Palladium-catalyzed enantioselective cyclization of silyloxy-1,6-enynes

Article abstract of DOI:10.1021/ja068723r

The enantioselective intramolecular addition of silyl enol ethers and silyl ketene aminals onto alkyne is described. The reaction employs DTBMSegphos-Pd(II) or Binaphane-Pd(II) complexes as catalysts for the formation of methylene cyclopentane adducts fro

Full text of DOI:10.1021/ja068723r

Published on Web 02/17/2007
Palladium-Catalyzed Enantioselective Cyclization of Silyloxy-1,6-Enynes
Britton K. Corkey and F. Dean Toste*
Department of Chemistry, UniVersity of California, Berkeley, California 94720
Received December 5, 2006; E-mail: fdtoste@berkeley.edu
Transition-metal-catalyzed cycloisomerization and cyclization
reactions of enynes have emerged as powerful methods for the
construction of hetero- and carbocyclic compounds.1 More recently,
enantioselective cycloisomerization of 1,6- and 1,7-enynes has been
employed in the preparation of enantioenriched 1,4-diene containing
structures.2-4 Despite its potential utility, the related enantioselective
cycloisomerization of heteroatom-substituted alkenes5 has not been
While the use of ((R)-DTBM-Segphos)Pd(OTf)2 as a catalyst
reported. Herein we report the first enantioselective cyclization
reactions of 1,6-enynes containing silyloxy-substituted olefins.
On the basis of our recent report on palladium-catalyzed enantio-
selective 5-exo-dig addition of 1,3-dicarbonyl compounds to
alkynes,6 we hypothesized that similar catalysts might promote the
enantioselective cycloisomerization of silyl enol ethers. To this end,
reaction of silyl enol ethers 1a (3:1 Z:E) and 1b (2:1 Z:E) catalyzed
by 10 mol % of ((R)-DTBM-Segphos)Pd(OTf)2 (A) cleanly afforded
methylene cyclopentane 2 in 63 and 77% ee, respectively (eq 1).
Furthermore, diastereomerically pure (E)-1b afforded 2 with greater
enantioselectivity (81% ee) than the corresponding (Z)-isomer (74%
ee). The enantioselectivity was further improved to 91% ee by
employing tert-butyldimethylsilyl enol ether (E)-1c.
provided modest enantioselectivities when non-aryl-substituted enol
ethers were employed, we were pleased to find that ((R)-Binaphane)-
Pd(OH2)2(OTf)2 (B)16 is a highly active and selective catalyst for
the cyclization of a greater range of substrates (Table 1, entries
5-10). For example, cyclization of indolyl enol ether 9 catalyzed
by 10 mol % of A cleanly afforded 10 but with only 7% ee, whereas
the same reaction catalyzed by 5% B gave ketone 10 in 89% ee
(entry 5). Moreover, whereas reactions with catalyst A usually
required 10% loading and several hours to complete, reactions
catalyzed by 5% B generally took place in minutes. Most notably,
Table 1. Enantioselective Pd-Catalyzed Cyclizationa
The fact that the silyloxy substituent and the olefin geometry
impact the enantioselectivity of the reaction (eq 1) suggests that
the silyl enol ether is intact during the enantiodetermining event.
We envisioned two potential mechanisms consistent with this
observation: (1) enantioselective addition of the enol ether to the
electrophilic Pd complex and the resulting C-bonded Pd enolate7
undergoes stereospecific8 insertion into the pendent acetylene or
(2) addition of the enol ether onto a Pd(II) activated alkyne.9,10
Given the ease with which Pd enolates undergo protonation,11 the
observation that very little hydrolysis of the enol ether occurs during
the cyclization reaction suggests these intermediates are not involved
in this reaction.12,13 Therefore, we propose that the latter mechanism
is operative in the Pd-catalyzed cyclization. Additionally, the
proposed transition state (TS)14 for this pathway accounts for the
observation that (E)-1d, in which the aryl group is placed under
the forming five-membered ring in TS, reacted significantly slower
than (Z)-1d.15 Moreover, in TS, the olefin substituents are larger
than the alkyl group regardless of the olefin geometry; therefore,
the same enantiomer is obtained from either olefin isomer.
Initial investigation of the reaction scope indicated that tert-
butyldimethylsilyl enol ethers derived from aryl ketones underwent
efficient cyclization giving methylene cyclopentane adducts with
good to excellent enantioselectivities (Table 1, entries 1-4).
Notably, the potentially enolizable tertiary stereocenter in 4 was
formed with good enantioselectivity (entry 2).
a Conditions A: 10% A, rt, 0.02 M 100:1 Et2O/AcOH; B: 5% B, rt,
0.02 M 100:1 Et2O/AcOH. b Conditions: 10% A, 0 °C, 0.02 M 100:1 Et2O/
AcOH. c Conditions: 5% B, rt, 0.02 M 100:1 dichloromethane/AcOH as
solvent. Enol ethers shown are the major isomer obtained from the
corresponding ketone (see Supporting Information).
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J. AM. CHEM. SOC. 2007, 129, 2764-2765
10.1021/ja068723r CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Total Synthesis of (-)-Laurebiphenyla
catalyst B and compound 23 (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
References
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4104. (b) Lie, A.; Waldkirch, J. P.; He, M.; Zhang, X. Angew. Chem.,
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2002, 124, 8198. (d) Lie, A.; He, M.; Zhang, X. J. Am. Chem. Soc. 2003,
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Ito, Y. Angew. Chem., Int. Ed. Engl. 1996, 35, 662. (g) Hatano, M.; Terada,
M.; Mikami, K. Angew. Chem., Int. Ed. 2001, 40, 249. (h) Hatano, M.;
Mikami, K. J. Am. Chem. Soc. 2003, 125, 4704. For a review, see: (i)
Fairlamb, I. J. S. Angew. Chem., Int. Ed. 2004, 43, 1048.
(3) For enantioselective alkoxycyclization of enynes, see: (a) Charruault, L.;
Michelet, V.; Taras, R.; Gladiali, S.; Geneˆt, J.-P. Chem. Commun. 2004,
850. (b) Mun˜oz, M. P.; Adrio, J.; Carretero, J. C.; Echavarren, A. M.
Organometallics 2005, 24, 1293.
a Reagents and conditions: (a) TEA, TBS-OTf, CH2Cl2, 72% Z, 19%
E; (b) 10% A, Et2O, HOAc, rt, 96% yield, 95% ee (91% recovered catalyst
after recrystallization); (c) 10% Pd(OAc)2, 22% PPh3, HCO2H, TEA, DMF,
80 °C, 96%; (d) CF3C(O)OOH, BF3•Et2O, CH2Cl2, -10°C, 48% (59%
brsm); (e) LAH, THF; (f) K2CO3, MeI, DMF; (g) Dess-Martin periodinane,
NaHCO3, CH2Cl2, 81% over three steps; (h) TsNHNH2, HCl, MeOH, 73%
(84% brsm); (i) NaH, o-dichlorobenzene, 160 °C, 2 min; then Br2, CH2Cl2,
68%; (j) t-BuLi, 0.5 equiv of CuCN, tetramethylquinone, Et2O, -78 °C to
rt, 51%; (k) NaH, EtSH, DMF, 150 °C, 70%.
(4) For a recent report of enantioselective cycloisomerization of dienes, see:
Feducia, J. A.; Campbell, A. N.; Doherty, M. Q.; Gagne´, M. R. J. Am.
Chem. Soc. 2006, 128, 13290.
(5) For recent examples of transition-metal-promoted reaction of silyl enol
ethers with alkynes, see: (a) Maeyama, K.; Iwasawa, N. J. Am. Chem.
Soc. 1998, 120, 1928. (b) Imamura, K.; Yoshikawa, E.; Gevorgyan, V.;
Yamamoto, Y. Tetrahedron Lett. 1999, 40, 4081. (c) Iwasawa, N.;
Maeyama, K.; Kusama, H. Org. Lett. 2001, 3, 3871. (d) Iwasawa, N.;
Miura, T.; Kiyota, K.; Kusama, H.; Lee, K.; Lee, P. H. Org. Lett. 2002,
4, 4463. (e) Nevado, C.; Ca´rdenas, D. J.; Echavarren, A. M. Chem.sEur.
J. 2003, 9, 2627. (f) Staben, S. T.; Kennedy-Smith, J. J.; Huang, D.;
Corkey, B. K.; LaLonde, R. L.; Toste, F. D. Angew. Chem., Int. Ed. 2006,
45, 5991.
(6) Corkey, B. K.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 17168.
(7) For recent examples of enantioselective reactions proceeding through
palladium enolates generated from silyl enol ethers, see: (a) Sugiura, M.;
Nakai, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 2366. (b) Haiwara, E.;
Fujii, A.; Sodeoka, M. J. Am. Chem. Soc. 1998, 120, 2474. (c) Fujii, A.;
Haiwara, E.; Sodeoka, M. J. Am. Chem. Soc. 1999, 121, 5450.
(8) For examples of stereospecific insertion of alkynes into Pd(II)-sp3-C
bonds, see: (a) Spencer, J.; Pfeffer, M. Tetrahedron: Asymmetry 1995,
6, 419. (b) Portscheller, J. L.; Lilley, S. E.; Malinakova, H. C. Organo-
metallics 2003, 22, 2961.
(9) A related mechanism involving olefin activation is proposed for the Pd-
(II)-mediated cycloalkenylation. See: Kende, A. S.; Roth, B.; Sanfilippo,
P. J.; Blacklock, T. J. J. Am. Chem. Soc. 1982, 104, 5808.
(10) Alkyne activation by Pd(II) was excluded in isomerization of 1,6-
enynes: (a) Mikami, K.; Hatano, M. Proc. Natl. Acad. Sci. U.S.A. 2004,
101, 5767. In contrast, see: (b) Nevado, C.; Charrualt, L.; Michelet, V.;
Nieto-Oberhuber, C.; Mun˜oz, M. P.; Me´ndez, M.; Rager, M.-N.; Geneˆt,
J.-P.; Echavarren, A. M. Eur. J. Org. Chem. 2003, 706.
the Pd-catalyzed cyclizations to form amides 14 and 16 represent
rare examples of enantioselective catalysis employing O-silyl ketene
aminals.17 Catalyst B also allows for the enantioselective preparation
of spiro-stereocenters (entries 6, 7, 9, and 10). For example, reaction
of 2-silyloxy indole 17a afforded spiro-oxindole 18a in 83% yield
and 91% ee (entry 9).
The utility of the Pd-catalyzed method for enantioselective
formation of all carbon quaternary centers is illustrated in the total
synthesis of (-)-laurebiphenyl (24), a rare example of a dimeric
cyclolaurane-type sesquiterpene (Scheme 1). Originally isolated
from Laurencia nidifica, laurebiphenyl (24) was recently shown
to possess moderate cytotoxicity against a variety of cell lines.18
Conversion of ketone 1919 to the corresponding (Z)-enol ether in
72% yield sets the stage for the Pd-catalyzed enantioselective
cyclization. Treatment of the enol ether with 10% A resulted in
clean conversion to cyclopentane 20 in 95% ee and 96% yield.
Upon completion of the reaction, the Pd catalyst can be recovered,
recrystallized (91% yield), and reused without any loss of activity
(see Supporting Information).
(11) (a) Albe´niz, A. C.; Catalina, N. M.; Espinet, P.; Redo´n, R. Organometallics
1999, 18, 5571. See also: (b) Burkhardt, E. R.; Bergman, R. G.;
Heathcock, C. H. Organometallics 1990, 9, 30.
(12) In contrast to reported Pd-catalyzed enantioselective protonolysis of TMS-
enol ethers,7b racemic ketone 26 was formed in 5% conversion from the
hydrolysis of TBS-enol ether 25.
Ketone 20 was subjected to a reductive Heck cyclization followed
by Baeyer-Villager oxidation to afford lactone 21, which was
converted to aldehyde 22 in three steps. Conversion of aldehyde
22 to the corresponding tosyl hydrazone, followed by diazo
decomposition, gave the crude cyclopropane product, which was
immediately brominated to give 23.20 Ullman coupling of aryl
bromide 23 forged the biaryl bond, and subsequent demethylation
furnished (-)-laurebiphenyl (24).21
(13) Dihydropyran 27, from which Pd enolate formation is unlikely, undergoes
efficient cyclization under similar conditions to afford spiro-bicycle 28.
In conclusion, the first enantioselective Pd-catalyzed addition
of silyl enol ethers and silyl ketene aminals onto alkynes has been
developed. The reaction provides rapid access to highly function-
alized enantioenriched methylene cyclopentane adducts, as exempli-
fied by its application to the preparation of (-)-laurebiphenyl. In
a broader sense, the reactions reported herein significantly extend
the scope of Pd-catalyzed enantioselective enyne cyclization
reactions to include heteroatom and tetrasubstituted olefins.
(14) This proposed transition resembles that calculated for the Pt-catalyzed
cyclization of enol ether with alkynes.5h
(15) Pd-catalyzed reactions of (Z)-1b, 1c, and 1d all required 6-8 h to reach
completion. In contrast, (E)-1d reached 50% conversion after 8 h.
(16) See the Supporting Information for an X-ray structure of complex B.
(17) (a) Trost, B. M.; Brennan, M. K. Org. Lett. 2006, 8, 2027. For examples
employing N,O-enol carbonates, see: (b) Hills, I. D.; Fu, G. Angew. Chem.,
Int. Ed. 2003, 42, 3921. (c) Shaw, S. A.; Aleman, P.; Vedejs, E. J. Am.
Chem. Soc. 2003, 125, 13368. (d) Shaw, S. A.; Aleman, P.; Christy, J.;
Kampf, J. W.; Va, P.; Vedejs, E. J. Am. Chem. Soc. 2006, 128, 925.
(18) (a) Shizuri, Y.; Yamada, K. Phytochemistry 1985, 24, 1385. (b) Sun, J.;
Shi, D.; Ma, M.; Li, S.; Wang, S.; Han, L.; Yang, Y.; Fan, X.; Shi, J.;
He, L. J. Nat. Prod. 2005, 68, 915.
Acknowledgment. We gratefully acknowledge the University
of California, Berkeley, NIHGMS (R01 GM073932-01), Merck
Research Laboratories, Bristol-Myers Squibb, Amgen Inc., DuPont,
GlaxoSmithKline, and Eli Lilly & Co. for financial support. We
thank Takasago for their generous donation of the SEGPHOS
ligands.
(19) Ketone 19 was prepared in four steps from 2-iodo-5-methylbenzoic acid
(see Supporting Information).
(20) The absolute stereochemistry of bromide 23 was determined by X-ray
crystallography (see Supporting Information).
(21) The optical rotation of synthetic 24 ([R]D ) -14.5°) is opposite that of
the natural product ([R]D ) +15.2°).
Supporting Information Available: Experimental procedures,
compound characterization data (PDF), and X-ray structure data for
JA068723R
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