Direct synthesis of (+)-erogorgiaene through a kinetic enantiodifferentiating step

Article abstract of DOI:10.1002/anie.200462227

(Chemical Equation Presented) The combined approach of C-H activation and a Cope rearrangement catalyzed by a rhodium catalyst [Rh₂(R-dosp) ₄] (dosp = (N-dodecylbenzenesulfonyl)prolinate) is shown to be a very effective method for the construction of the three stereogenic centers (marked in red, see scheme) present in the diterpene erogorgiaene (1).

Full text of DOI:10.1002/anie.200462227

Angewandte
Chemie
Natural Product Synthesis
a reaction that is notable for its very high diastereoselectivity
and enantioselectivity.[5] Application of this methodology to
the retrosynthetic analysis of (+)-erogorgiaene revealed that
the unsaturated ester 6 would be a very desirable precursor to
1. Reaction of the vinyldiazoacetate 5 with the dihydronaph-
thalene (S)-4 would be expected to readily form 6 with the
desired relative stereochemistry (Scheme 2).
Direct Synthesis of (+)-Erogorgiaene through a
Kinetic Enantiodifferentiating Step**
Huw M. L. Davies* and Abbas M. Walji
(+)-Erogorgiaene is a member of the marine diterpenes
isolated from the West Indian sea whip Pseudopterogorgia
elisabethae and displays promising activity against Mycobac-
terium tuberculosis H37Rv.[1] Several important biologically
active secondary metabolites have been isolated from the
Pseudopterogorgia corals.[2] Consequently, there has been
extensive activity directed towards the synthesis of these
natural products.[3] Even though these compounds are not
especially complex, a major challenge associated with their
synthesis has been the control of the three stereocenters
(marked in red, 1–3, Scheme 1), common to all of them. The
Scheme 2. Retrosynthetic analysis of (+)-erogorgiaene (1).
During the analysis of this synthetic problem, we recog-
nized that the synthesis offered a very exciting opportunity for
enantiomer differentiation, such that the racemic dihydro-
naphthalene (Æ )-4 could be used as starting material. Even
though the exact mechanism of these carbenoid reactions is
not known, we have developed models that are excellent at
predicting the stereochemical outcome of this chemistry.[5b,6]
Applying these models to the [Rh2(R-dosp)4]-catalyzed
reaction of (Æ )-4 with 5, it was revealed that only (S)-4
À
would be capable of a matched combined C H activation/
Cope rearrangement to form 6 whereas (R)-4 would be
matched for a cyclopropanation to form 7 (Scheme 3). This
Scheme 1. Diterpenes isolated from Pseudopterogorgia elisabethae.
stereocontrol has been challenging because of the lack of
functional groups near to the stereogenic centers. This has
meant that many of the syntheses have been very lengthy with
considerable functional group interconversions, and even
then the stereocontrol has been less than satisfactory.[3] The
only reported synthesis of (+)-erogorgiaene (1), described by
Hoveyda and co-workers, employed a chiral-catalyst-control-
led conjugate addition in a sequential manner to set up the
desired stereocenters.[4]
Here we illustrate through the enantioselective synthesis
of (+)-erogorgiaene (1) a potentially general strategy to the
synthesis of this class of diterpenes. The key step is our
À
recently discovered combined C H activation/Cope rear-
rangement
catalyzed
by
dirhodium
tetraprolinate
[Rh2(dosp)4] (dosp = (N-dodecylbenzenesulfonyl)prolinate),
[*] Prof. H. M. L. Davies, A. M. Walji
Department of Chemistry
À
Scheme 3. Stereochemical prediction for combined C H activation/
Cope rearrangement strategy.
University at Buffalo
The State University of New York
Buffalo, NY 14260-3000 (USA)
Fax: (+1)716-645-6547
would be a very exciting outcome because the dihydronaph-
thalene (Æ )-4 could potentially be used as the limiting agent,
as both enantiomers would be consumed but would form
different products.
To test this possibility, the reaction of dihydronaphthalene
8 with the phenylvinyldiazoacetate 9 was used as a model
reaction (Scheme 4). We were delighted that the reaction
E-mail: hdavies@acsu.buffalo.edu
[**] This work was supported by the National Science Foundation (CHE-
0092490). We thank Oksana O. Gerlits for the X-ray crystallographic
analysis.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2005, 44, 1733 –1735
DOI: 10.1002/anie.200462227
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1733

Communications
reaction catalyzed by [Rh2(R-dosp)4] is truly exceptional and
À
results in a 1:1 mixture of the combined C H activation
product 6 and the cyclopropane 7 with just a trace of the
diastereomer 13. Furthermore, 6 was formed in 90% ee.
The synthesis of (+)-erogorgiaene (1) was readily com-
pleted as illustrated in Scheme 6. Owing to the tendency of 6
Scheme 4. Preliminary modeling studies and determination of absolute
configuration: ORTEP drawing of 12. DCC=dicyclohexyl carbodiimide,
DMAP=4-dimethylaminopyridine.
Scheme 6. Total synthesis of (+)-erogorgiaene (1). PCC=pyridinium
chlorochromate.
catalyzed by [Rh2(S-dosp)4] gave a 1:1 mixture of the
À
combined C H activation/Cope rearrangement product 10
and the cyclopropane 11 in a combined yield of 80%.
Remarkably, both products were produced in 98% ee and
essentially as single diastereomers. The relative and absolute
stereochemistry of 10 was confirmed by conversion of 10 into
the crystalline p-bromobenzoate 12 whose configuration was
confirmed by X-ray crystallography.[7]
Having successfully completed the model studies, atten-
tion was then directed towards the total synthesis of
erogorgiaene. The key step is the rhodium-catalyzed reaction
between the vinyldiazoacetate 5 and the dihydronaphthalene
(Æ )-4 (Scheme 5). A comparison between the reaction of 5
to undergo a retro-Cope rearrangement, the combined
mixture of 6 and 7 was globally hydrogenated, and the ester
was reduced to the alcohol 14, which was isolated in 31%
overall yield from the dihydronapthalene (Æ )-4 (62% yield
from the matched enantiomer (R)-4). Oxidation of 14 to the
aldehyde with pyridinium chlorochromate (PCC) followed by
a Wittig reaction completed the total synthesis of (+)-
erogorgiaene (1).
À
In summary, we have demonstrated that the combined C
H activation/Cope rearrangement protocol is an exceptional
method for the construction of the three stereogenic centers
common to the numerous diterpenes isolated from Pseudop-
terogorgia elisabethae. The synthetic potential of this chemis-
try was demonstrated by means of a very direct synthesis of
erogorgiaene. Further studies are in progress to apply this
methodology to other members of this class of diterpenes.
Received: October 6, 2004
Revised: December 8, 2004
Published online: February 11, 2005
À
Keywords: C H activation · enantioselectivity ·
natural products · terpenoids · total synthesis
.
Scheme 5. Influence of catalyst [Rh2(R-dosp)4] on product distribution.
with (Æ )-4 catalyzed by either rhodium octanoate or [Rh2(R-
dosp)4] is very informative because it demonstrates the
important role of [Rh2(R-dosp)4] not only to induce the
[1] A. D. Rodriguez, C. Ramirez, J. Nat. Prod. 2001, 64, 100 – 102.
Erogorgiaene displayed 96% inhibition of Mycobacterium tuber-
culosis H37Rv at 12.5 mgmLÀ1
.
À
enantioselectivity but also to achieve an effective C H
[2] a) S. A. Look, W. Fenical, R. S. Jacobs, J. Clardy, Proc. Natl. Acad.
Sci. USA 1986, 83, 6238 – 6240; b) A. D. Rodriguez, Y.-P. Shi,
Tetrahedron 2000, 56, 9015 – 9023; c) A. D. Rodriguez, Tetrahe-
dron 1995, 51, 4571 – 4618, and references therein.
[3] Selected examples: Pseudopterosins: E. J. Corey, S. E. Lazerwith,
J. Am. Chem. Soc. 1998, 120, 12777 – 12782; Pseudopteroxazole:
transformation. The reaction between 5 and (Æ )-4 catalyzed
by rhodium(ii) octanoate results in the formation of only a
À
trace of the combined C H activation/Cope rearrangement
product 6. The major products are the diastereomeric cyclo-
propanes 7 and 13 (as racemic mixtures). In contrast, the
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Chemie
J. P. Davidson, E. J. Corey, J. Am. Chem. Soc. 2003, 125, 13486 –
13489; Elisabethins: T. J. Heckrodt, J. Mulzer, J. Am. Chem. Soc.
2003, 125, 4680 – 4681; Colombiasin A: a) K. C. Nicolaou, S. A.
Synder in Classics in Total Synthesis II, Wiley-Interscience,
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[6] a) D. T. Nowlan III, T. M. Gregg, H. M. L. Davies, D. A. Single-
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[7] O. O. Gerlits, P. Coppens, Private Communication, 2004. CCDC-
242585 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.a-
c.uk/data_request/cif.
[4] R. R. Cesati, J. De Armas, A. H. Hoveyda, J. Am. Chem. Soc.
2004, 126, 96 – 101.
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