Total synthesis of polyoxygenated cembrenes

Article abstract of DOI:10.1002/anie.200800626

(Chemical Presented) A convergent approach for the stereoselective construction of polyoxygenated cembrenes is reported. Key steps in the synthesis are an asymmetric domino multicomponent allylation, a modified Myers a-alkylation, and a ring-closing metathesis.

Full text of DOI:10.1002/anie.200800626

Communications
DOI: 10.1002/anie.200800626
Natural Product Synthesis
Total Synthesis of Polyoxygenated Cembrenes**
Lutz F. Tietze,* C. Christian Brazel, Sören Hölsken, Jörg Magull, and Arne Ringe
Dedicated to Professor Helmut Schwarz on the occasion of his 65th birthday
Numerous new biologically active and structurally interesting
diterpenes containing a characteristic oxygenated 14-mem-
bered carbon ring system, which is derived formally from (+)-
cembrene (1),[1] have been isolated from terrestrial and
marine sources over the last few years (Scheme 1).[2] The
Retrosynthetically, cembrene 3 may be broken down into
the two almost equally sized building blocks 5 and 6 that can
be coupled with one another by a nucleophilic epoxide
opening (Scheme 2).[7] The tertiary alcohol function in 5 can
Scheme 1. (+)-Cembrene and oxygenated derivatives.
oxygenated cembrenes display amongst others anti-HIV
activity, anti-inflammatory properties, and neuro- and cyto-
toxicity.[3] Sarcophytol A (2), isolated from soft coral, for
example inhibits tumor growth and serves as the lead
structure for the development of other pharmacologically
active compounds.[4]
It is therefore essential for ongoing investigations that
efficient strategies are developed for the synthesis of oxy-
genated, especially the more complex polyoxygenated, cem-
brenes,[5] which would allow general access to differently
substituted compounds, and thereby make them available for
testing. We describe here a stereoselective total synthetic
access to the bicyclic polyoxygenated cembrene 3 with six
stereogenic elements and four oxygen atoms. Compound 3
was structurally characterized as part of biosynthetic studies
on polyoxygenated cembrenes occurring in Greek tobacco
plants.[6] In addition an epimer of compound 3 was prepared.
Scheme 2. Retrosynthetic analysis of compound 3.
be constructed in a highly stereoselective domino multi-
component allylation[8] of the aliphatic ketone 8, whereas the
dithiane 6 is accessible by a modified Myers alkylation.[9] The
14-membered macrocycle is constructed by ring-closing
metathesis.[10] The benzyl ether 10 with d.r. = 95:5 is obtained
by allylation of the ketone 8 with the silyl ether 9[8c] and allyl
silane
7 under trifluoromethanesulfonic acid catalysis
(Scheme 3). Reductive cleavage of the benzyl group with
subsequent p-methoxybenzyl protection of the resulting
tertiary alcohol and Sharpless dihydroxylation[11] afforded
the diol 11 with d.r. = 91:9, which was transformed into the
epoxide 5.[12]
In the construction of the building block 6, initially a
diastereoselective a-alkylation of the pseudoephedrine amide
16 with the triflate 13 was carried out, followed by oxidation
of the secondary alcohol function to give the ketoamide 17,
which could be enriched to d.r. = 99:1 by crystallization
(Scheme 4).[9a] Triflate 13 was synthesized in quantitative
yield from 12 by reaction with Tf2O, and amide 16 was
accessible from 14 in 94% yield by acylation with the acid
chloride 15. Reductive amide cleavage of 17 with LDA and a
borane–ammonia complex,[9] and oxidation of the primary
alcohol to the aldehyde with subsequent Wittig–Horner
[*] Prof. Dr. Dr. L. F. Tietze, Dipl.-Chem. C. C. Brazel, Dr. S. Hölsken
Institut für Organische und Biomolekulare Chemie
Georg-August-Universität Göttingen
Tammannstrasse 2, 37077 Göttingen (Germany)
Fax: (+49)551-399-476
E-mail: ltietze@gwdg.de
Prof. Dr. J. Magull, Dipl.-Chem. A. Ringe
Institut für Anorganische Chemie
Georg-August-Universität Göttingen
Tammannstrasse 4, 37077 Göttingen (Germany)
[**] This work was supported by the Deutsche Forschungsgemeinschaft
and the Fonds der Chemischen Industrie. We thank BASF, Bayer-
Schering, Evonik, Symrise, and Wacker for the provision of
chemicals.
Supporting information for this article is available on the WWW
under http://www.angewandte.com or from the author.
5246
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 5246 –5249

Angewandte
Chemie
olefination led to the a,b-unsaturated ester 18 in 79 % yield
over three steps. Compound 18 was reduced to the allyl
alcohol with DIBAL-H, then oxidized to the a,b-unsaturated
aldehyde with MnO2, and subsequently converted into the
dithiane 6 with propane-1,3-dithiol.
The secondary alcohol 19 was then obtained in 92% yield
from the dithiane 6 and the epoxide 5 by nucleophilic epoxide
opening[7] and was converted into the primary alcohol 20 by
acetylation and cleavage of the silyl protecting group
(Scheme 5). Compound 20 was oxidized to the corresponding
aldehyde in 88% yield by using SO3·pyridine under mild
Parikh–Doering conditions[13] and subsequently converted
directly to the triene 21 by a Wittig carbonyl olefination in
89% yield. Only decomposition occurred under Dess–Martin,
Swern, and TPAP oxidation conditions, presumably owing to
the sensitivity towards oxidation of the dithiane and p-
methoxybenzyl ether groups in 20. The ring-closing meta-
thesis was carried out with the Grubbs catalyst 22[14]
(7 mol%) and provided the macrocycle 23 as a uniform Z
diastereoisomer in an astonishingly good yield of 89%.
The orientation of the newly formed double bond and the
relative configuration of the stereogenic centers in 23 were
determined unambiguously by X-ray structure analysis.[15]
The absolute configurations of the stereogenic centers in 23
were derived from the known configurations of 10 and 17.[8,9a]
Since the corresponding stereogenic centers in the product 23
have an R configuration at C-10 and an S configuration at C-
17 as in 10 and 17, respectively, it is also confirmed that no
intermediate isomerization has occurred. The use of other
catalysts for the metathesis, such as the Fürstner catalyst
Neolyst M1,[16] afforded complex mixtures of dimers. Inter-
estingly, the protective groups of the hydroxy groups at C-8
and C-10 have a large influence upon the metathesis. No ring-
closure could be achieved by using a triisopropylsilyl group at
C-8, which is presumably attributable to steric reasons.
For the diastereofacial introduction of the methyl groups
at C-1 of ketone 4 it was necessary to carry out a reprotection
of the macrocycle 23 by using the sterically demanding
triisopropylsilyl protecting group at C-13. For this purpose the
acetyl group was removed under basic conditions, and the
resulting secondary alcohol was converted over two steps to
24 with triisopropylsilyl triflate in 80% yield. Subsequent
oxidative cleavage of the p-methoxybenzyl ether with
dichloro-5,6-dicyano-p-benzoquinone and of the dithiane
with bis(trifluoroacetoxy)iodobenzene[17] led to the ketone 4
in 80% yield over two steps. Ketone 4 was epoxidized
regioselectively with dimethyldioxirane[18] leading to the
formation of two diastereoisomers 25a and 25b in a ratio of
40:60. Under acidic conditions, the main diastereoisomer 25b
underwent a nucleophilic intramolecular epoxide ring open-
ing leading to 26, which contains a tetrahydrofuran moiety
(Scheme 6).[19]. A regioselective 1,2-addition of methyl-
lithium to the carbonyl group in 26, which however in spite
of the sterically demanding triisopropylsilyl group at the
neighboring position took place with only low diastereose-
lectivity, led to the diols 27 and 28 in a ratio of 40:60. As
expected, the main product 28 was formed by an attack anti to
the substituent at C-3.[20] Fortunately, it was possible to
separate the two diastereoisomers 27 and 28. The final steps in
Scheme 3. a) 20 mol% TfOH, CH2Cl2, ꢀ196!ꢀ908C; b) Li, DBBP,
=
THF, ꢀ78!ꢀ458C, 71% over 2 steps; c) PMBOC( NH)CCl3, 7 mol %
La(OTf)3, toluene, RT, 77%; d) 1 mol % K2OsO2(OH)4, 5 mol%
(DHQD)2Pyr, K3[Fe(CN)6], K2CO3, tBuOH/H2O (1:1), 08C; e) PivCl,
pyridine, CH2Cl2, 08C!RT, 64% over 2 steps; f) MsCl, NEt3, cat.
DMAP, CH2Cl2, RT, 83%; g) K2CO3, MeOH, RT, quant. DBBP=4,4’-di-
tert-butylbiphenyl, (DHQD)2Pyr=hydroquinidine-(2,5-diphenyl-4,6-pyri-
midinediyl)diether, DMAP=4-(dimethylamino)pyridine, Ms=methane-
sulfonyl, Piv=pivalyl, PMB=4-methoxybenzyl, THF=tetrahydrofuran,
Tf =trifluoromethanesulfonyl.
Scheme 4. a) Tf2O, CH2Cl2, ꢀ78!08C; b) NEt3, THF, 08C, 97%;
c) LDA, LiCl, THF, ꢀ788C!RT, then 13, ꢀ78!ꢀ208C, 83% over 2
steps; d) (COCl)2, DMSO, CH2Cl2, ꢀ788C, then NEt3, RT, 79%;
e) BH3·NH3, LDA, THF, 08C!RT, 89%; f) IBX, DMSO, MS 4 Š, RT,
quant.; g) (EtO)2P(O)CH2CO2Et, NaH, THF, 08C!RT, 89%; h) DIBAL-
H, CH2Cl2, ꢀ788C, quant.; i) MnO2, CH2Cl2, RT; j) HS(CH2)3SH,
BF3·Et2O, Et2O, ꢀ408C, 75% over 2 stages. DIBAL-H=diisobutylalu-
minum hydride, DMSO=dimethyl sulfoxide, IBX=1-hydroxy-1,2-ben-
ziodoxol-3(1H)-one 1-oxide, LDA=lithium diisopropylamide, MS=mo-
lecular sieves.
Angew. Chem. Int. Ed. 2008, 47, 5246 –5249ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5247

Communications
Since NOE investigations on
the molecules to determine the
relative configuration of the
newly formed stereogenic cen-
ters were generally poorly pre-
dictive, an X-ray structure anal-
ysis was carried out on the final
product 3.[21]. Compound 3 was
synthesized in an overall yield of
2.7% over 24 steps; this corre-
sponds to an average yield of
86% for each step. The analyt-
ical data of the synthetic mate-
rial is identical to that for the
polyoxygenated cembrene de-
scribed by Wahlberg et al.[6,22]
.
In conclusion, by using ring-
closing metathesis for the con-
struction of the 14-membered
carbon ring, a stereoselective
Tietze allylation and a stereose-
lective Myers alkylation, we
have developed a new and effi-
cient route to complex polyoxy-
genated cembrenes, which offers
a high degree of flexibility in
respect of stereochemical varia-
tions and functionalization.
Scheme 5. a) 6, nBuLi, THF, HMPA, ꢀ78!ꢀ558C, then 5, THF, ꢀ558C!RT, 92%; b) Ac2O, pyridine,
cat. DMAP, RT, quant.; c) TBAF·3H2O, THF, RT, quant.; d) SO3·pyridine, NEt3, DMSO, RT, 88%;
e) KHMDS, Ph3PMeBr, THF, ꢀ788C, then 08C, 89%; f) 7 mol % 22, CH2Cl2, 408C, 89%; g) NaOMe,
MeOH, Et2O, 408C, 89%; h) TIPSOTf, 2,6-lutidine, CH2Cl2, 08C, 90%; i) DDQ, CH2Cl2, buffer pH 7, 08C,
81%; j) (CF3CO2)2IPh, MeOH/THF/H2O (10:5:1), RT, 99%. DDQ=2,3-dichloro-5,6-dicyano-p-benzoqui-
none, HMPA=hexamethylphosphoric triamide, KHMDS=potassium bis(trimethylsilyl)amide, TBAF=
tetra-n-butylammonium fluoride, TIPS=triisopropylsilyl.
Received: February 7, 2008
Published online: June 4, 2008
Keywords: allylation ·
.
cembrenes · epoxidation ·
metathesis · terpenoids
[1] W. G. Dauben, W. E. Thies-
sen, P. R. Resnick, J. Am.
Chem. Soc. 1962, 84, 2015 –
2016.
[2] a) J. R. Hanson, Nat. Prod.
Rep. 2006, 23, 875 – 885;
b) J. R. Hanson, Nat. Prod.
Rep. 2005, 22, 594 – 602; c) I.
Wahlberg, C. R. Enzell, Nat.
Prod. Rep. 1987, 4, 237 – 276.
[3] a) M. I. Nieto, N. Gonzµlez, J.
Rodríguez, R. G. Kerr, C.
JimØnez, Tetrahedron 2006,
62, 11747 – 11754; b) P. Rad-
hika, P. R. Rao, J. Archana,
N. K. Rao, Biol. Pharm. Bull.
Scheme 6. a) DMDO, acetone, CH2Cl2, ꢀ858C; b) 10 mol % CSA, CH2Cl2, ꢀ78!08C, 49% for 26 over 2
steps via 25b, 40% for 25a; c) MeLi, Et2O, ꢀ1108C!RT, 30% for 27, 45% for 28; d) TBAF·3H2O, THF,
RT; e) 10 mol % TPAP, NMO, MS 4 Š, CH2Cl2, RT, 74% for 29 over 2 steps, 77% for 3 over 2 steps.
DMDO=dimethyldioxirane, TPAP=tetra-n-butylammonium perruthenate, NMO=N-methylmorpholine
N-oxide.
2005,
28,
1311 – 1313;
c) A. D. Rodríguez, I. C.
Piæa, A. L. Acosta, C. L.
Barnes, Tetrahedron 2001, 57, 93 – 107; d) M. A. Rashid, K. R.
Gustafson, M. R. Boyd, J. Nat. Prod. 2000, 63, 531 – 533.
the synthesis of the polyoxygenated cembrene 3 comprised
cleavage of the TIPSgroup and oxidation of the resulting
secondary alcohol to the ketone in 73% yield over two steps
by using tetra-n-butylammonium perruthenate and N-meth-
ylmorpholine-N-oxide. The diastereoisomer 29 was obtained
analogously from 27.
[4] a) I. Katsuyama, H. Fahmy, J. K. Zjawiony, S. I. Khalifa, R. W.
Kilada, T. Konoshima. M. Takasaki, H. Tokuda, J. Nat. Prod.
2002, 65, 1809 – 1814; b) T. Zhang, Z. Liu, Y. Li, Synthesis 2001,
5248
www.angewandte.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 5246 –5249

Angewandte
Chemie
393 – 398; c) J. Lan, Z. Liu, H. Yuan, L. Peng, W.-D. Z. Li, Y. Li,
Y. Li, A. S. C. Chan, Tetrahedron Lett. 2000, 41, 2181 – 2184.
[5] M. A. Tius, Chem. Rev. 1988, 88, 719 – 732.
[6] I. Wahlberg, I. Forsblom, C. Vogt, A.-M. Eklund, T. Nishida,
C. R. Enzell, J.-E. Berg, J. Org. Chem. 1985, 50, 4527 – 4538.
[7] a) A. B. Smith III, S. M. Pitram, A. M. Boldi, M. J. Gaunt, C.
Sfouggatakis, W. H. Moser, J. Am. Chem. Soc. 2003, 125, 14435 –
14445; b) L. F. Tietze, H. Geissler, J. A. Gewert, U. Jakobi,
Synlett 1994, 511 – 512; c) B.-T. Gröbel, D. Seebach, Synthesis
1977, 357 – 402.
[14] M. Scholl, S. Ding, C. W. Lee, R. H. Grubbs, Org. Lett. 1999, 1,
953 – 956.
[15] Single-crystal structure analysis of compound 23: C32H48O4S2,
monoclinic, space group P2(1), T= 133(2) K, a = 11.0076(5), b =
9.2718(3), c = 30.9119(16) Š, V= 3133.3(2) Š3, Z = 2, 1 =
1.189 Mgmꢀ3, R1 = 0.0582, wR2 = 0.0662.[21]
[16] a) A. Fürstner, O. Guth, A. Düffels, G. Seidel, M. Liebl, B.
Gabor, R. Mynott, Chem. Eur. J. 2001, 7, 4811 – 4820; b) A.
Fürstner, Angew. Chem. 2000, 112, 3140 – 3172; Angew. Chem.
Int. Ed. 2000, 39, 3012 – 3043.
[8] a) L. F. Tietze, T. Kinzel, S. Schmatz, J. Am. Chem. Soc. 2008,
130, 4386 – 4395; b) L. F. Tietze, T. Kinzel, S. Schmatz, J. Am.
Chem. Soc. 2006, 128, 11483 – 11495; c) L. F. Tietze, S. Hölsken,
J. Adrio, T. Kinzel, C. Wegner, Synthesis 2004, 2236 – 2239.
[9] a) L. F. Tietze, C. Raith, C. C. Brazel, S. Hölsken, Synthesis 2008,
229 – 236; b) A. G. Myers, B. H. Yang, H. Chen, L. McKinstry,
D. J. Kopecky, J. L. Gleason, J. Am. Chem. Soc. 1997, 119, 6496 –
6511.
[10] A. Gradillas, J. PØrez-Castells, Angew. Chem. 2006, 118, 6232 –
6247; Angew. Chem. Int. Ed. 2006, 45, 6086 – 6101.
[11] a) Q.-H. Fan, Y.-M. Li, A. S. C. Chan, Chem. Rev. 2002, 102,
3385 – 3466; b) H. C. Kolb, M. S. VanNieuwenhze, K. B. Sharp-
less, Chem. Rev. 1994, 94, 2483 – 2547.
[17] G. Stork, K. Zhao, Tetrahedron Lett. 1989, 30, 287 – 290.
[18] M. Gibert, M. Ferrer, F. Sµnchez-Baeza, A. Messeguer, Tetrahe-
dron 1997, 53, 8643 – 8650.
[19] A. D. Rodríguez, J. J. Soto, C. L. Barnes, J. Org. Chem. 2000, 65,
7700 – 7702.
[20] P. C. Astles, E. J. Thomas, J. Chem. Soc. Perkin Trans. 1 1997,
845 – 856.
[21] Single-crystal structure analysis of compound 3: C20H34O4,
monoclinic, space group P2(1), T= 133(2) K, a = 6.3368(5), b =
13.5693(10), c = 11.4017(8) Š, V= 971.21(13) Š3, Z = 2, 1 =
1.157 Mgmꢀ3, R1 = 0.0589, wR2 = 0.1008. CCDC-676776 (23)
and CCDC-676777 (3) contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif..
[12] a) A. B. Smith III, D.-S. Kim, J. Org. Chem. 2006, 71, 2547 – 2557;
b) L. A. Paquette, J. Chang, Z. Liu, J. Org. Chem. 2004, 69,
6441 – 6448.
[13] J. R. Parikh, W. v. E. Doering, J. Am. Chem. Soc. 1967, 89, 5505 –
5507.
[22] Rotation of the synthesized compound 3: [a]2D0 = + 39.48 (c =
0.35, chloroform); literature value: [a]2D0 = + 388 (c = 0.18,
chloroform).[6]
Angew. Chem. Int. Ed. 2008, 47, 5246 –5249ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5249