Synthesis of 1,2- and 1,4-amino alcohols from 1,3-dienes via oxazines. Rearrangements of 1,4-amino alcohol derivatives to oxazolines

Article abstract of DOI:10.1016/j.tet.2010.03.059

Conjugated dienes were converted to 1,2-oxazines by reaction with an acyl nitroso dienophile. The oxazines were reduced to 1,4-N-acetylamino alcohols, which were rearranged to the corresponding oxazolines upon treatment with methanesulfonyl chloride or an

Full text of DOI:10.1016/j.tet.2010.03.059

Tetrahedron 66 (2010) 3761–3769
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Synthesis of 1,2- and 1,4-amino alcohols from 1,3-dienes via oxazines.
Rearrangements of 1,4-amino alcohol derivatives to oxazolines
*
Lukas Werner, Jason Reed Hudlicky, Martina Wernerova, Tomas Hudlicky
Chemistry Department and Centre for Biotechnology, Brock University, 500 Glenridge Avenue, St. Catharines, Ontario L2S 3A1, Canada
a r t i c l e i n f o
a b s t r a c t
Article history:
Conjugated dienes were converted to 1,2-oxazines by reaction with an acyl nitroso dienophile. The
oxazines were reduced to 1,4-N-acetylamino alcohols, which were rearranged to the corresponding
oxazolines upon treatment with methanesulfonyl chloride or anhydride. The oxazolines yielded 1,2-N-
acetylamino alcohols upon hydrolysis. Thus either 1,4- or 1,2-N-acetylamino alcohols are available from
1,3-dienes via this methodology. Experimental and spectral data are provided for all new compounds.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 15 February 2010
Received in revised form 13 March 2010
Accepted 15 March 2010
Available online 20 March 2010
Keywords:
Oxazines
1,2-Amino alcohols
1,4-Amino alcohols
Hetero Diels–Alder reaction
Oxazolines
1. Introduction
nitroso dienophile to the diene in acetonide 2,2 derived in two steps
from ethyl benzoate via enzymatic oxidation.3 Reduction of oxazine 3
In 2009 we published a concise formal synthesis of oseltamivir
(Tamiflu) (1), in which a key step involved the 1,3-transposition of an
allylic alcohol via oxazoline, as outlined in an abbreviated form in
Figure 1.1 The synthesis started with the [4þ2] cycloaddition of acyl
produced the N-protected form of 1,4-amino alcohol 4, which upon
exposure to methanesulfonyl chloride rearranged cleanly to oxazo-
line 5. Hydrolysis of 5 provided the corresponding 1,2-amino alcohol
derivative 6, whichwasthenconvertedtooseltamivirinseveralsteps.
1,3-diene
1,4-amino alcohol
CO2Et
CO2Et
EtO2C OH
Hetero-Diels-Alder
O
reduction
O
O
O
O
N
O
O
Ac
4
NHAc
3
2
1,3-transposition
1,2-amino alcohol
CO2Et
CO2Et
O
CO2Et
O
hydrolysis
steps
H2N
O
NHAc
O
HO
O
O
NHAc
N
5
oseltamivir 1
6
Figure 1. Oseltamivir synthesis via 1,4- and 1,2-amino alcohol derivatives.
When the process pictured in Figure 1 is viewed from the vantage
point of functional transformations a possibility emerges of con-
verting conjugated dienes selectively into either 1,4- or 1,2-amino
* Corresponding author. E-mail address: thudlicky@brocku.ca (T. Hudlicky).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.03.059

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L. Werner et al. / Tetrahedron 66 (2010) 3761–3769
alcohol derivatives. The latter group of compounds can also be
obtained as either cis- or trans-isomers by further manipulations of
oxazolines of type 5. The conversion of cyclic as well as acyclic dienes
to oxazines with various nitroso dienophiles is amply documented in
the literature.4 The conversion of the oxazines to 1,4-amino alcohol
derivatives is also well precedented, especially so in the area of
conduramine and amino cyclitol synthesis.5 We were, however,
surprised when the search of the literature revealed very few ex-
amples, mostly pertaining to six-membered ring systems, of the
conversion of 1,4-N-acylamino alcohols to their oxazolines6 and/or
to the corresponding 1,2-derivatives. Olivo reported a convenient
and general preparation of vinyl aziridines from 1,4-N-acylamino
alcohols (obtained by oxazine reduction) via a vinylogous Mitsunobu
reaction and observed competing oxazoline formation in some
cases.7 Most of the literature on oxazolines, useful as ligands, is
concerned with their synthesis from 1,2-amino alcohols.8 A recent
report described the ruthenuium-catalyzed rearrangement of cyclic
oxazines directly to cis or trans 1,2-amino alcohol derivatives.9 We
therefore chose to investigate the generality of the premise of con-
verting oxazines derived from cyclic and acyclic dienes to both
regioisomers of amino alcohols. In this paper we report the details of
transforming 1,4-N-acylamino alcohols to the corresponding oxa-
zolines via rearrangements of their mesylates.
case of alcohol 37 the major product from the reaction performed at
room temperature was identified as chloride 39. The 1H NMR
spectrum of compound 39 revealed two equal magnitude coupling
constants (J4,5¼J4,NHAc¼9.9 Hz) and one small one (J3,4¼3.3 Hz) for
proton H-4 (4.35 ppm, ddd). Even though the ring is not in a perfect
chair conformation because of the presence of double bond, these
values correspond to standard axial-equatorial coupling (J¼3.3 Hz),
which indicates cis orientation of the chlorine and acetamido
substituents.
We therefore decided to investigate the reaction process in
detail for this particular case. The results of this study are shown in
Scheme 1.
The products of the reaction were markedly different depending
on the reagents as well as the temperature. With mesyl chloride and
triethylamine several intermediates could be observed during the
reaction of alcohol 37. At room temperature the reaction mixture
consisted of oxazoline 38 (14%), chloride 39 (32%), and triethyl am-
monium salts (either or both 42 and/or 43) (~30%). However, if the
reaction mixture was heated to 40 ꢀC the content of oxazoline 38
increased to 30–40% (vide 1H NMR). This observation indicated that
intermediates 39 and 42/43 are further transformed to the desired
oxazoline. The 1H NMR spectrum of compound 42 showed three
equally large couplings for H-4 (4.54 ppm, ddd, J3,4¼J4,5
¼
J4,NHAc¼9.0 Hz), which indicates trans orientation of substituents at
positions C-3/C-4 and C-4/C-5. In a separate experiment chloride 39
was cleanly transformed to oxazoline 38 upon heating at 80 ꢀC in the
presence of Et3N. Without Et3N present in reaction mixture chloride
39 did not cyclize, which also strongly supports the assigned cis
orientation of acetamido and chloro substituents. Similar experiment
with triethyl ammonium salts 42/43 showed that heating of the
ethanolic solution of the salt 42 to 80 ꢀC in the presence of NaHCO3
also led to oxazoline 38 as a major product. We assume that oxazoline
38 is formed from the quarternary salts 42/43 via SN2 process.
Chloride 39 cannot undergo such a direct displacement to the oxa-
zoline and must be first transformed by Et3N via SN2 process to the
quarternary ammonium salts 42/43 with trans orientation of the
acetamido and triethyl ammonium moieties required for the second
SN2 displacement.
The entire process of transformation of 1,4-N-acetylamino
alcohols to the oxazolines and the corresponding 1,2-N-acetylamino
alcohols was optimized and reduced to a one-pot procedure. The
use of dichloroethane as solvent allowed the reaction to be heated
to 80 ꢀC after the observation of the mesylate 41 at 0 ꢀC. After
mesylation the reaction mixture is concentrated, diluted with EtOH
and the pH is adjusted to ~8 with 1 M NaOH or with NaHCO3 (the
latter conditions were used in the study of mechanism). After 1–2 h
at reflux the chloride and the quarternary ammonium salt are
transformed to the oxazoline, at which point the pH is adjusted to
~10 and the oxazoline is hydrolyzed to the corresponding 1,2-N-
acetyl amine after 16 h at reflux. In the case of oxazolines 5 and 25
CaCO3 or acetic acid were used for hydrolysis in order to prevent
hydrolysis of the ester moiety. In addition, oxazoline can be cleanly
prepared at room temperature. When methanesulfonyl anhydride
is used instead of mesyl chloride the allylic alcohol 37 was smoothly
transformed to oxazoline 38 in 68% isolated yield.
2. Results and discussion
Based on the observations made during the oseltamivir syn-
thesis we chose to investigate a series of cyclic dienes and their
conversion to the corresponding oxazines whose reduction would
provide the 1,4-amino alcohols that are suited for oxazoline for-
mation and hence for the generation of 1,2-amino alcohols by
hydrolysis.
The results of our studyare summarized inTable 1. In each case the
hetero Diels–Alder cycloaddition was conducted according to stan-
dard protocols (AcNHOH, NaIO4) to prepare 1,2-oxazines 3,1 8,10 13,11
18, 23, 28, 30, and 36 in the yields indicated. In the case of acyclic
diene 22 the yield of the oxazine can be improved by using more
equivalents of the nitroso dienophile. Diene 27 provided a mixture of
regioisomers 28 and 30 (3:1). Lower yields of oxazine were obtained
from diene 35 because of its tendency to aromatize under the re-
action conditions to cyclohexyl phenol. Oxazines derived from
cyclopentadiene, cyclohexadiene, and cycloheptadiene containing
various N-acyl groups (tert-Boc, Cbz, Bz, etc.) are frequently described
in the literature, however, N-acetyl derivatives are far less common.
Anoxazinederived from methyl sorbatewas prepared from1-chloro-
1-nitrosocyclohexane providing, after hydrolysis of the iminium ion,
the parent system as a hydrochloride salt.12 The oxazines derived
from dienes containing electron withdrawing groups are usually
formed regioselectively in an inverse-electron-demand cycloaddi-
tion. Cycloadditions with unsymmetrical dienes usually produce
mixtures of regioisomers with the major product favoring the
placement of oxygen at the more electrophilic site of the diene.
13
Reduction of the oxazine adducts was performed with Mo(CO)6
to afford 1,4-N-acetylamino alcohols 4,1 9,14 14, 19,15 24, 29, 31, and
37. We found this procedure experimentally more suitable than the
usual Na(Hg) or Al(Hg) method16 that is often used. Conversion of
the 1,4-N-acetylamino alcohols to the corresponding oxazolines was
initially accomplished by treatment with methanesulfonyl chloride
at room temperature. Oxazolines 10, 15, 20, and 25 were too volatile
to allow for accurate determination of isolated yields and were
therefore directly converted to the 1,2-acetylamino alcohols. The less
volatile oxazolines 5, 32, 34, and 38 permitted isolation and full
characterization prior to their conversion to the 1,2-amino alcohol
derivatives by base-catalyzed hydrolysis. We observed several in-
termediates during monitoring of the reactions by TLC and obtained
lower yields of oxazolines at the expense of other products. In the
The reaction of the 1,2-acylamino derivative 40 with mesyl
chloride proceeded along a similar pathway with one exception
being the generation of the diastereomeric allylic chloride 45
(observed in 1H NMR, not isolated) by a SN2 reaction of the mesy-
late 41. Stereochemistry of these labile compounds 41 and 45 was
confirmed by performing the reaction in CDCl3 and measuring the
1H NMR spectra at two different temperatures. Proton H-3
(5.12 ppm, dd) in compound 41 displayed two small interactions
(J3,4¼3.0 Hz, J2,3¼5.7 Hz), which is in accordance with the similar
‘cis coupling’ observed in compound 39 (J3,4¼3.3 Hz) as well as in
the acetamido alcohol 40 (J3,4¼3.6 Hz). Mesylate 41 was reasonably

L. Werner et al. / Tetrahedron 66 (2010) 3761–3769
3763
Table 1
Synthesis of 1,4- and 1,2-amino alcohol derivatives from cyclic dienes
Enrty
Diene
Oxazine
1,4-Amino alcohol
Oxazoline
CO Et
1,2-Amino alcohol
CO Et
2
2
EtO C
O
CO Et
2
OH
2
O
O
CO Et
O
O
2
O
O
O
1
O
5 54%
O
HO
O
N
O
Ac
3 90%
N
NHAc
6 72% [47%]
NHAc
a
4 93%
2
OH
O
HO
O
N
2
NHAc
Ac
N
NHAc
7
a
11 20%
8 89%
9 51%
10
OH
O
NAc
HO
O
3
NHAc
N
NHAc
14 47%
a
12
16 39%
13 68%
15
NHAc
N
O
NHAc
HO
N
O
OH
Ac
a
17
4
5
19 42%
21 32%
20
18 90%
CO2Et
CO Et
CO Et
CO2Et
CO Et
2
2
2
O
NAc
OH
NHAc
H
O
HO
NHAc
N
26 67% (1:1)a
22
23 46%
24 65%
25
OH
O
O
O
O
O
O
O
O
6
O
O
O
NAc
HO
O
N
NHAc
NHAc
a
32 25%
27
33 37%
28 60%
29 68%
NHAc
O
O
N
O
O
O
NAc
O
O
O
OH
31 95%
30 25%
34 57%
O
OH
O
O
O
O
O
O
7
O
O
O
O
O
O
N
O
HO
Cl
Ac
N
NHAc
39 32%
NHAc
37 69%
NHAc
a
36 43%
40 58%
38 68%
35
aThe yields for 1,2-amino derivatives are reported for the two-step sequence from 1,4-amino alcohols.

3764
L. Werner et al. / Tetrahedron 66 (2010) 3761–3769
Ms2O, DCM, rt (68%)
(direct SN2')
OH
1
O
O
6
MsCl, Et3N, DCE
-78 °C to rt
O
O
O
O
2
O
O
O
O
+
+
+
5
Et3N
X
3
4
O
MsO
Cl
NHAc
N
38
NHAc
37
NHAc
41*
NHAc
39
42 X = MsO
43 X = Cl
OMs
O
Et3N, rt
80 °C
NaHCO3, EtOH
O
NHAc
44
O
O
NHAc
O
O
O
O
O
O
O
+
MsCl, Et3N, DCE
-78 °C to 0 °C
rt
Et3N
X
O
O
HO
MsO
Cl
N
NHAc
40
NHAc
NHAc
45
42 X = MsO
43 X = Cl
38
41*
80 °C
rt
* mesylate 41 is stable up to 0 °C
Scheme 1.
stable at 0 ꢀC, thus allowing for the determination of its structure.
However, warming the NMR tube to room temperature led to the
transformation of mesylate 41 to chloride 45, with the latter
compound exhibiting the typical ‘trans coupling’ for proton H-4
(3.94 ppm, ddd, J3,4¼J4,5¼J4,NHAc¼9.6 Hz), in accordance with the
previously assigned configuration of the quarternary salt 42
(J3,4¼J4,5¼J4,NHAc¼9.0 Hz).
Finally, it should be noted that 1,2-amino alcohol derivatives
containing the allylic olefin moiety and prepared by this method
could also be obtained by nucleophilic opening of vinyl aziridines
where such aziridines are available regioselectively from 1,3-di-
enes. The opposite regiochemistry of 1,2-amino alcohol de-
rivatives, in which the acyl amine is allylicaly disposed, is easily
accessible by the reaction of the Burgess reagent with vinyl
oxiranes as previously demonstrated.17 Thus the current method
provides a good complement to the existing methodology espe-
cially in cases where regioslective aziridination or epoxidation of
conjugated dienes might be problematic or non-selective while
the oxazine formation of polarized dienes proceeds with excel-
lent regioslectivity.
All intermediates converged to oxazoline 38 with increasing
temperature of the reaction. A standard sample of the pure quar-
ternary salt 42 was also prepared by this method because reaction
with mesyl chloride provides quarternary salt as a mixture of
chloride and mesylate counter ions.
Finally, we should point out the distinct probability of a rear-
rangement of 44 to 41, as shown in Scheme 1. Mesylate 44, derived
form the allylic alcohol 37, may rearrange to mesylate 41 at tem-
peratures above 0 ꢀC, as shown in Scheme 1. While we did not di-
rectly observe the putative [3,3] sigmatropic rearrangement of
44–41 we obtained evidence of this rearrangement (vide NMR) for
the case of the substrate containing the ethyl ester moiety: the
mesylate prepared form 4 partially rearranged to the mesylate de-
rived from 6 (this mesylate was isolated and matched with the
corresponding mesylate prepared earlier during in synthesis of
oseltamivir1) before the conversion to either a chloride or an am-
monium salt and ultimately to oxazoline 5.
4. Experimental section
4.1. General procedure for the preparation of oxazines
To a stirred solution of the diene in MeOH (10 mL/g of diene)
at room temperature was added freshly grounded NaIO4
(1.5 equiv) followed by the addition of a solution of acetohy-
droxamic acid (1.5 equiv) in MeOH (10 mL) dropwise over
5 min. The resulting suspension was stirred for 20 h, quenched
by the slow addition of satd NaHCO3 (~5 mL), diluted with
methylene chloride (100 mL) and filtered through filterpaper.
The filtrate was washed with NaHCO3 (2ꢁ10 mL) and the
combined aqueous layer re-extracted with methylene chloride
(20 mL). The combined organic layers were dried over MgSO4
and concentrated under vacuo. The crude oxazine was purified
by column chromatography with a solvent system of hexanes/
ethyl acetate.
3. Conclusions
We have demonstrated that 1,3-dienes can be effectively con-
verted to either 1,4- or 1,2-N-acetylamino alcohols via their oxa-
zines obtained by hetero Diels–Alder cycloaddition with an acyl
nitroso dienophile. This approach is stereoselective and general for
5-, 6-, and seven-membered rings, however, in cases of acyclic di-
enes affords mixture of diastereoisomers. The cycloadditions pro-
ceed via inverse-electron-demand and are completely
regioselective when the diene is suitably polarized by an electron
withdrawing group. With non-polarized dienes regioisomers may
be formed with substrates that do not exhibit additional steric bias.
The 1,4-acylamino alcohol derivatives yield 1,2-acylamino de-
rivatives via hydrolysis of the corresponding oxazolines.
4.1.1. 2-Oxa-3-azabicyclo[2.2.1]hept-5-ene, 3-acetyl (8)10. Compound
7: (4.55 g, 68.86 mmol), (NaIO4: 20.01 g, 93.51 mmol), (CH3CON-
HOH: 8.14 g, 108.46 mmol); yield of 8 (8.52 g, 61.27 mmol, 89%) as
a yellow oil. Rf¼0.25 (hexane/ethyl acetate 1:1).
4.1.2. 2-Oxa-3-azabicyclo[2.2.2]oct-5-ene, 3-acetyl (13)11. Compound
12: (1.63 g, 20.34 mmol), (NaIO4: 6.53 g, 30.53 mmol),

L. Werner et al. / Tetrahedron 66 (2010) 3761–3769
3765
(CH3CONHOH: 2.29 g, 30.50 mmol); yield of 13 (2.10 g, 13.72 mmol,
68%) as a yellow oil. Rf¼0.30 (hexane/ethyl acetate 1:1).
727, 691; 1H NMR (CDCl3, 300 MHz)
d
6.36 (d, 1H, J¼8.1 Hz), 6.31
(dd, 1H, J¼5.7, 8.4 Hz), 4.87 (ddd, 1H, J¼1.8, 4.8, 5.4 Hz), 4.58 (dd,
1H, J¼4.8, 6.9 Hz), 4.19 (d, 1H, J¼7.2 Hz), 2.02 (s, 3H), 1.98 (s,
4.1.3. 2-Oxa-3-azabicyclo[3.2.1]non-5-ene, 3-acetyl (18). Compound
17: (1.00 g, 10.62 mmol), (NaIO4 3.41 g, 15.93 mmol), (CH3CONHOH:
1.2 g, 15.99 mmol); yield of 18 (1.59 g, 90%) as a brown liquid:
3H), 1.32 (s, 6H) ppm; 13C NMR (CDCl3, 75 MHz)
d 177.0, 137.7,
127.0, 110.8, 77.6, 74.0, 71.0, 60.9, 25.7, 25.5, 24.5, 21.3 ppm; MS
(EIþ) m/z %: 239 (8), 224 (11), 208 (6), 139 (9); HRMS (EIþ) calcd
for C12H17N1O4 239.11591 found 239.11576.
Rf¼0.30 (hexane/ethyl acetate 1:1); IR (KBr, cmꢂ1
)
n
3476, 2938,
6.26
2360, 1646, 1454, 1379, 1157, 1113; 1H NMR (300 MHz, CDCl3)
d
(dd, 1H, J¼7.2, 8.7 Hz), 6.15 (dd, 1H, J¼6.9, 6.9 Hz), 5.18 (m, 1H),
4.1.7. 1-Cyclohexyl-5,6-O-isopropylidene-2-oxa-3-azabicy-
clo[2.2.2]oct-7-ene-5,6-diol, 3-acetyl (36). To a stirred solution of
(2R,3S)-2,3-dihydroxy-1-cyclohexylcyclohexa-4,6-diene19
4.67–4.63 (m, 1H), 1.99 (s, 3H), 1.91–1.28 (m, 6H) ppm; 13C NMR
(75 MHz, CDCl3)
d 166.9, 129.5, 127.2, 76.3, 50.2, 29.7, 28.6, 20.8,
18.4 ppm; MS (EIþ) m/z %: 167 (Mþ): 125 (26), 79 (20), 75 (19), 57
(17), 43 (100). HRMS calcd for C9H13NO2: 167.09407 found:
167.09463.
(500 mg, 2.58 mmol) in 2,2-dimethoxypropane (10 mL) was added
p-toluenesulfonic acid (catalytic amount) at room temperature.
After complete consumption of starting material (TLC analysis),
a spatula tip of solid NaHCO3 was added. The intermediate ace-
tonide 35 was not isolated. Then NaIO4 (825 mg, 3.86 mmol),
MeOH (5 mL) was added to the reaction mixture followed by the
dropwise addition of a solution of acetohydroxamic acid (290 mg,
3.86 mmol) in MeOH (5 mL) over 5 min. The resulting solution was
stirred for 20 h, quenched by the slow addition of satd NaHCO3
(~2 mL), diluted with methylene chloride (50 mL) and filtered
through filterpaper. Filtrate was extracted with NaHCO3 (2ꢁ5 mL)
and combined aqueous layer re-extracted with methylene chloride
(10 mL). The combined organic layers were dried over MgSO4 and
concentrated under vacuo. The crude material was purified by
column chromatography with a solvent system of hexanes/ethyl
4.1.4. 1-Oxa-2-aza-3-methyl-6-carboethoxycyclohex-4-ene
(23). Compound 22: (5.00 g, 35.67 mmol), (NaIO4: 22.88 g,
107.00 mmol), (CH3CONHOH: 8.04 g, 107.00 mmol); yield of 23
(3.49 g, 16.41 mmol, 46%) as a yellow oil: Rf¼0.20 (hexane/ethyl
acetate 3:1); IR (KBr, cmꢂ1
) n 3491, 2984, 2937, 2360, 1755,
1669, 1412, 1276, 1203, 1078, 1030; 1H NMR (300 MHz, CDCl3)
d
5.87 (ddd, 1H, J¼10.2, 2.4, 3.9 Hz), 5.79 (d, 1H, J¼10.2 Hz),
4.97–4.93 (m, 1H), 4.70–4.68 (m, 1H), 4.16 (q, 2H, J¼7.2 Hz),
2.03 (s, 3H), 1.23 (t, 6H, J¼7.2 Hz) ppm; 13C NMR (75 MHz,
CDCl3)
d 169.0, 166.6, 130.6, 121.4, 77.2, 61.8, 47.2, 20.1, 17.5,
14.0 ppm; MS (EIþ) m/z %: 213 (M): 171 (76), 156 (33), 141 (23),
98 (62), 43 (100); HRMS Calcd for C10H15NO4: 213.10042 found:
213.10011. Anal. Calcd for C10H15NO4: C, 56.33; H, 7.09. Found:
C, 56.47; H, 7.18.
acetate (4:1) to yield 36 (340 mg, 43% over two steps); mp¼104–
20
107 ꢀC (ethyl acetate/hexane); [
a
]
D
ꢂ51.4 (c 1, CHCl3); Rf¼0.85
(hexane/ethyl acetate 1:1); IR (KBr, cmꢂ1
1654, 1620, 1457, 1414, 1387, 1272, 1211, 1162, 1097 cmꢂ1
(300 MHz, CDCl3)
)
n
3449, 2932, 2859,
1H NMR
;
4.1.5. 1-Methyl-5,6-O-isopropylidene-2-oxa-3-azabicyclo[2.2.2]oct-
7-ene-5,6-diol, 3-acetyl (28). To a stirred solution of 1-methyl-
(2R,3S)-2,3-dihydroxy-1-methylcyclohexa-4,6-diene18 (2.29 g,
18.18 mmol) in 2,2-dimethoxypropane (25 mL) was added p-tol-
uenesulfonic acid (catalytic amount) at room temperature. After
complete consumption of starting material (TLC analysis), a spat-
ula tip of solid NaHCO3 was added. The intermediate acetonide 27
was not isolated. Then NaIO4 (5.83 g, 27.27 mmol) and MeOH
(20 mL) was added to the reaction mixture prior to the dropwise
d
6.40 (dd, 1H, J¼6.0, 8.1 Hz), 6.15 (d, 1H,
J¼8.4 Hz), 5.27 (br s, 1H), 4.34 (m, 2H), 1.93–1.87 (m, 5H), 1.74 (s,
3H), 1.65–1.62 (m, 1H), 1.28–1.05 (m, 11H) ppm; 13C NMR (75 MHz,
CDCl3)
d 172.5, 131.5, 131.0, 110.3, 82.3, 75.9, 73.3, 49.1, 41.3, 26.9,
26.6, 26.4, 26.3, 26.2, 25.6, 25.2, 21.6 ppm; MS (EIþ) m/z %: 307 (M)
(55), 292 (16), 249 (13), 232 (31), 190 (17), 175 (18), 160 (21), 83
(45), 55 (40), 43 (100); HRMS calcd for C17H25NO4: 307.17840
found: 307.17836.
addition of
a
solution of acetohydroxamic acid (2.05 g,
4.1.8. 1-Carboethoxy-5,6-O-isopropylidene-2-oxa-3-azabicy-
clo[2.2.2]oct-7-ene-5,6-diol, 3-acetyl (3)20. For complete experi-
mental and spectral data see Ref. 20a.
27.27 mmol) in MeOH (20 mL) over 5 min. The resulting solution
was stirred for 20 h, quenched by the slow addition of satd
NaHCO3 (~5 mL), diluted with methylene chloride (100 mL) and
filtered through filterpaper. Filtrate was washed with NaHCO3
(2ꢁ10 mL) and combined aqueous layer re-extracted with meth-
ylene chloride (20 mL). The combined organic layers were dried
over MgSO4 and concentrated under vacuo. The crude material
was purified by column chromatography with a solvent system of
4.2. General procedure for oxazine reduction with Mo(CO)6
To a stirred solution of oxazine in 15:1/CH3CN/H2O (10 mL/
3 mmol) was added molybdenum hexacarbonyl (2 equiv). The re-
action was brought to reflux for 4–16 h, cooled to room tempera-
ture, filtered through a plug of Celite, and concentrated. The crude
material was purified by column chromatography with ethyl ace-
tate as the solvent.
hexanes/ethyl acetate (4:1) to yield 28 (720 mg, 60% over
20
two steps); mp¼79–81 ꢀC; [
a
n
]
¼ꢂ27.5 (c 1, CHCl3); Rf¼0.75
D
(ethyl acetate); IR (KBr, cmꢂ1
)
3448, 2991, 2922, 2360, 1656, 1618,
1410, 1387, 1276, 1209, 1184, 1162, 1087, 1058 cmꢂ1
(300 MHz, CDCl3)
;
1H NMR
d
6.46 (dd, 1H, J¼6.3, 8.1 Hz), 6.14 (d, 1H,
4.2.1. 1-Hydroxy-4-acetylamino-cyclopent-2-ene (9). Compound 8:
(4.0 g, 28.76 mmol), (Mo(CO)6: 11.39 g, 43.11 mmol); yield of 9
(2.05 g, 14.53 mmol, 51%). Rf¼0.40 (ethyl acetate/ethanol 5:1).
J¼8.4 Hz), 5.48 (m, 1H), 4.49 (dd, 1H, J¼4.2, 6.9 Hz), 4.18 (d, 1H,
J¼6.9 Hz), 2.01 (s, 3H), 1.57 (s, 3H), 1.32 (s, 3H), 1.30 (s, 3H) ppm;
13C NMR (75 MHz, CDCl3)
d 171.5, 133.4, 130.8, 110.6, 78.5, 78.0,
73.2, 49.2, 25.6, 25.4, 21.4, 19.9 ppm; MS (EIþ) m/z %: 239 (M): 224
(15), 109 (24), 97 (19), 92 (26), 85 (13), 43 (100); HRMS calcd for
C12H17NO4: 239.11579 found: 239.11576.
4.2.2. 1-Hydroxy-4-acetylamino-cyclohex-2-ene (14). Compound
13: (1.98 g, 12.94 mmol), (Mo(CO)6: 4.44 g, 16.81 mmol); yield of
14 (937 mg, 6.05 mmol, 47%). Rf¼0.10 (ethyl acetate).
4.1.6. 1-Methyl-5,6-O-isopropylidene-3-oxa-2-azabicyclo[2.2.2]oct-
4.2.3. 1-Hydroxy-4-acetylamino-cyclohept-2-ene (19). Compound
18: (500 mg, 2.99 mmol), (Mo(CO)6: 1.19 g, 4.49 mmol); yield of
19 (211 mg, 42%); mp¼146–148 ꢀC (ethyl acetate/hexane);
7-ene-5,6-diol, 2-acetyl (30). Regioisomer 30 (25%) as white solid;
mp¼93–94 ꢀC (ethyl acetate/hexane); Rf¼0.5 (hexane/ethyl ace-
20
tate 3:1); [
a
]
D
þ60.1 (c 1, CHCl3); Rf¼0.82 (ethyl acetate 1); IR
Rf¼0.10 (ethyl acetate); IR (KBr, cmꢂ1
) n 3358, 3287, 3086, 2929,
(KBr, cmꢂ1) 3066, 2997, 2977, 2939, 2926, 2907, 1687, 1612, 1431,
1382, 1365, 1260, 1212, 1160, 1084, 1064, 1007, 974, 889, 850,
2851, 1638, 1555, 1450, 1372, 1297, 1125, 1058, 1026; 1H NMR
(300 MHz, CDCl3)
d
5.82 (m, 2H), 5.56 (ddd, 1H, J¼1.8, 3.9,

3766
L. Werner et al. / Tetrahedron 66 (2010) 3761–3769
13.5 Hz), 4.55 (m, 1H), 4.42 (d, 1H, J¼5.1 Hz), 2.00 (s, 3H), 1.89–
for C17H27NO4: 309.19401 found: 294.17053. Anal. Calcd for
C17H27NO4: C, 65.99; H, 8.80. Found: C, 66.27; H, 8.92.
1.64 (m, 6H) ppm; 13C NMR (75 MHz, CDCl3)
d 169.0 137.5, 133.0,
71.3, 50.0, 36.0, 33.6, 23.8, 23.5 ppm; MS (EIþ) m/z %: 169 (M): 167
(19), 151 (34), 149 (41), 110 (40), 109 (47), 82 (39), 70 (46), 56 (88),
43 (100). Anal. Calcd for C9H15NO2: C, 63.88; H, 8.93. Found: C,
63.60; H, 8.88.
4.2.8. (1S, 2R, 3S, 6R)-6-Acetylamino-1,2-O-isopropylidene-3-car-
boethoxycyclohex-4-ene, 1,2,3-triol (4)20. For complete experimen-
tal and spectral data see Ref. 20a.
4.2.4. Ethyl 2-hydroxy-4-acetylamino-hex-3-enoate (24). Compound
23: (1.00 g, 4.69 mmol), (Mo(CO)6: 1.86 g, 7.04 mmol); yield of 24
(653 mg, 65%); mp¼113–115 ꢀC (ethyl acetate/hexane); Rf¼0.10
4.3. General procedure for the conversion of 1,4-amino
alcohols to 1,2-isomers via oxazolines
(ethyl acetate); IR (KBr, cmꢂ1
)
n
3361, 3240, 2983, 1725, 1644, 1541,
6.58 (d, 1H,
1384, 1215, 1108, 1024; 1H NMR (300 MHz, CDCl3)
d
To the pre-cooled (4 ꢀC) solution of 1,4-amino alcohols (2 mL
dichloroethane/100 mg of substrate) was added MsCl or Ms2O
(5 equiv) followed by dropwise addition of Et3N (10 equiv). Reaction
mixture was then stirred in cooling bath and spontaneously allowed
to room temperature. After reached room temperature the mixture
was heated 4 h to 60 ꢀC. On preparative scale the oxazoline was di-
rectly hydrolyzed without isolation. Reaction mixture was concen-
trated, dissolved in EtOH (4 mL) and the pH of the ethanolic solution
was adjusted to ~8 with NaOH (1 M). The mixture was then heated to
90 ꢀC for 1 h, the pH was then adjusted to ~10 with NaOH (1 M), and
the heating continued for the next 16 h. After complete disappear-
ance of intermediary oxazoline was reaction mixture concentrated
and washed between dichloromethane (20 mL) and H2O (2ꢁ3 mL).
Aqueous layer was re-extracted with dichloromethane (10 mL) and
combined organic layer dried over MgSO4 and concentrated under
vacuum. Chromatography of crude [10 mL SiO2, ethyl acetate/hex-
ane] afforded corresponding 1,2-isomers.
J¼6.6 Hz), 5.50 (dd, 1H, J¼8.1, 10.8 Hz), 5.40 (dd, 1H, J¼9.9, 9.9 Hz),
5.11 (d, 1H, J¼7.8 Hz), 4.81–4.73 (m, 1H), 4.27 (br s, 1H), 4.20 (q, 2H,
J¼7.2 Hz), 1.91 (s, 3H), 1.26–1.21 (m, 6H) ppm; 13C NMR (75 MHz,
CDCl3)
d 172.8, 170.4, 135.3, 127.6, 67.5, 61.4, 43.1, 23.1, 20.3,
14.1 ppm; MS (EIþ) m/z %: 215 (M): 156 (21), 142 (56), 112 (36), 100
(84), 82 (100), 60 (47), 43 (73). Anal. Calcd for C10H17NO4: C, 55.80;
H, 7.96. Found: C, 55.82; H, 8.11.
4.2.5. (1S, 2R, 3S, 6R)-6-Acetylamino-1,2-O-isopropylidene-3-meth-
ylcyclohex-4-ene, 1,2,3-triol (29). Compound 28: (720 mg,
3.01 mmol), (Mo(CO)6: 1.19 g, 4.52 mmol); yield of 29 (494 mg,
20
68%); mp¼148–151 ꢀC (ethyl acetate/hexane); [
a
]
ꢂ119.7 (c 1,
D
CHCl3); Rf¼0.23 (ethyl acetate); IR (KBr, cmꢂ1
) n 3433, 3379, 2991,
2924, 2907, 2856, 1741, 1650, 1512, 1460, 1382, 1308, 1252, 1211,
1166, 1109, 1063, 1045, 1022 cmꢂ1; 1H NMR (300 MHz, CDCl3)
d 6.64
(d, 1H, J¼8.4 Hz), 5.92–5.89 (m, 2H), 4.47 (ddd, 1H, J¼2.1, 4.8,
9.0 Hz), 4.41 (dd, 1H, J¼2.1, 6.6 Hz), 4.25 (d, 1H, J¼6.6 Hz), 3.04 (br s,
1H), 1.95 (s, 3H), 1.44 (s, 3H), 1.36 (s, 3H), 1.32 (s, 3H) ppm; 13C NMR
4.3.1. 1-Hydroxy-2-acetylaminocyclopent-4-ene (11). Compound 9:
(300 mg, 2.13 mmol), (MsCl: 823
21.26 mmol); yield of 11 (59 mg, 0.419 mmol, 20%); Rf¼0.45 (ethyl
acetate/ethanol 5:1); IR (KBr, cmꢂ1
3425, 3335, 2362, 1645, 1554,
1384, 1046; 1H NMR (300 MHz, CDCl3)
6.54 (br s, 1H), 6.00–5.97
mL, 10.63 mmol), (Et3N: 2.96 mL,
(75 MHz, CDCl3)
d 169.9, 135.8, 128.9, 108.3, 81.3, 77.3, 68.4, 47.6,
26.6, 26.1, 24.6, 23.5 ppm; MS (EIþ) m/z %: 226 (MꢂMe), 182 (32),
141 (57),124 (27),112 (29), 99 (44), 81 (22), 56 (21), 43 (100); HRMS
calcd for C12H19NO4: 241.13141 found: 226.10793. Anal. Calcd for
C12H19NO4: C, 59.73; H, 7.94. Found: C, 59.91; H, 8.04.
)
n
d
(m, 1H), 5.88–5.84 (m, 1H), 4.63–4.61 (m, 1H), 4.34 (dddd, 1H,
J¼4ꢁ6.3 Hz), 3.04 (br s, 1H), 2.77–2.68 (m, 1H), 2.28–2.18 (m, 1H),
2.01 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3)
d 170.9, 134.5, 131.8,
4.2.6. N-((3aR,4S,7R,7aS)-7-Hydroxy-2,2,4-trimethyl-3a,4,7,7a-tet-
rahydrobenzo[d][1,3]dioxol-4-yl)acetamide (31). Compound 30:
74.3, 51.2, 37.4, 23.3 ppm; MS (EIþ) m/z %: 141 (M): 98 (9), 85 (10),
82 (38), 70 (14), 60 (26), 56 (15), 43 (100); HRMS calcd for
C7H11NO2: 141.07867 found: 141.07898.
(70 mg, 0.29 mmol), (Mo(CO)6: 165 mg, 0.63 mmol); yield of 31
20
(67 mg, 95%); [
a
]
þ47.6 (c 1, CHCl3); Rf¼0.26 (ethyl acetate);
D
IR (KBr, cmꢂ1) 3321, 3074, 2989, 2938, 2900, 2875, 1657, 1548,
1456, 1446, 1383, 1303, 1265, 1212, 1163, 1136, 1070, 1028, 879,
4.3.2. 1-Hydroxy-2-acetylaminocyclohex-5-ene (16). Compound 14:
(297 mg, 1.910 mmol), (MsCl: 743 mL, 9.570 mmol), (Et3N: 2.67 mL,
781, 705, 607; 1H NMR (CDCl3, 300 MHz)
d 5.89 (br s, 1H), 5.82
19.14 mmol); yield of 16 (116 mg, 39%); mp¼108–110 ꢀC (ethyl
(dd, 1H, J¼2.1, 9.9 Hz), 5.72 (dd, 1H, J¼2.1, 9.6 Hz), 4.68 (d, 1H,
J¼7.8 Hz), 4.32 (dd, 1H, J¼4.5, 8.1 Hz), 4.28 (m, 1H), 1.96 (s, 3H),
1.47 (s, 3H), 1.36 (s, 3H), 1.20 (s, 3H) ppm; 13C NMR (CDCl3,
acetate/EtOH); Rf¼0.15 (ethyl acetate); IR (KBr, cmꢂ1
) n 3281, 3178,
3082, 2905, 2835, 1643, 1562, 1433, 1384, 1066; 1H NMR (300 MHz,
CDCl3)
d
6.19 (br s, 1H), 5.91 (ddd, 1H, J¼2ꢁ3.6, 10.2 Hz), 5.82 (dddd,
75 MHz)
d 169.9, 134. 6, 128.2, 108.6, 80.7, 69.4, 55.6, 26.4,
1H, J¼1.8, 2.1, 4.5, 10.2 Hz), 4.09 (dd, 1H, J¼2ꢁ4.2 Hz), 4.01 (dddd,
1H, J¼3.6, 7.2, 11.7,15.3 Hz), 2.01 (s, 3H),1.82–1.74 (m, 1H),1.70–1.60
24.6, 24.0, 22.0 ppm; MS (FABþ) m/z %: 242 (99), 224 (100),
184 (57), 124 (35); HRMS (FABþ) calcd for C12H20N1O4
242.13671 found 242.13923.
(m, 1H) ppm; 13C NMR (75 MHz, CDCl3)
d 169.9, 131.8, 127.2, 65.0,
48.9, 24.7, 23.5, 23.1 ppm; MS (FABþ) m/z %: 156 (MþþH): 96 (34),
81 (43), 69 (82), 60 (57), 55 (71), 43 (78); HRMS calcd for C8H13NO2:
155.09463 found: 156.10245. Anal. Calcd for C8H13NO2: C, 61.91; H,
8.44; N, 9.03. Found: C, 62.08; H, 8.44; N, 8.96.
4.2.7. (1S, 2R, 3S, 6R)-6-Acetylamino-1,2-O-isopropylidene-3-cyclo-
hexylcyclohex-4-ene, 1,2,3-triol (37). Compound 36: (2.961 g,
9.63 mmol), (Mo(CO)6: 7.63 g, 28.90 mmol); yield of 37 (2.05 g,
20
69%); mp¼162–165 ꢀC (ethyl acetate); [
a
)
]
ꢂ132.4 (c 1, CHCl3);
4.3.3. 1-Hydroxy-2-acetylaminocyclohept-6-ene (21). Compound
19: (86 mg, 0.509 mmol), (MsCl: 228 mL, 2.96 mmol), (Et3N:
D
Rf¼0.35 (ethyl acetate); IR (KBr, cmꢂ1
n
3386, 3345, 2990,
2936, 2853, 1730, 1631, 1534, 1452, 1383, 1300, 1252, 1215,
0.82 mL, 5.91 mmol); yield of 21 (28 mg, 0.163 mmol, 32%);
1099, 1064, 1052, 1018 cmꢂ1
;
1H NMR (300 MHz, CDCl3)
d
6.56
Rf¼0.15 (ethyl acetate); IR (KBr, cmꢂ1
)
n
3391, 3284, 3034, 2925,
(d, 1H, J¼9.0 Hz), 6.13 (d, 1H, J¼9.6 Hz), 6.02 (dd, 2H, J¼6.3,
9.9 Hz), 4.55 (m, 1H), 4.39 (m, 2H), 2.47 (br s, 1H), 1.94 (s, 3H),
1.88–1.62 (m, 5H), 1.35 (s, 3H), 1.30 (s, 3H), 1.27–1.14 (m,
2843, 1655, 1549, 1383, 1066; 1H NMR (300 MHz, CDCl3)
d 5.94–
5.85 (m, 2H), 5.65–5.60 (m, 1H), 4.52–4.51 (m, 1H), 4.24–4.20
(m, 1H), 3.24 (br s, 1H), 2.26–2.17 (m, 1H), 2.02 (s, 3H), 2.13–1.98
(m, 2H), 1.88–1.77 (m, 1H), 1.66–1.54 (m, 1H), 1.49–1.34
6H) ppm; 13C NMR (75 MHz, CDCl3)
d 169.5, 133.5, 130;.4,
108.0, 78.5, 77.6, 71.8, 47.3, 43.3, 26.6, 26.5, 26.4, 25.7, 25.6,
24.3, 23.5 ppm; MS (EIþ) m/z %: 294 (MꢂMe), 250 (38), 209
(90), 183 (49), 163 (51), 83 (85), 55 (47), 43 (100); HRMS calcd
(m, 1H) ppm; 13C NMR (75 MHz, CDCl3)
d 171.1, 133.8, 132.0, 72.9,
52.5, 32.0, 28.2, 23.4, 21.5 ppm; MS (FABþ) m/z %: 170 (MþþH):
152 (59), 110 (66), 69 (56), 55 (94), 43 (87); HRMS calcd for

L. Werner et al. / Tetrahedron 66 (2010) 3761–3769
3767
20
C9H16NO2: 170.11803 found: 170.11810. Anal. Calcd for
C9H15NO2: C, 63.88; H, 8.93. Found: C, 63.66; H, 8.80.
yield of 34 (20 mg, 57%); mp¼56–59 ꢀC (CHCl3); [
a
]
ꢂ92.5 (c 1,
D
CHCl3); Rf¼0.40 (hexane/ethyl acetate 1:1); IR (KBr, cmꢂ1) 2986,
2966, 2926, 2879, 1667, 1450, 1384, 1315, 1239, 1227, 1164, 1092,
4.3.4. (syn and anti)-Ethyl 4-hydroxy-5-acetylamino-hex-2-enoate
1039, 927, 867, 769, 638; 1H NMR (CDCl3, 300 MHz)
d 5.79 (d, 1H,
(26). Compound 24: (72 mg, 0.334 mmol), (Ms2O: 146 mg,
J¼10.2 Hz), 5.59 (ddd, 1H, J¼1.2, 3.3, 10.2 Hz), 4.61 (d, 1H, J¼3.3 Hz),
0.836 mmol), (Et3N: 233
isomer: 20 mg, 28%) as a yellow oil; Rf¼0.60 (dichloromethane/
MeOH 10:1); IR (KBr, cmꢂ1
3444, 2982, 1711, 1658, 1548, 1448,
1383, 1282, 1182, 1038, 983; 1H NMR (300 MHz, CDCl3)
6.88
mL, 1.672 mmol); yield of 26 (upper Rf
4.55 (m, 1H), 4.45 (dd, 1H, J¼0.9, 4.8 Hz), 1.94 (s, 3H), 1.37 (s, 6H),
1.35 (s, 3H) ppm; 13C NMR (CDCl3, 75 MHz)
d 164.2, 130.6, 122.4,
)
n
109.2, 78.9, 77.6, 71.4, 67.8, 28.1, 26.8, 24.8, 14.5 ppm; MS (EIþ) m/z
%: 223 (1), 208 (100), 165 (34), 124 (49); HRMS (EIþ) calcd for
C11H14N1O3 208.09758 found 208.09737.
d
(dd, 1H, J¼4.5, 15.6 Hz), 6.28 (d, 1H, J¼8.1 Hz), 6.09 (dd, 1H, J¼1.5,
15.6 Hz), 4.26 (dd, 1H, J¼1.8, 2ꢁ4.5 Hz), 4.16 (q, 2H, J¼7.2 Hz), 4.06–
3.99 (m, 1H), 3.30 (br s, 1H), 1.95 (s, 3H), 1.26 (t, 3H, J¼7.2 Hz), 1.19
4.3.8. (3aR,5aR,8aR,8bS)-2,2,7-Trimethyl-4-cyclohexyl-3a,5a,8a,8b-
tetrahydro[1,3]dioxolo[4,5-e][1,3]benzoxazole (38). To the pre-
cooled (4 ꢀC) solution of 37 (100 mg, 0.32 mmol) in
dichloroethane (2 mL) was added Ms2O (28 mg, 1.61 mmol) in one
(d, 3H, J¼6.9 Hz) ppm; 13C NMR (75 MHz, CDCl3)
d 171.0, 166.5,
147.3, 122.0, 73.5, 60.6, 49.7, 23.2, 17.0, 14.2 ppm; MS (FABþ) m/z %:
216 (100), 198 (20), 156 (35); HRMS calcd for C10H18NO4: 216.12094
found: 216.12358.
portion followed by dropwise addition of Et3N (450 mL,
Yield of 26 (lower Rf isomer (28 mg, 39%)) as a yellow oil; Rf¼0.5
3.23 mmol). Reaction mixture was then stirred in cooling bath and
spontaneously allowed to 15 ꢀC. TLC showed almost complete
disappearance of the starting alcohol. The mixture was then di-
luted with ethyl acetate (30 mL) and washed with 5% solution of
citric acid (2ꢁ3 mL) and then with satd solution of NaHCO3 (3 mL).
Organic layer was dried over MgSO4, filtered, and concentrated
under vacuum. Chromatography of crude [5 mL SiO2, hexane/ethyl
(dichloromethane/MeOH 10:1); IR (KBr, cmꢂ1
) n 3473, 2983, 2936,
1756, 1724, 1661, 1523, 1383, 1309, 1222, 1205, 1057, 1044, 983, 785;
1H NMR (300 MHz, CDCl3)
d
6.79 (dd,1H, J¼6.3,15.6 Hz), 6.13 (d,1H,
J¼15.6 Hz), 5.50 (dd, 1H, J¼6.9, 6.9 Hz), 4.21 (q, 2H, J¼7.2 Hz), 3.50
(m, 1H), 2.19 (s, 3H), 1.39 (d, 3H, J¼6.3 Hz), 1.30 (t, 3H,
J¼7.2 Hz) ppm; 13C NMR (75 MHz, CDCl3)
d 169.9, 165.3, 139.7,
126.0, 73.9, 60.9, 49.8, 20.9, 14.9, 14.2 ppm; MS (FABþ) m/z %: 216
(100), 156 (30); HRMS calcd for C10H18NO4: 216.12358 found:
216.12038.
acetate 4:1/2:1] afforded oxazoline 38 as a white solid (64 mg,
20
68%); mp¼46–49 ꢀC (ethyl acetate); [
a
]
þ92.4 (c 0.5, CHCl3);
D
Rf¼0.35 (hexane/ethyl acetate 3:1); IR (KBr, cmꢂ1
) n 3448, 2926,
2854, 1668, 1450, 1384, 1236, 1070 cmꢂ1 1H NMR (300 MHz,
;
4.3.5. (1S, 2R, 5R, 6R)-6-Acetylamino-1,2-O-isopropylidene-3-methyl-
CDCl3)
d
5.36 (d, 1H, J¼3.3 Hz), 5.10 (dd, 1H, J¼3.0, 8.4 Hz), 4.73
cyclohex-3-ene,
1,2,5-triol
(33). Compound
29:
(174 mg,
(dd, 1H, J¼2.4, 5.1 Hz), 4.57 (d, 1H, J¼5.1 Hz), 4.50 (m, 1H), 2.32–
2.18 (m, 1H), 1.98 (d, 3H, J¼1.5 Hz), 1.91–1.65 (m, 4H), 1.41 (s, 3H),
1.33 (s, 3H), 1.48–1.10 (m, 5H), 1.00 (dddd, 1H, J¼3.0,
0.722 mmol), (MsCl: 321 mL, 4.15 mmol), (Et3N: 1.15 mL,
8.29 mmol); yield of 33 (65 mg, 0.270 mmol, 37%); mp¼91–94 ꢀC
20
(ethyl acetate); [
(KBr, cmꢂ1
NMR (300 MHz, CDCl3)
a
]
ꢂ74.8 (c 1, CHCl3); Rf¼0.30 (ethyl acetate); IR
3ꢁ12.3 Hz) ppm; 13C NMR (75 MHz, CDCl3)
d 166.1, 146.4, 115.9,
D
)
n
3342, 2986, 2360, 1655, 1551, 1384, 1219, 1076; 1H
6.18 (br s, 1H), 5.65 (m, 1H), 4.37 (d, 1H,
108.6, 74.7, 74.2, 70.8, 63.6, 39.4, 33.2, 30.9, 27.9, 26.7, 26.6, 26.5,
26.3, 14.3 ppm; MS (EIþ) m/z %: 276 (M -Me): 234 (18), 192 (18),
175 (57), 55 (19), 43 (61), 41 (20); HRMS calcd for C17H25NO3:
276.15997 found: 276.16038.
d
J¼5.4 Hz), 4.31–4.26 (m, 2H), 4.14 (ddd, 1H, J¼3.6, 2ꢁ8.4 Hz), 1.99
(s, 3H), 1.83 (s, 3H), 1.41 (s, 3H), 1.34 (s, 3H) ppm; 13C NMR (75 MHz,
CDCl3)
d 171.4, 135.4, 125.9, 109.6, 75.2, 73.9, 65.1, 52.1, 27.8, 26.1,
23.4, 20.5 ppm; MS (EIþ) m/z %: 226 (MꢂMe), 208 (15),142 (61),124
(53), 84 (86), 43 (100); HRMS calcd for C12H16NO4: 226.10738
found: 226.10793.
4.3.9. Ethyl (3aR,5aR,8aR,8bS)-2,2,7-trimethyl-3a,5a,8a,8b-tetrahy-
dro[1,3]dioxolo[4,5-e][1,3]benzoxazole-4-carboxylate (5)1. To a stir-
red solution of allylic alcohol 4 (400 mg, 1.33 mmol) in methylene
chloride (5 mL) was added NEt3 (0.74 mL, 4.0 mmol), DMAP (cata-
lytic amount), and methanesulfonyl chloride (0.16 mL, 1.4 mmol) at
room temperature. The resulting solution was stirred for 4 h before
being quenched by the slow addition of satd NaHCO3 (5 mL), and
then extracted into ethyl acetate (3ꢁ5 mL). The combined organic
layers were washed with brine (1ꢁ2 mL), dried over NaSO4, and
concentrated under reduced pressure. The crude material was
purified via flash column chromatography with a solvent system of
hexanes/ethyl acetate (1:2) to yield 5 (204 mg, 54%) as a white-
4.3.6. (3aR,4S,5R,7aR)-2,6-Dimethyl-4–5-O-isopropyliden-3a,4,5,7a-
tetrahydrobenzo[d]oxazole-4,5-diol (32). A stirred solution of 29
(55 mg, 0.178 mmol) in methylene chloride (1 mL) was cooled to
ꢂ78 ꢀC prior to the addition of methanesulfonyl chloride (69
mL,
0.890 mmol) and triethylamine (0.248 mL, 1.78 mmol). The re-
action was spontaneously brought to ꢂ10 ꢀC, then diluted with
methylene chloride (20 mL), and washed with 5% citric acid (2 mL)
and satd NaHCO3 (2 mL). The organic layer was dried over MgSO4
with a spatula tip of solid NaHCO3, filtered, and concentrated under
vacuo The crude material was purified via column chromatography
yellow solid: Rf 0.40 (hexanes/ethyl acetate 1:4); mp¼54–55 ꢀC
23
(ethyl acetate/hexanes); [
a]
þ150.4 (c 1.25, CHCl3); Rf¼0.25
D
in a solvent system of hexane/ethyl acetate (1:1) to yield 32 (10 mg,
(hexane/ethyl acetate 4:1); IR (film)
n
3543, 2986, 1722, 1667, 1372,
6.56 (d, J¼3.0 Hz, 1H), 5.14
20
25%); [
a]
þ34.8 (c 0.5, CHCl3); Rf¼0.60 (ethyl acetate); IR (film)
n
1218 cmꢂ1; 1H NMR (600 MHz, CDCl3)
d
D
3443, 2985, 2933, 2360, 2340, 1667, 1452, 1438, 1383, 1312, 1236,
(dd, J¼2.9, 8.5 Hz, 1H), 4.93 (d, J¼5.2 Hz, 1H), 4.86 (dd, J¼2.7, 5.1 Hz,
1H), 4.58 (d, J¼8.4 Hz, 1H), 4.27–4.34 (m, 2H), 1.97 (d, J¼1.3 Hz, 3H),
1.42 (s, 3H), 1.34 (t, J¼7.2 Hz, 3H), 1.32 (s, 3H) ppm; 13C NMR
1226, 1175, 1073, 1032 cmꢂ1 1H NMR (300 MHz, CDCl3)
;
d
5.38
(m, 1H), 4.99 (m, 1H), 4.72 (dd, 1H, J¼2.4, 5.1 Hz), 4.49 (ddd, 1H,
J¼1.5, 1.5, 8.7 Hz), 4.38 (d, 1H, J¼4.8 Hz), 1.95 (d, 3H, J¼1.5 Hz), 1.84
(s, 3H), 1.40 (s, 3H), 1.34 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3)
(150 MHz, CDCl3)
d 165.9, 165.6, 133.3, 130.5, 109.1, 73.6, 73.2, 68.9,
64.3, 61.2, 27.8, 26.3, 14.2, 14.1 ppm; MS (EI) m/z (%): 266 (MꢂCHþ3 ),
43(52), 136(19), 266(100); HRMS calcd for C13H16NO5 266.1028
found 266.1032.
d
165.7, 138.0, 118.8, 108.8, 74.3, 74.3, 72.9, 63.9, 27.8, 26.6, 19.5,
14.3 ppm; MS (EIþ) m/z %: 223 (M) 208 (100), 166 (29), 124 (41), 107
(14), 95 (17), 43 (67); HRMS calcd for C12H17NO3: 223.12133 found:
223.12084.
4.3.10. (1S, 2R, 5R, 6S)-6-Acetylamino-1,2-O-isopropylidene-5-chloro-
3-cyclohexylcyclohex-3-ene-1,2-diol (39). To the pre-cooled (4 ꢀC)
solution of 37 (300 mg, 0.97 mmol) in dichloroethane (6 mL) was
4.3.7. (3aS,4R,5S,7aS)-2,3a-Dimethyl-4-5-O-isopropyliden-3a,4,5,7a-
tetrahydrobenzo[d]oxazole-4,5-diol (34). Compound 31: (38 mg,
added MsCl (375
mL, 4.85 mmol) followed by dropwise addition of
0.16 mmol), (MsCl: 55 mg, 0.32 mmol), (Et3N: 110 mL, 0.79 mmol);
Et3N (1.35 mL, 9.70 mmol). Reaction mixture was then stirred in

3768
L. Werner et al. / Tetrahedron 66 (2010) 3761–3769
cooling bath and spontaneously allowed to warm up. The mixture
was then heated to 60 ꢀC. After 4 h TLC showed complete disap-
pearance of starting alcohol, and new spots of oxazoline 38
(Rf¼0.75 ethyl acetate), chloride 39 (Rf¼0.80 ethyl acetate), quar-
ternary ammonium salts 42 and/or 43 (Rf¼0.60 dichloromethane/
MeOH 5:1) and couple others byproducts were seen. The mixture
was then concentrated and the crude material was purified via
column chromatography in a solvent system of hexane/ethyl ace-
Celite and concentrated. The crude material was purified via flash
column chromatography with a solvent system of hexanes/ethyl
acetate(1:4) to yield 6 (616 mg, 72%) as a white solid: Rf 0.23
(dichloromethane/MeOH 96:4); mp¼115–118 ꢀC (ethyl acetate/
23
hexanes); [
a
]
D
ꢂ54.3 (c 1.7, CHCl3); IR (film)
n 3307, 2624, 2247,
1718, 1655, 1541, 1247, 1069 cmꢂ1; 1H NMR (300 MHz, CDCl3)
d 7.01
(d, J¼3.1 Hz, 1NH), 5.76 (br s, 1NH), 5.01 (d, J¼5.6 Hz, 1H), 4.73
(t, J¼3.4 Hz, 1H), 4.53 (q, J¼5.9 Hz, 1H), 4.47 (t, J¼5.8 Hz, 1H), 4.26–
4.31 (m, 2H), 3.07 (br s, 1OH), 2.04 (s, 3H), 1.42 (s, 6H), 1.36
tate (4:1/3:1) to yield 39 (128 mg, 45%) and white solid of 39
20
(100 mg, 32%); mp¼163–165 ꢀC (ethyl acetate/hexanes);
[a
]
(t, J¼7.1 Hz, 3H) ppm; 13C NMR (150 MHz, CDCl3)
d 171.6, 165.4,
D
ꢂ160.2 (c 1, CHCl3); Rf¼0.80 ethyl acetate; IR (KBr, cmꢂ1
)
n
3325,
141.0, 130.3, 109.9, 73.8, 69.8, 68.8, 61.3, 52.3, 27.48, 25.7, 23.4,
14.2 ppm; MS (FAB) m/z (%): 299 (Mþ), 29(34), 43(71), 136(29),
182(23), 242(100); MS (EI) m/z (%): 284 (MꢂCHþ3 ), 43(100), 84(25),
142(23), 284(17); HRMS calcd for C13H18NO6 284.1134 found
284.1132. Anal. Calcd C, 56.18; H, 7.07. Found: C, 56.22; H, 7.17.
2993, 2926, 2876, 2854, 1645, 1536, 1457, 1383, 1220, 1073 cmꢂ1; 1H
NMR (300 MHz, CDCl3)
d
5.90 (d, 1H, J¼7.8 Hz), 5.81 (d, 1H,
J¼6.0 Hz), 4.70 (dd, 1H, J¼3.6, 4.0 Hz), 4.65 (d, 1H, J¼5.7 Hz), 4.35
(ddd, 1H, J¼3.3, 9.9, 9.9 Hz), 4.27 (dd, 1H, J¼5.7, 9.9 Hz), 2.18–2.10
(m, 1H), 2.08 (s, 3H), 1.89–1.71 (m, 5H), 1.50 (s, 3H), 1.41 (s, 3H),
1.36–1.17 (m, 5H) ppm; 13C NMR (75 MHz, CDCl3)
d
170.5, 145.1,
4.3.13. (3aS,4R,5S,7aR)-4-Acetamido-7-cyclohexyl-N,N,N-triethyl-
2,2-dimethyl-3a,4,5,7a-tetrahydrobenzo[d][1,3]dioxol-5-ammonium
methanesulfonate (42). A solution of 41 (53 mg; 0.17 mmol) in dry
dichloromethane (2 mL) was stirred under argon and cooled in
liquid N2/acetone bath to ꢂ78 ꢀC. Then Ms2O (60 mg; 0.34 mmol)
was added in one portion and the mixture was stirred again at
ꢂ78 ꢀC. After 5 min Et3N (0.71 mL; 5.12 mmol) was added dropwise
but quickly to the flask and the stirring continued for additional
2.5 h, during, which the temperature of the cooling bath raised
slowly to ꢂ5 ꢀC. Then the reaction mixture was stirred at room
temperature for 20 h. TLC (ethyl acetate) did not show any starting
alcohol, but there was a significant spot at the baseline. The sol-
vents were evaporated and the chromatography of residue (ethyl
acetate/ethyl acetate/MeOH 7:1) afforded salt 42 (40 mg) as
122.9, 109.6, 73.4, 73.3, 57.6, 50.5, 41.8, 32.6, 31.4, 27.8, 26.6, 26.4,
26.1, 25.9, 23.5 ppm; MS (EIþ) m/z %: 312 (MꢂMe) 276 (98), 234
(38), 192 (38), 175 (68), 43 (100); HRMS calcd for C17H26ClNO3:
327.1601 found: 312.13665. Anal. Calcd for C17H26ClNO3: C, 62.28;
H, 7.99. Found: C, 62.44; H, 8.06.
4.3.11. N-((3aS,4R,5R,7aR)-7-Cyclohexyl-5-hydroxy-2,2-dimethyl-
3a,4,5,7a-tetrahydrobenzo[d][1,3]dioxol-4-yl)acetamide (40). To the
pre-cooled (4 ꢀC) solution of 37 (300 mg, 0.97 mmol) in di-
chloroethane (6 mL) was added MsCl (375 mL, 4.85 mmol) followed
by dropwise addition of Et3N (1.35 mL, 9.70 mmol). Reaction mix-
ture was then stirred in cooling bath and spontaneously allowed to
reach ambient temperature. The mixture was then heated for 4 h at
60 ꢀC. TLC showed complete disappearance of starting alcohol, and
new spots of oxazoline 38 (Rf¼0.75 ethyl acetate), chloride 39
(Rf¼0.80 ethyl acetate), quarternary ammonium salts 42 and/or 43
(Rf¼0.60, dichloromethane/MeOH (5:1)) and a couple of other
byproducts were observed. The mixture was then concentrated and
the residue dissolved in EtOH (8 mL). After addition of NaOH (4 mL,
1 M) the mixture was heated 1 h to 90 ꢀC. Then mostly presence of
oxazoline 38 was observed by TLC, and pH of reaction mixture was
changed from ~8 to ~10 with NaOH (4 mL, 1 M) and mixture was
heated to 90 ꢀC additional 16 h. After complete disappearance of
intermediary oxazoline was reaction mixture concentrated and
partitioned between dichloromethane (40 mL) and H2O (2ꢁ4 mL).
Aqueous layer was re-extracted with dichloromethane (20 mL) and
combined organic layer dried over MgSO4 and concentrated under
vacuum. Chromatography of crude [15 mL SiO2, ethyl acetate]
a yellowish oil and oxazoline 39 (10 mg).
20
Rf¼0.6 (dichloromethane/MeOH 5:1); [
a
]
ꢂ36.5 (c 1, MeOH);
D
IR (KBr, cmꢂ1) 3589, 3440, 3429, 3302, 3285, 3238, 3190, 3051,
2989, 2976, 2929, 2879, 2853, 2756, 2739, 2677, 2627, 2603, 2492,
1661, 1644, 1551, 1523, 1475, 1453, 1435, 1427, 1398, 1383, 1328,
1289, 1241, 1209, 1140, 1009, 979, 927, 891, 874, 851, 804, 567; 1H
NMR (CDCl3, 300 MHz)
d
8.99 (d, 1H, J¼9.0 Hz), 5.61 (d, 1H,
J¼1.2 Hz), 4.97 (dd, 1H, J¼1.2, 9.0 Hz), 4.54 (ddd, 1H, J¼9.0, 9.0,
9.0 Hz), 4.50 (d,1H, J¼5.4 Hz), 4.39 (dd,1H, J¼5.4, 7.5 Hz), 3.68–3.48
(m, 6H), 2.80 (s, 3H), 2.19 (m, 1H), 2.09 (s, 3H), 1.88–1.68 (m, 5H),
1.37–1.15 (m, 10H) ppm; 13C NMR (CDCl3, 75 MHz)
d 171.7, 147.9,
115.7, 110.2, 71.5, 69.7, 53.8, 46.9, 46.0, 42.8, 39.5, 32.5, 31.3, 27.8,
26.5, 26.3, 26.2, 25.9, 23.4, 9.3, 8.6 ppm; MS (FABþ) m/z %: 393 (45),
292 (14), 234 (11), 175 (31); HRMS (FABþ) calcd for C23H41N2O3
(cation without methanesulfonate counterion); 393.31172 found
393.30982.
afforded 40 as a white solid (173 mg, 58%); mp¼158–160 ꢀC (ethyl
20
acetate/hexane); [
a
]
D
ꢂ48.1 (c 1, CHCl3); Rf¼0.35 (ethyl acetate); IR
(KBr, cmꢂ1
) n 3382, 3276, 2931, 2853, 1646, 1534, 1384, 1218, 1063;
Acknowledgements
1H NMR (300 MHz, CDCl3)
d
5.86 (d, 1H, J¼7.9 Hz), 5.72 (d, 1H,
J¼4.8 Hz), 4.60 (d, 1H, J¼5.7 Hz), 4.41 (dd, 1H, J¼3.9, 3.9 Hz), 4.32
(dd, 1H, J¼5.4, 8.4 Hz), 4.24 (ddd, 1H, J¼3.6, 8.4, 8.4 Hz), 2.19–2.08
(m, 1H), 2.05 (s, 3H), 1.90–1.70 (m, 5H), 1.46 (s, 3H), 1.40 (s, 3H),
The authors are grateful to the following agencies for financial
support of this work: Natural Sciences and Engineering Research
Council of Canada (NSERC), (Idea to Innovation and Discovery
Grants); Canada Research Chair Program, Canada Foundation for
Innovation (CFI), Research Corporation, TDC Research, Inc.; Brock
University; and the Ontario Partnership for Innovation and Com-
mercialization (OPIC).
1.35–1.10 (m, 5H) ppm; 13C NMR (150 MHz, CDCl3)
d 171.0, 144.5,
123.6, 109.5, 74.0, 73.1, 65.6, 52.1, 41.6, 32.9, 31.5, 27.9, 26.7, 26.4,
26.2, 26.1, 23.6 ppm; MS (EIþ) m/z %: 309 (M): 294 (18), 276 (23),
192 (44), 142 (75), 84 (100), 43 (63); HRMS calcd for C17H27NO4:
309.19449 found: 309.19401. Anal. Calcd for C17H27NO4: C, 65.99; H,
8.80. Found: C, 65.79; H, 8.93.
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