Arylacetic acid derivatization of 2,3- and internal erythro-squalene diols. Separation and absolute configuration determination

Article abstract of DOI:10.1016/j.tet.2004.09.059

We have studied a new approach for the resolution and absolute configuration determination of the enantiomers of squalene diols as intermediate precursors in the chemical synthesis of different squalene oxides (SOs); (3R)- and (3S)-2,3-SO, (6R,7R)- and (6

Full text of DOI:10.1016/j.tet.2004.09.059

Tetrahedron 60 (2004) 11519–11525
Arylacetic acid derivatization of 2,3- and internal
erythro-squalene diols. Separation and absolute configuration
determination
*
Jose-Luis Abad and Francisco Camps
´
Department of Biological Organic Chemistry, IIQAB-CSIC, Jordi Girona 18-26, 08034 Barcelona, Spain
Received 23 April 2004; revised 3 September 2004; accepted 17 September 2004
Available online 8 October 2004
Abstract—We have studied a new approach for the resolution and absolute configuration determination of the enantiomers of squalene diols
as intermediate precursors in the chemical synthesis of different squalene oxides (SOs); (3R)- and (3S)-2,3-SO, (6R,7R)- and (6S,7S)-6,7-SO,
and (10R,11R)- and (10S,11S)-10,11-SO. Monoderivatization of the corresponding racemic squalene diol intermediates with pure
stereoisomers of (S)-(C)-methoxyphenyl acetic acid ((S)-(C)-MPA), (S)-(C)-9-anthrylmethoxyacetic acid ((S)-(C)-9-AMA) and (S)-(C)-
acetoxyphenylacetic acid ((S)-(C)-APA) afforded the diastereomeric esters which could be easily separated by column flash
chromatography with silica gel. In addition, the absolute configuration for these diastereoisomers of the derivatized diols was
advantageously inferred from 1H NMR data according to the models depicted for these derivatizing chiral agents. In order to demonstrate the
absolute configuration assignment of the different stereoisomers, (S)-(C)-AMA showed the larger Dd by 1H NMR, however, (S)-(C)-MPA
esters were much more stable derivatives.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
using as derivatizing agents chiral aryl acetic acids currently
applied to determine the absolute configuration of second-
ary alcohols. For this purpose, the (S)-(C)-MPA, (S)-(C)-
APA, and (S)-(C)-9-AMA diastereomeric esters from the
above squalene diols were prepared (Fig. 1) and separated
by flash chromatography with silica gel. In addition, we
present here the 1H NMR data needed for the easy
assignment of the absolute configuration of the derivatized
secondary carbinols present in 2,3- and erythro-squalene
diols and we compare these results with the more
cumbersome assignation from data previously obtained for
the above squalene diols derivatized with MTPA.1
In the past years, we developed a route to synthesize and
determine the absolute configuration of the different
enantiomers of the squalene oxides using 2,3- and
erythroK6,7- and 10,11-squalene diols (Sdiols) as inter-
mediates. In this case, the resolution of the corresponding
Sdiols was achieved by derivatization with MTPA
(Mosher’s acid, a-methoxy-a-trifluoromethylphenylacetic
acid). In addition, we demonstrated that these enantiomers
of the internal SOs were valuable substrates for inhibitory
studies of squalene epoxidase (SE) leading to the epoxida-
tion at both terminal double bonds of the squalene chain but
affording regioselective and asymmetric ratios of enantio-
mers of squalene dioxides.1 Likewise, we studied the
activity and interactions of the resulting squalene dioxides
with oxidosqualene-lanosterol cyclase (OSLC), another key
enzyme in the cholesterol biosynthesis.1
2. Results and discussion
2.1. Preparation, derivatization and separation of the
2,3- and erythro-squalene diols
So far, there have been a great number of studies for the
synthesis of chiral squalene epoxides. In most of these
syntheses, 2,3-squalene diols were used as versatile key
intermediates in the preparation of enantiomerally pure
2,3-squalene oxides. Other approaches were reported by
using chiral synthons,2 by enantioselective reactions3 or by
chemical resolution of the diols.1,4 among others.
Previously, we had performed the chemical resolution
In this paper, we report a practical new approach to resolve
both enantiomers of the different squalene diols with high
enantiomeric excesses by simple flash chromatography
Keywords: Squalene oxides; Squalene diols; Resolution; Enantiomers;
Derivatization; Arylacetic acids.
* Corresponding author. Tel.: C343 400 6100; fax: C343 204 5904;
e-mail: jlaqob@iiqab.csic.es
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.09.059

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J.-L. Abad, F. Camps / Tetrahedron 60 (2004) 11519–11525
Figure 1. Arylacetic esters of 2,3- and erythro-6,7- and 10,11-squalene diols.
strategy involving the formation of the (R)-MTPA esters of
the corresponding enantiomers of 2,3-, erythro-6,7- and
erythroK10,11-squalene diols. The obtained esters were
submitted to HPLC chromatographic resolution and used for
further determination of the absolute configuration of the
stereogenic centers present at the squalene skeleton for each
diastereoisomer. But HPLC chromatographic resolution by
reverse phase HPLC was very tedious and difficult.
2.2. Absolute configuration determination of the
2,3-, erythro-6,7- and erythro-10,11-squalene diols
Since Mosher7 proposed 1H NMR to determine the absolute
configuration of stereogenic centers of secondary alcohols
derivatized with MTPA, many other researchers have
reported similar methodologies and derivatizing agents.
1
Most of these methodologies try to visualize important H
NMR chemical shifts changes due to the diamagnetic effect
of the aromatic ring(s) on certain protons of the derivatized
molecule. Obviously, the success to determine the absolute
configuration of a derivatized alcohol by 1H NMR depends
on the Dd value calculated from the different chemical shifts
for the same hydrogen of both diastereoisomers. The greater
is this anisotropy effect in both diastereomers, the easier is
the proton chemical shifts differentiation and therefore the
absolute configuration determination. When we applied this
technique to determine the absolute configuration of the
squalene diols derivatized with (R)-MTPA by NMR, the
chemical shifts signals of the diasteromeric derivatives were
too close with only small Dd values among 0.15–0.05 ppm,
complicating the assignment process. However, the recent
availability of acids like MPA, APA and 9-AMA has
facilitated the application of the corresponding stereoche-
mical models for the assignment of absolute configurations.
In order to extend the use of this methodology, we present
here a comparative study of the Dd values obtained for the
assignment of the absolute configuration of the squalene
diols and we compare these results with the previously
studied derivatives obtained with Mosher’s acid (MTPA).
Our ongoing interest in resolving secondary alcohols with
lipases5 has led us to undertake the search for a new
enzymatic strategy. In this context, specific lipases could be
able to remove selectively the arylacetic group from the
derivatized diasteromeric (S)-(C)-esters of the correspond-
ing squalene diols. As a result, we would be able to separate
both enantiomers of the racemic mixture facilitating the
stereochemical studies of the resolved diol intermediate and
determining the absolute configuration of both diastero-
meric esters. Consequently, we decided to prove this
strategy for arylacetic derivatized compounds which could
be potential substrates with acylases or lipases and had been
utilized in determining the absolute configuration of
secondary alcohols, such as (S)-(C)-MPA, (S)-(C)-APA,
and (S)-(C)-9-AMA esters. In this context, some represen-
tative model secondary alcohols were derivatized and
enzymatically hydrolyzed but results were not so good as
anticipated and this approach was disregarded.
2,3-Squalene diol, erythro-6,7- and erythroK10,11-squal-
ene diol were prepared according to procedures previously
reported1 and derivatization with (S)-(C)-MPA, (S)-(C)-
APA, and (S)-(C)-9-AMA, was achieved by one of these
two methods: (1) By previous preparation of the proper acid
chloride and then reaction with the squalene diol in presence
1
To this aim, H, 13C NMR, DQFCOSY and XH-CORFE
spectra for the different arylacetic esters were registered,
and interpretation of COSY and HETCOR data allowed the
1
assignments of H and 13C NMR signals, which readily
6
of DMAP and NEt3 or (2) by using a carbodiimide in
demonstrated that another difference between them was the
asymmetric diamagnetic effect of the aromatic ring(s) on the
1H NMR chemical shifts for the hydrogens with respect to
each diastereoisomer.
presence of DMAP.5 Apparently, no important racemiza-
tions have been reported under the derivatization conditions
described for these two methods and yields used to be higher
than 90%.
The 1H and 13C NMR chemical shift increments (Dd) in each
pair of diastereomeric esters are shown in Schemes 1–3.
1H NMR Dd calculations showed a similar sign behavior for
the squalene diols substituents in all arylacetic esters. As we
had checked previously for aliphatic chains, hydrogens at b
position from the carbinol exhibited the highest shielding
effect.8 As expected, (S)-(C)-9-AMA showed the most
important shielding values for both diastereomeric esters
(i.e., 1 ppm for hydrogens at b position). However, results
using APA were comparable to those obtained with MPA
(i.e., 0.4 ppm for hydrogens at b position), but much better
than those reported with MTPA (i.e, 0.15 ppm for hydro-
gens at b position). Likewise, 13C NMR chemical shift
assignments showed a 13C NMR Dd behavior similar to that
Surprisingly, when we analyzed the reaction mixture by
TLC we observed high differences of Rf in the TLC plate for
all the squalene arylacetic esters prepared. As an example,
TLC separation of diasteromeric esters was better for the
derivatizing acid in the order 9-AMAO APAzMPA and
for the derivatized diol in the order 10,11-O6,7-O2,3-
squalene diol. As we expected, stability of products
followed the order MPA OO APA O 9-AMA, since
after 1 year of storage only 4% of MPA derivatized product
1
was isomerized. H, 13C NMR and HPLC-MS-FIA data
allowed us to determine that the two major products formed
corresponded to the monoderivatized diastereoismers at the
secondary carbinol of the squalene diol.

J.-L. Abad, F. Camps / Tetrahedron 60 (2004) 11519–11525
11521
Scheme 1. 1H and 13C NMR chemical shift differences (in ppm) for the positions closest to the substituted carbinolic center for the aryl acetic esters of the 2,3-
squalene diol skeleton.
Scheme 2. 1H and 13C NMR chemical shift differences (in ppm) for the positions closest to the substituted carbinolic center for the aryl acetic esters of the 6,7-
erythro-squalene diol skeleton.
Scheme 3. 1H and 13C NMR chemical shift differences (in ppm) for the positions closest to the substituted carbinolic center for the aryl acetic esters of the
10,11-erythro-squalene diol skeleton.
observed for 1H NMR9 and the highest anisotropy effect was
observed for the carbons located at b position from the
carbinol substitution. (cf Schemes 1–3).
the optical purity of the enantiomerically pure squalene
diols were in agreement with the enantiomeric purity of the
ester precursors. However, rederivatization with (S)-(C)-
MPA of each one of the resulting squalene diols and TLC
and HPLC analysis of the resulting esters showed that there
was 6-8% of isomerized alcohol. This isomerization was
much more important (up to 12%) for squalene diols
previously derivatized with (S)-(C)-APA and by the acyl
chloride method. These results are somewhat worse than
those observed for the derivatized squalene diols obtained
after rederivatization with MTPA that showed 5% of
isomerization. In spite of the higher degree of isomerization,
any of the recovered enantiomerically enriched squalene
diols could be useful as squalene oxides intermediates to
perform any biological experiment.
Comparison with the corresponding stereochemical models
for (S)-(C)-MPA,10 (S)-(C)-APA,11 and (S)-(C)-9-
AMA12 allowed us to determine the absolute configuration
of the stereocenter of each diastereoisomer in the deriva-
tized carbinol resulting in the “S” configuration for the less
polar diastereoisomer (ca Rf 0.4, hexane–MTBE 7:3).
Reduction or saponification of individual isomers of Sdiols
esters with LiAlH4/Diethyl Ether or K2CO3 in MeOH,
respectively, gave rise to the enantiomeric diols. As
expected, sign of the optical rotation of the released
squalene diol confirmed the absolute configuration assign-
ment. Since resolution has been so good, we expected that
In conclusion, we have improved the methodology for

11522
J.-L. Abad, F. Camps / Tetrahedron 60 (2004) 11519–11525
the separation and absolute configuration determination of
the different squalene diol stereoisomers that afford the
biologically active squalene oxides. In this context, MPA
esters of squalene diols are the most appropriate and stable
derivatized intermediates to separate and determine the
absolute configuration of the enantiomers of the squalene
diols.
3.2. Preparation of esters by the carbodiimide
methodology. General procedure
A mixture of DMAP (0.2 mmol), arylacetic acid
(0.32 mmol), N-(3-dimethylaminopropyl)-N0-ethylcarbodi-
imide hydrochloride (0.3 mmol) and squalene diol
(0.2 mmol) in 2 mL of CH2Cl2 was stirred for 1 h at RT,
washed with NaHCO3 solution, concentrated at reduced
pressure and purified by flash chromatography on silica gel
using a gradient of 0–30% MTBE in hexane (85–92%
yield).
3. Experimental
General methods. The liquid chromatography-mass
spectrometry analyses (HPLC-MS-FIA) were performed
with an apparatus with a chemical ionization interface
at atmospheric pressure and diode array detector
(CH3CN/H2O (80:20) at 1 mL/min; positive mode). All
1H NMR spectra were acquired at 300 MHz, and 13C NMR
spectra, at 75 MHz in freshly neutralized CDCl3 solutions,
and chemical shifts are given in ppm using as internal
standards Si(CH3)4 for 1H, and CDCl3 for 13C. The standard
1H DQFCOSY and XH-CORFE spectra for the
determination of the absolute configuration of (S)-(C)-9-
AMA, (S)-(C)-MPA and (S)-(C)-APA esters were
recorded at 25 8C using the same concentration for both
diastereomeric pairs as described elsewhere.1 All IR spectra
were run as film.
3.2.1. (S)-(C)-a-Methoxy-a-(9-anthryl)-acetate of (3S)-
2,3-squalene diol (higher Rf in TLC). RfZ0.22; IR 3450,
2965, 2925, 2855, 1750 (CO), 1450, 1380, 1190, 1115,
730 cmK1; 1H NMR d 8.61 (d, JZ8 Hz, 2H), 8.47 (s, 1H),
8.02 (dd, J1Z8 Hz, J2Z1 Hz, 2H), 7.60–7.40 (4H), 6.33
(s, 1H), 5.20–5.00 (5H), 4.73 (dd, J1Z10 Hz, J2Z2.5 Hz,
1H), 3.46 (s, 3H), 2.20–1.92 (18H), 1.68 (s, 3H), 1.60
(bs, 12H), 1.58 (s, 3H), 1.60–1.20 (4H), 0.58 (s, 1H), 0.46
(s, 3H), 0.41 (s, 3H); 13C NMR d 170.7, 135.1, 135.0, 134.9,
133.9, 131.3, 131.2, 130.4, 129.3, 129.2, 127.1, 126.8,
125.1, 124.9, 124.4, 124.3, 124.2, 80.8, 77.2, 71.8, 57.4,
39.7, 39.7, 39.7, 36.0, 28.3, 27.9, 26.7, 26.6, 25.7, 25.3,
23.9, 17.7, 16.0, 16.0; HPLC-MS-FIA m/z 710 (M%CC18),
692 (M%C), 677 (M%CK18C3), 427 (M%CK265);
[a]DZC43.4 (cZ1, 98% de).
Unless otherwise stated, organic solutions obtained from
workup of crude reaction mixtures were dried over MgSO4.
The purification procedures were carried out by flash
chromatography on silica gel (230–400 mesh) and products
were obtained as oils unless otherwise specified. Visualiza-
tion of UV-inactive materials was accomplished by soaking
the TLC plates in an ethanolic solution of anisaldehyde and
sulfuric acid (v/v/v, 96:2:2). Optical rotations were
determined at 258 in CHCl3 solution at the specified
concentration (g/100 mL). Enantiomeric and diastereomeric
excesses (ee and de) values of the corresponding (S)-(C)-
arylacetic diastereomeric esters were calculated by NMR or
by HPLC analyses using Spherisorb ODS-2 (5 mm) columns
(10!0.6 cm and 15!1 cm, respectively) and eluting with
CH3CN–H2O mixtures at 1 mL/min. All TLC plates were
eluted with hexanes–MTBE 7:3.
3.2.2. (S)-(C)-a-Methoxy-a-(9-anthryl)-acetate of (3R)-
2,3-squalene diol (lower Rf in TLC). RfZ0.08; IR 3450,
2965, 2925, 2855, 1750 (CO), 1450, 1380, 1190, 1115,
730 cm K1; 1H NMR d 8.61 (d, JZ8 Hz, 2H), 8.47 (s, 1H),
8.02 (d, JZ8 Hz, 2H), 7.60–7.40 (4H), 6.35 (s, 1H),
5.20–5.00 (4H), 4.73 (dd, J1Z10 Hz, J2Z2 Hz, 1H), 4.23
(m, 1H), 3.44 (s, 3H), 2.14–1.92 (12H), 1.79 (s, 1H), 1.78 (s,
3H), 1.68 (d, JZ1 Hz, 3H), 1.60 (bs, 9H), 1.54 (d, JZ1 Hz,
3H), 1.32 (m, 2H), 1.11 (s,3H), 1.06 (s,3H), 0.98 (d, JZ
1 Hz, 3H), 1.10–0.7 (2H); 13C NMR d 171.4, 135.1, 134.9,
133.3, 131.5, 131.2, 130.5, 129.2, 129.2, 127.1, 126.6,
125.0, 124.4, 124.4, 124.4, 124.2, 124.1, 80.6, 77.3, 72.5,
57.4, 39.7, 39.7, 39.5, 34.8, 28.2, 27.9, 26.7, 26.6, 26.6,
25.7, 24.2, 17.7, 16.0, 15.2; HPLC-MS-FIA m/z 710
(M%CC18), 691 (M%CK1), 677 (M%CK18C3), 427
(M%CK265); [a]DZC77.6 (cZ1, 98% de).
3.1. Preparation of esters from the acid chloride.
General procedure
3.2.3. (S)-(C)-a-Methoxy-a-(9-anthryl)-acetate of
(6R,7S)-6,7-squalene diol (higher Rf in TLC). RfZ0.47;
IR 3450, 2965, 2925, 2855, 1750 (CO), 1450, 1380, 1190,
Oxalyl chloride (370 mL, 4.2 mmol) was added to a mixture
of the corresponding acid [(S)-(C)-APA, -MPA, -9-AMA]
(0.7 mmol) and DMF (10 mL, 0.12 mmol) in 30 mL of
hexane at room temperature. After 2 days, solvent was
evaporated to dryness at reduced pressure to afford the acid
chloride. The freshly prepared acid chloride [APA-Cl,
MPA-Cl, 9-AMA-Cl] was dissolved in 4 mL of CH2Cl2 and
added to a solution of the squalene diol (250 mg,
0.56 mmol), Et3N (240 mL, 1.7 mmol) and DMAP (60 mg,
0.55 mmol) in 20 mL of CH2Cl2. After 30 min, water was
added (10 mL), decanted and the organic solution was dried,
concentrated at reduced pressure to a residue which was
purified by flash chromatography on silica gel using a
gradient of 0–30% MTBE (methyl tert-butyl ether) in
hexane (83–89% yield).
1
1115, 730 cmK1; H NMR d 8.59 (bb, 2H), 8.47 (s, 1H),
8.01 (d, JZ8 Hz, 2H), 7.62–7.42 (4H), 6.32 (s, 1H), 5.22–
5.02 (4H), 4.76 (dd, J1Z10 Hz, J2Z2.5 Hz, 1H), 4.23
(t, JZ10 Hz, 1H), 3.46 (s, 3H), 2.16–1.90 (12H), 1.68
(d, JZ1 Hz, 3H), 1.62 (d, JZ1 Hz, 3H), 1.60 (bs, 12H),
1.59 (s, 3H), 1.56 (s, 3H), 1.60–1.10 (3H), 1.37 (s, 3H), 0.87
(m, 1H), 0.63 (m, 1H), 0.45 (m, 1H), 0.39 (s, 3H); 13C NMR
d 170.6, 135.2, 134.8, 134.1, 131.3, 131.3, 131.2, 130.4,
129.3, 129.2, 127.1, 126.7, 125.1, 124.8, 124.3, 124.2,
124.1, 123.9, 80.1, 77.2, 73.5, 57.3, 39.7, 39.7, 36.5, 36.2,
28.3, 28.2, 27.5, 26.7, 26.6, 25.6, 25.5, 22.1, 21.2, 17.6,
17.4, 16.0, 16.0, 16.0; HPLC-MS-FIA m/z 710 (M%CC18),
692 (M%C), 675 (M%CK18C1), 427 (M%CK265);
[a]DZC43.4 (cZ1, 98% de).

J.-L. Abad, F. Camps / Tetrahedron 60 (2004) 11519–11525
11523
3.2.4. (S)-(C)-a-Methoxy-a-(9-anthryl)-acetate of
(6S,7R)-6,7-squalene diol (lower Rf in TLC). RfZ0.15;
IR 3450, 2965, 2925, 2855, 1750 (CO), 1450, 1375, 1190,
3.2.8. (S)-(C)-a-Methoxy-a-(phenyl)-acetate of (3R)-2,3-
squalene diol (lower Rf in TLC). RfZ0.15; IR 3510, 2965,
2925, 2855, 1750 (CO), 1455, 1380, 1190, 1115, 730 cmK1
;
1115, 730 cmK1; H NMR d 8.59 (bb, 2H), 8.47 (s, 1H),
1H NMR d 7.52–7.42 (2H), 7.30–7.42 (3H), 5.20–5.05 (4H),
4.81 (s, 1H), 4.78 (dd, J1Z10 Hz, J2Z2.5 Hz, 1H), 4.76
(t, JZ6 Hz, 1H), 3.44 (s, 3H), 2.14–1.86 (18H), 1.68 (d, JZ
1 Hz, 3H), 1.60 (bs, 9H), 1.58 (d, JZ1 Hz, 3H), 1.60–1.20
(5H), 1.38 (d, JZ1 Hz, 3H), 1.16 (s, 3H), 1.16 (s, 3H); 13C
NMR d 170.8, 136.3, 135.1, 135.0, 134.9, 133.5, 131.2,
128.8, 128.6, 127.1, 124.9, 124.4, 124.2, 82.7, 80.3, 72.4,
57.3, 39.7, 39.7, 39.6, 35.3, 28.2, 28.1, 26.7, 26.6, 25.7,
24.7, 17.6, 16.0, 16.0, 15.7; HPLC-MS-FIA m/z 610
(M%CC18), 593 (M%CC1), 575 (M%CK18C1), 427
(M%CK165); [a]DZC28.8 (cZ1, 98% de).
1
8.01 (d, JZ8 Hz, 2H), 7.60–7.40 (4H), 6.35 (s, 1H), 5.18–
4.98 (4H), 4.78 (dd, J1Z10 Hz, J2Z2 Hz, 1H), 4.28 (t, JZ
6.5 Hz, 1H), 3.43 (s, 3H), 2.16–1.90 (10H), 1.90–1.64 (4H),
1.68 (s, 6H), 1.59 (s, 6H), 1.56 (s, 3H), 1.60–1.08 (6H), 1.05
(s, 3H), 0.98 (s, 3H), 0.84 (m, 2H); 13C NMR d 171.2, 134.9,
134.8, 133.6, 131.9, 131.4, 131.2, 130.5, 129.2, 129.1,
127.1, 126.5, 125.0, 124.3, 124.3, 124.2, 80.1, 77.3, 74.0,
57.4, 39.7 37.2, 34.9, 28.0, 28.0, 27.7, 26.7, 26.6, 25.7, 23.7,
21.9, 17.6, 17.6, 16.0, 15.2; HPLC-MS-FIA m/z 710
(M%CC18), 692 (M%C), 675 (M%CK18C1), 427
(M%C K265); [a]DZC50.8 (cZ1, 98% de).
3.2.9. (S)-(C)-a-Methoxy-a-(phenyl)-acetate of (6R,7S)-
6,7-squalene diol (higher Rf in TLC). RfZ0.30; IR 3525,
2965, 2925, 2855, 1750 (CO), 1455, 1375, 1200, 1175,
3.2.5. (S)-(C)-a-Methoxy-a-(9-anthryl)-acetate of (10R,
11S)-10,11-squalene diol (higher Rf in TLC). RfZ0.48; IR
3530, 2975, 2935, 2860, 1750 (CO), 1445, 1380, 1180, 1110,
725 cmK1; 1H NMRd 8.62 (bb, 2H), 8.47 (s, 1H), 8.01 (d, JZ
8 Hz, 2H), 7.62–7.42 (4H), 6.32 (s, 1H), 5.20–5.00 (4H), 4.79
(dd, J1Z10 Hz, J2Z2 Hz, 1H), 4.48 (t, JZ7 Hz, 1H), 3.46
(s, 3H), 2.16–1.90 (12H), 1.85 (m, 2H), 1.68 (s, 6H), 1.62 (s,
3H), 1.60 (bs, 9H), 1.70–1.10 (4H), 1.37 (s, 3H), 0.66 (s, 1H),
0.64 (m, 1H), 0.43 (m,1H), 0.39 (s, 3H); 13C NMR d 170.6,
136.0, 135.0, 131.3, 131.3, 131.2, 130.4, 129.3, 129.2, 127.1,
126.7, 125.1, 124.3, 124.2, 124.1, 123.8, 123.3, 80.0, 77.1,
73.5, 57.4, 39.7, 39.7, 39.6, 36.4, 29.4, 26.7, 26.6, 26.6, 25.7,
24.7, 22.2, 21.1, 17.7, 16.1, 16.0, 15.7; HPLC-MS-FIA m/z
710 (M%CC18), 692 (M%C), 675 (M%CK18C1), 427
(M%CK265); [a]DZC41.1 (cZ1, 98% de).
1
1115, 1000, 730, 695 cm K1; H NMR d 7.52–7.42 (2H),
7.30–7.42 (3H), 5.20–5.02 (4H), 4.94 (m, 1H), 4.83
(dd, J1Z10 Hz, J2Z3 Hz, 1H), 4.78 (s, 3H), 3.43 (s, 3H),
2.14–1.80 (18H), 1.80–1.54 (4H), 1.68 (d, JZ1 Hz, 3H),
1.66 (d, JZ1 Hz, 3H), 1.60 (bs, 9H), 1.56 (bs, 6H), 1.26
(s, 1H), 1.18 (m, 2H), 0.87 (s, 3H); 13C NMR d 170.3, 136.5,
135.2, 134.9, 134.1, 131.9, 131.3, 128.9, 128.7, 127.2,
124.9, 124.4, 124.2, 124.2, 124.1, 82.6, 79.8, 74.0, 57.2,
39.7, 39.7, 37.1, 36.0, 28.3, 28.2, 27.6, 26.7, 26.7, 25.7,
22.9, 21.8, 17.7, 17.6, 16.0, 16.0; HPLC-MS-FIA m/z 610
(M%CC18), 593 (M%CC1), 575 (M%CK18C1), 427
(M%CK165); [a]DZC21.2 (cZ1, 98% de).
3.2.10. (S)-(C)-a-Methoxy-a-(phenyl)-acetate of
(6S,7R)-6,7-squalene diol (lower Rf in TLC). RfZ0.25;
IR 3505, 2965, 2925, 2855, 1750 (CO), 1455, 1375, 1200,
3.2.6. (S)-(C)-a-Methoxy-a-(9-anthryl)-acetate of (10S,
11R)-10,11-squalene diol (lower Rf in TLC). RfZ0.20; IR
3530, 2975, 2935, 2855, 1745 (CO), 1445, 1380, 1180, 1110,
725 cmK1; 1H NMRd 8.60 (bb, 2H), 8.46 (s, 1H), 8.00 (d, JZ
8 Hz, 2H), 7.60–7.40 (4H), 6.34 (s, 1H), 5.16–4.92 (4H), 4.85
(dd, J1Z10 Hz, J2Z2 Hz, 1H), 4.59 (t, JZ7 Hz, 1H), 3.42
(s, 3H), 2.14–1.85 (12H), 1.74 (m, 2H), 1.68 (d, JZ1 Hz,
3H), 1.66 (d, JZ1 Hz, 3H), 1.61 (s, 3H), 1.58 (bs, 6H), 1.54
(d, JZ1 Hz, 3H), 1.70–1.10 (6H), 1.06 (s, 3H), 0.88 (s, 3H),
1.10–0.80 (2H); 13C NMR d 171.3, 135.5, 135.5, 134.8,
131.4, 131.4, 130.8, 130.5, 129.2, 129.1, 127.1, 126.5, 125.0,
124.3, 124.2, 124.1, 124.0, 122.7, 80.3, 77.4, 74.1, 57.4, 39.7,
39.4, 37.1, 29.2, 26.7, 26.6, 26.4, 25.7, 23.8, 23.6, 21.8, 17.7,
17.6, 15.9, 15.9, 15.3; HPLC-MS-FIA m/z 710 (M%CC18),
692 (M%C), 675 (M%CK18C1), 427 (M%CK265);
[a]DZC57.4 (cZ1, 98% de).
1
1175, 1115, 1000, 730, 695 cmK1; H NMR d 7.52–7.42
(2H), 7.30–7.42 (3H), 5.20–5.02 (4H), 4.82 (dd, J1Z10 Hz,
J2Z3 Hz, 1H), 4.80 (s, 3H), 4.81 (m, 1H), 3.43 (s, 3H),
2.14–1.80 (18H), 1.78–1.30 (5H), 1.68 (bs, 6H), 1.62 (d, JZ
1 Hz, 3H), 1.60 (bs, 9H), 1.37 (d, JZ1 Hz, 3H), 1.12
(s, 3H); 13C NMR d 170.7, 136.3, 135.0, 134.9, 133.8,
132.0, 131.2, 128.8, 128.6, 127.1, 124.8, 124.4, 124.2,
124.2, 82.7, 79.8, 74.0, 57.3, 39.7, 39.7, 37.4, 35.4, 28.2,
28.1, 27.8, 26.7, 26.6, 25.7, 23.5, 22.0, 17.6, 16.0, 16.0,
15.7; HPLC-MS-FIA m/z 610 (M%CC18), 593 (M%CC1),
575 (M%CK18C1), 427 (M%CK265); [a]DZC26.0 (cZ1,
98% de).
3.2.11. (S)-(C)-a-Methoxy-a-(phenyl)-acetate of
(10R,11S)-10,11-squalene diol (higher Rf in TLC). RfZ
0.35; IR 3520, 2965, 2925, 2855, 1750 (CO), 1455, 1375,
3.2.7. (S)-(C)-a-Methoxy-a-(phenyl)-acetate of (3S)-2,3-
squalene diol (higher Rf). RfZ0.22; IR 3510, 2965, 2925,
1
1
2855, 1750 (CO), 1455, 1380, 1190, 1115, 730 cmK1; H
1200, 1175, 1115, 1000, 730, 695 cmK1; H NMR d 7.52–
NMR d 7.52–7.42 (2H), 7.30–7.42 (3H), 5.22–5.00 (5H),
4.80 (s, 1H), 4.79 (dd, J1Z10 Hz, J2Z3 Hz, 1H), 3.44
(s, 3H), 2.14–1.86 (18H), 1.68 (d, JZ1 Hz, 3H), 1.60
(bs, 12H), 1.56 (d, JZ1 Hz, 3H), 1.60–1.20 (5H), 0.94
(s, 3H), 0.91 (s, 3H); 13C NMR d 170.4, 136.5, 135.1, 135.0,
134.9, 133.8, 131.2, 129.0, 128.7, 127.2, 125.0, 124.4, 124.3,
124.2, 82.6, 80.5, 72.3, 57.3, 39.7, 39.7, 39.6, 35.9, 28.3,
28.0, 26.7, 26.7, 26.6, 25.9, 25.7, 24.6, 17.7, 16.0, 16.0;
HPLC-MS-FIA m/z 610 (M%CC18), 593 (M%CC1), 575
(M%CK18C1), 427 (M%CK165); [a]DZC25.0 (cZ1,
98% de).
7.42 (2H), 7.42–7.28 (3H), 5.18–5.02 (4H), 4.95 (m, 1H),
4.86 (dd, J1Z9.5 Hz, J2Z3.5 Hz, 1H), 4.78 (s, 1H), 3.43 (s,
3H), 2.14–1.80 (18H), 1.80–1.60 (2H), 1.68 (bs, 6H), 1.60
(bs, 9H), 1.56 (bs, 6H), 1.27 (s, 1H), 1.18 (m, 2H), 0.87
(s, 3H); 13C NMR d 170.3, 136.5, 136.0, 135.5, 135.0,
131.4, 131.2, 128.9, 128.7, 127.3, 124.3, 124.2, 124.1,
124.0, 82.6, 79.8, 74.0, 57.3, 39.7, 39.7, 37.1, 29.3, 26.7,
26.6, 25.7, 24.6, 22.8, 21.7, 17.7, 16.0, 16.0, 15.9;
HPLC-MS-FIA m/z 610 (M%CC18), 593 (M%CC1), 575
(M%CK18C1), 427 (M%CK265); [a]DZC27.0 (cZ1,
98% de).

11524
J.-L. Abad, F. Camps / Tetrahedron 60 (2004) 11519–11525
3.2.12. (S)-(C)-a-Methoxy-a-(phenyl)-acetate of (10S,
11R)-10,11-squalene diol (lower Rf in TLC). RfZ0.27; IR
3520, 2965, 2925, 2855, 1750 (CO), 1455, 1375, 1200, 1175,
1055, 740, 695 cmK1; 1H NMR d 7.56–7.44 (2H), 7.43–7.35
(3H), 5.85 (s, 1H), 5.18–5.05 (5H), 4.85 (dd, J1Z10 Hz,
J2Z2.5 Hz, 1H), 4.77 (m, 1H), 2.21 (s, 3H), 2.16–1.80
(18H), 1.68 (bs, 6H), 1.62 (d, JZ1 Hz, 3H), 1.60 (bs, 9H),
1.70–1.20 (4H), 1.35 (s, 3H), 1.26 (s, 1H), 1.18 (s, 3H); 13C
NMR d 170.6, 168.8, 135.1, 134.9, 133.8, 133.5, 132.1,
131.2, 129.4, 128.8, 127.6, 124.8, 124.4, 124.2, 124.2, 80.5,
75.0, 74.1, 39.7, 37.5, 35.3, 28.2, 28.1, 27.8, 26.7, 26.6,
25.7, 23.3, 22.0, 20.7, 17.7, 16.0, 15.7; HPLC-MS-FIA m/z
638 (M%CC18), 621 (M%CC1), 603 (M%CK18C1), 427
(M$K193); [a]DZC29.0 (cZ1, 98% de).
1
1115, 1000, 730, 695 cmK1; H NMR d 7.52–7.42 (2H),
7.40–7.28 (3H), 5.18–5.02 (4H), 4.92 (m, 1H), 4.86 (ca, 1H),
4.81 (s, 1H), 3.44 (s, 3H), 2.16–1.80 (18H), 1.80–1.30 (5H),
1.68 (bs, 6H), 1.60 (bs, 9H), 1.58 (d, JZ1 Hz, 3H), 1.33
(d, JZ1 Hz, 3H), 1.26 (s, 1H), 1.11 (s, 3H); 13C NMR d
170.7, 136.3, 136.0, 135.7, 134.9, 131.4, 131.2, 128.8, 128.6,
127.0, 124.3, 124.2, 124.1, 124.0, 123.0, 82.8, 79.9, 74.1,
57.3, 39.7, 39.7, 39.6, 37.4, 29.3, 26.7, 26.6, 26.5, 25.7, 24.1,
23.6, 21.9, 17.7, 16.0, 16.0, 15.8; HPLC-MS-FIA m/z 610
(M%CC18), 593 (M%CC1), 575 (M%CK18C1), 427
(M$ K265); [a]DZC26.6 (cZ1, 98% de).
3.2.17. (S)-(C)-a-Acetoxy-a-(phenyl)-acetate of
(10R,11S)-10,11-squalene diol (higher Rf in TLC). RfZ
0.40; IR 3530, 2965, 2925, 2855, 1750 (CO), 1455, 1375,
1
3.2.13. (S)-(C)-a-Acetoxy-a-(phenyl)-acetate of (3S)-2,3-
squalene diol (higher Rf in TLC). RfZ0.30; IR 3510,
2970, 2925, 2855, 1750 (CO), 1450, 1380, 1200, 1175,
1115, 730, 695 cmK1; 1H NMR d 7.58–7.46 (2H), 7.44–7.32
(3H), 5.93 (s, 1H), 5.24–5.02 (5H), 4.79 (dd, J1Z10 Hz,
J2Z2.5 Hz, 1H), 2.21 (s, 3H), 2.14–1.84 (18H), 1.68 (d, JZ
1 Hz, 3H), 1.60 (bs, 12H), 1.57 (bs, 3H), 1.60–1.20 (5H),
0.95 (s, 6H); 13C NMR d 170.5, 168.6, 135.1, 135.1, 134.9,
133.9, 133.8, 131.2, 129.4, 128.8, 127.6, 125.0, 124.4,
124.3, 124.2, 81.2, 74.8, 72.2, 39.7, 39.7, 39.6, 35.6, 28.3,
28.2, 26.7, 26.6, 25.7, 24.6, 20.8, 17.7, 16.0, 16.0; HPLC-
MS-FIA m/z 638 (M%CC18), 621 (M%CC1), 603 (M%CK
18C1), 427 (M$K193); [a]DZC26.0 (cZ1, 98% de).
1230, 1180, 1060, 740, 695 cmK1; H NMR d 7.55–7.44
(2H), 7.43–7.34 (3H), 5.93 (s, 1H), 5.15–5.03 (4H), 4.95
(m, 1H), 4.84 (dd, J1Z9 Hz, J2Z3.5 Hz, 1H), 2.21 (s, 3H),
2.14–1.76 (18H), 1.68 (bs, 6H), 1.60 (bs, 9H), 1.56 (bs, 6H),
1.70–1.20 (2H), 1.37 (s, 1H), 1.28–1.13 (3H), 0.91 (s, 3H);
13C NMR d 170.5, 168.5, 136.1, 135.6, 134.9, 133.9, 131.5,
131.3, 129.4, 128.8, 127.6, 124.4, 124.2, 123.9, 123.2, 80.6,
74.8, 73.9, 39.7, 39.7, 37.1, 29.6, 26.7, 26.6, 26.6, 25.7,
24.4, 22.7, 21.6, 20.8, 17.7, 16.0; HPLC-MS-FIA m/z 638
(M%CC18), 621 (M%CC1), 603 (M%CK18C1), 427
(M$K193); [a]DZC31.2 (cZ1, 98% de).
3.2.18. (S)-(C)-a-Acetoxy-a-(phenyl)-acetate of
(10S,11R)-10,11-squalene diol (lower Rf in TLC). RfZ
0.30; IR 3520, 2965, 2925, 2855, 1750 (CO), 1455, 1375,
3.2.14. (S)-(C)-a-Acetoxy-a-(phenyl)-acetate of (3R)-
2,3-squalene diol (lower Rf in TLC). RfZ0.16; IR 3510,
2970, 2925, 2855, 1750 (CO), 1450, 1380, 1200, 1175,
1115, 730, 695 cmK1; 1H NMR d 7.58–7.46 (2H), 7.44–7.32
(3H), 5.86 (s, 1H), 5.22–5.02 (4H), 4.80 (dd, J1Z10 Hz,
J2Z2 Hz, 1H), 4.74 (t, JZ6 Hz, 1H), 2.20 (s, 3H), 2.14–
1.85 (18H), 1.70–1.20 (5H), 1.68 (d, JZ1 Hz, 3H), 1.60
(bs, 9H), 1.58 (d, JZ1 Hz, 3H), 1.36 (d, JZ1 Hz, 3H), 1.21
(s, 6H); 13C NMR d 170.7, 168.9, 135.1, 135.0, 134.9,
133.5, 133.4, 131.2, 129.4, 128.8, 128.8, 127.6, 124.8,
124.4, 124.2, 80.9, 75.0, 72.3, 39.7, 39.7, 39.6, 35.2, 28.2,
28.0, 26.7, 26.6, 26.0, 25.7, 25.1, 20.7, 17.6, 16.0, 16.0,
15.7; HPLC-MS-FIA m/z 638 (M%CC18), 621 (M%CC1),
603 (M%CK18C1), 427 (M$K193); [a]DZC27.4 (cZ1,
98% de).
1
1230, 1180, 1060, 740, 695 cmK1; H NMR d 7.56–7.44
(2H), 7.43–7.33 (3H), 5.86 (s, 1H), 5.17–5.01 (4H), 4.95–
4.85 (2H), 2.20 (s, 3H), 2.18–1.82 (14H), 1.68 (bs, 6H), 1.62
(d, JZ1 Hz, 3H), 1.60 (bs, 6H), 1.57 (d, JZ1 Hz, 3H),
1.72–1.20 (2H), 1.27 (d, JZ1 Hz, 3H), 1.18 (s, 3H); 13C
NMR d 170.6, 168.9, 135.9, 135.7, 134.9, 133.4, 131.4,
131.2, 129.4, 128.8, 127.6, 124.3, 124.2, 124.1, 122.9, 80.6,
75.0, 74.1, 39.7, 39.6, 37.4, 29.3, 26.7, 26.6, 26.5, 25.7,
24.0, 23.3, 21.9, 20.7, 17.7, 16.0, 16.0, 15.8; HPLC-MS-FIA
m/z 638 (M%CC18), 621 (M%CC1), 603 (M%CK18C1),
427 (M$K193); [a]DZC36.0 (cZ1, 98% de).
3.3. Preparation of squalene diols by reduction of
arylacetic esters. General procedure
3.2.15. (S)-(C)-a-Acetoxy-a-(phenyl)-acetate of (6R,7S)-
6,7-squalene diol (higher Rf in TLC). RfZ0.40; IR 3520,
2965, 2925, 2855, 1750 (CO), 1455, 1375, 1230, 1175, 1055,
740, 695 cmK1; 1H NMR d 7.56–7.44 (2H), 7.43–7.35 (3H),
5.91 (s, 1H), 5.20–5.05 (5H), 4.94 (m, 1H), 4.84 (dd, J1Z
10 Hz, J2Z2.5 Hz, 1H), 2.21 (s, 3H), 2.14–1.80 (18H), 1.68
(d, JZ1 Hz, 3H), 1.66 (d, JZ1 Hz, 3H), 1.60 (bs, 9H), 1.60–
1.20 (2H), 1.57 (bs, 6H), 1.40 (s, 1H), 1.28–1.13 (3H), 0.91
(s, 3H); 13C NMR d 170.5, 168.5, 135.1, 134.9, 134.1, 133.9,
131.9, 131.2, 129.4, 128.8, 127.6, 124.9, 124.4, 124.2, 124.1,
80.6, 74.8, 73.9, 39.7, 37.1, 35.7, 28.3, 28.2, 27.9, 26.7, 26.6,
25.7, 22.7, 21.7, 20.7, 17.6, 17.6, 16.0; HPLC-MS-FIA m/z
638 (M%CC18), 621 (M%CC1), 603 (M%CK18C1), 427
(M$K193); [a]DZC38.6 (cZ1, 98% de).
A solution of the corresponding arylacetic ester in Et2O,
maintained under nitrogen atmosphere and at room
temperature, was treated with 4.5 molar equiv of LiAlH4.
The mixture was stirred until the reaction was completed.
After the usual workup, the residue was purified by flash
chromatography using as eluent hexanes–MTBE 85:15 to
afford the corresponding enantiomeric diol (87–93% yield).
Squalene diols reobtained by reduction with LiAlH4 of the
corresponding (R)-(K)-MPA derivatives showed the
following optical rotations: (3S)-2,3-Dihydroxy-2,3-
dihydrosqualene (from higher Rf) [a]DZK11.8 (cZ1,
97% ee); (3R)-2,3-Dihydroxy-2,3-dihydrosqualene (from
lower Rf) [a]DZC11.4 (cZ1, 97% ee); (6R,7S)-6,7-
Dihydroxy-6,7-dihydrosqualene (from higher Rf)
[a]DZK10.0 (cZ1, 97% ee); (6S,7R)-6,7-Dihydroxy-6,7-
dihydrosqualene (from lower Rf) [a]DZC10.2 (cZ1, 97%
ee); (10R,11S)-10,11-Dihydroxy-10,11-dihydrosqualene
3.2.16. (S)-(C)-a-Acetoxy-a-(phenyl)-acetate of (6S,7R)-
6,7-squalene diol (lower Rf in TLC). RfZ0.26; IR 3520,
2965, 2925, 2855, 1750 (CO), 1455, 1375, 1230, 1175,

J.-L. Abad, F. Camps / Tetrahedron 60 (2004) 11519–11525
11525
2. Abdallah, M. A.; Shah, J. N. J. Chem. Soc., Perkin Trans. I
(from higher Rf) [a]DZK6.6 (cZ1, 97% ee); (10S,11R)-
10,11-Dihydroxy-10,11-dihydrosqualene (from lower Rf)
[a]DZC6.5 (cZ1, 97% ee). These data are in agreement
with the previously reported optical rotations for these
compounds.1
1975, 888–894.
3. Crispino, G. A.; Sharpless, K. B. Tetrahedron Lett. 1992, 33,
4273–4274.
4. Boar, R. B.; Damps, K. J. Chem. Soc., Perkin Trans I 1977,
709–712.
´
5. Abad, J.-L.; Soldevila, C.; Clapes, P.; Camps, F. J. Org. Chem.
Acknowledgements
2003, 68, 5351–5356.
6. Ward, D. E.; Rhee, C. K. Tetrahedron Lett. 1991, 42,
7165–7166.
Financial supports of this work by CICYT and FEDER
(grant AGL-2001-0585) and Comissionat per a Universitats
i Recerca from the Generalitat de Catalunya (grant
2001SGR-00342) are gratefully acknowledged. J.-L. A.
thanks the Spanish Ministry of Science and Technology for
a ‘Ramon y Cajal’ contract.
7. Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95,
512–519.
`
8. Abad, J.-L.; Fabrias, G.; Camps, F. J. Org. Chem. 2000, 65,
8582–8588.
9. Kanger, T.; Lopp, M.; Mu¨raus, A.; Lohmus, M.; Kobzar, G.;
¨
Pehk, T.; Lille, U. Synthesis 1992, 925–927.
10. Trost, B. M.; Belletire, J. L.; Godleski, S.; McDougal, P. G.;
Balkovec, J. M. J. Org. Chem. 1986, 51, 2370–2374.
11. Chataigner, I.; Lebreton, J.; Durand, D.; Guingant, A.;
References and notes
´
Villieras, J. Tetrahedron Lett. 1998, 39, 1759–1762.
´
12. Seco, J. M.; Quin
˜oa, E.; Riguera, R. Tetrahedron 1999, 55,
569–584.
`
1. Abad, J.-L.; Casas, J.; Sanchez-Baeza, F.; Messeguer, A.
J. Org. Chem. 1995, 60, 3648–3656.