Transformation of α,β-epoxyesters into 2,3-dideuterioesters promoted by samarium diiodide

Article abstract of DOI:10.1021/jo026043a

An easy and general sequenced elimination/reduction process by means of samarium diiodide, in the presence of D₂O, provides an efficient method for synthesizing 2,3-dideuterioesters 2. The reaction can be also carried out in the presence of H₂O instead of D₂O, yielding the corresponding saturated esters 4. Other deuterated esters have been also obtained. A mechanism to explain this synthesis has been proposed.

Full text of DOI:10.1021/jo026043a

SCHEME 1. Syn th esis of 2,3-Did eu ter ioester s
Tr a n sfor m a tion of r,â-Ep oxyester s in to
2,3-Did eu ter ioester s P r om oted by
Sa m a r iu m Diiod id e
J ose´ M. Concello´n,* Eva Bardales, and Ricardo Llavona
Departamento de Quı´mica Orga´nica e Inorga´nica,
Facultad de Quı´mica, Universidad de Oviedo,
J ulia´n Claverı´a, 8, 33071 Oviedo, Spain
In addition, we also reported the transformation of
2-halo-3-hydroxyesters or amides into 2,3-dideuteri-
oesters or amides, respectively, by using samarium
diiodide and D2O.7
jmcg@sauron.quimica.uniovi.es
Received J une 11, 2002
In this paper, we describe a novel transformation of
R,â-epoxyesters 1 into 1,2-dideuterioesters 2 based on the
ability of samarium diiodide to produce sequential or-
ganic reactions.8 Thus, a â-elimination reaction of R,â-
epoxyesters 1 promoted by SmI2 and a 1,4-reduction of
the obtained R,â-unsaturated esters 3 with D2O in the
presence of SmI2, afforded the corresponding 2,3-dideu-
terioesters 2. This transformation can be also carried out
in the presence of H2O instead of D2O, isolating the
corresponding saturated esters. Moreover, this methodol-
ogy can be also applied to prepare 2-deuterio- or 3-deu-
terioesters and 2-deuterio-3-hydroxyesters.
Abstr a ct: An easy and general sequenced elimination/
reduction process by means of samarium diiodide, in the
presence of D2O, provides an efficient method for synthesiz-
ing 2,3-dideuterioesters 2. The reaction can be also carried
out in the presence of H2O instead of D2O, yielding the
corresponding saturated esters 4. Other deuterated esters
have been also obtained. A mechanism to explain this
synthesis has been proposed.
The successive treatment of epoxyesters 1 with a
solution of SmI2 (5 equiv) in THF for 2 h, at room
temperature or at reflux, and further treatment with D2O
(2 mL) for 12 h (room temperature) or 30 min (reflux),
afforded the corresponding 2,3-dideuterioesters 2 in high
yield (Scheme 1).
This transformation was complete and took place
through an efficient sequenced elimination/reduction
process. No important amount of byproducts were ob-
served on the crude reaction. The obtained results in the
synthesis of 2,3-dideuterioesters 2 an their corresponding
yields after column chromatography are shown in Table
1.
In the case of disubstituted R,â-epoxyesters, the reac-
tion was carried out at room temperature. When the
starting compounds were tri- or tetrasubstituted R,â-
epoxyesters, the synthesis of 2,3-dideuterioesters was
carried out at reflux, since the reaction was incomplete
at room temperature. Moreover, when tetrasubstituted
R,â-epoxyesters were used as starting compounds, an
increase of the amount of samarium diiodide was neces-
sary to obtain 2,3-dideuterioesters. The decrease of the
reactivity of the starting 2,3-epoxyesters to enhance the
substitution on the oxirane ring could be due to the
increase of steric hindrance.
Epoxides are important in organic synthesis because
these compounds can be easily manipulated in variety
of synthetically useful reactions. In this sense, an oxirane
ring can be opened by a variety of nucleophiles affording
1,2-difunctionalized systems and can undergo rearrange-
ment reactions such as chain-elongation or ring-expan-
sion processes.1 However, the reduction of epoxides to
hydrocarbons has been scarcely reported,2 and to the best
of our knowledge, no general transformation of R,â-
epoxyesters into saturated esters has been published.3
In addition, the synthesis of dideuterio compounds from
epoxides has not been reported either. For these reasons,
and taking into account the usefulness of isotopically
labeled compounds to establish the mechanism of organic
reactions and the biosynthesis of many natural com-
pounds,4 the development of an effective general method
for the synthesis of 2,3-dideuterioesters from R,â-ep-
oxyesters is of significant value.
Previously, we reported a new synthetic application of
samarium diiodide to promote â-elimination reactions
with total or high diastereoselectivity from functionalized
halohydrines or related compounds.5 More recently, we
have also described the deoxygenation reaction of R,â-
epoxyesters promoted by samarium diiodide, obtaining
(E)-R,â-unsaturated esters with total or high stereo-
selectivity.6
All epoxyesters 1 used as starting compounds were
easily prepared by reaction9 of the corresponding potas-
(1) For a review on epoxide chemistry and reactivity, see: (a) Rao,
A. S.; Panikar, S. K.; Kirtane, J . G. Tetrahedron 1983, 39, 2323-2365.
(b) Gorzynski-Smith, J . Synthesis 1984, 629-656. (c) For some recent
synthetic application of epoxides, see: Taylor, S. K. Tetrahedron 2000,
56, 1149-1163. (d) Hinterding, K.; J acobsen, E. N. J . Org. Chem. 1999,
63, 2164-2165.
(5) (a) Concello´n, J . M.; Bernad, P. L.; Pe´rez-Andre´s, J . A. Angew.
Chem. 1999, 111, 2528-2530; Angew. Chem., Int. Ed. 1999, 38, 2384-
2386. (b) Concello´n, J . M.; Pe´rez-Andre´s, J . A.; Rodr´ıguez-Solla, H.
Angew. Chem. 2000, 112, 2866-2868; Angew. Chem., Int. Ed. 2000,
39, 2773-2775. (c) Concello´n, J . M.; Pe´rez-Andre´s, J . A.; Rodr´ıguez-
Solla H. Chem. Eur. J . 2001, 7, 3062-3068. (d) Concello´n, J . M.;
Bernad, P. L.; Bardales, E. Org. Lett., 2001, 3, 937-939.
(6) Concello´n, J . M.; Bardales, E. Org. Lett. 2002, 4, 189-191.
(7) Concello´n, J . M.; Rodr´ıguez-Solla, H. Chem. Eur. J . 2001, 7,
4266-4271.
(8) For recent reviews on sequenced reactions promoted by sa-
marium diiodide: (a) Molander, G. A.; Harris, C. R. Chem. Rev. 1996,
96, 307-338. (b) Molander, G. A.; Harris, C. R. Tetrahedron 1998, 54,
3321-3354.
(2) (a) Fry, J . L.; Mraz, T. J . Tetrahedron Lett. 1979, 20, 849-852.
(b) Van Temelen, E. E.; Gladysz, J . A. J . Am Chem. Soc 1974, 96,
5290-5291.
(3) Transformation of 2,3-epoxy-3-phenylpropionic acid ethyl ester
into 3-phenylpropionic acid ethyl ester by using a borohydride exchange
resin has been described: Sim, T. B.; Yoon, N. M. Bull. Chem Soc.
J pn. 1997, 70, 1101-1107.
(4) Mann, J . Secondary Metabolism; Oxford University Press: Ox-
ford, 1986; p 23.
10.1021/jo026043a CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/22/2003
J . Org. Chem. 2003, 68, 1585-1588
1585

TABLE 1. Syn th esis of 2,3-Did eu ter ioester s 2
SCHEME 2. Syn th esis of Sa tu r a ted Ester s
2a
R1
R2
R3
R4
yieldb (%)
2a c
2bc
2c
2d
2e
2f
2g
2h
2i
p-(MeO)Ph
MeCH(Ph)
n-Bu
C7H15
cyclohexyl
Ph
H
H
H
H
H
H
H
H
H
H
Ph
Me
Me
i-Pr
Et
Et
Et
Et
Et
Et
Et
81
49
61
70
81
64
68
62
67
85
71
Me
Me
Bu
Me
C6H13
Me
Me
Me
TABLE 2. Syn th esis of Sa tu r a ted Ester s 4
p-(MeO)Ph
MeCH(Ph)
4
R1
R2
R3
R4
yielda (%)
d
C9H17
H
Me
Et
4c
4e
4g
n-Bu
cyclohexyl
p-(MeO)Ph
H
H
H
Ph
Me
Me
i-Pr
Et
Et
71
82
70
2j
2k
Ph
Ph
Et
a
a
Unless otherwise noted, reactions were carried out under
Isolated yield after column chromatography based on com-
b
reflux in THF. Isolated yield after column chromatography based
on compound 1. The reaction was carried out at room temper-
ature.
pound 1.
c
d
C9H17/Me2CdCH(CH2)2CH(Me)CH2.
sium enolates of R-chloroesters10 (generated by treatment
of R-chloroesters with potassium hexamethyldisilazide at
-78 °C) with aldehydes or ketones, at -78 °C and further
heating to room temperature.11
The position of deuteration was established by 1H and
13C NMR spectrometry of the compounds 2, while com-
plete deuterium incorporation (>99%) was determined
by mass spectroscopy.12 The obtained 2,3-dideuterioesters
2 were isolated as mixture of diastereoisomers (ranging
between 1:1 and 2:1) due to the fact that incorporation
of deuterium generates two new stereogenic centers.
It can be seen from Table 1 that this methodology to
obtain 2,3-dideuterioesters 2 is general. The oxirane ring
of the starting epoxyesters can be di-, tri-, or tetrasub-
stituted, and R1, R2, R3, and R4 can be varied widely.
Thus, R1 can be aliphatic (linear, branched, or cyclic),
unsaturated, or aromatic; R3 could also be changed using
different R-haloesters to prepare the starting epoxyesters,
and the reaction was unaffected by the presence of bulky
groups R4 on the carbonyl ester (Table 1, compound 2c).
The synthesis of 2,3-dideuterioesters also showed toler-
ance to the presence of other CdC (Table 1, compound
2i) and methoxy groups (Table 1, compounds 2a and 2g).
It is noteworthy that D2O is the cheapest deuteration
reagent to obtain organic compounds isotopically labeled
with deuterium. Only a few examples of the synthesis of
1,2-dideuterioesters have been reported.7
F IGURE 1. Synthesis of 3- or 2-deuterioesters.
SCHEME 3. Syn th esis of
2-Deu ter io-3-h yd r oxyester s
respectively. The reaction of 2c with LDA and further
hydrolysis afforded the corresponding 3-deuterioester 5c
(90% yield) and the successive treatment of 4c with LDA
and D2O gave the 2-deuterioester 6c (89% yield).
The transformation of starting compounds 1 into
2-deuterio-3-hydroxyesters 7 can be achieved by modify-
ing the proposed methodology. In this respect, treatment
of 1c and 1k with a solution of samarium diodide in THF
and D2O at reflux gave the corresponding monodeuter-
ated 3-hydroxyesters 7c and 7k in 60 and 68% yield,
respectively (Scheme 3).13
The synthesis of nondeuterated saturated esters 4 can
be also carried out starting from the same epoxyesters 1
by treatment with H2O instead of D2O and no important
differences were observed (Scheme 2 and Table 2).
Other deuterated esters, such as 2- or 3-deuterioesters
and 2-deuterio-3-hydroxyesters, can be prepared with the
described methodology (Figure 1). Thus, starting from
isopropyl 2,3-epoxy-2-phenylheptanoate, the correspond-
ing 2,3-dideuterated ester 2c or saturated ester 4c
(without deuterium) were obtained by using D2O or H2O,
Mech a n ism . Synthesis of 2, 4, and 7 may be explained
by assuming that the metalation of 1 with SmI2 generates
the enolate intermediate 8, which (in the absence of D2O
or H2O) eliminates affording (E)-R,â-unsaturated esters
3 with total or high diastereoselection.6 When the reac-
tion of 1 with SmI2 is carried out in the presence of D2O,
the corresponding 2-deuterio-3-hydroxyester 7 is isolated.
The 1,4-reduction promoted by SmI2 of the obtained R,â-
unsaturated esters 3 is initiated by oxidative addition of
SmI2 to generate the enolate radical 9,14 which, after a
second electron transfer from SmI2 and hydrolysis with
D2O or H2O, affords the corresponding compound 2 or 4
(Scheme 4).
(9) Rosen, T. Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 2; p 409.
(10) Compounds 1f and 1h were obtained from the corresponding
R-bromoesters.
(11) Preparation of R,â-epoxyesters can be also accomplished by
epoxidation of R,â-unsaturated esters: Meth-Cohn, O.; Moore, C.;
Taljaard, H. T. J . Chem. Soc., Perkin Trans. 1 1988, 2663-2674.
(12) MS and HRMS spectra of compounds 2, 5, 6, and 7 show a lack
of a peak or a very weak peak of the [M]+ of the corresponding
nondeuterated compound, indicating a presence of the nondeuterated
compound <1%.
(13) The transformation of R,â-epoxyesters into 3-hydroxyesters, by
using SmI2 in the presence of HMPA and N,N-dimethylaminoethanol,
has been previously described: Otsubo, K.; Inanaga, J .; Yamaguchi,
M. Tetrahedron Lett. 1987, 28, 4437-4440.
(14) Fujita, Y.; Fukuzumi, S.; Otera, J . Tetrahedron Lett. 1997, 38,
2121-2124.
1586 J . Org. Chem., Vol. 68, No. 4, 2003

Gen er a l P r oced u r e for th e Syn th esis of Ep oxyester s 1.
To a -78 °C stirred solution of the corresponding 2-haloester
(2.5 mmol) in dry THF (4 mL) was added dropwise potassium
hexamethyldisilazide (6.5 mL of 0.5 m solution in toluene, 3.25
mmol). After the mixture was stirred for 10 min, a solution of
the corresponding aldehyde or ketone (2.5 mmol) in dry THF (4
mL) was added dropwise at -78 °C, and the resulting mixture
was allowed to warm to room temperature. The resulting
solution was quenched with aqueous saturated solution of NH4-
Cl (20 mL). Usual workup provided crude 2,3-epoxyesters 1,
which were purified by column flash chromatography over silica
gel (hexane/ethyl acetate) provided pure compound.
SCHEME 4. P r op osed Mech a n ism
Gen er a l P r oced u r e for th e Syn th esis of 2,3-Did eu ter io-
ester s 2 a n d Sa tu r a ted Ester s 4. A solution of SmI2 (2.3 mmol)
in THF (24 mL) was added dropwise, under nitrogen atmo-
sphere, to a stirred solution of the corresponding R,â-epoxyester
1 (0.4 mmol) in THF (4 mL) at room temperature or at reflux
(see Table 1). After the mixture was stirred for 2 h, D2O or H2O
(2 mL) was added to the solution. The mixture was stirred for
12 h (room temperature) or 30 min (reflux). Then the reaction
was quenched with aqueous HCl (0.1 M, 10 mL). Usual workup
afforded crude 2,3-dideuterioesters 2 or saturated esters 4, which
were purified by column flash chromatography over silica gel
(hexane/ethyl acetate).
Meth yl 2,3-dideu ter io-3-[(4-m eth oxy)ph en yl]pr opan oate
1
(2a ): Rf ) 0.4 (hexane/AcOEt 5/1); H NMR (CDCl3, 200 MHz)
δ 7.13 (2 H, d, J ) 8.7 Hz), 6.84 (2 H, d, J ) 8.7 Hz), 3.80 (3 H,
s), 3.68 (3 H, s), 2.97-2.84 (1 H, m), 2.67-2.54 (1 H, m); 13C
NMR (CDCl3, 75 MHz) δ 173.3 (C), 157.9 (C), 133.0 (C), 129.1
(CH), 113.8 (CH), 55.1 (CH3), 51.4 (CH3), 35.5 (CHD, t, J ) 20.0
Hz), 29.6 (CHD, t, J ) 22.0 Hz); MS (70 eV) m/z 196 (14) [M]+,
37 (6), 122 (98), 59 (97); IR (neat) 2958, 1738, 1614, 1513, 1464.
Anal. Calcd for C11H12D2O3: C, 67.32; H, 8.22. Found: C, 67.41;
H, 8.18.
Meth yl 2,3-d id eu ter io-4-p h en ylp en ta n oa te (2b): Rf ) 0.4
(hexane/AcOEt 5/1); 1H NMR (CDCl3, 200 MHz) δ 7.29-7.16 (10
H, m), 3.62 (6 H, s), 2.73-2.70 (2 H, m), 2.20-2.17 (2 H, m),
1.90-1.83 (2 H, m), 1.28 (3 H, s), 1.26 (3 H, s); 13C NMR (CDCl3,
75 MHz) δ 174.0 (C), 172.8 (C), 146.1 (C), 145.6 (C), 128.4 (CH),
128.3 (CH), 126.9 (CH), 126.6 (CH), 126.3 (CH), 126.1 (CH), 51.4
(CH3), 42.2 (CHD, t, J ) 19.8 Hz), 39.2 (CH), 35.9 (CHD, t, J )
19.8 Hz), 32.7 (CHD, t, J ) 19.8 Hz), 31.9 (CHD, t, J ) 19.8
Hz), 22.1 (CH3), 21.5 (CH3); MS (70 eV) m/z 194 (6) [M]+, 120
(42), 105 (100), 77 (33), 59 (20); IR (neat) 2967, 1744, 1615, 1459,
1210. Anal. Calcd for C12H14D2O2: C, 74.19; H, 9.34. Found: C,
74.01; H, 9.28.
In conclusion, the SmI2-promoted elimination/reduction
sequence (in the presence of D2O or H2O) provides an
efficient method for synthesizing 2,3-dideuterioesters or
nondeuterated saturated esters. Others deuterated esters
such as 2-deuterio- or 3-deuterioesters and 2-deuterio-
3-hydroxyesters can be also obtained. The present method
is easy, simple, general and the starting compounds are
easily available. In addition, cheap D2O is used to obtain
the isotopically labeled products. A mechanism to explain
this synthesis has been proposed.
Isop r op yl 2,3-d id eu ter io-2-p h en ylh ep ta n oa te (2c): Rf )
0.3 (hexane/ethyl acetate 20/1); 1H NMR (CDCl3, 200 MHz) δ
7.32-7.23 (10 H, m), 5.04-4.96 (2 H, m), 2.08-1.981 (m, 1 H),
1.77-1.62 (m, 1 H), 1.48-1.18 (12 H, m), 1.23 (6 H, d, J ) 6.2),
1.14 (6 H, d, J ) 6.2), 0.87 (6 H, t, J ) 6.8); 13C NMR (CDCl3, 75
MHz) δ 173.6 (C), 139.4 (C), 128.3 (CH), 127.7 (CH), 126.9 (CH),
67.7 (CH), 51.5 (CD, t, J ) 19.2 Hz), 33.1 (CHD, t, J ) 19.8 Hz),
31.5 (CH2), 27.0 (CH2), 22.4 (CH2), 21.7 (CH3), 21.5 (CH3), 13.9
(CH3); MS (70 eV) m/z 250 (1) [M]+, 163 (36), 92 (100), 77 (3), 43
(63); IR (neat) 2969, 1743, 1615, 1473, 1262. Anal. Calcd for
Exp er im en ta l Section
Gen er a l Meth od s. Reactions requiring an inert atmosphere
were conducted under dry nitrogen, and the glassware was oven
dried (120 °C). THF was distilled from sodium/benzophenone
ketyl immediately prior to use. All reagents were purchased in
the higher quality available and were used without further
purification. Isopropyl 2-chloro-2-phenylpropanoate was pre-
pared by treatment of 2-chlorophenylacetyl chloride with iso-
propyl alcohol, and in turn, 2-chlorophenylacetyl chloride was
obtained according to literature from the corresponding car-
boxylic acids.15 Samarium diiodide was prepared by reaction of
CH2I2 with samarium powder.16 Compounds were visualized on
analytical thin-layer chromatograms (TLC) by UV light (254
nm). All NMR spectra were registered at room temperature. 1H
NMR spectra were recorded at 200 or 300 MHz. 13C NMR spectra
and DEPT experiments were determined at 50 or 75 MHz.
Chemical shifts are given in ppm relative to tetramethylsilane
(TMS), which is used as an internal standard, and coupling
constants (J ) are reported in Hz. GC-MS and HRMS were
measured at 70 eV. Only the most important IR absorptions (in
cm-1) and the molecular ions and/or base peaks in MS are given.
C
16H22D2O2: C, 76.75; H, 10.47. Found: C, 76.84; H, 10.50.
Eth yl 2,3-Did eu ter io-2-m eth yld eca n oa te (2d ).7
Eth yl 3-Cycloh exyl-2,3-d id eu ter io-2-m eth ylp r op a n oa te
(2e).7
Eth yl 2-bu tyl-2,3-d id eu ter io-3-p h en ylp r op a n oa te (2f): Rf
1
) 0.5 (hexane/ethyl acetate 5/1); H NMR (CDCl3, 200 MHz) δ
7.28-7.14 (10 H, m), 4.16 (2 H, q, J ) 7.1), 4.04 (2 H, q, J )
7.1), 2.89 (1 H, s), 2.72 (1 H, s), 1.81-1.02 (15 H, m), 1.13 (3 H,
t, J ) 7.1), 0.89-0.84 (6 H, m); 13C NMR (CDCl3, 75 MHz) δ
175.6 (C), 174.3 (C), 139.3 (C), 128.7 (CH), 128.1 (CH), 126.1
(CH), 60.2 (CH2), 59.9 (CH2), 47.1 (CD, t, J ) 19.7 Hz), 59.9
(CHD, t, J ) 19.8 Hz), 31.6 (CH2), 30.1 (CH2), 29.3 (CH2), 22.4
(CH2), 22.3 (CH2), 14.2 (CH3), 14.1 (CH3), 13.8 (CH3), 13.7 (CH3);
MS (70 eV) m/z 236 (15) [M]+, 179 (21), 163 (12), 92 (100), 77
(3); IR (neat) 1728, 1452, 1367, 1249. Anal. Calcd for C15H20
D2O2: C, 76.23; H, 10.23. Found: C, 76.18; H, 10.26.
-
(15) Harpp, D. N.; Bao, L Q.; Black, C. J .; Gleason, J . G.; Smith, R
A. J . Org. Chem. 1975, 40, 3420-3426.
(16) Namy, J . L.; Girard, P.; Kagan, H. B. Nouv. J . Chem. 1981, 5,
479-484.
E t h yl 2,3-Did eu t er io-2-m et h yl-3-[4-(m et h oxy)p h en yl]-
p r op a n oa te (2g).7
J . Org. Chem, Vol. 68, No. 4, 2003 1587

Eth yl 2,3-Did eu ter io-2-h exyl-4-p h en ylp en ta n oa te (2h ).7
Eth yl 2,3-d id eu ter io-2,5,9-tr im eth yld ec-8-en oa te (2i): Rf
) 0.3 (hexane/AcOEt 20/1); 1H NMR (CDCl3, 200 MHz) δ 5.14-
5.06 (1H, m), 4.13 (2 H, q, J ) 7.2 Hz), 2.18-1.02 (8 H, m), 1.69
(3 H, s), 1.60 (3 H, s), 1.26 (3 H, t, J ) 7.2 Hz), 1.14 (3 H, s),
0.87 (3 H, d, J ) 6.4 Hz); 13C NMR (CDCl3, 75 MHz) δ 176.9
(C), 131.0 (C), 124.8 (CH), 60.0 (CH2), 39.3 (CD, t, J ) 20.4 Hz),
36.9 (CH2), 34.1 (CH2), 32.3 (CH), 30.4 (CHD, t, J ) 20.4 Hz),
25.6 (CH3), 25.4 (CH2), 19.4 (CH3), 17.5 (CH3), 14.2 (CH3); MS
(70 eV) m/z 242 (11) [M]+, 140 (10), 111 (7), 103 (100), 69 (83);
IR (neat) 2965, 2860, 1736, 1674, 1462. Anal. Calcd for
C15H26D2O2: C, 74.33; H, 12.47. Found: C, 74.45; H, 12.54.
Eth yl 2,3-d id eu ter io-2-m eth yl-3-p h en ylbu ta n oa te (2j): Rf
) 0.4 (hexane/ethyl acetate 10/1); 1H NMR (CDCl3, 200 MHz) δ
7.36-7.16 (10 H, m), 4.20 (2 H, q, J ) 7.2), 3.93 (2 H, q, J )
7.2), 1.31 (3 H, t, J ) 7.2), 1.27 (3 H, s), 1.26 (3 H, s), 1.19 (3 H,
s), 1.03 (3 H, t, J ) 7.2), 0.94 (3 H, s); 13C NMR (CDCl3, 75 MHz)
δ 176.3 (C), 175.6 (C), 144.9 (C), 144.3 (C), 128.3 (CH), 128.1
(CH), 127.4 (CH), 127.3 (CH), 126.3 (CH), 126.2 (CH), 60.1 (CH2),
59.8 (CH2), 46.2 (CD, t, J ) 20.1 Hz), 46.1 (CD, t, J ) 20.7 Hz),
42.8 (CD, t, J ) 20.1 Hz), 41.9 (CD, t, J ) 19.8 Hz), 20.4 (CH3),
17.6 (CH3), 16.0 (CH3), 14.2 (CH3), 14.1 (CH3), 13.8 (CH3); MS
(70 eV) m/z 208 (5) [M]+, 135 (4), 106 (100), 77 (17); IR (neat)
2980, 1732, 1653, 1507, 1277. Anal. Calcd for C13H16D2O2: C,
74.96; H, 9.68. Found: C, 74.80; H, 9.63.
Eth yl 2,3-d id eu ter io-2-m eth yl-3-p h en ylp en ta n oa te (2k ):
Rf ) 0.3 (hexane/ethyl acetate 10/1); 1H NMR (CDCl3, 200 MHz)
δ 7.41-7.12 (10 H, m), 4.19 (2 H, q, J ) 7.2), 3.88 (2 H, q, J )
7.2), 1.30 (6 H, t, J ) 7.2), 1.23 (3 H, s), 0.98 (6 H, t, J ) 7.2),
0.90 (3 H, s), 0.72 (4 H, q, J ) 7.2); 13C NMR (CDCl3, 75 MHz)
δ 176.5 (C), 175.6 (C), 142.6 (C), 142.0 (C), 128.2 (CH), 127.9
(CH), 126.3 (CH), 126.2 (CH), 60.1 (CH2), 59.7 (CH2), 50.3 (CD,
t, J ) 21.2 Hz), 49.9 (CD, t, J ) 19.8 Hz), 45.3 (CD, t, J ) 20.4
Hz), 27.2 (CH2), 24.5 (CH2), 15.9 (CH3), 14.8 (CH3), 14.2 (CH3),
13.8 (CH3), 12.0 (CH3), 11.8 (CH3); MS (70 eV) m/z 222 (4) [M]+,
149 (3), 120 (65), 91 (100), 77 (20); IR (neat) 2972, 1731, 1507,
1461, 1270. Anal. Calcd for C14H18D2O2: C, 75.63; H, 9.97.
Found: C, 75.74; H, 9.89.
Isop r op yl 2-p h en ylh ep ta n oa te (4c): Rf ) 0.2 (hexane/ethyl
acetate 20/1); 1H NMR (CDCl3, 200 MHz) δ 7.35-7.25 (5 H, m),
5.08-4.96 (1 H, m), 3.51 (1 H, t, J ) 7.7), 2.13-1.30 (8 H, m),
1.25 (3 H, d, J ) 6.2), 1.16 (3 H, d, J ) 6.2), 0.89 (3 H, m); 13C
NMR (CDCl3, 75 MHz) δ 173.3 (C), 139.5 (C), 128.3 (CH), 127.7
(CH), 126.8 (CH), 67.6 (CH), 51.9 (CH), 33.5 (CH2), 31.4 (CH2),
27.1 (CH2), 22.3 (CH2), 21.6 (CH3), 21.4 (CH3), 13.8 (CH3); MS
(70 eV) m/z 248 (1) [M]+, 161 (27), 105 (37), 91 (100), 77 (7); IR
(neat) 3030, 2931, 1729, 1602, 1455. Anal. Calcd for C16H24O2:
C, 77.38; H, 9.74. Found: C, 77.29; H, 9.80.
Eth yl 3-cycloh exyl-2-m eth ylp r op a n oa te (4e): Rf ) 0.4
(hexane/AcOEt 10/1); 1H NMR (CDCl3, 200 MHz) δ 4.19-4.04
(4 H, m), 2.58-2.46 (2 H, m), 1.83-0.75 (26 H, m), 1.25 (6 H, t,
J ) 6.9 Hz), 1.12 (6 H, d, J ) 6.9 Hz); 13C NMR (CDCl3, 75 MHz)
δ 177.2 (C), 59.9 (CH2), 41.5 (CH2), 36.8 (CH), 35.3 (CH), 33.2
(CH2), 26.5 (CH2), 26.2 (CH2), 17.5 (CH3), 14.2 (CH3); MS (70
eV) m/z 198 (1) [M]+, 115 (35), 102 (100), 83 (14), 73 (11); IR
(neat) 2924, 1736, 1450, 1378, 1257. Anal. Calcd for C12H22O2:
C, 72.68; H, 11.18. Found: C, 72.52; H, 11.12.
(C), 139.5 (C), 128.4 (CH), 127.8 (CH), 126.9 (CH), 67.7 (CH),
51.9 (CH), 33.1 (CHD, t, J ) 19.6 Hz), 33.5 (CH2), 27.1 (CH2),
22.4 (CH2), 21.7 (CH3), 21.5 (CH3), 13.9 (CH3); IR (neat) 2969,
1743, 1615, 1473, 1262. Anal. Calcd for C16H23DO2: C, 77.06;
H, 10.10. Found: C, 77.21; H, 10.06.
Isop r op yl 2-Did eu ter io-2-p h en ylh ep ta n oa te 6c. To a
stirred solution of lithium diisopropylamide (0.48 mmol) in THF
(5 mL) was added a solution of the compound 4c (0.4 mmol) in
THF (4 mL), under nitrogen atmosphere, dropwise at -78 °C.
After being stirred for 30 min, the reaction mixture was
quenched with D2O (2 mL). Usual workup provided 3-deuterio-
esters 6c. Compound 6c was >98% pure, and further purification
was not necessary: Rf ) 0.3 (hexane/ethyl acetate 20/1); 1H NMR
(CDCl3, 200 MHz) δ 7.32-7.24 (10 H, m), 5.04-4.96 (2 H, m),
2.17-1.20 (16 H, m), 1.23 (6 H, d, J ) 6.6), 1.14 (6 H, d, J )
6.6), 0.90-0.82 (6 H, m); 13C NMR (CDCl3, 75 MHz) δ 173.6 (C),
139.4 (C), 128.3 (CH), 127.7 (CH), 126.9 (CH), 67.7 (CH), 51.5
(CD, t, J ) 20.8. Hz), 33.4 (CH2), 31.4 (CH2), 27.1 (CH2), 22.3
(CH2), 21.7 (CH3), 21.5 (CH3), 13.9 (CH3); IR (neat) 2969, 1743,
1615, 1473, 1262. Anal. Calcd for C16H23DO2: C, 77.06; H, 10.10.
Found: C, 77.00; H, 10.15.
Gen er a l P r oced u r e for th e Syn th esis of 2-Deu ter io-3-
h yd r oxyester s 7. A solution of SmI2 (1.6 mmol) in THF (19
mL) and D2O (2 mL) was added dropwise, under nitrogen
atmosphere, to a stirred solution of the corresponding 2,3-
epoxyester 1 (0.4 mmol) in THF (4 mL) at room temperature.
After being stirred for 30 min under reflux, the reaction was
quenched with aqueous HCl (0.1 M, 20 mL). Usual workup
afforded crude 2-deuterio-3-hydroxyesters 7, which were purified
by column flash chromatography over silica gel (10:1 hexane
ethyl acetate).
Isopr opyl 2-deu ter io-3-h ydr oxy-2-ph en ylh eptan oate (7c):
Rf ) 0.3 (hexane/ethyl acetate 5/1); 1H NMR (CDCl3, 200 MHz)
δ 7.39-7.31 (5 H, m), 5.10-4.97 (1 H, m), 4.20-4.17 (1 H, m),
2.37-2.18 (1 H, s, br), 1.58-1.20 (6 H, m), 1.26 (3 H, d, J )
6.2), 1.15 (3 H, d, J ) 6.2), 0.91 (3 H, t, J ) 7.1); 13C NMR (CDCl3,
75 MHz) δ 172.7 (C), 135.2 (C), 129.0 (CH), 128.5 (CH), 127.5
(CH), 72.1 (CH), 68.2 (CH), 57.3 (CD, t, J ) 19.5 Hz), 33.9 (CH2),
27.7 (CH2), 22.5 (CH2), 21.6 (CH3), 21.3 (CH3), 13.9 (CH3); IR
(neat) 2956, 1725, 1449, 1262, 1107. Anal. Calcd for C16H23DO3:
C, 72.42; H, 9.50. Found: C, 72.56; H, 9.44.
Eth yl 2-deu ter io-3-h ydr oxy-2-m eth yl-3-ph en ylpen tan oate
1
(7k ): Rf ) 0.2, 0.4 (hexane/ethyl acetate 5/1); H NMR (CDCl3,
200 MHz) δ 7.42-7.21 (10 H, m), 4.24 (2 H, q, J ) 7.2), 4.07 (1
H, s), 3.87 (2 H, q, J ) 7.2), 3.75 (1 H, s), 1.96-169 (4 H, m),
1.32 (6 H, m), 0.94 (3 H, s), 0.92 (3 H, t, J ) 7.2), 0.68 (3 H, t, J
) 7.1), 0.66 (3 H, t, J ) 7.2); 13C NMR (CDCl3, 75 MHz) δ 177.5
(C), 176.9 (C), 145.2 (C), 142.4 (C), 127.9 (CH), 127.7 (CH), 126.3
(CH), 125.4 (CH), 77.1 (C), 76.9 (C), 60.7 (CH2), 60.3 (CH2), 48.4
(CD, t, J ) 19.8 Hz), 47.0 (CD, t, J ) 20.1 Hz), 34.4 (CH2), 31.4
(CH2), 14.1 (CH3), 13.6 (CH3), 12.5 (CH3), 11.8 (CH3), 7.7 (CH3),
7.4 (CH3); MS (70 eV) m/z 237 (1) [M]+, 208 (5), 135 (75), 77
(45), 100 (57); IR (neat) 2979, 1706, 1461, 1280, 1080. Anal. Calcd
for C14H19DO3: C, 70.86; H, 8.92. Found: C, 70.71; H, 8.99.
Ack n ow led gm en t. We thank III Plan Regional de
Investigacio´n del Principado de Asturias (PB-EXP01-
11) and Ministerio de Educacio´n y Cultura (BQU2001-
3807) for financial support. J .M.C. thanks Carmen
Ferna´ndez-Flo´rez for her time. E.B. thanks to Princi-
pado de Asturias for a predoctoral fellowship. We thank
Robin Walker for his revision of the English.
Eth yl 2-Meth yl-3-[4-(m eth oxy)p h en yl]p r op a n oa te (4g).7
Isop r op yl 3-Did eu ter io-2-p h en ylh ep ta n oa te 5c. To a
stirred solution of lithium diisopropylamide (0.48 mmol) in THF
(5 mL) was added a solution of the compound 2c (0.4 mmol) in
THF (4 mL), under nitrogen atmosphere, dropwise at -78 °C.
After being stirred for 30 min, the reaction mixture was
quenched with H2O (2 mL). Usual workup provided 3-deuterio-
esters 5c. Compound 5c was >98% pure and further purification
was not necessary: Rf ) 0.3 (hexane/ethyl acetate 20/1); 1H NMR
(CDCl3, 200 MHz): δ ) 7.34-7.25 (10 H, m), 5.07-4.92 (2 H,
m), 3.50 (2 H, d, J ) 7.9), 2.12-1.98 (1 H, m), 1.86-1.62 (1 H,
m), 1.45-1.09 (12 H, m), 1.24 (6 H, d, J ) 6.4), 1.15 (6 H, d, J
) 6.4), 1.01-0.77 (6 H, m); 13C NMR (CDCl3, 75 MHz) δ 173.6
Su p p or tin g In for m a tion Ava ila ble: Experimental data
for compounds 1a -k and 13C NMR spectra of 2, 4, 5c, 6c, and
7c,k . This material is available free of charge via the Internet
at http://pubs.acs.org.
J O026043A
1588 J . Org. Chem., Vol. 68, No. 4, 2003