Enantioselective annulation using Nazarov reagent: Synthesis of (+)-preoleanatetraene

Article abstract of DOI:10.1055/s-2005-864798

The enantioselective synthesis of preoleanatetraene (1) has been accomplished via a convergent approach of two C-15 synthons. The key step of this synthesis has been an interesting enantioselective variant of the Robinson annulation using the Nazarov reag

Full text of DOI:10.1055/s-2005-864798

LETTER
789
Enantioselective Annulation Using Nazarov Reagent: Synthesis of
(+)-Preoleanatetraene
Enantioselective
A
l
nnulati
e
on
U
sing N
j
a
zarov
a
Reagent ndro F. Barrero,*a Simeón Arseniyadis,b José F. Quílez del Moral,a M. Mar Herrador,a Antonio Rosellóna
a
Departament of Organic Chemistry, Institute of Biotechnology, University of Granada, Avda. Fuentenueva, 18071 Granada, Spain
Fax +34(95)8243318; E-mail: afbarre@goliat.ugr.es
b
Institute de Chimie de Substances Naturelles, CNRS, 91198 Gif-sur-Yvette, France
Received 18 January 2005
Abstract: The enantioselective synthesis of preoleanatetraene (1)
has been accomplished via a convergent approach of two C-15 syn-
thons. The key step of this synthesis has been an interesting enantio-
selective variant of the Robinson annulation using the Nazarov
reagent and a chiral enamine to obtain the bicyclic moiety A. This
asymmetric methodology opens the access to other irregular triter-
pene skeletons whose biogenetic implication should not be underes-
timated.
HO
achilleol A (2)
H
H
H
HO
HO
Key words: preoleanatetraene, annulation, asymmetric synthesis,
terpenoids, natural products, total synthesis
achilleol B (3)
R
Since the isolation of achilleol A (2) and achilleol B (3)
from Achillea odorata by our group in 1990,1 a number of
partially cyclized triterpenes – some of them, as 1 and 4,
possessing only two or three rings of the usually fully cy-
clized pentacyclic system – have been described
(Figure 1).2 Recently, two compounds, 5 and 6, with a
new related tetracyclic triterpene skeleton have been re-
ported.2d The occurrence of these irregular triterpenes in
nature suggests the existence of enzymes able to promote
cyclizations at different levels from both 2,3-oxide
squalene cyclase (OSC) and squalene cyclase (SC).3 Fur-
thermore, the description of most of these compounds
during the last decade permits to suggest that with the
development of isolation and identification techniques,
new examples of these irregular triterpenes, are likely to
be reported in the near future.
5 R = H, β-OH
6 R = H, β-OAc
camelliol A (4)
Figure 1 Chemical structures of 2–6.
H
+
COOMe
NH
Y
O
9
10
H
Ph
A
X
1
B
3
X
HO
HO
C
The importance of these natural products for a deeper un-
derstanding of the biogenetic pathways of living organ-
isms prompted us to find an expedient route to most of
these compounds, a challenge that we started to face with
the synthesis of preoleanatetraene (1). Prior to this work,
we have reported the synthesis of the monocyclic triter-
pene achilleol A (2) through a radical cyclization mediat-
ed by Ti(III) of an epoxide precursor.4
+
A
X
4
D
X
5, 6
X = SO2Ph
R
Y = leaving group
Our retrosynthetic planning to these types of natural prod-
ucts is based on the convergent approach of a common bi-
cyclic precursor (A) and the corresponding C-15 moiety
(Scheme 1). The key step in the synthesis of this common
bicyclic system was projected to be an enantioselective
variant of the Robinson annulation using the Nazarov
E
Scheme 1 Rethrosynthetic analysis for 1, 3, and 4–6.
reagent, despite the noticeable absence of precedents from
literature of asymmetric versions of this reaction.5 Revi-
sion of the literature led us to two previous syntheses of
derivatives of A by van Tamelen6 and Heathcock7 in their
approaches to the synthesis of b-amyrin. Although the rel-
evance of the work developed by the mentioned authors is
undoubted, it was limited to obtain A in a racemic way.8
SYNLETT 2005, No. 5, pp 0789–0792
2
1.
0
3.
2
0
0
5
Advanced online publication: 09.03.2005
DOI: 10.1055/s-2005-864798; Art ID: G02805ST
© Georg Thieme Verlag Stuttgart · New York

790
A. F. Barrero et al.
LETTER
Thus, our objective was not only to achieve the synthesis in four steps with a yield of 63%, which improves previ-
of A enantioselectively but also to improve the efficiency ously described procedures considerably.
of some of the transformations described in the precedent
reports.
A complete spectroscopic study of 14 including 1D and
2D NMR allowed us to confirm both the structure and the
cis-interannular junction presented in this compound.14
O
The stereochemistry assigned to 14, together with a selec-
tion of NOEs observed for this compound, is depicted in
NH2
ref.7
a
+
Figure 2. Fundamental for the assignment of the relative
stereochemistry at C-4a and C-8a were the NOE-DIFF
correlations between H-8a and the methyl group at C-4a
H
O
Ph
O
8
7
and the b-methyl group at C-7, which also defines the ma-
d
jor conformation in solution.
b
+
NH
O
O
O
COOMe
COOMe
12
9
11
H
Ph
c
e
f
OH
H
H
H
COOMe
COOMe
OH
15
13
14
Scheme 2 Reagents and conditions: a) benzene, molecular sieves,
48 h, 74%; b) methyl 3-oxo-4-pentenoate (10), benzene, 1 h, 70 °C,
21% of 11, and 20% of 12; c) KF, MeOH, D, 6 h, quantitative; d) H2-
Pd/C, EtOAc, 72 h, 91%; e) (i) Tf2O, (i-Pr)2EtN, CH2Cl2, –78 °C to
–50 °C, 30 min; (ii) CuBr·SMe2, MeLi, THF, –15 °C, 30 min, 91% in
two steps; f) LAH, Et2O, 0 °C, 30 min, 79%.
Figure 2 Relative configurations and selected NOEs for 14.
At that moment, we decided to test the coupling step using
an easily accessible model. With this purpose, we turned
our efforts to achieve an enantioselective access to the
non-natural b-polypodatetraene 20,15 a bicyclic triterpene
also involved in mechanistic studies of the biosynthesis of
polycyclic triterpenoids, as 2,3-monoepoxide has been
reported to enzymatically cyclize to onocerane deriva-
tives.16
Basing ourselves on the work of Heathcock, ketone 8 was
obtained starting from dimethyl dimedone 7 (Scheme 2).
Once large quantities of 8 were at disposal, it was decided
to study the feasibility of obtaining the conjugated keto
ester 12 using an enantioselective version of the Robinson
annelation with the Nazarov reagent. With the assumption
of preoleanatetraene (1) possessing an absolute configura-
tion R at C-10, enamine 9 was prepared (in equilibrium
with the corresponding imine) by treating 8 with (S)-phe-
nylethylamine.9 Treatment of 9 with freshly prepared
Nazarov reagent 1010 led to a mixture of the desired keto
ester 12 and its acyclic precursor.11 Quantitative cycliza-
tion was achieved by treatment of 11 with KF in MeOH.
The global yield in the enantioselective Robinson annula-
tion process was 41%, the enantiomeric excess obtained
being 80%.12
The bicyclic synthon 17 was prepared from (–)-drimenol
(Scheme 3). As anticipated, the coupling process between
17 and the lithium derivative from farnesylphenylsulfone
(18) proceeded smoothly in 72% yield. Reductive elimi-
nation of the phenylsulfonyl group using sodium-amal-
gam gave 20 in 44% yield; when this reaction was
achieved with Li-ethylamine, the yield was improved up
to 79%.
Once the conditions for the final steps of the synthesis of
1 were established, we proceeded to react allylic bromide
21 with the corresponding anion of farnesylphenyl-
sulfone17 to gratifyingly obtain the desired diastereomeric
mixture of sulfones 22 in good yield. Finally, exposure of
22 to Li-EtNH2 led to the formation of preoleanatetraene.
Moving forward with the synthetic planning, the catalytic
reduction of 12 with H2-Pd/C at 3 atm led stereoselective-
ly to cis-decaline 13, which according to its NMR spectra
appears in solution as the enolic form of the ketone carbo-
nyl group. The introduction of the methyl group on the
double bond was initially tried by treatment of 13 and of
its phosphate derivative with Me2CuLi. Unfortunately,
under different conditions tested, the reaction did not
work. The desired conversion was carried out by treating
the corresponding enol triflate with MeLi in the presence
of the complex CuBr·SMe2.13 Reduction of the conjugated
ester with LiAlH4 afforded finally the bicyclic alcohol 15.
This achievement permitted the conversion of 12 into 15
1
MS, H NMR and 13C NMR spectroscopy of this com-
pound coincided completely with those of the natural
product. The sign of the optical rotation [a]D of both the
synthetic and the natural polypodatetraene were coinci-
dent {[a]D value for natural 1: +13.9 (CHCl3); [a]D value
for synthetic 1: +11.0 (CHCl3)}, which let us assign the
absolute stereochemistry of the natural product to that
shown in Scheme 4.
Synlett 2005, No. 5, 789–792 © Thieme Stuttgart · New York

LETTER
Enantioselective Annulation Using Nazarov Reagent
791
OH
Acknowledgment
OH
This research was supported by the Spanish Dirección General de
Investigación Científica y Técnica (DGESIC; Proyecto BQ 2002-
03211).
a
b
16
(–)-drimenol
Br
References
PhO2S
(1) (a) Barrero, A. F.; Álvarez-Manzaneda, E. J.; Álvarez-
Manzaneda, R. Tetrahedron Lett. 1989, 30, 3351.
(b) Barrero, A. F.; Álvarez-Manzaneda, E. J.; Álvarez-
Manzaneda, R. Tetrahedron 1990, 46, 8161.
c
(2) (a) Arai, Y.; Hirohara, M.; Ogawa, R.; Masuda, K.;
Shiojima, K.; Ageta, H.; Chang, H. C.; Chen, Y. P.
Tetrahedron Lett. 1996, 37, 4381. (b) Akihisa, T.; Arai, K.;
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D.; Cerda-Garcia-Rojas, C. M.; Torres-Valencia, J. M.;
Joseph-Nathan, P. Org. Lett. 2004, 6, 173.
17
19
d
20
(3) Although the biosynthesis of b-amyrin is known to proceed
via 2,3-oxidosqualene, the fact that b-amyrin has been
obtained after enzymatic cyclization of the 2,3-epoxide of
racemic 1 should be also taken into account. Furthermore,
oxidosqualene cyclase mutagenesis experiments, included
those in which achilleol A and camelliol C are
Scheme 3 Reagents and conditions: a) (i) PCC, CH2Cl2, 50 min;
(ii) K2CO3, MeOH, 2 h; (iii) NaBH4, MeOH, 2h, 46% in three steps;
b) PBr3, Et2O, 0 °C, 30 min, 90%; c) 18, n-BuLi, THF, –78 °C, 10
min, then 17, 4 h, 72%; d) Li, EtNH2, THF, –78 °C, 2 h, 79%.
biosynthesized by mutant OSC, suggested that relatively few
changes in the enzyme are needed to alter product
specificity. These findings ultimately supported the
existence of alternative pathways in the biosynthesis of
terpenoids. For OCS mutagenesis experiments, see:
(a) Segura, M. J. R.; Jackson, B. E.; Matsuda, S. P. T. Nat
Prod. Rep. 2003, 20, 304. (b) Wendt, K. U.; Schulz, G. E.;
Corey, E. J.; Liu, D. R. Angew. Chem. Int. Ed. 2000, 39,
2812. (c) For biosynthesis of b-amyrin from the 2,3-epoxide
of racemic 1, see: Horan, H.; McCormick, J. P.; Arigoni, D.
J. Chem Soc., Chem. Commun. 1973, 3, 73.
a
b
PhO2S
15
H
H
Br
21
22
(4) Barrero, A. F.; Cuerva, J. M.; Alvarez-Manzaneda, E. J.;
Oltra, E.; Chahboun, R. Tetrahedron Lett. 2002, 43, 2793.
(5) To our knowledge, only Theodorakis et al. have assayed the
enantioselective variant of this reaction in their synthesis of
(–)-acanthoic acid. Although the condensation reaction was
attempted in the presence of different optically active
catalysts, the highest ee obtained were of 60%: Ling, T.;
Chowdhury, C.; Kramer, B. A.; Vong, B. G.; Palladino, M.
A.; Theodorakis, E. A. J. Org. Chem. 2001, 66, 8843.
(6) Van Tamalen, E. E.; Seiler, M. P.; Wierenga, W. J. Am.
Chem. Soc. 1972, 94, 8229.
H
c
1
Scheme 4 Reagents and conditions: a) PBr3, Et2O, 0 °C, 30 min,
90%; b) 18, n-BuLi, THF, –78 °C, 10 min, then 21, 4 h, 72%; c) Li,
EtNH2, THF, –78 °C, 2 h, 89%.
(7) Ellis, J. E.; Dutcher, J. S.; Heathcock, C. H. J. Org. Chem.
1976, 41, 2670.
In conclusion, with the synthesis of 1, we have proved that
reasonable ee could be obtained using an enantioselective
variation of the Robinson annulation with a Nazarov re-
agent. With the aim of widening the scope of this reaction,
new chiral amines and different annulation conditions are
projected to be attempted. On the other hand, we have also
opened an enantioselective approach to irregular triterpe-
nes possessing the bicyclic moiety A, the syntheses of
some of them are currently being addressed in our labora-
tory. Furthermore, the assignment of the absolute config-
uration of (+)-preoleanatetraene has also been described.
(8) Reports by Barton and van Tamelen, showing that the use of
different epimers in OSC-induced cyclizations, led to
different results constituted an additional argument to pursue
the enantioselective synthesis of these irregular triterpenes:
Abe, I.; Rohmer, M.; Preswich, G. D. Chem. Rev. 1993, 93,
2189.
(9) D’Angelo, J.; Desmaële, D.; Dumas, F.; Guingant, A.
Tetrahedron: Asymmetry 1992, 3, 459.
(10) (a) Nazarov, I. N.; Zavyalov, S. I. Zh. Obshch. Khim. 1953,
23, 1703; Chem. Abstr. 1954, 48, 13667h. (b) Zibuck, R.;
Streiber, J. M. Org. Synth. 1993, 71, 236.
(11) Procedure for the Enantioselective Variant of the
Robinson Annulation Using the Nazarov Reagent and a
Chiral Enamine: Synthesis of Bicyclic 12.
A stirred solution of enamine 9 (486 mg, 2 mmol) and
Synlett 2005, No. 5, 789–792 © Thieme Stuttgart · New York

792
A. F. Barrero et al.
LETTER
(14) All new compounds gave satisfactory analytical and
Nazarov reagent 10 (256 mg, 2 mmol) in dry benzene (2 mL)
was heated at 65–70 °C for 1 h. Then was added 0.5 mL of a
solution of 125 g of NaOAc, 25 mL of H2O and 25 mL of
HOAc. The mixture was heated for 1 h, washed with H2O,
sat. aq NaHCO3, and brine. The organic layer was dried over
Na2SO4 and concentrated under reduced pressure. The
resulting crude product was purified by column
chromatography (hexane–t-BuOMe, 4:1) to afford 150 mg
of 11 (20%) and 106 mg of 12 (21%). Keto ester 12 was
isolated as colorless oil. [a]D –49.7 (c 0.7, CHCl3). 1H NMR
(400 MHz, CDCl3): d = 3.79 (s, 3 H), 2.52 (ddd, J = 5.4,
14.3, 17.0 Hz, 1 H), 2.40 (dt, J = 3.9, 17.0 Hz, 1 H), 2.15 (d,
J = 14.6 Hz, 1 H), 1.98 (dd, J = 1.3, 14.6 Hz, 1 H), 1.86 (td,
J = 4.6, 13.7 Hz, 1 H), 1.78 (dq, J = 3.2, 13.6 Hz, 1 H),
1.47–1.67 (m, 3 H), 1.28–1.37 (m, 1 H), 1.23 (s, 3 H), 1.00
(s, 3 H), 0.82 (s, 3 H). 13C NMR (100 MHz, CDCl3):
d = 195.0, 167.7, 166.4, 132.3, 52.0, 43.0, 37.8, 37.1, 34.4,
34.0, 33.5, 32.4, 32.0, 24.6, 22.3. IR (film): 2945, 2866,
1735, 1671, 1617, 1465, 1353, 1227, 1131, 1008 cm–1.
HRMS–FAB: m/z calcd for C15H22O3Na [M + Na]+:
273.1467; found: 273.1463.
spectroscopic data.
Compound 14: colorless oil. [a]D +30.8 (c 0.5, CHCl3). 1H
NMR (400 MHz, C6D6): d = 3.51 (s, 3 H), 2.68 (dd, J = 2.9,
12.4 Hz, 1 H), 2.03 (s, 3 H), 1.97–2.07 (m, 2 H), 1.84 (ddd,
J = 6.8, 11.8, 24.5 Hz, 1 H), 1.57–1.65 (m, 2 H), 1.35 (dt,
J = 3.9, 13.6 Hz, 1 H), 1.25 (td, J = 3.4, 13.6 Hz, 1 H), 1.15
(br d, J = 13.6 Hz, 1 H), 1.08 (t, J = 13.0 Hz, 1 H), 1.02 (s,
3 H), 0.93 (s, 3 H), 0.93 (s, 3 H), 0.73 (dd, J = 6.9, 14.7 Hz,
1 H). 13C NMR (100 MHz, C6D6): d = 169.0, 142.8, 129.3,
50.7, 43.8, 40.0, 36.5, 34.8, 33.1, 31.4, 31.1, 31.0, 27.0, 26.3,
24.1, 21.9. IR (film): 2949, 2922, 2851, 1713, 1640, 1464,
1258, 1063, 804 cm–1. HRMS–FAB: m/z calcd for
C16H26O2Na [M + Na]+: 273.1831; found: 273.1830.
(15) (a) (+)-a- and (+)-g-polypodatetraenes have been isolated
form the leaves of Polypodium and Polystichum species:
Shiojima, K.; Arai, Y.; Masuda, K.; Kamada, T.; Ageta, H.
Tetrahedron Lett. 1983, 24, 5733. (b) Although recently
both polypodatetraenes have been reported from (–)-albi-
canol and (–)-drimenol by Akita et al., the method used by
these authors supposed an elongation of the carbon chain of
the sesquiterpenic precursors, as a previous step to the key
C-20+C-10 coupling process: Kirosita, M.; Ohtsuka, M.;
Nakamura, O.; Akita, H. Chem. Pharm. Bull. 2002, 50, 930.
(16) Van Tamalen, E. E.; Hopla, R. E.; Kont, W. E. J. Am. Chem.
Soc. 1979, 101, 6112.
(12) The enantioselectivity of the annelation reaction could be
measured after treating 15 with (S)-2-acetoxypropionyl
chloride. The diastereomeric ratio of the corresponding
lactates was determined by 1H NMR (800 MHz)
spectroscopy, by integrating the AB quartets of the major
and minor components.
(17) Eis, K.; Schmalz, H. G. Synthesis 1997, 202.
(13) Bertz, S. H.; Gibson, C. P.; Dabbagh, G. Tetrahedron Lett.
1987, 28, 4251.
Synlett 2005, No. 5, 789–792 © Thieme Stuttgart · New York