Expedient route to the functionalized calyciphylline a- Type skeleton via a michael addition- RCM strategy

Article abstract of DOI:10.1021/ol202000w

An efficient, robust, and scalable strategy to access the functionalized core of calyciphylline A-type alkaloids has been developed starting from commercially available 3-methylanisole. Key features of this approach are an intramolecular Michael addition/allylation sequence and a ringclosing metathesis step.

Full text of DOI:10.1021/ol202000w

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5132–5135
Expedient Route to the Functionalized
Calyciphylline A-Type Skeleton via a
Michael AdditionÀRCM Strategy
Filippo Sladojevich,† Iacovos N. Michaelides,† Benjamin Darses ,†,§ John W. Ward,‡,
and Darren J. Dixon*,†
Chemistry Research Laboratory, Department of Chemistry, University of Oxford,
Mansfield Road, Oxford, OX1 3TA, U.K., and School of Chemistry, The University of
Manchester, Oxford Road, Manchester, M13 9PL, U.K.
darren.dixon@chem.ox.ac.uk
Received July 25, 2011
ABSTRACT
An efficient, robust, and scalable strategy to access the functionalized core of calyciphylline A-type alkaloids has been developed starting from
commercially available 3-methylanisole. Key features of this approach are an intramolecular Michael addition/allylation sequence and a ring-
closing metathesis step.
Daphniphyllum alkaloids are a structurally diverse group
of natural products found in the genus Daphniphyllum
(Daphniphyllaceae).1 The structural complexity and bio-
logical significance of the members of this family has led to
significant interest from the synthetic community.2 Among
the vast family of Daphniphyllum alkaloids, we were parti-
cularly intrigued by the calyciphylline A-type alkaloids,
given their unique structural features and the fact that
there are no reports of total syntheses of any member of
this subgroup.
Following the discovery of calyciphylline A,3 19 calyci-
phylline A-type alkaloids have been isolated: daphniglau-
cins DÀH (leaves of D. glaucescens),4 longistylumphylline A
(leaves of D. longistylum),5 daphnilongeranins AÀC (stems
and leaves of D. longeracemosum),6 daphniyunnines AÀE
(stems and leaves of D. yunnanense),7 longeracinphyllins
† University of Oxford.
‡ The University of Manchester.
§ Current address: Institut de Chimie des Substances Naturelles, UPR 2301
CNRS, Centre de Recherches de Gif, Avenue de la Terrasse, 91198 Gif-
sur-Yvette Cedex, France.
(3) Morita, H.; Kobayashi, J. Org. Lett. 2003, 5, 2895–2898.
(4) Takatsu, H.; Morita, H.; Shen, Y.-C.; Kobayashi, J. Tetrahedron
2004, 60, 6279–6284.
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860.
(6) Yang, S.-P.; Zhang, H.; Zhang, C.-R.; Cheng, H.-D.; Yue, J.-M.
J. Nat. Prod. 2006, 69, 79–82.
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Current address: School of Chemistry, University of Edinburgh, The
King's Buildings,West Mains Road, Edinburgh EH9 3JJ, U.K.
(1) For a review on Daphniphyllum alkaloids, see: Kobayashi, J.;
Kubota, T. Nat. Prod. Rep. 2009, 26, 936–962.
(2) For some recent synthetic approaches to Daphniphyllum alka-
loids, see: (a) Ikeda, S.; Shibuya, M.; Kanoh, N.; Iwabuchi, Y. Org. Lett.
2009, 11, 1833–1836. (b) Dunn, T. B.; Ellis, J. M.; Kofink, C. C.;
Manning, J. R.; Overman, L. E. Org. Lett. 2009, 11, 5658–5661.
Prod. 2006, 69, 553–557.
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J. Nat. Prod. 2006, 69, 1074–1076.
(9) Mu, S.-Z.; Li, C.-S.; He, H.-P.; Di, Y.-T.; Wang, Y.; Wang, Y.-H.;
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10.1021/ol202000w
Published on Web 09/07/2011
2011 American Chemical Society

A and B (leaves of D. longeracemosum),8 and daphnipaxia-
nines AÀC (leaves and fruits of D. paxianum).9 Some
representative structures are illustrated in Figure 1.
I could be achieved via Pd-catalyzed enolate alkenylation
using the chemistry previously developed by Bonjoch2c
and ring E could be formed via alkyne carbocyclization
using methodologies previously developed within our10 or
other research groups.11 In our plans, ring D would be
installed through intramolecular ring closing metathesis
(RCM) from precursor III and the five-membered ring C
through intramolecular Michael addition of a precursor
bearing structural similarities to compound IV.
Our route toward the synthesis of the ACD core is
presented in Scheme 2. Amine 10 was prepared starting
from the known ketone 812 via enolate formation and
subsequent γ-iodination to give intermediate 9.13 Inter-
mediate 9 has limited stability14 and was therefore directly
used without any purification for the alkylation of benzy-
lamine, yielding 10 in a satisfactory 56% yield from ketone
8. For the success of the alkylation step, the use of DMSO
and a short reaction time was found to be crucial in order
to avoid the formation of aromatic side products. Amine
10 smoothly reacted with acid chloride 11 to provide amide
12 as a mixture of two inseparable diastereoisomers in
76À91% yield.
Figure 1. Representative calyciphylline A-type alkaloids.
All 19 compounds present a characteristic core structure
based on four 6À6À5À7-fused rings (ABCD rings in
Scheme 1). As part of a long-term synthetic program to
develop a general strategy for the synthesis of various
calyciphylline A-type alkaloids, we decided to center our
attention on the total synthesis of daphniyunnine B (5).7
Herein we present our efforts toward the synthesis of the
functionalized ADC core (structure II, Scheme 1) of this
structurally complex natural product.
Scheme 2. Synthesis of Tricyclic Compound 16
Our retrosynthetic analysis identified the tricyclic struc-
ture of type II (Scheme 1) as a potentially flexible pre-
cursor, bearing four of the six stereocenters present in the
target molecule, including the two contiguous quaternary
stereocenters.
Scheme 1. Retrosynthetic Analysis of Daphniyunnine B
(10) Yang, T.; Ferrali, A.; Sladojevich, F.; Campbell, L.; Dixon, D. J.
J. Am. Chem. Soc. 2009, 131, 9140–9141. For other examples of
cyclizations involving unactivated alkynes from our group, see: (a)
Yang, T.; Ferrali, A.; Sladojevich, F.; Dixon, D. J. J. Am. Chem. Soc.
2009, 131, 9140–9141. (b) Wang, H.-F.; Yang, T.; Xu, P.-F.; Dixon, D. J.
Chem. Commun. 2009, 3916–3918. (c) Li, M.; Yang, T.; Dixon, D. J.
Chem. Commun. 2010, 46, 2191–2193. (d) Barber, D. M.; Sanganee, H.;
Dixon, D. J. Chem. Commun. 2011, 47, 4379–4381.
(11) (a) For a comprehensive review on addition of metal enolates to
ꢀ ꢁ
ꢀ
unactivated carbonÀcarbon multiple bonds, see: Denes, F.; Perez-Luna,
A.; Chemla, F. Chem. Rev. 2010, 110, 2366–2447. For other examples of
carbocyclizations involving unactivated alkynes, see: (b) Binder, J. T.;
Crone, B.; Haug, T. T.; Menz, H.; Kirsch, S. F. Org. Lett. 2008, 10,
1025–1028 and references cited therein. (c) Davies, P. W.; Detty-
Mambo, C. Org. Biomol. Chem. 2010, 8, 2918–2922.
We envisaged that structure II could be converted to the
advanced precursor I using relatively straightforward
transformations. Construction of ring B from intermediate
Org. Lett., Vol. 13, No. 19, 2011
5133

When amide 12 was treated with KHMDS in THF, it
was cleanly converted to the expected Michael addition
product with complete stereocontrol, yielding the expected
cis-fused adduct. We found it convenient to combine the
Michael addition step, with a tandem enolate allylation
reaction through sequential addition of KHMDS followed
by tosylate 13 and catalytic 18-crown-6. This protocol
allowed the isolation of enol ether 14 in 78% yield, as a
single diastereomer, starting from precursor 12. The
relative stereochemistry of the Michael adduct was un-
equivocally established by single-crystal X-ray crystallo-
graphic analysis on compound 14.15 Heating enol ether 14
in refluxing mesitylene yielded the Claisen product 15 as a
diastereomeric mixture (6:1 dr by 1H NMR) in 63% yield.
Compound 15 was found to be perfectly poised for the
subsequent RCM step. Refluxing 15 in dry CH2Cl2 with
5 mol % of first-generation Grubbs catalyst furnished the
tricyclic core 16 in almost quantitative yield. The diaster-
eomeric excess was not affected by the RCM step, and 16
was isolated as a 6:1 mixture of two separable diastereoi-
somers. Once a robust protocol was established for the
preparation of tricyclic ACD core, we turned our attention
to the possibility of using the RCM step for directly
installing a ketone on the C-10 of the seven-membered
ring. We therefore decided to perform the Michael addi-
tion/allylation cascade in the presence of enol ether 17.
Although proceeding with a lower yield in comparison
with the formation of 14, we were pleased to observe that
the Michael addition/allylation sequence took place with
the desired stereo- and regiocontrol and allowed us to
isolate intermediate 18 in 52% yield.
Scheme 3. Synthesis of Tricyclic Compound 20 via Enol Ether
Ring-Closing Metathesis
product was isolated in 70% yield as a separable mixture of
two diastereomeric products when GrubbsÀHoveyda II was
used in toluene at 85 °C. The use of Grubbs II under similar
reaction conditions was also effective, but proceeded in a
slightly lower yield (61%). To the best of our knowledge, this
is one of the rare examples of enol ether RCM being used for
the construction of a 7-membered ring.17
Finally, we considered the possibility of installing the
two stereocenters at C-6 and C-8 (Scheme 4). The problem
was addressed using tricyclic structure 16, easily available
on a multigram scale using the protocol previously de-
scribed in Scheme 2. Stereo- and regioselective alkylation
of 16 on C-8 proved to be troublesome. Standard Michael
acceptors such as methyl vinyl ketone (MVK) or methyl
acrylate did not react under a variety of conditions.
Furthermore, ketone 16 was surprisingly unreactive to-
ward a variety of common alkylating reagents. We finally
identified that the combination of allyltosylate 13 and
catalytic 18-crown-6 furnished the O-alkylated product
21 in almost quantitative yield and with complete regios-
electivity. Subsequent Claisen rearrangement afforded the
carbon allylated product in good yield and in 2.6:1 dr in
favor of 22. Unfortunately, the two diastereoisomers at
C-8 proved to be very difficult to separate via standard
flash column chromatography. Nevertheless, compound
22 could be isolated in 60% yield. Subsequent Krapcho
dealkoxycarbonylation also proved to be problematic with
a screen of different conditions typically affording the
desired product 25 as the minor diastereoisomer.
Heating a freshly prepared batch of intermediate 18 in
refluxing mesitylene furnished the desired rearranged pro-
duct 19 with the expected regioselectivity in 53% yield
(Scheme 3). In this case, the required reaction time was
longer than in the case of enol ether 14, as expected for allyl
enol ethers with similar substitution patterns.16 The sub-
sequent RCM step did not proceed in the presence of
Grubbs I catalyst (no product was observed in refluxing
CH2Cl2 or in toluene at 85 °C). Pleasingly, the desired
(12) See the Supporting Information for references regarding the
preparation of compound 8.
(13) Parker, K. A.; Fokas, D. J. Org. Chem. 1994, 59, 3933–3938.
(14) Intermediate 9 was always used within 1À2 h from its prepara-
tion, without any purification, and was stored in the dark.
(15) Data were collected at low temperature [Cosier, J.; Glazer, A. M.
J. Appl. Crystallogr. 1986, 19, 105] using an Enraf-Nonius KCCD
diffractometer [Otwinowski, Z.; Minor, W. Processing of X-ray Dif-
fraction Data Collected in Oscillation Mode Methods Enzymol; Carter,
C. W., Sweet, R. M., Eds.; Academic Press: New York, 1997; p 276]. The
crystal structures of 14 and 25 were solved using SIR92 [Altomare, A.;
Cascarano, G.; Giacovazzo, C.; Guagliardi, A.; Burla, M. C.; Polidori,
G. Camalli, M. J. Appl. Crystallogr. 1994, 27, 435] and refined using the
CRYSTALS software suite [Betteridge, P. W.; Carruthers, J. R.;
Cooper, R. I.; Prout, K.; Watkin, D. J. J. Appl. Crystallogr. 2003, 36,
1487], and H atoms were treated in the usual manner [Cooper, R. I.;
Thompson, A. L.; Watkin, D. J. J. Appl. Crystallogr. 2010, 43, 1100] as
per the Supporting Information (CIF). Crystallographic data (excluding
structure factors) for 14 and 25 have been deposited with the Cambridge
Crystallographic Data Centre (CCDC 838995 and 838996), and copies
of these data can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif.
(17) For an example of enol ether RCM in natural product total
€
synthesis, see: Oliver, S. F.; Hogenauer, K.; Simic, O.; Antonello, A.;
Smith, M. D.; Ley, S. V. Angew. Chem., Int. Ed. 2003, 42, 5996–6000.
For representative examples of cyclic enol ether synthesis through olefin
metathesis reactions, see: (a) Fujimura, O.; Fu, G. C.; Grubbs, R. H.
J. Org. Chem. 1994, 59, 4029–4031. (b) Sturino, C. F.; Wong, J. C. Y.
Tetrahedron Lett. 1998, 39, 9623–9626. (c) Clark, J. S.; Kettle, J. G.
Tetrahedron 1999, 55, 8231–8248. (d) Rainier, J. D.; Allwein, S. P.; Cox,
J. M. J. Org. Chem. 2001, 66, 1380–1386. (e) Liu, L.; Postema, M. H. D.
J. Am. Chem. Soc. 2001, 123, 8602–8603. (f) Sutton, A. E.; Seigal, B. A.;
Finnegan, D. F.; Snapper, M. L. J. Am. Chem. Soc. 2002, 124, 13390–
13391. (g) Hekking, K. F. W.; van Delft, F. L.; Rutjes, F. P. J. T.
Tetrahedron 2003, 59, 6751–6758. (h) Lee, A.-L.; Malcolmson, S. J.;
Puglisi, A.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2006, 128,
5153–5157.
(16) Martın Castro, A. M. Chem. Rev. 2004, 104, 2939–3002 and
´
references cited therein.
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Org. Lett., Vol. 13, No. 19, 2011

single-crystal X-ray analysis of a crystalline sample
(Scheme 4).15
Scheme 4. Synthesis of Tricyclic Compound 25
In summary, we have developed a practical and scalable
route to the tricyclic [5À6À7] skeleton of calyciphylline
A-type alkaloids. Our strategy is based on an intramole-
cular Michael addition, a ring-closing metathesis, and a
Claisen rearrangement as pivotal steps and allows for the
efficient and rapid construction of four stereocenters,
including the two contiguous quaternary stereocenters at
C-5 and C-8. One of the rare examples of enol ether RCM
for the construction of a 7-membered ring has been
reported and allows the straightforward installation of
the ketone present on the 7-membered ring of daphniyun-
nine B. Further studies toward the total synthesis of
daphniyunnine B and other members of the calyciphylline
A-type alkaloids are currently under investigation in our
laboratories and will be reported in due course.
Acknowledgment. We thank the EPSRC (Leadership
Fellowship to D.J.D., postdoctoral fellowships to F.S and
B.D., and studentship to J.W.W.), the EC [IEF to F.S.
(PIEF-GA-2009-254068)], AstraZeneca (studentship to
J.W.W.), Andrew Kyle, David Barber of the Department
of Chemistry, University of Oxford, for X-ray analysis,
and the Oxford Chemical Crystallography Service for the
use of the instrumentation.
Given the difficulties in the two steps required for
converting 16 to 25, we decided to invert the order of the
Claisen and Krapcho steps. This approach proved success-
ful and amenable to scale up (conversion of 24 to 25 was
carried out on a greater than 1 g scale). Dealkoxycarbo-
nylation of 16 with wet DMSOÀLiCl afforded 23 as a
diastereomeric mixture at C-6 and C-8. The inseparable
mixture was treated with allyl tosylate/18-crown-6 and
allylated with complete regiocontrol to give 24 as 3.2:1
diastereomeric mixture at C-6. Subsequent Claisen rear-
rangement of 24 afforded a mixture of three diastereoi-
somers out of which 25 was the main component and was
easily isolated via chromatography in 58% yield. Final
confirmation of the stereochemistry of 25 was obtained via
Supporting Information Available. Experimental pro-
cedures and spectral data for compounds 10À12, 14À16,
and 18À25 and CIF files for compounds 14 and 25. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 19, 2011
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