An enantioselective total synthesis of helioporins C and e

Article abstract of DOI:10.1021/ol302898h

A short and enantioselective total synthesis of helioporins C and E, which are bioactive marine diterpenes containing a serrulatane or amphilectane skeleton, was elaborated. The chirogenic step, i.e. a Cu(I)-catalyzed allylic alkylation of a cinnamyl chlo

Full text of DOI:10.1021/ol302898h

ORGANIC
LETTERS
2012
Vol. 14, No. 23
5996–5999
An Enantioselective Total Synthesis
of Helioporins C and E
€
Wibke Lolsberg, Susen Werle, Jorg-Martin Neudorfl, and Hans-Gunther Schmalz*
€
€
€
€
Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Koln, Germany
schmalz@uni-koeln.de
Received October 21, 2012
ABSTRACT
A short and enantioselective total synthesis of helioporins C and E, which are bioactive marine diterpenes containing a serrulatane or
amphilectane skeleton, was elaborated. The chirogenic step, i.e. a Cu(I)-catalyzed allylic alkylation of a cinnamyl chloride with methylmagnesium
bromide, proceeded with virtually complete enantioselectivity (99% ee) in the presence of a chiral phosphine-phosphite ligand. The other
stereocenters were diastereoselectively established through Me2AlCl-mediated cationic cyclization and Ir-catalyzed hydrogenation.
The helioporins, for instance helioporin C (1) and
helioporin E (2), are marine metabolites isolated by Higa
and co-workers from the blue coral heliopora coerulae and
were found to exhibit antiviral and cyctotoxic activities.1
These polycyclic diterpenes possess a serrulatane or an
amphilectane skeleton and closely resemble the agly-
cones of the earlier discovered seco-pseudopterosins2 and
pseudopterosins,3 respectively.
Some years ago, in the course of our work on the use of
chiral areneÀCr(CO)3 complexes as synthetic building
blocks we revised the initial stereochemical assignments
of helioporins C and D through stereorational total synthe-
sis of the proposed structures and by chemical correlation
with the seco-pseudopterosin aglycone.4 Our stereostructural
proposal was later confirmed by Corey and co-workers in a
total synthesis of helioporin E.5
We here describe a novel, short, and enantioselective
synthetic approach toward the helioporins (C and E)
exploiting various metal-catalyzed transformations and,
in particular, an asymmetric Cu-catalyzed allylic substitu-
tion reaction to set up the first chirality center.
Our synthetic strategy (Scheme 1) implies a late stage
divergence toward either 1 or 2. We envisaged that the
central allylic alcohol intermediate 3 could be prepared
from calamenene 4, which in turn might be accessible by
Lewis acid initiated diastereoselective cyclization of 5, in
analogy to a transformation previously described.6
Furthermore, we intended to assemble the cyclization
precursor 5 through hydroboration/Suzuki coupling from
the terminal olefin 6. This first chiral intermediate was
projected to be prepared from the cinnamyl chloride 7
applying our recently developed protocol7 for Cu(I)-
catalyzed asymmetric allylic alkylation.
(1) Tanaka, J. I.;Ogawa, N.;Liang, J.;Higa, T.Tetrahedron 1993, 49, 811.
(2) Look, S. A.; Fenical, W. Tetrahedron 1987, 43, 3363.
(3) (a) Look, S. A.; Fenical, W.; Jacobs, R. S.; Clardy, J. J. Proc. Natl.
Acad. Sci. U.S.A. 1986, 83, 6238. (b) Look, S. A.; Fenical, W.; Matsumoto,
G. K.; Clardy, J. J. Org. Chem. 1986, 51, 5140. (c) Potts, B. C.; Faulkner,
D. J. J. Nat. Prod. 1992, 55, 1707. (d) Mayer, A. M. S.; Jacobson, P. B.;
Fenical, W.; Jacobs, R. S.; Glaser, K. B. Life Sci. 1998, 62, 401. (e) Ata, A.;
Kerr, R. G.; Moya, C. E.; Jacobs, R. S. Tetrahedron 2003, 59, 4215. (f)
Rodrıguez, I. I.; Shi, Y. P.; Gracıa, O. J.; Rodrıguez, A. D.; Mayer,
The synthesis of the cinnamyl chloride 7, i.e. the
projected substrate for the enantioselective allylic
alkylation, started with the directed ortho-metalation
of 2,3-dimethoxy-toluene (8) with tert-BuLi/TMEDA
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A. M. S.; Sanchez, J. A.; Ortega, E.; Gonzalez, J. J. Nat. Prod. 2004, 67,
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1672. (g) Duque, C.; Puyana, M.; Narvaez, G.; Osorno, O.; Hara, N.;
Fujimoto, Y. Tetrahedron 2004, 60, 10627. For a reviewon pseudopterosin
syntheses, see: (h) Heckrodt, T. J.; Mulzer, J. Top. Curr. Chem. 2005, 244,
1. See also: (i) Cooksey, J. P.; Kocienski, P. J.; Schmidt, A. W.; Snaddon,
T. N.; Kilner, C. A. Synthesis 2012, 44, 2779 and references cited therein.
(4) (a) Geller, T.; Jakupovic, J.; Schmalz, H.-G. Tetrahedron Lett.
(5) Lazerwith, S. E.; Johnson, T. W.; Corey, E. J. Org. Lett. 2000, 2, 2389.
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2007, 18, 3555.
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1998, 39, 1541. (b) Horstermann, D.; Kociok-Kohn, G.; Schmalz, H.-G.
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r
10.1021/ol302898h
Published on Web 11/13/2012
2012 American Chemical Society

Scheme 1. Retrosynthetic Analysis
Scheme 2. Preparation of Cinnamyl Chloride 7
with high regioselectivity (g99:1) and in virtually enantiopure
form (99% ee) even on a multigram scale.12
Scheme 3. Cu(I)-Catalyzed Asymmetric Alkylation of 7 with
MeMgBr in the Presence of the Phosphine-Phosphite Ligand 12
under apolar solvent conditions (pentane/Et2O = 10:1)
followed by bromination of the aryllithium intermediate.
Cleavage of the methoxy groups of 9 with BBr3 and sub-
sequent methylenation of the resulting catechol with
CH2Cl2/CsF8 afforded the benzodioxole 10, which turned
out to be rather volatile. Treatment of 10 with n-BuLi
(BrÀLi exchange) followed by 1,2-addition of the inter-
mediate aryl lithium species to acrolein gave the allylic
alcohol rac-11. Chlorination (under allylic rearrangement)
was achievedunder MoffatÀSwern conditions9 toyield the
cinnamyl chloride 7 in quantitative yield (Scheme 2).
Noteworthy, a direct ortho-functionalization of
(nonbrominated) benzodioxoles (e.g., debrominated
10 or benzodioxole itself) through lithiation (with n-BuLi
or tert-BuLi) could not be achieved.
The absolute configuration of 6 was confirmed (to be S)
by comparison of the TDDFT-calculated13 and measured
circular dichroism (CD) spectra.14
The enantioselective conversion of 7 into the chiral build-
ing block 6 was performed under the previously reported
conditions7 for the Cu-catalyzed allylic alkylation10 of
cinnamyl chlorides using Grignard reagents as nucleophiles
(Scheme 3). Thus, 7 was reacted with Me-MgBr in the pres-
ence of catalytic amounts of the (S,S)-TADDOL-derived
chiral phosphine-phosphite ligand 1211 and CuBr•SMe2 un-
der appropriate cooling (À78 °C). Much to our satisfaction,
the desired product 6 was obtained in excellent yield (97%),
(12) For the synthesis of a compound related to 6 through asym-
metric hydrovinylation, see: Mans, D. J.; Cox, G. A.; RajanBabu, T. V.
J. Am. Chem. Soc. 2011, 133, 5776.
(13) (a) Calculation of the CD spectrum in MeOH was performed with:
Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant,
J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.;
Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada,
M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.;
Hratchian, H. P.; Cross, J. B.; Adamo, C.; Jaramillo, J.; Gomperts, R.;
Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.;
Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.;
Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain,
M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski,
J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.;
Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.;
Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen,
W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03, revision d.02;
Gaussian, Inc.: Pittsburgh, PA, 2003. (b) A B3LYP functional with TZVP
(triple-ζ basis set with polarisation functions) basis set was applied.
(8) Clark, J. H.; Holland, H. L.; Miller, J. M. Tetrahedron Lett. 1976,
38, 3361.
(9) Yin, J.; Gallis, C. E.; Chisholm, J. D. J. Org. Chem. 2007, 72, 7054.
(10) For recent reviews, see: (a) Harutyunyan, S. R; den Hartog, T.;
Geurts, K.; Minnaard, A. J.; Feringa, B. L. Chem. Rev. 2008, 108, 2824. (b)
Geurts, K.; Fletcher, S. P.; van Zijl, A. W.; van Minnaard, A. J.; Feringa,
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B. L. Pure Appl. Chem. 2008, 80, 1025. (c) Alexakis, A.; Backvall, J.-E.;
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Org. Lett., Vol. 14, No. 23, 2012
5997

The cyclization precursor 5 was prepared from olefin 6
by Suzuki coupling of the in situ formed borane 13 with
the vinyl iodide 15, which in turn was synthesized from
propargylic alcohol 14 in 69% yield through Zr-catalyzed
methyl-alumination/iodination15 followed by acetylation
of the alcohol functionality (Scheme 4).16
Pd-allyl intermediate17 (in the presence of catalytic
amounts of a Pd0 source with or without addition of a
base) only led to the formation of uncyclized products
with an isomerized double bond.
Since the steroisomers of 4 were not separable, the
synthesis was continued with the 4:1 mixture. The side
chain was elongated through Lewis acid mediated carbonyl-
ene reaction18 employing the silyl-protected glycolalde-
hyde 16, which was prepared from ethylene glycol in two
steps.19 This way, the alcohol 17 was obtained in 68% yield
(as a 1:1 mixture of epimers) besides 16% of reisolated
starting material.20 The homo-benzylic stereocenter was
then set up in a highly diastereoselective manner by
hydrogenation of the exocyclic double bond using the
iridium catalyst 18 developed by Pfaltz and co-workers.21
In the presence of 2 mol % of 18 at 50 bar of H2 a full
conversion of 17 was achieved within 96 h. After purifica-
tionby flash columnchromatographyamixture(ca. 1:1) of
19a and its desilylated congeneer 19b was isolated in 78%
yield. In a one-pot procedure, the desilylation was com-
pleted by treatment with tetrabutylammonium fluo-
ride followed by oxidative cleavage of the glycole 19b
with periodic acid to afford the aldehyde 20 in quanti-
tative yield (Scheme 5). At this stage, 1H NMR analy-
sis allowed determination of the selectivity of the pre-
vious hydrogenation step as >95:5 in favor of the
desired diastereoisomer. To complete the carbon
skeleton the aldehyde 20 was reacted with isobutenyl-
magnesium bromide to afford a 1:1 epimeric mixture of
the acid-sensitive intermediate 3 in 85% yield after pur-
ification on Celite.
Having successfully prepared the key allylic alco-
hol 3 we next investigated its oxidation to helioporin
C (1) as a first target structure (Scheme 6). Using either
Jones reagent or Dess-Martin periodinane (DMP) the
product was contaminated with major amounts of 2
(and its diastereomer) resulting from acid-triggered
cyclization. However, this side reaction could be sup-
pressed by using DMP in the presence of 3 equiv of
pyridin. This way, helioporin C (1) was obtained in
86% yield.
Next, the cationic cyclization of 3 to helioporin E (2) was
investigated. While this transformation takes place readily
in the presence of a Brønsted or Lewis acid, the challenge
was to achieve a significant level of diastereoselectivity. By
employing MeSO3H (30 mol %) as an acid at very low
temperatures in CH2Cl2/pentane (3/1), the product, i.e.
helioporin E (2), was formed in 98% yield, however, as a
3:1 mixture of epimers, which could not be separated by
chromatography.
Scheme 4. Synthesis of the Cyclization Precursor 5
The use of the iodo-allyl acetate 15 (instead of the cor-
responding bromo-allyl-TBS-ether)6 in the Pd-catalyzed
Suzuki coupling was not trivial. However, this reac-
tion was achieved in 70% yield employing 10 mol %
of Pd(dppf)Cl2/AsPPh3 at slightly elevated tempera-
tures (40 °C) for 48 h. Under these comparably mild con-
ditions, the direct introduction of the allylacetate moiety
was possible without much loss associated with the forma-
tion of reactive π-allyl-Pd intermediates.
According to the devised strategy (Scheme 1), the
(diastereoselective) FriedelÀCrafts-type cyclization of the
allylic acetate 5 was investigated next (Scheme 5). Using
Me2AlCl (2.5 equiv), as reported earlier for a similar
system,6 the reaction proceeded smoothly to give prefer-
entially the trans-calamenene 4; however, the diastereo-
selectivity did not exceed a 4:1 ratio evenatÀ15°C in CCl4.
Thus, in comparison to the related veratrol-derived sub-
strate, the (more electron rich) benzodioxole 5 reacted
faster but with lower diastereoselectivity. Variation of both
the solvent and the Lewis acid did not lead to an
improvement. Also, attempts to achieve the cycliza-
tion by intramolecular arylation of an electrophilic
(17) (a) Xu, Q.-L.; Dai, L.-X.; You, S.-L. Org. Lett. 2012, 14, 2579.
(b) Nemoto, T.; Ishige, Y.; Yoshida, M.; Kohno, Y.; Kanematsu, M.;
Hamada, Y. Org. Lett. 2010, 12, 5020.
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(14) (a) Jaffe, H. H.; Orchin, M. In Theory and applications of
(18) Mikami, K.; Shimizu, M. Chem. Rev. 1992, 92, 1021.
(19) (a) Rico, J. G.; Oh, Y.-I.; Condon, B. D.; McDougal, P. G.
J. Org. Chem. 1986, 17, 3388. (b) Aszodi, J.; Bonnet, A.; Teusch, G.
Tetrahedron 1990, 5, 1579.
(20) For unknown reasons, the conversion of 4 was never complete
even after prolonged reaction times even using an excess of Me2AlCl.
(21) Roseblade, S. J.; Pfaltz, A. Acc. Chem. Res. 2007, 40 (12), 1402.
ultraviolet spectroscopy; Wiley: New York, 1962; p 242. (b) Pescitelli,
G.; Di Bari, L.; Caporusso, A. M.; Salvadori, P. Chirality 2008, 20, 393.
(15) (a) Rand, C. L.; Van Horn, D. E.; Moore, M. W.; Negishi, E.-i.
J. Org. Chem. 1981, 46, 4093. (b) Wang, G.; Negishi, E.-i. Eur. J. Org.
Chem. 2009, 1679.
(16) The expected (E) configuration of 15 was confirmed by a
NOESY experiment.
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Org. Lett., Vol. 14, No. 23, 2012

Scheme 5. Conversion of 5 into the Allylic Alcohol 3 as a Late Key Intermediate
this case through diastereoselective hydride transfer from
Et3SiH to a benzylic carbenium ion.
Scheme 6. Preparation of the Helioporins C (1) and E (2) from
Allylic Alcohol 3 and Derivative 21 from Helioporin C (1)
Scheme 7. Proposed Intermediates in the Conversion of 21 to 1
To conclude, we have elaborated a short total synthesis
of helioporins C and E exploiting a series of catalytic steps.
We are currently trying to improve the diastereoselectivity
of the cyclization step and to apply the strategy to the
synthesis of structurally related marine diterpenoids and
analogs, which are of high pharmacological interest.
Acknowledgment. This work was supported by the
University of Cologne. We thank the Chemetall GmbH
for valuable gifts of organolithium and Grignard reagents.
Interestingly, dihydro-helioporin E (21) was obtained
with excellent diastereoselectivity (>95:5) by treatment of
1 with MeSO3H in the presence of Et3SiH (Scheme 6). We
assume this transformation to proceed via 22 as an inter-
mediate, which is converted to 23 and further to 21 in two
subsequent ionic hydrogenation steps (Scheme 7). Thus,
the configuration at the new stereocenter is established in
Supporting Information Available. Experimental pro-
cedures and analytical data. This material is available free
of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 23, 2012
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