An Approach to Serrulatane Diterpenes via endo-Selective Conjugate Nucleophilic Addition to Arene-Cr(CO)3 Complexes

Article abstract of DOI:10.1021/ol026827a

(Matrix Presented) Starting from a nonracemic planar-chiral arene tricarbonyl chromium complex, the serrulatane diterpenoid (+)-20-methoxy-serrulat-14-en-7,8-diol was synthesized in a highly stereoselective fashion. The key step of the synthesis is an end

Full text of DOI:10.1021/ol026827a

ORGANIC
LETTERS
2002
Vol. 4, No. 22
3915-3918
An Approach to Serrulatane Diterpenes
via endo-Selective Conjugate
Nucleophilic Addition to Arene-Cr(CO)3
Complexes
Florian Dehmel, Johann Lex, and Hans-Gu1nther Schmalz*
Institut fu¨r Organische Chemie, UniVersita¨t zu Ko¨ln, Greinstrasse 4,
D-50939 Ko¨ln, Germany
schmalz@uni-koeln.de
Received August 30, 2002
ABSTRACT
Starting from a nonracemic planar-chiral arene tricarbonyl chromium complex, the serrulatane diterpenoid (+)-20-methoxy-serrulat-14-en-7,8-
diol was synthesized in a highly stereoselective fashion. The key step of the synthesis is an endo-selective conjugate nucleophilic addition
of lithio-methylphenyl sulfone to a 1-ethylidene-tetralin-Cr(CO)3 derivative. By employing different substrates and nucleophiles it was shown
that the surprising and rather general endo selectivity must result from a unique complex induced proximity effect under participation of the
Cr(CO)3 moiety.
Serrulatane diterpenes, such as 1, 2, and 3 (Figure 1), were
isolated from the leaves of certain Eremphila bushes occur-
ring in western Australia.1 These compounds are structurally
related but stereochemically different to some marine diter-
penoids, i.e., the helioporins2 and the seco-pseudopterosins,3
which show an epimeric structure at C-11 and an opposite
absolute configuration. Despite their interesting structural and
biological features, such serrulatanes have received only little
recognition by synthetic chemists in the past and only a single
total synthesis of a racemic compound (rac-3) has been
reported in the literature.4 This may reflect the difficulty of
setting up the three stereocenters with the correct relative
and absolute configuration.
We here report a short, efficient, and completely stereo-
selective entry toward compounds related to 1 by exploiting
arene-Cr(CO)3 chemistry.5 Moreover, we show that the
unusual endo selectivity of conjugate nucleophilic addition6
(1) (a) Ghisalberti E. L. Phytochemistry 1994, 35, 7. (b) Tippett, L. M.;
Massy-Westropp, R. A. Phytochemistry 1993, 33, 417. (c) Forster, P. G.;
Ghisalberti, E. L.; Jefferies, P. R.; Poletti, V. M.; Whiteside, N. Phytochem-
istry 1986, 25, 1477. (d) Croft, K. D.; Ghisalberti, E. L.; Jefferies, P. R.;
Stuart, A. D. Aust. J. Chem. 1979, 32, 2079. (e) Croft, K. D.; Ghisalberti,
E. L.; Jefferies, P. R.; Proudfoot, G. M. Aust. J. Chem. 1981, 34, 1951.
(2) (a) Tanaka, J.-i.; Ogawa, N.; Liang, J.; Higa, T.; Gravalos, D. G.
Tetrahedron 1993, 49, 811. For the revision of the configurational
assignment of the helioporins, see: (b) Geller, T.; Jakupovic, J.; Schmalz,
H.-G. Tetrahedron Lett. 1998, 39, 1541. (c) Ho¨rstermann, D.; Schmalz,
H.-G.; Kociok-Ko¨hn, G. Tetrahedron 1999, 55, 6905. (d) Lazerwith, S. E.;
Johnson, T. W.; Corey, E. J. Org. Lett. 2000, 2, 2389.
Figure 1. Structures of selected natural serrulatanes (1, 2, and 3)1
and of 11-epi-helioporin B (4).2
(3) Look, S. A.; Fenical, W. Tetrahedron 1987, 43, 3363.
10.1021/ol026827a CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/03/2002

to 1-ethylidene-tetralin-Cr(CO)3 derivatives, used as a key
step in this synthesis, is rather general and must result from
an unprecedented attracting interaction of the nucleophile
with the metal carbonyl unit.
On the basis of the experience we had collected during
our previous work on the syntheses of 11-epi-helioporin B
(4)7 and the nor-seco-pseudopterosin aglycon,8 we considered
complex 5 as a suitable precursor for 1 and related
compounds. We envisioned that 5 could be prepared by
nucleophilic addition/protonation from the 1-ethylidene-
tetralin complex 6, which in turn should be accessible via 7
starting from the planar-chiral building block 8 (Scheme 1).
Figure 2. Stereochemical course of the nucleophilic endo addition
to 6 and subsequent protonation
Scheme 1. Retrosynthetic Analysis
(protection) of the most acidic aromatic position. Benzylic
alkylation of 11 with n-BuLi and chloromethyl(methyl)ether
(MOMCl) and subsequent (in situ) desilylation with TBAF/
H2O afforded 12 as a sole regio- and diastereomer. The
aromatic methyl substituent was finally introduced by another
deprotonation/alkylation sequence to afford the envisioned
key intermediate 6 in good overall yield (Scheme 2).
Scheme 2. Synthesis of the Key Intermediate 6a
While the configuration at C-1 would be controlled by
Cr(CO)3-assisted benzylic exo alkylation,9 the question was
whether the attack of a suitable nucleophile would again oc-
cur in an endo fashion, as it was observed for a related sub-
strate in the above-mentioned synthesis of 4.7 As shown in
Figure 2, such an endo addition of a nucleophile to 6 would
result in the formation of a Cr(CO)3-stabilized benzylic anion
of type 9, which on protonation (from the exo face) would
give rise to a product of type 10 possessing exactly the con-
figuration found in natural serrulatanes such as 1, 2, and 3.
Applying the protocols developed before in the enantio-
meric series,7 the readily accessible, optically active complex
(+)-8 () 96% ee)10 was converted into the 1-ethylidene
derivative 11 by CeCl3-mediated addition of vinylmagnesium
chloride, vinylogous ionic hydrogenation, and silylation
a Key: (a) CH2dCHMgCl, CeCl3, THF; (b) Et3SiH, Me2AlCl/
EtAlCl2, CH2Cl2; (c) n-BuLi, TMSCl, THF; 35-65% (3 steps);
(d) n-BuLi, THF/HMPA (12:1), -70 to 0 °C, 1.5 h then MOMCl,
-78 °C, 0.5 h; then H2O, TBAF, 0 °C, 1.5 h; (e) n-BuLi, THF,
-78 °C, 1 h then MeI; 65% (2 steps).
Treatment of 6 with 2-lithio-acetonitrile (prepared from
MeCN and LDA in THF) in dioxane/HMPA at 5 °C afforded
a mixture of the diastereomeric conjugate addition products
13a/13b (d.r. ) 12:1; HPLC) in 43% yield. Additionally,
significant amounts (36%) of the nucleophilic ipso-substitu-
tion product 14 were obtained (Scheme 3).11 When lithio-
methylphenyl sulfone was used as a nucleophile under similar
conditions, the diastereomerically pure endo addition product
15 was formed in good yield, and only traces of a substitution
product corresponding to 14 could be detected by NMR.
The stereochemical assignments were unambiguously
confirmed by X-ray crystallography of the (main) addition
products 13a and 15.
(4) Uemura, M.; Nishimura, H.; Minami, T.; Hayashi, Y. J. Am. Chem.
Soc. 1991, 113, 5402.
(5) For recent overviews on arene-Cr(CO)3 chemistry, see: (a) Schmalz,
H.-G.; Siegel, S. In Transition Metals for Fine Chemicals and Organic
Synthesis; Bolm, C., Beller, M., Eds.; VCH: Weinheim, 1998; Vol. 1. (b)
Hegedus, L. S. Transition Metals in the Synthesis of Complex Organic
Molecules, 2nd ed.; University Science Books, 1999; Chapter 10.
(6) For exo-selective conjugate nucleophilic addition in arene-Cr(CO)3
chemistry, see: (a) Semmelhack, M. F.; Seufert, W.; Keller, L. J. Am. Chem.
Soc. 1980, 102, 6584. (b) Uemura, M.; Minami, T.; Hayashi, Y. J. Chem.
Soc., Chem. Commun. 1982, 1193.
(7) Dehmel, F.; Schmalz, H.-G. Org. Lett. 2001, 3, 3579.
(11) Byproducts resulting from SNAr reactions of OMe groups are
occasionally observed in arene-Cr(CO)3 chemistry; see for instance: (a)
Reference 7. (b) Rose-Munch, F.; Chavingnon, R.; Tranchier, J.-P.;
Gagliardini, V.; Rose, E. Inorg. Chim. Acta 2000, 300-302, 693. For recent
reviews see: (c) Rose-Munch, F.; Gagliardini, V.; Renard, C.; Rose, E.
Coord. Chem. ReV. 1998, 178-180, 249. (c) Rose-Munch, F.; Rose, E.
Eur. J. Inorg. Chem. 2002, 1269.
(8) Majdalani, A.; Schmalz, H.-G. Tetrahedron Lett. 1997, 38, 4545.
(9) For a review, see: Davies, S. G.; McCarthy, T. D. In ComprehensiVe
Organometallic Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, G.,
Eds.; Pergamon Press: New York, 1995; Vol. 12, p 979.
(10) Schmalz, H.-G.; Millies, B.; Bats, J. W.; Du¨rner, G. Angew. Chem.
1992, 104, 640; Angew. Chem., Int. Ed. Engl. 1992, 31, 631.
3916
Org. Lett., Vol. 4, No. 22, 2002

Scheme 3a
Figure 3. Two conformers of 6 in the crystalline state.
a Key: (a) LiCH2CN, 1,4-dioxane/HMPA (5:1), 5 °C, 1 h, then
NH4Cl/H2O, rt, 43% of 13a/13b (d.r. ) 12:1); 36% of 14; (b)
LiCH2SO2Ph, 1,4-dioxane/HMPA (5:1), 5 °C to room temperature,
4 h (d.r. > 97:3); (c) sunlight, air, MTBE, rt, 55% (over 2 steps).
indicates some hindrance of the exo attack by the pseudoaxial
methoxymethyl substituent. However, it is not obvious at
all why the endo attack should be favored for steric reasons,
even in the one conformer (Figure 3, right) where the
ethylidene unit is deviated out of the aromatic plane away
from the shielding Cr(CO)3 tripod.
To investigate the influence of the pseudoaxial substituent
on the selectivity in the conjugate addition to 1-ethylidene-
tetralin-Cr(CO)3 derivatives such as 6, we decided to employ
related compounds lacking a shielding benzylic substituent
(Scheme 5).
Having found suitable conditions for performing the
crucial conjugate addition to 6, the sulfone 16, obtained from
the primary addition product 15 by decomplexation, was
further converted as shown in Scheme 4.
Scheme 4a
Scheme 5
a Reagents and conditions: (a) n-BuLi, THF/HMPA (10:1), -78
°C, 1.5 h, then prenyl bromide, -78 °C, 15 min, 82% (d.r. ) 3:1);
(b) Na/Hg (5% Na), MeOH/THF (1:1), rt, 18 h, 84%; (c) LiSEt,
DMF, 145 °C, 4h, 99%.
Initial attempts to react complex ent-77 with the nucleo-
philes used above resulted in the exclusive formation of
nucleophilic substitution products related to 14. However,
the methylated derivative 20a (prepared from ent-7 with
n-BuLi/MeI) underwent the desired conjugate addition to
afford mixtures of the endo and exo products 21a and 22a
in acceptable yields (Scheme 5, Table 1). Only minor
amounts ()15%) of nucleophilic substitution products were
formed in these cases. The unsubstituted (parent) 1-ethyl-
idene-tetralin complex 20b also reacted with nucleophiles
in a conjugate fashion.
The completion of the side chain (as it is found in 1) was
achieved by R-alkylation of the sulfone function with prenyl
bromide to give 17 as a mixture of diastereomers. Desulfur-
ization with sodium amalgam provided the trimethoxy-
serrulatane 18 in good yield. Treatment of 18 with LiSEt in
refluxing DMF12 cleanly led to cleavage of the aryl methyl
ethers providing (+)-19 ([R]D +17.2, c 0.51 in CHCl3) in
almost quantitative yield (Scheme 4).13 This way, the
monomethyl ether of 1 was synthesized from the chiral
building block 8 in only 10 steps with 15% overall yield.
Having thus demonstrated the power of the chosen strategy
for the efficient and highly stereoselective synthesis of
serrulatanes of type 1, we were still puzzled about the nature
of the observed endo selectivity in the nucleophilic addition
to the double bond of 6.14
As suitable nucleophiles, a series of lithiated nitriles and
lithio-methylphenyl sulfone were studied. While certain
reactions proceeded smoothly in THF, mixtures of THF or
1,4-dioxane with HMPA were necessary in most cases to
(13) Initial attempts to cleave all three methoxy groups in 18 in one
step (using reagents such as BBr3, TMSI, or AlCl3/DMS) were not
successful.
(14) It is a generally accepted rule in arene-Cr(CO)3 chemistry that
nucleophiles attack the ligand from the exo face. For rare exceptions, see
ref 7 as well as: (a) Schmalz, H.-G.; Jope, H. Tetrahedron 1998, 54, 3457.
(b) Sarkar, A.; Ganesh, S.; Sur, S.; Mandal, S. K.; Swamy, V. M.; Maity,
B. C.; Kumar, T. S. J. Organomet. Chem. 2001, 624, 18.
On first glance, one may be tempted to explain the
observed endo selectivity using simple steric arguments.7
Indeed, the X-ray crystal structure of substrate 6 (Figure 3)
(12) LiSEt was prepared from n-BuLi and EtSH, see also ref 2b.
Org. Lett., Vol. 4, No. 22, 2002
3917

Table 1. Results of the Nucleophilic Additions Employing
Substrates 20a and 20b According to Scheme 5a
yield
ratioc
entry substrate
Li-Nuc
conditionsa (%)b
21/22
1
2
3
4
5
6
7
8
9
20a
20a
20a
20a
20b
20b
20b
20b
20b
LiCH2CN
A
A
B
C
C
A
B
A
C
39
57
68
82
72
47
75
86
62
92:8
>98:2
78:22d
35:65
>98:2
82:18
>98:2d
15:85
10:90
LiCH2SO2Ph
LiCH(TMS)CN
LiCMe2CN
LiCH2CN
LiCH2SO2Ph
LiCH(TMS)CN
LiCMe2CN
LiCMe2CN
Figure 4. Preferred endo addition through precoordination of the
nucleophile to a carbonyl ligand.
assume that the (smaller) nucleophiles are guided to the endo
face of the double bond through coordination of the lithium
atom to a carbonyl ligand (Figure 4). While such complex
induced proximity effects16 are rather common in reactions
of organolithium compounds with organic molecules bearing
polar functional groups, it has (to the best of our knowledge)
never been observed that carbonyl ligands of arene-Cr(CO)3
complexes are able to participate in such processes.17
In summary, we have explored the stereochemical course
of conjugate nucleophilic additions to 1-ethylidene-tetralin-
Cr(CO)3 complexes and have corroborated the surprising
endo preference as a rather general phenomenon. While the
synthetic value of such reactions was demonstrated in an
efficient synthesis of a serrulatane diterpenoid, mechanistic
considerations led to the identification of a unique endo-
directing role of the Cr(CO)3 group, i.e., the active participa-
tion of a carbonyl ligand as a lithium-coordinating site.
a A: Li-Nuc, 1,4-dioxane/HMPA (5:1), 5 °C to rt, 1.5 to 16 h (TLC
control). B: Li-Nuc, THF/HMPA (5:1), -78 °C to rt, 2.5 to 4 h (TLC
control). C: Li-Nuc, THF, -78 °C to room temperature, 1.5 to 4 h;
b Isolated yield of the purified diastereomeric mixture. c Determined by 1H
NMR. d Determined by H NMR after desilylation (CsF, MeCN).
1
obtain significant conversions. The results of the various
experiments are summarized in Table 1.
The stereochemical assignments are based on X-ray crystal
structure analyses of compounds 21a (Nuc ) CH2SO2Ph),
22a (Nuc ) CMe2CN), and 22b (Nuc ) CMe2CN) in
combination with NMR spectroscopic correlations.
As shown in Table 1 all the reactions employing LiCH2-
CN, LiCH2SO2Ph, or LiCH(TMS)CN15 as a nucleophile
proceeded with a pronounced endo selectivitysin analogy
to the results obtained with substrate 6. Only with LiCMe2-
CN as a sterically more demanding nucleophile were the exo
products preferentially formed.
These results allow the conclusion that the substituent in
the benzylic position (as in 6) exerts no significant influence
on the stereochemical course of the addition reactions.
Moreover, it becomes apparent that the unusual endo
selectivity cannot be attributed to steric effects, as the
(“normal”) exo pathway becomes predominant with increas-
ing bulkiness of the nucleophile.
Acknowledgment. This work was supported by the
Deutsche Forschungsgemeinschaft and the Fonds der Che-
mischen Industrie (Kekule´ stipend for F. D.). We thank Dr.
Hans Schmickler for NMR spectroscopic support. Generous
gifts of chemicals from Chemetall AG and Degussa AG are
highly appreciated.
Supporting Information Available: Experimental pro-
cedures and characteristic data for all new compounds and
details of the X-ray crystal structure analyses of compounds
6, 13a, 15, ent-7, 21a (Nuc ) CH2SO2Ph), 22a (Nuc )
CMe2CN), and 22b (Nuc ) CMe2CN). This material is
available free of charge via the Internet at http://pubs.acs.org.
The preference for the endo attack must consequently
result from an attracting interaction (kinetic effect). We
OL026827A
(15) With this nucleophile, the crude addition product was protodesily-
lated (CsF in CH3CN) prior to purification; compare: (a) Tomioka, K.;
Hagiwara, A.; Kaga, K. Tetrahedron Lett. 1988, 29, 3095. (b) Brummond,
K. M.; Liu, J. Org. Lett. 2001, 3, 1347. (c) Paquette, L. A.; Friedrich, D.;
Pinard, E.; Williams, J. P.; Laurent, D. St.; Roden, B. A. J. Am. Chem.
Soc. 1993, 115, 4377.
(16) Beak, P.; Meyers, A. I. Acc. Chem. Res. 1986, 19, 356.
(17) Very recently, it was shown that carbonyl ligands of arene-Cr(CO)3
complexes are also able to act as acceptors for H-bonds: Camiolo, S.; Coles,
S. J.; Gale, P. A.; Hursthouse, M. B.; Mayer, T. A.; Paver, M. A. Chem.
Commun. 2000, 275.
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Org. Lett., Vol. 4, No. 22, 2002