Efficient route to optically pure polyfunctionalized cyclooctanes

Article abstract of DOI:10.1016/S0040-4039(01)02126-8

A short and efficient synthesis of enantiopure highly functionalized eight-membered carbocyclic rings is described from 1,2:5,6-bis-epoxides issued from d-mannitol. The key cyclization step involves the metathesis of 1,9-diene using Grubbs' catalyst or the pinacolic coupling of 1,8-dialdehyde resulting from the oxidative cleavage of the previous diene. In the specific case of ring-closing metathesis cyclization, the influence of a conformationally restricted diene compared to that of a flexible one has been evaluated.

Full text of DOI:10.1016/S0040-4039(01)02126-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 245–248
Efficient route to optically pure polyfunctionalized cyclooctanes
Christine Gravier-Pelletier, Olivia Andriuzzi and Yves Le Merrer*
Universit e´ Ren e´ Descartes, Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR 8601 CNRS,
45, rue des Saints-P e` res, 75270 Paris Cedex 06, France
Received 28 September 2001; accepted 8 November 2001
Abstract—A short and efficient synthesis of enantiopure highly functionalized eight-membered carbocyclic rings is described from
,2:5,6-bis-epoxides issued from -mannitol. The key cyclization step involves the metathesis of 1,9-diene using Grubbs’ catalyst
1
D
or the pinacolic coupling of 1,8-dialdehyde resulting from the oxidative cleavage of the previous diene. In the specific case of
ring-closing metathesis cyclization, the influence of a conformationally restricted diene compared to that of a flexible one has been
evaluated. © 2002 Elsevier Science Ltd. All rights reserved.
The conversion of carbohydrate derivatives into carba-
sugars, sugars for which the endocyclic oxygen atom
has been replaced by a methylene group, is well docu-
OH
HO
HO
CH3
1
mented for the C5 and C6 series and this has given rise
NH
HO
O
OH
to interesting biologically active compounds such as
trehazolamines, conduritols or inositols. However, only
a few approaches have been dedicated to analogous
HO
OH
OH
HO
HO
O
Valienamine
O
OH
OH
HO
NH
O
2
3
OH
O
routes in the C7 and C8 series. In the latter case, the
unfavorable thermodynamic factors are claimed to limit
HO
HO
HO
OH
OH
4
OH
the access to C8 cyclitols.
Voglibose
Acarbose
As part of our ongoing research on the synthesis of new
glycosidases inhibitors and especially on the synthesis
of new potential drugs to treat non-insulino-dependant
Figure 1. Examples of non-insulino-dependant diabetes thera-
peutic agents.
(
NID) diabetes, we considered the structure of either
voglibose itself or valienamine as an essential core unit
of acarbose (Fig. 1).
Our retrosynthetic analysis (Scheme 1) involves two
different pathways, namely the carbocyclization of
enantiomerically pure 1,9-diene and the carbocycliza-
tion of 1,8-dialdehyde which results from oxidative
cleavage of the previous diene. The key step requires
either an intramolecular cycloaddition by ring-closing
metathesis (RCM) or a pinacolic coupling (PC). The
synthetic route begins with C2-symmetrical bis-epoxides
5
6
Both voglibose and acarbose display powerful a-D-
glucosidase inhibition and have already found thera-
peutic application in NID diabetes. In this context, our
goal was to develop a straightforward and efficient
route to cyclooctanic carbasugar analogs in order to
study the effect of an increase in the flexibility of the
resulting targets on the expected enhanced adaptability
of cyclooctanic structure within the active site of the
enzyme. Furthermore, the availability of various
configurations of the carbasugar should enable us to
examine the consequence of different distributions of
the hydroxyl groups on the activity.
easily available from
D-mannitol.
Although ring-closing metathesis has been largely used
7
in the synthesis of heterocyclic compounds and in that
1
a,1c,1e,2a,2b
of C5 to C7 cyclitols,
only a few examples
3a,3b
deal with the obtention of C8 cyclitols
and the
has prompted us
to submit our results. First, the regiospecific opening
of C2 symmetrical -ido bis-epoxide 2, readily available
3b,3d
recent work published in this field
Keywords: cycloctane; metathesis; 1,9-diene; 1,8-dialdehyde; pinacolic
coupling; Grubbs’ catalyst.
8
L
9
*
Corresponding
author.
Tel.:
+33(0)142862176;
fax:
+
33(0)142868387; e-mail: yves.le-merrer@biomedicale.univ-paris5.fr
from D-mannitol, by an excess of lithium divinyl
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02126-8

2
46
C. Gra6ier-Pelletier et al. / Tetrahedron Letters 43 (2002) 245–248
PO
P'O
OP
OP'
*
*
*
*
RCM
PO
HO
HO
OH
*
OH
*
*
OP
*
PO
*
OP
*
*
P'O
OP'
*
*
* *
*
PC
O
O
A
B
A, B = OH, CH 2OH,
NHR, CH 3, ...
PO
*
OP
*
P'O
OP'
*
*
O
O
Scheme 1. Retrosynthetic analysis.
1
0
cyanocuprate was carried out at −78°C to cleanly
afforded the enantiopure polyhydroxylated cyclooctane
1
1
afford the diene 3 in 90% yield (Scheme 2). The
carbocyclization involving Grubbs’ commercially avail-
able ruthenium catalyst [(PCy ) Cl RuꢀCHPh, up to 13
derivative 6a in 97% yield. Alternatively, the epoxida-
15
tion of the double bond in the presence of meta-
chloroperbenzoic acid and sodium hydrogenocarbonate
cleanly gave the enantiopure epoxide 7 in 92% yield.
3
2
2
mol%], 0.005 M in CH Cl at 20°C for 96 h, efficiently
2
2
gave the expected cyclooctene 4 in 87% yield. The
simplicity of both the H and C NMR spectra of 4
revealed the retention of the C2-axis of symmetry and
showed the formation of the thermodynamically more
stable cis-cyclooctene. It is worthy of note that, in our
case, RCM led to the cyclized product at 20°C without
requiring the protection of the two hydroxyl groups of
1
13
12
We next turned to the second proposed pathway
involving the pinacolic coupling of 1,8-dialdehyde. For
that purpose (Scheme 4), the secondary alcohol func-
tions of the diol 3 were protected as their tert-
butyldimethylsilyl ethers (TBDMSCl, imidazole, DMF)
to give the entirely protected compound 8. Ozonolysis
of both double bonds of 8 in dichloromethane and
methanol followed by the decomposition of the result-
ing ozonide by trimethylphosphite, furnished the
expected dialdehyde 9 in 70% yield. Reductive coupling
was then carried out by samarium diiodide (0.1 M in
1
3
the diol 3.
Both hydroxyl groups were then protected as their
tert-butyldimethylsilyl ethers 5 (TBDMSCl, imidazole,
DMF) prior to exploring the synthetic potentialities at
the newly created double bond of this enantiomerically
pure polyhydroxycyclooctenic structure (Scheme 3).
syn-Dihydroxylation by a 5 mol% aqueous solution of
osmium tetroxide, in dichloromethane, in the presence
of N-methylmorpholine oxide and tert-butanol
1
6
THF) in the presence of tert-butanol and HMPA to
promote the cyclization. In these conditions, efficient
cyclization occurred affording the cyclooctanediol
skeleton in 62% yield as a 1:1 diastereomeric mixture of
14
17
cis and trans cycloadducts 6a and 6b. The cis relation
O
O
O
O
HO
OH
HO
OH
O
O
Grubbs catalyst,
up to13 mol %,
(H2C=CH) 2CuCNLi 2 , 6eq., THF
-78°C to 20°C
CH2Cl 2
O
O
90%
87%
2
3
4
Scheme 2.
O
O
O
O
O
O
O
OP
PO
OP
PO
OP
OsO 4 5 mol%
NMO
mCPBA
NaHCO 3
97%
92%
HO OH
O
4
: P = H
TBDMSC l
7%
6
a : P = TBDMS
5 : P = TBDMS
7 : P = TBDMS
8
Scheme 3.
(P = TBDMS)
O
O
O
O
O
O
O
O
O
O
HO
OH
PO
OP
PO
OP PO
OP
PO
OP
TBDMSC l
ImH, DMF
1. O 3, CH 2Cl 2, MeOH
SmI 2, in THF
+
2. P(OMe) 3, 20°C, 16 h
-20°C to 0°C
tBuOH, HMPA HO OH
HO OH
O
O
94%
70%
62%
3
8
9
6a
1 : 1
6b
Scheme 4.

C. Gra6ier-Pelletier et al. / Tetrahedron Letters 43 (2002) 245–248
247
ship in 6a has been shown by comparison with the same
References
compound previously obtained by syn-dihydroxylation
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Due to the poor observed diastereoselectivity of pina-
colic coupling cyclization, it is obvious that RCM
followed by syn-dihydroxylation or syn-epoxidation
was a better method to reach the targeted compounds.
So, we proceeded to the generalization of the RCM to
other substrates displaying different configuration and/
or higher flexibility of the backbone in order to test the
presumed entropic assistance to the cyclization process
of the acetonide moiety in the conformationally
restricted diene 3 (Scheme 5). To this end, both
D-
manno-1,9-dienes 12 and 13 were prepared from the
9,18
corresponding
the same conditions as the diene 3. As for the
tonide diene 3, the -manno-acetonide diene 12 was
isolated in good yield (80%). However, our previous
D
-manno-bis-epoxides
according to
L
-ido-ace-
D
1
9
work has shown that bis-opening of flexible di-O-ben-
zyl-bis-epoxide by a nucleophile is competitive with
O-cyclization involving the alcoholate resulting from
the nucleophilic opening of a single epoxide moiety.
Nevertheless, the low temperature of the reaction
4. Miller, S. J.; Kim, S.-H.; Chen, Z.-R.; Grubbs, R. H. J.
Am. Chem. Soc. 1995, 117, 2108–2109.
(
−78°C) allowed us to minimize the O-cyclization and
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the expected diene 13 was isolated in 30% yield. To our
great satisfaction, RCM of both dienes 12 and 13, in
the same conditions as above, efficiently afforded the
12
12
corresponding cycloadducts 14 and 15 in 65 and
0% non-optimized isolated yield.
5
8
. A part of this work was previously presented as a poster:
Gravier-Pelletier, C.; Andriuzzi, O.; Le Merrer, Y. Poly-
functionalized Cyclooctanes as carbohydrate mimics or
scaffolds. De la conception a` la r e´ alisation en pharma-
cochimie, Proceedings of the XVEME Journ e´ es Franco-
Belges de Pharmacochimie, Namur (Belgium), May
31st–June 1st, 2001.
In summary, RCM was a powerful method to reach
polyhydroxycyclooctene structures displaying diverse
configurations and allowing various, either rigid or
flexible, protective groups for the central diol. In this
study, protection of hydroxyl groups at homoallylic
positions proved to be unnecessary since the RCM
occurred in good to excellent yield. Furthermore, syn-
diol or syn-epoxide resulting from dihydroxylation or
epoxidation of cyclooctenic structure may be consid-
ered as key intermediates in the obtention of the
targeted C8-amino cyclitols. Work on the synthesis of
voglibose mimics is now in progress and will be
reported in due course.
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10. For an analogous reaction on
D-manno-bis-epoxide, see:
Sani e` re, M.; Le Merrer, Y.; Barbe, B.; Koscielniak, T.;
Micas-Languin, D.; Dumas, J.; Depezay, J. C. Angew.
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11. All new compounds were characterized by analytical and
Acknowledgements
spectroscopic data. Yields are given for isolated, chro-
matographically purified products.
12. Selected physical data for 4, 14 and 15:4: H NMR (250
1
We thank James McCabe (Centre for Technical Lan-
guages, Universit e´ Ren e´ Descartes, Paris 5) for his
critical reading of this manuscript.
MHz, CDCl , l ppm): 5.78–5.73 (m, 2H, H1,8), 3.83–3.74
3
(m, 2H, H3,6), 3.70–3.58 (m, 2H, H4,5), 2.46–2.24 (m, 4H,
H2,2%,7,7%), 1.35 (s, 6H, Me), the following coupling con-
stants can be found by proton selective irradiations J2,2%:
13
1
3.9 Hz, J1,2=3.5 Hz, J1,2%=6.8 Hz. C NMR (62.5
MHz, CDCl , l ppm): 127.7 (C ), 108.9 (CMe ), 82.2,
3
1,8
2
1
7
2.5 (C3,4,5,6), 30.3 (C2,7), 26.8 (CMe ). 14: H NMR (250
PO
OP
2
PO
OP
PO
OP
MHz, CDCl , l ppm) 5.81–5.67 (m, 2H, H1,8), 4.23 (s,
HO
OH
3
(H2C=CH) 2CuCNLi 2
RCM
HO
OH
2
H, H4,5), 4.19–4.11 (m, 2H, H3,6), 2.50–2.31 (m, 4H,
H2,2%,7,7%), 1.42 (s, 6H, Me). C NMR (62.5 MHz, CDCl3,
O
O
13
1
0 : P = CMe 2
12 : P = CMe 2 (80%)
13 : P = Bn (30%)
14 : P = CMe 2 (65%)
15 : P = Bn (50%)
l ppm): 128.0 (C1,8), 108.2 (CMe ), 77.0, 67.5 (C3,4,5,6),
2
11 : P = Bn
1
2
9.0 (C2,7), 27.2 (CMe ). 15: H NMR (250 MHz, CDCl ,
2
3
l ppm) 7.36–7.26 (m, 10H, Ph), 5.70–5.60 (m, 2H, H1,8),
Scheme 5.
4.85 (AB, 2H, JA,B=11.4 Hz, CH Bn), 4.53 (A%B%, 2H,
2

2
48
C. Gra6ier-Pelletier et al. / Tetrahedron Letters 43 (2002) 245–248
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13
(
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(
3
Ar
1
27.6, (C1,8), 74.2 (PhCH ), 78.3, 71.0 (C3,4,5,6), 29.7
17. The proportion of the two possible trans derivatives 6b
has not been determined.
2
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2
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