The catalytic asymmetric total synthesis of elatol

Article abstract of DOI:10.1021/ja710294k

Described in this report is the first total synthesis of elatol, a halogenated sesquiterpene in the chamigrene natural product family. The key disconnections in our synthetic approach include an enantioselective decarboxylative allylation to form the all-carbon quaternary stereocenter and a ring-closing olefin metathesis to concomitantly form the spirocyclic core as well as the fully substituted chlorinated olefin. This strategy represents a general platform for accessing the chamigrene natural product family, as demonstrated by the synthesis of (+)-laurencenone B as an intermediate in our route. Copyright

Full text of DOI:10.1021/ja710294k

Published on Web 12/29/2007
The Catalytic Asymmetric Total Synthesis of Elatol
David E. White, Ian C. Stewart, Robert H. Grubbs, and Brian M. Stoltz*
DiVision of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125
Received November 13, 2007; E-mail: stoltz@caltech.edu
The chamigrene subclass of sesquiterpenes, characterized by a
spiro[5.5]undecane core, is an ever-growing family of natural
products (Figure 1).1 Well over 100 members have been isolated
thus far, and many of these compounds exhibit a diverse array of
biological activity.1c In particular, elatol (1),2 one of the most widely
studied chamigrenes, displays antibiofouling activity,3a,b antibacterial
activity (including human pathogenic bacteria),3c-e antifungal
activity,3f and cytotoxicity against HeLa and Hep-2 human carci-
noma cell lines.3g Despite the interesting bioactivity and compact
structure of these molecules, no general strategy for their preparation
has been developed, and to the best of our knowledge, no total
synthesis of elatol has been reported in the 33 years since its original
isolation.4,5
Figure 1. Examples of chamigrene natural products.
Scheme 1
Structurally, elatol (1) consists of a densely functionalized A
ring bearing three stereocenters, including an all-carbon quaternary
stereocenter, which is vicinal to a second, nonstereogenic quaternary
carbon. Within the B ring is also a fully substituted chlorinated
olefin. We envisioned a strategy toward these challenging motifs
based on methodological advances recently reported by our
laboratories. Specifically, enantioselective decarboxylative allyla-
tion6 could generate the all-carbon quaternary stereocenter, while
ring-closing metathesis (RCM)7 could be employed to concomi-
tantly provide the tetrasubstituted olefin and the spirocyclic core
of 1 (Scheme 1). Importantly, this approach serves as a general
platform to access the chamigrene family.
We envisioned 1 to ultimately arise from sequential reductive
olefin transposition and diastereoselective reduction of R-bromoke-
tone 10. In turn, compound 10 would be obtained from bromination
of the enone resulting from 1,2-addition of a methyl anion to
spirocycle 11. Intermediate 11 itself could be the product of RCM
of R,ω-diene 12. Although generation of a fully substituted
chlorinated olefin via RCM has not been previously reported,8 we
anticipated that the improved reactivity of catalyst 227 (vide infra)
might be sufficient for this transformation. Access to 12 would be
possible via enantioselective decarboxylative allylation of an
appropriately substituted vinylogous ester derivative (i.e., 13),
employing the Pd(0) complex of a phosphinooxazoline (PHOX)
ligand. This would constitute a previously unexplored substrate class
with this catalyst system.9 Finally, enol carbonate 13 could be
derived from commercially available dimedone (14).
Our synthetic efforts began with the condensation of isobutyl
alcohol and dimedone (14) to provide known vinylogous ester 15
(Scheme 2).10 Direct alkylation of vinylogous ester 15 with 4-iodo-
2-methyl-1-butene was sluggish; however, a two-step procedure
involving conjugate addition to methyl vinyl ketone (MVK)
followed by Wittig methylenation afforded olefin (()-16 in good
yield. Selective enolization of vinylogous ester (()-16 and trapping
with chloroformate 17 allowed access to enol carbonate 13 in 73%
yield. In our initial attempt, application of our standard reaction
conditions11 for Pd-catalyzed asymmetric alkylation to enol carbon-
ate 13 provided desired alkylation adduct (+)-12, but in low yield.12
We reasoned that the poor reactivity of enol carbonate 13 in the
enantioselective allylation reaction could stem from one of three
possibilities: (1) slow oxidative addition to the allyl carbonate
moiety, (2) slow decarboxylation to reveal the active enolate
Scheme 2a
a dmdba ) bis(3,5-dimethoxybenzylidene)acetone.
intermediate, or (3) slow alkylation of the enolate intermediate to
provide the desired product 12. In order to discern between these
scenarios, we ran a set of control reactions outlined in Scheme 3.
Exposure of enol carbonate 13 to conditions developed in our
laboratories for enantioselective decarboxylative protonation13 led
to rapid formation of olefin 16.14 Furthermore, removal of the
2-chloro substituent on the allyl fragment resulted in facile
decarboxylative allylation of enol carbonate 19 to yield bis(olefin)
20. On the basis of these results, we concluded that slow alkylation,
not slow oxidative addition or decarboxylation, was most likely
the problematic step in this transformation.
In order to enhance the reactivity of our π-allyl Pd(II) electro-
phile, we attempted to increase its electrophilicity by incorporating
electron-withdrawing substituents into the PHOX ligand frame-
work.15 Ultimately, asymmetric alkylation employing ligand 21 in
benzene at 11 °C afforded the best balance between reactivity and
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J. AM. CHEM. SOC. 2008, 130, 810-811
10.1021/ja710294k CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3a
References
(1) (a) Erickson, K. L. Constituents of Laurencia. In Marine Natural
Products: Chemical and Biological PerspectiVes; Scheuer, P. J., Ed.;
Academic Press: New York, 1983; Vol. V, pp 131-257. (b) Dorta, A.;
D´ıaz-Marrero, A. R.; Cueto, M.; D’Croz, L.; Mate´, J. L.; Darias, J.
Tetrahedron Lett. 2004, 45, 7065-7068.
(2) Originally isolated from the marine alga Laurencia elata: Sims, J. J.;
Lin, G. H. Y.; Wing, R. M. Tetrahedron Lett. 1974, 15, 3487-3490.
(3) (a) Granado, I.; Caballero, P. Sci. Mar. 1995, 59 (Supl. 1), 31-39. (b)
de Nys, R.; Leya, T.; Maximilien, R.; Afsar, A.; Nair, P. S. R.; Steinberg,
P. D. Biofouling 1996, 10, 213-224. (c) Mart´ın, J. D.; Pe´rez, C.; Ravelo,
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G. M.; Wright, A. D. J. Nat. Prod. 1997, 60, 967-970. (g) HeLa: IC50
) 4.1 mM (lag phase), 1.3 mM (log phase); Hep-2: IC50 ) 2.4 mM (lag
phase), 2.0 mM (log phase); Dias, T.; Brito, I.; Moujir, L.; Paiz, N.; Darias,
J.; Cueto, M. J. Nat. Prod. 2005, 68, 1677-1679.
a Conditions: (a) HCO2H, Pd(OAc)2 (10 mol %), 18 (12.5 mol %), MS
4 Å, benzene, 40 °C, (b) Pd(dmdba)2 (10 mol %), 18 (13 mol %), benzene,
40 °C.
Scheme 4
(4) For the preparation of elatol (1) via the degradation of iso-obtusol, see:
(a) Gonza´lez, A. G.; Darias, J.; D´ıaz, A.; Fourneron, J. D.; Mart´ın, J. D.;
Pe´rez, C. Tetrahedron Lett. 1976, 17, 3051-3054. (b) Gonza´lez, A. G.;
Mart´ın, J. D.; Mart´ın, V. S.; Mart´ınez-Ripoll, M.; Fayos, J. Tetrahedron
Lett. 1979, 20, 2717-2718. (c) Gonza´lez, A. G.; Mart´ın, J. D.; Mart´ın,
V. S.; Norte, M.; Pe´rez, R. Tetrahedron Lett. 1982, 23, 2395-2398.
(5) For lead references on the total syntheses of other chamigrene natural
products, see: (a) Taber, D. F.; Sikkander, M. I.; Storck, P. H. J. Org.
Chem. 2007, 72, 4098-4101. (b) Srikrishna, A.; Lakshmi, B. V.; Mathews,
M. Tetrahedron Lett. 2006, 47, 2103-2106. (c) Chen, Y.-J.; Wang, C.-
Y.; Lin, W.-Y. Tetrahedron 1996, 52, 13181-13188. (d) Hatsui, T.; Wang,
J.-J.; Takeshita, H. Bull. Chem. Soc. Jpn. 1994, 67, 2507-2513. Also see
ref 3c.
(6) (a) Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 15044-
15045. (b) Mohr, J. T.; Behenna, D. C.; Harned, A. M.; Stoltz, B. M.
Angew. Chem., Int. Ed. 2005, 44, 6924-6927.
(7) Stewart, I. C.; Ung, T.; Pletnev, A. A.; Berlin, J. M.; Grubbs, R. H.;
Schrodi, Y. Org. Lett. 2007, 9, 1589-1592.
(8) For the preparation of trisubstituted chloroalkenes via RCM, see: (a) Chao,
W.; Weinreb, S. M. Org. Lett. 2003, 5, 2505-2507. (b) Chao, W.; Meketa,
M. L.; Weinreb, S. M. Synthesis 2004, 2058-2061. For the preparation
of a fully substituted vinyl fluoride via RCM, see: (c) Marhold, M.; Buer,
A.; Hiemstra, H.; van Maarseveen, J. H.; Haufe, G. Tetrahedron Lett.
2004, 45, 57-60.
selectivity, providing vinylogous ester 12 in 82% yield and 87%
ee (Scheme 4). Gratifyingly, when R,ω-diene 12 was subjected to
our standard RCM reaction conditions with catalyst 22, the desired
fully substituted chloroalkene (+)-11 was produced in 97% yield.16
Addition of methyllithium in the presence of CeCl3 then provided
(+)-laurencenone B ((+)-7)17 after acid-mediated elimination and
hydrolysis.18 Enone (+)-7 was subsequently bis-halogenated with
Br2 to generate dibromide 10 in g8:1 dr.19 Finally, the crude
R-bromoketone 10 was doubly reduced with DIBAL to afford elatol
(1) (3.9:1 syn:anti,20 11:1 SN2′:SN2). Overall, enantioenriched (+)-
laurencenone B ((+)-7) was prepared in seven steps and 34% yield
from dimedone (14), while enantioenriched (+)-elatol (1) was
prepared in nine steps and 11% yield.21
We have successfully developed a concise enantioselective route
to the chamigrene natural product family, culminating in the first
total syntheses of elatol (1) and (+)-laurencenone B ((+)-7), as
well as the first preparation of a fully substituted chlorinated olefin
via RCM. Moreover, we have demonstrated the ability of the key
enantioselective alkylation reaction to access sterically encumbered
enantioenriched vinylogous esters. The application of these methods
to the syntheses of other chamigrene natural products and a full
exploration of both vinylogous esters in enantioselective decar-
boxylative alkylation and vinyl chlorides in RCM are the focus of
ongoing studies.
(9) Trost has recently reported the use of vinylogous ester and thioester
derivatives in enantioselective decarboxylative allylation using a chiral
bis(phosphine)-Pd(0) complex: Trost, B. M.; Bream, R. N.; Xu, J. Angew.
Chem., Int. Ed. 2006, 45, 3109-3112.
(10) House, H. O.; Fischer, W. F., Jr. J. Org. Chem. 1968, 33, 949-956.
(11) Use of Pd2(dba)3 in lieu of Pd(dmdba)2 led to significantly less conversion.
(12) For convenience, the enantioselective allylation reaction with 13 was
optimized in the opposite enantiomeric series.
(13) Mohr, J. T.; Nishimata, T.; Behenna, D. C.; Stoltz, B. M. J. Am. Chem.
Soc. 2006, 128, 11348-11349.
(14) A separate experiment revealed no reactivity in the absence of a Pd(0)
catalyst.
(15) For preliminary results on the rate acceleration of enantioselective
decarboxylative allylation of enol carbonates with electron-deficient PHOX
ligands, see: Tani, K.; Behenna, D. C.; McFadden, R. M.; Stoltz, B. M.
Org. Lett. 2007, 9, 2529-2531.
(16) (H2IMes)(PCy3)(Cl)2RudCHPh produced significant product for this
transformation under similar reaction conditions (2.5 mol% catalyst, C6D6,
60 °C), but at a slower rate than catalyst 22: 85% conversion after 24 h
as measured by 1H NMR .
(17) (a) For the isolation of laurencenone B (7) from the marine alga Laurencia
obtusa, see: Kennedy, D. J.; Selby, I. A.; Thomson, R. H. Phytochemistry
1988, 27, 1761-1766. Neither the absolute configuration nor the optical
rotation was specified. (b) For the preparation of (+)-laurencenone B ((+)-
7) via the degradation of elatol (1), see: Brennan, M. R.; Erickson, K. L;
Minott, D. A.; Pascoe, K. O. Phytochemistry 1987, 26, 1053-1057.
(18) Discrepancies between the published 1H NMR data for the natural product
(ref 17a) and that of the synthetic material exist. No 13C NMR data was
available for comparison. 1H and 13C NMR data for semisynthetic (+)-
laurencenone B ((+)-7) (ref 17b) matched that of our synthetic material.
See the supporting information for a detailed comparison.
(19) Purification of R-bromoketone 10 was hampered by its poor stability to
silica gel and reverse phase HPLC.
(20) Determined by quenching the reaction at -78 °C in a separate run, result-
ing in the isolation a 3.9:1 mixture of alcohol diastereomers favoring i.
Acknowledgment. We thank the NIH-NIGMS (R01 GM080269-
01, R01 GM31332-05, postdoctoral fellowships to D.E.W. and
I.C.S.), Abbott, Amgen, Bristol-Myers Squibb, Merck, and Caltech
for generous funding; Materia, Inc. for their kind donation of
catalyst 22 used in these studies; Professors Mercedes Cueto and
Karen L. Erickson for their kind donation of natural samples of
elatol (1); Brinton Seashore-Ludlow for experimental assistance;
and Professor Peter B. Dervan and David M. Chenoweth for use
of their HPLC.
(21) Synthetic (+)-elatol ((+)-1) was identical in all respects to a natural sample
provided by Prof. Mercedes Cueto except for the magnitude of its optical
rotation: [R]23 +92.09° (c 0.22, CHCl3, synthetic), [R]25 +109.78° (c
0.045, CHCl3, Dnatural). Based on 87% ee, the expected [R]DD value for the
synthetic material would be +95.5°, which differed from the observed
value by 3.6%.
Supporting Information Available: Experimental details. This
material is available free of charge via the Internet at http://pubs.acs.org.
JA710294K
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