Stereocontrol in radical Mannich equivalents for aminosugar synthesis: haloacetal and 2-(phenylthio)vinyl tethered radical additions to α-hydroxyhydrazones

Article abstract of DOI:10.1016/j.tet.2008.10.013

Studies of stereocontrol in two types of radical equivalents of Mannich addition reactions offer new insights for application to aminosugar synthesis. In the first method, haloacetal addition (Ueno-Stork reaction) is extended to dihydroxyhydrazones, leading to an adduct with the unexpected 3-epi-l-daunosamine configuration. A neighboring α-benzyloxy substituent causes a dramatic reversal of stereocontrol compared with hydrazones where this substituent is absent; vicinal dipole repulsion is proposed to account for the diastereoselectivity. In the second method, radical addition-cyclization with thiophenol and treatment with fluoride leads to diastereoselective group transfer from a silicon-tethered ethynyl group to the C{double bond, long}N bond of hydrazones, affording anti-hydrazino alcohols with a trans-2-(phenylthio)vinyl substituent. The one-pot process occurs under neutral, tin-free radical conditions, and offers stereocontrol which is complementary to the haloacetal method. Synthetic utility of the radical Mannich concept is demonstrated in a brief asymmetric synthesis of N-trifluoroacetyl-l-daunosamine from achiral precursors.

Full text of DOI:10.1016/j.tet.2008.10.013

Tetrahedron 64 (2008) 11549–11557
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Stereocontrol in radical Mannich equivalents for aminosugar synthesis: haloacetal
and 2-(phenylthio)vinyl tethered radical additions to a-hydroxyhydrazones
*
Gregory K. Friestad , Tao Jiang, Gina M. Fioroni
Department of Chemistry, University of Iowa, Iowa City, IA 52242, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Studies of stereocontrol in two types of radical equivalents of Mannich addition reactions offer new
insights for application to aminosugar synthesis. In the first method, haloacetal addition (Ueno–Stork
Received 29 August 2008
Received in revised form 1 October 2008
Accepted 2 October 2008
reaction) is extended to dihydroxyhydrazones, leading to an adduct with the unexpected 3-epi-
L-dau-
nosamine configuration. A neighboring -benzyloxy substituent causes a dramatic reversal of stereo-
a
Available online 14 October 2008
control compared with hydrazones where this substituent is absent; vicinal dipole repulsion is proposed
to account for the diastereoselectivity. In the second method, radical addition–cyclization with thio-
phenol and treatment with fluoride leads to diastereoselective group transfer from a silicon-tethered
ethynyl group to the C]N bond of hydrazones, affording anti-hydrazino alcohols with a trans-2-(phe-
nylthio)vinyl substituent. The one-pot process occurs under neutral, tin-free radical conditions, and of-
fers stereocontrol which is complementary to the haloacetal method. Synthetic utility of the radical
Keywords:
Radical cyclization
Stereoselectivity
Aminosugars
Hydrazones
Mannich concept is demonstrated in a brief asymmetric synthesis of N-trifluoroacetyl-L-daunosamine
from achiral precursors.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
(silyl ether or acetal linkages) so that the C–C bond is constructed
via cyclization, in which the internal conformational constraints
can control diastereoselectivity. Several functionalized C1 and C2
units can be installed in this fashion; after removal of the tether this
achieves ‘formal acyclic stereocontrol’. The relevant methods we
have developed include Si-tethered additions of hydroxymethyl11
(Fig. 1, A), vinyl12 (B), and 2-(thiophenyl)vinyl13 (C) groups. The
latter are radical equivalents of an acetaldehyde Mannich re-
action.14 The resulting hydroxyalkyl amine structures are found in
a variety of common compound classes of interest for their
biological activity, including sphingolipids,15 hydroxylated pyrroli-
dines and piperidines (‘azasugars’),16 and aminosugars.17
To complement the Si-tethered ethynyl cyclizations (Fig.1, C) we
have also developed a variation on the theme of Mannich equiva-
lents, which engages an acetal tether to connect a two-carbon alkyl
halide radical precursor to the imino acceptor (Fig. 1, D).18 This
transformation adds an acetaldehyde equivalent to the C]N bond
A carbon–carbon bond construction approach to
a-branched
amines may create both a stereogenic center and a C–C bond in
a single synthetic transformation.1 Among the methods for ster-
eocontrolled additions to C]N bonds are a wide range of methods
involving carbon nucleophiles, including Mannich reactions, which
have been extensively developed to the point of widespread
application.1a,2 Radical additions are complementary to existing
methodology for additions to imino compounds;3,4 the radical in-
termediates are non-basic, avoiding aza-enolization,5 are chemo-
selective, and can be generated under mild conditions. Such
features avoid some of the problems inherent to carbanion-type
organometallic reagents. For example, reactions of carbon centered
radicals permit the presence of –OH or –OR groups at the b-position
of carbonyl or imine compounds without concern for base-induced
elimination.
In the ideal scenario, the addition of functionalized radicals to
imino compounds could be accomplished in an intermolecular
fashion with some acyclic stereocontrol. Although a number of such
intermolecular addition methods are now known,6–9 the radicals
employed in those studies have rarely accommodated additional
functionality. Our alternative strategy employs temporary tethers10
of a-hydroxyhydrazones, directly affording furanose or pyranose
aminosugar structures.
The radical Mannich methodologies C and D appear to be
well-suited to syntheses of 3-aminosugars containing the b-ami-
noaldehyde functional group array. However, the underlying
methodology for additions to C]N bonds via the acetal tether has
only been examined in simple a- and b-hydroxyhydrazones, and
methodology for conversion of the 2-(phenylthio)vinyl adducts to
aminosugars was not yet demonstrated. Here we describe stereo-
control studies directed toward application of radical Mannich
* Corresponding author. Tel.: þ1 319 335 1364; fax: þ1 319 335 1270.
E-mail address: gregory-friestad@uiowa.edu (G.K. Friestad).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.10.013

11550
G.K. Friestad et al. / Tetrahedron 64 (2008) 11549–11557
Silicon-Tethered Atom Abstraction/Cyclization
2. Results and discussion
NX
NX
NHX
Bu3Sn•
Br
2.1. Haloacetal method
R
R
R
A
•
O
O
OH OH
The haloacetal radical cyclization was first introduced by Ueno24
for the functionalization of butyrolactones and by Stork25 for the
construction of bicyclic acetals and lactones in the early 1980s, and
numerous synthetic applications have followed.26 Despite the
broad utility of the Ueno–Stork haloacetal cyclization for addition
to alkenes, imine acceptors have rarely been used.14b,27 We envi-
sioned application of 6-exo haloacetal cyclization for direct access
to aminosugars from achiral precursors (Scheme 2). In an attempt
Si
Si
functionalized C1
and C2 fragments
Silicon-Tethered Addition/Cyclization
NX
NX
NHX
R
PhS•
PhS•
R
R
B
•
•
O
O
O
O
SPh
SPh
OH
Si
Si
to access L-daunosamine and expand on the prior findings re-
NX
NX
NHX
R
garding stereocontrol in Ueno–Stork reactions,28,18 we initiated
a study of the stereochemical outcome of haloacetal cyclizations
R
R
SPh
OH
C
Si
Si
using an a,b-dioxygenated imino compound as the radical acceptor.
THIS WORK:
acetaldehyde
Mannich
Acetal-Tethered Atom Abstraction/Cyclization
OH
OEt
equivalents
NX
NHX
R
R
NHX
OR
D
O
O
n
•
Bu3Sn•
O
R
O
O
NH2
NNPh2
X
Crotonaldehyde
D
O
OH
L-daunosamine
OH
OEt
OEt
OEt
Scheme 2.
Figure 1. Summary of the temporary tether strategy for addition of functionalized
radicals to imino compounds.
Monobenzyl-protected dihydroxyhydrazone 1 (Scheme 3) was
prepared from commercially available trans-crotonaldehyde by
a three-step method12 involving condensation with diphenylhy-
drazine, Sharpless asymmetric dihydroxylation29 (89% ee), and
stannylene-mediated hydroxyl differentiation.30 Reaction of 1 with
N-iodosuccinimide (NIS) in ethyl vinyl ether afforded iodoacetal 2
in modest yield as a mixture of diastereomers (Scheme 3). Cycli-
zation using typical tin-mediated conditions (1.2 equiv Bu3SnH,
0.02 M in refluxing benzene) initiated by 2,20-azobisisobutyroni-
trile (AIBN) resulted in the formation of a mixture of three cyclized
products 3a–c in a ratio of 5.0:3.8:1 (58% yield).
equivalents to aminosugar synthesis, including a surprising re-
versal of diastereoselectivity in a 6-exo Ueno–Stork haloacetal cy-
clization of an
a,b-dihydroxyhydrazone, expansion of our
preliminary study of 2-(phenylthio)vinyl addition,13 and an appli-
cation of the latter to synthesis of a biologically relevant target, the
aminosugar L-daunosamine.
Daunosamine was specifically of interest for its ongoing bi-
ological relevance; for example, the daunosamine nitrogen serves
as a linkage point to construct dimeric or chimeric structures re-
lated to DNA-binding antitumor agent daunomycin.19 Furthermore,
beneficial effects on DNA-binding thermodynamics in dimeric an-
alogs of daunomycin have been attributed in part to electrostatic
attractions between the DNA and the ammonium cation within the
daunosamine segments.20 Considering their biological importance,
it is not surprising that numerous strategies to access aminosugars
have been reported, the vast majority of which involve functional
group interconversions from other carbohydrates.17,21
OBn
OBn
NNPh2
H
NIS, EVE
40%
O
OH
N
I
NPh2
1
OEt
2
OBn
A potentially efficient approach to L-daunosamine involves
NHNPh2
Bu3SnH
AIBN
58%
+
addition of an acetaldehyde equivalent to a 2,3-dihydroxyimine
acceptor (Scheme 1). Among several prior approaches to daunos-
amine are nitrone cycloadditions22 and Mannich-type re-
actions,23,42 which accomplish this same bond construction using
negatively charged or polarized acetaldehyde enolate equivalents.
We sought to develop a complementary alternative, which would
involve a non-polar acetaldehyde radical Mannich equivalent
according to Scheme 1 and Figure 1.
O
OEt
+
3a
OBn
OBn
NHNPh2
NHNPh2
O
O
OEt
OEt
3b
3c
ratio a/b/c = 5.0 : 3.8 : 1.0
OH
OH NH2
OH
O
CHO
Scheme 3.
NH2
HO
L-daunosamine
The relative configurations of isolated 3a were determined
through straightforward analysis of the coupling constants among
hydrogens at C1–C3, and were found to correspond to an equatorial
CHO
OR NX
OR
anomer with the configuration of L
-3-epi-daunosamine (Fig. 2).31
or
CHO
+
Unfortunately, efforts to isolate the two minor components 3b and
3c in pure form were unsuccessful, although the 1H NMR coupling
constants obtained in a spectrum of the mixture clearly indicated
•
Scheme 1.

G.K. Friestad et al. / Tetrahedron 64 (2008) 11549–11557
11551
H1
OBn
dipole
Ph2NHN
BnO
•
repulsion
NHX
OH
NH2
O
O
O
OEt
NX
O
O
MINOR
OBn
J = 9.4 Hz
H3
OH
L-3-epi-daunosamine
(3c, 6%)
OEt
NX
OEt
BnO
E ( ,cis)
H2ax
3a
J = 4.5 Hz
•
O
OBn
BnO
Figure 2. Diagnostic coupling constants for assignment of relative configurations of
the major diastereomer 3a.
NHX
OEt
-2
-anomer:
O
•
MINOR
OEt
NX
F ( ,trans)
(3b, 22%)
both were axial anomers.32 The second component 3b had the
same configuration as 3a at C3 (i.e., the stereocenter generated
during the radical cyclization). Minor component 3c exhibited
a large axial–axial coupling between H2ax and H3, consistent with
the equatorial N-substituent at C3, as required for L-daunosamine.
Therefore, combining the anomers 3a and 3b, the C3 diastereomer
OEt
chairlike TS
OBn
dipole
repulsion
EtO
BnO
NHX
X
NX
O
O
O
OBn
NOT
ratio of the radical cyclization at C3 was 8.8:1, favoring the relative
•
NX
OBS.
OEt
configuration found in L-3-epi-daunosamine.
G ( ,cis)
These results and the prior findings18 with less-substituted
analog 4 lacking the 2-OBn group exhibit a dramatic reversal of
the diastereoselectivity at the nitrogen-bearing stereocenter
(Scheme 4). The stereocontrol in Ueno–Stork cyclizations emanates
from the Beckwith–Houk chairlike transition state model,33 with
perturbations originating in the anomeric effect.34,28 Haloacetal
cyclizations of hydrazones such as 4 may be explained analogously,
and due to the replacement of the typical Ueno–Stork C]C
acceptor with a polarized C]N bond, a 1,3-diaxial dipole repulsion
effect is superimposed upon the usual stereocontrol model.18
The surprising diastereoselectivity in formation of 3 called for
further analysis of these models to accommodate the interesting
reversal of stereocontrol affected by the additional alkoxy
substituent.
O
•
OBn
EtO
OEt
NHX
BnO
-2
O
MAJOR
-anomer:
•
(3a, 30%)
NX
twist TS
H ( ,trans)
OEt
Figure 3. Proposed stereocontrol models for formation of 3a–3c (X¼NPh2). Vicinal
dipole repulsion with the -OBn substituent restricts conformation of the hydrazone.
a
distribution. Thus, in addition to the anomeric effect examined
previously by Renaud and Schiesser and coworkers,28 effecting
stereocontrol in these cyclizations requires careful consideration of
a dominant vicinal dipole repulsion and less important 1,3-diaxial
dipole repulsions.
Despite the rather complicated stereocontrol models outlined
above, the resulting stereocontrol (3a,b/3c¼8.8:1) is sufficient for
practical application, with the assumption that a mixture of
anomers 3a,b can be further processed in a stereoconvergent
manner (for example, via oxidation or oxocarbenium-mediated
processes at the anomeric center). The net result in this case is
a very rapid access, from crotonaldehyde via asymmetric catalysis,
(a)
Without -alkoxy substitution (ref. 18)
N-NPh2
NHNPh2
dr 4:1
α
Bu3SnH
AIBN
O
O
O
I
5
OEt
OEt
4
to an aminosugar analog of the 3-epi-L-daunosamine configuration.
(b) With -alkoxy substitution
OBn
OBn
2.2. Si-tethered ethynyl method
N-NPh2
NHNPh2
dr 8.8:1
α
Bu3SnH
AIBN
To generate the alternative L-daunosamine configuration, we
regarded our Si-tethered strategy to be quite reliable, and indeed
O
I
3
OEt
OEt
2
we had shown that vinyl adduct 6 (Fig. 4, R¼COCF3) could be effi-
Scheme 4.
ciently transformed to methyl N-trifluoroacetyl-L-daunosamini-
de.21a A limiting factor to the net efficiency of that sequence was the
requirement for an aldehyde-selective Wacker oxidation, for which
the optimal selectivity was 82:18. We envisioned avoiding this late-
stage oxidation step, and consequently we explored the re-
placement of the silicon-tethered vinyl group with an ethynyl
group as the radical precursor.
In analogy with the earlier study,18 a series of twist and chair
transition states leading to 3 may be proposed (Fig. 3), all having
ethoxy substituents in the pseudoaxial orientation due to the
anomeric effect. Previously, diastereomer 5 (Scheme 4) was at-
tributed to a transition state analogous to E, and no diastereomer
was found with a configuration corresponding to the transition
state F, an observation suggesting the importance of a 1,3-diaxial
dipole repulsion between C]N and OEt groups.18 In contrast, with
an additional alkoxy substituent present for cyclization of the more
substituted analog 2, the minor amount of 3c (6% vs 22% of 3b)
suggests E is less favorable than F. It may be inferred that the vicinal
dipole repulsion in E is more unfavorable than the 1,3-dipole re-
OH NHR
OH
OH
6
oxidation
to aldehyde
(ref. 21a)
O
NH2
?
HO
L-daunosamine
OH NHR
OH
pulsion in F. Thus, the major C3 configuration arising from
a
-2 is
SPh
reversed by the presence of the
a-benzyloxy substituent as
a consequence of vicinal dipole repulsion.35 A transannular dipole
repulsion between pseudoaxial OBn and OEt substituents would be
7
THIS WORK:
oxidation not required
expected to further destabilize G (b,cis). Finally, transition state H
relieves both vicinal and 1,3-diaxial dipole repulsions, suggesting it
should be the most favorable, consistent with the observed product
Figure 4. Comparison of oxidative and non-oxidative routes from radical adducts to
L-daunosamine.

11552
G.K. Friestad et al. / Tetrahedron 64 (2008) 11549–11557
Intermolecular addition of heteroatom radicals, such as thiyl
Considering the abundant methods for conversion of vinyl sul-
(e.g., PhSꢀ) or stannyl (e.g., Bu3Snꢀ), to an alkene or alkyne can ini-
tiate a cyclization event when a second radical acceptor moiety is
appropriately situated (Fig. 1, B and C).36 In using the silicon-teth-
ered vinyl addition to access 6, fluoride-induced thiolate elimina-
tion had occurred during removal of the silicon tether. This
returned the vinyl functionality present in the original radical
precursor, resulting in a net vinyl addition process with excellent
stereocontrol. We hypothesized that an analogous sequence (Eq. 1)
might take place using an ethynyl group as a silicon-tethered rad-
ical precursor, a reaction type, which, to our knowledge, was
without direct precedent.37 Because of the additional options
available for functionalization of alkynes, an ethynyl group addition
would be a potentially useful complement to our vinyl addition
methodology.
fides to carbonyl compounds,41 vinyl sulfides 9a–9e are masked
b
-aminoaldehydes, and thus these reactions are a radical equiva-
lent of an acetaldehyde Mannich reaction. Furthermore, vinyl sul-
fides have been observed to undergo direct acid-catalyzed
cyclization with a remote hydroxyl group to afford cyclic hemi-
thioacetals42 (i.e., thioglycosides), an attractive entry to precursors
for glycoside and oligosaccharide synthesis.
2.3. Synthesis of N-trifluoroacetyl-L-daunosamine
An application to a brief asymmetric synthesis of an aminosugar
was exploited in order to demonstrate the utility of the ethy-
nylsilanes as radical Mannich equivalents. Previously, 2,3-
dihydroxyaldehyde hydrazones derived from glyceraldehyde or
crotonaldehyde were successfully employed for vinyl group additi-
on,12 furnishing allylic hydrazines such as 6 through vinyl group
transfer from the proximal hydroxyl group via 5-exo cyclization.21a
Simply applying the silicon-tethered radical precursor to both hy-
droxyl groups obviates the protection and hydroxyl differentiation
sequences common in carbohydrate manipulations.
NX
NX
NHX
R
R
PhS•
R
ð1Þ
•
O
O
SPh
OH
Si
Si
Ultimately, our examination of this ethynyl group transfer hy-
pothesis of Eq. 1 revealed that the alkyne was not regenerated.38
A series of
-hydroxyhydrazones11,12 were silylated with chloro-
To access the aminosugar L-daunosamine, crotonaldehyde (10,
Scheme 6) was converted to known dibenzylhydrazone 12 via
Sharpless asymmetric dihydroxylation of hydrazone 11 (89% ee).21a
Silylation of 12 with chlorodimethylethynylsilane39 afforded 13 in
93% yield (Scheme 6), which in turn was submitted to thiyl addi-
tion–cyclization according to the standard method as described
above;43 hydrazinodiol 14 was obtained in 43% yield upon treat-
ment with methanolic KF. Among the four possible diastereomers,
which could be formed, the major isomer was assigned the E olefin
configuration according to the large 1H NMR olefinic vicinal cou-
pling constant (15 Hz), and the 3,4-anti relative configuration (dr
9:1) by analogy to 9d. After our preliminary communication of this
reaction, TBAF in THF was found to be superior to the original KF/
MeOH conditions, and the whole sequence 12/14 could be
deployed with the only intermediate purification being a brief fil-
tration of 13 through silica gel. Together these changes improved
the yield of 14 to 83%. The adduct in this case is an open-chain form
a
dimethylethynylsilane39 to afford hydrazones 8a–8e (Scheme 5)
in 83–93% yields. Sequential treatment with thiophenol/AIBN
and TBAF (or refluxing methanolic KF) led to allylic anti-hydrazino
alcohols 9a–9e, predominantly as the (E)-isomers.38 Thus, rather
than regenerating the alkyne by thiolate elimination, simple pro-
todesilylation occurred upon fluoride treatment, affording the 2-
(phenylthio)vinyl adducts. Assignment of configurations in 9 rests
40
on chemical correlation of 9d; both 9d and known compound 9d00
afforded the same reduction product 9d0 (Scheme 5). Difference
NOE data supported the E configuration of 9d, and the assignment
of anti relative configuration in the amino alcohol was also con-
sistent with the chemical correlation of a related compound
to L-daunosamine (vide infra). The preference for the anti di-
astereomer is in close agreement with the corresponding reactions
of vinylsilanes, which proceed via 5-exo cyclization of an alkyl
radical,11,12 though the ethynylsilane cyclizations are slightly less
selective.
of L-daunosamine, prepared in 53% overall yield from crotonalde-
hyde. Conversion to the aminosugar via simple functional group
transformations would confirm the absolute and relative stereo-
chemical assignments.
NPh2
N
NHNPh2
SPh
PhSH, AIBN
Cl
R
AD-mix α
c-C6H12, reflux
Si
X
OH NNBn2
OH
H
R
Et3N,
MeSO2NH2
then TBAF
O
H
CH2Cl2, 0 °C
OsO4, t-BuOH
Si
OH
10 (X = O)
Bn2NNH2
toluene (98%)
12 (70%, 89%ee)
8a (R=H)
9a, 68%
11 (X = NNBn2)
8b (R=Me)
8c (R=i-Bu)
8d (R=i-Pr)
8e (R=Ph)
9b, 64%, dr 78:22
9c, 51%, dr 86:14
9d, 68%, dr 96:4
9e, 70%, dr >98:2
Si
O
PhSH, AIBN
NNBn2
Si
OH NHNBn2
OH
PhH, reflux
b
H5
SPh
then F–
a
HO
H4
O
NOE data:
H1
a: H1
b: H1
H4 = 6%
H5 = 3%
13 (93%)
14 (dr 90:10)
with KF: 43%
with TBAF: 83%
Ph2NNH
SPh
H2
Scheme 6.
(E)-9d
H2, Raney Ni
Spontaneous cyclization to a thiopyranoside was envisaged
upon exposure of 14 to anhydrous HCl, based on a close pre-
cedent.42 Unfortunately, this cyclization was not achieved with 14,
perhaps due to the proximity of the basic nitrogen, a protonated
form of which might inhibit acid-catalyzed cyclization44 (an amide
had been used in the precedent). Direct treatment of diol hydrazine
NHNPh2
NHNPh2
H2, Raney Ni
OH
OH
9d'
9d''
Scheme 5.

G.K. Friestad et al. / Tetrahedron 64 (2008) 11549–11557
11553
14 with HgCl2 also gave none of the expected product. On the other
4. Experimental section
hand, a different order of events proved successful. Protection of 14
as an acetonide (Scheme 7) followed by TFA-assisted N–N bond
cleavage45 furnished the corresponding amide 15 in 73% yield. The
aldehyde was then unveiled from the vinyl sulfide by treatment
under Grieco’s conditions entailing in situ generation of hydrogen
iodide in moist acetonitrile in the presence of mercuric chlo-
ride.46,47 This furnished 51% of anomeric mixture 16a and 16b, from
which 16a was separated by recrystallization. This material showed
good agreement with the literature 1H NMR data for N-tri-
4.1. Materials and methods
Reactions employed oven- or flame-dried glassware under ni-
trogen unless otherwise noted. THF, diethyl ether, benzene, and
toluene were distilled from sodium/benzophenone ketyl under
argon. CH2Cl2 was distilled from CaH2 under argon or nitrogen.
Alternatively, these solvents were purchased inhibitor-free and
were sparged with argon and passed through columns of activated
alumina prior to use (dropwise addition of blue benzophenone
ketyl solution revealed that THF purified in this manner sustained
the blue color more readily than the control sample purified by
distillation). Nitrogen was passed successively through columns of
anhydrous CaSO4 and R3-11 catalyst for removal of water and
oxygen, respectively. All other materials were used as received from
commercial sources unless otherwise noted. Thin-layer chroma-
tography (TLC) employed glass 0.25 mm silica gel plates with UV
indicator. Flash chromatography columns were packed with 230–
400 mesh silica gel as a slurry in the initial elution solvent. Gradient
flash chromatography was conducted by adsorption of product
mixtures on silica gel, packing over a short pad of clean silica gel as
a slurry in hexane, and eluting with a continuous gradient from
hexane to the indicated solvent. Radial chromatography refers to
centrifugally accelerated thin-layer chromatography performed
with a Chromatotron using commercially supplied rotors. Melting
points are uncorrected. Nuclear magnetic resonance (NMR) data
were obtained at operating frequencies of 500 or 300 MHz for 1H
and 125 or 75 MHz for 13C. Infrared spectra were recorded using
a single beam FT-IR spectrophotometer by standard transmission
methods or by use of an attenuated total reflectance (ATR) probe.
Optical rotations were determined using a digital polarimeter op-
erating at ambient temperature. Low resolution mass spectra were
obtained using sample introduction by dip, liquid chromatography,
or gas chromatography. High resolution mass spectra and com-
bustion analyses were obtained from external commercial and in-
stitutional services. Chromatographic diastereomer ratio analyses
fluoroacetyl-L-daunosamine, as well as the expected physical (mp
30
146–148 ꢁC, lit. 146–147 ꢁC) and chiroptical properties ([
a
]
D
ꢂ120,
20
lit. [
a]
ꢂ127).48 Further confirmation was obtained upon expo-
D
sure of 16a (or the mixture 16a/16b) to anhydrous HCl in MeOH,
after which the methyl pyranosides 17a/17b could be identified by
spectroscopic comparison with data from the literature.49 This
mixture of methyl glycosides was identical to material produced
through a different route.21a Thus, the chemical correlation of 14 to
L-daunosamine ultimately confirmed the stereochemical course of
the tandem thiyl radical addition–cyclizations using the tethered
ethynylsilane as a radical precursor.
1) Me2C(OMe)2
TsOH (95%)
2) n-BuLi, TFAA
3) SmI2 (73%, 2 steps)
NHTFA
14
SPh
O
O
15
OR
OR
O
TMSCl, NaI, HgCl2
O
+
CH3CN, H2O (51%)
NHTFA
NHTFA
HO
16b (R = H)
17b (R = Me)
HO
16a (R = H)
HCl, MeOH
17a (R = Me)
Scheme 7.
employed GC–MS with 15 mLꢃ0.25 mm I.D.ꢃ0.25
m F.T. 5%-phenyl-
95%-dimethylsiloxane column and helium as mobile phase or HPLC
with Microsorb-MV Si 8um 100A or Chiralcel OD columns (2-
propanol/hexane as mobile phase) or Chirex 3014 column (chlo-
roform/hexane as mobile phase).
One final note is offered regarding the synthetic potential of vinyl
sulfides such as 15; OsO4-catalyzed dihydroxylation has recently
been exploited to convert related vinyl sulfides to pyranoses bearing
hydroxyl groups at the 2-position (pyranose numbering).50 Al-
though we have not completed such experiments, this published
method for transformation of vinyl sulfides to carbohydrates may
confer broader applicability upon the methodology outlined herein.
4.2. Haloacetal cyclizations
4.2.1. Iodoacetal 2
A mixture of N-iodosuccinimide (0.19 g, 0.82 mmol) and freshly
distilled ethyl vinyl ether (EVE, 5 mL) was stirred at 0 ꢁC for 2 h. A
solution of alcohol 121a (117 mg, 0.33 mmol) in EVE (3 mL) was
added. After 10 h at 0 ꢁC, the mixture was partitioned between
saturated aqueous sodium thiosulfate and ether, washed with
brine, dried over Na2SO4, and concentrated. Radial chromatography
eluting with 10:1 hexane/ethyl acetate afforded, as an inseparable
diastereomeric mixture, iodoacetal 2 (72.5 mg, 0.13 mmol, 40%) as
3. Conclusion
Two alternative methods have been developed for introduction
of the 2-acetyl fragment in radical equivalents of an acetaldehyde
Mannich addition reaction. Haloacetal 6-exo radical cyclization is
altered by the presence of a 2-benzyloxy substituent to invert the
previously established stereochemical course, leading to the 3-epi-
L
-daunosamine configuration. The 2-(phenylthio)vinyl group can
be installed via diastereoselective tin-free radical addition to
-hydroxyhydrazones via 5-exo cyclization of a silicon-tethered
a pale yellow oil; IR (film) 1592, 1495, 1299, 1213, 1050 cmꢂ1
;
1H
NMR (500 MHz, CDCl3) 7.43–7.25 (m, 9H), 7.18–7.15 (m, 2H), 7.09–
d
a
7.06 (m, 4H), 6.41 (d, J¼7.3 Hz, 0.5H), 6.35 (d, J¼7.4 Hz, 0.5H), 4.74
(dd, apparent triplet, J¼5.4 Hz, 0.5H), 4.68 (dd, apparent triplet,
J¼5.9 Hz, 0.5H), 4.64 (d, J¼12.4 Hz, 0.5H), 4.61 (d, J¼12.5 Hz, 0.5H),
4.52 (d, J¼12.0 Hz, 0.5H), 4.51 (d, J¼12.2 Hz, 0.5H), 4.08 (dd, ap-
parent triplet, J¼7.1 Hz, 0.5H), 4.06 (dd, apparent triplet, J¼7.4 Hz,
0.5H), 3.84 (dddd, apparent quintet, J¼6.4 Hz, 0.5H), 3.80 (dddd,
apparent quintet, J¼6.4 Hz, 0.5H), 3.66–3.59 (m, 1H), 3.53–3.45 (m,
1H), 3.19–3.11 (m, 2H), 1.19 (dd, apparent triplet, J¼6.9 Hz, 1.5H),
ethynyl group. Since stereocontrolled intermolecular radical addi-
tion methods to install the 2-acetyl unit are currently unavailable,
these tethered approaches offer potentially useful alternatives.
The utility of the 2-(phenylthio)vinyl addition method is high-
lighted in a synthesis of N-trifluoroacetyl-L-daunosamine from
achiral precursors using a combination of asymmetric catalysis and
diastereoselective radical addition. The radical Mannich strategy
avoids a late-stage oxidation and affords N-trifluoroacetyl-
L-dau-
1.16–1.10 (m, 4.5H); 13C NMR (125 MHz, CDCl3)
d
143.6, 143.5, 138.4,
nosamine in 17% overall yield from crotonaldehyde.51
138.3, 135.5, 135.4, 129.8, 129.7, 128.3, 128.2, 127.9, 127.8, 127.5,

11554
G.K. Friestad et al. / Tetrahedron 64 (2008) 11549–11557
124.5,124.4,122.3,102.6,100.5, 83.1, 82.2, 75.4, 73.4, 70.8, 61.5, 61.4,
17.8, 16.8, 15.0, 14.9, 6.3, 6.0; MS (CI) m/z (relative intensity) 559
([MþH], 10%), 315 (100%); Anal. Calcd for C27H31N2O3I: C, 58.07; H,
5.60; N, 5.02. Found: C, 58.11; H, 5.53; N, 4.99.
d
7.40–7.35 (m, 6H), 7.17–7.10 (m, 4H), 6.45 (d, J¼5.7 Hz,1H), 4.71 (m,
apparent quintet, J¼6.3 Hz, 1H), 2.44 (s, 1H), 1.37 (d, J¼6.4 Hz, 3H),
0.30 (s, 3H), 0.28 (s, 3H); 13C NMR (125 MHz, CDCl3)
143.7, 140.1,
d
129.7,124.2,122.3, 93.4, 87.9, 70.3, 22.1, 0.6, 0.5; MS (EI) m/z (relative
intensity) 322 (Mþ, 15%), 168 (100%). Anal. Calcd for C19H22N2OSi: C,
70.77; H, 6.88; N, 8.69. Found: C, 71.25; H, 6.85; N, 8.79.
4.2.2. Aminosugars 3a–3c
To a solution of iodoacetal 2 (67.8 mg, 0.12 mmol) in benzene
(6 mL) were added 2,20-azobisisobutyronitrile (AIBN, 10 mol %) and
Bu3SnH (0.06 mL, 0.15 mmol). The reaction mixture was de-
oxygenated via nitrogen bubbling through a syringe needle for
20 min, then heated at reflux for 10 h. The solvent was removed and
the residue was partitioned between CH3CN and hexane. Concen-
tration of the CH3CN fraction and flash chromatography (hexane/
ethyl acetate) afforded a mixture of aminoglycosides 3a, 3b, and 3c
(dr 5.0:3.8:1.0) as a pale yellow oil (30.5 mg, 58%). Major di-
4.3.3. Ethynylsilyl ether 8c (R¼i-Bu)
26
Colorless oil; [
a
]
ꢂ29.9 (c 1.6, CHCl3); IR (film, CHCl3) 3275,
D
2957, 2035, 1592, 1496, 1054 cmꢂ1 1H NMR (500 MHz, CDCl3)
;
d
7.40–7.35 (m, 4H), 7.17–7.10 (m, 6H), 6.39 (d, J¼6.4 Hz, 1H), 4.61
(ddd, J¼8.2, 6.0, 6.0 Hz, 1H), 2.42 (s, 1H), 1.73 (m, apparent nonet,
J¼6.7 Hz, 1H), 1.57 (ddd, J¼13.7, 8.2, 6.1 Hz, 1H), 1.39 (ddd, J¼13.5,
7.7, 5.8 Hz, 1H), 0.96 (d, J¼6.6 Hz, 3H), 0.95 (d, J¼6.6 Hz, 3H), 0.30 (s,
3H), 0.28 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 143.8, 139.9, 129.7,
astereomer 3a: 1H NMR (500 MHz, CDCl3)
d
7.31–7.24 (m, 9H),
124.2, 122.4, 93.3, 88.1, 72.6, 45.0, 24.1, 23.0, 22.4, 0.9, 0.4; MS (CI)
m/z (relative intensity) 365.1 ([MþH]þ, 60%), 162.3 (100%). Anal.
Calcd for C22H28N2OSi: C, 72.48; H, 7.74; N, 7.68. Found: C, 72.21; H,
7.71; N, 7.60.
7.07–7.03 (m, 6H), 4.86 (dd, J¼9.4, 2.2 Hz, 1H), 4.48 (d, J¼12.1 Hz,
1H), 4.43 (d, J¼12.1 Hz, 1H), 4.18 (qd, J¼6.6, 1.9 Hz, 1H), 3.95 (dq,
J¼9.4, 7.1 Hz, 1H), 3.77 (s, 1H), 3.50 (dq, J¼9.6, 7.1 Hz, 1H), 3.53–3.46
(m, 1H), 3.22 (dd, apparent t, J¼2.2 Hz, 1H), 2.00 (ddd, J¼13.9, 9.4,
4.5 Hz, 1H), 1.59 (ddd, apparent dt, J¼13.9, 2.2 Hz, 1H), 1.24 (d,
J¼6.5 Hz, 3H), 1.20 (dd, apparent triplet, J¼7.1 Hz, 3H); 13C NMR
4.3.4. Ethynylsilyl ether 8d (R¼i-Pr)
26
Pale yellow oil; [
a
]
þ2.7 (c 0.6, CHCl3); IR (film, CHCl3) 3274.0,
D
(125 MHz, CDCl3)
d
148.3, 138.4, 129.3, 128.2, 127.9, 127.6, 122.8,
2961.0, 2036.0, 1592.0, 1496.0, 1047.0 cmꢂ1
CDCl3)
;
1H NMR (500 MHz,
120.5, 97.8, 74.6, 72.5, 69.5, 63.8, 53.5, 31.7, 16.9, 15.1; MS (CI) m/z
(relative intensity) 433 ([MþH]þ, 60%), 387 (30%), 361 (17%). Anal.
Calcd for C27H32N2O3: C, 75.15; H, 7.24; N, 6.49. Found: C, 74.89; H,
7.48; N, 6.39 (diastereomeric mixture). Minor diastereomer 3b: 1H
d
7.41–7.37 (m, 4H), 7.17–7.10 (m, 6H), 6.40 (d, J¼6.4 Hz, 1H),
4.22 (dd, J¼6.9, 6.9 Hz, 1H), 2.44 (s, 1H), 1.79 (m, apparent octet,
J¼6.8 Hz, 1H), 0.95 (d, J¼6.7 Hz, 3H), 0.85 (d, J¼6.8 Hz, 3H), 0.30 (s,
3H), 0.28 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 143.8, 139.4, 129.7,
NMR (500 MHz, CDCl3)
d
7.32–6.98 (m, 15H), 4.80 (dd, J¼3.2, 2.9 Hz,
124.2, 122.4, 93.3, 88.1, 79.1, 33.5, 18.3, 18.3, 0.8, 0.3; MS (EI) m/z
(relative intensity) 350 (Mþ, 10%), 167 (100%). Anal. Calcd for
C21H26N2OSi: C, 71.93; H, 7.47; N, 8.02. Found: C, 71.89; H, 7.51; N,
7.95.
1H), 4.58–4.45 (m, 3H), 4.30 (qd, J¼6.7, 1.5 Hz, 1H), 3.76 (dq, J¼9.75,
7.1 Hz, 1H), 3.55–3.35 (m, 3H), 2.17 (ddd, J¼14.4, 3.8, 3.8 Hz, 1H),
1.51 (br d, J¼14.3 Hz, 1H), 1.21 (dd, apparent t, J¼7.1 Hz, 3H), 1.16 (d,
J¼6.7 Hz, 3H). Minor diastereomer 3c: 1H NMR (500 MHz, CDCl3)
d
4.92 (br d, J¼3.1 Hz, 1H), 3.84 (q, J¼6.6 Hz, 1H), 3.67–3.60 (m, 1H),
4.3.5. Ethynylsilyl ether 8e (R¼Ph)
26
2.01 (ddd, J¼12.5, 12.4, 3.2 Hz, 1H), 1.75 (dd, J¼12.5, 3.0 Hz, 1H);
several 3c resonances were unresolved from those of 3b.
Pale yellow oil; [
a
]
D
ꢂ86.5 (c 0.95, CHCl3); IR (film, CHCl3) 3271,
3029, 2036,1592, 1496, 1215, 1054 cmꢂ1; 1H NMR (500 MHz, CDCl3)
7.40–7.32 (m, 8H), 7.27–7.23 (m, 1H), 7.16–7.10 (m, 6H), 6.51 (d,
J¼6.6 Hz, 1H), 5.65 (d, J¼6.6 Hz, 1H), 2.45 (s, 1H), 0.35 (s, 3H), 0.32
(s, 3H); 13C NMR (125 MHz, CDCl3)
143.7, 141.4, 138.8, 129.7, 128.2,
d
4.3. General procedure A: preparation of dimethylethynylsilyl
ethers 8a–8e
d
127.3, 126.1, 124.3, 122.4, 93.7, 87.7, 75.8, 0.8, 0.3; MS (CI) m/z (rel-
ative intensity) 385.1 ([MþH]þ, 35%), 384 (Mþ, 100%), 285 (75%),
162 (75%). Anal. Calcd for C24H24N2OSi: C, 74.96; H, 6.29; N, 7.29.
Found: C, 74.80; H, 6.37; N, 7.40.
A solution of a-hydroxy hydrazone in dry methylene chloride
(1 M) under nitrogen was treated sequentially with triethylamine
(1.2 equiv) and chlorodimethylethynylsilane39 (1.15–1.2 equiv) at
0 ꢁC. After 2 h, the mixture was warmed to room temperature,
concentrated, and diluted with ether. The precipitated salts were
filtered off and washed three times with ether. Concentration of the
combined filtrates and flash chromatography (10:1 hexane/ethyl
acetate) furnished the silyl ethers 8a–8e as pale yellow oils. A
closely related procedure of similar effectiveness involves replacing
dichloromethane with toluene or benzene and incorporating
a catalytic amount of DMAP (ca. 10 mol %) in the procedure above;
simple filtration of the reaction mixture through a short plug of
silica gel furnished material of sufficient purity for the thiyl addi-
tion–cyclization process.
4.4. General procedure B: tandem thiyl addition–cyclization
and desilylation
A solution of ethynylsilyl ether in cyclohexane (0.1 M) was de-
oxygenated (N2, via syringe needle) for ca. 10 min, then heated to
reflux. A solution of 2,20-azobis(isobutyronitrile) (AIBN, 10 mol %)
and thiophenol (1.4 equiv) in benzene (1 M in PhSH) was added via
syringe pump (0.34 mL/h). Additional portions of AIBN (3ꢃ10 mol %)
were added in 3 h intervals until the reaction was complete (as
judged by TLC), then the cooled reaction mixture was concentrated.
The residue was dissolved in THF (1 M) and treated with tetrabu-
tylammonium fluoride (1 M in THF, 3 equiv) at room temperature
for ca. 1 h. When complete (as judged by TLC), the reaction mixture
was diluted with hexane, washed with water, dried overNa2SO4, and
concentrated. Flash chromatography (hexane/ethyl acetate) fur-
nished the vinyl sulfides 9a–9e and 14 as mixtures of diastereomers
in the ratios previously described,13 from which pure diastereomers
were isolated by radial chromatography (hexane/ethyl acetate).
4.3.1. Ethynylsilyl ether 8a (R¼H)
Pale yellow oil; IR (film, CHCl3) 3275, 2035, 1596, 1496,
1055 cmꢂ1
;
1H NMR (500 MHz, CDCl3)
d
7.40–7.35 (m, 6H), 7.17–
7.10 (m, 4H), 6.55 (t, J¼5.2 Hz, 1H), 4.44 (d, J¼5.2 Hz, 2H), 2.43 (s,
1H), 0.30 (s, 6H); 13C NMR (125 MHz, CDCl3)
143.6, 135.7, 129.7,
d
124.3, 122.4, 93.7, 87.3, 64.1, ꢂ0.1; MS (EI) m/z (relative intensity)
308 (Mþ, 25%), 168 (100%). Anal. Calcd for C18H20N2OSi: C, 70.09; H,
6.54; N, 9.08. Found: C, 70.16; H, 6.65; N, 8.96.
4.4.1. Vinyl sulfide (Z)-anti-9a (R¼H)
4.3.2. Ethynylsilyl ether 8b (R¼Me)
Pale yellow oil; IR (film, CHCl3) 3396, 2925, 1588, 1496, 1272,
26
Pale yellow oil; [
a
]
ꢂ24.1 (c 0.90, CHCl3); IR (film, CHCl3) 3275,
1025 cmꢂ1
;
1H NMR (500 MHz, CDCl3)
d
7.35–7.20 (m, 13H),
D
2973, 2035, 1591, 1496, 1060 cmꢂ1 1H NMR (500 MHz, CDCl3)
;
7.05–7.00 (m, 2H), 6.45 (d, J¼9.5 Hz, 1H), 5.85 (dd, J¼9.5, 8.7 Hz,

G.K. Friestad et al. / Tetrahedron 64 (2008) 11549–11557
11555
1H), 4.24 (br s, 1H), 4.20–4.16 (m, 1H), 3.85–3.80 (ddd, J¼11.1, 4.2,
3.9 Hz, 1H), 3.72–3.66 (ddd, J¼11.0, 7.8, 5.9 Hz, 1H), 1.87 (dd, J¼7.9,
reaction was complete within 10 min, as judged by TLC (>95%
conversion by NMR). Flash chromatography (10:1 hexane/ethyl
acetate) afforded 9d0, which was identified by comparison with
4.3 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 148.1 135.4, 129.4, 129.2,
12
129.0, 128.6, 128.4, 126.75, 122.6, 120.5, 63.4, 58.3; MS (CI) m/z
(relative intensity) 363.3 ([MþH]þ, 25%), 117.1 (100%). Anal. Calcd
for C22H22N2OS: C, 72.90; H, 6.12; N, 7.73. Found: C, 72.57; H, 6.41;
N, 7.51. For the major diastereomer (E)-anti-9a, which was not
obtained in pure form, 1H NMR spectroscopy showed vinylic signals
at 6.40 (dd, J¼15.0, 0.4 Hz) and 5.78 (dd, J¼15.1, 7.9 Hz, 1H).
a sample of 9d0 obtained by reduction of 9d00 using the same
26
procedure (reaction time 5 h); [
a
]
þ43.9 (c 0.80, CHCl3); IR (film,
D
CHCl3) 3487, 2961, 1589, 1497, 1271, 1029 cmꢂ1; 1H NMR (500 MHz,
CDCl3) 7.33–7.29 (m, 4H), 7.15–7.10 (m, 4H), 7.05–7.00 (m, 2H),
d
3.95 (br s, 1H), 3.49 (br d, J¼9.2 Hz, 1H), 2.92 (ddd, J¼9.0, 2.7, 2.7 Hz,
1H), 2.50 (br s, 1H), 1.76–1.67 (m, 1H), 1.64–1.55 (m, 1H), 1.42–1.32
(m, 1H), 1.05 (d, J¼6.5 Hz, 3H), 0.90 (t, J¼7.6 Hz, 3H), 0.75 (d,
4.4.2. Vinyl sulfide (E)-anti-9b (R¼Me)
J¼6.7 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 148.5, 129.2, 122.8,
26
Pale yellow oil; [
a]
ꢂ3.5 (c 1.7, CHCl3); IR (film, CHCl3) 3434,
120.8, 75.6, 60.3, 29.7, 20.3, 18.7, 18.4, 11.1; MS (CI) m/z (relative
intensity) 299.3 ([MþH]þ, 30%), 168 (100%). Anal. Calcd for
C19H26N2O: C, 76.47; H, 8.78; N, 9.39. Found: C, 76.83; H, 8.79; N,
9.10.
D
2974,1588,1495,1271,1077 cmꢂ1; 1H NMR (500 MHz, CDCl3)
d 7.35–
7.30 (m, 9H), 7.15–7.10 (m, 4H), 7.05–7.00 (m, 2H), 6.36 (d, J¼15.2 Hz,
1H), 5.85(dd, J¼15.3, 9.0 Hz,1H), 4.11 (s,1H), 4.07 (brq, J¼6.4 Hz,1H),
3.53 (dd, J¼8.9, 2.7 Hz, 1H), 2.39 (s, 1H), 1.16 (d, J¼6.5 Hz, 3H); 13C
NMR (125 MHz, CDCl3)
d
147.9, 134.5, 130.1, 129.3 (2C), 129.1, 127.3,
4.6. Synthesis of N-TFA-L-daunosamine
127.0, 122.7, 120.4, 66.9, 65.8, 18.3; MS (CI) m/z (relative intensity)
377.6 ([MþH]þ, 80%), 193.1 (100%). Anal. Calcd for C23H24N2OS: C,
73.37; H, 6.42; N, 7.44. Found: C, 73.14; H, 6.47; N, 7.31.
4.6.1. Bis(dimethylethynylsilyl) ether 13
To a mixture of 1221a (173 mg, 0.581 mmol) and DMAP (ca.
5 mg) in toluene (10 mL) and triethylamine (0.22 mL, 1.45 mmol) at
0 ꢁC was added chlorodimethylethynylsilane39 (d 0.88 g/mL,
0.22 mL, 1.45 mmol). After 2 h at room temperature, the mixture
was filtered, and the filtrate was concentrated and partitioned be-
tween water and ethyl acetate. The organic phase was washed with
brine, dried (Na2SO4), and concentrated. Flash chromatography
(10:1 hexane/ethyl acetate/5:1 hexane/ethyl acetate) furnished
silyl ether 13 (249 mg, 93%) as a pale yellow oil; IR (film, CHCl3)
4.4.3. Vinyl sulfide (E)-anti-9c (R¼i-Bu)
28
Pale yellow oil; [
a]
ꢂ12.0 (c 1.25, CHCl3); IR (film, CHCl3) 3447,
D
3060, 2955, 1588, 1495, 1272, 1071, 1025 cmꢂ1; 1H NMR (500 MHz,
CDCl3) 7.31–7.22 (m, 9H), 7.14–7.11 (m, 4H), 7.05–7.00 (m, 2H),
d
6.35 (d, J¼15.1 Hz, 1H), 5.90 (dd, J¼15.2, 8.9 Hz, 1H), 4.09 (s, 1H),
4.00–3.95 (m, 1H), 3.52 (dd, J¼8.9, 2.4 Hz, 1H), 2.35 (s, 1H), 1.80–
1.72 (m, 1H), 1.45 (ddd, J¼14.0, 9.3, 5.6 Hz, 1H), 1.12 (ddd, J¼13.1, 8.1,
3.6 Hz, 1H), 0.92 (d, J¼6.7 Hz, 3H), 0.89 (d, J¼6.6 Hz, 3H); 13C NMR
3275, 2970, 2035, 1601, 1495, 1454, 1255, 1071 cmꢂ1
(500 MHz, CDCl3)
;
1H NMR
(125 MHz, CDCl3)
d
147.96, 134.65, 129.96, 129.28, 129.08, 128.79,
d
7.35–7.22 (m, 10H), 6.40 (d, J¼6.6 Hz, 1H), 4.40
127.70, 126.93, 122.72, 120.36, 68.70, 65.28, 41.85, 24.65, 23.34,
22.08; MS (CI) m/z (relative intensity) 419 ([MþH]þ, 80%), 164
(100%). Anal. Calcd for C26H30N2OS: C, 74.60; H, 7.22; N, 6.69.
Found: C, 74.32; H, 7.28; N, 6.43.
(s, 4H), 4.25 (dd, J¼6.4, 5.7 Hz, 1H), 3.95 (dddd, J¼6.4, 6.4, 6.4,
5.7 Hz, 1H), 2.40 (s, 1H), 2.39 (s, 1H), 1.10 (d, J¼6.3 Hz, 3H), 0.28 (s,
3H), 0.27 (s, 3H), 0.25 (s, 3H), 0.24 (s, 3H); 13C NMR (125 MHz,
CDCl3)
d 137.8, 133.5, 128.4, 127.7, 127.0, 93.1, 92.9, 88.5, 88.5, 78.5,
72.2, 57.6, 19.0, 0.9, 0.8, 0.5, 0.5; MS (EI) m/z (relative intensity) 462
(Mþ, 2%), 335 (100%), 127 (70%). Anal. Calcd for C26H34N2O2Si2: C,
67.49; H, 7.41; N, 6.05. Found: C, 67.40; H, 7.46; N, 6.02.
4.4.4. Vinyl sulfide (E)-anti-9d (R¼i-Pr)
26
Pale yellow oil; [
a
]
ꢂ6.8 (c 1.15, CHCl3); IR (film, CHCl3) 3485,
D
2960,1588,1495,1272,1060 cmꢂ1; 1H NMR (500 MHz, CDCl3)
d 7.35–
7.25 (m, 9H), 7.15–7.10 (m, 4H), 7.05–7.00 (m, 2H), 6.37 (d, J¼15.5 Hz,
1H), 5.93 (dd, J¼15.3, 9.1 Hz, 1H), 4.00 (s, 1H), 3.72 (dd, J¼9.1, 2.5 Hz,
1H), 3.49 (ddd, J¼9.0, 2.0, 2.0 Hz, 1H), 2.60 (s, 1H), 1.72–1.62 (m, 1H),
1.03 (d, J¼6.6 Hz, 3H), 0.82 (d, J¼6.7 Hz, 3H); 13C NMR (125 MHz,
4.6.2. (E,2S,3S,4S)-4-(N,N-Dibenzylhydrazino)-6-(phenylthio)hex-
5-ene-2,3-diol ((E)-14)
From bis(silyl) ether 13 (167 mg, 0.36 mmol) by general pro-
cedure B was obtained 14 (125 mg, 83%, dr 9:1) as a light yellow oil,
which was carried forward as a diastereomeric mixture. Radial
CDCl3)
d 148.0, 134.5, 130.0, 129.4, 129.2, 129.0, 127.0, 126.9, 122.8,
120.5, 75.5, 62.8, 30.4,19.8,18.4;MS(CI)m/z (relativeintensity)405.3
([MþH]þ, 10%), 221 (35%), 117.2 (100%). Anal. Calcd for C25H28N2OS:
C, 74.19; H, 6.97; N, 6.96. Found: C, 74.05; H, 7.00; N, 7.04.
chromatography afforded an analytical sample of the major di-
26
astereomer; [
a
]
ꢂ32.0 (c 1.2, CHCl3); IR (film, CHCl3) 3400, 3028,
D
1583, 1453, 1027 cmꢂ1 1H NMR (500 MHz, CDCl3)
; d 7.40–7.28 (m,
15H), 6.21 (d, J¼15.1 Hz,1H), 5.65 (dd, J¼15.3, 8.8 Hz,1H), 3.73 (ABq,
JAB¼12.9 Hz, Dn¼67.4 Hz, 4H), 3.59 (m, apparent quintet, J¼6.4 Hz,
1H), 3.42–3.37 (m, 2H), 2.55 (br s, 2H), 1.06 (d, J¼6.3 Hz, 3H); 13C
4.4.5. Vinyl sulfide (E)-anti-9e (R¼Ph)
This compound was obtained as a pale yellow oil, ca. 90%
purity by 1H NMR; inseparable impurities were not identified; IR
NMR (125 MHz, CDCl3)
d 137.3, 134.6, 130.0, 129.6, 129.1, 128.4,
(film, CHCl3) 3462, 3059, 1588, 1494, 1272, 1027 cmꢂ1
;
1H NMR
128.2, 127.8, 127.6, 127.0, 75.6, 67.7, 62.0, 61.3, 18.1; MS (CI) m/z
(relative intensity) 435.9 ([MþH]þ,100%), 195.2 (80%). Anal. Calcd
for C26H30N2O2S: C, 71.86; H, 6.96; N, 6.45. Found: C, 72.06; H, 7.02;
N, 6.56.
(500 MHz, CDCl3)
d 7.40–7.18 (m, 12H), 7.12–7.00 (m, 8H), 6.12 (dd,
J¼15.1, 0.5 Hz, 1H), 5.80 (dd, J¼15.2, 8.8 Hz, 1H), 4.97 (d, J¼4.2 Hz,
1H), 4.12 (br s, 1H), 3.75 (dd, J¼8.7, 4.6 Hz, 1H), 2.65 (s, 1H); 13C
NMR (125 MHz, CDCl3)
d 147.7, 140.2, 134.4, 130.0, 129.3, 129.1,
129.0, 128.3, 127.8, 126.8, 126.4, 122.7, 120.4, 73.1, 66.7; MS (CI) m/z
(relative intensity) 439.8 ([MþH]þ, 10%), 330.7 (100%), 255.6
(40%).
4.6.3. N-Trifluoroacetamide 15
A solution of adduct 14 (180 mg, 0.42 mmol, dr 9:1), obtained as
described above, and TsOH$H2O (79 mg, 0.42 mmol) in 2,2-dime-
thoxypropane (15 mL) was stirred at room temperature for 1 h. The
mixture was diluted with ether, washed with aqueous NaHCO3,
dried over Na2SO4, and concentrated. Flash chromatography (SiO2
column packed with 1% Et3N in 20:1 petroleum ether/ethyl acetate
and eluted with 20:1 petroleum ether/ethyl acetate) afforded the
acetonide derivative (190 mg, 0.40 mmol, 95%) as a light yellow oil,
still containing the minor diastereomer; IR (film) 2983, 1455, 1378,
4.5. Stereochemical proof of 4d by chemical correlation:
reduction of 9d
Raney Ni (100 mg, in aqueous suspension) was washed with
ethanol (2ꢃ10 mL) and THF (2ꢃ10 mL), then suspended in THF
(10 mL). A solution of vinyl sulfide 9d (25 mg) in THF (1 mL) was
added, and the mixture was stirred under H2 (1 atm, balloon). The
1243, 1173, 1089 cmꢂ1 1H NMR (500 MHz, CDCl3)
; d 7.37–7.34 (m,

11556
G.K. Friestad et al. / Tetrahedron 64 (2008) 11549–11557
6H), 7.33–7.30 (m, 6H), 7.28–7.23 (m, 3H), 6.15 (d, J¼15.2 Hz, 1H),
5.55 (dd, J¼15.2, 8.8 Hz, 1H), 3.81–3.73 (m, 1H), 3.79 (d, J¼13.2 Hz,
2H), 3.67 (d, J¼13.0 Hz, 2H), 3.62 (dd, J¼8.5, 2.2 Hz, 1H), 3.27 (dd,
J¼8.7, 2.4 Hz, 1H), 3.00–2.80 (br s, 1H), 1.35 (s, 3H), 1.29 (s, 3H), 1.11
ether, washed with saturated aqueous NaHCO3, dried over Na2SO4,
and concentrated. Filtration through a short pad of silica gel, eluting
with 1:1 petroleum ether/ethyl acetate, afforded the anomeric
mixture (8.8 mg, 100% yield) of known methyl pyranosides 17a and
17b.21a,49 The same mixture of isomers was obtained employing
anomeric mixture 16a/16b in this procedure. Varying amounts of
known methyl furanoside isomers52 were observed in different
runs of this experiment, as described by Harding.49
(d, J¼5.6 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 138.2, 130.6, 130.1,
129.5, 129.1, 128.2, 127.2, 126.9, 126.4, 108.1, 83.1, 72.9, 61.7, 61.5,
27.3, 26.8, 18.2; MS (CI) m/z (relative intensity) 476 ([MþH]þ, 100%),
366 (20%), 263 (24%), 211 (35%). Anal. Calcd for C29H34N2O2S: C,
73.38; H, 7.22; N, 5.90. Found: C, 73.32; H, 7.05; N, 5.79.
To a solution of the acetonide obtained as described above
(150 mg, 0.317 mmol) in THF (6 mL) at ꢂ78 ꢁC was added n-BuLi
(2.5 M, 0.38 mL, 0.95 mmol). After 1 h, trifluoroacetic anhydride
(freshly distilled from P2O5, 0.26 mL,1.9 mmol) was added dropwise
over 2 min, whereupon the red color turned to yellow. The reaction
mixture was allowed to warm to room temperature over 2 h, par-
titioned between saturated aqueous NH4Cl and ethyl acetate, and
dried over Na2SO4. Concentration and flash chromatography (SiO2
column packed with 1% Et3N in 20:1 petroleum ether/ethyl acetate
and eluted with 20:1 petroleum ether/ethyl acetate) afforded the N-
Acknowledgements
We thank NSF (CHE-0096803 and CHE-0749850) and the Uni-
versity of Iowa for generous support. The assistance of Koushik
Banerjee, Joe Cannistra, An Ji, and Gopeekrishnan Sreenilayam
(University of Iowa) in acquiring spectroscopic data is appreciated.
References and notes
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trifluoroacetamide (135.6 mg, 75%).
A solution of the N-tri-
fluoroacetamide (246 mg) in 10:1 THF/MeOH (10 mL) was treated
with freshly prepared SmI2 (0.2 M in THF, 17.3 mL, 3.45 mmol) until
the blue color of SmI2 persisted for 15 min. After concentration, the
residue was triturated with Et2O and the soluble portion was puri-
fied by flash chromatography (SiO2 column packed with 1% Et3N in
20:1 petroleum ether/ethyl acetate and eluted with 5:1 petroleum
ether/ethyl acetate) to afford 15 (133 mg, 82%) as a diastereomeri-
cally pure colorless oil. In another run, without purification of the
intermediate trifluoroacetamide, 15 was obtained in 73% yield for
18
the two steps; [
a
]
þ46.8 (c 0.795, CHCl3); IR (film) 3291,1701,1540,
D
1210, 1171 cmꢂ1; 1H NMR (500 MHz, CDCl3)
d 7.40–7.25 (m, 5H), 6.66
(d, J¼7.5 Hz,1H), 6.58 (d, J¼15.2 Hz,1H), 5.63 (dd, J¼15.1, 8.7 Hz,1H),
4.59 (ddd, apparent dt, J¼8.7, 2.7 Hz, 1H), 3.85 (dddd, apparent dq,
J¼8.4, 6.1 Hz,1H), 3.66 (dd, J¼8.5, 2.8 Hz,1H),1.40 (s, 3H),1.30 (s, 3H),
1.29 (d, J¼6.2 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 156.3 (quartet,
2JCF¼37.5 Hz), 131.8, 130.3 (quartet, 1JCF¼196 Hz), 122.1, 109.2, 82.8,
73.4, 52.3, 27.3, 26.6, 17.3; MS (CI) m/z (relative intensity) 376
([MþH]þ,15%), 360 (15%). Anal. Calcd for C17H20NO3F3S: C, 54.39; H,
5.37; N, 3.73. Found: C, 54.61; H, 5.39; N, 3.75.
´
G. K.; Qin, J.; Suh, Y.; Marie, J.-C. J. Org. Chem. 2006, 71, 7016–7027; (f) Korapala,
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4.6.4. N-Trifluoroacetyl-L
-daunosamine48 (16)
7. (a) Miyabe, H.; Ushiro, C.; Naito, T. Chem. Commun. 1997, 1789–1790; (b) Miyabe,
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623–638.
9. For other selected approaches to intermolecular radical addition to C]N bonds,
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To a mixture of NaI (190 mg, 1.27 mmol) and HgCl2 (265 mg,
0.98 mmol) in CH3CN (2 mL) was added TMSCl (0.16 mL,
1.27 mmol). After 5 min, water (10% v/v in CH3CN, 0.45 mL,
2.5 mmol) was added and stirring was continued for another 5 min.
A solution of compound 15 (79 mg, 0.21 mmol) in CH3CN (2 mL)
was added. After 7 h, the reaction mixture was partitioned between
ethyl acetate and saturated aqueous NaHCO3. The organic phase
was dried over Na2SO4 and concentrated in vacuo. The yellow solid,
which remained was triturated with ethyl acetate (3ꢃ0.5 mL), and
the soluble portion was subjected to flash chromatography (1:1
petroleum ether/ethyl acetate, then ethyl acetate) to afford an
anomeric mixture of
a- and b-pyranoses 16a and 16b (26.4 mg,
51%) as a pale yellow solid.47 Recrystallization from petroleum
ether/ethyl acetate afforded the
a
-anomer 16a: mp 146–148 ꢁC;
30
20
[
a]
ꢂ120 (c 0.070, MeOH) [lit. mp 146–147 ꢁC; [
a
]
D
ꢂ127 (c 0.10,
D
MeOH)];48 1H NMR (300 MHz, CD3CN)
d 7.30 (br s, 1H), 5.21–5.18
(m, 1H), 4.33–4.28 (m, 1H), 4.10 (qd, J¼6.5, 2.2 Hz, 1H), 4.00 (dd,
J¼3.6, 1.8 Hz, 1H), 3.51 (dd, J¼6.8, 2.2 Hz, 1H), 3.04 (d, J¼7.0 Hz, 1H),
1.87 (dddd, J¼12.8, 12.8, 3.5, 1.8 Hz, 1H), 1.62 (dddd, J¼12.8, 4.8, 1.1,
1.1 Hz, 1H), 1.10 (d, J¼6.6 Hz, 3H). The 1H NMR spectrum in DMSO
was in agreement with the literature data.48
12. (a) Friestad, G. K.; Massari, S. E. Org. Lett. 2000, 2, 4237–4240; (b) Friestad, G. K.;
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4.6.5. Methyl N-trifluoroacetyl-
The -anomer 16a (8.2 mg, 0.034 mmol) was taken up in 0.1 M
methanolic HCl (2 mL). After 16 h, the mixture was diluted with
L-daunosaminides (17a and 17b)
a

G.K. Friestad et al. / Tetrahedron 64 (2008) 11549–11557
11557
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´
`
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