A domino ring-closing metathesis as a key-step in the synthesis of chiral lactones from D-mannitol

Article abstract of DOI:10.1016/j.tetlet.2005.03.189

Chiral lactones were synthesized in six steps from D-mannitol. The key-step was a domino ring-closing metathesis reaction leading to the symmetric cleavage of a D-mannitol triene derivative and to the formation of two molecules of the desired lactone.

Full text of DOI:10.1016/j.tetlet.2005.03.189

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3867–3870
A domino ring-closing metathesis as a key-step in the synthesis
of chiral lactones from D-mannitol
*
Bastien Nay, Nicolas Gaboriaud-Kolar and Bernard Bodo
Laboratoire de Chimie et Biochimie des Substances Naturelles—UMR 5154 CNRS, Mus e´ um National d’Histoire
Naturelle, 63 rue Buffon, 75005 Paris, France
Received 1 March 2005; revised 21 March 2005; accepted 25 March 2005
Available online 12 April 2005
Abstract—Chiral lactones were synthesized in six steps from D-mannitol. The key-step was a domino ring-closing metathesis
reaction leading to the symmetric cleavage of a D-mannitol triene derivative and to the formation of two molecules of the desired
lactone.
ꢀ
2005 Elsevier Ltd. All rights reserved.
Lactones hold an important place in the natural product
field and are widely spread allover the biogenetic catego-
ries. Particularly, there are numerous examples of five-
and six-membered chiral lactones, which often exhibit
pheromonal, medicinal, flavoring, or olfactive properties:
the whisky lactone (1) is an oak-derived flavor found in
Diels–Alder reactions and we explored an original and
practicable strategy toward this precursor.
5
Ring-closing metathesis (RCM) has provided an
important route to lactone synthesis and the involve-
ment of unsaturated esters as metathesis substrates has
often been reported in the last few years either in the
1
wines; the skin-irritant massoialactone (3), which also
produces systolic standstill in frog heart muscle has been
6
7
furanone or in the pyranone series. Some tandem pro-
cesses have been used, especially RCM coupled to cross
isolated from the bark of Cryptocarya massoia and in
2
7a
the defense secretions of Camponotus ants, while prelac-
tones such as 4 are metabolites produced by some
metathesis to form a-alkenyl lactones. We now report
an original strategy leading to 5- or 6-membered chiral
3
polyketide-producing Streptomyces species. Further-
more, simple lactones such as furanone 2 have been used
lactones (I) via domino RCM performed on C -symmet-
2
ric trienes (II) synthesized from D-mannitol (Scheme 1).
as starting materials in the total synthesis of natural
4
products or medicines. To this end we needed to make
use of the butenolide 2 as an asymmetric dienophile in
Alkenes II were derived from intermediate (2S,5S)-3-
hexene-1,2,5,6-tetraol, which was regarded as a synthetic
equivalent of (S)-3-buten-1,2-diol, which is commer-
cially but expensively available although it can be
O
O
O
O
HO
O
5
-hydroxymethyl-
whisky lactone (1)
2(5H)-furanone (2)
O
O
O
domino
RCM
n
HO
TBSO
C5H11
O
O
O
O
OTBS
(II)
n
O
(I)
n
O
metathetic
equivalence
(
-)-massoialactone (3)
OH
O
(III)
prelactone C (4)
RCM
O
n
TBSO
Keywords: Domino metathesis; Chiral pool; Lactones.
*
Corresponding author. Tel.: +33 1 40 79 56 09; fax: +33 1 40 79 31
5; e-mail: bnay@mnhn.fr
Scheme 1. Synthetic plan for the lactones and evidence for ꢀmetathetic
equivalenceꢁ of the intermediates II and III.
3
0
040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.189

3868
B. Nay et al. / Tetrahedron Letters 46 (2005) 3867–3870
Table 1. Conditions for the esterification of diol 8
OMe
O O
OH
O
a
OMe
D-mannitol
O O
OMe
OH
OTBS
O
R
OH
5
n
conditions
n = 0-2
TBSO
OMe
OTBS
OTBS
OH
R
O
b
OMe
O O
n
8
10a-d
Products Yields (%)
O
c
OMe
O O
OMe
n (R)
(H)
Reagents and conditions
6
0
Acryloyl chloride, NEt
DCM, 0 ꢁC
Vinylacetic acid, DCC,
3
,
10a
10b
10c
10d
71
82
80
56
OMe
OH
HO
1 (H)
2 (H)
d
OH
DMAP, DCM, rt
4-Pentenoyl chloride, py,
OH
7
OH
DCM, 0 ꢁC
TBSO
OTBS
3
0 (Me) Methacryloyl chloride, NEt ,
(E)
DCM, 0 ꢁC
OR
(R = H, 57%)
(R = TBS, 11%)
8
9
Scheme 2. Synthesis of the intermediate diol 8: (a) butanedione,
BF ÆOEt , H(OMe) , methanol (52% after recrystallization from
hexane); (b) PPh , imidazole, I , toluene, reflux (82%); (c) TFA/H O/
CH OH 25:65:10, rt (quant.); (d) TBSCl (1.9 equiv), NEt (2 equiv),
DMAP (0.1 equiv), DCM/DMF 9:1, 0 ꢁC ! rt.
OTBS
TBSO TBSO
O
O
O
3
2
3
3
2
2
O
O
n
O
n
n
3
3
O
[Ru]
[Ru]
TBSO
O
n
synthesized from D-mannitol. From a metathetic point
of view the C -symmetric intermediates II were indeed
TBSO
TBSO
O
2
2
× O
O
equivalent to intermediates III, but clearly allowed for
symmetric domino processes. With regard to the
use of an internal double bond as a metal-directing
relay, the strategy can be related to ꢀrelay ring-closing
metathesisꢁ, which has also been used to synthesized,
O
n
[Ru]
n
Scheme 3. Supposed pathway for the domino metathesis reaction
initial incorporation of the catalyst at one of the terminal olefins).
(
6
b
a,b-disubstituted butenolides.
A five step synthesis of the (E)-alkene 8 (Scheme 2) from
8
cient (entry 2) and was used systematically in the next
experiments.
D-mannitol has been described, but the compound was
herein obtained by sequential butanediacetal diprotec-
9
10
tion, dihydroxy-elimination, deprotection and then
1
The synthesis of furanone 11a, which started at low cat-
alyst loading (5 mol %) required regular additions of G2
(up to 30 mol % over 96 h) to be completed (entry 3).
The enantiomeric purity was checked by NMR in
1
silylation reactions. The (E)-stereochemistry of the
double bond was firstly assigned on the basis of the
1
0
dihydroxy-elimination mechanism (diol 5 to alkene 6,
step b) and was confirmed by NMR analysis of the
desymmetrized side-product 9. A characteristic coupling
constant of 15.7 Hz between the two ethylenic protons
was indeed observed. The metathesis substrates 10a–d
were then obtained after esterification of the diol 8
1
3
the presence of the chiral chemical shift reagent
(+)-Eu(hfc) . A dramatic loss of ee was observed, due
3
to partial racemization at the stereogenic center
(ee = 0.38) in these conditions. This problem was readily
circumvented by using directly a 30 mol % loading
of the Grubbsꢁ catalyst G2 in toluene at 80 ꢁC, thus
greatly shortening the time of the reaction, which was
completed in 2 h (entry 4). No racemization was
observed under these conditions and the product 11a
was obtained in 71% yield and >0.99 enantiomeric
(
Table 1).
The metathesis step was performed on the trienes 10a–d.
It was expected to involve two RCM in a domino pro-
cess (Scheme 3). A symmetric cleavage of the relaying
internal double bond would then allow the formation
of 2 equiv of the expected lactone.
1
4,15
excess.
The methacrylate 10d gave no reaction at all, the
starting material being recovered (Table 2, entry 5).
Obviously, the use of this electron-poor 1,1-disubsti-
tuted terminal olefin was detrimental to reaction initia-
tion. It also showed that the ruthenium catalyst could
not be incorporated through the internal double bond,
thus supporting the reaction pathway of Scheme 3.
When the vinylacetate 10b was used in the presence of
10 mol % G2 (entry 6), the enantiomerically pure b,
Preliminary trials (Table 2, entries 1 and 2) were succes-
sively performed on the diacrylate 10a in the presence of
1
0 mol % of the first or the second generation Grubbsꢁ
catalysts (G1 and G2, respectively). Previous reports
1
2
by Grubbs and co-workers had shown that a,b-unsat-
urated carbonyl compounds were poorly incorporated
by G1 and that G2 was more active thanks to its N-het-
erocyclic ligand. Indeed, the catalyst G2 was more effi-

B. Nay et al. / Tetrahedron Letters 46 (2005) 3867–3870
3869
Table 2. Results of the metathesis step
catalyst
MesN NMes
(
G1 or G2)
PCy3
Ru
PCy3
G1
1
0a-d
11a-d Cl
Cl
0
.02 M
G1: DCM, reflux
G2: toluene, 80°C
Ru
PCy3
Cl
Ph
Cl
Ph
G2
Substrate
Catalyst (equiv)
Time (h)
Product
Yield (%)
a
a
c
1
2
3
10a
10a
10a
G1 (10)
G2 (10)
48
48
96
O
6
O
O
TBSO
34
b
G2 (30)
75
R
1
1a (R = H)
d
4
5
10a
10d
G2 (30)
G2 (30)
2
71
—
a,e
24
11d (R = Me)
O
TBSO
f
6
10b
G2 (10)
4
80
1
1b
OTBS
OTBS
O
O
7
10c
G2 (5)
1.5
81
O
O
1
1c
a
b
c
d
e
f
Starting material recovered.
· 5 mol % over 96 h.
Ee = 0.38.
Ee > 0.99.
No reaction.
6
56% yield after 12 h with 5 mol % of G2.
c-unsaturated d-lactone 11b was obtained in 80% yield
diol esters (see Scheme 1). The reaction will be of interest
in the synthesis of lactone containing natural products.
Studies will be pursued to enlarge the applications of
the strategy (synthesis of cyclic ethers) and to reach
the opposite enantiomeric series (that could be done
via Mitsunobu esterification of the diol 8).
1
6
after 4 h. Considering the possibility to synthesize lar-
ger lactones (n > 1, Schemes 1 and 3), the reaction was
applied to the 4-pentenoate diester 10c. Instead of the
expected hexenolide, the 14-membered macrodiolide
11c was obtained in 81% yield after 1.5 h and in the pres-
ence of 5 mol % of G2 (entry 7). The structure of this
macrocyclic compound was unambiguously established
1
Acknowledgments
7
by 2D NMR and mass spectrometry. It displayed a
C -symmetry axis passing over both double bonds and
2
Dr. Alain Blond and Alexandre Deville are gratefully
acknowledged for multidimensional NMR experiments.
making the olefinic protons of the newly formed double
bond chemically equivalent. No (E)- or (Z)-type cou-
pling constant could therefore be observed and the trans
stereochemistry was determined on the basis of NOE
experiments and IR spectroscopy. This configuration is
in accordance with the observations concerning the ther-
modynamically favored formation of (E)-olefins in mac-
References and notes
1
2
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1
8
rocycles in the presence of G2. Furthermore the
exposition of compound 11c to hydrolytic conditions
gave back the diol 8 and thus supported the structural
assignment. During these metathesis steps, the
competition between both types of ring closing (lactone
vs macrodiolide) thus appeared to favor the 5- and 6-
membered lactones while the [14]-macrocycle was pre-
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3
4
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This work brings some new examples in the domino
metathesis field with an application to the synthesis of
asymmetric lactones. The originality of the method
consisted in the use of chiral trienes (10) derived from
D-mannitol and thus having a C -symmetry axis. They
2
were used as metathetic equivalents of (S)-3-buten-1,2-

3870
B. Nay et al. / Tetrahedron Letters 46 (2005) 3867–3870
1
3
6
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C NMR (75 MHz, CDCl
83.4, 122.6, 154.4, 173.0. IR (film, NaCl): m = 1765 cm
HR-MS (CI+, CH ): m/z calculated for C H O Si
3
): d = ꢀ5.1, 18.3, 25.8, 63.0,
ꢀ
1
.
1
4
11 21
3
2
0
(MH+): 229.1260; observed: 229.1257. ½aꢁ ꢀ136 (c 0.85,
D
2
D
0
CHCl
3
) (Ref. 15a: ½aꢁ ꢀ136, c 1.13, CHCl
3
; Ref. 15b:
2
0
½aꢁ ꢀ146, c 0.20, CHCl
3
). Ee >0.99. Colorless syrup.
D
7
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f 2
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1
16. Data for compound 11b: H NMR (300 MHz, CDCl
3
):
), 0.89 (s, 9H,
C@O), 3.76 (dd, J = 3.3,
10.7 Hz, 1H, TBSOCH ), 3.87 (dd, J = 4.4, 10.7 Hz, 1H,
7
1
2
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d = 0.06 and 0.07 (2s, 6H, Si(CH
SiC(CH ), 3.07 (m, 2H, CH
3 2
)
3
)
3
2
2
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tion conditions; (b) Michel, P.; Ley, S. V. Synthesis 2003,
TBSOCH
(2m, 2H, HC@CH).
d = ꢀ5.4, 18.4, 25.9, 30.5, 65.0, 80.0, 123.2, 123.7, 169.0.
2
), 4.95 (m, 1H, CH
2
CHCH@CH), 5.86 and 5.93
1
3
1
C
NMR (75 MHz, CDCl ):
3
8
9
ꢀ
1
4
IR (film, NaCl): m = 1734 cm . HR-MS (CI+, CH ): m/z
4
23 3
calculated for C12H O Si (MH+): 243.1416; observed:
2
0
243.1413. ½aꢁ ꢀ159 (c 1, CH
3
OH). Ee >0.99. Colorless
D
syrup. R = 0.4 (DCM/MeOH 99:1).
f
1
17. Data for compound 11c: H NMR (300 MHz, CDCl3):
1598–1602; (c) Ley, S. V.; Michel, P. Synthesis 2004, 147–
150.
d = 0.05 and 0.06 (2s, 12H, Si(CH
SiC(CH ), 2.20 and 2.45 (2m, 4H, @CH–CH
4H, CH –C@O), 3.69 (dd, J = 4.8, 11.1 Hz, 1H, TBSO-
3
)
2
), 0.88 (s, 18H,
1
1
0. Garegg, P. J.; Samuelsson, B. Synthesis 1979, 469–470.
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)
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2
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2H, @CHCH ), 5.74 (dd, J = 2.5, 4.8 Hz, 2H, @CHCH).
C NMR (75 MHz, CDCl ): d = ꢀ5.2, 18.3, 25.9, 28.0,
a b a b
H ), 3.75 (dd, J = 7.0, 11.1 Hz, 1H, TBSOCH H ),
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2
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3
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1
1
33.3, 63.9, 74.6, 129.6, 131.6, 172.4. IR (film, NaCl):
ꢀ
1
9
2, 6979–6980.
m = 1751 cm . HR-MS (CI+, CH
4
): m/z calculated for
1
4. Data for compound 11a: H NMR (300 MHz, CDCl ):
20
D
C H O Si (MH+): 513.3068; observed: 513.3064. ½aꢁ
3
26 49
6
2
d = 0.06 and 0.07 (2s, 6H, Si(CH ) ), 0.87 (s, 9H,
+61 (c 2.5, CH Cl ). Colorless solid, mp = 38 ꢁC. R = 0.5
3
2
2
2
f
SiC(CH
3.93 (dd, J = 4.5, 10.7 Hz, 1H, TBSOCH
3
)
3
), 3.80 (dd, J = 6.3, 10.7 Hz, 1H, TBSOCH
2
),
(DCM).
2
), 5.05 (m, 1H,
CH CHCH@CH), 6.16 (dd, J = 2.0, 5.7 Hz, 1H, HC@
18. (a) Lee, C. W.; Grubbs, R. H. J. Org. Chem. 2001, 66,
7155–7158; (b) Macrocyclic lactone formation via RCM
has also been well documented in Ref. 5f.
2
CHC@O), 7.50 (dd, J = 1.5, 5.7 Hz, 1H, HC@CHC@O).