Desymmetrization of cyclohexa-1,4-dienes - A straightforward route to cyclic and acyclic polyhydroxylated systems

Article abstract of DOI:10.1002/1099-0690(200212)2002:23<4037::AID-EJOC4037>3.0.CO;2-3

A straightforward route to polyols, amino polyols, polysubstituted lactols and lactones from readily available arenes has been devised. It uses a three- or four-step sequence involving a Birch reduction of the arene, followed by desymmetrization through d

Full text of DOI:10.1002/1099-0690(200212)2002:23<4037::AID-EJOC4037>3.0.CO;2-3

FULL PAPER
Desymmetrization of Cyclohexa-1,4-dienes ؊ A Straightforward Route to
Cyclic and Acyclic Polyhydroxylated Systems
Yannick Landais*[a] and Elisabeth Zekri[a]
Keywords: Alkenes / Aminohydroxylation / Hydroxylation / Ozonolysis / Silicon
A straightforward route to polyols, amino polyols, polysubsti-
lysis workup conditions, cyclic or acylic synthons were ob-
tuted lactols and lactones from readily available arenes has tained in generally high overall yields and with excellent
been devised. It uses a three- or four-step sequence involving
a Birch reduction of the arene, followed by desymmetrization
through dihydroxylation or aminohydroxylation and, lastly,
levels of stereocontrol.
( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
ozonolysis of the remaining olefin. Depending on the ozono- 2002)
Introduction
pioneered by Woodward and Corey,[5] relies on the con-
formational preferences that exist in six-membered ring sys-
tems, allowing the construction of highly substituted rings
possessing several adjacent stereocenters in a highly ste-
reocontrolled manner. The ring opening can then be carried
out by mild and efficient processes such as ozonolysis[6] or
BaeyerϪVilliger rearrangement.[7] Organometallic pro-
cesses have also recently been used for the same purpose.[8]
We provide here a full account of our investigations into
the desymmetrization of cyclic dienes by various asymmet-
ric processes and the subsequent elaboration of the re-
sulting intermediates by ozonolysis.[9] These studies have
been carried out with cyclohexadienylsilanes and have been
extended to non-silylated analogs, thus offering access to a
wider range of useful synthons.
During the course of our ongoing efforts to develop
straightforward and stereocontrolled routes to useful syn-
thons from readily available organosilanes, we have recently
reported an efficient access to various types of cyclitols,
ranging from conduritols (3, Scheme 1) to carba-sugars and
carba-C-disaccharides.[1] The methodology is based on the
desymmetrization of simple and easily accessible cyclohexa-
1,4-dienes such as 1, through asymmetric Sharpless dihy-
droxylation and aminohydroxylation. The diastereoselective
and enantioselective dihydroxylation of a single double
bond thus offered an entry to homochiral allylic systems,
which could be functionalized further. The most remark-
able results were obtained with silylcyclohexa-2,5-dienes,
which upon desymmetrization afforded new optically active
allylsilanes. These could then be converted into an array of
useful polysubstituted cyclohexanes.[1] The second double
bond was functionalized by epoxidation or cyclopropan-
ation (route a, Scheme [2] It was then envisioned that cleav-
age of the double bond of 2 by ozonolysis (route b,
Scheme 1) might also provide ready access to acyclic syn-
thons such as 4, possessing several contiguous stereogenic
centers. Such an approach would also create useful addi-
tional functionalities (such as carbonyl or hydroxy groups),
permitting further elaboration of these intermediates. Al-
though acyclic stereocontrol[3] has been used as a method of
choice for the setting up of chains with adjacent stereogenic
centers of determined relative configurations, functionaliz-
ation and subsequent ring opening of cyclic precursors may
offer a very attractive alternative.[4] Such an approach, as
Scheme 1
Results and Discussion
Preparation of the Precursors
[a]
´
Laboratoire de Chimie Organique et Organometallique,
University Bordeaux-I,
The diene precursors (1, Scheme 1) were prepared by two
different and complementary routes. The first one relied on
the Birch reduction of the corresponding arenes 5.[10] In the
´
351 Cours de la Liberation, 33405 Talence Cedex, France
Fax: (internat.) ϩ 33-5/56846286
E-mail: y.landais@lcoo.u-bordeaux.fr
Eur. J. Org. Chem. 2002, 4037Ϫ4053  2002 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/02/1223Ϫ4037 $ 20.00ϩ.50/0
4037

Y. Landais, E. Zekri
FULL PAPER
second approach, silylated dienes were prepared by donor increases the rate of the reaction with certain sub-
metalation of cyclohexa-1,4-dienes, followed by silylation strates, a larger quantity of alcohol will then slow the reac-
with the appropriate chlorosilanes.[11] In our preliminary tion down, by decreasing the conductivity. Nevertheless, the
studies,[1a] Birch chemical reduction (Li, NH3) was success- results summarized in Table 1 demonstrate that the electro-
fully used to provide the desired dienes in good yields. The chemical Birch reduction can be a valuable tool, and it was
same method was employed with arenes 5aϪb and gave the found to be particularly attractive for sensitive substrates,
desired dienes 6aϪb in good yield.[1f] The use of these con- as shown by the clean reduction of siloxane 5e (Entry 9).
ditions with arylsilane 5c, however, provided the over-re- Moreover, we did not observe any desilylation,[12] which
duced products 7c and 8c, which could not be separated may occasionally occur under the basic conditions of the
from the desired diene 6c (Scheme 2). Moreover, the Birch Birch reduction. Finally, through the use of a tubular flow
reduction requires large quantities of NH3, a method un- cell, we were able to extend the method to a large-scale
suitable for laboratory scaling up (Table 1, Scheme 2). preparative reduction of 5f (Entry 13, conditions C).[14] Un-
Hence, an alternative method involving electrochemical re- der these conditions, up to 20 g of mesitylene 5f could be
duction was successfully developed on precursors 5aϪb[1f,12] reproducibly transformed into 6f in very high yield. Condi-
and then extended to other arenes (Scheme 2, Table 1). This tions C were very similar to conditions A and B described
reduction was carried out in an undivided cell equipped above, except that the electrolysis was carried out at a con-
with a sacrificial aluminum anode[13] and a stainless steel stant current of 1 A and that Me3SiCl was added to the
grid cathode. The reactions were performed by means of an medium to remove residual water originating from the tech-
intensiostatic method (0.1 A in small cells) in a THF/ nical grade solvents used in the pilot scale cell.
HMPA mixture (8:2) and with anhydrous LiCl as sup-
porting electrolyte. Under such conditions, HMPA-solvated
electrons reduced the arenes, while tBuOH Ϫ which is not
reduced at this potential Ϫ acted as a proton donor. It is
interesting to notice that, as the reaction proceeds, the
amount of aluminum salts increases, thus improving the
conductivity of the medium. The amount of LiCl necessary
(4 equiv.) was therefore limited, the aluminum salts working
as co-supporting electrolytes. After extensive experimental
studies, conditions A were found to be the most appropriate
for the reduction of arylsilanes (Entries 1 and 3, Table 1),
while conditions B were found to be the best for non-silyl-
ated arenes (Entries 12Ϫ14, Table 1). The regioselectivity of
Scheme 2
the reaction was excellent, only cyclohexa-1,4-dienes being
observed. As summarized in Table 1 (Scheme 2), the desired
dienes were obtained under the appropriate conditions in
high yields and with no over-reduction products, in all cases
except for that of 5c. It is interesting to note that for the
non-silylated arenes 5fϪg (Entries 12 and 14) or the alkyl-
substituted arylsilanes (5d, Entry 8), a larger amount of
tBuOH had to be employed (conditions B). For 5fϪg this
may be explained by the absence of the silyl group, known
to activate the arene towards reduction.[10a] The first step
of a Birch reduction involves the formation of a radical an-
ion, which exists in equilibrium with the arene. The reduc-
tion then evolves with the protonation of the radical anion
either by the solvent (NH3) or by a proton source (tBuOH),
forming a new radical that is further reduced. The rate of
the Birch reduction depends on this first step and thus on
Table 1. Electrochemical Birch reduction of arenes 5aϪg (Scheme
2)
Entry Precursor Product Cond.[a] Ratio (%)[b] Yield (%)[c]
5/6/7/8
1
2
3
4
5
6
7
8
9
5a
5a
5b
5b
5c
5c
5d
5d
5e
5f
6a
6a
6b
6b
6c
6c
6d
6d
6e
6f
A
B
A
B
A
D
A
B
B
A
B
C
B
0:100:0:0
5:30:50:15
0:100:0:0
0:70:0:30
1:85:2:12
2:85:5:8
50:50:0:0
0:100:0:0
0:100:0:0
50:50:0:0
0:100:0:0
0:100:0:0
0:100:0:0
90
25
87
60
50
30
50
75
99
45
98
94
80
the concentration of the radical anion. With alkyl substitu- 11
12
5f
6f
ents, which are electron-donating groups, the concentration
13
5f
5g
6f
6g
of radical anion must be less important and therefore the
14
equilibrium probably lies to the left (towards the arene). A
larger amount of protonating agent in the medium is thus
required in order to shift the equilibrium. On the other
hand, with arylsilanes such as 5aϪb, in which the radical
anion is stabilized by the silyl group, the addition of a larger
amount of tBuOH results in the formation of over-reduc-
[a]
Conditions A: tBuOH (4 equiv.), I ϭ 0.1 A; conditions B:
tBuOH (22 equiv.), I ϭ 0.1 A; conditions C: tubular flow cell, THF/
HMPA (8:2), LiCl (4 equiv.), tBuOH (22 equiv.), I ϭ 1 A; condi-
tions D: tBuOH (3 equiv.), I ϭ 0.1 A. [b] Estimated from 1H NMR
[c]
(250 MHz) and GC analysis of the crude reaction mixture. Isol-
ated yields of dienes 6 after purification through column chromato-
tion products (Entries 2 and 4). If the quantity of proton graphy.
4038
Eur. J. Org. Chem. 2002, 4037Ϫ4053

Desymmetrization of Cyclohexa-1,4-dienes
FULL PAPER
As shown in Table 1, arylsilane 5c gave varying amounts 19F NMR investigation of the corresponding Mosher’s es-
of over-reduced products whatever the conditions used ter. The structure of 11 is attractive, as ozonolysis of the
(Entries 5Ϫ6). Monitoring of the progress of the reaction double bond should provide a polypropionate fragment
by GC showed that over-reduced products 7c and 8c were with three contiguous stereocenters. However, although the
formed simultaneously with the diene 6c, indicating that regio- and the diastereocontrol were high, the poor yield
they probably have very similar reduction potentials. Com- and enantioselectivity precluded the use of such an ap-
pound 6c was therefore more conveniently prepared by proach for the preparation of homochiral synthons.
metalation of cyclohexa-2,4-diene 9 with sBuLi and silyl-
ation of the resulting carbanion with iPr3SiCl
(Scheme 3).[11] This simple procedure also worked well for
other silanes such as 5aϪb, but is not applicable to polysub-
stituted arenes such as 6f. The two methods developed in
these studies are thus complementary, and offer a rapid
entry to cyclohexa-2,4-dienes.
Scheme 5
We thus turned our attention towards Sharpless asym-
metric dihydroxylation, which was found to be more prom-
ising in terms both of yield and of stereoselectivity.[1,22] As
summarized in Table 2, yields and stereoselectivities largely
Scheme 3
depend on the nature of the ligands used during the dihy-
droxylation. When we compared the behavior of silylated
Desymmetrization of Precursors 6a؊g
and non-silylated dienes 6aϪe and 6fϪg, respectively, we
noticed, as before, that the silyl group controlled the dias-
tereofacial selectivity more efficiently than a methyl group
did[1a,1f] (compare Entries 1Ϫ10 and 13Ϫ17, Table 2, see
also Scheme 6), the osmium reagent approaching in an anti
fashion in both cases.[23] This is not too surprising in view
of the steric hindrance and the electronic effect of the silyl
group. The best enantioselectivities for silyldienes 6cϪe
(Entries 4, 6 and 12) were obtained with (DHQ)2PYR,
known to be the best ligand for the dihydroxylation of (Z)-
and cyclic dienes,[22a] in good agreement with our own re-
sults reported earlier with analogs 6aϪb (Entries 1Ϫ2).[1]
It is noteworthy that precursor 6c, bearing the large triiso-
propylsilyl (TIPS) group, behaves quite differently from its
analogs. Large amounts of meso-tetrol (vide infra), isolated
as the acetonide 13b, were formed upon bis(dihydroxylation)
(Scheme 7). This had been observed earlier with 6b, but not
to such an extent. A 6:4 ratio of 12c/tetrol was observed with
quinuclidine as a ligand (Entry 3), while an 8:2 ratio was
obtained with (DHQ)2PYR (Entry 4). The large amount of
tetrol formed in this case may be attributed both to the size
of the TIPS group and, more importantly, to its lipophilicity
relative to the analogs 6aϪb. This would then imply that the
smaller amounts detected with the analogs 6aϪb were due
to the polar nature of the tetrol, which may remain in the
aqueous layer after workup. Although this has not been
Our preliminary investigations into the desymmetrization
of dienes 6aϪg were carried out by hydroboration and
epoxidation. The former process has been used with success
in the past in the desymmetrization of cyclopentadienes and
cyclohexa-2,4-dienes,[15] while the latter has never been in-
vestigated in enantiopure series.[16] Epoxidation of 6f was
first performed in racemic series with reagents such as
mCPBA, oxone/CH3COCF3 or oxone/acetone. None of
these methods were able to provide the desired monoepox-
ide but mainly caused aromatization of the diene. Similarly,
attempted asymmetric epoxidation under the chiral oxirane
conditions recently reported by Shi[17] resulted in aromatiz-
ation and no trace of monoepoxide. We were finally able to
isolate the bis(epoxide) 10 as a single diastereomer with the
relative configuration as shown (Scheme 4), albeit in low
yield, by the use of an oxirane produced in situ from the
mixture oxone/CH3COCF3.[18,19]
Scheme 4
In view of the poor results obtained with epoxidations, firmly established, the presence of the tetrol could be indic-
we next turned our attention to asymmetric hydroboration. ative of a kinetic amplification effect.[24] It is also interesting
1
Our preliminary investigations were carried out with pre- to notice that according to H NMR studies, the tetrol pos-
cursors 6d and 6f and Brown’s dilongifoleneborane[20] and sesses a meso configuration, indicating that the second dihy-
diisopinocampheylboranes.[15c] While 6d either was reco- droxylation again occurred anti relative to the silyl group.
vered unchanged or simply decomposed under the hydro-
During dihydroxylation of non-silylated dienes, it was
boration conditions, diene 6f was converted into an alcohol, found that the nature of the ligands had a profound effect
the structure and relative configuration of which were tent- not only on the enantioselectivity but also on the diastereo-
atively assigned as 11 from 1H NMR studies (Scheme 5).[21] selectivity of the process. The best results in terms of dias-
An enantiomeric excess of 20% was finally determined by tereofacial selectivity were obtained with achiral quinuclid-
Eur. J. Org. Chem. 2002, 4037Ϫ4053
4039

Y. Landais, E. Zekri
FULL PAPER
Table 2. Asymmetric dihydroxylation of dienes 6aϪf (Scheme 6)
Entry
Precursor
Diols
Ligand
Conditions
de (%)[a]
eemaj. (%)
eemin. (%)
Configuration[b]
Yield (%)[c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
6a
6b
6c
6c
6d
6d
6d
6d
6d
6d
6e
6e
6f
12a
12b
12c
12c
12d
12d
12d
12d
12d
12d
12e
12e
12f
12f
12f
12f
12f
12f
12g
(DHQ)2PYR
(DHQ)2PYR
quinuclidine
(DHQ)2PYR
quinuclidine
(DHQ)2PYR
(DHQ)2PHAL
(DHQD)2PHAL
(DHQ)2AQN
(DHQD)2AQN
quinuclidine
0 °C, 12 h
0 °C, 12 h
2 °C, 4 h
Ͼ 98
Ͼ 98
Ͼ 98
Ͼ 98
Ͼ 98
Ͼ 98
Ͼ 98
Ͼ 98
؊
60[d]
71[b]
Ϫ
Ϫ
؊
؊
؊
؊
؊
؊
؊
؊
؊
؊
؊
؊
؊
50[g]
18[g]
32[g]
؊
(1S,2S,3S)
(1S,2S,3S)
Ϫ
(1S,2S,3S)
Ϫ
(1S,2S,3S)
(1S,2S,3S)
(1R,2R,3R)
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
85[1f]
80[1f]
65[e]
75[e]
84
84
73
87
0
2 °C, 4 h
40[d]
Ϫ
2 °C, 48 h
2 °C, 72 h
0 °C, 96 h
0 °C, 72 h
0 °C, 96 h
0 °C, 96 h
2 °C, 12 h
2 °C, 12 h
10 °C, 8 h
r.t., 96 h
10 °C, 16 h
10 °C, 14 h
10 °C, 24 h
0 °C, 96 h
0 °C, 72 h
47[d]
5[d]
27[d]
Ϫ
Ϫ
Ϫ
53[d]
Ϫ
؊
0
57
Ͼ 98
Ͼ 98
88
(DHQ)2PYR
quinuclidine
70
36[f]
0
6f
(DHQ)2PYR
(DHQ)2PHAL
(DHQD)2PHAL
(DHQ)2AQN
(DHQD)2AQN
quinuclidine
؊
Ϫ
6f
60
40
60[g]
70[g]
30[g]
؊
(1R,2S,3R)
(1S,2R,3S)
(1R,2S,3R)
Ϫ
52
55
40
0
6f
6f
70
6f
؊
6g
؊
؊
؊
Ϫ
61
[a]
1
[b]
[c]
Estimated from the H NMR spectrum (250 MHz) of the crude reaction mixture.
See text. Isolated yields after purification by
column chromatography. Estimated from the H and 19F NMR (250 MHz) spectra of the corresponding Mosher’s esters. Estimated
yield of the diol in the diol/tetrol mixture. [f] Isolated yield of major diastereomer after recrystallization. [g] Determined by HPLC analysis
on a Chiralcel OD column (hexane/iPrOH, see Exp. Sect. for details).
[d]
1
[e]
dienes. This may be explained by invoking a poor fitting of
the substrate in the pocket formed by the complex osmium
ligands.[1f] Finally, though, we were pleased to observe that
dihydroxylation of 6f with (DHQ)2PHAL gave a good com-
promise, 12f being obtained in reasonable yield with 60%
de and 60% ee for both diastereomers (Entry 15).
The absolute configurations of diols 12cϪe obtained with
(DHQ)2PYR as a ligand were assumed to be the same as
those of the diols 12aϪb, previously determined unambigu-
ously through chemical correlations.[1a,1c,1f] For non-silyl-
ated analogs 12fϪg, assumption of the absolute configura-
tions was made by use of the Sharpless mnemonic device[22]
(quadrant method, Figure 1), and these were found to be in
good agreement with results obtained from dihydroxylation
on related dienes.[25]
Scheme 6
Scheme 7
ine. The major isomer 12f was thus obtained with 88% de
(Entry 13) and in 36% yield after crystallization. A good
enantioselectivity but a poor diastereoselectivity in favor of
the major isomer 12f was obtained with commercially avail-
able (DHQD)2PHAL (Entry 16). Moreover, the minor iso-
mer was obtained with a rather poor enantioselectivity
(18% ee). Better diastereocontrol was observed with
(DHQ)2AQN, but the enantioselectivities for both isomers
were low (Entry 17). It was noteworthy that the diastereom-
Figure 1. Quadrant method for rationalization of asymmetric dihy-
droxylation (AD) enantiofacial selectivity
Such encouraging results obtained during the dihy-
eric ligand (DHQD)2AQN gave no reaction either with 6f droxylation of precursors 6cϪg prompted us to investigate
(Entry 18) or with 6d (Entry 9), indicating that a minor the analogous aminohydroxylation, which would give rise
change in the nature of the ligand had an important effect to useful amino alcohol intermediates for organic syn-
on the rate of the reaction. The same holds for the ligand thesis.[26] As summarized in Table 3 (Scheme 8), the influ-
(DHQ)2PYR, which was very efficient for silylation of di- ence of various parameters such as the nature of the li-
enes 6aϪe but did not give any reaction with non-silylated gands, the amino group and the solvents were studied. The
4040
Eur. J. Org. Chem. 2002, 4037Ϫ4053

Desymmetrization of Cyclohexa-1,4-dienes
FULL PAPER
best results were obtained with mesyl- and tosyl-protected limits the turnover rate of the reaction.[22a,26,27] The moder-
amino groups, acetyl protection providing only dihy- ate corrected yields are due to the sensitivity of diene 6c
droxylation
products.[26e]
The
carbamate
group towards the silica gel used for purification, since the crude
(NHCO2Et), used successfully in our previous studies,[1b,1f] yield was generally high and no byproducts were detected
was not a good candidate in this context, due to the lability during the reaction.
of this amino protecting group under the reductive ozono-
lysis conditions (vide infra). It is noteworthy that the mesyl
and tosyl groups were introduced with the aid of the easily
handled chloramine-M (MsNClNa) and chloramine-T
(TsNClNa). The latter reagent is commercially available
and does not require the chlorination of the amino group
prior to the aminohydroxylation process. Aminohydroxyl-
ation of 6a thus afforded the amino alcohol 14a as an insep-
Scheme 8
arable mixture of two regioisomers, 14aa and 14ab, in low
yield but with complete diastereocontrol (Entry 1, Table 3).
A similar trend was observed with the TIPS analogs 6c
(Entry 2). Better results were obtained with cyclohexa-1,4-
diene 9, which gave the desired amino alcohol 14c in reas-
onable yield and with 36% ee (Entry 3). When we turned
our attention towards sterically more demanding amino
groups such as tosylamine, we were pleased to find that
even better enantioselectivity could be attained (Entry 4).
Although the yields were moderate, complete regio- and di-
astereocontrol was also observed with precursor 6c, with
chloramine-T as a source of amine and oxidizing agent
(Entries 5Ϫ9). It is noteworthy that the enantioselectivity
varies according to the nature of the solvent. With the
chiral ligand (DHQ)2PYR, for instance, the amino alcohol
14e was obtained with a 20% ee in CH3CN/H2O (Entry 5)
but with 54% ee and a better yield in nPrOH/H2O (Entry
7). This probably reflects the lipophilicity of 6c and its low
solubility in acetonitrile and water. Better solubility of the
diene is observed in alcoholic media, explaining the better
results in these solvents. However, the degree of conversion
of the starting diene is generally low, due to slow turnover
The structure of the major regioisomer 14e was deter-
mined by 1H NMR experiments (COSY), which unambigu-
ously showed that the aminohydroxylation of 6c gave the
regioisomer with the most hindered substituent close to the
silyl group, in good agreement with previous observations
on closely related analogs.[1b,1f] The origin of the regioselec-
tivity was explained in terms of specific coordination of the
diene inside the U-shaped binding pocket provided by the
(DHQ)2PYRϪosmium complex, preceding the [3ϩ2] addi-
tion process involved in asymmetric aminohydroxylation
(AA) and AD reactions.[1f,28] Finally, with reference to earl-
ier studies,[1f] the absolute configuration of 14e was as-
sumed to be the same as that of diols 12aϪe, obtained by
use of the same chiral ligand [i.e., (1S,2S,3S) when
(DHQ)2PYR was used].
Functionalization of Diols and Amino Alcohols by
Ozonolysis
As mentioned above, functionalization of allylsilanes
rates.[26] Further addition of osmium salt and ligand to the 12aϪe and 14aϪe can be carried out in a number of ways.
reaction mixture was shown to improve the level of conver- We have shown previously that epoxidation, dihy-
sion slightly. The high lipophilicity of diene 6c probably re- droxylation and cyclopropanation can afford useful inter-
tards the hydrolysis of the osmium azaglycolate and thus mediates for organic synthesis.[1] It was anticipated that ox-
Table 3. Asymmetric aminohydroxylation of dienes 6 and 9 (Scheme 8)
Entry Precursor Product
Conditions[a] Ligand
R in NHR group Regioselectivity (%)[b] de (%)[c] eemaj. (%)[d] Yield (%)
1
2
3
4
5
6
7
8
9
6a
6c
9
14aa ϩ 14ab A
14ba ϩ 14bb A
(DHQ)2PYR Ms
(DHQ)2PYR Ms
(DHQ)2PHAL Ms
(DHQ)2PHAL Ts
(DHQ)2PYR Ts
(DHQD)2PYR Ts
(DHQ)2PYR Ts
(DHQ)2PYR Ts
(DHQ)2PHAL Ts
50:50
66:33
Ϫ
Ͼ 98
Ͼ 98
Ϫ
23
15
36
66
20
60
54
66
28
28
10
57
46
30
46
14c
14d
14e
14e
14e
14e
14e
A
B
B
C
C
D
D
9
Ϫ
Ϫ
6c
6c
6c
6c
6c
Ͼ 98
Ͼ 98
Ͼ 98
Ͼ 98
Ͼ 98
Ͼ 98
Ͼ 98
Ͼ 98
Ͼ 98
Ͼ 98
52
30[e]
24[e]
[a]
Conditions A: MsNClNa (3 equiv.); K2OsO4·2H2O (0.04 equiv.), nPrOH/H2O (1:1), ligand (0.05 equiv.); conditions B: TsNClNa (3
equiv.); K2OsO4·2H2O (0.04 equiv.), CH3CN/H2O (1:1), ligand (0.05 equiv.); conditions C: TsNClNa (3 equiv.); K2OsO4·2H2O (0.04
equiv.), nPrOH/H2O (1:1), ligand (0.05 equiv.); conditions D: TsNClNa (3 equiv.); K2OsO4·2H2O (0.04 equiv.), tBuOH/H2O (1:1), ligand
[b]
[c]
[d]
(0.05 equiv.).
As measured after purification of the regioisomers.
Estimated by 1H NMR (250 MHz).
Determined by HPLC
analysis on a Chiralcel OD column (hexane/iPrOH, 9:1). Corrected yield after purification by chromatography and recovery of the
[e]
starting diene.
Eur. J. Org. Chem. 2002, 4037Ϫ4053
4041

Y. Landais, E. Zekri
FULL PAPER
idative cleavage (i.e., ozonolysis or BaeyerϪVilliger reac-
tion) of the remaining double bond of 12aϪg and 14aϪe
should ideally give rise to intermediates possessing useful
functionalities that could be functionalized further. In view
of the sensitivity of our diols 12aϪe and amino alcohols
14a and 14e towards desilylation, it was expected that
ozonolysis of the remaining double bond should be the
mildest process with which to open our cyclic systems.
Careful control of the workup conditions after ozonolysis
should also ensure the introduction of functionalities such
as diols or lactols.[6bϪ6g]
The first attempts were made on the diacetate of 12b.
Unfortunately, ozonolysis in CH2Cl2/MeOH with sub-
sequent reduction of the ozonide resulted only in decom-
position of the diacetate. In order to establish whether the
dialdehyde (i.e., α-silyl aldehyde) was effectively formed
upon ozonolysis workup, a second attempt was made with
the more robust acetonide 15 and, immediately after the
workup, an excess of a vinyl Grignard reagent was added
at low temperature to the intermediate (Scheme 9). This re-
sulted in the formation, albeit in low yield, of 16 as a mix-
ture of stereoisomers, thus indicating that the dialdehyde
had been effectively formed but probably decomposed dur-
ing the workup due to the lability of the silyl group α to the
aldehyde function.[29]
Scheme 10
Scheme 9
It was thus decided that the reduction of the ozonide
Interestingly, the result of the ozonolysis process could
should be followed by complete reduction of the sensitive be modified by simply reducing the amount of NaBH4 ad-
dialdehyde into a diol.[6b,30] The acetonide 15 was subjected ded at the end of the reaction (conditions B). When only 1
to ozonolysis (conditions A), as above, followed by addition equiv. of NaBH4 was added to the ozonides generated from
of an excess of NaBH4, which afforded the diol 17a in excel- olefins 18aϪb, partial reduction occurred to afford the oxe-
lent yield (Scheme 10). Similarly, the inseparable mixture of pane lactols 20aϪb in moderate yield after chromatography
mono- and bis(acetonide) 13a and 13b (Scheme 7) provided (Scheme 11). This unexpected result is noteworthy and con-
the diol 17b in 30Ϫ34% overall yield from diene 6c. The stitutes a straightforward means to differentiate the two
steric hindrance induced by the TIPS group was deliberately ends of the amino polyol chains of 19aϪb. We have not
used to differentiate the two ends of the chain in 17b. For been able to establish the origin of the complete regioselec-
instance, treatment of 17b in the presence of MsCl and tivity of this process firmly, although it appears to be
pTsCl selectively afforded mesylate 17c and tosylate 17d, mainly steric, the less hindered end of the system (away
respectively. It is noteworthy that the same reactions per- from the TIPS group) being attacked by the reducing
formed on the analog 17a gave mixtures of mono- and di- agent first.
protected tosylates and mesylates, demonstrating the
The above results encouraged us to apply our methodo-
unique properties of the TIPS group as compared with the logy to the synthesis of simple polypropionate fragments,
less hindered silyl groups. Finally, the aminohydroxylation the goal being that the stereochemistry of such synthons
products 14dϪe were submitted to the same conditions (A) would be installed by dihydroxylation of suitable pre-
after TIPS protection of their alcohol functions. The de- cursors. Dienes such as 6d and 6f, containing resident
sired amino polyols 19aϪb were thus obtained in moderate methyl groups present in the polypropionate targets, were
to good yields from 18aϪb (Scheme 10).
thought to constitute suitable candidates.[6cϪ6e] The qua-
4042
Eur. J. Org. Chem. 2002, 4037Ϫ4053

Desymmetrization of Cyclohexa-1,4-dienes
FULL PAPER
produced the desired lactols 24aϪc, in each case as a 6:4
mixture of diastereomers. It is interesting to note that when
ozonolysis of 23aϪb was followed by treatment with Me2S
between 0 °C and room temperature (conditions D), acetals
25aϪb were formed instead of lactols 24aϪb. Acetal 25a
was obtained as a single diastereomer, the stereochemistry
of which at the lactol center was not determined. Lactols
24aϪc were oxidized with PCC on alumina[33] to afford the
corresponding lactones 26aϪc in 64% and 44% overall yield
from mesitylene 12f and 26% overall yield from 12g, re-
spectively. NOE experiments carried out on lactone 26a un-
ambiguously established the relative configurations of the
lactones as well as those of the cyclohexene precursors
12fϪg.
Scheme 11
ternary OH group would then be removed by
BartonϪMcCombie deoxygenation[31] starting from thi-
ocarbonate intermediates (Scheme 12). It was anticipated
that a tertiary radical could then be formed and trapped
stereoselectively by use of a tin hydride. Compounds 12d
and 12f were thus converted into the desired cyclic thiocar-
bonates 21aϪb in excellent yields and submitted to
BartonϪMcCombie conditions.[31,32] Unfortunately, the si-
lylated precursor 21a gave degradation products under
these conditions, while 21b was recovered unchanged. Inter-
estingly, a similar attempt with thiocarbonate 22, prepared
in 98% yield from 12f, gave the carbonate 21b through nu-
cleophilic displacement of the thiocarbonyl group.
Scheme 13
We have thus shown that highly functionalized five-mem-
bered ring lactones possessing three contiguous stereogenic
centers could be prepared in high overall yield from inex-
pensive arenes. It is noteworthy that this approach also al-
lowed the creation of an otherwise difficult to install qua-
ternary stereogenic center. It was then envisioned that a
Scheme 12
Having established the viability of our strategy of trans- similar strategy could be applied to the silylated analogs.[34]
formation of dienes into acyclic polyols and amino polyols, In view of the poor stability of α-silyl aldehydes obtained
we then focused our attention towards the formation of re- from precursors such as 15,[29] the sterically more hindered
lated cyclic systems such as lactols and lactones. It was envi- TIPS analog 12c was deemed to constitute a more suitable
sioned that a partial reduction of the dialdehyde interme- candidate for our purposes. The unique steric hindrance
diate should offer a rapid route to five-membered ring lac- provided by the TIPS group in 12c was used to protect se-
tones,[6b] one of the resident hydroxy groups preventing lectively the hydroxy group on the position remote from the
complete reduction through the formation of a hemiacetal. silyl group. The monobenzyl ether 27, obtained in moderate
This was first tested on diols 12fϪg, which were protected yield, was then subjected to ozonolysis (conditions C), pro-
either as monoacetates 23a and 23c or as benzyl ether 23b viding the α-silyl aldehyde 28 in 60% yield as a single dia-
before being subjected to ozonolysis (Scheme 13). Reduc- stereomer after treatment with Me2S (Scheme 14). Surpris-
tion of the ozonide with Me2S at 0 °C (conditions C) then ingly, 28 was found to be remarkably stable and could be
Eur. J. Org. Chem. 2002, 4037Ϫ4053
4043

Y. Landais, E. Zekri
FULL PAPER
THF (70 mL), HMPA (18 mL), tBuOH (2.16 mL, 26 mmol) and
trimethylphenylsilane (5a, 1 g, 6.5 mmol) were introduced under ni-
trogen into a one-compartment cell, fitted with a sacrificial anode
of aluminum and a cylindrical stainless grid, and containing LiCl
(0.86 g, 20.6 mmol) as supporting electrolyte. Electrolysis (constant
current 0.1 A) was then initiated and maintained for 5 h. Stirring
was then continued for 3 h until the starting material had disap-
peared (monitored by GC). The mixture was then diluted with
pentane (80 mL) and treated dropwise at Ϫ78 °C with a 10% solu-
tion of HCl (100 mL). The organic layer was decanted. The aque-
ous layer was extracted with diethyl ether (3 ϫ 10 mL), and the
combined extracts were washed with HCl (10%, 5 ϫ 100 mL), and
then with a saturated solution of NaHCO3 (3 ϫ 50 mL) and with
brine (2 ϫ 30 mL). The solution was dried with MgSO4 and the
solvents were removed in vacuo to afford 6a as a colorless oil
(0.88 g, 90%), used in the next step without further purification.
Spectroscopic data for 6a were consistent with those described in
the literature.[1f,12]
purified by chromatography on silica gel. α-Silyl aldehydes
are valuable intermediates for organic synthesis and can be
elaborated further in a stereocontrolled manner into allylsil-
anes by means of Wittig reactions[35a] or into β-hydroxysil-
anes[35b] through addition of organometallic reagents.
Moreover, the lactol function may also serve for the intro-
duction of an additional chain at C-5, which should give
rise to useful intermediates for the synthesis of ubiquitous
naturally occurring 2,4,5-trisubstituted tetrahydrofurans.
Scheme 14
Metalation of Cyclohexa-1,4-diene 9. (Cyclohexa-2,5-dienyl)triiso-
propylsilane (6c): A solution of sBuLi in hexane (1.6 , 6.2 mL,
10 mmol) and TMEDA (1.5 mL, 10 mmol) were added dropwise at
Ϫ78 °C to a solution of cyclohexa-1,4-diene (0.94 mL, 10 mmol)
in anhydrous THF (15 mL). The pale yellow solution was stirred
for 3 h at Ϫ45 °C, and treated with a solution of chlorotriisopropyl-
silane (2.16 mL, 10 mmol) in THF (4 mL). After 0.5 h at Ϫ45 °C,
the mixture was allowed to warm to room temp. and quenched
with a saturated solution of NH4Cl (20 mL). The organic layer was
decanted and the aqueous layer was extracted with diethyl ether (3
ϫ 20 mL). The combined extracts were washed with brine (2 ϫ
20 mL) and dried with MgSO4, and the solvent was removed in
vacuo. Chromatography on silica gel (cyclohexane) afforded 6c as
white crystals (2.22 g, 93%), which were recrystallized from cyclo-
hexane; m.p. 37 °C. IR (film, KBr): ν˜max ϭ 2935 cmϪ1, 2873, 1625
(CϭC), 1546, 1501, 1380, 1251, 1100, 830, 818, 702. 1H NMR
(CDCl3): δ ϭ 5.84Ϫ5.78 (m, 2 H, CHϭCH), 5.75Ϫ5.52 (m, 2 H,
CHϭCH), 2.83Ϫ2.69 (m, 3 H, CHSi, CH2), 1.18 [sept, J ϭ 7.1 Hz,
3 H, HC(CH3)2], 1.15 [br. s, 18 H, HC(CH3)2] ppm. 13C NMR
(CDCl3): δ ϭ 127.98 (CHϭCH), 122.02 (CHϭCH), 27.48 (CHSi),
27.10 (CH2), 19.72 [HC(CH3)2], 18.54 [HC(CH3)2], 13.35
[HC(CH3)2], 12.26 [HC(CH3)2] ppm. C15H28Si (236.47): calcd. C
76.19, H 11.93, Si 11.88; found C 75.53, H 12.33, Si 12.14 ppm.
Conclusion
We have reported here on a straightforward route to po-
lyols, amino polyols, polysubstituted lactols and lactones, in
four steps starting from readily available arenes. The meth-
odology relies on a sequence of three key steps: Birch reduc-
tion of the arene, followed by desymmetrization through
dihydroxylation or aminohydroxylation, and final ozono-
lysis of the remaining double bond. Depending on the
ozonolysis workup conditions, cyclic or acylic synthons
were obtained in generally high overall yield. This strategy
represents an attractive alternative to acyclic stereocontrol
and should find interesting applications in total synthesis
of natural compounds.
Experimental Section
General Remarks: 1H and 13C NMR spectra were recorded with
Bruker AC 250 (1H: 250 MHz, 13C: 83 MHz), Bruker AC 200 (1H:
200 MHz, 13C: 67 MHz) and Bruker DPX 200 instruments, with
CDCl3 as internal reference unless otherwise indicated. The chem-
ical shifts (δ) and coupling constants (J) are expressed in ppm and
Hz, respectively. IR spectra were recorded with a PerkinϪElmer
Paragon 1000 FT-IR spectrophotometer. High- and low-resolution
mass spectra were recorded with a Micromass autospec-Q mass
spectrophotometer (EI, 70 eV, LSIMS with a 3-nitrobenzyl alcohol
matrix). Elemental analyses were performed by the CNRS laborat-
ory at Vernaison (France). Melting points were not corrected and
determined by use of a Stuart Scientific apparatus (SMP3). Gas
chromatography was run with a Hewlett Packard Instruments,
48490 series equipped with an SPB-1 column. HPLC was per-
formed with a Waters 600 machine equipped with a 996 photodiode
array detector and a Chiralcel OD column. Kugelrohr distillations
were performed with a Büchi GKR-50 apparatus. Merck silica gel
60 (70Ϫ230 mesh) and (0.063Ϫ0.200 mm) were used for flash chro-
matography. CH2Cl2 and Et3N were distilled from CaH2. THF, di-
ethyl ether, hexane and DME were distilled from sodium/benzo-
phenone. Chlorosilanes were distilled from magnesium. tBuOH was
dried with CaO, and MeOH was distilled from magnesium.
General Procedure for the Preparation of Cyclohexa-2,5-dienes
6aϪg. Conditions B. (2,6-Dimethylcyclohexa-2,5-dienyl)trimethylsil-
ane (6d): Conditions B were identical to conditions A except for
the amount of tBuOH (22 equiv. instead of 4). Compound 5d (2 g,
11.2 mmol) was treated according to conditions B for 8 h, and af-
forded diene 6d (1.51 g, 75%), which was used in the next step with-
out further purification. IR (film, KBr): ν˜max ϭ 3019 cmϪ1, 2961,
1932, 1681 (CϭC), 1445, 1246, 1190, 1104, 1049, 1025, 836, 755,
1
693, 622. H NMR (CDCl3): δ ϭ 5.33 (m, 2 H, ϭCH), 2.57 (m, 2
H, CH2), 2.31 (s, 1 H, SiCH), 1.74 (m, 6 H, ϭCCH3), 0.06 [s, 9 H,
Si(CH3)3] ppm. 13C NMR (CDCl3): δ ϭ 136.02 (ϭCCH3), 116.79
(ϭCH), 42.28 (CH2), 28.17 (HCSi), 23.65 (ϭCCH3), Ϫ0.60
[Si(CH3)3] ppm.
(Cyclohexa-2,5-dienyl)isopropoxydimethylsilane (6e): On subjection
to conditions B, arylsilane 5e (1 g, 5.1 mmol), after 5 h, gave the
diene 6e (1 g, 99%) as a colorless oil, used in the next step without
further purification. IR (film, KBr): ν˜max ϭ 3025 cmϪ1, 2969, 2925,
2637, 2368, 1939, 1741, 1623 (CϭC), 1463, 1449, 1380, 1367, 1257,
1
1100, 1029, 938, 881, 798, 654. H NMR (CDCl3): δ ϭ 5.57Ϫ5.66
General Procedure for the Preparation of Cyclohexa-2,5-dienes
(m, 4 H, CHϭCH), 4.03 (sept, J ϭ 6.1 Hz, 1 H, OCH(CH3)2], 2.70
6aϪg. Conditions A. (Cyclohexa-2,5-dienyl)trimethylsilane (6a): (m, 2 H, CH2), 2.39 (m, 1 H, SiCH), 1.15 (d, J ϭ 6.1 Hz, 6 H,
4044 Eur. J. Org. Chem. 2002, 4037Ϫ4053

Desymmetrization of Cyclohexa-1,4-dienes
FULL PAPER
OCH(CH3)2], 0.13 [s, 3 H, Si(CH3)2], 0.06 [s, 3 H, Si(CH3)2] ppm. tion of diisopinocampheylborane[15c] (2.21 mmol) in THF (20 mL).
13C NMR (CDCl3): δ ϭ 123.5 (CHϭCH), 122.6 (CHϭCH), 67.12 The reaction mixture was stirred at 0 °C for 24 h and then oxidized
[HC(CH3)2], 31.80 (HCSi), 31.01 (CH2), 26.15 [HC(CH3)2], Ϫ2.19,
Ϫ2.22 [Si(CH3)] ppm.
by addition of distilled water (3 mL), an aqueous solution of
NaOH (3 , 2.3 mL, 6.9 mmol) and a solution of H2O2 (50%,
0.5 mL, 7.4 mmol). The organic layer was decanted and the aque-
ous layer was extracted with diethyl ether (3 ϫ 10 mL). The com-
bined extracts were washed with brine (10 mL) and dried with
MgSO4, and the solvents were removed in vacuo. The brown res-
idue (0.73 g) was purified by chromatography on silica gel (cyclo-
hexane/EtOAc, 80:20), to afford the crystalline alcohol of pinene
(0.5 g) and the alcohol 11 as a colorless oil (0.08 g, 23%, 20% ee as
estimated from 19F NMR of the corresponding Mosher’s ester). IR
(film, KBr): ν˜max ϭ 3608 cmϪ1, 3355, 2922, 2360, 1452, 1394, 1366,
2,4,6-Trimethylcyclohexa-1,4-diene (6f): On subjection to condi-
tions B, mesitylene (5f, 3 g, 25 mmol), after 53 h, gave the diene 6f
(3 g, 98%) as a colorless oil, used in the next step without further
purification. IR (film, KBr): ν˜max ϭ 3922 cmϪ1, 2958, 2548, 2341,
1853, 1697, 1607, 1451, 1384, 1260, 1068, 1055, 1017, 927, 869,
1
823, 687, 656. H NMR (CDCl3): δ ϭ 5.24 (m, 2 H, ϭCH), 2.65
(m, 1 H, CH3CH), 2.36 (br. s, 1 H, CH2), 1.61 (s, 6 H, ϭCCH3),
0.93 (d, J ϭ 7.1 Hz, 3 H, CHCH3) ppm. 13C NMR (CDCl3): δ ϭ
130.13 (ϭCCH3), 125.12 (ϭCH), 35.84 (CH2), 32.22 (CHCH3), 23
(ϭCCH3), 22.47 (CHCH3) ppm.
1
1260, 1039, 1004, 928, 784, 761. H NMR (CDCl3): δ ϭ 5.04 (m,
1 H, ϭCH), 3.50 (s, 1 H, OH), 2.91 (d, J ϭ 7.5 Hz, 1 H, HCOH),
2.20Ϫ1.92 (m, 4 H, CH2, 2 ϫ HCCH3), 1.71 (s, 3 H, ϭCCH3),
1.08 (m, 3 H, HCCH3), 0.92 (m, 3 H, HCCH3) ppm. 13C NMR
(CDCl3): δ ϭ 130.1 (ϭCCH3), 126.12 (ϭCH), 79.09 (CHOH),
44.15 (CH2), 35.27 (HCCH3), 32.20 (HCCH3), 26.44 (ϭCCH3),
20.20 (HCCH3), 18.13 (HCCH3) ppm. C9H16O (140.22): calcd. C
77.09, H 11.50, O 11.41; found C 76.63, H 11.31, O 12.06.
2,4,6-Trimethylcyclohexa-1,4-diene (6f). Conditions C: LiCl (28 g,
0.67 mol) was dissolved in a mixture of THF (600 mL), HMPA
(320 mL) and tBuOH (360 mL, 3.7 mol). After homogenization,
the solution was poured into the tubular flow cell,[14] and mesi-
tylene (5f, 23 mL, 0.17 mol) was added, followed by chlorotrime-
thylsilane (4 mL). Electrolysis (constant current 1 A) was then initi-
ated and maintained for 24 h. The mixture was diluted with pent-
ane (800 mL) and then treated dropwise at Ϫ78 °C with a 10%
solution of HCl (800 mL), and the organic layer was decanted. The
aqueous layer was extracted with diethyl ether (3 ϫ 500 mL) and
the combined extracts were washed with HCl (10%, 5 ϫ 500 mL),
a saturated solution of NaHCO3 (3 ϫ 200 mL) and brine (2 ϫ
300 mL). The solution was dried with MgSO4 and the solvents were
removed in vacuo to afford 6f as a colorless oil (20.3 g, 94%), used
in the next step without further purification. The spectroscopic
data for 6f were consistent with those described above.
General Procedure for the Sharpless Asymmetric Dihydroxylation
of Dienes 6. 1,3,5-Trimethylcyclohex-4-ene-1,2-diol (12f): AD-mix
{K3[Fe(CN)6] (9.8 g, 30 mmol), K2CO3 (4.12 g, 30 mmol), quinucli-
dine (11.2 mg, 0.1 mmol), K2OsO4·2H2O (34 mg, 0.1 mmol)}, H2O
(50 mL) and tBuOH (50 mL) were placed in a 250-mL flask. The
solution was stirred for 5 min and methanesulfonamide (0.95 g,
10 mmol) was added. The orange solution was cooled to 10 °C and
6f (1.22 g, 10 mmol) was introduced with vigorous stirring. After
the mixture had been kept for 0.5 h at room temp., sodium sulfite
(10 g) was added and the solution was stirred at room temp. for
0.75 h. The aqueous layer was extracted with EtOAc (3 ϫ 50 mL)
and the combined extracts were washed with an NaOH solution
(10%, 20 mL) and brine (20 mL). The organic layer was dried with
MgSO4 and the solvents were evaporated in vacuo to give the crude
diol 12f as a yellow solid (0.85 g, 54%, 88% de). The major diaster-
eoisomer 12f was obtained pure after recrystallization from petro-
leum ether (0.56 g, 36%); m.p. 110 °C. IR (film, KBr): ν˜max ϭ 3582
cmϪ1 (OH), 2959, 2359, 1549 (CϭC), 1461, 1378, 1256, 1006, 784.
1H NMR (CDCl3): δ ϭ 5.20 (m, 1 H, ϭCH), 3.15 (m, 1 H,
HCOH), 2.15Ϫ2.30 (m, 3 H, CH2, CHCH3), 1.92 (s, 1 H, OH),
1.80 (s, 1 H, OH), 1.69 (m, 3 H, ϭCCH3), 1.34 (s, 3 H, CH3COH),
1.16 (d, J ϭ 6.6 Hz, 3 H, CHCH3) ppm. 13C NMR (CDCl3): δ ϭ
129.82 (ϭCCH3), 125.44 (ϭCH), 78.81 (HCOH), 71.27
(HOCCH3), 43.74 (CH2), 35.53 (HCCH3), 25.65 (ϭCCH3), 22.76
(HOCCH3), 18.46 (HCCH3) ppm. MS (EI): m/z (%) ϭ 138 (37)
[Mϩ· Ϫ 18], 123 (75) [Mϩ· Ϫ 18 Ϫ CH3], 101 (30), 74 (64)
[CH3COCH2OHϩ·], 55 (32), 43 (100) [CH3COϩ]. C9H16O2
(156.22): calcd. C 69.19, H 10.32, O 20.49; found C 68.81, H 10.92,
O 20.27.
1,5-Dimethylcyclohexa-1,4-diene (6g): On subjection to conditions
B, m-xylene (5g, 2 g, 18.8 mmol) gave, after 72 h, the diene 6g
(1.65 g, 80%) as a colorless oil, used in the next step without further
purification. IR (film, KBr): ν˜max ϭ 2962 cmϪ1, 2925, 2866, 2660,
2360, 1853, 1696, 1447, 1387, 1375, 1261, 1096, 1015, 928, 807. 1H
NMR (CDCl3): δ ϭ 5.43 (m, 2 H, ϭCH), 2.70 (m, 2 H, CH2), 2.30
(m, 2 H, CH2), 1.67 (s, 6 H, CH3) ppm. 13C NMR (CDCl3): δ ϭ
130.15 (ϭCCH3), 125.18 (ϭCH), 35.9 (CH2), 32.3 (CH2), 23.11 (ϭ
CCH3) ppm.
Bis(epoxide) (10): Trifluoroacetone (0.81 mL, 8.9 mmol) was added
dropwise at 0 °C to a mixture of a solution of Na2EDTA (4 ϫ
10Ϫ4 , 4 mL, 1.63 µmol) and diene 6f (0.1 g, 0.81 mmol) in
CH3CN (6 mL). A mixture of NaHCO3 (0.53 g, 6.3 mmol) and
oxone (2.51 g, 0.1 mmol) was then added to the reaction medium
in portions so as to maintain the pH at 7. The medium was then
allowed to warm to room temp. and the reaction mixture was
poured into water. The layers were decanted and the aqueous layer
was extracted with CH2Cl2. The combined organic layers were then
dried with MgSO4 and the solvents were evaporated under vacuum
to give 10 as a solid (10 mg, 8%), which was recrystallized from
petroleum ether; m.p. 70 °C (petroleum ether). IR (film, KBr):
ν˜max ϭ 3000 cmϪ1, 1428, 1300, 1150, 952 (CϪO), 890, 775, 740.
1H NMR (CDCl3): δ ϭ 3.10 (q, J ϭ 7.6 Hz, 1 H, CH3CH), 3.08
(s, 2 H, CHO), 2.85 (d, J ϭ 16.8 Hz, 1 H, CHaHb), 2.39 (d, J ϭ
16.8 Hz, 1 H, CHaHb), 1.85 (s, 6 H, CH3CO), 1.51 (d, J ϭ 7.6 Hz,
3 H, CH3CH) ppm. 13C NMR (CDCl3): δ ϭ 61.63 (CHO), 55.02
(OCCH3), 32.94 (CH2), 28.80 (OCCH3), 23.74 (HCCH3), 15.26
(CH3CH) ppm. C9H14O2 (154.21): calcd. C 70.10, H 9.15, O 20.25;
found C 70.10, H 9.11, O 20.29.
Sharpless Dihydroxylation of Diene 6f in the Presence of
(DHQD)2PHAL. 1,3,5-Trimethylcyclohex-4-ene-1,2-diol (12f):
Upon treatment according to the general procedure above, 6f
(0.3 g, 2.45 mmol), when treated at 10 °C for 14 h with
(DHQD)2PHAL, afforded the diol 12f as a yellow solid (0.21 g,
55%, 40% de). eemaj. ϭ 70%, eemin. ϭ 18% as measured by HPLC
(chiral column Chiracel OD): 1 mL/min, 220 nm, hexane/iPrOH
(97:3), tR (min) ϭ 7, 8, 11, 13.
Sharpless Dihydroxylation of Diene 6f in the Presence of
(DHQ)2PHAL. 1,3,5-Trimethylcyclohex-4-ene-1,2-diol (12f): Upon
treatment according to the general procedure above, 6f (0.3 g,
2.45 mmol), when treated at 10 °C for 16 h with (DHQ)2PHAL,
(1R*,2R*,6S*)-2,4-6-Trimethylcyclohex-3-enol (11): 2,4,6-Cyclo-
hexa-1,4-diene (6f, 0.3 g, 2.46 mmol) was added at 0 °C to a solu-
Eur. J. Org. Chem. 2002, 4037Ϫ4053
4045

Y. Landais, E. Zekri
FULL PAPER
afforded the diol 12f as a yellow solid (0.20 g, 52%, 60% de).
eemaj. ϭ 60%, eemin. ϭ 50% measured by HPLC as above.
diol (12d): Upon treatment according to the general procedure
above, 6c (0.3 g, 1.67 mmol), when treated at 0 °C for 96 h with
(DHQ)2PHAL, afforded the diol 12d as an oil (0.26 g, 73%, Ͼ 98%
de), used in the next step without further purification. ee ϭ 5%
measured from 1H and 19F NMR of the corresponding Mosher es-
ter.
Sharpless Dihydroxylation of Diene 6f in the Presence of
(DHQ)2AQN. 1,3,5-Trimethylcyclohex-4-ene-1,2-diol (12f): Upon
treatment according to the general procedure above, 6f (0.3 g,
2.45 mmol), when treated at 10 °C for 24 h with (DHQD)2PHAL,
afforded the diol 12f as a yellow solid (0.15 g, 40%, 70% de).
eemaj. ϭ 30%, eemin. ϭ 32% measured by HPLC as above.
Sharpless Dihydroxylation of Diene 6c in the Presence of
(DHQ)2PYR. (2,4-Dimethyl-3-trimethylsilyl)cyclohex-4-ene-1,2-diol
(12d): Upon treatment according to the general procedure above, 6c
(0.3 g, 1.67 mmol), when treated at 2 °C for 72 h with (DHQ)2PYR,
afforded the diol 12d as an oil (0.30 g, 84%, Ͼ 98% de), used in the
next step without further purification. ee ϭ 47% measured from
1H and 19F NMR of the corresponding Mosher ester.
Sharpless Dihydroxylation of Diene 6c in the Presence of
(DHQ)2PYR. (3-Triisopropylsilyl)cyclohex-4-ene-1,2-diol (12c):
Upon treatment according to the general procedure above, 6c
(0.20 g, 0.84 mmol), when treated at 0 °C for 4 h, afforded a mix-
ture (0.27 g) containing diol 12c [40% ee, measured from 1H and
19F NMR of the corresponding Mosher bis(ester)] and the corres-
ponding tetrol as a minor product (80:20, measured after protec-
tion as acetonide). This oil was used in the next step without fur-
ther purification. IR (film, KBr): ν˜max ϭ 3569 cmϪ1 (OH), 2945,
2884, 1625 (CϭC), 1553, 1499, 1379, 1251, 1103, 829, 820, 700. 1H
NMR (CDCl3): δ ϭ 5.78Ϫ5.42 (m, 2 H, CHϭCH), 4.09 (m, 1 H,
CHOH), 3.94Ϫ3.73 (m, 1 H, CHOH), 3.50 (s, 2 H, OH), 2.72Ϫ2.63
(m, 3 H, CH2, CHSi), 1.13Ϫ1.20 [sept, 3 H, CH(CH3)2], 1.10 [br.
s, 18 H, HC(CH3)2] ppm. 13C NMR (CDCl3): δ ϭ 127.61 (CHϭ
CH), 121.53 (CHϭCH), 70.82 (CHOH), 69.02 (CHOH), 30.10
(CHSi), 27.00 (CH2), 19.40 [HC(CH3)2], 12.12 [HC(CH3)2] ppm.
MS (LSIMS): m/z (%) ϭ 293.2 (100) [M ϩ Na]. HRMS: calcd. for
C15H30OSi [M ϩ Na] 293.191279; found 293.192143.
Sharpless Dihydroxylation of Diene 6e in the Presence of Quinuclid-
ine. 3-(Dimethylisopropoxysilyl)cyclohex-4-ene-1,2-diol (12e): Upon
treatment according to the general procedure above, 6e (0.3 g,
1.53 mmol), when treated at 0 °C for 12 h with quinuclidine, af-
forded the diol 12e as an oil (0.20 g, 57%, Ͼ 98% de), used in the
next step without further purification. IR (film, KBr): ν˜max ϭ 3435
cmϪ1 (OH), 2973, 2252, 1587 (CϭC), 1383, 1255, 1118, 1012, 907,
1
827, 732, 650. H NMR (CDCl3): δ ϭ 5.59Ϫ5.42 (m, 2 H, CHϭ
CH), 4.02 [sept, J ϭ 6.1 Hz, 1 H, OCH(CH3)2], 3.98 (m, 1 H,
HCOH), 3.90 (dd, J ϭ 2.1, J ϭ 7.6 Hz, 1 H, HCOH), 3.36 (s, 2 H,
OH), 2.37Ϫ2.16 (m, 2 H, CH2), 1.88 (m, 1 H, SiCH), 1.16 [d, J ϭ
6.1 Hz, 6 H, OCH(CH3)2], 0.22 [s, 3 H, Si(CH3)2], 0.13 [s, 3 H,
Si(CH3)2] ppm. 13C NMR (CDCl3): δ ϭ 123.48 (HCϭCH), 122.63
(HCϭCH), 70.00 (HCOH), 67.45 (HCOH), 67.00 [OCH(CH3)2],
31.94 (SiCH), 31.08 (CH2), 25.71 [OCH(CH3)2], Ϫ2.18 [Si(CH3)2]
ppm.
Sharpless Dihydroxylation of Diene 6c in the Presence of Quinuclid-
ine. (3-Triisopropylsilyl)cyclohex-4-ene-1,2-diol (12c): Upon treat-
ment according to the general procedure above, 6c (0.20 g,
0.84 mmol), when treated at 2 °C for 4 h, afforded a mixture
(0.23 g) containing diol 12c and the corresponding tetrol as a minor
product (60:40, measured after protection as acetonide). This oil
was used in the next step without further purification.
Sharpless Dihydroxylation of Diene 6e with (DHQ)2PYR. 3-(Di-
methylisopropoxysilyl)cyclohex-4-ene-1,2-diol (12e): Upon treat-
ment according to the general procedure above, 6e (1.93 g,
9.84 mmol), when treated at 0 °C for 12 h with (DHQ)2PYR, af-
forded the diol 12e as an oil (1.58 g, 70%, Ͼ 98% de), used in the
next step without further purification. ee ϭ 53% measured from
1H and 19F NMR of the corresponding Mosher ester.
Sharpless Dihydroxylation of Diene 6d in the Presence of
(DHQD)2PHAL. (2,4-Dimethyl-3-trimethylsilyl)cyclohex-4-ene-1,2-
diol (12d): Upon treatment according to the general procedure
above, 6d (0.3 g, 1.67 mmol), when treated at 0 °C for 72 h with
(DHQD)2PHAL, afforded the diol 12d as a yellow solid (0.31 g,
87%, Ͼ 98% de), used in the next step without further purification.
1,5-Dimethylcyclohex-4-ene-1,2-diol (12g): According to the general
procedure described above for the Sharpless dihydroxylation, diene
6g (1 g, 9.2 mmol), when treated at 0 °C for 72 h with quinuclidine,
afforded diol 12g as an oil (0.80 g, 61%), used in the next step
without further purification. IR (film, KBr): ν˜max ϭ 3425 cmϪ1
(OH), 2967, 2912, 2249, 1630 (CϭC), 1451, 1379, 1261, 1105, 1048,
1
ee ϭ 27% estimated from H and 19F NMR of the corresponding
Mosher ester. IR (film, KBr): ν˜max ϭ 3422 cmϪ1 (OH), 2956, 1550
(CϭC), 1438, 1380, 1304, 1251, 1197, 1144, 1105, 1053, 972, 923,
1
838, 784, 761, 685. H NMR (CDCl3): δ ϭ 5.35 (m, 1 H, ϭCH),
1
907, 731, 649. H NMR (CDCl3): δ ϭ 5.23 (m, 1 H, ϭCH), 3.58
3.52 (t, J ϭ 5.2 Hz, 1 H, HCOH), 2.52Ϫ2.22 (m, 2 H, CH2), 1.85
(s, 1 H, SiCH), 1.52 (m, 3 H, ϭCCH3), 1.35 (s, 3 H, CH3COH),
0.10 [br. s, 9 H, Si(CH3)3] ppm. 13C NMR (CDCl3): δ ϭ 130.00 (ϭ
CCH3), 118.72 (ϭCH), 76.52 (HOCH), 71.14 (HOCCH3), 46.67
(HCSi), 33.32 (CH2), 25.17 (ϭCCH3), 24.29 (HOCCH3), 1.21
[Si(CH3)3], 1.03 [Si(CH3)3] ppm. MS (EI): m/z (%) ϭ 214 (6) [M؉·],
(t, J ϭ 5.1 Hz, 1 H, HCOH), 2.28Ϫ2.04 (m, 6 H, 2 ϫ CH2, 2 ϫ
OH), 1.96 (d, J ϭ 1.5 Hz, 3 H, ϭCCH3), 1.65 (s, 3 H, CH3COH)
ppm. 13C NMR (CDCl3): δ ϭ 132.48 (ϭCCH3), 116.97 (ϭCH),
72.37 (HCOH), 72.00 (HOCCH3), 41.92 (CHCH2), 31.75
(CH2CH), 24.77 (ϭCCH3), 23.26 (HOCCH3) ppm.
196 (9) [M؉· Ϫ 18], 181 (12) [M؉· Ϫ 18 Ϫ CH3], 124 (45) [M؉·
Ϫ
Acetonide 13a and Bis(acetonide) 13b: pTsOH (catalytic amount)
was added to a solution of 12c (0.24 g, 0.89 mmol) in 2,2-dime-
thoxypropane (10 mL). The reaction mixture was stirred for 12 h
at room temp. and the solvent was removed under vacuum. A sat-
urated solution of NaHCO3 (10 mL) was then added, and the aque-
ous layer was extracted with diethyl ether (3 ϫ 5 mL). The com-
bined extracts were washed with brine (5 mL) and dried with
MgSO4, and the solvent was removed in vacuo. Column chromato-
graphy of the residue (cyclohexane) afforded a 60:40 mixture
(0.28 g) of 13a and the corresponding bis(acetonide) 13b. 13a: IR
(film, KBr): ν˜max ϭ 3054 cmϪ1, 2918, 2978, 2900, 1412, 1415, 1365,
1288, 1215, 1051, 1041, 835, 805, 698. 1H NMR (CDCl3): δ ϭ
6.12Ϫ6.08 (m, 1 H, CHϭCH), 5.93Ϫ5.87 (m, 1 H, CHϭCH), 4.77
Si(CH3)3ϪOH], 109 (64) [124 ϪCH3], 91 (18) [124 Ϫ H2O], 73 (100)
[Si(CH3)3ϩ], 43 (39) [CH3COϩ·]. HRMS: calcd. for C11H22O2Si [M
ϩ Na]: 214.138910; found 214.138550.
Sharpless Dihydroxylation of Diene 6c in the Presence of Quinuclid-
ine. (2,4-Dimethyl-3-trimethylsilyl)cyclohex-4-ene-1,2-diol (12d):
Upon treatment according to the general procedure above, 6c
(0.3 g, 1.67 mmol), when treated at 2 °C for 48 h with quinuclidine,
afforded the diol 12d as an oil (0.30 g, 84%, Ͼ 98% de), used in the
next step without further purification.
Sharpless Dihydroxylation of Diene 6c in the Presence of
(DHQ)2PHAL. (2,4-Dimethyl-3-trimethylsilyl)cyclohex-4-ene-1,2-
4046
Eur. J. Org. Chem. 2002, 4037Ϫ4053

Desymmetrization of Cyclohexa-1,4-dienes
FULL PAPER
(dd, J ϭ 2.1, 5.8 Hz, 1 H, SiCCHO), 4.65 (ddd, J ϭ 4.6, 5.8 Hz,
1 H, CH2CHO), 2.69Ϫ2.51 (m, 3 H, CH2, CHSi), 1.80 [s, 3 H,
to 0:100), afforded a 66:33 mixture of two regioisomers 14ba and
14bb (14 mg, 10%, Ͼ 98% de). eemaj. ϭ 15% and eemin. Ͻ 2% meas-
O2C(CH3)2], 1.68 [s, 3 H, O2C(CH3)2], 1.44 [m, 3 H, HC(CH3)2], ured by HPLC (chiral column Chiracel OD): 0.4 mL/min, 220 nm,
1.06 [s, 18 H, CH(CH3)2] ppm. 13C NMR (CDCl3): δ ϭ 128.32 hexane/iPrOH (9:1), tR (min) ϭ 18, 20, 24 and 27. IR (film, KBr):
(CHϭCH), 121.55 (CHϭCH), 108.23 [O2C(CH3)2], 74.61 (HCO),
73.62 (HCO), 32.17 (CH2), 29.03 (CHSi), 28.05 [O2C(CH3)2], 25.15 (CϪS). H NMR (CDCl3): δ ϭ 5.64 (m, 1 H, CHϭCH), 5.40 (m,
ν˜max ϭ 3595 cmϪ1 (OH), 1725 (CϭC), 1399, 1283 (SϭO), 962, 903
1
[O2C(CH3)2], 20.18 [HC(CH3)2], 12.20 [HC(CH3)2]. 13b: IR (film,
1 H, CHϭCH), 4.99 (dd, J ϭ 8.8, 3.9 Hz, 1 H, NH), 4.76 (d, J ϭ
KBr): ν˜max ϭ 2945 cmϪ1, 2899, 1586, 1511, 1401, 1150, 1112, 835, 8.5 Hz, 1 H, NH), 4.09 (m, 1 H, CHOH), 3.99 (m, 1 H, CHOH),
1
799, 700. H NMR (CDCl3): δ ϭ 4.53 (dd, J ϭ 11.3, 7.0 Hz, 2 H, 3.90 (m, 1 H, CHNH), 3.69 (m, 0.33 H, CHNH), 3.04 (s, 1 H,
SiCCHO), 4.36 (m, 2 H, CH2CHO), 2.56 (m, 3 H, CH2, CHSi), CH3), 2.97 (s, 2 H, CH3), 2.44 (m, 2 H, OH, CHaHb), 2.04 (m, 2
1.78 [s, 6 H, O2C(CH3)2], 1.62 [s, 6 H, O2C(CH3)2], 1.44 [sept, 3 H, H, SiCH, CHaHb), 1.07 [m, 21 H, SiCHCH3)] ppm. 13C NMR
HC(CH3)2], 1.06 [s, 18 H, HC(CH3)2] ppm. 13C NMR (CDCl3): (CDCl3): δ ϭ 127.84, 126.92, 121.31, 120.49 (CϭC), 70.06, 67.48
δ ϭ 109.00 [O2C(CH3)2], 73.77 (CHO), 73.76 (CHO), 32.14 (CH2), (CHOH), 55.89, 52.97 (CHNH), 42.52, 42.42 (CH3), 33.77 (SiCH),
28.08 [O2C(CH3)2], 27.02 (CHSi), 25.08 [O2C(CH3)2], 20.10
30.32, 27.27 (CH2), 19.43, 19.38 (SiCHCH3), 11.95 (SiCHCH3)
[HC(CH3)2], 12.93 [SiCH(CH3)2] ppm. C21H40O4Si (384.63): calcd. ppm. MS (LSIMS): m/z (%) ϭ 370.1 (100), 304.1 (71), 252.1 (56).
C 65.58, H 10.48, O 16.64, Si 7.30; found C 65.71, H 10.35, O
16.24, Si 7.70.
HRMS: calcd for C16H33NO3SSi [M ϩ Na] 370.184814; found
370.184565.
Preparation of CH3SO2NClNa: Solid NaOH (2 g, 0.05 mol) was
N-(6-Hydroxycyclohexyl-3-enyl)methanesulfonamide (14c): On sub-
added to a solution of methanesulfonamide (4.81 g, 0.05 mol) in jection to conditions A, diene 9 (0.2 g, 2.5 mmol) in the presence of
water (40 mL), followed by tert-butyl hypochlorite (5.63 mL). The
mixture was stirred overnight. Water and tBuOH were then evapor-
ated under reduced pressure to afford the chloramine salt as a white
solid (7.5 g, 98%), used in the next step without further purifica-
tion.
(DHQ)2PHAL, after 4 h at room temp. and purification by column
chromatography on silica gel (cyclohexane/EtOAc, 60:40 to 0:100),
afforded compound 14c as a white solid, which was recrystallized
from cyclohexane (0.28 g, 57%). ee ϭ 36% measured by HPLC
(chiral column Chiracel OD): hexane/iPrOH (9:1), 0.4 mL/min,
220 nm, tR (min) ϭ 46 and 48; m.p. 91 °C (cyclohexane). IR (film,
KBr): ν˜max ϭ 3565 cmϪ1 (OH), 1689 (CϭC), 1406, 1299, 1274 (Sϭ
O), 1158 (SϭO), 895, 689 (CϪS). 1H NMR ([D6]DMSO): δ ϭ 6.42
(s, 1 H, NH), 5.14 (m, 2 H, CHϭCH), 4.37 (m, 1 H, CHNH), 3.48
(m, 1 H, CHOH), 2.56 (s, 3 H, SO2CH3), 1.93Ϫ1.66 (m, 2 H, CH2)
ppm. 13C NMR ([D6]DMSO): δ ϭ 125.33Ϫ125.08 (CHϭCH),
67.33 (HCOH), 53.58 (CHNH), 40.45 (CH3SO2), 33.53 (CaH2),
29.02(CbH2) ppm. MS (EI): m/z (%) ϭ 191 (1.4) [M؉·], 160 (0.6),
136 (16), 95 (58), 80 (100), 58 (20), 30 (45). HRMS: calcd. for
C7H13O3NS [Mϩ·] 191.061615; found 191.061665.
General Procedure for the Sharpless Asymmetric Aminohydroxyl-
ation of Dienes 6aϪc and 9. N-(2-Trimethylsilyl)(6-hydroxycyclohex-
3-enyl)methanesulfonamide (14aa), and N-(2-Trimethylsilyl)(2-hy-
droxycyclohex-3-enyl)methanesulfonamide (14ab). Conditions A: In
a 100-mL flask equipped with a magnetic stirrer and a thermo-
meter, a solution of (DHQ)2PYR (0.057 g, 0.065 mmol) in n-pro-
panol (8 mL) was added to a solution of CH3SO2NClNa (0.60 g,
3.93 mmol) in water (8 mL). After homogenization, K2OsO4·2H2O
(0.017 g, 0.05 mmol) and then diene 6a (0.2 g, 1.31 mmol) were ad-
ded at room temp. and the reaction mixture rapidly turned green.
The mixture was stirred for 0.5 h (the color had turned brown at
the end of the reaction), sodium sulfide (1.97 g, 15.7 mmol) was
then added, and the resulting mixture was stirred for 0.3 h. The
aqueous layer was extracted with EtOAc (3 ϫ 50 mL) and the com-
bined extracts were washed with water (20 mL) and brine (2 ϫ
N-(6-Hydroxycyclohex-3-enyl)-4-methylbenzenesulfonamide (14d).
Conditions B: On subjection to conditions B, diene 9 (0.5 g,
6.25 mmol) in CH3CN (45 mL) and water (45 mL) in the presence
of (DHQ)2PHAL, after 4 h at room temp. and purification by col-
umn chromatography on silica gel (CH2Cl2/EtOAc, 95:5 to 80:20),
20 mL), and then dried with MgSO4. The solvents were evaporated afforded compound 14d as a white solid, which was recrystallized
in vacuo to afford a residue, which was purified by chromatography from cyclohexane (0.77 g, 46%). ee ϭ 66% measured by HPLC
on silica gel (cyclohexane/EtOAc, 60:40 to 0:100). This afforded a (chiral column Chiracel OD): hexane/iPrOH (9:1), 0.4 mL/min,
1:1 mixture of the two regioisomers 14aa and 14ab (0.097 g, 28%,
220 nm, tR (min) ϭ 38 and 40. The spectroscopic data are consist-
Ͼ 98% de). ee ϭ 27% and 3% measured by HPLC (chiral column ent with those described in the literature.[26]
Chiracel OD): 0.4 mL/min, 220 nm, hexane/iPrOH (9:1), tR
General Procedure for the Sharpless Asymmetric Aminohydroxyl-
(min) ϭ 16, 23, 28 and 34. IR (film, KBr): ν˜max ϭ 3575 cmϪ1 (OH),
ation of Dienes 6c. Conditions D. N-[6-Hydroxy-2-(triisopropylsilyl)-
cyclohex-3-enyl]-4-methylbenzenesulfonamide (14e): A solution of
(DHQ)2PYR (0.018 g, 0.02 mmol) in tBuOH (3 mL) was added to
a solution of TsNClNa 3H2O (0.35 g, 1.48 mmol) in water (3 mL)
in a 500-mL flask equipped with a magnetic stirrer and a thermo-
meter. After homogenization, K2OsO4·2H2O (5.6 mg, 0.017 mmol)
and then diene 6c (0.1 g, 0.42 mmol) were added at room temp.
and the reaction mixture rapidly turned green. The mixture was
stirred for 1 h (the color had turned brown at the end of the reac-
tion), solid sodium sulfide (0.63 g, 5.04 mmol) was added, and the
resulting mixture was stirred for 0.3 h. The aqueous layer was ex-
tracted with EtOAc (3 ϫ 50 mL) and the combined extracts were
washed with water (20 mL) and brine (2 ϫ 20 mL) and then dried
with MgSO4. The solvents were evaporated in vacuo to afford a
residue, which was purified by chromatography on silica gel (cyclo-
hexane/EtOAc, 85:15). This afforded the starting diene 6c and the
desired compound 14e as a colorless oil (0.122 g, 30% corrected
1
1627 (CϭC), 1400, 1302, 1250 (SϭO), 978, 694 (CϪS). H NMR
(CDCl3): δ ϭ 5.48 (m, 2 H, CHϭCH), 5.01 (s, 1 H, NH), 3.97Ϫ3.68
(m, 2 H, CHOH, CHNH), 3.05 (s, 3 H, SO2CH3), 3.00 (s, 3 H,
SO2CH3), 1.82 (m, 3 H, CH2, CHSi), 0.04 [s, 6 H, Si(CH3)3], 0.03
[s, 3 H, Si(CH3)3] ppm. 13C NMR (CDCl3): δ ϭ 125.56, 125.3,
121.66, 121.16 (2 ϫ CϭC, 2 isomers), 70.72, 66.98 (2 ϫ CHOH, 2
isomers), 57.79, 52.58 (2 ϫ CHNH, 2 isomers), 43.60, 42.10 (2 ϫ
SO2CH3, 2 isomers) 36.48 (CHSi), 30.48 (CH2), 27.21 (CH2), Ϫ2.00
(SiCH3) ppm. MS (LSIMS): m/z (%) ϭ 286.0 (100), 240.1 (43).
HRMS: calcd. for C10H21NO3SSi [M ϩ Na] 286.090914; found
286.091633.
N-(2-Triisopropylsilyl)(6-hydroxycyclohex-3-enyl)methanesulfon-
amide (14ba) and N-(3-Triisopropylsilyl)(2-hydroxycyclohex-4-enyl)-
methanesulfonamide (14bb): On subjection to conditions A, diene
6c (0.1 g, 0.42 mmol), after 1 h at room temp. and purification by
column chromatography on silica gel (cyclohexane/EtOAc, 70:30
Eur. J. Org. Chem. 2002, 4037Ϫ4053
4047

Y. Landais, E. Zekri
FULL PAPER
yield, Ͼ 98% de). ee ϭ 66% measured by HPLC (chiral column
Chiracel OD): hexane/iPrOH (9:1), 0.4 mL/min, 220 nm, tR
tals, which were recrystallized from a cyclohexane/diethyl ether 95:5
mixture (0.52 g, 85%). M.p. 114 °C (cyclohexane/diethyl ether,
(min) ϭ 26 and 28. IR (film, KBr): ν˜max ϭ 3612 cmϪ1 (NH), 1731, 95:5). IR (film, KBr): ν˜max ϭ 3225 cmϪ1 (OH), 3154 (OH), 2252,
1
1394, 1257 (SϭO), 947, 899 (CϪS). H NMR (CDCl3): δ ϭ 7.79 1793, 1562, 1469, 1381 (CϪO), 1095 (CϪO), 912, 794, 742, 684.
(d, J ϭ 8.2 Hz, 2 H, Ph), 7.31 (d, J ϭ 8.2 Hz, 2 H, Ph), 5.52 (m, 2
H, CHϭCH), 4.90 (d, J ϭ 8.5 Hz, 1 H, NH), 3.87 (m, 1 H,
1H NMR (CDCl3): δ ϭ 4.37Ϫ4.30 (m, 1 H, OCHCH2), 4.20 (dd,
J ϭ 5.1, 10.3 Hz, 1 H, CHOCHSi), 3.76Ϫ3.90 (m, 2 H, CH2OH),
CHOH), 3.63 (m, 1 H, CHNH), 2.45 (m, 2 H, CHaHb, OH), 2.42 3.74Ϫ3.66 (m, 2 H, CH2OH), 1.70 (m, 1 H, SiCH), 1.55 (m, 2 H,
(s, 3 H, PhCH3), 2.10 (m, 1 H, CHaHb), 2.01 (m, 1 H, CHSi), 0.95 CH2), 1.41 [s, 3 H, C(CH3)2], 1.28 [s, 3 H, C(CH3)2], 0.89 [s, 9 H,
(m, 21 H, SiCHCH3) ppm. 13C NMR (CDCl3): δ ϭ 143.70, 137.22
(CSO2, CCH3), 129.71 (Car), 127.28 (CϭC), 125.83 (Car), 121.69
C(CH3)3], 0.03 [s, 3 H, Si(CH3)2], 0.00 [s, 3 H, Si(CH3)2] ppm. 13C
NMR (CDCl3): δ ϭ 105.90 [C(CH3)2], 89.45 (CH2OH), 78.93
(CϭC), 66.71 (CHOH), 55.15 (CHNH), 32.91 (CHSi), 30.66 (CH2OH), 61.59 (CHO), 61.08 (CHO), 31.95 (CHSi), 27.91 (CH2),
(CH2), 21.39 (PhCH3), 18.74, 18.66 (SiCHCH3), 11.35 (SiCHCH3) 27.10 [C(CH3)3], 25.24 [C(CH3)2], 16.82 [C(CH3)3], Ϫ6.77
ppm. MS (LSIMS): m/z (%) ϭ 446.2 (100), 423.2 (6), 380.1 (32), [Si(CH3)2] ppm. C15H32O4Si (304.50): calcd. C 58.78, H 11.18, O
328.1 (54), 284.1 (11). HRMS: calcd. for C22H37NO3SSi [M ϩ Na]
20.88, Si 9.16; found C 58.48, H 10.44, O 22.48, Si 8.60.
446.216114; found 446.215587.
Diol 17b: On subjection to the ozonolysis conditions A reported
for 15, a 60:40 mixture of 13a and bis(acetonide) 13b (0.19 g), after
column chromatography on silica gel (cyclohexane/EtOAc, 70:30),
afforded recovered bis(acetonide) 13b (46 mg, 57%) and diol 17b
(86 mg, 30%, 3 steps from 6c) as a colorless oil. IR (film, KBr):
ν˜max ϭ 3758 cmϪ1, 3517, 2893, 2607, 2268, 1973, 1899, 1747, 1694,
β-Hydroxysilane 16: Ozone was bubbled at Ϫ78 °C through a solu-
tion of alkene 15 (0.14 g, 0.52 mmol) in a 1:1 mixture of CH2Cl2
(1.5 mL) and MeOH (1.5 mL). After few minutes, the mixture
turned deep blue. When no trace of the starting material could be
detected by TLC, excess ozone was purged with nitrogen until the
blue color had totally disappeared. Me2S (0.25 mL, 2.63 mmol) was
then added, and the solvents were evaporated at 0 °C under re-
duced pressure. The residue was dissolved in dry THF (10 mL) and
a solution of vinylmagnesium bromide in THF (1 , 1.15 mL,
1.15 mmol) was added dropwise at 0 °C. The reaction mixture was
then stirred at room temp. for 12 h and the excess of Grignard
reagent was hydrolysed with a saturated solution of NH4Cl. The
organic layer was decanted and the aqueous layer was extracted
with EtOAc (4 ϫ 10 mL). The combined extracts were washed with
brine (20 mL) and dried with MgSO4, and the solvents were evap-
orated under vacuum to give an oil, which was purified by chroma-
tography on silica gel (cyclohexane/EtOAc, 70:30), affording 16 as
1
1193, 1156, 1093, 1057, 802, 697. H NMR (CDCl3): δ ϭ 4.34 (m,
2 H, 2 ϫ CH2OH), 4.18 (m, 2 H, 2 ϫ CH2OH), 3.76 (m, 2 H, 2 ϫ
CHO), 3.40 (m, 2 H, OH), 1.85 (m, 3 H, CH2, CHSi), 1.36 [s, 3 H,
O2C(CH3)2], 1.26 [s, 3 H, O2C(CH3)2], 1.05 [m, 21 H, HC(CH3)2]
ppm. 13C NMR (CDCl3): δ ϭ 107.07 [O2C(CH3)2], 81.57 (CHO),
80.31 (CHO), 63.68 (CH2OH), 61.87 (CH2OH), 33.58 (CH2), 29.40
[O2C(CH3)2], 27.90 (CHSi), 26.81 [O2C(CH3)2], 20.22 [HC(CH3)2],
13.12 [HC(CH3)2] ppm. MS (LSIMS): m/z (%) ϭ 369 (63) [M ϩ
Na], 310 (10), 281 (5), 271 (34), 227 (100). HRMS: calcd. for
C18H38O4Si [Mϩ ϩ Na] 369.240565; found 369.243535.
Diol 17b: On subjection to the ozonolysis conditions A reported
for 15, an 80:20 mixture of 13a and bis(acetonide) 13b (0.19 g),
after column chromatography on silica gel (cyclohexane/EtOAc,
70:30), afforded recovered bis(acetonide) 13b (50 mg, 36%) and diol
17b (0.10 mg, 34%, 3 steps from 6c) as a colorless oil. Spectroscopic
data are identical to those of the sample obtained above.
a mixture of stereoisomers (50 mg, 27%). IR (film, KBr): ν˜max
ϭ
3601 cmϪ1 (OH), 1749, 1257 (CϪO), 1021 (CϪO). 1H NMR
(CDCl3): δ ϭ 5.83 (m, 2 H, CHϭCH2), 5.16 (m, 4 H, CHϭCH2),
4.32 (m, 4 H, CHOH), 3.74 (m, 2 H, CHO), 1.60 (m, 3 H, CH2,
CHSi), 1.27 [s, 3 H, C(CH3)2], 1.21 [s, 3 H, C(CH3)2], 0.89 [s, 9 H,
SiC(CH3)3], 0.10 [s, 3 H, Si(CH3)2], 0.08 [s, 3 H, Si(CH3)2] ppm.
13C NMR (CDCl3): δ ϭ 142.17, 141.35 (CH2ϭCH), 115.14, 114.42
(CH2ϭCH), 106.26 [C(CH3)2], 76.20, 72.68 (CHOH), 70.63, 61.72
(CHO), 30.54 (CHSi), 30.07 (CH2), 28.34 [C(CH3)2], 26.10
[SiC(CH3)3], 16.20 [SiC(CH3)3], Ϫ3.02, Ϫ3.63 (SiCH3) ppm. MS
(LSIMS): m/z (%) ϭ 379.2 (38) [M ϩ Na], 268.1 (100), 228.1 (63).
HRMS: calcd. for C19H36NaO4Si [Mϩ ϩ Na] 379.228058; found
379.226167.
Mesylate 17c: Methanesulfonyl chloride (23.6 µL, 0.29 mmol) was
added at 0 °C to a solution of 17b (0.1 g, 0.29 mmol) in anhydrous
pyridine (5 mL). The mixture was stirred for 8 h at 0 °C and an
additional quantity of methanesulfonyl chloride (23.6 µL,
0.29 mmol) was then added to complete the reaction. The mixture
was allowed to warm to room temp. and the solvents were evapor-
ated under reduced pressure. The residue was purified by column
chromatography on silica gel (cyclohexane/EtOAc, 70:30), af-
fording 17c as a colorless oil (67 mg, 55%). IR (film, KBr): ν˜max ϭ
3788 cmϪ1 (OH), 3534, 2904, 2637, 1779, 1697, 794, 702. 1H NMR
(CDCl3): δ ϭ 4.49 (m, 1 H, CHaHbOMs), 4.38 (m, 1 H, CHaHb-
OMs), 4.29 (m, 2 H, CHOH), 3.95 (dd, J ϭ 10.5, 3.4 Hz, 1 H,
CHO), 3.79 (d, J ϭ 10.5 Hz, 1 H, CH2CHO), 3.01 (s, 3 H,
SO2CH3), 2.26 (m, 2 H, CH2), 1.75 (m, 1 H, CHSi), 1.58 (m, 1 H,
OH), 1.39 [s, 3 H, C(CH3)2], 1.31 [s, 3 H, C(CH3)2], 1.20 (m, 3 H,
SiCHCH3), 1.08 (m, 18 H, SiCHCH3) ppm. 13C NMR (CDCl3):
δ ϭ 106.35 [C(CH3)2], 80.35 (CHOCH2), 76.16 (CHO), 68.32
(CH2OH), 62.77 (CH2OMs), 37.28 (CH2), 30.52 (CH3SO2), 28.60,
26.75 [C(CH3)2], 25.80 (CHSi), 19.25 (SiCHCH3), 12.10
(SiCHCH3).
General Procedure for the Ozonolysis of Allylsilanes. Conditions A.
Diol 17a: Ozone was bubbled at Ϫ78 °C through a solution of
alkene 15 (0.54 g, 2.01 mmol) in a 1:1 mixture of CH2Cl2 (5 mL)
and MeOH (5 mL). After a few minutes, the mixture turned deep
blue. When no trace of the starting material could be detected by
TLC, excess ozone was purged with nitrogen until the blue color
had totally disappeared. Solid NaBH4 (76 mg, 2 mmol) was then
added, and the mixture was allowed to warm to room temp. An
excess of NaBH4 (0.076 g, 2 mmol) was then introduced, and the
mixture was stirred for 12 h. The reaction mixture was then hy-
drolyzed with a saturated solution of NH4Cl (5 mL). The organic
layer was decanted and the aqueous layer was extracted with
EtOAc (5 ϫ 5 mL). The combined extracts were washed with a Tosylate 17d: Triethylamine (0.11 mL, 0.75 mmol), pTsCl (0.07 g,
saturated solution of NH4Cl (5 mL) and brine (2 ϫ 10 mL), and
then dried with MgSO4. The solvents were removed in vacuo and
the residue was purified by column chromatography on silica gel
(cyclohexane/EtOAc, 70:30), affording the diol 17a as white crys-
0.37 mmol) and 4-DMAP (catalytic amount) were successively ad-
ded to a solution of alcohol 17b (0.13 g, 0.37 mmol) in anhydrous
CH2Cl2 (10 mL). After 12 h at room temp., the reaction mixture
was hydrolyzed with distilled water (10 mL). The organic layer was
4048
Eur. J. Org. Chem. 2002, 4037Ϫ4053

Desymmetrization of Cyclohexa-1,4-dienes
FULL PAPER
decanted and the aqueous layer was extracted with CH2Cl2 (3 ϫ
10 mL). The combined extracts were washed with brine (2 ϫ
10 mL) and dried with MgSO4, and the solvents were removed in
vacuo. The residue was purified by column chromatography on sil-
CH), 4.78 (d, J ϭ 4.2 Hz, 1 H, NH), 4.09 (m, 1 H, CHOSi), 3.74
(br. s, 1 H, CHNH), 2.38 (m, 1 H, CHaHb), 2.39 (s, 3 H, PhCH3),
2.13 (m, 1 H, CHaHb), 2.01 (m, 1 H, CHSi), 1.04 (m, 21 H, OSi-
CHCH3), 0.96 (m, 21 H, SiCHCH3) ppm. 13C NMR (CDCl3):
ica gel (cyclohexane/EtOAc, 70:30), to afford 17d as a colorless oil δ ϭ 143.70, 137.20 (SO2Car, CarCH3), 130.28, 128.21 (Car), 127.68,
(0.101 g, 55%). IR (film, KBr): ν˜max ϭ 3758 cmϪ1 (OH), 3521, 121.31 (CϭC), 68.28 (CHOSi), 56.54 (CHNH), 32.22 (CH2), 22.38
2899, 2628, 1767, 1701, 1204, 798, 699. 1H NMR (CDCl3): δ ϭ (PhCH3), 20.03, 19.88, 18.94, 18.90, 18.85 (OSiCHCH3), 13.27,
7.81 (d, J ϭ 8.3 Hz, 2 H, CHar), 7.35 (d, J ϭ 8.3 Hz, 2 H, CHar),
12.68 (SiCHCH3) ppm. MS (LSIMS): m/z (%) ϭ 579.3 (10), 536.2
4.27Ϫ4.17 (m, 4 H, CH2OH, CH2OTs), 3.92 (dd, J ϭ 4.6, 10.6 Hz, (57), 409.3 (30), 328.1 (100), 284.1 (32). HRMS: calcd. for
1 H, CHaO), 3.75 (m, J ϭ 10.6 Hz, 1 H, CHbO), 2.46 (s, 3 H, C31H57NO3SSi [Mϩ] 579.359774; found 579.359211.
CH3Ph), 2.29Ϫ2.11 (m, 1 H, OH), 1.85Ϫ1.55 (m, 3 H, CH2, CHSi),
Diol 19a: On subjection to the ozonolysis conditions A reported
1.30 [s, 3 H, O2C(CH3)2], 1.27 [s, 3 H, O2C(CH3)2], 1.17Ϫ1.10 [m,
for 15, allylsilane 18a (0.36 g, 0.86 mmol), after column chromato-
21 H SiCH(CH3)2] ppm. 13C NMR (CDCl3): δ ϭ 145.45 (CarCH3),
graphy on silica gel (cyclohexane/EtOAc, 60:40), afforded diol 19a
134.31 (CarS), 130.66 (Car), 128.88 (Car), 107.17 [O2C(CH3)2], 81.25
(0.16 g, 40%) as a colorless oil. IR (film, KBr): ν˜max ϭ 3858 cmϪ1
,
(CHO), 77.31 (CHO), 69.83 (CH2OH), 53.55 (CH2OTs), 31.42
(CH2), 29.36 [O2C(CH3)2], 26.71 [O2C(CH3)2], 27.75 (HCSi), 22.49
(CH3Ph), 20.17 [SiCH(CH3)2], 13.04 [SiCH(CH3)2].
3625 (NH), 3600 (OH), 1395 (CϪO), 1076 (CϪO), 946, 697. 1H
NMR (CDCl3): δ ϭ 7.73 (d, J ϭ 8.2 Hz, 2 H, Ph), 7.28 (d, J ϭ
8.2 Hz, 2 H, Ph), 4.98 (d, J ϭ 8.8 Hz, 1 H, NH), 3.63 (m, 6 H, 2
ϫ CH2OH, CHNH, CHOSi), 2.75 (br. s, 1 H, OH), 2.38 (s, 3 H,
PhCH3), 2.09 (br. s, 1 H, OH), 1.71 (m, 4 H, 2 ϫ CH2), 0.93 (m,
21 H, SiCHCH3) ppm. 13C NMR (CDCl3): δ ϭ 143.45, 137.93
(SO2Car, CarCH3), 129.62, 126.80 (Ph), 73.07 (CHNH), 58.60, 58.34
(CH2OH), 53.88 (CHOSi), 36.33, 30.31 (CH2), 21.40 (CH3), 18.03,
17.98 (SiCHCH3), 12.54 (SiCHCH3) ppm. MS (LSIMS): m/z (%) ϭ
482.2 (100) [M ϩ Na], 416.2 (6.8), 268.1 (10). HRMS: calcd. for
C22H41NO5SSi [Mϩ ϩ Na] 482, 237244; found 482, 237421.
4-Methyl-N-[6-(triisopropylsilyloxy)cyclohex-3-enyl]benzenesulfon-
amide (18a): A solution of 14d (0.1 g, 0.37 mmol) in anhydrous
THF (2 mL) was added at 0 °C to a suspension of NaH in mineral
oil (60%, 60 mg, 1.5 mmol) in THF (10 mL). The reaction mixture
was stirred for 0.5 h, chlorotriisopropylsilane (0.34 mL, 1.5 mmol)
was then added dropwise at 0 °C, and the reaction mixture was
allowed to warm to room temp. After 8 h at room temp., the reac-
tion mixture was cooled to 0 °C and excess sodium hydride was
hydrolyzed with a saturated solution of NH4Cl (10 mL). The or-
ganic layer was decanted and the aqueous layer was extracted with
diethyl ether (3 ϫ 20 mL). The combined extracts were washed with
a saturated solution of NH4Cl (10 mL) and brine (10 mL) and then
dried with MgSO4, and the solvents were removed in vacuo. Col-
umn chromatography of the residue on silica gel (cyclohexane/
EtOAc, 90:10) afforded 18a as a colorless oil (0.13 g, 82%). IR
(film, KBr): ν˜max ϭ 3622 cmϪ1 (NH), 1720, 1401, 1267 (SϭO), 907
(CϪS). 1H NMR (CDCl3): δ ϭ 7.79 (d, J ϭ 8.9 Hz, 2 H, Ph), 7.31
(d, J ϭ 8.9 Hz, 2 H, Ph), 5.55 (br. s, 2 H, CHϭCH), 4.75 (d, J ϭ
8.0 Hz, 1 H, NH), 4.08 (m, 1 H, CHOSi), 3.45 (br. s, 1 H, NCH),
2.55 (s, 3 H, CH3), 2.20 (m, 4 H, CH2), 1.15 (m, 21 H, SiCHCH3)
ppm. 13C NMR (CDCl3): δ ϭ 145.30, 137.25 (SO2Car, CarCH3),
131.62, 127.43 (Car), 124.68, 123.76 (CϭC), 68.87 (CHOSi), 57.62
(CHNH), 32.22, 37.42 (CH2), 22.45 (PhCH3), 20.43, 20.01, 18.99,
18.94, 18.87 (OSiCHCH3) ppm. MS (LSIMS): m/z (%) ϭ 423.2
(100). HRMS: calcd. for C22H37NO3SSi [Mϩ] 423.226341; found
423.226312.
Diol 19b: On subjection to the ozonolysis conditions A reported
for 15, allylsilane 18b (0.18 g, 0.31 mmol), after column chromato-
graphy on silica gel (cyclohexane/EtOAc, 60:40), afforded diol 19b
(0.143 mg, 75%) as a colorless oil. IR (film, KBr): ν˜max ϭ 3858
cmϪ1, 3625 (NH), 3600 (OH), 1395 (CϪO), 1076 (CϪO), 946, 697.
1H NMR (CDCl3): δ ϭ 7.73 (d, J ϭ 8.2 Hz, 2 H, Ph), 7.28 (d, J ϭ
8.2 Hz, 2 H, Ph), 4.95 (d, J ϭ 8.8 Hz, 1 H, NH), 3.65 (m, 6 H, 2
ϫ CH2OH, CHNH, CHOSi), 2.80 (br. s, 1 H, OH), 2.42 (s, 3 H,
PhCH3), 2.00 (br. s, 1 H, OH), 1.66 (m, 3 H, SiCH, CH2), 0.92 (m,
42 H, SiCHCH3) ppm. 13C NMR (CDCl3): δ ϭ 143.87, 138.01
(SO2Car, CarCH3), 129.96, 126.85 (Ph), 72.99 (CHNH), 58.75, 58.21
(CH2OH), 54.01 (CHOSi), 36.01 (CH2), 21.23 (CH3), 19.25, 18.04
(SiCHCH3), 12.54, 11.13 (SiCHCH3, SiCH) ppm. MS (LSIMS):
m/z (%) ϭ 615.4 (100) [M ϩ Na], 610.2 (8), 457.1 (25). HRMS:
calcd. for C31H61NO5SSi2 [Mϩ
615.380954.
ϩ Na] 615.380901; found
General Procedure for Ozonolysis of Olefins 18aϪb. Conditions B.
Oxepane 20a: Ozone was bubbled at Ϫ78 °C through a solution of
4-Methyl-N-[2-(triisopropylsilyl)-6-(triisopropylsilyloxy)cyclohex-3- alkene 18a (0.158 g, 0.37 mmol) in a 1:1 mixture of CH2Cl2 (5 mL)
enyl)]benzenesulfonamide (18b):
A
solution of 14e (0.12 g,
and MeOH (5 mL). After a few minutes, the mixture turned deep
blue. When no trace of the starting material could be detected by
TLC, excess ozone was purged with nitrogen until the blue color
had totally disappeared. Powdered NaBH4 (14 mg, 0.37 mmol) was
0.28 mmol) in anhydrous THF (2 mL) was added at 0 °C to a sus-
pension of NaH in mineral oil (60%, 45 mg, 1.12 mmol) in THF
(10 mL). The reaction mixture was stirred for 0.5 h, chlorotriiso-
propylsilane (0.25 mL, 1.2 mmol) was then added dropwise at 0 °C, then added, and the mixture was allowed to warm to room temp.
and the reaction mixture was allowed to warm to room temp. After and stirred for 12 h. The reaction mixture was then hydrolyzed with
8 h at room temp., the reaction mixture was cooled to 0 °C and a saturated solution of NH4Cl (5 mL). The organic layer was de-
excess sodium hydride was hydrolyzed with a saturated solution of
NH4Cl (10 mL). The organic layer was decanted and the aqueous
layer was extracted with diethyl ether (3 ϫ 20 mL). The combined
extracts were washed with a saturated solution of NH4Cl (10 mL)
canted and the aqueous layer was extracted with EtOAc (5 ϫ
5 mL). The combined extracts were washed with a saturated solu-
tion of NH4Cl (5 mL) and brine (2 ϫ 10 mL), and then dried with
MgSO4. The solvents were removed in vacuo and the residue was
and brine (10 mL) and then dried with MgSO4, and the solvents purified by column chromatography on silica gel (cyclohexane/
were removed in vacuo. Column chromatography of the residue on
silica gel (cyclohexane/EtOAc, 95:5) afforded 18b as white crystals,
which were recrystallized from cyclohexane (0.16 g, 96%). M.p. 101
EtOAc, 80:20), affording the lactol 20a as a colorless oil (50 mg,
30%). IR (film, KBr): ν˜max ϭ 3886 cmϪ1 (OH), 3754 (NH), 1426
(CϪO), 1267 (SϭO), 904 (CϪS), 762. 1H NMR (CDCl3): δ ϭ 7.76
(d, J ϭ 8.3 Hz, 2 H, Ph), 7.27 (d, J ϭ 8.3 Hz, 2 H, Ph), 5.20 (t,
°C (cyclohexane). IR (film, KBr): ν˜max ϭ 3624 cmϪ1 (NH), 1734,
1
1261 (SϭO), 947, 895 (CϪS). H NMR (CDCl3): δ ϭ 7.76 (d, J ϭ J ϭ 6.5 Hz, 1 H, NCH), 4.13 (t, J ϭ 2.7 Hz, 1 H, CHOH), 4.02
8.2 Hz, 2 H, Ph), 7.24 (d, J ϭ 8.2 Hz, 2 H, Ph), 5.41 (m, 2 H, CHϭ
Eur. J. Org. Chem. 2002, 4037Ϫ4053
(m, 1 H, NH), 3.75 (m, 3 H, OCH2, CHOSi), 2.83 (br. s, 1 H, OH),
4049

Y. Landais, E. Zekri
FULL PAPER
2.41 (s, 3 H, PhCH3), 2.10 (dd, J ϭ 3.0, 6.7 Hz, 2 H, CH2CHN), CH), 4.21 (d, J ϭ 5.1 Hz, 1 H, HCO), 2.50 (m, 1 H, HCCH3), 2.26
1.93 (m, 1 H, CHaHb), 1.65 (m, 1 H, CHaHb), 0.87 {m, 21 H, (s, 2 H, CH2), 1.72 (m, 3 H, ϭCCH3), 1.52 (s, 3 H, OCCH3), 1.09
Si[CH(CH3)2]3} ppm. 13C NMR (CDCl3): δ ϭ 144.77, 135.93 (d, J ϭ 7.3 Hz, 3 H, HCCH3) ppm. 13C NMR (CDCl3): δ ϭ 191.12
(CSO2, CCH3), 130.69, 130.06, 129.38, 128.62 (CHar), 86.25 (CϭS), 133.55 (ϭCCH3), 124.03 (ϭCH), 90.63 (HCO), 89.68
(CNH), 77.96 (CHOH), 77.33 (CHOSi), 67.77 (OCH2), 42.56 (CH3CO), 36.65 (CH2), 33.81 (CH3CO), 27.26 (ϭCCH3), 23.18
(CH2), 38.69 (CH2CHN), 22.37 (PhCH3), 18.77 {Si[CH(CH3)2]3}, (HCCH3), 16.63 (HCCH3) ppm. MS (EI): m/z (%) ϭ 198 (81), 138
12.58 {Si[CH(CH3)2]3} ppm. MS (LSIMS): m/z (%) ϭ 480.1 (30) (45), 121.0 (100), 95 (54), 43 (52). HRMS: calcd. for C10H14O2S
[M ϩ Na], 440.1 (100), 414 (13), 248 (7). HRMS: calcd. for
[Mϩ] 198.071452; found 198.071144.
C22H39NO5SSi [Mϩ ϩ Na] 480.221594; found 480.221085.
Thionocarbonate 22: Anhydrous pyridine (0.15 mL, 1.92 mmol) was
added at room temp. to a solution of diol 12f (0.1 g, 0.64 mmol) in
dry CH2Cl2 (10 mL). The mixture was then cooled to 0 °C and a
solution of PhOCSCl (0.2 mL, 1.28 mmol) in CH2Cl2 (2 mL) was
added dropwise at 0 °C. The reaction mixture was stirred at room
temp. for 12 h, and was then hydrolyzed with water (5 mL). The
Oxepane 20b: On subjection to the ozonolysis conditions B re-
ported for 18a, allylsilane 18b (0.159 g, 0.27 mmol), after column
chromatography on silica gel (cyclohexane/EtOAc, 80:20), afforded
lactol 20b (90 mg, 54%) as a colorless oil. IR (film, KBr): ν˜max
ϭ
3864 cmϪ1 (OH), 3789 (NH), 1410 (CϪO), 1275 (SϭO), 919
(CϪS). 1H NMR (CDCl3): δ ϭ 7.71 (d, J ϭ 8.3 Hz, 2 H, Ph), 7.22 organic layer was decanted and the aqueous layer was extracted
(d, J ϭ 8.3 Hz, 2 H, Ph), 5.44 (m, 1 H, NCH), 4.32 (d, J ϭ 3.0 Hz, with CH2Cl2 (2 ϫ 10 mL). The combined extracts were then
1 H, CHOH), 4.14 (d, J ϭ 3.6 Hz, 1 H, NH), 3.92 (m, 2 H, OCH2), washed with brine (10 mL) and dried with MgSO4, and the solvents
3.88 (d, J ϭ 2.7 Hz, 1 H, CHOSi), 2.93 (m, 1 H, OH), 2.34 (s, 3 were evaporated under vacuum. The residue was purified by chro-
H, PhCH3), 2.18 (m, 3 H, CH2, CHSi), 1.10 (m, 21 H, OSiCHCH3), matography on silica gel (cyclohexane/EtOAc, 9:1) to afford 22 as
0.81 (m, 21 H, SiCHCH3) ppm. 13C NMR (CDCl3): δ ϭ 143.64, a yellow oil (0.184 g, 98%), used in the next step without further
1
134.51 (CSO2, CCH3), 129.61, 127.6 (Ph), 85.05 (CHNH), 74.70 purification. H NMR (CDCl3): δ ϭ 6.81 (m, 5 H, Ar), 5.37 (m, 1
(CHOH), 71.51 (CHOSi), 60.95 (OCH2), 43.19 (CH2), 34.73
H, ϭCH), 4.18 (d, J ϭ 5.2 Hz, 1 H, CHOCS), 2.72 (s, 1 H, OH),
(CHSi), 21.32 (PhCH3), 19.20, 19.07, 17.83, 17.81 (SiCHCH3), 2.43 (m, 3 H, CHCH3, CH2), 1.73 (s, 3 H, CH3COH), 1.53 (s, 3 H,
12.37, 11.27 (SiCH) ppm. MS (LSIMS): m/z (%) ϭ 636.3 (100) [M CH3Cϭ), 1.10 (d, J ϭ 7.1 Hz, 3 H, CH3CH) ppm. 13C NMR
ϩ Na], 354.2 (14). HRMS: calcd. for C31H59NO5SSi2 [Mϩ ϩ Na] (CDCl3): δ ϭ 191.7 (CϭS), 157.2 (OCar), 141.5 (CϭC), 130.2 (Car),
636.355023; found 636.355284.
121.4 (Car), 124.5 (CϭC), 116.7 (Car), 91.5 (CHO), 72.2
(CH3COH), 44.1 (CH2), 24.3 (CHCH3), 23.1, 22.4, 14.8 (CHCH3,
CH3Cϭ, CH3COH).
Thionocarbonate 21a: A solution of thiocarbodiimidazole (0.17 g,
0.93 mmol) in dry toluene (25 mL) was added dropwise to a solu-
tion of diol 12d (0.1 g, 0.46 mmol) in toluene (5 mL) and the mix-
ture was stirred for 8 h at room temp. The solvent was then evapor-
ated under vacuum and the residue was dissolved in EtOAc
General Procedure for Acetylation of Diols 12aϪf. 6-Hydroxy-2,4,6-
trimethylcyclohex-3-enyl Acetate (23a): DMAP (10 mg), triethylam-
ine (0.26 mL, 1.92 mmol), and then acetic anhydride (0.18 mL,
(20 mL). The yellow mixture was washed with HCl solution (10%), 1.92 mmol) were added to a solution of diol 12f (0.1 g, 0.64 mmol)
water (10 mL) and finally with brine (3 ϫ 10 mL). The organic
layer was dried with MgSO4 and the solvent was removed in vacuo.
in anhydrous CH2Cl2 (20 mL). The reaction mixture was stirred for
2 h at room temp. and then hydrolyzed with water (10 mL). The
Filtration of the residue through a short pad of silica gel (petroleum organic layer was decanted and the aqueous layer was extracted
ether/EtOAc, 80:20) afforded 21a as a brown solid, which was
recrystallized from petroleum ether/diethyl ether (0.11 g, 93%).
M.p. 103 °C (petroleum ether/diethyl ether, 95:5). IR (film, KBr):
with CH2Cl2 (3 ϫ 20 mL). The combined extracts were washed
with brine (20 mL) and dried with MgSO4, and the solvent was
removed in vacuo. Column chromatography on silica gel (cyclohex-
ν˜max ϭ 3787 cmϪ1, 3150, 2784, 2223, 1657, 1547, 1310, 1238, 1194, ane/EtOAc, 70:30) afforded the acetate 23a as a yellow oil (0.12 g,
1163, 1072, 918, 784, 761. 1H NMR (CDCl3): δ ϭ 5.48 (d, J ϭ
95%), used in the next step without further purification. IR (film,
6 Hz, 1 H, ϭCH), 4.80 (d, J ϭ 4.9 Hz, 1 H, HCO), 2.41Ϫ2.28 (m, KBr): ν˜max ϭ 3472 cmϪ1, 2966, 2359, 1743, 1453, 1375, 1237, 1035,
1
2 H, CH2), 2.18 (s, 1 H, SiCH), 1.75 (m, 3 H, ϭCCH3), 1.71 (s, 3
915, 876, 786, 761. H NMR (CDCl3): δ ϭ 5.11 (m, 1 H, ϭCH),
H, CH3C), 0.15 [s, 9 H, Si(CH3)3] ppm. 13C NMR (CDCl3): δ ϭ 4.60 (d, J ϭ 9.4 Hz, 1 H, HCOAc), 2.41 (s, 1 H, OH), 2.23Ϫ2.16
190.46 (CϭS), 138.38 (ϭCCH3), 113.94 (ϭCH), 94.24 (HCO), (m, 1 H, HCCH3), 2.06 (s, 3 H, OCOCH3), 2.00 (m, 2 H, CH2),
85.55 (CH3CO), 41.75 (CH2), 28.35 (SiCH), 26.24 (CH3CO), 24.58 1.58 (s, 3 H, ϭCCH3), 1.09 (s, 3 H, HOCCH3), 0.89 (d, J ϭ 7.0 Hz,
(ϭCCH3), 0.52 [Si(CH3)3] ppm. MS (EI): m/z (%) ϭ 256 (0.4), 179 3 H, HCCH3) ppm. 13C NMR (CDCl3): δ ϭ 170.98 (CϭO), 130.40
(4), 107 (68), 91 (30), 73 (100), 45 (13). HRMS: calcd. for
(ϭCCH3), 125.13 (ϭCH), 80.42 (HCOAc), 70.72 (HOCCH3),
44.24 (CH2), 32.78 (HCCH3), 25.73 (ϭCCH3), 22.90 (HOCCH3),
20.90 (OCOCH3), 18.10 (HCCH3) ppm.
C12H20O2SSi [Mϩ] 256.095330; found 256.056230.
Thionocarbonate 21b: A solution of thiocarbodiimidazole (0.46 g,
1.86 mmol) in dry toluene (7 mL) was added dropwise to a solution 2-Benzyloxy-1,3,5-trimethylcyclohex-4-en-1-ol (23b): Diol 12f
of diol 12f (0.1 g, 0.64 mmol) in toluene (5 mL) and the mixture (0.1 g, 0.64 mmol) and KI (0.2 g, 1.23 mmol) were added at 0 °C
was stirred for 8 h at room temp. The solvent was then evaporated to a suspension of NaH in mineral oil (60%, 0.05 g, 1.25 mmol) in
under vacuum and the residue was dissolved in EtOAc (20 mL).
The yellow mixture was washed with HCl solution (10%), water
(10 mL) and finally brine (3 ϫ 10 mL). The organic layer was dried
with MgSO4 and the solvent was removed in vacuo. Filtration of
the residue through a short pad of silica gel (petroleum ether/
EtOAc, 80:20) afforded 21b as a yellow solid, which was recrystal-
anhydrous THF (10 mL). After dropwise addition of a solution of
benzyl bromide (0.23 mL, 1.92 mmol) in THF (5 mL), the reaction
mixture was allowed to warm slowly to room temp. and stirred
overnight. The flask was then cooled to 0 °C and excess sodium
hydride was hydrolyzed by careful addition of a saturated solution
of NH4Cl (10 mL). The organic layer was decanted and the aque-
lized from petroleum ether/diethyl ether (0.11 g, 86%). M.p. 75 °C ous layer was extracted with diethyl ether (3 ϫ 20 mL). The com-
(petroleum ether/diethyl ether, 95:5). IR (film, KBr): ν˜max ϭ 2963 bined extracts were washed with brine (2 ϫ 20 mL) and dried with
cmϪ1, 2368, 2217, 1799, 1732, 1669, 1455, 1313, 1285, 1268, 1088,
1020, 953, 799, 699, 668. H NMR (CDCl3): δ ϭ 5.38 (m, 1 H, ϭ
MgSO4, and the solvents were removed in vacuo. Column chroma-
tography on silica gel (cyclohexane/EtOAc, 80:20) afforded 23b as
1
4050
Eur. J. Org. Chem. 2002, 4037Ϫ4053

Desymmetrization of Cyclohexa-1,4-dienes
FULL PAPER
a brown solid, which was recrystallized from cyclohexane (0.12 g,
75%). M.p. 140 °C (cyclohexane). IR (film, KBr): ν˜max ϭ 3576
cmϪ1, 3013, 2931, 1498, 1452, 1502, 1116, 1057, 699. 1H NMR
(dd, J ϭ 7.9, 5.1 Hz, 1 H, HCOH), 4.91 (dd, J ϭ 6.4, 4.8 Hz, 1 H,
HCOH), 4.61 (d, J ϭ 11.4 Hz, 1 H, OCHaHb), 4.48 (d, J ϭ
11.4 Hz, 1 H, OCHaHb), 4.00 (d, J ϭ 10.3 Hz, 1 H, HCOBn), 3.70
(CDCl3): δ ϭ 7.43Ϫ7.22 (m, 5 H, Har), 5.22 (m, 1 H, CHϭC), 4.74 (m, 2 H, HCOBn, OH), 2.71 (d, J ϭ 16.7 Hz, 1 H, CHaHb), 2.64
(s, 2 H, OCH2), 3.10 (d, J ϭ 8.4 Hz, 1 H, CHO), 2.61Ϫ2.54 (s, 1 (d, J ϭ 14.3 Hz, 1 H, CHaHb), 2.48 (d, J ϭ 14.3 Hz, 1 H, CHaHb),
H, OH), 2.34 (m, 1 H, HCCH3), 2.20 (s, 2 H, CH2), 1.73 (s, 3 H, ϭ
2.39 (d, J ϭ 16.7 Hz, 1 H, CHaHb), 2.27 (m, 1 H, HCCH3), 2.14
CCH3), 1.41 (s, 3 H, HOCCH3), 1.18 (d, J ϭ 7.9 Hz, 3 H, HCCH3) (s, 3 H, CH3CO), 2.03 (s, 3 H, CH3CO), 1.36 (s, 3 H, CH3CCH2),
ppm. 13C NMR (CDCl3): δ ϭ 137.59 (CarCH2), 131.23 (Car), 1.14 (s, 3 H, CH3CCH2), 1.13 (d, J ϭ 5.7 Hz, 3 H, HCCH3), 1.11
129.40 (HCϭ), 128.90 (Car), 126.99 (HCϭ), 124.69 (Car), 88.68 (d, J ϭ 7.0 Hz, 3 H, HCCH3) ppm. 13C NMR (CDCl3): δ ϭ 209.24
(COCH2), 74.50 (OCH2Ph), 68.15 (CH3COH), 44.62 (CH2), 35.43 (CϭO), 128.92, 128.81, 128.54, 128.39, 128.21, 128.13 (Ph), 102.75,
(HCCH3), 27.84 (ϭCCH3), 23.99 (HOCCH3), 19.91 (HCCH3) 98.62 (CHOH), 88.45, 86.18 (HCOBn), 74.15, 73.61 (OCH2), 66.91
ppm. MS (LSIMS): m/z (%) ϭ 269.2 (100), 229.2 (73). HRMS:
(CH3CCH2), 53.70, 53.14 (CH2CϭO), 44.95, 44.42 (HCCH3),
32.76, 32.12 (CHCH3), 23.93, 23.75 (CH3CO), 21.98 (CH3CCH2)
ppm. C16H22O4 (278.34): calcd. C 69.04, H 7.97, O 22.99; found C
69.05, H 8.12, O 22.83.
calcd. for C16H22O2 [Mϩ ϩ Na] 269.151750; found 269.151769.
2-Hydroxy-2,4-dimethylcyclohex-3-enyl Acetate (23c): On subjec-
tion to the general acetylation procedure reported for the prepara-
tion of 23a, diol 12g (0.1 g, 0.69 mmol), after column chromatog-
Lactol 24c: On subjection to the ozonolysis conditions C, olefin
raphy (cyclohexane/EtOAc, 70:30), afforded the acetate 23c as a 23c (0.1 g, 0.54 mmol), after column chromatography on silica gel
yellow oil (0.12 g, 95%). IR (film, KBr): ν˜max ϭ 3458 cmϪ1, 2964,
(cyclohexane/EtOAc, 70:30), afforded lactol 24c as a brown oil
1742, 1372, 1260, 1101, 1031, 789, 762. 1H NMR (CDCl3): δ ϭ (36 mg, 32%, 20% de). IR (film, KBr): ν˜max ϭ 3890 cmϪ1 (OH),
5.24 (m, 1 H, ϭCH), 4.81 (m, 1 H, HCOAc), 2.24 (m, 3 H, ϭ
CHϪCH2), 2.13 [m, 2 H, ϭC(CH3)ϪCH2], 2.06 (s, 3 H, OCOCH3),
2900, 1745 (CϭO), 1732 (CϭO), 1468, 1402 (CϪO), 1287 (CϪO),
1100 (CϪO), 790, 782. H NMR (CDCl3): δ ϭ 5.21 (dd, J ϭ 3.4,
1
1.63 (s, 3 H, ϭCCH3), 1.18 (s, 3 H, HOCCH3) ppm. 13C NMR 8.6 Hz, 1 H, HCOH), 5.01 (dd, J ϭ 1.9, 5.6 Hz, 1 H, HCOAc),
(CDCl3): δ ϭ 171.52(CϭO), 131.52 (ϭCCH3), 117.28 (ϭCH), 4.94 (dd, J ϭ 1.9, 5.6 Hz, 1 H, HCOAc), 3.30 (s, 2 H, CH2CO),
74.92 (HCOAc), 70.00 (HOCCH3), 43.07 [ϭC(CH3)ϪCH2], 28.56
2.68 (m, 2 H, CH2), 2.13 (s, 3 H, COCH3), 2.04 (s, 3 H, OCOCH3),
(ϭCHCH2), 25.25 (ϭCCH3), 23.13 (HOCCH3), 21.22 (OCOCH3) 1.27 (s, 3 H, CH3) ppm. 13C NMR (CDCl3): δ ϭ 207.55 (CH2CO),
ppm.
171.77 (OCOCH3), 84.73 (HCOH), 78.60 (HCOAc), 55.92
(CH3CCH2), 53.88 (CH2CO), 39.79 (HCCH2), 32.97 (CH3CCH2),
23.50 (CH3COCH2), 21.95 (OCOCH3) ppm. C11H18O4 (214.26):
calcd. C 55.55, H 7.46, O 36.99; found C 55.30, H 7.66, O 37.04.
General Procedure for the Ozonolysis of Alkenes 23aϪc. Lactol 24a:
Ozone was bubbled at Ϫ78 °C through a solution of 23a (0.1 g,
0.50 mmol) in a 5:1 mixture of CH2Cl2 (15 mL) and MeOH
(13 mL). After a few minutes, the solution turned deep blue. When
no trace of the starting material could be detected by TLC, excess
ozone was purged with nitrogen until the blue color had totally
disappeared. Me2S (0.18 mL, 2.5 mmol) was then added, and the
mixture was allowed to warm to 0 °C. The solvents were evaporated
under reduced pressure and the residue was purified by column
chromatography on silica gel (cyclohexane/EtOAc, 70:30), af-
fording the lactol 24a as a brown oil (87 mg, 76%, 20% de). IR
General Procedure for the Ozonolysis of Alkenes 23aϪc. Conditions
D. Acetal 25a: Ozone was bubbled at Ϫ78 °C through a solution
of alkene 23a (0.1 g, 0.50 mmol) in a 5:1 mixture of CH2Cl2
(2.5 mL) and MeOH (0.5 mL). When no trace of the starting mat-
erial could be detected by TLC, excess ozone was purged with ni-
trogen until the blue color had totally disappeared. Me2S (0.19 mL,
2.5 mmol) was added and the mixture was allowed to warm to
room temp. The solvents were evaporated under reduced pressure
(film, KBr): ν˜max ϭ 3886 cmϪ1 (OH), 2927, 1742 (CϭO), 1728 (Cϭ and the residue was purified by column chromatography on silica
O), 1567, 1424, 1396 (CϪO), 1271 (CϪO), 1045 (CϪO), 791, 762.
gel (cyclohexane/EtOAc, 70:30), affording the acetal 25a as a color-
1H NMR (CDCl3): δ ϭ 5.13 (d, J ϭ 10.3 Hz, 1 H, HOCH), 4.96
less oil (90 mg, 73%, Ͼ 98% de). IR (film, KBr): ν˜max ϭ 1739 cmϪ1
(d, J ϭ 8.1 Hz, 1 H, HCOAc), 4.42 (d, J ϭ 9.1 Hz, 1 H, HCOAc), (CϭO), 1732 (CϭO), 1572, 1403, 1278 (CϪO), 795, 754. 1H NMR
3.20 (m, 1 H, OH), 2.97 (d, J ϭ 17.7 Hz, 1 H, CHaHb), 2.83 (d, (CDCl3): δ ϭ 4.89 (d, J ϭ 6.8 Hz, 1 H, CHOH), 4.57 (d, J ϭ
J ϭ 17.7 Hz, 1 H, CHaHb), 2.77 (d, J ϭ 15.7 Hz, 1 H, CHaHb),
2.64 (d, J ϭ 15.7 Hz, 1 H, CHaHb), 2.40 (m, 1 H, HCCH3), 2.25 H, CHaHb), 2.61 (d, J ϭ 15 Hz, 1 H, CHaHb), 2.20 (m, 1 H,
(m, 1 H, HCCH3), 2.14 (s, 3 H, OCOCH3), 2.12 (s, 3 H, OCOCH3), CH3CH), 2.15 (s, 3 H, OCOCH3), 2.05 (s, 3 H, CH3CO), 1.25 (s,
2.06 (s, 3 H, CH3CO), 2.05 (s, 3 H, CH3CO), 1.26 (s, 3 H, CH3), 3 H, CH3), 1.13 (d, J ϭ 7.1 Hz, 3 H, CH3CH) ppm. 13C NMR
3.9 Hz, 1 H, CHOAc), 3.31 (s, 3 H, OCH3), 2.75 (d, J ϭ 15 Hz, 1
1.12 (d, J ϭ 7.1 Hz, 3 H, CH3CH), 1.06 (d, J ϭ 6.8 Hz, 3 H,
(CDCl3): δ ϭ 207.1 (CϭO), 171.0 (OCϭO), 109.28 (CH3OC),
CH3CH), 1.04 (s, 3 H, CH3) ppm. 13C NMR (CDCl3): δ ϭ 209.27 82.42(COAc), 82.26 (CCH2), 55.46 (CH2), 53.46 (OCH3), 45.25
(CH3COCH2), 171.25 (OCOCH3), 98.19 (HCOH), 80.48 (CH3CH), 31.94 (CH3CϭO), 22.43 (OCOCH3), 21.04 (CH3CCH2),
(HCOAc), 53.03 (CH3CCH2), 52.61 (CH2), 42.93 (HCCH3), 31.51 15.45 (CHCH3) ppm.
(CH3COCH2), 23.04 (CH3CCH2), 20.79 (OCOCH3), 11.10
Acetal 25b: On subjection to the ozonolysis conditions D, olefin
(CH3CH) ppm. MS (EI): m/z (%) ϭ 231 (3) [Mϩ· Ϫ OH], 170 (4.5),
23b (0.1 g, 0.40 mmol), after column chromatography on silica gel
152 (8), 130 (29), 113 (20), 101 (57), 82 (29), 43 (100). C11H18O5
(230.26): calcd. C 57.38, H 7.88, O 34.74; found C 57.68, H 8.08,
O 34.24.
(cyclohexane/EtOAc, 70:30), afforded the acetal 25b as a colorless
oil (95 mg, 80%, 20% de). IR (film, KBr): ν˜max ϭ 2954 cmϪ1
1
(CϪHar), 1764 (CϭO), 1400 (CϪO), 1275 (CϪO), 789. H NMR
Lactol 24b: On subjection to the ozonolysis conditions C, olefin
23b (0.16 g, 0.64 mmol), after column chromatography on silica gel
(cyclohexane/EtOAc, 80:20), afforded lactol 24b as yellow crystals
recrystallized from petroleum ether (0.13 g, 76%, 20% de). M.p. 81
(CDCl3): δ ϭ 7.29 (m, 5 H, Ph), 4.58 (s, 2 H, OCH2Ph), 4.45 (d,
J ϭ 4.5 Hz, 1 H, MeOCH), 3.61 (d, J ϭ 7.9 Hz, 1 H, CHOBn),
3.32 (s, 3 H, OCH3), 2.57 (d, J ϭ 13.7 Hz, 1 H, CHaHb), 2.46 (d,
J ϭ 13.7 Hz, 1 H, CHaHb), 2.16 (s, 3 H, CH3CO), 2.17 (m, 4 H,
°C (petroleum ether). IR (film, KBr): ν˜max ϭ 3886 cmϪ1 (OH), CH3CO, CHCH3), 1.30 (s, 3 H, CH3), 1.24 (s, 3 H, CH3), 1.09 (d,
2934, 1752 (CϭO), 1610, 1557, 1520, 1494, 1400 (CϪO), 1275
J ϭ 7.0 Hz, 3 H, CH3CH), 1.03(d, J ϭ 6.7 Hz, 3 H, CH3CH) ppm.
1
(CϪO), 791, 762. H NMR (CDCl3): δ ϭ 7.30 (m, 5 H, Har), 5.08 13C NMR (CDCl3): δ ϭ 207.40 (CϭO), 137.20 (OCH2Car), 128.15,
Eur. J. Org. Chem. 2002, 4037Ϫ4053
4051

Y. Landais, E. Zekri
FULL PAPER
127.45 (Ph), 109.06 (CHOCH3), 88.35 (CHOBn), 72.89 (OCH2),
56.13 (CH3CCH2), 55.34 (OCH3), 53.41 (CH2CϭO), 44.86
a solution of benzyl bromide (44 µL, 0.37 mmol) in THF (1 mL),
the reaction mixture was allowed to warm slowly to room temp.
(CH3CH), 32.10 (CH3CH), 22.45 (CH3CϭO), 15.81 (CH3CCH2) and stirred overnight. The flask was then cooled to 0 °C and excess
ppm. MS (LSIMS): m/z (%) ϭ 315 (80) [Mϩ ϩ Na], 261 (100).
sodium hydride was hydrolyzed by careful addition of a saturated
HRMS: calcd. for C17H24O4 [Mϩ ϩ Na] 315.157229; found solution of NH4Cl (5 mL). The organic layer was decanted and the
315.157494.
aqueous layer was extracted with diethyl ether (3 ϫ 10 mL). The
combined extracts were washed with brine (2 ϫ 10 mL) and dried
with MgSO4, and the solvents were removed in vacuo. Column
chromatography on silica gel (cyclohexane/EtOAc, 90:10) afforded
27 as a pale yellow oil (54 mg, 40%). IR (film, KBr): ν˜max ϭ 3487
cmϪ1 (OH), 3019, 2975, 2210, 1689, 1500, 1347, 1081, 827, 767,
691. 1H NMR (CDCl3): δ ϭ 7.35 (m, 5 H, Ph), 5.61 (m, 1 H, CHϭ
CH), 5.47 (m, 1 H, CHϭCH), 4.66 (d, J ϭ 12.2 Hz, 1 H, OCHaHb),
4.57 (d, J ϭ 12.2 Hz, 1 H, OCHaHb), 4.22 (m, 1 H, CHOH), 3.70
(m, 1 H, CHOBn), 2.15 (m, 3 H, CH2, CHSi), 1.69 (s, 1 H, OH),
1.07 (m, 21 H, SiCHCH3) ppm. 13C NMR (CDCl3): δ ϭ 138.68
(CH2Car), 128.83, 128.19 (Ph), 127.15, 120.29 (CϭC), 75.12
(CHOH), 70.50 (OCH2Ph), 63.39 (CHOBn), 32.12 (SiCH), 24.44
(SiCHCH3), 19.32 (SiCHCH3), 11.88 ppm.
General Procedure for the Oxidation of Lactols 24aϪc. Lactone 26a:
A solution of lactol 24a (55 mg, 0.23 mmol) in dry CH2Cl2 (2 mL)
was added with vigorous stirring to a suspension of PCC (0.17 g,
0.76 mmol) and neutral alumina (0.34 g) in CH2Cl2 (2 mL). The
reaction mixture, which turned dark brown, was stirred overnight
and then filtered through a short pad of Florisil. The solid residue
was washed several times with diethyl ether. The solvents were re-
moved under reduced pressure, and the residue was purified by
column chromatography (cyclohexane/EtOAc, 70:30), affording
26a as a yellow oil (48 mg, 89%). IR (film, KBr): ν˜max ϭ 2927
cmϪ1, 1789 (CϭO), 1741 (CϭO), 1557, 1454, 1372 (CϪO), 1237
(CϪO) 1044 (CϪO), 794, 760. 1H NMR (CDCl3): δ ϭ 5.25 (d, J ϭ
8.2 Hz, 1 H, HCOAc), 2.97 (d, J ϭ 18.0 Hz, 1 H, CHaHb), 2.82 (d,
J ϭ 18.0 Hz, 1 H, CHaHb), 2.79 (dq, J ϭ 8.2, 7.3 Hz, 1 H,
HCCH3), 2.10 (s, 3 H, COCH3), 2.07 (s, 3 H, OCOCH3), 1.37 (d,
J ϭ 7.3 Hz, 3 H, CH3CH), 1.24 (s, 3 H, CH3CCH2) ppm. 13C
NMR (CDCl3): δ ϭ 205.45 (CH3COCH2), 176.12 (CH3COO),
172.13 (CHCOO), 82.48 (CHOAc), 79.27 (CH3CCH2), 51.40
(CH2CO), 40.48 (CH3CH), 30.99 (CH3COCH2), 29.69
(CH3CCH2), 21.29 (CH3COO), 13.10 (CH3CH) ppm. MS
(LSIMS): m/z (%) ϭ 251.0 [M ϩ Na], 229.0 [M؉· ϩ 1]. HRMS:
calcd. for C11H17O5 [Mϩ ϩ 1] 229.108063; found 229.107599.
α-Silyl Aldehyde 28: On subjection to the ozonolysis conditions C,
olefin 27 (60 mg, 0.16 mmol), after column chromatography on sil-
ica gel (cyclohexane/EtOAc, 80:20), afforded lactol 28 as a colorless
oil (40 mg, 60%, Ͼ 98% de). IR (film, KBr): ν˜max ϭ 3754 cmϪ1
(OH), 1784 (CϭO), 1421 (CϪO), 1283 (CϪO), 789. 1H NMR
(CDCl3): δ ϭ 9.69 (d, J ϭ 4.4 Hz, 1 H, HCϭO), 7.28 (m, 5 H, Ph),
4.93 (dd, J ϭ 5.9, 1.9 Hz, 1 H, CHOH), 4.68 (dd, J ϭ 10.9, 4.9 Hz,
1 H, CHOBn), 4.88 (s, 2 H, OCH2Ph), 3.64 (m, 1 H, OCH), 2.78
(dd, J ϭ 15.6, 4.4 Hz, 1 H, HCCϭO), 2.21 (m, 2 H, CHaHb), 1.90
(m, 2 H, OH, CHaHb), 1.22 (m, 21 H, SiCHCH3) ppm. 13C NMR
(CDCl3): δ ϭ 201.22 (CϭO), 138.23 (CarCH2), 128.78, 128.72,
128.45, 128.13 (Ph), 105.84, 104.92 (CHOH), 83.75 (CHOBn),
72.24 (OCH2), 51.89 (OCHCH), 38.44 (CH2), 19.32 (CHCHSi),
12.67 (SiCHCH3), 1.14 (SiCHCH3) ppm. C22H36O4Si (392.63):
calcd. C 67.30, H 9.24, O 16.30, Si 7.15; found C 67.10, H 9.01, O
16.54, Si 7.35.
Lactone 26b: On subjection to the oxidation conditions reported
for lactol 24a, lactol 24b (0.13 g, 0.46 mmol), after column chroma-
tography on silica gel (cyclohexane/EtOAc, 70:30), afforded lactone
26b as a colorless oil (97 mg, 77%). IR (film, KBr): ν˜max ϭ 1795
cmϪ1 (CϭO), 1732 (CϭO), 1562, 1485 (CϪO), 1223 (CϪO) 752,
770. 1H NMR (CDCl3): δ ϭ 7.30 (m, 5 H, Ph), 4.63 (d, J ϭ
11.6 Hz, 1 H, OCHaHb), 4.53 (d, J ϭ 11.6 Hz, 1 H, OCHaHb), 4.09
(d, J ϭ 8.8 Hz, 1 H, CHOBn), 2.83 (d, J ϭ 16 Hz, 1 H, CHaHb),
2.71 (m, 1 H, CHCH3), 2.48 (d, J ϭ 16 Hz, 1 H, CHaHb), 2.09 (s,
3 H, CH3CO), 1.35 (s, 3 H, CH3), 1.32 (d, J ϭ 7.1 Hz, 3 H,
CHCH3) ppm. 13C NMR (CDCl3): δ ϭ 206.25 (CH2CϭO), 176.47
(CϭO), 138.52 (CH2Car), 129.5, 128.8 (Ph), 85.73 (CHOBn), 84.08
(OCCH3), 74.61 (CH2Ph), 52.29 (CH2CϭO), 42.05 (CHCH3),
32.73 (CH3CϭO), 22.29 (OCCH3), 14.74 (CHCH3) ppm. C16H20O4
(276.33): calcd. C 69.54, H 7.30, O 23.16; found C 69.38, H 7.48,
O 23.14.
Acknowledgments
We gratefully acknowledge the CNRS and the Region Aquitaine
for a grant to E. Z. and for financial support. We thank Prof. C.
Biran, Dr. P. Clavel and Dr. G. Lessenne (University Bordeaux-1)
for technical assistance and helpful discussions during the studies
on the Birch electrochemical reductions. Prof N. Abd Rahman
(University of Malaya, Malaysia) is acknowledged for fruitful dis-
cussions.
Lactone 26c: On subjection to the oxidation conditions reported
for lactol 24a, lactol 24c (36 mg, 0.16 mmol), after column chroma-
tography on silica gel (cyclohexane/EtOAc, 70:30), afforded lactone
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,
[1c]
R. Angelaud, Y. Landais,
[1d]
2982, 1767 (CϭO), 1723 (CϭO), 1471, 1399 (CϪO), 1321 (CϪO),
R. Angelaud, Y.
1
1084 (CϪO), 800, 764. H NMR (CDCl3): δ ϭ 4.94 (dd, J ϭ 1.9,
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[1f]
Y. Landais, Chimia 1998, 52, 104Ϫ111.
R.
5.6 Hz, 1 H, HCOAc), 3.38 (s, 2 H, CH2CO), 2.71 (m, 2 H, CH2),
2.15 (s, 3 H, COCH3), 2.09 (s, 3 H, OCOCH3), 1.31 (s, 3 H, CH3)
ppm. 13C NMR (CDCl3): δ ϭ 207.85 (CH2CO), 172.01 (OC-
OCH3), 170.11 (CH2COO), 80.00 (HCOAc), 54.92 (CH3CCH2),
53.88 (CH2CO), 39.82 (HCCH2), 33.18 (CH3CCH2), 22.30
(CH3COCH2), 20.99 (OCOCH3) ppm. C10H14O5 (214.22): calcd. C
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