Enantioselective synthesis of a trans-7,8-dimethoxycalamenene

Article abstract of DOI:10.1021/ol071228v

trans-7,8-Dimethoxy-11,12-dehydrocalamenene, a projected intermediate for the total synthesis of marine serrulatane and amphilectane diterpenes, was efficiently synthesized. Starting from a styrene, asymmetric Rh-catalyzed hydroboration using a novel chiral P.P-bidentate ligand afforded an organoboron intermediate (93% ee) which was directly used for C-C bond formation (double homologation, Suzuki coupling). The 1,4-trans-disubstituted tetralin skeleton was selectively formed by a Friedel-Crafts-type catlonic cyclization under strictly aprotic conditions (Me₂AlCl) to suppress a remarkable proton-catalyzed disproportionation via diastereoselective hydride transfer.

Full text of DOI:10.1021/ol071228v

ORGANIC
LETTERS
2007
Vol. 9, No. 18
3555-3558
Enantioselective Synthesis of a
trans-7,8-Dimethoxycalamenene
Susen Werle, Thorsten Fey, Jo1rg M. Neudo1rfl, and Hans-Gu1nther Schmalz*
Institute of Organic Chemistry, UniVersity of Cologne, Greinstr. 4, 50939 Ko¨ln,
Germany
schmalz@uni-koeln.de
Received May 24, 2007
ABSTRACT
trans-7,8-Dimethoxy-11,12-dehydrocalamenene, a projected intermediate for the total synthesis of marine serrulatane and amphilectane diterpenes,
was efficiently synthesized. Starting from a styrene, asymmetric Rh-catalyzed hydroboration using a novel chiral P,P-bidentate ligand afforded
an organoboron intermediate (93% ee) which was directly used for C
trans-disubstituted tetralin skeleton was selectively formed by a Friedel Crafts-type cationic cyclization under strictly aprotic conditions (Me2AlCl)
to suppress a remarkable proton-catalyzed disproportionation via diastereoselective hydride transfer.
−C bond formation (double homologation, Suzuki coupling). The 1,4-
−
Over the past 20 years, several aromatic diterpenes with an
amphilectane or serrulatane skeleton were identified as
bioactive metabolites from marine soft corals, especially
Pseudopterogorgia elisabethae.1 Prominent representatives
of such compounds (Figure 1) are the anti-inflammatory
All of these compounds possess a tetralin substructure
formed by rings A and B with the same relative (trans)
configuration of the benzylic substituents (stereocenters C-3
and C-6)sas a consequence of a 1,4-trans-disubstituted
(1) For reviews, see: (a) Heckrodt, T. J.; Mulzer, J. Top. Curr. Chem.
2005, 244, 1-41. (b) Rodriguez, A. D. Tetrahedron 1995, 51, 4571-4618.
For additional leading references, see: (c) Rodriguez, I. I.; Shi, Y.-P.; Garcia,
O. J.; Rodriguez, A. D.; Mayer, A. M. S.; Sanchez, J. A.; Ortega-Barria,
E.; Gonzalez, J. J. Nat. Prod. 2004, 67, 1672-1680. (d) Ata, A.; Win, H.
Y.; Holt, D.; Holloway, P.; Segstro, E. P.; Jayatilake, G. S. HelV. Chim.
Acta 2004, 87, 1090-1098.
(2) (a) Look, S. A.; Fenical, W.; Jacobs, R. S.; Clardy, J. Proc. Natl.
Acad. Sci. U.S.A. 1986, 83, 6238-6240. (b) Look, S. A.; Fenical, W.;
Matsumoto, G. K.; Clardy, J. J. Org. Chem. 1986, 51, 5140-5145. For
enantioselective syntheses, see: (c) Broka, C. A.; Chan, S.; Peterson, B. J.
Org. Chem. 1988, 53, 1584-1586. (d) Corey, E. J.; Carpino, P. J. Am.
Chem. Soc. 1989, 111, 5472-5474. (e) Majdalani, A.; Schmalz, H.-G.
Synlett 1997, 1303-1305. (f) Corey, E. J.; Lazerwith, S. E. J. Am. Chem.
Soc. 1998, 120, 12777-12782. (g) Kocienski, P. J.; Pontiroli, A.; Qun, L.
J. Chem. Soc. Perkin Trans. 1, 2001, 2356-2366.
(3) (a) Tanaka, J.; Ogawa, N.; Liang, J.; Higa, T.; Gravalos, D. G.
Tetrahedron 1993, 49, 811-822. For syntheses and stereostructural revision,
see: (b) Geller, T.; Jakupovic, J.; Schmalz, H. G. Tetrahedron Lett. 1998,
39, 1541-1544. (c) Lazerwith, S. E.; Johnson, T. W.; Corey, E. J. Org.
Lett. 2000, 2, 2389-2392.
Figure 1. Structures of some amphilectane diterpenoids.
pseudopterosins,2 the antiviral and cytotoxic helioporins,3 and
the pseudopteroxazoles,4 the latter exhibiting promising
antibiotic activities against Mycobacterium tuberculosis
H37Rv.
(4) (a) Rodriguez, A. D.; Ramirez, C.; Rodriguez, I. I.; Gonzalez, E.
Org. Lett. 1999, 1, 527-530. For syntheses and stereostructural revision,
see: (b) Davidson, J. P.; Corey, E. J. J. Am. Chem. Soc. 2003, 125, 13486-
13489. (c) Harmata, M.; Hong, X. C. Org. Lett. 2005, 7, 3581-3583.
10.1021/ol071228v CCC: $37.00
© 2007 American Chemical Society
Published on Web 08/04/2007

tetralin derivative (erogorgiaene) serving as a common
biosynthetic intermediate.1a,5
Using 3 as a substrate, we next studied its asymmetric
Rh-catalyzed hydroboration to establish the first (benzylic)
stereocenter. Initially, we performed the reaction according
to Hayashi9b using catecholborane and a catalyst prepared
in situ from [Rh(COD)2]BF4 and (R)-BINAP in DME as a
solvent at -78 °C. However, after addition of pinacol,11 the
boronate 8 was obtained with an enantiomeric purity of only
63% ee,12 a rather low value as compared to 96% ee obtained
for the hydroboration of simple styrene under the same
conditions.9b By screening a library of chiral phosphite-
phosphane ligands developed in our laboratory,13 we identi-
fied the TADDOL14-derived ligand 7 as particularly well
suited. Under optimized conditions, the enantioselective
hydroboration of 3 proceeded smoothly on a multigram scale
to afford pure 8 in 93% ee and 80% isolated yield after
chromatography (Scheme 3).15
We describe here an efficient and highly stereoselective
synthetic entry to the calamenene 1, a trans-1,4-disubstituted
tetralin derivative representing a promising precursor for the
synthesis of the marine diterpenes mentioned above.6 Also,
the bis-O-demethylated compound corresponding to 1 is a
known anti-infective constituent of the plant Guardiola
platyphylla.7
According to the retrosynthetic analysis sketched in
Scheme 1, we optimistically planned to build up the trans-
Scheme 1. Retrosynthetic Analysis
Scheme 3. Enantioselective Hydroboration of 3
tetralin through a diastereoselective cyclization8 from a
precursor of type 2. This compound in turn might be derived
from the styrene derivative 3 by means of enantioselective
hydroboration9 and subsequent coupling reactions of the
organoboron intermediates.
Building block 3, needed as a substrate for the planned
hydroboration, was prepared from commercially available
2,3-dimethoxytoluene (4) by directed ortho-metalation/
formylation and subsequent methylenation of the aldehyde
5 employing Nysted reagent (6)10 in the presence of BF3
etherate (Scheme 2). Noteworthy, much lower yields were
The absolute configuration of the hydroboration product
816 was proven by X-ray crystal structure analysis of its
tricarbonylchromium complex (Figure 2).
Scheme 2. Preparation of the Styrene 3
(8) Only few and little convincing examples exist for the diastereo-
selective synthesis of tetralins through cationic cyclization: (a) Appelbe,
R.; Casey, M.; Dunne, A.; Pascarella, E. Tetrahedron Lett. 2003, 44, 7641-
7644. For an exceptional case employing a Co2(CO)6-complexed propargylic
cation, see: Jackson, S. R.; Johnson, M. G.; Mikami; M.; Shiokawa, S.;
Carreira, E. M. Angew. Chem., Int. Ed. 2001, 40, 2694-2697.
(9) (a) Burgess, K.; Ohlmeyer, M. J. J. Org. Chem. 1988, 53, 5178-
5179. (b) Hayashi, T.; Matsumoto, Y.; Ito, Y. J. Am. Chem. Soc. 1989,
111, 3426-3428. For leading reviews, see: (c) Hayashi, T. In Compre-
hensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H.,
Eds.; Springer-Verlag: Heidelberg 1999; Vol. 1, pp 351-364. (d) Crudden,
C. M., Edwards, D. Eur. J. Org. Chem. 2003, 4695-4712. (e) Carroll, A.
M.; O’Sullivan, T. P.; Guiry, P. J. AdV. Syn. Catal. 2005, 347, 609-631.
(10) Matsubara, S.; Sugihara, M.; Utimoto, K. Synlett 1998, 313-315.
(11) Chen, A. C.; Ren, L.; Crudden C. M. Chem. Commun. 1999, 611-
612.
(12) The enantiomeric excess of 8 was determined by means of GC using
a chiral stationary phase (6T-2,3-methyl-â-cyclodextrin) after oxidation of
8 to the corresponding phenylethanol derivative (H2O2, NaOH, H2O/MeOH).
(13) (a) Kranich, R.; Eis, K.; Geis, O.; Mu¨hle, S.; Bats, J. W.; Schmalz,
H.-G. Chem. Eur. J. 2000, 6, 2874-2894. (b) Blume, F.; Zemolka, S.; Fey,
T.; Kranich, R.; Schmalz, H.-G. AdV. Synth. Catal. 2002, 344, 868-883.
(c) Velder, J.; Weidner, I.; Schmalz, H.-G. Unpublished results.
(14) For, a review see: Seebach, D.; Beck, A. K.; Heckel, A. Angew.
Chem., Int. Ed. 2001, 40, 92-138.
obtained in the latter transformation under conventional
Wittig conditions.
(5) (a) Kerr, R. G.; Kohl, A. C.; Ferns, T. A. J. Industr. Microbiol.
Biotech. 2006, 33, 532-538. (b) Ferns, T. A.; Kerr, R. G. J. Org. Chem.
2005, 70, 6152-6157.
(6) We had previously reported an enantioselective synthesis of cis-
calamenenes related to 1 exploiting arene-Cr(CO)3 complexes: (a)
Schmalz, H.-G.; Arnold, M.; Hollander, J.; Bats, J. W. Angew. Chem., Int.
Ed. Engl. 1994, 33, 109-111. (b) Schmalz, H.-G.; Hollander, J.; Arnold,
M.; Du¨rner, G. Tetrahedron Lett. 1993, 34, 6259-6262. For a review, see:
(c) Schmalz, H.-G.; Gotov, B.; Bo¨ttcher, A. In Arene Metal Complexes;
Ku¨ndig, E. P., Ed. Top. Organomet. Chem. 2004, 7, 157-179.
(7) Wahyouno, S.; Hoffmann, J. J.; Bates, R. B.; McLaughlin, S. P.
Phytochemistry 1991, 30, 2175-2182.
(15) Small amounts of the nonbranched isomer of 8 were also isolated,
the regioisomeric ratio being 87:13 as determined by NMR from the crude
product mixture prior to chromatography.
(16) A pure sample of 8-Cr(CO)3 was obtained by refluxing 8 with
Cr(CO)6 under argon in Bu2O/THF (6:1) for 18 h, followed by chromato-
graphic purification and crystallization from heptane.
3556
Org. Lett., Vol. 9, No. 18, 2007

Surprisingly, GC-MS analysis of the crude product (Figure
3) revealed the formation of a 1:1 mixture of two products
Figure 2. Structure of 8-Cr(CO)3 in the crystalline state.
Figure 3. GC-MS of the crude product resulting from the
cyclization of 11 according to Scheme 5.
The conversion of 8 into the cyclization precursor 11 was
achieved as shown in Scheme 4. To prepare for the side chain
(with m/z ) 258 and 262, respectively), none of them
showing the molecular weight of the expected cyclization
product 1 (m/z ) 260). Repetition of the cyclization reaction
in dichloromethane (0 to 20 °C) in the presence of different
common Lewis acids such as BF3·etherate (1.0 equiv, 1 h),
scandium triflate (1.1 equiv, 40 min), TMS-triflate (0.75
equiv, 1 h), or AlMe3 (0.3 equiv, 12 h) gave more or less
identical results (Scheme 5).
Scheme 4. Preparation of the Cyclization Precursor 11
Scheme 5. Cyclization of 11 under “Protic” Conditions
elongation by means of an sp2-sp3 Suzuki cross coupling,17
8 was first double homologated through two subsequent
treatments with bromochloromethane and n-butyllithium
under in situ quench conditions at low temperature.11,18 The
boronate 9, thus obtained in high yield (under optimized
conditions), was then first activated by addition of sec-
butyllithium19 before it was reacted with the substituted vinyl
bromide 1020 in the presence of 5 mol % of Pd(dppf)Cl2.
Fluoride-induced cleavage of the TBS-ether and O-acetyl-
ation finally afforded the desired allylic acetate 11 in good
overall yield.
We next investigated the projected cationic (Friedel-
Crafts-type) cyclization of 11 (see Scheme 1). In a first
experiment, a solution of the acetate 11 in a 3:1 mixture of
trifluoroacetic acid and acetic acid was stirred for 5 days at
20 °C, according to the protocol of Ma and Zhang.21
The two reaction products, which obviously result from
an unexpected disproportionation process, were identified as
the cis-calamenene 12 and the naphthalene derivative 13 by
means of NMR spectroscopy.22,23
While, according to TLC analysis, the conversion of 11
accordant to Scheme 5 was quantitative in all cases within
a few minutes once the temperature had reached a critical
value (ca. 0 °C), a more careful monitoring of the BF3-
mediated reaction (using initially only 0.3 equiv) revealed
the occurrence of three major transient species with the
(desired) mass of m/z ) 260.
We therefore reasoned that the formation of 12 and 13
might result from a proton-catalyzed secondary process. To
probe this hypothesis, we reacted the cyclization precursor
11 again, however under strictly aprotic conditions by
(17) Selected reviews: (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995,
95, 2457-2483. (b) Suzuki, A. J. Organomet. Chem. 1999, 576, 147-
168.
(18) (a) Sadhu, K. M.; Matteson, D. S. Organometallics. 1985, 4, 1687-
1689. (b) Chen, A. C.; Ren, L.; Crudden, C. M. J. Org. Chem. 1999, 64,
9704-9710. (c) Ren, L.; Crudden, C. M. Chem. Commun. 2000, 721-
722. For a first example of a high-yield sequential double CH2-insertion,
see: (d) Fey, T. Dissertation, University of Cologne, Germany, 2005.
(19) Zou, G.; Falck, J. R. Tetrahedron Lett. 2001, 42, 5817-5819.
(20) Compound 10 was prepared in 71% yield from methyl (E)-3-
bromometacrylate (Aberhart, D. J.; Tann, C.-H. J. Chem. Soc., Perkin Trans.
1, 1979, 939-942) by reduction (DIBAH, DCM) and O-protection (TBS-
Cl, imidazole, DMF).
(22) From the NMR spectra of the mixture, the signals of compounds
12 and cis-1 could be unambiguously assigned by comparision with the
spectrum of authentic samples of the pure cis isomers obtained in this
laboratory by stereo-rational synthesis; see refs 6a and 6b as well as: Arnold,
M. Dissertation, Universita¨t Frankfurt 1994.
(23) After completion of our experimental work, Kraus and Jeon
independently reported the related observation that the TFA-mediated (ref
20) cyclization of compound rac-11, prepared by a different route, leads to
disproportionation to afford a mixture of two products, one of them being
a cis-calamenene; see: Kraus, G. A.; Jeon, I. Org. Lett. 2006, 8, 5315-
5316.
(21) Ma, S.; Zhang, J. Tetrahedron 2003, 59, 6273-6283.
Org. Lett., Vol. 9, No. 18, 2007
3557

employing Me2AlCl (1 equiv) as a “proton-scavenging”
Lewis acid (Scheme 6).24
abstracts a hydride26 from 16 to give rise to 12 and a new
benzylic cation (17), from which the naphthalene 13 is
generated by proton loss.
While the cis diastereoselectivity of the formation of 12
certainly results from the hydride donor 16 to approaching
the cation 15 from the less hindered face (Figure 4), the
Scheme 6. Cyclization of 11 under “Aprotic” Conditions
Much to our satisfaction, the envisioned trans-dehydro-
calamenene 1 was formed under these conditions in almost
quantitative yield and with very good diastereoselectivity (up
to 10:1), if benzene was used as a solvent.25 In dichloro-
methane or 1,2-dichloroethane somewhat lower trans/cis
selectivities were obtained (3:1 and 5:1, respectively).
The trans configuration of the main product (1) was
unambiguously proven by comparing its NMR data with
those reported by Wahyouno.7 In addition, a spectrum of an
authentic sample of cis-16a,22 allowed its reliable identification
as the minor isomer in the mixture. As a most characteristic
feature, the signals of the two olefinic protons (isopropenyl
side chain) are strongly split in the trans isomer (4.21 and
4.83 ppm) while they are virtually isochronic (4.92 ppm) in
the cis isomer.
Figure 4. Diastereoselective hydride transfer between a dihydro-
naphthalene and a benzylic cation (red).
preferred formation of the trans-configurated product 1 in
the Me2AlCl-mediated cyclization of 11 is not easily
explained. Actually, the stereochemical outcome contradicts
the prediction of Kraus23 that the cationic cyclization should
proceed via a chairlike transition state (with the benzylic
methyl group taking a pseudoaxial position to avoid allylic
strain) to give a cis product.
The surprising formation of 12 and 13 from 11 can be
rationalized in terms of the mechanistic picture given in
Scheme 7. At first, proton-catalyzed double bond migration
In conclusion, we have elaborated a stereoselective
synthetic route to the nonracemic trans-calamenene 1 (6
linear steps and 57% overall yield starting from 3). The novel
combination of (1) catalytic asymmetric hydroboration, (2)
double homologation, and (3) Suzuki coupling may prove
of value for other applications, as does the new chiral P,P-
ligand 7. Moreover, a remarkable trans-selective cationic
cyclization was achieved, and important insight into the
chemical and stereochemical aspects of the proton-catalyzed
disproportionation process23 was gained.
Scheme 7. Suggested Mechanism of the Formation of
Compounds 12 and 13 from 11
Acknowledgment. This work was supported by the
European Commission (Ligbank) and the Fonds der
Chemischen Industrie. We thank Ingo Weidner and Janna
Velder, University of Cologne, for preparing and providing
ligand 7.
Supporting Information Available: Experimental pro-
cedures and analytical data. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL071228V
(24) Snider, B. B.; Rodini, D. J.; Karras, M.; Kirk, T. C.; Deutsch, E.
A.; Cordova, R.; Price, R. T. Tetrahedron 1981, 37, 3927-3934.
(25) The quality of the Me2AlCl (1 M in hexanes or 0.9 M in heptane)
is very important. At least 1 equiv of active reagent seems to be necessary
to achieve full conversion. An excess of reagent usually leads to lower
selectivity. Also, reagent taken from a freshly opened bottle gave the product
with a diastereomeric ratio of only 6:1.
(26) For a recent treatment of hydride transfer reactions between
carbocations and unsaturated organic compounds, see: (a) Mayr, H.; Lang,
G.; Ofial, A. R. J. Am. Chem. Soc. 2002, 124, 4076-4083. (b) Wu¨rthwein,
E.-U.; Lang, G.; Schappele, L. H.; Mayr, H. J. Am. Chem. Soc. 2002, 124,
4084-4092.
leads from the primary cyclization product (1) to its isomers
14 and 16. In the key disproportionation step, the benzylic
cation 15 formed by protonation of either 14 or 16 now
3558
Org. Lett., Vol. 9, No. 18, 2007