Cyclization of α,δ-dihydroxyepoxide derivatives. Stereochemical studies

Article abstract of DOI:10.1055/s-2002-19792

The influence of different protecting groups in the cyclization of highly substituted α,δ-dihydroxyepoxides has been studied. It is possible to control the opening or the cyclization of the epoxide depending on the protecting group used.

Full text of DOI:10.1055/s-2002-19792

PAPER
175
Cyclization of , -Dihydroxyepoxide Derivatives. Stereochemical Studies
Cyclizationof
,
-
.
Dihydroxyep
D
oxide Derivatives
í
.
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tereo
e
c
hemica
l
S
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tudies ,* R. F. Moro, W. Lumeras, L. Rodríguez, I. S. Marcos, P. Basabe, R. Escarcena, J. G. Urones
Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad de Salamanca, Plaza de los Caídos 1–5, 37008, Salaman-
ca, Spain
Fax +34(923)294574; E-mail: ddm@usal.es
Received 10 September 2001; revised 26 November 2001
diastereomers 2a and 3a (Scheme 1, Table). As can be
Abstract: The influence of different protecting groups in the cy-
seen, there is a slight preference for the anti form 2 when
clization of highly substituted , -dihydroxyepoxides has been
the protecting group possesses an ester function. The ste-
reochemistry of these epoxides was established later on,
based upon the results of the cyclization reaction.
studied. It is possible to control the opening or the cyclization of the
epoxide depending on the protecting group used.
Key words: tetrahydropyrans, epoxides, cyclization, stereochemis-
try
2,2,6,6-Tetrasubstituted tetrahydropyrans are found in
marine natural products, which often have very interesting
biological activities.1 For example, Isodehydrothyrsiferol
and Usneoidone E have been isolated as anti-tumour
agents from Laurencia viridis and Cystoseira usneoides
respectively (Figure 1).
Scheme 1 Epoxidation reaction of allylic alcohols to form epoxi-
des.
Table Influnce of Protecting Groups (PG) on the Ratio of Diaste-
reomers 2a–d and 3a–d Formed from 1a–d
PG
H
Yield (%)
Ratio 2/3
1:1
1a
1b
1c
1d
99
85
90
89
Bn
Ac
Bz
1:1
3:2
3:2
Various protecting groups were used on the secondary hy-
droxyl group in order to study the influence of the protect-
ing groups on the regio and stereoselectivity of the
cyclization reaction.
Figure 1 Structures of anti-tumour agents isodehydrothyrsiferol
and usneoidone E from Laurencia viridis and Cystoseira usneoides
respectively.
When compound 2a was treated under acidic conditions,
(CSA/CH2Cl2, –40 °C)8 the tetrahydropyran 4a and ox-
epane 5a were obtained in a 3:2 ratio. The structure of 5a
was established by two-dimensional NMR techniques.
The stereochemistry was expected to be that shown in
Scheme 2, with retention of configuration at both stereo-
genic centres. This was confirmed by an NOE between the
hydrogen at C-3 and the methyl at C-2 The stereochemis-
try of 4a was established by X-ray analysis.8 The cycliza-
tion had taken place with inversion of configuration at C-
2. The stereochemistry of 3a was established by compari-
son with 2a, which differs only in the stereogenic center
at C-2. Treatment of 3a under the same conditions as 2a
gave only the tetrahydropyran 6a, with total regioselectiv-
ity and inversion at C-2 (Scheme 2). Thus the cyclization
of the syn-epoxide goes with total stereoselectivity and re-
gioselectivity. The lack of regioselectivity in the case of
cyclization of the anti-epoxide has been explained in a
previous paper8 (Scheme 2).
Much work has been directed towards the formation of
tetrahydropyrans using olefins,2 epoxides3 and organome-
tallics.4 In our case, we seek to control the cyclization by
using a protecting group that will induce the formation of
the required tetrahydropyran. In this paper, we describe
the influence of different protecting groups in the cycliza-
tion of , -dihydroxyepoxides in acidic media5 and the es-
tablishment of the stereochemistry of these compounds.
Prior to the cyclization reactions, we studied the influence
of the protecting group (PG) on the epoxidation of the al-
lylic alcohols to the corresponding epoxides6 (Scheme 1).
Compound 1a has been synthesised previously and used
for halocyclizations.7 Compound 1a was submitted to ep-
oxidation with MCPBA to yield the expected mixture of
Synthesis 2002, No. 2, 01 02 2002. Article Identifier:
1437-210X,E;2002,0,02,0175,0184,ftx,en;E06101SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

176
D. Díez et al.
PAPER
When substrate 2d was submitted to the cyclization con-
ditions, a mixture of five compounds were obtained, com-
prising 10, 11, 6d, 12 and 5d, which were separated by
column chromatography. Only four compounds (13, 14,
4d and 15) were obtained in the cyclization of 3d. The
stereochemistry of 4d was established by X-ray analysis.8
(Scheme 4).
The structure of these compounds was determined as fol-
lows.
Due to their similarity, all compounds obtained in the cy-
clization of 2d were submitted to treatment with acetic an-
hydride in pyridine at r.t.
Scheme 2 Cyclisation reactions of the anti and syn-epoxides 2a and
3a respectively.
Compounds 12 and 5d did not react under these condi-
tions, but showed bands due to a tertiary hydroxyl group
in their IR spectra, so they could only be a tetrahydrofuran
or an oxepane ring. The tetrahydrofuran ring was assigned
to 12 due to the presence in the 1H NMR spectrum of an
AB system at = 4.37 and 4.17 ppm (CH2OBz geminal
pair) and the signal of a proton at = 4.01 double doublet
(CH at position 3). For 5d the oxepane structure was as-
signed based on the signal at = 5.00 ppm (multiplet) for
the CH-OBz proton, and the doublet signals at = 3.79
and 3.22 ppm for the CH2 geminal to oxygen.
In the case of precursors 2b and 3b (which possess a ben-
zyl protecting group), the cyclization reaction gave the
tetrahydropyrans 4b and 6b as the major products together
with small amounts of oxepanes 5b and 7b (Scheme 3). In
this case, the cyclization occurs as expected with high ste-
reo and regioselectivity. The stereochemistry of 4b and 6b
was confirmed by hydrogenolysis (H2, Pd/C, EtOH) af-
fording diols 4a and 6a in excellent yield (94% and 96%,
respectively).
In contrast, when 6d was acetylated, there were no hy-
droxyl group bands in the IR spectrum of the resulting
acetyl derivative, 18, and a tetrahydropyran structure was
assigned from the 1H NMR signals. (Scheme 5)
The acetylation of 10 and 11 gave 16 and 17 respectively,
in which only one hydroxyl group was acetylated, two hy-
droxyl groups on tetra substituted carbons remaining un-
affected (Scheme 5). This suggested that both structures
were acyclic compounds. The structures of 10 and 11
could be deduced from the changes in their 1H NMR spec-
tra, where signals corresponding to CH2OH at 3.48 and
3.29 ppm in 10 change to 4.01 and 4.16 ppm in 16, and the
signal corresponding to H-3 at 3.53 ppm in 11 changes to
Scheme 3 Cyclisation reactions of the benzylated anti and syn-epo-
xides 2b and 3b respectively.
Scheme 4 Cyclisation reactions of the benzoylated anti and syn-epoxides 2d and 3d respectively.
Synthesis 2002, No. 2, 175–184 ISSN 0039-7881 © Thieme Stuttgart · New York

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Cyclization of , -Dihydroxyepoxide Derivatives. Stereochemical Studies
177
5.10 ppm in 17. In summary, 10 and 11 were acyclic com-
pounds, 12 a tetrahydrofuran, 6d a tetrahydropyran and 5d
an oxepane. By comparison, the products of cyclization of
3d were the acyclic compounds 13 and 14, the tetrahydro-
pyran 4d and the tetrahydrofuran 15.
Scheme 7 Stereochemistry of compounds 4d, 5d and 6d.
In the case of the oxepane 5d, an NOE was observed be-
tween H-3 and the methyl group on C-2, so the stereo-
chemistry was concluded to be 2R,3S (Scheme 7).
The absolute configuration of the acyclic compounds was
easily established. Compound 10 was tosylated to give the
tosyl derivative 21. When 21 was treated in basic condi-
tions it led to the syn-epoxide 3d, which transforms
smoothly, in the reaction conditions, to 15 (Scheme 8).
Scheme 5 Conversion of 10, 11 and 6d to their corresponding ace-
tates to determine their structures.
The stereochemistry of all the compounds resulting from
the cyclization of 2d and 3d was established. Saponifica-
tion of 15 with potassium hydroxide in methanol gave diol
19 (Scheme 6), whose stereochemistry has been assigned
and confirmed by single crystal X-ray analysis in a previ-
ous paper.7 Therefore, the stereochemistry for 15 is 2S,3R.
The only difference between epoxides 2a and 3a is the
stereochemistry at C-2, and both tetrahydrofurans are gen-
erated by the same mechanism, so 12 must be 2R,3R
(Scheme 4). As can be seen, in this case the cyclization
takes place with inversion of configuration at C-3 and re-
tention at C-2.
Scheme 8 Stereochemistry of compound 10.
Therefore, the stereochemistry for 10 is 2S,3S and hence
the stereochemistry for 13 is 2R,3S arising from the open-
ing of the other epoxide, 3d, under acidic conditions
(Scheme 4).
The stereochemistry of 14 was established as shown in
Scheme 9. Benzoylation of 13 and 14 separately led to the
same compound, 22, so both acyclic compounds, 13 and
14, have the same configuration on C-2 and C-3 (2R,3S).
This means that the opening of epoxide under acidic con-
ditions gave two acyclic compounds with retention on C-
3 and inversion on C-2.
Scheme 6 Saponification of compound 15.
The stereochemistry of tetrahydropyrans 6d and 4d were
easily established by 1H NMR studies of these compounds
and their acetyl derivatives 18 and 20, resulting from the
treatment of 6d and 4d with Ac2O in pyridine (Scheme 7).
The coupling constants in the 1H NMR spectrum of 18 for
H-3 (4.6 and 11.0 Hz) place it in an axial position; howev-
er, H-3 in 20 must be equatorial (J = 6.0 and 3.2 Hz). Tak-
ing this into account, together with the NOE’s observed
between H-3 and the CH2OH in 4d and between H-3 and
the methyl group on C-2 in 20, we propose the stere-
ochemistry shown in Scheme 7.
Scheme 9 Stereochemistry of compound 13.
For the same reason as above, the absolute configuration
for 10 and 11 was established as 2S,3S (Scheme 5).
The structure of 4d was confirmed by single crystal X-ray
analysis8 and was established as 2S,3S. Consequently the
stereochemistry for 6d is 2R,3S following the same rea-
soning as for the tetrahydrofuran.
Thus, the stereochemistries of all compounds produced in
the opening of the epoxides 2d and 3d with a benzoate as
protecting group were determined.
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178
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The mixture was then poured into sat. NaCl (100 mL) solution, ex-
tracted with EtOAc (4 100mL) and finally dried over Na2SO4. Re-
moval of the solvent under reduced pressure gave 472 mg of a crude
oil that was purified by chromatography on silica gel (EtOAc–hex-
anes, 15:85) to give the benzyl derivative 1b (268 mg, 67%) as a
colorless oil.
When the protecting group was acetyl, in the case of sub-
strates 2c and 3c, only the acyclic compounds were ob-
tained with inversion of configuration at C-2 and
migration of the acetate giving 8 and 9 respectively. The
structure of these products was confirmed by comparison
of the NMR data for 8 and 9 with 11 and 14 (Scheme 10).
20
[ ]D –38.3 (c 1.00, CHCl3).
IR (neat): 3430, 3071, 3032, 2971, 2864, 1649, 1454, 1373, 1069,
905, 735, 696 cm–1.
1H NMR (400 MHz, CDCl3): = 7.34–7.32 (5 H, m, Ph), 4.99 (1 H,
br s, HA-1), 4.94 (1 H, br s, HB-1), 4.50 (1 H, d, J = 11.8 Hz, O-
CHH-Ph, HA), 4.27 (1 H, d, J = 11.8 Hz, O-CHH-Ph, HB), 3.72 (1
H, t, J = 5.7 Hz, H-3), 1.82–1.30 (4 H, m, H-4, H-5), 1.70 (3 H, s,
H-9), 1.20 (6 H, s, H-7, H-8).
13C NMR (100 MHz, CDCl3): = 16.7, 28.6, 29.3, 29.4, 40.0, 70.1,
70.5, 83.9, 113.8, 127.4, 127.8, 128.3, 138.8, 144.6.
Anal. Calcd for C16H24O2: C, 77.37; H, 9.74. Found: C, 77.54; H,
9.68.
Scheme 10 Stereochemistry of compounds 2c and 3c.
Acetic Acid (1S)-1-(3-Hydroxy-3-methyl-butyl)-2-methyl-allyl
Ester (1c)
The cyclization of epoxides syn and anti (2 and 3 respec-
tively) proceeds in the following way. Without protection
the cyclization in acidic media is regioselective in the case
of syn-epoxide, giving a tetrahydropyran with inversion of
the stereochemistry at C-2. If the protecting group is ben-
zyl the cyclization is regioselective giving mainly tetrahy-
dropyrans with inversion at C-2, together with a small
amount of the corresponding oxepan with no change in
the stereochemistry. In the case of an acetyl group only
acyclic compounds are produced, with migration of the
acetyl group to the primary hydroxyl function and inver-
sion at C-2. When the group is a benzoyl a mixture of acy-
clic compounds with inversion at C-2 and cyclic
compounds are obtained. The cyclic compounds are te-
trahydropyrans (obtained with retention at C-2) tetrahy-
drofurans (obtained with retention at C-2 and inversion at
C-3) and an oxepane (obtained with retention at both C-2
and C-3).
Distilled Ac2O (0.5 mL) was added to a solution of 1 (47 mg, 0.30
mmol) in pyridine (2 mL). After 12 h the reaction was quenched
with ice, diluted in H2O (50 mL) and extracted with Et2O (3 50
mL). The organic layer was washed with aq solutions of 10% HCl
(25 mL), 5% NaHCO3 (25 mL), brine and finally dried over
Na2SO4. The solvent was evaporated under reduced pressure to give
a crude oil that was purified by chromatography on silica gel (Et2O–
hexanes, 1:1) to give 1c (53 mg, 90%).
IR (neat): 3450, 2970, 1740, 1650, 1360, 1250, 1010, 910 cm–1.
1H NMR (400 MHz, CDCl3): = 5.18 (1 H, t, J = 5.9 Hz, H-3), 4.97
(1 H, s, HA-1), 4.88 (1 H, s, HB-1), 2.07 (3 H, s, CO2Me), 1.73 (3 H,
s, H-9), 1.50–1.35 (4 H, m, H-4, H-5), 1.22 (6 H, s, H-7, H-8).
13C NMR (100 MHz, CDCl3): = 18.0, 21.0, 27.4, 29.2, 29.3, 39.1,
70.4, 77.5, 112.8, 143.0, 170.2.
HRMS–FAB: (m/z) [M + H]+ calcd for C11H21O3, 201,1491; found,
201.1491.
Benzoic Acid (1S)-1-(3-Hydroxy-3-methyl-butyl)-2-methyl-all-
yl Ester (1d)
A solution of 1 (607 mg, 3.84 mmol) in THF (30 mL) under argon
was treated with a 1.6 M solution of n-BuLi in hexanes (2.4 mL,
3.84 mmol) at –78 °C. After 30 min of stirring, the solution was
added to BzCl (1.08 g, 7.68 mmol) in 30 mL of THF at 0 °C, and
the resulting mixture was stirred for 2 h. The reaction was quenched
by the addition of 10% Na2CO3 (30 mL) and THF was then evapo-
rated. After dilution with H2O (50 mL), the mixture was extracted
with Et2O (3 150 mL) and finally dried over Na2SO4. The solvent
was evaporated under reduced pressure to give a crude oil that was
purified by chromatography on silica gel (Et2O–hexanes, 2:8) to
give 1d (995 mg, 95%).
Unless otherwise stated, all chemicals were commercially available
and were used without further purification. Melting points were de-
termined with a Kofler hot stage melting point apparatus and are un-
corrected. IR spectra were recorded on a BOMEM 100 FTIR
1
spectrophotometer. H and 13C NMR spectra were performed in
CDCl3 and referenced to the residual peak of CHCl3 at 7.26 ppm
1
and 77.0 ppm, for H and 13C respectively, in a Bruker WP-200
SY and a Bruker DRX 400 MHz. Chemical shifts are reported in
ppm and coupling constants (J) are given in Hz. MS were performed
in a VG-TS 250 spectrometer at 70 eV ionizing voltage. Mass spec-
tra are presented as m/z (% relative intensity). HRMS were recorded
in a VG Platform spectrometer using Electronic Impact (EI) or Fast
Atom Bombardment (FAB) techniques. Optical Rotations were de-
termined in a Perkin-Elmer 241 polarimeter in 1 dm cells. Diethyl
ether, THF and benzene were distilled from sodium. Pyridine and
CH2Cl2 were distilled under argon from CaH2.
IR (neat): 3420, 2972, 1727, 1655, 1460, 1284, 1120, 910, 715 cm–1.
1H NMR (400 MHz, CDCl3): = 8.09 (2 H, m, Ar), 7.40–7.62 (3 H,
m, Ar), 5.45 (1 H, t, J = 6.7 Hz, H-3), 5.09 (1 H, s, HA-1), 4.98 (1 H,
br s, HB-1), 1.90 (2 H, m, H-4), 1.81 (3 H, s, H-9), 1.55 (2 H, m, H-
5), 1.24 (6 H, s, H-7, H-8).
13C NMR (100 MHz, CDCl3): = 18.2, 27.7, 29.3 (2 C), 39.2, 70.6,
78.2, 113.1, 128.4, 129.6, 130.4, 132.8, 143.0, 165.8.
HRMS–FAB: (m/z) [M + H]+ calcd for C14H27O3, 263.1647; found,
(5S)-5-Benzyloxy-2,6-dimethyl-hept-6-en-2-ol (1b)
To a suspension of NaH (60%, 71 mg, 1.78 mmol) in THF (3 mL)
under argon, was added 1 (256 mg, 1.618 mmol) dissolved in THF
(5 mL) at 0 °C. After 10 min of vigorous stirring, BnBr (0.21 mL,
1.78 mmol) was added and the reaction mixture was stirred at r.t. for
12 h. The reaction was quenched by the addition of H2O (2 mL).
263.1640.
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Cyclization of , -Dihydroxyepoxide Derivatives. Stereochemical Studies
179
Preparation 2a and 3a
Anal. Calcd for C16H24O3: C, 69.20; H, 10.32. Found: C, 69.16: H,
10.08.
To a solution of 1 (77 mg, 0.487 mmol) in CH2Cl2 (5 mL) was added
MCPBA (117 mg, 0.681 mmol) at 0 °C, and the mixture was stirred
for 16 h. The reaction mixture was diluted with EtOAc (50 mL) and
the organic extract was washed with aq solutions of 10% Na2CO3
(25 mL), brine (25 mL) and finally dried over Na2SO4. Removal of
the solvent under reduced pressure gave a crude oil that was purified
by chromatography on silica gel (EtOAc–hexanes, 2:8) to give a
mixture (1:1) of the epoxides 2a and 3a (84 mg, 99%).
(5S,2´S)-5-Benzyloxy-2-methyl-5-(2´-methyl-oxiranyl)-pentan-
2-ol (3b)
[ ]D20 –43.90 (c 0.80, CHCl3).
IR (neat): 3400, 3032, 2971–2870, 1454, 1377, 1096, 1072, 909,
737, 698 cm–1.
1H NMR (400 MHz, CDCl3): = 7.37–7.30 (5 H, m, Ph), 4.82 (1 H,
d, J = 11.8 Hz, O-CHH-Ph, HA), 4.52 (1 H, d, J = 11.8 Hz, O-CHH-
Ph, HB), 2.98 (1 H, dd, J = 10.0, 5.0 Hz, H-3), 2.62 (1 H, d, J = 4.5
Hz, HA-1), 2.54 (1 H, d, J = 4.5 Hz, HB-1), 1.80–1.20 (4 H, m, H-4,
H-5), 1.37 (3 H, s, H-9), 1.21 (6 H, s, H-7, H-8).
13C NMR (100 MHz, CDCl3): = 15.6, 27.7, 29.3, 29.5, 40.2, 49.8,
58.7, 70.5, 71.8, 83.8, 127.5, 127.9, 128.3, 138.7.
(1S,2R)-4-Methyl-1-(2-methyl-oxiranyl)-pentane-1,4-diol (2a)
20
[ ]D –6.90 (c 1.20, CHCl3).
IR (neat): 3400, 2969–2859, 1464, 1379, 1281, 1215, 1150, 1071,
909, 719, 698 cm–1.
1H NMR (200 MHz, CDCl3): = 3.60 (1 H, m, H-3), 2.90 (1 H, d,
J = 4.8 Hz, HA-1), 2.63 (1 H, d, J = 4.8 Hz, HB-1), 1.81–1.42 (4 H,
m, H-4, H-5), 1.36 (3 H, s, H-9), 1.24 (6 H, s, H-7, H-8).
13C NMR (50 MHz, CDCl3): = 17.7, 27.5, 29.0, 29.1, 39.6, 51.0,
59.1, 70.5, 72.7.
HRMS–FAB: (m/z) [M + H]+ calcd for C9H19O3, 175.1334; found,
Anal. Calcd for C16H24O3: C, 69.20; H, 10.32. Found: C, 69.59: H,
10.23.
Preparation of 2c and 3c
To a solution of 1c (53 mg, 0.27 mmol) in CH2Cl2 (2 mL) was added
MCPBA (52 mg, 0.3 mmol) and the mixture was stirred for 24 h.
The solvent was evaporated and the reaction mixture was diluted
with of Et2O (150 mL). The organic layer was washed with aq an
solution of 10% Na2CO3 (25 mL), H2O (25 mL) and finally dried
over Na2SO4. Removal of the solvent under reduced pressure gave
a crude oil that was purified by chromatography on silica gel (Et2O–
hexanes, 1:1) to give the epoxides 2c (31 mg, 52%) and 3c (21 mg,
37%) as colorless oils.
175.1339.
(1S,2S)-4-Methyl-1-(2-methyl-oxiranyl)-pentane-1,4-diol (3a)
[ ]D20 – 9.5 (c = 1.4, CHCl3).
IR (neat): 3400, 2960–2870, 1464, 1364, 698, 667 cm–1.
1H NMR (200 MHz, CDCl3): = 3.38 (1 H, m, H-3), 2.82 (1 H, d,
J = 4.8 Hz, HA-1), 2.64 (1 H, d, J = 4.8 Hz, HB-1), 1.80–1.40 (4 H,
m, H-4, H-5), 1.35 (3 H, s, H-9), 1.25 (3 H, s, H-7 or H-8), 1.24 (3
H, H-7 or H-8).
Acetic Acid (1S,2R)-4-Hydroxy-4-methyl-1-(2-methyl-oxiran-
13C NMR (50 MHz, CDCl3): = 16.0, 27.8, 29.3, 29.4, 39.7, 52.3,
59.9, 70.5, 75.2.
yl)-pentyl Ester (2c)
[ ]D –11.10 (c 1.20, CHCl3).
20
IR (neat): 3420, 2970, 1740, 1380, 1250, 1050, 760 cm–1.
HRMS–FAB: (m/z) [M]+ calcd for C9H18O3, 174.1256; found,
1H NMR (400 MHz, CDCl3): = 4.61 (1 H, dd, J = 9.5, 5.9 Hz, H-
3), 2.81 (1 H, d, J = 5.7 Hz, HA-1), 2.59 (1 H, d, J = 5.7 Hz, HB-1),
2.08 (3 H, s, CO2Me), 1.90–1.45 (4 H, m, H-4, H-5), 1.34 (3 H, s,
H-9), 1.24 (6 H, s, H-7, H-8).
174.1281.
Anal. Calcd for C9H18O3: C, 62.04; H, 10.41. Found: C, 61.90; H,
10.71.
13C NMR (100 MHz, CDCl3): = 16.7, 20.8, 25.3, 29.2, 29.3, 39.2,
53.0, 56.4, 70.5, 76.0, 170.2.
HRMS–FAB: (m/z) [M]+ calcd for C11H21O4, 217.1440; found,
Preparation of 2b and 3b
To a solution of 1b (306 mg, 1.232 mmol) in CH2Cl2 (2 mL) was
added MCPBA (318 mg, 1.848 mmol) at 0 °C, and the mixture was
stirred for 14 h. The reaction mixture was diluted with H2O (50 mL),
extracted with EtOAc (4 100 mL) and the organic layer washed
with aq solutions of 5% NaHCO3 (50 mL), brine (50 mL) and final-
ly dried over Na2SO4. Removal of the solvent under reduced pres-
sure gave a crude oil (416 mg) that was purified by chromatography
on silica gel (EtOAc–hexanes, 2:8) to give the epoxides 2b (135 mg,
41%) and 3b (135 mg, 41%) as colorless oils.
217.1432.
Acetic Acid (1S,2S)-4-Hydroxy-4-methyl-1-(2-methyl-oxiran-
yl)-pentyl Ester (3c)
IR (neat): 3420, 2970, 1740, 1380, 1250, 1050, 760 cm–1.
1H NMR (400 MHz, CDCl3): = 4.68 (1 H, t, J = 6.6 Hz, H-3), 2.75
(1 H, d, J = 5.7 Hz, HA-1), 2.64 (1 H, d, J = 5.7 Hz, HB-1), 2.10 (3
H, s, CO2Me), 1.80–1.40 (4 H, m, H-4, H-5), 1.37 (3 H, s, H-9), 1.22
(6 H, s, H-7, H-8).
13C NMR (100 MHz, CDCl3): = 17.2, 20.9, 25.9, 29.1, 29.5, 39.2,
51.9, 57.4, 70.4, 76.8, 170.3.
(5S,2´R)-5-Benzyloxy-2-methyl-5-(2´-methyl-oxiranyl)-pentan-
2-ol (2b)
20
[ ]D –20.60 (c 0.90, CHCl3).
IR (neat): 3400, 3032, 2970–2870, 1454, 1375, 1101, 1072, 909,
739, 698 cm–1.
HRMS–FAB: (m/z) [M + H]+ calcd for C11H21O4, 217.1440; found,
217.1446.
1H NMR (200 MHz, CDCl3): = 7.35–7.32 (5 H, m, Ph), 4.67 (1 H,
d, J = 11.5 Hz, O-CHH-Ph, HA), 4.46 (1 H, d, J = 11.5 Hz, O-CHH-
Ph, HB), 3.04 (1 H, t, J = 6.0 Hz, H-3), 2.74 (1 H, d, J = 5.0 Hz, HA-
1), 2.67 (1 H, d, J = 5.0 Hz, HB-1), 1.82–1.20 (4 H, m, H-4, H-5),
1.34 (3 H, s, H-9), 1.22 (6 H, s, H-7, H-8).
13C NMR (50 MHz, CDCl3): = 16.3, 26.7, 29.2, 29.5, 39.9, 53.9,
56.9, 70.6, 72.2, 82.2, 127.7 (2 C), 128.4, 138.6.
Preparation of 2d and 3d
To a solution of 10 (995 mg, 3.64 mmol) in CH2Cl2 (20 mL) was
added MCPBA (1.58 mg, 7.3 mmol) and the mixture was stirred for
48 h. The solvent was evaporated and the reaction mixture was di-
luted with Et2O (400 mL). The organic layer was washed with an aq
solution of 10% Na2CO3 (50 mL), H2O (50 mL) and finally dried
over Na2SO4. Removal of the solvent under reduced pressure gave
a crude oil that was purified by chromatography on silica gel (Et2O–
HRMS (CI, NH3): (m/z) [M + H]+ calcd for C16H25O3, 265.1804;
found, 265.1800.
Synthesis 2002, No. 2, 175–184 ISSN 0039-7881 © Thieme Stuttgart · New York

180
D. Díez et al.
PAPER
hexanes, 2:8) to give the epoxides 2d (531 mg, 53%) and 3d (345
Cyclization of 3a
mg, 34%) as colorless oils.
To a solution of 3a (24 mg, 0.138 mmol) in CH2Cl2 (2.5 mL) under
argon was added CSA (6.4 mg, 0.027 mmol) at –40 °C and the re-
action mixture was stirred for 12 h allowing the temperature to rise
to r.t. After addition of Et3N (0.35 mL), the solvent was evaporated
and the residue purified by chromatography on silica gel (EtOAc–
hexanes, 3:7) to give the tetrahydropyran 6a (16 mg, 67%).
Benzoic Acid (1S,2R)-4-Hydroxy-4-methyl-1-(2-methyl-oxiran-
yl)-pentyl Ester (2d)
20
[ ]D –10.90 (c 1.70, CHCl3).
IR (neat): 3475, 2972, 1721, 1453, 1273, 1114, 1032, 950, 715 cm–1.
1H NMR (400 MHz, CDCl3): = 8.09 (2 H, m, Ar), 7.40–7.60 (3 H,
m, Ar), 4.95 (1 H, t, J = 6.7 Hz, H-3), 2.80 (1 H, d, J = 4.5 Hz, HA-
1), 2.66 (1 H, d, J = 4.5 Hz, HB-1), 1.90 (2 H, m, H-4), 1.55 (2 H, m,
H-5), 1.45 (3 H, s, H-9), 1.21 (6 H, s, H-7, H-8).
13C NMR (100 MHz, CDCl3): = 17.5, 26.1, 29.1, 29.6, 39.3, 52.0,
57.8, 70.5, 77.4, 128.4, 129.7, 130.2, 133.1, 166.0.
(2R,3S)-2-Hydroxymethyl-2,6,6-trimethyl-tetrahydro-pyran-3-
ol (6a)
20
[ ]D +5.80 (c 0.50, CHCl3).
IR (neat): 3256, 1985–1880, 1472, 1456, 1377, 1136, 1074, 1049,
667 cm–1.
1H NMR (400 MHz, CDCl3): = 3.81 (1 H, dd, J = 5.6, 10.0 Hz, H-
3), 3.49 (1 H, d, J = 11.0 Hz, HA-10), 3.32 (1 H, d, J = 11.0 Hz, HB-
10), 1.90–1.41 (4 H, m, H-4, H-5), 1.28 (3 H, s, H-9), 1.17 (6 H, s,
H-7, H-8).
13C NMR (100 MHz, CDCl3): = 18.4, 25.2, 27.30, 32.7, 36.8, 68.5,
68.9, 72.2, 76.7.
HRMS–EI: (m/z) [M]+ calcd for C9H18O3, 174.1256; found,
HRMS–FAB: (m/z) [M + H]+ calcd for C16H23O4, 279.1596; found,
279.1596.
Benzoic Acid (1S,2S)-4-Hydroxy-4-methyl-1-(2-methyl-oxiran-
yl)-pentyl Ester (3d)
[ ]D20 –19.10 (c 0.70, CHCl3).
IR (neat): 3475, 2972, 1721, 1453, 1273, 1114, 1032, 950, 715 cm–1.
174.1263.
1H NMR (400 MHz, CDCl3): = 8.02 (2 H, m, Ar), 7.40–7.60 (3 H,
m, Ar), 4.85 (1 H, t, J = 6.7 Hz, H-3), 2.89 (1 H, d, J = 5.0 Hz, HA-
1), 2.60 (1 H, d J = 5.0 Hz, HB-1), 1.91 (2 H, m, H-4), 1.55 (2 H, m,
H-4), 1.38 (3 H, s, H-9), 1.21 (6 H, s, H-7, H-8).
13C NMR (100 MHz, CDCl3): = 16.7, 25.5, 29.3 (2 C), 39.3, 53.4,
56.6, 70.5, 76.8, 128.4, 129.7, 130.2, 133.1, 165.8.
Anal. Calcd for C9H18O3: C, 62.04; H, 10.41. Found: C, 61.81; H,
10.23.
Cyclization of 2b
To a solution of 2b (134 mg, 0.507 mmol) in CH2Cl2 (5 mL) under
argon was added CSA (12 mg, 0.051 mmol) at –40 °C and the reac-
tion mixture was stirred for 48 h allowing the temperature to rise to
r.t. After addition of Et3N (0.4 mL), the solvent was evaporated and
the residue purified by chromatography on silica gel (EtOAc–hex-
anes, 1:9) to give the tetrahydropyran 4b (115 mg, 86%) and the ox-
epan 5b (5 mg, 4%) as colorless oils.
HRMS–FAB: (m/z) [M + H]+ calcd for C16H23O4, 279.1596; found,
279.1597.
Cyclization of 2a
To a solution of 2 (14 mg, 0.0803 mmol) in CH2Cl2 (1 mL) under
argon was added CSA (12 mg, 0.051 mmol) at –40 °C and the reac-
tion mixture was stirred for 12 h allowing the temperature to rise to
r.t. After addition of Et3N (0.2 mL), the solvent was evaporated and
the residue purified by chromatography on silica gel (EtOAc–hex-
anes, 3:7) to give the tetrahydropyran 4a (8 mg, 56%) and the ox-
epan 5a (6 mg, 43%).
(2S,3S)-(3-Benzyloxy-2,6,6-trimethyl-tetrahydro-pyran-2-yl)-
methanol (4b)
20
[ ]D +46.40 (c 0.70, CHCl3).
IR (neat): 3400, 2970–2870, 1454, 1366, 1101, 1072, 1030, 997,
737, 698 cm–1.
1H NMR (400 MHz, CDCl3): = 7.35–7.31 (5 H, m, Ph), 4.66 (1 H,
d, J = 11.7 Hz, O-CHH-Ph, HA), 4.42 (1 H, d, J = 11.7 Hz, O-CHH-
Ph, HB), 3.74 (1 H, d, J = 11.7 Hz, HA-10), 3.61 (1 H, d, J = 11.7 Hz,
HB-10), 3.37 (1 H, dd, J = 3.7, 8.2 Hz, H-3), 2.00–1.81 (2 H, m, H-
4), 1.82–1.40 (2 H, m, H-5), 1.27 (3 H, s, H-9), 1.26 (3 H, s, H-7),
1.22 (3 H, s, H-8).
13C NMR (100 MHz, CDCl3): = 20.5, 25.1, 29.3, 30.8, 33.6, 67.0,
70.9, 71.6, 75.4, 80.1, 127.6, 127.8, 128.5, 138.1.
HRMS–FAB: (m/z) [M + H]+ calcd for C16H25O3, 265.1804; found,
(2S,3S)-2-Hydroxymethyl-2,6,6-trimethyl-tetrahydro-pyran-3-
ol (4a)
20
[ ]D +3.90 (c 1.20, CHCl3).
IR (neat): 3400, 2970–2870, 1458, 1368, 1233, 1101, 1057, 995,
688 cm–1.
1H NMR (400 MHz, CDCl3): = 3.69 (1 H, dd, J = 4.6, 2.2 Hz, H-
3), 3.60 (2 H, m, H-10), 2.02–1.71 (2 H, m, H-4), 1.72–1.30 (2 H,
m, H-5), 1.27 (3 H, s, H-7), 1.25 (3 H, s, H-8), 1.15 (3 H, s, H-8).
13C NMR (100 MHz, CDCl3): = 24.0 (2 C), 28.4, 30.3, 321, 69.7,
71.3, 72.5, 74.4.
265.1804.
HRMS–FAB: (m/z) [M + H]+ calcd for C9H19O3, 175.1334; found,
175.1311.
(3R,4S)-4-Benzyloxy-3,7,7-trimethyl-oxepan-3-ol (5b)
IR (neat): 3400, 2970–2870, 1456, 1375, 1098, 737, 698 cm–1.
1H NMR (400 MHz, CDCl3): = 7.36–7.29 (5 H, m, Ph), 4.68 (1 H,
d, J = 11.3 Hz, O-CH2-Ph, HA), 4.63 (1 H, d, J = 11.3 Hz O-CH2-
Ph, HB,), 3.81 (1 H, d, J = 11.1 Hz HA -2,), 3.57 (1 H, d, J = 11.1 Hz,
HB -2), 3.51 (1 H, dd, J = 3.3, 7.9 Hz, H-4), 1.9–1.2 (4 H, m, H-5
and H-6), 1.28 (3 H, s, H-10), 1.23 and 1.22 (3 H each, s, H-8 and
H-9).
13C NMR (100 MHz, CDCl3): = 20.7, 25.0, 29.1, 29.5, 40.8, 52.6,
70.9, 74.3, 74.6, 83.1, 127.6, 127.7, 128.5, 138.3.
HRMS–FAB: (m/z) [M + H]+ calcd for C16H25O3, 265.1804; found,
(3R,4S)-3,7,7-Trimethyl-oxepane-3,4-diol (5a)
[ ]D –13.40 (c 0.40, CHCl3)
IR (neat): 3388, 2964, 2942, 2888, 1379, 1362, 1074, 667, 650 cm–1.
1H NMR (400 MHz, CDCl3): = 3.84 (1 H, d, J = 11.2 Hz, HA-2),
3.60 (1 H, d, J = 11.2 Hz, HB-2), 3.61 (1 H, m, H-4), 1.91–1.40 (4
H, m, H-5, H-6), 1.26 (9 H, s, H-8, H-9, H-10).
13C NMR (100 MHz, CDCl3): = 21.2, 25.76, 29.2, 30.6, 41.0, 52.1,
71.2, 74.2, 76.6.
20
265.1835.
HRMS–FAB: (m/z) [M + H]+ calcd for C9H19O3, 175.1334; found,
175.1352.
Synthesis 2002, No. 2, 175–184 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Cyclization of , -Dihydroxyepoxide Derivatives. Stereochemical Studies
181
Cyclization of 3b
Benzoic Acid (1S,1´S)-1-(1´,2´-Dihydroxy-1´-methyl-ethyl)-4-
To a solution of 3b (135 mg, 0.511 mmol) in CH2Cl2 (5 mL) under
argon was added CSA (12 mg, 0.051 mmol) at –40 °C and the reac-
tion mixture was stirred for 48 h allowing the temperature to rise to
r.t. After addition of Et3N (0.4 mL), the solvent was evaporated and
the residue purified by chromatography on silica gel (EtOAc–hex-
anes, 1:9) to give the tetrahydropyran 6b (102 mg, 76%) and the ox-
epan 7b (15 mg, 11%) as colorless oils.
hydroxy-4-methyl-pentyl Ester (10)
[ ]D –39.70 (c 0.70, CHCl3).
IR (neat): 3420, 2972, 1710, 1450, 1284, 1120, 955, 715 cm–1.
1H NMR (400 MHz, CDCl3): = 8.06 (2 H, m, Ar), 7.60 (1 H, m,
Ar), 7.48 (2 H, m, Ar), 5.06 (1 H, dd, J = 10.5, 1.9 Hz, H-3), 3.48 (1
H, d, J = 11.8 Hz, HA-1), 3.29 (1 H, d, J = 11.8 Hz, HB-1), 2.15–1.51
(4 H, m), 1.60–1.45 (2 H, m), 1.25 (3 H, s, H-7), 1.23 (3 H, s, H-8),
1.17 (3 H, s, H-9).
20
(2R,3S)-(3-Benzyloxy-2,6,6-trimethyl-tetrahydro-pyran-2-yl)-
13C NMR (100 MHz, CDCl3): = 17.7, 23.2, 29.2, 29.3, 40.3, 66.8,
70.7, 73.5, 76.3, 128.6, 129.2, 129.8, 133.6, 167.8.
methanol (6b)
[ ]D +41.40 (c 0.70, CHCl3).
20
HRMS–FAB: (m/z) [M + H]+ calcd for C16H25O5, 297.1702; found,
297.1700.
IR (neat): 3400, 2970–2870, 1454, 1364, 1127, 1099, 1049, 993,
735, 698 cm–1.
1H NMR (400 MHz, CDCl3): = 7.35–7.31 (5 H, m, Ph), 4.65 (1
H, d, J = 11.7 Hz, O-CHH-Ph, HA), 4.51 (1 H, d, J = 11.7 Hz, O-
CHH-Ph, HB), 3.63 (1 H, dd, J = 4.4, 10.8 Hz, H-3), 3.48 (1 H, d,
J = 10.5 Hz, HA-10), 3.31 (1 H, d, J = 10.5 Hz, HB-10), 2.00–1.40
(4 H, m, H-4, H-5), 1.30 (3 H, s, H-9), 1.19 (6 H, s, H-7, H-8).
13C NMR (100 MHz, CDCl3): = 19.0, 21.3, 27.1, 32.6, 36.5, 67.9,
71.2, 71.9, 75.6, 76.6, 127.34, 127.34, 128.3, 139.0.
Benzoic Acid (2S,3S)- 2,3,6-Trihydroxy-2,6-dimethyl-heptyl
Ester (11)
20
[ ]D –12.00 (c 1.10, CHCl3).
IR (neat): 3405, 2972, 1705, 1452, 1379, 1317, 1281, 1117, 712
cm–1.
1H NMR (400 MHz, CDCl3): = 8.06 (2 H, m, Ar), 7.58 (1 H, m,
Ar), 7.46 (2 H, m, Ar), 4.53 (1 H, d, J = 11.5 Hz, HA-1), 4.27 (1 H,
d, J = 11.5 Hz, HB-1), 3.53 (1 H, d, J = 8.2 Hz, H-3), 1.85–1.55 (4
H, m), 1.29 (3 H, s, H-9), 1.25 (3 H, s, H-7), 1.23 (3 H, s, H-8).
HRMS (CI, NH3): (m/z) [M + H]+ calcd for C16H25O3, 265.1804;
found, 265.1807.
13C NMR (100 MHz, CDCl3): = 20.4, 25.5, 28.9, 30.1, 40.8, 68.9,
70.9, 74.1, 76.4, 128.4, 129.7, 130.00, 133.3, 167.0.
(3S,4S)-4-Benzyloxy-3,7,7-trimethyl-oxepan-3-ol (7b)
IR (neat): 3400, 2970–2870, 1454, 1377, 1092, 737, 698 cm–1.
1H NMR (400 MHz, CDCl3): = 7.37–7.30 (5 H, m, Ph), 4.71 (1 H,
d, J = 11.1 Hz, O-CHH2-Ph, HA), 4.65 (1 H, d, J = 11.1 Hz, O-
CHH-Ph, HB,), 3.65 (1 H, m, H-4), 3.64 (1 H, d, J = 10.8 Hz, HA -
2,), 3.45 (1 H, d, J = 10.8 Hz, HB -2), 1.80–1.52 (4 H, m, H-5, H-6),
1.28 (3 H, s, H-10), 1.23 (3 H, s, H-8), 1.22 (3 H, s, H-9).
13C NMR (100 MHz, CDCl3): = 21.4, 24.4, 29.0, 29.6, 40.0, 50.7,
70.7, 74.2, 75.4, 81.3, 127.9, 127.9, 128.5, 138.0.
HRMS–FAB: (m/z) [M + H]+ calcd for C16H25O5, 297.1702; found,
297.1708.
Benzoic Acid (2R,2´R)-2-(5´,5´-dimethyl-tetrahydro-furan-2´-
yl)-2-hydroxy-propyl Ester (12)
20
[ ]D +2.00 (c 1.0, CHCl3).
IR (neat): 3507, 2972, 1723, 1452, 1366, 1275, 1117, 1028, 712
cm–1.
LRMS (CI, NH3): (m/z) = 265 (15) [M + H]+, 191 (44), 175 (99),
1H NMR (400 MHz, CDCl3): = 8.06 (2 H, m, Ar), 7.60–7.40 (3 H,
m, Ar), 4.37 (1 H, d, J = 11.0 Hz, HA-9), 4.17 (1 H, d, J = 11.0 Hz,
HB-9), 4.01 (1 H, dd, J = 7.6, 6.3 Hz, H-5), 2.10–1.60 (4 H, m. H-4,
H-5), 1.24 (3 H, s, H6), 1.22 (3 H, s, H-7), 1.21 (3 H, s, H-10).
157 (17), 108 (60), 99 (87), 91 (57), 81 (9).
HRMS–FAB: (m/z) [M + H]+ calcd for C16H25O3, 265.1804; found,
265.1802.
13C NMR (100 MHz, CDCl3): = 20.1, 26.3, 28.0, 28.7, 38.6, 70.1,
71.8, 81.4, 81.5, 128.3, 129.7, 130.61, 132.8, 166.4.
HRMS–FAB: (m/z) [M + H]+ calcd for C16H23O4, 279.1596; found,
Hydrogenolysis of Compound 4b
To a solution of 4b (97 mg, 0.414 mmol) in EtOH (10 mL) was add-
ed 10% Pd/C catalyst (9 mg) and this was vigorously stirred at r.t.
under hydrogen. After 2 h the mixture was filtered through Celite™
and concentrated to give an oil, which was purified by column chro-
matography (EtOAc–hexanes, 4:6) to give the diol 4a (70 mg,
96%).
279.1596.
Benzoic Acid (2R,3S)-2-Hydroxymethyl-2,6,6-trimethyl-tetra-
hydro-pyran-3-yl Ester (6d)
20
[ ]D –8.60 (c 1.30, CHCl3).
Hydrogenolysis of Compound 6b
IR (neat): 3519, 2972, 1721, 1450, 1278, 1114, 715 cm–1.
To a solution of 6b (95 mg, 0.414 mmol) in EtOH (10 mL) was add-
ed 10% Pd/C catalyst (9 mg) and this was vigorously stirred at r.t.
under hydrogen. After 2 h the mixture was filtered through Celite™
and concentrated to give an oil, which was purified by column chro-
matography with (EtOAc–hexanes, 4:6) to give the diol 6a (67 mg,
94%)
1H NMR (400 MHz, CDCl3): = 8.00 (2 H, m, Ar), 7.56 (1 H, m,
Ar), 7.44 (2 H, m, Ar), 5.20 (1 H, dd, J = 11.0, 4.6 Hz, H-3), 3.33 (2
H, s, H-10), 2.10–1.72 (4 H, m), 1.35 (3 H, s, H-7), 1.34 (3 H, s, H-
8), 1.25 (3 H, s, H-9).
13C NMR (100 MHz, CDCl3): = 19.4, 21.6, 27.3, 32.1, 35.8, 67.5,
70.4, 72.3, 75.5, 128.5, 129.5, 130.2, 133.0, 165.7.
Cyclization of 2d
HRMS–FAB: (m/z) [M + H]+ calcd for C16H23O4, 279.1596; found,
279.1602.
To a solution of 2d (234 mg, 0,841 mmol) in CH2Cl2 (10 mL) at
–40 °C was added CSA (18 mg, 0.09 mmol) and the reaction mix-
ture was stirred for 12 h allowing the temperature to rise to r.t. After
addition of Et3N (0.8 mL), the solvent was evaporated and the resi-
due purified by chromatography on silica gel (Et2O–hexanes,
1:9 1:1) to give 10 (8 mg, 5%), 11 (43 mg, 28%), 12 (12 mg, 8%),
6d (62 mg, 44%), and 5d (20 mg, 14%).
Benzoic Acid (3R,4S)-3-Hydroxy-3,7,7-trimethyl-oxepan-4-yl
Ester (5d)
20
[ ]D +47.80 (c 0.60, CHCl3).
IR (neat): 3509, 2974, 1721, 1452, 1277, 1175, 1113, 1071, 712
cm–1.
Synthesis 2002, No. 2, 175–184 ISSN 0039-7881 © Thieme Stuttgart · New York

182
D. Díez et al.
PAPER
1H NMR (200 MHz, CDCl3): = 8.04 (2 H, m, Ar), 7.57 (1 H, m,
Ar), 7.48 (2 H, m, Ar), 5.00 (1 H, d, J = 5.4 Hz, H-4), 3.79 (1 H, d,
J = 12.9 Hz, HA-2), 3.39 (1 H, br s, OH), 3.22 (1 H, dd, J = 12.9, 1.6
Hz, HB-2), 2.00–1.30 (4 H, m, H-5, H-6), 1.25 (3 H, s, H-8), 1.22 (3
H, s, H-9), 1.16 (3 H, s, H-10).
1H NMR (400 MHz, CDCl3): = 8.08 (2 H, m, Ar), 7.40–7.65 (3 H,
m, Ar), 5.08 (1 H, dd, J = 5.4, 3.2 Hz, H-3), 3.65 (1 H, dd, J = 11.7,
6.3 Hz, HA-10), 3.49 (1 H, dd, J = 11.7, 6.3 Hz, HB-10), 2.25 (1 H,
t, J = 6.3 Hz, OH), 2.20–1.50 (4 H, m), 1.38 (3 H, s, H-7), 1.32 (6
H, s, H-8 and H-9).
13C NMR (50 MHz, CDCl3): = 21.2, 22.6, 27.5, 27.8, 32.4, 65.6,
72.6, 75.9, 77.8, 128.5, 129.5, 130.3, 133.1, 165.5.
13C NMR (100 MHz, CDCl3): = 21.8, 23.9, 29.2, 31.3, 32.3, 67.1,
72.0, 72.5, 75.1, 128.5, 129.7, 130.4, 133.1, 166.2.
HRMS–FAB: (m/z) [M + H]+ calcd for C16H23O4, 279.1596; found,
HRMS–FAB: (m/z) [M + H]+ calcd for C16H23O4, 279.1596; found,
279.1595.
279.1596.
Cyclization of 3d
Benzoic Acid (1S,1´S)-1-(2´-Acetoxy-1´-hydroxy-1´-methyl-
ethyl)-4-hydroxy-4-methyl-pentyl Ester (16)
To a solution of 3d (116 mg, 0.42 mmol) in CH2Cl2 (10 mL) at
–40 °C was added CSA (9 mg, 0.042 mmol) and the reaction mix-
ture was stirred for 12 h allowing the temperature to rise to r.t. After
addition of Et3N (0.4 mL), the solvent was evaporated and the resi-
due purified by chromatography on silica gel (Et2O–hexanes,
1:9 1:1) to give 13 (36 mg, 49%), 14 (8 mg, 11%), 15 (11 mg,
16%) and 4d (16 mg, 23%).
Distilled Ac2O (0.25 mL) was added to a solution of 10 (5 mg, 0.017
mmol) in pyridine (0.5 mL). After 12 h the reaction was quenched
with ice, diluted with H2O (50 mL) and extracted with Et2O (2 50
mL). The organic layer was washed with aq solutions of 10% HCl
(20 mL), 5% NaHCO3 (20 mL), brine (20 mL) and finally dried over
Na2SO4. The solvent was evaporated under reduced pressure to give
a crude oil that was purified by chromatography on silica gel (Et2O–
hexanes, 5:95) to give 16 (4 mg, 73%).
Benzoic Acid (1S,1´R)-1-(1´,2´-Dihydroxy-1´-methyl-ethyl)-4-
hydroxy-4-methyl-pentyl Ester (13)
[ ]D –21.40 (c 1.20, CHCl3).
IR (neat): 3412, 2972, 1713, 1452, 1281, 1115, 1028, 756, 712 cm–1.
1H NMR (400 MHz, CDCl3): = 8.08 (2 H, m, Ar), 7.40–7.70 (3 H,
m, Ar), 5.30 (1 H, t, J = 6.5 Hz, H-3), 3.59 (1 H, d, J = 11.2 Hz, HA-
1), 3.48 (1 H, d, J = 11.2 Hz, HB-1), 1.95–1.50 (4 H, m), 1.28 (3 H
s, H-7), 1.23 (3 H s, H-8), 1.22 (3 H s, H-9).
13C NMR (100 MHz, CDCl3): = 20.4, 24.3, 29.1, 29.8, 39.9, 67.9,
70.7, 75.1, 78.5, 128.6, 129.8, 130.0, 133.4, 167.4.
IR (neat): 3420, 2939, 1725, 1271, 1090, 1046, 710 cm–1.
20
1H NMR (200 MHz, CDCl3): = 8.03 (2 H, m, Ar), 7.61–7.40 (3 H,
m, Ar), 5.27 (1 H, dd, J = 11.3, 3.0 Hz, H-3), 4.16 (1 H, d, J = 11.6
Hz, HA-1), 4.01 (1 H, d, J = 11.6 Hz, HB-1), 2.10 (3 H, s, CO2Me),
1.33 (3 H, s, H-9), 1.23 (3 H, s, H-7), 1.21 (3 H, s, H-8).
HRMS–FAB: (m/z) [M + H]+ calcd for C18H27O6, 339.1808; found,
339.1805.
Benzoic Acid (2S,3S)-3-Acetoxy-2,6-dihydroxy-2,6-dimethyl-
heptyl Ester (17)
HRMS–FAB: (m/z) [M + H]+ calcd for C16H25O5, 297.1702; found,
Distilled Ac2O (0.5 mL) was added to a solution of 11 (15 mg, 0.05
mmol) in 1 mL of pyridine. After 12 h the reaction was quenched
with ice, diluted in H2O (50 mL) and extracted with Et2O (2 50
mL). The organic layer was washed with aq solutions of 10% HCl
(2 10 mL), 5% NaHCO3 (2 10 mL) and brine (2 10 mL) and
dried over Na2SO4. The solvent was evaporated under reduced pres-
sure to give a crude oil that was purified by chromatography on sil-
ica gel (Et2O–hexanes, 5:95) to give 17 (10 mg, 60%).
297.1702.
Benzoic Acid (2R,3S)- 2,3,6-Trihydroxy-2,6-dimethyl-heptyl
Ester (14)
20
[ ]D –8.60 (c 0.60, CHCl3).
IR (neat): 3410, 2971, 1721, 1279, 1117, 712 cm–1.
1H NMR (400 MHz, CDCl3): = 8.04 (2 H, m, Ar), 7.70–7.40 (3 H,
m, Ar), 4.46 (1 H, d, J = 11.4 Hz, HA-1), 4.23 (1 H, d, J = 11.4 Hz,
HB-1), 3.58 (1 H, m, H-3), 1.9–1.6 (4 H, m), 1.28 (6 H, s, H-7 and
H-8), 1.25 (3 H, s, H-9).
13C NMR (100 MHz, CDCl3): = 20.0, 25.5, 29.3, 29.9, 40.4, 69.6,
70.80, 74.2, 74.8, 128.5, 129.7, 130.0, 133.2, 166.9.
IR (neat): 3472, 2972, 1726, 1275, 1113, 1038, 714 cm–1.
1H NMR (400 MHz, CDCl3): = 8.06 (2 H, m, Ar), 7.52 (1 H, m,
Ar), 7.46 (2 H, m, Ar), 5.10 (1 H, dd, J = 10.8, 2.8 Hz, H-3), 4.31 (1
H, d, J = 11.6 Hz, HA-1), 4.28 (1 H, d, J = 11.6 Hz, HB-1), 2.09 (3
H, s, CO2Me), 1.95–1.40 (4 H, m, H-4 and H-5), 1.31 (3 H, s, H-9),
1.23 (3 H, s, H-7) 1.22 (3 H, s, H-8).
HRMS–FAB: (m/z): [M + H]+ calcd for C16H25O5, 297.1702; found,
13C NMR (100 MHz, CDCl3): = 20.5, 21.0, 24.0, 29.2, 29.6, 39.8,
68.8, 70.7, 73.51, 76.4, 128.5, 129.6, 129.7, 133.3, 166.7, 170.7.
HRMS–FAB: (m/z) [M + H]+ calcd for C18H27O6, 339.1808; found,
297.1701.
Benzoic Acid (2S,2´R)-2-(5´,5´-Dimethyl-tetrahydrofuran-2´-
yl)-2-hydroxy-propyl Ester (15)
339.1808.
20
[ ]D +4.20 (c 1.10, CHCl3).
IR (neat): 3495, 2972, 1723, 1452, 1368, 1277, 1115, 1028, 712
cm–1.
Benzoic Acid (2R,3S)-2-Acetoxymethyl-2,6,6-trimethyl-tetra-
hydropyran-3-yl Ester (18)
1H NMR (400 MHz, CDCl3): = 8.05 (2 H, m, Ar), 7.40–7.60 (3 H,
m, Ar), 4.30 (2 H, s, H-9), 3.99 (1 H, t, J = 6.7 Hz, H-5), 2.1–1.6 (4
H, m), 1.32 (3 H, s, H-6), 1.25 (6 H, s, H-7, H-10).
13C NMR (100 MHz, CDCl3): = 21.8, 26.4, 27.8, 28.7, 38.8, 69.1,
72.5, 81.1, 82.4, 128.4, 129.7, 130.3, 133.0, 166.6.
HRMS (CI, NH3): (m/z) [M + H]+ calcd for C16H23O4, 279.1596;
found, 279.1594.
Distilled Ac2O (0.5 mL) was added to a solution of 6d (25 mg, 0.09
mmol) in pyridine (1 mL). After 12 h the reaction was quenched
with ice, diluted in H2O (50 mL) and extracted with Et2O (3 50
mL). The organic layer was washed with aq solutions of 10% HCl
(2 20 mL), 5% NaHCO3 (2 20 mL) and brine (2 20 mL) and
finally dried over Na2SO4. The solvent was evaporated under re-
duced pressure to give a crude oil that was purified by chromatog-
raphy on silica gel (Et2O–hexanes, 5:95) to give 18 (23 mg, 77%).
[ ]D20 +55.00 (c 1.40, CHCl3).
IR (neat): 2983, 1754, 1725, 1457, 1380, 1273, 1112, 718 cm–1.
1H NMR (400 MHz, CDCl3): = 8.02 (2 H, m, Ar), 7.55 (1 H, m,
Ar), 7.45 (2 H, m, Ar), 5.12 (1 H, dd, J = 10.0, 6.0 Hz, H-3), 4.10 (1
Benzoic Acid (2S,3S)-2-Hydroxymethyl-2,6,6-trimethyl-tetra-
hydro-pyran-3-yl Ester (4d)
20
[ ]D +17.80 (c 0.50, CHCl3).
IR (neat): 3495, 2972, 1721, 1279, 1111, 712 cm–1.
Synthesis 2002, No. 2, 175–184 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Cyclization of , -Dihydroxyepoxide Derivatives. Stereochemical Studies
183
H, d, J = 12.3 Hz, HA-10), 3.85 (1 H, d, J = 12.3 Hz, HB-10), 2.01
(3 H, s, COOCH3), 1.80–1.50 (4 H, m, H-4 and H-5), 1.38 (3 H, s,
H-7), 1.33 (3 H, s, H-8), 1.23 (3 H, s, H-9).
13C NMR (100 MHz, CDCl3): = 19.98, 20.9, 21.7, 28.4, 31.4, 34.7,
68.9, 71.1, 72.0, 74.2, 128.4, 129.5, 130.2, 133.1, 165.62, 170.9.
30 min more whereupon the solution was extracted with Et2O
(3 50 mL) and the combined organic layers were successively
washed with H2O, aq solution of 20% Cu2SO4 (2 15 mL), 5%
NaHCO3 (2 15 mL), brine (2 15 mL) and dried over Na2SO4.
Removal of the solvent gave crude tosyl derivative 21 (18 mg, 80%)
as an oil.
Anal. Calcd for C18H24O5: C, 67.48; H, 7.55. Found: C, 67.48; H,
7.54.
IR (neat): 3451, 2972, 1717, 1599, 1452, 1362, 1179, 990, 841, 714
cm–1.
(2S,2´R)-2-(5´,5´-Dimethyl-tetrahydrofuran-2´-yl)-propane-
1,2-diol (19)
1H NMR (400 MHz, CDCl3): = 7.93 (2 H, m, Ar), 7.73 (2 H, m,
Ar), 7.58 (1 H, m, Ar), 7.43 (2 H, m, Ar), 7.24 (2 H, m, Ar), 5.19 (1
H, m, H-3), 3.98 (1 H, d, J = 9 Hz, H-1A), 3.93 (1 H, d, J = 9 Hz, H-
1B), 2.36 (3 H, s, Ar-CH3), 2.00–1.40 (4 H, m, H-4, H-5), 1.29 (3 H,
s, H-9), 1.20 (3 H, s, H-7), 1.19 (3 H, s, H-8).
15 (16 mg, 0.06 mmol) was dissolved in KOH–MeOH (1 mL, 2%
solution) and stirred for 2 h at r.t. After that time, the solvent was
evaporated, the residue dissolved in H2O and extracted with EtOAc
(3 50 mL). The organic layer was washed with 10% HCl (2 20
mL), 5% NaHCO3 (2 20 mL) and brine (2 20 mL) and finally
dried over Na2SO4. Removal of the solvent under reduced pressure
gave a crude oil that was purified by chromatography on silica gel
(Et2O–hexanes, 1:1) to give the tetrahydrofuran 19 (7.5 mg, 72%).
Basic Hydrolysis of 21
Tosyl derivative 21 (18 mg, 0.04 mmol) was dissolved in anhyd
MeOH (1 mL) and K2CO3 (40 mg) was added. The reaction mixture
was stirred at r.t. for 1 h, extracted with EtOAc (3 50 mL) and fi-
nally dried over Na2SO4. Removal of the solvent under reduced
pressure gave a crude oil that was purified by chromatography on
silica gel with Et2O–hexanes, (1:9) as eluent to give the epoxide 3d
(3 mg, 27%) and tetrahydrofuran 15 (5 mg, 45%). It is important to
note that if the reaction is left to conclusion (3 h), only 15 is isolated
(70%).
Mp = 53–55 °C (recrystallized from EtOAc–hexanes).
20
[ ]D +12.80 (c 1.30, CHCl3).
IR (neat): 3400, 2970–2870, 1460, 1360, 1140, 1050, 935, 890
cm–1.
1H NMR (200 MHz, CDCl3): = 3.96 (1 H, t, J = 6.6 Hz, H-5), 3.71
(1 H, d, J = 11.3 Hz, HA-9), 3.37 (1 H, d, J = 11.3 Hz, HB-9), 2.00–
1.65 (4 H, m, H-3, H-4), 1.23 (3 H, s, H-6), 1.21 (3 H, s, H-7), 1.08
(3 H, s, H-10).
13C NMR (50 MHz, CDCl3): = 20.8, 27.0, 27.7, 28.7, 38.6, 67.6,
73.0, 81.2, 84.1.
MS (EI): m/z (%) = 174 (48) [M]+, 157 (72), 143 (25), 125 (15), 100
(2R,3S)-Benzoic Acid 3-Benzoiloxy-2,6-dihydroxy-2,6-dime-
thyl-heptyl Ester (22)
To a solution of 13 (6 mg, 0.02 mmol) in CH2Cl2 (1 mL) was added
BzCl (0.1 mL) and Et3N (0.2 mL). After 12 h the reaction was
quenched by the addition of 0.2 mL of 10% Na2CO3 and the mixture
was stirred for one additional hour. It was washed with aq solutions
of 10% HCl (2 15 mL), 10% Na2CO3 (2 15 mL), H2O (2 15
mL) and finally dried over Na2SO4. Removal of the solvent under
reduced pressure gave a crude oil that was purified by chromatog-
raphy on silica gel (Et2O–hexanes, 2:8) to give 22 (7 mg, 75%) as a
colorless oil.
(100), 82 (48), 76 (12), 70 (9), 57 (8).
HRMS–EI: (m/z) [M + H]+ calcd for C9H19O3, 175.1334; found,
175.1360.
Anal. Calcd for C9H18O3: C, 62.04; H, 10.41. Found: C, 62.49; H,
10.52.
20
[ ]D +20.60 (c 1.00, CHCl3).
IR (neat): 3503, 2972, 1717, 1452, 1271, 1111, 710 cm–1.
Benzoic Acid (2S,3S)-2-Acetoxymethyl-2,6,6-trimethyl-tetra-
hydropyran-3-yl Ester (20)
1H NMR (200 MHz, CDCl3): = 8.07–8.02 (4 H, m, Ar), 7.52–7.65
(2 H, m, Ar), 7.49–7.42 (4 H, m, Ar), 5.43 (1 H, dd, J = 9.7, 3.2 Hz,
H-3), 4.47 (1 H, d, J = 11.3 Hz, HA-1), 4.30 (1 H, d, J = 11.3 Hz,
HB-1), 2.60 (1 H, br s, OH), 2.00–1.41 (4 H, m, H-4, H-5), 1.37 (3
H, s, H-9), 1.20 (6 H, s, H-7, H-8).
13C NMR (50 MHz, CDCl3): = 21.0, 24.4, 29.1 (2 C), 39.9, 69.2,
70.5, 74.1, 78.0, 128.4, 129.7 (2 C), 133.1, 166.7.
Distilled Ac2O (0.5 mL) was added to a solution of 31 (12 mg, 0.04
mmol) in pyridine (1 mL). After 12 h the reaction was quenched
with ice, diluted in H2O (50 mL) and extracted with Et2O (3 50
mL). The organic layer was washed with aq solutions of 10% HCl
(2 20 mL), 5% NaHCO3 (2 20 mL), brine (2 20 mL) and final-
ly dried over Na2SO4. The solvent was evaporated under reduced
pressure to give a crude oil that was purified by chromatography on
silica gel (Et2O–hexanes, 5:95) to give 4d (11 mg, 85%).
Anal. Calcd for C23H29O6: C, 68.81; H, 7.28. Found: C, 68.78; H,
7.34.
IR (neat): 2974, 1740, 1723, 1452, 1371, 1277, 1113, 1045, 712
cm–1.
(2R,3S)-Benzoic Acid 3-Benzoiloxy-2,6-dihydroxy-2,6-dime-
thyl-heptyl Ester (22)
1H NMR (400 MHz, CDCl3): = 8.03 (2 H, m, Ar), 7.45 (2 H, m,
Ar), 7.41 (1 H, m, Ar), 5.04 (1 H, dd, J = 6.0, 3.2 Hz, H-3), 4.22 (1
H, d, J = 10.9 Hz, HA-10), 4.06 (1 H, d, J = 10.9 Hz, HB-10), 1.98
(3 H, s, CO2Me), 2.11–1.50 (4 H, m, H-4, H-5), 1.36 (1 H, s, H-9),
1.31 (3 H, s, H-7), 1.29 (3 H, s, H-8).
13C NMR (100 MHz, CDCl3): = 20.7, 21.5, 24.1, 29.2 (2 C), 32.2,
68.0, 71.6, 71.9, 73.9, 128.5, 129.6, 130.4, 133.0, 165.6, 170.6.
To a solution of 14 (15 mg, 0.05 mmol) in CH2Cl2 (1 mL) was added
BzCl (0.2 mL) and Et3N (0.2 mL). After 12 h the reaction was
quenched by the addition of 10% Na2CO3 (0.3 mL) and the mixture
was stirred for one additional hour. It was washed with aq solutions
of 10% HCl (2 15 mL), 10% Na2CO3 (2 15 mL), H2O (2 15
mL) and finally dried over Na2SO4. Removal of the solvent under
reduced pressure gave a crude oil that was purified by chromatog-
raphy on silica gel (Et2O–hexanes, 2:8) to give 22 (15 mg, 75%) as
a colorless oil.
Anal. Calcd for C18H24O5: C, 67.48; H, 7.55. Found: C, 67.50; H,
7.51.
Benzoic Acid (1S,1´S)-4-Hydroxy-1-[1´-hydroxy-1´-methyl-2´-
(toluene-4-sulfonyloxy)-ethyl]-4-methyl-pentyl Ester (21)
To a solution of 10 (14 mg, 0.05 mmol) in pyridine (0.5 mL) at 0 °C
was added TsCl (11 mg, 0.06mmol) and the mixture was stirred at
0–5 °C for 12 h. Ice (1 g) was added and the stirring continued for
Acidic Treatment of Compound 2c
Acetic Acid (2S,3S)-2,3,6-Trihydroxy-2,6-dimethyl-heptyl
Ester (8)
A solution of 2c (10 mg, 0.046 mmol) in CH2Cl2 (1 mL) at –40 °C
was treated with CSA (1.2 mg, 0.005 mmol). After 12 h Et3N (0.01
Synthesis 2002, No. 2, 175–184 ISSN 0039-7881 © Thieme Stuttgart · New York

184
D. Díez et al.
PAPER
mL) was added and the solvent evaporated. The residue was puri-
fied by column chromatography on silica gel (Et2O–hexanes, 3:7) to
give 8 (4 mg, 40%) as a colorless oil.
IR (neat): 3400, 2970, 1740, 1380, 1240, 1040 cm–1.
1H NMR (200 MHz, CDCl3): = 4.17 (1 H, d, J = 11.4 Hz, HA-1),
4.02 (1 H, d, J = 11.4 Hz, HB-1), 3.50 (1 H, m, H-3), 2.11 (3 H, s,
CO2Me), 1.83–1.40 (4 H, m), 1.25 (6 H, s, H-7, H-8), 1.18 (3 H, s,
H-9).
13C NMR (50 MHz, CDCl3): = 19.6, 20.7, 25.4, 29.2, 29.8, 40.2,
69.1, 70.7, 73.8, 74.6, 171.2.
Acknowledgements
The authors thank the CICYT and Junta de Castilla y León (SA13-
00B) for financial support and the Spanish Ministerio de Educación
y Ciencia for a doctoral fellowship to W. L.
References
(1) For reviews see: (a) Yasumoto, T.; Musata, M. Chem. Rev.
1993, 93, 1897. (b) Shimizu, Y. Chem. Rev. 1993, 93, 1685.
(c) Scheuer, P. J. Tetrahedron 1994, 50, 3.
(2) (a) Gruttadauria, M.; Aprile, C.; Serena Riela, S.; Noto, R.
Tetrahedron Lett. 2001, 42, 2213. (b) Vidari, G.; Di Rosa,
A.; Zanoni, G.; Bicchi, C. Tetrahedron Asymmetry 1999, 10,
3547.
HRMS–FAB: (m/z) [M + H]+ calcd for C11H23O5, 235.1546; found,
235.1540.
Reaction of 3c in Acidic Conditions
(3) For leading references see: (a) Gillaume, P.; Baylon, C.;
Heck, M. P.; Mioskowski, C. Tetrahedron Lett. 2000, 41,
3829. (b) Vidari, G.; Di Rosa, A.; Castronovo, F.; Zanoni, G.
Tetrahedron Asymmetry 2000, 11, 981. (c) Crotti, P.; Di
Bussolo, V.; Favero, L.; Pineschi, M.; Marianucci, F.; Renzi,
G.; Amici, G.; Roselli, G. Tetrahedron 2000, 56, 7513.
(d) Benedetti, F.; Berti, F.; Norberdo, S. Tetrahedron Lett.
1998, 39, 7971. (e) Nicolaou, K. C.; Prasad, C. V. C.;
Somers, P. K.; Hwang, C. K. J. Am. Chem. Soc. 1989, 111,
5335.
(4) (a) Mukai, C.; Ikeda, Y.; Hanaoku, M. Tetrahedron Lett.
1994, 35, 2179. (b) Suzuki, T.; Sato, O.; Hirama, M.
Tetrahedron Lett. 1990, 31, 4747.
(5) Garcia, C.; Soler, M. A.; Martin, V. S. Tetrahedron Lett.
2000, 41, 4127.
Acetic Acid (2R,3S)-2,3,6-Trihydroxy-2,6-dimethyl-heptyl
Ester (9)
A solution of 3c (14 mg, 0.064 mmol) in CH2Cl2 (1 mL)at –40 °C
was treated with CSA (1.5 mg, 0.006 mmol). After 6 h Et3N (0.01
mL) was added and the solvent evaporated. The residue was puri-
fied by column chromatography on silica gel (Et2O–hexanes, 3:7) to
give 9 (6 mg, 43%) as a colorless oil.
IR (neat): 3400, 2970, 1740, 1380, 1240, 1040 cm–1.
1H NMR (200 MHz, CDCl3): = 4.28 (1 H, d, J = 12.8 Hz, HA-1),
4.05 (1 H, d, J = 12.8 Hz, HB-1), 3.47 (1 H, d, J = 10.0 Hz, H-3),
2.13 (3 H, s, CO2Me), 1.26 (3 H, s, H-7 or H-8), 1.25 (3 H, s, H-7
or H-8), 1.20 (3 H, s, H-9).
13C NMR (50 MHz, CDCl3): = 20.3, 20.9, 25.4, 29.0, 30.1, 40.8,
68.5, 70.8, 73.8, 76.3, 171.5.
(6) For leading references see: (a) Chautemps, P.; Pierre, J. L.
Tetrahedron 1976, 32, 549. (b) Rossiter, B. E.; Verhoeven,
T. R.; Sharpless, K. B. Tetrahedron Lett. 1979, 4733.
(7) Díez Martin, D.; Marcos, I. S.; Basabe, P.; Romero, R. E.;
Moro, R.; Lumeras, W.; Rodríguez, L.; Urones, J. G.
Synthesis 2001, 1013.
HRMS–FAB: (m/z) [M + H]+ calcd for C11H23O5, 235.1546; found,
235.1550.
(8) Díez Martin, D.; Moro, R. F.; Lumeras, W.; Rodríguez, L.;
Marcos, I.; Basabe, P.; Romero, R. E.; Urones, J. G. Synlett
2001, 1332.
Synthesis 2002, No. 2, 175–184 ISSN 0039-7881 © Thieme Stuttgart · New York