Isomannide and isosorbide as new chiral auxiliaries for the stereoselective synthesis of tertiary α-hydroxy acids

Article abstract of DOI:10.1016/S0040-4020(02)00024-8

Isomannide and isosorbide are selectively protected to provide new chiral auxiliaries suitable for the preparation of enantiopure tertiary α-hydroxy acids. Diastereoselective additions of organozinc reagents on the derived phenylglyoxylates afford the desired α-hydroxy acids with 60-99% ee after saponification. Both absolute configurations of the α-hydroxy acids can be accessed, by adapted choice of either the starting diol or the protecting group.

Full text of DOI:10.1016/S0040-4020(02)00024-8

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 1541±1549
Isomannide and isosorbide as new chiral auxiliaries for the
stereoselective synthesis of tertiary a-hydroxy acids
p
 Â
Andre Loupy and Daphne A. Monteux
   Ã
Laboratoire des Reactions Selectives Sur Supports, ICMO, Universite de Paris-Sud, bat 410, 91405 Orsay, France
Received 29 June 2001; revised 10 October 2001; accepted 3January 2002
AbstractÐIsomannide and isosorbide are selectively protected to provide new chiral auxiliaries suitable for the preparation of enantiopure
tertiary a-hydroxy acids. Diastereoselective additions of organozinc reagents on the derived phenylglyoxylates afford the desired a-hydroxy
acids with 60±99% ee after saponi®cation. Both absolute con®gurations of the a-hydroxy acids can be accessed, by adapted choice of either
the starting diol or the protecting group. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
starch industry by-products, isosorbide 1 and isomannide
2 are an attractive class of readily accessible chiral auxili-
aries.16a,b In the present study, we illustrate their synthetic
value through preparation of new mono-protected deriva-
tives, and their application for the stereoselective synthesis
of tertiary a-hydroxy acids.
Chiral tertiary a-hydroxy acids constitute important
building blocks1a±c and synthetic intermediates2a,b for the
preparation of complex biologically active substances.3 As
a consequence, numerous studies have been devoted to their
asymmetric synthesis during the last few years. They
involve classical4 diastereoselective additions of organo-
metallics to a-keto esters bearing cyclohexane based
chiral auxiliaries such as (i) (2)-menthol,7a,b (ii) 8-phenyl-
menthol,8a,b (iii) chiro-inositol derivatives9 (iv) trans-2-
phenylcyclohexanol10 and the derived 2-nitroxy11 and
2-aryloxy12 analogues. To the best of our knowledge, the
only alternate types of auxiliaries are 20-substituted-1,10-
binaphtalenols,13 2,5-bis(methoxymethoxymethyl) pyrro-
lidine,14 (dl) 2-hydroxyheptahelicene or secondary anthryl
alcohols, and (2)-quinine.15 However, their application has
been restricted to the introduction of methyl and phenyl
groups. In the ®rst two examples, low selectivities were
obtained when compared with generic auxiliaries. In the
case of hydroxyhelicenes and anthryl alcohols, only dia-
stereoisomeric mixtures of a-hydroxy esters were isolated
due to the use of racemic auxiliaries. Therefore, (2)-quinine
remains the uniquely interesting candidate, although reac-
tions with other nucleophiles are needed to assess the scope
and limitations.
As shown in previous reports,16a,17 isosorbide 1 and isoman-
nide 2 can be selectively mono-benzylated to afford exo or
endo benzylated isosorbide 3 and 4, and mono-benzylated
isomannide 5. In a preliminary phase of our work, the
preparation of compounds 3 and 4 were optimized and the
puri®cation of the protected derivatives 3±5 simpli®ed.
Thus, endo-benzylated isosorbide 4 was prepared at room
temperature instead of 908C, which prevented degradation
of the reaction mixture. Compounds 3±5 were then obtained
as pure products by precipitation from cold Et2O instead of
¯ash chromatography. These improvements prompted us to
articulate the synthesis of mono-methylated isosorbides 9,
10 and isomannide 11 on the benzylated products 3±5
instead of the corresponding mono-acetates.18 Thus,
mono-benzylated intermediates 3±5 were converted quanti-
tatively into compounds 6±8 in only 5 h by reaction with
iodomethane under solvent free phase transfer catalysis
(KOH, Aliquat 336). Hydrogenolysis performed on inter-
mediates 6±8 for 2 h afforded the desired mono-methylated
isosorbides 9, 10 and, isomannide 11 in quantitative yields
(Scheme 1).
2. Results and discussion
As a consequence, the 48 h required for the preparation of
the mono-acetates are now circumvented and compounds
9±11 are obtained through a straightforward sequence.
The preparation of the chiral a-keto esters 12±18 as starting
materials for the synthesis of the derived a-hydroxy acids
was then achieved. The obtained mono-protected auxiliaries
3±5, and 11 were converted in 55% to quantitative yield into
the derived phenylglyoxylates 13±15, 17, 18 and pyruvates
As a part of our efforts to develop chemical applications for
Keywords: isosorbide; isomannide; a-hydroxy acids; asymmetric additions.
Corresponding author. Address: Novartis Forschungsinstitut GmbH,
Therapeutic Area Dermatology, Brunner Straûe 59, 1235 Vienna, Austria.
Tel.: 143-1-866-34-90-86; fax: 143-1-866-34-593;
e-mail: daphne.monteux@pharma.novartis.com
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00024-8

1542
A. Loupy, D. A. Monteux / Tetrahedron 58 (2002) 1541±1549
Scheme 1.
12, 16 via azeotropic condensations with the corresponding
a-keto acids (Scheme 2).
conditions. In this case, no degradation of the dioxabi-
cyclo[3.3.0]octane unit was observed, attesting to the
compatibility of the isosorbide and isomannide derived
auxiliaries under these reaction conditions.
Interestingly, the phenylglyoxylate 13 was alternatively
prepared in only 6 min under microwave irradiation in
80% yield, comparable with the use of classical heating
We have then focused our work on condensations of
Scheme 2.

A. Loupy, D. A. Monteux / Tetrahedron 58 (2002) 1541±1549
1543
Scheme 3.
compounds 12±18 with various organometallic species. A
®rst group of experiments was conducted with organozinc
reagents, prepared in situ by reactions of Grignard reagents
with zinc chloride.7a During the optimization of the reaction
conditions, performed with a test set composed of com-
pound 13 and EtMgCl, we found that the yield and stereo-
selectivity are strongly dependant on (i) the relative
amounts of zinc chloride and the Grignard reagent, (ii) the
temperature, and (iii) the way the electrophile and the
nucleophile are added to each other.
to preserve a good degree of selectivity with less reactive
derivatives (entries f±h) (Scheme 3).
The a-hydroxy acids 20a±h were obtained as (R) isomers in
accordance with the Whitesell's model,19 in comparable
yields and diastereoselectivities when compared to classical
auxiliaries.12,7a Attempts to introduce the particularly
hindered tert-butyl group resulted in only 27% yield
(entry e), while reaction with allylzinc chloride proceeded
with low selectivity as previously reported (entry f).20 In the
later case however, introduction of an allyl group on
compound 13 could be achieved in a more selective manner
via a SnCl4 mediated addition of trimethylallylsilane.21
Thus, the desired a-hydroxy ester 19f was isolated in 51%
yield with an improved 65% de (72% ee for 20f after
saponi®cation). As previously observed with the use of
microwave irradiation, the chiral auxiliary showed excellent
stability towards reactions performed in the presence of a
strong Lewis acid.
Thus, we determined that adding 2 equiv. of ZnCl2 and the
a-keto ester, on a pre-reacted mixture of 4 equiv. of ZnCl2
and of Grignard reagent at 2208C, lead to the best results.
By pre-mixing 2 equiv. of ZnCl2 with the a-keto ester
before the introduction on the nucleophile, 1 equiv. is
implicated in the precomplexation of the dicarbonyl moiety
while the second is probably involved in the complexation
of the two ethers oxygens of the bicyclic core. These con-
ditions were then successfully applied to the condensation
of other nucleophiles with compound 13 (entries a±e),
although a decrease in temperature to 2788C was required
In order to monitor the in¯uence of protecting groups on the
stereoselectivity of the reaction, an additional attempt was
Scheme 4.

1544
A. Loupy, D. A. Monteux / Tetrahedron 58 (2002) 1541±1549
Scheme 5.
performed on exo-O-methylated compound 14 with
iPrZnCl. In this case, no variation was observed. The
desired substituted mandelic acid 20b was isolated as the
(R) isomer with equivalent diastereoselectivity and yield (90
and 50% respectively) as obtained from compound 13
(Scheme 3, entry b), suggesting that the protecting group
does not participate to the induction. However a dramatic
decrease in selectivity was observed by changing over the
positions of the a-keto ester and of the protecting group.
Therefore, additions of alkylzincs on compound 15 afforded
the desired a-hydroxy esters 21a±d in only 12±27% de
(Scheme 4).
a and c). However, by placing the benzyl protecting group in
close contact with the reactive center, selective introduction
of nucleophiles is enhanced. Thus, hydroxy esters 22a,b
were isolated with .99 and 94% de when derived from
isomannide based compounds 17 and 18, while analogous
hydroxy esters 19b,d were obtained from a-keto ester 13
with 88 and 65% de, respectively. Since such a dramatic
increase in stereoselectivity was not observed with product
22c resulting from addition on methyl protected compound
18, the presence of a p-stacking between the dicarbonyl
moiety and the phenyl ring of protecting group was
hypothesized. A calculation of the most favored confor-
mation of compound 17 (SYBYL 6.3, minimum global
energy 36.8 Kcal/mol) con®rmed a perfect parallelism
between the phenyl moieties of the keto-ester and of the
protecting group, and revealed a distance between the two
The present set of reactions suggests that a high level of
stereo-induction can only be reached when the reactive
center is located inside the 1208 dihedral angle formed by
the bicyclic skeleton. Since the protecting group cannot
participate in the induction when placed on the opposite
side of the molecule, a last series of reactions was performed
on isomannide derived a-keto esters 17 and 18. In this case,
the reactive site and the protecting groups are both located
into the cavity of the auxiliary (Scheme 5).
22
Ê
rings characteristic for p-stacking (3.25 A) (Scheme 6).
3. Conclusion
In summary, mono-protected compounds 3±5 and 9±11
derived from isosorbide 1 and isomannide 2 were
established as attractive alternatives to the classical chiral
auxiliaries used for the asymmetric synthesis of tertiary
a-hydroxy acids. Thus, hydroxy acids 20 and 23 were
obtained after saponi®cation in 60±99% ee by the addition
of organozinc reagents to a-keto esters 13, 14, 17 and
18. However, when compared to the commonly used
As observed with alkylations of a-keto ester 13, the desired
hydroxy esters 22a±c are obtained with high stereo-
selectivity when prepared from compounds 17 and 18.
Remarkably, both absolute con®gurations of the asym-
metric center created can be selectively obtained by an
adapted choice of the protecting group (Scheme 5, entries
Scheme 6.

A. Loupy, D. A. Monteux / Tetrahedron 58 (2002) 1541±1549
1545
20
[a]D ˆ11388 (c 1, CHCl3); Anal. Calcd for C13H16O4: C,
auxiliaries, isosorbide and isomannide derived auxiliaries
advantageously allow the selective synthesis of tertiary
a-hydroxy acids in both enantiomeric forms, by an adapted
choice of either the protecting group or of the starting diol.
66.09; H, 6.83. Found: C, 65.69; H, 6.76.
4.3. General procedure for the preparation of com-
pounds 6±8
Compounds 3, 4 or 5 (2 g, 8.47 mmol), potassium hydroxide
(0.66 g, 10.2 mmol) and Aliquat 336 (0.34 g, 0.85 mmol)
were mixed and shaken for 20 min at rt. Methyl iodide
(0.63mL, 10.2 mmol) was added and the resulting mixture
was stirred for 5 h at 308C. Dilution with Et2O (50 mL)
followed by ®ltration over a pad of Celite, and concentration
under vacuum gave a crude product which afforded
compounds 6, 7 or 8 (2.11 g, quant) as yellow oils, upon
¯ash column chromatography on silica gel (pentane/ethyl
acetate: 50/50).
4. Experimental
4.1. General methods
1H, 13C NMR spectra were recorded on a 250 MHz NMR
spectrometer (250 and 62.5 MHz, respectively) using
CDCl3 as solvent and tetramethylsilane as internal standard.
Solvents were distilled under argon immediately before use
from sodium/benzophenone. All other reagents were
obtained from commercial sources and were used without
puri®cation.
4.3.1. (1R,4S,5R,8R)-4-Benzyloxy-8-methoxy-2,6-dioxa-
bicyclo-[3.3.0]octanol. 6: ($98%) spectral data were
found identical to those published.18
4.2. General procedure for the preparation of com-
pounds 3±5
4.3.2. (1R,4S,5R,8R)-8-Benzyloxy-4-methoxy-2,6-dioxa-
bicyclo[3.3.0]octanol 7. ($98%), 1H NMR d 3.38 (s,
3H), 3.62 (dd, Jˆ7.0, 8.4 Hz, 1H), 3.82±3.85 (m, 2H),
3.95±4.00 (m, 2H), 4.03 (dt, Jˆ5.6, 7.0 Hz, 1H), 4.49 (d,
Jˆ4.2 Hz, 1H), 4.55 (d, Jˆ11.2 Hz, 2H), 4.65 (dd, Jˆ5.6,
4.2 Hz, 1H), 4.77 (d, Jˆ11.2 Hz, 2H), 7.30±7.40 (m, 5H);
13C NMR d 56.9, 69.2, 72.1, 72.8, 78.9, 80.0, 85.6, 85.7,
128.0, 137.6; IR (nmax, cm21, ®lm) 1100, 1210, 1360, 1450,
Compound 3 was synthesized according to a described pro-
cedure.18 Compound 4 was obtained by adapting a known
protocol18 and performing the reaction at room temperature
instead of 908C. Both products were obtained by precipi-
tation from cold diethyl ether. All spectral data were found
identical to those reported18 except the following.
20
2850±3000; [a]D ˆ11148 (c 1.35, CHCl3); Anal. Calcd
4.2.1. (1R,4S,5R,8R)-4-Benzyloxy-2,6-dioxabicyclo[3.3.0]-
octanol 3. White solid (40%), 1H NMR d 2.73(d, Jˆ7.1 Hz,
1H), 3.58 (dd, Jˆ5.9, 9.7 Hz, 1H), 3.85 (dd, Jˆ6.2, 9.7 Hz,
1H), 3.88 (dd, Jˆ3.5, 10.3 Hz, 1H), 4.09 (d, Jˆ10.3Hz,
1H), 4.12 (d, Jˆ3.5 Hz, 1H), 4.28 (dddd, Jˆ5.1, 5.9, 6.2,
7.1 Hz, 1H), 4.53(d, Jˆ4.8 Hz, 1H), 4.58 (d, Jˆ2.8 Hz,
2H), 4.64 (dd, Jˆ4.8, 5.5 Hz, 1H), 7.30±7.40 (m, 5H).
for C14H18O4: C, 67.18; H, 7.25. Found: C, 67.40; H, 7.24.
4.3.3. (1R,4R,5R,8R)-8-Benzyloxy-4-methoxy-2,6-dioxa-
bicyclo[3.3.0]octanol 8. ($98%), 1H NMR d 3.45 (s,
3H), 3.72±3.80 (m, 2H), 3.87±4.12 (m, 4H), 4.53±4.54
(m, 2H), 4.55 (d, Jˆ12.3Hz, 2H), 4.73 (d, Jˆ12.3Hz,
2H), 7.30±7.40 (m, 5H); 13C NMR d 58.1, 70.7, 70.9,
72.2, 79.1, 79.9, 80.3, 81.7, 128.0, 137.5; IR (nmax, cm21
,
4.2.2. (1R,4S,5R,8R)-8-Benzyloxy-2,6-dioxabicyclo[3.3.0]-
octanol 4. White solid (60%), 1H NMR d 1.78 (d, Jˆ5.0 Hz,
1H), 3.58 (dd, Jˆ7.5, 8.8 Hz, 1H), 3.83 (dd, Jˆ6.3, 8.8 Hz,
1H), 3.97±4.00 (m, 2H), 4.03 (ddd, Jˆ6.3, 7.5, 7.6 Hz, 1H),
4.31 (bs, 1H), 4.40 (d, Jˆ5.0 Hz, 1H), 4.55 (d, Jˆ11.2 Hz,
1H), 4.70 (dd, Jˆ5.0, 7.5 Hz, 1H), 4.75 (d, Jˆ11.2 Hz, 1H),
7.30±7.40 (m, 5H).
®lm) 1080, 1100, 1150, 1220, 1370, 1380, 1450, 2850±
20
3000; [a]D ˆ11608 (c 1.11, CHCl3); Anal. Calcd for
C14H18O4: C, 67.18; H, 7.25. Found: C, 67.55; H, 7.26.
4.4. General procedure for the preparation of com-
pounds 9±11
4.2.3. (1R,4R,5R,8R)-4-Benzyloxy-2,6-dioxabicyclo[3.3.0]-
octanol 5. Isomannide 2 (1 g, 6.85 mmol), potassium
hydroxide (0.44 g, 6.85 mmol) were dissolved in H2O
(3.5 mL) and the resulting solution was heated to re¯ux
for 20 min. The mixture was cooled to rt, benzyl chloride
was added dropwise (0.78 mL, 6.85 mmol). The solution
was re¯uxed for additional 3h before an acidic quench
(HCl 2N, 3.5 mL) and extraction with ethyl acetate (3£
2 mL). The combined organic layers were dried (MgSO4)
and concentrated under vacuum. The crude product was
then precipitated in cold Et2O (5 mL) to give 5 (0.73g,
Pd/C (,30 mg) was added to a solution of 6, 7 or 8 (0.2 g,
0.85 mmol) in absolute ethanol (15 mL) and the mixture
was stirred for 2 h under hydrogen atmosphere. After ®l-
tration of the suspension over a pad of Celite followed
by extensive washes (ethanol), the combined layers were
concentrated to afford pure compounds 9, 10 or 11
(126 mg, quant).
4.4.1. (1R,4S,5R,8R)-8-Methoxy-2,6-dioxabicyclo[3.3.0]-
octanol 9. Colorless oil ($98%), spectral data were found
identical to those published.18
1
45%) as a white solid. Mpˆ938C, H NMR d 2.85 (d, Jˆ
8.5 Hz, 1H), 3.74±3.80 (m, 2H), 4.02±4.05 (m, 2H), 4.08
(dd, Jˆ4.8, 8.1 Hz, 1H), 4.29 (dq, Jˆ5.5, 8.5 Hz, 1H), 4.50
(dd, Jˆ4.6, 5.5 Hz, 1H), 4.57 (dd, Jˆ4.6, 4.8 Hz, 1H), 4.58
(d, Jˆ11.8 Hz, 1H), 4.78 (d, Jˆ11.8 Hz, 1H), 7.30±7.40 (m,
5H); 13C NMR d 71.4, 72.3, 72.6, 74.9, 78.9, 80.6, 81.7,
128.0, 131.0; IR (nmax, cm21, ®lm) 1220, 2850±3000, 3400;
4.4.2. (1R,4S,5R,8R)-4-Methoxy-2,6-dioxabicyclo[3.3.0]-
octanol 10. Colorless oil ($98%), H NMR d 2.85 (bs,
1
1H), 3.40 (s, 3H), 3.57 (dd, Jˆ6.2, 9.4 Hz, 1H), 3.90 (m,
3H), 4.06 (d, Jˆ9.6 Hz, 1H), 4.27 (dt, Jˆ5.0, 6.2 Hz, 1H),
4.47 (d, Jˆ4.5 Hz, 1H), 4.60 (dd, Jˆ4.5, 5.0 Hz, 1H); all
other spectral data were found identical to those reported.14

1546
A. Loupy, D. A. Monteux / Tetrahedron 58 (2002) 1541±1549
4.4.3. (1R,4R,5R,8R)-4-Methoxy-2,6-dioxabicyclo[3.3.0]-
Jˆ6.9, 10.4 Hz, 1H), 4.00±4.05 (m, 2H), 4.08 (dt, Jˆ6.8,
6.9 Hz, 1H), 4.55 (d, Jˆ12.1 Hz, 1H), 4.61 (d, Jˆ5.2 Hz,
1H), 4.72 (dd, Jˆ5.2, 6.9 Hz, 1H), 4.78 (d, Jˆ12.1 Hz, 1H),
5.45 (dd, Jˆ3.2, 3.5 Hz, 1H), 7.30±7.40 (m, 5H), 7.51 (dd,
Jˆ6.9, 8.6 Hz, 2H), 7.68 (dd, Jˆ6.9, 8.6 Hz, 1H), 7.98 (d,
Jˆ6.9 Hz, 2H); 13C NMR d 70.6, 72.5, 73.3, 78.8, 80.1,
80.7, 85.6, 128.4, 135.1, 137.5, 162.8, 185.3; IR (nmax,
1
octanol 11. Colorless solid ($98%); mpˆ728C; H NMR
d 2.46 (d, Jˆ8.7 Hz, 1H), 3.49 (s, 3H), 3.65±3.77 (m, 2H),
3.90±4.15 (m, 3H), 4.29 (qd, Jˆ5.8, 8.7 Hz, 1H), 4.53(dd,
Jˆ 4.9, 5.8 Hz, 1H), 4.57 (dd, Jˆ4.4, 4.9 Hz, 1H); 13C NMR
d 58.4, 71.0, 72.3, 74.9, 80.2, 81.5, 81.9; IR (nmax, cm21
®lm) 1400, 1450, 2850±3000, 3450; [a]D ˆ11138 (c 1.41,
CHCl3); Anal. Calcd for C7H12O4: C, 52.49; H, 7.55. Found:
C, 52.78; H, 7.31.
,
20
cm21, ®lm) 1180, 1450, 1600, 1690, 1740, 2850±3000;
20
[a]D ˆ1818 (c 1.64, CHCl3); Anal. Calcd for C21H20O6:
C, 68.47; H, 5.47. Found: C, 68.07; H, 5.74.
4.5. General procedure for the preparation of com-
pounds 12±18
4.5.5. [4-(1R,4S,5R,8R)-8-Benzyloxy-2,6-dioxabicyclo-
[3.3.0]octane]-(2-oxo)-propanoate 16. Orange oil (70%);
1H NMR d 2.48 (s, 3H), 3.69 (dd, Jˆ5.9, 8.9 Hz, 1H), 3.89
(dd, Jˆ7.4, 8.9 Hz, 1H), 4.02±4.13(m, 3H), 4.56 (d, Jˆ
11.9 Hz, 1H), 4.60 (d, Jˆ2.9 Hz, 1H), 4.77 (dd, Jˆ2.9,
5.9 Hz, 1H), 4.80 (d, Jˆ11.9 Hz, 1H), 5.26 (dd, Jˆ2.9,
3.1 Hz, 1H), 7.30±7.40 (m, 5H); 13C NMR d 26.6, 70.5,
72.3, 73.4, 78.8, 80.3, 82.0, 85.5, 128.0, 137.5, 160.0,
191.0; IR (nmax, cm21, ®lm) 1210, 1410, 1510, 1730,
According to the nature of the ketoester prepared, either
glyoxylic or pyruvic acids (1.5 equiv.) and para-toluene-
sulfonic acid (3% mol) were added to solutions of com-
pound 3±5 or 11 in toluene (0.15 M). A Dean±Stark
apparatus was adapted and the mixture was re¯uxed for
24 h. The solution was washed with saturated aqueous
NaHCO3 and then with H2O until neutral pH was obtained.
After drying (MgSO4), the organic layer was concentrated
under vacuum to afford a crude product which was puri®ed
by ¯ash column chromatography on silica gel (pentane/
ethyl acetate: 50/50).
20
2850±3000; [a]D ˆ11008 (c 0.98, CHCl3); Anal. Calcd
for C16H18O6: C, 62.74; H, 5.92. Found: C, 62.44; H, 5.81.
4.5.6. 4-(1R,4R,5R,8R)-8-Benzyloxy-2,6-dioxabicyclo-
[3.3.0]octane]-(2-oxo-2-phenyl)-ethanoate 17. Yellow oil
1
(55%); H NMR d 3.60 (dd, Jˆ8.7, 8.8 Hz, 1H), 3.92 (dd,
4.5.1. [8-(1R,4S,5R,8R)-4-Benzyloxy-2,6-dioxabicyclo-
[3.3.0]octane]-(2-oxo)-propanoate 12. Yellow oil (quant);
1H NMR d 2.50 (s, 3H), 3.86 (dd, Jˆ4.4, 10.4 Hz, 1H),
3.90±4.13 (m, 4H), 4.55 (d, Jˆ4.5 Hz, 1H), 4.59 (s, 2H),
4.82 (dd, Jˆ4.5, 5.9 Hz, 1H), 5.25 (ddd, Jˆ5.6, 5.8, 6.1 Hz,
1H), 7.35 (m, 5H); 13C NMR d 26.6, 70.5, 72.3, 73.4, 78.8,
Jˆ6.9, 8.8 Hz, 1H), 4.00±4.20 (m, 3H), 4.54 (dd, Jˆ3.2,
4.9 Hz, 1H), 4.58 (d, Jˆ11.8 Hz, 1H), 4.73(d, Jˆ11.8 Hz,
1H), 4.90 (dd, Jˆ4.9, 5.9 Hz, 1H), 5.35 (ddd, Jˆ4.9, 5.6,
5.9 Hz, 1H), 7.30±7.40 (m, 5H), 7.49 (dd, Jˆ7.4, 7.8 Hz,
2H), 7.65 (dd, Jˆ7.1, 7.5 Hz, 1H), 8.08 (d, Jˆ7.2 Hz, 2H);
13C NMR d 70.2, 71.0, 72.4, 75.9, 78.4, 80.3, 80.4, 128.0,
134.9, 137.4, 163.3, 186.0; IR (nmax, cm21, ®lm) 1200,
80.3, 82.0, 85.5, 128.0, 137.5, 160.0, 191.0; IR (nmax, cm21
,
®lm) 1220, 1430, 1530, 1740, 2850±3000; Anal. Calcd for
C16H18O6: C, 62.74; H, 5.92. Found: C, 62.41; H, 5.87.
20
1450, 1600, 1680, 1740, 2850±3000; [a]D ˆ11748 (c
1.12, CHCl3); Anal. Calcd for C21H20O6: C, 68.47; H,
5.47. Found: C, 68.85; H, 5.37.
4.5.2. [8-(1R,4S,5R,8R)-4-Benzyloxy-2,6-dioxabicyclo-
[3.3.0]octane]-(2-oxo-2-phenyl)-ethanoate 13. Sticky
1
4.5.7. 8-(1R,4R,5R,8R)-4-Methoxy-2,6-dioxabicyclo-
[3.3.0]octane]-(2-oxo-2-phenyl)-ethanoate 18. Yellow oil
beige oil (95%); H NMR d 3.79 (dd, Jˆ3.5, 10.1 Hz,
1H), 3.95 (dd, Jˆ5.3, 10.1 Hz, 1H), 4.10±4.13 (m, 3H),
4.57 (d, Jˆ5.3Hz, 1H), 4.58 (s, 2H), 5.06 (dd, Jˆ5.3,
5.4 Hz, 1H), 5.40 (ddd, Jˆ5.3, 5.4, 5.7 Hz, 1H), 7.35±
7.40 (m, 5H), 7.52 (dd, Jˆ7.2, 7.9 Hz, 1H), 7.69 (dd,
Jˆ7.4, 7.9 Hz, 1H), 8.11 (d, Jˆ7.2 Hz, 2H); 13C NMR d
70.3, 71.1, 72.8, 75.7, 80.4, 82.5, 86.2, 130.0, 133.3, 137.2,
163.0, 186.0; IR (nmax, cm21, ®lm) 1450, 1600, 1680, 1750,
1
(68%); H NMR d 3.41 (s, 3H), 3.51 (dd, Jˆ7.5, 8.9 Hz,
1H), 3.83±4.11 (m, 4H), 4.52 (dd, Jˆ4.4, 5.9 Hz, 1H), 4.90
(t, Jˆ5.9 Hz, 1H), 5.31 (dt, Jˆ5.9, 6.1 Hz, 1H), 7.47 (dd,
Jˆ5.9, 7.4 Hz, 2H), 7.62 (dd, Jˆ5.9, 7.4 Hz, 1H), 8.02 (d,
Jˆ5.9 Hz, 2H); 13C NMR d 57.8, 70.0, 71.0, 76.0, 79.5,
80.5, 81.0, 128.0, 135.0, 163.0, 185.9; IR (nmax, cm21
,
20
20
®lm) 1300, 1450, 1600, 1685, 1740, 2850±2950; [a]D
11378 (c 1.25, CHCl3); Anal. Calcd for C15H16O6: C, 61.64;
ˆ
2850±3000; [a]D ˆ1768 (c 1, CHCl3); Anal. Calcd for
C21H20O6: C, 68.47; H, 5.47. Found: C, 68.22; H, 5.75.
H, 5.52. Found: C, 61.31; H, 5.53.
4.5.3. [8-(1R,4S,5R,8R)-4-Methoxy-2,6-dioxabicyclo[3.3.0]-
octane]-(2-oxo-2-phenyl)-ethanoate 14. Beige solid recrys-
4.6. General procedure for the preparation of com-
pounds 19, 21, 22
1
tallized from hexanes (65%); mpˆ808C; H NMR d 3.39 (s,
3H), 3.76 (dd, Jˆ3.5, 10.9 Hz, 1H), 3.85±4.07 (m, 4H), 4.51 (d,
Jˆ6.2 Hz, 1H), 5.01 (t, Jˆ6.2 Hz, 1H), 5.40 (ddd, Jˆ5.9, 6.0,
6.2 Hz, 1H), 7.52 (dd, Jˆ7.8, 7.9 Hz, 2H), 7.69 (dd, Jˆ6.2,
7.8 Hz, 1H), 8.12 (d, Jˆ6.2 Hz, 2H); 13C NMR d 57.0, 70.5,
72.6, 75.6, 80.5, 84.9, 85.9, 129.0, 135.0, 163.0, 186.0; IR
(nmax, cm21, ®lm) 1100, 1200, 1350, 1450, 1680, 1725,
A solution of ZnCl2 in Et2O (1 M, 1 mmol) was added to
ketoesters 13, 15, 17 or 18 (0.5 mmol) in THF (5 mL). In a
separated ¯ask, a solution of Grignard reagent (2 mmol) was
added drop by drop to a solution of ZnCl2 (2 mmol). Both
¯asks were then gently shaken for 1 h at rt. The solution
of the prepared organozinc reagent was then slowly added to
the solution of the pre-complexed ketoester pre-cooled to
the temperature of choice. After complete conversion of the
starting material (TLC monitoring), saturated aqueous
NH4Cl (4 mL) is added and the mixture is warmed up to
rt. Extraction of the solution with Et2O (2£5 mL), followed
20
2850±2950; [a]D ˆ1798 (c 1.23, CHCl3); Anal. Calcd
for C15H16O6: C, 61.64; H, 5.52. Found: C, 61.28; H, 5.41.
4.5.4. [4-(1R,4S,5R,8R)-8-Benzyloxy-2,6-dioxabicyclo-
[3.3.0]octane]-(2-oxo-2-phenyl)-ethanoate 15. Orange oil
(87%); 1H NMR d 3.70 (dd, Jˆ6.9, 10.4 Hz, 1H), 3.89 (dd,

A. Loupy, D. A. Monteux / Tetrahedron 58 (2002) 1541±1549
1547
by drying and concentration of the combined organic layers
afford crude compound 19, 21 or 22, which are puri®ed by
¯ash column chromatography on silica gel (pentane/ethyl
acetate gradients).
3.68±4.18 (m, 5H), 4.52±4.57 (m, 3H), 4.86 (dd, Jˆ4.5,
5.9 Hz, 1H), 4.98±5.09 (m, 1H), 5.12 (q, Jˆ5.9 Hz, 1H),
7.27±7.33 (m, 8H), 7.68±7.73 (m, 2H); 13C NMR d 25.6,
69.8, 71.4, 72.9, 75.6, 78.2, 80.4, 82.9, 86.3, 128.0, 136.0,
138.0, 174.0; IR (nmax, cm21, ®lm) 1100, 1250, 1720, 2850±
20
4.6.1. [8-(1R,4S,5R,8R)-4-Benzyloxy-2,6-dioxabicyclo-
[3.3.0]octane]-(2-hydroxy-2-phenyl)-butanoate 19a. Color-
3000, 3400; [a]D ˆ1368 (c 0.55, CHCl3); Anal. Calcd for
C25H30O6: C, 70.40; H, 7.09. Found: C, 70.48; H, 7.13.
1
less oil (65%); H NMR d 0.90 (dd, Jˆ6.6, 7.9 Hz, 3H),
2.19±2.21 (m, 2H), 3.20 (dd, Jˆ3.9, 10.5 Hz, 1H), 3.61 (d,
Jˆ10.5 Hz, 1H), 3.80±3.97 (m, 3H), 4.41 (d, Jˆ5.3Hz,
1H), 4.50 (s, 2H), 4.80 (dd, Jˆ5.3, 5.4 Hz, 1H), 4.83±4.87
(m, 1H), 5.13(q, Jˆ5.4 Hz, 1H), 7.32±7.38 (m, 8H), 7.61
(d, Jˆ5.3Hz, 2H); 13C NMR d 7.9, 32.2, 70.6, 71.1, 72.2,
75.6, 78.5, 80.6, 82.5, 86.2, 127.0, 137.4, 141.3, 174.6; IR
(nmax, cm21, ®lm) 1220, 1430, 1500, 1730, 2850±3000,
4.6.6. [8-(1R,4S,5R,8R)-4-Benzyloxy-2,6-dioxabicyclo-
[3.3.0]octane]-(2-hydroxy-2-phenyl)-pent-4-enoate 19f.
1
Yellow oil (50%); H NMR d 2.80 (dd, Jˆ7.5, 14.9 Hz,
1H), 3.02 (dd, Jˆ7.5, 14.9 Hz, 1H), 3.25 (dd, Jˆ4.5,
10.4 Hz, 1H), 3.60±4.05 (m, 4H), 4.47±4.52 (m, 3H), 4.78
(dd, Jˆ4.5, 5.9 Hz, 1H), 4.83±4.86 (m, 1H), 5.06±5.26 (m,
3H), 5.82 (ddt, Jˆ7.1, 7.4, 7.6 Hz, 1H), 7.33±7.38 (m, 8H),
7.60 (d, Jˆ7.5 Hz, 2H); 13C NMR d 44.2, 70.4, 71.2, 72.4,
75.6, 80.5, 80.6, 82.8, 86.3, 119.5, 128.0, 132.3, 137.4, 140.8,
173.8; IR (nmax, cm21, ®lm) 1200, 1420, 1500, 1720, 2850±
20
3600; [a]D ˆ1498 (c 0.98, CHCl3); Anal. Calcd for
C23H26O6: C, 69.33; H, 6.58. Found: C, 68.94; H, 6.61.
20
4.6.2. [8-(1R,4S,5R,8R)-4-Benzyloxy-2,6-dioxabicyclo-
[3.3.0]octane]-(2-hydroxy-3-methyl-2-phenyl)-butanoate
19b. Yellow oil (78%); 1H NMR d 0.75 (d, Jˆ6.2 Hz, 3H),
1.00 (d, Jˆ6.2 Hz, 3H), 2.65 (d, Jˆ6.2 Hz, 1H), 3.25 (dd,
Jˆ3.7, 10.0 Hz, 1H), 3.65 (d, Jˆ10.0 Hz, 1H), 3.82±4.00
(m, 3H), 4.41 (d, Jˆ5.0 Hz, 1H), 4.48 (s, 2H), 4.75 (dd, Jˆ
5.0, 6.2 Hz, 1H), 4.82±4.87 (m, 1H), 5.08 (q, Jˆ6.2 Hz,
1H), 7.33±7.36 (m, 8H), 7.67 (d, Jˆ7.5 Hz, 2H); 13C
NMR d 15.7, 17.0, 35.2, 70.5, 71.0, 72.2, 75.8, 80.5, 80.7,
82.5, 86.2, 128.0, 137.4, 140.7, 174.9; IR (nmax, cm21, ®lm)
3000, 3600; [a]D ˆ1448 (c 0.79, CHCl3); Anal. Calcd for
C24H26O6: C, 70.23; H, 6.38. Found: C, 70.12; H, 6.41.
4.6.7. [8-(1R,4S,5R,8R)-4-Benzyloxy-2,6-dioxabicyclo-
[3.3.0]octane]-(2-cyclohexyl-2-hydroxy-2-phenyl)-ethano-
ate 19g. Yellow oil (62%); 1H NMR d 1.02±1.85 (m, 10H),
2.22±2.27 (m, 1H), 3.23 (dd, Jˆ3.0, 9.5 Hz, 1H), 3.61±3.65
(m, 2H), 3.82±3.95 (m, 2H), 4.40 (d, Jˆ4.5 Hz, 1H), 4.50
(s, 2H), 4.75 (dd, Jˆ4.5, 5.9 Hz, 1H), 4.83±4.86 (m, 1H),
5.05±5.16 (m, 1H), 7.30±7.35 (m, 8H), 7.60 (d, Jˆ7.5 Hz,
2H); 13C NMR d 25.5, 27.2, 45.3, 70.7, 71.2, 72.3, 75.8,
20
1220, 1420, 1520, 1720, 2850±3000, 3600; [a]D ˆ1398 (c
0.98, CHCl3); Anal. Calcd for C24H28O6: C, 69.89; H, 6.84.
Found: C, 69.67; H, 6.84.
80.6, 80.9, 82.7, 86.4, 128.0, 137.0, 140.4, 174.9; IR (nmax,
20
cm21, ®lm) 1200, 1730, 2850±3000, 3600; [a]D ˆ1398 (c
0.78, CHCl3); Anal. Calcd for C27H32O6: C, 71.66; H, 7.13.
Found: C, 71.54; H, 7.34.
4.6.3. [8-(1R,4S,5R,8R)-4-Benzyloxy-2,6-dioxabicyclo-
19c.
[3.3.0]octane]-(2-hydroxy-2-phenyl)-hexanoate
1
Yellow oil (75%); H NMR d 0.90 (dd, Jˆ5.9, 7.1 Hz,
3H), 1.22±1.42 (m, 4H), 1.95±2.30 (m, 2H), 3.20 (dd,
Jˆ3.6, 10.7 Hz, 1H), 3.61 (d, Jˆ10.7 Hz, 1H), 3.80±4.00
(m, 3H), 4.41 (d, Jˆ4.8 Hz, 1H), 4.50 (s, 2H), 4.79 (dd,
Jˆ4.8, 5.9 Hz, 1H), 4.83±4.87 (m, 1H), 5.11 (q, Jˆ
5.9 Hz, 1H), 7.32±7.38 (m, 8H), 7.60 (d, Jˆ7.1 Hz, 2H);
13C NMR d 13.9, 22.6, 25.5, 38.9, 70.6, 71.0, 72.2, 75.5,
4.6.8. [8-(1R,4S,5R,8R)-4-Benzyloxy-2,6-dioxabicyclo-
[3.3.0]octane]-(2-hydroxy-2,3-diphenyl)-propanoate 19h.
1
Colorless oil (58%); H NMR d 3.25 (d, Jˆ14.3Hz, 1H),
3.30 (dd, Jˆ3.6, 9.5 Hz, 1H), 3.61 (d, Jˆ14.3Hz, 1H), 3.68
(d, Jˆ9.5 Hz, 1H), 3.82±4.00 (m, 3H), 4.42 (d, Jˆ4.8 Hz,
1H), 4.50 (s, 2H), 4.75 (dd, Jˆ4.8, 5.9 Hz, 1H), 4.82±4.87
(m, 1H), 5.00 (q, Jˆ5.9 Hz, 1H), 7.18±7.40 (m, 13H), 7.70
(d, Jˆ7.1 Hz, 2H); 13C NMR d 45.4, 70.3, 71.2, 72.5, 75.8,
78.6, 80.7, 82.7, 86.2, 128.0, 135.6, 137.4, 141.3, 173.8;
IR (nmax, cm21, ®lm) 1200, 1420, 1500, 1720, 2850±3000,
78.1, 80.6, 82.5, 86.2, 128.0, 137.4, 141.5, 174.6; IR (nmax
,
cm21, ®lm) 1200, 1710, 2850±3000, 3550; [a]D ˆ1198 (c
1.08, CHCl3); Anal. Calcd for C25H30O6: C, 70.40; H, 7.09.
Found: C, 70.46; H, 7.23.
20
20
3500; [a]D ˆ178 (c 1, CHCl3); Anal. Calcd for C28H28O6:
C, 73.03; H, 6.13. Found: C, 73.39; H, 6.51.
4.6.4. [8-(1R,4S,5R,8R)-4-Benzyloxy-2,6-dioxabicyclo-
[3.3.0]octane]-(2-hydroxy-4-methyl-2-phenyl)-pentano-
ate 19d. Colorless oil (48%); 1H NMR d 0.90 (d, Jˆ7.1 Hz,
6H), 1.82±1.86 (m, 1H), 2.11±2.14 (m, 2H), 3.23 (dd, Jˆ
3.6, 9.5 Hz, 1H), 3.61 (d, Jˆ9.5 Hz, 1H), 3.80±4.00 (m,
3H), 4.42 (d, Jˆ4.8 Hz, 1H), 4.50 (s, 2H), 4.80 (dd, Jˆ
4.8, 5.9 Hz, 1H), 4.83±4.87 (m, 1H), 5.10 (q, Jˆ5.9 Hz,
1H), 7.32±7.38 (m, 8H), 7.64 (d, Jˆ7.1 Hz, 2H); 13C
NMR d 23.3, 24.3, 34.0, 47.3, 70.5, 71.1, 72.4, 76.5, 78.6,
4.6.9. [4-(1R,4S,5R,8R)-8-Benzyloxy-2,6-dioxabicyclo-
[3.3.0]octane]-(2-hydroxy-2-phenyl)-butanoate
21a.
1
Yellow oil (48%); H NMR d 0.92 (dd, Jˆ5.9, 7.1 Hz,
3H), 1.92±2.30 (m, 2H), 3.55±4.20 (m, 5H), 4.50 (d,
Jˆ4.8 Hz, 1H), 4.55 (d, Jˆ11.9 Hz, 1H), 4.70 (dd, Jˆ4.8,
5.9 Hz, 1H), 4.77 (d, Jˆ11.9 Hz, 1H), 5.25 (d, Jˆ3.6 Hz,
1H), 7.30±7.45 (m, 8H), 7.57 (d, Jˆ7.0 Hz, 2H); 13C NMR
d 8.0, 32.5, 60.0, 70.5, 72.5, 73.1, 78.7, 80.0, 80.6, 85.4,
128.0, 137.5, 141.3, 174.2; IR (nmax, cm21, ®lm) 1200,
80.6, 82.6, 86.2, 128.0, 137.4, 142.3, 175.0; IR (nmax, cm21
,
20
20
®lm) 1100, 1200, 1720, 2850±3000, 3500; [a]D ˆ1358 (c
0.87, CHCl3); Anal. Calcd for C25H30O6: C, 70.40; H, 7.09.
Found: C, 70.36; H, 7.16.
1400, 1500, 1715, 2850±3000, 3500; [a]D ˆ1898 (c
1.39, CHCl3); Anal. Calcd for C23H26O6: C, 69.33; H,
6.58. Found: C, 68.95; H, 6.66.
4.6.5. [8-(1R,4S,5R,8R)-4-Benzyloxy-2,6-dioxabicyclo-
[3.3.0]octane]-(3,3-dimethyl-2-hydroxy-2-phenyl)-butano-
4.6.10. [4-(1R,4S,5R,8R)-8-Benzyloxy-2,6-dioxabicyclo-
[3.3.0]octane]-(2-hydroxy-3-methyl-2-phenyl)-butanoate
21b. Light yellow oil (51%); 1H NMR d 0.80 (d, Jˆ7.0 Hz,
1
ate 19e. Light yellow oil (27%); H NMR d 1.05 (s, 9H),

1548
A. Loupy, D. A. Monteux / Tetrahedron 58 (2002) 1541±1549
3H), 1.02 (d, Jˆ7.0 Hz, 3H), 2.60 (h, Jˆ7.0 Hz, 1H),
3.55±4.18 (m, 5H), 4.50±4.65 (m, 2H), 4.70 (dd, Jˆ4.8,
5.9 Hz, 1H), 4.77 (d, Jˆ11.9 Hz, 1H), 5.20 (d, Jˆ
3.6 Hz, 1H), 7.28±7.41 (m, 8H), 7.61 (d, Jˆ8.0 Hz,
2H); 13C NMR d 15.7, 17.1, 35.6, 60.0, 70.6, 72.5,
73.1, 79.0, 80.1, 80.7, 85.3, 128.0, 137.6, 140.7,
174.7; IR (nmax, cm21, ®lm) 1200, 1450, 1510, 1725,
4.6.15. [8-(1R,4R,5R,8R)-4-Methoxy-2,6-dioxabicyclo-
[3.3.0]octane]-(2-hydroxy-3-methyl-2-phenyl)-butanoate
22c. Light yellow oil (70%); 1H NMR d 0.75 (d, Jˆ6.0 Hz,
3H), 1.00 (d, Jˆ6.0 Hz, 3H), 2.70 (h, Jˆ6.0 Hz, 1H), 3.05
(dd, Jˆ8.3, 9.5 Hz, 1H), 3.43 (s, 3H), 3.50±4.08 (m, 4H),
4.42 (dd, Jˆ4.5, 5.2 Hz, 1H), 4.70 (dd, Jˆ5.2, 5.9 Hz, 1H),
4.80 (dd, Jˆ5.1, 5.9 Hz, 1H), 5.11 (q, Jˆ5.6 Hz, 1H), 7.25±
7.40 (m, 3H), 7.66 (d, Jˆ7.1 Hz, 2H); 13C NMR d 15.7,
17.0, 35.0, 58.2, 69.3, 71.5, 75.9, 79.9, 80.2, 80.7, 80.8,
128.0, 140.6, 175.1; IR (nmax, cm21, ®lm) 1240, 1350,
20
2850±3000, 3500; [a]D ˆ1688 (c 2.24, CHCl3); Anal.
Calcd for C24H28O6: C, 69.89; H, 6.84. Found: C, 69.54;
H, 6.96.
20
1450, 1710, 2850±3000, 3430; [a]D ˆ1808 (c 1.01,
4.6.11. [4-(1R,4S,5R,8R)-8-Benzyloxy-2,6-dioxabicyclo-
[3.3.0]octane]-(2-hydroxy-2-phenyl)-hexanoate 21c. Light
yellow oil (65%); 1H NMR d 0.87±0.92 (m, 3H), 1.11±1.50
(m, 4H), 1.96±2.28 (m, 2H), 3.55±4.13 (m, 5H), 4.48 (d,
Jˆ4.8 Hz, 1H), 4.53(d, Jˆ10.7 Hz, 1H), 4.65 (dd, Jˆ4.8,
5.9 Hz, 1H), 4.75 (d, Jˆ10.7 Hz, 1H), 5.22 (d, Jˆ3.5 Hz,
1H), 7.25±7.40 (m, 8H), 7.55 (d, Jˆ7.1 Hz, 2H); 13C NMR
d 14.0, 22.6, 25.6, 39.1, 60.3, 70.4, 72.4, 73.1, 78.8, 79.8,
80.6, 85.3, 128.0, 137.4, 141.4, 174.3; IR (nmax, cm21, ®lm)
CHCl3); Anal. Calcd for C18H24O6: C, 64.27 H, 7.19.
Found: C, 64.27; H, 7.21.
4.7. General procedure for the preparation of com-
pounds 20and 23
A solution of KOH (2.5 mmol) in H2O (2 mL) was added to
compounds 19 or 22 (0.5 mmol) in MeOH (2 mL). The
resulting mixture was heated up to re¯ux until complete
conversion of the starting material (TLC monitoring in pen-
tane/AcOEt/MeOH:70/23/311%AcOH). After concen-
tration of the mixture, H2O (2 mL) was added and the
aqueous layer was extracted with ethyl acetate (3£5 mL).
Aqueous HCl (2N) was added until acidic pH was reached
and the aqueous layer was further extracted with ethyl
acetate (3£5 mL). The combined organic layers were
dried (MgSO4), ®ltered and concentrated under vacuum to
afford pure compound 20 or 23. (the acido-basic washing
sequence was repeated when compounds were isolated with
unsatisfactory purity).
20
1200, 1430, 1530, 173074, 2850±3000, 3500; [a]D ˆ1748
(c 2.1, CHCl3); Anal. Calcd for C25H30O6: C, 70.40; H, 7.09.
Found: C, 70.03; H, 7.15.
4.6.12. [4-(1R,4S,5R,8R)-8-Benzyloxy-2,6-dioxabicyclo-
[3.3.0]octane]-(2-hydroxy-2-phenyl)-pent-4-enoate 21d.
1
Colorless oil (25%); H NMR d 2.79±2.82 (m, 1H), 2.97±
3.02 (m, 1H), 3.57±4.20 (m, 5H), 4.48 (d, Jˆ4.5 Hz, 1H),
4.55 (d, Jˆ11.9 Hz, 1H), 4.68 (dd, Jˆ4.5, 5.9 Hz, 1H), 4.76
(d, Jˆ11.9 Hz, 1H), 5.10±5.35 (m, 3H), 5.78±5.81 (m, 1H),
7.30±7.45 (m, 8H), 7.55 (d, Jˆ7.4 Hz, 2H); 13C NMR d
43.9, 60.3, 70.4, 72.5, 73.1, 78.9, 80.0, 80.6, 85.3, 119.3,
20
128.0, 132.0, 137.5, 140.8, 173.6; [a]D ˆ1638 (c 2.60,
All analytical data corresponding to compounds 20a±d,f,g
and 23a±c were found identical to those disclosed in the
literature.6,7a,23
CHCl3); Anal. Calcd for C24H26O6: C, 70.23; H, 6.38.
Found: C, 70.62; H, 6.71.
4.6.13. [4-(1R,4R,5R,8R)-8-Benzyloxy-2,6-dioxabicyclo-
[3.3.0]octane]-(2-hydroxy-3-methyl-2-phenyl)-butanoate
22a. Yellow oil (53%); 1H NMR d 0.75 (d, Jˆ7.1 Hz, 3H),
1.00 (d, Jˆ7.1 Hz, 3H), 2.65±2.68 (m, 1H), 3.15 (dd, Jˆ5.9,
9.5 Hz, 1H), 3.48 (dd, Jˆ8.3, 9.5 Hz, 1H), 3.60±4.20 (m,
3H), 4.40 (dd, Jˆ4.8, 5.9 Hz, 1H), 4.50 (d, Jˆ11.9 Hz, 1H),
4.66 (dd, Jˆ4.8, 5.9 Hz, 1H), 4.70 (d, Jˆ11.9 Hz, 1H), 5.10
(q, Jˆ5.9 Hz, 1H), 7.30±7.40 (m, 8H), 7.55 (d, Jˆ7.1 Hz,
2H); 13C NMR d 15.7, 17.0, 35.2, 69.1, 71.4, 72.5, 75.9,
Acknowledgements
We are grateful to the University of Paris-Sud and CNRS
for ®nancial supports and to MERS for a grant (D. M.). We
thank also Dr Christophe Chassaing for stimulating dis-
cussions.
78.4, 79.2, 80.3, 80.5, 128.0, 137.4, 140.7, 175.1; IR (nmax
,
cm21, ®lm) 1250, 1730, 2850±3000, 3500; [a]D ˆ1828 (c
1.01, CHCl3); Anal. Calcd for C24H28O6: C, 69.89; H, 6.84.
Found: C, 69.57; H, 6.49.
20
References
1. (a) Visser, T. J.; Van Waarde, A.; Doze, P.; Wegman, T.;
Vaalburg, W. Synapse 2000, 35, 62. (b) Subrahmanyam, D.;
Sarma, V. M.; Venkateswartu, A.; Sastry, T. V. R. S.; Srinivas,
A. S. S. V.; Krishna, C. V.; Deevi, D. S.; Kumar, S. A.; Babu,
M. J.; Damodaran, N. K. Bioorg. Med. Chem. Lett. 2000, 10,
369. (c) Mayer, P.; Brunel, P.; Imbert, T. Bioorg. Med. Chem.
Lett. 1999, 9, 3021.
4.6.14. [4-(1R,4R,5R,8R)-8-Benzyloxy-2,6-dioxabicyclo-
[3.3.0]octane]-(2-hydroxy-4-methyl-2-phenyl)-pentano-
1
ate 22b. Yellow oil (23%); H NMR d 0.93(d, Jˆ7.4 Hz,
3H), 1.80±1.85 (m, 1H), 2.00±2.20 (m, 2H), 3.08 (dd,
Jˆ8.4, 8.9 Hz, 1H), 3.43 (dd, Jˆ7.0, 8.9 Hz, 1H), 3.85±
4.05 (m, 3H), 4.40 (dd, Jˆ4.85, 5.9 Hz, 1H), 4.50 (d, Jˆ
11.9 Hz, 1H), 4.68 (dd, Jˆ4.5, 5.9 Hz, 1H), 4.70 (d,
Jˆ11.9 Hz, 1H), 5.10 (q, Jˆ5.9 Hz, 1H), 7.27±7.40 (m,
8H), 7.66 (d, Jˆ7.0 Hz, 2H); 13C NMR d 23.2, 24.4, 34.0,
47.3, 69.7, 71.4, 72.6, 75.8, 78.1, 78.4, 80.3, 80.8, 128.0,
2. (a) Hauser, F. M.; Ganguly, D. J. Org. Chem. 2000, 65, 1842.
(b) Vladu, B.; Woynarowski, J. M.; Manikumar, G.; Wani, M.;
Wall, M. E.; Von Hoff, D. D.; Wadkins, R. M. Mol. Pharma-
col. 2000, 57, 243.
3. Wang, Z.; Xu, G.; Wang, D.; Pierce, M. E.; Confalone, P. N.
Tetrahedron Lett. 2000, 41, 4523.
4. Note: Alkylations of 2-substituted 1,3-dioxolan-4-ones5 or
additions to chiral ketooxazolines6 have been proposed as
20
137.1, 142.2, 175.4; [a]D ˆ1788 (c 1.00, CHCl3); Anal.
Calcd for C25H30O6: C, 70.40; H, 7.09. Found: C, 70.16; H,
7.36.

A. Loupy, D. A. Monteux / Tetrahedron 58 (2002) 1541±1549
1549
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