.0 equiv) in EtOH/
EtOAc (4:1, 3 mL) at 258C. The resultant suspension was then equipped
witha balloon containing hydrogen gas (pressure of ~2 atm) and allowed
to stir for 24 hat 25 8C. Upon completion, the reaction contents were fil-
tered through Celite and concentrated to give the desired deprotected
sulfamidate in high purity.
Data for 179: Rf =0.47 (silica gel, EtOAc); IR (film): nmax =3275, 2907,
1748, 1461, 1361, 1261, 1167, 1114, 1079, 1015, 950, 862, 768, 721,
575 cmꢀ1 1H NMR (400 MHz, CDCl3): d=8.41 (brs, 1H), 3.73 (s, 3H),
;
3.70 (t, J=4.8 Hz, 4H), 3.33 ppm (t, J=4.8 Hz, 4H); 13C NMR
(100 MHz, CDCl3): d=151.8, 66.1, 53.4, 46.4 ppm; HRMS (MALDI-
FTMS) calcd for C6H12N2O5SNa+ [M+Na]+: 247.0359; found: 247.0361.
Data for 169: Rf =0.22 (silica gel, CH2Cl2); IR (film): nmax =3548, 3254,
2925, 1454, 1389, 1295, 1201, 1154, 1014, 914, 703 cmꢀ1
;
1H NMR
(500 MHz, CDCl3): d=4.61 (brs, 1H), 3.58 (t, J=5.2 Hz, 2H), 3.47 (t,
J=5.2 Hz, 2H), 2.82 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=50.5,
39.7, 32.7 ppm; HRMS (MALDI-FTMS) calcd for C3H9N2O4S+ [M+H]+:
137.0379; found: 137.0373.
Data for 181: Rf =0.63 (silica gel, EtOAc); IR (film): nmax =3256, 2957,
1742, 1466, 1420, 1355, 1308, 1238, 1155, 1062, 950, 856, 759, 591 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d=8.19 (brs, 1H), 4.51 (s, 2H), 3.79 (t, J=
6.4 Hz, 2H), 3.75 (s, 3H), 3.03 ppm (t, J=6.4 Hz, 2H); 13C NMR
(100 MHz, CDCl3): d=151.6, 53.6, 51.7, 50.6, 30.9 ppm; HRMS
(MALDI-FTMS) calcd for C5H10N2O4S2Na+ [M+Na]+: 248.9974; found:
248.9981.
Data for 170: Rf =0.10 (silica gel, CH2Cl2); IR (film): nmax =3559, 3264,
2944, 2854, 1636, 1444, 1397, 1303, 1220, 1159, 1064, 1025, 1003, 726 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d=4.32 (brs, 1H), 3.50 (m, 2H), 3.22–3.14
Chem. Eur. J. 2004, 10, 5581 – 5606 www.chemeurj.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5603

K. C. Nicolaou et al.
FULL PAPER
Data for 183: Rf =0.20 (silica gel, MeOH/CH2Cl2, 3:97); IR (film): nmax
=
Dodd, Org. Lett. 2002, 4, 2481–2483; c) J.-L. Liang, S.-X. Yuan, J.-S.
Huang, W.-Y. Yu, C.-M. Che, Angew. Chem. 2002, 114, 3615–3618;
Angew. Chem. Int. Ed. 2002, 41, 3465–3468.
3260, 2959, 1731, 1510, 1468, 1351, 1250, 1215, 1162, 1030, 962, 865, 826,
772, 587, 541 cmꢀ1 1H NMR (400 MHz, CDCl3): d=7.53 (d, J=8.8 Hz,
;
2H), 7.24 (d, J=8.8 Hz, 2H), 5.84 (s, 1H), 5.70 (brs, 1H), 4.12 (s, 3H),
4.07 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=158.0, 152.1, 128.3,
124.8, 114.5, 55.4, 53.5 ppm; HRMS (MALDI-FTMS) calcd for
C9H12N2O5SNa+ [M+Na]+: 283.0359; found: 283.0359.
[11] For selected primary literature related to bothsulfamidate synthesis
and nucleophilic ring-opening, see: a) L. Wei, W. D. Lubell, Org.
Lett. 2000, 2, 2595–2598; b) L. T. Boulton, H. T. Stock, J. Raphy,
D. C. Horwell, J. Chem. Soc. Perkin Trans. 1 1999, 1421–1429; c) D.
Ok, M. H. Fisher, M. J. Wyvratt, P. T. Meinke, Tetrahedron Lett.
1999, 40, 3831–3834; d) B. M. Kim, S. M. So, Tetrahedron Lett. 1998,
39, 5381–5384; e) B. Aguilera, A. Fernandez-Mayorales, C. Jaramil-
lo, Tetrahedron 1997, 53, 5863–5876; f) M. E. Van Dort, Y.-W. Jung,
P. S. Sherman, M. R. Kilbourn, D. M. Wieland, J. Med. Chem. 1995,
38, 810–815; g) K. K. Andersen, M. G. Kociolek, J. Org. Chem.
1995, 60, 2003–2007; h) M. Okuda, K. Tomioka, Tetrahedron Lett.
1994, 35, 4585–4586; i) K. K. Andersen, D. D. Bray, S. Chumpradit,
M. E. Clark, G. J. Habgood, C. D. Hubbard, K. M. Young, J. Org.
Chem. 1991, 56, 6508–6516; j) G. J. White, M. E. Garst, J. Org.
Chem. 1991, 56, 3177–3178; k) J. E. Baldwin, A. C. Spivey, C. J.
Schofield, Tetrahedron: Asymmetry 1990, 1, 877–880; l) D. Alker,
K. J. Doyle, L. M. Harwood, A. McGregor, Tetrahedron: Asymmetry
1990, 1, 873–876; m) T. A. Lyle, C. A. Magill, S. M. Pitzenberger, J.
Am. Chem. Soc. 1987, 109, 7890–7891.
Data for 185: Rf =0.53 (silica gel, EtOAc); IR (film): nmax =3465, 3111,
2954, 2225, 1743, 1607, 1507, 1460, 1361, 1225, 1161, 955, 932, 879, 832,
1
767, 573 cmꢀ1; H NMR (400 MHz, CD3OD): d=7.42 (d, J=8.8 Hz, 2H),
7.08 (d, J=8.8 Hz, 2H), 4.71 (brs, 2H), 3.42 ppm (s, 3H); 13C NMR
(100 MHz, CD3OD): d=153.4, 143.4, 134.6, 119.8, 119.0, 107.6, 53.6 ppm;
MS (ESI) calcd for C9H9N3O4SNa+ [M+Na]+: 278; found: 278.
Data for 187: Rf =0.14 (silica gel, EtOAc); IR (film): nmax =3248, 2945,
2838, 1749, 1467, 1361, 1237, 1149, 1073, 983, 860, 776, 584 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d=7.91 (brs, 1H), 4.49 (t, J=5.2 Hz, 1H),
3.76 (s, 3H), 3.40 (s, 6H), 3.39 (m, 2H), 3.01 ppm (s, 3H); 13C NMR
(100 MHz, CDCl3): d=151.7, 103.7, 54.7, 53.4, 52.7, 37.2 ppm; HRMS
(MALDI-FTMS) calcd for C7H16N2O6SNa+ [M+Na]+: 279.0621; found:
279.0622.
[12] For literature pertaining to the ubiquity and uses of b-aminoalcohols
in synthesis, see: a) The Merck Index, Vol. 7, 12th ed., Chapman &
Hall, New York, 1996; b) G. Sh aw, inComprehensive Heterocyclic
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Acknowledgement
We thank Drs. D. H. Huang, G. Siuzdak, and R. Chadha for NMR spec-
troscopic, mass spectrometric, and X-ray crystallographic assistance, re-
spectively. Financial support for this work was provided by The Skaggs
Institute for Chemical Biology, the National Institutes of Health (USA),
predoctoral fellowships from the National Science Foundation, Pfizer,
and Bristol–Myers Squibb (all to S.A.S.), postdoctoral fellowships from
the Royal Society Fulbright Commission (to D.A.L.) and the Skaggs In-
stitute for Chemical Biology (to X.H.), and a grant from American Bio-
Science.
[13] Interestingly, attempted carbamate-based AA (see referen-
ce [15a,b]) on the olefinic precursor to 5 led to the desired product
in modest yield withlittle control of regioselectivity, while concur-
rent efforts employing the Ritter reaction under acidic conditions
led solely to decomposition: a) C. M. Bellucci, A. Bergamini, P. G.
Cozzi, A. Papa, E. Tagliavini, A. Umani-Ronchi, Tetrahedron:
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5604
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Burgess Reagent
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[20] The relative facility of these preparations implies that virtually any
carbamate-based Burgess-type salt can be accessed by this approach.
Moreover, our handling of 48–51 suggests that they possess unique
thermal and moisture-sensitivity profiles relative to 1, physical fea-
tures which could prove significant in effecting transformations typi-
cally achieved by the Burgess reagent on recalcitrant substrates. It is
important to note, however, that while carbamate-derived Burgess-
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[27] CCDC-174599 (36), CCDC-230677 (42), and CCDC-230678 (86)
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge via www.ccdc.cam.ac.uk/
conts/retrieving.html (or from the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB21EZ, UK; fax: (+44)1223-
336-033; or deposit@ccdc.cam.uk).
[28] It is important to note that this protocol does not provide a general
synthesis of aminals from lactols, as a number of conventional lac-
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products, many are polymeric in nature, suggesting side-reactions in-
itiated by the free alcohol with the sulfamidate ring either in intra-
or intermolecular modes.
[32] It is important to note that although the nitrogen atom attached to
the Burgess reagent is nucleophilic enough to attack an epoxide ring
in the absence of direct Lewis acid activation, we could not induce
similar attack onto the olefin of an a,b-unsaturated ester.
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are available commercially as their HCl salts. In order to obtain the
yields disclosed above these starting materials were converted to
their free-base form prior to reaction. Failure to perform this simple
step led either to drastically reduced yields of the sulfamide product,
or no detectable reaction whatsoever.
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Chem. Eur. J. 2004, 10, 5581 – 5606
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K. C. Nicolaou et al.
FULL PAPER
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Received: May 20, 2004
Published online: October 7, 2004
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