Effects of α-alkoxy substitution and conformational constraints on 6-exo radical cyclizations of hydrazones via reversible thiyl and stannyl additions

Article abstract of DOI:10.1016/j.tet.2007.06.117

Access to multifunctional hydrazones of relevance to dysiherbaine synthesis studies is described. Subsequent radical cyclizations of multifunctional hydrazones via a Si- and C-linked tethering strategy are shown to function effectively in 6-exo fashion. C

Full text of DOI:10.1016/j.tet.2007.06.117

Tetrahedron 63 (2007) 9373–9381
Effects of a-alkoxy substitution and conformational constraints
on 6-exo radical cyclizations of hydrazones via
reversible thiyl and stannyl additions
*
Gregory K. Friestad and Alex K. Mathies
Department of Chemistry, University of Iowa, Iowa City, IA 52242, United States
Received 26 April 2007; revised 13 June 2007; accepted 29 June 2007
Available online 10 July 2007
Abstract—Access to multifunctional hydrazones of relevance to dysiherbaine synthesis studies is described. Subsequent radical cyclizations
of multifunctional hydrazones via a Si- and C-linked tethering strategy are shown to function effectively in 6-exo fashion. Conformational
constraints are proposed to play a key role in suppressing unproductive premature reduction pathways. The stereochemical outcomes suggest
that minimizing the dipole repulsion between neighboring C]N and C–O bonds favors a Ca–C(]N) dihedral angle placing the C]N bond
axial within a chairlike transition state, in contrast to the usual Beckwith–Houk model.
Ó 2007 Elsevier Ltd. All rights reserved.
NHMe
NHMe
OH
1. Introduction
H
H
NH2
OH
HO
HO
O
HO2C
Amino alcohols and polyhydroxylated amines are important
substructures of biologically active compounds, and include
sphingolipids,1 azasugars,2 and aminosugars.3,4 An interest-
ing conjugate of amino acid and aminosugar functionality is
found in the neuroexcitotoxin (–)-dysiherbaine (1, Scheme
1), which was isolated from the Micronesian marine sponge
Dysidea herbacea in 1996.5 Neurotoxins are in high demand
to study glutamate receptors and associated central nervous
system function, and 1 is a non-NMDA glutamate agonist
with 5-fold selectivity for KA versus AMPA receptors.6
Synthetic studies toward 1 have led to total syntheses by
Hatakeyama,7 Snider,8 Sasaki,9 and Chamberlin,10 as well
as preparation of analogs.11 Through our prior studies of
Si-tethered12 and acetal-tethered13 radical additions to imino
compounds14 for synthesis of chiral hydroxyalkylamines,
practical understanding of stereocontrol in these processes
has been emerging. With predictions of relative configura-
tion thus available, we became attracted to the prospect of
testing the stereocontrol models on more complex substrates
of relevance to synthesis of dysiherbaine and related com-
pounds. The aminosugar 2 (Scheme 1) was judged to be
an important subgoal to be pursued via allylic amine 3,
which in turn could arise through stereocontrolled vinyl
addition to imino compound 4.
O
O
HO2C
H
Dysiherbaine (1)
2
OH NR
R
OP HN
3
•
O
O
OP OP
3
Ph
O
4
tether
to C3
• vinyl radical addition for
Si
O
C–C bond construction
• temporary tether: avoids
unfavorable intermolecular
addition, provides stereo-
control via C3-hydroxyl
NNBn2
O
5
Ph
Scheme 1.
The key C–C bond construction for synthesis of the aminosu-
gar would entail stereocontrolled delivery of a tethered vinyl
radical synthon via the 6-exo cyclization implied by structure
5. We have previously shown that this strategy offers high
diastereoselectivity for Si-tethered vinyl group transfer to hy-
drazone acceptors via the 5-exo cyclization mode.12b–e How-
ever, prior attempts in the 6-exo mode using vinylsilyl ethers
linked to acyclic b-hydroxyhydrazones were previously
found to suffer b-elimination during preparation of the sub-
strates, premature reduction during thiyl-mediated vinyl
Keywords: Radical cyclization; Stereoselectivity; Aminosugars; Dysiher-
baine.
* Corresponding author. Tel.: +1 319 335 1364; fax: +1 319 335 1270;
e-mail: gregory-friestad@uiowa.edu
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.06.117

9374
G. K. Friestad, A. K. Mathies / Tetrahedron 63 (2007) 9373–9381
addition, and poor diastereoselectivity.12e,f It was not alto-
gether clear whether these challenges could be met in this
more highly functionalized system, but it was envisioned
that the additional conformational constraints imposed by
the benzylidene acetal of the cyclic substrate 5 could be ben-
eficial. Tests of this hypothesis are reported herein. In the
course of these studies, a modification of the currently
accepted Beckwith–Houk stereocontrol model15 for 6-exo
radical cyclization was required in order to accommodate un-
expected results with a-alkoxyhydrazones.
OH NHNBn2
i) PhS•
(conditions below)
5
ii) TBAF, THF
O
O
dr >98:2
Ph
8
initiator PhS• source
temperature
yield
PhSH
PhSH
AIBN
ABC
light
80 °C
80 °C
r.t.
55%
10%
10%
52%
PhSSPh
PhSH
Et3B/O2
r.t.
2. Results and discussion
NC
N
N
AIBN =
N
N
CN
CN
2.1. Si-tethered cyclizations
Formation of the radical cyclization precursor 5 began with
transformation of D-arabitol (Scheme 2) to the correspond-
ing benzylidene derivative16 (mixture of regioisomers17)
and oxidative cleavage with sodium periodate to afford
threose derivative 6. Alternatively, reaction of D-galactose
with benzaldehyde dimethyl acetal produced a single ben-
zylidene derivative,18 then periodate cleavage furnished 6
in 67% yield for the two steps.19 Condensation of 6 with di-
benzylhydrazine afforded hydroxyhydrazone 7, and installa-
tion of the silicon-tethered radical precursor was achieved in
excellent yields, furnishing the vinylsilyl ether 5.
NC
ABC =
Scheme 3.
non-reductive conditions. However, initiation with triethyl-
borane/oxygen conditions afforded results similar to those
obtained with AIBN.
The vinyl transfer process 5/8 is envisioned to involve the
sequence of steps shown in Scheme 4, including (a) genera-
tion of PhSꢀ upon heating PhSH in the presence of AIBN, (b)
PhSꢀ addition to the terminus of the vinyl group, (c) cycliza-
tion of the resulting carbon-centered radical 9, (d) H-atom
abstraction from thiophenol by aminyl radical 10, (e) fluo-
ride-induced cleavage of Si–O bond in 11, and (f) desilyla-
tive b-elimination with loss of PhSꢁ from an intermediate
of the type illustrated in hypervalent silicate 12 to reform
the alkene in the observed product.
1) PhCHO, HCl
D-arabitol
OH
2) NaIO4
27% (2 steps)
O
O
O
1) PhCH(OMe)2,
TsOH, DMF
Ph
D-galactose
2) NaIO4, NaHCO3
67% (2 steps)
6
Bn2NNH2
MgSO4
PhCH3
98%
Si
Si
O
SPh
O
SPh
•
Si
O
PhS•
OH
NNBn2
•
5
NNBn2
Si
Cl
O
O
O
O
O
NNBn2
NNBn2
Et3N, DMAP
9
10
O
O
O
O
Ph
Ph
THF
PhSH
5
7
Ph
>99%
Ph
F
–
F
SiMe2
Scheme 2.
Si
HO
O
SPh
SPh
2 F–
With silyl ether 5 in hand, the radical addition–cyclization
using tin-free thiyl-mediated reaction conditions was next
examined (Scheme 3).12b,d Upon heating a mixture of 5,
PhSH, andAIBNinbenzene, followedbyexposuretofluoride
ion, vinyltransfer from silicon totheiminocarbonoccurred to
afford 8 in moderate yield. This result was a dramatic depar-
ture from our prior attempts with acyclic precursors in which
the premature reduction predominated under these condi-
tions.12f Even more surprisingly, only one diastereomer could
be detected, whereas the only prior examples of 6-exo Si-teth-
ered additions to C]N bonds were non-diastereoselective.12f
NHNBn2
NHNBn2
8
O
O
O
12
11
Ph
Ph
Scheme 4.
For subsequent elaboration toward aminosugars, direct dihy-
droxylation of hydrazine 8 was desirable, but allylic amines
are troublesome substrates without prior acylation.20 Treat-
ment of 8 with Boc2O furnished an O-acylated derivative,
presumably 13 (Scheme 5), as benzoic anhydride also prefer-
entially acylated the hydroxyl function in 8 to afford 14. Sil-
ica gel chromatography of the O-Boc derivative afforded
68% of cyclic carbamate 15.21 More importantly, when
NOE data were obtained for the cyclic carbamate 15, the cor-
relation was between Ha and Hc as depicted in Scheme 5, with
no observed NOE between Ha and Hb. This offered strong
Further optimization of the radical cyclization was attemp-
ted using different initiators (Scheme 3). Replacing AIBN
with ABC (1,1-azodicyclohexanecarbonitrile) produced
much lower yields (10%), as did photochemical activation
of phenyl disulfide to directly generate thiyl radicals under

G. K. Friestad, A. K. Mathies / Tetrahedron 63 (2007) 9373–9381
9375
evidence for the indicated stereostructure bearing the unde-
sired configuration at the newly formed amine center. Prelim-
inary examination of dihydroxylation of 15 showed some
promise,22 but these experiments were postponed pending
further examination of the unexpected stereoselectivity in
the radical addition.
(Fig. 1). Are such conformational constraints sufficient to
enable the 6-exo cyclization, or is some further effect of
the a-oxygen required?
In order to gain some further insight, a substrate was
prepared, which lacked the a-alkoxy substituent, yet main-
tained the conformational constraints of 5. Racemic b-
hydroxyhydrazone 16 (Scheme 6) was obtained from the
corresponding b-hydroxyester by reduction (DIBAL), con-
densation with Ph2NNH2 (b-hydroxy hydrazones prepared
with Bn2NNH2 are more prone to b-elimination), and desi-
lylation (TBAF). Silylation of 16 furnished cyclization pre-
cursor 17 in 88% yield. Upon exposure to the thiyl-mediated
addition conditions there was no detectable cyclization. As
in other unsuccessful 6-exo radical cyclizations,12f TLC in-
dicated conversion of 17 to a new compound, presumably
via addition of PhSH across the vinyl group (the new com-
pound was converted back to hydroxyhydrazone 16 upon
treatment with TBAF). This observation suggests that in
this case the hydrogen atom abstraction from PhSH super-
cedes cyclization of the carbon-centered radical of the type
illustrated in Figure 1. Thus the conformational constraint
alone is insufficient to accelerate the 6-exo cyclization,
and it can be proposed that the a-alkoxy substituent plays
a more active role than previously expected.
O
BocO
O
NHNBn2
O
NNBn2
Boc2O
SiO2
8
+ 8 (30%)
pyridine
(flash
O
O
O
chrom.)
100%
13
15 (68%)
Ph
Ph
conv.
Ph
nOe data:
Ha ←→ H
X
a ←→ Hbc
O
BzO
O
NHNBn2
H
Bz2O, DMAP
CH2Cl2
O
8
Hb
O
O
N
>99%
14
Ha
O
NBn2
Ph
Hc
Scheme 5.
The foregoing results raised two fundamental questions of
relevance to the understanding of radical cyclization to
imino compounds. First, why are these thiyl-mediated
6-exo cyclizations with the Si-tethered vinyl group success-
ful, where several other related 6-exo cyclizations have
failed?12e,f Second, why does the diastereoselectivity defy
the usual predictions of the Beckwith–Houk model?
In prior work, the Beckwith–Houk model effectively pre-
dicted the configuration obtained in thiyl-mediated vinyl
additions to hydrazones.12d,e In the case of 5, the Beckwith–
Houk model predicts transition state A (Fig. 2), which mini-
mizes strain by orienting substituents equatorially, including
the C]N bond. However, the observed product configura-
tion suggests a strong preference for transition state B with
the C]N bond in an axial position. To explain these results,
we suggest that the a-alkoxy substituent increases the energy
of A through a vicinal dipole repulsion due to the gauche re-
lationship of the C]N and C–O bonds. In transition state B,
the dihedral angle is 180ꢂ, minimizing the dipole repulsion
and thus favoring reaction through B to the observed config-
uration. To test this hypothesis, a diastereomeric hydrazone
19 (Scheme 7) was designed, which would possess a gauche
relationship with the neighboring C–O bond in both transi-
tion state models A0 and B0. All substituents could occupy
an equatorial position in structure A0, so the Beckwith–
Houk model would predict excellent stereocontrol. In
contrast, our hypothesis incorporating the dipole repulsion
predicts a lower diastereomeric ratio for this substrate.
2.2. Factors enabling the Si-tethered 6-exo cyclization
Previously, irreversible generation of more reactive vinyl
radicals from a vinyl bromide was required for the Si-teth-
ered 6-exo cyclization to hydrazones.12f In contrast, in this
work compound 5 cyclizes smoothly in the 6-exo cycliza-
tion, even with the reversible thiyl addition method. Key
structural differences are the presence of the alkoxy substit-
uent adjacent to the imino acceptor carbon and conforma-
tional restrictions imparted by the benzylidene acetal ring
Si
Si
2
O
SPh
O
3
SPh
•
•
vs.
1
NNBn2
NNBn2
O
O
unsuccessful,
no cyclization
successful
cyclization
The requisite hydrazone 20 was prepared from commer-
cially available 4,6-O-benzylidene-D-glucose (Scheme 7)
by periodate cleavage and condensation with Bn2NNH2 to
afford crystalline 19, followed by silylation with chlorodi-
methylvinylsilane. Cyclization of 20 under the thiyl-
mediated conditions resulted in a 53% yield of 21 with a
diastereomeric ratio of 70:30.23 The complete stereocontrol
Ph
Key Structural Differences
• conformationally constrained C2–C3 bond
• α-alkoxy substituent adjacent to C=N
Figure 1. Comparison of structural features in unsuccessful and successful
6-exo cyclizations.
i) PhSH, AIBN
PhH, 80 °C
OH
OH NHNPh2
Si
Si
O
Cl
NNPh2
( )-16
Et3N, DMAP
88%
ii) TBAF, THF
H
NNPh2
( )-17
18
Scheme 6.

9376
G. K. Friestad, A. K. Mathies / Tetrahedron 63 (2007) 9373–9381
Ph
Ph
O
O
O
O
O
O
XN
Si
Si
SPh
SPh
NX
A
B
equatorial C=N is gauche to α-C–O bond
axial C=N is anti to α-C–O bond
(inconsistent with product configuration)
(predicts observed product configuration)
Ph
O
Ph
O
O
O
O
O
XN
Si
Si
SPh
SPh
NX
A'
B'
Control experiment: Both A' and B' place the C=N gauche to α-C–O bond
Prediction: If dipole repulsion effect is operative, selectivity should be lower
Figure 2. Transition state models for 6-exo cyclizations of diastereomeric hydrazones.
Ph
OH
1) NaIO4
NaHCO3
Si
Ph
HO
O
Cl
O
O
NNBn2
O
SnBu3
NNBn2
O
OH
•
Et3N, DMAP
96%
2) Bn2NNH2
MgSO4
O
O
HO
O
M
ylidene-
4,6-O-benz
Ph
19
73% (2 steps)
O
O
O
D-glucose
M
XN
Si
Ph
SPh
A''
C
OH NHNBn2
Si
i) PhSH, AIBN
PhH, 80 °C
O
O
Figure 3. Potential for use of Lewis acid chelation to override dipole repul-
sion.
NNBn2
ii) TBAF, THF
O
O
dr 70:30
O
53%
Ph
Ph
20
21
would provide a handle for stereocontrolled hydroxyl intro-
duction.
Scheme 7.
Alkylation of 7 with propargyl bromide in the presence of
sodium iodide gave high yields of propargyl ether 22
(Scheme 8), conveniently purified by recrystallization
from a 3:1 mixture of hexane and ethyl acetate. Exposure
to tributyltin hydride in the presence of AIBN led to smooth
conversion to vinylstannane 23. Although the cyclization
could be accomplished in benzene, DMF was preferred, of-
fering a 90% yield over 12–24 h. Alternatively, microwave
irradiation in DMF (0.5 M) produced 23 in 10–15 min. Pro-
todestannylation was achieved readily upon transmetalation
with n-BuLi and treatment with propionic acid, used
from 5 changed to very weak diastereoselectivity from 20,
consistent with the prediction in Figure 2. This provides ex-
perimental support for the hypothesized dipole repulsion
modification to the Beckwith–Houk model.
2.3. Preliminary study of C-linked cyclization
In light of the undesired configuration emanating from the Si-
tethered cyclization above, a revised plan was formulated to
explore the possibility of modified conditions to reverse the
stereocontrol. Use of a Lewis acid for two-point binding be-
tween the C]N and C–O bonds could potentially restrict
conformer populations to the gauche conformer in transition
state A00 (Fig. 3). Unfortunately, identifying a Lewis acid
compatible with both the thiyl conditions and the Si-tether
functionality was non-trivial. Instead, a propargyl ether was
selected as a C-linked radical precursor, with recognition
of some advantages over the temporary Si-tether. First, the
more robust ether linkage would potentially accommodate
a variety of Lewis acids in the radical addition. Second, the
alkyne could serve as a precursor of more reactive vinyl rad-
icals such as C in the presence of Lewis acid-compatible tin
reagents. Third, the pyran ring found in dysiherbaine would
be formed directly in the cyclization, which could avoid sub-
sequent steps to elaborate that ring. After a 6-exo radical
cyclization via C and removal of tin, the exo-methylene
O
O
SnBu3
KH, NaI, THF
Bu3SnH, AIBN
DMF
NHNBn2
NNBn2
7
Br
O
O
O
O
92%
22
23
Ph
Ph
heat, 80 °C, >12 h: 90%
μwave, 15 min: 87%
O
1) Bu3SnH, AIBN, DMF, 80 °C
NHNBn2
22
2) n-BuLi; propionic acid
O
O
80% (2 steps)
24
Ph
Scheme 8.

G. K. Friestad, A. K. Mathies / Tetrahedron 63 (2007) 9373–9381
9377
stoichiometrically to preserve the benzylidene acetal. Di-
4. Experimental section
4.1. Materials and methods
rectly applying the protodestannylation to the crude cycliza-
tion product (after filtration through silica gel to remove
excess tin hydride) furnished 24 in 80% yield for the two
steps. It is noteworthy that this differentially functionalized
compound is obtained with complete diastereoselectivity in
48% yield from D-galactose.
Reactions were employed on an oven- or flame-dried glass-
ware under nitrogen 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 the 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 chromatography
(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 cen-
trifugally 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
Assignment of configuration of 24 by NMR was accom-
plished with COSY and NOESY experiments on the diben-
zoyl derivative 26, prepared by successive hydrolysis and
benzoylation (Scheme 9). The NOESY spectrum suggested
the chair conformation indicated below, based on a crosspeak
for H2–H6a. The equatorial orientation of H4 was then in-
ferred from crosspeaks between H6e–H5Z and H5E–H4. No
through-space interaction of H4 with H2 or H6a was detected.
O
O
1) TsOH, MeOH
NHNBn2
24
NHNBn2
2) BzCl, Et3N, DMAP
O
O
RO
OR
75% (2 steps)
25 (R = H)
Ph
26 (R = Bz)
H5Z
H5E
Bz
nOe data:
H6e
O
H4 ←→ H , H
X
6a
O
H
H
H
2 ←→ H26a
6e ←→ H5Z
5E ←→ H4
H4
BzO
H3
H6a
NHNBn2
H2
Scheme 9.
1
500 or 300 MHz for H and 125 or 75 MHz for 13C and
The results suggest that the dipole repulsion stereocontrol
model operative in the Si-tethered cyclizations also confers
excellent selectivity in the propargyl ether cyclization. The
greater stability of the propargyl ether radical precursor
offers greater opportunities for potential modification of re-
action conditions, for example, with Lewis acidic additives.
chemical shifts are reported in parts per million (ppm). Infra-
red spectra were recorded using a single beam FTIR spec-
trophotometer by standard transmission methods or by use
of an attenuated total reflectance (ATR) probe. Optical
rotations were determined using a digital polarimeter operat-
ing at ambient temperature. Low resolution mass spectra
were obtained using sample introduction by dip, liquid
chromatography or gas chromatography. High resolution
mass spectra and combustion analyses were obtained
from external commercial and institutional services.
Chromatographic diastereomeric ratio analyses employed
GC–MS with 15 mꢃ0.25 mmꢃ0.25 mm (lꢃi.d.ꢃf.t.) 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 (chloroform/hexane as
mobile phase).
3. Conclusions
A four-carbon trihydroxylated hydrazone prepared from ara-
bitol or galactose undergoes highly stereoselective 6-exo
radical cyclization onto the hydrazone unit; reversible thiyl
radical addition to silicon-tethered vinyl group initiates the
cyclization. Because the product configuration was opposite
to that predicted by the Beckwith–Houk model for applica-
tion to the dysiherbaine aminosugar, interesting fundamental
issues of stereocontrol emerged. In order to rationalize unex-
pected stereoselectivity, a dipole repulsion model is pre-
sented as a modification of the Beckwith–Houk model for
a-alkoxyhydrazones. Cyclizations using stannyl addition
to a propargylic ether were examined, resulting in a very
efficient preparation of aminosugar 24 in 48% yield from
D-galactose. Although these more robust substrates should
be amenable to Lewis acid chelation and potential reversal
of stereocontrol, preliminary experiments toward this end
have not identified conditions for such a reversal. The dipole
repulsion stereocontrol model, and studies designed to mod-
ulate it, may offer new possibilities for synthetic application
of stereocontrolled radical additions to polyhydroxylated
chiral amine targets.
4.1.1. 1,1-Dibenzyl-2-(((2S,4R,5R)-5-hydroxy-2-phenyl-
1,3-dioxan-4-yl)methylene)hydrazine (7). To a solution
of aldehyde 624 (1.16 g, 5.58 mmol) in toluene (12 mL)
were added dibenzylhydrazine (1.42 g, 6.70 mmol) and
magnesium sulfate (30 mg). After 24 h, concentration and
flash chromatography (5:1 to 1:1 hexanes/ethyl acetate) af-
forded 7 (2.20 g, 98%) as a colorless oil. [a]2D4 ꢁ41.3 (c
0.725, CHCl3); IR (film) 3452 (br), 3060, 2923, 2848,
1
1601, 1493, 1452, 1078, 1027 cmꢁ1; H NMR (500 MHz,
CDCl3) d 7.51–7.49 (m, 2H), 7.36–7.21 (m, 13H), 6.63
(d, J¼4.8 Hz, 1H), 5.61 (s, 1H), 4.50 (d, J¼4.8 Hz, 1H),
4.40 (s, 4H), 4.28 (dd, J¼12.0, 1.5 Hz, 1H), 4.07
(d, J¼12.0 Hz, 1H), 3.77 (d, J¼7.3 Hz, 1H), 3.28 (d,

9378
G. K. Friestad, A. K. Mathies / Tetrahedron 63 (2007) 9373–9381
J¼7.3 Hz, 1H); 13C NMR (125 MHz, CDCl3) d 137.7,
136.9, 130.5, 128.9, 128.5, 128.1, 127.6, 127.2, 126.1,
101.4, 79.3, 72.1, 65.4, 57.4; MS (CI) m/z (relative intensity)
403 ([M+1]+, 100%), 385 (7%), 297 (24%), 279 (18%), 198
(15%). Anal. Calcd for C25H26N2O3: C, 74.60; H, 6.51; N,
6.96. Found: C, 74.36; H, 6.67; N, 6.62.
(500 MHz, CDCl3) d 8.08–8.04 (m, 2H), 7.63–7.22 (m,
18H), 5.55 (s, 1H), 5.48–5.38 (m, 1H), 5.12 (d, J¼
10.3 Hz, 1H), 5.03 (d, J¼17.1 Hz, 1H), 4.81 (s, 1H), 4.38
(d, J¼13.0 Hz, 1H), 4.04 (d, J¼12.7 Hz, 1H), 3.89 (d, J¼
9.1 Hz, 1H), 3.76 (d, J¼8.6 Hz, 1H), 3.76 (d, J¼13.5 Hz,
2H), 3.69 (d, J¼13.4 Hz, 2H); 13C NMR (125 MHz,
CDCl3) d 171.1, 165.8, 137.9, 137.8, 135.9, 133.7, 133.2,
130.2, 129.9, 129.8, 129.6, 129.3, 129.2, 128.5, 128.4,
128.3, 128.0, 127.0, 126.4, 119.4, 101.5, 78.7, 69.6, 65.9,
62.0, 60.5 (includes 13C peaks for inseparable byproduct);
MS (CI) m/z (relative intensity) 535 ([M+1+], 100%), 444
(16%), 429 (50%), 338 (35%), 211 (70%).
4.1.2. 1,1-Dibenzyl-2-(((2S,4R,5R)-5-(dimethyl(vinyl)si-
lyloxy)-2-phenyl-1,3-dioxan-4-yl)methylene)hydrazine
(5). To a solution of hydrazone 7 (77 mg, 0.19 mmol) tri-
ethylamine (0.08 mL, 0.57 mmol), and DMAP (3 mg) in
THF (2 mL) was added dimethylvinylchlorosilane
(0.08 mL, 0.57 mmol). After 4 h, concentration and flash
chromatography (10:1 hexanes/ethyl acetate) afforded 5
(93 mg, 100%) as a colorless oil. [a]2D4 ꢁ22.5 (c 0.855,
CHCl3); IR (film) 3060, 2862, 1844, 1594, 1494, 1474,
4.1.5. (2S,4aR,8S,8aR)-7-(Dibenzylamino)-2-phenyl-8-vi-
nyl-tetrahydro[1,3]dioxino[4,5-e][1,3]oxazin-6(7H)-one
(15). To a solution of hydrazine 8 (60 mg, 0.140 mmol) in
CH2Cl2 (2 mL) was added pyridine (0.01 mL, 0.14 mmol)
followed by Boc2O (31 mg, 0.14 mmol) at 0 ꢂC. After 4 h,
concentration and flash chromatography (5:1 hexanes/ethyl
acetate) afforded 15 (43 mg, 68%) as a colorless solid; mp
166–167 ꢂC. [a]D27 +104 (c 1.36, CHCl3); IR (film) 2864,
1701, 1385, 1260, 1102 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d 7.45–7.21 (m, 15H), 5.80 (ddd, J¼16.9, 9.7, 9.7 Hz, 1H),
5.40 (s, 1H), 5.25 (d, J¼10.0 Hz, 1H), 5.07 (d, J¼17.2 Hz,
1H), 4.57 (d, J¼13.4 Hz, 1H), 4.35 (d, J¼12.1 Hz, 1H),
4.31 (d, J¼12.1 Hz, 1H), 4.25 (d, J¼13.6 Hz, 1H), 3.88 (dd,
J¼12.7, 1.4 Hz, 1H), 3.79 (dd, J¼3.7, 1.2 Hz, 1H), 3.74 (d,
J¼12.0 Hz, 1H), 3.69 (d, J¼1.3 Hz, 1H), 3.09 (dd, J¼9.3,
3.7 Hz, 1H); 13C NMR (125 MHz, CDCl3) d 151.3, 138.2,
137.5, 137.2, 134.0, 130.3, 129.1, 189.9, 128.2, 128.1,
128.0, 127.7, 127.2, 126.1, 119.0, 100.7, 73.2, 69.2, 68.2,
67.1, 60.8, 54.1; MS (CI) m/z (relative intensity) 457
([M+1+], 100%), 397 (62%). Anal. Calcd for C28H28N2O4:
C, 73.66; H, 6.18; N, 6.14. Found: C, 73.41; H, 6.26; N, 6.10.
1096, 1068, 840 cmꢁ1 1H NMR (300 MHz, CDCl3) d
;
7.55–7.52 (m, 2H), 7.38–7.22 (m, 13H), 6.69 (d, J¼6.2 Hz,
1H), 6.08–5.69 (m, 3H), 5.60 (s, 1H), 4.49 (dd, J¼6.2,
1.7 Hz, 1H), 4.36 (s, 4H), 4.10 (ABX, JAB¼12.2 Hz, JAx
¼
1.6 Hz, JBx¼1.5 Hz, Dn¼30.5 Hz, 2H), 3.71–3.68 (m, 1H),
0.09 (s, 3H), 0.04 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 138.2, 137.7, 137.4, 133.3, 131.5, 128.7, 128.5, 128.1,
127.7, 127.2, 126.3, 101.2, 81.2, 72.3, 67.0, 57.4, ꢁ1.4,
ꢁ1.8; MS (EI) m/z 487 ([M+1]+, 90%), 403 (50%), 381
(75%), 351 (75%), 297 (80%), 279 (100%). Anal. Calcd
for C29H34N2O3Si: C, 71.57; H, 7.04; N, 5.76. Found: C,
71.43; H, 7.18; N, 5.82.
4.1.3. 1,1-Dibenzyl-2-((S)-1-((2S,4R,5R)-5-hydroxy-2-
phenyl-1,3-dioxan-4-yl)allyl)hydrazine (8). To a solution
of hydrazone 5 (846 mg, 1.74 mmol) in refluxing deoxygen-
ated cyclohexane (17.4 mL) was added a solution of AIBN
(371 mg, 2.26 mmol) and thiophenol (0.55 mL, 5.2 mmol)
in deoxygenated benzene (9.4 mL) over 12 h via syringe
pump and heating was continued at reflux for 10 h. The sol-
vent was replaced with THF (17.4 mL), and a solution of
TBAF (1 M in THF, 3.83 mL, 3.83 mmol) was added. After
16 h, concentration and flash chromatography (20:1 to 1:1
hexane/ethyl acetate) afforded 8 (391 mg, 55%) as a color-
less oil. [a]2D3 +28.0 (c 0.575, CHCl3); IR (film) 2973,
2361, 1655, 1531, 1453, 1339, 1148, 1114 cmꢁ1; 1H NMR
(300 MHz, CDCl3) d 7.48–7.22 (m, 15H), 5.66–5.49 (m,
1H), 5.47 (s, 1H), 5.35 (dd, J¼17.3, 2.0 Hz, 1H), 5.23 (dd,
4.1.6. rac-2-((cis-2-Hydroxycyclohexyl)methylene)-1,1-
diphenylhydrazine (16). To a solution of ethyl cis-2-(tert-
butyldimethylsilyloxy)cyclohexane carboxylate25 (1.52 g,
5.30 mmol) in CH2Cl2 (7 mL) was added diisobutylalumi-
num hydride (1.2 M in hexane, 5.3 mL, 6.4 mmol) over
30 min at ꢁ78 ꢂC. After 2 h, the reaction was quenched
with saturated aqueous sodium potassium tartrate (300 mL),
extracted with CH2Cl2 (3ꢃ100 mL), dried over MgSO4, and
concentrated. The residue (crude aldehyde) was dissolved in
pyridine (5 mL). Diphenylhydrazine hydrochloride (1.29 g,
5.83 mmol) was added. After 16 h, the mixture was concen-
trated and purified by flash chromatography (10:1 petroleum
ether/EtOAc) to afford the corresponding hydrazone (1.72 g,
80%) as a colorless oil. IR (film) 3060, 3027, 2931, 2856,
J¼10.0, 2.1 Hz, 1H), 4.02 (ABX, JAB¼11.9 Hz, JAx
¼
1.9 Hz, JBx¼1.2 Hz, Dn¼70.8 Hz, 2H), 3.71 (s, 4H), 3.67–
3.65 (m, 2H), 3.50 (s, 1H), 1.60 (br s, 1H); 13C NMR
(75 MHz, CDCl3) d 137.8, 137.7, 136.8, 129.6, 129.0,
128.2, 128.1, 127.1, 126.1, 118.7, 101.5, 80.5, 72.8, 64.3,
62.5, 60.5; MS (EI) m/z (relative intensity) 431 ([M+1]+,
100%), 325 (60%), 301 (90%), 211 (60%).
1591, 1494, 836 cmꢁ1 1H NMR (300 MHz, CHCl3) d
;
7.39–7.34 (m, 4H), 7.14–7.09 (m, 6H), 6.58 (d, J¼5.98 Hz,
1H), 3.99–3.94 (m, 1H), 2.48–2.40 (m, 1H), 1.88–1.26 (m,
8H), 0.75 (s, 9H), ꢁ0.03 (s, 3H), ꢁ0.18 (s, 3H); 13C NMR
(125 MHz, CDCl3) d 144.3, 142.8, 129.5, 123.7, 122.4,
69.7, 46.0, 33.3, 25.7, 25.3, 24.7, 20.4, 17.9, ꢁ4.3, ꢁ5.1;
MS (CI) m/z (relative intensity) 409 ([M+1]+, 84%), 277
(22%), 168 (100%). Anal. Calcd for C25H36N2OSi: C,
73.48; H, 8.88; N, 6.86. Found: C, 73.43; H, 8.99; N, 6.70.
To a solution of the hydrazone obtained as described above
(490 mg, 1.20 mmol) in THF (12 mL) was added tetrabutyl-
ammonium fluoride (1 M in THF, 1.4 mL, 1.4 mmol). After
30 min, the reaction was concentrated and filtered through
silica gel, eluting with ethyl acetate. Concentration afforded
4.1.4. 1,1-Dibenzyl-2-((S)-1-((2S,4R,5R)-5-benzyloxy-2-
phenyl-1,3-dioxan-4-yl)allyl)hydrazine (14). To a solution
of hydrazine 8 (219 mg, 0.509 mmol) in CH2Cl2 (25 mL)
was added N,N-dimethylaminopyridine (93 mg, 0.76 mmol)
followed by benzoic anhydride (173 mg, 0.764 mmol). After
3 h, additional benzoic anhydride was added (151 mg,
0.667 mmol). After another 4 h, concentration and flash
chromatography (10:1 hexane/EtOAc) afforded 14 (326 mg,
100%) as a yellow oil. This material contained an unidenti-
fied benzoyl-derived compound in a ratio of ca. 1.5:1. IR
(film) 3031, 1718, 1694, 1452, 1271, 1092 cmꢁ1; 1H NMR

G. K. Friestad, A. K. Mathies / Tetrahedron 63 (2007) 9373–9381
9379
16 (280 mg, 79%) as a colorless oil. IR (film) 3432 (br),
2930, 2847, 1590, 1495, 1296, 1211 cmꢁ1 1H NMR
ethyl acetate. Concentration afforded 20 (96%) as a colorless
oil. [a]2D3 +3.77 (c 0.610, CHCl3); IR (film) 2922, 1596,
;
(300 MHz, CHCl3) d 7.49–7.28 (m, 4H), 7.18–7.02 (m,
6H), 6.58 (d, J¼3.9 Hz, 1H), 4.26–4.21 (m, 1H), 2.45–
2.28 (m, 1H), 1.94–1.22 (m, 9H); 13C NMR (75 MHz,
CDCl3) d 143.7, 142.2, 129.8, 124.2, 122.3, 68.0, 44.0,
32.1, 25.8, 25.0, 20.9; MS (CI) m/z (relative intensity) 317
([M+Na]+, 15%), 295 ([M+1]+, 100%), 277 (12%), 168
(27%); HRMS (EI) calcd for C19H22N2O 294.1734, found
294.1732.
1493, 1452, 1098, 1012 cmꢁ1 1H NMR (300 MHz,
;
CDCl3) d 7.47–7.44 (m, 2H), 7.36–7.19 (m, 13H), 6.43 (d,
J¼6.44 Hz, 1H), 6.00–5.65 (m, 3H), 5.52 (s, 1H), 4.38
(ABq, J¼15.4 Hz, Dn¼16.1 Hz, 4H), 4.21–4.11 (m, 2H),
3.75 (ddd, J¼10.9, 10.0, 5.0 Hz, 1H), 3.61 (t, J¼10.3 Hz,
1H), 0.11 (s, 3H), 0.07 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 137.7, 137.5, 137.2, 133.7, 129.7, 128.8, 128.5,
128.2, 127.7, 127.2, 126.2, 100.8, 82.9, 71.6, 64.9, 57.6,
ꢁ1.5, ꢁ1.7; MS (CI) m/z (relative intensity) 487 ([M+1]+,
100%), 403 (10%), 381 (14%). Anal. Calcd for
C29H34N2O3Si: C, 71.57; H, 7.04; N, 5.76. Found: C,
71.52; H, 7.26; N, 5.75.
4.1.7. rac-2-((cis-2-(Dimethylvinylsilyloxy)cyclohexyl)-
methylene)-1,1-diphenylhydrazine (17). To a solution of
hydrazone 16 (90 mg, 0.306 mmol), triethylamine
(0.05 mL, 0.34 mmol), and N,N-dimethylaminopyridine
(4 mg) in THF (3 mL) was added dimethylvinylchlorosilane
(0.05 mL, 0.34 mmol). After 4 h, the reaction mixture was
concentrated and filtered through silica gel, eluting with
ethyl acetate. Concentration afforded 17 (102 mg, 88%) as
a colorless oil. IR (film) 2930, 2848, 1590, 1495, 1252,
4.1.10. 1,1-Dibenzyl-2-(1-((2R,4S,5R)-5-hydroxy-2-
phenyl-1,3-dioxan-4-yl)allyl)hydrazine (21). To a solution
of hydrazone 20 (964 mg, 1.98 mmol) in refluxing deoxy-
genated benzene (20 mL) was added a solution of AIBN
(325 mg, 1.98 mmol) and thiophenol (0.63 mL, 5.94 mmol)
in deoxygenated benzene (8 mL) over 16 h. After an addi-
tional 10 h under reflux, tetrabutylammonium fluoride
(1 M in THF, 4.4 mL, 4.4 mmol) was added and the mixture
was allowed to cool to ambient temperature. After 24 h, con-
centration and flash chromatography (10:1 to 1:1 Hex/
EtOAc) afforded 21 (452 mg, 53%, dr 70:30) as a colorless
oil. Diastereomer 1: [a]2D5 +7.0 (c 0.90, CHCl3); IR (film)
1
1019 cmꢁ1; H NMR (300 MHz, CHCl3) d 7.41–7.29 (m,
4H), 7.16–7.04 (m, 6H), 6.54 (d, J¼5.8 Hz, 1H), 6.07–
5.80 (m, 2H), 5.63 (dd, J¼18.5, 5.8 Hz, 1H), 4.04–3.79
(m, 1H), 2.56–2.23 (m, 1H), 1.91–1.15 (m, 8H), 0.01 (s,
6H); 13C NMR (75 MHz, CDCl3) d 144.4, 143.0, 138.1,
132.5, 129.6, 123.7, 122.4, 70.2, 45.6, 33.2, 25.2, 24.6,
20.5, ꢁ1.4, ꢁ1.5; MS (EI) (relative intensity) m/z 378
(M+, 55%), 276 (8%), 195 (12%), 167 (100%); HRMS
(EI) calcd for C23H30N2OSi 378.2129, found 378.2127.
3580, 3384 (br), 3030, 2925, 2853, 1453, 1392, 1075 cmꢁ1
;
1H NMR (500 MHz, CDCl3) d 7.48–7.30 (m, 15H), 5.90
(ddd, J¼17.8, 10.1, 7.7 Hz, 1H), 5.44 (s, 1H), 5.30 (d, J¼
10.3 Hz, 1H), 5.29 (d, J¼17.1 Hz, 1H), 4.18 (dd, J¼10.5,
5.0 Hz, 1H), 3.81–3.65 (m, 7H), 3.47 (dd, J¼10.5, 10.5 Hz,
1H), 3.38 (br s, 1H), 2.94 (br s, 1H); 13C NMR (125 MHz,
CDCl3) d 137.8, 137.1, 135.4, 129.6, 128.9, 128.4, 128.2,
127.5, 126.2, 118.2, 101.4, 80.8, 70.8, 63.2, 63.0, 59.9; MS
(EI) m/z (relative intensity) 430 (M+, 27%), 429 (100%), 339
(10%), 282 (45%), 251 (15%). Anal. Calcd for C27H30N2O3:
C, 75.32; H, 7.02; N, 6.51. Found: C, 75.08; H, 7.28; N, 6.33.
Diastereomer 2: [a]2D5 ꢁ4.6 (c 0.85, CHCl3); IR (film) 3399
4.1.8. 1,1-Dibenzyl-2-(((2R,4S,5R)-5-hydroxy-2-phenyl-
1,3-dioxan-4-yl)methylene)hydrazine (19). To a mixture
of 4,6-O-benzylidene-D-glucose (2.73 g, 13.1 mmol) and
NaHCO3 (3.3 g, 39 mmol) was added a solution of NaIO4
(6.44 g, 30.1 mmol) in water (60 mL) over 30 min. After
2 h, the mixture was concentrated to a white solid, which
was triturated four times with hot EtOAc. The soluble por-
tion was concentrated to afford the crude aldehyde, which
was taken up in toluene (40 mL). To this solution was added
dibenzylhydrazine (3.0 g, 14 mmol). After 36 h, concentra-
tion and flash chromatography (10:1 to 1:1 hexanes/ethyl
acetate) afforded a solid, which was recrystallized from di-
ethyl ether/petroleum ether to afford 19 (3.83 g, 73%) as
a colorless solid; mp 44.0–44.5 ꢂC. [a]D24 ꢁ6.47 (c 0.665,
CHCl3); IR (film) 3444 (br), 3030, 2852, 1955, 1601,
1
(br), 3031, 2854, 1495, 1452, 1391, 1075 cmꢁ1; H NMR
(300 MHz, CDCl3) d 7.41–7.27 (m, 15H), 5.73 (ddd,
J¼17.3, 10.2, 8.5 Hz, 1H), 5.29 (s, 1H), 5.24 (dd, J¼17.3,
1.0 Hz, 1H), 5.21 (dd, J¼10.2, 1.6 Hz, 1H), 4.23 (dd, J¼
8.6, 3.1 Hz, 1H), 3.86 (d, J¼13.0 Hz, 2H), 3.70 (d, J¼
13.1 Hz, 2H), 3.62–3.43 (m, 4H), 3.36 (dd, J¼8.4, 7.1 Hz,
1H), 2.94 (br, 1H); 13C NMR (125 MHz, CDCl3) d 137.8,
136.7, 136.5, 129.7, 128.7, 128.6, 128.4, 128.1, 127.6,
125.9, 118.4, 100.4, 82.1, 65.7, 65.3, 60.9; MS (CI) m/z (rel-
ative intensity) 431 ([M+1]+, 100%), 301 (100%). Anal.
Calcd for C27H30N2O3: C, 75.32; H, 7.02; N, 6.51. Found:
C, 75.31; H, 7.20; N, 6.45.
1392, 1075 cmꢁ1 1H NMR (500 MHz, CDCl3) d 7.48–
;
7.25 (m, 15H), 6.64 (d, J¼2.35 Hz, 1H), 5.50 (s, 1H), 4.38
(s, 4H), 4.36 (dd, J¼10.8, 5.2 Hz, 1H), 4.19 (dd, J¼8.8,
2.7 Hz, 1H), 3.97 (ddd, J¼9.5, 9.0, 5.1 Hz, 1H), 3.70 (dd,
J¼10.5, 10.5 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 37.4, 136.7, 129.0, 128.7, 128.3, 127.8, 127.5, 127.4,
126.1, 101.3, 80.4, 70.1, 65.2, 57.8; MS (CI) m/z (relative in-
tensity) 403 ([M+1]+, 100%), 301 (100%). Anal. Calcd for
C25H26N2O3: C, 74.60; H, 6.51; N, 6.96. Found: C, 74.87;
H, 6.64; N, 6.89.
4.1.11. 1,1-Dibenzyl-2-(((2S,4R,5R)-2-phenyl-5-(prop-2-
ynyloxy)-1,3-dioxan-4-yl)methylene)hydrazine (22). To
a mixture of potassium hydride (30% in mineral oil, 71 mg,
0.53 mmol) in THF (1 mL) was added a solution of 7
(192 mg, 0.48 mmol) in THF (1 mL) over 20 min. Sodium
iodide (72 mg, 0.48 mmol) was added, followed by prop-
argyl bromide (0.08 mL, 0.72 mmol). After 16 h, concentra-
tion and recrystallization from 3:1 hexanes/ethyl acetate
afforded 22 (195 mg, 92%) as a light yellow solid; mp 49–
50 ꢂC. [a]D25 ꢁ23.0 (c 0.95, CHCl3); IR (film) 3288, 3030,
4.1.9. 1,1-Dibenzyl-2-(((2R,4S,5R)-5-(dimethyl(vinyl)si-
lyloxy)-2-phenyl-1,3-dioxan-4-yl) methylene)hydrazine
(20). To a solution of 19 (835 mg, 2.07 mmol), triethylamine
(0.87 mL, 6.2 mmol), and N,N-dimethylaminopyridine
(25 mg, 0.207 mmol) in THF (21 mL) was added dimethyl-
vinylchlorosilane (0.86 mL, 6.2 mmol). After 4 h, the reac-
tion mixture was filtered through silica gel, eluting with
1
2850, 2105, 1599, 1452, 1075 cmꢁ1; H NMR (500 MHz,

9380
G. K. Friestad, A. K. Mathies / Tetrahedron 63 (2007) 9373–9381
CDCl3) d 7.56–7.46 (m, 2H), 7.37–7.20 (m, 13H), 6.67 (d,
J¼6.1 Hz, 1H), 5.63 (s, 1H), 4.58 (dd, J¼6.1, 1.8 Hz, 1H),
4.43 (dd, J¼12.5, 1.5 Hz, 1H), 4.42 (ABq, J¼15.4 Hz, Dn¼
23.0 Hz, 4H), 4.04 (dd, J¼16.4, 2.4 Hz, 1H), 4.02 (dd, J¼
12.5, 1.5 Hz, 1H), 3.89 (dd, J¼16.4, 2.3 Hz, 1H), 3.59 (d,
J¼1.7 Hz, 1H), 2.30 (t, J¼2.4 Hz, 1H); 13C NMR (125 MHz,
CDCl3) d 137.9, 137.5, 131.1, 128.8, 128.5, 128.1, 127.7,
127.2, 126.2, 101.2, 80.4, 79.7, 74.5, 72.1, 68.8, 57.6, 57.0;
MS (CI) m/z (relative intensity) 441 (M+, 100%), 335
(30%). Anal. Calcd for C28H28N2O3: C, 76.34; H, 6.41; N,
6.36. Found: C, 76.51; H, 6.37; N, 6.44.
3.18 (d, J¼12.6 Hz, 2H), 2.62 (d, J¼1.3 Hz, 1H), 1.88 (s,
1H); 13C NMR (75 MHz, CDCl3) d 140.8, 138.2, 137.7,
130.0, 128.7, 128.2, 128.0, 127.3, 126.3, 115.2, 101.2,
75.2, 70.2, 68.1, 66.0, 60.9, 60.0; MS (EI) m/z (relative inten-
sity) 442 (M+, 3%), 351 (5%), 211 (50%), 91 (50%). Anal.
Calcd for C28H30N2O3: C, 75.99; H, 6.83; N, 6.33. Found:
C, 75.63; H, 6.81; N, 6.13.
4.1.14. (2R,3R)-4-(2,2-Dibenzylhydrazinyl)-2-(hydroxy-
methyl)-5-methylene-tetrahydro-2H-pyran-3-ol (25). To
a solution of 24 (65 mg, 0.15 mmol) in methanol (0.7 mL)
was added p-toluenesulfonic acid (7 mg). After 1 h, concen-
tration and flash chromatography (1:1 to 1:3 hexanes/ethyl
acetate) afforded 25 (40 mg, 75%) as a yellow oil. [a]D23
ꢁ49.5 (c 0.810, CHCl3); IR (film) 3583, 3415 (br), 2924,
4.1.12. 1,1-Dibenzyl-2-((2S,4aR,8S,8aR)-2-phenyl-7-
((tributylstannyl)methylene)-hexa-hydropyrano[3,2-
d][1,3]dioxin-8-yl)hydrazine (23). To a solution of 22
(54 mg, 0.123 mmol) in deoxygenated DMF (6.2 mL) at
80 ꢂC was added a solution of AIBN (10 mg, 0.062 mmol)
and tributyltin hydride (0.04 mL, 0.15 mmol) in deoxygen-
ated DMF (0.5 mL) over 12 h via a syringe pump. After an
additional 10 h at 80 ꢂC, the mixturewas partitioned between
brine (20 mL) and diethyl ether (2ꢃ20 mL). The organic
phase was washed with brine (2ꢃ40 mL), dried, and concen-
trated. Flash chromatography (10:1 to 3:1 hexanes/ethyl ace-
tate) afforded 23 (81 mg, 90%) as a light yellow oil. [a]D26
ꢁ77.6 (c 0.650, CHCl3); IR (film) 2925, 2851, 1603, 1453,
1
1493, 1452, 1067, 920 cmꢁ1; H NMR (300 MHz, CDCl3)
d 7.39–7.25 (m, 10H), 5.11 (s, 1H), 5.05 (s, 1H), 4.02–
3.86 (m, 4H), 3.68 (dd, J¼9.3, 2.7 Hz, 1H), 3.48–3.25 (m,
5H), 2.95–2.90 (m, 1H), 2.33 (br s, 1H), 2.29 (d,
J¼9.2 Hz, 1H), 1.64 (t, J¼6.3 Hz, 1H); 13C NMR
(75 MHz, CDCl3) d 141.2, 137.9, 129.9, 128.2, 127.2,
116.9, 73.8, 69.7, 68.9, 64.0, 62.4, 61.0; MS (CI) m/z (rela-
tive intensity) 377 ([M+Na]+, 60%), 355 ([M+1]+, 100%),
355 (10%), 301 (15%). Anal. Calcd for C21H26N2O3: C,
71.16; H, 7.39; N, 7.90. Found: C, 71.66; H, 7.69; N, 7.85.
1
1396, 1370, 1112, 1091, 1018 cmꢁ1; H NMR (300 MHz,
CDCl3) d 7.51–7.24 (m, 15H), 5.82 (s, 1H, satellite peaks in-
dicated JSn–H¼60.4 Hz), 5.35 (s, 1H), 4.1 (d, J¼12.4 Hz,
1H), 3.95–3.82 (m, 4H), 3.75 (d, J¼1.3 Hz, 1H), 3.50–3.45
(m, 3H), 3.38 (dd, J¼12.4, 1.6 Hz, 1H), 2.47 (s, 1H), 2.15
(s, 1H), 1.60–1.38 (m, 6H), 1.36–1.18 (m, 6H), 0.87–0.80 (m,
15H); 13C NMR (75 MHz, CDCl3) d 149.5, 138.5, 137.8,
130.1, 129.9, 128.8, 128.2, 128.1, 127.2, 126.5, 101.5, 75.4,
70.0, 69.8, 65.7, 63.9, 60.7, 29.1, 27.2, 13.7, 10.3; MS (CI)
m/z (relative intensity) 733 ([M+1]+, 70%), 732 (90%), 442
(42%), 212 (100%). Anal. Calcd for C40H56N2O3Sn: C,
65.67; H, 7.72; N, 3.83. Found: C, 65.94; H, 7.98; N, 3.55.
4.1.15. 1,1-Dibenzyl-2-((2R,3R)-3-benzoyloxy-2-(benzoyl-
oxymethyl)-5-methylene tetrahydro-2H-pyran-4-yl)hydr-
azine (26). To a solution of 25 (72 mg, 0.203 mmol),
triethylamine (0.07 mL, 0.81 mmol), N,N-dimethylamino-
˚
pyridine (10 mg), and 4 A MS in CH2Cl2 (2 mL) was added
benzoyl chloride (0.09 mL, 0.81 mmol). After 12 h, the re-
action mixture was poured into brine (10 mL), extracted
with CH2Cl2 (2ꢃ10 mL), dried, and concentration and flash
chromatography (1:1 petroleum ether/EtOAc) afforded 26
(111 mg, 97%) as a light yellow solid; mp 144–147 ꢂC. IR
(film) 3583, 3064, 3031, 2847, 1722, 1712, 1451, 1268,
1
1111 cmꢁ1; H NMR (300 MHz, CDCl3) d 8.42–6.88 (m,
4.1.13. 1,1-Dibenzyl-2-((2S,4aR,8S,8aR)-7-methylene-2-
phenyl-hexa-hydropyrano[3,2-d][1,3]dioxin-8-yl)hydr-
azine (24). A solution of 22 (344 mg, 0.781 mmol), AIBN
(64 mg, 0.39 mmol), and tributyltin hydride (0.26 mL,
0.94 mmol) in deoxygenated DMF (35 mL) was heated at
80 ꢂC for 16 h. The mixture was partitioned between brine
(50 mL) and diethyl ether (2ꢃ50 mL). The organic phase
was washed with brine (2ꢃ75 mL), dried, and concentrated.
The residue was dissolved in THF (16 mL) and n-butyl-
lithium (1.6 M in THF, 1.22 mL, 1.95 mmol) was added at
ꢁ78 ꢂC. After 1 h propionic acid (0.12 mL, 1.64 mL) was
added. Concentration and flash chromatography (10:1 to
1:1 hexanes/ethyl acetate) afforded 24 (265 mg, 80%) as
a colorless solid. [a]D24 ꢁ25.2 (c 1.10, CHCl3); IR (film)
3411, 3064, 3027, 2923, 2848, 1452, 1090, 1023 cmꢁ1; 1H
NMR (300 MHz, CDCl3) d 7.52–7.25 (m, 15H), 5.41 (s,
1H), 5.06 (s, 1H), 5.04 (s, 1H), 4.03 (s, 1H), 3.97 (d,
J¼12.7 Hz, 2H), 3.90 (dd, J¼12.3, 1.3 Hz, 1H), 3.81 (dd,
J¼2.2, 1.1 Hz, 1H), 3.54 (d, J¼2.4 Hz, 1H), 3.50 (d, J¼
12.7 Hz, 2H), 3.44 (dd, J¼12.4, 1.8 Hz, 1H), 2.51 (d,
J¼1.2 Hz, 1H), 2.41 (br s, 1H); 1H NMR (600 MHz,
C6D6) d 7.73–7.66 (m, 2H), 7.32–6.92 (m, 13H), 5.53 (s,
1H), 4.77 (s, 1H), 4.76 (s, 1H), 4.14 (dd, J¼12.2, 1.3 Hz,
1H), 4.00 (s, 2H), 3.90–3.88 (m, 1H), 3.67 (d, J¼12.6 Hz,
2H), 3.53 (d, J¼2.3 Hz, 1H), 3.43 (dd, J¼12.2, 1.8 Hz, 1H),
20H), 5.39 (d, J¼2.2 Hz, 1H), 5.08 (s, 1H), 4.96 (s, 1H),
4.19 (dd, J¼11.6, 8.2 Hz, 1H), 4.15 (d, J¼11.7 Hz, 1H),
4.05 (d, J¼11.9 Hz, 1H), 4.02 (d, J¼11.9 Hz, 2H), 3.87
(dd, J¼11.6, 3.5 Hz, 1H), 3.69 (d, J¼2.5 Hz, 1H), 3.49 (d,
J¼12.5 Hz, 2H), 3.32 (dd, J¼8.0, 3.3 Hz, 1H), 2.45 (br s,
1H); 13C NMR (125 MHz, CDCl3) d 166.2, 165.7, 140.8,
137.9, 133.0, 132.8, 130.1, 130.0, 129.9, 129.8, 129.7,
128.4, 128.3, 128.2, 127.3, 115.8, 70.7, 70.6, 68.3, 64.9,
60.9, 59.2; MS (EI) m/z (relative intensity) 563 (M+, 1%),
429 (25%), 325 (100%), 254 (25%), 221 (20%); HRMS
(EI) calcd for C35H34N2O5 562.2469, found 562.2473.
Acknowledgements
We thank NIH (NIGMS, GM-67183) for generous support of
this work.
Supplementary data
1H NMR peak assignments and NOESY results for 15, 24,
and 26 were provided. Supplementary data associated with
this article can be found in the online version, at
doi:10.1016/j.tet.2007.06.117.

G. K. Friestad, A. K. Mathies / Tetrahedron 63 (2007) 9373–9381
9381
Yamashita, K.; Kiguchi, T. Heterocycles 2000, 53, 2611–
2615; (j) Sasaki, M.; Maruyama, T.; Sakai, R.; Tachibana, K.
Tetrahedron Lett. 1999, 40, 3195–3198.
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1
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