Application of chiral tethers to intramolecular [2 + 2] photocycloadditions: Synthetic approach to (-)-italicene and (+)-isoitalicene

Article abstract of DOI:10.1016/S0040-4039(00)01933-X

A synthetic approach to (-)-italicene and (+)-isoitalicene, sesquiterpenes which possess the rare tricyclo[5.4.0.0^1,5] undecane skeleton has been developed using a key step a highly regio- and diastereoselective [2 + 2] photocycloaddition. (S)-

Full text of DOI:10.1016/S0040-4039(00)01933-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 255–259
Application of chiral tethers to intramolecular [2+2]
photocycloadditions: synthetic approach to (−)-italicene and
(+)-isoitalicene
Sophie Faurea and Olivier Pivab,*
aLaboratoire de Photochimie, UMR 6519 CNRS, Universite´ de Reims Champagne-Ardenne UFR Sciences, BP 1039,
F.51689 Reims cedex, France
bLaboratoire de Chimie Organique, Photochimie et Synthe`se, UMR 5622 CNRS, Universite´ Claude Bernard-Lyon I,
43, Bd du 11 novembre 1918, F.69622 Villeurbanne, France
Received 31 August 2000; accepted 30 October 2000
Abstract—A synthetic approach to (−)-italicene and (+)-isoitalicene, sesquiterpenes which possess the rare tricyclo[5.4.0.01,5
]
undecane skeleton has been developed using as key step a highly regio- and diastereoselective [2+2] photocycloaddition. (S)-Lactic
acid plays the role of a chiral removable tether group during the building of the cyclobutane ring. © 2000 Elsevier Science Ltd.
All rights reserved.
(−)-Italicene 1 and (+)-isoitalicene 2, two sesquiterpe-
nes isolated from the essential oil of Helicrysum
italicum1 are used nowadays as fragrance and natural
insecticide in the mediterranean area. They possess both
a cyclobutane framework which is relatively unusual in
natural products (Scheme 1). To date, few approaches
or total syntheses have been reported and none was
totally stereocontrolled.2–4
While [2+2] cycloadditions5,6 can be considered as the
most powerful way to prepare such 4-membered ring
skeleta, we have investigated more particularly the
asymmetric synthesis of these two compounds. Our
approach was based on the use of a- or b-hydroxyacids
as chiral tether for the intramolecular photocycloaddi-
tion process that we recently reported in a preliminary
communication (Scheme 2).7a Because the chiral auxil-
iary is connected both to the alkenone and the alkene
moieties by two ester functionalities, this tether group
can be removed in one single step to deliver the cy-
clobutane adduct in enantiomeric enriched form. The
(-)-1
(+)-2
Scheme 1.
O
O
O
O
O
OH
O
O
O
O
O
O
O
O
O
(-)-1
3
4
O
Scheme 2.
Keywords: italicene; cycloadditions; templates; metathesis; radicals.
* Corresponding author. Fax: +33-4-72-44-81-36; e-mail: piva@univ-lyon1.fr
0040-4039/01/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01933-X

256
S. Faure, O. Pi6a / Tetrahedron Letters 42 (2001) 255–259
hυ
O
O
(λ = 254 nm)
LiAlH4
Et2O
OH
O-Bn
O-Bn
N
OH
6
7
5a
85% (2 steps)
CH2Cl2, 10°C
O
O
O
5a
4
O
TBDPSO
R-O
OH
O
O
DCC, DMAP
CH2Cl2, 0°C
DCC, DMAP
CH2Cl2, 0°C
O
O
n-Bu4NF
THF
81%
9 (R = TBDPS)
10 (R = H)
8
89%
98%
3a
Scheme 3.
O
O
R
R
O
R
R
R
R
O
O
hυ
+
O
O
(λ = 366 nm)
O
O
O
O
CH2Cl2
O
O
O
O
81%
92%
12a (R = CH3)
12b (R = H)
97/ 3
93/ 7
11a (R = CH3)
11b (R = H)
3a (R = CH3)
3b (R = H)
O
O
O
O
O
CH3O-Na+
TMSO
OTMS
+
O
O
O
O
CH3OH, ∆
TMSOTf
CH2Cl2,
O
OCH3
OH
O
O
O
78%
-30°C
82%
O
11a
13
14
15
(+)-CSA, toluene, ∆
Scheme 4.
any trace of the other regioisomer, as already noticed
with similar starting material 3b (R=H).7b The high
level of induction (d.e.=94%) was easily determined by
1H NMR performed on the crude mixture before any
purification step. This value appeared slightly better
than the one observed for the unsubstituted butenyl
derivative 11b (R=H, d.e.=86%). Moreover, the
stereocourse of the reaction was attributed thanks to
CD analyses on 11a and 13 and comparison with
previous results in this field.7 Removal of the chiral
tether group was next performed by action of sodium
methoxide, followed by treatment under slightly acidic
conditions to favor lactonisation of the intermediate
methyl hydroxyester 14 (Scheme 4).
easy cleavage is therefore one of the major advantage of
this method, compared to other recent diastereoselec-
tive [2+2] photocycloadditions using different tempo-
rary chiral linkers.8
Starting oxoester 3a was prepared from the known
oxoacid 4,9 protected (S)-lactic acid 8 and homoallylic
alcohol 5a (Schemes 2 and 3). This compound has been
prepared by alternative routes but the more efficient
combined the photodeconjugation10 and reduction of
benzyl 4-methyl-2-pentenoate 6.
Irradiation of 3a (R=CH3) was carried out in CH2Cl2
(10−2 M) at rt and under a 366 nm wavelength and led
to the formation of adduct 11a in good yield and
excellent regio- and diastereoselectivities. Only the for-
mation of the straight compound was observed without
To reach the tricyclo[5.4.0.01,5] undecane skeleton, we
investigated first a ring-closing metathesis (RCM) from

S. Faure, O. Pi6a / Tetrahedron Letters 42 (2001) 255–259
257
diene 18.11 This reaction has now emerged as a promis-
ing and powerful process for the synthesis of cycloalke-
nes since the discovery of efficient ruthenium12 and
molybdenum13 catalysts. Therefore, after protection of
13 under Noyori’s conditions14 and action of MeLi in
THF,15 hydroxymethylketone 16 was directly oxidised
with TEMPO using Einhorn’s conditions16 to ketoalde-
hyde 17. Double Wittig reaction17 was conducted on 17
but, while the aldehyde reacted totally, the more hin-
dered keto function was only partially converted into
the methylene group. Using a large excess of reagents
resulted only in degradation of the material. Fortu-
nately, 18 and 19 were easily separated by flash-chro-
matography. Typical RCM conditions (10% Grubbs’
catalyst, high dilution conditions) were applied to 18.
When performed at rt, no coupling occurred. By heat-
ing to 40°C, 18 was slowly converted into dimer 20
(E/Z=75/25) resulting from a self-coupling process,
while phenyl derivative 21 was also obtained as the only
by-product (Scheme 5). The lack of reactivity of 18 for
the intramolecular coupling could be attributed to the
steric hindrance generated by the presence of a quater-
nary center a to one of the CꢀC bonds. Such limitations
for the RCM has been widely reported, especially with
the ruthenium catalyst used therein.11,18
5-exotrig process should take place and provide the
expected tricyclo[5.4.0.01,5] undecane system. Lactone
15 was therefore reduced with L-selectride to lactol 22
in 90% yield. No further reduction occurred at this
stage as already pointed out by Denmark et al.21 By a
Wittig olefination using an excess of reagents, 22 was
converted into unsaturated alcohol 23, subsequently
transformed into alkenyl iodide 25.22 Standard radical
cyclisation conditions applied to this substrate fur-
nished two diastereomers 26 and 27 in good yield but
moderate selectivity (81/19). The relative configuration
of the new stereogenic center was assigned by compari-
1
son of its H NMR spectrum and especially the chemi-
cal shift of CH3 on carbon-7 with those of the natural
products 1 and 2, which possess the same stereodefined
tricyclic core.23 Therefore, the major diastereomer 26
appeared as a potential precursor of (+)-isoitalicene
(Scheme 6).
Attempts to introduce on 26 the methyl group in
a-position of the carbonyl functionality appeared more
difficult than expected, even by varying the nature of
the base, solvent and additives. By contrast, starting
from ketolactone 13, methylation took place nicely
(Scheme 7). Thus, introduction of the methyl sub-
stituent should be made before the radical sequence.
Work is now underway to follow this strategy to com-
plete the total and asymmetric synthesis of 1 and 2.
Since the RCM approach was not efficient, we chose a
new strategy based on a radical cyclisation process19 of
iodoalkene 25. According to the Baldwin’s rules,20
a
O
O
O
O
O
O
O
MeLi
(1.5 equiv.)
TEMPO (0.1 equiv.)
NCS (1 equiv.)
O
O
CHO
n-Bu4NCl (1 equiv.)
CH2Cl2 / H2O
THF, -78°C
O
OH
15
16
17
62% (2 steps)
O
O
PCy3
O
O
Cl
Cl
Ru
Ph
PCy3
CH3P(Ph)3+ Br-
(2.6 equiv.)
(0.1 equiv.)
18
20
CH2Cl2
34%
+
62%
E/Z =
75/25
40°C, 24h
O
O
t-BuOK (2.4 equiv.)
THF, 0°C -> 70°C
+
O
O
O
O
O
19
27%
21
< 5%
Ph
Scheme 5.

258
S. Faure, O. Pi6a / Tetrahedron Letters 42 (2001) 255–259
O
O
O
O
O
O
CH3P(Ph)3+ Br-
(2.6 equiv.)
L-Selectride
(3 equiv.)
O
HO
THF, -78°C
90%
t-BuOK (2.4 equiv.)
THF, 0°C -> 70°C
74%
O
O
OH
15
22
23
O
O
CH3SO2-Cl
NaI, acetone, ∆
DMAP, CH2Cl2, r.t.
75%
99%
OMs
I
24
25
O
O
n-Bu3Sn-H (1.4 equiv.)
AIBN (0.4 equiv.)
+
Ph-H, 80°C
84%
7
7
26
27
81 / 19
Scheme 6.
O
O
O
O
t-BuLi (1 equiv.)
CH3-I (2 equiv.)
t-BuLi (1 equiv.)
CH3-I (2 equiv.)
THF (0° -> 20°C)
THF (0° -> 20°C)
O
O
O
O
26
28
traces
13
29
69%
Scheme 7.
Acknowledgements
Piva-Le Blanc, S.; Bertrand, C.; Pete, J.-P.; Faure, R.;
Piva, O. J. Org. Chem. submitted.
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Weinheim, 2000; pp. 275–395. (b) Booker-Milburn, K. I.;
Gulten, S.; Scharpe, A. Chem. Commun. 1997, 1385–
1386. (c) Bach, T.; Kru¨ger, C.; Harms, K. Synthesis 2000,
305–320.
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Fakunle, C. O.; Piva, O. Tetrahedron, in press.
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S.F. thanks MENRT for a Ph-D grant. CNRS and
Re´gion Rhoˆne-Alpes are gratefully acknowledged for
financial support to O.P. (AIP CNRS 1999–2001 and
Programme Emergence).
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