Synthesis of aromatic sphingosine analogues by diastereoselective amination of enantioenriched trans-γ,δ-unsaturated β-hydroxyesters

Article abstract of DOI:10.1021/jo501533g

An effective route to N-Boc-protected aromatic sphingosine analogues is accomplished. The strategy is based on the diastereoselective amination of enantioenriched trans-γ,δ-unsaturated β-hydroxyesters to establish anti,N-Boc-α-hydrazino-β-hydroxyesters. N

Full text of DOI:10.1021/jo501533g

Note
pubs.acs.org/joc
Synthesis of Aromatic Sphingosine Analogues by Diastereoselective
Amination of Enantioenriched trans-γ,δ-Unsaturated β‑Hydroxyesters
Zhipeng Dai and Thomas K. Green*
Department of Chemistry and Biochemistry, Institute of Arctic Biology, University of Alaska, Fairbanks, Alaska 99775, United States
S
* Supporting Information
ABSTRACT: An effective route to N-Boc-protected aromatic
sphingosine analogues is accomplished. The strategy is based
on the diastereoselective amination of enantioenriched trans-
γ,δ-unsaturated β-hydroxyesters to establish anti,N-Boc-α-
hydrazino-β-hydroxyesters. Nonreductive E1cB elimination is
essential for the successful N−N bond cleavage of hydrazine
while preserving the trans double bond. Either the (3R,2S) and
(3S,2R) enantiomer of N-Boc-protected sphingosine analogues
has been synthesized in five steps with excellent optical purity
with ∼99% ee and >99% de.
phingolipids serve as extra- and intracellular mediators in
cell signaling,1−5 including regulation of antiproliferative
biological activities of several aromatic ceramide analogues,
which were able to reverse fumonisin B1 (FB1) inhibited
ceramide synthesis.18,19 Murakami et al. made aromatic
sphingosine derivatives, which have been suggested as EDG/
S1P receptor (endothelial differentiation gene family of
sphingosine 1 phosphate receptors) inhibitors that block S1P-
mediated Ca2+ increase.21 In 2011, several aromatic ceramide
analogues were synthesized by Moreno et al.25
S
and apoptotic responses in various cancer cells,6,7 serving as
messengers for controlling cell growth, maturity, survival, and
death. To date, over 70 syntheses of analogues of (−)-D-erythro-
sphingosine, which serves as the backbone of the majority of
sphingolipids, have been reported.8−16 With the emergence of
the aromatic sphingosine analogue FTY720 (Figure 1) for the
Most syntheses of sphingosine analogues use the amino acid
L-serine as starting material,18,20,21,24,25,27,31,32 but there are
limitations with this approach as discussed by Yang and
Liebeskind.9 Specifically, few methods based on L-serine are
able to deliver sphingosine in >99% ee. Yang and Liebeskind
report one of the few exceptions using peptidyl thiol ester−
boronic acid cross-coupling. They were able to achieve high
enantiopurity of (−)-D-erythro-sphingosine in 71% yield over
six steps starting with N-Boc-L-serine. High diastereoselectivity
was also achieved with de >94%, which was improved to 99%
through recrystallization.
Figure 1. Structures of aromatic sphingosine analogues with biological
activity.
Given the potential high value of sphingosine analogues as
described above,17−28 alternative syntheses which are not L-
serine-based may be of synthetic value if they are highly
stereoselective, provide good yields in a reasonable number of
steps, are scalable, and provide versatility in the potential
number of sphingosine analogues that it can provide. Herein we
report an alternative synthetic route to obtain a family of
aromatic sphingosine analogues. The route employs trans-γ,δ-
unsaturated β-hydroxyesters as starting materials, as shown in
Figure 2. Enantioenriched (R)-1A, (R)-1B, and (S)-1B (≥99%
ee) were recently prepared for the first time in our lab by
reduction of the corresponding trans-γ,δ-unsaturated β-
treatment of multiple sclerosis,17 the development of other
aromatic analogues of sphingosine have received increased
attention compared to natural sphingosines due to their
enhanced aqueous solubility, cell permeability, and bioactiv-
ity.18−28 Kim et al. produced sphingosine analogue SG-12,
which possesses an aromatic ring in place of the unsaturated
C
14 and lacks the C4−C5 trans double bond.22 SG-12 exhibited
specific inhibitory effects against sphingosine kinase 2. A
synthesis of BML-258 was the subject of a patent by Zipkin24
utilizing Garner aldehyde-based strategies. BML-258 is a water-
soluble sphingosine analogue, which is evaluated as an SK1
selective inhibitor and shown to be efficacious both in vitro and
in vivo.29,30 Van Overmeire et al. synthesized and evaluated the
Received: July 10, 2014
© XXXX American Chemical Society
A
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Figure 2. Structure of trans-γ,δ-unsaturated β-hydroxyesters. Enantioenriched (≥99%) (R)-1A, (R)-1B, and (S)-1B were prepared from reduction of
corresponding trans-γ,δ-unsaturated β-ketoesters by ketoreductases.33 (S)-1A (ee 75%) was prepared according to the literature.34 Racemic-1C and
racemic-1D were prepared from reduction of corresponding trans-γ,δ-unsaturated β-ketoesters by NaBH4.
Scheme 1. General Reaction Scheme for the Stereospecific Synthesis of Ceramide and Sphingosine Derivatives from trans-γ,δ-
Unsaturated β-(S)-Hydroxyesters (S)-1A and (S)-1B
ketoesters with ketoreductases (KRED).33 Our ability to
produce highly stereochemically enriched sphingosine ana-
logues by the described synthetic route is dependent on the use
of these enantioenriched starting materials.
according to the method of Genet
̂
and co-workers.36−39 In
order to obtain high diastereoisomeric excesses, the zinc
enolate form of β-hydroxyesters 1 was required by adding 1.1
equiv of MeZnBr followed by 2 equiv of LDA. Then,
electrophilic amination was achieved through Michael addition
after addition of DBAD with a yield of 50−60%. Unreacted β-
hydroxyesters 1 could be recovered without racemization. Due
to the rigid zinc enolate form of β-hydroxyesters 1, the anti-
configurational relationship of diastereoisomer between the
hydroxyl and hydrazino functionalities was obtained with
excellent diastereoisomeric excesses of >99%.
The synthetic pathway is displayed in Scheme 1, which
shows the stereoselective synthesis of sphingosine analogues
starting from trans-γ,δ-unsaturated β-hydroxyesters (S)-1A
(75% ee) and (S)-1B (≥99% ee). Racemic-1C, racemic-1D,
and highly enantioenriched (R)-1A and (R)-1B (≥99% ee)
were also used as starting materials. The configurations,
diastereoisomeric excesses, and isolated yields of all inter-
mediates and final sphingosine analogues are listed in Table 1.
The N-protected sphingosine analogues are obtained in 32−
41% yield in five or six steps from the trans-γ,δ-unsaturated β-
hydroxyesters 1. The use of enantioenriched (R)-1A, (R)-1B,
and (S)-1B results in products of (R)-7A, (R)-7B, and (S)-7B
with 99.6, 99.2, and 98.8% ee, respectively, as determined by
chiral capillary electrophoresis, and with >99% de as
determined by quantitative NMR techniques.35
Although syn-diastereoisomers were not available for
comparison, we observed no quantifiable minor resonances in
1
the H NMR spectra of intermediates 2 using quantitative
techniques for diastereomer detection,35 thus establishing a
1
minimum of 99% de for intermediates 2. Also, the H NMR
chemical shifts of both (2S,3R)-7A (anti) and (2S,3S)-7A (syn)
have been reported,40 which show significant differences in
their 3.0−5.5 ppm spectral regions. Whereas our anti-7A
spectrum agrees well with the literature, we observe no
resonances for the syn product, although 13C NMR satellite
The diastereoselective formation of anti-N-Boc-α-hydrazino-
β-hydroxyesters 2 was performed via electrophilic amination of
β-hydroxyesters 1 with di-tert-butylazodicarboxylate (DBAD)
B
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Table 1. Configuration, Diastereoisomeric Excesses and Isolated Yields of All Intermediates Synthesized from Corresponding
Racemic and Enantioenriched trans-γ,δ-Unsaturated β-Hydroxyesters
a
b
Numbering system corresponds to compound names in the Experimental Section. The percent ee was measured by chiral capillary electrophoresis
35
1
and HPLC, and the percent de was measured by quantitative H NMR techniques.
resonances could be quantified, consistent with a minimum of
99% de in the final products.35
protected ketal 6 in 87% yield. Alternatively, in the specific
cases of (S)-4A and racemic-4C, the ketal was refluxed with
methyl bromoacetate and Cs2CO3 in acetonitrile to directly
yield 6 in 94 and 93% yield, respectively. The one-step reaction
significantly improves the yield and is preferred. Compound 6
was conveniently deprotected to obtain the N-Boc-protected 7
in 92−96% yield. Chiral HPLC was employed to all
intermediates, which demonstrate that high stereochemical
purity was preserved throughout the pathway of 2 to 7. Chiral
capillary electrophoresis, using sulfoalkylated cyclodextrins as
chiral selectors,44,45 was also applied to (R)-7A, (R)-7B, and
(S)-7B to quantitatively establish 99.6, 99.2, and 98.8% ee,
respectively, for these final products.
The Garner aldehyde (serine-derived oxazolidine) route to
aromatic ceramide analogues18,24,40 is a well-established
synthetic route to the aromatic substrates described here. For
example, Van Overmeire et al. synthesized a series of related
compounds including (2S,3R)-7A in 35% yield in three steps
from the serine-derived aldehyde.18 Murakami and Furusawa
also synthesized this molecule with a modified Garner aldehyde
route in 43% yield in two steps by alkenylation in place of
alkynylation.40 Diastereoselectivity in the alkenylation step was
modest with anti/syn ratio of 15:1, which required further
purification, reducing the overall yield to 11%. Zipkin et al.
A number of methods are available for cleaving N−N bonds
of hydrazines to obtain the corresponding amino products, but
most of these methods involve exposure to either reductive or
oxidative conditions.41 Recently, nonreductive cleavage of the
N−N bond of several diethoxycarbonyl hydrazine derivatives
was reported by Magnus et al.,41 and several of their reactions
illustrated the advantage of using nonreductive conditions to
preserve a carbon−carbon double bond in the substrate.
However, efforts using similar conditions to cleave the N−N
bond of intermediates 2 were unsuccessful, with a complex
mixture of products forming. Therefore, hydroxyester 2 was
effectively reduced to the diol 3 with excess NaBH4 in
methanol,42,43 followed by protection of diol 3 in the form of
ketal 4 in 94% yield. We then found that the N−N bond of the
di-tert-butylcarbonyl hydrazine derivatives 4 could be conven-
iently cleaved using the same E1cB reaction conditions
employed by Magnus et al.41 This reaction can be performed
in either one or two steps. In two steps, ketal 4 was N-alkylated
with methyl bromoacetate in the presence of Cs2CO3 at 50 °C
to obtain alkylated ketal 5 which was isolated and purified in
98% yield. Alkylated ketal 5 was then reacted further at reflux
with Cs2CO3 to undergo N−N bond cleavage to N-Boc-
C
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synthesized a precursor to BML-25824 which differs only
slightly from (2R,3S)-7B (para-pentyl versus para-butyl group)
in three steps from the Garner aldehyde in 34% overall yield.
Diastereoselectivity was modest with anti/syn ratio of 7.5:1.
Our synthesis compares well with the synthetic scheme of
Moreno et al.,25 who used a chiral epoxide as starting material
to produce (2S,3R)-7A in five steps with an overall yield of 16%
yield. Our synthesis also compares well to that of Yang and
Liebeskind, whose synthesis of (−)-D-erythro-sphingosine in six
steps was 71% from N-Boc-L-serine. Our lower overall yield is
primarily attributed to inefficiency of the electrophilic
amination of β-hydroxyesters 1 to anti-N-Boc-α-hydrazino-β-
hydroxyesters 2, with yields of 50−60%, which are similar to
yields reported by Greck et al.22
We have developed an effective route for synthesis of
sphingosine analogues starting from racemic and enantio-
merically enriched trans-γ,δ-unsaturated β-hydroxyesters. The
synthetic pathway can be accomplished in five or six steps in
32−41% overall yield. Strategies of diastereoselective formation
of hydrazino and nonreductively eliminatived cleavage of the
hydrazino N−N bonds are essential to the stereoselective
formation of an amino group. Either (2S,3R) or (2R,3S)
enantiomer of aromatic sphingosine analogues is synthesized
with ∼99% ee and ∼99% de. No loss of stereochemistry is
detected over the entire synthesis.
anhydrous THF at 0 °C was added 1.1 equiv of zinc methyl bromide
(1.1 mmol, 0.4 M in THF). The reaction mixture was stirred for 1 h.
After the reaction mixture was cooled to −78 °C, 2.0 equiv of LDA
(2.0 mmol, 2 M in heptane/THF/ethylbenzene) was added dropwise.
After 1 h at −78 °C, 2.0 equiv of DBAD (2.0 mmol) in 1.0 mL of
anhydrous THF was added slowly, and the reaction mixture was
stirred for another 2 h. Addition of 4.0 mL of saturated NH4Cl
solution (aq) was used to quench the reaction at −78 °C followed by
warming to room temperature. The mixture was concentrated in vacuo
at 60−70 °C, and the resulting mixture was extracted with EtOAc (2 ×
10 mL). The combined extracts were dried over anhydrous Na2SO4
and concentrated in vacuo to afford crude product. Purification was by
column chromatography on silica gel using 100% CH2Cl2 to elute
unreacted DBAD, then gradient elution using 10:1 CH2Cl2/EtOAc
eluent to afford anti-N-Boc-α-hydrazino-β-hydroxyesters 2.
(E)-Di-tert-butyl 1-(1-Ethoxy-3-hydroxy-1-oxo-5-phenylpent-4-
en-2-yl)hydrazine-1,2-dicarboxylate (2A): (2S,3S)-2A (287 mg,
23
590
58%); white solid, mp 153−155 °C; [α] +105 (c = 1.71, CHCl3);
(2R,3R)-2A (184 mg, 58%); white solid, mp 154−155 °C.
Diastereomeric excess (de) >99% (anti): 1H NMR (300 MHz,
CDCl3) δ 7.15−7.28 (5H), 6.77 (s, 1H), 6.65 (dd, J = 3.0, 15.0 Hz,
1H), 6.15 (dd, J = 3.0 Hz, 15.0 Hz, 1H), 5.09−5.37 (br, 1H), 4.90 (m,
1H), 4.53−4.72 (br, 1H), 4.23 (m, J = 6.0 Hz, 2H), 1.45 (s, 9H), 1.28
(t, J = 6.0 Hz, 3H), 1.26 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 169.5,
169.3, 156.6, 155.0, 137.0, 129.8, 128.4, 127.9, 127.4, 126.5, 83.1, 82.4,
82.1, 69.8, 65.6, 63.4, 61.6, 28.0, 14.3; HRMS (ESI-TOF) calcd for
C23H34N2O7Na (M + Na)+ 473.2264, found 473.2271.
(E)-Di-tert-butyl 1-(5-(4-Butylphenyl)-1-ethoxy-3-hydroxy-1-oxo-
pent-4-en-2-yl)hydrazine-1,2-dicarboxylate (2B): (2S,3S)-2B (164
23
590
EXPERIMENTAL SECTION
mg, 50%); white solid, mp 125−127 °C; [α] +130 (c = 0.23,
■
CHCl3); (2R,3R)-2B (228 mg, 60%); slightly yellow solid, mp 124−
General Experimental Methods. All chemicals were of the
highest purity unless otherwise noted. Zinc bromide was dried in an
oven at 110 °C for a minimum of 24 h before using. Methylzinc
bromide was prepared via the reaction of zinc bromide and
methylmagnesium bromide.46 THF was freshly distilled from sodium
metal with a benzophenone ketal indicator. Acetone was dried by
simple distillation and stored over molecular sieves (4 Å, 8−12 mesh).
Acetonitrile was distilled from CaH2 and stored over 4 Å molecular
sieves. Aluminum-coated silica gel WF254s plates were used to monitor
reaction products and flash chromatography eluents. Column
chromatography was performed with silica gel (40−60 μm, 230−400
mesh).
23
590
126 °C; [α] −89 (c = 0.56, CHCl3). Diastereomeric excess (de)
>99% (anti): 1H NMR (300 MHz, CDCl3) δ 7.21 (d, J = 9.0 Hz, 2H),
7.08 (d, J = 9.0 Hz, 2H), 6.85 (dd, J = 3.0, 15.0 Hz, 1H), 6.11 (dd, J =
3.0, 15.0 Hz, 1H), 5.11−5.38 (br, 1H), 4.91 (m, 1H), 4.50−4.70 (br,
1H), 4.21 (m, J = 6.0 Hz, 2H), 2.58 (t, J = 6.0 Hz, 2H), 1.57 (m, 2H),
1.47 (s, 9H), 1.36 (m, 2H), 1.33 (t, J = 6.0 Hz, 3H), 1.30 (s, 9H), 0.91
(t, J = 6.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 169.6, 169.3, 157.2,
156.5, 155.2, 155.1, 142.3, 134.4, 129.8, 128.4, 126.8, 126.4, 83.1, 82.4,
82.1, 70.0, 65.6, 63.4, 61.6, 35.3, 33.4, 28.0, 22.2, 14.3, 14.0; HRMS
(ESI-TOF) calcd for C27H42N2O7Na (M + Na)+ 529.2884, found
529.2886.
Racemic anti-(E)-Di-tert-butyl 1-(1-Ethoxy-3-hydroxy-1-oxo-5-(p-
tolyl)pent-4-en-2-yl)hydrazine-1,2-dicarboxylate (2C): 302 mg, 55%;
white solid, mp 163−164 °C. Diastereomeric excess (de) >99% (anti):
1H NMR (300 MHz, CDCl3) δ 7.19 (d, J = 9.0 Hz, 2H), 7.08 (d, J =
9.0 Hz, 2H), 6.75 (s, 1H), 6.63 (d, J = 15.0 Hz, 1H), 6.10 (dd, J = 3.0
Hz, 15.0 Hz, 1H), 5.11−5.38 (br, 1H), 4.90 (m, 1H), 4.53−4.73 (br,
1H), 4.23 (m, J = 6.0 Hz, 2H), 2.32 (s, 3H), 1.47 (s, 9H), 1.31 (s, 9H),
1.30 (t, J = 6.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 169.5, 169.3,
157.2, 156.6, 155.0, 137.2, 134.2, 129.8, 129.1, 126.8, 126.4, 83.1, 82.4,
82.1, 70.0, 65.6, 63.4, 61.6, 28.0, 21.2, 14.3; HRMS (ESI-TOF) calcd
for C24H36N2O7Na (M + Na)+ 487.2415, found 487.2419.
Racemic anti-(E)-Di-tert-butyl 1-(5-(4-Chlorophenyl)-1-ethoxy-3-
hydroxy-1-oxopent-4-en-2-yl)hydrazine-1,2-dicarboxylate (2D): 382
mg, 58%; white solid, mp 169−170 °C. Diastereomeric excess (de)
>99% (anti): 1H NMR (300 MHz, CDCl3) δ 7.20−7.28 (m, 5H), 6.72
(s, 1H), 6.85 (d, J = 15.0 Hz, 1H), 6.15 (dd, J = 3.0, 15.0 Hz, 1H),
5.10−5.38 (br, 1H), 4.91 (m, 1H), 4.54−4.70 (br, 1H), 4.21−4.29 (m,
2H), 1.47 (s, 9H), 1.31 (t, J = 6.0 Hz, 3H) 1.29 (s, 9H); 13C NMR (75
MHz, CDCl3) δ 169.5, 169.3, 157.3, 156.6, 155.1, 155.0, 135.5, 133.0,
128.7, 128.6, 128.4, 127.7, 83.3, 82.5, 82.2, 69.6, 65.5, 63.3, 61.7, 28.0,
14.3; HRMS (ESI-TOF) calcd for C23H33N2O7ClNa (M + Na)+
507.1869, found 507.1877.
General Procedure for Synthesis of anti-2-Di-tert-butoxy-
carbonyl Hydrazino 1,3-Diol (3). Into a solution of anti-N-Boc-α-
hydrazino-β-hydroxyesters (2) (1 mmol) in 25 mL of methanol, was
added 3 equiv of NaBH4 every 15 min until the starting material was
consumed as indicated by TLC. A total of 36−51 equiv was added.
Afterward, the reaction was quenched with saturated NH4Cl (aq) (10
NMR spectra were obtained on an FT-NMR spectrometer
operating at 300 MHz for 1H NMR and 75 MHz for 13C NMR
unless otherwise noted. Assignments were made by 1H, 13C, and
gCOSY techniques. Chemical shifts were reported in parts per million
1
(ppm, δ) relative to tetramethylsilane (TMS, δ 0.00 ppm). H NMR
splitting patterns are designated as singlet (s), doublet (d), triplet (t),
doublet of doublets (dd), multiplet (m), broad (br). Coupling
constants (J values) are reported in hertz (Hz). For quantitative
1
diastereomer analysis, H NMR spectroscopy was employed at 600
MHz with 25 s relaxation delay, no spinning, and no line broadening.35
HPLC was performed with an isocratic pump and UV−visible
detector. A cellulose column (50 × 4.60 mm) was used for the chiral
separation at 23 °C. The mobile phase consisted of hexanes and
isopropyl alcohol in the ratio of 90:10 and flow rate of 0.5 mL/min.
Detection was at 254 nm. Accurate mass spectra were obtained on all
compounds by electrospray ionization (positive ion mode) with a
TOF analyzer. Capillary electrophoresis was used for estimation of %
ee of the final products. Chiral selectors were single isomer
sulfoalkylated cyclodextrins synthesized and characterized in our
lab.44,45 Capillary; 50 μm i.d., 48.5 cm total length, 40.0 cm length to
detector. Background electrolyte (BGE); 20 mM phosphate buffer, pH
2.5, 7.5, or 10 mM cyclodextrin. Voltage; −15 or −22 kV (reverse
polarity). Detection at 254 nm. Pressure injection; 50−150 mbar·s.
Detection at 254 nm. Sample; ∼1 mg/mL dissolved in 2:1 methanol/
water.
General Procedure for Diastereoselective Formation of anti-
N-Boc-α-hydrazino-β-hydroxyesters (2). Under N2, to a solution
of trans-γ,δ-unsaturated β-hydroxyesters (1) (1.0 mmol) in 2.0 mL of
D
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23
mL), and the reaction mixture was concentrated in vacuo and
extracted twice with EtOAc. The combined extracts were washed with
brine, dried over anhydrous Na2SO4, and the organic solvent was
removed by rotovaporization at 60−70 °C. Purification by column
chromatography on silica gel using 5:3 CH2Cl2/EtOAc as eluent
afforded the product.
94%); colorless oil; [α] −56 (c = 0.61, CHCl3); (4R, 5S)-4B (42
590
23
mg, 94%); colorless oil; [α] +67 (c = 0.30, CHCl3); 1H NMR (300
590
MHz, CDCl3) δ 7.28 (d, J = 6.0 Hz, 2H), 7.10 (d, J = 6.0 Hz, 2H),
6.63 (d, J = 15.0 Hz, 3H), 5.85−6.11 (br, 2H), 4.55 (m, 1H), 3.75−
4.26 (br, 1H), 4.01 (br, 2H), 2.58 (t, J = 6.0 Hz, 2H), 1.58 (m, 2H),
1.55 (s, 3H), 1.48 (s, 9H), 1.46 (s, 3H), 1.39 (s, 9H), 1.32 (m, 2H),
0.92 (t, J = 6.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 156.6, 155.8,
154.6, 154.3, 142.9, 134.4, 133.6, 128.2, 126.7, 126.5, 126.2, 125.6,
98.6, 82.3, 81.9, 81.6, 71.6, 61.0, 60.5, 56.3, 53.6, 35.6, 33.5, 29.0, 28.1,
28.0, 22.3, 19.4, 13.9; HRMS (ESI-TOF) calcd for C28H44N2O6Na (M
+ Na)+ 527.3092, found 527.3088.
anti-(E)-Di-tert-butyl 1-(1,3-Dihydroxy-5-phenylpent-4-en-2-yl)-
hydrazine-1,2-dicarboxylate (3A): (2R,3S)-3A (142 mg, 85%);
23
colorless oil; [α] −18 (c = 1.13, CHCl3); (2S,3R)-3A (52 mg,
590
23
590
1
88%); colorless oil; [α] +10 (c = 0.49, CHCl3); H NMR (300
MHz, CDCl3) δ 7.24 (m, 5H), 6.60 (d, J = 15.0 Hz, 1H), 6.35 (br,
1H), 6.21 (br, J = 6.0, 15.0 Hz, 1H), 2.85−4.98 (br, 6H), 1.47 (s, 9H),
1.42 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 158.5, 157.8, 155.4,
136.3, 132.3, 129.1, 128.5, 127.9, 126.6, 82.6, 82.4, 81.9, 72.0, 64.7,
62.4, 59.2, 28.1; HRMS (ESI-TOF) calcd for C21H32N2O6Na (M +
Na)+ 431.2153, found 431.2147.
Racemic anti-(E)-Di-tert-butyl 1-(2,2-Dimethyl-4-(4-methylstyryl)-
1,3-dioxan-5-yl)hydrazine-1,2-dicarboxylate (4C): 61 mg, 94%;
white solid, mp 138−139 °C; H NMR (300 MHz, CDCl3) δ 7.25
1
(d, J = 6.0 Hz, 2H), 7.08 (d, J = 6.0 Hz, 3H), 6.62 (d, J = 15.0 Hz,
1H), 5.86−6.30 (br, 2H), 4.53 (br, 1H), 3.75−4.26 (br, 1H), 4.00 (br,
2H), 2.31 (s, 3H), 1.54 (s, 3H), 1.47 (s, 9H), 1.43 (s, 3H), 1.37 (s,
9H); 13C NMR (75 MHz, CDCl3) δ 156.6, 155.8, 154.6, 154.3, 137.8,
133.6, 133.4, 129.2, 126.7, 126.5, 126.1, 125.5, 98.6, 82.2, 81.8, 81.6,
72.2, 71.6, 60.9, 60.5, 56.3, 53.4, 29.0, 28.1, 28.0, 21.2, 19.6, 19.4;
HRMS (ESI-TOF) calcd for C25H38N2O6Na (M + Na)+ 485.2622,
found 485.2632.
anti-(E)-Di-tert-butyl 1-(5-(4-Butylphenyl)-1,3-dihydroxypent-4-
en-2-yl)hydrazine-1,2-dicarboxylate (3B): (2R,3S)-3B (290 mg,
23
80%); colorless oil; [α] −35 (c = 0.29, CHCl3); (2S,3R)-3B (53
590
23
mg, 81%); colorless oil; [α] +83 (c = 0.24, CHCl3); 1H NMR (300
590
MHz, CDCl3) δ 7.26 (d, J = 9.0 Hz, 2H), 7.12 (d, J = 9.0 Hz, 2H),
6.58 (d, J = 15.0 Hz, 1H), 6.34 (br, 1H), 6.17 (dd, J = 6.0, 15.0 Hz,
1H), 3.35−5.00 (br, 5H), 2.59 (t, J = 6.0 Hz, 2H), 2.0 (s, 1H), 1.58
(m, 2H), 1.48 (s, 9H), 1.45 (s, 9H), 1.34 (m, 2H), 0.92 (t, J = 6.0 Hz,
3H); 13CNMR (75 MHz, CDCl3) δ 158.5, 157.7, 155.4, 143.0, 133.6,
132.3, 128.6, 127.9, 126.5, 82.7, 82.5, 81.9, 72.4, 64.6, 62.6, 59.3, 35.4,
33.6, 28.1, 22.3, 13.9; HRMS (ESI-TOF) calcd for C25H40N2O6Na (M
+ Na)+ 487.2779, found 487.2792.
Racemic anti-(E)-Di-tert-butyl 1-(4-(4-Chlorostyryl)-2,2-dimethyl-
1,3-dioxan-5-yl)hydrazine-1,2-dicarboxylate (4D): 157 mg, 93%;
white solid, mp 165−166 °C; 1H NMR (300 MHz, CDCl3) δ 7.30 (d,
J = 9.0 Hz, 2H), 7.26 (d, J = 9.0 Hz, 2H), 6.63 (d, J = 15.0 Hz, 1H),
6.00−6.55(br, 2H), 4.56 (br, 1H), 4.00−4.39 (br, 1H), 4.01 (br, 2H),
1.54 (s, 3H), 1.48 (s, 9H), 1.44 (s, 3H), 1.36 (s, 9H); 13CNMR (75
MHz, CDCl3) δ 156.6, 155.8, 154.6, 154.3, 134.9, 133.4, 132.3, 131.7,
128.6, 128.6, 127.9, 127.8, 98.6, 82.2, 81.8, 81.6, 71.8, 71.1, 80.8, 60.4,
56.4, 53.3, 28.9, 28.1, 28.0, 19.4; HRMS (ESI-TOF) calcd for
C24H35N2O6ClNa (M + Na)+ 505.2076, found 505.2068.
General Procedure for Synthesis anti-2-Alkylhydrazino
Acetonide of 1,3-diol (5). Into a suspension solution of anti-2-di-
tert-butoxycarbonyl hydrazine acetonide of 1,3-diol (4) (0.242 mmol)
and Cs2CO3 (0.61 mmol) in 2.5 mL of CH3CN under N2 was added
methyl bromoacetate (0.484 mmol) in 0.5 mL of CH3CN. The
reaction mixture was stirred at 50 °C for 3−8 h as indicated by TLC
plate (eluent, 10:1 CH2Cl2/EtOAc). After the reaction was completed,
2.0 mL of saturated NH4Cl (aq) was added to quench the reaction.
The solution was then extracted with EtOAc (2 × 5 mL). The
combined extracts were washed with brine, dried over anhydrous
Na2SO4, and the solvent was removed in vacuo. The anti-2-
alkylhydrazino acetonide of 1,3-diol (5) was purified by flash
chromatography on silica gel using 10:1 CH2Cl2/EtOAc as eluent.
All intermediates 5 revealed complicated NMR spectra due to the
presence of a number of rotamers (see Supporting Information). A
temperature study was carried on 5C to provide evidence for
rotamerism of these compounds.
Racemic anti-(E)-Di-tert-butyl 1-(1,3-Dihydroxy-5-(p-tolyl)pent-4-
en-2-yl)hydrazine-1,2-dicarboxylate (3C): 350 mg, 83%; white solid,
mp 165−167 °C; 1H NMR (300 MHz, CDCl3) δ 7.24 (d, J = 6.0 Hz,
2H), 7.10 (d, J = 6.0 Hz, 2H), 6.58 (d, J = 15.0 Hz, 1H), 6.36 (br, 1H),
6.18 (dd, J = 6.0, 15.0 Hz, 1H), 3.50−4.70 (br, 5H), 2.50−3.10 (br,
1H), 2.32 (s, 3H), 1.48 (s, 9H), 1.42 (s, 9H); 13C NMR (75 MHz,
CDCl3) δ 158.5, 157.7, 155.4, 137.8, 133.4, 132.2, 129.3, 127.9, 126.5,
82.7, 82.5, 81.9, 72.3, 64.6, 62.5, 59.3, 28.1, 21.2; HRMS (ESI-TOF)
calcd for C22H34N2O6Na (M + Na)+ 445.2309, found 445.2305.
Racemic anti-(E)-Di-tert-butyl 1-(5-(4-Chlorophenyl)-1,3-di-
hydroxypent-4-en-2-yl)hydrazine-1,2-dicarboxylate (3D): 162 mg,
1
83%; white solid, mp 159−160 °C; H NMR (300 MHz, CDCl3) δ
7.25 (s, 4H), 6.55 (d, J = 15.0 Hz, 1H), 6.35 (br, 1H), 6.20 (dd, J =
6.0, 15.0 Hz, 1H), 2.85−4.90 (br, 6H), 1.47 (s, 9H), 1.41 (s, 9H); 13C
NMR (75 MHz, CDCl3) δ 158.4, 157.8, 155.4, 135.1, 133.3, 130.6,
129.9, 128.9, 127.7, 82.5, 82.0, 71.8, 64.5, 62.5, 59.3, 28.1; HRMS
(ESI-TOF) calcd for C21H31N2O6ClNa (M + Na)+ 465.1763, found
465.1764.
General Procedure for Synthesis of anti-2-Di-tert-butoxy-
carbonyl Hydrazino 1,3-Diol Ketal (4). Under N2, the mixture of
anti-2-di-tert-butoxycarbonyl hydrazino 1,3-diol (3) (0.15 mmol) and
10% molar equiv of p-toluene sulfonic acid monohydrate (0.015
mmol) in 5.0 mL of anhydrous acetone was stirred at room
temperature until the reaction was completed as monitored by TLC
plate (eluent, CH2Cl2/EtOAc = 5:3) (24 h). The reaction mixture was
quenched with 5% NaHCO3 and extracted by CH2Cl2. The combined
organic layers were dried over anhydrous Na2SO4 and removed in
vacuo. The product was purified by flash chromatography on silica gel
using 10:1 CH2Cl2/EtOAc as eluent.
anti-(E)-Di-tert-butyl 1-(2,2-Dimethyl-4-styryl-1,3-dioxan-5-yl)-2-
(2-methoxy-2-oxoethyl)hydrazine-1,2-dicarboxylate (5A): (4S,5R)-
5A (96 mg, >99%); colorless oil; [α] −63 (c = 1.76, CHCl3); H
23
590
1
NMR (300 MHz, CDCl3) δ 7.23−7.26 (m, 5H), 6.50−6.62 (m, 1H),
6.05−6.26 (m, 1H), 3.31−5.36 (m, 9H), 1.34−1.68 (m, 24H); 13C
NMR (75 MHz, CDCl3) a large number of 13C resonances were
observed due to the presence of several rotamers at 25 °C; see
Supporting Information for detailed peak listing; HRMS (ESI-TOF)
calcd for C27H40N2O8Na (M + Na)+ 543.2677, found 543.2689.
anti-(E)-Di-tert-butyl 1-(4-(4-Butylstyryl)-2,2-dimethyl-1,3-diox-
anti-(E)-Di-tert-butyl 1-(2,2-Dimethyl-4-styryl-1,3-dioxan-5-yl)-
hydrazine-1,2-dicarboxylate (4A): (4S, 5R)-4A (147 mg, 94%);
23
colorless oil; [α] −40 (c = 0.75, CHCl3); (4R,5S)-4A (51 mg, 93%);
590
23
1
an-5-yl)-2-(2-methoxy-2-oxoethyl)hydrazine-1,2-dicarboxylate
colorless oil; [α] +44 (c = 0.45, CHCl3); H NMR (300 MHz,
590
23
(5B): (4S,5R)-5B (46 mg, 94%); colorless oil; [α] −65 (c = 0.77,
CDCl3) δ 7.37 (d, J = 6.0 Hz, 2H), 7.20−7.32 (m, 3H), 6.66 (d, J =
15.0 Hz, 1H), 6.00−6.35 (br, 2H), 4.56 (m, 1H), 3.70−4.28 (br, 1H),
4.02 (br, 2H), 1.55 (s, 3H), 1.48 (s, 9H), 1.45 (s, 3H), 1.37 (s, 9H);
13C NMR (75 MHz, CDCl3) δ 156.6, 155.8, 154.6, 154.3, 136.4, 136.2,
133.3, 128.4, 127.9, 127.3, 126.7, 126.6, 98.6, 82.2, 81.8, 81.6, 72.0,
71.4, 60.9, 60.5, 56.2, 53.4, 29.0, 28.1, 28.0, 19.6, 19.4; HRMS (ESI-
TOF) calcd for C24H36N2O6Na (M + Na)+ 471.2466, found 471.2470.
anti-(E)-Di-tert-butyl 1-(4-(4-Butylstyryl)-2,2-dimethyl-1,3-diox-
an-5-yl)hydrazine-1,2-dicarboxylate (4B): (4S, 5R)-4B (55 mg,
590
23
590
CHCl3); (4R, 5S)-5B (28 mg, 95%); colorless oil; [α] +83 (c =
0.24, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.22 (m, 2H), 7.11 (m,
2H), 6.47−6.59 (m, 1H), 5.99−6.20 (m, 1H), 3.32−5.30 (m, 9H),
2.58 (t, J = 6.0 Hz, 2H), 1.26−1.68 (m, 28H), 0.92 (dt, J = 3.0, 6.0 Hz,
3H); 13C NMR (75 MHz, CDCl3) a large number of 13C resonances
were observed due to the presence of several rotamers at 25 °C; see
Supporting Information for detailed peak listing; HRMS (ESI-TOF)
calcd for C31H48N2O8Na (M + Na)+ 599.3303, found 599.3309.
E
dx.doi.org/10.1021/jo501533g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Racemic anti-(E)-Di-tert-butyl 1-(2,2-Dimethyl-4-(4-methylstyryl)-
1,3-dioxan-5-yl)-2-(2-methoxy-2-oxoethyl)hydrazine-1,2-dicarboxy-
48.9, 28.7, 28.2, 19.5; HRMS (ESI-TOF) calcd for C19H26NO4ClNa
(M + Na)+ 390.1443, found 390.1448.
1
late (5C): 26 mg, 98%; colorless oil; H NMR (600 MHz, CDCl3) δ
General Procedure for Synthesis of trans-4,5-Unsaturated
anti 2-Boc-amino 1,3-Diol (7). A mixture of anti 2-Boc-amino
acetonide of 1,3-diol (6) (0.1 mmol) and 10 mol % of TsOH (0.05
mmol) in 10.0 mL of 80% EtOH in H2O (v/v) was stirred at reflux
until the starting material was consumed as indicated by TLC plate
(eluent, CH2Cl2/EtOAc = 5:3). After the reaction was completed
(usually 1 h), the reaction was quenched by 4 mL of 5% NaHCO3.
The mixture was concentrated in vacuo at 60−70 °C, extracted by
EtOAc, and dried over anhydrous Na2SO4. The product was isolated
by column chromatography on silica gel using 5:3 CH2Cl2/EtOAc as
eluent.
7.23−7.26 (m, J = 3.0, 6.0 Hz, 1H), 7.18−7.21 (m, J = 6.0 Hz, 1H),
7.10 (dd, J = 3.0, 6.0 Hz, 2H), 6.49−6.58 (m, 1H), 6.01−6.19 (m,
1H), 3.33−5.31 (m, 9H), 2.33 (s, 3H), 1.35−1.68 (m, 24H); 13C
NMR (150 MHz, CDCl3) a large number of 13C resonances were
observed due to the presence of several rotamers at 25 °C; see
Supporting Information for detailed peak listing; HRMS (ESI-TOF)
calcd for C28H42N2O8Na (M + Na)+ 557.2833, found 557.2852.
Racemic anti-(E)-Di-tert-butyl 1-(4-(4-Chlorostyryl)-2,2-dimethyl-
1,3-dioxan-5-yl)-2-(2-methoxy-2-oxoethyl)hydrazine-1,2-dicarboxy-
late (5D): 134 mg, 99%; colorless oil; 1H NMR (300 MHz, CDCl3) δ
7.26 (m, 4H), 6.46−6.59 (m, 1H), 6.05−6.25 (m, 1H), 3.28−5.32 (m,
9H), 1.35−1.67 (m, 24); 13C NMR (75 MHz, CDCl3) a large number
of 13C resonances were observed due to the presence of several
rotamers at 25 °C; see Supporting Information for detailed peak
listing; HRMS (ESI-TOF) calcd for C27H39N2O8ClNa (M + Na)+
577.2287, found 577.2299.
General Procedure for Synthesis of anti-2-Boc-amino
Acetonide of 1,3-Diol (6). Into a suspension solution of 5 (0.22
mmol) in 5.0 mL of CH3CN under argon was added 3 equiv of
Cs2CO3 (0.66 mmol), and the reaction mixture was refluxed for over
20 h until the starting material was consumed as indicated by TLC
plate (eluent, 10:1 CH2Cl2/EtOAc). The reaction was quenched with
saturated NH4Cl (aq) and then extracted twice with EtOAc. The
combined extracts were washed with brine and dried over anhydrous
Na2SO4. The solvent was removed in vacuo. The product 6 was
purified by flash chromatography on silica gel using 10:1 CH2Cl2/
EtOAc as eluent.
anti-(E)-tert-Butyl (1,3-Dihydroxy-5-phenylpent-4-en-2-yl)-
23
carbamate (7A): (2R,3S)-7A (28 mg, 96%); colorless oil; [α]
590
23
+13 (c = 2.40, CHCl3); (2S,3R)-7A (10 mg, 93%); colorless oil; [α]
590
−9 (c = 0.57, CHCl3), lit.25 −19.4; H NMR (300 MHz, CDCl3) δ
1
7.21−7.39 (m, 5H), 6.68 (d, J = 15.0 Hz, 1H), 6.26 (dd, J = 6.0, 15.0
Hz, 1H), 5.42 (d, J = 6.0 Hz, 1H), 4.53 (t, J = 6.0 Hz, 1H), 3.97 (dd, J
= 3.0, 12.0 Hz, 1H), 3.76 (dd, J = 3.0, 12.0 Hz, 1H), 3.72 (br, 1H),
3.05 (br, 2H), 1.42 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 156.3,
136.3, 131.8, 128.6, 128.5, 127.9, 126.6, 80.0, 74.6, 62.5, 55.4, 28.3;
HRMS (ESI-TOF) calcd for C16H23NO4Na (M + Na)+ 316.1519,
found 316.1524.
anti-(E)-tert-Butyl (5-(4-Butylphenyl)-1,3-dihydroxypent-4-en-2-
yl)carbamate (7B): (2R,3S)-7B (16 mg, 94%); white solid, mp 94−
23
96 °C; [α] +10 (c = 0.97, CHCl3); (2S,3R)-7B (10 mg, 95%); white
590
23
590
1
solid, mp 96−98 °C; [α] −15 (c = 0.67, CHCl3); H NMR (300
MHz, CDCl3) δ 7.29 (d, J = 9.0 Hz, 2H), 7.13 (d, J = 9.0 Hz, 2H),
6.67 (d, J = 15.0 Hz, 1H), 6.21 (dd, J = 6.0, 15.0 Hz, 1H), 5.36 (d, J =
9.0 Hz, 1H), 4.54 (t, J = 3.0 Hz, 1H), 3.99 (dd, J = 3.0, 12.0 Hz, 1H),
3.76 (dt, J = 3.0, 12.0 Hz, 1H), 3.71 (m, 1H), 2.84 (br, 2H), 2.59 (t, J
= 6.0 Hz, 2H), 1.54−1.65 (m, 2H), 1.44 (s, 9H), 1.29−1.41 (m, 2H),
0.92 (t, J = 6.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 156.2, 142.9,
133.7, 131.8, 128.7, 127.4, 126.5, 79.9, 74.9, 62.6, 55.4, 35.4, 33.6, 28.3,
22.3, 13.9; HRMS (ESI-TOF) calcd for C20H31NO4Na (M + Na)+
372.2145, found 372.2156.
anti-(E)-tert-Butyl (2,2-Dimethyl-4-styryl-1,3-dioxan-5-yl)-
23
590
carbamate (6A): (4S,5R)-6A (46 mg, 85%); colorless oil; [α]
−25 (c = 0.79, CHCl3); (4R,5S)-6A (18 mg from (4R,5S)-4A, 94%);
colorless oil; [α] +21 (c = 0.24, CHCl3), lit.23 +17.2; 1H NMR (300
23
590
MHz, CDCl3) δ 7.38 (m, 2H), 7.20−7.32 (m, 3H), 6.65 (d, J = 15.0
Hz, 1H), 6.18 (dd, J = 6.0, 15.0 Hz, 1H), 4.43 (d, J = 9.0 Hz, 1H), 4.27
(br, 1H), 4.00 (dd, J = 6.0 Hz, 1H), 3.72 (m, 1H), 3.61 (m, 1H), 1.53
(s, 3H), 1.46 (s, 3H), 1.35 (s, 9H); 13C NMR (75 MHz, CDCl3) δ
155.1, 136.3, 133.6, 128.4, 127.9, 126.7, 126.6, 98.8, 79.8, 74.6, 63.0,
49.1, 28.7, 28.2, 19.6; HRMS (ESI-TOF) calcd for C19H27NO4Na (M
+ Na)+ 356.1832, found 356.1841.
Racemic anti-(E)-tert-Butyl (1,3-Dihydroxy-5-(p-tolyl)pent-4-en-
1
2-yl)carbamate (7C): 29 mg, 95%; white solid, mp 57−59 °C; H
NMR (300 MHz, CDCl3) δ 7.26 (d, J = 6.0 Hz, 2H), 7.11 (d, J = 6.0
Hz, 2H), 6.63 (d, J = 15.0 Hz, 1H), 6.20 (dd, J = 6.0, 15.0 Hz, 1H),
5.41 (d, J = 6.0 Hz, 1H), 4.51 (dd, J = 3.0, 6.0 Hz, 1H), 3.97 (dt, J =
3.0, 12.0 Hz, 1H), 3.75 (dt, J = 3.0, 12.0 Hz, 1H), 3.72 (m, 1H), 3.31
(d, J = 3.0 Hz, 1H), 3.00 (s, 1H), 2.33 (s, 3H), 1.43 (s, 9H); 13C NMR
(75 MHz, CDCl3) δ 156.3, 137.8, 133.5, 131.8, 129.3, 127.4, 126.5,
80.0, 74.7, 62.6, 55.5, 28.4, 21.2; HRMS (ESI-TOF) calcd for
C17H25NO4Na (M + Na)+ 330.1676, found 330.1671.
anti-(E)-tert-Butyl (4-(4-Butylstyryl)-2,2-dimethyl-1,3-dioxan-5-
yl)carbamate (6B): (4S,5R)-6B (25 mg, 95%), white solid, mp
23
118−120 °C; [α] −61 (c = 0.49, CHCl3); (4R,5S)-6B (13 mg,
590
23
86%); white solid, mp 119−121 °C; [α] +59 (c = 0.17, CHCl3); 1H
590
NMR (300 MHz, CDCl3) δ 7.30 (d, J = 6.0 Hz, 2H), 7.11(d, J = 6.0
Hz, 2H), 6.63 (d, J = 15.0 Hz, 1H), 6.12 (dd, J = 6.0, 15.0 Hz, 1H),
4.37 (br, 1H), 4.25 (br, 1H), 4.02 (dd, J = 6.0 Hz, 1H), 3.71 (m, 1H),
3.59 (m, 1H), 2.58 (t, J = 6.0 Hz, 2H), 1.58 (m, 2H), 1.53 (s, 3H),
1.46 (s, 3H), 1.35 (s, 9H), 1.32 (m, 2H), 0.92 (t, J = 6.0 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 155.1, 142.9, 133.7, 128.5, 126.6, 125.5,
98.8, 79.9, 74.7, 63.0, 49.2, 35.4, 33.5, 28.7, 28.2, 22.3, 19.6, 13.9;
HRMS (ESI-TOF) calcd for C23H35NO4Na (M + Na)+ 412.2458,
found 412.2468.
Racemic anti-(E)-tert-Butyl (5-(4-Chlorophenyl)-1,3-dihydroxy-
pent-4-en-2-yl)carbamate (7D): 15 mg, 92%; white solid, mp 66−
68 °C ; 1H NMR (300 MHz, CDCl3) δ 7.27 (m, 4H), 6.65 (d, J = 15.0
Hz, 1H), 6.25 (dd, J = 6.0, 15.0 Hz, 1H), 5.38 (d, J = 9.0 Hz, 1H), 4.53
(dd, J = 3.0, 6.0 Hz, 1H), 3.98 (dt, J = 3.0, 12.0 Hz, 1H), 3.78 (dt, J =
3.0, 12.0 Hz, 1H), 3.72 (m, 1H), 3.24 (d, J = 3.0 Hz, 1H), 2.77 (s,
1H), 1.43 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 156.2, 134.8, 133.5,
130.5, 129.3, 128.8, 127.8, 80.1, 74.6, 62.5, 55.4, 28.4; HRMS (ESI-
TOF) calcd for C16H22NO4ClNa (M + Na)+ 350.1130, found
350.1124.
Racemic anti-(E)-tert-Butyl (2,2-Dimethyl-4-(4-methylstyryl)-1,3-
dioxan-5-yl)carbamate (6C): 14 mg, 87%; white solid, mp 144−145
°C; 1H NMR (300 MHz, CDCl3) δ 7.28 (d, J = 6.0 Hz, 2H), 7.10 (d, J
= 6.0 Hz, 2H), 6.62 (d, J = 15.0 Hz, 1H), 6.11 (dd, J = 6.0, 15.0 Hz,
1H), 4.41 (d, J = 9.0 Hz, 1H), 4.25 (br, 1H), 4.00 (dd, J = 6.0 Hz, 1H),
3.71 (m, 1H), 3.63 (m, 1H), 2.32 (s, 3H), 1.53 (s, 3H), 1.46 (s, 3H),
1.35 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 155.1, 137.8, 133.7,
133.5, 129.2, 126.6, 125.5, 98.8, 97.8, 74.7, 63.0, 49.1, 28.8, 28.2, 21.2,
19.6; HRMS (ESI-TOF) calcd for C20H29NO4Na (M + Na)+
370.1989, found 370.1993.
ASSOCIATED CONTENT
* Supporting Information
■
S
1H and 13C NMR spectra are available for compounds 2−7.
Chiral HPLC chromatograms are also available for compounds
6 and 7. Chiral capillary electropherograms are available for
compounds 7A. This material is available free of charge via the
Internet at http://pubs.acs.org.
Racemic anti-(E)-tert-Butyl (4-(4-Chlorostyryl)-2,2-dimethyl-1,3-
dioxan-5-yl)carbamate (6D): 67 mg, 83%; white solid, yield 83%, mp
1
147−148 °C; H NMR (300 MHz, CDCl3) δ 7.28 (ddd, J = 3.0, 6.0
Hz, 4H), 6.66 (d, J = 15.0 Hz, 1H), 6.16 (dd, J = 6.0, 15.0 Hz, 1H),
4.51 (br, 1H), 4.24 (br, 1H), 3.97 (dd, J = 6.0 Hz, 1H), 3.66 (m, 2H),
1.52 (s, 3H), 1.46 (s, 3H), 1.35 (s, 9H); 13C NMR (75 MHz, CDCl3)
δ 155.1, 134.9, 133.5, 132.0, 128.6, 127.9, 127.4, 98.8, 79.8, 74.6, 62.9,
AUTHOR INFORMATION
Corresponding Author
*E-mail: tkgreen@alaska.edu.
■
F
dx.doi.org/10.1021/jo501533g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(37) Labeeuw, O.; Phansavath, P.; Genet
2003, 44, 6383.
(38) Greck, C.; Bischoff, L.; Ferreira, F.; Pinel, C.; Piveteau, E.;
̂
, J.-P. Tetrahedron Lett.
Notes
The authors declare no competing financial interest.
Genet, J. P. Synlett 1993, 475.
REFERENCES
■
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