Desymmetrisation and ring opening of cyclohexa-1,4-dienes. An access to highly functionalised cyclic and acyclic systems

Article abstract of DOI:10.1016/S0040-4039(01)01318-1

Acyclic and cyclic synthons are readily available in three steps starting from substituted arenes. Birch reduction of the latter followed by desymmetrisation through Sharpless AD reaction then ozonolysis thus afforded five-membered ring lactols and acycli

Full text of DOI:10.1016/S0040-4039(01)01318-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6547–6551
Desymmetrisation and ring opening of cyclohexa-1,4-dienes. An
access to highly functionalised cyclic and acyclic systems
Yannick Landais* and Elisabeth Zekri
Laboratoire de Chimie Organique et Organom e´ tallique, 351 Cours de la Lib e´ ration, 33405 Talence Cedex, France
Received 5 July 2001; revised 20 July 2001; accepted 21 July 2001
Abstract—Acyclic and cyclic synthons are readily available in three steps starting from substituted arenes. Birch reduction of the
latter followed by desymmetrisation through Sharpless AD reaction then ozonolysis thus afforded five-membered ring lactols and
acyclic polyols with good to excellent stereocontrol in high yields. © 2001 Elsevier Science Ltd. All rights reserved.
Total synthesis of complex natural products possessing
arrays of contiguous stereocentres such as polyketide-
derived natural products in the polyether macrolide and
polyene families still continue to be a matter of strong
interest. Acyclic stereocontrol has been used extensively
in this respect to set up chains with adjacent stereogenic
centres, having the correct relative configurations.
Diastereo- and enantioselective addition of nucleophiles
to carbonyl groups and additions of electrophiles to
double bonds are amongst the most efficient methods
have been created, ring opening can be carried out
through various methods depending on the remaining
functionalities and the substitution pattern on the ring.
Ozonolysis and Baeyer–Villiger reactions are often used
in this context due to their mildness and high level of
4
selectivity. Recently, transition metal complexes have
also been shown to mediate efficiently ring-opening
5
processes. We report here on a novel approach
towards acyclic and cyclic synthons using this concept
as applied to highly functionalised cyclohexene rings.
1
for this purpose. Functionalisation then ring opening
of a cyclic precursor may however offer a very attrac-
tive alternative to acyclic stereocontrol. Conforma-
We recently described a very straightforward method to
access, in a limited number of steps, five- and six-mem-
bered rings having multiple stereocentres. Our
approach was based on a sequence involving a Birch
reduction of arylsilane precursors followed by a desym-
metrisation of the silylcyclohexa-1,4-dienes using
Sharpless asymmetric dihydroxylation (AD reaction) or
amino-hydroxylation (AA reaction). The resulting diols
or amino-alcohols were then elaborated further to
provide conduritols, carba-sugars as well as carba-C-
2
6
tional preferences, particularly in six-membered ring
systems, have thus allowed the elaboration of highly
substituted rings possessing several contiguous stereo-
genic centres in a very stereocontrolled manner. Such a
strategy pioneered by Corey and Woodward to access
macrocyclic polypropionate subunits has since been
recognised as a valuable method for the synthesis of
3
other natural products. Once the stereogenic centres
R
OH
O
R
R
R
R’
HO
O
OH
OH
R’
R’
1
R R’ OH OH
R’
R’
R’
R’
R’
R’
R = H, SiR3, Me
R’ = H, Me
3
4
5
OH OH
2
Scheme 1.
*
0
Corresponding author. Tel.: +0033 5 57 96 22 89; fax: 0033 5 56 84 66 46; e-mail: y.landais@lcoo.u-bordeaux.fr
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01318-1

6
548
Y. Landais, E. Zekri / Tetrahedron Letters 42 (2001) 6547–6551
disaccharides with complete diastereocontrol and good
levels of enantioselectivity. We report here on an exten-
sion of this strategy to the synthesis of cyclic and
acyclic synthons such as 1 and 2 possessing several
contiguous stereocentres starting form readily available
arenes 5 (Scheme 1). The desymmetrisation of dienes 4
will be carried out using the powerful Sharpless AD
over-reduction in the same conditions and was thus
better prepared through metallation and silylation with
the suitable chlorosilane (Scheme 2).
9
Dienes 7a–d were then subjected to the Sharpless dihy-
droxylation conditions to afford the corresponding
diols 8a–d with yields and stereoselectivities depending
on the nature of the substrates and the ligands (Scheme
3, Table 1). As already reported from our previous
7
reaction, the diols 3 being then opened through
ozonolysis.c–eA careful control of the work-up
4
6
conditions
after ozonolysis will then ensure the
studies, the silicon group efficiently controlled the
introduction of useful functionalities such as diols or
lactols.
diastereofacial selectivity, the approach of the osmium
reagent occurring exclusively anti relative to the silicon
group (Table 1, entries 6–8). Not surprisingly, the
methyl group as in 7a led to a much lower level of
Dienes 7a–d were prepared through electrochemical
6f,8
10
Birch reduction of arenes 6a–d or metallation–silyla-
diastereocontrol, also favouring the anti diol 8a
9
tion of cyclohexa-1,4-diene. Birch reduction of 6a–c
(entries 1–4). Importantly, the nature of the Sharpless
ligand had a profound effect not only on the enantiose-
lectivity but also on the diastereofacial selectivity of the
gave the corresponding dienes 7a–c in 80–94% yields. In
contrast, the arylsilane 6d led to large amounts of
R
R
1
. s-BuLi, THF
Alanode, THF-HMPA 8:2
TMEDA, -78°C
t-BuOH, LiCl
2. R3SiCl
R’
R’
R’
R’
RT, 8 h
6
a, R = Me, R’ = Me
7a, R = Me, R’ = Me (94%)
7b, R = H, R’ = Me (80%)
6
b, R = H, R’ = Me
6
6
c, R = SiMe t-Bu, R’ = H
7c, R = SiMe t-Bu, R’ = H (93%)
2
2
d, R = Si(i-Pr) , R’ = H
7d, R = Si(i-Pr) , R’ = H (93%)
3
3
Scheme 2.
R
R
R
OH
OH
OH
K OsO ,2 H O, K Fe(CN)
K OsO ,2 H O, K Fe(CN)
2 4 2 3 6
2
4
2
3
6
1
2
1
2
MeSO NH , ligand
MeSO NH , ligand
2 2
2
2
OH
R’
R’
t-BuOH-H O 1:1
t-BuOH-H O 1:1
2
2
8
c, R = SiMe t-Bu
Ligand (see table 1)
7a, R = Me, R’ = Me
7b, R = H, R’ = Me
Ligand (see table 1)
8a, R = Me
8b, R = H
2
8
d, R = Si(i-Pr)3
7
c, R = SiMe t-Bu, R’ = H
2
7
d, R = Si(i-Pr) , R’ = H
3
Scheme 3.
Table 1. Sharpless asymmetric dihydroxylation of dienes 7a–d (Scheme 3)
Entry
Diene
Conditions
Ligand
d.e. (%)a
e.e. (%) majorb
e.e. (%) minorb
Config.
Yield (%)
1
2
3
4
5
6
7
8
7a
7a
7a
7a
7b
7c
7d
7d
10°C, 8 h
10°C, 14 h
10°C, 16 h
10°C, 24 h
0°C, 72 h
0°C, 4 h
Quinuclidine
88
40
60
70
–
\98
\98
\98
–
–
–
37
55
52
40
61
(DHQD) PHAL
70
60
30
–
50
–
18
60
32
–
–
–
1R,2Sd
1S,2Rd
1S,2Rd
–
2
(DHQ) PHAL
2
(DHQ) AQN
2
Quinuclidine
e
(DHQ) PYR
1S,2S
–
1S,2S
87
2
f
0°C, 4 h
0°C, 4 h
Quinuclidine
100
100
c
e
f
(DHQ) PYR
40
–
2
a
Estimated from the 1H NMR of the crude reaction mixture.
b
c
d
e
f
®
Determined by HPLC analysis on a Chiralcel OD column (hexane–i-PrOH 97:3).
Measured using 1H and 19F NMR of the corresponding Mosher’s esters.
7a,b
Assumed configurations at C-1 and C-2 based on Sharpless quadrant device
See Ref. 6.
Total yield of the mixture 8d/tetrol (see text).
(see Fig. 1).

Y. Landais, E. Zekri / Tetrahedron Letters 42 (2001) 6547–6551
6549
DHQD ligands
NW
NE
DHQD
DHQ
R
Me
Me
RS
RM
RL
H
H H
SW
SE
DHQ ligands
Figure 1. Quadrant method for rationalisation of AD enantiofacial selectivity.
7a,b
process. Achiral quinuclidine was found to be the most
efficient ligand in term of diastereocontrol leading to 8a
with 88% d.e. (entry 1). A relatively high enantioselec-
tivity but poor diastereoselectivity in favour of the
major isomer 8a was obtained with commercially avail-
ity. The much lower amount of tetrol detected with
other dienes (i.e. 7a–c) may thus be due to the highly
polar nature of the tetrols in these cases which remain
15
in the aqueous layer after work-up.
11
able (DHQD) PHAL (entry 2). With this ligand, the
Selective monoacetylation and monobenzylation of
diols 8a,b, using standard protocols, were then carried
out, affording the alcohols 9a–c in high yields. Ozonol-
ysis of the latter were then performed in a CH Cl –
2
minor isomer was obtained with a poor enantioselectiv-
12
ity. Conversely, (DHQ) AQN led to better diastereo-
2
control but to low enantiocontrol for both
2
2
diastereomers (entry 4). (DHQ) PHAL was found to be
MeOH mixture at low temperature leading after
2
a good compromise, with 60% d.e. and 60% e.e. for
both diastereomers (entry 3). It is also worthy of note
that the successful ligand for the dihydroxylation of
reductive work-up with Me S to the desired lactols
2
16
17
10a–c with the stereochemistry as shown (Scheme 4).
6
f
Similarly, protection of the diols 8c,d as reported gave
the corresponding acetonides 11a,b which were submit-
ted to the ozonolysis. Considering that a silyl group
might be too good a leaving group when located a to
dienylsilanes (i.e. (DHQ) PYR, entries 6 and 8) was
2
totally inefficient for non-silylated analogues and did
not afford any product with diene 7a. Finally, we
18
noticed that TIPS(i-Pr Si)-diene 7d behaved differently
an aldehyde function, a reductive work-up with
3
from its analogues (entries 7 and 8). Large amounts of
NaBH was first carried out after the ozonolysis. It was
4
13
a tetrol (isolated as its bis-acetonide) resulting from a
double dihydroxylation were observed during desym-
thus found that ozonolysis of 11a,b led, after reduction
of the ozonide, to the corresponding diols 12 (85% yield
1
4
19
metrisation of 7d. While a 6:4 ratio of 8d/tetrol was
from 11a) and 13 (30% overall yield from 7d, three
obtained when quinuclidine was used as a ligand (entry
steps) (Scheme 5). We were also pleased to observe that
free hydroxy groups in 13 could be differentiated, thus
allowing further manipulations of these intermediates.
Mesylate 14 was thus prepared in 55% yield from 13,
demonstrating that the presence of the bulky TIPS
7
8
), an 8:2 ratio was obtained with (DHQ) PYR (entry
). The larger amount of tetrol observed with 7d com-
2
pared to its analogues could be attributed both to its
much larger size and to its more important lipophilic-
6
f
R
R
R
OR’
Ac O, NEt , DMAP
2
3
OH
OH
OR’
OH
O
CH Cl , RT
O3, CH2Cl2-MeOH (5:1)
78°C, 1 h, then Me S
2
2
or
HO
-
O
2
NaH, BnBr, KI
THF, RT
8
a, R = Me
9a, R = Me, R’ = Ac (93%)
9b, R = Me, R’ = Bn (99%)
10a, R = Me, R’ = Ac (76%)
10b, R = Me, R’ = Bn (73%)
10c, R = H, R’ = Ac (32%)
8
b, R = H
9
c, R = H, R’ = Ac (94%)
Scheme 4.
SiR3
SiR3
Me C(OMe)
2
2
R Si
3
O
OH
OH
O
O
p-TsOH
O , CH Cl -MeOH (5:1)
3 2 2
HO
OR’
RT, 2 h
-78°C, 1 h, then NaBH4
O
8
c, SiR = SiMe t-Bu
11a
11b
12, SiR = SiMe t-Bu, R’ = H
3 2
3
2
8
d, SiR = Si(i-Pr)
13, SiR = Si(i-Pr) , R’ = H
3 3
3
3
MsCl, Pyr.
1
4, SiR = Si(i-Pr) , R’ = Ms
0°C (55%)
3
3
Scheme 5.

6
550
Y. Landais, E. Zekri / Tetrahedron Letters 42 (2001) 6547–6551
3. (a) Woodward, R. B.; et al. J. Am. Chem. Soc. 1981, 103,
Si(i-Pr)3
OH
OBn
O3
O
3210–3212; (b) Corey, E. J.; Cheng, X.-M. The Logic of
Chemical Synthesis; Wiley Interscience: Toronto, 1989.
4. (a) Krow, G. R. In Comprehensive Organic Synthesis;
Trost, B. M.; Fleming, I., Eds. The Baeyer–Villiger reac-
tion; Pergamon Press: Oxford, 1991; Vol. 7, pp. 671–688;
CH Cl -MeOH (5:1)
2
2
HO
-
78°C, 1 h
then Me S
O
H
OBn
H
2
Si(i-Pr)3
16 (60%)
1
5
(
b) Lee, D. G.; Chen, T. In Comprehensive Organic
Synthesis; Trost, B. M.; Fleming, I., Eds. Cleavage reac-
tions; Pergamon Press: Oxford, 1991; Vol. 7, pp. 541–591;
Scheme 6.
(
c) Schreiber, S. L.; Claus, R. E.; Reagan, J. Tetrahedron
group efficiently prevents the formation of the mesylate
b to silicon.
Lett. 1982, 23, 3867–3870; (d) Acena, J. L.; Arjona, O.;
Leon, M.; Plumet, J. Tetrahedron Lett. 1996, 37, 8957–
8
960; (e) Arjona, O.; Menchaca, R.; Plumet, J. J. Org.
Finally, based on the above observation, it was decided
to use purposely the unique steric bulk of the TIPS
Chem. 2001, 66, 2400–2413; (f) Donohoe, T. J.; Raoof,
A.; Linney, I. D.; Helliwell, M. Org. Lett. 2001, 3,
8
18,20
group to prepare fragile a-silylaldehydes.
These
61–864; (g) Taber, D. F.; Nakajima, K. J. Org. Chem.
001, 66, 2515–2517.
aldehydes are valuable intermediates which can be con-
verted stereoselectively into allylsilanes through Wittig
2
5
. (a) Millward, D. B.; Sammis, G.; Waymouth, R. M. J.
Org. Chem. 2000, 65, 3902–3909; (b) Lautens, M.; Rovis,
T. J. Am. Chem. Soc. 1997, 119, 11090–11091; (c) Laut-
ens, M.; Klute, W. Angew. Chem., Int. Ed. Engl. 1996, 35,
2
1a
reactions or into b-hydroxysilanes through addition
2
1b
of organometallic reagents.
Selective monobenzyla-
tion of the diol 8d, away from the TIPS group, thus led
to the alcohol 15 (40%) which was submitted to the
4
42–445.
6. (a) Angelaud, R.; Landais, Y. J. Org. Chem. 1996, 61,
202–5203; (b) Angelaud, R.; Landais, Y.; Schenk, K.
ozonolysis (Scheme 6). Reductive work-up with Me2S
as above furnished the lactol 16 in 60% yield as one
5
diastereomer having the required a-silylaldehyde
Tetrahedron Lett. 1997, 38, 1407–1411; (c) Angelaud, R.;
Landais, Y. Tetrahedron Lett. 1997, 38, 8841–8844; (d)
Angelaud, R.; Landais, Y.; Parra-Rapado, L. Tetra-
hedron Lett. 1997, 38, 8845–8848; (e) Landais, Y. Chimia
moiety.
As a summary, we have described here a short, general
and stereocontrolled access to highly functionalised
cyclic and acyclic intermediates, using a Birch reduc-
tion–dihydroxylation–ozonolysis sequence starting from
simple arenes. As shown with lactols 10a–c, otherwise
difficult to control quaternary stereogenic centres can
be installed stereoselectively in only four steps from
inexpensive aromatic substrates. Application of this
methodology to the synthesis of naturally occurring
tetrahydrofurans is now underway.
1998, 52, 104–111; (f) Angelaud, R.; Babot, O.; Charvat,
T.; Landais, Y. J. Org. Chem. 1999, 64, 9613–9624; (g)
Landais, Y.; Parra-Rapado, L. Eur. J. Org. Chem. 2000,
2
. (a) Kolb, H. C.; vanNieuwenhze, M. S.; Sharpless, K. B.
Chem. Rev. 1994, 94, 2483–2547; (b) Kolb, H. C.;
Andersson, P. G.; Sharpless, K. B. J. Am. Chem. Soc.
, 401–418.
7
1
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8
1
Org. Chem. 1995, 60, 5537–5539; (c) Eaborn, C.; Jackson,
R. A.; Pearce, R. J. Chem. Soc., Perkin Trans. 1 1974,
Acknowledgements
2055–2061.
9. Roberson, C. W.; Woerpel, K. A. Org. Lett. 2000, 2,
We thank the Region Aquitaine and the CNRS for
their financial support. We are also indebted to Dr. G.
Lessenne and Dr. P. Clavel for their help during elec-
trochemical reductions.
621–623.
10. Compound 8a was readily separated from the minor
diastereomer through crystallisation.
11. Assumption on the absolute configuration of 8a was
7a,b
based on Sharpless mnemonic device
and is consistent
with results obtained recently during AD reaction on
related dienes, see: Corey, E. J.; Noe, M. C. J. Am. Chem.
Soc. 1994, 118, 11038–11053.
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1
13. H NMR of the bis-acetonide protected tetrol showed
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also took place anti relative to the silicon group. The
bis-acetonide could not be separated from the monoace-
tonide 11b and was thus isolated after the ozonolysis of
11b (Scheme 5).
2
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14. This may indicate that a kinetic amplification operates
during the dihydroxylation process. A careful investiga-
tion of the possible implication of this phenomenon in
our desymmetrisation process is currently underway. For
a closely related example of kinetic amplification, see:

Y. Landais, E. Zekri / Tetrahedron Letters 42 (2001) 6547–6551
6551
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1
19. The protection–ozonolysis sequence was carried out on the
13
6. The lactols 10a–c were obtained as a mixture of
diastereomers (lactol centre), respectively: 6:4 for 10a; 7:3
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20. Enders, D.; Lohray, B. B. Angew. Chem., Int. Ed. Engl.
1
for 10b and 6:4 for 10c, as estimated from the H NMR
1987, 26, 351–352.
of the crude reaction mixtures.
21. (a) Bhushan, V.; Lohray, B. B.; Enders, D. Tetrahedron
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1
7. The relative configuration of 10a (and consequently of 10b)
was determined from NOE experiments performed on
the corresponding lactone. This also allowed us to deter-