Homologous mukaiyama reactions via trapping of the nazarov intermediate with silyloxyalkenes

Article abstract of DOI:10.1021/ol201125h

Treatment of 1,4-pentadien-3-ones and silyloxyalkenes with BF ₃?OEt₂ at room temperature or lower initiates a domino process consisting of sequential 4π electrocyclization and capture of the resulting cyclopentenyl cation by the elec

Full text of DOI:10.1021/ol201125h

ORGANIC
LETTERS
2011
Vol. 13, No. 14
3584–3587
Homologous Mukaiyama Reactions via
Trapping of the Nazarov Intermediate with
Silyloxyalkenes
Yen-Ku Wu, Robert McDonald,† and F. G. West*
Department of Chemistry, University of Alberta, E3-43 Gunning-Lemieux Chemistry Centre,
Edmonton, AB T6G 2G2, Canada
frederick.west@ualberta.ca
Received April 27, 2011
ABSTRACT
Treatment of 1,4-pentadien-3-ones and silyloxyalkenes with BF3 OEt2 at room temperature or lower initiates a domino process consisting of
3
sequential 4π electrocyclization and capture of the resulting cyclopentenyl cation by the electron-rich trap. The overall process furnishes 1,4-
dicarbonyl products containing highly substituted cyclopentanones in good yields and with the establishment of up to five new stereocenters.
The Nazarov reaction as conventionally practiced en-
tails the treatment of cross-conjugated 1,4-dien-3-ones
with stoichiometric Lewis or Brønsted acid to effect an
electrocyclic closure of the resulting pentadienyl cation,
with termination by elimination to furnish cyclopentenone
products.1 There has been considerable recent interest in
expanding the versatility of this well-established reaction,
including the use of catalytic acid,2 asymmetric induc-
tion,3 unconventional pentadienyl cation precursors,4 and
interception of the cyclized intermediate withelectrophiles5
or nucleophiles.6
In this latter category, while a wide range of traps has
been applied successfully, it is notable that relatively little is
known about the effectiveness of olefins with enolate-like
reactivitytointercept the Nazarov intermediate. Anallenyl
vinyl ketone was shown by Marx and Burnell to react with
(4) Recent examples:(a) Grant, T. N.; West, F. G. J. Am. Chem. Soc.
2006, 128, 9348–9349. (b) Lemiere, G.; Gandon, V.; Cariou, K.; Hours,
A.; Fukuyama, T.; Dhimane, A.-L.; Fensterbank, L.; Malacria, M.
J. Am. Chem. Soc. 2009, 131, 2993–3006. (c) Rieder, C. J.; Winberg,
K. J.; West, F. G. J. Am. Chem. Soc. 2009, 131, 7504–7505. (d) Shimada,
N.; Ashburn, B. O.; Basak, A. K.; Bow, W. F.; Vicic, D. A.; Tius, M. A.
Chem. Commun. 2010, 3774–3775. (e) Bow, W. F.; Basak, A. K.; Jolit,
A.; Vicic, D. A.; Tius, M. A. Org. Lett. 2010, 12, 440–443. (f) Wu, Y. K.;
West, F. G. J. Org. Chem. 2010, 75, 5410–5413. (g) Spencer, W. T., III;
Levin, M. D.; Frontier, A. J. Org. Lett. 2011, 13, 414–417.
(5) (a) Janka, M.; He, W.; Haedicke, I. E.; Fronczek, F. R.; Frontier,
A. J.; Eisenberg, R. J. Am. Chem. Soc. 2006, 128, 5312–5313. (b)
Fujiwara, M.; Kawatsura, M.; Hayase, S.; Nanjo, M.; Itoh, T. Adv.
Synth. Catal. 2009, 351, 123–128. (c) Nie, J.; Zhu, H.-W.; Cui, H.-F.;
Hua, M.-Q.; Ma, J.-A. Org. Lett. 2007, 9, 3053–3056.
† X-ray Crystallographic Lab, Department of Chemistry, University of
Alberta.
(1) Reviews: (a) Pellisier, H. Tetrahedron 2005, 61, 6479–6517.
(b) Frontier, A. J.; Collison, C. Tetrahedron 2005, 61, 7577–7606.
(c) Tius, M. A. Eur. J. Org. Chem. 2005, 2193–2206. (d) Nakanishi,
W.; West, F. G. Curr. Opin. Drug Discov. 2009, 12, 732–751.
(2) (a) Vaidya, T.; Atesin, A. C.; Herrick, I. R.; Frontier, A. J.;
Eisenberg, R. Angew. Chem., Int. Ed. 2010, 49, 3363–3366. (b) He, W.;
Herrick., I. R.; Atesin, T. A.; Caruana, P. A.; Kellenberger, C. A.;
Frontier, A. J. J. Am. Chem. Soc. 2008, 130, 1003–1011. (c) Amere, M.;
Blanchet, J.; Lasne, M.-C.; Rouden, J. Tetrahedron Lett. 2008, 49, 2541–
2545.
(6) (a) Marx, V. M.; Cameron, T. S.; Burnell, D. J. Tetrahedron Lett.
2009, 50, 7213–7216. (b) Rieder, C. J.; Fradette, R. J.; West, F. G.
Heterocycles 2010, 80, 1413–1427. (c) Scadeng, O.; Ferguson, M. J.;
West, F. G. Org. Lett. 2011, 13, 114–117. (d) Marx, V. M.; Lefort, F. M.;
Burnell, D. J. Adv. Synth. Catal. 2011, 353, 64–68. For a recent review,
see:(e) Grant, T. N.; Rieder, C. J.; West, F. G. Chem. Commun. 2009,
5676–5688.
(3) (a) Walz, I.; Togni, A. Chem. Commun. 2008, 4315–4317.
(b) Banaag, A. R.; Tius, M. A. J. Org. Chem. 2008, 73, 8133–8141.
(c) Rueping, M.; Ieawsuwan, W. Adv. Synth. Catal. 2009, 351, 78–84.
(d) Yaji, K.; Shindo, M. Synlett 2009, 2524–2528. (e) Basak, A. K.;
Shimada, N.; Bow, W. F.; Vicic, D. A.; Tius, M. A. J. Am. Chem. Soc.
2010, 130, 8266–8267. (f) Cao, P.; Deng, C.; Zhou, Y. Y.; Sun, X. L.;
Zheng, J. C.; Xie, Z.; Tang, Y. Angew. Chem., Int. Ed. 2010, 49, 4463–
4466. (g) Huang, J.; Leboef, D.; Frontier, A. J. J. Am. Chem. Soc. 2011,
133, 6307–6317.
(7) Marx, V. M.; Burnell, D. J. J. Am. Chem. Soc. 2010, 132, 1685–
1689.
r
10.1021/ol201125h
Published on Web 06/23/2011
2011 American Chemical Society

several enol ethers and a silyl enol ether, providing 1,
4-dicarbonyl adducts and in some cases formal [3 þ 2]-
cycloadducts.7 This result stands in contrast to the earlier
observation that vinyl sulfides primarily undergo 3 þ 2
trapping.8 An important distinction in these cases is the
relative nucleophilicity of the traps, with enol derivatives
lying further to the extreme on the π-nucleophilicity scale
than vinyl sulfides.9 Moreover, allenyl ketones appear to
undergo very rapid Nazarov cyclization, and the cyclized
intermediateisexpected tobelonger-lived due toits greater
conjugative stabilization. With this in mind, we examined
Lewis acid treatment of simple 1,4-dien-3-one substrates in
the presence of silyloxyalkenes as a more appropriate
comparison to the vinyl sulfide results. If trapping were
successful, this tranformation would offer the potential for
establishing up to four stereocenters around the cyclopen-
tanone ring, and possibly a fifth one adjacent to the
exocyclic carbonyl. Such a process would be homologous
with the well-established Mukaiyama addition,10 since
attack by the enol nucleophile would take place R to the
cyclopentanone carbonyl, and would result in versatile 1,
4-dicarbonyl products.11 Here we describe our preliminary
results, consisting of the efficient and regioselective trap-
ping of the Nazarov intermediate derived from a structu-
rally diverse set of dienone substrates using silyl enol
ethers, silyl ketene acetals, and mixed ketene S,O-acetals.
The possibility of competing Mukaiyama Michael addi-
tion to the Lewis acid-activated dienones was a concern,
and so initial studies utilized dibenzylidenepentanone 1a
(Scheme 1), previously demonstrated to undergo rapid
electrocyclization even at low temperature.12 In the event,
Scheme 1. Interrupted Nazarov Reaction of 1a with Silyl Ketene
Acetal 2a
The generality of this domino process with dienones
1aꢀ1e and a variety of oxygenated πꢀnucleophiles 2aꢀ2e
was examined (Table 1). Not unexpectedly, dienone 1a
offered a remarkable reaction profile, in which the inter-
molecular capture of the Nazarov intermediate with di-
methyl ketene acetal 2b, ketene S,O-acetal 2c and silyl enol
ethers 2dꢀ2e13 gave the corresponding ester 3b, thioester
3c, ketone 3d and aldehyde 3e/4e in good to excellent yields
(entries 1ꢀ5). Among these adducts, thioester derivatives
are particularly noteworthy due to the versatility in sub-
sequent functional group manipulations.14 Epimerization
of cisꢀtrans 4e to transꢀtrans 3e readily occurred in the
presence of catalytic amount of base (eq 1). As in the case
with 1a and 2aꢀ2e, interrupted Nazarov reactions of
dienone 1b and electronꢀrich alkenes 2bꢀ2e proceeded
in good yields and excellent diastereoselectivity (entries 6ꢀ8).
Notably, contiguous quaternary centers can be efficiently
created by employing β-disubstituted silyloxyalkenes as
traps to the cyclopentenyl cations derived from symme-
trical dienones 1a and 1b (entries 2, 5 and 6). In general, the
higher reaction temperature was found to be crucial for
Nazarov cyclizations of less reactive substrates 1bꢀ1e in
order tosuppress the undesiredMichael addition pathway.
treatment of 1a with 1.1 equiv of BF3 OEt2 in the presence
3
of silyl ketene acetal 2a at ꢀ78 °C provided adduct 3a
as a single diastereomer in 78% yield. The structural
assignment of 3a was unambiguously determined by
X-ray diffraction analysis. The absence of any Mukaiyama
Michael addition products with the highly nucleophilic 2a
was especially encouraging. The relative stereochemistry
of 3a indicated that 2a approached exclusively anti to the
β-phenyl substitution as shown in transition state (A) to
generate a quaternary stereocenter, and a highly stereo-
selective protonation of intermediate B furnished a densely
substituted cyclopentanone 3a.
(8) Mahmound, B.; West, F. G. Tetrahedron Lett. 2007, 48, 5091–
5094.
(9) Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66–
77.
(10) (a) Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH:
Weinheim, Germany, 2004. (b) Mukaiyama, T.; Kobayashi, S. Org. React.
1994, 46, 1–103.
To assess the potential for regiocontrol in the trapping
process, unsymmetrically substituted dienones 1c and 1d
were studied with several oxygenated alkenes. While
(11) For recent synthesis of 1,4-dicarbonyl substrates employing
umpolung strategies, see: (a) Shen, Z. L.; Goh, K. K. K.; Cheong,
H. L.; Wong, C. H. A.; Lai, Y. C.; Yang, Y. S.; Loh, T. P. J. Am. Chem.
Soc. 2010, 132, 15852–15855. (b) DeMartino, M. P.; Chen, K.; Baran,
P. S. J. Am. Chem. Soc. 2008, 130, 11546–11560. (c) Nahm, M. R.;
Potnick, J. R.; White, P. S.; Johnson, J. S. J. Am. Chem. Soc. 2006, 128,
2751–2756. (d) Mattson, A. E.; Bharadwaj, A. R.; Zuhl, A. M.; Scheidt,
K. A. J. Org. Chem. 2006, 71, 5715–5724. (e) Rossle, M.; Werner, T.;
Baro, A.; Frey, W.; Christoffers, J. Angew. Chem., Int. Ed. 2004, 43,
6547–6549. (f) Kerr, M. S.; de Alaniz, J. R.; Rovis, T. J. Am. Chem. Soc.
2002, 124, 10298–10299.
(13) Use of alkyl enol ethers as trapping reagents gave intractable
material within which neither homologous Mukaiyama adducts nor the
simple cyclopentenones resulting from elimination could be detected.
(14) (a) Ley, S. V.; Woodward, P. R. Tetrahedron Lett. 1987, 28,
3019–3020. (b) Yamashita, Y.; Saito, S.; Ishitani, H.; Kobayashi, S.
J. Am. Chem. Soc. 2003, 125, 3793–3798. (c) Prokopcova, H.; Kappe,
C. O. Angew. Chem., Int. Ed. 2009, 48, 2276–2286.
(12) Giese, S.; West, F. G. Tetrahedron 2000, 56, 10221–10228.
Org. Lett., Vol. 13, No. 14, 2011
3585

Table 1. Intermolecular Trapping of Nazarov Intermediate with Electron-Rich Oxygen-Substituted Alkenesa
entry
dienone
R1
R2
R3
R4
alkene
R5
R6
R7
temp (°C)
products (yield %)b
1
1a
1a
1a
1a
1a
1b
1b
1b
1c
1c
1c
1d
1d
1e
1e
Me
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Ph
Ph
Ph
H
Ph
Me
Me
Me
Me
Me
Me
Me
Me
H
2a
2b
2c
2d
2e
2b
2c
2d
2a
2c
2d
2c
2d
2c
2d
H
OMe
OMe
St-Bu
Ph
TBS
TMS
TBS
TBS
TMS
TMS
TBS
TBS
TBS
TBS
TBS
TBS
TBS
TBS
TBS
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
rt
3a (78)
2
Me
Ph
Me
H
3b (87)
3
Me
Ph
3c (98)
4
Me
Ph
H
3d (78)
5
Me
Ph
Me
Me
H
H
3e (44)/4e (19)
3f (59)
6
Me
Me
OMe
St-Bu
Ph
7
Me
Me
0
3g (64)
8
Me
Me
H
0
3h (66)
9
Me
Ph
H
OMe
St-Bu
Ph
0
5i (67)
10
11
12
13
14
15
Me
Ph
H
H
0
3j (71)
Me
Ph
H
H
0
3k (66)
Me
(CH2)3
(CH2)3
(CH2)3
(CH2)3
H
St-Bu
Ph
0
3l/5l (67; 7:1)c
3m/4m (66; 30:1)d
3n/5n (78; 3:1)c
6 (62)e
Me
H
H
0
(CH2)3
(CH2)3
H
St-Bu
Ph
rt
H
rt
a Standard procedure: BF3 OEt2 (1.1 equiv) was added to a solution of dienone 1 and electron-rich olefin 2 (2 equiv) in CH2Cl2 (0.05 M in 1) at the
3
indicated temperature. After 15 min, the reaction was quenched with sat. aq NaHCO3, followed by extraction, drying (MgSO4) and chromatographic
purification. b Isolated yield. c Inseparable mixture; the ratio was determined by integration of 1H NMR signals. d Minor product could not be isolated in
pure form but was tentatively assigned as 4m. e A mixture of two diastereomers (ratio ca. 20:1) was obtained. The minor product was inferred to be
isomeric at the carbinol carbon.
conjugate addition of silyl ketene acetal 2a to the less
substituted terminus of 1c gave only 1,5-keto ester 5i under
various conditions (entry 9), complete regioselective cap-
ture of the Nazarov intermediate derived from 1c was
observed in the use of less nucleophilic traps 2c and 2d,
providing substituted cyclopentanones 3j and 3k respec-
tively in good yields and with complete selectivity for
attack at the less substituted end of the cyclopentenyl
cation (entries 10 and 11). In the case of cyclopentenyl-
containing substrate 1d, the bicyclic cationic intermediate
underwent selective attack by 2c at the bridgehead carbon
to furnish 3l, along with minor amounts of 1,4-adduct 5l
(entry 12). On the other hand, 1d reacted smoothly with 2d
while with E attack occurs exclusively from the convex
face.
The behavior of bicyclic dienone 1e in this domino
sequence was also investigated (entries 14 and 15). The
slow rate of electrocyclization in this case necessitated
conducting the reactions at rt, and even so the adduct 3b
was accompanied by significant amounts of Michael ad-
duct 5n. The cis-anti-cis ring-fusion stereochemistry of 3n
was confirmed by 2D-TROESY experiments, and is con-
sistent with other trapping processes involving 1e.6a,16 More
intriguingly, 1e and 2d reacted under typical reaction con-
ditions to provide an unusual product whose spectral data
indicated the presence of a hydroxyl and two phenyl groups.
The structure of this compound was tentatively assigned as
6, which is presumed to arise from a domino Nazarov
electrocyclization/homologous Mukaiyama addition/Mu-
kaiyama aldol process.17 This unusual reactivity was ob-
served only in this instance, and it merits further study.
Finally, (Z)ꢀenol silyl ether 2f was used to examine the
question of stereocontrol at an exocyclic stereocenter
(Scheme 3). Treatment of 1a and 2f under standard
in the presence of BF3 OEt2 to afford 3m (entry 13).
3
The high regioselectivity seen with 1c,d is rationalized as
shown in Scheme 2. In the case of differentially substituted
cyclopentenyl cation C, selective attack at the less sub-
stituted end may result from greater accessibility as well as
the incipient generation of the more substituted enolate D
rather than D0. On the other hand, selective attack at the
bridgehead carbon of bicyclic cation E may be attributed
to the reduced strain experienced by enolate F relative to
F0.15 Apart from the observed regioselectivity, both cases
displayed complete facial diastereoselectivity: with C the
nucleophile approaches opposite the bulky phenyl group,
(16) Giese, S.; Kastrup, L.; Stiends, D.; West, F. G. Angew. Chem.,
Int. Ed. 2000, 39, 1970–1973.
(17) For an elegant demonstration of the cascade Mukaiyama aldol
reaction, see: (a) Albert, B. J.; Yamamoto, H. Angew. Chem., Int. Ed.
2010, 49, 2747–2749. (b) Boxer, M. B.; Akakura, M.; Yamamoto, H.
J. Am. Chem. Soc. 2008, 130, 1580–1582 and references therein.
(15) Similar selectivity is noted in ref 6b.
3586
Org. Lett., Vol. 13, No. 14, 2011

transition states corresponding to T1 and T2, allowing
other possible orientations to compete, and leading to the
minimal selectivity observed.
Scheme 2. Regioselective Trapping of Unsymmetrical Nazarov
Intermediates
Scheme 3. Stereoselective Interrupted Nazarov Reaction with a
(Z)-Enol Silyl Ether
conditions furnished 3o and 4o, each consisting of two
diastereomers in a 3:2 ratio at the branched carbon on the
side chain. The less stable 4o could easily be converted into
3o in the presence of base catalyst; however, no epimeriza-
tion took place at the R carbon on the side-chain. In
contrast, use of unsymmetrical dienone 1c resulted trap-
ping with complete regio- and diastereoselectivity to pro-
vide a single product 3p, remarkably establishing five
new stereocenters in a single transformation. Although
it was not possible to ascertain the relative configura-
tion at the exocyclic stereocenter using direct methods,18
BaeyerꢀVilliger oxidation afforded the lactone 7 as a
crystalline solid, whose analysis by X-ray diffraction al-
lowed for rigorous assignment of all five stereocenters. The
effectof the C-2 substituent on the stereochemicaloutcome
of these cases is clearly profound, but the role it plays is
difficult to discern. In the case of 3p, there are two open
transition states, T1 and T2, with relatively small antici-
pated steric demand. Of these two, T2 may derive addi-
tional stabilization through interactions of developing
partial charges, and would lead to the relative configura-
tion shown for 3p. Replacement of the C-2 hydrogen with
methyl, as in 1a, will increase the steric demand in the open
The interrupted Nazarov reaction of silyloxyalkenes is
general and efficient, providing access to highly substitu-
teded carbocycles in good yields through what amounts to
a homologous Mukaiyama addition. Excellent diastereo-
facial selectivity and regioselectivity were seen in the attack
of the olefin traps on the cyclized intermediates, with the
establishment of up to five new stereocenters. Potential
application of this domino process to natural product
synthesis and the use of other π-nucleophiles with eno-
late-type reactivity will be described in due course.
Acknowledgment. We thank NSERC for support of
this work. Y.K.W. gratefully thanks the Alberta Innovatesꢀ
Technology Futures for a PhD graduate scholarship.
Supporting Information Available. Experimental proce-
dures and characterization data for 3aꢀh, 3jꢀp, 4e, 4m, 4o,
5i, 6 and 7, and X-ray crystallographic data for 3a and 7.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(18) Matsumori, N.; Kaneno, D.; Murata, M.; Nakamura, H.;
Tachibana, K. J. Org. Chem. 1999, 64, 866–876. This approach was
used successfully by Marx and Burnell (ref 7), but in the case of 3p, the
3
observed JC,H couplings fell in an intermediate range, precluding
stereochemical assignment with confidence.
Org. Lett., Vol. 13, No. 14, 2011
3587