A new cross-coupling-based synthesis of carpanone

Article abstract of DOI:10.1021/ol9017326

Carpanone has been stereoselectively synthesized in 55% yield and six steps from sesamol. The key step of the synthetic sequence is the direct introduction of the propenyl side chain via a Suzuki-Miyaura cross-coupling reaction. The subsequent Pd(II)-cata

Full text of DOI:10.1021/ol9017326

ORGANIC
LETTERS
2009
Vol. 11, No. 19
4378-4381
A New Cross-Coupling-Based Synthesis
of Carpanone
Fre´de´ric Liron,† Francesco Fontana,†,‡ Jean-Olivier Zirimwabagabo,†
Guillaume Prestat,† Jamshid Rajabi,† Concetta La Rosa,‡ and Giovanni Poli*,†
Institut Parisien de Chimie Mole´culaire UMR CNRS 7201, FR2769 Institut de Chimie
Mole´culaire, UPMC UniV Paris 06, Place Jussieu, 75005, Boite 183, Paris, France,
and UniVersita` degli Studi di Milano, DISMAB Sezione Chimica Organica
“A.Marchesini”, Facolta` di Farmacia, V. Venezian 21, I-20133 Milano, Italy
gioVanni.poli@upmc.fr
Received July 28, 2009
ABSTRACT
Carpanone has been stereoselectively synthesized in 55% yield and six steps from sesamol. The key step of the synthetic sequence is the
direct introduction of the propenyl side chain via a Suzuki-Miyaura cross-coupling reaction. The subsequent Pd(II)-catalyzed oxidative coupling
yields carpanone as a single diastereoisomer independently of the geometric configuration of the starting precursor. A new mechanism is
proposed for this transformation.
Carpanone 1a is a hexacyclic lignan isolated as a racemic
mixture from the bark of the carpano tree found on
Scheme 1. Previous Strategy To Obtain Carpanone 1a
Bougainville Island and containing five contiguous stereo-
genic centers.1 Although carpanone itself displays no inter-
esting biological activity, closely related congeners have
shown promising activity such as antihypertensive,2 anti-
malarial,3 antibacterial,3 and hepatoprotective4 properties.
Thus, the challenging structure of carpanone and the potential
biological applications of its analogues make this structure
a highly interesting target. Although the synthesis of car-
panone has been achieved by quite a few research groups,
all reported approaches rely on the elegant biomimetic
approach pioneered by Chapman5 et al. almost 40 years ago.
† UPMC.
This approach involves a Claisen rearrangement-isomerization
sequence followed by a stereoselective oxidative coupling
(Scheme 1).6,7 Although efficient, the Claisen-based route
to the cyclization precursor is not straightforward. We thus
speculated that an aryl-vinyl cross-coupling reaction could
represent a valid and modern alternative to introduce the
requisite propenyl moiety directly, possibly in a stereose-
lective fashion. Structural and geometrical variations on the
‡ Universita` degli Studi di Milano.
(1) Brophy, G. C.; Mohandas, J.; Slaytor, M.; Sternhell, S.; Watson,
T. R.; Wilson, L. A. Tetrahedron Lett. 1969, 10, 5159–5162.
(2) Wang, E. C.; Shih, M. H.; Liu, M. C.; Chen, M. T.; Lee, G. H.
Heterocycles 1996, 43, 969–975.
(3) (a) Muhammad, I.; Li, X.-C.; Jacob, M. R.; Tekwani, B. L.; Dunbar,
D. C.; Ferreira, D. J. Nat. Prod. 2003, 66, 804–809. (b) Muhammad, I.; Li,
X.-C.; Dunbar, D. C.; El Sohly, M. A.; Khan, I. A. J. Nat. Prod. 2001, 64,
1322–1325.
(4) Sung, S. H.; Kim, Y. C. J. Nat. Prod. 2000, 63, 1019–1021.
10.1021/ol9017326 CCC: $40.75
Published on Web 09/02/2009
 2009 American Chemical Society

alkene would also provide an interesting diversity-oriented
strategy. Furthermore, as the reported oxidative coupling
requires stoichiometric amounts of Pd salts,5 we planned also
to develop a greener variant, catalytic in palladium.8
The first step of our retrosynthetic strategy retraces
Chapman’s seminal paper, wherein carpanone is derived from
carpanization9 of propenyl sesamol 3 but as a catalytic
variant. Methodological differentiation of our route comes
next, deriving 3 from a regioselective cross-coupling based
propenylation of sesamol 2 (Scheme 2).
Scheme 4. Preparation of Boronate 5
Scheme 2. Envisaged Retrosynthesis of Carpanone
was initially borylated14 to give the corresponding boronate
5 in excellent yield.
The Suzuki-Miyaura cross-coupling step using (E)-1-
bromopropene was next studied (Table 1). The influence of
Introduction of the propenyl moiety via transition-metal-
catalyzed ortho-directed C-H activation was tested first.
However, use of Pd- and Rh-catalyzed conditions known to
promote ortho functionalization of phenols met with failure
under a wide range of reported experimental conditions
(Scheme 3).10,11
Table 1. Optimization of the Suzuki-Miyaura Cross-Coupling
base
entry (3 equiv)
catalyst
(10 mol %)
yielda
(%)
Scheme 3. Attempted Ortho C-H Activation of Sesamol
solvent T (°C)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
KOH
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(dppf)
PdCl2(dppp)
Pd(dba)2/Xantphosb
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
Tol
Tol
Tol
Tol
Tol
Tol
Tol
Tol
Tol
Tol
Tol
DME
Et2O
THF
DMF
20
80
80
80
80
80
110
20
20
20
20
20
20
20
20
27
10
25
0
0
0
24
60
20
0
MeONa
tBuOK
NaOAc
K2CO3
Et3N
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
Ortho halogenation of sesamol was next con-
sidered.12Accordingly, standard O-silylation of sesamol and
treatment of the resulting ether with NIS gave smoothly
iodide 4 in excellent yield and total regioselectivity (Scheme
4).13 Stille and Negishi cross-coupling reactions with the
corresponding metalated propenyl derivative led to unsatis-
factory results under a range of conditions. We thus focused
on the Suzuki-Miyaura cross-coupling. To this purpose, 4
0
23
13
4
27
a Isolated yields. b 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene.
(5) (a) Chapman, O. L.; Engel, M. R.; Springer, J. P.; Clardy, J. C.
J. Am. Chem. Soc. 1971, 93, 6697–6698. See also: (b) Majetich, L. G.;
Wheless, K. In MicrowaVe Heating in Organic Chemistry: An Update;
Kingston, H. M., Haswell, S. J., Eds.; ACS: Washington, D.C., 1997;
Chapter 8, pp 455-501.
the base was first examined using PdCl2(PPh3)2 as the
palladium source and toluene as the solvent. Only alkoxide
bases and KOH allowed formation of some coupled product
(entries 1-3), albeit in a low yield, whereas NaOAc, K2CO3
(6) (a) Lindsley, C. W.; Chan, L. K.; Goess, B. C.; Joseph, R.; Shair,
M. D. J. Am. Chem. Soc. 2000, 122, 422–423. (b) Baxendale, I. R.; Lee,
A.-L.; Ley, S. V. J. Chem. Soc., Perkin Trans. 1 2002, 1850–1857. (c)
Goess, B. C.; Hannoush, R. N.; Chan, L. K.; Kirchhausen, T.; Shair, M. D.
J. Am. Chem. Soc. 2006, 128, 5391–5403. (d) Daniels, R. N.; Fadeyi, O. O.;
Lindsley, C. W. Org. Lett. 2008, 10, 4097–4100.
(10) (a) Bedford, R. B.; Coles, S. J.; Hursthouse, M. B.; Limmert, M. E.
Angew. Chem., Int. Ed. 2003, 42, 112–114. (b) Bedford, R. B.; Hazelwood,
S. L.; Horton, P. N.; Hursthouse, M. B. Dalton Trans. 2003, 4164–4174.
(c) Bedford, R. B.; Limmert, M. E. J. Org. Chem. 2003, 68, 8669–8682.
(d) Oi, S.; Watanabe, S.-I.; Fukita, S.; Inoue, Y. Tetrahedron Lett. 2003,
44, 8665–8668. (e) Satoh, T.; Inoh, J.; Kawamura, T.; Kawamura, Y.; Miura,
N.; Masakatsu, N. Bull. Chem. Soc. Jpn. 1998, 71, 2239–2246. (f) Satoh,
T.; Kawamura, Y.; Miura, N.; Nomura, M. Angew. Chem., Int. Ed. 1997,
36, 1740–1742. (g) Dunina, V.; Gorunova, N.; Stepanova, A.; Zykov, A.;
Livantsov, V.; Grishin, K.; Churakov, V.; Jyudmila, G. Tetrahedron:
Asymmetry 2007, 18, 2011–2015.
(7) During the redaction of this paper, introduction of the propenyl
moiety via a Wittig condensation was disclosed: Fadeyi, O. O.; Daniels,
R. N.; DeGuire, S. M.; Lindsley, C. W Tetrahedron Lett. 2009, 50, 3084–
3087.
(8) During the course of this work, a paper appeared dealing with a
Cu-catalyzed oxidative coupling. See ref 6d.
(9) For convenience, we propose to define “carpanization” as the
conversion of 2-propenylsesamol into carpanone. This oxidative coupling
is the result of more than one elementary step, and its mechanism appears
to be reagent dependent (see the text).
Org. Lett., Vol. 11, No. 19, 2009
4379

and Et3N gave no reaction (entries 4-6). Raising the
temperature from 80 to 110 °C led to no change (entry 7),
whereas running the reaction at rt improved the yield up to
60% yield (entry 8). Bidentate ligands proved less efficient
(entries 9-11). Finally, various solvents of increasing
polarity were shown to be less efficient than toluene (entries
12-15).
The final steps of the synthesis involve deprotection of
the TBS ether and subsequent carpanization.15 Use of a
stoichiometric amount of PdCl2, according to Chapman’s
protocol,5 led to carpanone 1a in 56% yield (Table 2, entry
In all cases studied, the relative configuration of the five
stereogenic centers appeared to be fully controlled, as
carpanone was always isolated as a single diastereoisomer
out of the 16 possible. We then wondered if a change of the
stereochemistry of the alkene precursor would have modified
the outcome of the reaction. If so, this would represent an
efficient way to introduce stereochemical diversity into the
carpanone core. Accordingly, we decided to apply the above
studied cross-coupling protocol to obtain the (Z)-alkene 6b
and test it for carpanization. In the event, the Suzuki-Miyaura
cross-coupling reaction between boronic ester 5 and (Z)-1-
bromopropene using aqueous KOH as the base gave the
desired (Z)-olefin in excellent yield (Scheme 5).17
Table 2. Carpanization of (E)-Propenyl Sesamola
Scheme 5. Preparation of Alkene 6b
oxidant
(equiv)
yieldb
(%)
entry
co-oxidant
solvent
1
2
3
4
5
6
7
8
9
PdCl2 (1.0)
PdCl2 (0.1)
PdCl2(0.1)
CuCl2 (0.1)
FeBr3 (0.1)
PhI(OAc)2 (0.55)
CAN (0.55
DDQ (0.55)
O2
MeOH/H2O
MeOH/H2O
MeOH/H2O
MeOH/H2O
MeOH/H2O
CH2Cl2
MeCN
THF
MeOH/H2O
56
48
82
73
0
CuCl2
O2
O2
Alkene 6b was then submitted to O-silyl deprotection
followed by carpanization (Table 3). Quite unexpectedly,
O2
36
41
0
Table 3. Carpanization of (Z)-Propenyl Sesamola
55c
a Reaction conditions: (a) substrate (0.1 mmol), THF (0.5 mL), TBAF
(0.3 mmol), rt, 30 min; (b) NaOAc (0.12 mmol), oxidant, MeOH (0.3 mL),
H2O (0.3 mL), O2, 50 °C, 4 h b Isolated yields. c Spectroscopic yield from
1H NMR of the crude mixture with 1,4-dioxane as the internal standard.
1). Interestingly, when a catalytic amount of PdCl2 was used
together with CuCl2 as the co-oxidant, a comparable yield
of carpanone was obtained (48%, entry 2). Use of O2 as a
co-oxidant led to an excellent 82% yield (entry 3). Catalytic
CuCl2 under an O2 atmosphere led to a similar yield (73%,
entry 4). Other oxidizing systems such as FeBr3/O2,
PhI(OAc)2,6a,c,16 or DDQ, led to less satisfactory results
(entries 5-8). Much to our surprise, autoxidation of 6a to
carpanone occurred also rather efficiently in O2 atmosphere
in the absence of any transition-metal catalyst (entry 9).
entry
oxidant (equiv)
co-ox
1a/1b
yieldb (%)
1
2
3
PdCl2 (0.1)
CuCl2 (0.1)
PhI(OAc)2 (0.55)
O2
O2
100:0
63:37
77
40
traces
a Reaction conditions: 6b (0.34 mmol), NaOAc (1.26 equiv), oxid.,
MeOH (0.5 mL), H2O (0.5 mL), O2, 50 °C, 4 h. b Isolated yields.
treatment of the in situ obtained Z3 with catalytic PdCl2 in
the presence of O2 gave again natural carpanone 1a (entry
1). Cu catalysis gave instead an inseparable 63:37 mixture
of natural carpanone 1a and the diastereomeric structure 1b,
as assigned on the basis of NOESY experiments (entry 2).
Lastly, PhI(OAc)2 gave only traces of carpanone (entry 3).
The above results add some relevant pieces of information
on the mechanism of carpanization, whose state of knowl-
edge is still far from satisfactory (Scheme 6). As to this issue,
Chapman5 postulated for the Pd(II)-promoted transformation
involvement of the bis-phenoxy Pd(II) intermediate I which
would undergo stereoselective phenol ꢀ,ꢀ-coupling to give
(11) See Supporting Information
.
(12) The cross-coupling of unprotected electron-rich phenols is not an
efficient process. See for example (a) Jinno, S.; Okita, T.; Inouye, K. Bioorg.
Med. Chem. Lett. 1999, 9, 1029–1032. (b) Jinno, S.; Otsuka, N.; Okita, T.;
Inouye, K. Chem. Pharm. Bull. 1999, 47, 1276–1283, See Supporting
Informationfor more details on the attempted cross-coupling reactions on
the free or protected halogenated sesamol
(13) Carmen, M.; Jose, C. L.; Ruano, G.; Sanz, G.; Toledo, M. A.;
Urbano, A. J. Org. Chem. 1995, 60, 5328–5331
.
.
(14) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60,
7508–7510
.
(15) As the free phenol resulting from the deprotection of 6a was very
sensitive, we carried out the two steps in a single pot
.
(16) Although refs 6c and 7 report that PhI(OAc)2 is incapable of
bringing about carpanization, in our hands this reagent did produce 1a,
although in modest yield.
(17) Under our previously optimized conditions (Table 1, entry 8), no
reaction occurred.
4380
Org. Lett., Vol. 11, No. 19, 2009

PhI(OAc)2, as opposed to PdCl2, to cyclize Z3 is compatible
with the different mechanisms postulated for the two
reagents. Validation of the mechanism associated with
PhI(OAc)2 came from submission of an isomer of 2-prope-
nylsesamol to this reagent, so as to obtain an intermediate
incapable of undergoing a Diels-Alder cycloaddition reac-
tion. Indeed, treatment of 6-allylsesamol 723,24 with
PhI(OAc)2 afforded 8 as the only observable product
(Scheme 7), thereby supporting the mechanism associated
Scheme 6. Proposed Carpanization Mechanisms
Scheme 7
.
Test To Prove the Mechanism Associated with
Path B
with path B. Although further studies will be needed to obtain
a more satisfactory picture of the subtle details of the
carpanization steps, it is clear that this intriguing transforma-
tion follows specific reagent-dependent mechanisms.
In conclusion, we have developed a new synthesis of
carpanone. This new approach features the direct and
stereoselective incorporation of the propenyl moiety onto
sesamol, affording carpanone in six steps and 55% overall
yield and lends itself to a diversity-oriented synthesis of
analogues. Furthermore, the Pd(II)-promoted carpanization
originally developed by Chapman could be rendered catalytic
in Pd(II), establishing that the (E)- as well as the (Z)-propenyl
precursors give rise to the same natural product. On the other
hand, PhI(OAc)2 was able to carpanize only the E-configured
precursor. Last, but not least, the mechanism of action of
PhI(OAc)2 originally proposed by Shair could be confirmed,
whereas a new mechanistic path is proposed for the Pd(II)-
catalyzed carpanization.
the C2-symmetric bis-enone II (path A). Final endo-selective
hetero-Diels-Alder cycloaddition (HDA) affords carpanone.
On the other hand, on the basis of the results obtained on
analogues less electron rich than propenylsesamol, Shair
postulated for PhI(OAc)2 a dimerizative addition of the
phenolic hydroxyl function para to an oxidant-activated
substrate molecule to give adduct III, followed by an endo-
selective Diels-Alder (DA) cycloaddition (path B)6a Coming
back to our results, the stereoconvergence observed in the
present study under Pd(II) catalysis suggests a Z-to-E Pd-
catalyzed isomerization prior to carpanization via a common
intermediate (Scheme 6).18,19
Furthermore, the recent results by Sigman and co-
workers20 on the aerobic hydroalkoxylation of phenol-
containing styrenes suggest to us a new appealing mecha-
nistic hypothesis for the Pd(II)-catalyzed carpanization of
2-propenylsesamol, wherein the first C-C bond formation
is triggered by a carbopalladative ꢀ,ꢀ-coupling to give
intermediate IV21(Scheme 6, path C).
Acknowledgment. Financial support of this research by
UPMC and CNRS is gratefully acknowledged. The sponsor-
ship of COST Action D40 “Innovative Catalysis: New
Processes and Selectivities” is kindly acknowledged.
Loss of HX and Pd(0) would then merge IV into the
previously evoked Pd(II)-mediated stream.22 The failure of
(18) For Pd(II). catalyzed isomerization of similar systems. (a) Giles,
R. G. F.; Son, V. R. L.; Sargent, M. V. Aust. J. Chem. 1990, 43, 777–781.
(b) Ju, J.; Gaunt, M. J.; Spencer, J. B. J. Org. Chem. 2002, 67, 4627–4269.
(c) Thiery, E.; Chevrin, C.; Le Bras, J.; Harakat, D.; Muzart, J. J. Org.
Chem. 2007, 72, 1859–1862. (d) Fan, J.; Wan, C.; Wang, Q.; Gao, L.; Zheng,
Supporting Information Available: Experimental pro-
cedures, copies of 1H and 13C NMR spectra, and full
spectroscopic data for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
X.; Wang, Z. Org. Biomol. Chem. 2009, 7, 3168–3172
.
(19) Performing the experiments of entries 1, 2 or 3 of table 3 in the
presence of TEMPO as the radical trap did not allow isolation of a TEMPO
adduct. For a carpanization under free-radical conditions, see: Matsumoto,
OL9017326
M.; Kuroda, K. Tetrahedron Lett. 1981, 22, 4437–4440
.
(22) Carpanization experiments from E3 conducted in the presence of
several chiral ligands gave almost racemic material.11
(23) Prepared in two steps from sesamol according to described
(20) Gligorich, K. M.; Schultz, M. J.; Sigman, M. S. J. Am. Chem. Soc.
2006, 128, 2794–2795.
(21) For a vinylogous nucleophilic behavior of 2-propenyl-phenol see:
Cornia, M.; Merlini, L.; Zanarotti, A. Gazz. Chim. Ital. 1977, 107, 299–
304.
procedures. See refs 5 and 6d
(24) Attempts to convert 7 into 3, or directly into carpanone, via a Pd(II)
catalyzed process were unsuccessful
.
.
Org. Lett., Vol. 11, No. 19, 2009
4381