Effect of substituents on the ring-closing metathesis reaction in the synthesis of functionalized nonanolactones

Article abstract of DOI:10.1055/s-2008-1032072

The synthesis of functionalized nine-membered ring lactones based on sequential esterification and ring-closing metathesis (RCM) reactions is reported. The effects of olefin substitution and allylic and homoallylic oxygenated substituents on the RCM react

Full text of DOI:10.1055/s-2008-1032072

LETTER
339
Effect of Substituents on the Ring-Closing Metathesis Reaction in the
Synthesis of Functionalized Nonanolactones
Effect of
S
a
ubstituents
c
on RCMin
i
the Sy
n
nthesis of
N
t
onanol
o
a
ctones Ramírez-Fernández, Isidro G. Collado, Rosario Hernández-Galán*
Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Cádiz, Campus Universitario Puerto Real, Polígono Rio San
Pedro s/n, 11510 Puerto Real, Cádiz, Spain
E-mail: rosario.hernandez@uca.es
Received 16 November 2007
RCM has been used to a great extent in the formation of
Abstract: The synthesis of functionalized nine-membered ring lac-
many ring systems but only two reports have described its
tones based on sequential esterification and ring-closing metathesis
application to the synthesis of the nine-membered-ring
(RCM) reactions is reported. The effects of olefin substitution and
lactone of halicholactone.10 To our knowledge it has never
allylic and homoallylic oxygenated substituents on the RCM reac-
tion is analyzed. An unusual cyclization stereochemistry has been been used for the construction of a highly substituted me-
observed, leading to a stereoselective olefin formation in the syn-
dium-ring lactone.
thesis of nonanolactones. The high selectivity can be rationalized by
interaction/coordination of the homoallylic or allylic hydroxyl
group with the ruthenium metal center in the ruthenacyclobutane in-
termediate.
O
O
OH
O
O
O
OH
Key words: ring-closing metathesis, nonanolactones, botcinolide,
Botrytis cinerea
HO
HO
O
OH
OH
HO
HO
Medium-ring natural lactones (8–11-membered rings)
constitute a reduced number of metabolites which have at-
tracted considerable attention due to the range of biologi-
cal activity they exhibit.1 Specifically, naturally occurring
nonanolactones are categorized as rare species of organic
molecules and only a few limited compounds have been
isolated to date.
O
OH
O
RCM
O
OH
O
HO
OH
Botcinolide was first reported in 19932 and its structure
was elucidated by extensive spectroscopic studies, sug-
gesting that it was a lactone with a nine-membered ring.
However, Nakaijama et al. have recently revised the struc-
tures of several botcinolides derivatives renaming them as
botcinins.3,4 Independently, Chakraborty and Goswami5
and later Shiina et al.6 have described the synthesis of the
nonanolactone ring of 2-epibotcinolide which involved
fifteen and fourteen steps, respectively, several of which
led to mixtures of diastereomeric or dimeric products. As
a result, they questioned the structure of the proposed 2-
epibotcinolide.
OH
O
HO
OH
Brown
crotylboration
OH
Evans aldol
condensation
A
B
Scheme 1 Retrosynthetic pathway for the synthesis of botcinolides;
fragments A and B
Our research group was very interested in the synthesis
and structural characterization of botcinolide toxins and
their derivatives.2 We therefore used tandem esterifica-
tion–RCM reactions as a way to approach the synthesis of
the highlighted functionalized nonanolactones. In so do-
ing, the botcinolide ring was disconnected to fragments A
(C1–C4) and B (C5–C8) via esterification and intramolecu-
lar alkene metathesis (Scheme 1).
There is only a relatively small number of methods used
for closure of lactone rings, the most popular being mac-
rolactonization under high dilution conditions.7,8 Good
yields were observed in the preparation of five- to eight-
and twelve- to eighteen-membered-ring lactones. Howev-
er, the yield of nine-membered-ring lactones was almost
zero.8 A revision by the Illuminati group concluded that
producing medium-sized-ring compounds is difficult due
to both enthalpic and entropic factors.9
The closure of the nonanolactone ring precursor of the
botcinolide skeleton by RCM presents a double challenge:
The high activation enthalpy for the formation of a nine-
membered ring has to be overcome and the high degree of
substitution of both olefinic partners might hamper the
formation of the intermediate metallacyclobutane. In this
paper we analyze the effects produced by the substitution
SYNLETT 2008, No. 3, pp 0339–0342
x
x.
x
x.
2
0
0
8
Advanced online publication: 23.01.2008
DOI: 10.1055/s-2008-1032072; Art ID: D37207ST
© Georg Thieme Verlag Stuttgart · New York

340
J. Ramírez-Fernández et al.
LETTER
degree of both olefinic chains on the RCM reaction which when the reaction was performed with 2 and catalytic
are still not completely understood. amounts of (i-PrO)4Ti (see Table 1).
A number of lactones were synthesized as models for this In addition when reaction was performed with 2 over
study. The synthesis of the simplest lactones was achieved three days, an E/Z-isomerization was detected and an E/Z
starting from commercially available acids and alcohols. ratio of 1:3 was obtained. These preliminary results
Pent-5-enoic acid and 2-methylpent-5-enoic acid were showed a peculiarly inert behavior of the simplest diene
condensed with pent-4-en-1ol and hex-4-en-1-ol in the esters with catalyst 1 in their conversion into nonanolac-
presence of DCC and DMAP to afford the diene ester sub- tone; so we designed all of our experiments using catalyst
strates for the metathesis reaction. Different reaction con- 2.
ditions were evaluated. The best results were obtained by
treatment of 1.2 equivalents of acids and one equivalent of
alcohols with 1.5 equivalents of DCC and catalytic
Attempts to generate di- and trisubstituted lactones were
made using the diene esters 6, 10a–c and 14a and 14b
(Scheme 2).
amounts of DMAP (0.2 equiv) using toluene as a solvent
Nine-membered lactone rings with a trisubstituted double
(91–98% yield).
bond were synthesized using ester 6 as model substrate.
Alkylation of oxazolidinone 4 with 2-methyl allyl bro-
PCy3
mide and subsequent oxidative cleavage of the oxazolidi-
N
N
Mes
Mes
Ph
Cl
Cl
none ring gave rise to (2R)-2,4-dimethylpent-4-enoic acid
(5) which was esterified with commercial pent-4-en-1-ol
yielding 6 (61%; Scheme 2).
Cl
Ru
Ru
Ph
Cl
PCy3
PCy3
1
2
Protecting groups for allylic and homoallylic alcohol have
previously been documented to have an influence on me-
tathesis reactions.11 Therefore, the effect of the free hy-
droxyl group, with the hydroxyl protected as its ether
(TBDMS and OBz ethers) or ester (OAc) both at the C-3
allylic and at the C-2¢ homoallylic positions was investi-
gated.
Figure 1 Commercially available metathesis catalysts
The ring-closing reaction of the four diene esters 3a–d
was performed by using 5% or 20% of the catalyst in
CH2Cl2 at 40 °C and 60 °C. No cyclized products were ob-
served when the first-generation catalyst (1; Figure 1) was
used. However, when catalytic amounts of (i-PrO)4Ti
were used, cyclized compounds were detected but intrac-
table reaction mixtures were obtained. Use of the second-
generation Grubbs catalyst (2; Figure 2) gave the desired
cyclized products as a mixture of cis and trans isomers
(1:1) between 52% and 88% yields. The yield decreased
b-Hydroxyester derivatives were synthesized by means of
Evans asymmetric aldolization followed by esterification.
Reaction of chiral, commercially available oxazolidinone
4 and methacrolein provided the corresponding aldol ad-
duct 7 as an essentially single stereoisomer establishing
two new stereocenters with good yields.12 Oxidative
cleavage of the auxiliary using hydrogen peroxide–lithi-
Table 1 RCM of Simple Nonanolactones
O
R1
O
O
1
R1
O
8
1 or 2
1
O
O
R2
8
+
4
CH2Cl2
R1
5
4
5
3a: R1 = R2 = H
3b: R1 = Me; R2 = H
3c: R1 = H; R2 = Me
3d: R1 = R2 = Me
E
Z
Ester
Conditions
Yield (%)
Ratio E/Z
3a
40 °C, 5% cat. 2, 12 h
40 °C, 20% cat. 2, 12 h
52
85
1:1
1:1
3b
40 °C, 5% cat. 2, 12 h
40 °C, 20% cat. 2, 12 h
54
83
1:1
1:1
3c
60 °C, 5% cat. 2, 12 h
60 °C, 20% cat. 2, 12 h
79
88
1:1
1:1
3d
60 °C, 5% cat. 2, 12 h
60 °C, 20% cat. 2, 12 h
64
87
1:1
1:1
3a–3d
50 °C, 5% cat. 1/(i-PrO)4Ti, 12 h
50 °C, 5% cat. 2/(i-PrO)4Ti, 12 h
50 °C, 20% cat. 2, 36 h
–
–
1:1
1:3
32–51
85–88
Synlett 2008, No. 3, 339–342 © Thieme Stuttgart · New York

LETTER
Effect of Substituents on RCM in the Synthesis of Nonanolactones
341
Synthesis of chiral acids
O
O
O
O
c
a,b
N
O
O
Br
OH
6
Bn
5
4
O
OBn
O
d
N
O
O
b,c
OR
O
e
OH
O
O
Bn
O
(8
OH
N
O
b
f,c
Bn
7
10a: R = Ac
10b: R = Bn
10c: R =TBS
HO
9
Synthesis of chiral alcohols
O
OTBS
O
i,j
g,h
OH
OBn
OBn
EtO
H
11
12
k
O
OTBS
l
OH
O
OR'
13
14a R = TBS
14b R = OH
m
Scheme 2 Synthesis of chiral fragments for RCM. Reagents and conditions: (a) NaHMDS, –78 °C; (b) H2O2, LiOH, THF; (c) DCC, DMAP,
pent-4-en-1-ol; (d) n-Bu2BOTf, DIPEA, CH2Cl2, methacrolein, –78 °C to 0 °C; (e) triflic acid, benzyl 2,2,2-trichloroacetimidate, 0 °C; (f) for
10a: Ac2O, Py, CH2Cl2, 24 h; for 10c: TBSCl (4 equiv), imidazole, DMAP, 12 h; (g) BnBr, NaH, DMF; (h) DIBAL-H, CH2Cl2, –90 °C; (i) (+)-
Ipc2B–(Z)-crotyl, THF, –78 °C; (j) TBSTf, 2,6-lutidine, DMF; (k) DDQ (4 equiv), CH2Cl2–phosphate buffer (pH 7), 70 °C; (l) DCC, DMAP,
pent-4-enoic acid; (m) TBAF, THF.
um hydroxide in THF–water, protection of the hydroxyl underwent cyclization to give a 1:1 mixture of cis and
group with different groups, and esterification with pent- trans isomers.
3-en-1-ol afforded the expected esters 10a–c.
Especially interesting was the cyclization of dienes 6 and
Alcohol 13 was synthesized by crotylboration of (S)-2- 14b to give, in theory, the thermodynamically less stable
benzyloxypropanal followed by protection with TBSTf E-isomers. The RCM reaction is believed to proceed un-
and debenzylation. Esterification with pent-4-enoic acid der thermodynamic control14 so these results were com-
under usual conditions afforded ester 14a which was pletely unexpected, indicating a possible kinetic control of
transformed into 14b using tetrabutylammonium fluoride the stereochemistry.
(TBAF) in THF.
Esters 3b and 6 are only different in the vinylic methyl
RCM reactions of the six diene esters (6, 10a–c, 14a,b) group. It is believed that this methyl group interferes with
were performed using the reaction conditions described the RCM, yielding even less than does the corresponding
above. The results summarized in Table 2 show that the ester without such a substituent (3b),15 but in this case its
RCM was not compatible with the presence of the TBS presence seems to determine the E-olefin stereochemistry.
group, probably due to steric reasons (entry 10c and 14a).
Double bond geometry in RCM is determined by the ruth-
It was noted, however, that the RCM reaction is compati- enacyclobutane intermediates produced in the reaction;16
ble with vinylic, allylic and homoallylic methyl groups so cis- or trans-ruthenacyclobutane intermediate lead to
and with the presence of allylic and homoallylic oxygen the Z- or E-stereoisomer, respectively. At present, the rea-
functions. Nevertheless, these have a dramatic effect on sons why these substituents interfere in the RCM mecha-
the cyclization stereochemistry. All the diene esters that nism are not completely understood. Some examples of
underwent cyclization rendered only one isomer,13 in kinetically controlled RCM stereochemistry have recently
sharp contrast with less functionalized dienes which all been reported for the synthesis of carbocycles.17 The se-
Synlett 2008, No. 3, 339–342 © Thieme Stuttgart · New York

342
J. Ramírez-Fernández et al.
LETTER
Table 2 RCM of Polyfunctionalized Nonanolactonesa
O
R1
R2
O
R4
R6
O
R4
O
R1
R2
R2
R3
R4
R5
O
O
R5
R3
R1
R5
R6
R6
R3
Ester
6
Yield (%)
62
Product
(E)-19a: R1 = R3 = Me; R2 = R4 = R5 = R6 = H
10a
10b
10c
14a
14b
58
(Z)-19b: R1 = R3 = Me; R2 = OAc; R4 = R5 = R6 = H
(Z)-19c: R1 = R3 = Me; R2 = OBn; R4 = R5 = R6 = H
19d: R1 = R3 = Me; R2 = OTBDMS; R4 = R5 = R6 = H
19e: R1 = R2 = R3 = H; R4 = R6 = Me; R5 = OTBDMS
(E)-19f: R1 = R2 = R3 = H; R4 = R6 = Me; R5 = OH
46
n.r.b
n.r.b
71
a Reaction conditions: 2, CH2Cl2, 50 °C, 12 h.
b No reaction.
(6) Shiina, I.; Takasuna, Y.; Suzuki, R.; Oshiumi, H.;
Komiyama, Y.; Hitomi, S.; Fukui, H. Org. Lett. 2006, 8,
5279.
(7) Parenty, A.; Moreau, X.; Campagne, J. M. Chem. Rev. 2006,
106, 911.
(8) Hundsdiecker, H.; Erlbach, H. Chem. Ber. 1947, 80, 129.
(9) (a) Galli, C.; Illuminati, G.; Mandolini, L. J. Am. Chem. Soc.
1973, 95, 8374. (b) Galli, C.; Illuminati, G.; Mandolini, L.;
Tamborra, P. J. Am. Chem. Soc. 1977, 99, 2591. (c) For a
review, see: Illuminati, G.; Mandolini, L. Acc. Chem. Res.
1981, 14, 95.
(10) For RCM approaches to the synthesis of nine-membered-
ring lactones, see: (a) Takahashi, T.; Wataqnabe, H.;
Kitahara, T. Heterocycles 2002, 58, 99. (b) Baba, Y.; Saha,
G.; Nakao, S.; Iwata, C.; Tanaka, T.; Ibuka, T.; Ohishi, H.;
Takemoto, Y. J. Org. Chem. 2001, 66, 81.
(11) (a) Sheddan, N. A.; Airon, V. B.; Mulzer, J. Tetrahedron
Lett. 2006, 47, 6689. (b) Castoldi, D.; Caggiano, L.; Bayón,
P.; Costa, A. M.; Cappella, P.; Sharonm, O.; Gennari, C.
Tetrahedron 2005, 61, 2123. (c) Caggiano, L.; Castoldi, D.;
Beumer, R.; Bayón, P.; Telser, J.; Gennari, C. Tetrahedron
Lett. 2002, 44, 7913.
(12) (a) Gage, J. R.; Evans, D. A. Org. Synth. 1989, 68, 77.
(b) Días, L. C.; Bau, R. Z.; De Sousa, M. A.; Zukerman-
Schpector, J. Org. Lett. 2002, 4, 4325.
lectivity is believed to be due to the functionality around
the ruthenacyclobutane intermediate that favors the trans-
ruthenacycle leading to the less stable E-isomer. Hence,
the E-olefin selectivity obtained for ester 14b could be ra-
tionalized by coordination of the homoallylic alcohol with
the ruthenium metal center in the ruthenacyclobutane in-
termediate. The resulting arranged intermediate imposes
added steric/electronic restrictions leading to higher se-
lectivities for the E-olefin RCM product via a kinetic pro-
cess.18 On the other hand, the Z-stereoisomers obtained
from compounds 10a and 10b could be explained by in-
teraction/coordination of the protected allylic alcohols
with the ruthenium which favors the cis-ruthenacycle
leading to the corresponding Z-isomers. Computational
studies of this unusual cyclization stereochemistry are un-
derway to provide a satisfactory explanation of these re-
sults.
Acknowledgment
This work was supported by the Spanish Science and Technology
Ministry through project AGL2006-13401-C02-01.
(13) The geometry of double bond for lactones 19a–c was
determined on the basis of NOE experiments. In addition the
E-geometry of 19f was assigned by coupling constant
between olefinic protons.
(14) (a) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res.
1995, 28, 446. (b) Baylon, C.; Heck, M. P. J. Org. Chem.
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(15) Kirkland, T. A.; Grubbs, R. H. J. Org. Chem. 1997, 62, 7310.
(16) Handbook of Metathesis, Vol. 1–3; Grubbs, R. H., Ed.;
Wiley-VCH: Weinheim, 2003.
(17) Castoldi, D.; Caggiano, L.; Panigada, L.; Sharon, O.; Costa,
A. M.; Gennari, C. Chem. Eur. J. 2006, 12, 51.
(18) Engelhardt, F. C.; Schmitt, M. J.; Taylor, R. E. Org. Lett.
2001, 3, 2209.
References and Notes
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