Study on the stereochemical control of dihydroxylation of vinyl epoxides and their derivatives

Article abstract of DOI:10.1016/j.tet.2012.02.029

The results obtained from a study on the stereochemical control in the dihydroxylation of the double bond of vinyl epoxides and their derivatives (bromo derivatives, azido derivatives and vinyl aziridines) are presented herein. A significant diastereosele

Full text of DOI:10.1016/j.tet.2012.02.029

Tetrahedron 68 (2012) 2984e2992
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Study on the stereochemical control of dihydroxylation of vinyl epoxides
and their derivatives
Giuliana Righi a, Emanuela Mandic’ b, Gaia Clara Mercedes Naponiello b, Paolo Bovicelli c,
,
Ilaria Tirotta b
*
a CNR-ICB Unity of Rome, P.le A. Moro, 5, 00185 Rome, Italy
b Department of Chemistry, “Sapienza” University of Rome, P.le A. Moro, 5, 00185 Rome, Italy
c CNR-ICB Unity of Sassari, Traversa La Crucca 3, Baldanica, I-07040 Sassari, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 October 2011
Received in revised form 22 January 2012
Accepted 13 February 2012
Available online 21 February 2012
The results obtained from a study on the stereochemical control in the dihydroxylation of the double
bond of vinyl epoxides and their derivatives (bromo derivatives, azido derivatives and vinyl aziridines)
are presented herein. A significant diastereoselectivity was observed for the bromo derivatives, azido
derivatives and N-protected vinyl aziridines, whereas vinyl epoxides and unprotected vinyl aziridines
showed no diastereoselectivity. The results obtained are generally consistent with the Kishi model.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Dihydroxylation
Vinyl epoxides
Vinyl aziridines
Azidoalcohols
Bromohydrins
1. Introduction
A subsequent dihydroxylation reaction of the alkene could lead
to four adjacent stereogenic centres in a controlled fashion, thus
Optically active aminopolyalcoholic fragments1 can be found in
a wide range of natural or synthetic biologically active compounds
such as azasugars,2 sphingoid structures3 and sialic acids.4 Our
research group has been focused for many years on this field and
the elaboration of optically active aziridines and epoxides has been
targeted as a convenient approach to the synthesis of these frag-
ments.5 Recently we have developed suitable methodologies6,7 for
the regio- and stereoselective nucleophilic opening of vinyl epox-
ides and vinyl aziridines. As shown in Fig. 1 it is possible to regio-
selectively introduce a nucleophile, such as halides or azides, in
the allylic position exploiting its inherent reactivity.
providing useful precursors of aminopolyalcoholic structures. The
dihydroxylation reaction is characterized by a syn stereospecificity.
Moreover a preexisting stereocenter adjacent to the double bond
can direct the osmium tetroxide approach preferentially on one of
the two faces of the olefin leading to different extents of diaster-
eoselectivity.8 A large number of studies have appeared in the lit-
erature on this matter but only a few of them9 pertain to vinyl
epoxides, vinyl aziridines and their derivatives, substrates of choice
for this work.
2. Results and discussion
With the purpose of identifying the substrate leading to the best
stereochemical control of the dihydroxylation and therefore the
most suitable for synthetic applications, the reaction was carried
out on: unsaturated azidoalcohols (type A), bromohydrins (type B),
epoxides (type C) and differently protected aziridines (type D)
(Fig. 2). Moreover the R group and the protective group (P) on the
aziridine ring were varied in order to investigate the possible in-
fluence of steric hindrance on the diastereoselectivity of the
reaction.
Fig. 1. Regioselective and stereospecific nucleophilic opening reactions of vinyl ep-
oxides and aziridines.
* Corresponding author. Tel.: þ39 (0)6 490422; fax: þ39 (0)6 49913628; e-mail
address: ilaria.tirotta@gmail.com (I. Tirotta).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.02.029

G. Righi et al. / Tetrahedron 68 (2012) 2984e2992
2985
Fig. 2. Substrates of choice.
Scheme 2. Reagents and conditions: (a) m-CPBA, CH2Cl2, 0 ꢀC (83%); (b) TEMPO, IBDA,
CH2Cl2, rt (72%); (c) LiOH, TEPA, THF, 70 ꢀC (88%); (d) LiBr, Amberlyst15, acetone, rt
(90%).
2.1. Synthesis of the substrates
2.2. Dihydroxylation reactions
All the substrates were synthesized starting from the corre-
sponding allylic alcohol10 following the same synthetic path
(Scheme 1).
All the compounds synthesized were then submitted to the
dihydroxylation reaction. The results are summarized in Table 1.
The ratio of the two diastereomers was determined from the in-
tegrals of the 1H NMR spectra of the mixture. The attribution of
each signal to the appropriate diastereomer was made in different
ways depending on the class of the substrate.
Table 1
Diasteroselective dihydroxylation reaction on differently functionalized vinyl com-
pounds: results
Entry
Olefin
R
Diols
Ratio
1
2
3
4a
4b
5a
24a/24a0
24b/24b0
16a/16a0
60:40
55:45
90:10
Scheme 1. Reagents and conditions: (a) m-CPBA, CH2Cl2, 0 ꢀC; (b) TEMPO, IBDA,
CH2Cl2, rt; (c) LiOH, TEPA, THF, 70 ꢀC; d) BF3$Et2O, TMSN3, CH2Cl2, 0 ꢀC to rt; (e) PPh3,
acetonitrile, rt to 70 ꢀC; (f) Et3N, ClCOOEt, dry Et2O, 0 ꢀC to rt; (g) Boc2O, DMAP, dry
CH2Cl2, rt; (h) LiBr, Amberlyst15, acetone, rt; (i) NaN3, dry DMF, rt.
4
5b
16b/16b0
90:10
Epoxy alcohols 2a and 2b were obtained via
a non-
asymmetric epoxidation11 reaction and then converted into the
corresponding epoxy aldehydes 3a and 3b using the well known
TEMPO/IBDA method, which is mild enough to preserve the ep-
oxide function. A subsequent HornereEmmons reaction afforded
5
6
6a
6b
27a/27a0
27b/27b0
50:50
50:50
a,b-unsaturated epoxy esters 4a and 4b, which are the first
substrates of study.
The oxirane ring of compounds 4a and 4b was then regio-se-
lectively and stereo-specifically opened using a method12 recently
developed by our group. Using BF3$OEt2 as the Lewis acid and
TMSN3 as the azide source it is possible to exploit the reactivity of
the allylic position and regio-selectively introduce the azide group
in this position, obtaining anti-azidoalcohols 5a and 5b. These
compounds were then converted into the corresponding azir-
idines 6a and 6b via a well-known procedure.13 The aziridines
were finally protected as ethyl and tert-butyl carbamate (com-
7
8
7a
7b
28a/28a0
28b/28b0
90:10
90:10
9
8a
8b
29a/29a0
29b/29b0
85:15
87:13
pounds 7a, 7b, 8a, 8b). a,b-Unsaturated esters 4a and 4b were also
used to prepare four more substrates. A first regio- and stereo-
selective LiBr/Amberlyst15 mediated ring opening reaction14 led
to the corresponding anti-bromohydrins 9a and 9b. Then a sub-
stitution reaction using NaN3 in DMF afforded syn-azidoalcohols
10a and 10b.
10
syn-Bromohydrin 15 was obtained starting from cis-2-hexen-1-
ol following the same synthetic pathway described before for
compounds 10a and 10b (Scheme 2).
11
9a
20a/20a0
75:25
(continued on next page)

2986
G. Righi et al. / Tetrahedron 68 (2012) 2984e2992
Table 1 (continued )
These results seem to indicate that the stereochemistry of the re-
action is not affected by the azide group in the allylic position and
may be driven instead by the OH group in the homoallylic position.
These data also indicate that the steric hindrance of the R group on
the epoxide ring does not influence the stereochemistry of the
reaction.
Entry
Olefin
R
Diols
Ratio
12
13
14
9b
20b/20b0
22a/22a0
18b/18b0
70:30
75:25
90:10
2.2.2. Bromo derivatives. Similar considerations can be made for
the anti-bromohydrins 9a and 9b (Scheme 5). We can assert again
that the steric hindrance of the R group has little influence on the
reaction.
15
10a
15
10b
18a/18a0
90:10
2.2.1. Azido derivatives. As shown in Schemes 3 and 4 the dihy-
droxylation reaction on both anti (5a, 5b) and syn (10a, 10b) azido
derivatives led to a mixture of diols in a 90:10 diastereomeric ratio.
In both cases the recognition of the stereochemistry of the major
product was made by converting the mixture into the corre-
sponding 1,3-acetonides. It is known15 that these compounds have
characteristic signals in the 13C NMR spectrum depending on their
stereochemistry: an anti-acetonide (e.g., compound 17a0) shows
a signal at w100 ppm for the ketalic carbon and two very close
signals at w25 ppm for the C(CH3)2, whereas in a syn-acetonide
(e.g., compound 17a) the ketalic carbon shows a signal at w98 ppm
and the C(CH3)2 two different signals at w19 and w30 ppm. In both
cases the major product proved to be a syn-acetonide indicating
that the major diols were compounds 16a, 16b, 18a and 18b.
Scheme 5. Reagents and conditions: (a) OsO4, NMO, H2O/acetone, rt (70e80%); (b)
2,2-dimethoxypropane, p-toluensulfonic acid, acetone, rt (90e95%).
The bromotriols mixtures obtained were chromatographically
inseparable. Therefore, to fully characterize the major products, the
mixtures were converted into the corresponding 1,3-acetonides:
the prevalent compounds turned out to be syn-acetonides 21a and
21b thus indicating an anti correlation between the Br and the diol
in compounds 20a and 20b (major products of the dihydroxylation
reaction).
An anti correlation between the bromine and the diol moiety
was also observed in the dihydroxylation of syn-bromohydrin 15
(Scheme 6).
Scheme 3. Reagents and conditions: (a) OsO4, NMO, H2O/acetone, rt (84e87%); (b)
2,2-dimethoxypropane, p-toluensulfonic acid, acetone, rt (90e95%).
Scheme 6. Reagents and conditions: (a) OsO4, NMO, H2O/acetone, rt (75%); (b) 2,2-
dimethoxypropane, p-toluensulfonic acid, acetone, rt (93%).
Unlike that observed with the azidoalcohols, these results seem
to indicate that the configuration of the bromine is actually able to
influence the OsO4 attack, leading in all cases to a product with an
anti correlation between the Br and the diol moiety. This could be
justified by the different steric hindrance exerted by bromine
compared to the azide.
2.2.3. Epoxides. In the case of vinyl epoxides, the oxirane ring did
not affect the diastereoselectivity of the dihydroxylation reaction:
Scheme 4. Reagents and conditions: (a) OsO4, NMO, H2O/acetone, rt (85e89%); (b)
2,2-dimethoxypropane, p-toluensulfonic acid, acetone, rt (90e95%).

G. Righi et al. / Tetrahedron 68 (2012) 2984e2992
2987
4a and 4b gave an inseparable mixture with a syn correlation be-
tween the ring and the diol moiety in the main product (Scheme 7).
dihydroxylation reaction on both the COOEt protected compounds
7a and 7b led to a mixture with a 90:10 diastereomeric ratio
(Scheme 10).
Scheme 10. Reagents and conditions: OsO4, NMO, H2O/acetone, rt (70e73%).
Similarly, the diol mixtures obtained from Boc protected com-
pounds 8a and 8b showed a diastereomeric ratio of 85:15 and 87:13
(Scheme 11).
Scheme 7. Reagents and conditions: (a) OsO4, NMO, H2O/acetone, rt (70%); (b) 2,2-
dimethoxypropane, p-toluensulfonic acid, acetone, 0 ꢀC (80%).
At first the stereochemical assignment of the epoxy-diols was
based on their spectroscopic characteristics. As reported in the
literature,16 the general trend for epoxy alcohols is that the 1H NMR
signal for the CHOH of the syn-diastereomer is more shielded than
the one for the anti-diastereomer (Fig. 3). Our experimental data
were in line with the literature: the signal of the CHOH adjacent to
the oxirane ring falls at w3.8 ppm for compounds 24a and 24b and
is shifted 0.1 ppm upfield in compounds 24a0 and 24b0 (w4.0 ppm).
Scheme 11. Reagents and conditions: OsO4, NMO, H2O/acetone, rt (70e75%).
This extremely different reactivity between protected and un-
protected aziridines can be explained by the high steric hindrance
exerted by the protective group on the double bond.
The stereochemical assignment of the major diastereomers was
made, as well as for the epoxy-diols, by comparison with literature
data,17 which pointed, in all our cases, towards the compounds with
an anti correlation between the ring and the diol moiety as the
major ones. We want to point out that the comparison was made
with aziridino-alcohols, assuming that their chemical shift trend is
similar to the aziridino diols one as it has been noted for epoxides.
Therefore this assignment is still speculative.
Fig. 3. Chemical shifts for a general CHOH adjacent to an oxirane ring as reported in
the literature.
To confirm the stereochemical assignment, the previously de-
termined stereochemistry of the bromotriols was exploited. Com-
pound 20a was converted into a 1,2-acetonide (26), subsequently
submitted to a ring closing reaction that gave an epoxy acetonide,
which proved to be spectroscopically identical to 25a (Scheme 8),
the major epoxy acetonide obtained from the protection of the 24a/
24a0 mixture.
3. Conclusions
In conclusion, the results obtained from this study show that the
presence of a bromo alcohol, an azido alcohol or an N-protected
aziridine moiety on the double bond is able to induce a significative
stereochemical control in the dihydroxylation reaction. In contrast,
when the olefin is substituted with an epoxide or an unprotected
aziridine almost no stereoselectivity is observed. These results are
consistent with Kishi’s model,18 where the osmium attack occurs
leading to a product characterized by an anti correlation between
the diol and the group adjacent to the double bond. The azido
derivatives and the epoxides are exceptions: in the former case the
osmium attack seems to be led by the OH group in the homoallylic
position; the latter case seems to represent an exception to the
Kishi’s rule as no selectivity is observed.
The relevant diastereoselection obtained in some cases allows
the preparation of attractive compounds having at least four con-
tiguous stereogenic centres, useful intermediates in the synthesis
of a wide range of biologically active compounds such as, for ex-
ample, aminosugars. Studies in this direction are currently under
investigation.
Scheme 8. Reagents and conditions: (a) 2,2-dimethoxypropane, p-toluensulfonic acid,
acetone, 0 ꢀC (80%); (b) KOH, MeOH, reflux.
2.2.4. Aziridines. The unprotected aziridine ring did not affect the
diastereoselectivity of the reaction leading for both compounds 6a
and 6b to a chromatographically inseparable mixture with a di-
astereomeric ratio of 50:50 (Scheme 9).
As shown in Table 1 completely different results were obtained
when the nitrogen was protected as carbamate. The
4. Experimental
4.1. General
NMR spectra were recorded on a VARIAN Mercury 3000 in-
strument (1H, 300 MHz; 13C, 75 MHz). Chemical shifts were
Scheme 9. Reagents and conditions: (a) OsO4, NMO, H2O/acetone, rt (70%).

2988
G. Righi et al. / Tetrahedron 68 (2012) 2984e2992
calculated from the residual solvent signals of dH 7.24 ppm and dC
77.0 ppm in chloroform-d. HRMS were performed on a Q-TOF MI-
CRO spectrometer (Micromass, now Waters, Manchester, UK)
equipped with an ESI source. All chromatographic purifications
were performed on silica gel (100e200 mesh from E. Merck, Ger-
many). Thin layer chromatography (TLC) was performed on pre-
coated silica gel 60 F254 aluminium sheets (Merck Italia) and
spots were visualized under UV torch. Organic solvents used for the
chemical synthesis and for chromatography acquired from Merck
Italia were of analytical grade.
CH2ꢂ2þCH3ꢂ2), 0.78 (3H, t, J 7.3 Hz, CH2CH2CH3); 13C NMR
(75 MHz, CDCl3) d: 165.1, 160.7, 143.4, 124.0, 62.1, 60.13, 45.4, 43.2,
32.7, 19.8, 14.1, 13.9, 13.2; HRMS (ES Q-TOF): [MþH]þ, found
256.1543. C13H21NO4 requires 256.1549.
4.2.2.2. (E)-Ethyl 3-((2R
iridin-2-yl)acrylate (7b). Pale yellow oil (289 mg, 98% yield); IR
(neat, cmꢁ1): 2955, 2860, 1725, 1250; 1H NMR (300 MHz, CDCl3)
*
,3R
*
)-3-(N-ethoxycarbonyl)cyclohexylaz
d
:
6.29 (1H, dd, J 9.4, 15.4 Hz, CH]CHCO), 6.08 (1H, d, J 15.4 Hz,
CHCO), 4.22e4.00 (4H, m, COCH2CH3ꢂ2), 2.89 (1H, dd, J 2.8, 9.4 Hz,
CHeCH]CH), 2.38e2.29 (1H, m, cyclohexyleCH), 1.99e0.96 (17H,
4.2. Synthesis of the substrates
m, cyclohexylþCOCH2CH3ꢂ2); 13C NMR (75 MHz, CDCl3)
d: 165.2,
161.0, 143.6, 124.2, 62.3, 60.3, 50.3, 42.3, 39.5, 30.2, 29.6, 26.0, 25.5,
25.3, 14.1, 14.0; HRMS (ES Q-TOF): [MþH]þ, found 296.1865.
C16H25NO4 requires 296.1862.
The following compounds were prepared following already
known procedures and all experimental data were consistent with
the ones reported in the literature:
2a,b,19 3a,20 3b,21 4a,22 4b,23 5a,7a 5b,24 8a.24
4.2.3. General procedure for the Boc protection. Under nitrogen at-
mosphere, 1 mmol of the appropriate substrate was dissolved in
10 mL of anhydrous dichloromethane. Boc2O of 1.1 mmol (248 mg,
0.2 mL) and a catalytic amount of DMAP were then added and the
reaction mixture stirred at room temperature for 12 h or until
consumption of the substrate (TLC monitoring). The solvent was
then evaporated under reduced pressure to give the desired
product, which was used without any purification.
4.2.1. General procedure for the aziridine ring formation. To a stirred
solution of the appropriate substrate (1 mmol) in anhydrous ace-
tonitrile (1 mL), PPh3 (1.2 mmol, 314 mg) was added under nitrogen
atmosphere and the flask equipped with a monitoring device for
the nitrogen release. After 2 h the reaction mixture was brought to
the reflux temperature and stirred for 12 h. The solvent was then
removed under reduced pressure, the crude dissolved in 4 mL of
cold Et2O, filtered, concentrated and purified by flash chromatog-
raphy on silica gel (hexane/AcOEt 7:3) to give the desired product.
4.2.3.1. (E)-Ethyl
3-((2R
*
,3R )-3-(N-tert-butoxycarbonyl)cyclo-
*
hexylaziridin-2-yl)acrylate (8b). Pale yellow oil (317 mg, 98% yield);
IR (neat, cmꢁ1): 3020, 2915, 1730, 1245; 1H NMR (300 MHz, CDCl3)
4.2.1.1. (E)-Ethyl
(6a). Pale brown oil (166 mg, 90% yield); IR (neat, cmꢁ1): 2935,
2400, 1720; 1H NMR (300 MHz, CDCl3)
: 6.30 (1H, dd, J 8.8, 15.4 Hz,
3-((2R
*
,3R
*
)-3-propylaziridin-2-yl)acrylate
d: 6.33 (1H, dd, J 9.4, 15.4 Hz, CH]CHCO), 6.10 (1H, d, J 15.4 Hz,
CHCO), 4.20 (2H, q, J 7.2 Hz, COCH2CH3), 2.87 (1H, dd, J 2.8, 9.4 Hz,
CHeCH]CH), 2.36e2.31 (1H, m, cyclohexyleCHeN), 1.99e1.58
(5H, m, cyclohexyl), 1.42 (9H, s, C(CH3)3), 1.25 (3H, t, J 7.2 Hz,
COCH2CH3), 1.22e1.07 (6H, m, cyclohexyl); 13C NMR (75 MHz,
d
CH]CHCO), 5.87 (1H, d, J 15.4 Hz, CHCO), 4.20 (2H, q, J 7.2 Hz,
COCH2CH3), 2.13 (1H, dd, J 2.2, 8.8 Hz, CHeCH]CH), 1.94e1.85 (1H,
m, CH2CHeN), 1.42e1.21 (5H, m, CH2ꢂ2þNH), 1.11 (3H, t, J 7.2 Hz,
COCH2CH3), 0.78 (3H, t, J 7.3 Hz, CH2CH2CH3); 13C NMR (75 MHz,
CDCl3) d: 165.7, 160.4, 144.2, 124.0, 81.7, 60.4, 50.4, 42.5, 39.7, 30.3,
29.8, 27.8, 26.0, 25.6, 25.4, 14.2; HRMS (ES Q-TOF): [MþH]þ, found
CDCl3)
d
: 166.2, 148.6, 121.4, 60.2, 40.5, 37.8, 35.4, 20.4, 14.1, 13.7;
324.2179. C18H29NO4 requires 324.2175.
HRMS (ES Q-TOF): [MþH]þ, found 184.1335. C10H17NO2 requires
184.1338.
4.2.4. General procedure for the LiBr/Amb15 ring opening re-
action. LiBr (4 mmol, 260 mg) and Amberlyst15 (1 mmol, 212 mg)
were added to 1 mmol of the appropriate substrate dissolved in
8 mL of acetone and the mixture stirred overnight. After filtration,
the mixture was concentrated in vacuo and the residue taken up in
5 mL of ethyl acetate, neutralized and washed with 5 mL of brine.
The organic layer was dried on Na2SO4 and the solvent evaporated
under reduced pressure to give the desired product that was used
without any purification.
4.2.1.2. (E)-Ethyl 3-((2R
(6b). Pale yellow oil (90% yield); IR (neat, cmꢁ1): 2940, 2410, 1725;
1H NMR (300 MHz, CDCl3)
: 6.41 (1H, dd, J 8.8,15.4 Hz, CH]CHCO),
*
,3R
*
)-3-cyclohexylaziridin-2-yl)acrylate
d
5.99 (1H, d, J 15.4 Hz, CHCO), 4.18 (2H, q, J 7.2 Hz, COCH2CH3), 2.31
(1H, dd, J 2.8, 8.8 Hz, CHCH]CH), 1.82 (1H, dd, J 2.8, 7.7 Hz, cyclo-
hexyleCHeNH), 1.77e1.56 (6H, m, cyclohexylþNH), 1.20e0.85 (9H,
m, cyclohexylþCOCH2CH3); 13C NMR (75 MHz, CDCl3)
d: 166.0,
148.9, 121.2, 60.2, 46.0, 41.8, 36.7, 30.9, 30.3, 26.2, 25.7, 25.6, 14.1;
HRMS (ES Q-TOF): [MþH]þ, found 224.1655. C13H21NO2 requires
224.1651.
4.2.4.1. (E)(4R
(9a). Pale yellow oil (238 mg, 90% yield); IR (neat, cmꢁ1): 3315,
2915, 1720, 1245, 550; 1H NMR (300 MHz, CDCl3)
: 7.03 (1H, dd, J
*
,5S
*
)-Ethyl 4-bromo-5-hydroxyoct-2-enoate
d
4.2.2. General procedure for the COOEt protection. Under nitrogen
atmosphere 1 mmol of the appropriate substrate was dissolved in
3 mL of anhydrous diethyl ether. Et3N of 1.2 mmol (121 mg, 0.2 mL)
and 1.2 mmol (130 mg, 0.1 mL) of ethyl chloroformate were then
added and the reaction mixture stirred at room temperature for 3 h
or until consumption of the substrate (TLC monitoring). The mix-
ture was then filtered through a Celite pad and the solvent evap-
orated under reduced pressure to give the desired product, which
was used without any purification.
9.9, 15.4 Hz, CH]CHCO), 5.99 (1H, d, J 15.4 Hz, CHCO), 4.59 (1H, dd,
J 3.3, 9.9 Hz, CHeBr), 4.20 (2H, q, J 7.2 Hz, COCH2CH3), 3.96e3.80
(1H, m, CHeOH), 2.40 (1H, br s, OH), 1.61e1.39 (4H, m, CH2ꢂ2), 1.30
(3H, t, J 7.2 Hz, COCH2CH3), 0.92 (3H, t, J 7.3 Hz, CH2CH2CH3); 13C
NMR (75 MHz, CDCl3) d: 165.12, 141.9, 124.2, 73.6, 60.5, 57.1, 35.7,
18.7, 13.9, 13.5; HRMS (ES Q-TOF): [MþH]þ, found 265.0436.
C10H17BrO3 requires 265.0439.
4.2.4.2. (E)(4R
2-enoate (9b). Pale yellow oil (289 mg, 95% yield); IR (neat, cmꢁ1):
3290, 2945, 1715, 1250, 685, 560; 1H NMR (300 MHz, CDCl3)
: 7.15
*
,5S
*
)-Ethyl 4-bromo-5-cyclohexyl-5-hydroxypent-
4.2.2.1. (E)-Ethyl 3-((2R
idin-2-yl)acrylate (7a). Pale yellow oil (248 mg, 97% yield); IR (neat,
cmꢁ1): 2925, 1720, 1255, 1120; 1H NMR (300 MHz, CDCl3)
: 6.40
*
,3R
*
)-3-(N-ethoxycarbonyl)propylazir-
d
(1H, dd, J 10.2, 15.6 Hz, CH]CHCO), 6.02 (1H, d, J 15.6 Hz, CHCO),
4.79 (1H, dd, J 3.8, 10.2 Hz, CHeBr), 4.18 (2H, q, J 7.2 Hz, COCH2CH3),
3.64 (1H, dd, J 3.8, 7.7 Hz, CHeOH), 2.8 (1H, br s, OH), 1.8e0.93 (14H,
d
(1H, dd, J 8.8, 15.4 Hz, CH]CHCO), 6.09 (1H, d, J 15.4 Hz, CHCO),
4.22e4.00 (4H, m, COCH2CH3ꢂ2), 2.81 (1H, dd, J 2.8, 8.8 Hz,
CHeCH]CH), 2.53e2.45 (1H, m, CH2CH), 1.72e1.10 (10H, m,
m, cyclohexylþCOCH2CH3); 13C NMR (75 MHz, CDCl3)
d: 165.6,
140.7, 125.6, 76.9, 64.7, 60.9, 39.8, 29.2, 28.1, 26.2, 25.9, 25.5, 14.2;

G. Righi et al. / Tetrahedron 68 (2012) 2984e2992
2989
HRMS (ES Q-TOF): [MþH]þ, found 305.0750. C13H21BrO3 requires
(2H, q, J 7.2 Hz, COCH2CH3), 3.97e3.88 (1H, m, CH2CHOH), 3.85 (1H,
dd, J 0.5, 9.6 Hz, CHOHeCHOH), 3.62 (1H, dd, J 5.6, 9.6 Hz, CHN3),
1.71e1.46 (7H, m, CH2ꢂ2þOHꢂ3), 1.3 (3H, t, J 7.2 Hz, COCH2CH3),
305.0753.
4.2.4.3. (E)(4R
(15). Pale yellow oil (238 mg, 90% yield); IR (neat, cmꢁ1): 3310,
2915, 1720, 1240, 550; 1H NMR (300 MHz, CDCl3)
: 6.90 (1H, dd, J
*
,5R
*
)-Ethyl 4-bromo-5-hydroxyoct-2-enoate
0.9 (3H, t, J 6.6 Hz, CH2CH2CH3); 13C NMR (75 MHz, CDCl3)
d: 173.3,
73.6, 73.2, 71.3, 65.9, 62.4, 34.7, 18.7, 14.2, 14.1; HRMS (ES Q-TOF):
d
[MþH]þ, found 262.1406. C10H19N3O5 requires 262.1403.
9.7,15.4 Hz, CH]CHCO), 5.90 (1H, d, J 15.4 Hz, CHCO), 4.47 (1H, dd, J
5.1, 9.7 Hz, CHeBr), 4.20 (2H, q, J 7.2 Hz, COCH2CH3), 3.65e3.51 (1H,
m, CHeOH), 2.96 (1H, br s, OH), 1.55e1.30 (4H, m, CH2ꢂ2), 1.20 (3H,
t, J 7.2 Hz, COCH2CH3), 0.80 (3H, t, J 6.7 Hz, CH2CH2CH3); 13C NMR
4.3.2. (2S
*
,3R
*
,4S
*
,5S )-Ethyl 4-azido-2,3,5-trihydroxyoctanoate
*
(16a0) (data given only for the signal(s) used to calculate the ratio
between the two diastereomers). 1H NMR (300 MHz, CDCl3)
(1H, d, J 0.6 Hz, CHOHeCO).
d: 4.4
(75 MHz, CDCl3) d: 165.6, 143.4, 123.6, 73.0, 60.8, 58.6, 36.5, 18.7,
14.1, 13.8; HRMS (ES Q-TOF): [MþH]þ, found 265.0438. C10H17BrO3
requires 265.0439.
4.3.3. (2R
*
,3S
*
,4S
*
,5S )-Ethyl 4-azido-5-cyclohexyl-2,3,5-trihydroxy-
*
pentanoate (16b) (data given only for the major product). Pale yel-
4.2.5. General procedure for the nucleophilic substitution (BreN3).
Under nitrogen atmosphere NaN3 (4 mmol, 260 mg) was added to
1 mmol of the appropriate substrate dissolved in 1 mL of anhydrous
DMF and the mixture left stirring at room temperature until com-
plete consumption of the substrate. The mixture was then diluted
with 3 mL of ethyl acetate and washed with 5 mL of brine. The
organic layer was dried on Na2SO4 and the solvent evaporated
under reduced pressure to give the desired product, which was
used without any purification.
low oil (241 mg, 80% yield); IR (neat, cmꢁ1): 3300, 2910, 2120, 1720,
1770; 1H NMR (300 MHz, CDCl3)
d: 4.43 (1H, d, J 0.5 Hz, CHOHeCO),
4.28e4.05 (4H, m, COCH2CH3þCHOHeCHOHþcyclohexyleCHOH),
3.65e3.63 (1H, m, CHN3), 1.88e1.44 (8H, m, cyclohexylþOHꢂ3),
1.34e0.8 (9H, m, cyclohexylþCOCH2CH3); 13C NMR (75 MHz, CDCl3)
d
: 173.1, 83.4, 78.1, 74.7, 71.5, 62.2, 40.4, 30.1, 29.2, 26.4, 25.9, 25.6,
14.2; HRMS (ES Q-TOF): [MþH]þ, found 302.1711. C13H23N3O5 re-
quires 302.1715.
4.3.4. (2S
*
,3R
*
,4S
*
,5S )-Ethyl 4-azido-5-cyclohexyl-2,3,5-
*
4.2.5.1. (E)(4S
(10a). Yellow oil (204 mg, 90% yield); IR (neat, cmꢁ1): 3305,
3050, 2890, 2125, 1720; 1H NMR (300 MHz, CDCl3)
: 6.78 (1H, dd, J
*
,5S
*
)-Ethyl 4-azido-5-hydroxyoct-2-enoate
trihydroxypentanoate (16b0) (data given only for the signal(s) used
to calculate the ratio between the two diastereomers). 1H NMR
d
(300 MHz, CDCl3)
4.3.5. (2R ,3S ,4R
d
: 4.39 (1H, d, J 0.4 Hz, CHOHeCO).
7.2, 15.9 Hz, CH]CHCO), 6.01 (1H, d, J 15.9 Hz, CHCO), 4.20 (2H, q, J
7.2 Hz, COCH2CH3), 3.95e3.75 (1H, m, CHN3), 3.60e3.45 (1H, m,
CHeOH), 2.40 (1H, br s, OH), 1.61e1.11 (4H, m, CH2ꢂ2), 1.30 (3H, t, J
7.2 Hz, COCH2CH3), 0.92 (3H, t, J 7.3 Hz, CH2CH2CH3); 13C NMR
*
*
*
,5S )-Ethyl 4-azido-2,3,5-trihydroxyoctanoate (18a)
*
(data given only for the major product). Pale yellow oil (198 mg, 76%
yield); IR (neat, cmꢁ1): 3280, 2910, 2120, 1720, 1780; 1H NMR
(75 MHz, CDCl3)
d
: 165.34, 141.48, 124.41, 72.55, 67.31, 60.47, 35.17,
(300 MHz, CDCl3) d: 4.26 (1H, d, J 2.6 Hz, CHOHeCO), 4.2 (2H, q, J
18.37, 13.80, 13.52; HRMS (ES Q-TOF): [MþH]þ, found 228.1345.
7.2 Hz, COCH2CH3), 4.08 (1H, dd, J 2.6, 6.3 Hz, CHOHeCHOH),
3.78e3.70 (1H, m, CH2CHOH), 3.38 (1H, dd, J 2.4, 6.3 Hz, CHN3),
1.67e1.33 (7H, m, CH2ꢂ2þOHꢂ3), 1.27 (3H, t, J 7.2 Hz, COCH2CH3),
C10H17N3O3 requires 228.1348.
4.2.5.2. (E)(4S
2-enoate (10b). Brown oil (254 mg, 95% yield); IR (neat, cmꢁ1):
3300, 3055, 2910, 2120, 1730; 1H NMR (300 MHz, CDCl3)
: 6.83
*
*
,5S )-Ethyl 4-azido-5-cyclohexyl-5-hydroxypent-
0.9 (3H, t, J 7.3 Hz, CH2CH2CH3); 13C NMR (75 MHz, CDCl3)
d: 173.4,
71.4, 71.1, 70.4, 65.5, 62.3, 36.3, 19.2, 14.2, 13.9; HRMS (ES Q-TOF):
d
[MþH]þ, found 262.1400. C10H19N3O5 requires 262.1403.
(1H, dd, J 7.5, 15.8 Hz, CH]CHCO), 6.04 (1H, d, J 15.8 Hz, CHCO),
4.31e3.98 (3H, m, CHN3þCOCH2CH3), 3.28 (1H, dd, J 5.4 Hz,
CHeOH), 2.65 (1H, br s, OH), 1.94e0.93 (14H, m, cyclo-
4.3.6. (2S
*
,3R
*
,4R
*
,5S )-Ethyl 4-azido-2,3,5-trihydroxyoctanoate
*
(18a0) (data given only for the signal(s) used to calculate the ratio
hexylþCOCH2CH3); 13C NMR (75 MHz, CDCl3)
d: 165.5, 141.9, 124.5,
between the two diastereomers). 1H NMR (300 MHz, CDCl3)
(1H, d, J 1.5 Hz, CHOHeCO).
d: 4.41
77.2, 64.9, 60.7, 40.0, 29.6, 27.0, 26.0, 25.9, 25.7, 14.0; HRMS (ES Q-
TOF): [MþH]þ, found 268.1663. C13H21N3O3 requires 268.1661.
4.3.7. (2R
*
,3S
*
,4R
*
,5S )-Ethyl 4-azido-5-cyclohexyl-2,3,5-
*
4.3. General procedure for the dihydroxylation reaction
trihydroxypentanoate (18b) (data given only for the major pro-
duct). Pale yellow oil (236 mg, 78% yield); IR (neat, cmꢁ1): 3290,
To a solution of 1 mmol of the appropriate substrate in 9 mL of
acetone/water (8:1) were added 2 mmol (270 mg) of NMO and
0.63 mL of a 2.5% solution of OsO4 in tert-butanol (0.05 mmol of
OsO4) and the mixture left stirring overnight at room temperature.
The reaction was then quenched with 5 mL of a saturated solution
of Na2S2O3, the mixture left stirring for 1 h and then transferred in
a separating funnel. The aqueous layer was extracted with 10 mL of
ethyl acetate, the combined organic layers dried over Na2SO4 and
the solvent removed under reduced pressure. The residue was then
purified by chromatography on silica gel to give the mixture of the
desired products.
2910, 2120, 1725, 1780; 1H NMR (300 MHz, CDCl3)
d: 4.36 (1H, d, J
2.6 Hz, CHOHeCO), 4.33e4.21 ( 3H, m, COCH2CH3þCHOHeCHOH),
3.69 (1H, dd, J 2.0, 6.7 Hz, cyclohexyleCHOH), 3.45 (1H, dd, J 2.0,
8.4 Hz, CHN3), 2.0e1.50 (8H, m, cyclohexylþOHꢂ3), 1.34e0.8 (9H,
m, cyclohexylþCOCH2CH3); 13C NMR (75 MHz, CDCl3)
d: 172.8, 75.9,
73.9, 71.0, 64.6, 62.5, 41.2, 29.1, 26.3, 25.9, 25.8, 25.5, 14.2; HRMS (ES
Q-TOF): [MþH]þ, found 302.1717. C13H23N3O5 requires 302.1715.
4.3.8. (2S
*
,3R
*
,4R
*
,5S )-Ethyl 4-azido-5-cyclohexyl-2,3,5-
*
trihydroxypentanoate (18b0) (data given only for the signal(s) used
to calculate the ratio between the two diastereomers). 1H NMR
The chromatographically inseparable mixtures 20a/20a0, 20b/
20b0, 22a/22a0, 24a/24a0, 24b/24b0 were subsequently converted
into the corresponding acetonides to allow a full characterization.
(300 MHz, CDCl3)
d: 4.41 (1H, d, J 2.0 Hz, CHOHeCO).
4.3.9. (2R ,3S )-Ethyl 3-((2S
*
*
*
,3R )-3-propylaziridin-2-yl)-2,3-
*
dihydroxy propanoate (27a/27a0) (data given for the inseparable
mixture). Pale brown oil (153 mg, 70% yield); IR (neat, cmꢁ1): 3300,
4.3.1. (2R
*
,3S
*
,4S
*
,5S )-Ethyl 4-azido-2,3,5-trihydroxyoctanoate
*
(16a) (data given only for the major product). Pale yellow oil
2920, 2415, 1725; 1H NMR (300 MHz, CDCl3)
d: 4.32e4.20 (6H, m,
(200 mg, 77% yield); IR (neat, cmꢁ1): 3290, 2905, 2125, 1725, 1780;
CHOHeCOꢂ2þCOCH2CH3ꢂ2), 3.73 (1H, dd, J 2.1, 4.8 Hz, CHOHe-
1H NMR (300 MHz, CDCl3)
d: 4.45 (1H, d, J 0.5 Hz, CHOHeCO), 4.2
CHOH), 3.65 (1H, dd, J 2.3, 4.9 Hz, CHOHeCHOH), 2.8e2.3 (4H, br s,

2990
G. Righi et al. / Tetrahedron 68 (2012) 2984e2992
OHꢂ4), 2.12e2.0 (2H, m, CH2CHꢂ2), 1.95e1.83 (2H, m,
CHeCHOHꢂ2), 1.54e1.37 (8H, m, CH2ꢂ4), 1.35e1.20 (6H, m,
COCH2CH3ꢂ2), 0.98e0.83 (6H, m, CH2CH2CH3ꢂ2); 13C NMR
diastereomers). 1H NMR (300 MHz, CDCl3)
6.6 Hz, CHOHeCHOH).
d: 3.7 (1H, dd, J 1.6,
(75 MHz, CDCl3)
d
: 172.7, 73.5, 72.8, 72.7, 71.9, 61.8, 39.1, 38.6, 35.7,
4.3.17. (2R
*
,3S
*
)-Ethyl
3-((2S
*
,3R )-3-cyclohexyl-(N-tert-butox-
*
35.5, 35.4, 34.9, 20.8, 14.2, 13.9.
ycarbonyl)aziridin-2-yl)-2,3-dihydroxy propanoate (29b) (data given
only for the major product). Pale yellow oil (233 mg, 65% yield); IR
(neat, cmꢁ1): 3295, 2920, 1740; 1H NMR (300 MHz, CDCl3)
d: 4.38
4.3.10. (2R
*
,3S
*
)-Ethyl 3-((2S
*
,3R )-3-cyclohexylaziridin-2-yl)-2,3-
*
dihydroxy propanoate (27b/27b0) (data given for the inseparable mix-
(1H, d, J 0.5 Hz, CHOHeCO), 4.25 (2H, q, J 7.2 Hz, COCH2CH3), 3.97
(1H, dd, J 5.0, 1.8 Hz, CHOHeCHOH), 2.5 (1H, dd, J 3.5, 5.0 Hz,
CHeCHOH), 2.36 (1H, dd, J 3.5, 7.5 Hz, cyclohexyleCH), 2.05e1.59
(7H, m, cyclohexylþOHꢂ2), 1.4 (9H, s, C(CH3)3), 1.34e1.00 (9H, m,
ture). Brown oil (180 mg, 70% yield); IR (neat, cmꢁ1): 3295, 2920,
2410, 1725; 1H NMR (300 MHz, CDCl3)
d: 4.33e4.14 (6H, m,
CHOHeCOꢂ2þCOCH2CH3ꢂ2), 3.69 (1H, dd, J 4.5 Hz, CHOHeCHOH),
3.60 (1H, dd, J 2.2, 4.8 Hz, CHOHeCHOH), 3.4e2.9 (4H, br s, OHꢂ4),
2.4e2.3 (2H, m, CHꢂ2), 2.2e2.1 (2H, m, CHeCHOHꢂ2),1.9e1.5 (10H,
m, cyclohexyl), 1.4e0.9 (18H, m, cyclohexylþCOCH2CH3ꢂ2); 13C
cyclohexylþCOCH2CH3); 13C NMR (75 MHz, CDCl3)
d: 172.9, 161.1,
81.2, 72.4, 70.8, 62.2, 46.4, 42.7, 41.0, 39.7, 30.3, 28.0, 26.3, 25.8, 25.6,
14.2; HRMS (ES Q-TOF): [MþH]þ, found 358.2225. C18H31NO6 re-
quires 358.2229.
NMR (75 MHz, CDCl3)
d: 172.4, 73.9, 73.5, 73.2, 72.9, 62.1, 39.8, 39.0,
35.9, 35.8, 35.6, 34.9, 20.8, 14.2, 13.9.
4.3.18. (2S
*
,3R
*
)-Ethyl 3-((2S
*
,3R )-3-cyclohexyl-(N-tert-butoxy car-
*
4.3.11. (2R
*
,3S
*
)-Ethyl
3-((2S
*
,3R )-3-propyl-(N-ethoxycarbonyl)
*
bonyl)aziridin-2-yl)-2,3-dihydroxy propanoate (29b) (data given
aziridin-2-yl)-2,3-dihydroxy propanoate (28a) (data given only for
the major product). Pale brown oil (182 mg, 63% yield); IR (neat,
only for the signal(s) used to calculate the ratio between the two
diastereomers). 1H NMR (300 MHz, CDCl3)
9.5 Hz, CHOHeCHOH).
d: 3.9 (1H, dd, J 1.6,
cmꢁ1): 3280, 2925, 1740; 1H NMR (300 MHz, CDCl3)
d: 4.37 (1H, d, J
1.7 Hz, CHOHeCO), 4.27 (2H, q, J 7.2 Hz, COCH2CH3), 4.16 (2H, q, J
7.2 Hz, NCOCH2CH3), 3.99 (1H, dd, J 1.7, 4.9 Hz, CHOHeCHOH),
2.63e2.56 (1H, m, CH2CH), 2.49 (1H, dd, J 3.4, 4.9 Hz, CHeCHOH),
2.1 (2H, br s, OHꢂ2), 1.81e1.4 (4H, m, CH2ꢂ2), 1.35e1.20 (6H, m,
COCH2CH3ꢂ2), 0.9 (3H, t, J 7.4 Hz, CH2CH2CH3); 13C NMR (75 MHz,
4.4. General procedure for the acetonide formation
Appropriate substrate of 1 mmol was dissolved in 10 mL of ac-
etone. To the mixture 2,2-dimethoxypropane (1.4 mmol, 0.17 mL)
and a catalytic amount of p-toluensulfonic acid were added and the
mixture left stirring at room temperature until complete con-
sumption of the substrate. The reaction crude was diluted with
10 mL of Et2O and filtered through a basic alumina pad; the solvent
was then removed under reduced pressure and the residue purified
by chromatography on silica gel to give the mixture of the desired
products.
CDCl3) d: 165.1, 160.7, 71.9. 69.1 62.1, 60.13, 45.4, 43.2, 32.7, 19.8, 14.1,
13.9, 13.2; HRMS (ES Q-TOF): [MþH]þ, found 290.1600. C13H23NO6
requires 290.1604.
4.3.12. (2S
*
,3R
*
)-Ethyl
3-((2S
*
,3R )-3-propyl-(N-ethoxycarbonyl)
*
aziridin-2-yl)-2,3-dihydroxy propanoate (28a0) (data given only for
the significant signals). 1H NMR (300 MHz, CDCl3)
1.5 Hz, CHOHeCO).
d: 4.34 (1H, d, J
To obtain 1,2-acetonides the reaction needs to be carried out at
ꢁ20 to 0 ꢀC (kinetic control conditions) whereas at room temper-
ature for 1,3-acetonides (thermodynamic control conditions).
4.3.13. (2R
*
,3S
*
)-Ethyl 3-((2S
*
,3R )-3-cyclohexyl(N-ethoxycarbonyl)
*
aziridin-2-yl)-2,3-dihydroxypropanoate (28b) (data given only for
the major product). Pale yellow oil (217 mg, 66% yield); IR (neat,
4.4.1. (R
*
)-Ethyl 2-((4S
*
,5S
*
,6S )-5-azido-2,2-dimethyl-6-propyl-1,3-
*
cmꢁ1): 3295, 2920, 2410; 1H NMR (300 MHz, CDCl3)
d: 4.32 (1H, d, J
dioxan-4-yl)-2-hydroxyacetate (17a). Pale yellow oil (271 mg, 90%
0.5 Hz, CHOHeCO), 4.29e4.06 (5H, m, COCH2CH3ꢂ2þCHOHeCHOH),
2.5(1H, dd, J3.6 Hz, CHN), 2.4(1H,dd, J3.6,6.0 Hz,CHN), 2.21(2H, brs,
OHꢂ2), 2.01e1.56 (5H, m, cyclohexyl), 1.36e0.96 (12H, m, cyclo-
yield); IR (neat, cmꢁ1): 3280, 2925, 2125, 1735; 1H NMR (300 MHz,
CDCl3)
d: 4.37 (1H, d, J 1.9 Hz, CHOH), 4.2 (2H, q, J 7.2 Hz,
COCH2CH3), 3.89 (1H, dd, J 1.9, 10.0 Hz, CHeCHOH), 3.6 (1H, ddd, J
2.5, 8.0, 10.0 Hz, CH2CH), 3.35 (1H, dd, J 10.0 Hz, CHN3), 2.53 (1H, br
s, OH), 1.82e1.41 (4H, m, CH2ꢂ2), 1.37 (3H, s, CCH3), 1.33 (3H, s,
CCH3), 1.28 (3H, t, J 7.2 Hz, COCH2CH3), 0.9 (3H, t, J 7.4 Hz,
hexylþCOCH2CH3ꢂ2); 13C NMR (75 MHz, CDCl3)
d: 172.8, 172.7, 72.4,
69.7, 62.3, 62.2, 45.4, 43.0, 39.5, 30.8, 30.0, 26.3, 25.8, 25.6, 14.4, 14.2;
HRMS (ES Q-TOF): [MþH]þ, found 330.1914. C16H27NO6 requires
330.1917.
CH2CH2CH3); 13C NMR (75 MHz, CDCl3)
d: 172.1, 98.9, 73.5, 71.8,
70.0, 61.8, 58.6, 35.0, 29.2, 19.2, 18.1, 14.3, 13.9; HRMS (ES Q-TOF):
4.3.14. (2S
*
,3R
*
)-Ethyl 3-((2S
*
,3R )-3-cyclohexyl(N-ethoxycarbonyl)
*
[MþH]þ, found 302.1719. C13H23N3O5 requires 302.1716.
aziridin-2-yl)-2,3-dihydroxypropanoate (28b0) (data given only for the
signal(s) used to calculate the ratio between the two diastereomers). 1H
4.4.2. (R
*
)-Ethyl 2-((4S
*
,5S
*
,6S )-5-azido-2,2-dimethyl-6-cyclohexyl-
*
NMR (300 MHz, CDCl3)
4.3.15. (2R ,3S )-Ethyl
d
: 4.29 (1H, d, J 0.8 Hz, CHOHeCO).
1,3-dioxan-4-yl)-2-hydroxyacetate (17b). Colourless oil (317 mg,
93% yield); IR (neat, cmꢁ1): 3290, 2920, 2120, 1735; 1H NMR
*
*
3-((2S ,3R )-3-propyl-(N-tert-butoxycarb
*
*
onyl)aziridin-2-yl)-2,3-dihydroxy propanoate (29a) (data given only
for the major product). Pale brown oil (190 mg, 60% yield); IR (neat,
(300 MHz, CDCl3) d: 4.43 (1H, dd, J 1.8, 9.0 Hz, CHOH), 4.2 (2H, q, J
7.2 Hz, COCH2CH3), 3.9 (1H, dd, J 1.8, 9.4 Hz, CHeCHOH), 3.65e3.45
(2H, m, CHeCHN3þCHN3), 2.9 (1H, d, J 9.0 Hz, OH), 1.84e1.57 (5H,
m, cyclohexyl), 1.39e1.11 (15H, m, cyclohexylþC(CH3)2þ
cmꢁ1): 3300, 2920, 1735; 1H NMR (300 MHz, CDCl3)
d: 4.38 (1H, d, J
0.5 Hz, CHOHeCO), 4.2 (2H, q, J 7.2 Hz, COCH2CH3), 3.88 (1H, dd, J
0.5, 5.2 Hz, CHOHeCHOH), 2.58e2.50 (1H, m, CH2CHN), 2.45 (1H,
dd, J 3.3, 5.2 Hz, CHeCHOH), 2.3 (2H, br s, OHꢂ2), 1.78e1.39 (13H,
m, CH2ꢂ2þC(CH3)3), 1.29 (3H, t, J 7.2 Hz, COCH2CH3), 0.95 (3H, t, J
COCH2CH3); 13C NMR (75 MHz, CDCl3)
d: 165.8, 99.0, 75.8, 73.7,
70.3, 61.9, 54.9, 39.1, 30.0, 29.3, 26.8, 26.5, 26.4, 25.7, 19.2, 14.0;
HRMS (ES Q-TOF): [MþH]þ, found 342.2023. C16H27N3O5 requires
342.2029.
7.4 Hz, CH2CH2CH3); 13C NMR (75 MHz, CDCl3)
d: 165.2, 159.2, 80.9,
71.9, 69.1, 60.5, 45.8, 43.1, 33.1, 31.2, 27.9, 14.4, 14.0; HRMS (ES Q-
TOF): [MþH]þ, found 318.1917. C15H27NO6 requires 318.1917.
4.4.3. (R
*
)-Ethyl 2-((4S
*
,5R
*
,6S )-5-azido-2,2-dimethyl-6-propyl-1,3-
*
dioxan-4-yl)-2-hydroxyacetate (19a). Yellow oil (277 mg, 92%
yield); IR (neat, cmꢁ1): 3285, 2920, 2125, 1735; 1H NMR (300 MHz,
4.3.16. (2S
*
,3R
*
)-Ethyl
3-((2S
*
,3R )-3-propyl-(N-tert-butox-
*
ycarbonyl)aziridin-2-yl)-2,3-dihydroxy propanoate (29a0) (data
CDCl3)
d
: 4.44e4.11 (3H, m, COCH2CH3þCHOH), 3.91 (1H, dd, J 1.7,
given only for the signal(s) used to calculate the ratio between the two
10.0 Hz, CHeCHOH), 3.6 (1H, ddd, J 2.5, 7.9, 10.0 Hz, CH2CH), 3.38

G. Righi et al. / Tetrahedron 68 (2012) 2984e2992
2991
(1H, dd, J 10.0 Hz, CHN3), 2.5 (1H, br s, OH), 1.82e1.41 (4H, m,
CH2ꢂ2), 1.37 (3H, s, CCH3), 1.33 (3H, s, CCH3), 1.28 (3H, t, J 7.2 Hz,
COCH2CH3), 0.9 (3H, t, J 7.4 Hz, CH2CH2CH3); 13C NMR (75 MHz,
signal(s) used to calculate the ratio between the two dia-
stereomers). 1H NMR (300 MHz, CDCl3)
CHeCOOEt).
d: 4.35 (1H, d, J 7.0 Hz,
CDCl3) d: 172.1, 98.9, 73.6, 71.9, 70.0, 61.8, 58.6, 35.1, 29.8, 19.2, 18.2,
14.4, 13.9; HRMS (ES Q-TOF): [MþH]þ, found 302.1719. C13H23N3O5
4.4.11. (4R
*
,5S
*
)-Ethyl 2,2-dimethyl-5-((2R
*
,3S )-3-cyclohexyloxiran-
*
requires 302.1716.
2-yl)-1,3-dioxolane-4-carboxylate (25b). Colourless oil (155 mg,
52% yield); IR (neat, cmꢁ1): 2920, 1750, 880; 1H NMR (300 MHz,
4.4.4. (R
*
)-Ethyl 2-((4S
*
,5R
*
,6S
*
)-5-azido-2,2-dimethyl-6-cyclohexyl-
CDCl3) d: 4.44 (1H, d, J 7.7 Hz, CHeCO), 4.2 (2H, q, J 7.2 Hz,
1,3-dioxan-4-yl)-2-hydroxyacetate (19b). colourless oil (325 mg,
COCH2CH3), 4.02 (1H, dd, J 5.0, 7.7 Hz, CHeCHCO), 2.99 (1H, dd, J
2.2, 5.0 Hz, CHeOeCH), 2.93 (1H, dd, J 2.2, 5.4 Hz, cyclohexyleCH),
1.84e1.57 (5H, m, cyclohexyl), 1.46 (3H, s, CCH3), 1.43 (3H, s, CCH3),
1.39e1.11 (9H, m, cyclohexylþCOCH2CH3); 13C NMR (75 MHz,
95% yield); IR (neat, cmꢁ1): 3280, 2920, 2120, 1740; 1H NMR
(300 MHz, CDCl3) d: 4.45 (1H, dd, J 4.3, 7.4 Hz, CHOH), 4.2 (2H, q, J
7.2 Hz, COCH2CH3), 3.80 (1H, dd, J 3.0, 7.4 Hz, CHeCHOH), 3.60 (1H,
dd, J 4.8 Hz, CHeCHN3), 3.35 (1H, dd, J 3.0, 4.8 Hz, CHN3), 2.6 (1H, d,
J 4.3 Hz, OH), 1.84e1.57 (5H, m, cyclohexyl), 1.39e1.11 (15H, m,
CDCl3) d: 170.4, 112.2, 79.3, 76.4, 61.7, 60.3, 56.7, 39.7, 29.8, 29.4,
26.3, 25.7, 25.6, 14.3; HRMS (ES Q-TOF): [MþH]þ, found 299.1854.
cyclohexylþC(CH3)2þCOCH2CH3); 13C NMR (75 MHz, CDCl3)
d
:
C16H26O5 requires 299.1858.
170.8, 99.0, 75.8, 73.7, 70.3, 61.9, 54.9, 40.0, 30.0, 29.3, 26.8, 26.5,
26.4, 25.7, 19.2, 14.3; HRMS (ES Q-TOF): [MþH]þ, found 342.2023.
C16H27N3O5 requires 342.2029.
4.4.12. (4S
*
,5S
*
)-Ethyl 2,2-dimethyl-5-((2S
*
,3S )-3-cyclohexyl ox-
*
iran-2-yl)-1,3-dioxolane-4-carboxylate (25b0) (data given only for the
signal(s) used to calculate the ratio between the two dia-
4.4.5. (R
*
)-Ethyl
2-((4R
*
,5S
*
,6S
*
)-5-bromo-2,2-dimethyl-6-propyl-
stereomers). 1H NMR (300 MHz, CDCl3)
CHeCO).
d: 4.3 (1H, d, J 8.2 Hz,
1,3-dioxan-4-yl)-2-hydroxyacetate (21a). Light orange oil (229 mg,
68% yield); IR (neat, cmꢁ1): 3300, 2920, 1750, 550; 1H NMR
(300 MHz, CDCl3) d: 4.57 (1H, dd, J 1.7, 9.2 Hz, CHOH), 4.41e4.14
Acknowledgements
(3H, m, CHeBrþCOCH2CH3), 3.95e3.86 (2H, m, CHeOꢂ2), 2.85
(1H, d, J 9.2 Hz, OH), 1.82e1.41 (4H, m, CH2ꢂ2), 1.37 (3H, s, CCH3),
1.33 (3H, s, CCH3), 1.28 (3H, t, J 7.2 Hz, COCH2CH3), 0.9 (3H, t, J
We thank MIUR (Ministry of University and Research, Rome) for
partial financial support (PRIN 2008: Stereoselective synthesis and
biological evaluation of new compounds active towards proteic
targets involved in viral pathologies, cell growth and apoptosis.)
7.4 Hz, CH2CH2CH3); 13C NMR (75 MHz, CDCl3)
d: 172.3, 98.9,
75.5, 73.4, 70.7, 61.8, 48.3, 35.4, 29.4, 19.3, 18.1, 14.5, 13.9; HRMS
(ES Q-TOF): [MþH]þ, found 339.0805. C13H23BrO5 requires
339.0807.
References and notes
4.4.6. (S
*
)-Ethyl 2-((4S
*
,5S
*
,6S )-5-bromo-2,2-dimethyl-6-propyl-1,3-
*
1. (a) Pulz, R.; Schade, W.; Reissing, H.-U. Synlett 2003, 405e407; (b) Bergmeier, S.
C. Tetrahedron 2000, 56, 2561e2576; (c) Polt, R.; Sames, D.; Chruma, J. J. Org.
Chem. 1999, 64, 6147e6158; (d) Righi, P.; Marotta, E.; Rosini, G. Chem.dEur. J.
1998, 4, 2501e2508; (e) Annunziata, R.; Cinquini, M.; Cozzi, F.; Raimondi, L.;
Restelli, A. Helv. Chim. Acta 1985, 68, 1217e1225.
dioxan-4-yl)-2-hydroxyacetate (21a0) (data given only for the sig-
nal(s) used to calculate the ratio between the two diastereomers). 1H
NMR (300 MHz, CDCl3)
d
: 4.50 (1H, dd, J 1.5, 8 Hz, CHOH).
2. (a) Ichikawa, Y.; Igarashi, Y.; Ichikawa, M.; Suhara, Y. J. Am. Chem. Soc. 1998, 120,
3007e3018; (b) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron:
Asymmetry 2000, 11, 1645e1680; (c) Afarinkia, K.; Bahar, A. Tetrahedron:
Asymmetry 2005, 16, 1239e1287.
3. (a) Liao, J.; Tao, J.; Lin, G.; Liu, D. Tetrahedron 2005, 61, 4715e4733; (b) Koshinen,
P. M.; Koshinen, A. M. P. Synthesis 1998, 1075e1091.
4.4.7. (R )-Ethyl 2-((4R
*
*
,5S ,6R )-5-bromo-2,2-dimethyl-6-propyl-
*
*
1,3-dioxan-4-yl)-2-hydroxyacetate (23). Pale brown oil (237 mg,
70% yield); IR (neat, cmꢁ1): 3290, 2920, 1745, 560; 1H NMR
(300 MHz, CDCl3) d: 4.54 (1H, dd, J 4.2, 8.4 Hz, CHeBr), 4.41 (1H, dd,
4. (a) Liu, Z.; Wang, B.; Zhao, L.; Li, Y.; Shao, H.; Yi, H.; You, X.; Li, Z. Bioorg. Med.
Chem. Lett. 2007, 17, 4851e4854; (b) Altamore, T. M.; Duggan, P. J.; Krippner, G.
Y. Bioorg. Med. Chem. 2006, 14, 1126e1133; (c) Masuda, T.; Shibuya, S.; Arai, M.;
Yoshida, S.; Tomozawa, T.; Ohno, A.; Yamashita, M.; Honda, T. Bioorg. Med.
Chem. Lett. 2003, 13, 669e673.
5. (a) Righi, G.; Ciambrone, S.; D’Achille, C.; Leonelli, A.; Bonini, C. Tetrahedron
2006, 62, 11821e11826; (b) Righi, G.; Ciambrone, S.; Bonini, C. Synth. Commun.
2006, 36, 1157e1165; (c) Righi, G.; Ciambrone, S.; Bonini, C. Bioorg. Med. Chem.
2008, 16, 902e908; (d) Righi, G.; Ferrara, A.; Mari, A.; Bovicelli, P. Synth. Com-
mun. 2010, 40, 1650e1657.
6. (a) Righi, G.; Bovicelli, P.; Antonioletti, R.; Fazzolari, E. Tetrahedron Lett. 2000, 41,
9315e9318; (b) Righi, G.; Bovicelli, P.; Potini, C. Tetrahedron Lett. 2002, 43,
5867e5869.
7. (a) Righi, G.; Salvati Manni, L.; Bovicelli, P.; Pelagalli, R. Tetrahedron Lett. 2011,
52, 3895e3896; (b) Righi, G.; Marucci, C.; Bovicelli, P.; Tirotta, I. Synthesis,
submitted for publication.
J 1.2 Hz, CHOH), 4.34e4.13 (3H, m, CHeCHOHþCOCH2CH3), 3.76
(1H, ddd, J 4.2, 8.0, 12.2 Hz, CH2eCH), 2.45 (1H, br s, OH), 1.71e1.19
(13H, m, CH2ꢂ2þC(CH3)2þCOCH2CH3), 0.9 (3H, t,
J 7.4 Hz,
: 172.3, 101.8, 76.4, 74.5,
CH2CH2CH3); 13C NMR (75 MHz, CDCl3)
d
69.0, 62.0, 54.9, 35.9, 23.9, 23.6, 18.8, 14.3, 13.9; HRMS (ES Q-TOF):
[MþH]þ, found 339.0809. C13H23BrO5 requires 339.0807.
4.4.8. (S
*
)-Ethyl
2-((4S
*
,5S
*
,6R )-5-bromo-2,2-dimethyl-6-propyl-
*
1,3-dioxan-4-yl)-2-hydroxy acetate (230) (data given only for the sig-
nal(s) used to calculate the ratio between the two diastereomers). 1H
NMR (300 MHz, CDCl3)
d: 4.49 (1H, dd, J 4.0, 8.9 Hz, CHeBr).
4.4.9. (4R ,5S )-Ethyl 2,2-dimethyl-5-((2R
*
*
*
,3S )-3-propyloxiran-2-
*
8. (a) Kolb, H. C.; Van Nieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94,
2483e2547; (b) Kishi, Y.; Cha, J. K.; Christ, W. J. Tetrahedron 1984, 40,
2247e2255; (c) Sharpless, K. B.; Kolb, H. C.; Anderson, P. G. J. Am. Chem. Soc.
1994, 116, 1270e1278; (d) Hermitage, S. A.; Murphy, A.; Nielsen, P.; Stanley, M.
R. Tetrahedron 1998, 54, 13185e13202.
yl)-1,3-dioxolane-4-carboxylate (25a). Colourless oil (147 mg, 57%
yield); IR (neat, cmꢁ1): 2915, 1750, 880; 1H NMR (300 MHz, CDCl3)
d: 4.44 (1H, d, J 7.7 Hz, CHeCOOEt), 4.2 (2H, q, J 7.2 Hz, COCH2CH3),
9. (a) Kim, N.; Choi, J.; Cha, J. J. Org. Chem. 1993, 58, 7096e7099; (b) Yadav, J. S.;
Raju, A.; Rao, P.; Rajaiah, G. Tetrahedron: Asymmetry 2005, 16, 3283e3290;
Moran, E.; Tellew, J.; Zhao, Z.; Armstrong, E. J. Org. Chem. 1993, 58, 7848e7859.
10. For the substrates with R¼cyclohexyl the appropriate alcohol 1b is not com-
mercially available and it was synthesized from the cyclo-
hexanecarboxaldehyde. A HornereEmmons reaction, followed by a reduction
of the ester using DIBAL, led to alcohol 1b with an overall yield of 97%.
11. For the purposes of this work it is not mandatory to have optically active
compounds, all the molecules are intended as racemates and the stereochem-
istry is only reported as the relative one
4.02 (1H, dd, J 5.0, 7.7 Hz, CHeCHCOOEt), 2.99 (1H, ddd, J 2.2, 5.2,
7.4 Hz, CHeOeCHeCH), 2.93 (1H, dd, J 2.2, 5.0 Hz, CH2eCH),
1.64e1.48 (4H, m, CH2ꢂ2), 1.46 (3H, s, CCH3), 1.43 (3H, s, CCH3), 1.28
(3H, t, J 7.2 Hz, COCH2CH3), 0.9 (3H, t, J 7.4 Hz, CH2CH2CH3); 13C
NMR (75 MHz, CDCl3) d: 170.4, 112.2, 78.9, 76.3, 61.7, 57.7, 56.1, 33.8,
26.7, 25.9, 19.4, 14.3, 14.0; HRMS (ES Q-TOF): [MþH]þ, found
259.1549. C13H22O5 requires 259.1545.
12. See Ref. 7a.
4.4.10. (4S
*
,5S
*
)-Ethyl 2,2-dimethyl-5-((2S
*
,3S
*
)-3-propyloxiran-2-
13. Legters, J.; Thijs, L.; Zwanemburg, B. Recl. Trav. Chim. Pays-Bas 1992, 111, 1e15.
14. See Ref. 6.
yl)-1,3-dioxolane-4-carboxylate (25a0) (data given only for the

2992
G. Righi et al. / Tetrahedron 68 (2012) 2984e2992
15. Rychnovsky, S. D.; Rogers, B.; Yang, G. J. Org. Chem. 1993, 58, 3511e3515.
16. (a) Adam, W.; Nestler, B. J. Am. Chem. Soc. 1993, 115, 7226e7236; (b) Miheclich,
E. D. Tetrahedron Lett. 1979, 20, 4729e4732.
17. (a) Hwang, G. I.; Chung, J. H.; Lee, W. K. J. Org. Chem. 1996, 61, 6183e6188; (b) Andres,
J. M.; de Elena, N.; Pedrosa, R.; Pretz-Encavo, A. Tetrahedron 1999, 55, 14137e14144.
18. See Ref. 8b.
20. De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G. J. Org. Chem.
1997, 62, 6974e6977.
21. Righi, G.; Chionne, A.; Bonini, C. Eur. J. Org. Chem. 2000, 18, 3127e3132.
22. Miyashita, M.; Mizutani, T.; Tadano, G.; Iwata,, Y.; Miyazawa, M.; Tanino, K.
Angew. Chem., Int. Ed. 2005, 44, 5094e5097.
23. Righi, G.; Bovicelli, P.; Barontini, M.; Tirotta, I. Green Chem. 2012, 14,
495e502.
24. See Ref. 23.
19. Gao, Y.; Klunder, J. M.; Hanson, R. M.; Masamune, H.; Ko, S. Y.; Sharpless, K. B.
J.Am. Chem. Soc. 1987, 109, 5765e5779.