Expeditious divergent synthetic approach to polycyclic terpene-like molecules

Article abstract of DOI:10.1002/chem.201003261

The domino effect: The combination of two multiple bond-forming transformations; a consecutive Wolff rearrangement/acylketene-trapping cross metathesis reaction and a domino Michael-aldol reaction, in a one-pot operation, provides a straightforward access to terpene-like tricyclo[7.2.1.0 ^1,6]dodecane compounds (see scheme). A prolonged domino reaction leads to terpene-like bicyclo[5.4.0]undecane compounds.

Full text of DOI:10.1002/chem.201003261

DOI: 10.1002/chem.201003261
Expeditious Divergent Synthetic Approach to Polycyclic Terpene-Like
Molecules
[
a]
Thomas Boddaert, Yoann Coquerel,* and Jean Rodriguez*
Small-molecule natural products (SMNPs) are privileged
molecular architectures for the discovery of new therapeutic
agents. The importance of natural product based drugs in
the human pharmacopoeia is considerable, with only a very
[1]
small proportion of true unmodified natural products. The
integration of natural-product-inspired compounds into me-
dicinal chemistry and chemical biology research programs
can only be realized successfully if efficient synthetic meth-
ods are available to solve the problem of compound supply
and give a rapid access to focused small collections of these
[2]
compounds. Sequential multiple bond-forming transforma-
[3]
tions (MBFTs), which include consecutive and domino re-
actions, have already proven well suited for this purpose, al-
[
4]
lowing simplification of synthetic schemes.
highly desirable and methodologies versatile enough to
allow the efficient synthesis of both diastereomers (con-
1
,6
The tricyclo[7.2.1.0 ]dodecane ring system, often incorpo-
rating a heteroatom, is found in several classes of terpe-
noids, which generally possess important biological activities
[6]
trolled relative configuration at C6) of the substituted and
functionalized target ring system in only a few chemical op-
erations would be of value. Herein, we report a protection-
free stereodivergent approach for the expeditious synthesis
[5]
(
see compounds 1–5). Previous analyses of the various bio-
logical activities observed in these classes of terpenoids have
allowed the identification of several key structural factors
required for good activity and that are specific to each class
1
,6
of 3-oxa- and 3-aza-tricyclo[7.2.1.0 ]dodecane compounds
based on the synergic combination of MBFTs recently de-
veloped in our laboratory. This methodology has been ex-
[5]
of products. However, overall the most essential structural
factor common to compounds 1–5 and their congeners
tended to the synthesis of the 9-oxa-bicyclo AHCTUNGTERNNUN[G 5.4.0]undecane
ring system, another scaffold found in naturally occurring
terpenes.
1
,6
might be the rigid tricyclic [7.2.1.0 ] dodecane framework,
which allows the positioning of different functional and
binding groups of the molecules in well-defined topologies,
suitable for good interactions with proteins.
We decided to target molecules of type 6 because of their
structural similarity to natural products 1–5. Indeed, com-
pounds of type 6 exhibit the same tricyclic ring system with
incorporation of a heteroatom in the 3-position as found in
compounds 4 and 5, but also in compounds 1 and 2, al-
though at a different position of the ring system. Com-
pounds of type 6 also incorporate R (R=alkyl) substitu-
ent(s) at C10 as found in all compounds 1–5 and their con-
geners, and, importantly, compounds 6 also exhibit three
oxidized positions, with carbon atoms C2, C8 and C12
bonded to an oxygen atom as in natural products 2 and 3,
and in part in 4 and 5. Our retrosynthetic analysis for com-
pounds of type 6 (Scheme 1) has led to a strategy involving
just two reactions; an intramolecular domino Michael–aldol
reaction from the 1,3-dicarbonyl compound 7, which should
In this respect, synthetic methods for the stereoselective
1
,6
preparation of the tricyclo[7.2.1.0 ]dodecane scaffold are
[
a] Dr. T. Boddaert, Dr. Y. Coquerel, Prof. Dr. J. Rodriguez
Institut des Sciences Molꢀculaires de Marseille
iSm2–UMR CNRS 6263, Aix-Marseille Universitꢀ
Centre Saint Jꢀrꢁme, Service 531
1
3397 Marseille cedex 20 (France)
Fax : (+33)491-289-187
E-mail: yoann.coquerel@univ-cezanne.fr
jean.rodriguez@univ-cezanne.fr
Supporting information for this article (including full experimental
details and compound characterization) is available on the WWW
under http://dx.doi.org/10.1002/chem.201003261.
2048
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Chem. Eur. J. 2011, 17, 2048 – 2051

COMMUNICATION
ied for the preparation of bicyclo
ACHTUNGTRENNUNG
[11]
tems,
2
3
gave the desired tricyclic product 6a efficiently as a mixture
of two diastereomers (>90% yield, from crude NMR data).
However, compound 6a partially decomposed during silica
gel chromatography and only 55% (diastereomeric ratio
Scheme 1. Retrosynthetic analysis.
(
d.r.)=1:1) of product could be isolated. Thus, the diaste-
reomeric mixture of crude hydroxy ketone 6a was directly
[12]
oxidized with 2-iodoxybenzoic acid (IBX) in ethyl acetate
be obtained by a consecutive reaction involving a Wolff re-
arrangement/acylketene-trapping cross metathesis (CM) se-
quence from the simple diazo compounds 8.
to afford the diastereomerically pure diketone 6b (in 69%
overall, from 7a), which confirmed the excellent diastereo-
selectivity of the Michael addition. Upon storage, the bridg-
ing ketone in 6b was hydrated, and the resulting crystallized
We first examined the preparation of compounds of type
6
in the 3-oxa series (X=O). According to the planned syn-
thetic scheme, we attempted the preparation of compound
a from 2-diazo-1,3-cyclohexanedione (8a) by an innovative
material 6b·H O was analyzed by X-ray diffraction tech-
2
[13]
niques to give the structures of 6a and 6b (Scheme 2).
A similar strategy was used in the 3-aza series for the ex-
peditious synthesis of compound 6c (Scheme 3). The Wolff
7
[7]
consecutive reaction. Thus, a microwave-assisted Wolff re-
arrangement of 8a in the presence of homoallyl alcohol
(
1 equiv) generated the corresponding ring-contracted b-ke-
[8]
toester, which was then directly treated with acrolein and
the Grubbs–Hoveyda precatalyst 9 under microwave irradia-
[
9]
tion to efficiently produce 7a in a single consecutive reac-
tion (Scheme 2). In early trials, the reaction was complicated
1
,6
Scheme 3. Synthesis of
Bn=benzyl; DBU=1,8-diazabicycloAHCUTNGTRENNUNG
a
3-aza-tricyclo[7.2.1.0 ]dodecane compound.
[5.4.0]undec-7-ene
rearrangement/acylketene-trapping CM consecutive reaction
was performed as before, but with a slight excess of diazo
compound 8b to consume the residual secondary amine,
[14]
which would deactivate the CM catalyst.
The resulting
product mixture of 7b was simply concentrated, diluted in
methanol, and treated with DBU to promote the intramo-
lecular domino Michael–aldol reaction, allowing the isola-
tion of 6c as a single diastereomer in 59% yield from 8b, as
[13]
confirmed by X-ray diffraction. A remarkable feature of
this synthetic sequence is that compound 6c, which exhibits
1
,6
a 3-aza-tricyclo[7.2.1.0 ]dodecane framework with four con-
trolled stereogenic centers, is obtained by a one-pot combi-
nation of two MBFTs: a consecutive reaction followed by a
1
,6
Scheme 2. Synthesis of 3-oxa-tricyclo[7.2.1.0 ]dodecane compounds.
Mes= mesityl; IBX=2-iodoxybenzoic acid.
[3]
domino reaction in a practical one-pot operation.
Our early attempts to isolate 7b by flash chromatography
on silica gel were complicated by partial spirocyclization re-
actions. However, this reactivity was advantageous for the
stereodivergent synthesis of 6d (Scheme 4); the treatment
of crude 7b with silica gel in a one-pot operation afforded
the spiro compound 11 as a 7:1 mixture of diastereomers.
The relative configuration of the major diastereomer of 11,
as depicted in Scheme 4, was determined by comparing the
characterization data to that of a previously reported deriva-
tive (see the Supporting Information for details). The crude
diastereomeric mixture of 11 was treated with DBU in
by the domino formation of the undesired intermolecular
Michael addition product 10, and no spiro product resulting
from the intramolecular Michael addition of 7a could be de-
tected. In this reaction, formation of compound 10 is possi-
bly catalyzed by the Lewis acid properties of the ruthenium
species generated during the metathesis catalytic cycle or
[15]
[10]
their degradation products.
With 7a optimized, we turned our attention to the key in-
tramolecular domino Michael–aldol step. Related intermo-
lecular domino Michael–aldol reactions have been well stud-
Chem. Eur. J. 2011, 17, 2048 – 2051
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2049

Y. Coquerel, J. Rodriguez and T. Boddaert
formation of 15 is believed to result from a six-step process:
first, the domino Michael–aldol sequence from 7a afforded
6
a in a comparable manner as described in Scheme 2. Then,
and in contrast to the intermolecular version of the reac-
[19c]
tion,
both diastereomers of 6a underwent the expected
domino retro-Dieckmann fragmentation with methanol,
most probably with different kinetics, to afford two diaste-
reomeric series of bicyclic cycloheptanols 16a and 16b.
Under the basic reaction conditions, 16a and 16b are in dy-
namic equilibrium with their diastereomers 17a and 17b,
[20]
both of which undergo a trans-lactonization, followed by
an irreversible elimination reaction to afford the monocyclic
carboxylates 18a and 18b. Upon treatment with hydrochlo-
ric acid, the water-soluble d-hydroxy carboxylates 18a and
18b undergo lactonization to produce the bicyclic d-lactones
15a and 15b, respectively. Remarkably, compounds 15a and
15b (d.r.=7:1) were obtained from the diazo compound 8a
in 45% yield overall, following two successive MBFTs,
which involved four very simple components: diazo 8a, ho-
moallylic alcohol, acrolein, and methanol (Scheme 5).
1
,6
Scheme 4. Stereodivergent synthesis of 3-aza-tricyclo[7.2.1.0 ]dodecane
compounds. Bn=benzyl; DBU=1,8-diazabicyclo[5.4.0]undec-7-ene
AHCTUNGTRENNUNG
methanol to produce the diastereomer aldol products 6c–
e. An analytical sample of the major diastereomer 6e, crys-
tallized from the 1:7 mixture of 6d/6e, was then analyzed by
6
[13]
X-ray diffraction to obtain the structure. The d.r. of the
products tends to indicate that retro-Michael processes did
[16]
not occur under the conditions of the reaction, which im-
portantly allowed the synthesis of products 6d and 6e with
an inverted relative configuration at C6 when compared to
6
c, thus paving the way to a concise and stereodivergent ap-
proach to compounds of type 6 in the aza series.
Finally, we explored the possibility of in situ retro-Die-
1
,6
ckmann fragmentation of the tricyclo[7.2.1.0 ]dodecane 6a
to afford the 9-oxa-bicyclo[5.4.0]undecane ring system; a
AHCTUNGTRENNUNG
framework found for example in the insect antifeedant 2,3-
secoaromadendrane sesquiterpenes plagiochilide (12) and
[
17]
plagiochiline (13),
or the rearranged xenicane diterpene
[
18]
florxenilide C 14. For this purpose, we used our previously
developed conditions for the domino Michael–aldol–retro-
[19]
Dieckmann sequence (MARDi cascade). Thus, the treat-
ment of compound 7a with DBU in methanol, followed by
aqueous acidic workup, afforded directly the cycloheptenes
15a and 15b as a 7:1 mixture of diastereomers (62% yield),
Scheme 5. Synthesis of 9-oxa-bicyclo AHCUTNGTERNNNU[G 5.4.0]undecane compounds.
with the major isomer exhibiting a cis-fused d-lactone. The
In summary, expeditious stereoselective syntheses of ter-
pene-like molecules have been accomplished by combina-
tions of MBFTs, sometimes in a one-pot procedure, from
very simple, abundant, and cheap starting materials. A rapid
increase of natural-product-like complexity was achieved
with good to excellent diastereoselectivities. The tricyclic
compounds 6 were obtained from the diazo compounds 8 in
one or two chemical operations involving the formation of
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Chem. Eur. J. 2011, 17, 2048 – 2051

Divergent Synthesis of Polycyclic Terpene-Like Molecules
COMMUNICATION
five chemical bonds (and two bonds breaking events) to-
gether with four new stereocenters, whereas the synthesis of
lated compounds, see : a) M. Presset, Y. Coquerel, J. Rodriguez,
Eur. J. Org. Chem. 2010, 2247–2260; for 2 and related compounds,
see : b) J.-M. Gao, W.-J. Wu, J.-W. Zhang, Y. Konishi, Nat. Prod.
Rep. 2007, 24, 1153–1189; for 3–5 and related compounds, see:
c) H.-D. Sun, S.-X. Huang, Q.-B. Han, Nat. Prod. Rep. 2006, 23,
673–698.
15 involved two reactions and more than ten bond-forming/
breaking events. The avoidance of protecting-group chemis-
try and the strictly minimized number of purification pro-
cesses undoubtedly contributed to the overall efficiency of
the approach. The implementation of the methodologies
presented herein, with the addition of more substituted and
functionalized reaction partners, is expected to translate into
a focused library of SMNP-like compounds, hopefully en-
dowed with biological activities, and suitable for integration
into medicinal chemistry and chemical biology research pro-
grams.
[
6] The numbering of atoms proposed in the structure of tricy-
1
,6
clo[7.2.1.0 ]dodecane will be used throughout the manuscript.
7] For previous preparation of analogues of 7 in two steps, see: T. Bod-
daert, Y. Coquerel, J. Rodriguez, Adv. Synth. Catal. 2009, 351, 1744–
1748; erratum: T. Boddaert, Y. Coquerel, J. Rodriguez, Adv. Synth.
Catal. 2009, 351, 2541.
[
[
8] The reaction in CH
in toluene: M. Presset, Y. Coquerel, J. Rodriguez, J. Org. Chem.
009, 74, 415–418.
9] For reviews, see: a) Y. Coquerel, J. Rodriguez, Eur. J. Org. Chem.
008, 1125–1132; b) F. Nicks, Y. Borguet, S. Delfosse, D. Bicchielli,
L. Delaude, X. Sauvage, A. Demonceau, Aust. J. Chem. 2009, 62,
84–207; for related CM reactions, see: c) A. Michaut, T. Boddaert,
2 2
Cl was equally efficient, although slower than
2
[
2
1
Experimental Section
Y. Coquerel, J. Rodriguez, Synthesis 2007, 2867–2871; d) T. Bod-
daert, Y. Coquerel, J. Rodriguez, C. R. Chim. 2009, 12, 872–875; for
discussion, see: e) D. Dallinger, M. Irfan, A. Suljanovic, C. O.
Kappe, J. Org. Chem. 2010, 75, 5278–5288.
See the Supporting Information for general experimental information,
full experimental procedures, characterization data of all compounds, and
NMR spectroscopy of all new compounds.
[
10] a) S. Fustero, D. Jimꢀnez, M. Sꢄnchez-Rosellꢅ, C. del Pozo, J. Am.
Chem. Soc. 2007, 129, 6700–6701; b) J.-R. Chen, C.-F. Li, X.-L. An,
J.-J. Zhang, X.-Y. Zhu, W.-J. Xiao, Angew. Chem. 2008, 120, 2523–
2
526; Angew. Chem. Int. Ed. 2008, 47, 2489–2492; c) H. Fuwa, K.
Acknowledgements
Noto, M. Sasaki, Org. Lett. 2010, 12, 1636–1639.
11] a) M.-H. Filippini, R. Faure, J. Rodriguez, J. Org. Chem. 1995, 60,
6872–6882; b) M.-H. Filippini, J. Rodriguez, Chem. Rev. 1999, 99,
27–76.
[
Financial support from the French Research Ministry, the Universitꢀ
Paul Cꢀzanne, and the CNRS is gratefully acknowledged.
[
[
12] J. D. More, N. S. Finney, Org. Lett. 2002, 4, 3001–3003.
13] CCDC-794646 (6b·H O), 794647 (6c) and 794648 (6e) contain the
2
Keywords: consecutive reactions · domino reactions · one-
pot reactions · natural products · terpenoids
supplementary crystallographic data for thie paper. These data can
be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[
14] a) E. Vedrenne, H. Dupont, S. Oualef, L. Elkaꢆm, L. Grimaud, Syn-
lett 2005, 670–672. For a review on olefin metathesis reactions in
the presence of a basic amine, see: b) P. Compain, Adv. Synth. Catal.
2007, 349, 1829–1846.
[
[
1] a) G. M. Cragg, P. G. Grothaus, D. J. Newman, Chem. Rev. 2009,
1
7
09, 3012–3043; b) D. J. Newman, G. M. Cragg, J. Nat. Prod. 2007,
0, 461–477.
[15] A. K. Banerjee, M. S. Laya Mimꢅ, W. J. Vera Vegas, Rus. Chem.
Rev. 2001, 70, 971–990.
[16] The aldolization may however be reversible under the reaction con-
ditions.
[17] a) Y. Asakawa, M. Toyota, T. Takemoto, Tetrahedron Lett. 1978, 19,
1553–1556; b) Y. Asakawa, M. Toyota, T. Takemoto, I. Kubo, K.
Nakanishi, Phytochemistry 1980, 19, 2147–2154.
2] a) R. M. Wilson, S. J. Danishefsky, J. Org. Chem. 2006, 71, 8329–
351; b) C. Cordier, D. Morton, S. Murrison, A. Nelson, C. OꢃLeary-
8
Steele, Nat. Prod. Rep. 2008, 25, 719–737; c) P. A. Wender, V. A.
Verma, T. J. Paxton, T. H. Pillow, Acc. Chem. Res. 2008, 41, 40–49;
d) K. Kumar, H. Waldmann, Angew. Chem. 2009, 121, 3272–3290;
Angew. Chem. Int. Ed. 2009, 48, 3224–3242.
[
3] For efforts to clarify the terminologies of MBFTs, see: a) L. F.
Tietze, U. Beifuss, Angew. Chem. 1993, 105, 137–170; Angew. Chem.
Int. Ed. Engl. 1993, 32, 131–163; b) L. F. Tietze, Chem. Rev. 1996,
[18] Y.-B. Cheng, J.-Y. Jang, A. T. Khalil, Y.-H. Kuo, Y.-C. Shen, J. Nat.
Prod. 2006, 69, 675–678.
[19] a) Y. Coquerel, D. Bensa, V. Moret, J. Rodriguez, Synlett 2006,
2751–2754 (erratum: Y. Coquerel, D. Bensa, V. Moret, J. Rodriguez,
Synlett 2006, 3368); b) Y. Coquerel, D. Bensa, A. Doutheau, J. Ro-
driguez, Org. Lett. 2006, 8, 4819–4822; c) Y. Coquerel, M.-H. Fili-
ppini, D. Bensa, J. Rodriguez, Chem. Eur. J. 2008, 14, 3078–3092;
d) I. Reboul, T. Boddaert, Y. Coquerel, J. Rodriguez, Eur. J. Org.
Chem. 2008, 5379–5382.
9
6, 115–136; c) Domino Reactions in Organic Synthesis (Eds.: L. F.
Tietze, G. Brasche, K. M. Gericke), Wiley-VCH, Weinheim, 2006;
d) Y. Coquerel, T. Boddaert, M. Presset, D. Mailhol, J. Rodriguez in
Ideas in Chemistry and Molecular Sciences: Advances in Synthetic
Chemistry (Ed.: B. Pignataro), Wiley-VCH, Weinheim, 2010, Chap-
ter 9, pp. 187–202.
[
[
4] Recent reviews: a) K. C. Nicolaou, J. S. Chen, Chem. Soc. Rev. 2009,
[20] The trans-lactonization possibly proceeded through initial opening
of the fused lactone with methanol, particularly in the case of 17b.
38, 2993–3009; b) B. B. Tourꢀ, D. G. Hall, Chem. Rev. 2009, 109,
4439–4486; c) C. Grondal, M. Jeanty, D. Enders, Nat. Chem. 2010,
2, 167–178.
5] The following review articles include analyses of previous synthetic
Received: November 12, 2010
Published online: January 24, 2011
1
,6
approaches to tricyclo[7.2.1.0 ]dodecane compounds: for 1 and re-
Chem. Eur. J. 2011, 17, 2048 – 2051
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2051